JPS6010038B2 - Method for producing 7β-amino-cephem-4-carboxylic acid compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a 7-amino-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-3-ene-4-carboxylic acid compound, particularly of the formula [In this formula, Ac is carbon is an acyl group of an organic carboxylic acid in one atom milk mass, and R is an organic group forming a protected carboxyl group with the group -C(=○)-○- in the formula] 3,4- expressed as
The present invention relates to a method for producing a 1-oxide of a 76-aminosephemu-4-carboxylic acid compound having a double bond at the position thereof or a salt of these compounds having a salt-forming group.

Acyl stem Ac refers to the acyl group of an organic carboxylic acid having one carbon atom, especially aliphatic, cycloaliphatic, alicyclo-aliphatic, aromatic, araliphatic, and aliphatic which may be substituted. These are the acyl groups of monocyclic or polycyclic-aliphatic carboxylic acids (including formic acid) and the acyl groups of carbonic acid semi-derivatives.

The protected carboxyl group of the formula -C(=○)-○-R2 is primarily an esterified carboxyl group, but can also be a common mixed anhydride group.

The group R2 is an organic group with preferably 18 carbon atoms, which together with the group -C(=○)-0- form an esterified carboxyl group which is preferably easily cleavable. be able to.

Such groups are, for example, aliphatic, cycloaliphatic, cycloaliphatic,
Aromatic or araliphatic radicals, especially optionally substituted hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic-aliphatic radicals. Substrates 2 may also include organometallic groups such as organosilyl groups or corresponding organostannyl groups, in particular optionally substituted aliphatic hydrocarbon groups having preferably up to 18 carbon atoms. It can also be a silyl group or a stannyl group substituted by 1 to 3 hydrocarbon groups.

Furthermore, R2 as a group which together with the group -C(=0)-○- forms mainly a mixed anhydride group is in particular an organic carboxylic acid having preferably one carbon atom, e.g. It is an acyl group of an aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic carboxylic acid or an acyl group of a carbonic acid semi-derivative such as a carbonic acid half-ester.

The general terms described herein have, for example, the following meanings.

Aliphatic groups (including corresponding aliphatic groups of organic carboxylic acids)
as well as the corresponding ylidene radicals are optionally substituted monovalent or divalent aliphatic hydrocarbon radicals, in particular lower alkyl radicals which can have up to 7 and preferably up to 4 carbon atoms, lower It is an alkenyl group, a lower alkynyl group or a lower alkylidene group.

Such groups may optionally be substituted by functional groups, such as free or etherified or esterified hydroxyl or mercabuto groups, such as lower alkoxy groups, lower alkenyloxy groups, lower alkylenedioxy groups, a phenyloxy group or a phenyl lower alkoxy group, a lower alkylthio group, an optionally substituted phenylthio group or a phenyl lower alkylthio group, an optionally substituted lower alkoxycarponyloxy group or a lower alkanoyloxy group, or Ha o. Gen atoms, as well as oxo groups, nitro groups, optionally substituted amino groups such as di-lower alkylamino groups, lower alkylene amino groups, oxa-lower alkylene amino groups or aza-lower alkylene amino groups, as well as acylamino groups such as lower alkanoylamino groups, optionally substituted carbamoylamino/groups, ureidocarbonylamino or guanidinocarbonylamino groups, azide groups, acyl groups such as lower alkanoyl and penzoyl groups, Certain carboxyl groups, such as carboxyl groups in the form of salts, esterified carboxyl groups such as lower alkoxycarbonyl groups, when substituted such as N-lower alkyl or N,N-dilower alkyl-carbamoyl groups; a carbamyl group, which may be further substituted by a ureidocarbonyl group or a guanidinocarbonyl group, or a cyano group, a sulfo group which may be functionally altered, such as by a sulfamoyl group or a sulfo group in the form of a salt; It can be mono-, di- or polysubstituted. The divalent aliphatic group of the aliphatic carboxylic acid is, for example, a lower alkylene group or a lower alkenylene group, which may be monosubstituted, disubstituted or polysubstituted, as the case may be, for example, as in the aliphatic groups mentioned above. can.

Alicyclic or cycloaliphatic groups (including cycloaliphatic or cycloaliphatic groups in corresponding organic carboxylic acids) and corresponding cycloaliphatic or cycloaliphatic ylidene groups are replaced. monovalent or divalent alicyclic or alicyclic-aliphatic hydrocarbon groups, such as monocyclic, bicyclic or polycyclic cycloalkyl or cycloalkenyl groups, which may be
Furthermore, it is a cycloalkylidene group, a cycloalkyl group, a cycloalkenyl-lower alkyl group, or a -lower alkenyl group, and a cycloalkyl-lower alkylidene group or a cycloalkenyl-lower alkylidene group.

In these groups cycloalkyl and cycloalkylidene have, for example, up to 12 ring carbon atoms, for example 3 to 8 ring carbon atoms.
and cycloalkenyl has, for example, up to 12 ring carbon atoms, such as 3 to 8, such as 5 to 8, preferably 5 or 6, and 1 double bond. or two, and alicyclic-
The aliphatic part of the aliphatic group can have up to 7, preferably up to 4 carbon atoms, for example. These cycloaliphatic or cycloaliphatic groups may be substituted if desired, for example by aliphatic hydrocarbon groups, e.g. They can be mono-, di- or poly-substituted with functional groups such as group hydrocarbon groups. Aromatic groups (including the corresponding aromatic groups of carboxylic acids) are optionally substituted aromatic hydrocarbon groups, such as monocyclic, bicyclic or polycyclic aromatic hydrocarbon groups, in particular Phenyl groups and biphenylyl or naphthyl groups, which can optionally be mono-, di- or polysubstituted, such as the aforementioned aliphatic and cycloaliphatic hydrocarbon groups.

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

Aroaliphatic groups (including araliphatic groups in the corresponding carboxylic acids) and also araliphatic ylidene groups include, for example, optionally substituted araliphatic hydrocarbon groups, such as optionally substituted monocyclic rings. optionally substituted aliphatic hydrocarbon radicals, such as aliphatic hydrocarbon radicals having up to three formula, bicyclic or polycyclic aromatic hydrocarbon radicals, in particular phenyl-lower alkyl radicals or phenyl-lower alkenyl radicals, as well as phenyl-lower alkynyl radicals and also phenyl-lower alkylidene radicals, and such radicals have, for example, 1 to 3 phenyl groups and optionally contain, for example, the aforementioned aliphatic and cycloaliphatic radicals. Like the formula radicals can be mono-, di- or polysubstituted in the aromatic and/or aliphatic moieties.

In particular, monocyclic groups with aromatic character,
Cyclic or polycyclic azacyclic, thiacyclic, oxacyclic,
Thiazacyclic, thiadiazacyclic, oxaazacyclic, diazacyclic, triazacyclic or tetraazacyclic groups and further correspondingly partially or totally saturated groups, these polycyclic groups being Some may be mono-, di- or polysubstituted, such as the alicyclics mentioned above.

The aliphatic moiety in a polycycloaliphatic 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). An aliphatic group, especially the acyl group of a lower alkyl half-ester of carbonic acid (this is e.g.
- or 8) and acyl groups of lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half-esters of carbonic acid, which may be substituted in the organic group. . The acyl group of the carbonic acid half ester is further defined as the corresponding group of the lower alkyl half ester of carbonic acid, the lower alkyl part of which has a heterocyclic group, for example one of the aforementioned heterocyclic groups of aromatic character; Both alkyl groups and heterocyclic groups can be optionally substituted. Additionally, the acyl group of the carbonic acid semi-derivative can be an optionally N-substituted carbamoy group, such as an optionally halogenated N-lower alkylcarbamoyl group. Lower alkyl groups include, for example, methyl,
Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertiary-butyl, as well as n-pentyl, isobentyl, n-hexyl, isohexyl or n-heptyl groups, and lower alkenyl groups, for example vinyl, allyl, It can be an isoprobenyl, 2- or 3-methallyl or 3-butenyl group, a lower alkynyl group can be, for example, a propargyl or 2-butynyl group, and a lower alkylidene group can be, for example, an isobropylidene or isobutylidene group.

The lower alkylene group is, for example, 1,2-ethylene/1,2-
or a 1,3-propylene or 1,4-butylene group, and lower alkenylene is, for example, a 1,2-ethenylene or 2-butene-1,4-ylene group.

Cycloalkyl groups are, for example, cyclopropyl to cyclobutyl, cyclobentyl, cyclohexyl or cycloheptyl groups, as well as adamantyl groups; cycloalkenyl groups are, for example, cycloprobenyl groups, 1-, 2- or 3-cyclobentenyl groups, 1-, 2- or 3-cyclohexenyl group, 3-cyclohebutenyl group or 1,4-
In the cyclohexagenyl group, the cycloalkylidene group is, for example, a cyclobentridine group or a cyclohexylidene group.

Siku. Alkyl-lower alkyl or cycloalkyl-lower alkenyl groups are, for example, cyclopropyl, cyclobentyl, cyclohexyl or cycloheptyl.
Methyl group, -1,1- or -1,2-ethyl group, -1
, 1-, -1,2- or -1,3-propyl, -vinyl or -allyl, cycloalkenyl-
Lower alkyl or cycloalkenyl-lower alkenyl groups are, for example, 1-, 2- or 3-cyclobentenyl-
, 11, 2- or 3-cyclohexenyl- or 11, 2- or 3-cycloheptenyl-methyl group, 11,
1- or -1,2-ethyl group, -1,1-, -1,2
- or -1,3-propyl group, -vinyl group or -allyl group. A cycloalkyl-lower alkylidene group is, for example, a cyclohexylmethylene group and a cycloalkenyl-lower alkylidene group is, for example, a 3-cyclohexenylmethylene group. Naphthyl group is 1- or 2-
-naphthyl group, and the biphenylyl group is, for example, 4-biphenylyl group.

Phenyl-lower alkyl or phenyl-lower alkenyl groups are, for example, penzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylprobyl, diphenylmethyl, trityl, 1- or 2-naphthylmethyl, etc. group, styryl group or cinnamyl group,
A phenyl-lower alkylidene group is, for example, a penzylidene group.

A double ring group is especially a double ring group which may be substituted with aromatic character, such as a corresponding monocyclic monoazacyclic, monothiacyclic or monooxacyclic group, such as a 2-pyryl group or a 3-pyryl group. -pyryl group, such as pyryl group, 2-, 3-
or a pyridyl group and a pyridinium group such as a 4-pyridyl group, a chenyl group such as a 2- or 3-chenyl group, or a furyl group such as a 2-furyl group, a bicyclic monoazacyclic, monooxacyclic or monothiacyclic group. a formula group such as an indolyl group, such as a 2- or 3-indolyl group, 2
A quinolinyl group such as a 1- or 4-quinolinyl group, an inquinolinyl group such as a 1-isoquinolinyl group, a penzofuranyl group such as a 2- or 3-benzofuranyl group, or a penzochenyl group such as a 2- or 3-benzothienyl group, a monocyclic diaza ring. a 1,2,4 -triazolyl group such as -triazo-3-yl group, tetrazolyl group such as 1- or 5-tetrazolyl group, oxazolyl group such as 2-oxazolyl group, isoxazolyl group such as 3-isooxazolyl group, 2-thiazolyl group thiazolyl group, such as
An isothiazolyl group such as 3-isothiazolyl group, or 1,2,4-thiadiazol-3-yl group or 1,3,
1,2,4- such as 4-thiadiazol-2-yl group
or a 1,3,4-thiadiazolyl group, or a bicyclic diazacyclic, thiazacyclic or oxaazacyclic group such as a penzimidazolyl group such as a 2-benzimidazolyl group, a 2-penzoxacyclic group, A penzoxazolyl group such as a zolyl group or a penzthiazolyl group such as a 2-benzthiazolyl group.

Corresponding partially or totally saturated groups are for example 2
- a tetrahydrothienyl group such as a tetrahydrochenyl group, a tetrahydrofuryl group such as a 2-tetrahydrofuryl stalk, or a piveridyl group such as a 2- or 4-piveridyl group. A polycyclic-aliphatic radical is a polycyclic radical, in particular a lower alkyl radical or a lower alkenyl radical bearing the above-mentioned radicals. Said heterocyclic group is substituted, for example, by an optionally substituted aliphatic hydrocarbon group, in particular a lower alkyl group such as a methyl group, or by a functional group, such as for example said aliphatic hydrocarbon group. be able to. Lower alkoxy groups are, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-ptoxy, isoptoxy, secondary ptoxy, tertiary ptoxy, h-pentoxy or tertiary pentoxy. These groups can be substituted, for example in halogeno-lower alkoxy groups, especially in 2-halogeno-lower alkoxy groups, such as in 2,2,2-trichloroethoxy, 2-promethoxy or 2-iodoethoxy groups. A lower alkenyloxy group is, for example, a vinyloxy group or an allyloxy group, a lower alkylenedioxy group is, for example, a methylenedioxy group, an ethylenedioxy group or an inpropylenedioxy group, and a cycloalkoxy group is, for example, a cyclobentyloxy group, A cyclohexyloxy group or an adamantyloxy group, and a phenyl-lower alkoxy group is, for example, a penzyloxy group or a 1- or 2-
A phenylethoxy group, and a heterocyclic oxy group or a heterocyclic-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-pyridyl-lower alkoxy group such as a furfuryloxy group.
-thenyl-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, pendylthio groups, and mercapto groups etherified with heterocyclic or heterocyclic-aliphatic groups are in particular imidazolylthio groups, such as 2-imidazolylthio groups, thiazolylthio groups, such as 2-thiazolylthio groups. , 1,2,4- or 1,3,4-thiadiazolylthio groups, such as 1,2,4-thiadiazol-3-ylthio group or 1,3,4-thiadiazol-2-ylthio group, or 1-methyl-5- A tetrazolylthio group such as a tetrazolylthio group.

, esterified hydroxyl groups are inter alia halogen atoms such as fluorine, chlorine, bromine or iodine atoms, and lower alkanoyloxy groups such as acetoxy or propionyloxy groups, lower alkoxycarbonyloxy groups such as methoxycarbonyloxy groups, ethoxy carbonyloxy group or t-butyloxycarbonyloxy group,
2-halogeno lower alkoxycarbonyloxy group, such as 2,2,2-trichloroethoxycarponyloxy group,
A 2-promethoxycarbonyloxy group or a 2-hodoethoxycarbonyloxy group, or a phenylcarbonylmethoxycarbonyloxy group, such as a phenacyloxycarbonyloxy group.

Examples of the lower alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, and n-carbonyl group.

Poxycarbonyl group, isof. Ropoxycarbonyl group,
It is a t-butoxycarbonyl group or a t-bentoxycarbonyl group. N-lower alkyl-carbamoyl group or N,N-di-lower alkyl-carbamoyl group is, for example, N
-Methylcarbamoyl group, N-ethylcarbamoyl group,
N,N-dimethylcarbamoyl group, N,N-jethylcarbamoyl group, N-lower alkylsulfamoyl group is, for example, N-methylsulfamoyl group or N,N-jethylcarbamoyl group.
-dimethylsulfamoyl group. Carboxyl or sulfo groups in the form of alkali metal salts are, for example, carboxyl or sulfo groups in the form of sodium or potassium salts.

A lower alkylamino group or a di-lower alkylamino group is, for example, a methylamino group, an ethylamino group, a dimethylamino group or a jetylamino group; a lower alkyleneamino group is, for example, a pyrrolidino group or a piveridino group; is, for example, a morpholyl group, and the aza-lower alkyleneamino group is, for example, a piperazino group or a 4-methylpiverazino group.

Acylumino groups are particularly carbamoylamino groups, lower alkylcarbamoylamino groups such as methylcarbamoylamino groups, ureidocarbonylamino groups, guanidinocarbonylamino groups, acetylamino groups, and acetylamino groups. Lower alkanoylamino groups, such as pionylamino groups, and also phthalimide groups or sulfoamino groups, which can optionally be present in the form of salts, such as alkali metal salts such as sodium or ammonium salts. Lower alkanoyl groups are, for example, acetyl or propionyl groups. 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 diphenylmethoxycarbonyl group or a Q-4-biphenyly-Q-methylphenylene group. It is a toxic carponyl group.

A lower alkoxycarbonyl group whose lower alkyl group has, for example, a monocyclic monoazacyclic, monooxacyclic or monothiacyclic group is a furyl-lower alkoxycarbonyl group such as furfuryloxycarbonyl or a 2-tenyl group. It is a chenyl-lower alkoxycarbonyl group such as an oxycarbonyl group. The acyl group c is especially an acyl group of an organic carboxylic acid or a 6-amino-
The acyl group contained in the naturally occurring or biosynthetically, semi-synthetically or totally synthetically produced, preferably pharmacologically active N-acyl derivative of benicillanic acid or 7-amino-cephalosporanic acid compounds, or easily removed. It is an acyl group that can

The acyl group Ac contained in the pharmacologically active N-acyl derivatives of 6-amino-benicillanic acid or 7-aminocephalosporanic acid is defined inter alia by the formula [in which n is 0 and RI is a hydrogen atom or optionally substituted alicyclic or aromatic hydrocarbon groups, optionally substituted heterocyclic groups and preferably having aromatic character;
is a functionally modified (preferably etherified) hydroxyl or mercapto group or an optionally substituted amino group, or n is 1 and RI is a hydrogen atom or an optionally substituted amino group; aliphatic, cycloaliphatic,
cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon groups;
optionally substituted enocyclic groups or polycyclic ring-aliphatic groups, the heterocyclic group preferably having aromatic character and/or having a quaternary nitrogen atom, functionally modified ( hydroxyl or mercapto groups, which may be etherified or esterified (preferably etherified or esterified), carboxyl groups which may be functionally modified, acyl groups, amino/groups which may be substituted or azido groups; and the groups RO and Rm are both hydrogen atoms, or n is 1, and RI is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic The hydrocarbon radicals of the group or the heterocyclic radicals thereof are preferably optionally substituted heterocyclic or dicyclic-aliphatic radicals having aromatic character, and are functionally modified (preferably a hydroxyl group or mercapto group which may be etherified), an amino group which may be substituted, a carboxyl group or sulfo group which may be functionally modified, an azide group or a halogen atom, and Rm is is a hydrogen atom, or n is 1 and the groups R and R are each a functionally modified (preferably etherified or esterified) hydroxyl group or a carboxyl group which may be functionally modified; and Rm is a hydrogen atom, or n is ], and RI is a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon. is a group and R
n and R disks are aliphatic, cycloaliphatic, cycloaliphatic or araliphatic hydrocarbons which may both be substituted and which are bonded to the carbon atoms in the formula by double bonds. or n is 1, and RI is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group or its enocyclic The group is preferably an optionally substituted heterocyclic or heterocyclic-aliphatic group having aromatic character, an optionally substituted aliphatic, alicyclic, alicyclic- an aliphatic, aromatic or araliphatic hydrocarbon group, and Rm is a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon is a group].

In the acyl group of formula (IA), for example, n is 0 and RI is a hydrogen atom or a cycloalkyl group having 5 to 7 ring carbon atoms (which may optionally be substituted by an amino group or by an alkali metal salt). optionally substituted by a sulphoamino group, which may be in the form of a salt such as phenyl, naphthyl or tetrahydronaphthyl, which may optionally be substituted, can be substituted by a hydroxyl group, a lower alkoxy group such as a methoxy group and/or a halogen atom such as chlorine],
A cyclic group such as a 4-isooxazolyl group, which may optionally be substituted by a lower alkyl group such as a methyl group and/or a phenyl group, and the phenyl group N-substituted by a lower alkyl group which may be substituted, e.g. Substituted is preferably an amino group, or n is 1 and RI is a lower alkyl group, which optionally preferably includes a halogen atom such as a chlorine atom, a hydroxyl group and/or a chlorine atom. [can be substituted by phenyloxy, amino and/or carpoxyl groups which may optionally contain halogen atoms],
Furthermore, lower alkenyl groups, phenyl groups (which may optionally be substituted, for example by hydroxyl groups, halogen atoms such as chlorine atoms and/or phenyloxy groups, which may be substituted), substituted Pyridyl group, pyridinium group, chenyl group, 1-imidazolyl group or 1-tetrazolyl group (
These may be substituted, for example, by lower alkyl groups such as methyl groups, amino/aminomethyl groups), lower alkoxy groups, which may be imitated, such as methoxy groups, optionally e.g. hydroxyl groups and (
or) a phenyloxy group which may be substituted by a halogen atom such as a chlorine atom, a lower alkylthio group e.g. Occasional phenylthio group, 2-imidazolylthio group, 1,2,4-triazol-3-ylthio group, 1,3,4-triazol-2-ylthio group, 1,2,4-thiadiazol-3-ylthio group, e.g. 5 -Methyl-1,2,4-thiadiazole-
3-ylthio group, 1,3,4-thiadiazol-2-ylthio group such as 5-methyl-1,3,4-thiadiazol-2-ylthio group or 5-tetrazolylthio group such as 1-methyl-5-tetrazolylthio group. groups, halogen atoms in particular chlorine or bromine atoms, carpoxyl groups which may be functionally modified, e.g. lower alkoxycarbonyl groups such as methoxycarbonyl or ethoxycarbonyl groups, cyano groups or N-substituted e.g. methyl groups. a carbamoyl group which may be substituted with a lower alkyl group or a phenyl group, a lower alkanoyl group which may be substituted, such as an acetyl group, a propionyl group or a penzoyl group, or an azide group; Rm is a hydrogen atom, or n is 1, and RI is a phenyl or chenyl group which may be substituted, for example with a hydroxyl group and/or a halogen atom such as a chlorine atom, and also 1, 4-cyclohexagenyl group, and an amino group that may be substituted with RO', such as a lower alkoxycarbonylamino group such as a t-butyloxycarbonylamino group or a 2,2,2-trichloroethoxycarbonylamino group or a 2-halogen/lower alkoxycarbonylamino group, or a carbamoylamino group which may be substituted, such as a guanidinocarbonylamino group, or a sulfamino group, which may optionally be in the form of a salt, e.g. an alkali metal salt. , azide groups, carboxyl groups, cyano groups, sulfo groups, which can be in the form of salts such as alkali metal salts or in esterified form, such as lower alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl groups; Hydroxyl groups that may be modified, such as t-butyloxycarbonyloxy groups and 2,2,2-
a lower alkoxycarbonyloxy group such as trichloroethoxycarbonyloxy group or 2-ha; a geno-lower alkoxycarponyloxy group, an optionally substituted lower alkoxy group or a phenyloxy group, or a halogen atom, such as a chlorine atom or a bromine atom, and Rm is a hydrogen atom, or n is 1; ,
RI 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 the groups RI, RO, and R are all A lower alkyl group is, for example, a methyl group. Such acyl groups Ac are, for example, formyl, cyclobentylcarbonyl, Q-aminocyclobentylcarbonyl or Q-aminocyclohexylcarbonyl, which may be substituted amino groups, e.g. in salt form. or by an acyl group which can preferably be easily cleaved when treated with an acidic agent such as trifluoroacetic acid or a chemical reducing agent such as zinc in the presence of aqueous acetic acid; Depending on the acyl group that can be converted into such an acyl group, preferably 2,2,2-trichloroethoxycarbonyl group, 2-promethoxycarbonyl group, 2-sodoethoxycarbonyl group, t-butoxycarbonyl group. or with an amino group substituted by a suitable acyl group of a carbonate half-ester, such as a phenacyloxycarbonyl group, or by an acyl group of a carbonate half-amide, such as a carbamoyl group or an N-methylcarbamyl group, or by a trityl group. ), 2,6-dimethoxybenzoyl group, tetrahydronaphthyl group, 2-methoxynaphthyl group, 2-ethoxynaphthyl 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-isooxazolylcarbonyl group, 2-chloroethylaminocarbonyl group, acetyl group, propionyl group, butyryl group, Hexanoyl group, octanoyl group, acrylyl group, crotonyl group, 3
-putenoyl group, 2-pentenoyl group, methoxyacetyl group, methylthioacetyl group, butylthioacetyl group,
Allylthioacetyl group, chloroacetyl group, bromoacetyl group, dibromoacetyl group, 3-chlorp.

pionyl group, 3-promopropionyl group, aminoacetyl group or 5-amino-5-carboxyvaleryl group [which may be substituted, for example, as described above, with amino/groups and/or functionally modified azidoacetyl group, carboxyacetyl group, which may be in the form of a salt, e.g. sodium salt, or in the form of an ester, e.g. a lower alkyl ester, e.g. methyl ester or ethyl ester; , methoxycarbonylacetyl group, ethoxycarbonylacetyl group, bis-methoxycarbonylacetyl group, N-phenylcarbamoylacetyl group, cyanoacetyl group, Q-cyanopropionyl group, 2-cyano-3,3-dimethylacrylyl group, Phenylacetyl group, Q-prophenylacetyl group, Q-azidophenylacetyl group, 3-chlorophenylacetyl group, 4-aminomethylphenylacetyl group (for example, an amino group that may be substituted as described above) ), phenacylcarbonyl group, phenyloxyacetyl group, 4-trifluoromethylphenyloxyacetyl group, penzyloxyacetyl group, phenylthioacetyl group, bromphenylthioacetyl group, 2-phenyloxypropionyl group, Q-F enyloxyphenylacetyl group, Q-methoxyphenylacetyl group, Q-ethoxyphenylacetyl group, Q-methoxy 3,4-dichlorophenylacetyl group, Q-cyanophenylacetyl group, especially phenylglycyl group, 4 -Hydroxyphenylglycyl group, 3-
chloro-4-hydroxyphenylglycyl group or 3,
5-dichloro-4-hydroxyphenylglycyl group (in these groups the amino group can optionally be substituted, e.g. as mentioned above), as well as pendylthioacetyl group, benzylthiopropionyl group, Q-
carboxyphenylacetyl group (which optionally has a functionally modified carboxyl group, e.g. as mentioned above), 3-phenylpropionyl group, 3-(3-cyanophenyl)-propionyl group, 4-(3- methoxyphenyl)-butyryl group, 2-pyridylacetyl group, 4
- an aminopyridinium acetyl group (which optionally carries an amino group substituted e.g. as mentioned above), 2
-thhenylacetyl group, 2-tetrahydrothenylacetyl group, Q-carboxy 2-thhenylacetyl group or Q-carpoxy 3-thhenylacetyl group (which may optionally be a functionally modified carboxyl group, e.g. as mentioned above). a Q-cyano-2-thhenylacetyl group, a Q-amino-2-thhenylacetyl group or a Q-amino-3-thhenylacetyl group (which optionally carries an amino group substituted, for example, as described above); , Q-sulfophenylacetyl (which optionally has a functionally modified sulfo group, such as the carboxyl group), 3-chenylacetyl, 2-
Furylacetyl group, 1-imidazolylacetyl group, 1-
Tetrazolylacetyl group, 3-methyl-2-imidazolylthioacetyl group, 1,2,4-triazole-3-ylthioacetyl group, 1,3,4-triazole-2-ylthioacetyl group, 5-methyl- 1,2,4-thiadiazole-3-ylthioacetyl group, 5-methyl-1
, 3,4-thiadiazol-2-ylthioacetyl group or 1-methyl-5-tetrazolylthioacetyl group. The organic group R2 forming an esterified carboxyl group which can preferably be easily split with the group -C(=○)-○- has an atomic weight of, for example, 19 or more as a halogen atom. It is a 2-halogeno lower alkyl group with

Such a group is similar to the group -C(=○)-○-,
Esterified carboxyl groups that can be 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 that can be easily converted into such groups. Forms an esterified carboxyl group. Such groups are, for example, 2,2,2-trichloroethyl or 2-iodoethyl, or 2-chloroethyl or 2-promethyl, which can easily be converted into 2-iodoethyl. Furthermore, by treatment with zinc in the presence of a chemical reducing agent such as aqueous acetic acid under neutral or slightly acidic conditions or by treatment with a suitable nucleophile such as sodium thiophenolate. Based on an esterified carboxyl group that can be easily split into -
C(=○)-○- and other groups R2
Examples include an arylcarbonylmethyl group (aryl is in particular a phenyl group which may be substituted) and preferably a phenacyl group.

Furthermore, the radical R2 can also be an arylmethyl group, the aryl group of which is a monocyclic, preferably substituted, aromatic hydrocarbon radical.

Such groups include esterified carboxyl groups -C(=○)-○- which can be easily cleaved under neutral or acidic conditions by irradiation, preferably by ultraviolet radiation.
Form it properly. Such an aryl group can be used as a substituent, especially a lower alkoxy group such as a methoxy group [these groups or the preferred phenyl group, the 31-position, the 4-position
- and/or the 5-position] and/or especially a nitro group, which in the case of the preferred phenyl group is preferably in the 2-1 position. Such basic R needles, especially 31 or 4
-methoxybenzyl group, 3,5-dimethoxybenzyl group, 2-nitrobenzyl group or 4,5-dimethoxy2
It is a nitrobenzyl group. Furthermore, the group R2 together with the group -C(=0)10- forms an esterified carpoxyl group which can be easily cleaved under acidic conditions, e.g. by treatment with trifluoroacetic acid or formic acid. It can also be the base R base.

Such radicals include, inter alia, methyl groups polysubstituted by optionally substituted hydrocarbon groups or carbocyclic aryl groups with electron-donating natural substituents or oxygen or sulfur atoms as ring members. a methyl group monosubstituted by a heterocyclic group of aromatic character, or a ring member in a polycyclic aliphatic hydrocarbon group or in an oxaalicyclic or thiaalicyclic group. It forms the ring member in the Q-position relative to the oxygen or sulfur atom. Among the polysubstituted methyl groups R, preferred are, for example, t-butyl group, t-pentyl group, benzhydryl group, 4,4'-dimethoxy-penzhydryl group, or 2-(4-piphenylyl)-2-
A bropyl group and a methyl group R with the above-mentioned substituted aryl or heterocyclic group, such as 4-methoxybenzyl group, 3,4-dimethoxybenzyl group or 2
-furyl group.

A polycyclic aliphatic hydrocarbon group in which the methyl group R backside preferably constitutes a triple-branched ring member is, for example, 1
- an adamantyl group such as an adamantyl group, and the above-mentioned oxaalicyclic or thiaaliphatic group
2,3-dihydro-2-pyranyl group or a corresponding sulfur compound. Furthermore, the group R2 can be an esterified carboxyl group which can be cleaved by hydrolysis under weakly basic or slightly acidic conditions, for example, as a group -C(=○)-○
It can also be a group R6 formed with -. Such a group R6 is based on an activated ester group.
It is preferable that the group is always formed with C(=○)-○-, for example, a nitrophenyl group such as a 4-nitrophenyl group or a 2,4-dinitrophenyl group, or a 4-nitrobenzyl group. nitrophenyl-lower alkyl group such as 2,4,6-trichlorophenyl group and 2,3,4,5
, 6-pentachlorophenyl, and also cyanomethyl and acylaminomethyl groups such as phthaliminomethyl and succinyliminomethyl, as well as trityl or bis(4)
-A bis-aryloxymethyl group such as toxyphenyloxy-5-methyl group. In addition, the group R2 represents an esterified carboxyl group that can be split under hydrogenation conditions with a carboxyl group -C(=○)-○-
It can also be a radical R room forming a substituent such as, for example, a penzyl group, a 4-methoxybenzyl group, a 4-nitrobenzyl group, a benzhydryl group or a 4,4-dimethoxybenzhydryl group. is a Q-aryl-lower alkyl group that may be

Furthermore, the group R2 can be used as a radical, especially a lower It can also be an alkanoyloxymethyl group, for example an acetoxymethyl group.

R2 as a silyl or stannyl group is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group such as a lower alkyl group, a cycloalkyl group, a phenyl group or a phenyl-lower alkyl group. It is preferred to have and mainly tri-lower alkylsilyl groups such as trimethylsilyl or tri-lower alkylstannyl groups such as tri-n-butylstannyl.

Furthermore, an acyl group, preferably forming a mixed anhydride group which can be cleaved by hydrolysis, together with a group -C(=0)-○- is, for example, an acyl group of the above-mentioned organic carboxylic acid or carbonic acid semi-derivative. One acyl group, for example a lower alkanoyl group such as an acetyl group or a lower alkoxycarbonyl group such as an ethoxycarbonyl group.

Salts are especially metal or ammonium salts, for example alkali metal or alkali metal salts, such as sodium, potassium, magnesium or calcium salts, and also ammonium salts with ammonia or suitable organic amines.

Organic amines which can be used for the formation of the salts are, in particular, aliphatic, cycloaliphatic, cycloaliphatic and araliphatic primary, secondary or tertiary monoamines, diamines or polyamines and double cyclic 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-aminobenzoic acid- Basic aliphatic esters of carboxylic acids such as 2-jethylaminoethyl ester, lower alkylene amines such as 1-ethylpiveridine, cycloalkylamines such as bicyclohexylamine or N,N' -penzylamines such as dibenzylethylenediamine and also pyridine type bases such as pyridine, collidine or quinoline. Compounds having a basic group in Ac in formula (1) form acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid or with suitable organic carboxylic acids such as trifluoroacetic acid or sulfonic acids. You can also do that. The compounds of formula (1) exhibit pharmacologically valuable properties or can be used as intermediates for the production of compounds exhibiting such properties.

In formula (1), Ac is the acyl group Ac present in the pharmacologically active N-acyl derivative of the 6-amino-benham-3-carboxylic acid compound or the 7-aminoceph-3-em-4-carboxylic acid compound, and R is the physiologically active N-acyl derivative. Compounds that are organic groups that can be easily split under conditions are those of microorganisms such as Staphylococcus auris.
occ female ame ship) (e.g. about 0.006 ~
0.02 evening/k9p. o. Gram enterobacteria such as Escherichia coli (at a dosage of
iacoli) (for example, about 0.001 to 0.0 in mice)
5th evening/k9p. o. gram-negative bacteria such as Klebscilla pneumonia (K1e
Proteus pneumoniae), Proteus
Pfote vulgaris or Salmonella typhosa
, especially effective against penicillin-resistant bacteria.

The new compounds according to the invention can therefore be used correspondingly, for example in the form of antimicrobially active preparations. In formula (1), R is preferably an organic group forming an easily splittable esterified carboxyl group with the group -C(=○)10-. , are valuable intermediates that can be easily converted into the aforementioned pharmacologically active compounds, eg as described below.

Particularly valuable compounds of formula (1) are Ac
Particularly pharmacologically active (e.g. highly active) N-acyl derivatives which are naturally occurring or can be produced biosynthetically, semi-synthetically or totally synthetically, of 6-amino-benicillanic acid compounds or 7-aminocephalosporanic acid compounds. an acyl group contained in an ester that can be easily hydrolytically or hydrogenolytically cleaved when R is treated with water, an acidic agent, or a chemical reducing agent under neutral or weakly acidic conditions. -C (=○) - an esterified carboxyl group or an esterified carboxyl group that can be easily cleaved under physiological conditions or an esterified carboxyl group that can be converted into such a carboxyl group
10- Organic groups formed together with, for example, trimethylsilyl group, t-butyl group, diphenylmethyl group, 2
, 2,2-trichloroethyl group, 2-chloroethyl group,
2-bromoethyl group, 2-iodoethyl group, phenacyl group, 4-methoxybenzyl group, diphenylmethyl group, 4
. It is a salt of such a compound.

In particular, Ac in formula (1) is 6-amino-benham 3-
Carboxylic acid compound or 7-aminoseph-3-em-
Acyl groups contained in the N-acyl derivatives, which can be prepared by fermentation of 4-carboxylic acid compounds (i.e. naturally occurring) or biosynthetically, such as phenylacetyl or phenyloxyacetyl groups, which may be substituted;
and also optionally substituted lower alkanoyl or lower alkyl groups such as 4-hydroxy-phenylacetyl, hexanoyl, octanoyl,
3-hexanoyl group, 5-amino-5-carboxyvaleryl group, n-butylthioacetyl group or allylthioacetyl group and especially phenylacetyl group or phenyloxyacetyl group, 6-aminobenam-3-carboxylic acid compound or 7-amino/-cefu Acyl groups contained in highly active N-acyl derivatives of 3-M-4-carboxylic acid compounds, such as formyl, 2-chloroethylcarbamoyl, cyanoacetyl or 2-thenyl acetyl, especially phenylglycyl [ The phenyl group in this group is a hydroxyl group and/or a phenyl group which may be substituted with a halogen atom, such as a chlorine atom, such as a phenyl group, a 3- or 4-hydroxyphenyl group, a 3
-chloro-4-hydroxyphenyl group or 3,5-dichloro-4-hydroxyphenyl group, and the amino group may be optionally substituted and, for example, a sulfoamino group or hydrolytically a cleavable trityl group or an optionally substituted carbamoyl group, such as an optionally substituted ureidocarbonyl group such as a ureidocarbonyl group or an N3-trichloromethylureidocarbonyl group, or a guanidinocarbonyl group; or preferably easily cleaved when treated with a chemical reducing agent such as zinc in the presence of an acid such as trifluoroacetic acid or aqueous acetic acid. or convertible into such acyl groups, preferably suitable acyl groups of carbonic acid half-esters, such as 2,2,2-
trichloroethyloxycarbonyl group, 2-chloroethoxycarbonyl group, 2-fromethoxycarbonyl group,
an amino group substituted by a 2-iodoethoxycarbonyl group, a t-butoxycarbonyl group or a phenacyloxycarbonyl group or a carbonic acid hemiamide acyl group, such as a carbamoyl group or an N-methylcarbamoyl group, or the amino group is a lower an alkyl group, e.g. linked to the nitrogen atom of the 7-amino group via a methylene group which may have two methyl groups], as well as a chenylglycyl group such as a 2-thenylglycyl group (which may be substituted e.g. as described above). may have a 1-amino group) or a 1-amino/-cyclohexylcarbonyl group (
This may optionally have substituted amino groups, e.g. The carboxyl group may also have a carboxyl group in the form of a salt such as a sodium salt or a carboxyl group in the form of an ester such as a lower alkyl ester such as methyl or ethyl ester or a phenyl-lower alkyl ester such as diphenylmethyl ester) or a Q-sulfophenylacetyl group (which may optionally have a functionally modified sulfo group, such as the carboxyl group mentioned above) or a Q-hydroxy-phenylacetyl group (which may optionally have a functionally modified sulfo group, such as the carboxyl group mentioned above) hydroxyl groups, especially acyloxy groups, where the acyl group is preferably an acyl group that can be easily cleaved by treatment with an acid reagent such as trifluoroacetic acid or a chemical reducing agent such as zinc in the presence of acetic acid. Alternatively, it is an acyl group that can be converted into such an acyl group, preferably a suitable acyl group of carbonic acid half ester, such as 2,2,2-trichloroethyloxycarponyl group, 2-chloroethoxycarponyl group, 2- Frommethoxycarbonyl group, 2
R is an acyl group represented by the formula (IA);
with a chemical reducing agent under neutral or weakly acidic conditions, hydrolytically with an acidic agent or preferably under weakly basic conditions,
an organic group in which an esterified carboxyl group which can be easily cleaved by hydrogenolysis or under physiological conditions is formed with the group -C(=○)1○-;
Methyl groups polysubstituted with optionally substituted hydrocarbon groups, such as lower alkyl groups, in particular t-butyl or diphenylmethyl groups and 2,2,2-trichloroethyl, 2-iodoethyl or This 2
-2-chloroethyl or 2-fromethyl groups that can be easily converted into iodoethyl groups, and 4-methoxybenzyl or 4-nitrobenzyl groups and also diphenylmethyl groups, 4,4'-dimethoxydiphenylmethyl groups, trityl groups, or Bis(4-toxyphenyloxy)-methyl group and acetoxymethyl or pivaloyloxymethyl group.

The present invention mainly provides that in formula (1), Ac is a formula (in this formula, ~ is a phenyl group, a 3- or 4-hydroxyphenyl group, a 3-chloro-4-hydroxyphenyl group, a 3,5-dichloro-4-hydroxyphenyl group) or a 2-chenyl group, and R is a hydrogen atom or an optionally protected amino group, carboxyl group or sulfo group,
For example, an acylamino group such as a t-butoxycarbonylamino group, a 2,2,2-trichloroethoxycarbonylamino group, a 2-sodoethoxycarbonylamino group, a 2-furomethoxycarbonylamino group, or a 2-guanylureido group. , and also esterified carboxyl groups or acyloxy groups such as sulfamino or tritylamino or diphenylmethoxycarbonyl groups, such as t-butoxycarbonyloxy groups, 2,2,2
- trichloroethoxycarponyloxy, 2-iodoethoxycarponyloxy or 2-fromethoxycarbonyloxy), and R is a highly branched lower alkyl group at the Q-position. For example, t-butyl group, 2-halogeno lower alkyl group such as 2,2,2-trichloroethyl group, 2-iodoethyl group or 2-bromoethyl group, phenacyl group, 4-nitrobenzyl group, 4-methoxybenzyl group, substituted compounds or salt-forming groups which may contain a diphenylmethyl group such as a penzhydryl group or a 4,4'-dimethoxydifermethyl group, a trityl group or a bis-(4-methoxyphenyloxy)-methyl group; It is related to the production of salts of chemical compounds.

The present inventor substitutes the formin group with a hydrogen atom in the 3-formylucephem-4-carboxylic acid compound represented by the formula and, if desired, converts the resulting compound of formula (1) into a compound of formula (1). and (or) if desired, convert the resulting compound with a salt-forming group into a salt or convert the resulting salt into the free compound or other salt, and (or) if desired, convert the resulting compound with a salt-forming group into a salt. It has surprisingly been found that compounds of formula (1) or salts thereof can be obtained by separating a mixture of isomers into individual isomers.

In the raw material of formula (0), the acyl group Ac is a free functional group that may be present in this acyl group, such as an amino group,
Hydroxyl or carboxyl groups are protected by methods known per se, for example amino groups by acylation, tritylation, silylation or stannylation and hydroxyl or carboxyl groups by esterification, including for example silylation or stannylation. R is a group which can be protected, preferably an esterified carboxyl group which can be cleaved under mild conditions -C(=○)-
This is the group R2 which is formed at the same time as ○-.

Note that R2 is preferably an organic group of a sterically hindered alcohol, such as methanol with an optionally substituted aliphatic or aromatic hydrocarbon group. This group can have 3 predominantly aliphatic groups or 1 to 3, preferably 2, aromatic groups as substituents. R2 is primarily a diphenylmethyl group which may be substituted with a lower alkoxy group such as a methoxy group, such as a penzhydryl group or a 4,4'-dimethoxybenzhydryl group, but if suitably substituted. It can also be a pendyl group. The sterically hindered alcohol group can also be a highly branched lower alkanol group in the Q-position, such as a t-butyl group or a cycloalkanol or cycloalkenol group which can have an endo bridge; Such groups are, for example, 1-
It is an adamantyl group such as an adamantyl group. The free functional groups in the acyl group Ac and/or in the carboxyl protecting group R2 are preferably protected by methods known per se. In the raw material of formula (0), the formyl group is replaced with a hydrogen atom by decarbonylation.

This reaction is carried out by treatment with heavy metal rust which combines with carbon monoxide. Such heavy metal collar bodies are in particular rust bodies of platinum group metals. In addition to platinum, the platinum group metals include iridium or rhodium, as well as palladium and osmium. Preferably, the platinum group metal collar that absorbs carbon monoxide has an organic ligand.

These ligands can be bonded to the platinum group metal by means of heteroatoms, especially phosphorus atoms, or by way of subvalences of the platinum group metal, which form non-covalent bonds, by means of carbon atoms. In addition to these organic ligands, the above-mentioned complexes can carry substituents via the main valence (ie, covalent bonds), such as heteroatoms, in particular halogen atoms, such as chlorine atoms, or carbonyl groups. Carbon monoxide binding platinum group metal rust bodies of this type are capable of binding carbon monoxide via the main valence, ie by covalent bonds.
Examples of platinum group metal complexes include phosphorus-containing platinum group metal complexes, mainly phosphines having one, two or more phosphines.

Use platinum group metal coin body. These phosphines are preferably substituted with optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, predominantly lower alkyl groups such as n-butyl groups or, in particular, when substituted. It has a certain phenyl group, e.g. . In addition to these phosphorus-containing components such as the phosphines mentioned above, the platinum group metal rust bodies may also contain organic ligands, especially phosphorus-containing ligands such as phosphine in the phosphorus-containing platinum group metal bodies.
a suitable nitrile, such as acetonyl, non-covalently bonded to the metal atom, and/or a halogen, such as a chlorine atom, covalently bonded to the metal atom; It can have atoms or carbonyl groups. Such complexes are preferably bis-3-substituted phosphine-platinum halides, bis-3-substituted phosphine-carbonyl iridium halides or tris-3-substituted phosphine-iridium halides, mainly tris-3-substituted phosphine-rhodium halides. use.

In these, the phosphine substituents are preferably lower alkyl groups such as n-butyl groups and mainly phenyl groups, and the halogens are mainly chlorine. Phosphine-platinum group metal complexes capable of covalently bonding carbon monoxide are, for example, bistriphenylphosphine-platinum-rochloride [(C6day5)3P]2P to 12 or bistriphenylphosphine-platinum-rhochloride Iridium-rhochloride [(C6day5)3P]21r(C
O) CI, and trisutriphenylphosphine-iridium-1-chloride [(C6 public) 3P] 31r
C1, but mainly trisutriphenylphosphine-rhodium-1-chloride [(C6 ratio)3P]3RhCI
It is.

If desired or necessary, the decarbonylation reaction with the heavy metal key may be carried out using a suitable catalyst or activator, such as a Lewis acid such as boron trifluoride (for example, bis-triphenylphosphine-platinum chloride). perchlorates such as sodium perchlorate (which can be used for example bistriphenylphosphine-carbonyl iridium).

Can be done in the presence of a ride (can be used at any time). Furthermore, the reaction can be carried out in an inert solvent, in particular aliphatic or cycloaliphatic and especially aromatic hydrocarbons, such as benzene, toluene or xylene, halogenated hydrocarbons, such as methylene chloride or chlorobenzene. corresponding aliphatic or aromatic chlorohydrocarbon ethers such as aliphatic, cycloaliphatic or aromatic optionally mixed ethers such as di-n-butyl ether, dioxane, diphenyl ether or anisole,
It is carried out in the presence of nitriles, such as aliphatic or aromatic nitriles, such as acetonitrile or penzonitrile, or ketones, especially aliphatic ketones, such as lower alkanones, such as acetone, ethyl methyl ketone or imbutyl methyl ketone, or mixtures of these solvents.

In this case, the reaction is carried out cooled, at room temperature or under heat, for example in the range of about 10-150 qo, such as about 40-120 qo, and if necessary in a sealed container and/or
Perform under an inert gas such as nitrogen or argon. According to the process of the invention, free functional groups which are present in the raw materials and which do not take part in the reaction can be removed, if necessary by methods known per se, for example by acylation, mercapto groups and amino groups. Alternatively, it is possible to temporarily protect the enigmatic carboxyl groups by silylation and, for example, by esterification, including silylation, and to liberate these groups if desired after the end of the reaction by methods known per se.

The obtained compound of formula (1) can be converted into another compound of formula (1) by methods known per se.

In the compounds obtained, the acyl group Ac, in particular the easily removable acyl group, can be removed by methods known per se. The ethoxycarbonyl, 2-iodoethoxycarbonyl or phenacyloxycarbonyl group is preferably treated with a suitable metal or metal compound such as zinc or a divalent chromium compound such as the chloride or acetate of divalent chromium. The metal or metal compound can be removed by treatment in the presence of hydrogen depletion which together produces nascent hydrogen, preferably in the presence of aqueous acetic acid.

Further, in formula (1), the carboxyl group can be converted to [
For example, a compound whose carboxyl group is protected] by reaction with a suitable organohalogenophyte compound such as trimethylchlorosilane or an organohalogenotin (W) compound such as tri-n-butyltin chloride. If obtained, an imidohalide forming agent is used to remove the appropriate acyl group Ac (free functional groups that may be present in this group may optionally be protected). The imido halide obtained can be reacted with an alcohol and the iminoether thus formed can be cleaved. During the course of this reaction, carboxyl groups which have been protected, for example with organosilyl groups, can already be liberated. Imidohalide 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 phosphorus pentachloride, as well as pyrocatekyl-phosphorus trichloride, and halides, especially chlorides, of sulfur-containing acids or carboxylic acids,
For example thionyl chloride, phosgene or oxalyl chloride. For reaction with one of the above-mentioned imide halide formers, a suitable base, especially an organic base, especially a tertiary amine such as a tertiary aliphatic monoamine or diamine such as a tri-lower alkyl amine such as trimethylamine, triethylamine or ethyldiisopropylamine, or N,
N,N',N'-tetra-lower alkyl-lower alkylene diamines such as N,N,N',N'-tetramethyl-1,5-benzeneamine or NNN',N'-tetramethyl-1,6- hexylene diamines, monocyclic or bicyclic monoamines or diamines such as N-substituted (e.g. N-lower alkylated) alkylene amines,
Azaalkyleneamines or oxaalkyleneamines such as N-methylpiberidine or N-methylmorpholine, or 2,3,4,6,7,8-hexahydropyrrolo[1,21a]pyrimidine (i.e. diazabicyclononene , DBN), or a tertiary aromatic amine such as a di-lower alkylaniline such as N,N-dimethylaniline or especially the presence of a tertiary polycyclic, monocyclic or bicyclic base such as quinoline or inquinoline, especially pyridine. Preferably, the reaction is carried out in the presence of an aliphatic or aromatic hydrocarbon, which may preferably be halogenated (for example chlorinated), such as a solvent such as methylene chloride.

In this reaction, the imidohalide forming agent and the base can be used in approximately equimolar amounts, but the base may be used in excess or less than an equivalent amount, such as from about 0.2 to 1 times the amount or about 1 molar amount. It is also possible to use up to an excess amount, especially about a 3 to 5 times excess amount. While cooling the reaction with the imide halide forming agent, for example, about 150 to 11 o
It is preferred to carry out the reaction at 0°C, but the reaction can be carried out at higher temperatures, for example up to about 7°C, if the stability of the raw materials and the stability of the product permit higher temperatures. 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, especially c. Lower alkanols which may be substituted (e.g. chlorinated) or which additionally carry hydroxyl groups, such as ethanol, n-pro/f-ols, isopro/f-ols, n-butanols, especially methanol. , and 2,2,2-trichloroethanol, and also optionally substituted phenyl-lower alkanols such as penzyl alcohol are suitable. This alcohol is generally added in excess amount, e.g.
It is preferred to use an excess of up to 10,000 ml and to carry out the process with cooling, for example at about 150 to 11,000 ml. The iminoether product thus formed can advantageously be cleaved off without being isolated.

This splitting of the iminoether is accomplished by treatment with an appropriate hydroxy compound. Preferably, water or a hydrous warm mixture of an organic solvent such as an alcohol, in particular a lower alkanol such as methanol, is used for this. This step is generally carried out in an acidic soot, for example at a pH value of about 1 to 2, and the pH value is adjusted, if necessary, by the addition of a basic agent such as an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. Aqueous solutions or acids can be prepared by adding inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, fluoroboric acid, trifluoroacetic acid or p-toluenesulfonic acid. The three-step process for cleavage of the acyl group described above can be carried out without intermediate isolation of the imido-halide and imino-able intermediates, generally using a halogenated solvent such as methylene chloride in an organic solvent inert to the reactants. It is advantageous to carry out the reaction in the presence of optional hydrocarbons and/or in an inert gas such as nitrogen gas.

Certain acyl groups of the acylamino group in the compound obtained by the method of the present invention, especially the 5-amino-5-carboxyvaleryl group [its carboxyl group and/or
The amino group may be protected] by a nitrosylating agent such as nitrosyl chloride, a carbocyclic arene-diazonium salt such as benzenediazonium chloride or an N-halogen-amide or N-halogen-imide such as N-prom amber. The reaction product is treated with a reactant releasing a positive halogen atom such as an acidimide, preferably in a suitable solvent or solvent mixture such as a nitro-lower alkane or a cyano-lower alkane, and formic acid. Water or a lower alkanol such as methanol, or the Ac
If the amino group in is unsubstituted and the carboxyl group is protected, e.g. by esterification, the compound is dissolved in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, e.g. methylene chloride. It can also be cleaved off by standing at 1000 ml and, if necessary, the free or monoacylated amino compound thus obtained can be worked up by methods known per se.

The formyl group Ac can be treated with an acidic agent such as p-toluenesulfonic acid or hydrochloric acid, a weakly basic agent such as dilute ammonia or a decarbonylating agent such as tris-(triphenylphosphine)-rhodium chloride. It can also be removed by

In the obtained compound, the group represented by the formula -C(=○)-○-R2 can be changed to another group represented by this formula. For example, a 2-chloroethoxycarbonyl group or a 2-furomethoxycarbonyl group of the formula -C(=○)-○-R may be reacted with a solvent such as sodium iodide in the presence of a suitable solvent such as acetone. Treated with iodine salt2
- can be changed to iodoethoxycarbonyl group.
The carboxyl group protected with an organic silyl group or a stannyl group is formed by a method known per se.

In this regard, reference may be made, for example, to British Patent No. 107,353 or Dutch Application No. 67 No. 17,107. In compounds having an esterified carboxyl group, for example, an esterified carboxyl group -C(=○)-○-R2, which can be easily converted into a free carboxyl group, obtained by the method of the present invention, this group is It can be converted into a free carboxyl group by methods known per se, for example depending on the nature of the radical R2 being esterified.

For example, the formula -C(=○)-○1R form or -C(:○)
The -○-R group is generally associated with a chemical reducing agent such as a metal such as zinc or a reducing metal salt such as a chromium(0) salt such as chromium(0) chloride. Free carboxyl groups are then freed by treatment in the presence of a hydrogen donor capable of producing nascent hydrogen, such as an acid, especially acetic acid or formic acid, or in the presence of an alcohol (preferably to which water is added). can be changed to
The group of the formula -C(=○)-OR can be prepared, for example, by irradiation, preferably by ultraviolet irradiation, i.e. the R number is 31,4.
A penzyl group which may be substituted with a lower alkoxy group and/or a nitro group at the 1 and/or 5-1 positions will absorb short wavelength ultraviolet rays, e.g. For example, in the case of a penzyl group substituted with a nitro group at the 2-position, for example, 29
It can be liberated using ultraviolet rays with wavelengths longer than that of Mt. The group represented by the formula -C(=○)-OR may be treated 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. can be converted into a free carboxyl group by Also, the group -C(=○)-O
It can be converted to free carboxyl groups by hydrolysis, for example by treatment with weakly acidic or particularly weakly basic aqueous solutions, such as aqueous sodium bicarbonate or aqueous potassium phosphate buffers having a pH of about 7-9. Furthermore, the group -C(=○)-OR can be converted by hydrogenolysis, for example by treatment with hydrogen in the presence of a noble metal catalyst, such as a palladium catalyst. Carboxyl groups which have been protected, for example by silylation or stannylation, can be liberated by conventional treatment, for example with water or alcohol.

Furthermore, modified functional groups such as acylated amino groups or esterified carboxyl groups can be liberated in a manner known per se, e.g. The free functional groups can be modified, for example acylated or esterified, or substituted by methods known per se.
Thus, for example, an amino group can be converted to a sulfamino group by treatment with a trioxide, preferably in the form of a complex with an organic base such as a tri-lower alkylamine, such as triethylamine. Furthermore, the reaction mixture of the acid addition salt of 4-guanyl semicarbazide and sodium nitrite is added to the reaction mixture of the acyl group Ac in formula (1).
can be reacted with a compound in which is an optionally substituted glycyl group to convert the amino group into a 3-guanylureido group. The cef-2-em compound of formula (0) can be isomerized by treatment with a weakly basic agent and the corresponding cef-3-em compound formed is isolated.

Suitable isomerizing agents are, for example, organic nitrogen-containing bases, in particular aromatic tertiary heterocyclic bases, mainly bases of the pyridine type such as pyridine, collidine or lutidine, and also quinoline, tertiary aromatic bases such as aniline type. N,N-di-lower alkylanilines, such as N,N-dimethylaniline and N,N-diethylaniline, or tertiary aliphatic,
Azaalicyclic or araliphatic bases such as N,N,N-trilower alkylamines such as N,N,N-trimethylamine, N,N-dimethyl-N-ethylamine, N,N,
N-triethylamine or N,N-diisopropyl-
N-ethylamine, N-lower alkylazacycloalkanes such as N-methylpiveridine or N-phenyl lower alkyl-N,N-di-lower alkylamines such as N-benzy-N,N-dimethylamine and mixtures thereof, such as mixtures of pyridine and triethylamine. It is a mixture of a pyridine type base such as and N,N,N-tri-lower alkylamine. Furthermore, inorganic or organic salts of bases, in particular salts of moderately strong or strong bases with weak acids, such as sodium acetate, triethylammonium acetate or N acetate.
- It is also possible to use alkali metal or ammonium salts of lower alkane carboxylic acids, such as methylpiveridine, as well as other similar bases or mixtures of such basic agents. The isomerization reaction with a basic agent can be carried out, for example, in the presence of a suitable carboxylic acid derivative such as a carboxylic acid anhydride or chloride to form a mixed anhydride, for example using pyridine in the presence of hot acetic acid. can.

In this case, preferably in an anhydrous medium, solvents such as aliphatics, which may be halogenated (e.g. chlorinated),
in the presence or absence of a cycloaliphatic or aromatic hydrocarbon or a solvent mixture (the base, which is liquid under the reaction conditions used as a reactant, can simultaneously serve as a solvent), under cooling, at room temperature or under heat, It is preferably carried out at a temperature range of from about 130 qo to about 1100 qo, under an inert gas such as nitrogen, and/or in a sealed container. The Cef 3-em compounds thus formed can be separated from any Cef 2-em compounds that may still be present by methods known per se, such as adsorption and/or crystallization. Suitable oxidizing agents for oxidizing the 1-position of cef-2-em compounds include inorganic peracids, organic peracids, or peracids having a reduction potential of at least 11.5 volts and comprising nonmetallic elements. Mixtures of hydrogen oxide and acids, especially organic carboxylic acids, having a dissociation constant of at least 10-5 may be mentioned.

Suitable inorganic peracids are periodic acid and persulfuric acid. Organic peracids are the corresponding percarboxylic and persulfonic acids, which can be added as such or can be formed in the reaction using at least equivalent amounts of hydrogen peroxide and carboxylic acid. . In this case, if carboxylic acid such as acetic acid is used as a solvent, it is suitable to use this carboxylic acid in large excess. Suitable peracids are, for example, peracids,
Peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid or p-
Toluene persulfonic acid. Additionally, a sufficient amount of a catalytic acid having a dissociation constant of at least 105 may be added to oxidize the hydrogen peroxide.

The acid can also be added in low concentrations, for example 1-2% or less, or in higher amounts. The action 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.

That is, oxidation with a percarboxylic acid is carried out in the presence of an acid having a dissociation constant of at least 10@-5. The effectiveness of the acid in this case depends on its strength. Acids suitable as catalysts are, for example, acetic acid, perchloric acid or trifluoroacetic acid. Generally, the oxidizing agent is present in at least an equimolar amount, preferably from about 10 to
A 20% excess of ink or a large excess, ie up to one stitch or more, can be used. This oxidation is carried out under mild conditions, for example at about 150 to 1100 qO, preferably about 110 to 140 qO. The formula obtained in this way (1
) in the 1-oxide of the cef-3-em compound,
Ac and/or R can be modified, split or introduced within the scope of the definition.

The isomeric mixture of Q-1-oxide and 8-1-oxide can be separated, for example, by chromatography. The 1-oxide of the cef-3-em compound of formula (1) can be reduced by methods known per se by treatment with a reducing agent, if necessary in the presence of an activator. The reducing agent is catalytically activated hydrogen (the catalyst is a noble metal catalyst including palladium L platinum or rhodium,
(always with a suitable carrier such as carbon or barium sulfate), reducing zinc, iron, copper or manganese cations (with corresponding inorganic or organic compounds or in the form of key bodies, e.g. chlorides, fluorides, acetates or formates, chlorides, sulfates, oxalates or succinates of iron 0, chlorides, benzoates or oxides of copper 1, or chlorides of manganese, as sulfates, acetates or oxides or as rust forms with key bodies such as ethylenediaminetetraacetic acid or nitrilotriacetic acid), reducing dithionite anions, ferrous anions or ferrous cyanide anions. (corresponding inorganic or organic salts such as sodium hydrosulfite, potassium hydrosulfite, sodium iodide, potassium iodide,
(used in the form of an alkali metal salt such as sodium ferrocyanide or potassium ferrocyanide or in the form of a corresponding acid such as hydroiodic acid), inorganic or organic compounds of reducing trivalent phosphorus (e.g. phosphine; esters, amides and halides of acids, phosphonic acids or fumed phosphoric acids, as well as phosphorus-sulfur compounds corresponding to these phosphorous oxygen compounds (where the organic groups are mainly aliphatic L aromatic or araliphatic groups, e.g. substituted lower alkyl group, phenyl group or phenyl lower alkyl group]), such as triphenylphosphine, tri-n-butylphosphine, diphenylphosphine acid ester, diphenylchlorophosphine,
．． phenyldichlorophosphine, benzenephosphonic acid dimethyl ester, butanephosphonic acid methyl ester, phosphite triphenyl ester, phosphite trimethyl ester, phosphorus trichloride, phosphorus tribromide and others], reducing halogens Poppy, elementary compounds (at least one hydrogen atom is bonded to poppy and elementary, and in addition to halogen atoms such as chlorine, bromine, and iodine, organic groups such as lower alkyl groups and phenyl groups that may be substituted) They may also contain aliphatic or aromatic groups such as chlorosilane, fromomsilane, dichlorosilane, trichlorosilane, dipromosilane, tribromosilane, diphenylchlorosilane, dimethylchlorosilane, etc.), reducing groups such as Quaternary chlormethylene iminium salts, especially chloride or bromide, in which the iminium group is substituted by a divalent organic group or two monovalent organic groups, e.g. an optionally substituted lower alkylene or lower alkyl group. and hydrogenation in the presence of a suitable activating agent such as cobalt chloride D) Examples include metal hydrides such as sodium boron. Activators used in conjunction with said reducing agents which themselves do not exhibit Lewis acid rod properties, i.e. especially hydrosulfite, iodide or ferrocyanide reducing agents and halogen-free trivalent phosphorus reducing agents. Activators used in any case or in catalytic reduction are in particular organic carboxylic acid halides or sulfonic acid halides and also halides of sulfur, phosphorus or silicon whose secondary hydrolysis constant is equal to or higher than that of penzoyl chloride. , such as phosgene, oxalyl chloride, acetic chloride, acetic bromide, chloroacetyl chloride, pivalic acid chloride, 4-
Methoxybenzoic acid chloride, 4-Sia/benzoic acid chloride, p-toluenesulfonic acid chloride, methanesulfonic acid chloride, thionyl chloride, phosphorus oxychloride,
Phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenephosphonic acid dichloride, dimethylchlorosilane or trichlorosilane and also suitable acid anhydrides such as trifluoroacetic anhydride or cyclic sultones such as ethane sultone, 1,3-propanesal tons, 1,
4-butane sultone or 1,3-hexane sultone.

Preferably, the reduction is carried out in the presence of a solvent or solvent mixture.

These solvents depend, inter alia, on the solubility of the raw materials and on the type of reducing agent, for example to facilitate lower alkane carboxylic acids such as acetic acid or ethyl acetate or their esters in the catalytic reduction, and for example to carry out substitutions (e.g. halogenation or nitration). ) aliphatic, which may be
cycloaliphatic, aromatic or araliphatic hydrocarbons such as benzene, methylene chloride, chloroform or nitromethane,
suitable acid derivatives such as lower alkane carboxylic acid esters or nitriles such as ethyl acetate or acetonitrile;
or amides of inorganic or organic acids such as dimethylformamide or hexamethylphosphoramide, ethers such as diethyl ether, tetrahydrofuran or dioxazo, ketones such as acetone or sulfones, especially aliphatic sulfones such as dimethylsulfone or tetramethylene sulfone, etc., in combination with chemical reducing agents. Use together. Preferably, these solvents are anhydrous. The reaction is generally carried out at temperatures of about 120 to 1100 OO, and can be carried out at much lower temperatures--if very reactive activators are used. The salt of the compound of formula (1) is produced by a method known per se. Thus, the salts can be produced, for example, by treatment with a metal compound such as an alkali metal salt of the appropriate carboxylic acid, such as the sodium salt of ethylcabronic acid or ammonia or a suitable organic amine. For this purpose, it is preferred to use the salt-forming agent in stoichiometric or slightly excess amounts. Acid addition salts of the compound of formula (1) having a basic group can also be obtained by conventional methods, for example by treatment with an acid or a suitable anion exchanger. The inner salt of a compound of formula (1) having a salt-forming amino group and a free carboxyl group can be prepared by neutralizing the salt, such as its acid addition salt, with, for example, a weak base to the isohaze point or by liquid ion exchange. produced by treatment with a chemical agent. The salts can be converted into the free compounds in conventional manner, for example by treating metal and ammonium salts with suitable acids, and acid addition salts, for example by treating with suitable basic agents.

The isomer mixture obtained is separated into the individual isomers by methods known per se, for example by fractional crystallization, adsorption chromatography (lamb chromatography or thin layer chromatography) or other suitable separation methods. Can be done.

The obtained racemate is treated by a conventional method, if appropriate, after introducing a suitable salt-forming group, for example, to form a diastereomer salt mixture with an optically active salt-forming agent, and this mixture is divided into each diastereomer. The individual enantiomers can be resolved by separating the diastereomeric salts and converting the diastereomeric salts thus separated into the free compounds or by fractional crystallization from optically active solvents. The present invention
It also includes specific examples in which a compound produced as an intermediate in the process is used as a raw material 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. The raw materials and reaction conditions are preferably selected in such a way that the compounds mentioned above as particularly preferred can be obtained.

The invention also relates to the 1-oxides of compounds in formula (1) in which Ac and R have the preferred meanings given above, as well as the salts of such compounds with salt-forming groups.

The raw materials of formula (0) used in the process of the invention are known or prepared by methods known per se.

That is, for example, by the method described in the specification of Dutch Patent No. 6815631, for example, when R2
is preferably a hydrogen atom), the acetoxymethyl group is hydrolyzed in a weakly basic soot such as an aqueous sodium hydroxide solution of pH 9 to 10, or Suitable estefuses such as Rhizobium toritori (Rhi
zobium tritolii), Rhizobium lupinii (RhiZobium lupinii), Rhizopium japonicum (Rhizobimm nuponlc)
m) or Bacterium subtilis (mother cteri)
by treatment with a suitable enzyme from Mt. , the raw material of formula (b) is obtained.

The above oxidation reaction can be carried out, for example, in US Pat. No. 3,351,599.
6, i.e. oxidizing metal compounds such as chromium trioxide and manganese dioxide or 2,3-dichloro-5,6-dicyano-1
, 4-benzoquinone or advantageously with an aliphatic sulfoxide such as a di-lower alkyl sulfoxide such as dimethyl sulfoxide or a lower alkylene sulfoxide such as tetramethylene sulfoxide in the presence of an aliphatic carboxylic anhydride such as acetic anhydride. (preferably with an excess of sulfoxide and using an equimolar amount of acid anhydride compared to the sulfoxide), about 150 to 17
This can be carried out by further treatment at 0°C, if desired, in the presence of an inert solvent such as benzene or toluene. The cef-2-em raw material of formula (b) can also be obtained by total synthesis, ie by the method described in Austrian Patents 263,768 and 264,537.

The carbon monoxide-binding heavy metal rust bodies used in the reaction of the process according to the invention are triturated with the corresponding heavy metal halides, optionally in the form of hydrates, such as rhodium chloride or iridium chloride, for example by methods known per se. It is prepared by reacting a phosphine such as phenylphosphine, preferably in excess, in the presence of a suitable solvent such as a lower alkanol such as ethanol, preferably at elevated temperature.

Generally, the desired substance is obtained in crystalline form. Next, the present invention will be explained in more detail with reference to Examples.

Example 1 3- dissolved in 250' of anhydrous degassed benzene
Formyl-78-phenylacetylaminoseph-2-emu-4Q-carboxylic acid diphenylmethyl ester 1.
The solution of 0.5 mL is treated with 1.87 mL of tris-triphenylphosphine-rhodium chloride under argon.

After heating to 70 oo for 2 hours and at reflux temperature for 5 additional hours, the reaction solution is left to stand for 16 hours.

The fine precipitate was filtered off, the filtrate was filled with carbon monoxide to remove excess rhodium rust, the excess rhodium rust reacted with carbon oxide, and the residue was evaporated to dryness. Dissolve in a small amount of methylene chloride. After standing for 20 minutes at 4°C, the lemon-yellow precipitate containing bistriphenylphosphine-carbonylrhodium chloride is filtered off, washed with bentane and dried.

The mother liquor was evaporated to dryness under reduced pressure and silica gel 7
Chromatograph on a 5 tater. The amorphous 78-phenylacetylaminosefu-2-em-4Q-luponic acid diphenylmethyl ester, which is pure by thin layer chromatography, is eluted with a 4:1 mixture of toluene and methylene chloride. The unchanged starting material is eluted with a 3:7 mixture of toluene and methylene chloride. The analytical product of 78-phenylacetylaminosefu 2-emu 4Q-carboxylic acid diphenylmethyl ester was purified again by chromatography on silica gel, lyophilized from dioxane and under high vacuum at room temperature. Let dry inside for 30 hours.

Layer chromatogram (plate, generated with iodine vapor, 254
Identified by ultraviolet light of m Buddha) Rf = 0.53 (system: toluene,
acetone 4:1), Rf=0.75 (system: toluene-acetone 2:1), Rf=0. (system: toluene/ethyl acetate 1:1), Rf = 0.56 (system: toluene/ethyl acetate 2:1) and Rf = 0.36 (system: toluene/ethyl acetate 4:1), ultraviolet absorption spectrum Input max=24
8hm (go = 5200) and ^mln = 242mr (
5050) (95% aqueous ethanol solution), and ^max = 247m (5300) and mj
n=243hA (5250) (methylene chloride solution)
, Infrared absorption spectrum (methylene chloride solution) 4.29 French, 5.62 French, 5.72 French, 5.93 French, 6.23 French,
6.64 Buddha, 6.68 one, 6.88 Buddha, 7.16r, 7
．． 58 mu, 8.14 Buddha, 8.35 Buddha, 8.50 mountain, 8.
65-1, and characteristic bands at 10.18 mm. The above raw materials are produced as follows.

3.40 g of 3-acetoxymethyl-76-phenylacetylaminocephalic acid-2-em-4Q-carboxylic acid was suspended in 70 g of distilled water, and while stirring in a Vipro mixer, it was mixed with an IN aqueous sodium hydroxide solution. pH7.
Process until it reaches 3.

The solution is heated to 35 qo in a thermostatic bath and treated with a mixture of 0.4 parts of cell lyophilizate from Bacillus subtilis ATCCG 633 and 3 parts of water. The pH is kept constant at 7.4 by adding an aqueous solution of sodium hydroxide IN. Approximately 2. After an instant, half of the theoretical consumption of sodium hydroxide is reached. The mixture is allowed to react completely until the sodium hydroxide solution is no longer consumed and the reaction solution does not change further even after standing for several hours at room temperature. The solution is covered with 300 g of cold ethyl acetate and acidified to pH 2.0 with 5 molar aqueous phosphoric acid with thorough stirring. After separating the phases, the aqueous phase is saturated with sodium chloride and extracted two more times with cold ethyl acetate.
Combine the organic phases and add 5 ml of saturated aqueous sodium chloride solution.
Wash 5 times with 0.0° C., dry with sodium sulfate and evaporate. The residue consists croftographically of a single substance, 3-hydroxymethyl-76-phenylacetylaminosefu-2-em-4Q-carboxylic acid, and after repeated crystallization from a mixture of ethyl acetate and cyclohexane. It is obtained in the form of white needle-like crystals melting at 156-156.5 qo. 2.79 ml of 3-hydroxymethyl-78-phenylacetylaminose-2-hemu-4Q-carboxylic acid was dissolved in 85 g of anhydrous dioxane and 2.29 g of 2,3-dichloro-5,6-dicyano-1,4-penzoquinone. Process.

The clear reaction mixture is left at 45°C for 2 hours and then at about 5°C for 2 hours. The 2,3-dichloro-5,6-dicyanohydroquinone thus precipitated as slope-like crystals is filtered off, the filtrate is evaporated to dryness under reduced pressure, and the residue is dissolved in a small amount of ethyl acetate and filtered. The ethyl acetate solution is diluted to 240 ml and extracted with cooling once with 120 ml of 0.5 molar aqueous dipotassium hydrogen phosphate solution and twice with 90 ml of aqueous 0.5 molar dipotassium hydrogen phosphate solution. Add 150% ethyl acetate to the aqueous phase.
The kite was washed twice with ice-cold ethyl acetate, covered with ice-cold 250% ethyl acetate, and washed with concentrated phosphoric acid to pH 2.
Adjust to 1. The aqueous phase is separated, saturated with sodium chloride and extracted with 150 and 130' of ethyl acetate. The organic extracts were dissolved in a saturated aqueous sodium chloride solution.
Wash 4 times with 0.0° C., dry with sodium sulfate and evaporate. An amorphous product is thus obtained. This substance is macroscopically a single substance according to thin layer chromatography. This is chromatographed on 180 ml of silica gel. Thus, according to thin layer chromatography, 3-formyl-73-phenyl acetylaminoseph-
The 2-em-4Q-carboxylic acid is eluted with a 4:1 mixture of methylene chloride and ethyl acetate. Thin layer chromatogram (silica gel plate) Rf = 0.39 (system: n-butanol/acetic acid/water 75:7.5:21) Rf = 0.27 (system: n-butanol/ethanol/water 40 :10:50)
, and Rf=0.53 (system: n-butanol, acetic acid,
Wed 40:10340). The pure product is further isolated from the impure section by repeated column chromatography. This material crystallizes from a mixture of methanol and methylene chloride with inclusion of methanol. Melting point 137.5-138. yo, [Q] color. :+5
80 Soil 10 (C=1.168% in dioxane), UV absorption spectrum (95% ethanol solution) included max=2
88h〃(go=18850) and ^min: 248h
Buddha (go = 2075). 3-formyl-78-phenylacetylamide/-cefu2-em-4Q-carboxylic acid 10
y is a 4:1 mixture of dioxane and methanol250
The mixture is dried and treated with a solution of 1.5 molar equivalents of diphenyldiazomethane in cyclohexane.

The reddish-purple solution is left to stand for 2 hours at room temperature and then evaporated to dryness under reduced pressure. Dissolve the residue in hot methylene chloride.
If this solution is diluted with cyclohexane while heating,
3-formyl-73-phenylacetylaminoseph-
2-em-4Q-carboxylic acid diphenylmethyl ester is obtained in virtually quantitative yield in the form of fine, dark-brown felt needles. Melting point 175.5-17 o (height correction, decomposition), [Q] color 0 = 1513 o ± lo (C = 1.084 in chloroform), thin layer chromatogram (silica gel) Rf = 0.35 (system :Toluene acetone 80:
20) and Rf = 0.58 (system: toluene acetone 65:35), ultraviolet absorption spectrum (95% ethanol solution) ^max = 289hr (20200) and ^min = 248hr (2100), red The external absorption spectrum is 2.92 mm, 3.53 mm, 5 mm in methylene chloride.
．． 59 m, 5.72 m, 5.91 m, 6.34 m, 6.
61r and 6.67 buddhas and 3.00 buddhas in key oil,
5.63 Buddha, 5.76 Mu, 5.96 Buddha (double belt), 5.
99〃 and 6.58 muco characteristic band. Example 2 A solution of 0.485 ml of 78-phenylacetylaminocephalic acid diphenylmethyl ester dissolved in 15% of anhydrous methylene chloride in an ice bath was prepared in an ice bath.
3-chloroperbenzoic acid cooled to 0.1 °C and purified
Add 90 evenings.

This clear solution was allowed to stand at room temperature for 1 hour and then diluted with methylene chloride.
The mixture is diluted with 0.0% and extracted twice with 10% each of 5% sodium bisulfite solution, 0.5 molar dipotassium hydrogen phosphate solution and distilled water. The aqueous phases are re-extracted with a small amount of methylene chloride and then discarded. The organic extracts are dried with magnesium sulfate and concentrated to a small volume. After adding the diethyl ether and a small amount of cyclohexane while still warm, the 1-oxide of 73-phenylacetylaminoceph 3-emu-4-carboxylic acid diphenylmethyl ester precipitates out as a bulky colorless crystalline product. Melting point 192-200 qo (decomposed). This crystalline product and mother liquor were both obtained by thin layer chromatography (silica gel plate, system: toluene/acetone 4
According to 1), it still contains a small amount of raw material. The product is chromatographed on 25 days of silica gel.

A small amount of unchanged raw material is mixed with methylene chloride and methyl acetate.
:1 mixture. The 1-oxide of 78-phenylacetylaminoceph 3-em-4-carboxylic acid diphenylmethyl ester is eluted with a 9:1 and 6:1 mixture of methylene chloride and methyl acetate. This product crystallizes in the form of spherical agglomerates from a mixture of methylene chloride and diethyl ether. After drying in a high vacuum for 17 hours at 300°C, it melts while decomposing at a temperature of 1 spot to 202°C (height correction). [Q] Color o=111 is ±l
o (C=0.667 in chloroform), thin layer chromatogram (silica gel, color developed with iodine vapor) Rf=0.0
8 (system: toluene/ethyl acetate 2:1), Rf=0.1
7 (system: toluene/ethyl acetate 1:1), Rf=0.2
0 (system: toluene-acetone 4:1) and Rf=0.
57 (system: methylene chloride/acetone 6:1), ultraviolet absorption spectrum (95% ethanol aqueous solution max = 264
mm (Go = 60) and input min = 24 (Go =
3930), infrared absorption spectrum 2.93 peaks, 5.54
Buddha, 5.77 Buddha, 5.92〃, 6.09 Buddha, 6.68 Buddha, 7.15m, 8.13 mountain, 8.69m, 9.10A,
9.62 Mu, 9.84 Mountain, 10.18 Buddha and 10.
23 Buddha (methylene chloride solution) and 3.02 Buddha, 5.
53 mountains, 5.83 Buddhas, 6.06 Buddhas, 6.11〃, 6.5
2〃, 7.13〃, 7.76〃, 7.88 Buddha, 8.57
〃, characteristic band at 9.69 French and 10.44 mm (in mineral oil). Example 3 By choosing appropriate starting materials and following the same procedure as in Examples 1 and 2, the following compounds are obtained.

73-phenylacetylaminoseph-3-emu4-
Carboxylic acid diphenylmethylester-1-oxide, melting point 198-202°C (uncorrected), [Q] = 111
20±10 (c=0.667, black.

Claims (1)

[Claims] 1 Formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ In this formula, Ac is an acyl group of an organic carboxylic acid having up to 18 carbon atoms, and R is a protected carboxyl group -C ( The 3-formyl-2cephem-4-carboxylic acid compound represented by =O) is an organic group formed together with -O- is desorbed using a heavy metal complex of platinum group metal that combines with carbon monoxide. carbonylation and oxidation of the resulting compound in the 1-position, converting it to a cef-3em compound and, if desired, converting the resulting compound of formula (I) into a salt or converting the resulting salt into a salt. of formula (I) or other salts and/or, if desired,
There are formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (in which Ac and R have the meanings given above) that are characterized by the separation of the resulting isomer mixture into individual isomers. A method for producing a 1-oxide of a 7β-amino-3cephem-4-carboxylic acid compound or a salt of these compounds having a salt-forming group.