JPS6054320B2 - Method for producing O-substituted 7β-amino-3-cephem-3-ol-4-carboxylic acid compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to enol derivatives, specifically those having the formula [where R2 is a hydroxyl group or is protected in conjunction with the carbonyl group -C(=0)-] a group R3 forming a carboxyl group, and R3 is an alkyl group, an aralkyl group or an acyl group. It concerns the preparation of salts of such compounds with forming groups.

Enol derivatives according to the invention are ethers and esters of 3-cephemu-3-ol compounds.

The protected carboxyl group represented by the formula -C(=0)-R8 is mainly an esterified carboxyl group,
It can also be a common mixed anhydride group or an optionally substituted carbamoyl or hydrazinocarbonyl group.

Therefore, the group R8 is a hydroxyl group etherified with an organic group in which the number of carbon atoms forming the esterified carboxyl group with the group -C(=O)- is preferably up to 1. Something can happen.

Such organic radicals include, for example, aliphatic, cycloaliphatic, monoaliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic radicals. It is a monocyclic aliphatic group. The radical R may also be substituted with an organosilyloxy group or a hydroxyl group etherified with an organometallic group, such as the corresponding organostannyloxy group, in particular with preferably up to 1 carbon atoms. It can also be a hydrocarbon radical, for example a silyloxy or stannyloxy radical substituted by 1 to 3 aliphatic hydrocarbon radicals and optionally by a halogen atom, such as a chlorine atom.

The radical R3, which together with the radical -C(=0)- forms an anhydride radical, predominantly a mixed anhydride radical, is in particular an acyloxy radical, which preferably has up to 18 carbon atoms. organic carboxylic acids such as aliphatic, cycloaliphatic, monoaliphatic,
Corresponding groups of aromatic or araliphatic carboxylic acids or carbonic acid half derivatives such as carbonic acid half esters.

The group -C (=0) and the group R which together form a carbamoyl group are optionally substituted amino groups.

This substituent is an optionally substituted monovalent or divalent hydrocarbon radical having preferably up to 18 carbon atoms, such as an optionally substituted valent or divalent aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, as well as corresponding heterocyclic or cycloaliphatic radicals having two or more carbon atoms; (or) functional groups, such as hydroxyl groups which can be functionally modified, in particular free hydroxyl groups, and also etherified or esterified hydroxyl groups (the etherified or esterified groups being defined, for example, as defined above). and preferably up to 18 carbon atoms) or an acyl group of an organic carboxylic acid or carbonic acid semi-derivative having mainly carbon atoms, preferably in bulk. In the substituted hydrazinocarbonyl group represented by the formula -C(=O)-R, one or both nitrogen atoms may be substituted.

Substituents include mainly monovalent or divalent hydrocarbon groups which may be substituted, preferably having up to 18 carbon atoms, such as substituted monovalent or divalent hydrocarbon groups having up to 1 carbon atom. Monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, even up to 18 carbon atoms! Corresponding heterocyclic or heterocyclic monoaliphatic groups having up to Examples include groups. R3 as an acyl group is mainly an acyl group of an organic carboxylic acid including formic acid, such as an alicyclic, alicyclic monoaliphatic, araliphatic, heterocyclic or heterocyclic monoaliphatic carboxylic acid, especially an alicyclic Acyl groups of carboxylic acids, as well as aromatic carboxylic acids and carbonic acid semi-derivatives. The general terms described herein have, for example, the following meanings.

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

Such groups optionally include functional groups, such as free or etherified or esterified hydroxyl groups or mercapto groups, such as lower alkoxy groups, lower alkenyloxy groups, lower alkylene dioxy groups, a phenyloxy group or a phenyl lower alkoxy group that may be substituted, a lower alkylthio group, a phenylthio group that may be substituted or a phenyl lower alkylthio group, a heterocyclic monothio group or a heterocyclic monolower alkyl thio group, A lower alkoxycarbonyloxy group or a lower alkanoyloxy group that may be substituted, or a halogen atom, as well as an oxo group, a nitro group, and an amino group that may be substituted, such as a lower alkylamino group or a di-lower alkylamino group. , lower alkylene amino group, oxa lower alkylene amino group or aza lower alkylene amino group and acylamino group such as lower alkanoylamino group, lower alkoxycarbonylamino group, halogen lower alkoxycarbonylamino group, optionally substituted phenyl lower alkoxycarbonyl Amino groups, carbamoylamino groups that may be substituted, ureidocarbonylamino groups or guanidicarbonylamino groups, as well as sulfamino groups that may be present in the form of salts such as alkali metal salts, azido groups, lower alkanoyl groups or acyl groups such as the benzoyl group, carboxyl groups which may be functionally modified, e.g. carboxyl groups in salt form, esterified carboxyl groups such as the lower alkoxycarbonyl group, N-lower alkyl or N -N-di-lower alkyl-
An optionally substituted carbamoyl group, such as a carbamoyl group, an optionally substituted ureidocarbonyl or guanidinocarbonyl group, or a cyano group, an optionally functionally modified sulfo group, such as sulfamoyl. a sulfo group in radical or salt form;
or a phosphono group which may be O-mono or O.0''-di-substituted (the substituent being, for example, an optionally substituted lower alkyl group, phenyl group or phenyl lower alkyl group, Unsubstituted or 0-monosubstituted phosphono groups can be mono-, di- or polysubstituted (which can also be in the form of salts, such as alkali metal salts).Divalent aliphatic carbonyls Divalent aliphatic groups, including aliphatic groups of acids, are, for example, lower alkylene or lower alkenylene groups, which may optionally be mono-, di- or polysubstituted like the aliphatic groups mentioned above. and/or heteroatoms such as oxygen, nitrogen or sulfur atoms may be present in the chain.

Alicyclic or alicyclic monoaliphatic groups (including corresponding alicyclic or alicyclic monoaliphatic groups in organic carboxylic acids) and corresponding alicyclic or alicyclic -! Aliphatic ylidene groups are optionally substituted monocyclic or bicyclic alicyclic or alicyclic monoaliphatic hydrocarbon groups, such as monocyclic, bicyclic or polycyclic cycloalkyl groups or cycloaliphatic hydrocarbon groups. An alkenyl group, further a cycloalkylidene group, or a cycloalkyl4-or a cycloalkenyl-lower alkyl group or a mono-lower alkenyl group, furthermore 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. and the aliphatic part of the alicyclic monoaliphatic group can have, for example, up to 7, preferably up to 4 carbon atoms. These cycloaliphatic or cycloaliphatic groups may be substituted if desired by aliphatic hydrocarbon groups, for example by the above-mentioned optionally substituted lower alkyl groups. They can be monosubstituted, disubstituted or polysubstituted by functional groups, such as the aliphatic hydrocarbon groups mentioned above. 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 and biphenylyl or naphthyl groups, which may 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, in particular 1.multidot.2-phenylene radicals, which can optionally be mono-, di- or polysubstituted, such as the aforementioned aliphatic and cycloaliphatic hydrocarbon radicals.

The above-mentioned araliphatic groups (including araliphatic groups in the corresponding carboxylic acids) and also araliphatic ylidene groups are e.g. optionally substituted araliphatic hydrocarbon groups,
For example, optionally substituted aliphatic hydrocarbon groups having up to three optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon groups, especially phenyl group. 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 radicals and optionally contain, for example, the aforementioned fatty acids. It can be mono-, di- or polysubstituted in its aromatic and/or aliphatic portions, such as groups and cycloaliphatic groups.

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

The aliphatic moiety in a heterocycloaliphatic radical has, for example, the meaning given to the corresponding alicyclic monoaliphatic 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 a heterocyclic group). aliphatic groups), especially acyl groups of lower alkyl half-esters of carbonic acid (which can be substituted, for example, in the α- or β-position) and carbonic acid which may be substituted in its organic radicals. is preferably an acyl group of lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half ester.

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. An etherified hydroxyl group is defined primarily by a lower alkoxy group which may be substituted, the substituents being primarily free or functionally modified e.g. etherified or esterified hydroxyl groups, especially lower alkoxy groups or halogen atoms. ), and further lower alkenyloxy groups, cycloalkyloxy groups, or optionally substituted phenyloxy groups, and heterocyclic rings.
An oxy group or a heterocyclic mono-lower alkoxy group, especially a phenyl lower alkoxy group which may be substituted.

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

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

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

Lower alkylene groups are, for example, 1,2-ethylene groups, 1,2
- or 1,3-propylene group, 1,4-butylene group,
It is a 1,5-pentylene group or a 1,6-hexylene group, and the lower alkenylene group is, for example, a 1,2-ethenylene group or a 2-buten-1,4-ylene group.

The lower alkylene group with an intervening heteroatom is, for example, an oxa-lower alkylene group such as 3-oxa1●5-pentylene group, 3-thia1●thia lower alkylene group such as 5-pentylene group, or 3-lower alkyl-3 -Aza-1,5-pentylene group An aza-lower alkylene group such as, for example, 3-methyl-3-aza-1,5-pentylene group. Cycloalkyl groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and adamantyl; cycloalkenyl groups are, for example, cyclopropenyl, 1
-, 2- or 3-cyclopentenyl group, 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 It is a cyclohexylidene group.

A cycloalkyl-lower alkyl group or a cycloalkyl-lower alkenyl group is, for example, cyclopropyl-, cyclopentyl-, cyclohexyl- or cycloheptyl-
Methyl group, -11-ethylene group (]CH-CH3), -
12-ethylene group (-CH2-CH2-), -11-propylene group (>CH-CH2-CH3), -1●2-propylene group (-1℃H2-YH-℃H3), -1.3-propylene group .

577 group (-CH2-CH2-CH2-), -vinyl group or -allyl group, and the cycloalkenyl-lower alkyl group or the cycloalkenyl-lower alkenyl group is, for example, 1-, 2- or 3-cyclopentele-1- ,2
- or 3-cyclohexenyl or 1-, 2- or 3-cycloheptenyl-methyl group, -1●1-ethylene group (〉CH-CH3), -1,2-ethylene group (-C
H2-CH2-), -1,1-propylene group (〉CH-
CH2-CH3), -1.2-pA5OL/7 groups (1°C
H2-SH-℃H3), -13-propylene group (CH2
-CH2-CH2, -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. The naphthyl group is a 1- or 2-naphthyl group, and the biphenylyl group is, for example, a 4-biphenylyl group.

A phenyl-lower alkyl group or a phenyl-lower alkenyl group is, for example, a benzyl group, a 1- or '2-phenylethyl group, a 1-, 2- or 3-phenylpropyl group,
diphenylmethyl group, trityl group, 1- or 2-na7
A naphthyl-lower alkyl group such as a thylmethyl group, a styryl group or a cinnamyl group, and a phenyl-lower alkylidene group is, for example, a benzylidene group.

Heterocyclic radicals are in particular optionally substituted heterocyclic radicals with aromatic character, such as corresponding monocyclic monoazacyclic, monothiacyclic or monooxacyclic radicals, such as 2-
Pyryl groups such as pyryl and 3-pyryl, 2-, 3-
or pyridyl and pyridinium groups such as 4-pyridyl, thienyl groups such as 2- or 3-thienyl, or furyl groups such as 2-furyl, bicyclic monoazacyclic, monooxacyclic or a 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, 1
- isoquinolinyl group such as isoquinolinyl group, benzofuranyl group such as 2- or 3-benzofuranyl group or benzothienyl group such as 2- or 3-benzothienyl group, monocyclic diazacyclic, triazacyclic, tetraaza cyclic, oxazacyclic, thiazacyclic or thiazicyclic
Azacyclic groups, such as imidazolyl groups such as 2-imidazolyl groups, pyrimidinyl groups such as 2- or 4-pyrimidinyl groups, triazolyl groups such as 1,2,4-triazol-3-yl groups, 1- or 5 - a tetrazolyl group such as a tetrazolyl group, an oxazolyl group such as a 2-oxazolyl group, an isoxazolyl group such as a 3- or 4-isoxazolyl group, a thiazolyl group such as a 2-thiazolyl group, a 3- or 4-isothiazolyl group; or a 1,2,4- or 1,3,4-thiadiazolyl group such as a 1,2,4-thiadiazol-3-yl group or a l●3●4-thiadiazol-2-yl group, or a bicyclic diazacyclic, oxaazacyclic or thiazacyclic group such as a benzmidazolyl group such as a 2-benzimidazolyl group, a benzoxazolyl group such as a 2-benzoxazolyl group or a 2-benzthiazolyl group. This is a benzthiazolyl group.

Corresponding partially or totally saturated groups are for example 2
- a tetrahydrothienyl group such as a tetrahydrothienyl group, a tetrahydrofuryl group such as a 2-tetrahydrofuryl group, or a piperidyl group such as a 2- or 4-piperidyl group. Heterocyclic monoaliphatic radicals are heterocyclic radicals, in particular lower alkyl radicals or lower alkenyl radicals bearing the above-mentioned radicals. Said heterocyclic radicals are, for example, aliphatic or aromatic hydrocarbon radicals which may be substituted, in some cases by lower alkyl radicals such as methyl radicals, or optionally by halogen atoms such as chlorine atoms. It can be substituted by a substituted phenyl group, such as a phenyl group or a 4-chlorophenyl group, or by a functional group, such as the aforementioned aliphatic hydrocarbon groups. Lower alkoxy groups are, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-bentoxy or tertiary-bentoxy.

These groups include, for example, halogeno lower alkoxy groups, especially 2
-halogeno lower alkoxy group such as 2,2,2-trichloroethoxy, 2-chloro, 2-bromo or 2
- can be substituted as in the iodoethoxy 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 adamantyloxy group,
A phenyl-lower alkoxy group is, for example, a benzyloxy group or a 1- or 2-phenylethoxy group, a diphenylmethoxy group or a 4,4"-dimethoxydiphenylmethoxy group, and a heterocycle-oxy group or a heterocycle-mono-lower alkoxy group is Examples include a pyridyl-lower alkoxy group such as 2-pyridylmethoxy group, a furyl-lower alkoxy group such as furfuryloxy group, or a thienyl-lower alkoxy group such as 2-thenyloxy group.Lower alkylthio groups include, for example, methylthio group and ethylthio group. or an n-butylthio group, a lower alkenylthio group being, for example, an allylthio group, a phenyl-lower alkylthio group, for example a benzylthio group, and a mercapto group etherified with a heterocyclic group or a heterocyclic-aliphatic group. is particularly a pyridylthio group such as 4-pyridylthio group, an imidazolylthio group such as 2-imidazolylthio group, a thiazolylthio group such as 2-thiazolylthio group, 1
・2,4-thiadiazole-3-ylthio group and 1●3●
1, 2, such as 4-thiadiazole-2-ylthio group
4- or 1,3,4-thiadiazolylthio group or 1
A tetrazolylthio group such as -methyl-5-tetrazolylthio group.

Esterified hydroxyl groups are in particular 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, ethoxycarbonyloxy groups. or t-butyloxycarbonyloxy group, 2-halogeno lower alkoxycarbonyloxy group, such as 2.2●2-trichloroethoxycarbonyloxy group, 2-bromoethoxycarbonyloxy group or 2
-iodoethoxycarbonyloxy group, or arylcarbonylmethoxycarbonyloxy group, such as phenacyloxycarbonyloxy group.

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

The 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-diethylcarbamoyl group. , N-lower alkylsulfamoyl group is, for example, N
-methylsulfamoyl group or N-N-dimethylsulfamoyl group. Carboxyl or sulfo groups in the form of alkali metal salts are, for example, carboxyl or sulfo groups in the form of sodium or potassium salts.

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

Acylamino groups are in particular carbamoyl groups, lower alkylcarbamoylamino groups such as methylcarbamoylamino groups, ureidocarbonylamino groups, guanidinocarbonylamino groups, lower alkoxycarbonylamino groups such as methoxycarbonylamino groups, ethoxycarbonylamino groups or t-butoxycarbonyl groups. Amino group, 2.2.
Halogeno lower alkoxycarbonylamino groups such as 2-trichloroethoxycarbonylamino groups, phenyl lower alkoxycarbonylamino groups such as 4-methoxybenzyloxycarbonylamino groups, lower alkanoylamino groups such as acetylamino groups and propionylamino groups, Furthermore, it is a phthalimide group or a sulfamino group which can be in the form of a salt such as an alkali metal salt such as the sodium salt or an ammonium salt. Lower alkanoyl groups are, for example, formyl, acetyl, propionyl or pivaloyl.

0-Lower alkyl-phosphono group is, for example, O-methyl- or O-ethyl-phosphono group, and O●0''-di-lower alkyl-phosphono group is, for example, O●0-dimethyl-phosphono group or 0●0''-diethyl- The phosphono group, O-phenyl lower alkyl-phosphono group is, for example, O-benzyl-phosphono group, and the O-lower alkyl-0-phenyl lower alkyl-phosphono group is, for example, O-benzyl-0-methyl-phosphono group.

A lower alkenyloxycarbonyl group is, for example, a vinyloxycarbonyl group, and a cycloalco. The oxycarbonyl group and phenyl-lower alkoxycarbonyl group are, for example, adamantyloxycarbonyl group, benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, diphenylmethoxycarbonyl group or α-4-biphenylyl-α-methylethoxycarbonyl group.

A lower alkoxycarbonyl group whose lower alkyl group has, for example, a monocyclic monoazacyclic, monooxacyclic or monothiacyclic group is a furyl-4-mono-lower alkoxycarbonyl group such as a furfuryloxycarbonyl group or A thienyl-lower alkoxycarbonyl group such as a 2-thenyloxycarbonyl group. 2-lower alkylhydrazino group and 2●2-di-lower alkylhydrazino group are, for example, 2-methylhydrazino group or 2●
2-dimethylhydrazino group, and the 2-lower alkoxycarbonylhydrazino group is, for example, 2-methoxycarbonylhydrazino group, 2-ethoxycarbonylhydrazino group or t-butoxycarbonylhydrazino group,
The lower alkanoylhydrazino group is, for example, a 2-acetylhydrazino group.

The etherified hydroxyl group RG is preferably a readily cleavable or other functionally modified carboxyl group (e.g. a carbamoyl group or a hydrazinocarbonyl group) whenever the carbonyl group of j It forms an esterified carboxyl group that can be easily converted into

Such groups R3 include, for example, methoxy, ethoxy, n
- A lower alkoxy group such as a propoxy group or an isopropoxy group, which together with a carbonyl group forms an esterified carboxyl group, and these can be easily combined, especially in 2-cephem compounds. It can be converted to a free carboxyl group or to other functionally altered carboxyl groups. The etherified hydroxyl group RG forming an esterified carboxyl group which can be split particularly easily with the group -C (=0) is, for example, an etherified hydroxyl group RG having an atomic weight as a halogen atom of 19 or more. It is a 2-halogeno lower alkoxy group having a

Such groups, along with the group -C(=0)-, 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 an esterified carboxyl group that can be easily converted into such a group. For example, such a group is 2.2
- A 2-trichloroethoxy group or a 2-iodoethoxy group, or a 2-chloroethoxy group or a 2-bromoethoxy group that can be easily converted into a 2-iodoethoxy group. Additionally, by treatment with zinc in the presence of a chemical reducing agent such as aqueous acetic acid or with a suitable nucleophile, such as sodium thiophenolate, also under neutral or weakly acidic conditions. As the etherified hydroxy group RS, which forms an esterified carboxyl group which can be easily split by is in particular a phenyl radical which may be substituted) and preferably a phenacyloxy radical. Furthermore, the radical R can also be an arylmethoxy group, the aryl group of which is in particular a monocyclic, preferably substituted, aromatic hydrocarbon group.

Such groups together with the group C(=O) form an esterified carboxyl group which can be easily cleaved by irradiation, preferably UV irradiation, under neutral or acidic conditions. ing. The aryl group in such an arylmethoxy group is particularly a lower alkoxyphenyl group such as a methoxyphenyl group [the methoxy group is mainly 3-
, 4- and (or) in the 5-1 position] and/or especially a nitrophenyl group (the nitro group preferably being in the 2-1 position). Such groups are in particular lower alkoxy groups, such as methoxy and/or nitro-benzyloxy groups, primarily 3
- or 4-methoxybenzyloxy group, 3,5-dimethoxybenzyloxy group, 2-nitrobenzyloxy group or 4,5-dimethoxy-2-nitrobenzyloxy group. Furthermore, the etherified hydroxyl group R
A is a group that together with the group -C (=0) forms an esterified carboxyl group that can be easily cleaved under acidic conditions, for example by treatment with trifluoroacetic acid or formic acid. You can also do it.

Such groups are primarily 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. a methoxy group which is substituted or monosubstituted by a carbocyclic aryl group having an electron-donating substituent or by an aromatic heterocyclic group having an oxygen or sulfur atom as a ring member; or the methyl group forms a ring member in a polycyclic aliphatic hydrocarbon group or a ring member occupying the α-1 position relative to the oxygen or sulfur atom in an oxacycloaliphatic or thiacycloaliphatic group. It is a methoxy group. Among polysubstituted methoxy groups of this type, preferred are t-lower alkoxy groups, such as t-butyloxy or t-pentyloxy groups, optionally substituted diphenylmethoxy groups, such as diphenylmethoxy groups or 4. 4"-dimethoxydiphenylmethoxy group, furthermore, 2-(4-biphenylyl)-2-propyloxy group, and the above-mentioned methoxy group having a substituted aryl group or heterocyclic group is, for example, 4-methoxybenzyloxy group. or 3● α-lower alkoxyphenyl-lower alkoxy group such as 4-dimethoxybenzyloxy group or 2-
Furfuryloxy group such as furfuryloxy group.

A polycyclic aliphatic hydrocarbon radical having the methyl group of the methoxy group, preferably as a triple-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 oxer or thia alicyclic group having as a ring member at the alpha position relative to the oxygen or sulfur atom is, for example, a 2-oxer or 2-thia lower alkylene group or mono-lower alkenylene group having 5 to 7 ring atoms. , for example a 2-tetrahydrofuryl group, a 2-tetrahydropyranyl group or a 2,3-dihydro-2-pyranyl group or a corresponding sulfur compound group. Furthermore, the group R8 is an ether which together with the group -C(=0) forms an esterified carboxyl group which can be cleaved by hydrolysis, for example under weakly basic or weakly acidic conditions. It can also be a modified hydroxyl group.

Such groups are preferably etherified hydroxyl groups, such as 4-nitrophenyloxy groups or 2,4- Nitrophenyloxy group such as dinitrophenyloxy group, nitrophenyl lower alkoxy group such as 4-nitrobenzyloxy group, hydroxy-lower alkyl-benzyloxy group such as 4-hydroxy-3,5-t-butylbenzyloxy group Base, 2, 4, 6-
Polyhalogenophenyloxy groups such as trichlorophenyloxy and 2,3,4,5,6-penonetachlorophenyloxy groups, as well as cyanomethoxy groups and acylaminomethoxy groups such as phthaliminomethoxy or succinylaminomethoxy groups. It is. The group RS can also be an etherified hydroxyl group, always forming an esterified carboxyl group that can be split under hydrogenation conditions with the carbonyl group -C(=0)-; This is, for example, an .alpha.-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 R3 also represents an esterified carboxyl group that can be cleaved under physiological conditions.
(=O)- and etherified hydroxyl groups, mainly acyloxymethoxy groups (the acyl groups are, for example, groups of organic carboxylic acids, mainly lower alkanecarboxylic acids that may be substituted). or the acyloxymethyl moiety thereof forming a lactone group).

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 groups. , L-valyloxymethoxy group, L-leucyloxymethoxy group, and further phthalidyloxy group. R3 as a silyloxy group or a stannyloxy group is preferably an aliphatic, alicyclic, aromatic or araliphatic hydrocarbon group which may be substituted as a substituent, such as a lower alkyl group, a halogeno group. a lower alkyl group, a cycloalkyl group, a phenyl group or a phenyl lower alkyl group, or a functional group which may be modified, such as an etherified hydroxyl group such as a lower alkoxy group or a halogen atom such as a chlorine atom; There is... Mainly tri-lower alkylsilyloxy groups such as trimethylsilyloxy group, halogeno-lower alkoxy-lower alkyl groups such as chloro-methoxymethyl-silyl group, etc.
A silyl group or a tri-lower alkylstannyloxy group such as a tri-n-butylstannyloxy group.

R8 as an acyloxy group which together with the group -C(=0)- preferably forms a mixed anhydride group which can be cleaved by hydrolysis, is for example of the organic carboxylic acid or carbonic acid semi-derivative. a lower alkanoyloxy group, such as an acetyloxy group, a pivalyloxy group, containing an acyl group, which may optionally be substituted, preferably in the α-position, by a halogen atom, such as a fluorine or chlorine atom; or a trichloroacetyloxy group or a lower alkoxycarbonyloxy group such as a methoxycarbonyloxy group or an ethoxycarbonyloxy group.

Furthermore, RO as a group which always forms a carbamoyl group or a hydrazinocarbonyl group which may be substituted with a group -C(=0)- is, for example, an amino group, a methylamino group or an ethylamino group. lower alkylamino groups such as, di-lower alkylamino groups such as dimethylamino and diethylamino groups, lower alkyleneamino groups such as pyrrolidino and piperidino groups, oxa-lower alkyleneamino groups such as morpholino groups, hydroxyamino groups , a hydrazino group, a 2-lower alkylhydrazino group such as a 2-methylhydrazino group, or a 2,2-di-lower alkylhydrazino group such as a 2,2-dimethylhydrazino group.

R as an optionally substituted aliphatic hydrocarbon group
3 is in particular a lower alkyl group having up to 7, preferably up to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl; Alkenyl groups, such as allyl groups, have at least two groups between the t-amino group and the oxygen atom.
a t-amino-lower alkyl group, such as a 2- or 3-di-lower alkylamino-lower alkyl group, such as a 2-dimethylaminoethyl group, a 2-diethylaminoethyl group or a 3-dimethylaminopropyl group;
or its etherified hydroxyl group, especially an etherified hydroxy-lower alkyl group in which at least 2 carbon atoms are interposed between the lower alkoxy group and the oxygen atom, such as a 2- or 3-lower alkoxy lower alkyl group. For example, 2-methoxyethyl group or 2-ethoxyethyl group.

R3 as an aromatic aliphatic hydrocarbon group which may be substituted is mainly a phenyl lower alkyl group which may be substituted, especially a 1-phenyl lower alkyl group having 1 to 3 phenyl groups which may be substituted. An alkyl group such as a benzyl group or a diphenylmethyl group, the substituent of which is an esterified or etherified hydroxyl group such as a halogen atom such as fluorine, chlorine or bromine, or a lower alkoxy group such as a methoxy group. Can be mentioned. R3 as the acyl group of the aliphatic carboxylic acid is primarily an optionally substituted lower alkanoyl group, such as an acetyl group, a propionyl group or a pivaloyl group, which may be, for example, an esterified or etherified hydroxyl group, such as a fluorine group. or a halogen atom such as a chlorine atom or a lower alkoxy group such as a methoxy group or an ethoxy group.

As the acyl group of the aromatic carboxylic acid, R3 can be, for example, a benzoyl group which may be substituted, such as a benzoyl group, or an esterified or etherified hydroxyl group as a substituent, such as a halogen atom such as fluorine or chlorine, methoxy or a benzoyl group with a lower alkoxy group such as an ethoxy group or a lower alkyl group such as a methyl group. R3 as acyl group in the carbonic acid semi-derivative is in particular a lower alkoxycarbonyl group, such as a methoxycarbonyl group or an ethoxycarbonyl group. The salt is
Salts of compounds of formula (1) with free carboxyl groups, in particular salts of the formula (1), mainly metal or ammonium salts, for example salts of alkali metals or alkaline earth metals, such as the salts of sodium, potassium, magnesium or calcium; 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 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-aminobenzoic acid- 2-diethylaminoethyl.
basic aliphatic esters of rubonic acids, such as esters;
lower alkylene amines such as 1-ethylpiperidine,
cycloalkylamines such as bicyclohexylamine or benzylamines such as N-N-dibenzylethylenediamine and also salts of the pyridine type such as pyridine, colicine or quinoline. The compounds of formula (1) may also form acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid or with suitable organic carboxylic acids or sulfonic acids such as trifluoroacetic acid or 4-methylphenylsulfonic acid. can do. Compounds of formula (1) having free carboxyl groups can also be in the form of internal salts, ie in the form of dipolar ions. The novel compounds according to the invention are valuable intermediates for the production of pharmacologically active compounds, and are disclosed in, for example, Japanese Patent Application No. 48-74
354 into the pharmacologically active compounds.

The present invention particularly provides that in formula (1), R2 is a hydroxyl group,
Lower alkoxy group [which is optionally preferably α
In one position, for example, an optionally substituted aryloxy group, a lower alkoxyphenyloxy group such as 4-methoxyphenyloxy, a lower alkanoyloxy group such as acetyloxy or pivaloyloxy, a glycyloxy group, an L- Valyloxy group or L
-α-amino lower alkanoyloxy groups such as leucyloxy, arylcarbonyl groups such as benzoyl, or optionally substituted aryl groups such as phenyl, lower alkoxyphenyl such as 4-methoxyphenyl, 4-nitrophenyl; can be mono- or polysubstituted by a nitrophenyl group such as or a phenyl group such as 4-biphenylyl group or by a halogen atom such as a chlorine, bromine or iodine atom in the β-1 position. For example, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, t-butyloxy group or t-pentyloxy group, bis-phenyloxy-methoxy group which can be substituted with lower alkoxy, e.g. bis-4-methoxyphenyloxy-methoxy group,
lower alkanoyloxy-methoxy groups, such as acetyloxymethoxy or pivaloyloxymethoxy) groups,
α-amino lower alkanoyloxy-methoxy groups such as glycyloxymethoxy, phenacyloxy, phenyl lower alkoxy groups which may be substituted, especially 1-phenyl lower alkoxy groups such as phenylmethoxy groups (such groups are For example, substituents can have 1 to 3 phenyl groups, which may be substituted by lower alkoxy groups such as methoxy groups, nitro groups or phenyl groups), such as benzyloxy groups, 4-methoxybenzyl Oxy group, 2-biphenyly-2-propyloxy group, 4-nitrobenzyloxy group, diphenylmethoxy group, 4,4-dimethoxydiphenylmethoxy group or trityloxy group, or 2-halogeno lower alkoxy group such as 2,2. 2-doechloroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group or 2-iodoethoxy group], as well as 2-phthalidyloxy group and acyloxy group (for example, methoxycarbonyloxy group or ethoxycarbonyloxy group). or lower alkanoyloxy groups such as acetyloxy or pivaloyloxy), tri-lower alkylsilyloxy groups such as trimethylsilyloxy, or amino or hydrazino groups (these may optionally be can be substituted, for example, by 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. group, hydrazino group, 2
-2-lower alkylhydrazino group such as methylhydrazino group, 2●2 such as 2●2-dimethylhydrazino group
-dilower alkylhydrazino group or hydroxyamino group), and R3 is a lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or an n-butyl group, a lower alkenyl group such as an allyl group. , a phenyl lower alkyl group which may be substituted, in particular a 1-phenyl lower alkyl group with one or two phenyl groups which may be substituted with a lower alkoxy group such as, for example, a methoxy group, such as a benzyl group or a diphenyl group. a methyl group, a lower alkanoyl group such as an acetyl or propionyl group, a lower alkoxycarbonyl group such as a methoxycarbonyl group or a benzoyl group (this may optionally be a lower alkyl group such as a methyl group, a lower alkoxy group such as a methoxy group or a fluorine group) or salts of such compounds with salt-forming groups. Formula (1
) or the salts of these compounds with salt-forming salts, R2 is primarily 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 methoxy group or ethoxy group, 2-halogeno lower alkoxy group or 2,2,2-trichloroethoxy group, 2-iodo”
Ethoxy group or 2 that can be easily converted into this group
- 1 to 3 phenyl groups which can be substituted with a chloroethoxy group or a 2-bromoethoxy group, a phenacyloxy group, a lower alkoxy group or a nitro group
-Phenyl lower alkoxy group such as 4-methoxybenzyloxy group, 4-nitrobenzyloxy group, diphenylmethoxy group, 4●4''-dimethoxydiphenylmethoxy group or trityloxy group, lower alkanoyloxymethoxy group such as acetyloxymethoxy group or pivaloyloxymethoxy group, α-amino lower alkanoyloxymethoxy group, e.g. glycyloxymethoxy group, 2-
a phthalidyloxymethoxy group, a lower alkoxycarbonyloxy group such as an ethoxycarbonyloxy group or a lower alkanoyloxy group such as an acetyloxy group, and also a tri-lower alkylsilyloxy group such as a trimethylsilyloxy group, and R3 is primarily a lower alkyl group such as a methyl group. , ethyl or n-butyl, also lower alkenyl groups such as allyl, 1-phenyl lower alkyl groups such as benzyl or diphenylmethyl, but also lower alkanoyl groups such as acetyl or propionyl, lower alkoxycarbonyl groups such as methoxycarbonyl or benzoyl group.

The present invention mainly relates to formula (1) in which R2 is mainly a hydroxyl group, further a lower alkoxy group, particularly a highly branched lower alkoxy group at the α-position, such as a t-butoxy group,
2-halogeno lower alkoxy group such as 2,2,2-trichloroethoxy group, 2-iodoethoxy group or 2-
a bromoethoxy group, or a diphenylmethoxy group which may be substituted with a lower alkoxy group, e.g. a methoxy group, e.g. a diphenylmethoxy group or a 4●4''
-dimethoxydiphenylmethoxy, and also a tri-lower alkylsilyloxy group such as trimethylsilyloxy, and R3 is a lower alkyl group such as a methyl, ethyl or n-butyl group, a lower alkenyl group such as an allyl group or a phenyl lower alkyl group. 3-cephemu compounds, or salts of such compounds, in which groups such as benzyl, and also lower alkanoyl groups, such as acetyl or propionyl, or lower alkoxycarbonyl groups, such as methoxycarbonyl; for example, sodium salts of compounds in which R2 is a hydroxyl group; The present invention relates to alkali metal salts such as alkali metal salts, alkaline earth metal salts such as calcium salts, ammonium salts including amine salts, or inner salts of compounds in which R2 is a hydroxyl group. mainly,
In the 3-cefemu compound of formula (1) or a salt of such a compound, R2 is primarily a hydroxyl group, and also a lower group which may be substituted at the 2-1 position by a chloride atom, such as a chlorine, bromine or iodine atom. Alkoxy groups, especially highly branched lower alkoxy groups in the α-position, such as t
-butoxy group, 2-halogeno-lower alkoxy group, e.g. 2,2,2-trichloroethoxy group, 2-iodoethoxy group or 2-bromoethoxy group, or when substituted with a lower alkoxy group such as e.g. methoxy group; Certain diphenylmethoxy groups, such as diphenylmethoxy groups or 4●4″-dimethoxydiphenylmethoxy groups,
Furthermore, it is a tri-lower alkylsilyloxy group such as a trimethylsilyloxy group and R3 is a lower alkyl group such as a methyl, ethyl or n-butyl group, a lower alkenyl group such as an allyl group, a phenyl lower alkyl group such as a benzyl group.

The present invention primarily relates to 7β-amino-3-lower alkoxy-3-cepheme-4-carboxylic acids, the lower alkoxy groups of which have up to 4 carbon atoms, such as ethoxy or n-butoxy groups, but primarily methoxy groups. and their diphenylmethyl esters and 7β-amino-3-methoxy-3-cephemu-4-carboxylic acids and the corresponding diphenylmethyl esters.

According to the method of the present invention, the formula (in this formula, R2 and R3 have the same meanings as above, but R
2 is preferably a group RO, R8 is an amino-protecting group and R3 is a hydrogen atom or an acyl group, or R8 and R8 together represent a divalent amino-protecting group) , liberates the amino group at the 7-position and optionally converts the protected carboxyl group of formula -C(=O)-R gold into free or otherwise protected carboxyl group and/or optionally converting the resulting compound with the salt-forming group into a salt or converting the resulting salt into the free compound or other salt, and/or optionally converting the resulting By separating a mixture of isomeric compounds into individual isomers, compounds of formula (1) or salts thereof are obtained.

The amino protecting group R8 is a group that can be substituted with a hydrogen atom, mainly an acyl group M1, a triarylmethyl group, especially a trityl group,
and an organic silyl group or an organic stannyl group.

The group Ac, including the acyl group of the group R8, is mainly an acyl group of an organic carboxylic acid having preferably up to 1 carbon atom;
In particular, optionally substituted aliphatic, alicyclic monoaliphatic,
These are the acyl groups of aromatic, araliphatic, heterocyclic, or heterocyclic monoaliphatic carboxylic acids (including formic acid), and the acyl groups of carbonic acid semi-derivatives. The divalent amino protecting group formed by the linkage of R8 and R8 preferably has up to 18 carbon atoms. Divalent acyl groups of organic dicarboxylic acids, mainly diacyl groups of aliphatic or aromatic dicarboxylic acids.

In the compound of formula (X■), the protected amino group at the 7-position can be converted into a free amino group by methods known per se.

That is, an amino protecting group R8 or R8, in particular an easily cleavable acyl group, is prepared by a method known per se, for example a highly branched lower alkoxycarbonyl group in the α-position, such as a t-butoxycarbonyl group. By treating this with trifluoroacetic acid, 2-halogeno lower alkoxycarbonyl groups or phenacyloxycarbonyl groups such as 2●2●2-trichloroethoxycarbonyl group or 2-iodoethoxycarbonyl group can be Metals or metal compounds such as zinc or divalent chromium compounds such as divalent chromium chlorides or acetates, preferably hydrogen which together with this metal or metal compound form nascent hydrogen. It can be removed by treatment in the presence of a feedstock, preferably in the presence of aqueous acetic acid.

Furthermore, in the compound of formula (X■), formula -C (=0)
The carboxyl group of -R2 is preferably converted to a suitable organohalogenosilicon compound such as trimethylchlorosilane or an organohalogenotin (■) such as tri-n-butyltin chloride, preferably by esterification, including silylation. In the case of a carboxyl group protected by reaction with a compound, an acyl group R8 or R8 (free functional groups that may be present in these groups may optionally be protected) The resulting imide-halide 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. Imide-halide formers in which a halogen atom is bonded to an electrophilic central atom are especially acid halides, such as acid bromides and especially acid chlorides.

These are mainly acid halides of inorganic acids, especially phosphorus-containing acids, such as phosphorus oxyhalides, phosphorus trihalides and especially phosphorus pentahalides, such as phosphorus oxychloride,
Phosphorus trichloride and mainly 5. Phosphorus chloride, as well as pyrocatekyl-phosphorus trichloride, and acid chlorides, especially chlorides, of sulfur-containing acids or carboxylic acids, such as thionyl chloride, phosgene or oxalyl chloride. The above imide
For the reaction with one of the 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-diisopropyl-N- Ethylamine, or N″●N●N′●N″-tetra-lower alkyl-lower alkylene diamine, such as N-N-N″・N″-tetramethyl-1●5-pentylenediamine or N-N●N
″·N″-tetramethyl-1●6-hexylene diamine, monocyclic or bicyclic monoamine or diamine, e.g. N-substituted (e.g. N-lower alkylated) alkylene amine, azaalkylene amine or oxaalkylene amine ``for example, N-methylpiperidine or N-methylmorpholine, or 2,3●4,6●7,8-hexahydropyrrolo[1,2-a]pyrimidine (i.e., diazabicyclononene, DBN), or Tertiary aromatic amines such as di-lower alkylanilines such as N-N
- aliphatic or aromatic, which may preferably be halogenated (e.g. chlorinated), in the presence of dimethylaniline or especially a tertiary heterocyclic monocyclic or bicyclic base such as quinoline or isoquinoline, especially pyridine; Group hydrocarbons are reacted in the presence of a solvent 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, e.g. It is also possible to use up to an excess, especially about a 3- to 5-fold excess. The reaction with this imide-halide forming example is preferably carried out with cooling, e.g. from about -50 to +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 imide-halide product thus formed is generally not isolated but is reacted with an alcohol, preferably in the presence of one of the bases mentioned, to give the iminoether.

Alcohols include, for example, aliphatic or araliphatic alcohols, in particular lower alkanols which may be substituted, such as halogenated (e.g. chlorinated) or which additionally carry hydroxyl groups, such as ethanol, propanol, 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. This alcohol is generally used in excess, e.g. up to 10 CPi, and the process is continued with cooling, e.g.
Preferably, the temperature is 50 to +10°C. The iminoether product thus formed can advantageously be cleaved off without being isolated.

This splitting of the iminoether is achieved by treatment with a suitable hydroxyl compound, preferably by hydrolysis or even alcoholysis. Suitably, the alcoholysis is carried out following the formation of the iminoether using an excess of alcohol. In this case, preference is given to using water or alcohols, especially lower alkanols such as methanol, or mixtures of organic solvents such as alcohols with water. Among the acyl groups R8 of the acylamino group in the compound of formula (X■), for example, the 5-amino-5-carboxyvaleryl group [the carboxyl group can be removed, for example by esterification, in particular by the 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, e.g. a halogeno-lower alkanoyl group such as dichloroacetyl group or a phthaloyl group] of nitrosyl chloride. nitrosylating agents such as benzenediazonium chloride, carbocyclic arenediazonium salts such as benzenediazonium chloride, or reactive agents releasing positive halogen atoms such as N-halogenamides or N-halogenimides, preferably suitable treating a solvent or solvent mixture such as a nitro-lower alkane or a cyano-lower alkane in formic acid and mixing the reaction product with water or a lower alkanol such as methanol, a compound having a hydroxyl group, or or the amino group in the 5-amino-5-carboxyvaleryl group as group R8 is unsubstituted and the carboxyl group is protected, for example by esterification, and R8 is preferably an acyl group, but a hydrogen atom dioxane or a halogenated aliphatic hydrocarbon, for example methylene chloride, and if necessary the free or monoacylated amino compound thus formed. The cleavage can be effected by post-treatment by methods known per se.

The formyl group R8 may also be removed 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) monorhodium chloride. can.

A triarylmethyl group R8 such as a trityl group can be removed by treatment with an acidic agent such as an inorganic acid, such as hydrochloric acid.

The compound of formula (X■) is, for example, a cefhemu-3-one compound or its 2-one compound represented by the formula
The corresponding enol with a double bond in the 3- or 3.4-position is converted into an enol derivative with a functionally modified hydroxyl group of the formula -0-R3 in the 3-position and optionally a compound of the formula -C (=0)-obtained by changing the protected carboxyl group of R3 into a free or other protected carboxyl group.

This enol derivative can be produced by the method described above. Formula -C (=0
) - Protection of R8 In particular in compounds of formula (1) with an esterified carboxyl group, this can be converted into a free carboxyl group by methods known per se, for example depending on the nature of the group RG. can.

Esterification, for example by hydrolysis of carboxyl groups esterified with lower alkyl groups, in particular methyl or ethyl groups, in a weakly basic medium, e.g. alkali metal or alkaline earth metal hydroxides or carbonates, e.g. It can be converted into free carboxyl groups by treatment with an aqueous solution of sodium or potassium hydroxide, preferably at a pH value of about 9) to 10 and optionally in the presence of lower alkanols. A carboxyl group esterified with a suitable 2-halogeno lower alkyl group or arylcarbonylmethyl group can be reduced by a chemical reducing agent such as a metal such as zinc or a divalent chromium salt such as a chloride of divalent chromium. metal salts, generally treated in the presence of a hydrogen donor capable of producing nascent hydrogen by the metal, such as an acid, primarily acetic acid or formic acid, or an alcohol (preferably with the addition of water). Alternatively, the carboxyl group esterified with an arylcarbonylmethyl group can also be prepared by treating it with a nucleophilic, preferably salt-forming, reagent such as sodium thiophenolate or sodium iodide. , or a carboxyl group esterified with a suitable arylmethyl group [preferably the arylmethyl group is 3-, 4- and/or 5
For example, if a benzyl group is substituted in the - position by a lower alkoxy group and/or a nitro group, use UV radiation of, for example, 290w1,μ or less, and the arylmethyl group is substituted by a nitro group, for example in the 2-position. For example, if it is a benzyl group substituted with
[using long-wavelength ultraviolet light (e.g., longer wavelength ultraviolet light)], and carboxyl groups esterified with suitably substituted methyl groups, such as t-butyl or diphenylmethyl, can be treated with a suitable acidic solution, e.g., formic acid or trifluoroacetic acid. Actively esterified carboxyl groups and also carboxyl groups in anhydride form can be hydrated by treatment with agents, optionally with the addition of nucleophilic compounds such as phenol or anisole. Esterification can be cleaved by decomposition, for example by treatment with acidic or weakly basic aqueous agents such as hydrochloric acid, aqueous sodium bicarbonate or aqueous potassium phosphate buffers with a pH of about 7 to 9, and also by hydrogenolysis. The carboxyl group can be cleaved by treating it 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 in a conventional manner by treatment with, for example, water or an alcohol. Formula -C (=0)-
In the resulting compounds with an esterified group of R2, this group can be changed to a group of the same formula.

For example, converting a 2-chloroethoxycarbonyl group or a 2-bromoethoxycarbonyl group to a 2-iodoethoxycarbonyl group by treating with an iodine salt such as sodium iodide in the presence of a suitable solvent such as acetone. Can be done. The salt of the compound of formula (1) is produced by a method known per se.

That is, by treating a compound of formula (1) with an acidic group, for example with a suitable metal compound such as an alkali metal salt of a rubonic acid, for example the sodium salt of alpha-ethylcaproic acid, or with ammonia or a suitable organic amine. Then,
"The salts can be produced. For this purpose, it is preferred to use the salt-forming agent in stoichiometric amounts or in slight excess. Also, the acid addition salts of the compounds of formula (1) It can be obtained by conventional methods, for example by treatment with an acid or a suitable anion exchanger.Inner salts of compounds of formula (1) having a salt-forming amino group and a free carboxyl group can be obtained, for example, by treatment with an acid or a suitable anion exchanger. is formed by neutralizing a salt, such as its acid addition salt, to its isoelectric point, e.g. with a weak base, or by treatment with a liquid ion exchange agent.The salt can be converted into the free compound by conventional methods. I can do it.

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 is 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 suitable separation methods. Therefore, it can be separated into individual isomers.

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 The individual enantiomers can be separated by partitioning into diastereomeric salts and converting the thus separated diastereomeric salts into the free compounds and by fractional crystallization from optically active solvents. The present invention also includes embodiments 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. Note that the raw materials and reaction conditions are preferably selected so as to obtain the compounds listed above as particularly preferred.

In this specification, unless otherwise specified, the organic group indicated as j lower j has up to 7 carbon atoms, preferably up to 4 carbon atoms.

j The acyl group j has up to 2 carbon atoms, preferably up to 12 and mainly up to 7 carbon atoms. Next, the present invention will be explained in more detail with reference to Examples. Example 1 A solution of 7β-Tert-butoxycarboxylamino-3-methoxy-3-cephemu-4-carboxylic acid diphenylmethyl ester [4.96y (10 mmol)] in methylene chloride (25 ml) is treated with 25 ml of trifluoroacetic acid and 5 ml of anisole. .

The mixture is stirred for 1 hour at 0°C and then evaporated.

The residue is treated with 50 ml of water and extracted twice with ethyl acetate. The aqueous phase was brought to pH 4.0 by adding 0.1N aqueous sodium hydroxide solution. Adjust to l.

Adding acetone and stirring for 1 hour in an ice bath gives 7
β-amino-3-methoxy-3-cephemu-4 monocarboxylic acid precipitates. This is taken from door to door and then dried. Melting point: 300°C or higher (decomposition); Rf value: ~0.05 [silica gel, n-butanol/acetic acid/water (71.5:7.5:
21)]; W-spectrum (a). 1NNa0H)λ
．． ~=270r1WL (ε=7600); IR-spectrum (NujOl): 5.59, 6. I0s6.22,
6.44, 6.55μ and other absorption bands.

Example 2 0.52 g of 7β-monotritylamino-3-methoxy-3-cephemu-4-carboxylic acid diphenylmethyl ester (
A mixture of 1.0 mmol) and 5 ml of formic acid is heated at 50° C. and then evaporated.

The residue is dissolved in water and extracted twice with ethyl acetate. The aqueous phase was adjusted to pH4. Adjust to l. Add acetone to 0
After stirring for 1 hour at <RTIgt;C,</RTI> 7β-amino-3-methoxy-3-cefemu-4-carboxylic acid precipitates out. This is oven separated and dried under reduced pressure. IR-spectrum (Nu
jOl) Absorption band: 5.5g. 6.10, 6.22, 6.
44, 6.65μ, and others. Example 37 β-amino 3
-Methoxy 3-cephemu A suspension of 1.65 y of 4-carboxylic acid diphenylmethyl ester and 2 ml of anisole is mixed with 20 Rt of pre-cooled trifluoroacetic acid and stirred in an ice bath.

The mixture is diluted with 100 TfLt of cold toluene and evaporated under reduced pressure. The dark brown residue is dried under high vacuum and diethyl ether is added and stirred. The precipitate is separated off, washed with acetone and diethyl ether, and dried. The trifluoroacetate of 7β-amino-3-methoxy-3-cepheme-4-carboxylic acid thus obtained was dissolved in 10 ml of water, and this aqueous solution was mixed with 10 ml of ethyl acetate.
Wash twice with 1ml each and add a 10% methanol solution of triethylamine to bring the pH to 4.5. Dilute this with acetone and stir at 0°C for 1 hour. The precipitate is filtered off, washed with a 1:2 mixture of acetone and diethyl ether and dried under high vacuum. 7β-amino-3-methoxy-3-cefemu-4-carboxylic acid is thus obtained in the form of an inner salt. Thin layer chromatogram (silica gel): Rf~0.16 (system: n-butanol/acetic acid/water 67:10:23), ultraviolet absorption spectrum (in 0.1N hydrochloric acid): λ. N8x=261 mμ (ε=5400).
The 7β-amino-3-methoxy-3-cefemu-4-carboxylic acid prepared by the above method can be treated with trimethylchlorosilane to convert its carboxyl group into a carboxyl group protected with a trimethylsilyl group (note that The amino group can be converted to a protected amino group as well by using an excess of silylating agent), thus treating the trimethyl-1-lucilylated 7β-amino-3-methoxy-3-cephemu-4-carboxylic acid with diphenylacetyl chloride. The amino group can then be acylated.

If this is worked up in the presence of water by a conventional method, 3-methoxy-7β-phenyl-5acetylamino-3-cephemu-4-carboxylic acid is obtained. Interpretation-spectrum (CH,
Cl2) Absorption band: 3.03s5.60s5.7 lines 5.9
2, &2 6.67μ. Example 47 1 g (2.82 mM) of β-amino-3-methoxyceph 3-M 0-4-carboxylic acid monohydrochloride dioxanate was suspended in 20 ml of dry methylene chloride, and added to it at room temperature under a nitrogen gas atmosphere. Add 1.65 mt of (trimethylsilyl)-acetamide.

After 4 hours, the clear solution was cooled to 0°C and solid D-α-phenylglycyl chloride hydrochloride 9 was added to it.
Add 00m9 (4.37wLM).

After 5 minutes, add 0.7 ml of propylene oxide (107T
Add LM).

This suspension was stirred for 1 hour at 0°C under a nitrogen gas atmosphere, and then 0.5 ml of methanol was added.
(D-α-phenylglycylamino)-3-methoxycefu-3-emu-4-carboxylic acid monohydrochloride precipitates out in the form of crystals. The hydrochloride was separated, dissolved in 9 ml of water, and the solution was diluted with 1N sodium hydroxide solution to pH 4.6.
Adjust to. The dihydrate of the inner salt of 7β-1(D-α-phenylglycylamino)-3-methoxyceph-3-emu-4-carboxylic acid thus produced is separated, washed with acetone and diethyl ether, and dried. Melting point 1
74-176℃ (decomposition), [α]? =+132Q(C=
0.71 ton in 0.1N hydrochloric acid), thin layer chromatogram (
Silica gel) Rf value ~ 0.18 [System: n-butanol/
Acetic acid/water (67:10:23)], UV-spectrum (
in 0.1N sodium bicarbonate solution): λ, o=26
9r1TrL (E=7000), IR-spectrum (mineral oil): 5.72, 5.94, 6.23 and 6.60μ
on the characteristic band. Example 5 7β-amino-3-methoxyceph 3-emu-4-carboxylic acid (inner salt) 993m9 (4.32rrLM)
was suspended in 10 ml of methylene chloride, and to this was added 1.37 ml of N.0-bis(trimethylsilyl)-acetamide.
(5.67 TI.M) and stirred at room temperature under nitrogen gas atmosphere.

The clear solution was cooled to 0°C and D-α-phenylglycyl. Acid chloride hydrochloride 1.11g (5.4T
rLM). 0% propylene oxide after 5 minutes.
Add 4ml (5.6mM).

This suspension is stirred at 0° C. for 1 hour under a nitrogen gas atmosphere, and then 0.6 ml of methanol is added. Thus crystallized 7β-(D-α-5 phenylglycylamide)-
3-Methoxycefu 3-emu 4-carboxylic acid monohydrochloride was separated by furnace, dissolved in 15 ml of water at 0°C, and 5 ml of 1N sodium hydroxide solution was added to this solution to bring the pH to about 4.
Adjust to. This solution was warmed to room temperature and triethylamine was added to adjust the pH to approximately 4.8, resulting in 7β-(D-α
-phenylglycylamide)-3-methoxycefu 3
-emu-4-carboxylic acid crystallizes out in the form of a dihydrate. I
R-spectrum (in mineral oil) singular band: 5.72, 5. Taste A
23 and 6.60μ. Example 6 A mixture of 7β-amino-3-methoxy 3-cephemu 4-carboxylic acid hydrochloride dioxanate (1 mmol) in water (20 ml) was cooled with an ice-methanol mixture until the pH reached 8.5. Treat with 1N aqueous potassium hydroxide solution.

The solution is evaporated under conditions of 0.1 Torr and 40°C and the residue is dried under high vacuum.

The obtained potassium salt was dissolved in 25 ml of dimethylformamide.
and -2 (generations) within 1 hour.
Treat with an equivalent amount of iodomethyl pivalate. The mixture is stirred three times at -20 DEG C. under a nitrogen atmosphere and, after dilution with ethyl acetate, is extracted twice with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel to give 7β-amino-3-methoxy-3-cephemu-4-carboxylic acid pivaloyloxymethyl ester. It may also contain some 2-cephem isomer.
Translation spectrum (methylene chloride): 1790-1 cm and other absorption bands. Example 7 p in water (20Tn1) and acetonitrile (20ml)
-Nitrobenzyl 7-amino-3-methoxy 3-cephemu 4-carboxylate (730 m9) solution is acidified temporarily to PHL with concentrated hydrochloric acid.

Immediately thereafter, pH the solution with 1N sodium hydroxide.
Back titrate to 2.5. The solution was then evaporated to dryness and the residue was dissolved in THF4Oml methanol 80ml
and 6 ml of water. This solution was then diluted to 5% for 2 hours at room temperature under 50 pSi hydrogen pressure.
Hydrogenation is carried out in the presence of 730 mg of palladium on carbon (pre-reduced in ethanol).
The catalyst is stripped off and washed with THF and water.

The combined wash and bottom liquids are evaporated and the aqueous residue is slurried with ethyl acetate. The pH of the slurry is adjusted to 3.5 and the aqueous phase is separated and washed with ethyl acetate.
When the aqueous phase is concentrated to a volume of 4 ml and then cooled, 7-amino-3-methoxy-3-cephemu-4-carboxylic acid precipitates as a crystalline solid. Infrared absorption spectrum (Nu
Mu11): Absorption peak at 5.61 microns (p-lactam carbonyl). N. M. R. (DMSOd6)
:6.35(S..2H,.C2H2), 6.20(S.
．． ．． 3H. ．． C3 methoxyl), 5.30 (DllH,
．． C6H) and 4.94(DllH,.C7H)TaU
signal to.

Ultraviolet absorption spectrum (PH7 buffer): λJ. 8O=
268n7TL (E=6500).

Example 8 4-Methylphenylsulfonate (1y
) is constantly shaken with a phosphate buffer of pH 7-8.

The organic phase is dried over sodium sulfate, saturated with hydrogen chloride at 0° C. and left at the same temperature for 3 minutes. The mixture is evaporated under reduced pressure at low temperature. The residue is dissolved in 4 ml of water and extracted with methylene chloride.
The aqueous phase is treated with 40 ml of dioxane. The crystals of 7β-amino-3-methoxy 3-cephemu 4-carboxylic acid hydrochloride dioxanate are separated and recrystallized from water and dioxane.

Melting point: 〉300℃. Ultraviolet spectrum (0.1N sodium bicarbonate): λ1~=270r17TL (ε=76
00).

[α] Bas0=+134r±1T (C=1; 0.5N sodium hydrogen carbonate). Example 9 Same as Example 1 or Example 2, but 7β-Tert-butoxycarbonylamino-3-methoxy-3-cephemu4
- Carboxylic acid diphenylmethyl ester or 7β-benzyloxycarbonylamino-3-methoxy-3-cephemu-4-carboxylic acid diphenylmethyl ester instead of 7β-tritylamino-3-methoxy-3-cephemu-4-carboxylic acid diphenylmethyl ester The following compound is obtained by treatment with an agent.

7β-amino-3-methoxy-3-cephemu-4-carboxylic acid; IR-spectrum (Nuune 1): Absorption band 5.5
9, 6.1 to 6.22, 6.4 tons 6.65μ, and others.

Example 10 Same as Example 1 or Example 2, except that 7β-Tert-
Butoxycarbonylamino-3-methoxy-3-cephemu-4-carboxylic acid diphenylmethyl ester or 7β
Monotritylamino-3-methoxy-3-cefemu-4-
7β-benzyloxycarbonylamino-3-n-butyloxy-3-cephemu-4-carboxylic acid diphenylmethyl ester, 7β-benzyloxycarbonylamino-3-ethyloxy-3-cephemu-4-carboxylic acid instead of carboxylic acid diphenylmethyl ester Diphenylmethyl ester, 7β-benzyloxycarbonyl-amino-3-benzyloxy-3-cephemu-4-carboxylic acid diphenylmethyl ester is treated with an acidic agent to obtain the following compound.

7β-amino-3-n-butyloxy-3-cephemu-4-carboxylic acid diphenylmethyl ester 7, IR-spectrum (CH2Cl2): absorption bands 5.63, 6.25 μ to 5.8: 7β-amino-3-ethyl Oxy-3-cephemu-4-carboxylic acid diphenylmethyl ester, I
R-spectrum (CH2Cl2): absorption band 5.6 tons5.
78, 6.24μ; and 7β-amino-3-benzyloxy-3-cefemu-4-carboxylic acid diphenylmethyl ester, IR-spectrum (CH2Cl2): absorption band 5.63, 5.8016.24μ.

Claims (1)

[Claims] 1 The following formula (XIII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XIII)▲Mathematical formulas,
There are chemical formulas, tables, etc. ▼ [In the formula, R_2 is a hydroxyl group or a group R^A_2
(The R^A_2 is a group that forms a protected carboxyl group in an esterified form when combined with the carbonyl group -C(=O)- in the formula); R_3
is an alkyl group or an aralkyl group; R^A_0 is an amino-protected acyl, triarylmethyl, organosilyl, or organostannyl group; and R^b_0 is hydrogen. liberating the amino group of; and optionally,
converting the resulting compound with a salt-forming group into a salt or converting the resulting salt into a free compound; and/or optionally,
There are formulas (I)▲mathematical formulas, chemical formulas, tables, etc.▼(I) [wherein R_2 and R_3 are the above-mentioned O-substituted 7β-, which has the same meaning]
A method for producing an amino-3-cephem-3-ol-4-carboxylic acid compound or a salt thereof. 2 The following formula (XIII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XIII) [In the formula,
R^A_0 is a group that forms a protected carboxyl group in an esterified form together with the carbonyl group -C(=0)- in the formula; R_3 is an alkyl group or an aralkyl group and R^A_0 is an amino-protected acyl, triarylmethyl, organosilyl, or organostannyl group; and R^b_0 is hydrogen, and the amino group at the 7-position is released with an acid rinse. and convert the protected carboxyl group of formula -C(=O)-R^A_0 into a free carboxyl group in the resulting compound by solvolysis or reduction; and optionally convert the salt-forming group converting the compound obtained into a salt or converting the salt obtained into a free compound; and/or optionally separating the mixture of isomeric compounds obtained into individual isomers,
There are formulas (I ′), ▲mathematical formulas, chemical formulas, tables, etc.▼(I
') [In the formula, R_3 has the same meaning as above] O-substituted 7β-amino-3-cephem-3
- A method for producing an all-4-carboxylic acid compound or a salt thereof. 3 The following formula (XIII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XIII) [R in the formula
_2 is a group R^A_2 (R^A_2 is a group that forms a protected carboxyl group in an esterified form when combined with the carbonyl group -C(=O)- in the formula ); R_3 is an alkyl group or an aralkyl group; R^A_0 is an amino-protected acyl, triarylmethyl, organosilyl, or organostannyl group; and R^b_0 is hydrogen, , release the amino group at position 7 with acid rinse;
And in the obtained compound, the formula -C(=O)-R^
A_0 is protected by removing the protecting group from the protected carboxyl group by solvolysis or reduction to form a free carboxyl group and reprotecting the free carboxyl group by treatment with an esterifying agent. converting the obtained carboxyl group into another protected carboxyl group; and optionally converting the resulting compound with a salt-forming group into a salt or converting the resulting salt into a free compound; and/or optionally converting the resulting compound with a salt-forming group into a free compound; There are formulas ( I ″), ▲ mathematical formulas, chemical formulas, tables, etc. ▼ ( I ″), which are characterized by the separation of a mixture of isomeric compounds into individual isomers.
) [wherein R^A_2 and R_3 have the same meanings as above] \O\-substituted 7β-amino-3
- A method for producing a cefem-3-ol-4-carboxylic acid compound or a salt thereof.