JPS5934196B2 - 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 [in which R2 is a hydroxyl group or is protected in conjunction with the carbonyl group -C(-0)]. 7β-amino-3-cephem-3-ol-4-carboxylic acid substituted with O, represented by a group R2 forming a carboxyl group, and R3 is an alkyl group, an aralkyl group or an acyl group] It relates to the preparation of acid compounds or salts of such compounds with salt-forming groups.

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

The protected carboxyl group represented by the formula -0(-0)-R combination 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 R is a hydroxyl group etherified with an organic group, preferably up to 18 carbon atoms, forming the carboxyl group esterified with the group -C(=O). can be.

Such organic radicals include, for example, aliphatic, cycloaliphatic, 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 by an organosilyloxy group or a hydroxyl group etherified with an organometallic group, such as the corresponding organostannyloxy group, in particular with preferably up to 18 carbon atoms. Hydrocarbon groups such as aliphatic hydrocarbon groups 1-
It can also be a silyloxy or stannyloxy group substituted by three and optionally by halogen atoms, such as chlorine atoms.

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

The group R1f which together with the group -C(-0) forms a carbamoyl group is an optionally substituted amino group.

This substituent is an optionally substituted monovalent or divalent hydrocarbon radical having preferably up to 18 carbon atoms, such as an optionally substituted valent or divalent aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, as well as corresponding heterocyclic or heterocyclic monoaliphatic radicals having up to 18 carbon atoms and (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 having, for example, the abovementioned meanings); and preferably have up to 18 carbon atoms) or an acyl group, predominantly an acyl group of an organic carboxylic acid or carbonic acid semi-derivative, preferably having up to 18 carbon atoms. In the substituted hydrazinocarbonyl group represented by the formula -C(-0)-R, one or both nitrogen atoms may be substituted. Substituents are mainly monovalent or divalent hydrocarbon radicals having preferably up to 18 carbon atoms, which may be substituted, such as substituted hydrocarbon radicals having up to 18 carbon atoms. monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic monofatty acid, aromatic or araliphatic hydrocarbon radicals which can be used, as well as corresponding heterocyclic or heterocyclic monoaliphatic radicals having up to 18 carbon atoms. and/or functional groups, such as acyl groups, which mainly include acyl groups of organic carboxylic acids or carbonic acid semi-derivatives having preferably up to 18 carbon atoms. 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 alkylenedioxy groups, optionally substituted phenyloxy group or phenyl lower alkoxy group, lower alkylthio group, optionally substituted phenylthio group or phenyl lower alkylthio group, heterocyclic-thio group or heterocyclic mono-lower alkylthio group, substituted lower alkoxycarbonyloxy or lower alkanoyloxy groups, or halogen atoms, as well as oxo groups, nitro groups,
Possibly substituted amino groups, such as substituted alkylamino groups, di-lower alkylamino groups, lower alkylene amino groups, oxa-lower alkylene amino groups or aza-lower alkylene amino groups, and acylamino groups, such as lower alkanoylamino groups, lower alkoxycarbonyl An amino group, a halogeno lower alkoxycarbonylamino group, a phenyl lower alkoxycarbonylamino group that may be substituted, a carbamoylamino group that may be substituted, a ureidocarbonylamino group or a guanidinocarbonylamino group, and an alkali metal salt. sulfoamino groups, which may be present in the form of salts such as sulfoamino groups, azide groups, acyl groups such as lower alkanoyl groups and benzoyl groups, carboxyl groups which may be functionally modified, e.g. carboxyl groups in the form of salts, Esterified carboxyl groups such as lower alkoxycarbonyl groups, N
An optionally substituted carbamoyl group such as a mono-lower alkyl mono- or N-N-di-lower alkyl-carbamoyl group, an optionally substituted ureidocarbonyl or guanidinocarbonyl group, or a cyano group, a functional a sulfo group which may be modified as a sulfamoyl group or a sulfo group in the form of a salt, or a phosphono group which may be O-mono- or ho-σ-di-monosubstituted, the substituent being For example, a lower alkyl group which may be substituted, a phenyl group or a nearly phenyl lower alkyl group, and an o-unsubstituted or o-monosubstituted phosphono group is in the form of a salt such as an alkali metal salt. can be mono-, di- or polysubstituted. The divalent aliphatic group including the aliphatic group of the divalent aliphatic carboxylic acid is, for example, a lower alkylene group or a lower alkenylene group. It may be substituted or polysubstituted and/or there may be intervening heteroatoms such as oxygen, nitrogen or sulfur atoms in the chain.

Alicyclic or monoaliphatic groups (including corresponding cycloaliphatic or monoaliphatic groups in organic carboxylic acids) and corresponding cycloaliphatic or monoaliphatic ylidene groups are substituted. monocyclic or bicyclic alicyclic or alicyclic monoaliphatic hydrocarbon groups, such as monocyclic, bicyclic or polycyclic cycloalkyl or cycloalkenyl groups, as well as cycloalkylidene groups, or cycloalkyl- or cycloalkenyl mono-lower alkyl group or mono-lower alkenyl group, furthermore cycloalkyl-mono-lower alkylidene group or cycloalkenyl-mono-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 may be cycloaliphatic or cycloaliphatic groups, if desired, e.g. by optionally substituted aliphatic hydrocarbon groups, e.g. Thus, they can be mono-, di- or polysubstituted by functional groups such as, for example, 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 monosubstituted, such as the aliphatic and cycloaliphatic hydrocarbon groups mentioned above;
It can even be di- or polysubstituted.

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

The above-mentioned araliphatic groups (including araliphatic groups in the corresponding carboxylic acids) and also araliphatic ylidene groups are e.g. optionally substituted araliphatic hydrocarbon groups,
For example, optionally substituted aliphatic hydrocarbon groups having up to trivalence with optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon groups, especially phenyl lower alkyl groups or phenyl-lower alkenyl groups, as well as phenyl-lower alkynyl groups and also phenyl-lower alkylidene groups, and such groups have, for example, 1 to 3 phenyl groups and optionally e.g. Like the aliphatic and cycloaliphatic groups mentioned above, they can be mono-, di- or polysubstituted in their aromatic and/or aliphatic portions. Heterocyclic groups (including those in heterocyclic monoaliphatic groups and the corresponding heterocyclic groups or heterocyclic monoaliphatic groups in carboxylic acids) are particularly monocyclic as well as bicyclic or polycyclic groups with aromatic character. cyclic aza, thiacyclic, oxacyclic, thiazacyclic, thiadiazacyclic, oxaazacyclic, diazacyclic, triazacyclic or tetraazacyclic groups and further corresponding partially or As wholly saturated heterocyclic groups, such groups may optionally be mono-, di- or polysubstituted, such as the alicyclic groups described 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 acyl groups of lower alkenyl, cycloalkyl, phenyl or phenyl mono-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
A corresponding group of a lower alkyl half ester of carbonic acid whose lower alkyl moiety has a heterocyclic group, for example one of said heterocyclic groups of aromatic character, wherein the lower alkyl group and the heterocyclic group are Both may be substituted as the case may be. 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 primarily a lower alkoxy group which may be substituted, the substituents being mainly free or functionally modified e.g. etherified or esterified hydroxyl groups, in particular lower alkoxy groups or norogen atoms. ), furthermore lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy groups, as well as heterocyclic-oxy or heterocyclic mono-lower alkoxy groups, in particular optionally substituted phenyl lower It is an alkoxy group. Examples of amino groups that may be substituted include amino groups, lower alkylamino groups, di-lower alkylamino groups, lower alkylene amino groups, oxa lower alkylene amino groups, thia lower alkylene amino groups, aza lower alkylene amino groups, and hydroxyamino groups. basis,
They are a lower alkoxyamino group, 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. Lower alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertiary-butyl, and n-butyl.
- pentyl group, isopentyl group, n-hexyl group, isohexyl group or n-heptyl group, and lower alkenyl groups are, for example, vinyl group, allyl group, isopropenyl group, 2- or 3-methallyl group or 3-butenyl group. A lower alkynyl group can be, for example, a propargyl group or a 2-butynyl group, and a lower alkylidene group can be, for example, an isopropylidene 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.

A lower alkylene group with an intervening heteroatom is, for example, an oxa-lower alkylene group such as a 3-oxa-1,5-pentylene group, a thia-lower alkylene group such as a 3-thia-1,5-pentylene group, or a 3-lower alkylene group such as a 3-oxa-1,5-pentylene group. Alkyl-3-aza-1,5-pentylene group e.g. 3-methyl-3-aza-
It is an aza lower alkylene group such as 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, cyclopentylidene group or It is a cyclohexylidene group.

Cycloalkyl-lower alkyl or cycloalkyl-lower alkenyl groups are, for example, cyclopropyl-, cyclopentyl-, cyclohexyl- or cycloheptyl-methyl groups, -1,1-ethylene group (CH3CH(111,
), -1,2-ethylene group (-CH2-CH2-), -
1.1-propylene group (CH3CH2CH(), -1.
2-propylene group (-CH2-CH-CH3) or -1
・3-propylene group (-CH2CH2-CH2-), -
vinyl or -allyl, and the cycloalkenyl-lower alkyl or cycloalkenyl-lower alkenyl groups are, for example, 1-, 2- or 3-cyclopentyl-
, 1- 2- or 3-cyclohexenyl- or 1-
2- or 3-cycloheptenyl-methyl group, -1.
1-ethylene group (CH3CH<), -1,2-ethylene group (-CH2-CH2-), -1,1-propylene group (
CH3CH2CH (), -1,2-propylene group (-C
H2-CH-CH,) or -1,3-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.

Phenyl-lower alkyl or phenyl-lower alkenyl groups are, for example, benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl, trityl, 1- or 2-naphthylmethyl. A group such as a naphthyl-lower alkyl 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-pij-nodyl, 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 ring formula, oxaazacyclic, thiazacyclic or thiadiazacyclic radicals, e.g. imidazolyl groups such as 2-imidazolyl groups, pyrimidinyl groups such as 2- or 4-pyrimidinyl groups, 1,2,4-triazol-3-yl a triazolyl group such as a 1- or 5-tetrazolyl group, an oxazolyl group such as a 2-oxazolyl group, an isoxazolyl group such as a 3- or 4-isoxazolyl group, a 2-thiazolyl group, etc. a thiazolyl group, an isothiazolyl group such as a 3- or 4-isothiazolyl group, or a 1,2,4 group such as a 1,2,4-thiadiazol-3-yl group or a 1,3,4-thiadiazol-2-yl group - or a 1,3,4-thiadiazolyl group, or a bicyclic diazacyclic, oxaazacyclic or thiazacyclic group such as a benzimidazolyl group such as a 2-benzimidazolyl group, a 2-benzoxazolyl group, etc. benzoxazolyl group or benzthiazolyl group such as 2-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. A heterocyclic monoaliphatic radical is a heterocyclic radical, in particular a lower alkyl radical or a lower alkenyl radical bearing the above-mentioned radicals. Said heterocyclic radicals are for example aliphatic or aromatic hydrocarbon radicals which may be substituted, in particular by lower alkyl radicals such as methyl radicals or optionally by halogen atoms such as chlorine atoms. Substituted phenyl groups can be substituted, for example by phenyl or 4-chlorophenyl groups, or by functional groups, such as for example the aliphatic hydrocarbon groups mentioned above. Lower alkoxy groups are, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tertiary-butoxy, n-pentoxy or tertiary-pentoxy.

These groups include, for example, halogenomono-lower alkoxy groups, especially 2
-halogenomono-lower alkoxy group such as 2,2,2-trichloroethoxy, 2-chloro-, 2-bromo- or 2
It can be substituted as in the -iodo-ethoxy group. Lower alkenyloxy groups are, for example, vinyloxy or allyloxy groups, lower alkylenedioxy groups are, for example, methylenedioxy, ethylenedioxy or isopropylidenedioxy groups, and cycloalkoxy groups are, for example, cyclopentyloxy, cyclohexyloxy. group 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 also a heterocyclic monooxy group or a heterocyclic monooxy group. Lower alkoxy groups are, for example, pyridyl-lower alkoxy groups such as 2-pyridylmethoxy groups, furyl-lower alkoxy groups such as furfuryloxy groups or thienyl-lower alkoxy groups such as 2-thenyloxy groups. Lower alkylthio groups are, for example, methylthio, engineered tylthio or n-butylthio, lower alkenylthio are, for example, allylthio, phenyl-lower alkylthio are, for example, benzylthio, and heterocyclic or Mercapto groups etherified with monocyclic aliphatic groups are particularly pyridylthio groups such as 4-pyridylthio groups,
an imidazolylthio group, such as a 2-imidazolylthio group;
Thiazolylthio groups such as 2-thiazolylthio groups, 1.
2,4-thiadiazole-3-ylthio group or 1,3,4
-1,2,4 such as thiadiazole-2-ylthio group
- or 1,3,4-thiadiazolylthio group or 1-
A tetrazolylthio group such as methyl-5-tetrazolylthio group.

Esterified hydroxyl groups are inter alia halogen atoms such as fluorine, chlorine, bromine or iodine atoms, and lower alkanoyloxy groups such as acetoxy or propionyloxy groups, lower alkoxycarbonyloxy groups such as methoxycarbonyloxy, ethoxycarbonyloxy or t-butyloxycarbonyloxy group, 2
-halogeno lower alkoxycarbonyloxy group e.g. 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-pentoxycarbonyl. 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
one diethylcarbamoyl group, while the N-lower alkylsulfamoyl group is, for example, an N-methylsulfamoyl group or an 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 a di-lower alkylamino group is, for example, a methylamino group, an ethylamino group, a dimethylamino group or a diethylamino group, a lower alkyleneamino group is, for example, a pyrrolidino group or a piperidino group, an oxa-lower alkyleneamino group is, for example, a morpholino group, a thia lower alkyleneamino group is, for example, a thiomorpholino group, and an aza-lower alkyleneamino group is, for example, a piperazino group or a 4-methylpiperazino group.

Acylamino groups are in particular carbamoylamino groups, lower alkylcarbamoylamino groups such as methylcarbamoylamino groups, ureidocarbonylamino groups, guanidinocarbonylamino groups, lower alkoxycarbonylamino groups such as methoxycarbonylamino groups, ethoxycarbonylamino groups or t-butoxy carbonylamino group, 2
・Halogeno lower alkoxycarbonylamino group such as 2.2-trichloroethoxycarbonylamino group, 4-
methoxybenzyloxycarbonylamino, phenyl lower alkoxycarbonylamino groups, lower alkanoylamino groups such as acetylamino and propionylamino groups, and also phthalimide groups or salts such as alkali metal salts or ammonium salts such as sodium salts. It is a sulfamino group that can be in the form of Lower alkanoyl groups are, for example, formyl, acetyl, propionyl or pivaloyl.

The 0-lower alkylphosphono group is, for example, an o-methyl- or o-ethylphosphono group, and the 0,0'-di-lower alkylphosphono group is, for example, an o-0'-dimethyl-phosphono group or an o.♂-diethyl group. -phosphono group, o-phenyl lower alkyl-phosphono group is, for example, o-benzyl-phosphono group, and o-lower alkyl-0'-phenyl lower alkyl-phosphono group is, for example, o-benzyl-d-methyl-phosphono group.

A lower alkenyloxycarbonyl group is, for example, a vinyloxycarbonyl group, and a cycloalkoxycarbonyl group and a phenyl-lower alkoxycarbonyl group are, for example, an adamantyloxycarbonyl group, a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, a diphenylmethoxycarbonyl group. or α-4-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-lower alkoxycarbonyl group such as a furfuryloxycarbonyl group or a -thienyl-lower alkoxycarbonyl group, such as -thenyloxycarbonyl group. 2-lower alkylhydrazino group and 2,2-di-lower alkylhydrazino group are, for example, 2-methylhydrazino group or 2,2-di-lower alkylhydrazino group.
-dimethylhydrazino group, and the 2-lower alkoxycarbonylhydrazino group is, for example, a 2-methoxycarbonylhydrazino group, a 2-ethoxycarbonylhydrazino group, or a t-butoxycarbonylhydrazino group, and a lower alkanoylhydrazino group. is, for example, a 2-acetylhydrazino group.

The etherified hydroxyl group A, whenever with the carbonyl group in the formula, is preferably a readily cleavable or other functionally altered carboxyl group, such as
It forms an esterified carboxyl group that can be easily converted into a carbamoyl group or a hydrazinocarbonyl group.

Such groups R 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. An etherified hydroxyl group forming an esterified carboxyl group which can be split particularly easily with the group -C(=O), for example... is a 2-halogeno-lower alkoxy group having 19 or more.

Such groups, as well as C(-0) groups, are easily cleaved by treatment with zinc in the presence of chemical reducing agents such as aqueous acetic acid under neutral or weakly acidic conditions. or an esterified carboxyl group that can be easily converted into such a group.

Such groups are, for example, 2.2.2-trichloroethoxy or 2-iodoethoxy, or 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into 2-iodoethoxy. Furthermore, by treatment with zinc in the presence of a chemical reducing agent such as aqueous acetic acid under neutral or weakly acidic conditions or with a suitable nucleophilic reagent such as sodium thiophenolate. The etherified hydroxyl group R group, which forms an easily cleavable esterified carboxyl group with the group -C(=O), includes an arylcarbonylmethoxy group (arylcarbonylmethoxy group). is in particular a phenyl radical which may be substituted) and preferably a phenacyloxy radical.

Furthermore, the group 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(-0)- 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-
, 4-1 and/or 5-1] 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 groups, 3,5-dimethoxybenzyloxy groups, 2-nitrobenzyloxy groups or It is a 4,5-dimethoxy-2-nitrobenzyloxy group. Furthermore, the etherified hydroxyl group R may be an esterified carboxyl group which can be easily cleaved under acidic conditions, for example by treatment with trifluoroacetic acid or formic acid, as a group -C(-0). It can also be a group formed in

Such groups are mainly composed of hydrocarbon groups, in particular aliphatic or aromatic hydrocarbon groups, the methyl group of which may be substituted, e.g. by lower alkyl groups such as the methyl group and/or by phenyl groups. a methoxy group which is substituted or monosubstituted by a carbocyclic aryl group bearing 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-position relative to the oxygen or sulfur atom in an oxacycloaliphatic or thiacycloaliphatic group. It is a methoxy group. Among this type of polysubstituted methoxy groups, 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, further 2-(4-biphenylyl)-2-propyloxy group, and the above-mentioned methoxy group having a substituted aryl group or heterocyclic group is, for example, 4-methoxy an α-lower alkoxyphenyl-lower alkoxy group such as a benzyloxy group or a 3,4-dimethoxybenzyloxy group or a 2-
Furfuryloxy group such as furfuryloxy group.

A polycyclic aliphatic hydrocarbon group having the methyl group of the methoxy group, preferably as a triple branched ring member, is, for example, an adamantyl group such as 1-adamantyl group, and the methyl group of the methoxy group is an adamantyl group, such as a 1-adamantyl group, and The above-mentioned oxa- or thia-monoalicyclic group having as a ring member at the α-position relative to the oxygen or sulfur atom is, for example, a 2-oxa- or 2-thia monolower alkylene group having 5 to 7 ring atoms, or A mono-lower alkenylene group, such as 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 R together with the group -C(-0)- forms an esterified carboxyl group which can be cleaved by hydrolysis, e.g. under weakly basic or acidic conditions. It can also be an etherified hydroxyl group.

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, 4-hydroxy-3.5-t
-Hydroxy-mono-lower alkyl-benzyloxy groups such as -butyl-benzyloxy groups; Halogenophenyloxy groups, as well as cyanomethoxy groups and acylaminomethoxy groups, such as phthaliminomethoxy or succinyliminomethoxy groups. The group R may also be an etherified hydroxyl group that together with the carbonyl group -C(-0) form an esterified carboxyl group that can be split under hydrogenolysis conditions. I can do it,
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. Also,
The R group converts the esterified carboxyl group, which can be cleaved under physiological conditions, into the carbonyl group -C(-0
) Etherified hydroxyl groups, mainly acyloxymethoxy groups, which are formed in combination with the acyl group (the acyl group is, for example, an organic carboxylic acid group, mainly a lower alkane carboxylic acid group 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 alpha-amino-lower alkanoyloxymethoxy groups, such as glycyloxy. These include a methoxy group, an L-valyloxymethoxy group, an L-leucyloxymethoxy group, and a phthalidyloxy group. The R group as a silyloxy group or a stannyloxy group is preferably an aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group which may be substituted as a substituent, such as a lower alkyl group, a halogeno lower alkyl group, A cycloalkyl group, a phenyl group or a phenyl lower alkyl group, or a functional group that may be modified, such as an etherified hydroxyl group such as a lower alkoxy group or a chlorine atom, etc. , mainly tri-lower alkylsilyloxy groups such as trimethylsilyloxy group, halogenomono-lower alkoxymono-lower alkyl- such as chloro-methoxy-methyl-silyl group
A silyl group or a tri-lower alkylstannyloxy group such as a tri-n-butylstannyloxy group.

The R group 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 a lower alkanoyloxy group, such as an acetyloxy group, which has a derivative acyl group and can optionally be substituted, preferably in the α-position, by a halogen atom, such as a fluorine or chlorine atom; A pivalyloxy group, a trichloroacetyloxy group, or a lower alkoxycarbonyloxy group, such as a methoxycarbonyloxy group or an ethoxycarbonyloxy group.

Further, the R group which is a group that forms a carbamoyl group or a hydrazinocarbonyl group which may be substituted with a C(-0) group is, for example, an amino group, a methylamino group or an ethylamino group. 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-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, with 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 mono-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, e.g. 2- or 3-lower alkoxy- A lower alkyl group is, for example, a 2-methoxyethyl group or a 2-ethoxyethyl group.

R3 as the optionally substituted aromatic aliphatic hydrocarbon group is mainly a optionally substituted phenyl lower alkyl group, especially a 1-phenyl lower alkyl group having 1 to 3 optionally substituted phenyl groups. 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 a fluorine, chlorine or bromine atom 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. R3 as the acyl group of the aromatic carboxylic acid 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 a chlorine atom, 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 alkali metals or alkaline earth metals, such as mainly metal or ammonium salts, for example salts of sodium, potassium, magnesium or calcium; Ammonia or an ammonium salt with a suitable organic amine.

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, 2-hydroxyethylamine, hydroxy mono-lower alkyl amines such as bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, 4-amino basic aliphatic esters of carboxylic acids such as benzoic acid-2-diethylamino-ethyl ester, lower alkylene amines such as 1-ethylpiperidine, cycloalkylamines such as bicyclohexylamine or N-N-dibenzylethylenediamine; such as benzylamine and also pyridine type salts such as pyridine, colicin or quinoline. The compounds of formula (1) may also be prepared in acid addition salts, for example 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 be formed. 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, which can be converted into the aforementioned medicinally active compounds, for example, by the method described in Japanese Patent Application No. 74354/1983.

The present invention particularly provides that in formula (1), R2 is a hydroxyl group,
a lower alkoxy group (which in some cases is preferably α
In one position, for example, an optionally substituted aryloxy group, lower alkoxyphenyloxy group such as 4-methoxyphenyloxy group, lower alkanoyloxy group such as acetyloxy group or pivaloyloxy group, glycyloxy group , α-amino lower alkanoyloxy groups such as L-valyloxy or L-leucyloxy, arylcarbonyl groups such as benzoyl, or optionally substituted aryl groups such as phenyl, 4-methoxyphenyl, etc. monosubstituted or polysubstituted by a lower alkoxyphenyl group, a nitrophenyl group such as a 4-nitrophenyl group, or a phenyl group such as a 4-biphenylyl group or by a halogen atom such as a chlorine, bromine or iodine atom in the β-position. (can be substituted) such as a methoxy group,
Ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, t-butyloxy or t-pentyloxy, bisulfenyloxy-methoxy groups which may be substituted with lower alkoxy, e.g. bis-4-methoxy Phenyloxy-methoxy group, lower alkanoyloxy-methoxy group such as acetyloxymethoxy group or pivaloyloxymethoxy group, α-amino lower alkanoyloxy-methoxy group such as glycyloxymethoxy group, phenacyloxy group, which may be substituted phenyl lower alkoxy groups, especially 1-phenyl lower alkoxy groups such as phenylmethoxy groups (
Such groups can, for example, have substituents such as 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. , 4methoxybenzyloxy group, 2-biphenylyl-2-propyloxy group, 4-nitrobenzyloxy group, diphenylmethoxy group, 4.l-dimethoxydiphenylmethoxy group or trityloxy group, or 2-halogeno lower alkoxy groups such as 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy), as well as 2-phthalidyloxy and acyloxy groups (e.g. methoxycarbonyloxy). and lower alkoxycarbonyloxy groups such as ethoxycarbonyloxy groups or lower alkanoyloxy groups such as acetyloxy and pivaloyloxy groups), trilower alkylsilyloxy groups such as trimethylsilyloxy groups, or amino groups or hydrazino groups (these may optionally 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 dimethylamino group, etc. a di-lower alkylhydrazino group such as a di-lower alkylamino group, a hydrazino group, a 2-methylhydrazino group,
2,2-di-lower alkylhydrazino group such as 2,2-dimethylhydrazino group or hydroxyamino group), and R3 is a lower alkyl group such as methyl group, ethyl group, n-propyl group, isopropyl group. or an n-butyl group, a lower alkenyl group such as an allyl group, an optionally substituted phenyl lower alkyl group, in particular one phenyl group that may be substituted with a lower alkoxy group, such as for example a methoxy group, or 1-phenyl lower alkyl groups with two groups, such as benzyl or diphenylmethyl groups, lower alkanoyl groups, such as acetyl or propionyl groups, lower alkoxycarbonyl groups, such as methoxycarbonyl groups or benzoyl groups, which optionally contain lower 3-cephem compounds which may be substituted with alkyl groups, lower alkoxy groups such as methoxy groups, or halogen atoms such as fluorine or chlorine atoms, or salts of such compounds with salt-forming groups; It is related to. In the 3-cephem compound of formula (1) or the salts of these compounds having a salt-forming group, R2 is primarily a hydroxyl group, a lower alkoxy group, especially a lower alkoxy group highly branched in the α-position, such as a t- Butoxy group, further methoxy group or ethoxy group, 2-halogeno lower alkoxy group or 2.2
・Substituted with a 2-trichloroethoxy group, a 2-iodoethoxy group, or a 2-chloroethoxy group or a 2-bromoethoxy group, a phenacyloxy group, a lower alkoxy group, or a nitro group that can be easily converted into this group. 1-phenyl lower alkoxy group having 1 to 3 phenyl groups, such as 4-methoxybenzyloxy group,
4-nitrobenzyloxy group, diphenylmethoxy group,
4,4'-dimethoxydiphenylmethoxy group or trityloxy group. Lower alkanoyloxymethoxy groups such as acetyloxymethoxy or pivaloyloxymethoxy groups, α-amino lower alkanoyloxymethoxy groups such as glycyloxymethoxy group, 2-phthalidyloxymethoxy group, lower alkoxycarbonyloxy groups such as ethoxycarbonyloxy or a lower alkanoyloxy group such as an acetyloxy group, furthermore a tri-lower alkylsilyloxy group such as a trimethylsilyloxy group, and R3 is primarily a lower alkyl group such as a methyl, ethyl or n-butyl group, furthermore a lower alkenyl group 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.

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, 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 A 3-cephem compound having an alkyl group such as a benzyl group, further a lower alkanoyl group such as an acetyl group or a propionyl group, or a lower alkoxycarbonyl group such as a methoxycarbonyl group, or a salt of such a compound, such as a sodium compound in which R2 is a hydroxyl group. It relates to alkali metal salts such as salts, alkaline earth metal salts such as calcium salts, or ammonium salts including amine salts, or inner salts of compounds in which R2 is a hydroxyl group.

Primarily, in the 3-cephem compound of formula (1) or the salts of such compounds, R2 is primarily a hydroxyl group, which may also be substituted at the 2-1 position by a halogen atom, such as a chlorine, bromine or iodine atom. Lower alkoxy groups, especially highly branched lower alkoxy groups in the α-position, such as t-butoxy, 2-halogenomono-lower alkoxy groups, such as 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromo an ethoxy group, or a diphenylmethoxy group which may be substituted with a lower alkoxy group, e.g. a methoxy group, such as a diphenylmethoxy group or a 4,4'-dimethoxydiphenylmethoxy group, as well as a trimethylsilyloxy group. It is a tri-lower alkylsilyloxy group and R3 is a lower alkyl group such as methyl, ethyl or n-butyl, a lower alkenyl group such as allyl group, a phenyl lower alkyl group such as benzyl group.

The present invention mainly focuses on 7β-amino-3-lower alkoxy-
3-cephem-4-carboxylic acids (the lower alkoxy groups of which have up to 4 carbon atoms, such as ethoxy or n-butoxy, but mainly methoxy) and their diphenylmethyl esters and mainly 7β-
Amino-3-methoxy-3-cephem-4-carboxylic acid and the corresponding diphenylmethyl ester.

According to the method of the present invention, for example, a cefem-3-one compound represented by the formula or its 2-
The corresponding enol with a double bond at the 3- or 3.4-position is converted into an enol derivative with a functionally modified hydroxyl group at the 3-position of the formula -0-R3 and the desired in the compound of formula (1) obtained by converting the protected carboxyl group of formula 1C(=0)-R into a free or other protected carboxyl group and/or optionally converting the converting the compound with the obtained salt-forming group into a salt or converting the resulting salt into the free compound or other salt, and/or optionally separating the resulting mixture of isomeric compounds into individual isomers. By doing so, a compound of formula (1) or a salt thereof is obtained.

Cefem-3-one compounds of formula () can be in the keto and/or enol form.

Generally, compounds of formula () are converted from the enol form to enol derivatives of formula (1). Furthermore, mixtures of compounds of formula () and corresponding 1-oxides can also be used as raw materials, such that mixtures of compounds of formula () and corresponding 1-oxides are obtained as products. Therefore, the expression ()
The compounds can be used in pure form or in the form of the crude reaction mixture obtained during their preparation. Compounds of formula () can be converted into enol derivatives by methods known per se. That is, an enol ether [ie, a compound in which R3 in formula (1) is a hydrocarbon group which may be substituted] can be obtained by any method suitable for etherification of an enol group.

Etherification agents include diazo compounds of the formula corresponding to the optionally substituted hydrocarbon group R3, principally optionally substituted diazo lower alkanes such as diazomethane, diazoethane or diazo-n
-butane, optionally substituted phenyldiazo lower alkanes, such as 1-phenyldiazo lower alkanes such as phenyldiazomethane and diphenyldiazomethane, are preferably used.

These reactants can be dissolved in a suitable inert solvent such as an aliphatic solvent such as hexane, cyclohexane, benzene or toluene,
Cycloaliphatic or aromatic hydrocarbons, halogenated aliphatic hydrocarbons such as methylene chloride, lower alkanols such as methanol, ethanol or t-butanol, ethers such as di-lower alkyl ethers such as diethyl ether or tetrahydrofuran, in the presence of a cyclic ether such as dioxane or a solvent mixture thereof and with a diazo compound at room temperature or under slight heating, further if necessary in a sealed container and/or under nitrogen gas. Use under inert gas. moreover,
Enol ethers of formula (1) can be produced by treatment with reactive esters of alcohols of the formula corresponding to the optionally substituted hydrocarbon group R3.

Suitable esters are primarily strong inorganic or organic acids, such as hydrochloric acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, halogenosulfuric acids such as sulfuric acid or fluorosulfuric acid, or strong organic sulfonic acids such as fluorine. Lower alkanesulfonic acids, which may be substituted with halogens, or aromatic sulfonic acids, which may be substituted with lower alkyl groups such as methyl groups, halogen atoms such as bromine, and/or nitro groups. esters with benzenesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid. These etherifying agents are particularly di-lower alkyl sulfates such as dimethyl sulfate, and also lower alkyl fluorosulfates such as methyl fluorosulfate or lower alkyl methanesulfonates which may be halogen-substituted such as methyl trifluoromethanesulfonate. Esters are generally defined as solvents such as aliphatic, cycloaliphatic or aromatic hydrocarbons which may be halogenated such as chlorinated, ethers such as methylene chloride, dioxane or tetrahydrofuran, lower alkanols such as methanol or the like. Use in a mixture of In this case, suitable condensing agents such as carbonates or bicarbonates of alkali metals such as sodium or potassium (generally in the case of sulfuric acid esters) or organic bases such as N.N-diisopropyl-
Preference is given to using generally sterically hindered tri-lower alkyl amines such as N-ethylamine (preferably in the case of halogenosulfuric acid lower alkyl esters or methanesulfonic acid lower alkyl esters which may be halogen-substituted). The reaction is operated cooled, at room temperature or under heat, for example from about -20 to 50°C, and if necessary in a sealed vessel and/or under an inert gas such as nitrogen. Furthermore, the enol can be prepared by treatment with a compound having 2 to 3 etherified hydroxyl groups of the formula on the same aliphatic carbon atom, namely the corresponding acetal or orthoester, in the presence of an acidic agent. It can also create ether.

Therefore, a Gem-lower alkoxy lower alkane such as 2,2-dimethoxypropane is used as an etherifying agent in the presence of a strong organic sulfonic acid such as p-toluenesulfonic acid and in a suitable solvent such as methanol. In the presence of a lower alkanol or di-lower alkyl- or lower alkylene-sulfoxide, such as dimethyl sulfoxide, or tri-lower alkyl orthoformate, such as orthoformate triethyl ester, in the presence of a strong inorganic acid such as sulfuric acid or p- It can be used in the presence of a strong organic sulfonic acid such as toluenesulfonic acid and in the presence of a suitable solvent such as a lower alkanol such as ethanol or an ether such as dioxane, such that R3 is a methyl or ethyl group. A compound of formula (1) is obtained which is a lower alkyl group such as. Furthermore, the compound of formula () can be added to a tri-R3-oxonium salt (so-called Mehrwein salt) represented by the formula or a di-R3O-carbenium salt represented by the formula (or X1 is a halonium ion such as a bromonium ion). The enoyl ether of formula (1) can also be obtained when treated with a di-R3-halonium salt represented by formula (1).

Such reactants are mainly tri-lower alkyloxonium salts, di-lower alkoxycarpenium salts or di-lower alkylhalonium salts, in particular the corresponding salts with complex fluorine-containing acids, such as the corresponding tetrafluoroborates. , hexafluorophosphate, hexafluorantimonate or hexachlorantimonate. Such reactants are, for example, trimethyloxonium- or triethyloxonium-hexafluorantimonate, -hexachloroantimonate, hexafluorophosphate or -tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethyl Bromonium-hexafluorantimonate. These etherifying agents are preferably carried out in an inert solvent such as an ether such as diethyl ether or tetrahydrofuran or a halogenated hydrocarbon such as methylene chloride or a mixture thereof, if necessary a base such as a preferably sterically hindered in the presence of an organic base such as tri-lower alkylamine e.g. N-N-diisopropyl-N-ethylamine and cooled, at room temperature or under slight heating e.g. and/or under an inert gas such as nitrogen. Furthermore, by treating the compound of formula (■) with a 1-R3-triazene compound (■) substituted at the 3-position (i.e., a compound with the substitution -N-N-NH-R3), , an enoyl ether of formula (1) is produced.

The substituent on this 3-nitrogen atom is an organic group bonded via a carbon atom, preferably a carbocyclic aryl group, such as an optionally substituted phenyl group, e.g. a lower alkyl phenyl group such as a 4-methylphenyl group. It is the basis. Such triazene compounds include 3-aryl-1-lower alkyl triazenes such as 3-(4-methylphenyl)-1
-Methyltriazene, 3-(4-methylphenyl)-
1-ethyl triazene, 3-(4-methylphenyl)
-1-n-propyl-triazene or 3-(4-methylphenyl)-1-isopropyl-triazene, 3-aryl-1 lower alkenyl-triazene, e.g.
methylphenyl)-aryl-triazene or 3-aryl-1-phenyl lower alkyl-triazene e.g.
-(4-methylphenyl)-1-benzyroot triazene. These reactants are generally dissolved in an inert solvent such as a hydrocarbon which may be halogenated such as benzene or an ether or a solvent mixture and cooled, at room temperature or preferably at an elevated temperature, e.g.
°C, if necessary in a sealed container and/or under an inert gas such as nitrogen. Enoyl esters, ie compounds of formula (1) in which R3 is an acyl group, can be obtained by any method suitable for esterification of an enoyl group.

In this case, in order to prevent free amino groups from being simultaneously acylated in the compound of formula (■), it is preferable to protect the amino group at the 7-position. As an acylating agent,
Carboxylic acids of the formula corresponding to the acyl group or their reactive acid derivatives, in particular the corresponding anhydrides (this is the intramolecular anhydride of carboxylic acids, i.e., ketene, or the intramolecular anhydride of carbamic and thiocarbamic acids, i.e. Isocyanates and isothiocyanates, or mixed anhydrides such as hydrohalic acids such as hydrofluoric acid and hydrochloric acid, hydrocyanic acid, lower alkyl halogenoformates such as the ethyl and isobutyl esters of chloroformic acid, or trichloroacetic acid chloride. halides such as the corresponding fluorides and chlorides, as well as pseudohalides, cyanocarbonyl compounds or lower alkoxycarbonyloxycarbonyl compounds corresponding to their carboxylic acids, such as ethoxycarbonyloxycarbonyl compounds or isobutoxycarbonyloxycarbonyl compounds) or activated esters, such as esters with vinyl alcohols (i.e., enoyl), of lower alkane carboxylic acids such as isopropenyl acetate ester; and if necessary in the presence of a suitable condensing agent, for example in the presence of a carbodiimide compound such as di-hexylcarbodiimide or a carbonyl compound such as diimidazolyl carbonyl if an acid is used. For example with a basic agent in the presence of a tri-lower alkylamine such as triethylamine or a heterocyclic base such as pyridine and with an acidic agent such as an inorganic acid such as sulfuric acid or with an ester with a vinyl alcohol. Operate in the presence of a strong sulfonic acid such as p-toluenesulfonic acid.

This acylation reaction can be carried out in the absence or presence of a solvent or solvent mixture, cooled, at room temperature or under heat and if necessary in a sealed container and/or under an inert gas such as nitrogen. can. Suitable solvents are, for example, aliphatic, cycloaliphatic or aromatic hydrocarbons which may be substituted, especially chlorinated, such as benzene or toluene;
In this case, suitable esterifying agents such as acetic anhydride can also be used as diluents. In the above etherification or esterification reaction, depending on the raw materials and reaction conditions, a pure compound of formula (1) or a mixture with a corresponding 2-cephem compound can be obtained.

The latter is formed when using a compound of formula () which contains heavy metal compounds, such as compounds of divalent chromium, or when this compound is not isolated from the compound of formula () during its preparation, and the corresponding impure formula It is produced when using the compound () or when it is reacted under basic conditions. The mixture thus obtained is chromatographed (column, paper and thin layer chromatography) using suitable adsorbents and eluents, such as silica gel or aluminum oxide, by force methods known per se, for example by suitable separation methods. Separation can be achieved by adsorption and fractional elution, including (graphs), further by fractional crystallization, solvent partitioning, and the like. In the thus obtained compound having a protected carboxyl group and/or a protected amino group in formula (1), these groups are removed by a method known per se, for example, according to the method described below. Each can be converted into a free carboxyl group or another protected carboxyl group.

The compound of formula () used in the above method for producing the compound of formula (1) is produced, for example, as follows.

In 3-cepheme compounds of the formula (in which Rt is a hydrogen atom or preferably an amino-protecting group such as an acyl group and R2 is preferably a hydroxyl group but also a group R), acetyloxy The methyl group can be hydrolyzed in a weakly basic medium such as aqueous sodium hydroxide solution at pH 9-10 or with a suitable esterase such as RhizOb.
Rhizobium lupinii (Rh)
izObiumlupinii), RhizObiumjapOnicum or Bacillus subtilis
llS) to convert it into a hydroxymethyl group, and the free carboxyl group of formula 1C(=0)-R2 is functionally converted by an appropriate method (e.g., diphenyldiazomethane, esterification by treatment with a diazo compound) and the hydroxymethyl group is treated with a halogenating agent such as a chlorine purifier such as thionyl chloride or a N-methyl-N-mericyclohexyl-carbodiimidium iodide. It is converted to a halogenomethyl group such as a chloromethyl group or an iodomethyl group by treatment with a decolorizing agent.

Either the chloromethyl group can be converted directly into a methylene group by, for example, treating it with a suitable divalent chromium compound, e.g., an inorganic or organic salt such as divalent chromium chloride or acetate, in a suitable solvent such as dimethyl sulfoxide. , or indirectly to its iodomethyl group (which is produced, for example, by treating a chloromethyl compound with a metal iodide such as sodium iodide in a suitable solvent such as acetone) and then convert the iodomethyl The compound is converted to methylene groups by treatment with a suitable reducing agent such as zinc in the presence of acetic acid. The compound represented by the formula thus obtained [this is the formula (
(obtained from the compound of After liberation, the compound of formula () can be converted into the desired compound of formula () by oxidatively degrading the methylene group.

In the compounds of formula (), the protected amino group in the 7-position can be converted into a free amino group by methods known per se. That is, a highly branched lower alkoxycarbonyl group at the α-position, such as a t-butoxycarbonyl group, can be prepared using a method known per se to convert an amino-protecting group R to a particularly easily cleavable acyl group. By treatment with trifluoroacetic acid, 2.2.2-
A 2-monohalogeno-lower alkoxycarbonyl group, such as trichloroethoxycarbonyl group or 2-iodoethoxycarbonyl group, or phenacyloxycarbonyl group may be combined with a suitable metal or metal compound such as zinc or divalent chromium chloride or acetate. a divalent chromium compound, advantageously in the presence of a hydrogen donor which together with this metal or metal compound forms nascent hydrogen, preferably in the presence of hydrated acetic acid. It can be removed by

Furthermore, in compounds of formula (), the carboxyl group of formula -C(-0)-R2 is preferably converted to a suitable organic halide, such as trimethylchlorosilane, preferably by esterification, including silylation. elementary compound or 卜. In the case of a carboxyl group protected by reaction with an organo-rogenotin compound such as R-n-butyltin chloride, the acyl group R the resulting imide-halide is reacted with an alcohol and the iminoether thus formed is Can be divided.

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 5-halogenides, such as phosphorus oxychloride, phosphorus trichloride and mainly phosphorus pentachloride. and phosphorus pyrocatechyl trichloride, as well as acid halides, especially chlorides, of sulfur-containing or carboxylic acids, such as thionyl chloride, phosgene or oxalyl chloride. For reaction with one of the above imide-halide formers, a suitable base, especially an organic base, especially a tertiary amine such as a tertiary aliphatic monoamine or a diamine such as a tri-lower alkyl amine such as trimethylamine, triethylamine or N-N-diisopropyl- N-ethyl-amine, or N-N-V-mertetra-lower alkyl-lower alkylene diamine, such as N-N-V-N'-tetramethyl-
1,5-pentylenediamine or N・N-N'・N'
-tetramethyl-1,6-hexylene diamine, monocyclic or bicyclic mono- or diamines, such as N-substituted (e.g. N-lower alkylated) alkylene amines, azaalkylene amines or oxaalkylene amines, such as N- Methylpiperidine or N-methylmorpholine, or 2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine (i.e. diazabicyclononene, DBN), or tertiary aromatic In the presence of an amine such as a di-lower alkylaniline such as N-N-dimethylaniline or especially a tertiary heterocyclic monocyclic or bicyclic base such as quinoline or isoquinoline, especially pyridine, preferably... chlorination)
The reaction is carried out in the presence of a solvent such as an aliphatic or aromatic hydrocarbon, such as methylene chloride.

In this reaction, the imide-halide forming agent and the base can be used in approximately equimolar amounts, but the base can be used in excess or in less than an equivalent amount, e.g. It is also possible to use up to an excess, especially a 3- to 5-fold excess. Preferably, the reaction with the imide-halide forming agent is 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 imino ether.

Alcohols include, for example, aliphatic or araliphatic alcohols, especially lower alkanols which may be substituted, such as logenated (e.g. chlorinated) or which additionally carry hydroxyl groups, such as ethanol, propanol, butanol. , especially methanol, as well as 2,2,2-trichloroethanol and 2
2-halogeno lower alkanols such as monopromoethanol and also optionally substituted phenyl monolower alkanols such as benzyl alcohol are suitable.
This alcohol is generally used in excess, e.g. up to a 100-fold excess, 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 hydroxy 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, water or an alcohol, especially a lower alkanoyl such as methanol,
In the acylamino group R group of the acylamino group in the compound of formula (), it is preferable to use a mixture of an organic solvent such as an alcohol or an organic solvent with water, for example, a 5-amino-5-carboxyvaleryl group [the carboxyl group for example by esterification, in particular by diphenylmethyl groups, and/or amino groups by e.g. acylation, in particular acyl groups of organic carboxylic acids, such as halogeno-lower alkanoyl groups such as dichloroacetyl groups or pthalol. ] is a nitrosylating agent such as nitrosyl chloride, a carbocyclic arenediazonium salt such as benzenediazonium chloride or an N-halogen-amide or N-halogen-imide such as N-halogen-amide or N-halogen-imide. - with a reactant releasing a positive halogen atom, such as a bromosuccinimide, preferably in a suitable solvent or solvent mixture such as a nitro-lower alkane or a cyano-mono-lower alkane and formic acid; The reaction product is mixed with water or a compound having a hydroxyl group such as a lower alkanol such as methanol, or the amino group in the 5-amino-5-carboxyvaleryl group as the group R is unsubstituted and the carboxyl group is protected, e.g. by esterification, by standing in a suitable solvent such as dioxane or a halogenated aliphatic hydrocarbon, e.g. The monoacylated amino compounds can be cleaved off by working up by methods known per se.

The formyl group Rh 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 such as a trityl group can be removed by treatment with an acidic agent such as an inorganic acid, such as hydrochloric acid.

In order to oxidatively split the methylene group of the compound of formula () while forming an oxo group at the 31-position of the cephame ring, it is preferable to perform treatment with ozone to generate an ozone compound.

In this case, ozone is generally used as a solvent such as a lower alkanol such as an alcohol such as methanol or ethanol.
lower alkanones, such as ketones, such as acetone, aliphatic, cycloaliphatic or aromatic hydrocarbons, which may be halogenated, halogenated lower alkanes, such as methylene chloride or carbon tetrachloride, or solvent mixtures, including aqueous mixtures; for example about -90 to + in and under cooling or heating
Use at 40℃. In this way, the ozonide produced as an intermediate is reductively split.

In this case, catalytically activated hydrogen, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst such as a nickel or palladium catalyst (preferably supported on a suitable support such as calcium carbonate or charcoal), or a chemical Reducing agents such as heavy metal alloys or heavy metal amalgams, reducing heavy metals such as hydrogen donors such as zinc in the presence of acids such as acetic acid or alcohols such as lower alkanols, reducing inorganic salts such as hydrogen donors such as acetic acid, etc. alkali metal iodides such as sodium iodide or reducing organic compounds such as formic acid, reducing sulfide compounds such as di-lower alkyl sulfides such as dimethyl sulfide, phosphine, etc. Reducing organophosphorus compounds (which may have optionally substituted aliphatic or aromatic hydrocarbon groups as substituents)
For example, trilower alkylphosphine such as tri-n-butylphosphine or triarylphosphine such as triphenylphosphine, and phosphites having an aliphatic hydrocarbon group as a substituent which may be further substituted. For example, tri-lower alkyl phosphites such as trimethyl phosphite (which is generally in the form of the corresponding alcohol adduct) or phosphorous acids with optionally substituted aliphatic hydrocarbon groups as substituents. Triamides such as hexa-lower alkyl phosphite triamides such as hexamethyl phosphite triamide (which is preferably in the form of the methanol adduct) or tetracyanoethylene can be used. The generally unisolated ozonide mentioned above is cleaved under the conditions normally employed for its preparation, ie in the presence of a suitable solvent or solvent mixture and upon cooling or slight heating. By carrying out this oxidation reaction, a compound of formula () or the corresponding 1-oxide or a mixture of both these compounds is obtained. Such a mixture can be separated into the compound of formula () and the corresponding 1-oxide by, for example, fractional crystallization or chromatography (eg column chromatography, thin layer chromatography). To convert the compound of formula () into the enol derivative of formula (1), it is used without isolation after its preparation.

That is, a compound of formula (), preferably in the form of a crude reaction mixture, can be prepared from a compound of formula (1) in one go, preferably in the form of a crude reaction mixture.
) can be converted into the corresponding enol derivative. In the compound of formula (1) having a protected especially esterified carboxyl group of formula 1C(-0)-R obtained by the method of the present invention, this can be prepared by a method known per se. For example, depending on the type of radical R,
It can be converted into a free carboxyl group.

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 oxide 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). Possibly, the carboxyl group esterified with the arylcarbonylmethyl group can also be prepared by treating it with a nucleophilic, preferably salt-forming, reagent such as sodium thiophenolate or sodium iodide. ,
A carboxyl group esterified with a suitable arylmethyl group can also be prepared by, for example, irradiation [preferably the arylmethyl group is esterified with a lower alkoxy group and/or in the 3-, 4- and/or 5-position]. For example, if the benzyl group is substituted with a nitro group, use ultraviolet light of 290 mμ or less, and if the arylmethyl group is a benzyl group substituted with a nitro group at the 2-1 position, for example, [using long-wavelength ultraviolet light], or carboxyl groups esterified with suitably substituted methyl groups, such as t-butyl or diphenylmethyl, with a suitable acidic agent such as formic acid or trifluoroacetic acid. Actively esterified carboxyl groups and also carboxyl groups in anhydride form can be prepared by hydrolysis, for example by treatment with nucleophilic compounds such as phenols or anisole. , an esterified carboxyl group that can be cleaved by treatment with an acidic or weakly basic aqueous agent such as aqueous sodium bicarbonate or an aqueous potassium phosphate buffer with a pH of about 7-9, and also by hydrogenolysis. can be split by treatment with hydrogen in the presence of a noble metal catalyst, such as a palladium catalyst. Carboxyl groups which have been protected, for example by silylation or stannylation, can be liberated in a conventional manner by treatment with, for example, water or an alcohol.

In the resulting compounds with an esterified group of the formula -C(=O)-R2, this group can be changed to another 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. I can do it. 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 with a metal compound such as an alkali metal salt of the appropriate carboxylic acid, such as the sodium salt of alpha-ethylcaproic acid, or with ammonia or a suitable organic amine. Then,
The salt can be produced. 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) can also be obtained by conventional methods, for example by treatment with an acid or a suitable anion exchanger. The inner salt of the compound of formula (1) having a salt-forming amino group and a free carboxyl group is
For example, it is produced by neutralizing a salt, such as its acid addition salt, to its isoelectric point with, for example, a weak base or by treating it with a liquid ion exchange agent. The salt can be converted into the free compound by conventional methods.

For example, metal and ammonium salts can be converted to the free compounds by treatment with a suitable acid, and acid addition salts can be converted into the free compounds, for example by treatment with a suitable basic agent. The isomer mixture obtained can be subjected to methods known per se, such as fractional crystallization of the mixture of diastereomeric monoisomers, adsorption chromatography (column chromatography or thin layer chromatography) or other methods. It can be separated into individual isomers by appropriate separation methods.

The obtained racemate is treated by a conventional method, if appropriate, after introducing a suitable salt-forming group, for example, to form a diastereomeric monosalt mixture with an optically active salt-forming agent, and this mixture is converted into each diastereomer. Separation into the individual enantiomers can be achieved by partitioning into monosalts and converting the diastereomeric monosalts thus separated into the free compounds, or by fractional crystallization from optically active solvents. The present invention is. It 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 mentioned above as particularly preferred.

In this specification, unless otherwise specified, organic groups indicated as "lower" have up to 7 carbon atoms, preferably up to 4 carbon atoms.

"Acyl group" has up to 20 carbon atoms, preferably 12
It has up to 7 pieces and mainly 7 pieces. Next, the present invention will be explained in more detail with reference to Examples. Example 1 4-methylphenyl sulfonate of 7β-amino-cephaem-3-one-4ξ-monocarboxylic acid-diphenylmethyl ester (which is mainly in the enol form, i.e. 7β-amino-3-cephaem-3-ol-4 - 0.507 of carboxylic acid diphenyl methyl ester (present as 4-methylphenyl sulfonate) in methanol 25T11
1 and at 0° C. add a solution of diazomethane in diethyl ether until the yellow color disappears.

This is stirred in an ice bath for 10 minutes and then evaporated. The residue is chromatographed on silica gel. The oily 7β-dimethylamino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is eluted with a 2:1 mixture of toluene and ethyl acetate. Thin layer chromatogram (detected with silica gel, iodine vapor): Rf
~0.39 (system: ethyl acetate), ultraviolet absorption spectrum (
in ethanol): λMax 265 mμ (ε-6100)
, Infrared absorption spectrum (in methylene chloride): 3.33μ
, characteristic bands at 5.63μ, 5.81μ and 6.23μ. Further elution with ethyl acetate elutes oily 7β-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester. Thin layer chromatogram (silica gel, detected with iodine vapor): Rf ~ 0.20 (
System: ethyl acetate), UV absorption spectrum (in ethanol): λMax = 265 m (ε-5900), infrared absorption spectrum (in methylene chloride): 2,98 μ, 3.33
Characteristic bands at μ, 5.62μ, 5.81μ and 6.24μ. Instead of diazomethane, dimethyl sulfate in the presence of anhydrous potassium carbonate or 1-methyl-3-(4-
(methylphenyl) monotriazene, or trimethyloxonium-tetrafluoroporate or diisopropyl-triazene in the presence of diisopropyl-ethyl-amine.
Using trifluoromethanesulfonic acid methyl ester in the presence of ethylamine, the desired 7β-amino-3
-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained. Furthermore, if diazo-n-butane, 1-ethyl-3-(4-methylphenyl)-triazene or 1-benzyl-3-(4-methylphenyl)-triazene is used, 7β
monoamino-3-n-butyloxy-3-cephemu-4-
Carboxylic acid diphenyl methyl ester, 7β-amino-
3-ethyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester or 7β-amino-3-benzyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

7β-amino-3-n-butyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester: IR-spectrum (CH2Cl2) absorption band, 5.63μ, 5.80
μ, 6.25μ; 7β-mono-3-ethyloxy-3
-Cefem-4-1 carboxylic acid diphenyl methyl ester: IR-Svector (CH2Cl2) absorption band, 5.64
μ, 5.78μ, 6.24μ; 7β-amino-3-benzyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester: IR-spectrum (CH2Cl2) absorption band, 5.63μ, 5.80μ, 6 .24 μo The raw materials used in the above examples can be made, for example, as follows.

Crude sodium salt of 3-hydroxymethyl-7β-phenylacetylamino-3-cephem-4-carboxylic acid [
This is Bacillus subtilis (Bacillus SU
The sodium salt of 3-acetoxymethyl-7β-phenylacetylamino-3-cephem-4-carboxylic acid was enzymatically deacetylated using a purified enzymatic extract from strain ATCC 6633 (S) strain ATCC 6633 and the reaction solution was lyophilized in vacuo. made by] 11.827
200T of water! Dissolve LtvC in ethyl acetate 400ml
and acidify to a pH value of 2 by adding a concentrated aqueous phosphoric acid solution.

The aqueous phase is separated and re-extracted twice with 150 ml portions of ethyl acetate. The combined organic extracts are washed four times with 50 ml portions of water, dried over magnesium sulfate, and concentrated to approximately 400 ml. Mix this solution with excess diphenyldiazomethane,
After standing for 3 hours at room temperature, the granular crystalline precipitate is filtered off. The filtrate is concentrated to about 200 ml, diluted hot with cyclohexane and, after cooling to room temperature, left at about 40° C. for a while. The precipitate is filtered off and recrystallized from a mixture of acetone and cyclohexane. Thus obtained 3-hydroxymethyl-7β-phenylacetylamino-3-
Cefem-4-carboxylic acid diphenylmethyl ester dissolves at 176-176.5°C (uncorrected). [α] Kaichiichi 67±15 (c-1.231% in chloroform)
, thin layer chromatogram (detected with silica gel, iodine vapor or ultraviolet light of λ = 254 mμ): Rf = 0.42 (system: chloroform/acetone 4:1), Rf - 0.43 (
System: toluene/acetone 2:1) and Rf=0,41
(System: salt, methylene, acetone 6:1). 3-Hydroxymethyl-7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester 1.03
y and N-methyl-N·V-dicyclohexacylcarbodiimidium iodide 1.

05y and 25ml of anhydrous tetrahydrofuran under nitrogen.
1fC. Melt and heat to 35°C for 1 hour.

To this was further added 1,057 ml of N-methyl-N-N'-dicyclohexylcarbodiimidium iodide dissolved in 15 ml of anhydrous tetrahydrofuran and left under nitrogen at room temperature for 17 hours. The reaction mixture is evaporated under reduced pressure in a rotary evaporator. The residue was dissolved in methylene chloride and filtered through a 50f column of silica gel (added with 10% distilled water). This was washed four times with 100 ml of methylene chloride each time. The eluent was concentrated to a small volume and silica gel column (9
0y, inactivated by addition of 10% distilled water). 3:7 of toluene and methylene chloride
Non-polar impurities are eluted with a total volume of 900 d of the mixture. Next, from two elution sections of 200 d of methylene chloride, 3-
Iodomethyl-7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester is produced. This thin layer chromatography homogeneous section is vacuum lyophilized from benzene. Infrared absorption spectrum (in methylene chloride): 3.00μ, 5.62μ, 5.82μ,
5.95μ, 6.70μ, 7.32μ and 8.16μ
on the characteristic band. The above iodinating agent is produced as follows.

Dissolve freshly distilled N-M-dicyclohexylcarbodiimide 427 in 90 ml of methyl iodide at room temperature under nitrogen in a 250 ml round-bottomed flask equipped with a magnetic stirrer, reflux condenser and an upright nitrogen balloon and dissolve this colorless mixture. The reaction mixture is stirred at a bath temperature of 70° C. for 72 hours.
After this reaction time, the excess methyl iodide is distilled off from the reddish-brown solution under reduced pressure and the viscous reddish-brown residue is dissolved in 150 d of anhydrous toluene at 40°C. The crystalline material thus spontaneously crystallized within a few hours was separated from the mother liquor using an upright nitrogen balloon through a glass filter, avoiding air, and the reaction vessel was rinsed three times with 25 d each of ice-cold anhydrous toluene. Then, wash the pale yellow crystalline substance on the glass filter with the same toluene until it becomes colorless. 0.1mlHg and after drying for 20 hours at room temperature, N-methyl-N-N
L-dicyclohexylcarbodiimidium iodide is obtained in the form of colorless crystals.

Melting point 111-113°C, infrared absorption spectrum (in chloroform): characteristic bands at 4.72μ and 6.00μ. 3-iodomethyl-7β-phenylacetylamino-3-cephem-4- dissolved in 15d of 90% aqueous acetic acid.
A solution of 0.400 y of carboxylic acid diphenyl methyl ester is cooled to 0° C. in an ice bath, and 2.0 f of zinc dust is added in portions with thorough stirring.

After reacting for 30 minutes at 0°C, unreacted zinc powder was filtered off using a diatomaceous earth preparation on a nitrogen filter.The filter residue was suspended in fresh methylene chloride and filtered several times. conduct.

The combined filtrates are concentrated under reduced pressure, mixed with anhydrous toluene and evaporated to dryness under reduced pressure. While stirring the residue, add 50ml of methylene chloride and 0.0ml of dipotassium hydrogen phosphate.
．． The aqueous phase was separated and extracted twice with 30 d of methylene chloride each, and then discarded. The organic extracts are washed several times with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on a 22y column of silica gel (added with 10% water). The 3-methylene-7β phenylacetylaminocephalic acid diphenyl methyl ester is eluted with methylene chloride and methylene chloride containing 2% methyl acetate and is taken as crystals from a mixture of methylene chloride and hexane. Melting point 144-147
°C, [α] Blue 1118 ± 1 melting point (c= in chloroform
0.715), ultraviolet absorption spectrum (in 95% ethanol aqueous solution): λMax - 254 mμ (ε - 1540) and 260 mμ (ε = 1550), infrared absorption spectrum (in methylene chloride): 2.94μ, 5.65μ, 5.7
Characteristic bands at 4μ, 5.94μ, 6.26μ and 6.67μ. Dissolve in 80ml of anhydrous methylene chloride and cool at -15°C.
A solution of 2.07 mL of 3-methylene-7β-phenylacetylaminocephalic acid diphenyl methyl ester-4α monocarboxylic acid cooled to Stir for 1 hour at −10 to −5° C. under nitrogen.

The reaction mixture was then cooled to -25°C and diluted with anhydrous methanol 2
5 ml for 1 hour at -10°C and then at room temperature for 1 hour.
．． Stir for 5 hours. Add this to 0 of potassium dihydrogen phosphate.
．． 80 ml of a 5 molar aqueous solution are mixed, the pH value is adjusted to 2 with a 2.0% phosphoric acid aqueous solution, and the mixture is stirred at room temperature for 30 minutes. Separate the organic phase.

The aqueous phase is extracted twice with 150 g of methylene chloride and the organic solutions are combined, dried over sodium sulphate and evaporated. The oily residue was dissolved in 25 ml of ethyl acetate and 4-methylphenylsulfonic acid monohydrate 1414
7 in 25 ml of ethyl acetate at 0°C. A bulky precipitate is thus formed, which is filtered off and washed with cold ethyl acetate and diethyl ether.
Dry and recrystallize from a mixture of methylene chloride and diethyl ether. In this way, 4-methylsulfonic acid salt of 7β-amino-3-methylene-cephaam-4α-monocarboxylic acid diphenylmethyl ester is obtained in the form of colorless needles. ．． Melting point 153-155°C, [α]D-14±1 (c-0.97 in methanol), ultraviolet absorption spectrum (in ethanol): λMax = 2.57 mμ (ε
-1500), infrared absorption spectrum (in methylene chloride)
:3.5μ, 5.60μ, 5.73μ, 8.50μ, 1
Characteristic bands at 9.68μ and 9.92tt. 4-Methylphenylsulfonate of 7β-amino-3-methylene-cephaam-4α-monocarboxylic acid diphenylmethyl ester dissolved in 50 ml of methanol and cooled to -60°C
．． A stream of a mixture of oxygen and ozone (containing 0.35 mmol of ozone per minute) is passed through the solution of 5537 for 4 minutes. The pale blue solution is mixed after a further 5 minutes with 0.3 d of dimethyl sulfide. This mixture was heated to -70°C for 15
Stir for 2 minutes, 1 hour at -12°C and 1 hour in an ice bath, then evaporate. Dissolve the residue in a small amount of methylene chloride, add diethyl ether until cloudy and leave to stand. If the huge crystalline red powdery precipitate thus formed is filtered out, 7β-aminosephem-3-one-
4- of 4ξ monocarboxylic acid diphenyl 2-methyl ester
Gives methyl phenyl sulfonate. It exists primarily in the enol form, i.e. as the 4-methylphenyl sulfonate of 7β-amino-3-cephem-13-ol-4-carboxylic acid diphenylmethyl ester.
Do 3. Melting point 143-145°C (with decomposition), thin layer chromatogram (silica gel): Rf ~ 0.28 (system: ethyl acetate/pyridine/water 85:10:5), ultraviolet absorption spectrum (in ethanol): λMax 262 mμ ( ε−
3050) and 282 mμ 3 (ε-3020), infrared absorption spectrum (in methylene chloride): 5.58 μ, 5
．． Characteristic bands at 77μ (shoulder), 6.02μ and 6.22μ.

Example 2 7β-amino-3-methoxy-3-cephem-44-
A suspension of 1.657 ml of carboxylic acid diphenyl methyl ester and 2 ml of anisole was pre-cooled with 2 trifluoroacetic acids.
0 ml and stir in an ice bath for 15 minutes.

The mixture is diluted with 100 ml 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 filtered off, washed with acetone and diethyl ether and dried. Thus obtained 7β-amino-3-methoxy-
The trifluoroacetate of 3-cephem-4-carboxylic acid is dissolved in 10 ml of water, the aqueous solution is washed twice with 10 d each of ethyl acetate, and a 10% methanol solution of triethylamine is added 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. Thus 7β-amino-
3-Methoxy-3-cephem-4-carboxylic acid is 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), UV absorption spectrum (in 0.1N hydrochloric acid): λMax-261 mμ (ε-5400).

7β-amino-3methoxy- prepared by the above method
3-Cefem-4-carboxylic acid can be treated with trimethylchlorosilane to convert its carboxyl group into a carboxyl group protected by a trimethylsilyl group (note that the amino group can also be converted into a carboxyl group protected by a trimethylsilyl group by using an excess of the silylating agent). The trimethylsilylated 7β-amino-3-methoxy-3-cephem-4-carboxylic acid can then be treated with phenylacetyl chloride to convert the amino group into an acyl group. can.

If this is worked up in the presence of water by a conventional method, 3-methoxy-7β-phenylacetylamino-3-cephem-4-carboxylic acid is obtained. 3-Methoxy7β-phenylacetylamino-3-cephem-4-carboxylic acid:
IR spectrum (CH2Cl2) absorption band, 3.03μ,
5.60μ, 5.74μ, 5.92μ, 6.24μ, 6
．． 67 μo of p-nitrobenzyl J-amino-3-hydroxy-3-cephem-4-in dry tetrahydrofuran (35 mO)
To the stirred suspension of carboxylate hydrochloride (445 immediately) is added 1 equivalent of triethylamine and then an excess of 10 ml of an ethereal solution of diazomethane.

After 30 minutes, the solvent and excess diazomethane are evaporated and the residue is dissolved in a mixture of water and ethyl acetate.

The organic phase is separated, washed with water and dried. The dried ethyl acetate solution is evaporated to dryness to obtain p-nitrobenzyl J-amino-3-methoxy-3-cepheme-4-carboxylate. By rubbing with diethyl ether, the product is obtained as crystals. Infrared absorption spectrum (Nuj
OlMull): 2.99 (amide), 5,75 (broad, β-lactam and ester carbonyl) and 5.98
(Amidocarbonyl) Absorption peak in microns. Ultraviolet absorption spectrum (ethanol): absorption maximum 268 mμ, ε
-146,000N. M. R. (DMSOd7): 7.1
0 (wide Sl2HlC7NH2), 6.22 (Sl2H.
．． C2H2), 6.20 (s, 3H,.C3 methoxymethyl), 5.27 (d, 1H..C6H), 4.93 (
DllH, C7H), 4.60 (Sl2Hl ester C
H2) and 2,35-1.6(Ql4Hl aromatic H)T
Signal to au.

Example 4 p- in water (20 ml) and acetonitrile (20 ml)
A solution of nitrobenzyl J me[amino-3-methoxy-3-cephem-4-carboxylate (730 W) was temporarily acidified 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 methanol80ml
and 6 d of water. This solution is then hydrogenated in the presence of 730 Watts of 5% palladium on carbon (pre-reduced in ethanol) for 2 hours at room temperature under 50 psi hydrogen pressure. Remove the catalyst and wash with THF and water.

The combined washings and solution A 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-cephem-4-carboxylic acid precipitates as a crystalline solid. Infrared absorption spectrum (Nu
jOlMull): Absorption peak at 5.61 microns (β-lactam carbonyl). N. M. R. (DMSOd6
): 6.35 (Sl2HlC2H2), 6.20 (Sl
3HsC3methoxyl), 5.30(DllH..C6
H) and 4.94 (DllH..C7H) signal to Tau.

Ultraviolet absorption spectrum (PH7 buffer): λMax26
8 mμ (ε=6500).

Example 5 A solution of 4-methylphenyl sulfonate (1 g) of 7β-amino-3-methoxy-3-cephem-4α-monocarboxylic acid diphenyl methyl ester in methylene chloride (20d) was added to a phosphate buffer solution at pH 7-8. Shake thoroughly.

The organic phase is dried over sodium sulfate, saturated with hydrogen chloride at 0.degree. C. and left at the same temperature for 30 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-cephem-4-carboxylic acid hydrochloride dioxanate are separated and recrystallized from water and dioxane.

Melting point: 〉300'CO Ultraviolet spectrum (0.1N sodium bicarbonate): λ
MO-270 mμ (ε-7600).

"α] Ao-+134 (±17 (c-1; 0.5N sodium bicarbonate).

Example 6 2. in 23 ml of dimethylacetamide cooled to 0°C.
3y 7β-an-3-methoxy-3-cephem-4-
1 to a suspension of carboxylic acid under nitrogen and with vigorous stirring.
．． Add 3 ml of 1,8-diazabicyclo[5,4,O] undecar J.

After 10 minutes from this, add 3.6 to this solution within 10 minutes.
Add iodomethyl pivalate from step 7. After stirring for a further 10 minutes, the reaction mixture is diluted with 60 ml of cold ethyl acetate and washed with 10% aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, treated with charcoal, and passed through Iflo (▲wood). ▲The solution was treated with ethyl acetate and 1.5N hydrogen chloride (8.2m0).

Take the precipitate ▲ and leave it at room temperature, 0.05m77! Dry with Hg for 16 hours. 7βamino-3-methoxy-3-cephem-4-carboxylic acid pivaloyloxymethyl ester is obtained.

Rf (free base) ~ 0.64 (silica gel/acetic acid); UV-spectrum (ethanol) λMax
= 27.2 nm (ε~7400).

Example 7 p-nitrobenzyl J me[amino-3-methoxy-3
-Cefem-4-carboxylate hydrochloride 30
Stirring of p-nitrobenzyl J me[amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride of 445W1f7 in methylene chloride of m1.
To the resulting suspension, 131 m9 of mono-trimethylsilylacetamide were added and the mixture was stirred at room temperature for 30 minutes.

Add excess diazomethane in ether and add 20
After a few minutes, the mixture was evaporated to remove the solvent and excess diazomethane. The residue is treated with 1 ml of methanol and then dissolved in an ethyl acetate-water mixture.

The ethyl acetate phase was separated, washed with water and dried.
The reaction product, p-nitrobenzyl J-amino-3-methoxy-3-cephem-4-carboxylate hydrochloride, was precipitated by passing hydrogen chloride through the dry ethyl acetate phase. N. M. R. (D
MSOd6): Signal, 6.97+ (BrOads.
3H. NH3), 6.31(s)2H. ．． C2-H
2), 6.23(s)3H,. C3 methoxyl), 5.
39 (d, IH, C6H), 5.05 (d) IH,
．． C7H), and 2.5-1.92·(q,4H, aromatic H)tau.

The starting material can be produced as follows.

(a) p-nitrobenzyl 7-amino-3-methylenecephalic acid 4-carboxylate hydrochloride 10m
To a solution of 965 m9 (2 mmol) of p-nitrobenzyl J me[phenoxyacetamido-3-methylenecephalic acid 4-carboxylate] in methylene chloride of 1757
nf7 dry pyridine and 460Tn9 phosphorus pentachloride were added and the mixture was stirred at room temperature for 6 hours.

．． '1 ml of isobutanol was added to the mixture, which was then stored at o 0 C overnight. The reaction product formed as a crystalline precipitate, p-nitrobenzyl J me[amino-3-methylenecephalic acid-4-carboxylate hydrochloride, was filtered off to give 430W19 (58% yield). Elemental analysis: C,5Hl6N3O5SCICHN Theoretical value: 46.694.1810.89 Measured value: 46.404.2010.62.

IR (NujOlMull): carbonyl absorption 5.65
μ (β-lactam) and 5.75μ (ester).

N. M. R. (DMSOd6): Signal 6.34 (2
d) 2H. C2-H2), 4.98(d) IH. C6
-H), 4.7~4.4(m, 6H, C4-H,
esters CH2, C4-CH2 and C7-H), and 2.4-1.6 (m) 4H) aromatic H) tau.

(b) p-Nitrobenzyl J amino-3-hydroxy-3-cepheme 4-canoleboxylate hydrochloride 3.85 V of p-nitrobenzyl J prepared as described above in 600 ml of methanol. Amino 13
- A solution of methylene cephalic acid 4-carboxylate hydrochloride was cooled in an acetone-dry ice bath.

Ozone was bubbled into the reaction mixture for approximately 20 minutes, during which time the reaction mixture developed a light blue color. The reaction mixture was then flushed with nitrogen to drive off excess ozone. The intermediate ozonide was then decomposed by passing sulfur dioxide through the reaction mixture until the iodized curry starch reaction of the reaction mixture became negative.

The reaction mixture was evaporated in vacuo and the residue was dissolved in methylene chloride. Dissolved in 200 ml of IN hydrogen chloride.

The solution was evaporated to dryness and the remaining reaction product was dissolved in acetone. By cooling, 3.15V p-
Nitrobenzyl J me[amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride precipitated as a crystalline solid. IR (NujOlMull):
Carbonyl reaction, 5.55μ (β-lactam carbonyl), and 5.02μ (ester carbonyl hydrogen attached to 3-hydroxy).

Claims (1)

[Claims] 1 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R^
A_2 is a group that forms a protected carboxyl group together with the carbonyl group -C(=O)- in the formula. -3-one tautomeric compound or its salt is treated with an etherification agent that introduces an alkyl or aralkyl group R_3; and, if desired, the resulting compound with a salt-forming group is converted into a salt or the resulting There are formulas ▲mathematical formulas, chemical formulas, tables, etc.▼ (I) characterized by converting the salt into the free compound; and/or optionally separating the resulting mixture of isomeric compounds into individual isomers. (In the formula, R^A_2 has the above meaning, R
_3 is an alkyl group or an aralkyl group) A method for producing a 0-substituted 7β-amino-3-cephem-3-ol-4-carboxylic acid compound or a salt thereof. 2 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^A_2 is the carbonyl group -C (=O) in the formula
3-hydroxy-3-
A cefem compound or a corresponding cefam-3-one tautomeric compound or a salt thereof is treated with an etherification agent that introduces an alkyl or aralkyl group R_3; and in the resulting compound the formula -C(=O)-R ^A_2's protected carboxyl group is converted into a free carboxyl group by solvolysis or reduction; and, if desired, the resulting compound with the salt-forming group is converted into a salt or the resulting salt is converted into a free compound or Formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ ( I ′) characterized by changing to other salts; and/or optionally separating the resulting mixture of isomeric compounds into individual isomers. A method for producing a 0-substituted 7β-amino-3-cephem-3-ol-4-carboxylic acid compound represented by the formula (wherein R_3 is an alkyl group or an aralkyl group) or a salt thereof. 3 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R^
A_2 is a group which forms a protected carboxyl group in an esterified form when combined with the carbonyl group -C(=O)- in the formula] 3-hydroxy-3- Cefem compound or equivalent cefem-3
- Treating the on tautomer compound or its salt with an etherification agent to introduce an alkyl group or an aralkyl group R_3;
And in the obtained compound -C(=O)-R^A_
2 by removing the protecting 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 obtained compound into a salt or converting the obtained salt into the free compound or other salt; and/or optionally converting the obtained There are formulas, mathematical formulas, chemical formulas, tables, etc. that are characterized by separating a mixture of isomeric compounds into individual isomers.
2 has the above-mentioned meaning, and R_3 is an alkyl group or an aralkyl group.