JPS5976089A - Manufacture of o-substituted 7beta-amino-3-cephem-3-ol-4-carboxylic acid compounds - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to enol derivatives, specifically those having the formula [In this formula, R2 is a hydroxyl group or Cal in the formula is protected together with a nyl group -C(-□)-] and R5 is an alkyl group, an aralkyl group, or an acyl group. The present invention relates to the preparation of salts of phosphoric acid compounds or such compounds having salt-forming properties.

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

The protected carboxylic group of the formula -C(=O)-2 is primarily an esterified carboxylic group, but it can also be a common mixed anhydride group or a carbamoyl group that may be substituted (6) or The hydrazinocal can also be a nyl group.

Therefore, the radical is a hydroxyl group etherified with an organic group in which the car esterified with the group -C(-〇)- is preferably up to 18 carbon atoms forming the xyl group. Something can happen. Such organic radicals include, for example, aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic radicals. It is a ring-aliphatic group.

The radical R8 can also be an organosilyloxy group or a hydroxyl group etherified with an organometallic group, such as a corresponding organostannyloxy group, in particular a optionally substituted hydrocarbon having preferably up to 18 carbon atoms. The radicals can also be, for example, silyloxy or stannyloxy radicals substituted by 1 to 3 aliphatic hydrocarbon radicals and optionally by helogne atoms, such as chlorine atoms.

The radical R'2, which together with the radical -C(=O)- forms an anhydride radical, predominantly a mixed anhydride radical, is in particular an acyloxy radical, which radical preferably has up to 18 carbon atoms. Organic carboxylic acids such as aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic caldenic acids or the corresponding groups of carbonic acid semi-derivatives, such as carbonic acid half esters.

The group R'2, which together with the group --C(=O)-- forms a carbamoyl group, is an optionally substituted amine group. This substituent is an optionally substituted monovalent or divalent hydrocarbon group having preferably 18 carbon atoms, such as an optionally substituted monovalent hydrocarbon group having up to 18 carbon atoms. or a divalent aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group,
Furthermore, corresponding heterocyclic or heterocyclic-aliphatic radicals having up to 18 carbon atoms and/or functional groups such as hydroxyl groups, in particular free hydroxyl groups, which can be functionally modified, such as -r - a telified or esterified hydroxyl group (the etherified or esterified group has, for example, the meaning given above and preferably has up to 18 carbon atoms) or an acyl group, which preferably has up to 18 carbon atoms; It is an acyl group of an organic carboxylic acid or carbonic acid semi-derivative having up to 1,000 carbon atoms.

Substituted hydrazinocal of the formula -c(-o)-? In the nyl group, one or both nitrogen atoms can be substituted.

Substituents are mainly monovalent or divalent hydrocarbon radicals which can be substituted, preferably having up to 18 carbon atoms, such as monovalent, which can be substituted, having up to 18 carbon atoms. or divalent aliphatic, cycloaliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, as well as corresponding heterocyclic or heterocycloaliphatic radicals having up to 18 carbon atoms and (or ) Functional groups such as acyl groups are mentioned, mainly acyl groups of organic carboxylic acids or carbonic acid semi-derivatives having preferably up to 18 carbon atoms. R5 as an acyl group is mainly an acyl of an organic carganic acid including formic acid, such as an alicyclic, alicyclic-aliphatic, araliphatic, heterocyclic or heteromonoaliphatic carganic acid. groups, especially acyl groups of aliphatic carboxylic acids, and also 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 contain, for example, 7 and preferably up to 4 carbon atoms. , a lower alkenyl group, a lower alkynyl group or a lower alkylidene group. Such groups are optionally substituted by functional groups, for example free or etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy groups. phenyloxy group or phenyl lower alkoxy group, lower alkylthio group, optionally substituted phenylthio group or phenyl lower alkylthio group, heterocycle-thio group or heterocycle-lower alkylthio group, optionally substituted A certain lower alkoxycarbonyloxy group or lower alkanoyloxy group, or a halodane atom, as well as an oxo group, a nitro group, an optionally substituted amino group such as a lower alkylamino group, a di-lower alkylamino group, a lower alkyleneamino group,
Oxa lower alkylene amino group or aza lower alkylene amino group and acylamino group such as lower alkanoylamino group, lower alkoxyl is nylamino group, -
- Rodan 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 salt form such as azido groups, acyl groups such as lower alkanoyl and benzoyl groups, carboxyl groups which may be functionally modified e.g. carboxyl groups in salt form , esterified carboxyl groups such as lower alkoxycarbonyl groups, optionally substituted carbamoyl groups such as N-lower alkyl- or N,N-di-lower alkyl-carbamoyl groups, substituted a ureidocarvinyl group or a guanidinocarbonyl group, or a cyano group, which may contain
A sulfo group which may be functionally modified, e.g. a sulfamoyl group or a sulfo group in the form of a salt, diluted or O-
a phosphono group which may be mono- or 0,0'-di-substituted, the substituent being for example a lower alkyl group which may be substituted, a phenyl group or a phenyl-lower alkyl group, and a 0-unsubstituted or the 0-mono-substituted phosphono group can be mono-, di- or poly-substituted (which can also be in the form of a salt, such as an alkali metal salt).

Divalent aliphatic groups, including the aliphatic groups of divalent aliphatic acids, are, for example, lower alkylene groups or lower alkenylene groups, which may be mono- or di-substituted like the aliphatic groups mentioned above. Alternatively, it can be substituted with 361J and/or there can be a petro atom such as an acid, nitrogen or sulfur atom interposed in the chain.

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

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

The divalent aromatic group of the aromatic carboxylic acid is especially 1.2-
71% of J-lene groups and 1,2-phenylene groups, which can optionally be mono-, di- or polysubstituted, such as the aforementioned aliphatic and cycloaliphatic hydrocarbon groups. .

The above-mentioned araliphatic radicals (including the araliphatic radicals in the corresponding caldicic acids) and also the araliphatic ylidene radicals are, for example, optionally substituted araliphatic hydrocarbon radicals,
For example, optionally substituted aliphatic hydrocarbon radicals with up to three optionally substituted monomial, binomial or polynomial aromatic hydrocarbon groups, in particular phenyl-lower alkyl radicals or phenyl- lower alkenyl radicals, as well as phenyl-lower alkynyl radicals and castor phenyl-lower alkylidene radicals, and such radicals may contain, for example, 1 to 3 phenyl radicals and optionally contain, for example, the aliphatic and aliphatic radicals mentioned above. Like cyclic groups, they can be mono-, di- or polysubstituted in their aromatic and/or aliphatic parts.

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

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

The acyl group of the carbonate semiconductor is the acyl group of the corresponding half ester (the organic group of this ester group is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group or heterocycle). - aliphatic groups), especially the acyl groups of lower alkyl half esters of carbonic acid (which are e.g.
acyl group of a lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half ester of carbonic acid which may be substituted in the - or β-position) and which may be substituted in the organic group. is preferred. The acyl group of the carbonic acid half ester is further defined as the corresponding group of the lower alkyl half ester of carbonic acid, the lower alkyl part of which has a heterocyclic group, for example one of the aforementioned heterocyclic groups of aromatic character, Both alkyl groups and heterocyclic groups can be optionally substituted. Furthermore, the acyl group of the carbonic acid semiconductor can also be a carbamoyl group, which may be N-substituted, such as an N-lower alkylcar-9 moyl group, which may be rhodanated.

An etherified hydroxyl group is primarily a lower alkoxy group which may be substituted, the substituents being primarily free or functionally modified e.g. etherified or esterified hydroxyl groups, in particular lower alkoxy groups or -
・Rhodan atom), and further lower alkenyloxy groups, cycloalkyloxy groups, or phenyloxy groups that may be substituted, and heterocyclic-oxy groups or heterocyclic-lower alkoxy groups, especially when substituted. is a phenyl lower alkoxy group.

Examples of amino groups that may be substituted include amino groups,
lower alkylamino group, di-lower alkylamino group, lower alkyleneamino group, oxa-lower alkyleneamino group,
Thia lower alkylene amino group, aza lower alkylene amino group 1. They are a hydroxyamino group, a lower alkoxyamino group, a lower alkanoyloxyamino group, a lower alkoxycardanylamino group, or a lower alkanoylamino group.

Examples of optionally substituted hydrazino groups include hydrazino, 2-lower alkylhydrazino, 2,2-di-lower alkylhydrazino, 2-lower alkoxycarbunylhydrazino, or 2-lower alkanoylhydrazino. It is a sono group.

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

Lower alkynyl groups are, for example, 1.2-ethylene groups, 1.2
- or 1,3-zolopyrene group, 1,4-butylene group,
The lower alkenylene group may be, for example, a 1,5-pentylene group or a 1,6-hexylene group, or a 1,2-ethenylene group or a 2-buten-1,4-ylene group. Lower alkylene groups with intervening heteroatoms are, for example, oxa-lower alkylene groups such as 3-oxa-1,5-hexylene groups, thia lower alkylene groups such as 3-thia-1,5-pentylene groups, or 3-lower alkylene groups such as 3-thia-1,5-pentylene groups. Alkyl-3-azo-1
, 5-benzene group e.g. 3-methyl-3-aza-1,
It is an aza lower alkylene group such as 5-pentylene group.

Cycloalkyl groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl groups, and adamantyl groups; cycloalkenyl groups are, for example, cyclozolobenyl, 1-12
- or 3-cyclolinthenyl group, 1-12-4' or 3-cyclohexenyl group, 3-cycloalkyl group or 1,4-cyclohexagenyl group, where the cycloalkylidene group is, for example, cyclopentylidene group. or a cyclohexylidene group. Cycloalkyl-lower alkyl group or cycloalkyl-lower alkenyl group il: Examples of evacyclopropyl-, cyclopentyl-, cyclohexyl- or cycloheptyl-methyl group, -1,1- or -1,2-ethyl group, -1, 1-1-1,2- or -1,3-propyl group, -vinyl group or -allyl group, where the cycloalkenyl-lower alkyl group or the cycloalkenyl-lower alkenyl group is, for example, 1-12-
or 3-cyclopentele, 1-12-1 or 3-cyclohexenyl- or 1-12- or 3-cyclohezotenyl-methyl group, -1,1- or -1,2-ethyl group, -1,1 -1-1°2- or -1,3-propyl group, -vinyl group or -allyl group. A cycloalkyl-lower alkylidene group is, for example, a cyclohexylmethylene group, and a cycloalkenyl-lower alkylidene group is, for example, a 3-cyclohexenylmethylene group.

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-t-phenylzolobyl, diphenylmethyl, trityl, 1- or 2 - a naphthyl-lower alkyl group such as a naphthylmethyl group, a styryl group or a cinnamyl group; the phenyl-lower alkylidene group is, for example, a penzolidene group.

Heterocyclic radicals are in particular heterocyclic radicals which may be substituted with aromatic character, such as corresponding monomial monoazacyclic, monothiacyclic or monooxacyclic radicals, such as 2-
Pyryl group such as pyryl group and 3-pyryl group, 2-13-
or pyridyl groups and pyridinium groups such as 4-pyridyl groups, chenyl groups such as 2- or 3-chenyl groups, or furyl groups such as 2-furyl groups, monoazacyclics, monooxacyclics or monothiacyclics Indolyl group, such as 2- or 3-indolyl group, 2
- or a quinolinyl group, such as a 4-quinolinyl group, 1-
Isoquinolinyl group such as isoquinolinyl group, benzofuranyl group such as 2- or 3-benzofuranyl group or unapensochenyl group such as 2- or 3-benzochenyl group, monocyclic diaza ring, triaza ring, tetraaza ring oxazacyclic, thiazacyclic or thiazoazocyclic radicals, for example imidazolyl radicals such as 2-imidazolyl radicals, pyrimidinyl radicals such as 2- or 4-pyrimidinyl radicals, 1,2.4-)riazo-3 a triazolyl group such as -yl group, a tetrazolyl group such as 1- or 5-tetrazolyl group, an oxasilyl group such as 2-oxasilyl group, an isoxasilyl group such as 3- or 4-isoxasilyl group, 2 - a thiazolyl group such as a thiazolyl group, an isothiazolyl group such as a 3- or 4-inchazolyl group, or a 1.2.4-thiadiazole-
a 1,2,4- or 1,3,4-thiadiazolyl group, such as a 3-yl group or a 1,3,4-thiadiazol-2-yl group; Cyclic groups such as benzimidazolyl groups such as 2-benzimidazolyl groups, benzoxasilyl groups such as 2-pe/zuoxazolyl groups, or benzthiazolyl groups such as 2-benzthiazolyl groups.

Corresponding partially or totally saturated groups are for example 2
- a tetrahydrochenyl group such as a tetrahydrochenyl group, a tetrahydrofuryl group such as a 2-tetrahydrofuryl group, or a pilysyl group such as a 2- or 4-piperizole group. A hetero-aliphatic radical is a heterocyclic radical, in particular a lower alkyl radical or a lower alkenyl radical with the above-mentioned radicals.

Said heterocyclic groups are, for example, aliphatic or aromatic hydrocarbon radicals which may be substituted by a lower alkyl group such as a methyl group or optionally by a halogen atom such as a chlorine atom. The phenyl group can be substituted by a phenyl group or a 4-chlorophenyl group or by a functional group, such as the aliphatic hydrocarbon group mentioned above.

Lower alkoxy groups include, for example, methoxy, ethoxy, n
-propoxy group, isobutoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tertiary-butoxy group, n-
A pentoxy group or a tertiary pentoxy group. These groups may be substituted, for example in halodanor lower alkoxy groups, especially in 2-halogeno-lower alkoxy groups, such as in 2.2.2-trichloroethoxy, 2-chloro-12-bromo- or 2-iodo-ethoxy groups. I can do it. The lower alkenyloxy group is, for example, a vinyloxy group or an allyloxy group, the lower alkylenedioxy group is, for example, a methylenedioxy group, an ethylenedioxy group or an inpropylidenedioxy group, and the cycloalkoxy group is, for example, a cyclopentyloxy group, A cyclohexyloxy group or an adamantyloxy group, a phenyl-lower alkoxy group is, for example, a benzyloxy group or an adamantyloxy group.
-1 or 2-7 enylethoxy group, diphenylmethoxy group or 4,4'-dimethoxydine phenylmethoxy group, and heterocycle-oxy group or heterocycle-lower alkoxy group is, for example, 2-pyridylmethoxy group. A pyridyl-lower alkoxy group such as, a furyl-lower alkoxy group such as a furfuryloxy group, or a thenyl-lower alkoxy group such as a 2-thenyloxy group.

Lower alkylthio groups are, for example, methylthio, ethylthio or n-butylthio, lower alkenylthio groups are, for example, allylthio groups, phenyl-lower alkylthio groups are, for example, benzylthio groups, and also heterocyclic or heterocyclic groups. The mercapto group etherified with an aliphatic group is particularly a pyridylthio group such as 4-pyridylthio group, an imidazolylthio group such as 2-imidazolylthio group, a thiazolylthio group such as 2-thiazolylthio group,
1.2.4-thiadiazol-3-ylthio group or 1.3
．． 1,2 such as 4-thiadiazol-2-ylthio group
．． A tetrazolylthio group such as a 4- or 1,3.4-thiadiazolylthio group or a 1-methyl-5-tetrazolylthio group.

Esterified hydroxyl groups include hydroxyl atoms, such as fluorine, chlorine, bromine or iodine atoms, as well as lower alkanoyloxy groups, such as acetoxy or zolopionyloxy groups, and lower alkoxycarbunyloxy groups, such as methoxycarbonyloxy. group, ethoxycarbonyloxy group or t-butyloxycal is a nyloxy group, 2-heroke9-lower alkoxycar? For example, if 2,2.2-trichloroethoxycar is a nyloxy group, 2-bromoethoxycar is a nyloxy group, or 2-iodoethoxycar is a nyloxy group, or aryl car? Nylmethoxycal is a nyloxy group. Ehaphenaciloxincal is a nyloxy group.

Examples of lower alkoxycarbyl groups include methoxycarbyl groups, ethoxycarbyl groups, and n-propoxycarbyl groups.
Nyl group, ingropoxycal? Nyl group, t-butoxycar? Nyl group or t-pentoxycarbunyl group.

N-lower alkyl-carno-tetramoyl group or N.

N-dilower alkyl-carbamoyl groups include, for example, N-methylcarnoZmoyl group, N-ethylcarbamoyl group, N,
N-dimethylcarbamoyl group, N,N-diethyl group, N-lower alkylsulfamoyl group, for example, N-methylsulfamoyl group
, N-dimethylsulfamoyl group.

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

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 dilazono group or a 4-methylpiperazino group.

Acylamino groups are particularly carbamoylamino groups, lower alkylcarbamoylamino groups such as methylcarbamoylamino groups, ureidocarbonylamino groups, guanidinocarbonylamino groups, lower alkoxycarbonylamino groups such as methoxycarbonylamino groups, ethoxycarbonylamino groups, etc. nylamino group or t-butoxycar is nylamino group, 2
．． 2. When a halogeno lower alkoxylic group such as 2-trichloroethoxycarbonylamino group is a nylamino group, 4-
A phenyl lower alkoxylic group is a nylamino group such as a methoxybenzyloxycar group, a lower alkanoylamino group such as an acetylamino group or a gropionylamino group, and a phthalimide group or a salt such as an alkali metal salt such as a sodium salt. It is a sulfamino group that can be in the form of an ammonium salt.

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

0-Lower alkylphosphono group is, for example, 0-methyl- or 0-ethyl-phosphono group, and 0110'-di-lower alkyl-phosphono group is, for example, 0,0'-dimethyl-phosphono group or 0,0'-diethyl- Phosphono group, 0-phenyl lower alkyl-phosphono group is, for example, 0-benzyl-
The phosphono group and the 〇-lower alkyl-O'-phenyl lower alkyl-phosphono group are, for example, O-benzo-O'-
It is a methyl-phosphono group.

Is the lower alkenyl oxycar the nyl group a side-group vinyl oxycar? Nyl group, cycloalkoxycar is a nyl group and phenyl-lower alkoxycarbunyl group is, for example, adamantyloxycarbunyl group, benzyloxycar is a nyl group, 4-methoxybenzyloxycar? Nyl group, diphenylmethoxycarbonyl group or α-4-biphenylyl-α-methylethoxycar is the nyl group. A lower alkoxycarbonyl group whose lower alkyl group has, for example, a monocyclic monoazacyclic, monooxacyclic or monothiacyclic group is a furyl-lower alkoxycarginyl group, such as a furfuryloxycarbunyl group; 2-thenyloxycar is a thenyl-lower alkoxycar & nyl group such as a nyl group.

The 2-lower alkylhydrazino group and the 2,2-di-lower alkylhydrazino group are, for example, a 2-methylhydrazino group or a 2,2-dimethylhydrazino group, and the 2-lower alkylhydrazino group is a 2-lower alkylhydrazino group. In the nylhydrazino group, for example, 2-methoxycar is a nylhydrazino group, 2-ethoxycar is a nylhydrazino group or t-butoxycaryfnylhydrazino group, and lower alkanoylhydrazino group is, for example, 2-
It is an acetylhydrazino group.

The etherified hydroxyl group, together with the carbunyl group in the formula, is preferably easily cleavable or easily converted into other functionally altered carboxyl groups (e.g. carbamoyl or hydrazinocarbunyl groups). It forms an esterified carboxyl group that can be converted into

Such a group R'2 is, for example, a methoxy group, an ethoxy group,
lower alkoxy groups, such as n-zoropoxy or isopropoxy, which together with the carbunyl group form an esterified carboxyl group;
In these, especially in 2-cephem compounds, free cals can be easily converted into xyl groups or other functionally modified cals can be converted into xyl groups.

An etherified hydroxyl group R'2 forming an esterified carboxyl group which is particularly easily cleavable together with the group -C(=O)- can be, for example,
- is a 2-halogeno-lower alkoxy group having an atomic weight of 19 or more as a rhodane atom. Such groups, together with the group -C(=O)-, can be easily cleaved by treatment with zinc in the presence of a chemical reducing agent such as aqueous acetic acid under neutral or slightly acidic conditions. or an esterified carboxyl group that can be easily converted into such a group. Such groups are for example 2.2.2-)
It is a lychloroethoxy group or a 2-iodoethoxy group, or a 2-chloroethoxy group or a 2-bromoethoxy group that can be easily converted into a 2-iodoethoxy group.

Additionally, it can be easily treated with zinc in the presence of a chemical reducing agent such as aqueous acetic acid under neutral or weakly acidic conditions, or by treatment with a suitable nucleophile such as sodium thiophenolate. An esterified carboxyl group that can be split into a group -C(=O)
As the etherified hydroxy group formed with -, the arylcar is a nylmethoxy group (aryl is in particular a phenyl group which may be substituted) and preferably a phenacyloxy group.

Furthermore, the radical can also be an arylmethoxy group, the aryl group of which is in particular a monocyclic, preferably substituted, aromatic hydrocarbon group. Such groups are esterified cals which can be easily cleaved under neutral or acidic conditions by irradiation, preferably UV irradiation, forming a xyl group together with the group -C(=0)-. . The aryl group in such an arylmethoxy group is particularly a low R alkoxyphenyly group such as a methoxyphenyl group [
The methoxy group is mainly 3-14- and/or
5-position] and/or especially a nitrophenyl group, the nitro group preferably being in the 2-position. Such radicals are especially lower alkoxy-1, such as methoxy- and/or nitro-benzyloxy radicals, primarily 3- or 4-methoxybenzyloxy radicals, 3,5-dimethoxybenzyloxy radicals, 2-nitropenzyloxy radicals or 4゜5-dimethoxy-2-nitropencyloxy group.

Furthermore, the etherified hydroxyl group R'2 can be converted into 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(=O)-. It can also be a group formed together.

Such groups primarily include hydrocarbon groups, the methyl group of which may be substituted, especially aliphatic or aromatic hydrocarbon groups, such as polysubstituted lower alkyl groups such as methyl groups and/or phenyl groups. a methoxy group or its methyl group which is monosubstituted by a carbocyclic aryl group having an electron-donating substituent or by an aromatic heterocyclic group having an oxygen or sulfur atom as a member; is a methoxy group such that it constitutes the mono-member in a polycyclic aliphatic hydrocarbon group or the mono-member occupying the α-position relative to the oxygen or sulfur atom in an oxacycloaliphatic or thiacycloaliphatic group.

Among polysubstituted methoxy groups of this type, preferred are t-lower alkoxy groups, such as t-butyloxy or t-pentyloxy groups, optionally substituted diphenylmethoxy groups, such as diphenylmethoxy groups, , 4'-dimethoxy-diphenylmethoxy group,
Further, the 2-(4-biphenylyl)-2-propyloxy group is υ, and the above-mentioned methoxy group having a substituted aryl group or heterocyclic group is, for example, a 4-methoxybenzyloxy group or a 3,4-dimethoxybenzyloxy group. α like a base
-Lower alkoxy phenyl-lower alkoxy group or 2
- a furfuryloxy group such as a furfuryloxy group. A polycyclic aliphatic hydrocarbon group having the methyl group of the methoxy group as a preferably triple-branched member is, for example, an adamantyl group such as -adamantyl group, and the methyl group of the methoxy group is The above-mentioned oxa- or thia-cycloaliphatic radicals having as a member α-position to the oxygen or sulfur atom are, for example, 2-oxa- or 2-thia-[1 alkylene radicals 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.

Additionally, the substrate contains etherified hydroxyl groups forming together with the group -C(=O)- an esterified carboxyl group that can be cleaved by hydrolysis, e.g. under weakly basic or slightly acidic conditions. It can also be a group. Such groups are preferably etherified hydroxyl groups, such as 4-nitrophenyloxy or 2,4-dinitrophenyloxy, forming together with an activated ester group -0(=0)-. nitrophenyloxy groups, nitrophenyl lower alkoxy groups such as 4-nitrobenzyloxy groups, hydroxy-lower alkylupentyloxy groups such as 4-hydroxy-3,5-t-butyl-benzyloxy groups, 2 ,4.
6-dolychlorophenyloxy group or 2,3,4,5.6
-polynophenoloxy groups such as -pentachlorophenyloxy groups, and also cyanomethoxy groups and acylaminomethoxy groups such as phthaliminomethoxy or succinyliminomethoxy groups.

In addition, the base material has an esterified carboxyl group that can be split under hydrogenolysis conditions to a carbonyl group -C (-
)- can also be an etherified hydroxyl group, for example a lower alkoxy group, such as a benzyloxy, a 4-methoxybenzyloxy group or a 4-nitrobenzyloxy group; It is an α-phenyl lower alkoxy group which can be substituted with a nitro group.

The substrate also contains an esterified cal that can be split under physiological conditions to convert the xyl group to the +p-nyl group.
(:(,7Q,)- together with etherified hydroxyl groups, mainly acyloxy, dimethoxy groups (the acyl groups are e.g. organic carboxylic acids, mainly lower alkanecarboxylic acids which may be substituted) or the acyloxymethyl moiety thereof forming a lactone group).Such etherified hydroxyl groups may be lower alkanoyloxymethoxy groups such as acetyloxymethoxy groups or Piparoyloxymethoxy group, amino-lower alkanoyloxymethoxy group, especially α-amino-lower alkanoyloxymethoxy group, such as glycyloxymethoxy group, L-valyloxymethoxy group, L-leucyloxymethoxy group, and also phthalidyloxy group. It is the basis.

R as a silyloxy or 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 --logno-lower alkyl group, cycloalkyl group, phenyl group or phenyl lower alkyl group,
or a functional group which may be modified, such as an etherified hydroxyl group such as a lower alkoxy group or a chlorine atom such as a chlorine atom, 9 or primarily a tri-lower alkylsilyloxy group such as a trimethylsilyloxy group. a halogeno-lower alkoxy-lower alkyl-silyl group such as a chloro-methoxy-methyl-silyl group or a tri-lower alkylstannyloxy group such as a tri-n-butylscunyloxy group.

R8 as an acyloxy group, which together with the group -C(=O)- preferably forms a mixed anhydride group which can be cleaved by hydrolysis, is for example an acyl group of the organic carganic acid or carbonic acid semi-derivative. lower alkanoyloxy groups such as acetyloxy, biparyloxy or trichloroacetyloxy groups or lower Alkoxycarbonyloxy radical example evamethoxycal? Nyloxy group or ethoxycarbonyloxy group.

Furthermore, R2 as a group formed together with a carbamoyl group or a hydrazinocarbonyl group which may be substituted with the group -C(=0)- is, for example, an amino group, a methylamino group or an ethylamino group. lower alkylamino groups, di-lower alkylamino groups such as dimethylamine and diethylamino groups, lower alkylene amino groups such as pyrrolidino and piperidino groups, oxa-lower alkylene amino groups such as morpholino groups, hydroxyamino groups, hydrazino groups; group, 2- such as 2-methylhydrazino group
A lower alkylhydrazino group or a 2,2-di-lower alkylhydrazino group such as a 2°2-dimethylhydrazino group.

R as an optionally substituted aliphatic hydrocarbon group
3 is in particular a lower alkyl group having 7 carbon atoms, preferably up to 4 carbon atoms, such as methyl, ethyl, n-propyl, isobutyl, n-butyl, isobutyl or sec-butyl; Lower alkenyl groups such as allyl groups, t-amino-lower alkyl groups with at least two carbon atoms interposed between the t-amino group and the oxygen atom, such as 2- or 3-di-lower alkylamino-lower alkyl groups; groups such as 2-dimethylaminoethyl, 2-diethylaminoethyl or 3-tmethylaminozolobyl, or their etherified hydroxyl groups, especially at least 2 carbon atoms between the lower alkoxy group and the oxygen atom; are intervening etherified hydroxy-lower alkyl groups, such as 2- or 1d3-lower alkoxy-lower alkyl groups, such as 2-methoxyethyl or 2-ethoxyethyl groups. R3 as an aromatic aliphatic hydrocarbon group which may be substituted is mainly a phenyl lower alkyl group which may be substituted, especially a 1-phenyl lower alkyl group having 1 to 3 phenyl groups which may be substituted. An alkyl group such as a benzyl group or a diphenylmethyl group, the substituent of which may be a side group such as an esterified or etherified hydroxyl group, such as an atom, a chlorine or bromine atom, a rhodane atom, or a methoxy group. Examples include lower alkoxy groups.

Aliphatic cal number? R3 as the acyl group of the phosphoric acid is primarily an optionally substituted lower alkanoyl group, such as an acetyl group, a propionyl group or a pinogloyl group, which may be, for example, an esterified or etherified hydroxyl group, such as a fluorine or It can be substituted by a halogen atom such as a chlorine atom or a lower alkoxy group such as a methoxy or ethoxy group. R3 as the acyl group of the aromatic carboxylic acid can be, for example, an optionally substituted benzoyl group, such as a benzoyl group or an esterified or etherified hydroxyl group as a substituent, such as a fluorine or chlorine atom. It is a benzoyl group having a rhodan atom, a lower alkoxy group such as a methoxy group or an ethoxy group, or a lower alkyl group such as a methyl group.

R3 as the acyl group of the carbonic acid semi-derivative is particularly a lower alkoxy group such as methoxycarbunyl group or ethoxyel group. It is a nyl group.

Is salt especially free calcium? Salts of compounds of formula (1) having a xyl group, mainly metal salts or ammonium salts,
For example, alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines. Organic amines which can be used for the formation of salts are in particular aliphatic, cycloaliphatic, cycloaliphatic and araliphatic primary, secondary or tertiary monoamines, diamines or polyamines, and rarely heterocyclic bases. Such amines include lower alkyl amines such as triethylamine, hydroxy-lower alkyl amines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri(2-hydroxyethyl)-amine, 4-amino Cal? such as benzoic acid-2-diethylamino-ethyl ester? basic aliphatic esters of acid, such as 1-ethylpiperidine, alkylene amines, cycloalkylamines such as bicyclohexylamine or benzyl amines, such as N,N'-dibenzylethylenediamine, and also pyridine, colicin or The compounds of formula (I) are salts of the pyridine type, such as quinoline.The compounds of formula (I) may also be salts of acid salts, such as inorganic acids such as hydrochloric acid, sulfuric acid or cynic acid, or suitable organic carbonic or sulfonic acids such as trifluoroacetic acid. Alternatively, an acid addition salt can be formed with 4-methylphenylsulfonic acid.

Compounds of formula (1) in which the free cal has a xyl group 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 preparation of pharmacologically active compounds, which can be converted into said pharmacologically active compounds, for example, by the method described in Japanese Patent Application No. 48-74354.

The present invention particularly provides that in formula (1), R2 is a hydroxyl group,
Lower alkoxy group [which is optionally preferably α
- position, for example, an aryloxy group that may be substituted, such as a lower alkoxyphenyloxy group such as 4-methoxyphenyloxy group, a lower alkanoyloxy group such as acetyloxy group or pivaloyloxy group, a glycyloxy group, L- Valyloxy group or L
- an α-amino lower alkanoyloxy group such as a leucyloxy group, an aryl group such as a benzoyl group, or an optionally substituted aryl group such as a phenyl group, a lower alkoxyphenyl group such as a 4-methoxyphenyl group, 4 - by a nitrophenyl group such as a nitrophenyl group or a phenyl group such as a 4-biphenylyl group or in the β-position) can be mono- or polysubstituted by a rhodane atom such as a chlorine, bromine or iodine atom. ] For example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, t-butyloxy or t-pentyloxy, bis-phenyloxy-methoxy which may be substituted with lower alkoxy. For example, a bis-4-methoxyphenyloxy-methoxy group, a lower alkanoyloxy-methoxy group such as an acetyloxymethoxy group or a piparoyloxymethoxy group,
α-ami.

lower alkanoyloxy-methoxy groups such as glycyloxymethoxy, phenacyloxy, optionally substituted phenyl lower alkoxy groups, especially 1-phenyl lower alkoxy groups such as phenylmethoxy groups (such groups include e.g. (can have 1 to 3 phenyl groups which may be substituted by substituents e.g. lower alkoxy groups such as methoxy groups, nitro groups or phenyl groups), e.g. benzyloxy groups, 4-methoxybenzyloxy groups, 2-biphenylyl-2-'propyloxy group, 4-nitrobenzyloxy group, diphenylmethoxy group, 4,4'-dimethoxy-diphenylmethoxy group or trityloxy group, or 2-1-rhodan lower alkoxy group, e.g. 2,2゜2-trichloroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group or 2-iodoethoxy group], and 2-phenacyloxy group and acyloxy group (for example, methoxycal is a nyloxy group, ethoxycal is a nyloxy group) or lower alkanoyloxy groups such as acetyloxy or pivaloyloxy), tri-lower alkylsilyloxy groups such as trimethylsilyloxy, or amino or hydrazino groups (these may For example, it can be substituted by a lower alkyl group such as a methyl group or a hydroxyl group.For example, an amino group, a lower alkylamino group such as a methylamino group, a di-lower alkylamino group such as a dimethylamino group, a hydrazino group. base, 2
-2-lower alkylhydrazino group such as -methylhydra sono group, 2.
2-di-lower alkylhydrazino group or hydroxyamino group), and R3 is a lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or a butyl group, a lower alkenyl group, e.g. Allyl groups, phenyl lower alkyl groups which may be substituted, especially 1-phenyl lower alkyl groups with one or two phenyl groups which may be substituted with lower alkoxy groups such as methoxy groups, e.g. Benzyl group or diphenylmethyl group, lower alkanoyl group such as acetyl group or propionyl group, lower alkoxyl group? a nyl group, such as a methoxycarbonyl group or a benzoyl group, which may be optionally substituted with, for example, a lower alkyl group such as a methyl group, a lower alkoxy group such as a methoxy group, or a halodane atom such as a fluorine or chlorine atom; 3-cephem-compounds having a salt-forming group or salts of such compounds having a salt-forming group.

In the 3-cephem compounds of the formula (1) or the salts of these compounds with salt-forming salts, the radical is primarily a hydroxyl group, a lower alkoxy group, especially a highly branched lower alkoxy group in the α-position. For example, a t-butoxy group, a methoxy or ethoxy group, a 2-halogeno lower alkoxy group''! , or 2.2.2-) lychloroethoxy group, 2
-Iodoethoxy group or a 2-chloroethoxy group that can be easily converted into this group Maft is a phenyl group substituted with a 2-bromoethoxy group, phenacyloxy group, lower alkoxy group or nitro group. 1-3
1-phenyl lower alkoxy group such as 4-methoxybenzyloxy group, 4-nitropentyloxy group,
Diphenylmethoxy group, 4,4'-dimethoxyduphenylmethoxy group or trityloxy group, lower alkanoyloxymethoxy group, acetyloxymethoxy group or piparoyloxymethoxy group, α-amino lower alkanoyloxymethoxy group, e.g. Examples of syloxymethoxy group, 2-phthalidyloxymethoxy group, lower alkoxycarbunyloxy group, and t-ethoxy group include nyloxy group or lower alkanoyloxy group such as acetyloxy group, and tri-lower alkylsilyloxy group such as trimethylsilyloxy group. and R3 is primarily a lower alkyl group such as a methyl, ethyl or n-butyl group, also a lower alkenyl group such as an allyl group, a 1-phenyl lower alkyl group such as a benzyl group or a diphenylmethyl group, but also a lower alkanoyl group. For example, an acetyl group or a propionyl group, a lower alkoxycar is a nyl group, and a t it'methoxycar is a nyl group or a benzoyl group.

The present invention mainly relates to formula (1) in which R2 is mainly a hydroxyl group, further a lower alkoxy group, particularly a lower alkoxy group highly branched at the α-position, such as a t-butoxy group,
2-halogeno-lower alkoxy groups such as 2, 2, 2
-) a lychloroethoxy group, a 2-iodoethoxy group or a 2-bromoethoxy group, or a diphenylmethoxy group, for example a diphenylmethoxy group, which may be substituted with a lower alkoxy group, such as a methoxy group;
．． 4'-dimethoxy-diphenylmethoxy, in some cases a tri-lower alkylsilyloxy group such as trimethylsilyloxy, and R3 is a lower alkyl group such as a methyl, ethyl or n-butyl group, a lower alkenyl group such as an allyl group. or a phenyl lower alkyl group such as a benzyl group, further a lower alkanoyl group such as an acetyl group or a propionyl group, or a lower alkoxycarbonyl group having a side chain ld'methoxycarbonyl group, or a salt of such a compound, such as when R2 is hydroxyl. an alkali metal salt such as a sodium salt, an alkaline earth metal salt such as a calcium salt, or an ammonium salt, including an amine salt, of the compound that is a group;
This relates to an inner salt of a compound in which is a hydroxyl group.

Primarily in the 3-cephem compound of formula (1) or in the salts of such compounds, R2 is primarily a hydroxyl group, further substituted in the 2-position by a halogen atom, such as a chlorine, bromine or iodine atom. Certain lower alkoxy groups, especially highly branched lower alkoxy groups in the α-position, such as the t-butoxy group, 2-/NN lovino-level alkoxy groups, such as the 2°2.2-tIJ chloroethoxy group,
a 2-iodoethoxy group or a 2-bromoethoxy group, or a diphenylmethoxy group, for example a diphenylmethoxy group or a 4,4'-dimethoxy-diphenylmethoxy group, which may be substituted with a lower alkoxy group, such as a methoxy group; a tri-lower alkylsilyloxy group such as a trimethylsilyloxy group, and R3
is a lower alkyl group such as methyl group, ethyl group or n-
butyl group, lower alkenyl group such as allyl group, phenyl lower alkyl group such as benzyl group.

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

According to the method of the present invention, the formula % formula % (in this formula, R2 and R3 have the same meanings as above, but R
2 is preferably a group R)2, where R is an amino-protecting group and R8 is a hydrogen atom or an acyl group, or both R8 and R8 represent a divalent amino-protecting group) In the compound obtained, the amino group at the 7-position is liberated and, optionally, in the resulting compound of formula (I), the protected cal of the formula -C(=O)- bow frees the xyl group from the free or other Cal H who was on probation? xyl group and (or) optionally converting the resulting compound with the salt-forming group into a salt or converting the resulting salt into the free compound or other salt, and (or) optionally converting the resulting compound with the salt-forming group into a By separating the mixture of isomeric compounds obtained into individual isomers, the compound of formula (1) or a salt thereof is obtained.

Amino-protecting groups include groups that can be substituted with hydrogen atoms, mainly acyl groups, Ac, triarylmethyl groups, especially trityl groups,
and an organic silyl group or an organic stannyl group.

The group Ac, including the acyl group of the group R8, is primarily an acyl group of organic carboxylic acids having preferably up to 18 carbon atoms, in particular optionally substituted aliphatic, cycloaliphatic, aromatic groups. , acyl groups of araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acids (including formic acid) and JR
J is a semiconductor sil group.

The divalent amino protecting group formed by the linkage of the radicals R8 and R6 is in particular a divalent acyl group of an organic dicarboxylic acid having preferably up to 18 carbon atoms, mainly aliphatic or aromatic. It is a diacyl group of dicarboxylic acid.

In the compounds of formula (XI[I), 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 in the α-position of a tert-butoxycarbonyl group is prepared by a method known per se, in particular an amino-protecting group or R'', in particular an easily cleavable acyl group. By treatment with otrifluoroacetic acid, a 2-halogeno lower alkoxycarbyl group or a phenacyloxycarbyl group, such as a 2,2,2-trichloroethoxycarbunyl group or a 2-iodoethoxycarbyl group, can be converted into a A suitable metal or metal compound, for example zinc or a divalent chromium compound such as a chloride or acetate of divalent chromium, preferably a hydrogen donor which forms nascent hydrogen together with this metal or metal compound. , preferably in the presence of aqueous acetic acid.

Furthermore, in the compound of formula (Xllll), formula -C(-
〇) The carboxyl group of -R2 is preferably converted into a suitable organohalogenosilicon compound such as trimethylchlorosilane or) an organohalogenosilicon compound such as )'J-n-butyltin chloride, preferably by esterification, including silylation. (IV) In the case of a carboxyl group protected by reaction with a compound, an acyl group R8 or R8 (free functional groups that may be present in these groups may optionally be protected). The resulting imide-halide can be reacted with an alcohol and the iminoether thus formed can be completely cleaved. During the course of this reaction, the protective The carboxyl group protected by the side group Ir!organosilyl group can already be liberated.

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

These are mainly inorganic acids, especially sulfur-containing acids.
Phosphorus oxyhalides, phosphorus 3-rhodanide and especially phosphorus pentahalides, such as phosphorus oxychloride, phosphorus trichloride and mainly phosphorus pentachloride, as well as pyrocatekyl-phosphorus trichloride, and sulfur. Acid halides, especially chlorides, of containing acids or caldic acids, such as thionyl chloride, fosquine or oxalyl chloride.

To react with one of the above imide-halide forming agents,
Generally suitable bases, especially organic bases, and tertiary amines such as tertiary aliphatic monoamines or diamines such as tri-lower alkyl amines such as trimethylamine, triethylamine or N,N-diisozorobyl-N-ethyl-amine, or N,N,N' , N'-tetra-lower alkyl-lower alkyl diamines such as N , N
, N', N'-tetramethyl-1,5-bentisine cyamine or N.

N, N', N'-tetranthyl-1,6-hexylene diamine, monocyclic or bicyclic mono- or diamines such as N-substituted (e.g. N-lower alkylated) alkylene amines, aza Alkylene amines or oxaalkylene amines such as N-methylbis-syn or N-methylmorpholine, or 2,3,4,6
,7.8-hexahydrovirolo[112'-a)pyrimidine (i.e. diazabicyclononene, DBN)
, or a tertiary aromatic amine, such as a lower alkylaniline, such as N,N-trimethylaniline, or especially a tertiary heterozygote or diaphragm base, such as quinoline or isoquinoline, preferably in the presence of bilicin.・
aliphatic or aromatic hydrocarbons which may be modified (e.g. chlorinated); reacted in the presence of a solvent such as methylene chloride;

In this reaction, the imide-halide forming agent and the base can be used in approximately equimolar amounts, but the base can be used in excess or in less than an equivalent amount, e.g. Excess amounts can also be used, especially about a 3 to 5 times excess amount.

Preferably, the reaction with the imido-ride 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 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;
In particular lower alkanols which may be substituted, such as halogenated (e.g. chlorinated) or which additionally bear a hydroxyl group, such as evaporative ethanol, zolopanol, butanols, especially methanol, as well as 2.2.2- 2-halogeno lower alkanols, such as trichloroethanol or 2-bromoethanol, and also optionally substituted phenyl-lower alkanols, such as benzyl alcohol, are suitable. This alcohol
Kan is generally used in excess, for example up to 100 times,
And while cooling the process, for example, about -50 to +10
Preferably, it is carried out at °C.

The iminoether product thus formed can advantageously be cleaved off without being isolated. The splitting of this iminoether can be achieved by treating it with an appropriate hydroxy compound.
Preferably it is achieved by hydrolysis or even alcoholysis. Suitably, alcoholysis is carried out using an excess of alcohol following the formation of the iminoether.

In this case, preference is given to using water or alcohols, especially lower alkanols such as methanol, or mixtures of organic solvents such as alcohols with water.

In the acyl group R8 of the acylamino group in the compound of formula (XI[l), for example, 5-amino-5-cal can be replaced by an oxy-valeryl group [the cal can be replaced by a xyl group, for example by esterification, in particular by a diphenylmethyl group, and(
or) the amino group may be protected, for example by acylation, in particular by a halogeno-lower alkanoyl group or phthaloyl group, such as the acyl group of the organic carboxylic acid, e.g. Agent 1. Carbon Xi-type arene-diazonium salts such as benzenediazonium chloride or N
- Halogen-amide or N-halogen-imide A reactive agent releasing a positive halogen atom, such as for example N-bromosuccinimide, preferably together with a suitable solvent or solvent mixture, for example nitro-lower alkanes or cyano-lower alkanes. in formic acid and the reaction product is mixed with water or a compound having a hydroxyl group such as a lower alkanol such as methanol, or in 5-amino-5-caldexyparyl group as a radical. Dioxane or a halogenated aliphatic carbide, if the amino group is unsubstituted and the carboxyl group is protected, for example by an ester, and the atom is preferably an acyl group but can also be a hydrogen atom. The hydrogen can be cleaved off by standing in a suitable solvent, such as methylene chloride, and if necessary working up the free or monoacylated amino compound thus formed by methods known per se. .

The formyl group R8 is removed by treatment with an acidic agent such as p-)luenesulfonic acid or hydrochloric acid, a weakly basic agent such as dilute ammonia or a decalcifying agent such as tris-(triphenylphosphine)-rhodium chloride. You can also do that.

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

The compound of formula (XI) is, for example, a cephem-3-one compound represented by the formula or its 2,
The corresponding enol with a double bond in the 3- or 3,4-position is converted into an enol derivative with a functionally modified hydroxyl group of the formula -〇-R3 in the 3-position, and optionally a compound of the formula 9. A free or other protected carboxyl group of -C(=O)-2 is obtained by converting it into a xyl group. This enol derivative can be produced by the method described above.

Formula -C(=O)-RA obtained by the method of the present invention.

protection, especially for formulas with esterified carboxylic groups (
In the compounds of I), the free cals can be converted into xyl groups by methods known per se, for example depending on the type of substrate. Esterification, for example carboxylic groups esterified with lower alkyl groups, especially methyl or ethyl groups, by hydrolysis in a weakly basic medium,
hydroxides or carbonates of, for example, alkali metals or alkaline earth metals (e.g. water-oxides), preferably in an aqueous solution of potassium hydroxide or potassium hydroxide, preferably at a value of about 9 to 10 and optionally in the presence of lower alkanols. It can be converted to a free carboxylic group by treatment with . A carboxyl group esterified with a suitable 2-halogeno lower alkyl group or arylcarbonylmethyl group can be reduced by a chemical reducing agent such as a metal such as zinc or a divalent chromium salt such as a chloride of divalent chromium. nascent hydrogen can be produced by the metal, generally by treatment in the presence of a hydrogen donor such as an acid, typically acetic acid or formic acid, or an alcohol (preferably with the addition of water). , and also carboxyl groups esterified with arylcarbonylmethyl groups) by treatment with a nucleophilic, preferably salt-forming, reagent such as IJium thiophenolate or sodium iodide. A carboxyl group esterified with an arylmethyl group can be esterified by, for example, irradiation [preferably, the arylmethyl group is
A benzyl group which may be substituted with, for example, a lower alkoxy group and/or a nitro group in the 14- and/or 5-positions has a total UV irradiation of, for example, 290 mμ or less, and the arylmethyl group has, for example, a 2-
For a benzyl group substituted with a nitro group at the position, for example, use long wavelength ultraviolet rays of 290 mμ or more],
- Caloxyl groups esterified with suitably substituted methyl groups such as butyl or diphenylmethyl groups are treated with suitable acidic agents such as formic acid or trifluoroacetic acid, and optionally with phenol or anisole. The active esterified carboxyl group and also the carboxyl group in anhydride form can be hydrolyzed by treatment with nucleophilic compounds such as hydrochloric acid,
The esterification can be cleaved by hydrogenolysis by treatment with an acidic or weakly basic aqueous agent, such as an aqueous solution of IJ (bicarbonate) or an aqueous buffered solution of about 7-9% potassium sulfate, and also by hydrogenolysis. The carboxyl group is, for example, NoJ? It can be split by treatment with hydrogen in the presence of a noble metal catalyst such as a radium catalyst.

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

In the resulting compounds having an esterified group of the formula -0(=O)-R2, this group can be changed to another group of the same formula. For example, 2-chloroethoxycarol is formed by treating a nyl group or a 2-bromoethoxycarbonyl group with an iodine salt such as sodium iodide in the presence of a suitable solvent such as acetone to form a 2-iodoethoxycaryl group. can be changed to the base.

Salts of compounds of formula (I) are prepared by methods known per se. That is, by treating a compound of formula (1) with an acidic group, for example with a metal compound such as a suitable alkali metal salt of caldicic acid, for example the sodium salt of α-ethylcaproic acid, or with ammonia or a suitable organic amine, The salt can be produced. For this purpose, it is preferred to use a stoichiometric amount or a slight excess of the salt former. 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. Inner salts of compounds of formula (1) having a salt-forming amine group and a free carboxyl group can be prepared by neutralizing the salt, such as its acid addition salt, to its isoelectric point with, for example, a weak base or by liquid ion exchange. produced by treatment with a chemical 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 resulting isomer mixture can be separated by methods known per se, for example by fractional crystallization of the mixture of diastereoisomers, adsorption chromatography (column chromatography or thin layer chromatography) or other suitable separation methods. Can be separated into isomers. The obtained racemate is treated by a conventional method, if appropriate, after introducing all suitable salt-forming groups, for example, to form a diastereomer salt mixture with an optically active salt-forming agent, and this mixture is divided into each diastereomer. By separating into mer salts and converting the thus separated noastereomer salts into free compounds,
Alternatively, it can be separated into individual enantiomers by fractional crystallization from an optically active solvent.

The present invention also includes embodiments in which a compound produced as an intermediate in the process is used as a raw material and the remaining process steps are carried out or the process is interrupted at any stage.

Furthermore, the raw materials can be used in the form of derivatives or generated during the reaction.

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

In this specification, unless otherwise specified, organic groups indicated as "lower" have up to 7 carbon atoms, preferably up to 4 carbon atoms. "Acyl group" has 2 carbon atoms
It has up to 0, preferably up to 12 and mainly up to 7.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1゜7β-jert-butoxylic? A solution of xylamino-3-methoxy-3-cephem-4-carganic acid diphenylmethyl ester [4,96 g (10 mm IJ mono)] in methylene chloride (25 me) and 25 m/trifluoroacetic acid
and 5 ml of anisole. The mixture is stirred for 1 hour at 0°C and then evaporated. residue sound water 50
m1 and extracted twice with ethyl acetate. 0. The pH of the aqueous phase is adjusted to 4.1 by adding an aqueous solution of IN hydroxide.

After complete addition of acetone and stirring for 1 hour in a water bath, 7
β-amino-3-methoxy-3-cephem-4-carboxylic acid precipitates. This is separated in a furnace and then dried.

Melting point: 300°C or higher (decomposition); Rf value: ~0.05 [silical, n-butanol/acetic acid/water (71.5 nia,
5:21)); UV-xd (0, lNNaOH)
:λmax-270nm (ε=7600): IR-spectrum (Nujol): 5.59.6.10.6.2
2°6.44, 6.65μ and other absorption bands.

Example 2゜7β-tritylamino-3-methoxy-3-cephem-
4-Carganic acid diphenylmethyl ester 0.521
(1.0 mmol) and 5 ml of formic acid is heated at 50° C. for 15 minutes and then evaporated. The residue is dissolved in water and extracted twice with ethyl acetate. The aqueous phase is adjusted to pH 4.1. Addition of acetone and stirring for 1 hour at 0°C yields 7β-amino-3-methoxy-3
-Cephem-4-carboxylic acid precipitates. This is sent door to door and dried under reduced pressure. IR-spectrum (nujol
) Absorption band: 5.59, 6.10, 6.22, 6.
44, 6.65μ, and others.

Example 3 A suspension of 1.65 g of 7β-amino-3-methoxy-3-cephem-4-caldenic acid diphenylmethyl ester and 2 ml of anisole was pre-cooled with 20 ml of trifluoroacetic acid.
/ and stir in a water bath for 15 minutes. The mixture is diluted with 100 m/l of cold toluene and evaporated under reduced pressure. The dark brown residue is dried under high vacuum and diethyl ether is added and stirred. The precipitate is separated from all households,
Wash with acetone and diethyl ether and dry.

The thus obtained trifluoroacetate of 7β-amino-3-methoxy-3-cephem-4-carboxylic acid was added to 10 ml of water.
This aqueous solution was washed twice with 10 ml each of ethyl acetate, and a 10-thimethanol solution of triethylamine was added to adjust the pH to 4.5. Dilute this with acetone and stir at 0°C for 1 hour.

The whole precipitate was separated and mixed with acetone and diethyl ether.
=2 mixture and dry under high vacuum. 7β-amino-3-methoxy-3-cephem-4-carboxylic acid is thus obtained in the form of an inner salt. Thin layer chromatogram (silica gel): Rf ~ 0.16 (system: n-butanol/acetic acid/water 67:10:23), ultraviolet absorption wave chromatogram (
0, IN hydrochloric acid): λmaX = 261 mμ (ε = 54
00).

The 7β-amino-3-methoxy-3-cephem-4-caldenoic acid prepared by the above method can be treated with trimethylchlorosilane to convert its carboxyl group into a carboxyl group protected with a trimethylsilyl group (in addition, The silylating agent can be used in excess to convert the amino group into a protected amino group as well), thus trimethylsilylated 7β-amino-3-methoxy-3
-Cephem-4-calanoic acid can be treated with phenylacetyl chloride to acylate its amino groups. If this is post-treated in the presence of water by a conventional method, 3-
Methoxy-7β-phenylacetylamine-3-cephem-4-carboxylic acid is obtained. TR-spectrum (C
H2Cl2) absorption band: 3.03, 5.60,
5.74. ．． 5.92, 6°24.

6.67μ.

Example 4 7β-Amino-3-methoxy-ceph-3-em-4-calanoic acid hydrochloride dioxane) 1.
! i' (2.82mM) in 20ml of dry methylene chloride.
1.65 ml of bis-(trimethylsilyl)-acetamide was added to this at room temperature under a nitrogen gas atmosphere.
Add f. After 40 minutes, the clear solution is cooled to 0 DEG C. and 900 m9 (4 DEG 37 mM) of solid D-.alpha.-phenylglycyl chloride hydrochloride are added thereto. After 5 minutes, propylene oxide O, Tml (10mM
) is added. This suspension was heated to zero in a nitrogen gas atmosphere.
Stir for 1 hour at °C, then add methanol 0.5 ml k
When added, 7β-(D-α-phenylglycylamino)
-3-Methoxy-cef-3-em-4-carboxylic acid hydrochloride precipitates out in the form of crystals. Separate this hydrochloride kP, water 9
ml and this solution is hydroxylated with IN) IJ
Adjust the pH to 4.6 with a diuretic solution. 7 generated in this way
The dihydrate of the inner salt of β-(D-α-phenylglycylamine)-3-methoxy-cef-3-em-4-carboxylic acid is taken from house to house, washed with acetone and diethyl ether, and dried. Melting point 174 to 176°C (decomposition), [α]
, -+132° (C=0.714, in 0.IN hydrochloric acid), thin layer chromatogram (silica dal): Rf value ~ 0
18 [System: n-butanol/acetic acid/water (67:10:2
3)), UV-spectrum (in sodium bicarbonate solution at 0, IN): λmaX=269 nm (ε=7000
), IR-spectrum (mineral oil): characteristic bands at 5.72, 5.94°, 6.23 and 6.60μ.

Example 5 993 μm (4,32 mM) of 7β-amino-3-methoxy-cef-3-em-4-carboxylic acid (inner salt) was suspended in 10 ml of methylene chloride and treated with N.

O-bis-(trimethylsilyl)-acetamide 1.3
Add 1 ml (5.6 mM) f and stir for 45 minutes at room temperature under a nitrogen gas atmosphere. The clear solution is cooled to 0° C. and D-α-7enylglycylic acid chloride-hydrochloride 1.111/(5.4 mM) is added. 0.41 nI of propylene oxide after 5 minutes! (5,
6mM). This suspension was stirred at 0°C for 1 hour under a nitrogen gas atmosphere, and then mixed with 0.6 methanol of methanol.
Add f. Thus crystallized 7β-(D-α-phenylglycylamide)-3-methoxy-cef-3-em-
The 4-caldic acid hydrochloride was separated from the furnace, dissolved in 15 mJ of water at 0°C, and 5 m of IN sodium hydroxide solution was added to this solution.
/2 and adjust the pH to about 4. This solution was heated to room temperature, and triethylamine was added to bring the pH to about 4.8.
7β-(D-α-phenylglycylamide)
-3-Methoxy-cef-3-em-4-carboxylic acid crystallizes in the form of crab hydrate. IR-spectrum (in mineral oil) singular bands: 5.72.5.94.623 and 6.60μ.

Example 6 A warm mixture of 7β-amino-3-methoxy-3-cephem) 4-carboxylic acid hydrochloride dioxanate (1 mmol) in water (20 m7') was cooled with an ice-methanol mixture until Pll was dissolved. IN until it reaches 8.5
Treat with aqueous potassium hydroxide solution.

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

The potassium salt obtained is dissolved in 25 ml of trimethylformamide and treated at -20° C. within 10 minutes with 1 equivalent of iodomethyl bivalate. The mixture is stirred for 30 minutes at −20° C. under a nitrogen atmosphere and, after dilution with ethyl acetate, extracted twice with a saturated aqueous IJ solution, dried over sodium sulfate and evaporated.

The crude product was chromatographed on silica gel to give 7
β-Amino-3-methoxy-3-cephem-4-cal?
hyvaloyloxymethyl ester. This is 2
- May contain some cephem isomers. IR-spectrum (methylene chloride): 1790''-'cIn and other absorption bands.

Example 7 A solution of p-nitrobenzyl 7-amino-3-methoxy-3-cephem-4-carboxylate (730 μm) in water (20 m) and acetonitrile (20 m) is temporarily acidified to pH 1 with concentrated hydrochloric acid. . Immediately thereafter, add this solution to I
Back titrate to 2.5 with N sodium hydroxide. Next,
The solution was evaporated to dryness and the residue was dissolved in 40 m THF.
1, 80 ml of methanol and 6 ml of water. Thereafter, this solution 'i51' radium on carbon (pre-reduced in ethanol) 7301n9 was heated under 50 psi hydrogen pressure for 2 hours at room temperature.
Hydrogenation in the presence of.

The catalyst is stripped off and washed with THF and water. The combined wash and P solutions are evaporated and the aqueous residue is slurried with ethyl acetate. The pH'i 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 cooled, 7-amino-3-methoxy-3-cephem-4-carboxylic acid precipitates as a crystalline solid. Infrared absorption spectrum (Nuj61 M
): Absorption peak at 5.61 microns (p-lactam carinyl).

N0M-Ro(p MSOd6): 635 (s
, 2H.

C2H2) 1 6.20 (813H, c5 methoxyl).

5.30 (d, IH, C6H) and 4.94 (a, IH
.

CyH) Signal to tau.

Ultraviolet absorption spectrum (pH7 buffer): λmax26
8 mμ (ε=6.500).

Example 8゜4-methylphenylsulfone of 7β-amino-3-methoxy-3-cephem-4α-caldenic acid diphenylmethyl ester in methylene chloride (20+++l) (1
, 9) is shaken with a phosphate buffer of pH 7-8. The organic phase was dried over sodium sulfate and
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 41 nl of water and extracted with methylene chloride. The aqueous phase is treated with 40 m/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°C.

Ultraviolet spectrum (0, IN sodium bicarbonate): λ
rn, Lx=270mμ (g=76o0).

[α几′=+134°±1°(C=1:0.5N sodium hydrogen carbonate)].

Example 9 Same as Example 1 or Example 2, but 7β-tert-butoxycarbonylamino-3-methoxy-3-cephem-
4-Carcenoic acid diphenylmethyl ester or 7β-tritylamino-3-methoxy-3-cephem-4-carcenoic acid diphenylmethyl ester + 7) lK7β-benzyloxycal is nylamino-3-methoxy-3-cephem-4- Caldenic acid diphenylmethyl ester e The following compound is obtained by treatment with an acidic agent. 7β-amino-3-methoxy-3-cephem-4-carboxylic acid;
IR-spectrum (nujol): absorption band 5.59
゜6.10, 6.22, 6.44, 6.65μ, and others.

Example 10 As in Example 1 or Example 2, except that 7β-tart-butoxycarbonylamino-3-methoxy-3-cephem-
7β-penzyloxycarbnylamino-3-n-butyloxy-3 in place of 4-carboxylic acid diphenylmethyl ester or 7β-tritylamino-3-methoxy-3-cephem-4-carcenoic acid diphenylmethyl ester
-Cephem-4-cardenic acid diphenylmethyl ester, 7β-penzyloxycarbnylamino-3-ethyloxy-3-cephem-4-calcardenic acid diphenylmethyl ester, 7β-penzyloxycardenylamino-3 The following compound is obtained by treating -benzyloxy-3-cephem-4-carnic acid diphenylmethyl ester with an acidic agent. 7β-amino-3-n-butyloxy-3-cephem-4-caldenic acid diphenylmethyl ester, ■R-spectrum (CH2Cl2): absorption band 5.63° 5.80, 6.25μ; 7β-amino-3
-Ethyloxy-3-cephem-4-calanoic acid diphenylmethyl ester, IR-spectrum (CH2Cl2
): absorption bands 5.64, 5.78, 6.24μ; and 7β-amino-3-pencyloxy-3-cephem-4-caldenic acid diphenylmethyl ester, IR-spectrum (CH2Cl2): absorption band 5. 63.5.8
0゜(79) 925-

Claims (1)

[Claims] 1. The following formula (XI) [In the formula, R2 is a hydroxyl group, or a group R2 (the R'
2 is a group forming a protected carboxyl group together with the carbonyl group -C(=0)- in the formula; R3 is an alkyl group or an aralkyl group, and p
: R8 is an amino-protecting group that can be removed by acidolysis; and R8 is hydrogen. ] In the compound represented by the following, the amino group at position 7 is released by acidolysis; converting the compound obtained into a salt or converting the compound obtained into a free compound; and/or optionally separating the mixture of isomeric compounds obtained into individual isomers. 〇-Substituted 7β-amino-3-cephem-3 represented by the formula % [wherein R2 and R3 have the same meanings as above]
-All-4-Cal? A method for producing a phosphoric acid compound t or a salt thereof. 2. The following formula (XI) [wherein R'2 is a group in which the protected car together with the carbonyl group -c(=o)- in the formula forms a xyl group: R5 is an alkyl group or an aralkyl group; R8 is an amine protecting group that can be removed by acidolysis; and R6 is hydrogen. The formula -c(=o)-R angle-protected carboxyl group is added to the compound
by solvolysis or reduction to the free carboxyl group; and, if desired, converting the resulting compound with a salt-forming group into a salt or the resulting salt into the free compound;
and/or optionally characterized in that the mixture of isomeric compounds obtained is separated into individual isomers,
I′), OOH [wherein R3 has the same meaning as above] 〇-substituted 7β-amino-3-cephem-3-ol-4-cal? A method for producing compound e or a salt thereof. 3. The following formula (xm) [In the formula, R2 is a hydroxyl group or a radical (R1, is protected in an esterified form together with the car?nyl group -C(-〇)- in the formula) R3 is an alkyl group or an aralkyl group); R3 is an amino-protecting group which can be eliminated by acidolysis; and N is hydrogen. ,], the amino group at the Schiff position is liberated by acidolysis; and in the obtained compound, the protected cal of the formula -c(-o)-R'2 is solvolyzed from the xyl group. Alternatively, the protected carboxylic group can be converted into a xyl group by removing the xyl protecting group by reduction to form a free carboxyl group, and then reprotecting the free carboxyl group by treatment with an esterifying agent. into a xyl group; and optionally convert the resulting compound with a salt-forming group into a salt or convert the resulting salt into a free compound; and/or optionally convert the resulting mixture of isomeric compounds into individual 〇-substituted 7β-amino- 3-cephem-3
- A method for producing an all-4-carganic acid compound or its salt.