DE2606192A1 - PROCESS FOR PRODUCING AMINO COMPOUNDS - Google Patents

Description

CiBA-GUGY AG, Basel, Switzerland

■ ··. ß \

■ - ■>

Case 4-9795 / +
Germany

Process for the preparation of amino compounds

The present invention is a new process for the preparation of amino compounds, in particular of 7β-amino-3-amino "3-cephem-4-carboxylic acid compounds the formula

(I)

NH-R,

wherein R-, an amino protecting group, and R ^ is hydrogen or an acyl group Ac, or R-. and R, together represent a divalent amino protective group, Rrj ¹ represents a radical which, together with the carbonyl group -C (= 0) - forms a protected carboxyl group and R represents! hydrogen or an optionally substituted aliphatic or cycloaliphatic !! Coal water

60 9 836/0966

75.11.330

ORiQINAL INSPECTED

rest stands, and salts of such compounds.

The compounds of the formula I are valuable intermediates for the preparation of antibiotically active products Cephera derivatives.

An amino protecting group, R, is one by water. replaceable group, primarily an acyl group Ac, also a triarylmethyl, especially the trityl group, as well as an organic silyl, or an organic

Stannyl group. A group Ac, which can also stand for a radical R, primarily represents the acyl radical of an organic one Carboxylic acid, preferential prices with up to 18 carbon atoms, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid (incl. Formic acid), as well as the acyl radical of a carbonic acid half-derivative

father. - · ·

A Ή One formed by the radicals R, and R .. together

divalent amino protective group is in particular the divalent "acyl radical of an organic dicarboxylic acid, preferential prices with up to 18 carbon atoms, primarily the diacyl radical of an aliphatic or aromatic dicarboxylic acid, furthermore

6 0 9838/096 6

the acyl radical of a, preferably substituted in the α-position, For example, oc-aminoacetic acid containing an aromatic or heterocyclic radical, in which the aruino group has a, preferably substituted, e.g. two lower alkyl, such as methyl groups containing methylene radical with the stick

Away

atom-linked. The radicals R, and R, can be taken together also an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably with up to 18 carbon atoms, represent.

A protected carboxyl group of the formula

A "

~ C (= O) -R.2 is primarily an esterified carboxyl group, but can also be a usually mixed anhydride group or an optionally substituted carbamoyl or hydrazinocarbonyl group represent. . ■

The group R ^. can therefore one, through an organic Remainder etherified hydroxyl group, in which the organic radical preferably contains up to 18 carbon atoms, which together with the -C (= 0) group an esterified carboxyl group forms. Such organic radicals are, for example, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted ones Hydrocarbon radicals of this type, as well as heterocyclic ones or heterocyclic-aliphatic radicals.

R 0 9 Ρ- 3 6 / Q 9 6 6

26Ü6192

The group R "can also represent an organic silyloxy radical, as well as a hydroxyl group etherified by an organometallic radical, such as a corresponding organic Stannyloxy group, in particular a hydrocarbon radical optionally substituted by 1 to 3, preferably with up to 18 carbon atoms, such as aliphatic hydrocarbon radicals, and optionally substituted by halogen such as chlorine Silyloxy or stannyloxy group.

_{A radical R 9 which forms a} primarily mixed anhydride group with a -C (= 0) group is, for example, halogen, such as chlorine or an acyloxy radical, in which acyl is the corresponding radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acid or a carbonic acid half-derivative, such as a carbonic acid half-ester. -. '

. A with a -C (= 0) group a carbamoyl-

A '

group-forming radical R ₀ is an optionally substituted amino group in which substituents are optionally substituted monovalent or bivalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted monovalent or bivalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or

609 83 6/0966.

araliphatic hydrocarbon radicals with up to 18 carbon atoms, also corresponding heterocyclic or hoterocyclic-aliphatic Residues with up to 18 carbon atoms and / or functional groups, such as optionally functionally modified, in particular free hydroxy, and also etherified or esterified hydroxy, in which the etherifying or esterifying radicals have, for example, the meanings given above and preferably contain up to 18 carbon atoms, as well as acyl radicals, primarily of organic carboxylic acids and of carbonic acid half-derivatives, preferably with up to 18 carbon atoms.

In a substituted hydrazinocarbonyl group of the formula -C (= 0) -R «, one or both nitrogen atoms can be substituted be, where as substituents primarily optionally substituted monovalent or bivalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted, monovalent or bivalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals

"With up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms, and / or functional groups, such as acyl radicals, primarily of organic carboxylic acids or of carbonic acid semi-derivatives, preferably with up to 18 carbon atoms, come into question.

Π 0 9836/0966 *

An aliphatic or cycloaliphatic hydrocarbon radical Ro has up to 18 carbon atoms.

In the description above and below The general terms used have the following meanings, for example: - ■ '

An aliphatic radical, including the aliphatic A radical e5.ner corresponding organic carboxylic acid, as well as a corresponding ylidene radical, is an optionally substituted one monovalent or divalent aliphatic hydrocarbon radical, in particular lower alkyl, and lower alkenyl or Lower alkynyl, furthermore lower alkylidene, e.g. up to 7, preferably can contain up to 4 carbon atoms. Such radicals can optionally be replaced by functional groups, e.g. by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or Phenyl-lower alkoxy, lower alkylthio'or optionally substituted Phenylthio, phenyl lower alkylthio, heterocyclyl

60 9036/0966

thio or heterocyclyl-lower alkylthio, optionally substituted lower alkoxycarbonyloxy or lower alkanoyloxy, or halogen, furthermore by oxo, nitro, optionally substituted amino, for example lower alkylamino, di-lower alky! ! amino, optionally substituted Pbenylniederalkoxycarbonylam5.no _s optionally substituted carbamoylamino, Ur eidocarbony1-amino or Guanidinocarboiiylamino, further optionally in the salt, such as alkali metal salt form vorliegendes sulfoamino, azido, acyl, such as lower alkanoyl or Benzo3'l, optionally functionally modified carboxyl, such as in salt form Any carboxyl present, esterified carboxyl such as lower alkoxycarbonyl, optionally substituted carbamoyl such as N-lower alkyl- or Ν, Ν-di-lower alkylcarbamoyl, furthermore optionally substituted ureid.ocarbonyl or guanidino carbonyl, or cyano, optionally functionally modified sulfo, such as sulfamoyl or sulfo present in salt form, or optionally O-mono- or 0,0-disubstituted phosphono, in which substituents are, for example, optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, where O-unsubstituted or O -monosubstituted phosphono can also be present in salt or alkali metal salt form, be mono-, di- or polysubstituted. .

60Π836 / 0966

26U6192 ■ • rf ·

A divalent aliphatic radical, including the corresponding radical of a divalent aliphatic carboxylic acid, is , for example, lower alkylene or lower alkylene, which is optionally mono-, di- or poly-substituted and / or by heteroatoms such as oxygen, nitrogen or sulfur, for example like an aliphatic radical specified above can be interrupted.

A cycloaliphatic or cycloaliphatic-aliphatic radical, including the cycloaliphatic or cycloaliphatic-aliphatic radical in a corresponding organic carboxylic acid or a corresponding cycloaliphatic or cycloaliphatic-aliphatic ylidene radical is an optionally substituted, mono- or bivalent, cycloaliphatic or cycloaliphatic-hydroaliphatic radical, for example , bi- or polycyclic cycloalkyl or cycloalkenyl, also cycloalkylidene, or cycloalkyl or cycloalkenyl lower alkyl or lower alkenyl, also cycloalkyl lower alkylidene or cycloalkenyl lower alkylidene, in which cycloalkyl and cycloalkylidene e.g. up to 12, such as 3-8, preferably 3- contains 6 ring carbon atoms, whilst cycloalkenyl, for example, up to 12, such as 3-8, for example having 5-8 ₅ preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatischaliphatischcn residue example, up to 7, preferably up to 4 Kohlenstoffato me can contain. The above cycloaliphatic

•
6 ηίμ 38/0966

26U6 192

see or cycloaliphatic-aliphatic radicals, if desired, e.g. by optionally substituted aliphatic hydrocarbon radicals, V7 "ie by the above, ge ~ 'optionally substituted lower alkyl groups, or then, e.g. such as the above-mentioned aliphatic hydrocarbon radicals, be mono-, di- or polysubstituted by functional groups.

An aromatic reads, including the aromatic radical of a corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon radical, for example a mono-, bi- or polycyclic aromatic hydrocarbon radical, in particular phenyl, as well as biphenylyl or naphthyi, which may be, for example, such as the above-mentioned aliphatic and cycloaliphatic Hydrocarbon radicals can be mono-, di- or poly-substituted.

A divalent aromatic radical, e.g., an aromatic carboxylic acid, is primarily 1,2-arylene, in particular 1,2-phenylene, optionally such as those mentioned above aliphatic and cycloaliphatic hydrocarbon radicals, mono-, di- or polysubstituted.

An araliphatic radical, including the araliphatic radical in a corresponding carboxylic acid, also includes araliphatic ylidene radical is, for example, an optionally substituted araliphatic hydrocarbon radical such as a optionally substituted, e.g. up to three, given

00 ^ 036/0 9GΠ

_ * ". ■ '26U6192 _ · 40 ·

if substituted mono-, bi- or polycyclic, aromatic Aliphatic hydrocarbon radical containing carbon-hydrogen radicals and represents primarily phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl, furthermore phenyl lower alkylidene, such radicals containing e.g. 1-3 phenyl groups and optionally, e.g. such as Above aliphatic and cycloaliphatic radicals * im aromatic and / or aliphatic part mono-, di- or polysubstituted could be. .

Heterocyclic groups, including those in heterocyclic-aliphatic radicals, including heterocyclic groups or heterocyclic-aliphatic groups in corresponding carboxylic acids, are in particular monocyclic ^, as well as bi- or polycyclic aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza-, triaza- or tetrazacyclic radicals of aromatic character, furthermore corresponding partial or fully saturated heterocyclic radicals of this type, such radicals optionally, e.g. such as the above-mentioned cycloaliphatic Radicals, mono-, di- or polysubstituted can be. The aliphatic part in heterocyclic-aliphatic Has residues, for example, for the corresponding cycloaliphatic-aliphatic or araliphatic radicals given meaning.

The acyl radical of a carbonic acid half derivative is preferably the acyl radical of a corresponding one. Halbesters,

8 0 9 B 3 6/0 9 6 6

~ 11 «.

. V 6 Ü 6 192

wherein the organic radical of the ester group is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or a heterocyclic-aliphatic radical, primarily the acyl radical of an optionally substituted lower alkyl half-ester of carbonic acid, for example in the <x ~ or p-position, and one Lower alkenyl, cycloalkyl, phenyl or phenyl lower alkyl balbesters of carbonic acid which may optionally be substituted in the organic Eest. Acyl radicals e5.nes carbonic acid half-ester are also corresponding radicals of lower alkyl half-esters of carbonic acid in which the lower alkyl part contains a heterocyclic group, e.g. one of the above-mentioned heterocyclic groups of aromatic character, whereby both the lower alkyl radical and the heterocyclic group can optionally be substituted. The acyl radical of a carbonic acid half 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 optionally substituted lower alkoxy, in which substituents primarily represent free or functionally modified, such as etherified or esterified hydroxyl groups, in particular lower alkoxy or halogen, furthermore lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy,

609B36 / 0966

so? ie ileterocyclyloxy or heterocyclyl-lower alkoxy, in particular also optionally substituted phenyl-lower alkoxy.

An optionally substituted amino group is, for example, amino, lower alkylamino, di-lower alkylamino, lower alkylenamino, Oxaniederalkylenamino, thianiederalkylenamino, Azaniederalky1enamino, Hydroxyamino, Niederalkoxyamino, Lower alkanoyloxyamino, lower alkoxycarbonylamino or lower alkanoylamino.

An optionally substituted hydrazino group is, for example, hydrazino, 2- ^{lower alk}> r} lhydrazin0j 2,2-di-lower alkylhydrazino ^ -lower alkoxycarbonylhydrazino or 2-lower alkanoylhydrazino.

Kiederalky1 is e.g. methyl, ethyl, n-propyl, Msopropyl, η-butyl, isobutyl, sec-butyl or tert-butyl, as well as n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl, while lower alkenyl e.g. vinyl, allyl, isopropyl, 2- or S-methally! or 3-butenyl, lower alkynyl e.g. propargyl or 2-butynyl, and lower alkylidene, for example, isopropylidene or isobutylidene.

Lower alkylene is, for example 1,2-Aetbylen, _1} 2- or 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, whilst lower alkenylene, for example 1,2-ethenylene or 2-butene Is -1,4-ylene. Lower alkylene interrupted by heteroatoms

60 ? - 836/0966.

, yf ₃ . · Ν 6 ί j 6 19

• is, for example, oxane-lower alkylene, such as 3-oxa-l, 5-pentylene, thian-lower alkylene, like "3-thia-1,5-pentylene, or asaniederalkylcn, such as 3-lower alkyl-3-aza-1,5-pentylene, e.g. 3-kethyl-3-aza-1,5-pentylene.

Cycloalkyl is e.g. cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl or cycloheptyl, as well as adainanfryl, cycloalkenyl e.g. cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl, and cycloalkylidene, e.g., cyclopentylidene or cyclohexylidene. Cycloalkyl lower alkyl or lower alkenyl is e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3 - propyl, vinyl or allyl, while cycloalkenyl lower alkyl or lower alkene} '! e.g. 1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl- or 1-, 2- or 3-cyclohepterrylri; ethyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, -vinyl or -allyl represents. Cycloalkyl-lower alkylidene is, for example, 3-Cycloh exenylmethy1en.

Kapthyl is 1- or 2-naphthyl, while biphenylyl

e.g. represents 4-biphenylyl.

Is phenyl-lower alkyl or phenyl-lower alkenyl e.g. benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, Diphenylmethyl, trityl, styryl or cinnamyl, Naphthyl-lower alkyl, e.g. 1- or 2-kaphthyl methyl, and Phen3'-lower alkylidene e.g. benzylidene.

i, 0 H H 3 R / 0 9 6 fi

Heterocyclic radicals are primarily ^r - p - if necessary substituted heterocyclic radicals of aromatic character, for example corresponding monocyclic, monoaza-, ir, onothia or monooxacyclic radicals, such as pyrryl, e.g. 2-pyrryl or 3-pyrryl, pyridyl, e.g. 2 -, 3- or 4-pyridyl, also pyridinium, thienyl, eg 2- or 3-thienyl, or furyl, eg 2-Fu ^ l, bicyclic monoaza, monooxa or monothiacyclic radicals such as indolyl, eg 2- or 3 -Indolyl, quinolinyl, for example 2- or 4-quinolinyl, isoquinolinyl, for example 1-isoquinolinyl, benzofuranyl, for example 2- or 3-benzofuranyl, or benzothienyl, for example 2- or 3-benzothienyl, monocyclic diaza-, triaza-, tetraza -, oxaza-, thiaza- or thiadiazacyclic radicals, v? ie iridazolyl, eg 2-imidazolyl, pyriraidinyl, eg 2- or 4-pyrimidiriyl, triaizolyl, eg 1,2,4-triazol-3-yl, tetrazolyl, eg 1- or 5-tetrazolyl, oxazolyl, e.g. 2-oxazolyl, isoxazolyl, e.g. 3- or 4-isoxazolyl, thiazolyl, e.g. 2-thiazolyl, isothiazolyl, e.g. 3- or 4-isothiazolyl or 1,2,4- or 1, 3,4-thi adiazolyl, for example 1,2,4-thiadiazol-3-yl or i, 3,4-thiadiazol-2-yl, or bicyclic diaza, oxaza- or thiazacyclic radicals, such as benzimidazolyl, for example 2-benzimidazolyl, benzoxazolyl, for example 2 -Benzoxazolyl, or benzthiazolyl, e.g. 2-Benzthiazolyi. Corresponding partially or completely saturated residues

Π η η 336/0966

261) 6 192

are e.g. tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, or piperidyl, e.g..? - · or 4-piperidyl. Heterocyclic-aliphatic radicals are heterocyclic " Groups, especially the above, contain Lower alkyl or lower alkenyl. The aforementioned Ho.to 1: 0 cyclyl residues can, for example, by optionally substituted aliphatic or aromatic hydrocarbon radicals, in particular Lower alkyl, such as methyl, or optionally phenyl substituted, e.g., by halogen, such as chlorine, e.g., phenyl or 4-chlorophenyl, or, e.g. like the aliphatic hydrocarbon radicals, substituted by functional groups s a.

Lower alkoxy is e.g. methoxy, ethoxy, n-propyloxy, Isopropyloxy, 11-butyloxy, isobutyl'oxy, sec-butyloxy, tert-butyloxy, n-pentyloxy or tert-pentyloxy. These groups may be substituted, e.g. as in halo-lower alkoxy, especially 2-halo-lower alkoxy, e.g., 2,2,2-tri ~ chloro-, 2-chloro-, 2-bromo- or 2-iodoethoxy. Lower alkenyloxy is e.g. vinyloxy or allyloxy, Niederall ^ lendioxy e.g. methylenedioxy, ethylenedioxy or isopropylidenedioxy, Cycloalkoxy, e.g. Cyclopent} 0.oxy, cyclohexyloxy or adamantyl oxy, phenyl-lower alkoxy, e.g. benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, or heterocyclyloxy or heterocyclic lower alkoxy, e.g.

98-36 / 0 9

Pyridyl lower alkoxy, such as 2-pyridylniethoxy, furyl lower: ilko :: y, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy.

Lower alkylthio is for example methylthio, ethylthio or n-butylthio, lower alkenylthio such as allylthio, and phenyl-lower alkylthio, for example benzylthio, while by heterocyclyl radicals or radicals heterocyclylaliphatische etherified mercapto particular Py'ridylthio, for example 4-pyridylthio, imidazolylthio, thiazolylthio, for example 2-thiazolylthio ₃ 1.2 , 4- or 1,3,4-thiadiazolylthio, for example 1,2,4-thiadiazol-3-ylthio or 1,3 _> 4-thiadiazol-2-ylthio, or tetrazolylthio, for example 1-methyl-5-tetrazol3 ⁷ lthio are.

Esterified hydroxyl groups are primarily halogen, for example fluorine, chlorine, bromine or iodine, as well as lower alkoxycarbonyloxy, for example methoxycarbonyloxy, ethoxycarbonyloxy or t-butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-Trichloräthoxycarbonyloxy, 2-Bromäthoxycarbon3 ⁷ loxy or 2-Jodäthoxycarbonyloxy, or Arylcarbonylmethoxycarbonyloxy, e.g. Phenacyloxycarbonyloxy ..

Lower alkoxycarbony-1 is e.g. methoxycarbonyl, Ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl or tert-pentyloxycarbonyl.

6 0VG36 / 0966 -

2BUBI92

N-lower-alkyl- or N, N-diniedaralkyl-carbarr.oy 1 is e.g. N-Methylcarba: noyl, N-Aethylcarbanioyl, Ν, Κ-Dirr.Gthyl - carbamoyl or Ν, Ν-diethylcarbainoyl, while N-lower alkylsulfamoyl e.g. N-methylsulfamoyl or Ν, Ν-dimethylsulfamoyl represents. . .

A carboxyl present in alkali metal salt form or 5JuIfο is e.g. one present in sodium or potassium salt form Carboxyl or SuIfο.

Kiederalkylaraino- or Diniedcralkylap.iino is, for example, methylamino, ethylamino, dimethylamine or diethylamino, lower alkylenamino, for example pyrrolidino or piperidino, oxaniederalkylenarnino, for example morpholino, thiiederalkylenamino, for example thiomorpholine, and aza-loweralkylenamino, for example piperazino or 4-methylpiperazino. Acylamino stands in particular for carbamoylamino, lower alkylcarbamoylamino ", such as l ^ iethj ^ lcarbaiiK ^ lamino, ureidocarbonylainino, guanidinocarbonylami.no, lower alkoxycarbonylamino, for example methoxycarbonylainino, ethoxycarbonylainino, ethoxycarbonylamino, -2, oxyloxycarbonylamino, -2, 2-halo carbonylamino, such as 2-halo-carbonylamino, 2-halo-carbonylamino, such as 2-halo-carbonylamino, Trichloräthox3'carbon} ⁷ lAIT! ino, Phenylniederalkoxj'carbonylamino such as 4-methoxybenzyloxycarbonylamino, Niederallcanoylamino, such as acetylamino or pro- pionylamino ^1, further for phthalimides, or optionally in the salt, such as alkali metal eg sodium, or Ammoniunsalzforrn, vorliegendes SuIfoamino .

f. ii'ni

26U6 192

Lower alkanoyl is, for example, formyl, acetyl, propionyl or pivaloyl.

. O-lower alkyl-phosphono is, for example, O-methyl- or O-ethyl-phosphono, Oj 0,0'-di-lower alkyl-phosphono, e.g. .0,0-Diinethyl-phosphono or O ₅ O ¹ -diethylphosphono, O-phenyl-lower alkyl-phosphono, e.g. O-benzyl-phosphono, and O-IT-lower alkyl-0'-phenyl-lower alkyl-phosphono, e.g. O-methyl-0 ' -benzy1-phosphono.

Lower alkenyloxycarbonyl is e.g. Vinyloxycarbonyl, while cycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl, e.g. Adarnantyloxycarbonyl, Benzyloxycarbon} ^ !, 4-Methoxybenzyloxycarbonyl, Diphenylmethoxycarbonyl or α-4-biphenyl-amethyl-sthoxycarbonyl represent. Lower alkoxycarbonyl, wherein Lower alkyl e.g. a monocyclic, monoaza-, monooxa- or contains monothlacyclic group is e.g. Furylnlederalkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl lower alcohol>; y ~ carbonyl, such as 2-thenyloxycarbonyl.

. 2-Niedera-lkyl- and 2,2-Diiederalkylhydrazi.no is έ.Β. 2-methylhydrazino or 2,2-dimethylhydrazino, 2-lower alkoxycarbonylhydrazino ζ.B. 2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert-but} ^ loxycarbonylhydrazino, and lower alkanoyl hydrazino, e.g., 2-acetyl hydrazino.

CuHH-3 6/0 9

• Af,

An acyl group Ac stands in particular for one

in a naturally occurring or in a bio, semi- or totally synthetically producible, preferably phar:.: acological effective N-acyl derivative of a 6-amino-penara-3-carboxylic acid or 7 ~ Amino-3 ~ cephe: n-4-carboxylic acid verbiridun3 contained acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, or an easily cleavable acyl radical, in particular a carbonic acid half-derivative.

One in a pharmacologically active N-acyl derivative a G-amino-penam-S-carboxylic acid or 7-amino ~ 3-cephem- ■ 4-carboxylic acid compound contained acyl radical Ac. is primarily a group of the formula

_P II ■

. O

. R ¹¹¹

where η is 0 and R. is hydrogen or optionally one substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted th heterocyclic radical, preferably of aromatic character, a functionally modified e.g. esterified or

26Ü6192

etherified hydroxy or mercapto or an optionally substituted amino group, or where η is 1, R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, C3 ^T cloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical , wherein the heterocyclic radical preferably has aromatic character and / or a quaternary nitrogen atom, an optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or an azido group, and each the radicals R and R are hydrogen, or where η is 1, R is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic denotes a hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has an aromatic character.

609836/096 6

2 B U 619 2

has, R an optionally functionally modified, e.g. esterified or etherified hydroxyl or mercapto groups such as a halogen atom, an optionally substituted amino group, an optionally functionally modified carboxyl or sulfo group, an optionally O-mono- or 0,0'-disubstituted

TTT

te is a phosphono group, or an azido group, and R is hydrogen, or where η is 1, any of R and R radicals are functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R is hydrogen, or where η is 1, R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic.

CO 9036/0 966

- 26ÜB192

means aromatic or araliphatic hydrocarbon radical and II and R together are optionally substituted by a double bond with the carbon atom linked aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical, or in which η is 1 and R is a optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or one optionally substituted heterocyclic or heterocyclic aliphatic radical, in which heterocyclic radicals are preferred have aromatic character, R an optionally substituted aliphatic, cycloaliphatic ^, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R is hydrogen or one, optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical mean

In the abovementioned acyl groups of the formula A, for example, η is 0 and R ^{1 is} hydrogen or an optionally, preferably in the 1-position by optionally protected amino, acylamino, in which acyl is primarily the acyl radical of a carbonic acid half-ester, such as a lower alkoxycarbonyl, 2 -Halogeniederalkoxycarbonyl- or Phenylni.eeer-

6 0 9836/096 6-

26D6192

alkoxycarbonyl radical, or one, optionally in Sal ·?.: -, for example alkali metal salt form, substituted cycloalkyl group with 5-7 ring carbon atoms, one optionally, preferably by hydroxy, lower alkoxy, for example methoxy, acyloxy, where acyl is primarily for the Ac3 ^ 1 radical of a carbonic acid half ester, such as a lower alcohol: -:} ^r ~ carbonyl, 2 ~ halo-lower alkoxycarbonyl ~ or phenyl-lower alkoxycarbonyl radical, and / or halogen, e.g. chlorine, substituted phenyl, naphthyl or tetrahydronaphthyl group, one optionally, e.g. by lower alkyl, for example methyl, and / or phenyl, which in turn may carry substituents such as halogen, for example chlorine, substituted heterocyclic group, such as a -4-isoxazolyl group, or a lower alkyl radical preferably containing, for example, an optionally substituted, such as halogen, for example chlorine N ~ substituted amino group, or η for 1, R for an optionally, preferably by halogen, such as chlorine, by given all substituted, such as hydroxy, acyloxy, in which acyl has the meaning given above, and / or halogen, e.g. chlorine, containing phenyloxy, or by optionally protected amino and / or carboxy substituted lower alkyl group, e.g. for an S-amino-S-carboxy- propyl radical with optionally protected amino and / or carboxy group, for example silylated, such as tri-lower alkylsilylated, for example trimethylsilylated, amino or

60983 6/0966

26Q6192

Acylamino, such as Kiederalkanoylaniino-, Halogenniederalkanoylamino- or P-thaloylamino group, and / or silylated, such as tri-lower alkylsilylated, e.g. trimethylsilylated, or esterified! - as by lower alkyl, 2-halo-lower alkyl or phenyl lower alkyl, e.g., diphenyl methyl, esterified Carboxy group, for a lower alkenyl group, for an optionally substituted, as optionally, e.g. as indicated above, acylated hydroxy and / or halogen, e.g. chlorine, furthermore, optionally estimated, e.g. as indicated above, acylated amino-lower alkyl, such as aminomethyl, or optionally, e.g., as indicated above, phenyloxy containing acylated hydroxy and / or halogen, e.g., chlorine Phenyl group, which is optionally, e.g. by lower alkyl, such as methyl, or optionally protected, e.g. acylated, amino or aminomethyl substituted as indicated above Pyridyl, e.g. 4-pyridyl, pyridinium, e.g. 4-pyridinium, Thienyl, e.g. 2-thienyl, furyl, e.g. 2-furyl, imidazole ·} ^, e.g. 1-imidazolyl, or tetrazolyl, e.g. 1-tetrazoiyl group, e-an optionally substituted lower alkoxy, e.g. methoxy group, an optionally substituted, as optionally protected, e.g. acylated as indicated above, hydroxy and / or halogen, such as chlorine, containing phenyloxy group, a lower alkylthio, e.g. n-butylthio, or lower alkenylthio, e.g. allylthio group, one optionally, e.g. by

ü Π Π Β 3 6 / Q 9 6 6

2 6 (J ß 19 2

Lower alkyl, V7ie methyl, substituted phenylthio-, pyridylthio-, for example 4-pyridylthio-, 2-imidazolylthio-, 1,2,4-triazol-3-ylthio-, 1,3 _} 4-triazol-2-ylthio-, l , 2,4-thiadiazol-3-ylthio ~, such as 5-methyl-1,2,4-thiadiazol-3-ylthio-, 1,3,4-thiadiazol-2-ylthio-, such as methyl-1,3, 4-thiadiazol-2 ~ ylthio, or 5-tetrazolylthio, such as 1-methyl-5-tetrazolylthio group, a halogen, in particular chlorine or bromine atom, an optionally functionally modified carboxyl group, such as lower alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, cyano or optionally, for example by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl, for example acetyl or propionyl, or benzoyl group, or an azido group, and R 'and R for hydrogen j or η for 1 , R for lower alkyl or an optionally acylated hydroxyl and / or calogen, eg chlorine, substituted phenyl, furyl, eg 2-furyl, thienyl, eg 2 - or 3-thienyl, or isothiazolyl, e.g. 4-isothiazolyl group,

II

furthermore for a 1,4-cyclohexadienyl group, R for optionally protected or substituted amino, e.g. amino, acylamino, such as lower alkoxycarbonylamino, 2-halo-lower ~ alkoxycarbonylamino or optionally substituted, such as lower alkoxy, e.g. methoxy, or nitro-containing phenyl

60PP36 / 0966

lower allox-rycarhonylamino, for example tert. -Butyloxycarbcnylarr.ino, 2,2,2-ΪrichloräühoMycarbonylamino, 4-Methoxybenzyloxycarbcnylamino or Diphenylmethyloxycarbonylamino, Arylsulfonylanino, for example 4-Kethylphenylsulfonylaui5.no, tritylamino-amino or arylthioamylthio-substituted eg , eg ethoxycarbonyl, or Niecleralkanoyl, eg acetyl, containing 2-propvlidenainino, V7ie l-ethox} ^T -carbon3 = ^r l-2-propylidenarr _! ino, or optionally substituted carbamo3 ⁷ laniino, such as guanidinocarbony! amino, or a suIfoarnino group, optionally present in salt, e.g. alkali metal salt form, an azido group, optionally in salt, e.g. alkali metal salt form or in protected, such as esterified form, e.g. as lower alkoxy carbonyl -, for example methoxycarbonyl or ethoxycarbonyl, or a phenyloxycarbonyl group, for example diphenylmethoxycarbonyl group, a cyano group, a sulfo group, an optionally functionally modified hydroxy group, where functionally modified hydroxy, in particular acylox} * -, such as .Formyloxy, as well as lower alkoxycarbonyloxy, 2- Halogenniederalkoxycarbon) 'loxy or optionally substituted, such as lower alkoxy, e.g. Methox}', or nitro-containing phenyl-lower alkoxycarbonyloxy, e.g. tert-butyloxycarbonyloxy, 2,2,2-trichloroethoxycarbonyloxy, 4-methoxybenzyloxycarbonyl

BOH836 / 0 966

■ '".' 2 6 ü ß 192

oxy or diphenylmethoxycarbonyloxy, or where applicable: represents substituted lower alkoxy, e.g. methoxy, or phenyloxy, an O-lower alkyl or 0,0'-di-lower alkyl-phosphono group, e.g. O-methyl-phosphono or O ₃ 0'-dimethylphosphono, or a halogen atom, for example chlorine or bromine, and R for hydrogen, or η for 1, R and R each for halogen, for example bromine, or lower alkoxycarbonyl, for example methoxycarbonyl, and R ~ for hydrogen, or η for 1, R for an optionally , for example by optionally acylated hydroxyl and / or halogen, for example chlorine, substituted phenyl, furyl, for example 2-furyl, or thienyl, for example 2- or 3-thienyl, or isothiazolyl, for example 4-isothiaz-olyl group, furthermore for a 1, A-cycloliexadienyl group, R for optionally, for example as indicated above, protected aminomethyl, and

JII - "· £

R ". Represents hydrogen, or η represents 1 and each of the groups R, R ¹¹ and R ^{111 represents} lower alkyl, for example methyl.

Such acyl radicals Ac are e.g. formyl, cyclopentylcarbonyl, oc-aminocyclopentylcarbonyl or a-amino-cyclohexylcarbonyl (with optionally substituted amino group, e.g. 3. optionally present in salt form suIfoamino group, or one, by one, preferably easily, e.g. when treating 'with an acidic agent such as trifluoroacetic acid, reductive, e.g. when treating with a chemical reducing agent

b η:; a 3 6/0 9 G 6

■ ■ - 28 -

agents, such as zinc in the presence of aqueous acetic acid, or catalytic hydrogen, or hydrolytically cleavable or an acyl radical that can be converted into such, preferential prices a suitable acyl radical of a carbonic acid half-ester, such as lower alkoxycarbonyl, e.g. tert.-butyloxycarbonyl, 2-Kalo · ge n- never the alkoxy carbonyl, e.g. 2,2, 2-Trichlora * thy loxy carbonyl, 2-bromoethoxycarbonyl or 2-Jodätboxycarbon} '- l, arylcarbonylmethoxycarbonyl, e.g. phenacyloxycarbonyl, optionally substituted, such as lower alkoxy, e.g. methoxy, or nitro-containing phenyl-lower alkoxycarbonyl, e.g. 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-substituted, such as N-lower alkyl, for example N-methylcarbamoyl, and also by trietyl, also by arylthio, for example 2-nitfophenylthio, arylsulfonyl, for example 4-methyl-phenylsulfonyl 1- ^{lower alkox) 7} carbonyl-2-propylidene, e.g. l-ethoxycarbonyl-2-propylidene, substituted amino group), 2,6-dimethoxybenzoyl, 5,6,7, 8-Tetrahydro-naphthcyl, 2-methoxy-1-naphthoyl, 2-ethoxy-lnaphthoyl, benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 5-methyl-3-phenyl-4-isoxazolylcarbonyl, 3- (2-chlorophenyl) -S-niethyl-4- isoxazolylcarbonyl-, 3- (2,6-dichlorophenyl) -5-meth3 ⁷ l-4-isoxazolylcarbonyl, 2-chloroethylaniinocarbonyl, acetyl, propionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acrylyl, crctonoyl, 3-butenoyl, 2- Pentenoyl, methoxyacetyl,

CO £ 336/0966 -

26D6 192

Butylthioacetyl ,. Allylthioacetyl, methylthioacetyl, chloroacetyl, Bro ~ .acetyl, D'ibromoacetyl, 3-chloropropionyl, 3-bronipropionyl, Aminoacetyl or 5 - amino-5-carboxy ~ valeryl (rait optionally, e.g. as indicated, as indicated by a monoacyl or diacyl radical, e.g. an optionally halogenated lower alkanoyl radical, like acetyl or dichloroacetyl, or phthaloyl, substituted amino group and / or optionally functional modified, e.g. in salt, such as sodium salt, or in ester, such as lower alkyl, e.g. methyl or ethyl, or aryl lower alkyl, e.g. Diphenylniethylesterform, present carboxyl group), Azidoacetyl, carboxyacetyl, methoxycarbony! Acetyl, Ethoxycarbony / acetyl, bis-methoxy-carbonylacetyl, N-phenylcarbamoylacetyl, Cyanoacetyl, α-cyanopropionyl, 2-cyano-3,3-di ~ meth3'l-acrylyl, phenyl acetyl, α-broniphenylacetyl, cc-azidophenylacetyl, 3-chlorophenylacetyl, 2- or 4-aminoruethylphenyl-acetyl (with optionally substituted amino group, e.g. as indicated), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, Bromophenylthioacetyl, 2-phenyloxypropionyl, a-phenyloxyphenylacetyl, a-methoxyphenylacetyl, a-ethoxyphenylacetyl, a-methoxy-3,4-dichlorophenylacetyl, a-cyano-phenylacetyl, in particular • phenylglycyl, 4-hydroxyphenylglycyl, 3 ~ chloro-4-hydroxyphenylglycyl, S ^ -Dichlor-A-hydroxy-phen ^^ lgljOyl, a-Amino-α- (1,4-cyclohexadienyl) -acetyl, a-Amino-α- (1-cyclohexenyl) -acetyl, α-amino-: -

B 0 9 8 3 6/0 9 6 6.

methyl-a-pheny / acetyl or ct-hydroxyphenylacetyl, where in an existing amine group, if appropriate, ζ J. as stated above, can be substituted and / or an existing, aliphatic and / or phenolically bonded hydroxyl group optionally, analogously to the amino group, e.g. by a suitable acyl radical, in particular by formyl or a Acyl residue of a carbonic acid half ester, can be protected), or α-0-methyl-phosphono-phenylacetyl or α-Ο, Ο-diruethylphosphono-phenylacetyl, also ßenzylthioacetyl. Benzylthiopropionyl, a-Carboxypheny! acetyl (with if necessary, e.g. like given above, functionally modified carhoxy group), 3-phenylpronionyl, 3- (3-cyanophenyl) propionyl, 4- (3-methoxyphenyl) -butyryl, 2-pyridy / acetyl, 4 ~ amino ~ pyridinium acetyl (optionally substituted with »e.g. as indicated above, amino group), 2-thienylacetyl, 3-thienylacetyl, 2-tetrahydrothienylacetyl, 2-Furylacetyl, l-Imidazolylacetj ^ l, 1-Tetrazolylacetyl, a-Ca.rboxy-2-thienylacetyl or cc-Carboxy-3-thienylacetyl (if necessary with functional, e.g. as stated above, modified carboxyl group), a-cyano-2-thienylacetyl, cc-amino-a- (2-thienyl) -acetyl, a-amino-α- (2-furyl) -acetyl or α-amino-α- (4-isothiazolyl) acetyl (optionally with, e.g. as stated above, substituted amino group), a-sulfo-

B 0.9 836/0966

26Π6192

phenylacetyl (if necessary with, e.g. like the carboxyl group, functionally modified sulfo group), 3-methyl-2-iraidr:;: olylthioacetyl, 1,2,4-triazol-3-ylthioacetyl, 1,3,4-triazol-2-ylthioacetyl, 5-methyl-1,2-thiadiazol-S-ylthioacetyl, 5-liethyll, 3,4-thiadiazol-2-ylthioacetyl or 1-methyl-5-tetrazolylthioacetyl.

An easily cleavable acyl radical Ac, in particular a carbonic acid half-ester, is primarily an acyl radical of a carbonic acid half-ester that can be split off by reduction, e.g. when treating with a chemical reducing agent, or by acid treatment, e.g. with trifluoroacetic acid, such as one, preferably on the carbon atom in the α-position to the oxy group multiply branched and / or aromatically substituted lower alkoxycarbonyl group or a methoxycarbonyl group substituted by arylcarbonyl, in particular benzoyl radicals, or in.ß-position substituted by halogen atoms lower alkoxycarbonyl radical, eg tert. -Butyloxycarbonj ^'r l, t-Pentylox.ycarbon}' · !, Phenacyloxycarbo ^ l, 2,2,2-trichloroethoxycarbonyl or 2-Jodäthoxycarbonyl or that can be converted in the latter group, such as 2-chloro- or 2- Bromäthoxycarbonyl, furthermore, preferably polycyclic, cycloalkoxycarbonyl, for example Adair.antyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, primarily a-phenyl-lower alkoxycarbonyl, v. ⁷ orin

G0: JÖ3G / 0966

261) 6192

the α-position is preferably polysubstituted, e.g. diphenylmsthoxycarbcnyl or α-4-ΒiphenyIyI-α-methyl-ethyloxy ■ carbonyl, or fiiryl-lower alkoxycarbonyl, primarily α-furyl-lower alkoxycarbonyl, e.g., furfuryloxycarbonyl.

One formed by the two residues R. and R. divalent acyl group is e.g. the acyl radical of a lower alkane or lower alkenedicarboxylic acid, such as succinyl, or an o-arylenedicarboxylic acid, such as phthaloyl.

Away

Another divalent radical formed by the groups R 1 and R 4 is, for example, one which is substituted, in particular in the 2-position, for example optionally substituted phenyl or thienyl, and in the 4-position optionally by lower alkyl, such as methyl, mono- or disubstituted l-0xo-3-aza-1,4-butylene radical, for example 4,4-dimethyl-2-phenyl-loxo-3-aza-1,4-but3 ^r len.

An etherified hydroxyl group R ~ forms, together with the carbonyl group, an esterified carboxyl group which can be easily split or converted into another functionally modified carboxyl group, such as a carbamoyl or hydrazinocarbonyl group. Such a group R ₂ is, for example, lower alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy, which together with the carbonyl group forms an esterified carboxyl group which, in particular in 2-C ephernverbungen, easily converts into a free carboxyl group

Π 0: i H 3 6/0 9 6 6

group or another functionally modified carboxyl group can be transferred.

An etherified hydroxyl group R ", which together with a -C (= 0) grouping a particularly easily cleavable one forms esterified carboxyl group, stands for example for 2-halo-lower alkoxy, wherein halogen preferably has an atomic weight greater than 19. Such a radical forms together with the -C (= 0) group one when treating with chemical reducing agents under neutral or weakly acidic conditions, e.g. with zinc in the presence of aqueous acetic acid, easily cleavable esterified carboxyl group or one into one easily convertible esterified carboxyl group and is e.g. 2,2,2-trichloroethoxy or 2-iodoethoxy, furthermore 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter.

A An etherified hydroxy group R ₉ , which together with

the -C (= 0) grouping also when treating with chemical Reducing agents under neutral or weakly acidic conditions, e.g. when treating with zinc in the presence of aqueous acetic acid, furthermore when treating with a suitable one nucleophilic reagent, e.g. sodium thiophenolate, is an easily cleavable esterified carboxyl group, is an arylcarbonylmethoxy group, wherein aryl stands in particular for an optionally substituted phenyl group, and preferably Phenacyloxy.

B 0 9 8 3 6/0 9 6 6

26UBI92

The group R. can also represent an aryl methoxy group stand in what. Aryl, especially a monocyclic one, preferably means substituted aromatic hydrocarbon radical. Such a radical forms together with the -C (= 0) group one when irradiating, preferably with ultraviolet! Light, easily fissile under neutral or acidic conditions, esterified carboxyl group. An aryl radical in such an arylmethoxy group is in particular lower alkoxyphenyl, e.g. Methoxyphenyl (where methoxy is primarily divided into 3-, 4- and / or 5-position), and / odei: especially nitrophenyl (v. ~ obei Nitro is preferably in the 2-position). Such leftovers are special Lower alkoxy, e.g. methoxy, and / or nitrobenzyloxy, primarily 3 ~ or 4-methoxybenzyloxy, 3,5-dimethoxybenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitro-benzyl ~ oxy.

An etherified hydroxy group R _? can also represent a radical which, together with the -C (= 0) grouping, forms an esterified carboxyl group which can be easily cleaved under acidic conditions, for example on treatment with trifluoroacetic acid or formic acid. Such a radical is primarily a methoxy group, in which methyl by optionally substituted hydrocarbon radicals, in particular aliphatic or aromatic carbon hydrogen radicals, such as lower alkyl, for example

6 ΓΙ 9 836/0966.

260B 19 2

Methyl and / or phenyl _{3 is} polysubstituted or is monosubstituted by an electron-donating carbocyclic aryl group having substituents or a heterocyclic group of aromatic character having oxygen or sulfur as a ring member, or is then a ring member in a polycycloaliphatic hydrocarbon radical or in an oxa or thiacycloaliphatic reads which means the ring member representing the α-position to the oxygen or sulfur atom. Preferred polysubstituted methoxy groups of this type are tert-lower alkoxy, for example tert-butyloxy or tert-pentyloxy, optionally substituted diphenylmethoxy, for example diphenylmethoxy or 4,4 ^1- dimethoxy-diphenylmethoxy, and also 2- (4-biphenylyl) -2-propyloxy , while a methoxy group containing the above-mentioned substituted aryl group or the heterocyclic group is, for example, oc-lower alkoxyphenyl-lower alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or furfuryloxy, V7ie 2-furfuryloxy. A polycycloaliphatic hydrocarbon radical in which methyl of the methoxy group is a, preferably triple, branched ring member is, for example, adamantyl, such as 1-adamantyl, and an above-mentioned oxa or thiacycloaliphatic radical in which methyl of the methoxy group is the α-position to the oxygen or sulfur atom Representative ring member is', means, for example, 2-oxa- or 2-thio-lower alkylene or lower alkenylene with 5-7 ring atoms, such as

9036/0966

26Π'6 Ί 9 2

2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl or corresponding Schv? efel analogs.

A.
The remainder of IU can also be an etherified hydroxy group

represent which, together with the —C (= 0) grouping, form a hydrolytic, for example, under weakly basic or acidic conditions; forms cleavable esterified carboxyl group. Such a radical 5.St preferably an etherified hydroxyl group which forms an activated ester group with the -C (= 0) group, such as nitrophen3 ^r loxy, e.g. 4-nitrophenyloxy or ^{2,4-dinitrophen3 r} loxy, nitrophenyl-lower alkoxy, e.g. 4-nitrobenzyloxy, hydroxy -Lower alkyl-benzyloxy, for example 4-hydroxy-3,5-tert-butyl-benzyloxy, ■ polyhalophenyloxy, for example 2,4,6-trichlorophenyloxy or 2,3j4,5,6 ~ pentachlorophenyloxy, also cyanomethoxy, and acylamino methoxy, e.g. Phthalin inomethoxy or succinyliminomethoxy.

A ■

The group R "can also be one, together with the

Carbony! Grouping of the formula -C (= 0) - one among hydrogenolytic Conditions represent cleavable -esterified carboxyl group-forming etherified hydroxyl group, and is e.g. α-phenyl-lower alkoxy which is optionally substituted, for example by lower alkoxy or nitro, such as benzyloxy, 4-methoxybenzyloxy or 4-nitrobenzyloxy.

The group R ^ can also form an esterified carboxyl group which can be cleaved under physiological conditions together with the carbonyl group -C (= 0) -

609836/0966

26Π6192

ethereal hydroxyl group, primarily an acyloxvmethoxy group, wherein acyl is e.g. the radical of an organic carboxylic acid, primarily one which is optionally substituted Means lower alkanecarboxylic acid, or wherein acyloxyn-ethyl forms the remainder of a lactone. Hydroxy groups etherified in this way are lower alkanoylox} '- niethoxy, e.g. acetyloxyniethyloxy or Pivaloyloxymethoxy, amino-lower alkanoyloxyniethoxy, in particular a-Affiino-lower alkanoyloxymethoxy, e.g. glycyloxyraethoxy, L-valyloxymethoxy L-leucyloxymethoxy, also phthalidyloxy.

A silyloxy or stannyloxy group R ₉ preferably contains, as substituents, optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, halo-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, or optionally modified functional groups , such as etherified hydroxyl, for example lower alkoxy groups, or halogen, for example chlorine atoms, and is primarily tri.niedera.lkylsilyloxy, for example trimethylsilyloxy, hcilogen-lower alkoxy-lower alkylsilyl, for example chloromethoxymethyl-silyl, or tri-lower alkylstannyloxy, for example tri -n-butylstannyloxy.

A together with a -C (= 0) grouping one, preferably hydrolytic, cleavable mixed anhydride group-forming acyloxy radical R "contains, for example, the acyl radical one of the above-mentioned organic carboxylic acids or carbon

6 0 9 8 3 6/0966

Acid half-derivatives, and is, for example, optionally, as per Halogen, e.g. fluorine or chlorine, preferably in the α-position, substituted lower alkanoyloxy, e.g., acetyloxy, pivalyloxy or trichloroacetyloxy, or lower alkoxycarbonyloxy, e.g. Methoxycarbonyloxy or ethoxycarbonyloxy.

One, together with a -C (= 0) grouping one optionally substituted carbamoyl or hydrazinocarbynyl group forming radical R "is, for example, amino, lower alkylamino or Diniederalkylaniino, such as Kethylamino, Aethylainino, Dimethylamine » or Diathylaivd.no, lower alkylenamino, e.g., pyrrolidino or piperidino, oxaniederalkylenamino, e.g. morpholino, Hydroxyamino, hydrazino, 2-lower alkylhydrazino or 2 ", 2-di-lower alkylhydrazine Oj e.g., 2-methylhydrazino or 2,2-dimethylhydrazino. · - ·.

An optionally substituted aliphatic hydrocarbon radical R ^ is in particular liiederalkyl, as well as lower alkenyl or lower alkynyl, with, for example, up to 7, preferably up to 4 carbon atoms, which radicals, for example, by hydroxy, lower alkoxy, such as methoxy, halogen, such as chlorine, aryl, e.g. phenyl, or phenyl which is mono- or polysubstituted by lower alkoxy, such as methoxy, halogen, such as chlorine, or nitro, or by heterocyclic radicals, such as in particular nitrogen, oxygen and / or sulfur-containing heteroaromatic radicals, for example pyridyl, furyl or thienyl, or by cycloaliphatic radicals, such as cyclohexyl, mono-, di- or polysubstituted.

609B36 / 0966

2HU6192

An optionally substituted cycloaliphatic radical R is in particular cycloalkyl or cycloalkenyl with up to, for example, 12, such as 3-8, preferably 5 or 6 ring carbon atoms, which radicals are substituted, for example, by lower alkyl, such as methyl, or like the aliphatic radicals R ₃ can.

Salts are those of compounds

the formula. I with a sour group like one Carboxy, sulfo or phosphono group, primarily metal or ammonium salts such as alkali metal and alkaline earth metal, e.g., sodium, potassium, magnesium or calcium salts, as well Ammonium salts with ammonia or suitable organic amines, primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic ^ primary, secondary or tertiary mono-, di- or polyamines, as well as heterocyclic ones Bases for salt formation come into question, such as lower alkylamines, e.g. triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid-2-diethylamino-ethyl ester, Lower alkyleneamines, e.g. 1-ethyl-piperidine, cycloalkylamines,

6Π 9836/0966

for example bicyclohexylamine, or benzylamines, for example N ₃ N '-dibenzylethylenediamine, and also bases of the pyridine type, for example pyridine, collidine or quinoline. Compounds of the formula I can also contain acid addition salts, e.g. with inorganic acids such as hydrochloric acid,

Sulfuric acid or phosphoric acid, or with suitable organic Carboxylic or sulfonic acids, e.g. trifluoroacetic acid or Form p-toluenesulfonic acid. Compounds of the formula I. urit. an acidic and a basic group can also in the form of internal salts, i.e. in the zwitterionic form ». 1-oxides of compounds of the formula I with salt-forming Groups can also form salts, as described above.

609836/0966

The invention relates in particular to the preparation of 3-cephern compounds of the formula 1, in which R-, one, in one fermentative (i.e. natural

occurring) or bio-, semi- or totally synthetically producible, in particular pharmacologically active, such as highly active N-acyl derivative of a 6ß-anrino ~ penam-3 ~ carboxylic acid or ip-hni.- no-3-cepheni-4-carboxylic acid compound containing acyl radical , as one of the abovementioned acyl radicals of the formula A denotes, v? obei in this R ″, R, R ″ and η primarily have the preferred meanings, R, stands for hydrogen, or in which R. and R. together form one in 2 -Position preferably ,, eg by

609836/0966

an aromatic or heterocyclic radical, such as phenyl and preferably in_4-position, for example by two lower alkyl, such as methyl, substituted l-oxo-3-aza-1,4-butylene radical, R ^ for optionally, preferably in the «position, for example optionally substituted aryloxy, such as lower alkoxyphanyloxy, for example 4-methoxyphenyloxy, lower alkanoyloxy, for example acetyloxy or pivaloyloxy, a-amino lower alkanoyloxy, for example glycyloxy, L-valyloxy or L-leucyloxy, arylcarbonyl, for example benzoyl, such as: .- or optionally substituted - Phenyl, lower alkoxyphenyl, for example 4-methoxyphenyl, kitrophenyl, for example 4-nitrophenyl, or biphenylyl, for example 4-biphenylyl, or in the β-position by halogen, for example. Chlorine, bromine or iodine, mono- or polysubstituted lower alkoxy, such as lower alkoxy, for example methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy or tert-pentyloxy, or even bis-phenyloxy substituted by lower alkoxy -niethoxy, for example bis-4-methoxyphen3 ^ 1oxy-inethoxy, lower alkanoyloxy-methoxy, for example acetyloxymethoxy or pivaloyloxym'ethoxy, α-amino-lower alkanoyloxy-methoxy, for example glycyloxymethoxy, phenacyloxy, optionally substituted phenyl-lower alkoxy, such as phenyl-phenyl-lower alkoxy, in particular 1-phenyl-lower alkoxy Rests 1-3 may contain phenyl radicals substituted, for example by _{lower alkoxy, such as methoxy, nitro or phenyl:} e.g. benzyloxy, 4-methoxy-benzyloxy, 2-biphenylyl-2-propyloxy _:

H05J836 / 0966

4-nitrobenzyloxy, diphenylraethoxy, 4,4'-dirnethoxy-diphenylmethoxy or trityloxy, or 2-ilalogene-lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, also for 2-phthalidyloxy , and for acyloxy, such as lower alkoxycarbonyloxy, z-.B. Methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, for example acetyloxy or pivaloyloxy, for tri-lower alkylsilyloxy, for example trimethylsilyloxy, or for optionally, for example by lower alkyl, ν? Ie methyl. or hydroxy-substituted amino or hydrazino, for example amino, lower alkyl or di-lower alkylaraino, such as methylamino or dimethylamino, hydrazino _} 2-lower alkyl or 2,2-dinicderalkylhydrazino, for example 2-methylli3 ^ drazino or 2,2-dimethylhydrazino, or kydroxyaraino and R represents "hydrogen" or lower alkyl, in particular methyl, or salts of such compounds.

First and foremost in a 3-cephem connection is the

A formula I, or in a salt of such a compound, R for

- · 0 ¹ A a 3 B / 0 9 6 6

an acyl radical contained in remote orientational (ie naturally occurring) or biosynthetically producible N-acyl derivatives of 6β- amino-penani-3-carboxylic acid or 7β- amino-3-cepheni-4-carboxylic acid compounds ,. especially of the formula A, wherein

R ₅ R, K. ~ and η primarily have the preferred meanings, V7ie an optionally substituted, for example by hydroxy, phenylacetyl or phenyloxyacetyl radical, furthermore an optionally substituted, for example by Niederall ^ lthio, or Niederalkenyithio, and optionally substituted, such as ac } ⁷ lated amino and / or functionally modified, such as esterified carboxyl, substituted lower alkanoyl or lower alkenoyl radical, 2.B. 4-Hydroxypheny! Acetyl, hexano} ⁷ !, Octanoyl or n-but} ⁷ ! -. thioacetyl, and in particular 5-amino-5-carboxy ~ valeryl, in which the amino and / or the carboxy ~ o groups are optionally protected and are present, for example, as acylamino or esterified carboxyl, phenylacetyl or pheny ^ xyacety ^ or an in highly effective N-acyl derivatives of öjS-amino-penam-S-carboxylic acid or 7β-Α ~ ά-no-3-cephem-4-carboxylic acid compounds occurring acyl radical, in particular of the formula A, in which R, R, R and η are primarily have the preferred meanings such as formyl, 2-haloethylcarbamoyl, for example 2-chloroethylcarbamoyl, cyanoacetyl, phenylacetyl, thieny / acetyl, for example 2-thieny / acetyl, or tetrazolylacetyl, for example 1-tetrazolylacetyl, but especially in the α-position by a cyclic one like a cycloaliphatic ^ aromatic

G0vo3B / 0966

2606 I 92

see or heterocyclic, primarily monocyclic Radical and substituted by a functional group, primarily amino, carboxy, sulfo or hydroxyl groups Acetyl, in particular phenylglycyl, in which phenyl optionally, e.g. by optionally protected hydroxy} such as acyloxy, e.g., optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and / or by halogen, e.g. Chlorine, substituted phenyl, e.g. phenyl, or 3- or 4-hydroxy-, 3-chloro-4-hydroxy ~ or 3> 5-dichloro-4-hydroxyphenyl (if necessary also with protected, such as acylated Kydroxygruppe), and wherein the amino group is optionally can also be substituted and, for example, a suIfoamino group or an anion group which may be present in salt form represents, the hydrolytically cleavable as a substituent Trityl group or primarily an acyl group, such as an optionally substituted carbamoyl, such as an optionally substituted ureidocarbonyl group, e.g., ureidocarbonyl or N'-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group, e.g. guanidinocarbonyl, or one, preferably slightly, e.g. Treatment with an acidic agent, such as trifluoroacetic acid, further reductive, as in treatment with a chemical reducing agent, like zinc in the presence of aqueous acetic acid, or with catalytic hydrogen, or hydrolytically

60 9 836/0966

-. " ^4ö - 2 6 U 6 1 9 2

cleavable or an acyl radical that can be split off in such a way, preferably a suitable acyl radical of a carbonic acid half-ester, such as one of the above-mentioned, ζ.B. optionally halogen- or benzoyl-substituted lower alkyloxycarbonyl radicals, for example tert-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-jcdethoxycarbonyl, or phenacyloxy carbonyl, optionally lower alkoxy- or nitro-substituted ^{7-phenoxy- or nitro-substituted phenoxy} -Kethoxybenzyloxyca.rbonyl or Diphenyliüethoxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-Meth ^ 'lcarbarr.oyl, also one with a nucleophilic reagent, V7ie hydrocyanic acid, sulphurous acid or thioacetic acid, cleavable arylthio- or trio-aryl-lower alkyl, for example 2-nitrothio- or aryl-aryl-lower alkyl , an arylsulfonyl radical that can be split off by means of electrolytic reduction, e.g. 4-methylphenylsulphonyl, or a 1-lower alkoxycarbynyi or l-lower alkanoyl-2-propylidene radical that can be split off with an acidic agent, such as formic acid or aqueous mineral acid, e.g. hydrochloric or phosphoric acid, 'for example 1-ethoxycarbonyl-2-propylidene, e nthält, also α- (1,4-cyclohexadienyl) -glycyl, α- (1-cyclohexenyl) -glycyl, α-thienylglycyl, such as a-2- or

a.-3-thienylglycyl, a-furylglycyl, such as a-2-furylglycyl, a-isothiazolylglycyl, such as a-4-isothiazolyl-glycyl, whereby in such Residues the amino group, e.g. as for a phenylglycyl residue

60 9 836/0966

may be indicated, substituted or slotted, also α.-Carboxy-pheny! acetyl or a-Carboxy-thienylacetyl, e.g. α-Car-. boxy-2-thienylacetyl (possibly with functionally modified, e.g. in salt, such as sodium salt form, or in ester, such as lower alkyl, e.g. methyl or ethyl, or phenyl lower alkyl, e.g. Diphenylmethyl-

ester form, present carboxyl group), ct-sulfophenylacetyl (optionally also with, for example like the carboxyl group, functionally modified sulfo group), a-phosphono, aO-methylphosphono or a-0,0 ¹ -dirr.ethylphosphono-phenylacetyl, or a -Hydroxyphenylacetyl (optionally with a functionally modified hydroxyl group, especially with an acyloxy group, in which acyl is easily cleavable, e.g. when treating with an acidic agent such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid or an acyl radical which can be converted into such a radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as one of the abovementioned, for example a lower alkoxycarbonyl radical optionally substituted by halogen or benzoyl, for example "2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodo-sthoxycarbonyl, tert-butyloxj'carbonyl or phenacyloxycarbonyl, also means formyl), and 1-amino-cyclohexylcarbonyl, aminomethylphenylacetyl, such as 2- or 4-aminomethyl-

609836/0966

2 6 U 619 2

phenylacetyl, or aminopyridinium acetyl, e.g., 4-aminopyridinium acetyl (if necessary also with, e.g. as indicated above, substituted areino group), or pyridylthioacetyl,

b "A

e.g. 4-Pyridylthioacetylj and R, for hydrogen, or R, and R- together for one, preferably in the 2-position, by optionally protected by hydroxy, such as Ac3'loxy, e.g. optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and / or by halogen, for example chlorine, substituted phenyl, for example phen} 'l, or 3- or 4-hydroxy-, 3-chloro-4-hydroxy ~ or 3,5-dichloro-4-hydroxyphenyl (optionally also with protected , for example as indicated above, acylated hydroxyl group) substituted l-oxo-3-aza-1,4-butylene radical, which optionally contains two metal alkyls, such as methyl, in the 4-position, and R1 represents lower alkoxy, in particular α-polybranched Lower alkoxy, for example tert-butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, for example 2,2j2-trichloroethoxy, 2-iodoethoxy or 2-chloroethoxy "or 2-bromoethoxy, phenacyloxy, 1-phem ^, which can be easily converted into this Lower alkoxy with 1-3 Phe ^^ l radicals optionally substituted by lower alkoxy or nitro, for example 4-met hoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4 ^f -dimethoxy-diphenylmethoxy or trityloxy, lower alkanoyloxymethoxy, e.g. acetyloxymethoxy or pivaloyloxymethoxy, a-amino lower alkano3'-lox3 ^T methoxy, e.g. glycyloxymethoxy,

609836/0966

2-phthalidyloxymethoxy, lower alkoxycarbonyloxy, e.g. ethoxycarbonyloxy, or lower alkaiioyloxy, ζ.13. Acetyloxy, furthermore Tri-lower alkylsilyloxy, e.g., trimethylsilyloxy, and R stands in particular for hydrogen, or also for lower alkyl, especially methyl.

The invention relates primarily to the preparation of 3-cephem compounds of the formula I in which R, a Acyl group of the formula

(X) _m CH C - (B),

where R is phenyl or hydroxyphenyl, e.g., 3- or 4-hydroxya

phenyl, also hydroxy-chlorophenyl, e.g. 3-chloro-4-hydroxy ~ phenyl- or 3,5-dichloro-4-hydroxyphenyl, especially in such Residues of hydroxy substituents through acyl radicals, such as optionally • halogenated lower alkoxycarbonyl radicals, e.g. tert-butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, can be protected

nen, as well as thienyl, for example 2- or 3-thienyl, also pyridyl, for example 4-pyridyl, aminopyridinium, for example 4-aminopyridiniura, furyl, for example 2-furyl, isothiazolyl, for example 4-isothiazolyl, "or tetrazolyl, for example 1-tetrazolyl , or 1,4-cyclohexadienyl or 1-cyclchexenyl is, X is oxygen or sulfur, m is 0 or 1, and R _{b is} hydrogen or, if m is 0, for amino, and protected amino »such as acylamino, for example -α-polybranched Niedera.lkoxycarbonylamino, such as tert-butyloxycarbonylamino, or 2-Kalogeniederalkoxycarbonylaniino, such as 2,2 ^ -Trichloräthoxycarbonylamino, 2-Jodäthoxycarbpnylamino or 2-bromoethoxycarbonylaraino, or optionally lower alkoxy- or 4-phenoxy carbonyl-oxycarnooxy, or optionally lower alkoxy- or 4-carbonyl methoxycarnooxybenzino, or, for example, diphenoxy- or 4-methoxycarbonyl-methoxycarbonylamino-benzino-benzyloxy- or diphenylamycarbonyl-methoxycarbonylamino-benzyloxy- or diphenylamycarbonyl-methoxycarbonylamino-benzyloxy- or 3-Guanylureido, further sulfoamino or Tritylainino and Arylthioamino, for example 2-Nitrophenj ^T lthioaraino, arylsulfonylamino, for example 4-Methylphenylsulfonylaiaino, or. l-lower alkoxycarbonyl-prop-2 3'-lidenamino _J, for example 1-ethoxycarbonyl-2-propylideneamino, carboxy or carboxy in salt, for example alkali metal, such as sodium salt form, as well as protected carboxy, for example esterified carboxy, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, SuIfο or in salt form -, e.g. alkali metal, such as sodium salt form present SuIfo, as well as protected SuIfο, hydroxy, and protected hydroxy, such as acyloxy, e.g. a-polybranched lower

609836/0966. '

alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichlorathoxy ~ carbonyioxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, furthermore formyloxy, or O-lower alkylphosphono- or 0,0'-di-lower alkylphosphono or 0,0'-di-lower alkyl Methylphosphono or .0,0 ¹ --Dirne'thylphosphono, or denotes a 5-amino-5-carboxyvaleryl radical, in which the Am5.no and / or carboxy groups can also be protected and, for example, as acylamino, for example lower alkanoylamino, such as acetylamino Halo-lower alkanoylamino, such as dichloroacetylamino, benzoylamino or phthaloyl · · amino, or as an esterified carboxy, such as phenyl-lower alkoxycarbonyl, for example diphenyl methoxycarbonyl, are preferably present, m preferably being 1 when R is phenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl, and m is and is R, is different from hydrogen when R is phenyl, hydroxyphenyl, hydroxy-chlorophenyl, thienyl, furyl, isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, R _{1 is} water erstoff means R ^ for

Lower alkoxy, especially a-polyverzweigtes lower alkoxy, for example tert-butyloxy, 2-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-bromoethoxy Jodäthox3 ⁷ barren _2-y or optionally substituted, for example lower alkoxy, for example methoxy, substituted diphenylmethoxy , e.g. Diphenylmethoxy or 4,4 ^f -Dimethoxydiphenylmethoxy or p-Kitrobensylo; i; y, fe'_T, er Triniederalkyl-

B.n9H3B / Q96 6

silyloxy, for example tri-methylsiloxy, and R ₃ stands in particular for Wasserfitoff or also for lower alkyl, in particular methyl or salts of such compounds.

Primarily stands in 3-cephem compounds of the formula I, as well as in salts of such compounds

lo for the acyl radical of the formula B, in which R is phenyl, I " ^a

and also hydroxyphenyl , for example 4-hydroxyphenyl, thienyl, for example 2- or 3-thienyl, 4-isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, X oxygen, m O or 1, and R hydrogen or, if m O represents, amino, as well as protected amino, such as acylamino, e.g. a-polybranched Niederalkcxy-

carbonylriirj.no, such as tert. -Butyloxycarbonylamino, or 2-halogen-lower alkoxycarbonylamino, for example 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino, or optionally lower alkoxy or nitro-substituted · tes, such as phenyl-lower alkoxycarbonylainylamino, such as phenyl-lower alkoxycarbonylainylamino, such as phenyl-lower alkoxycarbonylainylamino, e.g. , for example a-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbo ^ 'loxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-tric.hloräthoxycarbonylox} ^, 2-iodoethoxycarbonyl- oxy or 2-bromoethoxycarbonyloxy, or for formyloxy a 5-amino-5-carboxy-valeryl radical, V7orin, the amino and carboxy group can also be protected and, for example, as acylamino, e.g. lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, benzoylamino, or phthaloylamino, or as esterified carboxy like 'phenyl-

B Π c \ 8 3 6/0 9 6 6

lower alkoxycarbonyl, for example diphenylinethoxycarbonyl, vo.viegen, v? obei preferably denotes m 1 when R 1 is phenyl or hydroxyphenyl, Pv ₁ is hydrogen, HV ₁ bedc-utei; α-polybranched lower alkoxy, for example tert-butyloxy, or 2-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally substituted by lower alkoxy, x ^ ie mothoxy, diphenylmethyloxy, e.g. Diphenylmethoxy or 4,4'-dimethoxydiphenylmetboxy, or prNitrobonzyloxy, also tri-lower alkylsilyloxy, eg tri-ethylsilylox) "and R" means hydrogen or methyl.

The invention relates primarily to the production of 7ß ~ (D "OC" tert. -Butylcarbonylamino-a-R -acetylamino) -

s.

3-atnino-3-: cephem-4-carboric acid esters, in which R is phenyl,

4-hydroxyphenyl, 2-thienyl, 1,4-cyclohexadienyl or 1-cyclohexenyl and the ester group in the 4-position is the diphenylmethyl ", p-nitrobenzyl or 2,2,2-trichloroethyl ester group represents.

The 7β-amino-3-amino-3-cephem-4-carboxylic acid compounds which can be prepared according to the invention of the formula I are known in part (J.C.S. Chem. Comm. 1974, p.1012), or can analogously the known synthesis. Starting, for example, from the known 2-thienyl-acetamido-3-formyl-2-cephem-4-carboxylic acid dipheiiylmethyl ester, but at least six reaction stages are necessary to get to the corresponding 3-amino-

l; 0 0 836/0966

3-cephem-4-carboxylic acid ester. A shorter procedure which starts from cheaper and easily accessible starting materials and proceeds with good yields, is therefore desirable.

A new process has now been found which, starting from known 3-hydroxy-3-cephein-4-carboxylic acid compounds, 3-Auino-3-cephem-4-carboxylic acid compounds of formula I in an advantageous manner in a single reaction stage.

The new process for the preparation of 3-amino-3-cephem-4-carboxylic acid compounds of the formula I is characterized in that a 7j3-Aüiino-3-hydroxy-3-cephem-4-carboxylic acid compound the formula

AbA

in which R 1, R 1 and R "have the meaning given under formula I in Presence of a tertiary aromatic amine with a salt of an amine of the formula ILNR ", in which R ~ is mentioned under formula I. Has meaning, implements ..

Suitable salts of amines of the formula H ^ NR «are for example of organic acids, such as given

609 0 36/0966

optionally substituted aliphatic, cycloaliphatic !! or aromatic carboxylic or sulfonic acids, v; ie lower alkanecarboxylic acids, e.g. acetic acid, cycloalkanecarboxylic acids, such as cyclo-

hexanecarboxylic acid, benzoic acid, Niederalkansulfonsi-'uren, v.-ie Methanesulphonic acid, aryl, such as benzene or p-toluenesulphonous acid, or Of inorganic acids, especially mineral acids such as sulfur or phosphorus-containing oxygen acids, e.g. Sulfuric or phosphoric acid, or especially of hydrohalogen acids, such as hydrogen fluoride, hydrogen chloride or Hydrobromic acid derived.

Preferred acid addition salts of amines of the formula H ^ RR «are their hydrohalides, such as fluorides, bromides or -iodides and especially the hydrochlorides.

Suitable tertiary aromatic amines are, for example monocyclic or bicyclic and contain 1 to 3 tertiary ring nitrogen atoms. -Highlight are optionally substituted, such as by lower alkyl, e.g., methyl, halogen, e.g. Chlorine, or lower alkoxy, e.g. methoxy, or aryl, such as phenyl, mono-, di- or polysubstituted pyridine, e.g. 2-, 3- or 4-picoline, 2,3-, 2,4- or 2,6-lutidine, collidine, 2-, 3- or 4-chloropyridine, 2- or 4-methoxypyridine, 2- or 4-phenylpyridine, or preferably unsubstituted pyridine, also optionally substituted pyrazine, pyrimidine, pyridazine, quinoline, isoquinoline or quinoxaline as indicated.

P. Π μ P 3 R / 0 9 B R

The acid addition salts of amines from Fcrir.eL ItL! \ R " are in at least equimolar amounts, preferably iia lieberschuss, i.e. in about 2 to 10 times the molar amounts. The tertiary aromatic amine present in the reaction is also used in at least equimolar amounts, but preferably in excess, about 2 to 10 times molar or even larger Excess used.

The reaction is carried out in a suitable organic Solvent carried out.

Suitable inert organic solvents are, for example, aliphatic, cycloaliphatic or aromatic Alcohols such as lower alkanols, e.g. methanol, ethanol, cyclohexanol or phenol, polyhydroxy compounds such as polyhydroxy alkanes, e.g. dihydroxy lower alkanes, such as ethylene ~ or Propylene glycol, carboxylic acid esters, e.g. lower carboxylic acid lower alkyl esters, such as ethyl acetate, ethereal solvents such as dioxane, tetrahydrofuran or polyethers such as dimethoxyethane, lower carboxamides, such as dimethylformamide, lower alkyl nitriles, such as acetonitrile or lower sulfoxides such as dimethyl sulfoxide, or the tertiary aromatic amines mentioned, such as pyridine, or mixtures thereof, with at room temperature or elevated temperature, e.g. between about 20 and about 100 ° C, preferably between about 30 and 60 ° C, and if desired in an inert gas such as nitrogen atmosphere is used.

Γ. Π ^r i B 3 6/0 9 6 ß

In a preferred Ausführungsforrn r.an provides compounds of formula I here, wherein R "is hydrogen, by reacting a compound of formula II with Anshoniumchlorid, is heated in the presence of pyridine, in a lower alkanol such as ethanol at about 50 ° C to. ■

The e "_" i.inaungsger;: * - '"ssen establishable connections of formula I, and salts of such compounds with Salt-forming groups can be used, for example, to connect 7β-amino-3-acylamino-3-cephem-4-carboxylic acid compounds formula

. ο =

-NO,

(in)

to manufacture j

a j *

wherein R _{1 is} hydrogen or an acyl group R. ", where

Away
R ₁ , R, and R have the meanings given under formula I, R ″ stands for hydroxy or for a group R ₂ mentioned under formula I and R 1 stands for an acyl group. Compounds of the formula III are obtained by mixing a 7β-amino-3-amino-3-cephem-4-carboxylic acid compound of the formula I with an acid of the formula HO-R., (IV) or an amide-forming,

f; 0 ^c ! fl 36/0966

2 6 U 6 1 9 2

acylated reactive derivative thereof, and if desired, in a compound obtained, a protected carboxyl group -CC = O) -Rl is converted into a free carboxyl group,

and / or, if desired, 5 within the definition of the end substances a compound obtained is converted into another compound, and / or, if desired, a compound obtained with a salt-forming group into a salt or a preserved one Salt converted into the free compound or into another salt, and / or, if desired, a mixture obtained from Separates inner compounds into the individual isomers.

An acyl group R, k; mn as Ac has the same meaning

A A

as have the acyl group R ₁ , where R, and R, can be the same or different, or also for an aminothiocarbonyl group which is optionally monosubstituted or disubstituted by an aliphatic, cycloaliphatic or aromatic hydrocarbon radical or for an equally monosubstituted hydroxyl or mercaptothiocarbonyl group stand.

For example, R can be an acyl group of

Formula (A), in particular a lower alkanoyl group, such as the acetyl group.

Aliphatic substituents of the amino, hydroxy or Mercaptothiocarbonyl groups R are, for example, optionally substituted lower alkyl radicals with, for example, up to 7, preferred up to 4 carbon atoms represented by lower alkoxy such as

609836/0966

2BÜ6 1 92

Methoxy, halogen such as chlorine, aryl such as phenyl, or by lower alkoxy, such as methoxy, halogen, such as chlorine, or nitro or Polysubstituted phenyl, containing heterocyclic radicals, such as in particular nitrogen, oxygen and / or sulfur heteroaromatic residues, e.g. pyridyl, furyl or thienyl, or can be mono-, di- or polysubstituted by cycloaliphatic radicals such as cyclohexyl.

Cycloaliphatic substituents of the amino, hydroxy or mercaptothiocarbonyl groups R ^ are, for example, cycloalkyl with up to e.g. 12, such as 3-8, preferably 5 or 6 ring carbon atoms, which radicals are, for example, by lower alkyl, such as methyl, lower alkoxy, such as methoxy or halogen, such as chlorine, can be substituted.

Aromatic substituents of the amino, hydroxy or Mercaptothiocarbonyl groups R are, for example, phenyl or by lower alkyl, such as methyl, lower alkoxy, such as methoxy, halogen, such as chlorine or nitro mono-, di- or polysubstituted phenyl.

If a free acid of the formula IV is preferred

with protected, optionally present functional groups , V7ie an optionally present amino group, is used for the acylation, one usually uses suitable condensing agents, such as carbodiimides, for example N, N'-di-

π η ~? n π / Q 9 Π β

ethyl-, Ν, Ν'-dipropyl-, N, N ¹ -diisopropyl-, N ₅ N'-dicyclohexyl- or N-ethyl-N ¹ -S-diirietlrylaminopropyl-carbodiimide, suitable carbony compounds, for example carbonyldiinidazole, or isoxazolinium salts, for example N-ethyl-5-phenylisoxazoliniuni-S '-sulforiat and N-tert. -Butyl-5-methyl-iscxazolinium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The condensation reaction is preferably carried out in one of the anhydrous reaction media mentioned further below, for example in methylene chloride or dimethylformamide or acetonitrile.

A z'Unid-forming, functional derivative of an acid, preferably with protected functional if any Groups, such as an optionally present amino group primarily an anhydride of such acid, including, and preferably, a mixed anhydride. Mixed anhydrides are e.g. those with inorganic acids, especially with hydrohalic acids, i.e. the corresponding acid halides, e.g. chlorides or bromides, also with hydrazoic acid, i.e. the corresponding acid azides, with a phosphoric acid, e.g. phosphoric acid or phosphorous acid, with a sulfurous acid, e.g. Sulfuric acid, or with hydrocyanic acid. More mixed Anhydrides are e.g. those with organic acids

B Π ^r JR? G / 0 9 ß ß

• ', - 2 6 Π 6 19 2

ren, such as organic carboxylic acids, as with optionally, e.g.

by halogen, such as fluorine or chlorine, substituted lower alkanecarboxylic acids, e.g. pivalic acid or trichloroacetic acid, or with half-esters, especially lower all-half-esters, the Carbonic acid, like your ethyl or isobutyl half ester of carbonic acid, or with organic, especially aliphatic or aromatic, sulfonic acids, e.g. p-toluenesulfonic acid.

Furthermore, internal anhydrides, such as ketenes, e.g. diketene, isocyanates (i.e. internal anhydrides of carbamic acid compounds) or internal anhydrides of carboxylic acid compounds with carboxy-substituted hydroxy or amino groups, such as mandelic acid-O-carboxanir ^ drid or that 'Use anhydride of 1-N-carboxyamino-cyclobexanecarboxylic acid. ...

Other acid derivatives suitable for reaction with the free amino group are activated esters, usually with protected, possibly existing functional Groups, such as esters with vinylogous alcohols (i.e. enols), such as vinylogous lower alkanols, or aryl esters, such as preferably e.g. by nitro or halogen, such as chlorine, substituted phenyl esters, e.g. pentachlorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl ester, heteroaromatic esters, such as benzotriazole esters, or diacylimino esters,. such as succinylimino or phthalylimino esters.

6 Π ^ 8 3 6/0 9 6 6

Further acylation derivatives are, for example, substituted ones Formimino derivatives such as substituted N, N-dimethylchloroforrairainoderivatives of acids, or N-substituted Ν, Ν-diacylamines, like an N, N-diacylated aniline.

The Acy Lie-tion with an acid derivative, such as a Anhydride, and especially with an acid halide, can be used in Presence of an acid binding agent, e.g. an organic base such as an organic amine e.g. tertiary amine, such as tri-lower alkylamine, e.g. triethylamine, or in particular N-methyl-NjN-di-isopropylamine, or N-N-di-lower alkyl-aniline, e.g. Ν, Ν-dimethylaniline, or a base of the pyridine type, e.g. pyridine, or organic metal compounds, especially alkali metal, such as lithium or sodium compounds, such as lower alkyl, e.g., butyl, or aryl, e.g. Phenyllithium, or alkali metal amines, such as lithium or Sodium di-lower alkyl, such as diisopropylamine, or an inorganic one Base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. sodium, potassium or calcium hydroxide, carbonate or bicarbonate, be performed.

The above acylation can be carried out in an aqueous or

preferably non-aqueous solvent or solvent mixture are made, for example in a carbon

609836/0966

acid amide, such as Ν, Ν-di-lower alkyl amide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. ketylene chloride, Carbon tetrachloride or chlorobenzene, a ketone, e.g. acetone, an ester, e.g. ethyl acetate, or a

Nitrile, for example acetonitrile, or mixtures thereof, and, if necessary, at a reduced or increased temperature, for example at about -20 ° to about 150 ° C, in particular at about 20 ° to about 80 ° C, and / or in an inert gas , e.g. nitrogen atmosphere. In the above N ~ acylation reactions. one can start from compounds of the formula I in which R ₂ ^ ie has the above meaning, and compounds with free carboxyl groups of the formula -C (= 0) -R ₉ , in which R _{9 is} hydroxy, also in the form of salts, for example Ammonium salts, such as with triethylamine, can be used; in the acylation product obtained, the protected carboxyl group can in a manner known per se, for example as described below, including by hydrolysis or alcohol

se, to be released.

60 Π 836/0966

An Acy! Group can also be introduced by one a compound of formula I wherein the 3-amino group a ylidene radical (which can be obtained, for example, by treating a compound of the formula I in which R ^ is hydrogen, with an aldehyde, such as an aliphatic, aromatic or araliphatic aldehyde) carries, e.g. according to the above Methods acylated, and the Acj'lierungsprodukt, preferably in neutral or weakly acidic medium, hydrolyzed.

An acyl group. also be introduced gradually. Thus, one can, for example, in a compound of formula I having a free 3-amino group, a halogen-lower alkanoyl, for example Brcmacetylgruppe, or for example by treatment with a Kohlensäuredihalogenid, such as phosgene, a halocarbonyl, for example chlorocarbonyl, and introduce a thus obtainable K- (Halo-lower alkanoyl) - or N- (halocarbonyl) -araino compound with suitable exchange reagents, such as HN-containing compounds, for example tetrazole, Thiov he bonds, -zB 2-mercapto-l-methyl-imidazole, or metal salts, for example Catalyst azide or alcohols, such as lower alkanols, for example tert-butanol, react and thus obtain substituted N-lower alkanoyl or N-hydroxycarbonylamino compounds.

γ; η - a 3 6/0 9 B β

The reaction of a free 3-amino group can also be carried out with thiophosgene analogously to that with phosgene. In both reactions, the corresponding isocyanates or isorhodanates can occur as intermediate products, which are obtained by treatment with suitable amines, alcohols or mercaptans in the corresponding urea, urethane, mercaptan carbonylamino, or thiourea, thiourethane, and mercaptothiocarbonylamine compounds the formula I can be converted.

Free functional parts can be used in both reactants Groups temporarily protected during the acylation reaction in a manner known per se and after Acylation can be released by methods known per se, e.g. as described above.

Obtained compounds of the formula HX, the

Suitable intermediates for the preparation of pharmacologically more active end products can be through various per se known additional measures "converted into such active end products will.

In the acylation process and any additional measures to be carried out, if necessary, Free functional groups not participating in the reaction in the starting materials or in the process compounds available, e.g., free amino groups, e.g.

0 Q 3 B 3 6/0 9 6 6

Acylating, tritylating or silylating, free hydroxyl or mercapto groups, e.g. by etherification or esterification, and free Carboxyl groups e.g. through esterification, including silylation, in temporarily protected in a manner known per se and in each case after the reaction has taken place, in a manner known per se, if Desired, individually or together, released V7erden. So can one preferably e.g. amino, hydroxy, carboxyl or phosphorus

From phono groups in an acyl radical R or R, for example in the form of acylamino, such as those mentioned above, e.g. 2,2,2-trichloroethoxycarbonylamino, 2-brornethoxycarbonylamino, 4-methoxybenzylcxycarbonylamino, diphenylmethoxycarbonylamino or tert- Butyloxycarbonylamino, of aryl or aryl-lower alkylthioamino, for example 2-nitrophenylthioamino, or arylsulfonylamino, for example 4-methylphenylsulfonylamino, or of 1 ^{-lower alkoxycarbon3 T} 1 "2-propylidene amino groups, or of acyloxy .-Butyloxycarbonyloxy, 2,2,2-trichlorethoxycarbonyloxy or 2-bromoethoxycarbonyloxy groups, or of esterified carboxy groups, such as the above, e.g. diphenylmethoxycarbonyl groups, or 0,0'-disubstituted phosphona, such as the above, e.g. 0, 0'-Diniederalkylphosphono-, for example 0,0'-dimethyl -phosphonogrupp en, protect and subsequently, optionally after conversion of the protective group, for example a 2-Brornäthoxycarbonylin a 2-iodo-ethoxycarbonyl group in an

609S36 / 0968

in a known manner and depending on the type of protective group, e.g. a 2,2,2-trichloroethoxycarbonylamino or 2-iodoethoxycarbonylamino group by treating with suitable reducing agents, v; *. e zinc in the presence of aqueous acetic acid, ei-ne Diphenylmethcxycarbonylamino- or tert. -Butyloxycarbonylarino group by treatment with formic or trifluoroacetic acid, an aryl or aryl lower alkylthioamino group by treatment with a nucleophilic reagent such as sulphurous acid, a Arylsulfonylamino group by means of electrolytic reduction, a 1-lower alkoxycarbonyl-2-propylidene amino group by treating with aqueous mineral acid, or a tert. -Butylox} '- carbonyloxy group by. Treatment with formic or triflucressetic acid, or a 2,2,2-trichloroethoxycarbonyloxy group by treatment with a chemical reducing agent such as zinc in the presence of aqueous acetic acid or a Diphenylmethoxyca.rbonylgruppe by treatment with formic or trifluoroacetic acid or by hydrogenolysis, or a 0,0'-disubstituted Cleavage of the phosphono group by treatment with an alkali metal halide, e.g., partially, if desired.

In an obtainable compound of the formula III with a protected, in particular esterified Carboxyl group of the formula -C (= 0) -R ^ can be used in

A known manner, e.g. 3. depending on the type of group R ^, in the free carboxyl group are converted. An esterified,

· / 096fi

- 63 -

■ 26Ü6192

e.g. by a lower alkyl radical, in particular methyl or Ethyl, or carboxyl group esterified by a benzyl radical, can be obtained by hydrolysis in a weakly basic medium, e.g. by treating with an aqueous solution of an alkali metal or Alkaline earth metal hydroxides or carbonates, e.g. sodium or Potassium hydroxide, preferably at a pH of about 9 to 10, and optionally in the presence of a lower alkanol, in converted to a free carboxyl group. One by a suitable 2-halo-lower alkyl or an A ^ lcarbonylmethylgruppe esterified carboxyl group can be obtained, for example, by treatment with a chemical reducing agent such as a metal, e.g. Zinc, or a reducing metal salt, such as a chromium-II-salt, ' e.g. chromium-II-chloride, usually in the presence a hydrogen-donating agent that works together with the. Metal can produce nascent hydrogen, like one Acid, primarily acetic and formic acid, or an alcohol, with water preferably added, one through an Arj'lcarbonylmethylgruppe esterified carboxyl group as well by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, an esterified by a suitable arylmethyl group Carboxyl group e.g. by irradiation, preferably with ultraviolet light, e.g. below 290 mu if the aryl methyl group e.g. if appropriate in 3-, 4- and / or

Π OB B36 / 0966

2606 Ί 92

5-position, for example benzyl radical substituted by lower alkoxy and / or nitro groups, or with longer-term ultraviolet light, e.g. above 290 nm, if the aryl-ethyl group is, for example, a benzyl radical substituted in 2-position by a nitro group, a by a suitably substituted methyl group, such as tert-butyl or diphenylmethyl, esterified carboxyl group, for example by treatment with a suitable acidic agent such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, an activated esterified carboxyl group, also a Carboxyl group present in anhydride form by hydrolysis, e.g. by treatment with an acidic or weakly basic aqueous agent, such as hydrochloric acid or aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer from pH about 7 to about 9, and a hydrogenolytically cleavable esterified carboxyl group by hydrogenolysis, e.g. by treatment with hydrogen i n the presence of a noble metal, e.g. palladium catalyst, are cleaved.

A carboxyl group protected by, for example, silylation or stannylation can be obtained in a conventional manner, e.g. Treat with water or an alcohol.

Obtained compounds of the formula II can

can be converted into other compounds of the formula III in a manner known per se.

609836/0966

In a received connection, e.g. an Air.ino-

Away
protecting group R, or R ,, in particular an easily cleavable acyl group, in a manner known per se, e.g. an α-polybranched lower alcohol: -: carbonyl group, such as tert. -Butyloxycarbonj ^r l, by treatment with trifluoroacetic acid and a 2-calogen-lower alkoxycarbonyl group, such as 2,2,2-trichloroethox} ⁷ carbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treatment with a suitable reducing metal or corresponding metal compound, e.g. zinc, or a chromium (II) compound, such as chloric or acetate, advantageously in the presence of a hydrogen-generating agent which noses together with the metal or the metal compound, preferably in the presence of hydrous acetic acid.

Furthermore, in a compound of the formula III obtained in which R "is different from hydrogen in particular, un'ü wherein a carboxyl group of the formula -C (= 0) -R " preferably one, e.g., by esterification, including by silylation, e.g., by reaction with a suitable organic Halosilicon or halotin IV compound, such as Trimethylchlorosilane or tri-n-butyltin chloride, protected

a b represents a carboxyl group, an acyl group R, or R, in which any free functional groups that may be present are slit by treating with an imide halide-forming agent Means, reaction of the imide halide formed with an alcohol and cleavage of the imino-Sfcher formed, be split off, with a protected, e.g. a

609836/0966

Protected by an organic silyl radical, carboxyl group can be released during the course of the reaction.

Imide balogenide forming agents in which halogen is bound to an electrophilic Zcntralatom, are mainly acid halides, such as acid broinides and especially acid chlorides, These are primarily acid halides of inorganic acids, especially of phosphorus-containing acids, vie phosphorus oxy-, phosphorus tri- and especially phosphorus pentahalides, e.g. phosphorus oxychloride, phosphorus trichloride, and primarily phosphorus pentachloride, also pyrocatechyl phosphorus trichloride.

The reaction with one of the imide halide-forming agents mentioned is usually in the presence of a suitable, in particular organic base, primarily a tertiary amine, for example a tertiary aliphatic mono- or diamine, such as a tri-lower alkyl amine, for example trimethyl, triethyl or Ν, Ν-diisopropyl-N-ethyl-amine, also an N, N, N ¹ , N ¹ -tetra-lower alkyl-lower alkylenediamine, for example Ν, Ν, Κ ¹ , N'-tetramethyl-1,5-pentylenediamine or Ν , Ν, Ν ', Ν ^1- tetramethyl-1,6-hexylenediamine, a mono or bicyclic mono- or diamine, such as an N-substituted, e.g. N-lower alkylated, alkylene, azaalkylene or oxaalkylene amine,

for example N-methylpiperidine or N-methylmorpholine, furthermore 2, 3, 4j 6, 7j 8-hexahydro ~ pyrrolo [1,2-a] pyrimidine (D! azabicyclo- nene; DBK), or a tertiary aromatic amine such as one Di-lower alkyl aniline, for example N ₅ N-dimethyl aniline, or primarily a tertiary heterocyclic, mono- or bicyclic base such as quinoline or isoquinoline, in particular pyridine, preferably in the presence of a solvent such as an optionally halogenated, for example chlorinated, aliphatic or aromatic hydrocarbon, such as methylene chloride, made. Approximately equiinolar amounts of the imide halide-forming agent and the base can be used; The latter can, however, also be present in excess or deficiency, for example in about 0.2 to about 1-fold amount or then in about up to 10-fold, in particular about 3 to 5-fold excess.

The reaction with the imide halide forming agent is preferably carried out under cooling, e.g. carried out from about -50 ° C to about + 10 ° C, but can also work at higher temperatures, e.g. up to about 75 ° C, if the stability of the starting materials and Allow products to have an elevated temperature.

The imide halide product that is commonly used further processed without isolation, is procedurally with an alcohol, preferably in the presence of one of the

G Π 9 8 3 6/0 9 6 p

2 6 CJ ß 1 9 2

above-mentioned bases, converted to the iminoether. Suitable alcohols are e.g. aliphatic and araliphatic alcohols in primarily optionally substituted, V7ie .halogenated, e.g. chlorinated, or containing additional hydroxyl groups, Lower alkanols, e.g. ethanol, propanol or butanol, in particular methanol, furthermore 2-halo-lower alkanols, e.g. 2,2,2-trichloroethanol or 2-bromoethanol, and optionally substituted phenyl lower alkanols, such as benzyl alcohol. Usually one uses an, e.g. up to about 100-fold, excess of the alcohol and works preferably with cooling, e.g. at temperatures from about -50 ° C to about 10 ° C.

The IminoMtherprodukt can advantageously without Isolation to be subjected to cleavage. The cleavage of the imino ether can be achieved by treatment with a suitable hydroxy compound, preferably by means of hydrolysis, furthermore by alcoholysis, the latter when using an excess of the alcohol can take place directly after the imino ether formation can be achieved. One preferably uses Water or an alcohol, especially a lower alkanol such as methanol, or an aqueous mixture of an organic Solvent such as an alcohol. You usually work in an acidic medium, e.g. at a pH of around 1 to about 5, which can be added, if necessary, by adding a

609836/0966

basic agent, such as an aqueous alkali metal hydrc.nycs, e.g. sodium or potassium hydroxide, or an acid, e.g. a mineral acid, or an organic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, trifluoroacetic acid or p-toluenesulfonic acid.

The three-stage process described above for splitting off an acyl group is advantageously carried out without isolating the irnide halide and imino ether intermediates, usually in the presence of an organic solvent which is inert towards the reactants, such as an optionally halogenated hydrocarbon, e.g. methylene chloride, and / or in an inert gas atmosphere such as a nitrogen atmosphere.

If the imide halide intermediate product obtainable by the above process is reacted with a salt, such as an alkali metal salt of a carboxylic acid, in particular a sterically hindered carboxylic acid, instead of an alcohol, a compound of the formula III is obtained in which both radicals R ₁ and R, Represent acyl groups. In a compound of the formula III, V7orin at- ~

away
de radicals R ₁ and R represent acyl groups, one of these groups, preferably the less sterically hindered one, for example by hydrolysis or aminolysis, can be selectively removed.

609336/0968

261) 6192

In a compound of the formula III, before in

Away

R and R ₁ together with the nitrogen atom represent a phthalimido group, this can be converted into the free amino group, for example by hydrazinolysis, ie when treating such a compound with hydrazine.

Certain acyl radicals R, an acylamino group in According to the invention available compounds, such as the S-Amino-S-carboxy-valeryl radical, in which carboxyl, e.g. by esterification, in particular by diphenylmethyl, and / or the amino group, e.g. by acylating, especially by an acyl. residue of an organic carboxylic acid, such as halo-lower alkanoyl, such as dichloroacetyl or phthaloyl, optionally protected, can also be treated with a nitrosating agent, like nitrosyl chloride (only if the amino group in the acyl residue is unprotected) with a carbocyclic arene diazonium salt, such as benzene diazonium chloride, or with a positive halogen donating agent, such as an N-halo-amide or -imide, e.g., N-bromosuccinimide, preferably in a suitable one Solvent or solvent mixture, such as formic acid, together with a nitro- or cyano-lower alkane and addition of the reaction product with a hydroxyl-containing agent such as Water or a lower alkanol, e.g. methanol, or, if im

A ·

5-Amino-5-carboxy-valeryl radical R, which substitutes the amino group and the carboxy group - e.g. is protected by esterification, and R, preferably represents an acyl radical, but also

Can mean hydrogen by letting it stand in an ir.erten Solvents such as dioxane or a halogenated aliphatic Hydrocarbon, e.g. methylene chloride, and, separ necessary to work up the free or monoacylated amino compound according to methods known per se, are split off. ". ·

A formula group, R, can also be created by treating with an acidic agent, e.g. p.Toluenesulfon- or Chlorwassor- - chemical acid, a weakly basic agent, e.g. diluted Ammonia, or a decarbonylating agent, e.g. tris (triphenylphosphine) rhodium chloride, split off vjerden.

A triarylmetbyl, such as the trityl group R, can 2 B. by treating with an acidic agent such as a mineral acid, e.g. hydrochloric acid In a compound of formula III, wherein

away

R? and R, represent hydrogen, one can use the free Amir.ogruppe Substitute according to methods known per se, primarily by treatment with acids, such as a carboxylic acid, or acylate reactive derivatives thereof.

If a free acid, preferably with protected, optionally present functional groups, vrie an optionally present amino group, is used for the acylation, suitable condensation agents, such as carbodiimides, for example K, N'-di-

609836/0966

BATH ORIGINAL

/ 6U6-192

ethyl-, N, N'-dipropyl-, N ₁ N ¹ -diisopropyl-, N, N ¹ -dicyclohexyl- or N-ethyl-N ¹ -S-dimethylaminopropyl-carbodiimide, suitable carbony compounds, for example carbonyldiireidazole, or isoxazolinium salts , for example N-ethyl-5-phenylisoxazolinium-3 ^! sulfonate and N-tert-butyl-5-methyl-isoxazolinium perchlorate, or a suitable acylamino compound, ζ .B. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline.

The condensation reaction is preferably carried out in one of the anhydrous reaction media mentioned below, for example in methylene chloride or dimethylformamide or acetonitrile.

An amide-forming, functional derivative of an acid, preferably with protected optionally present Groups, such as an optionally present amino group, is primarily an anhydride of such an acid, including and preferably, a mixed anhydride. Mixed anhydrides are, for example. those with inorganic acids, in particular with hydrohalic acids, i.e. the corresponding acid halides, e.g. chlorides or bromides, also with hydrazoic acid, i.e. the corresponding acid azides, with a phosphoric acid, e.g. phosphoric acid or phosphorous acid, with a sulphurous acid, e.g. sulfuric acid, or with hydrocyanic acid. More mixed Anhydrides are, for example, those with organic acids

r η ο ο Q κ / η Q R p.

BATH ORIGINAL

26U6

ren, such as organic carboxylic acids, as with optionally, e.g. lower alkanecarboxylic acids substituted by halogen, such as fluorine or chlorine, e.g. pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl half-esters, of carbonic acid, such as the ethyl or isobutyl half-ester of carbonic acid, or with organic, especially aliphatic or aromatic, sulfonic acids, e.g. p-toluenesulfonic acid.

Furthermore, internal anhydrides can be used as acylating agents, such as ketenes, e.g. diketene, isocyanates (i.e. internal anhydrides of carbamic acid compounds) or internal anhydrides

. of carboxylic acid compounds with carboxy-substituted hydroxyl or amino groups, such as mandelic acid-O-carboxanhydride or that Use anhydride of 1-component carboxyamino-cyclohexanecarboxylic acid.

Further acid derivatives suitable for reaction with the free amino group are activated esters, usually with protected, possibly existing functional

-Gruppen, Xv ¹ Ie esters mit- vinylogous alcohols (ie enols), such as vinylogous lower alkanols, or aryl esters, such as preferably, for example by nitro or halogen, such as chlorine, substituted phenyl esters, for example pentachlorophenyl, 4-nitrophenyl or 2,4 -Dinitropheni ^ lester, heteroaromatic esters, such as benzotriazol esters, or diacylimino esters, such as succinylimino or phthalylimino esters.

Further acylation derivatives are e.g. substituted formimino derivatives, such as substituted N, N-dimethylchloro- £ ormimino derivatives of acids, or N-substituted Ν, Ν-diacylamines, like an N, N-diacylated aniline.

Acylation with an acid derivative such as a Anhydride and in particular with an acid halide, in the presence of an acid-binding agent, for example one organic base, such as an organic amine, e.g. a tertiary amine, such as tri-lower alkylamine, e.g. triethylamine, Ν, Ν-di-lower alkyl-aniline, e.g. Ν, Ν-dimethylaniline, or one Base of the pyridine type, e.g. pyridine, an inorganic base, e.g. an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2-alkylene oxide such as Ethylene oxide or propylene oxide are carried out.

The above Ac3'lation can be in an aqueous or preferably non-aqueous solvent or solvent mixture be made, for example in a carboxamide, such as Ν, Ν-di-lower alkylamide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. methylene chloride, Carbon tetrachloride or chlorobenzene, a ketone, e.g. Acetone, an ester, e.g. ethyl acetate, or a

Π Π ° H 3 ß / 0 9 ß 6

-SC-

Nitrile, e.g. acetonitrile, or mixtures thereof, and, if necessary in the case of reduced or increased temperature and / or in an inert gas, e.g. nitrogen atmosphere.

In the above N-acylation reactions, it is possible to start from compounds of the formula III, in which R _{9 has} the above meaning, compounds with free carboxyl groups of the formula -CC = O) -R ₂ in which R _{2 is} hydroxy, also in the form of salts, for example ammonium salts, such as with triethyiamine, or in the form of a compound with a, by reaction with a suitable organic phosphorus halide compound, such as with a lower alkyl or lower alkoxy phosphorus dihalide, such as methylphosphorus dichloride, etherealphosphorus dibromide - or methoxyphosphorus dichloride, protected carboxyl group can be used; in the acylation product obtained, the protected carboxyl group can in a manner known per se, 2.B. as described above, including by hydrolysis or alcohol se, are released.

An acyl group can also be introduced in the following:

a - b a compound of the formula III, in which R and R ..

together for a ylid residue (which can also be added later, e.g.

1 b through. Treating a compound wherein Rt and R, hydrogen represents, with an aldehyde, such as an aliphatic, aro ~ a-

G I \. B 3 6/0 0 δ 6

26Ü6I92

table or araliphatic aldehyde) stands, e.g. acylated by the methods given above, and that Acylation product, preferably in a neutral or weakly acidic medium, hydrolyzed.

In doing so, an acyl group lean η also gradually introduced will. For example, in a compound of the formula III with a free amino group, a halogen-lower alkanoyl, e.g. bromoacetyl group, or e.g. by treatment with a carbonic acid dihalide, such as phosgene, an Ilalogencarbonyl-, e.g. chlorocarbonyl group, and a thus obtainable N- (halo-lower alkanoyl) - or N- (ilalogencarbonyl) -amino compound with suitable exchange reagents, such as basic compounds, e.g. tetrazole, thio compounds ", e.g. 2-mercapto-1-raethyl-imidazole, or metal salts, e.g. Sodium azide or alcohols, such as lower alkanols, e.g. tert-butanol, convert and so to substituted N-lower alkanoyl or N-hydroxycarbonylamino compounds arrive.

In both reactants, free functional groups can temporarily be found during the acylation reaction be protected in a manner known per se and after the acylation by methods known per se, e.g. as above described, are released.

600836/0966

The acylation can also by replacement of an already existing acyl group by another, vorzr-gs ^r;. Else sterically hindered acyl group, effected for example by thy method described above, by preparing the Iinidhalogenidverhindung, these are treated with a salt of an acid and one of the acyl groups present in the product obtainable in this way, usually the veniger sterically hindered acyl group, hydrolytically split off.

Furthermore, for example, a compound of the formula UI in which R ^ is substituted, preferably in the α-position. te Glycyl group, such as phenylglycyl, and II, represent hydrogen, with an aldehyde, e.g. formaldehyde, or a ketone, such as lower alkanone, e.g. acetone, to form compounds of formula I, wherein R and It ^ together with one nitrogen atom, preferably in the 4-position substituted, optionally substituted in the 2-position Represent 5-oxo-1,3-diaza-cyclopentyl radical.

In a preserved compound with an esterified !! Grouping of the formula -C (= 0) -R ₂ , this can be converted into another esterified carboxy group of this formula, for example 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment with an iodine salt such as sodium iodide in the presence of a suitable solvent such as acetone , in 2-iodoethoxycarbonyl.

609836 / $ 096

. Mixed anhydrides can be made by a compound of the formula III with a free carboxyl group of the formula -CC = O) -Rp, preferably a salt, especially an alkali metal, ζ.B. Sodium, or ammonium, e.g. triethylammonium salt thereof, with a reactive Derivative, such as a halide, e.g. the chloride, an acid, e.g. a haloformic acid lower alkyl ester or a Niederalkanecharbonsäurechlorid, converts.

In a compound obtainable according to the process with a free carboxyl group of the formula -C (= 0) -R ₉ , such a group can also be converted into an optionally substituted carbamoyl or hydrazinocarbonyl group, preferably reactive, functionally modified derivatives, such as the above-mentioned acid halides, in general Reacts esters, as well as the above-mentioned activated esters, or mixed anhydrides of the corresponding acid with ammonia or amines, including hydroxylamine, or hydrazines.

One through an organic silyl or stannyl group Protected carboxyl group can be formed in a manner known per se, e.g. by adding compounds of the formula I, where R «is hydroxy, or salts, such as alkali metal, e.g., sodium salts thereof, with a suitable silylating or stannylating agent such as any of the above Treated silylating or stannylating agents; please refer

603836/0966

e.g. British patent Mr. 1.073.530 or Dutch exposition No. 67/17107.

Furthermore, modified functional substituents in groups R ,, R ,, R ,,, R ~ and / or R ,, such as substituted amino groups, acylated hydroxyl groups, esterified carboxy groups or O ₃ O'-disubstituted phosphono groups, according to methods known per se, for example the above described, release,

A b or free functional substituents in groups R- ,, R ,, R ", R ^ and / or R ,, such as free amino, hydroxy, "carboxy or phosphono groups, according to processes known per se, e.g. acylation or Esterification or substitution, functional modification. For example, an amino group can be treated with sulfur trioxide, preferably in the form of a complex with an organic base such as a tri-lower alkylamine, e.g., triethylamine, into a Convert suIfoamino group. Furthermore, you can use the reaction mixture, obtained by reacting an acid addition salt of 4-guanylsemicarbazide with sodium nitrate with a compound of the formula III, in which, for example, the amino protective group R represents an optionally substituted glycy group, convert and so d. convert the amino into a 3-guanylureido group. Compounds with aliphatically bonded halogen, for example with an optionally substituted halogen, can also be used a-bromoacetyl grouping, with esters of phosphorous acid, such as Tri-lower alkyl phosphite compounds, convert and thus arrive at the corresponding phosphono compounds.

ßOP336 / 0966

Salts of compounds of the formula III can produced in a manner known per se. So you can Salts of such compounds with acidic groups z.3. by treating with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. the sodium salt of a-ethylcaproic acid, or with ammonia or a suitable organic amine, preferably stoichiometric Quantities or only a small excess of the salt-forming agent used. Acid addition salts of compounds of the Formula III with basic groups is obtained in conventionally, for example by treatment with an acid or a suitable anion exchange reagent. Internal salts of. Compounds of the formula III which contain a salt-forming amino group and a free carboxyl group can e.g. by neutralizing salts, such as acid addition salts, on the isoelectric point, e.g. with weak bases, or are formed by treatment with liquid ion exchangers.

Salts can be added to the free compounds in the usual way be converted, metal and ammonium salts e.g. by treating with suitable acids, and acid addition salts, for example by treating with a suitable basic agent.

Mixtures of isomers obtained can after per se

R Π H R 3 6/0 9 6 6

known methods, separated into the individual isomers, Mixtures of diastereoisomeric isomers e.g. by fractionated Crystallization, adsorption chromatography (column or thin-layer chromatography) or other suitable separation processes. Racemates obtained can, if appropriate, in a customary manner after the introduction of suitable salt-forming groups, e.g. by forming a mixture of cLiastereomers. SaIsen with optically active salt-forming agents, separating the mixture into the diastereomeric salts and converting the salts into the free compounds or by fractional crystallization from optically active solvents into which antipodes are separated.

Such starting materials are preferably used and the reaction conditions chosen so that one of the initially Compounds listed as particularly preferred arrives.

The compounds of the formula III x ^ iron are valuable pharmacological properties or can be used as intermediates for the preparation of such. links of the formula III, in which, for example, R. for one in pharmacologically effective N-acyl derivatives of 6β-amino-penam-3-carboxylic acid or 7β-amino-3-cephem-4-carboxylic acid compounds occurring

b a

Acyl radical Ac and R .. is hydrogen, or in which R-, and R., together one in the 2-position preferably, e.g. by one aromatic or heterocyclic radical, and preferably in the 4-position, e.g. by 2 lower

609836/0966

alkyl, such as methyl, substituted l-oxo-3-aza-1,4-butylene radical represent R ~ hydroxyl or a combination of the carbonyl group an etherified hydroxyl group which forms an esterified carboxyl group which is easily split under physiological conditions R ~ means, R ~ for hydrogen or an optionally substituted aliphatic or cycloaliphatic !! Hydrocarbon residue and R, stands for an acyl group, where in an Ac3'l radical R-, optionally present functional groups, such as amino, carboxy, hydroxy and / or SuIfο, usually in present in free form, or salts of such compounds with salt-forming Grujjpen, sim.1 for example in vitro against microorganisms, such as gram-positive bacteria, e.g. Staphylococcus aureus or resistant staphylococci, effective at concentrations of about 1-5 mcg / ml, as shown to inhibit the growth of such Can detect microorganisms in the standard disk and plate test.

In vivo, for example with subcutaneous application to the mouse, an antibacterial effect against staphylococci is shown, such as Staphylococcus aureus, in doses of about 35 to 55 mg / kg.

These compounds can therefore, for example, in the form of antibiotic preparations, for the treatment of corresponding Infections are used.

Because of their antibiotic activity, 7ß ~ (D-oc-phenylglycylamino) -3-acetylamino -3-cephem-4-carboxylic acid are particularly useful
and also the 7ß- (D-or- phenylglycylamino) -3-phenyl-

6 0 9836/0966

acetylamino-4-cephem-4-carboxylic acid should be mentioned.

Compounds of the formula III in which the radicals R, and R "' stand for hydrogen, and R ", R" and R, which in the context n; it the formula. I have given meanings or where R .. a, of a pharmacologically active N-acyl derivative of 6/3 amino-penam-3-carboxylic acid or 7β-amino-3-cepheiu-4-carboxylic acid compounds occurring acyl residue different amino protective group and R, denote hydrogen, or R, and R- together one, of one in the 2-position preferably, e.g.

an aromatic or heterocyclic radical, and in the 4-position preferably! e.g. substituted by 2 lower alkyl such as methyl l-Oxo-3-aza-1,4-butylene radical, various divalent ones Represent amino protecting group, and R stands for hydroxy,

away
-or R, and R, have the meanings given above, R ^ represents a, together with the -C (= 0) grouping, a, preferably easily cleavable, protected carboxyl group-forming radical R, where a so protected carboxyl group is different from a physiologically cleavable carboxyl group, and R and R, the meanings given above, are valuable intermediates which can be converted into the above-mentioned pharmacologically active compounds in a simple manner, for example as just described.

ΠΠ9Β36 / 0966

The pharmacologically usable compounds of the formula III can be used, for example, for the production of pharmaceutical preparations, v? Elche a V7irl; yr..vc; Amount of active substance or in a mixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carrier substances which are suitable for enteral or preferably parenteral administration. For example, tablets or gelatine capsules are used which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, for example silica, talc, stearic acid or salts. thereof ,, such as magnesium or calcium stearate, and / or Polyäthylor.-glycol, have; Tablets also contain binders, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatine, tragacanth, methyl cellulose, sodium carboxy3 ⁷ methyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrating agents, e.g. starches, agar, • alginic acid or a salt thereof such as sodium alginate. and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Furthermore, the new pharmacologically active compounds can be used in the form of injectable, for example intravenously administrable, preparations or of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, it being possible for these to be prepared, for example, from lyophilized preparations which contain the active substance alone or together with a carrier material, for example mannitol, before use. the

609836/0966

Pharmaceutical preparations can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts to regulate the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable substances, are made in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing. process, manufactured and contain from about 0.1 ° L to 100%, in particular from about 1 % to about 50 %, lyophilisates up to 100% of the active ingredient. . . . ■

In connection with the present description, contain organic radicals designated by "lower", if not expressly defined, up to 7, preferably up to 4 carbon atoms; Acyl radicals contain up to 20, preferably up to 12 and primarily up to 7 carbon atoms. . · ■

The following examples are provided for illustration the invention; Temperatures are given in degrees Celsius. The cephem compounds mentioned in the examples have the R configuration in the 6- and 7-positions.

609836/0966

example 1

A solution of 10.0 g (16.2 mol) 7β- (Da-tert-butyl oxycarbonylamino-α-phenyl-ace.tylair.ino) -S-hydroxy-S-cepheni-A-carboxylic acid diphenyliriethyl ester in 250 ml absolute ethanol is stirred with 4.30 g (80 ml-iol) ammonium chloride and 10 ml (120 πϊΜοΙ) pyridine for 30 hours at 50 ° under nitrogen. Insolubles are filtered off, the filtrate is evaporated in vacuo and the residue is crystallized from methylene chloride-pentane. The 7β - (Da-tert-butyloxycarbonylamino-a-phenyl-acetylamino) -3-amino-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained in the form of colorless crystals from the srap. 135-138 °. [aJ ^ "+ 49 + 1 °

(c = 1.19: CHCl ₀ ); UV spectrum (C ₀ H ₁ .OH):> = 290 mu ^ = 12'50O)

ο i. D max

IR spectrum (CH ₂ Cl ₂ ): bands at 2.86; 2.92; 2.98; 5.63; 5.67 sh; 5.90 sh; 5.94; 6.18; 6.50; 6.68 ρ etc. ■

Example 2 - ..

A solution of 1.23 g of crude 7/3 (D-a-tert-butyloxycarbonylamino-a-phenylacetylamino) -3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester (-v 50%) in 25 ml of absolute ethanol is mixed with 202 mg of methylamine hydrochloride and 0.35 ml Pyridine warmed to 50 ° for 24 hours and then evaporated

RO 2 836/0966

Preparative layer chromatography of the residue yields the 7β- (Da-tert-butyloxycarbonylamino-a-phenyl-acetylamino) -3-methylamino-3-cephem-4-carboxylic acid-diphenylmethyl ester, which is obtained from methylene chloride / diethyl ether / hexane in the form of colorless crystals from the snip. 218-220 ° C crystallized, [α] = + 62 ° + 1 ° ( _c = 1.159; CIICl ₃ ) ί UV spectrum ( ^C ₂ ^H ₅ ^OH ) = ^ _mx ⁼ 307 mu (E. = 14'10O) ; mp (c = 3500); IR spectrum (CH ₂ CL ₂ ): bands at 2.93; 3.03; 5.64 sh; - 5.69; 5.83; '5.91;6.02;6.24; 6.70 u.

Example 3

A solution of 485 mg (ImMoI) 7ß-phenoxyacetylamino -3-hydroxy-3-cephem-4-carboxylic acid p ~ nitrobenzyl ester in 8 ml absolute ethanol is mixed with 212 mg (4.0 mKol) ammonium chloride and 0.48 ml (λ / 6mMol) Pyridine was stirred for 30 hours at 50 ° under nitrogen. The solubles are filtered off, the filtrate is taken up in methylene chloride, washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is crystallized from methylene chloride and gives the 7β-phenoxyacetylamino -3-amino-3-cephem-4-carboxylic acid p-nitrobenzyl ester; Melting point 205 ° (decomposition) j UV spectrum (C _? H 0H): Xmax = 287 ima (£ = 17,200) j shoulder at 277 mu

609836/0966

(ε = 167ΟΟ); IR spectrum $ ujol): bands at 2.92; 3.00; 5.72; 5.92; 5.99; 6.19; 6.57 ^; Rf value 0.24 (silica gel; toluene / Ethyl acetate 1: 1). The mother liquors can be prepared by preparative thick layer chromatography on silica gel with toluene / ethyl acetate 1: 1 further quantities of the substance can be obtained.

Example 4

The following compounds can be prepared analogously starting from appropriate starting materials will:

7 [beta] (2-thienyl) acetylamino) -3-amino-3-cephem-4-carboxylic acid diphenylmethyl ester;

7p- (2-Phenylacetylamino) -3-amino-3-cephem-4-carboxylic acid diphenylethyl ester;

7 β - (4-hydroxy p "j any la ce ty! Amino - 3-amino-3-cephem-4-carboxylic acid dipheny] methyl ester;

7β- [D-cx-tert. -Butyloxycarbonylarnino - «- (1,4-cyclohexadienyl) ^{-acet3 T} l amino] -3 -amino -3-cephem-4-carboxylic acid diphenylmethyl ester; 7β- [D-β-tert-butyloxycarbonylamino-a- (4-hydroxyphenyl) acetylamino] -S-amino-S-cephem ^ -carboxylic acid diphenylmethyl ester; 7β- [Da-tert-butyloxycarbonylamino-α- (2-thienyl) acetylamino] -3-amino-3-cephem-4-carboxylic acid diphenylmethyl ester; 7β- (D-α-Hydroxy-α-phenyl-acetylamino) -3-amino-3-cephem-4-carboxylic acid diphenylmethyl ester;
and the corresponding p-nitrobenzyl and 2,2,2-trichloroethyl esters and salts thereof.

609836/0966

. - 94 -

Example 5

A solution of 1.23 g (2.0 mmol) 7 / 3- [Da-tert. -Butyloxycarbonylamino-a-phenyl-acetyl amino) -3-amino-S-cephem-4-carboxylic acid diphenylmethyl ester in Λθ ml benzene is mixed with 0.57 ml (8.0 mmol) acetyl chloride and 0.C6 ml (5 mmol) ethyl diisopropylarain Warmed to 50 ° for 24 hours, then diluted with toluene and washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated in vacuo. Preparative layer chromatography of the crude product on four 100 mm silica gel plates (mobile phase: toluene / ethyl acetate 3: 1) yields the 7/3 [Da-tert-butyloxycarbonylamino-a-phenyl-acetylamino) -3-acetylamino-3-cephem -4-carboxylic acid diphenylmethyl ester, which crystallizes from methylene chloride-pentane in the form of colorless prisms; M.p. 150-152 ° C.

UV spectrum (C ₀ H ₀ OH):>. = 305 mu (E = 10 'SOO); IR spectrum A e- max J

): Bands at 2.91; x 3.05; 5.58; 5.82; 5.89; 5.20; 6.73 p.

The connection obtained can be further processed as follows: · - "

6nfl8'3R / nQfifi

a) A solution of 1.31 g (2.0 mmol) 7ß- (D-a-tert-butyloxycarbonylamino-ex-phenyl -acetylamino) -3-acetylamino -3 -cephem-4-carboxylic acid dipheiiylmethyl ester and 1.09 g (10 tuMol)

• Anisole in 6.5 ml of methylene chloride is stirred with 6.12 ml (80 roMol) of trioluoroacetic acid for 30 minutes in an ice bath, treated with 100 ml of cold toluene and evaporated in vacuo. The residue is digested with diethyl ether and the insoluble precipitate is filtered off The trifluoroacetate of 7β- (D-phenylglycylamino) -3-acetylamino-3-cephem-4-carboxylic acid is obtained % triethylamine in methanol adjusted to pH about A.5. By adding acetone a gelatinous precipitate is obtained, which is filtered off and washed thoroughly with acetone, methylene chloride and diethyl ether. Phenylglycylamino) -S-acetylamino-S-cephem-A-carboxylic acid ^ melts at

180 ° (decomposition). UV spectrum (O, H ₁ -OH) .: ^ _n : 290 mu

ζ. D max *

(6 = 10,200); IR spectrum (Nuj oil): bands at 5.65; 5.93; 6.20 ρ etc..

ti η ί »836/0966

Example 6

A solution of 1.23 g (1.95 mmol) of 7β- (D-oc-tert, -Butyloxycarbonylamino -a-phenylacetylamino) -3 -amino -3-cephein-4-carboxylic acid-diphen.ylmethylester in 40 ml of benzene is mixed with 1.06 ml ( 8.0 iriMöl) Phenylacetylcblorid and 0.86 ml (5.0 mmol.) ethyldiisopropylamine and stirred for 24 hours at 50 ⁰ C. The reaction mixture is diluted with toluene, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. After preparative silica gel layer chromatography, the residue gives the 7β- (D-cxtert. -Butyloxycarbonylamino-a-phenylacetylainino ^ -phenylacetylamino-4-carboxylic acid diphenylmethyl ester, which is recrystallized from methylene chloride / diethyl ether;

on

Melting point 128-130 ° C; [α] ^ ^υ = -28 ° + 1 ° (c = 0.920); UV spectrum (ethanol) .- A = 308 nm (S = 10200); IR spectrum (CH ₂ Cl): bands at 2.93; 3.07; 5.60: 5.80; 5.91; 6.21; 6.60; 6.68 u.

The connection obtained can be further processed as follows:

■ a) A solution of 1.06 g (1.45 mmol) of 7β- (D-cc-tert. -Butyloxycarbonylamino -a-phenylacetylamino) -3-phenylacetylamino -4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride, 0.79 ml (7.25 mmol) of anisole and 4.44 ml (58 mmol) of tri-

fi 0 ■■■ »8 3 β / 0 9 6 6

FluoroessigSciure stirred in an ice bath for 30 minutes, treated with 100 ml of cold toluene and evaporated in vacuo. The residue is digested with diethyl ether, the insoluble residue is washed with diethyl ether and dried in a high vacuum. The trifluoroacetate of 7β- (D-α-phenylglycylamino) -3-phenylacetylamino-3-cephem-4-carboxylic acid obtained is dissolved in approx. 20 ml of acetone / methanol / water 5: 2: 3 and filtered The pH of the filtrate is adjusted with a 10% solution of triethylamine in methanol to about 5. By adding acetone, a precipitate is obtained which is filtered off and dried in a high vacuum. phenylacetylami.no-4-cephem-4-carboxylic acid melts at about 170 ⁰ C under clogging: [ "L = + 61 ° + (c = 0.688; 0.1 N HCl) -UV spectrum (ethanol): λ = 292 mu

J III 3 X /

(£ = 11700), · IR spectrum (Nujol): bands at 2.90; 3.12; 5.64; 5.87; 6.16, U.

Example 7

Dry ampoule or vials containing 0.5 g of the inner salt of 7 / 3- (D-a-phenylglycyl-amino) -S-acetylamino ^ -cephem ^ - Carboxylic acids are produced as follows:

Composition (for 1 ampoule or vial)

Inner salt of 7ß- (Da-phenylglycyl-amino) -3-acetylamino-3-cephem-4-carboxylic acid 0.5 g

Mannitol · 0.05 g

609836/0966

93 -

A sterile aqueous solution of the inner salt of 7 / 3- (D-aphenylglycyl-amino) -3-axetylarcino-3-cephem-4-carboxylic acid and the mannitol is under aseptic conditions in a 5 ml ampoule, len or 5 ml.-ViaIs subjected to freeze-drying and the Ampoules or vials sealed and checked.

Example ο ....

Capsules containing 0.25 g of the inner salt of the

7 / 3- (D-a-phenyl-glycylamino) -3-acetylamino-3-cephem-4-carboxylic acid j are made as follows:

Put us together; (for 4000 capsules):

7ß- (Da-phenylglycyl-arxLno) -3-acetyl- inner salt

amino-3-cephern-4-carboxylic acid 250,000 g

Corn starch '50,000 g

Polyvinylpyrrolidone 15,000 g

Magnesium stearate 5,000 g

Ethanol q.s.

80.M 836/0966.

The inner salt of the 7 ß- (Da-phenyl-glycylamino) -3-acel: yLa :: ano-3-cephem-4-carboxylic acid and the corn starch are mixed and 'with a solution of the polyvinylpyrrolidone in 50 g of Aethar.ol moisturizes. The moist mass is printed through a sieve with a mesh size of 3 .mm and dried at 45 °. The dry granulate is driven through a sieve with a mesh size of 1 mm and mixed with 5 g of magnesium stearate. The mixture is filled into size 0 push-fit capsules in portions of 0.320 g.

6 09836/0966

Claims (21)

Patent claims: Process for the preparation of compounds of the formula NH-R, Away where R, represents an amino protecting group, and R, for water A ■ b material or an acyl group Ac, or R, and R "together represent a divalent amino protective group, R £ represents a radical which, together with the carbonyl group -C (= 0) - forms a protected carboxyl group, and R _{3 represents} hydrogen or an optionally substituted aliphatic or cycloaliphatic hydrocarbon radical, and salts of such compounds, characterized in that a 7β-amino-3-hydroxy-3-cephem-4-carboxylic acid compound of the formula (H) -OH 60 9 836/0966 wherein R-,, R. and R "have the meaning given under formula I, in the presence of a tertiary aromatic amine with a salt of an amine of the formula EUNRo, in which R ~ is mentioned under formula I. Has meaning, converts, and, if desired, a received one Compound converted into a salt or a salt obtained into the free compound. 2. The method according to claim 1, characterized in that compounds of the formula II are used as starting materials, wherein R, represents the acyl radical of an organic carboxylic acid having up to 18 carbon atoms and R, is hydrogen Away denotes, or in which R, and R-, together represent the divalent acyl radical an organic dicarboxylic acid with up to 18 carbon atoms or an organic ylidene radical with up to 18 represent carbon atoms and R ~ one through an organic Represents radical with up to 18 carbon atoms etherified hydroxyl group. 3. The method according to any one of claims 1 or 2, characterized in that compounds of the formula II as Starting materials used, in which R is a group of the formula R ¹¹ O 1 Il - (C) _n - C - (A) 6ΠΗ836 / 0966 2 6 O 6 Ί 9 2 represents where η is O and R. is hydrogen or optionally one substituted cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted one heterocyclic radical, preferably of aromatic character, a functionally modified, e.g. esterified or denotes etherified hydroxyl or mercapto or an optionally substituted amino group, or in which η denotes 1, R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic A radical in which the heterocyclic radical is preferably of aromatic character and / or a quaternary one Has nitrogen atom, an optionally functionally modified, preferably etherified or esterified hydroxy or mercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally represents substituted amino group or an azido group, and each of the radicals R and R is hydrogen, or \? orin η is 1, R is an optionally substituted one aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has an aromatic character 609836/0966 26Π6192 v? eist, R an optionally functionally modified, e.g. esterified or etherified hydroxyl or mercapto group, such as a halogen atom, an optionally substituted amino group, an optionally functionally modified carboxyl or sulfo group, an optionally O-mono- or 0,0'-disubstituted one Is phosphono group, or an azido group, and R is hydrogen, or where η is 1, any of R and R radicals are functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, TTT · ■ and R is hydrogen, or where η is 1, R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R and R together are an optionally substituted aliphatic, cycloaliphatic linked to the carbon atom by a double bond , cycloaliphatic-aliphatic or araliphatic hydrocarbon radical, or in which η is 1, and R ^{1 is} an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or a given fi Π η R 3 R / Π Π Β 6 if substituted heterocyclic or heterocyclic aliphatic A radical in which heterocyclic radicals preferably have an aromatic character, R an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R is hydrogen or optionally one substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical mean, R-. stands for hydrogen, or v7orin Away
R ₁ and R, together one preferably in the 2-position, for example by an aromatic or heterocyclic radical, such as phenyl, and preferably in the 4-position, for example by two lower alkyl, such as methyl, substituted l-0xo-3-aza-1, 4-butylene radical ■ A and R ~ for optionally in the α-position by optionally substituted aryloxy, lower alkanoyloxy, cc-amino-lower-alkanoyloxy, Arylcarbonyl, or optionally substituted aryl, or in the β-position by halogen, mono- or poly-substituted Lower alkoxy, bis-phenyloxy-methoxy which may be substituted by lower alkoxy, a-amino-lower alkanoyloxy-methoxy, Phenacyloxy, optionally substituted phenyl-lower alkoxy, such radicals 1-3 optionally, e.g. may contain phenyl radicals substituted by lower alkoxy, such as methoxy, nitro or phenyl, also for 2-phthalidyloxy, as well as for acyloxy, for tri-lower alkylsilyloxy, or for ? ■ · 0 - L * 3 6/0 9 6 6 optionally substituted by lower alkyl or hydroxy Amino or hydrazino. 4. The method according to any one of claims 1 to 3, characterized in that compounds of the formula II as Starting materials used in which R is an acyl group of the formula · O ^R a CX) _m CH C ^R b represents, wherein R is phenyl, hydroxyphenyl, hydroxy-chlorophenyl, where in such radicals hydroxy substituents can be slit through acyl radicals, as well as thienyl, pyridyl, aminopyridinium, Furyl, isothiazolyl, tetrazolyl, 1,4-cyclohexadienyl or 1-Cyclohexenyl is, X is oxygen or sulfur, ta stands for 0 or 1, and R, for hydrogen or, if m is 0, for amino, as well as protected amino, carboxy or protected carboxy, suIfο or protected suIfο, hydroxy, as well as protected hydroxy, or denotes a 5-amino-5-carboxyvaleryl radical, in which the amino and / or carboxy groups can also be protected, where preferably m is 1 when R is phenyl, hydroxyphenyl, hydroxychlorophenyl or Is pyridyl, and m is 0 and R, is different from hydrogen when R is phenyl, hydroxyphenyl, hydroxy-chloro 6 0 ^ 36/0966 phenyl, thienyl, furyl, isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, R-, is hydrogen, and R ~ for lower alkoxy, 2-halo-lower alkoxy, or optionally Diphenylmethoxy substituted by lower alkoxy or represents tri-lower alkylsilyloxy. 5. The method according to any one of claims 1-4, characterized in that starting materials of the formula II used, in which R- stands for the acyl radical of the formula B, wherein R is phenyl, hydroxyphenyl, thienyl, 4-isothiazolyl, 3. 1,4-cyclohexadienyl or 1-cyclohexenyl, X oxygen, in 0 or 1, and R, hydrogen or, when m represents 0, Amino, protected amino, hydroxy or protected hydroxy, where preferably _m_ is 1 when R is phenyl or hydroxyphenyl, or in which R- is a 5-amino-5-carboxy-valeryl radical stands in which the amino and carboxy group b - A can also be protected, R, represents hydrogen and R ^ α-polybranched lower alkoxy, 2-halo-lower alkoxy, optionally methoxy-substituted diphenylmethyloxy, or means p-nitrobenzyloxy. 6. The method according to any one of claims 1-5, characterized characterized in that 7β- (D-oc-tert--Butyloxy carbonylamino-a-phenyl-acetylamino) -3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester er ial used as the country of origin. 6 09836/0966 7. The method according to any one of claims 1-6, characterized in that a salt of an amine of the formula H ₂ NRo is used, wherein R ~ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl or cycloalkenyl, which radicals can optionally be substituted . 8. The method according to any one of claims 1-7, characterized in that a salt of an amine of the formula H ₂ NRo is used, wherein R ~ is hydrogen or methyl. 9. The method according to any one of claims 1-8, characterized in that the salt of an amine of the formula H ₂ NRo, the salt of a carboxylic, sulfonic or mineral acid is used. 10. The method according to any one of claims 1-9, characterized in that the salt of an amine of the formula H «NRo, a hydrohalide thereof is used. 11. The method according to any one of claims 1-10, characterized in that the salt of an amine of the formula H9NR0 using the hydrochloride thereof. 609836/0966 12. The method according to any one of claims 1-11, characterized characterized that one is called a tertiary aromatic amine optionally substituted pyridine, pyrazine, pyrituidine, Pyridazine, quinoline, isoquinoline or quinoxaline used. 13. The method according to any one of claims 1-12, characterized characterized in that pyridine is used as the tertiary aromatic amine. 14. The method according to any one of claims 1-13, characterized in that the reaction in a suitable organic solvent executes at room temperature or elevated temperature. 15. The method according to any one of claims 1-14, characterized characterized in that compounds of the formula I, wori.n R, the acyl radical of an organic carboxylic acid with up to 18 represents carbon atoms and R, represents hydrogen, Away
or in which R ₁ and R 1 together represent the divalent acyl radical of an organic dicarboxylic acid with up to 18 carbon atoms or an organic ylidene radical with up to 18 carbon atoms, R "represents a hydroxy group etherified by an organic radical with up to 18 carbon atoms and R" represents hydrogen or an aliphatic or : .- >, '■ i ύ I 0 9 6 6 Ί BOB 192 cycloaliphatic hydrocarbon radical with up to Represents 18 carbon atoms, or produces salts thereof, 16. The method according to any one of claims 1-14, characterized characterized in that compounds of the formula I in which R is a group of the formula R ¹¹ 0 R ¹ - (C) _n - C - (A) represents where η is 0 and R. is hydrogen or optionally one substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted one heterocyclic radical, preferably aromatic character. ters, a functionally modified, e.g. esterified or denotes etherified hydroxyl or mercapto or an optionally substituted amino group, or in which η denotes 1, R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic. A radical in which the heterocyclic radical is preferably of aromatic character and / or a quaternary one 6 09836/0966 Has nitrogen atom, an optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto group, optionally a functionally modified one Carboxyl group, an acyl group, an optional is substituted amino group or an azido group, and each of the radicals R 'and R "is hydrogen, or where η is 1, R is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic one or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has an aromatic character II
has, R an optionally functionally modified, eg esterified or etherified hydroxyl or mercapto group, such as a halogen atom, an optionally substituted amino group, an optionally functionally modified carboxyl or sulfo group, an optionally O-mono or 0, O ¹ -disubstituted phosphono group, or an azido group, and R ″ stands for hydrogen, or where η stands for 1, each of the radicals R and R stands for a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R stands for hydrogen, or where η stands for 1 R is hydrogen or an optionally substituted aliphatic, cycloalphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical 6 0 9 8 3 6/0966 26-6-92 TT TTT and R and R represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical connected by a double bond to the carbon atom, or where η stands for 1, and R an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclischaliphatic radical, in which heterocyclic radicals preferably have aromatic character, R an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical, and R is hydrogen or an optionally substituted aliphatic, cycloaliphatic -aliphatic, aromatic or araliphatic hydrocarbon radical, R _{1 is} hydrogen, or wor in Away
R ^ and R, together one preferably in the 2-position, for example by ei.nen aromatic or heterocyclic radical, such as phenyl, and preferably in the 4-position, for example by two lower alkyl, such as methyl, substituted l-oxo-3-aza- L, 4-butylene radical represent R2 for optionally substituted in the α-position by optionally substituted aryloxy, lower alkanoyloxy, a-amino-lower alkanoyloxy, arylcarbonyl, or optionally substituted aryl, or in the β-position by halogen, mono- or poly- '<ü / U G B B substituted lower alkoxy, optionally by lower alkoxy substituted bis-phenyloxy-methoxy, cc-amino-lower alkanoyloxy-methoxy, Phenacyloxy, optionally substituted phenyl-lower alkoxy, such radicals 1-3 optionally, e.g. substituted by lower alkoxy such as methoxy, nitro or phenyl May contain phenyl radicals, furthermore for 2-phthalidyl oxy, as well as for acyloxy, for tri-lower alkylsilyloxy, or for optionally substituted by lower alkyl or hydroxy Amino or Etydrazino and R "hydrogen, lower alkyl, Lower alkenyl, lower alkynyl, cycloalkyl or cycloalkenyl denotes which radicals can optionally be substituted or produces salts thereof. 17. The method according to any one of claims 1-14, characterized characterized in that compounds of the formula I in which R _{1 is} an acyl group of the formula -Q · ■ R _a . (X) _m CH C (B), represents where R _{& is} phenyl, hydroxyphenyl, hydroxy-chlorophenyl, where in such radicals hydroxy substituents can be protected by acyl radicals, as well as thienyl, pyridyl, aminopyridinium, furyl, isothiazolyl, tetrazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, X is oxygen or represents sulfur, m represents 0 or 1, and R _{fe represents} hydrogen or, when m -SiS / 0966 O represents, for amino, as well as protected amino, carboxy or protected carboxy, sulfo or protected sulfo, hydroxy, and protected hydroxy, or a 5-amino-5-carboxyvaleryl radical denotes in which the amino and / or carboxy groups can also be protected, where preferably m denotes 1, when R is phenyl, hydroxyphenyl, hydroxychlorophenyl or Is pyridyl, and m is 0 and R, is different from hydrogen, if R is phenyl, hydroxyphenyl, hydroxyl-chloro- σ. ^u phenyl, thienyl, furyl, isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, R, denotes hydrogen, and R2 is lower alkoxy, 2-halo-lower alkoxy, or optionally Diphenylmethoxy substituted by lower alkoxy or represents tri-lower alkylsilyloxy, and R " is hydrogen or methyl, or prepares salts thereof. 18. The method according to any one of claims 1-14, characterized in that compounds of the formula I, wherein R- represents the acyl radical of the formula B, wherein R is phenyl, hydroxyphenyl, thienyl, 4-isothiazolyl, el 1,4-cyclohexadienyl or 1-cyclohexenyl, X is oxygen, m is 0 or 1, and R is hydrogen or, if m is 0, Amino, protected amino, hydroxy or protected hydroxy, where preferably m is 1 when R is phenyl or hydroxyphenyl, or in which R is a 5-amino-5-carboxy-valeryl radical stands in which the amino and carboxy group b A can also be protected, R, represents hydrogen, R ₉ t, 0 H rf 3 6/0 9 6 6 α-polybranched lower alkoxy, 2-halo-lower alkoxy, optionally methoxy-substituted diphenylmethyloxy, or p-nitrobenzyloxy and R “is hydrogen or Is methyl, or prepares salts thereof. 19. The method according to any one of claims 1-14, characterized in that the 7ß- (D-cc-tert-butyloxycarbonylamino-α-phenyl-acetyl amino) -S-amino-S-cephem ^ -carboxylic acid diphenylmethyl ester manufactures. 20. The method according to any one of claims 1-14, characterized in, that the 7ß- (D-oc-tert. -Butyloxy carbonylamino -α-phenyl-acetylamino) -S-methylamino-S-cephem ^ -carboxylic acid diphenylmethyl ester manufactures. 21. The method according to any one of claims 1-14, characterized characterized in that the yβ-phenoxyacetylamino-B-amino-3-cephem-4-carboxylic acid p-nitrobenzyl ester manufactures. 609836/0966