DE2528044A1 - METHODOLOGICAL PROCESS FOR THE PRODUCTION OF METHYL DERIVATIVES - Google Patents

Description

CLBA-GEIGY AG. CH-4002 Basel

MA- C3C1C3Y

4-9480 / +

GERMANY

Methodological procedure for the production of methyl derivatives

The present invention relates to a methodological process for the production of methyl derivatives, especially of 7β-amino-3-methyl-3-cephem-4-carboxylic acid compounds the formula

- O

(IA).

R "

a A

wherein R, represents hydrogen or an aromatic protecting group R, and R, represents hydrogen or an acyl group Ac

away

^ and R- ^ together form a bivalent amino protection

stands, or

509882/0987

represent a group and R ~ for hydroxy or a, together with the carbonyl group —C (= O) - a radical R which forms a split carboxyl group, as well as 1-oxides of 3-cephem compounds of formula IA, and the corresponding 2-cephem compounds the formula

(IB)

wherein R ^, R ^ and R ^ have the meanings given above, or Salts of such compounds with salt-forming groups.

In 2-cephem compounds of the formula IB with the The double bond in a 2.3 division has the optionally slotted one Carboxyl group of the formula -C (O) -R ^ preferably the α-configuration. ".

A An amino protecting group R ₁ is a

Substance replaceable group, primarily an acyl group Ac, also a triarylmethyl, especially the trityl

£ 09882/0987

group, as well as an organic silyl, and an organic Stannyl group. A group Ac, which is also used for a remainder R ;? can stand, is primarily the acyl radical of a organic carboxylic acid, preferably with up to 18 carbon atoms, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic sh-aliphati see, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid (including formic acid), as well as the acyl radical of a carbonic acid half-derivative represent.

away
A divalent amino protective group formed by the radicals R! R and R ^ together is in particular the divalent acyl radical of an organic dicarboxylic acid, preferably with up to 18 carbon atoms, primarily the diacyl radical of an aliphatic or aromatic dicarboxylic acid, and also the acyl radical of an in ^ position preferably substituted, eg containing an aromatic or heterocyclic radical, o ^ -aminoacetic acid, in which the amino group is connected to the nitrogen radical via a, preferably substituted, eg two lower alkyl, such as methyl group-containing methylene radical

a b atom is connected. The radicals R ^ and R! R can also be used together an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably with up to 18 carbon atoms. - 4 -

509882/098?

- ⁴ - .25280AA

A protected carboxyl group of the formula -C (= 0) -R ₂ is primarily an esterified carboxyl group, but can also represent a usually mixed anhydride group or an optionally substituted carbamoyl or hydrazinocarbonyl group.

The group R ₂ can therefore be a hydroxyl group etherified by an organic radical, in which the organic radical preferably contains up to 18 carbon atoms, which together with the -C (= O) group forms an esterified carboxyl group. Such organic radicals are, for example, aliphatic, C3 ⁷ cloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic-aliphatic radicals.

The group R ₂ can also represent an organic silyloxy radical and a hydroxy 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

Carbon atoms, such as aliphatic hydrocarbon radicals, and optionally substituted by halogen, such as chlorine-substituted Silyloxy or stannyloxy group.

A with a -C (= 0) grouping is a primarily

mixed, anhydride group-forming radical R ₂ is for example

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Halogen, such as chlorine or an acyloxy radical, in which acyl is the corresponding Residue 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.

One with a -C (= 0) group forming a carbamoyl group Rp is an optionally substituted amino group, wherein substituents are optionally substituted monovalent or divalent 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 optionally functionally modified, in particular free, hydroxy etherified or esterified hydroxy, in which the etherifying or esterifying radicals, for example, have the meanings given above have and preferably contain up to 18 carbon atoms, and acyl radicals, primarily of organic carboxylic acids and carbonic acid half derivatives, preferably with up to 18 carbon atoms.

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In a substituted hydrazinocarbonyl group of the formula

A.
-CC = O) -R ₂ can be substituted for one or both nitrogen atoms

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 from organic carboxylic acids or of carbonic acid semi-derivatives, preferably with up to 18 carbon atoms, are possible.

Those used in the description above and below General terms have the following meanings, for example:

An aliphatic radical, including the aliphatic radical of a corresponding organic carboxylic acid, as well as a corresponding ylidene radical is an optionally substituted monovalent or divalent aliphatic hydrocarbon radical, in particular lower alkyl, as well as lower alkenyl or lower alkynyl, furthermore lower alkylidene, e.g. up to 7, can preferably contain up to 4 carbon atoms. Such radicals can optionally be replaced by functional groups, e.g.

- 7 5 0 §882 / 0907

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, heterocylylthio or heterocyclyl lower alkylthio, optionally substituted Lower alkoxycarbonyloxy or lower alkanoyloxy, or Halogen, furthermore by oxo, nitro, optionally substituted amino, e.g. lower alkylaraino, di-lower alkylamino, Lower alkylenamino, oxaniederalkylenaraino or aza loweralkylenamino and acylamino, such as lower alkanoylamino, lower alkoxycarbonylamino, halo-lower alkoxycarbonylamino, optionally substituted phenyl-lower alkoxycarbonylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylaraino, also optionally sulfoamino present in salt, such as alkali metal salt form, Azido, acyl, such as lower alkanoyl or benzoyl, optionally functionally modified carboxyl, such as present in salt form Carboxyl, esterified carboxyl such as lower alkoxycarbonyl, " optionally substituted carbamoyl, such as N-lower alkyl or Ν, Ν-di-lower alkylcarbamoyl, further optionally substituted ureidocarbonyl or guanidinocarbonyl, or Cyan, possibly functionally modified suIfο, such as Sulphamoyl or sulpho present in salt form, or optionally 0-mono- or 0, 0-disubstituted phosphono, wherein

509882/0987

Substituents e.g. optionally substituted lower alkyl, Represent phenyl or phenyl-lower alkyl, where O-unsubstituted or O-monosubstituted phosphono can also be present in salt form, such as alkali metal salt form, mono-, di- or be polysubstituted.

A divalent aliphatic radical, including the corresponding radical of a divalent aliphatic carboxylic acid, is e.g. Niederalkylen or Niederalkenylon, which optionally, e.g. as an aliphatic radical indicated above, mono-, di- or polysubstituted and / or by heteroatoms, such as Oxygen, nitrogen or sulfur can be interrupted.

A cycloaliphatic or cycloaliphatic-aliphatic Remainder, including the cycloaliphatic or cycloaliphatic-aliphatic Remainder in a corresponding organic carboxylic acid or a corresponding cycloaliphatic or cycloaliphatic Sch- aliphatic ylidene radical is an optional substituted, mono- or divalent cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, e.g. mono-, 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. contains up to 12, such as 3-8, preferably 3-6, ring carbon atoms, while cycloalkenyl e.g. contains up to

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25280U

to 12, such as 3-8, e.g. 5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds and the aliphatic part of a cycloaliphatic-aliphatic radical, e.g. up to 7, preferably up to 4, carbon atoms may contain. The above cycloaliphatic or cycloaliphatic-aliphatic Residues can, if desired, e.g. by optionally substituted aliphatic hydrocarbon radicals, as by the above-mentioned optionally substituted lower alkyl groups, or then, for example as those Above-mentioned aliphatic hydrocarbon radicals, mono-, di- or polysubstituted by functional groups.

An aromatic radical, including the aromatic radical of a corresponding carboxylic acid, is an optionally substituted one aromatic hydrocarbon radical, e.g. a mono-, bi- or polycyclic aromatic hydrocarbon radical, in particular phenyl, as well as biphenylyl or naphthyl, which optionally, for example like the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals, mono-, di- or can be polysubstituted.

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, can be mono-, di- or polysubstituted.

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509882 / O9Ö7

An araliphatic residue including the araliphatic residue in a corresponding carboxylic acid, furthermore an araliphatic ylidene radical, is, for example, an optionally substituted one araliphatic hydrocarbon radical, such as an optionally substituted, e.g. up to three, optionally substituted mono-, M- or polycyclic, aromatic hydrocarbon radicals having aliphatic hydrocarbon radical and is primarily phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl, also phenyl-lower alkylidene such radicals contain e.g. 1-3 phenyl groups and optionally, e.g. such as the above-mentioned aliphatic groups and cycloaliphatic radicals, in the aromatic and / or aliphatic part can be mono-, di- or polysubstituted.

Heterocyclic groups, including those in heterocyclic aliphatic Radicals, including heterocyclic 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 partially or completely saturated heterocyclic radicals of this type, such radicals optionally, e.g. as the above-mentioned cycloaliphatic radicals can be mono-, di- or polysubstituted. The aliphatic

- 11 5Ö9882 / Ö987

Part in heterocyclic-aliphatic radicals has, for example, that for the corresponding cycloaliphatic-aliphatic or araliphatic Remnants given meaning.

The acyl radical of a carbonic acid half-derivative is preferably the acyl radical of a corresponding half-ester, in which 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, eg ins- or ß Position, substituted lower alkyl half-ester of carbonic acid, as well as a lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half-ester of carbonic acid which is optionally substituted in the organic radical. Acyl radicals of a 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 cerocyclic groups of aromatic character, where 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.

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£ 09882/0987

An etherified hydroxy group is primarily optional substituted lower alkoxy, in which substituents are primarily free or functionally modified, such as etherified or esterified hydroxyl groups, in particular lower alkoxy or halogen, also lower alkenyloxy, Cycloalkyloxy or optionally substituted phenyloxy, and also heterocyclyloxy or hemocyclyl-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, Azaniederalkylenamino, Hydroxyamino, lower alkoxyamino, lower alka-

oxy
noyMmino, lower alkoxycarbonylamino or lower alkanoyl

amino.

An optionally substituted hydrazino group is, for example * Hydrazino, 2-lower alkylhydrazino, 2,2-biniederalkylhydrazino, 2-lower alkoxycarbonylhydrazino or 2-lower alkanoylhydrazino.

Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, as well as n-phentyl, isopentyl, n-hexyl, isohexyl or n-heptyl, while

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Lower alkenyl e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl, lower alkynyl e.g. propargyl or 2-butynyl, and lower alkylidene e.g. isopropylidene or Can be isobutylidene.

Lower alkylene is, for example, 1,2-ethylene, 1,2- or 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, while lower alkenylene e.g. 1,2-ethylene or 2-butene-1, 4-ylene. Lower alkylene interrupted by heteroatoms is, for example, oxane-lower alkylene, such as 3-0xa-1,5-pentylene, thiane-lower alkylene, such as 3-thia-1,5-pentylene, or aza-lower alkylene, such as 3-lower alkyl-3-aza-1,5-pentylene, e.g., 3-methyl-3-aza-1,5-pentylene.

Cycloalkyl is e.g. cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl or cycloheptyl, as well as adainantyl, cycloalkenyl e.g. cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,3-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 alkenyl e.g. 1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl- or 1-, 2- or 3-cycloheptenyl-, methyl, -1,1- or Represents -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, vinyl or allyl. Cycloalkyl-lower alkylidene e.g. 3-cyclohexenyl-

methylene.

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5Ö98Ö2 / 0987

Naphthyl is 1- or 2-naphthyl while biphenylyl is e.g. Represents 4-biphenylyl.

Phenyl-lower alkyl or phenyl-lower alkenyl is e.g. benzyl,

1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diephenylmethyl, Trityl, styryl or cinnamyl, naphthyl-lower alkyl e.g. 1- or 2-naphthylmethyl, and phenyl lower alkylidene e.g. Benzylidene.

Heterocyclic radicals are primarily optionally substituted heterocyclic radicals of aromatic character, for example corresponding monocyclic, monoaza-, monothia- or monooxacyclic radicals, such as pyrryl, for example 2-pyrryl or 3-pyrryl, pyridyl, for example 2-, 3- or 4-pyridyl , also pyridinium, thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals, such as indolyl, for example 2- or 3-indolyl, quinolinyl, for example Z- 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, such as imidazolyl, e.g. 2-imidazolyl, pyrimidinyl, e.g. 2- or 4-pyrimidinyl, Triazolyl, e.g., 1,2,4-triazol-3-yl, tetrazolyl, e.g., 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-

- 15 SÖ3882 / Ö987

Thiadiazolyl, e.g. 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza-, oxaza- or thiazacyclic ones Radicals such as benzimidazolyl, e.g. 2-benzimidazolyl, benzoxazolyl, e.g., 2-benzoxazolyl, or benzthiazolyl, e.g., 2-benzthiazolyl. Corresponding partially or fully saturated radicals are, for example, tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, or piperidyl, e.g. 2- or 4-piperidyl. Are heterocyclic-aliphatic radicals Hterocyclic groups, especially those mentioned above, containing Lower alkyl or lower alkenyl. The above-mentioned heterocyclyl 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, be substituted by functional groups.

Lower alkoxy is e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec, -butyloxy, tert-butyloxy, n-pentyloxy or tert-pentyloxy. These groups can be substituted be, e.g. as in halo-lower alkoxy, especially 2-halo-lower alkoxy, e.g. 2,2,2-trichloro-, 2-chloro-, 2-bromo- or 2-iodoethoxy. Lower alkenyloxy is, for example, vinyloxy or allyloxy, lower alkylenedioxy, e.g. methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy, e.g. cyclopentyl

- 16 -

oxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy, e.g. benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, or heterocyclyloxy or heterocyclyl-lower alkoxy, e.g. pyridyl-lower alkoxy, such as 2-pyridylmethoxy, Furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy.

Lower alkylthio is, for example, methylthio, ethylthio or n-butylthio Lower alkenylthio e.g. allylthio, and phenyl-lower alkylthio e.g. benzylthio, while by heterocyclyl radicals or heterocyclylaliphatic radicals etherified mercapto groups, in particular pyridylthio, e.g. 4-pyridylthio, imidazolylthio, e.g. 2-ImidazoTylthio, Thiazolyl thio, e.g. 2-Thiazolylthio, 1,2,4- or 1,3,4-thiadiazolylthio, e.g., 1,2,4-thiadiazol-3-ylthio or 1,3,4-thiadiazol-2-yl-thio, or tetrazolylthio, are e.g. 1-methyl-5-tetrazolylthio.

Esterified hydroxyl groups are primarily halogen, e.g. fluorine, chlorine, bromine or iodine, as well as lower alkanoyloxy, e.g. Acetyloxy or propionyloxy, lower alkoxycarbonyloxy, e.g. Methoxycarbonyloxy, ethoxycarbonyloxy or tert-butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, e.g. 2,2,2-trichloroethoxycarbonyloxy, 2-bromoethoxycarbonyloxy or 2-iodoethoxycarbonyloxy, or arylcarbonylmethoxycarbonyloxy, e.g. Pehnacyloxycarbonyloxy.

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509882/0987

Lower alkoxycarbonyl is e.g. methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl or tert-pentyloxycarbonyl.

N-lower alkyl- or Ν, Ν-di-lower alkyl-carbamoyl is e.g. N-methylcarbamoyl, N -ethylcarbamoyl, N, N-dimethylcarbamoyl or N, N-diethylcarbamoyl, while II-lower alkylsulfaraoyl e.g. represents N-methylsulfaraoyl or Ν, Ν-dimethylsulfamoyl.

A carboxyl or sulfo present in alkali metal salt form is, for example, one present in the sodium or potassium salt form Carboxyl or sulfo.

Lower alkylamino or di-lower alkylamino is e.g. methylamino, Ethylamino, dimethylamino or diethylamino, lower alkylenamino e.g. pyrrolidino or piperidino, oxaniederalkylenaraino e.g. morpholino, thianiederalkylenamino e.g. thiomorpholino, and aza-lower alkyleneamino, e.g., piperazino or 4-methylpiperazino. Acylamino stands in particular for carbamoylamino, Lower alkylcarbamoylamino, such as methylcarbamoylamino, Ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or tert-butyloxycarbonylamino, halo-lower alkoxycarbonylamino, such as 2,2,2-Trichloräthoxycarbonylainino, Phenylniederalkoxycarbonylamino, v / ie 4-methoxybenzyloxycarbonylamino, Lower alkanoylamino, such as acetylamino or propionylamino,

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S09882 / Ö987

also for phthalimides), or optionally in salt, such as Alkali metal, e.g. sodium, or ammonium salt form, present sulfoarnino.

Lower alkanoyl is, for example, formyl, acetyl, proponyl or Pivaloyl.

O-lower alkyl-phosphono is e.g. O-methyl- or O-ethylphosphone, Ο, Ο'-di-lower alkyl-phosphono, e.g. 0,0-dimethylphosphono or Ο, Ο'-diethylphosphono, O-phenyl-lower alkylphosphono, e.g. O-benzyl-phosphono, and O- ^{lower alkyl-O 1} -phenyD-lower alkyl-phosphono, for example O-benzyl-0'-methylphosphono.

Lower alalenyloxycarbonyl is, for example, vinyloxycarbonyl, while Cycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl, e.g. adamantyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, Diphenylmethoxycarbonyl or q, -4-biphenyl -. "_.- methylethoxycarbonyl represents. Lower alkoxycarbonyl, wherein lower alkyl e.g., a monocyclic, monoaza-, monooxa-, or monothiacyclic Group is, for example, furyl-lower alkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl-lower alkoxycarbonyl, such as 2-thenyloxycarbonyl.

For example, 2-lower alkyl and 2,2-di-lower alkyl hydrazino is 2-methyl hydrazino or 2,2-dimethylhydrazino, 2-lower alkoxycar-

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bonylhydrazino, e.g., 2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert-butyloxycarbonylhydrazino, and lower alkanoyl hydrazino, e.g., 2-acetyl hydrazino.

An acyl group Ac stands in particular for one in one naturally occurring or in a bio-, semi- or totally synthetically producible, preferably pharmacologically active N-acyl derivative of a 6-amino-penam-3-carboxylic acid or Y-amino - ^ - cephem- ^ carboxylic acid compound contained acyl radical 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 of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound The acyl radical Ac contained is primarily a group of the formula

^R < ^C > n ^C

R ¹¹¹

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 one, e.g. esterified or etherified

- 20 5098Ö2 / O987

Hydroxy or mercapto or an optionally substituted amino group, or where η is 1, R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclicaliphatic radical, in which the heterocyclic radical preferably aromatic character and / or a quaternary nitrogen atom on v / eist, an optionally functionally modified, preferably etherified or esterified hydroxy or Hercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or an azido group, and each of the radicals R ¹¹ and R ¹¹¹ denote hydrogen, or where η denotes 1, R denotes an optionally substituted 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 aromatic character, R is an optionally functionally modified, for example 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 0-mono- or Ο, Ο'-disubstituted phosphono group, or an azido group, and R represents

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Is hydrogen, or where η is 1, each of the radicals R ^{1 and} R is a 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 a optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R and R together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical, or v / orin η for 1 and R is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic R est, v / orin heterocyclic radicals preferably have aromatic character, R is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical.

In the above acyl groups of the formula A, η is, for example O and R for hydrogen or an optionally, preferably

509882/0987 _T 22 -

wise in 1-digit by possibly protected amino, Acylamino, where acyl primarily represents the acyl radical of a carbonic acid half-ester, such as a lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl radical, or one, optionally in salt, e.g. alkali metal salt form present sulfoamino group, substituted cycloalkyl group with 5-7 ring carbon atoms, one optionally, preferably by hydroxy, lower alkoxy, e.g. methoxy, acyloxy, in which acyl primarily represents the acyl radical of a

Carbonic acid half-ester, such as a lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl radical, and / or halogen, e.g. chlorine, substituted phenyl, Naphthyl or tetrahydronaphthyl group, optionally substituted by, e.g., lower alkyl, e.g., methyl, and / or phenyl, the in turn can carry substituents such as halogen, e.g. chlorine, substituted heterocyclic group such as a 4-isoxazolyl group, or a lower alkyl radical 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 optionally substituted, such as hydroxy, acyloxy, wherein 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 a 3-amino ~ 3-carboxy-propyl radical with optionally protected amino and / or carboxy group, e.g.

- 23 §03882 / 0987

silylated, such as tri-lower alkylsilated, e.g. trimethylsilylated, Amino or acylamino, such as lower alkanoylamino, halo-lower alkanoylamino or phthaloylamino, and / or silylated, four-lower alkylsilylated, e.g. tri-ethylsilylated, or more esterified, such as by lower alkyl, 2-halo-lower alkyl or phenyl-lower alkyl, e.g. diphonylmethyl, esterified 'carboxy group, for a nioderalkenyl group, for an optionally substituted, such as optionally, e.g. as stated above, acylated hydroxyl and / or halogen, e.g. chlorine, also optionally protected, e.g. as stated above, acylated, amino-lower alkyl, such as aminomethyl, or optionally substituted, such as optionally, e.g. above, acylated hydroxy and / or halogen, e.g., chlorine, phenyl containing phenyl group optionally, e.g. by lower alkyl, such as methyl, or optionally protected, e.g. acylated as indicated above, Amino or aminoethyl, substituted pyridyl, e.g. 4-pyridyl, Pyridinium, e.g. 4-pyridinium, l'hienyl, e.g. 2-thienyl, Furyl, e.g., 2-furyl, imdiazolyl, e.g., 1-imidazolyl-, or Tetrazolyl, e.g., 1-tetrazolyl group, an optionally substituted one Lower alkoxy, e.g. methoxy, one 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 optionally, e.g. by lower alkyl, such as methyl, substituted

- 24 509882/0987

ated phenylthio, pyridylthio, e.g. 4-pyridylthio, 2-imidazolylthio, 1 ^^ - triazol - ^ - ylthio-, 1, 3,4-triazol-2-ylthio-, 1 ^^ - thiadiazol ^ -ylthio -, such as 5-methyl-1,2,4-thiadiazol-3-ylthio-, 1,3,4-'J? hiadiazol-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, e.g. methoxycarbonyl or ethoxycarbonyl, cyano or optionally, e.g. 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 ¹¹ and R ¹¹¹ for hydrogen, or η for 1, R ¹ for lower alkyl or an optionally acylated hydroxyl and / or halogen, eg chlorine, substituted phenyl, furyl, eg 2-furyl, thienyl, eg 2- or 3-thienyl, or isothiaz olyl, for example 4-isothiazolyl group, also for a 1 ^ -Cyclohexadienj ^ lgruppe, R ~ for optionally protected or substituted amino, for example amino, acylamino, such as lower alkoxycarbonylamino, 2-halo-lower alkoxycarbonylamino or optionally substituted, such as lower alkoxy, for example methoxy, or nitro containing Phenyl lower alkoxycarbonylamino, e.g. tert-butyloxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino or diphenylmethyloxycarbonylamino, arylsulfonylamino, e.g. 4-methylphenylsulfonylamino, tritylamino, arylthioamino,

- 25 S09882 / Q9-8.7

- 25 - 2523044

such as nitrophenylthioamino, e.g. 2-nitrophenylthioamino, or Tritylthioamino or optionally substituted, such as lower alkoxycarbonyl, e.g. ethoxycarbony1, or lower alkanoyl, e.g. acetyl containing 2-propylideneamino, such as 1-ethoxycarbonyl-2-propylideneamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or a, optionally in salt, e.g., alkali metal salt form SuIfοamino group, an azido group, an optionally in salt, e.g., alkali metal salt, form or in slotted, such as esterified form, e.g. as lower alkoxycarbonyl, e.g. Methoxycarbonyl or ethoxycarbonyl, or as phenyloxycarbonyl, e.g., a diphenylmethoxycarbonyl group, a cyano group, a sulfo group, an optional functionally modified kydroxy group, with functionally modified hydroxy in particular acyloxy, such as formyloxy, and lower alkoxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy or optionally substituted, such as lower alkoxy, e.g. kethoxy, or nitro-containing phenyl-lower alkoxycarbonyloxy, e.g. tert-butyloxycarbonyloxy, 2,2,2-trichloroethoxycarbonyloxy, 4-methoxybenzyloxycarbonyloxy or diphe ^ lmethoxycarbonyloxy, or optionally substituted lower alkoxy, e.g. methoxy, or phenyloxy, an O-lower alkyl or Ο, Ο'-di-lower alkyl-phosphono group, e.g. O-methylphosphono or Ο, Ο'-dirnethylphosphono, or a halogen atom, e.g. chlorine or bromine, and R for hydrogen, or η for 1, R and R each for halogen, e.g. bromine, or lower alkoxycar-

- 26 5098Ö2 / O987

bonyl, e.g. methoxycarbonyl, and R for hydrogen, or η for 1, R for an optionally acylated hydroxyl and / or halogen, e.g. chlorine, substituted phenyl, furyl, e.g. 2-furyl- , or thienyl, for example 2- or 3-thienyl, or isothiazolyl, for example 4-isothiazolyl group, also for a 1,4-cyclohexadienyl group, R for optionally protected aminomethyl, for example as indicated above, and R for hydrogen , odor η for and each of the groups R ¹ , R ¹¹ and R ^{111 are} lower alkyl, for example methyl.

Such acyl radicals Ac are e.g. Pormyl, Cyclopentylcarbonyl, q.-aminocyclopentylcarbonyl or ^ -amino-cyclohexylcarbonyl (with optionally substituted amino group, e.g. optionally sulfoamino group present in salt form, or one, by one, preferably Mcht, e.g. when treating with a acidic agents such as trifluoroacetic acid, reductive, e.g. when treating with a chemical reducing agent such as zinc in Presence of aqueous acetic acid or catalytic hydrogen or hydrolytically cleavable or an acyl radical which can be converted into such an acyl radical, preferably a suitable one Acyl radical of a carbonic acid half ester, such as lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, 2-halo-lower alkylcarbonyl, e.g. 2,2,2-trichloroethyloxycarbonyl, 2-bromoathoxycarbonyl or 2-iodoethoxycarbonyl, arylcarbonylraethoxycarbonyl, e.g. phenacyloxycarbonyl, optionally substituted, such as lower alkoxy,

- 27 509882/0007

eg methoxy, or nitro-containing phenyl-lower alkoxycarbonyl, eg 4-I-lethoxy-benzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid half-amide, vie carbaraoyl or N-substituted, such as N-lower alkyl-, eg N-methylcarbamoyl, as well as by trityl, also by arylthio, eg 2-nitrophenylthio, arylsulfonyl, e.g. 4-methylphenylsulfonyl or 1-kiederalkoxycarbonyl-2-propylidene, e.g. 1 ~ ethoxycarbonyl-2-propylidene, substituted amino group), 2,6-dinethoxybenzoyl, 5,6,7 * 8-tetrahydro-naphthoyl, 2-methoxy-1-naphthoyl, 2-ethoxy-1-naphthoyl, benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 5-ethyl-3-phenyl-4-isoxazolylcarbonyl, 3- (2 ~ chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, 3 - (2.6 _T dichlorophenyl) -5-iaethyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acrylic, crotonoyl, 3-butenoyl, 2-pentenoyl, kethoxyacetyl, butylthioyl , Allylthioacetyl, methylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bro mpropionyl, aminoacetyl or 5-amino-5-carboxy-valeryl (with optionally, e.g. optionally functionally 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. diphenylmethyl ester, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonyl

- 28 509882/0987

acetyl, bis-raethoxycarbonylacetyl, N-phenylcarbamoylacetyl, Cyanoacetyl, q-cyanopropionyl, 2-cyano-3,3-dimethyl-acrylyl, Phenylacetyl, <^ - bromophenylacetyl, c ^ -azido-phenylacetyl, 3-chlorophenylacetyl, 2- or 4-aminomethylphenyl-acetyl (with optionally substituted amino group, e.g. as indicated), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, Benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, it-phenyloxyphenylacetyl, f (_- methoxyphenylacetyl, '/ ^ - ethoxy-phenylacetyl, r-c-methoxy-3> 4-dichlorophenylacetyl, ^ -Cyan-phenylacetyl, especially phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl, 3 »5-dichloro-4-hydroxyphenylglycyl, ^ .- amino -) - (1,4-cyclohexadienyl) acetyl, ; t-amino -:; _- (i-cyclohexenyl) acetyl, ίχ-aminomethyl - ^ - phenylacetyl or .7 ^ -hydroxyphenylacetyl, an amino group present in these radicals being optionally substituted, for example as indicated above can and / or an existing, aliphatic and / or phenolic bonded hydroxyl group, if appropriate, analogously to the amino group, e.g. by a suitable acyl radical, in particular by formyl or an acyl radical of a carbonic acid half ester), or. ^ - O-methyl-phosphonophenylacetyl or (^ -0,0-dimethyl-phosphono-phenylacetyl, also benzylthioacetyl, benzylthiopropionyl, i ^ -Carboxyphenylacetyl (with optionally, e.g. as stated above, functionally modified carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) propionyl, 4- (3-methoxyphenyl) butyryl,

- 29 -

S09882 / O9-87

-29- £ 528044

2-pyridylacetyl, 4-arainopyridiniumacetyl (if necessary with, e.g. as stated above, substituted amino group), 2-thienylacetyl, 3-thienylacetyl, 2-tetrahydrothienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, iL-carboxy-2-thienylacotyl or Ci-carboxy-3-thienylacetyl (optionally with a functionally modified carboxyl group, e.g. as stated above, v-cyano-2-thienylacetyl, C ^ -amino -: ^ - (2-thienyl) -acetyl, l-amino-.v- (2-furyl) -acetyl or 'L-amino-i- (4-isothiazolyl) ~ acetyl (optionally with, e.g. as stated above, substituted amino group), tf-sulfophenylacetyl (optionally with, e.g., the carboxyl group, functionally modified sulfo group), 3-methyl-2-imidazolyl-thioacetyl, 1,2,4-triazole-3-3 "l-tb.ioacetyl, 1,3,4-Tria ^ ol-2-ylthioacetyl, 5-methyl-1,2,4-thiadiazol-3-ylthioacetyl, 5-methyl-1,3,4-thiadiazol-2-ylthioacetyl or 1-Kethyl-5-tetrazolylthioacetyl.

An easily cleavable acyl residue Ac, in particular a carbonic acid half-ester, is primarily a reduction, e.g. when treating with a chemical reducing agent, or by acid treatment, e.g. with trifluoroacetic acid, Cleavable acyl radical of a half ester of carbonic acid, such as one, preferably on the carbon atom in r <_- position to Oxy group multiply branched and / or aromatically substituted lower alkoxycarbonyl group or an arylcarbonyl, in particular benzoyl radicals substituted methoxycarbo-

- 30 -

nyl group, or lower alkoxycarbonyl radical substituted in / "'position by halogen atoms, for example tert-butyloxycarbonyl, tert-pentyloxycarbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a radical convertible in the latter, v / ie 2- Chloro- or 2-bromoethoxycarbonyl, furthermore, preferably polycyciisches, cycloalkoxycarbonyl, for example adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, primarily c ^ -phenyl-lower alkoxycarbonyl, in which the ^ -position is preferably polysubstituted, eg diphenylmethoxycarbonyl or ((_-k- biphenylyl) C (.- methyl-ethyloxycarbonyl, or furyl-lower alkoxycarbonyl, primarily Q-furyl-lower alkoxycarbonyl, for example furfuryloxycarbonyl.

A b A divalent acyl group formed by the two radicals R ₁ and R 1 is, for example, the acyl radical of a lower alkane or lower alkali dicarboxylic acid, such as succinyl, or an o-arylenedicarboxylic acid, such as phthaloyl.

Away

Another bivalent one formed by the groups R. and R. The radical is, for example, a substituted, for example optionally substituted, phenyl, especially in the 2-position, or Thienyl, containing, and optionally through in the 4-position Lower alkyl, such as methyl, mono- or disubstituted 1-oxo-3-aza-1,4-butylene radical, e.g. 4,4-dimethyl-2-phenyl-1-oxo-3-aza-1,4-butylene.

- 31 -

5098Ö2 / O987

An etherified hydroxy group forms FU together with the
Carbonyl grouping an esterified carboxyl group, preferably easily cleavable or easily convertible into another functionally modified carboxyl group, such as a carbamoyl or hydrazinocarbonyl group. Such a group R ~ 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 is in
2-cephem compounds easily into a free carboxyl group
or can be converted into another functionally modified carboxyl group.

An etherified hydroxy group Rp »which, together with a -C (= 0) grouping, forms a particularly easily cleavable esterified carboxyl group, is, for example, 2-halo-lower alkoxy, in which halogen preferably has an atomic weight of more than 19. Such a radical, together with the -CC = O) group, forms one when treated with chemical reducing agents under neutral or weakly acidic conditions, for example with zinc
in the presence of aqueous acetic acid, easily cleavable esterified carboxyl group or an esterified carboxyl group that can be easily converted into a see and is, for example, 2,2,2-trichloroethoxy or 2-iodoethoxy, furthermore 2-chloroethoxy or
2-bromoethoxy, which can easily be converted into the latter.

- 32 509882/0987

An etherified hydroxy group Rp, which together with the
-C (= 0) grouping also when treating with chemical reducing agents under neutral or weakly acidic conditions, for example when treating with zinc in the presence of
aqueous acetic acid, furthermore on treatment with a suitable nucleophilic reagent, for example sodium thiophenolate, easily cleavable esterified carboxyl group is one
Arylcarbonylmethoxy group, in which aryl stands in particular for an optionally substituted phenyl group, and preferably phenacyloxy.

The group R ₂ can also stand for an aryl methoxy group,
wherein aryl is in particular a monocyclic, preferably
means substituted aromatic hydrocarbon radical. Such a radical, together with the -C (= 0) grouping, forms an easily cleavable upon irradiation, preferably with ultraviolet light, under neutral or acidic conditions,
esterified carboxyl group. An aryl residue in one
Arylmethoxy group is in particular lower alkoxyphenyl, for example methoxyphenyl (where methoxy is primarily in the 3-, 4- and / or 5-position), and / or especially nitrophenyl (where nitro is preferably in the 2-position). Such remnants are
especially lower alkoxy, for example methoxy, and / or nitrobenzyloxy, primarily 3- or 4-methoxybenzyloxy, 3,5-dimethoxy-benzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitrobenzyloxy.

- 33-509832 / 0987

An etherified hydroxyl group Rp 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 is polysubstituted by optionally substituted hydrocarbon radicals, in particular aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, e.g. methyl and / or phenyl, or by an electron-donating substituent, carbocyclic aryl group or a, Oxygen or sulfur as a ring member having heterocyclic group of aromatic character is monosubstituted, or then a ring member in a polycycloaliphatic hydrocarbon radical or in an oxa or thiacycbaliphatic radical the '/ position to the oxygen or sulfur atom is the ring member.

Preferred polysubstituted methoxy groups of this type are tert-lower alkoxy, e.g. tert-butyloxy or tert-pentyloxy, optionally substituted diphenylmethoxy, e.g., diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also 2- (4-biphenylyl) -2-propyloxy, while one containing the above substituted aryl group or the heterocyclic group Methoxy group e.g. a-lower alkoxy-phenyl-lower alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or furfuryl

- 34 509882/0987

oxy, v / ie is 2-furfuryloxy. A polycycloaliphatic one Hydrocarbon radical in which methyl is the methoxy group represents a, preferably three-fold, branched ring member is, for example, adamantyl, such as 1-Ada.mantyl, and an above-mentioned oxa- or thiacycloaliphatic radical in which methyl is the methoxy group that the ^ .- position to the oxygen or sulfur atom A representative ring member means, for example, 2-oxa- or 2-thiane-lower alkylene or -lower alkenylene with 5-7 ring atoms, v / ie 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulfur analogues.

The radical R ₂ can also represent an etherified hydroxyl group which, together with the -C (= 0) grouping, forms an esterified carboxyl group which can be cleaved hydrolytically, for example under weakly basic or acidic conditions. Such a radical is preferably an etherified hydroxy group which forms an activated ester group with the -C (= 0) group, such as nitrophenyloxy, e.g. 4-nitrophenyloxy or 2,4-dinitrophenyloxy, nitrophenyl-lower alkoxy, e.g. 4-nitrobenzyloxy, hydroxy-lower alkylbenzyloxy, e.g. 4 Hydroxy-3,5-tert-butyl-benzyloxy, polyhalophenyloxy, for example 2,4,6-trichlorophenyloxy or 2,3,4,5,6-pentachlorophenyloxy, also cyanomethoxy, and acylaminomethoxy, for example phthaliminomethoxy or succinyliminomethoxy.

The group R ₂ can also be one, together with the carbonyl grouping of the formula -C (= 0) - one under hydrogenolytisehen

- 35 S038Ö2 / 0987

conditions represent a cleavable esterified carboxyl group-forming etherified hydroxyl group, and is, for example, optionally, e.g. by lower alkoxy or nitro, substituted oL-phenyl-lower alkoxy, such as benzyloxy, 4-methox3'-benzyloxy or 4-nitrobenzyloxy.

The group R ₂ can also be an etherified hydroxyl group which, together with the carbonyl group -C (= O) - forms an esterified carboxyl group which can be cleaved under physiological conditions, primarily an acyloxymethoxy group, in which acyl is, for example, the remainder of an organic carboxylic acid, in particular one optionally substituted lower alkanecarboxylic acid, or v / orin acyloxymethyl forms the residue of a lactone. Hydroxy groups etherified in this way are lower alkanoyloxymethoxy, for example acetyloxymethyloxy or pivalojrloxymethoxy, amino-lower alkanoyloxymethoxy, especially i (-amino-lower alkanoyloxymethoxy, for example glycyloxymethoxy, L-valyloxymethoxy phidthaloxy, furthermore L-valyloxymethoxy L-leuthaloxy.

A silyloxy or stannyloxy group contains Rp as substituents preferably 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 Hydroxy, e.g., lower alkoxy groups, or halogen, e.g.

- 36 50 9 882/0987

Chlorine atoms, and is primarily tri-lower alkylsilyloxy, e.g. trimethylsilyloxy, halo-lower alkoxy-lower alkylsilyl, e.g. chloromethoxymethylgilyl, or tri-lower alkylstamiyloxy, e.g. trin-n-butylstannyloxy.

One together with a -C (= 0) grouping, preferably hydrolytically, cleavable mixed anhydride group-forming acyloxy radical Rp contains e.g. the acyl radical of one of the above organic carboxylic acids or carbonic acid half-derivatives, and is, for example, optionally, such as by halogen, e.g., fluorine or Chlorine, preferably in the '{position, substituted lower alkanoyloxy, e.g. acetyloxy, pivalyloxy or trichloroacetyloxy, or lower alkoxycarbonyloxy, e.g. methoxycarbonyloxy or Ethoxycarbonyloxy.

_{A radical R 2 which} , together with a -C (= O) group, forms an optionally substituted carbamoyl or hydrazinocarbonyl group is, for example, amino, lower alkylamino or di-lower alkylamino, such as methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino, e.g. pyrrolidino or piperidino, oxane-lower alkylene for example morpholino, hydroxyamino, hydrazino, 2-lower alkylhydrazino or 2,2-di-lower alkylhydrazino, for example 2-methylhydrazino or 2,2-diinethylhydrazino.

Salts are in particular those of compounds of the formulas IA and IB with an acidic group, such as a carb

- 37 509882/0987

oxy, sulfo or phosphono group, primarily metal or ammonium salt, such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, where primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, as well as heterocyclic bases are suitable for the salt formation, such as lower alkyl amines, e.g. triethylamine, K ^ 'droxy-lower alkyl amines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. 4-ainobenzoic acid-2 ~ d.läthylaminoethylester, Lower alkyleneamines, e.g. 1-ethyl-piperidine, Cycloalkylamines, e.g. bicyclohexylamine, or Benzyla-nine, e.g. Ν, Ν'-dibenzyl-ethylenediamine, also bases of the pyridine type, e.g. pyridine, collidine or quinoline. Compounds of the formulas IA and IB which have a basic group can also acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. trifluoroacetic acid or p-toluenesulphonic acid. Compounds of the formulas IA and IB with an acidic and a basic group can also be used in the form of internal salts, i.e. in zwitterionic form. 1-oxides of compounds of the formula IA with salt-forming groups can likewise form salts, as described above.

- 38 S09882 / 0987

The compounds of the present invention have valuable pharmacological properties or can be used as intermediates for the preparation of such. Compounds of the formula IA, in which, for example, R? for a pharmacologically active N-acyl derivative of 6 / ^! -Amino-penam-3-carboxylic acid- or If-- amino-3-cephera - 4-carboxylic acid compounds Acyl radical Ac and RJ stand for hydrogen

or in which Ri "and R ^ together are 1-oxo-3-aza-1,4 substituted in the 2-position, for example by an aromatic or heterocyclic radical, and in the 4-position preferably, for example by 2-lower alkyl, such as methyl -butylene radical and R _{2 is} hydroxyl or an etherified carboxyl group which, together with the carbonyl group, forms an esterified carboxyl group which is easily cleavable under plrysiological conditions

A ι

Hydroxy group R ^, where in an acyl radical R ^ optionally existing functional groups, such as amino, carboxy, hydroxy and / or sulfo, usually in the free Present form, or salts of such compounds with salt-forming groups and their antibiotic effects known.

Compounds of the formula IB or 1-oxides of compounds of

away
Formula IA, in which R., R ^ and Rp have the meanings given in connection with the formula IA, or compounds

a b of the formula IA, in which the radicals RÜT and R ^ j are hydrogen stand, or R ^ one, of one in pharmacologically active

509882/0987

N-acyl derivatives of 6 / ″ -amino-penam-3-carboxylic acid or T ^ -amino-3-cephem ~ 4-carboxylic acid compounds occurring Acyl radical different amino protective group and R ,, hydrogen

away
or R. and R. together are 1-oxo-3-aza substituted in the 2-position, for example by an aromatic or heterocyclic radical, and in the 4-position preferably, for example by 2-lower alkyl, such as methyl -1,4-butylene radical represents various divalent amino protective groups-

and Rp is hydroxy, or R ^ and R ,, have the meanings given above ₅ and R2 is a radical Rp which, together with the -C (= 0) grouping, forms a preferably easily cleavable, protected carboxyl group , whereby such a valued carboxyl group differs from a physiologically cleavable carboxyl group, are valuable intermediates which can be converted into the above-mentioned pharmacologically active compounds in a simple manner, for example as described below.

The invention relates in particular to the preparation of 3-cephem compounds of the formula IA, in which R ^ is hydrogen or preferably one, in a fermentative (i.e. naturally occurring) or bio-, semi- or totally synthetic preparable, in particular pharmacologically active, such as highly active N-acyl derivative of a 6, "'- amino-penam-3-carboxylic acid or 7; '- amino-3-cephem-4-carboxylic acid compound Acyl radical, v / ie one of the abovementioned acyl radicals of the formula A

- 40 509882/0987

means, where in this R, R, R and η primarily have the preferred meanings, R ^ for hydrogen

away
or in which Rür and R. together represent a 1-oxo-3- substituted in the 2-position, for example by an aromatic or heterocyclic radical, such as "tienyl, and in the 4-position preferably, for example by two lower alkyl, such as methyl aza-1,4-butylene radical, and R £ for hydroxy, for optionally, preferably in the α-position, for example by optionally substituted aryloxy, such as lower alkoxyphenyloxy, for example 4-methoxyphenyloxy, lower alkanoyloxy, for example acetyloxy, or pivaloyloxy, ^ -amino-lower alkanoyloxy, for example Glycyloxy, L-valyloxy or L-leucyloxy, arylcarbonyl, e.g. benzoyl, or optionally substituted aryl, such as phenyl, lower alkoxyphenyl, e.g. 4-methoxyphenyl, nitrophenyl, e.g. 4-nitrophenyl, or biphenylyl, e.g. 4-biphenylyl, or in / '- 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, optionally substituted by lower alkoxy tes bis-phenyloxymethoxy, for example bis-4-methoxyphenyloxymethoxy, lower alkanoyloxymethoxy, for example acetyloxymethoxy or pivaloyloxymethoxy, ^ -amino-lower alkanoyloxymethoxy, for example glycyloxymethoxy, phenacyloxy, optionally substituted phenyl-lower alkoxy, in particular 1oxy-phenyl-lower alkoxy, such as phenyl-lower alkoxy, where phenyl-lower alkoxy is optionally substituted, such as phenyl-lower alkoxy -3 optionally, for example by lower alkoxy, such as methoxy, nitro or phenyl, substi-

- 41 509882/0987

may contain tuated phenyl radicals, for example benzyloxy, 4-methoxy-benzyloxy, 2-biphenylyl-2-propyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxydiphenylmethoxy or trityloxy, or 2-halo-lower alkoxy, for example 2,2,2 -TrI-chloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, also for 2-phthalidyloxy, as well as for acylxy, such as lower alkoxycarbonyl ογ.γ , for example methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, for example acetyloxy-loweroxyalkyl, for example acetyloxy-oxy-oxyloxy or pivalyloxy , for example trimethylsilyloxy, or for amino or hydrazino which is optionally substituted, for example by lower alkyl, such as methyl or hydroxy, for example amino, lower alkyl or di-lower alkyl, such as methylamines or dimethylamines, hydrazino, 2-lower alkyl or 2,2-di-lower alkyl hydrazino, for example 2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamines, as / ie the 1-oxides thereof, also the corresponding 2-cephem compounds of the formula IB. or salts of such compounds with salt-forming groups.

Primarily in a 3-cephern compound there is the formula IA, as well as in a corresponding 2-cephem compound of the formula IB, furthermore in a 1-oxide of a j5 - cephem compound of formula IA, or in a salt of such a compound with salt-forming groups R ^ for hydrogen or one in fermentative (i.e. naturally occurring) or biosynthetically producible N-acyl derivatives of 6 / * - amino-penam-3-carbon-

- 42 -

S09882 / 0987

Acyl radical containing acid or 7 / i'-araino-3-cephem-4-carboxylic acid compounds, in particular of the formula A, v / orin R, R, R and η primarily have the preferred meanings, such as one, if appropriate, for example by Hydroxy, substituted phenylacetyl or phenyloxyacetyl radical, also an optionally substituted, for example by lower alkylthio or lower alkenylthio, acylated amino and / or functionally modified, such as esterified carboxyl, substituted lower alkanoyl or lower alenoyl radical, for example 4-hydroxy -phenylacetyl, hexanoyl, octanoyl or n-butyl-thioacetyl, and in particular 5-amino5-carboxy-valeryl, in which the amino and / or carboxyl groups are optionally protected and are present, for example, as acylamino or esterified carboxyl, phenylacetyl or phenyloxyacetyl, or one in highly effective N-acyl derivatives of 6r-amino ~ penam-3-carboxylic acid or 7; '^; -Amino-3-cephem-4-carboxylic acid compounds occurring acyl radical, in particular of the formula A, v / orin R, R, R and η primarily have the preferred meanings, such as formyl, 2-haloethylcarbamoyl, e.g. 2-chloroethylcarbamoyl, Cj ' anacetyl, phenylacetyl, thienylacetyl, for example 2-thienylacetyl, or tetrazolylacetyl, for example 1-tetrazolylacetyl, but especially in the <* position by a cyclic, such as a cycloaliphatic, aromatic or heterocyclic, primarily monocyclic radical and by a functional group in primarily amino, carboxy, sulfo or hydroxyl-substituted acetyl, in particular phenylglycyl,

- 43 509882/0987

wherein phenyl is optionally, e.g., optionally protected Hydroxy, such as acyloxy, e.g. optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and / or phenyl substituted by halogen, e.g. chlorine, e.g. phenyl, or 3- or 4-hydroxy-, 3-chloro-4 ~ represents hydroxy- or 3,5 ~ dichloro-4-hydroxyphenyl (optionally also with a split, such as acylated hydroxyl group), and in which the amino group can optionally also be substituted and, for example, one which is optionally present in salt form Represents a sulfoamino group or an amino group which has a hydrolytically cleavable trityl group as a substituent or primarily an acyl group, such as an optionally substituted carbamoyl, such as an optionally substituted one Ureidocarbonyl group, e.g. ureidocarbonyl or N'-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group, e.g. guanidinocarbonyl, or one, preferably Mcht, e.g. when treating with one acidic agents, such as trifluoroacetic acid, also reductive, such as when treating with a chemical reducing agent, such as Zinc in the presence of aqueous acetic acid, or with catalytic hydrogen, or hydrolytically, abr.cleavable 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 above, e.g., optionally halogen or benzoyl-substituted lower alkyloxycarbonyl radicals, e.g. tert-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, 2-

- 44-509882 / 0987

Chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, odor phenacyloxycarbonyl, optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonyl, for example 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid half-amide, such as a nucleic acid, furthermore a cyanophilic or sulfuric reagent with a hydrocarbyl or sulphurous reagent Acid or thioacetic acid amide, cleavable arylthio or aryl-lower alkylthio radical, for example 2-nitrophenylthio or tritylthio, an arylsulfonyl radical that can be cleaved off by means of electrolytic reduction, for example 4-methylphenylsulfonyl, or one that can be cleaved with an acidic agent, such as hydrochloric acid or aqueous mineral acid, for example 1-lower alkoxycarbonyl or "i-lower alkanoyl-2-propylidene radical, for example 1-ethoxycarbonyl-2-propylidene, contains, furthermore t <- (i, 4-cyclohexadienyl) -glycyl, ct- (i-cyclohexenyl) -glycyl, ^ -Thienylglycyl, such as <£ -2- or fl-3-thienylglycyl, £ -furylglycyl, such as ^ -2-fur ylglycyl, (f (-Isothiazolylglycyl, such as << - 4lsothiazolyl-glycyl, where in such radicals the amino group, e.g. as indicated for a phenylglycyl radical, can be substituted or protected, furthermore tJ'-carboxy-phenylacetyl or q -carboxy-thienylacetyl, e.g. (^ -Carboxy-2-thienylacetyl (optionally with a 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), q-sulfo-phenylacetyl (optionally

509882/0987

also with, for example, like the carboxyl group, functionally modified sulfo group), c (-phosphono, ^ -O-methylphosphono- or <£ -0, O'-dimethylphosphono-phenylacetyl, or i \ -hydroxyphenylacetyl (optionally with functionally modified hydroxyl group , in particular with an acyloxy group, in which acyl is an acyl radical that can be cleaved off, preferably easily, for example 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 one that can be converted into such an acyl radical, preferably a suitable one Acyl radical of a carbonic acid half-ester, such as one of the above, e.g. lower alkoxycarbonyl radical optionally substituted by halogen or benzoyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl or phenacyloxycarbonyl, also means formyl) , and 1-amino-cyclohexylcarbonyl, aminomethylphenylacetyl, such as 2- or 4-aminomethylphenylacetyl , or Amino-pyridiniumacetyl, e.g. 4-aminopyridiniuinacetyl (optionally also with, for example, as stated above, substituted amino group), or pyridylthioacetyl, e.g. 4-pyridylthioacetyl, and R ₁ for hydrogen, or R ^ and EJ together for one, in 2- Position preferably, optionally by 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-

- 46 509882/0987

hydroxy- or 3> 5-dichloro-4-hydroxyphenyl (if necessary also with a protected, e.g. acylated hydroxyl group as stated above), substituted 1-0xo-3 ~ aza-1,4-butylene radical stand, which in the A position optionally has two lower alkyl, as contains methyl, and Rp represents hydroxy, lower alkoxy, in particular q-polybranched lower alkoxy, e.g. tert -butyloxy, also kethoxy or / ithoxy, 2-halo-lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-iodoethoxy or the slightly in this convertible 2-chloroethoxy or 2-bromoethoxy, phenacyloxy, 1-phenyl-lower alkoxy with 1-3, optionally through Lower alkoxy or nitro-substituted phenyl radicals, e.g. 4-l-ethoxybynzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4 ' Dimethoxy-d-i.plienylmethoxy or trityloxy, lower alkanoyloxymethoxy, e.g. acetyloxymethoxy or pivaloyloxymethoxy, Q.-amino lower alkanoyloxymethoxy, e.g. glycyloxymethoxy, 2-phthalidyloxymethoxy, lower alkoxycarbonyloxy, e.g. ethoxycarbonyloxy, or lower alkanoyloxy, e.g. acetyloxy, also tri-lower alkylsilyloxy, e.g. trimethylsilyloxy.

The invention relates primarily to the preparation of 3-cephem compounds of the formula IA in which R ^ is hydrogen or an acyl group of the formula

O
R _a - (X) _1n -CH- C- (B),

- 47 - S09882 / 0987

where R is phenyl or hydroxyphenyl, e.g. 3- or 4-hydroxyphenyl, furthermore hydroxy-chlorophenyl, e.g. 3 ~ chloro-4-hydroxyphenyl- or 3,5-dichloro-4-hydroxyphenyl, with hydroxy substituents in such radicals by AcA'l radicals, such as, if appropriate halogenated ^ lower alkoxycarbonyl radicals, e.g. tert-butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, protected as well as thienyl, e.g. 2- or 3-thienyl, furthermore Pyridyl, e.g. 4-pyridyl, aminopyridinium, e.g. 4-aminopyridiniura, Furyl, e.g. 2-furyl, isothiazolyl, e.g. 4-isothiazo-IyI, or tetrazolyl, e.g. 1-tetrazoyl, or also 1,4-cyclohexadienyl or 1-cyclohexenyl, X is oxygen or represents sulfur, m represents 0 or 1, and R represents hydrogen or, if m represents 0, represents / unino, as well as protected amino such as acylamino, e.g. q-polybranched Lower alkoxycarbonylamino, such as tert -Butyloxj'carbonylainino, or 2-halo-lower alkoxycarbonylaraino, e.g. 2,2,2-trichloroethoxycarbonylamino, 2-Jodäthoxycarbonylarnino or 2-Bromäthoxycarbonylamino, or, if appropriate, Niederalkoxj '' - or Nitro-substituted phenyl-lower alkoxycarbonyl-lamino, e.g. 4-methoxybenzyloxycarbonylamino or diphenylmethoxycarbonylamino, or 3 ~ guanylureido, also sulfoamino or tritylamino, so / ie arylthioamino, e.g. 2-nitrophenylthioamino, Arylsulfonylamino, e.g., 4-methylplienylsulfonylamino, or i-lower alkoxycarbonyl-2-propylideneamino, e.g. 1-ethoxycarbonyl-2-prop3''lidenamino, Carboxy or in salt, e.g., alkali metal, such as sodium salt form, as well as

509882/0987

protected carboxy, for example esterified carboxy, v / ie phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, sulfo or sulfo present in salt, for example alkali metal, such as sodium salt form, as well as protected sulfo, hydroxy, and protected hydroxy, vie acyloxy, e.g. ^ -polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, furthermore formyloxy, or 0-lower alky] .phosphono or 0,0'-di-lower alkylphosphono, eg or 0,0 '~ dimethylphosphono, or denotes a 5-amino-5-carboxy-caleryl radical, in which the amino and / or carboxy groups can also be protected and, for example, as acylamino, e.g. lower alkanoylamino, v / ie acetylamino, Halogenniederalkanoylamino, v / ie dichloroacetylamino, benzoylamino or phthaloylamino, or /. as an esterified carboxy, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, where preferably m is 1 when R is phenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl, and m is 0 and R is different from hydrogen when R _{o is} phenyl, hydroxyphenyl, hydroxy represents chlorophenyl, thienyl, furyl, isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, R, - V on Hydrogen and R ₂ is tert / ^primarily for hydroxy, also lower alkoxy, in particular q -polyverzweigtes lower alkoxy, for example. Butyloxy, 2-halo-lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally,

- 49 509882/0987

for example by lower alkoxy, for example kethoxy, substituted diphenylmethoxy , for example diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, also tri-lower alkylsilyloxy, for example trimethylsilyloxy, and the 1-oxides of such 3-cephem compounds of the formula IA, and also the corresponding 2- Cephem compounds of the formula IB, or salts, in particular pharmaceutically usable, non-toxic salts of compounds with salt-forming groups, such as alkali metal, for example sodium, or alkaline earth metal, for example calcium salts, or ammonium salts, including those with amines, of compounds , in which Rp stands for hydroxy, or internal salts ~ of compounds in which Rp stands for hydroxy and which contain a free amino group in the acyl radical of the formula B.

Primarily in 3-cephem compounds of the formula IA, furthermore in corresponding 2 cephem compounds of the formula IB, as well as in salts, in particular in pharmaceutically / usable, non-toxic salts of such compounds with salt-forming groups, as in the Salts mentioned in the preceding section R ^ for hydrogen, for the acyl radical of the formula B, in which R _& phenyl, and hydroxyphenyl, for example 4-hydroxyphenyl, thienyl, for example 2- or 3-thienyl, 4-isothiazolyl, 1,4-cyclohexadienyl or 1-Cyclohexenyl, X is oxygen, m O or 1, and R ^ is hydrogen or, if m is 0, amino, and protected amino, such as acylamino, for example t £ -polybranched lower alkoxycarbonylamino, such as tert-butyloxycarbonyl

- 50 509882/0987

amino, or 2-halo-lower alkoxycarbonylamino, for example 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonylamino, for example 4-methoxyben-zyloxy, such as hydroxy, or hydroxy-protected or hydroxy q-polybranched lower alkoxycarbonyloxy, v / ie tert-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, v / ie 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, also means forniyloxy, or carboxy-valeryl radical, in which the amino and carboxy group can also be protected and, for example, as acylamino, e.g. lower alkanoylamino, v / ie acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, benzoylamino, or phthaloylamino, or as an esterified carboxy, e.g. are present, where m is preferably 1 when R is phenyl or hydroxyphenyl, R. st ellt is hydrogen and R ₂ is primarily hydroxy, also optionally in the 2-position halogen, eg chlorine, bromine or iodine-substituted lower alkoxy, in particular α- polybranched lower alkoxy, eg tert -butyloxy, or 2-halo-lower alkoxy,. for example 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally lower alkoxy, such as methoxy-substituted diphenylmethyloxy, for example diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, or p-nitrobenzyloxy, also tri-lower alkylsilyloxy, e.g. Triniethylsilyloxy.

- 51 509882/0987

The invention is primarily important for the preparation of 7p- (DC ^ -amino-c ^ -R -acetylamino) -3-methyl-3-cephem-A-carboxylic acids, v / orin R "for phenyl, 4-hydroxyphenyl , 2-thienyl, 1, A-cyclohoxadienyl or 1-cyclohexenyl, and their pharmaceutically acceptable, especially internal salts, and especially for the preparation of 3-methyl- 7ß- (D - ^ - phenyl-glycylamino) -3 ~ cephem -4-carboxylic acid and its pharmaceutically acceptable salts, especially its inner salt. The susceptible antibiotic properties of these compounds, especially when administered orally, against both gram-positive and gran-negative bacteria, are known.

After the statute of limitations according to the invention, compounds of the Formula IA, their 1-oxides, compounds of the formula IB and 53a] ze of such compounds with salt-forming. Groups made, by making a compound of the formula

(II)

509882/0987 - 52 -

AB A

wherein R7, R. and Rp have the meanings given under formula IA, and Y represents a leaving group, or a tautomer thereof, treated in a polar, aprotic solvent with a nucleophilic catalyst, and, if desired, in a compound obtained Formula IA and IB

/ \ A converts the protected carboxyl group of the formula -CC = O) -R ₂ into the free or into another protected carboxyl group, and / or, if desired, splits off an amino protective group R ^ or converted into another amino protective group and / or, if if desired, a compound obtained is converted into another compound within the definition of the end substances, and / or, if desired, a compound obtained with a salt-forming group is converted into a salt or a salt obtained is converted into the free compound or into another salt, and / or, if desired, separating a resulting mixture of isomeric compounds into the individual isomers.

In a starting compound of the formula II, a leaving group Y is, for example, a group -S-R, (formula Ha), a group -SOp-Rr (formula lib) bonded to the thio group -S- with the sulfur atom or a group -S-SOo-R- /, (Formula lic).

In the group -S-R, R, is an optionally substituted one heteroaromatic radical with up to 15, preferably up to 9 carbon atoms, and at least one ring nitrogen atom

- 53 5G9882 / 0987

and optionally a further ring heteroatom, such as Oxygen or sulfur, which radical with one of its ring carbon atoms, which with a ring nitrogen atom through a Double bond is linked to the thio group -S- is bonded. Such radicals are monocyclic or bicyclic and can, for example, by lower alkyl, such as methyl or ethyl, lower alkoxy, such as methoxy or ethoxy, calogen, such as Fluorine or chlorine, or aryl, v / ie phenyl, may be substituted.

Such radicals R _v are, for example, monocyclic, five-membered thiadiasacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclic radicals of aromatic character, but in particular monocyclic five-membered diazacyclic, oxy-zacyclic and thiazacyclic radicals, benzacacyclic, benzacycyclic-benzacyclicclic, and / or primarily the corresponding eneoxy-cacyclic radicals of aromatic character, and or primarily the corresponding eneoxy-cacyclic radicals benzthiazacyclic radicals in which the heterocyclic part is five-membered and has aromatic character, it being possible for a substitutable ring nitrogen atom to be substituted, for example by lower alkyl, in radicals R-. Representative of such groups R 1 are 1-methylinidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-2-yl , 1,3-0xazol-2-yl, 1,3, ^z t ^{-oxadiazol-2-3 r} l, 1,3,4,5-0xatriazol-2-yl. 2-quinolyl, i-methj-1-benzimidazol-2-yl, benzoxazol-2-yl and especially benzthiazol-2-yl. V / other groups R are acyl radicals of organic carboxylic or thiocarboxylic acids, such as optionally substituted ali-

- 54 5098Ö2 / 0987

phatic, cycloaliphatic, araliphatic ^ or aromatic acyl or thioacyl groups with up to 13, preferably up to 10, carbon atoms, such as lower alkanoyl, e.g. acetyl or propionyl, lower thioalkanoyl, e.g. thioacetyl or thiopropionyl, cycloalkanecarbonyl, e.g. cyclohexanecarbonyl, e.g. , Thiobenzoyl, naphthylcarbonyl, naphthylthiocarbonyl, heterocyclic carbonyl or thiocarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, 2- or 3-thenoyl, 2- or 3-furoyl, 2-, 3- or 4-pyridylthiocarbonyl, 2- or 3 - ThJDthenoyl, 2- or 3 - thiofuroyl, or corresponding substituted, for example by lower alkyl, such as methyl, halogen, such as fluorine or chlorine, lower alkoxy, such as methoxy, aryl, such as phenyl, aryloxy, v / ie phenyloxy, mono- or polysubstituted acyl or thioacyl groups. ru can also be an aliphatic radical substituted in the 1-position by an ether or thioether grouping, for example lower alkoxy, v / ie methoxy, lower alkyltbio, such as methylthio, and the like substituted lower alkyl, v / ie methoxymethyl, ethoxyinethyl or methylthiomethyl, or R ^ can also be an optionally substituted vinyl radical, for example vinyl or vinyl substituted in the 1- and / or 2-position by lower alkyl, lower alkenyl, lower alkylene or aryl, v / ie 1-butenyl, 1-cyclohexenyl or 2-phenylvinyl, or R ₇ can also be optionally substituted aromatic hydrocarbon radical, for example phenyl or naphthyl or substituted phenyl

- 55 503882/0987

or naphthyl, such as XyIyI, tolyl, chlorophenyl, bromophenyl, Nitrophenyl, methoxyphenyl, diraethoxyphenyl, dichlorophenyl, Chloraltrophenyl, chloronaphthyl, hethoxynaphthyl or Nitronaphthyl.

In the groups -SO ₂ -R ^ and -S-SC ^ -R ^, R ^ is an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 18, preferably up to 10, carbon atoms. Suitable groups R. are, for example, optionally substituted, v / ie by lower alkoxy, v / ie hethoxy, halogen, v / ie fluorine, chlorine or bromine, aryl, v / ie phenyl, aryloxy, v / ie phenyloxy, mono- or poly-substituted alkyl , in particular lower alkyl, v / ie methyl, ethyl or butyl groups, alkenyl, v / ie allyl or butenyl groups, cycloalkyl, such as cyclopentyl or cyclohexyl groups, or optionally through lower alkyl, v / ie methyl, lower alkoxy, v / ie Methoxy, halogen, such as fluoro, chlorine or bromine, aryl, v / ie phenyl, aryloxy, v / ie phenyloxy, or nitro, mono- or polysubstituted haphthyl or, in particular, phenyl groups, for example phenyl, ο-, m- or preferably p-tolyl, o-, m- or preferably p-methoxyphenyl, o-, m- or p-chlorophenyl, p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl or 1- or 2-naphthyl.

In a starting material of the formula II, R- is preferably for one, with the -C (= O) group one, in particular

509882/0987 ~ ^3β ~

under mild conditions, cleavable, esterified carboxyl group-forming, etherified hydroxyl group, v / obei if necessary Functional groups present in a carboxyl protective group Rp are protected in a manner known per se, e.g. as indicated above could be. A group Rp is, for example, in particular an optionally halogen-substituted lower alkoxy group, such as α-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halo-lower alkoxy in which halogen is e.g. chlorine, bromine or iodine, primarily 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, or optionally one substituted, such as lower alkoxy, e.g. methoxy, or nitro containing 1-phenyl-lower alkoxy group, such as, if appropriate, e.g. v / ie indicated, substituted benzyloxy or diphenylmethoxy, e.g. benzyloxy, 4-methoxybonzyloxy, 4-nitrobenzyloxy, Diphenylmethoxy or 4,4 '~ dimethoxy-diphen3' "lmethoxy, also an organic silyloxy or stannyl oxy group, such as tri-lower alkylsilyloxy, e.g. trimethylsilyloxy or else Halogen, e.g. chlorine. The amino group FC in a starting material of the formula II is preferably an acyl group Ac, \ in front of any free functional groups present, e.g. amino, hydroxyl, carboxyl or phosphone groups, in a manner known per se, amino groups e.g. by the above-mentioned acyl, trityl, silyl or stannyl, as well as substituted thio or sulfonyl radicals, and hydroxy, carboxy or phosphono groups e.g. by the above-mentioned ether or Ester groups, including silyl or stannyl groups,

n, and r? Hydrogen. 509882/0987-57

protects can be, and R ^ hydrogen.

25280U

Nucleophilic catalysts suitable for the ring closure reaction are, for example, anions of im used Solvent-soluble salts and bases.

Suitable anions are, for example, halide, especially iodide anions, or sulfur nucleophiles, such as rhodanide anions, Xanthogenotaniorxen, especially alkyl, such as lower alkyl, e.g. methyl or ethyl xanthate anions, optionally substituted aliphatic, cycloaliphatic or aromatic Dithiocarboxylic acid anions such as dithioformate, e.g. Azidodithioformate, dithioacetate, dithiocyclohexyl carboxylate, or dithiobium anions, or thiosulfonate anions of the formula 'S-SOp-R / ,, wherein R ^ the above Has meanings. The anions are in the form of their soluble salts, such as their alkali, e.g. lithium or sodium salts added to the reaction mixture.

Suitable bases are inorganic or organic * in nature, v; ie metal hydroxides, in particular alkali or alkaline earth metal hydroxides, e.g. lithium, sodium, potassium, calcium or magnesium hydroxide, or in particular nitrogen bases, which contain one to three nitrogen atoms, such as ammonia, optionally substituted aliphatic, cycloaliphatic, aromatic, heterocyclic and heteroaromatic, primary, secondary or tertiary amines, such as mono-, di- or trialkyl-, especially -lower-alkyl-, e.g. -methyl-, -ethyl- or

- 53 509882/0987

25280U

isopropylamine, mono-, di- or tricycloalkyl, such as -lower cycloalkyl-, for example -cyclopentyl- or -cyclohexylamine, primary, secondary or tertiary arylamines, for example unsubstituted or N-mono- or N, N-di-lower alkyl-substituted aniline, such as N-methyl -aniline or Ν, Ιν-dimethylaniline, or optionally substituted pyrrolidines, piperidines or pyridines, or corresponding diamines, v. ^r ie lower alkylenediamines, for example 1,2-ethylenediamine or IJ, II'-dimethyl-1,2-ethylenediamine. Suitable bases are also optionally N- or O-substituted hydroxylamine, for example IT-lower alkyl, such as N-methylhydroxylamine or O-lower alkyl, such as O-ethylhydroxylaiains or in particular unsubstituted hydroxylamine, or optionally substituted, such as lower alkylated hydrazine, for example N-methyl hydrazine, N, H-dimethyl hydrazine, N, N'-dimethyl hydrazine or, in particular, unsubstituted hydrazine. Furthermore, bicyclic amidines, such as diaza-bicycloalkenes, for example 1,5-diazabicyclo |] 4.3-0] non-5-en or 1,5-diasabicyclo [_p.4.0.J undec-5-en, or substituted, eg guanidines which are polysubstituted by lower alkyl, such as tetramethylguanidine, are used.

The amount of the nucleophilic catalyst to be used depends on the acidity of the acid to be split off in the reaction H-Y off. If this H-Y is a relatively weak acid H-S-R-, is sufficient catalytic amounts of nucleophilic catalyst, preferably about 0.5 to about 1.0 equivalents, if H-Y is one

509682/0987 -59-

If the relatively strong acid is H-SO ₂ -R ^ or HS-SO ₂ -R ^, it is advantageous to use more than one equivalent, preferably about 1.1 to about 1.5 equivalents, of the nucleophilic catalyst.

The reaction according to the invention is carried out in a suitable polar, aprotic solvent, in particular in a Ν, ΙΪ-di-lower alkylcarboxamide, such as dimethylformamide or Ν, Ν-dimethylacetamide, a di-lower alkyl sulfoxide, such as dimethyl sulfoxide, a hexane-lower alkylphosphoric acid triaaide, such as hexamethylphosphoric acid triliamide, such as hexamethylphosphoric acid triliamide ketone such as di-lower alkyl, for example acetone, or in a mixture thereof, at temperatures between about -50 and +50 ⁰ C, preferably at about -20 ⁰ C to etv / a + 25 ° C, and particularly at about -20 ⁰ C. .

Particularly preferred nucleophilic catalysts and solvents, in particular also for converting compounds of the formula II in which Y is a group -SR ₇ , are ammonia gas or an aqueous, about 20-24> a-strength ammonia solution, as well as mono- or di-lower alkylamines, v / ie methylamine or dimethylamine, or lower alkylenediamines, such as 1,2-ethylenediamine, as well as hydroxylamine or hydrazine or a corresponding aqueous, about 20-40% amine solution, in dimethylacetamide or especially dimethylformamide, also sodium rhodanide in dimethylformamide, acetone, acetonitrile, Dimethyl sulfoxide or hexamethylphosphoric acid triamide, and sodium iodide in di-

- 60 SÖ98S2 / 0987

methylformamide. The reagents and solvents used do not need to be absolutely anhydrous, but can contain up to 10 % Y / water.

In a preferred embodiment, the reaction is carried out with ammonia gas or an aqueous, about 20-24% strength, ammonia solution carried out in dimethylformamide at a temperature of -20 C.

The known basic isomerization of compounds of the formula II, v / orin Y represents a group of the formula -S-R- and R, the benzthiazol-2-ylthio radical, to tautomeric Compounds of the formula

O = -

^CH 3 (III)

(Lit .: I. Kamiya et al. Tetrahedron Letters, No. 32, 1973 , p. 3001), as well as from end products of the formula IA to end products of the formula IB either do not occur at all or only to a small extent under these preferred conditions.

A compound of the formula III formed as a by-product, or starting material of the formula II, can be used in the reaction

- 61 -

509882/0987

tion solution by adding a reducing agent, v / ie one complex borohydrides, e.g. sodium borohydride, selectively destroyed v / earth.

A compound of the formula III formed as a by-product can also, if necessary _after its isolation, by treatment with one of the strong organic bases mentioned, in particular a bicyclic amidine, v / ie diazabicycloalkane, for example 1,5-diazabicyclo [4.3 · θ3 non -5-ene or 1,5-diazabicyclo [5.4.0jundec-5-ene, or a substituted guanidine, for example polysubstituted by lower alkyl, such as tetramethylguanidine, in a mixture consisting of a compound of the formula IA and a compound of the formula isomeric thereto IB transferred v / ground.

The conversion of a compound of the formula III optionally obtained as a by-product into compounds of the formula IA and 13 takes place under the influence of the aforementioned strong Bases in the same solvents and under the same reaction conditions v / ie the inventive method of Compounds of the formula II to the compounds of the formulas IA and IB.

In the ring closure reaction according to the invention one can ever compounds of the formula IA or IB or mixtures of compounds which are uniform according to the starting material and reaction conditions

S09882 / O987 " ⁶² '

Orifices of the formulas IA and IB are obtained. Mixtures obtained can in a manner known per se, e.g. with the help of suitable separation methods, e.g. by adsorption and fractionated Elution, including chromatography (column, paper or plate chromatography) using suitable adsorption media, like silica gel or aluminum oxide, and eluents, furthermore separated by fractional crystallization, solvent distribution, etc.

Obtained compounds of the formulas IA and IB, the suitable intermediates for the preparation of pharmacologically more active End products can be converted into such active end products by various additional measures known per se will.

In the method according to the invention, as well as in any additional measures to be carried out, if necessary, free functional groups that do not participate in the reaction in the starting materials or in the compounds obtainable according to the process, e.g. free amino groups e.g. Acylation, tritylation or silylation, free hydroxyl or mercapto groups, e.g. by etherification or esterification, and free carboxyl groups, e.g. by esterification, including silylation, are 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 collectively, are released.

509882/0987

- 63 -

For example, amino, hydroxy, carboxyl

A b or phosphoric groups in an acyl radical R. or FL · for example in the form of acylamino, vie the abovementioned, for example 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylaraino, ^ -ethoxybenzyloxycarbonylaraino, diphenylmethoxycarbonylamino or tert .-Eutyloxycarbonylaniino, of aryl or aryl-lower alkylthioamino, for example 2-nitrophenylthioamino, or arylsulfonylainino, for example 4-methylphenylsulfonylamino, or of 1-I-lower alkoxycarbonyl-2-propylidenearaino groups, for example, such as the acyloxy groups mentioned above .-Butyloxycarbonyloxy, 2,2,2-trichlorethoxycarbonyloxy or 2-bromoethoxycarbonyloxy groups, for example of esterified carboxy groups, such as those mentioned above, for example diphenylmethoxycarbonyl groups, or '. O, O'-disubstituted phosphono, such as those mentioned above, for example Ο, Ο'-di-lower alkylphosphono-y, for example Ο, Ο'-diiriethylphosphono groups, protect and subsequently, if necessary after conversion of the protective group, for example a 2-bromoethoxycarbonyl into a 2 ~ Iodine ethoxycarbonyl group, in a manner known per se and depending on the type of protective group, for example a 2,2,2-trichloroethoxycarbonylamino or 2-iodoethoxycarbonylamino group by treatment with suitable reducing agents, such as zinc in the presence of aqueous acetic acid, a diphenylmethoxycarbonylamino or tert .-Butyloxycarbonylamino group by treatment with formic or trifluoroacetic acid, an aryl or aryl-lower alkylthioamino group by treatment with a nucleophilic reagent, such as sulfurous acid, an arylsulfonylamino group by means of electrolytic

509082/0987 - 64 -

table reduction, an i-lower alkoxycarbonyi-2-propylideneamino group by treatment with aqueous mineral acid, or a tert-butyloxycarbönyloxy group by treatment with Formic or trifluoroacetic acid, or a 2,2,2-trichloroethoxycarbonyioxy group by treating with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, or a Dipheriylmethoxycarbonylgruppe by treatment with formic or trifluoroacetic acid or by hydrogenolysis, or a 0,0'-disubstituted phosphono group by treating with an alkali metal halide if desired, e.g., partially cleaving.

In a compound of the formula obtainable according to the invention IA or IB with a protected, in particular esterified, carboxyl group of the formula -CK = O) -R ;; can this in itself

A known method, e.g. depending on the type of group Rp, into the free carboxyl group converted v / ground. An esterified, for example by a lower alkyl radical, in particular methyl or Ethyl, esterified carboxyl group, especially in a 2-cephem compound of the formula IB, by hydrolysis in a weakly basic medium, e.g. by treatment with a aqueous solution of an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. sodium or potassium hydroxide, preferably at a pH of about 9 to 10, and optionally in the presence of a lower alkanol, into a free one Carboxyl group can be converted. One through a suitable one

. - 65 5 9

2-halo-lower alkyl or an arylcarbonylmethyl group 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 Presence of a hydrogen-releasing agent which, together with the metal, is able to generate nascent hydrogen, such as an acid, primarily acetic and formic acid, or an alcohol, preferably water adds, a carboxyl group esterified by an arylcarbonylmethyl group also by treatment with a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate or sodium iodide, by any suitable one Aryl methyl group esterified carboxyl group, for example by irradiation, preferably with ultraviolet light, e.g. below 290 ιημ, if the arylmethyl group e.g. an optionally in the 3-, 4- and / or 5-position, e.g. by IJi ederalkoxy- and / or represents a benzyl radical substituted by nitro groups, or with longer-wave ultraviolet light, e.g. via 290 BU, if the Arylnie thy I group e.g. one in the 2-position is a benzyl radical substituted by a nitro group, a carboxyl group esterified by a suitably substituted methyl group, such as tert-butyl or diphenylmethyl e.g. by treatment with a suitable acidic agent such as formic acid or trifluoroacetic acid, optionally under Adding a nucleophilic compound such as phenol or anisole,

5Ö9882 / Ö987 " ⁶⁶ "

an activated esterified carboxyl group, furthermore a carboxyl group present in anhydride form by hydrolysis, e.g. by treating with an acidic or weak base marriage aqueous agents 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 one esterified carboxyl group by hydrogenolysis, e.g. by treatment with hydrogen in the presence of a noble metal, e.g. palladium catalyst, split v / ground.

A protected e.g. by silylation or stannylation Carboxyl group can be released in the usual way, e.g. by treatment with water or an alcohol.

Compounds of the formula IA or IB obtained can be converted into other compounds of the formula IA in a manner known per se or IB transferred.

In a compound obtained, for example, an amino protective

Away
group K ^ or R., in particular an easily cleavable acyl group, in a manner known per se, for example a t '^ - polybranched lower alkoxycarbonyl group, such as tert-butyloxycarbonyl, by treatment with trifluoroacetic acid and a 2-halo-lower alkoxycarbonyl group, such as 2, 2,2-Trichloräthoxycarbonyl or 2-Jodäthoxycarbonyl, or a Phenacyloxycarbonylgruppe by treatment with a suitable reducing

509862/0987 - 67 -

25280A4

Metal or corresponding metal compound, e.g. zinc, or a chromium II compound, such as chloride or acetate, advantageously in the presence of a hydrogen generating nascent together with the metal or the metal compound By means of, preferably in the presence of water-containing acetic seeds, split off v / ground.

Furthermore, in a compound of the formula IA or IB obtained, in which a carboxyl group of the formula -CC = O) -Rp is preferred one, e.g., by esterification, including by silylation, e.g., by reaction with a suitable organic Halosilicon or halotin IV compounds, such as trimethylchlorosilane or tri-n-butyltin chloride, protected carboxyl group, an acyl group R? or R -,., wherein optionally present free functional groups are optionally protected by treatment with an imide halide-forming Means, reaction of the imide halide formed with an alcohol and cleavage of the ■ formed Imino ethers, with a protected, e.g. a carboxy group protected by an organic silyl radical can be released in the course of the reaction.

Imide halide forming agents in which halogen is bound to an electrophilic Central atom is bonded, are mainly acid halides, such as acid broynides and especially acid chlorides. It these are primarily inorganic acid halides

509862/0987

Acids, especially of phosphorus-containing acids, such as phosphoroxy, Phosphorus tri- and especially phosphorus pentahalides, e.g., phosphorus oxychloride, phosphorus trichloride, and primarily Line phosphorus pentachloride, also pyrocatechyl phosphorus trichloride, as well as acid halides, especially chlorides, of sulfur-containing acids or of carboxylic acids, such as thionyl chloride, -Phosgene or oxalyl chloride.

The reaction with one of the imide halide-forming agents mentioned is usually carried out in the presence of a suitable, in particular organic base, primarily a tertiary amine, e.g. a tertiary aliphatic mono- or diamine, such as a tri-lower alkyl amine, e.g. trimethyl, triethyl or Ν, Ν-diisopropyl-N-ethyl-amine, also one Ν, Ν, Ν ', Ν'-tetra-lower alkyl-lower alkylenediamine, e.g. N, N, N ', N'-tetramethyl-1,5-pentylenediamine or N, N, N ', N'-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, e.g., N-methylpiperidine Qder N-methylmorpholine, also 2,3,4,6,7,8-hexahydro-pyrrolo £ i, 2-a] pyrimidine (diazabicyclonones; DBN), or a tertiary aromatic amine such as a di-lower alkylaniline, e.g. Ν, Ν-dimethylaniline, or primarily one tertiary heterocyclic, mono- or bicyclic base, such as quinoline ^ or isoquinoline, in particular pyridine, preferably in the presence of a solvent, such as a given

- 69 50 9 88 2/098 7

if halogenated, e.g. chlorinated, aliphatic or aromatic hydrocarbon such as methylene chloride. Approximately equimolar amounts of the imide halide compound and the base can be used; However, the latter can also be in excess or deficiency, e.g. in about 0.2 to about 1 times the amount or then in about up to 10 times, in particular about 3 to 5 times over shot, be present.

The reaction with the imide halide-forming agent is preferably carried out with cooling, for example at temperatures from about -5O ⁰ C to about +10 ⁰ C, but it is also possible to work at higher temperatures, ie up to about 75 ° C, if the Stability of the starting materials and products allow an increased temperature.

The Imidhalοgenidprοdukt, which one usually without Isolation is further processed according to the process with an alcohol, preferably in the presence of one of the above Bases, converted to the imino ether. Suitable alcohols are, for example, aliphatic as well as araliphatic alcohols, in the first place Line optionally substituted, such as 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, as well as given

5Ö98S2 / O987 -70-

if substituted phenyl-lower alkanols, such as benzyl alcohol. Usually one uses a, for example, times 100 to about, excess of the alcohol and preferably operates under cooling, for example at temperatures of about -50 ⁰ C to about 1O ° C.

The imino ether product can advantageously be subjected to cleavage without isolation. The cleavage of the imino ether can be achieved by treatment with a suitable hydroxy compound, preferably by means of hydrolysis, furthermore by alcoholysis, v / whether the latter, when using an excess of alcohol, can be achieved directly after the imino ether formation. It is preferred to use water or an alcohol, especially a lower alkanol, for example methanol, or an aqueous mixture of an organic solvent, such as an alcohol. One usually works in an acidic medium, for example at a pH of 1. ^r ert from about 1 to about 5, which can be obtained, if necessary, by adding a basic agent, such as an aqueous alkali metal hydroxide, e.g. sodium or potassium hydroxide, or an acid, e.g. a mineral acid, or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid , Hydrofluoric acid, trifluoroacetic acid or p-toluenesulfonic acid.

The above-described three-step process for cleaving an acyl group is advantageously carried out without isolating the Imide halide and mineral ether intermediates, more commonly

509802/0987 - 71 -

wisely In the presence of an organic solvent that behaves inert towards the reaction participants, such as an optionally halogenated hydrocarbon, e.g. methylene chloride, υηα / or in an inert gas atmosphere, such as a nitrogen atmosphere.

If the intermediate imide halide obtained by the above process is used rather than with an alcohol with a salt such as an alkali metal salt of a carbon, in particular a sterically hindered carboxylic acid, a compound of the formula IA or IB is obtained, in which both

away
R ^ and R ^ represent acyl groups.

In a compound of formula IA or IB in which both

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

In a compound of the formulas IA or IB, where R> and R ^ together with the nitrogen atom form a phthalimide group represent, this can e.g. by hydrazinolysis, i.e. when treating such a compound with hydrazine, into the free amino group are converted.

Certain acyl radicals R ^ an acylamino group in the invention available compounds, such as the 5-amino-5-

•. - 72 -

509802/0987

carboxy-vaieryl radical, in which carboxyl, e.g. by esterification, in particular by diphenylmethyl, and / or the amino group, e.g. by acylation, in particular by an acyl radical an organic carboxylic acid, such as halo-lower alkanoyl, such as dichloroacetyl, or phthaloyl, optionally protected can also be obtained by treating with a nitrosating agent such as nitrosyl chloride with a carbocyclic Arene diazonium salt, such as benzene diazonium chloride, or with a positive halogen donating agent, such as N-halo-amide or -imide, e.g. N-bromosuccinimide, preferably in a suitable solvent or solvent mixture, such as formic acid, together with a nitro or cyano-lower alkane and adding the reaction product with a hydroxyl-containing agent, such as water or a lower alkanol, e.g. methanol, or, if in the 5-amino-5-carboxyvaleryl radical R ^ the amino group is unsubstituted and the carboxy '· - group is protected e.g. by esterification, and R ^ preferably stands for an acyl radical, but can also mean hydrogen, by leaving to stand in an inert solvent, such as dioxane or a halogenated aliphatic hydrocarbon, e.g. methylene chloride, and, if necessary, work-up the free or monoacylated amino compound is split off by methods known per se.

A formyl group EL. "Can also be obtained by treating with a acidic agents, e.g. p.toluene sulphon or hydrogen chloride

50 98 8 2/0987

acid, a weak "basic middle"]., e.g. dilute Ammonia, or a decarbonylating agent, e.g. tris (tripheny! Phosphine) rhodium chloride, split off v / earth.

A triarylmethyl, such as the trityl group R ^ can, for example, by Treatment with an acidic agent, v; ie a mineral acid, e.g. hydrochloric acid, can be split off.

a b In a compound of formula IA or IB, wherein R ^ and R ^ Represent hydrogen, you can post the free amino group Substitute known methods, primarily by treatment with acids, such as carboxylic acids, or reactive ones Acylate derivatives thereof.

If a free acid, preferably with protected, optionally present functional groups, such as an optionally present araino group, is used for the acylation, suitable condensing agents such as carbodiimides, for example N, N'-diethyl-, Ν, Ν'-dipropyl- , N, l \ ^TI ~ diisopropyl-, N, N'-bicyclohexyl- or N-ethyl-N'-3-dimethylaminopropyl-carbodiimide, suitable carbony compounds, for example carbonyldiimidazole, or isoxazolinium salts, for example N-ethyl-5-phenylisoxazolinium- 3'-sulfonate and N-tert-butyl-5-methyl-isoxazolinium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

509882/0987 - 74 -

528044

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

An amide-forming, functional derivative of an acid, preferably with protected optionally present groups, such as an optionally present amino group, is in primarily an anhydride of such acid, including, and preferably, a mixed anhydride. Mixed anhydrides are, for example, 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 sulphurous acid, e.g. sulfuric acid, or with hydrocyanic acid. Other mixed anhydrides are, for example, those with organic acids, such as organic carboxylic acids, such 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 alkyl half-esters, carbonic acid, such as the ethyl or isobutyl half ester carbonic acid, or with organic, especially aliphatic or aromatic, sulfonic acids, e.g. p-toluenesulfonic acid.

- 75 -

509882/0987

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 hydroxy or Amino groups, v / ie mandelic acid-O-carboxy anhydride or that Use anhydride of 1-N-carboxyamino-cyclohexanecarboxylic acid .

Further ones suitable for reaction with the free amino group Acid derivatives are activated esters, usually with protected functional groups that may be present, like esters with vinylogous alcohols (i.e. enols), - like vinylogous Lower alkanols, or aryl esters, v / ie preferably ", e.g. by Nitro or halogen, v / ie chlorine, substituted phenyl esters, e.g. pentachlorophenyl, 4-nitrophenyl or 2,4-diitrophenyl ester, heteroaroroatic esters, such as benzotriazol esters, or diacylimino esters, v / ie succinylimino or phthalylimino esters.

Further acylation derivatives are e.g. substituted formimino derivatives, such as substituted Ν, Ν-dimethylchloroformimino derivatives of acids, or N-substituted Ν, Ν-diacylamines, such as a Ν, Ν-diacylated aniline.

Acylation with an acid derivative, v / ie an anhydride and in particular with an acid halide, can -in ■ presence-

- 76 50 988 2/0987

25280U

an acid-binding agent, for example an organic one 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 a pyridine type base such as pyridine, 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, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.

The above acylation can be carried out 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 nitrile, e.g. acetonitrile, or mixtures thereof, and, if necessary, at a reduced or elevated temperature and / or in a Inert gas, e.g. nitrogen atmosphere.

In the above N-acylation reactions one can use of compounds of the formulas IA or IB, in which Rp has the above meaning, compounds with free carboxyl groups

- 77 -509882/0987

25280U

of the formula -C (= 0) -R ₂ , in which R ^ is hydroxy, also in the form of salts, for example ammonium salts, such as with triethylamine, or in the form of a compound with one, by reacting with a suitable organic phosphorus halide compound, such as with a lower alkyl or lower alkoxy phosphorus dihalide, such as methylphosphorus dichloride, ethylphosphorus dibromide or kethoxyphosphorus dichloride, protected carboxyl group can be used; In the acylation product obtained, the protected carboxyl group can be released in a manner known per se, for example as described above, including by hydrolysis or alcoholysis.

An acyl group can also be introduced by adding a

a b compound of formula IA or IB, wherein R ^ and. R ^ together for a ylid remnant (which can also be added later, e.g. through

away

Treating a compound in which R ^ and R "are hydrogen, mi "c an aldehyde, v / ie an aliphatic, aromatic or araliphatic aldehyde) stands, for example acylated by the methods given above, and that Acylation product, preferably in a neutral or weakly acidic medium, hydrolyzed.

An acyl group can also be introduced in stages. For example, ir.n can be converted into a compound of the formula IA or IB with a free amino group a halo-lower alkanoyl, e.g. broraacetyl group, or e.g. by treating with a

- 78 509882/0987

Carbonic acid dihalide, such as phosgene, a halocarbonyl, e.g. chlorocarbonyl group, and one thus obtainable N- (halo-lower alkanoyl) or M- (halocarbonyl) amino compound with suitable exchange agents such as basic Compounds, e.g. tetrazole, thio compounds, e.g. 2-mercapto-1-methyl-imidazole, or metal salts, e.g. sodium azide, or alcohols, v / ie lower alkanols, e.g. tert-butanol, convert and so to substituted N-lower alkanoyl resp. N-hydroxycarbonylamino compounds arrive.

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

The acylation can also be carried out by replacing an existing one Acyl group by another, preferably sterically hindered acyl group, e.g. by the method described above, take place by preparing the imide halide compound, treating it with a salt of an acid and a the acyl groups present in the product obtainable in this way, usually the less sterically hindered acyl group, split off hydrolytically.

- 79 509882/0987

Furthermore, for example, a compound of the formula IA or IB, v / orin R? one, preferably substituted in the <? position Glycyl group, such as phenylglycyl, and R ^ represent hydrogen, with an aldehyde, e.g. formaldehyde, or a ketone, such as lower alkanone, e.g. acetone, and thus to combine

A b fertilize the formula IA or IB get, v / orin R ^ and R ^

together with the nitrogen atom one, preferably in the 4-position substituted 5-Οχο-Ί, 3-diaza-cyclopentyl radical which is optionally substituted in the 2-position.

β b In a compound of the formula IA or IB, in which R. and R. ^ are hydrogen, the free amino group can also be introduced by introducing a triarylmethyl group, for example by treatment with a reactive ester of a triarylmethanol, such as trityl chloride, preferably in the presence of a basic one By means of such as pyridine.

An amino group can also be introduced by introducing a silyl and Stannyl group to be protected. Such groups are introduced in a manner known per se, for example by treatment with a suitable silylating agent, such as with a dihalodiniederalkjrl-silane, Lower alkoxy-lower alkyl-dihalosilane or tri-lower alkyl-silyl-halide, e.g. dichlorodimethylsilane, Kethoxymethyl-chlorosilane, trimethylsilyl chloride or dimethyl-tert-butyl-silyl chloride, v; obei one such silyl halide compounds are preferably in the presence

- 80 -

509882/0987

a base, e.g., pyridine, is used, with an optionally N-mono-lower alkylated, Ν, Ν-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkylsilyl) amine (see e.g. British Patent No. 1.073-530), or with a silylated carboxylic acid amide, such as a bis-tri-lower alkylsilyl-acetamide, e.g. Bis-trimethylsilyl-acet-amide, or trifluorosilylacetarnide, furthermore with a suitable stannylating agent such as a Bis- (tri-lower alkyl-tin) oxide, e.g. bis (tri-n-butyl-tin) ~ oxide, a tri-lower alkyl tin hydroxide, e.g. triethyl tin hydroxide, a tri-lower alkyl-lower alkoxy-tin, tetra-lower alkoxy-tin or tetra-lower alkyl tin compound, such as a tri-lower alkyl tin halide, e.g. tri-n-butyl tin chloride (see e.g. dutch design brochure 67/11107).

In a compound of the formula which can be obtained according to the process IA or IB, the one-free carboxyl group of the formula -C (= 0) -Rp contains, such can be converted into a protected carboxyl group in a manner known per se. So you get Esters e.g. by treatment with a suitable diazo compound such as a diazo lower alkane, e.g. diazomethane or diazobutane, or a phenyldiazo lower alkane, e.g. diphenyldiazomethane, if necessary, in the presence of a Lewis acid such as e.g. boron trifluaride, or reaction with an alcohol suitable for esterification in the presence of an esterifying agent, such as a carbodiimide, e.g. dicyclohexylcarbodiimide,

- 81 50988 2/0987

and carbonyldiimidazole, also with an N, N '- disubstituted O- or S-substituted isourea or isothiourea, in which an O- and S-substituent, e.g. lower alkyl, in particular tert-butyl, phenyJjiie, alkyl or cycloalkyl, and N- or Li'-substituents, e.g. lower alkyl, in particular Are isopropyl, cycloalkyl or phenyl, or by any other known and suitable esterification process such as Reaction of a salt of acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid. Furthermore can Acid halides, such as chlorides (produced e.g. by

yl
act with oxalic chloride), activated esters (formed, for example, with N-hydroxy nitrogen compounds, such as N-hydroxysuccinimide) or mixed anhydrides (obtained, for example, with haloformic acid lower alkyl esters, such as ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid) converted into an esterified carboxyl group with alcohols, optionally in the presence of a base such as pyridine.

In a compound obtained with an esterified moiety of the formula -C (= O) -Rp can be esterified into another Corboxjrgruppe of this formula can be converted, e.g. 2-chloroethoxycarbonyl or 2-Bromoätho :: ycarbonyl by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable one Solvent, such as acetone, in 2-iodoethoxycarbonyl.

- 82 -

509882/0987

5280U

Mixed anhydrides can be prepared by using a compound of the formula IA or IB with a free carboxyl group of the formula -CC = O) -Rp, preferably a salt, in particular an alkali metal, e.g., sodium, or ammonium, e.g., triethylammonium salt thereof with a reactive one Derivative, such as a halide, e.g. Niederalkanecharbonsäurechlorid, converts.

In a process available in connection with a free carboxyl group of the formula -C (= O) -Rp can be such can also be converted into an optionally substituted carbamoyl or hydrazinocarbonyl group, preference being given to reactive, functionally modified derivatives, such as the above-mentioned acid halides, generally esters, such as also the above activated esters, or mixed anhydrides of the corresponding acid with ammonia or amines, including hydroxylamine, or hydrazines.

One protected by an organic silyl or stannyl group Carboxyl group can be formed in a manner known per se, e.g. by adding compounds of the formulas IA or IB, where R ^ is hydroxy, or salts, such as alkali metal, e.g. sodium salts thereof, with a suitable SiIylierungs- or stannylating agents treated as one of the aforementioned silylating or stannylating agents; please refer

- 83 -

509882/0987

e.g. British Patent No. 1,073,530 resp. ^r . Dutch edition No. 67 / 17107-

Furthermore, discussed functional substituents can be found in Groups RV ', R ^ and / or R ^ »v / ie substituted amino groups, acylated hydroxyl groups, esterified carboxyl groups or Ο, Ο'-disubstituted phosphono groups according to known ones Methods such as those described above, or

A b free functional substituents in groups R ^, R. and / or Rp, v / ie free amino, hydroxy, carboxy or phosphono " groups, functionally modify according to processes known per se, e.g. acylation or esterification or substitution. For example, an amino group can be removed by treatment with Schv.'efeltrioxyd, preferably in the form of a complex with an organic base, such as a tri-lower alkylamine, e.g. triethylamine, convert into a sulfoamino group. Further can the reaction mixture obtained by reacting an acid addition salt of a 4-guanylsemicarbazide with sodium nitrite, with a compound of formula IA or IB, wherein

e.g. the amino protecting group R ^ is an optionally substituted one Glycyl group, convert and so convert the amino into a 3-guanylureido group. You can also get connections with aliphatically bonded halogen, for example with an optionally substituted C 1-4 bromoacetyl group with Esters of phosphorous acid, such as tri-lower alkyl phosphite compounds, convert and 'so to corresponding phosphorus compounds reach.

- 84 -

509882/0987

2 5 2 8 O A

Obtained cephem compounds of the formulas IA and IB can by oxidation with suitable oxidizing agents, such as those described below, in 1 - oxides of the corresponding 3-oephem compounds the formula IA are converted. Obtained 1-oxides of 3-cepheni compounds of the formula IA can by reduction with suitable reducing agents, such as those described below, to the corresponding 3-cephem compounds reduce the formula IA. In these reactions, care must be taken that, if necessary, free functional groups are protected and, if desired, are subsequently released again.

Obtained cephem compounds can be isomerized. Thus obtained 2-cephem compounds of the formula IB, or mixtures of 2- and 3-cephem compounds obtained, Convert into the corresponding 3-cephem compounds of the formula IA, ^ by adding a 2-cephem compound of the formula IB, or a mixture consisting of a 2- and 3-cephem compound, wherein free functional groups optionally, e.g. as indicated, may be temporarily protected, isomerized,. For example, 2-cephem compounds of the formula IB insert »in which the group of the formula -C (= O) -Rp a represents free or protected carboxyl group, a protected carboxyl group also being formed during the reaction can be. <

- 85 -

SO9882 / 098 7

So you can isomerize a 2-cephem compound of the formula IB, by treating them with a basic agent and from an optionally obtained mixture of equal amounts of the 2- and 3-cephem compounds, the corresponding 3-cephem compound of the formula IA is isolated.

Suitable isomerizing agents are, for example, organic nitrogenous bases, v. ^r he tertiary heterocyclic bases of aromatic character, and primarily tertiary aliphatic, azacycloaliphatic or araliphatic bases, v / ie N, N, N-trinieder alkylamines, e.g. Ν, Ν, Ν-trimethylamine, N, N-dimethyl-N- ethylamine, Ν, Ν, Ν-triethylamine or Ν, Ν-diisopropyl-N-ethylamine, N-lower alkyl-azacycloalkanes, for example N-methylpiperidine, or N-phenyl-lower-alkyl-IT, N-di-lower alkyl-amines, for example N-benzyl -N, N-dimethylamine, so / ie mixtures thereof, such as the mixture of a base of the pyridine type, for example pyridine, and a Ν, Ν, Ν-trinieeal alkylamine, for example pyridine and triethylamine. In addition, it is possible to use exclusively inorganic or organic salts of bases, in particular of medium to strong bases with various acids, v / ie alkali metal or ammonium salts of lower alkanecarboxylic acids, for example sodium acetate, triethylammonium acetate or H-ethyl piperidine acetate, as well as other analogous bases or mixtures of such basic agents can be used.

- 86 509882/0987

The above isomerization with basic agents can, for example, be carried out in the presence of a derivative of a carboxylic acid which is suitable for the formation of a mixed anhydride, such as a carboxylic acid anhydride or halide, for example with pyridine in the presence of acetic anhydride. It is preferably carried out in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, with bases used as reactants and bases liquid under the reaction conditions also serving as solvents may, if necessary, while cooling or heating, preferably in a temperature range of about -30 ⁰ C to about +100 ⁰ C, in an inert gas, for example nitrogen atmosphere, and / or in a closed vessel,

Leave the 3-cephem compounds of the formula IA obtainable in this way in a manner known per se, e.g. by adsorption and / or crystallization, of any still present Separate 2-cephem compounds of the formula IB.

The isomerization of 2-cephem compounds of the formula IB can also be carried out by oxidizing these in the 1-position, if desired, an obtainable mixture of isomers the 1-oxides of 3-cephem compounds of the formula

- 87 509682/0987

IA separates, and the thus obtainable 1-oxides of the corresponding 3-cephem compounds of the formula IA reduced.

Suitable oxidizing agents for the oxidation in the 1-position of 2-cephem compounds are inorganic peracids which have a reduction potential of at least +1.5 volts and consist of non-metallic elements, organic per-acids or mixtures of V, ^r ater material peroxy ά and acids, in particular organic carboxylic acids, with a dissociation constant of at least 10 are possible. Suitable inorganic peracids are periodic and persulfuric acid. Organic peracids are the corresponding percarbonuride persulfonic acids, which can be added as such or formed in situ by using at least one equivalent of arsenic peroxide and one carboxylic acid. It is advisable to use a large excess of the carboxylic acid if, for example, acetic acid is used as the solvent. Suitable peracids are, for example, performic acid, peracetic acid, pertrifluoroacetic acid, permaleic acid, perbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid.

The oxidation can also be carried out using hydrogen peroxide carried out with catalytic amounts of an acid having a dissociation constant of at least 10 using low concentrations, e.g. 1-2S-6 and less, but also larger amounts of acid can be used.

- 88 -

509862/0987

The effectiveness of the mixture depends in the first place on the strength of the acid. Suitable mixtures are, for example, those of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.

The above oxidation can be carried out in the presence of suitable catalysts carried out v / earth. For example, oxidation with percarboxylic acids can be caused by the presence of an acid with

■ ■ - 5

a dissociation constant of at least 10, the effectiveness of which depends on their strength. Acids suitable as catalysts are, for example, acetic acid, perchloric acid and trifluoroacetic acid. Usually at least equimolar amounts of the oxidizing agent are used, preferably a slight excess of about 10% to about 20%. The oxidation is carried out under mild conditions, eg at temperatures of et v / a -50 C to about +100 C, preferably from -10 C to about +40 eta ⁰ C.

The oxidation of 2-cephem compounds to the 1-oxides of the corresponding 3-cephem compounds can also be achieved by treatment with ozone, furthermore with organic hypohalite compounds such as lower alkyl hypochlorites, for example tert-butyl hypochlorite, which can be obtained in the presence of inert solvents such as optionally halogenated hydrocarbons, such as methylene chloride, and used at temperatures from about -10 ⁰ C to about +30 ⁰ C, with periodate compounds such as alkali

"■■■; ■ - 89 -

509882/0987

2528ÜU

metallperjodaten, for example potassium periodate, which are preferably used in an aqueous medium at a pH of about 6 and at temperatures of about -10 ⁰ C to about +30 ⁰ C, with iodobenzene dichloride, which is in an aqueous medium, preferably in the presence of an organic base, for example pyridine, and with cooling, for example at temperatures from about -20 ° C. to about ⁰ ° C., or carried out with any other oxidizing agent which is suitable for converting a thio group into a sulfoxide group.

In the 1-oxides of 3-cephem compounds thus obtainable of the formula IA, especially in those compounds in π b

which Rür, Rir and R _{2 have} the preferred meanings given above, the groups R ^, R and / or R ₂ can be converted into one another, split off or introduced within the defined framework. A mixture of isomers Or and / M - oxides can be separated, for example by chromatography.

The reduction of the 1-oxides of 3-cephem compounds of the Formula IA can be prepared in a manner known per se by treating with a reducing agent, if necessary, in the presence an activating agent. Possible reducing agents are: Catalytically activated ones Hydrogen, using noble metal catalysts which contain palladium, platinum or rhodium and which are used

- 90 S09882 / 0987

optionally used together with a suitable carrier material, such as carbon or barium sulfate; reducing tin, Iron, copper or manganese cations, which are in the form of corresponding compounds or complexes of an inorganic or organic nature, e.g. as tin-II-chloride, -fluoride, acetate or formate, iron (II) chloride, sulfate, oxalate or succinate, copper (I) chloride, benzoate or oxide, or Manganese II chloride, sulfate, acetate or oxide, or as complexes, e.g. with ethylenediaminetetraacetic acid or nitrilotriacetic acid, uses v / earth; reducing dithicnite, iodine or iron (II) cyanide anions, which are in the form of corresponding inorganic or organic salts, such as alkali metal, e.g. sodium or potassium dithionite, sodium or Potassium iodide or iron (II) cyanide, or in the form of the corresponding acids, such as hydriodic acid, are used will; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, also esters, amides and Halides of phosphinous, phosphonous or phosphorous acid, as well as these phosphorus-oxygen compounds corresponding Phosphorus sulfur compounds, in which organic Residues primarily aliphatic, aromatic or araliphatic Radicals, e.g. optionally substituted lower alkyl, Represent phenyl or phenyl lower alkyl groups, such as triphenylphosphine, tri-n-butylphosphine, methyl diphenylphosphinate, Diphenylchlorophosphine, phenyldichlorophosphine, dimethyl benzene phosphonate, butane

- 91 -

509882/0937

methyl phosphate, triphenyl phosphate, trirethyl phosphate, phosphorus trichloride, phosphorus tribromide, etc .; reducing halosilane compounds ,. the at least one hydrogen atom bonded to the silicon atom and those other than halogen; such as chlorine, bromine or iodine, also organic radicals such as aliphatic or aromatic groups, e.g. optionally substituted lower alkyl or phenyl groups, v / ie chlorosilane, bromo-, silane, di- or trichlorosilane, di- or tribroinsilane, Diphenylchlorosilane, dimethylchlorosilene, etc .; reducing quaternary chloromethylene iminium salts, in particular chlorides or bromides, in which the lininium group is substituted by one divalent or two monovalent organic radicals, v / ie optionally substituted lower alkylene or lower alkyl groups, v. ^r ie N-chloromethylene-NjN-diethyl-iminium chloride or N-chloromethylene-pyrrolidinium chloride and complex metal hydrides, v / ie sodium borohydride, in the presence of suitable activating agents, v / ie cobalt-II chloride and borane dichloride.

As activating agents used together with those of the above-mentioned reducing agents, which oneself do not have Lewis acid properties, i.e. primarily together with the dithionite, iodine or iron (II) cyanide and the non-halogenated trivalent phosphorus reducing agents or in catalytic reduction

- 92 5 09882/0987

Used v / ground are in particular organic carboxylic and sulfonic acid halides, also sulfur, phosphorus or Silicon halides with the same or greater second order hydrolysis constant than benzoyl chloride, e.g. phosgene, Oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride, Pivalic acid chloride, 4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulfonic acid chloride, methanesulf ons only echlorid, thionyl chloride, phosphorus oxychloride, Phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, Benzolphosphonigsauredichloride, Dimethylchlorosilan or Trichlorsiiari, also ■

509882/098 7

«4

suitable acid anhydrides, such as trifluoroacetic anhydride, or cyclic sultones, such as ethanesultone, 1,3-propanesultone, 1,4-butane sultone or 1,3-hexane sultone should be mentioned.

The reduction is preferably carried out in the presence of solvents or mixtures thereof, the selection thereof primarily due to the solubility of the starting materials and the choice of reducing agent is determined, such as lower alkanoic acids or esters thereof such as acetic acid and ethyl acetate in catalytic reduction, and e.g. optionally substituted, such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic Hydrocarbons, e.g. benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives such as lower alkanecarboxylic acid esters or nitriles, e.g. ethyl acetate "or acetonitrile, or amides of inorganic or organic Acids, e.g. dimethylformamide, dimethylacetamide or hexa-methylphosphoramide, Ethers, e.g. diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. acetone, or sulfones, in particular aliphatic sulfones, e.g. dimethyl sulfone or tetramethyl sulfone on, etc., together with the chemical reducing agents, these solvents preferably containing no water. Usually, temperatures of about −20 ° C. to about 100 ° C. are used, with the use of very reactive activators the reaction at deeper Temperatures can be carried out.

S09882 / 0987

In the 3-cepheni compounds of the formula IA obtainable in this way, R * R ^ and / or R ₃ , as described above, can be converted into other groups R *, R ₁ or R ₂ .

Salts of compounds of the formulas IA and IB can be prepared in a manner known per se. So you can use salts of such compounds having acidic groups, for example by treatment with metal compounds such as alkali metal salts of suitable ones Carboxylic acids, e.g. the sodium salt of cc-ethyl-caproic acid, or with ammonia or a suitable organic amine, preferably stoichiometric amounts or only a small excess of the salt-forming agent is used. Acid addition salts of compounds of Formulas IA and IB with basic groups are obtained in the usual way Manner, for example by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of the formulas IA and IB, which have a salt-forming amino group and contain a free carboxyl group, for example by neutralizing salts, such as acid addition salts, on the isoelectric Point, e.g. with weak bases, or by treating with

509882/0987

'- ■ .. ' ¹ ^ '' . 2529044

liquid ion exchangers are formed. Salts of 1-oxides of compounds of the formula IA with salt-forming groups can be prepared in an analogous manner.

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

Mixtures of isomers obtained can be separated into the individual isomers by methods known per se V7crdenj mixtures of diastereomeric isomers e.g. by fractional crystallization, adsorption chromatography (column or thin-layer chromatography) or other suitable ones Separation process. Obtained racemafce can in usual V7eise, if necessary after introduction of suitable salt-forming Groupings, e.g. by forming e5.nes mixture of diastereoisomeric salts with optically active salt-forming Means separating the mixture into the diastereoisomeric salts and converting the separated salts into the free compounds or by fractional crystallization from optically active solvents into which antipodes are separated.

509882/0 9 87

The method also includes those embodiments according to which compounds obtained as intermediates and in particular as by-products of the formula III, as starting materials are used and the remainder of the process steps are performed with them, or the process on any Stage is canceled; Furthermore, starting materials can be in the form used by derivatives or formed during the reaction.

Such starting materials are preferably used and the reaction conditions are chosen so that the compounds listed at the beginning as being particularly preferred are obtained.

The method according to the invention is distinguished from one another hitherto known processes are characterized by the fact that it is made from cheap, easily accessible starting materials, such as the 1-oxides the fermentatively producible penicillins G or V and the 6-aminopenicillanic acid, whose reactive groups Protected in some known way and easily released again after the reaction, it proceeds under very mild basic or neutral conditions and at low temperature that the ring closure is carried out in one stage takes place (compared to the two-stage according to NL 72.08671 Synthesis) that high yields are achieved and the end products are obtained in great purity (including the production the intermediate products required according to the invention are carried out with high

509882/0987

high yields) that with relatively short reaction times comes and that by-products of the formula III which may be formed in small amounts also convert into the desired pharmacologically active end products of the formula IA can be converted.

A particular advantage of the method according to the invention compared to the known rearrangements of penicillin-1-oxides under acidic conditions (US Patent 3,275,626, DOS 2344-130, JA 9007-299) consists in the fact that the starting materials can also contain protective groups which can be split off under acidic conditions.

The starting materials used according to the invention of the formulas II and III can be prepared, for example, according to the following reaction scheme:

S0tM2 / O§i7

ff

0-

(IV)

.N

O = C-R ^

CH,

CH,

O = J

(II)

S-Y

-N

ο-6-ή

CH

Ha: Y = -SR, Hb: Y = ~ ^S0 2 ~ ^R 4

Hc: Y = -S-SO ₀ -R,

2

1\

0,

(III)

, S-Y -CH

-N

0 = C-R

3.

-CH, \ 2 -

IHa: Y = -SR ₃ IHb: Y = -SO ₂ -R, IHc: Y = -S-SO ₀ -R.

2

509ΙΙ2 / § 7

Starting compounds of the formula IV are known or can be prepared by known processes.

Compounds of the formula Ha and IHa are also known or can according to the Dutch patent specification 72.08671 can be manufactured.

Compounds of the formula Hb can be obtained from compounds of the formula IV by reaction with a sulfinic acid of the formula HSO ₂ -R ^ or a sulfonyl ^{cyanide of the formula N S} C-SO ^ -R ^. Compounds of the formula Hc: can be obtained from compounds of the formula IV by reaction with a thiosulfonic acid of the formula HS-SO ^ -Ra. The reaction takes place in an inert solvent or solvent _mixture, for example an optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic! or aromatic hydrocarbons like. Pentane, hexane, cyclohexane, benzene, toluene, methylene chloride, chloroform or chlorobenzene, an aliphatic, cycloaliphatic or aromatic alcohol, much lower alkanol, for example methanol, ethanol, cyclohexanol or phenol, a polyhydroxy compound, for example a polyhydroxyalkane such as dihydroxy lower alkane, for example Ethylene or propylene glycol, a lower ketone such as acetone or methyl ethyl ketone, an ethereal solvent such as diethyl. Jither, dioxane or tetrahydrofuran, a lower carbon

5 09 88 270 987

528044

acid amide, - such as dimethylform or dimethylacetamide, a lower dialkyl sulfoxide such as dimethyl sulfoxide and the like or mixtures thereof.

The reaction takes place at room temperature or preferably at an elevated temperature, e.g. at the boiling point of the solvent used, if desired in one Inert gas such as nitrogen atmosphere.

The reaction with the sulfonyl cyanide of the formula N = C-SO ₉ -R ^ is accelerated by adding compounds which produce halogen anions. Suitable compounds providing halogen anions are, for example, quaternary ammonium halides, in particular chlorides and bromides, such as those optionally substituted on the _{lower alkyl groups, for example by aryl 3} such as phenyl, mono- or polysubstituted tetra-lower alkyl ammonium halides such as tetraethyl or benzyl triethylammonium chloride or - bromide. The halogen anion-donating compounds are added in amounts of from about 1 to about 50 mol percent, preferably from about 2 to about 5 mol percent.

S09882 / 0987

-VtC- ■

25280Α4

Compounds of the formula Hb and Hc can also be obtained by converting a compound of the formula Ha iniU into a heavy metal sulfinate of the formula M (SO ₀ -R.) Or with a heavy metal thiosulfonate of the formula M (S-SO ₉ -Ra ), V7orin M represents a heavy metal cation and η means the value of this cation. Suitable heavy metal sulfinates or thiosulfonates are in particular those which have a greater solubility product in the reaction medium used than the heavy metal compounds of the formula M (-SR) formed during the reaction. Suitable heavy metal cations M are in particular those which form particularly sparingly soluble sulfides. These include, for example, the monovalent or divalent cations of

• H-copper, mercury, silver and tin, "where copper-- and Silver cations are preferred.

The heavy metal sulfinate or thiosulfonate can either be used as such or formed in situ during the reaction, for example from a sulfinic acid of the formula HSO ₀ -R. or a thiosulfonic acid der

Formula HS-SO ₂ -R, or a soluble salt thereof, e.g. an alkali metal, such as sodium salt, and a heavy

509882/0987

-μί-

metal salt, the solubility product of which is greater than that of the heavy metal sulfinate formed. Or thiosulfonate, for example a metal nitrate, acetate or sulfate, e.g. silver nitrate, mercury-II-diacetate or copper (II) sulfate or a soluble chloride, like tin (II) chloride dihydrate.

The implementation of a compound of the formula Ha with the Schwennetallsulfinat of the formula K '(SO ^ -R.) Or thiosulfonate of the formula H (S-SOp-R,) can be used in an inert organic solvent, in water or in a solvent mixture consisting of water and a water-miscible solvent. Suitable inert organic Solvents are, for example, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, Cyclohexane, benzene, toluene, xylene, or aliphatic, cycloaliphatic or aromatic alcohols, such as lower alkanols, e.g. methanol, Aethanbl, cyclohexanol or phenol, polyhydroxy compounds, such as polyhydroalkanes, e.g. dihydroxy lower alkane, such as ethylene or propylene glycol, carboxylic acid esters, e.g. lower carboxylic acid lower alkyl esters such as ethyl acetate, lower ketones, such as acetone or methyl ethyl ketone, ether-like solvents, v; ie dioxane, tetrahydrofuran or the like Polyethers, v? Ie dimethoxyethane, lower carboxamides, many dimethylformamide, lower alley nitriles, such as acetonitrile

509882/0987

or lower sulfoxides such as Diirethylsulfoxid. In water or The reaction proceeds in particular in mixtures of water and one of the solvents mentioned, including in emulsions usually much faster than in the organic solvents alone.

)) 5.e reaction temperature is usually at room temperature, but can be lowered to slow down the reaction or to accelerate it, for example up to the boiling point of the solvent used, with wan at can work with normal or increased pressure.

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 serve to illustrate the invention; Temperatures are given in degrees Celsius.

5098Ö2 / 0987

example 1

Dimethylformamide is passed through a short column of ba ~ secure aluminum oxide (Woelm activity I) filtered and then gives a positive test for amines with 2,4-Dinitrofluorbenzcl. A mixture of 101 mg of 2- [4- (2-benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid-2,2,2-trichloroethyl ester in 10 ml of this basic dimethylformamide is stirred for 20 minutes at room temperature. the The reaction mixture is dissolved in 150 ml of 5% strength aqueous sodium carbonate solution and added 50 ml of ethyl acetate. The organic phase is separated off with water and saturated aqueous Washed sodium chloride solution, dried over sodium sulfate and freed from solvent in vacuo. From the backlog consisting of a mixture of 7ß-phenoxyacetamido-3-methylceph-3-em-4-carboxylic acid-2,2,2-trichloroethyl ester and 2- [4- (2-Benzthiazolyldithio) -S-phenoxyacetamido ^ -oxoazetidin-1-yl] -3-methyl-crotonic acid-2,2,2-trichloroethyl ester in a ratio of about 9: 1 is made by crystallization from hot isopropanol the pure 7ß-phenoxyacetamido-3-methyl-ceph-3-em-4-carboxylic acid 2,2,2-trichloroethyl ester obtained, melting point 113-116 ° C.

509882/0987

2523044

The starting material can be obtained as follows:

Analogously to Example 4b), 498 mg (1 mM) of 6-phenoxyacetamido-penicillanic acid-2,2,2-trichloroethyl ester-lβ-oxide are obtained and 200.7 mg (1.2 ErM) 2-mercaptobenzothiazole of 2- [4- (benzthiazol-2-yl-dithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid 2,2,2-trichloroethyl ester obtain; Melting point 144-149 ° G (from methylene chloride / pentane), Rf value = 0.5 (silica gel; Ether).

Example 2

The 7β-phenoxyacetamido-3-methyl-ceph-3-em-4-carboxylic acid 2j2j2-trichloroethyl ester is also obtained if, instead of the basic diinethylformamide according to Example 1, 10 ml of dimethyl acetamide containing 10 mg of 60% strength aqueous dimethylamine is used as a solvent.

Example 3

A solution of 111 mg of 2- [4- (2-Benzthiazolyldithio) Diphenylmethyl 3-phenoxyacetamido-2-oxoazetidin ~ l-yl] -3-methylenebutyrate in 10 ml of basic dimethylformamide (according to Example 1) is stirred for 15 minutes at room temperature. Working up according to Example 1 gives the 7β-phenoxyacetainido-3-methyl-ceph-3-em-4-carboxylic acid diphenylmethyl ester,

509882/0987

AT THE

The starting material can be obtained as follows:

a) From 100 g (27.3 mM) 6-phenoxyacetamido-penicillanic acid-lß-oxide, 500 ml of dioxane and 58.4 g (30 ml!) Of diphenylmethy! Diazomethane After about 2 hours, the 6-phenoxyacetamidopenicillanic acid-diphenylmethylester-1ß-oxide obtain; Melting point 144-146 ° C (ethyl acetate / petroleum ether).

b) Analogously to Example 4b), 292 g (55 mm, M) 6-phenoxyacetamido-penicillanic acid-diphenylmethyl ester-lß-oxide and 99 g (59.5 ml ·!) 2-mercaptobenzothiazole of 2- [4- (benzthiazole- 2-yldithio) -3-phenoxyacetairado-2-oxoazetidin-1-yl] »3-n; diphenylmethyl ethylenebutyrate obtained; Melting point 140-141 ° C (from toluene / ether).

Example 4

A solution of 103 mg of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid p-nitrobenzyl ester in 10 ml of dimethylacetamide containing 21 mg of triethylamine is stirred for 15 minutes at room temperature. Working up according to Example 1 gives the 7β-phenoxyacetamido ^ -methyl-ceph-S-em ^ -carboxylic acid p-nitrobenzyl ester.

S09882 / O987

/in

The starting material can be obtained as follows:

a) A solution of 36.6 g (0.1 M) 6-phenoxyacetamidopenicillanic acid l / i-oxide, 11.1 ml (0.11 M) triethylamine and 23.8 g (0.11 M) p-nitrobenzyl bromide in 200 ml dimethylformamide is for 4 hours at room temperature under nitrogen touched. The reaction solution is then introduced into 1.5 l of ice water, and the precipitate is filtered off, dried and recrystallized twice from ethyl acetate-methylene chloride. The colorless, crystalline 6-phenoxyacetamidopenicillanic acid pnitrobenzyl ester-lß-oxide melts at 179-180 ° C.

^b ) A solution of 5.01 g (10 mM) 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester-lβ-oxide and 1.67 (10 mm) 2-mercaptobenzt.hiazole in 110 ml dry toluene is refluxed under a nitrogen atmosphere for 4 hours. The solution is concentrated to approx. 25 ml by distillation and diluted with approx. 100 ml of ether. The rejected

509802/0987

dene product is uirikristallisiert from methylene chloride-ether and ir.an receives the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-meth3- ^T len-butyric acid-nitrobenzyl ester from Melting point 138-141 ° C.

c) To a solution of 3.25 g (5.0 niM) 2- [4- (Benzthi & r-.ol-2-yldithio) -S-phenoxyacetamido-P.-oxoazetidin-1-yl] -3-methyl-en-butyric acid p-nitrobenzyl ester 1.06 g of finely powdered silver nitrate are added to 200 ml of acetone / water 9: 1 C ⁷ Iv) ". Immediately afterwards, the solution of 890 mg (5 mg) of sodium p-toluenesulfinate in 100 ml of the same solvent mixture is added (within ten minutes A light yellow precipitate forms immediately. After stirring for one hour at room temperature, it is filtered with the addition of Celite. The filtrate is diluted with water and extracted twice with ether. The combined ether extracts are dried over sodium sulfate and, after concentration, give the Pale yellow solid 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-rcethylene butyric acid, cp-nitrobenzyl ester. Rf value - 0.24; IR spectrum (in

509882/0987

Cl ₂ ): characteristic bands at 3.90, 5.56, 5.70, 5.87, 6.23, 6.53, 6.66, 7.40, 7.50, 8.10, 8.72, 9.25, 10.95 p. The product can be used in the subsequent reaction without further purification.

The same connection can also be obtained by the following methods:

ei) To a solution of 3.25 g (5.0 mM) 2- [4- (Benzthiazcl 2-yldithio) -3-phenoxyacetamido ~ 2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester in 200 ml acetone / water 9: 1 ( ^v / v), 1.58 g (1.2 equivalents) of silver p-toluenesulfinate are added in portions over a period of 10 minutes. The suspension is stirred for one hour at room temperature, filtered and processed further as described in Example 4c). The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-meth3'len-butyric acid-p-nitrobenzyl ester] is obtained in quantitative yield.

Silver p-toluenesulfinate is made by combining aqueous solutions of equimolar amounts of silver nitrate and sodium p ~ toluenesulfinate are obtained as a colorless precipitate. The product is dried in vacuo for 24 hours.

509882/0987

cii) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl ] -3-methylenebutyric acid p-nitrobenzyl ester can also analogously to Example 4ci) from 3.25 g of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidinl-yl] -3-methylenebutyric acid p-nitrobenzyl ester and 1.87 g (2 equivalents) copper-II-di-p-toluenesulfinate in quantitative Yield can be obtained.

The copper-II-di-p-toluene sulfinate is made by reacting of copper sulfate and sodium p-toluenesulfinaf- (2 eq.) preserved in water. After filtering off, the salt is dried in vacuo at 60 ° C for 12 hours.

ciii) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetan \ ido-2-oxoazetidin-l-yl] ~ 3-methylenebutyric acid p-nitrobenzyl ester can also analogously to Example 4 ei) from 130 mg of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-iriethylene-butyric acid p-nitrobenzyl ester and 85 mg (2 equivalents)

Get tin-II-di-p-toluenesulfinate.

The tin-II-di-p-toluenesulfinate is made by reacting of tin (II) chloride (2H ^ O) and sodium p-toluenesulfinate in Get water. After filtering off and washing with water, the salt is in a vacuum for about 12 hours at 50-60 ° C dried.

S09882 / 0987

civ) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-ynethylanobutyric acid p-nitrobenzyl ester can also be prepared analogously to Example lei) from 130 mg 2- [4- (benztbiazole -2-yldithio) -3 - phenoxyacetaraido-2-oxoazetidin-l-3 ⁷ l] 3-methyl-butyric acid p - nitrobenzyl ester and 102 mg (2 equivalents) are obtained mercury-II-di-p-toluene sulfinate. The mercury-II-di-p-toluenesulfinate is obtained by reacting mercury-II-di-acetate and sodium p-toluenesulfinate in water. After filtering off and washing with water, the salt is dried in vacuo at 50-60 ° C for about 12 hours.

cv) A solution of 517 mg (1.02 mM) 6-phenoxyacetamido-penicillanic acid-p-nitrobenzyl ester-1β-oxide and 187 mg (1.2 IfM) p-toluenesulfinic acid in 10 ml 1,2-dimethoxyethane is refluxed for 4.5 hours in a nitrogen atmosphere heated, whereupon a further 308 mg (1.98 mM) p-toluenesulfinic acid dissolved in 2 ml of 1,2-dimethoxyethane in five portions at 45 minute intervals. After 4.5 hours the reaction mixture is poured into 100 ml of 5% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are ir.with water

B09882 / 0987

and saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is chroniatographed on silica gel thick-layer plates with toluene / ethyl acetate 2: 1 and gives the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-o: ioazetidin-1-yl] -3-me t hy 1 enbu 11 er s au r c- ρ -nitr ob enzy 1 est eic .

cvi) A mixture of 250 mg (0.5 mM) 6-phenoxyacetarnidopenicillanic acid p-nitrobenzyl ester-lß-oxide, 110 mg (0.61 mM) p-toluenesulphonyl cyanide and 5 mg (0.022 mM) benzyl-triethylammonium chloride in 2 ml of dry, peroxide-free dioxane stirred under argon at 110 ° C. for 4.5 hours. The solvent is evaporated in vacuo and the remaining yellow oil is chroniatographed on acid-washed silica gel. Elution with 30% ethyl acetate in toluene gives the 2- [4- (p-toluenesulfonylthio) ~ 3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methylenebutyric acid p-nitrobenzyl ester.

cvii) A mixture of 110 mg (0.61 niM) p-toluenesulfonyl cyanide and 4.5 mg (0.021 mM) tetraethylammonium bromide in 1 ml of pure dioxane is at 110 ° C under argon for 30 Minutes stirred. A suspension of 250 mg (0.5 mg) of G-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester is then added.

509882/0987

Lβ oxide in 1 ml of dioxane was added and the resulting solution was stirred for 4 hours at 110 ° C. under argon. The solvent
■ is removed in vacuo, the crude product is dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic phase is made with magnesium sulfate
dried and freed from solvent in vacuo and gives crude p-nitrobenzyl 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetarnido-2-oxoazetidin-1-yl] -ß-methylenebutyric acid.

Example 5

A solution of 3.28 g of 2- [4- (2-Benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid-2,2,2-trichloroethyl ester in 15 ml according to Example 1 The basic dimethylformamide produced is stirred for 60 minutes at room temperature, then at about -15 ° C (ice-salt bath)
a solution of 20 mg of sodium borohydride in 1 ml of dimethylformamide is added and the mixture is stirred for a further 5 minutes. Working up according to Example 1 gives crude 7ß-phenoxyacetamido-3-methyl-ceph-3-em-4-carboxylic acid 2,2,2-trichloroethyl ester, the
the by-product 2- [4- (2-Benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methyl-crotoric acid-2,2,2-

does not contain trichloroethyl ester.

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Example 6

A solution of 390 mg of sodium rhodanide in 20 ml Dimethylformamide is mixed with 219 mg of 2- [4- (2-benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid-2,2,2-trichloroethyl ester added and stirred for 15 minutes at room temperature (22 ° + 5 °). The reaction solution is with 100 ml of ethyl acetate are added and 250 ml of 5% aqueous sodium carbonate solution are added one after the other, three times with 100 ml each time Water and once with saturated, aqueous sodium chloride solution washed, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is hot from 5 ml Isopropanol recrystallizes and gives the 7/3-phenoxyacetamido-3-methyl-ceph-3-em-4-carboxylic acid-2, 2,2-trichloroethyl ester with a melting point of 113-116 °.

Example 7

The yß

2,2,2-trichloroethyl ester is also obtained if 390 mg of sodium rhodanide with 219 mg of 2- [4- (2-benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylen-butyric acid 2,2,2-trichloroethyl ester are stirred for 4 hours at 10 ° C. in 20 ml. Dimethylformamide / water 9 _: 1 and the work-up is carried out as in Example 6.

509 8 82/0987

Example 8

A solution of 200 mg of sodium rhodanide in 10 ml of dimethylformamide is mixed with 100 mg of 2- [4- (2-benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin ~ l-yl] -3-methylenebutyric acid · - added p-nitrobenzyl ester and stirred for 15 minutes at room temperature. Working up according to Example 6 gives the 7β-phenoxyacetamido-3-methyl-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester

Example 9

A solution of 200 mg of sodium rhodanide and 100 mg of 2- [4- (2-benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methylenebutyric acid-2j2,2-trichloroethyl ester in 15 ml of acetone is 15 hours at Stirred at room temperature and then freed from the solvent in vacuo. The residue is taken up in methylene chloride and successively with 5% aqueous sodium carbonate solution, water and saturated
washed aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated in vacuo. Preparative thick layer chromatography on silica gel with toluene / ethyl acetate 2: 1 as the mobile phase gives the

609862/0987

AAf.

252804 /.

7/3-Phenoxyacetamido-3-methyl-ceph-3-em-4-carboxylic acid 2,2,2-trichloroethyl ester melting point 113-116 ° (isopropariol).

Example 10

The 7-β -Phenoxyacetamido 3-methyl-ceph-3-em-4-carboxylic acid-2,2,2-trichloroethyl may also be obtained if the reaction according to Example 9 as a solvent in 25 ml of acetonitrile. The work-up is carried out analogously to Example 9.

Example 11

The 7ß-phenoxyacetamido-3-methyl-ceph-3-em-4-carboxylic acid 2j2,2-trichloroethyl ester can also be obtained if the reaction according to Example 9, instead of sodium rhodanide is carried out in the presence of 313 mg of sodium iodide. The work-up is carried out according to Example 9.

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/in-

Example 12

A solution of 89 mg of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido ] -3-methyl-crotonic acid p-nitrobenzyl ester in 4 ml tetrahydrofuran (distilled over sodium in the presence of benzophenone) containing 41.6 µl 1,5-diazabicyclo [5.4.0] undec-5-en is 35 under a nitrogen atmosphere Stirred minutes at room temperature. The reaction mixture is poured into a 10% aqueous citric acid solution and rr.it 25 ml of ethyl acetate extracted. The organic phase is successively mixed with water, aqueous sodium hydrogen carbonate solution, again washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and in vacuo evaporated. The residue contains 7β-phenoxyacetamido-3-methyl-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester and 7jS-phenoxyacetamido-3-methy1-ceph-2-em-4α-carboxylic acid p-nitrobenzyl ester in a ratio of about 3: 1, which can be separated from by-products by chromatography on silica gel.

Example 13

A solution of 1 g of 2- [4- (2-Benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid p-nitrobenzyl ester and 355 mg of sodium p-toluene thiosulfonate

509882/0987

/IN THE

(G. Troeger, T. Volkmer, J. Prakt. Chem. JO_, 382) in 10 ml acetone is gerlihrt k \ hours at room temperature, filtered and then ¹ freed from solvent in vacuo. The residue is taken up in 100 ml of ethyl acetate, washed successively with water, 5% aqueous sodium carbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and freed from the solvent in vacuo. The residue is chromatographed on 40 g of silica gel with toluene / ethyl acetate 2: 1 as the mobile phase and gives the 7β-phenoxyacetamido-S-methyl-ceph-S-em - ^ - carboxylic acid p-nitrobenzyl ester.

Example 14

A solution of 55 mg of 2- [4- (p-toluenesulfonyldithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl) -3-methylenebutyric acid-p nitrobenzyl ester in 10 ml Diinethylforir.amid is with a Drops of 40% aqueous dimethylarain are added and the mixture is kept at 0 ° C stirred for 15 minutes. The reaction mixture is diluted with 25 ml of ethyl acetate and successively with 100 ml

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4-n

-129-

5% aqueous sodium carbonate solution, 100 ml 10% aqueous citric acid solution, 100 ml of water and 25 ml of saturated Washed sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue will Chromatographed on silica gel thick-layer plates with toluene / ethyl acetate 2: 1 as the mobile phase and gives the 7/3-phenoxy-acetamido-3-methyl-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in pure form.

The starting material can be produced as follows:

A solution of 1 g of 2- [4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester 500 mg (1.1 equivalents) of silver p-toluene thiosulfonate are added in 10 ml of acetone and the mixture is carried out for 22 hours stirred at evacuation peratur. The reaction mixture is filtered and washed with acetone. The filtrate is evaporated to about 3 ml and a little diethyl ether is added. The crystalline 2- [4- (p-Toluenesulfonyldithio) -3-phenoxyacetamido ~ 2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester is suction filtered and recrystallized from methylene chloride / diethyl ether; Melting point 129-131 ° C.

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Silver p-toluene thiosulfonate is prepared by combining obtained aqueous solutions of equivalent amounts of silver nitrate and sodium p-toluene thiosulfonate. The crystals will be suction filtered, washed with water and dried in a high vacuum at 80 ° C .; Melting point 174-176 ° C.

Example 15

A solution of 117 mg (0.194 mM) of 2- [4- (2-Benzthiazolyldithio) -S-phenoxyacetamido-Z-oxoazetidin-1-yl] -3-methylene-butyric acid benzyl ester in 2 ml of dimethyl sulfoxide is at 15 ° C with 12 mg (0.150 mM) of a 407o strength aqueous Added methylamine solution and stirred for 20 minutes at the same temperature. The reaction mixture is with 25 ml Ethyl acetate diluted, one after the other with 1070% aqueous citric acid, water, twice 57% aqueous Sodium carbonate solution, water and saturated aqueous sodium chloride solution, washed over anhydrous sodium sulfate dried and evaporated in vacuo. The residue is recrystallized from methylene chloride / diethyl ether and gives the 7β-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid benzyl ester with a melting point of 152-153 ° C.

509882/0987

a.

-ιζί-

The starting material can be prepared as follows

will:

a) To a solution of 36.6 g (0.1 mol) of 6-phenoxyacetamido-penicillanic acid-lß-oxide in 150 ml of dry dimethylformamide, while cooling with tap water, 20 ml (14.6 g, 0.145 mol) triethylamine and 17 ml (24.5 g, 0.143 mol) Benzyl bromide added. The mixture is kept at room temperature for 20 hours stirred, then poured onto ice water. The precipitate is filtered off with suction, washed with approx. 1000 ml of water, Dried in vacuo at 40 ° for 2 days, then taken up in 200 ml of methylene chloride and dried again with sodium sulfate. The white foam remaining after evaporation of the solvent in vacuo is dissolved in 150 ml of ethyl acetate dissolved and left to stand first at room temperature, then at -20 °, with pure 6-phenoxyacetamido-penicillansa'urebenzylester-lß-oxide crystallized. Melting point 139-14O ° C; IR spectrum (methylene chloride); characteristic bands

on
5.55, 5.75, 5.90>i; [α] ^ ^υ = + 174 ° + 1 ° (c = 1, chloroform).

The mother liquor can be chromatographed on 250 g of acid-washed silica gel with toluene-ethyl acetate (1: 1) additional amounts of the crystalline benzyl ester isoxide can be obtained.

509882/0987

b) 4.56 g (10 nmoles) of 6-phenoxyacetamido-penicillanic acid benzyl ester lp-oxide and 1.84 g (11 mmol) -2-mercaptobenzothiazole are refluxed (bath temperature 135 °) in 100 ml of toluene for 5 hours. The mixture is left to stand the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid benzyl ester crystallized out. The crystals are filtered off with suction, washed with 50 ml of toluene and dried in a high vacuum. By chromatography the mother liquor on 70 g of acid-washed silica gel with toluene-ethyl acetate (3: 1) can add further amounts of the crystalline product can be obtained. Melting point of the pure product 150-153 ° C; IR spectrum (methylene chloride):

20th

characteristic bands at 5.60, 5.75, 5.9Q ₁ U; [α] = -112 ° + 1 ° (c = 1; chloroform).

Example 16

A solution of 0.263 g (0.5 mM) 2- [4- (2-Benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid methyl ester in 1 ml dimethylformamide is at -20 ° +5 ⁰ C with stirring, 1 ml of an anhydrous solution of 0.165 mM ammonia in dimethylformamide is added dropwise and the mixture is kept at the same temperature for 1 hour.

S09882 / 0987

25280U

tergerUhrt. After passing in 10 mg (0.25 mM) of gaseous hydrogen chloride, the dimethylformamide is distilled off in vacuo, the residue is taken up in 5 ml of ethyl acetate, washed successively with twice 5 ml of 5% aqueous sodium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is recrystallized from methylene chloride / diethyl ether and gives the 7ß- • Phenoxyacetamido-S-methyl-S-cephem-A-carboxylic acid methyl ester with a melting point of 138-140 ° C, which corresponds to that according to RB Morin et al., J Amer. Chem. Soc. 91. » ¹ ^ Ol (1969), manufactured product is identical.

The starting material can be produced as follows:

A solution of 19.25 g (50 mmol) of 6-phenoxyacetamido-penicillan acid methyl ester-lβ-oxide and 9.4 g (55 mmol) of 2-mercaptobenzothiazole in 500 ml of dry toluene Boiled under reflux for 8 hours and then in a vacuum constricted. The residue is heated (- ~ · 80 °) in 400 ml of ethyl acetate dissolved, treated with 0.2 g of activated charcoal: and suction filtered through an electrically heated glass frit. On cooling, the methyl 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazel.idin-1-yl] -3-methylen-buttors'ate separates from melting point 132 ^ 134 ° C. Further quantities of this compound can be obtained from the mother liquors can be obtained (melting point 135 'v / 137 ° C).

509882/0987

Example 17

A solution of 682.5 mg (1 mM) 2- [4- (2-Benzthiazolyldithio) -3-phenoxyacetamido-2- oxoazetidin-1-yl] -3-methylin-butyric acid-diphenylmethyl ester in 5 ml dimethylformamide is at -25 +5 ° C ⁰ dropwise and while stirring with 78 of a 24% aqueous ammonia solution mg (containing 1.25 equivalents NH-), and stirring continued for 30 minutes at the same temperature. The reaction mixture is diluted with 15 ml of ethyl acetate, washed successively with 50 ml of 10% aqueous citric acid, 10 ml of water, twice 10 ml of 57 ° aqueous sodium carbonate solution and 10 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is recrystallized from diethyl ether or methylene chloride / diethyl ether and gives 7β-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid diphenylmethyl ester with a melting point of 155-156 ° C.

509882/0987

ASf

Example 18

A solution of 500 mg of crude 2- [4- (2-benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid p-nitrobenzyl ester (approx. 90% pure) is dissolved in 3 ml of dimethylformamide and added dropwise at -25 ° + 5 ° C and 40 mg of a 24% strength aqueous ammonia solution (containing 0.9 equivalents of NH 2) were added with stirring and 30 minutes stirred further at the same temperature. Working up of the reaction mixture as in Example 17 and crystallization from methylene chloride / diethyl ether gives the 7ß-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid p-nitrobenzyl ester from melting point 189-191 ° C, the melting point and mixed melting point with a prepared according to Hatfield and in E.H. Flynn "Cephalosporins and Penicillins", Academic Press, New York, 1972, page 670, the published preparation is identical

Example 19

a) A solution of 214 mg (0.32 mM) 2- [4- (2-Benzthia · zolyldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid-2,2,2 -trichloroethyl ester in 3 ml of dimethylformamide is at -25 ° +5 ⁰ C with 13 mg of a 24% aqueous

509882/0987

AU

Rigen ammonia solution (containing 0.65 equivalents of NHL) was added and stirring was continued for 30 minutes at the same temperature, work-up of the reaction mixture analogously to Example 17 and
Crystallization from isopropanol gives the 7β-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with a melting point of 115-117 ° C.

b) The same compound is obtained if, under otherwise identical conditions, instead of the aqueous ammonia solution, 0.75 equivalents of anhydrous ammonia gas are used.

c) The same compound is obtained if, under otherwise identical conditions, instead of the aqueous ammonia solution, 0.24 mM anhydrous ethylenediamine can be used.

d) The same compound is obtained if, under otherwise identical conditions, instead of the aqueous ammonia solution, 0.5 equivalents of anhydrous cyclohexylamine are used.

e) The same compound is obtained if, under otherwise identical conditions, instead of the aqueous ammonia solution, 1.15 equivalents of 10% aqueous sodium hydroxide solution can be used.

509882/0987

-yn-

/ W-

2523044

Example 20

A solution of 95 mg of 2- [4- (2-benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid-2,2,2-trichloroethyl ester in 1.5 ml of dimethyl sulfoxide is mixed with 13 mg of 20% aqueous ammonia solution (containing 1.25 Equivalents NiL.) Are added and the mixture is stirred at room temperature for 4 minutes. Working up the reaction mixture analogously to the example 17 gives a 4: 1 mixture of 7β-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid 2j2,2-trichloroethyl ester and the corresponding 2-cephem derivative from which the 3-cephem compound is obtained from melting point 114-116 ° C by crystallization from diethyl ether.

Example 21

A solution of 98 mg (0.165 mM) 2- [4- (2-Benzthiazolyldithio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-methylene butyric acid diphenylmethyl ester in 1.5 ml of dimethylformamide is 30 minutes at -25 ° + 5 ° C with 1.1 equivalents of a 24% aqueous ammonia solution and then stirred Worked up analogously to Example 17. The 7β-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained

B09882 / 0987

in the form of a colorless foam; Rf α 0.62 (silica gel; toluene / Ethyl acetate 2: 1); IR spectrum (in methylene chloride): characteristic bands at 5.60; 5.80; 5.95; 6.70; 7.30; 8.20 µ.

The starting material can be produced as follows:

a) A mixture of 37.24 g (0.1 mol) of penicillin G potassium salt in 90 ml of water, 7.3 ml of acetone and 150 ml Chloroform is added with stirring at 0 ° C for 40 minutes mixed with 19.4 ml of 40 percent peracetic acid. After a further 15 minutes, the mixture is added in portions at the same temperature 28 g (0.1.5 mol) benzophenone hydrazone, then 6.3 rr.l 1 percent aqueous potassium iodide solution and then a mixture of 32.5 ml of 10 percent sulfuric acid and 28 ml of 40 percent peracetic acid dropwise within 1.5 hours admitted. When the addition is complete, the mixture is stirred for 30 minutes at 0 ° C., warmed to 15 ° and with 400 ml Diluted chloroform. The aqueous phase is separated off and the organic phase successively with 300 ml of 5 percent strength aqueous sodium bisulfite solution, 300 ml saturated aqueous sodium bicarbonate solution and 300 ml saturated washed aqueous sodium chloride solution over sodium sulfate dried and evaporated in vacuo. The E indair.p for Uckstand is recrystallized from ethyl acetate / petroleum ether

509882/0987

■ 0

and gives the δ-phenylacetamidopenicillanic acid diphenylmethyl ester-lβ-oxide, melting point 139 ° C; Thin-layer chromatogram (silica gel): Rf value _x 0.4.0 (system toluene / ethyl

. acetate 1: 1), IR spectrum (methylene chloride): characteristic Bands at 2.94, 5.56, 5.70, 5.92 and 6.57; i.

b) A mixture of 5.165 g (10 mmol) of 6-phenylacetamidopenicillanic acid ~ diphenylmethyl ester-lß-oxide in 50 ml of toluene and 0.5 ml of glacial acetic acid is mixed with 1.83 g (11 mmol) of 2-mercaptobenzothiazole and 2 hours in one with a reflux apparatus provided with a water separator is boiled. On cooling, the 2- [4- (benzthiazol-2-yldithio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl ester spontaneously crystallizes out. After recrystallizing once from methylene chloride / diethyl ether, crystals with a melting point of 134-136 ° C are obtained; Thin-layer chromatogram (silica gel): Rf value i / O.52 (system toluene / ethyl acetate 1: 1); UV spectrum (ethanol): χ _max = 269 mu ( t = 12700); IR spectrum (methylene chloride): characteristic bands at 2.90, 5.60, 5.72, 5.92 and 6,

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y & 6_

Example 22

A solution of 103 mg (0.195 mM) 2- [4- (2-Benzthiazolyldithio) -S-phthalimido ^ -oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl ester in 1.5 ml dimethylformamide is 30 minutes at - stirred 25 ° +5 ⁰ C with 0.9 equivalents of a 24% aqueous ammonia solution and then in analogy to example 17 worked up. The 7β-phthalimido-3-methyl-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained; Nuclear Magnetic Resonance Spectrum (DMSO-dg): S, 2.17 (3H, s); 3.47 (2H ₅ AB); 5.31 (IH, d; J = 4.5 Hz) ₄ 5.98 (IH, d; J = 4.5 Hz) _; 6.93 (IH, s); 6.2-6.7 (10H, m); 6.90 (4H, s).

The starting material can be produced as follows:

a) A solution of 10 g of 6/3 phthalimido penicillanic acid in 60 ml of tetrahydrofuran, 7.0 g of diphenyldiazomethane are added while cooling in an ice bath, at 0 ° C. for 1 hour stirred further and then left to stand for 15 hours at the same temperature. The reaction mixture is in vacuo evaporated, the residue dissolved in methylene chloride, evaporated again, then dissolved in 290 ml of methylene chloride and at 0 ° C with stirring within 10 minutes with 6.5 g of m-chloroperbenzoic acid offset. After stirring for a further 30 minutes

50 9 882/0987

the reaction mixture is washed with aqueous sodium bicarbonate, dried with sodium sulfate and evaporated in vacuo The residue is chromatographed on silica gel with toluene / ethyl acetate 4: 1 and gives 6β-phthalimidopenicillanic acid-diphenylmethyl ester-lβ-oxide.

b) A solution of 5.3 g of 6-phthalimido-penicillanic acid-diphenylmethyl ester-1-oxide in 100 ml of benzene is refluxed with 1.82 2-mercaptobenzothiazole for 2.5 hours. the The reaction mixture is evaporated and dried in a high vacuum and gives the 2- [4- (2-benzthiazolyldithio) -3-phthalimido-2-oxoazetidin-l-yl] -3-methylenebutyric acid diphenylmethyl ester with a melting point of 137-138 ° C.

Example 23

A solution of 50 mg of 2- [4- (2-Benzthiazolyldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid tert-butyl ester in 1 ml of hexamethylphosphoric triamide containing 5 mg of 20% aqueous ammonia solution is 20 minutes stirred in an ice bath. The reaction mixture is diluted with diethyl ether in succession as indicated in Example 17 washed, dried and evaporated. From the back

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432

-νά-

stood, consisting of a 1: 2 mixture of 7ß-phenoxyacetarnido-3-methyl-3-cephem-4-carboxylic acid tert. -butylester and deir, 2- [4- (2-Benzthiazolyldithio) -3-phenoxyacetamide-2-oxoazetidine l-yll-S-methylcrotonic acid tert-butyl ester, can be determined by chromatography on silica gel with toluene / ethyl acetate 2: 1 as the mobile phase (Rf: 0.52) of the 7β-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid tert-butyl ester can be obtained. IR spectrum (in methylene chloride): characteristic bands at 5.60; 5.90; 6.60; 7.35; 8.20 ρ.

The starting material can be obtained as follows:

A solution of 422 mg (1 mM) 6ß-phenoxyacetamido-

penicillanic acid tert-butyl ester-lß-oxide (DOS 2.011.376) and 167 mg (1 mM) 2-mercaptobenzothiazole in 10 ml dry toluene is slowly refluxed under a nitrogen atmosphere tempera door heated and then refluxed for 4 hours. The toluene is distilled off and the residue with Treated diethyl ether whereby the 2- [4- (2-Benzthiazolyldithio) -S-phenoxyacetamido ^ -oxoazetidin-1-yl] -3-methylene-butyric acid tert-butyl ester is obtained in pure form.

509882/0987

Example 24

A solution of 268 mg (0.4 mM) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methylene-butyric acid diphenylmethyl ester in 2 ml of dimethylformamide containing 50 mg of a 20% aqueous ammonia solution (1.8 equivalents NH ₃ ) is stirred for 1 hour at -25 ° + 5 ° C and then worked up as in Example 17. The crude product is recrystallized from methylene chloride / diethyl ether and gives the 7β-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid diphenylmethyl ester with a melting point of 152-154 ° C.

Example 25

A solution of 256 mg (0.4 mM) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid p-nitrobenzyl ester in 2 ml dimethylformamide containing 50 mg of a 20% aqueous ammonia solution (1.25 equivalents of NH ₃ ) is stirred for 1 hour at -25 ° + 5 ° C. and then worked up as in Example 17. The residue is recrystallized from methylene chloride / diethyl ether and gives the 7β-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid p-nitrobenzyl ester with a melting point of 188-190 ° C.

509882/0987

Example 26

Analogously, starting from suitable compounds of the formula II and optionally by suitable postoperations, the following connections can be obtained:

3-methyl-7β- (D-cc-phenylglycyl-amino) -3-cephem-4-carboxylic acid or salts thereof; the inner salt of 3-methyl-7ß- (D-ocphenylglycyl-amino) -3-cephem-4-carboxylic acid; 7β-Amino-3-methyl 3-cephem-4-carboxylic acid diphenylmethyl ester or salts thereof and the 7β-amino-3-methyl-3-cephem-4-carboxylic acid or salts thereof.

509882/0987

Claims (1)

Claims 1. Process for the preparation of 7ß-amino-3-methyl-3- cephem-4-carboxylic acid compounds of the formula . ο (IA), egg A. wherein R is hydrogen or an amino protecting group R, and R, represents hydrogen or an acyl group Ac, or R- and R, together represent a divalent amino protective group represent and R ~ for hydroxy or one, together ir.it the carbonyl group -C (= 0) - a protected carboxyl group radical R "forming, as well as 1-oxides of 3-cephem compounds of the formula IA, and the corresponding 2-cephem compounds of the formula i \ . 0: N J-CH. O = CR _r (IB) 509882/0987 where R?, RZ * and R have the meanings given above, or Salts of such compounds with salt-forming groups, characterized in that a compound of the formula b / \ CH Γ 3 (II) O = C-R ^ AT? A.
wherein R ^, R and R _{2 have} the meanings given under formula IA, and Y represents a leaving group, or a tautomer thereof, treated in a polar, aprotic solvent with a nucleophilic catalyst, and, if desired, in a compound of the formula IA obtained or IB, the protected carboxyl group of the formula -CC = O) -R _7, converted into the free or into another protected carboxyl group, and / or _m, if desired, an amino R-. cleaved or converted into another amino protective group and / or, if desired 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 in a salt or a salt obtained in the free Compound or converted into another salt, and / or, if desired, a mixture of isomeric compounds obtained is separated into the individual isomers. 509882/0987 4Z
- yri - 2. The method according to claim 1, characterized in that that starting materials of the formula II are used in which R ₁ denotes an acyl group Ac, in which any free functional groups present can be slotted, R denotes hydrogen, R denotes an esterified carboxyl group which forms an esterified carboxyl group with the -C (= 0) group , etherified hydroxyl group, where any functional groups present in a carboxyl protective group R ~ can be slit, and Y is a group -S-Ro _{5 is} a group -SC ^ -R / or a group - bonded to the thio group -S- with the sulfur atom S-SO ^ -Ra means. 3. The method according to claim 2, characterized in that p ^
that R _{2 represents} an optionally substituted 1-phenyl-lower alkoxy or an optionally halogen-substituted lower alkoxy group. 4. The method according to claim 2, characterized in that R ^ benzyloxy, p-nitrophenyloxy, diphenylmethoxy, tert-butyloxy or 2,2,2-trichloroethoxy. 5. The method according to claim 1 or 2, characterized in that Y is a group -S-R., Wherein R "is optionally substituted aromatic heterocyclic radical with up to 15 carbon atoms and at least one R ^ 'ng nitrogen atom and optionally a further ring heteroatom, which radical S09382 / O987 with one of its ring carbon atoms, that with a ring nitrogen atom is linked by a double bond, is bonded to the thio group -S-. 6. The method according to any one of claims 1, 2 or 5, characterized in that R ~ a benzdiazacyclic, benzoxazacyclic or benzthiazacyclic radical, in which the heterocyclic part is five-membered and aromatic Has character. 7. The method according to any one of claims 1, 2 or 5, characterized in that R ~ is benzthiazol-2-yl. 8. The method according to claim 1 or 2, characterized in that R- is an optionally substituted aliphatic, represents cycloaliphatic, araliphatic or aromatic acyl or thioacyl group with up to 18 carbon atoms. 9. The method according to claim 1 or 2, characterized in that R "an optionally in the 1-position by a Ether or thioether groups of substituted aliphatic Radical, an optionally substituted vinyl radical or an optionally substituted aromatic hydrocarbon radical is. 10. The method according to claim 1 or 2, characterized in that Y is a group -SO ₂ -R, or -S-SO ₂ -R ₇ , wherein R is an optionally substituted, aliphatic, 60908 27 0987 cycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 18 carbon atoms. 11. The method according to any one of claims 1, 2 or 10, characterized in that R, an optionally substituted Alkyl, alkenyl or cycloalkyl group, or a mono- or represents polysubstituted naphthyl or phenyl group. 12. The method according to any one of claims 1, 2, 10 or 11, characterized in that Y is a group -SO-R, wherein R, phenyl, p-tolyl, p-methoxyphenyl or p-nitrophenyl is. 13. The method according to any one of claims 1-12, characterized in that that as a nucleophilic catalyst, the anion of a salt or soluble in the solvent used a base is used. 14. The method according to claim 13, characterized in that the iodide anion, the rhodanide anion, or a thiosulfonate anion of the formula ^ S-SO ₇ -R ₇ in the form of a soluble sodium salt is used as the nucleophilic catalyst. 15. The method according to claim 13, characterized in that a nitrogen base as a nucleophilic catalyst to three nitrogen atoms is used. 509882/0987 252 ^ 044 16. The method according to claim 15, characterized in that the nitrogen base is ammonia. 17. The method according to claim 15, characterized in that the nitrogen base is monomethylamine or dimethylamine. 18. The method according to any one of claims 1 to 17, characterized in that the reaction is carried out in an N, N-di-lower alkylcarboxamide, a di-lower alkyl sulfoxide, a hexane-lower alkyl phosphoric acid triamide, a nitrile, a ketone or in a mixture thereof. 19. The method according to any one of claims 1-13 and 15-18, characterized in that a compound of the formula II in dimethylformamide at a temperature of approx. -20 to approx. + 25 ° C with ammonia gas, an approx. 20-24% aqueous ammonia solution, Treated methylamine or dimethylamine or a corresponding about 20-40% aqueous amine solution. 20. The method according to claim 19, characterized in that a compound of formula II at about -20 ° C in dimethylformamide treated with ammonia gas or an approximately 20-24% aqueous ammonia solution. S09S82 / 0987 2528QU 21. The method according to any one of claims 1-20, characterized characterized in that in a compound obtained, Away
• where R-, or R ^ is an acyl group, splitting off a suitable acyl group, for example by treating with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleaving the imino ether formed, and replacing it with hydrogen. 22. The method according to any one of claims 1-21, characterized in that one obtained compound protects a free amino group, e.g. acylated. 23. The method according to any one of claims 1- 22, characterized in that in the inventive method or in any additional measures to be carried out the reaction not participating free functional groups in the starting materials or in the process available Compounds are temporarily protected and, if desired, released after the reaction has taken place. 24. The method according to any one of claims 1-23, characterized in that one i _n a compound obtained Protected carboxyl group of the formula -C (= 0) -R ₂ converted into a free carboxyl group by alkaline or acidic hydrolysis, alcoholysis, acidolysis, or by treatment with a reducing agent or by irradiation. 509882/0987 25. The method according to any one of claims 1-24, characterized characterized in that one obtained a compound of the formula IB or a obtained mixture consisting of a compound of the formula IB and a compound of the formula IA is converted into a 1-oxide of a compound of the formula IA. 26. The method according to any one of claims 1-25, characterized in that a 1-oxide of a compound is obtained of the formula IA reduced to a compound of the formula IA. 27. The method according to any one of claims 1-26, characterized in that there is obtained as intermediate products Compounds used as starting materials and the rest Carries out process steps with these, or terminates the process at any stage. .28. Method according to one of claims 1-27 ", characterized characterized in that starting materials are used in the form of derivatives or formed during the reaction. 29. The method according to any one of claims 1-28, characterized characterized in that 3-cephem compounds of the formula IA according to claim 1 or 1-oxides thereof, furthermore the corresponding 2-cephem compounds of the formula IB according to claim 1, as well as salts of such compounds with salt-forming groups, wherein R-. 509882/0987 Hydrogen or one, in a fermentative or bio, Half-ocier K-acyl derivative that can be produced by synthesis a Gβ-amino-pcnam-S-carboxylic acid or 7p-amino-3-cepherr; -4-carboxylic acid compound represents acyl radical, R. represents hydrogen, and R represents hydroxy, optionally substituted Is lower alkoxy, acyloxy, tri-lower alkylsilyloxy, or optionally substituted amino or hydrazino. 3G. Process according to one of claims 1-29, characterized in that ir.an 3-cephen / compounds of the formula IA according to claim 1 or 1-oxides thereof, as well as corresponding 2-cephem compounds of the formula IB according to claim 1, furthermore salts of such compounds with salt-forming groups. produces, wherein R, hydrogen, a fermentatively or biosynthetically producible N-acyl derivatives of 6ß-aminopenam-3-carboxylic acid or 7β-amino-3-cephem-4-carboxylic acid compounds containing acyl radical, or a highly effective N-acyl derivative of 6ß-amino-penam-3-carboxylic acid or 7β-amino-3-cephem-4-carboxylic acid compounds occurring Acyl radical means, R, stands for hydrogen, and R "hydroxy, lower alkoxy, 2-halo-lower alkoxy, phenacyloxy, 1-Phenyl-lower alkoxy with 1-3, optionally with lower alkoxy or nitro-substituted phenyl radicals, lower alkanoyloxymethoxy, a-amino lower alkanoyloxymethoxy, lower alkoxy 5098 8 2/0987 - yd - 25280A4 carbonyloxy or lower alkanoyloxy, or in which R "has the meanings given above and R.! ¹ and RT together represent an 1-oxo-3-aza-1,4-butylene radical which is substituted in the 2-position by optionally substituted phenyl and optionally contains two lower alkyl groups in the 4-position. 31.- The method according to any one of claims 1-30, characterized in that 3-cephem compounds of the formula IA according to claim 1 or 1-oxides thereof, and corresponding 2-cephem compounds of the formula IB according to claim 1, furthermore salts of such compounds with Salt-forming groups, in which R ₁ and R ~ have the meanings given in claim 30, and R. for hydrogen or a group of the formula R ¹¹ 0 I H (c) _n —c— (A) 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 of aromatic character, a functionally modified, e.g. esterified or etherified hydroxyl or mercapto group, or a 509Ö82 / 0987 optionally substituted araino group, or where η is 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 radical, in which the heterocyclic radical is preferably aromatic and / or has 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 of the radicals R and R is hydrogen, or in which η stands for 1, R an optionally substituted aliphatic, cycloaliphatic, C3 ^r cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or a given An optionally substituted heterocyclic or heterocyclischaliphatic radical in which the heterocyclic radical preferably has aromatic character, R is an optionally functionally modified, for example esterified or etherified, hydroxyl or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, an optionally Οη-Γιΐοο - or O-disubstituted phosphono group η halogen atom be
509882/0987 Azido group or a halogen atom, and R for water is hydrogen, or where η is 1, each of the radicals R and R is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R represents hydrogen, or in which η stands for 1, R Hydrogen or an optionally substituted aliphatic, cycloaliphaticj cycloaliphatic-aliphatic, means aroniatic or araliphatic hydrocarbon radical and R and R together an optionally substituted, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic linked by a double bond to the carbon atom or araliphatic hydrocarbon radical, or in which η is 1, and R is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic Hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic A radical in which heterocyclic radicals preferably have an aromatic character, R an optionally substituted one aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aroitic or araliphatic hydrocarbon radical and R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic 509802/0987 phatic-aliphatic, aromatic or araliphatic Hydrocarbon radical, or in which R "denotes has the meanings given above and R ₁ and R 1 together represent a l-oxo-3-aza-1,4-butylene radical which is optionally substituted in the 2-position and contains two lower alkyl groups in the 4-position. 32. The method according to any one of claims 1 ~ 31 »thereby characterized in that 3-cephem or 2-cepheru compounds of the formula IA or IB according to claim 1 or salts thereof Compounds with salt-forming groups, in which R, denotes hydrogen, R, denotes hydrogen, an acyl group of the formula (B) where R is phenyl, hydroxyphenyl, hydroxychlorophenyl, 2- or 3-thienyl, pyridyl, aminopyridinium, furyl, isothiazyl, tetrazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, it being possible for hydroxy substituents in such radicals to be protected by acyl radicals, X Represents oxygen or sulfur, m represents O or 1, and R, represents hydrogen or, if m represents O, optionally protected amino, carboxy, sulfο or hydroxy, or O-lower alkylphosphono ^{or O, O 1 -di} 509882/0987 lower alkyl-'phosphono, or a 5-amino-5-carboxyvaleryl radical means what the amino and carboxy groups are optionally are slotted, and R "given in claim 30 Has meanings. ., ·· ■■ - ■■■■ 33 ... ,., yerfa.hren, according to -one, of claims L-, 32, characterized in that 3-CephcKi compounds dor formula IA as addressed .. 1 ,, as well as -deren; 1 — Oxides, and also the corresponding 2-Cphein. Compounds. ; of the formula IB geinä'ss claim I ₃ or salts of those compounds '- with salt-forming groups, in which R, hydrogen,' or an e.g. 4-hydroxy el phenyl, thienyl, zS> 2- or 3 "-thieriylV ^ isothiazolyl, -1,4-cyclohexadienyl or 1-cyclohexenyl. X is oxygen, m is 0 or 1, and R. is hydrogen or, if. m _: O is . amino, geschütztös amino, such as acylamino, ^eg, cc-lower alkoxycarbonylamino polyverzweigtes ,. as .tert.-butyloxycarbonylamino, or 2-HalbgenniederalkoxyGarbonyläirano, 2,2, 2-Tribhloräthoxycarbonylamino, 2-Jodäthox) ^{7 7} carbon lamino} or 2- Bromäthoxycarbonyla-minp ^, ode.r if necessary Kiederalkpxy- or NitrosubstituxertsS; Phen ^ l-iiiederalkoxycarbonylamino, ζ.B, 4.-Hethoxy ~ benzyloxy, carbox3y3.aniin, o, rder Hydroxy, as well as, protected hydroxy, like acyloxy , e.g. a-polybranched lower alkoxycarbonyloxy, v? ie tert-butyloxj'-carbonylox) ', or 2-halogen ÖFUGINAL INSPECTED lower alkoxycarbonyloxy, such as 2,2,2-Trichloräthoxycarbonyloxy, 2-JodäthoxycarbonyIoxy or 2-Bromathoxycarbonyloxy, also mean formyloxy, or for a 5-amino-5-carboxy-valeryl radical, in which the amino and carboxy group can also be slotted and, for example, as acylamino , for example lower alkanoylamino, such as Acetylarfo.no, Kalogenneideralkanoylaraino as dichloroacetylamino, Benzoylainino or phthaloylamino, or as esterified carboxyl, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, are present, preferably m is 1 when R is phenyl or hydroxy-phenyl, R ₁ is Represents hydrogen, and R ~ hydroxy, optionally in the 2-position halogen-, e.g. chlorine-, brom- or iodine-substituted lower alkoxy, in particular α-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halo-lower alkoxy, e.g. 2, 2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally kxederalkoxy, such as methoxy-substituted diphenylmethyloxy, for example diphenylmethoxy or 4,4'-di-inethoxy-diphenylin is ethoxy, p-nitrobenzyloxy, also tri-lower alkylsilyloxy, for example trimethylsilyloxy. 34. The method according to any one of claims 1-33, characterized in that 7 / 3- (D-a-amino-a-R -acetylamino) -3- Si methyl-3-cephem-4-carboxylic acid, where R is phenyl, 4-hydroxy ORIGINAL INSPECTED JGV phenyl, 2-thienyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, and lower alkoxy contains up to 4 carbon atoms, and the internal salts thereof. 35. The method according to any one of claims 1-33, characterized in that the 7ß-phenoxyacetamido-3-methylceph-3-em-4-carboxylic acid p-nitrobenzyl ester manufactures. 36. The method according to any one of claims 1-33, characterized in that the 7β-phenoxyacetamido-3-methylceph-3-em-4-carboxylic acid diphenylmethyl ester manufactures. 37 .. The method according to any one of claims 1-33, characterized in that the 7ß-phenoxyacetamido-3-methylceph-3-em-4-carboxylic acid 2,2,2-trichloroethyl ester manufactures, 38. The method according to any one of claims 1-33, ^ thereby characterized that the .3-methyl-7ß- (D-a-phenylglycyl_- amino) -3-cephem-4-carboxylic acid or salts thereof. Process according to one of Claims 1-33, characterized in that the inner salt of 3-methyl-7ß, - (D-a-phenylglycyl-amino) -3-cephem-4-carboxylic acid manufactures. S098Ö2 / .0 98T ; 25280A4 40. The method according to any one of claims L-33, characterized in that the 7β-amino-3-methyl-3-cephein-4-carboxylic acid diphenylmethyl ester or salts thereof are prepared. 41. The method according to any one of claims 1-33, characterized in that the 7ß-amino-3-methyl-3-cephem-4-carboxylic acid or making salts thereof. 42. The method according to any one of claims 1-33, characterized in that that the 7ß-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid diphenylmethyl ester manufactures. 43. The method according to any one of claims 1-33, characterized in that that the 7ß-phthalimido-3-methyl-3-cephem-4-carboxylic acid diphenylmethyl ester manufactures. . 44. The method according to any one of claims 1-33, characterized in that that the 7ß-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid tert-butyl ester manufactures. '' 45. The process described in Examples 1-44 for the preparation of the compounds described in Claim 1. 46. The process described in Examples 15-26 for the preparation of the compounds described in Claim 1. 50 98 ^ 2/0 9 87.
ORiGiNALINSPECTED 47. The compounds obtainable according to one of claims 1-5, 7-18, 21-41 and 45. 48. The compounds obtainable according to one of claims 6, 19, 20, 42-44 and 46. CIBA-GEIGY AG 509882/0987