DE2151560A1 - Mercapto alcohols - Google Patents

Description

CIBA-GEIGY AG, BASEL (SWITZERLAND)

Case 4-7211 / 1-4 / +

Germany

Mercapto alcohols

The present invention relates to 3-amino-4- (2-hydroxyethylthio) -2-oxo-azetidine compounds the formula

^R i \ i ³ I ⁴

NS — CH-CH-OR ₂ idf CH CH (I)

O = C KH

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a A

in which R is hydrogen or an amino protective group R,

b A

R represents hydrogen or an acyl group Ac, or R and R ₁ together represent a divalent aminoprotective group, R represents hydrogen or an acyl radical Ac, and each of the radicals R and R represents hydrogen or an organic radical bonded via a carbon atom, or salts of such compounds with salt-forming groups.

An amino protecting group R is one through hydrogen replaceable group, primarily an acyl group Ac

a triarylmethyl, especially the trityl group, as well as an organic SiIy1- and an organic stannyl group. A group Ac primarily represents the acyl radical of an organic carboxylic or sulfonic acid, in particular the acyl radical an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid (including formic acid), as well as the acyl radical of a carbonic acid semi-derivative.

A b One formed by the radicals R ₁ and R. together

The divalent amino protective group is, in particular, the divalent acyl radical of an organic dicarboxylic acid, primarily the Diacyl radical of an aliphatic or aromatic dicarboxylic acid, furthermore the acyl radical of an, preferably in the α-position substituted α-aminoacetic acid, e.g. containing an aromatic or heterocyclic radical, in which the amino group

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via one, preferably substituted, e.g. two lower alkyl, such as containing methyl groups, methylene radical with the

Away

Nitrogen atom is connected. The radicals R ₁ and R ₁ together can also represent an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical.

An acyl residue Ac is primarily the acyl residue of an organic carboxylic acid, especially a slightly through Hydrogen-replaceable acyl radical of a carbonic acid half-derivative.

An organic radical bonded via a carbon atom is primarily an optionally substituted one Hydrocarbon radical, in particular an optionally substituted one aliphatic also cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. It is preferably from the R ~ and R radicals, at least one, usually at least Ro for hydrogen.

The general terms used in the description above and below have the following meanings, for example:

An aliphatic radical, including the aliphatic radical of a corresponding organic carboxylic acid, as well a corresponding ylidene radical is an optionally substituted monovalent or divalent aliphatic Hydrocarbon radical, especially lower alkyl, as well as

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Lower alkenyl or lower alkynyl, also lower alkylidene, for example up to 7, preferably up to 4 carbon atoms may contain. Such radicals can optionally through functional groups, e.g. through free, etherified or esterified Hydroxy or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted Phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phenylthio or phenyl-lower alkylthio, Lower alkoxycarbonyloxy or lower alkanoyloxy, or halogen, furthermore by oxo, nitro, optionally substituted amino, e.g. di-lower alkylamino, lower alkylenamino, Oxaniederalkylenamino or aza-loweralkylenamino, also acylamino, such as lower alkanoylamino, optionally substituted Carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, Azido, acyl, such as lower alkanoyl or benzoyl, optionally functionally modified carboxyl, such as carboxyl present in salt form, esterified carboxyl, such as lower alkoxycarbonyl, optionally substituted carbamoyl, such as N-lower alkyl or Ν, Ν-di-lower alkylcarbamoyl, also optionally substituted ureidocarbonyl or guanidinocarbonyl, or cyano, optionally functionally modified suIfo, such as sulfamoyl or suIfο present in salt form, mono-, be di- or polysubstituted.

The divalent aliphatic radical of an aliphatic carboxylic acid is, for example, lower alkylene or lower alkenylene, the

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optionally, for example as an aliphatic radical indicated above, can be mono-, di- or polysubstituted.

A cycloaliphatic or cycloaliphatic-aliphatic Remainder, including the cycloaliphatic or cycloaliphatic-aliphatic Remainder in a corresponding organic carboxylic acid or a corresponding cycloaliphatic acid or cycloaliphatic-aliphatic ylidene radical is an optionally substituted, mono- or bivalent one cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, e.g. mono-, bi- or polycyclic Cycloalkyl or cycloalkenyl, and also cycloalkylidene. or cycloalkyl- or cycloalkenyl-lower alkyl or -lower alkenyl, also cycloalkyl-lower alkylidene or cycloalkenyl-lower alkylidene, wherein cycloalkyl and cycloalkylidene, for example, up to 12, such as 3-8, preferably 3-6 ring carbon atoms, while cycloalkenyl contains e.g. up to 12, such as 3-8, e.g. 5-8, preferably 5 or 6 ring carbon atoms, as well as 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic The radical, for example, can contain up to 7, preferably up to 4 carbon atoms. The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, e.g. by optionally substituted aliphatic hydrocarbon radicals, as by the above-mentioned optionally substituted lower alkyl groups, or then, e.g.

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like the above-mentioned aliphatic hydrocarbon radicals, be mono-, di- or polysubstituted by functional groups.

The aromatic group including the aromatic group of a corresponding carboxylic acid is a optionally substituted aromatic hydrocarbon radical, e.g. a mono-, bi- or polycyclic aromatic Hydrocarbon radical, especially phenyl, as well Biphenylyl or naphthyl which may optionally, e.g. the above-mentioned aliphatic and eyeloaliphatic hydrocarbon radicals, can be mono-, di- or polysubstituted.

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

The araliphatic residue, including the araliphatic A radical in a corresponding carboxylic acid, furthermore an araliphatic ylidene radical, is, for example, an optionally substituted araliphatic hydrocarbon radical such as an optionally substituted, e.g., up to three, optionally substituted mono-, bi- or polycyclic, Aliphatic hydrocarbon radical containing aromatic hydrocarbon radicals and primarily represents

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Line 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. like the above-mentioned aliphatic and cycloaliphatic radicals, in the aromatic and / or aliphatic Part can be mono-, di- or polysubstituted.

Heterocyclic groups such included in heterocyclic-aliphatic radicals, including heterocyclic oder'heterocyclisch-aliphatic groups in appropriate carboxylic acids, are especially monocyclic, as well as bi- or polyc3 ⁷ clische, aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza-, triaza- or tetrazacyclic radicals of aromatic character, furthermore corresponding partially or completely saturated radicals, it being possible for these heterocyclic radicals to be mono-, di- or polysubstituted, for example like the above-mentioned cycloaliphatic radicals. The aliphatic part in heterocyclic-aliphatic radicals has, for example, the meaning given for the corresponding cycloaliphatic-aliphatic or araliphatic radicals.

The acyl radical of a carbonic acid half derivative is preferably the acyl radical of a corresponding half ester, wherein the organic residue of the ester group is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or

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represents a heterocyclic-aliphatic radical, primarily the acyl radical of an optionally, e.g. in α- or / 3-position, substituted lower alkyl half-ester of carbonic acid, and one optionally in the organic residue. substituted lower alkenyl, cycloalkyl, phenyl or Phenyl-lower alkyl semiesters of carbonic acid. Acyl residues of a carbonic acid half ester are also corresponding residues of lower alkyl half esters of carbonic acid, in which the Lower alkyl moiety is a heterocyclic group such as any of the above contains heterocyclic groups of aromatic character, both the lower alkyl radical, as well as the heterocyclic group can optionally be substituted. The acyl radical of a carbonic acid half derivative can also an optionally N-substituted carbamoyl group such as an optionally halogenated N-lower alkylcarbamoyl group.

Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl or tert-butyl, as well as n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl, while lower alkenyl e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl, lower alkynyl e.g. propargyl or 2-butynyl, and lower alkylidene e.g. isopropylidene or isobutylidene can be.

Lower alkylene is, for example, 1,2-ethylene, 1,2- or 1,3-propylene or 1,4-butylene, while lower alkenylene e.g. 1,2-ethenylene or 2-butene-1,4-ylene.

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Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl, cycloalkenyl e.g. 2-cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4- Cyclohexadienyl, and cycloalkylidene, for example cyclopentylidene or cyclohexylidene. Cycloalkyl-lower alkyl or lower alkenyl is, for example, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1,1- or -l, 2-ethyl _# -1,1-, -1,2- or -1,3-propyl , vinyl or allyl, while cycloalkenyl lower alkyl or lower alkenyl, for example 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl or 1-, 2- or 3-cycloheptenylmethyl, -1, Is 1- or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, vinyl or allyl. Cycloalkyl-lower alkylidene is, for example, cyclohexylmethylene, and cycloalkenyl-lower alkylidene is, for example, 3-cyclohexenylmethylene.

Naphthyl is 1- or 2-naphthyl while biphenylyl 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, Diphenylmethyl, trityl, 1- or 2-naphthylmethyl, Styryl or cinnamyl, phenyl lower alkylidene e.g. benzylidene.

Heterocyclic radicals are primarily optionally substituted aromatic heterocyclic radicals Character, e.g. corresponding monocyclic, monoaza-, monothia- or monooxacyclic radicals such as pyrryl, e.g. 2- pyrryl or 3-pyrryl, pyridyl, e.g. 2-, 3- or 4-pyridyl

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also pyridinium, thienyl, e.g. 2- or 3-thienyl, or furyl, e.g. 2-furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals, such as indolyl, e.g. 2- or 3-indolyl, quinolinyl, e.g. 2- or 4- Quinolinyl, isoquinolinyl, for example 1-isoquinolinyl, benzofuranyl, for example 2- or 3-benzofuranyl, or benzothienyl, for example 2- or 3-benzothienyl, monocyclic diaza, triaza, tetraza, thiaza, thiadiaza or oxazacyclic radicals, such as Imidazolyl, for example 2-imidazolyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, triazolyl, for example 1,2,4-triazol-3-yl, tetrazolyl, for example 1- or 5-tetrazolyl, oxazolyl, for example 2-oxazolyl , Isoxazolyl, for example 3-isoxazolyl, thiazolyl, for example 2-thiazolyl, isothiazolyl, for example 3-isothiazolyl ^v or 1,2,4- or 1,3,4-thiadiazolyl, for example 1 , 2 , 4-thiadiazol- 3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza, thiaza or oxazacyclic radicals, such as benzimidazolyl, for example 2-benzimidazolyl, benzoxazolyl, for example 2-benzoxazolyl, or benzthiazolyl, for example 2-benzthiazolyl. Corresponding partially or completely saturated radicals are, for example, tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, or piperidyl, for example 2- or 4-piperidyl. Heterocyclic-aliphatic radicals are heterocyclic groups, in particular those containing lower alkyl or lower alkenyl. The above-mentioned heterocyclyl radicals can, for example, by optionally substituted aliphatic hydrocarbon radicals, in particular lower alkyl, such as methyl

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thyl, or, e.g. like the aliphatic hydrocarbon radicals, be substituted by functional groups.

Lower alkoxy is, for example, methoxy, ethoxy, n-propy oxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy or tert-pentyloxy. These Groups can be substituted, e.g. as in halo-lower alkoxy, especially 2-halo-lower alkoxy, e.g. 2,2,2-trichloro-, 2-bromo or 2-iodoethoxy. Is lower alkenyloxy e.g. vinyloxy or allyloxy, lower alkylenedioxy e.g. methylenedioxy, Ethylenedioxy or isopropylidenedioxy, cycloalkoxy e.g. cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy e.g. benzyloxy or 1- or 2-phenylethoxy, or heterocyclyloxy or heterocyclyl-lower alkoxy, e.g. pyridylnealkoxy, such as 2-pyridylr-ethoxy, Furyl-lower alkoxy, such as furfuryloxy. or thienyl-lower alkoxy, like 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 heterocycly radicals or heterocyclylaliphatic radicals etherified mercapto groups, in particular imidazolylthio, e.g. 2-imidazolylthio, Thiazolylthio, e.g. 2-thiazolylthio, 1,2,4- or 1,3, ^ - thiadiazolylthio, e.g. l, 2,4-thiadiazol-3-ylthio or 1,3 * ^ - thiadiazol-2-ylthio, or tetrazolylthio, e.g., 1-kethyl-5-tetrazolylthio are.

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Esterified hydroxyl groups are primarily halogen, e.g. fluorine, chlorine, bromine or iodine, as well as lower alkanoyloxy, e.g. acetyloxy or propionyloxy.

Lower alkoxycarbonyl is e.g. methoxycarbonyl, Ethoxycarbonyl, η-propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl or tert-pentyloxycarbonyl.

N-lower alkyl- or Ν, Ν-di-lower alkyl-carbamoyl is e.g. N-methylcarbampyl, N-ethylcarbamoyl, N, N ~ dimethylcarbamoyl or Ν, Ν-diethylcarbamoyl, while N-lower alkylsulfaraoyl e.g. N-methylsulfamoyl or Ν, Ν-dimethylsulfaraoyl represents.

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

Lower alkylamino or di-lower alkylamino is e.g. methylamino, ethylamino, dimethylamino or diethylamino, Lower alkylenamino e.g. pyrrolidino or piperidino, Oxane-lower alkylenamino, e.g., morpholino, and azo-lower alkylenamino, e.g., piperazino or 4-methylpiperazino. Acylamino stands in particular for carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkanoylamino, like Acetylamino or Propiοnyland no, also for Phthalimido,

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or optionally in salt, such as alkali metal, e.g. sodium, or Ammoniumsalζform, present sulfoamino.

Lower alkanoyl is, for example, acetyl or propionyl.

Lower alkenyloxycarbonyl is e.g. vinyloxycarbonyl, while cycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl e.g. adamantyloxycarbonyl, benzyloxycarbonyi, diphenylmethoxycarbonyl or α-4-biphenylyl-α-methyl-ethoxycarbonyl represents. Lower alkoxycarbonyl, in which lower alkyl is, for example, monocyclic, monoaza, monooxa or monothiacyclic Group is, for example, furyl-lower alkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl-lower alkoxycarbonyl, e.g., 2-thenyloxycarbonyl.

An acyl group Ac stands in particular for one in a naturally occurring or in a bio, semi- or that can be produced entirely synthetically, preferably pharmacologically effective N-acyl derivative of 6-amino penicillanic acid or 7-amino-cephalosporanic acid compounds containing acyl radical of an organic carboxylic acid or one Carbonic acid half-derivative or an easily cleavable acyl radical of a carbonic acid half-derivative.

One in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid contained acyl radical Ac ^ is primarily a group of the formula

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R ¹¹

I ₍ c) _n c (IA)

R ¹¹¹

where η is O and R is hydrogen or optionally one substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified one, preferably denotes etherified 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 carbon dioxide or optionally one substituted heterocyclic or heterocyclic-aliphatic Radical in which the heterocyclic radical is preferably aromatic and / or quaternary Has nitrogen atom, an optionally functional modified, preferably etherified or esterified hydroxyl or mercapto group, one optionally functional modified carboxyl group, an acyl group, a optionally substituted amino group or an azido group represents, and each of the radicals R and R was

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is hydrogen, or where η is 1, R is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic aliphatic A radical denotes in which the heterocyclic radical preferably has an aromatic character, R an optionally functionally modified, preferably etherified, hydroxyl or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, a Represents azido group or a halogen atom, and R represents hydrogen, or wherein η represents 1, each of the radicals R and R a functionally modified, preferably etherified or esterified hydroxyl group or an optionally means functionally modified carboxyl group, and

III I

R is hydrogen, or where η is 1, R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, denotes an aromatic or araliphatic hydrocarbon radical and R and R together optionally represent one substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic

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represent phatic 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 one heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals are preferably aromatic Have character, R an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R is hydrogen or an optionally substituted one aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon rest mean.

In the above acyl groups of the formula IA

for example η stands for 0 and R stands for hydrogen or an optionally preferably in the 1-position by amino or an optionally in salt, e.g. alkali metal salt form sulfoamino group present, substituted cycloalkyl group with 5-7 ring carbon atoms, one optionally, preferably by hydroxy, lower alkoxy, e.g. methoxy, and / or halogen, e.g. chlorine, substituted phenyl-, naphthyl- or Tetrahydronaphthyl group, one optionally, e.g. Lower alkyl, e.g. methyl and / or phenyl, which in turn are sub-

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substituents such as halogen, e.g. chlorine, may carry substituted heterocyclic groups 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, optionally substituted phenyloxy, amino and / or carboxy containing such as hydroxy and / or halogen, e.g. chlorine containing lower alkyl group, furthermore a lower alkenyl group, an optionally substituted one, such as hydroxy, halogen, e.g. chlorine, and / or optionally substituted one Phenyl group containing phenyloxy, an optionally substituted, e.g. by amino or aminomethyl, pyridyl, Pyridinium, thienyl, 1-imidazolyl or 1-tetrazolyl group, an optionally substituted lower alkoxy group, one optionally, e.g. by hydroxy and / or Halogen, such as chlorine, substituted phenyloxy group, a lower alkylthio or lower alkenylthio group, an optionally, e.g. by lower alkyl, such as methyl, substituted phenylthio-, 2-imidazolylthio- l, 2,4-triazol-3-ylthio-, l, 3,4-triazol-2-ylthio-, l, 2,4-thiadiazol-3-ylthio-, such as 5-methyl-1,2,4-thiadiazol-3-ylthio-, 1,3,4-thiadiazol-2-ylthio-, such as 5-methyl-l, 3,4-thiadiazol-2-ylthio-, or 5-tetrazolylthio-, such as l-methyl-5-tetrazolylthio group Halogen, especially chlorine or bromine atom, a given

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if functionally modified Garboxygruppe _s such as lower alkoxycarbonyl, cyano or optionally, for example by phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl or Benzoy! group, or an azido groups and R ¹¹ and R ¹¹¹ for hydrogen, or η for 1, R ¹ for an optionally substituted phenyl or thienyl group, for example by hydroxy and / or halogen, for example chlorine, also for a 1,4-cyclohexadienyl group, R for an optionally substituted amino, for example optionally substituted carbamoylamino group, such as guanidinocarbonylamino, or one, optionally Sulfoamino group in salt form, for example alkali metal salt form, an azido group, a carboxyl group optionally in salt form, for example alkali metal salt form or in esterified form, for example as lower alkoxycarbonyl group, a cyano group, a sulfo group, an optionally substituted lower alkoxy or phenyloxy group or a halogen atom, for example chlorine or bromine, and R for hydrogen, or η for 1, R and R each for halogen, eg bromine, or lower alkoxycarbonyl, eg methoxycarbonyl, and R for hydrogen, or η for 1, and each of the groups R ¹ , R ¹¹ and R ¹¹¹ for lower alkyl, eg methyl.

Such acyl radicals Ac are e.g. formyl, cyclopentylcarbonyl, α-aminocyclopentylcarbonyl or a-aminocyclohexyl- carbonyl (with optionally substituted alkyl group, e.g. optionally present in salt form sulfoaiiiincgruppe,

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or one, 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, cleavable or convertible into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half-ester such as 2,2,2-trichloroethyloxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl, phenacyloxycarbonyl, or a carbonic acid half-amide such as carbamoyl or N-methylcarbamoyl, substituted amino group) 2,6-dimethoxybenzoyl, tetorahydronaphth, 2-methoxy-naphthoyl, 2-ethoxy-naphthoyl, benzyloxycarbony1, hexahydrobenzyloxycarbonyl, 5-methyl-3-pkenyl-4-isoxazolylcarconyl, 3- (2-chlorophenyl ^N -5-methyl-4-isoxazoly! Carbonyl-, 3- ( 2,6-dichloropheny1) -5-methy1-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, methylthioacetyl, butylt hioacetyl, allylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl or 5-amino-5-carboxyl-valeryl (with optionally substituted amino group, e.g. as indicated, and / or optionally functionally modified, e.g. in salt such as sodium salt, or in ester, such as lower alkyl, e.g. methyl or ethyl ester form, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacety1, ethoxy

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carbonylacetyl, bismethoxycarbonylacetyl, N-phenylcarbamoylacetyl, Cyanoacetyl, a-cyanopropionyl, 2-cyano-3,3-dimethylacrylyl, Phenylacetyl, a-bromophenylacetyl, a-azido-phenylacetyl, 3-chlorophenylacetyl, 4-aminoethylphenyl-acetyl, (with optionally substituted amino group, e.g. as stated), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethyl-phenyloxyacetyl, Benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, a-phenyloxyphenylacetyl, a-methoxyphenylacetyl, a ~ ethoxyphenylacetyl, a-methoxy-S ^ -dichloro-phenylacetyl, a-cyano-phenylacetyl, in particular phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl or 3,5-dichloro-4-hydroxyphenylglycyl (in which case the amino group in these radicals, e.g., as indicated above, may be substituted), furthermore benzylthioacetyl, benzylthiopropionyl, α-carboxyphenylacetyl (with optionally, e.g. as stated above, functionally modified carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) propionyl, 4- (3-methoxyphenyl) butyryl, 2-pyridylacetyl, 4-aminopyridiniumacetyl (optionally with, for example, as indicated above, substituted amino group), 2-thienylacetyl, 2-tetrahydrothienylacetyl, α-carboxy-2-thienylacetyl or tt-carboxy-3-thic-nylacetyl (optionally with a functionally modified carboxyl group, e.g. as stated above), a-cyano-2-thienylacetyl, α-amino-2-thienylacetyl or α-amino-3-thienylacetyl

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(optionally with, for example as stated above, substituted amino group), α-sulfo-phenylacetyl (optionally with, for example, like a carboxy group, functionally modified sulfo group), 3-thienylacetyl. 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, 3-methyl-2-imidazolylthioacetyl, 1,2,4-triazol-3-ylthioacetyl, 1,3,4-triazol-2-ylthioacetyl, 5-methyl-1, 2, Jf-thiadiazol-J-ylthioacetyl, 5-methyl-1,3 _/ 4-thiadiazol-2-ylthioacetyl or 1-methyl-5-tetrazolylthioacetyl.

An easily cleavable acyl radical Ac, in particular the acyl radical of a carbonic acid half-ester, is primarily one by 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 several times in the α-position branched or by acylcarbony1-, in particular Benzoyl radicals, or those substituted in the jS-position by halogen atoms Lower alkoxycarbonyl radical, e.g. tert-butyloxycarbonyl, tert-pentyloxycarbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a residue that can be converted into the latter, such as 2-chloro- or 2-bromoethoxycarbonyl, furthermore, preferably polycyclic, cycloalkoxycarbonyl, e.g. adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, primarily cc-phenyl-lower alkoxycarbonyl, in which the α-position is preferred is polysubstituted, e.g. diphenylmethoxy-

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carbonyl or α-4-biphenylyl-α-methyl-ethyloxycarbonyl ·, or Furyl-lower alkoxycarbonyl, primarily α-furyl-lower alkoxycarbonyl, e.g., furfuryloxycarbonyl.

Organic radicals R1 and R2 are primarily Line optionally substituted aliphatic hydrocarbon radicals, such as optionally substituted by halogen Lower alkyl radicals, and also phenyl lower alkyl groups.

An acyl group Ac is primarily an esterified carboxyl group that can be cleaved under mild conditions of the formula -CC = O) -X, where X- ,, e.g. stands for the remainder of the formula -O-R, which together with the Carbonyl grouping when treated with chemical reducing agents under neutral or weakly acidic conditions easily cleavable esterified carboxyl group forms. In this group, R is a 2-halo-lower alkyl radical, in which halogen preferably has an atomic weight of over 19, especially a 2-polychloro-lower alkyl, like 2-polychloroethyl radical, primarily the 2,2,2-trichloroethyl radical, as well as the 2,2,2-trichloro-l-methyl-ethyl radical, but can also, for example, a 2-bromo-lower alkyl, such as 2-polybromo-lower alkyl, like 2,2,2-bromoethyl, furthermore the 2-bromoethyl radical, or a 2-iodine-lower alkyl, e.g. in particular the 2-iodoethyl radical, mean.

Another group X ,, which, together with the carbonyl grouping, is one when treating with chemical reducing agents easily under neutral or weakly acidic conditions

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represents cleavable esterified carboxyl group is the group

-0-R ^b , where R ^{b is} an arylcarbonylmethyl group and preferably

² *

have the unsubstituted phenacyl radical, as well as one in the aromatic Partly substituted, such as by lower alkyl or lower alkoxy groups, or halogen atoms substituted phenacyl radical.

The group X ₁ can also represent the remainder of the formula - ° - ^R ₂ which, together with the carbonyl group, represents an esterified carboxyl group which is easily cleavable on irradiation under neutral or weakly acidic conditions. In this group, R ^C stands for an arylmethyl group, in which aryl denotes an optionally substituted phenyl group, the substituents of which are primarily functional groups, such as free or functionally modified carboxyl groups, for example carboxy, lower oxycarbonyl, carbamoyl or cyano groups, optionally substituted amino, such as di-lower alkyl-amino groups, or acyl, such as lower alkanoyl groups, but in particular functionally modified, in particular esterified, hydroxy or mercapto groups, such as acyloxy, e.g. lower alkanoyloxy groups, or halogen atoms and primarily etherified hydroxy or mercapto groups, such as lower alkoxy groups, and also lower alkylthio groups ( which are primarily in the 3-, k- and / or 5-position in the preferred phenyl radical) and / or above all nitro groups (in the preferred phenyl

209819/1159

rest are preferably in 2-divisions). Such groups R are in particular by lower alkoxy, such as methoxy groups, preferably in J) -, ² J- and / or 5-position, and / or by nitro groups, preferably in the 2-position, substituted 1-phenylethyl or benzhydryl, primarily benzyl radicals, in particular the 3- or 4-methoxybenzyl, 3,5-dimethoxy-benzyl, 2-nitrobenzyl or 4,5-dimethoxy-2- nitro-benzyl radical.

A group -X can also be the radical of the formula -OR ^d ' ¹ 2

represent, which together with the carbonyl group an esterified carboxyl group which is easily cleavable under acidic conditions forms. Such a radical R is primarily a methyl group, which is replaced by an electron-donating substituent having, carbocyclic aryl group or by an oxygen or is monosubstituted with sulfur atoms as ring members, heterocyclic group of aromatic character, or then in an oxa or thiacycloaliphatic radical that which represents the α-position to the oxygen or sulfur atom Ring member means.

A carbocyclic aryl group containing electron-donating substituents in the aryl radical is primarily the Phe nyl radical, suitable substituents which are preferably in the p- and / or o-position of the phenyl radical, e.g. free or preferably functionally modified, such as esterified and primarily etherified hydroxyl groups, such as lower alkoxy

209819/1159

groups, as well as corresponding free or functionally modified Mercapto groups, also aliphatic, cycloaliphatic, aromatic or araliphatic ^, optionally suitably substituted Are hydrocarbon radicals, especially lower alkyl groups, or aryl, e.g. phenyl groups.

A heterocyclic group of aromatic character containing oxygen or sulfur atoms as ring members represents above all a puryl, e.g. 2-furyl radical, or a Thienyl, e.g. 2-thienyl radical.

An oxa and thiacycloaliphatic radical linked in the α-position is primarily a 2-oxa or 2-thiacycloalkyl and 2-oxa or 2-thiaeycloalkenyl group in which the Kethyl group R _{3 is} the ring member adjacent to the ring oxygen or ring sulfur atom represents, and which preferably contains ^ -6 ring carbon atoms, · 'primarily a 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2- pyranyl radical or a corresponding sulfur analog.

Preferred radicals R ₂ are ² -kethoxybenzyl and O>, h ~ dimethoxybenzyl radicals, and 2-tetrahydrofuryl, 2-tetrahydropyi ^ anyl or 2,3-dihydro-2-pyranyl groups.

An esterified carboxyl group of the formula -C (= - O) -X which can also be cleaved under acidic conditions is the group of Formula -CC = O) -O-R ^ in which R ° is preferably a multiple in the α-position substituted methyl radical, such as one in the α-position several times'

209819/1159

branched lower alkyl, e.g. tert-butyl or tert-pentyl, a cycloalkyl, e.g. adamantyl group, a polyarylmethyl, e.g. benzhydryl or trityl group, and also a 2- (4-biphenylyl) -l-methyl-ethyl group is.

Another easily cleavable esterified carboxyl group

f pe of the formula -C (= O) -X is a group of the formula -C (= O) -O-R,

f
where R _{2 stands} for an organic radical which forms an esterified carboxyl group, cleavable under hydrolytic conditions, together with the carboxyl group, such as an activated ester group and in particular denotes a cyanomethyl, 4-nitrophenyl, 4-nitrobenzyl, phthalimidomethyl or succinimidomethyl group. .

Salts of compounds of the formula I are in particular acid

a b addition salts of those compounds in which R and R ^ stand for hydrogen; suitable acids are primarily inorganic acids, such as hydrohalic acids, e.g. hydrochloric, Hydrobromic or hydroiodic acids, sulfuric or phosphoric acids, as well as strong organic ones Carboxylic or sulfonic acids.

As shown below, the compounds of the formula I are valuable intermediates for the preparation of pharmacologically active compounds.

209819/1159

Particularly valuable as intermediate products are compounds of the formula I in which R is hydrogen or the acyl group Ac ¹ , which represents a, in a preferably pharmacologically active, fermative (ie naturally occurring) or synthetically producible N-acyl derivative of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid

acyl radical containing bonds or an easily cleavable> a carbonic acid semi-derivative,
ren acyl radical i / stands, R? Hydrogen denotes, R ₂ denotes hydrogen

or an easily cleavable acyl radical of the formula -C (= O) -X, represents, in which X, stands for an etherified hydroxyl group which, together with the carbonyl grouping, is one under mild Conditions means cleavable carboxyl group, and each of the groups Ro and R, hydrogen or an optionally e.g. by free or functionally modified, such as etherified or esterified hydroxyl or mercapto groups, e.g., lower alkoxy, lower alkylthio or lower alkanoyloxy groups or halogen atoms, or optionally functional modified carboxyl groups, such as lower alkoxycarbonyl, carbamyl or cyano groups substituted lower alkyl, in primarily a methyl radical, or an optionally, e.g. such as the above-mentioned lower alkyl radical or by lower alkyl radicals, substituted phenyl or phenyl-lower alkyl, e.g. benzyl radical, where preferably R «» but also R, stand for hydrogen.

First and foremost, there is a connection between the

209819/1159

mel I R-. for hydrogen or one, in fermentative (i.e. natural occurring) or biosynthetically producible N-acyl derivatives of o-amino-penam-S-carboxylic acid or 7-aminoceph-3-em-4-carboxylic acid compounds containing acyl radical, such as an optionally substituted phenylacetyl or Phenyloxyacetyl radical, furthermore an optionally substituted lower alkanoyl or lower alkenoyl radical, e.g. 4-hydroxyphenylacetyl, hexanoyl, octanoyl, 3-hexenoyl, S-amino-S-carboxy-valeryl, n-butylthioacetyl or Allylthioacetyl, and especially phenylacetyl or phenyloxyacetyl, one of the highly effective N-acyl derivatives of e-amino-penam-S-carboxylic acid or 7-amino-ceph-3-em-4-carboxylic acid compounds Occurring acyl radical, such as formyl, 2-chloroethylcarbamoyl, cyanoacetyl or 2-thienylacetyl, in particular phenylglycyl, in which phenyl optionally by hydroxy and / or halogen, e.g. chlorine, substituted phenyl, e.g. phenyl, or 3- or 4-hydroxyphenyl, Is 3-chloro-4-hydroxyphenyl or 3,5-dichloro-4-hydroxyphenyl, and in which the amino group is optionally substituted and, for example, an optionally present in salt form, SuIfo · amino group or an amino group which is an optionally substituted carbamoyl, such as an optionally substituted ureidocarbonyl group, e.g. ureido

3
carbonyl or N-trichloromethylureidocarbonyl, or an optionally substituted one. Guanidinocarbonyl group,

209819/1159

e.g. guanidinocarbonyl, or one, preferably light, e.g. when treating with an acidic agent, such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous Acetic acid, cleavable acyl radical or an acyl radical which can be converted into such, preferably a suitable acyl radical a carbonic acid half ester, such as 2,2,2-trichloroethyloxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl, or phenacyloxycarbonyl, or a carbonic acid half-amide such as carbamoyl or N-methylcarbamoyl, or in which the amino group with the nitrogen atom of the 3-amino group by an optionally lower alkyl, such as two methyl-containing methylene groups is linked, furthermore thienylglycyl, such as 2-thienylglycyl (optionally with, e.g., as indicated above, substituted amino group), or 1-amino-cyclohexylcarbonyl (optionally with, for example, as indicated above, substituted amino group), furthermore a-carboxy-phenylacetyl or a-carboxy-2-thienylacetyl (optionally with functionally modified, e.g. in salt, such as sodium salt form, or in ester, such as lower alkyl e.g. methyl or ethyl, or phenyl lower alkyl, e.g. diphenylmethyl ester form, carboxyl group present) or oc-sulfo-phenylacetyl (optionally with, e.g. such as the carboxyl group, functionally modified sulfo group), or a slightly, especially under acidic conditions

209819/1159

genes, e.g. when treating with trifluoroacetic acid, or reductive, e.g. with zinc in the presence of aqueous Acetic acid, easily cleavable acyl residue of a carbonic acid half-ester, such as tert-butyloxycarbonyl, phenacyl

carbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxy- t or f

carbonyl in the latter UberfUhrbaren 2-bromoethoxycarbonyl, R, for hydrogen and R ^ for hydrogen or a slightly, E.g. as indicated, cleavable acyl radical of a carbonic acid half ester, such as a radical of the formula -CC = O) -O-R ^, -CC = O) -O-R or -CC = O) -O-Rf, e.g. the tert-butyloxycarbonyl-, 2,2,2-trichloroethoxycarbonyl- or 2-iodoethoxycarbonyl or the 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl radical which can be converted into the latter, also the phenacyloxycarbonyl radical, while Ro is hydrogen and R, - primarily hydrogen, also optionally substituted by halogen, e.g. fluorine, lower alkyl, primarily methyl or ethyl, or phenyl-lower alkyl, in particular benzyl.

The invention relates primarily to compounds of the formula

R {NHS-CH ₂ -CH ₂

CH CH (IB)

O = C SH

209819/1159

where R-! Hydrogen or an acyl group of the formula

Il
Ar CH C (IC)

means in which Ar is phenyl, 3- or 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl or 2-thienyl represents, and R represents hydrogen, or preferably protected amino, carboxy or sulfo, such as acylamino, e.g. tert-butyloxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino or 2-iodomethoxycarbonylamino, as well as or esterified carboxy, such as diphenylmethoxycarbonyl, and in which R «is hydrogen or an acyl radical of a carbonic acid half-ester, such as 2,2,2-trichloromethoxycarbonyl, which can easily be replaced by hydrogen, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, phenacyloxycarbonyl or tert-butyloxycarbonyl means.

According to the invention, the mercapto alcohol compounds of the formula I obtained by using a bis (cis-3-N-R, -N-R, -amino-2-oxo-4-azetidinyl) disulfide compound the formula

< A

N S S N

CH CH CH CH ^Λ 1

¹¹ 'I (II)

O = C NH Hl! C = O ^UJJ

209819/1159

with an oxirane compound of the formula

R- HC- CH R (III)

with simultaneous treatment with a reducing agent, and, if desired, in a compound obtained of formula I, in which R ~ represents hydrogen, the hydroxyl group is converted into an acyloxy group and / or, if desired, in an available compound the group RV ^ and / or the radical R, or representing an acyl group Ac

Away
splits off a divalent amino protective group formed by R, and R, and optionally protects the free amino group in a compound obtainable in this way, and / or converts a salt obtained into the free compound or into another salt and / or a free compound into a salt, and / or, if desired, separating a mixture of isomers obtained into the individual isomers.

Chemical reducing agents, e.g. suitable reducing agents, are primarily used as reducing agents Metals, as well as reducing metal compounds, e.g. metal alloys or amalganies, as well as strongly reducing ones Metal salts. Zinc, zinc alloys,

209819/1159

e.g. zinc copper, or zinc amalgam, also magnesium, which are preferably in the presence of hydrogen donating agents that

along with the metals, metal alloys and amalgamation yarn capable of generating nascent hydrogen, zinc e.g. advantageously in the presence of acids, such as organic carboxylic, e.g. lower alkanecarboxylic acids, in primarily acetic acid, or acidic agents such as ammonium chloride or pyridine hydrochloride, preferably with the addition of V / water, as well as in the presence of alcohols, especially aqueous alcohols such as lower alkanols, e.g. methanol, ethanol or isopropanol, optionally together with an organic Carboxylic acid can be used, and alkali metal amalgams such as sodium or potassium amalgam, or aluminum amalgam , preferably in the presence of moist solvents such as Ethers or lower alkanols. ...

Strongly reducing metal salts are primarily chromium-II compounds, e.g. chromium-II-chloride or chromium-II-acetate, which are preferably in the presence of aqueous media containing organic solvents which are miscible with water, such as Lower alkanols, carboxylic acids, such as lower alkanecarboxylic acids or derivatives, such as optionally substituted, e.g. lower alkylated, Amides thereof, or ethers, e.g. methanol, ethanol, acetic acid, dimethylformamide, tetrahydrofuran, dioxane, ethylene glycol

209819/1159

kol dimethyl ether or diethylene glycol dimethyl ether is used will. ·. ''

The reaction according to the invention is preferably carried out in the presence of a solvent, primarily a solvent which is miscible with water, such as a lower alkanol, e.g. ethanol, an ether, e.g. tetrahydrofuran, or a lower alkanecarboxylic acid, e.g. acetic acid, or a solvent, usually in the presence of V / ater carried out, being carried out under mild conditions, usually at room temperature or with cooling, for example at about -20 ⁰ C to about +10 ⁰ C, if necessary also at elevated temperature, for example at temperatures up to about ICO C, and / or in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere works.

In a compound of the formula I obtainable according to the process in which R _{2 is} hydrogen, the free hydroxyl group can be removed by methods known per se, for example by treatment with carboxylic acids or reactive acid derivatives thereof, such as halides, for example chlorides, anhydrides (including the internal anhydrides of Carboxylic acids, ie ketenes, or of carbamic or thiocarbamic acids, ie isocyanates or isothiocyanates, or mixed anhydrides, such as those that can be formed, for example, with chloroaric acid lower alkyl esters or trichloroacetic acid chloride, or activated esters are to be understood as acylated. If necessary, one works in the presence of suitable

209819/1159

Neten condensation agents, when using acids e.g. in the presence of carbodiimides, such as dicyclohexylcarbodiimide, and when using reactive acid derivatives e.g. in the presence of basic agents such as triethylamine or pyridine.

An acyl group can also be introduced stepwise; in this way one can obtain a connection according to the process with a carbonyl dihalide, such as phosgene, and the halogen, e.g., chlorocarbonyloxy, compound formed with an alcohol, e.g. 2,2,2-trichloroethanol, 2-bromoethanol, Phenacyl alcohol or tert-butanol, treat, and so gradually the hydroxyl group with an etherified hydroxycarbonyl, e.g. the 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl, Phenacyloxycarbonyl or tert-butyloxycarbonyl group, acylate. The acylation reaction can be carried out in the presence or absence of solvents or solvent mixtures, if necessary under cooling or heating., in a closed vessel under pressure and / or in an inert gas, e.g. nitrogen atmosphere, may be carried out in stages.

In a compound obtained, an amino protective group R. or R, in particular an easily cleavable acyl group, in a manner known per se, for example a tert-butyloxycarbonyl group by treatment with trifluoroacetic acid and a 2,2,2-trichloroethoxycarbonyl, 2-iodoethoxycarbonyl or phenacyloxycarbonyl group by treating with a suitable

209819/1159

metal or a metal compound, e.g. zinc, or a chromium-II compound, such as chloride or acetate, advantageously in the presence of a hydrogen-generating, hydrogen-releasing hydrogen which is nascent together with the metal or the metal compound By means, preferably of hydrous acetic acid, are split off. Furthermore, one can in a received

A b bond of the formula I is a suitable acyl group R or R, in split off in a manner known per se, if desired, after protecting functional groups in such a radical (e.g.

by acylation, esterification or silylation), e.g. by Treating with a suitable inorganic acid halide such as phosphorus pentachloride, preferably in the presence a basic agent such as pyridine to form an imide halide, Reacting the imide halide with an alcohol such as lower alkanol, e.g. methanol, and cleaving the imino ether, e.g. in an aqueous medium, preferably under acidic conditions, one sets that obtainable by the above cleavage process Imide halide intermediate instead of with an alcohol with a salt such as an alkali metal salt of a carbon, in particular a sterically hindered carboxylic acid, one obtains

From a Ν, Ν-diacylamino compound of the formula I, wherein R "and R.T Represent acyl groups.

In a compound of the formula I in which both radicals

Away

R ₁ and R _{1 represent} acyl groups, one of these groups, preferably the less sterically hindered, for example by hy-

209819/1159

drolysis or aminolysis, can be selectively removed.

Away

In a compound of formula I, wherein R ₁ and R ₁ together represent with the nitrogen atom a phthalimido group, for example, this can _raz inolyse, ie in treating such a compound with hydrazine to be converted into the free amino group by Hy <. 3

Certain acyl radicals of an acylamino group in accordance with the invention available compounds, in particular the 5-amino-5-earboxyvaleryl radical, can also be treated 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 an 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, Adding a hydroxyl-containing agent, such as water or a lower alkanol, e.g. methanol, to the reaction product and, if necessary, working up the free amino compound after known methods, are split off.

A formyl group R, can also be obtained by treating with an acidic agent, e.g. p-toluenesulphonic or hydrochloric acid, a weakly basic agent, e.g. diluted ammonia, or a decarbonylating agent, e.g. tris (triphenylphosphine) rhodium chloride, be split off.

A triary! Methyl, such as trityl group R, can e.g.

209819/1159

by treatment with an acidic agent such as a mineral acid, e.g., hydrochloric acid.

a b In a compound of the formula I, in which R, and R-,

Represent hydrogen, the free amino group can by acylation methods known per se, for example by treatment with Carboxylic acids or reactive acid derivatives thereof, such as halides, e.g. fluorides or chlorides, or anhydrides (Including the internal anhydrides of carboxylic acids, i.e. ketenes, or of carbamic or thiocarbamic acids, i.e. isocyanates or isothiocyanates, or mixed anhydrides, such as those which, for example, with chloroformic acid-lower alkyl, such as ethyl esters, or trichloroacetic acid chloride are to be understood) or activated esters, as well as with substituted formimino derivatives, such as substituted N, N-dimethylchloroformimino derivatives, or an N-substituted Ν, Ν-diacylamine, such as a Ν, Ν-diacylated aniline, acylated are, if necessary, in the presence of suitable condensing agents, when using acids, for example from Carbodiimides, such as dicyclohexylcarbodiimide, if used of reactive acid derivatives, e.g. of basic agents such as triethylamine or pyridine, where one works optionally also starting from salts, e.g. ammonium salts of compounds of the formula I in which R2 is hydrogen can.

An acyl group can also be introduced by

209819/1159

away

one a compound of formula I, wherein R ^ and R-, for hydrogen stand, with an aldehyde, such as an aliphatic, aromatic or araliphatic aldehyde, reacts the resulting Schiff's base, for example, acylated by the methods given above and the acylation product, preferably in neutral or weakly acidic medium, hydrolyzed.

An acyl group can also be introduced in stages. For example, you can use a compound of the formula I with a free amino group a halo-lower alkanoyl, e.g. bromoacetyl group, or e.g. by treating with a Introducing carbonic acid dihalide such as phosgene, a halocarbonyl such as chlorocarbonyl group, and one thus obtainable N- (halo-lower alkanoyl) - or N- (halocarbonyl) -amino compound with suitable exchange reagents, 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, such as lower alkanols, e.g. tert-butanol, implement and so to substituted N-lower alkanoylamino or N-hydroxycarbony! amino compounds reach. Further, for example, one can use a compound of formula 1 in which R is a, preferably glycyl group substituted in the α-position, such as phenylglycyl, and R, represent hydrogen, with an aldehyde, e.g. formaldehyde or a ketone such as lower alkanone e.g.

Acetone, react and thus arrive at compounds of the formula I,

Away
wherein R, and R, together with the nitrogen atom, in

209819/1159

4-position preferably substituted, optionally in the 2-position substituted S-oxo-l ^ -diaza-cyclopentyl radical represents.

In both reaction participants can during the Acylation reaction free functional groups may be temporarily slit in a manner known per se and after the acylation are released by methods known per se. For example, amino or carboxyl groups can preferably be used in the Acyl radical during the acylation reaction, e.g. in the form of Acylamino, such as 2,2,2-Trichloräthoxycarbonylamino-, 2-Bromoäthoxycarbonylamino- or tert-butyloxycarbonylamino, or in the form of esterified carboxyl groups, e.g. as diphenylmethoxycarbonyl groups protect and subsequently, if necessary after conversion of the protective group, e.g. a 2-bromoethoxycarbonyl- into a 2-iodoethoxycarbonyl group, e.g., by treating with suitable reducing agents, such as zinc in the presence of aqueous acetic acid, or by treatment with trifluoroacetic acid, or by hydrogenolysis to cleave such protected groups.

¹ The acylation can also be carried out by replacing an existing acyl group with another, preferably sterically hindered acyl group, for example by the method described above, by preparing the imide halide compound, treating it with a salt of an acid and one of the products available in this way Acyl group

209819/1159

pen, usually the less sterically hindered acyl group, split off hydrolytically.

a b In a compound of the formula I, 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 agent, such as pyridine.

An amino group can also be introduced by introducing a Si-IyI- and stannyl group are protected. Such groups are introduced in a manner known per se, for example by treatment with a suitable silylating agent, such as a tri-lower alkyl silyl halide, e.g. trimethylsilyl chloride, or an optionally N-mono-lower alkylated, Ν, Ν-di-lower alkylated, N-tri-lower alkylsxlylxerten or N-lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkyl-silyl) -amine, (see e.g. British Patent No. 1,073,530), or with an appropriate one Stannylating agent, such as a bis (trx-lower alkyltin) 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, as well as a tri-lower alkyl tin halide, e.g. tri-n-butyl tin chloride (see e.g. Dutch Auslegeschrift 67/17107).

209819/1159

Salts of compounds of the formula I can be prepared in a manner known per se, acid addition salts of compounds with basic groups e.g. by treatment with an acid or a suitable anion exchange reagent. Salts can be converted into the free compounds in the usual way, acid addition salts, e.g. by treatment with a suitable basic agent.

Mixtures of isomers obtained can be obtained by methods known per se, e.g. by fractional crystallization, Adsorption chromatography (column or thin-layer chromatography) or other suitable separation processes, can be separated into the individual isomers. Racemates obtained can in customary, if appropriate after temporarily introducing salt-forming groups, e.g. by forming a mixture of diastereoisomers Salts with optically active salt-forming agents, separation of the mixture into the diastereoisomeric salts and over-

lead the separated salts into the free compounds or by fractional crystallization from optically active solvents, into the antipodes

be separated. . · .. ·. · ■

The process also encompasses those embodiments of which are obtained as intermediate products Compounds used as starting materials and the remaining

209819 / 11S9

process steps carried out with these, or the proceeding is discontinued at any stage; Furthermore, starting materials can be in the form of derivatives used or formed during the reaction. . · '· ■.

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

The starting materials of the formula II used according to the process are obtained when a compound of formula

(III)

wherein Y represents an optionally substituted methylene group, oxidized, and in a compound of the formula obtained

R ^a _R ^a

o \ / o

N S S N

ο CH CH CH CH ^R o

Il Il (Ha)

O = C NH HN C = O

209819/1159

wherein R and R represent hydrogen or together represent an optionally substituted methylene group, if desired, according to Cleavage of a latter, into the amino group a protective group R. and / or R, introduces.

In a compound of the formula III, Y is preferably a mono- or disubstituted methylene group, where substituents are preferably optionally substituted, mono- or divalent hydrocarbon radicals, in the first place Line corresponding aliphatic hydrocarbon radicals, such as lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, η-butyl or isobutyl groups, furthermore lower alkylene, e.g. 1,4-butylene or 1,5-pentylene groups, as well as the corresponding cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic «hydrocarbon radicals, such as cycloalkyl, e.g. cyelopentyl or cyclohexyl, phenyl or phenyl lower alkyl, e.g. benzyl or phenylethyl groups. Y stands primarily for the isopropylidene or the isobutylidene group, ie. for one through two methyl group. pen or an isopropyl group substituted methylene radical. Oxidizing agents used in accordance with the method are primarily those which cause the formation of disulfide compounds be used under conditions under which the ß-lactam ring is not affected. It is these in particular Halogen, like bromine and primarily iodine, that one

209819/1159

advantageously iii presence of organic solution " agents, e.g. optionally substituted hydrocarbons, such as aromatic hydrocarbons, e.g. benzene, · Ethers, such as cyclic ethers., E.g. tetrahydrofuran or dioxane, alcohols, such as lower alkanols, e.g. methanol or Ethanol, or carboxylic acids, such as lower alkanecarboxylic acids, e.g. acetic acid, or solvent mixtures and optionally in the presence of water, with cooling (e.g. temperatures down to about -30 C), at room temperature or under mild conditions Heating is also used, if necessary, under an inert gas such as nitrogen atmosphere. .

Further suitable for the oxidation of starting materials

Suitable oxidizing agents are oxidizing heavy metal carboxylates, preferably IV lead carboxylates, such as IV lead alkanoates, in particular lower alkanoates and primarily lead tetraacetate, also lead tatrapropionate or lead tetrastearate, and optionally substituted lead trabenzoates, for example 3 lead tetrazoate or lead tetrazoate as well as thallium-III-carboxylates, e.g. Thalliura-III-acetate, or mercury-II-carboxylates, such as mercury-II-acetate, these oxidizing agents, if desired, in situ , e.g. by reaction of lead dioxide or mercury-II- oxide can be formed with an organic carboxylic acid such as acetic acid.

It is advantageous to use the above difficult 209819/1159

metal carboxylates, in particular the corresponding lead-IY compounds, in the presence of a light source, preferably using ultraviolet and longer-wave wavelengths such as visible light, optionally with the addition of suitable sensitizers. The UV light preferably has a main wavelength range of more than 20 m / ij, primarily from about 300 m / i to about j> 5 ° ^R; This can be achieved, for example, by suitable filtering of the ultraviolet light through an appropriate filter, for example a Pyrex filter, or by suitable solutions, v / ie salt solutions, or other liquids which absorb shorter-wave light, such as benzene or toluene Ultraviolet light is preferably generated by means of a high pressure mercury vapor lamp.

Oxidation with a heavy metal carboxylac-oxidizing agent is usually in the presence of a suitable diluent such as benzene, or acetonitrile Acetic acid, if necessary, carried out with cooling or with heating and / or in an inert gas atmosphere.

Oxygen (e.g. as pure oxygen or in the form of of air) in the presence of one used as a catalyst Heavy metal, e.g. Copper (II) or iron (III) salts, such as Ferric chloride or ferric sulfate, and preferably

209819/1159

in the presence of a solvent, such as acetic acid, Hypohalogeni Compounds, in particular alkali metal hydpohalites, e.g. sodium hypoiodite, and organic hypohalites, such as tert-butyl hypochlorite, suitable iron (III) salts and complexes, such as iron (III) chloride, preferably in the presence an organic solvent, e.g. ether, acetic acid, or ethanol, and optionally water, or potassium ferric anide, 1,2-Dijodätban in the presence of an organic Solvent e.g. acetone, tetrahydrofuran or ethanol, or thiocyanogen in the presence of a suitable organic Solvents such as acetic acid can be used. In a disulfide compound obtainable according to the process

away

bond of the formula Ha, in which the radicals R and R together

oo

Men represent an optionally substituted methylene group, such can be replaced hydrolytically by hydrogen will; this elimination can, if the oxidation reaction is carried out in the presence of water, even during this take place.

In a disulfide compound of the formula Ha obtainable according to the process in which the amino groups are unsubstituted or contain an optionally substituted methylene radical as a substituent, these groups can be protected, for example acylated, by methods known per se, for example as described above. A by the groups R ^a and

209819/1159

R ₀ formed, optionally substituted methylene radical, possibly in modified form, are split off.

The intermediates of the formula III, in which Y represents a disubstituted methylene group, required to prepare the starting materials are known (see, for example, Austrian Patent No. 264 533) or can be prepared by the processes used for the known compounds. Compounds in which Y is an unsubstituted or monosubstituted methylene group can be obtained, for example, when a compound of the formula III in which Y is a disubstituierte.Methylene group, with an aldehyde or a reactive derivative, such as a hydrate or a reactive polymeric product converts such aldehyde. This reaction is usually carried out in a solvent ¹ , such as a water-miscible organic solvent, such as a water-miscible alcohol or ether, for example dioxane. or made in a suitable mixture of solvents. It is preferred to add water and work in the presence of an acidic agent, such as an inorganic or organic acid, for example an organic carboxylic or preferably sulfonic acid, v / ie p-toluenesulfonic acid, if desired or necessary, with cooling or preferably heating and / or in a closed vessel and / or in an inert gas atmosphere, for example under nitrogen.

209819/1159

The compound of formula III wherein Y 'is a methylene radical substituted by the isopropyl group can be produced from readily available starting materials, if you have a penam-3-carboxylic acid compound IVa with the formula

S. CH CH '\ / CH-

O = C N °

CH-

^R o

in which Ac represents the acyl radical of an organic carboxylic acid, in which any free functional groups present, such as hydroxyl, mercapto and, in particular, amino and carboxyl groups, are optionally protected, e.g. by acyl groups or in the form of ester groups, and R stands for a carboxyl group -C (= O) -OH, (compound IVa) or a salt thereof into the corresponding acid azide compound of the formula IV, wherein

R represents the azidocarbonyl radical -C (= O) -N (compound IVb) ο ^ά

transferred this to the corresponding with the elimination of nitrogen Isocyanate compound having the formula IV, wherein R is the isocyanato group -N = C = O means (compound IVc) converted and simultaneously or subsequently with a compound of the formula H-X2 (V), wherein X «represents an etherified hydroxy group which

209819/1159

together with a carbonyl group forms an esterified carboxyl group which can be cleaved under neutral or acidic conditions, and in a compound of the formula IV obtained in which R _{Q is} the radical of the formula -NH-C (= 0) -X ₂ (compound IVd), replacing the acyl radical Ac with hydrogen and, if desired, replacing it with an acyl group which can be split off in the following step. In the so obtainable penam compound of the formula

CH CH

O = CH 0 _(VI) .

S H

NH-CX ₂ 0

where R- ^ is hydrogen or an acyl group Ac ⁰ which can be split off under the reaction conditions of the following process step, the group of the formula -C (= 0) -X ₂ is split under neutral or weakly acidic conditions with simultaneous or subsequent treatment with water and that any 4, ^ - Dimeth5a-5-thia-2,7-diazabicyclo [4.2.0] oet-2-en-8-one formed is separated off or the carbon-nitrogen double bond is reduced in this.

An acyl group Ac occurring in the compounds of the formula IV can be any acyl radical of an organic

209819/1159

Represent carboxylic acid with optionally slotted functional groups, primarily an acyl radical contained in fermentatively or biosynthetically producible N -Acy Ideriva th of the 6-aminopenam-3-carboxylic acid compounds, such as a monocyclic arylacetyl or aryloxyacetyl · *. » "also an optionally substituted ^{lower alkanoyl or lower alkenoyl, for example the J} f-hydroxyphenylacetyl, hexanoyl, octanoyl, 3-hexenoyl, 5-amino-5-carboxy-valerr7l-, n-butylthioacetyl or allylthioacetyl- , in particular the phenylacetyl or phenyloxyacetyl radical, or then an acyl radical, preferably easily cleavable under acidic conditions, such as the acyl radical of a half ester of carbonic acid, for example the tert-butyl oxycaebonyl radical.

The conversion of an acid compound IVa or a suitable salt, in particular an ammonium salt, into the Corresponding acid azide IVb can, for example, be converted into a mixed anhydride (e.g. by treatment with a lower alkyl haloformate, such as ethyl chloroformate, in the presence of a basic agent such as triethylamine) and treating such an anhydride with an alkali metal azide, such as sodium azide. The acid azide compound IVb obtainable in this way can be used in the presence or absence of a compound of formula V under the reaction conditions, e.g. when heating, converted into the desired isocyanate compound IVc

209819/1 159

that usually does not need to be isolated and can be converted directly into the desired compound of the formula VI in the presence of a compound of the formula V.

Etherified hydroxyl groups X ^, which together with the. Carbonyl groups form an esterified carboxyl group which can be cleaved under neutral or weakly acidic conditions, are in particular the groups of the formula -0-R ^, -0-R and -0-R ^c , in which R ^a , R and R ^c correspond to the above-mentioned radicals R ^, R ₂ and R «correspond.

The reaction of a compound of formula IVc with. a compound of the formula V, in particular with a 2-haloethanol R -OH, e.g. with 2,2,2-trichloro- or 2-bromoethanol, an arylcarbonylmethanol R -OH, e.g. phenacyl alcohol, or

an arylmethanol R -OH, e.g. 4,5-dimethoxy-2-nitro-benzyl alcohol, is optionally in an inert solvent, e.g. in a halogenated hydrocarbon such as carbon tetrachloride, Chloroform or methylene chloride, or in an aromatic solvent such as benzene, toluene or chlorobenzene, preferably with heating.

The acylamino group Ac-HN- can be cleaved by methods known per se, for example by treating a compound with an imide halide forming agent, reacting the

209819/1159

resulting Iraidhalogenids with an alcohol and cleavage of the formed imino ethers, are split off, whereby a, e.g. by an organic silyl radical protected carboxyl group can be released during the course of the reaction, e.g. during treatment with an alcohol.

Imide halide-forming agents in which halogen is bound to an electrophilic central atom are mainly acid halides, such as acid bromides and especially acid chlorides. These are primarily inorganic acid halides Acids, especially of phosphoric acids, such as phosphoroxy, Phosphorus tri- and especially phosphorus pentahalides, e.g. phosphorus oxychloride, phosphorus trichloride, and primarily Phosphorus pentachloride, also pyrocatechyl phosphorus trichloride, and also 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 mentioned imide halide-forming agents is preferably carried out in the presence of a suitable / especially organic base, primarily a tertiary amine, e.g. a tertiary aliphatic mono- or diamine, such as a tri-lower alkylamine, e.g. trimethyl-, triethyl- or ethyldlisopropylamine, also a Ν, Ν, Ν ', Ν'-tetra-lower alkyl-lower alkylenediamine, for example N, N, N ¹ , N'-tetramethyl-1,5-pentylenediamine or N, N, N ¹ , N'-tetramethyl-1 , 6-hexylenediamine, a mono- or bicyclic mono- or diamine, v / ie an N-

209819/1159

substituted, e.g. N-lower alkylated, alkylene, azaalkylene or oxaalkyleneamine, e.g. N-methyl-piperidine or N-methyl-morpholine, also 2,3,4,6,7,8-hexahydro-pyrrolofl, 2-a] pyriraidin (diazabicyclonones; DBN), or a tertiary aromatic amine such as a di-lower alkyl aniline, e.g. Ν, Ν-dimethylaniline, or primarily a tertiary heterocyclic, mono- or bicyclic base, such as quinoline or isoquinoline, especially pyridine, preferably in the presence a solvent such as optionally halogenated, e.g., chlorinated, aliphatic or aromatic Hydrocarbon such as methylene chloride. You can use approximately equimolar amounts of the imide halide-forming Use agent and base; However, the latter can also be in excess or shortfall, e.g. about 0.2 to about 1-fold Amount or then in an approximately up to 10-fold, in particular approximately 3-5-fold excess, be present.

The reaction with the Imidhalogenid-forming agent is preferably, for example, carried out under cool at temperatures of about -50 ⁰ C to about +10 ⁰ C, but wherein it is also possible at higher temperatures, ie, for example, work to about 75 ° C, if the Stability of the starting materials and products allow an increased temperature.

The imide halide product commonly found further processed without insulation, is carried out according to the procedure

209819/1159

with an alcohol, preferably in the presence of one of the above Bases, converted to the imino ether. Suitable alcohols are e.g. aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, e.g. chlorinated, or containing additional hydroxyl groups, Lower alkanols, e.g. ethanol, n-propanol, isopropanol or n-butanol, especially methanol, also 2,2,2-trichloroethanol, and optionally substituted phenyl-lower alkanols, such as benzyl alcohol. Usually one uses one, e.g. up to about 100 times, excess of the alcohol and works preferably with cooling, e.g. at temperatures from about -50 C to about 10 C.

The imino ether product can advantageously be subjected to cleavage without isolation. The split of the Imino ethers can be obtained by treating with a suitable hydroxy compound be achieved. It is preferable to use water or an aqueous mixture of an organic solvent, such as an alcohol, especially a lower alkanol such as methanol. Usually one works in an acidic medium, e.g. at a pH of about 1 to about 5, which can be adjusted, 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, adjust.

209819/1159

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

An acyl group Ac which can be split off under the reaction conditions of the conversion of a compound of the formula VI into a compound of the formula III, in which Y is a 1-isobutylidene group, is, for example, a group of the formula -C (= O) -X, in which X- is the above has given meaning, in particular a group of the formula -C (= O) -OR ^a , -C (= O) -OR ^b or -C (= O) -OR °, in which R, R and R have the meanings given above , but can also represent any other acyl group which can be split off under the reaction conditions mentioned, in particular a group which can be split off under acidic conditions.

Such an acyl group can be introduced in a manner known per se, for example as described above.

The cleavage of the group -C (= O) -X ₂ in an intermediate of the formula VI depends on the nature of this group, the cleavage being carried out in the presence of at least one mole,

209819/1159

normally makes an excess of water, or the reaction product subsequently treated with v / ater.

The cleavage of an esterified carboxyl group of the formula -C (= O) -X _? , which in a compound of the formula VI can also represent the radical Ac, and in which X _{p represents} the group -0-R or -0-R, is obtained by treatment with a chemical reducing agent in the presence of an at least equimolar amount, usually in the presence an excess of water. You work under mild conditions, usually at room temperature or even with cooling.

Chemical reducing agents are the reducing agents mentioned in the above-described method according to the invention of this type, such as reducing metals, metal alloys or metal compounds, preferably in the presence of hydrogen donors Agents, primarily zinc in the presence of aqueous acetic acid.

In a compound of formula VI wherein X _{p is}

R represents a radical of the formula -OR ^C , the group of the formula -C (-O) -Xp, which can also represent the group Ac °, can be cleaved by irradiation with light, preferably with ultraviolet light. Depending on the nature of the substituent R ^C, longer-wave or shorter-wave light is used. So

209819/1159

are for example groups of the formula -CC = O) -OR ^, where R ^ is a substituted by a nitro group in the 2- £ position of the aryl radical, optionally further substituents, v. ^r ie lower alkoxy, for example methoxy groups, having arylmethyl, in particular benzyl radical, for example the ^, S-dimethoxy ^ -nitro-benzyl radical, by irradiation with ultraviolet light with a "wavelength range of over 290 πιμ, those in which R one optionally in "} -, 4- and / or 5-position, for example arylraethyl, for example benzyl, substituted by lower alkoxy and / or nitro groups, cleaved by irradiation with ultraviolet light with a wavelength range of less than 290 μm. In the first case one works with a high pressure mercury vapor lamp, whereby one preferably uses Pyrex glass as filter, for example with a main wavelength range of about 315 μm, in the latter case with. a low-pressure mercury vapor lamp, for example with a main wavelength range of about 25 ^ ηιμ.

The irradiation reaction is carried out in the presence of a suitable polar or non-polar organic solvent or a mixture made; Solvents are, for example, optionally halogenated hydrocarbons, such as optionally chlorinated lower alkanes, e.g. methylene chloride, or optionally chlorinated eenzenes, e.g. benzene, also alcohols, "such as lower alkanols, e.g. methanol, or ketones, such as lower alkanones, e.g. acetone. The reaction is preferably carried out at room temperature od ^ r, if necessary, with cooling, usually

209819/1159

in an inert gas, e.g. nitrogen atmosphere. she will preferably made in the presence of water; but you can also treat the irradiation product with water afterwards, e.g. by working up the product obtained in the presence of water.

Any formed as an intermediate

especially in the non-reductive cleavage of a group of the formula -C (= O) -X ₂ in a compound of the formula VI, in which X represents the group of the formula -0-R, and also in the cleavage of a group of the formula - C (= 0) -X _o in a compound of the formula VI, in which X _{g represents} the group of the formula -0 ~ R _Q , occurs with the aid of a strongly reducing metal salt, can be converted into the desired 3 ~ isopropyl- ^{i by exhaustive reduction} t-thia-2,6-diazabicyclo [3.2.0] heptan-7-one can be converted or then separated from a mixture with the latter. One uses to reduce the carbon-nitrogen double bond in 4,4-dimethyl ~ 5-thia-2,7-diazabicyclo [4.2.0] oct-2-en-8-one, which with simultaneous rearrangement to 3 ~ 1 ^s oP ^r opy ^ · "4-thia-2,6-diazabicyclot3.2.0Jheptan-7-one runs, preferably former reducing agents, primarily reducing metal or metal compounds, such as those mentioned above, preferably in the presence of hydrogen donating agents, in particular zinc in the presence of an acid, such as acetic acid, or a--

209819/1159

Alcohol. · "

A mixture of the 3-I ^so P ^ro Py! - ^i} - ' ^t hia-2,6-diazabicyclo [3.2.0] heptane-7-cns and the 4,4-dimethyl-5-thia-2.7 -diazabicyclo [4.2.0] oet-2-en-8-one, as it is primarily in a reductive cleavage of the group of the formula -C (= 0) -X in a starting material of the formula VI, wherein Xp is a group of Formula -0-R or -0-R means, arises, and the individual compounds can be separated by known separation methods, for example by fractional crystallization, adsorption chromatography (column or thin-layer chromatography) or other suitable separation processes.

In the preparation of compounds of the formula VI, intermediate products can be incorporated into one another at suitable stages be transferred. So z-, 3. an aliphatically bound Chlorine, especially Eroma 10121 in the remainder X, like the 2-bromine

ethyloxy residue, e.g. by treating with a suitable iodized salt, such as an alkali metal, e.g. potassium iodide, replaced by an iodine atom in a suitable solvent such as acetone, E.g. the 2-bromoethyl radical is converted into the 2-iodoethyl radical will, " ·

As mentioned, the compounds of the formula I are valuable intermediates, which are particularly useful for Manufacture of pharmacologically fourfold compounds, e.g. 3.

2098 19/1159 BADORfGlNAL

of the 7β-amino-ceph-3-em-4-carboxylic acid type and N-acyl derivatives thereof, the latter in particular, with effects against microorganisms such as gram-positive and gram-negative bacteria suitable to be convicted.

So you can a compound of formula I, wherein R-

and R, have the meanings given above and preferably

a A

are hydrogen, R is an amino protective group R, R is as defined above and the radical R _{2 is} the acyl radical of the formula -CC = O) -X, with a compound of the formula

Il a
O = CH C - 0 r £ (VII),

in which R _{5 represents} an organic radical which, together with the -C (= 0) -O grouping, forms a protected carboxyl group, or a reactive derivative thereof, and in the addition compound of the formula

_p ARR, 0

^R l \ PI ⁴ Il

NS — CH — CH — O — C — X _n

R ^ CH CH (VIII)

O = C N

CHOH

O = CO-R ^
0

convert the secondary hydroxy group into a reactive esterified hydroxy group. The reactive ester of formula

209819/1159

"A R_ R. O

^R l \ I ⁵ I ⁴ I "

NS-CH-CH-O-CX _n

Rf CH CH

¹ I j (ix),

O = C N

CHZ

O = C-C-R ^

wherein Z is a reactive esterified hydroxy group, in primarily a halogen, especially chlorine or bromine, as well as an organic sulfonyloxy, e.g. 4-methylphenylsulfonyloxy or methylsulfonyloxy group, is added a phosphine compound of the formula

l

(χ)

wherein, each of R, R, and R represents an optional

ei O O

substituted hydrocarbon radical is around and is so, if necessary, after splitting off the elements of an acid Formula H-Z (XIa) from a phosphonium salt compound of the formula available as an intermediate

209819/1159

ΐ \

R, R.

I ³ I ⁴ ι

S-CH-CH-O-C-X.

riTT fin

O = C N

CH-P-R,

O = C-

(XI)

the phosphoranylidene compound of the formula

R, E, possibly via

O = C--

-K

\ l ^a

\. · Ir ——It ₁

O = C-O-R,

(Xu)

in which the esterified carboxyl group -C (= O) -X. splits. A compound of the formula is obtained in this way

209819/1159

CH-O = C-

R, R,, 3 | 4

S-CH-GH-OH

-CH

-N

\ i

o = c-o-r;

(XIII)

In a compound of the formula XIII, in which Ro and R, stand for hydrogen, the hydroxyl group is oxidized to the oxo group. In such a obtainable C eph-3-end compound the formula

1\

Ή — CH

O = C-

CH,

-N / CH \ 0

[XIV),

in which R- represents an amino protecting group R-, R, the has the meaning given above, and R ^ for the organic radical

Rc stands, and the ring closure from the under.den reaction conditions formed but not isolated carbonyl compound of the formula

209819/1 159

N S-CH-CHO

¹ I CH CH

I I (XIVa),

O = C N R

\ i ^a

R.
c

O = C

arises, if desired, a protective group R, and / or R, split off and optionally in a compound obtainable in this way, the free amino group is split, and / or, if desired, a protected carboxyl group of the formula -CC = O) -OR ₅ in the free carboxyl group or another protected carboxyl group of the formula -CC = O) -OR, - converted and, if appropriate, in a compound obtainable in this way, a free carboxyl group is converted into a protected carboxyl group of the formula -CC = O) -OR ₁ -, 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, a mixture of isomers obtained can be separated into the individual isomers.

In a compound of the formula I to be used as starting material, in which R _{2 is} the acyl radical of the formula -CC = O) -X, the acylated hydroxyl group is in particular a group of the formula -0-C (O) -OR *, -0 -CC = O) -OR ^, -0-CC = O) -

209819/1159

OR ^, -OC (= O) -Rq, -OC (= O) -OR® or -OC (= O) -OR ^, where R *, R _Q , R ^, R _Q , R® and R _{q have} the meanings given above and are primarily 2,2,2-trichloroethyl, phenacyl, 4,5-dimethoxy-2-nitro-ben2yl or tert-butyl radicals.

In a glyoxylic acid compound of the formula VII, the radical R- is primarily a group R ^a , R, R ^c ,

_> ^rr OOO

^R o ' ^R o ^{and R} o

The addition of the glyoxylic acid ester compound of

Formula VII to the nitrogen atom of the lactam ring of a compound of formula I, takes place preferably at an elevated temperature, primarily at about 50 C to about 150 C, namely in the absence of a condensate and / or without the formation of a salt. Instead of the free glyoxylic acid ester compound also a reactive oxo derivative thereof, primarily a hydrate / used v / ground, where one water formed when using the hydrate, if necessary, by distillation, -z.B. azeotropic, can remove.

It is preferable to work in the presence of a suitable solvent, such as dioxane or toluene, or Solvent mixture, if desired or necessary, in a closed vessel under pressure and / or in the Atmosphere of an inert gas such as nitrogen.

209819/1159

In a compound of the formula VIII, the secondary hydroxyl group can be converted in a manner known per se into a reactive hydroxyl group esterified by a strong acid, in particular into a halogen atom or into an organic sulfonyl oxy group. For example, suitable halogenating agents are used, such as a thionyl halide, e.g. basic, primarily an organic basic agent, such as an aliphatic tertiary amine, for example triethylamine or diisopropylethylamine, or a heterocyclic base of the pyridine type, for example pyridine or Colliüin, carried out WiI ¹ C-, Ve' ^ r-gsv / iron works one in the presence of a suitable solvent ,, s, B. Dioxane or tetrahydrofuran, or a solvent mixture, if necessary, with cooling and / or in the atmosphere of an inert gas such as nitrogen.

In a compound of the formula IX obtained, can one reactive esterified hydroxyl group Z into another reactive esterified one in a manner known per se Hydroxy group are converted. For example, you can have a chlorine atom by treating the corresponding chlorine compound with a suitable bromine or iodine reagent, in particular with

209819/1159

an inorganic bromide or iodide salt, such as lithium bromide, preferably in the presence of a suitable solvent. * like ether / replace with a bromine or iodine atom. In a compound of formula X each means

of the groups R, R. and R primarily an optionally, * ^ a b c

e.g. by etherified or esterified hydroxyl groups, such as lower alkoxy groups or halogen atoms, substituted lower alkyl radicals or an optionally, e.g. by aliphatic hydrocarbon radicals, such as lower alkyl groups, or etherified or esterified hydroxyl groups, such as lower alkoxy groups or halogen atoms, or nitro groups, substituted phenyl radical.

The reaction of a compound of formula IX with the

Phosphine compound of the formula X, in which each of the groups R,

• · a

R. and R primarily for phenyl, as well as a lower alkyl, in particular the n-biityl radical is preferred in the presence of a suitable inert solvent such as an aliphatic, cycloaliphatic ^ or aromatic Hydrocarbon, e.g. hexane, cyclohexane, benzene or toluene, or an ether, e.g. dioxane, tetrahydrofuran or Diethylene glycol dimethyl ether, or a solvent mixture made. If necessary, one works under cooling oder.at an elevated temperature and / or in the atmosphere of an inert gas such as nitrogen.

An intermediately formed phosphonium salt compound of the formula XI usually spontaneously loses the elements of the acid of the formula H-Z (XIa); if necessary, the phosphonium

209819/1159

salt compound by treating with a weak base, such as an organic base, e.g. diisopropylethylamine or pyridine, decomposed and converted into the phosphoranylidene compound of the formula XII.

The cleavage of the esterified carboxyl group of the

Formula -CC = O) -X ₁ in a compound of the formula XII can be carried out in various ways depending on the nature of the group X.

will. So one can create a grouping -C (= 0) ~ X, where X is the

a b ■ ■

Group of the formula -0-R or -0-R, by treatment with a chemical reducing agent, for example one of the abovementioned reducing agents such as zinc, advantageously in the presence of an acid or an alcohol, optionally with the addition of water , for example in the presence of aqueous acetic acid, is used, and a grouping of the formula -C (= 0) -X in which X represents the group of the formula -0-R ^C

J-X O

by exposure to light, especially with ultraviolet Light, split; these cleavage reactions can be carried out according to the methods described above.

An esterified carboxyl group of the formula

d e

-CC = O) -OR or -CC = O) -OR can by treating with a ^v ' ο ο

acidic agents, especially with an acid such as a strong organic carboxylic acid, e.g. an optionally substituted one, lower alkanecarboxylic acid, preferably containing halogen atoms, such as acetic acid or trifluoroacetic acid,

209819/1159

can also be cleaved with formic acid or a strong organic sulfonic acid, e.g. p-toluenesulfonic acid. An excess of an acidic reagent which is liquid under the reaction conditions is usually used as a diluent and works at room temperature

or with cooling, for example at about -20 ⁰ C to about + 10 ° C.

■ · ■ f

An esterified carboxyl group -C (= O) -O-R

can hydrolytically under neutral or weakly acidic or basic conditions, for example at a pH of about h to about 9 *, for example by treatment with water, a weakly acidic agent such as a weak acid or a weakly acidic buffer solution, or a weakly Basic agents, such as an alkali metal hydrogen carbonate, such as sodium hydrogen carbonate, or a suitable buffer (pH about 7 to about 9) > such as a dipotassium hydrogen phosphate buffer, in the presence of water and preferably an organic solvent such as methanol or acetone, split v / ground.

In a compound of the formula XII, the esterified carboxyl groups of the formulas -C (~ O) -X and -C (= O) -OR, - preferably differ from one another in such a way that, under the same conditions of cleavage of the esterified carboxyl group of the formula-C (= 0) -X ₁ the esterified carboxyl group of the formula -C (= O) -OR remains intact. For example, the esterified carboxyl group of the formula -CC = O) -X _{1 represents} a treatment

209819/1159

esterified carboxyl group which can be cleaved with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, for example a grouping of the formula -C (= O) -OR ^a or

b a

-C (= 0) -0-R _Q , in which R ^ is preferably the 2,2,2-trichloroethyl radical and R is primarily the phenacyl group, the esterified carboxyl group of the formula -CC = O) -OR _5, for example for one of the esterified carboxyl groups -C (= O) -OR, - cleavable on treatment with a suitable acid such as trifluoroacetic acid, for example for a grouping of the formula -CC = O) -OR ", in which R is preferably the tert-butyl group represents.

• The oxidation of a compound of the formula xiil can

Surprisingly, can be carried out by treatment with an oxidizing organic sulfoxide compound in the presence of agents with dehydrating or water-absorbing properties. As oxidizing sulfoxo compounds. Aliphatic sulfoxide compounds are primarily suitable, such as di-lower alkyl sulfoxides, primarily dimethyl sulfoxide, or lower alkylene sulfoxides , for example tetramethylene sulfoxide. Acid anhydrides are primarily to be mentioned as gowns with dehydrating or absorbing properties,

209819/1159

in particular anhydrides of organic * such as aliphatic or aromatic carboxylic acids, e.g. anhydrides of lower alkanoic acids, in particular acetic anhydride, also propionic anhydride, or benzoic anhydride, and anhydrides of inorganic acids, especially phosphoric acids, such as Phosphorus pentoxide. The above anhydrides, primarily of organic carboxylic acids, e.g., acetic anhydride, are preferred in about a 1: 1 mixture with the sulfoxide oxidizing agent used. Other dehydrating or dehydrating agents are carbodiimides, primarily dicyclohexylearbodiimide, also diisopropylcarbodiimide, or ketenimines, e.g. diphenyl-N-p-tolylketenimine; these reagents are preferred used in the presence of acidic catalysts such as phosphoric acid or pyridinium trifluoroacetate or phosphate.

Sulfur trioxide can also be used as a dehydrating or -absorbing agent can be used, usually in the form of a complex, e.g. with pyridine, for use brings. .

The sulfoxide oxidizing agent is usually used in excess. Liquid under the reaction conditions Sulphoxide compounds, especially dimethyl sulphoxide, can, for example, serve as solvents at the same time; as a solvent Inert diluents such as benzene or mixtures of solvents can also be used.

209819 / 11B9

The above oxidation reaction is, if desired, with cooling, but mostly at room temperature or easily elevated temperature. In accordance with the procedure, a Aldehyde compound of the formula XIVa obtainable as an intermediate under the reaction conditions and without being isolated to be ring-closed directly to the 7β-amino-ceph-3-em-4-carboxylic acid compound of the formula XIV.

In a compound of formula XIV obtained in which R-. is preferably hydrogen, can be an amino protective group R-, in particular an easily cleavable acyl group, in a manner known per se, a tert-butyloxycarbonyl group for example by treating with trifluoroacetic acid and a 2,2,2-trichloroethoxycarbonyl group by treatment with a suitable metal or a metal compound, e.g. tin, or a chromium-II compound, such as chloride or acetate, advantageously in Presence of a hydrogen-releasing hydrogen-generating, hydrogen-releasing substance which noses together with the metal or the metal compound By means of preferential prices of acetic acid containing water. Furthermore, in a received compound of the formula XIV, in which a carboxyl group -C (^ O) -O-R is preferred one e.g. by esterification, including by silylation or stannylation, e.g. with a suitable organic halosilicon or halogen-tin-IV compound, such as trimethylchlorosilane, represents protected carboxyl group, a suitable acyl group R ^, wherein any free functional groups present are preferably are protected by treatment with 'an imide halide

209819/1159

forming agents, such as a suitable inorganic acid halide, e.g. phosphorus pentachloride, preferably in the presence of a basic agent such as pyridine, reacting the resulting Imide halide with an alcohol such as lower alkanol, e.g. methanol, and cleavage of the imino ether formed in an aqueous or alcoholic medium, preferably under acidic conditions.

gen, to be split off. A triaryl methyl group R ₁ can, for example

be split off as described above.

ab In a compound of the formula XIV, wherein R-. and R ₁

Mean hydrogen, the free amino group can by substitution processes known per se, e.g. as described above, protected, especially acylated.

In a compound of the formula XIV with an esterified carboxyl group, the latter e.g. Carboxyl group convertible esterified carboxyl group of the formula -C (= O) -O-R represents, this can in a manner known per se, e.g. depending on the type of esterifying radical R into which the free carboxyl groups are converted, a grouping of the formula

-C (= O) -OR or -Cf = O) -OR e.g. by treating with a ^% 'ο ο

chemical reducing agents, such as a metal, e.g. zinc, or a reducing metal salt, such as a chromium-II salt, e.g. Chromium (II) chloride, usually in the presence of a hydrogen donor Means that is able to generate nascent hydrogen together with the metal, such as an acid, primarily Acetic acid, 'or an alcohol, being preferred Adding water, a grouping of the formula -C (- O) -O-R e.g.

209819/1159

^{! 75} 2151S60

by irradiation, preferably with ultraviolet light, using shorter-wave ultraviolet light, for example below ΐημ, if R is, for example, an arylmethyl radical optionally substituted in ~ $ - , K- and / or 5-position, for example by lower alkoxy and / or nitro groups represents, or with longer-wave ultraviolet light, for example over 290 m / ^ - if R ° is, for example, an arylmethyl radical substituted in the 2- position by a nitro group

d e

means a grouping -CC = O) -O-R or -C (= O) -O-R e.g.

by treating with an acidic agent such as formic acid or trifluoroacetic acid and a grouping -C (= O) -O-R e.g. Hydrolysis, e.g. by treatment with a weakly acidic or weakly basic agent such as aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer.

In a compound of the formula XIV, a grouping of the formula -C (= O) -O-R can be converted into another of this formula for example a 2-bromoethozycarbonyl group of the formula -C (= O) -O-R by treating with an iodized salt, such as sodium iodide, in the presence of a suitable solvent, such as acetone, into a 2-iodoethoxycarbonyl group.

A carboxyl group protected e.g. an alcohol.

In a compound of the formula XIV with a group of the formula -C (= 0) -0-R, in which R is hydrogen, can

209819/1159

the free carboxyl group in a manner known per se, for example by treatment with a diazo compound such as a diazo lower alkane, for example diazomethane or diazoethane, or a phenyl diazo lower alkane, for example phenyldiazomethane or diphenyldiazomethane, or by reaction with an alcohol suitable for esterification in the presence an esterification agent., such as a carbodiimide, for example dicyclohexylcarbodiimide, and carbonyldiimidazole, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid In addition, acid halides, such as chlorides (produced, for example, by treatment with oxalyl chloride), or activated esters (produced, for example, with N-hydroxy nitrogen compounds), or mixed anhydrides (such as, for example, with haloformic acid lower alkyl esters, such as ethyl chloroformate, or with haloacetic acid re-halides, such as trichloroacetic acid chloride ₅ , mixed anhydrides formed) are converted into esters by reaction with alcohols, optionally in the presence of a base such as pyridine.

In the above process steps, if necessary, free functionalities which do not participate in the reaction can

209819/1159

Groups in the reactants, for example, free hydroxy, mercapto and amino groups, for example by acylation, tritylation or silylation, and free carboxyl groups by, for example, \ ^r eresterung, incl. Silylation, in a known V / else temporarily protected and after the reaction, respectively if desired, released in a manner known per se.

The compounds of the formula XIV, in particular those in which R, stands for an acyl radical contained in pharmacologically active, naturally occurring or biosynthetically or semi- or totally synthetically producible N-acyl derivatives of β-amino penicillanic acid or Y-amino cephalosporanic acid compounds, and R ₁ denotes hydrogen and R denotes hydrogen or an organic radical R that can be easily split off under physiological conditions are against microorganisms such as gram-positive bacteria, e.g. against Staphylococcus aureus (e.g. in mice in doses of about 0.0001 to about 0.02 g / kg po, preferably from about 0.001 to about 0.01 g / kg pc), and garm-negative bacteria, for example Escherichia coli (for example in mice in doses of about 0.001 to about 0.05 g / kg pc, preferably from about 0.005 to about 0.04 po), in particular also effective against penicillin-resistant bacteria and can be used in the form of antibacterial preparations.

209819/1159

The invention is described in the following examples. The temperatures are given in degrees Celsius.

209819 / 11SS

Example 1:

A solution of 0.35 g of bis (cis-2-oxo-3ß ~ phenylacetylamino-4ß-azetidinyl) disulfide in ΐβ ml 9: 1 mixture of acetic acid and VJasser is at about 5 with about 3.2 g of ethylene oxide, then mixed with 3.5 g of zinc dust, the reaction mixture is for 15 minutes at about 5 and for 30 minutes at room temperature stirred, then filtered. The filter residue is washed with acetone and the filtrate is evaporated. The residue is taken up in about 150 ml of ethyl acetate and the solution with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and washed with 100 ml of a saturated aqueous sodium chloride solution, dried and evaporated. The residue is obtained together with an analogous solution from 0.15 g of bis (cis-2-oxo-; 5β-phenylacet-: / Iarnino-4β-azetid.inyl) disulfide obtained crude product chromatographed on 50 g of silica gel. The 4ß- {2-hydroxyethylthio) -3ß-phenylacetylamino-azetidin-2-one is eluted with a 19: 1 mixture the formula

C-HN S-CH ₀ -CH ₀ -OH

\ / ^{2 2}

CH CH

I I

O = C NH

209819/1159

as a uniform product which, after crystallization from a mixture of acetone and diethyl ether, melts at 141-142; [a] _ = +44 ± 2 (c = 0.571 in ethanol); Thin-layer chromatography (silica gel; developing with iodine): Rf 0/45 (system: ethyl acetate / acetone 1: 1); Infrared absorption spectrum (in mineral oil): characteristic bands at 3, Ο1μ, 5.68μ, 6.01μ, 6.43μ and 6.52μ.

The starting material can be prepared as follows:. ·

15 ml of a sulfonic acid type ion exchanger (H ^ form) are carried out by treating with. a solution of 5 nil Triethylamine in 100 ml V / water in the triethylammonium salt form about ,, wasscht.die column with 300 ml of water neutral and treated with a solution of. 2 g of the sodium salt of penicillin-G in 10 ml v / water and then eluted with water. A volume of ^ 5 nil is withdrawn and at a pressure of 0.01 mm Hg lyophilized. The crude triethylammonium salt thus obtained Penicillin-G is dissolved in methylene chloride, the solution is dried over sodium sulfate, filtered and evaporated. "." ··

A solution of the penicillin-G-triethylammonium salt obtainable in this way in a mixture of ² ×) ml of methylene chloride and 10 ml of tetrahydrofuran is cooled to -10 and slowly

• ■ ·

while stirring with 2.9 ml of a 10 ml solution of 2 ml chlorine

209819/1159

ethyl formate in tetrahydrofuran was added. The mixture is stirred for 90 minutes at -5 ° to 0 °, then treated with a solution of Oj395 S sodium azide in H ml of water and the mixture is stirred for 30 minutes at -5 ° to 0 °. The organic extracts are then diluted with 100 ml of ice water and extracted three times with 75 ml of methylene chloride each time. The organic extracts are washed with water, dried and evaporated at room temperature under reduced pressure. This gives the amorphous penicillin-G-azide, infrared absorption spectrum (in methylene chloride): characteristic bands at 3. 5μ, 4.71μ, 5.62μ, 5, δθμ, 5, 9Vj β, β9μ and 8.50 .

A solution of I ₄ 72 g of penicillin G azide in 30 ml of benzene is with- 1.5 mL of 2,2,2-trichloroethanol was added and stirred for 25 hours at 70th A regular evolution of nitrogen is observed during the first 15 minutes and after a few hours the product separates out of the solution. It is diluted with 60 ml of hexane while stirring, cooled and filtered after 15 minutes. The filter residue is washed with a 2: 1 mixture of benzene and hexane and with cold ether. The pure 2,2-dimethyl-6β-phenylacetylamino-3- (2,2,2-trichloroethoxycarbonylamino) -penam, which melts at 223-223.5 °, is obtained in this way; [cÜq = + 172 ° (c = 1.018 in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04μ, 5.77μ, 6.97μ, β, 70μ, 8.3μ, 9.17μ / 9.62μ and 11.85μ.

2 0 9819/1159

The product can also be obtained by heating 0.03 g of penicillin-G azide in 2 ml of benzene to 70 minutes for 20 minutes and evaporating the reaction mixture under reduced pressure to obtain the 3-J ^s o ^c y ^an ato-2 _> 2-dimethyl-6β-phenylacetylamino penam; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.0μ, 4.48μ, 5.62μ, 5.96μ and 6.7μ; obtained and this converted by reaction with 2,2,2-trichloroethanol in the desired 2,2-dimethyl-6 ß-phenylacetylami.no-3 .- (2,2,2-trichloräthoxycarbonylamino) -penam. "- ·" · .- ■■

A solution of 11.0 g of 2,2-diraethyl-6ß-phenylacetyl-

amino-3- (2,2,2-trichlorethoxycarbonylamino) -penam in a mixture of 2 ^ 40 ml of anhydrous methylene chloride and 25, 6 ml of pyridine is under a nitrogen atmosphere at -10 with l66 ml'einer 10 ^ solution of phosphorus pentachloride added in methylene chloride and then stirred at 0 for 1 ) 0 minutes. Then 120 ml of absolute methanol are added with vigorous cooling (-10 °) and stirring is continued for 2 hours. Man

mixed with 80 ml of water, adjusts the pH value (in with V / water diluted samples measured) with about 9 ml of a 2-n. watery Sodium hydroxide solution to 3> 3 and leaves during one React hour at 0 and for a further hour at 20 °. It is then poured into 500 ml of a 1-m. 'With stirring. watery Dipotassium hydrogen phosphate buffer solution and provides the pH fourth by adding 50 / Sißer aqueous tripotassium phosphate

209819/1159 ■ »<W9nal

solution from 6.5 to 7.0. The aqueous phase is separated off and washed twice with 200 ml of methylene chloride each time; the three organic solutions are each washed twice with water,. combined, dried over sodium sulfate and under reduced

evaporated under pressure. The crystalline residue is taken up in HO ml of a 1: 1 mixture of benzene and hexane; the mixture is cooled at 0 ° for 15 minutes and the precipitate is filtered off. This gives 6β-amino-2,2-dimethyl-3- (2,2,2-trichlorethoxycarbonylarnino) -penam, which melts at 179-Ιδθ (corr.); Infrared absorption spectrum: characteristic bands (in methylene chloride) at 2.90μ, 5.58μ, 6.62μ, 7.17μ, 7.27μ, 8.32μ, 8.4βμ, 8.82μ, 9.25μ and 9.62μ; (in Nujöl) at 2.95μ, 3.01μ, 3.11μ> 5.6V, 5, δθμ, β, 35μ, 7.6θμ, 7ί87μ * δ, ΟΟμ, 8.27μ, 8.65μ, 8.7Ομ , 9> ΐ6μ and 9 ^ 57μ; Thin-layer chromatogram (silica gel): Rf = 0.17 (in the toluene / acetone system 8: 2) and Rf = 0.13 (in the toluene / acetone 6-III system); characteristic yellow coloration with ninhydrin-collidine (free 'amino group). · ^

A mixture of 0.05 ß-amino-2,2-dimethyl-3- (2,2,2-trichloroethoxycarbonylamino) -penam and 0.1 gr ^ instaub in 2 ml of a 1: 1 mixture of acetone and V After adding 0.2 ml of acetic acid, the water is fibrated at 45 kHz (ultrasound) for one hour, then diluted with 50 ml of water. It is extracted with 50 % acetic acid, ^ rocknoi

209819/1159 ^ßAD

the organic Extrakfc over sodium sulfate and evaporated

- S.

reduced pressure. The residue is recrystallized from a mixture of methylene chloride and hexane and obtained as the 3-I ^s ° P ^r ^ ~ ^thia opyl- -2 _i 6-diazabicyclo [3 "2.0] heptan-7-one _J. P. 151-155 J Thin layer chromatography: Rf = 0.17 (system; toluene / acetone 8: 2) and Rf = 0.38 (system: toluene / acetone 6: 4).

In the above procedure, instead of de? Acetic acid 0.2 g ammonium chloride or 0.2 g pyridine hydrochloride used will. . ■ '

A solution of 1.64 g of 3-isopropyl-4-thia-2,6-diazabicyclo [3.2.0] heptan-7-one in 33 ml of a 1:! mixture of acetic acid and water is added within 10 minutes with 71.7 ml a 0.5-n. Solution of iodine in ethanol added, during a Left to stand at room temperature for an hour and then concentrated under reduced pressure. The dried under high vacuum Residue with the bis ~ (cis ~ 2-oxo-3ß-amino ~ azetidin ~ 4ß-yl) -di ~ sulfide is suspended in 9 ° ml of acetonitrile and at 0 ° with 4.5 ml of pyridine and 4.5 ml of phenylacetic acid chloride were added.

It is left at 0 ° for 15 minutes and for one hour

stand at room temperature and then evaporate under reduced pressure. One triturates for 30 minutes with 10 ml of one 1:! - Mixture of dioxane and water and the residue is taken up in ethyl acetate; the solution is saturated with a th aqueous sodium hydrogen carbonate solution and a saturated

209819/1159

th aqueous sodium chloride solution, dried and evaporated. The oily residue is on 100 g of pure silica gel Ehromatographiert; the oily bis (cis-2-oxo-3ß-phenylacetylamino-4ß-azetidinyl) disulfide is with a 19: 1 mixture of ethyl acetate and acetone eluted and converted into a finely powdered amorphous form by lyophilization; Thin-slice o-matogram (Silica gel): Rf ^ 0.36 (system: ethyl acetate / Acetone 1: 1); Infrared absorption spectrum (in potassium bromide): characteristic bands at 3, θ8μ, 5, β2μ, 5.97μ and 6.51μ.

The bis-Ccis ^ -oxo ^ ß-phenylacetylamino- ^ ß-azetidinyl) disulfide can also be obtained as follows:

A solution of O _# 317 g of 3 _/ 3-dimethyl-4-thia-2 _/ 6-diaza-

bicyclo [3.2.0] heptan-7-one in 3.0 ml of methylene chloride v; ird with 0.254 g of iodine in 12.0 ml of benzene are added; this immediately creates a voluminous brown precipitate! The mixture is during Shaken from time to time for 10 minutes at room temperature, then filtered and the filter residue washed with benzene and pentane and suspended in 8.0 ml of acetonitrile. The suspension 2.0 ml of pyridine are added to give a clear yellow solution which is cooled to + 10 ° and dropwise under Stir mixed with 0.4 ml of phenylacetic acid chloride. The reaction mixture will stand for 20 minutes at room temperature left then concentrated under reduced pressure to a weight of 1.9 g. The yellow syrupy residue will taken up in 50 ml of ethyl acetate and the solution with

209819/1159

Washed 50 ml of water, then evaporated. The residue will crystallized from a mixture of methanol, methylene chloride and hexane. The bis (cis - ^ - oxo-Oß-phenylacetylamino-Jiss-azetidinyl) disulphide After recrystallization from acetone and methylene chloride, it melts at 152-155 ° (analysis preparation: 156.5-158.5 °).

. Example 2:

A mixture of 0.10 g of bis (cis-2-oxo-3ß-phenylacetylaini no-4ß-azetidinyl) disulfide and 1.0 g of 1,2-propylene oxide in 5 ml Glacial acetic acid and 0.5 ml of water are mixed with 1.0 g of zinc dust at 0. The reaction mixture is at about 0 for 30 minutes and stirred for a further 30 minutes at room temperature, then filtered through a preparation of diatomaceous earth. It is washed with acetone and the filtrate is evaporated. The residue is in 100 ml of ethyl acetate added; the organic solution is mixed with 50 ml of water, 50 ml of a saturated aqueous sodium hydrogen carbonate solution and 50 ml of a saturated aqueous Sodium chloride solution washed; the aqueous washing solutions are back-extracted with 100 ml of ethyl acetate. the combined organic solutions are dried over sodium sulfate and evaporated; the residue is on 10 g of silica gel chromatographed. It is eluted with ethyl acetate,

209819/1159

Contains 5 % acetone and receives the chromatographically uniform 4ß- (2-hydroxypropylmercapto) -jjß-phenylacetylamino-azetidine-2-in the formula

SCH ₂ C ⁰

CH CH ^0H

Il
0 = - C NH ^J

which crystallizes on spraying with methylene chloride and melts in the form of colorless crystals at 102-106 °; Thin layer chromatogram (Silica gel): Rf ^ <- 0.44 (system: ethyl acetate / A cetone 1: 1; Developing with iodine).

Example 3 ^:

A mixture of 0.10 g of bis (cis-2-oxo-3ß-phenylacetylamino-4ß-azetidinyl) disulfide and 1.0 g of 1,2-butylene oxide in 1.0 g of zinc dust is added to 5 ml of glacial acetic acid and 0.5 ml of water. The reaction mixture is for 30 minutes at about

0 and stirred for a further J> 0 minutes at room temperature, then filtered through a diatomaceous earth preparation. Man

209819 / 11B9

washes with acetone and evaporates the piltrate. Of the. The residue is taken up in 100 ml of ethyl acetate; the organic solution is washed with 50 ml of water of a saturated aqueous sodium hydrogen carbonate solution and 50 ml of a saturated aqueous sodium chloride solution; the aqueous washing solutions are back-extracted with 100 ml of ethyl acetate. The combined organic solutions are dried over sodium sulfate and evaporated; the residue is chromatographed on 10 g of silica gel. It is eluted with ethyl acetate and ethyl acetate containing 5 % acetone and the chromatographically uniform 4 [beta] (2-hydroxybutylmercapto) -3 [beta] -phenylacetylamino-azetidin-2-one of the formula is obtained

OH

which is crystallized from a mixture of methylene chloride and hexane and melts ^{at IO8-II7 0;} Thin-layer chromatogram (silica gel): Rf ~ 0.49 (system: ethyl acetate / acetone 1: 1; develop with iodine). According to the NMR spectrum, the substance consists of a mixture (approx. 1: 1) of the two diastereoisomeric compounds, which are in the configuration at the carbon atom substituted by the hydroxyl group and ^tCi '"209819/1159

Example 4:

A solution of 0.61 g of 4ß- (2-Hydroxyäthylmercapto) -3 / 3-phenylacetylamino-azetidin-2-one in 10 ml of tetrahydrofuran is added dropwise at 0 ° with 1.38 g of 2,2,2-trichloroethyl chloroformate in 5 ml of tetrahydrofuran, then 1.06 g of pyridine in 5 ml of tetrahydrofuran. The reaction mixture is stirred under a nitrogen atmosphere for 15 minutes at 0 ° and for 2 hours at room temperature, then taken up in 150 ml of methylene chloride. It is washed with a saturated aqueous sodium chloride solution, dried and evaporated. The residue is chromatographed on 50 times the amount of silica gel; the 3ß-phenylacetylamino- ⁱ l-ß- [2- (2,2,2-trichlorethoxycarbonyloxy) -äthylmercapto] -azetidin-2-one of the formula '' is eluted:

with a 1: 1 mixture of methylene chloride and ethyl acetate. After crystallization and recrystallization once from diethyl ether, the product is obtained in the form of colorless needles, mp 99-101; Thin-layer chromatogram (silica gel): Rf- ^ O.46 (system: ethyl acetate; development with iodine); IaJ = + 3 ° ± 2 ° (c = 0.518 in chloroform); Infrared absorber

209819/1159

tion spectrum (in methylene chloride): characteristic bands at 2.88μ, 5.58μ, 5 _# 64μ, 5.92μ and 6.62μ.

Example 5;

A solution of 5.63 g of bis [cis -3j3- (N-tert-butyloxycarbonyl-D-a-phenylglycyl) amino-2-oxo-43-azetidinyl] disulfide about 60 g of ethylene oxide and 56 g of zinc dust are added to 190 ml of a 9: 1 mixture of acetic acid and water, and stirred vigorously for one hour at room temperature. It is filtered and the piltrate is concentrated, takes in Ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dry over sodium sulfate and evaporate. The residue is chromatographed on 150 g of silica gel; one elutes with ethyl acetate and thus obtains the 3i3- (N-tert-butyloxycarbonyl-D ~ a-phenylglycyl) -aiftino-4 £ - (2-hydroxyethylthio) -azetidin-2-one, the formula

(CH,), C-O-C-NH

^^ Il O = C-0

209819/1159

which, after crystallization from a mixture of acetone and diethyl ether, melts at 130-131 °; Ia] ^ ⁰ = -64 ° ± 2 ° (c = 0.622 in ethanol): thin-layer chromatogram (silica gel; development with iodine vapor): Rf ^ - 0.47 (system: ethyl acetate / acetone 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90μ, 3.00μ, 3.25μ, 3.34μ, 5.61μ, 5.83μ, 5.91μ, 6.68μ, 7.29μ, 8.58μ and 9.02μ.

Example 6:

A solution of 4.80 g, cooled to 0, is added

3a- (N-tert-butyloxycarbonyl-Da-phenylglycyl) -amino-4 / J- (2-hydroxyethylthio) azetidin-2-one and 7.74 g of 2,2,2-trichloroethyl chloroformate in 100 ml of tetrahydrofuran within 10 minutes with a solution of 5.9 g of pyridine in 50 ml of tetrahydrofuran, stirred for 15 minutes at 0 and for 30 minutes at room temperature and concentrated. It is taken up in 500 ml of methylene chloride, washed twice with 100 ml of a saturated aqueous sodium chloride solution and evaporated. The residue is chromatographed on 300 ml of silica gel, eluted with a 4: 1 mixture of methylene chloride and ethyl acetate, the non-crystalline 3/3 (N-tert-butyloxycarbonyl-da-phenylglycyl) "? Jmino- 40-i 2- (2 _g 2, 2-trichler-;. Lho ;; ycarbonyloxy) -äthylthio] - r.zccidin-k or. Eier Fcrr; .3l

209819/1159

O O

CH-CJ-HN S-CH-CH-O-C-O-CH ^ CCl

^ 2 2 3

CH CH ·.

(H ^ C) ^ C-O-C-NH I I

Il 0 = 0 M

Thin-layer chromatography (silica gel; development with iodine vapor): Rf λ; 0.55 (system: ethyl acetate) and Rf / ν / 0.19 (system: Toluene / ethyl acetate 1: 1): Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00μ, 3.35μ, 3.42μ, 5.61μ, 5.66μ, 5.85μ, 5.92μ, 6.75μ, 7.06μ, 8.14μ and 8.61μ.

The starting material can be obtained as follows:

A solution of 10.0 g of 3-isopropyl-4-thia-2,6-diaza ~ bicyclo [3.2.0] heptan-7-one in 200 ml of a 1: 1 mixture of Acetic acid and water are added dropwise within 15 minutes with 436 ml of a 0.2 molar solution of iodine in ethanol added and, after standing for one hour at room temperature, evaporated under reduced pressure. The residue containing the bis (cis-33-amino-2-oxo-4i3-azetidinyl) disulfide, ■ is dried under high vacuum and processed further without cleaning.

209819/1159

The crude product obtainable by the above process is in 200 ml of a 1: 1 mixture of tetrahydrofuran and Dissolved water, mixed with 8.4 ml of triethylamine and slowly to a mixture of N-tert-butyloxycarbonyl-D-a-phenylglycine cooled to -10, 8.95 ml of triethylamine and 8.40 g of isobutyl chloroformate were added dropwise to 170 ml of tetrahydrofuran. To one hour at 0 and a further hour at room temperature, the reaction mixture is concentrated to half and in 800 ml of ethyl acetate were added. It is washed twice with 200 ml of a saturated aqueous sodium hydrogen carbonate solution each time and twice with 200 each of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporates. The residue is chromatographed on 500 g of silica gel. The bis- [cis-3β- (N-tert-butyloxycarbonyl-D-α-phenylglycyl) -amino-2-oxo-4β-azetidinyl] -disulfide is eluted with ethyl acetate. The amorphous product melts at ■

163-166 ° with decomposition; [a] J ° = + 145 ° + 1 ° (c = 0.930 in ChIo-

D -

roform); Thin-layer chromatogram (silica gel; development with iodine vapor): Rf ^ 0.33 (system: ethyl acetate); Ultraviolet absorption spectrum (in Aethahol): Λ = 257 ταμ

Small

(£ = 2200); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.9μ, 2.98μ, 3.34μ, 5.63μ, 5.9μ, 6.68μ, 7.29μ, 8.11μ, 8.58μ and 9.53μ.

209819/1159

Example 7:

A mixture of 0.71 g of 4 £ - (2-hydroxypropylthio) -3ß-phenyl-acetylamino-azetidin-2-one in 25 ml of tetrahydrofuran is mixed at 0 with 0.72 ml of 2,2 _/ 2-trichloroethyl chloroformate and 0 , 83 ml of pyridine in 15 ml of tetrahydrofuran were added. The mixture is stirred for 30 minutes at 0 and for 45 minutes at room temperature, concentrated under reduced pressure to about a quarter of the volume, diluted with methylene chloride and washed with a saturated aqueous sodium chloride solution. The organic solution is dried over magnesium sulphate and evaporated under reduced pressure. The crude product is chromatographed on 90 g of silica gel, the 3/3-Phenylacetylamino ~ 4 £ - [2- (2,2,2-trichloräthoxycarbonyloxy) propylthio] -azetidin-2-one with methylene chloride and methylene chloride, containing 10% up to 20% ethyl acetate eluted, thin-layer chromatogram (silica gel): Rf = 0.53 (system: ethyl acetate); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3, Ο3μ, 3.46μ, 5.62μ, 5.67μ, 5.81μ, 5.92μ and 6.7Ομ.

209819/1159

Example 8:

A mixture of 1 g of bis [cis-3/3-phenylacetylamino-2-oxo-4) 3-azetidinyl] disulfide in 50 ml of acetic acid and 5 ml of water is treated with 1.1 g of 3-fluoro-1,2 ~ propylene oxide and 10 g zinc dust added. The mixture is stirred for 1 hour at room temperature, filtered, the filtrate is concentrated and the residue is taken up in ethyl acetate; The organic solution is washed with an aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried and evaporated. The crude product is chromatographed on 40 g of silica gel and the 4B- (3-fluoro-2-hydroxypropylthio) ~ 3ß-phenylacetylamino-azetidin-2-one is eluted with ethyl acetate, thin-layer chromatogram (silica gel): Rf = 0.31 (system: Ethyl acetate); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.02μ, 3.43μ, 5.63μ, 5.9μ (broad), 6.7μ and 7.16μ.

Example 9:

A mixture of 0.330 g 4ß- (3-fluoro-2-hydroxy-propylthio) -3 £ -phenylacetylamino-azetidin-2-one in 20 ml tetrahydrofuran at 0 ° with 0.495 g of chloroformic acid 2,2, 2- trichloräthylcster and then dropwise with a solution

of 0.370 g of pyridine dissolved in 10 ml of tetrahydrofuran;. '/ :. M ^r , m

2 0 9819 / 11S9 "D

stirs for 30 minutes at 0 and for 45 minutes Room temperature, filtered through a preparation of diatomaceous earth and evaporate the filtrate to dryness under reduced pressure. The residue is dissolved in 300 ml of ethyl acetate absorbed, the organic solution with aqueous sodium ' bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The crude product is chromatographed on 30 g of silica gel and the 4β- [3-fluoro-2- (2,2,2-trichlorethoxycarbonyloxy) propylthio] -3β-phenylacetylamino-azetidin-2-one eluted with a 1: 1 mixture of methylene chloride and ethyl acetate, thin-layer chromatography (silica gel): Rf = 0.52 (System: ethyl acetate); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3, Ο2μ, 3.45μ, 5.60μ, 5.78μ, 5.92μ, 6.74μ and 7.08μ.

The compounds of the present invention can be further processed, for example, as follows:

A: A mixture of 1.0 g of 3ß-phenylacetylamino-4ß- [2- (2,2,2-trichlorethoxycarbonyloxy) ethyl mercapto] azetidin-2-one and 3.0 g of glyoxylic acid tert-butyl ester hydrate in 50 ml Benzene is refluxed for 16 hours with separation of water, then cooled and twice with each 25 ml of distilled water, dried over sodium sulfate

209819/1159

dries and evaporated. The a-hydroxy-a-2-οχο-3i5-phenylacetylamino- '* ß- [2- (2,2,2-trichloroethoxycarbonyloxy) -ethy! Mercapto] -l-azetidinyl ^ -acetic acid-tert. butyl ester, which is further processed without cleaning *

The crude α-hydroxy-α- {2-0x0-3 / 3-phenylacetylamino-4β - [2- (2,2,2-trichlorethoxycarbonyloxy) -ethylmercapto] -1-azetidinyIj-acetic acid tert.- obtainable by the above process butyl ester is dissolved in 20 ml of a 1: 1 mixture of dioxane and tetrahydrofuran and at -10 ° dropwise with 0.54 ml of pyridine in 2 ml of dioxane and O ₇ 48 ml of thionyl chloride in 10 ml of a 1: 1 mixture of dioxane and Tetrahydrofuran added. The reaction mixture is stirred for 30 minutes at -10 ° to -5 ° and for one hour under a nitrogen atmosphere, the precipitate is filtered off and the FiItrat with the a-chloro-a-j2-oxo-3.beta.-phenylacetylarnino- ^J 4ß- [2 - (2,2,2-trichloroethoxycarbonyloxy) -äthylmercapto] -l-azetidinyl | -tert.-butyl acetate evaporated; the product is processed in its raw state.

A solution of that obtainable by the above procedure crude α-chloro-α- £ 2-0x0-3 / 3-phenylacetylamino-4β- [2- (2,2,2-trichloroethoxycarbonyloxy) ethyl mercapto] -1-azetidinyl £ -acetic acid acid tert-butyl ester in 30 ml of a 1: 1 mixture of dioxane and tetrahydrofuran is with 1.15 g tripheny! phosphine and 0.35

209819/1159

ml of pyridine are added and the mixture is heated at 50 for 2 hours, then evaporated to dryness. The residue is chromatographed on 30 g of pure silica gel, using a 1: 1 mixture of toluene and ethyl acetate to ^{obtain the a-f2-oxo-30-phenylacetylaraino- i} fß- [2- (2,2,2-trichloroethoxycarbonyloxy) - ethyl mercapto] -l-azetidinyl {-a-tripheny! phosphoranylideneacetic acid tert-butyl ester eluted, which with a little triphenylphosphine-. oxide is contaminated and by means of preparative thin-layer chromium

inatography (silica gel; development with iodine) can, R f ^ 0.57 (system: toluene / acetone 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00μ, 3.42μ, 5.68μ, 5.97μ, 6 <1Ομ and 6.65μ.

A mixture of 0.225 g of a- £ 2-Oxo-3/3-p} -! Enylacetylamino-40-ί 2- (2,2,2-trichlorethoxycarbonyloxy) -atjiylmercaptoj-

tert-butyl l-azetidinylj-a-triphenylphosphoranylidene-acetic acid in 10 ml of a 9: 1 mixture of acetic acid and water * is mixed with 3.0 g of zinc dust and for 45 minutes at 15 stirred. It is filtered and the piltrate is evaporated; the residue is taken up in 50 ml of ethyl acetate and the solution with 25 ml of a saturated aqueous sodium hydrogen carbonate solution and washed twice with 25 ml each time of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The α- [40- (2-hydroxy-

209819/1159

ethyl mercapto) -2-OXO-3 / 3- phenylacetylamino-l-azetidinylj-α-triphenylphosphoranylidene-acetic acid tert-butyl esterj Thin layer chromatogram (Silica gel; development with iodine): Rf ^ 0.24 (System: toluene / acetone 1: 1). .

A mixture of 0/221 g of the crude d- [4β ~ (2-Hydroxyä thy lmercapto) - 2-oxo- 3/3-phenylamino -1 -azetidinyl 3 a-triphenylphosphoranylidene-acetic acid tert-butyl ester ' in 5 ml of dimethyl sulfoxide and 5 ml of acetic anhydride are left to stand for 16 hours at room temperature and then concentrated under reduced pressure. The residue is taken up in 100 ml of toluene; the organic solution is washed three times with 50 ml of distilled water each time, dried over sodium sulfate and evaporated. The oily residue is chromatographed on 10 g of silica gel; the desired 7ß-pkenylacetylamino-ceph - ^ - em - ^ - carbo-nsaure-tert. -butyl ester, which is formed by ring closure from the non-isolated a - ('4p-? ormylmethylmercapto-2-oxo-3ß-phenylacetylamino-1-azetidinyl) -a-triphenylphosphoranylidene-acetic acid tert-butyl ester is formed by ring closure : 1 mixture of toluene and ethyl acetate eluted; Thin-layer chromatogram (silica gel): Rf ^ 0.48 (system: toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in pure etha- 'ηοΐ): λ _χ 258 mji; Infrared absorption spectrum (in methylene): characteristic bands at 3.00μ, 3.48μ, 5.62μ,

2 0 9 8 19/1158

Butyloxycarbonyl-D-a-phenylglycyl) -amino-4ß- [2- (2,2,2-tri- chloroethoxycarbonyloxy) ethylthio] -2-oxo-1-azetidinylj-α-triphenylphosphoranylidene-acetic acid tert-butyl ester eluted with a 1: 1 mixture of toluene and ethyl acetate; Thin-layer chromatogram (silica gel; development with iodine vapor): Rf ~ 0.25 (system: toluene / ethyl acetate 1: 1); Infrared absorption spectrum X in methylene chloride): characteristic bands at 3.00μ, 3.44μ, 5.67μ, 5.86μ, 5.92μ, 6.14μ and 6.76μ.

A solution of 1.74 g of α- ^ 3 £ - (N-tert-butyloxycarbonyl-Da-phenylglycyl) -amino-40- [2- (2 _f 2,2-trichlorethoxycarbonyloxy) ethylthioJ-2-oxo-1- azetidinyIr-a-triphenylphosphoranylidene-acetic acid tert-butyl ester in 65 ml of a 9: 1 mixture of acetic acid and water is mixed with 12 g of zinc dust and stirred for one hour at room temperature. It is filtered through a diatomaceous earth preparation, the filtrate is evaporated and the residue is taken up in 500 ml of ethyl acetate. It is washed twice with 100 ml of a saturated aqueous sodium hydrogen carbonate solution and with 100 ml of a saturated aqueous sodium chloride solution, the organic phase is dried over sodium sulfate and evaporated. This gives the α- [3α- (N-tert-butyloxycarbonyl-Da-phenylglycyl) -amino-4α- (2-hydroxyethylthio) -2-oxo-1-azetidinyl ] -a- (triphenylphosphoranylidene) -acetic acid-tert .-buty! ester, thin-layer chroma-

2098 19/1159

togram (silica gel; developing with iodine vapor): Rf ^ 0.29 (System: toluene / acetone 3: 2); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00μ, 3.42μ, 5.68μ, 5.86μ, 5.93μ, 6.16μ, 6.75μ and 8.75μ.

A mixture of 1.53 g of crude α- [3α- (N-tert-butyloxycarbonyl-Da-phenylglycyl) -amino-4a- (2-hydroxyethylthio) -2-oxo-l-azetidinyl] -α- (triphenylphosphoranylidene) -acetic acid tert-butyl ester in 60 ml of a l: l mixture of prostitute thy lsu If oxy d and acetic anhydride is left to stand for 16 hours at room temperature under a nitrogen atmosphere, then held at 50 for a further 2 hours. It is concentrated, taken up in 50O ml of toluene and washed three times with 100 ml of water each time. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on 120 g of silica gel and the 7β- (N-tert-butyloxycarbonyl-D-a-phenylglycylJ-amino-ceph-S-em- ^ carboxylic acid tert-butyl ester eluted with a B: 2 mixture of toluene and ethyl acetate. The product crystallizes from a mixture of Diethyl ether and pentane, mp 159-161 °; lo] ^ ° = + 29 ° +. 2 ° (c = 0.521 in chloroform); Thin layer chromatography (silica gel; Development with iodine vapor): Rf ^^ - 0.67 (system: toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in ethanol): λ = 255 ΐημ (£ = 5400); Infrared absorption spectrum (in methylene chloride): characteristic

2098 19/1159

6,10μ, 6, βγμ, 7Λ5μ> 7 ', H ^ ₃ 7 * 70μ, 8,65μ and

A mixture of 0.03 g of 7β-phenylacetylamino-ceph-3-em-4-carboxylic acid tert-butyl ester and 0.5 ml of trifluoroacetic acid is left to stand for one hour at room temperature. The trifluoroacetic acid is then removed under reduced pressure and the residue is taken to dryness twice with 5 ml each of a mixture of benzene and chloroform. The residue is chromatographed on silica gel 5 S and the 7.beta.-phenylacetylamino-ceph-3-em ~ 4-carboxylic acid with methylene chloride containing 5 o acetone, e3.uiert.?; Thin layer chroma to gram (silica gel: development with iodine): Rf ~ 0.49 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30). .

B:. A mixture of 13.5 g of glyoxy acid tert-butyl ester hydrate in 160 ml of toluene is dehydrated by distilling off about 80 ml of toluene, and 5.29 g of 3β- (N-tert-butyloxycarbonyl-da ~ phenylglycyl) - amino-4 ^ - [2- (2,2,2-trichlorathoxycarbonyloxy) ethylthio] azetidin-2-one and the reaction mixture is heated at 90 for 16 hours under a nitrogen atmosphere. After cooling, it is diluted with toluene to a volume of 150 ml, washed five times with 100 ml of water each time, dried over sodium sulfate and evaporated.

209819/1 159

The residue contains the a- $ 30- (N-tert-butyloxycarbonyl-D-a-phenylglycyl) ~ amino-4 £ - [ 2- (2, 2,2-trichlorethoxycarbony1-oxy) -ethylthio-2-oxo-1-azetidinylt -a-hydroxy-acetic acid tert-butyl ester and is processed further without cleaning.

The oily product is dissolved in 100 ml of a 1: 1 mixture of tetrahydrofuran and dioxane and added at about -5 ° with 2.24 ml of pyridine and within 10 minutes with 2.00 ml of thionyl chloride in a 1: 1 mixture of tetrahydrofuran and dioxane. After standing at -5 for 30 minutes, that becomes Cooling bath removed; the mixture is stirred for a further hour at room temperature, filtered through a Diatoxneenerdepraparat and evaporates. The residue contains the α-chloro-α- (3β- (N-tert-butyloxycarbonyl-D-a-phenylglycyl) amino-4 £ - [2- (2,2,2-trichloro thoxycarbony loxy) -äthylthiöJ-2-oxo-1-azetinylj -acetic acid tert-butyl ester and is processed further without cleaning.

The above crude product is dissolved in 100 ml of a 1: 1 mixture of tetrahydrofuran and dioxane, and 4.86 g are added Triphenylphosphine and 0.7 5 ml of pyridine and heated under a nitrogen atmosphere for 10 hours at 50 °. The dark red one The solution is concentrated, the residue is taken up in methylene chloride and the mixture is washed twice with 100 ml of water washed, then evaporated. The residue is chromatographed on 200 g of silica gel, the a- [3 / 3- (N-tert.-

209819/1159

The one after the above process as a crude product

available a-chloro-ap-oxo-Sfl-phenylacetylamino-

4ß-I 2- (2,2,2-trichlorethoxycarbonyloxy) propylthio] -1-azetidinylj-acetic acid tert-butyl ester in 25 ml of a 1: 1 mixture of tetrahydrofuran and dioxane is mixed with 0.812 g of triphenylphosphine and 0.12 ml of pyridine were added and kept at 50 for 10 hours. It is diluted with 300 ml of methylene chloride, the organic solution is washed twice with ml of water each time, dried over sodium sulfate and evaporated. The crude product is chromatographed on 70 g of silica gel; with a 1: 1 mixture of toluene and ethyl acetate is the. o - ^ _ 2-Oxo-3ß-phenylacetylamino-4ß- [2- (2,2,2-trichlorethoxycarbonyloxyl) propylthio] -1-azetidinyll-a-triphenylphosphoranylidene-acetic acid tert-butyl ester eluted, thin-layer chromatography (silica gel): Rf = 0.22 (system: toluene / ethyl acetate 1: 1); Infrared absorption spectrum in methylene chloride): characteristic bands at 3, Ο2μ, 3.45μ, 5.67μ, 5.85μ, 5.91μ, 6.15μ and 6.75μ.

A mixture of 0.562 g of a- [2-oxo-3 -phenylacetylamino-£ 43-1 2- (2,2, 2-trichloräthoxycarbonyloxy) propylthio -1 J ~ ^ -a-azetidinyl triphenylphosphoranylidan-acetic acid tert-butyl ester 4 g of zinc dust are added to 20 ml of a 9: 1 mixture of acetic acid and water and the mixture is stirred at room temperature for 1 hour. The zinc is filtered off, washed with acetone and evaporated under reduced pressure

209819/1159

dry up. The residue is dissolved in 300 ml of ethyl acetate added, the organic solution twice with 50 ml of an aqueous sodium hydrogen carbonate solution and washed once with 50 ml of a saturated aqueous sodium chloride solution, dried and evaporated. You get so the a-I40- (2-hydroxypropylthio) -2-oxo-3ß-phenylacetylamino-l-azetidinylj-a-triphenylphosphoranylidene-acetic acid tert-butyl ester, Thin-layer chromatogram (silica gel): Rf = 0.38 (system: toluene / acetone 1: ^ L); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3, Ο3μ, 3.44μ, 5.67μ, 5.86μ, 5.93μ, 6.17μ and 6.75μ.

D: A mixture of 0.203 g of 4β- [3-fluoro-2- (2,2,2-trichloroethoxycarbonyloxy) propylthio] -3 / 3-phenylacetylanino-azetidin-2-one 0.730 g of anhydrous tert-butyl glyoxylate is added in 20 ml of toluene and during Heated for 15 hours in a nitrogen atmosphere at 90 °, then diluted with 150 ml of toluene. You wash five times 30 ml each Viasser, dried over magnesium sulfate and steamed

a. The crude α- [4β- [3-fluoro-2- (2,2,2-trichlorethoxycarbonyloxy) propylthio] -2-oxo-3β-phenyl-acetylamino-1-azetidinylj-α-hydroxy-acetic acid tert-butyl ester is processed further without cleaning.

209819/1159

see bands at 2.68μ, 2.89μ, 3.33μ, 5.57μ, 5.79μ, 5.88μ, 6.08μ, 6.22μ, 6.7Ομ, 7.15μ, 7.28μ, 7.68μ _/ 8.04μ, 8.64μ, 9.05μ, 9.52 μ..υηα 9.79μ.

■ A mixture of 0.6367 g of 7β- (N-tert-butyloxycarbonyl-Da-phenylglycyl) -amino-ceph-3-em-4-carboxylic acid tert-butyl ester in 30 ml of trifluoroacetic acid is left to stand for 15 minutes at room temperature , then treated with 100 ml of toluene and evaporated. The residue is taken up again in 100 ml of a 3: 1 mixture of toluene and methanol, evaporated under reduced pressure and dried under high vacuum. The white powdery residue is dissolved in 5 ml of methanol and treated with 13 ml of a 1% solution of triethylamine in diethyl ether, a voluminous new precipitate being formed. The solvent is evaporated off under reduced pressure, the residue is slurried in methylene chloride and suction filtered. It is washed with about 150 ml of methylene chloride and dried under high vacuum. 7/3 (Da-phenylglycyl) -aminoceph-3-em-4-carboxylic acid is thus obtained in the zwitterionic form as a pale yellowish, amorphous powder, thin-layer chromatogram (silica gel; development with iodine vapor): Rf ^ O, 29 ( System: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in water): Λ. = 250 ΐημ ( t = 4300).

209819/1 159

C: A mixture of 0.706 g of 3ß-phenylacetylamino-4 / 3- [2- (2,2,2-trichloroethoxy-carbonyloxy) -propylthio] -azetidin-2-one and 2.7 g of anhydrous tert-butyl glyoxylate in 50 ml Toluene is heated under nitrogen at 90 ° for 16 hours and then diluted with toluene to a volume of 300 ml. It is washed five times with 50 ml of water each time, dried over sodium sulfate and evaporated under reduced pressure. Of the crude cc- (2 ~ Oxo-3 £ -phenylacetylamino-40 - [2- (2, 2,2-trichloroethoxycarbonyloxy) -propylthio] -l-azetidinylj-cc-hydroxy-acetic acid-tert.-butyl ester is processed further without cleaning.

A solution of 1.73 of the crude cc- (2-0xo-3/3-phenylacetylamino-4 £ - [2- (2,2,2-trichloroethoxy-carbonyloxy) -propylthio] -1-azetidinylJ -a-hydroxy- tert-butyl acetate in 25 ml of a 1: 1 mixture of tetrahydrofuran and dioxane is added at -5 ° and in a nitrogen atmosphere with 0.37 ml of pyridine and 0.33 ml of thionyl chloride in 10 ml of tetrahydrofuran and added for 30 minutes -5 and stirred for 1 hour at room temperature. The pyridine hydrochloride is filtered off and the filter residue is washed with diethyl ether. The filtrate is taken to dryness under reduced pressure and dried under high vacuum. The a- chloro-a- {2 ~ oxo-30 -phenylacetylamino-4/3 ~ [2- (2,2,2-trichloroethoxy-carbonyloxy) -propylthioJ-l-azetidinylj-acetic acid tert-butyl ester is obtained as a dark oil and processed further without purification.

209819/1159

A mixture of 0.36 g of a- [4 £ - [3-fluoro-2- (2,2,2 ~ trichloroethoxycarbonyloxy) propylthio] ~ 2-oxo-3j3-pheny 1-acetylamino-1-azetidinyl ^ -a-hydroxy-acetic acid tert-butyl ester in 10 ml of a l: l mixture of tetrahydrofuran and dioxane is at -5 ° with 0.08 ml of pyridine and 0.07 ml Thionyl chloride added and for 30 minutes at -5 and for 1 hour at room temperature under one Stirred in a nitrogen atmosphere. It is filtered from pyridine hydrochloride off, the filtrate is evaporated to dryness under reduced pressure and the residue is dried under High vacuum. The crude a-chloro-a- ^ 4 / 3- [3-fluoro-2- (2, 2,2-trichlorethoxycarbonyloxy) propionylthio] ~ 2-oxo-3ß-phenylacetylamino-l-azetidinylj-acetic acid-tert.- butyl ester is processed further without cleaning.

The crude <z-chloro-a {4jB- [3-fluoro-2- (2 ', 2,2-trichlorethoxycarbony loxy) propylthio] -2-oxo-3/3-phenylacetylamino-1- obtainable by the above process azetidinyl] tert-butyl acetate is taken up in 15 ml of a mixture of tetrahydrofuran and dioxane, 0.170 g of triphenylphosphine and 0.03 ml of pyridine are added and the mixture is warmed to 50 for 10 hours. It is concentrated, diluted with methylene chloride and washed twice with 50 ml of water each time. The organic phase is dried over magnesium sulfate and evaporated and the residue is chromatographed on 15 g of silica gel. With a 1: 1 mixture of toluene and acetic acid

209819/1159

ethyl ester is the a- {4 £ - [3 ~ fluoro-2- (2,2,2-trichlorethoxycarbonyloxy) propylthio] ^ - oxo-S / S-phenylacetylamino-1-azetidinylj-a-triphenylphosphoranylidene-acetic acid-tert. -butyl ester eluted, thin-layer chromatogram (silica gel): Rf = 0.25 (system: toluene / ethyl acetate 1: 1).

A mixture of 0.105 g of ct- {4j3- [3-Flupr-2- (2,2,2-trichloroethoxycarbonyloxy) -propylthioJ ^ -oxo-S-3-phenylacetylamino-1-azetidinylj-α-tripheny! Phosphoranylidene-acetic acid-tert-butyl ester in 10 ml of a 9:! mixture of acetic acid and water is treated with 1 g of zinc dust, kept at room temperature for 45 minutes and filtered through a diatomaceous earth preparation. It is washed with acetone, the filtrate is evaporated and taken up in ethyl acetate. The organic solution is washed with an aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried and evaporated. The residue is purified by means of preparative thin-layer chromatography (silica gel; system: toluene / acetone 1: 1). The band with Rf - 0.5, which is identified under the ultraviolet light, is scratched out and extracted with a 9: 1 mixture of acetone and methanol. It is filtered, evaporated and so the a- [4 / 3- (3-fluoro-2 ~ hydroxy-propylthio) -2-oxo-30-pheny lacety lamino-1-aze tidiny 1J -cc-tr iphenylphos-

209819/1159

Phoranlyiden-acetic acid-tert-butyl ester, which in the ultraviolet absorption spectrum (in methylene chloride) shows the following characteristic bands: 3.00p, 3.44μ, 5.67μ, 5.85μ (wide), 6.21μ, 6.71μ and 7.3Ομ.

209819/1159

Claims (56)

Claims Process for the preparation of 3-amino-4- (2-hydroxy-sthylthio) -2-oxo-azetidine compounds the formula ^R i \ I ³ I ⁴ NS-CH-CH-0-R _R b / \ / 1 CH CH Il O = C NH wherein Rf is hydrogen or an amino protecting group R, R ^ represents hydrogen or an acyl group Ac ^, or R ^ and R, together mean a divalent amino protecting group, R2 for Is hydrogen or an acyl radical AC2, and each of the radicals Ro and R, for hydrogen or one, via a carbon atom bonded organic radical, or salts of such compounds with salt-forming groups, characterized in that that one has a bis-Ccis-3-N-R, -N-R, -amino-2-oxo-4-azetidinyl) disulfide compound the formula N S S N "1 CH CH CH CH R II II O = C NH HN C = O with an oxirane compound of the formula 209819/1159 ¹ tue) R HC— ^: CH R (III) reacts with simultaneous treatment with a reducing agent, and, if desired, in a compound obtained, of formula I, in which R ^ is hydrogen, the hydroxyl group is converted into an acyloxy group, and / or, if desired, the group R- and / or the group in an available compound radical R- representing an acyl group Ac. or one by R., and R, splits off the divalent amino protective group formed and optionally the free one in a compound obtainable in this way Amino group protects, and / or, if desired, a salt obtained into the free compound or into another salt and / or a free compound converted into a salt, and / or, if desired, a mixture of isomers obtained into the separates individual isomers. 2. The method according to claim 1 for the preparation of compounds of the formula I according to claim 1, wherein R ?, R ₂ , Ro and R / have the meanings given in claim 1 and R-, hydrogen, or salts of such compounds with salt-forming groups , characterized in that a bis (cis-3-NR ^ -NR ^ -amino-2-oxo-4-azetidinyl) disulfide compound of the formula II, in which R has the meaning given in claim 1 and R-, Represents hydrogen, with a 209819/1159 Oxirane compound of the formula III reacts with simultaneous treatment with a reducing agent, and, if desired, in a compound of the formula I obtained in which R _{2 is} hydrogen, converts the hydroxyl group into an acyloxy group, and / or, if desired, in an available compound splits off the group R- and optionally protects the free amino group in a compound obtainable in this way, and / or, if desired, converts a salt obtained into the free compound or into another salt and / or a free compound into a salt, and / or, if desired, separating a mixture of isomers obtained into the individual isomers. 3. The method according to claim 1, characterized in that the reducing agent used is chemical reducing agents used. 4. The method according to claim 2, characterized in that the reducing agent used is chemical reducing agents used. 5. The method according to claim 3, characterized in that reducing metals or metal compounds, such as Metal alloys, amalgams or salts used as reducing agents. 6. The method according to claim 4, characterized in that 209819/1159 that reducing metals or metal compounds, such as metal alloys, amalgams or salts, are used as reducing agents used. 7. The method according to claim 5, characterized in that zinc, zinc alloys or zinc amalgam or magnesium, preferably in the presence of hydrogen donors Agents, such as acids, acidic agents or alcohols, preferably used with the addition of water as a reducing agent. 8. The method according to claim 6, characterized in that zinc, zinc alloys or zinc amalgam or magnesium, preferably in the presence of hydrogen donating agents such as acids, acidic agents or alcohols, preferably used as a reducing agent with the addition of water. 9. The method according to claim 7, characterized in that that zinc in the presence of a lower alkyl carboxylic acid, especially acetic acid, or an alcohol, such as lower alkanol, preferably used with the addition of water as a reducing agent. 10. The method according to claim 8, characterized in that zinc in the presence of a lower alkyl carboxylic acid, in particular Acetic acid, or an alcohol such as lower alkanol, is used as a reducing agent, preferably with the addition of water . 209819/1159 11. The method according to claim 5, characterized in that one alkali metal amalgams or aluminum amalgam, preferably used as a reducing agent in the presence of moist solvents. 12. The method according to claim 6, characterized in that one alkali metal amalgams or aluminum amalgam, preferably used as a reducing agent in the presence of moist solvents. 13. The method according to claim 5, characterized in that chromium-II compounds, e.g. chromium-II-chloride or Chromium-II-acetate, preferably used in the presence of aqueous media as a reducing agent. 14. The method according to claim 6, characterized in that Chromium-II compounds, e.g. chromium-II-chloride or chromium-II-acetate, preferably in the presence of aqueous media used as a reducing agent. 15. The method according to any one of claims 1, 3, 5, 7, 9, 11 and 13, characterized in that in a process according to the invention obtainable compound of formula I, wherein R _{2 is} hydrogen, the free hydroxyl group by treatment with carboxylic acids or acylated reactive acid derivatives thereof. 16. The method according to any one of claims 2 209819/1159 12 and 14, characterized in that in a process according to obtainable compound of the formula I, wherein R ^ is hydrogen, the free hydroxyl group by treating acylated with carboxylic acids or reactive acid derivatives thereof. 17. The method according to any one of claims 1, 3, 5, 7, 9, 11, 13 and 15, characterized in that intermediate compounds are used as starting materials and the remaining process steps are carried out with them, or the process is terminated at any stage will. 18. The method according to any one of claims 2, 4, 6, 8, 10, 12, 14 and 16, characterized in that intermediate compounds are used as starting materials and the remaining process steps are carried out with them, or the process is terminated at any stage will. 19. The method according to any one of claims 1, 3, 5, 7, 9, 11, 13, 15 and 17, characterized in that starting materials used in the form of derivatives or formed during the reaction. 20. The method according to any one of claims 2, 4, 6, 8, 10, 209819/1 159 12, 14, 16 and 18, characterized in that starting materials are used in the form of derivatives or during the reaction are formed. 21. The method according to any one of claims 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20, characterized in that compounds of the formula I according to claim 1, wherein R, hydrogen or one, in one preferably pharmacologically active, naturally occurring or synthetically producible N-acyl derivative of the acyl radical containing 6-amino-penicillanic acid or 7-amino-cephalosporanic acid compounds or an easily cleavable acyl radical of a carbonic acid semi-derivative, R represents _{hydrogen, R 2 represents} hydrogen or an easily cleavable acyl radical of the formula -C (= 0) -X, where X-. represents an etherified hydroxyl group which, together with the carbonyl group, represents an esterified carboxyl group which can be cleaved under mild conditions, and each of the groups R 1 and R represents hydrogen or an optionally substituted lower alkyl, phenyl or phenyl-lower alkyl radical. 22. The method according to any one of claims 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20, characterized in that one compounds of formula I according to claim 1, wherein away
R,, Rj and R, which have the meanings given in claim 21 and R- is hydrogen. 209819/1159 23. The method according to any one of claims 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19, characterized in that one compounds of formula I according to claim 1, in which R- represents a naturally occurring or biosynthetically producible or one in highly effective N-acyl derivatives of 6-amino-penam-3-carboxylic acid or 7-amino-ceph-3-em-4-carboxylic acid compounds occurring acyl radical or an easily cleavable acyl radical of a carbonic acid half ester, R, Hydrogen means, R “is hydrogen or an easily cleavable one Represents acyl radical of a carbonic acid half ester, Ro is hydrogen and R, hydrogen, a lower alkyl group optionally substituted by halogen or a phenyl-lower alkyl group mean. 24. The method according to any one of claims 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20, characterized in that one compounds of the formula I according to claim 1, wherein R-. , R ,, Ky and R- have the meanings given in claim 23, and R, represents hydrogen or a lower alkyl group. 25. The method according to any one of claims 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19, characterized in that one compounds the formula 209819/1159 Rj-NH CH CH I I O = C NH wherein R-ί is hydrogen or an acyl group of the formula 0
Il
Αι— CH-C - (IC) I.
R. denotes in which Ar is phenyl, 3- or 4-hydroxyphenyl, 3-chloro4-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl or 2-thienyl, and R is hydrogen, or, preferably protected, Amino, carboxy or SuIfο, and R ^ for hydrogen or an easily replaceable by hydrogen
Represents acyl radical of a carbonic acid half ester. 26. The method according to any one of claims 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19, characterized in that compounds of the formula IB according to claim 25, wherein Rl and Ar are those given in claim 25 Have meanings
and R represents hydrogen, tert-butyloxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino, 2-iodoethoxycarbonylamino or diphenylmethoxycarbonyl
and R ^ hydrogen, 2,2,2-trichloroethoxycarbonyl, 2-chloro 209819/1159 ethoxycarbonyl, 2-bromoathoxycarbonyl, 2-iodoethoxycarbonyl, Means pheacyloxycarbonyl or tert-butyloxycarbonyl. 27. The method according to any one of claims 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19, characterized in that one compounds of the formula IB according to claim 25, wherein Ri and R «have the meanings given in claim 25, Ar Is phenyl, 2- or 4-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl or 2-thienyl, and R is hydrogen or optionally slotted amino, carboxy or suIfο means. 28. The method according to any one of claims 2, 4, 6, 8, 10, 12, 14, 18 and 20, characterized in that the 4ß- (2-Hydroxyäthylthio) -3ß-phenylacetylamino-azetidin-2-one manufactures. 29. The method according to any one of claims 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20, characterized in that the 3ß-Phenylacetylamino-4ß-12- (2,2,2-trichloroethoxycarbonyloxy) -ethylthiol-azetidin-2-one manufactures. 30. The method according to any one of claims 2, 4, 6, 8, 10, 12, 14, 18 and 20, characterized in that the 3ß- (N-tert -butyloxycarbonyl-Da-phenylglycyl) -amino-4ß- (2-hydroxyHthylthio) -azetidin-2-one produces. 209819/1159 31. The method according to any one of claims 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20, characterized in that the 3ß- (N-tert-Butyloxycarbonyl-D-a-phenylglycyl) -amino-40- [7- (2,2,2-trichloroethoxycarbonyloxy) -ethylthio] -azetidin-2-one manufactures. 32. The procedure described in Examples 1-4. 33. The procedure described in Examples 5 and 6. 34. The procedure described in Examples 7-9. 35. The compounds obtained by the process of claims 25 and 26. 36. The according to the method of claims 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 23, 27 and 34 available connections. 37. The compounds obtained by the process of claims 30 and 31. 38. The according to the method of claims 2, 4, 6, 8, 10, 12, 14, 16, 18, 20-22, 24, 28, 29 and 32 compounds available. 209819/1159 39. 3-Amino-4- (2-hydroxyethylthio) -2-oxo-azetidine compounds of the formula / S- P. I ⁴ N —CH
I. -CH- -CHOIR I.
-NH ^α 1 CH-
I. I.
o-c— wherein R, hydrogen or an amino protective group Ry represents R-. represents hydrogen or an acyl group Ac, or a b
R, and R, together represent a divalent amino protective group, R ^ represents hydrogen or an acyl radical Ac ~, and each of the radicals R- and R, represents hydrogen or an organic radical bonded via a carbon atom, or salts of such compounds with salt-forming groups. 40. Compounds of the formula I according to claim 39, wherein R,, R _? , Ro and R / have the meanings given in claim 39, and R, represents hydrogen, or salts of such compounds with salt-forming groups. 41. Compounds of formula I according to claim 39, wherein Rf is hydrogen or one, preferably pharmacologically effective, naturally occurring or synthetically producible N-acyl derivative of 6-amino-penicillanic acid 209819/1159 or acyl radical containing 7-amino-cephalosporanic acid compounds or an easily cleavable acyl radical of a carbonic acid half derivative, R represents hydrogen, I ^ represents hydrogen or an easily cleavable acyl radical of the formula -CC = O) -X ₁ , in which X represents an etherified hydroxyl group which, together with the carbonyl group, denotes an esterified carboxyl group which can be cleaved under mild conditions, and each of the groups R ~ and R denotes hydrogen or an optionally substituted lower alkyl, phenyl or phenyl-lower alkyl radical. 42. Compounds of the formula I according to claim 39, woa b rin R ,, R ,, R2 and R, the meanings given in claim 41 have and R- is hydrogen. 43. Compounds of the formula I according to claim 39, wherein Rf is a naturally occurring or biosynthetic or one in highly effective N-acyl derivatives of 6-amino-penam-3-carboxylic acid or 7-amino-ceph-3-em-4-carboxylic acid compounds occurring acyl radical or an easily cleavable acyl radical of a carbonic acid half ester, R, Represents hydrogen, R £ hydrogen or an easily cleavable one Represents acyl radical of a carbonic acid half ester, R ^ is hydrogen and R, hydrogen, optionally through Halogen-substituted lower alkyl group or a phenyl lower alkyl group. "- 209819/1159 44. Compounds of the formula I according to claim 39, wherein Rf, R,, Rp and R ~ the meanings given in claim 43 and R, represents hydrogen or a lower alkyl group. 45. Compounds of Formula RJ — HN S — CH ₂ —CH ——O — R ' CH CH (IB) O = C MH wherein R ₁ 'is hydrogen or an acyl group of the formula • Il
Ar— CH-C— (Ic) I.
R. means in which Ar is phenyl, 3- or 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl or 2-thienyl represents, and R fllr hydrogen or, preferably slotted, Amino, carboxy or sulfo, and R, for hydrogen or represents an acyl radical of a carbonic acid half-ester which can easily be replaced by hydrogen. 46. Compounds of the formula IB according to claim 45, where 209819/1159 rin R ^ and Ar have the meanings given in claim 45, and R for hydrogen, tert-butyloxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino, 2-iodoethoxycarbonylaraino or diphenylmethoxycarbonyl, and R ~ hydrogen, 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, Means phenacyloxycarbonyl or tert-butyloxycarbonyl. 47. Compounds of the formula IB according to claim 45, wherein R ₁ * and R ~ have the meanings given in claim 45, Ar is phenyl, 3- or 4-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl or 2-thienyl, and R is hydrogen or optionally protected amino, carboxy or sulfo. 48. 4β- (2-Hydroxyethylthio) -Sβ-phenylacetylamino-azetidin-2-one. 49. 4ß- (2-Hydroxypropylthio) -ßß-phenylacetylamino-azetidin-2-one. 50. 4β- (2-Hydroxybutylthio) -Sβ-phenylacetylamino-azetidin-2-one. 51. 3ß-Phenylacetylamino-4ß- [2- (2,2,2-trichloroethoxycarbonyloxy) ethylthio] -azetidin-2-one. 209819/1 159 52. Sβ-CN-tert-butyloxycarbonyl-D-α-phenylglycyl) -amino-4β- (2-hydroxyethylthio) -azetidin-2-one. 53. 3 / 5- (N- tert -butyloxycarbonyl-D-α-phenylglycyl) amino-4β- [2- (2.2 , 2-trichlorethoxycarbonyloxy) ethylthio] azetidin-2-one. 54. 3ß-Phenylacetylamino-4ß- [2- (2,2,2-trichloroethoxycarbonyloxy) propylthio] -azetidiri-2-one. 55. 3ß-Phenylacetylamino-4ß- (3-fluoro-2-hydroxypropylthio) -azetidin-2-one. 56. 3ß-Phenylacetylaraino-4ß- [2-fluoro-2- (2,2,2-trichlor · ethoxycarbonyloxy) propylthio] azetidin-2-one. 209819/1159