CA1140554A - Process for the manufacture of 2-(2-oxoazetidin-1-yl)-crotonic acid derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention concerns a process for the manufacture of esters of 2-[4-(substituted-thio)-3-acylamino-2-oxoazeti-din-1-yl]-3-substituted-amino-crotonic acids by treatment of 2-[4-(substituted-thio)-3-acylamino-2-oxoazetinin-1-yl-3-hydroxycrotonic acids or sulphonic acid esters thereof with primary or secondary amine.

Description

i:~4t~S~

Ihesubject of the present invention is a process for the manu facture of 2-(2-oxoazetidin-1-yl)-crotonic acid compounds of the formula - P~b/~ 3 /~4 (II)J

N C~sN

O= C ~
wherein Rla represents an acyl group of the formula RI _ ~ _ (Al), wherein RI represents hydrogen, cyclopentyl, cyclohexyl or cycloheptyl, or such cycloalkyl which is substituted in the l-position by amino protected amino, sulphoamino or sulphoamino in khe ~orm of an alkali metal salt, or R re-presents phenyl, naphthyl or tetrahydronaphthyl group or phenyl, naphthyl or tetrahydronaphthyl substituted by hy-droxyl, protected hydroxyl, and/or by halogen or R re-presents 4-isoxazolyl, or RI represents an amino group which is N-substituted by lower alkyl or halogen substituted lower alkyl, or Ral represents an acyl group of the formula I ~
R - CH2 - - (A2)r ~llerein R represents lower alkyl, halogeno-lower alkyl, phenyloxy-lower alkyl, hydroxyphenyloxy-lower alkyl, protected hydroxy-phenyloxy-lower alkyl, halogeno-phenyloxy-lower alkyl, or lower alkyl substituted by amino and/orcarboxyl, wherein amino is free or protected andcarbo~yl is free or protected, or R represents lower alkenyl, phenyl, hydroxyphenyl, protected hydroxyphenyl, halogeno-phenyl, hydroxy-halogeno-phenyl, protected hydroxy-halogeno-phenyl, amino-lower alkyl-phenyl protected amino-lower alkyl-phenyl, phenyloxyphenyl, or R represents pyridyl, pyridinium, thienyl, ~uryl, imidazolyl or tetra2Glyl, or these hetero-cyclic groups substitu-ted by lower alkyl, amino, protected amino, aminomethyl or protected aminomethyl, or RI represen~s lower alkoxy, phenyloxy, hydroxyphenyloxy, protected hydroxy-phenyloxy, halogeno-phenyloxy, lower alkylthio, lower alkenyl-thio, phenylthio, pyridylthio, 7 -imidazolylthio, 1,2,4-tri-azol-3-ylthio, 1,3,4-triazol-2-ylthio, 1,2,4-thiadiazol-3-ylthio, 1,3,4-thiadiazol-2-ylthio, or 5-tetrazolylthio and these heterocyclylthio groups, substituted by lower alkyl, or RI represents halogeno, lower alkoxycarbonyl, cyano, carbamoyl, N lower alkyl-carbamoyl, N-phenylcarbamoyl, lower alkanoyl, benzoyl or azido, or Rl represents an acyl group of the ormula II ~
R - ~H - _ (A3), ~4`~

wherein RI represents lower alkyl, phenyl, hydroxy-phenyl, protected hydroxyphenyl, halogeno-phenyl, hydroxy-halogenophenyl, protected hydroxy-haloyeno-phenyl, furyl, thienyl, or isothiazolyl, and also represents 1,4-cyclo-hexadienyl, and R I represents amino, protected amino, guanidinocarbonyl-amino, sulphoamino, sulphoamino in alkali-metal salt-form, azido, carboxyl, carboxyl in alkali-metal salt-form, protected carboxyl, cyano, sulpho, hydroxyl, protected hydroxyl, O-lower alkyl-phosphono, O,O'-di-lower alkyl-phosphono or halogeno or Rl repr~sents a qroup of the formula ~II Q
RI _ ~H - ~ ~ (A4), wherein RI and RII each represent halogeno t or lower alkoxycarbonyl, or Ral represents a group of the ormula ~II R
R - ~H - ~ - ~ 5), wherein RI represents phenyl, hydroxyphenyl, protected hydroxyphenyl, hydroxy-halogeno-phenyl, protected hydroxy-halogeno-phenyl, furyl, thienyl, isothiazolyl or 1,4-cyclohexadienyl, and RII represents aminomethyl or protected aminomethyl or Rl represents a group of the formula ~II

~III (A6)~

wherein each of the groups R , R and R represents lower alkyl, and RbL represents hydrogen, or Rla and RbL
together represent l-oxo-3-aza-1,4-butylene, such group substituted in the 2-position by a group R as defined under formula ~A3) and such group substituted in the 4-position by lower alkyl, the group -N(R4a) (R4b) denotes a secondary amino group, wherein one of the substitu~nts Ra4 and Rb4 represents hydrogen and the other represents lower alkyl, lower aLkoxy-lower alkyl, lower alkyl thio-lower alkyl, cyclohexyl-lower alkyl, phenyl-lower alkyl, thienyl-lower alkyl, cycloalkyl wi~h 3 to 7 carbon atoms, or 5UC~ cycloalkyl substituted by lower alkyl, lower alkoxy, lower alkylthio, cyclohexyl, phenyl, or furyl, or wherein -N(R4a) (Rb4)denotes a tertiary amino group, wherein each o the substituents Ra4 and Rb, independent o~ each other is lower alkyl, lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, cyclohexyl-lower alkyl, phenyl-lower alkyl, thienyl-lower alkyl, cycloalkyl with 3 to 7 carbon atoms, or such cycloalkyl substituted by lower alkyl, lower alkoxy, lower alkylthio, cyclohexyl, phenyl, or furyl, or wherein N-(R4) (R4) i9 l-aziridinyL, l-pyrrolidinyl, l~piperidyl, lH-2,3,4,5,6,7-hexahydroaze-pinyl, 4-morpholinyl, 4-thio-morpholinyl, l-piperazinil, or 4-methyl-l-piperazinyl, Y represents a leaving group of the formula -S-~4, wherein R4 is a monocyclic five membered diazacyclic, oxazacyclic, thiazacyclic, thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclic or a corresponding dicyclic benzdiazacyclic, benzoxazacy~lic or benzthiazacy~lic radical of aromatic character which radical is bonded to the thio group -S- by one of its ring carbon atoms, which is bonded to a rin~ nitrogen atom by a double bond, or such group substituted by lower alkyl, lower alkoxy, halogen or phenyl, or wherein R4 denotes lower alkanoyl, lower thioalkanoyl, cycloalXane carbonyl, cycloalkanethio-carbonyl, benzoyl, thiobenzoyl, naphthyl-carbonyl, naphthylthio-carbonyl, pyridylcarbonyl, thenoyl, furoyl, pyridylthiocarbonyl, thiothenoyl or thiofuroyl, or represents such an acyl or thioacyl group which is monosubstituted or polysubstituted by lower alkyl, halogen, lower alkoxy, phenyl or phenyloxy, which groups R~ have up to 18 carbon atoms, or Y represents a leaving group of the formula -S02-R5, wherein R5 represents unsubstitu-ted or lower alkoxy-, halogeno, phenyl-, or phenyloxy-monosubstituted or -polysubstituted lower alkyl, lower alkenyl, cyclopentyl or cyclohexyl or R5 represents naphthyl,or phenyl, or naphthyl or phenyl monosubstitu-ted or polysubstituted by lower alkyl, lower alkoxy,halogen, phenyl, phenyloxy, or nitro, which groups R5 have up to 18 carbon atoms, and R2 represents a group which together with the carbonyl grouping -C(=O)- forms a protected esterified carboxyl group, characterised in that a compound of the formula Ra : f ~_y 3 (YII)~
/~~

wherein Rla, Rbl, R2 and Y have the above meaning, or a sulphonic acid ester thereof of the formula ~N ~ ~ S-Y
/ (YIII)) ----N~Fc; - - o-so~-Rs O= C-~

5~

wherein ~1, Rl, R2, Y and R5 have the above meaning, is trea-ted with a p.rimary or secondary amine of the formula NH(R4)(Rb), wherein R~ and Rb have the above meaninys, or with a salt thereof and, iE desired, a resulting compound of -the formula II, wherein Y represents a group of the ~ormula -S-R4 can be converted into a compound of the formula II, wherein ~ is a group of the formula -S02-RS, by reac-tion with a heavy metal sulphinate of the formula Mn (-S02-R5), wherein M represents a heavy metal cation and n denotes -the valency of this cation.
The amination is carried out at temperatures between about -l()''C and about ~100C.

In a compound of the formula II, tl~e amino group -N~R4a)(~b) can be in the trans-position ~cro~onic acid conflguration) or in the cis-position ~isocrotonlc acld configurat10n) relative to the carboxyl group.

In the -S-R4 group,R4 is forexample 1-methyl-imidazol-2yl, 1,~-thiazol-2-yl, 1,3,4-~hiadiazol-2-yl, 1,3,4,5-thla-trlazol-2-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4t5-oxatria~ol-2-yl, 2-qulnolyl, l-methyl-benzimida-zol-2-yl, benzoxazol-2-yl and especially benzt~liazol-2-yl.
Further groups R4 are for exampLe acyl or thioacyl groups monosubstituted or polysubstir~uted by lower alkyl, such as methyl, halogen, such as fluorine or chlorine, lower alkoxy, such as methoxy, aryl, such as phenyl, or aryloxy, such as phenoxy.

L~
~ .

In the -S02-R5 group, the group R5 is for example un-substituted or lower alkoxy-, such as methoxy-, halogen-, such as fluorine-, chlorine- or bromine-, aryl-, such as phenyl-, and aryloxy-,such as phenoxy-, mono-substituted or -polysubstituted alkyl groups, especially lower alkyl groups, such as methyl, ethyl or butyl groups, alkenyl groups, such as allylor butenyl groups, cyclo-alkyl groups, such as cyclopentyl or cyclohexyl groups, or naphthyl or , especially, phenyl groups which are optionally monosubstituted or polysubstituted by lower alkyl, such as methyl, lower alkoxy, such as methoxy, halogen, such as fluorine, chlorine or bromine, aryl, such as phenyl, aryloxy, such as phenoxy, or nitro, for example phenyl, o~, m- or, preferably, p-tolyl, o-, m- or,preferably, p-methoxyphenyl, o-, m- or p-chlorophenyl , p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl or 1- or 2-naphthyl.

The compounds of the present invention are intermediates useful for example according to canadian Patent Specifi-cation S. No. 246,040 for the manufacture of enol derivatives, especially 7~-amino-3-cephem-3-ol-4-carbo-xylic acid compounds of the formula SS~
_ 9 _ - Rb ~ ~ /S (IA) O N ~ O-R3 0~;~

wherein Rl and Rl have the meanings under formula II, and R2 represents hydroxyl or a radical R2 which together with the carbonyl grouping -C(=O)- forms a protected esterified carboxyl group and R3 represents hydrogen, lower alkyl or optionally substituted a-phenyl-lower alkyl, as well as l~oxides of 3-cephem compounds of the formula IA and the corresponding 2~cephem compounds of the formula H
S ~ (IB) o ~ ~ O-R3 O~C~2 wherein Rl, Rl, R2 and R3 have the abovementioned meanings, or salts of such compounds having salt-forming groups.
In 2-cephem compounds of the formula I~ having the double bond in the 2,~-position, the optionally protected carbo~yl group of the formula -C(-O)-R2 preferably has the ~-configuration, ss~
- lG -~he compounds of the formulae IA and IB, which are suitable intermediates for the manufacture of pharmacolo-gi&ally more active end products, can be converted into such active end products by various additional measures which are themselves known.
An amino group can be protected by a group which can be replaced by hydrogen. Such amino protectlve group is above all an acyl group Ac, also a triarylmethyl group, especially the trityl group, as well as an organic silyl group, or an organic stannyl group. A group Ac above all represents the acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, especially the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cyclo-aliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid (including formic acid) and the acyl radical of a carbonic acid half-derivative.
A bivalent amino protective group, is, in parti-cular, the bivalent acyl radical of an organic dicar-boxylic acid, preferably with up to 18 carbon atoms, above all the diacyl xadical of an aliphatic or aromatic di-carboxylic acid, and also the acyl radical of an a-amino-acetic acid which is preferably substituted in the a-position and contains, for example, an aromatic or hetero-cyclic radical, and wherein the amino group is bonded to the nitrogen atom via a methylene radical which is preferably substituted and, for example, contains two lower alkyl groups, such as methyl groups. The bivalent amino protective ' ' ` .

- il -group can also represent an organic ylidene radical, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphati.c or araliphatic ylidene radical, preferably with 18 carbon atoms.
A protected carboxyl group of the formula -C(-O)-R2 i~ an esterified carboxyl ~roup.
The group R2 can therefore be a hydroxyl group etherified by an organic radical, wherein the organic radical preferably contains up to 18 carbon atoms, which together with the -C(=O)- grouping forms an esterified carboxyl group.
Examples of such organic radicals are aliphatic, cycloali-phatic, cycloaliphatic~aliphatic, aromatic or araliphatic radicals, especially optionally substituted hydrocarbon radicals of this nature, as well as heterocyclic or hetero-cyclic-aliphatic radicals.
~ he group R2 can also represent an organic silyloxy radical as well as a hydroxyl group etherified by an organo-metallic radical, such as an appropriate organic stannyloxy group, especially a silyloxy or stannyloxy group which is substituted by l to 3 optionally substituted hydrocarbon radicals, preferably with up to 18 carbon atoms, such as aliphatic hydrocarbon radicals, and optionally by halogen, such as chlorine.

S~

The general concepts used in the preceding and follow-ing description have, for example, the following meanings:
An aliphatic radioal 9 includi.ng the aliphatic radical of &n appropriate organic carboxylic acid, as well as an appropriate ylidene radical, is an optionally substi-tuted mono-valent or divalent aliphatic hydrocarbon radical, especially lower alkyl, as well as lower alkenyl or lower alkinyl, and also lower alkylidene which can contain, for example, up to 7, pre~erably up to 4, carbon atoms. Such radicals can optionally be monosubstituted, disubstituted or polysubstituted by functional groups, for example by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phe~yl-lower alkoxy, lower alkylthio or option-ally substituted phenylthio, phenyl-lower alkylthio, hetero-cyclylthio or heterocyclyl-lower al~ylthio, opt~onally sub-stituted lower alkoxycarbonyloxy or lower alkanoyloxy, or halogen, also b~ oxo, nitro, optionally substituted amino, for example lower alkylamino, di-lower alkylamino, lower alkylene-ami~o, oxa-lower alkylene~m;no or aza-lower alkyleneamino, as well as acylamino, such as lower alkanoylamino, lower alkoxy-carbonylamino, halogeno-lower alkoxycarbonylamino, optionally substituted phenyl-lower alkoxycarbonylamino, optionally sub-stituted carbamoylamino, ureidocarbo~ylamino or guanidinocar-bonylamino and also sulphoamino which is optionally present in the ~orm of a salt, such as in the form of an alkali metal salt, azido, acyl, such as lower alkanoyl or benzoyl, optionally functionally modified carboxyl, such as carbo~yl present in s~

the form of a salt, esterified carboxyl, such as lower alkoxy-carbonyl, optionally substituted carbamoyl, such as N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl and also option-ally substituted ureidocarbonyl or guanidinocarbonyl, or cyano, optionally functionally modi~ied sulpho, such as sulphamoyl or sulpho presen~ in the ~orm of a salt, or optionally O-mono-substi~uted or O,O-disubstituted phosphono, wherein substitu-ents represent, ~or example, optionally substitu-ted lower alkyl, phenyl or phenyl-lower alkyl, it also being posslble for O-unsubstituted or O-monosub~tituted phosphono -to be in the form of a sal-t, such as in the form of an alkali metal salt.
A divalent aliphatic radical, including the appro-priate radical of a divalent aliphatic carboxylic acid, is, for example, lower alkylene or lower alkenylene, which can optionally be monosubs~ituted, disubstituted or polysubstituted, for example like an aliphatic radical indicated abo~e, and/or b interrupted by hetero-atoms9 such as oxygen, nitrogen or sulphur.
A cycloaliphatic or cycloaliphatic-aliphatic radical, including the cycloaliphatic or cycloaliphatic-aliphatic radi-cal in a~ appropriate organic carboxylic acid or an appropriate cycloaliphatic or cycloaliphatic-aliphatic ylidene radical, is an optionally substituted, monovalent or divalent, cyclo-aliphatic or cycloaliphatic~aliphatic, hydrocarbon radical, for example monocyclicl bicyclic or polycyclic cycloalkyl or cycloalkenyl, and also cycloalkylidene or cycloalkyl- or cycloalkenyl-lower alkyl or -lower alkenyl, as well as cyclo-alkyl-lo~er alkylidene or cycloalkenyl-lower alkylidene, wherein cycloalkyl and cycloalkylidene contain, for example, up to 12, such as 3-8, preferably ~-6, ring carbon atoms, whilst cycloalkenyl contains, for example, up to 12, such as ~-8, for example ~-8, pre~erably 5 or 6, ring carbon atoms and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic radical can contain, for example, up to 7 9 pre~er-ably up to 4, carbon atoms. The above cycloaliphatic or cycloaliphatic-aliphatic radicals 5~n, i~ desired, be mono-substituted, disubstituted or polysubstituted, for example by optionally substituted aliphatic hydrocarbon radicals, such as by the abovementioned optionally substituted lower alXyl groups9or~ for example like the abo~ementioned al~phatic hydrocarbon radica~ 5, by ~unctional groups.
hn aromatic radicalg including the aromatic radical of an appropriate carboxylic acid~ is an optionally substituted aromatic hydrocarbon radical, for example a monocyclic, bi-cyclic or polycyclic aromatic hydrocarbon radical, especially phenyl, as well as biphenylyl or naphthyl~ which can option-ally be monosubstituted, disubstituted or polysubsti~uted, for example liXe the abo~ementioned aliphatic and cycloaliphatic hydrocarbon radicals.
A divalent aromatic radical~ ~or axample of an aroma-tic carboxylic acid, is above all 1,2-arylene, especially 1,2-phenylene, which can optionally be monosubstituted, disubstitu-ted or polysubstituted, for example like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals.
An araliphatic radical, including the araliphatic radical in an appropriate carboxylic acid, and also an arali-4~S'~- 15 -phatic ylidene radical, is, for example, an optionally substituted araliphatic hydrocarbon ra~ical, such as an ali-phatic hydrocarbon radical whi~h is optionally substituted and possesses, for example, up to three optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon radi-cals, and above all represents phenyl-lower alkyl or phenyl-lower alken~l as well as phenyl-lower alk n~l and also phenyl-lower alkylidene, it being possible for such radicals to contain, ~or example, 1~3 phenyl groups and to be optionally monosubstituted~ disubstituted or polysubstituted in the aromatic and/or aliphatic part, for ex~mple like the above mentioned aliphatic and cycloaliphatic radlcals.
Heterocyclic groups9 including those in heterocyclic-aliphatic radicals, including heterocyclic or heterocyclic-~liphatic grOUp9 in appropriate carboxylic acids, are especi-ally monocyclic, as w211 as bicyclic or polycyclic, azacyclic, thiacyclic, oxacyclic, thiazacyclic, thiadiazacyclic 3 oxaza-cyclic, diazacyclic, triazacyclic or tetrazacyclic radicals of aromatic character, and al~o appropriate partially or wholly saturated heterocyclic radicals of this nature,and such radi-cals can optionally be monosubstituted, disubstituted or poly-substituted, ~or example like the abovementioned cycloaliphatic radicals. The aliphatic part in heterocyclic-aliphatic radicals has, ~or example, the meaning indicated for the corresponding cycloaliphatic-aliphatic or araliphatic radicals.
The acyl radical of a carbonic acid half-derivative is preferably the acyl radical of an appropriate half-ester, wherein the organic radical o~ the ester group represents an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or a heterocyclic-aliphatic radical, above all the acyl radical of a lower alkyl half-ester of carbonic acid which is optionally substi~uted, for example in the a- or ~-position, as well as o~ a lower alkenyl, cycloalkyl, phenyl or phen~l-lower alkyl half-ester o~ carbonic ~cid which is optionally subs~ituted in the orga~ic radical.
Acyl radicals of a carbonic acid half-ester are furt~ermore appro~riate radicals of lower alkyl half-esters of carbonio acid, in which the lower alkyl part contains a heterocyclic group, for example one of the abovementionsd heterocyclic groups of aromatic character 7 and both the lower alkyl radical and the heterocyclic group can optionally be su~stitute~
The acyl radical of a carbonic acid half-deri~ati~e can also be an optionally N-substituted carbamoyl group, such as an optionally halogenated N-lower alkylcarbamoyl group.
An etherified hydroxyl group is abo~e all optionally substituted lower alkoxy, wherein substituents above all represent ~ree or ~unctionally modified, such as etherified or esterified, hydroxyl groups, especially lower alkoxy or halogen, also lower alkenyloxy~ cyclo~lkyloxy or optionally substituted phenyloxy, as well as heterocyclyloxy or hetero-cyclyl-lower alkoxy and especially also optionally substituted phenyl-lower alkoxy.
An optionally substituted amino group is, for example, amino, lower al~ylamino, di-lower alkylamino, lower aikyle~e-amino, oxa-lower alkyleneamino, thia-lower alkyleneamino, aza-5~1 lower alkyleneamino, hydroxyamino, lower alkoxyamino, lower alkanoyloxyamino, lower alkoxycarbonylamino or lower alkanoyl-amino.
An optionally substituted hydrazino group is, for exa~ple~ hydrazino, 2-lower alkylhydrazino, 2,2--di-lower alkylhydrazino, 2-lower alkoxycarbonylh~drazino or 2-lower alkanoylhydrazino.
Lower alkyl i~, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl as well as n-pentyl9 isopentyl, n-hexyl, isohexyl or n-heptyl, whilst lower alken~l can be9 for example, vinyl, allyl, ~so-propenyl, 2- or 3-methallyl or 3-butenyl, lower alkinyl can be, for example, propargyl or 2-~uti~yl and lower alkylidene can be, ~or example, isopropylidene or isobutylidene.
Lower alkylene is, ~or example, 1,2-ethylene, 1,2- or 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, whilst lower alkenylene is, for example, 1,2-ethenylene or

2-buten-1,4-ylene. Lower alkylene interrupted by hetero-atoms is, for example, oxa-lower alkylene, such as 3-oxa-1,5-pentylene, thia-lower alkylene, such as 3-thia 1,5 pentylene, or aza-lower alkylene, such as 3-lower alkyl-3-aza-1~5-pentylene, ~or example 3-methyl-3-aza-1,5-pentylene.
Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl, cycloalkenyl is, ~or example, cyclopropenyl, 1-, 2- or ~-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadie~yl, and cycloalkylidene is, ~or example, cyclopentylidene or cyclohexylidene. Cycloalkyl-lower S~'~

alL~1 or -lower alkenrl is, for example~ cyclopropyl-, cyclopentyl-, cyclohexyl- or cycloheptyl~methyl, ~ or -~2--ethyl, -1,1-, -1 9 2- or -1,3-propy~ -vinyl or -allyl, whilst cycloalkenyl-lo~er alkyl or -lower alkenyl represents ?
~or example, 1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclo-hexenyl- or 1-, 2- or 3-cycloheptenyl-methyl, ~ or ~,2-ethyl, -1~1-, -1,2- or -1,3-propyl, -vinyl or -allyl.
Cycloalkyl-lower alkylidene is, for example, 3-cyclohexenyl-methylene.
Naphthyl is 1- or 2-naphthyl, ~hilst biphenylyl represe~ts, for ex~mple, 4-biphenylyl.
Phenyl lower alkyl or phenyl-lower alXenyl is, for example, benzyl, 1- or 2-phenylethyl, 1-, 2- or 3 phenylpropyl, diphenylmethyl, trityl, sty~yl or ci~na~yl, naphthyl lower alkyl is, for example~ 1- or 2-naphth~lmethyl a~d phenyl-lower alkylide~e is, ~or example, benzylidene.
Heterocyclic radicals are, above all, optionally sub-stituted heterocyclic radicals of aromatic character? for example appropriate monocyclic, monoazacyclic, monothiacyclic or monooxacyclic radicals, such as pyrryl, for example 2-pyrryl or 3-pyrryl, pyrid~l, for example 2-, 3- or 4-pyridyl and also pyridinium, thienyl, for example 2- or 3 thien~Jl, or furyl, ~or example 2-furyl, bicyclic monoazacyclic, monooxa-cyclic or monothiacyclic radicals, such as indolyl, for example 2- or ~-indolyl, quinolinyl, for example 2- or 4-quinolinyl, isoquinolinyl, ~or example 1-isoquinolinyl, benzo-furanyl, for example 2- or ~-benzo~uranyl, or benzothienyl, for example 2- or 3-benzothierlyl, monocyclic diazacyclic~
triazacyclic, tetræacyclic, oxazacyclic, thiazacyc}ic or S5~

thiadiazacyclic radicals, such as imidazolyl, for example 2-imidazolyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, triazolyl, for example l,2,4-triazol-3-yl, tetrazolyl, for example 1- or 5-tetra201yl, oxa~olyl, for exzmple 2-oxazolyl, isoxazolyl, for example 3- or 4-isoxazolyl, thiazolyl, for example 2-thiazolyl, isothiazolyl, for example 3- or 4-iso-thiazolyl, or 1,2,4- or 1,3,4-thiadiazolyl, ~or example 1,2,4-thiadiazol-~ yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza-cyclic, oxazacyclic or thiazacyclic radicals, such as benz-imidazolyl, for example 2-benzimidazolyl, benzoxazolyl, :Eor example 2-ben~oxazolyl9 or benzthiazolyl, for example 2~-benz-thiazolyl. Appropriate partially or wholly saturated radicals are, for example, tetrahydrothienyl, such as 2-tetrah~drothienyl, tetrahydro~uryl, such as 2-te-trahydrofur;l, or piperidyl, for example 2- or 4-piperidyl. Hetero-cyclic-aliphatic radicals are lower alkyl or lower alkenyl containi~g heterocyclic ~roups, especially those mentioned above. The abovementioned heterocyclyl radicals can be su~stituted, for example by optionally substituted aliphatic or aromatic hydrocarbon radicals, especlally lower alkyl, such as m~thyl, or phenyl which is optionally substituted, for example by halogen such as chlorine, for example phenyl or 4-chlorophenyl, or, for example like the aliphatic hydro-carbon radicals, by functional groups.
Lower alkoxy is~ for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, n-pentoxy or tert.-pentoxy. These groups can be substituted, for example as in halogeno-lower alkoxy, 5~'~

especially 2-halogeno-lower alkoxy, for example 2,2,2-tri-chloro-ethoxy, 2-chloroethoxy 3 2-bromoethoxy or 2-iodoethoxy.
Lower alkenyloxy is, for example, vinyloxy or allyloxy, lower alkylenedioxy is, for example, methylenedioxy, ethylenedio~y or isopropylidenedioxy, cycloalkoxy is, ~or example, cyclo-pentoxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy is, for example, benzyloxy, 1- or 2-phenyletho~y~ diphenyl-methoxy or 494'-dimethoxy-diphe~ylmethoxy and heterocyclyloxy or heterocyclyl-lower alkoxy is, for exam~le, pyridyl-lower al~oxy, such as 2-pyridylmethoxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy.
Lower alkylthio is, for example, methylthio, ethylthio or n-butylthio, lower al~enylthio is, for exa~ple, allylthio and phenyl-lower alkylthio is, for examplet benzylthio, whilst mercapto groups etherified by heterocyclyl radicals or hetero-cyclyl-aliphatic radicals are especially pyridylthio, for example 4-pyridylthio t imidazolylthio, thiazolylthio, for example 2-thiazolylthio, 1,2,4- or 1,3,4-thiadiazolylthio, for example 1,2,4-thiadiazol-~-ylthio or 1,~,4-thiadia~ol-2-ylthio, or tetrazolylthio, for ex~mple l-methyl-5-tetrazolyl-thio.
Esterified hydroxyl groups are above all halogen, for example fluorine, chlorine, bromine or iodine, as well as lower alkoxycarbonyloxy, for example methoxycarbonyloxy, ethoxycarbonyloxy or tert.-butoxycarbonyloxy, 2-halogeno-lower alkoxycarbonyloxy~ for example 2,2~2-trichloroethoxy-carbonyloxy, 2-bromoethoxycarbo~yloxy or 2-iodoethoxycarbonyl-oxy, or arylcarbonylmethoxycarbonyloxy, for example phenacyl-55'~
_ 21 oxycarbo~yloxy.
Lower alkoxycarbonyl is, for example, m~thoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert.-butoxycarbonyl or tert.-pentoxycarbonyl~
N- lower alkyl- or N,N-di-lower alkyl-carbamoyl is, for e~ample, N-methylcarbamoyl, N-eth~lcarbamoyl, N,N-dimethyl-carbamoyl or N,N-diethylcarbamoyl, whilst N-:Lower alkylsulpha-mo~l represents, for example, N-methylsulphamoyl or N,N-dimethylsulphamoyl.
A carboxyl or sulpho present in the form of an alkali metal salt is, ~or example, a carboxyl or sulpho present in the form ofthesodium or potassium salt.
Lower alkylamino or di-lower alkylamino is, for example, methylamino, eth~lamino, dimethylamino or diethylamino, lower alk~l2neamino is, ~or example, pyrrolidino or piperidino, oxa-lower alkyleneamino is, for example, morpholino, thia-lower alkyleneamino is, for exa~ple, thiomorpholino and a~a-lower alkyleneamino is, ~or example, piperazino or 4-methyl piperazino. Acylamino in particular represents carbamoyl-amino~ lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxy-carbonylamino, for example methoxycarbonylamino, ethoxycarbon-ylamino or tert.-butoxycarbonylamino, halogeno-lower alkoxy-carbonylamino 7 such as 2,2,2-trichloroethoxycarbonylamino, phenyl-lower alkoxycarbonylamino, such as 4-methoxyben~yloxy-carbonylamino, lower alkanoylamino, such as acetylamino or propionylamino, and also ph~halimido, or sulphoamino which is optionally present in the form of a salt, such as in the form o~ an alkali metal salt, for example in the form of the sodium - ?2 -salt, or in the form of the ammonium salt.
Lower allcanoyl is, for e~ample, formyl, acetyl, pro-pionyl or pivaloyl.
O~lower alkyl-phosphono is, ~or example, O-methyl-or ~-ethyl-phosphono~ O,O'-di-lower alkyl-phosphono is, for example, O,O-dimethyl-phosphono or O,O'-diethylphosphono, O-phenyl-lower alk~l-phosphono.is, for example, O-benzyl-pho~phono and O-lower alkyl-O'-phenyl-lower alkyl-phosphono is, for example, O-benzyl-O'-meth~l-phosphono.
Low~r alkenyloxycarbonyl is, for example, vinyloxy-carbonyl, whil~t cycloalko~ycarbonyl and phenyl-lower alkoxy-carbonyl represent, for example, adamantyloxycarbonyl, benzyl-oxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethoxy-carbonyl or ~-4-biphenyl-a-methyl-ethoxycarbon~l~ Lower alkoxycarbonyl 9 wherein lower alkyl contains 3 for example, a monocyclic, monoazacyclic, monooxacyclic or monothiacyclic group, is, for example, furyl-lower alXoxycarbon~1, such as furfury~oxycarbonyl, or thienyl-lower alkoxycarbonyl, such as 2-thenyloxycarbon~
2-lower alkyl- and 2,2-di-lower alkyl-hydrazino is, for example, 2-methylhydrazino or 2,2-dimethylhydrazino, 2-lower alkoxycarbonylhydrazino is, for example, 2-methoxy-carbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert.-butoxycarbonylhydrazino and lower alkanoylhydraæino is, for exa~ple, 2-acetylhydrazino.
~ n acyl group Ac in particular represents an acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, contained in a N-acyl derivative, which is .

naturally occurring or can be prepared biosynthetically, semi-synthetically or entirely synthetically and is preferably phar~acologically active, of a 6-amino-penam-3-carboxylic acid co ound or 7-amlno-3-cephem-4-carboxylic acid co~paund, or represents an easily removable acyl radical, especially of a carbonic acid half~derivative.
An acyl radical Ac contained in a pharmacologically active N acyl deri~ati~e of a 6-amino-penam~3-carboxylic acid compound or 7-amino-3-cephem-4-carboxylic acid compound is above all a group of the ~ormula ~II

(A) -- tC)~--I n wherein n represents O and RI denote~ hydrogen or an option-ally substituted cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical~
pre~erably of aromatic character, a functionally modified, for example esterified or etherified, hydroxyl or mercapto group or an optionally substituted amino group, or wherein n represents 1, RI represents hydrogen or an optionally sub-stituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,.
aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, wherein the heterocyclic radical preferably possesses aroma-tic character and/or a quaternary nitrogen atom, an option-- 2~ -ally function211y modified, pre~erably etheri~ie~ or esteri~ied, hydroxyl or mercapto group, an optionally functionally modi-fied carboxyl group, an acyl group, an optionally substituted amino group or an azido group and each o~ the radicals RII ar,d RIII denotes hydrogen, or wherein n represents 1, RI denotes an optionally substituted aliphatic, cycloaliphatic, cyclo-aliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or hetero-cyclic-aliphatic radical 9 wherein the heterocyclic r~ical pre~er-ably possesses aromatic character, RII denotes an optionally functionally modifîed, for example esterified or etheri~ied, hydro.Yyl or mercapto group, such as a halogen atom~ an option-ally substituted amino group, an optionally functionally modified carboxyl or sulpho group, an optionally O-monosub-stituted or O,O'-disubstituted phosphono group or an azido group, and R~II represents hydrogen, or wherein n represents 1, each of the radicals RI and RII de~otes a ~unctionally modi-fied, preferably etheri~ied or esteri~ied, hydroxyl group or an optionally functionally modified carboxyl group and RIII
represents hydrogen, or wherein n represents 1, RI denotes hydrogen or an optionally substituted aliphatic, cycloali-phatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and RII and RIII together represent an optionally substituted aliphatic, cycloaliphatic, cycloali-phatic-aliphatic or araliphatic hydrocarbon radical which is bonded to the carbon atom by a double bond, or w~erein n represents 1 and RI denotes an optionally substituted ali-SS'9L

phatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic~aliphatic radical, wherein heterocyclic radicals preferably possess aromatic character, RII denotes an optionally substituted aliphatic, cycloali-phatic, cycloallphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and RIII denotes hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-ali-phatic, aromatic or araliphatic hydrocarbon radical.
In the abovementioned acyl groups o~ the ~ormula A, for example, n represents O and RI represen-ts hydrogen or a cycloalkyl group with 5-7 ring carbon atoms which is option-ally substituted, pre~erably in the l-position, by optionally protected amino, acylamino, wherein acyl above all represents the acyl radical of a carbonic acid half-ester, such as a lower alkox~carbonyl, 2-halogeno-lower alkoxycarbonyl or phen~l-lower alkoxycarbonyl radical, or a sulphoamino group which is optio~ally present in the form of a salt, for example in the form of an alkali metal salt, a phenyl, naph~hyl or tetrahydronaphthyl group which is optionally sub-stituted, preferably by hydroxyl, lower alkoxy, for example methoxy, acyloxy, wherein acyl above all represents the acyl radical of a carbonic acid half-ester, such as a lower alkoxycarbonyl, 2-halogeno-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl radical, and/or halogen, for example chlor ne, a heterocyclic group which is optionally substitu-ted, for example by lower alkyl, for example methyl, æ~d/or 5~

phenyl, which can in ~urn carry substituents, such as halogen, for example chlorine, such as a 4-isoxazolyl group, or an amino group which is preferably N-substituted, for example by an optionally substituted lower alkyl radical, such as a lower alkyl radic~l containing halogen~ for example chlorine, or n represen-ts 1, R represents a lower alkyl group which is optionally substituted, preferably by halo~en, such as chlor-ine, by phenyloxy which is optionally substituted, such as phenyloxy containing hydroxyl, acyloxy, wherein acyl has ~he ~bo~ementioned meaning, and/or halogen, for example chlorine, or by optionally protected amino and/or carboxyl, for example a 3-amino-3-carboxypropyl radical which has an optionally protected ~mino and/or carboxyl group, for example a silylated, such as tri-lower alkylsilylated, ~or example trimethylsi ated, amino or acylamino 9 such as lower alkanoylamlno, halogeno-lower alkanoylamino or phthaloylamino group~ and/or a silylated, such as tri-lower alkylsilylated, for example trimeth~lsilylated, carboxyl group 9 or an esterified car~oxyl group, such as a carboxyl group which is esterified by lower alkyl, 2-halogeno-lower alkyl or phenyl-lower alkyl, for example diphenylmethyl, or represents a lower alke~yl group, a phenyl group which is optionally substituted, such as a phenyl group which contains hydroxyl which is optionally acylated, for example as indicated above, and/or halogen, for example chlorine, and also amino-lower alkyl, such as amino-methyl, which is optionally protected, for example acylaled as indicated above, or contains phenyloxy which possesses ~ 5 ~ ~

hydroxyl which is optionally acylated, ~or example as indicated above, and/or halogen, for example chlorine, or represents a pyridyl, ~or example 4-pyridyl, pyridinium, for example 4-pyridinium, thienyl, for example 2-thienyl, furyl, ~or example 2-furyl, imidazolyl~ ~or example l-imidazolyl, or tetrazolyl, for example l-tetrazolyl group which is optionally substituted, for example by lower alkyl, such as methyl, or by amino or a~inomethyl which are optionally protected, ~or example acylated as indicated abo~e, or represent~ an option-ally substituted lower alkoxy group, for example a methoxy group, a phenyloxy group which is optionally substituted, such as a phenyloxy group which contains optionally protected hydroxyl, for example hydroxyl acylated as indicated abo~e, and/or halogen, such as chlorine, or represents a lower alkyl-thio, for example n-butylthio, or lower alkenylthio, for example allylthio group9 a phenylthio, pyridylthio, ~or example 4-pyridylthio, 2-imidazolylthio, 1,2,4-triazol-3-ylthio, 1,3,4-triazol-2-ylthio, 1,2,L~-thiadiazol-~-ylthio, such a~ 5-methyl-1,2,4-thiadiazol-3-ylthio, 1,3 9 4-thiadia~ol-2-ylthio, such as methyl-1,3,4-thiadiazol-2 ylthio, or 5-tetrazolylthio, such as l-methyl-5-tetrazolylthio group, optionally substituted, for example by lower alkyl, such as methyl, or represents a halogen atom, especially a chlorine or bromine atom, an optionally functionally modified carboxyl group, such as lower alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, cyano or carbamoyl which is optionally N-substituted, for example by lower alkyl, such 5~

as methyl, or phenyl, or represents an optionally substituted lower alkanoyl group, for example an acetyl or propionyl group, or a benzoyl group or an azido group, and R~I and RIII
represent hydrogen, or n represents 1, RI represents lower alkyl or a phenyl, furyl, for example 2-furyl, thienyl, ~or example 2- or 3-thienyl, or isothiazolyl, for example 4-iso-thiazolyl group which is optionally substituted, such as substituted by hydroxyl which is optionally acylated, for example as indicated above, and/or by halogen, for example chlorine, and also represents a l,4-cyclohexadienyl group, RII represents optional~y protected or substituted amino, for example amino, acylamino, such as lower alkoxycarbonylamino, 2-halogeno-lower alkoxycarbonylamino or optionally substituted phen~l-lower alkoxycarbonylamino such as phenyl-lower alkoxy-carbonylamino which contains lower alkoxy, ~or example methoxy, or nitro, for example tert.-butoxycarbonylamino, ~,2,2-tri-chloroethoxycarbonylamino, 4-metho~benzyloxycarbonylamino or diphe~ylmethoxycarbonylamino, arylsulphonylamino, for example 4-methylphenylsulphonylamino, tritylamlno, arylthioamino, such as nitrophenylthioamino, for example 2-nitrophenylthio-amino, or tritylthioamino or 2-propylideneamino which is optionally substituted, such as 2-propyli~eneamino which con-tains lower alkoxycarbonyl, for example ethoxycarbonyl, or lower alkanoyl, for example aoetyl, such as l-ethoxycarbonyl-2-propylideneamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or a sulphoamino group which is optionally present in the form o~ a salt, ~or example in 5~:~

the form of æn alkali metal salt, an az'do ~rou?, a earbo~yl group which is optionally present in the form of a sait, for example in the ~orm of an alkali metal salt, or in a protected form, such as in an esterified ~orm, for example as a lower alkoxycarbonyl group, ~or example a methoxycarbonyl group or ethoxycarbonyl group, or as a phenyloxycarbonyl group, for example a diphenylmethoxycarbonyl group, a cyano group, a sulpho group, an optionally functionally modified hydroxyl group9 wherein functionally modi~ied hydroxyl in particular represents acyloxy, such as formyloxy, as well as lower al~oxycarbonylo~y, 2-halogeno-lower alkoxycarbonyloxy or phenyl-lower alkoxycarbonyloxy which is optionally substi.tuted, such as phenyl-lo~er alkoxycarbonyloxy which contains lower alkoxy, for example methoxy, or nitro, for example tert.-~butoxycarbonyloxy, 2,2,2-trichloroethoxycarbonylo~y, 4-mathoxy-benzyloxycarbonyloxy or diphe~ylmethoxycarbonyloxy, or option-ally substituted lower alkoxy, for example methoxy, or phen-oxy, a O-lower alkyl-phosphono group or O,O'-di-lower alkyl-phosphono group, for example O-methyl-phosphono or o,o t _ dimethylphosphono, or a halcgen atom, for example chlorirle or bromine, and RIII represents hydrogen, or n represents 1~ RI
and RII each represent halo~en, for example bromine, or lowar alkoxycarbonyl, for example methoxycarbonyl, and RIII repres-ents hydrogen, or n represents 1, RI represents a phenyl~
furyl, for example 2-~uryl, or thienyl, for example 2- or 3-thienyl, or isothiazolyl, for example 4-isothiazoly-, group, which is optionally substituted, for example by hydroxyl which is optionally acylated, ~or example as indicated above, 5~'~

~ 30 -and/or by h~logen, for example chlorine~ and also represents a l,4-cyclohexadienyl group, RII represents aminomet~yl which is optionally protected, for example as indicated above, and R II represents hydrogen or n represents 1 and each o~ the groups RX, RI~ and RIII represents lower alkyl, for example methyl.
Such acyl radicals Ac are, for example, formyl, cyclo-pentylcarbonyl, a-aminocyclopentylcarbonyl or a-aminocyclohexyl-carbonyl (with an optionally substituted amino group, for example a sulphoamino group which is optionally present i.n the form of a salt, or an amino group which is substituted by an acyl radic~l which can be split off~ preferably easily, ~or example on treatment with an acid agent, such as trifluoro-acetic acid, or by reduction, for example on treatment with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, or catalytic hydrogen, or hydrolytically, or an acyl radical which can be converted into such a radical, preferably a suitable acy~ radical of a carbonic acid half-ester, such as lower alkoxycarbony~, for example tert.-butoxy-carbonyl, 2-halogeno-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodo-ethoxycarbo~yl, arylcarbonylmethoxycarbonyl, for example phenacyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, such as phenyl-lower alkoxycarbonyl containing lower alkoxy, for example methoxy, or nitro, for example 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or of a 5~

carbonio acid half-amide, such as carbamoyl or N-substituted carbamoyl, such as N-lower alkylcarbamoyl, for example N-methylcarbamoyl, as w211 as by trityl, also by arylthio, for example 2-nitrophenylthio~ arylsulphonyl, for example 4-methylphenylsulphonyl or 1-lower alXoxycarbonyl~2-propylidene, for example l-ethoxycarbo~yl-2-propylidene), 2,6-dimethoxy-benzoyl, 5~6,7,8-tetrahydronaphthoyl, 2-methoxy-1-naphthoyl, 2-ethoxy-1-naphthoyl, benzyloxycarbonyl, hexahydrobenzyloxy-carbonyl, 5-methyl-3-phenyl-4-isoxazolylrarbonyl, 3-(2-chloro-phenyl)-5-methyl-4-isoxazolylcarbonyl, 3-(2 9 6-di~hlorophenyl)-5-methyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, propio~yl, butyryl, pivaloyl~ hexa~oyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pe~tenoyl, methoxyacetyl, butylthioacetyl, allylthloacetyl, methylthioacetyl, chloro-acetyl J bromoacetyl, dibromoacetyl, 3-chloropropionyl, ~-bromopropionyl, aminoacet~l or 5-amino-5-carboxy-valeryl (with an amino group which is optionally su~stitutedl for ex mple as indicated, such as substituted by a monoacyl or diacyl radical, for example an optionally halogenated lower alkanoyl radical, such as acetyl or dichloroacetyl, or phthaloyl, and/or with an optionally functionally modified carboxyl group, for exa~ple a carboxyl group present in the ~orm of a salt, such as a sodium salt, or in the form of an ester, such as a lower alkyl es-ter, for example a me~hyl or ethyl ester, or an aryl-lower alkyl ester, for example diphenylmethyl ester), azidoacetyl, carboxyacetyl, methoxy-carbonylacetyl, ethoxycarbonylacetyl, bis-methoxycarbonyl-5'~

acetyl, N phenylcarbamoylace-tyl, cyanoacetyl, ~-cyanopropionyl, 2-cyano-3,3-dimethyl-acrylyl, phenylacetyl~ a~bromophenyl-ace~yl, a-azidophenylacetyl 7 3-chlorophenylacetyl t 2~ or 4-aminomethylphenylacetyl (with an amino group which is option ally substituted, for example as indicated), phenacylcarbonyl, phenoxyacetyl, 4-trifluoromethylphenoxyacetyl, benzyloxy-acetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenoxy-propionyl, a-phenaxyphenylacetyl) ~ methoxyphen~lacetyl, a-ethoxyphenylacetyl, a-methoxy-3~4-dichlorophen~lacetyl~ a-cyanophenylacetyl, especially phenylglycyl, 4-hydroxyphenyl-glycyl, 3-chloro-4-~ydroxyphe~ylglycyl, 3,5-dichloro-4-hydroxyphenylglycyl, a-amino-a-(1,4-cyclohexadienyl)~acetyl, a-amino-a-(l-cyclohexenyl)-acetyl, a aminomethyl-a-phenyl-acetyl or a-hydroxyphenylacetyl, (it being possible, in these radicals, for an amino group which is present to be optionally substituted~ for axample as indicated above, and/or an ali-phatic and/or phenolically bonded hydroxyl group which is present.to be optionally protected, analogously to the amino group, for example by a suitable acyl radical, especially by formyl or by an acyl radical of a carbonic acid half-ester), or a-O-methyl-phosphono-phenylacetyl or a-O,O~dimethyl-phos-phono-phenylacetyl, also benzylthioacetyl, benzylthiopropionyl, -carboxyphenylacetyl (with a carboxyl group which is option-ally functionally modified, for example as indicated above),

3-phe~ylpropionyl, 3-(~-cyanophenyl)-propio~yl, 4 (3-methoxy-phenyl)-butyry]., 2-pyridylacetyl, 4-amino-pyridiniumacetyl (optionally with an amino group which is substituted, or s~

example as indicated above), 2-thienylacetyl, 3-thienylacetyl, 2-tetrahydrothienylacetyl) 2-furyiacetyl, l-imidazolylace~yl, l-tetrazolylacetyl, -carboxy-2-thienylacetyl or a-carboxy-3-thienylacetyl (optionally with a carbo~yl group which is ~unctionally modified, for example as indicated above), cyano-2-thienylacetyl, a-amino-a-(2-thienyl)-acetyl, a-~m;n a-(2-furyl)-acetyl or a-amino-a-(4-isothiazolyl)-acetyl (optionally with an amino group which is substituted, or example as indicated above), -sulphophenylacetyl (optionally with a sulpho group which is ~unctionally modified, for example like the carboxyl group), 3-methyl-2-imldazolylthio-acetyl, 1,2,4-triaæol-3-ylthioacetyl, 1,3,4-triazol 2 ylthio-acetyl, 5-methyl-1,2,4-thiadiazol-~-ylthioacetyl, 5-methyl-1,3,4-thiadiazol-2-ylthioacetyl or l-methyl-5-tetrazolylthio-acetyl.
An easily removable acyl radical Ac, especially of a carbonic acid half-ester, is above all an acyl radical of a half-ester of carbonic acid which can be split o~f by reduction, for exam?le on treatment with a chemical reducing agent, or by treatment with acid, ~or example with trifluoro-acetic acid, such as a lower alkoxycarbonyl group which pre-ferably has multiple branching and/or an aromatic substituent on the carbon atom in the a-position to the oxy group, or a methoxycarbonyl group which is substituted by arylcarbo~yl, especially benzoyl, radicals, or a lower alkoxycarbonyl radical which is substituted in the ~-position by halogen atoms, for example tert.-butoxycarbonyl, tert~-pentoxycarbon-yl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a radical which can be converted into - 3~ -the latter, such as 2-chloroethox~carbonyl or 2-bromoethoxy-carbonyl, and also preferably polycyclic cycloalkoxycarbonyl, for example adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycar~onyl, above all -phenyl-lower alkoxy carbonyl, w~erein the x-position is pre~erably polysubstituted~
for example diphenylmethoxycarbonyl or a-4-biphenylyl-a-methyl-etho~ycarbonyl~ or furyl-lower alkoxycarbonyl, above all a-furyl-lower alkoxycarbonyl, for example furfurylo~ycarbonyl.
A divalent acyl group formed by the two radicals R
and Rlb is, for example, the acyl radical of a lower alkane-dicarboxylic acid or lower alkensdicarboxylic acid, such as ~uccinyl, or of a o-arylenedica~boxylic acid, such as phthaloyl.
A further divalent radical formed by the groups Rl~
and Rlb is, for example, a l-oxo 3-aza-19h-butylene radical which is substituted, especially in the 2-position, and con-tains, ~or example, optionally substituted phenyl or thienyl, and is optionally monosubstituted or disubstituted by lower alkyl, such as methyl, in the 4-position, for example 4,4 dimethyl-2 phenyl-1-oxo-3-aza-1,4-~utylene.
An etherified hydroxyl group R2A forms, together with the carbonyl grouping 9 an esterified carboxyl group which can preferably be split easily or can be converted easily into another functionally mo~ified group, such as into a carbamoyl or hydrazinocarbonyl group. Such a group R2A is7 ~or example, lower alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy, which, together with the carbonyl grouping, forms an esterified carboxyl group, which can easily be converted, especially in 2-cephem compounds, into a free carboxyl group 5~i~

or into another functionally modi~ied carboxyl group.
An etherified hydroxyl group R2A which, together with a -C(=O)- grouping, forms an esterified carboxyl group which can be split particularly easily, represents, for examDle, 2-halogeno-lower alkoxy, wherein halogen preferably has an atomic weight o~ more than 19. Such a radical ~orms, together with the -C(=O)- grouping, an esterif.ied carboxyl group which can be split easily on treatment with chemical reducing agents under neutral or weakly acid conditions, for example with zinc in t~e presence of aqueous acetic acid, or a~ esterified carboxyl group which can be con~erted easily into such a group and is, for example, 2,2,2-trichloroethoxy or 2-iodoethoxy, ~nd also 2-chloroethoxy or 2-bromoethoxy, which can easily be con~erted into the latter.
An etherified hydroxyl group R2~ which, together with the -C(=O)- grouping, represents an esterified carboxyl group which can also be split easily on -treatment with chemical reducing agents under neutral or weakly acid conditions, ~or example on treatment with zinc in the presence of aqueous acetic acid, and also on treatment with a suitable nucleophil-ic reagent, for example sodium thiophenolate, is an aryl-carbonylmethoxy group, wherein aryl in particular represents an optionally substituted phenyl group, and preferably phenacyloxy.
The group R2A can also represent ~n arylmethoxy group, ~L'~SS~

wherein aryl in particular denotes a monocyclic, preferably substituted, aromatic hydrocarbon radical. Such a radical forms, together with the -C(=O)- grouping, an esterified carboxyl group which can be split easily on irradiation, pre-~erably with ultraviolet light~ under neutral or acid con-ditions~ An aryl radical in such an arylmethoxy group is, in particular, lower alkoxyphenyl, for example methoxyphenyl (wherein methoxy is above all in ~he 3-, 4- a~d/or 5-position~, and/or above all nitrophenyl (wherein nitro is preferably in the 2-position). Such ~adicals are, in particular, lower alkoxybenzyloxy, for example methoxybenzyloxy, and/or nitro-benzyloxy, aboYe all 3- or 4-methoxybenzyloxy, 3,5-dimethoxy-benzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitrobenzyloxy.
An etherified hydroxyl group R2A can also represen-t a radical which 9 together with the -Ct~O)- group~ng, ~orms an esterified carboxyl group which can be split easily under acid conditions, ~or example on treatment with trifluoroacetic acid or ~ormic acid. Such a radical is,above all,a methoxy group, in which methyl is polysubstituted by optionally ~ub-stituted hydrocarbon radicals, especially aliphatic or aroma-tic hydrocarbon radicals, such as lower alkyl, ~or example methyl, and/or phenyl, or is monosubstituted by a carbocyclic aryl group which contains elec-tron-donating substituents or by a heterocyclic group of aromatic character which contains oxygen or sulphur as a ring member, or in which methyl denotes a ring member in a polycycloaliphatic hydrocarbon radical or denotes the ring mem~er which represents the a-position 5'~

rQlative to the oxygen or s~phur atom in an oxacycloaliphatic or thiacycloaliphatic radical.
Preferred polysubstituted methoxy groups of this nature are tert.-lower alkoxy, for example tert -butoxy or tert.-pentoxy, optionally substituted diphenylmethoxy~ for example diphenylmethoxy or 4,4'~dimethoxy-diphenylmethoxy, and also 2-(4-biphenylyl)-2-propoxy, whilst a methoxy group which contains the abovementioned substituted aryl group or the heterocyclic group is, ~or example, ~-lower alkoxy-phenyl-lower alkoxy, such as 4-methoxybenzyloxy or ~,4-dimethoxy-benzyloxyJ or furfuryloxy~ such as 2-furfuryloxy. A poly-cycloaliphatic hydrocarbon radical in which the methyl of the methoxy grou~ represents a branched, pre~erably triply branched, ri~g member is~ for example, adamantyl; such as l-adamantyl, and an abovementioned oxacycloaliphatic or thiac~cloaliphati~
radical,wherein the methyl of the methoxy group is the ring member which represents the -position relative to the oxy-gen or sulphur ato~,denotes for example, 2-oxa- or 2-thia-lower alkylene or lower alkenylene with 5-7 ring atoms, such as 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulphur analogues.
The radical R2A can also represent an etherified hydroxyl group which, together with the -C(=O)- grouping, forms an esterified carboxyl group which can be split hydrolytically, for exa~ple under weakly basic or weaXly acid conditions. Such a radical is ~re~erably an etherified hydroxyl group which ~orms an acti~ated ester grou~ with the 55~

-C~=O)- grouping, such as nitrophenoxy, ~or example 4-nitro-phenoxy or 2,4-dinitrophenoxy, nitrophenyl-lower alkoxy, for ex2mple 4-nitrobenzyloxy, hydroxy-lower alkyl-benzylox~, for example 4-hydroxy-3,5-tert.-butyl-ben~yloxy 7 polyhalogenophen-oxy, for example 2,4,6-trichlorophenoxy or 2,3,475,~-penta-chlorophenoxy, and also cyanomethoxy, as wel.l as acylamino-methoxy, ~or example phthaliminomethoxy or succinyliminomethoxy.
. The gro~p R2A can also represent an etherified hydroxyl group which, together with the carbonyl grouping of the formula -C~=O)-, forms an esterified carboxyl group which can be split under hydrogenolytic conditions and is, for example, a-phenyl-lower alkoxy which is optionally substituted, for example by lower alkoxy or nitro, such as benzyloxy9 4-methoxybenzyloxy or 4-nitrobenzyloxy.
The group R2A can also be an ethari~ied hydrox~l group which, together with the carbonyl grouping -C(=O)-, forms an esterified carboxyl group which can be split under physiological conditions~ abo~e all an acyloxymethoxy group, wherein acyl danotes, ~or example~ the radical of an organic carboxylic acid, above all of an optionally substituted lower alkarecarboxylic acid, or wherein acyloxymethyl forms the residue of a lactone. Hydroxyl groups etherified in this way are lower alkanoyloxy-methoxy, for example acetyloxymeth-oxy or pivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, especially a-amino-lower alkanoyloxymethoxy, ~or example glycyloxymethoxy, L-valyloxymethoxy, L-leucyloxymethoxy and also phthalidyloxy.

_ ~9 _ A silylox~ or stannyloxy group R2A pre~erably contains, as substituents, optionally sub tituted aliphatic, cyclo-aliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, halogeno-lower alkyl, cycloalkyl, phenyl or -phenyl-lower alkyl groups, or optionally modified functional groups, such as etherified hydroxyl groups, for examole lower alkoxy groups, or halogen atoms, for exampl.e chlorine atoms, and above all represents tri-lower alkylsilyloxy, ~or example trimethylsilyloxy, halogeno-lower alkoxy-lower alkylsilyl, for example chloro-m~thoxy-methyl-silyl, or tri-lower alkyl-st~nylo.~ fer example tri-n-butylstannyloxy.
In a compound o the formula II, R2 prefer-ably rep~esents an etherified h~droxyl group which, with the -C(-O)- grouping, ~orms an esteri~ied carboxyl group which can be ~plit, especiall~ under mild conditions~ lt being possible for any function~l groups which may be present in a carboxyl protective group R2A to be protected in a manner which is in itself known, for example as indicated above. A group R2A
is, ~or example, ir~ palticular an optionally halogen-substituted lower alkoxy group, such as methoxy, a-poly-branched lower alkoxy, for example tert.~butoxy~ or 2-halogeno-lower alkoxy, wherein halogen represents, for example, chlorine, bromine or iodine, above all 2,2,2-trichloroethoxy, 2-bromoethoxy or 2-iodoethoxy, or an optionally substituted l-phenyl~lower alkoxy group, such as a l-phenyl-lower alkoxy group containing lower alkoxy, for example methoxy, or nitro, such as benzyloxy or diphenylmethoxy which is optionally substituted, for exa~ole as indicated, for exa~ple ben~yloxy, 4-methoxybenzyloxy, 4-5~

nitrobenzyloxy, diphenylmethoxy or 4,4~-dimethoxy-diphenyl-methoxy, and also an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, for example trimethylsilyloxy, or halogen, for ~xample chlorine. Preferably, in a starting material of the formula II, the radical Rla denotes an acyl group Ac, wherein any free ~unc~ional groups which may be present, for example amino, hydroxyl, carboxyl or phosphono groU?s, can be protected in a manner which is in itself known~ amino ~rou?s, for example, by the abovementioned acyl, trityl, silyl or stan~yl radicals, as well as substituted thio or sulphonyl radicals, and hydroxyl, carboxyl or phosphono groups, for example, by the abovementioned ether or ester groups, inc:Lud-ing silyl or stannyl groups, and Rlb denotes hydrogen.
In a secondary amino group -N(R4)~R4), R4a or R4b are, for example, optio~ally substituted alkyl groups, especially lower alkyl groups, for example alkyl groups, especially lower alkyl groups, substituted by lower alkoxy, such as methoxy, lower alkylthio, such as methylthio, cyclo-alkyl, such as cyclohexyl9 aryl, such as phenyl~ or hetero-cyclyl, such as thienyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, 2-ethoxyethyl, 2-methylthioethyl, cyclohexyl~ethyl, benzyl or thienylmethyl.
Cycloaliphatic hydrocarbon radicals ~ a or R4b are, for example, optionally substituted cycloalkyl groups, for example cyclo-alkyl groups substituted by lower alkyl, such as methyl, lower alkoxy, such as methoxy, lower alkylthio, such as methylthio, cycloalkyl, such as cyclohexyl, aryl, such as 5~,~

phenyl, or heterocyclyl, such as ~uryl, such as cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl which are optionally substituted as indicated.
In tertiary amino groups -N(R4)(R4), each o~ the sub-stituents R4a and R4b denotes one of the indicated aliphatic or cycloaliphatic hydrocarbon radicals, and R4a and R4b can be identical or different and the two substituents R4a and R4b can be li~ked together by a carbon-carbon bond or via an oxygen or sulphur atom or via an optionally substituted, such as lower alkylated, for example methylated, nitrogen atom.
Suitable tertiary amino groups N(R4)(R4) are, for example, dimethylami~o, diethylamino, N-methyl-ethylamino, di~
isopropylc~.~lno, N-methyl-isopropylamino, dibutylamino, N-methyl~isobutylamino, dicyclopropylami~o, N-methyl-cyclo--propylamino, dicyclopentylamino, N-methyl-cyclopentylamino, dlcyclohexylamino, N-methyl-cyclohexylamino, dibenzylamino, N-methyl-benzylamino, N-cyclopropyl-benzyl~mino~ l-aziridinyl~
l-pyrrolidi~l, l-piperidyl, lH-2,3,4,5,6,7-hexahydroazepinyl,

4-morpholinyl, 4-thiomorpholinyl, l-piperazinyl or 4-methyl-l-piperazinyl.
The compounds of the present invention can be used as intermediate products for the manufacture of compounds of the ~ormula IAg l~herein, for example, Rla represents an acyl radical Ac occurring in pharmacologically active N-acyl deriva-tives of 6~-~m;no-penam-3-carboxylic acid compounds or 7~-amino-~-cephem-4-carboxylic acid compounds and Rlb represents hydrogen, or wherein Rla and Rlb together represent a l-oxo-~-aza-1,4-butylene radical which is pre~erably substituted in the - ~l2 2-positio~, for example by an aromatic or heterocyclic radical, ~nd preferably substituted in the 4-position, for example by 2 lower alkyls, such as methyl, R2 denotes hydroxyl or an etherified h~droxyl group R2A which, together with the carbonyl group, forms an esterified carboxyl group ~hich can be split easily under physiological conditions, and R3 denotes lower al~yl, and functional groups which may be present in an acyl radical Rla, such as amino~ carboxyl, hydro~yl and/or sulpho, are usually in the free form, or salts of such compounds having salt-forming groups, are effecti~e, on parenteral and/or oral administration) against micro-organisms~ such as Gram-positive bacteria, for example Sta~hy1ococcus aureus, Streptococcu_ ~y~ and ~ , (for example in mice at doses of abou~ 0.001 to about 0~02 g/kg, gi~en subcutaneousl~
or perorally), and Gram-negative bacteria, for example ~ch~ b~!L~ L~ yc~g~, ~b b~__. DC~Y~ Y!~ a~ a~:b_: y4~yaYy, Proteus vul~aris ~LY~Y~ _},_~ and Proteus mirabilis, (for example in mice at doses of about 0.001 to about 0~15 g/kg given subcutaneously or perorally), and especially also against penicillin-resist-ant bacteria, and are of low toxicity. These new compounds can therefore be used, for example in the fo~m of preparations having an antibiotic action 9 for the treatment o~ corres-ponding infections.
Compounds of the formula I3 or l-oxides of compounds of the formula IA, wherein Rla, ~lb, R2 and R3 have the mean-ings indicated in the context of the formula IA, or compounds of the formula IA wherein R~ has the abo~ementioned meaning s~
- ~3 -and the radicals Rla and Rlb represent hydrogen, or Rla denotes an amino protective group which differs from an acyl radical occurring in pharmacologically active N-acyl deriva-tives of 6~-amino-penam-3-carboxylic acid compounds or 7~-amin^o-~-cephem-4-carbo~lic acid compounds and Rl denotes hydrogen, or Rla and Rlb together represent a divalent amino protective group which differs ~rom a l~oxo-3-aza-1,4-butylene radical which i~ pre~erably substituted in the 2-position, for example by an aromatic or heterocyclic radical, and preferably substituted in the 4-position, for example by 2 lower alkyls, such as methyl, and R2 represents hydroxyl, or Rla and Rlb have the abovementioned m~anings, R2 represents a radical R2A
which, together with the -C(=O)- grouping, forms a protected carboxyl group which preferabl~ can be split easily~ a carbox-yl group protected in thls way differinO from a physiologically splittable carboxyl group, and R3 has the abovementioned mean-ings, are valuable intermediate products which can be con-verted in a simple manner, for example as will be described below, into the abovementioned pharmacologically active compounds.
The invention relates in particular to intermediates useful for the manufacture of 3-cephem compounds of the ~ormula IA, wherein Rla denotes hydrogen or preferably an acyl radical contained in a ~erment atively obtainable (that is to say naturally occurring} or biosynthetically, semi-synth~tically or total-synthetically obtainable, ~n particular phar~acologically active, such as highly active, N-acyl derivative o~ a 6~-amino-penam-~-~ 5 ~
carboxylic acid oompound or 7~amino~-cephem-4-carboxylic acid compound, such as one of the abovementioned acyl radi-cals of the formula A, in which RI, RII, RIII and n above all have the preferred meanings, and Rlb represents hydrogen, or wherein Rla and Rlb together represent a lloxo-3-aza-1,4 butylene radical which is preferably substituted in the 2-position~ for example by an aromatic or heterocyclic radical, such as phenyl, and preferably substituted in the 4-position, for examplebytwo lower alkyls, such as methyl, R2 represents hydroxyl9 lower al~oxy which is optionally monosubstituted or polysubstituted, preferably in the ~-position, for example by optionally substituted aryloxy, such as lower alkoxyphenoxy, for example 4-methoxyphenoxy, lower alkanoyloxy, for example acetoxy or pivaloyloxy, a-amino-lower alkanoyloxy, for example glycyloxy, L-valyloxy or L-leuc~loxy, arylcarbonyl, for example ben20yl, or optionally substitu~ed aryl, such as phenyl, lower alkoxyphenyl, ~or example 4 methox~phenyl, nitrophenyl, for example 4-nitrophenyl, or biphenylyl, for example 4-biphenylyl, or in the ~-position by halogen, for example chlorine, bromine or iodine, such as lower alkoxy, for example methoxy, ethoxy 9 n-propoxy, isopropoxy, n-butoxy) ter~-butoxy or tert.-pentoxy, bis-phenoxy-methoxy which is optionally substituted by lower alkoxy, for example bis-4-methoxyphenoxy-methoxy, lower alkanoyloxy-methoxy, for example acetox~methoxy or pivaloyloxymethoxy, ~-amino-lower al~anoyl-oxy-methoxy, for example glycyloxymethoxy, phenacyloxy, option-ally substituted phe~yl-lower alkoxy, especially l-phenyl-lower alkoxy, such as phenylmethoxy, it being possible for such radicals to contain 1-3 phenyl radicals which are option-~ 3 - ~15 -ally substituted, for exa~ple by lower alkoxy, such as meth-oxy, nitro or phenyl, for e~ample benzyloxy, 4-metho~J
benzyloxy, 2-biphenylyl-2-propoxy, 4-nitro-benzylo~y, diphenyl-methoxy, 4,4'-dimethoxy~diphenylmethoxy or trityloxy, or 2-halogeno-lower alko~y, for example 2,2~2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy~ and a}so repres-ents 2-phthalidyloxy, as well as acyloxy, such as lower alkoxy-carbonyloxy, for example methoxycarbonyloxy or ethoxycarbonyl-oxy, or lower alkanoyloxy, for example acetoxy or pivaloyloxy, tri-lower alkylsilyloxy, for example trimethylsilyloxy, or amino or hydrazino which are optionally substituted, for example by lower alkyl, such as methyl, or hydroxyl, for example amino, lower alkylamino or di-lower alkylamino, such a~ methylamino or dimethylamino, hydrazino or 2-lower alkyl-hydrazino or 2,2-di-lower alkylhydrazino, for example 2-methyl-hydrazino or 2,2-dimethylhydraz~nQ, or represents hydroxyl-amino,.~nd R3 represents hydrogen, lower alkyl, especially methyl, or benzyl or diphenylmethyl which are optio~ally sub-stituted, ~or example by halogen or lower alkoxy, as well as the 1-oxides thereof and also the corresponding 2-cephem com-pounds of the formula IB, or salts of such com?ounds ha~ing salt-forming groups.
Above all, in a 3-cephem compound of the formula IA, and in a corresponding 2-cephem compound o~ the formula IB, and also in a l-oxide of a 3-cephem compound of the formula ~A, or in a salt of such a compound having salt-forming groups, Rla represents ~ydrogen or an acyl radical contained in fermentatively obtainable ~that is to say naturally occur-ring) or biosynthetically obtainable N-~cyl derivatives o~

5S~IL
- ~6 -6~-amino-penam-3-carboxylic acid compounds or 7~-amino-3-cephem-4-carboxylic acid compounds, especially an acyl radical of the ~ormula A7 wherein RI, RII, RIII and n above all have the preferred meanings, such as a phenylacetyl or phenoxy-acetyl radical which is optionally substituted, for example by hydroxyl, and also a lower alkanoyl or lower alkenoyl radical which is optionally substituted, for example by lower alkyl-thio or lower alkenylthio as well as by optionally substituted, such as acylated, amino and/or functionally modified9 such as esterified 9 carboxyl, for example 4-hydroxy-phenylacetyl, hexanoyl, oct~noyl or n-butylthioacetyl, and especially 5-amino-5~carboxy-valeryl, wherein tho amino groups and/or the carboxyl groups are optionally protected and are present, for e~ample, as acylamino or, ~espectively, esterified carboxyl, phenylacetyl or phenoxyacetyl, or an acyl radical occurring in highly active N-acyl derivatives of 6~-amino-penam-3-carboxylic acid compollnds or 7~-amino-3-cephem-4-carboxylic acid com-pounds, especially an acyl radical o~ the formula A, wherein RI, RII, RIII and n above all have the preferred meanings, such as formyl, 2-halogeno-ethylcarbamoyl, for example 2-chloroethylcarbamoyl 9 cyanoacetyl, phenylacetyl, thienylacetyl, for example 2-thienylacetyl, or tetrazolylacetyl, for example l-tetrazolylacetyl, but especially acetyl which is substituted in the a~position by a cyclic, such as a cycloaliphatic, aromatic or heterocyclic, above all monocyclic, radical and by a functional group, above all amino, carboxyl, sulpho or hydroxyl groups, especially phenylglycyl, wherein phenyl

5~

represents phenyl which is optionally substituted, for example by optionally protected hydroxyl~ such as acyloxy, for example optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoylo~y, and/or by haiogen1 for example chlorine, for example phenyl, or 3- or 4-h~droxy-phenyl, 3-chloro-4-hydroxy-phenyl or 3,5-dichloro-4-hydroxy-phenyl (optionally also with a protected, such as acylated, hydroxyl group), and wherein the amino group can optionally also be substituted and represents, for exa~ple, a sulphoamino group which is option-ally present in the LOrm of a salt, or an amino group which contai~s, as substituents, a trityl group which can be split of~ hydrolytically, or above all an acyl group, such as an optionally substituted carbamoyl group, such as an optionally substituted ureidocarbon~l group, for example ureidocarbonyl vr N'-trichloromethylureidocarbonyl, or ~n optionally substitu-ted guanidinocarbonyl group, for example guanidinocarbonyl, or an acyl radical which can ~e split off, preferably easily, for example on treatment with an acid agent9 such as trifluoro-acetic acid, and also reductively, such as on treatment with a chemical reducing agent, such as zinc in the preser~ce of aqueous acetic acid, or with catalytic hydrogen? or hydrolyti-cally, or an acyl radical which can be converted into such a radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as one of those mentioned above, for example optionally halogen-substituted or benzoyl-substituted lower alkoxycarbonyl radicals, for example tert.-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbo~yl, - 48 ~
2-bromoethoxycarbonyl 9 2-iodoethoxycarbonyl, or phenacyloxy-carbonyl, optionally lower alkoxy-substituted or nitro-substituted phenyl-lower alkoxycarbonyl, ~or example 4-methoxy-benzoyloxycarbonyl or diphenylmethoxycarbonyl, or of a carbonic acid hal~-amide, such as carbamoyl or N-methylcarbamoyl, and also an arylthio or aryl lower alkylthio radical which can be split off with a nucleophilic reagent7 such as hydrocyanic acid, sulphurous acid or thioacetic acid amide, for example 2-nitro-phenylthio or tritylthio, an arylsulphonyl radical which can be split off by means of electrolytic reduction, for example 4-methylphenylsulphonyl, or a l-lower alkoxycarbonyl-2-pro-pylidene radical or l-lower alkanoyl-2 propylidene radical which can be split o~f with an acid agen-t, such as formic acid or an aqueous mineral acid, ~or example hydrochloric acid or phosphoric acid, for example l-ethoxycarbonyl-2-propylidene~and also represents a-(1,4 cyclohexadienyl)-glycyl~ a~ cyclohexenyl)-glycyl, a-thienylglycyl, such as a-2- or a-3-thienylglycyl, a-furylglycyl, such as a-2-furylglycyl, a-isothiazolylglycyl, such as a-4~isothiazolylglycyl, it being possible, in such radicals, for the amino group to be substituted or protected, ~or example as indicated for a phenylglycyl radlcal, and also a-carboxy-phenylacetyl or a-carboxy-thienylacetyl, for example a-carboxy-2-thie~ylacetyl (optionally wi~h a functionally modified carboxyl group, for example a carboxyl group present in the form of a salt, such as in the form o~ a sodium salt, or in the form of an ester, such as in the form o~ a lower alkyl ester, for example a methyl or ethyl esler, or a phenyl-lower alkyl ester, for exa~ple a diphenylmethyl ester), -sulpho-phenylacetyl (optionally also with a sulpho group which is functionally modified, ~or example like the carboxyl group) 9 a-phosphono-, -O-methyi-phosphono- or a-~,O'-dimethyl-phosphono-phenylacetyl, or a-hydroxy-phenylacetyl (optionally with a fu~ctionally modified hydroxyl group, especially with an acyloxy group, wherein acyl denotes an acyl radical which can be split o~f, preferably easily, for example on treatment with an acid agent, such as tri~luoroacetic acid, or with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid~ or an acyl radical which can be converted into such a radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as one of those mentioned above~
~or example a lower alkoxycarbonyl radical which i~ optionally substituted by halogen or ben~oyl, for example 2,2,2-tri-chloroethoxycarbonyl~ 2-chloroethoxycarbonyl, 2-bromoethoxy-carbonyl, 2-iodoethoxycarbonyl, tert.-butox~carbonyl or phen-acyloxycarbonyl, and also formyl), as well as l-amino-cyclo-hexylcarbo~yl, aminomethylphenylacetyl, such as 2- or 4-amino-methylphenylacety~ or amino-pyridiniumacetyl, ~or example 4 aminopyridiniumacetyl (optionally also with an amino group which is substituted, for example as indicated above), or pyridylthioace-tyl, for example 4-pyridylthioacetyl, and Rlb represents hydroge~, or Rla and Rlb together represent a 1-oxo-3-aza-1,4-butylene radical, which is preferably substituted in the 2-position by phenyl, which is optionally substituted by protected hydroxyl, such as acyloxy, for example option-S5~- 50 -ally halogen-substituted lower alkoxycarbonyloxr or lower alkanoyloxy, and/or by halogen, Por example chlorine 9 for example phenyl, or 3- or 4-hydroxy-phenyl, 3-chloro-4-hydroxy-phenyl or 3,5-dichloro-4-hydroxy-phenyl ~optionally also with a protected hydroxyl group~.for example a hydroxyl group acylated as indica~ed above) and ~hich in the 4-position optionally contains two lower alkyl, such as methyl, and R2 represents hydroxyl, lower alkoxy, especial:Ly a-poly-br~ched lower alkoxy, for example tert.-butoxy, and also methoxy or ethoxy, 2-haloge~o-lower alkoxy, for example 2,2,2-trich3.oro-ethoxy, 2-iodoethoxy~ or 2-chloroethoxy or 2-bromoethoxy which can e2sily be converted into the latter, phenacyloxy, l-phenrl-lower alko~y with 1-3 phenyl radicals, which are optionally substituted by lower alkox~ or nitro, for example 4-methoxy-benzyloxy, 4-nitrobenzyloxr, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy 9 lower alkanoyloxymethoxy, for example acetoxymethoxy or pivaloyloxymethoxy, a-amino-lower alkanoylo~ymethoxy, for example glycyloxymethoxy, 2-phthali-dyloxymethoxy, lower alkoxycarbonyloxy, ~or example ethoxy-carbonyloxy, or lower alkanoyloxy, ~or example acetoxy, and also tri-lower alkylsilyloxy, for example trimethylsilyloxy, and R3 represents hydrogen, lower alkyl, especially met~yl, or benzyl or diphenylmethyl which are optionally substituted, for example by halogen, such as chlorine or bromine, or ower al~oxr. such as m~thoxy, The invention above all relates to intermediates of the formula II useful for the manufacture of 3-cephem compounds of the formula IA, wherein Rla denotes hydrogen or an acyl group of the formula (B) Ra ~)m--CH--C --wherein Ra denotes phenyl or hydroxyphenyl, for example 3- or 4-hydroxyphenyl, and also hydroxy-chlorophenyl, for example 3-chloro-4-hydroxyphenyl or ~,5-dichloro-4-hydroxyphenyl, it being possible for hydroxy substituents in such radicals to be protected by acyl radicals, such as optionally halogenated lower alkoxycarbonyl radicals, ~or example tert. butoxycarbon-yl or 2,2,~-trichloroethoxycarbonyl, as well as thienyl, for example 2~ or 3-thienyl, and also pyridyl, for example 4-pyridyl, aminopyridinium, for example 4-aminopyridini~, furyl, for example 2-furyl, isothiazolyl, for example 4-isothiazolyl 9 or tetrazolyl, for example l-tetrazolyl, or also 1,4-cyclo-hexadienyl or l-cyclohexenyl, X represents oxygen or sulphur~
m represents 0 or 1 and Rb represents hydrogen or, when m represent~ 0, Rb represents amino, as well as protected amino, such as acylamino, for example a-poly-branched lower alkoxy-carbonylamino, such as tert.-butoxycarbonylamino, or 2-halogeno-lower alkoxycarbonylamino, for example 2,2,2-tri-chloroethoxycarbonylamino t 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino, or optionally lower alko~y-substitu-ted or nitro-substituted phenyl-lower alkoxycarbonylamino, ~or example 4-methoxybenzyloxycarbonylamlno or diphenylme~hoxy-5~'~

carbonylamino, or 3-guanylureido, and also sulphoamino or tritylamino, as well as arylthioamino, for example 2-nitro-phenylthio~mino, arylsulphonylamino, for example 4-methyl-phenylsulphonylamino~ or l-lower alkoxycarbonyl~-2-propylidene-amino, for sxam~le l-ethoxycarbonyl-2-propylideneamino, carboxyl or carboxyl present in the form of a salt, ~or example in the form o~ an alkali metal salt, such as in the form of the sodium salt, as well as protected carboxyl, for example esteri-fied carboxyl, such as phenyl-lower alkoxycarbo~yl, for example diphenylmethoxycarbonyl, sulpho or sulpho present in the form of a salt, ~or example in the form o~ an alkali metal salt, such as in the form of the sodium salt, as well as protected sulpho, hydroxyl? as well as protected hydroxyl, such as acyloxy, for example a-poly-branched lower alko~ycarbonyloxy, such as tert.-butox~carbonyloxy, or 2-halogeno-lower alkoxy-carbonyloxy, such as 2,2~2-trichloroethoxycarbonyloxy, 2-iodo-ethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, and also formyl-oxy, or O-lower alkylphosphono or O,O' di-lower alXylphosphono, for example O-methylphosphono or O,O'-d~methylphosphono, or denotes a 5-amino-5-carboxy-Yaleryl radical, wherein the amino groups and/or carboxyl groups can also be protected and are present, ~or example, as acylamino, for example lower alkanoyl-amino, such as acetylamino, haloge~o-lower alkanoyl~;no, such as dichloroacetylamino, benzoylamino or phthaloylamino, or, respectively, as esterified carboxyl, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, a~d m preferably denotes 1 when Ra represents phenyl, hydroxyphenyl, 55f~

hydroxychlorophenyl or pyridyl and m denotes O and Rb differs from hydrogen when Ra represents phenyl, hydroxyphenyl, hydroxy~chlorophenyl, thienyl, furyl, isothiazolyl, 1,4-cyclohexadie~yl or l-cyclohexenyl, Rlb denotes hydrogen, R2 above all represents hydroxyl an~ also represents lower alkoxy, especially a-poly-branched lower alkoxy, ~or example tert.-buto~y, 2-halogeno-lower alkogy, for example 2,2,2-tri-chloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or diphenylmeth-oxy which is optionally substituted, for exa~ple by lower alkoxy, for example methoxy~ for example diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, and also tri-lower alkylsilyloxy, for example trimethylsilylox~, and R~ denotes hydragen, lower alkyl, for example methyl, ethyl or n-butyl, as well as benzyl or diphenylmethyl which is optionally substituted, for example by halogen, such as chlorine or brominey or lower alkoxy, such as methoxy, as well as the l-oxides of such 3-cephem compounds of the ~ormula IA and also the corresponding 2-cephem com-pounds of the formula IB, or salts, especially pharmaceutically usable, non-toxic salts, o~ such compounds having salt-forming groups, such as al~ali metal salts, for example sodium sal~s, or alkaline earth metal salts, for example calcium salts, or ammonium salts, including those with amines, of compounds wherein R2 represents hydroxyl and which contain a free a~ino group in the acyl radical of the formula B.
Above all~ in 3-cephem compounds of the formula IA, and also in corresponding 2-cephem compounds o~ the formula IB, as well as in salts, especially in phar~aceutically usable, S5f~

non-toxic salts, of such compounds having salt--forming groups, as in the salts mentioned in the preceding paragraph9 Rla represents hydrogen or the acyl radical of the formula B, wherein Ra denotes phenyl, as well as hydro~phenyl, ~or example 4-~ydroxy-phenyl, thienyl, for exa~ple 2- or 3-thienyl, 4-isothiazolyl, 1,4-cyclohexadienyl or l-cyclohexenyl, X
denotes oxygen, m denotes O or 1 and Rb denotes hydrogen or, when m denotes 0, amino, as well as protected amino, such as acylamino, ~or example a-poly-branched lower alkoxycarbonyl-amino, sl~ch as tert.-butoxycarbonylamino, or 2-halogeno-lower alkoxycarbon~lamino, for example 2,292-trichloroethoxycarbon-ylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycarbo~lyl-amino, or optionally lower alkoxy-sub~tituted or nitro-substi-tuted phenyl-lower alkoxycarbonylamino, for example 4-methoxy~-benzyloxycarbonylamino, or hydroxyl, as well as protected hydroxyl, such as acyloxy, for example -poly-branched lower alkox~carbonyloxy, such as tert.-butoxycarbonyloxy, or 2-halogeno-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxy-carbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyl-oxy, and also formyloxy, or represents a 5-amino-5-carboxy-valeryl radical, wherein the amino group and the carboxyl group can also be protected and are present, for example~ as acylamino, for example lower alkanoylamino, such as acetyl-amino, halogeno-lower alk2noylamino, such as dichloroacetyl-amino, benzoylamino, or phthaloylamino, or, respectively, as esterified carboxyl, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, and m preferably denotes 1 when Ra i5 phenyl or hydroxyphenyl, Rlb represents hydrogen, R2 above all denotes hydroxyl and also lower a~koxy which is optionally substituted in the 2-position by halogen, for ex~mple chlorine, bromine or iodine, especially a-poly~-branched lower alkoxy, for example tert~-butoxy, or 2~halogeno-lower aIkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromo-e~hoxy, or diphenylmethoxy optionally subst:ituted by lower alkoxy, such as metho~y, for example dipheTlylmetho~y, or 4,4'-dimethoxy-diphenylmethoxy~ or p-nitrobenzyloxy, and also tri-lower alkylsilyloxy, ~or example trimethylsilyloxy, ~nd R3 denotes hydrogen, lower alkyl, especially methyl,or a ben2yl or diphen~lmethyl group which is optionally substituted by halogen~ for example chlorine or bromine, or lower aIkoxy, for example methox~
The invention above all serves for the manufacture of intermediates of the formula II useful for the manufacture of 7~-(D-~-amino-a-Ra-acetylamino)-3-lower alkoxy-3-cephem-4-7~-(D-a-am~no-a-Ra-acetylamino)-3-lower alkoxy-3-cephem-4-~carboxylic acids, wherein Ra represents phenyl, 4-hydroxy-phenyl, 2-thienyl, 1,4 cyclohexadienyl or l-cyclohexenvl, and lower alkoxy contains up to 4 carbon atoms and represents, for example, ethoxy or n-butoxy, but above all methoxy, and the inner salts thereo~, and above all of 3-methoxy-7~-(D-a-phenylglycylamino)-3-cephem-4-carboxylic acid and its inner saltg and for the manufacture of 3-hydroxy-3-cephem-4-carboxylic acid compounds which can serve as intermediate pro-ducts for the manufacture of these 3-lower alkoxy-3-cephem-4-carboxylic acid compounds; in the abovementioned concentrat-ions, especially on oral administration, these 3-lower alkoxy-compounds display excellent antibiotic properties, both against Gram-negative and especially against Gram-negative bacteria, and are of low toxicity.

The process according to the in~ention is dis~inguis~-ed ! relative to previously known processes, by the fact that it starts from inexpensive, easily accessible starting mater-ials, such as, in particular, the l-oxides of the fermentative-ly obtainable penicillins G or V and of 6-~ino-penicillanic acid, the reactive groups of which can be protected in ~ny known manner and can easily.be liberated again after the re-action, and that the manufacture of the intermediate products required according to the invention takes place with high yields. In particular9 the process al50 permits the direct manufacture of compounds of the formula I wherein R3 denote~ hydrogen, without a hydroxyl protective group R3 having to be split off.
The starting materials of the formula I.I, used accord-ing to the in~ention, can be manufactured, for example, in accordance with the following equation.

s'_~

~ O ~a ~N H H '~ N H H S
hl ~ S ~CH3 stag~ R

i~ 3 . \rC-CH~
~IV) I)=C~ ) O= C E~2 Ya Y = - S -R4 stage ~a/ Vb Y = - S02 -R5 stage 2 ~:H ~ei~ 3 ~ 3 ~C ~
~VII) o=d ~
YIIa: Y - -S-R VIa Y = -S-R4 VIIb : Y = -SO ~-R5 ~b Y - -S02-r~5 i s~ag~- 4 \~age 5a H3 ~? ~ H3 R4 O ~' O ?~ ' /
\FC----O-S02-~5 ~r~_N
(VIII) O= C-R2. ~Tl) O= t:-R2 R4 YIIIa: Y = -S-R4 IIa: Y = -S-~4 VlIIb: Y - -SO -R IIb Y = -S02-R5 5~

-~ 58 -Starting compounds o~ the formula IV are known or can be manu~actured according to known processes.
Compounds of the formula Va are also ~no~n or can be manufactured according to Netherlands Patent Specification 72/Q8671.
Compou~ds of the formula Vb can be obtained from com-pounds of the formula IV by reaction with a sulphinic acid o~
the formula HSO~-R5 or a sulpho~yl cyanide of ~he for~ula N~C-S02-R5. m e reaction is _ ~
carried out in a~ inert solvent or solvent mixture, for example an optionally halo~enated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, such as pentane, hexane, cyclohexane, benzene, toluene, methylene chloride, chloroform or chlorobenzene, an aliphatic, cycloaliphatic or aromatic alcohol, such as a lower alkanol, for example methanol or ethanol5 cyclohexanol or phenol, a polyhydroxy compound, for example a polyhydroxyalkane, such as a dihydro~y-lower alkanel for example ethylene glycol or propylene glycol, a lower ketone, such as acetone or meth~l ethyl ketone, an ether-like solvent, such as diethyl ether, dioxane or tetra-hydrofurane, a lower carboxylic acid amide, such as dimethyl-formamide or dimethylacetamide, a lower dialkylsulphoxide, such as dimethylsulphoxide and the like or mixtures thereof.
The reaction is carried out at room temperature or preferably at elevated temperature, for example at the boiling point of the solvent employed, if desired in an inert gas atmosphere, such as a nitrogen atmosphere.

s' - 5~ -The reaction with the sulphonyl cyanide of the formula N--C-S02-~ is accelerated by the addition of compounds which provide h~logen anions. Examples of suitable compounds which provide halogen anions are quaternary ammonium halides, especially chlorides and bromides, such as tetra-lower alkyl-ammonium halides which are optionally substitute~ at the lower alkyl groups, for example monosubstituted o:r polysubstituted by aryl~ such as phenyl, suGh as tetraethylammonium chloride or bromide or benzyltriethylammonium chloride or bromide.
m e compounds which provide halogen anions are added in amounts o~ about 1 to about 50 mol per cent, preferably of about 2 to about 5 mol per cent.
Compounds o~ ~he formula Vb Ican also be obtained by reacting a compound of the ~ormula IV with a hea~y metal sulphinate of the ~ormula ~ ( S2~R~)nJwherein M
represents a heavy metal cation and n denotes the v~lency of this cation. Suitable heavy metal sulphinates ~ are in particular those which have a higher solubili~ product in the reaction medium used than the heavy metal compounds o~ the formula ~ I(-S-R4)n which are formed during the reaction. Suitable heavy metal cations are, in particular, those which form particularly sparing-ly soluble sulphides. These include, for example, ~he monovalent or divalent cations of copper 3 mercury, silver and tin, copper~+ and silver+ cations being preferred.
The heavy metal sulphi~ate or heavy metal thiosulphon-ate can either be employed as such or can be formed in si~u during the reaction, for example from a sulphinic acid of the :~5S'l formllla HS02-R~ or from a soluble salt thereof, for example an alkali metal salt, such as a sodium salt, and a heavy metal salt, the solubility product o~ which is greater than that of the heavy metal sulphinate or heavy metal thiosulphonate formed, for example a heavy metal nitrate, acetate or sulphate, for example silver nitrate, mercury-Il diacetate or copper-II
sulphate, or a soluble chloride, such as tir..-II chloride di-hydrate.
The reaction of a compound of the formula Va with the heavy metal sulphinate of the formula I~n~( S02-R5)n can be carried out in an inert organic solvent, in water or i.n a solvent mixture consisting o~ water and a water-miscible solvent. Suitable inert organic solvents are, for examnle, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene or xylene, or.
aliphatic,.icycloaliphatic or aromatic alcohols, such as lower alkanols, for example methanol or ethanol, cyclohexanol or phenol, polyhydroxy compounds, such as polyhydrox~alkanes, for example dihydroxy-lower alkanes, such as ethylene glycol or propylene glycol, carboxylic acid esters, for example lower carboxylic acid lower alkyl esters, such as ethyl acetate, lower ketones, such as acetone or methyl ethyl ketone, ether-like solvents, such as dioxane or tetrahydrofurane or poly-ethers, such as dimethoxyethane, lower carboxylic acid amides, such as dimethylformamide, lower alkylnitriles, such as acetonitrile, or lower sulphoxi~es, such as dimethylsulphoxide.

S~.~

-- o l me reaction usuall~ proceeds considerably more rapidly in water or especially in mixtures of ~ater and one of the sol-vents mentionedy including emul~ions, than in the organic solvents alone~
m e reaction temperature is usually room temperature but can be lowered in order to slow down the reaction or raised, say up to the boiling point of the sol~ent employed, to accelerate the reaction, it being possible to carry out the reaction under normal pressure or elevated pressure.
In a resulting compound of the formula V, a group Rla, Rlb or R2A can be converted in~o another group Rla9 Rl~ or R2 ~ by various additional measures which are in them-selves known.

In stage 2 and 3 or 2a, a compound of the formula V
can be con~erted into a compound of the formula VIl by o~i-dative degradation of the methylene group to an oxo group.
The oxidative elimination of the methylene group in compounds of the for~ula V, with the ~ormation of an oxo group, can be carried out by forming an ozonide compound of the fo~mula Vl by treatment with ozone. In this reaction, ozone is usually e~ployed in the presence of a solvent, such as an alcohol, for example a lower a~kanol, such as methanol or ethanol, a ketone, for example a lower alkanone, such as acetone~ an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, for example a halogeno-lower alkane, such as methylene chloride or carbon tetrachloride, or of a s~a solvent mixture, including an aqueous ~ixture, and with cool-ing or slight warming, for example at tempera-tures from about -90C to about ~40C~
An ozonide of the formula ~Ia, obtained as an inter-medi~te product, can, optionally without isolation, be con-verted into a compound of the formula VIb by reaction with a heavy metal sulphinate of the formula Mn ( SO-R5) , analogously to the conversion of compounds of the formula Va to compound~ of the formula Vb, An ozonide of the formula V can be split by reduction in stage 3 to give a compound o~ the ~ormula VII, for which reaction it is possible to use catalytically activated hydro-gen, f`or example hydrogen in the presence of a heavy metal hydrogenation catalyst, such as a nickel catalyst and also a palladium catalyst 9 preferably on a suitable carrier, such as calcium carbonate or charcoal, or chemical reducing agents, such as reducing heavy metals, including heavy metal alloys or heavy metal amalgams, for example zinc, in the presence of a hydrogen donor, such as an acid, for example acetic acid, or of an alcohol, for axample a lower alkanol, reducing inor-ganic salts, such as alkali metal iodides~ for example sodium iodide, in the presence of a hydrogen donor, such as an acid, for example acetic acid, or a reducing sulphide co~pound, such as a di-lower alkyl sulphid , ~or exa~ple dimethyl sulph-ide, a reducing organic phosphorus compound, such as a phos-phine, which optionally can contain substituted aliphatic or aromatic hydrocarbon radicals as substituents, such as tri-lower alkylphosphines, for example tri-n-butyl-phosphine, or triarylphosphines~ for example triphenylphosphine, a~d also pho~phites, which optionall~ contain substituted aliphatic hydrocarbon radicals as sub~tituents, such as tri-lower alkyl-phosphites, usually in the form of correspo~ldLng alcohol adduct compounds, such a~ trimethyl-phosphite, or phosphorous acid triamides, which optionally contain substituted aliphatic hydrocarbon radicals as substituents, such as hexa lower alkyl-phosphorous acid triamides, for example hexamethylphosphorous acid triamide, the latter preferably being in the fo~ of` a metha~ol adduct, or tetracyanoethylene. Splittin~ of the ozonide, which is usually not isQlatad, normally takes place under conditions which are employed for its manufacture, that is to say in the presence of a suitable solvent or solvent mixture and with cooling or slig~t warming.
Enol compounds of the formula VII can also be present in the tautomeric keto form.
A~ enol compound of the formula VIIa can be converted into a compound of the formula VIIb by reaction with a heavy metal sulphinate of the formula Mn ( S02-R5)n, analogously to the conversion of compounds of the formula Va ~o compounds of the formula Vb.
In a resulting compound of the ~ormula VII, a group R1a, R1b or R2A can be converted into another group Rla, R

Lf~5S~

or R2 by various additional measures which are in them-selves known.
In the 4th stage, a resulting enol compound of the formula YII is converted into a compound of the formula VIII
by esterification.
In order to manufacture sulphonic acid esters of the ~ormula VIII, a compound o~ the formula VII is esteri~ied with a reactive functional derivative of a sulphonic acid of the formula HO-S~2-R5, wherein R5 has the meaning indicated for R5 under Y.
- Within the scope of meaning~ for R59 these two groups can be either identical or differe~t in a compound of the formula VIII.
The reactive functional derivatives of a sulphonic acid of the formula HO-S02-R~ which are used are, for example, their reactive anh~drides, especially the mixed anhydrides with hydrogen halide acids, for example their chlcrides, such as mesyl chloride and p-toluenesulphonic acid chloride.
The esterification is carried out, preferably in the presence of an organic tertiary nitrogen base, such as pyri-dine~ triethylamine or ethyl-diisopropylamine, in a suitable inert solvent, such as an aliphatic, cycloaliph~tic or aroma-tic hydrocarbon, such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon, for example methylene chloride, or an ether, such as a di-lower alkyl ether, for example diethyl ether, or a cyclic ether, for 5~

example tetrahydrofurane or dioxane, or in a solvent mlxture, and, depending on the reacti~ity of the esterlfying reagent, with cooling, at room temperature or with slight warming; that is to say at temperatures from about -10C to about +50C, and also, if necessa~y, in a closed vessel and/or under an inert gas atmosphere, for example a nitrogen atmosphere.
The sulphonic acid ester of the formula VIII can either be isolated or can be further processed in the same reaction mixture.
A compound of the formula VIIIa can be converted into a compound of the formula VIIIb by reaction with a heavy metal sulphinate of the formula Mn ( S02-R5)n, analo~ously to the conversion of compounds of the formula Va into compounds of the formula Vb~

In a compound of the formula VIII, a group R~' 1 or R2 can be converted into another group Rl, Rl or R2 ' by various additionall measures which are in themselves known. According to process of the invention a sulphonic acid ester of the formula VIII is converted into a compound of the formula II by treatment with a primary or secondary amine of the formula H-N(R4)(R4).
The amination is caxried out in a suitable inert organic solvent, such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon~ such as methylene chloride, or an ether, such as a di-lower alkyl ether, for example diethyl ether, or a cyclic ether, for example tetra-hydrofurane or dioxane, or in a solvent mixture a~d, depending on the reactivity of the group -0-S02-R5 and of the amine used, at temperatures between about -10C and about 50C~ preferably at about 0C to about 20C, if necessary in a closed vessel and/or under an inert gas atmosphere, for example a nitrogen atmosphere.
A compound of the formula II can also be obtained in stage 5a by treating a compound of the for~ula VII with a salt of a primary or secondary amine of the formula H-N(R4)(R4), for example a hydrogen halide addition salt, such as a hydrochloride, in the presence of a tertiary base, such as pyrid~ne, in a suitable sol~ent, such as a lower alcohol, for ~xample absolute ethanol, at te~peratures from about 20 to about 100C~ preferably from about 40 to about 60C.
A compound of the formula IIa can be converted into a compound of the formula IIb by reaction with a heavy metal sulphinate of the formula Mn~( S02-R5)n - -analogously to the conversion of compounds of the formula Vato compounds of the formula ~b In a resulting compound of the formula II, it is possible, taking the enamine function into account~ to convert a group Rla, Rlb or RzA into another group Rla, Rlb or R2 .
In the context of the present description, the organic radicals described as "lo-wer'l contain, unless expressly de-fined, up to 7, preferably up to 4, carbon atoms; acyl radicals contain up to 20, preferably up to 12 and above all up to 7, carbon atoms.

5~i~

Th~ examples which follow serve to illustrate the invention; temperatures are given in degrees Centigrade.
The cephem compounds men~ioned in the examples possess the R-configuration in the 6-position and 7-position and the azetidinone compounds mentioned in the examDles possess the R-configuration in the 3-position and 4-position.
Example 1 A solution of 160 mg (0.23 mmol) of a mixture con-sisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-pyrrolidyl)-crotonic acid p-nitro-benzyl ester and the corresponding iqocrotonic acid ester in 3 ml of dry acetonitrile is heated under nitrogen for about 4 hours at 80G until no ~urther starting material can be detected by thin layer chromatograph~ (silica gel; toluene/
ethyl acetate, 1:1). The heating bath is remo~ed, p-toluenesulphonic acid (about 0.23 mmol) and 0.2 ml of water are added to the reaction mixture containin~ the 7~-phenoxy-acetamido-3-pyrrolidino-cephem-4-carboxylic acid p-nitro-benzyl ester and the mixture is stlrred for a ~urther 2 hours at room temperature. The reaction mixture is dilutecl with benzene, washed with water, dried over sodium sulph~te a~d evaporated in vacuo. The residue is triturated at 0C
with diethyl ether and gives the pale yellow 7~-phenoxyacet-amido-3-hydroxy-3-cephem-4-carboxylic acid ~-nitrobenzyl ester.
IR spectrum (methylene chloride): characteristic bands at 2.95; 3.3; 5.6; 5.75 (sh); 5.9; 5.95 (sh); 6.55; 7.45; 8.15 and 8.3~; NMR spectrum ~deuterochloroform): ~ in ppm: 3.4 (ZH, 2, J = 17 Hz); 4.57 (2H, s); 5.06 (lH, c; J=5;~z);

55~

5.35 (2H, q, J = 14 H~); 5.7 (lH, dd, J - 5.10 Hz); 6.8-~.4 (lOH, c) and 11.4 (lH, br.s.).
The starting materials c~n be obtained as follows:
a) A solution of 36.6 0 (0.1 mol) of 6-phenoxyacetamido-penicillanic acid l~-oxide, 11.1 ml (0,11 mol) of triethyl-amine and 23.8 g (0.11 mol) of p-nitrobenzy] bromide in 200 ml of dimethylformamide is stirred under nitrogen for 4 hours at room tempQrature. The reaction solution is then intro-duced into 1.5 1 of ice water and the precipitate is filtered off, dried and recrystallised twice from ethyl acetate/methyl-ene chloride. The ~olourless crystalline 6-phenoxyacet~m;do-penicillanic acid p-nitrobenzyl ester l~-oxide melts at 1.79-180C.
b) A solution of 5.01 g (10 mmols) o~ 6-phenoxyacetamido~
penicillanic acid p-nitrobenzyl ester l~-oxide and 1.67 g (10 mmols) of 2-mercaptobenzthiazole in 110 ml of dry toluer~e is boiled under reflux in a nitrogen atmosphere for 4 ho~rs.
The solution is concentrated to about 25 ml by distillation and diluted with about 100 1 o~ ether. The product which has separated out is recrystallised from methylene chloride/
ether and 2-~4-(benzthiazol-2-yldithio)-3-pheno~yacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid p-nitrobenzyl ester of melting point 138-141C is obtained.
c) 1.06 g of ~inely powdered silver nitrate are added to a solution of 3.25 g (5.0 mmols) of 2-[4-~benzthiazol-2-yl-dithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid p-nitrobenzyl ester in 200 ml of acetone/water, 9:1 (v/v). Immediately afterwards, a solution of 890 mg (5 mmols) of sodium p-toluenesulphinate in 100 ml of the same solvent mi~ture is introduced (in the course o~ ten minutes).
A pale yellow precipitate forms immediately. After stir-ring for one hour at room ~emperature, the mixture is filtered, wi~h addition of Celite. m e ~iltrate is diluted with water and extracted twice with ether. The combined ether extracts are dried over sodium sulphate and, after concen-trating, give pale yellow, solid 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-methylenebutyric acid p-nitrobenzyl ester. Thin layer chromatogram on silica gel (toluene/ethyl acetate, 2~ Rf value = 0.24; IR spectrum (in CH2C12): characteristic bands at 3,90, 5.55, 5.70, 5.87,

6.23, 6.53, 6.66, 7.40~ 7,50~ 8~10, 8.72, 9.25 a~d 10.95~.
The product can be employed without ~urther purification in the subsequent reactionq m e same compo~ld can also be obtained in accordance with the following methods:
ci) 1.58 g (1.2 e~uivalents) of silver p-toluenesulphina~e are added in portions, in the course of 10 minutes, to a solu-tion of 3.25 g (5.0 mmols~ of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-ylJ-3-methylenebutyric acid p-nitrobenzyl ester in 200 ml of acetone/water9 9:1 (v/v).
The suspension is stirred for one hour at room temperature, ~iltered and further processed as described in ~xample lc).
2-~4-(p]Toluenesulphonylthio)-~-phenoxyacetamido-2-oxoazetidin-l-yl]-~-methylenebutyric acid p-nitrobenzyl ester is obtained in quantitative yield.
Silver p-toluenesulphinate is obtained as a colourless precipitate by combining aqueous solutions of equimolar amounts of silver nitrate ~nd sodium p-toluenesulphinate. The ssL-~- 70 -product is dried in vacuo for 24 hours.
cii) 2-[4-(p-Toluenesulphonylthlo)-3-phenoxyacetamido-2-oxoa~etidin-l-yl]-3-methylenebutyric acid p-nitrobenzyl ester can also be obtained, in quantitative yield 3 analogously to Example lci) from 3.25 g of 2-[4-~benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid p-nitrobenzyl ester and 1.87 g (2 equivalents) of copper-II
di-p-toluenesulphinatel Copper-II di-p-toluenesuiphinate is obtained by re-acting copper sulphate and sodium p-toluenesulphinate (2 equivalents) in water. After ~iltering o~f, the salt is dried in vacuo for 12 hours at 60C.
ciii) 2-[4-(p-Toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-l-yl]-3-methyl-enebutyric acid p-nitrobenzyl ester can also be obtained analogously to Example lci) ~rom 130 mg of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxo-azetidin-l-yl]-3-methylenebutyric acid p-nitrobenzyl ester and 85 mg (2 equivalents) of tin-II di-p-toluenesulphinate.
Tin-II dl-p-toluenesulphinate is obtained by reacting tin-II chloride ~2H20) and sodium p-toluenesulphinate in water. A~ter filtering off and washing with water, the salt is dried in vacuo for about 12 hours at 50-60C.
civ) 2-~4-(p-Toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-l-yl]-3-methylenebutyric acid p-nitrobenzyl ester can also be obtained analogously to Example lci) from 130 mg of 2-~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxo-azetidin-l-yl]-~-methylenQbutyric acid p-nitrobenzyl ester and 102 mg (2 equivalents) of mercu~ -II di-p-toluenesulphin-ate.

s~

Mercury-II di-p-toluenesulphinate is obtained by re-acting mercury-II diace~ate and sodiu p-toluenesulphinate in water. After filtering off and washing with water, the salt is dried in vacuo fvr about 12 hours at 50-60C.
cv)- A solution of 517 mg ~1.02 mmols) of 6-phenoxyacet-amidopenicillanic acid p-nitrobenzyl ester l~-oxide and 187 mg (1.2 mmols) o~ p-toluenesulphinic acid in 10 ml of 1,2-dimethoxyethane (or dioxane) is heated under reflux for 4.5 hours in the presence of 3.5 g of a 3A mole~ular sieve and in a nitrogen atmosphere, after which a further ~08 mg ~1.98 mmols) of p-toluenesulphinic acid~dissolved in 2 ml of 1,2-dimetho~yethane,are added in five portions at 45 minute intervals. After 4.5 hours the reaction mix*ure is poured into 100 ml of 5% strength aqueous sodium bicarbonate solu-tion and the mixture is extracted with e-~hyl acetate. The combined organic phases are washed with ~Yater and saturated aqueous sodium chloride solution~ dried over magnesium sul-phate and evaporated. The residue is chromatographed on silica gel thick layer plates with toluene/ethyl acetate, 2:1, and gives 2 ~4 (p-toluenesulphonylthio)-~-phenoxyacetamido-2-oxoazetidin-l-yl~-3-methylenebutyric acid p-nitrobenzyl ester.
c~i) A mixture of 250 mg (0.5 mmol) of 6-phenoxyacetamido-penicillanic acid p-nitrobenzyl ester l~-oxide, 110 mg (0.61 mmol) of p-toluenesulphonyl cyanide and 5 mg (0.022 mmol) of benzyl-triethylammonium chloride in 2 ml of dry, peroxide-free dioxane is stirred under argon for 4.5 hours at 110C. The solvent is evaporated off in vacuo and the residual yellow oil is chromatographed on acid--~ashed silica gel. Elution Si5~

with 30,o~ ethyl acetate in toluene gives 2-[4-(p-toluene-sulpho~ylthio)-3-phenoxyacetamido-2-oxoazetldin 1-yl)-3-meth~lenebu~yric acid p-nitrobenzyl ester.
cvii) A mixture of 110 mg (0.61 mmol) of p-tolusnesulphonyl cyanide ~d 4.5 mg (0.021 mmol)~of tetraethylammonium bromide in 1 ml of pure dioxane is stirred at 110C for 30 m~nutes, under argon. A suspension of 250 mg (0.5 mmol) of 6-henoxyacetamidopenicillanic acid p-nitrobenzyl ester l~-oxide in 1 ml of dioxa~e is then added and the resulting solution is stirred for 4 hours at 110C, under argon. The solvent is removed in vacuo~ the crude product is dissolved in eth~1 ace-tate and the ~olution is washed with water and saturated aqueous sodium chloride solution. The organic phase is dried with magnesium sulphate and freed from solvent in vacuo a~d gives crude 2-~4-(p-toluenesulphonylthio)-3-phenoxy-acetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid p-nitrobenzyl ester.
d) 1.1 equivalents of ozone are passed into a solution of 1.92 g (3.0 mmols) of 2-~4-(p toluenesulphonylthio)-~-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid p-nitrobenzyl ester in ~0 ml o~ dry methyl acetate, at -78C, in the course of ~3 minutes. Immediately thereafter 9 excess ozone is removed by means of a stream of nitro~en (15 ~inutes at -78C). 2.2 ml of dimethyl sulphide tlO
equivalents) are added and the solution is warmed to room temperat~re. After leaving to stand for 5 hours, the solvent is distilled off in vacuo and the residual colourless oil is taken up in 100 ml of benzene. The benzene 901u-tion is washed ~ith three 50 ml portions of saturated sodiu~
chloride solution~ dried over magnesium sulphate and concen-trated to dryness in vacuo. A~ter recrystallising the residue from toluene, 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonic acid p-nitrobenzyl ester of melting point 159-160C is obtained.
di) The crude 2-[4-(p-toluenesulphonylthio)-3-phenoxy-acetamido-2-oxoa~etidin-1-yl]-3-methylenebutyric acid p-nitrobenzyl ester, obtained according to Example l.cvii), is dissolved in 20 ml of methyl acetate and ozonised at -70C
~ntil no further starting material is present, according to a thin layer chromatogram. A stream o~ nitrogen is then passed ~hrough the solution æ~d the latter is warmed to 0-5C.
A solutiorl o~ 300 mg of sodium bisulphite in 5 ml of water is added and the mixture is stirred for about 5 minutes until no further ozonide can be detected with potassium iodide/starch paper. The mixture is diluted with ethyl acetate, the aqueous phase is separated off, and the organic phase is washed with water, dried o~er magnesium sulphate and freed from sol~ent in vacuo The crude product is dissolved in 3 m~
of methylene chloride and 15 ml of toluene are added. The precipitate is ~iltered of~f and the filtrate is eva~orated in vacuo. The residue is recrystallised from methanol and gives 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazstidin-l-yl~-3-hydroxycrotonic acid p-nitrobenzyl ester of melting point 159-160C.
e) A solution of 641 mg (1 mmol) of 2-[4-(p-toluene-sulphonylthio)-3-phenoxyacetamido-2-oxoazetidîn-1-yl]~3-hydroxycrotonic acid p-nitroben7yl ester in 5 ml of d~y pyri-dine is cooled to ~10C in an acetone/ice bath, 285 mg (1.5 mmols) of p-toluenesulphonyl chloride are added and the mix-ture is stirred under a nitrogen atmosphere for about 5 hours until no further starting material can be detected by thin layer chromatography (silica gel: toluene/ethyl acetate~ 1:1).
The reaction solution is diluted with 50 m~ of benzene, washed with water, ice-cold 10% strength aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. This gives pale yellow coloured 2-~4-(p-toluenesulphonylthio)~3 phenoxyaceta-mido-2-oxoazetidin 1-yl]-~-p-toluenesulphonyloxy-crotonic acid p-nitrobenzyl ester, which is sufficiently pure for ~urther processing. IR spectrum (methylene chloride): characteris-tic bands at 5.6, 5.8; 5.9; 6.55; 7.45; 8.55 and 8.75u; NMR
spectrum (deuterochloroform): ~ in ppm: 2.4 (6H, ~); 2.45 (3H, s); 4.4 (2H, q, J - 15 Hz); 5.3 (ZH, s); 5.3 (lH, dd, J = 5.10 Hz); 5.8 (lH d; J - 5 Hz) and 6.6-8.4 (18 H, c).
f) A solution of 80 mg (0.1 mmol) o~ 2-~4-(p-toluene-sulphonylthio)-3-phenoxyacetamido-2 oxoazetidin-l-yl]-~-p-toluenesulphonyloxy-croto~ic acid p-nitrobenzyl ester and 0~0175 ml of pyrrolidine (0.21 mmol) in 2 ml of dry tetra~
hydrofurane is stirred for about 1 hour under a nitrogen atmosphere until no further starting material can be detected by thin layer chromatography (silica gel: toluene/ethyl acetate, 1:1).. The reaction mixture is diluted with 10 m~
o~ benzene, washed with twice 5 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on silica gel thick layer plates with toluenelethyl acetate, 1:1, and gives s~

a mixture consisting of colourless 2-[4-(p-toluenesulphonyl-thio)-~-phenoxyacet2mido-2-oxoazetidin-l-yl~-3-(l-pyrrolidyl)-crotonic acid p-nitrobenzyl ester and the corresponding iso-crotonic acid ester. IR spectrum (methylene chloride):
characteristic bands at 5.6; 5.95; 6.55; 7.45 &nd 8.75~;
N~R spectrum (deuterochloroform): ~ in ppm: 1.6-Z.2 and 3.0-3.8 (8H, c); 2.08 and 2.27 (3H, s); ?.38 and 2.~9 (~H, s); 4.42 (2H, q, J = 15 Hz); 4.8-6.0 t4H, c) Qnd 6.6-8.4 (14H, c)s The same compounds can also be obtained as follows:
~i) A solution~ cooled to --10C, of 256 mg (0.4 mmol) of 2-~4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonic acid p-nitrobenzyl ester in 5 ml of dry methylene chloride is treated, under nitrogen, with 0.1115 ml (Q.8 mmol~ of triethylamine and then with 0.062 ml (0.8 mmol) of methanesulphonyl chloride. After one hour, 0.104 ml (1.24 m~ols) of freshly distilled pyrrolidine is added and the mixt~re is stirred for a further 2 hours at -10C. The reaction solution is diluted with 20 ml of methylene chloride, washed with three times 15 ml of water, dried ovar sodium sulphate and evaporated in vacuo. The residue is triturated with diethyl ether and gives a mixture which consists of pale yello~ 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-pyrrolidyl)-crotonic acid p-nitroben~yl ester and the corresponding iso-crotonic acid p-nitrobenzyl ester and which can be employed in this form in the next stage.

s~

The m~thanesulphonic acld ester which is formed as an intermediate product can also be isolated or prepared as follows:
fii) A solution, cooled to -10~, of 128 mg (0.2 mmol) of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-l-yl]~3-hydroxycrotonic acid p-nitrobenzyl ester in 1 ml o~
dry methyle~e chloride is treated, under nitrogen, with 0.042 ml ~O.~ mmol) of triethylamine and 0.017 ml (Oo22 mmol) of methanesulphonyl chloride and the mixture is stirred for 30 minutes at the same temperature. The reaction mixture is diluted with lO ml of methylene chloride; washed with 3 times 10 ml of saturated aqueous sodium chloride solution, dried over sodillm sulphate and evaporated in vacuo. m e residue, which contains 2-[4-(p-toluenesulphonylthio)-3-phenoxyacet-amidD-2-oxoaze~idin-l-yl]-3-methanesulphonyloxy-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester, cannot easily ~e purified by chromatography because of instability but is su~ficiently pure to enable it to be further processed [for example according to Example l~i)].
IR spectrum (meth~lene chloride): characteristic bands at 5.55; 5.7; 5.8; 6.55; 7.45; 8.55 and 8.75~, NMR
spectrum (deuterochloroform): ~ in ppm: 2.37 (3H, s); 2.39 and 2.5 (3H/ s); 3.12 and 3.27 (3H, s); 4.39 and 4.41 (2H, s); 5.2 (lH dd, J = 5.10 Hz); 5.25 (2H, s); 5.88 and 5.95 (lH, d, J = 5 Hz) and 6.6-8.4 ~15 H, c).
Exam~le 2 .
A solution of 148 mg (0.2 mmol) of a mixture consisting s~'~

of 2-~4-(p-toluenesulphonylthio)-3-phenoxyacetamido~2-oxo2ze-tidin-l-yl]-3-(N-methylcyclohexylamino)-crotonic acid p-nitro-ben~yl ester and the corresponding isocrotonic acid ester, in 3 ml of dry acetonitrile, is heated under nitrogen for about 4 hours at 80C until no ~urther starting material can ba detected by thin layer chromatography tsilica gel: toluene/
ethyl acetate, 1:1). The heating bath is removed, ~8 mg ~0.2 mmol) of p-toluenesulphonic acid and about O.2 ml of water are added to the reaction mixture and the mixture is stirred for a further 2 hours at room temperature. The reaction mixture is diluted with be~zene, washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is triturated at 0C with diethyl ether and gives pale yellow 7~-phenoxyacetamido-3-hydroxy-3-cephem-4-càrboxylic ~cid p-nitrobenzyl ester. IR spectrum ~methylene chloride):
~haracteristic bands at 2.95; ~3; 5.6; 5.75 (sh); 5.9; 5.95 (sh); 6.557 7.45, 8015 and 8.3~; NMR spectrum (deutero-chloroform)O ~ in ppm: 3.4 (zH, q, J = 17 H~); 4.57 (2H, s); 5.06 (lH, d; J = 5 Hz); 5.35 (2H, q, J = 14 Hz); 5.7 (lH dd, J = 5, 10 Hz); 6.8-8.4 (lOH, c) and 11.4 (lH, br.s.).
The starting material can be obtained as follows:
O.056 ml (O.42 m~ol) o~ N methyl-N-cyclohexylamine are added to ~ solution of 160 mg (0.2 mmol) of 2-[4-(p-~oluene-sulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-~-p-toluenesulphonyloxy-crotonic acid p-nitrobenzyl ester in 2 ml of dry tetrahydrofurane, in a nitrogen atmosphere and whilst stirring, and the mixture is stirred for about a further 2 hours at room tem~erature until no further starting materi~l 5~

can be detected by thin la~er chromatography (silica gel:
toluene/ethyl acetate, 1:1). The reaction solution is diluted with benzene, washed several times with water, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on 10 g of acid-washed silica gel with ben~ene/ethyl acetate, 3:1. A mixture consisting o~
2-~4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoaze~
tidin-l-yl]-3-(N-methylcyclohexyylamino)-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester is obtained as a pale yellow oil. IR spectrum (methylene chloride): characteristic bands at 2.95; ~ 4; 5.6; 5.8; 6.55;

7.4 and 8.75~.

Analogously to Example 1, it is possible, starting ~rom a mixture consisting o~ 2 ~4-p-(toluenesulphonylthio)-3 phenoxyacetamido)-2-oxoazetidin-1-yl~ cyclohexylamino-crotonic acid p-nitrobe~zyl ester and the corresponding iso-crotonic acid ester, to prepare 7~-phenoxyacetamido-3-cyclo-hexylami~o-cephem-4-carboxylic acid p-nitrobenzyl ester (a mixture o~ 2- and 3-cephem derivatives) and from this to prepare 7~-phenoxyacetamido-~-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester.
The starting material oan be obtained as ~ollows:
a) A solution of 160 mg (0.2 mmol) of 2-E4-p-(toluene-sulphonylthio)-3-phenoxyacetamido)-2-oxoazetidin-1-yl~-3-p-toluenesulphonyloxy-crotonic acid p-nitrobenzyl ester in 2 ml of dry tetrahydrofurane is treated, under nitrogen, with 0.0577 ml (0.5 3mol) of cyclohexylamine a~d the mixture is stirred for 1 hour at room temperature. The reaction s~

solution is diluted with benzene, washed with water, dried over sodium sulphate and evaporated in vacuo. The residue, which contains a mixture consisting of 2-[4-p-~toluenesulphon-ylthio)-3-phenoxyacetamido)-2~oxoa~etidin-1-yl]-3-cyclohexyl-amino-crotonic acid p-nitroben7yl ester and the corresponding isocrotonic acid ester, can be further processed without purification. IR spectrum (methylene chloride): character-istic bands at 2.9; 3.4; ~.5; 5.9; 6.0; 6.25; 6.55; 7.45; 8.10 and 8.75~; NM~ spectrum (deuterochloroform): ~ in ppm:
1.8-2.0 (llH, c) 2.02 (3H, s); 2.35 (3H~ s); 4 4~ ~H) s);
~.95 (lH dd, J = 5.10 Hz); ~.17 ~2H, s); 5.80 (lH, d, J =
5 Hz) and 6.6-9.2 (15H~ c).
ExamDle 4 a) 3 ml of an ethereal diazomethane solution ~0.5 ~olar, 1.5 equivalents) are added in th~ course of about 10 minutss to a solution, cooled to 0C, of 485 m~ of 7~phenoxyaceta-mido-3-hydroxy-3-cephem-4-carboxylic acid p nitrobenzyl ester in 10 ml o~ dry chloroform. The pale yellow solution is stirred;for 1 hour at 0C 9 flushed with nitrogen in order to remo~e excess diazomethane and concentrated in vacuo. The residue is recrystallised from methylene chloride and gives 7~-phenoxyacetamido-3-methoxy-3-cephe~-4-carboxylic acid p-nitrobenzyl ester of melting point 140.5-142C.
The same compound can also be obtained by means of phase transfer catalysis, as follows:
ai) A suspension of 4.85 g o~ 7~-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 5~

25 ml of carbon tetrachloride and 27 ml of water is treated, at 20, whilst stirring vigorously, successively with 3.0 g of potassium bicarbonate, 3.8 ml of dimethyl sulphate and 1.93 g of tetrabutylammonium bromide. The mixture is stirred vigorously for 4 hours at 20. After diluting with 50 mi of water, the mix*ure is extracted with twice 50 ml of methylene chloride. 7~-Phenoxyacetamido~ methoxy-3-cephem~4-carboxylic acid p-nitrobenzyl ester is obtained by evaporating the extracts,previou~ay driel over sulphate, and crystallising the residue from methylene chloride/diethyl ether.
b) A solutio~ of 250 mg (0.5 mmol) of 7~-phenoxyacetc~mido~
3-methoxy!3-cephem-4-carboxylic acid p-nitrobenzyl ester in 2 ml of methanol/tetrahydrofurane, 1:1, is added to a mixture of 5% palladium/charcoal in 2 ml o~ the same solvent, which mixture has been prehydrogenated ~or one hour u~der atmos--pheric pressure~ and the reaction mixture is hydrogenated for 3 hours at room temperature and under atmospheric pressure.
After this time, about 90~ of the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is taXen up in 10 ml of ~ethylene chloride and extracted with twice 10 ml of ~ strength aqueous ~odium bicarbonate solution.
The combined bicarbonate extracts are neutralised at 0C with dilute hydrochloric acid and e~tracted with ~ times 10 ml of methylene chloride. The organic phase is dried over sodium sulphate and freed from the solvent in vacuo. After crystallisation from chloroform/pentane, the residue gives 7~-phenoxyacetamido-~methoxy-3-cephem-4-carboxylic acid of SS~

melting point 173-174C.
c) 0~7 ml (5.7 mmols) of dimethyl-dichlorosilane are added to a suspension of 2.55 g (7 mmols) of 7~-phenoxyacet-amid~3-methoxy-ceph-3-em-4-carboxylic acid and 2.9 ml (22~4 mm~ls) of N,N-dimethylaniline in 11 ml of absolute methylene chloride~ under nitrogen at 20C, and the mixture is then stirred for 30 mi~utes at the same temperature. m e result-ing clear solution is cooled to -20C, 1.6 g (7.7 mmols) of solid phosphorus pentachloride are added and the mixture is stirred for 30 mLnutes. A pre-cooled (-20C) mixture of O.g ml (7 mmols) of N,N-dimethylaniline and 0.9 ml o~ n-butan-ol is added at the same temperature in the course of 2 to 3 minutes, 10 ml o~ pre-cooled (-20C) o~ n-butanol are then added rapidly and the mixture is then stirred ~or 20 minutes at -20C and for 10 minutes wi~hout cooling. 0.4 ml of water is added at about -10C, the mixture is stirred for about 10 minutes in an ice bath (0C~, 11 ml o~ dio~ane are then added and 5 after stirring for a further 10 mi~utes at 0C, about 4.5 ml of tri-n-butylamine are added in portions until samples diluted with water assume a constant pH value of 3.5. A~ter stirring for 1 hour at 0C, the precipitate is filtered o~f, washed with dioxane and recrystallised ~rom water/dioxane. The resulting 7~-amino-3-methoxh-ceph 3-em-4-carboxylic acid hydrochloride dioxanate has a melting point of above 300C. Thin layer chromatogram: R~ value 0.17 (silica gel; system, n-butanol/carbon tetrachloride/methanol/
formic ac-d/water, 30:40:20:5:5).
ci~ A suspension of 11.75 g of 93 per cent stre~gth 5~

- 8~ -(corresponding to 10.93 g of 100% strength~ of 7~-phenoxy-acetamido-3-methoxy-ceph-3-em-4-carboxylic acid and 13.4 ml (12.73 g) of N,N-dimethylaniline in 47 ml o~ absolute methyl-ene chloride (distilled over P205) is treated, at ~20C, under nitrogen, with 3.6 ml (3.87 g) of dimethyldichlorosilane and the ~ixture is then stirred for ~0 minutes at the same tempera-ture. The solution, which is now clear, is cooled to -18/-19 and 7.8 g of solid phosphorus pentachloride are added, the internal temperature rising to -10~ After stirring ~or 30 minutes in a bath at -20, the clear solution is added dropwise, in the course o~ about 7 minutes, to a mixture, cooled to -20, o~ 47 ml of n-butanol (anhydrous, dried over Sikkan) and 4.4 ml (4.18 g) of dimethylaniline.
The internal temperature rises to -8. The mixture is stirred for a further 30 ~inutes, initially in a bath at -20 and subsequently in an ice bath (0), so that a final internal temperature of -10 is reached. A mixture o~ 47 ml o~
dioxane and 1.6 ml of water is added dropwise at ~his tempera-ture (time taken, about 5 minutes). The product thereupon crystallises out slowlyO After stirring for a further 10 mlnutes, the pH of the mixture, in an ice bath, is brought to a value of between 2.2 and 2.4, and kept at this value, by adding about 9.5 ml of tri-n-butylamine, in portions, in the course of about 1 hour (the first 3 ml are added in the ~irst ~ minutes). The product is then filtered o~f, washed, in portions, with about 30 ml of dioxane and then with abou-t 15 ml o~ methylene chloride and crystalline 7~-amino-3-methoxy-ceph~3-em-4-carboxylic acid hydrochloride dioxanate 55~

~ 3 -is thus obtained; melting point above 300C; UV spectru~
(in 0.1 N sodium bicarbonate): ~max = 270 m~ ( = 7,500);
IR spectrum (nujol): characteristic bands at S.62; 5.80; 5,88;
6.26; 6.55; 7.0~; 7~45; 7.7Z; 7.96; 8.14, 8.25; 8045; 8.64;
8.97; 9.29; 10.40 and 11.47 m~; [~20 = ~134 ~ 1 (c = l;
0.5 N sodium bicarbonate solution).
The zwit~er ion of 7~-amino-3-methoxy-ceph-3-em-4-carboxylic acid can be obtained from the resulting h~dro-chloride dioxanate by treating a 20% streng-th aqueous solution o~ the latter with 2 N sodium hydroxide solution until the pH
reaches a value of 4.1 (isoelectric point); when ~iltered off and dried, the zwitter ion has a melting point of aboVe 300C, W spectrum (in 0.1 N sodium bicarbonate solution) AmaX =
270 nm ( F - 7,600)~ m in layer chromatogram: Rf value identical to that o~ the hydrochloride (silica gel, same system); ~}20 _ ~232 ~ 1 (c = l; 0.5 N sodium ~ic~rbo~at2 solution).
d) 1.65 ml of bis-(trimethylsilyl)-acetamide are added to a suspensio~ of 1 g (~82 m~ols) of 7~-~m;no-~-methoxy ceph-3-em-4-carboxylic acid hydrochloride dioxanate in 20 ml of dry methylene chloride, at room.temperature under a nitrogen atmosphere. A~ter 40 minutes, the clear solution is cooled to 0C and 900 mg (4.37 mmol5) of solid D-a-phenyl-glycyl acid chloride hydrochloride are added. Five min-utes later, 0.7 m~ (10 mmols) of propylene oxide are added.
The suspension is then stirred for l hour at 0C under a nitrogen atmosphere, after which 0.5 ml of methanol are added, whereupon 7~-(D-a-phenylglycylamino)-3-methoxy-ceph-3-em-4-s~

carboxylic acid hydrochloride precipitates in a crystalline form. The hydrochloride is ~iltered off and d1ssolved in

9 ml of wa-ter and the pH of the solution is ad~usted to 4.6 with 1 N sodium hydroxide solution. The dihydrate of the inner salt of 7~-(D--phenylglycylamino)-3-methoxy~ceph-3-em-4-carboxylic acid, which precipitates out, is filtered off, washed with acetone and diethyl ether and dried; melting point 174-176 (decomposition); [a~29 = ~132 (c = 0.714;
in 0.1 N hydrochloric acid); thin layer chromatogram (silica gel): Rf value - 0.18 (system: n-butanol/acetic acid/water, 67:10:23) W spectrum (in 0.1 N aqueous sodium bicarbon-ate solution) ~max = 269~ (~ = 7,000); IR spectrum (in miner-al oil): characteristic bands at 5.72, 5.94, 6.2~ and 6.60~.
di) 1.37 ml (5.6 mmols) of N,N-bis-(~rimethylsilyl~-acetamide are added to a suspension of 993 mg (4.32 mmols) of 7~-amino-3-methoxy-ceph-~-em-4-carboxylic acid (i~ner salt) in 10 ml of methylene chloride and the mixture is st'rred for 45 minutes at room temperature under a nitrogen atmosphere.
The clear solution is cooled to 0C and 1.11 g (5.4 mmols) of D-~-phenylglycyl acid chloride hydrochloride are added.
A~ter 5 minutes~ 0.4 ml (5.6 mmols) of propylene oxide i~
added. The suspension is then stirred for 1 hour at 0C
under a nitrogen atmosphere and subsequently 0.6 ml of methanol is added. 7~-(D-a-Phenylglycylamido)-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride which crystallises out, is filtered off and dissolved in 15 ml of water at 0C and the pH of the solution is adjusted to about 4 with 5 ml of 1 N sodium hydroxide solution. The pH of tha solution, which is S5'~

war~ed to room temperature, is brought to about 4.8 with triethylamine, whereupon 7~-(D-~-phenylglycylamido)-3-methoxy-ceph-3-em-4-carbo.~ylic acid crystallises out in tha form of the dihydrate.
Exam~le ~
A solution of 158.2 g (0.2 mol) of a mixture consist-in~ of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacet~m;do-3-oxo-azetidin-l-yl~ pyrrolidyl)-crotonic acid diphenylme-thyl ester and the corresponding isocro~onic acid ester in 1,500 ml of dry acetonitrile is heated under nitrogen for about 5 hours at 80C ~ntil no further starting material can be detected by thin layer chromatographr (silica gel; toluene/ethyl actate, ~ The heating bath is removed and the reaction mix-ture ? which contains 7~-phenoxyacetamido-3-pyrrolidino-cephem-4-carboxylic acid diphenylmethyl es~er, is treated with 200 ml OI O. 1 N HCl ~nd stirred for a furt~er 3 hours at room tempera~ure. The reaction mixture is evaporated in vacuo, The residue is taken up in ethyl acetate, washed successively with dilute sulphuric acid, water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solution and dried over sodium sulphate. The solution is evaporated in vacuo and the crude 7~-phenoxy-acetamido-3-h~droxy-~-cephem-4-carboxylic acid diphen~lmethyl ester is purified by means of column chroma-tography (silica gel; toluene/ethyl acetate J 4.1); thin layer chromatogram:
Rf value 0.24 (silica gel; to].uene/ethyl acetate, 1:1).

:~4(~5'~

The resulting product can be further processed as follows i) The resulting 7~-phenoxyacetamido-3 h~droxy-3-cephem-4-carboxylic acid diphanylmethyl ester is taken up in methanol and treated, at 0C, with an excess of an ethereal solution of diazomethane. After a reaction time o~ 5 minutes, the solution is concentrated completely and the oily residue is chromatographed on silica gel thick layer plates (toluene/
ethyl acetate~ 3:1). The silica gel in the zone at Rf =
0.19 is extracted with ethyl acetate and gives 7~-phenoxy-acetamido-3-methoxy-ceph-3-em 4-carboxylic acid diphenylmethyl ester; melting point 120C (from ether), I~ spectrum (in CHC13); 3~10, 1775, 1700, 1690 and 1600 cm 1 ii) It is also possible, analogously to Example 4ai), to convert the resulting 7~-phenoxyacetamido-~-hydrox~-3-cephem-4-carboxylic acid diphenylmethyl ester into the 7~-phenoxy-acetamido-~-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester by me~s of dimethyl sulphate and potassium ~icarbonate according to the phase transfar method.
iii) 3.87 ml of anisole is added to a solution of 2.0 g (~.78 mmols) o~ 7~-phenoxyacetamido-3-methoxy-ceph-~-em-4-carboxylic acid diphenylmethyl ester in ~ ml of methylene chloride and the mixture is cooled to 0C and, a~ter adding 1.2 ml of trifluoroacetic acid, left to stand ~or 1 hour~
The reaction mixture is concentrated in vacuo and the residue is crystallised from acetone/ether. 7~-Phenoxyacetamido-3-methoxy-ceph-3~em-4-carboxylic acid of meltin~ point 170C
(decomposition) is obtained.

- ~7 -The starting material can be prepared as follows:
a) 6-Phenoxyacetamidopenicillanic acid diphenylmethyl ester l,B-oxide o~ melting point 144-146C (ethyl acetate/
petroleum ether), is obtained from lC0 g (27.3 mmols) of 6-phenoxyacetamidopenicillanic acid l~-oxide, 500 ml of dioxane and 58.4 g (30 mmols~ of diphe~ylmethyldiazometh~ne a~ter about 2 hours.
b) Analogously to Example lb)y 2 [4-(benzthiazol-2-yl-dithio)-~-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester, of melting point 140-141C
(from toluene/ether), is obtained from 292 g (55 mmols) of 6-phenoxyaceta~idopenicillanic acid diphenylmethyl ester 1~-oxide and 99 g (59.5 ~ols) of 2-mercaptobenæthiazole.
c) ~nalogously to Example lc), 2-~4-(p-toluenesulphonyl-thio)-3-pheno~yaceta~ido-2-oxoazetidin-1-yl]-~-methylenebutyr-ic acid diphenylmethyl ester is obtained from 10 g (14.7 m~ols) o~ 2-~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxo-azetidin-l-~l]-3-methylenebutyric acid diphenylmethyl ester in 50 ml o~ ethyl acetate and 4.92 g (24.98 mmols) o~ finely powdered silver p-toluenesulphinateZ~r stirring for 7 hours at room temperature, R~ value = 0.28 (silica gel, toluene/
ethyl acetate, 3:13; IR spectrum (CHC13): 1782, 1740, 1695, 1340 and 1150 cm 1.
d) Analogously to Example ld), 2-~4-(p-toluenesulphonyl-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonic acid diphenylmethyl ester of melting point 142-143C (from ether/pentane), is obtained ~rom 10.8 g (16.2 mmols) of 2-~4-(p-toluenesulphonylthio)-~-phenoxyacet~m;do-2-oxoazetidin-1-yl]-t~ S~

3-methylenebutyric acid diphenylmethrl ester in 1 1 of methyl-ene chloridD and 1.1 equivalents of ozone.
e) A solution, cooled to -10C, of 134.4 g (0.2 mol) of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-l-yl]-3-hydroxycrotonic acid diphenylmethyl ester in 500 ml o~
dry methylene ch~oride is treated, under nitrogen, with ~4.8 ml (0.25 mol) of triethylamine and then with 24.5 ml (0.25 mol) of methanesulphonyl chloride~ After 20 minutes, 47 ml (0.~5 mol) of freshly distilled pyrrolidine are added and the mixture is stirred ~or a further 2~ hours at -10C. The reaction solution is washed with three times 150 ml of wa-ter, dried over sodium sulphate and evaporated in vacuo~ The residue is dried to a foam and gives a mixture which consists of pale yellow 2-~4 (p-toluenesulphonylthio)-3-phenoxyaceta~
mido-2-oxoazetidin-1-yl]-3~ pyrrolidyl)-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester and which can be employed in this form in the next stage.

Analogously to ~cample 4d, it is possible, by reacting 1.16 g (3 mmols) of 7~-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride dioxanate, which is obtainable according to the invention, with 1.5 ml (6.2 ~mols) of bis-(trimethylsilyl)-acetamide and subsequently reacting the reaction product a) with 765 mg (3.6 mmols) of D-a-amino-(2-t~ienyl)-acetic acid chloride hydrochloride, to obtain 7~-[D--amino-a-(2-thienyl)-acetylamino]-~-methoxy-3-cephem-4-carboxylic acid in the form o~ the inner salt, melting point 140 (with decompo-S'.-~
_ ~9 _ sition); thin layer chromatogram (silica gel; identification with iodine): Rf - 0 22 (system: n-butanol/acetic acid/
water, 67:10:23) and Rf ~ 0.53 (system: isopropænol/formic acid/water, 77:4:19); ultraviolet absorption spectrum:
~m~x = 235 m~ ( - 11,400) and AshOuld~r - 272 m~ ( ~ 6,100) in 0.1 N hydrochloric acid, and ~max = 238 mu (E = 11,800) and ~shoulder = 267 m~ ( f = 6,500) in 0.1 N aqueous 30dium bicarbo~ate solution~
b) with 940 mg (4.5 mmols) of 3--amino-(1,4-cyclohexadienyl)-acetic acid chloride hydrochloride, to obtain 7~-[D-a-amino-a-(1,4-cyclohexadienyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylic acid in the form o~ the inner salt, melting point 170 (with decomposition); thin layer chromatogram (silica gel; identi~ication with iodine~: Rf ~ 0.19 (sys~em:
n-butanol/acetic acid/water, 67:10:23) and Rf ~ 0.58 (system:
isopropanol/~ormic acid/water, 77:4:19); ultraviolet absorption spectrum: ~max = 267 mu ( F = 6,300) in 0.1 N
hydrochloric acid, znd ~max = 268 m~ ( = 6,600) in 0.1 N
aqueous sodium bicarbonate solution, ~a]20 = +88 + 1 (c =
1.06; 0.1 N hydrochloric acid), a~d c) with 800 mg (3.6 mmols) of D-a-amino-4-hydroxyphenylacetic acid chloride hydrochloride, to obtain 7~-~D-a-amino--~4-hydroxyphenyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylic acid in the form o~ the inner salt, melting point = 24~-244.5C
(sintering starts ~rom 231) (with decomposition); thin layer chromatogram (silica gel; identi~ication with iodine):
Rf ~ 0.24 ~system: n-butanol/acet~ acid/water, 67:10:23) and Rf ~-0.57 (system: isopropanol/formic acid/water, 77:4:19);

;I 5~

ultraviolet absorption spectrum: ~max = 228 m~ ( - 12,000) and 271 m~ (e - 6,900) in 0,1 N hydrochloric acid, and ~max =
227 m~ (~ = 10,500) and Ashoulder = 262 mu (~ = 8,000) in 0.1 N aqueous sodium bicarbonate solution, ~a]D= +165 + 1 (c = 1.3; 0.1 N hydrochloric acid).
~e~:Z, The compo~nds which follow can be mæ~ufactured ~nal-ogously from suitable intermediate products obtainable according to the invention:
7~-phenoxyacetamido-3-hydroxy-3-cephem~4~carbo~1ic acid diphenylmethyl ester 7 7~-phenylacetamido-~-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 7~-amino-3-hydroxy-3-cephem-4-carboxylic acid diphenyl-methyl ester, 7~-~D-a-tert.-butox~carponylamino-a-phenylacetylamino]-3-hydroxy-3-cephem-4-carbox~lic acid diphenylmethyl e~ter, 7,B-(5-benzoylRmino-5-diphenylmethoxycarbonyl-valeryl-amino)-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 7~-[~-a-tert.-butoxycarbonylamino--~4-hydroxyphenyl)-acetyl~mino]-3-hydroxy-3-cephem-4-carboxylic acid diphenyl-methyl ester, 7~-~D-a-tert.-butoxycarbonylamino-a-(2-thienyl)-acetyl~m;no]-3-hydroxy-3-cephem-4-carboxylic acid diphenyl-met~yl ester, 7~-[D-a tert~-butoxycarbonylamino a-(3-thienyl)-acetylamino~-3-hydroxy-3 cephem-4-carboxylic acid dipheny~-methyl ester 9 7~-~D-a-tert.-butoxycarbonylamino-a-(2-furyl)-acetyl amino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 7~ -a-tert.-butoxycarbonylamino-a-(4-isothiazolyl)-acetylamino~ hydroxy-3-cephem-4-carboxylic acid diphenyl-methyl ester, 7~-[D-a-tert.~butoxycarbonyl~mino a-(1,4-cyclohexa-dien~l)-acetylamino]-3-hydroxy-3-cephem-4-carboxylic acid dlphenylmethyl ester, 7~-~2-thie~yl)-acetylamino-3-hydroxy-3-cephem-4~carboxylic acid diphenylmethyl ester, 7~-(1-tetrazolyl)-acetylamino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 7~-(4-pyridylthio)-acetylamino-3-hydro~y-~-cephem-4 carboxylic acid diphenylmethyl.ester, 7~-(4~aminopyridinium-acetylamino)-3-hydroxy-3-cephem-4-carboxylic acid diphen~lmethyl ester, and 7~-~D-a-(2,2,2-trichloroethoxycarbonyloxy)-a-phenyl-acetylamino]-3-hydrox~-3-cephem-4-carboxylic acid diphenyl-methyl ester and corresponding compounds etheri~ied at the 3-hydrox-yl group, for example ~ -methoxy-7~-phenoxyacetamido-3-cephem 4-carboxylic acid diphenylmethyl ester, 3-methoxy-7~-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester, 3-methoxy-7~-amino-3-cephem-4-carboxylic acid diphenyl-methyl ester and salts thereof, 3-methoxy-7~-phenylacetylamino-3-cephem-4-carboxylic acid or salts thereof, 3-methoxy-7~-(D-a-tert.-butoxycarbonyl2mino--phenyl-acetylamino)-3-cephem-4-carboxylic acid diphenylmethyl ester, ~ -methoxy-7~ -a-phenylglycyl~mino)-3-cephem-4-carboxylic acid or salts thereof~
3-n-butoxy-7~-phenylacetylami~o-3-cephem-4-carboxylic acid diphenylmethyl ester, 3-n-butoxy-7~-(D-a-tert.-butoxycarbonyl~mino-a-phsn acetylamino)-3-cephem-4-carboxylic acid diphanylmethyl ester 3-n-butoxy-7~-(D-a-phenylglycylamino)-3-cephem-4 carboxylic ~cid or salts thereof~
~ -methoxy-7~-phenylacetylamino-3-cephem-4-carboxylic acid methyl ester, 3-ethoxy-7~-(D-a-tert.-butoxycarbonylamino-a-phenyl-acetylamino)-3-cephem-4-carboxylic acid diphenylmethyl ester, 3-ethoxy-7~ (D-a-phenyl~lycylamino)-3-cephem-4-carboxylic acid or salts thereof, ~ -benzyloxy-7~-(D-~-tert.-butoxycarbonylamino--phenylacetyl~mino~-3-cephem-4-carboxyllc acid diphenylmethyl ester, s~

3-benzyloxy-7~-(D-a-phenylglycylamino)-3-cephem-4-carboxylic acid or salts thereof, 7~-(5-benzoylamino~-5~diphenylmethoxycarbonyl valeryl-amino)-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 7~-~D-a-tert.-butoxycarbonylamino-~-phenylacetylamino)-3-methoxy-3-cephem-4-carboxylic acid or salts thereo~
7~-[D--tert.'butoxycarbonylamino-a-(2-thienyl)-acetylamino~-3-methoxy-3-cephem-4-carboxylic acid diphenyl-methyl ester~
7~-[D~a-tert.-butoxycarbonylamino-~-(1,4-cyclohexa-dienyl)-acetylamino]-3-methoxy-3-cephem-~-carboxylic acld diphenylmeth~l ester, 7~ -a-amino-a-(1-cyclohexen-1-yl)-acetylamino]-~-methoxy-3-cephem-4-carboxylic acid or salts thereo~, 7~-[D-~-tert.-butoxycarbonylamino-a-(4-hydroxyphenyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylic acid diphenyl-methyl ester, 7~-~D-a-amino-a-(4-hydroxyphenyl)-acetylamino~-3-methoxy-3-cephem-4-carboxylic acid or salts thereofc and 7~-~D-a-tert. butoxycarbonyla~ no-a-(4-isothiazolyl)-acetylamLno]-3-methoxy-~cephem-4-carboxylic acid diphenyl-methyl ester, as well as the corresponding ceph-2-em compounds and the isomer mixtures consisting of the ceph-3-em compounds and the ceph-2-em compounds~ as well as the l-oxides of the corresponding ceph-3-em compounds~

Claims (9)

_ 94 _ Patent Claims

1. Process for the manufacture of a 2-(2-oxoazetidin-1-yl)-crotonic acid compound of the formula (II), wherein R? represents an acyl group of the formula (A1), wherein RI represents hydrogen, cyclopentyl, cyclohexyl or cycloheptyl, or such cycloalkyl which is substituted in the 1-position by amino protected amino, sulphoamino or sulphoamino in the form of an alkali metal salt, or RI re-presents phenyl, naphthyl or tetrahydronaphthyl group or phenyl, naphthyl or tetrahydronaphthyl substituted by hy-droxyl, protected hydroxyl, and/or by halogen or RI re-presents 4-isoxazolyl, or RI represents an amino group which is N-substituted by lower alkyl or halogen substituted lower alkyl, or R? represents an acyl group of the formula (A2), wherein RI represents lower alkyl, halogeno-lower alkyl, phenyloxy-lower alkyl, hydroxyphenyloxy-lower alkyl, protected hydroxy-phenyloxy-lower alkyl, halogeno-phenyloxy-lower alkyl, or lower alkyl substituted by amino and/or carboxyl, wherein amino is free or protected and carboxyl is free or protected, or RI represents lower alkenyl, phenyl, hydroxyphenyl, protected hydroxyphenyl, halogeno-phenyl, hydroxy-halogeno-phenyl, protected hydroxy-halogeno-phenyl, amino-lower alkyl-phenyl protected amino-lower alkyl-phenyl, phenyloxyphenyl, or RI represents pyridyl, pyridinium, thienyl, furyl, imidazolyl or tetrazolyl, or these hetero-cyclic groups substituted by lower alkyl, amino, protected amimo, aminomethyl or protected aminomethyl, or RI represents lower alkoxy, phenyloxy, hydroxyphenyloxy, protected hydroxy-phenyloxy, halogeno-phenyloxy, lower alkylthio, lower alkenyl-thio, phenylthio, pyridylthio, 2-imidazolylthio, 1,2,4-tri-azol-3 ylthio, 1,3,4-triazol-2-ylthio, 1,2,4-thiadiazol-3-ylthio, 1,3,4-thiadiazol-2-ylthio, or 5-tetrazolylthio and these heterocyclylthio groups, substituted by lower alkyl, or RI represents halogeno, lower alkoxycarbonyl, cyano, carbamoyl, N-lower alkyl-carbamoyl, N-phenylcarbamoyl, lower alkanoyl, benzoyl or azido, or R? represents an acyl group of the formula (A3), wherein RI represents lower alkyl, phenyl, hydroxy-phenyl, protected hydroxyphenyl, halogeno-phenyl, hydroxy-halogenophenyl, protected hydroxy-halogeno-phenyl, furyl, thienyl, or isothiazolyl, and also represents 1,4-cyclo-hexadienyl, and RII represents amino, protected amino, guanidinocarbonyl-amino, sulphoamino, sulphoamino in alkali-metal salt-form, azido, carboxyl, carboxyl in alkali-metal salt-form, protected carboxyl, cyano, sulpho, hydroxyl, protected hydroxyl, O-lower alkyl-phosphono, O,O'-di-lower alkyl phosphono or halogeno or R? represents a group of the formula (A4), wherein RI and RII each represent halogeno, or lower alkoxycarbonyl, or R? represents a group of the formula (A5), wherein RI represents phenyl, hydroxyphenyl, protected hydroxyphenyl, hydroxy-halogeno-phenyl, protected hydroxy-halogeno-phenyl, furyl, thienyl, isothiazolyl or 1,4-cyclohexadienyl, and RII represents aminomethyl or protected aminomethyl or R? represents a group of the formula (A6) ?

wherein each of the groups RI, RII and RIII represents lower alkyl, and R? represents hydrogen, or R? and R?
together represent 1-oxo-3-aza-1,4-butylene, such group substituted in the 2-position by a group RI as defined under formula (A3) and such group substituted in the 4-position by lower alkyl, the group -N(R4a) (R4b) denotes a secondary amino group, wherein one of the substituents R? and R? represents hydrogen and the other represents lower alkyl, lower alkoxy-lower alkyl, lower alkyl thio-lower alkyl, cyclohexyl-lower alkyl, phenyl-lower alkyl, thienyl-lower alkyl, cycloalkyl with 3 to 7 carbon atoms, or such cycloalkyl substituted by lower alkyl, lower alkoxy, lower alkylthio, cyclohexyl, phenyl, or furyl, or wherein -N(R?) (R?)denotes a tertiary amino group, wherein each of the substituents R? and R?, independent of each other is lower alkyl, lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, cyclohexyl-lower alkyl, phenyl-lower alkyl, thienyl-lower alkyl, cycloalkyl with 3 to 7 carbon atoms, or such cycloalkyl substituted by lower alkyl, lower alkoxy, lower alkylthio, cyclohexyl, phenyl, or furyl, or wherein N-(R?) (R?) is 1-aziridinyl, 1-pyrrolidinyl, 1-piperidyl, 1H-2,3,4,5,6,7-hexahydroaze-pinyl, 4-morpholinyl, 4-thio-morpholinyl, 1-piperazinil, or 4-methyl-1-piperazinyl, Y represents a leaving group of the formula -S-R4, wherein R4 is a monocyclic five membered diazacyclic, oxazacyclic, thiazacyclic, thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclic or a corresponding dicyclic benzdiazacyclic, benzoxazacyclic or benzthiazacyclic radical of aromatic character which radical is bonded to the thio group -S- by one of its ring carbon atoms, which is bonded to a ring nitrogen atom by a double bond, or such group substituted by lower alkyl, lower alkoxy, halogen or phenyl, or wherein R4 denotes lower alkanoyl, lower thioalkanoyl, cycloalkane carbonyl, cycloalkanethio-carbonyl, benzoyl, thiobenzoyl, naphthyl-carbonyl, naphthylthio-carbonyl, pyridylcarbonyl, thenoyl, furoyl, pyridylthiocarbonyl, thiothenoyl or thiofuroyl, or represents such an acyl or thioacyl group which is monosubstituted or polysubstituted by lower alkyl, halogen, lower alkoxy, phenyl or phenyloxy, which groups R4 have up to 18 carbon atoms, or Y represents a leaving group of the formula -SO2-R5, wherein R5 represents unsubstitu-ted or lower alkoxy-, halogeno, phenyl-, or phenyloxy-monosubstituted or -polysubstltuted lower alkyl, lower alkenyl, cyclopentyl or cyclohexyl or R5 represents naphthyl, or phenyl, or naphthyl or pnenyl monosubstitu-ted or polysubstituted by lower alkyl, lower alkoxy, halogen, phenyl, phenyloxy, or nitro, which groups R5 have up to 18 carbon atoms, and R? represents a group which together with the carbonyl grouping -C(=O)- forms a protected esterified carboxyl group, characterised in that a compound of the formula (VII), wherein R?, R? , R? and Y have the above meaning, or a sulphonic acid ester thereof of the formula (VIII) wherein R?, R?, R?, Y and R5 have the above meaning,is treated with a primary or secondary amine of the formula NH(R?) (R?), wherein R? and R? have the above meanings, or with a salt thereof and, if desired, a resulting compound of the formula II, wherein Y represents a group of the formula -S-R4 can be converted into a compound of the formula II, wherein Y is a group of the formula -SO2-R5, by reaction with a heavy metal sulphinate of the formula Mn+(-SO2-R5), wherein M represents a heavy metal cation and n denotes the valency of this cation.

2. Process according to Claim 1, characterised in that in a starting material of the formula VII or VIII R? re-presents phenylacetyl, phenyloxyacetyl or D-.alpha.-tert.-butyloxy-carbonylamino-.alpha.-phenylacetyl and R? is hydrogen.

3. Process according to Claim 1, characterised in that in a starting material of rhe formula VII or VIII R? re-presents benzyloxy, p-nitrobenzyloxy, diphenylmethoxy, lower alkoxy, 2-halogeno-lower alkoxy, or halogen.

4. Process according to Claim 1, characterlsed in that in a starting material of the formula VII or VIII Y denotes a -SO2-R5 group, wherein R5 represents an unsubstituted or methoxy-?
fluorine-, chlorine-, bromine-, phenyl-, or phenyloxy-mono-substituted or polysubstltuted lower alkyl group, alkenyl group, cyclopentyl or cyclohexyl group, or a naphthyl group, or a phenyl group which is optionally monosubstituted or polysubstituted by methyl, methoxy, fluorine, chlorine, bromine, phenyl, phenoxy or nitro.

5. Process according to Claim l, characterised in that in a starting material of the formula VII or VIII Y denotes a -S-R4 group, wherein R4 denotes 1-methyl-imidazol-2-yl, 1-,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5-thia-triazol-2-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4, 5-oxatriazol-2-yl, 2-quinolyl, 1-methyl-benzimidazol-2-yl, benzthiazol-2-yl or benzoxazol-2-yl.

6. Process according to Claim 1, characterised in that a starting material of the formula VII or VIII is used, wherein R1 is phenoxyacetyl, Y is p-toluenesulphonyl, R?
is p-nitrobenzyloxy, R? is hydrogen, so as to produce 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-cyclohexylamino crotonic acid p-nitro-benzyl ester, the corresponding isocrotonic acid ester or a mixture thereof.

7. Process according to Claim 1, characterised in that a starting material of the formula VII or VIII is used, wherein R? is phenoxyacetyl, Y is p-toluenesulphonyl, R?
is p-nitro-benzyloxy, R1 is hydrogen, so as to produce 2-[4-(2-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-(N-methylcyclohexylamino)-crotonic acid p-nitrobenzyl ester, the corresponding isocrotonic acid ester or a mixture thereof.

8. Process according to Claim 1, characterised in that a starting material of the formula VII or VIII is used, wherein R? is phenoxyacetyl, Y is p-toluenesulphonyl, R?
is p-nitrobenzyloxy, R? is hydrogen, so as to produce 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-[1-pyrrolidyl)-crotonic acid diphenyl-methyl ester,the corresponding isocrotonic acid ester or a mixture thereof.

9. A compound of the formula (II) wherein R?, R?, R?, R?, R? and Y have the meanings indicated in Claim 1, whenever prepared by a process according to Claim 1, or an obvious chemical equivalent thereof.