CA1084054A - Process for the manufacture of 3-hydroxy-crotonic acid derivatives - Google Patents

Abstract

Process for the Manufacture of 3-Hydroxy-crotonic Acid Derivates Abstract of the Disclosure 3-Hydroxycrotonic acid derivatives of the formula (VI), wherein R? represents an acyl group R? represents a radical which together with the carbonyl grouping -C(=O)- forms a protected carboxyl group, and Y denotes a leaving group, and their salts are prepared in that a compound of the formula

Description

1~84~

Canada 4-9304/1-3/+/D

Process for the Manufacture of 3-Hydrox~-corotonic Acid Derivates The subject of the present in~ention is a process for the manufacture of a compound of the formula Ra l~ HH H S-Y
r i/
(VI), I CH
0. ~ 1 3 ~ C - OH
O = C - R2 wherein Rla represents an acyl group of the formula I ..

2 C (A') , wherein RI represents lower alkyl, halogeno-lower alkyl, phenyloxy-lower alkyl, hydroxyphenyloxy-lower alkyl, protected hydroxyphenyloxy-lower alkyl, halogeno-phenyloxy-lower alkyl, or lower alkyl substituted by amino and car-boxyl, wherein amino is free or protected and carboxyl is free or protected, or RI represents lower alkenyl, phenyl, hydroxyphenyl, protected hydroxyphenyl, halogenophenyl, hydroxy-halogeno-phenyl, protected hydroxy-halogeno-phenyl, amino-lower alkyl-phenyl, protected amino-lower alkyl-phenyl, phenyloxyphenyl, or RI represents pyridyl, thienyl, furyl, imidazolyl or tetrazolyl, or these heterocyclic groups substituted by lower alkyl, amino, protected amino, aminomethyl or protected aminomethyl, or RI represents lower alkoxy, phenyloxy, hydroxy-phenyloxy, protected hydroxy-phenyloxy, halogenophenyloxy, lower alkylthio, lower alkenylthio, phenylthio, pyridylthio, 2 imidazolyl-thio, 1,2,4-triazol-3-ylthio, 1,3,4-triazol-2-ylthio, J

10840~4 1,2,4-thiadiazol-3-ylthio, 1,3,4-thiadiazol-2-ylthio, or 5-tetrazolylthio, and these heterocyclylthio groups, sub-stituted by lower alkyl, or RI represents halogeno, lower alkoxycarbonyl, cyano, carbamoyl, N-lower alkyl-carbamoyl, N-phenylcarbamoyl lower alkanoyl, benzoyl, or azido, or Rla represents an acyl group of the formula RII o R - CH - C - ~A") wherein RI represents lower alkyl, phenyl, hydroxyphenyl, protected hydroxyphenyl, halogenophenyl, hydroxy-halogeno-phenyl, protected hydroxy-halogeno-phenyl, furyl, thienyl, or isothiazolyl, or 1,4-cyclohexadienyl, and RII repre-sents amino, protected amino, azido, carboxyl, protected carboxyl, cyano, sulpho, hydroxyl, protected hydroxyl, O-lower alkyl-phosphono, O,O'-di-lower alkylphosphono or halogeno, R2 is halogen or together with the carbonyl grouping -C(=O)- forms an esterified, protected carboxyl group, and Y represents a leaving group of the formula -S-R4, wherein R4 is 1-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-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, or Y represents a leaving group of the formula -S02-R5, wherein R5 represents phenyl, or phenyl substituted by lower alkyl, lower alkoxy, halogen, phenyl, phenyloxy or nitro, and their salts, which compounds are useful according to Canadian Patent No. 1 059 988 for the manufacture of 7~-amino-3-cephem-3-ol-4-carboxylic acid compound of the formula ~Bi~
~,.......

-~, 1084~154 Ra H
H ~ Sl O ~ O - R3 ( IA), O=C - R2 wherein Rla has the meanings mentioned under formula VI, R~ represents hydroxyl, or a group R2A which is halogen or which together with the carbonyl grouping -C(=O)- forms an esterified, protected carboxyl group, and R3 represents hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl or tri-lower alkyl silyl, the corresponding 2-cephem compound of the formula Rla H H
H~ S ~

O ~ L o R3 (I13) O=C - R2 wherein Rl, R2 and R3 have the abovementioned meanings, or a mixture of a compound of the formula IA and IB, or salts of such compounds with salt-forming groups.
I~ 2-cephem compounds of the formula IB having the double bond in the 2,3-position, the optionally protected carboxyl group of the formula -C(=O)-R2 preferably has the a-configuration.
In the new compounds of the formula VI of the present invention an amino group can be protected by a group which can be replaced by hydrogen. Such amino protecti~e 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 . .

1084(~54 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, cycloaliphatic-aliphatic, aromatic, araliphatic, hetero-cyclic 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 radical of an aliphatic or aromatic di-carboxylic acid, and also the acyl radical of an ~-amino-acetic acid whlch is preferably substituted in the a-position and contains, for example, an aromatic or heterocyclic 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 group can also represent an organic ylidene radical, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferabli with 18 carbon atoms.

A protected carboxyl group of the formula -C(=O)-R2 isan esterified carboxyl group.

The group R2 can therefor 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-D

L~
. . I . ., ~, .

phatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, especially optionally substituted hydrocarbon radicals of this nature, as well as heterocyclic or hetero-cyclicaliphatic radicals.
The group R2 can also represent an organic silyloxy radical as well as a hydroxyl group etherified by an or-ganometallic radical, such as an appropriate organic stannyloxy group, especially a silyloxy or stannyloxy group which is substituted by 1 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.
A lower alkyl group R3 has up to 7, preferably up to 4, carbon toms and is, in particular, methyl.
Phenyl-lower alkyl, diphenyl-lower alkyl and tri-lower alkyl silyl groups R3 are useful as hydroxyl protective groups.
In the groups -S02-R5 is R5 a phenyl group which is 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 phenyloxy, 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, or p-nitrophenyl.
The general concepts used in the prededing and following description have, for example, the following meanings:
D

~';
. ., Phenyl-lower alkyl, diphenyl-lower alkyl and tri-lower alkyl silyl groups R3 are useful as hydroxyl protective groups.

In the groups -S02-R5 is R5 a phenyl group which is 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 phenyloxy, 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, or p-nitrophenyl.

The general concepts used in the preceding and following description have, for example, the following meanings:

An aliphatic radical, including the aliphatic radical of an appropriate organic carboxylic acid, as well as an appropriate ylidene radical, is an optionally substituted monovalent or divalent aliphatic hydrocarbon radical, ... .

, ' ' ' ': ~ ' ' iO8 40 54 especially lower alkyl, as well as lower alkenyl or lower alkinyl, and also lower ~k-~lidene ~hich can contain, for example, up to 7, preferably up to 4, carbon atoms. Such radicals can optionally be monosubstituted, disubstituted or polysubstituted by fu~ctional groups, for example by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower aIkylenedioxy, option-ally substituted pheryloxy or phenyl-lower alkoxy, lower 0 alkylthio or optionally substituted phenylthio, phenyl-lotrer alkylthio, heterocyclylthio or heterocyclyl-lower alkylthio, optionally substituted lower alkoxycarbonyloxy or lower alk-- anoyloxy, or halogen, ~lso by oxo, nitro, option~lly substitu-ted ~no, for example lower alkylamino, di-lower alkylamino, lower aIkyleneamino, oxa-lower alkyleneamino or aza-lower a~kyleneamino, as well as acylamino, such as lower alkanoyl-~m~ no, lower alkoxycarbonylamino~ halogeno-lower alkoxycar-bonylamino, optionally substituted phenyl-lower alXoxycarbo-nylamino, optionally substituted carbamoylamino, ureidocar-bonylamino or guanidinocarbonylamino and ~lso s-~lpho ino which is optionally present in the form of a salt, such as in the form of an alkali metal salt, azido, acyl, such as lower alkanoyl or benzoyl, option~lly functionally modified car-boxyl, such as carboxyl present in the form o~ a salt, esteri~ied carboxyl, such as lower ~lkoxycarbonyl, optionally substituted carbamoyl, such as N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl and also optionally substituted urei-docarbonyl or guanidinocarbonyl, or nitrile, optionally .

- ' fu~ctionally modified s~lpho, such as s~lphamoyl or sulpho present in the form of a salt, or optionally O-monosubsti~u-ted or O,O-disubstituted phosphono, wherein substituents represent, for example, optionally substituted lower alXyl, phenyl or phenyl-lower alkyl, it also being possible for Q-unsubstituted or O-monosubstituted phosphono to be in the form of a s~lt, such as in the form of an alk~li metal salt.
A bivalent aliphatic radic~l, including the approp-riate radical of a bivalent aliphatic carboxylic acid, is, for example, lower alkylene or lower alkenylene, which can optionally be monosubstituted, disubstituted or polysubst~tu-ted, for example like an aliphatic radical indicated abo~e, and/or be interrupted by hetero-atoms, such as oxygen, nitro-gen or sulphur.
A cycloaliphatic or cycloaliphatic-~iphatic radic~l, including the cycloaliphatic or cycloalipha~ic-aliphatic radical in an appropriate org~n~c carboxylic acid or an appropriate cycloaliphatic or cycloaliphatic-aliphatic yli-dene radical, is an optionally substituted, mono~alent or bi-valent, cycloaliphatic or cyclo~liphatic-aliphatic hydrocar-bon radical, for ex mple monocyclic, bicyclic or polycyclic cycloalkyl or cycloalkenyl, and also cyclo lkylidene, or cycloalkyl- or cycloalkenyl-lower alkyl or -lower alXenyl, as well as cycloalkyl-lower alkylidene or cycloalkenyl-lower aIkylidene, wherein cycloalkyl and cycloalkylidene contains, for example, up to 12, such as 3-8, preferably 3-6, ring car-bon atoms, whilst cycloalker.yl contains, for example, up to .

10 8 4~54 12, such as 3-8, for ex2mple 5-8, preferably 5 or 6, ring carbon atoms and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic radical c~n contain, for example, up to 7, preferably up to 4, carbon atoms. m e above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, be monos~-bstituted, disubs~ituted or po~y-substituted, for example by optionally substi~uted aliphatic hydrocarbon radicals, such as by the abovementioned option-ally substituted lower al~yl groups or, for example, like the abo~ementioned aliphatic hydrocarbon radicals, by functional groups.
An aromatic radical, including the aromatic radical of an appropriate carboxylic acid, is an option~lly substit~-ted aromatic hydrocarbon radical, for example a ~onocyclic, bicyclic or polycyclic aromatic hydrocarbon radical, esp~ci-ally phenyl, as well as biphenylyl or n2phthyl, which can optionally be monosubstituted, disubstituted or polysubstitu-ted, for example like the abovement~oned aliphatic and cyclo-iphatic hydrocarbon radicals.
A bivalent aromatic radical, for example ~ an aromatic carboxylic acid, is above all 1,2-arylene, especially 1,2-phenylene, which can optionally be monosubstituted, disuDsti-tuted or polysubstituted, for example like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals.
An araliphatic radical, including the aralipha'ic radical in an appropriate carboxy;ic acid, and also an arali-phatic ylidene radical, is, for example, an optionally _ g _ :

~08 4054 substituted arPliph2tic hydrocarbon r2dical, such as an ali-phatic hydrocarbon radicPl which is optionally substituted and pos~esses, for exP~ple, up to three optionally substitu-ted monocyclic,bicyclic or polycyclic aromatic hydrocarbon radicals, and above all represents phenyl-lower alkyl or phenyl-lower ~lkenyl as well as phenyl-lower alkinyl 2nd also phenyl-lower alkylidene, it being possible for such radicals to contain, for example, 1-3 phenyl groups ~nd to be option-o ~lly monosubstituted, disubstituted or polysubstituted in the aromatic and/or aliphatic part, for example like the above-mentioned aliphatic and cycloaliphatic radicals.
Heterocyclic groups, including those in heterocyclic-aliphatic radicals, including heterocyclic or heterocyclic-aliphatic groups in appropriate carboxylic acids, are especi-~lly monocyclic, as well as ~icyclic or polycyclic, azacyclic, ~hiacyclic, oxacyclic, thiazacyclic, thiadiazacyclic, oxaza-cyclic, diazacyclic, triazacyclic or tetrazacyclic radicals o~ aromatic character, and also appropriate partially or wholly saturated heterocyclic radicals of this nature and such radicals can optionally be monosubstituted, disubsiitu-ted or polysubstituted, for example like the abovementioned cycloaliphatic radicals. ~he aliphatic part in heterocyolic-aliphatic radicals has, for example, the meanin~ indicated for-the correspon~ing cycloaliphatic-aliphatic or araliphatic radicals.
The acyl radical of a carbonic acid half-derivative is preferably the acyl radical of an appropriate half-ester, , ~0 8 4~ 54 wherein th~ organic radic~l of the ester group represents an optionally substituted aliphatic, cycloal phatic, aromaiic or araliphatic hydrocar~on radical or a heterocyclic-aliphatic radical, abo~e all the acyl radical of a lo~ler alkyl half-ester of carbonic acid ~Ihich is optionally substituted, for eY.a ple in the - or ~-position, as well zs of a lower alk-enyl, cycloalkyl, phenyl or phenyl-lower alkyl half-ester of carbonic acid which is optionally substituted in the organic radical. Acyl radicals of a carbonic acid half-ester are ~urthermore appropriate radicals of lower alkyl half-esters of carbonic acid, in which the lower alXyl part contains a heterocyclic group, for example one of the abovementioned heterocyclic groups of aromatic character, ~nd both the lower alkyl radical and the heterocyclic group can optionally be substituted. The acyl radical of a carbonic acid half-deri~ative can ~lso be an optionally N-subs~itu~ed carbamoyl group, such as an optionally halogenated N-lower alkylcar-bamoyl group.
An etherified hydroxyl group is abo~e all optionally substituted lower alkoxy, where~n substituents above all represent free or functionally modified, such as etherified or esterified, hydroxyl groups, especially lower alXoxy or halogen, also lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, as well as heterocyclyloxy or hetero-cyclyl-lower alkoxy especially also optionally substituted phenyl-lower ~lkoxy.
An optio~ally substitu~ed amino group is, for .
' ~

.

.

exam~le, ~mino, lower alkylamino, di-lower alkyl2mir.o, lower alkyleneam~no, oxa-lower ~lkyleneamino, thia-lower alkylene-amino, aza-lower alkyleneamino, hydL~oxyamino, lower a koxy-amino, lower alkanoyloxyamino, lower alkoxycarbonyl~mino or lower alk~oylamino.
An option~lly subs~ituted hydrazino g,oup is, for example, hydrazino, 2-lower alkylhydrazino, 2,2-di-lower alk-ylhydrazino, 2-lower alkoxycarbonylhydrazino or 2-lower alk-znoylhydrazino.
Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, as well as n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl, whilst lower alkenyl can, for ex mple, be vinyl, allyl, ~30-propenyl, 2- or 3-methallyl or 3-butenyl, lower ~l~inyl can, for example, be propargyl or 2-butinyl and lower alkylidene can, for example, be isopropylidene or isobutylidene.
Lower alkylene is, for example, 1,2-ethyler.e, 1,2-or 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexyl-ene, 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 al~ylene, such as 3-oxa-1,5-pentylene, th1a-lower alkylene, such as 3-thia-1,5-pentylene, or aza-lower alkylene, such as 3-lower alkyl-3-aza-1,5-pentylene, for example 3-methyl-3-aza-1,5-pentylene.
Cycloa~syl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl as well as adamantyl, cycloalkenyl is, for example, cyclopropenyl, 1-, 2- or 3-, , .
. ~

~084~S54 cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl and cycloalkylidene is, for example, cyclo~entylidene or cyclohexylidene. Cycloalkyl-lower alkyl or -lower alkenyl is, for example, cyclopropyl-, cyclopen-tyl-, cyclohexyl- or cycloheptyl-methyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, -vinyl or -allyl, whilst cyclo-alkenyl-lower alkyl or -lower alkenyl represents, for example, 1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexen-O yl- or 1-, 2- or 3-cycloheptenyl-methyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, -vinyl or -allyl. Cycloalkyl-lower alkylidene is, for example, 3_cyclohexenylmethylene.
Naphthyl is 1- or 2-naphthyl, whilst biphenylyl representis, for example, 4-biphenylyl.
Phenyl-lower alkyl or phenyl-lower al~enyl is, for example, benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenyl-propyl, diphenylmethyl, trityl, styryl or cinniamyl, n2ph~hyl-lower alkyl is, for example, 1- or 2-naph~hylmethyl and phenyl-lower alkylidene is, for example, benzylidene.
~' Heterocyclic radicals are above all optionally sub-~tituted heterocyclic radicals of aromatic character, for example appropriate monocyclic, monoazacyclic, monothiacyclic or monooxacyclic radicals, such as pyrryl, for example 2-pyr-ryl or 3-pyrryl, pyridyl, for example 2-, 3- or 4-pyridyl and also pyridLnium, thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl, bicyclic monoazacyclic, monooxa-cyclic or monothiacyclic radicals, such as indolyl, for example 2- or 3-indolyl, quinolyl, for example 2- or 4-10 8 4~54 quinolyl, isoquinolinyl, for example l-isoquinolinyl, oenzo-furanyl, for example 2- or 3-benzofuranyl, or benzoth~enyl, for example 2- or ~-benzothienyl, monocyclic diazacyclic, triazacyclic, tetrazacyclic, oxazacyclic, thiazacyclic or ~hiadiazacyclic radtcals, such as imidazolyl, for exa~ple 2-imidazolyl, pyrimldinyl, for example 2- or 4-pyrimidinyl, triazolyl, for example 1,2,4-triazol-3-yl, te~razolyl, for example 1- or 5-tetrazolyl, oxazolyl, for exa~ple 2-ox~zolyl, isoxazolyl, for example 3- or 4-isoxazolyl, ~hiazolyl, for example 2-thiazolyl, isothiazolyl, for example 3- or /l iso-thiazolyl, or 1,2,4- or 1,3,4-thiadiazolyl, for example 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic di~zacyclic, oxazacyclic or thiazacyclic radicals, such as benzimidazolyl, for example 2-benzimidazolyl, benzoxazolyl, for example 2-benzoxazolyl, or benzthiazolyl, for ex~mple 2-benzthiazolyl. Appropriate partially or wholly satu~ated radicals are, for example, tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydro-furyl, or piperidyl, for example 2- or 4-piperidyl.
Heterocyclic-aliphatic radic~ls are lower alkyl or lower alk-enyl containing heterocyclic groups, especi~ly those men-~ioned above. m e a~ovementioned heterocyclyl radicals can be substituted, for example by optionally substituted ali-phatic or ~romatic hydrocarbon radicals, especially lower alkyl, such as methyl, or phenyl which is optionally substi-tuted, for example by halogen such as chlorine, for exa3ple phenyl or 4-chlorophenyl, or~ for example like the aliphatic _ 14 -iO8 4054 ~ydrocarbcn radicals, by functional ~roups.
Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutcxy, sec.-butoxy, tert.-butoxy, n-pentoxy or tert.-pentoxy. mese groups can be substituted, for example as in halog~lower alkoxy, especi-ally 2-halogeno-lower alkoxy, for example 2,2,2-trichloro-ethoxy, 2-chloroethoxy, 2-~romoethoxy or 2-iodoe~hoxy.
Lower alkenyloxy is, for example, ~inyloxy or ~llyloxy, lower alkylenedioxy is, for example, methylenedioxy, ethyl-enedioxy or isopropylidenedioxy, cyclo~lkoxy is, for example, cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy is, for example, benzyloxy, 1- or 2-phenylethoxy, di-phenylmethoxy or 4,4'-d~methoxy-diphenylmethoxy and hetero-cyclyloxy or heterocyclyl-lower alkoxy is, for example, pyri-dyl-lower alkoxy, such as 2-pyridylmethoxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy.
Lower alkylthio is, for example, methylthio, ethyl-thio or n-butylthio, lower alkenylthio is, for example, ~llylthio, and phenyl-lower alkylthio is, for exAmple, benzyl-thio, whilst mercapto groups etherified by heterocyclyl radi-cals or heterocyclyl-aliphatic radicals are especially pyri-dylthio, for example 4-pyridyithio, imidazolylthlo, thiazo-lylthio, for example 2-thiazolylthio, 1,2,4- or 1,3,4-thia-diazolylth~o, for example 1,2,4-thiadiazol-3-ylthio or 1,3,rl thiadiazol-2-ylthio, or tetrazolylthio, for example l-me~hyl-5-tetrazolylthic.

., , :
.
'~

Esterified hydroxyl groups are above ~11 halogen, for example fluorine, chlorine, bromine or iodi~e, as well as lower alXo~carbonyloxy, ~or example methoxycarbonylox~, ethoxycarbonyloxy or tert.-butoxycarbonyloxy, 2-halogeno-lower alkoxycarbonyloxy, for example 2,2,2-trich~oroethoxy-c~r~onyloxy, 2-bromoethoxycarbonyloxy or 2-iodoetho~ycarbo-nyloxy, or arylcarbonylmethoxycarbonyloxy, for example phen-acyloxycarbG~yloxy.
O Lower alkoxycarbonyl is, for example, methoxycar-bonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert.-butoxycarbonyl or tert.-pentoxycarbonyl.
N-Lower alkyl- or N,N-di-lower alkyl-carbamoyl is, for example, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimeth-ylcarbamoyl or N,N-diethylcarbamoyl, whilst N-lower al~ylsul-phamoyl represents, for example, N-methylsulph~moyl or N,N-~methylsulphamoyl.
A carboxyl or sulpho present i~ the form of an alkali metal salt is, for example, a carboxyl or sulpho present in the form of a sodium or potassium s~lt.
Lower alkylamino or di-lower alkylamino is, for example, methylamino, ethylamino, dimethylamino or diet~yl-amino, lower alkyleneamino is, for example, pyrrolidino or piperidino, oxa-lower alkyleneamino is, for example, mor~ho-lino, thia-lower alkyleneamino is, for example, thiomorpho-lino, and aza-lower ~lkylene~m;no is, for example piperazino or 4-methylpiperaz~no. Acylamino in particular represents carbamoylamino, lower alkylcarbamoyl~ino, such as methyl-i~84054 carbamoylamino, ureidocarbonylamino, ~uanidinocarbonylamino, lower ~lkoxycarbonylamino, for example methoxycarbonyl~;no, ethoxycarbonylamino or ~ert.-butoxycarbonylami~o, halogeno-lower alkoxycarbonylamino, such as 2,2,2-trichloroethoxycarb-onyl~m;no, phenyl-lower alkoxycarbonylamino, such as 4 meth-oxybenzyloxycarbonylamino, lower alkanoylamino, such as acet-ylamino or prop~onylamino, and also phthalimido, or sulpho-amino optionally present ~n the form of a salt, such as in the ~orm of an alkali metal s~lt, for example in the form of a sodium salt or mmonium salt.
Lower alkanoyl is, for example, ~ormyl, acetyl, pro-pionyl or pivaloyl.
0-Lower alkyl-phosphono is, for example 0-methyl- or 0-ethyl-phosphono, 0,0'-di-lower alkyl-phosphono is, for example, 0,0-dimethyl-phosphono or 0,0'-diethylphosphono, 0-phenyl-lower alkyl-phosphono is, for example,0-benzyl-phos-phono, and 0-lower alkyl-0'-phenyl-lower alkyl-phosphono is, for example, 0-benzyl-0'-methyl-phosphono.
O Lower alkenyloxycarbonyl is, for example, ~inyloxy-carbonyl, whilst cycloalkoxycarbonyl and phenyl-lower alkoxy-carbonyl represent, for example, adam~ntyloxycarbonyl, ben-zyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, diphenylmethoxy-~carbonyl or -4-hiphenyl- - methyl-ethoxycarbonyl. Lo~rer alkoxycarbonyl, wherein lower ~-kyl contains, for example, a monocyclic, monoazacyclic, monooxacyclic or monothiPcyclic group, is, for example, furyl-lower.~lXoxycarbonyl, such as furfuryloxycarbonyl, or thienyl-lower alkoxycarbor.yl, suc~

iO84054 as 2-thenyloxycarbonyl.
2-Lower alkylhydrazino and 2,2-di-lower alkylhydra-zino are, for example, 2-methylhydrazino or 2,2-dimethyl-hydrazino, 2-lower alkoxycarbonylhydrazino is, for example, 2-methoxycarbonylhydrazino, 2-ethoxycarbonylhadrazino is, for example, 2-acetylhydrazino.
An acyl group Ac in particular represents an acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, contained in a naturally occurring or bio-synthetically, semi-synthetically or total-syntheti-cally obtainable, preferably pharmacologically active, N-acyl derivative of a 6-amino-penam-3-carboxylic acid compound or 7-amino-3-cephem-4-carboxylic acid compoun, or represents an easily removable acyl radical, especially or a carbonic acid half-derivative.
Acyl radicals Rl are, for example acetyl, propionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acrylyl, crotonyl,

3-butenoyl, 2-pentenoyl, methoxyacetyl, butylthioacetyl, allylthioacetyl, methylthioacetyl, chloroacetyl, bromo-acetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, amlnoacetyl or 5-amino-5-carboxy-valeryl (with an amino group which is optionally substituted, for example as indicated, such as substituted by a monoacyl or diacyl radical, for example an opttionally halogenated lower alkanoyl radical, such as acetyl or di-chloroacetyl, or phthaloyl, and/or with an optionally functionally modified carboxyl group, for example a carboxyl L~
i . . , i, group present in the form of a salt, such as a sodium salt, or in the form of an ester, such as a lower alkyl ester, for example a methyl or ethyl ester, or an aryl-lower alkyl ester, for example diphenylmethyl ester), azidoacetyl, car-boxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bis-methoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyano-acetyl, a-cyanopropionyl, 2-cyano-3,3-dimethyl-acrylyl, phenylacetyl, a-bromophenylacetyl, a-azido-phenylacetyl, 3-chlorophenylacetyl, 2- or 4-aminomethylphenyl-acetyl (with an amino group which is optionally substituted, for example, as indicated), phenacylcarbonyl, phenoxyacetyl, phenylthioacetyl, a-cyano-phenylacetyl, especially phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxy-phenylglycyl, 3,5-dichloro-4-hydroxy-phenylglycyl, a-amino-a-(1,4-cyclohexadienyl)-acetyl, or a-hydroxyphenylacetyl (it being possible, in these radicals, for an amino group which is present to be optionally substituted, for example as indicated above, and~.or an aliphatic 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 acld half-ester), or a-O-methyl-phosphono-phenyl-acetyl or a-O,O-dimethyl-phosphono-phenyl-acetyl, a-carboxyphenylacetyl (with a carboxyl group which is optionally functionally modified, for example as indi-cated above~, 2-pyridylacetyl, 4-amino-pyridiniumacetyl (optionally wlth an amino group which is substituted, for example as indicated above), 2-thienylacetyl, 3-thienyl-acetyl, 2-furylacetyl, l-imidazolylacetyl, l-tetrazolyl-acetal, a-carboxy-2-thienylacetyl or a-carboxy-3-thienyl-acetyl (optionally with a carboxyl group which is functionally modified, ~'' ~'~1 .. ... -..

. - ~ . .

:.

for example as indicated above), a-cyano-2-thienylacetyl, a-amino-a-(2-thienyl)-acetyl, a-amino-a-(2-furyl)-acetyl or a-amino-2-(4-isothiazolyl)-acetyl (optionally with an amino group which is substituted, for example as indicated above), a-sulphophenylacetyl (optionally with a sulpho group which is functionally modified, for example like the carboxyl group), 3-methyl-2-imidazolylthioacetyl, 1,2,4-triazol-3-yl-thioacetyl, 1,3,4-triazol-2-ylthioacetyl, 5-methyl-1,2,4-thiadiazol-3-ylthioacetyl, 5-methyl-1,3,4-thiadiazol-2-ylthioacetyl or l-methyl-5-tetrazolylthioacetyl.
An easily removable amino protective group is an acyl radical of a carbonic acid half-ester, and is above aLl an acyl radical of a half-ester of carbonic acid which can be split off by reduction, for example on treatment with a chemical reducing agent, or by treatment with acid, for example with trifluoroacetic acid, such as a lower alkoxycarbonyl group whlch preferably has miltiple branching and/or an aromatic substituent on the carbon atom in the a-position to the oxy group, or a methoxy-carbonyl group which is substituted by arylcarbonyl, especlally benzoyl, radicals, or a lower alkoxycarbonyl radical which is substituted in the ~-position by halogen atoms, for example tert.-butoxycarbonyl, tert.-pentoxy-carbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxy-carbonyl or 2-iodoethoxycarbonyl or a radical which can be converted into the latter, such as 2-chloroethoxy-carbonyl or 2-bromoethoxycarbonyl, and also preferably polycyclic cycloalkoxycarbonyl, for example adamantyloxy-carbonyl, optionally substituted phenyl-lower alkoxy-carbonyl, above all a-phenyl-lower alkoxycarbonyl, . . .

. _ _ _ _ . , . . _ . , . _ . .. _ _ . . ... . .

wherein the a-position is preferably polysubstituted, for example diphenylmethoxycarbonyl, or 2-4-diphenylyl-a-methylethoxycarbonyl, or furyl-lower alkoxycarbonyl, above all a-furyl-lower alkoxycarbonyl, for example furfuryloxy-carbonyl.
A bivalent amino protective acyl group is, for example, the acyl radical of a lower alkanedicarboxylic acid or lower alkenedicarboxylic acid, such as succinyl, or an o-arylenedicarboxylic acid, such as phthaloyl.
A further bivalent amino protective radical is, for example, a l-oxo-3-aza-1,4-butylene radical which is substituted, especially in the 2-position and . ~ - i ~08 405 4 contains, for exa~ple, option~lly substituted phenyl or thi-enyl, 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-~-aza-1,4-butylene.
An etherified hydroxyl group R2 ~orms, together with the carbonyl grouping, an esterified carboxyl group which c~n preferably be split easily or c~n be converted easily into another functionally modified carboxyl group, such as into ~
carbamoyl or hydrazinoc rbonyl group. Such a group R2 is, for 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 con-~erted, especially in 2-cephem compounds, into a free car-boxyl group or into another functionally modified carboxyl grotlp .
An etherified hydroxyl group R2A which together with a -C(=0)- grouping forms an esterified carboxyl group which can be split particularly easily represents, for exa~ple, 2-halogeno-lower alkoxy, wherein halogen pre~erably has an weight above 19. Such a radical forms, toget~er with the -C(=~)- grouping, an esterified carboxyl group which can easily be split on treatment with chemical reducing age~ts under neutral or we~kly acid conditions, for exa~ple W~l zinc in the presence of aqueous acetic acid, or an esterified carboxyl group which can easily be con~erted into such a group and is, for ex2mple, 2,2,2-trichloroethoxy or 2-iodoethoxy, also 2-chloroethoxy or 2-~romoethoxy, ~hich can - ~B. ~

1~84~54 easily be converted into the lat~er.
An etherified hydroxyl group RA which together with the -C(=O)- groupirg represents an esterified carboxyl group which can also be split easily on treatment with chemical reducing agents under neutral or weakiy acid conditions, for example on treatment with zinc in t~e presence of aqueous aoetic acid, and also on treatment with a suitable nucleo-philic re2gent, for exi~ple sodium thiophenolate, is an aryl-carbonylmethoxy group, wherein aryl in partic~lar represents an optionally substituted phenyl group, and pre~erably phenacyloxy.
m e group R2 can i~lso represent an arylmethoxy grou~
wherein aryl in particular denotes a monocyclic, preferably subst~tuted, aromatic hydrocarbon radical. Such a radical forms, together with the -C~-O)- grouping, an esterified carboxyl group which can easily be split on irradiation, pre~erably with ultraviolet light, under neutral or acid conditions. An aryl radical in such an arylmethoxy grou~
is in particular lower alkoxyphenyl, for example methoxy-phenyl (wherein methoxy aoo~e all is in the 3-, 4- and/or 5-position) and/or above all nitrophenyl (wherein nitro is preferably in the 2-position). Such radicals are, in par-ticl~lar, lower alkoxy-benzyloxy, for example methoxy-benzyl-oxy, and/or nitro-benzyloxy, above ali 3- or 4-methoxy-benzyloxy, 3,5-dimethoxy-benzyloxy, 2-nitro-benzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy.
An etherified hydroxyl group R2 can also represent a - -1084~S4 radical which, together with the -C(=O)- groupir.g, forms an esterified carboxyl group which can easily be split under acid conditions, for example on treatment wi~h trifluoro-acetic acid or formic acid. Such a radical is abo~e all a methoxy group in ~rhich methyl is polysubstituted by option-ally substituted hydrocarbon radicals, especially aliphatic ~
or aromatic hydrocarbon radicals, such as lower ~kyl, for example methyl, and/or phenyl, or is monosubstituted by a carbocyclic aryl group possessing electron-donating substi-tuents or by a heterocyclic group of aromatic character pos-sessing oxygen or s1llphur as a ring member, or in which methyl denotes a ring member in a polycycloaliphatic hydro-carbon radical or denotes the ring member which represents the a-position to the oxygen or sulphur atom in ~n oxacyclo-aliphatic or t~iacycloaliphatic radical.
Preferred polysubstituted me~hoxy 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 ~lso 2-(4-biphenylyl)-2-propoxy, whilst a methoxy group which contains the abo~ementioned substituted aryl group or the heterocyclic group ~s, for example, a-lower alkoxy-phenyl-lower alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or furfuryloxy, such as 2-furfuryloxy.
A polycycloaliphatic hydrocarbon radical in which the methyl of the methoxy group reprPsents a branched, preferably triply branched, ring member, is, fo7 example, adaman~yl, such as ~ ~ ,3~ -l-adaman~yl, and an abovementioned oxacycloaliphatic or thia-cycloaliphatic radic~ herein the methyl of ~he methoxy group is the ring me~er which represents the a-position to the oxygen atom or sulphur atom, denotes, for example, 2-oxa-or 2-thia-lcwer al~ylene or -lower alkenylene with 5-7 ring atoms, such as ~-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulphur an~logues.
m e radical R2 can also represent an etherified hyd-roxyl group ~hich, together with ~he -C(=O)- grouping forms an esterified carboxyl group which can be split hydrolyti-cally, for example under weakly ~asic or weakly acid condi-tions. Such a radical is, preferably, an etherifi~d nyd-roxyl group which forms an activated ester group with the -C(=O)- grouping, such as nitrophenyloxy, for example 4-Ditrophenyloxy or 2,4-dinitrophenyloxy, nitrophenyl-lower alkoxy, for example 4-nitro-benzyloxy, nydroxy-lower alkyl-benæyloxy, for example 4-hydroxy-3,5-tert.-butyl-benzyloxy, polyhalogenophenyloxy, for example 2,4,6-trichlorophen~loxy or 2,3,4,5,6-pentachlorophenyloxy, and also cyanomethoxy, as well as acylaminomethoxy, for example phthali~inomethoxy or succinyliminomethoxy.
~ he group RA can also represent an etherified hyd-roxyl group which, together with the carbonyl groupirg 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 o~ n~ tro, such as benzyloxy, 4-methoxybenzyloxy or 4-nitrobenzyloxy.
The group R2 can also be an etherified hydroxyl group which, together with the carbonyl grouping -C(=O)-, forms an esterified carboxyl group which can be split under physiological conditions, above all an acyloxymethoxy group, wherein acyl denotes, for example, the radical of an organic carboxylic acid, above all of an optionally sub-stituted lower alkanecarboxylic acid, or wherein acyloxy-methyl forms the residue of a lactone. Hydroxyl groups etherified in this way are lower alkanoyloxymethoxy, for example acetoxymethoxy or pivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, especially a-amino-lower alkanoyloxy-methoxy, for example glycyloxymethoxy, L-valyloxymethoxy, L-leucyloxymethoxy and also phthalidyloxy.
A silyloxy or stannyloxy group R2 preferably contains, as substituents, optionally substituted ali-phatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, halogeno-lower alkyl, cyclo-alkyl, phenyl or phenyl-lower alkyl groups, or optionally modified functional groups, such as etherified hydroxyl groups, for example lower alkoxy groups, or halogen atoms, for example chlorine atoms, and above all represents tri-lower alkylsilyloxy, for example trimethylsilyloxy, halogeno-lower alkoxy-lower alkylsilyl, for example chloromethoxymethylsilyl, or tri-lower alkylstanyloxy, for example tri-n-butylstannyloxy.

~' ,..~. . '.

1~84054 The invention in particular relates to intermediates useful for the manufacture of compound of the formula IA or IB.
The compounds of the formula IA or IB possess valuable pharmacological properties or can be used as intermediate products respectively for the manufacture of such compounds. Compounds of the formula IA wherein, for example, R; represents an acyl radical occurring in pharma-cologically acitve N-acyl derivatives of 6~-amino-penam-3-carboxylic acid compounds or 7~-amino-3-cephem-4-carboxy-lic acid compounds, R2 dneotes hydroxyl or an etherified hydroxyl group R2 which, together with the carbonyl group, forms an esterified carboxyl group which can easily be split under physiological conditions, and R3 denotes lower alkyl, and functional groups which may be present in an acyl radical Rla, such as amino, carboxyl, hydroxyl and/or supho, are usually in the free form, or salts of such compounds having salt-forming groups, are effective, on parenteral and/or oral administratiGn, against micro-organisms such as Gram-positive bacteria, for example StYPhylococcus aureus, Streptococcus pyogenes and Dlplococcus pneumoniae (for example in mice at doses of about 0.001 to about 0.02 g/kg s.c. or p.o.), and Gram-negative bacteria, for example, Escherichia coli, Salmonella tYphimurium, Shigella flexneri, Klebsiella pneumoniae, Enterobacter cloacae, Proteus vulqaris, Proteus rettgeri and Proteus mirabilis (for example in mice in dcses of about 0.001 to about 0.15 g/kg s.c. or p.o.), and especially also against penicillin-resistant bacteria, and are of low toxicity. These new compounds can therefore be used, ... . .. . . .. . . . . . , . . . . ~

for example in the form of antibiotically activ2 prepara-tions, for the treatment of corresponding infections.

Compounds of the formula IB or l-oxides of compo.unds of the formula IA, wherein Rl, R2 and R3 have the meanings indicated in the context of the formula IA, or compounds of the formula IA, wherein R3 has the abovementioned meaning, the radical Ral denotes and amino protective ~roup different from an acyl radical occurring in pharmacologi-cally active N-acyl derivative of 6~-amino-penam-3-carboxylic acid compounds or 7~-amino-3-cephem-4-carboxylic acid compounds and R2 represents hydroxyl, or Rl has the abovementioned meanings, R2 represents a radical R2 which together with the -C(=O)- grouping forms a protected carboxyl group which can preferably be split easily, a carboxyl group protected in this was being different from a carboxyl group which can be split physiologically, and R3 has the abovementioned meanings, are valuable inter-mediate products, which can be converted in a simple manner, for example as is described below, into the abovementioned pharmacologically active compounds.
The invention in particular relates to intermediates useful for the manufacture of the formula IA, wherein Rla denotes an acyl radical of the abovementioned formula A' or A" in which RI and RII above all have the preferred meanings, R2 represents hydroxyl, lower alkoxy which is optionally monosubstituted or polysubstituted, preferably in the a-position, for example by optionally substltuted aryloxy, such as lower alkoxyphenyloxy, for example 4-methoxyphenyloxy, lower alkanoyloxy, for example acetoxy or pivaloyloxy, a-amino-lower alkanoyloxy, for example glycyloxy, L-valyloxy or L-leucyloxy, arylcar-1~84054 bonyl, for example benzoyl, or optionally substituted aryl, such as phenyl, lower alkoxyphenyl, for example 4-methoxy-phenyl, nitrophenyl, for example 4-nitrophenyl, or bi-phenylyl, for example 4-biphenylyl, or is monosubstituted or polysubstituted in the ~-position by halogen, for example chlorine, brom.ine or iodine, such as lower alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert.-butoxy or tert.-pentoxy, bis-phenyloxy-methoxy which is optionally substituted by lower alkoxy, for example bis-4-methoxyphenyloxy-methoxy, lower alkanoyl-oxy-methoxy, for example acetoxymethoxy or pivaloyloxy-methoxy, a-amino-lower alkanoyloxy-methoxy, for example glycyloxymethoxy, phenacyloxy, optionally substituted phenyl-lower alkoxy, especially l-phenyl-lower alkoxy, such as phenylmethoxy, with such radicals being able to contain 1-3 phenyl radicals which are optionally substituted, for example by.lower alkoxy, such as methoxy, nitro or phenyl, for example benzyloxy, 4-methoxy-benzyloxy, 2-biphenylyl-2-propoxy. 4-nitro-benzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or diphenylmethoxy or trityloxy, or 2-halogeno-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, and also 2-phthalidyloxy, and R3 represents hydrogen, lower alkyl, especially methyl, tri-lower alkylsilyl, for example trimethylsilyl, or benzyl or diphenylmethyl which are optionally substituted by halogen or lower alkoxy, and also the corresponding 2-cephem compounds of the formula IB, or salts of such compounds with salt-forming groups.

~' -- .. _ . . __ .. ___ , . .. .. . , ., _ _ .. . . ~ . . . _ .. .. . .. . . .

. . .
~. .

1084~54 Above all, in a 3-cephe~ compound of the formula IA, and in a corresponding 2-cephem compound of the formula IB, or in a salt of such a compound having salt-forming groups, Ral represents an acyl racidal of the formula A' or A", wherein RI and RII above all have the preferred meanings, such as a phenylacetyl or phenyloxyacetyl radical which is optionally substituted, for example by hydroxyl, also a lower alkanoyl or lower alkenoyl radical which is option-ally substituted, for example by lower alkylthio, or lower alkenylthio, as well as by optionally substituted, such as acylated, amino and/or functionally modified, such as esterified, carboxyl, for example 4-hydroxy-phenylacetyl, hexanoyl, octanoyl, or n-butylthioacetyl, and especially

5-amino-5-carboxy-valeryl, wherein the amino and/or the carboxyl groups are optionally protected and are present, for example, as acylamino or esterified carboxyl, phenyl-acetyl or phenyloxyacetyl, or an acyl radical occuring in highly active N-acyl derivatives of 6B-amino-penam-3-carboxylic acid compounds or 7B-amino-3-cephem-4-carboxylic acid compounds, especially of the formuL~ A' or A", where-in RII above all have the preferred meanings, such as formyl, cyanoacetyl, phenylacetyl, thienylacetyl, for example 2-thienylacetyl, or tetrazolylacetyl, for example l-tetrazolylacetyl, but especially acetyl substituted in the -position by a cyclic, such as a cycloaliphatic aro-matic or heterocyclic, above all monocyclic, radical and ' ' - - .

' - :

- 1084~54 by a functional group, abo~e all amino, carboxyl, sulpho or hydroxyl groups, especially phenylglycyl, wherein phenyl represents phenyl which is optionally substituted, for example by optionally protected hydroxy, such as acyloxy, for example optionally halogen-substituted lower alkoxycar-bonyloxy or lower alkanoyloxy, and~or by halogen, for example chlorine, for example phenyl or 3- or 4-hydroxy-phenyl, 3-chloro-4-hydroxyphenyl or 3,5-dichloro-4-hydroxy-phenyl (optionally also with a protected hydroxyl group, such as an acylated hydroxyl group), and wherein the amino group can also optionally be substituted and represents, for example, a sulphoamino group optionally present in the form of a salt, or an amino group which contains, as sub-stituents, a hydrolytically removable trityl group or above all an acyl group, such as an optionally substituted carbamoyl group, such as an optionally substituted ureido-carbonyl group, for example ureidocarbonyl or N'-trichloro-methylureidocarbonyl, or an optionally substituted guanidi-nocarbonyl group, for example guanidinocarbonyl, or an acyl radical which can be split off, preferably easily, for example on treatment with an acid agent, such as tri-fluoroacetic acid, or reductively, such as on treatment with a chemical reducing agent, such as zinc in the pre-sence of aqueous acetic acid, or with catalytic hydrogen, or hydrolytically, or an aryl radical which can be con-verted into such a radical, preferably a suitable acyl ,., ~"
,.. ' '' ' ' radical or a carbonic acid half-ester, such as one of the above-mentioned, for example optionally halogen-substi-tuted or benzoyl-substituted, lower alkoxycarbonyl radi-cals, for example tert.-butoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxy-carbonyl, 2-iodoethoxycarbonyl or phenacyloxycarbonyl, optionally lower alkoky-substituted or nitro-substituted phenyl-lower alkoxycarbonyl, for example 4-methoxy-benzyl-oxycarbonyl or diphenylmethoxycarbonyl, or suitable acyl radical or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, or an arylthio or aryl-lower alkylthio radical which can be split off with a nucleo-philic reagent, such as hydrocyanic acid, sulphurous acid or thioacetic acid amide, for example 2-nitro-phenyl-thio or tritylthio, an arylsulphonyl radical which can be split off by means of electrolytic reduction, for example 4-methylphenylsulphonyl, or a l-lower alkoxy-carbonyl or l-lower alkanoyl-2-propylidene radical which can be split off with an acid agent, such as formic acid or aqueous mineral acid, for example hydrochloric acid or phosphoric acid, for example l-ethoxycarbonyl-2-propyl-idene, and also a-(1,4-cycl~hexadienyl)-glycyl-,a-thi-enyl-glycyl, such as a-2- or a-3-thienylglycyl, a-furyl-' :

.

glycyl, such as a-2-furylglycyl, -isot~iazolylglycyl, such as a-4-isot~iazolyl-glycyl, i~ bei~g possible for the amino group in sucn radicals to be substituted or protected, for example as indicated for a phenylglycyl radical, also a-carboxy-phenylacetyl or a-carboxy-~hienylacetyl, for example a-carboxy-2-thienylacetyl (optionally with a functionally modified carboxyl group, for example a carboxyl group pre-se.~t in the form of a salt, such as a sodium salt, or in the form of an esier, such as a lower alkyl ester, for example methyl or ethyl ester, or phenyl-lower alkyl ester, for example diphenylme~hyl ester), a-sulpho-phenylacetyl (option-Rlly also with a sulpho group which is functionally modi-fied, for exa~ple like the carboxyl group), -phosphono-, -O-methyl-phosphono- or a-O,Ot-dimethyl-phosphono-phenylacetyl, or -hydroxy-phenylacetyl (optionally with a functionally modified hydroxyl group, especially with an acylo~J group, wherein acyl denotes an acyl radical which can be spiit off, preferably easily, for example on treatment wit~ an acid agent, such as trifluoroacetic acid, or with a chemical redu-cing 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 ac~d half-ester, such as one of the abo~ementioned lower koxycarbonyl radicals which are, for example, o~tion~lly substituted by halogen or benzoyl, for example 2,2,2-trichlo-roethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycar-bonyl, 2-iodoethoxycarbonyl, tert.-butoxycarbonyl or phenacyl-iO84054 oxycarbonyl, and also formyl), as well as aminomethyl-phenylacetyl, such as 2- or 4-aminomethylphenylacetyl, or amino-pyridiniumacetyl, for example 4-amino-pyridinium-acetyl (optionally also with an amino group which is sub-stituted, for example as indicated above), or pyridylthio-acetyl, for example 4-pyridylthioacetyl, and R2 represents hydroxyl, lower alkoxy, especially a-poly-branched lower alkoxy, for example tert.-butoxy, also methoxy or ethoxy, 2-halogeno-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-chloroethoxy or 2-bromoethoxy which can easily be converted into 2-iodoethoxy, phenacyloxy, 1-phenyl-lower alkoxy with 1-3 phenyl radicals which are op-tionally substituted by lower alkoxy or nitro, for example 4-methoxybenzyloxy, 4-nitro-benzyloxy, diphenylmethoxy, 4,4'-dimethoxydiphenylmethoxy or trityloxy, lower alkanoyl-oxymethoxy, for example acetoxymethoxy or pivaloyloxy-methoxy, a-amino-lower alkanoyloxymethoxy, for example gly-cyloxymethoxy, 2-phthalidyloxymethoxy, lower alkoxycarbo-nyloxy, for example ethoxycarbonyloxy, or lower alkanoyl-- 34~-: :
, : ' ', :

~84054 oxy, for example acetoxy, and also tri-lower alkylsilyloxy, for example trimethylsilyloxy, and R3 represents hydrogen, lower alkyl, especially methyl, tri-lower alkylsilyl, for example trimethylsilyl, or benzyl or diphenylmethyl which are optionally substituted, for example hy haloaen. such as chlorine or bromine, or lower alkoxy, such as methoxy.
The invention above all relates to intermediates useful for the manufacture of 3-cephem compounds of the formula IA, wherein RaL denotes hydrogen or an acyl group of the formula o Ra (X)m ~ - C (B) wherein Ra denotes phenyl or hydroxyphenyl, for example 3- or 4-hydroxyphenyl, also hydroxy-chlorophenyl, for example 3-chloro-4-hydroxyphenyl or 3,5-dichloro-4-hydroxy-phenyl, it being possible for hydroxy substituents in such radicals to be protected by acyl radicals, such as option-ally halogenated lower alkoxycarbonyl radicals, for example tert.-butoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, as well as thienyl, for example 2- or 3-thienyl, and also pyridyl, for example 4-pyridyl, aminopyridinium, for example 4-aminopyridinium, furyl, for example 2-furyl, isothiazolyl, for examp:Le 4-isothiazolyl, or tetrazolyl, for example 1-tetrazolyl, or 1,4-cyclohexadienyl or 1-cyclohexenyl, X represents oxygen or ' .

108~054 sulphur, m represents O or 1 a~d Rb represents h-~drogen, or, if m represents 0, Rb represents a~ino, as we~l as protected amino, such as acylamino, for example a-poly-Dr2nched lower alkoxycarbonylamino, such as tert.-butoxycarbonyla~no, or 2-halogeno-lower a~koxycarbonylamino, for example 2,2,2-tri-chloroethoxyc2rbonyl2mino, 2-iodoethoxycarbonyl~m;no or 2-bromoethoxycarb3nyl?mino, or optionally lower a koxy-subsii-tuted or nitro-substituted phenyl-lower alkoxycarbonylamino, for example 4-methoxybenzyloxycarbonylamino or diphenylmeth-oxycarbonyl mino, or 3-guanylureido, also sulpho~~no or tritylam~no, as well as arylthioamino, for example 2-nitro-phenylthioamino, arylslllphonyl~m~no, for example 4-methyl-phenylsulphonylaminoS or l-lower alkoxycarbonyl-2-propylidene-amino, for example l-ethoxycarbonyl-2-propyliderLe mino, car-boxyl, or carboxyl present in the form of a salt, for example an alkali metal salt, such as a sodium salt, as ~reli as pro-tected carboxyl, for exzmple esteri~ied carboxyl, such as phenyl-lower alkoxycarbonyl, for example diphenylmethox~car-bonyl, sulpho, or sulpho present in the form of a salt, for example an alkali metal salt, such as a sodium saltS as well as protected sulpho, hydroxyl, as well as protected hydroxyl, such as acyloxy, for example a-poly-branched lower alkoxyca--bonyloxy, such as tert.-butoxycarbonyloxyor2-halogeno-lower Alkoxycarbonyloxy~ such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, also formyloxy, or O-lower alkylphosphono or O,O'-di-lower alkyl-phosphono, for ex~mple O-met~ phosphono or O,O'-dimethyl-IB , ~

:: , :

l~s4as4 phosphono, or denotes a 5-amino-5-carboxy-valeryl radical, wherein the amino and/or carboxyl groups can also be pro-te~ted and are, for example, present as acylamino, for example lower alkanoylamino, such as acetylamino, halogeno-lower alkanoylamino such as dichloroacetylamino, benzoyl-amino or phthaloylamino, or as esterified carboxyl, such as phenyl-lower alkoxycarbonyl, for example diphenylmetho-xycarbonyl, and m preferably denotes 1 if Ra represents phenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl, and m denotes O and Rb differs from hydrogen if Ra represents phenyl, hydroxyphenyl, hydroxy-chlorophenyl, thienyl, fury~
isothiazolyl, or l,4-cyclohexadienyl, R2 ab~.ve all represents hydroxyl and also represents lower alkoxy, especially a-poly-branched lower alkoxy, for example tert.-butoxy, 2-halogeno-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or diphenyl-methoxy which is optionally substituted, for example by lower alkoxy, for example methoxy, for example diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, as well as tri-lower alkyls~lyloxy, for example trimethylsilyloxy, and ~3 denotes hydrogen, lower alkyl, for example methyl, ethyl or n-butyl, as well as tri-lower alkylsilyl, for example trimethylsilyl, and benzyl or diphenylmethyl which is optionally substituted for example by halogen, such as rhlorine or bromine, or lower alkoxy, such as methoxy, and also the corresponding 2-cephem compounds of the formula IB, or salts, especially pharmaceutically usable, non-toxic salts, of such compounds having sal'-forming groups, such as alkali metal salts, for example sodium salts, 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 amino group in the acyl radical of the formula B.
Above all, in 3-cephem compound of the formula IA, and also in corresponding 2-cephem compounds of the formula IB, as well as in salts, especially in pharmaceutically usable non-toxic salts, of such compounds which have salt-forming groups, as in the salts mentioned in the preceding paragraph, Ral represents, the acyl radical of the formula B wherein Ra denotes phenyl, as well as hydroxyphenyl, for example 4-hydroxy-phenyl, thienyl, for example 2- or 3-thienyl, 4-isothiazolyl, or 1,4-cyclohexadienyl, X den-otes oxygen, m denotes O or 1 and Rb denotes hydrogen, or, if m represents 0, denotes amino as well as protected amin~
such as acylamino, for example a-poly-branched lower al-koxy-carbonylamino, such as tert.-butoxycarbonylamino, or 2-halogeno-lower alkoxycarbonylamino, for example 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycar~onylamino, or optionally lower alkoxy-sub-stituted or nitro-substituted phenyl-lower alkoxycarbonyl-amino, for example 4-methoxybenzyloxycarbonylamino, or .
' .. . . .

~084054 hydroxyl, as well as protected hydroxyl, such as acyloxy, for example ~-poly-branched loweralkoxycarbonyloxy, such as tert.-butoxycarbonyloxy, or 2-halogeno-lower alkoxycar-bonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodo-ethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, and also formyloxy, or represents a 5-amino-5-carboxy-valeryl radi-cal, wherein the amino and car~oxyl group can also be protected and, for example, are in the form of acylamino, for example lower alkanoylamino, such as acetylamino, halo-geno-lower alkanoylamino, such as dichloroacetylamino, benzoylamino or phthaloylamino, or of esterified carboxyl, such as phenyl-lower alkoxycarbonyl, for example diphenyl-methoxycarbonyl, with m preferably denoting 1, if Ra is phenyl of hydroxyphenyl, R2 above all denotes hydroxyl and also lower alkoxy which is optionally halogen-substituted, for example chlorine-substituted, bromine-substituted or lodine-substituted, in the 2-position, especially ~-poly-branched lower alkoxy, fGr example tert.-butyloxy, or 2-halogeno-lower alkoxy, for example 2,2,2-trichloroethoxy, such as methoxy-substituted diphenylmethoxy, for example diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, or p-nitrobenzyloxy, and also tri-lower alkylsilyloxy, for example trimethyls.lyloxy, and R3 denotes hydrogen, lower alkyl, especially methyl, tri-lower alkylsilyl, for example trimethylsilyl, or a benzyl or diphenylmethyl group which is optionally substituted by halogen, for example chlorine - .

,. : .

1(~84~54 or bromine, or lower alkoxy, for example methoxy.
The invention above all relates to intermediates useful for the manufacture of 7~-(D-a-amino-a-R -acetyl-amino)-3-lower alkoxy-3-cephem-4-carboxylic acids, wherein Ra represents phenyl, 4-hydroxyphenyl, 2-thienyl, 1,4-cyclohexadienyl lower alkoxy contains up to 4 carbon atoms and represents, for example, ethoxy or n-butoxy, but above all methoxy, and the inner salts thereof, and above all 3-methoxy-7~-(D-a-phenyl-glycylamino)-3-cephem-4-carboxylic acid and the inner salt thereof: in the abovementioned concentrations, especiallv on oral administration, these compounds display excellent antibiotic properties both against Gram-positive and especially against Gram-negative bacteria, and are of low toxicity. The compounds of the formula IA or IB can be manufactured according to Canadian Patent No. 1 059 988.

According to the process of the invention, com-pounds of the formula VI are manufactured by treatment a compound of the formula Ral S-Y
CH2 (IV), O=~-RA2 wherein Ral, R2 and Y have the meanings mentioned under formula VI, the methylene group is converted into an oxo group by oxidative degradation with ozone in the presence of a solvent at temperatures of -90C to +40C.

The oxidative degradation of the methylene group is carried out with ozone and the ozonide of the formula ~084054 Ral . . S-Y
~&H2 ,8 (v) ~ - CH
O=~-RA
- obtained as an intermediate ?rcduct, wherein Rl, R2 and Y
have the meaning mentioned under formula VI, is reduced with catalytically activated hydrogen, a heavy metal, metal alloy or amalgam in the presence of a hydrogen doner, an alkali metal iodide in the presence of a hydrcgen donor, a di-lower alkylsulphide, or a reducing organic phosphorous compound.

The oxidative splitting off of the methylene group in compounds of the formula IV to form an oxo group can be carried out by forming an ozinide compound of the formula V by treatment with ozone. Herein, ozone is usually employed ln the presence of a solvent, such as an alcohol, for example a lower alkanol, such as methanol or ethanol, a ketone, for example a lower alkanone, such as acetone, an optionally halogenated aliphatic, cycloaliphatic o_ aromatic hydrocarbon, for example a halogeno-lower alkane, such as methylene chloride or carbon tetrachloride, or a solvent mixture, including an aqueous mixture, and with cooling or slight warming, for example at temperatures of about -90C to about +40C.

An ozonide of the formula V can be split by reduc-tion in stage 3, to give a compound of the formula VI, for which it is possible to use catalytically activated hydro-gen, for example hydrogen in the presence of a heavy metal hydrogenation catalyst, such as a nickel catalyst or a palladium catalyst, preferably on a suitable carrier, such . ,~ .,~
~ ~.

1~84054 as reducing hea~y metals, including heavy metal alloys oramalgams, for example zinc, in the presence of a hydrogen donor, such as an acid, for example acetic acid, or an alcohol, for example a lower alkanol, reducing inorganic 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, a reducing sulphide compound such as a di-lower alkylsulphide, for example dimethylsul-phide, a reducing organic phosphorus compound, such as a phosphine, which can optionally contain substituted ali-phatic or aromatic hydrocarbon radicals as substituents, such as tri-lower alkylphosphines, for example tri-n-butyl-phosphine, or triarylphosphines, for example triphenylphos-phine, also phosphites which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as tri-lower alkylphosphites, usually in the form of corre-sponding alcohol adduct compounds, such as trimethyl-phos-phite, or phosphorous acid triamides which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as hexa-lower alkylphosphorous acid triamides, for example hexamethyl-phosphorous acid tri-amide, the latter preferably in the form of a methanol adduct, or tetracyanoethylene. The splitting of the ozonide, which is usually not isolated, is normally carried out under the conditions which are employed for its manu-facture, that is to say in the presence of a suitable iO84054 solvent or sol~ent mixture, and ~ith cooling or slight warming.

Enol compounds of the formula VI can also be present in the tautomeric ketoform.

Compounds of the formula VI, wherein Y represents -S02-R5 can also be obtained bytreacting a compound of the formula VI, wherein Y represents the group -S-R4 with a heavy metal sulphinate of the formula Nn ( S02-R5)n, where-in M represents a heavy metal cation and n denotes the valency of this cation. Suitable heavy metal sulphinates are in particular those which have a higher solubility product in the reaction medium used than the heavy metal compounds of the formula M ~-S-R4)n which are produced during the reaction. Suitable heavy metal cations Mn are ln particular those which form particularly sparingly soluble sulphides. These include, for example, the mono-valent or divalent cations of copper, mercury, silver and tin, copper and silver cations being preferred.

The heavy metal sulphinate can either be employed as such or be formed in situ during the reaction, for example from a sulphinic acid of the formula I~S02-R5 or a soluble salt thereof, for example an alkali metal salt, such as a sodium salt, and a heavy metal salt of which the solubility product is higher than that of the heavy ~.~.
~.,.

1084~S4 metal sulphinate or heavy metal thiosulphonate produced, for example a heavy metal nitrate, acetate or sulphate, for example silver nitrate, mercury-II diacetate or copper-II sulphate, or a soluble chloride, such as tin-II
chloride dihydrate.

The reaction of a compound of the formula VI with the heavy metal sulphinate of the formula M ( S02-R5)n can be carried out in an inert organic solvent, in water or in a solvent mixture consisting of water and a water-miscible solvent. Suitable inert organic solvents are, for example, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene or xylene, or aliphatic, cycloaliphatic or aromatic alcohols, such as lower alkanols, for example methanol, ethanol, cyclohexanol or phenol, polyhydroxy compounds, such as polyhydroxyalkanes, 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, of polyethers, such as dimethoxyethane, lower carboxylic acid amides, such as dimethylformamide, lower alkyl nitriles, such as aceto-nitrile, or lower sulphoxides, such as dimethylsulphoxide.

1~8~0~4 In water, or especially in mixtures of water and one of the solvents mentioned, including in emulsions, the reaction usually takes place substantially more rapidly than in the organic solvents alone.

The reaction temperature is usually about room temperature but can be lowered to slow down the reaction or raised, say up to the boiling point of the solvent employed, to accelerate the reaction, it being possible to carry out the reaction under normal or elevated pressure.

An oxonide of the formula V, wherein Y represents the group -S-R4, obtained as an intermediate product can, optionally without isolation, be converted into a compound of the formula V, wherein Y represents the group -S02-R5, by reaction with a heavy metal sulphinate of the formula Mn ( S02-R5)n analogously to the convertion of compounds of the formuIa VI, wherein Y represents the group -S-R4 to compounds of the formula VI, wherein Y represents the group -S02-R5.

~o84054 In a starting material of the formula IV RA preferably represents an etherified hydroxyl group which, with the -C(=0)-grouping, forms an esterified carboxyl group which can be split, especially under mild conditions, it being possible for function-al groups which may be present in a carboxyl protective group RA2 to be protected in a manner which is in itself known, for ex-ample as indicated above. A group RA is, for example, in part-icular an optionally halogen-substituted lower alkoxy group, such as methoxy, ~-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-tri-chloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, or an optionally substituted l-phenyl-lower alkoxy group, such as a l-phenyl-lower alkoxy group which contains lower alkoxy, for example methoxy, or nitro, such as benzyloxy or diphenylmethoxy which are optionally substituted, for example as indicated, for example benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, and also an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, for ex-ample trimethylsilyloxy, or halogen, for example chlorine. Pre-ferably, in a starting material of the formula IV, the radical ~a, Rl denotes an acyl group, in which free functional groups which may be present, for example amino, hydroxyl, carboxyl or phos-phono groups, can be protected in a manner which is in itself known, amino groups, for example, by the abovementioned acyl, trityl, silyl or stannyl radicals as well as substituted thio or ~' , ' 1C~84054 sulphonyl radicals, and hydroxyl, carboxyl or phosphono groups, for example, by the abovementioned ether or ester groups, in-cluding silyl or stannyl groups.
In a resulting compound of the formula VI a group R~ or RA can be converted into another group R~ or R2 by various add-itional measures which are in themselves known.
The starting material of the formula IV used for the preparation of the formula VI can be manufactured, for example according to Canadian Patent No. 1,059,988.
In the context of the present description, the organic radicals described as "lower" contain, unless expressly defined, up to 7, preferably up to 4, carbon atoms; acyl radicals con-tain up to 20, preferably up to 12, and above all up to 7, car-bon atoms.
The examples which follow serve to illustrate the inven-tion. The cephem compounds mentioned in the examples possess the R-configuration in the 6- and 7-position, and the azetid-inone compounds mentioned possess the R-configuration in the 3-and 4-position.

1~8 4~5 4 Exam~le 1 A solution of 60 ~l (2 equivalents) of 1,5-diazabi-cyclo[5.4.0]undec-5-ene in l ml of tetrahydrofurane is added dropwise over the course of 5 minutes to a solution of 133 mg (0.2 mM) of an isomer mixture consisting of 2-[4-(p-toluene-sulphonylthio)-3-phenoxyacetamido-2-oxcazetidin-l-yl~-3-methoxy-crotonic acid p-nitrobenzyl ester and the corres~on~-ing isocrotonic acid ester, in the ratio o~ about 4:1, in 4 ~L
G of dry tetrahydrofurane. After standing at room temperature ~or 40 minutes, the mixture is diluted with 20 ml of benzene, cooled in an icebath and stirred for lO minutes with 10 ml of a lO~ strength citric acid solution. m e organic layer is separated off and washed successively with saturated sodium chloride solution, 10% strength sodillm bicarbor.ate solutior.
and sodium chloride solution. The solution is dried o~er magnesium s~llphate and concentrated in vacuo, and the resul~-i~g yellow oil is purified by chromatography-filtration or 4 g of acid-washed silica gel (2 kg of silica gel are stirred three times with 2 l of concentrated hydrochloric acid in each case for lO minutes, separated from the acid by decanting, washed with distilled water until neutral, rinsed with meth-anol and acti~ated for 60 hours at 120~), with benzene/ethyl acetate, 5:1, as the eluting agent. The fractions contair.ing the isomer mixture are combined and concentrated in vacuo.
A semi-solid isomer mixture, consisting of 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester and 7~-phenoxyacetamido-~-metho~y_ceph_2_em_4_carboxylic acid p_ nitrobenzyl ester in the ratio of about 1:3 is obtained and B ~

- 1084(~54 can ~e separated into the two isomers on Woelm silica gel (acti~ity III) with benzene/ethyl acetate, 5:1. The faster-running 7~-phenoxyacetamido-~-methoxy-ceph-2-em-4-carboxylic acid p-nitrobenzyl ester is recrystallised from methylene chloride/ether and has a melting point of 129-131.5C. The slower-ru~ing 7~-phenoxyacetamido-~-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester has a melting point of 140~5 - 142C (from methylene chloride/ether).
0 The products can be further converted as follows:
A 801ution, prepared at 0C, of 555 mg (1.11 mmols) of a crude mixture consisting of 7~-phenoxyacetamido-3-methoxy-ceph-2-em-4~-carboxylic acid p-nitrobenzyl ester and 7~-phenoxyacetamido-~-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the ratio of about ~:1, in 33 ml of tetrahydrofurane, is mixed, whilst stirring, with 16 ml of an 0.1 N potassium hydroxide solution which has been precooled to 0C. The mixture is stirred for a further ~ minutes at 0C, 100 ml of ice water and 100 ml of precooled methylene chlor-~ ;
ide are then added and the whole is stirred up briefly.
Addition of 1 ml of saturated aqueous sodium chloride solu-tion causes the two phases to separate. The organic phase is separated off, and the aqueous phase is again washed-with 20 ml of methylene chloride, then covered with 50 ml of methylene chloride and acidified with 20 ml of 2 N hydrochloric acid. After shaking up, the organic phase is separated o~
and the hydrochloric acid solution is extracted twice ~ore with 10 ml o~ methylene chloride at a ~ime. The co~ined ~9 methylene chloride extracts are dried over sodium sulphate and-evaporated in vacuo. The residue is recrystallised from methylene chloride/diethyl ether/pentane and gives7~-phenoxy-acetamido-3-methoxy-ceph-2-em-4-carboxylic acid of mel'ing point 142-145C.
The starting materials can be obtained as follows:
a) A solution of 36.6 g (0.1 M) o~ 6-phenoxyacetamido-penicillanic acid l~-oxide, 11.1 ml (0.11 M) of triethylamine O and 23.8 g (0.11 M) of p-nitrobenzyl bromide in 200 ml ~of di-methylformamide is stirred for 4 hours under nitrogen at room temperature. The reaction solution is then introduced into 1.5 1 of ice water and the precipitate is filtered off, dried and twice recrystallised from ethyl acetate-methylene chloride.
The colourless, crystalline 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester l~-oxide melts at 179-180C.
b) A solution of 5.01 g (10 ~) of 6-phenoxyacetamido-penicillanic acid p-nitrobenzyl ester l~-oxide and 1.67 g ~j (10 mM) of 2-mercaptobenzthiazole in 110 ml of dry toluene is boiled for 4 hours under reflux in a nitrogen atmosphere.
The solution is concentrated to approx. 25 ml by distilling o~f solYent and diluted with approx. 100 ml o~ ether. The product which has separated out is recrystallised from methy-lene chloride/ether and 2-~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~_3-methylene-butyric acid p-nitrobenzyl ester of melting point 138-141C is obtained.
c) 1.06g of finely powdered sil~er nitrate are added to a solution of 3.25 g (5.0 mM) of 2-[4-(benzthiazol-2-yldi-thio)-3-phenoxyacetamido-2-oxaazetidin-1-yl]-3-methylene-r~

~ Xc~ ~

but~ric acid p-nitrobenzyl ester in 20C ml of acetone/water, 9:1 (~/v). T~mediately a~te~wards, a solution of 890 mg (5 ~) of sodium p-toluenesulphinate in 100 ml of the same solvent mixture is introduced (over the course of 10 mi~utes).
A light yellow precipitate forms immediately. After stirring for one hour at room temperature, the mixture is filtered, with addition o~ Celite. The filtrate is diluted with water and twice extracted with ether. The combined ether extracts are dried over sodium sulphate and after concentra~ion~give pale yellow solid 2-r4-(p-toluenes-~lphonylthio)-3-phenoxy-acetamido-2-oxoazetidin-1-yl~-3-methylene-butyric acid p-nitrobenzyl ester. Thin layer chromatogram on silica gel (toluene/ethyl acetate, 2:1): Rf value = 0.24; IR spectrum (in CH2C12): characteristic bands at 3.90, 5.56, 5.70, 5.87,

6.23, 6.53, 6.66, 7.40, 7.50, 8.10, 8.72, 9.25 and 10.95 ~.
The product can be employed without further purification in the subsequent reaction.
-j The same compound can also be obtained in accordance with the following methods:
ci) 1.58 g (1.2 equivalents) of silver p-toluenesulphinate are added in portions for 10 minutes to a solution of 3.25 e (5.0 mM) of 2-~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxo2zetidin-l-yl~-3-methylene-butyric acid p-nitrobenzyl ester i~ 200 ml o~ acetone/water, 9:1 (v/v). The suspension is stirred for one hour at room temperature, ~iltered and then rurther processed as described in Example lc). 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-S/

~B ~

_ _ ~\ ~
~84054 3-methylene-butyric acid p-nitrobenzyl ester is obtained in quantitative yield.
Silver p-toluenesulphinate is obtair.ed as a colour-less precipitate by combining aqueous solutions of equimolar amounts of silver nitrate and sodium p-toluenesulphinate.
The product is dried in ~acuo for 24 hours.
cii) 2-~4-(p-Toluenesul~honylthio)-3-phenoxyacetamido-Z-oxoa7etidin-l-yl~-3-methylene-butyric acid ~-nitrobenzyl ester can also ~e obtained in quantitative yield, analogously-to Example lci) from ~.25 g of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2_oxoazetidin_1-yl~_3-methylene-butyric acid p-nitrobenzyl ester and 1.87 g (2 equivalents) of copper-II
di-p-toluenesulphinate.
Copper-II di-p-toluenesulphinate is obtzined by reac-tion of copper sulphate and sodium p-toluenesulphinate (2 equivalents) in water. After filtering off, the salt is dried in vacuo for 12 hours at 60C.
ciii) 2-[4-(p-Toluenesulphonylthio)_~-phenoxvacetamido-2-oxoazetidin-1-yl~-3-methylene-butyric acid p-nitrob_nzyl ester can also be obtained analogously to Example lci) from 130 mg of 2-r4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxo-azetidin-l-yl]-3-methylene-butyric acid p-nitrobenzyl ester and 85 mg (2 equi~alents) of tin-II di-p-toluenesulphinate.
Tin-II di-p-toluenesulphinate is obtained ~y reaction of tin-II chloride (ZH20) and sodium p-toluenesulphinate in water. After filtering off, and washing with water, the salt is dried in vacuo for about 12 hours at 50-60c.

__ _ - : :

1~84054 civ) 2-~4-(p-Toluenesulphonylthio)-3-phenoxyacetam~do-2-oxoazetidin-l-yl~-3-methylene-butyric acid p-nitrobenzyl ester can a~ beo~ ~ analogously to Example lci) from 130 mg of 2-~4-(benz~hiazol-2-yldithio)_3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-methylene-butyric acid p-nitrobenzyl ester and 102 mg (2 equivalents) of mercury-II di-p-toluenesulphinate.
Mercury-II di-p-toluenesulphinate is obtained by reaction of mercury-II diacetate and sodium p-toluenesulphin~e i~ water. After filtering off, and washing with water, the salt is dried in vacuo for about 12 hours at 50-60C.
cv) A solution of 517 mg (1.02 mM) of 6-phenoxyacet2mido-penicillanic acid p-nitrobenzyl ester l~-oxide and 187 mg (1.2 mM) of p-toluenesulphinic acid in 10 ml of 1,2-dimethoxy-ethane (or dioxane) is heated under reflux for 4.5 hours in the presence of 3.5 g of a molecular sieve 3A, and in a nitrogen atmosphere, after which a further 308 mg (1.98 mM) of p-toluenesulphinic acid, dissolved in 2 ml o~ 1,2-dimethoxy-O ethane, are added in five portions at 45 minute intervals.
After 4.5 hours, the reaction mixture is poured into 100 ml of 5% strength aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated by e~aporation. The residue ls chromatographed on silica gel thick layer plates with toluene/ethyl acetate, 2:1, and gives 2-~4-~p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazet-din-l-yl]_3-methylene-butyric acid p-nitrobenzyl ester.
r .S 3 ~ _ ,;~ _ - ~ ' .

1084(~54 c~.~i) A mixture of 250 mg (0.5 ~ of 6-phenox~acetamido-penicillanic acid p-nitrobenzyl ester l~-oxide, 110 m~ (0.61 ~) of p-toluenesulphonyl cyanide and 5 mg (0.022 ~M) of benzyltriethylammonium chloride in 2 ml of dry, peroxide-free dioxane is stirred under argon at 110C for 4.5 hours. The solvent is evaporated off in ~acuo and the yellow oil which remains is chromatographed on acid-washed silic2 gel.
~lution with 30% ethyl acetate in toluene gi~es 2-[4-(p_ toluellesulphonylthio)_3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-methylene-butyric acid p-nitrobenzyl ester.
c~ii) A mixture of 110 mg (0.61 mM) of p-toluenesulpho~yl cyanide and 4.5 mg (0.021 mM) of tetraethyl mmonium bromide in 1 ml of pure dioxane is stirred for 30 mlnutes at 110C under argon. A suspension of 250 mg (0.5 mM) of 6-phenoxyacet-amidopenicillanic acid p-nitrobenzyl ester l~-oxide in 1 ml of dioxane is then added and the resulting solution is stirred for 4 hours at 110C under argon. The sol~ent is removed in ~acuo, the crude product is di~sol~ed in ethyl acetate and the solution is washed with water and with saturated aqueous sodium chloride solution. The organic phase is dried with magnesium sulphate and freed from the sol~ent in ~acuo, giving crude 2-~4-(p-toluenesulphonylthio)-3-phenoxyaceta ~do-2-oxoazetidin-l-yl~-3-methylene-butyric acid p-nitrobenzyl ester.
d) 1.1 equi~alents of ozone are passed into a solution o~
1.92 g (3.0 mM) of 2-[4-(p-toluenesulphonylthio)-3-phenoxy-acetamido-2-oxoazetidin-1-yl~-3-methylene-butyric acid p-nitrobenzyl ester in 30 ml of dry methyl acetate, at -78C, ~ _ Bj ~4 ., ,. ~
.. . . ; .

over the course of 33 minutes. Tmmediately therealter, excess ozone is removed by means of 2 stream of nitrogen (15 minutes at -78C). 2.2 ml of dimethyl sulphide (10 equi~alents) are added and the solution is warmed to room temperature. After standing for 5 hours, the sol~ent is distilled off in vacuo and the colourless oil which remains is taken up in 100 ml of benzene. The ben2ene solution is washed with three 50 ml portions of saturated sodium chloride O solution, dried o~er magnesium sulphate and conc_ntrated to dryness in ~acuo. After recrystallising the residue from toluene, 2-r4-(p_toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-l-yl~-3-hydroxy-crotonic acid p-nitrobenzyl es~er of melting point 159-160C is obtained.
di) m e crude 2-~4-(p-toluenesulphonylthio)-3-phenoxy-acetamido-2-oxoazetidin-1-yl~-3-methylene-butyric acid p-nitrobenzyl ester obtained according to Example l.cvii) is dissol~ed in 20 ml of methyl acetate and ozonised at -70C
G until starting material is no longer present, according to a thin layer chromatogra~. A stream of nitrogen is then passed through the solution and the latter is warmed to 0-5C. A
solution of 300 mg of sodium bisulphite in 5 ml of ~ater is added and the mixture is stirred for about 5 minutes until no further ozonide is detectable by means of potassi~m iodide/
starch paper. The mixture is diluted with ethyl acetate, the aqueous phase is separated off and ~he organic phase is washed with water, dried o~er magnesium sulphate and freed from the sol~ent in ~acuo. The crude product is dissolved in L~

.

1~84C~54 3 ml of methylene chloride and 15 ml of toluene are zdded.
The precipitat2 is filtered off and the filtrate is concen-trated by evaporation in ~acuo. The residue is recrys~al-lised from methanol and gives 2-r4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2_oxoazetidin-1-yl~-3-hydroxy-crotonic acid p-nitrobenzyl ester of melting point 159-160C.
e) A solution of 1.9~ g of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacet~mido_2_oxo~zetidin-1-yl~-3-oxo-butyric acid p-nitrobenzyl ester (3.0 mM) in 15 ml of dry chloroform is cooled to 0C and 6 ml of a solution of diazomethane in ether (0.75 molar, corresponding to 1.5 equivalents) is added over the ~ourse of 10 minutes. The mixture is stirred for two hours at 0C, excess diazomethane is removed by means of a stream of nitrogen and the solvent is stripped off in ~acuo.
m e crude product is purified by filtration through Woelm s~lica gel (activity III, 40-fold amount), using benzene/
ethyl acetate, 5:1. The colourless oil obtained after dis-tilling off the sol~ent crystallises on standing. After recrystallisation from methylene chloride/ether, an isomer mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacet2mido-2-oxoazetidin-l-yl~-3_methoxy-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic ac,d ester in the ratio of about 4:1 is obtained. Melting poin~
o~ the mixture: 155-156.5C.
Exam~le 2 A solution of 279 mg of 2-~4-(p-toluenesulpho~ylthio)-3-phenoxyacetamido-2-oxoazetidin-l_yl~ hydroxy-crotonic S~

. . ..

108405~

acid diphenylmeth~-l ester (0.428 m~ol) in 4 ml of chloroform and 1 ml of hexamethyldisilazane is heated fcr or.e hour under reflux and evaporated in vacuo, and the oily residue is dried ~or one hour under a high vacuum. The silylated cr~de pro-duct consists of 2-r4-(p-'oluenesulphonylthio)-3-phenoxyaoet-amido-2-oxoazetidin-1-yl~-3-trimethylsilyloxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester.
The resulting crude product is taken u~ in ~ ml of dry -chloroform, the solution is cooled to 0C and 0.069 ml (0.47 mmolj of 1,5-diazabicyclo[5.4.0~undec-5-ene is added under nitrogen, whilst stirring. After a reaction time o~ 1 hour, the solution is mixed with 0.3 ml of acetic acid an~ diluted with chloro~orm. The chloroform solution is washed with dilute s~lphuric acid, water and dilute sodium bicarbonate solution. The aqueous phases are extracted with chlorofo~m snd the combir.ed organic phases are dried over sodium sulphate . ..
and concentra~ed in Yacuo. Crude 7~-phenoxyacetamido-3-hydroxy-ceph-3-e~-4-carboxylic acid diphenylmethyl ester is obtained. R~ value: 0.13 (silica gel; toluene/ethyl acetate, 3:1).
The restllting crude product is taken up in methanol and ~n excess of diazomethane solution in ether is added at 0C. A~ter a reaction time of 5 minutes, the solution is concentra~ed completely and the oily residue is chromato-graphed on silica gel thick layer plstes (toluene/ethyl acetate, 3:1). The silica gel of the zone at R = O.19 is . .

~08 405 4 extracted with ethyl acetate and gives 7~-pheno~yacet~ido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylme Lhyl ester;
melting poin~ 120C (from ether). IR spectrum (in C~C13):
3,310, 1,775, 1,700, 1,690 and 1,600 cm~l.
The starting material is prepared as follows:
a) 100 g (27.3 mM) of 6-phenoxyacetamido-penicillanic acid l~-oxide, 500 m- o~ dioxane and 58.4 g (~0 ~) of di-phenylmet~yldiazomethane after about 2 hours give 6-phenoxy-acetamidopenicillanic acid diphenylmethyl ester l~-oxide;
melting point 144-146C (ethyl acetate/petroleum ether).
b) Analogously to Example lb), 292 g (55 ~M) ol 6-phenoxyacetamido-penicillanic acid diphenylme~hyl este~
oxide and 99 g (59.5 mM) of 2-mercaptobenzthiazole give 2-t4-(benzthiazol-2-yldithio)-3-phe~oxyacetamido-2-oxoazetidin-1-yl~-3-methylene-butyric acid diphenylmethyl ester; melting po~nt 140-141C (from toluene/ether).
. c) Analogously to Example lc), 10 g (14.7 mM) of 2-~4-G (benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester in 50 m- of ethyl acetate and 4.92 g (24.98 m~I) of finely powdered sil~er p-toluenesulphinate on stirring for 7 hours at room -J em~era-ture gi~e 2-r4-(p-toluenesulphonylthio)_3-phenoxyacetamido-Z-oxoazetidin-l-yl~-3-methylene-butyric acid diphenylmethyl ester. Rf ~slue = 0.28 (silica gel, toluene/ethyl acetate, 3:1); IR spectrum (C~C13): 1,782, 1,740, 1,695, 1,340 and 1,150 cm~l.
2-r4-(p-T~luenesl~lphonylthio)_3_pheno~acetamidG-2-oxoazetidin-l-yl~-3-methylene-butyric acid diphenylmethyl ester can also be prepared as follows:
ci) A suspension of 106.5 g of 6-phenoxyacet2mido-penioil-lanic acid diphenylmethyl ester l~-oxide ~nd 33.8 g of 2-mercaptobenzthiazole in 900 ml of toluene and 9 ml of glacial 2cetic acid is boiled for 2 hours under nitrogen using a water separator, during which time about 4.5 ml of wate~ are separated off. The solution is cooled to room temper~ture, a total of 85.5 g of sil~er p-toluenesulphinate is added in portions o~er the course of 1 hour and the mixture is then stirred for a further 2 hours at 22C. The mixture is fil-tered through Hyflo and the ~iltrate is washed twice with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, concent ated in ~acuo to about 1 litre, decolorised with 30 g of Norit a~dcor.c~ d by eu~poraticn. ~he resulting yellow foam is crystallised rom methylene chloride/diethyl ether. Melting point 79-82C.
R~ value . 0.55 (s~lica gel; toluene/ethyl acetate, 3:1).
Further quantities of the substance can be obtained from the mother liquors by crystallisation from methylene chloride/
diethyl ether.
d) Analogously to ExampIe ld), 10.8 g (16.2 mM) of 2-~4_ (p-toluenesulphonylthio)-3-phenoxy2cetamido-2-oxoazetidin-l-yl~-3-methylene-butyric acid diphenylmethyl ester in~l 1 of methylene chloride and l.l equ~valents of ozone give 2-~4-(p-toluenesulphonylthio)-~-phenoxyacetamido-2-oxoazetidin-l-yl~-3-hydroxy-crotonic acid diphe~7ylmethyl ester; melting point

7 S~

, ' :.:' , :

142-143C (from ether/pentane).
The ozonisation can also be carried out at 0C:
15.2 mmols of ozone are passed into a solution of 9.23 g (13.& mmols) o~ 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido_2_oxoazetidin-1-yl~-3-methyler~e-butyric acid diphenylmethyl ester in 960 ml of methylene chloride at 0C
o~er the course of 19 minutes. 10 ml of dimethylsulphide are added to the clear reaction solution and the mixture is stir-red for 20 minutes at 5C- After conoentrating under a waterpump ~acuum, and drying the residue in a high vacuum, a light yellow foam results, which crys~allise from methylene chloride/hexane; the melting point of the resulting 2-[4-(p-toluenesulpho~ylthio)-3-pheno~Jacet~mido-2-oxoazetidin-1-yl3-3-hydroxy-crotonic acid diphenylmethyl ester is about 134-138C. Thin layer chromatogram: Rf ~alue ~ 0.46 ~silica gel; toluene/ethyl acetate, 3:1).
~ he same compound can also ~e obtai~ed in accordan~e with the following methods:
di) A solution of 684 mg (1 mM) oi 2-[4-~benzthiazol-2_ ylditnio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-hydroxy-crotonic acid diphenylmethyl ester in 20 ml of acetone/water, 9:1 (~/v) is stirred with 341 mg (1.3 mM3 of sil~er p-toluene-sulphinate ~or 60 m~rlutes at room temperature. The yellow reaction mixture ~s mlxed w~th 50 ml of acetone and filtered.
The filtrate is concentrated by e~aporation in vacuo and the residue is chromato&raphed on ~0 g of acid-washed silica gel using toluene/ethyl acetate, 4:1. The resulting 2_t4-(~-Go 1~ . ,~

-108 405~

toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yll-3-hydroxy-crotonic acid diphenylmethyl ester is recrystal-lised from ether/pentane and melts at 142-143C.
dii) A solution of 72.9 mg (0.1 mM) of the crude ozonide, obtained by ozonisation of 68.~ mg (0.1 mM) of 2-r4-benz-thiazol-2-ylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-~utyric acid diphenylmet~yl ester in ethyl acetate and evaporation of the solvent, in 2 ml of acetone/water, 9:1 f~ (r/~) is stirred with 35 mg (1.3 equivalents) of sil~e~ p-toluenesulphinate for one hour at room temperature. The reaction mixture is diluted with 3 ml of aceto~e and filtered.
0.2 ml of dimethylsulphide is added to the filtrate and the mixture is stirred for two ho~rs at rpom temperature (until it gi~es a negative io~ine-starch reaction). After remo~ing the sol~ent in ~acuo, the residue is chromatographed on 3 g of acid-washed silica gel, using toluene/ethyl acetate, 4:1.
The resulting 2-r4-(p-toluenesulphonylthio)-3-phenoxyacet-amids-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenyl-methyl ester is recrystallised from ether/pentane and melts at 142-143C. After a further recrystallisation,from methylene chloride/diethyl ether, a melting point of 144-145C (correc-ted) is obtained; ra]20 , -68 1 1 (c = l; chloroform);
thin layer chromatogram: R~ ~alue = 0.81 (silica gel;
methylene chloride/ethyl acetate, 8:2); W spectrum (ethyl alcohol): AmaX z 261 nm (e = 14,400); IR spectrum (Nu~ol):
characteristic bands at 3.00; 5.56; 5.93; 5.98; 6.06;
6.19; 6.25; ~.54; 6.70; 6.82; 7.02; 7.47; 8.03; 8.76;
~/
,.

_ .

:

9.53; 10.23; 10.60; 12.30; 13.26 and 14.~0 ~.
xa~le 3 0.12 ml o bis-trimethylsilyl-acetamide (0.508 ~mol) is added to a solution of 301 mg (0.462 mmol) o~ 2-~4-(p-toluenesulphonylthio)_3_phenoxyacetamido-2-oxoazetidin-1-yl3-3-hydroxy-crotonic acid diphenyl~ethyl es'er in 3 ml of l,Z-dimethoxyethane under a nitrogen at~osphere, and tne mixture is stirred for one hour at room temperature. The solution is com~letely concentrated by evaporation and the oily residue is dried for one hour under a high vacuum. The silylated crude product is taken up in 3 ml of dr-ied 1,2-dimethoxyetha~e and after cooling to QC 0.075 ml (0.508 mmol) of 1,5-diazabicyclo r5.4.0~undec-5-ene is added. After 6 hours' reaction time at 0C under a nitrogen atmosphere, 0.3 ml of acetic acid is added and the mixture is diluted with methylene chloride.
The methylene chloride solution is washed successi~ely with dilute sulphuric acid, water and dilute bicarbonate solution.
The aqueous phases are extracted with methylene chloride and i~.
the combined organic phases are dried with sodium sl~lphate, concentrated in vacuo and dried under a high ~acuum. Crude 7~-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carbox~lic acid diphenylmethyl ester is obtained. An excess of a solution o diazomethane in ether is added to the solution of the crude product in chloroform at 0C and the mixture is left to stand for 5 minutes at 0-C. It is then concentrated completely and the residue is chromatographed on silica gel, as in Example 2. 7~-Phenoxyacetamido-3-methoxy-ceph-3-em-4-car-G~
~B ~

boxylic acid diphenylmethyl ester; Rf ~alue = 0.19 (silica gel; toluene/ethyl acetate, 3:1); melting point 1~0C (from ether)l IR spectrum (in CHC13): 3,310, 1,775, 1,710, 1,690 and 1,600 cm~l~ is obtained.
Exam~le 4 0.045 ml (0.3 mmol) of 1,5-diazabicyclo~5.4.0~undec-5-ene is added to a solution of 100 mg (0.15 m~ol) of an iso-mer mixture consisting of 2-~4-(p-toluenesulphonylthio)-3-G ~henoxyacetamido-2-oxoazetidin-1-yl~-~-methoxy-crotoniG acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 4 ml of dry 1,2-dimethoxyethane whilst stirring in a nitrogen atmosphere. The solution is stirred for 40 minutes at room temperature under nitrogen and then cooled with ice, and 0.1 ml of acetic acid is added. The solu~ion, diluted with methylene chloride, is successi~ely washed with dilute sulphuric acid, water and dilute bicarbonate solution. The aqueous phases are extracted with ~ethylene chloride. m e combined organic phases are dried wlth sodium sulphate, con-centrated and completely freed from the sol~ent under a high ~acuum. The oily residue is chromatographed on a silica gel t~ic~ layer plate (running agent toluene/ethyl acetate, 3:1, de~eloped once). The two zones at Rf = 0.19 and 0.4 res-pecti~ely are jointly extracted with ethyl acetate and the resulting solution is concentrated.completely. An oily product is obtained, which consists of 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid dipher.ylme'hyl ester and the isomer 7~-phenoxyacetamido-3-methoxy-ceph-2-em-4-car-~3 .

boxylic acid diphenylmethyl ester in the ratio of 1:4. Rf ~alue = 0.14 and 0.32 respectively (silica gel, toluene/ethyl acetate, 3:1); IR spectrum (in CP.-C13): 3,400, 3,310, 1,785, 1,770, 1,750, 1,710, 1,690, 1,6~0 and 1,600 cm 1.
i) The ratio of resulting ceph-2-em to ceph-3-em deriva-tive depends, inter alia, on the solvent used for the cyclisa-t~on, on the concentration of the s~arting material and of the 1,5-diazabicyclor5.4.0]undec-5-ene and also on the reaction t~me. The table which follows lists some reactions which were carried out analogously to the abo~e example, in each case with 100 mg of an isomer mixture consisting of about 95%
o~ 2-[4-(p-toluenesl~lphonylthio)-~-phenoxyacetamido-2-oxo-azetidin-l-yl~-3-methoxy-isocrotonic acid diphenylmethyl ester and about 5~ ol the corresponding crotonic acid derivative.
The reaction time was 20 minutes in each case and the working up was carried out analogously to the precedi~g example.

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iO 8 40 54 a) The isomer mixture employed as the starting material can be obtained analogously to Example le) from 4 g (6.14 m of 2-[4-(p-toluenesulphonylthio)-3-phenQxyacet~mido-2-oxo-szetidin-l-yl]-3-hydroxy-crotonic acid diphenylmethyl ester and an excess of diazomethane solution in ether. The result-ing isomer mixture consiqting of 2-~l (p-toluenesulphonylthic)-3-phenoxyacetamido-2-oxoazetidin_l_yl~-3-methoxy-crotonic acid diphenylmethyl ester and the corres~onding isocrotonic asid diphenylmethyl ester (about 3:1) crystallises from ethyl ace-tate/pentane and has a melting point of 150-152C.
The isomer mixtuL-e employed as the st2rting material, or the crotonic acid and isocroton c acid derivative, can also be obtained as follows:
ai) A solution of 698 mg (1 mM) of an isomer mixture con-sisting of 2-[4-(benzthiazol_2_ylthio)_3_phenoxyacetamido_2-oxoazetidin-l-yl~-3-methoxy-crotonic acid dipher.ylmethyl ester and the correspor.ding isocrotonic acid diphenyl~ethyl ester in 20 ml of acetone/water, 9 1 (v/~) is stirred w~th 341 mg (1.3 mM) of silver p-toluenesulphinate for 1 hour at room temperature. The yellow reaction mixture is diluted with 50 ml of acetone and ~iltered. The filtrate s concentrated by eYaporation in ~acuo and the residue is chromatographed -on 30 g of acid-washed silica gel using toluene/ethyl acetate, 2:1.
An isomer mixture consisting of 2-~4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin_l_yl]_3_methoxy-crotonic acid diphenylmethyl ester and 2-E4_(p-toluenes-~lphony~thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic G~
r B' -,;L3Z -1~8 4~ 4 acid diphenylmethyl ester is obtained.-aii) The reaction described under ai) can also be carried out in tetrahydrofurane instead of in acetcne/.rater, in which case the mixture must be stirred for about 24 hours at room temperature.
aiii) 0.21 ml (1.2 mM~ o ethyl-diisopropylamine and 0.12 ml (1.5 mM) of fluorosulphonic acid methyl ester are added to a solution OL 336 mg (0.5 mM) of 2-[4-(p-toluenesulphonylthio)-~f 3-phenoxyacetamido-2-oxoazetidin-l_yl]-3-hydroxy-crotonic acid diphenylmethyl ester in 4 ml oi ethylene chloride at 0C
and the mix~ure is stirred for 30 minutes at 0C and a fu~-ther 30 minutes at room temperature. The reactio~ mixture is diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and dilute aqueous sodium bicarbonate solution and dried oYer sodium sulphate. The residue which remain~ after concentrating by evaporation is chromatographed on silica gel. With toluene/ethyl acetate, 4:1, a little - starting material is first eluted. Thereafter, an isomer mixture consisting o~ 2-[4-(p-toluenesulphonylthio)-3-phenoxy-acetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid d~phenyl-methyl ester and the corresponding isocrotonic acid diphenyl-methyl ester is isolated with toluene/ethyl acetate, 1:1.
ai~) 76 mg (0.5~ mM) of potassium carbonate and 0.088 ml (0.92 mM) of dimethyl sulphate are added to a solution o~ 300 mg (0.447 mM) of 2-~4-(p-toluenesulphonylthio)_~_phenoxJacet-amido-2-oxoazetidin-1-yl]-3-hydroxy_crOtonic acid diphenyl-methyl ester in 4 ml of acetone and the mixture is stirred for ~?

i~84054 5 hours at room temper2ture. The solution is then diluted with ethyl acetate, washed with ~rater and dri_d over sodium sulphate. After remGving the solvent, the residue is recrystallised from ethyl acetate/pentane, giving an isomer mixture consisting of 2-[4-(p-toluenesulphonyl~h~o)-3-phenoxy-acetamido-2-oxoazetidin-1-yl]-~-methoxy-crotonic acid diphenyl-methyl ester and the corresponding isocrotonic acid diphenyl-methyl ester.
av) 1.57 g of N,N'-dinitroso-N,N'-dimethyloxamide are added to a solution of 6.73 g of 2-~4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester (crystalline) in 67 ml of absolute tetrahydrofurane at -20C, and thereafter a solution of 0.57 ml (0.51 g) of ethylenediamine in 5 ml of tetrahydrofurane is added over the course of 15 minutes. After the addition, the mixture is stirred for 1 hour at 0C, 0.53 ml (11 mmol~ of glacial acetic acid and 6.7 g of Celite are added and the whole is filtered. The residue is washed with 5 times 20 ml o~ tetrahydrofurane. The filtrate and the wash liquids are combined, concentrated to approx. 20 g and m~xed ~ith 2~ ml of hexane. The crystals are filtered off, washed with tetra-hydro~urane/hexane, 1:2, and dried under a high vacuum. -The crystals consist in the main of 2-~4-(p-toluene-sulphonylthio)-3-phenoxyacetamido_2_oxoazetidin-1-yl~-3-methoxy-isocrotonic acid diphenylmethyl ester. A sample is recrystallised ~rom ethyl acetate/diethyl ether and gives the following an lytical data: melting point 167-169C; ~a~D =

~0 8 405 4 -30+1 (c=1; methylene ch.loride); thin layer chromatogram:-Rf value = 0.57 (silica gel; methylene chl~ride/eth-~l zce-tate/glacial acetic ac-d, 60:40:1), W spectru~ (ethyl alcohol): AmaX = 260 m~ (~ = 16,600); IR spectrum (NTu~ol) characteristic bands at 2.97; 5.62; 5.90; 6.27; 6.61;
6.66; 7.17; 7.53; 7.70; 7.~6; 8.02; 8.20; 3.80; 9.20;
10.26; 12.24 and 13.30 ~. NMR spectrum (100 megacycles/
second, in CD~13): ~ 2.32 (s/~H3); 2.34(s~CH3); 3.73 (s/OCH3); 4.30/4.44 (AB; J = 5/azetidine-4-C~-); 6.8-7.5 (m/l9 aromatic H, Nh-) ppm.
Apart from a l~ttle isocrotonic acid deri~ati~e, the mother liquor in the main contains 2-[4-(p-toluenesulphonyl-thio)-3-phenoxyacetami~o-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid diphenylmethyl ester, which after chromatographic ~ur-~ica-tion on silica gel has a melting point of 146-148C (correc-ted, from ethyl acetate/hexane); N~ spectrum (100 megacycles~
second, in CDC13): ô 2.08 ts/~inyl-cH3); 2.26 ts/aromatic -CH~); 3-70 (s/-OCH3); 4.47 (s/-OCH2CO-); 4.94 (dd/J = 5 and 8/azetidine-3-CH-); 5.83 (d/J=5/azetidine-4-CH-), 6.8-7.5 (m/l9 aromatic ~, -NH-) ppm; ra~D = + 21 1 1; (c = 1, ~ethylene chloride).
a~i) 3.78 g (30 mmols) of dimethylsulphate and 30 ml of 20 per cent strength aqueous potassium bicarbonate solution are added to a suspension of 6.72 g (10 mmols) of 2-r4-(p-toluene-sulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester (crystalline) and o.36 g (1 mmol) of tetra-n-butylammonium iodide in 100 ml of G~9 toluene and the mixture is stirred ~igorously for 4 hou~s at room temperature. During the first 15 minutes, the solid dissol~es. The mixture is diluted with toluene and washed with saturated aqueous sodium chloride solution. After dry-ing the organic phase with sodium sulphate, and concentrating it, crystallisation from ethyl acetate/diethyl ether gi~es 2-~4-(p-toluenesulphonylthio)-3-pheno~acet2mido-2-oxoazetidir~
l-yl]-3-methoxy-isocrotonic acid diphenylmethyl ester.
a~ii) 1.08 g (3 mmols) of tetrabutylammonium iodide ar.d 1.9 ml (2.52 g, 20 mmols) of dimethylsulphate are added to 2 suspension of 3.36 g (5 mmols) of 2-~4-~p-toluenesul~honyl-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester (crystalline) in 15 ml of carbon tetrachloride and 10 ml of water. The mixture is ~igorously stirred at room temperature and 1 N sodi~m hydroxide solution is added to it by means of an automatic titra~or in ~ufficie~t amount ~o keep the pH constant at 7Ø In the ,~ course o~ 4-5 hours, 1.5-2 equivalents of sodium hydroxide solution are consumed. The mixture is diluted with ethyl acetate and water and a little sodium chloride is added. The organic phase is dried o~er sodium sulphate and concentrated by evaporation. ~he residue is crystallised Lrom a little ethyl ace~ate/hexane, 1:1, and gi~es 2-~4-(p-toluenesulphonyl-thio)-~-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-iso-crotonic acid diphenylmethyl ester.
The isomer mixture employed as the starting material can also be obtained ~ia the corresponding 2-benzoxazole . ' ~0 1C~84~S4 derivativesas follows: -avi~i) A solution of 10 g of 6-phenoxyacetamido-penicill2nic acid diphenylmethyl ester l~-o~ide and 3 g of 2-mercapto-benzoxazole in 25 ml of dry tetra~lydrofur2ne is completely concentrated ~y evaporation in vacuo. The foam whirh remains is heated to 120C (oil bath temperature) for 70 minutes, under a waterpu~p vacuum. The fused residue is cooled and then chromatographed on 500 g of acid-washed silica gel, using toluene/ethyl acetate, 6:1 followed by 3:1. 2-~4-(Benzovazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-methylenQ-butyric acid diphenylmethyl ester is obtained in the form of a whi~e foam; IR spectrum (methylene chloride): character-istic bands at 5.6, 5.75, 5.90 and 6.7 ~.
aix~ Approximately one equivalent of ozone (in the form of an 2/3 mix~ure) is passed into a solution, cooled to -70C, of 3.35 g o~ 2-~4-(benzoxazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-methylene-butyric acid diphenylmethyl ester in 125 ml of ethyl acetate, until starting material is no longer detectable by thin layer chromatogr~hy (silica gel; toluene/ethyl acetate, 3:1). The solution is concen-trated by evaporation to about 50 ml in vacuo, mixed with 5 ml o~ d$methyl sulphide and stirred until the potassium iodide/starch test no longer gives a reaction. The mixture is concentrated by evaporation in vacuo, the residue is dis-~olved in 150 ml of benzene and the solution is washed with water. The organic phase is dried over sodium sulphate and concentrated by eveporation. m e residue is chromatographed 1~

on 150 g o~ acid-washed silica gel, using toluene/e~hy~ ace-tate, 4:1. 2-E4-(Benzoxazoi-2-yldithio)-3-pher.oxy2ce~-amido-2-oxoazetidir,-1-yl~-3-hydroxy-crotoniG acid diphenyl-methyl ester is obtained in the form of a white foam; IR
spectrum (methylene chloride): characteristic bands a~ 5.60, 5.90 and 6.0 ~.
ax) A solution of diazomethane in ether is added drop-wise to a solution of 1.7 g of 2-t4-(benzoxazol-2-yldi~hio)-0 3-phenoxyacetamido-2_oxoazetidin-1-yll-3-hydroxy-croton~c acid diphenylmethyl ester in 12.5 ml of methylene chloride 2t 0C, whilst stirring, until starting material is no longer detectable by thin layer chromatography (silica gel; toluene/
ethyl acetate, 3:1). The mixture is concentrated by evapora-~ion in ~acuo and the residue is c~xomatogra~hed on 80 g of acid-~ashed silica gel, using toluene/ethyl acetate, 2:1.
An 1somer mixture consisting of 2-[4-(benzoxazol-2-yl-dithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic G acid diphenylm thyl ester and the corresponding ~socrotonic ac~d diphenylmethyl ester in the ratio of about 5:~ is obtained; IR spectrum (methylene chloride): characteris'ic bands at 5.60, 5.85 sh, 5.90, 6.40 and 6.65.~.
axi) A solution of 682 mg (1 mM) of an isomer mixtur~ con-sisting of 2-~4-(benzoxazol-2-yldithio)-3-phenoxyacetamid 2-oxoazetidin-l_yl]-3-methoxy_crotonic acid dipnenylmethyl es~er and the corresponding isocrotonic acid d~phenylmetnyl ester ~n 20 ml of acetone/water, 9~ /v) is stirred with 350 mg (1.3 mM) of silver p-toluenesulphinate for 90 minutes 10 8 ~0 54 at room temperature. The mixture is filtered through Celite ~d the filtrate is concentrated to 5 ml in ~acuo and extracted with 30 ml of methylene chloride. The methy'ene chloride phase is dried over sodium sulphate and concentrated by evapora~ion in ~acuo. The residue is chroma~ographed on 30 g of acid-washed silica gel, using toluene/ethyl acetate, ~:~, and gives an isomer mixture consisting of 2-[4-(p-toluenesulphonylthio)_3_phenoxyaceta~ido-2-oxoazetidin-1--rl~-3-methoxy-crotonic acid diphenylmethyl ester and the corres-~nding isocrotonic acid diphenylmet~lyl ester.
E~m~le 5 A solution-of 300 mg (0.45 mmol) of the crystalline ~somer ~ixture, obtainable according to Example 4a), consist-~g of ~-~4-(p-to~uenesulphonylthio~3-phenoxace~amido-2-oxo-a~etidin_l_y~J_3_methoxy_crotonic acid diphenylmethyl ester ~ffd the correspond'ing isocrotonic acid es~er, in 4 ml of dry ~ d'imethoxyethane is s~irred with 0.134 ml (0.9 mmol) of G~ d'iazabicyclot5.4.0Jundec-5-ene at room temperature under ~it~ogen~ ~ter a react~on time of 40 minutes, the solution c-ooled' to O~C and' 0.4 ml of acetic acid, follo~red by 180 ~g ~ 6 mmois) of' ~-chloroperbenzoic acid ~85~ strength) are ad~ed. ~he solution is stirred for 10 minutes at 0C under ~-~t~o-gen, diluted w~th chioroform and washed with dilute sul-~ric acid'/sodium thiosulphate, water and dilute sodium bi-~a~bonate soiutio~. The aqueous phases are extracted with ~hloroLorm and the comblned organic phases are dried over ~odium sulphate, concentrated in vacuo and freed from the ~3 , ' sol~ent ur,der a high vacuum. The resulting crude pro~uct is separated on silica gel thick layer pla~es (running agent ethyl acetate, one development). The silica gel of the zone at Rf = 0.51 is extracted ~rith ethyl acetate, the resulting solution is concentrated and the residue is dried under a high ~acuum. 7~-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester l~-oxide is obtained as an oily resi-due which crystallises from methylene chloride/pentane, me~ting point 115-120C.
7~-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester la-oxide can be obtained by ext act-ing the silica gel of the zone at Rf = 0.22 with ethyl acetate, concentrating the solution on a rotary evaporator and drying the oily residue; melting point 175-180C (from chloroform).
The same compounds can also be prepared according to Example i) or ii):
i) A solution of 24.7 mg (36 mmols) of the crystallire isomer mixture obtainable according to Example 4a), cons~s~ing of 2-r4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxo-azetidin-l-yl]-3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester, in 24? ml of dry 1,2-dimetho~yethane is stirred with 8.22 ml (54 mmols) of 1,5-diazabicyclot5.4.0]undec-5-ene at room temperature under nitrogen. After a reaction time of 40 minutes, the solution ~s cooled to 0C and 3.73 ml of formic acid are added, followed by 37.3 ml (108 mmols) of performic acid (prepared ~rom 33 ml of hydrogen peroxide solution (30% strength.) and ~084(~54 100 ml of formic acid). The solution is stirred for 10 mi~utes at 0C under nitrogen, diluted with chloroform and washed with dilute sulphuric acid/sodium thios--lphate, water and dilute sodium bicarbonate solution. The aqueous phases are extracted with c~loroform and ~ne combined organic phases are dried o~er sodium sulphate, concentrated in ~2CUO a~d freed from the sol~ent under a high vacuum. The resulting crude product is crystallised from methylene chloride/pentane a~d gives 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester l~-oxide of melting ?oint 115-120~. -ii) A solution of 1.5 g (2.19 mmols) of the crystalline isomer mixture obtainable according to Example 4a), consisting of 2-r4-(p-toluenesulphonylth-o)-3-phenoxyacetamido-2-oxoaze-tidin-l-yl]-3-methoxy-crotonic acid diphenylme~h~l ester and the corresponding isocrotonic acid ester, in 7.5 ml of dry 1,2-dime+hoxyethane, is stirred with 0.43 ml (2.84 ~mols) of 1,5-diazabicyclot5.4.0~undec-5-ene at room temperature under nitrogen. After a reaction time of 40 m~nutes the solution is cooled to 0C and 0.375 ml (6.55 mmols) of acetic acid are sdded, followed by 0.667 ml (4.8 mmols) of 7.2 N peracetic acid. The solution is stirred for 20 minutes at 0C ur.der nitrogen and 0.24 ml of sodium bisulphite solution (20~
strength) is then added. 22.5 ml of water are added to the rsaction mixture whilst stirring ~igorously. Hereupon, a mixture of 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-car-boxylic acid diphenylmethyl ester l~-oxide and la-o~ide crystall-ses out. The prec~?itate is filtered off, t~ashed 1 7~

- with water and dried under a high vacuu~.
iii) 32.9 ml (216 mmols) of 1,5-diazabicyclo~5.4.0~undec-5-ene are added to a suspension of 9~.8 g (144 mmols) of Z-r4-(p-toluenesulphonylthio)-3-phenoxy2cetamido-2-oxoazetidi~
l-yl~-3-methoxy-isocrotonic acid diphenylmethyl ester in S88 ml of l,2-dimethoxyethane over the course of 2 mir.utes at room tempera~ure, under a nitrogen atmosphere, whilst stirrir.g.
m e solution, which is now clear, is stirred for a further 25 minu~es at room temperature and then cooled to 0C whils~
simultaneously adding 14.9 ml (395 mmols) of formic acid, and -after coolir.g to -20C 149 ml of a mixture of 66 ml of hydro-gen peroxide ( 30% strength) and 134 ml of formic acid (432 mmols of H202) are added dropwise. The reaction mixtuL~e is then stirred for 15 minutes at 0C and 37 g of sodi~m thio-sulphate dissol~ed in 500 ml of water are then added. Abou~
300 ml of water are added over the course of one hour at 5C.
After stirring for a further 2 to 3 hours at 5C, the cryst21-line precipitate, which consists in the mai~ of 7~-phenoxy-acetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenyi2ethyl ester l~-oxide is filtered off, washed with cold water (~C) and diethyl ether and dried o~er calcium chloride in a high Yacuum.
7 l~tres o~ water are added to the filtrate at 5C, whilst stirring vigorously. ~he initially oily precipitate, which solidifies on standing overnight, and which consists predominantly of 7~-phenoxyacetamido-3-methoxy-ceph-~-em-4-carboxylic acid diphenylmethyl ester la-oxide, is filtered ~ff, ... .

, ~_, , __ _ ... ,_ ,. _ _ . .... . ....

~08~064 washed with ice-cGld ~ater and dried over calcium chloride in a high vacuum.
iv) 34.35 g (50 mmols) of 2-[4-(p-toluenesulphonylthio)-3 phenoxyacetamido-2-cxoazetidin-1-yl~-3-methoxy-isocrotonic acid diphen~lmethyl ester are suspended in 340 ml of tetra-hydrofurane at 20C under a nitrogen atmosphere (the bulk of the material dissolves). After rapid addition of 11.4 ml (75 mmols) of 1,5-diazabicyclo[5.4.0~undec-5-ene, the solution is stirred for 15 minutes at 20C, 1.9 ml (30.2 mmols)-of glacial acetic acid are then added and the mixture is concen-trated to dryness in vacuo at 30C. The brown, foamy residue is dissol~ed in 130 ml of methylene chloride and the solution is washed successively with 60 ml of water, 30 ml of 0.5 N
hydrochloric acid, 30 ml of water, 30 ml of 1 M NaHC03 solu-tion and 30 ml of water. The aqueous phases are extracted with twice 10 ml of methylene chloride.
The combined methylene chloride phases are cooled to -10C without first drying them, and 7.0 ml of peracetic acid/acetic acid (containing ~50 mmols of peracetic acid) are added slowly (the tempera~ure rising to ~ + 10C). After stirring for 15 minutes at 0C - 5C, the excess peracetic acid is destroyed with aqueous sodium thiosulphate. The aqueous phase is separated off and washed with a little methylene chloride. The solution is dried o~er magnesium sulphate and concentrated in ~acuo. The light yellow resi-due, consisting of a mixture of 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid dipnenylmethyl ester l-oxide and 7~-phenoxyacetamido-3-methoxy-ceph_2_em_4_carboxylic acid .. -- ~43 _ 1084C~5.4 diphenylmethyl es~er l-oxide in the ratio of about 2:1, is dissolved in lZ0 ml of mono~lyme at room temperature ar~d 30 ml of water are added, whereupon 7~-phenylacetamido-~-methoxy-ceph-3-em-4-carboxyli~ acid diphen-ylme~hyl ester 1~-oxide first crystallises out. The thick crystal sludge is first stirred for half an hour and then 1~0 ml of water are added o~er the course of about 5 hours at room temperature, whilst stirring, ~Jhereupon the corresponding la-oxide also crystallises ou~. After stirring for a total of 17 hours, the mixture is cooled for 1 hour in an icebath and then ~
tered5 and the residue is washed with a little cooled mono-glyme/water, 1:1.5. The crystals are dried ~or 16 hours over P205 in a high ~acuum. 7~-Phenox~acetamido-3-methoxy-ceph-3-em-4-carbo,~ylic acid diphenylmethyl ester l~-oxide, to which some of the corresponding la-oxide still adheres, is obtained.
The l-oxides obtained can be further processed as follows:
a~ A solution of 150 mg (0.275 mmol) of 7~-phenoxyacet-amido-3-methoxy-ceph-3-em-4-carboxylic acid diphenyimetnyl ester l~-oxide in 3 ml of methylene chloride and 0.1 ml o~
dimethylformamide is cooled to 0C and 188 mg (1.37 mmols) of phosphorus trichloride are then added. The solution is stirred ~or 30 minutes at 0C, diluted with methylene chloride snd washed with aqueous sodium bicarbonate solution. The aqueous phase is extracted with methylene chloride and the combined organic phases are dried o~er sodium sulphate ~nd 7dP
B~ ~

,: -10 8 405 ~

concentrated in vacuo. The resulting crude 7~-phenoxyacet-amido-3-methoxy-ceph-3-em-4-c2rbox~-lic acid diphenylmethyl ester is recrystallised from ether; melting poi~t 120C.
ai) A suspension of 5.0 g (9.16 mmols) of 7~-phenoxy-acetamido-~-methoxy-ceph-3-em ~I-carboxylic acid diphenylmethyl ester la-oxide in 25 ml of methylen~ chloride and 1.25 ml of dimethylzcetamide is cooled to 0C and 1.69 ml (19.3 mmols) of phosphorus trichloride are then added. The solution is ; ~ stirred for 30 minutes at 0C, diluted with eihyl acetate and washed with aqueous sodium bicarbon2te solution. The aqueous ~
phase is extracted w$th ethyl acetate and the combined organic phases are dried over sodium sulphate and concentrated in ~acuo. The resulting crude 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is recrystal-lised from ether; melting poi~t 120C.
b) 0.87 ml of anisole is added to a solution of 2.0 g (3.78 mmols) of 7~-phenoxyacetamido-~-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride and the mixture is cooled to 0C and eft to stand for 1 hour a~ter adding 1.2 ml of trifluoroacetic acid. The reaction mixture is concentrated in ~acuo and the residue is crystallised from acetone/ether. 7~-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid of melting point 170C
(decomposition) is obtained.
The same compound can also be obtained without iso-lating the ester mentioned under a):
bi) A suspension of 3.0 g (5.5 mmols) of a mix'ure of 7~-r 7 L~L3~, ' ' ',, ': , .
.

~084054 phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester ~-oxide and la-oxide in 15 ml OL
methylene chloride and 0.75 ml of dimethylacetamide is coole~
to 0C and 0.966 ml (1.11 mmols) o~ phosphorus trichloride is then added. The solution is stirred at 0C for 40 minutes 4.65 ml (61 mmols) of trifluoroacetic acid are then added and stirring is continued for a further 30 minutes at 0C. The reaction solution is rendered neutral with saturated sodium bicarbonate solution and the organic phase is washed with dilute bicarbonate solution. The combined aqueous phases are washed twice ~rith ethyl acetate and brought to pH 2.6 with phosphoric acid. - The 7~-phenoxyacetamido-3-methoxy-ceph-3- -em-4-carboxylic acid which has precipitated is filtered off, washed with water and dried under a high ~acuum; melting point 170C (decomposition).
bii) A suspension of 53.4 ~ (97.7 mmols) of 7~-phenoxy-acetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester l~-oxide Cfrom Example 5iii] in ~20 ml of methylene chloride and 16 ml of dimethylacetamide is cooled to 0C and 17.3 ml (19.8 mmols) of phosphorus trichloride are added slowly. After stirring for 20 minutes at 0 - 5C, 80 ml (1.05 mol~ of trifluoroacetic acid are added dropwise. The clear solution is stirred for a further 20 mirutes at 0 - -5C and is then diluted with 1,300 ml of ethyl acetate and washed successi~ely with 240 ml of 2 M dipotassium phosp~ate solution, 100 ml of water ar.d 250 ml of hal~-saturated aqueous sodium chloride solution. 7~-Phencxyacetamido-3-methoxy-r- ~0 ~ _ A- ;

. .

' iO84054 ceph-3-em-4-carboxylic acid is extracted from the organic phase with 700 ml of saturated aqueous ~odium bicarbonate solution and the aqueous portion is washed twice with 400 ml of e'~hyl acetate. The organic phases are extracted twice with a total of 250 ml of a solution com~csed of 50 ml of saturated aqueous sodium bicarbonate solution, 100 ml of wa~er ~nd 100 ml of saturated aqueous sodium chloride solution.
The combined bicarbonate extracts are co~ered with 1,500 ml of ethyl acetate and the pH ~alue of the solution is adjusted to _ 2.5 with 20% strength phosphoric acid, while stirring ~igorously. The aqueous phase is re-extracted twice with 500 ml of ethyl acetate. The combined organic pnases are dried over magnesium sulphate, filtered and concentrated by evaporation in ~acuo. The residue, which crys~allises, is suspended in 1~0 ml of ethyl acetate and left to stand over-night at -10C. The pale yellow cr~Jstals of the res~lting 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-carbox~lic acid are filtered off, washed with cooled ethyl acetate and dried to constant weight unde~ a high ~acuum.
biii) A solution of 23.9 g o~ 7~-phenoxyacetamido-3-methox~-ceph-3-em-4-carboxylic acid diphenylmethyl ester la-oxide r~rom ExamPle 5iii~ in 140 ml of methylene chloride and 7.2 ml of dimethylacetamide is cooled to 0C and after slowly adding 7.8 ml of phosphorus trichloride the m~xture is stirred for a further 20 minutes at 0 - 5~. 36 ml of trifluoro-acetic acid are added dropwise to the reaction solution, and the mixture is then stirred for a further 20 mir.utes at 0 -7 ' 8V/
lB ~

1084~54 5C and thereafter worked up as described urder Example 5 bii).7~-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid is obtained in the form ol a light yellow crystalline material.
c) 0.7 ml t5.7 mmols) of dimethyl-dichloro-silane is added to a suspension of 2.55 g (7 mmols) of 7~-~henoxyace~-amido-3-methoxy-ceph-3_em_4-carboxylic acid and 2.9 ml (22.4 mmols) o~ N,N-dimethylaniline in 11 ml o~ absolute methylene chloride under nitrogen at 20C and the mixture is then stirred for 30 minutes at the same temperature. The resultin~ clPar ... .
solution is cooled to -20C, 1.6 g (7.7 mmols) o~ solid pkos- -phorus pentachloride are added and the mixture is stirred for 30 minutes. A precooled (-20C) mixture of 0.9 ml (7 ~mols) of N,N-dime~hylaniline and 0.9 ml of n-butanol is added over ~he course of 2 to 3 minutes at the same temperature, 10 ml of precooled (-20C) n-butanol are then added rapidly and the mixture is thereafter stirred for 20 minutes ~t -20C and 10 minutes without 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 of dioxane are then added and after stirringfor a further 10 mir.utes at 0C approx. 4.5 ml of tri-n-butylamine are added in portions until samples diluted with water assume a constant pH value of 3.5. After stirring for 1 hour at 0C, the precipitate is filtered off, ~ashed with dioxane and recrystallised from water/dioxane. The resulting 7~-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride dioxana~e has a melting poir.t in excess of 300C. Thin ayer chromato~ram: ~f ~alue 0.17 (silica gel; system n-butanol~

L~ _ ~_ ........

~.

iQ 8 405 4 carbon tetrachloride/methanol/for~c ac~d/water, 30:4~:20:5:5).
ci) 3.6 ml (3.87 g) of dimet~yld-chlorosilane are added to a suspension of 11.75 g ol 93 per cent strength (corr_sponding to 10.93 g of 100~ strength) 7~-~henoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid and 13.4 ml (12.73 g) of N,N-dimethylaniline in 47 ml of absolute meth~lene chloride (dis-tilled over P205) at + 20C under nitrogen, and the mixture is then stirred for 30 minutes at the same temperature. The solution, which is now clear, is cooled to -18C/-19C ~nd 7,8 g of solid phosphorus pentachloride are added, whereupo~
the internal temperature rises to -10C. After stirring for 30 ~inutes in a bath at -20C, the clear solution is added drop~ise, o~er the course of approx. 7 minutes, to a mixture, cooled to -20C, of 47 ml of n-~utanol (anhydrous, dried over Sik'~an) 2nd 4.4 ml ~4.18 g) of dimethyl~niline. Hereupon, the internal temperature rises to -8C. The mixture is stir red for a further 30 minutes, initially in the bath at -20C
and subsequently in an icebath (0C), so that a final internal temperature of -10C is reached. At this temperature, a mixture of 47 ml of dioxane and 1.6 ml of water is added drop-wise (duration approx. 5 minutes). ~ereupon, the product slowly crystallises out. After stirring for a fur~her 10 minutes, the mixture, in an icebath, is brougnt to a ~ ~alu~-of between 2.2 and 2.4, and kept thereat, by adding approx.
9.5 ml of tri.-n-butylamine in port~ons o~er the course of approx. 1 hour (the ~irst ~ ml being ~dded in the ~irst 5 minuteS). Thereafter the product is ~iltered off and washe-. .

. ~ .

in portions with 2pprox. 3C ml of dioxane ar.d then ~rith a~prox.15 ml of methylene chloride, thus gi~ing Cry5 ~alline 7~-~mino-3-methovy-ceph-~-em_4_carboxylic acid hydrochloride dioxan~te;
melting point above 300C; W spectrum (in 0.1 N sodium bicarbonate): AmaX = 270 m~ (~ = 7,600); IR spectrum (NuJol):
characteristic bands at 5.62; ~.80; 5.88; 6.26; 6.55;
7.03; 7.45; 7.72; 7.96; 8.14; 8.26; 8.45; ~.54; 8.97;
9.29; 10.40 and 11.47 m~; ~~20 = + 134 + 10 (c = l; 0.5 N sodium bicar~onate solution).
The zwitter-ion of 7~-amino-3-methoxy-ce~h-3-em-4-carbo~lic acid can be obtained from the resulting hyàrochloride dioxanate by adding 2 N sodium hydroxide solution to a 20~
strength aqueous solution o~ the dioxanate until the pH ~alue is 4.1 (isoelectric point); when filtered of~ and dried, the produc~ hzs a melting point in excess of 300C. W spectru~
(in 0.1 N scdium bicarbcnate solution) AmaX z 270 nm (E =
7,600). Thin layer chromatogram: Rf value iden~ical with that of the hydrochloride (silica gel; same system~; [a~D -., ~ 2~2 + 1 (c = l; 0.5 N sodium bicarbonate solution).d) 1.6~ ml of bis-(trimeth~lsilyl)-acet~mide are sdded to a suspension o~ 1 g (2.82 mmols) of 7~-amino-3-metho~y-ceph-3-em ~I-carboxylic acid hydrochloride dioxanate in 20 ml of dry methylene chloride at room temperature under a nit-ogen stmosphere. A~ter 40 minutes, the clear solution is cooled to 0C and 900 mg t4.37 mmols) of solid D-_phenylglycyl chloride hydrochloride are added. Five minutes latel, 0.7 ml (10 ~ols) of propylene oxide is added. The suspension is . - ' 108 4~54 then stirred lor 1 hour at 0C ~nder 2 n troge~ atmosphere and 0.5 ml of methanol is then added, whereupon 7~-(D-a-phenylglycylamino)-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride precipitates in a crystalline form. m e hydro-chloride is filtered off and dissolved in 9 ~1 of water, and t~e pH of the solution is adjusted to 4.6 witn 1 N sod um hvdroxide solution. The dIhydrate of the inner salt of 7~-(DLa-phenylglycyl2mino)_3_methoxy-ce~h_3_em-4-c2rboxylic acid which precipitates, is filtered off, washed with acetone and diethyl ether and dried; melting point 174-176C (decom-position); ~a~20 = + 132 (c = 0.714; in 0.1 N hydrochloric acid); thin layer chromatogram (silica gel): Rf ~alue ~ 0.1 (system: n-bu~anol/acetic acid/water, 67:10:2~). W spec-trum (in 0.1 N aqu_ous sodium bicarbonate solution) AmaX =
269 ~ (e = 7,000); IR spectrum (in mineral oil): characteris-tic bands at 5.72, 5.94, 6.23 and 6.60 ~.
di) 1.37 ml (5.6 mmols) of N,N~-bis-(trimet~ylsilyl)-acet-amide are added to a suspension of 993 mg (4.32 mmols) of 7~-amlno-3-methoxy-cep~-3-em-4-carboxylic acid (inner salt) in 10 ml of methylene chloride and the mixture is stirred for 45 minutes at room temperatur~ under 2 nitrogen a'mosphere.
The clear solution is cooled to 0C and 1.11 g (5.4 mmcls) of D-a-phenylglycyl chloride hydrochloride are added. After 5 ~
minutes, 0.4 ml (5.6 mmols) o~ propylene oxide is 2dded.
The suspension is then stirred for 1 hour at 0C under a nitrogen atmosphere and therea~ter o.6 ml of methanol is added.
7~-(D-~-Phenylglycylamido)-3-methoxy ceph-3-em-4-carbo~yli^

~5, ~

iO84054 acid hydrochloride, which crystallises out, is ~iltered o~f and dissolved in 15 ml o~ water at 0C, and the pH of the solution is adjusted to about 4 wiih 5 ml of 1 N sodium hydroxide solution. The solution is warmed to room temperz-ture and its pH is brought to about 4.8 with triethylamine, whereupon 7~-(D-a-phenylglycylamido)-3-methoxy-cepn-3-em-4-carboxylic acid crystallises out in the form of the dihydrate.
Exam~le 6 Ci A solution of 0.228 g (1.5 m~) of 1,5-diazabicyclo-[5.4.0]undec-5-ene in 10 ml of tetrahydrofura~e is added to a solution of 0.697 g (1.0 mM) of an isomer mixture consisting of 2-~4-(benzthiazol_2-yldithio)-3-phenoxyacet2mido-2-oxo-azetidin-l-yl~-3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocroto~ic acid dipheny~methyl ester in 4 ml of dry tetrahydrofurane. The mixture is stirred for 40 minu~es ai room temperature, diluted with 200 ml of ber2ene and washed successively with dilute hydrochlor~c acid, sodium bicarbonate solution and water. The organic ~hase is dried oYer sodium sulphate and the solvent is removed in vacuo.
The resulting crude product is chromatographed on 30 g of silica gel which has been washed with hydrochloric acid.
Toluene/ethyl acetate, 7:1, first elutes 2-mercaptobenzthiazole ~nd su~sequently 7~-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester. IR spectrum (in CH2C12):
5.60, 5.74, 5.90 and 8.28 ~.
The ester obtained can be conYerted into t~e free acid as follows:

F 1 L~

.

'--~
1~ 8 4054 i) A mlxture of ,3 mg ~0.1 mmol) of 7~-phenoxvaceia2ido-3-methoxy-ceph_2_em_4-czrboxylic acid diphenylmethyl ester, 0.07 ml of trifluoroacetic acid, 0005 ml of ~nisole and 0.5 ml of methylene chloride is stirred for 15 hours at 0C. The mixture is diluted with 5 ml of pentane/diethyl ether, 3:1, and shaken ~igorously. The white, amorp~.ous 7~-phenoxy~cet-amido-~-methoxy-ceph_2_em_4a_carboxylic acid which precipita~e~
is filtered off and washed with pentane/diethyl ether, ~:1.
IR spectrum (CH2C12): 5,60, 5.90 and 8.27 ~.
The starting material can be obtained as follows:
a) 1 equivalent of ozone (diluted with oxygen) is passed into a soluticn, cooled to -70C, of 681 mg (1.0 mM) of 2-~4-~benzthiazol-2-yldithlo)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-methylene-butyric acid dipheny~met~yl es~er in 30 ml of ethy acetate. The reaction solution is allowed to warm up, conce~trated to 10 ml in ~acuo, m~xed with 1.0 ml of dimethyl sulphide and stirred for 15 hours at room temperature. Sol-vent and excess reager.t are removed in ~acuo and the residue is chromatographed on 30 g of acid-wasned silica gel, using toluene/ethyl acetate, 4:1 (15 ml fractions). 2-[4-(Benz-thiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-hydroxy-crotonic acid diphenylmethyl ester is obtained as a solid amorphous substance. ~a~D = 130 + 1 (C~C13; c =
0.8) IR spectrum (CH2C12): 2.95, 5.60, 5.92, 6.04 and 8.10 ~.
b) A distilled solution of diazomethane in ether (con-taining 1.3 mM of diazomethane) is added to a solutior. of crude 2-~4-(benzthiazol-2-yldithio)-~-pheno.~yacetamido-2-oxo-

8 ~iE~,., -~ -... .

azetidin-l-yl~-3-hydroxy-crotonic ac-d di~henylmethyl ester, --obtained by ozonisation of ~81 mg (l.0 mM) of 2-~4-(be~z-thiazol-2-yldithio)_3-phenoxy~cetamido-2-oxoazetidin-l-yl~-3-methylene-butyric acid diphenylmethyl ester, i~ 5 ml of methylene chloride at 0C. The mixture is stirred for one no~r at 0C and washed with water, and the orOanic layer is dried over sodium sulphate. The solvents are removed in ~acuo and the residue is chromatographed on ~5 g of acid-washed silica gel, using toluene/ethyl acetate, 2:1. An isomer mixture consisting of 2-r4-(benzthiazol-2-yldithio)-3-phenoxyacetami~o-2-oxoazetidin-l-yl]-3-methoxy-crotonic acid diphenylmethyl ester and the correspondir.g isocrotonic acid diphenylmethyl ester is obtained. IR spectrum (in CH2C12): 5.60, 5.88, 6.67, 9.15 and 9,92 ~-Exam~le 7 Analogously to Example 4, 200 mg (0.307 mM) of an lsomer mixture consisting o~ 2-r4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-l-yl~-3-methoxy-cro'onic acid 2,2,2-trichloroethyl ester and the corresponding iso-crotonic acid 2,2,2-trichloroethyl ester and 0.09 ml (0.6 mM) of 1,5-diazabicyclor5.4.0]undec-5-ene, on stirring for 30 minutes at room temperature in 3 ml of 1,2-dimethoxyethane, give an isomer mixture consisting of 7~-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid 2,2,2-tr~c~loroethyl ester and 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid 2,2,2-trichloroethyl ester (in the ratio of about l:l).
R~ ~alu.es = 0.36 and 0.18 respecti~ely (silica gel; toluene/

~7 -,a~

' ' ~ .
' ' ' iO84~54 ethyl acetate, 3:1).
The starting material can be obtained as follows:
a) Analogously to Example lb), 498 mg ~1 mM) of 6-phenoxyacetamido-penicillanic acid 2,2,2-trichloroe~hyl ester ~nd 200.7 mg (1.2 mM) of 2-mercaptoben2thiazole gi~e 2-[4-(benzthiazol-2-yldithio)-3-pheroxyacetamido-2-oxoazetidin-1-yl~-3-methylene-butyric acid 2,2,2-trichloroethyl ester;
melting point 144-149C (from meihylene chloride/pentane), - ~ Rf value = 0.5 (silica gel; ether). - -b) Analogously to Example 6a), 647 mg (1 mM) of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-methylene-butyric acid 2,2,2-trichloroethyl ester and 1.2 equivalents of ozone, with subse~uent split~ing of the ozonide with dimethyl sulphide, giv~ 2-[4-(ben2thiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-hydroxy-crotonic acid 2,2,2-trichloroethyl ester; melting ~oint 129-130C (ether/petroleum ether).
c) Analogously to Example 6b), 5 g (7.71 mM) of 2-r4-(_, (benzthlazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-hydroxy-crotonic acid 2,2,2-trichloroethyl ester and ar.
excess of diazomethane gi~e the isomer mixture consisting of 2-r4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoaze-tidin-l-yl~-3-methoxy-crotonic acid 2,2,2-trichloroethyl ester and the corresponding isocrotonic ~cid 2,2,2-trichloroethyl ester; melting point 170-174C (from methylene chloride/
ether).
d) Analogously to ~xample lc), 1.9 g (2~87 mM) of an L,~ ~
~, . . . . .

1084~54 iso~er mixture consisting of 2-[4-(ber.zthiazol-2-yldith-o)-3-phenoxyacetamido_2_oxoazetidin_1_yl~-3-methoxy-crotonic acid 2,2,2-trichloroethyl ester and the corresponding isocrotonic acid 2,~,2-trichloroethyl ester, on stirring ,or fiv~ hours ~t room temperature with 0.8 g (4.05 mM) of sil~er p-toluenesul-ph nate in 35 ml of acetonitrile/ethyl acetate, ~:4, give an isomer mixture consisting of 2-~4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin_l-yl~-3-methoxy-crotonic acid O 2,2,2-trichloroethyl es~er and the corresponding $socrotonic~cid 2,2,2-trichloroethyl ester; melting point 155-158C
(lrom ethyl acetate/ether).
Exam~le 8 0.02 ml (0.16 mmol) of trimethylchlorosilane is added to a solution of 100 mg (0.14~ mmol) o~ 2-t4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-nydroxy-crotonic acid diphenylmethyl ester in 2 ml of dry methylene chloride at 0C. 0.0477 ml (0.32 mmol) of 1,5-diazabicyclo-G ~5.4.0~undec-5-ene is added to this solution under nit.ogen,whilst stirring, and the mixture i~ stirred for a further hour at 0C. After addition o~ 0.2 ml of acetic acid, the mixture is diluted with methylene chloride. The organic phase is successi~ely washed wit~ dilute sulphuric acid, water ar.d aqueous sodium bicarbon~te solution, dried o~er sodium sulphate and concentrated to dryness in Yacuo.
The resulting crude 7~-phenoxyacetamido-~-hydroxy-ceph-3-em-4-carboxylic ac~d diphenylmethyl ester is dissolYed in methanol and a sol~tion of diazomethane ln ether is added ~0 F~ - ~
~ ~ .
, .

- iO84(~54 at 0C. After lO minutes, the solution is carefully con-cen'rated and the residue is dried under a high vacuum. The residue is purified by thick layer chromatography (toluene/
ethyl acetate, 3:1, silica gel). After eluting the silica gel of the zone at Rf = 0~17 with ethyl acetate, and concen-trating the solution on a ro~ary evaporator, 7~-phenoxyacet-amido-3-methoxy-ceph-3-em-4-ca,boxylic acid diphenylmethyl ester is obtained; melting point 120C (from ether).
xam~le 9 A solution of 266 mg (0.5 m~) of a crude mixture con-sisting of 2-[4-(benzthiazol-2-yldithio)_3-phenoxyacet~ido-2-oxoazeti~in-l_yl]_3_methoxy-crotonic acid chloride and 2-~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-l-yl~-3-methoxy-isocrotonic acid chloride in 5 ml o~ dry methylene chloride is added dropwise o~er the course of 15 minutes at 0C, whilst stirring, to a solution of 0.10 ml of triethylamine in 0.5 ml of dry tert.-butanol and 3 ml of ~~ methylene chloride. Af'er a further 15 minutes stirrin~, the reaction mixture is diluted with methylene chloride, washed with water, with dilute hydrochloric acid and again with water, dried o~er sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 10 g of acid-washed silica gel, using toluene/ethyl acetate (4:1) as the running agent. 7~-Phenoxyacetamido-3-methox~-ceph-2-em-4-carboxylic acid tert.butyl ester is obtained. I~
sp~ctr~m (~n CH2C12): characteristic bands at 5.60, 5.77, .90 and 8.29 ~.
,~/ ' .
J

-` iO84054 - The starting material can be o~tained as follows:
a) A mixture of 0.7 ml of tri~luoroacetic acid, 0.6 ml o~
anisole and 2.5 ml of methylen2 chloride is added s owly to a solution of 698 mg (1 mM) of a mix~ure consisting of 2-[4-(benzthiazol_2_yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-ylJ-3-methoxy_crotonic acid diphenylmethyl ester ar.d 2-[4-~benzthiazol-2-ylàithio)_3-phenoxyacetamido-2-oxoazetidin-1-yl3-3-methoxy-isccrotonic acid diphenylmethyl ester in 1.5 ml of methylene chloride at 0C, while stirring. The reactio~
mixture is stirred for 3 hours at 0C and then shaken with 100 ml of ether/pentane, 1:3, and the precipitate is filtered off. It consists of a mixture of 2-r4-(benzthiazol-2-yldi-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-methoxy-crotonic acid and 2-r4-(benzthiazol-2-yldithio)-3-phenoxy-acetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid, and is washed ~rith 25 ml of ether/pentane, 1:3, and dried in vacuo.
IR spectrum (in CH2C12): characteristic bands at 5.60, 5.80, C' 5.94, 8.55 and 9.95 ~.
b) A solution of 5~2 mg (1.0 m~I) of a mixture consistir.g of 2-~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxo-azetidin-l-yl~-3-methox~y-crotonic acid and 2-~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid in 5 ml of dry dioxanej containing 10% of oxalyl chloride, is stirred for 15 hours at room temperature and then concentrated by e~aporation ln ~acuo. The solid, non-crystalline residue, conslstlng of a mixture of 2-E4-(benzthiazol-2-yldithio)-~-pher.oxyacetamidc-2-oxoazetifiin-1-

9~2 ,~ ~

, 1084~54 yl]-3-methoxy-crotonic acid chloride and 2-[4-(benzthiazol-2-yldit~io~3-phenoxyacetamido-2-oxoaze~idin-1-yl~-3-methoxF~-isocrotonic acid chloride can be conve-ted f~r~her without additional purification. IR spectrum (in CH2C12): c~arac-teristic bands at 5.58, 5.90 ar.d 9.95 ~.
Exam~le 10 A solution of 367 mg (0.5 mM) of a mixture consisting of 2-r4-(p-nitrobenzene5ulphor,ylth~o)_3-ph~noxyacetamido-2-oxoazetidin-l-yl]-3-methoxy-crotonic ~cid dipher.ylmeth-~l ester ar.d the corresponding isocrotonic acid diphenylmethyl ester, and 152 mg (1.0 mM) of 1,5-diazabicyclo[5.4.0~undec-5-ene in 10 ml of dry tetrahydrofurane is stirred ~or 40 minutes at room temperature. The reaction mixture is diluted with benzene, washed successi~ely with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution, dried o~er sodium sulphate and freed from the sol~ent in ~acuo. The residue is chromatographed on acid-washed silica gel, using toluene/ethyl acetate, 7:1, as the running age~t, whereby pure 7~-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester is obtained. Subse~uent elution wlth toluene/ethyl acetate, 2:1, results in the iso-lation of a mixture which i~ additicn to 7~-pheno.~yaceta~ido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester also contains 7~-phenoxyacetamido-~-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester.
The starting m~tsrials can be prepared as follows:
a) Analogously to Example 4ai), 348.5~ (0.5 ~;I) of an _~
,~.

isomer mix~ure consisting o~ 2-[4-(benzthiazol-2-yl'hio)-3- -phenoxyacetamido-2-oxoazetidin-1-yl~-3-methoxy-crotonic a~^id diphenylmethyl ester and the corresponding isocro~onic acid diphenylmethyl ester, ar.d 200 mg (0.68 ~) o~ silver p-nitrobenzenesulphinate, on stirring for one hour at 60C in 1~ ml of acetone~rater, 9:1, gi~e a mixture consisting of 2-~4-(p-nitrobenzenesulphonylthio)-3-phenoxyacetamido-2-oxo-azetidin-l-yl~-3-methoxy-crotonic acid diphenylme~hyl ester and the corresponding isocrotonic acid diphenylmethyl ester.
Silver p-nitrobenzenesulphinate is obtained by com-bining aaueous solutions of e~uimolar amounts of silver nitrate and sodium p-nitrobenzenesulphinate. The precipitate is filtered off and dried in ~acuo for 24 hours at 50-60C.
Exam~le 11 .
Ar~alogously to Example 10, 351.5 mg (0.5 m~l) of an isomer mixturs consisting of 2-t4-(p-methoxybenzenesulphon~l-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-metho~-crotonic acid diphenylmethyl ester and ~he corres~onding iso-crotonic acid diphenylmethyl ester, and 152 mg (1 m~) of 1,5-diazabicyclo~5.4.0~undec-5-ene, gi~e a mixture consisting of 7~-phenoxyacet2mido-3-methoxy-ceph-2-em-4-carboxylic acid ~iphenylmethyl ester and 7~-phenoxyacetamido-3-me~hoxy-ce~h-3-em-4-carboxylic acid diphenylmethyl ester, which can be separated into the t~Jo isomers by chromatography.
The starting m~terials can be obtained as follows:
a) Analogou~ly to Example 4ai), 697 mg (1 mM) of an isom~r mixture consisting o~ 2-[4-(benzthiezol-2-yl~.10)-3-9~
s .

phenoxyacet2~ido-2-oxoa~etidin_l-yl~-3-~ethox~--crotonic acid diphenylmethyl ester and the corresp~nding isocrotonic acid diphenylmethyl ester, and 361 mg (1.3 ~) o~ silver p-methox~-benzenesulphinate, on stirring for one hour at room te~pera-ture in 20 ml of acetone/water, 9:1, gi~e a mixture consisting o~ 2-~4-(p-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-l-yl~-3-methoxy-orotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl e~ter.
IR spectrum (in CH2C12): characteristic bands at 5.60-, 5.88, 6.18 and 8.76 ~.
Silver p-methoxybenzenesulphinate is obtained by com-bining aqueous solutions of equ~molar amounts of sil-~er ni~rate and sodium p-methoxybenzenesulphinate. ~he precipi~a~e ls filtered o~f and dried in vacuo for 24 hours at 50-60C.
Exam~le 12 Analogously to Example 10, 3~6.3 mg (0.5 ~ of an isomer mixture consisting of 2-(4-benzenesulphcnyltkio-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methoxy-crotonic ac d diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 152 mg (1 mM) of 1,5-diazabicyc o-[5.4.0]undec-5-ene, give a mixture consisting of 7~-phenoxy-acetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester and 7~-phenoxyacetamido-3-methoxy~ceph-~-em /~-carboxyl~c acid diphenylmethyl ester, which can be separated in~o the two ~somers by chromatography.
The starting materials can be obtained as lollows:
a) Analogously to Example 4ai), ~7 mg (1 ~M) o~ an . . .

10 8 4~5 4 iso~er mixt~re consisting of 2-~4-(~en2+hi~zol-2-yl~hio)~
phenoxyacetamido_2_oxoazetidin_l_yl~_3-methox~-croton c ccid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 324 mg (1.3 mM) of silver benzene-sul~hinate, on stirring for 90 minutes at room tem~eraturQ in 20 ml of acetone/water, 9:1, gi~e a mixture consisting of 2-(4-benzenesulphonylthio_3_phenoxyacetamido_2_oxo2zetid n-l-yl)-3-methoxy-crotonic acid diphenyl~ethyl ester and the corresponding isocrotonic acid diphenyl~ethyl ester. -IR
spectrum (in CH2C12): characteristic bands at 5.60, 5.88 and 8.74 ~.
Sil~er benzenesulphinate is obtained by combin ng aqueous solutions of equimolar amounts of silver nitrate and Qodium benzenesulphinate. The precipitate is ~iltered off and dried in ~acuo for 24 hours at 50-60C.
ExP~le 13 Analogously to Example 1, an isomer mixture consistinæ
of 7~-phenoxyacetamido-3-methoxy-ceFh-3-em-4-carboxylic acid p-nitrobenzyl ester and 7~-pheno~yacetamido-~-methoxy-ceph-2-em-4-carboxylic acid p-nitrobenzyl ester can be obtained from the isomer mixture consisting o~ 2-[4-(p-toluer.esul~honyl-thio)-3-phenoxyacet2mido-2-oxoazetidin-l-yl~-3-metho~J-crotonic acid p-nitrobenzyl ester and the correspond~ng iso--crotonic acid ester, by stirring ~or 12 to 14 hours at room temperat~e with tetramethylguanidine in tetrahydrofur2ne.
Exam~le 14-A mixture of 104.5 mg (0.15 ~) of an iscmer m xture consisting of 2-r4-(benzthiazol-2-ylthio)-3-phenoxy2cet~n-ido-2-oxoazetidin-1_yll-3_methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotoric acid dipheny~ethyl ester, 35 mg (0.225 mM) of p-toluenesulphinic acid ar.d 80 mg (0.525 ~M) of 1,5-diazabicyclo[5.4.0~undec-5-ene in 3 ml of dry tetrahydrofurane is stirred for 40 m~nutes at room tem-perature. The mixture is diluted with benzene and washed successively with dilute hydrochloric acid, with dilute aqueous sodium chloride solution, with 0.5 N sodium hydroxide solution and again with dilute aqueous sodium chlcride solution.
The organic phase is dried over sodium sulphate and freed ~rcm the solvent in ~acuo. Chromatography of the residue on 3.5 g of acid-~rashed silica gel, using toluene/ethyl acetate, 7:1, first gives pure 7~-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid diphenylmethyl ester. Toluene/e'hyl acetate, 2:1, subsequen~ly elutes 7~-pheno~yacetamido-3-methoxy-ceph-3-em-4-carboxylic acid d~phe~ylmethyl ester.
Exam~le 15 A mixture of 141 mg (0.2 ~) of 2-~4-(o-methoxyben7ene-~ phonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-methoxy-crotonic acid diphenylmethyl ester and 61 mg (0.4 mM) o~ 1,4-diazabicyclo~5.4.0~undec-5-ene in 4 ml of dry tetra-hydrofurane is stirred for 70 minutes at room temperatuL~e.
Working up analogously to Example 10 gi~es a crude mi~tur~
consisting of 7~-phenox~J~cetamido-3-methoxy-ceph-2-~m '~a-carboxylic acid diphenyl~ethyl este~ ar.d 7~-phenoxyace~2mido-3-methoxy-ceph-3-em-4-c~rboxylic acid diphenylmethyl ester in 9~
'`, ~ _ ~ _ iO 8 405 4 the ratio of about 4.4 : 1, which can be separa~ed in~o +he two isomers by chromatography on silica gel, analogously to Example 10.
The two compounds are produced in approximately ~he same ratio if 141 g (0.2 mM) of 2-~4-(o-methoxybenzenesul-phonylthio)-3-phenoxyacetamido_2-oxoazetidin-1-yl~-3-~ethoxy-isocrotonic acid diphenylmethyl ester are treated analogously.
The two isomeric starting materials can be obtained as follows:
a) 3 49 g (5 mM) of an ~somer mixture consisting of 2-r4-(benzthiazol-2-ylthio)-3-phenoxyacetamido-2-oxoazetidin 3-methoxy-crotonic acid diphenylmethyl ester and the corres-po~ding isocrotonic acid diphenylmethyl ester in the ratio of about 4:1 are stirred wit~ 1.82 g (6.5 mM) of silver o-methoxybenzenesulphinate in 100 ml of acetone/water, 9:1, for 130 minutes at room temperature. The mixture is ~iltered ar.
the filtrate is concentrated by evaporation in Yacuo. The residue is chromatographed on 140 g of acid-washed s$1ic2 gel, using toluene/ethyl acetate, 1:1. 50 ml fractions are collected; of these, fractions 7 to 13 contain pur~ 2-r4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-l-yl~-3-methoxy-isocrotonic acid diphenylmethyl ester, DR
spectrum (CH2C12): 5.60, 5.90, 8.72 and 9.15 ~, and fraction 25 and the subsequent fractions give pure 2-[4-(o-methoxybenzer.e sulphonylthio)-3-phenoxyacetamido-2_oxoazetidin-1-yl]_3-methoxy-crotonic acid diphenylmethyl ester, IR spectrum (CH2C12): 5.60, 5.90, 8.20, 8.30, 8.72,and 9.80 ~. Frac-iO8 4054 tions 14 to 24 contain mixtures of the two isomers.
Exam~le 16 A mixture of 57 mg (0.1 ~) of crude 2-[4-(c-methoxybenzenesulphonylthio)_3-phenoxyacetamido-2-oxoazet_din-l-yl~-3-methoxy_isocrotonic acid chloride and 43 mg (~.3 ~) of 1,5-diazabicyclor5.4.0]undec-5_ene in 2 ml of dry methy'_n2 chloride is st~rred for 80 minutes at room temperature. The mixture is diluted with methylene chloride, washed with dilu~e hydrochloric acid and water, dried over sodium s~lphate and freed from the solvent in vacuo. The residue is dissolved i~
0.5 ml of methylene chloride, 5 ml of pentane/diethyl ether, 3:1, are added, and the mixture is sha~en. The precipitate is filtered off and washed with pentane/diethyl ether, 3:1.
It cons~sts of fairly pure 7~-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid.
The starting mater~al can be obtained as follows:
a) A mixture of 703 mg (1 ~) of pure 2-~4-(o-methoxy-benzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid diphenylmethyl ester, 0.7 ml of triiluoroacetic acid and 0.66 ml of anisole in 4 ml of methylere chloride is stirred for 3 hours at 0C. 50 ml of pentane/diethyl ether, 3:1, are then added to the mixture an~
the whole is shaken vigorously. The white precipitate of pure 2-r4-(o-methoxyben2enesll~phonylthio)-3-pheno~yacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid is filtered off and washed with pentane/diethyl ether, 3:1. IR spectrum (CH2C12): 5.60, 5.93, 6.25 ar.d 8.72 ~.

b) One drop of dimethyl~ormamide in dioxane is added to a solution of ~4 mg (0.1 ~I) of 2-~4-(o-me~hoxybenzenesul-phonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-meihoxy-isocrotonic acid in 0.5 ml o~ a 10% strength solution of oxalyl chloride in dioxane, whereupon an eYolution OL gas occurs immediately. The mi~ture is stirred for 2 hours at room temperature and the solvent ar,d the excess oxalyl chloride are evaporated o~f in vacuo. The resi~ue is dried in a high vacuum and gives 2-~4-(o-methoxybenzenes-llph~nyl-thio)-3-pheno~yacetamido_2_oxoazetidin-1-yl]-3-methoxy-iso-crotonic acid chloride in the form of aclightly orange-coloured foam, IR spectrum (CH2C12): 5.60, 5.90 and 8.70 ~.
Exsm~le 17 A solution of 200 mg (0.254 mM) of 2-[4-(p-toluene-sulphonyltkio)-3-~D-a-tert.-butoxycarbonylamino-a-phenyl-acetylamino)-2-o~oaz_tidin-1-yl~-3-methoxy-crotonic acid diphenylmethyl ester ln 2 ml of dimethylformamide is stirred with 57 ~1 (0.38 mM) of 1,5-dlazabicyclo~5.4.0~undec-5-ene for 30 minutes at room temperature, ethyl acetate is then added and the mixture is washed with water and 2 N nydro-chloric acid until it gi~es an acid reaction, a~d witn saturated aqueous sodium chloride solution until it gives a neutral reaction. The organic phase is dried o~er sodium sulphate and concertrated by e~aporation in ~acuo. The residue is chromatographed on silica gel thic~ layer plates, using toluene/ethyl acetate, 1:1, as the running agent. 7~-(DLa-tert.bu~ylcarbonylamino--phenylacetylamino)-3-methoxy-/,~5 0 ,~ _~_ , ~ .

1084054ceph-2-em-4~-carboxylic acid diphen~lmethyl ester of melting poi~t 1~6-168C (methylene chloride/pentane); 'hin layer chromatog~ (silica gel; diethyl ether): Rf ~alue ~ C.51;
W spectrum (in ethanol): ~max = 257 m~ ( = 3,500); IR
spectrum (in methylene chloride): char~cteristic bands at 2.96, 5.63, 5.74, 5.85 (shoulder), 5.92, 6.16, 6.64 and 6.72 ~;
and 7~-(3--tert.butylcarbonylamino-a-phenyl-acetylamino)-3-methoxy-ceph-~-em-4-carboxylic acid diphenylmethyl este~ of melting point 162-163C (diethyl ether); thin layer chromato-gram: Rf value:_ 0.33 (silica gel; diethyl ethPr); W
spectrum (in ethanol) AmaX = 265 m~ ( E = 6,600); 280 m~
(shoulder) (~ = 6,200); IR spectr--~ (in methylene chloride):
2.92, 5.58, 5.64 (shoulder), 5.82, 6.22 and 6.67 ~ are obtained.
The compounds obtained can be converted further as follows:
a) A mixture of 8.8 g of 7~-(D--tert.~utoxycarbonyl-m~ no-a-phenyl-acetylamino)-~-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester. 8.6-ml of anisole 2nd 145 ml of trifluoroacetic acid is stirred for 15 minutes at 0C, 400 ml of pre-cooled toluene are then added and the mixture is con-centrated by e~aporation under reduced pressure. ~e residue i8 dried ur.der a high ~acuum, digested with dieth~l ether and filtered off. This gi~es the trifluoroacetate of 7~-(D-a-~henyl-glycylamino)-3-methoxy-~-cephem-4-ca~boxylic acid in the form of a powder. The mate~ial is dissol~ed in 20 ml o water, the solution is washed w~th ~wice 25 ml o~ ethyl /~/

.~

acetate and th ~H is ~djusted to a value of about 5 wi~h a - --20~ strength solution of trieth-~rl2mine in methanol, whereu~on a colourless precipitate forms. This mixture is stirred fo-one hour in an ice~ath, ?0 ml of acetone are then added and the whole is left to stand ~or 16 hours at about 4C. The colourless precipitate is filtered off, washed witn acetone and diethyl ether and dried under reduced pressure. This gives, in the form of a micro-crystalline powder, 7~-tD-a-phenyl-glycylamino)-~-methoxy-3-cephem-4-carboxylic acid as the inner salt, which furthermore is present in ~he form o~ 2 hydra~e, melting point 174-176C (wi~h deco~positio~);
ra]20 = ~ 14g (c = 1.03 in 0.1 N hydrochloric acid); thin layer chromatogram (silica gel; development with iodine):
Rf ~ 0.36 (system: n-butanol/pyridine/acetic acid/water, 40:24:6:30); ultraviolet absorption spectrum (in 0.1 N
aqueous sodium bicarbonate solution): Amay = 267 ~ (~ = 6,2~0);-infra-red absorption spectrum (in mineral oil): characterist c bands, inter alia, at 5.72 ~, 5.94 ~, 6 23 ~ and 6.60 ~.
b) A mixture of 0.063 g of 7~-(D--tert.~uto~Jcarbonyl-amino-a-phenylacetylamino)-3-methoxy-2-cephem-4a-carboxylic acid diphenylmethyl ester, 0.1 ml of anisole and 1.5 ml of trifluoroacetic acid is left to stand for 15 minutes at 0C
and is then concentrated by evaporation under reduced pressure.
The residue is digested with diethyl ether, filtered off ar.d dried. The colourless and pulverulent trifluoroacetate of 7~-(D-~-phenylglycylamino)-3-methoxy-2-cephem-4a-carboxylic acid, thus obtainable, ~s dissolved in 0.5 ml of w2ter 2nd 'he /6~Z
_~8 --.~

. ' : ' 108405~

pH of the solution is adjusted to a ~alue of aGout 5 ~y dro~-wise addition ol a 10~ strength solution of triethyla~ine in methanol. The mi~ture is stirred for one houL in an icebath and the colourless precipitate is filtered of. and d~ied in high vacuum. This glves 7~-(D-~-phenyl21ycylamir.o)-3-methoxy-2-cephem-4~_carbox~ylic acid as the irner salt, thin layer chromato~ram (silica gel; development w1th iodir.e):
Rf~ 0.44 (system: n-butanol/pyridine/acetic acid/~ater, 40:
~r~ 24:6:30); ultraviolet absorption spectrum (in 0.1 N aqueous sodium bicarbonate solution): AShc~lder = 260 ~. ~
c) A solution of 0.20 g of 3-chloro-perbenzoic ac~d in ~ ml of me~hylene chloride is added to a solution, cooled to 0C, of 0.63 g of 7~-(D-a-tert.-butoxycarbonylamino-a-phenyl-acetylamino)-3-meiho,Yy-2-cephem-4a-carboxylic acid diphenyl-meth,yl ester in 25 ml of methylene chloride. The mixture is stirred for 30 minu~es at 0C, 50 ml of methylene chloride are added and the whole is washed successively with 25 ml o a saturated aqueous sodium bicarbonate solutio~ and 25 ml of a saturated aqueous sodiu~ chloride solution. The organic phase ~s dried over sodium sulphate and concentrated by e~aporation under reduced pressure. The residue is crys~al-llsed from a mixture o~ methylene chloride and diethyl ether;
this gi~es 7~-(D-a-tert.-butoxycarbonylamino-a-phenyla~et~Jl-amino)-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester l-oxide in the form of colourless needles, melting point 172-175C; thin layer chromatogram tsi1ica g~ Rf ~
0.44 (system: ethyl acetate; development with iodine ~a?our);

/~ 3 L~;

.

ultraviolet absorption spectru~ (in ~thanol): AmaX = 277 m~
(F = 7,200); infra-red absorption spectrum (in methy'er.e chloride): characteristic bands at 2.96 ~, 5.56 ~, 5.71 ~, ,5.83 ~, 5.90 ~, 6.27 ~ and 6.67 ~.
d) 2.80 g o~ phosphorus trichloride are added to a solu-tion, cooled to -10C, o 1.30 g of 7~-(D-a-tert.-butoxy-csrbonylamino-a-phen~rl2cetylamino)-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester l-oxide in 30 ml of dimethylformamide, whilst excluding air. After standing for 15 minutes, the reaction m~xture is poured out onto a ~ix~ure o~ ice and an aqueous dipotassium hydrogen phosphate solutiQn;
the aqueous mixture is extracted with ~rice 100 ml of ethyl acetate. T,he organic extract is washed with a satura~ed aqueous sodium chloride sclution, dried o~er so~ium sulphate and evaporated. The residue is chromatographed on silica gel; amorphous 7~-(D--tert.-butoxycarbonylamino-a-phenyl-acetylamino)-3-methoxy-3-cephem 4-carboxylic acid diphenyl-methyl ester is eluted with diethyl ether as a substance which ~s pure according to thin layer chromatography, Rf~ 0.39 (system: diethyl ether; development with iodine vapo~-);
~a~D ~ 1 1 1 (c 0.981 in chloroform); ultraviolet absorption spectru~ (in ethanol): AmaX = 264 ~ 00);
infra-red absorption spectrum (in methylene chloride): ~
characteristic bands at 2.94 ~, 5.62 ~, 5.84 ~, 5.88 ~, 6.25 ~ and 6.70 ~.
The starting material can be obtained a~ follows:
e) 16.5 ml (0.12 mmol) of chloroformic acid isobutyl 108 4~54 ester are added to a solution, cooled to -15C, o~ ~1.2 g (0.12 mmol) of D-N-tert.buto~carbonyl-pher.ylglycine and 16.7 ml (0.12 mmol) of triethylamine in 300 ml of tetrahydro-furane and the mixture is stirred for 3C minutes at -10C.
A solution of 21.6 g (0.10 mmol) of 6-amino-penicillanic acid and 15.4 ml (0.11 mmol) o~ triethyl?~ine in 300 ml of tetra-hydrofurane/water, 2:1, is then added. The reac~ion mlxture is stirred for 1 hour at 0C and 2 hours at room te erature whilst ~eepln~ the pH ~alue constant at appro~. 6.9 by ad~ing triethylamine. The reaction mixture is adjusted to pH 2.0 at 5C by means of phosphoric acid and is saturated with sodium chloride and extracted with three times 500 ml of eihyl acetate; the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulpha~e znd concentr~ted by evaporation. The crude N-tert.butoxycar-bonyl-ampicillln obtained in the form of a light yellow ~oam has an Rf ~alue of ~ 0.6~ in a thin layer chromatogram (silica gel; ethyl acetate/n-butanol/pyridi:~e/acetic acid/
water, 42:21:21:6:10).
f) 21.6 ml of 30% strength hydrogen peroxide (0.2~ M) are added to a solution o~ 57.22 g of crude N-+ert.butoxy-carbonyl-ampicillin in 100 ml o glacial acetic acid over the course of 10 minutes and the mixture is stirred for 2.5 hours-at room temperature. The reaction mixture is ~hen poured onto 2 1 of ice water and the N-~ert.bu~oxycarbonyl-a~picillir, l-oxide obtained in the ~orm of a voluminous precipitate is filtered off, well washed ~ith water and dried in ~acuo.

: '' '"' ` ' - . ,.

A further auantity o~ crude N-tert.butylcarbonyl-ampicillin l-oxide can be obtained by extracting the filtr~te ~rith ethyl acetate. Thin layer chromatogram (silica gel; e~hyl aceta~e/
n-butanol/pynidine/acetic acid/water, 42:21:21:6:10): Rf ~alue ~ 0.30.
e) A solution of 42 g (0.23 M) of diphenyldiazometh2ne in 130 ml o~ dioxane is added to a mixture of 67.7 g of crude N-tert.butoxvcarbonyl-ampicillin l-oxide in 380 ml of di~xane O and the whole is stirred for 2.5 hours at room temperat~re.
A~ter adding 5 ml o~ glacial acetic acid, the mixture is con-centrated by evaporation in vacuo. The residue is digested with petroleum ether, the petroleum ether extract is discarded and the residue is crystallised from methylene chloride/eth~r/
hexa~e. N-tert.Butoxycarbonyl-ampicillin l-oxide diphenyl-methyl ester of melting point 164-166C is obtained; ~a~D , + 1l? f 1 ( C = 1, CHC13); IR spectrum (methylene chloride):
characteristic bands at 2.91, 2.94, 5.54, 5.69, 5.82 (shoulde~), f~ 5.88, 6.60 and 6.68 ~; thin layer chromatogram: Rf value 0.23 (sllica gel; toluene/ethyl acetate, 3:1).
h) A mixture of 11.2 g (17.7 mmols) of N-tert.-but3xy-carbonyl-ampicillin l-oxide diphenylmethyl ester and 3.26 g (19.5 mmols) of mercaptobenzthiazole in 170 ml of toluene is boiled for 3 hours in a re n ux apparatus equipped with a water separator, and is then concentrated by evapora'ion. The residue is chromatogra~hed cn silica gel, using toluene/ethyl acetate, 3:1, as the eluting agent and gives amorphouc 2-[4-(b~nzthiazol-2-yldithio)-3-(a-tert.butoxycarbonylamino-c-/0~ ' 1084~5~

phenylacetyl2mino)_2-oxoa etidin-1-yl~-3-methylene-bu~ric ~cid diphenylmethyl ester, thin layer chromatogr~m: Rf vzlue ~0.37 (silica gel; toluene/ethyl acetate, ~:1); IR spectrum (methylene chloride): characteristic bands at 2.94, 5.64, 5.76, 5.86 (shoulder), 5.91 and 6.71 ~.
i) 0.868 g (3.46 mmols) of sil~er toluenesulphinate is added to a solution of 2.34 g t3.0 mmols) of 2-~4-(~enzthiazol-2-yldithio)_3_(~-tert.butoxycarbonylamino-a-phenylacetyl~mi~o)-0 2-oxoazetidin-l_yl~-3-methylene-butyric acid diphenylmethyl ester in 30 ml of acetone/water, 9:1, at 0C, and the mixture i~ stirred for 1 hour in an icebath. The precipitate which has separated out is filtered off. The filtrate is taken up in toluene and extracted by shaking with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and, after e~aporation, gi~es amorphous 2-[4-(p-toluenesulphonylthio)-3-(a-tert.butoxycarbonylamino-~-phenylacetylamino)-2-oxoazetidln-1-yl~-3-methylene-bu~yric C acid dlphenylmethyl ester; thin layer chromatogram: Rf ~alue ~0.33 (silica gel; toluene/ethyl aceiate, ~:1); IR
spectrum (methylene chloride): characteristic bands at 2.9~, 5.57, 5.70, 5.82, 6.21 and 6.65 ~.
~) An ozone/oxygen stream ¢0.5 mmol per minute) is ~assed for 7 minutes into a solution, cooled to -70~C, of 2.30 g (3.0 mmols) of 2-~4-(p-toluenesulphonylthio)-3-(a-tert.butoxy-carbonylamino-c-phenylacetylamino)-2-oxoazetidin-1-yl~-3-methylene-bL~yric acid diphenylmethyl ester in 230 ml of methylene chloride. After ~dding 1 ml of dimethyl sulphide, /o7 l.~. -~ -' ' ' .
.' ' . ' , the solution is stirred for a ~urthe~ hour without cooling ar.d is then concentrated by e~aporation in ~acuo. T~e residu~ is recrystallised from methylene chloride/ether/hexane and g ~es 2-[4-(p_toluenesulphonylthio)_3~ tert.butoxycarbon~1amino-a-phenylacetylamino)-2-oxoazetidin-1-yl~-3-hydroxy-crotonic acid diphenylmethyl ester of melting point 182-184C; W
spectrum (ethanol): AmaX , 259 m~ ( = 13,400); IR spectrum (methylene chloride): characteristic bands at 2.92, 5.59, O ~.83, 5.92, 6.03 (shoulder), 6.18 and 6.68 ~; thin laye~
chromatogram: Rf ~alue ~ 0.55 (silica gel; toluene/ethyl acetate, 1:1).
k) A solution of 0.54 g (0.7 mmol) of 2-[4-(p-toluene-sulphonylthio)-3-(a-tert.butoxycarbonylamino-a-phenylace+yl-amino)-2-oxoazetidin-1-yl~-3-hydroxy-crotonic acid d~phenyl-methyl est~r in 20 ml of methyle~e chloride/methanol, 1:1, is stirred for 15 minutes with an excess of a solution of diazomethane in ether at 0C and ~s then concen~ra~ed by e~aporation in vacuo. Preparatl~e layer chromatcgraphy of the residue on silica gel, using toluene/ethyl acetate, 1:1, - as the runn ng agent, and elution of the zone whlch is ~isible ln W light gi~es 2-~4-(p-toluenesulphonylthio)-3-(a_tert.
butoxycarbonyl2mino-a-phenylacetylamino)-2-oxoazet~din-l-yl~-3-methoxy-crotonic acid diphenylmethyl ester, wh~ch is recrystallised from methylene chloride/diethyl ether/hexane.
Melting po~t 204-206C; W spectrum (ethanol): AmaX = 259 m~ ( = 16,000); IR spectrum (Nu~ol): c~.aracteristic bards at 2.93, 5.58, 5.80, 5.84, 5.93, 6.24 and 6.57 ~, thin lay~r .. /0~

~ ~ .

chromatogra~: Rf ~alue ~0.33 (silica gel; toluene/e~hyl acetate, 1:1).
~x~m~-e 18 A mixture of 670 mg (1 mmol) of 2-r4-(p-toluenesul-phonylthio)-3-phenylac~tamido-2-oxoazetidin.-1-yl]-3-methox~J-crotonic acid diphenylmethyl ester, 6.7 ml of 1,2-dimethoxy-ethane and 0.22 ml o~ 1,5-diazabicyclo[5.4.0]undec-5-ene is stirred for 25 mi~utes at room temperature under a nitrog~n atmosphere. The reaction mixture is diluted with toluene, washed successively with 2 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried o~er sodi~m sulphate and con-centrated by e~aporation in vacuo. The residue, after preparati~e thic~ layer chromatography on silica gel using toluene/ethyl acetate, 1:1, gives 7~-phenylacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester of melting point 166-169C (from methylene chloride/hexane), W
spectrum (ethanol): ~max - 258 m~ ( = 4,500), IR spectrum (methylene chloride): characteristic bands at 2.93, 5.62, 5.?3, 5.93 and 6.66 ~, Rf value~ 0.54 (silica gel; system toluene/ethyl acetate, 1:1), and amorphous 7~-phenylacetamido-3~methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, W spectrum (ethanol): AmaX - 258 m~ ( = 6,350), 264 m~ ( =
6,350), 282 m~ ( = 5,600) (shoulder), IR spectrum (methyler.e chloride): characteristic bands at 2.94, 5.63, 5.83, 5.94, 6.26 and 6~66 ~, Rf ~alue~-0.37 (silica gel; sys~em toluen~/
ethyl acetate, 1:1), 1~ the ratlo of 8:1.
~0~

The material car be processed ~urther as follows:
7~-Phenylacet2mido-3-me~hoxy-ceph-2-e.m-4-carboxylic acid diphenylmethyl ester can be converted, analogously to Example 17c), into 7~-phenylacetamido-~-methoxy-ce~h-3-em-4-carboxylic acid diphenylmeLhyl ester l-oxide of mel~ing ~oint 152-155C (from acetone/diethyl ether), Rf value 0.31 (silica ~el; system: ethyl acetate), W spectrum (in 95/~ strength ethanol): AmaX - 288 m~ (E = 3,610) and shoulder at A = 2.7 m~;
IR spectru~ (methylene chloride): characteristic band~ at 2.94, 5.59, 5.81, 5.95, 6.22 and 6.61 ~.
A purer product, which consists mainly of 7~-phenyl-acetamido-3-methoxy-ceph-3-em-4-carboxylic acid d~phenylmethyl ester l~-oxide, can be obtained as follows:
A solution of 6.7 g (10 mmols) of 2-[4-(p-toluenesul-phonylthio)-3-phenylacetamido_2_oxoazetidin-1-yl~-3-methoxy-isocrotonic acid diphenylmethyl ester in 67 ml of 2bsolute .tetrahydrofurane is stirred with 2.28 ml (15 mmols) of 1,5-G diazabicyclor5.4.0]undec-5-ene for 15 m,nutes at 20C, 0.7 mlof glacial acetic acid is added and the mixture is then con-centrated by e~aporation in vacuo. The oily, dark residue ls dissolved in 30 ml of methylene chloride and the solution is successively extracted by shaking with 15 ml of water, 10 ml of 0.5 N hydrochlor~c acid, 10 ml of saturated aqueous -sod~um bicarbonate solution and 10 ml of water. The aqueous phases are re-extracted with 10 ml of methyler.e chlorlde and the organic extracts are combined and stirred wl'h 2.24 ml o~
40~ strength peracetic acid for 15 minutes at O~C n an ice-D'. //0 L~ ~
.. .. ~

iO84054 bath. A solution of 1.50 g (6 mmols) of sodium t~.iosul?ha~e ' pentahydrate in 20 ml of water is then added to the r~action mixture, the whole is stirred for 10 minutes and the aquec~s phase is separated o~f. The org2nic phase is additionally washed with 10 ml of water, dried o~er sodium sl~lpha~e and concentrated by e~aporation in V2CU0. Crystallisation of t~e solid residue from methylene chloride/petroleum ether gi~res 7~-phenylacetamido_3-methoxy_ceph-3_em_4-carboxylic acid diphenylmethyl ester l~-oxide of melting point 175-176~;
th~n layer chromatogram (silica gel): Rf value -0.1 (toluene/
ethyl acetate, 1:1), W spectrum (ethanol): AmaX = 279 m~
( - 7,300); IR spectrum (methylene chloride): characterist c bands at 2.94; 5.56; 5.78; 5.91; 6.20 and 6.67 ~.
7~-Phenylacetamido-3-methoxy-ceph-~em-car~ox~ylic acid diphenylmethyl ester can be obtained from the 1-oxides analogously to Example 17e).
From this ester, crude 7~-phenylacetamido-3-~ethoxy-ceph-3-em-4-carboxylic acid can be obtained by saponification analogously to Example 17a), and can be puri~ied by chro~ato-graphy on silica gel (containing 5% of water) using methylene chloride containing 30-50~ oi acetone, followed by lyophili sation from dioxane; W spectrum (in 95~ strength ethanol):
~max e 265 ~ ( = 5~800); IR spectrum (methylene chloride):
characteristic bands at 3.03, 5 . 60 ~ 5.74, 5.92, 6.24 and 6.67 The start~ng materia' an~ the lntermediate produc~
csn be prepared as follows:

/~
~ 1 - 17, -.
' .

iO84054 a) 19.4 ml of 40 per cent strength peracetic aci~ are added over the course of 40 minutes to a mixture of 37.24 g (O.1 mol) of the potassium salt of penicillin G in 90 ml of water, 7.3 ml of acetone and 150 ml of chloroform whilst stirr~ng at 0C. After a furth~r 15 minutesS 28 g (0.15 mol?
of benzophenone-hydr2zone are added ~n portions at the s~me temperature, followed by 6.3 ml of 1 per cent strength a~ueous potassium iodide solution and then follotYed by a mixtur_ of 32.5 ml of 10 per cent strength sulphuric acid and 2~ ml of 40 per cent strength peracetic acid, added dropwise o~e~ the course of 1.5 hours. After completion of the addition, the mlxture is stirred or a further 30 minutes at 0C, warmed to 15C and diluted with 400 ml OL chloroform. The aqueous phase is se~arated off and the organic phase is successively washed with 300 ml of 5 per cent strength aqueous sodium bi-sulphite solution, 300 ml of saturated aqueous sodium bi-carbonate solution and 300 ml of saturated aqueous sodium chloride solution, dried o~er sodium sulphate and concentrated by e~aporation in ~acuo. The evaporation residue is recrysta'-lised from ethyl acetate/~etroleum ether and gives 6-pnenyl-acetamidopenicillanic acid diphenylmethyl ester l~-oxide, melting point 139C; thin layer chromatogram (silica gel):
Rf Yalue ~ 0.40 (system toluen~/ethyl acetate, 1:1), IR spec- -trum (methylene chloride): characteristic bands at 2.94, 5.56, 5.70, 5.92 and 6.57 ~
b) 1.83 g (11 mmols) of 2-mercaptobenzthiazole are a~ded to 8 mixture of 5.165 g (10 mmols) of 6-phen~lac~tam-do~eni-cillanic acid diphenylmethyl es~er l~-oxide in 50 ml of ,/æ
, ,,, _~ _ 1084()54 toluene and 0.5 ml of glacial acetic acid and the mixture is boiled for 2 hours in a reflux apparatus provided with a water separator. On cooling, 2-[4-(benzthiazol-2-yldithio)-~-phenylacetamido_2_oxoazetidin_1_yl]_3-methylene-bu'~ric acid diphenylmethyl ester crystallises out spontaneously.
After recrystallising it once from me+hylene chloride/diet~yl ether, crystals of melting point 134-136C are obtained;
thin layer chromatogram (silica gel): Rf value ~0.52 (syste~
~J toluene/ethyl acetate, 1:1), W spectrum (ethanol): ~max =
269 m~ (~ = 12,700); IR spectrum (methylene chloride):
characteristic bands at 2.90, 5.60, 5.72, 5.92 and 6.61 ~.
c) The product obtained under b) does not have to be isolated for further con~ersion. After cooling, the reac-tion mixture can be diluted directly with ~0 ml of toluene, ~fter which it is mixed with 3.95 g (15 mmols) of sil~er p-toluenesulph~ate and stirred for 2 hours at room temperat-~re.
The yellow precipitate which has separated out is filtered off through Hyflo and rinsed with toluene. The filtrate is extrac~ed by shaking with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. The e~aporation residue is taken up in toluene and petroleum ether is added. The precipitate is filtered off and recrystallised from ethy} acetate/pet-roleum ether. The resulting 2-r4-(p-toluenesulphonylthio~-3-phenylacetam1do-2-oxoazetidin-l-yl~-3-methyle~e-butyric acid diphenylmethy~ ester has a melting point of 75C; thin layer chromato~ram (~ilica ~el): Rf value ~ 0.47 (system toluene/ethyl acetate, 1:1), W spectrum (ethanol): AmaX =
259 m~ (F = 4,300); IR spectrum (methylene chloride):
characteristic bands at 2.92, 5.62, 5.74, 5.94 and 6.6~ ~.
d) A solution of 655 mg (1 m~I) of 2-[4-(p-toluenesul-phonylthio)-3-phenylacet~mido_2-oxoazetidin-1-yl~-3-methylene-butyric acid diphenylmethyl ester in 65 ml of methylene chloride is treated with an ozone/cxygen mixture at -65C
until a slight blue colouration results. After addition of 0.5 ml of dimethyl sulphide, the mixture is allowel to warm up to room temperature and is then concentrated by e~a~orat~o~ ~
~n vacuo. The resulting crude 2-~4-(p-toluenesulphonylthio)-3-phe~ylacetamido-2-oxoazetidln-l_yl]_3-hydroxy-cr~tonic acid diphenylmethyl ester, Rf value ~ 0.46 (silica gel; sy-tem toluene1e~hyl acetate, 1:1), IR spectrum (meth~-lene chlo.ide):
~haracteristic bands at 2.95, 5.60, 5.98, 6.18 and 6.61 ~, ca~
be converted further without additional purifi ation.
e) The crude product obtained ~nder d) is dissol~ed in 20 ml oi methanol and a solution of diazomethane in ether is added at 0C until a yellow colouration persists. After e~aporatin~ off the sol~ent in vacuo, the residue i8 purlfied by preparati~e thic~ layer chromatography on silica gel, usir.g toluene/ethyl acetate, 1:1, as the running agent. 2-~4-(p-Toluenesulphonylthio)-3-phenylacetamido-2-o~oazetidin-1-yl~-3-methoxy-crotonic acid diphenylmethyl ester, Rf ~alue _0.2 (sllica gel; system toluene/ethyl acetate, 1:1), IR spect u~
(methylene chloride): characterlstic bands at 2.94, 5.61, 5.96, 6.24 ar.d 6.6Z ~, is obtained alongside a little 2-[4-iO8 405 4 (p-toluenesulphonylthio)-3-~henylacetamido-2-oxo2zetidi~-l-yl]-3-methoxy-~socrotonic acid diphenylmethyl ester.
Exam~le 19 . 5.20 ml (35 mmols) of 1~5-diazab~cyclor~.4.ol~de 5-ene are added to a solution of 6.C5 g (10 mmols) of a 3:1 m~xture of the isomeric 2-r4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin_l_yl~-3_methoxy-crotonic acid benzyl ester and 2-~4-(p-toluenesulphonylthio)-3~pheno~acet-amido-2-oxoazetidin-1-yl~-3-methoxy-isocrotonic acid benzyl ester and 2.33 g (15 mmols) of p-toluer.es--lphinc acid in 200 ml of absolute tetrahydrofurane at room temperature, whilst stirring. The mixture is stirred for a further 40 mi~u~es a~
room temperature, mixed with 500 ml of methyle~e chloride and washed successi~ely with 200 ml of 0.5 N hydrochloric acid, 200 ml of water, 200 ml of 0.5 N sodium bicarbon~te and 200 ml of water. The methylene chloride phase is dried over sodium sulphate and concentrated by e~a~oration i~ ~acuo.
The resldue is chroma~ographed on 200 g of acid-washed silica gel, using toluene/ethyl acetate, 3:1, and 7~-phe~o~Jace~-am~do-3-methoxy-ceph-2-em-4a-carboxylic acid benzyl ester of melting point 148 - 151C ls obtained by adding d~ethyl ether to the fractions. IR spectr-~m (methylene chloride): char-acterlstic bar.ds at 5.60, 5.75, 5.90,and 8.25 ~; ~]DO =
284 + 1 (c _ l; c'~loro~orm).
Toluene/e~hyl acetate, 2:1, elutes 7~-phenoxyacet-amido-~-methoxy-ceph-3-em-4-carboxyl~c acid benzyl es~er, which can also be precipitated with diethyl ether, and has 2 3~ //S

~' :
: :

iO8 405 4 melting po nt of 89-91C; IR ~pectrum (methylene chlcride): -characteristic bands at 5.60, 5.85 a~d 5.90; ~a]D = +4~ +
1 (c = l; chlorofor~
The ratio of the ceph-2-em compound to the ceph-3-em compound is about ~
The compounds can be further con~erted as follows:
15 ml o~ pre-cooled 0.1 N potassium hydroxide solution sre added, whilst stirring, to a solution prepared at 0C, o~
454 mg (1 mmol) of an approx. ~:1 mixture of 7~-phenoxy~cet-amido-3-methoxy-ceph-2-em-4a-carboxylic acid benzyl ester ar.d 7~-phenoxyacetAmido-3-methoxy-ceph_3-em_4-carboxylic acid benzyl ester in 30 ml of tetrahydro~urane. The mixture is stirred ~or a further 5 minutes at 0C, 100 ml of ice water and 100 ml of pre-cooled methylene chloride are then added and the whole is stirred ~igorously. Addition oi a little saturated aqueous sodium chloride solution causes the mixture to separate into two phases. The methylene chloria~ phase separated off and the aqueous phase is wsshed with a fur-ther 30 ml of methylene chloride. The zqueous phase is co~ered with 50 ml of methylene chloride, 10 ml of 2 N hydro-chloric acid are added and the mixture is thoroughly chaken.
After separating off the organic phase, the a~ueous phase i5 extracted twic~ more with 30 ml 0~ me~hylene chloride at a time. The combined methylene chloride extracts are dried o~er sodiu~ sulphate and concentrated by evaporation in V2CUO.
The resulting white foam crystallises on addition of chloro-form and diethyl ether and gi~es 7~-phenoxyacetamido-~-_ ~ _ ~, 1089U~5 4methoxy-ceph-2_em_4~_carboxyl~c acid of melting point 142C
(decomposi~ion). IR spectrum (KBr): char2cteristic bands at 5.65, 5.75 and 5.95 ~.
The starting material can be prep2red as follows:
a) 20 ml (14.6 g, 0.145 mol) of triethyla~ine and 17 ml (24.5 g, 0.143 mol) of benzyl bromide are added to a svlution of 36.6 g (0.1 mol) of 6-phenoxyacetamido-penicillanic acid l~-oxide in 150 ml of dry dimethyl~ormamide whilst cooling with tap water. The mixture is stirred for 20 hours at room temperature and is then poured onto ice water. ~he precipi-tate is filtered off, washed ~Jith approx. 1,000 ml of wa~er, dried for 2 days in vacuo at 40C, then taken up in 200 ml of methylene chloride and again dried with sodium sulphate.
The white foam which remains a~ter e~aporatlng of~ the sol-vent in ~acuo is dissolved in 150 ml of ethyl acetate and the solution is left to stand first at room temperature and then at -20C, whereupon pure 6-phenoxyacet~mido-pe~icillar.ic 2cid benzyl ester l~-ox~de crystallises. Melting point 139-140C;
IR spectrum (methylene chloride); characteristic bands at 5.55, 5.75 and 5.90~; ~a]20 ~ + 174 + 1 (c - 1, chloroform).
Further quantities of the crystalline benzyl ester l~-oxide can be obtained from the mother liquor by chromato-graphy on 2~0 g of acid-washed silica gel, using toluene/
ethyl acetate (1 ~
b) 4~56 g (10 mmols) of 6-phenoxyacet~mido-penicilla~ic acid benzyl ester l~-oxide and 1.84 g ~11 mmo}s) of 2-mercap~o-benzthiazole in 100 ml of toluene are heated for ~ houL~s un~er // ~7 _~ _ : .

1084~S4 reflux (bath ~e~perature 137C). The mLxture is left to stand, whereupcn 2-r4-(benzthiazol-2-yldithio)-3-phe~o~Jacet-amido-2-oxoazetidin-l_yl]-3-methylene-butyric acid benzyl ester crystallises out. The crystals are filtered off, wsshed with 50 ml of toluene and dried in a high vacu~m.
Further quantities of the crystalline product can be obtained by chromatography of the mother liquor on 70 g of acid-washed silica gel, using toluene/ethyl acetate (3:1). Melting point of the pure product 150~ 153C; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.75 and 5.90 ~;
ta]20 = -112 f 1 (C = l; chloroform).
c) An oxygen/o-one mixture is passed through 2 solution of 6.06 g (10 mmols) of 2-r~l (benzthiazol-2-yldithio)-3-phenoxy-aceta~ido-2-oxoazetidin-l_yl~-~-methylene-butyric acid benzyl ester in 300 ml of methylene chloride at -20C
until the st2rting matèrlal has been completely ozonised (as checked by means of thin layer chromatogr2~hy on silica gel, using toluene/ethyl acetate, 1:1). 50 ml of 10~
"c, strength aqueous sodi~m bis~phite solution are then added to the mixture which is stirred until (after 5 minutes) ozon~de is no longer detectable with potassium iodide/starch.
300 ml of water are added to the mixture and the product is partitioned be~ween the two phases produced. The organic phase is dried o~er sodium sulphate and freed from the sol~ent.
~he residue is triturated in 100 ml of ether-pentane (1:1) at 0C, whereupon 2-[4-(benzthiazol_2_yldithio)-3-pheno~J2cet_ amido-2-oxoa~etidin-1-yl]-3-hydroxy-crotonic acid benzyl ester ~ //6~

melting point 58-62C, crystallises out; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.90 and 6 00 ~a~20 _92 + 1 (c = 1, chloroform).
d~ 6.08 g (0.01 mol) o~ 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2_oxoazetidin-l yl~-3_hydroxy-crotonic acid benzyl ester and 3.50 g (0.013 mol) of silver p-toluenesul-phinate are stirred in 200 ml of ecetone-water (9~ or 60 minutes at room temperature. The yellow precipitate formed is ~iltered oif through Cellit, the residue is washed with acetone and the filtrate is concentrated in ~acuo to a ~olume of approx. 20 ml. The product is then partitioned betl~een methylene chloride and dilute aqueous sodium sulphate solution.
m e organic phase is dried o~er sodium sulphate and +he sol-~ent is evaporated in vacuo. The residue is taken up in 70 ml of ethyl acetate, if necessary with warming, freed from a little insoluble matter by filtration and again concen~rated by e~aporation. On addition of 100 ml of ether-pentane at 0C, 2-~4-(p-toluenesl~lphonylthio)-3-phenoxyacetamido-2-oxo-azetidin-l-yl~-3-hydroxy-crotonic acid berzyl ester of melting polnt 1~1-152C crystallises out; IR spectrum (methyl2ne chloride): characteristic bands at 5.60, 5.90j 6.oo and 8.75 r;
ta~20 ~ -16 + 1 (c - l; chloroform).
e) A solution of diazomethane in ether is added dropwise to a solution of 5.97 g (0.01 mol) of pure 2-~4-(p-toluene-sulphonylthio)-3-phenoxyacetamido-2-oxoazetldin-1-yl~-3-hydroxy-crotonic acid benzyl ester in 50 ml of methylene chloride at 0C, whilst stirring, until the starting materia has been comple~ely methyla~ed (checked by thin layer chror.a,o-grzphy on silica gel, using to~uene/ethyl acetat~ 1). Ex-cess diazomethane is neutralised by a few drops o~ glacial ac~-tic acid (but an excess of glacial acetic acid shculd be avo~d_~
after which the mixture is concentra~ed by evaporation in vacuo, The yellowish, foam-like residue is crystallised from diethyl ether/pentane (1:1), gi~irg an isomer mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxo2ze~ldin-l-yl]-3-methoxy-crotonic acid benzyl ester and 2-~4-(p-to~uene-sulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-~Jl]-3-me'~hc~v-isocrotonic acid benzyl ester in the ratio of about 3:1.
m e two isomers can be separated by repeated chL~omato-graphy on silica gel, using toluene/ethyl acetate, 1:1. The resulting ~-[4-(p-toluenesl1lphonylthio)-3-phenoxyaceta~ido-2-oxoazetidin-l-yl]-3-methoxy-crotonic acid be~7yl ester has a melting point of 166-168C; [a]20 = -36 - 1 (c = l; chloro-form); IR spectrum (methyle~e chloride): charac~eristic b2r.d at 5.60, 5.80, 5.90 and 8.72~; NMR spectrum (chloroform):
characteristic bands at 2.12 (s); 5.00 (dd); 5.90 (d) ppm;
thin layer chromatogram: Rf ~alue ~0.10 (silica g_l; toluene/
e~hyl acetate, 1:1). m e re`sulting 2-~4-(p-toluene$ulphonyl-thio)-3-phenoxyacetamido-2-oxo2zetidin-l-yl]-3-methoxy-iso-crotonic acid benzyl ester has a melting point of 59-63C;
~a~20 = -1 + 1 (c = l; chloro~orm); IR spect~um (methylene chloride): characteristic bands at 5.60, 5.87 sh. 5.90 and 8.72~; NMR spectrum (chloro orm): characteristic ba,ds at 3.23 (s), 5.45 ~d,d), 5.73 (d) ppm; thin layer ch~om2~0~r2m:

t . /~
_~ _ Rf value -0.13 (silica gel; toluene/e~hyl acetate, 1 Exa~le 20 302 mg (2 mmols) of 1,5-diazabicyclc~5.4.0]~ndec-5-ene are added to a solution of 534 mG (1 mmol) of a mixture consisting of 2-[4-(~-toluenesulphonyl~hio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methoxy-isocroionic acid methyl ester and 2-~4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxo-azetidin-l-yl)-3-methoxy-crotonic acid methyl ester in the ratio of about 4:1, in 20 ml of tetrahydrofurane, whilst stirring. The mixture is then stirred for 40 minutes, diluted wiZh 70 ml of methylene chloride and washed successive-ly with dilute hydrochloric acid, with water, with dilute aqueous sodium bicarbonate solution and again wi~h water.
The organic phase is dried over sodium sulphate and concen-trated by e~aporation in vacuo. The residue is chromato-graphed on 15 g of acid-washed silica gel usirg toluene/ethyl acetate, 2:1 followed by 1:1, resulting in the elution of, first, pure 7~-phenoxyacetamido-3-me~hoxy-ceph-2-em 4-carboxylic acid methyl ester, IR spectrum (i~ methylene chloride): characteristic bands at 5.60, 5.70, 5.90 and &.25~, followed by pure 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-carbox~lic acid methyl ester, IR spectrum (in methylene chlor-ide): characteristic bands at 5.60, 5.85, 5.90 and 7.10~, in the form of colourless foams.
The compounds obtained can be further con~erted as follows:
15 ml of cooled 0.1 N aqueous potassium hydroxide /~L/

108~054 solution are added, wnilst stirring, to a solution, co-oled in an ice ~a'h, o~ 382 mg of 7~-phenoxyacetamido-3-me~oxy-ceph-2-em-4_carboxylic acid methyl ester in 30 ml ol tetr2-hydrofurane. After 5 minutes, 100 ~1 of water and 70 ml of methylene chloride are added and the mixture is acidi~ied by - adding 10 ml of 1 N aqueous hydrochloric acid. The methy-lene chlor~de phase is separated off and the aqueous phase is extracted with 30 ml of methylene chloride. The combin.ed ~J organic phases are dried over sodium sulphate and concentrated by e~aporation in ~acuo. The residue is crystallised from chloroform/diethyl ether and gives 7~-phenoxyacetamido-2-methoxy-ceph-2-em-4a-carboxylic acid of melting point 142~
(decomposition).
The same compound, of melting point 142C (decompcsi-tion) is obtained when 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid methyl ester is saponified with 0.1 potassium hydroxide solution, as described earlier.
o The starting materials can be prep~red as follows:
a) A solution of 19.25 g (50 mmols) of 6-phenoxyacet-amido-penicillanic acid methyl ester l~-oxide and 9.4 g (55 mmols) of 2-mercap'oben2thiazole in 500 ml of dry toluene is boiled for 8 hours under re n ux and then concentrated in ~acuo. The residue is dissol~ed in 400 ml of ethyl acetate whilst warming (~ 80C) and the solution is treated with 0.2 g of acti~e charcoal and filtered through an electrically heated glass ~r~t. On cooling, 2-r4-(benzthiazol-2-yldithio)-3-phenoxyacet2mido-2-oxoazetidin-l-yl]-3-methylene-butyric ac~d methyl este- of melting point 132 ~134C separ~tes ou~.
~urther quantitiPs of this compound (melting poin~ 135 ~ 137CC) can be obtained from the mcther li~uors.
b) An ozone/oxygen mixture is passed through a solution of 20.6 g (40 mmols) of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxo2zetidin-l-yl]-3-methylene-butyric acid methyl ester in 400 ml of acetone at -20C until no further starting material is detectable by +hin layer chroma~ogr~phy (silica gel, toluene/ethyl acetate, 1:1). 40 ml of dim2thyl-sulphide are then added to the mixture and the whole is stirred for 3 days at room temperature until ozone is no longer detectable with potassium iodide/starch. The mixture is concentrated by evaporation in vacuo and the liquid resi-due is poured onto 400 ml of ice water. The precipita~e is filtered o~f, washed with 200 ml of ice water, dried in vacuo -and crystallised from diethyl ether/pentane at 0C. The resulting 2-[4-(benzthiazol_2-yldithio)_3-phenoxyacotamido_2_ oxoazetidin-l-yl~-3-hydroxycrotonic acid methyl ester has 2 melting point of 127rV130C; IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.90, 6.00 and 8.10 ~. Further quantities of t~e product can be obtained by chromatography of the mother liquors on silica gel, using toluene/ethyl acetate, 3~
c) Sufficient of a solution of diazomethane in ether is added to a solution o~ 4.85 g (0.01 moi) of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-hydroxy-crotonic acid methyl ester in 50 ml of methylene chloride at ' _~

._ 108 4~5 4 0C, whilst stirring, that after periods of stirring of 15 minutes starting material is in each case no longer detect-able by thin layer chromatography (silica gel, toluene/ethyl acetate, 1:1). Excess diazomethane is neutralised with a minimum amount of acetic acid and the mixture is concentrated by e~aporation in ~acuo. The residue consists of a mixture of 2-[4-(benzthiazol_2-yldithio)_3_phenoxyacetamido-2-oxo-azetidin-l-yl~-3-methoxy-isocrotonic scid methyl ester and 2-[4-(benzthiazol-2-yldithi~L3_phenoxyacetamido_2_oxoszetidin-l-yl]-3-methoxy-crotonic acid methyl ester in the ratio of about 4:1. IR spectrum (in methylene chloride): character-istic bands at 5.60, 5.85, ~.90, 9.05 and 10.00 ~.
d) A mixture comprising 5.03 g (0.01 mol) of a mixture o~
2-E4-(benzthiazol-2-yldithio)_3_phenoxyacetamido-2-oxoazetidin-l-yl]-3-methoxy-lsocrotonic acid methyl ester and the corres-ponding crotonic acid methyl ester in the ratio of about 4:1, 3.50 g (0.013 mol) of sil~er p-toluenesulphinate and 200 ml oi acetone~water, 9:1, is stirred for 40 minutes at room temperature and the~ filtered through Cellit. The filter residue is washed with acetone and ~he comblned filtrates are concentrated in vacuo to a ~olume of about 20 ml. After adding lO0 ml of methylene chloride and 100 ml of dilute aqueous sodium sulphate solution, the whole is shaken thoroughly, the aqueous phase is separated off and the methy-lene chloride phase is dried o~er sodium sulphate and concen-trated by e~aporation in vacuo. The residue is purified by trituration with diethyl ether/pentane at 0C and is filtered /.~2y .
~. ~

iO8 405 4 off. A mixture of 2-r4-(p-toluenesulphonylthio)-3-pheno~-acetamido-2-oxoazetidin-1-yl)-3-methoxy-isocro~onic acid methyl ester and 2-~4-(p-toluenesulphonylthio)-3-pheno~y-acetamido-2-oxoazetidin-1-yl~-3-methoxy-crctonic acid methyl ester in the ratio of about 4:1 is obtained in the for~ of a white po~wder. IR spectrum (in methylene chloride) character-istic bands at 5.60, 5.85, 5.90 and 8.75 ~.
Fxam~le 21 O A solution of 731 mg (1 mmcl) of a 1:1 mixture,con-sisting of 2-[4-~p-toluenesulphonylthio)-3-phenoxyacetamido-2- ~
oxoazetidin-l-yl~-3-benzoxy-crotonic acid p-nitrobsnzyl ester and the corresponding isocrotonic acid p-nitrobenæyl ester in a mixture of 0.185 ~1 (1.2 mmols) of 1,5-diazabicyclor5.4.0]
undec-5-ene in 20 ml of dry tetrahydrofurane is stirred or precisely 35 minutes at room temperature. 50 ml of methyle~e chloride are added to the mixture ar.d the whole 's washed successi~ely with dilute hy~rochloric acid, water and dilute C aqueous sodium bicarbonate solution. The org~nic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 25 mg o~ acid-washed silica gel, using toluene/ethyl ace~ate (3:1). A
mixture consisting of the ceph-2-em compound and ~he ceph-3-em compound in the ratio of about 3:1 is obtained; this mix-ture can be separated by repeated chromatography into the pure isomers, giving 7~-phenoxyacetamido-3-benzoxy-ce?n-2-em-4a-carboxylic acid p-nitrobenzyl ester o melting point 160C-162C (diethyl ether/pentane); IR spectrum (methylene /c?~
, 3~ ~

. . - .
:

chloride): characteristic bands at 5.6, 5.7, 5.9 and 7.4 ~, and 7~-phenoxyacetamido-3-ben2oxy-ceh-3-em-4-carboxylic ac d p-nitrobenzyl es~er in the form of a colourless foam, IR spectrum (methylene chloride): charac~eristic bands at 5.6, 5.8 sh, 5.9, 7.9 and 8.4 ~.
The isomer mixture obtained can be further converted as follows:
The isomer mixture obtained, consisting of 7~-phenoxy-acetamido-3-benzoxy-ceph-2-em-4a-carboxylic acid p-nitrobenzyl ester and 7~-phenoxyacetamido-3-benzoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the ra~io of about 3:1, is d~s-solved in 8 ml of trifluoroacetic acid and the solutio~ is stirred for 90 minutes at room temperature. The react~on mixture is then concentrated by evaporation in vacuo a~d residual tr~fluoroacetic acid is repeatedly driven off with toluene. The residue is chromatographed on 20 g of acid-washed silica gel, using toluene/ethyl acetate (3:1), gi~ir,g 7~-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic ac~d p-nitrobenzyl ester in the form of a colourless foam. 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): characteristic bands at 3.4 (ZH, A~ q, J s 17 Hz), 4.57 (2X, s), 5.06 (IH, d, J . 5 Hz), 5.35 (ZH, AB q, J - 14 Hz), 5.7 (lH, dd, J = 5, 10 Hz), 6.8-8.4 (lOH, c), 11.4 (IH, br.s.) ppm.
The s~arting material can be pre~ared as follows:
30 ml of the solution prepared "in situ" (from N-_ ~ _ iO8 4054 benzyl-N-nitrotoluenesulphonG~ide) of 1.2 g (approx. 10 ~ols) of phenyldiazomethane in ether is added, at room temper2ture, to a solution of 1.282 g (2 mmols) of 2-~4-(p-toluenesul?honyl-thio)_3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid p-nitrobenzyl ester in 4 ml of distilled dioxane.
The mixture is boiled for 6 hours un der r_flux at 45C bath temperature, diluted with 100 ml of methylene chloride and then washed with 100 ml of water. The organic phase is dried o~er sodium s~lphate, concentrated by evaporation in vacuo ar~d dried in a high ~acuum. The resulting yellow oil is chromato-graphed on 100 g of acid-washed silica gel, using toluene/
ethyl acetate, 3:1 and 2:1, as the running agents. An iso-mer m~xture consisting of 2-~4-(p-toluenes~phonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-benzoxy-crotonic acid p-nitrobenzyl ester and 2-[4-(p-toluenesulphonylthio)-3-phe~oxyacet2~ido-2-oxoazetldin-l-yl~-3-benzo~-isocrotonic acld p-n$trobenzyl e~ter in the ratio of about 1:1 is obtaine~;
this can be separated into the indi~idual isomers by repealed chromatography, a~ described earlier. IR spectr~m of ~he faster-running crotonic acid deri~ati e (methy'ene chloride~:
characteris~ic ba~ds at 5.6, 5.80, 5.90 and 8.75 ~; NMR
spectrum (deuterochloroform): characteristic bands at 2.2 (s), 5.05 (dd), 5.93 (d) ~pm; thin layer chromatogr2m: R~ ~alue ~0.3 (silica gel; toluene/ethyl acetate,2:1); IR spect~-~of the slower-runnir.g isocrotonic acid deri~ati~e (methylene chlorlde): characteristic bands at 5.5, 5.85 sh, 5.90 ar.d 8.75 ~ R spectrum (deuterochloroform): ch~racter'stic ' .

bands at 2.5 (s), 5.41 (dd), 5.77 (d) ppm; thin layer chromatogram: Rf value ~ 0.25 (silica gel; toluene/ethyl acetate, 2:1).
Exam~le 22 405 mg (0.5 mmol) of an isomer mixture consisting of 2-r4-(p-toluenesulphonylthio)-3-Fhenoxyacetami~o-2-oxoazetidin l-yl~-3-diphenyl~ethoxy_crotonic acid p-nitrobenzyl ester and the corresponding isomeric isocrotonic acid ester are dissolved in 8 ml of dry tetrahydrofurane containing 0.9 ml (0.6-mmol) of 1,5-diazabicyclo~5.4.0]ur,dec-1-ene and the solution is stirred for precisely 45 minutes at room temperature. The yellow reaction mixture is then diluted with 25 ml of methy-lene chloride and washed with 0.5 N hydrochloric acid, w~ter and dilute aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulphate and concen~rated by evaporation.
An isomer mixture consisti~g of 7~-phenoxyacet2mido-3-diphenylmothoxy-ceph-2-em-4a-carboxylic acid p-nitrobenzyl ester and 7~-phenoxyacetamido-3-diphenylmet'noxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester is obtained; IR spectruD
(methylene chloride): characteristic bands at 5.60, 5.70, 5.90, 6.5~ and 7.40 ~.
The resl~lting isomer mixture of the two compounds can be further converted as follows:
A solution of 340 mg of the resulting isomer mixtuL~e, consisting of 7~-phenoxyacetam$do-3-diphenylmethoxy-ce~h-2-em-4a-carboxylic acid p-n$trobenzyl ester and 7~-phenoxyacet-/~
~` _,~94 _ io84054 amido-3-diphenyl~ethoxy-ceph-3-em-4-carbcxylic acid p-nitro-benzyl ester, in a mixtuhe of 0.5 ml of trifluoroacetic acid and 9.5 ml of methylene chloride is stirred for 40 minutes at room temperature. The mixture is concentrated by ev2poration in vacuo, toluene is added to the residue, and the mixture is again concentrated by evaporation. The resulting residue (which still contains trifluoroacetic acid) is chromatographed on 15 g of acid-~rashed silica gel t using toluene/ethyl acetate (3:1), whereby ?~-phenoxyacetamido-3-hydroxy-ceph-3-e~-4-carboxylic acid p-nitrobenzyl ester is obtained; 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.~ ~; N~ spec--tr~m (deuterochloroform): characteristic bands at 3.4 tZH, AB q, ~ z 17 Hz), 4.57 (2H, s), 5.06 (lH, d,~ z 5 H~), 5.3 (ZH, AB q, ~ z 14 Hz), 5.7 (lH, dd,l z 5, 10 Hz), 6.8-8.4 (10 H, c), 11.4 (lH, br. s.) ppm.
The starting material can be obtained as fo;lows:
G A solution of 350 mg (1.75 mmols) of diphenyldi2zo-methane in 0.3 ml of dioxane is added to a solution of 641 mg (1 mmol) of 2-~4-(p-toluenesulphonylthio)-3-pheno~yacetamido-2-oxoazetidin-1-yl~-3-hydroxy-crotonic acid p-n~trobenzyl ester in 0.5 ml of distilled dioxane and the reaction mixtur_ is warmed to 50C for 36 hours, without stirring. The mix-ture is concentrated by eYaporation in Yacuo, the dioxane which remains ~s driYen off by adding toluene and agair con-centrating by eYaporation, and the residue is chromat3gr2~hed on 20 g of acid-washed silica gel, using toluene/ethyl aceta'e (7:1) and (3:1).
An isomer mixture consisting of 2-[4-(p-toluenesu'-phonylthio) 3-phenoxyacetami~o-2-oxoazetidin-1-yl]-3-di-phenylmethoxy-crotonic acid p-nitrobenzyl ester and 2-r4-(p-toluenesulphonylthio)_3_phenoxyacetamido-2-oxoazetidin-1-yi~-3-diphenyl~ethoxy-isocrotonic acid p-nitrobenzyl ester is obtained, ~R spectrum (methylene chloride): characteristic bands at 5.6, 5.85 sh, 5.9, 6.25, 6.55, 7.43 and 8.75 ~.
Exam~le 23 800 mg (5.25 mmols) of 1,5-diazabicyclo[5.4.0~undec-5-ene are added to a solution of ~33 mg (1.5 mmols) OL an isomer mixture consisting of 2-{4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-l_yl]-3_benzoxy-crotonic acid met~yl ester and the corresponding isocrotonic acid methyl estçr, in the ratio of about 1:1, and 350 mg (2.25 mmols) of p-toluenesulphinic acid in 30 ml of dry tetr~hydrofurane, and the reaction mixture is stirred for precisely 40 minutes at room temperature. It is then diluted with lC0 ml of benzene and washed with dilute aqueous hydrochloric acid, with water, with dilute aqueous sodium hydroxide solution and again with water. The benzene phase is dried over sodium sulphate ar.d concentrated by evaporation in vacuo. Chromatogra~hy using toluene/ethyl acetate (5:1) on silica gel gives an isomer mix-ture consisting of 7~-phenoxyacetamido-3-benzoxy-ceph-3-em ~-carboxylic acid methyl ester and 7~-phenoxyacetamido-3-benzoxy-ceph-2-em ~I-carboxylic acid methyl ester: IR spectru~
(methylene chloride): characteristic bands at 5.60, 5.72, /~0 -~ _ `: :
.

.

iO84~54 5.85 sh and 5.90 ~. -The starting material can be prepared as follows:
960 mg (approx. 8 mmols) of freshly distilled phenyl-diazomethane are added to a solution of 483 mg (1 mmol) o 2-[4-benzthi2zol-2_yldithio)_3_phenoxyacetamido-2-oxoazetidin-l-yl]-3-hydroxy-crotonic acid methyl ester in 1.5 ml of methylene chloride/diethyl ether and the reaction mixture is stirred for 20 hours at 0C, then diluted with methylene chloride and washed with water. The organic phase is dried o~er sodium sulphate and concentrated by evaporation in ~acuo. ~
The residue is dried in a high ~acuum and then chromatographe~
on 10 g of acid-washed silica gel, using toluene/ethyl aceta~e (2:1), gi~ing an isomer mixture consisting of 2-t4-(~enzthiazol-2-yldith~o)_3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-benzoxy-crotonic acid methyl ester and the corresponding isocrotonic acid methyl ester in the ratio of about 1:1; IR spectrum (methylene chloride): characteristic bands at 5.6, 5.85 sh, ~) 5~9 and 9.9 ~.
Exam~le 24 Analogously to Example 5 d, reaction of 1.16 g (3 mmols~
of 7~-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochlori~e dioxanate, obtainable according to the invention, with 1.5 ml (6.2 mmols) of bis-(trimethylsilyl)-scetamide and subsequently wit~
a) 765 mg (3.6 mmols) of D-a-amino-(2-thienyl)-acetyl chloride hydrochloride give 7~ -a-amino-a-(2-thienyl)-acetyl-am~no~-3-methoxy 3-cephem-4-carboxylic acid in the form of the .. /~/
L~

10 8 4~54 inner salt, meltin~ point 140C (with decomposition); thin layer chrom2togram (silica gel; identilica~ion with iodine):
Rf~,0.22 (system: n-butanol/ac~tic acid/water, 67:10:23) and Rl~ 0.53 (system: isopropanol/for ic acid/water, 77:4:19);
ultraYiolet absorption spectrum: AmaX = 23~ m~ (~ = 11,400) and AShoulder = 272 m~ (~ = 6,100) in 0.1 N hydrochloric acid, and AmaX = 238 m~ ~ = 11,800) and AShoulder = 267 m~ ( =
6,500) in 0.1 N aqueous sodium bicarbonate solution.
~~; If stage a) is replaced by reacti~n with b) 940 mg (4.5 mmols) of D-a-amino-(1,4-cyclohexadienyl)- -acetyl chloride hydrochloride, 7~-[D-a-amino-a-(1,4-cyclo-hexadienyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylic acid is obtained in t~e form of the inner salt, melting poi~t 170C (with decomposition); thin layer chromatogram (silica gel; identi~ication with iodine): .Rf~ 0.19 (system: n-butanol/acetic acid/water, 67:10:23) and Rf~ 0.58 (sys+em:
isopropanol/formic acid/water, 77:4:19); ultra~iolet absorp-,- tlon spectrum: Am2X . 267 m~ 6,300) in 0.1 N hydrochloric acld, and AmaX = 268 m~ t~ = 6,600) in 0.1 N aqueous sodium bicarbonate solution, ~a~20 _ + 88 + 1 (c = 1.06; 0.1 N
hydrochloric acid).
If stage a) is replaced by reaction with c) 800 mg (3.6 mmols) of D--amino-4-hydroxypher.ylacetyl chloride hydrochloride, 7~-[D-a-amino-~-(4-hydroxyphenyl)-ace~ylamino~-~-methoxy-3-cephem-4-carboxylic acid is obtained ~n the form of the inner salt, melting point = 243 - 244.5C
(with sintering starting from 231C onwards) (wi.th decomposi-: ~,. _~ _ B~

.

tion); thin layer chromatogram (silica gel; identificationwith iodine): Rf~ 0.24 (system: n-butanol/acetic acid/water, 67:10:23) ar.d Rf ~ 0.57 (system: isopropanollformic acid/
water, 77:4:19); ultra~iolet absorption spectrum: AmaX =
228 m~ (e = 12,000) and 271 m~ (~ = 6,900) in 0.1 N hydro-chloric acid, and AmaX = 227 m~ ( = 10,500) and AShoulder =
262 m~ (~ = 8,000) in 0.1 N aqueous sodium bicarbonate sol~-t~on, ra~20 + 165 + 1 (c = 1.3; 0.1 N hydrochloric acid).
Exa~le 25 m e following compounds can be prepared analogously from suitable intermediate products obtainable in accordance with the in~entlon: 7~-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester or salts thereof, 3-n-butoxy-7~-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, 3-n-butoxy-7~-(D-a-tert.-butoxycarbonylamino-a-phenyl-acetylamino~-3-cephem-4-carboxylic acid diphenylmetnyl ester, 3-n-butoxy-7~-(D-~-phenylglyc-flamino)-3-cephem-4-c2rboxylic acid or salts thereof, 3-methoxy-7~-phenylacetylamino-3-cephem-4-carboxylic acid methyl ester, 3-ethoxy-7~-(D-a-tert.-butoxycarbonylamino--phenylacetylamino)-3-cephem-4-carboxylic acid diphenylmethyl ester, 3-ethoxy-7~-(D-a-phenylglycylamino)-3-cephem-4-carboxylic acid or salts thereof, 3-benzoxy-7~-(DLa-tertO-butoxycarbonylamino--phenylacetylamino)-3-cephem-4-carboxylic acid diphenylmethyl ester, 3-benzoxy-7~-(D--phenylglycylamino)-3-cephem-4-carboxylic acid or salts thereo~, 7~-(5-benzoylamino-5-diphenylmethoxycarbonylv21erylamino)-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 7~-/~ 3 iO8405~
(DL-tert._butoxycarbonylamino__phen~lacetylamino)-3-methoxy-3-cephem-4-carboxylic acid or salts thereof, 7~-~D-a-ter~.-butoxycarbonyla~ino-a-(2-thienyl)-acetylamino~-3-metho~J-3-cephem-4-carboxylic acid diphenylme~hyl es~er, 7~-[D-a-ter~.-butoxycarbonyl2mino-_(1,4-cyclohexadienyl)-acetylaminol-3-methoxy-3-cerhem-4-carboxylic acid diphenylmethyl ester, 7~-~D ~-amino-a-(l-cyclohexen-l-yl~-acetylamino]-3-methoxy-3-cephem-4-carboxylic acid or salts thereof, 7~-[D-a-tert.-butoxycarbonylamino-a-(4-hydroxyphenyl)-2cetylamino~-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 7~-[D-a-tert.-butoxycarbonylamino-a-t4-isothiazolyl)-acetyl-amino~-3-methoxy-3-cephem-4-carboxylic acid diphenylmeihyl ester, 7~-(D-a-tert.-butoxycarbonylamino--phenylacetylamino)-3-methoxycarbonyloxy-3-cephem-4-carboxylic acid d phenylmethy ester, as well as the corresponding ceph-2-em ccm~ounds and the isomer mixtures consisting of the ceph-3-em compounds and the ceph-2-e~ compounds, and also the l-oxides o~ the cor-es-pondlng ceph-3-em compounds.

Claims (12)

What we claim is:

1. Process for the manufacture of a compound of the formula (VI), wherein R? represents an acyl group of the formula (A'), wherein RI represents lower alkyl, halogeno-lower alkyl, phenyloxy-lower alkyl, hydroxyphenyloxy-lower alkyl, pro-tected hydroxyphenyloxy-lower alkyl, halogeno-phenyloxy-lower alkyl, or lower alkyl substituted by amino and car-boxyl, wherein amino is free or protected and carboxyl is free or protected, or RI represents lower alkenyl, phenyl, hydroxyphenyl, protected hydroxyphenyl, halogenophenyl, hydroxy-halogeno-phenyl, protected hydroxy-halogeno-phenyl, amino-lower alkyl-phenyl,protected amino-lower alkyl-phenyl, phenyloxyphenyl, or RI represents pyridyl, thienyl, furyl, imidazolyl or tetrazolyl, or these heterocyclic groups substituted by lower alkyl, amino, protected amino, amino-methyl or protected aminomethyl, or RI represents lower alkoxy, phenyloxy, hydroxy-phenyloxy, protected hydroxy-phenyloxy, halogenophenyloxy, lower alkylthio, lower alkenylthio, phenylthio, pyridylthio, 2-imida-zolylthio, 1,2,4-triazol-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, subtituted 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 (A"), whreein RI represents lower alkyl, phenyl, hydroxyphenyl, protected hydroxyphenyl, halogenophenyl, hydroxy-halogeno-phenyl, protected hydroxy-halogeno-phenyl, furyl, thienyl, or isothiazolyl, or 1,4-cyclohexadienyl, and RII represents amino, protected amino, azido, carboxyl, protected carboxyl, cyano, sulpho, hydroxyl, protected hydroxyl, O-lower alkyl-phosphono, O,O'-di-lower alkyl-phosphono or halogeno, R? is halogen or together with the carbonyl grouping -C(=O)-forms an esterified, protected carboxyl group, and Y represents a leaving group of the formula -S-R4, wherein R4 is 1-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4,5-oxatriazol-2-yl, 2-quinolyl, 1-methyl-benzimi-dazol-2-yl, benzthiazol-2-yl or benzoxazol-2-yl, or Y represents a leaving group of the formula -SO2-R5, wherein R5 represents phenyl, or phenyl substituted by lower alkyl, lower alkoxy, halogen, phenyl, phenyloxy or nitro, and their salts, characterised in that in a compound of the formula IV

(IV), wherein R?, R? and Y have the meanings mentioned under formula VI, the methylene group is converted into an oxo group by oxidative degradation with ozone in the presence of a solvent at temperatures of -90°C to +140°C.

2. Process according to claim 1, characterised in that the oxidative degradation of the methylene group is carried out with ozone and the ozonide of the formula (V) obtained as an intermediate product, wherein R?, R? and Y
have the meaning mentioned under formula IV, is reduced with catalytically activated hydrogen, a heavy metal, metal alloy or amalgam in the presence of a hydrogen donor, an alkali metal iodide in the presence of a hydrogen donor, a di-lower alkylsulphide, or a reducing organic phosphorous compound.

3. Process according to claim 1 or 2, characterised in that in a resulting compound of the formula VI, wherein Y
denotes a leaving group -S-R4, wherein R4 has the above mentioned meaning, the -S-R4 group is optionally converted into a -SO2-R5 by treatment with a heavy metal sulphinate of the formula Mn+(-SO2-R5)n, wherein R5 has the meaning defined in claim 1, M represents a heavy metal cation, such as copper, mercury, silver or tin and n denotes the value of this cation.

4. Process according to anyone of claims 1 to 2, characterised in that a compound of the formula IV, wherein R? is phenoxyacetyl, R? p-nitrobenzyloxy and Y is p-toluene-sulphonyl, is treated with ozone followed by treatment with dimethyl sulphide, so as to produce 2-[4-(p-toluenesulphonyl-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy--crotonic acid p-nitrobenzyl ester.

5. Process according to anyone of claims 1 to 2, characterised in that a compound of the formula IV, wherein R? is phenoxyacetyl, R? is diphenylmethoxy and Y is p-toluene-sulphonyl, is treated with ozone followed by treatment with dimethyl sulphide, so as to produce 2-[4-(p-toluenesulphonyl-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy--crotonic acid diphenylmethyl ester.

6. Process according to anyone of claims 1 to 2, characterised in that a compound of the formula IV, wherein R? is phenoxyacetyl, R? is diphenylmethoxy and Y is benzthia-zol-2-yl-thio, is treated with ozone followed by treatment with dimethyl sulphide, so as to produce 2-[4-(benzthiazol--2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3--hydroxy-crotonic acid diphenylmethyl ester.

7. Process according to anyone of claims 1 to 2, characterised in that a compound of the formula IV, wherein R? is phenoxyacetyl, R? is 2,2,2-trichloracetyl and Y is benzthiazol-2-yl-thio, is treated with ozone followed by treatment with dimethyl sulphide, so as to produce 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazet-idin-1-yl]-3-hydroxy-crotonic acid 2,2,2-trichloroethyl ester.

8. Process according to anyone of claims 1 to 2, characterised in that a compound of the formula IV, wherein R? is D-.alpha.-tert.-butoxycarbonylamino-.alpha.-phenylacetyl, R? is diphenylmethoxy and Y is p-toluenesulphonyl, is treated with ozone followed by treatment with dimethyl sulphide, so as to produce 2-[4-(p-toluenesulphonylthio)-3-(D-.alpha.-tert.-butoxycarbonylamino-.alpha.-phenylacetamido)-2-oxoazetidin-1-yl]--3-hydroxy-crotonic acid diphenylmethyl ester.

9. Process according to anyone of claims 1 to 2, characterised in that a compound of the formula IV, wherein R1 is phenylacetyl, R? is diphenylmethoxy and Y p-toluene-sulphonyl, is treated with ozone followed by treatment with dimethyl sulphide, so as to produce 2-[4-(p-toluenesulphonyl-thio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-hydroxy--crotonic acid diphenylmethyl ester.

10. Process according to anyone of claims 1 to 2, characterised in that a compound of the formula IV, wherein R? is phenoxyacetyl, R? is methoxy and Y is benzthiazol-2--yl-thio, is treated with ozone followed by treatment with dimethyl sulphide, so to produce 2-[4-(benzthiazol-2-yldi-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy--crotonic acid methyl ester.

11. Process according to anyone of claims 1 to 2, characterised in that a compound of the formula IV, wherein R? is phenoxyacetyl, R? is diphenylmethoxy and Y is benz-oxazol-2-yl-thio, is treated with ozone followed by treat-ment with dimethyl sulphide, so as to produce 2-[4-(benz-oxazol)-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]--3-hydroxy-crotonic acid diphenylmethyl ester.

12. A compound of the formula (VI) wherein R?, R? and Y have the meanings mentioned under formula VI in claim 1, whenever prepared according to a process of claims 1 or 2, or an obvious chemical equivalent thereof.