CA1086755A - Process for the manufacture of 3-methylene-butyric acid derivatives - Google Patents

Abstract

Process for the Manufacture of 3-Methylene-butyric Acid Derivatives Abstract of the Disclosure 3-Methylene-butyric acid derivatives of the formula (IVb or IVc) wherein R? represents an acyl group, R? is halogen or to-gether with the carbonyl grouping -C(=0)- forms an esteri-fied, protected carboxyl group and Y denotes a group of the formula -S02-R5 (IVb) bonded by the sulphur atom to the thio group -S-, or a group -S-S02-R5 (IVc), wherein R5 represents an optionally substituted aliphatic, cyclo-aliphatic, araliphatic or aromatic hydrocarbon radical with up to 18 carbon atoms, are prepared a) by treatment of esters of penicillanic acid-1-oxid compounds with a sulphinic acid of the formula H-S02-R5, a sulphonyl cyanide of the formula N?C-S02-R5 or a thiosulpho-nic acid of the formula H-S-S02-R5, or b) by treatment of esters of compounds of the formula IVa, wherein Y represents a group of the formula -S-R4, wherein R4 is an aromatic heterocyclic radical, with a heavy metal sulphinate of the formula Mn+(?S02-R5)n or with heavy metal thiosulphinate of the formula Mn+(?S-S02-R5)n.

Description

i7SS

The subject of the pre~ent inventi~n is a process for the manufacture o~ 3-methylene-butyric acid derivatives o~ the formula H }I

CE~ (IVb or IVc) 0= 4 - M 11 2 \~-C-CH3 O=C-R2 wherein ~1 represents an acyl group o~ the formula O
~ 1l R--C~2 - C ~ ~A'), wherein R represents lower alkyl, halogeno lower alkyl, phenyloxy-lower alkyl, hyd~oxyphenyloxy-lower alkyl, pro-tected hydroxyphenyloxy-lower:alkyl, halogeno-phenyloxy-lower alkyl, or lower alkyl ~ubs~ituted by ~mino and car-boxyl, wherein amino is free or protected and ca~boxyl is free or protected, or RI represen~s lower alkenyl, phenyl, hydroxyph~yl, prot~cted hydroxyphenyl, halogenophenyl, hydroxy-halogeno-phenyl, prote~ted hydroxy-halogeno-phenyl, ~mino-lower alkyl-phenyl, protected am~no-lower alkyl-phenyl, phenyloxyphenyl, ~r RI repr~sents pyridyl, thienyl, ~uryl, im~dazolyl or tetrazolyl, or these heterocyclic groups substituted by lower alkyl, am~no, pso~ected amino, amino-methyl or protected aminomethyl, or RI represents lower al~oxy, phenyloxy, hydroxy-phenyloxy, protected hydroxy- :
phenyloxy, halogenophenyloxy, l~wer alkylthio, lower alkenylthlo, phenylthio, pyridylthio, 2-imidazolylthio, 1,~,4-trlazol-3-ylthio, 1,3,4-triazol-2-ylthio, . ~ .

~ .

. .. .... , . , ,. ,. - . . ... . .. -. ~ : - . : . .
. .- . : : - ~ . :-, , . : . . . :

;'7SS
1,2,4-thiadlazol-3-ylthlo, 1,3,4-thladlazol-2-ylthlo, or 5-tetrazolylthio, and these heterocyclylthlo groups, Substitut~d by lower alkyl, or RI represents halogeno, lower alkoxycarbonyl, cyano, carbamoyl, N-lower alkyl-carbamoyl, N-ph~nylcarbamoyl, lower al~anoyl, benzoyl, or azido, or Rl represents an acyl group of the formula R I O
R - CH - C ~ (A~), wherein ~ represen~s lower alkyl,~phenyl, hydroxyphenyl, protected hyd~oxyphenyl, halogenophenyl, hydroxy-halogeno-phenyl, protected hydroxy-halogeno-phenyl, furyl, thienyl, or isothia~olyl or 1,4-cyclohexadienyl, and R~I represents amlno, protected amlno, azido, car~oxyl, protected car~oxyl, cyano, sulpho, hydro~yl, proteGted hydroxyl, O-lower alkyl-phosphono, O,O'-di-lower al~ylphosphono or halogeno, R2 is halogen or together with the carbonyl group~ng -C~O)- fosms an estsrl~ied, protected ~rboxyl group, and Y represents a leaving group of the formula -S02-R5 (IVb) or -S-SQ2-RS (IVc) wherein R5 represen~s phenyl, or phenyl substltuted by lower alkyl, low~r alkoxy, halogen, phenyl, phenyloxy, or nltro, and their salts, which aompounds are useful~for example according to Canadian Patent No. 1059 988!for the manufacture o~ 7~-amlno-3-cephem-3-ol-4-carboxylic acid compound.~ of the formula ~ : .

... . : . . - , , . : , . . : . . - :
.: .. , ~ : . .. .
., : , .. : . . ..

~0~1~;'7S~i;

Ra H
S~.
i --i T
0=~ O-R3 (IA), 0 i R2 wherein Rl has the meanings mentioned . unde~ fo~mula IV, R2 represents hydroxyl, or a group ~ which is ha~ogen or whlch together wlth ~he carbonyl grouping -C(~O~;- orms an esterified; protected carboxyl group, and R3 represents hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl or trl~lower alkyl 5ilyl, the corresponding 2-cephem compound of the formula Rl ~ H
S~ , ~ !i~ j~ o- R3 I A
: O=~-R2 wherein Ral, R2 and R3 have ~he abovementloned mean~nys, or a mixture of a compound of the formula IA and IB, or salts of such compounds with salt-orming groups.

In 2-cephem compounds of the ~ormula IB ha~ing the double bond in the 2,3-position, ~he optionally protected carboxyl group of the ~ormula -C(=O)-R2 preferably has the -configuration.

In the new compounds of the formula IVb and IVc of the present lnvent~on an amino group can be protected by a group which can be replaced by hydrogen. Such amino protectice 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 groupO ~ group Ac abo~e all represents : - 3 - .
~: ' ~08675~;i 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 ~he aoyl radical of a carbonic acid half-deri~ati~e.

A bi~alent amino protect~ve group, is, in partlcular, the bivalent acyl radlcal of an organic dicarboxylic acid, preferably with up to 18 carbon atoms, above all the diacyl radlcal of an al~phatic or aromatic dicarboxylic acid, and also the acyl radical of an a-amino~acetic acid which is preferably substituted in ~he a-pOSitiOn and contains, for example, an aromatic or heterocyclic radical, and wherein the amino group is bond2d to the nitrogen atom via a methyle-ne ~adical whiah is preerably substituted and, for example, contains two lower alkyl gxoups, such as methyl groups. The bi~alent amino protective group can al~o represent an orga nic ylidene radical, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, prefèrably with 18 carbon atoms.

A protected carboxyl group of the formula -C(=O~-.R2 is an esterified carboxyl group.

The group R2 can t~erefore be a hydroxyl group etherlfied by an organic radical, wherein the organic radical preerabIy aontains up to 18 carbon atoms, which together with the -C.(=~)- grouping forms an esterlfied carboxyl group. Examples of organic radicalsare aliphatic,cycloali-' ~ ' - . . . : .
~, . . .. , -:: , , : ; . . , - :
.. . . .
. . .... : . . .
.

~L~86~SS

phatlc, cycloaliphakic-aliphatic, aromatic or araliphatic radicals, especially optionally substituted hydrocarbon radi-cals of this nature, as well as heterocyclic or heterocyclic-aliphatic radicals.

The group R2 can alsorepresentan organic sllylo~y xadical as well as a hydroxyl group etheri~ied by an organo-me~allic radicalj such as an appropriate organic stannyloxy group, especially silyloxy or s~annyloxy group which is - -substituted by 1 ~o 3 optionally ~ubstituted hydrocarbon radlcals, preferably with up to 18 caxbon atoms, such as allphatic hydrocarbon radicals, and optionally by halogen, such as chlorine.

In the groups -S02-RS is R5 a phenyl group which is optionally monosubstituted or polysubs~l~uted by lower alkyl, such as methyl, lower alkoxy, such as methoxy, halo-gen, such as ~luorine, chlorine or bromine, aryl, such as ph~nyl, 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.
.

.. .. .... ... . ..

- : , . , -- : .: . . : ~: - . :

;7SS

The general concepts used in the preceding and ollowing description ha~e, 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 monoYalent or divalent aliphatic hydrocarbon radical, :: :

, ~

, - ~ . ~, , ~ -. . , , -~ 8~ S
especially lo~Yer alkyl, as well as lo~rer alkenyl or lo~er alkinyl, a~d also lo~er alkylidene whic.h oaIl contain, for example7 up to 7, preferably up to 4, carbon atomsO Such radicals c~n optionally be monosubstitu~ed, disubstituted or polysubstituted by f~nc~ional groups, ~or example by free, e~herified or esterified hydroxyl or merCapto groups, such as lower alkoxy, lower alkenyloYy, lower alkylene~ioxy~ option-ally substi~uted phenylox~ or phenyl-lo~rer alkoxy, lower alkylthio or optionally substituted phenylthiog phenyl-lo~rer alkylthio, heterocyclylthio or heterocyclyl lotrer alkylthio~
optionally substituted lower alkoxycarbcnyloxy or lower alk-anoyloxy, or halogen~ also by oxo, nitro,.optionally substitu-ted amino, for example lo~er alkylamino, di-lower alkylamino, lower alkyleneamino, oxa-lower alkyleneamino or aæa-lower alkyleneamino, as well as acylamino, such as lo~rer alkanoyl-amino 9 lo~er alkoxycarbonylamino 9 halogeno-lot~er alkox~rczr-bonylamino, option211y substituted phenyl-lower alkoxycarbo-~ylamino~ optionall~ subs'-tuted carbamoylamino, ureidocar-bonylamino or guanidinocarbonylamino 2nd also sulphoamir.o which is optionall~ present in the form of a salt, such as in the form OL an alkali metal salt, azidoj acyl, such as lower al~anoyl or benzoyl, optionally functionally modified car-boxyl9 such as carboxyl present in the form of a salt, esterified carboxyl, such as lower alXoxycarbonyl, optionally substituted carbamoyl, such as N-lo~er alkyl~arbamoyl or M,N-di-lower alkylcarb~mo~l and also optionally substituted uLrei-docarbonyl or guanidinocarbonyl, Qr nitrile, optionally ' :' . ~ ~, .. , .. , . ~ . ,, . . ., .. -.

11~J8~;'7SS
func~ionally modified sulpho, such as sulphamoyl or sulpho present in the ~orm o~ a salt, or optionally O-monosubstitu- .
ted or O,O-disubstituted phosphono, wherein substituents represent, for examp.e, optionally substituted lo~rer alkyl, phenyl or phenyl-lower alkyl, it also being possible for 0-unsubstituted or O-monosubstituted phosphono to be iIl the form of a salt, such as in the form of an alkali metal salt.
A bivalent aliphatic radical, including ihe approp- -riate radical Gf a bivalent aliphatic carboxylic acidt is, for example, lower alkylene or lower alkenylene, which can optionally be monosubstituted9 disubstituted or polysubstitu-~ed, for example like an aliphatic radical indicated above, and/or be interrupted by hetero-a~oms~ such as oxygen, nitro- ' gen or sulphurO
A cycloaliphatic or cycloaliphatic-aliphatic radical, including the cycloaliphatic or cycloaliphatic-aliphatic radical in an appropriate organic carboxylic acid or an appropriate cycloaliphatic or cycloaliphatic-aîiphatic yli-dene ~adical, is an optionally substi~uted, mono~alent or bi- ~
Yalentt cycloaliphatic or cycloaliphatic-aIiphatic hydrocarr bon radical9 fvr example monocyclic, bicyclic or polycyclic cycloalkyl or cycloalkenyl~ a~d also cycloalkylidene, or cycloalkyl- or cycloalkenyl-lower ~lkyl or -lower alkenyl, as well as cycloal~yl-lower alkylidene or cycloalkenyl-lo~rer alkylidene, wher~in cycloalkyl and cycloalkylidene contains, ~or example9 u~ to 12, such as 3-8~ preferably 3-6, ring car-bon atoms, whilst cycloalkenyl contains, for example, up to :~

.. . ..... . : . ,. . .. ., . , .. . ~ . , . . ~ . ~ ; - , , .;., ~ ~ ' -, . .

6'7~5 12, such as ,~,-8, for example 5-8, preferably 5 or 6, ring carbon atoms and l to 2 double bonds, and the aliphatic part o~ a cycloal iphatic-alipha ~,ic radical can contain, for example, up to 7, ~referably up to 4, carbon atoms . The above cycloaliphatic or cycloaliphatic-ali phatic radicals can, if desired, be monosubstituted, disubsti'~u~ed or poly-substitutedy for ex~mple by optionally subs~ituted aliphatic hydrocarbon radicals, such as ~y the abovementioned option-ally substituted lower alkyl groups or, ~or example, like the abovementioned aliphatic hydrocarbon radicals, by func'-ional group~O
An aromatic radicalg including the aromatic radical of an appropriate carboxylic acid, is an optionally substitu-ted aromatic hydrocarbon radical, for example a monocyclic, bicyclic or polycyclic aromatic hydrocarbon radical, especi-al~y phenyl, as ~rell as biphenylyl or naphthyl, which can optionally be monosubstituted, disubsti~u,~ed or polysubstitu-ted, for example like the abovementioned aliphatic and cyclo-aliphatic hydrocarbon radicals~
A bivalent arom~,~ic radical, for example ~ an aromatic car~o~ylic acid, is above all 1,2~-arylene, especially 1,2- :
phenylene, which can optionally be monosubstituted, disubsti-tuted or polysubstituted, ~or example like t~e abovementioned aliphatic ar.d cycloaliphatic hydrocarbon radic~ls.
An aralipha~ic radical, including the araliphat~c radical in an appropriate carboxylic acid~, and also ar arali-phatic ylidene radical, iS7 for example, an o~tionally - 9 - . :

.

108~:;'7S5 su~stitut~d ar~liphatic hydrocarbon radical, ~uch as an ali-phatic hydrocarbon radical ~Ihic~ is optionally substituted and possess~s, for exam~le, up to three Gptionally substitu-ted monocyclic,bicyclic or polycyclic aromatic hydrccarbon radicals, &nd above all represents phenyl-1o~rer alkyl or phenyl-lo~er alkeny~ as well as phenyl-lower alkinyl and also phenyl-'o~er alkylidene9 't being possible for such radicals to contain, for example, 1-3 phenyl groups and to be opt~on- -^~ ally monosubstituted, disubstiiuted or polysubstitu1ed ir ~he aromatic and/or aliphatic part, ~or example like the above-mentioned aliphatic and cycloaliphatic radicals.
. Heterocyclic groups~ including ~hose in heterocyclic-aliphatic radicals, including heterocyclic or hPterocyclic-aliphatic groups in appropriate carboxylic acids, are esp~ci-ally monocyclic, as well as bicyclic or polycyclic, azacyclic, thiacyclic, oxacyclic 9 thiazacyclic~ thiadiazacyclic, o~aza-cyclic, diazacyclic, triazacyclic or tetrazacyclic radicals O o~ arom2tic characterg and also appropriate partially or wholly satura~ed heterocyclic radicals of this nature and .
such radicals can optionally be monosubstituted, disuDsti~u-ted or polysubstîtuted, for example like the abovementioned cycloalipha~ic radicals. The aliphatic part in heterocyclic-aliphatic radicals h&s, for ex~mple, the meanln~ indicated ~or ~he corresponding cycloaliphatic-aliphatic or araliphatic radicals.
m e acyl radical of a carbonic acid-half-derivative is preferably ~h~ acyl radical of an appropriate half-ester, ,~ - 10 -,, ... .. .. , , ` ~ , !

" ., , ' ' ~.' ' ; , ' . , , . ' ' ' ' ' ~6'~S~
~herein the organic radica~ of the ester group represents an optionally substitu-ted aliphati~; cycloaliphatic, aro~a~ic or araliphatic hydrocarbon radicalor a heterocyclic-aliphatic radical~ above all the acyl radical of a lo~;er alkyl hall-ester of carbonic acid ~hich is optionall~- substituted, ~or example in the a- or ~-position, as ~Jell as of a lower alk-enyl, cycloalkyl, phenyl or phenyl-lo~er alkyl hall-es'~er of carbonic acid ~Ihich is optionally substituted in the organic radical Acyl radicals o~ a carbonic acid h~ es~er are furthermore appropriate radicals of lo~rer alkyl half-esters of carbonic acid, in which the lower alkyl part contaLns a heterocyclic group~ for example one of the a~ovementioned het~rocyclic groups of aromatic character~ and bot~ the lower alkyl r~dical an~ the heterocyclic group can optionally ~e substituted. me acyl radical of a carbonic acid hal~-~erivati~e car also be an optiona~ly ~-substi~uted carb~moyl gro~p, such as an optionally halogenated N-lo-~rer alk.ylcar bamoyl group. -~
~n etherified hydroxyl group is above all optionally substituted lower alkoxy, wherein su~stituents above all represent free or functionaIly modified~ such as etherilied or es~erified, hydroxy~ groups, especially lower alkoxy or halogen, also lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, as well as heterocyclyloxy or hetero-cyclyl-lower alkoxy especi~lly also Op tJ onally substitu~ed phenyl-lower alkoxy.
An optionally substituted amino group is, ~or ~ l0l~6~55 example, amino, lo-~er alkylamino, di-lower alkylamlno, lo-~er alkyleneamino~ oxa-lower alkyle~eamino, thia-lower alkyiene-amino, aza-lower alkyleneamino, hy~roxyamino, lo~Jer alkoxy-amino, lower alkanoyloxya~ino, lower alkoxycarbonylamino or lower alkanoylamino.
~ n optionally substituted hydrazino group is, for example, hydrazino, 2-lower alkylhydrazino, 2,2-di-lo.Jer alk-ylhydrazino, 2-lower alkoxycarbonylhydra7ino or 2-lower alX-anoylhydrazino.
Lower alkyl is, for example, methyl, etnyl, n-propyl, isopropyl, n-butyl, isobutyl, sec~-butyl or tertO butyl, as well as n-pe~tyl, isopentyl, n-hexyl, isohexyl or n-heptyl, whilst lot~er alkenyl can, for example, be ~in~l, allyl, iso-propenyl, 2- or 3-methallyl or 3-butenyl, lower alkinyl can, ~or example, be propargyl or 2-butinyl and lower ~lkylidene can, ~or example, be isopr~pylidene or ~sobutylidene.
Lswer alkylene is, for example, 1,2-ethylene, 1,2-or 1,3-propylene, 1,4~butylene, 1,5-pentylene or 1,6-hexyl-ene, whilst lower ~lkenylene is~ for ex mple, 1,2 ethenylene -or 2-buten-1,4-ylene. Lower alky;ene interrupted by hetero-a~oms is, for example, oxa;lower alkylene, such as ~-oxa-1,5-pentylene, thia-lower alkylene 9 such as 3-thia 1,5-pentylene, or aza-lower alkylene, such as 3-lower al~yl-3-aza-1,5-pentyle~le, for example 3-methyl-3-aza-1,5-pentyleneO
Cycloalkyl is, for example 9 cyclopropyl, cyclobutylg cyclope~yl, cyclohexyl or cycloheptyl as well as adamantyl, oycloalkenyl 1s, for example, cyclopropenyl, 1-~ 2- or 3 -,`, .',"' .' ' . . ' ' ,: ' . ' . ~ . '. ' . : . . . ' ' . .

~8~ 5 cyclopenteny~ , 2- or 3-cy~lohexenyl, 3-c~cloheptenyl or 1,4-cyclohexadienyl and cycloalkylidene is, ~or example, cyclopentylidene or cyclohexylidene. Cycloal~yl-lower alkyl or -lower alkeny. is, for example, cyclopropyl-, cyclopen-tyl-, cyclohexyl- or cycloheptyl-methyl, -l,l- or -l,2-ethyl,

2- or -l,~-propyl, -vinyl or -allyl, whilst cyclo-alkenyl-lower alkyl or -lower alkenyl represents, for example, l-, 2- or 3-cyclopentenyl-, 1-~ 2- or 3-cyclohexen-r~ yl- or 1-, 2- or 3-cycloheptenyl-methyl, -1,1- or -1,2-eihyl, l,2- or -1,3-propyl~ -~inyl or allyl. CycloalXyl~
lower al~ylidene is, for example, 3-cyclohex~nylmethylene.
Naphthyl is l- or 2-naphthyl, ~hilst biphenylyl represents, for example, 4~biphenylyl.
Phenyl-lower alkyl or phenyl-lower al~enyl is, for example, benzyl ? 1- or 2-phenylethyll l-, 2- or 3-phenyl-propyl, diphenylmethyl, trityl, styryl or cinna~yl, naphthyl-lower alk~l is~ for example, l- or 2~naphthylmethyl and phenyl-lower alkylidene isg ~or example, benzy~idene.
Heterocyclic radicals are above all optionally sub- - ;
stituted heterocyclic radicals o~ aromatic character, for j example appropria~e monocyclic, monoazacyclic, monothiacyclic or monooxacyclic radicals, such as pyrryl, for example 2-p~r-ryl or 3-pyrryl, pyridylg for example 2-, 3- or 4-pyridyl and also pyridinium, thienyl, for example 2- or 3-thien~l, or ~uryl, ~or example ~-furyl, bicyclic monoazacyclic, monooxa-cyclic or monothiacyclic radicals, such as indolyl, for example 2- or 3-indolyl, quinolyl, for example 2- or 4-- 13 -~

;'1 "

., ,.; . , .. ~ ... ,. - ,, .: . ... : , .. .. -quinolyl, isoquinolinyl, for example l-isoquinoli~yl, ~enzo-furanyl, for example 2- or 3-benzo~uranyl 9 or benzothienyl, for example 2- or 3-benzothienyl, monocyclic diazacyclic, triazacyclic, tetrazacyclic, oxazacyclic, thiaz2cyclic or thiadiazacyclic radicals ) such as lmidazolyl, ~or example 2-imidazolyl, pyrimidinyl, for ~xample 2- or ~P~J~rimidinY1, triazolyl, for example 192~-triazol-3-yl, tetrazolyl~ for example 1- or 5-tetrazolyl, oxazolyl, for exa~ple 2-ox~zolyl, isoxazolyl, for example 3- or 4-isoxazolyl, ~hia~olyl7 ~or example 2-thiazolyl~ isothia~olyl, for example ~-- or 4-iso-thiazolyl, or 1,294- or 1,3,4-thiadiazolyl, for example 1,2,4-thiadiazol-~-~1 or 1,394-thiadiazol-2-yl, or bicyclic diazacyclic, oxazacycl~ c or thiazacyclic radicals, such as benzimidazolyl, for example 2-benzimidazolyl, benzoxazolyl, for`example 2-benzoxazolyl, or benz~hiazolyl, ~or example 2- - -benzthiazolyl. Appropriate partially or wholly saturated radicals are, for example, tetrahydrothien~rl, such as 2-tetrahydrothienyl, tetrahydrofuryl~ such as 2-tetrahydro furyl, or piperidyl, ~or example 2- or 4-piperidyl. -~
Heterocyclic-aliphatic radicals are lower alkyl or lower alX-enyl containing heterocyclic groups 9 especially those men-tioned abov~. me abovementioned heterocyclyl radicals can be substitl1ted, ~or example by optionally substituted ali-phatic or arom tic h~drocarbon radicals, especially lower alkyl, such as methyl, or phenyl which is optionally ~ubstl-~uted, for example by halogen such as chlor ne, for example phenyl or 4-chlorophenyl, or, ~or exam~le like the aliphatic .
:

la~6~ss hydrocarbon radicals, by functional groups.
Lower alkoxy is, for example 9 methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso~utoxy, sec.~butox~J, tert.-butoxy, n-pentoxy or tert.-pentoxy. These groups c~n be substituted, for example as in halog~lower alkoxy, especi-ally 2 halogeno-lo~Jer alkoxy, for example 2,2,2-trichloro-etho~y, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy~
Lower lkenyloxy is, for example, ~inyloxy or allylo~y~
lower alkylenedioxy is, ~or example, methylenedioxy, ethyl-enedio~y or isopropylidenedioxy, cycloalkoxy is, ~or xample, cyclo~entyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy is, ~or example, be~zyloxy, 1- or 2-pher.ylethoxy, di-phenylmethoxy or 4,4'-dimethoxy-diphenylme~hoxy and hetero-cyclyloxy or heterocyclyl-lower alkoxy is, for ex~mple, pyri dyl-lower alkoxy 9 such as 2-pyridylmethoxy, furyl-lower alkoxy, such as ~urfuryloxy, or thlenyl-lower alkoxy9 such as 2-thenyloxy.
Lower alkylthio is, for example, methyl-thio, ethyl-thio or n-butylthio, lower alke~ylthio.is~ for example~
allylthio, and phenyl-lower alkylthio is, for example, benzyl-thio, whilst mercapto groups etherifi-d by heterocyclyl radi o~ls or he~erocyclyl-aliphat~c radicals are especially pyri-dylthio, for example 4-pyridylthio, imidazolyl~hio, thiazo-lylth~o, for example 2-thiazolylthio, 1~2,4- or 1,3,4-thia-diazol~Jithio, for example 1~2,4-thiadia~ol-3-ylthio or 1,3,4-:
~hiadiazol-2-ylthio, or tetrazolylthio, ~or example l-methyl 5-tetrazolylthio.

. ~ .
1 , :

Esterified hydroxyl groups are above all halogen, for example ~luorine, chlorine, ~romine or iodine, as well as lower alkoxycarbonylo.~y, for exa~ple me ~hoxycarbonylo~, -ethoxycarbonyloY~ or tert~-butoxycarbonyloxy, 2-halo~eno-lower alkoxycarbonyloxy, for example 2,2 5 2-trichloroethoxy-carbonylo~ , 2-bromoethox~rca~bonyloxy or 2-iodoethoxycarbo-nyloxy, or arylcarbonylmethoxycarbonyloxy, for example phen-acyloxycarbonyloxy~
Lower alkoxycarbonyl is, ~or example, me~hoxycar-bonyl, ethoxycarbonyl, n-propoxycarbo~yl, isopropoxycarbonyl, tert.-butoxycarbonyl or tert.-pentoxycarbonyl.
N-Lower alkyl- or N,N-di-lower ~lkyl-carbamoyl is, ~or example, N methylcarbamoyl, N-ethylcarbamoyl, N,N-dimeth-ylcarbamoyl or N,N-diethylcarbamoyl, whilst N-lower al~ylsul-ph2moyl represents, for example~ N-me~hylsulphamoyl or N,N-dimethylsulphamoyl.

A carboxyl or sulpho presen-t in the form of an alkali metal sal-t is t for example, a carboxyl or sulpho present in ~he ~orm o~ a sodlum or potassium salt.
Lower alkylamino or di lower alkylamino is 3 ~or example, methylamino, ethylamino~ dimethylamino or diethyl-amino, lower alkyleneam~no is, ~or example, pyrrolidino or piperidino 9 oxa-lower alkyleneamino is, for example, morpho-lino, thia-lower alkyleneamlno is, for example, thiomorpho-lino, and aza-lower alkyleneamino is7 for example piperazino :
or 4-methylpiperazino. Acylamino in particular represents carbamoylamino, lo~er alkylcarbamoylamino, such as methyl-,.~",.. , . , . , , . ....... . . . . , ............. , -. . .

. ~ .. , ~ . . . . . , ,~ , ., -, ................. -~ ;'7S~
carbamoylzmino 9 ureidocarbonylamino, guanidinocarbonyl~mino, lower alkoxycarbonylamino, for example m~thoxycarbonylamino, ethoxycarbonylamino or tert.-butoxycarbonylamiro, halogeno-ldwer alkoxycarbonylamino, such as 2, 2, 2-tric~.oroethoxycarb-onylamino, phenyl-lower alkoxycarbonylamino, such as 4-meth-oxybenzyloxycarbon~Jlamino, lower alkanoylamino, such as ace~-ylamino or propionylamino~ and also phthalimido, or sulpho-amino optionally prese~t in the form of a saltg such as in : the ~orm of an alkali metal salt, for example in the form o~
a sodium salt or ammonium salt.
Lo~er alkanoyl is, for example, formyl, ace ~yl, pro-pion~l or pivaloyl~
O-Lower alkyl-phosphono is, for example O me~hyl- or O-ethyl-phosphono, O,Or-di-lower alkyl-phosphono is, for example, O,O-dimethyl-phosphono or O,O'-die~hylphosphonos 0-phenyl lower alkyl-phosphono is, for example,O-ben~yl-phos-phono, and O-lower alkyl-O'-phenyl lower alkyl-phosphono is, ~or example, O-benzyl-O '-methyl~phosphono.
Lower lkenyloxycarbonyl is, for example, ~inyloxy- -carbo~yl, whilst cycloalkoxycarbonyl and phenyl-lower alkox~--carbonyl reprssent, for ex~mple~ adamantyloxycarbonyl, ben-zyloxycarbonyl, 4-methoxy~benzyloxycarbonyl, diphenylmethoxy-carbonyl or a-4 biphenyl-~ - methyl-ethoxycarbonyl. Lower alkoxycarbonyl, wherein lower alkyl contains, for exampleg a monocyclic, monoazacyolic, monooxacyclic or monothiacyclic group, is, for example, ~uryl-low~r alkoxycarbonyl, such as.
~urfuryloxycarbonyl, or thienyl-lower alkoxycarbonyl, such - 17 ~

.
- : : : ~ , . -. . .

6'7S5 as 2-thienylox.ycarbonyl.
2-Low~r alk~lhy~ o and 2~2~di lower alkylhydr~-z~o are, ~or exar~l~, 2-~et~ylhy~az~o or ~, 2-dimethg-1-hydrazi~o, 2-lower al~;o~cycarbonylh~draz~o ls, f or e~l~
2~ ho~carbor~lh~r~o ~ 2-~tho: cycarbo~g lhydrazi~o or 2-~.-bu~oxy~arbo~ h~z~o a~d law~r alka~oy o is, ror e~l~, 2~
A2~ ac~ ~ro~ Ac ~ part~cular ~epre~s~ts ~ aoyl rad~cal o~ ~rL org~¢ oas~bo~l ic a~ d7 ~ rabl~ to 18 ~o~ ato~, ~orL~ed ~ a 2~t~ a~y oocl~rri~g or ~io-~t;he~lc 1.1~, ~e~ e~ca:Ll r or totalsy~t~etica~ly ob~bJe, pr~i~rably phaxmac~l~call~ ac~g N-acsrl deri ~atltr~ o~ a ~ o~p~car~ s~ld ~o~pou~ or 7-amislo-~ce~h~ car~oxylic acld ccmpo~d7 or repr~3e~ts a~
oa~ily ~oYabl~ acyl r~dic 1 l ~specia~ o~ ~ oarbo~c acid ~alf~r~a~
~ :~cyl rad~cal~ ~ a~e, ~or ~x ~ pl~
ac~tyl, ~oplo~yl, buty~yl, pl~aloyl, hexanoyl, ~o~l, ac~ l, crotonyl~ 3~-~utenoyl, ~-pente~ ~
o~l, m~o~a~ , bu~l~:Lloac~t:yl, allyl~loac~l9 m~
t~oacetyl, cblo~oac~l9 brosl~oa~etyl, d~ro~oaeetyl, 3 c~oro~rop~o~ anoprop~o~ Qm~o~ce~rl or 5~ m~Lo~
oarbo:c~ral~rl (~:L'~ a~ an~o group w~çh i3 op~o~
subst~tute~ ~or eæample a~ i~ca~d, ~uch as subs~t~t~d ~,a mo~oac~l or diac~l rad~cal~ ~or e~le ~ op~o~
~aloge~at~d low~r alka~o~ radlcal, ~uch a~ acetyl o~
~loro~c~yl, or ph~aloyl? andjor ~i~h an optlo~a:Uy ~unc-~o~ od~ ed carboæyl ~ a ~or ~xasspl~ a carbo:~l J
.

. . - ' : - ~ ' . ' . , - :

36'7SS
~sroup pr~s~ 02~ o~ a ~æll~ ~ a ~od~1lm 8a~, or ~ ~e fo~ o~ ~r, ~uch as a lower alk~rl o~ter, i~or e~le ~ ~èl~yl or ~t~yl e~tor, or ~ aryl-lower alkyl ~t~r" ~or ~xa~l~ dlpher~l~thyl ~ster~9 azidoacetyl, car-boxyac~ e~o~carbo~lac~lJ ~thoxycarbo~ylacet~lt bi~
Dl*thox5rcar~o~:Lylaoet~1, N-ph~rly~ car~o ~lacetyl, c~a~oace~l, ~-c5ra~lopropi~ 2~oyaao~3,~mo~yl-~crgl~rl 9 phe~ylacety~, a-bro~o~he~ylac~ ido-phen~lace~l, 3~hlorophe~yl-~c~*l, 2- or 4-a~o~e~lp~e~-a~1 (wi~ an ~irlo group ionally s~b~ti.1;ut4d~ ~or e~a~ple9 as ir ~ cated3, p~e~ lcar~ p~e~o~ya¢~tyl f phenylthloa~etyl, orey~no-phe~yla~etyl, e-~pecially phenylglycyl, 4~hydroxy-phe~ylgl~cyl, 3-chloro-4~hydroxyph~yl~ly~yl, 3,5-dlchlo~o-4~hydroxy-phenylglycyl, Q~amiAo-~ ~tl~4-cyclohexadienyl)-acetyl~
or a-hydroxyphenylac~tyl; ~it ~lng poss~bl~,~A th~s~ ra~lcal~, ~or an ~lno group which ~9 pæ~ to bq optionally 5ub8~1~ut~ 0~ ~æa~ple ~ ~nd1c t~ :
a~ove, and~or an ~liphatl~ ~nd~or pheno~ally ~ond~d h ~ oxyl ~rou~ whi~h ~ pr~se~t to b~ ~pt~onally pro~ct~d9 s~logousl~ ~o the a~i~o ~soup, or exaD~le b~ a su~table ~cyl r~dical~ esp~c~ally ~y ~or~yl or by an ac~l radical of a ~arbonlo acld h~ G~tsr)~ or a-O-~ethyl~p~os~hono-phe~yl-~c~tyl or O,O-aimeth~l~pho~phoao-ph~rlacetyl, ~-ca~boxy-phe~ylae~yl~w~h a eas~ox~1 group whleh 1~ op~o~ally ~ ti~nally ~odlgl~d, ~or ~xampl~ as ln~leated abov~), 2-pyrldylaeet~l, 4-~mlno~pyridi~iumse~tyl(optio~ally with an a~lno group wh~ch ~s ~ubstltuted,or axa~pl~ 8 lndlc ted abov~), 2~ enyla~Qtyl, 3-thlenylacQtyl, 2 ~ur~lae~tyl, l;l~ldQzol~l~e~l t l~t~trazol~lacetyl, a-e~rboxy-2-thi~ylae~yl ~r e-earbo~3~hl~1ace~yl (optlo~-all~ w~th ~ car~oxyl ~rou~ Wh~c~ u~c~io~ally ~odi~led, , ; . ~
: ~ -19-. .: , ~, ~ ... . ' , , , : . ~ . ,, ..... , ' ' : ,, . , :
: : , . ` , . :

i5 for exampl~ as ~dica~d abov~), a~cyano-2-t~enylacetyl, a-am~o~a- ( 2-~ienyl ) -acetyl, a amirlo-a- ( 2 furyl )-acetyl or a-~o ~ othlazolyl)-acetyl (optionally wlth ar~ o group w~lc~ 1~ substituted, ~or e~a~le a~ i~dicated above ) 9 a ~ulphopheslylac~tyl (opt~onally wi~ a sulpho group which i~
~unc~iona:lly modified, ~or e:cample llk~ the carboxyl gro~),

3-me~hy~-2-l~ldazolyl ~lo~oety~9 1~9l~trlazol yl-thloace-t~ 4-triazol-2-yl~hloacetyl~ 5-methyl-1~2 9 4-thladiazol-3-yl~oac~tyl, 5 ~thyl-l 9 3~4-tk~adiazol-2-ylthloacetyl or l-methyl -5-tetrazolyl~oacel;yl .
An ea~ remo~able amlno pro~ective group 18 an acyl rad~cal of a carbonl~ acid hal~-ester,and ls above all an acyl radlcal o~ a hal~-ester of carbonlc acld wh~ch ~an b~ spll~ off by redu~tion,for example on treatment wl~h a chemical reduclng agent,or by treatment with acld,for example wlth tr~fluoroacetic acldt ~uch a~ a lower ~Ikoxycarbo~yl group whlah pre erably ha~ multiple bra~chlng a~d/or a~ aromatic subst~tue~t on ~he carbon atom i~ ~e a position to th@ oxy group, or a me~oxy-c~bo~yl gro~ w~ich 1~ subst~tuted by arylcarbonyl, especl-~lly be~zo~, radicals, or a lower alkoxycarbonyl radical which is sub~titlllted ~ the ~-po~1tioll by h~logen atoms~ for example tert.-butoæycarbo~yl, ~ert.-pe~toxycarbonyl 7 phen-acylox~rcarbony}, 2, 2, 2-t:richloroe~kox~carbonyl or 2-iodoe th-oxycarbonyl or a radlc 1 whlc~ c~ b~ co2lverted i~to the lat-ter1 such as 2-chloroe~oxycarbonyl or 2-bromoetho:cycarbo~yl, SQ pr~erably pol~cyclic cycloalXoxycarbonyl, ~or example adaman~loxycarbo~yl, optlonally substitu~ed phenyl- :
lower alkoxycarbos~yl, above all a-phenyl-lower alkoxycarbonyl, , -~ 20 .
.. ~ . . : . .. .. .
- . :.. : . - , ,. . : . . - :

-1~36'~SSi wherein ~he a-positlon .~s pre~erably poly~ub~tltu~ed, ~or example dlphenylmethoxycarbonyl,or a-~l diphenylyl--methyl-et~oxycarbonyl, or ~uryl-lower alXoxycarbonyl, abo~e Pll a-x~yl-lower alkox~carbo~yl, for ~xan~ple furfuryloxycarbonyl.
A blvalent amlno protective acyl group iq, ~or example, the a~yl radlcal o~ a lower alkanedicarboxylic a~id or lower alkenedlcarboxyllc acld, ~ch as u~clnyl~ or an o-aryLenedlcarboxylic aaid, ~ch a~ ph~haloyl.
A further bivalent amlno protecti~e radlaal i9, fo~ example, a l-oxo-3-aza~1,4-bu~ylene radical which is 8ubstituted,espe~1all~ in the 2-positlon and ' .
:

B: :

,... .. , .. , . . -. . , .. ; ,. , .. . ... .. . ~ . . . . .. ~ . .

i'755 contains, for example, optionally su~stituled phenyl or ~hi-enyl, ard is optionally monosubstituted or disubs-tituted by lower al~yl, such as methyl9 in the 4-position9 ~or example

4,4-dimethyl-2-phenyl-1-oxo-3-aza-1,4-butylene.
An etherified hydroxyl group RA forms, together with the carbonyl grouping~ an esterified carboxyl group ~h-ch c~n preferably be split easily or can be converted easily into snot~er ~ctiona~y modified carboxyl group, such as-into a carbamoyl or hydrazinocarbonyl group. Such a group RA is, ~or example, lower alkoxy9 such as methoxy, ethoxy9f n-propoxy or isopropoxy, which, together with the carbonyl grouping, forms an esteri~ied carboxyl group 9 which can easily be con-verted, especially in 2-cephem compounds, into a ~ree car-boxyl group or in~o ~not~er fu~ctionally modified carboxyl group .
An etheri~ied hydroxyl group R2 which together with a -C(=O)~ grouplng forms an esteri~ied carboxyl group whlch can be split particularl~ easily repre~ents9 ~or examplel 2-h ogeno-lower lkoxy, wherein halogen pr~ferably has an atomic weight above 19. Such a radical ~orms, together with t~e -C(=O)- g~ouping~ an es~erified carboxyl group which can easily be split on treatment with chemical reducing agents under neutral or weakly acid conditions, ~or example With zlnc in the presence of aqueous acetic acid, or an esterified carboxyl group which can easily be converted into such a group a~d i~ or example9 2,2,2-trichloroethoxy or 2- ;
iodoethoxy, also 2-chloroethoxy or 2bromoethoxy~ which can '.

.

: . . : ; . .. ... - .. .. .. ... . . - . . -~ '755 easily be converted into the latter.
. An etherified hydroxyl group ~ which together with the -C(_O)- grouping represents an esterified carboxyl group which can also be spli~ easily on treatment with chemical reducing agen~s under neutral or ~eakly acid conditions9 for example on treatment with zinC in the presence of aqueous ace~ic acid, a~d ~so on treatment wi~h a suitable nucleo-philic reagent, ~or ex~ple sodium thiophenolate, is an aryl carbonylmethoxy group, wherein aryl in particular represe~ts ~-an optionally substltu~ed phenyl group, and ~re4erably phena~yloxy.
~ he group R2 can also represent an arylmethoxy group wherein aryl in particular denotes a monocyclic, pre~erably substitu~ed, aroma~ic hydrocarbo~ ~adical~ Such a radical forms~ together with the -C(=O)- grouping~ an esterified carboxyl group whlch can easily be split on irradiation, pre~erably with ultra~iolet light, under neutral or acid conditions. An aryl radical in ~uch an arylmethoxy group is i~:particlllar lower alkox~,~henyl, for example methoxy- -phenyl (wherein methoxy abo~e all is in ~he 3;, 4- and/or 5-position) and/or abo~e all nitrophenyl (wherein nitro is pr~erabl~ in the 2 positlon~. Such radicals are, in par-ticular, lower alkoxy-benzyloxy, for ex~m~le methoxy-benzyl-oxy, and/or ~itro-benzyloxy, above all 3- or 4-methoxy- :
benzyloxy, 3,5-dimethoxy-benzyloxy, 2-nitro-benzyIoxy or 4,5-dim~thoxy-2-nitro-benzyloxyO
An etherified hydroxyl group R2 can also represent a ~ ~3 .- ., . . ~ , . .- ~ . .- - . ............... - ............ ...

..
. , . ~ ; . ~ - ~ - ,.

~6'75S
radical which, together with the -C(-O)- groupingy forms an esteri~ied carboxyl group whi.ch can easily be split under acid conditicns~ for example on treatment with trifluoro-acetic acid or formic acid. Such a radical is above all a methoxy group i~ which methyl is polysubsti~u~ed by op~ion-ally s~bstîtuted hydrocarbon radicals, especially aliphatic -or aromatic hydrocarbon radical~, such as lower alkyl,.for example methyl, and/or phenyl, or is monosubs~ituted by a carbocyclic aryl group possessing electron-donating substi-tuents or by a heterocyclic group of aromatic character pos-sessing oxygen or sulphur as a ring member, or in which methyl denotes a ring member ln a polycycloallphatic hydro-carbo~ radic~l or denotes t~e ring member which ~epre~ents the a position to the oxygen or sulphur atom in an oxacyclo-. .
aliphatic or thiacycloaliphatio radical.
Pre~erred polysubstituted methoxy groups of thisnature are ~erv.-lower alkoxy, for example tert.-butoxy or tert.-pentox~, optionally substituted diphenylmethoxyJ for example diphenylmethoxy or 4S4'-dimethoxy-diphenylmethoxy, and ~lso 2-(4~biphenylyl)-2-propoxy, whilst a methoxy group whlch contains the abovemention~d substi'~uted aryl group or the heterocyclic group is, for example~ a-lower alkoxy-phenyl-lower alkoxy, such as 4-me~hoxybenzyloxy or 3,4-dimethoxybenzyloxy, or furfuryloxy, such as 2-furfuryloxy. ~ ;
A polycycloaliphatic hydrocarbon radical in which the methyl.
o~ the methoxy group represents a branched9 preferably tr~ply branche~, r~g member, is, fo- example, adamantyl, such as :: ' . , .. . . . . ~ ,. . . . . .. .. . .

\
36'7SS
l-adamantyl, and an abovementioned oxacycloaliphatic or thia-c~cloaliphat-c radical wherein the methyl o~ the methoxy group is the ring member which represents the a-position to the oxygen atom or sulphur atom, denotes, ~or example, 2-oxa-or 2-t~ia-lower al~ylene or -lower alkenylene wi~h 5-7 ring atoms, such as 2 tetrahydrofuryl, 2tetrahydropyranyl or 2,3-dihydro~2-pyranyl or corresponding sulphur analogues.
The radical R2 can also represent an etherified hyd-roxyl group ~rhichJ together with the -C(=O) groupLng forms ~
an esteri~ied carboxyl group which can be split hydrolyti- s cally, for example under weakly hasic or weakly ac~d condi-tions. Such a radical is~ preferably~ an etherified hyd-roxyl group which forms an activated ester group wi~h the -C(=O)- grouping, such as nitrophenyloxy, 'or example 4-nitrophenyloxy or 2~4-dlnitrophenyloxy, nitrophenyl-lower lkoxy, for example 4~nitro-benzyloxy5 hydroxy-lower al~yl-benzyloxy, for ex~mple 4-hydroxy 3,5-tert.-butyl-benzyloxy~
polyhalogenophenyloxy, for example 2,4,6-trichTorophen~lo~y or 2,3 9 4,5,6-pentachlorophe~yloxy, and also cyanomethoxy, as well as acylaminomethoxy, for example phth liminomethoxy or succi~yliminomet~oxy.
~he group R2 can also represent an etheri~ied hyd-roxyl group which9 together Wlth the carbonyl grouping of the formula -C(=O)-, ~Orm5 an esterified carboxyl group which can be split under hydrogenolytic conditions and is, for example9 a-phenyl-lower alkoxy~ which is optionally substituted, ~or example by lower alkoxy or nitro9 such as benzyloxy, 4 , ~

.,. ~ , :-, ..... , . ~ - . : . . - ..
,, , , . .. .. ,, : ~ . . . . .:

.~3~3~;755 methoxybenzrl.oxy or 4--nitrobenzyloxy .
~ Che ~oup R2 carl also be an etheri~led hydroxyl group which,, tuge~her with the carbonyl grou~?ing -C(=O)-, îorms an esterified carboxyl group which can b~ spllt under physio logica~ co~dltio~ls9 abo~re all ~ Rcyloxyme~oxy group, ~erein ~oyl dexLote3, ~or example, the r~dlcal o~ a~ orgar~ic ~arboxylic ~cid, abo~re all o~ op~lo~a3 ly substi~t~d lower alkE~eoarboxylic scid,, or wh~re~n acylo~e~yl ~orm~ the rësidue o~ R lactone. E~ydroxyl groups e~herl~led iIl this way are lower alk~oyloxymethoxy, for example acetoxymet~:Loxy or pivaloyloxymethoxy, amino-l~wer alkanoyloxym~hoxy, ~speoially a-amino-lower Alkanoyloxgmethoxy, ~sr example glycyloxyme thoxy, L-valyloxymethoxy, L-leucyloxymethoxy and ~l~o pht~alidyloxy.
~ silyloxy or 3tan~ylo:ey group R;~ preferably cor~talns, as sub~itue~, op~ioslally sub~tltu~ed al~phatic, cycloa~
phatio; ~o~at$c or araliphatlo hydrocarbon radical~, such as lower a~rl, ~aloge~o-l~wer alkyl, cy~ls~cyl, phenyl or phen~l-lower alkyl grou~p or optionally mod~ied ~unctional gro~ , such aq etheri~ed hydroxyl groups, for example lower alkoxy grou~s, or halogen a~om~, for example chlorine atoms, and abov~ all represealts ~l~lower ~kylsilyloxy, ~or example tr1me~yl ilyloxy 7 h~l oge~o lower alkoxy-lower alkylsilyl, ~or exampl@ chlorome~hoxyme~ylsilyl~ or tri-lower alkylstan-:` nyloxy, ~or example tri-n-butylstannyloxyg : , ' .: :

. ~ . I ~ ' . ',' ~ , . . ' ' . ! . ' ' ' ' ' ' ' ' ' ' ' ' :, . , , . , , ' . , ' . ` .

'755 The invention in particular relates to intermediates of the formula IVb or IVc use:Eul for the manufacture of com-pounds ~f the formula IA or IB.
The c'ompounds 'of tti~ formula IA- or IB possess valuable pharmacolog~cal properties or can be used as intermediate pro-ducts respectively ~or the ~anufacture of such compounds.Co~pourlds o~ or~a Ifl where~, ror example, ~1 repre-an a~yl rad~21 ~ occurri~g in pha~acologiGal'Y
aeti~e N-acyl d~r~a~i~res ~f` 6~ ~1no-pe~-3- carbcxylic ~acid compounds or 7~-amino-3-cephem-4-carboxylic acld ~ompound-~, ~2 denot~ hydroxyl o:r an ~theri~ed hydroxyl gro~p ~ whlch,` ~gct~er w~ ~e c~bo~yl $roup9 ~05~1S Em ~steri~ed ~ oxyl ~ou~ w~ich ca~ ~ s~ly ~e split us~der phys~ological ~osldition~ d R3 dexlot~s ~ower a~CyL7 E~d ~tio~al ~oup3 whlch ~y be pros~s~t ~ a~ ~o~l radical ~ 9 ~lch as ~aiao ,, car~oxyl D hydrox3rl a~d/or ~ulpho ~ ars usu~lly ln t~o ~ree for~, or ~ o~ ~ch ~o~po~ds haYing g ~FOU~89 aro e~ec~ o~ par~ eral alldlor oral ~d~i~lstrat~o~, aga:~st ~icro~org~ such as Gra~-po~ re bac~erla9 ~or exa~le ~y~, ~
p~oQene~ and 9~b~ (~or ex~ple ~i ~c~ ~t a~ses O~e ~b~ 0.001 to abou~ 0.02 g/Xg cO or P~-)t ~d Os~ega~ive ~acter~ a, ~r ~xampl~, ~b~ ~ 11 a~d Proteus ~Eg~ (~or exa~ple ~ s~ce in dos~
oS abou~ 0.001 ~ aboùt 0.15 g/kg s.~. or p.o.), as~d especi-ally 8~0 agai~s~ pen~ci~ res~starlt bacteria, and are Or ~ow toxici~ ~e~ w ~o~ou~s can ~aere~ore ~e us~d9 -, .. .: . i .. . . . .
., . , ! : '~ '.

' ' . ' ' . ' ' '.`.' ' ~ ' ' ' ' ' : .' ' ' . " - ' ' ' ' '~' ' .: ", ' ' . ', ', : , ' , , ,, .. .. ,, ' ;';YS5 ~or exa~ple i~ ~he ~orm o~ antl'Diotically ~ctlve prepa~ationq, for ~e treatme~ o~ corr~spor~ 6 ~ection~.

o~pounds o~ the ~o~Dula ~ or l-oxides of compounds of ~e ~ormul~ IA, where~ R;" R2 and R3 have the mean-l~gs ~di~ated in ~e eo2ltext of the formula IA v or compo~ds Of ~ ~ox~ula IA, wher~l~ R3 has t~e abovementioned meanin~, ~ sadlc. Rl derlotes an a~:!.no prote~c:tl~ro gro~p dl~Qren~ om ~ ~cyl ~ad~ ~al o~cur-r~g ~ phas~acologic~ a~ti-~ N-~yl d~rl~ati~e~ 0~ 6~-e~3-carbc~ acid co~pounds or 7~ cephe~-4~¢a~ox~. iC acid com;~ou~ nd P.2 r~p~e~cnt~ hyd~oxyL, or~ll h~s the a~o~ n~iosled mea~ngs,~2 r~pr~s~ts a radical ~
wh~ coget~er w~t:h the ~ 0)~ o~p:Lng for~s . prot~cted car-~oxyl group whic~ c~ pre~er~ly be ~pl~ ea~ily,~ car~oxyl group p~oeted ~n ~ht~ w s bei~g ~ ~rent ~rom ~ cas~oxyl ~roup which can ~e split physio~ogically, ~nd R3 h~ the above-~ntlo~ed ~ean~ngs, ase ~aluable~ ink~ediate produc~s,whi~h ~an bo ~oD~st~ ~n a ~ple ms~a~r~ ~or ex~mpl~ a5 t~ de3 c~i~ed ~elsw~ i~to the a~oY~ io~ phar~acologloally ac~iYo oompound~
The invention in partlcular relates to intermediates of the form~la IVb and IVc useful for the manufacture of compounds of the formula IA, wherein Rl denotes an acyl ra~i-cal of the abovementioned ~o~ula A' ~r Aw ~n wh~6h ~ and R~ a~ove all ha~e the prefQrrod mea~ings, ~2 repres~nt3 hydroxyl, lower ~lk~xy whlch is cpt~onally ~ono~ubstituted or poly-substltu~ed, preferably i~ the c-posltion, ~or example hy optionally subs~itutPd arylo2y~ such as low~r alkox~phe ylo.~y, for~example 4~e~hox~ph~ioxy, lower lkano~loxy, fo-~ample ac~toxy or pi~ralo~loxy; e ~i:r~lower alkasLoyloxy, ~or e~a~ple gl~c~lo~ Yal~lox~ or ~leu~loxy~ a~rloar~ :

~ ~ . . . . ...... . .. . ... .

~ ' ' . ~' ' ~ , ' : ' :. .~ ' ' ' , : ' ~L6~3~6'YSS
bonyl, ~or ~XE~:L~ ber~og~l, or optlo~all y substituted aryl 9 su~h a~ ~he~yl, lower al~{oxypheny~ 9 rOr exa~ple 4--methoxyphe-~yl, ~ rophe~yl, LOr exa~le 4-~itrophe~yl~ or blphe~yly~, for exa~l~ 4-b~phenylyl, or ~5 mo~osu~sti.~u~.ed or polysub-~ltut~t is~ po~l~ion by ~8Loge~, for exampl~ ehlorirLe, bro~ or iodl~sv ~ 8!~ lo~e~ ai~ox~, ~or exa~le ~etboxy, ~ oa~ propo:~, isopropo%g~, a~bu~o~t t~ bu~oxy sr t~t~_p~o~, bi~ph~lox~e~o~ whl~ optio~ally ~3titut~d b~ low~r ~l~oxy, ~or ~mpl~ b~ 2~0x~he~yl-ox~ ~Loæ3r, lower ~noylo;~-m~oxy, ~or exampl~ aceto~
me~oæ~ or piYalo~loxyme~ho~t ~ lower ~a~oyloxy~ ~ ~
~etho~, ~or e~le glyc~ox~et~o~9 phesla~yloæy, optio~
allg- subs~ ed phe~yl-lower a:L~oxy, aspec ally 1 pherlyl-lowe~ alkoxy, SUCil as phe~y~ethoxy, with such rad~cals be~n~
abl2 to Co~al~ 1 3 pherlyl radicals w~ich are sp~;ior~ y sub-~tll:ut~d, ~ær exa~l~ by lower ~lkoxy, such ~s ~et~o;cy9 ~t~o or p~erlyl, ~or exa~ple be~ylo~, 4_~e~oxy be~yloxy, 2-blph~ 2-propo~. ~i~ro-berl~ylo%y" dipheny~et~oxy, 4,4'-dimet~oxy-diphe~yl~et;hoxy or tr~tglo2~, or 2-halogeno-lower a:l~o~ or exa~le 2~292-t;rlchloroe~ox~r, 2ohloroeth-oxy~ rom~ ioxy or 2-~odoet~oac~ lso 2-p~thalidgloxyg ~d R3 r~s~ent hydrffgesl, low~r a~Xyl, e9~ecialï~ methyl, trl-}ower allcylsllyl, ~or example tr~nethylsllyl, or benzyl or dlphenylm~yl wh~ ch a~e op~lon~lly ~ubstl~u~ed by halogen or lower alXoxy, and al~o the ~o~respond~ng 2-cephe~ co~pound~ o~ the formula , o~ salts a~ ~uch co~pol~nd~ wi~ salt for~lng ~roups.

, :
: '~

.. . :.
.

. . . - : . , . -; . -. . .. .:
,. . . . . , . - . .

': ~ ~ : , . ~ , 1 8~'75~
Abo~ all, irl a 3~c~phem ~ompou~d o~ ~be fonnula ~A, and ~n a corre~por~tlDg 2~cephem compoun~ of the formula Ii3, or in a salt o~ ~uch a compound ha~ing salt-formlng gro~ps, ~1 repre~nts an acyl radlcal of the ~or~ula ~' or A~, wherein ~I and RII above all ha~e ~he pre-ferred ~eanings,~uch as a phenylacetyl or phenyloxyacetyl radl-cal whlch 1~ op~onally ~ubstltu~ed,~or ex~mple by hydroxyl,als~
l~wer alkanoyl or low~r al~oyl radlc~l wh~ch i~ opt~n-~lly ~llbsti~ut~d9 or ~xamp~ by low~r alkylthlo, or lower alXealyl~o, ~5 well a~ by optio~ally gub~ ed, suc~ ~s acylated, a~o and/or ~motio~ally ~o~fied,, sueh as esteri-~iad, carbax~rl,, rOr example 4-hydro~ phenyl~cetyl, hexanoyl, octanoyl or ~-but~lthlo~oe~;yl9 e~d ~pe~ially 5~ 5- :
carboxy-~ralex~ r~ ~o a~d/or ~ carboxyl grouos ar~ option~ly protected a~d are preseat, for exa~le, as acyla~ino or esteri~ oa~boxyl~ pher~ylace~yl or phenyloxy-a~e~yl, or an ~cyl rad~cal occurri~ highly actiYe N-acyl ~erl-ral:l~res o~ 6~-~o-po2~ 3~oarbox~11e a~d ~o~ourlds cr 7~-~aino~ ephem-4_carboxyl~o a~id oompou~ds " especially o~
th~ ~omula A~ or A", whereln ~ an~ ~S~ a~ove all ha~e th~
preferred m~aX~ngs, such as formyl, cyanoace~yl,phenylace~yl, thi~ylaoetyl, for ~x~mpl~ Z-thienylace~yl, or te~razolyl-~cetyl, ~or exampl~ 1-tetrazolylacetyl, bu~ especially acetyl ~ubsti~uted ~3~ the a-po~itio~ by a cyclic" such as a cyclo~
aliphatic~ aromatic or heter~cyclic7 abo~re all monocyclic, radisal a~d by a functio~a:l. group, abo~e all amino, carboxyl, sulpho or hydroxyl: ~roup~, especlally phenylglyc~l,, wherein ph~nyl represent~ ~henyl wh:~ch is optlonall~ substltuted, for example by optionally protected hydroxyl, such as aGyloxy9 ~or ,exa~plè optionally halogen ubstituted lower alkoxycar : --3 0--... ., - . . i , .

~ 7S S
bonyl~xy or lower alkanoyloxy, and/or by halogen, for example ~h~orine, for example phenyl or 3- or 4-hydroxyphenyl, 3-c~ oro-4-hydro~yphe~yl or 3,5-dichloro-4~hydr~xy-phenyl ~optionally al~o with a protected hydroxyl group, such as an acylated hy~roxyl group), and wherein the am~no group can al80 optio~ally b~ su~tltuted ant repr~sents, for example7 a ~ulphoa~no ~ro~p ~p~o~al~y pr~sen~ in.~h~ ~or~ of a salt, or a~ aDi~o group whlch co~talns9 as substl~ents, a hydro-lyticaily r~movable trltyl group or above all an acyl group, ~uch a~ an ~ptionall~ sub~tituted carbamoyl group~ such ~s æ~
optionally ~ubstitut~d ureidocarbo~yl group~ for exa~ple urei~ooarbo~yl or N'-trlchloro~ethylureidocarbonyl, or an optionally sub~ti~ut~d guanldl~ocarbonyl group, ~or ex~mple ~anidinocarbo~yl, or ~n acyl ra~ioal w~-~ch can be ~pl1~ o~, prefer~bly ea~lly, ~or example o~ ~reatmen~ with an acid a~en~ such as tri~luoroa~etic a~d, or reducti~ely, such as on treatment wi~h a chentlc t red~cinæ agent, such as zinc ln th~ pre enc~ o~ aqueo~ls ace~c ac:id, or wi~h cataIytic hydro- .
gen, ~r hy ~ olytica~ly, or an acyl r cal which oan be con-~erted into such a radical, pref erably a sultable acyl radi-cal o~ a oarborlic acid half-ester,, such as one of the ~bove-mentioned, ~or example optionally ~halogen-sub~ituted or berl-zoyl-substi tu~ed, lower alkoxycarbonyl rad~cals, for exa~ple tert. -buto~qcarbonyl, Z ~ 2, ~ trlc~loroe~oxycarbonyl 9 2-chloroethoxyc~rbonyl, 2-bromoetlloxycarbonyl, 2-iodoethoxycar-bonyl or phen~cyloxycarbo~yl, optionally lower allsoxy-substi .~
.~ . , ~ .
.

r -31~6'755 ~ted or ni~ro-substituted phenyl-low~r alkoxycarbonyl, for ex~le 4~methoxy-be2~zy~ oxycarbonyl or diphenylmethoxycar-bo~yl, or a ~uitable acyl radical of a carbonic acid ha:Lf-amiae, ~uch as carba~oyl or N-me~hylcarbamoyl, or an aryl-thio or aryl-lo~er a:Lkylthio ra~cal wh~Lch oan be pllt oîf ~ 1BOP~O r~ t, ~ch a~ h~o~anic acld~
p~u:ro~ aci~ or ~loaGetic acld ~l~e,, ~o~ ex~pl~
~n~O ~ ulph~yl ~ can ~ plit o~ ~ ~ o~ o r~duc~io~, ~or e~:a~le 4~e~ylph~ ulpho~rl9 or ~ l~low~r a:U~o:æ~oa~bo~rl or 1-14wer ~1~o~1-2-propy~ide~l~ radical w~ arL b~ spLlt o.
w~ ~ acld ag~ or~c a~ or aqueous ~ral a~ld, ~Eo~ ~drochlvri~ acid or ~hospi~ori~ acid" ~or e~le l-e~o~car~o~rl~ 2-p~opy~ide~eD ~d also ~_(1,4 ~yclohexaai~yl ~ ~; gl~ thl-rcr~ 2- or ~ rlg~y~yl, ... .

, ~ ; :
.

. , ., .. , ; .. , ., . . .. . , , . - ~ .. . .. . .. . .

.. .: .. : : . . ... .. .. : . . ., ,, . . : - . ..

~¢~86~S5 glycyl, such as a-2-furylglycyl, a-isothiazolylglycyl, such as a-4-isothia~olyl-glycyl, it being possible for the ~mino group in such radicals to be substituted or protected, for example as indicated ~or a phenylglycyl radical, also ~-carbox~-phenylacetyl or a-carboxy-thienylacetyl, for example a-carboxy-2-t~ie~ylacetyl (optionally ~ith a functionally modi~ied carboxy~ group, for example a carboxyl group pre-s.ent in the form of a s~lt, such a~ a sodium salt, or in the form o~ an ester, such as a lower alXyl ester, ~or example methyl or ethyl est~r, or phenyl-lower alkyl ester, for - -example diphenylmethyl ester), -sulpho-phenylacetyl (op-ion- .
ally also with a sulpho group which is functionally modi-~ied, for example like the carboxyl group), -phosphono-7 ~-O methyl-phosphono- or a-O 90 '-dimethyl-phosphono-phenylacetyl, or a-hydroxy-phenylacetyl ~optio~ l1y wi~h a functionally ~ -~odi~ied hydroxyl group~ especially with an acyloxy group, wherein acyl denotes an acyl radical which can be split off, preferably easily, ~or example on treatment ~i~h an acid agent, such as trifluoroacetic acid9 or wi~h a chemical redu- ~
cing agent9 such as zinc Ln the presence of-aqueous acetic acid9 or an acyl radical which can be converted into such a radical, preferably a suitable acyl radic~l o~ a carbo~ic acid half-este~, such as one o~ ~he aboveme~tioned lower alkoxycarbonyl radicals which are~ ~or example, optionally substituted by ~alogen o~ benzoyl, for example 2,2,2-trichlo-roethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoe~hoxycar-bonyl, 2 iodoethoxyca~konyl, tert.-butoxycarbonyl or phenacyl-B 3~

::

'., `: ' . :` . . ` ' . . .' ' . .' ' . . ' .

67~;;5 oxyc~onyl, and al~o ~ormyl), a~ well ~3 amln~meth~l-phenylacetyl, such a~ 2- oder 4-aminomethylphenylacetyl, or aminff-pyri~lnlumacetyl, ~or example 40amlno-pyridlnium-ace~yl toptionally also wl~h an amlno group which is ~ubstltuted, for exampl~ as lndlcated above), cr pyrldylthio-ace~yl, or example 4-pyridylthloacetyl,and ~2 represents hy-~oxyl,lower alkoxy,e~pec~ally a poly-b~an~h~d lower alkoxy,~r ~xample tert.Obutoæy~ al~o ~ethoxy ~r o~hoxy~ 2-h~logeno-lower al~ox;r" ~or exatnple 2~2,2-~rlchloroethoxy~ 2-lod~e~h-oxy os~ 2~hloro~tho~r ox~ 2-bro~lo0~oaey w~lch c~n eas~ly be converted into 2-iodoe~hoxy, phe~acylo~y" l-phenyl-lower slkox~ with 1-~ phe~yl rad~.c~ w~.ch are optionally subs~i-tuted by lower alko:cy or nltro7 ~or eæa~mple 4-methoxyberlzyl-oxy, ~rli~ro-b~nzyloxy a diphenyl~ethoxy9 4,4~-dlme~oxy-diphenylm~thoxy or tr~loxy~ oWQr alkanoylox~ethoxy9 for example ac~toxy~ethoxy or p~ .oylo~cymethoxy, ~ a~inolower , I

~34 . ~ '' .

; --.. ... ~ . ..... ... .. ... ,.. .. , - ... .. . . ... . . .. . . . . . . . .

3~6'755 al~sa~oylo~m~ ox~, rOr ex~ple glycyloxy~etho:cy, 2-ph~ali_ dyloxymetho~yl lcwer al}coxycarborlyloxy, :tor ex~mple ethoxg_ carbony~oxg" or. lower alk~noyloxy, for examp~ e aceto~7 and al~o tri-lowe~ lsilyloxy, for exal3ple ~i~ ylsilyloxy, a~d R3 represents ~ydroge~, lower a:Lkyl, essecially met}~yl~
tri-lower alkylsilyl, .. . .. . .
~r ex~ met~ylsi~yl, orb~nzyl or dipheny~ethyl wh~ch are op~io~211y substituted~ f~r ex~le by halogen~ such as chlor~ or bro~e~. oi ~wer alLC0:~9 such as me~oxy,.
. The ihvention above all relates to intermediates o the formula IVb and ~Vc useful or the manuacture of 3-cephem ~o~spo~s oi~ :~e ror~la I~, w~erei~ Rl ~eno~.es ~ydrogen or ~ acyl group o~ the formula 11 ' .
R--(X) ~B~

w~erei~ Ra d~rlo.,~s phenyl or hydr~x~he2lylll îor exa~le 3- or 4-hydroxyphenyl, also hydroxy-c~lor~her~,yl, for ex~e ~-o~loro~ ydrox~henyl or ~595-di.c~.oro-4--hydroxy-henyl, ~t ~ei~g possible for hydro~ subs'i~ ts :~n s~lch radic~ls ~,o be pro~ected by ~çyl radicals, such as optio2~211y h~lo~;enate~
lower a:L~oxycarbonyl rad~i~als, ~or example tert. ~U.,OXjC ~-boxlyl or 2~2,Z-tric~loroethoxycarbony~,, as wel~ as thienyl, :Eor examp~ 2- or 3-~hie.~y~9 and a'1so pyrityl, for ex~ple 4 pg~dyl, ami~opyridis~um, ~or example ~ami~op,~ di.~~
furyl~ ~or exaIrrole 2-Iuryl, isot~.azolyl, ~o~ e:~ mple 4-iso-~azol~l" or~etrazolyl, for ex~rple l-tetrazol71, or 1,4-cyclohexad~eslyl or l-cy~loh~xe~yl9 X represents o~Jge~ or ~35~

~ ;'75~
s7l1phur, m represents O or 1 and Rb represents hydrogen, or9 if m represents O, Rb represen-ts amino~ as ~ell as protected amino, such as acylaminc, for ~xample a-poly-branched lo~.ler alkoxycarbon~lamino) such as tert.-butoxycarbonylamino, or 2-halogeno-lo~er alkoxycarbonylamino, for example 2,2,2-tri-chloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino~ or optionally lower alkoxy-suDsti-tuted or nitro-substituted phenyl lo~ler alkoxycarbonyl~mino, for example 4-methoxybenzyloxycarbonylamino or diphenylmeth-ox~carbo~yl~mino, or 3-guanylureido, also sulphoamino or tritylamino, as well as arylthioamino 9 ~or example 2-nitro- :
phenylthioamino, arylsulphonylamino, for example 4-methyl- . . .
phenylsulphonylamino 9 or l-lower alkoxycarbonyl-2-propylidene-amino, for example I-ethoxycarbonyl-2-propylideneamino, car-boxyl, or carboxyl present in the form of a s?lt~ for example an alkali metal salt, such as a sodiu~ salt 9 as well as pro-tected carboxyl, for example esterified carboxylt such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycar-bonyl, sulpho9 or sulpho present in the ~orm of a salt9 for example an lkali metal ~alt, such as a sodium salt, as well as protected sulpho, hydroxyl, as well as protected hydroxylg such as acyloxy, ~or example ~ poly-branched lower alkoxycar-bo~yloxy, such as tert~-butoxyc~rbonyloxyor2-halogeno-lcwer al~oxycarbonyloxy, such as 2 9 2 9 2-trichloroethoxycarbonylo~, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, also .
formyloxy, or O-lower alkylphosphono or O,O'-di-lower al~yl- :
phosphono, for example O-methyl phosphono or O,O'-dime~hyl ,~ _ 6~7Ss phospho~o~ or ~e~otos a 5-~mlno-5~car~axy~ radical, w~ere~ '~ a~o ~d/or carboxyl grou~ oan also be protec-ted a~d are, ~or e~le, prese~:Lt as acylami~o ~ ~or exar~ple lower ~a~o~l~m~o, such ~s ac~rlam~o, ~alog~no~lower allcarlog~lami~o ~uch a d~chloro~c~lam~no" be~zoylam~o or s~t~aloyla~ino,, or ~ ~s~e~ d ~arboxg~ uch ~15 phenyl0 ~ow~r ~oxycarboa:lyl, ~or eæa2~l~ diphe~ylm~oxgcarbo~yl, a~d p~ably de~otes 1 ~ Ra ropse~e~ ph~nyl, ~roxy-phe~, hg~oxy~oroph~rLyl or p~idyl, ~d m denotes O arld rs :~ro~ h~ogen ~ Ra r~pre~ phenylg hydroxy phenyl, h~roac~-c~orophe~g~l, tk~e~l, ~uryl" ~so~azolyl, or 1, 4~ycl~h~xa~e~1, R2 abo~ a~ ~pres~ gdroxyl ~ also reprose~s lower ~l~o~ ~sciall~ ~pvl~ ~ac~d low~r E~cOxy9 ~or ~xa~ple uto~, 2~halog~ 1Ow~r. a~lcoæy~, ~GS` ~scaD~ple 2,2,Z-t:~ic~log~oethoxy7 ~-~odo~t;hoxy or 2-bromoe~hox~, or aiphe~y~
~et~xy ~ch ~ion~r substl~:ut~d~, ~or exan~
r a~ox~" or ~le ~ox~, ~or ~ple d~pher~g~lme~-oxy or 4~4~ et~ox~dip~ ~e~:~" a~ ~ as tr1 lower ~s~s.ilrloæy, ~or exa~lé ~ rl$ily~o;cy~ and R3 d~notes ~roge~, lowe~ alkyl, or exa~la ~t~yl, et~yl or ~ but~
a~ wsll as t~i-lower a~lsilyl, rOr exa~le ~met~ylsilyl, a~d ben~rl or dipher~ e~ w~ 1~ opt~oDall~ su~tit;u~ed ~or e~l~ by haloge~, ~uch a~ chlorine or bro~ine, or lower a3koxy, ~ueh a~ ~tho~" and ~l~o the corre3-ponding 2-~ephem c:ompou~s o~ the formula Is, ~r 3 7 _ :

SS
~alts,, o~pecl~ly p~ ac~u~ical:l.y u~;able~ r~on-toxic s~ts, o~ ~uCh co~pou~ds hav~ 8alt~Sorm~g group~, ~uc~ a~ alkali m~tsl 8 lt~, ~or ~xa~10 ~od~tum 3~ , or ~kali~e earth ISt~ 3alt8, ~or exa~ ¢alcium salt~ ,, or ~mmo~um salts 9 1~c Ll~ 108e Wit~l ~ni~ae~ ~ of compou~ds wherei~ R2 repre--~ts hr~ " ~d w~ch ~on~ o group 1~ ~e a~yl rad~al o~ ormlala B~
Ab~re ~1, i~ 3~ce~heDl co3~po~d~ oX ~ ~ormula ~A, ~d ~ 0 i n co~e~po~ o~ph~m ~oDIpour:lds c~ he ~o:rmula 19, as ~ell a8 i~ ~alt~, e8pecg.a~.1y ~ parma¢eu~ica:Lly usable ~on~to~c sa~t~" of sueh coD~ound~ whlch ha~ orming grOUp~9 ~18 g~ ~e 3alt3 me~tio~d ~ ~he prece~g par~ra~h~
Rl r~pr~sent~, the acy~ ~ad~ ~l o~ th~ ~orm~
~ R~ d~ e~ pho~yl~, a~ we~1 a~ h~oxypheslyl, ~or exan~ hydrox3r-pheD.yl, t~ ~yl~or ~x~mple 2~ or 3-thie~yl9 ot~iazolyl, or 1,4~cyc~.ohexadienyl, a~ den ot~s oscyge~, ~ d.erlot~ss 0 or ~L and R~ de~ot~s hydrog~ r, i~
a repr~s~ O, ~enol:~ ~o, as well A8 pro~ec~d ami:no~, ~oh a8 acylan~ o, ~or ~xa~ple ~-poly~-bra~ch0d lower alkoxy-carboDglami~o~ ~ch as t~ bu~oxy~arbo~ylamirlo, or 2-halo geno-l~w~r alko~cyGarbo~yl~m~ot ~or ~ 2 ,292- tric~loro ~oxyc~rbo~yl~ o" 2-iodo~:hox~t:arbo~ylam~o or 2-bro~o~
ethoxycsrbonylaml~, or op~ona:Lly lower a~koxy-~ubstltuted or ~i~ ub3titut~d pl~yl-lo~er alkoxycar~onylamislo" îor ex~l~ 4~ ~oxyberlzylos:ycarbor~ylami~c~ or ~ydroxyl, as well ~ pro~ected ~ydroxylj ~ueh a~ scyloxy, for exa~ple ~-p~ly-braslch~d lo~er al~so~eycarbor~yloxy, ~uch as t~r~.-bu~oxy- :

.J ~ 38- :~

~ ,; ., ~ - . . .. .. .

~.~38~'7S 5 carbonylo~y~ or 2-halo~eno-lo~rer ~lkoxy~arbonylox~, such as 2~2,2-tr~chlo~oethoxycarbonyloxy~ 2-~odoe~hoxycarbonyloxy or ' 2-~romoethoxycarbonyloxy, and al50 ~ormylo~y, or represents a 5~amino-5-carboxy ~aleryl radicalg ~erein ~he amino and carboxgl group can al~o be protected a~d~ ~or e~ample, are in the ~o~ ~ acyl2mi~0~ or ~xample low~r a~a~oylzmin~, such as acetylas~o7 halog~ lower alka5~0ylS~ ino~ such as ~chlo-roace~l~m~o, benzG~lami~o or phth~loy~ no7 or o~ este~i-;~ed car~ox~rl9 such as phenyl lowe~ alkoxy~arbonyl~ for .
example dipheny~me~oxycarbonyla wi~ m pr~erab~y denotl~g Ra.~s phe~yl or hydroxyphe~yl, R2 2bo~ al' e~otes hydroxyl a~d also lower alkoxy whi~h is o~ally halogen-su~sti~;uted~ ~or example ch3.orine-substitu-ted, bro~e-subs~i~u~ed or io ~ e-su~s~uted~ ln ~he 2-~osi~io~, espa~i~l}~ ~-poly-bra~c~ed lower alkQX~, for e~ample ter~ oxy, or ~-halog~o ower ~Ikoxy, lor exz~le 2,2,2-~richloroe~ho~y, suoh as m~hoxy-subs~ituted diphenyl-me~ho~y1 ror exampl~ d~phenylme~hoxy or 4,4~-di~etho~y-diphe-~y~me~hoxy, or p-nitrobe~zylsxy, a~d also tri-lower alkylsil-yloxy, ~or example trime~hylsilyloxy, a~d R3 de~otes hyd~ogen, lower alkyl, ~speci~lly m~hyl, tri~lower alXylsilyl, ~or ~ le trime~hylsilyl, or a be~2yl or dlphenyl~e~hyl group which is optlo~1ly substitut~d by haloge~, ~or exzm~le chio-rine or brom~ne, or lower a~koxy, ~or example methoxy.
~ he invention above all relates to ~ntermediates of the~ormula Ivb and IVc useful for the manufacture of 7~ a-amino-a-Ra-acetylamis~o)_3-lower jslkoxy-3-cephem 4-c~rboxyl~c ac~ds, wherein Ra represe~ts phenyl, 4-hy~o~-, . . ., ~. . . .

. . ~ . . . . . .

~ S 5 phenyl, 2-thienyl, 1,4~cyclohexadi~nyl lower alkoxy contains up to 4 c~rbon a~oms and represents, ~or example, ethoxy or n-~u~oxy, but above all methoxy, and the lnner salts thereof.
~nd above all 3-methoxy-7B-~Da-phenyl-glycylami~o)-3-cephem-4-c~rboxyl~c acid and the inner salt thereof: ln the abovemen-tioned concentrations, especially on oral ~dmlnistration, these compounds dlsplay excellent antibiotic properties both against ~r~m-po~itlve an~ especially against Gram-negative bacteria, and are o low toxiclty. The compounds o the ormula IA or I~ can be man~factured ~ecording ~o Canad~an Pate~ ~o.
1 ~5g g88~

Accordlng to the process of the lnvention, compounds of the ormula IVb or IVc are manufactured by : ~ treating a compound of the formula al a compound of the formula Rl O
~N ~ S CH IIII~

N ~ C~3 O~G- ~

: wherein Rl and R2 have the ~eaning given under formula IVb or IVc, is reacted with a sulphinic acid of the formula ~S02~ a sulphonyI c~anide o' the Cormula ~-C-SO~-P~; or a thiosulphonic acid of the formula H-S-S02-R5, or .
b) a compound of the formula , : . .
~ 40 -. ..
; ~ .
.

. . . ,. . ~.~ . . .. . . .

~J~6'~SS

N ~ ~ S-S~R4 ~1 C~
~ ~1 2 (IVa) ~rC-c~3 wherein Rl and RA have the above meanings and R4 is l-methyl-imidazol-2-yl~ 1,3-~hiaæol-2-yl, 1,3,4-thiadiazol- -2-yl, 1~3,4,5-thia~riazol-2-yl, 1,3~oxazol-2-yl, 1,3,4-oxadiazol~yl, 1,3,4,5-oxatriazol-~-yl, 2-quinolyl~
me~hyl-ben2imidazol ~yl, benzthiazol-2 yl or benzoxazol-2-yl, is ré~cted ~ith a hea~y metal sulphina~e of the ~-f~rmula Mn t S02-R5):n or with a heavy metal thiosulphonate df the formula Mn ( S-S02-R5) , wherein M represents a heavy metal cation and n denotes the valency of this cation and R5 ha~ the above mean~ngs, and, i~ required, in a re-sulting compound of the formula IVb or IVc the protected carboxyl group of~the formula -C~O)-RA is converted into another pr~tected carboxyl qroup, and, i~ re~luired, wi~hin the definition of the end products a resulting compound ls converted into another compound and, if required~a re-sulting compound having a salt-forming group is converted into a salt or a resulting salt is converted into the~
free comp~und or into another salt,:and, if requiredi a :re~ulti~g mixture of isomers is separated in~o the indivi-dual isomers..
In a st~rting material of formula III or IVa, R2 preferably represents an eth~rified hydroxyl group.which, with the -C(rOj-grouping, forms an e~terlfied carboxyl group which can be split, especially under mild conditions, it being possible for functional groups whi~h may be present in a carboxyl : protective group ~ to be protected in a manner which ~s in :

. .. .. .. ~ : .: - . : :

;'755 ltself known, for example as indicated above. A group R~ is, f~r example, in particular an optionally halogen-substituted lower alkoxy group, such as methoxy, ~-poly-branched lower alkoxy, for example ~ert.-butox~, or 2-halogeno-lower alkoxv. wherein halogen represents, for exampIe, ~hlorine, bromine or lo~ine, abo~e all 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, or an optlonally 9ubstituted l-phenyl-lower alkoxy group, such as a l-phenyl lower alkoxy group which conta~ns lower alkoxy, for example methoxy, or nitro, ~uch as benzyloxy or diphenylmethoxy which are optionally substituted, for example benzyloxy, 4-methoxyben~yloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'~dimethoxy diphenylmethoxy, and also an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, for example trimethylsilyloxy, or halogen, ~or e~ample chlori~e. Preferably, in a starting material of the formula III or IVa, the radical ~1 denotes an amino protective group RI, such as an ~cyl group Ac 9 in which ree ~unc~ional groups which may be pre ent, for example amino~ hydroxyl,carboxyl or phosphono groups, can ~e pro-tected in a manner which is in itself known, amino groups, ~:
for example, by the abovementioned acyl, trityl, silyl ox stannyI radicals as well as subs~ituted thio or sulphonyl-radicals, and hydroxyl, carboxyl or phosphono groups, for example, ~y the abovementioned ether or e~ter groups, lncluding silyl or stannyl groups~

,;, : , .:

;~.6~i'7S5 Startlng compo~ds of the f ormula III are known orcan be prepar~d according to known processe5.
Compounds of the formula IVa are also k~own or can be prepared according to Netherlands Patent Speci~ication 72/08 ~ ~71 ~

Compounds a~ the ~oTmula IVb can be obtained ~rom compounds of the ~ormula ~II by reaction ~ith a sulphir~lc acid oî the formula HS02-R5 or a su:Lphonyl cy~nide OI the ~Eormu:La ~-C-S02-R5a CompouIlds of the formula IVc can be ~btained ~rom oompound~ o~ the ~ormula III by reaction wl~,h a thiosulphonic acid o~ the ~ormula H-S-Sû2-R5. The reac~ion 18 carried out ln an inert sol~rent or sollrent m~xture, i~or ~x~ple an optionally halogenatedi such as ohlor~ated, ~liphatic, oy~loaliphatic or aromati¢ hydroo~arbon, ~uch as . ~
: pentane, hexane, cy~lohexane, benzene, ~oluene~ methylene chloride, chloro~orm or ch~orobenzene 7 a~ aliphatic, cycloali-:phatlo or aromatic alcohol~ such as a lower alkanol, ~orexample me~hanol, e~hanol~ cyclohexanol or phenol, a poly-hydroxy co~oundsg for example a polyhydroxyalkane~ such as a dihydrox~-lower alkane, for~example ethylene glycol or : propylene glyool, a lower keto~e, such as Qcetone or methyl ; ~ ethyl~etone,`an ether-like solYent, such as die~hyl ether, 43_ :
: -~ 755 dioxane or tetrah~dro~urane, a lower carboxy~ic acid a~ide~
such as dimethylformamide or dimethylacetamide t a lower di- -:
alkyl sulphoxide, such as dimethylsulphoxide and the like, or mixtures thereof.
The reac~ion i~ carried out at r~om temperature or preferably at elevated temperature, for example at the boil- -ing point of the solvent empioyed, if desired in an inert gas a~osphere, such as a nitrogen atmosphere.
me reaction with the sulphonyl cyanide of the ~or- :
mula N_C-S02-R5 is accelerated by addition of compounds which provide halogen anions. Examples of suitable compounds which provide halogen anions are quaternary ~mmonium halides, especially chlorides and bromides, such as tetra-lower al~yi-ammonium halides o~tionally substituted at the lower alkyl grbups, ~or exam~le by aryl, such as phenyl, such as te~ra-ethylammoniu~ chloride or bromide or be~zyltr~e~hyla~monium chloride or bromide. The compounds which provide halo~en anlo~s are added in amounts of about 1 to abou~ 50 mol per cent, pre~erably o~ about 2~to about 5 mol per cent.
Compounds of the formula IVb and IVc can also be obtained by reacting a compound of the formula IVa wi~h a hea~y ~etal sulphinate of the formula ~ ~( SO~-R5)~ or with a hea~y met~l thiosulphonate of the formula Mn~( S-S02-~5)n, wherein M repres~nts a heavy metal cation and n ~enotes the ~alency o~ this cation. Suitabl~ heavy metal sulphir.ates or -heavy metal thiosulphonates are in parti~ular those which have a higher solubility product in the reaction medium used B ~
., :

', . : ' ' ~ ~ ~ '., , ' . ' ' . ' ' . . ' ' ' ' .

6~S5 than the heav~ metal compounds o~ the formula Irln~(-S-R~)n which are produced during the reaction Suitable he~
metal cations ~ are in particular those which form particular-ly sparingly soluble sulphides. These include, for e~a~pl~, the monovalent or dival~nt cations o~ copper, mercury, silver and tin, copper++ and silver~ ca~ions being preferred.
~he heavy metal sulphinate or hea~y metal thiosul--phonatP can either be employed as such or be formed in situ .during the reac~ion, ~or example from a sulphinic acid of the ~ormula H~02-R5 or a thiosulphonic acid o~ the ~ormula H-S-S02-~5, or a soluble salt thereof, ~or example an alkali metal salt, such as a sodium salt, and a heavy metal salt of which the solubility product is higher than that o~ the heavy met~l sulphinate or heavy metal thiosulphonate produced, ~or example a heavy me~al nitrate, acetate or sulphate, for example silver ni~rate, mercury-lI diacetate or copper-II
s~lphate, or a soluble chloride, such as ~in-II chloride dihydrate.
The reaction of a compound of the formula IVa with ~hP
heavy metal sulphinate of the formula ~+(-S02-R5)n or the heavy metal thiosulphonate of ~he formula ~+(~S S02-R5~n can be carried out in an inert organic solvent, in water or in a sol~ent mixture consisting of water and a water miscibl~ sol_ vent. Suitable inert organic solvents are, ~or example, alipha~ic, cycloaliphatic or aromatic hydrocarbons ? such as pentane, hexane, cyclohexane, benzene, toluene or xylene, or alipha~ic, cycloalipha~ic or aromatic alcohols, such as lower ~; :

.. - . ... ~. - ~ . . . . . . . . . - .. . .

~¢~ 55 alkanolsg ~or example me~ ol~ ethanol, cyclohexa~ol ~r phenol, polyhydroxy rom~oundsl such æs polyhydro~yalk2nes, for example dihydroxy-lower alkanes 9 such as ~thyle~e glycol or propylene glycol~ carboxyl$c ~cid esters, for exa~ple lower carboxylic acid lower al~;yl est~rs, such as et~yl ac~ta~, lower k~to~es, s~oh as acetone or msthyl e~hyl ketone~ e~her-llk~ sol~ent~O such as dioxane ~r tetrahydr~-fur~ne or polyethers, such as dimethoxyQthane, lower carbo.~y-~ic acid amides, such as dime-~hylformamide~ lower alky~
riles:, such as ace~onitrile, or lower sulphoxides, such as dimethylsulphoxide. I~ water, or especially in ~ixtures of wa~er and one of the sol~ents ment~oned, ~cluding ~n emu~;
s~ons, ~he reactio~ usuall~ ~ak~ place substanti lly more rapidly ~han i~ the org~nlc sol~e~ts P70~e.
. ~ me reao~ion ~emperature ~ usu21~ y about room temperature but can b~ lower~d ~o slow down the reaction or ~aised9 say up to the ~oiling poin~ of the so~v~nt empl~yed to accelarate the rea~on, ~ being po~sible ~o car~y out t~e reactlon under normal or ele~ated pressuh~
In a resulting compound of ~he formula Ivb or IVc, a qroup Ral or R2 can be converted into another group Rl or ~ by varlous additional measures which are in themselve~ known.
.

`

ss The processes for the manufacture of compound of the formula IA or IB are distinguished, relative to previously known processes, by the fact that it starts from inexpen-sive, easily accessible s~artlng materlals, such as, ln :
particular, the l-oxides of the ermentatively preparable penicillins G or ~ and of 6-amino-pen~clllanic acid, of whlch ~he reac~i~e groups can be protected ln any known manner and can ea~ily be liberated agaln after the reac~ionO and that the manu~acture of the intermediate products required according to the invention takes place wi~h hlgh yield3.

The .q~ar~ing materials of the ~rmula II used for the prepa~ation of compounds of the ormula IA or IB can be manufactured, for example, in accordance wlth ~he following F~actLon scheme:

~' ~ -I r ~ 4 7 _ : -'~

` CH3 StEIge 1~ Rl ~ CY.z ~C~3 ~rC-CH
(III) o=l ~ (IV~ o= C-~2 S~ge 2a/ IVa ~ ~ -S-R4 Iltc Y _ S-S02 R5 ¦~ Stage 2 3 ~ C--CH
~FC~ O~ cr-P~

~Ia Y ~ _9-R4 ~a: y 5 _~4 :
YIb: Y - ~ S02-R5 ~rb Y ~ 2-R5 ~ C ~ S02-R5 YC Y - -S-SC)2-R7 I
¦ ~ta~ge 4 R~ ~ Ra 1~N 8 8 S-Y H

N ~ b 3 ~- ~ \t ~--~3 oS C-R ~ o-~-RA
Ila ~ R4 ( IA) IIb: Y - S02-~s IIc: Y 2~ -5-S02-R5 : ` ~ B ~ ~

:.' : ~

.. ... . - . . . . ~ . - . . . , - , . . .. . , . . . . - ..

. .. ~ , . .. ~ : -.

;
Ji!~7S5 The proce~ses Eor the manufacture oE compounds of the formula V, VI, II and I are described in Canadian Patent No. 1 059 988, ~:n '.he co~text o~ ~e present des~r~p biol~, the or~2-n~ radic 1 s deseribed as "lower" conta~ less ex~re~s' ~-~de~ed, ~p to 79 pre:l~erably un ~o 4~ carbcn at~ms; acy r2d~cals eoRtai~ up to ~0, pre~rably UD ~o 12,, a~d abol.-e a~
up to 7 ,, ~rbon a-'~om~ . :
me exa~ples wh~ch follol,J ser~re to i~lus.,ra~,e t.he in~ren..io~. ~e cephem coD~polmds ~e~tio~ed in ~ exz~:rp~es possess the R-cor~'i~;ura~o~ ~ ~e ~ ar~d 7-posi..~on, ~d ~le azetid~no~e ccmpo~ds me2~ioned possess tl~e R-corfiO~-a~
in 'the 3- a~d ~positio~

' ~

' :' ~ .

'. ' : ' ' ~ _ 49 _ :

:
.

, ' " : :: ' ':: .: :: .' ' ... . ' :,~ . . . ., ', Exa~le 1 ~ solution o~ 60 ~1 (2 equivalents) o~ 1,5-diazabi-cyclor5.4.0~undec-5-ene in 1 ml of tet-ahydrofurane is added drop~rise over the course of 5 minutes to a solution of 13~ mg (0.2 mM) of an isomer mixture consisting of 2-~4-(p-toluene-sulphonylthio)-3-phenoxyacet~mido-2-oxoaze~idin-1-yl]-3-me~hoxy-crotonic acid p-nitrobenzyl ester and the correspond- -ing isocroto~ic acid ester, in the ratio of about 4:1, in 4 ml -of dry tetrahydrofurane. After st~nding at room tempera~ e _ for 40 minutes, the mixture is diluted with 20 ml o~ benzene, cooled in an icebath and stirred for 10 minutes ~ith 10 ml o~
a 10% strength citric acid solution. The organ~c layer is separated o~ and washed successi~ely with satuL~ated sodium chloride solution, 10~ strength sodium bicarbonate solution and sodium chloride solution. The solution is dried over magnesium sulphate and concentrated in vacuo, and the resul~-ing yellow oil is puri~ied ~y chromatography-filtration on 4 g o~ acid-washed silica gel (2 kg of silica gel are stirred three times with 2 1 of concentrated hydrochloric acid in each ca~e ~or 10 minutes, separated ~rom the acid by decanting, washed with distilled water un~il neutral9 rinsed with meth-anol and ac~i~ated for 60 hours at 120~), with benzene/eth~l a~etate, ~:19 as the eluting agent. The fract.io~s containing the isomer mixture are combined and concontrated in ~2CUO.
A semi-solid i~omer mixture, consisting o~ 7~-phenoxyacetamido-3~methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl e3te. and 7~-phenoxyaGe~amido-3-methoxy-oeph-2_0m_4-carboxylic acid p- -nitrobenzyl ester in the ratio o~ about 1:3 is obtained and ~ ~B

. . . .. . .. ....... . . ... .. . . . .. . .. . .
. ~ .. . .. .. ........ . . . . . . .. . .
.. . .. .. ~., . .... .... .. . ... . . .. . . ~.

.,... . .. ,~ . . ~ .. . .. , ~ .

. . ~ . . - .. ~, , ~.6)~ 5S
can be separated into the two isomers on Woelm s~l~ca gel (activity III) with ben~ene/e-,hyl acetate, 5~1. The ~aster-running 7~-phenoxyacetamido-3-methoxy-ceph-2-em-4-c2rboxylic acid p-nitrobenzyl ester is recrystallised ~rom methylene chloride/ether a~d has a melting point of 129-131.5C.- The slower-running 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid p-ni~robenzyl ester has a melting point o~
14005 - 14ZC (from methylene chloride/ether)~ -O me products can be further converted as Iollows: -_ A solution, prepared at O~C, of 555 mg (1.11 mmols) of a crude mixture consisting of 7~-phenoxyacetamido-3-metho~y-ceph-2-em-4a-carboxylic acid p-ni~robenzyl ester and 7~-phenoxyacetamido-3 methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the ratio of about 3:1, in 33 ml of ~etrahydro~urane, is mixed, whiist stirring, with 16 ml o~ an 0.1 N potassium hydroxide solution ~ich has been precooled to 0C. The mixture is stirred for a ~urther 5 minutes at 0C, 100 ml o~ ice water and 100 ml of precooled methylene chlor- :
ide are then added and the whole is stirred up brief~y.
Addition of 1 ml o~ saturated aqueous sodium chloride solu-tion causes the two phases to separate. T~e organic phase is separated o~f, and the aqueous phase is again washed with 20 ml of methylene chloride, then covered ~ith 50 ml o~
methylene chloride and acidified with 20 ml of 2 N hydrochloric :~
acid. A~ter shak~ng up, the or~anic phase is separated of~
and the ~ydrochloric acid solution is extracted ~wice more with 10 ml of methylene chloride a~ a time. The combined Sl 1~ _ :

~ 5S

me~hylene chloride extrac~s are dried over sodiu~ sulphate and e~aporated in vacuo. The residue is recrystallised from methylen~ chloride/diethyl ether/pen~ane and giv~ 7~-pheno~J-acetamido-3-methoxy ceph-2-em-4a-carboxylic acid of melting point 142-145C.
The star-ting materials can be obtained as follo~s:
a~ A solut~on o~ 36~6 g (O 4 1 M) of ~-phenoxyacetamido pe~licillan~c acid l~-oxide, 11.1 ml (0.11 M) of triethvlamine and 23.8 g (0.11 M) o~ p-nitrobenzyl bromide in 200 ml of di- _ methylformamide is s~irred for 4 hours under nitrogen at roo~
temperature~ The reactio~ solution is then introduced in~o 1.5 1 of ice water and the precipitate is ~ ered o4~, dried and twice recrystallised from et~yl acetate~methylene ch.oride.
The colourless, crystalline 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl es~er l~-oxide me~ts at 179-180Co b) A solution o~ 5.01 g (10 mM) o~ 6-phenoxyacetamido-pen~cillanic acid p-nitrobenzyl ester l~-oxide and 1.67 g (10 mM) of 2-mercaptobe~zthiazole in 110 ml o~~dry tol~ene i5 boiled ~or 4 hours under reflux in a nitrogen atmosphere. - ;
The solution i5 concentrated to approx. 25 ml by distilling off solve~t and diluted with approx. 100 ml o~ ether. The product ~hich has se~arated out is recrystalli~ed from meth-~-lene chloride/ether and 2r4-(benzthiazol-2-yldithio)-~-phenoxyacetamido-2-oxoazetidin-l-yl~ methylene0butyric acid p-nitrobenzyl ester of melting ~oint 138-141C is obtained.
o) 1.06g of ~inely po~rdered silver nitrate are added to a solution o~ 3.25 g (5.0 m~l) o~ 2-[4-(benzthiazol-2-yldi-thio)_3 phenoxyacetamido-2-oxaazetidin-1-yl~ 3wmethylene-_..~. ~

` -, butyric acid p-nitroben~yl ester in 200 ml of acetone/~Jater, 9:1 t~/v). I~mediately afterwards, a soluti~n of 890 mg ~ ) of sodium p-toluenesulphinate in 100 ml o~ the same solvent mixture is introduced (over the course of 10 minutes).
A light yellow precipitate forms ~mmedial;ely. A~ter stirring for one hour at room temperature, the ~ixt~re is filtered, with addition of Celite. The filtrate is diluted with water and ~wice extracted with ether. The combined ether e~trac~s are dried over sodium sulphate and after concentration gi~e --pale yellow solid 2-~4-(p-toluenesulphonylthio)-3-phenoxy- :
acetamido-2-oxoazetidin-l_yl~-3-methylene-but~ric acid p- -nitrobenzyl ester. Thin layer chromato~ram on silica gel (toluene/ethyl acetate, 2~ Rf ~alue = O.24; IR spectr (in CH2C12): characteristic bands at 3.90, 5.56 a 5 . 70 ~ 5 . 87 6.23~ 6.53~ 6.66~ 7.40~ 7.50~ 8.10, 8.72, ~.25 and 10.95 l~
The product can be employed without f~rther ~urification in the subsequsnt reaction. : -e ~ame compound can also be obtained in accordance with the fol~owing methods: ~
ci) 1.58 g (1.2 equivalents) of sil~er p-toluenesulphinate are~added in portions ~or 10 minutes to a solution of ~.25 g ~5.0mM) o~ 2-~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-l-yl~-3-methylene-butyric acid p-nitrobenz-~l ester i~ 200 ml of acetone/water, 9~ /v). The suspension i5 stirred for one hour at room temperature, filtered and then ~urther processed as described in Example lc). 2 [4_(p_ toluenesulphonylthio)-3-phenoxyac~tzmido-2 oxoazetidin-1-yl~
;,. ` ~ r~AG/~ k ~' S~ , ~ .. : . - , . .. , ,, ... ., ., . . . . - . ., . ~ . . .

~ 75S

3-me~hylene-butyric acid p-nitrobenzyl ester is obtained in quantitative yield.
Silver p-toluenesulphinate is obtain~d as a colour-le~s precipitate by combining aqueous solutions of equimolar amounts o~ silver nitra~e and sodium p-toluenesulphinate.
The pro~uct is dried in vacuo for 24 hours.
cii) 2-[4-(p-Toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin l-y~3-methylene-butyric acid p-nitroben~yl ester can also be o~ained in qua~titative yield, analogously to ~ .
Example lci) from 3~25 g of 2-[4-(ben2thiazol-2-yldithio)-~phenox~aceta~ido-2-oxoazetidin-l-yl~ met~ylene-butyric acid p-nitrobenzyl ester and 1.87 g (2 equi~ale~ts) o~ copper-lI
di-p-toluenesulphinate.
Copper II di-p-toluenesulphinate is obtained by reac-tion of copper sulphate and sodium p-toluenesulphinate (2 equiYalen~s) in ~rater. A~ter filtering o~, the sal~ is dried in vacuo for 12 hours at 60C.
Ciii) 2-~4-tp~To7uenesulphoslylthio)-3-phenoxy~ce..amido-2-oxoaze~idin-l-yl~-3-methylene;butyric acid p-nitrobenzyl ester -can also be obtained analogousl~J to Example lci) from 130 mg o~ 2-C4-(benzthiazol-2~-yldithio)_3;phenoxyacetamido~2-oxo-szetidin-l-yl]-3~methylene-butyric acid p-nitrobenzyl ester and 85 mg (2 ~qui~alents) o~ ti~ II di p-~oluenesulphinateO
Tln-II di~p-~oluenesulphinate is obtained by reaction of tin-II chloride (2H20) 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.

~r;~' 5~

~.~3~;'75~i -civ) 2-[4_(p_Toluenesulp~lonylthio)-3~henoxyaceta~ido-2-oxoazetidin-l-yl~_3-methylene_buty~ic acid p-nitrobenzyl ester can a~obeo~ ana~ogously to Example lci) from 130 mg o~ 2-~4-(benzthiazol-2-yldithio)-3-phenGxyacetamido-2-oxoazetidin-1-yl]-3 methylene-but~ic acid p-nitrobenzyl ester and 102 mg (2 equivalents) of mercury-II di-p-~oluenesulphinate.
Mercury-II di p-toluenesulphina~e is obtained by re~ction o~ mercury-II diacetate and sodium p-toluenesulphir,av~
O in water. After filtering of~, and washing ~rith water, the ~-salt is dried in ~acuo ~or about 12 hours at 50-60C.
cv) A solution of 517 m~ (1.02 mM) of 6-phenoxyacetamido penicillanic acid p-nitrobenzyl ester 1~-oxide and 187 mg (1.2 mM) of p-toluenesulphinic acid in 10 ml o~ 1,2-dimethoxy-ethane ~or dioxane) is heated under reflux for 4.5 hours in the presence o~ 3.5 g of a molecular sieve 3A, and in a nitrogen atmosphe-e, after w~ich a further 308 mg (1.98 ~) of p-toluenesu7phinic acid, dissolved i~ 2 ml of 1,2-dimethoYy-O ethane, are added i~ fi~e portions at 45 minute intervals.
A~ter 4.5 hours, the reaction mixture is poured ir~to 100 ml of 5% ~trength aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases . are washed with water and saturated aqueous sodium chloride solution, dried o~er mag~esium sulphate and concentrated by evaporation. me residue is chromatographed on silica gel thick layer plates with toluene/et~yl acetate, 2:1, and gi~es 2-~4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-o~oazetidin-l-yl~-3-methylene bu~yric acid p-nitrobenzyl e~ter.

B

~.63~6'7S~

cvi) A mix-t~re of 250 mg to.5 mM) o~ 6-phenoxyacetamido penicillanic acid p nitrobenzyl ester l~-oxide, 110 mg (0.61 mM) of p toluenesulphonyl cyanide and 5 mg (0.022 ~) of b~nzyltriethylammonium chloride in 2 ml of dry, peroxide-~ree dioxane is stirred under argon at 110C for 4.5 hours. The solvent is evaporated off in vacuo and the yello~ oil which remains is chromatographed on acid-washed silica gel.
Elution with 30% ethyl acetate in toluene gives 2-[4-(p_ toluenesulphonylthio)_3_phenoxyacetamido-2-oxoazetid'inA~l-yl3-3 methylene-butyric acid p-nitrobenzyl ester.
cvii) A mixture of 110 mg (0.61 mM) of p-toluenesulphonyl cyanide and 4.5 mg tO.021 mM) o~ ~etraethyla~monium bromide ir, 1 ml of pure dioxane is stirred for 30 minutes at 110C under argon. A suspension o~ 250 mg (0.5 mM) of 6-phenoxyacet am~dopenicillanic acid p-nitrobenzyl ester l~-oxide.in 1 ml of dioxane is then added and the resulting solution is stirred ~or 4 hours at 110~ under argon. The solvent is removed in vacuo, the crude product is dissol~ed in ethyl acetate and the solution~is washed with water and with saturated aquesus sodium chloride solution. The orgar.ic phase is dried with magnesium sulphate and ~reed from the solvent in ~acuo, gi~ing crude 2-~4-(p-toluenesulphonylthio)_3_phenoxyacetamido_2_ oxoazetidin-l yl]-3-met}lylene-butyric acid p-nitrobenzyl ester.
.
d) 1.1 equivalents of ozone are passed into a solution o 1.92 g (3.0 mM) o~ 2-~4-(p_toluenesulphonylthio)_3-phenoxy-acetamido-2-oxoazetidin-1-yl~-3-methylene-butyrlc acid p-nitrobenzyl ester in 30 ml of dry met~yl aoetate, a~ -78C, :, Ç~5S
over ~he course o~ 33 minutes. Immediately thereafter, excess ozone is remo~ed by means of a stre~m.of nitrogen (15 mi~utes at -78C). 2.2 ml o~ dimethyl sulphide (10 e~ulvalents) are added and the solution is warmed to room temperature. After stan~ing for 5 hours, the solvent is distilled off in vacuo and t~e colourless oil which remai~s is taken up in 100 ml of ben~ene. ~he benzene solution i5 washed with three 50 ml portio~s o~ saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness in vacuo. After recrystallising ~he residue ~om tolue~e, 2-t4~(p toluenesulphonylthio)~3-phenoxyacetamido-2-oxoazetidin-l-yl~-3-hydroxy-c~otonic acid p-nitrobenzyl ester o~ me~ting point 159-160C is obtained.
d~) The crude 2-~4-(p-toluenesulphonylthio)-3-ph~noxy-acetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid p-~itrobenzyl ester obtained according to Example l.cvii) is dissolved in 20 ml o~ me~hyl acetate and ozonised at -70C
until starting material is no longer present, according to a ~hin layer chromatogramO A stream of nltroge~ is then passed through the solution and the latter is warmed to 0-5C. A
solu~io~ of 300 mg of sodium bisulphite in 5 ml of water is added and the mixture is stirred for about 5 minutes until no -.
~urther ozonide is detectable by means of potassium iodide/
~tarch paper. The mixture i~ diluted with ethyl acetate, the aqueo~ts phase is se~arated of~ and the organic phase is washed with water, dried over magnesium sulphate and freed ~rom the sol~ent in vacuo. ~he crude ~roduct is dissolved in ~17 ':

~ 55 3 ml o~ methylene chloride and 15 ml of toluene are added.
The precipitate is ~iltered o~f and the filtrate is concen- -trated by evapora~ion i~ vacuo. The residue ~s recrystal-lised from methanol and gi~es 2 r4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2_oxoazetidin-l_yl~-3 hydroxy-crotonic acid p-nitrobenzyl ester o~ melting pcint 159-160C.
e~ A solution o~ 1.93 g of 2-r4-(p-toluenesulphon-ylthio)-3-phenoxyacetamido-2-oxoazetidin-1 yl~-3-oxo-bu~yric-acid p-nitrobenzyl ester (~.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 tne course of 10 minutes. The mixture is stirred ~or two hours at 0C, excess diazometha~e is removed by means rt~ a stream of ni-trogen and the solvent is stripped off in vacuo.
me crude product is puri~ied by ~21tra~ion through ~oelm s~lica gel ~acti~ity III, 4C~fold amount)~ using benzene/
e~hyl acetate 3 5:1. The oolourless oil obtained a~ter dis-ti~lin~ off t~e solYent crystallises on standing. After 0 recr~stallisation from methylene chloride/etherl an iso~er mixture con5isting o~ 2 [4-(p-toluenesulphonylthio) 3 phenoxyacetamido-2-oxoazetidin-1-yl~-3-methoxy-crotonic acid p-nitrobenzyl ester and the correqponding isocrotonic acid ~ster in the ratio of about 4:1 is obtained. Melting point o~ the mlxture: 155-15605C.
Exam~le 2 A solu~ion o~ 279 mg of 2-[4-(p-toluenesul~honylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-~-hydroxy-crotonic ._ .

~ - ~ ~

~ 55 acid diphenylme-thyl es~er (0.428 mmol) in 4 ml o~ chloroform and 1 ml o~ hexamethyldisilazane is heated ~or one hour under reflux and evaporated in ~acuo, a~d the oily residue is dried for one hour under a high vacuumO The silylate~ crude pro-duct consi~ts of 2.[4 (p-toluenesul~honylthio)-~-phenoxyacet~
amido-2-oxoazeiidin-l_yl~3_trimeth-jlsll-jloxy-crotonic acid diphenylmet~yl ester and the corresponding isocrotonic acid diphenylmethyl ester.
The resulti~g crude product is taken up in 3 ml of dr~
chloro~orm, the solution is cooled to 0C and o.o6s ml (0.~7 mmol) o~ 195-diazabicyclo~5.4.0~undec-5-ene is added under -:
ni~rogen, whilst stirring. After a reaction ~ime of 1 hour, the solution i~ mixed with 0.3 ml of acetic acid and dilu~ed with chloro~orm. me chloro~orm solution is washed wi~h dilute sulphuric acid~ water and dilute sodium ~ic~rbonate solution~ The aqueous phases are extracted with chloro~orm and the combined organic phases are dried over sodium sulphate and concentrated in ~acuo. Crude 7~-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained. R~ ~alue: 0.1~ (silica gel; toluene~ethyl acetate, 3~
The resulting crude product is ~aken up in methanol a~d an excess o~ diazome~hane solution in ether is added at .
0C~ A~ter a reaction time of 5 minutes, the solution is concentrated completely and the oily residue is chromato-graphed on silica gel thick layer plates (toluene/ethyl :~
ace~ate, 3:1). The silica gel o~ the zone at Rf , 0.19 is ~.
.
, i s 7 ., ,, . , ;; .~ ~, . ., . , , ~

~ 7S5 extracted with ethyl acetate and gives 7~-pheno~yaceca~ido-~-methoxy-ceph-~-em-4-carbox~lic acid diphenylm~th~ll ester;
melting point 120C (from ether). IR spectrum (in CHC13):
3,310, 1~775, 19700, 1,690 and 1,600 cm 1, me ~arting material is pre~ared as ~ollows:
~) 100 g (27.~ ~) of 6-phenoxyacetamido-penic~llan~c acid l~-oxide~ 500 ml o~ dioxane and 58.4 g (30 m~) o~ di-phsnylmethyldiazomethane a~ter about 2 hours g~ve 6-phenoxy acetamidopenicillanic acid diphenylmethyl ester 1~-o~ide; --melting point 144-146C (ethyl acetate/petroleum ether)~
b~ Analogously to Example lb), 292 g (55 mM3 of 6-phenoxyacetamido-penicillanic acid diphenylmethyl ester 1~
oxide and 99 g (59.5 mM) of 20mercaptobenzthiazole give 2 ~4-tber2thiazol-2-yldithio)_3_phenoxyacetamido 2-oxoazetidin~
yl~ methylene-butyric acid diphenylmet~yl ester; melting point 140-141C (~rom tolue~e~ether).
c) Analogously ~o Example lc), 10 g (14.7 mM) of 2-[4-(benzthiazol-2-yldithio)_3-phenoxyacetamido 2-oxoazetidin 1-yl~-3-methyle~e-bu~yric acid diphenylmethyl ester in 50 ml of ethyl acetate and 4.92 g (24.98 mM) of finely po~dered silv-er p-toluenesulphinate on stirring for 7 hours at room tempera-ture g~e 2-~4-(p-toluenesulphonylthio)-3-phenoxyacetamido~-o~oazetidin-l-yl]-~ methylene-bu~yric acid d~phenylmethyl eæter. Rf ~alue = 0.28 (sillca ge , toluene/ethyl acetate, 3:1); IR spectrum (CHC13): 1,782, 1,740, 1,695, 19340 and 1,150 cm~l.
2-~4 (p-~oluenesulphonylthio)_3_phenoxyacetamido-2 .
B : ~

. ~ .; . . .. , . ~ , .. . .. . . .

~3~'7~S

oxoazetidin-l-yl] 3-methyl~ne-butyric a~id diphenylmethyl ester can also be prepared as ~ollo~.Ys:
ci) A suspension o~ 106.5 g o~ 6-pheno~yacetamido-penici~
lanic acid diphenylmethyl ester l~-oxide and 33.8 g of 2 mercaptobenz~hiazole in 900 ml.o~ toluene and 9 ml of glacial acetic acid is boiled for 2 hours under nitrogen using a water separator, during which time about 4.5 ml of water are separa~ed of~. The solution is cooled to room temperature, a total o~ 85.5 g of silver p-toluenesulphin ~e is added in ~~~~
portions over the course o 1 hour and the mixture is then stirred for a ~ur~her 2 hours at 22C. The mixture is fil-tered tl~rough Hyflo and the ~iltrate is washed ~wice with .saturated aqueous sodium chloride solution. me organic phase is dried over magneslum sulphate, co~centrated in vacuo to about 1 litre, decolorised wi~ 30 g of ~orit an.dcor~ d bye~raticn. ~he resulting yellow foam is crystallis~ rom me~hylene chloride/diethyl e~her. Melting point 79-82C.
R~ ~alue = 0.55 (sllica gel; toluene/ethyl acetate, 3:1). ~ .
Further quantities-o~ the substance can be obtained from the mother liquors by crystallisation ~rcm methylene chlorida/:~
diethyl ether. ~.
d) Analogously to Example ld)9 10.8 g ~16.2 mM) of 2-[4- -(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1 yl] 3-methylene-butyric acid diphenylmethyl es~er in 1 1 of methylene chloride and 1.1 equl~alents of ozone gi~e 2-~4 (p-tolue~esulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-hydrox~--crotonic acid diphsnylmethyl ester; melti~g point -- .,. .. . - -, , , ., . ~ :;, , . . ~

~ 6'7~S

142-143C (~rom ether/pent~ne).
The ozonisation can also be carried ou~ at 0C:
15.2 mmols o~ ozone are passed into a solution of 9.23 g (13.8 m~ols) of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido_2_oxoazetidin-l_yl~ methyler~e-butyric acid diphenylmethyl ester i~ 960 ml of methylene chloride at 0C
over the course of 19 mi~ute~. 10 ml of dim_~hylsulphide are added to the clear reaction solution and the mixture is stir-red for 20 minutes at ~C~ A~ter concentrating unde~ a ~~
waterpump ~acuum9 and drying the residue in a high vacuum, a lig~ yellow ~oam results~ which crystallises from methylene chloride/hexane; the melting poi~t of the resul~ing 2-~4-(p-toluenesulpho~yltkio)-3-phe~ox~acetami~o-2 oxoazetidin-l-y~]-3-hydroxy-crotonic acid diphenylmethyl ester is abou~ 134-138C. Thi~ layer chromatogram: Rf value ~ o.46 ~silica gel; toluene/ethyl acetate, 3~
m e same compou~d can also be obtained in accordance with the following me~hods:
di) A solution of 684 mg (1 ~M) o~ 2 [4-(benzthiazol 2 yldithio)-3-phenox~acetamido 2~oxoazetidin-1-yl~ 3-hydroxy crotonic aci~ d~phenylmethyl ester in 20 ml of acetone~water, 9:1 (v/v) is stirred with 341 mg (1~3 mM) of silver PDtO1Uene - -sulphinate for 60 minutes at room temperature. $he yellow reaction mixture is mixed with 50 ~1 of acetone and filtered.
me filtrate is concentrated by e~aporation in vacuo and the residue is chromatographed on 30 g of acid-washed silioa gel using toluene/et~yl acetate, 4:10 The resul~ing 2-E4 ~P-... . ., , .. .. ~. ....... .. .. , :., . : . . -.
- . .. .. -. . . . . ~

136~55 toluenesulphon~lthio)_3_pheno~Jace~amido-2~oxoazetidin-1-yl 3 - -3-hydroxy-croto~c acid diphenylmethyl ester is recrystal-lised from ether/pentane and melts a~ 142-143C.
dii) A solution OI 72.9 rag ~0~1 mM) of th~ crude ozonide~
obtained by ozonisation of 68.1 mg (0.1 mM) of 2_E4 benz-thiazol-2-yl~hio)_3_phenoxyace~amido-2-oxoazetidin l-yl~-3 metnylene-bu~yric acid diphenylmet~yl ester in ethyl acetate and evaporation ol the sol~e~t, in 2 ml o~ acetone/water, 9:1 -O (~/v) is stirred with 35 mg (103 equivalents) of sil~er p- -. toluenesulphinate ~or one hour at room tempera~ure. The reaction mixture is diluted ~ith 3 ml of acetone and filtered.
0.2 ml of dimethylsulphide is added to the ~iltrate and ~he mixture is stirred ~or two hours at r,oom temperature (until i~
gives a negati~e iodine tarch reaction). A~ter removing the solve~t in ~acuo, the residue is chromatographed on 3 g o~
acid-washed silica gel, usin~ toluene~ethyl acetate, 4:1.
The resulting 2-C4-(p-toluenesulphonylthio)-3-phenoxyacet-amido-2-oxoazetidin-l~yl~-3-hydroxy-crotor.ic acid diphenyl-methyl ester 1~ recrystallised from ether/pentane and melts at ~~
142-143C. AYter a further recrystallisation,~rom methyle~e chloride/diethyl ether~ a melting point of 144-145C (corr.ec-ted) is obtai~ed; r~20 = -68o + 1 (c = l; chlorofor~
thin laye~ ohroma~og~am: Rf ~alue = 0.81 (silica gel;
methylene chloride/ethyl acetate, 8:2~; W spectrum (ethyl A alcohol): AmaX = 261 nm (~ = 14,400); IR spectrum (Nujol~:
characteristic bands at 3.00; 5.56; 5.93; 5.98; 6.o6;
6.193 6.25; 6.54; 6.70; 6.82; 7.02; 7.47; 8.03; 8.76;
~ ~r~A~n~k ~3 " ~ .

. . ". - . . . ,. . , ~ . ..

. . . .. . .
- . -. : ~; . . . . , :

.~0~
9.53; 10.23; 10.60; 12.30; 13.26 and 14.30 ~.
Exam~le 3 . . .~
0012 ml ol bis-trimethylsilyl-acetamide (0.508 mmol) is added to a solution of 301 mg to.462 mmol) o~ 2 ~4-(p-toluenesulphonylthio)_3_phenoxyacet2mido-2-oxoa~etidin l-yl]-3-hydroxy~crotonic acid diphenylmethyl ester in 3 ml of 1J2-dimethoxye~hane ~nder a nitrogen atmosphere, a~d the mixture i~ stirred for one hour at room ~emperat~re~ The solution is coD letely concent~ated by evaporation and the oily Pesidue is-dried for on~ hour under a high vacuumO The silyla~ed crude product 1s taken up in 3 ml of dried 1,2-dime~hoxye~hane a~d a~ter cooling ~o 0C 0.075 ml (0.508 mmol) o~ 1,5-diazabicyclo C5-4.0]und~c-5-ene is added. After 6 hours' reaction time at 0C under a nitrogen atmosphere~ 0.3 ml of acetic acid is added and th~ mixture is diluted wi~h met~ylene chloride.
The methylene chloride solution is washed successively with dilute s~lphuric acid 9 water and dilute bicarbo~ate sollltion.
The aqueous phases are extracted wit~ methylene chloride and the combined organic phases are dried with sodium sulphate, concentrated in ~acuo and dried under a high vacuum. Crude 7~-phenoxyacetamido-3-hydroxy-ceph-~-em-4-carbo~lic acid diphenylmethyl ester is obtained. An excess of a solution of .
diazomethane in ether ls added to the solution o~ the crude product in chloro~orm at 0C and the mixture is left to stand ~or S m~nutes at 0C. It is then conce~trated co~ple~ely and the residue is chromatogra~hed on silica gel, as in Example 2. 7~-Pheno~Jacetamido-3-methoxy-ceph-3-em-4-car- :~

1~ ' :

~ 6'7SS
bo~Jlic acid diphenylmethyl ester; Rf value = 0.19 (silica gel, toluene/ethyl acetate, 3:1); melting point 12QC (from ether)~ IR spectrum (in CHC13): 3,310, 1,775, 1,710, 1,690 and 1,600 cm~l~ is obtained~ .
~xam~le 4 _. .
0.045 ml (0.3 mmol) o~ 1,5-diazabicyclo~5.4.0~undec-

5-ene is added ~o a ~olu~ion o~ 100 mg (0.15 mm~1) of an iso-mer mixture consi~ti~g o~ 2-~4~(p toluenesulphonylthio)~ -phenoxyacetamido-2-oxoazetidin-l_yl 3 -3-methoxy-crotor~ic acid diphenylmethyl ester and ~he corresponding isocrotonic acid ester i~ 4 ml o~ dry 1,2-dime~hoxyet~a~e whilst s~irring in a ni~rogen 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 solution, diluted with methylene chloride, is successi~ely washed wi~h dilute sulphuric acid, water a~d dilute bicarbonate solution. The aqueous ph ~es are ex~tracted with methylene chloride. The combined org~nic phases are dried with sodium ~ulphate, con centrated and completely freed ~rom the solvent under a high vacuum. The oily residue is chromatographed on a silica gel thick layer plate (running agent toluene/ethyl acetate, 3:1, developed once). The two zones at Rf _ 0.19 a~d 0.4 res- ' pectively are jointly extracted with ethyl acetate and the resulting solution is concentrated.completely. An oily product is obtained, which co~sists of 7~-~henoxyacetamido~3-methoxy-ceph 3-em-4-carboxylic acid diphenylme~-h~l ester and the isomer 7~-phenoxyacetamido 3-methoxy-ceph-2-em 4~car-~5 _ ~ _ i. .. ............. ~ , , ~ . . , -, , . . ~ . . .. .
`. . . . ~ .; . . ~ ., . - . , .
.. . ; . ., . .. , . -,, .. ... , - . ., ~

.- . . . .. . .
, :~.q)8~;~5 boxylic acid diphenylmethyl ester in the ra~io of 1:4~ R~
value = 0.14 and 0.32 respecti~ely (s~.lica gel, toluene/ethyl aoetate~ ~:1); IR spec~rum (in CHCl~): 3,400, 3,3107 1,785, 1,770, 1,750, 1,710, 1,690, 19630 and 1,600 cm~l.
i) The ratio o~ resulting ceph-2-em to ceph-3 em deriva tive depends, in~er alia, on the solvent used for the cyclisa tio~, on the concentration o~ the starti~g material and of the 1,5-diazabicyclo~5,4.0]undec~5-ene and also on the reactio~ .
9 ~ime. 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 ~5~ -of 2-[4;(p-toluenesulphonylthio) 3-phenoxyaceta~ido-2-oxo-aze~idin-l-yl~-3-methoxy-isocrotonic acid diphenylmethyl ester and about 5~ o~ the correspondinO crotonic acid derivative.
The reaction time wa~ 20 minutes in each case a~d the working up was oarried out a~alogously to the precedin~ ex~mple.

(~) ' ' .

- ..

~ G ~ ;
~ _ .

-, . ~ . ,~ .. . . . ,. . ; , .. .

J~ 7~S

~o I
~ ~ ~U~
a~ *, s~ o ~a .. .. .. 1~ -q~ ~ ~1 ~ ~ cn o~ ~D
0~3h ~ ? ~
~ .
~:~ . .
. ~
~ .
~1 .9~ U~
N ~ ~i ~i r~ ~ ~1 ~ 0 1~ 1~ . .
^U`.
~1~ .
. - . .
q~ ~
~ .~ . -~0~ ~
v ~q - -o ~
~ ~ o , ., -o~
~Q ~
~ ,, ~ s o ~ C~
.. . . ~

~. .. , .. .. ~ .. .. .. . . .. . ., . . , .. . . ~ . .
. . . . . . . . . . . .

Jl.~J~ 75S
a) The isomer mix~ure employed as the startin~ ~zterial can be obtained analogously to Example le) from 4 g (6.14 m of 2-r4-(p-toluenesulphonylthio)-3-phe1~oxyace~amido-2-oxo-aze~idin-1-yl]-3-hydroxy-crotonic aci~ diphenylmethyl ester and an excess of diazomethane solution in e~her. The result-ing isomer mixture consisti~g of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidln-l_yl]-3-met~oxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester (about 3:1) crystallis0s from ethyl ace~
tate/pentane and has a melting point o~ 150-152CI
The isomer mixtuh-e employed as the starting material, or the crotonic acid a~d isocrotonic acid de~i~ati~e5 can also be obtained a~ ~ollows:
ai) A solution of 698 mg (1 mM) o~ an isomer mix~ure con-sisting o~ 2-~4-(benzthiazol_2-ylthio)-3 phen~x~acetamido~2- . :
oxoazetidi~ yl~3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester in - 20 ml o~ acetone~water, 9:1 (v/~) is stirred with 341 mg ~1.3 mM) of sil~-er p-toluenesulphinate for 1 hour at room temperature. The yellow reaction mixture is diluted with 50 ml o~ acetone and filtered. The filtrate is concentrated by evaporation in ~acuo a~d the residue is chrom~tographed on 30 g o~ acid-washed silica gel using toluena/ethyl acet~te, 2:1.
An isomer mlxture consis~ing o~ 2-~4-(p-toluenesulphon~lthio)-3-phenoxyacetamido-2-oxo2ze~idin-l-yl]-3_methoxy crotonic acid diphenylmethyl e~ter and 2 ~4-~p toluenesulphonyl~hio)-3-phenoxyacetamido-2-oxoazetidin-l_y;~_3_methoxy-isocrotonic !
, ,~ ~2 acid diphenylmethyl ester is obtained.
aii) The reaction described under ai) can ~lso be carried out in tetrahydrolurane ins~ead o~ in acetone/water, in .~hich case the mixture must be stirred for about 24 hours at room temperature .
aiii) 0~21 ml (1.2 mM) of ethyl-diisopropylamine and 0.12 ml tl.5 ~) of fluorosulphonic acid methyl ester are added -~o a solution of 336 mg (0.5 m~) of 2-~4-(p-toluenssulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic ~~~
acid diphe~ylmethyl ester in 4 ml of ethylene chloride ~t 0C
and the mixture is stirred for 30 minutes at 0C and a further 30 minutes at room temperature. The reaction mixture is di~uted with e~hyl acetate, washed with saturated aqueous sodium chloride solu,,ion and dilute aqueous sodiu~ bicarbonate solution and dried over sodium sulphate. The residue which remains a~ter concen~rating by e~aporation is chrom~togr~phed o~ silira ge~, With toluene/ethyl acetate9 4:1, a lit~le start~ng ma~erial is first eluted. merea~ter, an ~somer mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenox~~
acetamido-2-oxoazetidin-1-yl~-3-methoxy~crotonic acid dipher.yl-methyl ester and the correspo~ding isocrotonic acid diphenyl-meth~l ester is isolated with toluene/ethyl acetate, 1 1D
ai~) 76 mg (0.55 ~$) o~ potassium carbonate and 00088 ml (0.92 mM) o~ dimet~yl sulphate are added to a sol~tion of 3C0 mg (0.447 mM) of 2-[4-(p-toluenesulphonylthio)_3_phenoxyacet-amido-2-oxoazetidln-1-y~]-3-hydroxy-crotonic acid diphenyl methyl ester in 4~ml of aoetone and the mixture is stirred fo~ ~
B -~
~ . .

. .
. .

. .. , .

:~.q3~ ss 5 hours at room temperature. The solution is then diluted with e~hyl aceta~e, washed with water and dried over sodium sulphate. After remo~ing the sol~ent, the residue is recrystallised from ethyl acetate/pentane, 2iving an iso~er mixture consis~ing o~ ~-[4-(p~toluenesulphonylthio)-3-phenoxy-acetamido-2-oxoazetidi~ yl~-3 methoxy-crotonic acid diphenyl-me~hyl ester and t~e cQrresponding isocrotonic acid diphenyl-methyl ester.
av~ 1.57 g of N,N'-dinitroso-N,~t'-dimethyloxamide are added to a solution of ~.73 g of 2-[4-(p-toluenesulphonyl~hio)-3-phenoxyacetamido-Z oxoazetidin-l yl]-~-hydrox~--croto~ic acid diphenylmethyl ester (crystalline) i~ 67 ml of absolu~e tetrahydro~urane at -20C, and thereafter a solution of 0.57 ml (0.51 g) o~ e~hylenediamine in 5 mI o~ tetrahydro~uL~ane is added o~er the course of 15 mi~utes. After ~he addition, ~he mixture is s~irred ~or 1 hour at 0C, 0.53 ml (11 mmo~) o~
glacial acetic acid and 6.7 g of Celite are added and the wllole is filtered. The residue is washed with-5 times 20 ml o~ tetrahydro,urane. The fil~rate and the wash liquids are combined, concentra-ted to approx. 20 g and mixed with 20 ml o~
hexane. The crystals are filtered o~f, washed with tetra-h~drofurane/hexane, 1:2, and dried under a high vacuum.
The crystals consist in the main o~ 2-~4-(p-toluene-sulphonylthio) -3-phenoxyacetamido-2-oxoazetidin-i yl~-3-methoxy~isocrotonic acid diphenylmethyl ester. A sample ls recrystallised ~rom ethyl ac~tate/diethyl ether and gives the ~ollowing analytical data: melting ~oin~ 167-169C; [a~20 =

7~
. .

:~ ~3~K75~
~30+1 (C=l; methylene chlorid~); thin layer chroma~ogram:
Rf value = 0.57 (silica gel; methylene chlorid~/ethyl ace- ~
tate/glacial acetic acid, 60:40:1); W spectrum (ethyl alcohol): AmaX = 260 m~ (E = 16,600); ~R spectrum (Nujol):
characteristic bands at 2.97; 5.62; 5.90; 6.27; 6.61;

6.66; 7.17; 7.53; 7.70; 7.96; 8.02; 8.2G; 3.80; 9.20;
10.26; 12.24 ~nd 13.30 ~. N~R spectrum (100 megacycles/
second, in CDC13): o 2.32 (s/~H3); 2.34(s/CH3); 3-73 (s/OCH3); 4.30~4044 (A~; J = 5/azetidine-4-CH ); 6.8-7.5 (m/l9 aromatic H, MH) ppm.
Apart from a little isocrotonic acid deri~ative, the mother liauor in the main contains 2-r4-(p toluenesulphonyl-thio)-3_phenoxyacetamido-2_oxoazetidin_1-yl]-3~methoxy-crotonic acid diphenylmethyl ester, which after chroma~ographic ~uri~icP-tion on silica gel has a melting point of 146~ 8C (correc-ted, lrom ethyl acetate/hexane); N~ spectrum (lOO megacycles se'cond, in CDCl3): ~ 2008 (s/vinyl-CH3); 2.26 (s/aromatic -C~3); 3-70 (s/-OCH3); 4.47 ~s/-OCH2CO-); 4.94 (dd~J = 5 and 8/azetidine-3-CH-); 5.83 (d/J-5/a~etidine-4-CX-), 6.8- -

7.5 (m/l9 aroma~ic H, -NH-) ppm; Ea]20 a ~. 21 ~ 1; (c = 19 methylene chloride).
a~) 3.7~ g (30 mmols) o~ dimet~yl~ulphate and 30 ml o~ 20 per cen~ strength aqueous potassium bicarbonate solution are added to a suspension of 6.72 g (10 mmols) of 2-~4-(p-toluene-sulphonylthio)-3-pheno~ acetamido-2-oxoaze~idin-1-yl~
hydroxy-crotonic acid diphenylmethyl ester (crystalline) and 0.36 g (l mmol) o~ tetra n-bu~ylammonium iodide in 100 ml o~
.
\

toluene a~d the mixture is stirred ~igorously for 4 hours at room temperature. During the ~irst 15 minutes, the solid dissolves. The mixture is diluted with toluene and washed with saturated aqueous sodium chloride solution. After dry-ing the organ~ c phase with sodium sulpha~e, and conce~' rati~g it, c~ystalli3a~ion ~rom ethyl acetate/diethyl ether gives 2-~4-~p-toluenesulphonylt~io)_3_phenoxyacetamido-2-oxoazetidi~-l-yl~-3-methoxy-isoorotonic acid diphenylmethyl e~ter.
avii) ~.08 g (3 ~mols~ of tetrabutylammonium iodide and 1.9 ml (2.52 g, 20 m~ols) of dimethylsulphate are added to a suspensio~ of 3.36 g (5 mmols) o. 2 ~4-(p-toluenesulph~r.yl-thio)-3-pheno-.~yacetamido-Z~oxoazetidin-l-yl~-~-hydro~y- -crotonic acid diphenyl~ethyl ester ~crystall~ne) in 15 ml o~.
carbon tetrachloride and 10 ml o~ water. The mixture is ~igorously stirred at room temperature and 1 N sodium h~-droxide ~olution is added to it by mea~s o~ an au~omatic titrator in suf~icient amount to kee~ t~e pH constant at 7Ø In the course o~ 4-5 hours~ 1.5-2 e~uivalents of sodium hydroxide solutio~ are consumed. The mixture is dilu~ed with eth~l acetate and water and a little sodium chloride is added. The orga~ic phase is dried over sodium sulphate and concentrated . .
by evaporation. me residue is crystallised from a little :
ethyl aceta~e/hexane, 1:1, and gi~es 2-[4-(p-toluenesulphonyl-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-iso-crotonic acid diphen~lmethyl ester.
The isomer mixtul~e em~loyed .:as the starting material can also be obtained ~ia the corresponding 2-ben2oxazole .
.~, ;., ~c~3 ' ._ .

~ 6~SS
derivativ~ as follo~rs:
a~iii) A solution of 10 g of 6-phenoxyacetamido-penicillanic acid diphenylmethyl ester l~-oxide and 3 g of 2-mercapto-benzoxazole in 25 ml o~ dry tetrahydro~urane is compl~tely concentrated by evaporation in vacuo. The ~oam which remai~s is heated to 120C (oil bath temperature) ~or 70 minutes, under a waterpump vacuum. The fused ~esidue ~s cooled and then chromatographed on 500 g o~ acid-washed silica gel, usir.g toluene/ethyl acetate~ 6:1 followed ~y 3:1. 2 [4 (Benzoxa701-2-yldithio)-~-phenox~acetamido-2~oxoazetidin-1-yl]-~-meihylene-butyric acid diphenylmethyl ester is obtained in the ~orm of a tYhite ~oam; IR spectrum (methylen.e chloride): character-istic bands at 5.6, 5.75, 5.90 and 6.7 ~.
aix) Approximately one equivale~t o~ ozone (in the form of an 2/3 mixture) is passed into a solution, cooled to ~70C, of 3.35 g o~ 2 ~4-(benzoxazol-2-yldithio)-3-pbeno~Jacetamido-2-oxoazetidin-1-yl]-3-methylene butyric aoid diphenylme-~hyl ester in 125 ml o~ ethyl acetate, until starti~g material is ~o longer detectable by thin layer chromatography (silica gel; ~oluene/ethyl acetata, 3:1). The solution i~ concen~
trated by evaporation to about 50 ml in vacuo, mixed with 5 ml of dimethyl sulphide and stirred until the potassium iodide/starch test no longer gi~es a reaction. The mixture is concentrated by e~aporation in va~uo, the residue is dis~
sol~red in 150 ml of be~zene and t~e solution is washed with ~ater. The organic phase is dried o~er sodium sulphate and con~entrated by e~aporatio~. The residue is chromatogra?hed ..
.. :. ~. ., -~6~55 on 150 g o~ acid-washed silica gel, usi~g tolue~e/ethyl ace-tate9 4:1. 2-~4-(Benzo~azol-2-yldithio)-~ phenoxyacet-amido-2-oxoazetidin-1_-yl]-3_hydroxy-crotonic acid dipkenyl~
methyl ester is obtained in the form o~ a white foam; IR
spectrum (methylene chloride): characteristic ba~ds a~ 5.~0, 5.90 and 6.0 ~.
ax) A solution of diazomethane in ether is added drop-wise to a solution of 1.7 g o~ 2-f4 (benzoxazol-2-yldithio~- :
3-phe~oxyacetamido-2-oxoazetidin~l_yl]-3-hydroxy-crotonic G acid diphenylmethyl ester in 12.5 ml of methylene c~loride at 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-tion in ~acuo and the residue is chromatographed on 80 g o~
acid-w~shed silica gel, using toluene/ethyl acetate, 2~
An isomer mix~ure consisting o~ 2-[4~(benzoxazol-2-yl-dithio)-~-phenoxyacetamido-2-oxoazetidin-1-yl~-3-methoxy-cro~onic acid diphenylmethyl ester ~nd the corresponding isocrotonic acid diphenylmethyl ester in the rztio of about 5:1 is obtair~ed; IR spectrum (me~hylene chloride): characteri~.tic bands at 5.60, 5.85 sh 9 5.90, 6.40 and 6.65 ~.
axi) A solutio~ of 682 mg (1 m~) o~ an isomer mixture con sisting of 2-~4-(ben~oxa201~ ldlthio)_3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-metho~y crotonic acid diphenylmethyl ester a~d the corresponding isocrotonic acid diphenylmethyl ester in 20 ml of acetone/water~ 9:1 (v/~) is stirred ~Yith 350 mg (1.3 mM) of sil~er p~toluenesulphinate Lor 90 minutes B ~

~ 7S S
at room temperature. The mixture is Liltered through Ceiite~
and the filtrate is concentrated to 5 ml in vacuo an.d extracted with 30 ml of methylene chloride. The methylene chloride phase is dried over sodium sulphate and concentrated by e~aporat~on in vacuo. The residue is chromatographed cn 30 g of acid-washed silica gel, using toluene/ethyl acetate, ~ and gives an isomer mixture consisting of 2-[4-(p-toluenesulphon~lthio)-3-phenoxyace~amido-2 oxoazeiidin-l~y-1~
3-metho~J crotonic aci~ diphenylmPthyl es~er and the corres-ponding isocroto~ic acid diphenylmethyl ester.
Exam~e 5 A so1ution of 300 mg (0.45 mmol) of the crystalline isomer mixture, obtainable acoording to Example 4a), consist-ing of 2-~4-(p-toluenesulphonylthio~3-phenox~cetamido-2~oxo-azetidin-1-yl]-3-methoxy-croto~ic acid diphenylmethy-l ester and the corresponding isocrotonio acid es~er, in ~ ml of dry 1,2-dimethoxyethane is stirred with 0.134 ml (O.g mmol) of 1,5-diazabicyclo~5.4.0~undec-5-ene at room temperaiure under ~itrogen. A~ter a reaction time o~ 40 minutes, the 301ution is cooled to 0C and 0~4 ml of aoetic acid, ~ollowed by 180 mg (1.36 mmols) of m-chloroperbe~zoic acid ~85~ strength) are added. '~he solution is stirred ~or 10 minutes at 0C under nitrogen, diluted with chloroform and washed wit~ dilute sul-phuric acid/sodium thio~ulphate, water and dilute sodium bi-carbonate solution. The aqueous phases are extracted with chloroform and the combined organic phases are dried over sodium sulphate, ~onoentra~ed in ~acuo and freed fro~ the ~7S
~ . .

,, ', ," . ' '"'," ,.', ''.' "' ''','.' '.' ,. '. " . ',' ' '" '' ' `.' " ~ "'' ' .

~0~6~S ~
solvent under a hi~h vacuum. The resulting cru~e produc' is separated on silica gel thick layer plates (running agen~ -e~hyl acetate, one development)~ The silica gel of the zone at R~ - 0.51 is extracted with ethyl acetateJ the resulting solution is concentrated and the residue is dried under a high ~acuum~ 7~-Phenoxyacetamido-3-me'vhoxy-ceph-3-em-~-^arboxylic acid diphenylmethyl ester l~-oxide is obt.ained as an oily resi-du~ which cryst~llises from methylene chloride/pent~ne, melting point 115-120C.
7~-Phenoxyacetamido-3-methoxy-ceph-3-em-4 carboxylic acid dlphenylmethyl ester la-oxide C2n be obtained by extract- -ing *he silica gel of the zone at Rf = 0.22 with ethyl acetate,~
~oncentrating the solution on a rotary evaporator and dryi~g the oily residue; melting point 175-180C (from chloro~orm), The same oompounds can also be prepared according to Example i) or ii):
i) A solution o~ 24.7 mg t36 mmols) o~ the crystallin~
isomer mixture o~tainable according to Example 4a), consisting O of 2-~4-(p-toluenesulphonylthio)-3_phenox~acetamido-2--oxo-azetidin l-yl]-~-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester, in 247 ml of dry 1,2-dimethoxyethane is stirred with 8.22 ml (54 mmols) o~ 1,5-diazabicyclo~5.4.0]undec-5-ene at room temperature under nitrogen. A~ter a reaction time of 40 minutes, the solu~ion i8 cooled to 0C and 3.73 ml of formic acid are ~dded, -~ollowed by 37.3 ml (108 mmols) o~ performic acid (prepared from 33 ml of hydro~en peroxide solution (30~ ~trength~ and ... . . .. . . . -- - : - ~

~o~ ss 100 ml o~ formic acid). The solution ~s stirred ~or 10 minutes at 0C under nitrogen, diluted wi-th chloro~orm and washed with dilute sulphuric aoid/sodium thiosul~h2te, water and dilute sodium bicarbonate solution. The aqueous phases are extracted with chloroform and the combir.ed organic phas~s are dried over sodium sulphate, concentrated in ~acuo and ~reed from the solvent under a high vacuum. The resulting crude product is crystàllised ~rom me~hylene chloride/pert~n~
and gives 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl es~er l~-oxide of mel~ing poin~ 115~120C.
ii) A solu~ion of 1.5 g (2.19 mmols) o~ the crystalline isomer mixture obtainable according to Example 4a), consisting -of 2-[4-(p-toluenesulphonyl-thio)_3 phenoxyacetamido-2 oxoaze-tidin-l yll-3-methoxy-crotonic acid diphe~ylmethyl ester a~.d the corresponding isocro~onic acid ester, in 7.5 ml of dry 1,2-dimethoxyethane, is stirred with 0.4~ ml (2.84 mmols) o~
1,5-diazabicyc~o[5.4.0]u~dec-5-ene at room tempera~ure under nitrogen. A~ter a reaction time o~ 40 mi~utes the solution O is c0016d to 0C and 0.375 ml (6~5~ mmols) of acetic acid are added, followed by 0.667 ml (4.8 mmols) of 7.2 N peracetiG
acid. The solution is stirred ~or 20 minutes at ~C under nitrogen and 0.24 ml o~ sodium bisulphite solution (20~
strength) is then added. 22.5 ml of water are added to the reaction mixture whilst stirring vigorously. Hereupon, a mixture of 7~-phenoxyacetamido-3 methoxy-ceph-3-em-4-car ~oxylic acid diphenylmetilyl ester l~-oxide and la-oxide crystallises ou~. The precipitate is ~iltered olf, washed ~ .. - . . .. - . . . . . . .

~ 08~ S
with water and drie~ under a high vacuum.
iii) 32.9 ml (216 mmols) of 1,5 diazabicyclo~5.4.0~undec-5-ene are added ~o a suspension o~ g8.8 g (14~ mmols) o~ 2-C4-(p toluenesulphonylthio)-3-phenoxyaceta~ido-2-oxoaz~tldin l~yl] 3-methoxy-isocrotonic acid diphenylmethyl ester in 988 ml ol 1,2-dimethoxyethane over the course of 2 minutes at room temperature, under a nitrogen atmosphere, whilst stirring. --The solution, whish is now clear, is s~irred lor a further 25 minutes at room temperature and then cooled to 0C whilst simultaneousl~ adding 14.9 ml (395 mmols) o~ form~c acid, and after cooling to -20C 149 ml o~ a mixture 04 66 ml OL hyd~o-gen peroxide ( 30% strength) and 1~4 ml o~ fo~mic acid (4~2 mmols o~ H202) are added dropwise. The reaction mixture is then stirred for 15 minutes at 0C and ~7 g of sodium thio-sulphate dissQlved in 500 ml of water are then added. About 300 ml of water are added over the course of one hour at 5C.
A~ter stirring ~or a ~urther 2 to 3 hours at 5C, the crystal-l$ne precipitate, which consists in ~he main of 7~-phenoxy- ;
acetamido ~-methoxy-ceph-3-em-4 carboxylic ac~d diphenylmethyl ester l~-oxide is fil~ered o~f, washed wi~h cold water (3C) and diethyl ether and dried oYer calcium chloride in a hi~h ~acuum.
7 litres of water are added ~o the fiItra~e at 5C, ~hil~t stirring vigorously. The initially oily precipitata, Which solidifies on standing overnight, and which consists predominantl~ of 7~-phenoxyacetamido-3-methoxy-ceph-3-em-4- ;
carboxylic acid diphenylmethyl ester la-oxide~ is ~ilter~d o~, B ~ :

1(3~il675~
washed with ice-ccld ~ater and dried over calciu~ chloridQ ir.
a hi~h vacuum.
i~) 34~35 g (50 mmols) o~ 2-~4-(p-toluenesulphonyl~hio)~3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-~thoxy-isocrotonic acid diphenylme~hyl ester are suspended in ~40 ml of tetra-hydro~urane a~ 20C under a ~itrogen atmosphere (the bulk of the material dissolves~. After rapid addition o~ 11.4 ml (75 mmols) of ~,5-diazabicyclo[5.4.0]unde~-5-ene9 the solut on is stirred for 15 minutes at 20C, l.g ml (30~2 mmols) o~
glacial ac~tic acid are then added and the mixture i~ concen trated to dryness in vacuo at 30C. The bro~m~ foamy residue is dissolved in 130 ml of methylene chlorile and the solution is washed successi~ely ~ith 60 ml of water, 30 ml of 0.5 ~
hydrochloric acid, 30 ml of water, 3G ml of 1 M ~aHC03 solu-tion and 30 ml of water. The aqueous phases are extracted ~-with ~Yice 10 ml o~ methylene chloride.
The combined methylene chloride phases are cooled to -10C without ~irst drying them, and 7.0 ml of peracetic O acid/acetic acid (containing ~50 mmols of peracetic acid) are added slowly (the temperature risi~g to ~ ~ 10C). After stirring for 15 minutes at 0C - 5~j the e~c~ss perace~ic acid is destroyed with aqueous sodium thiosulphate. The a~ueous phase is separated off and washed ~ith a little me~hylene chloride. The solution is dried o~er magnesium sulphate and concentrated in vacuo. The light yellow resi-dueg consisting of a mixture of 7~ phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester l-oxide and 7~-phsnoxyacetamido-3;methoxy-ceph-2-em_4_carboxylic acid ~ 7~

. . , . . . , ~ . ... . . . .. ..

-.,. ,: , . :. - . . -~ 0~6~S S
diphenylme~hyl ester l-oxide in ~he ratio of about 2:1, is dissolved in 120 ml o~ monoglyme at room temperature and ~0 ml of water are added, whereupon 7,B-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester 1~-oxide ~irst crystallises out. The thick crystal sludge is ~irst s-tirred for half an hour and ~hen 15C ml of wa~er are added over the course of about 5 hours at room temperature9 w~ilst stirring, whereupon 'he corres~ondlng l~-oxide also crystallises out. After stirri~g :Eor a total o. 17 hours, th~ mixture i5 cooled ~or 1 hour in arl iceba~h and then fil-tered, and the residue is washed with a little cosled mono-glyme/water, 1:1.5. The crystals ar dried for 16 hours over P205 in a high vacuum. 7~Phenoxy2cetamido-3-methox~-ceph-3~em-4-carboxylic acid diphenylmethyl ester l~-oxide, to which some of the correspondi~g l~-oxide still adheres, is obtained.
me l-oxides obtained can be further procassed as follows:
a~ A solution of 150 mg (0.275 mmol) OL 7~-phenoxyacet~
amido-3-methoxy-ceph 3-em-4 carboxylic ac~d diphenyimeth~l ester l~-oxide in 3 ml of methylene chloride and 0.1 ml of dimethylformamide is cooled to 0C and 188 mg (1.~7 mmols) o~
phosphorus trichloride are t~en added. The solution is stirred for 30 minutes at 0C, diluted with m~th~lene chloride and ~ashed with aqueous sodium bicarbonate solution. The ~`
aqueous phase is extracted with methylene chloride and the combined organic phases are dried o~er sodium sulpha~e and ~ 7~ ~
concentrated in vacuo. The re~ult~ng crude 7~-pheno~yacet-amido-3-methoxy_ceph_3-em-4-carboxylic acid diph2nylmethyl ester is recr~stallised from ether; melting point 120C.
ai) A suspension of 5.0 g (9.16 mmols) OL 7~-phenoxy-acetamido-3-methoxy-ceph 3-em-4-carboxylic acid diphenylméthyl ester la-oxide in 25 ml of methylene chloride and 1.25 ml of dimethylacetamide is cooled '~o 0C and 1.69 ml (1903 mmols) of phosphorus trichloride are then added. The solu~-ion is stirred for 30 minutes at 0G, dilu~ed with ethyl acetate and washed ~rith aqueous sodium bicarbonate solution. me aqueous phase is extracted with ethyl aceta~te and the combined organic ~ :
phases are dried over sodium sl~lpha~e and concentrated in vacuo7 me resul~ing crude 7~-phenoxyacetamido~ ethoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is recr~Jstal- - -lised from ether~ melting point 120C.
b) 0.87 ml of anisole is added ~o a solution o~ 2~0 g (3.78 mmols) of 7~-phenoxyacetamido-3-methoxy ceph-3-em-4-carboxylic acid d~phenylmethyl ester in 5 ml o~ methylene ohloride and the mixture is cooled to 0C and left to stard ~or 1 hour a~er adding 1.2 ml of trifluoroacetic acid. The reaction mixture is concentrated in vacuo and the resldue is . .
crystallised ~rom acetone/ether. 7~-Phenoxyacetamido-3- .
methoxy-ceph-3-em-4-carboxylic acid of melting point 170C
tdecomPosition) is obtained.
The same compound can also be obtained witkout iso- -lating the ester mentioned under a):
bi) A suspension of ~0O g (5.5 mmols) of a mixture o~ 7~-g~ , .
, ;'75Sphenoxyace'amido-~-methoxy~ceph-3-em-4-carboxylic acid diphenylmethyl ester l~-oxide and la-oxide ~n 15 ml of methylene chloride and 0.75 ml of dimethylacetamide is cooled ~o 0C and 0.966 ml (1.11 mmols) of phGsphorus ~richloride is then added. The solution is stirred at 0C for 40 minutes 4~65 ml (61 mmols) o~ tri~luoroacetic acid are then added and s~irring is continued for a further 30 minutes at 0C. The reaction solution is rendered neutral with saiurated sodium bicarbonate solution and the organic phase~is washed with dilute bicarbona~e solution. The combined aqueous phases are washed ~.Yice with 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 ~iltered ofl, washed with water and dried under a high vacuum; melting point 170C (decomposition).
bii) A suspension of 53.4 g ~g7.7 mmols) o~ 7~-phenox7 acetamido-3-methoxy ceph-3-em-4-carboxylic acid diphenylmet~yl ester l~-oxide ~from Example 5iii~ in 320 ml o~ met~ylene chloride and 16 ml of dimethylacetamide is cool~d to 0C and 17.3 ml (19~8 mmols) o~ phosphorus trichloride are added : :
slowly. After stirring for 20 minutes at 0 - 5C, 80 ml (1.05 mol~ of tri~luoroacetic acid are added dropwise. The clear solution is stirred for a further 20 minutes at 0 -5C and is then diluted with l,300 ml o~ ethyl acetate and washed successively with 240 ml of 2 M dipotassium phosphate solution, 100 ml of water and 250 ml of half-saturated aqueous sodium chloride solution. 7~-Phenoxyacetamido-3 methoxy-B~ ~
.

.. ~ . . . . ..

'7S5;
ceph-3-em-4-carboxylic acid is extracted fro~ the organic phase with 700 ml of saturated aqueous sodium bicarbonate solution and the aqueous portion is washed twice with 400 ml of ethyl acetate. The organic phases are extracted '~rice wit~ a total of 250 ml of a solution composed of 50 ml of saturated aqueous sodium bicarbonate solutio~ lCO ml of ~later and 100 ml o~ saturated aaueous sodium c'nloride solu~ion.
~ne combined bicarbonate extracts are covered ~.~ith 1,500 ml o~ ethyl acetate and the pH value of the ~olution is adjusted fj to ~ 2~5 wi~h 20% strength phosphoric acid, while s~irring ~igorously. The aqueous phase is re-extracted twice with 500 ml of ethyl acetate. The combined organic phases are.
dried o~er magnesium sulphate, ~iltered and concentr2ted b e~aporation in vacuo. The residue~ which cryst211ises, is . .
suspended in 130 ml of eth~l acetate and left to stand o~er-~igh~ at 10C. The pale yellow crystals of ~he resulting 7~-phenox~acetamido-~-methoxy-ceph-3-em-4-carboxylic acid are filtered off, washed with cooled ethyl acetate and dried to O constant weight under a.high ~acuum.
biii) A solution o~ 23.9 g o~ 7~-phe~oxyacetamido-3-methoxy-ceph-~-em-4 carboxylic acid diphenylmethyl ester la-oxide t~rom ExamPle 5iii] in 140 ~1 of methylene chloride and 7.2 ml o~ dimethylacetamide is cooled to 0C and a~ter slowly adding 7.8 ml of phosphorus trichloride the mixture is stirred for a further 20 minutes at 0 - 5C. 36 ml o~ trifluoro acetic acid are added dropwise to t~e reaction solution, and the mix.~ure is then stirred for a ~urther 20 mlnutes at 0 ~-.
~3 .:, , . . :..... , .... .- . , .... - - . - .. .
~, . .~, . ,,: : .. .. ... . : . . :

. ' ' ' . ' ' . . . ', '.. , ' .' , ~ ' ~ ~' , ' . '' `, ~ . ' ~ ' . ' ' ' , , ., ' ' ,, , ' ~

~ 0~6~55 5C and therea~ter worked up as described under Example 5 bii).
7~-Phenoxyacetamido-3_~e~hoxy-ceph-3-em-4-carboxylic acid is obtained in the ~orm o~ a li~ht yellow crystalline material.
c~ 0.7 ml (5.7 mmols) of dimethyl-dichloro-silane is added to a suspension of 2.55 g (7 mmols) o~ 7~-phenoxyacet-ami~o-3-methoxy-ceph_3-em_4-carboxylic acid and 2.9 ml (Z2.4 mmols~ of N,N~dimethylaniline in 11 ml of absolute methyler.e chloride under nitrogen at 20C and the mixture is then stirr~d ~or 30 minutes at the same tempera~ure. The resulting clear solution is cooled to -20C, 1.6 g (7.7 mmols) of solid phos-phorus pentachloride are added and the mixture is stirred for 30 minutes. A precooled (-20C) mixture o~ 0.9 ml ~7 mmols) o~ N,N-dimethylaniline and 0.9 ml of n-butanol is added over the course of 2 to 3 minute~ at the same temperature, 10 ml o~
precooled ( 20C) n-butanol are then added rapidly and the mixture is therea~ter stirred ~or 20 minutes at 2nc and 10 minutes without cooling. 0.4 ml of water is added at about -10C, th~ mixture is stirred for about 10 minutes ~n an iceW
bath (0C), 11 ml of diox~ne are then added and after stirring for a further 10 mi~u~es at 0C approx. 4.5 ml of tri-n-b~tylamine are added in portions unti~ samples diluted wi'h water assume a constant pH value o~ 3.5. After stirring ~or 1 hour at 0C, the precipitate is filtered off, washed ~.Yith dioxane and recrystallised ~rom water/dioxane. -The resulting 7~ amino-3-methoxy-ceph-3-em-4_carboxylic acid hydrochloride dioxanate has a melting point in excess o~ 300C. Thin layer chromatogram: R~ ~alue 0.17 (silica gel; system n-butanol/
.' ~.. , ~Y

.

1~8G';'55 carbon tetrachloride/methanol/~ormic acid/~ate~, 30:40:20:~:5).
ci) 3.~ ml (3.&7 g) of dimethyldichlorosilana are added to a suspensio~ of 11.75 g of 93 per cent streng~h (correspo~ding to 10.93 g of 100~ strength) 7~-phenoxyace~amido-~-metho~y-ceph ~-em-4-carboxylic acid and 13.4 ml (12~73 g) of N,N-dimethylan~ e in 47 ml o~ absolute methylene chloride (dis-tilled over P205) at ~ 20C under nitro~en, and the mixture is the~ stirred for ~0 minutes a~ the same temperature. T~e solution, whieh is no~ clear, is cooled to 18C/-19C ~nd 7.8 g of solid phosphorus pentachloride are addedg whereupon the internal temperature rises to -10C. A~ter stirring ~o~
30 minutes in a bath at -20C, the cl~ar solution is added dropwise, oYer the co~rse o~ approx. 7 minutes9 to a mixture, cooled to -20C, o~ 47 ml o~ n~butanol (anhydrous, dried o~er Si~san) and 4.4 ml (4018 g) of dimethylanilineO Here~lpo~, the interna~ temperature r~es to -8C. The mixtuL~e is st~r red for a further 30 minutes, init~ally in ~he bath at -20C
a~d subse~uently i~ a~ icebath (0C), so that a final internal :
t8mperature of -10C is reached. At this temperature, a mixture o~ 47 ml o~ dioxane and 1.6 ml of wa~er is added drop-wise (duration approx. 5 minutes). Hereupon, the product slowly crystallises out. A~ter stirring ~or a ~urther 10 mi~utes, the mixture, in a~ icebath, is brought to a pH value o~ be~Yeen ~.2 and 2.4, and kept thereat, ~y adding approx.
9.5 ml o~ tri-n-butylamin~ in portions ov~r the course of approx. 1 hour (the flrst 5 ml being added in the ~irst 5 minutes). Thereafter the product is ~iltered olf and washed 85~
~ - ' , . .
. ~ .

., .. . ., .. ~ , . . ., . .. , .. . .. ... . .. . . . . -~ ~ 7~S
in portion3 with approx. 30 ml o~ dioxane an~ ther. with apprcx.
15 ml ol methylene chloride~ thus gl~ing crystalline 7~-a~ino- -3-methoxy ceph-3-em-4-carboxylic acid nydrochloride dioxanate;
melting point abo~e 300C; W SpeC~rt~ (in Ool N sodiu~
bicarbonate): AmaX = 270 m~ (F - 77500); IR spectrum- (Nujol) charac.teristic bands at 5.62; 5.80; 5.88; 6.26; 6.55;
7.03; 7.4~; 7.72; 7~96; 8.14; 8.269 8~45; 8.64; 8.97;
9.29, 10.40 and 11.47 m~; ~a~20 ~ ~ 134~ ~ 10 (c - l; 0.5 N sodium bicarbonate solution).
The zwitter-ion of 7~-amino-3-methoxy~ceph-3-em-4-carboxylic acid can be obtained from the resul~ing hydrochlorid~
dioxanate by adding 2 N sodi~m hydroxide solution to a 20%
strength aqueous solu~ion o~ the diox~nate un~il the pH value is 4.1 (isoelectric po~nt); when ~ ered of~ and dried7 the product has a melting poin~ in excess of 300C. W spectrum (in 0.1 N sodium bic2rbon ~e sol~tion) AmaX = 270 nm (~ =
7,600). Thin layer chromatogram: R~ ~alue iden~ical with ~hat o~ the hydrochloride (silica ge~, same system); ~ a~ 20 =
232 1 1 (c = 1; 0.5 N sodium bicarbonate solution). -d) 1.65 ml o~ bis-(trimethylsilyl)-acetamide are added to a ~uspension of 1 g (2O82 ~mols) o~ 7~-ami~o-3-methoxy-ceph;
3-em-4-carboxylic acid hydrochlorids dioxanate in 20 ml of dry methylene chloride at room temperature under a nitrogen a~mosphere. A~ter 40 minutes, the clear 301utio~ iS cooled to 0C and 900 ~g (4.37 mmol~) o~ solid D-~-phenylglycyl chloride hydrochloride are added~ Fi~e minutes later, 0.7 m~
(10 ~ols) o~ propylene oxid.e is added. The suspension is ~
., , ,. ~ _ - ., , . .~, . . , . , , , . - : - .

- , .~. "...... ~ . . . .. .

~86'7S5 then stirred for 1 hour at 0C u~d~r a ni-trog~n atmosph-re and 0~5 ml of methanol is then added, whereupon 7~-(D-a-phenylglycylafflino~-3_me~hoxy-ceph-3~em-4-carboxylic acid hydrochlorid~ precipita~as in a crystalline form. The h~rdro-chloride is filtered o~ and d~ssolved in 9 ~1 of wate~, and the p~ o~ ~he solution iS adjus~ed to 4.6 With 1 N sodium hydroxide solu~ion. The dihydra~e of the inner salt of 7~-(D-~-phenylglycylamino)_3_methoxy_cep~_3 ~m-4-carboxylic aci d ~hiCh preCipitate~ is riltered o~, washed with acetone and diethyl ether and dr~ed; mel~ing point 174-176C (decom-position); ~a]~ = ~ 132 (c = 0.714; in 0.1 N hydrochloric acid); thin layer chromatogram (sllica gel): Rf ~alue ~ 0.18 tsYstem: n-butanol/acetic acid/water, 67 10 23)o UV Spec-trum tin 0.1 N aqueous sodium bicarbonate solution) A~aX =
269 ~ (~ _ 7,000); IR spectrum (i~ mi~eral oil): characteris-tiC bands at 5.72, 5.94, 6.23 and 6.6~ ~.

di) 1,37 ml (5.6 mmols) of M,~-bis-(trimethyls~lyl)-acet-i amide are added to a sus~ensio~ o~ 993 mg (4.3~ mmols) of 7 amino-3-methoxy-oeph~3-em-4-carboxylic acid (inner salt) in 10 ml o~ methylene chloride ar.d the mix~ure is stirred ~or 45 minutes at room temperature under a nitrogen atmosphere.
The clear solution is cooled to 0C and 1.11 g (5.4 mmo~s) o~
D-a_phen~lg~ycyl ~hloride hydrochloride are added. A~ter 5 -minutes, 0.4 ml (5.6 mmols) o~ propylene oxide is added.
The susp~nsion is then stirred ~or 1 hour al; ~C u~de~ a ~ltrogen atmosphere and t~erea~ter 0.6 ml of methanol i5 added.
7~ L~_~nenylglycyl~mido)-3 me~hoxy-ceph-3 em-4 carboxylic , .. . .. ... .. , - . . - .. . . . . ..

acid hydrochloride, which crystallises out, is filtered o~
and dissolved in 15 ml o~ water at 0C, and the pH OL the solut~on is ad~usted to about 4 with 5 ml of 1 N sodium hydroxide solution. The solution i~ warmed to room tempera-ture and its pH is brought to abou~ 4.8 with trietr.ylamine, whereupon 7~-(D-a-phenylglycylamido)-3-methoxy-ceph 3~em-4~
carboxylic acid crystall~es out in the ~orm o~ the dihydr~te.
Exam~le 6 A solution o~ 0 . 228 g (1, 5 m3~) of 1, 5-diazabicyolo-.~ .
[5.4.0]undec-5-ene in 10 ml of tetrahydro~urane is a~ded to solution o~ 0.697 g (1.0 mM) of a~ isomer mixture consisting of 2-~4-(benzthiazol-2-yldithio)_3-phel~oxyaceta~ido-2-oxo azetidin-l-yl]-3-methoxy-croto~ic acid diphenylmethyl ester a~d the corresponding isocrotonic acid diphenylmethyl es~er in 4 ml o~ dry ~etrahydrofura~e. me m~xture is stirred ~or 40 minutes at room temperature, d~ ted with 200 ml of benzene and washed successively with dilute hydrochloric acidl qodi~m bicarbo~ate solution and water. The organic phase ~s dried o~er sodium sulphate and the sol~ent is removed in ~acuo.
The re5ulting crude product is chromatographed on ~0 g o~
silica gel which has bee~ washed with hydrochloric acid.
Toluene/ethyl acetate, 7~ irst elutes 2-mercaptobenzthiazole and subsequently 7~-phenoxyacetamido-3-methox~-ceph-2-em-4~
carboxylic acid diphenylmethyl e~ter~ IR spectrum (in C~2C12):
5060, 5.74, 5.90 and 8.28 ~
The ester obtained can be con~erted into the gree acid as ~ollow~: .
.

. , .

.. . , . . . . . . . . ~ . . . .

. .~ , .

,.~, ' ' ~ . , ' ' ~ 0~75S
i) A ~ixture of 53 mg (0.1 mmol) o~ 7~-phenoxyaccltamido-3-methoxy-ceph-2_em_4~-carboxylic acid diphenylme~Jl ester, 0.07 ml o~ tri~luoroace~ic aoid, 0006 ml of anisole and 0.5 ml of methylene chloride is stirred for 1~ hours at 0C. The mixture is diluted with 5 ml of pentane/die~hyl ether, 3:1, and shake~ vigorously. The white, amor~hous 7~-phe~oxyacet-amido-3-methoxy-ceph 2-em-4~ carboxylic acid which precipita~s is ~iltered of~ and was~ed with pentane/diethyl ether, 3:1.
IR spectrum (~12C12): 5,60, 5.90 and 8.27 ~.
The s~ar~ing ma~erial can be obtained as follows:
a) 1 equivalent of ozone (diluted with oxygen) is passed into a solution, cooled to -70C, o~ 681 mg (1.0 mM) o~ 2-~4- :
(benzthiazol-2-yldithio) 3-pheno~yacetamido-~-oxoazetidin~
yl]-3-methylene~butyric acid diphenylmethyl ester in 30 ml o~
ethyl acetate. The reaction solution is ~llowed to w2rm Up, concentrated to 10 ml in vacuo, mixed with 1~0 m~ of dime~hyl -sulphide and stirred for 15 hours at room tempera'uL~e. Sol-~ent and excess reagent are remo~ed in ~acuo and the ~e~idue is c~romatographed on 30 g o~ acid-washed silica gel, using toluene/ethyl acetate, 4:1 (15 ml ~ractions). 2 r4-(~enz- -thiazol-2-yldithio)-3-phenoxyacetamido-2-oxoaze~idin~
3-~ydroxy-crotonic acid diphenylmethyl ester is ob~ained as a solid amorphous substance. ~a~D = 130 ~ 1 (CHC13; c =
0.8) IR spectr~m (CH2el2): 2.95, 5.60, 5.92, 6.04 and 8.10 u.
b? A distilled soluiion o~ diazomethane in ether (con taining 1.3 ~M of diazomethane) i~ added to a solutio~ o~
crude 2-~4-(benzthiazol-2-yldithio) ~-pheno~acetamido-2 oxo-.

~ .............. . ~ .. .... -.
.. ': ~, ' . ' ~ ' :, ' .

~ 0~6'7S ~
azetidin-l_yl3_3-hydroxy-crotonic acid diphenylmsth~J1 ester, obtained by ozonisation of 681 mO (1.0 mM) o~ 2-[4-(benz-thiazol-2-yldithio)_3_phenoxyacetamido-2-oxoazetidin-~ yl~-3-methylene-butyric acid diphen71methyl ester, in 5 ~1 o~
met~ylene chloride a~ 0C. The mixture is stirred for-on2 hour at 0C a~d washed with water, and the organ.ic layer is dried over sodium ~ulphate. Th2 sol~en~s are remo~ed in ~vacuo and ths residue is chromatographPd on 35 g of aci~-washed silica gel 3 using toluene/e~hyl acetate, 2:1. An isomer mixture consisting o~ 2-~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]_3-methoxy-crotonic ac~d diphenylmethyl es~er and t~e corresponding isocrotonic acid diphenylmethyl ester is obtained. IR spectrum (in ~H2C12): 5.60, 5~88, 6.67, g.l5 and 9,92 ~.
Examr~le~
Analogou~ly to Example 4, 200 mg (0.307 mM~ of an isomer mixture consisting of 2-~4~(p-toluenesulphonylthio)-phenoxyacetamido-2-oxoazetidin-1-yl~-3-me~hoxv-cro~onic acid 2,2,2-trichloroethyl ester and the correspondin~ iso- -crotonlc acid 2,2,2-trichloroethyl e~ter and 0~09 ml (0,6 ~.) o~ 1,5-diazabicyclo[5.4.0]undec-5-ene, on stirring ~or 30 minutes at room temperature in 3 ml of 1,2~dimethoxyethane, give an i~omer m~xture consisting o~ 7~-phenoxyacet2mido-~-me~hoxy-ceph-2-em-4-carboxylic acid 2,2~2-trichloroethyl ~ter and 7~-phenoxyacetamido-3 me~hoxy-ceph-3-em 4-carboxylic acid 2,2,2-trichloroet~yl ester (in the ratio of about 1:1).
R~ values ~ 0.36 and 0.18 respecti~ely (silica gel; toluene/

;~ 0 :

~ 0~7SS
ethyl acetate, 3:1).
The s~arting material can be obtained as 40110ws:
a) Analogously to Example lb), 498 mg (1 mM) o~ 6~
phenoxyacetamido-penicillanic acid 2,2,2-trichloroethyl ester and 200.7 mg (1.2 ~i) o~ 2-mercaptoben7.th~azole give .2;[4-(be~zthi~zol 2-yldithio)-3-phenoxyacetamido-2-oxoa7.e~idin-l-yl~-3-methylene-butyric acid 2,2,2-trichloroetllyl ester;
~elting point 144-149C tfrom methylene chloride/pentar.e), Rf ~alue = 0.5 (silica gel; ether3.
b) - Analogously to Example 6a), 647 mg (1 ~I) of 2-~4 (benz~hiazol-2-yldithio)_3_phenoxyacetamido_2-oxoaze~idin-yl~-3-methylene-butyric acid 2,2 7 2-trichloroethyl es~er and 1.2 e~u~alent~ of ozone, with subsequen~ splitting o~ the ozonide with dimethyl sulphide, give 2-~4~(benzthiazol-2-yldithio)-3 phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy- -crotonic acid 2,2,2-trichloroethyl ester; melting poi~t 129 130C (ether~petroleum ether).
c) ~nalogously to Example 6b), 5 g (7.71 mM) o~ 2-[4-(benzthiazol-2-yldithio)~3-phenoxyacetamido-2 oxoazetidin-l~
yl~-3-hydrcxy-crotonic acid 2,2,2-trichloroethyl e~te~ and an excess of diazomethane give the isomer mixture consisting of 2-[4-(benzthiazol-2 yldithio)-3-phenoxyacetamido-Z-oxoaze-tidin-l-yl~-3-methoxy-crotonic acid 2,2,~-trichloroethyl e~ter and the corre8ponding isocrotonic acid 2,2,2-trichloroethyl 0ste~; melting point 1700174C (from methylene chloride/ .
ether), d) Analogously to Example lc)7 1-9 g (2.87 mM) of an .. . , ... - . . .. ... . . ... . .

~86'7SS

isomer mixture consis~ing of 2-~4-(benzthlazol-2-yldithio~-3-phenoxyacetamido_2_oxoazetidin-1-yl~-3-me~hoxy-crotonic acid 2,2,2-trichloroethyl ester and the oorrespond~ng i~ocrotonic acid 2,2,2-trichloroethyl ester, on stirrin~ for ~ive hours a~ -room temperature with 0.~ g (4.05 mM) of silver p-toluenesul-phinate in 3~? ml o~ acetonitrile/ethyl acetate, 3:4, give a~
isomer mix~ure consisting o~ 2-r4-(p-toluenesulphonyl~hio~-3 phenoxyacetamido~2~oxoazetiain-1_yl]_3-met'noxy-crotonic acid 2,2,2 trichloroethyl e~ter and the correspondi~g isoç~otonic acid 2,2,2-trichloroethyl ester; melling point 1~?5-158C
(from ethyl acetate/ether).
Exam~le 8 , 0.02 ml (0.16 mmol) o4 trimethylchlorosila~e is added to a solution o~ 100 mg (0.145 mmol~ o~ 2-[4~(benzth~ azol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-hydroxy-crotonic acid diphenylmethy' e~ter i~ 2 ml of dry methylene chloride at 0CO 0.0477 ml (0.32 mmol) of 1,5-diaza~icyclo-E5.4-O~undec 5-ene is ~dded to this solu~ion ùnder nitrogen, whil~t stirring, and the mixture is stirred for a ~urther hour at 0C. A~ter addition of 0.2 ml of acetic acid9 the mixture is diluted wlth methylene chloride. The organic phase is successively washed with dilute sulphuric acid, water and aqueous sodium bicarbonate solutio~, dried over sodium ~ulpha~e and concentrated to dryne~s in ~acuo.
The resulting crude 7~-phenoxyacetamido-3~hydroxy-ceph~-em-4-carboxylic acid dipnenylmethyl e~ter is dis301~ed in me-thanol a~d a solutio~ of diazomethane ~n ether i~ added ' ~ : 9 . ::

at 0C. After 10 minutes, tile solution i~ care~ully con-centrated and the residue is dried under a high vaeuum. The residue is puri~ied by thick layer chromatography (toluene/
ethyl acetate, 3:1, silica gel). A~ter eluting the siiica gel of the zo~e a~ R~ = 0.17 with ethyl ace~ate, and concen-tra~ing the solution on a rotary e~aporator, 7~-p~enoxyacet-amido 3-methoxy-ceph-3-em-4 carboxylic acid diphenylmethyl ester is obtained; melting point 120C (from ether).
Exam~le 9 A solution o~ 266 mg (0.5 mM) o~ a crude mixture con-sisting of 2-C4-(benzthiazol-2_yldi-thio)-3-phenoY~yacetamido-2-oxoazetidin-l-y~ metho~J-crotonic acid chloride and 2-r4 -(benzthiazol_2-yldithio)_~_phenoxyacetamidoO2-oxoazetidin.
yl~-3 methoxy-isocrotonic acid chloride in 5 ml of dry methylene chloride i~ added dropwise o~er the course of 15 ml~utQs at 0C~ whilst stirring, to a solution of 0.10 ml o~
triethylamine in 0.5 ml of dry tert.-bu~anol and 3 ml of methylene chloride. A~ter a further 15 minutes stirring 9 the reactio~ mixture is diluted with methylene chloride, washed with water, with dilute hydrochloric- acid and again with water9 dried o~er sodium sulphate and concentr~ted by . .
e~aporation in vacuo. The r~sidue is chromatographed on 10 g Q~ acid-washed sillca gel, uslng toluene/ethyl acetate (4:1 as the running agent. 7~-Phenox~acetamido-3-methoxy-ceph-2-em-4-carbo~lic acid tert.butyl ester is obtained. IR
~pectrum (in CH2C12): characteristic bands at 5.60, 5.77, 5.90 and 8.29 ~.

~8~l;7S5 The star-ting matarial can be obtained as ~ollo~rs:
a) h mi~.~ure o~ 0.7 ml o~ trl~luoroacetic acid, 0.6 ml of anisole and 2.5 ml o~ methylene chloride is added slcwly to a solution of 698 mg (1 m~I) o~ a mixt~re consisting o~ 2_~4-~benzthiazol-2 yldithio)-~-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy_crotonic acid diphenylmethyl ester and 2-~4-(benzthiazol-2-yldithio)_3_phenoxyacetam~do-2_oxoaze~idin~
yl~ ~-methoxy-isocro~onic acid diphenylme~hyl ester in 1.5 ~1 of methylene chloride at 0C 9 while stirring. The reaci.ion mixture is stirred ~or 3 hour a~ 0~ and th~n shaken ~.rith 100 ml of ether/pentane~ 1:3, and ~he precipitate is filtered o~f. It consists of a mixture o~ 2-[4-(benzthiazo -2-yldi- -thio)~3-phenoxyacet~mido-2_oxoazetidin-1-yl]-3 methoxy crotonic acid and 2-~4-(benzthiazol-2-yldithio)-3 pher.oxy-acetami~o-2oxoazetidin-l~yl~-3-methoxy-isocrotonic acid 9 znd is washed with 25 ml o~ ether/pentane, 1:3, and dried in ~acuo.
IR spectrum (in ~H2C123: character~stic bands at 5.60, 5.80, - 5.94, 8.55 and 9.95 ~. ^
i~ b) A solution o~ 5~2 mg (1.0 mM) of a mixture con~isting o~ 2-r4-(benzthiazol-2-yldithio)-3-phenoxyace~amido-2-oxo-azetidin l_ylJ-3_methoxy_cro~onic acid and 2-[4-tbe~zthiazol-2-yldithio)-~-phenoxyacetamido-2-oxoazetidin-1-yl~ methoxy-~ 'iSocrotonic acid i~ 5 ml o~ dry dioxane, containing 10~ of oxalyl chloride 9 iS stirred for 15 ho~rs at room temperature and then concentrated by e~aporation in vacuo. The solid, non-crystalline res~due, consisting of a mixture of 2-~4-(benzthiazol-2~yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-- . :.; . . , . . . , . - , , .
- . , ~ . . . . .............. .. . . . .... . .

.. i ' ~ - : : - :.

~ 0~7SS
yl~-3~methox~-crotonic acid chloride and 2-~4-(benz~hiazol-2-yldithio~3-phenoxyacetamidc-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid chloride can be converted further without additional puri~ication. IR spectrum (in CH2C12): c~arac-~eristic band~ at 5.58, 5.90 and 9.95 ~
Exam~le 10 ~-A s~lution o~ 367 mg (0.5 mM) o~ a mixtu~e cons~sting o~ 2;[4-(p-nitrobenzenesu~phonylthio)-~-phenox-race~amido-2 oxo~zetidin-l-yl] 3-methoxy-crotonic acid diphe~ylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 152 mg (1.0 mM) o~ 1,5-diazabicyclo~5.4.0]undeC
5-ene in 10 ml o~ dry tetrahydro~urane is stirr~d for 40 :
minutes at room temperature. The reaction mixture is diluted with benzene, washed successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonata solution, dried o~er sodium st~lphate and f~eed from the sol~ent in ~acuo. Tha residue is chromatographed on acid-~ashed silica gel, using toluene/ethyl acetate, 7:1~ as the running agent, ~- whereby pure 7~-phenoxyacetamido-3-methoxy-ceph-2-em-4- .
carboxylic acid diphenylmethyl ester is obtained. Subsequent elution ~ith toluene/elhyl acetate, 2:1, results in th~ iso~
lation of a mixture which in additio~ to 7~-pheno~acetamido-3.-methoxy-ceph-2-em-4-carbo~ylic acid.diphenylme~hyl ester also contains 7~-pheno~yacetamido-3-methoxy-ceph-~-em 4 oarboxylic acid diphenylmethyl ester.
i . The starting materials c~n be prepared as ~ollo~s:
a) Analogously t~ Example 4ai), 348.5mg (0.5 mM~ o~ an ; ~
.

.
~086755 isomer mixture consistin6 o~ 2~ (benzthiazol-2 ylthio)-3-phenoxyacetamido-2~oxoazetidin-1-y~ -me~hoxy-crotGnic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 200 mg (0.68 mM) o~ silver p nltroben2enesulphinate, on stirring for one hour at 60C in 10 ml of acetone/water, 9:1, gi~e a mixture consisti~g o~ 2-~4-(p~nitrobenzenesulphonylthio)-3-phenoxyacetamldo-2~oxo-azetidin-l yl~-3-mathoxy-crotonic acid diphenylmethyl es~er and the corresponding isocrotonic acid diphenylmethyl ester. -_ Silver p-nitrobe~zenesulphinate is obtained by com-bining aa,ueous solutlons o~ equimolar amounts of silver nitrate and sodium p-nitrobenzenesulphinate. The precip~tate is ~iltered off ~nd dried in ~acuo ~or 24 hours at 50-60C.
~Q~ .
Analogously to Example 10, 351.5 mg (0.5 mM) o~ a~
isomer mixture consisting o~ 2-[4-(p-methoxybenzenesulphonyl-thio)-3-phenoxyacetamido 2-oxoazetidi~-l yl]-3~methoxy-crotonic acid diphenylmethyl ester and ~he correspondin~ iso-cro~onic acid diphenylmethyl ester, and 152 mg ~l m~I) o~ 1,5- ~
diazabioyclo[5.4.0]undec-5 ene~ give a mixture consisting o~
?~-phenoxyacetamido-3-methoxy-ceph~2-em-4-c2rboxylic acid diphenylmethyl ester and 7~-phenoxyacetamido-3-met~oxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, w~ich can be separated into the two isomers by chromatography~
The starting materials can be obtained as follow3:
a) An~logously to Example 4~1), 697 mg (1 ~1) o~ an omer mixture con~isting o~ 2-~4-(benzthiazol-2-ylthio)-3-~O~ '755ii phe..oxyacetamido-2-oxoazetidin-1-yl~-3-metho~y-cro~onic acid dip~.enylmethyl es~er and ~he corresponding isocrotonic acid diphenylmethyl es~er, and 361 mg (1.3 mM) o~ sil~er p methoxy-benzenesulphinateg on stirring for one hour a~ ro~m tempera-ture in 20 ml o~ acetone/~Jater, 9 1, give a mixture consisting of 2 [4-(p-methoxyben2enesu~phonyl'hio)-3-phenoxyace~amido-2-oxoazetidin-l-yl~_3_methoxy_crotonic acid diphenylmethyl es~er and the corre.sponding isocrotonic acid diphenylmethyl ester.

IR spectrum tin ~H2C12): characterl~tic bands ~t 5.60, 5.88, 6.18 and 8.76 ~. -Sil~er p-methoxybenzenesulphinate is obtained by co~-bining aqueous solutions o~ eq-~imolar amou~ts of sil~er n~'-rate~
and sodium p-metho~ybenzenesulphinate. rne precipitate is ~iltered O~L and dried in ~acuo for 24 hours at 50-60~C.
Exa~le 12 Analogously to Example 10, 336.3 mg (005 mM) o~ an isomer-mixture consisting of 2 (4-benzenesulphonylthio-3-phenoxyacetamido-2 oxoazetidin-l~yl)-3-methoxy-cro~onic acid diphenylmethyl ester and the corresponding isocrotonic acld diphenylmethyl ester, and 152 mg (1 mM) o~ 1,5~diazabicyclo~ . .
~5.4.0]undec-5-e~e, give a mixture consis'in~ of 7~-pheno~y-acetamido-3-methoxy-ceph-2 em 4-carboxylic acid diphenylmeth~rl e8ter and 7~-phenox~acetamido ~-me~hoxy-ceph-3-em 4-carboxylic acid diphenylme~hyl e~ter, which can be separated into the two isomers by chromato~raphy.
The starting materials can be obtained a~ ~o~lows:
a) Analogously ~o Example 4ai), 697 mg (1 mM) of an ,. ,: ` _ ~L

101~75S
isomer mi~ture consisting of 2~[4-(benzthia201-2-yl'~hio)-3-phenoxyacetamido-2-oxoazetidin_l-yl~-~-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 324 mg (1.3 mM) of sil~er benzene- -sulphinate, on stirring for 90 minutes at room temperature ir.
20 ml of acetone/water, 9:1, gi~e a miY~ture consisting o~
2-(4-benzenes~lphonylthio-3-phenoxyace~ami~o 2-oxoa~e~idin-1 yl) 3-methoxy-crotonic acid diphenylmethyl ester ~nd-the correspondin~ isocrotonic acid diphenyimethyl ester. IR
spectrum (in CX~C12): c~aracteristic ban~s at 5.60, 5.88 ard

8.74 ~.
Sil~er benzenesulphinate is obtained by combining aqueous solutions of equimolar amounts of silver ni~rate and sodium benzenesu~phinate. The precipitate is filtered olf and dried in ~acuo for 24 hours at 50-60C.
~ ' .
Analogously to Example 1, an isomer mixture consisting o~ 7~-phenoxyacetamido 3-methoxy-ceph-3-em~4-carbo~ylic acid C p-nitrobenzyl ester and 7~-phenoxyace~amido-3-metho~y-ceph-2-em-4-carbo-~y~ic acid p-n~trobe~zyl ester ca~ bs obtained ~rom ~he isomer mix~ure consisting o~ 2~r4-(p~toluenesulphonyl-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid p-nitrobenzyl ester and.the corresponding iso-crotonic acid ester, by stirring ~or 12 to 14 hours at room temperature with tetramethylguanidine in tetrahydrofur~.e.
Exam~le 14 A mixtur~ of 104.5 mg (0.15 ~) of an isomer mixtuLe ~ .
B ~

; . . . . ... . . .. .. . . . ... . . . . . . .
. .. ~ . ` .. ~ . ~. ... - .- . .. .. - . .. . .. . . . - . .. .. . . . . . .
.. .. . ........... ... ... ~ . ..... .... . .. ... ...... ............ .. .. . ..

~O~
consisting o~ 2-~4-(benzthiazol-2-ylthio)-3-phenoxyacetamido- -2-oxoa~etidin-1-yl~-3-methoxy-crotonic acid diph~nylmethyl ester and the corresponding isocrotonio acid diphenylmethyl ester, 35 mg (0.225 mM) of p-toluenesulphinic acid and 80 mg (0.525 mM) o~ 1,5-diazabicyclo~5.4.0]undec-5-ene in 3 ml of dry tetrahydro~l~rane is stirred ~or 40 minutes at room tem-perature. me mixture is dilu~ed with benæene and washed successively with dilute hydrochloric acid, with dilute aqueous sodium chloride solutioni wi~h 0.5 N sodium h~droxide solutio~ and again with dilute aqueous sodium chloride solu~ion.
me organic phase is dried over sodium sulphate and freed from the solvent in vacuo. Chromatography of the residue on 3.5 g o~ acid-washed silica gel, using toluene/ethyl ac tate, 7:1, ~rst gi~es pure 7~-phenoxyacetamido-3-methoxy-ceph~2-em-4a-carboxylic acid diphenylmethyl ~ster. Toluene/ethyl acetate, 2:1, subsequently elutes 7~-pheno~yace~amido-3-methoxy-ceph-3-em-4-carboxylic acid diphe~ylmethyl ester.

A mixture o~ 141 mg (002 mM) of 2~4-(o-methoxybenze~e-s~phonyl~hio)-3-phenoxyacetamido-2-oxoazetidin~l-yl]-3 methoxy-crotonic acid diphenylmethyl ester and 61 mg ~0.4 mM) o 1,4-diazabicyclor5.4.03undec-5-ene in 4 ml o~ dry tetra-hydro~urane is stirred for 70 minutes at room temperature.
Working up a~alogously to Example 10 gi~es a crude mix~t-~re oon~isting of 7~-phenoxyacet~mido-3-methoxy-ceph-2-em-4a-carboxylic acid di~henylmeth~Jl ester and 7~-phenoxyacetamido-~methoxy-ceph-3-em-4 carboxylic acid diphenylmethyl ester in :~ ' ~6'~SS
the ratio of about 4.4 : 1, which can be separated into ~he two isomers by chromatography on silica gel, analogously to Example 10.
The two compounds are produced in approximately the same ratio i~ 141 g (0.2 mM) of 2-[4-(o-methoxybe~2~ne-3ul-phonylthio)-3-phenoxyacetamido-2-oxoazetidin-l-yl~-3-methoxy-isocrotonic acid diphenylmethyl ester are treated analogously.
The two isomeric starting materials can be obtainQd as .
follows:
a) 3.49 g (5 mM) o~ an isomer mixture conslsting of 2-[4-(benzthiazol-2-ylthio)_3_phenoxyacetamido-2-~xoazetidin-l-yl~-3-methoxy crotonic acid diphenylmethyl ester and the corres- .
~onding isocrotonic acid diphenylmethyl ester in the ratio o~
about 4:1 are stirred with 1.82 g ~6.5 m~I) of si7ver o- -methoxybenzenesulphinate in 100 ml of acetone/water, 9~ or 130 minutes at room temperature. The mixture is filtered ar.d the ~iltrate is concentrat~d by evaporation in ~racuo. The residue is chromatographed on 140 g o~ acid-~ashed silica gel, 3 usi~g toluene/ethyl acetat~ 1. 50 ml ~ractions are collected; of these, ~ractions 7 to 13 contain purP 2-[4-(o-methoxybenzenesulphonylthio)-3-phe~oxyacetamido-2-oxoazetidin;
l-yl~-3-methoxy-isocrotonic acid diphenylmethyl ester, IR
spectrum (CH2C12): 5.609 5.909 8.72 and 9.15 ~, and ~raction 25 and the subseque~t fractions.give pure 2-[4~(o_methoxybenzene ~ulphonylthio)-3-phenoxyaceta~ido-2-oxoaze~idin-1-yl]-3-methoxy-crotonic acid diphenyImethyl ester, IR spectrum tCH2C12): 5.60~ 5.90, 8.20, 8.30, 8.729and 9.80 ~. Erac- ~
.

~ ' /~ :

t:~'7'SS
tions 14 to 24 contain mixtures o~ ~he ~o isomers.
Exam~le 16 A mi~ture o~ 57 mg (0.1 mM) of crude 2_r4-(o-me~hoxybenzenesul~honylthio)-3-ph~noxyacetamido-2-oxoazetidin~
l-yl~-3-methoxy-isocrotonic acid chloride and 43 mg (0.3 ~M) o~ 1,5-diaza~icyclo~5.4.0]undec-5_ene in 2 ml of dry me~hylene chloride is stirred for 80 minutes at room temperature. The mixture is diluted with metnylene chloride; was~ed with dilute hydrochloric ac~d and water, drie~ o~er sodium sulphate and ~reed from the solven~ in vacuo. The residue is dissol~ed in 005 ml ol methylene chloride, 5 ml o~ pentane/diet~yl ether, :-3:1, are added, and the mixture is shaken. The precipi~ate is filtered o~f and washed with pentane/diethyl ether, 3:1.
It consist~ of fairly pure 7~-phenoxyacetamido-~-methoxy-ceph-2-em-4-carboxylic acid.
me starting material can be o~tained as fo~lows:
a) A mixture of 703 mg (1 mM) of pure 2-r4-(o-metnoxy~
benzenesulphonylthio)-3 phenoxyacetamido-2-oxoazetidlnl-yl~
.C3 3-methoxy-isocrotonic acid diphenylmet~yl ester, 0.7 ml of trifluoroacetic aci~ and 0~66 ml of a~isole in 4 ml of methylene chloride is stirred for 3 hours at 0C. 50 ml o~ :
pentane/diethyl ether, 3:1, are then added to the mixture and ~.
the whole is shaken ~igorously. The white precipitate of pure 2 r4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2_oxoazetidin-l_ylJ-3_methoxy-isocrotonic acid is filtered - -~ of~ and washed with pentane/diethyl ether9 3:10 IR spectrum (CH2C12):. 5.60, 5.93, 6 25 and 8.72 ~.

7 ) / 0 /

~ 86~7SS
b) One drop of dimethylform2mide in dioxane is added to a solution of 54 mg (0.1 mM) of 2-r4-(o methoY~ybenze~.esul- -phonylthio)-3-phenoxyacetamido-2-oxoaze~idin- -yl~-3-me~hoxy-isocrotonic acid in 0.5 ml of a 10% strength solution o~
oxalyl chloride in dioxane, whereupon an e~olution of gas occurs immediately. The mix~ure is stirred for 2 hours at room temperature and the solvent and the excess oxalYl -chloride are e~a~orated c~ in ~acuo. The residue is dried i~ a high vacuum and gi~es 2-t4-(o-methoxybenzenesul~honyl- -thio)-3-phenoxyacetamido_2_oxoazetidin-1-yl~-3-methoxy-iso-crotonic acid chloride in the form o~ a~lightly orange-coloured foam, IR spectrum (CH2C12): 5.60, 5.90 and ~.70 ~.
Exam~le 17 __ A solution of 200 mg (0.254 mM) o~ 2-~4-(p-~oluene~
sulphonylthio)-3-(D-a-tert.-butoxycarbo~y?amino-a-phenyl acetylamino)-2-oxoazetidinOl-yl~-3-methoxy~crotonic acid diphe~ylmethyl ester in 2 ml of dimethylformamide is stirred with 57 ~1 (0.38 ~M) o~ 1,5-diazabicyclo[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 hydro-chloric acid until lt gives an acid reaction, and with : -.
saturated aqueous sodium chloride solution ur.til it ~i~es a neu~ral reaction. The organi~ phase is dried over sodium sulphate and concentrated by e~aporation in vacuo. The residue is chromatographed o~ silica gel thick layer plates, using toluene/ethyl acetate, 1:1, as the running agent. 7~-~D-~-tert.butylcarbo~ylamino-~-phenylacetylamino) 3-~Pthoxy-`B ~ ~

.. .. .. , . .. . . . ... ., . . . ~; . . . . . .. . . . . ...

~ 0816';'S5 ceph-2-em-4a-carboxylic acid ~iphenylme~hyl es~er o~ melting point 166-168C (methylen~ chloride/pentane); thin layer chromatogram (silica gel; diethyl ether): R~ value ~ 0.51;
W spec~rum (in ethanol): ~max = 257 m~ (~ = 3,500); IR
spectrum (in methylene chloride): characteristic bands at 2.96, 5.63, 5074, 5.85 (shoulder), 5.92, 6.16, 6.64 and 6.72 ~;
and 7,B-(D-~-tert.~utylcarbonylamino-~-phenyl-acety~amino)-3 me~hoxy-ceph-3-eln 4-carboxylic acid diphenylmeth~l ester o~
melting point 162-163~ (diethyl ether); thin layer chromat~-gram: Rf value:~ 0.33 (silica gel, diethyl ether); W
spectrum (in ethanol) ~max - 265 m~ (~ = 6,600); 280 m~
(shoulder) (~ = 6,200); XR spectrum (in m~thylene chlorid~
2.92, 5.58, 5.64 ~shoulder) D 5.82, 6.22 and 6.67 ~ are obtained.
The compou~ds obtained can be converted further as ~llows:
a) A mixture of 8,8 g o~ 7~ (D-a-tertObutoxycarbonyl-amino-a-phenyl-ace~ylamino) 3-methoxy-~-cephem-4-carboxylic f~ acid diphe~ylmethyl ester. 8.6 ml of anisole and 145 ml o~
trifluoroacetic acid is stirred for 15 mi~utes at 0C, 400 ml of pre-cooled toluene are then added and tlle mixture is con-centrated by e~aporation under reduced pressure. The residue is dried unde~ a high vacuum, digested with die~hyl ether and fil~ered of~. This gives the trifluoroacetate of 7~-(D-a-phenyl-glycylamino)-~-methoxy-3-cephem-4-carboxylic acid in the ~orm of a powder. The material is dissolved in ?0 ml of . water, the solution is washed with-twice 25 ml o~ ethyl ~:

~ 6~S
acet~te and the pH is adjusted to a value o~ about 5 ~rith ~
20~' strength solution o~ trlethylamine in methanol, whereupon a colourless precipitate forms. This mixture is stirred ~or one hour in an icebath, 20 ml of ace~one are then added znd the whole is left to stand for 16 hours at about 4C. The colourless precipitate is filtered o~f, washed wi~h acetone and diethyl ether and dried under reduced pressure. This gives, in the form of a micro-crystalline powder~ 7~-(D-a~
phenyl-glycylamino)~3-methoxy-3-cephem-4-carboxylic acid as the i~ner salt, which furthermore is present in the form o~ 2 hydrate, melting point 174-176C (with decomposition);
[a]20 - ~ 149 (c = 1.03 in 0.1 N ~ydrochloric a¢id~; thin layer chromatogram (silica gel; de~elopment with iodine):
Rf ~V0.36 (sys~em: n butanol/pyridine/acetic acid/water, 40:24:6:30); ultraviolet absorption spectrum (in 0.1 N
aqueous sodium bicarbonate solution): A~aX = 267 ~ (E = 6,200)$
i~ra red absorptio~ spec~rum (in mineral oil): characteristic bands, inter alia~ at 5.72 ~, 5.94 ~, 6 ~ ~ and 6.60 ~.
b) A mixture o~ 0.063 g of 7~-(D-~-tert.butoxycarbonyl-amino-~-phenylacetylamino)-3-methoxy-2~cephem-~-carboxylic acid diphenylmethyl ester, 0~1 ml of anisole and 1.5 ml o~
tri~Iuoroacetic acid is le~t to stand ~or 15 minutes at 0C
and is then concentrated by e~aporPtion under reduced pressur~.
me residue is digested with diethyl ether, ~iltered off and dried. The colourless and pulverulen~ tri~luoroacetate of ~
7~-(D-~-phenylglycylamino)-3~methoxy-2-cephem-4a-carboxylic acid, thus obtainable, is difisolved in 0.5 ml of water and the ; ' :

~ 6~755 pH oi~ ~he solution is adjusted ,o a ~alue o~ about 5 ~y drop-wise addition o~ a lO~o streng~h solut~on o~ triethylamine in methanol. The mixture is st~rred for one hour in an icPb~th and the colourless precipitate i~ filtered off and dried in a high ~acuum. This gives 7~-(D--phenylglycyl~mino)-3-methoxy-2-caphem_4a_carboxylic acid as the inner s~ hin layer chromatogram (silica gelS development with io~in~):
Rf~ 0.44 (system: n-butanol/pyridine/acetic acid/water, 40:
24:6:3Q); ultraviolet absorption spectrum (in 0.1 N aqueo~2 ~ .
sodium bicarb~nate solution): ASh~ulder c) A solution of 0020 g o~ 3;;chloro perbenzoic acid i~
5 ma o~ methylene c.hloride is added to a solution, ~oled ~o 0C, o~ 0~63 g o~ 7~-(D-a-tert.-buto~ycarbonylam~no-a-phenyl-acetylamino)-3-metho.Yy-2-cephem-4_carboxylic acid diphenyl-methyl es~er in 25 ml of methylene chloride. The m-ix~ure is stirred ~or ~0 minutes at 0C, 50 ml o methylene chloride are added ar.d the whole is washed successively ~ith 25 ml o~
a saturated aqueous sodium bicarbonate solution and 25 ml o~
a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated by e~aporation under reduced pressure. The residue i~ crystal-lised ~rom a mixture o~ methylene chloride and diethyl ethe~;
this giYes 7~-(D-a-tert.~butoxycarbonylamino-a-phenylace~yl- -amino)-3-methoxy-3-cephem-~-carbo~ylic acid diphenylmethyl ester l-oxide in the form of colourless needles, melting point 172-175C; thin layer chromatogram (silica gel): Rf~
0.44 (system: ethyl acetate; developme~t with iodine v~pour);

- , , ~

i'7SS
.. .~
ultraviolet a~sorption spectrum (i~ ethanol): Amay - 277 m~
7~200); infra-red absorption spectrum (in methylene chloride): characteristic ban~s ~t 2.96 ~, 5.56 ~, 5.71 ~, ~ ~ 5.83 ~ 7 5.90 ~, 6.27 ~ and 6.67 ~ .
.; . d) 2.80 g of phosphorus trichloride are added to a solu-.~ tion, cooled to 10C, o~ 0 g of 7~-(D-~-tert. butoxy~
.. ; . .
j ca~bony~am~o~a-phenylacet~Jlamino)-3-methoxy-3-cephem-4-~ carboxylic acid diphenylmethyl ester l-oxide in 30 ml- o~
J dimet~yl~ormamide, whilst excluding air. After standing ~or 15 minutes, tke reaction mixture is ~oured out onto a mixture of ice and an aqueous dipotassium hydrogen phos~hate solution;
the aqueous mixture is extracte~ with twice 100 ml of ethyl acetate. The organic ext.ract i~ washed with a sat~J~ated aqueous sodium chloride solution, dried o~er sodium sulpha~e and evaporated~ Th~ residue is chromatographed on silica gel; amorphous 7~(D-~ tert.~butoxycarbo~yl2mino-a-phenyl acetylamino) 3-methoxy-3-cephem-4 carboxylic acld diphenyl-methyl ester is eluted with diethyl ether as a substance which is pure accordlng to thin lay~r chromatography, R~ Q.39 (system: diethyl ether; de~elopment wi~h iodine Yapour);
. ~J~ 1 ~ 1 (c - o. 981 i~ chloro~orm); ultraviolet absorption ~pectrum (in ethanol): ~m æ = 264 ~ ~ = 6,300);
infra-red absorption spectrum (i~ methylene chloride):
characteristic bands at 2.94 ~, 5.~2 ~, 5.84 ~, 5.88 ~, :
6.25 ~ and 6.70 ~
me starting material oa~ be obt~ined as ~ollows:
e) 16.5 ml (0.12 ~mol) of chloro~ormic acid isobutyl B ~6 ., ':
, . , ... ~ ~ . , ,, .. ... . ,.. - , . - .

"` . ~V~'75~

ester are add~d to 2 solution, cooled to -lSUC, of 31/2 æ
(0.12 mmol) o~ D-N-tert.butox~carbonyl-phenylglyoine and 16.7 ml (0.12 mmol) o~ trietnylamine in 300 ml of tetrahydro-~urane and the mixture is stirred for 30 minutes at -10C.
A solution o~ 21.6 g (0.10 mmol) o~ 6-amino-penicillanic acid and 15.4 ml (0.11 mmol) of triethylamine in ~00 ml of ~etra-hydro~urane/wa~r, 2:1~ is th~n added. The reaction mixture . is stirred ~or 1 hour at 0C and 2 hours at room temperature whilst keeping the pH value constan~ at approx. 6.9 by addi~g ~ triethylamine. The react~on miY~ture is ad~usted to pH 2.0 at 5C by means of phosphoric acid and is sat~rated with sodium chloride and eY.~racted with three times 50C ml of ethyl -acetate; ~he organio phase is washed wit~ saturated aqu~ous godi~m chloride solution, dried oYer sodium sulpha~e snd concentrated by eva~oratlon. The crude ~-tert.butoxycar-bonyl-ampicillin obtRined i~ th~ form o~ a light yellow ~oa~
has an Rf ~alue o~ ~0.65 in a thin layer chromatogram (silica gel; ethyl acetate/n-butanol/pyridine~acetic acid~
~-~ wa-ter, 42:21:21:6:10~. .
f) ~.6 ml of 30% strength hydrogen ~eroxide (0125 M) are added to a solution of 57.22 g o~ crude.N-tert.butoxy-carbonyl-ampicillin in 100 ml o~ g~acial ace-tic acid o~er the course of 10 mi~utes and the mixture is stirred ~or 2.5 hours ~t roo~ temperature. The re2c~ion mi.xture i5 then poured o~to 2 1 of ice wat~r and t~e N-tert.b~oxycarbonyl-ampicillir,.~
l-oxide obtained in the ~orm o~ a voluminous ~recipitate is ~iltered off, well washe~ with watQr and dried in ~acuo.
/~7 ~.o~yss A further ~uan~ity o~ crude N-tert.butylcarbonyl-ampicillin l-oxide can be obtained by extracting the ~iltrate ~rith ethyl -acetate. Thin layer chromatogram (silica gel; ethyl acetate/
n-butanol/pyridine/acetic acid~water, 42~ 21:6:10): Rf ~alue ~ 0.30.
g) ~ solution of 42 g (0~23 ~) o~ diphe~yldiazomethane in 1~0 ~1 o~ dioxane is add~d to a mixture of 67.7 g of crude ~ tert.bu~oxycarbonyl-am~iclllin i-oxide in 380 ml ol dioxane -and the whole is stirred for ~05 hours a~ room temperature.
After addi~g 5 ml o~ glacial acetic acid, the mixture ~s con-centrated by evaporation in ~acuo. The residue is digested with petroleum ether, the petroleum et~er extract is discarded and the residue is crystalliged from me~hylene chloride/ether~
hexane. N-tert.Butoxycarbonyl-ampicillin l-oxide dip~eny~-methyl ester o~ melting point 164-166C is obtained; [a]20 =
~ 1l? ~ 1 (c = 1, CHC13); IR spectrum (methylene c~loride): ~
characteristic bands at 2.91~ 2.94, 5,54, 5~699 5.82 (shoulder), 5.88~ 6.60 and 6.68 ~; thin layer chromatogram: Rf value 0.23 (silica gel; toluene~ethyl acetate, 3 1)o h) A mixture o~ 11.2 g (17.7 mmols) of N~tert.-bu~oxy-carbo~yl-ampicillin l oxide diphenylmethyl ester and 3.26 g :
(19.5 mmols) o mercaptobenzthiazole 1~ 170 ml OL toluene is boiled for 3 hours in a re~lux app~ra~us equipped wit~ a water sepqrator, and is then concentrated by evaporation. The residue is chromatographed o~ silica gel, u~ing toluene/e~hyl acetate~ 3:1~ as the elut~ng agent and gi~es amorphous 2~4- :
(b~nzthiazol-2-yldi~hio)-3~ ert.butoxycarbonylamino-~-i~v j O ~ , , c~

. ... - . ., . .. , ~ . ~, . - ..

, SS
phenylacetylamino)-2-oxoazetidin~ 3-methy~ene-butvric acid diphenyl~:aethyl ester, thin layer chr~ma'~ogram: Rf value ~0.37 (silica gel; toluene/e~hyl acetate, ~1); IR spectrum (methylene chloride): characteristic ~ands at 2.94, 5.64, 5.76, 5.86 (shoulder), 5~91 and 6.71 ~. -i) 0.868 g (3.46 mmols) of silver toluenesulphinate is added to a solution o~ 2034 g (3.0 mmols) of 2-[4-(benzthiazol-2-yldithio)_3-(a_tert.bu~oxycarbonylaminora-phenyl2cetylamino)-2-oxoazetidin-l-yl~ me~hylene-butyric acid diphenylmet~lyl J ester in ~0 ml of acetone/water, 9:1, at 0C, and the mixture i~ stirred for 1 hour in an icebath. The precipita~e which has separa~ed out is filtered o~. The filtrate is t~ken up in tolue~e and eY.tracted by shaking with saturated aqueous sodium chloride sol~tion. The organic phase is dried oYer sodium sulphate ar.d, after e~aporation, gi~e~ amorphous 2 [4 (p-toluenesulphonylthio)-3-(a tert.butoxycarbonylamino~-phenylacetylamino)-2-oxoazetidin 1-yl]-3-me'hylene-bu~yric acid diphenylmeth~l ester; thin layer chromatogram: Rf `~ ~alue ~0.3~ (silica gel; toluenelethyl acetate~ ~:1); IR
spectrum (methylene chloride): characteristic bands at 2.93, 5.57, 5.70, 5.82~ 6.21 and 6.65 ~.
J) An ozone/ox~gell stream (0.5 mmol per minute) is ~as~ed ~or 7 minutes i~to a solution, cooled to -70C, o~ 2.30 g (3~.0 mmols) of 2-~4-(p-toluenesulphonylthio)~3-(a-tert.~utox~-carbonylamino-a-phenylacetylamino)-2 oxoazetidin-l-yl~-3-methyIene-butyric acid diphenylmethyl ester in 230 ml of methyle~e chloride. After adding l ml of dlmethyl sulphide, _ ~5 .. , : , .

~:186'~'S~

the solution is s~irred ~or a ~urth~r hour without coGlirg and is then concentrat~d by evapoi~ation in vacuo. The residue is recrystallised ~rom methylene chloride/ether/h~xane and gi~es 2-~4-(p-toluenesulphonylthio)-3-~a-tert.bu~oxycarbonyla2ino-a-phenylacetylamino)-2-oxoazetidin-1-yl~-3-hydro~y-cro~onic acid diphenylmethyl ester of melting point 182-184C; W
spectrum (e~hanol): AmaX = 259 ~ = 13,400~; IR spectrum (methyler.e chloride): characteristic bands at 2.92, 5.59, 5.83, 5.92, 6~0~ (shoulder)~ 6.18 and 6.68 ~; thin la~Jer chromatogram: R value ~ 0.55 (silica gel; toluene/ethyl ace~ate, 1~
k) A solu~ion of 0.54 g (0.7 mmol) of 2-[4 (p-toluene- :
sulphonylthio)-3-(a~tert.bu~ox~carbonyl2mino-a~phenylacetyl~
amino)~2-oxoazetidin-1-yl]~3-hydroxy-cro~onic acid diphenyl-methyl ester in 20 ml o~ methylene chloride/methanol, 1 is stirred for 15 minu~es with an excess o~ a solution o~
di~zomethane in ether at 0C and is then concentrated by e~aporation in vacuo. Prepara~ive l~yer chromat~gra~hy of ~he residue on silica gel, using toluene/ethyl acqtate 9 ~
as the runnlng agent, and elution o~ the zone which is visible in W light gi~es 2-~4-(p-toluenesulphonylth~o)-3 (a-tert.
butoxycarbo~ylamlno-a-phenylacetylamino~-2-oxoazetidin-1-yl~-3-methoxy-crotonic acid diphenylmethyl ester, w~ich is recrystallised ~rom methylene chloride/diethyl ether/hexane.
Melt$ng point 204-206C; W spectrum (ethanol): ~max = 259 m~ ( = 16,000); IR spectrum ~Nu~ol): characteristic bands at 2.93, 5.58, 5.80, 5.849.5.93, 6.24 and 6.57 ~; ~hin layer _ ~ ,,"
.

chromatogram: R~ value ~0.33 (silica gel; toluene/etk.yl acetate, 1 ~xa~le 18 A mixture of 670 mg (1 mmol~ o~ 2-[4-(p-tol~lenesul-phonylthio)-3-phenylace~amido-2-oxoazetidin-l~yl~ methoxy-crotonic acid diphenylmethyl ester, 6.7 ml of 1,2-dimethoxy-ethane and 0.22 ml o~ 1,5-dia2abicyclo~5.4.0]undec-5-ene is stirred ~or 25 minutes at room temperature under a nitrogen atmosphere. Tbe reaction mixture is diluted with ~oluene, washed successively wit~ 2 N hydrochloric acid, saturated aqueous sodium bicarbonate solutio~ and saturated aauecus sodium chloride solution, dried over sodium sulphate and con- -centrated by evaporation in vacuo. The residue, a~ter preparative thick 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 me~hyle~e chloride/hexane), W
spectrum (ethanol): Am~X = 258 m~ ( = 4,500),^IR spectrum (methylene chloride): characteristic bands at 2.93, 5.62, 5.73, 5.93 and 6.66 ~, Rf Yalue~ 0.54 (silica gel; system ~oluene/ethyl acetate, 1:1), and amorphous 7~-phenylacetamid~-3 methoxy-ceph-3-em-4-carboxylic acid diphenyl.methyl ~ster, UV spectrum (et~anol): AmaX = 258 m~ (E = 6,350~, 264 m~ ( a 6,350)9 282 m~ (~ = 5,600) (shoulder3, IR spectrum tmethyle~e chloride): characteristic bands at 2.94, 5.63, 5.83, 5.94, 6.26 and 6.66 ~, Rf value~ 0.37 (silica gel; system toluene/
ethyl acetate, 1:1), i~ the ratio of 8:1.
, me material can be processed ~urther as follo~Js:
7~-Phenylacetamido 3-methoxy-ceph-2~em-4a-carboxy'ic acid diphenylmethyl ester can be converted, analogously to Example 17c), into 7~-phenylacetamido-3-methox~-ceph-3-em--4-carboxylic acid diphen~71methyl es~er l-oxide of melting poi~t 152-155C (~rom acetone/diethyl ether), R~ value 0.31 (siiica gel; sy~tem: ethyl acetate), W spectrum (in 95% strength ethanol): AmaX = 288 m~ ( = 3,610) and shoulder at ~-= 247 ~;
IR spectrum (meth~lene chloride~: characteristic bands at 2.94, 5.5g, 5.81, 5.95~ 6.22 and 6.61 ~.
A purer product, which consists mainly o~ 7~-phenyl-acetamido-3-methoxy-ceph-3-em_4_carboxylic acid diphenylmethyl -ester l~-oxid~, can be obtained as follows:
A solution of 6.7 g (10 mmols) of 2-~4-(p-~oluenesul- -phonylthio)-3-pheny~acetamido-2-oxoazetidin-l-yi~-3-methoY~y-isocrotonic acid diphenylmethyl ester in 57 ml o~ absoiute :
.tetra~ydrofurane is stirred with 2.28 ml (15 mmols) o~ 1,5- :
diazabicyclo~.4.0~undec-5-ene for 15 minutes ~t 20C, 0.7 ml o~ glacial acetic acid is added and the mixture is then con-centrated by e~aporation in ~acuo. The oily, dar~ residue is dissolved in 30 ml of methyle~e chloride and t~e solution is succ~ssi~ely extracted by shaking with 15 ml of water9 ~10 ml o~ 0~5 N hydrochloric acid9 10 ml o~ saturated aqueous sodium bicarbonate solu~ion and lO ml o~ water. The aqueous phases are r~-extracted with lO ml of me~hylene chlor~de and the organic extracts are combined and stirred with 2.24 ml o~
40~ strength perace~ic acid for 15 minutes at 0C in an ice-'7bath. A solution o~ 1~50 g (6 mmols) of sodium thiosu~phate pentahydrate in 20 ml o~ water i~ th~n added to the reaction mixture, the whole is stirred for 10 minu~es and the aqueous phase is separated o~f. The orgar.ic phas~ is additionally washed with 10 ml o~ water, dried over sodium sulphate and concentrated by e~aporation in vacuo. Crystallisation of the solid residue from me~.ylene chloride/petroleum ether ~i~re~
7~ phenylacetamido_3-methoxy-ceph-3-em-~-carbo~ylic acid diphenylmethyl ester l~-oxlde o~ melting point 175-176C;
-thin layer chromatogram (silica gel):- Rf value -0.1 (toluene/
ethyl acetate, 1:1), UY spectrum (ethanol): ~max a 279 m~
(E = 7,300); IR spectrum (methylene chloride): charac~erist~c bands a-t 2.94; 5.56; 5.78; 5.91; 6020 and 6.67 ~.
~ -Phenylacetamido-3-methoxy-ceph~3-em-carbo~ylic ac~
diphenylmetnyl ester can be obtained ~rom the 1-oxides analogously to Example 17e).
From ~hls ester, crude 7~-pheny1acetamido-3-me-thoxy-eeph-3-em-4-carboxyllc acid can be obtained by saponification " . analogously to Example 17a), and can be puri~ied by chromato~
graphy on silica gel (containi~g 5% of water) us~ng methylene c~loride containing 30-50~ o~ acetone, followed by lyop11ili sation from dioxane; W spectrum (in 95% strength ethanol):
~ax = 265 m~ ( = 5,800); IR spectrum (me-thylene chloride):
characteristic bands at 3.03, 5.60, 5.74, 5.92, 6.24 and 6.67 ~. -The ~tartlng material and the intermediate product~
can be prepared as ~ollow~:
`' 11~ , B

~ 3867SS
a) 19.4 ml o~ 40 per cent strengt11 peracetic acid are added over the course o~ 40 minutes to a mixture of 37.24 (0.1 mol) of the potassium salt of penicillin G in 90 ml o~
water, 7.3 ml of acetone and 150 ml of ohloroform whilst stirring at 0C. A~ter a fur~her 15 minu~es, 28 g (0.15 mol) of benz~phenone-hydrazone are added in portions at the same temperature, follo~ed by 603 ml of 1 per cent strength aaueous potassium iodide solution an~ then followed by a mixture ol 32.5 ml o~ 10 per cent strength sulphuric acid and 28 ml o~ -40 ser cent stren~th peracetic acid, added dropwis~ over t~e ~ourse of 1.5 hours. A~ter completion of the addition, the mixture i5 stirred.~or a fur~her 30 minutes 2t 0C, warmed to 15C and diluted with 400 ml of chloroform. The aqueous phase is separated off and the organic phase is successi~ely washed with 300 ml of 5 per cent strength aqueous sodlum bi-sulphite solution, 300 ml o~ satur2ted aqueous sodium bi-carbonate solution and 300 ml of saturated aqueous sodium chloride solution, dried o~er sodium sulphate and concentrate~d '. by evaporation in ~acuo. The evaporation res~due is recrysta~-lised ~rom ethyl acetate/petroleum ether and gi~es 6-phenyl-acet~midopenicillanic acid diph~nylmethyl ester l~-oxide, melting poirt 139C; thin layer chromatogram (silica gel):
Rf value ~0.40 (system tolue~e/ethyl acetate, 1~1), IR spec-trum (methylene chloride): characteristic bands a~ 2.94 9 5.56;
5.70, 5c92 and 5.57 ~ .
b? 1.83 g (11 mmols) o~ 2-merca~tobenzthiazole are added to a mixture of 5.165 g (10 mmols) of 6 phenylacetamido~eni-cillanic acid dipkenylmethyl ester l~-oxide in 50 ml of ,,,., . ,... ... -~ - , ~ '7S 5 toluene and O.5 ml o~ glacial acetic acid and the ~iY~tuue is boiled for 2 hours in a reflux apparatus provided with a water separator. On coolir.g, 2-~4-(benzthiazol-2-yldithio)-3-phenylace~amido-2-oxoazetidin-1-yl~ methylene-butyric acid diphenylmethyl ester crystallises out spontaneous~y.
After recrystallising it once ~rom methylene chloride/diethyl ether, crystals of melting point 134-136C are obtained;
thin layer chromato~ram tsilica gel~: Rf value ~0.52 (system toluene/ethyl acet~te, 1:1), W spectrum (etha~ol): ~ax a 269 m~ ( F = 12,700); IR spectrum (methylene chloride):
characteristic bands at 2.90 9 5.60, 5.72, 5.g2 and 6.61 ~.
c) The product obtained under b) does not have to be isolated ~or further conversio~. After cooli~g, the reac tion mixture can be diluted directly with 30 ml of toluene, after which it is mixed with 3.95 g (15 mmols) of silver p-tolue~esulphir.a~e and stirred ~or 2 hours at room temperat~l~e.
The yellow precipitate whic~ has separated out is filtered o~f through Hy~lo and rinsed with toluene. The ~iltrate is r~.
-: extracted by shakin~ with saturated aqueous sodium chloride solutio~, dried o~er sodium sulphate and concentrated by evaporation in ~acuo. The e~apor~tion residue is taken up in toluene and petroleum etker is added. The precipitate is filtered off and recrystallised from ethyl acetate/pet-roleum ether. The resultlng 2-[4-(p-toluenesulphonylthio)~
3-phenylacetamido-2-oxoa2etidin-l-yl]-3-methylene 'DUt9~iC ~ ' acid diphenylmethyl ester has a melting point of 75C~ t~in lay~r chromatogram (silica gel): R~ ~alue~ 0.47 tsys~em : //L~--~ 675 ~
toluene/ethyl acetate, l:l), UV spectruM (e~hanol): hmaX =
759 m~ 4,300); IR spectrum ~methylen~ chloride):
characteristic bands at 2.92, 5.62, 5.74, 5.94 and 6.6~ ~O
d) A solution o~ 655 mg (l ~M) of 2-~4-(p-toluenesul-phonylthio)-3-phenylacetamido-2-oxoazetidin-l-yl~-3-methylene-butyric acid diphenylmethyl ester in 65 ml of methylene chloride is treated with an ozone/oxygen mixture ai -65C
until a slight blue colouration results. A~ter additio~ ol -O.5 ml o~ dimet'nyl sulphide, the mi~ture is allowed to warm Up t~ room temperat~re and is then concentrated by evapora~ o~ . -in vacuo. The requlting crude 2-~4-(p tol~ene~ulphonylthio)-3-phenylacet2mido~.2-oxoazetidin-l_yl~_3-hydroxy-crotonic acid dip~enylmethyl ester, R~ ~alue~ 0.46 ~sllica gel; system toluene/e~hyl acetate, l:l), IR spectrum (methylene chloride~:
characteristic bands at 2~95, 5.60, 5.98, 6.18 and 6.6l ~, can be conve~ted further withollt additional purification.
e) The crude product obtained u~der d) is dissolved,i~ .
20 ml of methanol and a solution o~ diazomethane in ether i3 added at 0C until a yellow colouxation persists. A~ter e~aporatin~ of~ the solvent in vacuo, the re~due is purified by preparati~e thick layer chromatography on silica gel, using toluen~/ethyl acetate, l:l, as the running agent. 2_~4_(p_ Toluenesulpho~yl~hio)-3-phenylacetamido-2-o~oazetldin-1-yl]-3-methox~crotonio acid diphenylmethyl ester, R~ Yalue -0.2 (~ilica gel; sy~em toluene/eth~rl acetate, l:l), IR spectr~
(methylene chloride): characterist~c bands at 2.94, 5.61, 5.g6, 6.24 and 6.62 ~, is obtained alongside a little 2 ~4 , ` B ~
.

~31L0~;'7SS
(p-toluenesulphonylthio)-3~phenylacetamido-2-oxoaze~idin~
- yl]-3-methoxy-isocrotonic acid diphenylmethyl ester.
Ex2m~1e 19 __ . ~.20 ml (3.5 mmols) of 1,5-diazabicyclo~5.4.0]undec-5ene are added to a solution of 6.06 g (10 mmols) of a ~:1 mixture OL the isomeric 2_~4 (p-toluenesulphonylth~o)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methox~r-~crotonic acid benzyl ester and 2-[4-(p-toluenesul~honyl~hiQ)-~-phenoxyacst-amido-2-oxoazetidln-l.yl]-3-methoxy-isocrotonic aci~ ben~yl ester and 2.33 g (15 mmols~ of p-toluenesulphinc acid in 200 ml o~ absolute tetrahydrofurane at room temperaturel whils~
stirring. me mixture is stlrred ~or a further 40 mi~u'es at -room temperature, mixed with 500 ml of methylene chloride and washed successively with 200 ml of 0.5 N ~ydrochloric acid, 200 ml o~ water, 200 ml o~ 0.5 N sodium bicarbor,ate and 200 ml o~ ~ater. The methylene chloride phase i9 dried o~er sodium sulphate and concentrated by evaporation in vacuo.
me residue is chromatographed on 200 g o~ acid-washed silica ,. ,,~
~ gel, using tolue~e/ethyl acetate, 3:1, and 7~-phenoxyacet-. amido-3-methoxy-ceph-2 em-4~-carboxylic acid benzyl e~tsr o~
me~ting point 148 - 151C is obtained by adding diethyl ether to the ~ractions. IR spectrum (methylene chloride): char acteristic bands at 5.60, 5.75, 5.9û,and 8L25 ~; [a]20 =
+284 ~ 1 (c = 1 chloroform).
Toluene/ethyl acetate, 2:1, elutes 7~-phenoxyace~- ~
amldo-3-~ethox~r ceph-3-em-4-carbox~rlic acid benzyl ester, which oan also be preoipitated with d~ethyl ethe-, and has a :

~ . ~ , .. . ,, , . , ' , ; : .

melting point o~ 89-91C; IR spectrum (met~ylene chloride3:
characteristic bands at 5.60, 5.85 and 5.90; ~a~20 = ~47 1 (c ~ l; chloroform).
The ratio of the ceph-2-em compound to the ceph~3-em compound is about ~
me compo~nds ca~ be ~urther converted as follows:
15 ml of pr~-cooled 0.1 N potassiwm hydroxide solution ~re added, whilst stirring, to 2 solution prepared at-0C, o~
4~4 mg (l mmol) o~ an approx~ 3:1 mixture of 7~-phenox~tacet-~mido 3-~ethoxy-ceph-2-em-4a-carboxylic acid ~enzyl ester and 7~-phe~oxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid benzyl ester in 30 ml of tetrahydrofurane. The mixture is stirred for a ~urther 5 mi~utes at 0C, 100 ml o~ ice water and lO0 ml of pre cooled me~hy~ene chloride are ~hen added and the whole is stirred ~igorausly. Addition o~ a little saturated aqueous sodium chloride solution causes the mixtur~
to separate into two phases. The methylene chloride phase is separated off and the aqueous phase is washed with a ~ur-~her 30 ml o~ methylene chlor~de. The aqueous phase is co~ered with 50 ~1 of methylene chloride, 10 ml o~ 2 N hydro : -chloric acid are added and the mixture is thoroughly shaken.
A~ter separati~g of~ the organic phaseg t~e aqueous phase is extracted ~ lce more wit~ 30 ml o~ methylene chloride at a time. me combined methyle~e chloride ex~racts are dried o~er sodium sulphate and co~centrated by e~aporation in vacuo. ~`
The resulting white foam cry~tall~ses on addit~on of chloro- :
~orm and diethyl ether a~d gives 7~-pho~oxyacetamido-3- -.

, . .. . .... . . . ... .. .. . . . . . . . . . . . . .

~ 6'~ ~methoxy-ceph-2_em_4a_carbo~1~c ac~d o~ melting polnt 142C
~decompositio~). IR spec~r~ (KBr): characteristic bands a~ 5.65, 5.75 and 5.95 ~.
The starting material can be prepared as follows:
a) 20 ml (14.6 g, 0.1~5 mol) of triethylamine and 17 ml ~24.5 g, 0.143 mol) of benzyl ~romide are added to a solution o~ 35.6 g (0.1 mol) o~ 6-phenoxyacetamido-penicill2nic acid l~ oxide in 150 ml of dry dimethyl~orm2mide whilst cooling with tap water. The mixture is stirred for 20 hours at room r~
-~ temperature and is then pour~d onto ice water. The precipi-~a~e is filtered off, washed with approx. 11000 ml of water9 dried for 2 days in vacuo at 40C, then taken -~p in 200 ml o~ -methylene chloride a~d again dried with sodium sulphate.
The white foam ~Yhich remains a~ter evaporating off the sol-~ent in vacuo is dissolYed in 150 ml o~ ethyl acetate and th~
~olution is le~t to stand ~irst at roo~ temper2ture'and then at -20C, whereupon pure 6phenoxyacetamido-penicillanic acid ben~yl ester l~-oxide cr~stallises. Melting-point 139-140C;
f~ R spectrum (methylene chloride); characteristic bands at 5155~ 5.75 and 5.90~; ra]D = ~ 174 ~ 1 (c = 1, chloro~orm).
Further quantities o~ the crystalline ber2yl ester l~-oxide can be obtained from the mother liquor by chromato-: graphy on 250 g o~ acid-washed silica gel, using toluene~
ethyl acetate (l : 1).
b~ 4.56 g (10 mmols) o~ 6-phenoxyacetamido-penicillanic acid benzyl ester 1~-oxide a~d 1.84 g (11 mmo7s) Gf 2-ma~ca~o-benzthiazole in lO0 ml o~ toluene are heated Lor 5 hours ~n.de~r T~
: ~ ~39 ~ 5~
refl~ (bath temperat~e 135C). The mixture is lef-t to . stand, ~rhereupon 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacet-amido-2-oxoazetidin-1-yl~-3-methylene-butyric acid benzyl ester crystallises out. The crystals are filtered of~, washed ~ith 50 ml of tolue~e and dried in a high ~acuum.
Further quantities of the crystalline product can be obtained by chromatography of the mother liquor on 70 g of acid~washeâ
silica gel, using tolue~e/etnyl acetate (3:1). Melting point o~ the pure product 150~ 153C; IR spect~um (methylene f'J chloride): characteristic bands at 5~60, 5.75 and 5;S0 ~, [a~2~ = ~112 ~ 1 (c = l; chloroform).
c) An oxygen/ozone mixture is passed through a solution - .
o~ 6.06 ~ (10 mmols) o~ 2 [4-(benzthiazol 2 yldithio)-3 phenoxy-acetamido-2-oxoazetidin-l-yl~-3-methyl2ne-butyric acid benzyl ester in 300 ml of methylene chloride at -20C .
until ~he starting matPr~al has been completely ozonised (as checked by means of thin layer chromatogr~phy on silica gel, using toluene/ethyl acetate, 1:1). 50 ml of 10~
strength aqueous sodium bis~lphite solution are then added ~o t~e mixture which is ~tirred until (after 5 minutes) ~ozonide ~s no longer detectable with potasslum iodide/starch, 300 ml o~ water are added to the mixture and the product is partitioned between the ~wo phases produced. The organic phase is dried over sodium sulphate and ~reed ~rom the solven~.
The residue is triturated in 100 ml of ether-pen~ane (1:1) at 0C, whereupon 2-~4-(benzthiazol-2-yldithio) ~-phenoxyacet-amido 2-oxo2zetidin-l-yl]~3-hydroxy-crotonic acid ben~yl este;~

: . ., -~ 67~ S
melting point 58-62C, crystallises out; IR spectrum (meth~lene chloride): charaoteristic bands at 5.60, 5.90 a~d 6.00 ~; [~]DO _ -92 + 1 tc = 1, chloro~orm).
d) 6.08 g (0.01 mol) of 2-r4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-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 acetone-water (9:1) for 60 min~tes at room temperature. The yellow prec~pitate formed ~ i~ filtered off through Celli~, the residue is ~ashe~ wi~h --3 acetone and the filtrate is concen~rated in ~acuo to a volume o~ approx. 20 ml. The product is then partitioned between methylene chloride and dilute aqueous sodium sulphate solution.~
The organic phase is dried over sodium sulpha~e and the sol-vent is ev~porated i~ ~acuo. The residue is taken up in 70 ml of ethyl acetate, i~ nècessary with warming, ~reed ~rom a little insoluble matter by filtration and again concentrated by evaporatio~. On addition o~ 100 ml of ether-pen'ane at 0C~ 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxo~
azetidin-l-yl~-3-hydroxy-crotonic acid benzyl ester of melting point 151-152C crystallises out; IR spectrum ~methylene chloride3: characteristic bands at 5~60, 5.90, 6.00 and 8.7~ ~;
~a~20 = -16 + 1 (c = l; chloro~orm).
~ e~ A solution o~ diazomethane in ether is added dropwise to a solution o~ 5.97 g (0.01 mol) o~ pure 2-~4-(p-toluene- -sulphonylthio)-3-phenoxyacetamido-2~oxoaze~idin-1-yl~-3- ~
hydrox~-crotonic acid benzyl ester in 50 ml o~ methylene chloride at 0C, whilst stirring~ until the starting material ~ ~ ~l;~a~f~ J~1 ~a~6~YSS
has been com~letely methyla~ed (checked by thin layer c~omato- -graphy on silica gel, using toluene/ethyl aceta.,e, 1;1), EX- -cess diazomethane is neu~ralised by a ~e~ dro~s of glacial ace-tic acid (but an excess of glacial acetic acid should be a~oided) after ~Jhich the mixture is concentrated by evapora~ion in vacuo, The yellowish~ foam-like residue is crystallised from diethyl ether/pent~ne (1:1), giving an isomer mixture consisting o4 ~- -~4-(p~toluenesulp~onylthio)-3 phenoxyacetamido-2-oxoazetid~n-1-yl]-3 methoxy-crotonic acid benzyl es~er and 2-[~-(p-toluene-sulphonylthio)-3-phenoxyacetamido-2-oxoazetidin~l-yl]-3-me~hoxy-isocrotonic acid benzyl ester ~n the ratio of about 3:1.
The two isomers can be separated by repeated chromato-graph-y on silica gel, using toluene/ethyl acetate, 1:1. The resulting 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetam~do-2-oxoazetidi~ yl]-3-methoxy-Grotonic acid benzyl ester has a melting ~oint of 166-168C; [a]20 = -36 ~- 1 (c = l; chloro ~orm); IR spectrum (methylene chloride~: characteristic bands at 5.60, 5.80, 5.90 and 8.72~; NMR spectrum (c~loroform): :
characteris~ic bands at 2.12 (s~; 5.00 (dd); 5.90 (d) pp~
thln layer chromatogram: Rf ~alue _0.10 (silica gel; toluene~
ethyl aceta~e, 1~ he resul~ing 2-[4~(p-toluenesulphonyl- -thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-methoxy-iso-croto~ic acid benzyl ester has a melting point of 59-63CC;
~a]20 - -1 1 (c = l; chloro~orm?; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.87 sh. 5.90 and 8.72~; NMR spectrum (chloro~orm): characteristic bands at 3.23 (s), 5.45 (d,d), 5.73 (d) ppm; thi~ layer chromatogram:
:

~ ~ J ~
,. . .

' ' ' ` ~ ~ ': ` . ' ' . ' : ' ' ' ' ' . . . '' ~0~6'~S

Rf value -0.13 (silica gel; toluene/eth~l acetatef l:1).
~xam~le 20 302 mg (2 mmols) o~ 1,5-diazabicyclo[5~4.0]~ndec-5-ene are added to a solu~ion o~ 534 mg (1 mmol) o~ a ~ixture consisting of 2-{4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methoxy-isocrotonic acid methyl ester and 2-~4-(p-~oluenesulphonylthio) 3-phenoxyacetamido-2-oxc-azetidin-l-yl )-3-methoxy-crotonic acid methyl ester in the ,~ ratio o~ abou~ 4:1, in 20 ml o~ tetrahydro~urane, ~hilst ---stirring The mixture is then stirred for 40 minu~es, diluted ~ith 70 ml of methylene chloride and ~Jashed successi~e-ly with dilute hydrochloric acid, with water, wi~h dilute aqueous sodium bicarbona~e solution and again ~rith water.
~he organic phase is dried over sodium sulph~te and concen-trated by evaporation in vacuo. The residue is chromato-graphed on 15 g o~ acid-~shed silica gel using toluene/'ethyl acetate, 2:1 ~ollowed by 1:1, resulti~g in the elution ol, A~ ~irst, pure 7~-phenoxyacetamido-3-me~hoxy-ceph-2-em-4a-~ carboxylic acid methyl ester5 IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.70, 5.90 and 8~25~, ~ollowed by pure 7~-phenoxyacetamido-3-methoxy ceph-3-em-4-carboxylic acid methyl ester, IR spectrum (in methylene chlor- -ide~: c~araCteristiC bands at 50603 5.85, 5090 ~nd 7.10~, in ~he form of colourless foams. - ;
me compounds ob~ained can be further con~erted as ~ollows:
15 ml o~ cooled 0.1 N aqueous potassium hydroxide : ~3 86'7SS
solution are added, w~ilst stirring, to a solu-tion, cooled in an ice bath, of 382 mg of 7~-phenoxyacetamido-3-methoxy-ceph-2-em 4a-carboxylic acid meth~l ester in 30 ml o~ tetra-hydrofurane. After 5 minl1tes,. 100 ml 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 chloride phase is separated olf and the a~ueous phase is extra ted with 30 ml of methylene chloride. ~le combined ,; organic phases are dried over sodium sulphate and coacentr2tea---by evaporation in ~acuo. The residue is crystallised ~rom chloro~orm/diethyl e-ther and gives 7~-phenoxyace~amido-3-methoxy-ceph-2-em-4~-carboxylic acid o~ meltir.g point 142C
(decomposition).
The same compound, of melting point 142C (decom~os~-tion) is obtained when 7~-phenoxyacetamido-3-methoxy-ceph-3-em 4-carboxylic acid mPthyl ester is saponified with 0.1 N
potassium hydroxide solution9 as described earlier.
The starting materials can be prepared as ~ollows:
~` A solution o~ 19.25 g (50 mmols) o~ 6-phenox~acet-amido-penicillanic acid methyl ester l~-oxide and 9.4 g (~5 mmols) of 2-mercaptobenzthiazole in 500.ml of dry toluene is boiled for 8 hours under r.eflux and then concentrated in vacuo. The residue is dissolved in 400 ml o~ ethyl acetate whilst warming (~ 80C) and the solution is trsated with 0~2 g of active charcoal and filtered through an electrically heated glass ~rit. On cooling, 2-~4-(benzthiazol_2_yldithio)-3-phenoxyacetamido 2-oxoazetidin-l-yl~-3-methylene-butyric acid :~

.. :. . . . ~.. . . :

. ~ ,. . .. . . . . - , ,, ~ (~8~'~SS
methyl es Ler of melting point 132 ~134C separates out.
Further quantities OL this compound (melting point 135 ~ 137C) can be obtained ~rom the mother liquors.
b) An ozone/oxygen mixture is passed through a solu~ion of 20.6 g (40 mmols) of 2-[4-(benz~hiazol-2-yldi~hio)-3-phenoxyacetamido-2 oxoazetidin-1-yl~-3-methylene-butyric acid met~yl ester in 400 ml of acetone at -20C until no further star~ing material is detectable by thin layer chroma~ography (sllica gel, toluene/ethyl 2cetate, 1:1). 40 ml of dimethyl-sulphide are then added to the mixture and the whole is stirred for 3 days at room temperature until o~one is no lo~ger detectable wi~h 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 precipitate is ~iltered of~, washed with 200 ml of ice water, dried in vacuo nd crystallised from diethyl ether/pentane at 0C. me resul~ing 2-[4-(benzthiazol-2-yldithio~-3-pheno.Yyacetamido-2-oxoazetidin-l-yl~-3-hydro~ycrotonic acid m~thyl^ ester has a melting point o~ 127~ 1~0G; IR spectrum (i~ methylene chloride): characteristic bands at 5.60, 5.90, 6.00 and 8.10 ~. Further quantities of the product can be obtained b~ chromatography o~ the mother liquors on silic~ gel, using toluene/ethy~ ace~ate~ 3:1.
c) Suf icient of a ~olution of diazomethane in ether is added to a solution of 4085 g (0.01 mol) o~ 2~4-(benzthiazol- ~
2-yldithio) 3-phenoxyacetamido-2oxoazetidin-l yl~-3-hydro~
crotonic acid methyl ester in 50 ml of ~ethylene chloride at :

.. .; , . '.. '~, , , . . .. ~ . . .. , ' ' .. . . - ' ' . ~8t;~S ~
0C, whilst stirrlng~ that after periods of sti~ring of 15 minutes star~ing material is in each case no longer detect-able by thin layer chromatography (silica gel, toluene/ethyl acetate, 1~ Excess diazomethane is neutralised with a minimum amount o~ acetic acid ar.d the mixture is concentrated by e~aporation in vacuo. The residue consists of a mixture of 2-[4-(benzthiazol-2 yldithio)-3-phenoxyacetamido-2-oxo-az~tidin-l yl~ 3-methoxy-isocrotonic acld methyl ester and 2-[4 (benzthia201-2-yldithi~L3-phenoxyacetamido-2-oxoazetidin~
1 yl]-3-methoxy-crotonic acid methyl es~er in the ratio o~
about 4:1. IR speotrum (~n me~hylene chloride): cha.acter~
istic bands at 5.60, 5085, 5.90~ 9.05 and 10~00 ~, d) A mixture comprising 5.03 g (0.01 mol) o~ a mlxture ol 2-~4-(benzthiazol_2_yldithio)_3_phenoxyacetamido-2-oxoazetidi~-l~ylJ-3_methoxy isocrotonic acid methyl e~ter and the corres-ponding crotonic acid methyl ester in the ra~io o~ about 4~
3.50 g (0.01~ mo;) o~ sil~er p-toluenesulphi~ate and 200 ml o~ acetone/water9 9:1, is stirred for 40 minutes at room temperature and then ~iltered through ~ellit. The filter resldue is washed with acetone and the combined ~iItrates are concentrated in ~acuo to a volume of about 20 ml. After adding 100 ml o~ methylene chlor~de and 100 ml of dilute a~ueous sodium sulphate solution, the whole is shaken thoroughly, the aqueous phase is separated off and the meth~- :
lene chloride phase is dried o~er sodium sulphate and conce~
~rated by evaporation in ~acuo. The residue is puri~ied by trituration with diethyl ether/penta~e at oC and is filtered 1(~86'7~;;S
o~. A mixture o~ 2-~4-(p-toluenesulphonylthio)-3-phenoxy-acetamido-2-oxoazetidin-1-yl)-3-methoxy-isocrotonic acid methyl ester and 2-[4-(p-toluenesulphonylthio)-~-pheno~-acetamido-2-oxoazetidin-1-yl~-3-methoxy-crotonic acid methyl ester in the ratio of about 4:1 is obtained in the form of a white powder. ~R spectrum (in methylene chloride~ ch~r2cter-ist~c ba~ds at 5.60, 5,85, 5.90 and 8.75 ~.
Exam~le 21 A solution of 731 mg (1 mmol) of a 1:1 mixture con-sisting of 2~4-(p-toluenesulphonylthio) 3-phenoxyacetamido~2-oxoazetidin-l yl~-3-benzoxy-crotonic acid p-nitroben2yl ester and the corresponding isocrotonic acid p-nitrobenzyl ester in a mixture c~ 0~185 ml (1.2 mmols) o~ 1,5 diazabicyclo~.4.0~
undec-5-ene in 20 ml of dry tetrahydro~urane is stirred for precisely 3~ mi~utes at room temperature. 50 ml of methylene chloride are added to the mixture and the whole is washed ~ ;
successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution. The orga~ic phase i~
dried over sodium sulphate and concentrated by evapora~ion i~ -vacuo. The residue is chro~atographed on 25 mg o~ acid washed silica gel, using toluene/ethyl acetate (3:1). A
mixture consisting of the ce~h-2-em compound and the ceph-3-em compound in the ratio of a~out 3:1 is obtained; this mix-ture can be separated by repeat~d chromatography into the pure isomers, givi~g 7~-phenoxyacetamido-3-ber.zoxy-ceph-2 em-4-carb~xyllc acid p-nitrobenzyl este~ of meltin~ point 160C-162~ (diethyl ether/~entane); IR spectrum (methylene lB . 1c~ 1 : .

6~755 ch~oride): characteristic bands at 5.6, 5.7, 5.9 and 7.4 ~, and 7~phenox~acetamido-3-benzcxy-ceph-~-em-4-carboxylic acid p-nitrobenzyl ester in the form o~ a colourless ~oam, IR spectrum ~methylene chloride): characteristic bar.ds at 5.6, 5.8 sh, 509, 7.9 and 8.4 ~. -The i~omer mixture obtained can be further conver~edas follows:
The isomer mixtur~ obtained, consisting of 7~-phenoxy-acetamido-~-benzoxy ceph-Z-em-4a-carboxylic aoid p-ni~robe~-yl ester and 7~-phenoxyacetamido ~-benzoxy-ceph-3em-4-carboxy~ic acid p-nltro~enzyl ester in the ratio o~ abo~t 3:1, is dis-solved in 8 ml of trifluoroacetic acid and the solu~ion is stirred for 90 minutes at room temperature. The reaction mixture is then concentr~ted by evaporation in vaGuo and residual trifluoroacetic acid is repeatedly driven off with toluene. The residue is chromatographed on 20 g of acid~
washed silica gel, using toluene/ethyl acetate t3~ giving 7~ phenoxyacetamido~-hydroxy-ceph-3-em-4-c2rboxylic acid p-nitrobenzyl ester in the form of a colourless foam. IR
spectrum (methylene chlo~ide): characteristic bands at 2.95 7 3.3, 5.6, 5.75 sh, 5.9, 5.95 sh, 6.55, 7045~ 8.15 and 8.3 ~;
NMR spectrum tdeuterochloro~orm): characteristic bands at 3.4 (:2H, AB q, J = 17 Hz), 4.57 (2H, s), 5.06 (lH, d, J = 5 Hz~, 5.35 ~2H, AB q, J = 14 Hz)~ 5.7 (lH, dd, J - 5~ 10 Hz), .8-8.4 (lOH, c), 11.4 (lH, br.s.) ppm.
The starting material can be prepared as follows:
30 ml o~ the solution prepared ~in si1u" (from N~

~ L~)86755 benzyl~N-nitrotoluenesulphonamide) o4 1.2 g tappro~. 10 mmols) of phenyldiazomethane in ether is added, at room temperature, to a solution of 1.282 g (2 mmols) of 2-~4-(p-toluenesulphonyl-thio)-3 phenoxyaceiamido 2roxoazetidin-1-yl]-3-hydroxy-crotonic acid p-nitrobenzyl ester in 4 ml of distilled dioxane.
The mixture is boiled for 6 hoursun der re~lux at 45C ~ath temperature, dilu~ed with 100 m' of methylene chloride and ~hen washed with 100 ml of water. The organic phase is driQd over sodium sulphate, concentrated by evaporation in vacuo and dried in a high ~acuum, The resulting ye~low oil is chromato-graphed on 100 g o~ acid-washed silica gel, using toluene/
ethyl acetate~ 3:1 and 2:1, as the running agen~s. An iso-mer mixture consisting o~ 2-r4-(p-~oluenesulphonylthio3-3- -phenoxyacetamido-2-oxoazetidin-1-yl~-3~benzoxy-crotonic acid p-nitrobenzyl ester and 2-[4-(p-toluen3sulphonylthio)-3- -phenoxyacetamido-2-oxoazetidin-1-yl~-3_benzoxy-isocro~onic acid p-nitrobenzyl ester in the ratlo of about l:l is obtained;
thi~ can be separated into the indi~idual isomers ~y repeated ,. .
- chromatography, as described earlier. IR spectrum of the ~aster-running crotonic acid deri~ative (m~thylene chloride):
characteristic bands at 5.6, 5.80, 5.90 and 8075 ~; NMR
spectrum (deuterochloroform)0 characteristic bands at 2.2 (5 ), 5.05 (dd), 5.93 (d) ppm; thin layer chromatogram: ~f value .
0.3 (silica gel; toluene/ethyl acetate92:1); IR spectrum of ~he slower-running isocrotonic acid derivat~e (methy'ene chloride): characteristic bands at 506, 5.85 sh, 5.90 and 8.75 ~; NMR ~pectrum (deuterochloro~orm): characteristic ~ , /~ q . .

~' '. :' ' : ' ~ ,, . ' ', - -~86'~5S
bands at 2.5 (s), 5.41 (dd), 5.77 (d) ppm; thin la~er chromatogram: R~ value~0.25 (silica gel; toluene/ethyl acetate, 2:1) A
Exam~le 22 ~, 405 mg (0.5 mmol) of an isomer mixture consisting of 2-r4-(p-loluenesulphonylthio)-~-pnenoxyacetamido-2-oxoazetid~n l-yl~-3-diphenylmet~oxy_crotonic acid p-nitrobenzyl ester and the corresponding isomeric isocro~onic acid es~er are dissolved in 8 ml o~ dry tetrahydro~urane co~aining 0.9 ml (0~6 mmol) _~
of 1,5-diazabicyclo~5.400]undec-l-ene and the solution i5 stirred for precisely 45 minutes at room temperature. The y~ellow reaction mixture is then dilu~ed with 25 ml of methy-lene chloride and washed with 0.5 N hydrochloric acid9 water and dilute aqueous sodium ~icarbonate solution. '~he orga~ic phase is dried over sodium sulphate a~d concen~rated by evaporation.
An isomer mixture consi~ting o~ 7~-phenoxyacet~mido-3-diphenylmethoxy-ceph-2-em-4a-carboxylic acid ~-nitrobenzyl ester and 7~-phenoxyacetamido-~-diphenylmethoxy-ceph-3-em-4- -carboxylic acid p-ni~robenzyl ester i~ obtained; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.70, 5~90, 6.55 and 7.40 ~.
The resulting isomer mixture of the ~o compounds can be ~urther converted as follows:
A solution of 340 mg of the resulting isomer mixture9 consisting of 7~-~henoxyacetamido-3-diphenylmethoxy-ceph-2-em-4-carboxylic acid p-nitrobenzyl ester and 7~-phenoxyacet-.

~8~SS
amido 3-diph~nylmethox~-ceph-3-em 4-carboxylic ~cid p~nitro- ~
benzyl ester, in a mixture of 0.5 ml o~ tri~luoroacetic acid and 9.5 ml of methylene chloride is stirred for 40 minutes at room temperature. The mixture is concentrated by evaporation in ~acuo, 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 o~ acid~washed silica gil, using toluene/ethyl ace~ate whereby 7~-phenoxyacetamido-3-hydroxy-ceph-3-em-4- _ carboxylic acid p ni~robenzyl ester is obtained; IR spectrum tmethylene chloride): characteristic bands at 20 95, 3.3, 5.6 5.75 sh, 5.9, 5.95 sh, 6.5~9 7.45, 8.15 and 8.3 ~; NMR spec- .
trum (deuterochloro~orm): characteristic bands at 3.4 (ZH9 AB q, ~ , 17 Hz), 4.57 t2Hj s), 5.06 (lH, d,~ = 5 Hz), ~.35 t2H, AB q9 ~ = 14 Hz), 5.7 (lH, dd,~ = 5, 10 Hz), 6.8~8.4 (10 H~ c), 1104 (lH, br. s.) ppm.
me starting material can be obtained as follows:
A solution o~ 350 mg tl.75 mmols) o4 diphenyldiazo~ :
,~ ~. . .
methane in 0.3 ml o~ dioxane is added to a solution of 641 mg (1 mmol) of 2-[4-tp-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin 1-ylJ-3-hydroxy-crotonic acid p-nitrobenzyl ester in 0.5 ml of distilled dioxane and the reaction mixture is warmçd to 50C ~or 36 hours, without stirring. The mix-ture is concentrated by evaporation in ~acuo, the dioxana which rem~ins is driven o~ by adding toluene and again con-centrating by evaporation, and the residue is chromatographed on 20 g o~ acid-washed silica gel, using toluene/ethyl acetaie D

~ 131 `.... _ ~ _ . .,~ .

.. . . . . , . ~ . . .. . . ~ . .. ...... ~ ... . .. . .
.. i . ~` . . - - .. .. . . ..... . . ... .. ...

~ 0~6'75 (7:1) and (3:1).
An 1somer mixture consisting of 2-[4-(p-toluenesul-phonylthio)-3-phenoxyacetamido 2-oxo~zetidin-1-yl~ 3-di-phenylmethoxy-cro~onic acid p-nitrobenzyl ester and 2-[4-(p-toluenesulph~nylthio)_3_phenoxyacetamido_2-oxoazetidin-1-yl]-~-diphenylmethoxy_isocrotonic-acid p-nitrobenzyl ester is obtained, IR spectrum (me~hylene chloride): characteristic bands at 5.6, 5.85 sh, 5.9, 6.25, 6.559 7.43 and 8075 ~.
Exam~le 2~
800 mg (5.25 mmo~s) of 1,5-diazabicyclor5.4.0~undec-5-ene are added to a solution of 933 mg (lo 5 ~mols) of an isomer mixture consisting of 2-[4 (benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl~-3-benz~x-y-crstonic acid methyl ester and the corresponding isocrotonic ac~d methyl ester, ~n the ratio of about 1:1, and 350 mg (2.25 mmols~ of p-toluenesulphinic acid in 30 ml of dry tetra~ydrofurane, and the reaction mixture is stirred ~or precisely 40 mi~utes at room temperature. Tt is then diluted with 10~ ml of benzene and washed with dilute aqueous hydrochloric acid, with water, with dilute aqueous sodium hydroxide soluticn and a~ain with water. The benzene phase ls dried o~er sodium sulphate and concentrated by evaporation in ~acuo. Chromatography using toluene¦ethyl acetate (5:1) on silica gel gives an isomer mix-ture consisting of 7~-phenoxyacetamido 3-be~zoxy-ceph-3 em-4-carboxylic acid methyl e5ter ana 7~-phenoxyacetamido-3- ~
benzoxy-ceph-2-em-4-carboxylic acid methyl ester: IR spectrum (methylene chloride): characteristic bands at 5.60, 5.72/

~L~)8~;~7S~
5.85 sh and 5.90 ~
The starting materlal can be prepared as ~ollows: -960 mg (approx. 8 mmols) o~ freshly distilled phenyl-diazomethane are added to a solution o~ 483 mg (1 mmol) o~ 2-C4-benzthiazol~2-yldithio)~3-phe~oxyacetamido-2~oxoazetidin l-yl]-3-hydroxy crotonic acid methyl ester in 1.5 ml of methylene chloride/diethyl ether and the reaction mix~ure is stirred for 20 hours at 0C, the~ diluted with meth-~lene chloride and washed with water. The organic phasè is dried --3 over sodium sulphate and concen~rated by e~aporatio~ i~ vacuo.
me residue is dried in a high vacuum and ~hen chromatographed on 10 g of acid-washed silica gel, using toluene/ethyl acetate--~(2:1), gi~i~g an isomer mixture consisting o~ 2-[4~(benz~hiazol-2~yldit~io)_~_phenoxyacetamido_2_oxoazetidin_1_ylJ-~_~enzoxy- :
crotonlc acid methyl est~r and th~ corresponding isocrotonic sGid methyl ester in the ratio o~ about 1:1; IR spectru~
(met~ylene chloride~: characteristic bands at 5.6, 5.85 sh, 5.~ and 9.9 ~
~ ~ .
Ana~ogously to Exam~le 5 d, reaction o~ 1.16 g (3 mmols~
o~ 7~-amino-3~methoxy-ceph-~-em~4-carboxylic acid hydrochloride dioxanate, obtainable according to the in~ention, with 1.~ ~
(6~2 mmols) of bis-(tr~methylsilyl)-acetamide and subsequently with a) 765 mg (3.6 mmols) of D--amino-(2-thlenyl3_acetyl ~hloride hydrochlo~ide give 7~-~D-a-amino a-(2-thie~yl)~acetyl-amino~ methoxy-3-cephem-4-carboxyllc acid in the ~orm o~ the ~ L~D15~;'7$5 inner salt, mel~ing point 140C (~rith decomposition); thin layer chroma-togram (silica gel; identi~icat:lon with iodine):
Rf~ O.22 (system: n-butanol/acetic acid/water, 67:10:23) and Rf~ 0.53 (system: isopropanol/~o~mic acid/water, 77:4:19);
ultraviolet absorption spectrum: ~max = 2~5 m~ 11,400) a~d AShoulder = 272 m~ ( = 6,100) in 0.1 N hydrochloric acid, d A 278 m~ ( f = 11 ~ 800) and Ashoulder 6,500) ln 0.1 N aqueou~ sodium bicarbonate solution.-I~ stage a) is replaced by reaction wi~h b) 940 ~g (4.5 mmols) o~ D-a-amino-(1,4 cyclohexadien~l) -acetyl chloride h~Jdrochloride, 7~-~D a-amino-a-(1,4-cyclo-hexadienyl)-acetylaminoJ~3-methoxy_3_cephem_4_carboxylic acid is obtained in the form o~ the inner salt, melt~ng point 170C (with decomposition); thin layer chroma~ogram (sil~ca gel; identification with iodine): .R~ 041g (system: n-butanol/acetic acidlwater, 67:10:23~ and R~~ 0.58 (system:
isopropanol/formic acid/water, 77:4:19), ultraviolet absorp-tion spectrum: AmaX O 267 m~ (~ = 6t300) in 0.1 N hydrochloric acid, and AmaX = 268 m~ (~ = 6,600) in Ool N aqueous sodium bicarbonate solution~ ta~20 _ ~ 88 ~ 1 (c = 1.0~; 0.1 N
hydrochloric acid).
I~ stage a) is replaced by reaction with 800 mg (3.6 mmols) of D;a-amino-4 hydrox~ henylacetyl chloride hydrochloride, 7~[D-a-amino-a-(4-hydroxyphenyl)-acetylamino~-3-methoxy-3-cephem-4-carboxylic acid is obtained in t~e ~orm af the inner salt, melting point = 243 244.5C
~with si~tering starting ~rom 231C onwards) twilh decomposi-l3~ -~" ' ' '''"'"
.... . . . , ., , ... . . -! . , I , , ~ " " , : . , , ,, . . ' . ', , . , .' . ., . ~ ' . . .

., . ` .: . ,. . ' . ~ ' ~ '. ' ' ' , ', ' ' ' ' . '. , . . , ' ', ' ' . , ' .
' ' f;?7S5i tion); thin layer chromatogram (silic~ gel; identi~ication with iodine); ~ 0.24 (system: n-butanol/acetic acid/water, 67:10:2~) and Rf ~0.57 (system: isopropanol/formic acid/
water, 77:4:19); ultr~violet absorption spectrum: AmaX =
228 m~ (F = 12,000) and 271 m~ (~ = 6,900) in 0.1 N hydro-chloric acid, and AmaX = 227 m~ ( - 10 9 500 ) and ~s~oul~er =
262 m~l t~ - 8,000) in 0.1 N aqueous sodium bicarbon~-,e sol~-tiorl, ~a]20 = + 165 + 1 (c = 1.3; 0.1 NhydrGchloric acid)~

r ~
The following compounds can be preparea analogously ~rom suitable intermediate products obtainable in accordailce with ~he invention: 7~-amino-3-methoxy-3-cephem-4 carboxylic acid diphenylmeth~l ester or salts thereof, 3-n-butoxy-7~- -phenylacetylamino-3_cephem-4-carboxylic acid diphenylmethyl ester, 3-n-butoxy-7~-(D-a-tert.-butox~Jcarbonylamino-~-phenyl-acetylamino)-3-cephem-4~carboxylic acid diphenylmethyl ester, 3-n-butoxy-7~-(D--phenylglycylamino)-3-cephem-4-carboxylic acid or salts thereof 9 3-methoxy-7~-phenylacetylamino-3-cephem-4-carboxylic acid methyl ester, 3-ethoxy-7~-(D~a ~ert.
bu-~oxycarbonylami~o-a-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_tert.-butoxycarbonylamino-~-phenylacetrlamino)-3-cephem- .
4-carboxylic acid diphenylmethyl ester, 3-benzoxy-7~-(D-~
phenylglycylamino)-3-cephem-4-carboxylic acid or salts thereof~
7~-(5-benzoylamino-5-diphenylmethoxycarbonylvalerylamino)-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 7~-13~
-'`_J ~, .,`'!~ , .

10~6755 (D-a-tert.-butoxycarbonylamino-~-phenylace~yla~ino)-3-methoxy-3-cephem-t~-carbo~ylic acid or salts thereoî, 7,~-[D-a tert.-butoxycarbonylamino-a-(2-thien~Jl)-acetylamino]-3-methoxy-3-cephem-4~carboxy1ic acid diphenyl~e~hyl ester, 7~-[D-~-tert.-butoxycarbonylamino-a-(1,4-cyclohexadienyl) acetylamino~-3-methoxy-3 cephem-4-carboxylic acid diphenylmethyl ester, 7~-[D-a-amino-a-(l-cyclohexe~-l-yl)-acetylamino]-3-methoxy-3-cephem-4-carboxylic acid or salts thereof, 7~-~D-a-ter~
butoxycarbonylamino-~_(4-hydroxyphenyl)-acetylamino]~3- . _ methoxy.3-cephem-4-carboxylic acid diphenylmethyl ester, 7~-rD-a-tert.-butoxycarbonylamino--(4~isothiazolyl)-acetyl-amino~-3-methoxy-~-cephem-4 carboxylic acid diphenylmethyl ester, 7~-tD-~-tert.-bu~oxycarbonylami~o~ henylacetylamino)~

3-methoxycarbonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester, as well as the correspondlng ceph-2-em co~pou~ds an~

the ~somer mi~ures consisting o~ the ceph-3-em compounds ana the ceph 2-em compounds, and also the l-oxides o~ the corres-pondlng cepn-3-em c:ompounds.

' - - :

,j. .
L~
_ t36

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the manufacture of a compound of the formula (IVb or IVc) wherein R? represents an acyl group of the formula (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 carboxy, wherein amino is free or protected and carboxyl is free or protected, or RI represents lower alkenyl, phenyl, hydroxyphenyl, protected hydroxyphenyl, halogeno-phenyl, hydroxy-halogeno-phenyl, protected hydroxy-halogeno-phenyl, amino-lower alkyl-phenyl, protected amino-lower alkyl-phenyl, phenyloxyphenyl, or RI represents pyridyl, thienyl, furyl, imidazolyl or tetrazolyl, or these heterocyclic groups substituted by lower alkyl, amino, protected amino, aminomethyl or protected amino-methyl, or RI represents lower alkoxy, phenyloxy, hydroxy-phenyloxy, protected hydroxyphenyloxy, halogenophenyloxy, lower alkylthio, lower alkenylthio, phenylthio, pyridylthio, 2-imidazolylthio, 1,2,4-triazol-2-ylthio,1,3,4-triazol-2-ylthio, 1,2,4-thiadiazol-3-ylthio, 1,3,4-thiadiazol-2-yl-thio, or 5-tetrazolylthio, and these heterocyclylthio groups, substituted by lower alkyl, or RI represents halogeno, lower alkoxycarbonyl, cyano,carbamoyl, N-lower alkylcarbamoyl, N-phenylcarbamoyl, lower al-kanoyl, benzoyl, or azido, or R? represents an acyl group of the formula (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, caxboxyl, protected carboxyl, cyano, sulpho, hydroxyl, protected hydroxyl, O-lower alkylphosphono, O,O'-di-lower alkyl-phoshono or halogeno, R? represents a group which together with the carbonyl grouping -C(=O)-forms an esterified, protected carboxyl group, and Y denotes a group of the formula -S02-R5 (IVb) bonded to the thio group -S- by the sulphur atom, or a group of the formula -S-S02-R5 (IVc), wherein R5 is an unsubstituted or by lower alkoxy-, halogen-, aryl-, or aryloxy-mono-substituted or -polysubstituted lower alkyl group, alkenyl group, cycloalkyl group, or a naphthyl, or a phenyl group which is unsubstituted or monosubstituted or polysubstituted by lower alkyl, lower alkoxy, halogen, aryl, aryloxy, or nitro, as well as salts thereof, characterised in that a) a compound of the formula (III) wherein R? and R? have the meaning given under formula IVb or IVc, is reacted with a sulphinic acid of the formula HSO2-R5, a sulphonyl cyanide of the formula N?C-SO2-R5 or a thiosulphonic acid of the formula H-S-SO2-R5, or b) a compound of the formula (IVa) wherein R? and R? have the above meanings and 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, is reacted with a heavy metal sulphinate of the formula Mn+(-SO2-R5)n or with a heavy metal thiosulphonate of the formula Mn+(-S-SO2-R5)n, wherein M represents a heavy metal cation and n denotes the valency of this cation and R5 has the above meanings, and, it required, in a re-sulting compound of the formula IVb or IVc the protected carboxyl group of the formula -C(=O)-R? is converted into another protected carboxyl group, and, if required, within the definition of the end products a resulting compound is converted into another compound and, if required,a re-sulting compound having a salt-forming group is converted into a salt or a resulting salt is converted into the free compound or into another salt, and, if required, a resulting mixture of isomers is separated into the indivi-dual isomers.

2. Process according to Claim 1, characterised in that in a starting material of the formula III or IVa R? re-presents phenylacetyl, phenyloxyacetyl or D-.alpha.-tert.-butyl-oxycarbonylamino-.alpha.-phenylacetyl.

3. Process according to Claim 1, characterised in that in a starting material of the formula III or IVa R? represents benzyloxy, p-nitrobenzyloxy, diphenylmethoxy, lower alkoxy or 2-halogeno-lower alkoxy.

4. Process according to Claim 1, characterised in that in a starting material of the formula IVa R4 represents benzthiazol-2-yl or benzoxazol-2-yl.

5. Process according to Claim 1, characterised in that a starting material of the formula III or IVa is used, wherein R? is phenyloxyacetyl and R? is p-nitro-benzyloxy, so as to produce the 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid p-nitrobenzyl ester.

6. Process according to Claim 1, characterised in that a starting material of the formula III or IVa is used, wherein R? is phenyloxyacetyl and R? is diphenylmethoxy, so as to produce the 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester.

7. Process according to Claim 1, characterised in that a starting material of the formula III or IVa is used, wherein R? is D-.alpha.-tert.-butyloxycarbonylamino-.alpha.-phenyl-acetyl and R? is diphenylmethoxy, so as to produce the 2-[4-(p-toluenesulphonylthio)-3-(D-.alpha.-tert.butoxycarbonyl-amino-.alpha.-phenylacetamido)-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester.

8. Process according to Claim 1, characterised in that a starting material of the formula III or IVa is used, wherein R? phenylacetyl and R? is diphenylmethoxy, so as to produce the 2-[4-(p-toluenesulphonylthio)-3-phenyl-acetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid di-phenylmethyl ester.

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