Note: Descriptions are shown in the official language in which they were submitted.
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,
-- 1 --
. ~ .
~ .
. .. .... , . , ,. ,. - . . ... . .. -
. ~ : - . : . .
. .- . : : - ~ . :-, , . : . . . :
;'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
-- 2 --
~ : .
... . : . . - , ,
. : , . . : . . - :
.: .. , ~ : . .. .
., : ,
.. : . . ..
~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-
- 4 -
' ~ '
- . . . : .
~, . . .. , -
:: , , : ; . . , - :
.. . . .
. . .... : . . .
.
~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,
:: :
- 6 -
, ~
, - ~ . ~, , ~ -. . , , -
~ 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
- 8 -
:~
.. . ..... . : . ,. . .. ., . , .. . ~ . , . . ~ . ~ ; - , ,
.;., ~ ~ ' -
, . .
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
- 12 -
-,`, .',"' .' ' . . ' ' ,: ' . ' . ~ . '. ' . : . . . ' ' . .
~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
- 14 -
.
:
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.
- 15 -
. ~ .
1 , :
S5
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-
- 16 -
,.~",.. , . , . , , . ....... . . . . , ............. , -. . .
. ~ .. , ~ . . . . . , ,~ , ., -, ................. -
~ ;'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
' .
:
21-
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
: , '
--26--
.: :
. ~ . 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
2 7-
-, .. .: . 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~ :
-28-
~ ~ . . . . ...... . .. . ... .
~ ' ' . ~' ' ~ , '
: ' :. .~ ' ' ' , : '
~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.
, :
: '~
29-
.. . :.
.
. . . - : . , . -; . -
. . .. .:
,. . . . . , . - . .
': ~ ~ : , . ~ , 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
-31-
.~
.~ . , ~ .
.
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,
... .
,
~ ; :
.
--3 2--
. , ., .. , ; .. , ., . . .. . , , . - ~ .. . .. . .. . .
.. .: .. : : . . ... .. .. : . . ., ,, . . : - . ..
~¢~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~-
, . . ., ~. . . .
-39-
. . ~ . . . . . .
~ 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~
- 42 -
,;, : , .:
;~.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.
.
- 46
`
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 ~ ~
-- 48 --
:.' : ~
.. ... . - . . . . ~ . - . . . , - , . . .. . , . . . . - ..
. .. ~ , . .. ~ : -
.
;
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-
_..~. ~
` -
755
,
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
, .. . .. ... .. , - . . - .. . . . . ..
67SS
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
. ::
6S
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
97
,. ,: ` _ ~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
_ ~ ,,"
.
5 5
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.
,
75S
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
:
~ . ~ , .. . ,, , . , ' , ; : .
7S5
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
