Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~l2~6~3~
This invention relates to novel cephalosporins,
processes for producing said cephalosporins, an antibacterial
agen-t containing said cephalosporins. In particular the present
invention relates to intermediates for the producting of said
cephalosporins and a process for producing said intermediates.
This applica-tion is a divisional application of
copending application No. 441,286 filed November 16, 1983 which
is directed to the novel cephalosporins and their preparation.
1~
The present inventors have conducted studies with the
ajm of discovering compounds having a broad antibacterial spec-
trum, exhibiting an excellent antibacterial activity against
gram-position and gram-negative bacteria, being stable to ~.-
lactamase produced by bacteria, having a low texicity, being at
the same time well absorbable upon oral or parenteral adminis-
tration and having an excellent therapeutic effect on ~he
diseases of human beings and animals. As a result, it has been
found that novel cephalosporins characterized in that a
2~ substituted or unsubstituted 2,3-dioxo-1,2,3,4-te-trahydropyra-
zinyl, 2-oxo-1,3-dihydropyrazinyl, 3,6-dioxo-1,2,3,6-tetra-
hydropyridazinyl or 6-oxo-1,6-dihydropyridazinyl group is
attached to the exomethylene group at the 3-positlon of the
cephem ring through a carbon-nitrogen bond and the following
~5 group is attached to the amino group at the 7-position, have the
above-mentioned excellent properties:
'
.; .
:`
-, ~
,- ' . . . .' ': .,
~2'~
5 ~ N ~ A-CO-
S R4
1 wherein A, R~ and R5 are as defined below.
It is an object of this invention to provide
novel cephalosporins having the above-mentioned chemical
structural characteristic features, having a broad
5 antibacterial spectrum, being stable against ~-lactamase
produced by bacteria, having a low toxicity, being well
absorbed upon oral or parenteral administration, and
having an excellent therapeutic effect on the diseases
of human beings and animals.
It is another object of this invention to j
provide a process for producing said novel cephalosporins.
It is a further object of this invention to
provide an antibacterial agent containing said cephalos-
porins.
lS It is a still further object of this invention to
provide intermediates for the production of said novel
cephalosporins and to provide a process or producing
said intermediates.
Other objects and advantages of this invention
will become apparent from the following description.
According to this inven~ion, there is provided
a novel cephalosporin, particularly a cephalosporin re-
presented by the following formula, or a salt thereof:
- ~ ' ':'': - '. ' " ''. ' '
, - . -; ., :
~: .
'- . ' ': ', ~
~2~6~3~
N ~ A--CONH ~1~ ~ 2
R5--l~ S R4 ~N~ CH2R [ I ]
COOR
1 wherein Rl represents a hydrogen atom or a carboxyl-
protecting group; R2 represents a group of ~he formula,
~ N ~--R9-~ ~ 12
R13
J~Rl 4
i I in which R6 represents a hydrogen atom~
-N ~ `R15
a hydroxyl groupj a nitro group, a carbamoyl group,
a thiocarbamoyl group, a sulfamoyl group or a sub-
stituted or unsubstituted alkyl, alkenyl, alkynyl,
alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl,
aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cyclo-
alkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl,acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl,
cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl,
alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl,
dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl,
alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyl-
sulfonylthiocarbamoyl, arylsulfonylthiocarbamoyl,
alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl,
` . ' . ~ . : , '' . ' .
.
' ~
~2~
1 alkylideneamino, cycloalkylmethyleneamino, arylmethylene-
amino, heterocyclic me-thyleneamino, or heterocyclic
R16
group, or a group of the formula, -M < 17 ~each o~
R16 and R17, which may be the same or different, re-
presents a hydrogen atom or an alkyl group or R16 and
R17 together with their adjacent nitrogen atom may
form a ring); each of R7, R8 R9 R10 Rll 12 14
and R15r which may be the same or different, represents
a hydrogen atom, a halogen a~om or a substituted or
unsubstituted alkyl, aralkyl or aryl group; R13 represents
a hydrogen atom, a halogen atom, a carboxyl, sulfo,
carbamoyl or t~iocarbamoyl group, or a substituted or
unsubstituted alkyl, aralkyl, aryl, alkoxy, alkylthio,
acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxy-
carbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkyl-
sulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkyl-
carbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkyl-
thiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkyl-
sulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonyl-
thiocarbamoyl or arylsulfonylthiocarbamoyl group; R3represents a hydrogen atom or an alkoxy group; R4
represents a hydrogen atom or a halogen atom; R5
represents a hydrogen atom or a protected or unprotected
amino group; and A represents a group of the formula~
--C--
-CH2- or a group of the formula, N in which R
~R18
.: . ~ -, . . : . .
.. ", ' ' " ' ~ ", ,...... ' : . ,
:~2~ L39
1 represents a hydrogen atom, a substituted or unsubstituted
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl,
aryl, heterocyclic group or a hydroxyl-pro-tecting group;
or a group o the formula, ~P \ 20 (each of Rl9 and R ,
which may be the same or different, represents a hydroxyl,
alkyl, aralkyl, aryl, alkoxy, aralkyloxy, or aryloxy
group), and the bond ~vvmeans that the compound may be
a syn-isomer or an anti-isomer or a mixture thereof.
This invention also provides a process for
producing said cephalosporins and salts thereof, an anti-
bacterial agent containing said cephalosporins, inter-
mediates for the production o said cephalosphorins and
a process for producing said intermediates.
This invention will be further illustrated
in detail ~elow.
Herein, unless otherwise speciied, the term
"alkyl" means a straight or branched chain Cl 14alkyl
and includes, for example, methyl, ethyl, n-propyl, iso-
propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl,
hexyl, heptyl, octyl, dodecyl, lauryl and the like; the
term "alkoxy" means -O-alkyl in which the alkyl is as
deined above; the term "lower alkyl" means a straight
or branched chain Cl 5alkyl and includes, ~or example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec.-butyl, tert.-butyl, pentyl and the like; the term
"lower alkoxy" means -O-lower alkyl in which the lower
-- 5 --
:.. , -, . .
- , ~ ~ .
-: . . , ;
- ~ .
- - : ~ . .
- -. ' ~ . :: .
- . .
1 alkyl is as defined above, the term "acyl" means
a formyl grou~; a C2 5alkanoyl group which includes,
for example, acetyl, propi.onyl, isovaleryl, pivaloyl,
pentanecarbonyl and the like; a C5 8cycloalkanecarbonyl
group which includes, for example, cyclopentylcarbonyl,
cyclohexylcarbonyl and the like; an aroyl group which
includes, for example, benzoyl, toluoyl, 2-naphthoyl
and the like; and a he~erocyclic carbonyl group which
includes, for example, thenoyl, 3-furoyl, nicotinoyl
and the like, the term "acyloxy" means -O-acyl in
which the acyl is as defined above; the term "alkylthio"
means -S-alkyl in which the alkyl is as defined above;
the term "alkenyl" means C2 1Oalkenyl and includes, for
example, vinyl, allyl, isopropenyl, 2-pentenyl, butenyl
and the like; the term "alkynyl" means C2 lOalkynyl
and includes, for example, ethynyl, 2-propynyl and the
like; the term "cycloalkyl" means ~3 7cycloalkyl and
includes, for example, cyclopropyl, cyclobutyl, cyclo-
pentyl, cyclohexyl, cycloheptyl and the like; the term
"alkadienyl" means C4 1Oalkadienyl and includes, for
example, 1,3-butadienyl, 1,4-hexadienyl and the like; the
term "cycloalkenyl" means C5 7cycloalkenyl and includes,
for example, cyclopentenyl, cyclohexenyl and the like;
the term "cycloalkadienyl" means C5 7cycloalkadienyl and
includes, for example, cyclopentadienyl, cyclohexadieny~
and the like; the term "aryl'' includes, for example, phenyl,
naphthyl, indanyl and the like; the term "aralkyl"
includes, for example~ benzyl, phenethyl, 4-methylbenzyl,
'
.
, . . ' ', . , ., ' '`" ',, '
.
'. ~ ' ~ ~ ' ' '
,~ ' ' . ' ,
~;27~
1 naphthylmethyl and -the like; the ~erm "heteroc~clic group"
means a heterocyclic yroup containing at least one he-tero
atom selected from oxygen, nitrogen and sulur and in~
cludes, for exàmple r furyl, thienyl, pyrrolyl, pyrazolyl,
imidazol~l, thiazolyl, isothiazolyl, oxazolyl, lsoxazol~l,
thiadiazolyl, oxadiazolyl, thiatriazolyl, oxa-triazolyl,
triazolyl, tetrazolyl, pyridyl, 4-~5-metyl-2-pyrrolinyl),
4-(2-pyrrolinyl), N-methylpiperidinyl, quinolyl, phenazinyl,
1~3- benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl,
ben20thiazolyl, phthalidyl, coumarinyl and the like; the
term "heterocyclic alkyl" means a group consisting of
the above-defined heterocyclic group and the above-
defined alkyl group; and the term "halogen atom" includes,
for example, fluorine, chlorine, bromine and iodine.
The symbol Rl in the formulas in this
specification represents a hydrogen atom or a carboxyl-
protecting group, and the carboxyl-protecting group
includes those which are conventionally used in the fields
of penicillins and cephalosporins, for example, an
ester-forming group which can be removed by a catalytic
hydrogenation, a chemical reduction, or a treatment under
other mild conditions; an ester-forming group which can
be easily removed in a living body; or an organic silyl-
containing group, an organic phosphorus-containing group,
or an organic tin-containing group or the like, which
can easily be removed upon treating with water or an
alcohol; and other various well-known ester-forming
groups.
7 --
.- , . . . . .
.
,: . , .
.. , ~ .
~:7~ 3~
1 Amon~ these protecting groups, preferable
groups are as follows:
(a) alkyl groups, for example, Cl 4alkyl,
(b) substituted lower alk.yl groups wherein a~ least
one of the substituents is selected from a halogen atom,
or a nitro, acyl, alkoxy, oxo, cyano, hydroxyl, cyclo-
alkyl, aryl, alkylthio, alkylsulfinyl, alkylsul~onyl,
alkoxycarbonyl, 5-alkyl-2-oxo-1,3-dioxol-4-yl, l-indanyl,
2-indanyl, ~uryl, pyridyl, 4-imidazolyl, phthalimido,
succinimido, azetidino, aziridino, pyrrolidino, piperidino,
morpholino, thiomorpholino, N-lower-alkylpiperazino,
pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl,
oxatriazolyl, tria~olyl, tetrazolyl, quinolyl, phenazinyl,
lS benzo~uryl, benzothienyl, benzoxazoly~, benzothiazolyl,
coumarinyl, 2,5-dimethylpyrrolidino, 1,4,5,6-tetrahydro-
pyrimidinyl, 4-methylpiperidino, 2,6-dimethylpiperidino,
4-(S-methyl-2-pyrrolinyl)~ 4-(2-pyrrolinyl), N-methyl-
piperidinyl, 1,3-benzodioxolanyl, alkylamino, dialkyl-
amino, acyloxy, acylthio, acylamino, dialkylaminocarbonyl,alkoxycarbonylamino, alkenyloxy, aryloxy, aralkyloxy,
cycloalkyloxy, cycloalkenyloxy, heterocyclic oxy, alkoxy-
carbonyloxy, alkenyloxycarbonyloxy, aryloxycarbonyloxy,
aralkyloxycarbonyloxy, heterocyclic oxycarbonyloxy,
alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,
cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, hetero-
cyclic oxycarbonyl or alkylanilino group or an alkylanilino
yroup substitu~ed by a halogen atom, a lower alkyl or
lower alkoxy ~roup,
- :.- . , . . :
'
- :, ' .~ .: .
.. :
. .
~276~L3~
1 (c) cycloalkyl group; lower alkyl-substituted cyclo-
alkyl group; or (2,2-di~lower-alkyl-1,3-dioxol-4-yl)methyl
groups,
(d) alkenyl groups,
~e) alkynyl groups,
(f) phenyl group; substituted phenyl groups wherein
at least one of the substituents are selected from the
substituents specifically mentioned in above (b); or aryl
groups such as groups represented by the formula:
_~yl
wherein -Y - is -CH=CH-O-, -CH=CH S-, -CH2CH2S-,
-CH=N-CH=N-, -CH=CH-CH=CH-, -CO-CH=CH-CO-, or -CO-CO-
CH=CH-, or a substituted derivative thereof wherein tpe
substituents are selected from those specifically mentioned
in above (b), or groups represented by the formula:
~ ~ 2
lS wherein -Y - is a lower alkylene group such as -tCH2)3-
or -ICH2)4-, or a substituted derivative thereof wherein
the substituents are selected from those specifically
mentioned in above (b),
(g) aralkyl groups su¢h as benzyl or substituted
benzyl groups wherein at least one of the substituents
are selected from those specifically mentioned in above (b),
(h) heterocyclic group or substituted heterocvclic
groups wherein at least one of the substituents are
selected from those speciically mentioned in above ~b),
_ g _
: . - .
`' ~ :' ' , ' ' ~
: . , ' :.
- . . ::. , .
3~
1 ~i) indanyl or phthalidyl groups or substituted
deriva~ives thereof wherein the substituents are methyls
or halogens; tetrahydronaphthyl groups or substituted
derivatives thereof wherein the substituents are methyls
s or halogens; trityl, cholesteryl, bicyclo[4,4,0]decyl;
or the like,
(j) phthalidylidene-lower-alkyl groups or substituted
derivatives thereof wherein the substituents are haloyens
or lower alkyl groups.
The above-mentioned carboxyl-protecting groups
are typical examples, and the carboxyl-protecting group
may also be selected from the other protecting groups
described in the following literature: U.S. Patent Nos.
3,499,909, 3,573,296 and 3,641,018; DT-OS Nos. 2,301,014,
2,253 r 287 and 2,337,105.
Among these carboxyl-protecting groups, pre-
ferable are diphenylmethyl, 5-lower alkyl-2-oxo-1,3-
dioxol-4-yl-lower alkyl groups, acyloxyalkyl groups,
acylthioalkyl yroups, phthalidyl group, indanyl group,
phenyl group, substituted or ur.substituted phthalidylidene
lower alkyl groups or those groups which can easily be
removed in a living body such as groups represented by the
ollowing formulas: -CH(CH2)mOR21, -CHOCOOR 1, and
122 R22
-CH(CH2)mCOOR21 wherein R21 represents a known substituted
l23
or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic
or heterocyclic group; R22 represents a hydrogen atom or a
-- 10 --
, ~
.: : . , . :,
.. .. . : , .
~7~i~3~
1 known substituted or unsubstituted alkyl, alkenyl, aryl,
aralkyl, alicyclic or heterocyclic group; R23 represents
a hydro~en atom, a halogen atom or a known substituted
or unsubstituted alkyl, cycloalkyl, aryl or heterocyclic
group, or -(CH2) COOR (R has the same meaning as
defined above, and n represents 0, 1 or 2); and m repre-
sents 0, 1 or 2.
More specifically, there may be used 5-lower
alkyl-2-oxo-1,3-dioxol-4-yl-methyl groups such as S-
methyl-2-oxo-1,3-dioxol-4-yl-methyl, 5-ethyl-2-oxo-1,3-
dioxol-4-yl-methyl, 5-propyl-2-oxo-1,3-dioxol-4-yl-
methyl and the like; acyloxyalkyl groups such as acetoxy-
methyl, pivalovloxymethyl, propionyloxymethyl, butyryl-
oxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-
acetoxyethyl, l-acetoxy-n-propyl, l-pivaloyloxyethyl, 1-
pivaloyloxy-n-propyl and the like; acylthioalkyl groups
such as acetylthiomethyl, pivaloylthiomethyl/ benzoyl-
thiomethyl, p-chlorobenzoylthiometh~l, l-acetylthioethyl,
l-pivaloylthioethyl, 1-benzoylthioethyl, l-(p-chloro-
benzoylthio)ethyl and the like; alkoxymethyl groups suchas methoxymethyl, ethoxymethyl, propoxymethyl, isopro-
poxymethyl, n-butyloxymethyl and the like; alkoxycarbonyl-
oxyalkyl groups such as methoxycarbonyloxymethyl,
ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, iso-
propox~carbonyloxymethyl, n-butoxycarbonyloxymethyl,
tert.-butoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl,
1- ethoxycarbonyloxyl~hyl 3 l-vropoxycarbonyloxyethyl,
l-isopropoxycarbonyloxyethyl, l-tert.-butoxycarbonyl-
-- 11 ~
.,
. . . . .: . ~, . . -
,; ~ :
.. . , :, .
-': :. ' ,. ,' .... : ':
,
' .: '. . . :
, '
. . .
. : ..
~7~3~
- 1 oxyethyl, l-n-butoxycarbonyloxyethyl and the like;
alkoxycarbonylmethyl groups such as methoxycarbony].-
methyl, ethoxycarbonylmethyl and the like; phthalidyl
group; indanyl group; phenyl group; phthalidilidene-
alkyl groups such as 2-(phthalidylidene)ethyl, 2-(5-
fluorophthalidylidene)ethyl, 2 (6-chlorophthalidylidene)-
ethyl, 2-(6-methoxyPhthalidylidene)ethyl and the like; etc.
R represents a group of the formula:
N ~ 6 \~N \N~ N~
O O O
in which R6 represents a hydrogen atom, a hydroxyl group,
a nitro group, a carbamoyl group, a thiocarbamoyl group,
a sulfamoyl group, or a substituted or unsubstituted alkyl,
alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl,
cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio,
acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cyclo-
alkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl,alkylsulfonyl, cycloalkylsulfo~yl, arylsulfonyl, hetero-
cyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl,
alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl,
acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonyl-
carbamoyl, alkylsulfonylthiocarbamoyl, arylsulfonylthio~carbamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythio-
carbonyl, alkylideneamino, cycloalkylmethyleneamino,
arylmethyleneamino, heterocyclic methyleneamino or
- 12 -
, - ~
' ~ , ' ' ': ,
~- ~ .,..... , , '
. . . . . .
.
.. ' . . - ' . .
: ~, -- - ., , ' .
/R16
-~ l heterocyclic group; a group of the formula, -N\ R17
(each of R16 and R17, which may be the same or different,
represents a hydrogen atom or an alkyl group, or R16 and
R17 together with their adjacent nitrogen atom may form a
ing), each of R , R8, ~9, R10 Rll Rl~ Rl4 15
which may be the same or different, represents a hydrogen
atom, a halogen atom, or a sub~tituted or unsubstituted
alkyl, aralkyl or aryl group; Rl3 represents a hydrogen
atom, a halogen atom, a carboxyl group, a sulfo group, a
carbamoyl gxoup, a thiocarbamoyl group, or a substituted
or unsubstituted alkyl, aralkyl, aryl, alkoxy, alkylthio,
acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxy-
carbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkyl-
sulf~nyl, arylsulfon rl, heterocyclic sulfonyl, alkvl-
carbamoyl, dialkylcarbamoyl, alkvlthiocarbamoyl, dialkyl-
thiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkyl-
sulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonyl~
thiocarbamoyl or arylsulfonylthiocarbamoyl group. ~n each
of the groups for R6 and R13 mentioned above, the term
~0 "cycloalkyloxy" means -O-cycloalkyl, the term "aryloxy"
means -O-aryl, the term "alkoxycarbonyl" means ~ O-alkyl,
the term "cycloalkyloxycarbonyl" means -Il-O-cycloalkyl,
the term "acyloxycarbonyl" means -C-O-acyl, the term
"aralkyloxycarbonyl" means -~-O-aralkyl, the term
"alkylsulfonyl" means -S02-alkyl, the term "cycloalkyl-
sulfonyl" means -S02-cycloalkyl, the term "arylsulfonyl"
- 13 -
-
. ~ ' . ,'' .' .
,
3~
1 means -S02-aryl, the term "heterocyclic sulfonyl" means
-S02-heterocyclic ring, the term "alkylcarbamoyl" means
alkyl
-C-NH-alkyl, the term "dialkyl carbamoyl" means -C-N
O O
the term "alkylthiocarbamoyl" means -C-NH-alkyl, the term
alkyl
"~ialkylthiocarbamoyl" means -C-N/ , the term "acyl-
¦¦ \ alkyl
carbamoyl" means -C-NH-acyl, the term "acylthiocarbamoyl"
means -C-NH~acyl, the term "alkylsulfonylcarbamoyl" means
-C-NH~S02-alkyl, the term "arylsulfonylcarbamoyl" means
O
-C-NH-S02-aryl, the term "alkylsulfonylthiocarbamoyl"
means -C-NH-S02-alkyl, the term "arylsulfonylthiocarbamoyl
means -C-NH-S02-aryl, the term "alkylsulfamoyl" means
-S02-NH-alkyl, the term "dialkylsulfamoyl" means
alkyl
S2 N~ lk 1~ the term alkoxythiocarbonyl" means -C-O-alkyl,
the term "alkylideneamino" means -N=CH-alkyl, the term
"cycloalkylmethyleneamino" means -N=CH-cycloalkyl,
the term "arylmethyleneamino" means -N=CH-aryl,
~ , , . ~ ~ . . . .
~7 6i~
1 and the term "heterocyclic methyleneamino" means -N=CH-
heterocyclic ring.
/R16
The groups of the formula, -N 17
wherein R16 and R17 have the same meanings as defined above
include amino group, alkylamino groups represen-ted by
alkyl
-NH-alkyl, dialkylamino groups represented by -N\
alkyl
and groups represented by the formulas -N~ , -N~,
-N 0, -N NH, -N ~-alkyl, -N ~ , -N ~ ,
~ /N~l /N=N
-N ' -N~G~)=O ' -N S, -N S2 ~ -N~ -N~ or
f N=N
0 -N ¦ -
\~= N
The substituents for the various groups men-
tioned above include halogen atoms, alkyl groups, aralkyl
groups, aryl groups, alkenyl groups, hydroxyl group, oxo
group, alkoxy groups, alkylthio groups, nitro group,
cyano group, amino group, acyl groups, acyloxy groups,
carboxyl group, carbamoyl group, sulfo group, sul~amoyl
group, alkylamino groups represented by -NH-alkyl, dialkyl-
/alkyl
amino groups represented by -N . , acylamino groups
\ alkyl
:- 15 -
. \
.
- :: . . , , . :
. . :.:
,
1 represented by -NH-acyl, alkoxycarbonyl groups re-
presented by -C-O~alkyl, acylalkyl groups such as acetyl-
methyl, propionylmethyl and the like, aminoalkyl groupssuch as aminomethyl, aminoethyl and the like, N-alkyl-
aminoalkyl groups such as N-methylaminomethyl, N-methyl-
aminoethyl and the like, N,N-dialkylaminoalkyl groups
such as N,N-dimethylaminomethyl, N,N-dimethylaminoethyl
and the liXe, hydroxyalkyl groups such as hydroxymethyl,
hydroxyethyl and the like, hydroxyiminoalkyl groups.such
as hydroxyiminomethyl, hydroxyiminoethyl and the like,
alkoxyalkyl groups such as methoxymethyl, methoxyethyl,
ethoxymethyl, ethoxyethyl and the like, carboxyalkyl
groups such as carboxymethyl, carboxyethyl and the like,
alkoxycarbonylalkyl groups such as methoxycarbonylmethyl,
methoxycarbonylethyl, ethoxycar~onylmethyl, ethoxycarbo-
nylethyl and the like, aralkyloxycarbonylalkyl groups such
as benzyloxycarbonylmethyl, benzyloxycarbonylethyl and
the like, sulfoalkyl groups such as sulfomethyl, sulfo-
ethyl and the like, sulfamoylal.kyl groups such as sulfa-
moylmethyl, sulfamoylethyl and the like, carbamoylalkylgroups such as carbamoylmethyl, carbamoylethyl and the
like, carbamoylalkenyl groups such as carbamoylallyl and
the like, N-hydroxycarbamoylalkyl groups such as N-hydroxy-
.carbamoylmethyl, N-hydroxycarbamoylethyl and the like,
a group of the formula -C = C\-R 4 in which R 4 represents
0~0 :
- 16
- . . . , , :
: ~, - . . . : . :
~ . . : . . , : - ~ .
3~
1 a lower alkyl group, etc. The above-mentioned various
groups as to R6, R7, ~8, R9 R10 Rll R12 R13 Rl~ a d
R15 may be substituted by at least one of the above-
mentioned substituents. Among the above substituents,
the hydroxyl group, the amino group and the carbaxyl
group may be protected by ~ suitable protecting group
usually a~ailable in the art. The hydroxyl-protecting
groups include all hydroxyl~protecting groups which can
be usually used, such as easily remo~able acyl groups,
ln for e~ample, ben~yloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxy-
carbonyl, 4-(4-methoxyp~enylazo)benæyloxycarbonyl, tert.-
butoxycarbonyl, l,l-dimethylpropoxycarbonyl, isopropoxy-
carbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxy-
carbonyl, 2,2,2-tribromoethoxycarbonyl, 2-furfuryloxy-
carbonyl, l-adamantyloxycarbonyl, l-cyclopropylethoxy-
carbonyl, 8-quinolyloxycarbonyl, formyl, acetyl, chloro-
acetyl, benzoyl, trifluoroacetyl and the like; alkyl-
sulfonyl groups, for example, methanesulfonyl, ethane-
sulfonyl and the like; arylsulfonyl groups, for example,
phenylsulfonyl, toluenesulfonyl and the like; benzyl
group; diphenylmethyl group; trityl group; methoxymethyl
group; tetrahydropyranyl group; tetrahydrofuranyl group;
2-nitrophenylthio group; 2,4 dinitrophenylthio group; and
the like.
In addition, the amino-protecting groups
include all usually usable amino-protecting groups such
- 17 -
; ~' ' ~ '; ' , "' ' :
.
1 as easily removable acyl groups, fo~ example, 2,2,2-
trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,
benzyloxycarbonyl, p-toluenesul~onyl, 4-nitrobenzyloxy-
carbonyl, 2-bromobenzyloxycarbonyl, acetyl, (mono-, di-,
tri-)chloroacet~l, trifluoroacetyl, formyl, tertO-amyloxy-
carbonyl, tert.-butoxycarbonyl, 4-methoxybenzyloxycarbo-
nyl, 3/4~dimethoxybenzyloxycarbonyl, 4-(phenylazo)-
benzyloxycarbonyl, 4-(~-methoxyphenylazo)benzyloxycarbo-
nyl, pyridine-l-oxide-2-yl-methoxycarbonyl, 2-furyloxy-
carbonyl, diphenylmethoxycarbonyl, l,l-dimethylpropoxy-
carbonyl, isopropoxycarbonyl, l-cyclopropylethoxycarbonyl,
phthaloyl, succinyl, l-adamantyloxycarbonyl, 8-quino-
lyloxycarbonyl and the like; further easily removable
groups, for example, trityl, o-nitrophen~lsulfonyl,
2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-
chlorobenzylidene, 2-hydroxy-l~naphthylmethylene, 3-
hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propyli-
dene, l-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-
2-butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-pro-
pylidene, 1-[N-~2-methoxyphenyl)carbamoyl]-2-propylidene,
l-[N-I4-methoxyphenyl)carbamoyl]-2-propylidene, 2-ethoxy-
carbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene,
2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene,
4~ ni~rofurfurylidene and the like: di- or tri-alkylsilyl
group, and the like. Then, the carboxyl-protecting groups
include all usually usable carboxyl-protecting
groups, and there are cases where the carboxyl group is
protected by such a group as methyl, ethyl, n-propyl, iso-
propyl, ter-t.-butyl, n-butyl, benzyl, diphenylme.thyl,
- 18 -
.
- ' ' ':
l t.rilyl, ~-nitrobenzyl, 4-methoxybenzyl, benzoylmethyl,
acetylmethyl, 4-nitrobenzoylmethyl, p-bromobenzoyl-
methyl, ~-methanesulonylbenzoylmethyl, phthalimido-
methyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2-propenyl,
l,l-dimethylpropyl, acetoxymethyl, propionyloxymethyl,
pivaloyloxymethyl, 3-methyl-3-butynyl, succinimido-
methyl, l-cyclopropylethyl, methylthiomethyl, phenylthio~
methyl, dimethylaminomethyl, quinoline-l-oxide-2-ylmethyl,
pyridine-l-oxide-2-ylmethyl, b.is(p-mathoxyphenyl~methyl
l~ and the like, where the carboxyl group is protected by
a non-metal compound such as titanium tetrachloride, and
where the carboxyl group is protected by a silyl compound
such as dimethylchlorosilane as described in Japanese
.Patent Application Kokai (laid-Open) No. 7073/71 and Dutch
Patent Application No. 7105259 (Laid-Open).
R5 represents a hydrogen atom or a protected or
unprotected amino group, and such amino-protecting groups
include many groups usually employed in the fields of
penicillins and cephalosporins, specifically all the
amino-protecting groups mentioned above as to R2.
A represents a group of the formula, -CH2- or
--C--
a group of the formula, N in which Rl8 represents a
oR18
hydrogen atom; a substituted or unsubstituted alkyl, alke-
nyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, hete-
rocyclic group or a hydroxyl-protecting group, or a group
.:: - 1 9
: . .
,
` . ' . ~ ~ . ' ' '. ' ' '
. - . . . . .
' . .: : . '':' :
.
3~
1 of the formula, ~P / 20 (each of Rl9 and R20, which may be
the same or dif~erent, represents a hydroxyl, alkyl,
aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group) and
the bond ~A~ means that the compound may be a syn-
isomer or an anti-isomer or a mixture thereof. The said
hydroxyl-protecting group includes the hydroxyl-protecting
groups mentioned as to R2. In addition, the above~mentioned
various yroups for R18 may be substituted by at least one
substituent selected from halogen atoms, oxo group, cyano
group, hydroxyl group, alkoxy groups, amino group, alkyl-
amino groups, dialkylamino groups, heterocyclic ~roups
and groups of the formulas -COORl, -CON ~ 25' -N ~ R226 ,
-NHCoR25 and -Il<oR26 wherein Rl has the same meaning as
defined above, and each of R25 R26 a d R27
the same or different, represents a hydrogen atom, an
alkyl group, an aralkyl group or an aryl group. Among
these substituents, the hydroxyl group, the amino group,
and the carboxyl group may be protected respectively by
the hydroxyl-protecting group and the amino-protecting
group mentioned as to R2 and the carboxyl-protecting
group mentioned as to Rl.
The oximes of the Eormula, N include syn-
OR 8
and anti-isomers and mixtures thereof.
- 20 -
' - , .~ ' ' ' ' . ''' . , ,~
.
-
~276~
l In the R5~ ~ group of each formula in
R
this invention, there are tautomers as shown by the
following equilibrium formulas where R5 is a protected
or unprotected amino group, and such tautomers are
included in this invention:
R ~S ~ ~ S ~ 4
wherein R4 and R5 have the same meanings as defined above,
and RSa represents a protected or unproteGted imino group.
In the above formulas, the imino-protecting group for R5a
includes those groups used in the fields of penicillihs
and cephalosporins, and specifically, same groups as the
monovalent groups among the amino-protecting groups
mentioned above as to R2.
When the -CH2R2 group in the formula [I] is a
group of the formula:
-CH2-N N-R6 R - N ~ wherein R6, R , Rll
and R12 have the same meanings as defined above, there
are tautomers as shown in the following equilibrium formulas
when each of R6 and R10 is a hydrogen atom, and the
tautomers are also includ~ed in this invention:
O O ~ O OH
-CH2-N Na = -CH2-N N
- 21
... . . . . . . .
. .
. : .: .
: ~, ':: . : :, . .
~.;, : '
3~
R
-CH2-N 12 ~ -- -CH2--N R12
O O
1 The ~alts of ~he compounds of formul~ [I] include sal-ts at
the basic group and the acidlc group which are well-known
in the fields o~ penicillins and cephalosporins. The
salts at the basic group include salts with mineral acids
such as hydrochloric acid, nitric acid, sul~uric acid
and the like; salts with organic carboxylic acids such as
o~alic acid, succinic acid, ~ormic acid, trichloroacetic
acid, trifluoroacetic acid and the like; ànd salts with
sulfonic acids such as methanesulfonic acid, ethanesulfo-
nic acid, benzenesulonic acid, toluene-2-sulfonic acid,
toluene-~-sulfonic acid, mesitylenesul~onic acid ~2,4,6-
trimethylbenzenesulfonic acid), naphthalene-l-sulfonic
acid, naphthalene - 2-sulfonic acid, phenylmethanesulfonic
acid, benzene-1,3-disulonic acid, toluene-3,5-disulfonic
acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-
disulfonic acid, napthalene-2,7-dis~l~onic acid, benzene-
1,3,5-trisulfonic acid, ~enzene-1,2,~-trisulfonic acid,
naphthalene-1,3,5-trisulonic acid and the like. The salts
at the acidic group include salts with alkali metals such
as sodium, potassium, and the like; salts with alkaline
earth me~als such as calcium, magnesium and the like;
ammonium salts; and salts with nitrogen-containing organic
bases such as procaine, dibenzylamine, N-benz~
phenethylamine, l-ephenamine~ N,N-dibenzylethylenediamine,
.. . . . , :. . . . .
-. . ' -:~ . , .: . , : .
- - ., : .. '
- . - -:: . . . ~ : . ,
' ' ' , ' . .
~2~ 3~
1 triethylamine, trimethylamine, tr.ibutylamine, pyridine,
NrN-~imethylaniline, . N-methylpiperidine, N-methylmorpho-
line, diethylamine, dicyclohexylamine and the like.
This invention includes all optical isomers and
the racemic compounds of cephalosphorins of -the formula
~I] and their salts, and also all crystal forms and
hydrates o the said compounds. More specifically, pre-
ferable examples of the compounds represented by the formula
--C--
[I] are~ oximes in which A is a yroup of the formula, N
OR18
particularly syn-isomers thereof, in which R18 is preferably
an alkyl group, especially methyl, ethyl; or a substltuted
alkyl group, especially -CX2COORl or -C-COORl (Rl has the
CH3
same meaning as defined abo~e).
Preferable examples of R2 are groups of the
formula, -~=J_R6 in which R is a hydrogen atom, a sub-
stituted or unsubstitute~?lower ~kyl ~roup or a ~roup o~ the
R16
ormula, -N/ 17 (R and R have the same meanings
as defined above); groups of the formula, R ~ N
N~ ` R9
in which each of R7, R8 and R9, which may be the same
- 23 -
.
. .
. , . . . . '
.
1 or different, represents a hydrogen atom or an alkyl
R10 o R~1
group; groups of the formula, N~ in which
o
each of R10, Rll and R12, which may be the same or dif-
ferent, represents a hy ~ gen atom, a halogen atom or
an alkyl groupt and groups of the formula, I ~ ~
~\ R
in which each of R13, R14 and R15, which may be the
same or different, represents a hydrogen atom or an
alkyl group.
Next, pharmacological effects are shown on -
some typical compounds represented by the formula .[I].
1) Antibacterial activity ~Table 1~
According to the standard method of Japan
Society of Chemotherapy l'iCHEMoTHERAPY", Vol. 23, pp. 1-2
(1975)], a bacterial solution obtàined by culturing in
Heart Infusion broth (manufactured by Elken Kagaku) at
37C for 20 hours was inoculated onto a Heart In~usion
agar containing a drug and cultured at 37C ~or 20 hours,
after which the growth ~of the bacteria was observed, to
determine the minimum concentration at which the growth
o the bacteria:was inhibited a~ MIC l~g/ml). The amount
- 24 -
~'~7~
- 1 of the inoculated bacteria was 104 cells/plate
(106 cells/ml~. The MIC values of the following test
compounds are as shown in Table 1:
(A) trifluoroacetic acid salt of 7-[2-(2-amino-
thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{~1-(2,3-
dioxo-1,2,3,4-tet~ahydropyrazinyl)]methyl}-~3-cephem-
~-carboxylic acid,
~B) trifluoroacetic acid salt of 7-[2-(2-amino-
thiazol-4-yl~-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-
methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-
-cephem-4-carboxylic acid,
(~) trifluoroacetic acid salt of 7-[2-(2-amino~
thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-
ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-
~3-cephem-4-carboxylic acid,
(D) trifluoroacetic acid salt of 7-[2-(2-amino-
thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-
isopropyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-
~3-cephem-4-carboxylic acid,
(E) trifluoroacetic acld salt of 7-[2-(2-amino-
thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-
dimethylamino-2,3~dioxo-1,2,3,4-tetrahydropyrazinyl)]-
methyl}-~3-cephem-4-carboxylic acid,
(F) 7-[2-(2~aminothiazol-4-yl)-2-(syn)-carboxy-
methoxyiminoacetamido]-3-~[1-(2,3-dioxo-1,2,3,4-tetra-
hydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid,
(G) trifluoroacetic acid salt of 7-[2-(2-amino-
thiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamido]-3-
- 25 -
.
: . .
.
, -
- :
,
6~
1 {[1-(4-methyl-2,3-dioxo-1,2,3,4--tetrahydropyrazinyl)]-
methyl}-~3-cephem-4-carbo~ylic acid,
IH) trifluoroacetic acid salt of 7-[2-(2-amino-
thiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamido]-3-
{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-
methyl}-~3-cephem-4-carboxylic acid,
(I) ~rifluoroacetic acid salt of 7-[2-(2-amino-
thiazol-4-yl)-2-(syn~-carboxymethoxyiminoacetamido]-3-
{[1-(4-dimethylamino-2,3-dioxo-1,2,3,4-tetrahydro-
pyrazinyl)]methyl}-~3-cephem-4-carboxylic acid,
(J) txifluoroacetic acid salt of 7-[2-(2-amino-
thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(2-
oxo-1,2-dihydropyrazinyl)]methyl}-~3-cephem-4-carboxylic
acid,
(K) tri~luoroacetic acid salt of 7-[2-(2-amino-
thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(3,6-
dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-Q3-cephem-
4-carboxylic acid,
(L) formic acid salt of 7-[2-~2-aminothiazol-4-yl)-
2-lsyn)-carboxymethoxyiminoacetamido~-3-{[1-(3,6-dioxo-
1,2,3,6-tetrahydropyridazinyl)]methyl}-Q3-cephem-4-
carboxylic acid,
(M) trifluoroacetic acid salt of 7-[2-(2-amino-
thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(3-
methyl-6-oxo-1,6-dihydropyridazinyl)]methyl}-Q3-cephem-
4-carboxylic acid, and
(N) formic acid salt.of 7-[2-~2-aminothiazol-
4-yl)-2-tsyn)-carboxymethoxyiminoacetamido]-3-
- , . :. ~ ...... . . .
.. ~ . . . .
- . . , ~ . . .:
: .
39
1 {[1-~3-methyl-6-oxo-1,6-dihydropyridazinyl~]methyl}-~ -
cephem-4-carboxylic acid.
27 -
: :
3~
_ _ _ _ _ _
a~ co co
,~ ~ ,~ ~ ,~,-, ~ ,_
,, . .. l l . . . . . . ,
o o o o oo o C~ o
1Vll _ Vll Vll Vll_ __ _ ~J
_ __ _ _ __ __ ~D _ O
C~ ~ ~ ~ ~ ~ r~ r~ ,_~ r-l ~~ Lr~ ~
H H . . . . . . . . . . .
~ O O O O O O O O O O ~ ~
vn Vll VllVllVllVll Vll ~1
_ _ _ _ _. . ~9 In
r~ r~ ~ r~ ~ r~ r~ r~ ~ r~ I
. . . . . . . . . . .
O O O O O O O O O O ~ U~
_ Vll Vll Vll Vll Vll Vll Vll V
~ D
r~ r~ r~ r~ r~ U~
. . . . . . ~ . . . .
OO O O O O O O O O r-l
vn _ vn VllVllVllVllVO
a~ co
r-~r-l r-l ~) ~`1 r-l r-l r-~ r~ r-~
. . . . . . . . . . .
OO O O O O O O O O O
VllVllVll VllVllVllVllVll
_ _~ CO
,~ ,~ ,~ ,~ ,~ ,~ ,~ ,~ n ,_
~ ~ . . . . . . . . . . .
-rl O O O O O O O O O r-l O
vn Vll vn Vll Vll Vll Vll Vll Vll
~r~ _ __
~n ~9
r~ r~ r~ r~ ~ ~ r~ r~ ~ ~ In
r-l ~'1 ~ . . . . . . . . . . .
O O O O O O O O O O r-l
~D r-~ Vll vn Vll vn_ vu Vll Vll _
r~ __ __ _ _ _ __
`~ r~ r~ r~ r~ r~ r~ r~ r~ r~ ~D ~ In
C~ . . . ., . . . . . . . .~
O O O O O O O O O r-l O ~9
Vll Vll Vll Vll Vll Vll Vll Vll Vll
_ _
~r~ r~ r~ r~ r~ ~ r~ r~ r~ r~ ~ L~
m . . . . . . . . .. . ~
O O O O O O O O O O ~I
'¢ VU Vll VllVll Vll vnvu Vll
_ _ _ ~ _
r~ r~ r~ r~r~ r~ r~ ~ ~r~ ~U~
. . . . . . . . . . . .
O O O O O S~ O O O O O~1
\'D VU vn vnVllVll vnvn vnvn ~
*
o *
'Cl er ~ ~ r~ ~ 0
O r~ * ~ ~D ~ ~~D r~
n er~r ,~ ~ ~ r~I` r~cn
O ~ l l l H l l Z l Z
Q. ¦ ~ ~ ~ 3 HE~ E-l ~ Zt~
E31 u~ u~
U~
~C (1~ 1~1 11~ (U (I) .,1 ~r~ U~ ~r~ Ul
~ ) ~r~ ~rl ~r-l O O ~rl r~l ~rl .,1 O
m l ~ ~ ~ u~ u~ ~ ,~ h ~a ~:
¦ ~ H E~ ~ ~ ~J S-l h O ~ ::1 .
1.~ ro ,o Q s:: ~ E~ E3 ~ E~ ~ ~ ~
I~ c~ O . . . . . .
I t~ . . . ~ ~ O O O ~) .
I s~ . . ~1 ,~ ,~ a~ a) s~ ~ ~ .,, u~
_ K _ u~ _ ~ _ ~ ~ _
-- 28 -
, .:
- :
. ' : ' ' , .
. : .
... .
3~
U~ ~
.,,
~ ~,
.,, ~
~, o
o
s~ ~
~n
f~
U~ ,,
5~
o
.,,
~ U~
,, o
.,. ..
C)
.,, .~ .
a
U
*
~C
.. .
~ .
Z;
~ _ ~_ ___, ~ ~ ,, I~ _ '
Z; . . . , , . . : . . . .
o o oo o o o o o
_ _ Vll _ __ Vll Vll Vll Vll Vll .
~ 1-1 t~ t~l~I ~I C~ ~ CO .
~ ~ . . . ~ l i . . . . . . l
~0 _ 01~ C~ O _ O O Cl O O O _
:~ CO : ~O :
~11~ ~ ~1 U~ ~1 ~ ~ ~
~ ~. . . l l . . . . . ~ l
O O O O r-~ O O O ~
.4 vn _ vn _ vn vn vn co _
~I ~ ~I ~I ~ :,~ ~I ~ I~
E~ K . . . l l . . . .. . i
o o o o o o o o o
Vll Vll ~ Vll VII Vll Vll Vll
~ - 29 -
`: `. ,` - : -. . . : ., .. . : . , .' ... .
. . , , . ~ , ,
.. . :
3~31
1 2) Urinary recovery
A test compound was orally administered to mice
~ICR, male, 4 weeks old) in an amount of 1 my/mouse, and
a urinary recovery was determined. The results obtained
are shown in Table 2.
In the test compounds (No. 1 and No. 2), the ester
group is easily removed in a living body, whereby the com-
pounds are converted into the corresponding free carboxylic
acids. Therefore, the urinary recovery was determined by
quantitatively measuring the free carboxylic acids
excreted into urine.
Administration method: A test compound sus-
pended in 0.5~ CMC (Carboxy Methyl Cellulose) was orall.y
administered.
Quantitative measurement method: The amount of
free carboxylic acid was measured by bioassay ~a paper-disc
methodj usi~g the test organism mentioned in Table 2.
~ - 30 -
, - : , : .
~7~3~
.
# . .
~ ~ ~ .. , ,,
,~ ~ _ +, ~, ~,
~ ~ o~o
~ O~ a~ . ~
~ a~ ~ o o
~ ~i
R . o
~n ~ ~ ~ ~
" U~ ~ ~ o
a) ~ ~ o
a E~ ~ U _~ .
/~ ~ ~ ~ ~=C t~
~,~
~;~n
~ u ~ ~û~ ~
D
U : O .q
l ' ~ , .
~ ~ ~ u~
-z = ,~ ~ Z
:
-- 3 1
: . ` , . : .
. :. . ` , ` . .
- ~- . : . . ~ . ` ., ` . ` . .
:, : ` ` ` . : `. :
`` . , ~ . : ` . . .
:' : '' ,` ,.. ~ : ~ . ,
. . . . .
12'76~3~
1 3) Acute toxicity
LD50 values of the following test compounds
were 3 g/kg or more when the compounds were intravenously
administered to mice (ICR, male, body weight 20-24 g).
Test compounds:
o Sodium 7-[2-t2-aminothiazol-4-yl)-2-(syn)-
methoxyiminoacetamido]-3-{[1-(2,3-dioxo-1,2,3,4-tetra-
hydropyrazinyl)]methyl}-~3-cephem-4-carboxylate,
o sodium 7-[2-~2-aminothiazol-4-yl)-2-(syn)-
methoxyiminoacetamido]-3-{[1-(4-methyl-2,3-dioxo-1,2,3,4-
tetrahydropyrazinyl)]methyl}-a3-cephem-4-carboxylate,
o sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-
methoxyiminoacetamido]-3-{[1-(3,6-dioxo-1,2,3,6-tetra-
hydropyridazinyl)]methyl}-a3-cephem-4-carboxylate, and
o sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-
methoxyiminoacetamido]-3-{[1-(3-methyl-6-oxo-1,6-dihydro-
pyridazinyl)]methyl}-Q3-cephem-4-carboxylate.
Next, an explanation is made below of production
processes.
The compound of this invention can be preparéd
by the following proces~e~:
~ ~.
; `
`: :
~ - 32 -
- . . .- .- : - .. . . ... .. . . .
~76~3~
H h ~;
U~ X
,_ O O
~ O H O ~ O ~
m ~ X u~ o
`--æ r_ ~,
h ~__ _~, H L
~ æ '' cz) _~ m \~ ~
~ I I ~ ~ o ~
m o~
m \\ ~ m
Z o o rd
o
C~ o _ s~
~ ~ Z =\~n
z;"~,~q '
P~ ~
/ ~ m~ ~
~Y ~ /~o ~ ~
o ~ ~ ' ~ o o
~ 1 ~ ~ ~ . u
o ~ ~ 1,~ Pæ o ~ *
o ~ 1~ o
u a)I t) U
X U~ o
1~H rl I-- ~ H
I U ~ ~ h
O I o a
z u~ I _~ u
~~ a) 5~ I p ~ o ~
~ I _ U
1~; 0 ~ I ~ol X .~.
. ¦ go h
~, m
U
H ~ ~~ ~ 5~ 0 \\
H I I~ h h a) ~\\
H H~0 0 ~3 ~\\
\\ \\
H H ~ \\ ~
~; O ` ` O ~\ t`l O h
o c~ O \\ m
P:; IY; .C ~ t)M O O rl \\ V 1:~ H rC
_ o ~ I 1~ J o
r O H H 1~) rl /~\ O
o ~ `~ U ~I H H ~ O tl~ U ~ O ~ O
~ H H S-l .C U ~IJ O ~ / r-l ~ rl h
~ ~t Z ~ ~~ ~ o ~ ~æ
5-1 ~ O ~ ~ O S~ h al 13
P. ~; O P:; O O ~ ~d -
- 33 -
- ' - .
. .
.
~7~i~3~
o
,_ O R
O 1~ h
u~
X
x m o .~,
'' 0
X I ~ h O
.,~
`~ h ~ 1
O ~ ~
OU ~ X X ~1
o
,~ o a~~1 o o ~ r~ o4~
~ O .~ ~ O ~ ~ o
U3 ~ C~ ~ a) Q, ~ u~ ~ tn o
~ ~J h ~) ~r ~H S~
~ =~ ~ ~ ~0 ~ mJ`~o ~ ~
Z ~ Z ~ ~)
O O ,1 0 ~r
V P; V ~ U~
~= Z~O o V=Zv~ O
o o
V U H O Z U~
x ~ ~ XI ~ X c ~
~ I ~=( V~ o
O C~ ~1(1) I z
U ,,~ ~0~I ~o U~ o o ~
H u~ h ¦ 0 fi 0
m~ 1 ~
oo~l ~ D 0
mO
o
o C) _ Z---mO
~,~-- o u~ O H ~ ~>
~ ~ m ~ 0 ~ u
V ~ ~ ~ ~ O V 0 . o
O O ~ h O a
~rl a) ~ h.C:~
~ 0
-- 3 4 --
.~: '; ' ' ' ~ -
. : . . ~ . : .
,
3~
a~
U~
" ~ ,. . .
co~o ~ ~ k~
Z o o P~ o
~'`~ ~P:;/ ~ ~z--~ Z--Z
R O ~
H H H H
H H H H
H H H H
O O O O
.. . .
a)
O
Z
.
- 35 -
- . . -
... .. ..
: :, .. . ., . ~ ......... . ..
, - : :
, . . ; .,,: '
., .. . ~.
: , , , . - ,,
3~
Production Route 2
R3
R30-CoNH t ~S~[XVI]
~ N ~ CH2X
COORl
or a salt thereof
3~
(conver- HN NR [III-a]
sion at ~=J
3-position) or a salt thereof
R3
R -CONH t ~S~ o o I
N ~ CH2N NR6
COOR
~ _ [XVII]
R3
R30-CoNH~ S~ O O
O N ~ CH2N~ NR
COORl J
or salts thereof -
¦ (conversion into ~3-cephem)
R3
R30-CoNH ~
N ~ CH2N~==JNR [XVIII]
COoRl
or a salt thereof
deacylation)
(Cont'd)
: - 36 -
.
,. ~ -:
,
- : : . ' ': . : '
- , , . ; .
~276~3~
Production Route 2 (Cont'd)
`I
R,3
N ~ CH2N~=~NR [XIX]
COOR
or a salt thereo~
- 37 -
3~
``~ 1 In the above formulas, R 9 R , R , R , R , R ,
7 8 9 R10 Rll R12 R13 R14, R15, R , ~ and the
bond ~~~ have the same meanings as defined above; R18a
represents the groups for R18 except a hydrogen atom; R28
represents an amino group, or a group of the formula,
32> C=C-NH- in which each of R31, R and R , which may
be the same or different, represents a hydrogen atom or
an organic residue not participating in the reaction, or
R34
a group o the formula, 35> C=N- in which each of R34
and R35, which may be the same or different, represents
a hydrogen atom or an organic residue not participating
in-the reaction; R29 represents a substituted or
unsubstituted acyloxy or carbamoyloxy group; R30 represents
benzyl, phenoxymethyl or a group of the formula,
R5 ~ ~ A in which R4, R5 and A have the same
S `R4
meanings as defined aboveS X represents a halogen atom;
~Z represents >S or >S~O; and the dotted line in the
rins represents a double bond between the 2- and 3-
positions or the 3- and 4-positions.
A further detailed explanation is made below.
R28 represents an amino group, a group of the formula,
- 38 -
. , - - . :
.. . . .
- '~ -
~ , .
- . . .
:. . . :
- ~ ', ': ' ' '
R31 R34\
1 32/ C=C-NEI- or a group of the ~ormula, 35/ C=N~, and
R31
the group of the formula, 32> C=C- H- includes the group
R31 R
of the formula, 32/ CH-f~N- which is i~s isomer. The
R33
organic xesidues not participa-ting in the reaction for
R31, R32, R33, R34 and R35 include those well-known in
the art, speciically substituted or unsubstituted aliphatic
residues, alicyclic residues, aromatic residues, aromatic-
aliphatic residues, heterocyclic residues, acyl groups
and the like. More specifically, the following groups
are included:
(1) aliphatic residues: alkyl group5t alkenyl
groups,
~2) alicyclic residues: cycloalkyl groups;
cycloalkenyl groups,
~3) aromatic residues~ aryl groups,
l4) aromatic-aliphatic xesidues: aralkyl groups,
~5) heterocyclic residues: heterocycllc groups,
~6) acyl groups: ac~l groups which can be derived
rom organic carboxylic acids which include aliphatic
carboxylic acids, alicyclic carboxylic acids and alicyclo-
aliphatic carboxylic acids; and also include aromatic
aliphatic carboxylic acids, aromatic-oxyaliphatic
carboxylic acids, aromatic-thioaliphatic carboxylic acids,
h~erocyclic aliphatic carboxylic acids, heterocyclic-
oxyaliphatic carboxylic acids, and heterocyclic-
- 39 -
: - . . .
.
,
' ' -' , - . - ,. ~ ' . . :
., ~ . ,:
.,
1 thioaliphatic carboxylic acids, in which an arvma-~c residue
or a heterocyclic group is bonded, directly or through an
oxygen or sulfur atcm, to an aliphatic carboxylic acid;
organic carboxylic acids wherein an aromatic residue, an
aliphatic group or an alicyclic group is bonded to the
carbonyl group through an oxygen, nitrogen or sulfur
atom; aromatic carboxylic acids; heterocyclic carboxylic
acids; and the like.
The above aliphatic carboxylic acids include
formic acid, aceti~ acid, propionic acid, butanoic acid,
isobutanoic acid, pentanoic acid, methoxyacetic acid,
methylthioacetic acid, acrylic acid, crotonic acid and the
like, the above alicyclic carboxylic acids include
cyclohexanoic acid and the like and the above alicyclo-
aliphatic carboxylic acids include cyclopentaneace-tic
acid, cyclohexaneacetic acid, cyclohexanepropionic acid,
cyclohexadieneacetic acid and the like.
Also, the aromatic residues in the above-
mentioned organic carboxylic acids include phenyl,
naphthyl and the like.
. Each o~ the groups constituting these organic
carboxylic acids may be ~urther substituted by a sub-
stituent such as a halogen atom, a hydroxyl group, a pro-
tected hydroxyl group, an alkyl group, an alkoxy group, an
acyl group, a nitro group, an amino group, a protected amino
group, a carboxyl group, or a protected carboxyl group.
Also, the substituted or unsubstituted acyloxy
and carbamoyloxy groups for R29 include alkanoyloxy
- 40
: , . . ' ' : .
,
391
l groups such as acetoxy, propionyloxy, butyryloxy and
the like; alkenoyloxy groups such as acryloyloxy and -the
like; aroyloxy groups such as benzoyloxy, naphthoyloxy
and the like; and carbamoyloxy group. These yroups may
be substituted by one or more substituents such as
halogen atoms, nitro group, amino group, alkyl groups,
alkoxy groups r alkylthio groups, acyloxy gxoups, acylamino
groups, hydroxyl group, carboxyl group, sulfamoyl group,
carbamoyl group, alkoxycarbonylcarbamoyl groups, aroyl-
carbamoyl groups, alkoxycarbonylsulamoyl groups, arylgroups, carbamoyloxy group and the like.
In the above-mentioned substituents for R29,
hydroxyl group, amino group, carboxyl group and the like
may be protected with protecting groups which are usually
employed, and the protecting groups include, specifically
the hydroxyl-protecting groups, amino-protecting groups
and carboxyl-protecting groups which have been mentioned
above as to R .
~a) Conversion reaction at 3-position
7-Substituted or unsubstituted amino-3-substi-
tuted methyl cephem carboxylic acid of the formula [IV] or
a salt thereof can be produced in a high yield with a high
purity using an industrially easy procedure by reacting
a 2,3-dioxo-1,2,3,4-tetrahydropyrazine of the formula
[III-a], a 2-oxo-1,2-dihydropyrazine of the formula
[III-b], a 3,6-dioxo-1,2,3,6-tetrahydropyridazine of the
formula [III-c], or a 6-oxo-1,6-dihydropyridazine o the
- 41 -
\
. .
- '- , , - . ~ . . - ~ : , ,
': :- ' .......... . .
.
:: .,
. .
: , ,
~76~3~
1 formula [III-d], or a salt thereof with a cephalosporanic
acid represented by the foxmula [II] or a salt thereof
in the presence of an acid or a complex compound of an
acid, then if desired, remo~ing the pro-tecting group,
protecting the carboxyl group or converting the obtained
co~pound to a salt thereof. Further, the above-mentioned
2,3-dioxo-1,2,3,4-tetrahydropyrazine can be prepared by
the method described in the Journal of ChemiCal Society,
Perkin I, pp. 1888-1890 ~1975).
Furthermore, if necessary~ the substituent on
the amino group at the 7-position can be removed in a
conventional manner to form a 7-unsubstituted amlno
compound. According to this procedure, not only Q -
cephem compounds but also a2-cephem compounds can be
used as the starting compounds, and where the ~2_
cephem compounds are used as the starting compounds,
the reaction product ~2-cephem compounds are further
converted to ~3-cephem compounds.
Also, not only compounds where >Z is >S but
also compounds where >Z is >S~O can be used as the
starting materials, and in the latter case >S~O can be
converted to >S during the reaction or in an after-
treatment step.
If the 2,3-dioxo-1,2,3,4-tetrahydropyrazine of
the formula ~III-a], the 2-oxo-1,2-dihydropyrazine of
the formula ~III-b], the 3~6-dioxo-1,2,3,6-tetrahydro-
pyridazine of the formula [III-c] or the 6-oxo-1,6-dihydro-
pyridazine of the formula ~ d] which is used as
- 42 -
~' ' . ' ': '
.
,
, .
] a ~actant in the reaction, has a basic or acidic(~roup
as the substituentr these compounds may, if necessary,
be applied in the form of the corresponding salt to the
reaction. In this case, the sal-ts at the basic groups
and the salts at the acidie groups include those mentioned
as to the salts of the eompounds of the formula [I].
Also, the salts of the compounds of the formulas
[II] and [IV] inelude salts at the basie groups and at
the aeidie groups, and these salts inelude those mentioned
about the salts of the compounds of the formula [I]. The
salts of the eompounds of the formula [II] may be pre-
viously isolated and then used, or may be prepared in situ.
As the aeids or the eomplex eompounds of aeids
used in the reaetion, there are mentioned, for example,
protonic aeids, Lewis aeids or eomplex eompounds of Lewis
aeids. The protonie aeids inelude sulfurie aeids,
sulfonie acids and super aeids (super aeids means aeids
stronger than 100~ sulfurie aeid and ineludes some o
the above-mentioned s~f~ic aeids and sulfonie aeids).
More speeifically, the protonie aeids inelude sulfurie
aeids sueh as sulfurie aeid, ehlorosulfurie aeid,
fluorosulfurie aeid and the like, sulfonie aeids,
for example, alkyl lmono- or di-)sulfonie acids sueh
as methanesulfonic aeid, trifluoromethanesulfonie aeid
and the like, aryllmono-, di- or tri-)sulEonie acids such
as p-toluenesulfonie aeid and the like, super aeids, such
as perehlorie aeid, magie aeid ¦FSo3H-SbF5), FSO3H-AsF5,
CF3SO3H-SbF5, HF-BF3, H2SO4 SO3
- 43 -
, , :, . .
'- ' ~:, . :' ' ' ' ~ ' ,,' ' ' ' ' . '
The Lewis acids include, for example, boron tri-
fluoride, and the cornplex compounds of Lewis acids include
complex compounds of boron trifluoride with dialkyl ethers such
as diethyl ether, di-n-propyl ether, di-n~butyl ether and the
like; with amines such as ethylamine, n-propylarnine, n-butyl-
amine, triethanolamine and the like; with esters such as ethyl
formate, ethyl acetate and the like; with aliphatic acids such
as acetic acid, propionic acid and the like; and with nitriles
such as acetonitrile, propionitrile, and the like.
1~
The reaction is preferably conducted in the presence
of an organic solvent. The organic solvents used include all
organic solvents inert to the reaction, for example, nitro-
alkanes such as nitromethane, nitroethane, nitropropane and the
like; organic carboxylic acids such as formic acid, acetic acid,
trifluoroacetic acid, dichloroacetic acid, propionic acid and
the like; ketones such as acetone, methyl ethyl ketone, methyl
isobutyl ketone and the like; ethers such as diethyl ether,
diisopropyl ether, dioxane, tetrahydrofuran, ethyleneglycol
~0 dimethyl ether, anisole, 1,2-dimethoxyethane and the like;
esters such as ethyl forrnate, diethyl carbonate, methyl acetate,
ethyl acetate, ethyl chloroacetate, butyl acetate and the like;
niiriles such as acetonitrile, butyronitrile and the like; and
sulfolanes such as sulfolane and the like. These solvents may
~5 be used in admixture of two or more. In addition, complex
compounds formed from these organic solvents and Lewis acids can
be used as the solvent. It
~ 4 -
` ~ ~ ' ' ' ' `'`, '
- ,
; ` ~
3~
l is sufficient that the amount of the acicl or the complex
compound of the acid used is at least equimolar to the
amount of the compound represented by the formula [II] or
a salt thereof, and the amount may be varied depending
on the respective cases. In particular, the use in a
proportion of 2-lO moles per mole of the compound of the
formula [II] or a salt thereof is preferred. Where the
complex compound of the acid is used, it can be used per
sa as a solvent, and two or more of the complex compounds
ma~ be used in admixture.
It is sufficient that the amount of the
2,3-dioxo-1,2,3,4-tetrahydropyrazine of the formula
[III-a], the 2-oxo-1,2-dihydropyrazine of the ormula
~III-b], the 3,6-dioxo-1~2,3,6-tetrahydropyridazine o'f
lS the formula [III-c] or the 6-oxo-1,6-dihydropyridazine
of:the formula [III-d] or a salt thereof is at leask
equimolar to the amount of the compound represented by
the formula [II] or a salt thereof, and particularly,
the use in an amount of about 100-5.0 m~les Fer m~le is
pre~erred
This raaction is usually carried out at 0-80C,
and completes in ten minutes to thirty hours. The pre-
sence of water in the reaction system may cause undesirable
side reaations such as lactonization of the starting
material or products and cleavage of ~-lactam ring,
so that it is desirable to keep the system under the
anhydrous conditions. In order to fulfill this require-
ment, it is sufficient to add, to the reaction system,
- 45 -
, .
:
- : `,, .: ' ,
~: .
' ' ! . ., ' . , '
~ '. ' ,. ' " ' ~.,' ' '',. ' ~ ' , ,
1 a suitable dehydrating agent, for example, a phosphorus
compound such as phosphorus pentoxide, polyphosphoric
acid, phosphorus pentachloride, phosphorus trichloride,
phosphorus oxychloride or the like; an organic silylat-
5 ing agent such as NrO-bis(-trimethylsilyl)acetamide,
trimethylsilylacetamide, trimethylchlorosilane, dimethyl-
dichlorosilane or the like; an organic acid chloride such
as acetyl chloride, p-toluenesulonyl chloride or the like;
an acid anhydride such as acetic anhydride, trifluoroacetic
anhydride or the like; an inorganic dehydrating agent such
as anhydrous magnesium sulfate, ~nhydr~us calcium chloride,
a molecular sieve, calcium carbide or the like.
If a compound represented by the formula [II]
wherein Rl represents a carboxyl-protecting group is
used as the starting material, a compound represented by
the formula [IV] wherein Rl represents a hydrogen atom can,
in some cases, be directly obtained by the reaction, or
can be obtained by removing the protecting group in a
conventional manner.
Next, conversion reaction at 3-position, which
is described in Production Route 2, is explained.
The halogenated compound represented by the
formula [XVI] can be prepared according to the method
described in Tetrahedron Letters, No. 46, pp. 3991-3994
~1974) and Tetrahedron Letters No. 40, pp. 3915-3918
~1981).
The compound represented by the formula [XVII]
or a salt thereof can be prepared by the reaction of a
- 46 -
`.
, '~; ,` :
3~
1 halogenated compound represented by -the formula ~XVI] or
a salt thereo with a 2,3-dioxo-1,2,3,4--tetrahydro-
pyrazine of -the ~ormula ~III-a] or a salt thereof in the
presence of a base. The base includes ~k~i ~-~l carbona~
(~or example, so~um carbonate, potasslum ~rbonate, or ~e like);
alkali metal hydrogencarbonates ~for example, sodium
hydrogencarbonate, potassium hydrogencarbonate and the
like); alkali metal hydroxides (for example, sodium
hydroxide, potassium hydroxide, and the like); nitrogen-
containing organic bases, or example, triethylamine,pyridine, N,N-dimethylaniline and the like.
The conversion at 3-position is generally
carried out in a suitable solvent. The solvent includes
halogenated hydrocarbons such as chloroform, methylene
chloride and the like; ethers such as tetrahydrofuran,
dioxane and the like; N,N-dimethylformamide; N,N-dimethyl
acetamide; acetone; water; and mixtures therevf.
In this case, the compound represented by the
formula [III-a] or a salt ther~of is preferably used in
an amount of about 1.0-2.0 moles per mole of the compound
represented by the ormula ~XVI] or a salt thereof. The
reaction is generally carried out at a temperature of
0-50C fox 30 minutes to 10 hours.
The mixture of a ~- and ~3-cephem compound
thus obtained, that is, a compound represented by the
formula [XVII] or a salt thereof, can be easily converted
into the ~3-cephem compound, to prepare the compound of
the formula [XVIII] or a salt thereof, which is then
- 47 -
.: .
. : . .. .
. ~ .. .
.
. : , . ,- ~ ~ -' '.
~.;27~
: 1 converted into the compound of the formula [XIX] or a salt
thereof by the deacylation. Said convexsion reaction
and deacylation are known in -the fields of penicillins
and cephalosporins and are speciically described in khe
Journal of Organic Chemistry, Vol. 35, No. 7, pp. 2430-
2433 ~1970) and "Cephalosporins and Penicillins" Iby Flynn,
Academic Press), pp. 56-64.
If the substituents o the 2,3-dioxo-1,2,3,4-
tetrahydropyrazine of the ormula [III-a], the 2-oxo-
1,2-dihydropyrazine of the formula [III-bj, the 3,6-
dioxo-1~2,3,6-tetrahydropyridazine of the formula
[III-c], or the 6-oxo-1,6-dihydropyridazine of the formula
[III-d] or the salt thereof, which are used as the
reactants in the reaction, are substituted by a hydroxyl
group, an amino group, a carboxyl group or the like, these
groups may be protected by the above-mentioned protecting
groups prior to the reaction and subjected to a con-
ventional removal reaction after the completion of the
reaction to obtain a desired compoundO
Also~ the compound represented by the formula
[IV] or [XIX] can, i~ necessary, be protected at the
carboxyl group or converted into the salt according to a
conventional method, to obtain the objective compound.
Also, the compound represented b~ the formula [IV] wherein
R28 represents an amino group can be converted into a
reactive derivative at the amlno group or the compound
represented by the formula [XIX] as mentioned here.inater
by a conventional method.
- 48 -
- ,.
.
.
- ' , ~ . ' : . .: ' , ' .
.
~2~
1 ~b) Acylation
When the compound represenked by the ~ormula [V],
[VI], ~VII], [VIII] or [XIII], or a salt thereof, or a
reactive derivative thereof is reacted with a compound
represented by the formula [IV] or a salt thereof or a
reactive derivative at the amino group, a compound
represented by the formula [I]~ [IX], ~X], [XI] or [XIV],
or a salt thereof is obtained.
The salts of the ccmpound represented by the
formula [V], tVI], [VII], [VIII] or [XIII] include salts
at the basic group or the acidic group, which specifically
include those mentioned as to the salts o~ the compound
rspresented by the formula [I].
The reactive derivatives at the amino group of
the compound represented by the formula [IV] include all
derivatives which are often used in acylation, for
example, an isocyanate; a Schiff base produced by the
reaction of the compound represented by the formula [IV]
or a salt thereof ~ith a carbonyl compound such as an
aldehyde, a ketone, or the like Iketimine type or its
isomer, namely, enamine type); a silyl derivative, a
phosphorus derivative or a tin derivative, produced by
the reaction o~ a compound represenked by the ~ormula
~IV] or a salt thereof with a silyl compound such as
~5 bisltrimethylsil~l)acetamide, trimethylsilylacetamide,
trimethylsilyl chloride, or the like, a phosphorus com-
pound such as phosporus trichloride~ [ \PCl, L PCl,O/ CH3 O/
- 49 -
- . . . : . -: ,; , . . : , . ..
.
- - . . . . .
: . . ,
.
,
. . ' :. ' ' ~' ,' ' ' ' . :
ro\
~ O/ 3 2 )2PCl~ (CH3CH2)2PCl or -the like, or a -tin
compound such as (C4Hg)3SnCl or the like.
The reactive deri~atives of the compounds repre-
sented by the formulas [V]~ [VI], [VII], [VIII] and [XIII]
include specifically acid halides, acid anhydrides, mixed
acid anhydrides, active acid amides, active esters, reactive
derivativPs obtained by reaction of the compounds represent-
ed by the formulas [V], [VI], [VII], [VIII] and [XIII] with
a Vil~meier reagent. The mixed acid anhydride includes
a mixed acid anhydride with a monoalkyl carbona-~ such as
monoethyl carbonate, monoisobutyl carbonate and the like,
a mixed acid anhydride with a lower alkanoic acid which may
be substituted by a halogen, such as pivalic acid, tr'i-
chloroacetic acid or the like. The active acid amide
includes N-acylsaccharin, N-acylimidazole, N-acylbenzoyl
amide, N,N'-dicyclohexyl-N-acylurea, N-acylsulfonamide
and the like. The active ester includes cyanomethyl
ester, substituted phenyl esters, substituted benzyl
esters, substituted thienyl esters and the like.
Tha reactive derivatives obtained by reaction
with a Vilsmeier reagent include those obtained by re-
action with a-Vilsmeier reagent obtained by reacting an
acid amide such as N,N-dimethylformamide, N,N-dimethyl-
acetamide or the like with a halogenati~g agent such as
phosgene, thionyl chloride, phosphorus trichloride,
phosphorus tribromide, phosphorus oxychloride, phosphorus
pentachloride, trichloromethyl chloroformate, o~alyl
chloride or the like.
~ 50
.
.
- . . ~ - .
- .
- ~ .
:. . . .
- . .
~7~ L3~ `
1 I~ each of the compounds represented by the
formulas [V], [VI], [VII], [VIII] and [XIII] is used in
the ~orm of a free acid or a salt, a suitable condens-
ing agent is used. The condensing agent includes N,N'-
disubstituted carbodiimides such as N,N'-dicyclo-
hexylcarbodiimide; azolide compounds such as N,N'-
thionyldiimidazole; dehydrating agents such as N-
ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus
oxychloride, alkoxyacetylenes and the like; 2-halo-
genopyridinium salts such as 2-chloropyridiniummethyl
iodide and 2-fluoropyridiniummethyl iodide; and the
like.
This acylation reaction is usually carried
out in a suitable solvent in the presence or absence
of a base. As the solvent, there may be used a solvent
inert to the reaction, ~or example, a halogenated hvdro-
carbon such as chloroform, methylene chloride or the
like; an ether such as tetrahydrofuran, dioxane or the
like; N,N-dimethylformamide; N,N-dimethylacetamide;
acetone; water; or a mixture thereo~. As the base,
there may be used an inorganic base such as an alkali
metal hydroxide, an alkali metal hydrogencarbonate, an
alkali metal carbonate, an alkali metal acetate or the
like; a tertiary amine such as trimethylamine, trlethyl-
amine, tributylamine, pyridine, N-methylpiperidlne,
N-methylmorpholine, lutidine, collidine or the like; or
a secondary amine such as dicyclohe~ylamine, diethy-
lamine or the like.
~ 51 ~
: ~ . . : . . . . .
.. . ~. . .... ..
~: : :, ~.. - . :. , .
3~
The compound represented by the formula [IX]
or a salt thereof which can be converted into the
compound represented by the formula ~Ial or [lb] or a
salt- thereof can be produced by the following procedure:
In order to obtain the compound represented
by the formula [IX] or a salt thereof using the compound
represented by the formula [IV] or a salt thereof, a
4-halogeno-3-oxo-bu~yryl halide which is obtained by
the xeaction of diketene with a halogen such as
chlorine or bromine [Journal of the Chemical Society,
97, 1987 (1910)] may be reacted with the compound re-
presented by the formula [IV] or a salt thereof according
to a usual method. Reaction conditions and procedures
which are known in the art can be applied to this reac-
tion. And the salt of the compound represented by the
formula [IX] can easily be prepared according to a usual
method, and the salt includes the same salts as mentioned
above as to the salts of the compound represented by
the formula [I]. Although the compound represented by
the formula [IX] or a salt thereof may be isolated and
purified, it can be used for the subsequent reaction
without isolation.
In addition, the compound xepresented by the for- -
mura [V], [VI], [VII], [VIII] or ~XIII~ or a salt thereof
or a reactive derivative thereof is preferably used in an
amount of about one mole to several moles per mole of the
compound represented by the formula [IV] or a salt thereof
or its reactive derivative at the amino group. The reac-
tion is usually carried out at a temperature ranging from
- 52 -
-. ~ . : - ~ .
~6~3~
1 -50 to 40C. The reaction time is usually 1~ minutes to
4~ hours.
Furthermore, the compounds represente~ by the
formulas [I], [IX], [X], [XI~ and [XIV] wherein Rl is a
carboxyl-protecting group can be converted to the compounds
represented by the formulas [I], [IX], [X], [XI] and [XIV]
wherein Rl is a hydrogen atom, or their salts according to
the usual method; and similarly the compounds represented
by the general formulas [I], [~X], [X], [XI] and [XIV]
wherein Rl is a hydrogen atom can be converted to the com-
pounds represented by the formulas [I], [IX], [X], [XI] and
[XIV] wherein R is a carboxyl-protecting group or salts
thereof; and the salts of.the compounds represented by the
formulas [I], [IX], [X],.[XI] and [XIV] can be converted to
the corresponding.free acid forms, respectively.
Also, in this acylation reaction, if Rl, R and
R contain groups active to the reaction, these groups can
suitably be protected with conventional protecting groups
prior to the reaction, and the protecting groups can also
be removed b~ a usual method after the reaction.
The compound represented by the formula [I] or a
salt thereof of this invention obtained by the above-
mentioned method can be isolated by a conventional method.
(c) Nitrosation
Subse~uently, in order to obtain the compound
represented by the formula [X] or a salt thereof from the
compound represented by the formula [IX] or a salt thereof,
a nitrosating agent is rea~ted with the compound
- 53 -
, . , : , .
.
. ~ , ~. :' ' .' ' , ;
- - ~ ' '' . ~ -
:
.: . ', : . . .
~L27~
1 represented by the formula [IX] or a salt thereof. The
reaction is usually carried out in a solvent, and as the
solvent, there may be used a solvent inert to the re-
action such as water, acetic acid, benzene, methanol,
ethanol, tetrahydrofuran or the like. Preferable ex~mples
of the nitrosating agent include nitric acid and deriva-
tives thereof, for example, nitrosyl halides such as nitro-
syl chloride, nitrosyl bromide and the like, alkali metal
nitrites such as sodium nitrite, potassium nitrite and the
like, alkyl nitrites such as butyl nitrite, pentyl nitrite
and the like. I~ a nitrous acid salt is used as the nitro-
sating agent, it is preferable to carry out the reaction
in the presence of an inorganic or or~anic acid such as
hydrochloric acid, sulfuric acid, formic acid, acetic
acid or the like. I an alkyl nitrite is used as the
nitrosating agent, it is preferable to carry out the
reaction in the presence of a stron~ base such as an
alkali metal alkoxide or the like. The reaction is usually
carried out at a temperature ranging from -15 to 30C,
and the reaction time is usually 10 minutes to 10 hours~
The salt of the compound represented by the formula
[~] can easily be prepared according to a usual method,
and the salt includes the same salts as mentioned above
as to the salts of the compound represented by the
formula [I]. Althou~h the compound represented by the
formula [X] or a salt thereof thus obtained can be isolated
and purified by a well-known method, it can be used
for the subsequent reaction without isolation.
.
- 54 -
, . :, .
- . . . : . ~ .
~:7~
- l (d~ Etherifica-tion and phosphorylation
In order to obtai.n the compound represented by
the formula [XI] or a salt thereof from the compound
represented by the formula [X] or a salt thereof, the
compound represented by the formula [X] or a salt thereof
is subjected to etherification reaction or phosphoryla-
tion reaction.
The etherifica~ion reaction and the phosphoryla-
tion reaction can be carxied out by a usual method such
as described in Japanese Patent Application Kokai (Laid-
Open~ Nos. 137,988/78, 105,689/80, 149,295/80 and the
like.
For example, alkylation can be carried out
according to a usual method. The reaction is generally
carried out at a temperature of -20 to 60C and completes
in 5 minutes to 10 hours~
As the solvent, there may be used a solvent
inert to the reaction, for example, tetrahydro- .
uran, dioxane, methanol, ethanol, chloroform, methylene
chloride, ethyl acetate, butyl acetate, NrN-dimethyl-
formamide, N,N-dimethylacetamide,. water, or a mixture
thereof.
As the alkylating agent, there may be used, for
example, a lower alkyl halide such as methyl iodide,
methyl bromide, ethyl iodide, ethyl bromide or the like,
dimethyl sulfate, diethyl sulfate, diazomethane, diazo-
ethane, methyl p-toluenesulfonate or the like. If an
alkylating agent other than diazomethane and diazoethane
. - , . . . ... . . .
- -.. . : -
- ~ .- , . .
. . ' : ~ Y ..
'-
- . . ~: : ', . :
~.~76j~
1 is used, the reaction is carried out in the presence
of an alkali metal carbonate such as sodium carbonate,
potassium carbonate or the like; an alkali metal hydroxide
such as sodium hydroxide, potassium hydroxide-or the like;
or an organic base such as triethylamine, pyridine, N,N di-
methylaniline or the like.
Also, the salt of the compound repre.sented by the
formula [XI] can easily be obtained according to a usual
method, and the salt includes the same salts as mentioned
above as to the salts of the compound represented by the
formula ~I].
In addition, a protecting group can be introduced
and removed according to a usual method, whereby a compound
can be changed into a corresponding objective compound.
Although the compound represented by the formula
[XI] or a salt thereof thus obtained may be isolated and
purified by a usual method~ they can be used for the sub-
sequent reaction without isolation~
le) Ring closure reaction
The compound represented by the formula [Ia] or
[Ib] or a salt thereof of this invention can be obtained by
the reaction of the compound represented by the formula IIX],
[X] or [XI] or a salt thereof with the thioformamide or
thiourea represented by the formula [XII]. Thls reaction
is usually carried out in a solventO As the solvent,
there may be used a solvent inert to the reaction, for
example, water, methanol, ethanol, acetone, tetrahydrofuran,
- 56 -
~,
- .,
, "
: , .
.: . .
- ~ - . " .
~;~7~3~
1 dioxane, N,N dimethylformamide, N,N-dimethylace-tamide, N-
methylpyridone, alone or in admixture of two or more.
Although it is not essential to add an acid-removing agen-t,
the reaction sometimes proceeds smoothly by adding an
~cid-removing agent in such an amount that the cephalosporin
skeleton will no~ be influenced. The acid-removing agent
used for the reaction includes inorganic and organic bases
such as alkali metal hydroxides, alkali metal hydrogen~
carbonates, triethylamine, pyridine, N,N- dimethylaniline
and the like. The reaction is usually carried out at a tem-
perature of 0-100C. Thioformamide or thiourea is usually
used in an amount of about one mole to several moles
per mole of the compound represented by the formula [IX],
[X] or [XI] or a salt thereof. The reaction time is 1-48
hours, preerably 1-10 hours. Furthermore, in the compound
represented by the ~ormula [Ia] or [~b], the pr~tection of the carbonyl
group and removal of the c~xyl-protectm~ group or conversion of the product
to a salt can be carried out according to a usual method to
convert the compound to the corresponding objective
compound. If Rl, R , and R in the formula [Ia] or [Ib]
contain groups active to the reaction, these groups can be
suitably protected by a conventional protecting group
prior to the reaction and the protecting group can be
removed by a usual method after the reaction. The
objective compound represented by the formula [Ia] or
[Ib] or its salt thus obtained can be isolated by a
usual method.
- 57 -
- - : . . . ., .: .
- . . . , . ... :
- `- ' - '' ' ' .', ; .' ;~ '~' ' ' :, . -
-' '- : ~: , :
i ,
., ,: , . :.
1 (f) Qximina-tion
The compound represented by the formula [Ib]
or a salt thereof is obtained by reactirlg the compound
represented by the formula [XIV] or a salt thereoE with
the compound represented by the formula [XV] or a salt
thereof. The salt of the compound represented by the
formula ~XV] includes hydrochlorides, hydrobromides,
sulfates and the like. This reaction is usually carried
out not only in a solvent such as water, an alcohol,
N,N-dimethylacetamide or the like but also in other
solvents inert to the reaction or a mixed solvent there-
of. The reaction is carried out at a temperature of 0
to 100C, preferably in a range of 10 to 50C. The
reaction time is usually 10 minutes to 48 hours. The
compound represented by the formula ~XV] or a salt
thereof is used in an amount of about one mole tQ
several moles per mole of the compound represented by
the formula [xIvJ or a salt thereof. Although the
salt of the compound represented by the formula [XV]
~ can be usad per se for the reaction, it can also be
reacted in the presence of a base, for example, an
inorganic base such as an alkali metal hydroxide (for
example, sodium hydroxide, potassium hydroxide or the
like), an alkaline earth metal hydroxide ~for example,
magnesium hydro~ide, calcium hydroxide or the llke3,
an alkali metal carbonate (for example, sodium carbo-
nate, potassium carbonate or the like), an alkaline
earth metal carbonate (for example, magnesium carbonate,
calcium carbonate or the like), an alkali metal
- 58 -
. . : . . : .
' ` '' " ~ . '` ` ' ~ `" '
1 hydrogencarbonate (for example, sodium hydrogencarbonate,
potassium hydrogencarbonate or -the like~, an alkaline
earth metal ~hosphate (for exampl~, magnesium ~hosphate,
calcium phosphate or the like), an alkali metal hydro-
genphosphate (for example, disodium hydrogenpho~phate,dipotassium hydrogenphosphate) or an alkali metal
acetate (for example, sodium acetate, potassium acetate),
an organic base such as a trialkylamine (for example,
trimethylamine, triethylamine, or the like), picoline,
N-methylpyrro~idine, N-methylmorpholine, 1,5-diazabicyclo-
[4,3,0]-5-nonene, 1,4-diazabicyclo[2,2,2]octane, 1,5-
diazabicyclo[5,~,0]-7-undecene or the like. The com-
pound represented by the formula [Ih] or a salt thereof
of this invention thus obtained can undergo convers~on
of Rl in a conventional manner, and can also be isolated
by a usual method.
(g) Alkoxylation
The compound represented by the formula [IV]
wherein R3 is an alkoxy group can be synthesized from
the compound represented by the formula [IV] wherein
R3 is a hydrogen atom by a method known per se, for
example, the method described in the Journal of Synthetic
Organic Chemistry, Japan, 35, (7), 563-574 (1977).
Furthermore, the compoun~ represented by the
formula [I], [Ia], [Ib], [IX], [X], [XI] or [XIV]
wherein R3 is an alkoxy group can be synthesized from
the respective compound repres~ented by the formula
[I], [Ia], [Ib], ~IX], [X], [XI] or ` [XIV] wherein R3
- 59 -
:. ., . ,. ,: . : .......... ..
- ' : . ' ' ': . . .
- .
- . : . -
3~
1 is a hydrogen atom in a manner known per se, fox example,
the method described in Japanese Pa~ent Application Kokai
(Laid-Open~ Nos. 24,888~79 and 103,889/79.
The compound represented by the formula [I~ or
a salt thereof thus obtained can be adminis-tered to human
beings and animals in the form of a free acid or in the
~orm of a pharmaceuticall~ acceptable salt or ester for the
purpose of the treatment of and protection against
bacterial inections. It is pxeferable to parenterally
administer the compound in the orm of a free acid or a
pharmaceutically acceptable salt or orally administer the
compound in the form of a pharmaceutically acceptable ester.
In that case, it is sufflcient that the compound is formed
into a dosage form usually used in cephalosporin medi-
cines, for example, tablet, capsule, powder, fine granule,granule, syrup, injection lincluding drip), 5uppository or
the like. When the abo~e-mentioned medicine is formed
into a dosage form, there may be used diluents and/or
additives, for example, vehicles such as starch, lactose,
sugar, calcium phosphate, calcium carbonate or the
like; bonding agents such as gum arabic, starch, micro-
crystalline cellulose, carboxymethyl cellulose, hydroxy-
propyl cellulose or the like; lubricants such as talc,
magnesium stearate or the like, disintegrating agents
such as carboxymethyl calcium, talc or the like.
- 60 -
.
.
.
'
~ ;27~
1 When the compound represented by the formula
[I] or a salt thereof is administer~d, the dosage~
the administra~ion time and the administration
method can be varied depending on the symptoms of patient,
S and generally it is sufficient to administer orally or
parenterally to an adult in a dose of abou-t 50-5000 mg
in 1 to 4 portions a day.
This invention is explained below with reference
to Referential Examples and Examples which are merely by
way of illustration and not by way of limitation.
Referential Example 1
(1~ To a solution of 20.0 g of ethyl N-(2,2-di-;
ethoxyethyl)oxamate in 60 ml o ethanol was added 6.1 ml
o 70% by weight aqueous ethylamine solution, and the
mixture was subjected to reaction at room temperature
for 1 hour. After the completion of the reaction, the
precipitated crystals were collected by filtration and
recrystallized from ethanol to obtain 17.0 g (yield: 85.1%)
of N-ethyl-N'-f2,2-diethoxyethyl)oxamide having a melting
point of 131~132C.
IR (KBr) cm 1 vc O 1650
In a similar manner, the compounds shown in
Table 3 were obtained.
- 61 -
- :. .. . . . .
.
. .:. ; ~ , ,'
' -.,
~7~
Table 3
(CH3CH20) 2OElcH2NHcocoNHR6.
_ -1
Compound Solvent for m.p. IR (KBr) cm
recrystal- ( C) vc=o
R6 lization
-H Ethyl141-142 1650, 1635
acetate
-CH3 Ethanol135-136 1645
__
-~CH2)2CH3 Acetone 84-85 1645
/ CH3 .
\ CH Acetone145-146 1650, 1635
-(CH2)3CH3 n-Hexane111-112 1645
-(CH2)4CH3 n-Hexane 92-93 1650
.
-(CH2)5CH3 n-Hexane 87-88 1650
_
`-~CH2~7CH3 n-Hexane110-111 1645
-(CH~ CH3 n-Hexane 83-84 1645
_
E~thanol154-155 1640
_ _ _
-CH2- ~ n-Hexane113-114 1655
_ _ _
-CH2CH2OH Ethanol 118-119 _
N / C 3 . Ethanol 157-158 1645
CH3
OCH3
`~-~ _ 128-129 1655
-CH2- ~ -ocH3 . ~ _
- 62 -
- . ,
,~ , ~. ..
.
,," . ~ , ' ' ,.,, : " "' ~ ..
"
3~
1 (2) To a solution o the 17.0 g of N-ethyl-N'-
(2,2-diethoxyethyl~oxamide obtained in above
(1) in 85 ml of acetic acid was added 0.05 ml of con-
centrated hydrochloric acid. The mixture was refluxed for
30 minutes. After completion of the reaction, the solvent
was removed by distillation under reduced pressure, and
70 ml of acetone was added to the residue, and crystals
were collected by filtration. The crystals were recrystal-
lized rom methanol to obtain 6.8 g (yield: 61.8~) of 4-
ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a
melting point of 173-174QC.
IR (KBr) cm 1 vc O 1680-1620
In a similar manner, the compounds shown in
Table 4 were obtained.
- 63 -
\
.
.
- ' ' . ~ ~ ~. ,'' , '' . -
.~ .
. ' ', ~ ' '
- Table 4
~0
HN N-R6
Compound Solv n for (ocPj IR (KBr) cm 1
R6 lizationC=O
, _.
-H _ >280 1680-1640
-CH3 Ethanol 220-231 1690-1635
.
tCH2)2CH3 Acetone 182-183 1680-1640
~CH3 _ _
CH ~ CH Acetone215-219 1680, 1625
_
-(CH2)3CH3 Acetone149-150 1680, 1640
-(CH2)4CH3 Acetone171-172 1685, 1660,
l ,
``(CH2)5CH3 Acetone141-142 1620
. _ .
`(CH2)7CH3 Acetone145-146 1670, 1635
_ _ _
-~CH2)llcH3 Ethanol145-146 1660, 1625
- cetone254-255 1670, 1635
-CH2 ~ Acetic acid 225 1665, 1635
CH2CH2OCOCH3 Methanol178-180 1720, 1675,
_ _ .
< CH3 Ethanol229-230 1700-1625
OCH3 = _
\r-~ _ 175-176 1740-1620
.-.CH2 ~ OCH3 __
.
- 64 -
- : . . , . ,: : ~ . .
- - ; . - ..... . . ..
' - ~: ' , . .
3~
1 (3) To a suspension of 5.2 g of the 4-(2,4-
dimethoxybenzyl)-2~3-dioxo-1,2,3,4-tetrahydropyrazine
obtained in above (2) in 26 ml of NrN-dimethylformamide
was added 4.1 g of potassium carbonate, and the mixture
was stirred at room temperature for 30 minutes. Subsequ-
ently, 5.8 g of 4-bromomethyl-5-methyl-1,3-dioxol 2-one was
added thereto, and the mixture was subjected to reaction
at 50-60C for 3 hours. The reaction mixture was introduced
into a mixed solvent of 200 ml of ethyl acetate and 200 ml
of water, after which the organic layer was separated,
washed with 100 ml of water and dried over anhydrous
magnesium sulfate. The solvent was removed by distillation
under reduced pressure, and the residue was purified ~y a
column chromatoqraphy (Wa~o Silica Gel C-200 (a'.trademark), eluent;
chloroform) to obtain 4.9 g (yield, 66.0%, of 1-(2,4-
dimethoxybenzyl)-4~(5-methyl-2-oxo-1,3-dioxol-4-yl)-
methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a
melting ~oint of 154-156C.
IR (KBr) cm 1 vc=O 1820, 1675, 1630
In a similar manner, the compounds shown in
Table 5 were obtained.
- 65 -
, . ~. .
. .
, . , : ,
, : : . '.
.
, , ~ .
. . . - .:
.. . .
~7~3~
Table 5
3 ~ CH2-N -R6
_ .
Compound m.p. (C) IR ~KBr) cm : VC_O
R6 .
.
~ 188-190 1775, 1700, 1650
.
-CH2OCOCICH3)3 100-101 1750, 1690, 1660,
-CH2COOC¦CH3)3 105-L06 1740, 1690, 1650 .
-:66 -
`' ' . ` ' ` '` `.
7~3~
1 (4) In a mixed solvent of 37 ml of trifluoroacetic
acid and 10.8 g of anisole was dissolved 3.7 y of
1-(2,4-dimethoxybenzyl3-4-(5-methyl-2-oxo-1,3-dioxol-
4-yl)methyl-2,3-dioxo-1,2,3,4-tekrahydropyrazine ob-
tained in above (3) and the mixture was reacted at 50Cto 60C for 2 hours. Subsequently, the solvent was
removed by distillation under reduced pressure. To
the residue was added 30 ml of diethyl ether and crys-
tals were collected by filtration to obtain 2.0 g
(yield, 90.9%) of 4-(5-methyl-2-oxo-1,3-dioxol-4-yl)-
methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a
melting point of 225-226C.
IR (KBr) cm : VC O 1825, 1805, 1725, 1690, 1670~
In a similar manner, the compounds shown in
Table 6 were obtained.
- 67 -
.. , : . . .. .. .
- ''' ' ' .. : ~. . , . '~ , . -
- - - :'. -, .: . . : ~
' ' ' . ;., ~ ' ' ", ' : ' ' ~. ' .
~1.27~
Table 6
0~,0
HN N_R6
Compound -1
R6 m.p. (C) IR (KBr) cm : VC=O
. _
~ >270 1790, 1775, 1730,
_ ' .
-CH2OCOC(CH3)3 166-167 1740, 1700, 1660
,
-CH COOH 282 1730, 1670-1630
2 (decomp.)
1 (S) To a solu-tion o 2.6 g of 1-carboxymethyl-2,3~
dioxo-1,2,3f4-tetrahydropyrazine in 13 ml of N,N-dimethyl-
acetamide was added 3.9 g of diphenyldiazomethane at room
temperature, and the mixture was subjected -to reaction for
S or 10 minutes. Tha raactlon mixture was introduced
into a mixed solvent of 25 ml of ethyl acetate
and 25 ml of water, and the mixture was stirred for
15 minutes. Precipitated cr~7stals were collected by
iltration, and washed with 10 ml of ethyl acetate and
10 ml of diethyl ether in this order to obtain 2.9 g
- 68 -
- - . . ~ .- , ~ . .-
- ~ . :., .: . ,
- . : . ~ , . .. :
1 lyield, 80.4%) of l-diphenylmethyloxycarbonylmeth~l-2~3
dioxo-1,2,3,4-tetrahydropyrazine having a meltiny
point of 97-98C.
IR(KBr)cm 1 ~C=O 1750, 1675, 1645
Example 1
(1) To a solu'cion of 10 ml of ethyl acetate con-
taining 2.71 g of boron trifluoride were added 2.72 g of7-aminocephalosporanic acid (hereinafter referred to as
7-ACA) and 1.54 g of 4-ethyl 2,3-dioxo-1,2,3,4-tetrahy-
dropyrazine, and the mixture was subjected to reaction
at room temperature for 16 hours. After completion of
the reaction, the reaction mixture was introduced into
50 ml of methanol with cooling, and then 3.16 g of py-
ridine was added dropwise thereto. Precipitated crys-
tals were collected by fiItration, washed sufficiently
with 30 ml of methanol, and thereafter dried to obtain
3.10 g (yield, 88.1%~ of 7-amino-3-{[1-(4-ethyl-2,3-
dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-
carboxylic acid having a metling point of 191-195C
(decomp.).
IR (KBr) cm : vC=O 1795, 1670, 1620
NMR (CF3COOD~ ~ values:
1.44 (3H, t, J=7Hz, `~NCH2CH3),
3.69 (2H, bsj C2-H),
4.08 (2H, q, J=7Hz, ~ NCH2CH3),
5.14, 5.51 (2H, ABq, J-15Hz, S~ ),
5.48 (2H, s, C6-H, C7-H)j ~ 2
- 69 -
,, ~ ............... . , , , . :
.: . . ..
- : ' . ~ .,
' ' . .' ' ~ `
~ ~2~7~;~L3g3
1 6.74, 7.00 (2H, ABq, J-6Hz, ~ )
H H
t2) The conversion reaction at 3-position mentioned
in above (1) was carried out under the reaction condi-
tions shown in Table 7 to obtain 7-amino-3-{[1-14-ethyl-
2,3-dioxo-1,2,3,4-te-trahydropyrazinyl)]methyl}-~3-cephem-
4-carboxylic acid in the yi.elds shown in Table 7.
: - 70 -
.. . . . . . . .
. ~ , , , . .: ,
. : . . . .
- ~ :
- , ~ : .
. . ~
3~9
Table 7
Starting material Acid or Reaction Amount
No. Solvent complex condi- (Yield)
7-ACA HN N-CH2CH3 . of acid tions
_ _ _
Sulfo- Boron Room 2.6 g
1 2.72 g 1.54 g lane tri- tempera- (73.9%)
10 ml fluoride ture
2.71 g 2 hours
_ .
. Nitro- Boron Room 2.85 g
2 2.72 g 1.54 g methane tri- tempera- (81.0~)
14 ml fluoride- ture
ether 16 hours
5Co7mplex .
l 13) In a similar manner to that in above ll), the
compounds shown in Table 8 were obtained.
(In this case, the obiective compounds were obtained by
pouring into ice-water the reaction mixture after
completion of the conversion at 3-positlon and adjusting
to pH 3.5 with 28~ by weight aqueous ammonia solution with
ice-cooling.)
.
.. - : :
': - . . ' , ' :
' - ~ . .
~.~76~3~
_ _ _
` _
~1
I
~r co
In ~ ~ $
_ ~ ~ C~
.. ~ :q ,
~ $ C~ u~ / \\ _ r- ~
a) c~ ~ u~ a a
o
Z W ~ ~ ` ~D
~ /\ ~ N O ..
Y~ N m_~ ~ N
m~I~ 1l$ 1-
~_ ~ U
o 11 C~ ~ 11
U~ 1~
:~ m~~1 ~ N
~ ~ m l ~~ m
l ~
~; 11
_ ~ m :~:
~ ~ ~1
Z;
co o ~r ~ o ~o
.. . ~ . . ,_,
o~ ~ -- u~
~P~ _ ~ . _
m~3 ~ 1l
,1" o~ ~
o ~ o oo V~ ~
co ~ ~D
~1 ~ ~
.q ~rZ P~ ~
E~ ~ H ~ . _
I ~ . ~ -~ ,.
Z O .
C~ ~ ~1 ~
a~ :. :
O 1 0~ : :
__ : _ .
. m .
: o~ ,
~ O N ~ _
~ ~, ~: ~D ~ ~
_
o
_
.
- 7 2
~:
~.~7~3~
^~ ~ ,
m
m I ~ ~ o s~
~ ~ CO ~ ~ . ~ ~) ~ ~
_~ m ~ ~ -- ~ ~ ~ m I
~ ~) ~ a , ~ ~ ~ , U
m --~ D P::
m ~ ~ ~ --
~ ~ I ~O _ ~ . ~ o
/ \ ~Z\ ~ N ~ æ~ m ~ ,~, N
~ ` 5 ` / ~ ^ U U~
N ~ m ~ ~ N I N m ~ .
m ~ I ~ n m~` 5 ` I _ n
m 1~ ~ u r~
o m
m
I m
~ m I ~
:S: ~ m /\ m ~ ml m Ul m /\ m
o ~ ~ o ~ m
0O o er m o co m a~ c~
o ,~ o ~1 ~ 1~ ~
_
._
o oo o oooo
t
D
~ ~l ~l ~ ~l ~l
co
a)
A In
~ ~ _
,1 ~. a~
In ~ O
C) I O
~1 ~ ~ a)
-- ~ _
_
m~ m~
O~ZII , ~Z3)
~ .
_ __
-- 7 3
,
- : ` ~ - :' ' `
,
: . . ' . .
~;~7~3
~1
In ~ ~
ml :~1
R
~D ~ ~ 1
1- r` t~
U~ ~D _
._ O~u~oo
C~ ' a~ o ,
CO
a~
- -I
0~0
m--Z
~-- 74 --
:: , , , . . : :
.
1 ~4? The conversion reaction at 3-position mentioned
in above (13 was carried ouk under the reaction conditions
shown in Table 9 to obtain 7-amino-3-{[1-(3,6-dioxo-
1~2~3~6-tetrahydropyridazinyl)]methyl}-a3 -cephem-4-
carboxylic acid in the yields shown in Table 9.
Table 9
Starting Acid or Reaction Amount
No. material Sol- complex condi- (Yield)
. compound tions
7-ACA hyldeeiac vent of acid
_ _ _
Tri- Boron tri- Room 1.72 g
fluoro- fluoride- temper- (72 3%)
1 2.0 g 0.91 g acetic diethyl ature.
complex ___
Sul- Boron tri- Room 2.75 g
2 2.72 g 1.23 g folane fluor de temper- (84.9~)
3 hours
_ .
(5~ In a similar manner to that in above (1), the
crude crystals shown in Table 10 were obtained.
- 75 -
- - ,:, . , - , : :- . . -
: - . , - , . ,- , .
. '- '. ~ ' " ' ', -~ -
- ~ , : . . :
- -~
~ ~7~
Table 10
H 2N ~ S ~ CH R2
COOH
No Compound
. _
_ . _
1 -N N-H * 1
_ _ . __
2 O~,O
-N N-CH
~ 3 ;
_ _ .
0~0
3 - -N N-CH2CH2CH3
_ _ _
4 ~ 3
_ _, .
O~
-N N ~CH2 ) 3CH3
6 ~ 4 :
-N N{~
. ~
7 . C~ .
-N~C~N (CH2 ) 11CH3
_
- Cont ' d
- 76 ~
- . ~ - . . . .~ , . .
,, .. ,~ ,. . . . ..
, ... ..
- : , . . .. - :, . .. .
7~35~
` Table 10 (Cont 'd)
8 0~0
~ C 2 2 3
-N N-CH2--O
~ ¦ 0~,0
12 ~C1~3
_ ,
*2
N~ Cl
- Cont ' d
-- 77 ~
3~
Table 10 (Cont'd)
14 N ~ N~`C~
~ t ~
`
1 Note: The compounds in Nos. 10, 11, 12, 13, 14 and 15
were obtained by the reaction using sulfolane as
a solvent.
*1: This compound was obtained by the procedure
of introduction into methanol, filtration o~
insolubles and addition of pyridine into the
filtrate.
*2: The representat~on was taken because it was
not confirmed whether the chlorine atom was
~placed at 4- or S-position, and whether the
product was composed of a single compound or
a mixture. (Such representations in Tables
~ ~ 78 -
,. ~'' . : - ' ,`~ '....... ., .. , , . ::
: - . . ' :, ~ , ' : . .
`- : , . . ' '. . ' ' ~ ' . , :
,.
1 appearing hereinafter have the same meaning.)
*3: The representation means that the product was
a mixture of a 4-substituted compound and a 5-
substituted compound. (Such repxesentations
in Tables appearing hereinafter have khe same
meaning.)
Example 2
To a suspension of 3.0 g of the 7-amino~3-{[1-
l4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-
~3-cephem-4-carboxylic acid obtained in ~xample
1-(1) in 30 ml of methanol was added 1.62 g of p-toluene-
sulfonic acid monohydrate to form a solution, and then
5.0 g of diphenyldiazomethane was slowly added to the
solution, after which the resulting mixture was subjected
to reaction at room temperature for 15 minutes. After
completion of the reaction, the solvent was removed by
distillation under reduced pressure, and the residue thus
obtained was dissolved in a mixed solvenk of 20 ml of
ethyl acetate and 20 ml of water. The solution was
adjusted to pH 7.0 with sodium hydrogencarbonate. Sub-
sequently, the organic layer was separated and dried over
anhydrous magnesium sulfate, and the solvent was removed
by distillation under reduced pressure. The residue was
purified by a column chromatography (Wako Silica Gel C-200,
eluent; benzene:ethyl acetate ~ 1:4 by volume) to obtain
3.1 g (yleld, 70.3%) of diphenylmethyl 7-amino-3-{[1-
- 7g -
:
; .
,
~27~3g
l ~4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-
~3-cevhem-4-carboxylate having a melting point of 183-
186C (decomp.).
IR (KBr) cm : VC o 1765, 1730, 1680, 1630
In a similar manner, the compounds shown in
Table ll were obtained.
:
~ : - 80 -
3~
Table 11
H2Nr~ S ~
0~ ~CH2R
COOCH( ~ )2
Compound m.p. (C) IR ~Ksr) cm : VC=O
. . _
~4
-N NH 129-130 1765, 1725,
~=J (decomp.) 1690, 1630
0~,0- ' -- ~. ..................... .
-N N-CH 127-128 1770, 1725,
~ 3 - (decomp.) 1690, 1640
O o ~
~ 169-171 1765, 1730,
-N N ( CH2 ) 2OE13 (decomp.) 1685, 1635
. .__ _
~ ~ CH3 179-180.5 1760, 1720,
-N~ NCH~ (decomp.) 16O5, 1635
. ... __ .. :
O~O lôO-lB9 1760, 1725,
-N N (CH2)3CH3 (decomp.) 1680, 1630
~ ~ . , .
O ~ O 185-194 1765, 1730,
-N N (CH2)4cd3 Idecomp.) 1685, 1630 :~AA._
- Cont'd -
- : . . ,
' . ' ' ' `' ' ` ` ` ' ' ' ' ' . '
'
~ ~ ,. ... .
.. . . .. .
~;27~;~3~
" Table 11 (Cont'd)
.
Compound m.D. (C) IR (KBr) cm : v O
.. __ . . C--
O O ~ ''
~ 170-174 1765, 1730,
-N~ N(CH2)5CH3 (decomp.) 1685, 1635
~ 186-188 1765, 1730,
-N ~'(CH2)7CH3 (decomp.) 1685, 1635
.. _ .
O O
~ 164-172 1765, 1730,
-N ~(CH2)11CH3 (decomp.) 1685, 1635
O O
~ /--\ 165-168 1765, 1725,
-N N ~ (decomp.) 1680, 1625
_ _ , .
O O .
~ ~ 155-160 1770, 1725,
-N N-CH2 ~ (decomp.) 1680, 1630
. _
O O
~ 146-148 1770, 1725,
-N~ NCH2cH2OcocH3 tdecomp.) 1678, 1623
. ...... __
O O ~
~ CH3 172-175 1760, 1720,
-N N-N ~ . 1680) 1630
_ _ _
~ N 82-85 1775, 1720,
-N ~ (decomp.) 1650
O __
- Cont'd -
- - 82 -
- - ' ~ ~ . - .
- ~ ' -. ~ ' _ ' '
,
- ,~ .' ' ,'. ~ - ~ .
;~7~
` Table 11 (Cont'd)
. . _
Co~.pound m.p. (C) IR (~CBr) cm : v C=O
R2
C ~ HN 108-114 1765, 1725,
-N ~ (decomp.) 1650
.
O 132-135 17~0, 1730,
(decomp.~ 1665
O ' --- .... ..... __ _
H ~ 178-181 1780, 1730,
Cl (decomp.) 1660
O ~ O ~
HN ~ CH3 HN ~ 137-139 1780, 1730,
~ ~ + -h ~ CH (decomp.) 1660
O O, _ _ _
_ ____ _
N ~ 90-93 1770, 1720,
-N ~ ~ (decomp.) 1660
~ 2CH3 138-143 1770, 1720,
-~ ~ (decomp.) 1660
_ O _ ~ _
- 83 ~
' , '; ~ . , ' ., . ~ ''' , ,
. .
.. . .. ...
~ ` ~' ' " ', :
.. ~ . : : .. .. . .
~7~3~3
1 Example 3
In a mixed solvent of 25 ml of trifluoroacetic
acid and 10 ml of anisole was dissolved 4.9 y of
diphenylmethyl 7-amino-3-[1-(2,3-dioxo-1,2,3,4-tetra-
hydropyrazinyl)methyl]-~ -cephem-4-carboxylate
and the solution was subjected to reaction at
room temperature for 2 hours. After completion of
the reaction, the solvent was removed by distillation
under reduced pressure, and 50 ml of diethyl ether
was added to the residue, after which crystals were
collected by filtration. The crystals were suficiently
washed with 40 ml o diethyl ether and then dried to
obtain 4.25 g (yield, 97.0%) of trifluoroacetic acid salt
of 7-amino-3-{[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-
methyl}-~3-cephem-4-carboxylic acid having a melting point
of 105-106C (decomp.)
IR (KBr) cm : vC=O 1780, 1700-1630
NMR (CF3COOD) ~ values:
3.72 (2H, bs, C2-H), S
5.14, 5.52 (2H, ABq, J=15Hz, ~CH
5.44 (2H, s, C6-H, C7-H),
6.78, 6.g8 (2H, ABq, J=6Hz, ~ )
In a similar manner, the compounds shown in
Table 12 were obtained.
- 84 -
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- 1 Example 4
To a suspension of 5.0 g of 7-amino-3-{[1-(3-
methyl-6-oxo-1,6 dihydropyridazinyl)~methyl}-~3-cephem--
4-carboxylic acid in 15 ml of acetone were added 2.36 g
5 of 1,8-diazabicyclo[5,4,0]-7-undecene and 4.51 g of
pivaloyloxymethyl iodide at 10-15C, and the mixture was
subjected to reaction for 30 minutes. After completion
of the reaction, the reaction mixture was in~roduced into
a mixed solvent of 50 ml of watex and 50 ml of ethyl
10 acetate, and the organic layer was separated, washed with
water and then dried over anhydrous magnesium sulfate.
Subsequently, 10 ml of an ethyl acetate solution containing
1.40 g of oxalic acid was added thereto, and the precipit-
ated crystals were collected by filtration and washed with
15 ethyl acetate to obtain 4.59 g ~yield, 56.2%) of oxalic
acid salt of pivaloyloxymethyl 7 amino-3-{[1-(3-methyl-6-
oxo-1,6-dihydropyridazinyl)~methy1}-~3-cephem-4-carboxylate
having a melting point of 145-147C (decomp.).
IR (RBr) cm 1 vc=O 1790, 1750, 1660
NMR ~d6-D~1SO) ~ values:
1.21 (9H, s, -CH3x3).
2.29 (3H, s, ~ CH3),
3.52 (2H, bs, C2-H),
4.94, 5.33 ~2H, ABq, J=15Hz, S~ ),
~LCH2-
5.14 (lH, d, J=5Hz, C6-H),
5.76-6.23 (3H, m, C7-H, -OC~2O-~,
- 94 -
.
: ~
` . , -
1J~
-- 1 7.01, 7.53 (2E~, ABq, J=lOHz, ~ ),
7.44 (3H, bs, -NH~
E~ample 5
(1) To a solution of 2.69 g of 1-(5-methyl-2-oxo-1,3-
dioxol-4-yl)methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine in
27 ml of N,N-dimethylformamide was added 1.52 g of potas-
sium carbonate, and the resulting mixture was stirred at
room temperature for 20 minutes. Subsequently, 4.67 g of
tert -butyl 7-phenylacetamido-3-bromomethyl-~2-cephem-4-
carboxylate was added thereto with ice-cooling, and the mix-
ture was subjected to reaction at room temperature for 2
hours. The reaction mixture was introduced into a mlxed
solvent of 200 ml of ethyl acetate and 150 ml of water,
and the organic layer was separated, washed with 150 ml of
water, and then dried over anhydrous magnesium sulfate.
Subseqùently, the solvent was remo*ed by distillation under
reduced pressure, and the resulting residue was dissolved
in 100 ml of chloroform. To the solution was added 2~45 g
~purity, 70%~ of m-chloroperbenzoic acid, and the mixture
was subjected to reaction at room temperature for 1 hour.
The solvent was removed by distillation under reduced pre-
ssure, and to the xesidue were added 100 ml of ethyl ace-
tate and 100 ml of water. The organic layer was separated,
washed with 100 ml of water, and then dried over anhydrous
magnesium sulfate. The solvent was removed by distillation
under reduced pressure, and the resulting residue was puri-
fied by a column chromatography (Wako Silica Gel C-200,
- 95 -
-. . . , ... : . .
.. . , . , , ~ , ~ . . .
~ ~7~i~3~
1 eluent; chloroform) to obtain 2.70 g ~yield, 43.2% o~
tert.-butyl 7~phenylace-tamido-3-{[1-[4~(5-methyl-2-
oxo-1,3-dioxol-4-yl~methyl-2,3-dioxo-1,2,3,4-tetrahydro-
pyrazinyl]]methyl}-~3 cephem-4-carboxylate-1-oxide having
a melting point of 135-136C (decomp.).
IR (KBr) cm 1 vc_O 1820, 1790, 1720, 1685, 1650
(2) In a mixed solvent of 12 ml of N,N-dimethyl-
formamide and 6 ml of acetonitrile was dissolved 3.0 g
of tert.-butyl 7-phenylacetamido-3-{~ 4-(5-methyl-2-
oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-1,2,3,4-tetrahydro-
pyrazinyl]]methyl}-~3-cephem-4-carboxylate-1-oxide. To
the solution were added 1.0 g of stannous chloride and
1.58 g of acetyl chloride in this order with ice-cooling,
and the mixture was subjected to reaction at room temper-
ature for 30 minutes. The solvent was removed by distil-
lation under reduced pressure, and to the residue were
added 50 ml of ethyl acetate and 50 ml of water t after
which the resulting mixture was adjusted to pH 6.0 with
sodium hydrogencarbonate. Subsequently, the organic layer
was separated, washed with 50 ml of water, and then dried
over anhydrous magnesium sulfate. The solvent was removed
by distillation under reduced pressure, and the residue
was purified by a column chromatography (Wako Silica Gel
C-200, eluent; toluene:ethyl acetate = 3:2 by volume) to
obtain 2.12 g (yield, 72.4%) of tert.-butyl 7-phenyl-
acetamido-3-{[1-[4-(5-methyl 2 oxo-1,3-dioxol-4-yl)methyl-
2,3-dioxo-1,2,3,4-tertrahydropyrazinyl]]methyl}-~3-cephem-
4-carboxylate having a melting point of 120-122C
(decomp.).
- 96 -
.. . .
- . ~ ' ~ ' ,
: ' ' , '' : ' `
~76~3~
1 IR (KBr) cm 1 vc O 1820, 1775, 1715, 1685, 1645
NMR (CDC13) ~ values:
1.58 (9H, s, -C(CH3~3),
2.28 (3H, s, -CH3)
3.17, 3.61 (2H, ABg, J=18Hz, C2-H),
3.77 (2H, s, ~ CH2-)'
4.53, 5.13 (2H, ABq, J=15Hz, ~ ),
~ CH2
4.71 ~2H, s, ~NCH2-),
5.03 (lH, d, J=5Hz, C6-H),
5.93 (lH, dd, J=5Hz, J=8Hz, C7-H),
6.53, 6.89 (2H, ABq, J=ÇHz, ~ ),
H H
7.32-7.51 (5H, m, ~ ),
7.57 (lH, d, J=8Hz, -CONH-)
In a similar manner to that in above (1) and
15 (2), the compounds shown - in Table 13 were obtained.
-- 97 --
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-- 100 --
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1 (3) In 30 ml of anhydrous methylene chloride was
dissolved 2.0 g of tert.-butyl 7-phenylacetamido-3-{[1-
[4-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-
1,2,3,4-tetrahydropyrazinyl]]methyl}-~3-cephem-4-carbo-
xylate. To this solution were added 1.59 g of N,N-
dimethylaniline and 0.57 g of trimethylsilyl chloride in
this order, and the resulting mixture was stirred at
room temperature or 1 hour. The reaction mixture was
cooled to -40C, and 0.89 g of phosphorus pentachloride was
added thereto, and the mixture was subjected to reaction at
-30 to -20C for 2.5 hours. Subsequently, the reaction
mixture was cooled to -40C, and 5.2 g of anhydrous meth-
anol was added thereto, after which the reaction was con-
tinued with ice-cooling for 1 hour. To the reaction
mixture was added 20 ml of water and stirring
was continued for a further 30 minutes. Subsequently,
the reaction mixture was adjusted to pH 0.5 with 6 N
hydrochloric acid, and then the aqueous layer was sepa-
rated. To this aqueous layer was added 50 ml o~ ethyl
~o acetate, and the mixture was adjusted to pH 6~5 with sodium
hydrogencarbonate. The organic layer was separated, washed
with 50 ml of water, and then dried over anhydrous magne-
sium sulfate. The solvent was removed by distillation
under reduced pressure, and to the residue was added 50 ml
of diethyl ether. The crystals were collected by filtra-
tion to obtain 1.05 g (yield, 64.8%) of tert.-butyl 7-
amino-3-{[1-[4-~5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-
2,3-dioxo-1,2,3,4-tetrahydropyrazinyl]]methyl}-~3-cephem-
-- 101 --
.
.
.: . . . - :
.
~.27~
1 4-carboxylate having a melting point of 185-188C (decomp.).
IR (KBr) cm 1 vc O 1820, 1765, 1705, 1690, 1635
NMR (CDC13+d6-DMSO) ~ values:
1.52 (9H, s, -C(CH3)3), 2.24 (3~, s, -CH3),
3.46 (2H, bs, C2-H), 4.35, 5.08 (2H, AB~,
J=15Hz, S~ ),
CH2-
4.76-5.09 (4H, m, ~NCH2-, C6-H, C7-H),
6.74 (2H, s, ~ )
H
In a similar manner, the compounds shown in
Table 14 were obtained.
~ - 102 -
- , . ~ - ` , . ' ,' ' ' ' :' . ', ' '
- . . : .
- . : . ~ . .
-~. , ':,,. . ' ' ' . : .'.
6~3~
U ` ,~ W O
a) ~ .. ~ ~
~ ~ u m ~ ~1 1 0
~ ~ / -- ~
~ 5~ ' X ~ ~ I U
co _ ~q O ~ ~ m I
~ ~ N N 10 t'`l
* * ~ U /~
^ ~ ~ \\
. . ~ ~: n ~ u~
. . ~ 11 11~7 ` ` ~n
. . ~ m ~ ,4
. . ~ U ~ ~ N
. . ~ ~ _ ~
o ~ ~ ~ ~ ~ S: In
O ~3 ~ N00 ~`1
U~ U I¢ ~1: 0 ~1C.) --
~D ~ ~ U ` 11~o co Ur~
P~ I U IP~ 1
~g Q ~ ` CO . ~
o~ z ~ ~ ~ ~ ~ m
r ~ ~ ~ ~ ~
o"~æ ~ P; ~ O ~ ~_
~ m ~ m m u ~ m ~ m
m u z a~ a~ _ ~
U ~ _ _ ~ _ ~r) _
,1 o O ao ~ P I 1~ mu ~ ' '
\\ O In ~ 00 m l ~1 ~
\~U . O ~ Il ~ u
Z~ ~ f Pll~
~ r, O
~ ll
Z O ?
~r: m O O O O u~ O In ~ o
~ ~ t~ r~ ~ ~ ~ I` I` ~ ~D
_ I ~ 1
~ o
H
- ,
_
U ~ _ .
o ~ ~ ~ .
t) ~ O
~1 ~ ~ a)
~ ~1 ~ ~ ~
_
: ~ ~ ~
o ~ m ~ ~ :
:~ U:~ o~ ~ I U
U P~
lU ~ .
__ ::
.
- 103 -:
:
3~
~ ~v
x ~
x z _ m ~ ~
~ I In a~ ,J ~ ~
U ~ tN 11 0 -- N ,-
u~ vl m ~ o
Q ` ~m
m _ c~
_ ~ '"~ m
~ ¦ 1~ N N ~ ~)
Il~ ~ ~ ` I
t` 11 ~I CO u~ ~ N ~ m ,
~. ~ ~ tc s~ I o O
m
u~ ~ m ~ a
m ~ ~ 2 ~ m ~ ,, I ~
z; ~ m; N /\ '~ ~ 'I ~v
U~ O U~ V'~~ ~
co c~ a~ o ` ~ `
` ~ _ ~1
-~ m ~ m . m~r m\ /
~ ~ o~ ,
o m ~ u~ ou~ m~ I
Il~ O er U~ X~
"~ ~ r U ~D t.q * .
~ - -
~` ::~
r~ o o u~ O o .
E~ I` I` t- ~ ~O U~
,~ ,1 ,1 ,1 ~ 3
o
1 ~ ~,~
.. ~-,1' -
_ H 3
~ *
I Z
- 104 -
- :: ~ . .. .
,
: . - ::: . ~ :
.: . . . ..
1 Example 6
(l~ In 2.29 ml of N,N-dimethylacetamide and 4.58 ml
of acetonitrile was dissolved 2.29 g of 2-(2-formamido-
thiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, and to the
resulting solution was added dropwise 1.62 g of phospho-
rus oxychloride, after which the mixture was subjected to
reaction at -5 to 0C for 1 hour. Subsequently, 5.18 g of
diphenylmethyl 7-amino-3-{[1-(4-ethyl-2,3-dioxo-1,2l3,4-
tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate
was added ~o the reaction mixture, and the mixture was
subjected to reaction at -5 to 0C for l hour. After
completion of the reaction, the reaction mixture was
poured into a mixed solvent of 80 ml of water and 80 ml
of ethyl acetate, and the resulting solution was ad-
justed to pH 6.5 with sodium hydrogencarbonate. Subse-
quently, the organic layer was separated, and dried
over anhydrous magnesium sulfate. The solvent was re-
moved by distillation under reduced pressure, and to the
residue was added 60 ml of diethyl ether. Then, the
crystals were collected by filtration to obtain 6.05 g
(yield, 83.0~) of diphenylmethyl 7-[2-(2-formamldo-
thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-
ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~ -
cephem-4-carboxylate having a metling point of 165-168C.
IR (KBr) cm : VC o 1780, 1720, 1680, 1640
NMR (d6-DMSO) ~ values:
1.18 (3H, t, J~7Hz, -N-CH2CH3),
3 59 (2H, bs/ C2-H),
3.72 (2H, q, J=7Hz, >N-CH2CH3),
~- 105 -
.
~.2~3~
l 3.97 (3H, s, -OCH3),
4.42, 5.04 (2H, ABq, J-15Hz, S~ ),
~ 2
5.30 (lH, d, J=5Hz, C6-H),
6.02 (lH, dd, J=5Hz, J=8Hz, C7-H),
6.50, 6.62 (2H, ABq, J=6Hz, ~ ),
H H
7.04 (lH, s, -CH~ ),
N
7.17-7.82 (llH, m, ~ x2, ~ ),
8.63 (lH, s, HCo-j,
9.89 (lH, d, J=8Hz, -CONH-),
12.68 (lH, bs, HCONH-)
In a similar manner, the compounds shown in
Tables 15, 16 and 17 were obtained.
- 106~-~
~ .
.
'7~;~3~
Table 15
HCONH ~ ~ C- --CONH ~ ~ CH2R
\ OCH3 COOCH( ~ )2
(syn-isomer)
Compound -~ - m.p. (C) VC=O
O ~ O 120-125 1780, 1720,
-N N-CH3 H ~decomp.) 1680-1640
. - _
O O 154-156 1785, 1720,
,~ H (decomp.) 1685, 1645
-N N-~CH234C~3
.
O O H 131-136 1783, 1725,
. ~ (decomp.) 1680, 1645
-N N(CH2)5CH3 .
. _ ,.
H 180 182 1780, 1720,
O~ O (decomp.) 1680-1640
-N~=~h(CH2)7CH3 .
_ _
O O H 158-166 1780, 1725,
~ (decomp.) 1675, 1640 .
-N N-(CH2)11CH3 . .
_ _
~ H 126-138 1685, 1650
-N N-CH2 ~
~- l ~ ~ 1
- Cont'd -
- 107 -
. - , . . .
. ~ -
,
.~. .
-, . . . .
~ ;~7~
Table 15 (Cont' d)
O~O sr ( dec omp . ) 1675, 1640
- N N - CH 2 CH 3
O 171-173 1780t 1720,
HN ~ H ~decomp . 1690 - 650
_ _
148-151 1780, 1730,
N~ H ~decomp. ~ 1690 1660
_ ~
. ~ 191-195 1775, 1720,
~C~3~l L~ ~
- 108 -
. . \ .
.', ~ ' . -, . . . .
-, . . ~
, ~
- . . , , :
- . ~ ,: : . : . . - .
. ~ . .
: : ,
, -
6~
Table 16
ICH3 M C-CONH- ~S~
3 2 1 OCONH ~S ~ ¦¦ / ~ N ~ CH~R
OR COOCH( ~ )2
(syn-isomer)
.
CompoundRl8 m.p. tC) . IR (KBr) cm
O~ O 176-179 1780, 1720,
-N~=~NH . -CH3(decomp . ) 1680, 1640
. _ .
O O CH 152-155 1780, 1720y
~ - 3 (decomp. ) 1680, 1640
-N N- (CH2 ) 2CH3 .
... _...... .... _ . .
. 158-160 1780, 1720,
~ / 3 -CH3 (decomp.) 1680, 1640
-N NCH \
.. . . ` .'
166-167 1780, 1720,
O ~ O -CH3 (decomp.) 1685, 1645
-N~=~N- (CH2)3CH3 .
. _ ~ . _
162-165 . 1780, 17~0,
~=~ ~ -CH3 (decomp. ) 1680, 1640
, , _
145-147 1780, 1720,
O ~O -CH3 tdecomp , ~ 16S2, 1640
-N N-cH2cH2ococH3
~ ,~ _ ,- ' .. .
.
- Cont'd -
-- 109 --
- : . .. .
~7~3~
Table 16 (Cont' d)
. 138-144 1780, 1715,
O~ -CH 3 ( decomp . ) 1690, 1620
-N~N- (CH2) 7CH3
.
88-90 1780, 1720,
~ / 3 -CH3 1690-1620
-N~-N
_ ................................. _ ~
O O -CH C: ~ 131 1786, 1723,
~ 2 3 (decomp. ) 1684, 1645
-N N-CH2CH3 .
CH CH -CH 118-120 1780, 1720,
2 3 3 ~decomp. 1660
. _
O -CH 190-192 1780, 1720,
~e~
- Cont ' d -
- 110 -
, : . .
- . . . . .
:
- . -': . -' , . , : '
` ' " :` ','` ~ : ,
Table 16 (Cont' d)
. -CH 183-185 1780, 1720,
O 3 (decomp. ) 1670
--N ~ \ CE~
. ..... ... _ .
-CH 128-131 1780, 1720 ,
`N~l 3 (decomp. ) 1~80, 1 6
:, . . , . , :, : .
- . -. . : : . ,, . . ,: ~ . . .
, ~ . : :
. - , : ,.
,. ~ ;.' , : ,
- Table 17
CH
1 3 N C CONH ~ S~
CH 3CH2f -OCONH~S~ 1I J,_ N ~ CH2R
CH3 OCH3 COOC(CH3~3
(syn-isomer)
Compound m.p (C) IR (KBr) cm :
~ 141-1~3 1815, 1775,
-N N - CH CH (decomp.) 1710, 1680,
~=~ ~ O 3 1640
____ _ ~
154-156 1775, 1710,
O O (decomp.) 1700, 1680,
~ /O\ O 1650
-N N ~
_
85-88 1785, 1730,
O ~ O (decomp.) 1715, 1660
-N N-CH2OCOC(CH3)3 .
_I
144-146 1775, 1745,
O O (de~omp.) 1715, 1690,
-N N-CH2COOC~( ~ )2 1650
- 1l12 -
- , . , ~ . . . ~ . . .
:
.
- , : . . . . , . ~.
. . ~
,
.' : ;' "'' ' : ~ '
' ' ' ` : !,
~2~3~
1 (2) To a solution of 6.05 g of diphenylmethyl 7-
[2-(2-formamidothiazol~4-yl)-2-(syn)-methoxylminoace-
tamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro-
pyrazinyl)]methyl}-~3-cephem-4-carboxylate in 31 ml of
methanol was added 0.5 ml of concentra-ted hydrochloric
acid, and the mixture was subjected to reaction at 35C
for 2 hours. After completion of the reaction, -the sol-
vellt was removed by distillation under reduced pressure.
To the residue were added 100 ml of ethyl acetate and
100 ml of water, and the resulting solution was adjusted
to pH 6.0 with sodium hydrogencarbonate. Subsequently,
the organic layer was separated and dried over anhydrous
magnesium sulfate. The solvent was removed by distilla-
tion under reduced pressure, and to the residue was
added 50 ml of diethyl ether. The crystals were
collected by filtration to obtain 5.1 g (yield, 87.7~)
o diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-
methoxyiminoacetamido~-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-
tetrahydro~yrazinyl)]methyl}-~3-cephem-4-carboxylate
having a melting point of 165-167C.
IR (KBr) cm 1 vc=O 1780, 1720, 1680, 1640
NMR (d6-DMSO) ~ values:
1.18 (3H, t, J=7Hz, ~N-CH2CH3),
3.55 (2H, bs, C2-H),
3.75 ~2H, q, J=7Hz, ~N-CH2CH3),
3.90 (3H, s, -OCH3),
4.41, 5.02 (2H, ABq, J=15Hz, S ~ ~,
~ CH2-
5.26 ~lH, d, J=5Hz, C~-H),
- 113 -
~- ' . ' : " '
,
, ,''.'
~.Z7~g~3~
1 6.01 ~lH, dd, J-5Hz, J-8Hz, C7-H),
6.52, 6.65 (2H, ABq, J=6Hz, ~ ),
H H
6.88 (lH, s, ~ ),
S H
7.07 (lH, s, -CH ~
7.15-7.84 (lOH, m, ~ x2),
9.81 (lH, d, J=8Hz, -CONH-)
In a similar manner, the compounds shown in
Table 18 were obtained.
,
` - 114 -
. ~
- . . . , .. : . .
3~
Table 18
N ~ C-CONH ~ ~ ~
\OCH30 COOCH( ~ )2
(syn-isomer)
.
R2 R4 m.p. (C3 IR (KBr) cm :
_
O~ O 158-166 1780, 1720,
-N N-CH3 H (decomp.) 1680, 1640
151-156 1780, 1720,
O O H (decomp.) 1680, 1640
-N N-(cH2)4cH~ . . .
. .
150-156 1780, 1720,
O O EI (decomp.) 1680, 1640
-Nr-~N-~cH2)scH3 .
O~ O H 168-175 1775 1723,
-N N-(CH2~llcH3 .
. _ . _
O~ O H 161-166 1680, 1640
-N NCH2 ~
_
146 1780, 1720,
0~0 , Br Idecomp . ) 1680, 1640
-N NCH2CH3 : . .
.. , . . . _.
: .
- ~ont'd -
- - 115 -
.
31.Z7~3~
Tabl e 18 I Cont ' d )
175_1781780, 1720,
HN~ I H Idecomp. )685 - 1660
__
d 146-148 1780, 1720,
(deao~p . )166
:
- ~116 -
3~
1 (3) In a mixed solvent of 25.5 ml of trifluoroace-tic~
acid and 7.86 g of anisole was dissolved 5.1 g of diphenyl-
methyl 7-[2-(2-aminothiazol-4-yl)-2-~syn)-methoxyimino-
acetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro-
5 pyrazinyl)]methyl}-~3-cephem-4-carboxylate, and the solu-
tion was subjected to reaction at room temperature for
2 hours. After completion of the reaction, the solvent
was removed by distillation under reduced pressure. To the
residue was added 40 ml of diethyl ether and the crystals
lQ were collected by filtration to obtain 4.3 g (yield, 91.1~)
of trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4-
yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-
1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem 4-carboxylic
acid having a melting point of 155-157C ~decomp.).
IR (KBr) cm : vC=O 1775, 1710-1630
NMR td6-DMSO) ~ values:
1.21 (3H, t, J=7Hz, ~N-CH2CH3),
3.52 (2H, bs, C2-H),
3.73 (2H, q, J=7Hz, >N-CH2CH3),
3.96 (3H, s, -OCH3),
4.44, 5.12 (2H, ABq, J=lSHz, S ~ ),
~LCH2-
5.21 (lH, d, J=5Hz, C6-H),
5.83 (lH, dd, J=5Hz, J=8Hz, C7-H),
5.86 (3H, bs, -NH36~),
6.71 (2H, bs, ~ ),
H H
- 117 -
. .. . . ~ .
.
-., : .
1 6.95 (lH, s, ~ ),
S H
9.90 (lH, d, J=8Hz, -CONH-)
In a similar manner, the compounds shown in
Tables 19 and 20 were obtained.
~ 118~
$- ~ __
N l= < m I
.. ~
~ ~ O ~ $~
U~ ~ ~
m co ~ $ ~ z
~;- j j ~ W -I
_ I C~ I . Il ` ~ CO
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z zi ~ u' m ~ ~ Q ~
m x m ~ u m m x
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c~= æ ~r o ~ m o co u~
~r ~7 o ~ D CO .
a~ =( ._ _
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Q ~ ll
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.~; ...... r~
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_
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m~ - .
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- 119 -
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- 120 --
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m :~ m m m
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-- 122 --
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m ~ m c~~9 ~ ,ml I O m m m
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-- 124 --
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-- 125 --
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mu o ~ 1 1l U~ =~
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-- 126 --
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6~3~
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1 (4) In 30 ml of water was dissolved 6.35 g of
trifluoroace-tic acid salt of 7-[2~(2-aminothiazol-4-yl)-
~-(syn)-methoxyiminoacetamido]-3-{[1-(2,3-dioxo-
1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-
carboxylic acid, and the resulting solution wasadjusted to pH 7.4 with sodium hydrogencarbonateO Subse-
quently, this solution was purified by passing through an
Amberlite ~N~2 (a trademark) col ~ bo botain 4.7 ~ (yield, 86.6%) of
sodium 7-[2-(2-aminothiazol-4-yl)-2-~syn)-methoxyimino-
acetamido]-3-{[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-
methyl~-~3-cephem-4-carboxylate having a melting point of
200C or more.
IR (KBr) cm : VC O 1763, 1670, 1650-1620
In a similar manner, the ~ollowing compounds were
obtained:
o Sodium 7-[2-(2-aminothiazol~4-yl)-2-tsyn)-
methoxyiminoacetamido]-3-{[1-(4-methyl-2,3-dioxo-1,2,3,4-
tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate.
m.p.: 190-195C ~decomp.)
--1
IR ~KBr) cm o vC=O 1760, 1670, 1650, 1630
o Sodium 7-[2-(2~aminothiazol-4-yl)-2-lsyn)-
methoxyiminoacetamido]-3-~[1-(3,6-dioxo-1,2,3,6-tetra-
hydropyridazinyl)]methyl}-~3-cephem-4-carboxylate
O Sodium 7-[2-~2-aminothiazol-4-yl)-2-(syn)-
methoxyiminoacetamido]-3-{[1-l3-methyl-6-oxo-1,6-dihydrO_
pyridazinyl)]methyl}-~3-cephem-4-carboxylate.
-- 13g --
:. - .
' .. -: - , .
.
-- --
- . ` '
~7~i~3~
-- 1 Example 7
~1) To a solution of 3 g of 2-(2-tritylaminothiazol-
4-yl)-2-~syn)-tert.-butoxycarbonylmethoxyiminoacetic acid
in 15 ml of N,N-dimethylacetamide was added dropwise
0.93 g of phosphorus oxychloride at -10C, and the mixture
was subjected to reaction at -5 to 0C for 1 hour. This
solution was added dropwise to a solution of 19.4 ml of
anhydrous methylene chloride containing 1~94 g of 7-amino-
3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-
methyl}-~ -cephem-4-carboxylic acid and Z.25 g of bis(tri-
methylsilyl)acetamide at -5 to 0C. After completion of
th dropwise addition, the mixture was subjected to reaction
at the same temperature for 30 minutes and then at 0 to
10C for 30 minutes. After completion of the reaction,
methylene chloride was removed by distillation under
reduced pressure, and to the residue was added a mixed
solvent of 100 ml of saturated aqueous sodium chloride
solution and 100 ml of acetonitrile. Subsequently, the
organic layer was separated and washed twice with S0-ml
portions o saturated aqueous sodium chloride solution,
and then the solvent was removed by distillation under
reduced pressure. The resulting residue was dissolved
in 50 ml of methanol, after which 1 g of diphenyl-
diazomethane was added to the solution at 5 -to 10C,
and the mixture was subjected to reaction at the same
temperature for 30 minutes. After completion of the
reaction, the solvent was removed by distillation under
reduced pressure. The residue was puriied by a column
- 140 - -
'
.
,
,
-, -
~ ;~7~;~3~
1 chromatography (Wako Silica Gel C-200, eluent; benzene:
ethyl acetate=3:1) to ob~ain 1.6 g IYield, 27.8%) of
diphenylme~hyl 7-~2-(2-tritylaminothiazol~4-yl)-2-(syn~-
tert.-butoxycarbonylmethoxyiminoacetamido]-3-{[1-(4-ethyl-
2,3-dioxo-1,2,3,4-te-trahydropyrazinyl)]methyl}-Q3-cephem~
4-carboxylate having a melting point of 98-100C (decomp.).
IR (KBr) cm : VC O 1780, 1720l 1680~ 1630
NMR (d6-DMSO) ~ values:
1O17 (3H, t, J=7Hz, >N~l2~l3),
1.44 (9H, s, -c(cH3)3),
3.62 (2H, bs, C2-H),
3.74 (2H, q, J=7Hz, >N-CH2CH3),
4.55 (2H, s, -OCH2C-),
4.51, 5.16 (2H, ABq~ J=15Hz, S~ ),
-
lS 5.27 (lH, d, J=5Hz, C6-H),
5~87 (lH, dd, J=SHz, J-8Hz, C7-H),
6.55 (2H, bs, ~ ),
H H
6.80 (lH, s, -CH<),
N~r
6.97 [lH~ s, S~ ~)'
7.05-7.67 (25H, m, ~ x 5),
8.86 (lH, bs, ( ~ )3C-NH-),
9.54 ~lH, d, J=8Hz, -CONH-)
In a similar manner, the compounds shown in
Tables 21 and 22 were obtained.
- 141 -
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1 (2) In a mixed solvent of 8 ml of trifluoroace~ic
acid and 3 ml of anisole was d~ssolved 1.6 g of diphenyl-
methyl 7-[2-(2-tritylaminothiazol-4-yl)-2-(syn)-tert.-
butoxycarbonylmethoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-
dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-
carboxylate, and the solution was subjected to reaction
at room temperature for 1 hour. After completion of the
reaction, the solvent was removed by distillation under
resuced pressure. To the residue was added 10 ml of di-
ethyl ether and the crystals were collected by filtration.Then, the crystals obtained were dissolved in 20 ml of
50~ by weight aqueous formic acid solution, and the solution
was subjected to reaction at 45 to 55C for 1 hour. After
completion of the reaction, the precipitated crystals were
separated by filtration, and the solvent was removed by
distillation under reduced pressure. To the residue was
added 10 ml of ethyl acetate and the crystals were col-
lected by filtration. Subsequently, the crystals were
sufficiently washed with 10 ml of ethyl acetate
and dried to obtain 0.7 g ~yield, 80.7%) of 7-[2-
(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxyiminoaceta-
mido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyra-
zinyl)~methyl}-~3-cephem-4-carboxylic acid having a melt-
ing point of 139-140C (decomp.).
IR (KBr) cm 1 vc=O 1775r 1695, 1680, 1635
NMR (d6-DM~O) ~ values:
1.22 (3H, t, J=7Hz, ~NCH2CH3),
3.53 (2H, bs, C2-H),
_ 146 -
, . '' . "`.. " ~. ' ' . ~ ' -
''', ' ', .', . ~
.
" :' . , ' ~' . ', ' '
6~39
1 3.74 (2H, q, J=7Hz, ~NCH2CH3),
4.70 (2H, s, -OCH2CO-),
4.45, 5.10 (2H, AB~, J=15Hz, S ),
~L CH2-
5.23 (lH, d, J=5Hæ, C6-H),
5.90 (lH, dd, J=5Hz, J=8Hz, C7-H),
6.69 (2H, bs, ~ ),
H H
6.94 (lH, s, ~ ),
S H
9.70 (lH, d, J=8Hz, -CONH-)
In a similar manner, the compounds shown in
Table 23 were obtained.
::
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1 Example 8
(1) To a solution of 1.68 g of diketene in 8O40 ml
of anhydrous methylene chloride was added dropwise a
solution of 2.08 g of bromine in 6.25 ml of anhydrous
methylene chloride with stirring at -30C, and the mix-
ture was subjected to reaction at -30 to -20C for 30
minutes. The thus obtained reaction mix~ure was added
dropwise at -30C or less to a solution of 50 ml of
anhydrous methylene chloride containing 5.20 g of di-
phenylmethyl 7-amino-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4
tetrahydropyrazinyl)]methyl} ~3-cephem-4-carboxylate and
4.08 g of bis(trimethylsilyl~acetamide.
After completion of the dropwise addition, the
mixture was subjected to reaction at -30 to -20C ~or 30
minutes and then at 0 to 10C for 1 hour. After comple-
tion of the reaction, the solvent was removed by distil-
lation under reduced pressure, and the residue thus ob-
tained was dissolved in 50 ml of ethyl acetate and 40 ml
of water. Then the organic layer was separated, washed
with 40 ml of water and 40 ml of a saturated aqueous
sodium chloride solution in this order, and dried over
anhydrous magnesium sulfate. The solvent was removed
by distillation under reduced pressure. To the
residue was added 50 ml~of diisopropyl ether, ana the
thus obtained crystals were collected by filtration
to obt~in 5.85 g (yield, 85.6~) of diphenylmethyl
7_(4-bromq_3~ butyramido ) 3-{[1-(4-ethyl-2,3
28 dioxo-L~2~3~4-tetrahydropyrazinyl)]methyl}-
~3-cephem-4-carboxylate having a melting point of
- 156
- - ' .
. - : . : ~ -
- ~ . .. `:
.
.. ;
.
3~1
1 138-142C (decomp.).
IR (KBr) cm 1 vc 0 1778, 1720, 1680, 1640
NMR (d6-DMSO) ~ values:
1.22 (3H, t, J=7Hz, `NCH2CH3),
3.40 (2H, bs, C2-~),
3.85 (2H, q, J-7Hz, ~NCH2CH3),
3.87 (2H, bs, BrCH2COCH2-),
4.18 (2H, bs, BrCH2CO-),
4.47, 4.96 (2H, ABq, J-15Hz, S ~ ),
~C~12-
5.04 (lH, d, J=SHz, C6-H),
5.90 (lH, dd, J~5Hz, J=8Hz, C7-H),
6.15, 6.50 (2H, ABq, J=6Hz, ~ ),
6.98 (lH, s, -CH< ),
7.40 (lOH, bs, ~ x 2),
8.55 (lH, d, J=8Hz, -CONH-)
In a similar manner, the following compound was
obtained:
4.09 g ~yield, 62.6%) of diphenylmethyl 7-14-
bromo-3-oxo-bUtYr ~ d )-3-{[1-(3,6-dioxo-1,2,3,6-tetra-
~0 hydropyridazinyl)]methyl}-Q3-cephem-4-carboxylate having
a melting point of 124-126C (decomp.).
IR (KBr) cm 1 vc=O 1780, 1725, 1660
NMR (d6-DMSO) ~ values:
O O
Il 1i ~
3.49 (4H, bs, C2-H, -CCH2C-~,
- 157 -
,. , : ~ . ... , : . .
~ . - . , . :. , .
39
1 4.52 ~2~I, s, BrCH2C-),
5.06 (lH, bs, S ),
~)--CH2-
5.26 (lH, d, J=5Hz~ C6-H),
5.90 (lH, dd, J=SHz, J=8Hz, C7-H),
7.01~ 7.25 (2H, ABq, J=lOHz, ~ ),
7.09 (lH, s, -CH< ) 7
7.24-7.91 (lOH, m, ~ x 2),
9.34 (lH, d, J=lOHz, -CONH-)
(2) To a solution of 5 .50 g of diphenylmethyl 7j-(4-
10 brm-3~xobu ~ amido )-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-
tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate in
30 ml of acetic acid was added dropwise a solution of 5 ml
of water containing 0 .74 g of sodium nitrite with ice-
cooling over a period of 1 hour, and the resulting mixture
was subjected to reaction at room temperature for 2 hours.
After completion of the reaction, the reaction mixture was
poured into 500 ml o water to precipitate crystals. The
crystals were collected by filtration, washed sufficiently
with water, and dried. Thenj the crystals were dissolved
in 10 ml of chloroform and then purified by a column
chromatography (Wako Silica Gel C-200, eluent; benzene :
ethyl acetate=2:1 by volume), to obtain 3 .15 g ~yield,
54.9%) of diphenylmethyl~7-(4-bromo-2~hydroxyimino-3-
oxobutyramido ~)-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetra-
- 158 -
; '.''. ' ', .:' ' . ~ .
. -. , : .: , , . - . ,
-. , . -.- '-.. ~, ~: ' : ' . - . . ,
. ., . - .: ~. . : . . ,
~l~7;:~3~
1 hydropyrazinyl)]methyl}-A3-cephem-4-carboxylate having a
melting point of 127-132C (decomp.)
IR (KBr) cm : VC O 1778, 1720, 1680, 1635
NMR (CDC~3) ~ values:
1.26 (3H, t, J=7Hz, >NCH2CE13),
3.47 (2H, bs, C2-H),
3.81 (2H, q, J-7Hz, >NCH2CH3),
4.52 (2H, s, BrCH2CO-),
4.53, 4.78 (2H, ABq, J=15Hz, Sl ),
CH2 -
5.11 (lH, d, J=5Hz, C6-H),
5.80-6.15 (lH, m, C7-H),
6.13, 6.52 (2H, ABq, J=6Hz, ~ ),
7.02 (lH, s, -CH< ),
7.41 (lOH, bs, ~ x 2),
9.20 (lH, d, J=8Hz, -CONH-)
In a similar manner, the following compound was
obtained:
4.71 g (yield, 75.1%) of diphenylmethyl 7-(4-
bromo-2-hydroxyimino-3-oxobutry ~ do :~-3-{[1-(3,6-dioxo-
1,2,3,6-tetrahydropyridazinyl)]methyl}-~3-cephem-4-
carboxylate having a melting point of 138-141C (decomp.)
IR (KBr) cm : vc_O 1780, 1720, 1660
NMR (d6-DMSO) ~ values:
3.46 (2H, bs, C2-H),
4.62 (2H, s, BrCH2CO-)
- 159 -
- . :: ' : ' .' ' "' '
~ - . , ,
.. . . .. . . .
.
:. . :
~.~7~
1 4.96 (2H, bs, S~ ),
CH2
5.18 (lH, d, J=5Hz, C6-H),
5.93 (lH, dd, J-5Hz, Ja~Hz, C7-H)~
~,H
6.89, 7.13 (2H, ABq, J=lOHz, ~ ),
6.96 (lH, s, -CH< ),
7.13-7.72 (lOH, m, ~ x 2),
9.45 (lH, d, J=8Hz, -CONH-),
13.36 (lH, s, =N-OH)
(3) In 12 ml of N,N-dimethylacetamide were dissolved
lO 3.00 g of the diphenylmethyl 7-(4-bromo-2-hydroxyimino-3-
oYobu~yramido) :-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetra-
hydropyrazinyl)]methyl}-~3-cephem-4-carboxylate obtained
in above (2) and 0.42 g of thiourea, and the resulting
solution was subjected to reaction at room temperature for
3 hours. After completion of the reaction, the reaction
mixture was poured into a mixed solvent o 120 ml of
water and 240 ml of ethyl acetate. Subsequently, the
mixture was adjusted to pH 7.0 with sodium hydrogen-
carbonate, after which the organic layer was separated, and
washed with 50 ml of water and 50 ml of a saturated aqueous
sodium chloride solution in this order. After the organic
layer was dried over anhydrous magnesiam sulfate, the
solvent was removed by distillation under reduced pres-
sure. To the residue was;added 20 ml of diethyl ether and
the crystals were collected by filtration to obtain 2.10 g
160 -
~ .
.- , . - . . . . ~ . .
.. ~ ~ , . . . ... . . .
..
~ ~7~
1 (yield, 72.3~) oE diphenylmPthyl 7-[2-(2~aminothiazol-4-
yl)-2-(syn)-hydroxyiminoacet~mido]-3-{[1-(4-ethyl-2,3-
dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-c~phem-4-
carboxylate having a melting point of 137-140C ~decomp.).
IR (KBr) cm 1 vc 0 1778, 1720, 1680, 1640
NMR (d6-DMSO) ~ values:
1.19 (3H, t, J-7Hz, >NCH2CH3),
3.48 (2H, bs, C2-H),
3.68 (2H, q, J=7Hz, >NCH2CH3),
4.46, 5.04 (2H, ABq, J=15Hz, S~ ),
~J~CH2 -
5.28 (lH, d, J=5Hz, C6-H),
5.97 (lH, dd, J=5Hz, J=8Hz, C7-H),
6.57, 6.75 (2H, A~q, J=6Hz, ~ ),
H H
6.79 (lH, s, N ~ ),
S H
7.07 (lH, s, -CH< ),
7.53 (lOH, bs, ~ x 2),
9.70 (lH, d, J=8Hz, -CONH-)
(4) In a mixed solvent of 10.0 ml of trifluoroacetic
acid and 2.0 ml of anisole was dissolved 2.00 g of the
20 diphenylmethyl 7w[2-(2-aminothiazol-4-yl)-2 (syn)-hydro-
xyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetra-
hydropyrazinyl)lmethyl}-~3-cephem-4-carboxylate obtained
in above (3), and the resulting solution was subjected to
reaction at room temperature for 2 hours. After comple-
tion of the reaction, tha solvent was removed by
- 161 -
. ~ , .
: . :
~ ;276~35~
1 distillation under reduced pressure, and to the residue
was added 15 ml of diethyl ether, after which the crystals
were collected by filtration. Subsequently, the crystals
were sufficiently washed with 10 ml of diethyl ether and
then dried to obtain 1.62 g (yield, 87.6%) of trifluoro-
acetic acid salt of 7-~2-(2-aminothiazol-4-yl)-2-(syn)-
hydroxyiminoacetamido]-3-{[1-(4-ethyl 2,3-dioxo-1,2,3,4-
tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid
having a melting point of 112-118C IdecomP.).
IR (KBr) cm 1 vc O 1780, 1680, 1620
NMR (d6-DMSO) ~ values:
1.19 (3H, t, J=7Hz, ~N-CH2CH3),
3.47 (2H, bs, C2-H),
3.72 (2H, q, J=7Hz, >NCH2CH3),
4.45-6.70 (4H, m, S ~ , C6-H, C7-H),
CH2 -
6.59-6.83 (3H, m, ~ , N
Example 9
(1) To a solution of 7.1 g of diphenylmethyl
7-(4-bromo-2-hydroxyiminO-3-oxobutyramido 3_3_
{[1-~4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-
methyl}-~3-cephem-4-carboxylate in 70 ml of anhydrous
methylene chloride was slo~ly added a solution of
diazomethane in diethyl ether at -5 to 0C, and
the resulting solution was subjected to reaction at the
same temperature for 30 minutes. After confirming the
- 162 -
. . . -: . , : . . .
' ` '`. .: .: . :
1 disappearance of diazomethane, the solvent was removed by
distillation under reduced pressure. The~, the obtained
residue was purified by a column chromatoyraphy (Wako
Silica Gel C-200, eluent; benzene O ethyl acetate=3:1 by
volume) to obtain 2.32 g (yield, 32.0%) of diphenylmethyl
7-[4-bromo-2-(syn)-methoxyimino-3-X~butrYa~i~ ]-3-{[1-
~4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-
~ -cephem-4-carboxylate having a melting point of 135-
140C ¦decomp.).
IR (KBr) cm : Vc O 1778, 1720, 1682, 1638
NMR (CDC13) ~ values:
1.25 (3H, t, J=7Hz, >NCH2CH3),
3.48 (2H, bsr C2-H),
3.84 ¦2H, ~, J=7Hz, ~NCH2CH3),
4.00 (3H, s, -OCH3),
4.10 (2H, s; BrCH2CO-),
4.48, 4.67 (2H, ABq, J=15Hz,
~CH2-
5010 (lH, d, J=5Hz, C6-H),
6~05 (lH, dd, J=5Hz, J=8Hz, C7-H),
6.38, 6.73 12H, ABq, J=6Hz, ~ ),
H H
6.98 (lH, s, -CH <),
7.32 (lOH, bs, ~ x 2),
9.18 (lH, d, J=8Hz, -CONH-)
In a similar manner, the following compound was
obtained:
1.70 g (yield, 24.5%) of diphenylmethyl
~ 163 -
. : ~ . : . .
.: . . . .
- . . :. . ~
. .: :
1 7-[4-bromo-2-(syn)-me-thoxyimino-3 ,oxobu~do ]-3-{[1-
(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-~3-
cephem-4-carboxylate having a melting point o~ 145-148C
(dec.).
IR (KBr) cm : vc=O 1780, 1730, 1660
NMR td6-DMSO) ~ values:
3.49 (2Hs bs, C2-H),
4.03 (3H, s, -OCH3),
4.60 (2H, s, BrCH2CO-),
5.02 (2H, bs, S~ ),
--CH2 -
5.30 (lH, d, J=5Hz, C6-H),
6.02 (lH, dd, J=SHz, J=8Hz, C7-H),
\~H
6.92, 7.16 (2H, ABq, J=lOHz,
6.99 (lH, s, -CH ~),
7.17-7.78 (lOH, m, ~ x 23,
10.16 (lH, d, J=8Hz, -CONH-~
(2) In 14 ml of N,N dimethylacetamide were dissolved
2.3 g o~ diphenylmethyl 7-[4-bromo-2-(syn)-methoxy-
imino-3-oxO~utYraridO :~]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-
tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate and
0.32 g of thiourea, and the resulting solution was sub-
jected to reaction at room temperature for 3 hours. After
completion of the reaction, the reaction mixture was poured
into a mixed solvent o~ SO~ml of water and 150 ml of ethyl
acetate. Then, sodium hyc~ gencarbonate was added there-
- 164 -
.
. . ..
-. : . , .
~ ~7~;~3~
1 to adjust the mixture to pEI 6.7, and then the organic
layer was separated. The aqueous layer was further
extracted twice with 100-ml portions o~ ethyl acetate.
The combined or~anic layer was washed with water and
dried over anhydrous magnesium sulfate, and the sol-
vent was removed by distillation under reduced pres-
sure. To the residue was added 20 ml of diethyl
ether, and the crystals were collected by filtration
to obtain 1.92 ~ Iyield, 86.3~) of diphenylmethyl 7-
[2-t2-aminothiazol-4-yl~-2-tsyn)-methoxyiminoacetamido]
3-{~1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-
methyl}-~3-cephem-4-carboxylate having a melting point
of 165-167C.
IRtKBr)cm 1 vc O 1780, 1720, 1680, 1640
In a similar manner, the ~ollowing compound
was obtained:
o Diphenylmethyl 7-[2~t2-aminothiazol-4-yl~2-
tsyn)-methoxyiminoacetamido]-3-{[1-(3~6-dioxo-1~2,3~6-
tetrahydropyridazinyl~]methyl}-~3-cephem-4-carboxylate,
m.p., 175-178C tdecomp.)
IR (KBr) cm 1 vc O 1780, 1720, 1685-1660
The same ring-closure reaction as above was
conducted and then the reaction mentioned in Example
6-(3) or Example 7-(2) was conducted, to ohtain the
compounds shown in Tables 24, 25 and 26.
- 165
, - ~ ' ':
. ~ .. . . . .
. . - . ~ . ~ . :.... . .
- ~., , . .: , :
' . .,: ~: ',:, ~ . , ,
. , ~ . . . .
- .
.
. .
~ ~7~ 3~
o ¦ N ~ =o U ~=
- Z
- 166 -:
.
- .`. :: , - . ~ . ,
. . . , , , .: ,.
~ ~76~.3~
r ~.
~ m
: ~
-~ 167 - ~ -
~: :
.. ~ . .. . .. ...
: ~; .~ ` ,. , :
: . ` . ` ` . : : ` , ,
. . . : `
: - ~ .
- ` .. `: , , :, , `
.
:~ ~7~3~
_
m m u" ~
~Z~D o~z~D o~ I ~D
. .. _ D
U ~ O U
0~~ ~ 0~ ~ ~ 0~ ~ ~
. . . .. _
U U
U C~
~Z~l oX~ ~
-- 168 -- ~
\
.. . . . . . . .
.. . .: , :
: . ., ` : ' ' .,: ' ' .
'- ~ . . .
~.~76~3~3
. . . . ......
~ ~o ; ~
~ '~
U~ Or~
-- 169 --
.. . . :. , ~ :, .
:.
.
:. .: . . - ~ .,
.. `. ., . : ~` :
. ` .
~. . : ` . ~, ;.
` .
- . .. , . , : : .
. .. ., ` . .
~ ~'7~
Table 25
S ~r N O~ ~ 2
OR 18 COOH
(syn-isomer)
- - --......... ...... .
R RS R1 8
0~0 . . _ _
--N NCH2C~3 NH2- -CH2COOH
__ .. .. ...
--N~NCH2cH3 CP3COOH~NH2- -C-COOH
O O _ ,
--N N~3 NH 2 - -CH 2CH
lo~o ~ ~ ~
--N CH3 CF3COOH NH2- -CH2COOH
. ,~, . ___ , . . _ ..
--N,=,N-N~ 3 ¦ CF3COOH~ NH2- ¦ CH2COO
- Cont ' d
-- 170 --
.- , , , - ,, . , . , .:
6~3~
Table 25 (Cont ' d1 ~
j~j
N~ 3C130 3 ~ N 32--CH2COOEI
l~c32c=cc33 ~ ~
O NE32- -CH2COOH
. ....... ~ .. _ _.... . .
--N N ~) N12- -CH2COOH
O O ._ ....... _
--N NCH20COC (CH 3 j 3 NH2- -CH2COOH
1 ~ . _ _ .
- Cont'd -
- ~- 171
` ' , - ~,' - - - ,, ,
:: . ' , . :
-, . :'
~2~
Table 25 (Cont ' d)
--N~C 2COOH ~ NH2- ~-C}l COOH
~ . . _ _ .
--N ~NCH2CH3 HCOOH NH2~ CH2COO~)
2 3 HCOOH~NH2-- -CH ~<OO~
'0~0
--N NCH2CH3 HCOOH NH2--CH2COOCH2CH3
_ . .__ . _ ~ _.. _ ~__.
- 172 -
~;
- .. . ~
. : . : ' .: , ' ' ':: ' . : . . ' ., ' : . , '
''' -, ' ~ '- . '' . :
. .
3~
Table 26
H N~ CH R2
OCH3 O l I
COOR
(syn-isomer)
._. .
._ ._ . ___ . .
0~,0
-CHOCOC(CH3)3 -N NCH2CH3
CH3 .
-fHOCOC(C~3)3 - N NCH3 .
CH3
. _ . ............ . ._ . .,
~ 0~,0
-fHococ(cH3)3 - N N-(CH2)4CH3
CH3
_ _ .
~
-fHOCOC(CH313 ~N N-(CH2)5CH3
CH3
- Cont'd -
:
.
- 173 -
\ ~
' ~ . ', ' ' .', '' . . .. , , -
' `' ~ ' ~ ' ' ,- ,` ' '., . , ' : ,
~ . , .
3~
Table 26 (Cont 'd)
-C30COC ~C~3) 3 --N 2 ~C~12) 7CH3
_ ..
--fHOCOC (CH3) 3 ~ ( 2)11CH3
0~0
-CH20COC (CH3) 3 --M~ICH2CH3
... _ . .. . . _
0~,0
-cHocooc (CH3~ 3 --N~NCH2CH3
CH3
. . __ _ . _......... _
~ ; --~1NC1~2CI{3
.__ _ ... ---- - --- .
2 ) 3 ~3 --NNCH2CN3
. .__- .. .. ,
- Cont'd -
-- 174 --
- - - '. . ~ .. - - - , ' ' ' : .
` - ` - ` ' ~ ' , ' ~ ' ~ ' ' ' ' ' . . ,
,
~ ~7~3~
Table 26 tCont~d~
-CH~=C-CH3 0~<0
~ --N~NCH 2CH 3
--CH20COC (CH3) 3 ~D
.
CH 3
--C}120COC (CH3) 3 ¦--N~JJ
_ _ . . .
-C 3 20COC ( C 3 ) 3 3 IN ~
.. .. _ ~n ~ . ....... _ .. __
~ ~C (CH3 ) 3 ~
: .
- Con t ' d
'.
--~ 175 --
:::
- - . ~ . .... .
- -. -: ~ . - .
- : . i . . .
~.~7;~39
Table 26 (Cont'd)
CHococlcH3)3 CU~
. . . ...
0~,0
. -CH20COC(CH3)J -N N
Note: * Hydrochloride
l Physical properties (m.pO, IR and NMR spectra)
of the above compounds were the same as those obtained
in Examples 6, 7, 11 and 12.
:: :
:
- 176 -
.
- ~ . . . .
,.. ~ . ..
-- . - : ~: . . : . :
.. ... - . : . ~ ,. : , - :
3.~7~3~3
- 1 E~ample 10
(1) To a suspension of 2.2 g of 2-(2-formamido-
thiazol 4-yl)glyoxylic acid in 11 ml of N,N-dimethyl-
acetamide was added dropwise 1.8 g of phosphorus
oxychloride at -20C, and the resulting mixture was
subjected to reaction at the same temperature for 2
h~urs. Then, to this reaction mixture was added a
solution of 26 ml of methylene chloride containing
5.2 g of diphenylmethyl 7-amino-3-{[1 (4-ethvl-2,3-
dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-
~-carboxylate at -30 to -20C. After completion of
the dropwise addition, the mixture was subjected to
reaction at same temperature for one hour. After
completion of _he reaction, 70 ml of water and 50 ml
f methylene chloride ~ere added to the reaction
mixture. Then, sodium hydrogencarbona~e was added
thereto to adjust the mixture to pH 6.5, and the insolubles
were removed by filtration. The organic layer was
thereafter separated, washed with 100 ml of water and
10 ml of a saturated aqueous sodium chloride solution
in this order, and dried over anhydrous magnesium
sulfate. Subsequently, the solvent was removed
by distillation under reduced pressureO The residue
was purified by a column chromatography ~Wako Silica Gel
- 177 ~
.
.
, . . . .
. ~ ~ . . . . .
-' ' ' ' : ' '
~ ~'7~3~
1 C-200, eluent; chloroform:methanol=20:1 by volume) to
obtain 1.4 g (yield, 20.0~) of diphenylme-thyl 7-[2-(2-
formamidothiazol-4-yl)glyoxylamido]-3-{[1-~4-ethyl-2,3-
dioxo-1,2,3,4-tetrahydropyrazinyl)]me-thyl}-~3-cephem-4-
carboxylate having a melting point of 140-145C ~decomp.).
IR ~KBr) cm VC O 1780, 1720, 1680, 1670, 1640
NMR (d6-DMSO) ~ values:
1.20 (3H, t, J=7Hz, ~NCH2CH3),
3.50 (2H, bs, C2-H),
3.69 (2H, q, J=7Hz, ~NCH2CH3),
4.40, 5.00 (2H, ABq, J=15Hz, S ~ ),
~L CH2-
5.30 (lH, d, J=SHz, C6-H),
6.00 (lH, dd, J=5Hz, J=9Hz, C7-H),
6.50, 6.62 (2H, ABq, J=5Hz, ~ ),
H H
7.04 (lH, s, -CH~ ~,
7.30 (lOH, bs, ~ x 2),
8.64 (lH, s, N ~ ),
S H
8.81 ~lH, s, HCONH-),
10.20 ~lH, d, J=9Hz, -CONH-),
12.90 ~lH, bs, HCONH-~
In a similar manner, the following compound was
obtained: 0.09 g ~yield, 19.2%) of diphenylm~thyl 7-[2-
(2-formamidothiazol-4-yl)glyoxylamido~-3-{[1-(3,6-
dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-~3-cephem-
4-carboxylate,
- 178 -
-
.
.
: .. : . . . .~ . - .,
. . , ~. . . . .
3~
1 m.p.: 153-154C (decomp.).
IR (KBr) cm 1 ~C O 1780, 1725, 1690, 1665
NMR (CDCl3+d6-DMSOJ ~ values:
3.42 (2H, bs, C2-H),
4.96-5.40 (3H, m, S ~ , C6-H),
CH2 -
5.95 (lH, dd, J=5Hz, J=8Hz, C7-H),
6.72-7.78 (13H, m, -CH~ , ~ , ~ x 2~,
8.66 (lH, s, N
S H
8.73 (lH, s, HCO-),
9.86 llH, d, J=8Hz, -CONH-)
(2) To a solution of 7.0 g of diphenylmethyl
7-~2-(2-formamidothiazol-4-yl)glyoxylamido]-3-{[1-(4-
ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-
methyl}-~3-cephem-4-carboxylate in 35 ml of N,N-
lS dimethylacetamide was added l.~ g of methoxy-
amine hydrochloride with ice-cooling, and the resulting
mixture was subjected to reaction at 15-20C for 3 hours.
After completion of the reaction, the reaction mixture
was poured into a mixed solvent of 250 ml of water and
250 ml of ethyl acetate, and the organic layer was
separated, washed with 250~ml of water and 250 ml of a
saturated aqueous sodium chloride solution in this
order, and dried over anhydrous magnesium sulfate.
Then, the solvent was removed by distillation under
- 179 -
.: ~ ' .'; ' ', , ' : ' '
, . . ' ,
~ 27~i~3
1 reduced pressure. To the residue was added 50 ml of
diethyl ether, and the resulting crystals were collected
by filtration to obtain 6.1 g (yield, 83.7~) of diphenyl-
methyl 7-[2-(2-formamidothiazol-4-yl)-2~(syn)-methoxy-
iminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetra-
hydropyrazinyl)]methyl}-Q3-cephem-4~carboxylate having
a melting point of 165-168C.
IRtKBr) cm 1 VC O 1780, 1720, 1680, 1640
In a similar manner, the following compound
was obtained:
Diphenylmethyl 7-[2-(2-formamidothiazol-4-yl)-2-
(syn)-methoxyiminoacetamido]-3-{[1-(3,6-dioxo-1,2,3,6-
tetrahydropyridazinyl)]methyl}-Q3-cephem-4-carboxylatet
m.p. 171-173C (decomp.).
The same oximination reaction as above was
conducted, and then, the reaction mentioned in Example
6-(2), (3) and/or Example 7-(2) was conducted, to
obtain the following compound and the compounds shown
in Tables 27, 28 and 29:
o Tri~luoroacetic acid salt of ~-E 2-(2-amino-
5-bromothiazol-4-yl)-2-(syn)-methoxyiminoacetamidoJ-3-
{~1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)~-
methyl}-~-cephem-4-carboxylic acid
m.p.: 147C (decomp.)
25 IR(KBr) cm 1 vc~O 1775, 16~0, 1640
- 180 -
- . : ,:, ~- , ~ , ; , -
.
,, , ` ,', :,'', ', ' ' : ' ' ~
. : ~ . .: .: . : , . .
~ ~7~
,'`'~''
,~1/ l I
n ~ . ~ ~ ~
~: ~0 ~0
U
~ L
- 181
, ~ ~
. . .. , . ~ . ` ` .
.` . ~. . . . . . . . .
.
~ ~7~
. ... _ _
.~ . o~ .
o
~3 ~C ~
L~
8 2 -
: ` , : ... : .. .~ . . . .-- . . . . . .
.. : ,, ,. , . : .. . . ,, , :
. : : . :: . : . . . ..
3~
.. .. . ._
~ ~,
m D~ . ~
o~z~ o~z~ o~z3
. ..... _
~o ~
u m . u
~ o~cO o~ ~o, ..
Q ~ 0 ~J~ ml .
o~z~D 0~ 1 ~ 0
:
_ _ _ . . .'
~Z~I ~ ~ ~ oX~
::
- 183 -
\
35~
_ 1
~o ~ I
,
Xr~ V
4-
3~
Table 28
N\ O ~\CH2R
OR 1 ~ COOH
(syn-isomer)
F . ~ RS ~ R1 8
--N NCH2CH3 NH2-- --CE~2CH
_ _ _
~ 2C113 CF 3Coo ~ ' ~3 2 ~ =
--N NH NH 2 ~ -CE~ 2COOH
--N~CH3 CE'3COOEI ~ NH2- -CH2COOH
W-N~ 3 C~3COOi3~ N~ n 2~00~l ¦
- Cont ' d
- 185 -
- - . -: . . .: .
. . - -. - : .
' '
Table 28 (Cont ' d)
o ~HCOOH NH2- -CH2COOH
. ~ ..
--N ~ HCOOH: NH2- -CH 2CH
0~0 ...,, '-- ''-
--N NCH2C=C-CH ,
J ~ 3 NH2- -CH2COOH
O O - : . .... . I
--N N ~ NH2- -CH2COOH
~ ' . . _ __ . _
--N CH20cOc ~CH ) 3 NH2- -CH~COOH
:1
I . . . . __
- Cont'd -
~ 186 -
. .
-
, . , , . , '
- , . . , ., .: . ..
3~
.
Tabl~ 28 (Cont 'd)
--N NCH2cooH ~ NH2- ~ -Cl[2COOH
I .. . .. ~ ..... _. .. _. .
--N ~NCH2CH3 HCOOH- NH2- -CH2COO~)
-0~0 ~ ~ ... __ .
--N~CH2CH3 HCOOH~NH2-- --CH2COO &1
0~0 . _
--~ NCH2CH3 HCOOH~ NH2-- --CH2COOCH2CH3
-- 187 -
. . . . .. .. .
-
.
- ~:
~276~3~
.
Table 29
2 ~ CH2R
OCH3 O l 1
COOR
(syn-isomer)
Rl . . .~ .
. ,
0~,0
-CHOCOC(CH3)3 -N NCH2CH3
CH3 .
__ _ .
' 0~,0 ` `
-CHOCOC(CH3)3 -N NCH3
. : O
-fHOCOC(CH3)3 ~ ~ N-(CH2)4CH3
C~3
. . . _. : , '
~ 'OC~CH3i~ N N ~CH2)5CH3
:
: ~ - Cont'd -
,
.
~ 8 -
- . ... i , ... "............. .. . ..
Table 2 9 (Con t ' d )
0~/0
-FHOCOC (CE~3) 3 --N N (CE~2) 7CH3
CH3
.~ . . .. ___
0~ ,0
-I ~OCOC (CH3) 3 --N N [C~12)11CH3
_ - . . .
0~<0
--CH20COC (CH3) 3 --N~NCH2CH3
. _
0~,0
-CHOCOOC (CH3) 3 --N~NCH2CH3
CH3
.. . . _ .
--N NCH 2CH 3
. .
: 3~
- (CH2) 3CH3 --N NCH2CH3
. _ ._ ~: .. - ,,
- Cont'd -
-- 189 --
.
, ~
., , ~ ~ ..'; ' ' ' .
~7~3~
Table 29 :(Cont'd~
-CH2C=C--CH3 0~,0
l~o --N~NCH2CH3
--CH20COC ~CH3 ) 3 --I ~11 .
CH 20COC ~ CH3 ) 3
t 1120C ~ (CH 3 ) 3 HN~
-CH20COC (CH3) 3 f~
. ~ _ .~
- Cont'd -
-- 1 9 0
.
. : .
, . ~ . .
~ ~ , ``.' '. ." ,, -
~7~i~3
Table 29 (Cont'd~
-CIIOCOC ~CH3) 3 N ¦`~
_. . ._
~ O
-C~20COC(CH3)3 -N N ~
Note: * Hydrochloride ~
1 Physical properties Im. p ., IR and NMR spectra)
of the above compounds were the same as those obtained
in Examples 6, 7, 11 and 12.
.
-- 191 --
.
,' . ' ' ~ ' . ' .~;,, `, ' ' :
~. . . . . . .
~ ~ , - . .
6~3
1 Example 11
(1) In a mixed solvent of 37 ml of trifluoroacetic
acid and 10.8 g of anisole was dissolved 7.29 g of di-
phenylmethyl 7-[2-(2-formamidothiazol-4-yl)-2-(syn)-
m~thoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4
tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate,
and the resulting solution was subjected to reaction at
room temperature for 2 hours. After completion of the
reaction, the solvent was removed by distillation under
reduced pressure. To the resulting residue was added
50 ml of diethyl ether, and the crystals were collected
by filtration, washed sufficiently with 50 ml of diethyl
ether and dried to obtain 5.2 g (yield, 92.4%) of 7-[2-
(2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-
3-{ E 1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-
methyl}-~3-cephem-4-carboxylic acid having a melting
point of 155-158C Idecomp-)-
IR (KBr) cm 1 VC o 1775, 1710, 1675, 1640
NMR ~d6-DMSO) ~ values:
1.20 (3H, t, J=7Hz, ~NCH2CH3),
3.49 (2H, bs, C2-H),
3.73 (2H, q, J=7HZr ~NCH2CH3),
3.91 (3H, s, -OCH3),
4.42, 4.95 t2H, ABq, J-15Hz, S~ ),
~lCH2-
5.2I (lH, d, J=5Hz, C6-H),
5.89 (lH, dd, J=5Hz, J=8Hz, C7-EI),
6.65 (2H, bs, H~
- 192 -
'. ','' , ,, ',1 .
3~3
N lT-
1 7.46 (lH, s, ~ ~,
S H
8.59 (lH, s, HCONH-),
9.77 (lH, d, J=8Hz, -CONH-),
12.58 (lH, bs, HCONH-)
S In a similar manner, the compounds shown in
Table 30 were obtained.
.
~:
: ~
~ 193~
::
Table 30
N C CONH ~ `~
HCONH ~ ~N~--CH2R
OCH COOH
3 (syn-isomer)
Compound _IR (KBr )
. . m ~. (C) -1
_R2 .~ cm : VC=O
(~ O 195-198 1775, 1720,
)?~ (decomp.) 1680-1640 .
--NN-CH3
. .. _ .
O O
-N N- (CH2)4CH3 122-125 1775, 1680,
\~ (decomp.) 1640
.... _ . ~ ... ..
,0~0 l
-N N-~CH2)5CH3 165-170 1775, 1680,
(decomp. ) 1640
-. ......... _ . ,
0~0
-N N--~ ~O 195-198 1775, 1685,
\=~ ~decomp.) 1650
.. ~ .... ... __._ _ .. __ .
O O
~4 '
(CH2) 7CH3 155-158 1780, 1720, .
\~/ (decomp.) 1680-1640
.. _ ..... ___ _ .
0~0 ~ ~
(C 2) 11CH3 144-147 177 8, 1685,
~=~ (decomp. ) 1660 j 1645
_ ,
: '
- Cont'd -
-- 194 --
.
,, , . - . . . .
.. . , . :.
- . ;... .. . : :,
- , : : ,
~6~3~
Tablf~ 30 (Cont'd)
N ~ ~ .86-188 ~ 1775, 710,
-N (decomp. ) 1690, 1650
~C~3
N 218-221 1775, 1670,
-h~l ~decomp . ) 1 165 0
.
: ~ - 1 95 -
:.. . .,: .. .. , : . ,
~7~9
1 (2) To a solution of 5.63 g oE 7-[2-(2-
formamidothiazol-4-yl)-2-(syn)-methoxyiminoace-t-
amido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,~-te-trahydro-
p~razinyl)]methyl}-~3-cephem-4-carboxylic acid
in 25 ml of N,N-dimethylacetamide were added 1.52 g o~
1,8-diazabicyclo[5,4,0]-7-undecene and 3.84 g of 1-
pivaloyloxyethyl iodide with ice-cooling, and the
resulting mixture was subjected to reaction for 30
minu~es. After completion of the reaction, the reaction
mixture was poured into a mixed solvent of 100 ml of
water and 100 ml of ethyl acetate. Subsequently, the
organic layer was separated, washed with water, and then
dried over anhydrous magnesium sulfate. The sol~ent was
removed by distillation under reduced pressure. To the
residue was added 50 ml of diethyl ether, and the
crystals were collected by filtration to obtain 5.5 g
(yield, 79.6%) of l-pivaloyloxyethyl 7-[2-(2-~ormamido-
thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-
ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-
~3-cephem-4-carboxylate having a melting point o~
140-142C~
IR (KBr) cm 1 vc o 1780, 1740, 1680, 1640
In a similar manner, the compounds shown in
Table 31 were obtained. In this case, the compounds
shown in Table 31 can also be obtained by the same
method as in Example 6-(1), except that the correspond-
ing esters were substituted ~or the diphenylmethyl esters.
- 196 -
. . .: - - .
' ' ~
,:
- :' ,: '. '
. . , - .
6~3~
.
~ d
a~- W~ ~ _ ~ _
~ l= z & 3 ~&~ N ~ O ~= U
~h ~ ~ ~ ~ ~
oz, I I ~ , o~
&~ N ~ ¦ i ~
~ '
::
: - 197 ~-
.. . ........ . . .
. .
:; . , : : ` . ` ` `
,
:~ ~t7~
~,
~r ~ ~o ~1
CO CX: ~ o
~: . i ,,~ _
I o ; ~ ;
__ __ .__ -~ .
U~ o~ o~ ~j I
,,_ ~ .
m I Ou I o ¦ ~
U;-U ~ 1 ~1 U~
-- 198 -- .
~'
:', ~` . ` - ` :. ' . .,
'' . `: '
.
, ` ~, .. ... .
~- ` .' .'~'. " .' ,
, .
` ' ' ` , .
. . ` .
~ ~7~3~
I~ U~ ~o
In O
er` In
~ U~ CO
o .
In a) ~
~~ I o~ ~ ~
~o ~ ~ ¦ . t
____ _ _ _ __ _ A _ _ .
- 199 -
~` ' ' ' . ' ` '"' ' ''' ' . . ., " ~ ' ''
, ' ' ' ' ' ~
~ ~ 7~3~3
o l
o
,
~r
o
CO
,, , , ~
~ I ~,
E~
m~ ~\ .
U~ O
.5~ .
. ~.. . -
0: : *~ :~
~ ..
o~ .
Z
- .
~: :
200
:
.
`
- . ~ ~ . . .
.
.' ~- ' . '': .
- : .
3~
1 (3) To a solution of the 5.5 g of l-pivaloyloxy-
ethyl 7-[2-(2-formamidothiazol-4-yl)-2-(synl-methoxy-
iminoacetamido]-3-{[1~(4-ethyl-2,3-dioxo-1,2,3,4-
tetrahydropyrazinyl)lmethyl}-~3 cephem-4-carboxylate
obtained in above (2) in 27.5 ml of methanol was added
1.13 ml of concentrated hydrochloric acid, and the
res~lting mixture was subjected to reaction at 35C for
~ hours. After completion of the reaction, the solvent
was removed by distillation under reduced pressure. To
the residue were added 50 ml of ethyl acetate and 50 ml
of water, and the mixture was adjusted to pH 6.0
with sodium hydrogencarbonateO Subsequently, the
organic layer was separated and dried over anhydrous
magnesium sulfate, ater which the solvent was removed
by distillation under reduced pressure. To the residue
was added 45 ml of diethyl ether, and the crystals were
collected by filtration to obtain 4.65 g (yield, 88.1~)
of l-pivaloyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-
methoxyiminoacetamido]-3-{[1-t4-ethyl-2,3-dioxo-1,2,3,4-
tetrahydropyrazinyl)]methyl}-~ -cephem-4-carboxylate
having a melting point of 148-150C.
IR tKBr) cm 1 vc O 1780, 1740, 1680, 1640
NMR (d6-DMSO) ~ values:
0.90-1.3g (12H, m, -C~CH3)3, > NCH2CH3),
1.52 (3H, d, J=5Hz, -OICHO-),
CH3
3.52 (2H, bs, C2-H),
3.76 (2H, q, J=7Hz, ,~NCH2CH3),
- 201 -
.
.. . .
`'. '- ' ' ~ ' ., ~.
,
~.Z7~3~
l 3.88 (3H, s, -OCH3),
4.38, 5.04 (2H, ABq, J=15Hz, ~ ~,
~LCH2-
5.21 (lH, d, J=5Hz, C6-H~,
5.87 (lH, dd, J=5Hz, J=8Hz, C7-H),
6.61 ~2H, bs, ~ ),
H H
6.78 (lH, s, N ~ ~,
7.04 (lH, q, J=5Hz, -OCHO-),
7.22 (2H, bs, -NH2~,
9.67 (lH, d, J=8Hz, -CONH-)
In a similar manner, ~he compounds shown in
Table 32 were obtained.
- 202 -
. . . ~ ~ , .
: ~`- ' '', ', . ' .
~ ~ 7~3~
. ..
N ~ ~a
~ ~ ~_ m~l L I O ,, x ~ ~:
~ ^ o W
O C~) 11 2 00 ` ~r~
:~: I ~ A a~
Q
~ ~ ` m ~ J,
r
r~
1--Z ' U
L _ , o
Z~\u~ Q.
Z~
~C
. ,~,
~ P; 3~
U _
K U
~ _ U-U
-- 203 -
, . . ,,, : "
" - - . :. ' - . ' . ' ', ::
'.. ' `,' ~ . " .` .
`
- - - . . ' . . . .: . -
3~
. _ ~
r~) ~ r~ I m r~o I
Xl m m m ~ ~ o
~r r~ r~
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1 (4) To a solution of 1.05 g of the 7-[2-(2 formamido-
thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(2,3-
dimethyl-6-oxo-1,6-dihydropyrazinyl)]methyl}-~3-cephem-
4-carboxylic acid obtained in above ~1~ in 10 ml of
methanol was added 0.38 ml of concentrated hydrochloric
acid, and the resulting mixture was subjected to reackion
at 35C for 2 hours. After completion of the reaction,
the solvent was removed by distillation under reduced
pressure. To the residue was added 10 ml of diethyl
ether, and the crystals were collected by filtration to
obtain 0.43 g (yield, 84.8%) of hydrochloride o~ 7-~2-(2-
aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-
{[1-(2,3-dimethyl-6-oxo-1,6-dihydropyrazinyl)]methyl}-
~ -cephem-4-carboxylic acid having a melting point of
250C or more.
IR(KBr) cm 1 vc=O 1765, 1660, 1620
NMR(d6-DMSO) ~ values:
2.20 (6H, bs, -CH3 x 2),
3.18 (2H, bs, C2-H),
3.90 (3H, s, -oCH33,
4.94, 5.24 (2H, AB~, J=15Hz, ~ CH - )'
5.10 (lH, d, J~5HZ, C6-H),
5.78 (lH, dd, J=5Hz, J=8Hz, C7-H),
6.89 (lH, s, SN ~ H)'
7.82 (lH, s, ~ H),
9.79 (lH, dd, J=8Hz, -CONH-)
- 220 -
~, , '' ' ' ~`' ~'
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1 Example 12
(1) In a similar manner to that in Example 7-(1),
the compounds shown in Table 33 were obtained from the
starting materials shown below.
H ~ S ~ N
\OCH2COOR
(starting material,
syn-isomer)
NH2~ S ~ 0~0
N ~ CH2N N-CH2CH3
COOCH( ~ )2
\ /
0~ 1 2 ~=~ 2 3
OCH2COO~1 COOCH( ~ )2
(objective compound, syn-isomer)
- 221 -
- . . . . .
.. . , ~ . . .
- . . . , .. ~ ~ ,
. , .. , . .:
.. .: .
.. . .. .
Table 33
__ . . _ .. . . . _ __
¦ Objective Compound m.p. (C) IR (KBr)
Rl cm : VC O
__ .. _ . ._
f-~ 127-130 1780, 1720,
(decomp.) 1685, 1645
, _ ,, , _ A. __ _
127-130 1~80, 1720,
~ (decomp.) 1685, 1635
_
150-152 1780, 1720,
-CH2CH3 (decomp.) 1680, 1645
1 ~2) The compounds shown in Table 34 were obtained
by reacting the above-mentioned compounds in a similar
manner as in Example 7-~2).
- 222 -
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~ 1 Example 13
(1) To a solution of 2.72 g of 2-(2-tert.-amyloxy-
carboxamidothiazol-4-yl)acetic acid in 40 ml of anhydrous
methylene chloride was added 1.06 g of N-methylmorpholine,
and the mixture was cooled to -35C. Subsequen-tly, 1.12 y
of ethyl chlorocarbonate was added thereto, and the
mixture was subjected to reaction at -35 to -25C for
1.5 hours, after which 5.18 g of diphenylmethyl 7-amino-
3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-
methyl}-~3-cephem-4-carboxylate was added thereto, and
the mixture was subjected to reaction at 30 to -20C
for 1 hour and then at -10 to 10C for 1 hour. After
completion of the reaction, the solvent was removed by
distillation under reduced pressure. The residue was
dissolved in 40 ml of ethyl acetate and 30 ml of water.
The organic layer was separated, and 30 ml of water
was added again thereto. The mixture was adjusted to
pH 7.0 with sodium hydrogencarbonate with ice-caoling.
The organic layer was separated, washed with 30 ml of
water and 30 ml of a saturated aqueous sodium chloride
solution in this order, and dried over anhydrous
magnesium sulfate. The solvent was removed by distil-
lation under reduced pressure. To the residue was added
35 ml of diethyl ether, and the crystals were collected
by filtration to obtain 3.62 g (yield, 90.5%) of di-
phenylmethyl 7-[2-(2-tert.-amyloxycarboxamidothiazol-
4-yl)acetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-
tetrahydropyrazinyl1methyl}-~3-cephem-~-carboxylate
- 227 -
' ' ''
"~. :. ,, ,` .
.
.'~ ' :. `
7~
1 having a mPlting point o~ 152-154C (decomp.).
IR (KBr) cm : VC o 1780, 1720, 1685, 1640
In a similar manner, the following compound
was obtained: 6.15 g (yield, 82.7~ o~ diphenylmethyl
7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)acetamido]-
3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-
-cephem-4-carboxylate,
m.p.: 136-139C (decomp.)
IR (KBr) cm 1 vc O 1780, 1720, 1665
(2) The compounds shown in Table 35 were obtained
by subjecting the compounds obtained in above (1) to
reaction in the same manner'as in Example 6-(3).
- 228 -
.
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-- 230 --
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1 Example 14
In 48 ml of N,N-dimethylacetamide ~ere dissolved
6.82 g o~ diphenylmethyl 7-(4-brOmo-3-oxobut~r~o ~-3-
{[1-(4-ethyl-2,3-dioxo-1,2~3,4-tetrahydropyrazinyl)]-
methyl}-~3-cephem-4-carboxylate and 1 g of thiourea~ and
the mixture was subjected to reaction at room temperature
for 2 hours. After completion of the reaction, the
reaction mixture was poured into a mixed solvent of 500
ml of water and 500 ml of ethyl acetate, and the
n mixture was adjusted to pH 6.7 with sodium hydrogen-
carbonate. The organic layer was separated and
dried over anhydrous magnesium sulfate, and then the
solvent was removed by distillation under reduaed
pressure. Subsequently, the residue was dissolved in
33 ml of trifluoroacetic acid and 8 ml of anisole, and
the mixture was subjected to reaction at room temperature
for 1 hour. After completion of the reaction, the
solvent was removed by distillation under reduced pres-
sure. To the residue was added 40 ml of diethyl ether,
and the crystal5 were collected by filtration to obtain
4.50 g (yield, 74.1%~ of trifluoroacetic acid salt of
7-~2-(2-aminothiazol-4-yl)acetamido~-3-{[1-(4-ethyl-
2,3-dioxo~ ,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-
4-carboxylic acid having a melting point of 109-115C
(decn).
In a similar manner, the following compound was
obtained: Trifluoroacetic acid salt of 7-[2-(2-amino-
thiazol-4-yl~acetamido]-3-{[1-(3,6-dioxo-1,2,3,6-tetra-
- 231 -
,
' '
' ~ ,
', ' , '.
,
3~
l hydropyridazinyl)]methyl}-~3-cephem-4-carboxylic acid,
m.p.: 200C or more.
Physical properties (IR, NMR values) of this
compound were identical with those in Example 13-(2).
::
.
~ 23:2~
: : , , ~ . . .. ...
;~ ~7~3~
1 Preparation Example 1
An aqueous sodium salt solution of 7-[2-(2-
aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-
{[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-
cephem-4-carboxylic acid was treated in a conventional
manner to obtain a freeze-dried and sterilized sodium
salt. One gram (potency) of the sodium salt was dis-
solved in 20 ml of physiological saline solution to
obtain an injection.
Preparation Example 2
one gram (potency) of the freeze-dried
product obtained in Preparation Example 1 was dissolved
in 4 ml of 0.5% (WlV) aqueous lidocaine hydrochloride
solution to obtain a dilutable injection.
lS Preparation Example 3
One gram (potency) of the freeze-dried product
obtained in Preparation Example 1 was dissolved in
20 ml o~ 5% glucose solution to obtain an injection.
Moreover, the other compounds of the formula
[I] can also be formed into the corresponding
freeze-dried products (sodium salts) or injections
by processing them in the same manner as in Preparation
Examples 1 to 3.
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