Note: Descriptions are shown in the official language in which they were submitted.
1 337522
SYN-ISO~ER OF 3,7-DISUB~TITITTFD-3-C~PIIE~-4-C~RBOYYIIC
ACID CO~IPOUNDS AND PROCESSES FOR T~IE PREP~R~TI~N THEREO~
The present invention relates to new syn-isomer of
3,7-disubstituted-3-cephem-4-carboxylic acid compounds and
pharmaceutically acceptable salts thereof. More particularly,
it relates to new syn-isomer of 3,7-disubstituted-3-cephem-4-
carboxylic acid compounds and pharmaceutically acceptable sa]ts
thereof wllicll have antibacterial activities and to processe.s
for the preparation thereof, to pharmaceutical composition
comprising the same, and to a method of using the s~me therapeutic-
ally in the treatment o infectious diseases in human being and
animals.
Accordingly, it is one object of the present invention
to provide syn-isomer of 3,7-disubstituted-3-cephem-4-carboxyli-
acid compounds and pharmaceutically acceptable salts thereof,
which are highly active against a number of pathog~nic kacterja.
Another object of the present invention is to provide
processes for the preparation of syn-isomcr of 3;7-disubsti~liced-
3-cephem-4-carboxylic acid compounds and ~harmaceutically
acceptable salts thereof.
A ~urther object of the present invention is to provide
pharmaceutical composition comprising, as active ingredicnts,
said syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic zcid
compounds and pharmaceutically acceptable salts thereof.
Still furthcr object of the present invention is to
provide a method or the treatment of infectious diseases caused
by pathogenic bacteria in hum3n being and animals.
The ol~ject syn-isom~r of 3,7-disubstituted-3-cephenl-4-
carbo~ylic acid com~ounds are novel and can be represcnted by
the following formula (1):
1 337522
Rl- C-CONI~ ~ S ~
N oR2 ~ N ~ R4 (I)
R3
in which
Rl is a group of the formula:
R5 ~ wherein R5 is hydrogen, halogen, nitro, hydroxy, lower
alkoxy or acyloxy and R6 is hydroxy, lo~er alkoxy, acyloxy, acyl-
amino or di(lower)alkylamino;
a group of the ~ormula:
R7 N ~ wherein R7 is amino, protected amino, hydroxy or lower
alkyl; or
a group of the formula:
R8 ~ wherein R8 is lower alkyl and R9 is imino, protected
R S
imino or oxo;
R2 is an aliphatic hydrocarbon group which may have suitable
substituent(s);
R3 is carboxy or protected carboxy; and
R4 is acyloxymethyl, hydroxymethyl, formyl or a heterocyclic-
thiomethyl group which may have suitable sulstituent(s);
or R3 and R4 are linked together to form -COOCH2-.
With regard to the present invcntion, it is to be
noted that this invention is characterized ~y providing
syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid
compounds, which is represented by the formula (I), and the
said syn-isomer can be represented by the partial structure of
the formula: R C CO in their molecules, while the corresponding
N-OR
anti-isomer is represented by the partia] structure of the
1 337522
formula : Rl-C-CO-
R2O-N
Accordingly, in the following detailed explanations of this
invention in this specification and claims, it is to be under-
stood that the syn-isomers of the objcct compounds as well as
the starting compounds of this invention are represented by the
partial structure of the formula: -C-CO- in their molecules,
N-O-
provided that, in case that it is convenient for thc explanation
of this invention to express both of the syn-isomer and anti-
isomer by one general formula, they are represented by the
partial structure of the formula: -C-CO-
N~
o
The objcct compounds of the presellt invention (I) are
novel compounds and can be prepared by the Proccsses 1 to 8 as
mentioned below.
Process 1
~ ~ R4 ~ Rl-C-COOH ~ Rl-C-CONH ~ ~
R3 N_oR2 N-OR2o R
R3
(II) (III) (I)
or it6 reactive derivative or its reactive or a salt thereofat the amino group or a derivative at
salt thereof the carboxy group
or a salt thereof
1 337522
Process 2
Rla c CONH S
N oR2 ~ ~ R -~ R b-C-CONH
~ m~n~tion of the
protective group
of the amino (or imino)
(IV) (Ia)
or a salt thereof or a salt thereof
Process 3
Acylation of
the hydroxy group
} C-CONH- S RSa
HO N-OR O ~ ~ R6a ~ 1 2 ~ ~ R4
R3
(V) (Ib)
or a salt thereof or a salt thereof
Process 4 Elimination of the
protective group
1 S of the carboxy
R -C-CONH ,
2011 2 ~ N ~ R4 ~ Rl C CONH
(Va) tIC)
or a salt thereof or a salt thereof
Process 5
~ n~tion of the
1 S protective group
R -C-CONH ' ~ of the amino
N-OR2 O~ - ~ ~ CH2-OCONH-R a_ Rl-CH-CONH ~ S~
R3 N-OR2 o~N ~ CH2-OCONH2
R3
(Vb )
or a salt thereof (Id)
or a salt thereof
- 4
1 337522
Process 6
Rl-C-CONH ~ S Rl-C-CONH S
N oR2 ~ N ~ CH2-R4b+ R4C^ SH ~ N oR2 ~ ~ H2 s R4c
s (VC) (Vd) (Ie)
or a salt thereof or its reactive or a salt thereof
derivativ~ at the
mercapto group
., .. , ...... ~
--- Process 7
R -C-CONH ~ S ~ Acid Rl-C-CONI-I ~ S
N_oR2 o ~ ~ CH2OH ~ O ~ 1 2
R CO- O
(Ve~ (If)
or a salt thereof or a salt thereof
Process 8
Rl-C-CONH ~ S~ Oxidation R -C-CONH l,S~
N-OR2o N ~ C~2H - ~ oR2o ~ N ~ CHO
(ve) (Ig)
or a salt thereof or a salt thereof
- - wherein Rl, R2, R3, R4 and R5 are each as defined above;
Rla is a group of the formula:
R7a ~ in which R7a is protected amino; or
a group of the formula
~ 3 in which R8 is as defined abovc and R9a is protected
R9a S
imino;
1 337522
Rlb is a group of the formula:
N
~ S ~
a group of the formula:
R - ~ in which R8 is as defined above;
S
HN
RSa is hydrogen, halogen, nitro, lower alkoxy or acyloxy;
R6a is acyloxy;
R2a is protected carboxy(lower)alkyl;
R2b is carboxy(lower)alkyl; R4a is a protective group of amino;
R4b is a group which can be substituted by a group R4C-S-
wherein R4c is a heterocyclic group which may have suitable
substituent(s); and
R4c is as defincd above.
Among the starting compounds, the starting compound
(III), including the corresponding anti-isomer are novel and
can be prepared by the processes which are illustrated by the
following scheme.
RS ~ (VII) R ~ COCH3
(VI) (VIII)
RSC RSC
R6b ~ COCH Oxidation ~ COCOOIi
(IX) (X)
1 337522
iii)
R5C Elimination R5c
R10O~ COCOOH HO COCOOH
S (XI ) ( X I I )
(iV)
R5 R2 ONH2 ( XIV ) or a 5
R6 3 ~ cocooH salt thereof R6 ~ IC!-COOH
oR2
(XIII) tIIIa)
(2) (i)
R5 NH2OH or a salt R5
~3COCOOH thereof ~ C-COOII
HO HO N
OH
(XV) tXVI)
(ii)
~O~ Alkylation R ~3c-cooR8
oR2c ~R2d
(XVI I ) (XVI I I )
Hydro lys i s RS d
~ C- COOH
R8O N
~R2d
(IIIb)
1 337522
t3)
RS Acylation Rsa
HO ~ C-COOH R6a ~ C-COOH
OR oR2
tXIX) tIIIC)
t4) ti) Nitrosation
CH2 C~CH2~Z ~ XCH2Co c z R b-C-NH2
txx) OH ) R7C-~s ~ N
OH
(XXI) (XXIII)
liminatin, R7 ~ ~ I
OH
tXXIIIa)
tii)
7 ~ N ~ C Z Alkylation 7 ~ ~ jCI-Z
OH OR2e
tXXIV) tXXV)
Elimination 7d ~N ~ C-COOH
S N
OR e
tIIId)
- 8
1 337522
Al~ylation Halogenation
CH3-CO-C-Z ~ CH3CO-C-Z X-CH2CO-~-Z
N N N
OH ~R2e ~R2e
(XXVI) (XXVII) (XXVIII)
R7b- C-NH2
(XXII) R7 ~ ~11 Elimination , R7C ~ ~ 11
OR2e OR2e
tXXIX) (IIIe)
(6) (i) Amino-protecting
H2N ~ ~ CH2 - Z ) R7a, ~_ CH2 - Z
tXXX~ (XXXI)
(ii) Oxidation HydrQlysis
RlC-C~2-z -~ RlC-CO-Z ~ R -C-Z
(XXXII) (XXXIII) N
0~
/ (XXIII~)
~ / R20-NH2 or a salt
~ ~ (XIV) thereof
lc ~/ RlC-C- Z
R -COCOOH 2
\ R -ON112(XIv~ ~/ N
- (XXXIV) \ thereof.~ oR2
~ ~ (XXXV)
NH2H RlC c cOOH
or a salt thereo N
Rlc c cOOH oR2
Il
N (IIIf)
0 OH
(XXXVI)
1 337522
(iii) N Alkylation R8 N 8
OH OR2e
(XXXVII) (XXXVIII)
ydrolysis R8
N ~ C-COOH
R9a~ S~ 11
~R2e
(IIIg)
(7)
Amino-protecting
~ S~ 11 agent , R7a~ ~ C Za
~N 2 ~ 2
OR OR
(XXXIX) (IIIh)
in which R2, RS, R6, R5a, R6a, R7a, R8 and R9a are each as
defined above;
R5b is halogen;
Y is an acid rèsidue;
R10 is ar(lower)alkyl;
RSc is hydrogen, halogen or nitro;
R6b is lower alkoxy, ar(lower)alkoxy or acylamino;
R2C is hydrogen, lower alkyl or lower alkenyl;
R5d is hydrogen, halogen, nitro, hydroxy or lower alkoxy;
X is halogen;
Z is protected carboxy;
R7b is lower alkyl, amino or lower alkoxy;
R c is lower alkyl, amino or hydroxy;
- 10 -
1 337~22
R7d is lower alkyl;
R2e is lower alkyl;
RlC is a group of the formula:
R7 ~ ~ in which R7 is as defined above, or
S
a g~roup of the formula:
1 ~~ in which R8 and R9 are each as defined above;
R9 S
R2d is lower alkyl or lower alkenyl; and
Za is carboxy or protected carboxy.
The other starting compounds( I~r), tv), (Va)-(Vc) and
(Ve) are all novel compounds and can be prepared by the aore-
said Processes ] to 8.
Regarding the object com~ounds of the formulae (I),
(Ia) and (IC)-(Ig) J and the starting compounds of the formulae
(III), (IIIe), (IIIf), (IIIh), (IV), (Va)-(Vc), (Ve), (XXIII)-
~XXIIIb), (XXIX)-(XXXVII) and (XXXIX), it is to be understood
that said object and starting compounds include tautomeric
isomers relating to their thiazole groups. That is, in case
that the group represented by the formula:
N
R7e ~ ~ (wherein R7e is amino, protected amino or hydroxy)
in the formula of said object and starting compounds take the
formula: 7e ~ ~ (A) (R is as defined above), said group of
the frmUla R7e ~ ~ can be also alternatively represented by
its tautomeric formula: 7f 0~ ~ (B) (wherein R7f is imino9
protected imino or oxo). That is, both o the said groups
(A) and (B) are in the state of equilibrium as so-colled
1. 1 -- ~,,
, . . . ..
1 337522
- tautomeric forms which can be represented by the following equilibrium:
7e l 5~ R7
(~) (B)
(wherein R7e and R7f are each as defined above).
These types of tautomerism between 2-amino- and 2-
hydroxythiazole compounds and 2-imino-or 2-oxo-thiazoline
compounds as stated above have been well known in the literature,
and it is obvious to a person skilled in arts that both of the
tautomeric isomers are equilibrated and easily convertible
reciprocally, and accordingly it is to be understood that such
isomers are included within the same category of the compound
per se. Accordingly, the both of t:he tautomeric for~s of the
object compounds (I), (Ia) and (IC)-(Ig), and the starting
compounds (III), (IIIe), (IIIf), (IIIh), (IV), (Va)-(Vc), (Ve),
(XYIII)-(XXIIIb), (XXIX)-(XXXVII) and (XXXIX) ar.e clearly
included within the scope of the present invention. In the
present specification, claims and examples, the object and
starting compounds including the group of such tautomeric isomers
are represented by using one of the expressions therefor, that
is the formula~ " only for the convenient sake.
R7e S -
(A)
Furthermore, regarding the object compounds (I), (Ia)~
(Ic) and (Ig), and the starting compounds (II), (IV), tv) and
(Va), the compounds wherein R3 is carboxy and R4 is formyl can
be also regarded as substantially same compounds as the compounds
wherein R3 and R4 are linked together to form a group of the
- 12 -
1 337~22
formula: -COOCH(OH)- , i.e. so-called intramolecular hcmiacylal
type compounds, and accordingly both of them are understood to
be included within the same category of the compound per se
and therefore within the scope o~ the present invention.
Suitable pharmaceutically acceptahle sait of ~.e
object syn-isomer o~ 3,7-disubstituted-3-cel)hem-4-carboxylic
acid compounds (I) are conventional non-toxic salts and may
include an inorganic salt, for example, a mctal salt such as an
alkali metal salt (e.g., sodium salt, potassium salt, etc.)
and an alkaline earth metal salt (e.g., calcium salt, magnesium
salt, etc.), ammonium salt etc., an organic salt, for exa~ple,
an organic amine salt (e.~., trime~hylamine salt, triethylamine
salt, ethanolamine salt, diethanolamine salt, pyridine salt,
picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylene-
diamine salt, etc.) etc., an organic acid salt (e.g., acetate,
maleate, tartrate, methanesul~onate, benzenesulfonate, toluene-
sulfonate, etc.), an inor~anic acid salt (e.g., hydrochloride,
hydrobromide, sulfate, phosphate, etc.), or a sal~ wit~l an
amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.~,
and the like.
In thte above and subsequent descriptions of the present
specification, suitable examples and illustrations of the various
definitions which the prcsent invention intend to include within
the scope thereof are explained in details as follows.
The te.~m "lo-~er" is intended to mean 1 to 6 carbon -
atom(s), unless otherwise provided.
Aliphatic hydrocarbon group is intcnded to mean straight
or branched aliphatic hydrocarbon having 1 to 6 carbon a~om(s)
and may include lower alkyl, lower alkenyl and the like. ~nd
said aliphatic hydrocarbon grotlp may have 1 to 2 suitable
1 337522
~ substituent(s) such as carboxy, protected carboxy, arylthio,
lower alkylthio, aryl, acyloxy, lower alkoxy, aryloxy, a
heterocyclic group or the-like.
Suitable halogen may include chlorinè, bromine, fluorine
and iodine
Suitable lower alkoxy and lower alkoxy moiety in the
term "ar(lower)alkoxy" may include one which may be branched,
for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like, and
preferably one having 1 to 4 carbon atom(s), and more preferably
one having 1 to 2 carbon atom(s).
Suitable protected amino may include an acylamino and
amino group substituted by a conventional protective group other
than the acyl group such as benzyl or the like.
- 15 Suitable lower alkyl and lower alkyl moiety in the
terms "lower alkylthio", "carboxy(lower)alkyl", "protected
carboxy(lower)alkyl", "ar(lower)alkyl" and "di(lower)alkylamirlo"
may include one which may be branched, for cxample, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tert-butyl~pentylJ hexyl
and the like, and preferably one having 1 to 4 carbon atom(s),
and more preferably one having 1 to 2 carbon atom(s).
Suitable protected imino may include an acylimino and
imino group substituted by a conventional protective group other
than the acyl group such as benzyl and the like.
Suitable protected carboxy and protected carboxy
moiety in the term "protected carboxy(lower~alkyl" may include
esterified carboxy in which said ester may be the ones such as
lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester,
isopropyl ester, butyl ester, isobutyl ester, t-butyl ester,
pentyl ester, t-pentyl ester, hexyl ester, l-cyclopropylethyl
. - 14 -
1 337522
ester, etc.), whcrein lower alkyl moiety may be prefer~bly one
having 1 to 4 carbon atom(s); lower alkenyl ester (e.g., vinyl
ester, allyl ester etc.); lower alkynyl ester (e.g., ethynyl
ester, propynyl ester, etc ); mono(or di or tri)-halo(lower)-
alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester,
etc.);
lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester,
propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl
ester, pivaloyloxymethyl ester, hexanoyloxymcthyl ester, 2-acetoxy-
ethyl ester, 2-propionyloxyethyl ester, etc.);
lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl es.er,
2-mesylethyl ester etc.);
ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester
which may have one or more suitable substituent(s) (e.g., bcnzyl
ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phellethyl
ester, trityl ester, diphenylmet}lyl ester, bis(methoxyphenyl)-
methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-
ditertiarybutylben~yl ester, etc.);
aryl ester whicll may have one or more suitable substituent(s
(e.g., phenyl ester, tolyl ester, tertiarybutylphenyl ester,
xylyl ester, mesityl ester, cumenyl ester, etc.), and the like.
Preferable example of protected carboxy may be lower alkoxy-
carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxy-
carbonyl, etc.) having 2 to 7 carbon atoms, pre~erably one
having 2 to 5 carbon atoms.
~ Suitable aryl and aryl moiety in the terms "ar(lower)-
alkyl", "ar(lower)alkoxy", "arylthio" and "aryloxy" may include
phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl and the like,
wherein said aryl group may have 1 to 3 suitable substituent(s)
- 15 -
t 337522
such as halogen (e.g., chlorine, bromine, iodine or fluorine),
hydroxy, and the like.
Suitable heterocyclic group and heterocyclic moiety
in the term "a heterocyclicthiomethyl group which may have
suitable substituent(s)" means saturated or unsaturated,
monocyclic or polycyclic heterocyclic group containing at least
one hetero-atom such as an oxygen, sulfur, nitrogen atom and
the like.
And, es~ecially preferable heterocyclic group may be
heterocyclic group such as
unsaturated 3 to 8-membered (preferably 5 to 6 membered)
heteromonocyclic group containing 1 to 4 nitrogen atom(s), for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl
and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl
(e.g., 4~-1-1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl,
etc.)~ tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc;
saturated 3 to 8-membered (preferably 5 to 6 membered) hetero-
monocyclic group containing 1 to 4 nitrogen atom(s), for example,
pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen
atom(s), for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
etc.;
unsaturated 3-to 8-membered (preferab~y 5 to 6 membered) hetero-
monocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3
nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl,
(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
etc.) etc.;
saturated 3 to 8-membered (preferably 5 to 6 membered) hetero-
monocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3
- 16 -
1 337522
nitrogen atom(s), for example, morpholinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen
atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,
ben~oxadiazolyl, etc.;
unsaturated 3 to 8-membered (preferably 5 to 6 membered) hetero-
monocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3
nitrogen atom~s), for example~thiazolyl, thiadiazolyl (e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyi, etc.),
etc;
saturated 3 to 8-membered (preferably 5 to 6 membered) hetero-
monocyclic group containing 1 to 2 sulfur atomts) and 1 to 3
nitrogen atom(s~, for example, thiazolidinyl, etc.;
unsaturated 3 to 8 membered (preferably 5 to 6 membered)
heteromonocyclic grou~ containing a sulf~r atom, for example,
thienyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulf-lr
atom(s) and 1 to 3 nitrogen atom(s), for example, benzothia~olyl,
benzothiadi~zolyl, etc. and the like;
wherein said heterocyclic group may have 1 to 2 suitable
substituent(s) such as lower alkyl (e.g., methyl, ethyl, propyl,
isopro~yl, butyl, isobutyl, pcntyl, cyclopentyl, hexyl, cyclohexyl,
etc.), preferably one having 1 to 4 carbon atom(s); lower alkenyl
(e.g., vinyl, allyl, butenyl, etc.);
aryl (e.g., phenyl, tolyl, etc.); halogen (e.g., chlorine,
bromine, iodine or fluorine); amino; di(lower)alkylamino(lower)-
alkyl (e.g. dimethylaminomethyl, dimethylaminoethyl, diethyl-
aminopropy], ~iethylaminobutyl, etc.), pIeferably one having
3 to 6 carbon atoms; or the like.
Suitable ~ower alkenyl is one having 2 to 6 carbon atoms
and may include, for example, vinyl, al]yl, isopropenyl,
1 337522
l-propenyl, 2-butenyl, 3-pentenyl and the like, and preferably
one having 2 to 4 carbon atoms.
Suitable acyl moiety in the terms "acylaminO", "acyl-
imino", "acyloxy" and "acyloxymethyl" as mentioned zbove may
include carbamoyl, aliphatic acyl gro~p and acyl group containing
an aromatic or heterocyclic ring. And, suitable examples of
the said acyl may be lower alkanoyl (e.g., formyl, acetyl,
propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl,
succinyl, pivaloyl, etc.), preferably one ha~Ting 1 to 4 carbon
atom~s), more preferably one having 1 to 2 carbon atom(s);
lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g., methoxy-
carbonyl, ethoxycarbonyl, propoxycarbonyl, l-cyclopropylethoxy-
carbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl,
pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.),
preferably one having 3 to 6 carbon atoms;
lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl,
isopropanesulfonyl, butanesulfonyl, etc.), preferably one having
1 to 4 carbon atom(s), more preferably one having 1 to 2 carbon
atom(s);
arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.);
aroyl (e.g., benzoyl, toluoyl, naphthoyl, phtllaloyl, indancarbonyl,
--- etc.);
ar(lower)alkanoyl ~e.g., phenylacetyl, phenylpropionyl, etc.);
ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxy-
carbonyl, etc.); and the like.
The acyl moiety as stated above may have 1 to 3
suitable substituent(s) such as halogen (e.g., chlorine, bromine,
iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (e.g.,
methoxy, ethoxy, propoxy, isopropoxy, etc.), lower alkyl (e.g.,
methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl
- ]8 -
.,, - - ., .. A
1 33~5~2
~e.g., vinyl, allyl etc.~, acyl such as halo(lower)alkanoyl
(e.g., chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoro-
acetyl, etc.), aryl (e.g., phenyl, tolyl, etc.), or the like.
Suitable examples of the acyl having said subs`tituent(s) may
be mono(or di or tri)halo(lower)alkanoyl (e.g., tri1uoroacetyl,
trichloroacetyl, etc.), preferably one having 2 to 4 carbon
atoms;
mono(or di or tri)halo(lo~er)alkanoylcarbamoyl (e.g., trichloro
acetylcarbamoyl, etc.), preferably onc having 3 to 4 carbon
atoms; or the like.
Suitable protective group of amino for R4a may include
acyl such as halo(lower)alkanoyl (e.g., chloroacetyl, dichloro-
acetyl, trichloroacetyl, trifluoroacetyl, etc.), preferably
one having 2 to 3 carbon atoms, or the like.
Suitable acid residue may include a residue of an
acid such as an inorganic acid (e.g., hydrochloric acid,
hydrobromic acid, hydriodic acid, sulfuric acid, etc.) or an
organic acid (e.g., methancsulfonic acid, bcnzenesulfonic acid,
p-toluenesulfonic acid, etc.).
Sui~able example of a group which can be substituted
by a group R4C-S- may include an acid residue such as halogen,
azido or acyloxy wherein said halogen and acyl moiety of said
acyloxy are the same ones as aforementioned.
Among the suitable examples of each of the groups of
the object compounds as explained and illustrated above, the
prefered examples thereof are illustrated as follows.
Preferable example of R5 may be hydrogen halogen
(preferably chlorine~ or nitro;
preferable example of R6 may be hydroxy, lower alkoxy
(preferab ~ Cl-C4, more preferably Cl-C2), acyloxy[preferably
- 19 -
1 337522
lower alkanoyloxy (preferably Cl-C4, more preferably Cl-C2)
or carbamoyloxy], acylamino [preferably lower alkanesulfonyl-
amino (prefcrably Cl-C4, more preferably (Cl-C2)J or di(lower)-
alkylamino (whcrein the alkyl moiety is prefexably Cl-C4,
more preferably Cl-C2);
preferable example of R7 may be amino, protected amino
such as acylamino [prcferably lower alkancsulfonylamino (preferably
Cl-C4, more preferably Cl-C2), trihalo(lower)alkanoylamino
(preferably Cl-C4, morc preferably Cl-C2) lower alkoxycarbonylamino
(pre~erably C2-C7, more ~referably C3-C6) or lower alkanoylar,lino
(preferably Cl-C4, more preferably Cl-C2)], hydroxy or lower
alkyl (preferably Cl-C4, more preferably Cl-C2);
preferable example of R8 is Cl-C4 lower alkyl, more
prcferably Cl-C2 lowcr alkyl;
preferable example of R9 may be protected imino such
as acylimino [preferably lowcr alkanesulfonylimino (prcferably
Cl-C4, more preferably Cl-C2)];
preferable example of R2 may be lower alkyl (preferably
Cl-C4, more preferably Cl-C2, most ~referably Cl), lower alkenyl,
ar(lower)alkenyl [more prcferably phenyl(lower)alkenylJ,
carboxy(lower)alkyl, protccted carboxy(lower)alkyl [more prcfcrably
lowcr alkoxycarbonyl (prcferably C3-C6) (lower)alkyl], arylthio-
(lowcr)alkyl [rnore ~refcrably phenylthio(lower)alkyl], ar(lower)-
alkyl [more preferably phcnyl(]ower)alkyl] w}lich may have
halogen (prefcrably brominc) and hydroxy, thienyl(lower)alkyl or
aryloxytlower)alkyl [more preferably phcnoxy(lower)alkyl] which
may ha~e hydroxy, in which alkcnyl and alkenyl moiety is C2-C6,
prefcrably C2-C4, and alXyl moiety is prefcrably Cl-C4, more
preferably Cl-C2;
- 20 -
1 337~22
preferable example of R3 may be carboxy;
preferable example of R4 may be acyloxymethyl~preferably lower
alkanoyloxymethyl (in which alkanoyl moiety is preferably
Cl-C4, more preferably Cl-C2, most preferably C2, i.e. acetyl)
or carbamoyloxymethyl which may have trihalo(lower)al~anoyl
(in which trihalo mOietyis preferably-trichloroand alkanoyl
moiety is prefcrably C2-C~ , hydroxymcthyl, formyl, tetrazolyl-
thiomethyl which may have lower alkyl (preferably Cl-C4, more
preferably Cl-C2) or di(lower)alkylamino(lower)alkyl (in which
alkyl moiety is preferably Cl-C4, more prc~crably Cl-C2),
triazolylthiomethyl which may have lower ~lkyl (prcerably
Cl-C4, more preferably Cl-C2) or thiadiazol)~lthiomethyl which
may have lower alkyl (preferably Cl-C4, more preferably Cl-C2);
or R3 and R4 are linked together to form -COOCH2-
The various processes for preparing the object compounds
of the present invention are explained in details in the following.
Process 1:
The object compound (I) or a salt thercof can be
prepared by reacting the compound (II) or its reactive derivative
at the amino group or a salt thereof with the compound (III) or
its reactive derivative at the carboxy group or a salt thereof,
which is a fundamental method for preparing the object compound (I)
Suitable reactive derivative at the amino group of the
compound (II) may include conventional reactive derivative used
in amidation, for example, a silyl derivative formed by the
reaction of the compound (II) with a silyl compound such as
bis(t~imethylsilyl)acetamide, trimethylsilylacetamide or the
like.
Suitable salt of the compound (II) may i.nclude an acid
- 21 -
1 ~37522
addition salt such as an organic acid salt (e.g., acetate,
maleate, tartrate, benzenesulfonate, toluenesul~onate, etc.) or
an inorganic acid salt (e.g., hydrochloride, hydrobromide,
sulfate, phosphate, etc.); a salt with an inorganic base such
as an alkali metal salt (e.g., sodium salt, potassiu.m sal~, etc . ), .-
an alkaline earth metal salt (e.g., calcium salt, magnesium
salt, etc.) or ammonium salt; a salt with an organic base (e.g.,
triethylamine salt, pyridine salt, etc.); and the like.
Suitable reactive derivative at the carboxy group of
the compound (III) may include conventional one used in
amidation.
The salts of the compound (III~ may be salts with an
inorganic base such as an alkali metal salts (e.g., sodium or
potassium salt), or an alkaline earth metal salt (e.g., calcium
or magnesium salt), a salt with an organic base such as trimcthyl-
amine, triethylamine, pyridine, a salt with an acid (e.g.,
hydrochloric acid or hydrobromic acid) or the like.
The reaction is usually carried out in a conventional
solvent such as water, acetone, dioxane, acetonitrile, chloroform,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl
acetate, N,N-dimethylfor~a~ide, pyridine or any other organic
solvent which does not adversely influence to the reaction.
Among these solvents, hydrophilic solvents may be used in a
mixture with water.
The present reaction is preferably carried out in the
presence of a condensing agent such as so-called Vilsmeier reagent,
for example, (chloromethylene)-dimethylammonium ohloride
produced by the reaction of dimethylformamide with thionyl
chloride or phosgene, a compound produced by the reaction of
dimethylformamide with phosphorus oxychloride, etc., or the like.
,~
- 22 -
- 1 337~22
The reaction may be also carried out in the
presence of an inorganic or an organic base such as an
alkali metal hydroxide, an alkali metal bicarbonate,
alkali metal carbonate, alkali metal acetate, tri-
(lower)alkylamine, pyridine, N-(lower)-alkylmorphorine,
N,N-di(lower)alkylbenzylamine, N,N-di(lower)-
alkylaniline as exemplified below, or the like. When
the base or the condensing agent is in liquid, it can
be used also as a solvent. The reaction temperature is
not critical, and the reaction is usually carried out
under cooling or at ambient temperature.
In the present reaction, it is to be noted
that, in case that the starting compound (III) is
reacted with the compound (II) or its reactive
derivative at the amino group or a salt thereof in the
presence of, for example, phosphorus pentachloride,
thionyl chloride, etc., only the corresponding anti-
isomer to the object compound (I) or a mixture of the
corresponding anti-isomer and syn-isomer is always
given as an object compound even if the compound (III),
i.e, syn-isomer is used as a staring compound. It is
of course to be noted that the reaction of the
corresponding anti-isomer to the starting compound
(III) with the compound (II) can never produce the
object compound (I) of the present invention, i.e, syn-
isomer. It may be understood that such tendency and
singularity of the reaction as mentioned above is due
to the fact that the less stable syn-isomer tends to
isomerize partially or wholly to the corresponding more
stable anti-isomer in the course of the reaction, for
example, in so-called activation step of the compound
(III) so that the isomerized compound, i.e, the anti-
isomer corresponding to the object compound (I) can be
produced as an object compound.
- 23 -
1 337522
Accordingly, in order to obtain the object compound
(I), i.e., syn-isomer selectively and in high yield, it is
necessary to use the starting compound (III), i.e., syn-isomer
and to select a suitable reaction condition. That is, the
S object compound (I), i.e., syn-isomer can be obtained selectively
and in high yield by conducting the reaction, for example, in the
presence of a Vilsmeier reagent as mentione~ above etc. and
under around neutral condition.
Especially, in case that the starting compound (III)
wherein Rl is a group of ~he formula: ~N ~ is used,
the ob~ect compound (I),i.e., syn-isomer can be obtained
selectively and in high yield by conducting the present reaction
of the corresponding starting compound (III), i.e., syn-isomer
with the compound (II), for example, in the presence of a
Vilsmeier reagent produced by the reaction of dimethylformamide
witl~ phosphorus oxychloride and under around neutral condition.
And, in this case, it is to be noted that particularly good
results can be achieved by conducting the reaction in the presence
of more than two molar equivalents of phosphorus oxychloride to
each amount of the said starting compound (III), i.e., syn-isomer
and dimethylf^rlnamide as shown in the working examples.
Further, in this case, it is to be also noted that good results
can be achieved by conducting an activation step of thc starting
compound (III), i.e., syn^isomer in the presence of a silyl
compound [e.g. bis(trimethylsilyl)acetamide, trimethylsilylacet-
amide, etc.] and the like.
With regard to the reaction of the compound (II) with
the compound (III), it is to be noted that;
when the compound (II) wherein R4 is carbamoyloxymethyl group
- 24 -
1 337522
having acyl group is used as a starting compound, there may be
obtained occasionally either the object compound (I) wherein R4
is carbamoyloxymethyl group having acyl group or free carbamoyloxy-
methyl group according to reaction conditions;
when the compound (II) wherein R4 is hydroxymethyl group is used
as a starting compound, there may be obtained occasionally the
object compound (I~ wherein R3 and R4 are linked together to
form -COOC~12- ;
and ~urther the protected carboxy group or salts in the compound
(II) may be converted in~o free carboxy group; in the course
of thc rcaction or in post-treatment. Thcse cases are also
included within the scope of the present invention.
As clear from the explanation as stated above, it is
to be understood that the Process 1 is a fundamental and the most
advantageous method for preparing the object compound (I), i.e.
syn-isomer.
Process 2:
The object compound (Ia) or a salt thereof can be
prepared by subjecting the compound (IV) or a salt thereof te
elimination reaction of the protective group of the amino or
imino.
Suitable salt of the compound (IV) may include a metal
salt, ammonium salt, an organic amine salt and the like as
aforementioned.
The present elimination reaction is carried out in
accordance with a conventional method such as hydrolysis; reduction;
a method by reacting the compound (IV) wherein the protective
group is acyl group with iminohalogenating agent and then with
iminoetherifying agent, and, if necessary, subjecting the
resulting compound to hydrolysis; or the like.
- 25 -
1 337522
The hydrolysis may include a method usin~ an acid or base or
hydrazine and the like. These methods may be selected
depending on the kind of the protective groups to be eliminated.
Among these methods, hydrolysis using an acid is one
of the common and preferable method for eliminating the
protective groups such as substituted or unsubstituted alkoxy-
carbonyl (e.g., t-pentyloxycarbonyl, etc.), alkanoyl (e.g.,
formyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted
aralkoxycarbonyl (e.g., benzyloxycarbonyl, substituted benzyloxy-
carbonyl, etc.), substituted p}lenylthio, substituted aralkyli~.ene,
substitutcd alkylidene, substituted cycloalkylidene, or the like.
Suitable acid may include an organic or an inorganic acid, for
example, formic acid, trifluoroacetic acid, benzenesulfonic acid,
p-toluenesulfonic acid, hydroch]oric acid and the like, and pre-
ferable acid is an acid which can be easily removed from the
reaction mixture by a conventional manner such as distillation
under reduced pressure, for example, formic acid, trifluoroacetic
acid, hydrochloric acid, etc. The acid suitable for the
reaction can be selected according to the kind of protective
group to be eliminated. When the elimination reaction is
conducted with the acid, it can be carried out in the presence
or absence of a solvent. Suitable solvent may include an
organic solvent, water or a mixed solvent thereof. ~hen
trifluoroacetic acid is used, the elimination reaction may be
preferably carried out in the presence of anisole.
The hydrolysis using hydrazine is commonly applied
for eliminating the protective group, for example, succinyl or
phthaloyl.
The hydrolysis with a base is preferably applied for
eliminating acyl group, for example, haloalkanoyl (e.g.,
- 26 -
1 337522
trifluoroacetyl, etc.) etc Suitahle base may include, for
example, an inorganic base such as alkali meta] hydroxide (e.g.,
sodium hydroxide, potassium hydroxide, etc.), alkaline earth
metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide,
etc.), alkali metal carbonate (e.g., sodium carbonate, potassium
carbonate, etc.), alkaline earth metal carbonate (e.g., n;agnesium
carbonatc, calcium carbonate, etc.), alkali metal bicarbonate
(e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali
metal acctate (e.g., sodium acetate, potassium acetate, etc.),
alkaline carth metal phosphate (e.g., magnesium phosphate,
calcium p}lospllate, etc.), alkali metal hydrogcn phosphatc (e.g.,
disodium llydrogen pJlosph~te, dipotassium hydrogen phosp}late,
etc.), or the like, and an organic base such as trialkylamine
(e.g., trimethylamine, trieth)~laminc, etc.), picoline, N-methyl-
pyrrolidine, N-methylmorpholinc, 1,5-diazabicyclo[4,3,0Jnon-5-ene,
1,4-diazabicyclo[2,2,2]octanc, 1,5-diazabicyclo[5,4,0]undccene-5
or the like. The hydrolysis using a base is often c~rried
out in water or a hydrophilic organic solvent or a mixed solvent
thereof.
Among the protectivc groups, the acyl group can be
- - generally eliminate~ by hydrolysis as mentioned above or by the
other conventional hydrolysis. In case that the acyl group
is halogen substituted-alkoxycarbonyl or 8-quinolyloxycarbonyl,
they are eliminated by treating with a heavy metal such as
copper, zinc or the like.
The reductive elimination is gencrally applied for
eliminating the protective group, for examp]e, haloalkoxycarbonyl
(e.g., trich]oroethoxycarbollyl etc.), substituted or unsubstitllted
aralkoxycarbonyl (e.g., benzyloxycarhonyl, substituted benzyloxy-
carbonyl etc.), 2-pyridylmcthoxycarbonyl, ctc. Suitable
- 27 -
1 337522
reduction may include, for example, reduction with an alkali
metal borohydride (e.g., sodium borohydridc, etc.) and the
like.
Suitable iminohalogenating agent use~d in a ~ethod as
mentioned above may include phosphorus trichloride, phosphorlls
pentachloride, phosphorus tribromide, phosphorus pentabromide,
phosphorus oxychloride, thionyl chloride, phosgene and the like.
The reaction temperature is not critical, and the reac~ion is
usually carried out at ambient temperature or under cooling.
Suitable iminoetherifying age]lt reacted Wit}l thus obtaincd
reaction prodtlct may include an alcohol, metal alkoxide and
the like. Suitable alcohol may include alkanol (e.g.,
methanol, ethanol, propanol, isopropanol, butanol, t-butanol,
etc.) which may be substituted with alkoxy (e.g., methoxy,
ethoxy, propoxy, isopropoxy, butoxy, etc.). Suitable meLal
alkoxide may include alkali metal alkoxide (e.g., sodium
alkoxide, potassium alkoxicle, etc.), alkalinc earth metal
alkoxide (e.g., calcium alkoxide, barium alkoxide, etc.) and the
like. The reaction temperature is not critical, and the
reaction is usually carried Ollt under cooling or at ambient
temperature.
Thus obtained product is, if necessary, subjected to
hydrolysis. The hydrolysis can be readily carried out by
pouring the reaction mixture obtained above into water, but there
may be previously added a hydrophilic solvent (e.g., methanol,
ethanol, etc.), a base (e.g., alkali metal bicarbonate,
trialkylamine, etc.) or an acid (e.g., diluted hydrochloric
acid , acetic acid, etc.) to the water.
The reaction temperature is not critical and may be
- ~8 -
1 337522
suitably selected in accordance with the kind of the protective
group of the amino group and the elimination method as mentioned
above, and the present reaction is prcferably carried out under
a mild condition such as under cooling, at ambient tempe-rature
or slightly elevated temperature.
The present invention includes, within its scope, the
cases that the protected carboxy is trans~ormed into the ~ree
carboxy group; that when the compound tIV) wherein R4 is carbamoyl-
oxymethyl group having acyl grup is used as the starting compound,
there may be obtained occasionally either the object compound
(Ia) wherein R4 is carbamoyloxymethyl group havin~ acyl gI'OUp
or free carbamoyloxymethyl group according to reaction conditions;
and that when the compound (IV) wherein R4 is acyloxymethyl group
is used as the starting compound, there may be obtained occasional-
ly the object compound (Ia) wherein R3 and R4 are linked together
to form -COOC~l2- according to reaction conditions;
in the course of the reaction or in post-treatMent.
Process 3:
The object compound tIb) or a salt thereof can be
prepared by acylating the hydroxy group of the compound (V) or a
salt thereof.
Suitable salt of the compound (V) can also be referred
to the ones exemplified for thc compound (IV).
The acylating agent to be used for the present reaction
may include an aliphatic, aromatic and heterocyclic carboxylic
acid, and the corresponding sulfonic acid and thio acid which
have aforesaid acyl group as their acyl moieties, and reactive
derivatives of the above-mcntioned acids. Suitable rcactive
derivative of the above-mentioned acids may include an acid
halide, an acid anhydride, an activated amide, an activated ester,
29
1 337522
... .
and the like. Suitable example may be an acid chloride;
an acid azide; a mixed acid anhydride with an acid such as
substituted phosphoric acid (e.g., dialkylphosphoric acid,
phenylphosphoric acid, diphenylphosphoric aci~, dibcnzylphosphoric
acid, halogenated phosphoric acid, etc.), dialkylphosphorous
acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyi-
carbonic acid, aliphatic carboxylic acid (e.g., pivalic acid,
pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or
trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g.,
benzoic acid, etc.); a symmetrical acid anhydride; an activated
amide with imidazole, 4-substituted imidazolc, dimethylpyrazole,
triazole or tetrazole; or an activated ester [e.g., cyanomethyl
ester, methoxymethyl ester, dimethyliminomethyl ((CII3)2N = C~-)
ester, vinyl ester, propargyl estcr, p-nitrophenyl ester, 2,4-
dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl
ester, mesyl phenyl ester, phenylazophcnyl ester, phenyl thio-
ester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl
thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-
quinolyl thioester], or an ester with N,N-dimethylhydroxylam-:ne,
1-hydroxy-2-(lH)-pyridone, N-hydroxysuccinilllide, N-hydroxy-
phthalimide or l-hydroxy-~-chloro-lH-benzotriazole, and the like.
These reactive derivatives can be optionally selccted from them
according to the kind of the acylating agent to be used.
The acylating agent may further include aliphatic,
aromatic or heterocyclic isocyanate or isothiocyanate (e.g.,
methyl isocyanate, phcnyl ;socyanate, trichloroacetyl isocyanate,
methyl isothiocyanate, etc.) and haloformate (e.g., ethyl
chloroformate, benzyl chloroformate, etc.). In this case,
for example, whcn trichloroacetyl isocyanate is used as an
acylating agent, trichloroacetylcarbamoyl group is introduced
- 30 -
1 337522
as acyl group and said group may be converted to carbamoyl gTOUp
by treating with base, and when ethyl chloroformate is used as
an acylating agent, ethoxycarhonyl group is introduced as acyl
group.
The present reaction is carried out according to similar
reaction conditions to those of aforesaid reaction of the compound
(II) with thc compound (III), and is preferably carried out in
the presence of a base. In the reaction of the compound (V)
with an acylating agent, the protected carboxy group or salts
in the compound (V) may be converted into free carboxy group in
the course of the reaction or in post-treatment;
and when the compound (V) wherein R4 is carbamoyloxymethyl group
,, .. , ... ~ ~_ ,
having acyl group is used as the starting compound, there may be
obtained occasionally either the object compound (Ib) wherein R4
is carbamoyloxymethyl group having acyl group or free carbamoyloxy-
methyl group according to reaction conditions in the course of
the reaction or in post-treatment. These cases are also
included in the scope of the present invention.
Process 4:
The object compound (Ic) or a salt thereof can be
prepared by subjecting the compound (Va) or a salt thereof to
elimination rcaction of the protective group of the carboxy.
Suitable salt of the compound (Va) can be referred
to the ones exemplified for the compound (IV).
The present elimination reaction is carried out in
accordance with a conventional method such as hydrolysis
.. ..
or the like. The hydrolysis may include a method using
an acid or base and the like. These methods may be selected
depending on kind of the protcctive groups to be eliminated.
The hydrolysis using an acid is one of the most common
1 337522
and preferable methods for eliminating the protective groups
such as phenyl(lower)al~yl, substituted phenyl(lower)alkyl, lower
alkyl, substituted lower alkyl, or the likc. Suitable acid
may include inorganic or organic acid, for exa~ple, formic acid~
trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid,
hydrochloric acid, and the like. The present reaction m~y be
carried out in the presence o~ anisole. The acid suitablc
for the reaction can be selected according to the protec~ive
group to be eliminated and other factors.
The hydrolysis using an acid may be carried out in the presence
of a solvent, such as an organic solvent, water or a mixed
solvent thereof.
The reaction temperature is not critical and may be
suitably selected in accordance with the kind of thc protectivc
group and the elimination method, and the present reaction is
preferably carried out under a mild condition such as under
cooling, at ambient temperature or slightly warming.
The present invention includes, within its scope, the
cases that the protected carboxy group for R3 is transformed
into the free carboxy group; that the protected amino group is
transformed into the free amino group; that the protected imino
group is transformed into the free imino group; that the acyloxy
group is transformed into the hydroxy group; and/or that the
carbamoyloxymethyl group having acyl group is transormed into
the free carbamoyloxymethyl group; during the reaction or post-
treating in the present reaction.
Process 5:
, . . . . ~ .. . .
The object compound (Id) or a salt thereof can be
prepared by subjecting the compound (Vb) or a salt thereo to
elimination reaction of the protective group of the amino.
1 337522
Suitable salt of the compound (Vb) can be referred to
the ones exemplified for the compound (IV).
The present elimination reaction may include an
elimination method using a base, for example, an inorganic base
s such as an alkali metal hydroxide (e.g., sodium hydroxide,
potassium hydroxide, etc.), an alkali metal bicarbonate (e.g.,
sodium bicarbonate, potassium bicarbonate, etc.) or alkali mctal
carbonate (e.g., sodium carbonate, potassium carbonate, etc.),
an organic base such as an alkali metal alkoxide (e.g., sodium
methoxide, sodium ethoxide, etc.), a trialkylamine (e.g.,
trimethylamine, triethylamine, etc.), triethanolaminc, ~',N-
dimethylaniline, N,N-dimethylbenzylamine, N-methylmorpholine
or pyridine; and an elimination reaction using basic alumina,
basic ion exchange resin, acid (e.g., trifluoroacetic acid,
trifluoroacetic acid-anisole, etc.). The prescnt elimination
reaction is usually carried out in water, hydrophilic solvent
or a mixture thereof. The reaction temperature is not critical
and the reaction is preferably carried out at ambient temperature
or under cooling.
The present invention includes, within its scope, the
cases that the protected carboxy group or salts in the compound
(Vb) may be converted into free carboxy group, and that the
protected amino and/or imino group may be converted into the free
amino and/or imino group, respectively in the course of the
reaction or in post-treatment.
Process 6:
The object compound (Ie) or a salt thereof can be
prepared by reacting the compound (Vc) or a salt thereof with
the compound (Vd) or its reactive derivative at the mercapto
group.
- 33 -
1 337522
Suitablc salt o the compound (Vc) can be referred to
the ones exemplified for the compound (IV).
The suitable reactive derivativc at the mercapto group
of the compound (Vd) may include a metal salt ~such as alkaii
metal salts (e.g., sodium salt, potassium salt, etc.) or the like.
The present reaction may be carried out in a solven~
such as water, acetone, chloroform, nitrobcnzene, methylene
chloride, ethylene chloride, dimethylformamide, methanol,
ethanol, ether, tetrahydrofuran, dimethylsulfoxide, or any other
solvent which does not adversely affect the reaction, preferably
in ones having strong polarities. Among the solvents, hydro-
philic solvents may be used in a mixture ~ith water. The
reaction is preerably carried out in weekly basic or around
neutral condition. When the compound (Vc) and or the thiol
compound (Vd) is used in a free form, the reaction is preferably
conducted in the presence of a base, for example, inorganic
base such as alkali metal hydroxide, alkali metal carbonate,
alkali metal bicarbonate, organic base StlC]l as trialkylamine,
pyridine, and the like. The reaction temperaturc is not
critical, and the reaction is usually carried out at ambient
temperature or under warming. The reaction product can be
isolated from the reaction mixture by conventional methods.
The reaction of the compound (Vc) with the compound
(Vd) includes, within its scope, the cases that the protected
carboxy group or salts in the compound (Vc) may be converted
into free carboxy group; that the protected amino and/or imino
group may be converted into free amino and/or imino group;
and that the acyloxy group may be converted into hydroxy group;
respectively in the course of the reaction or in post-treatment.
- 34 -
1 337522
Process 7:
The object compound (If) or a salt thereof can be
prepared by treating the compound ~Ve) or a salt thereof with
an acid.
s Suitable salt of the compound (Ve) can be refcrred to
the ones exemplified for the compound (IV).
Suitable acid to bc used in the present reaction may
include an inorganic acid (e.g., hydrochloric acid, hydrobromic
....
acid, sulfuric acid, ctc.) or an organic acid (e.g., or~.ic
acid, acetic acid, etc.).
The prescnt reaction is usually carried out in a
sol~ent such as water, acetonc, acetic acid or any other solvent
which does not advcrsely influence the reaction. Among these
solvents hydrophi]ic solvcnts can be used as a mixture with water.
The reaction tem~erature is not critical and the
reactioJI is preferably carried out under cooling to warming.
Process ~:
The object compound (Ig) or a salt thereof can be
prepared by oxidizing the compound (Ve) or a salt thereof.
Suitable oxidizing agent used in the present reaction
may include Jones reagent being used by a combination of sulfuric
acid and chromium trioxide, manganese dioxide, a reagent being
used by a combination of dimethylsulfoxide and N,N'-dicyclohexyl-
carbodiimide etc., and the like.
The present reaction is usually carried out in a solvent
such as water, acetone, dimethylformamide or any other solvent
which does not adversely affect the reaction. These solvents
may be used as a mixture thereof.
The reaction temperature is not critical and the reaction
is preferably carried out under cooling or around ambient temperature
- 35 -
1 337522
Processes for ~reparing the starting compound (III)
i.e., syn-isomer and anti-isomer thereof used for References
are explained in details as follows.
(A) Process of (VI)+(VII) -~ ~VIII) [Scheme (l)(i)~
The compound (VIII) can be prepared by reacting the
compound (VI) with the compound (VII).
The present reaction is usually carried GUt in a
solvent such as water, eth.~llol, acetone, ether, dimethylformamide
or any other solvent which does not adversely influence the
present reaction. The reaction is preferably carried ou~ in
the presence of a base such as an inorganic base or an organic
base as aforementioned. The reaction tenlperature is not
critical and the reaction is usually carried out under cooling
to under heating of boiling point of the solvent.
(B) Processes of (IX) ~ (X) [Scheme (l)(ii)] and
(XXXII) ~XXXIII) [Scheme (6)(ii)]
The compounds (X) and (XXXIII) can be prepared by
oxidizing the comp~unds (IX) and (XXXII), respectively.
The present oxidation reaction is conducted by a
conventional method which is applied for the transformation of
so-called activated methylene group into carbonyl group. That
is, the present oxidation is conducted by a conventional n~ethod
such as oxidation by using a conventional oxidizing agent such
as selenium dioxide, potassium permanganate or tile like. The
present oxidation is usually carried out in a solvent which
does not adversely influence the reaction, for example, water,
dioxane, pyridine, tetrahydrofuran, and the like.
The reaction temperature is not critical and the
reaction is preferably carried out under warming to heating.
(C) Process of (XI)~(XII) [Scheme (1) tii.i)~
- 36 -
1 337522
The compound (XII) can be prepared by subjecting the
compound (XI) to elimination reaction of the ar(lower)alkyl
group.
The prescnt elimination method may include all
conventional methods used in the elil~ination reaction of the
ar(lower)alkyl group, for exampie, hydrolysis, reduction, etc.
The hydrolysis using acid is one of the most pre-
ferable method and the acid to be used may include an
inorganic acid (e.g., hydrochloric acid, hydrobromic acid~
etc.), an organic acid (e.g., formic acid, acetic acid,
trifluoroacetic acid, etc.) and a mixture thereof. The pre-
sent reaction can be carried out in a solvent such as water,
an organic solvent or a mixture thereof or without solvent.
The reaction temperature is not critical and the reaction is
preferably carried out undcr warming to heating.
(D) Processes of (XIII)+(~.IV) ~ (IIIa) [Scheme (1) (iv)],
(XXXIII)~(XIV) ~ (XXXV) [Scheme (6) (ii)~ and
~XXXIV)+(XIV) + (IIIf) [Scheme (6) (ii)]
The compounds (IIIa), (XXXV) and (IIIf) can be pre-
pared by reacting the compounds (XIII), (XXXIII) and (XXXIV)
with the compound (XIV) or a salt thereof, respectively.
Suitable salt of the compound (XIV) may include an
inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate,
etc.), an organic acid salt (e.g., acetate, p-toluenesulfonate,
etc.) and the like.
The present reaction is usually carried out in a
solvent such as water, an alcohol (e.g., methanol, ethanol,
etc.), a mixture thcreof or any other solvent which does not
adversely influence the present reaction.
The present reaction, in case that the compound
1 337522
(XIV) is used in its salt form, is preferably carried ou~
in the presence of a base, for example, an inorganic base
such as alkali metal (e.g., sodium, potassium, etc.),
alkaline earth metal (e.g., magnesium, calciùm, etc.), tile
hydroxide or carbonate or bicarbonat~ thereof or the like,
and an organic base such as alkali metal alkoxide (e.g.,
sodium methoxide, sodium ethoxide, etc.), trialkylamine
(e.g., trimethylamine, triethylamine, etc.), N,N-dialkylami3le
(e.g., N,N-dimethylaniline, etc.), N,N-dialkylbenzylamine
(e.g., N,N-dimethylbenzylamine, etc.), pyridine or the li~e.
The reaction tempcrature is not critical and the
reaction is usually carried out under cooling to heating.
In the present reaction, the mixture of syn- and
anti-isomers of the compound (IIIa), (XXXV) or (IIIf) may be
obtained according to reaction conditions etc., and in such
case, both isomers may be resolved by conventional manners
from the mixture. For example, the mixture is firstly
esterified and the resulting esters are resolv~d, for example,
by chromatography into each isomer. The resolved each
isomer of esters is hydrolyzed by a conventional method to
give the corresponding syn- or anti-carboxylic acid.
In order to obtain syn-isomer of the compound (IIIa),
(XXXV) or ~IIIf) selectively and in high yield the present
reaction is preferably carried out around neutral condition.
(E) Processes of (XV) ~(XVI) [Scheme (2) (i)] and
(XXXIV) + ~XXXVI) [Schme (6) (ii)]
The compounds (XVI) and (XXXVI) can be prepared by
reacting the compounds (XV) and (XXXIV) with hydroxylamine
or a salt thereof, respectively.
Suitable salt of hydroxylamine can be referred to
- 38 -
1 337522
the ones exemplified for the compound (XIV).
The reaction conditions of the present reaction
can also be referred to the ones exemplified for t.he pro-
cesses of tXIII)+(XIV) ~(IIIa), (XXXIII)+(XIV) ~ (XXXV) and
(XXXIV)+(XIV~ ~(IIIf) as mentioned in aforement oned (D).
(F) Processes of (XVII) ~ (XVIII~ [Scheme (2) (ii)~,
(XXIV) ~(XXV) [Scheme (4) (ii)]
(XXVI) +(XXVII) [Scheme (5)] and
(XXXVII) ~ (XXXVIII) LScheme (6) (iii)]
The compounds (XVIII), (XXV), (XXVII) and (XXXV~
can be prepared by alkylating the compounds (XVII), (XXIV~,
(XXVI) and (XXXVII), respectively.
The alkylating agent to be used in the prcsent
alkylation reaction may include di(lower)alkyl sulfate (e.g.,
dimethyl sulfate, diethyl sulfate, etc.), diazo(lower)alkane
(e.g., diazomethane, diazoethane, etc.), lower alkyl halide
(e.g., methyl iodide, ethyl iodide, etc.), lower alkyl sul-
fonate (e.g., methyl p-toluenesulfonate, etc.),~ and the like.
The reaction using di(lower)alkyl sulfate, lower
alkyl halide or lower alkyl sulfonate is usually carried out
in a solvent such as water, acetone, ethanol, ether,
dimethylformamide or any other solvent which does not adversely
influence the reaction.
The present reaction is preferably carried out in
the presence of a base such as an inorganic base or an organic
base as aforementioned.
The reaction temperature is not critical and the
reaction is usually carried out under cooling to heating around
boiling point of the solvent.
The rcaction using diazoalkane is usually carried
- 3~ -
1 337522
out in a solvent such as ether, tetrahydrofuran or the like.
The reaction temperature is not critical and tne
-~ reaction is usually carried out under cooling or at ambient
temperature.
(G) Processes of (XVIII) ~ (IIIb) [Scheme (2) (ii)l and
(XXXVIII) ~ (IIIg) [Scheme (6) (iii)]
The compounds (IIIb) and (IIIg) can be prepared by
subjecting the compounds (XVIII) and (XXXVIII) to hydrolysis,
respectively.
The hydrolysis is preferably carried out in the
presence of a base or an acid. Suitable base may include an
inorganic base and an organic base such as an alkali metal
(e.g., sodium, potassium, etc.?, an alkaline earth metal
(e.g., magnesium, calcium, etc.), the hydroxide or carbonate
or bicarbonate thereof, trialkylamine (e.g., trimethylamine,
- triethylamine, etc.), picoline, 1,5-diazabicyclo[4,3,01non-
5-ene, 1,4-diazabicyclo-[2,2,2]octane, 1,5-diazabicyclo[5,4,0]-
undecene-5, or the like.
Suitable acid may include an organic acid (e.g.,
formic acid, acetic acid, ~ropionic acid, trifluoroacetic
acid, etc.) and an inorganic acid (e.g., hydrochloric acid,
hydrobromic acid, sulfuric acid, etc.).
The reaction is usually carried out in a solvent
such as water, an alcohol (e.g., methanol, ethanol, etc.), a
mixture thereof or any other solvent which does not adversely
influence the reaction. A liquid base or acid can also be
used as the solvent.
The reaction temperature is not critical and the
reaction is usually carried out under cooling to warming.
- 40 -
1 337522
(H) Process of (XIX) + (IIIC) ~Scheme (3)]
The compound (IIIC) can be prepared by subjecting
the compound (XIX) to acylation.
The acylating agent to be used for the present
reaction and the reaction conditions of the present reaction
can be referred to the ones exemplified for Process 3.
(I) Process of (XX) ~ (XXI) [Scheme (4) (i)~
The compound (XXI) can be prepared by subjecting
the compound (XX) to nitrosation.
The nitrosating agent to be used for the present
reaction may include conventional agent which give C-nitroso
compound by reacting with activated methylene group, such as
nitrous acid, alkali metal nitrite (e.g., sodium nitrite,
etc.), lower alkyl nitrite (e.g., isopentyl nitrite, t-
butyl nitrite, etc.) or the like.
In case that salt of nitrous acid is used as
nitrosating agent, the present reaction is usually carried
, out in the pr_sence of an acid such as an inorganic acid or
an organic acid (e.g., hydrochloric acid, acetic acid, etc.)
In case that ester of nitrous acid is used, the present
reaction is preferably carried out in the presencc of a
strong base such as alkali metal alkoxide or the like.
The present reaction is usually carried out in a
solvent such as water, acetic acid, benzene, alcohol te.g.,
ethanol, methanol, etc.) or any other solvent which does not
adversely influence the reaction.
The reaction temperature is not critical and the
reaction is usually carried out under cooling or at ambient
-~ temperature.
- 41 -
1 337522
(J) Processes of (XXI)+(XXII) ~(XXIII) [Scheme (4) (i)]
and (XXVIII)+(XXII) ~(XXIX) [Scheme ~5)~
The compounds (XXIII~ and (XXIX) can be prepared by
reacting the compounds (XXI) and ~XXVIII) with the compound
(XXII), respectively.
The present reaction is usually carried out in a
solvent such as water, an alcohol (e.g., methanoi, ethanol,
etc.), benzene, dimethylacetamide, dimethyl~ormamidc,
tetrahydrofuran, a mixture thereof or an~ other solvent which
does not adversely influence the reaction.
The reaction temperature is not critical and the
reaction is usually carried out from ambient temperature to
under heating around the boiling pOillt of the solven~.
In ordcr to obtain syn-isomer of thc compound (XXIII)
or (XXIX) selectively and in high yield, it is necessary to
use syn-isomer of the starting compound (XXI) or (XXVIII) and
the present reaction is preferably carried out aroun~ neutral
condition in the presence of a base as aforement~oned.
Preferable example of base may be week base such as alka~
metal acetate (e.g., sodium acetate, potassium acetate, etc.),
alkali metal bicarbonate (e.g., sodium bicarbonate, potassium
bicarbonate, etc.), alkali metal carbonate (e.g., sodium
carbonate, potassium carbonate, etc.) or the like.
(K~ Processes of (XXIII) ~ (XXIIIa) [Scheme (4) (i)],
2S (XXV? ~ (IIId) [Scheme (4) (ii)], (XXIX) ~ (IIIe)
[Scheme (5)], (XXXIII) ~(XXXIV) [Scheme (6) (ii)~
and (XXXV) ~(IIIf) [Scheme (6) (ii)]
The compounds (XXIIIa), (IIId), (IIIe), (XXXIV) and
(IIIf) can be prepared by subjecting the compounds (XXIII),
(XXV), (XXIX), (XXXIII) and (XXXV) to elimination reaction of
- 42 -
1 337522
the protective group of the carboxy, respectively.
; In the present elimination reaction, conventional
methods used in the elimination reaction of the protected
carboxy, for example, hydrolysis etc. can be `applicable.
When the protective group is an ester, it can be eliminaLed
by hydrolysis.
The present hydrolysis is carried out according to
similar manners to those of processes (XVIII) ~(IIIb) and
(XXXVIII) ~ (IIIg) as mentioned in aforesaid (G).
(L) Process of (XXVII) ~(XXVIII) [Schcme (5)]
The compound (XXVIII) can be prepared by halogenating
the compound (XXVII).
The halogenating agent to be used in the prescnt
reaction may include a conventional halogellating agent used
in halogenation of so-called activated methylene group such
as halogen (e.g., bromine, chlorine, etc.),sulfuryl halide
(e.g., sulfuryl chloride, etc.), hypohalitc (e.g., hypochlorous
acid, hypobromous acid, sodium hypochlorite, etc.), N-
halogenated-imide (e.~., N-bromosuccinimide, N-bromophthalimide,
N-chlorosuccinimide, etc.) and the like.
The present reaction is usually carried out in a
solvent such as an organic acid (e.g., formic acid, acetic
acid, propionic acid, etc.), carbon tetrachloride or any
other solvent which does not adversely in~lucnce the reaction.
The reaction temperature is not critical and the
reaction is usually carried out under cooling~at ambiellt tem-
perature, under warming or heating.
(M) Processes of (XXX) ~ (XXXI) [Scheme t6) (i)~ and
(XXXIX)~ (IIIh) [Scheme (7)]
The compound (XX-XI) can be prepared by reacting the
- 43
1 337522
compound (XXX) or its reactive derivative at the amino group
or a salt thereof with an amino-protecting agent and the
compound (IIIh) can be prepared by reacting the compound
(XXXIX) or its reactive derivative at the amin`o group or a
salt thereof with an amino-protecting agent.
Suitable reacti~e derivative at the amino group of the compound
(XXX) or ~XXXIX) and suitable salt of the compound (XXX) or
(XXXIX) may include the same ones as illustrated in the
explanations of the reactive dcrivative at the amino group o~
the compound (II) and salt of the compound (II), respecti~ely.
Suitable amino-protecting agent may include acylating
agent which may include an aliphatic, aromatic and heterocyelic
carboxylic acid, and the corresponding sul~onic acid, haloformic
acid ester, isocyanic acid ester and carbamic acid, and the
corresponding thio acid thereof, and the reactive derivative
of the above acids.
Suitable reactive derivative of the above acids may
include the same ones as illustrated in the cxplanation of
Process 3 The example of the protective group (e.g. acyl
group) to be introduced into the amino group in the compound
(XXX) or (XXXIX) by the above amino-protecting agent (e.g.
acylating agent) may be the same protecting group (e.g., acyl
group) as illustrated in the explanation of the protective
group moiety (e.g., acyl moiety) in the term "acylamino".
The present amino-protecting reaction is carried
out in a similar manner as illustrated in thc reaction of the
compound (II) with the compound (III) (Process 1).
; (N) Process of (XXIIIb) ~ (XXXIII) [Scheme (6) (ii)l
The compound (XXXIII) can be prepared by subjecting
the compound (XXIIIb) to hydrolysis.
- 44 -
1 337522
The present hydrolysis is carried out in the presence
of alkali metal bisulfite (e.g., sodium bisulfite, etc.)
titanium trichloride, inorganic or organic acid such as
hydrohalogenic acid (e.g., hydrochloric acid, hydrobromic acid,
etc.), formic acid, nitrous acid or the like. Hydrohalogenic
acid is preferably used in a combination of aldehyde (e.g.,
formaldehyde, etc.).
The present reaction is usually carried out in a
solvent such as water, aqueous alcohol (e.g., aqueous methanol,
aqueous ethanol, etc.), water-acetic acid or any other solvent
which does not adversely influence the reaction.
The reaction temperature is not critical and the
reaction is usually carried out at ambient temperature, under
warming or heating.
In the present reaction, protected carboxy group may
be occasionally transformed into free carboxy group. l`his
case is also included in the scope of the present invention.
In the aforementioned reactions and/or the post-
treating of the reactions of the present inventio~i, the afore-
mentioned tautomeric isomers may be occasionally transformed
into the other tautomeric isomers and such case is also included
in the scope of the present invention.
In case that the object compound (I) is obtained in
a form of the free acid at 4 position and/or in case that the
object compound (I) has free amino group, it may be transformed
into its pharmaceutically acceptable salt as aforementioned by
a conventional method.
The object compound (I) and pharmaceutically acceptable
salt thereof of the present invention are all novel compounds
which exhibit high antibacterial activity, inhibiting the growth
- 45 -
1 337522
of a wide variety of pathogenic microorganisms including
Gram-positive and Gram-negative bacteria and are useful as
antibacterial agents. Particularly, it is to be noted that
the object compound (I), i.e., syn^isomer has much higher
S antibacterial activities than the corresponding anti-iso.ner
to the compound (I), and accordingly the object compound (I),
i.e., syn-isomer is characterized by having much superiority
to the corresponding anti-isomer ln the therapeutic vaiue.
Now, in order to show the utility of the object
compound (I), with regard to some representative compounds
of this invention, there are shown thc test data on the
in vitro anti-bacterial activity, the test data on in vivo,
i.e. the protecting effect against experimental in~ections
and the acute toxicity in the following. Additionally,
there are also shown the comparative test ~ata on in vitro
antibacterial activities relating to the corresponding anti-
isomer to the object compound (I) for the reference's sake
in the following.
Test compounds
tl) 7-[2-Methoxyimino-2-~3 hydroxyphenyl)acetamido]-3-
carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)
(2) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3~
methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer)
(3) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-
methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
acid (anti isomer)
(4) 7-~2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]^3-(1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer)
- 46 -
1 337522
(5) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-(i,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic aci~ ~syn
isomer)
(6) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetarllido~-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer)
(7) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (anti isomer)
(8) 7-[2-Methoxyinlino-2-(2-amino-1,3-thiazol-4-yl)ace~atnido]-
cephalosporanic acid (syn isomer)
(9) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
cephalosporanic acid (anti isomer)
(10) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acet-
amido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer)
(11) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acet-
amido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carbo-
xylic acid (anti isomer)
(12) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acet-
amido)cephalosporanic acid (syn isomer)
(13) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)
(14) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamidol-
3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer)
(15) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer)
(16) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
3-(S-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
~ 47 -
1 337522
carboxylic acid (syn isomer)
(17) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido~-
3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer)
(18) 7-~2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-
thiazol-4-yl}acetamido]-3-carbamoyloxymethyl-3-cephem-4-
carboxylic acid (syn isomer)
1. In vitro antibacterial activity:
Test Method
10 In vitro antibacterial activity was determined by
the two-fold agar-plate dilution method as described beloli.
One loopful o an overnight culture of each test
strain in Trypticase-soy broth (108 viable cells per ml.)
was streaked on heart infusion agar (HI-agar) containing
graded concentrations of antibiotics, and the minimal inhi-
bitory concentration (MIC) was expressed in terms of ~g/ml.
after incubation at 37C for 20 hours.
- 48 -
szs
SZO-O 6-0 6-0 01'0 01-0 SZ0 0 8L-0 1- 6-0 8L-0 50-0 1- 01-0 9S'1 8L'0SZ 8L'0 8L'05ll~q~ sna1Old
50-0 OZ-O 01-0 SO-O OZ-O SO~O 9S 1 1- 9S ~ 9S 1 01-0 SZ-9 01-0 8L-0 8L-0 SZ-9 6 0 6-0 ~L~ Ud ~ sqLII~
r 1- OZ-0 6-0 8L'0 01'0 9S-1 9S 1 S'ZI 8L-0 1- 01 0 S-ZI OZ-0 S ZI 1- OS 9S-1 9S I z-~r rHIN
(81) ~LI) (91) (Sl) (bl) (1) (Zl) (Il) (01) (6) (8) (L) (9) (S) (~) () (Z) (I)
spunodulo~ ~saL ~lla~ s~L
I hT ~_
S~,lnsa~ ~s~L
1 337522
As clearly seen from the above test results, the
object compounds (I) of the present invention, i.e., syn-
isomers have much higher antibacterial activity as compared
with the corresponding anti-isomers thereof.
2. Protecting effect against experimental infections in
mice:
Test Method
Male ICR strain mice aged 4 weeks, each weighing
20-23 g were used in groups of 8 mice. The test bacteria
were cultured overnight at 37C on IlI-agar and then suspended
in 2.5 - 5~ mucin solution to obtain the suspension correspond-
ing to each challenge cells. Mice were inoculated intra-
peritoneally with O.S ml of the suspension. A solution
containing each test compounds was given subcutaneously to the
mice in various dosage one hour after challenge. The ED50
values were calculated from the number of surviving mice for
each dosage after one week of observation.
r
. ~, ............
~ -- S O
851-1 Z0'0 5 Zl Z'0 81 ~olx5 ~ Fl~ eFIlaFI3[Ps8
au~rx. 3U~IX
om~3~ (9) -oln~a~ (9) Iul/slla~
spunod~o~ ~saL splmodLL~o~ ~,sa~L alq~
((3snoUI/)~ s (~I/~rt) U~ ,S p3sn ~0 ~ uall~ la~ ,saL
(I~IIIOSI U~tS) pl:)8
xoql~-b-ula~d3~--l~(~3uL~xol~oureql~--[opn~ ~n~-z)-z-ou~x0~3l~-z~-L aullxom~ *
OS SZ'9 SZ0 0> 901 olxo l su3s3~ F~ 3S
6Z-b 810 - 0 9SI 0> 9
00~ OOZ SZ 8
awlxoln~3~ tZI) (1)~-oln~ (Zl) (~l) ~/511~
sp~.o~o~ ~s~L spunodl~lo~ ~,s3~L alq~u~ asnoul/sll3~ ~FI~~ ~s3L
(3snou~ S ) Sa~ ) U~ S pasn ~o ~I~I a~uall~u,~
pl~ ~lu~Iodsol~u~a~op~ 3~ u3l~lL-z)-L :L~
ZOb'l lll O 180'0 SOO O> SOO O> 1- 8L 0 6-0 0-0> 0-0> gOl 6Z
S ZI8~- 0 8L 0 0 0> Z 801 901X9 Fl~ Fla~
T.~) tb) (S) (bl) t8) ~ ) (S) (bl) (8) lu~/sllao
spuno~uo~ ~s3,I, Sp~lOC~I'O~ ~sal, ala,~u~~snau/slla~ ~lla~,o~ ~saL
( asnoul / ~ ) ( ~ S) OSa~ rl) u~ 5 p3sn 30 ~ a~uall~u,~
a~l~ ul su0l~,03~uI le~uau~ dx~ ~ su~ 03~ vUI~,03~01d
5~1nS3~ ~53~1
3~ xoq~ b-ul3~ld3:~- ~
-OT~ -Z-lz~TP~T~-t~ 1-1~ 3u~-s)-- [0PTU1~3~ 1-10Z~ HI)-Z]-L ~T-PS :~N Z~
~n 8L 0Z O I O >901 01 x 5 5 6Z IIO~ e~ i3q~sa
Z81- 0 6L0 0 98- 0 S
1- 6-0 gL-0801
~N Z~:~ (I) (Z) ~,~N Z~) (I) (Z)
Tlll/ S ¦ 1 3~3 snolll/ sl T ~. ~
Sp~O~ 0~ ~,s~L sp~od~~ ~,S~L 3~ A 3~U~IleT'D ~Tl3~ sa~L
(3snou~ ) s)''a~ S p3Sn ~O ~
1 337522
- 3. Acute Toxicity in Mice:
The same strain mice as aforesaid protecting test against
experimental infections were used in groups of 10 mice.
Test compound ~) (2 g) was administered intràvenously to
said mice. All mice survived ~ithou. showing any disorder
after one week observation.
~or therapeutic administration, the objec~ compound (I)
of the present invention is uscd in the form of conver.tional
pharmaceutical preparation t~hich contains said compound, ~s
an active ingredient, in admixturc Wit}l a ph.-rmaccuticall~
acceptable carriers such as an organic or inorganic soli~l or
liquid excipient which is suitable for oral, parenteral or
external administration. The pharmaceutical preparations may
be in solid form SUC}I as capsule, tablet, dragee, ointmcnt or
suppository, or in liquid form such as solution, suspension,
or emulsion. If needed, there may be included in the above
preparations auxiliary substances, stabilizing agents, wetting
or emulsifying agents, buffers and the other cominonly used
additives.
While the dosage of the compounds may vary from and also
depend upon the age, conditions of the paticnt, a kind of disease,
a kind of the compound (I) to be applied, etc., an average single
dose of about 50 mg., 100 mg., 250 mg., and 500 mg. of the object
compound (I) of the present invention has proved to be e fective
in treating diseases infected by pathogenic bacteria.
In general, amounts between 1 mg. and about 1000 mg.
or even more niay be administered to a patient.
The follo~lng examples are givcn for the purpose of
illustrating the present invention:-
- 53 - ,.
, ~
1 337522
ExamPle 1
A mixture of dimethylformamide (2.81 g.) and
phosphorus oxychloride (5.36 g.) was warmed at 40C for
1 hour. After cooling, methylene chloride (60 ml.) was
added thereto and distilled off. To the residue was
added dry ethyl acetate (50 ml.). Then, 2-
methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn
isomer) (6.83 g.) was added thereto at 5C with
stirring under ice-cooling. The resultant mixture was
then stirred for 50 minutes at the same temperature.
On the other hand, 7-amino-3-(1-methyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (11.5 g.) and
bis(trimethylsilyl)acetamide (28.4 g.) were dissolved
in dry ethyl acetate (150 ml.) and stirred under
cooling, to which was at a time added the above
obtained solution at -40C. After stirring for 2 hours
at -30 to -20C, a saturated sodium chloride aqueous
solution (100 ml.) was added at -20C to the reaction
mixture. The mixture was stirred for 5 minutes. The
precipitates were filtered off and ethyl acetate layer
in the filtrate was separated. The aqueous layer was
extracted twice with ethyl acetate (50 ml.). Ethyl
acetate layer separated from the filtrate and the
extracts were combined. The combined ethyl acetate
solution was washed with a saturated sodium chloride
aqueous solution (50 ml.). To the ethyl acetate layer
was added activated charcoal and the mixture was
stirred for 5 minutes and filtered. Water (100 ml.)
was added to the filtrate and the resulting mixture was
adjusted to pH 7 with an aqueous solution of sodium
bicarbonate. The aqueous layer was separated, and
washed with methylene chloride. After the aqueous
layer was separated, methylene chloride was removed
from the aqueous layer by bubbling of nitrogen gas
under ice-cooling. After filtration, the aqueous layer
was adjusted
' ~;;r
~ - 54 -
1 337522
to pH 2 with 10% hydrochloric acid with stirring and ice-cooling.
Precipitating crystals were collected by filtration, washel
-~ with water and dried to give 7-[2-methoxyimino-2-(3-hydroxy-
phenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-y~l)thiomethyl-3-
S cephem-4-carboxylic acid (syn isomer) (11.3 g.).
I.R. spectrum (Nujol)
3250, 1770, 1725, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.76 (lH, d, J=8Hz)
6.7-7.40 (4H, m)
5.86 (lH, dd, J=5,8Hz)
5.18 (lH, d, J=5Hz)
4.34 (2~1, ABq, J=13Hz)
- 3.92 (6H, s)
3.72 (2H, ABq, J=17Hz)
Example 2
A mixture of dimethylformamide (1.41 g.) and phosphorus
oxychloride (2.95 g.) was warmed for 1 hour at 40C. After
cooling, methylene chloride (30 ml.) was added thereto and
distilled off. To the residue was added dry ethyl acetate
~20 ml.). 2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid
(syn isomer) (3.4 g.) was added thereto with stirring and ice-
cooling and the mixture was stirred for 30 minutes under ice-
cooling. On the other hand, 7-amino-3-carbamoyloxymethyl-3-
cephem-4-carboxylic acid ~4.8 g.) was dissolved in a solution
of trimethylsilylacetamide (27.5 g.) in dry ethyl acetate (70
ml.). To the solution was at a time added the above obtained
solution at -30C and the mixture was stirred for 1.5 hours at
-30 to -10C. A saturated sodium chloride aqueous solution
was added to the reaction mixture at -20C. The ethyl acetate
~ a~k
~ - 2
-55-
~ 337522
layer was separated and the aqueous layer was extracted with
ethyl acetate. Two ethyl acetate layers were combinea, ~ashed
with a sodium chloride aqueous solution and treated with activated
charcoal. After filtration, water (100 ml.) was added to the
S filtrate and the mixture was adjusted to pH 7 with a sodium
bicarbonate aqueous solution. The aqueous layer was separated
and ethyl acetate was added thereto. The mix~ure was adjusted
to pH 5 with 10% hydrochloric acid and the aqueous layer was
separated. Ethyl acetate was added thereto and the mixture
was adjusted to pH 2 with 10% hydrochloric acid. The e~nyl
acetate layer was separated and the aqueous layer was further
extracted with ethyl acetate. Two ethyl acetate layers
were combined, washed with a sodium chloride aqueous solution
and dried over magnesium sulfate. The solvent was distilled
off and the residue was pulverized with diisopropyl ether.
The powder was collected by filtration and dried to give 7-~2-
methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyl-oxyme~hyl-
3-cephem-4-carboxylic acid (syn isomer) (3.26 g.).
I.R. spectrum (Nujol)
3500-3200, 1765, 1720, 1655 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.64 (lH, d, J=8Hz)
6.70-7.20 (4H, m)
6.78 (2H, s)
5.92 (lH, dd, J=5,8Hz)
5.16 (lH, d, J=5H~
4.73 (2H, ABq, J=13Hz)
3.91 (3~l, s)
s- y ~ 3.72 (2H, ABqJ J=17Hz) ~r
~ - 3
-56-
1 337522
7-[2-Methoxyimino-2-(3-hydroxyphenyl~acetamido~-3-
carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.98
g.) was suspended in water (15 ml.) and dissolved by adding
sodium bicarbonate (0.35 g.) with stirring at ambient temperature.
The solution was lyophilized and dried to give sodium 7-[2-methoxy-
imino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-
4-carboxylate (syn isomer) (1.9 g.).
I.R. spectrum (Nujol)
3300, 1765, 1715, 1665 cm~
N.M.R. spectrum (D2O, ~)
ppm 6.83-7.60 (4H, m)
5.85 tlH, d, J=SHz)
5.17 (lH, d, J=SHz)
4.77 (2H, ABq, J=13Hz)
lS 4.03 (3H, s)
3.48 (2H, ABq, J=18Hz)
Example 3
A mixture of dry dimethylformamide (0.18 g.) and
phosphorus oxychloride (0.38 g.) was stirred for 30 minutes at
40C. Dry methylene chloride (15 ml.) was added thereto and
distilled off under reduced pressure. To the residue was
added dry ethyl acetate (lS ml.) and 2-methoxyimino-2-(3-chloro-
4-hydroxyphenyl)acetic acid (syn isomer) (0.53 g.) was added
thereto with stirring at -20C. The mixture was stirred fGr
1 hour below -10C. On the other hand, a mixture of 7-amino-
3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid
(1 g.), trimethylsilylacetamide (S g.) and dry ethyl acetate
(25 ml.) was stirred for 1 hour at ambient temperature.
To this solution was dropwise added the above obtained solution
with stirring below -10 and the resulting mixture was stirred
~ -4
-57-
~ 337522
. .
for 2 hours at the same temperature. Water (50 ml.) and
ethyl acetate (50 ml.) were added to the reaction mixture at
-20C and the mixture was shaken. The organic layer contzining
7-[2-methoxyimino-2-(3-chloro-4-hydroxyphenyl~)acetamido~-3-tri-
chloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic ac~d (syn
isomer) was adjusted to pH 7.0 by adding water (S0 ml.) and
sodium bicarbonate and the mixture was stirred for 2 hours at
ambient temperature. Ethyl acetate (S0 ml.) was added to
the aqueous layer and the mixture was adjusted to pH S.0 with
10% hydrochloric acid. The aqueous layer was separated,
adjusted to pH 2.0 with 10~ hydrochloric acid and extracted with
ethyl acetate (S0 ml.). The extract was washed with ice-
water and dried over magnesium sulfate. The solvent was
distilled off under reduced pressure. The residue was
lS thoroughly washed with ether, collected by filtration and dried
to give 7-[2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-
3-carbamoyloxymethyl-3-cephem-4-carboxylic acid tsyn isomcr)
(0.3 g.)-
I.R. spectrum (Nujol)
3450, 3300, 1770, 1730, 1715, 1660, 1650, 1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.72 (lH, d, J=8Hz)
7.48 (lH, d, J=2Hz)
7.40 (lH, dd, J=2,8Hz)
6.98 (lH, d, J=8Hz)
6.60 (2H, s)
5.70 (lH, q, J=SHz)
5.20 (lH, d, J=SHz)
4.74 (2H, ABq, J=13Hz)
3.90 (3H, s)
3.50 (2H, ABq~ J=18Hz)
-58- ~ ~ 5
~ 337522
Example 4
2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn
isomer) (1.1 g.) and 7-amino-3-trichloroacetylcarbamoyloxymethyl-
3-cephem-4-carboxylic acid (2.35 g.) were reacted and post-treated
according to a similar manner to that of Example 3 to give 7-[2-
methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-
3-cephem-4-carboxylic acid (syn isomer) (0.5 g.). This
compound is identified with the compound obtained in Example 2
by I.R. and N.M.R. spectra.
Example 5
(a) 2-t-Butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxy-
phenyl)acetic acid (syn isomer)(lg.) and 7-amino-3-(1-~ethyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1 g.) were
reacted according to similar manners to those of Examples 1 and
2 to gi~e powder of 7-[2-t-butoxycarbonylmethoxyimino-2-(3-chloro-
4-hydroxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thio-
methyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g.).
(b) The powder obtained in Example 5(a) (1.5 g.) was added
to a mixture of anisole (1.5 ml.) and trifluoroacetic acid (6 ml.)
and the resulting mixture was stirred for 30 minutes at ambient
temperature. The reaction mixture was adjusted to pH 8 by
adding a sodium bicarbonate aqueous solution (50 ml.), ethyl
acetate (50 ml.) and sodium bicarbonate under ice-cooling. The
aqueous layer was separated, adjusted to pH 5.0 with 10% hydro-
chloric acid and washed with ethyl acetate (50 ml.). The
aqueous layer was further adjusted to pH 2.0 with 10% hydrochloric
acid and extracted with ethyl acetate (100 ml.). The extract
was washed with water and dried over magnesium sulfate. The
solvent was distilled off under reduced pressure and the residue
was dissolved in pH 5.0 acetate buffer and subjected to column
~ _ 6
-59-
1 337522
chromatography on Woelm neutral alumina (trade mark: made by
ICN Company) using pH 5.0 acetate buffer as developing solvent.
The eluate was adjusted to pH 2.0 with 10% hydrochloric acid
under ice-cooling. Precipitating materia~s were collected
by filtration, washed with water and dried to give 7-~2-carboxy-
methoxyimino-2-(3-chloro-4^hydroxyphenyl)acetamido]-3-(;-methyl-
lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer) (0.5 g.), mp 145 to 148C (dec.).
I.R. spectrum (Nujol)
3400, 3200-3300, 2500-2600, 1780, 1720,
1670, 1600 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
7.50 (lH, d, J=2Hz)
7.45 (lH, d~,J=2,8Hz)
7.10 (lH, d, J=8Hz)
5.90 (lH, q, J=5Hz)
S,22 (lH, d, J=5Hz)
4.70 (2H, s)
4.35 (2H, ABqJ J=13Hz)
3.95 (3H, s)
,~
-~ 3.75 (2H, ABq, J=18Hz)
Example 6
(a) 2-(1-t-Butoxycarbonylethoxyimino)-2-(3-chloro-4-
hydroxyphenyl)acetic acid (syn isomer) (2 g.) and 7-amino-3-
(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
acid (2 g.) were reacted according to similar manners to those
of Examples 1 and 2 to give powder of 7-[2-(1-t-butoxycarbonyl-
ethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-
lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer) (3.6 g.).
~ - 7
-60-
1 337522
(b) The powder obtained in Example 6(a) (3.6 g.), anisole
(4 ml.) and trifluoroacetic acid (16 ml.) were reacted according
to a similar manner to that of Example 5(b) to give yel,ow powder
of 7-[2-(1-carboxyethoxyimino)-2-(3-chloro-4-~ydroxyphenyl)acet-
S amido]-3~ methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer) (2.0 g.), mp 147 to 151C (dec.).
I.R. spectrum (Nujol)
3500, 3250, 2500-2600, 1780, 1730, 1660, 1630,
1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.62 (lH, d, J=8Hz)
7.46 (lH, d, J=2Hz)
7.34 (lH, dd, J~2,8Hz)
7.04 (lH, d, J=8Hz)
5.90 (lH, q, J=SHz)
5.22 (lH, d, J=SHz)
4.73 (lH, q, J=6Hz)
4.33 (2H, ABq, J=13Hz)
4.00 (3H, s)
3.73 (2H, ABq, J=18Hz)
1.37 (3H, d, J=6Hz)
Example 7
The following compounds were obtained according to
similar manners to those of Examples 1 and 2
(1) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-~-(4H-
1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn ~
isomer). ~`
I.R. spectrum (Nujol)
3250, 1775, 1710, 1665 cm~l `
~ - 8
-61-
1 337522
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.67 (lH, d, J=8Hz)
8.40 tlH, s~
6.70-7.43 (4H, m)
5.82 (lH, dd, J~5,8Hz)
5.13 (lH, d, J=5Hz)
4.18 (2H, ABqJ J=13Hz)
3 90 (3H, s)
3 67 (2H, broad s)
(2) 7-[2-Methoxyimino-2-~3-hydroxyphcnyl)acetamidol-3-
(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1720, 1670 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.78 (lH, d, J=8Hz)
9.55 (lH, s)
6.70-7.40 (4H, m)
5.89 (lH, dd, J=5,8Hz)
5.22 (lH, d, J=5Hz)
4.46 (2H, ABq, J=13Hz)
3.92 (3H, s)
3.76 (2H, ABq, J=18Hz)
(3) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(5-
methyl-1,3,4-tniadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1720, 1670 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.72(1H, d, J=8 Hz~
6.62-7.40(4H, m)
E - 9
-62-
1 337522
S.94 (lH, dd, J-5,8Hz)
5.18 (lH, d, J=SHz)
4.18 (2H, ABq, J=13Hz)
3.8g (3H, s)
S 3.70 (2H, ABq, J=17Hz)
2.65 (3H, s)
(4) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-
cephalosporanic acid (syn isomer).
I.R. spectrum (Nujol)
3250, 1785, 1740, 1720 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.78 (lH, d, J=8Hz)
6.86-7.36 (4H, m)
S.86 (lH, dd, J=5,8Hz)
lS 5.18 (lH, d, J=5Hz)
4.84 (2H, ABq, J=13Hz)
E - lO
-63-
~ 337522
3.98 (3H, s)
3.54 (2H, ABq~ J=17Hz)
2.00 (3H, s)
. ~-- ~
(5) 7-[2-Methoxyimino-2-t3-methoxyphenyl)acetamido~-3-(1-
methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1720, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.78 (lH, d, J=8Hz)
6.95-7.54 (4H, m)
5.94 (lH, dd, J=5,8Hz)
5.18 (lH, d, J=SHz)
4.12 (2H, ABq~ J=13Hz)
3.92 (6H, s)
3.76 (3H, s)
3.72 (2H, ABq, J=18Hz)
(6) 7-[2-Methoxyimino-2-(4-hydroxyphenyl)acetamido]-3-(1-
methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1720, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J~8Hz)
7.44 (2H, d, J=8Hz)
6.84 (2H, d, J=8Hz)
5.86 (lH, dd, J=5,8Hz)
5.18 (lH, d, J=5Hz)
4.34 (2H, ABq, J-13Hz)
3.93 (3H, s)
E- 11
-64-
1 337522
3.87 (3H, s)
3.74 (2H, ABq, J=18Hz)
(7) 7-[2-Methoxyimino-2-(3-chloro-4-hydroxyphenyi)acetami~o]-
3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxyiic
S acid tsyn isomer), mp 145 to 148C (dec).
I.R. spectrum (Nujol)
3500, 3250, 2500-2600, 1780, 1720,
1655, 1625, 1600 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 10.80 (lH, broad s)
9.68 (lH, d, J=2Hz)
7.46 tlH, d, J-2Hz)
7.32 tlH, q, J=2,8Hz)
7.00 tlH, d, J=8Hz)
lS 5.80 (lH, q, J=5Hz)
5.16 tlH, d, J=SHz)
4.28 (2H, ABq, J=13Hz)
3.92 (3H, s)
3.87 (3H, s)
~ .. ,~.. ~ .
3.72 (2H, ABq, J=18Hz)
t8) 7-[2-Methoxyimino-2-(3-chloro-4-methoxyphenyl)acet-
amido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp 143 to 145C (dec.).
I.R. spectrum (Nujol)
3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.76 (lH, d, J=8Hz)
7.56 (lH, d, J=2Hz)
7.48 (lH, dd, J~2,8Hz)
7.22 (lH, d, J=8Hz)
~-12
-65-
~ 337522
5.84 (lH, q, J-SHz)
5.18 (lH, d, J=5Hz)
4.27 (2H, ABq, J=13Hz)
3.90 (6H, s)
3.88 (3H, s)
3.70 (2H, ABq, J=18Hz)
t 9) 7-[2-Methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetamido~-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 149 to 152C (dec.).
I.R. spectrum (Nujol)
3400-3450, 3200, 2500-2600, 1780,
1720, 1660, 1620, 1600, 1535, 1350 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.72 (lH, d, J=8Hz)
7.97 (lH, d, J=2Hz)
7.72 (lH, dd, J=2,8Hz)
7.21 (lH, d, J-8Hz)
5.82 (lH, q, J=5Hz)
5.16 (lH, d, J=5Hz)
4.3 (2H, ABq~ J=13Hz)
3.92 (3H, s)
3.87 (3H, s)
3.72 (2H, ABq~ Jsl8Hz)
~O) 7-[2-Allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acet-
amido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylic ac;d (syn isomer), mp 163 to 165C (dec.).
I.R. spectrum (Nujol)
3200-3300, 2500-2600, 1780, 1720,
1670, 1600 cm~
-66-
1 337522
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
7.40 (lH, d, J=2Hz)
7.30 (lH, dd, J=2,8Hz)
6.95 (lH, d, J=8Hz)
5.80 (2H, m)
5.30 (2H, d, J=8Hz)
S.10 (lH, d, J=SHz)
4.60 (2H, d, J=SHz)
4.27 (2H, ABq, J=13Hz)
3.85 (3H, s)
3.65 (2H, ABq, J=18Hz)
(1~ 7-~2-Allyloxyimino-2-(3-hydroxyphenyl)acetamido]~3-
(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
lS acid (syn isomer), mp 149 to 152C (dec.).
I.R. spectrum (Nujol)
3250-3350, 2550-2600, 1780, 1730, 1670,
1650, 1600 cm~l
N.M.R. spectrum ~d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
7.2-6.8 (4H, m)
6.1-5.8 (2H, m)
5.35 (2H, d, J=8Hz)
5.17 (lH, d, J=SHz)
4.7 (2H, d, J=SHz)
4.17 (2H, ABq, J=13Hz)
3.93 (3H, s)
3.75 (2H, ABq, J-18Hz)
(1~ Sodium 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-
cephalosporanate (syn isomer).
E - 14
-67-
1 337522
I.R. spectrum (Nujol~
3250, 1765, 1730, 1665 cm 1
N.M.R. spectrum (D2O, ~)
ppm 6.83-7.13 (4H, m)
5.83 (lH, d, J=5Hz)
5.17 (lH, d, J=5Hz)
4.82 (2H, ABq, J=13Hz)
4.03 (3H, s)
3.50 (2H, ABq, J=17Hz)
2.1 (31~, s)
(13) 7-[2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(4-hydroxy-
phenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-
-4-carboxylic acid (syn isomer), powder.
I.R. spectrum (Nujol)
3150, 1780, 1720, 1670 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.60 (lH, d, J=8Hz)
6.72-7.52 (7H, m)
5.80 (lH, dd, J=4,8Hz)
5.15 (lH, d, J=4Hz)
5.00 (2H, s)
4.28 (2H, ABq, J=13Hz)
3.90 (3H, s)
3.65 (2H, ABq, J=18Hz)
(14) 7-[2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyl)acet-
amido~-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), powder.
I.R. spectrum (Nujol)
3200-3300, 1780, 1720, 1660 cm 1
~ - 15
-68-
1 337522
N.M.R. spectrum td6-DMSO, ~)
ppm 9.77 (lH, d, J=8Hz)
6.7-7.7 (7H, m)
5.83 (lH, dd, J=5,8Hz)
S 5.29 (2H, s)
5.15 (lH, d, J=SHz)
4.3 (2H, ABq, J=13Hz)
3.92 (3~, s)
3.72 (2H, ABq, J=18Hz)
(15) 7-[2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-
3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
-~````~~~ acid (syn isomer), colorless powder, mp 153 to 156C (dec.).
I.R. spectrum (Nujol)
3450, 3250, 2550-2600, 1780, 1725, 1665,
1630, 1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.71 (lH, d, J-8Hz)
7.50 (lH, d, J=2Hz)
7.36 (lH, dd, J=2,8Hz)
7.03 (lH, d, J=8Hz)
5.83 (lH, q, J=SHz)
5.17 (lH, d, J=SHz)
4.33 (2H, ABq, J=13Hz)
4.17 (2H, q, J=7Hz)
3.97 (3H, s)
-- - 3.73 (2H, ABq, J=18Hz)
1.25 (3H, t, J=7Hz)
(16) 7-~2-Allyloxyimino-2-(3-methoxyphenyl)acetamido]-3-(1-
methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), powder, mp 135 to 138C (dec.)
~ - 16
-69-
1 337522
I.R. spectrum (Nujol)
3300, 2600, 1785, 1730, 1670, 1645, 1600 c,n 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.82 (lH, d, J=8Hz)
S 7.0-7.45 (4H, m)
5.8-6.2 (2H, m)
5.36 (2H, t, J=lOHz)
5.21 (lH, d, J=SHz)
4.72 (2H, d, J=SHz)
4.36 (2H, ABq, J=13Hz)
3.95 (3H, s)
3.91 (3H, s)
3.87 (2H, ABq, J=18Hz)
(17) 7-[2-Ethoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-
methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), yellow powder, mp 145 to 148C (dec.).
I.R. spectrum (Nujol)
3450, 3250, 2500-2600, 1775,
1720, 1665, 1620, 1600 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
6.8-7.4 (4H, m)
S.90 (lH, q, JsSHZ)
5.20 (lH, d, J=SHz)
4.36 (2H, ABq, J=13Hz)
4.20 (2H, q, J=7Hz)
4.00 (3H, s)
3.76 (2H, ABq, J=18Hz)
1.33 (3H, t, J=7Hz)
E - 17
-70-
1 337522
(18) 7-[2-Ethoxyimino-2-(3-methoxyphenyl)acetamido]^3-(1-
methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), pale yellow powder, mp 140 to 143C (dec.j.
I.R. spectrum (Nujol)
S 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm 1
N.M.R. spectrum (d6-~MSO, ~)
ppm 9.71 (lH, d, J=8Hz)
6.9-7.5 ~4H, m)
5.90 (lH, q, J=5Hz)
5.17 (lH, d, J=5Hz)
4.33 ~2H, ABq, J=13Hz)
4.20 (2H, q, J=7Hz)
3.95 ~3H, s)
3.85 (3H, s)
lS 3.75 ~2H, AB~, J=18Hz)
1.30 (3H, t, J=7Hz)
(19) 7-[2-Allyloxyimino-2-~3-chloro-4-methoxyphenyl)acetamido]-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid tsyn isomer), pale yellow powder, mp 153 to 156C (dec ).
I.R. spectrum ~Nujol)
3250, 2600, 1780, 1720, 1670, 1645,
1630, 1600 cm 1
N.M.~. spectrum ~d6-DMSO, ~)
ppm 9.65 (lH, d, J=8Hz)
7.27 (lH, d, J=2Hz)
7.20 (lH, dd, J=2,8Hz)
7.09 (lH, d, J=8Hz)
5.85-6.15 (2H, m)
S.lS (2H, t, J=9Hz)
S.OS (lH, d, J=SHz)
4.60 (2H, d, J=SHz)
_71_ E - 18
1 337522
3 95 (3H, s)
3.90 (3H, s)
3.47 (2H, ABq, J=18Hz)
(20) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido~-
3-carbamoyloxymethyl-3-cephem-4-carboxylic acîd (syn
isomer).
I.R. spectrum (Nujol)
3450, 3250, 1765, 1710, 1655, 1530 crn
N.M.R. spectrum (d6-DMSO, ~)
ppm : 9.77 (lri ~ d, J=8Hz)
7.6 -7.1 (4H, m)
6.56 (2H, s)
5.83 (lH, dd, J=4,8Hz)
5.20 (lH, d, J=4Hz)
4.76 (2H, ABq, J=13Hz)
3.94 (3H, s)
3.55 (2H, broad s)
2.28 (3H, s)
(21) 7-[2-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)-
acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyi-3-
cephem^4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3300, 1760, 1660, 1600, 1580, 1520 cm 1
.... , . ~,
- N.M.R. spectrum (d6-DMSO, ~)
ppm : 9.7 (lH, d, J=8Hz)
7.7 - 6.7 (9H, m)
5.8 - 5.4 (3H, broad s)
5.06 (lH, d, J=5Hz)
4.33 (2H, broad s)
3.9 (3H, s)
3.56 (2H, bro~d s)
~ - 19
-72-
1 337522
(22) 7-[2-Methoxyimino-2-(3-mesylaminophenyl)acetamidoj-3-
(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 155 C (dec.).
I.R. spectrum (Nujol)
3300, 1780, 1730, 1670 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.98 (lH, s)
9.81 (lH, d, J=9Hz)
9.62 (lH, s)
5.90 (lH, dd, J=S, 9Hz)
5.24 (lH, d, J=SHz)
4.49 (2H, ABq, J=14Hz)
3.98 (3H, s)
3.77 (2H, broad s)
2.96 (3H, s)
(2~) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido~-3-
(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer).
I.R. spectrum (Nujol)
3450, 3300, 3200, 17~0, 1725, 1670
1620, 1590, 1520 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.77 (lH, d, J=7Hz)
7.6 -6.8 (6H, m)
5.83 ~lH, dd, J=4, 7Hz)
5.17 (lH, d, J=4Hz)
4.31 (2H, ABq, J=14Hz)
3.96 (6H, s)
3.72 (2H, broad s)
3o
~- 20
1 337522
(24) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-
(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1735, 1675 cm 1
N.M.R. spectrum ~d6-DMSO, ~)
ppm 9.81 (lH, d, J=8Hz)
9.62 (lH, s)
6.7 - 7.58 ~4H, m)
5.87 (lH, dd, J=5, 8Hz)
5.2 (lH, d, J=SHz)
4.25, 4.63 (2H, ABq, J=14Hz)
3.9 (3H, s)
3.7 (2H, broad s)
(25) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamidoJ-3-
(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer).
I.R. spectrum (Nujol)
3250, 178Q, 1740, 1720, 1680 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.86 (lH, d, J=8Hz)
9.61 (lH, s)
7.00 - 7.65(4H, m)
5.84 (lH, dd, J=S, 8Hz)
5.2 (lH, d, J=5Hz)
4.25, 4.63 (2H, ABq, J=14Hz)
3.92 ~3H, s)
3.53, 3.86 (2H, ABq, J=19Hz)
2.3 (3H, s)
3o
E-21
-74-
i 337522
~26) 7-[2-(3-Phenylallyloxyimino)-2-(3-hydroxyphenylj-
acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp 138 to 142C (dec.)
I.R. spectrum (Nujol)
3300 - 3400, Z600, 1780,
1720, 1665, 1600 cm 1
N.~.R. spectrum (d6-~MSO, ~)
ppm 9.80 (lH, d, J=8Hz)
6.4 - 7.4 (llH, m)
5.8S (lH, dd, J=S, 8Hz)
5.20 ~lH, d, J=SHz)
4.83 (2H, d, J=SHz)
4.32 (2H, ABq, J=lSHz)
` 3.95 (3H, s~
3.68 (2H, ABq, J=18Hz)
(27) 7-[2-Methoxyimino-2-(4-dimethylaminophenyl)acetamidoj-
3-~1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 88C (dec.).
I.R. spectrum (Nujol)
3250, 1780, 1730, 1680, 1610 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.63 (lH, d, J=8Hz)
7.40 (2H, d, J=8Hz)
6.73 (2H, d, J=8Hz)
5.83 (lH, dd, J=S, 8Hz)
5.17 (lH, d, J=5Hz)
4.33 (2H, ABq, J=13Hz)
3.97 (3H, s)
3.87 (3H, s) ~;
3.73 (2H, broad s)
3.00 (6H, s)
E- 22
-75-
I '33752 Z
.. .. ... . . . . ..
(28) 7-r2-Methoxyimino-2-(3-hydroxyphenyl)acetamid 3 3-3-ri-(2-
dimethylaminoethyl)-I~-tetrazol-5-yl~thiomethyl-3-cephem-4-
carboxylic acid (syn isomer).
I. R~ spectrum ( NUJ ol)
1765 c2-l
N. M. R. spectrum (d6-3MSO, ~)
ppm 9.67 (1~, d, J=9Hz)
6.72-7.36 (4H, m)
5.78 (lH, dd, J=5, 9 Hz)
5.12 (lH, d, J=5 Hz~
4.55 (2H, broad s)
4.30 ~2H, broad s)
3.gO (3H, s)
3.40-3.80 (2H, m)
3.14 ~2H, broad 8 )
2.48 (6H, s)
(29) 7-[2-{2-(2-Hydroxyphenoxy)ethoxyimino~-2-(3-hydro~yphenyl)-
acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiometnyl-3-cephem-4-
carboxylic acid (syn isomer).
I. R. spectrum (Nujol)
3270, 1780, 1725, 1670, 1560 cm 1
N. M. R. spectrum (d6-DiISO,~ )
ppm6.5-7.4 (8H, m)
5.86(1H, dd, J=5, 8Hz)
5.14(lH, d, J=5Hz)
.0-4.6 (5H, m)
3.92(3H, s)
3.52, 3.70(2H, ABq, J=7Hz)
E_23
-7G -
1 331522
Example 8
A mixture of dimethylformamide (0.73g) and phosphorus
.oxychloride (1.6g) was warmed for 30 minutes zt 40C. Benzene
was added thereto and the mixture was concent~ated. The
residue was suspended in ethyl acetate (20 ml) and 2-methoxyimino-
2-(3-hydroxyphenyl) acetic acid (syn isomer) (1.9Sg) was added
thereto at -lS to -5C, after which the resulting mixture was
stirred for 30 minutes at the same temperature. On the other
hand, a solution of sodium hydroxide (0.9g) in water (5 ml) was
dropwise added at 0 to 5C over 25 minutes to a suspension of
7-aminocephalosporanic acid (2.7g) in water (12.Sml) an1 the
mixture was stirred for 5 minutes, after which acetone (20 ml)
was added thereto. To the resulting mixture containing sodium
7-amino-3-hydroxymethyl-3-cephem-4-carboxylate was dropwise
added at 0 to 5C over 3 minutes the above obtained ethyl aceta~e
solution keeping the pH value at 7.5 to 8.5 by adding triethyl-
amine. After stirring for 30 minutes, the organic solvents
were distilled off The aqueous layer was washed with ethyl
acetate (20ml), adjusted to pH 2.0 with hydrochloric acid ard
extracted with ethyl acetate (60ml) at 0 to 3C. The aqueous
layer was further extracted with ethyl acetate (30ml). The
combined ethyl acetate extracts were washed with a saturated
aqueous solution of sodium chloride and dried. The solvent
was distilled off and the residue was pulverized with
diisopropyl ether to give a mixture of 7-[2-methoxyimino-2-
(3-hydroxyphenyl)acetamido]-3-hydroxymethyl-3-cephem-4-
carboxylic acid'syn isomer)(I) and 6-[2-methoxyimino-2-(3-
hydroxyphenyl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]-furo-
[3,4-d][1,31thiazine-1,7(4H)-dione(syn isomer)~II) (2.64 g).
3o
E-24
-77-
1 337522
I.R. spectrum of (I) (Nujol)
3250, 1785, 1755, 1660, 1600, 1570, 1540 cm~
N.M.R. spectrum of (I) (d6-DMSO, ~)
ppm 9.83 (lH, d, J=8~1z)
7.~ - 6.75 (4H, m)
5.8 (lH, dd, J=5,8~z)
5.21 (lH, d, J=5Hz)
4.3 (2H, broad s)
3.95 (3H, s)
3.63 (2H, broad s)
I.R. spectrum of (II) (Nujol)
3250, 1785, 1755, 1660, 1600, 1570, 1540 cm~
N.M.R. spectrum of (II) (d6-DMSO, ~)
ppm 9.83 (lH, d, J=8Hz)
7.5 - 6.75 (4H, m)
6.02 (lH, dd, J=S, 8Hz)
5.21 (lH, d, J=SHz)
5.07 (2H, broad s)
3.95 (3H, s)
3.84 (2H, broad s)
Example 9
7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-
3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)
(0.23 g) was dissolved in pyridine (1 ml) with stirring and
ice-cooling, and acetyl chloride (0.082 g) was added thereto.
The mixture w~s stirred for 40 minutes under ice-cooling.
The reaction mixture was poured-into ice-water, acidified with
hydrochloric acid and extracted with ethyl acetate. The extract
was washed with a saturated aqueous solution of sodium chloride
and dried over magnesium sulfate. After treating with activated
~- 25
1 337522
charcoal, it was filtered and the filtrate was concentrated.
The residue was pulverized with diisopropyl ether to gi~e a
mixture of 7-[2-methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-
carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) and
7-[2-methoxyimino-2-(3-acetoxyphenyl)acetamido3-3-carbamoyloxy-
methyl-2-cephem-4-carboxylic acid ( syn isomer ) (0.18 g ).
N.M.R. spectrum (d6-DMS0, ~)
ppm : 9.82 (lH, d, J=8Hz)
9.77 (lH, d, J=8Hz)
7.6-7.1 (8H, m)
6.60 (lH, s)
6.56 (2H, s)
5.83 (lH, dd, J=4, 8Hz)
5.60 (lH, dd, J=4,8Hz)
5.24 (lH, d, J=4Hz)
5.20 (lH, d, J=4Hz)
4.84 ~lH, s)
4.76 (2H, ABq, J=13Hz)
4.56 (2H, broad s)
3.94 (6H, s)
3.55 (2H, broad s)
2.28 (6H, s
~0
~_26
-79-
~ 33 7522
Example lO
The following compounds were obtained according ~o
a similar manner to that of Example 9.
~1) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamidoJ-3-(1J3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxyii~c acid (syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1740, 1720, 1680 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.86 (lH, d, J=8Hz)
9.61 (lH, s)
7.00 - 7.65 (4H, m)
5.84 (lH, dd, J=5, 8Hz)
5.2 (lH, d, J=5Hz)
4.25, 4.63 (2H, ABq, J=14Hz)
3.92 (3Hf s)
3.53, 3.86 (~H, ABq, J=19Hz)
2.3 (3H, s)
(2) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer).
I.R spectrum (N~jol)
3450, 3300, 3200, 1780, 1725, 1670, 1620,
1590, 1520 cm~l
N.M.R. spectrum (d6-DMSO, ~)
2S ppm 9.77 (lH, d, J=7Hz)
7.6 - 6.8 (6H, m)
5.83 (lH, dd, J=4, 7Hz)
5.17 (lH, d, Js4Hz)
4.31 (2H, ABq, J=14Hz)
3.96 (6H, s)
E- 27
-80-
1 337522
3.72 (2H, broad s)
(3) 7-[2-Methoxyimino-2-(3-carbamoyl-oxyphenyl)acetamidol- -
3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1735, 1675 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.81 (lH, d, J=8Hz)
9.62 (lH, s)
6.7 - 7.58 (4H, m)
5.87 (1~, dd, J=S, 8Hz)
5.2 (lH, d, J=SHz)
- ~ 4.25, 4.63 (2H, ABq, J=14Hz)
3.9 (3H, s)
3.7 (2H, broad s)
Example 11
Phosphorus oxychloride (0.26 g.) was added under ice-
cooling to dimethylformamide (0.15 g.) and the mixture was warmed
at 40C for 1 hour. Ethyl acetate (l.S ml.) was added thereto
and to the mixture was at a time added 2-methoxyimino-2-(2-methyl-
1,3-thiazol-4-yl)acetic acid (syn isomer) (0.3 g.) with s~irring
and ice-cooling, after which the resulting mixture was stirred
for 20 minutes. at 0 to 5C. On the other hand, bis(trimethyl-
silyl)acetamide (1.2 g.) was added to a suspension of 7-amino-
3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
acid (0.53 g.) in ethyl acetate (7 ml.) and the mixture was
stirred at ambient temperature. To this solution was
dropwise added the above obtained ethyl acetate solution at -20C
and the mixture was stirred for 2 hours at -10 to-20C. Water
~O (20 ml.) was added to the reaction mixture below -25C and
-81- ~- 28
1 337522
ethyl acetate (20 ml.) was added thereto, after ~-hich the mixture
was stirred. An insoluble material was filtered off anG the
ethyl acetate layer was separated. Water ~15 ml.) w~s aaded
to the ethyl acetate iayer and the mixture was adjusted to ~H 7.5
with a saturated aqueous solution of sodium bicarbonate. lhe
aqueous layer was separated, washed with methylene chio-.^ide and
methylene chloride in tlle aqueous layer was removea by bu~bling
of nitrogen gas. The aqueous solution was adjusted to pH 2.2
with 10% hydrochloric acid and precipitates were collected by
fil~ration and dried to give 7-~2-methoxyimino-2-(2-methyl-l,3-
thiazol-4-yl)acetamido~-3-(1-methyl-lH-tetrazol-S-yl)thiometnyl-
3-cephem-4-carboxylic acid (syn isomer) (0.28 g.).
I.R. spectrum (Nujol)
1780, 1710, 1675 cm 1
N.M.R. spectrum (d6-DMSO, ~)
PPm 9.65 (lH, d, J=lOHz)
7.66 (lH, s)
5.81 (lH, dd, J=S,lOHz)
5.15 (lH, d, J=SHz)
4.31 (2H, ABq, J=13Hz)
3.93 (3~1, s)
3.90 (3H, s)
3.70 (2H, ABq, J=16Hz)
2.65 (3H, s)
.
-82- E- 29
1 337522
Example 12
Phosphorus oxychloride (0.89 g.) and d,y dimet..yl-
formamide (0.44 g.) were mixed under ice-cooling and ther.
warmed for 30 minutes at 40C. Dry methylene chloride (20 ml.)
was added thereto and then distilled off. To the residue
were added dry ethyl acetate (10 ml.) and then 2-methoxyimir.o-2-
~2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yljacetic acid (syn
isomer) (1.8 g.~ with stirring and ice-cooling. The mixture
was stirred for 40 minutes at the same tempera~ure to give ciear
solution. On the other hand, trimethylsilylacetamide (6.36 g.)
was added to a suspension of 7-aminocephalosporanic acid (1.65 g.)
in dry ethyl acetate (25 ml.) with stirrin~ at ambient tempcra~ure,
after which the mixture was stirred for 1 hour tO give a clear
solution. To this solution was at a time added the above-
obtained ethyl acetate solution with stirring at -20 to -25C,
and the resulting mixture was stirred for 2 hours at the same
temperature. Water (30 ml.) was added to the reaction mixture
at the same temperature, and then the mixture was stirred for 5
minutes at ambient temperature. The ethyl acetate layer was
separated, and the aqueous layer was further extracted wi~h ethyl
acetate. The ethyl acetate layerS werecombined and water ~0
ml.) was added thereto. The mixture was adjusted tG pH 7.5
with sodium bicarbonate, and the aqueous layer was separated.
Ethyl acetate (40 ml.) was added to the aqueous layer, and the
mixture was adjusted to pH 2.5 with 10% hydrochloric acid with
stirring and ice-cooling. The ethyl acetate layer was separated,
and the aqueous layer was further extracted twice with ethyl
acetate (30 ml.). The ethyl acetate layers were combined,
washed with an aqueous solution of sodium chloride and treated
with acti~ated charcoal. The solvent was distilled off to
E - 30
-83-
1 337522
give 7-~2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-
thiazol-4-yl}acetamidol cephalosporanic acid (syn isomer) (3.05
g.), mp 205C (dec.).
I.R. spectrum (Nujol~
325G, 1790, 1735, 1680, 1650 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.8 (lH, d, J=8Hz)
7.55 ~iH, s)
5.88 (11~, dd, J=5,8Hz)
5.25 (lH, d, J=5Hz)
4.8 (2H, ABq, J=1311z)
3.95 ~3H, s)
3.59 (2H, broad s)
2..03 (3~1, s)
Example 13
Phosphorus oxychloride (2.0 g.) was at a time added at
5 to 10C to a suspension of 2-methoxyimino-2-(2-amino-1,3-
thiazol-4-yl) acetic acid (syn isomer) (2 g.) in dry ethyl acetate
(20 ml.). After stirring for 20 minutes at 7 to 10C, bis-
(trimethylsilyl) acetamide (0.4 g.) was addeà thereto at the same
temperature. After stirring for 10 minutes at 7 to 10C,
phosphorus oxychloride (2.0 g.) was dropwise added there~o at the
same temperature. The resulting mixture was stirred for iO
minutes at 7 to 10C, and dry dimethylformamide (0.8 g.) was
dropwise added thereto at the same temperature. The mixture
was stirred for 30 minutes at 7 to 10C to give a clear solution.
On the other hand, trimethylsilylacetamide (7.35 g.) was added
to a suspension of 7-aminocephalosporanic acid (2.45 g.) in dry
ethyl acetate (8 ml.), after which the mixture was stirred at
~0 40C to give a clear solution. To this solution was at a time
~ - 3
--84--
1 337522
added the above-obtained ethyl acetate solution at -15C, and the
resulting mixture was stirred for 1 hour at -lG to -15C. The
reaction mixture was cooled to -30C, and water (80 ml.~ was
added thereto. The aqueous layer was separated, adjustea to
pH 4.5 with sodium bicarbonate and subjected to column chromato-
graphy on Diaion HP-20 resin (Trademark: prepared by Mitsubishi Chemical
Industries Ltd.) using 25% aqueous soiution of isopropyi alcohol
C as an eluent. The eluate was lyophilized to give 7-L2-
methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido~cephalosporanic
acid tsyn isomer) (1.8 g.), mp 227C (dec.).
I . R. spectrum (Nujol)
3300-3350, 1780, 1740, 167G cm 1
N.M.R. spectrum ~d6-DMSO, ~)
ppm 9.6 (lH, d, J=8Hz)
6.8 (lH, s)
5.8 ~lH, dd, J=5,8Hz)
5.2 (lH, d, J=5Hz)
4.87 (2H, ABq~ J=13Hz)
3.89 (3H, s)
3.6 (2H, broad s)
2.08 (3~, s)
Example 14
Phosphorus oxychloride (3.8 g.) was dropwise added
at 5 to 8C to a suspension of 2-methoxyimino-2-(2-amino-1,3-
thiazol-4-yl)acetic acid (syn isomer) (4.0 g.) in dry ethyl acetate
(40 ml.). After stirring for 30 minutes around 5C, bis(tri-
methylsilyl)acetamide (0.86 g.) was added thereto at the same
temperature. After stirring for 10 minutes at the same
temperature, phosphorus oxychloride (3 . 8 g. ) was dropwise added
thereto at 5 to 8C, after which the mixture was stirred for 30
E - 32
-85-
1 337522
minutes at the same temperature. Dry dimethylformamide
(1.6 g.) was dropwise added thereto at 5 to 7C, after which
the resulting mixture was stirred for 30 minutes at the same
temperature to give a clear solution. On the other hand,
S sodium acetate (3.3 g.) was added to a solution of 7-amino-
ce~halosporanic acid (2.7 g.) in an aqueous solution (20 ml.) of
sodium bicarbonate (1.7 g.), and then acetone (20 ml.) was added
thereto. To this solution was dropwise added the above-
obtained ethyl acetate solution with stirring at 0 to 5C keeping
the pH of this solution at 7.0 to 7.5 by 20% aqueous solution of
sodium carbonate. The mixture was stirred for 1 hour at the
same temperature. An insoluble material was filtered off,
and the aqueous layer in the filtrate was separated. The
aqueous layer was concentrated under reduced pressure to remove
the organic solvents, adjusted to pH 4.5 with sodium bicarbonate
and subjected to column chromatography on Diaion HP-20 resin
(Trademark: prepared by Mitsubishi Chemical Industries Ltd.)
using 25% aqueous solution of isopropyl alcohol as an eluent.
The eluate was lyophilized to give 7-[2-methoxyimino-2-(2-amino-
1,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer) (2.8
g.). This compound was identified with the compound obtained
in Example 13 by I.R. and N.M.R. spectra.
~ - 33
-86-
1 337522
Example 15
The following compounds were obtained according to
similar manners to those of Examples llto 14 .
(~ 7-[2-Methoxyimino-2-(2-mesylimino-3-methyl-2,3-
dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1718, 1675 cm~
N.M.R. spectrum (d6-D~ISO, ~)
ppm 9.80 (lH, d, J=8Hz)
7.08 (iH, s)
5.80 (lH, dd, J=5,8Hz)
5.18 (lH, d, J=5Hz)
4.34 (2H, ABq, J=13Hz)
3.99 (3H, s)
3.96 (3H, s)
3.72 (2H, ABq, J=17Hz)
3.66 (3H, s)
2.98 (3H, s)
(2) 7-[2-Methoxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)-
acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3300-3150, 1780, 1710, 1670 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.84 (lH, d, J=8Hz)
6.97 (lH, s)
5.76 (lH, dd, J=5,8Hz)
5.12 (lH, d, J=5Hz)
4.33 (211, AB , J=13Hz)
~-~4
-87-
1 337522
3.93 (6H, s)
3.74 (2H, ABq, J=17Hz)
2.96 (3H, s)
(~ 7-[2-Methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-
yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
1780, 1665 cm l
N.M.R. spectrum (d6-DMS0, ~)
ppm 11.67 (lH, s)
9.83 (lH, d, J=8Hz)
6.61 (1~, s)
5.80 (lH, dd, J=5.5,8Hz)
5.17 (lH, d, J=5.5Hz)
4.37 (2H, broad s)
4.00 (3H, s)
3.96 (3H, s)
3.75 (2H, broad s)
(4) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-
thiazol-4-yl}acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
1790, 1730, 1660 cm l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.73 (lH, d, J=8Hz)
7.53 (lH, s)
5.83 (lH, dd, J=5,8Hz)
5.15 (lH, d, J=5Hz)
4.33 (2H, broad s)
3.g3 (6H, s)
3.72 (2H, broad s)
~-~5
-88-
1 337522
(5) 7-~2-Methoxyimino-2-(2-t-pentyloxycarbonylamino-1,3-
thiazol-4-yl)acetamidoj-3-(5-methyl-1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3200, 1780, 1720, 1680 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.65 (lH, d, J=8Hz)
7.28 (lH, s)
5.80 (lli, dd, J=5,8Hz)
5.16 (lil, d, J=5Hz)
4.38 (211, ABq, J=13Hz)
3.86 (31i, s)
3.70 (2H, ABq, J=17Hz)
2.66 (3H, s)
1.78 (2H, q, J=8Hz)
1.44 (6H, s)
0.88 (3H, t, J=8Hz)
(6) 7-[2-Allyloxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)-
acetamidol-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
20 carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3100-3300, 1780, 1720, 1675 cm 1
N.M.R. spectrum (d6-D~ISO, ~)
ppm 9.90 (lH, d, J=8Hz)
7.00 (lH, s)
6.07-5.63 (2H, m)
5.43 (2H, d, J=8Hz)
5.18 (lH, d, J=5Hz)
4.70 (2H, d, J=SHz)
4.37 (2H, broad s)
~- 36
-89-
1 337522
3.98 (3H, s)
3.75 (2H, broad s)
3.00 (3H, s)
( 7) 7-[2-Allyloxyimino-2-(2-t~pentyloxycarbonylamino-i,3-
thiazol-4-yl)acetamido3-3-(1-methyl-lH-tetrazol-5-yl).niomethyl-
3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1720, 1678, 1625 cm~
N.M.R. spectrum (d6-DMSO,~)
ppm ; 9.74 (lH, d, J=8Hz)
7.31 (lH, s)
6.28 - 5.76 (2H, m)
5.28 (2h, dd, J=8, 16Hz)
5.18 (lH, d, J=5Hz)
4.66 (2H, d, J=SHz)
4.36 (2H, ABq, J=13Hz)
3.96 (3H, s)
3.74 (2H, ABq, Jz17Hz)
1.80 (2H, q, J=8Hz)
1.45 (6H, s)
0.89 (3H, t, J=8Hz)
( 8) 7-[2-Methoxyimino-2-(2-amino-1,3-~hiazol-4-yl)acetfimidoi-
3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer).
I.R. spectrum (Nujol)
3200, 1765, 1600 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm : 9.Sl (lH, d, J=8.5Hz)
7.22 (2H, broad s)
6.72 (lH, s)
5.59 (lH, dd, J=5, 8.5Hz)
5.00 (lH, d, J=SHz)
E-37
--90--
~ 337522
4.35 (2H, ABq, J=12Hz)
3 90 (3H, s)
3.81 (3H, s)
3.55 (2H, ABq, Jsl8Hz)
S ( 9) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazoi-4-yl)acetamido~-
3-(S-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4
carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3400-3150, 1770, 1670, 1625 cm^
N.M.R. spectrum (d6-DMSO, ~)
- ppm : 9.66 (lH, d, J=8Hz)
7.34 (2H, broad s)
6.76 (lH, s)
5.78 (2H, dd, J=5~8Hz)
lS 5.16 (lH, d, J=SHz)
4.40 (2H, ABq, J=14Hz)
3.85 (3H, s)
3.70 (2H, ABq, J=17Hz)
2.68 (3H, s)
(lO) 7-[2-Allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer).
I.R. spectrum (Nujol)
3100-3400, 1775, 1660, 1625 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm : 9.70 (lH, d, J=8Hz)
6.80 (lH, s)
6.30-5.60 (2H, m)
5.24 (2H, dd, J=8,16Hz)
5.15 (lH, d, J=5Hz)
~ - ~8
--91--
1 337522
4.63 (2H, d, J=SHz)
4.32 (2H, ABq, J=12Hz)
3.94 (3H, s)
3.70 (2H, ABq, J=17Hz)
~1 ) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido~-
3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp 145 to 147~C (dec.).
I . R. spectrum (Nujol)
3150 - 3400, 1780, 1725, 1680, 1640 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 12.58 (lH, broad s)
9.70 (lH, d, J=8Hz)
9.58 (l~i, s)
8.50 (lH, s)
7.40 (lH, s)
5.82 (lH, dd, J=5,8Hz)
5.17 (lH, d, J=5Hz)
4.43 (2H, ABq, J=13Hz)
3.88 (3H, s)
3.70 (2H, broad s)
(~2) 7-[2-Methoxyimino-2-(2-acetamido-1,3-thiazol-4-yl)acetamido]-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 171 to 173C (dec.).
I.R. spectrum (Nujol)
3500, 3250, 1780, 1720, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.65 (lH, d, J=8Hz)
7.3 (lH, s)
5.8 (lH, dd, J=5, 8Hz)
5.15 (lH, d, J-SHz)
E - 39
-92-
l 331522
4.35 (2H, broad s)
3.97 (3H, s)
3.9 (3H, s)
3.75 (2H, broad s)
2.15 (3H, s)
~) 7-[2-Methoxyimino-2 {2-(2,2,2-trifluoroacetamldo)-~,3-
thiazol-4-yl}acetamido]-cephalosporanic acid (syn isomer), mp
205C (dec.),
I.R. spectrum (Nujol)
3250, 1790, 1735, 1680, 1650 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.8 (lH, d, J=8Hz)
7.55 (lH, s)
5.88 (lH, dd, J~5, 8Hz)
5.25 (lH, d, JzSHz)
4.8 (2H, ABq, J=13~z)
3.95 (3H, s)
3 59 (2H, broad s)
2.03 (3H, s)
(14) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3
thiazol-4-yl}acetamido]-3-carbamoyloxymethyl-3-cephem-4-
carboxylic acid (syn isomer).
l.R. spectrum (Nujol)
3500, 3200, 1785, 1700, 1660 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.75 (lH, d, J=8Hz)
8.4 (2H, m)
7.53 (1~l, s)
6.6 (lH, m)
6.20 (lH, d, J=5Hz)
E-40
-93-
1 ~37 522
5.83 (lH, m)
4.77 ~2H, ABq, Js14Hz)
3.91 (3H, s)
3.55 (2H, m)
(1~ 7-[2-Methoxyimino-2-t2-(2,2,2-trifluoroacetamido)-1,3-
thiazol-4-yl}acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3200, 1780, 1720, 1650 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.81 (lH, d, J=8Hz)
9.6 (lH, m)
9.57 (lH, s)
7.56 (lH, s)
5.83 (lH, dd, J=5, 8Hz)
5.20 (lH, d, J=SHz)
4.47 (2H, ABq, J=14Hz)
3.96 (3H, s)
3.72 (2H, ABq, J=18Hz)
(16) 7-~2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido~-
3-hydroxymeth;1-3-cephem-4-carboxylic acid (syn isomer), mp
260 to 270C (dec.).
I.R. spectrum (Nujol)
3370, 3270, 1765, 1660, 1610, 1590, 1550 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.58 (lH, d, J-8Hz)
6.76 (lH, s)
5.75 (lH, dd, J=5, 8Hz)
~ - 41
-94-
1 337522
5.12 tlH, d, J~5Hz)
4.27 (2H, broad s)
3.85 (3H, s)
3.57 (ZH, broad s)
(17) 7-[2-Methoxyimino-2-(2-amino-l~3-thiazol-4-yl)acetamid
cephalosporanic acid (syn isomer), mp 227C (dec.).
I.R. spectrum (Nujol)
3300 - 3350, 1780, 1740, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.6 ~lH, d, J=8Hz)
6.8 (lH, s)
5.8 (lH, dd, J=5, 8Hz)
5.2 (lH, d, J=5Hz)
4.87 (2H, ABq, J=13Hz)
3.89 (3H, s)
3.6 (2H, broad s)
2.08 (3H, s)
(18) 7-[2-Methoxyimino-2-(2-amino-l~3-thiazol-4-yl)acetamid
3-carbamoyloxymethyl-3-cepham-4-carboxylic acid (syn isomer),
mp 210 to 220C (dec.).
I.R. spectrum (Nujol)
3250, 1765, 1650 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.64 (lH, d, J=8Hz)
7.4 (2H, m)
~ - 42
... .. .
-95-
1 3375~2
6.79 -(lH, s)
6.60 (2H, m)
5.77 (lH, dd, J=5, 8Hz)
5.16 (lH, d, J=5Hzl
4.75 (2H, ABq, J=12Hz)
3.87 (3H, s)
3.53 t2H, ABq, J=18Hz)
(l9) 7-[2-Methoxyimino-2-(2-amino-l~3-thiazol-4-yl)acetamido]
3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp 172 to 175C (dec.).
I.R. spectrum (Nujol)
3300, 1770, 1665 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.80 (lH, d, J=8Hz)
9.63 (lH, s)
6.95 (lH, s)
6.8 (2H, m)
5.82 (lH, dd, J=5, 8Hz)
5.22 (lH, d, J=5Hz)
4.48 (2H, ABq, J=lSHz)
3.97 (3H, s)
3.76 (2H, ABq, J=18Hz)
(20) 7-[2-Methoxyimino-2-(2-amino-l~3-thiazol-4-yl)acetamido]
3-(4-methyl-4~-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp 185C (dec.).
I.R. spectrum (Nujol)
3150 - 3350, 1770, 1710, 1660, 1630 cm 1
N.M.R. spectrum (d6-DMS0, ~)
ppm 9.61 (lH, d, J=8Hz)
8.69 (lH, s)
E-43
-96-
1 33?522
6.73 (lH, s)
5.72 (lH, dd, J=4, 8Hz)
5.1 (lH, d, J=4Hz)
4.1 (2H, ABq, J=13Hz)
3.87 (3H, s)
3.65 (2H, broad s)
3.s9 (3H, s)
(21) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-
thiazol-4-yl}acetamido~-3-hydroxymethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 155 to 160C (dec.).
I.R. spectrum (Nujol)
3250, 1780, 1730, 1660, 1585, 1520 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.76 (lH, d, J=8Hz)
7.57 (lH, s)
5.80 (lH, dd, J=4, 8Hz)
5.15 (lH, d, J=4Hz)
4.29 (2~l, s)
3.93 (3H, s)
3.60 (2H, s)
(22) 6-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
5a, 6-dihydro-3H,7H-azeto~2,1-b]furo[3,4-d]Ll,3]thiazine-1,7~4H)-
dione (syn isomer), mp 210 to 215C (dec.).
I.R. spectrum (Nujol)
3270, 1780, 1740, 1655, 1610, 1525 c~,-
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
7.26 (2H, broad s)
6.77 (lH, s)
5.93 (lH, dd, J=5, 8Hz)
E- 44
-97-
1 337522
S.16 (lH, d, J=SHz)
S.OS (2H, broad s)
- . 3.85 (3H, s)
3. 81 (2H, broad s)
E-45
-98--
1 337522
~23) 7-~2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
3-[1-(2-dimethylaminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
1765 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.56 ~lH, d, J=8Hz)
6.75 ~lH, s)
5.75 (lH, m)
L0 5.10 (lH, d, J=4Hz)
4.58 (2H, broad s)
4.32 (2H, broad s)
3.82 (3H, s)
3.68 (2H, broad s)
., .. ~.~,
L5 3.20 (2H, broad s)
2.50 (6H, s)
(24) 7-~2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-
acetamido]cephalosporanic acid (syn isomer).
I.R. spectrum (Nujol)
'0 3280, 1785, 1740, 1700, 1650 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 12.68 (lH, broad s)
9.68 (lH, d, J=8Hz)
8.54 (lH, s)
'5 7-45 (lH, s)
5.86 (lH, dd, J=5,8Hz)
5.20 (lH, d, J=5Hz)
4.90 (2H, ABq, J=8Hz)
3.61 (3H, broad s)
~0 2.06 (3H, s)
E - 46
_99_
1 3375~2
(25) 7-[2-Methoxyimino-2-(2-ethoxycarbonylamino-i,3-thiazol-
4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer).
I.R. specetum (Nujol)
S 3200, 1775, 1720, 1680, 1660 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 11.9 (lH, m)
9.70 (lH, d, J=lOHz)
9.55 (lH, s)
.0 7.31 (lH, s)
5.80 (lH, dd, J=5,10Hz)
5.18 (lH, d,J=5Hz)
4.44 (2H, ABq, J=16Hz)
4.22 (2H, q, J=7Hz)
3.89 (3H, s)
3.72 (2H, ABq~ J=16Hz)
1.23 (3H, t, J=7Hz)
~6) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-
thiazol-4-yl}acetamido~-3-formyl-3-cephem-4-carboxylic acid
0 (syn isomer) [or this compound can be represented as 3-hycroxy-
6-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-
yl}acetamido]-Sa,6-dihydro-3H,7H-azeto[2,1-b]furo~3,4-d~[1,3]-
thiazine-1,7(4H)dione (syn isomer)].
.R. spectrum (Nujol)
~S 3150, 1790, 1720, 1655, 1560,
1500 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.88 (lH, d, J=8Hz)
7.60 (lH, s)
~0 6.30 (lH, d, J=6Hz)
- 47
-100--
1 337522
6.05 tlH, dd, J=5,8Hz)
5.23 (lH, d, J=SHz)
3.96 (3H, s)
3.80 (2H, broad s)
(27) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yI)-
acetamido~-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3200-3300, 2600, 1780, 1720,
~ 1690, 1675 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 12.60 (lH, broad s)
9.70 (lH, d, J=8Hz)
8.50 (lH, s)
L5 7.44 (lH, s)
5.88 (lH, dd, J=5,8Hz)
S.l9 (lH, d, J=SHz)
.25 (2H, ABq~ J=13Hz)
3.95 (3H, s)
,0 3.85 (3H, s)
3.65 (2H, ABq~ J=18Hz)
(28) 7-~2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-
acetamido~-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid
(syn isomer).
!5 I.R. spectrum (Nujol)
3300, 1780, 1705, 1680 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 12.50 (lH, broad s)
9.67 (lH, d, J=8Hz)
8.50 (lH, s)
E - 48
--101--
t 337522
7.43 (lH, s)
6.58 (2H, broad s)
5.80 (lH, dd, J=5,8Hz)
5.16 (lH, d, J=SHz)
4.78 t2H, ABq~ J=14Hz)
3.95 (3H, s)
3.57 (2H, ABq~ J=18Hz)
~ - 49
-102_
1 33752~
Example 16
A solution of 7-[2-methoxyimino-2-{2-(2,2,2-trifluoro-
acetamido)-1,3-thiazol-4-yl}acetamido]-3-(1-methyl-lH-tetrazol-
S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g.)
S in a 0.1 N aqueous solution of sodium hydroxide (10.5 mi.) was
warmed at 45C for 6 hours. Water (15 ml.) and ethy; ace~ate
(30 ml.) were added to the reaction mixture and the resulting
mixture was adjusted to pH 3.5 with 10~ hydrocnloric acid.
The aqueous layer was separated, washed with ethyl acetate and
adjusted to pH 5.0 with an aqueous solution of sodium bicarbonate.
The aqueous solution was subjected to column chromatography on
Amberlite XAD-2 (20 ml.)(prepared by Rohm ~ Haas Co.) using 10~
ethanol as developing solvent. The eluate containing object
compound was collected and lyophilized to give 7-L2-methoxyimino-
lS 2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-
S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer~ (0.12 g.).
I.R. spectrum (Nujol)
3200, 1765, 1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.Sl (lH, d, J=8.SHz)
7.22 (2H, broad s)
6.72 (lH, s)
S.S9 (lH, dd, J=5,8.5Hz)
S.00 (lH, d, J=SHz)
4.35 (2H, ABq, J=12Hz)
3.90 (3H, s)
3.81 t3H, s)
-- 3.55 (2H, ABq, J=l~Hz)
~ II,qale~qri~
E - 5O
-103-
1 337522
Example 17
Trifluoroacetic acid (3 ml) was added ~nder ice-
cooling to 7-[2-methoxyimino-2-~2-t-pentyloxycarbonylamino-1,3-
thiazol-4-yl)acetamido~-3-(5-methyl-1,3,4-thiadiazoi-2-yl)-
S thiomethyi-3-cephem-4-carboxylic acid (syn isomer) (0.5 g) and
the mixture was stirred for 30 minutes at ambient temperatuïe.
~o the mixture was added ether and precipitating powder was
collected by filtration and dissolved in a mixture of water (20
ml) and an lN aqueous solution of sodium hydroxide to adjust
to pH 12 to 13. The solution was adjusted to pH 4.6 with lGgo
hydrochloric acid, washed with ethyl acetate ar.d methylene
chloride. Excess methylene chloride in the aqueous layer was
thoroughly removed by bubbling of nitrogen gas. The aqueous
layer was adjusted to pH 2 with stirring and ice-cooling to
lS precipitate powder. The powder was collected by filtration
and dried to give 7-~2-methoxyimino-2-(2-amino~1,3-thiazoi-4-
yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3
cephem-4-carboxylic acid (syn isomer) (0.128 g)
I. R. spectrum (Nujol)
3400-3150, 1770, 1670, 1625 cm~
N.M.R. spect~um (d6-DMSO, ~)
ppm : 9.66 (lH, d, J~8Hz)
7 34 (2H, broad s)
6.76 (lH, s)
5.78 (2H, dd, J=5, 8Hz)
5~16 (lH, d, J~SHz)
4,40 (2H, ABq, J 14Hz)
3 85 (3H, s)
3 70 (2H, ABq, J-17Hz)
2.68 (3H, s)
~ - 51
-104-
1 337522
Example 18
Trifluoroacetic acid (4 ml.) and anisole (2 ml.) were
added under ice-cooling to 7-[2-allyloxyimino -2-(2-t-penty-
loxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syr.
isomer) (0.9 g.) and the mixture was stirred for 40 minutes at
ambient temperature. The reaction mixture was post-treated
according to a similar manner to that of Example 17 to give
7-[2-allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido'-3-
(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer) (0.425 g.).
I.R. spectrum (Nujol~
3100-3400, 1775, 1660, 1625 c~
N.M.R. spectrum (d6-DMS0, ~)
ppm : 9.70 (lH, d, J=8Hz)
6.80 (lH, s)
6.30 - 5.60 (2H, m)
5.24 (2H, dd, J=8, 16Hz)
5.15 (lH, d, J=5Hz)
4.63 (2H, d, J=5Hz)
4.32 (2H, ABq, J=12Hz)
3.94 (3H, s)
3.70 (2H, ABq, J=17Hz)
Example l9
Disodium hydrogen phosphate (0.26 g) was added to
a suspension of 7-[2-methoxyimino-2-{2-(2,2,2-trifluoro-
acetamido)-1,3-thiazol-4-yl~acetamido~cephalosporanic acid(syn isomer)
(1 g) in water (15 ml). A saturated aqueous solution of
disodium hydrogen phosphate was further added thereto to
adjust the pH value of the mixture at 6. The resulting
E- 52
--105--
1 33752Z
mixture was stirred for 23 hours at ambient temperature.
The reaction mixture was adjusted to pH 4 under ice-cooting
with 10~ hydrochloric acid, washed with ethyl acetate and
adjusted to pH 2.5 with 10~ hydrochloric acid.
Precipitating crystals were collected by filtration, washea
with cold water and dried to give 7-[2-methoxyimino-2-(2-
amino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid
(syn isomer)(0.18 g), mp 227C (dec.).
I.R. spectrum (Nujol~
3300 - 3350, 1780, 1740, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.6 (lH, d, J=8Hz)
6.8 (lH, s)
5.8 (lH, dd, J=5, 8Hz~
i 5.2 (lH, d, J=SHz)
4.87 (2H, ABq, J=13H2)
3.89 (3H, s)
3.6 (2H, broad s)
....
2.08 (3H, s)
Example 20
7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-
1,3-thiazol-4-yl}acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid(syn isomer)(2~g) was suspended in a sol~tion
of sodium acetate trihydrate (74.8 g) in water (230 ml) and
the suspension was stirred for lS hours at ambient temperature.
The reaction mixture was adjusted to pH S.0 with conc.
hydrochloric acid and insoluble material was filtered off.
The filtrate was adjusted to pH 2.5 and precipitating
o crystals were collected by filtration and dried to give 7-
~- 53
-106-
1 337522
[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl~acetamido]-3-(l,
3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer) (14 g), mp 172 to 175C (dec.).
I.R. spectrum (Nujol)
3300, 1770, 1665 cm 1
N.M.R. spectrum (d6-DMS0, ~)
ppm 9.80 ~lH, d, J=8Hz)
9.63 (lH, s)
6.95 (lH, s)
6.8 (2H, m)
5.82 (lH, dd, J=5, 8Hz)
5.22 (lH, d, J=5Hz)
4.48 (2H, ABq, J=15Hz)
3.97 (3H, s)
3.76 (2H, ABq, J=18Hz)
~ - 54
-107-
1 337522
Example 21
7-[2-Methoxyimino-2-{2-~2,2,2-trifluoroacetamido)-1,3-
thiazol-4-yl}acetamido~-3-carbamoyloxymethyi-3-cephem-4-carbaxylic
acid (syn isomer) (3.5 g.) was suspended in a sc~~u~ion OI sodium
S acetate trihydrate (12.2 g.) in water ~30 ml.). Tne mixture
was stirred for lS hours at ambient temperature. The reaction
mixture was saturated with sodium chloride and adjusted to pH S.0
with conc. hydrochloric acid with stirring and ice-cooling.
Precipitatin~ insoluble material was filtcred of. The ;il~rate
0 was adjusted to pH 3.0 with conc. hydrochloric acid and furtn~r
adjusted to pH l.S with 10~ hydrochloric acid. Precipitates
were collected by filtration and dried to give 7-[2-metho~yimino-
2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-
cephem-4-carboxylic acid (syn isomer) ~2.1 g.), mp 210 to 220C
(dec-)-
I.R. spectrum (Nujol)
3250, 1765, 1650 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.64 (lH, d, J=8Hz)
0 7.4 (2H, m)
6.79 (lH, s)
6.60 ~2H, m)
5.77 ~lH, dd, J=5,8Hz)
5.16 (lH, d, J=SHz)
4.75 (2H, ABq~ J=12Hz)
3.87 ~3H, s)
3.53 ~2H, ABq~ J=18Hz)
Example 22
Conc. hydrochloric acid ~10.4 ml.) was added with
D stirring at ambient temperature to a sus~ension of 7-[2-methoxy-
3 - 55
-108-
1 337522
imino-2-t2-formamido-1,3-thiazol-4-yl)acetamido]cephalosporanic
acid (syn isomer) ~48.35 g.) in methanol (725 Ml.). Afte.
stirring for 3 hours at ambient temperature, tne reaction mixture
was adjusted to pH 4.5 with a~ueous solution of ar.lmonia and
methanol was distilled off. To the residue was added wa~er
(100 ml.). The mixture was adjusted to pH 6.5 with an aqueous
solution of sodium bicarbonate, and insolubie ma~erial was collected
by filtration to give 6-~2-methoxyimino-2-(2-am no-i,3-thiazo--4-
yl)acetamido]-Sa,6-dihydro-3H,7H-azeto[2,1-b]furo~3,4-d~Ll,3~-
thiazine-1,7(4H)dione (syn isomer) (6.5 g.). The filtrate
was adjusted to pH 4.5 with acetic acid, adsorbed by Diaion H?-20
resin (Trademark: prepered by Mitsubishi Chemica~ Industries Ltd.)
(600 ml.), washed with water (2 Q.) and then eluted with 25%
aqueous solution of isopropyl alcohol. Eluates containing the
L5 ob~ect compounds were collected and cooled after addition of
isopropyl alcohol (1/3 volume of the eluates). Precipitates
were collected by filtration, washed with isopropyl alcohol and
dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)-
acetamido]cephalosporanic acid (syn isomer~ (10.4 g.). The
'0 mother liquor was concentrated under reduced pressure until
crystals began to precipitate. To the residue was added
isopropyl alcohol (2/3 volume of the residue). The mixture
was cooled and precipitates were collected by ~iltration to give
the same object compound (5.8 g.). Total yield (16.2 g.).
!5 This compound was identified with the compound obtained in the
~oregoing Examples by I.R. and N.M.R. spectra.
Example 2~
7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-
acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
iO carboxylic acid (syn isomer) (10.8 g.) was added to methanol
~ - 56
-109--
-- 1 337522
(200 ml.), and phosphorus oxychloride (7.2 g.) was
dropwise added thereto with stirring and ice-cooling at
2 to 9C. After stirring for 1.5 hours at the same
temperature, the reaction mixture was concentrated
under reduced pressure on a water bath of 25 to 28C to
the volume of 100 ml. To the residue was added ether
(300 ml.) with stirring and ice-cooling Precipitates
were collected by filtration and dried to give 7-[2-
methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-
(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-
carboxylic acid hydrochloride (syn isomer) (12.3 g.).
This powder (12.3 g.) was suspended in water (100 ml.)
and dissolved by adjusting pH of the suspension to 7.5
by addition of a saturated aqueous solution of sodium
bicarbonate. To the solution was added ethyl acetate
(100 ml.), and the mixture was adjusted to pH 2.5 with
10% hydrochloric acid. Precipitates were collected by
filtration, washed with cold water and dried to give 7-
[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer) (6.1 g.). The aqueous
layer in the mother liquor was separated and stirred
under cooling after addition of sodium chloride.
Precipitates were collected by filtration to give the
same object compound (3.8 g.). Total yield (9.9 g.).
This compound was identified with the compound obtained
in the foregoing Examples by I.R. and N.M.R. spectra.
~ -- 110 --
1 337522
Example24
The following compounds were obtained according to
similar manners to those of Examples 16to 23.
(1) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamidG}-
3-hydroxymethyl-3-cephem-4-carboxylic acid (~yn isomer), mp
260 to 270C (dec.).
I.R. spectrum (~ujol)
3370, 3270, 1765 , 1~60, 1610, 1590, 1550 c~-
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.58 (lH, d, J-81iz)
6.76 ~lH, s)
5.75 ~lH, dd, J=5, 8Hz)
5.12 (lH, d, J=5~fz)
4.27 (2H, broad s)
3.85 (3H, s)
3.57 (2H, broad s)
3o
~ - 58
1 337522
~2) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido~-
3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 210 to 220 C (dec.3.
I.R. spectrum (Nujol
3250, 1765, 1650 c~
N.M.R. spectrum ~d6-DMS0, ~)
ppm 9.64 (lH, d, J=8Hz)
7.4 (2H, m)
6.79 ~, s)
IO 6.60 ~2H, m)
5.77 (lH, dd, J=5, 8Hz)
5.16 (1~, d, J=5Hz)
4.75 (2H, ABq, J=12Hz)
3.87 ~3H, s)
3.53 (2H, ABq, J=18Hz)
-- ~) 7-[2-Methoxyimino-2-(2-amino-],3-thiazol-4-yl)ace~amido'-
3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp 185C (dec.).
I.R. spectrum (~'ujol)
3150 - 3350, 1770, I710, 1660, 1630 cm 1
N.M.R. spectrum (d6-DMS0, ~)
ppm 9.61 (lH, d, J=8Hz)
8.69 (1~l, s)
6.73 (lH. s)
5.72 (lH, dd, J=4, 8Hz)
5.1 (lH, d, J=4Hz)
4.1 (2H, ABq, J=13Hz)
3.87 (3H, s)
3.65 (2H, broad s)
~O 3.59 (3H, s)
~-5g
-112-
1 337522
(4) 6-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-
yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4,-
d][l,3]thiazine-1,7(4H)-dione (syn isomer), mp 210 to
215C (dec.).
I.R. spectrum (Nujol)
3270, 1780, 1740,1655,1610,1525 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
7.26 (2H, broad s)
6.77 (lH, s)
5.93 (lH, dd, J=5, 8Hz)
5.16 (lH, d, J=5Hz)
5.05 ~2H, broad s)
3.85 (3H, s)
3.81 (2H, broad s)
(5) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-
yl)acetamido]-3-[1-(2-dimethylaminoethyl)-lH-tetrazol-
5-yl] thiomethyl-3-cephem-4-carboxylic acid (syn
isomer).
I.R. spectrum (Nujol)
1765 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.56 (lH, d, J=8Hz)
6.75 (lH, s)
5.75 (lH, m)
5.10 (lH, d, J=4Hz)
4.58 (2H, broad s)
4.32 (2H, broad s)
3.82 (3H, s)
3.68 (2H, broad s)
3.20 (2H, broad s)
2.50 (6H, s)
'~jif
i~,
- - 113 -
Example 25 1 337J22
A suspension of 7-~2-methoxyimino-2-{2-(2,2,2-
trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]cephalosporanic
acid (syn isomer) (2.76 g) and 4-methyl-4H-1,2,4-triazole-3-
thiol (0.63 g) in pH 6.4 phcsphate buffer solution (50 ml) was
adjusted to pH 6.4 with sodium bicarbonate and stirred for
6 hours at 65 to 70C. The reaction mixture was cooled and
ethyl acetate was added thereto. The mixture was adjusted to
pH 5 with 10~ hydrochloric acid and washed with ethyl acetate.
The aqueous layer was treated with activated charcoal and
adjusted to pl-l 2.7 with 10% hydrochloric acid with stirring
and ice-cooling. Precipitating crystals were collected by
filtration, washed with cold water and dried to give 7-~2-
methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-~4-
methyl-4H-1,2,4-triazol-3-yl)thiomethyi-3-cephem-4-carboxylic
acid (syn isomer) (0.7 g)J mp 185C ~dec.).
I.R. spectrum (NuJol)
31aO - 3350, 1770, 1710, 1660, i630 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.61 (lH, d, J=8Hz)
8.69 (lH, s)
6.73 (lH, s)
5.72 ~lH, dd, J=4, 8Hz)
5.1 (~H, d, J=4}-~z)
4.1 (2H, ABq, J=i3Hz)
3.87 (3H, s)
3.59 (3H, s)
3.65 (2H, broad s)
Example 26
The following compounds were obtained according to
a similar manner to that of Example 25~
E- 61
-114-
1 ~752Z
(1) 7-[2-Methoxyimino-2-(2-methy~ 3-thiazol-4-yl)acetamid
3-(1-methyl-lH-tetrazoi-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer).
I.R. spectrum (Nujol)
1780, 1710, 1675 cm i
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.65 (lH, d, J=lOHz)
7.66 (1~, s)
5.81 ~iH, dd, J=5, lOHz)
5.15 (lH, d, J=5Hz)
4.31 ~2H~ ABq, J=13Hz)
3.93 (3H, s)
3.90 ~3H, s)
3.70 (2H, ABq, J=16Hz)
2.65 (3H, s)
~2~ 7-[2-Methoxyimino-2-(2-mesylimino-3-methyl-2~3-dihydr
1,3-thiazol-4-yl)acetamido]-3-~1-methyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R~ spectrum (Nujol)
3250, 1780, 1718, 1675 cm~l
- N.M.R. spectrum (d6-DMSO, ~)
ppm 9.80 (i}~, d, J=8Hz)
7.08 (1~l, s)
5.80 (-H, dd, J=5, 8Hz)
5.18 (lH, d, J=5Hz)
4.34 (2H, ABq, J=13Hz)
3.99 (3H, s)
3.96 (3H, s)
3.72 (2H, ABq, J=17Hz)
3.66 ~3H, s)
2.98 (3H, s)
~3J 7-~2-Methoxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)-acet-
amido~-3-(l-methyl-lH-tetrazol-s-yl)thiomethyl-3-cephem-4^
carboxylic acid (syn isomer).
~5
1 337522
I.R. spectrum (Nujol)
3300 - 3150, 1780, 1710, 1670 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.84 (iH, d, J=8Hz)
6.97 (lH, s)
5.76 (lH, dd, J=S, 8Hz)
5.12 ~lH, d, J=5Hz)
4.33 (2H, ABq, J=131-lz)
3.93 (6H, s)
3.74 (2H, ABq, J=17Hz)
2.96 (3H, s)
(4) 7-[2-Methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-
yl)acetamido~-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
1780, 1665 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 11.67 (lH, s)
9.83 (lH, d, J=8Hz)
6.61 (lH, s)
5.80 (lH, dd, J=5.5, 8Hz)
5.17 (lH, d, J=5.5Hz)
4.37 (2H, broad s)
4.00 (3H, s)
3.96 (3H, s)
3.75 (2H, broad s)
(5) 7-~2-Allyloxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)-
acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem
4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) ;
E- 63
-11 6 -
1 337522
3100 - 3300, 1780, 1720, 1675 cm 1
N.M.R. spectrum (d6DMS0, ~)
ppm 9.90 (lH, d, J=8Hz)
7.00 (lH, s)
S 6.07 - 5.63(2H, m)
5.43 (2H, d, J=8Hz)
5.18 (lH, d, J=5Hz)
- -~ 4.70 (2H, d, J=SHz)
4,37 (2H, broad s)
3.98 (3H, s)
3.75 (2H, broad s)
3.00 (3H, s)
( 6J 7-[2-Methoxyimino-2-t2-amino-1,3-thiazol-4-yl)acetamido]-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
lS acid (syn isomer).
I.R. spectrum (Nujol)
3200, 1765, 1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm: 8.51 (l~l, d, J=8.5Hi)
7.22 (2H, broad s)
6.72 (lH, s)
S.S9 (lH, dd, J=5, 8.5Hz)
5.00 (lH, d, J=5Hz)
4.35 (2H, ABq, J=12Hz)
3.90 (3H, s)
3.81 (3H, s)
3.55 (2H~ ABq, J=18Hz)
( 7) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
3-(S-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer).
E- 64
-117-
1 337522
I.R. spectrum (Nujol)
3400 - 3150, 1770, 1670, 1625 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.66 (lH, d, J=8Hz)
7.34 (2H, broad s)
6.76 (lH, s)
5.78 (2H, dd, J=5, 8Hz)
5.16 (lH, d, J=5Hz)
4.40 (2H, ABq, J=14Hz)
3.85 (3H, s)
3.70 (2H, ABq, J=17Hz)
2.68 (3H, s)
(8) 7-[2-Allyloxyimino-2-(2-amino-1,3-thiazol-4-
yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3100 - 3400, 1775, 1660, 1625 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
6.80 (lH, s)
6.30 - 5.60(2H, m)
5.24 (2H, dd, J=8, 16Hz)
5.15 (lH, d, J=5Hz)
4.63 (2H, d, J=5Hz)
4.32 (2H, ABq, J=12Hz)
3.94 (3H, s)
3.70 (2H, ABq, J+17Hz)
(9) 7-[2-Methoxyimino -2-(2-formamido-1,3-thiazol-4-
yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer), mp 145 to 147C
(dec.).
, ~,
- 118 -
~: 1337S2~
:
I.R. spectrum (Nujol)
3150 - 3400, 1780, 1725, 1680, 1640 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 12.58 (lH, broad s)
9.70 (lH, d, J=8Hz)
9.58 (lH, s)
8.50 (lH, s)
7.40 (lH, s)
5.82 (lH, dd, J=S, 8Hz)
5.17 (lH, d, J=5Hz)
4.43 (2H, ABq, J=13Hz)
3.88 (3H, s)
3.70 (2H, broad s)
(1~ 7-[2-Methoxyimino-2-(2-acetamido-1,3-thiazol-4-yl)-
acetamido~-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp 171 to 173C (dec.).
I.R. spectrum (Nujol)
3500, 3250, 1780, 1720, 1670 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.65 (lH, d, J=8Hz)
7.3 (lH, s)
5.8 (lH, dd, J=5, 8Hz)
5.15 (lH, d, J=5Hz)
. 4.35 (2H, broad s)
3.97 (3H, s)
3.9 (3H, s)
3.75 (2H, broad s)
2.15 (3H, s)
~0
E- 66
l/q
3~5Z~
. . . . ..
(11) 7-~2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido~-
3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp 172 to 175C (dec.).
I.R. spectrum (Nujol)
3300, 1770, 1665 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.80 (lH, d, J=8Hz)
9.63 (1~l, s)
6.95 (1~, s)
6.8 (2H, m)
5.82 (lH, dd, J=5, 8Hz)
5.22 (lH, d, J=5Hz)
4.48 (2H, ABq, J=15Hz)
3 97 (3H, s)
3.76 (2H, ABq, J=18Hz)
3o
E-67
1 337522
(12) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
3-~1-(2-dimethylaminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
1765 cm l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.56 (lH, d, J=8Hz)
6.75 (lH, s)
5.75 (lH, m)
5.10 (lH, d, J=4Hz)
4.58 (2H, broad s)
4.32 (2H, broad s)
3.82 (3~1, s)
3.68 (2H, broad s)
3.20 (2H, broad s)
2.50 (6H, s)
(13) 7-~2-Methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazol-
4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3200, 1775, 1720, 1680, 1660 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 11.9 (lH, m)
9.70 (lH, d, J=lOHz)
9.55 (lH, s)
7.31 (lH, s)
5.80 (lH, dd, J=5,10Hz)
4.44 (2H, ABq~ J=16Hz)
4.22 (2H, q, J=7Hz)
3.89 ~3H, s)
E - 68
-121-
1 337522
3.72 (2H, ABq~ J-16Hz)
1.23 (3H, t, J=7Hz)
(14) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-
acetamidol-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3200-3300, 2600, 1780, 1720,
1690, 1675 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 12.60 (lH, broad s)
9.70 ~lH, d, J=8Hz)
8.50 (lH, s)
7.44 (lH, s)
5.88 (lH, dd, J=5,8Hz)
5.19 (lH, d, J=5Hz)
4.25 (2H, ABq, J=13Hz)
3 95 (3H, s)
3.85 (3H, s)
3.65 (2H, ABq, J=18Hz)
E - 69
-122-
1 3375~2
(15) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-
(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxyiic
acid (syn isomer).
I.R. spectrum (Nujol)
3250, 1770, 1725, 1670 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.76 (lH, d, J=8H2)
6.7-7.40 (4H, m)
5.86 (lH, dd, J=5, 8Hz)
5.18 (lH, d, J=SHz)
4.34 (2H, ABq, J=1;3Hz)
3.92 (6H, s)
3.72 (2H, ABq, J=17Hz)
~6) 7-[2-t-Butoxycarbonylmethoxyimino-2-(3-chloro-4-
S hydroxyphenyl)acetamido]-3-(1-methyl-lH-tetra,ol-S-yl)thio-
methyl-3-cephem-4-carboxylic acid (syn isomer), powder.
~7) 7-[2-Carboxy-methoxyimino-2-(3-chloro-4-hydroXyphenyl)acetamid
3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 145 to 148C (dec.).
~0 I. R. spectrum (Nujol)
3400, 3200 - 3300, 2500 - 2600, 1780, 1720,
1670, 1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
7.50 (lH, d, J=2Hz)
7.45 (lH, dd,J=2, 8Hz)
7.10 (lH, d, J=8Hz)
5.90 (lH, q, J=5Hz)
5.22 (lH, d, J=SHz)
4.70 (2H, s)
E- 70
-123-
1 337522
4.35 (2H, ABq, J=13Hz)
3.95 (3H, s)
3.75 (2H, ABq, J=1811z)
(18 ~-t2~ t-Butoxycarbonylethoxyimino )-2-(3-chloro-4-
hydroxyphenyl)acetamido~-3-(1-methyl-lH-tetrazoi-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer), powder.
~9) 7-[2-(1-Carboxyethoxyimino)-2-(3-chloro-4-hydroxyphenyl)-
acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer),mp 147 to 151C (dec.).
I.R. spectrum (Nujol)
3500, 3250, 2500 - 2600, 17~0, 1730, 1660, 1630,
1600 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.62 (lH, d, J=8Hz)
7.46 (lH, d, J=2Hz)
7-34 tlH, dd, J=2, 8Hz)
7.04 (lH, d, J=8Hz)
5.90 (lH, q, J=5Hz)
5.22 (lH, d, J=5Hz)
4.73 (lH, q, J=6Hz)
-- 4.33 (2H, ABq, J=13Hz)
4.00 (3H, s)
3.73 (2H, ABq, J=1811z)
1.37 (3H, d, J=6Hz)
(20) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-
(4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. spectrum (Nujol)
3250, 1775, 1710, 1665 cm~
E- 71
-124-
1 337522
N.~.R. spectrum (d6-DMSO, ~)
ppm 9.67 (lH, d, J=8Hz)
8.40 tlH, s)
6.70-7.43 ~4H, m)
5.82 (lH, dd, J=5, 8Hz)
5.13 (lH, d, J=5Hz)
4.18 (2H, ABq, J=13Hz)
3.90 (3H, s)
3.67 (2H, broad s)
(21) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-
(1,3,4-thiadiazol-2-yl)thiometllyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1720, 1670 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.78 (lH, d, J=8Hz)
9.55 (lH, s)
6.70-7.40 (4H, m)
5.89 (lH, dd, J=5, 8Hz)
5.22 (lH, d, J=SHz)
4~46 (2H, ABq, J=13Hz)
3.92 (3H, s)
3.76 (2H, ABq, J=18Hz~
(22~ 7-[2-~iethoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(S-
methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1720, 1670 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.72 (lH, d, J=8Hz)
E-72
-125-
1 337522
6.G2-7.40 (4H, m)
5.94 (lH, dd, J=S, 8Hz~
5.18 (lH, d, J-5Hz)
4.18 (2H, ABq, J=13Hz)
3.89 (3H, s)
3.70 (2H, ABq, J=17Hz)
2.65 (3H, s)
t2~ 7-[2-Methoxyimino-2-(3-methoxyphenyl)acetamidGî-3-(l-
methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
10(syn isomer).
I . R. spectrum (Nujol)
3250, 1780, 1720, 1670 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.78 (lH, d, J=8Hz)
6.95-7.54 (4H, m)
5.94 (lH, dd, J=5, 8Hz)
~ - 73
-126-
~ 337522
5.18 (lH, d, J=5Hz)
4.12 (2H, ABq, J=13Hz)
3.92 (6H, s)
3.76 (3H, s)
3.72 (2H, ABq, J=18Hz)
(24) 7-[2-Methoxyimino-2-(4-hydroxyphenyl)acetamido]-3-(i-
methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
10(syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1720, 1670 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
7.44 (2H, d, J=8Hz)
6.84 (2H, d, J=8Hz)
5.86 (lH, dd, J=5, 8Hz)
5.18 (lH, d, J=5Hz)
4.34 (2H, ABq, J=13Hz)
3'93 (3H, s)
3.87 (3H, s)
3.74 (2H, ABq, J=18Hz)
(25) 7-[2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-
3~ methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 145 to 148C (dec.).
E- 74
-127-
1 337522
I.R. spectrum (Nujol)
3500, 3250, 2500-2600, 1780, 1720,
165S, 1625, 1600 cm
N.M.R. spectrum (d6-DMSO, ~)
ppm 10.80 (lH, broad s)
9.68 (lH, d, J=2Hz)
7.46 (lH, d, J=2Hz)
7.32 (lH, q, J=2, 8Hz)
7.00 (lH, d, J=8Hz)
5.80 (lH, q, J=5Hz)
- 5.16 (lH, d, J=SHz)
4.28 (2H, ABq, J=13Hz)
3 92 (3H, s)
lS 3.87 (3H, s)
3.72 (2H, ABq, J=18Hz)
(26) 7-[2-Methoxyimino-2-(3-chloro-4-methoxyphenyl)acet-
amido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp 143 to 145C (dec.).
I.R. spectrum (~ujol)
3300, 2500-2600, 1785, 1730, 1670,
1630, 1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.76 (lH, d, J=8Hz)
7.56 (lH, d, J=2Hz)
7.48 (lH, dd, J=2, 8Hz)
E- 75
-128-
t ~37522
7.22 (l~, d, J=8Hz)
5.84 (lH, q, J=SHz)
5.18 (lH, d, J=5Hz)
4.27 (2H, ABq, J=13Hz~
3.90 (6H, s)
3.88 (3H, s)
3.70 (2H, ABq, J=18Hz)
~27) 7-[2-Methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetamido]-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 149 to 152C (dec.).
I.R. spectrum (Nujol)
3400 - 3450, 3200, 2500 - 2600, 1780,
1720, 1660, 1620, 1600, 1535, 1350 cm
N.M.R. spectrum (d6-DMSO, ~)
lS ppm 9.72 (lH, d, J=8Hz)
7.97 (lH, d, J=2Hz)
7.72 (lH, dd, J=2, 8Hz)
7.21 (lH, d, J=8Hz)
5.82 (lH, q, J=5Hz)
5.16 (lH, d, J=5Hz)
4.3 (2H, ABq, J=13Hz)
3.92 (3H, s)
3.87 (3H, s)
3.72 (2H, ABq, J=18Hz)
(28) 7-[2-Allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acet-
amido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp 163 to 165C (dec.).
I.R. spectrum (Nujol)
3200-3300, 2500-2600, 1780,
1720, 1670, 1600 cm~l
E-76
-129-
1 337522
N.M.R. spectrum (d6-DMSO, 6)
ppm 9.70 tlH, d, J=8Hz)
7.40 (lH, d, J=2Hz)
7.30 (lH, dd, J=2, 8Hz)
6.95 (lH, d, J=8Hz)
5.80 (2H, m)
5.30 (2H, d, J=8Hz)
5.10 (lH, d, J=5Hz)
4.60 (2H, d, J=5Hz)
4.27 (2H, ABq, J=13Hz)
3.85 (3H, s~
3.65 (2H, ABq, J=18Hz)
(29) 7-[2-Allyloxyimino-2-(3-hydroxyphenyl)acetamido]-3-
(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 149 to 152C ( dec.),
I.R. spectrum (Nujol)
3250 - 3350, 2550 - 2600, 1780, 1730,
1670, 1650, 1600 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
7.2 - 6.8 (4H, m)
6.1 - 5.8 (2H, m)
S.35 (2H, d, J=8Hz)
5.17 (lH, d, J=SHz)
4.7 (2H, d, J=5Hz)
4.17 (2H, ABq, J=13Hz)
3.93 (3H, s)
3.75 (2H, ABq, J=18Hz)
~O) 7-[2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(4-hydroxy-
phenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-
E- 77
-130-
1 337522
cephem-4-carboxylic acid (syn isomer), powder.
I.R. spectrum (Nujol)
3150, 1780, 1720, 1670 cm 1
N.M.R. spectrum ~d6-DMSO, ~)
S ppm 9.60 (lH, d, J=8Hz~)
6.72 - 7.52(7H, m)
5.80 (lH, dd, Jz4, 8Hz)
5.15 (lH, d, J=4Hz)
5.00 (2H, s)
4.28 (2H, ABq, J=13Hz)
3.90 (3H, s)
3.65 (2H, ABq, J=18Hz)
(311 7-[2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyl)acet-
amido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
lS carboxylic acid (syn isomer), powder.
I.R. spectrum (Nujol)
3200 - 3300, 1780, 1720, 1660 cm
N.M.R. spectrum (d6-DMS0, ~)
ppm 9.77 (lH, d, J=8Hz)
6.7 7.7 (7H, m)
5.83 (lH, dd, J=5, 8Hz)
5.29 (2H, s)
5.15 (lH, d, J=SHz)
4.3 (2H, ABq, J=13Hz)
3.92 (3H, s)
3.72 t2H, ABq, J=18Hz)
t32) 7-[2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), colorless powder, mp 153 to 156C (dec.)
E- 78
-131-
~ 337522
I.R. spectrum (Nujol)
3450, 3250, 2550 - 2600, 1780,
1725, 1665, 1630, 1600 cm~
N.M.R. spectrum (d6-DMSO,~)
ppm 9.71 (lH, d, J=8Hz~)
7.50 (lH, d, J=2Hz)
7.36 tlH, dd, J=2, 8Hz)
7.03 (lH, d, J=8Hz)
5.83 (lH, q, J=5Hz)
5.17 (lH, d, J=5Hz)
4.33 (2H, ABq, J=13Hz)
4.17 (2H, q, J=7Hz)
3.97 (3H, s)
3.73 (2H, ABq, J=18Hz)
1.25 (3H, t, J=7Hz)
(33) 7-[2-Allyloxyimino-2-(3-methoxyphcnyl)acetamido]-3-(1-
methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), powder, mp 135 to 138C (dec.).
I.R. spectrum (Nujol)
3300, 2600, 1785, 1730, 1670, 1645, 1600 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.82 (lH, d, J=8Hz)
7.0 - 7.45 (4H, m)
5.8 - 6.2 (2H, m)
5.36 (2H, t, J=lOHz)
5.21 (lH, d, J=5Hz)
4.72 (2H, d, J=5Hz)
4.36 (2H, ABq, J=13Hz)
3.95 (3H, s)
3.91 (3H, s)
E-79
-132_
1 337522
3.87 (2H, ABq, J=18Hz)
~4) 7-[2-Ethoxyimino-2-(3-hydroxyphenyl)acetamido~-3-(1-
methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), yellow powder, mp 145 to 148C (dec.~.
S I.R. spectrum (Nujol)
3450, 3250, 2500 - 2600, 1775,
1720, 1665, 1620, 1600 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
6.8-7.4 (4H, m)
5.90 (lH, q, J=5Hz)
5.20 (lH, d, J=SHz)
4.36 ~2H, ABq, J=13Hz)
4.20 (2H, q, J=7Hz)
lS 4.00 (3H, s)
3.76 ~2H, ABq, J=18Hz)
- 1.33 (3H, t, J=7Hz)
~5) 7-[2-Ethoxyimino-2-(3-methoxyphenyl)acetamido]-3-(1-
methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), pale yellow powder, mp 140 to 143C (dec.).
I.R. spectrum (Nujol)
3300, 2500 - 2600, 1785, 1730,
1670, 1630, 1600 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.71 (lH, d, J=8Hz)
6.9 - 7.5 (4H, m)
5.90 tlH, q, J=SHz)
5.17 (lH, d, J=SHz)
4.33 (2H, ABq, J=13Hz)
4.20 (2H, q, J=7Hz)
E-80
-133-
1 337522
3.95 (3H, s)
3.85 (3H, s)
3.75 (2H, ABq, J=18Hz)
1.30 (3H, t, J=7Hz)
(36) 7-[2-Allyloxyimino-2-~3-chloro-4-methoxyphenyl)acetamido]-
3~ methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), pale yellow powder, mp 153 to 156C (dec.).
I.R. spectrum (Nujol)
3250, 2600, 1780, 1720, 1670, 1645,
1630, 1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.65 (lH, d, J=8Hz)
7.27 (lH, d, J=2E~z)
7.20 (lH, dd, J=2, 8Hz)
lS 7.09 (lH, d, J=8Hz)
5.85 - 6.15(2H, m)
S.lS (2H, t, J=9Hz)
S.OS (lH, d, J=SHz)
4.60 (2H, d, J=SHz)
4.15 (2H, ABq, J=13Hz)
3.95 (3H, s)
3.90 (3H, s)
3.47 (2H, ABq, J=18Hz)
(37) 7-[2-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)-
acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol)
3300, 1760, 1660, 1600, 1580, 1520 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.7 (lH, d, J=8Hz)
E- 81
-134-
t }37522
7.7 - 6.7 (9H, m)
5.8 - 5.4 (3H, broad s)
5.06 (IH, d, J=SH2)
4.33 (2H, broad s)
3.9 (3H, s)
3.S6 (2H, broad s)
(38) 7-[2-Methoxyimino-2-(3-mesylaminophenyl)acetamido]-3-
(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp 155C (dec.).
I.R. spectrum (Nujol)
3300, 1780, 173~, 1670 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.98 (lH, s)
9.81 (lH, d, J=9Hz)
lS 9.62 (lH, s)
S.90 (lH, dd, J-5,9Hz)
5.24 (lH, d, J=SHz)
4.49 (2H, ABq, J=14Hz)
3.98 (3H, s)
3.77 (2H, broad s)
2.96 (3H, s)
(39) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-
(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer).
I.R. spectrum (Nujol)
3450, 3300, 3200, 1780, 1725,
1670, 1620, 1590, 1520 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.77 (lH, d, J=7Hz)
7.6 - 6.8 (6H, m)
E-~2
-135-
1 337522
5.83 (lH, dd, J=4, 7Hz)
5.17 ~lH, d, J=4Hz)
4.31 (2H, ABq, J=14Hz)
3.96 (6H, s)
3.72 (2H, broad s)
(40) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-
(1,3,4-thiadiazol-2-yl)thiome$hyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. spectrum (Nujol)
3250, 1780, 1735, 1675, cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.81 (lH, d, J=8Hz)
9.62 (lH, s)
6.7 - 7.58 (4H, m)
5.8 (lH, dd, J=5, 8Hz)
5.2 (lH, d, J=SHz)
4.25, 4.63(2H, ABq, J=14Hz)
3.9 (3H, s)
3.7 (2H, broad s)
(4~ 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-
(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acld
(syn isomer).
I.R. spectrum (Nujol)
~ S0, 1780, 1740, 1720, 1680 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.86 (lH, d, J=8Hz)
9~61 (lH, s)
7.00-7.65 (4H, m)
5.84 (lH, dd, J=5, 8Hz)
5.2 (lH, d, J=SHz)
4.25-4.63 (2H, ABq, J=14Hz)
3.92 (3H, s)
E-83
-136-
1 337522
3.53, 3.86 (2H, ABq, J=19Hz)
2.3 (3H, s)
(42) 7-[2-(3-Phenylallyloxyimino)-2-(3-hydroxypheny')acetamido]-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
- S acid (syn isomer), mp 138 to 142C (dec.).
I.R. spectrum (Nujol)
3300 - 3400, 2600, 1780,
1720, 1665, 1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.80 (lH, d, J=8Hz)
6.4 - 7.4 (llH, m)
5.85 (lH, dd, J=5, 8Hz)
5.20 (lH, d, J=SHz)
4.83 (2H, d, J=SHz)
4.32 (2H, ABq, J=lSHz)
3.95 (3H, s)
3.68 (2H, ABq, J=18Hz)
(43)7-[2-Methoxyimino-2-(4-dimethylaminophenyl)acetamido]-3-
tl-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephe~-4-carboxylic
acid (syn isomer), mp 88C (dec.).
I.R. spectrum (Nujol)
3250, 1780, 1730, 1680, 1610 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.63 (lH, d, J=8Hz)
7.40 (2H, d, J=8Hz)
6.73 (2H, d, J=8Hz)
5.83 (lH, dd, J=5, 8Hz)
5.17 (lH, d, J=SHz)
4.33 (2H, ABq, J=13Hz)
3.97 (3H, s)
E- 84
-137-
1 337522
3.87 t3H, s)
3.73 (2H, broad s)
3.00 (6H, s)
(44) 7-~2-Methoxyimino-2-(3-hydroxyphenyl)acetamido] -3-r ;-
(2-dimethylaminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer).
I. R. spectrum (Nujol)
1765 cm~l
N. M. R. spectrum (d6-DMS0, ~)
~ 10 ppm 9.67 (lH, d, J=9Hz)
6.72-7.36 (4H, m)
5.78 (lH, dd, J=5, 9Hz)
5.12 (lH, d, J=5Hz)
4.55 (2H, broad s)
4.~0 (2H, broad s)
3.90 (3H, ~)
3.40-3.80 (2H, m)
3.14 (2H, broad s)
2.48 (6H, s)
(45) 7-[2-~2-(2-Hydroxyphenoxy)ethoxyimino~-2-(3-hydroxyphenyl)-
- acetamido~-3-(1-~ethyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer).
I. R. spectrum (~ujol)
3~70, 1780, 1725, 1670, 1560 cm~
N. M. R. spectrum (d6-DMSO,~ )
ppm 6.5-7.4 (8H, m)
5.86(1H, dd, J=5, 8Hz)
5.14(1H, d, J=5Hz)
4.0-4.6 (6H, m)
3.92(3H, s)
~.52, 3.70(2H, ABq~ J=7Hz)
,, .. .... , .. ~ .
E- 85
-138-
1 337522
Example 27
A solution of 7-~2-methoxyimino-2-(2-amino-1,3-
thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic
acid tsyn isomer) (0.3 g) in a mixture of acetone (3 ml) and
water (1.5 ml) was adjusted to pH 2 with 6N hydrochloric acid
and stirred for 4 hours at ambient temperature. After the
acetone was distilled off, to the residue was added water (1 ml).
The mixture was adjusted to pH 7 with a saturated aqueous
solution of sodium bicarbonate and ice-cooled for 1 hour.
Precipitating crystals were collected by filtration, washed with
water and dried to give 6-[2-methoxyimino-2-(2-amino-1,3-thiazol-
4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-
thiazine-1,7(4H)-dione (syn isomer)(0.23g), mp 210 to 215 C(dec.).
I.R. spectrum (Nujol)
3270, 1780, 1740, 1655, 1610, 1525 cm 1
N.M.~. spectrum (d6-DMSO, ~)
ppm 9.70 (lH, d, J=8Hz)
7.26 (2H, broad s)
6.77 (lH, s)
5 93 (lH, dd, J=S, 8Hz)
5.16 (lH, d, J=5Hz)
5.05 (2H, broad s)
3.85 (3H, s)
3.81 (2H, broad s)
3o
E- ~6
-139-
1 337522
Example 28
The following compound was obtained according to a
similar manner to that of Example 27 .
6-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido] -5a,6-
dihydro-3H~7H-azeto[2~l-b]furo[3~4-d][l~3]thiazine-l~7(4H)
dione(syn isomer),
I.R. spectrum (Nujol)
3250, 1785, 1755, 1660, 1600, 1570, 1540 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.83 (lH, d, J=8Hz)
7.5 - 6.75 (4H, m)
6.02 (lH, dd, J=5, 8Hz)
5.21 (lH, d, J=5Hz)
5.07 (2H, broad s)
3.95 (3H, s)
3.84 (2H, broad s)
~0
E-87
-140-
- 1 337522
Example 29
7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-
1,3-thiazol-4-yl}acetamido]-3-hydroxymethyl-3-cephem-4-car~oxylic
acid tsyn isomer) (1.0 g.) was dissolved in a mixture of dimethyl-
formamide (6 ml.) and acetone (30 ml.). Jones reagent (1.25
ml.), which was prepared from conc. sulfuric acid (0.28 ml.),
chromium trioxide (0.33 g.) and water (0.9 ml.), was dropwise
added thereto over 2 minutes with stirring and cooling at 0 to 2C.
After stirring for 20 minutes at the same tempera'ure, the reaction
mixture was poured into ice-water (50 ml.). After acetone
was distilled off, the residue was twice extracted with ethyl
acetate (50 ml.). The extracts were washed with a saturated
aqueous solut,on of sodium chloride and dried over magnesium
sulfate. The solvent was distilled off and the residue was
pulverized with diisopropyl ether to give 7-[2-methoxyimino-2-
{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}-acetamido]-3-
formyl-3-cephem-4-carboxylic acid (syn isomer) [or this compound
can be represented as 3-hydroxy-6-[2-methoxyimino-2-{2-(2,2,2-
trifluoroacetamido)-1,3-thiazoi-4-yl}acetamido]-Sa,6-dihydro-3H,
7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)dione (syn isomer)]
~0.56 g.).
I.R. spectrum (Nujol)
3150, 1790, 1720, 1655, 1560,
1500 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.88 (lH, d, J=8Hz)
7.60 (lH, s)
6.30 (lH, d, J=6Hz)
6.05 (lH, dd, J=5,8Hz)
5.23 (lH, d, J=SHz)
E - 8
-141-
1 337522
3.96 (3H, s)
3.80 (2H, broad s)
Example 30
The following compounds were obtained by conducting
S elimination reaction of protective group of amino on carbamoyl
group according to a similar manner to that of Example 3.
(1) 7-[2-Methoxyimino-2-t2-amino-1,3-thiazol-4-yl)acetamido]-
3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 210 to 220C (dec.).
I.R. spectrum (Nujol)
3250, 1765, 1650 cm l
,,, .. , ~ . ._~
- N.M.R. spectrum (d6-DMSO, ~)
ppm 9.64 (lH, d, J=8Hz)
7.4 (2H, m)
6.79 (lH, s)
6.60 (2H, m)
5.77 (lH, dd, J=5,8Hz)
5.16 (lH, d, J=SHz)
` 4.75 (2H, ABq, J=12Hz)
3.87 (3H, s)
3.53 (2H, ABq, J=18Hz)
(2) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-
acetamido~-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. spectrum (Nujol)
- 3300, 1780, 1705, 1680 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 12.50 (lH, broad s)
9.67 (lH, d, J=8Hz)
8.50 (lH, s)
E - 89
-142_
1 337522
7.43 (lH, s)
6.58 (2H, broad s)
5.80 tlH, dd, J=5,8Hz)
5.16 (lH, d, J=SHz)
S 4.78 (2H, ABq, J=14Hz)
3.95 (3H, s)
3.57 (2H, ABq, J=18Hz)
. , ~ , . .
E - 9O
-143-
1 331522
Reference 1
Phosphorus pentachloride (3.3 g.) was added under ice-
cooling to a suspension of 2-methoxyimino-2-(2-amino-1,3-thiazol-
4-yl)acetic acid (syn isomer) (1.5 g.) in methylene chloride
S (30 ml.) and the mixture was stirred for 30 minutes at ambient
temperature. Methylene chloride was distilled off under reduced
pressure and acetone was added to the residue to give a suspension.
On the other hand, a suspension of 7-amino-3-(1-methyl-lH-tetra-
zol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.2 g.) in an
aqueous solution of sodium bicarbonate (0.76 g. in 50 ml. of
water) was stirred for 10 minutes and acetone (50 ml.) was added
thereto to give a solution. To the solution was dropwise
added the above obtained suspension containing acid chloride
with stirring and ice-cooling and keeping the solution at pH 7.5
lS to 8.5 with a 20% aqueous solution of sodium carbonate. The
mixture was stirred for 1 hour at 3 to 5C and pH 8Ø Acetone
was distilled off under reduced pressure and the residue was
adjusted to pH 7.4 with ~ saturated aqueous solution of sodium
bicarbonate and further adjusted to pH 4.5 with 10~ hydrochloric
acid with stirring and ice-cooling. Precipitates were
filtered off and the filtrate was saturated with sodium chloride,
adjusted to pH 2.5 with 10~ hydrochloric acid and stirred for
1 hour. Precipitates were collected by filtration, washed
with water and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-
thiazol-4-yl)acetamido]-3-(1 methyl lH tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (a mixture of syn and anti isomers)
(0.95 g-)-
I.R. spectrum (Nujol)
3400, 1775, 1710, 1670, 1630 cm 1
~ - 91
-144-
1 337522
N.M.R. spectrum (d6-D~SO, ~)
ppm 9.85 (lH, d, J=8Hz)
9.50 (lH, d, J=8Hz)
7.58 (lH, s)
6.87 (lH, s)
6.65 (4H, broad s)
5.77 (2H, m)
5.15 (2H, d, J=5Hz)
4.35 (4H, broad s)
4.06 (6H, s)
3.97 (6H, s)
3.75 (4H, broad s)
Reference 2
A suspension of phosphorus pentachloride (1.7 g.) in
methylene chloride (20 ml.) was changed to a solution by
stLrring for 2 hours at ambient temperature. 2-~ethoxyimino-
2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (0.8 g.)
was added thereto at a time at ambient temperature and the mixture
was stirred. Methylene chloride was distilled off under
reduced pressure and the residue was dissolved in acetone (20
ml.). On the other hand, 7-amino-3-carbamoyloxymethyl-3-
cephem-4-carboxylic acid (1.0 g.) was suspended in a solution
of sodium bicarbonate (0.59 g.) in water (20 ml.) and dissolved
by adding acetone (10 ml.). To this solution was dropwise
added the above obtained solution containing acid chloride with
stirring and ice-cooling and keeping the solution at pH 7.5 to
8.5 with a 20~ aqueous solution of sodium carbonate. After
stirring for 1 hour at pH 8 under ice-cooling, an insoluble
material was filtered off. Acetone was distilled off under
reduced pressure from the filtrate and an insoluble material was
E - 92
-145-
1 337522
filtered off. The filtrate was adjusted to pH 2.5 with 10~
hydrochloric acid. Precipitates were collected by filtration
and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)-
acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (a
mixture of syn and anti isomers) (0.4 g.). The fil~-rate was
saturated with sodium chloride and stirred under ice-cooling to
give precipitates. The precipitates were collected by
filtration and dried to give the same object compound (C.3 g ).
Total yield (0.7 g.).
I.R. spectrum (Nu3ol)
3400, 1775, 1705 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.71 (lH, d, J=8Hz)
9.42 (lH, d, J=8Hz)
7.70 (lH, s)
7.40 (4H, broad s)
7.00 (1l~, s)
6.61 (4H, s)
5.76 (2H, m)
5.16 (21T, d, J=4,5Hz)
4.76 (4H, ABq, J=12Hz)
3.98 (3H, s)
3.89 (3H, s)
3.53 (4H, ABq~ J=18Hz)
Reference 3
A mixture of dimethylformamide (0.22 g.) and phospllorus
oxychloride (0.46 g.) was warmed for 1 hour at 40C. The
mixture was dissolved in dry methylene chloride (20 ml.) and
2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-
4-yl)acetic acid (anti isomer) (0.73 g.) was added thereto with
E-9
-146-
1 337522
stirring and ice-cooling, after which the resulting mixture was
stirred for 1.5 hours under ice-cooling. On the other hand,
7-amino^3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-
carboxylic acid (0.82 g.) was dissolved in a so~ution of bis-
(trimethylsilyl)acetamide (1.5 g.) in dry methylene c'iloride
(20 ml.). To this solution was added at -30C the above
obtained methylene chloride solution, after which the mixture
was stirred for 2 hours at -5 to -20C. After distilling off
. . .
methylene chloride at low temperature, water was added to the
residue and the mixture was extracted with ethyl acetate. The
extract was washed with a sodium chloride aqueous solution and
water (SO ml.) was added thereto. The resulting mixture was
adjusted to pH 7 with an aqueous solution of sodium bicarbonate
and the aqueous layer was separated. The aqueous layer was
adjusted to pH 1.5, saturated with sodium chloride and extracted
with ethyl acetate. The extract was washed with a sodium
chloride aqueous solution and dried over magnesium sulfate.
The solvent was distilled off and the residue was pulverized by
a mixture of diisopropyl ether and ether. The powder was
collected by filtration and dried to give 7-[2-methoxyimino-2-
(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (anti isomer) (1.0 g.). This powder (1.0 g.) was
suspended in water (30 ml.) and dissolved by adjusting to p~-l 6
by an aqueous solution of sodium bicarbonate. After removing
the solvent by bubbling of nitrogen gas, the aqueous solution
was lyophilized to give sodium 7-[2-methoxyimino-2-(2-mesylimino-
3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-
lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate tanti isomer)
(0.98 g )
E- 94
. .
-147-
1 337522
I.R. spectrum (KBr)
1760, 1675 cm~l
N.M.R. spectrum (D2O, ~)
ppm 8.05 (lH, s)
5.76 (lH, d, J=5Hz)
5.16 (lH, d, J=5Hz)
4.14 (2H, ABq~ J=13Hz)
4.10 (31~, s)
4.02 (3H, s)
3.52 ~2H, ABq, J=17Hz)
3.45 (3H, s)
3.24 (3H, s)
Re~erence 4
The following compounds were obtained according to a
similar manner to.that of Reference 3.
(1) 7-t2-Methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetamido]-
3^(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid tanti isomer).
I.R. spectrum (Nujol)
~ 1790, 1720, 1680 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 9.53 (lH, d, J=8Hz)
8.27 (1~l, s)
5.83 (lH, dd, J=5.5, 8Hz)
5.15 (lH, d, J=5.SHz)
4.30 (2H, ABqJ J=14Hz)
4.00 (3H, s)
3.93 (3H, s)
3.70 (2H, AB~, J=16Hz)
2.65 (3H, s)
~ 95
-148-
1 337522
(2) 7-[2-~lethoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (anti isomer).
I.R. spectrum (Nujol)
3400, 1775, 1670 cm~l
N.M.R. spectrum (d6-DMS0, ~)
ppm 9.44 (lH, d, J=8Hz)
7.71 (1ll, s)
6.40 (2H, broad s)
5.77 (lH, dd, J=5,8Hz)
5.13 (lH, d, J=5Hz)
4.31 (2H, broad s)
4.00 (3H, s)
3.95 (3H, s)
3.70 (2H, broad s)
3o
E - 96
-149-
1 337522
( ~) 7-t2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-
cephalosporanic acid (anti isomer).
I.R. spectrum (Nujol)
3400-3100, 1780, 1730, 1675 cm 1
N.M.R. spectrum (d6-D,~SO, ~)
ppm 9.43 (lH, d, J=8l-lz~
9.16 (2H, broad s)
7.73 (i~l, s)
5.82 (11l, dd, J-5,8Hz)
5.18 (lH, d, J=5Hz)
4.90 (2H, ABq, J=13Hz)
4.03 (3'i, 5)
3.60 (2i-l, broad s)
2.07 (3ll, s)
( 4) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-
3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
(anti isomer), mp 152C (dec.).
I.R. spectrum (Nujol)
3300 - 3100, 1775, 1720, 1670, 1630 cm 1
2Q N.M.R. spectrum (d6-DMSO, ~)
ppm 12.63 (lH, broad s)
9.66 (lH, s)
9.57 (lH, d, J=8Hz)
8.50 (lH, s)
8.07 (lH, s)
5.75 (lH, dd, J=5,8Hz)
5.15 (lH, d, J=SHz)
4.27 (2H, ABq, J=13~z)
4.00 ~3H, s)
~O 3.70 (2H, broad s)
~~97
~150-
1 337522
(5) 7-[2-Methoxyimino-2-(3-hydroxyphc11yl)acetamido]-3-(l-
- `~~ methyl-lH-tetlazol^S-yl)thiomethyl-3-cephem-4-carboxylic acid
(anti isomer).
I.R. spectrum (Nujol)
3350, 1780, 1726, 16&0 cm l
N.M.R. spectrum (d6-D~5SO, ~)
ppm9.24 (l1-~, d, J=8Hz)
7.36-7.lO
} (411, m)
7.00-6.74
5.70 (l1{, dd, J=5,8ilz)
5.13 (lH, d, J=SHz)
4.34 (21l, ABq, J=1311z)
3.95 (61i, s)
3.72 (21-1, ABq, J=l711z)
. .
3o
~ - ~8
:.
-151--
1 337522
Preparation of the startin~ com~ounds to be used for the afore-
mentione~ Exam~les and References
Preparation 1
A mixture of 3-chloro-4-hydroxyacetophenone (11.9 g.),
benzyl chloride (9.35 g.), potassium carbonate ~14.5 g.) and
dimethylformamide (60 ml.) was stirred for 1 hour a~ 100C.
The reaction mixture was poured into water ~150 ml.~ and extracted
with ethyl acetate. The extract was washed with a sodium
chloride aqueous solution an~ dried over magnesium sulfate.
After distilling off the sol~-ent, the residue (18 g.) was recrystal-
lized from ethanol (160 ml.) to give 3-chloro-4-benzyloxyaceto-
phenone tl3.2 g.), mp 110 to 112C.
Preparation 2
1) Selenium dioxide powder (12.6 g.) was added over lO
minutes to a solution of 3-chloro-4-benzyloxyacetophenone (19.7
g.) in dry pyridine (100 ml.) with stirring at 100C, and the
mixture was stirred for 3 hours at the same temperature.
Precipitating selenium was filtered off and the filtrate was
concentrated. The residue was dissolved in water (150 ml.)
and the solution was washed with ether. The aqueous solution
was acidified under cooling with conc. hydrochloric acid and
extracted with ether. The extract was washed with a sodium
chloride aqueous solution, dried over magnesium sulfate and
concentrated to give 2-(3-chloro-4-benzyloxyphenyl)glyoxylic
acid (15.9 g.), mp 134 to 135C.
2) The following compounds were obtained according to a
similar manner to that of Preparation 2-1).
~1) 2-(3-Nitro-4-benzyloxyphenyl)glyoxylic acid, mp 161
, . . .~ .. ~
to 164C.
(2) 2-(3-Chloro-4-methoxyphenyl)glyoxylic acid, mp 81 to
82C.
I.R. spectrum (Nujol)
2500-2600, 1715, 1670, 1600 cm 1 E - ~9
-152_
1 337522
(3) 2-(3-Mesylaminophenyl)glyoxylic acid, mp 66 to 68C.
I.R. spectrum (Nu~ol)
3560, 3250, 1720, 1670 cm 1
Preparation 3
1) A mixture of 2-(3-nitro-4-benzyloxyphenyl)glyoxylic
acid ~30 g.), conc. hydrochloric acid (90 ml.) and acetic acid
(120 ml.) was stirred for 3 hours at 100C. To tne reaction
mixture was added under cooling ice-water (600 ml.) ana the
mixture was extracted with ethyl acetate. The extract was
washed with ice-water, dried over magnesium sulfate and
concentrated to dryness under reduced pressure. The residue
was recrystallized from a mixture of benzene: ether: petroleum
ether (2:1:4). The crystals were collected by filtration,
washed with benzene and dried under reduced pressure to give
2-(3-nitro-4-hydroxyphenyl)glyoxylic acid (19.0 g.), mp 139 to
140.5C.
2) The following compound was obtained according to a
similar manner to that of Preparation 3-1).
(1) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid, mp 114 to
116C.
Preparation 4
2-(3-Hydroxyphenyl)glyoxylic acid (3.32 g.) and lN-
methanol solution of hydroxylamine (45 ml.) were refluxed with
stirring for 25 minutes. The reaction mixture was concentrated
under reduced pressure. The residue was dissolved in lN-
aqueous solution of sodium hydroxide (70 ml.~. An aqueous
solution was washed with ether, acidified with dil. hydrochloric
acid and then extracted with ethyl acetate. The extract was
washed, dried and treated with an activated charcoal. The
solvent was distilled off to give 2-hydroxyimino-2-(3-hydroxy-
phenyl)acetic acid (a mixture of syn and anti isomers) (2.9 g.).
E -lOO
-153-
1 337522
I.R. s~ectrum (Nujol)
3200, 1700 cm 1
Preparation 5
l)(a) Phenolphthalein indicator (3 drops) was added to a
solution of O-methylhydroxylamine hydrochloride (5.5 g.) in
dry methanol (60 ml.). To the solution was dropwise added
with stirring at ambient temperature lN methanol solution of
sodium methoxide (65 ml.) until the color of thc solution was
changed to purplisll red. O-Methylhydroxylamine hydrochloride
was added thereto by small portions until the solution was changed
to colorless solution. The mixture was stirrcd for 30 minutes
at ambient temperature. After precipitating sodium chloride
was filtered off, 2-(3-hydroxyphenyl)glyoxylic acid (9.85 g.)
was added to the filtrate and the mixture was refluxed for 30
minutes. After methanol was distilled off at low temperature,
a saturated sodium chloride aqueous solution was added to the
residue. The mixture was adjusted to pH 1 with lOPo hydrochloric
acid and extracted with ether (300 ml.). The extract was
dried over magnesium sulfate. Ether was distilled off at
low temperature to give 2-methoxyimino-2-(3-hydroxyphenyl)acetic
acid (a mixturc of syn and anti isomers).
(b) This material was dissolved in ether (60 ml.) and a
solution of diazomethane in ether was gradually added thereto
under ice-cooling until the color of the mixture was changed to
yellow. Acetic acid was immediately added thereto and the
mixture was washed with a sodium bicarbonate aqueous solution
and a saturated sodium chloride aqueous solution and dried over
magnesium sulfate. Ether was distilled off to give oily
residue (10.8 g.). The oily residue was subjected to column
chromatograph~on silica gel (165 g.) using a mixture of benzene
E lOl
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1 337522
and ethyl acetate (9 : 1) as developing solvent. Firs~ly the
eluate containing syn isomer was eluted and the eluate was
collected and concentrated to give oily methyi 2-methoxyimino-
2-(3-hydroxyphenyl)acetate (syn isomer) (7.9 g.). The oil
S was allowed to stand to give crystals, mp 39.5 to 40.5C.
I.R. spectrum (Nujol)
3450, 1730 cm 1
N.M.R. spectrum (CDCQ3, ~)
ppm 6.7 - 7.42 (4H, m)
3.98 (311, s)
3.92 (3H, s)
After the eluate containing syn isomer was eluted,
then the eluate containing anti isomer was eluted. The eluate
was collected and concentrated to gi~e methyl 2-methoxyimino-2-
(3-hydroxyphenyl)acetate (anti isomer) (l.S g.). This
material was recrystallized from a mixture of benzene and
petroleum ether to give crystals, mp 96 to 98C.
I.R. spectrum (Nujol)
3350, 1715 cm 1
N.M.R. spectrum (CDCQ3, ~)
ppm 7.12 - 7.40 (lH, m)
6.96 - 7.02 (3H, m)
3.99 (3H, s)
3.~4 (3H, s)
(c) A 2N aqueoùs solution of sodium hydroxide (40 ml.)
was added with stirring at ambient temperature to a suspension
of methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (syn isomer)
(7.55 g.) in water (70 ml.) and the mixture was stirred for
1 hour at ambient temperature. The reaction mixture was
adjusted to pH 6.5 with 10% hydrochloric acid, subjected to
E -102
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~ 337522
salting-out and washed with ether (60 ml.). The aqueous
layer was adjusted to pH 1 with conc. hydrochloric acid and
extracted once with 100 ml. of and twice with 60 ml. of ether.
The extract was washed twice with a saturated sodium chloride
aqueous solution (60 ml.) and dried over magnesium sulfate.
Ether was distilled off to give oil. Benzene was added
thereto and removed (twice) to give crystals of 2-methoxyimino-
2-(3-hydroxyphenyl)acetic acid (syn isomer) (6.44 g.), mp 98
to 101C (dec.).
I . R. spectrum (Nujol)
3370, 1720 cm 1
An aqueous solution of 2N sodium hydroxide (8 ml.)
was added with stirring at ambient temperature to a solution of
methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (anti isomer)
(1.56 g.) in methanol (30 ml.). After stirring for 3 hours
at the same temperature, methanol was distilled off. To the
residue was added water and the mixture was washed with ether.
The aqueous layer was adjusted to pH 1 with 10% hydrochloric
acid, subjected to salting^out and extracted with ether. The
extract was washed with a sodium chloride aqueous solution and
dried over magnesium sulfate. Ether was distilled off to
give crystals of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid
(anti isomer) (1.07 g.). The crystals were recrystallized
from a mixture of petroleum ether and ether to give crystals
(0.7 g.), mp 99 to 101C (dec.).
I.~. spectrum ~Nujol)
3350, 1690 cm 1
2)(a) Phenolphthalein indicator (3 drops) was added to a
solution of 0-methylhydroxylamine hydrochloride ( 3.7 g.) in
dry methanol (45 ml.). To the solution was dropwise added
E -103
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1 337522
with stirring at ambient temperature lN methanol solution of
sodium methoxide (39 ml.) until the color of the solution was
changed to purplish red. O-Methylhydroxylamine hydrochloride
was added thereto by small portions until the solution was
S changed to colorless solution. The mixture was stirred for
30 minutes at ambient temperature. After precipitating
sodium chloride was filtered off, 2-(4-hydroxyphenyl)glyoxylic
acid (6.56 g.) was added to the filtrate and the mixture was
stirred for 1 hour at ambient temperature. After methanol
was distilled off at low temperature, a saturated sodium
chloride aqueous solution was added to the residue. The
mixture was adjusted to pH 1 with 10% hydrochloric acid,
subjected to salting-out and extracted with ether. The
extract was dried over magnesium sulfate. Ether was distilled
lS off at low temperature to give 2-methoxyimino-2-(4-hydroxyphenyl)-
acetic acid (syn isomer).
(b) This material was dissolved in ether (S0 ml.) and
a solution of diazomethane in ether was gradually added thereto
under ice-cooling until the color of the mixture was changed to
yellow. Acetic acid was immediately added thereto and the
mixture was washed with a sodium bicarbonate aqueous solution
and a saturated sodium chloride aqueous solution and dried
over magnesium sulfate. Ether was distilled off to give
oily residue (8 g.). The oily residue was subjected to
column chromat~graphy on silica gel using a mixture of ben~ene
and ethyl acetate (9 : 1) as developing solvent to give methyl
2-methoxyimino-2-(4-hydroxyphenyl)acetate (syn isomer) (6.39 g.).
I.R. spectrum (Nujol) `
3350, 1720 cm 1
E - 104
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1 337522
N.M.R. spectrum (CDC~3, ~)
ppm 7.40 (2H, d, J=8Hz)
6.80 (2H, d, J=8Hz)
3.96 (3H, s)
3.92 (3H, s)
(c) A 2N aqueous solution of sodium hydroxide (11 ml.)
was added with stirring at ambient temperature to a solution
of methyl 2-methoxyimino-2-(4-hydroxyphenyl)acetate (Syll isomer)
,, . . . ~ .~
-- ` (2.1 g.) in methanol (30 ml.) and the mixture was stirred for
18 hours at ambient temperature. The reaction mixture was
adjusted to pH 7 with 10% hydrochloric acid and methanol was
removed. To the residue was added water and the mixture was
washed with ether. The aqueous layer was adjusted to p~ 1
with 10% hydrochloric acid, subjected to salting-out and extracted
with ethyl acetate. The extract was washed with a saturated
sodium chloride aqueous solution and dried over magnesium sulfate.
Ethyl acetate was distilled off to give crystals of 2-methoxyimino-
2-(4-hydroxyphenyl)acetic acid (syn isomer) (1.5 g.).
I.R. spectrum (Nujol)
3150, 1700 cm 1
3)(a) Phenolphthalein indicator (2 drops) was added to a
solution of O-methylhydroxylamine hydrochloride (2.74 g.) in
dry methanol (30 ml.). To the solution was dropwise added
with stirring at ambient temperature lN methanol solution of
sodium methoxide until the color of the solution was changed
to purplish red. O-Methylhydroxylamine hydrochloride was
added thereto by small portions until the solution was changed
to colorless solution. The mixture was stirred for 1 hour
at ambient temperature. After precipitating sodium chloride
was filtered off, 2-(3-nitro-4-hydroxyphenyl)glyoxylic acid
E -105
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1 337522
(6.75 g.) was added to the filtrate and the mixture was stirred
for 1 hour at ambient temperature. After methanol was
distilled off at 35C, a saturated sodium chloride aqueous
solution was added to the residue. The mi~xture was adjusted
to pH 1 with 10% hydrochloric acid and extracted with ether.
The extract was dried over magnesium sulfate. Ether was
distilled off at 35C under reduced pressure to give yellow
crystals o~ 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetic
acid (a mixture of syn and anti isomers) (7 g.).
(b) This material was dissolved in a mixture of tetra-
hydrofuran (15 ml.) and ether (100 ml.) and a solution o~
diazomethane in ether was gradually added thereto at ambient
temperature until the color of the mixture was changed to
yellow. Acetic acid was immediately added thereto and the
lS mixture was concentrated to dryness at 35C under reduced
pressure. The residue was dissolved in a mixed solvent of
ethyl acetate and benzene (1 : 9) and subjected to column
chromatography on silica gel using the same mixed solvent as
developing solvent. The eluate containing syn isomer was
collected and concentrated to give methyl 2-methoxyimino-2-
(3-nitro-4-hydroxyphenyl)acetate (syn isomer) (3.7 g.), mp 93
to 95C.
I.R. spectrum (Nujol)
~ 3300, 1745, 1630, 1535, 1350 cm 1
N.M.R. spectrum (GDCQ3, ~)
ppm 10.87 (lH, s)
8.22 (lH, d, J=2Hz)
7.86 (lH, dd, J=2,8Hz)
7 20 (lH, d, J=8Hz)
4.03 (3H, s)
3.9s (3H, s)
~ -106
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1 337522
(c) A 2N aqueous solution of sodium hydroxide (14 ml.)
was added with stirring at ambient temperature to a solution of
methyl 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetate (syn
isomer) (3.5 g.) in methanol (70 ml.) and the mixture was stirred
S for 60 hours at ambient temperature. The reaction mixture
was concentrated to dryness at 40C under reduced pressure and
the residue was dissolved in water. The solution was washed
with ethyl acetate, adjusted to pH 1 with 10~ hydrochloric acid
under ice-cooling and extracted with ethyl acetate. The
extract was back-extracted with a saturated sodium bicarbonate
aqueous solution. The aqueous extract was adjustcd to pH 1
with conc. hydrochloric acid under ice-cooling and extracted
with ethyl acetate. The extract was washed with ice-water
and dried over magnesium sulfate. The solvent was concen-
trated to dryness at 40C under reduced pressure to give yellow
crystals of 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetic
acid (syn isomer) (3.2 g.), mp 142 to 143C (dec.).
I . R. spectrum (Nujol)
3300, 2500 - 2600, 1710, 1630,
1600, 1535, 1375 cm 1
N.M.R. spectrum (CDCQ3, ~)
ppm 10.67 (2H, s)
8.33 (lH, d, J=2Hz)
7.95 (lH, dd, J=2,8Hz)
7.22 (lH, d, J=8Hz)
4.13 (3H, s)
4)(a) 2-(3^Chloro-4-hydroxyphenyl)glyoxylic acid (6.45 g.)
and O-methylhydroxylamine hydrochloride (2.74 g.) were reacted
according to a similar manner to that of Preparation 5-3)(a)
to give oil of 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)-
acetic acid (a mixture of syn and anti isomers) (7 g.).
E -107
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1 337522
(b) 2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic
acid (a mixture of syn and anti isomers) (7 g.) ar,d diazomethane
(1.5 g.) were reacted and the product was purified by column
chromatography according to a similar manner to that of Prepa-
ration 5-3)(b) to give crystals of methyl 2-methoxyimino-2-(3-
chloro-4-hydroxyphenyl)acetate (syn isomer) (3.0 g.).
I.R. spectrum (Film)
3450, 1735, 1605, 1600 cm 1
N.M.R. spectrum (CDCQ3, ~)
ppm 7.55 (lH, d, J=2Hz)
7.37 (lH, dd, J-2,8Hz)
6.95 (lH, d, J=8Hz)
6.12 (1~l, s)
3.97 (3H, s)
3.91 (3~, s)
(c) Methyl 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)-
acetate (syn isomer) (2.6 g.) and a 2N aqueous solution of
sodium hydroxide (10.6 ml.) were treated according to a similar
manner to that of Preparation S-3)(c) to give 2-methoxyimino-2-
(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.4 g.),
mp 147 to 150C (dec.).
I.R. spectrum (Nujol)
3500, 2500 - 2600, 1745, 1610, 1600 cm 1
N.~l.R. spectrum (CDC~3, ~)
ppm 8.40 (2H, broad s)
7.65 (lH, d, J=2Hz)
7.40 (lH, dd, J=2,8Hz)
7.00 (lH, d, J-8Hz)
4.Q7 (3H, s)
E -108
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1 337522
S) 2-(3-Hydroxyphenyl)glyoxylic acid (2.0 g.) and O-allyl-
hydroxylamine hydrochloride (1.7 g.) were reacted according to
a similar manner to that of Prep~ration S-2)(a) to give oil of
- 2-allyloxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer)
s (2.7 g.).
I.R. spectrum (Film)
3350, 2550-2600, 1720, 1645, 1600 cm~l
6) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2 g.) and
O-allylhydroxylamine hydrochloride (1.1 g.) were reacted according
to a similar manner to that of Preparation 5-2)(a) to give oil
of 2-allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid
(syn isomer) (2.5 g.).
I R. spectrum (Film)
3450, 2600, 1730, 1700, 1650, 1610, 1600 cm 1
lS N.M.R. spectrum (d6-D~SO, ~)
ppm 9.5 - lO.S (2H, broad s)
7.52 (lH, d, J~2Hz)
7.42 (lH, dd, J=2,8Hz)
7.12 (lH, d, J=8Hz)
6.0 (lH, m)
5.40 (2H, t, J=8Hz)
. .
4.70 (2H, d, J=SHz)
7) A mixture of 2-(3-chloro-4-hydroxyphenyl)glyoxylic
acid (2.0 g.), O-t-butoxycarbonylmethylhydroxylamine (1.62 g.)
and methanol (20 ml.) was adjusted to pH 5 to 6 by adding an
lN methanol solution of sodium methoxide and stirred for 3 hours
at ambient temperature. The reaction mixture was concentrated
to dryness under reduced pressure and the residue was dissolved
in an lN aqueous solution of sodium hydroxide to adjust ~o pl~ 7Ø
The aqueous solution was washed with ether, adjusted to pH 2.0
E - lO9
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1 337522
with 10~ hydrochloric acid under ice-cooling and extracted with
ether. The extract was washed with water and dried over
magnesium sulfate. The solution was concentrated to dryness
under reduced pressure to give crystals of 2-t-butoxycarbonyl-
methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer)
.. ...
~2.6 g.), mp 116 to 118C (dec.).
I.R. spectrum (Nujol)
3250, 2600, 1735, 1690, 1670, 1610,
1590 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 11.00 (2H, broad s)
7.50 (lH, d, J=2Hz)
7.40 (lH, dd, J=2,8Hz)
7.08 (lH, d, J=8Hz)
4.68 (2H, s)
1.45 (9~, s)
8)(a)Potassium carbonate (49.7 g.) and dimethyl sulfate
(45.4 g.) were added to a solution of 2-hydroxyimino-2-(3-
hydroxyphenyl)acetic acid (a mixture of syn and anti isomers)
(18.1 g.) in dry acetone (250 ml.) and the mixture was refluxed
with stirring for 8.5 hours. After acetone was distilled
off, the residue was dissolved in water and extracted with
ethyl acetate. The extract was washed with a sodium chloride
aqueous solution ànd dried over magnesium sulfa~e. The
sol~ent was distilled off to give oil (24 g.). The oil was
subjected to column chromatography on silica gel using benzene
as developing solvent. ~irstly the eluate containing syn
isomer was eluted and the eluate was collected and concentrated
to give oil of methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate
(syn isomer) (9.2 g.).
E - llO
-163-
1 331522
I.R. spectrum (Film)
1738 cm 1
N.M.R. spectrum (CDC~3, ~)
ppm 7.47 - 6.77 (4H, m)
4.00 (3H, s)
3.92 (3H, s)
3.82 (3H, s)
After the eluate containing syn isomer was eluted,
then the eluate containing anti isomer was eluted. The eluate
was collected and concentrated to give methyl 2-methoxyimino-
2-(3-methoxyphenyl)acetate (anti isomer) (3.9 g.), mp 66 to 68C.
This substance was recrystallized from petroleum ether to give
prisms, mp 65 to 65.5C.
I . R. spectrum (Nujol)
1720 cm~l
N.M.R. spectrum (CDCQ3, ~)
ppm 7.14 - 7.44 tlH, m)
6.80 - 7.04 (3H, m)
4.02 (3H, s)
3.84 (3H, s)
3.76 (3H, s)
(b) Methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate
(syn isomer) (1.6 g.) and a 2N aqueous solution of sodium
hydroxide (4 ml.) were treated according to a similar manner
to that of Preparation 5-3) (c) to give oil of 2-methoxyimino-
2-(3-methoxyphenyl)acetic acid (syn isomer) (1.23 g.).
I.R. spectrum (Film)
1735 cm~l
Methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate
(anti isomer) (1.6 g.) and a 2N aqueous solution of sodium
, . . . , ~
E -111
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1 337522
hydroxide (4 ml.) were treated according to a similar manner to
that of Preparation 5-3)(c) to give colorless prisms of 2-methoxy-
imino-2-(3-methoxyphenyl)acetic acid (anti isomer) (1.3 g.), mp
97 to 98C.
I.R. spectrum (Nujol)
1695 cm~l
9)(a) A solution of diazomethane in ether was added at ambient
temperature to a solution of 2-methoxyimino-2-(3-chloro-4-
hydroxyphenyl)acetic acid (syn isomer) (7 g.) in dry ether (50
ml.) until the color of the mixture was changed to yellow.
Acetic acid ~a~ immediately added thereto and the reaction
mixture was concentrated to dryness at 35C under reduced
pressure. The residue was subjected to column chromatography
cn silica gel (120 g.) using a mixture of benzene and ethyl acetate
lS (9 : 1) as a developing solvent. The first eluate was collected
and concentrated at 40C under reduced pressure to give oil of
methyl 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetate (syn
isomer) (3.1 g.).
I.R. spectrum (Film)
2850, 1735, 1610, 1600, 1250 cm 1
N.M.R. spectrum (CDCQ3, ~)
ppm 7.57 (lH, d, J=2Hz)
7.37 (lH, dd, J=2,8Hz)
6.87 (lH, d, J=8Hz)
3.97 (31i, s)
3.91 (3~, s)
3.88 (3H, s)
(b) Methyl 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)-
acetate (syn isomer) (2.7 g.) and a 2N aqueous solution of
sodium hydroxide (10.6 ml.) were treated according to a simila~
E -112
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1 337522
manner to that of Preparation 5-3) (c) to give crystals of 2-
methoxyimino-2-~3-chloro-4-methoxyphenyl)acetic acid (syn isomer)
(2.6 g.), mp 133 to 135C (dec.).
I.R. spectrum (Nujol)
S 2500-2600, 1745, 1610, 1600 cm 1
N.M.R. spectrum (CDC~3, ~)
ppm 9.95 (1ll, broad s)
7.72 (1~, d, J=2Hz)
7.50 (1~l, dd, J=2,811z)
6.92 (1}l, d, J=8Hz)
4.08 (3~1, s)
3.95 (3~1, s)
lO)(a)A solution of 2-bromopropionyl bromide (25 g.) in dry
chloroform (50 ml.) was dropwise added with stirring and ice-
cooling to a solution of N,N-dimethylaniline (24 g.) in t-butanol
(11 g.) and the mixture was refluxed for 2 hours. After
cooling, the reaction mixture was poured into 6N sulfuric acid
(150 ml.) and extracted with ether. The extract was in turn
washed with 6N sulfuric acid, water, a 10~ potassium carbon1te
aqueous solution and water and dried over magnesium sulfate.
The solvent was distilled off to give oil of t-butyl 2-bromo-
propionate (21 g.).
(b) This oil (21 g.) was added with stirrin~ at ambient
temperature to a mixture of N-hydroxyphthalimide (16.3 g.),
triethylamine (24 g.), dimethylformamide (20 ml.) and dimethyl-
sulfoxide (20 ml.) and the resulting mixture was stirred for
4 hours at ambient tempera~ure. The reaction mixture was
poured into water (800 ml.) and precipitating materials were
collected by filtration, washed with water and dried to give
t-butyl 2-pht}lalimidoxypropiollate (22.7 g.).
E
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1 337522
(c) This compound (22.7 g.) was dissolved in methylene
chloride (200 ml.). A solution of 10~ hydrazine hydrate
(9 ml.) in methanol (20 ml.) was added thereto and the mixture
was stirred for 2 hours at ambient temperature. Precipitating
materials were dissolved by adding 5N aqueous solution of ammonia
and the aqueous layer was extracted with methylene chloride.
Two methylene chloride layers were combined and dried over
magnesium sulfate. The solvent was distilled off under reduced
pressure to give oil of 0~ t-butoxycarbonylethyl)hydroxylamine
(13.5 g.~.
I.R. spectrum (~ilm)
3350, 3250, 1745 cm 1
(d) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.)
and O-(l-t-butoxycarbonylethyl)hydroxylamine (3.2 g.) were
reacted according to a similar manner to that of Preparation
5-7) to give 2-(1-t-butoxycarbonylethoxyimino)-2-(3-chloro-4-
hydroxyphenyl)acetic acid (syn isomer) (3.3 g.), mp i48 to 151C.
I.R. spectrum (Nujol)
3450, 2500-2600, 1725, 1690, 1620, 1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 7.46 (1~-1, d, J=2Hz)
7.33 (lH, dd, J=2,81-lz)
7.07 (lH, d, J=8Hz)
4.67 (lH, q, J=6Hz)
l.S0 (12H, s)
11) Phenolphthalein indicator (3 drops) was added to a
solution o O-methylhydroxylamine hydrochloride (8.8 g.) in dry
methanol (60 ml.). To the solution was dropwise added with
stirring at ambient temperature lN methanol solution of sodium
methoxide (105 ml.) until the color of the solution was changed
-167-
1 337522
to pale pink. O-Methylhydroxylamine hydrochloride was added
thereto by small portions until the solution was changed to
colorless solution. The pH value of the solution was 8.0 to
8.5. The mixture was stirred for 30 minutes at ambient temperature.
S- After precipitating sodium chloride was filtered off, 2-(3-hydroxyphenyl)glyoxylic acid (16.6 g.) was added to the filtrate
and the mixture was stirred for 1 hour at ambient temlperature.
After methanol was distilled off at low temperature,water was added
to the residue. The mixture was adjusted to pH 7 with an
aqueous solution of sodium bicarbonate, washed with ether,
adjusted to pll 1 with 10% hydrochloric acid, subjected to
salting-out and extracted with ether. The extract was washed
with a saturated sodium chloride aqueous solution and dried
over magnesium sulfate. Ether was distilled off and the
operation that benzene was added to the residue and distilled
off was repeated twice to give crystals of 2-methoxyimino-2-(3-
hydroxyphenyl)acetic acid (syn isomer) (14.8 g.). This
compound was identified with the compound obtained in Preparation
5-l)(c) by I.R. spectrum.
12) A solution of 2-(3-methoxyphenyl)glyoxylic acid (1.8
g.) in an aqueous solution of sodium bicarbonate was adjusted
to pH 7Ø On the other hand, a solution of O-ethylhydroxyl-
amine hydrochloride (1.4 g.) in water (20 ml.) was adjusted to
pH 7.0 with sodium bicarbonate. Two solutions were combined
~ 25 together, adjusted to pH 5.5 with 10% hydrochloric acid and
stirred overnight at ambient temperature. The reaction
mixture was adjusted to pH 7.5 with sodiu~n bicarbonate and
washed with ethyl acetate. The aqueous layer was adjusted
to pH 1.0 with conc. hydrochloric acid under ice-cooling and
extracted with ethyl acetate. The extract was washed with
E - 115
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1 337522
ice-water and dried over magnesium sulfate. The sol~ent
was distilled off under reduced pTessure to give oil of 2-
ethoxyimino-2-(3-methoxyphenyl)acetic acid (syn isomer) (2.2 g.).
I.R. spectrum (Film)
2600, 1735, 1700, 1610, 1600 cm~l
13) The following compounds were obtained according to
similar manners to those of Preparation 5-5) to 5^7) and 5-10)
to 5-12).
(1) 2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid
tSYn isomer), oil.
I.R. spectrum (Film)
3450, 2250-2600, 1700-1720, 1610, 1600 cm 1
t2) 2-Ethoxyimino-2-~3-hydroxyphenyl)acetic acid (syn
isomer) oil.
I.R. spectrum (Film)
3400, 2600, 1700-1730, 1605, 1600 cm 1
(3) 2-(3-Hydroxy-4^bromobenzyloxyimino)-2-(4-hydroxyphcnyl)-
acetic acid (syn isomer), colorless powder.
I.R. spectrum (Nujol)
3500, 3200, 1700 cm 1
N.M.R. spectrum (d6-acetone, ~)
ppm 6.68-8.05 (7H, m)
5.15 (2H, s)
(4) 2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyl)acetic
acid (syn isomer), powder.
I.R. spectrum (Nujol)
1705 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 6.7-7.7 (7H, m)
5.2~ (2H, s)
E - 116
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1 337522
(S) 2-Allyloxyimino-2-(3-methoxyphenyl)acetic acid (syn
isomer), oil.
I.R. spectrum (Film)
3050-3100, 2600, 1730, 1645, 1610, 1600 cm~
N.M.R. spectrum (d6DMSO, ~)
ppm 7.00-7.50 (4H, m)
5.80-6.30 (lH, m)
5.33 (2H, t, J=9Hz)
4.70 (2H, d, J=SHz)
3.82 (3H, s)
(6) 2-Allyloxyimino-2-(3-chloro^4-methoxyphenyl)acetic
acid (syn isomer), pale yellow oil.
I.R. spectrum (Film)
3100, 2600, 1710-1730) 1645, 1610, 1600 cm 1
lS N.M.R. spectrum (d6-DMSO, ~)
ppm 7.63 (lH, d, J=2Hz)
7.50 (lH, dd, J=2,8Hz)
7.23 (lH, d, J=8Hz)
5.9-6.3 (lH, m)
5.33 (2H, t, J=9Hz)
4.73 (2H, d, J=5Hz)
3.91 (3H, s)
~7) 2-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)acetic
acid (syn isomer), oil.
I.R. spectrum ( Film )
3300, 1730 cm 1
N.M.R. spectrum (CDCQ3, ~) -
ppm : 6.8 - 7.7 (9H, m)
5.54 (2H, s)
~0
~ -1]7
-170-
1 337522
(8) 2-Methoxyimina-2-(3-mesylaminophenyl) acetic acid (syn
isomer), mp .28C (dec,).
I.R. spectrum (Nujol)
3300, 1740 cm~l
(9) 2-(3-Phenylallyloxyimino)-2-(3-hydroxyphenyl)acetic acid
(syn isomer), mp 115 to 116C.
I.R. spectrum (Nujol)
3400, 1725 cm 1
~10) 2-Methoxyimino-2-(4-dimethylamino-phenyl)acetic acid
(syn isomer), mp 88 to 89C (dec.).
I.R. spectrum (Nujol)
2700 - 2100, 1720, 1660, 1612, 1590 cm~l
14) Acetyl chloride (4.1 g.) was added with stirring and
ice-cooling to a solution of 2-methoxyimino-2-(3-hydroxyphenyl)-
acetic acid (syn isomer) (S g.) in pyridine (20 ml.) and the
mixture was stirred for 50 minutes at ambient temperature.
The reaction mixture was poured into ice-water, adjusted to
pH 2.1 and extracted three times with ether. The extract
was washed with a saturated sodium chloride aqueous solution
and dried over magnesium sulfate. The solvent was thoroughly
removed under reduced pressure to give 2-methoxyimino-2-(3-
acetoxyphenyl)acetic acid (syn isomer) (6.1 g.).
I.R. spectrum (Film)
3500, 2950, 1760, 1735, 1605, 1575, 1485, 1440,
1425, 1370 cm~l
N.M.R. spectrum (CDCQ3, ~)
ppm7.94 (lH, s)
7.6-7.0 (4H, m)
4.05 (3H, s)
2.30 (3H, s)
E- 11
-171-
~ 331522
~S) Trichloroacetyl isocyanate (70 ml) was dropwise added
over 6 minutes at ambient temperature to a solution of 2-
methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (40g)
in dry dioxane (200 ml), and the resulting mixture was stirred
for S hours at ambient temperature. Dioxane was distilled off
and to the residue were added ethyl acetate (200 mlJ and by
small portions water (200 ml) under ice-cooling. The mixture
containing trichloroacetylcarbamoyl 2-methoxyimino-2-(3-
trichloroacetylcarbamoyloxyphenyl)acetate was stirred for 5
hours at ambient temperature keeping the pH value of the
mixture at 6.0 to 6.4 by adding an aqueous solution of sodium
bicarbonate. The resulting mixture was wahsed twice with
ethyl acetate. The aqueous layer was adjusted to pH2 with a
10~ hydrochloric acid and extracted three times with ethyl
acetate. The combined ethyl acetate extracts were washed twice
with an aqueous solution of sodium chloride and dried over
magnesium sulfate. The solvent was distilled off and precipi-
tating crystals were collected by filtration to give colorless
crystals of 2-methoxyimino-2-(3-carbamoyloxyphenyl~acetic acid
(syn isomer) (lSg), mp 163C (dec.). The same compound (5.4g)
was obtained from the mother liquor.
I.R. spectrum (Nu~ol)
3480, 3360, 1730, 1660 cm~
N M.R. spectrum (d6-DMSO, ~)
ppm 3.97 (3H, s), 7.16 (2H, broad s), 7.1 - 7.7 (4H,
m), 9.7 (lH, broad s)
E- 119
-172_
~ 337522
Preparation 6
1) A solution of sodium nitrite (12.4 g.) in water (150
ml.) was dropwise added with stirring at S to 7C to a solution
of ethyl 4-bromoacetoacetate (30 g.) in acetic acid (200 ml.)
and the mixture was stirred for 2 hours at 10C. ~ater
(200 ml.) was added to the reaction mixture and the resultant
mixture was extracted with ether (S00 ml.). The extract
was washed twice with water (200 ml.) and with a sodium chloride
aqueous solution (200 ml.) and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure to give
yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoaceto-
acetate (a mixture of syn and anti isomers) (32.6 g.).
I.R. spectrum (Film)
3350, 1740, 1710, 1620 cm 1
N.M.R. spectrum (CDCQ3, ~)
ppm 8.75 (2H, broad s)
4.35 (8H, m)
1.35 (6H, m~
2) Pulverized potassium carbonate (160 g.) was added to
a solution of ethyl 2-hydroxyiminoacetoacetate (a mixture of
.. . .. ~
E-120
- -173-
1 337522
syn and anti isomers) (152 g.) in acetone (500 ml.). Dimethyl
sulfate (130 g.) was dropwise added thereto with stirring over
1 hour at 45 to 50C and the mixture was stirred for 2 hours.
An insoluble material was filtered off and the filtrate was
S concentrated under reduced pressure. The filtered insoluble
material was dissolved in water (500 ml.) and this solution was
added to the residue. The mixture was extracted twice with
ethyl acetate (300 ml.). The extract was washed twice with
water (200 ml.) and with a saturated sodium chloride aqueous
solution (200 ml.) and dried over magnesium sulfate. The
solvent was distilled off under reduced pressure and the residue
was distilled under reduced pressure to give colorless oil of
ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti
isomers) (145.3 g.), bp 55 to 64C/O.S mm Hg.
I.R. spectrum (Film)
1745, 1695, 1600 cm~
N.M.R. spectrum (CDCQ3, ~)
ppm 4.33 (4H, q, J=811z)
4.08 (3H, s)
3.95 (3H, s)
2.40 (31~, s)
1.63 (3H, s)
1.33 (6H, t, J=8Hz)
3) Bromine (100 g.) was dropwise addcd over 40 minutes
under reflux to a solution of ethyl 2-methoxyiminoacetoacetate
(a mixture of syn and anti isomers) (100 g.) in a mixture of
carbon tetrachloride (300 ml.) and acetic acid (300 ml.). The
mixture was stirred at 70 to 80C until the evolution of
hydrogen bromide ceased. The reaction mixture was washed
twice with water (300 ml.), a sodium bicarbonate aqueous solution
E ~121
-174-
1 337522
and a saturated sodium chloride aqueous solution and dried
over magnesium sulfate. The solution was treated with
activated charcoal (2 g.) and concentrated under reduced pressure
to give ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of
syn and anti isomers) (120.8 g.).
I.R. spectrum (Film)
1740, 1705, 1600 cm 1
N.M.R. spectrum (CDCQ3, ~)
ppm 4.17-4.54 (8H, m)
4.15 (3~, s)
4.13 (31-l, s)
1.33 (6H, t, J=8~-lz)
4) A mixture of selenium dioxide (11.1 g.), dioxane
(250 ml.) and water (5 ml.) was stirred for 15 minutes at 110
to 115C to give yellow solution. Ethyl 2-(2-mesylamino-
1,3-thiazol-4-yl)acetate (26.4 g) was added thereto with
stirring at the same temperature. After stirring for 1 hour,
the reaction mixture was decanted with heating and cooled to
precipitate yellow crystals. The crystals were collected
by filtration, washed with dioxane and ether and dried to give
ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate (23.5 g.).
I.R. spectrum (Nujol)
3300, 1718, 1682 cm 1
S) Ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylatc
(13.9 g.) was added with stirring at ambient temperature to a
solution of sodium hydroxide (5.0 g.) in water (150 ml.). The
mixture was stirred for 1 hour at ambient temperature, adjusted
to pH 7 with conc. hydrochloric acid and washed with ethyl
acetate. The aqueous layer was adjusted to p~l 0.5 with conc.
hydrochloric acid to precipitate yellow crystals. The crystals
E -122
-175-
1 3375~2
were collected by filtration, washed with water and dried to
give 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylic acid (10.16 g.).
I.R. spectrum (Nujol)
3350, 1725, 1650 cm~l
6) To a solution of ethyl 2-(2-amino-1,3-thlazol-4-yl)-
acetate (14 g.) in a mixture of pyridine (40 g.~ and methylene
chloride (300 ml.) was gradually added diethyl ether solution
of t-pentyl chloroformate (70 ml.) containing 0.35 mole o t-
pentyl chloroformate over 10 minutes at -20C Witll stirring, and
the mixture was stirred for 2 hours at the same temperature and
further stirred for 0.5 hour at 0C. ~fter the reaction, the
reaction mixture was poured into water (200 ml.), and then the
organic layer was separated. The organic layer was washed
with 2N hydrochloric acid, water, 5% sodium bicarbonate aqueous
solution and water in turn and then dried over magnesium sulfate.
The sol~ent was distilled off from the organic layer to give
dark brown oil of ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-
4-yl)acetate (12 g.).
I.R. spectrum (liquid)
1667, 1660 tC0) cm 1
N.M.R. spectrum (CDC~3,~)
ppm 3.75 (2H, s)
6.75 ~lH, s)
7) Ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)-
acetate (0.3 g.) and selenium dioxide (0.11 g.) were treated
according to a similar manner to that of Preparation 6-4) to
give brown oil of ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-
4-yl)glyoxylate (0.22 g.).
I.R. spectrum (liquid)
1720, 1690 (C0) cm 1
-176-
1 337522
N.M.R. spectrum (CICQ3,~)
ppm 8.3 (lH, s)
8) Ethyl 2-(2-t-~entyloxy,carbonylamino-1,3-thiazol-4-yl)-
glyoxylate ~2.8 g.) and a solution of sodium~hydroxidc (0.54 g.)
S in water (20 ml.) were treated according to a simiiar manner to
that of Preparation 6-S) to give brown powder of 2-(2-t-pentyloxy-
carbonylamino-1,3-thiazol-4-yl)glyoxylic acid (1.75 g.).
I.R. spectrum (Nujol)
1730, 1680 (C0) cm~l
N.M.R. spectrum (d6-dimethylsulfoxide, ~)
ppm 8.4 (lH, s)
9) A mixture of ethyl 2-hydroxyimino-2-(2-amino-1, 3-
thiazol-4-yl)acetate (a mixture of syn and anti isomers)
(0.37g), ethanol (5 ml), water (5 ml) and sodium bisulfite
",",,,,,,~ lS (0.72 g) was stirred for 12 hours at 65 to 70C. The
reaction mixture was concentrated and water (10 ml) was
added to the residue. The resulting mixture was subjected
to salting-out and extracted with ethyl acetate. The extract
was dried over magnesium sulfate and concentrated to give
yellow crystals of ethyl 2-(2-amino-1,3-thiazol-4-yl)-
glyoxylate (0.18 g), mp 115 to 120C.
I.R. spectrum (Nujol)
3420, 3250, 3120, 1730, 1665, 1612 cm 1
E - 12¢
-177-
1 337522
10) Sulfuryl chloride (235 ml.) was dropwise added over
20 minutes with stirring and ice-cooling to a solution of ethyl
2-methoxyiminoacetoacetate (syn isomer) (500 g.) in acetic acid
(500 ml.), and the mixture was stirred overnight under cooling
with water. Nitrogen gas was introduced to the reaction
mixture for 2 hours, and the resulting mixture was poured into
water (2.5 Q). After extracting with methylene chlGride
(500 ml.) and twice with methylene chloride (200 ml.), the
extracts were combined. The combined extracts were washed
with a saturated aqueous solution of sodium chloride, and
adjusted to pH 6.5 by adding water (800 ml.) and sodium
bicarbonate. Methylene chloride layer was separated, washed
with an aqueous solution of sodium chloride and dried over
magnesium sulfate. The solvent was distilled off to give
ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (559 g.).
I.R. spectrum (Film)
1735, 1705 cm 1
~ - 125
-178-
1 337522
Preparation 7
1) A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate
(a mixture of syn and anti isomers) (22.0 g.), thioacetamide
(7.5 g.) and benzene (100 ml.) was refluxed for 3 hours. After
cooling triethylamine (10 g.) was added thereto and the mixture
was stirred for 1 hour. An insoluble material ~as filtered
off and the filtrate was concentrated under reduced pressure
to give ethyl 2-hydroxyimino-2-(2-methyl-1,3^thiazol-4-yl)acetatc
(a mixture of syn and anti isomers) (8.6 g.). This substance
was subjected to column chromatography on silica gel (80 g.)
using benzene as developing solvent. Firstly the eluate
containing anti isomer was eluted, collected and concentrated
to give ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate
(anti isomer) (2.5 g.), mp 90 to 92C.
I.R. spectrum (Nujol)
1720 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 12.55 (lH, s)
8.25 (lH, s)
E - 126
-179-
1 337522
4.27 (2H, q, J-7Hz)
2.63 (3H, s)
1.25 (3H, t, J-7Hz)
After the eluate containing anti isomer was eluted,
the eluate containing syn isomer was eluted, collected and
concentrated to give ethyl 2-hydroxyimino-2-(2-methyl-1,3-
thiazol-4-yl)acetate (syn isomer) (0.5 g.), mp 134 to 136C.
I.R. spectrum (Nujol)
1720 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 11.81 (lH, s)
7.81 (lH, s)
4.35 (2l~, q, J=7Hz)
2.70 (3H, s)
1.30 (3H, t, J-7Hz)
2) Phenolphthalein indicator (3 drops) was added to a
solution of hydroxylamine hydrochloride (4.2 g.) in dry methanol
(60 ml.). To the solution was dropwise added with stirring
at ambient temperature lN methanol solution of sodium methoxide
(60 ml.) until the color of the solution was changed to
purplish red. Hydroxylamine hydrochloride was added thereto
by small portions until the solution was changed to colorless
solution. The mixture was stirred for 30 minutes at ambient
temperature. After precipitating sodium chloride was filtered
off, 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylic acid (12.5 g.)
was added to the filtrate and the mixture was refluxed with
stirring for l S hours. The reaction mixture was cooled to
precipitate crystals. The crystals were collected by filtration
and dried to give crude 2-hydroxyimino-2-(2-mesylamino-1,3-
thiazol-4-yl)acetic acid (a mixture of syn and anti isomers)
E -127
-180-
1 337522
(5.5 g.). The filtrate was concentrated to the volume of
1/4 and ether was added thereto. Precipitating crystals
were collected by filtration, washed with ether and dried to
give the same compound (8.78 g.). Total yield (14.3 g.).
3) A mixture of ethyl 2-hydroxyimino-4-~romoacetoac~ta~e
(a mixture of syn and anti isomers) (2.4g) and thiourea
(0.76 g) in ethanol (lS ml) was stirred for 1 hour at 60C.
Ethanol was distilled off under reduced pressure and ~ater
was added to the residue. The resultant mixture was
adjusted to pH 1.0 and washed with ethyl acetate. The
aqueous layer was adjusted to pH 4.5 with triethylamine and
extracted with ethyl acetate. The extract was washed with
water and a saturated sodium chloride aqueous solution and
dried over magnesium sulfate. The solvent was distilled
off under reduced pressure and the residue was subjected-to
column chromatography on silica gel using a mixture of ethyl
acetate and benzene (1:3) as developing solvent. Tl~e eluates
containing syn isomer were collected and conce~trated to give
ethyl 2-hydroxyimino-2-(2-amino-1, 3-thiazol-4-yl)acetate
tSYn isomer) (0 3 g)
I.R. spectrum (Nujol)
3450, 3300, 3200, 1725, 1620 cm~
N.M.R. spectrur.l (CDCQ3, ~)
ppm : 7.65 (lH, s)
5.33 (2H, broad s)
4.40 (2H, q, J-7.5Hz)
1.38 (3H, t, J=7.5~z)
After the eluates containing syn isomerswere collected, the
eluates containing a mixture of syn and anti isomers were
collected and concentrated to give ethyl 2-hydroxyimino-2-
E -12
-181-
- 1 337522
(2-amino-1,3-thiazol-4-yl)acetate (a mixture of syn and
anti isomers) (0.3 g.).
I.R. spectrum ~Nujol)
3400, 3300, 3200, 1715, 162~0 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm : 12.42 (lH, broad s)
11.55 tlH, s)
7.52 (1~, s)
7.12 (4H, broad s)
6.83 (1ll, s)
4.23 (4H, m)
1.26 (6H, m)
4) A solution of ethyl 2-hydroxyimino-2-(2-amino-1,3-
thiazol-4-yl)acetate (a mixture of syn and anti isomers)
(1.1 g) in an lN aqueous solution of sodium hydroxide (15
ml) was allowed to stand for 2 hours at ambient temperature.
The reaction mixture was adjusted to pH 3.5 with 10%
hydrochloric acid and precipitating crystals were collected
by filtration, washed with acetone and dried to give 2-
hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (a
mixture of syn and anti isomers) (0.52 g), mp lS4 to 186C
(dec.).
I.R. spectrum (Nujol)
3200, 1670, 1530 cm~
E -129
-182_
1 33752~
Preparation 8
l) Thioacetamide (3.8 g.) was added to a solution of
ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and
anti isomers) (12.6 g.) in ethanol (S0 ml.) and the mixture
was stirred for S hours at 50C. Ethanol was distilled off
under reduced pressure and water was added to the residue.
The resulting mixture was extracted with ethyl acetate. The
extract was in turn washed with water, a sodium bicarbonate
aqueous solution and a saturated sodium chloride aqueous solution
and dried over magnesium sulfate. The solvent was distilled
off under reduced pressure to give ethyl 2-methoxyimino-2-(2-
methyl-1,3-thiazol-4-yl)acetate (a mixture of syn and anti
isomers) (9.0 g.~.
2) A mixture of ethyl 2-methoxyimino-4-bromoacetoacetate
(a mixture of syn and anti isomers) (7.6 g.), O-ethyl thio-
carbamate (3.0 g.) and dimethylacetamide (5 ml.) was stirred for
3 hours at 50C. Ethyl acetate (50 ml.) was added to the
reaction mixture and the resulting mixture was washed with
water and with a satura~ed sodium chloride aqueous solution and
dried over magnesium sulfate. Ethyl acetate was distilled
off to give crystalline residue. The residue was washed with
diisopropyl ether to give ethyl 2-methoxyimino-2-(2-oxo-2,3-
dihydro-1,3-thlazol-4-yl)acetate (syn isomer) (2.35 g.).
I.R. spectrum (Nujol)
3200, 1735, 1680, 1650 cm 1
3o
E - 130
-183-
1 337522
N.M.R. spectrum (CDCe3, ~)
ppm 9.13 (lH, broad s)
6.37 (lH, s)
4.40 (2H, q, J=6Hz)
4.01 (3H, s)
1.38 (3H, t, J=6Hz)
The mother liquor of diisopropyl ether was
concentrated and the residue was subjected to column
chromatography on silica gel (70 g.) using a mixture of
benzene and ethyl acetate (9 : 1) as developing
solvent. The eluate containing syn isomer was
collected and concentrated to further give the above
obtained syn isomer (0.65 g.). Total yield (3.0 g.).
Thereafter a mixture of benzene and ethyl acetate (5:1)
was used as developing solvent. The eluate containing
anti isomer was collected and concentrated to give
ethyl 2-methoxyimino-2-(2-oxo-2,3-dihydro-1, 3-thiazol-
4-yl)acetate (anti isomer) (0.26 g.).
I.R. spectrum (Nujol)
3250, 3200, 1720, 1690 cm~
N.M.R. spectrum (CDCe3, ~)
ppm 9.90 (lH, broad s)
7.30 (lH, s)
4.40 (2H, q, J=6Hz)
4.03 (3H, s)
1.38 (3H, t, J=6Hz)
3~ A solution of ethyl 2-methoxyimino-4-
bromoacetoacetate (a mixture of syn and anti isomers)
(17.4 g.) and thiourea (5.4 g.) in ethanol (100 ml.)
was refluxed for 4 hours. The reaction mixture was
allowed to stand and cooled in refrigerator to
precipitate crystals. The crystals were collected by
filtration, washed with ethanol and dried to give ethyl
2-methoxyimino-2-(2
~7,
- 184 -
1 337522
amino-1,3-thiazol-4-yl)acetate hydrobromide (anti isomer) (9.5
g ). The filtrate and the washings were put together and
concentrated under reduced pressure. Water (lO0 ml.) was
added to the residue and the mixture was washed with ether.
The aqueous layer was alkalized with a 28% a~ueous solution of
ammonia and extracted with ethyl acetate. The extract was
washed with water and a saturated sodium chloride aqueous
solution and dried over magnesium sulfate. The solvent was
distilled off under reduced pressure to give crystalline substance
of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate
(syn isomer) (5.2 g.).
I.R. spectrum (Nujol)
3400, 3300, 3150, 1725, 1630, 1559 cm 1
N.M.R. spectrum (CDC~3, ~)
ppm 6.72 (1l~, s)
5.91 (2H, broad s)
4.38 (2H, q, J:7Hz)
4.03 (3H, s)
1.38 (3H, t, J-7Hz)
The above obtained ethyl 2-methoxyimino-2-(2-amino-1,3-
thiazol-4-yl)dcetate hydrobromide (anti isomer) (9.5 g.) was
suspended in ethyl acetate (200 ml.) and triethylamine (4.0 g.)
was added thereto. After stirring for 1 hour at ambient
temperature, an insoluble material waS filtered off and the
filtrate was concentrated under reduced pressure to give crystal-
line substance of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-
4-yl)acetate (anti isomer) (6.15 g.).
I.R. spectrum (Nujol)
3450, 3250, 3150, 1730, 1620 cm 1
E ~ 132
-185-
1 337522
N.M.R. spectrum (CDCQ3. ~)
ppm 7.50 (1'1~, s)
5.60 (2~l, broad s)
4.35 (2H, q, J=7Hz)
4.08 (3~-l, s)
1.33 (3H, t, J-7Hz)
4) Phenolphthalein indicator (3 drops) was added to a
solution of 0-methyl-hydroxylamine hydrochloride (-.25 g.) in
dry methanol (15 ml.). To the solution was dropwise added
with stirring at ambient temperature lN methanol solution of
sodium methoxide (13 ml.) until the color of the solution was
changed to purplish red. 0-Methylhydroxylamine hydrochloride
was added thereto by small portions until the solution was
changed to colorless solution. The mixture was stirred
for 30 minutes at ambient temperature. After precipitating
sodium chloride was filtered off, ethyl 2-(2-mesylamino-1,3-
thiazol-4-yl)glyoxylate (3.8 g.) was added to the filtrate and
the mixture was refluxed with stirring for 2 hours. After
methanol was distilled off, the residue was dissolved in ethyl
acetate. An insoluble material was filtered off and the
filtrate was concentrated. The residue was subjected to
column chromatography on silica gel using a mixture of benzene
and ethyl acetate (9:1) as developing solvent. The eluate
containing syn isomer was collected and concentrated to give
ethyl 2-methoxyimino-2-t2-mesylamino-1,3-thiazol-4-yl)acetate
(syn isomer) (2.8 g.).
I.R. spectrum (Nujol)
1725 cm
N.M.R. spectrum (CDCQ3,~)
ppm 6.76 (1~l, s)
E - 133
-186-
1 337522
4.44 (2H, q, J 7Hz)
4.04 (311, s)
3.04 (3H, s)
1.37 (3H, t, J-7Hz)
. ~ . .
5) Pulverized potassium carbonate (0.33 g.) was suspended
in a solution of ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-
4-yl)acetate (syn isomer) (0.5 g.) in acetone (20 ml-.).
A solution of dimethyl sulfate (0.3 g.) in acetone (5 ml.) was
dropwise added thereto with stirring at 40 to 45C. After
stirring for 2 hours at the same temperature, an insoluble
material was filtered off. The filtrate was concentrated
and water was added to the residue. The resulting mixture
was extracted with ethyl acetate. The extract was in turn
washed with water, a sodium bicarbonate aqueous solution and a
lS saturated sodium chloride aqueous solution and dried over
magnesium sulfate. The solvent was distilled off under
reduced pressure to give pale yellow oil of ethyl 2-methoxyimino-
2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer) (0.5 g.).
I.R. spectrum (Film)
1740, 1710, 1595 cm 1
N.M.R. spectrum (CDCQ3, ~)
ppm 7.40 (lH, s)
4.25 (2H, q, J~7Hz)
4 03 (3H, s)
2.73 (3~i, s)
1.38 (3H, t, J~7Hz)
6) 2-Hydroxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)-
acetic acid (a mixture of syn and anti isomeTs) (14.3 g.) obtained
in Preparation 7-2) was suspended in dry acetone (300 ml.).
To the suspension were added potassium carbonate (22.8 g.) and
E -1~4
-187-
1 337522
dimethyl sulfate (20.8 g.). The mixture was refluxed with
stirring for 9 hours. Acetone was distilled off rom the
reaction mixture and water was added to the residue. The
resulting mixture was extracted with ethyl acetate. The
extract was washed with a sodium chloride aqueous soiution
and dried over magnesium sulfate. The solvent was distilled
off to give oil (13 g.). The oil was subjected to column
chromatography on silica gel using a mixture of benzene and
ethyl acetate (9:1) as developing solvent. Firstly the
eluate containing anti isomer was eluted, collected and
concentrated. The residual oil (2.4 g.) was triturated under
cooling to crystallize. The crystals were collected by
filtration by adding petroleum ether to give methyl 2-methoxy-
imino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)-
acetate (anti isomer) (2.1 g.).
~ . . .
I.R. spectrum (Nujol)
1740 cm~l
N.M.R. spectrum (CDCQ3, ~)
ppm 7.90 (lH, s)
4.10 (3H, s)
3.90 (3H, s)
3.47 (3H, s)
3.07 (3H, s)
After the eluate containing anti isomer was eluted,
the eluate containing syn isomer was eluted, collected and
concentrated to give crystals of methyl 2-methoxyimino-2-(2-
- mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetate (syn
isomer) (5.5 g.).
I.R. spectrum (Nujol)
1740 cm 1
E -1~5
-188-
1 337522
N.M.R. spectrum (CDC~3, ~)
ppm 6.72 (1ll, s)
4.05 (3H, s)
3.92 (3H, s)
3.72 (3H, s)
3.01 (3H, s)
7) The following compound was obtained according to a
similar manner to that of Preparation 8-4).
Ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate
(syn isomer).
I.R. spectrum (Nujol)
3400, 3300, 3150, 1725, 1630, 1559 cm 1
N.M.R. spectrum (CDCQ3, ~)
ppm : 6.72 (lH, s)
5.91 (2~l, broad s)
4.38 (2H, q, J-7Hz)
4.03 (3H, s)
1.38 (3H, t, J-7Hz)
8 ) A mixture of acetic anhydride (6.1g) and formic acid (2 8g)
was stirred for 2 hours at 50C. The resulting mixture was
cooled and ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)-
acetate (syn isomer) (4.6g) was added thereto at 15C. After
the mixture was stirred for 3.5 hours at ambient temperature,
cooled water (100 ml) was added thereto. The resulting mixture
was extracted with ethyl acetate (200 ml). The extract was
washed with water and then with a saturated aqueous solution
of sodium bicarbonate until the washing was changed to weakly
alkaline solution. The extract was further washed with a satu-
rated aqueous solution of sodium chloride and dried over
magnesium sulfate. The solvent was distilled off and the
E- 136
-189-
1 337522
residue was washed with diisopropyl ether, collected by
filtration and dried to gi~e ethyl 2-methoxyimino-2-(Z-fornlamido-
1,3-thiazol-4-yl)acetate (syn isomer) (4.22g), mp 122 to 124~C
(dec.).
I.R. spectrum (Nujol)
3150, 1728, 1700 cm 1
N.M.R. spectrum (CDC13, ~)
ppm 12.58 (lH, broad s), 8.95(1H, s), 7.i7 (lH, s),
4.42 (2H, q, J=8Hz), 4.00 (3H, s), 1.3~ (3H, t,
JC8Hz)
9) Pyridine (3g.) was added to a solution of ethyl 2-
methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer)
(6.5 g.) in a mixture of ethyl acetate (60 ml.) and dimethylfor~m-
amide (20 ml.). To the solution was dropwise added with
stirring at 4C ethyl chloroformate (8 g.). After ad~ing
water (50 ml.) to the reaction mixture, the organic layer wasseparated, washed with water and then with a saturated aqueous
solution of sodium chloride and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure. The
residue was subjected to column chromatography on silica gel
(120 g.) using a mixture of ether and petroleum ether (5:2) as ~--
an eluent to give ethyl 2-methoxyimino-2-(2-ethoxycarbonylamino-
1,3-thiazol-4-yl)acetate (syn isomer) (5.4 g.).
N.M.R. spectrum (CDCQ3, ~)
ppm 9.36 (lH, broad s)
7.10 (lH, s)
4.00-4.66 (4H, m)
4.00 (3H, s)
1.20-1.60 (6H, m)
~-137
--190--
;~ 1 337522
10) Ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer)
(50 g.) was added over 3 minutes with stirring at ambient temper-
ature to a solution of thiourea (18.4 g.) and sodium acetate
(19.8 g.) in a mixture of methanol (250 ml.) and water ~Z50 ml.).
After stirring for 35 minutes at 40 to 45C, the reaction mixture
was cooled with ice and adjusted to pH 6.3 with a saturated
aqueous solution of sodium bicarbonate. After stirring for
30 minutes at the same temperature, precipitates were collected
by filtration, washed with water (200 ml.) and then with
diisopropyl ether (100 ml.), and dried to give colorless crystals
of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate
(syn isomer) (37.8 g.), mp 161 to 162C.
I.R. spectrum (Nujol)
3400, 3300, 3150, 1725, 1630, 1559 cm~
; N.~l.R. spectrum (CDC~3, ~)
ppm 6.72 (lH, s)
5.91 (2H, broad s)
4.38 (2H, q, J=7Hz)
4.03 (3H, s)
1.38 (3H, t, J=7Hz)
E - 138
--191--
37~22
11) Ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)-
acetate (anti isomer) (0.3 g.) and dimethyl sulfate (G.18 g.)
were reacted according to a similar manner to that of Preparation
8-5) to give pale yellow oil of ethyl 2-methoxyimino-2-(2-methyl-
1,3-thiazol-4-yl)acetate (anti isomer) (0.27 g.).
I.R. spectrum (Film)
1750, 1605 cm 1
N.M.R. spectrum (CDCQ3, ~)
ppm 8.07 (lH, s)
4.41 (2H, q, J~7Hz)
4.13 (3~, s)
2.75 (3H, s)
1.40 (3H, t, J~7Hz)
12~ The following compound was obtained according to a similar
manner to that of Preparation 8-8).
ethyl 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetate
(anti isomer), mp 96 to 99C (dec.).
I.R. spectrum (Nujol)
3150, 1740, 1650, 1600 cm~
N.M.R. spectrum (CDC13, ~)
ppm 11.20 (lH, broad s), 8.60 (lH, s), 7.90 (lH, s),
4.32 (2H, q, J=8Hz), 4.13 (3H, s), 1.32 (3H, t,
J-8Hz)
~0
E - 139
-192-
-- 1 337522
Preparation 9
1) Ethanol (10 ml.) was added to a suspension of ethyl
2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer)
t2.2 g.) in a lN aqueous solution of sodium ~ydroxide (12 ml.)
and the mixture was stirred for 15 hours at ambient temperature.
The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric
acid and ethanol was distilled off under reduced pressure. The
residual aqueous solution was washed with ethyl acetate, adjusted
to pH 2.8 with 10~ hydrochloric acid and stirred under ice-cooling
LO to precipitate crystals. The crystals were collected by
filtration, washed with acetone and recrystallized from ethanol to
give colorless needles of 2-methoxyimino-2-(2-amino-1,3-
thiazol-4-yl)acetic acid (syn isomer) (1.1 g.).
I.R. spectrum (Nujol)
3150, 1670, 1610, 1585 cm~
N.M.R. spectrum (d6-D~ISO, ~)
ppm 7.20 (211, broad s)
6.85 (lH, s)
3.83 (3H, s)
2) lN-Aqueous solution of sodium hydroxide (1.5 ml.) was
added to a solution of ethyl 2-methoxyimino-2-(2-methyl-1,3-
thiazol-4-yl)acetate (syn isomer) (0.3 g.) in ethanol (5 ml.)
and the resulting mixture was stirred for 2 hours at 40C.
The reaction mixture was adjusted to pH 7.0 with 10~ hydrochloric
acid, concentrated under reduced pressure, adjusted to pH l.S
with 10% hydrochloric acid and extracted with ethyl acetate.
The extract was washed with water and a saturated sodium chloride
E-140
-193-
-- 1 337522
aqueous solution and dried over magnesium sulfate. The
solvent was distilled off to give crystalline substance of
2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid (syn
isomer) (0.14 g.).
I.R. spectrum (Nujol)
1730 cm~l -
N.M.R. spectrum (d6-DMSO, ~)
- ppm 7.80 (lH, s)
3.85 (3H, s)
2.62 (3H, s)
3 ) The following compounds wcre obtained according to
similar manners to those of Preparation 9-1) to 9~).
(1) 2-Methoxyimino-2-(Z-oxo-2,3-dihydro-1,3-thiazol-4-yl)-
acetic acid (syn isomer).
I.R. spectrum (Nujol)
3250, 1710, 1650 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 10.61 (lH, broad s)
6.73 (lH, s)
0 3.95 (3H, s)
(2) 2-Methoxyimino-Z-(2-mesylamino-1,3-thiazol-4-yl)-
acetic acid (syn isomer).
I.R. spectrum (Nujol)
3150, 1720 cm~l
?5 N.M.R. spectrum (d6-DMSO, ~)
ppm 7.17 (lH, s)
3.93 (3H, s)
3,02 (3H, s)
(3) 2-Methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-
1,3-thiazol-4-yl)acetic acid (syn isomer).
I.R. Spectrum (Nujol)
1730 cm~l
E- 141
-194-
1 337522
(4) 2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)aceti.c
acid (syn isomer), mp 152C (dec.).
I.R. spect~um (Nujol)
3200, 2800 - 2100, 1950, 1600 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 8.60 (lH, s)
7.62 (lH, s)
3.98 (lH, s)
(5~ 2-Methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazol-4-yl)acetic
aoid (syn isomer).
I. R. s~ectrum (Nujol)
3200, 1730, 1710, 1690, 15iO cm~
N. M. R. spectrum (d6-DMSO, ~)
ppm 12.16 (lH, broad s)
7.50 (lH, g)
7.20 (lH, broad s)
4.25 (2E, q, J=7Hz)
3.93 (3H, s)
1.25 (3H, t, J=7Hz)
, ~0
E- 142
-195-
1 337522
4 ) Pyridine (5 ml.) was added to a suspension of 2-
methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer)
(2.0 g.) in ethyl acetate (20 ml.). A solution o~ bis(2,2,2-
trifluoroacetic)anhydride (2.5 g.) in ethyl acetate (3 ml.) was
dropwise added thereto with stirring at 5 to 7C and the mixture
was stirred for 30 minutes at 3 to 5C. Water (30 ml.) was
added to the reaction mixture and the ethyl acetate layer was
separated. The aqueous layer was further extracted with
ethyl acetate and two ethyl acetate layers were combined toge~her,
washed with-water and a saturated sodium chloride aqueous solution
and dried over magnesium sulfate. The solvent was distilled
off under reduced pressure to give 2-methoxyimino-2-[2-(2,2,2-
trifluoroacetamido)-1,3-thiazol-4-yl]acetic acid (syn isomer)
(0.72 g.).
I.R. spectrum (Nùjol)
1725, 1590 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 7.68 (lH, s)
3.91 (3H,s)
5 ) The following compound was obtained according to a similar
manner to that of Preparation 9 - 4).
2-Methoxyimino-2-(2-acetamido-1,3-thiazol-4-yl)acetic acid
(syn isomer), mp 184 to 185C (dec.).
I.R. spectrum (Nujol)
3200, 3050, 1695, 1600 cm 1
6) Phenolphthalein indicator (3 drops) was added tO a
solution of O-allyl-hydroxylamine hydrochloride (0.84 g.) in
dry methanol (10 ml.). To the solution was dropwise added
with stirring at ambient temperature lN methanol solution of
~O sodium methoxide (6 ml.) until the color of the solution was
E-143
-196-
- ~ 337522
.,
. "
changed to pale pink. O-Allylhydroxylamine hydrochloride was
added thereto by small portions until the solution was changed
to colorless solution. The mixture was stirred for 30
minutes at ambient temperature. After precipitating sodium
chloride was filtered off, 2-(2-t-pentyloxycarbonylamino-1,3-
thiazol-4-yl)glyoxylic acid (2.0 g.) was added to the filtrate
and the mixture was stirred for 1 hour at ambient temperature.
After methanol was distilled off at low temperature, the residue
was dissolved in an lN aqueous solution of sodium hydroxide.
LO The solution was washed with ether and ethyl acetate was added
thereto. The mixture was adjusted to pH 1.5 with phosphoric
acid and extracted with ethyl acetate. The extract was washed
with a sodium chloride aqueous solution and dried over magnesium
sulfate. Ethyl acetate was distilled off and the residue was
washed with diisopropyl ether, collected by filtration and dried
to give 2-allyloxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-
4-yl)acetic acid (syn isome~) (1.62 g.).
I.R. spectrum (Nujol)
3200, 1712 cm 1
N.M.R. spectrum (d6-DMSO, ~)
ppm 7.40 (lH, s)
6.24-5.76 (lH, m)
5.26 (2H,dd, J=9, lO~z)
4.65 (2H, d, J=5Hz)
1.78 (2H, q, J=8Hz)
1.44 (6H, s)
0.88 (3H, t, J=8Hz)
7) The following compounds were obtained according to a
similar manner to that of Preparation 9-6).
(1) 2-Methoxyimino-2-(2-t-pentyloxycarbony'amino-1,3-
E- 144
-197-
~ ~` . 1 337522
,,
thiazol-4-yl)acetic acid (syn isomer).
I.R. spectrum (Nujol)
3200, 1712 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 7.40 (lH, s)
3.88 (3H, s)
1.77 (2H, q, J~8Hz)
1.44 (6~1, s)
0.88 (3H, t, J~8Hz)
O (2) 2-Allyloxyimino-2-(2-mesylamino^1,3-thiazol-4-yl)-
acetic acid (syn isomer).
I.R. spectrum (Nujol)
3150, 1710, 1605 cm 1
(~) 2-Met~loxyimino-2-(2-amino-~,~-thiazol-4-yl)acetic
acid (syn iso~er).
I.R. ~pectrum (Nujol)
3150, 1670, 1610, 1585 cm 1
N.M.R. spectrum (d6-DMSO,~ )
ppm 7.20 (2H, broad 5 )
6.85 (lH, s)
~.83 (3H, s)
8) Ethyl 2-methoxyimino^2-(2-amino-1,3-thiazol-4-yl)acetate
hydrobromide (anti isomer) (15.5 g.) was dissolved in a solution
of sodium hydroxide (4.4 g.) in water (150 ml.) and the resulting
solution was stirred for 1 hour at ambient temperature. An
insoluble material was filtered off and the filtrate was adjusted
to pH 5.0 to precipitate crystals. The crystals were collected
by filtration and dried to give 2-methoxyimino-2-(2-amino-1,3-
thiazol-4-yl)acetic acid (anti isomer) (8.0 g.).
I.R. spectrum (Nujol)
~ 145
i
-198-
1 3 3 7 5 2 2
3150, 1655, 1595, 1550 cm~
N.M.R. spectrum (d6-DMSO, ~)
ppm 7.53 (lH, s)
7.23 (2H, broad s)
3.99 (3~, s)
~) The ollowing compounds were obtained according to similar
manner to that of Preparation 9-8).
(1) 2-Methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic
acid (anti isomer)
I.R. spectrum (Nujol)
1730, 1590 cm~l
N.M.R. spectrum (d6-DMSO, ~)
ppm 8.10 (1l~, s)
4.00 (3H, s)
2.65 (3H, s)
) 2-Methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-
1,3-thiazol-4-yl)acetic acid (anti isomer).
I.R. spectrum (Nujol)
1730 cm 1
~) 2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid
tanti isomer), mp 156 to 158C (dec.).
I.R. spectrum (Nujol)
3200, 2700 - 2100, 1690, 1590, 1560 cm~
N,M.R. spectrum (d6-DM~O,~)
ppm8.05 (IH, s)
4.02 (3H, 8)
~0
E-146
-199-
~.. ~7. .
t ~- 1 337522 The expression "such as" employed in the specification
means "for example" and is not intended to be construed as limit-
ing the values which it qualifies.
-~6~
;:
1 337522
SUPPLEME~T~RY DISCLOSURE
This disclosure and the Principal Disclosure are
concerned with new syn-isomers of 3,7-disubstituted-3-cephem-
4-carboxylic acid compounds and pharmaceutically acceptable
salts thereof.
In addition this disclosure is particularly con-
cerned with compounds of formula (I), as defined in the
Principal Disclosure, in which the aliphatic hydrocarbon
group R is a cyclic aliphatic hydrocarbon, particularly
a cyclo(lower) alkyl group, more particularly a cyclo(lower)-
alkyl group of 3 to 6 carbon atoms, including cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and the like;
especially preferred are cyclo(lower)alkyl groups of 5 to
6 carbon atoms.
Compounds of formula (I) in which R2 is a cyclic
aliphatic hydrocarbon group can be prepared in accordance
with any of processes l to 8 described in the Principal
Disclosure.
The invention is further illustrated by reference
to the following Examples, illustrating the invention in
particular and preferred embodiments, it will be evident
that variation of the Examples, such as in the starting
materials, in accordance with the invention will result
in the production of different compounds (I), of the
invention .
- 201 -
1 337522
PreParation of the Startinq ComPounds
Preparation S.D. 1
(1) 1-Allyl-lH-tetrazole-5-thiol (21.3 g) was added
at 76 to 78C to a solution of sodium bicarbonate
(10.6 g) in water (220 ml). Sodium 7-(5-amino-5-
carboxyvaleramido)cephalosporanate (54.9 g) was
added thereto over 15 minutes and the mixture was
stirred for 80 minutes at 76 to 78C. The reaction
mixture was adjusted to pH 3.0 with 6N hydrochloric
acid under ice-cooling and filtered. The filtrate
was subjected to column chromatography on non-ionic
adsorption resin "Diaion HP-20" (Trademark:
prepared by Mitsubishi Chemical Industries Ltd.)
and eluted with 30% aqueous solution of isopropyl
alcohol. The eluate was adjusted to pH 6.5 with
28% aqueous solution of ammonia, concentrated and
lyo,Philized to give ammonium 7-(5-amino-5-carboxy-
valeramido)-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylate (21.7 g).
I.R. (Nujol) : 3175, 1760, 1590 cm~l
N.M.R. (d6-DMSO, ~) : 1.23-2.42 (6H, m),
3.12 - 3.97 (3H, m), 4.37 (2H, broad
s), 4.80-5.15 (3H, m), 5.15-5.51
(2H, m), 5.51-6.25 (2H, m), 8.77
(lH, d, J=8Hz)
(2) N,N-Dimethylaniline (18.2 ml) was added to a
mixture of ammonium 7-(5-amino-5-carboxyvaler-
amido)-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylate (10.0 g), trimethylsilyl
chloride (20.9 ml) and methylene chloride (75 ml),
and the mixture was stirred under reflux for 2.5
hours. Phosphorus pentachloride (5.83 g) was added
thereto at -30 to -35C and the mixture was stirred
for 2 hours at the same temperature. 2-Ethoxy-
ethanol (38 ml) was added dropwise thereto at the
same temperature and the mixture was stirred for 1
- 202 -
1 337522
_
hour at the same temperature. Water (80 ml) was
added thereto at -5 to -10C over 10 minutes and
the resulting mixture was stirred for 5 minutes at
the same temperature. The aqueous layer was
separated and adjusted to pH 4.2 with 28% aqueous
solution of ammonia. Precipitates were collected
by filtration, washed with 70% aqueous acetone (40
ml) and methanol (40 ml), and dried to give 7-
amino-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (4.1 g).
I.R. (Nujol) : 3150, 1800, 1610, 1530 cm~l
N.M.R. (d6-DMSO, ~) : 3.65 (2H, ABq, J=18Hz),
4.33 (2H, ABq, J=13Hz), 6.38-4.70
(7H, m)
- 203 -
1 337522
PreParation S.D. 2
(1) Ethyl 2-hydroxyimino-2-(2-aminothiazol-4-
yl)acetate (syn isomer) (126.4 g), formic acid
(81:3 g) and acetic anhydride (180 g) were treated
in a similar manner to that of Preparation 9-4) to
give ethyl 2-hydroxyimino-2-(2-formamidothiazol-4-
yl)acetate (syn isomer) (109.6 g).
`- V,`
~ ; - 204 -
1 337522
I.R. (Nujol) : 3320, 3140, 3050, 1710,
1555 cm~l
N.M.R. (d6-DMSO, ~) : 1.30 (3H, t, J=7Hz,
4.33 (2H,q, J=7Hz), 7.54 (lH, s),
8.54 (lH, s), 11.98 (lH, s), 12.58
(lH, s)
(2) A mixture of chloromethylthiomethane (7.97 g),
powdered potassium iodide (15.1 g) and acetone (79
ml) was stirred at ambient temperature for an hour,
the resulting mixture was filtered and wa~hed with
a small amount of acetone. The washings and the
filtrate were combined and added to a stirred
suspension of ethyl 2-hydroxyimino-2-(2-
formamidothiazol-4-yl) acetate (syn isomer) (17.5
g) and powdered potassium carbonate (15.5 g) in
acetone (300 ml). The mixture was stirred at
ambient temperature for 3 hours, filtered and
washed with acetone. The washings and the filtrate
were combined and concentrated in vacuo. The
residue was dissolved in ethyl acetate, washed with
a saturated aqueous solution of sodium chloride
twice, dried over magnesium sulfate and
concentrated in vacuo. The oily residue was
subjected to column chromatography on silica gel
and eluted with chloroform to give ethyl 2-
methylthiomethoxyimino-2-(2-formamidothiazol-4-
yl)acetate (syn isomer) (2.4 g), mp. 130 to 131C.
I.R. (Nujol) : 3160, 3125, 3050, 1740,
1695 cm~l
N.M.R. (d6-DMSO, ~) : 1.32 (3H, t, J=7Hz),
2.22 (3H, s), 4.38 (2H, q, J=7Hz),
5.33 (2H, s), 7.67 (lH, s), 8.56
(lH, s)
.,~
. - 205 -
1 337522
(3) A mixture of ethyl 2-methylthiomethoxyimino-2-(2-
formamidothiazol-4-yl)acetate (syn isomer) (2.4 g),
lN aqueous sodium hydroxide (23.8 ml) and methanol
(19.8 ml) was stirred at 30C for 2.5 hours. The
resultant solution was adjusted to pH 7 with 10%
hydrochloric acid and methanol was distilled off in
vacuo. The aqueous solution was adjusted to pH 1,
with 10% hydrochloric acid under ice cooling, and
extracted with ethyl acetate three times. The
extracts were washed with a saturated aqueous
solution of sodium chloride, dried over magnesium
sulfate and concentrated in vacuo to give 2-
methylthiomethoxyimino-2-(2-formamidothiazol-4-
yl)acetic acid (syn isomer) (1 13 g), mp. 157C
(dec.).
I.R. (Nujol) : 3210, 3160, 3075, 1700,
1555 cm~l
N.M.R. (d6-DMSO, ~) : 2.24 (3H, s), 5.31
(2H, s), 7.61 (lH, s), 8.57 (lH, s),
12.73 (lH, s)
Preparation S.D. 3
The following compounds were obtained according
to similar manners to those of the foregoing Prepara-
tions.
(1) 2-Isopropoxyimino-2-(2-formamidothiazo~-4-yl)-
acetic acid (syn isomer), mp. 168 to 169C (dec.).
I.R. (Nujol) : 3200, 3130, 1710, 1600,
1560 cm~
(2) 2-Butoxyimino-2-(2-formamidothiazol-4-yl)acetic
acid (syn isomer).
I.R. (Nujol) : 3350, 3160, 3050, 1700, 1680,
1570 cm~
- 206 -
- 1 337522
(3) 2-Hexyloxyimino-2-(2-formamidothiazol-4-yl)
acetic acid (syn isomer), mp. 115 to 116C (dec.).
I.R. (Nujol) : 3170, 3070, 1720, 1700,
1660 cm~l
N.M.R. (d6-DMSO, ~) : 0.6-2.1 (llH, m), 4.15
(2H, t, J=6Hz), 7.53 (lH, s), 8.56
(lH, s), 12.69 (lH, s)
(4) 2-(2-Formyloxyethoxy)imino-2-(2-formamidothiazol-
4-yl)acetic acid (syn isomer).
I.R. (Nujol) : 3200, 1710, 1690 cm~l
(5) 2-Benzyloxyimino-2-(2-aminothiazol-4-yl)acetic
acid (syn isomer).
I.R. (Nujol) : 3330, 3200, 3100, 1660
1590 cm~l
(6) 2-Ethoxycarbonylmethoxyimino-2-(2-formamido-
thiazol-4-yl)acetic acid (syn isomer), mp. 110C,
(dec.)
I.R. (Nujol) : 3150, 1740, 1670, 1550 cm~l
(7) 2-t-Butoxycarbonylmethoxyimino-2-(2-formamido-
thiazol-4-yl)acetic acid (syn isomer), mp. 117C
(dec.)
I.R. (Nujol) : 3180, 3140, 1750, 1690,
1630 cm~l
(8) 2-(3-Isoxazolyl)methoxyimino-2-(2-formamido-
thiazol-4-yl)acetic acid (syn isomer), mp. 110C
(dec.).
I.R. (Nujol) : 3270, 3130, 1680, 1540 cm~
5~
~'~` X - 207 -
1 337522
(9) 2-ethoxycarbonylmethoxyimino-2-~2-aminothizol-
4-yl)acetic acid (syn isomer),
I.R. (Nujol) : 3170, 1720, 1660, 1620 cm~
N.M.R. (d6-DMSO, ~) : 1.27 (3H, t, J=7Hz),
4.25 (2H, q, J=Hz), 4.77 (2H, s),
6.96 (lH, s)
. .
(10) 2-(2-Ethoxyethoxy)imino-2-2-formamidothiazol-
4-yl)acetic acid (syn isomer).
I.R. (Nujol) : 3350, 3140, 1740, 1700 cm~
, ~.
~ - 207a -
1 337S22
Pre~ar~tio~ ~.~.4
The solution of 4-bromo-3-hydroxybenzyloxyamine
phosphate (17.4 g.~ in water ~200 ml.) a~a e.hanol
(200 ml.) was stirred at room temperature and adjusted
to pH 7.0 w}th sodium bicarbonate. 2-(2-Fo~amido-
thiazol-4-yl~glyoxylic acid (10.0 g.) was added to
the solution ~nd the resulting suspension was adjus.ed
to pH 4.0 to 4.5. After stirring the solution at
- room temperature for 2 hours, ethanol was removed
~rom the resultant solution in va~uo.
Ethyl acetate was added to aqueous residue and adjus.ed
to p~ 2.5 with 10~ hydrochloric acid. The ethyl
acetat~ 12yer was separatea, wasned wit~ water and
: dried over ~agnesium sulfate. ~he solution W2s con- -
-_ 15 ce~tra.ed in vacuo to give 2-(2-fo~mamidothiazol-4-
yl)-2-(4-bromo-3-hyaroxybe~zyloxyimino)~cetlc acid
(sy~ isomer, 14.8 g.).
Nu~ol 3350, 3150, 172Q, 168 ,
-20
N.M.R. & (DMSO-d6, ppm) : 5.1~ (2H, m), 6.8 (lH,
dd, 3=8Hz, 2Hz), 7.02 (lH, d, J=2Hz),
- - - 7.5 ~lH, d, Jz8Hz), 7.58 (lH, s)~
- 8.58 (lH, s), 10.3; (lH, broad s),
25 - 12.7 (lH, broad s)-.
.
.
- -- 208 --
1 337522
P`reparation ~,D. 5
(1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer,
40.0 g.), 4-fluorobenzyl chloride (43.6 g.), N,N-
dimethyl ormamide (60.0 ml), potassium carbonate
(52.0 g.) and ethyl acetate (60.0 ml.) were treated i~
- ~ conventional manner to give ethyl 2-(4-
fluoroben-yloxyimino)-3-oxobutyrate ~syn isomer,
64.4 g.~.
~0 ~.R. (Film): 3000, 2940, 1730, 1690, 1600 cm 1
N-M-R- (DMSO-d6, ~3: 1.21 (3H, t, J=7.0Hz),
2.34 (3H,. s), 4.26 (2~I, q, J=7.0Hz~,
5.32 (2H, s~, 6.97-7.73 (4H, m).
(2) Ethyl 2-~4-fluorobenzyloxyimino)-3-oxobu~yrate
(syn isomer, 64.0 g.) and sulfuryl chloride (35.6 g.)
and acetic acid (70.0 ml.) were treated in a similar
manner to that of Preparation 6 -lO) to give ethyl
20 2-~4-fluorobenzyloxyimino)-3-oxo-4-chlorobutyrate
(syn isomer, 29.55 g.).
I.R. ~Film) : 1720, 1600 c;n 1
N.M.R. (DMSO-d6, ô) : 1.20 (3H, t, J=7.0Hz),
4.28 (2~, q, J=7.OHz), 4.87 (2H, s),
5.36 ~2H, s), 7.00-7.75 (4H, m).
(3) Ethyl 2- (4-fluoroben2yloxyimino)-3-oxo-4^
chlorobutyrate (syn isomer, 29.0 g.), thiourea ~8.8 g.?'
sodium acetate ~7.9 g.), water ~72.5 ml .), tetrahydro-
furan ~60 ml.) and ethanol (72.5 ml.) were t~eated in
a similar manner to that of Preparation 8-io) to gi~e
ethyl 2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-
35 4-yl)acetate (syn isomer, 28.0 g.).
.
_ 209 --
1 337522
I.R. ~Nujol) : 3450, 315~, 3100, 1710, 1620 cm 1
N.M.R. ~DMS0-d6, ~ : 1.23 ~3H, t, J=7.0H~),
4.30 (2H, q, J=7Hz), 5.15 (2H, s),
6.90 ~lH, s), 6.95-7.60 (4H, m)
(4) Eth- 2-(4-fluorobenzyloxyim~no)-2-(2-
~minathiazol-4-yl)acetate (syn isomer, 25.5 g),
l-methylimidazole (1.3 g), lN sodium hydroxide solution
(118.3 ml.), methanol (250 ml.) and tetrahydrofur2n
(2~0 mL) were treated in a similar manner to that of
- 10 Preparation ~- 1) to give 2-(4-fluorobenzyloxyimino)-
- 2-~2-aminothiazol-4-yl)acetic acid ~syn isomer, 22.11 g.)~
I.R. (Nujol) : 3650, 3450, 3300, 3150, 1630 cm 1
N.M.R. (DM~O-d6, ~) : 5.16 ~2H, s), ~.88 (lH, s),
7.04-7.66 (4H, m)
--
- (5) 2- ~4-Fluorobenzyloxyimino) -2- (2-aminothiazol-
4-yl)acetic acid (syn isomer, 23.4 g.), bis-
(trimethylsilyl~acetamide (32.2 g.), 2-,2,2-trifluoro-
acetic anhydride (49.9 g.) and dry ethyl acetate
~234 ml.) were tIeated in a similar m~nner to that
of Preparationq~to give 2-~4-fluoroben7yloxyimino)-
2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl~ac~tic
- acid (sy~ isomer, 18.9 g.), mp. 180 to 182C.
-25 I.R. (Nujol) : 3200, 3150, 1730 cm l
.
- - N.M.R. (DMS0-d6, ~) : 5.2~ (2H, s), 7.02-7.60-
- - (4H, m), 7.72 (lH, s).
.
- -30 --Pre~aration ~.D. 6
(1-) The following comDound ~2S obtained b~
reacting et~yl 2-hydroxyimino-;-o~obutyrate ~syn
is~mer) with3,4-dichloro~en~yl
chloridein a cnn-~entiona~ ~nner~
: -
,
~ , - 210 -
1 337522
Ethyl 2-(3,4-dichlorobenzyloxyimino)-3-
oxobutyrate (syn isomer), oil.
I.R. (Film) : 1730, 1690, 1600, 1470, 1400,
1370, 1310, 1240, 1130, 1080,
1010 cm~l
N.M.R. (CCI4, ~) : 1.30 (3H, t, J=6Hz), 2.30
(3H, s), 4.30 (2H, q, J=6Hz), 4.47 (2H, s),
7.00-7.53 (3H, m)
(2) The following compound was obtained according
to a similar manner to that of Preparation 6-10.
Ethyl 2-(3,4-dichlorobenzyloxyimino)-3-oxo-
4-chlorobutyrate (syn isomer), oil.
I.R. (Film) :1740, 1710, 1590, 1470, 1400,
1370, 1320, 1260, 1200, 1130,
1010 cm~l
N.M.R. (CCI4, ~) : 1.37 (3H, t, J=6Hz), 4.23
(2H, q, J=6Hz), 4.43 (2H,s), 5.27
(2H, s), 7.10-7.60 (3H, m)
(3) The following compound was obtained according
to a similar manner to that of Preparation 8-10.
Ethyl 2-(3,4-dichlorobenzyloxyimino)-2-(2-amino-
thiazol-4-yl)acetate (syn isomer).
3~ I.R. (Nujol) : 3460, 1720, 1600, 1540, 1460,
1390, 1260, 1180, 1020, 1010, 880,
810 cm~l
N.M.R. (DMSO-d6, ~) : 1.25 (3H, t, J=7Hz),
4.30 (2H, q, J=7Hz), 5.17 (2H, s),
6.93 (lH, s), 7.27-7.73 (3H, m)
.,
~ ~ ~ - 211 -
1 337522
(4) The following compound was obtained according
to a similar manner to that of Preparation 9-1.
2-(3,4-dichlorobenzyloxyimino)-2-(2-
aminothiazol-4-yl)acetic acid (syn isomer).
I.R. (Nujol) : 3430, 1660, 1590, 1400,
1010 cm~l
N.M.R. (DMSO-d6, ~) : 5.23 (2H, s), 6.93 (lH, s),
7.30-7.77 (3H, m)
(5) The following compound was obtained according
to a similar manner to that of Preparation 9-4.
2-(3,4-dichlorobenzyloxyimino)-2-[2-(2,2,2-
trifluoroacetamido)thiazol-4-yl]acetic acid (syn
isomer).
I.R. (Nujol) : 1720, 1580, 1300, 1260, 1200,
1160, 1150 cm~1
N.M.R. (DMSO-d6, ~) : 5.40 (2H, s), 7.47-7.93
(4H, m)
- 212 -
,~. %
- 1 337522
Preparation S.D. 7
To a suspension of N-(cinnamyloxy)phthalimide
(21.0 g) in ethanol (200 ml) was added hydrazine
hydrate (8.3 g) at 60C and the mixture was stirred for
1.5 hours at the same temperature. To the mixture were
added conc. hydrochloric acid (22 ml) and water (220
ml) and the resulting mixture was filtered. The
filtrate was concentrated to give precipitates, which
were filtered off. The filtrate was adjusted to pH 7.0
and to the solution containing 0-cinnamyl hydroxylamine
were added ethanol (300 ml) and 2-(2-formamidothiazol-
4-yl)glyoxylic acid (10.0 g). The mixture was stirred
for 2 hours at pH 4.0 to 4.5. The reaction mixture was
concentrated and adjusted to pH 2.0 after addition of
ethyl acetate. The organic layer was washed with an
aqueous solution of sodium chloride, dried over
magnesium sulfate and evaporated to give 2-cinnamyl-
oxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn
isomer) (8.6 g.)
I.R. (Nujol) : 3400-3100, 1700, 1550 cm~l
N.M.R. (DMSO-d6, ~) : 4.85 (2H, d, J=5Hz),
6.2-6.93 (2H, m), 7.2-7.72 (5H, m),
7.6 (lH, s), 8.57 (lH, s), 12.7
(lH, broad s).
- 213 -
1 337522
Example S.D. 1
2-Allyloxyimino-2-(2-formamidothiazol-4-yl)-
acetic acid (syn isomer) (0.80 g) and dry ethyl acetate
(10 ml) were added at 0 to 5C with stirring to a
suspension of Vilsmeier reagent prepared from dry
dimethylformamide (0.25 g) and phosphorus oxychloride
(0.528 g) in dry ethyl acetate (0.75 ml) by
conventional method, and the resulting mixture was
stirred for 30 minutes at the same temperature to give
a yellow solution. The solution was added at -10C
with stirring to a solution of 7-amino-3-(1-allyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(1.11 g) and trimethylsilylacetamide (2.96 g) in dry
ethyl acetate (15 ml), and the mixture was stirred for
1.5 hours at the same temperature. After addition of
water (15 ml) to the reaction mixture, the ethyl
acetate layer was separated and extracted with an
aqueous solution of sodium bicarbonate (30 ml). The
aqueous extract was acidified to pH 2.0 with 10%
hydrochloric acid and extracted with ethyl acetate (150
ml). The extract was washed with water, dried and
evaporated. The residue was pulverized with
diisopropyl ether to give colorless powder of 7-[2-
allyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-
(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer) (1.48 g).
I.R. (Nujol) : 3180, 1775, 1665 cm~l
N.M.R. (d6-DMSO, ~) : 9.68 (lH, d, J=8Hz), 8.51
(lH, s), 7.40 (lH, s), 5.60-6.33 (3H, m),
4.85-5.57 (7H, m), 4.27-4.77 (4H, m), 3.70
(2H, ABq, J=18Hz)
- 214 -
- 1 337522
ExamPle S.D.2
The Vilsmeier reagent was prepared from dry
dimethylformamide (0.4 g), phosphorus oxychloride (0.9
g) and dry ethyl acetate (1.6 ml) by the conventional
method. Dry ethyl acetate (18 ml) was added thereto
and then 2-ethoxyimino-2-(2-formamidothiazol-4-yl)-
acetic acid (syn isomer) (1.3 g) was added thereto at
0C. The mixture was stirred for 30 minutes at the
same temperature. The resulting mixture was added
under -10C to a stirred solution of 7-amino-3-(1-
allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (1.8 g) and trimethylsilylacetamide (4.6 g) in dry
ethyl acetate (36 ml), and the mixture was stirred for
1 hour at the same temperature. To the reaction
mixture was added water (30 ml). The ethyl acetate
layer was separated and extracted with a saturated
aqueous solution of sodium bicarbonate (pH 7.5). The
aqueous layer was washed three times with ethyl acetate
and adjusted to pH 2.0 with conc. hydrochloric acid
after addition of ethyl acetate (100 ml). The ethyl
acetate layer was separated, washed with a saturated
aqueous solution of sodium chloride, dried over
magnesium sulfate, treated with an activated charcoal
and concentrated to dryness to give 7-[2-ethoxyimino-2-
(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer) (2.56 g).
I.R. (Nujol): 3200, 1765, 1665 cm~l
N.M.R. (d6-DMSO, ~) : 1.26 (3H, t, J=7.0Hz),
3.68 (2H, m), 4.18 (2H, q, J=7.0Hz),
4.36 (2H, ABq, J=14.OHz~, 4.75-5 57
(5H, m), 5.68-6.40 (2H, m), 7.37
(lH, s), 8.48 (lH, s), 9.60 (lH, d,
J=8.OHz)
~;r
Y ~ - 215 -
~r~ ~
1 337522
Example S.D.3
The Vilsmeier reagent was prepared from dry
dimethylformamide (0.209 g), phosphorus oxychloride
(0.434 g) and dry ethyl acetate (0.75 ml) by the
conventional method. Dry tetrahydrofuran (6.5 ml) was
added thereto and then 2-methylthiomethoxyimino-2-(2-
formamidothiazol-4-yl)acetic acid (syn isomer) (0.65 g)
was added thereto at 0C. The mixture was stirred for
30 minutes at the same temperature. The resulting
X - 216 -
1 337522
mixture was dropwise added at -5 to 0C to a stirred
solution of 7-amino-3-(1-allyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (1.25 g) in a
mixture of water (10 ml) and acetone (10 ml) keeping
the pH at 7.5 by triethylamine, and the mixture was
stirred for 30 minutes at the same temperature at pH
7.5. To the reaction mixture was added ethyl acetate
(60 ml) and the mixture was adjusted to pH 2.5 with 10%
hydrochloric acid. Insoluble material was filtered off
and the filtrate was extracted twice with ethyl
acetate. The combined extracts were washed twice with
a saturated sodium chloride aqueous solution and dried
over magnesium sulfate. The solvent was distilled off
and the residue was pulverized with diethyl ether to
give yellowish powder of 7-[2-methylthiomethoxyimino-2-
(2-formamidothiazol-4-yl)-acetamido]-3-(1-allyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer) (1003 g).
I.R. (Nujol): 3250, 3200, 1780, 1670,
1540 cm~l
N.M.R. (d6-DMSO, ~) : 2.23 (3H, s), 3.72
(2H, s), 4.38 (2H, ABq, J=14Hz),
4.8-5.6 (7H, m) 5.7-6.4 (2H, m), 7.48
(lH, s), 8.55 (lH, s), 9.75 (lH, d,
J=8Hz), 12.69 (lH, broad s)
Example S.D.4
The Vilsmeier reagent was prepared from dry
dimethylformamide (0.74 g), phosphorus oxychloride
(1.56 g) and dry ethyl acetate (2.0 ml) by the con-
ventional method. Dry tetrahydrofuran (15 ml) was
added thereto and then 2-(3-isoxazolyl)methoxyimino-2-
(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.50
g) was added thereto at 0C. The mixture was stirred
for 30 minutes at the same temperature. The resulting
mixture was added dropwise at -5 to 0C to a stirred
solution of 7-amino-3-(1-allyl-lH-tetrazol-5-yl)
- 217 -
, .. ,~
- 1 337522
thiomethyl-3-cephem-4-carboxylic acid (2.34 g) in a
mixture of water (11.5 ml) and acetone (11.5 ml)
keeping the pH at 7.5 by triethylamine, and the mixture
was stirred for 30 minutes at the same temperature at
pH 7.5. To the reaction mixture was added ethyl
acetate (60 ml) and the mixture was adjusted to pH 2.5
with 10% hydrochloric acid. Insoluble material was
filtered off and the filtrate was extracted twice with
ethyl acetate. The combined extracts were washed twice
with a saturated sodium chloride aqueous solution and
dried over magnesium sulfate. The solvent was
distilled off and the residue was pulverized with
diethyl ether to give yellowish powder of 7-[2-(3-
isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-
cephem-4-carboxylic acid (syn isomer) (2.15 g).
I.R. (Nujol): 3250, 1780, 1670, 1550 cm~
N.M.R. (d6-DMSO, ~): 3.72 (2H, s), 4.40
(2H, ABq, J=14Hz), 4.8-5.6 (7H, m),
5.6-6.5 (2H, m), 6.67 (lH, d, J=2Hz),
7.50 (lH, s), 8.56 (lH, s), 8.92
(lH, d, J=2Hz), 9.80 (lH, d, J=8Hz),
12.72 (lH, broad s)
Example S.D.5
Phosphorus oxychloride (1.0 g) was added at a
time to suspension of 2-benzyloxyimino-2-(2-amino-
thiazol-4-yl)acetic acid (syn isomer) (1.4 g) in dry
tetrahydrofuran (14 ml) at 2C and the mixture was
stirred for 15 minutes at 2 to 4C. Trimethylsilyl-
acetamide (1.0 g) was added dropwise thereto and the
resulting mixture was stirred for 20 minutes at 2 to
6C. Phosphorus oxychloride (1.0 g) was added thereto
and the mixture was stirred for 20 minutes. Dry
dimethylformamide (0.5 g) was added thereto at a time
at 4 to 6C and the mixture was stirred for 1 hour to
give a clear solution. On the other hand, trimethyl-
X - 218 -
1 337522
silylacetamide (5.3 g) was added to a stirred
suspension of 7-amino-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g) in dry
ethyl acetate (27 ml) and the solution was stirred for
30 minutes at 40C. To this solution was added the
above-obtained tetrahydrofuran solution at a time at
-30C, and the resulting mixture was stirred for 1 hour
at -5 to -20C. To the reaction mixture were added
water (30 ml) and ethyl acetate (20 ml). An organic
layer was separated and extracted with an aqueous
solution of sodium bicarbonate. The extract was
adjusted to pH 3.0 with 10~ hydrochloric acid.
Precipitates were collected by filtration, washed with
water to give 7-[2-benzyloxyimino-2-(2-aminothiazol-4-
yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer) (0.85 g).
I.R. (Nujol): 3350, 3230, 1780, 1675,
1635 cm~l
N.M.R. (d6-DMSO, ~) : 3.67 (2H, m), 4.40 (2H,
ABq, J=15.OHz), 4.85-5.56 (6H, m),
5.62-6.45 (2H, m), 6.77 (lH, s), 7.01-
7.65 (7H, m), 9.71 (lH, d, J=8Hz)
ExamPle S.D.6
The Vilsmeier reagent was prepared from dry
dimethylformaminde (0.44 g), phosphorus oxychloride
(0.9 g) and dry ethyl acetate (1.0 ml) by the
conventional method. Dry ethyl acetate (20 ml) was
added thereto and then 2-methoxyimino-2-(2-
formamidothiazol-4-yl)-acetic acid (syn isomer) (1.1 g)
was added thereto at -5 to 10C. The mixture was
stirred for 10 minutes at the same temperature. The
resulting mixture was dropwise added at O to 5C and pH
6.5 to 7.5 with stirring to a solution of 7-amino-3-(4-
allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-
carboxylic acid (2.12 g) and sodium bicarbonate (2 g)
X - 219 -
~ 1 337522
in a mixture of water (20 ml) and acetone (20 ml), and
the mixture was stirred for 20 minutes at the same
temperature. The aqueous layer was separated and
acetone was evaporated. The aqueous layer was adjusted
under ice-cooling and stirring to pH 3.0 with 10%
hydrochloric acid. Precipitates were collected by
filtration, washed with water and dried to give 7-[2-
methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-
(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer)(0.94 g).
I.R. (Nujol) : 3200, 1780, 1680, 1550 cm~
N.M.R. (d6-DMSO, ~) : 3.72 (2H, broad s),
3.93 (3H, s), 4.20 (2H, broad s), 4.65
(2H, m), 4.72-5.43 (3H, m), 5.55-6.45
(2H, m), 7.43 (lH, s), 8.55 (lH, s),
8.65 (lH, s), 9.68 (lH, d, J=8Hz),
12.82 (lH, m)
Example S.D.7
The following compounds were obtained
according to similar manner to those of Examples S.D.l
to S.D.6.
(1) 7-[2-Isopropoxyimino-2-(2-formamidothiazol-4-
yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer),
I.R. (Nujol) : 3220, 1780, 1670 cm~l
N.M.R. (d6-DMSO, ~) : 1.20 (3H, s), 1.32
(3H, s), 3.70 (2H, broad s), 4.07-4.87
(3H, m), 4.93-5.50 (4H, m), 5.67-6.23
(2H, m), 7.40 (lH, s), 8.50 (lH, s)
9.58 (lH, d, J=8Hz)
(2) 7-[2-Butoxyimino-2-(2-formamidothiazol-4-yl)- acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1780, 1695, 1675,
1655 cm~l
~,,
- 220 -
i 337522
_
N.M.R. (d6-DMSO, ~) : 0.88 (3H, m), 1.10-2.01
(4H, m), 3.71 (2H, m), 4.14 (2H, t,
J=7.OHz), 4.38 (2H, ABq, J=14.OHz),
4.83-5.51 (5H, m), 5.63-6.40 (2H, m),
7.42 (lH, s), 8.56 (lH, s), 9.65 (lH,
d, J=9.OHz)
(3) 7-[2-Hexyloxyimino-2-(2-formamidothiazol-4-
yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3175, 1780, 1757, 1684,
1640 cm~l
N.M.R. (d6-DMSO, ~) : 0.84 (3H, m), 1.06-2.03
(8H, m), 3.73 (2H, m), 4.14 (2H, t,
J=6.OHz), 4.40 (2H, ABq, J=14.OHz),
4.85-5.52 (5H, m), 5.75-6.45 (2H, m),
6.97 (lH, broad s), 7.41 (lH, s), 8.54
(lH, s), 9.63 (lH, d, J=8.OHz)
(4) 7-[2-(2-Formyloxyethoxy)imino-2-(2-formamido-
thiazol-4-yl)acetamido-3-(l-allyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3265, 1780, 1720, 1680 cm~l
N.M.R. (d6-DMSO, ~) : 3.74 (2H, m), 4.13-4.70
(6H, m), 4.85-5.53 (5H, m), 5.70-6.42
(2H, m), 7.48 (lH, s), 8.26 (lH, s),
8.56 (lH, s), 9.69 (lH, d, J=9.OHz)
(5) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-
formamido-thiazol-4-yl)acetamido]-3-(1-allyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. (Nujol) : 3500, 3280, 1780, 1735,
1690 cm~l
N.M.R. (d6-DMSO, ~) : 1.24 (3H, t, J=7Hz),
3.74 (2H, s), 4.20 (2H, q, J=7Hz),
4.42 (2H, s), 4.77 (2H, s), 4.5-5.6
(5H, m), 5.7-6.4 (3H, m), 7.50
X - 221 -
i
- 1 337522
(lH, s), 8.57 (lH, s), 9.68 (lH, d,
J=8Hz), 12.69 (lH, broad s)
(6) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-
formamido-thiazol-4-yl)acetamido]-3-(1-allyl-lH-
tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. (Nujol) : 3250, 1780, 1720, 1680,
1540 cm~l
N.M.R. (d6-DMSO, ~) : 1.44 (9H, s), 3.71 (2H,
ABq, J=18Hz), 4.37 (2H, ABq, J=14Hz),
4.62 (2H, s), 4.8-5.4 (5H, m), 5.5-6.4
(2H, m), 7.46 (lH, s), 8.52 (lH, s),
9.58 (lH, d, J=8Hz), 12.60
(lH, broad s)
(7) 7-[2-Ethoxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 1780, 1675, 1635 cm~l
(8) 7-[2-Isopropoxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3250, 1780, 1675,
1630 cm~l
(9) 7-[2-Butoxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1672 cm~l
(10) 7-[2-Hexyloxyimino-2-(aminothiazol-4-
yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3240, 1780, 1675,
1630 cm~l
(11) 7-[2-Allyloxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3210, 1788, 1675 cm~
_. ~
~ - 222 -
1 337522
-
(12) 7-[2-Ethoxycarbonylmethoxyimino-2-l2-amino-
thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 3230, 1780, 1680,
1630 cm~l
(13) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3330, 1780, 1730, 1680,
1630 cm~l
(14) 7-[2-Methylthiomethoxyimino-2-(2-
aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3270, 1760, 1650, 1520 cm~
(15) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-
aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3300, 1770, 1660, 1530 cm~l
(16) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-
yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1680, 1630 cm~l
(17) 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thio-
methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 1775, 1670, 1530 cm~l
(18) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-(2,2,2-
trifluoroacetamido)thiazol-4-yl)-acetamido]-3-(1-allyl-
lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. (Nujol): 3250, 3170, 1780, 1720,
1650 cm~
- 223 -
:,; ~.
: ~.
1 337522
-
N.M.R. (DMSO-d6, ~) : 3.64 (2H, m), 4.34 (2H,
ABq, J=14Hz), 4.79-5.44 (7H, m), 5.65-
6.27 (2H, m), 6.95-7.61 (4H, m), 7.51
(lH, s), 9.83 (lH, d, J=8Hz)
5 (19) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-
aminothiazol-4-yl)acetamino]-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 157 to 161C (dec.).
I.R. (Nujol) : 3500, 1770, 1660, 1630,
1600 cm~l
(20) 7-[2-(3,4-Dichlorobenzyloxyimino)-2-(2-
(2,2,2-trifluoroacetamido)thiazol-4-yl)acetamido]-3-(1-
allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer).
I.R. (Nujol) : 1770, 1650 cm~l
N.M.R. (DMSO-d6, ~) : 3.72 (2H, m), 4.40
(2H, m), 5.00-5.43 (7H, m), 5.73-6.60
(2H, m), 7.30-7.77 (4H, m), 9.90 (lH,
d, J=8Hz)
(21) 7-[2-(3,4-Dichlorobenzyloxyimino)-2-(2-
aminothiazol-4-yl)acetamino]-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 155 to 175C (dec.).
I.R. (Nujol) : 1770, 1660-1620, 1450 cm~
X - 224 -
1 337522
ExamPle S.D.8
Conc. hydrochloric acid (0.33 g) was added to
a solution of 7-[2-allyloxyimino-2-(2-formamidothiazol-
4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer) (1.30 g) in
methanol (13 ml) and the mixture was stirred for 4.5
hours at ambient temperature. The solvent was dis-
tilled off under reduced pressure and the residue was
dissolved in a saturated aqueous solution of sodium
bicarbonate (25 ml). The aqueous solution was washed
with ethyl acetate (25 ml) and adjusted to pH 2.0 with
10% hydrochloric acid. Precipitates were collected by
filtration, washed with water and dried to give color-
less powder of 7-[2-allyloxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer) (0.95 g).
I.R. (Nujol) : 3350, 3210, 1778, 1675 cm~l
N.M.R. (d6-DMSO, ~) : 3.68 (2H, ABq, J=18Hz),
4.40-4.71 (4H, m), 4.80-5.45 (7H, m),
5.64-6.24 (3H, m), 6.74 (lH, s), 7.35
(2H, broad s), 9.62 (lH, d, J=8Hz)
-
~; - - 225 -
- ~r
~0
1 337522
ExamPle S.D. 9
Conc. hydrochloric acid (0.9 g) was added at
ambient temperature to a solution of 7-[2-ethoxyimino-
2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-
X - 226 -
. ~,
1 337522
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer) (2.4 g) in a mixture of methanol (16.8 ml)
and tetrahydrofuran (4.8 ml) and the mixture was
stirred for 3 hours at 30C. The solvent was distilled
off under reduced pressure and the residue was dis-
solved in a saturated aqueous solution of sodium
bicarbonate. The aqueous solution was washed with
ethyl acetate and adjusted to pH 2.8 with
conc.hydrochloric acid. Precipitates were collected by
filtration, washed with water and dried to give 7-[2-
ethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1-
allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-
carboxylic acid (syn isomer) (1.72 g).
I.R. (Nujol) : 3350, 1780, 1675, 1635 cm~l
N.M.R. (d6-DMSO, ~) : 1.24 (3H, t, J=7.3Hz),
3.71 (2H, m), 4.13 (2H, q, J=7.3Hz),
4.37 (2H, ABq, J=13.5Hz), 4.80-5.53
(5H, m), 5.64-6.45 (2H, m), 6.77
(lH, s), 7.25 (2H, broad s), 9.62
(lH, d, J=8.OHz)
r:
'` X - 227 -
~ ,
1 337522
Example S.D.10
A mixture of 7-[2-methylthiomethoxyimino-2-
(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer) (0.95 g), conc.hydrochloric acid (0.324
g), methanol (9.5 ml) and tetrahydrofuran (2 ml) was
stirred for 2 hours at ambient temperature. The
solvent was distilled off under reduced pressure and
the residue was dissolved in a saturated aqueous
solution of sodium bicarbonate. The aqueous solution
was washed with ethyl acetate (25 ml) and adjusted to
pH 1.5 with 10% hydrochloric acid. Precipitates were
collected by filtration, washed with water and dried to
give 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer) (0.78 g).
I.R. (Nujol) : 3270, 1760, 1650, 1520 cm~
N.M.R. (d6-DMSO, ~) : 2.21 (3H, s), 3.72
(2H, s), 4.38 (2H, ABq, J=14Hz), 4.8-
5.6 (7H, m), 5.7-6.4 (2H, m), 6.80
(lH, s), 7.26 (2H, broad s), 9.66
(lH, d, J=8Hz)
Example S.D.ll
A mixture of 7-[2-(3-isoxazolyl)methoxyimino-
2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer) (1.5 g), conc.hydrochloric acid (0.497 g),
methanol (15 ml) and tetrahydrofuran (3 ml) was stirred
for 2 hours at ambient temperature. The solvent was
distilled off under reduced pressure and the residue
was dissolved in a saturated aqueous solution of sodium
bicarbonate. The aqueous solution
- 228 -
- 1 33752~
was washed with ethyl acetate (25 ml) and adjusted to
pH 1.5 with 10% hydrochloric acid. Precipitates were
collected by filtration, washed with water and dried to
give 7-[2-(3-isoxazolyl)methoxyimino-2-(2-aminothiazol-
4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer) (0.65 g).
I.R. (Nujol) : 3300, 1770, 1660, 1530 cm~l
N.M.R. (d6-DMSO, ~) : 3.71 (2H, s), 4.40 (2H,
d, J=14Hz), 4.8-5.6 (7H, m), 5.6-6.5
(2H, m), 6.62 (lH, d, J=2Hz), 6.83
(lH, s), 7.29 (2H, broad s), 8.92 (lH,
d, J=2Hz), 9.73 (lH, d, J=8Hz)
Example S.D.12
A mixture of 7-~2-methoxyimino-2-(2-form-
amido-thiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4-
triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer) (0.9 g), conc.hydrochloric acid (0.3 ml),
methanol (7 ml) and tetrahydrofuran (7 ml) was stirred
for 4.5 hours at ambient temperature. The solvent was
distilled off under reduced pressure and the residue
was dissolved in a saturated aqueous solution of sodium
bicarbonate. The aqueous solution was washed with
ethyl acetate (25 ml) and adjusted to pH 2.0 with 10%
hydrochloric acid. Precipitates were collected by
filtration, washed with water and dried to give 7-[2-
methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-
allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer) (0.5 g).
I.R. (Nujol) : 3350, 1775, 1670, 1530 cm~
N.M.R. (d6-DMSO, ~) : 3.65 (2H, broad s),
3.83 (3H, s), 4.15 (2H, broad s), 4.58
(2H, m), 4.77-5.5 (3H, m), 5.58-6.33
(2H, m), 6.73 (lH, s), 8.60 (lH, s),
9.58 (lH, d, J=8Hz)
~X
- 229 -
- 1 337 522
Example S.D.13
The following compounds were obtained accord-
ing to similar manner to those of Examples S.D.8 to
S.D.12
(1) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3230, 1780, 1675,
1635 cm~l
(2) 7-[2-Isopropoxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3250, 1780, 1675,
1630 cm~l
N-M-R- (d6-DMso~ ~) : 1-20 (3H, s),
1.30 (3H, s), 3.70 (2H, broad s), 4.30
(3H, m), 4.97-5.40 (4H, m), 5.63-6.27
(2H, m), 6.70 (lH, s), 9.55
(lH, d, J=8Hz)
(3) 7-[2-Butoxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1672 cm~l
N.M.R. (d6-DMSO, ~) : 0.91 (3H, t, J=6.0Hz),
1.18-1.96 (4H, m), 3.73 (2H, m), 3.87-
4.73 (4H, m), 4.83-5.57 (5H, m),
5.63-6.40 (2H, m), 6.74 (lH, s), 7.20
(2H, broad s), 9.55 (lH, d, J=8.OHz)
(4) 7-[2-Hexyloxyinino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3240, 1780, 1675,
1630 cm~l
N.M.R. (d6-DMSO, ~) : 0.85 (3H, m), 1.00-2.00
(8H, m), 3.68 (2H, m), 4.05 (2H, m),
4.37 (2H, m), 4.80-5.47 (5H, m), 5.60-
X - 230 -
1 337522
-
6.47 (2H, m), 6.69 (lH, s), 7.20 (2H,
broad s), 9.50 (lH, d, J=8.0Hz)
(5) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
I.R. (Nujol) : 3360, 3230, 1780, 1680,
1630 cm~l
N.M.R. (d6-DMSO, ~) : 1.21 (3H, t, J=7Hz),
3.68 (2H, s), 4.14 (2H, q, J=7Hz),
4.38 (2H, s), 4.66 (2H, s), 4.8-5.5
(5H, m), 5.6-6.4 (3H, m), 6.80
(lH, s), 7.20 (2H, broad s), 9.48
(lH, d, J=8Hz)
(6) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3330, 1780, 1730, 1680,
1630 cm~l
N.M.R. (d6-DMSO, ~) : 1.43 (9H, s), 3.67
(2H, s), 4.37 (2H, ABq, J=14Hz), 4.56
(2H, s), 4.8-5.5 (5H, m), 5.6-6.4
(2H, m), 6.78 (lH, s), 7.20 (2H,
broad s), 9.43 (lH, d, J=8Hz)
(7) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-
yl)-acetamido-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1680, 1630 cm~
(8) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp
157 to 161C (dec.).
I.R. (Nujol) : 3500, 1770, 1660, 1630,
1600 cm~l
N.M.R. (DMSO-d6, ~) : 3.69 (2H, m), 4.39 (2H,
ABq, J=14Hz), 4.75-5.48 (7H, m) 5.63-
.,--
~ - 231 -
1 337522
6.57 (2H, m), 6.76 (lH, s), 6.86-7.76
(4H, m), 9.67 (lH, d, J=8Hz)
(9) 7-[2-(3,4-Dichlorobenzyloxyimino)-2-(2-
aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 155 to 175C (dec.).
I.R. (Nujol) : 1770, 1660-1620, 1450 cm~
N.M.R. (DMSO-d6, ~) : 3.63 (2H, m), 4.33
(2H, m), 4.93-5.37 (7H, m), 5.67-6.40
(2H, m), 6.73 (lH, s), 7.10-7.70
(3H, m), 9.73 (lH, d, J=8Hz)
ExamPle S.D.14
Trifluoracetic acid (20 ml) was added under
ice-cooling to a stirred suspension of 7-[2-t-butoxy-
carbonylmethoxyimino-2-(2-aminothiazol-4-yl)acet-
amido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer) (2.05 g) in anisole (2
ml), and the resultant mixture was stirred for 2 hours
at ambient temperature. The reaction mixture was con-
centrated under reduced pressure and diethyl ether wasadded thereto. Precipitates were collected by
filtration, washed with diethyl ether, dried and
dissolved in an aqueous solution of sodium bicarbonate.
An insoluble material was filtered off and the filtrate
was adjusted to pH 3.2 with conc.hydorchloric acid.
Precipitates were collected by filtration, washed with
water and dried to give 7-[2-carboxymethoxyimino-2-(2-
aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
30 (0.8 g).
I.R. (Nujol) : 3360, 1780, 1680, 1630 cm~l
N.M.R. (d6-DMSO, ~) : 3.68 (2H, ABq, J=19Hz),
4.36 (2H, ABq, J=14Hz), 4.60 (2H, s),
4.60-6.2 (7H, m), 6.80 (lH, s), 7.24
(2H, broad s), 9.51 (lH, d, J=9Hz)
~;
- 232 -
1 337522
ExamPle S.D.15
To a solution of 7-[2-allyloxyimino-2-(2-
aminothiazol-4-yl)acetamido]cephalosporanic acid (syn
isomer) (4.8 g) in pH 6.4 phosphate buffer solution
(100 ml) was added 1-allyl-lH-tetrazole-5-thiol (2.1 g)
and then the mixture was stirred for 2 hours at 55 to
60C. The reaction mixture was cooled and adjusted to
pH 3.0 with 10% hydrochloric acid. Precipitates were
collected by filtration, washed with water and dried to
give 7-[2-allyloxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer) (2.0 g).
I.R. (Nujol) : 3350, 3210, 1778, 1675 cm~l
N.M.R. (DMSO-d6, ~) : 3.68 (2H, ABq, J=18Hz),
4.40-4.71 (4H, m), 4.80-5.45 (7H, m),
5.64-6.24 (3H, m), 6.74 (lH, s), 7.35
(2H, broad s), 9.62 (lH, d, J=8Hz)
ExamPle S.D.16
The following compounds were obtained
according to a similar manner to that of Example
S.D.15.
(1) 7-[2-Allyloxyimino-2-(2-formamidothiazol-4-
yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3180, 1775, 1665 cm~l
(2) 7-~2-Ethoxyimino-2-(2-formamidothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1765, 1665 cm~
- 233 -
- ~ 337522
(3) 7-[2-Methylthiomethoxyimino-2-(2-
formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. (Nujol) : 3250, 3200, 1780, 1670,
1540 cm~l
(4) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-
formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. (Nujol) : 3250, 1780, 1670, 1550 cm~l
(5) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3230, 1780, 1675,
1635 cm~l
(6) 7-[2-Methoxyimino-2-(2-formamidothiazol-4-
yl)-acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1780, 1680, 1550 cm~l
(7) 7-[2-Isopropoxyimino-2-(2-formamidothiazol-4-
yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
. X - 234 -
~..
1 337522
-
I.R. (Nujol) : 3220, 1780, 1670 cm~l
(8~ 7-[2-Bitoxyimino-2-(2-formamidothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1780, 1695, 1675,
1655 cm~l
(9) 7-[2-Hexyloxyimino-2-(2-formamidothiazol-4-
yl)-acetamido]-3(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3175, 1780, 1757, 1684,
1640 cm~l
(10) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-
formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. (Nujol) : 3500, 3280, 1780, 1735,
1690 cm~l
(11) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-
formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-
tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. (Nujol) : 3250, 1780, 1720, 1680,
1540 cm~l
(12) 7-[2-Ethoxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 1780, 1675, 1635 cm~
- 235 -
1 337522
(13) 7-[2-Isopropoxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3250, 1780, 1675,
1630 cm~l
(14) 7-[2-Butoxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1672 cm~l
(15) 7-[2-Hexyloxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3240, 1780, 1675,
1630 cm~l
(16) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-
aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 3230, 1780, 1680,
1630 cm~l
(17) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3330, 1780, 1730, 1680,
1630 cm~l
(18) 7-[2-Methylthiomethoxyimino-2-(2-aminothiazol-
- 236 -
1 331522
4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3270, 1760, 1650, 1520 cm~
(19) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-
aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3300, 1770, 1660, 1530 cm~l
(20) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1680, 1630 cm~l
(21) 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) :3350, 1775, 1670, 1530 cm 1
(22) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-
aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 157 to 161C (dec.).
I.R. (Nujol) : 3500, 1770, 1660, 1630,
1600 cm~
- 237 -
1 337522
(23) 7-[2-(3,4-Dichlorobenzyloxyimino)-2-(2-
aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 155 to 175C ~dec).
I.R. (Nujol) : 1770, 1660-1620, 1450 cm~
~'- X-
~- - 238 -
1 337522
ExamPle S.D.17
The Vilsmeier reagent was prepared from dry
dimethylformamide (0.139 g.), phosphorus oxychloride
(0.290 g.) and dry tetrahydrofuran (1.0 ml.) by the
conventional method. Dry tetrahydrofuran (3.0 ml.) was
added thereto and then 2-methylthiomethoxyimino-2-(2-
formamidothiazol-4-yl)acetic acid (syn isomer) (0.4 g.)
was added thereto at -5 to 0C. The mixture was stirred
for 30 minutes at the same temperature. The resulting
mixture was dropwise added at -5 to 0C to a stirred
solution of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid (0.725 g.) in a mixture of
water (7 ml.) and acetone (7 ml.) keeping the pH at 7.5
to 8.5 by triethylamine and the mixture was stirred for
30 minutes at the same temperature at pH 7.5 to 8.5.
Acetone was removed from the reaction mixture. To the
residue was added ethyl acetate and water and the
mixture was adjusted to pH 2.0 with 10% hydrochloric
acid. Insoluble material was filtered off and the
filtrate was extracted twice with ethyl acetate. The
combined extracts were washed twice with a saturated
sodium chloride aqueous solution and dried over
magnesium sulfate. The solvent was distilled off and
the residue was pulverized with diethyl ether to give 7-
[2-methyl-thiomethoxyimino-2-(2-formamidothiazol-4-
yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer) (0.64 g.).
I.R. (Nujol) : 3230, 1780, 1680, 1550 cm~l
N.M.R. (d6-DMS0, ~) : 2.22 (3H, s), 3.72 (2H,
ABq, J=18Hz), 4.44 (2H, ABq, J=14Hz),
5.18 (lH, d, J=5Hz), 5.23 (2H, s), 5.84
(lH, d,d, J=5 and 9Hz), 7.46 (lH, s),
8.52 (lH, s), 9.54 (lH, s), 9.74 (lH,
d, J=9Hz), 12.64 (lH, broad s)
X - 239 -
1 337522
ExamPle S.D.18
Phosphorus oxychloride (2.3 g.) was added at a
time to a suspension of 2-benzyloxyimino-2-(2-
aminothiazol-4-yl)acetic acid (syn isomer) (3.4 g.) in
dry tetrahydrofuran (30 ml.) at -3C and the mixture was
stirred for 20 minutes at the same temperature. Tri-
methylsilylacetamide (2.4 g.) and tetrahydrofuran (5
ml.) were added dropwise thereto and the resulting
mixture was stirred for 20 minutes at the same
temperature. Phosphorus oxychloride (2.3 g.) was added
thereto and the mixture was stirred for 30 minutes at 0
to 3C. Dry dimethylformamide (1.1 g.) was added
thereto at a time at 0 to 3C and the mixture was
stirred for 1 hour at the same temperature to give a
clear solution. On the other hand, trimethylsilyl-
acetamide (12.7 g.) was added to a stirred suspension of
7-amino-3-~1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (4.0 g.) in dry ethyl acetate (60 ml.)
and the solution was stirred for 1 hour at ambient
temperature. To this stirred solution was added the
above-obtained tetrahydrofuran solution at a time at
-20C, and the resulting mixture was stirred for 2 hours
at -5 to -15C. To the reaction mixture were added a
saturated aqueous solution of sodium chloride (50 ml.).
An organic layer was separated and extracted with a
saturated aqueous solution of sodium bicarbonate (pH
7.0). The extract was washed with ethyl acetate,
treated with an activated charcoal and adjusted to pH
4.5 with 10% hydrochloric acid. Precipitates were
collected by filtration, washed with water and dried to
give powder of 7-[2-benzyloxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer) (1.03 g.).
- 240 -
._.
- 1 337522
I.R. (Nujol) : 3320, 3200, 1770, 1670,
1610 cm~l
N.M.R. (d6-DMSO, ~) : 3.59 (2H, ABq,
J=18.OHz), 4.47 (2H, ABq, J=12.OHz),
5.09 (lH, d, J=4.OHz), 5.15 (2H, s),
5.73 (lH, d,d, J=4.0 and 8.0Hz), 6.74
(lH, s), 7.36 (5H, m), 9.56 (lH, s),
9.69 (lH, d, J=8.0Hz)
ExamPle S.D.l9
The Vilsmeier reagent was prepared from dry
dimethylformamide (0.667 g.), phosphorus oxychloride
(1.40 g.) and dry ethyl acetate (4 ml.) by the
conventional method. Dry ethyl acetate (16 ml.) was
added thereto and then 2-t-butoxycarbonylmethoxyimino-2-
(2-formamidothiazol-4-yl)acetic acid (syn isomer) (2 g.)
was added thereto at 0C. The mixture was stirred for
30 minutes at the same temperature. The resulting
mixture was added dropwise at -15C to a stirred
solution of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid (3.01 g.) and trimethyl-
silylacetamide (9.6 g.) in dry ethyl acetate (30 ml.),
and the mixture was stirred for 50 minutes at -15 to
-5C. To the reaction mixture was added water (50 ml.).
An insoluble material was filtered off and the filtrate
was extracted twice with ethyl acetate. The extracts
were washed twice with a saturated aqueous solution of
sodium chloride, dried over magnesium sulfate and
evaporated in vacuo. The residue was pulverized with
diethyl ether and the powder was collected by filtration
and dried to give 7-[2-t-butoxycarbonylmethoxyimino-2-
t2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thia-
diazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer) (2.67 g.).
X. - 241 -
~_t 1 337522
I.R. (Nujol) : 3225, 1780, 1725, 1685,
1550 cm~l
N.M.R. (d6-DMSO, ~) : 1.38 (9H, s), 3.64 (2H,
ABq, J=17Hz), 4.38 (2H, ABq, J=14Hz),
4.56 (2H, s), 5.12 (lH, d, J=5Hz), 5.77
(lH, d,d, J=5 and 9Hz), 7.38 (lH, s),
8.47 (lH, s), 9.49 (lH, s), 9.54 (lH,
d, J=9Hz), 12.57 (lH, broad s)
Example S.D.20
The following compounds were obtained accord-
ing to similar manners to those of Examples S.D.17 to
19 .
(1) 7-[2-Methylthiomethoxyimino-2-(2-formamido-
thiazol-4-yl)acetamido]-3-~1-methyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3250, 1780, 1675, 1550 cm~l
N.M.R. (d6-DMSO, ~) : 2.22 (3H, s), 3.72 (2H,
ABq, J=19Hz), 3.96 (3H, s), 4.33 (2H,
ABq, J=14Hz), 5.17 (lH, d, J=5Hz), 5.26
(2H, s), 5.85 (lH, d,d, J=5 and 8Hz),
7.48 (lH, s), 8.54 (lH, s), 9.78 (lH,
d, J=8Hz), 12.64 (lH, s)
(2) 7-[2-(2-Ethoxyethoxy)imino-2-(2-formamido-
thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3500, 3200, 1780, 1720,
1680 cm~l
N.M.R. (d6-DMSO, ~) : 1.13 (3H, t, J=7Hz),
3.2~4.0 (6H, m), 4.30 (2H, t, J=4Hz),
4.50 (2H, ABq, J=13Hz), 5.23 (lH, d,
J=5Hz), 5.87 (lH, d,d, J=5 and 8Hz),
Xl.
- 242 -
1 337522
7.48 (lH, s), 8.58 (lH, s), 9.60
(lH, s), 9.70 (lH, d, J=8Hz)
(3) 7-[2-(2-Formyloxyethoxy)imino-2-(2-formamido-
thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-
carboxylic acid (syn isomer).
I.R. (Nujol) : 1770, 1710, 1670 cm 1
N.M.R. (d6-DMSO, ~) : 3.50 (2H, m), 4.10~4.60
(4H, m), 4.79 (2H, m), 5.16 (lH, d,
J=5.0Hz), 5.81 (lH, d,d, J=5.0 and
8.0Hz), 6.58 (2H, broad s), 7.47
(lH, s), 8.28 (lH, s), 8.55 (lH, s)
(4) 7-[2-(2-Formyloxyethoxy)imino-2-(2-formamido-
thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3160, 1775, 1710, 1670 cm~
N.M.R. (d6-DMSO, ~) : 3.71 (2H, ABq,
J=18.0Hz~, 3.96 (3H, s), 4.00~4.54
(6H, m), 5.16 (lH, d, J=4.5Hz), 5.84
(lH, d,d, J=4.5 and 9.0Hz), 7.45
(lH, s), 8.24 (lH, s), 8.53 (lH, s),
9.70 (lH, d, J=9.OHz)
(5) 7-[2-(2-Formyloxyethoxy)imino-2-(2-formamido-
thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thio-
methyl-3-cephem-4-carboxylic acid (syn isomer).
X - 243 -
1 337522
-
I.R. (Nujol) : 3180, 1775, 1673 cm~l
N.M.R. (d6-DMSO, ~) : 3.75 (2H, m), 4.25~4.65
(6H, m), 5.22 (lH, d, J=5.0Hz), 5.88
(lH, d,d, J=5.0 and 9.0Hz), 7.49
(lH, s), 8.26 (lH, s), 8.57 (lH, s),
9.59 (lH, s), 9.71 (lH, d, J=9.OHz)
(6) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-form-
amido-hiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3250, 1775, 1720, 1680,
1540 cm~l
N.M.R. (d6-DMSO, ~) : 1.22 (3H, t, J=7Hz),
3.74 (2H, s), 4.20 (2H, q, J=7Hz), 4.77
(2H, s), 5.22 (lH, d, J=5Hz), 5.88
(lH, d,d, J=5 and 8Hz), 7.51 (lH, s),
8.58 (lH, s), 9.63 (lH, s), g.70
(lH, d, J=8Hz), 12.68 (lH, broad s)
X - 244 -
1 337522
(7) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-form-
amidothiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3250, 1780, 1725, 1680,
1540 cm~l
N-M-R- (d6-DMSO, ~) : 1.22 (3H, t, J=7Hz),
3.73 (2H, s), 3.97 (3H, s), 4.18
(2H, q, J=7Hz), 4.35 (2H, ABq, J=14Hz),
4.76 (2H, s), 5.18 (lH, d, J=5Hz), 5.86
(lH, d,d, J=5 and 9Hz), 7.48 (lH, s),
8.56 (lH, s), 9.67 (lH, d, J=9Hz),
12.69 (lH, broad s)
(8) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-
formamidothiazol-4-yl)acetamido]-3-(1-methyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer).
I.R. (Nujol) : 3180, 1785, 1725, 1690,
1550 cm~l
N-M-R- (d6-DMSO, ~) : 1.45 (9H, s), 3.72
(2H, ABq, J=17Hz), 3.96 (3H, s), 4.33
(2H, ABq, J=14Hz), 4.64 (2H, s), 5.17
(lH, d, J=5Hz), 5.84 (lH, d,d, J=5 and
9Hz), 7.46 (lH, s), 8.52 (lH, s), 9.62
(lH, d, J=9Hz), 12.61 (lH, broad s)
1 v,
~ ~b~ - 245 -
t 337522
-
(9) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-hexyl-lH-tetrazol-5-yl)thiomehtyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3250, 1780, 1680,
1633 cm~l
N.M.R. (d6-DMSO, ~) : 0.86 (3H, m), 0.97~1.53
(6H, m), 1.53~2.10 (2H, m), 3.70
(2H, m), 4.10~4.77 (4H, m), 5.00~5.50
(3H, m), 5.85 (lH, d,d, J=5.0 and
8.OHz), 6.80 (lH, s), 6.98~7.63
(7H, m), 9.71 (lH, d, J=8.OHz)
(10) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-form-
amidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1775, 1675, 1540 cm~
N.M.R. (d6-DMSO, ~) : 3.72 (2H, s), 4.45
(2H, ABq, J=13Hz), 5.18 (lH, d, J=5Hz),
5.30 (2H, s), 5.96 (lH, d,d, J=5 and
X
- 246 -
1 337522
8Hz), 6.67 (lH, d, J=2Hz), 7.50
(lH, s), 8.55 (lH, s), 8.90 (lH, d,
J=2Hz), 9.58 (lH, s), 9.79 (lH, d,
J=8Hz), 12.69 (lH, s)
(11) 7-[2-Methylthiomethoxyimino-2-(2-aminothiazol-
4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3340, 3200, 1775, 1670 cm~l
(12) 7-[2-Methylthiomethoxyimino-2-(2-aminothiazol-
4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thio-
methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3300, 1770, 1670, 1530 cm~l
(13) 7-[2-(2-Ethoxyethoxy)imino-2-(2-aminothiazol-
4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3160, 3100, 1780, 1670,
1630 cm~l
(14) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-amino-
thiazol 4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3220, 1780, 1680,
1630 cm~l
(15) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3230, 3100, 1780,
1680, 1630 cm~l
(16) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. tNujol) : 3300, 1775, 1730, 1675,
1630 cm~
X` - 247 -
1 337522
(17) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3340, 3200, 1775, 1675,
1630 cm~l
(18) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3230, 3110, 1775,
1675 cm~l
(19) 7-[2-Carboxymethoxyimino-2-(2-formamido-
thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3200, 1780, 1720, 1680,
1545 cm~l
(20) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3360, 3240, 3100, 1780, 1680,
1635 cm~l
X
- 248 -
1 337522
(Z~) 7-~2-~t-Butoxycarbonylmethoxyimino)-2-(2-
- ~ fo~mamidothia201-4-yl)acetamido]-3-~lH-tetra ol-5-yl)-
1~ thiomethyl-3-cephem-4-carboxyllc acid (syn isomer).
. r~ R. (Nujol) : 31tO, 1770, 17ZO, 1670 cm 1
- N.M.R. ~DMSO-d6, ~) : 1.44 (9H, s), 3.68 (2H, m),
~ 4.33 ~2H, AB~, J=12.0Hz), 4.6~ (2H, s),
5.16 (lH, d, J=5.OHz), 5.82 ~lH, dd,
J=;.O and 8.0H~), 7.43 (lH, s),
8.51 (lH, s), 9.56 ~lH, d, J=8.0Hz)
- (22-) -7-[2-(4-Fluorobenzyloxyimino)-2-{2-(2,2,2-
. trifluoroacetamido)~hiazol-4-yl}acetamido~-3-(1-methyl-
- l~-tet~azol-5-yl)-thiomethyl-;-cephem-4-c~rboxylic acid
(syn isomer).
-I.-~. (Nujol)- : 3370, 3180, 1760, 1710, 1680,
-3~ - 1650 cm ~
N.M.R. (DMSO-d6, ~) : 3.68 (2H, m), 3.92 ~3H, s),
4.32 (2H, m), 5.03-5.35 (3'~, m),
5.83 (lH, dd, J=5 and 8Hz),
6.99-7.70 (4H, m), 7.54 (lH, s),
3~ 9.87 (lH, d, Js8Hz)
- 249 -
-
-1 33~522
C2~) 7-~2-E~hoxycarDonylmethoxyimino-2-(2-formamido-
thiazol-i-yl) acetamido ] - 3-ClH-tetrazol-5;yl) t~Liomethyi -
3-cephem-4-car~oxylic acid Csyn isome ), mp 112 to 125C
(de~.).
I. R. (Nujol) : 3250, 1770, 1730 ? 1680 cm 1
N.M.R. (DMSO-d6, ~) : 1.20 (3H, t, J=8Hz),
3.71 (2H, m), 4.07 (2H, q, J=8Hz),
4.36 (2H, m), 4.77 (2H, m~,
5.20 ~lH, d, J=SHz), 5.88 (lH, dd, --
J=S and 8Hz), 7.50 (lH, s), 8.57 (lH, s),
g.67 (lH, d, J=8Hz), 12.38 ~lH, broad s)
.
(2~-) 7-~2-Benzyloxyimino-2-~2-aminothiazol-4-yl~-
IS acetamido~-3-(lH-tetrazol-S-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp 172 to 174C (dec.).
I. R. (Nujol) : 3250, 3150, 1`77Q, 1620 cm 1
N.M.R. (DMSO-d6, ~) : 3.67 ~2H, m), 4.33 C2H, m),
5.08-5.36 ~3H, m), 5.83 (lH, dd,
- J=4 and 8Hz), 6.88 (lH, s),
7.3~ (5H, s), 9.73 ~lH, d, J=8Hz)
(25) 7-[2-(4-Fluorobenzyloxyimino)-2-{2-~2,2,2-
trifluoroacetamido)thiazol-4-yl}acetamido~-3-(1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
(syrl iso~er). -
I. R. (Nujol) : 3200, 177Q, 1720, 1650 cm 1
N.M.R. (DMSO-d6, ô) : 3.73 (2H, ABq, Jz18Hz),
4.49 (2H, ABq, J=14Hz), 5.03-5.46 ~3H, m),
5.88 (lH, dd, J=4 and 8Hz),
7.03-7.84 (4H, m), 7.59 ~lH, s),
9.60 (lH, s), 9.88 (lH, d, J=8Hz)
3~
-- 250 --
1 337522
(2~ 7-~2-Cinnamyloxyimino-2-(2-formamidothiazol-4-
yl)acetamido~-3-(1,3,4-thiadiazol-2-yl)thiome;~yl-3-
cephem-4-carboxylic acid ~syn isomer).
I. R. (Nujol) : 3400-3100, 1780, 1680, 1540 cm 1
N.M.R. (DMSO-d6, ~) : 3.67 ~2H, m),
4.45 (2H, ABq, J=14Hz),
4.83 (2H, d, J=5Hz), 5.18 (lH, d, J=SHz),
5.87 (lH, dd, J=5 and 8Hz~, 6.65 (lH, s~,
6.12-7.0 (2H, m), 7.1-7.7 ~5H, m),
8.S3 (lH, s), 9.57 (lH, s),
9.73 (lH, d, J=8Hz), 12.6 ClH, broad s)
- (27) 7-~2-(4-Fluorobenzyloxyimino)-2-{2-(2,2,2- -
trifluoroacetamido)thiazol-4-yl}acetamido~-3-(lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
- (syn isomer).
I. R. (Nujol) : 3200, 1780, 1730, 1660 cm 1
20-
(2~ 7-~2-(4-Fluorobenzyloxyimino)-2-{2-(2,2,2-
trifluoroacetamido)thiazol-4-yl}acetamido3-cephalos-
~ poranic acid (syn isomer).-
I. R. (Nujol) : 3250, 1780, 1730, 166Q, 1630 cm
N.M.R. (DMSO-d6, ~) : 2.07 (3H, s), 3.59 (2H, m),
4.90 (2H, ABq, J=14Hz), 5.13-5.46 (3H, m),
5.90 ~lH, dd, J=5 and 8Hz),
7.30-7.77 (4H, m), 7.58 (lH, s),
;~ 9.68 (lH, d, J=4.0Hz)
(2g) 7-[2-(3,4-Dichlorobenzylo.xyimino)-2-{2-(2,2,2-
trifluoroacetami-do)thiazol-4-yl}acetamido~-cephalospora-
nic acid (syn isomer).
-35
~ 251 -
- 1 337522
I. R. ~Nujol) : 1780, 1730, 1650 cm 1
N~M.R. ~DMSO-d6, ~) . 2.03 ~3H, s), 3.57 ~2H, m~,
4.87 ~2H, ABq, J=12Hz), 5.17-5.23 ~3H, m},
5.~7 (tH, dd, J=6 and 8Hz),
S 7.33-7.73 (4H, m), g.87 tlH, d, J=gHz~
(3O) 7-[2-~3-Hydroxy-4-bromobenzyloxyimino)-2-(2-
formamidothiazol-4-yl)acetamido~-3-(1,3,4-thiadiazol-
: 2-yl)thiomethyl-3-cephem-4-carboxyllc acid (syn isomer).
~ I. R. (Nujol) : 3400-310~, 1780, 1680, 1540 cm 1
N.M.R. (DMSO-d6, ~) : 3.7 (2H, broad s~,
4.45 (2H, AB~, J-13~z), 5.13 (lH, d, J=~Hz),
5.18 (2H, s), 5.8Z ~lH, dd, J=S an~ 8Hz),
-1~ 6.97 ~lH, d, J=2Hz), 7.4 ~lH, s),
i.45 (l~,.d, J=8Hz), 8.5 (lH, s),
- 9.68 (1~, d, J=8Hz), 12.6 (lH, broad s)
:
~0 --- - - . .
-25
- t~) 7-~2-(t-Butoxycarbonylmethoxyimino)-2-(2-
aminothi~zol-4-yl)acetamido~-3-(lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
- --I-. R. (Nujol) : 3280, ~200, 1770, 1670, 1630 cm 1
(32) 7-[2-(4 -Fluoroben~yloxyimino) - 2 - (2 -aminothia~ol-
4-yl)acetami~o~-3-(1-methyl-lH-tetra~ol-5-yl)-thiomethyl-
3-cephem-4-ca~boxylic acid (syn isomer).
- 252 -
- 1337522
I. R. (Nujol) : 330a, 32ao, 177Q, 166Q, 162a, 160~-
(3~ 7-[2-Ethoxycarbonylmethoxyimino-2-~2-aminothiazol-
4-yl)acetamido~-3-(lH-tetra2O1-5-yl)thiomethyl-3-cepnem-
4-carboxylic acid (syn isomer), m? 168 to 185C ~dec.~.
I. R. ~Nujol) : 3250, 1765, 1670, 1625 cm 1
(~4 7-~2-(¢-Fluorobenzyloxyimino)-2-~2-aminothiazol-
4-yl)acetamido3-3-(1,3,4-thiadiazol-2-yl)thiomethyl-
3-ceph~m-4-carboxylic acid (syn isomer), mp 145 to 14gC
(dec.).
1'- - I. R. (Nujol) : 3250, 1765, 1650 cm 1
1~5 ) 7- ~2-Cinnamyloxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1,3,~-thiadiazol-2-yl-~thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
~0
I. R. ~Nujol) : 3350-3100, 1760, 1650, 1620,
1520 cm 1
~6) 7-~2-(4-Fluorobenzyloxyimino)-2-~2-aminothiazol-
4-yl)acetamido~-3-(lH-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer).
I. R. (Nujol) : 3300, 3200, 1770, 1660, 1630,
1600 cm 1
~7 ) 7-[2-(4-Fluoroben~yloxyimino)-2-(2-aminothiazol-
4-yl)acetamido]-cephalosporanic acid ~syn isomer),
mp 185 to 192CC (dec.~.
I. R. (Nujol) : 3380, 3250, 1780, 1700, 1650 cm 1
- 253 -
1 337522
(~ 7-~2-C3,4-Dichlorobenzyloxyimino)-2-C2-
- aminothiazol-4-yi)ace.amido~cephalosporanic acid
~syn isomer), mp 2Q0 to 205C ~dec.).
3 I. R. ~Nujol) : 1730, 16¢0, 160Q, 1230, 1020 cm
(~g) 7-[2-(;-Hydroxy-4-bromobenzyloxyimino)-2-(2-
~minothiazol-4-yl~acetamido]-3-(1,3,4-thiadiazol-2-
yl~thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
- 10
I. R. (Nujol) : 3400-3100, 1760, 1660, 1620,
1520 cm~l
(40) 7-r2-Carboxymethoxyimino-2-(2-aminothiazol-4-
-15 yl)acetamido]-3-(lH-tetrazol-5-yl)thiomethyl-3-cep~em-
4-carboxylic acid ~syn isomer), mp 178 to 190C (dec.)
I. R. (Nujol) : 3300, 3280, 1770, 1670, 1630 cm 1
~C ----
-
.
-. . ; . -
3~
_ 254 -
1 337522
Example S.D.21
A mixture of 7-[2-methylthiomethoxyimino-2-(2-
formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
(0.58 g.), conc. hydrochloric acid (0.405 g.), methanol
(8.7 ml.) and tetrahydrofuran (5 ml.) was stirred for 2
hours and 10 minutes at ambient temperature. The
solvent was distilled off under reduced pressure and the
residue was dissolved in a 10% aqueous solution of
sodium hydroxide (pH 7~8.5). An insoluble material was
filtered off and the filtrate was adjusted to pH 3.4
with 10% hydrochloric acid under ice-cooling and stirred
for 30 minutes. Precipitates were collected by
filtration, washed with water and dried to ~ive 7-[2-
methylthiomethoxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-
y - 255 -
1 33~52~
(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer) (0.4 g.).
I.R. (Nujol) : 3340, 3200, 1775, 1670 cm~
N.M.R. (d6-DMSO, ~) : 2.23 (3H, s), 3.74
(2H, s), 4.48 (2H, ABq, J=13Hz), 5.20
(lH, d, J=5Hz), 5.24 (2H, s), 5.83
(lH, d,d, J=5 and 9Hz), 6.83 (lH, s),
7.28 (2H, broad s), 9.62 (lH, s), 9.68
(lH, d, J=9Hz)
ExamPle S.D.22
A mixture of 7-[2-t-butoxycarbonylmethoxy-
imino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer) (2.3 g.), conc. hydrochloric acid (3.74 g.)
and methanol (35 ml.) was stirred for 2 hours and 40
minutes at ambient temperature. The solvent was
distilled off under reduced pressure and the residue was
dissolved in a 10% aqueous solution of sodium hydroxide
(pH 7~8). The aqueous solution was adjusted to pH 3.0
with 10% hydrochloric acid under ice-cooling and
stirring and stirred for 30 minutes. Precipitates were
collected by filtration, washed with water and dried to
give 7-[2-t-butoxycarbonylmethoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
(1.1 g.).
I.R. (Nujol) : 3300, 1775, 1730, 1675,
1630 cm~l
N.M.R. (d6-DMSO, ~) : 1.46 (9H, s), 3.67
(2H, s), 4.42 (2H, ABq, J=14Hz), 4.55
(2H, s), 5.16 (lH, d, J=5Hz), 5.78 (lH,
d,d, J=5 and 9Hz), 6.77 (lH, s), 7.21
(2H, s), 9.43 (lH, d, J=9Hz), 9.52
(lH, s)
~X
- - 256 -
-
~ 1 337522
ExamPle ~.~ 23
To a s~irred solution of sodium æcetate (2.7 g) in
water ~46 ml) was added 7^[2-~4-1uorobenzyloxyimino)-
2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}-acet~mido]-
S 3-(1,;,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-
carboxyl~c acid (syn isomer) ~2.3 g) and the mixture
w~s stirred for 20.5 hours at ambient temperature.
The reaction mixture w~s adjusted to pH 5.0 with 10%
hydrochloric acid af~er addition of ethyl acetate and
the resulting mixture was shaken. The a~ueous layer
was separated, w~shed twice with ethyl acetate and
adjusted to pH 3.0 with 10% hydrochloric acid.
Precipitates were collected by .iltration, washed with
water an~ dried to give 7-~2-(4-fluoro~enzyloxyimino~-
1; - 2-~2-aminothiazol-4-yl)acetamido~-3-(1,3,4-thiadiazol-
2-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn isomer)
(1.82 g), mp 145 to 149C (dec.).
I. R. (Nujol) : 3250, 1765, 1650 cm
N.M.R. (DMSO-d6, ~) : 3.73 ~2H, ABq, 3=18Hz),
4.48 (2H, ABq, J=14Hz), S.Ql-5.3g (3H, m),
5.85 ~lH, dd, J=4 and 8Hz), 6.83 (lH, s),
7.02-7.75 (4H, m), 9.63 (lH, s),
9.75 ~lH, d, J=8Hz)
2S
.
3~
_ 257 -
- 1 337522
Example S.D.24
The following compounds were obtained accord-
ing to similar manners to those of Examples S.D.21 to
23.
(1) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer).
I.R. ~Nujol) : 3320, 3200, 1770, 1670,
1610 cm~l
(2) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-hexyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3250, 1780, 1680,
1633 cm~l
(3) 7-[2-Methylthiomethoxyimino-2-(2-aminothiazol-
4-yl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thio-
methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3300, 1770, 1670, 1530 cm~
N.M.R. (d6-DMSO, ~) : 2.20 (3H, s), 3.72
(2H, s), 3.97 (3H, s), 4.36
(2H, s), 5.17 (lH, d, J=5Hz),
d~
J~ ~ - 258 -
~ ,~, .
1 337522
-
5.22(2H, s), 5.82 (lH, d,d,
J=5 and 8Hz), 6.82 (lH, s),
7.28 (2H, broad s), 9.60
(lH, d, J=8Hz)
(4) 7-[2-(2-Ethoxyethoxy)imino-2-(2-aminothiazol-
4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3160, 3100, 1780, 1670,
1630 cm~l
N.M.R. (d6-DMSO, ~) : 1.08 (3H, t, J=7Hz),
3.45 (2H, q, J=7Hz), 3.5~3.90 (4H, m),
4.20 (2H, t, J=4Hz), 4.47 (2H, ABq,
J=13Hz), 5.17 (lH, d, J=5Hz), 5.80
(lH, d,d, J=5 and 8Hz), 6.77 (lH, s),
9.55 (lH, s), 9.55 (lH, d, J=8Hz)
(5) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3220, 1780, 1680,
1630 cm~l
N.M.R. (d6-DMSO, ~) : 1.23 (3H, t, J=7Hz),
3.70 (2H, s), 3.97 (3H, s), 4.16 (2H,
q, J=7Hz), 4.35 (2H, s), 4.69 (2H, s),
5.15 (lH, d, J=5Hz), 5.80 (lH, d,d, J=5
and 9Hz), 6.81 (lH, s), 7.24
(2H, broad s), 9.54 (lH, d, J=9Hz)
(6) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3230, 3100, 1780, 1680,
1630 cm~l
X
- 259 -
1 337522
N.M.R. (d6-DMSO, ~) : 1.21 (3H, t, J=7Hz),
3.72 (2H, ABq, J=18Hz), 4.18
(2H, q, J=7Hz), 4.70 (2H, s), 5.20
(lH, d, J=5Hz), 5.84 (lH, d,d, J=5
and 8Hz), 6.84 (lH, s), 7.26 (2H, broad
s), 9.56 (lH, d, J=8Hz), 9.60 (lH, s)
(7) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3340, 3200, 1775, 1675,
1630 cm~l
N.M.R. (d6-DMSO, ~) : 3.68 (2H, s), 3.94
(3H, s), 4.32 (2H, ABq, J=14Hz), 4.70
(2H, s), 5.14 (lH, d, J=5Hz), 5.78
(lH, d,d, J=5 and 9Hz), 6.81 (lH, s),
7.1 (2H, broad s), 9.59 (lH, d, J=9Hz)
(8) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3230, 3110, 1775,
1675 cm~l
N.M.R. (d6-DMSO, ~) : 3.71 (2H, ABq, J=18Hz),
4.46 (2H, ABq, J=14Hz), 5.17 (lH, d,
J=5Hz), 5.27 (2H, s), 5.82 (lH, d,d,
J=5 and 8Hz), 6.66 (lH, s), 6.83 (lH,
s), 7.30 (2H, broad s), 8.87
(lH, s), 9.57 (lH, s), 9.75
(lH, d, J=8Hz)
(9) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-
30 yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 3240, 3100, 1780, 1680,
1635 cm~
- 260 -
- 1 337522
~0) 7-~2-Ben~yloxyimino-2-C2-aminothiazol-4-yl)-
.. . . . . .
acetamidoJ-3-(lH-tetrazol-S-yl? t~iomethyl-3-cep~em-
4-carboxylic 2cid (syn isomer~, mp ~72 to 174~ (dec.).
S I. R. ~Nujol) : 3250, 3150, 1770, 1620 cm 1
.. .i,~; .
: . - .
- : .
~0 ' .
(11) 7-~2-(t-Butoxycarbonylmethoxyimino~-2-(2-
aminothiaz~l-4-yl)acetamido]-~-(lH-tet azol-S-yl)- -
- thiomethyl-3-cephem-4-carboxylic acid (sy~ isomer).
I. R. (Nujol) : 3280, 3200, 1770, 1670-, 1630 cm 1
- . .
7-[2-(4-Fluoroben~yloxyimino)-2-~2-aminothiazol-
4-yl)acetam~do~ -3- (l-methyl-lH-tetrazol-S-yl~-thiomethyl-
~-cephem-4-carboxylic ~cid (syn isomer).
r. R. (Nujol) : 3300, 3200, 1770, 1660, 1620,
- 1600 cm 1
N.M.R. (DMSO-d6, ~) : 3.67 ~2H, m), 3.94 ~3H, s),
- 4.3Z (2H, m), 4.98-5.36 (3H, m),
3~ ~.78 (lH, dd, J=S and 8Hz), 6.72 (lH, s),
_ 261 -
1 337522
-
6.95-7.65 (4H, m), 9.65 (lH, d, J=8Hz)
(13) 7-2[2-Ethoxycarbonylmethoxyimino-2-(2-amino-
thiazol-4-yl)acetamido]-3-(lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer), mp 168 to 185C
(dec.).
I.R. (Nujol) : 3250, 1765, 1670, 1625 cm~
N.M.R. (d6-DMSO, ~) : 1.21 (3H, t, J=7Hz),
3.70 (2H, broad s), 4.18 (2H, q,
J=7Hz), 4.31 (2H, m), 4.72 (2H, broad
s), 5.17 (lH, d, J=4Hz), 5.82 (lH, dd,
J=4 and 7Hz), 6.83 (lH, s), 7.17 (2H,
broad s), 9.57 (lH, d, J=7Hz)
(14) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-amino-
thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 145 to 149C (dec).
I.R. (Nujol) : 3250, 1765, 1650 cm~l
(15) 7-[2-Cinnamyloxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-1(1,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350-3100, 1760, 1650, 1620,
1520 cm~l
N.M.R. (DMSO-d6, ~) : 3.47-3.97 (2H, m), 4.47
(2H, ABq, J=14Hz), 4.8 (2H, d, J=5Hz),
5.18 (lH, d, J=5Hz), 5.83 (lH, dd, J=5
and 8Hz), 6.83 (lH, s), 6.1-7.0 (2H,
m), 7.08-7.72 (5H, m), 9.6 (lH, s),
9.72 (lH, d, J=8Hz)
(16) 7-~2-(4-Fluorobenzyloxyimino)-2-(2-amino-
thiazol-
~: V
- 262
1 337522
_.
4-yl)acetamido]-3- (lH-tetra~ol-5-yl~thiomethyl-3-cephem-
4-carboxylic acid Csyn isomer).
.
I. R. ~Nujol) : 330a, 3200, 1770, 1660, 1630,
1600 cm 1
N.M.R. ~DMSO-d6, ~) : 3.69 (2H, ABa, 3=18Hz),
4. 35 (2H, ABq, J=15Hz), 4.93-5 .43 ~3H, m),
5 . 81 (lH, dd, J-5 and 8Hz), 6 . 80 ~lH, s),
6 .96-7. 70 ~4H, m~, 9. 73 (lH, d, J=8Hz)
(:L7) 7- ~2- ~4-Fluorobenzyloxyimino) -2- (2-aminothiazol-
4-yl)acetamido]cephalosporanic acid (sy~ isomer), mp
185 to 192C (dec.).
-1
I. R. (NU3O1): 3380, ;250, 1780, 1700, 1650 cm
N.M.R. (DMSO-d6, ~) : 2.Q2 (3H, s), 3.53 (2H, m),
4.84 (2H, ABq, J=13Hz), 5.13 (2H, s),
5.40 (lH, d, J=4Hz),
5. 79 (lH, dd, J=4 and 8Hz), 6 . 73 (lH, s),
Z0 6.96-7.63 (4H, m), 9.62 (lH, d, J=8Hz)
C~8) 7~ [2- (3,4-Dichlorobenzyloxyimino)-2-(2-amino-
thiazol-4-yl)acetamido] cephalosporanic acid- ~syn isomer),
mp 200 to 205C ~dec.).
2~
I. R. (Nujol): 1730, 1640, 16û0, 1230, 1020 cm 1
- N.M.R. (DMSO-d6, ~) : 2.00 (3H, s~, -
3.30 (2H, ABq, J=18Hz), 4 . 68-5 . 12 ~5H, m),
5 .60 (lH, dd, J=6 and 8Hz), 6. 72 (lH, s),
3a 7. 3Z- 7. 64 (3H, m), 9 . 60 (lH, d, J=8Hz)
( 1~3 7- [2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(2-
aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl3-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
3~
_ 263 --
3~52~ .
- I. R. (Nujol): 3400-31Q0, 17~0, 1660, 1620,
1520 cm
N.M.R. ~DMSO-d6? ~) : 3.72 C2H, broad s)~
4.47 (2H, ABq, J=14Hz), S.l (lH, d, J=5Hz),
5.22 (2H, s~, 5.83 ~lH, dd, J=5 and 8Hz),
6.85 (lH, s), 6.87 ~lH, dd, J-2 and 8Hz),
7.08 (lH, d, J=2Hz), 7.52 (lH, d, J=8Hz),
9.67 (lH, s), 9.77 ~lH, d, J=8Hz)
- (~O ) 7-t2-Carboxymethoxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(lH-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp 178 to 180C (dec.).-
- I. R. ~Nujol): 3300, 3280, 1770, 1670, 1630 cm 1
-
,
~ 20 -~ -
2~ -
;~
.
_ 264 -
- 1 337522
ExamPle S.D.25
Trifluoroacetic acid (4 ml.) was added under
ice-cooling to a stirred suspension of 7-[2-t-
butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)-
acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer) (1.0 g.) in anisole
(1 ml.), and the resultant mixture was stirred for 70
minutes at ambient temperature. The reaction mixture
was concentrated under reduced pressure and diethyl
ether was added thereto. Precipitates were collected by
filtration, washed with diethyl ether, dried, suspended
in water (10 ml.) and then dissolved in a 10% aqueous
solution of sodium hydroxide (pH 7-7.5). The solution
was adjusted to pH 3.0 with 10% hydrochloric acid under
ice-cooling and stirring and stirred for 30 minutes
under ice-cooling. Precipitates were collected by
filtration, washed with water and dried to give 7-[2-
carboxymethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-
3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer) (0.75 g.).
I.R. (Nujol) : 3360, 3240, 3100, 1780, 1680,
1635 cm~l
N.M.R. (d6-DMSO, ~) : 3.68 (2H, s), 4.46 (2H,
ABq, J=15Hz), 4.61 (2H, s), 5.17 (lH,
d, J=5Hz), 5.82 (lH, d,d, J=5 and 9Hz),
6.83 (lH, s), 7.23 (2H, broad s), 9.50
(lH, d, J=9Hz), 9.53 (lH, s)
ExamPle S.D.26
The following compounds were obtained accord-
ing to a similar manner to that of Example S.D.25.
_,_
X - 265 -
1 337522
(1) 7-[2-Carboxymethoxyimino-2-(2-formamido-
thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1780, 1720, 1680,
1545 cm~l
N.M.R. (d6-DMSO, ~) : 3.72 (2H, ABq, J=16Hz),
3.96 (3H, s), 4.35 (2H, ABq, J=14Hz),
4.67 (2H, s), 5.17 (lH, d, J=5Hz), 5.86
(lH, d,d, J=5 and 9Hz), 7.47 (lH, s),
8.52 (lH, s), 9.64 (lH, d, J=9Hz),
12.64 (lH, broad s)
(2) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3340, 3200, 1775, 1675,
1630 cm~l
(3) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-
yl)acetamido]-3-(lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp 178 to 180C (dec.).
I.R. (Nujol) : 3300, 3280, 1770, 1670,
1630 cm~l
N.M.R. (DMSO d6, ~) : 3.69 (2H, m), 4.32 (2H,
ABq, J=14Hz), 4.60 (2H, m), 5.14 (lH,
d, J=5Hz), 5.79 (lH, d,d, J=5 and 8Hz),
6.79 (lH, s), 9.47 (lH, d, J=8Hz)
~ ~r
- 266 -
~.
1 337522
Ex-ample ~);27
7-~2-(4-Fluorobenzyloxyimino)-2-~2-aminot~iazol-
4-yl)acetamido]cephalosporanic acid ~syn isomer) (1.1 g)
and 1,3,4-thiadiazole-2-thiol ~0.2~ g) were added to a
S stirred solution of sodium ~icarbonate (0.34 g) in pH
6.8 phosphate buffer ~30 ml) and the mixture was stirred
for 3 hours at 60 .o 65C. The reaction mixture was
cooled and adjusted to pH 3 with 10% hydrochloric acid.
Precipitates were collected by filtration, washed with
water and dried to gi~e 7-~2-(4-fluorobenzyloxyimino)-
2-(2-aminothiazol-4-yl)acet~amido~-3-(1,3,4-thiadiazol-2- --
yl)thiomethyl-~-cephem-4-carboxylic acid (syn isome~)
(0.45 g), mp 145 to 149C ~dec.).
-
1~ I. R. (Nujol) : 3250, 1765, 1650 cm 1
N.M.R. (DMSO-d6, ô) : 3.73 ~2H, 4Bq, J=18Hz),
4.48 (2H, ABq, J-14Hz), 5.01-5.39 (;H, m),
5.85 (lH, dd, J=4 and 8~z), 6.83 (lH, s),
7.02-7.7~ (4H, m), 9.63 (lH, s),
9.75 (lH, d, Jz8Hz)
mT-le ~ 2~ -
The following compounds were obtained according to
a similar manner to that of Example ~.D.27,
~1~ 7-t2-Methylthiomethoxyimino-2-(2-.ormamidothiazol-
4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I. R. (Nujol~: 3230, 1780, 1680, 1550 cm 1
(2) 7-t2-Benzyloxyimino-Z-(2-aminothiazol-4-yl)-
acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomet~yl-3-cephem-
3S 4-carboxylic acid (SyIl isomer).
_ 267 -
- 1 337522
I. R. (Nujol) : 332Q, 320~, 1770; 1670, 1610 cm 1
(3) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-forma2ido-
thiazol-4-yl)acetamido]-3-~1,3,4-thiadia7O1-2-y~-
S thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I. R. (Nujol) : 3225, 1780, 1725, 1685, 1550 cm 1
(4) 7-[2-Methylthiomethoxyimino-2-~2-formamidothiazol-
- 4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
I. R. (Nujol) : 3250, 1780, 1675, 1550 cm 1
1~ (5) 7-~2-(2-Ethoxyethoxy)imino-2-(2-formamidothiazol-
4-yl)acetamidoJ-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
.
I. R. (Nujol) : 3500, 3200, 1780, 1720, 1680 cm 1
(6) 7-~2-Ethoxycar~onylmethoxyimino-2-(2-formamido-
thiazol-4-yl)ace.amido]-3-(1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic æcid (syn isomer).
2S I. R. (Nujol) ; 3250, 1775, 1720, 1680t 1540 cm 1
- (7) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-formamido-
thiazol-4-yl)acetamido]-3-~1-methyl-lH-tetrazQl-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
3Q
I. R. (Nujol) : 3250, 1780t 1725, 1680, 154~ cm 1
~8) 7-~2-t-ButDxycarbonylmethoxyimino-2-(2-formamido-
thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetr~ol-5-yl)-
3~ thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
- _ 268 -
1 337522
I. R. CNujoll . 318~, 1785, 1725, 1690, 1~50 cm l -
(9) 7-~2-Benzyloxyimino-2-~2-aminothiazol-4-yl)-
acetamido~-3-(1-hexyl-lH-tetrazol-S-yl)thiomethyl-3-
cephem-4-carboxylic acid ~syn isomer).
I. R. (Nujol) : 3350, 3250, 1780, 1680, 163a cm 1
~10) 7-[2-(3-Isoxazolyl)methoxyimino-2-~2-formamido-
thiazol-4-yl)acetamid~1-3-(1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I. R. (Nujol) : 3200, 1775, 1675, 1540 cm 1
(11) 7-~2-Methylthiomethoxyimino-~-(2-aminothiazol-
4-yl)acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethy}-3-
;cephem-4-carboxylic acid ~syn isomer).
I. R. ~Nujol) : 3340, 3200, 1775, 167~ cm 1
- 20
~12) 7-~2-Methylthiomethoxyimino-2-(2-aminothiazol-
4-yl)acetamido~-3-(1-methyl-lH-tetrazol-S-yl)thiome.hyl-
3-cephem-4-carboxylic acid ~syn isomer).
I. R. ~Nujol) : 3300, 177G, 1670, 153B cm 1
~13) 7-[2-(2-Ethoxyethoxy)imino-2-(2-aminothiazol-
- 4-yl)acetamido]-3~ ,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid ~syn isomer).
I. R. ~Nujol) : 3160, 3100, 1780, 1670, 1630 cm 1
(14~ 7-~2-Ethoxycarbonylmethoxyimino-2-(2-amino-
thiazol-4-yl)ace;amido~-3-tl-methyl-lH-tetrazol-5-yl~-
thiomethyl-3-cephem-4-carboxylic acid ~syn isomer).
_ 269 -
-- 1 337522
I. R. (Nujol) : 3350, 322Q, 17~, 168Q~163Q cm..l
(lS) 7-[2-Ethoxycarbonylmethoxyimino-2-C2-aminothiazol-
4-yl)acetamido]-3-~1,3,4-thiadiazol-2-yl)-t~iomethyl-3-
S cephem-4-carboxyllc acid (s~ isomer).
I. R. (Nujol) : 3a50, 3230, 3100, 1780, 1680,
1630 cm 1
(16) 7-[2-t-Butoxyc2rbonylmethoxyimino-2-(2-amino-
thia ol-4-yl)acetamido~-3-~1,3,4-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
. I.. R. ~Nujol~ : 3300, 1775~ 1730, 1675, 1630 cm I
(17) 7-~2-Carboxymethoxyimino-2-(2-aminothiazol-4-
yl)acetamido~-3-~1-methyl-lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic.acid (syn isomer).
I. R. ~Nujol) : 3340, 3200, 1775, 1675, 1630 cm 1
(18~ 7-~2-~3-Isoxazolyl)methoxyimino-2-~2-amino-
thiazol-4-yl)acetamidoJ-3-~1,3,4-thiadiazol-2-yl3-
thiomethyl-3-cephem-4-c~rboxylic acid ~syn isomer).
~
- I. R. ~Nujol) : 3350, 3230, 3110, 1-775, 1675 cm 1 .
(19) 7-~2-Carboxymethoxyimino-2-~2-formamidothiazol-
4-yl)acetamido]-;-(1-methyl-lH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
I. R. (Nu~ol) : 3200, 1780, 1720, 1680, 1545 cm 1
(20) 7-[2-Carboxymethoxyimino-2-~2-aminothiazol-4-
yl)acetamido~-3-~1,3,4-thiadiazol-2-yl)thiomethyl-3-
- 270 -
~'
~3 .
` - 1 337522
.
cephem-4-cærboxylic acid Csyn isomer).
. .
I. R. (Nujol) : 3360, 3240, 3100, 1780, 1680,
1635 cm 1
.5
(21) 7-[2-(t-Butoxycarbonylmethoxyimino)-2-~2-
formamidothiazol-4-yl)acetamido]-3-(lH-.etrazol-S-yl)
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
- 10 I. R. ~Nujol) : 3170, 1770, 1720, 1670 cm 1
(22) 7-~2-Ethoxycarbonylmethoxyimino-2-(2-formamido-
thizzol-4-yl)acetamido]-3-(lH-tetrazol-S-yl)thiomethyl-
3-cephem-4-carboxylic-acid ~syn isomer), mp 112 to 125C
(dec.).
I. R. (Nujol) : 3250, 1770, 1730, 1680 cm 1
(23) 7-~2-Benzyloxyimino-2-~2-aminothiazol-4-yl)-
acetamido]-3-(lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp 172 to 174C (dec.).
I. R. (Nujol) : 3250, 3150, 1770, 1620 cm 1
(24) 7-~2-Cinnamyloxyimino-2-(2-formamidothiazol-4-
yl)acetamido]-3~ ,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I. R. ~Nujol) : 3400-;100, 1780, 1680, 1540 cm
- (25) 7-~2-~3-Hydroxy-4-bromobenzyloxyimino)-2-(2-
formamidothiazol-4-yl)acetamido]-3-(l~3~4-thiadiazol-2
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I. R. (Nujol) : 3400-3100, 1780, 1680, 1540 cm 1
~i _ 271 -
t 337522
(26) 7-[2-(t-Butoxycarbonylmethoxyimino)-2-~2-
-10 aminothiazol-4-yl)acetamido]-3-(lH-tetrazol-5-yl)-
thiomethyi-3-cephem-4-carboxylic acid ~syn isomer).
.
I. R. ~Nujol) : 3280, 3200, 1770, 1670, 1630 cm 1
t2~) 7-[2-(4-Fluorobenzyloxyimino~-2-(2-aminothiazol-
- 4-yl)acetamido3-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-
- 3-cephem-4-carboxylic acid ~syn isomer). :-:- - -
.
I. R. ~Nujol) : 3300, 3200, 1770, 1660, 16Z0,
~ - 1600 cm I
(28) 7-~2-Ethoxycarbonylmethoxyimino-2-(2-amino.hiazol-
4-yl)acetamido~-3-(lH-~etrazol-S-yl)thiomethyl-;-c~phem-
4-carboxylic acid ~syn isomer), mp 168 to 185C (dec.).-
- 25
-- - I. R. (Nujol) : 3250, 1765, 1670, 1625 cm 1 ~-
(2g) 7-t2-clnnamyloxyimino-2-~2-aminothiazol-4-yl)-
acetamido]-3-~1,3,4-thiadiazol-2-yl)thiomethyl-~-cephem-
4-carboxylic acid ~syn isomer).
I. R. ~Nujol) : 335~-3100, 1760, 1650, 16Z0,
- - , ,' . '
~O) 7-t2-(4-Fluorobenzyloxyimino)-2-(2-aminothiazol-
_ 272 --
1 33;7522
- 4-yl)acetamido~-3-~lH-tetra7O1-5-yl)thiomethyl-3-cephem-
- . 4-carboxylic acid Csyn isomer).
. .
I. R. ~Nujol) : 3300, 3200, 1770, 1660, 1630,
160Q cm-l
.
(3~ 7-~Z-(3-Hydroxy-4-bromo~enzyloxyimino)-2-~Z-
aminothia7O1-4.-yl)acetamido~-3-~1,3,4-`t~iadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
- I. R. (Nujol) : 3400-310.0, 1760, 1660, 16Z0,
1520 cm~l
.~ (3~ 7-t2-Carboxymethoxyimino-2-~2- minothiazol-4-
-I~ yl)acet~mido~-3-(}H-tetrazol-S-yl)thiomethyl-3-cephem-
4-car~oxylic acid (syn isomer), mp 178 to 180~ (dec.).
I. R. ~Nujol) : 3300, 3280, 1770, 1670, 1630 cm 1
~0
2~ . .
'- ' - -'
;O
-3~ .
. - 273 - -
Exam~le ~ ~2q 1 337522
Phosphorus oxychloride (974 mg) was added
dropwise over 3 minutes at -5 to -10C to a solution
of dimethylformamide ~464 mg) in tetrahydrofuran ~â ml).
S Tetrahydrofuran (12 ml) was added thereto and ~rter
10 minu.es, 2-cyclopentyloxyimino-2-~2-formamido-
thiazol-4-yl)acetic acid ~syn isomer)(1.5 g) ~as added
thereto at -5 to -10~C. The mixture was stirred for
10 minutes to give ~ clear solution. On the other
1-0 hand, 7-amino-3-~,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid (2.27 g) was dissolved under
stirring in a solution of triethylamine (1.3 g) in
50~ aqueous acetone (2a ml).
- To the solution was added dropwise with st;rring the
tetrahydrofuran solution obtained above at 0 to 5C
and at pH 6.5 to 7.5. After-stirring for 30 minutes
a, the same temperature, the reaction mixture ~as
poured in.o a mixture of ~-ater and ethyl acetate and
adjusted to pH 3.0 with 10% hydrochloric acid. After
filterrirg off an insoluble material, the filtrate was
twice extracted with ethyl acetate. The extracts
- were washed 3 times with a saturated a~ueous solution
of sodium chloride and dried over magnesium sulfate.
The solvent was distilled off and the residue was
triturated with diethyl ether, collected by filtration
and d,ied to give 7-[2-cyclopentyloxyimino-2-(2-
formamidothiazol-4-yl)acetamidol-3-(1,3,4-thiadiazol-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer~(2.8 g).
1. R. (Nujol) : 3240, 3180, 1780, 1670, 1540 cm
- 274 _
` t 337522
N.M.R. ~DMSO-d6, ô~ : 1.2-2.3 (8H, m), 3.72
(2H, s), 4.45 ~2H, A~q, J=14Hz), 4.74 ~lH, -'
broad s), 5.17 (lH, d, J=SHz), 5.82 (lH,
dd, J=S and 8Hz), 7.36 (lH, s), 8.56
~lH, s~, 9.52 ~lH, s), 9.55 (lH, d, J=8H ),
12.56 ~lH, broad s)
Exam~le S ~30
The following compounds were obtained according
to a similar manner to that of Example ~ ~ 29
~1) 7-[2-Cyclopentyloxyimino-2-{2-~2,2,2-
trifluoroacetamido)thiazol-4-yl}acetamido~cephalosporanic
acid (syn isomer), powder.
~2) 7-[2-Cyclopentyloxyimino-2-(2-aminothiazol-4-yl)-
- 15 acetamidolcephalosporanic acid ~syn isomer).
I.R. ~Nujol~ : 3270, 1760, 1650 cm 1
N.M.R. ~D~ISO-d6,~) : 1.27-2.17 (8H, m),
2.04 ~3H, s), 3.58 ~2H, m), 4.74 ~lH, m),
4.87 (2H, ABq, J=13.0Hz~, 5.17 (lH, d,
J=4.0Hz), 5.82 (lH, dd, J=4.0 and 8.0Hz),
6.74 (lH, s), 9.54 (lH, d, 3=8.0H7).
(3) 7-~2-Cyclopentyloxyimino-2-(2-formamidothia201-
4-yl)acetamido~-3-(lH tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3150, 1770, 1660 cm 1
N.~.R. (D~SO-d6,o~ : 1.37-2.33 ~8~, m),
3.75 (2H, m), 4.38 (2H, ABq, J=14.0Hz),
4.7~ (lH, m), 5.21 (lH, d, J=S.OHz),
5.88 (lH, dd, J=S.O and 8.0Hz),
1 _ - 275 -
7.42 (lH, s), 8.56 (lH, s), 9.62 (lH,
d, J=8.OHz)
~4) 7-~2-Cyclopentylo~yimino-2-(2-aminothiazol-4-yl)-
S acetamido~-3-(lH-tetrazol-S-yl)thiomethyl-a-cephem-4-
czrbo~ylic acid (syn isomer), mp 185 to 190C (dec.).
I.R. (~ujol) : 3260, 1760, 1640 cm 1
N.M.R. (DMSO-d6,~) : 1.17-2.30 (8H, m), 3.71
(2H, ABq, J=18.0Hz), 4.32 (2H, ABq,
J=13.0Hz), 4.68 (lH, m), 5.14 (lH, d, J=4.0Hz),
5.76 tlH, dd, J=4.0 and 8.0Hz), 6.71 (lH, s),
9.SO (lH, d, J=8.0Hz)
~S} 7-[2-Cyclopentyloxyimino-2-{2-(2,2,2-
lS trifluoroacetamido)thiazol-4-yl}acetamido]-3-(1-methyl-
lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer).
I.R. (Mujol) : a200, 1780, 1720, 1680, 1625 cm 1
N.M.R. ~DMSO-d6,~) : 1.34-2.23 (8H, m),
3.77 ~2H, m), 3.98 ~3H, s), 4.;6 (2~, m),
4.78 (lH, m), 5.21 (1~, d, J=4.0Hz),
5.87 (lH, dd, J=4.0 and 8.0Hz), 7.52
(lH, s), 9.71 ~lH, d, J=8.0Hz)
(6) 7-~2-Cyclopentyloxyimino-2-(2-aminothia:ol-4-yl)-
acetamido~-3-(1-me.hyl-lH-tetrazol-S-y~)thiomethyl-3-
cephem-4-carboxylic acid (syn isomer), mp 152 to 154C
(dec.).
I.R. ~Nu3ol) : 3aOO, ;200, 1770, 1660, 1620 cm 1
N.M.R. (D~ISO-d6,~) : 1.28-2.11 (8H, m),
- 276 -
.
~ 337522
- 3.74 (2H, m), 3.97 ~3H, s~, 4.35 (ZH, m),
4.72 (lH, m), 5.17 (lH, d, J=S.OHz),
5.80 (lH, dd, J=S.O and 8.0Hz), 6.74 (lH,
s), 9.54 (lH, d, J=8.0Hz)
(7) 7-[2-Cyclopentyloxyimino-2-(2 -2mi nothiazol-4-
yl)acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic acid ~syn isomer~.
I.R. (Nujol) . 3260, 1760, 1645, 1520 cm 1
N.M.R. (DMSO-d6,~) : 1.2-2.3 ~8H, m),
3.69 ~2H, s), 4.43 ~2H, ABq, J=14Hz),
4.66 ~lH, broad s), 5.12 ~lH, d, J=SHz),
5.73 ~lH, dd, J=5 and 8Hz), 6.67 (lH, s),
7.17 (2H, broad s), 9.43 ~lH, d, J=8Hz),
9.Sl (lH, s)
Example ~ 31
Conc. hydrochloric acid (1.8 gJ was added to a
solution af 7-~2-cyclopentyloxyimino-2-(2-
formamidothia~ol-4-yl)acetamido~-3-(1,3,4-thiadiazol-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
(2.7 g) in methanol (27 ml) and the mixture was
stirred for 2 hours at ambient tempera.ure. An insolu-
ble material was filtered off and ;he filtrate was
concen~ra;ed to dryness under reduced pressure and
the residue was triturated with diethyl ether and
dried to give 7-[2-cyclopentylo~yimino-2-~2-
amino~hia_ol-4-yl)acetamido]-3-~1,3,4-thiadiazol-2-
yl)thiomethyl-3-cephem-4-carbo~ylic acid hydrochloride
(syn isomer)(2.9 g). The powder (2.9 g) was dissol~ed
~ 277 _
- ~ 1 337522
~ in an aqueous solution of sodium hydroxide to adjust
pH 7.5. The solution was adjusted to pH 3.0 and ~'
pTecipitates were collected by filtration and washed
with water to give 7-[2-cyclopentylo~yimino-2-(2-
aminothiazol-4-yl)acetamido]-3-(1,~,~-.hiadia ol-2-
yl)thi~methyl-~-cephem-4-carbo~ylic acid (syn isomer)
~1.95 g)-
I.R. (Nujol~ 3260, 1760, 1645, 1520 cm 1
N-M-R- ~DMS0-d6,~) : 1.2-2.3 ~8H, m),
3.69 (2H, s~, 4.43 ~2H, ABqr J=14Hz),
4.66 (lH, broad s~, 5.12 (lH, d, J=SH~),
5.73 (lH, dd, J=S and 8Hz), 6.67 ~lH, s),
7.17 (2H, broad s), 9.43 ~lH, d, J=8Hz),
9.51 (1~, s)
Example ~ 32
7-[2-~yclopentyloxyimino-2-{2-(2,2,2-
;rifluoroacetamido)thiazol-4-yl}acetamido]-3-(1-
methyl-lH-tetra70l-;-yl)thiomethyl-3-cephem-4-
carboYylic acid (syn isomer)(2.~ g) was added to a
- solution of sodium acetate trihyd!rate (5.8 g) in
water ~25 ml), and tetrahydrofuran ~8.0 ml) was
added thereto to give clear so1ution. The solution-
was stirred for 16 hours at ambient temperature.
To the reaction mixture were added water and ethyl
acetate and the mi~ture was adjus.ed to pH 6.2 with
a saturated aqueous solution of sodium bicarbonate.
The separated aqueous layer was washed twice with
ethyl acetate and adjusted to pH 3.0 with 10% hydro-
- ~ chloric acid. PIecipitates were collected by
, _ 2Z8 -
1 337522
~.
filtration, wasned with water and dried under reduced
pTessure to give 7-[2-cyclopentyloxyimino-2-(2-
aminothiazol-4-yl)acetamido~-3-(1-methyl-lH-tetrazol-
5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer)(1.63 g), mp 152 to 154CC ~dec.).
I.R. (Nujol) : 3300, 3200, 1770, 1660, 1620 cm 1
N.M.R. (DMSO-d6,~) : 1.28-2.11 (8H, m), 3.74
(2H, m), 3.97 (3H, s), 4.35 (2H, m),
4.72 (lH, m), 5.17 (lH, d, J=5.0Hz),
5.80 ~lH, dd, J=5.0 and 8.0Hz), 6.74 (lH, s),
9.54 (lH, d, J=8.0Hz)
Exam~le S~33
The following compounds were ob~ained according
to similar manners to those of Examples ~iD 31 o~d 32.
(1) 7-~2-Cyclopentyloxyimino-2-(2-aminothiazol-4-
yl)ace.amido~cep'nalosporanic acid (syn isomer).
I.R. (Nu~ol) : 3270, 1760, 165~ cm 1
~.M.R. (DMSO-d6,~) : 1.27-2.17 (8H, m~,
2 . 04 (3H, s), 3.58 (2H, m), 4.74 (1~, m),
4.87 (2H, ABq, J=13.0Hz), 5.17 (lH, d,
Jz4.0Hz), 5.82 (lH, dd, J=4.0 and 8.0Hz)
- 6.74 (lH, s), 9. 54 ~lH, d, J=8.OHz)
25 (2) 7- [2-Cyclopentyloxyimino-2- (Z-aminothia~ol-
4-yl)ace.amido~-3-(1~-tet.azol-5-yl3thiomethyi-3-
cephem-4-carbo~ylic ~cid (syn isomer), mp 18~ to
190C ~dec.).
I.~. (Nu301) : 3260, 1760, 1640 cm 1
N.M R. ~DMSO-d6,~) : 1.17-2.30 (8H, m),
- 279 -
1 337522
..~
3.71 (2H, ABq, J=18Hz), 4.32 (2H, ABq,
J=13.0H~, 4.68 (lH, m), 5.14 (lH, d,
3=4.OH7), 5.76 (lH, dd, J=4.0 and 8.OHz),
6.71 (lH, s), 9.50 (1~, d, J=8.0Hz)
(3) 7-~2-Cyclo entylo~imino-2-(2-a~inothi~zol-4-yl)-
acetamido]-3-(1-allyl-IH-tetrazol-5-yl)thiometh~1-3-
cephem-4-carbox~lic acid (syn isomer), mp 140 ~o ~45 ~(dec.).
I R (~ujol): 3300, 1770, 1660, 1620 cm ~
N M R (d6-DMSO,~ 6-2.26(8~, n), 3.73
(2H, m), 4.41(2H, ABq, J=14Hz), 4.68(1H, m),
4.89-5.52(5H, m), 5.62-6.43(2~, m), 6.73(1~,
s), 9.51(1H,d, J=8Hz)
E~ample S. D. 34 - -
The following compound was obtained according t~
a s;~ r manner to that of E~ample S.D. 29 or Example
S.D. ~1.
7-[2-Cyclohe~yloxyimino-2-(2-aminothiazol-4-yl)acet-
amido~¢ephalos~oranic acid (syn isomer).
I P~ (~ujol): 3400-3200, 1780, 1740, 1670,
1630, 1530 cm 1
N M R (d6-DMSO,~): 9.~6 (lH, d,J=8Hz), 6.72
(lH, s), 5.76 (lH, ad, J=5 and 8 Hz), 5.10
(LH, d, J=5Hz), 1.84 (2H, ABq~ J=13Hz),
4000 (lH, m), 3,50 (2~, broad s), 2.00
(3H, s), 1.00-2.00 (lOH, m)
- 280 -
~ 337522
PreParation S.D.8
The following compounds were obtained in any
of a similar manner to those of aforesaid Preparations.
(1) Ethyl 2-cyclopentyloxyimino-3-oxobutyrate (syn
isomer), oil.
I.R. Film : 1740, 1670, 1495, 1430 cm~
max
N.M.R. ~(CC14, ppm) : 1.32 (3H, t, J=7Hz),
1.4-2.2 (8H, m), 2.33 (3H, s), 4.27
(2H, q, J=7Hz), 4.87 (lH, m)
(2) Ethyl 4-chloro-2-cyclopentyloxyimino-3-
oxobutyrate (syn isomer), oil.
I.R. Film : 1735, 1750, 1465, 1435 cm 1
max
N.M.R. ~(CC14, ppm) : 1.33 (3H, t, J=7Hz),
1.3-2.4 (8H, m), 4.28 (2H, q, J=7Hz)
4.46 (2H, s~, 4.86 (lH, s)
(3) Ethyl 2-(2-aminothaizol-4-yl)-2-
cyclopentyloxyiminoacetate (syn isomer), mp. 134 -136C.
I.R. Nujol : 3490, 3450, 3250, 3120, 1735,
~max 1540, 1460 cm~l
N.M.R. ~(DMSO-d6) : 1.25 (3H, t, J=7Hz), 1.62
(8H, broad s), 4.27 (2H, q, J=7Hz),
4.70 (lH, m), 6.85 (lH, s),
7.20 (2H, s)
(4) 2-(2-Aminothiazol-4-yl)-2-cyclopentyloxy-
iminoacetic acid (syn isomer), mp. 186C (dec.).
I.R. Nujol : 3330, 3120, 1635, 1450 cm~
max
N.M.R. ~(DMSO-d6) : 1.1-2.2 (8H, m), 4.68
(lH, m), 6.81 (lH, S), 7.18 (2H,
broad s).
'~ X
- 281 -
1 337522
l5) 2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-
2-cyclopentyloxyiminoacetic acid (syn isomer).
I.R. Nujol : 3200, 3130, 1720, 1590, 1580 cm~
max
N.M.R. ~(DMSO-d6) : 1.34-2.22 (8H, m), 4.81
(lH, m), 7.71 (lH, s)
(6) 2-Allyloxyimino-2-(2-formamidothiazol-4-yl)-
acetic acid (syn isomer).
I.R. (Nujol) : 3110, 1730, 1660, 1540 cm~l
N.M.R. (d6-DMSO, ~) : 4.70 (2H, m), 4.13-5.60
(2H, m), 5.73-6.27 (lH, m), 7.57
(lH, s), 8.35 (lH, s)
(7) To acetic anhydride (32 g.) was added formic
acid (14.4 g.) under ice-cooling and stirred at 40 to
45C for an hour. 2-(2-Aminothiazol-4-yl)-2-cyclo-
pentyloxyiminoacetic acid (syn isomer, 20 g.) and
tetrahydrofuran (100 ml.) were added to the solution
under ice-cooling and stirred at 35C for 3 hours.
After the solution was concentrated in vacuo, the
residue was pulverized with diisopropyl ether, and dried
over phosphorus pentoxide to give 2-(2-formamidothiazol-
4-yl)-2-cyclopentyloxyiminoacetic acid (syn isomer,
9 04 g ?, mp. 158C (dec.).
I.R. Nujol : 3100, 1730, 1695, 1685, 1550,
max 1495 cm~l
N.M.R. ~(DMSO-d6) : 1.2-2.3 (8H, m), 4.77 (lH,
quintet, J=4Hz), 7.93 (lH, s), 9.37
(lH, s).
Preparation S.D.9
The following compound was obtained in any of
a similar manner to those of aforesaid Preparations. 2-
Cyclohexyloxyimino-2-(2-aminothiazol-4-yl)acetic acid
(syn isomer), mp 148C (dec.).
- 282 -
