Note: Descriptions are shown in the official language in which they were submitted.
This invention relates to intermediates and their
preparations, useful in the prepara-tion of cephem compounds.
Mbre partieularly, the invention is concerned with intermediates
for new 7-substituted-3-eephem and cephamr4-carbo~ylic acid and
pharmaeeutically aeceptable salt thereof, whieh have ant~nicrobial
activities.
This applieation is a division of Canadian Patent
Application Serial No. 342,801 filed December 28, 1979.
The cephem compounds can be used in the prophylactic
13 and therap_utic treatment of infeetious diseases in hu~an being
and animals.
The new ~-substituted-3-eephen and cepham-4-earboxylie
aeids and pharmaeeutieally aceeptable salts -thereof, exhibit
exeellent antimicr~bial activities against a wide variety of
pathogenic mieroorganisms including Gram negative and Gram positive
bacteria.
,, -1-
-- 2 --
m e 7~substituted-3-cepl~em and cepham-4-c æboxylic
acids can be represented by the ollawing general formula (I).
Rl ~ ~ C-C~N.~ R (I)
~ R5
wherein Kl is amino or a protected amino, R is hydrogen, acyl,
aryl which may ke substituted with suitable substituent~s),
lower alXyl substituted with suitable substituentts), lower
alkenyl, lower aLkynyl~ cycloalkyl which may be substituted with
suitable substituent(s), cyclo(lawer)alkenyl, o~ S or O
containing 5-m~mbered heterocyclic group substituted with oxo
group(s), R3 is hydrogen or lower a~ylJ R4 is hydrogen; acyloxy
~lower)alkyl; acylthio(lawer)-alkyl; ~yridinium(lawer)aIkyl which
may be substltuted with suitable substituent~s); a ~eterocyclic-
-thio~ er~alkyl which may be substituted wi~h suitable substi-
tuent~s); lower alkyl; halogen; or hydroxy; and
, ,!
~8;Z~
R5 is carbo~y or a protected carboxy, wherein R5 is COO ~hen R4
is pyridinium(lower)alkyl which may be substituted with suitable
substituent(s), and the heavy solid line means single or double
bond.
The 7-substituted-3~cephem and cepham-4-carboxylic
acids (I) can be prepare~ by the following processes:
^ 4 - .
.
Proces s
___
H2NT~ 4 ~ R ~G-COO~
,. ~ R5 N
OR
~II) ~III)
or i*s reactive deTivative~ or :Lts reac~ive deriva-
at the amino group or a tive a~ the ca~boxy
salt ~hereof group or a salt thereof
Rl ~~'S~ C CONHT~ 3
~ 2 R5
OR
or a sal~ thereo
Process 2
~ Elimi:~ation of ~he
CONH~ ~ 3 protective group
N O1 N ~R4 f
OR~ ~5a
~Ia~
? ' or a. salt thereof
~1 ~Ls~ ~ ~ c ONH~ S~R
N O
~R2 ~OOH
~ Ib~
or a s alt ~he re of
3~
2~
.
Process 3
__
Rl~ ~C-CONH~A R4a R
OR R
. . (Ic)
or a salt thereo~ or its reactive derivative
1~
Rl~ C-CONH~S R3
5 ~ RS
OR
~Id~
or a sal-t thereof
Process 4
2~ 3 Elimi~a~io~ of ~he
Rl~rC-CONH~- S ~_ R pro~ec1:ive group of
~;~N, Il J~ N ~ R4c a~
ORZ R
I e ~
. or a salt thereof
~.l ~S~t G - ~ON~ R
3a ,
(I~)
o~ a salt thereof
3~
ElimlrLatio:n o:E the ~rotective
grou~ o~ ~o
CO~ R4 _ =~
S 2~ 5
(Ii)
~or a 8alt t~ereo~
CO~H~
O~ .5
or a ~alt thereo~
Process 6
.
:E limin~tio~ o~ the protec~i~e
R~C:~O~ 5~3 group of carbo:~r
~5 ~ L~ 4 ~ - - -
2d ~5 .
~ Ik)
or a salt l;hereo~
20 Rl_~R-COlii}~ R
(Il)
or a salt thereo~.
2~i ~
1 ~ ~ 3 ~5~teri~icatlorL
IT ~R4
0~
(Im)
or a ~alt thereoi~5
Rl~C_CO~ 4
0~
) or a salt thereof
_ _ _ _ _ _ _ _ . = _ . ~ . , _ _ . . .. . . . . .. .. . ..
c~ss 8
Elim; na~ioD- of the
Rl~ ,N C-C(~ R ~toC~i ~e ~7~}
OR R5
~ Ig)
or a salt thereo
N ~ CC~R3
~ 5
-
~Ih)
1~ - or a sal~ ~hereof
~ '
$~ CO~ S D~hydratio~
~ S~2 ~L ,
oe~ 8 ~3( t) there~
~; 2~ ~~'~
~Ip)
or a ~alt ~hereo~
~Process 10
a ~
CO~ n~roduct~.on o* ,~e
o~2c ~
3~ ~Ig)
or a ~ the~eo~
~8~
R~ CO~
~2b
(Ir)
or ~ ~alt thereoI
wher~i~ Rl~ R~ , R4 a~d RS are ead:L as defi~ed aDove;
RSa is a pro~ected ca~oxy;
R4b ~J3 pyr~di~e ~hich-may b~ s~bst~ted wit ~suitab~e
~ub~t ~t~s~ 03~ a gxou~? oi~ the ~o~s }it.4~E where~
~e :~ ac~l ~ a ~eter~cyclic ~Otlp whic~ may b~ $_
t~edL ~ith s~tabla ~bsti t~aerLt~ 9 3; ~~ ~ ~ ~
A is lower ~lXylene;
R4c is a h ~erol:yclicthio~lower~al.tcyl subs~itut d
with prosPc~ed am~oClower)alkyl;
R4d is a he~erocyclicthio(low~r~al~yl substituted
2Q wi~ ~ (lower) al~;yl;
R2a ~s a protective group of hydroxy;
R4a 1~ a ~roup w3~ c b~ sub~ti~ed wit~ a g~ p
fo~L: X4~ wherein R4~ i~ pyria~ -~hich
m~ be ~tit~e~ wlt~ able su~stitue~t(s) ~r
a group o~ the ~o~lao ~ 14~ whe:rQ~ X4e i~ a~ de~ined
a~o~e 9
~4~ i8 a8 eii:ned abo~e ;.
r~;eGt;~ otlower~
E~.2(~ l no~low~lr~
~o R~d i~ tec~;ed carbo~ lo~er)al~yl" ar(lower~al~yl
substi~ted wl~ protac~e~ oarbo~ r or cycloalk~l
3~b~tltute~ with pr~te~ed carbo~r9
R2~ ~3 car~ox;sr(lo~er)alk~l 3, ar~lower)~y~ tl~uted
with carF~o~ ~r c~cloal~l c~ubstitute~ w~t~ carboxy;
_ 9 _
R~ is an ester moiety of an esteri.fied carboxy represented by a
group of ,he fo.rmula: -COOR , R i5 protected amino(lower)alkyl
or ar(lo~ler)aIkyl substituted with protected amino(lower)alkyl, and
R g is amino(lower)alkyl or ar(lo~er)aIkyl substituted with amino
(low~r)aLkyl.
Thus in accordance with the invention there is provided
new intermediates of :Eormula (III),
R ~ ~ ~l~OC~I (III)
wherein R is amino or a protected amino and ~ is car~onyl or a
group of the formula:
in which R is hydrogen, acyl,aryl which may be substituted with
suitable substituent(s), lower alkyl substituted with suitable
substituent(s), lo~er alkenyl, lower alkynyl, cycloalkyl which
m~y be substituted with suitable substituent(s), cyclo(lower)-
alkenyl, or S or O containing 5-~embered heterocyclic group
substituted with oxo group(s), or a salt thereof.
In another aspect of the invention t~ere is ~rovided
processes for preparing the compounds (III).
The Compolmds (III) can be prepared by the following
preparations: .
~z~
- 9a -
~,~
~ ~ 1`
H
u~ u~ ~0
._. ~ r
h 1~ g
. "3p, ' . ~,.
O.'
H *
' ~
X~a I ~
W ~ ~ ~3 ~ ~
3 ~ tH P~. ~ 1
~: . ~
O
~Jl~ ~ tJ
O ~ t-t
~ ~;
~ h ~d
b_O
~cid and/or ïa N ~ ~CCOSR~ ~5CO~E
G=i-c~ R ~ 5~
XI) ( 5 ) ~ )
lg~COCOOE~ Elimi~?tlcn
5 ~'~5~ R7 ONH of the pro~ective
g~oup of amino
t ~ N~ COOH
~ Rla-(/ S,~
R~ - O~IHz OR~
XII ~ ~ I I I a)
\o~ a sal~ thereof
(6)~
N ~C-COOH
H2N~' S~N 1l
OR
~IIIb~
~2~ r~troduct:io~ o ~he
pro~ecti~re group
Rla~C-CO~ ~d N
OH ~ 8 ) ~ R7 a
~IIIc~ ~IIId)
El:~ination o~ the
.9~2
or a ~alt t~er~
~4~ .
3~ C~OC~ I~o~d~ grou~
3~ o~ amino R ~3;
S 2~ ~11) o~2
Introdtlct:{o~ of the
r 5 ~ ~bst~t~ent
e~o~ hydro~ 3roup .~ ..
S . oR2
~3 ~r ~OC)E~ c~zat~ orc ~ CCO~
O.pE~Z ~,
~S ~ ~E2~2:~ dE~'
(:~III)~T~ 2 2
a~ or a 3al~i thereo~
7 - -~ HS
~ or ~t thereo~
- ~15?~ ~ ~J~ H~
,10
~z; or a ~alt thereo~ or a salt there~i
wher~n R~ç, R2ag ~2~, R2g aIId Rl a~ eac~ d~i~ed
abo~e" R2h ~ aryl w~lc~,ma~ be sub~tlt~ted ~ h
table 3ub~Jcit;~en~(s) ~r cycloalkyl w~c~ may be ~
sti~ed l~:lt~L ~a~le ~stit~e:~t~),, Z ~ ~arb~F or
protec~ed ca~ 13 protec~ed ~nQ~ &6 )alkyl3,
~o(~3~6 j~t ~
R is a prQt:ecti~e g~oup o ca.boxy,
M is a~ a1~.all metal,
X ~ hydr~xy or ~ rQactive ~zr~ti~g,
3a R~ ~ a~no h~ a 3?r~te6:~:~e g~ s,
- 12 --
Rla is a protec~ed amino and
~.7 is lower alkyl.
I~ t~e obj ect compoun~ ~I) ~d ~e starting compound
g the partial struc ure represented by the formula:
- C - C O
5 2
O - R
is to be ullderstood to i~clude bo~}i o~ the geome~rical
10 s~ructures represented by the ~o~nulae:-
C - CO - - C - ~0 -
11 2 a~d 2 ll
N - C) - R R - O - N
(A~ (A')
In ~is specification~ with regard to all ~he compo~ds
ha~ing ths above me~tio~ed partial ~ructure9 the com-
pou~ds having the geometrical s~ructure showrl by ~he
formula ~A) are referred ~o as "syn iso;ner" alld ~he
~ compounds having the al~ernative one shown by the
ormula ~A' ) as ~ ti isomerl' .
Regarding the objec~ compound of the formula ~I~
a~d ~he star~ing compound of ~he formula ~III) as
men~io:ned above 3 i't is also to be u~ders~ood that said
2S object a~d starti:llg compounds may înclude tautomerie
lsomers relati~g *o ~heir thiadiazolyl gTOUp. That
is, i~L case ~hat: ~he group represented by ~he formula:
Rl~ (wher~i~ Rl is ami~o or a pro~cec~ed amino~ i~
formula of said objeGt a~d sta~t:in~ ::ompounds ~ake the
formula: M ~ l
(B) (wherein R is as defined aboYe),
N ~
said group of the for~ula~ S~ may be also
a~ e~ati~rely represent~d by i~s tau~omeric ~ormula:
- 13 --
R~ B ' ) (whereiIl Rl is imino or a prutected
imi~o) . That is, both of ~e said group ~B~ and ~B ')
may b~ in ~he state of equilibTium as so-called tauto-
S meric fo~ms which can be represented by ~he following
equilibrium:
R~ N t ~ S ,N
B ' )
(wheTei~ Rl a~d R~ a~e each as defined above). _
I~ ~he p~esent specification including claims
and examples 9 the ob j ert and starti~g compounds ha~ring
said gruup are represen~ed by using one of ~he
expressions ~herefor, namely 1:he formula- ~
" N ~ "
'N only for the conve~ient s al~e .
1~'
R
20Suitable pharmaceutically acceptab le s alts of
the obj~ct compound ~I) are ::o:nve~ ional ~on-toxic
salts a~d may include ~ inorganic salt" or example,
a metal salt such as an alkali metal salt (e.g.,
sodium salt, potassium salt, etc.) and an alkaline ear~h
me~al salt (e.g.a calcium sal~, ma~nesium sal~9 e~c.),
ammo~i~m salt etc.;
an organic ~ 1 ~ or example, an organic amine salt
~e~g~, trimethylami~e salt3 triethylami~e salt, pyridine
sal~ pTocai~ salt~ picoline salt, dicyclohe~ylamine
;O salt, N~N~-dibenzylethyle~e-diamine sal~, N-methylglu-
camine sal~, di~ha~olamine salt, triethanolamine salt9
tris(hydroxy~lethylamino~methane salt, phe~ylethyl-
be~zylamine salt; ~ibenzylethylened~a~i~e salt 9 e~c.)
~t~.:
3~ ~n organic CcL~o~yliC or sul,onic acid sal~ (~.g.,formate~
aceta~e 9 malea-e, ~ar~ra~e, m*thanesul~onate, benzene-
sallfo~ate ~ tolue~esulfona~e , !'tC .~; an inorganic acid
sal~ ~ . g ., hydrochlorlde " hy~lrobromide, sulICa~e
phosphate, etc . );
a sal~ with a ba~ic or acidic amino acid (e.g., arginine,
aspartic acid, glu~amic acid, lysi~e 9 e~c.) and the like .
In ~he above a~d subsequl nt descriptio~s o ~he
present speciica~ion, suitab le examples a~d
illustration of the variaus definitions which the presen~
i~ven~io~ inte~d5 to include withi~ the scope thereof
are explained in deta~l as fallows.
The term 'tlower" i5- used tc intend a group having
1 ~o 6 carbon atom~s~ ~ unless o~he~ise pTovided.
Suitable pro~ected amino may include ~ acylamino
1~ and amino group substitn~ed by a conventional
proptecti~e group other :th~ the acyl group, such as
ar~lowerjalkylte.g~ be~zyl9 trityl, etc~) ar(lower)-
alkylide~e(e.g. 9 ~enzylidene, etc.), lower alkylidene
suhstituted with lower alkoxycarbonyl or di~lower)-
.20 alkylam:ino(e Og. ~ l-ethoxycarbo~lyl-~-propylidene,
dime~hylami~ome~hylene, etc.) or the like.
Suitable protected imino may iIlclude an acylimino
and imino group substituted by a co~velltlonal
protectivP group o~her than the acyl gTOUp such as
2~ aforesaid ar~lower~ allcyl or the li~e .
Suitabl~ acyl a:nd acyl moie~y in ~he terms
"acylamiD~o"~ ?'acylimino"7 "acyloxy~lower) alkyl" a~d
lacylthia ~lower) all~yl~l may i~clude carbamoyl, aliphatic
~cyl group a~d acyl group containi~g a~ aromatic or
heterocyclic ring~ d" suitable examples of the
sald acyl may be lower alka~oyl (e.g. 9 fOTmyl9 acetyl,
propioIlyl, butyryl~ isobutyryl, valeryl/ isovalerylg
oxalyl, su~cinyl7 pivaloyl, etc.~ 9 preerably one
having 1 to 4 carbon atsmCs) ~ mor~ preferably one
3a ha~l~g 1 to 2 carboll a~om~s~;
...
- 15 -
lower alkox~Car~Onyl ha~ring 2 ~o 7 carborL atoms ~e .g. J
me~oxyc~rbonyl, et~oxycarbo~yl, propoxycarbo~yl, ~-
cyclopropylethoxycar~onyl, isop~opoxycarbonyl, buto~
ea~bonyl g t-buto~cycar~onyl, pentylo~yca.~onyl, t-
pentyloxycarbonyl, hexyloxycarbcnyl, et~ p~eferably
o~e havi~g a o 6 car~on atoms,
lowe~ ~Lka~esulfoIlyl (e . g ., me~syl ~ ethanesul~onyl,
propa:nesulfo~:Lyl, isopropanesulfonyl, bu~esulfo~yl,
~:t~
a~enesulfo~yl ~e ~g. ~ ben~enesulfo~yl, tosyl, etc,.3;
- aroyl ~e . g ~., ben~oyl, toluoyl, ~aph~hoyl, phthaloyl g
~da~carbonyl 9 etc ~ );
ar~lower)alka~oyl Ce.g., phe}~rlacetyl~ phe~ylpropiDnyl,
etc.); cyc~ oweP3alky~(lower)~ o~L(eOg<~ ~c.~he:cylacetyl~.
15 cyclopenty~eet;y~l~ e~cO );
a~lower~alkoxycarbo~yl ~eOg. be~zyloxycarboI~yl,
phe~ethyloxycarbo~yl" ~tc.~; a~d ~e like.
The acyl. aQd acyl m~iety as stated abo~re may have.
1 to ~ 5uitabte substi~ue~t(s~ such as haloge~L ~e.g., -
2a chlor~e, bromi~e, iod~ne or :Eluorirle) ~ hydroxy, cyano,~i~ro, luwer alkoxy ~e.g., m~thoxy3 ethoxy ~ propoxy,
- isopropoxy, e~c.), lower alkyl ~e .g. ,, me.~yl, ethyl,
pTopyl, isopropyl, butj~l" etc,~ 7 lower alke~yl ~2.g.,
vinyl, allyl, etc . ), aryl (e . g . ~ phenyl, ~olyl, e .c . ~,
~mino, pro~ec~ed ~ o? or the like.
P~e~rab le examp le of acyl havi~g s aid sub s titue~t (s )
may be di~lower)alkylc~rbamoyl ~e.g., dimethylcarbamoyl,
die~hylcarbamoyl~ dipropylcarbamoyl etc.), phenyl(lower)-
alka~o~l substitutea Nlth amino ~r lower alko~carbo~ylamino,
,~ cy~:Lo(lower)a~L~l~lower~alka~oyl ~ub~tituted with amin~, etc7
Suitable example of acyl for R2 may irLclude
halo(lower~al~a~Loyl" more pTeferably dihalo(lower~-
al~a~oyl ~e .g ., di ::hloroace~yl a dibromoacetyla etc .)
a~d the like~
aS
- 16 -
Suit2ble aTyl may include pheILyl, tolyl, xylyl,
mesityl, cumenyl arLd the like, ~ B~ aI'yl ~Otlp may b3
~ub~ l;ute~ h 1 to ~ ab.le substil;ue~(s) such 2
halcge~(~,g.~ chlorine,~ ~rom~, n~a~rl~e ar i.odina)9
ni~;roS~ lo-~rer alko~y(e.g. " met~o~ eth~ propo~y,
,~ but~; pe~l~y~ o~g he2~l0:~9 el;c O ? pr~e:rabl~ o~a hav~g
~ ~to ~ c~ at~m(s)~ halo(louer)~l ~e.g." chlor~
me~ 9 cllc~lo~meth~l" t~c~tlorometh~l7 ~rifl~romet~
~chloroe~-~l" stc..) ~ra~ Lb~ o:ne ha~g 1 ,,o 3 car~
10 a~om(~)~ pro~ected ca~ox~ a8 ~ rate~ below~ pr~erably
lower ~ko~car~ more ~el'erably o~e ~avirlg 2 to 4
~ar'b~ atom3, or th~ ltk~
Sui~able lower a~lcy~ aDd lower alkyl moie~y in
rms "acyloxy~lower~alkyl", '~acyl~io~lower~ lkyl"
~5 np~rid~iower~alkyln3 ~prc~tacted ami~o(loly-erja~y~
n~m~Lo~lowe~)21 ~ 1np nprstec~ed ca~bo ~ (lowe~)alkyln,
~arbo;~10wer)alkYl~ het~rsc3rclicthio(10wer)alk;~rl~
~d "ar(lower)al~l" ma~ lnclu~ raight or br~ched o~
havi~g 1 to 6 carbo~ atom(s3, such as methyl, e~hyl,
~ propyl, îsopropyl" bu~yl~ isobu~yl, 'cert-butyl, pe~tyl,
- tert-pe~tyl" hexy~ or ~he like,
~ ~ui~able ~ubstitue~ the t~rm ~ lowPr alkyl
3u~t~ted wit~ ~ui~a~l~ ~ubstgt~e~t~s~ ma~ incl~e
halogen ~e.g. chlorine J bromi~e, fluori~e or
iodi~e); cyanu; carbo.xy; protected car~oxy as.
I me~tio~d below; lower ~kylthio (e.g.~ me~hylthio,
-I e~hylthio, pr~pylthio, butylthio, etc.~ aryl (e.g.,
phe~yl, tolyl, xylylg mesityl, cumenyl, e~c.);
aryloxy ~e.g., ph noxy, tolylo~y~ mesityloxy, etc.)~
aoresaid acyl lower alkoxy~low~r)alkoxy Ce-g-9
methoxymethGxyJ methoxyethoxy, ethoxye~ho~
propoxyethoxy 9 bu~oxye~hoxy~ pentyloxymetho~y,
he~yloxymethoxy, hexyloxye~hoxy3 ~t~
.. . _ _ . .
. _ . _ _ . . . . ...... .. . . . . ., .. _ . ... . . . .
~ 17 -
prs:~te~tet~ a9 mentlo~e~ a~cYe~ pre~erab~ at y~m-
~mo~e ~s~erab:Ly ~owe:r alko-~car~o~glamino~ arpl~lower~-
~oylamino stl~sti~ted with a~no or lower alkoxyc2rbo
nylam~nog c~clo t lower)alkyl( 1 o~or)21ka~t~y~ 10 substituted
W~t~L amino amino; ~r the ll~ep where~ the a~ore-~qai~
ar~l group being t~e ~3U~8tit~t'~1 (9) 0~ lower alkyl
ma~ be ~u~stit~e~ w~th ~inolower)a:Lkyl (e.g~9 amino-
meth~ oet~yl~ proplyl, etcO) ~r pr~ec~e~ ~no-
er) alkyl
d ~table ~umber o~
subst ~e~tt~) 0~ lower alk~l group may be 1 to 36.
Suit~le pr~tected carboxy ma~ include esterified
carboxy in which said ester may be th~3 orLes such as
lawer alXyl est~r ~e.g., methyl ester, ethyl estio.r,
1~ propyl ester, isopropyl ~ster~ butyl es~er, isobutyl
ester, t-butyt es~er, pe~tyl Qster' t-peIltyl ester,
héxyl ester~ l-cyclopropylethyl ester" etc.), whe~ei~
lawer alkyl moie~y ma~ ~e preerably one having 1- to 4
carbo~ atom~s~; lower alke~yl ester ~e ~g~ ~ YlIlyl ester,
~a alI~l es~er, etc.); lower alkynyl ester (e.g., e~chynyl
ester~ propy~yl es~er , etc . ); moIlo Cor di ar tri) -halo - .
(lowe~al~yI ester ~e>a~.9 2-iodoe~hyl ester, 232~2-
trichloroethyl es~er3 e~c. );
lower al}caDoyloxy~lower~ al:kyl ester ~e .g . ~ aceto~cymethyl
2~ ester, propionyloxyme~hyl es~er, l~acetox~rprop~l est~r,
valeryloxyme ehyl ester, piva~ oyloxymethyl ester,
hexa~oyla~cymethyl es~er, l~ace-oxye~hyl ester, 2-propio
~yloxyethyl es~er,l i$0bll~l0:~et~l e~ter, e-.cO~;
lower al~;a~esulforLyl(lower) alkyl ester (e .g. " mesyl-
me~hyl ester~ 2-mesylethyl es~er e~c,~;
ar~lower)alkyl ester~ for example" phe~yl~lower)alkyl
es~er w:n~h m2y be subs.i~uted with o~e or mor~ sult-
able substituen~s~ ~e.g., ben7yl es~er" 4-methoxyben~yl
ester9 4~ robe~zyl es.er, phene~hyl ester, t~ityl
est~r, diphe~ylme~hyl ester " bis Cme~hoxyphecLyl~ me chyl
_ _ .. . . _ _ . .. , . _ . . _ . . , . . _ . . . .. _ . ~ .
.
es~er, ;,~-dimethoxybenzyl Pste~" ¢-~yd~oxy-;~5-diterti
arybu~ylb e~zy 1 e s te r, e tc . );
lower alko~:ycar~onylogy(lower)alkyl e~ter(e.g. / metho
~:ycarb~yl~xymet~yl es~ery ~tho~carbon;ylo~rmet~Lyl e~ ' er,
ethox~car~oxLyl~ethyl ester, 2tC~) which may be ~bst.
t~Lted wIt~ a~dopo
a heterocyclic ester~ preferably be~ etrahydro~ryl es~-
er w~ic~ ma~ be subst~t~te~ w~th ~ o group~ mo~e pr~e-
ra~ly pht~alidyl es~cr9o
~o arogloæy(lower)alk;yl ester ( eOg., be~zo~lox~thyl e~er9
be:~zoylo~eth~l ester~ toluoylo~ethyl e~er, etc. );
aryl ~ster ~hich may have o~e or more suitable substi-
tue~(s~ ~.g., phenyl ester, tolyl ester, tertiary-
bu~ylphe~yl e~ter;, xylyl . ster, mesityl e5ter, cumenyl
1~ ester~ etc.), and ~he liXe.
Preferable example of protected carbo.~y may be lower
al~oxy6arbo~yl ~e.g., me~hoxycarbo:llyl~ ethoxycarbonyl,
propoxyca~ollyl, butoxycarboD.yl, t-butoxyc~Lrbonyl, t- -
" ' pen1 yl9x}rcarbO~yl D hexyloxycarbo~yl, e~c . ~ havi~g 2 ~o
7 carbo~ atoms, p~eferably one hav~g 2 to 5 carbo~
~oms3 ph~ylClower)alkoxycarbonyl which may be sub-
s~ituted with ~itro ~.g., 4-~i~Tobe~zyloxycarbonyl,
be~yloxycarbo~yl9 4-ni~rophenethyloxycarbonyl, etc.),l
?5 lower alk~oylo~(lower~a~ko~carbo~l teOg~, acsto~-
m~tho~carbo~ pl~loylo:~etho~ycaxbon;yl~ he~a~oy~ ~F
m~t~oæ~earborur~ :.- .. .. .: ... . .. ~
l~a~to2c;yethox;srcarbo:~, l;acato:~propo~ car~o~l,.
obQtyr;y~o~etho~ or~l, etc~.~ p~sf~rab~y Q~8 ha~g
3~ to 8 car:bon ~toms;
lower alkox~ca:r~o~ylo~;sr(lo~er)alko2~earbo~1 te"g.9 et~o~
ear~on;y~ o:~etho~a~o~yl, etho~rcarb~ylox~propo~car~
etc,.) w~cl~ may ~e.su~stlt~ted wlt~ a~id~ pre~erably o~e
g 5 ~s 7 car~o~ at~lms"
3~
p~t~ id~lQ~y~ar~orryl; a~d
aroylo~(lower)alko~carbo~yl~ e~g., beI:L30ylo~methsx~--
car~o:tly~, 3e~ o~ethoæ;srca:rbo~ , atc,, ~ 9
Sui l~L~le lowe~ alke~yl may i:~clude ~ny~, allyl~
isoprope~y~ prctpe~l ~ 2-~te~yl~ 3-perD~er~ t~Le
e ~ p~ erably o~e ka~:~g 2 to 4 ~rbon atom~O
~ 3ui~Lb~e lower al~yl ma;~F ~cl~de o~e ~ g 2 to
6 car~o~s atoms, ~or e~ eth~ll9 2-pr~ , 2-
~tynyl~, 3~pent~? ~ 3~L~Xyllyl~ or t~e lIke~ p:re~:rabl~
o~e ha~ring 2 t~ 4 o~on at~n~
~ abla c~clo~l may ~clude ~ne ha~l~g 3 t~ 8
car~o:5 at~ ~or ~:~npleg cyclopropyl" cyclobut~l~
e~loper~tyl3, cyolohe~l, c~clo~ep~ or the li:ke,
pre:~erably one havi:~g 4 tc~ 7 car~on atoms6,
1~S~i~a~a ~bs~t~e t(~3 o~ cycloa:lkyl c~n be referred
to the orle~ as exempl~e~ ~or 9~aE)9t~'~ent~ ) ~n lo~er
al~ 9 a~d pre~erably car~o:~ or pra~ected carbo~
Sui~able cycïc~ wer~alke~syl may ~clu~e or~e havi~g
to 6 carbc~L atomsD f~r axample~ cyclope:~te~y1g cyclo--
~h~:ce~yl" . ~ the li~eS, preIa:rably o~e ~sving 5 or
car~on atom~
Sui~able S or O con~a~ng 5-~embered :~Leteroc~clic
gxoup may incl~de ~at~ate~ c3r u~at~a~e~ orle, ~or
e~ample,~ dihydro~ etrah~dro~ur;y:L" thiola~l
~5- or ~,h0 1 ike 3 which i~ st~ tlt~te~ wi th 1 ~r 2 a~o
gr~up( 9 ~ .,
- Su~able ~e~erocyc~i~ group and he~erocylie moie~y
î~ ~e ~erm '1a he~cerocycliGthio~lower)alXyl'~ means
sa~urated or ullsaturated9 monocyclic or polycyclic
~he~e~ocyclic group contaiIlinæ a~ leas~ one heéero-a~om
such as a~ o.cyge~, sulfur~ rLitrogen a~om and the like.
.4~d9 espec a:Lly pre~erably he~erocycl i~ g~oup may oe
heterocyclic group suc~ as
u~a;u~ated 3 to 8-membered heteromo~ocyclic group
con~ai~ Lg 1 t~ 4 ni~rogen atomCs~ ~ for example, pyrrolyl,
.
2~ -
pyrrolinyl, imidazolyl, pyrarolyl, pyridyl, and its
N-oxide, pyrimidy~, pyrazinyl., pyridazinyl~ triazolyl
~e.g., 4H-1,234-triazolyl, lH~-1,2,3-triazolyl, 2H-1,2,3-
triazolyl, e~c.) 3 te~razolyl ~e .g., lH-te~razolyl, 2H-
te~ra?olyl, etc~), dihydrotri~Lzi~ ete.;
s~urated 3 to 8-membered he~:eromonocyclic group con-
~aining 1 to 4 nitrogen atom( s), for example , pyrroli-
dinyl, imidazolidinyl, piperi.dino, piperazi~yl" etc.;
Imsa~urated conde:nsed heteroc:yclic group containing 1
to 5 nitrogen atom(s3, fo~ example, indolyl, isoindolyl,
indolizynyl, benzimidazolyl, qui:nolyl, isoquinolyl,
indazolyl, be~zotria~olyl9 te~razolopyridyl,
~etrazolopyridazinyl ~ dih;ydro~ria~ol opyrida~inyl, etc. "
unsatuTa~ced.3-~o 8-membered he~eromonocyclic group
co~taining 1 ~o 2 oxygen a~om(s~ and 1 to; nitrogen
atom~s), for example , oxazolyl , isoxazolyl J oxadiazolyl ,
~e . g., 1, 2 "4-oxadiazolyl, 1, 3 p4 -oxadiazolyl, 1, 2, 5 -
- oxadiazolyl ~ etc . ) etc .;
satura~d 3 ~o 8-membered heteromo:nocyclic group
.20 containing 1 to 2 oxygen atom~s~ and 1 'co 3 ni*rogen
~:om~s), for example, morpholinyl, etc.; .
unsatuTated condensed heterocyclic group contai~ g 1
to 2 oxygen ?Lom(s~ ~nd 1 to 3 nitrogen atom(s), for
example J ben~oxazolyl, ben20xadiazolyl 5 etc .;
~5 ullsaturated 3 to 8-membered heteromono~yclic group
co~taining 1 to 2 sulur atom(s) alld ï to 3 nitrogell
atom~s3 9 for example, thiazolyl, thiazoïinyl, ~hiadia~olyl
~e.g." 1J2,4-thiadia701yl9 1"3,4-~hiadia~olyl~ 192~5-
thiadiazoly:L, etc.), etc.;
satura~ed 3 to 8-membeTea heteromoIlocyclic group
containing 1 to 2 sulfur ~tom(s) and 1 to 3 ni~rogen
a~om~s), fo~ example, ~hiazolidi~yl g etc.;
u~sa~uTated 3 to 8-membered heteromonocyclic g;roup
con.aining a sulfur atom, for e:xalllpl~, ~hienyl, etc . 9
3~ uIlsa~uTa~ed ~ondellsed he~erocyc~ ic gr.oup containing 1
to 2 sulfur atom~s) and 1 to 3 nitrogen atom(s), for
ex2mple, benzothiazolyl, benzothiadiazolyl, etc. and
~he like;
wherein said.heterocyclic grOllp may be substi~uted with
l to 3 suitable subs~i~uent(s) such as lower alkyl
(e.g., methyl,-ethyl) pTopyl, isopropyl, butyl, iso-
butyl, pen~yl, cyclopentyl, hexyl, cyc~ohexyl$ etc.);
lower alkylthio ~e.g.~ methyl1thio, ethylthio, pro
pylthio ~ e~c . ); loweT alkenyl te.g., ~inyl, allyl 3
bute~yl, e~c.); lower alkenylthio ~e.g~, vinylthio,
~llylthio, but nylthio~ etc-); h~dr~Xy9
aryl ~e.g. 7 phenyl~ ~olyl, e*c.); halogen (e.g.,
chloTine, bromine, iodine or fluo~ine); amino; di~low~r~-
alkylamino(lower)alkyl ~e.g. 9 dimeLhylaminomethyl 7
dimet~y~aminoethyl, dimethylaminopropyl, di thyl-
aminopropyl, diethylaminobutyl, etc.); caTboxy~lower)-
allcyl (e.g., carboxymethyl, carboxyethyl~, ca.boxyp~opyl,
e~c.); esteTified caTboxy(lower3alkyl whe~ein ~he
esterified c~rboxy moi ty is exemplified abov~;
~0 amiIlo(low~r~alkyl (e.g~, aminome~:hyla aminoethyl,
am~nopropyl~ ninomethylethyl, aminobu~l, amino~e~ etc. ) ,,
protected amino ~lower) alkyl wherein the protected
amino and lower alkyl moieties are each as exempllfied
P 3 preferably loweT alkoxyca~bonylamino~lower)-
~5 alkyl ~e.g., methoxycarbonylaminornethyl, ethoxycarbonyl~
am~nome~thyl, t-butoxycarbonylamillomethyl g ~-~utoxy-
carboTlylaminoethyl, ~-bu~oxycarbonylaminopr~pyl 9 et:c . )
or lower alkanoylamino (lower~ al~;~l (e . g . ~ acetyl-
aminom~thyl, ace~ylaminoe thyl, acety.lam:i~opTopy
30 acetylala~omethylethyl3 etc.)9 car~oxy; oæ~;
es~erified carboxy as exemplified abo~e, preferably
lowe~ alkoxycarbonyl; lower alkoxy(lower)alkyl (e.g.,
methoxyme~hyl~ methoxyethylg methoxypropyl, ~thoxyme~hyl"
e~choxyethyl, P tC, ); hydroxy (lowe T) alkyl ~e, g ., hydrox~ -
3~ me~hyl 9 hydroxye~hyl " hydroxypTopyl , hydroxybutyl , e~c . ~;
.. . . .
-- .
.. . _ _ . ....
- 22 -
lower alkylt~lo~lower)alkyl ~2.g., methylthiomethyl~
methyl~hioethyl, methylthiopropyl, ethylthiomethyl,
etc.); sul:fo~low~r)alkyl ~e.g., sulfomethyl, sulfoethyl,
sul~opropyl9 sulfobutyl, etc,); acyl~lower)alXyl wherein
the acyl and lower al~cyl moieties are each as
exemplified above, preferab ly lo~er alkanesulfonyl-
(lower)alkyl (e.g,, mesylme~yl, mesylethyl, ethalle-
sulfonyl:methyl9 etc.~; acylaDlino~lower)alkyl wherei
~he acyl a~d lower al~cyl moie~ies a~e each as
exemplified above, preferably lower al~anesulfonyl-
am~o~lower~al~yl (e.g., mesylami~omethyl, mesyl-
~noe~hyl" mesylaminop~opyl, ethaIlesulfonylami~o-
me~yl~ etc~); carboxy(lower)alkylthio (e. g., carboxy-
methyl~h o, carboxyethylthio? e~c.) ,o, morpho~i 0(10s7er)
e. g. 9 morp~olinomethyl~ morp~olinoethyl, morp~o~ o
prop~l~ etc.~; piper~dino~lower)~l ~Og~p p~per~d~:~o
~et~yl" pipe3:ridinoethyl, piperidIDopropylp etc~.~; pipera-
zi~yl~l~wer~alkyl which may be ~ubstit~e~ with lower alkyl
~e.g.~4-methyl-1-piperazin~lpropyl, etc.); or the l~keO
S~itable sub~titue~t~ on pyridi~ (lower)a~ky~9 p~r~
d~ and py~d~ium ma~ be car~o~l a~d the li~eO
~uita~10 haloge~ ca~ be re~erred to the on~ as ~empl$-
~ie~ abo~.
Suitable lower alkylene may include straight or
branched bi~ale~ aliphatic hydrocar~on residue having
- 1 to 6 carbo~ a~om~s~9 such as me~hylene9 athylene9
methyle~hylene 9 propylene, trimethylene, 2-me~hyl~ri~
me~hylene or the like, and p~eerably one having 1 to
4 carbo~ atom(s~ 9 more preerably one having 1 to 2
3~ carbon atom~s) ~d ~e most preferably one having 1
carbon atom.
Suitable protected amino ~lower~ aïkyl and amino-
~lower) all~yl bei:rLg ~he subs~ituent o~ aL heterocyclicthio-
(l~wer)alkyl for R c and R and pr~tected am~no~o~er~.-
..
alkyl a~d a~i~o~lcwe~ 'cr ~?b alld ~.2~ a~d pr~ect~?d.
ca~ ~(lower)al~l a~ bo~(l~er)al~ ~or ~2~ ~d
:~2~ can ~ referred ~,~ t~e oIles a~ ~emplii~ed a~Dove.
Suita~le protecti~e glOU~ o:E hy~}roxy may i~clude
a~oresaid acyl3 ar~lower)alkyl, al:Ld the like.
~ able ~L4a m2~ iIlC~Ud2 ai~re~a:3.d ac~lo~r, h~log
a~id~ d the l~ev
Sui~ab~e R8 ma~ b~ ~tlar moiet;y a~ e~empl:L~ie~ ior
pr~ected car~
Su table prot~c~iYe group o~ carbaa~y may be
reer~ed o the o~es ~-xempIi~ied as aforeme~t~oned
es~er moiety ~n the esterified carb~ g~O~D ' Preerable
example of protactive gTOUp of car~oxy may be lower al~cyl
as me~tioned abo~e.
Sui~able alkali me~al ma~r ~nclude sodium, po Lassium~
lithium, e~c. .
~ 3~itable rea~i~e deri~tl~e o~ hydro~ ~or ~ may
i~lc7u~e ~r ac~ resid~ such a~ s:eor~a:id haloge2l o~
the lik2..
S~ltable am~o hav~g a p:zotec~l~e group for ~9
ma~ inc~u~2 ph~hall~do~ succi~ido9 et~o~ca~bo~y~
ami~c~ ~d t~ ke z, a~d ~re~erabl~ phth21~midoO
~5 Suitable ar(lower)~l m~y be
pre~Drably ph~yl(7 ower)alkyl ~ch aEF be~zyl, phen~t~l,
or th~ l~keO
~ ul~able (0~5~6)alkyl ~n the ~erms l7a~20(C5-C6)
a~l ~nd pro~e~tea amlno~C3~6 )alkyl" ma~ clude al~l
~av~g 3 to 6 carbo~ atoms, ~or e~ propyl~ ~s~prc~pyl"
b'~ 9 l~ut~:L, pe~ ex~l, or t~Ele lik~o
~ uitable pr~tec~ed am~no~lower)al~ d ~m~no(lower~
alkyl ior ~ d R2g a~d-protected amillo moiet~ i~ the
~e~s protected amint:,(C3~6~ 1n C~n be r~erre~ to
3~
.. . .. . . . .. .. ... . . . . . . . . . . . . . . . .
- 2~ -
the ones as mentioned above.
Preferred embodiments of the object campound(I) are as
follows.
Preferr~d en~diment of R is am~lo, acylamino(more preferably low~r
alkanoylamino) or di~lower)alkylarnino(lower)alkylidenea7nino; R2 is
hydrogen; aryl(more preferably phenyl); lower alkenyl; lower alkynyl;
cyano(lower)alkyl; ar(lower)alkyl ~more preferably phenyl(lo~7er)-
alkyl or triphenyl(lower)alkyl]; aryloxy(lower)alkyl[m~re preferably
phenoxy(l~er)alkyl]; halo(l~v7er)alkyl[more preferably trihalo(lo~ver)-
aLkyl]; lcwer alkylthio(lower)alkyl; esterified carboxy(lGwer)-
alkyl [~ore preferably lower alkoxy OE bonyl(lower)alkyl]; di(lo~er)-
aIkylcarbamoyl(lower)alkyl; lower alkoxy~lower)alkoxy(lower)aL~yl;
lower alk mesulfonyl(lower)alkyl; acylamino(lower)alkyl[more prefer-
ably lower alkoxy OE bonylamino(lower3alkyl3; amino(lo~7er)alkyl;
carboxy(lower)alkyl; cycloalkyl; cyclo(lower)alkenyl; aryl(more
preferably pnenyl) substituted with halogen, nitro and lGwer alkoxy,
nalo(lower)alkyl or lower alkox~7 OE bonyl; thiolanyl substituted with
2 oxo groups; ar(lower)alkyl substituted with carboxy or lcwer
alkoxycarbonyl; cycloalkyl substituted with carboxy or lower aLkoxy-
carbonyl; ar(lcwer)alkyl(preferably phenyl(low7er)aLkyl) substitutedwith amino(lower)aL~yl or lower alkoxycarbonylamino(lower)aLkyl;
cycloalkyloxy OE bonyl(low~r)alkyl; ar(lcwer)alkoxycarbonyl(lower)-
alkyl; ar(lower)aIkanoylamino(lower)alkyl substituted with amino or
lower alkcxycarbGnyla~Lno; cyclo(lower)aLkyl(lGwer)alkanoylamino-
~lower)alkyl; tetrahydrofuryl substituted with oxo group;
- 25
R3 is h~drogen or lower alkyl; R4 is hydrogen; acyloxy(lower)-
alkyl[more preferably lower alkanoyloxy(lower)alkyl o~ carDamoyloxy-
(lower)-alkyl, mos-t preferably lower alkanoyloxymethy or carbamoyloxy-
meth~-l]; acylthio(lower)alkyl [more preferably lower alkanoyltl-io-
(lower)alkyl, most preferably lower aIkanoylthiomethyl]; tetrazolyl-
thio(lower)alkyl (more preferabl~y tetrazolyltllicmethyl) substi-tuted
with lo~Ter alkyl, lower alkenyl, low~r alkoxy(lower)alkyl, lc~er
alkylthio(lower)alkyl, h~roxy(lower)alkyl, amino(lower)alkyl,
lo~r aIkoxycarbonyl~ino(lower)alkyl, lower alX~noylamino(lower)-
alkyl, di(lower)alkyla~ino(lower)alkyl, sulfo(lower)alkyl, OE boxy-
(lower)alkyl, aryl(more preferably phenyl),lower alkoxy OE bonyl-
(lGwer)alkyl, morpholino(lower)alkyl, piperidino(lower)a~yl or
piperazinyl(lower)alkyl substituted with lower alkyl; thiadiazolyl-
thio(lower)alkyl (mc)re preferably thiadiazolylthiomethyl) which may
be substituted with lower alkyl, lower alkoxy(lower)alkyl, lower
alkylthio(lower)alkyl, lower alkenylthio, OE boxy, lower alkoxy OE bonyl,
hydro~y(lower)alkyl, arnino(lower3alkyl) lower alkoxycarbonylamino-
~lower)alkyl, lower alkanesulfonyl(lower)alkyl, lower alkanesulfonyl-
a~ino(lower)alkyl or carboxy (lower) alkylthio; pyridinium(lower)-
alkyl substituted with carbamoyl; lower alkyl; halogen; hyclroxy;dihyclrotriazolopyridazlnyltllio(lower)alkyl(more preferably dihydro-
triazolopyridazinylthiamethyl) substituted with oxo and carboxy-
(lower)alkyl; dihydrotriazinylthio(lower)alkyl(more preferably
dihydrotriazinylthicmethyl) substituted with oxo, hy~roxy and lower
alkyl; or tetrazolopyridazinylthio(lower)alkyl~more preferably
tetrazolopyridazinylthiQmethyl); and R5 is carbo~y, phenyl(lower3-
aIkoxy OE ~onyl substituted with nitro, lc~ier
-- 26
alka~oylo~ l~wer) alko.~yoar~o~yl, lower alko~
car~o~ylo~ wer)alk~ carbo:~yl wh~ch may be
sub~ti~ted wit~ azido, phtha~idylo:~carbo~yl or
ar~yl t pre~e:~ bly b e~zo~l ) o~( lower~ a:Lko~ycarbolsyl;
wh~r~ 5 i~ CûO whe~
~4 i~ pyrid~ low~r) al~l. ~ab~tit~t ed wlth ca~bamoyl .
.
l~e processes ~o~ pxeparL~g the ob j ect coml~ouIlds
10 ar~ e;cplained i~ details ~ ~:he followi~g.
Process 1
The object compound ~I) c~ be prepared by
reacti:~Lg ~he ~ompound t~I~ or its reac~ive derivativ~
a~ the ~o g~oup or a salt ~er~o:~ with the compolmd-
}5 ~III) or its reac~ive deriva1:ive a~ the c~rboxy groupor a salt ~hereof.
Suitable reactive deri~ative at the amiIlo g~oup
of th~ compolmd (II3 may iDclude conven~ional reactive
deri~a~iv~ used i~ amida~io~, far ex mple, 5chiff's
~0 base ~ype imina or its tau~omeric e~ e t~pe isomer
formed by the re2c;ion of the com~au~d ~II) wi~h
a car~nyl compou~d; a silyl derivativ~ formed by ~he
reactio~ af the compou~d ~ wi :h a silyl compound
such as bis ~tTime~hyl,ilyl3 acetamide, ~rimethylsilyl-
25 acetamide or the like; a deri~ra~ive ~ormed by reactionof ~he compou~d ~ with pi~ospho~s trichloride o~
phosgelle, aD d ~:he liXe,
Suitable sal~ of ~e compou~ may include
an acid addif:ioD. sal~ such as a:ll orga:~lie acid salt
3~ ~e . g ., acetal:e, male ate, .artrat2, benzeIlesul ~oIla
tollle~esulfo~ate 9 etcO) or an i~organic acid sal~
~e .g. 5 ~ydrochloride, hydrobromide 9 sula.e ~ phospha.e,
e c . ) 5,
- 27
.
a metal salt ~e.g,, sodium salt, poLassium salt, cal-
cli~m salt, magnesium salt~ etc.); amDIonium salt; an
organic amine salt ~e.g., tri.e~hylamine salt9
dioyclohexylamine salt, etc.), and ~he like~
Suitable reac~ive deri~atiYe a~ the carboxy
group of the compound ~ may include an acid halide,
an acid a:c~hyd~ide ~ an activcLted amide, an ac~iva~ed
es~er3 and the like. The suitable example may be an
acid chloride; an acid azide; a mixed acid anhydTide
wi~h an acid such as substitutsd phosphoric acid ~e .g, 9
- dialkylphosp~oric acid, phenylphosphoric acid, diphenyl-
phosphoric acid, dibenzylphosphoric acid, halogenated
- phosphoric acid, etc~), dialkylphosphorous acid,
sulfur~us acid9 ~hiosulfuric acid9 sulfuric acid,
alkylcaTbonic acid~ aliphatic carboxylic acid (e.g.,
pivalic acid, penta~oir. acid, isope~tanoic acid,
2-ethylbu~yTic acid3 acetic acid or ~richloro-
acetic acid, e~cO) or aromatic carb3xylic ~cid (e.g.,
benzoic acid9 e~c.3; a symmeerical acid anhydride; an
activatPd amide with imidazole, dimethylpyrazole ) ~ria-
zole or tetTazole; or an activate~ ~ster (e . g ., cyano-
methyl estsr~ methoxymethyl es~er, dime~hyliminomethyl
~(CH3~2N = CH-~ ester3 Yinyl es~er" propargyl este~
p-nitrophenyl ester, 2,4-dinitrophenyl ester~ trichloro-
phe~yl est~r3 pe~tachlorophenyl ester~ mesyl phenyl
ester~ phen~lazophenyl es~er, phenyl thioester, p-
~i~rophe~yl ~hioester, p-cresyl ~hioes~er, carbo~y-
methyl ~hioester9 pyranyl ester, pyridyl es~er, piperidyl
es~e~, 8-quinolyl ~hioes~er, or an ~ster with N,N-
dime~hylhydroxylami~e, l-hydroxy ~-~lH)-pyTidone 3 N-
hydroxysuccinimide~ N-hydroxyphthalimide OT l-hydroxy-
6-chloro-1~-benzotriazole, ~nd the like. These
reactive de:rivatives can ~e op~ionally select2d lro~
~hem according ~o the kind of the compound ~III) to be
3S used.
The sal.s of the compound ~III) may be salts
wi~h~ an inorganic base such as aIl alkali metal salts
~e.g" sodium or potassium s~lt) ~ o~ aD alkali:lle earth
metal salt (e .g. ) calcium or magnesium salt~, a salt
with a:n org2nic base sLIch as trimethylamine, trie~hyl-
e, pyridine~ a salt with a:n acid (e.g., hydrochloric --
acid OT hydrob~omic a~id~ or the liXe.
The reac~ion is usually carried ou~ in a con-
ve~tional solvent such as water " acetone 9 dioxane p
lD ace l.ollitrile t chloroform, m~thy1 ene chloride, ethylene
chloride, te~ahydrofllra~" ethyl acetate 9 N~N-dimethyl-
~ormamide, pyridine or ~y o~her organic solvent which
- does :llOt adversely influerlce to the reactio~ ong
~hese solYents, hydrophilic solvents may be ~csed in
mixture with wateT.
~1hen the compound ~ is used in ree acid. form
or its salt form in the reaction~ the rea ~ion is
prPe~ably caIried out i~ the pTesenee o a sonventional
conde~sing agen~ such as N9N-di~yclohexrlcarbodiimide;
N cyclohexyl-N'-msrpholinoe~hylca~bodiimide; N-cyclo-
h~xyl-N'-t4-diethylami~oryclshexyl)carbodiimide; N ~N-
diethylcarbodiimide; NgN-dlisopropylcarbodiimide; N-
e~hyl-N'-(3-dimethylami~opropyl3carbodiimide 9 N,N-
carbonylbis~2-methylimida201e); pen~ame~hylene-ketene-
N-cyclohexylimin ; dip~e~ylketene-N-cyclohexylimine,
e~hoxyace~yle~ ethyl polyphospha~e; isopropyl poly-
phospha~e; aie*hyl phospho~ochloridite; phosphorus
oxychlsride; phosphorus ~richloride; phosph~rus
pe~achlo~ide; thionyl chloride; oxaly~ chloride;
t~iphenylphosphinel N-e~hyl-7-hyd~oxybenzisoxazo~ium
1U~TObOra~e ~ ~-ethyl-5-phenyli~oxazolium-3'-sul~o~at~;
1- (p-ch~ orobe:rlzeneslll onyloxy) ~6-chloro-lH ben70tria~ole;
so-called Yilsmeier Teage~t ~ for exa~ple ~chlorome~hylene3
dime~hyla~moIIium chloride produced by ~he reactio~ of
dime~hylo~mamide wi~h thionyl chloride.~.phosge~e, .
~ %~
- ~ 9 - ~
a compound produced by ~he reaction o dime~hylformamide
with phosphorus oxychloride , e~c .; or ~he like .
The reac~ion may be also carried ou~ i~ the
pTesence o an inorgan~ c or a~. organic base such as an
alkali me~al hydroxide " an alkali metal bicarbona .e,
alkali me~al carbona~e 3 alkali. me~al acetate, tTi tlower) -
all~ylamine ~ pyridi~:Le, N- ~lower) alkylmorpholi~e, N ,N-di -
~lower) alkylbenzylamine, N ,N-dLi (lower) allcylaniline as
exempli:Eied below, or the like. When the base or ~he
1~ conde:nsing age~t is i~ l~quid, it c~ be used also as
- a solvent. The reaction tempera~ure is not cTitical,
~d the reac~io~ is usually carried out under cooling
or a* amkient tem?erature. --
In the prese~ Teaction, a syn-isomer of che
cbject compound ~I~ can be obtai:cled preferably by con-
ductixlg the reac~ion of ~che compound ~ with a syn-
isomer of the s~aTting compound ~III). -
In ~che preseIlt ~eac~ion, amino group for Rl in the
compo~nd ~III) may be converted into a protected amino
gTOUp to give th compound ~I) wherein Rl is a protected
amino, and acyl for R2 may be con~erted in~o hydroge~
in ~he course o~ the reactioIl according to reac~ion
conditions, ~d these cases are included wi~hin the
scope of ~che present reaction.
~5 P~ocess 2
___ _
The o~j~c~ compo-md (Ib~ or salt ~hereof caIl be
prepa~ed by subjec~i~g the compourld ~Ia3 or a salt
~he~eof to eliminatio:~ eaction of ~he pro~ective
g~oup of car~oxy.
3û Sui~a~le s~l~ of the compound (Ia) caIl be
re~erred to ~he acid addition salt exemplified foT ~he
compound (II).
The preseIlt reaction is car~ied out in accol darLce
w~ th a co:~lven.tional method such as hydrolysis,
3~ reduc~io~ o~ ~he like.
.
'2L~
- 3~ - .
In c~se that the protective group is ~ ester,
, he protective group can be eliminated by hydrolysis .
Hyd~olysis is preerably carried out i~ he presence o~
a base or 2n acidO Suitable base may include ~n i~or-
ganic base and an organic base such as &~ alkali metal
~e.g.; sodiumg potassium, etc:.) 9 an ~3.1Xaline earth
me~al ~e . g . , magnesium9 calci.um, etc . ~, the hydroxide
or carbonate or bicarbona~e t:hereof, trialkylamine
~eOg., ~rimethylamine, trie~hylamine, etc.), picoline,
1, 5 -diazabicyclo ~4 ~ 3, 0 ]none -5 -ene, 1 J 4 -diaza~icyclo ~2,
2~2~octane, 198-diazabicyclo~5,4,~Ju~dece~e-7, or the
like. Sui able acid may include an org~ic acid ~e.g.,
:Eormic acid, acetic acid, propionic acid, ~rifluoro-
acetic acid, etc .) ~nd an inorganic acid ~e . g ~, hydro-
lS chloriG acid, hydrobrom~c acid7 sul~uric acid9 e~c.).
The reactio:ll is usually carried out in a sol-
ve~:Lt such as wa~e~, an alcohol ~e.g~, methanol, ethant:?l,
e~c.), a mixture t~ereo:f or any o~h@r solve~ which does
nst adversely i~flu~nce to the reac~io~ A liq~d base
OI' acid ca:ll be also used as the solYerl~. The reaction
temper ture is no~ cri~ical a:nd the reaction is usually
carried out ullder cooli:~g to warmi~g.
~eduction can be applied preferably ~or elimi:~lation
of th~ protecti~e group such as 4-ni trobe~zyl,, ~-
iodoe~hyi~ Z"2"~-*richloro~$hyl, or ~he likeA The
reductio~ method applîcable or ~he elimina~ion reac~io~L
~ay i~clude ~ :for ~xampl~ ~ reduc~ion by using a
combi~ati~ o:E a me~al (e~gO~ zinca zinc amalgam" etc.
or a sal~ of chrome compound (e ~ g . 9 chromou~ chloride 9
chromous ace~ca~, etcq~ a~d a~ organic or i~organic
acid ~e .g. ~ ac:e~ic acid, propionic acid9 hyd:rochloric
acîd9 etcO~; and conventional ca~alytic reductio~ in the
` pTese~ce of a coIlve~LtioIlal metallic ca*alys~ (e~g. 9
palladi~ ccLrbon3 et~ 7)~
- 31 -
.
Process 3
. . . _ . .
- The object ~ompo~d ~Id) or a sal~ thereof can be
prepaTed by reaCtillg the compou:cld ~Ic) or a salt thereof
with the compound ~IV) or îts reac~ive derivative"
Sui~able salt of the compou~d (Ic) ca~ be refer~ed
to the ones exempli:Eied or ~he compound ~II).
Suitable reac~ive deriv~ re
o~ compo~d (I~) may incl7lde a m~tal salt such as a:~
~û alkali metal salt ~e.g,~ sodium salt, po~assium s lt,
etc.~ or the like.
- The prese~ reac~io~ may be carried out in a-sol~re~t
- such as water, phosphate bu~er; aceto~e, chlo~ofo~
nitrobellzene, me~hyle2le chloride, ethylene chloride,
.15 dime Lhylf o rmami de " me l:h~o l ~ e tha~:Lo l, e the r 3 - Le t ranydro -
fura~, dimethyl sulfoxide, or ~ny other organic sQlve~t
which does 3~ot adversely afec~ tho r~actiorL3, preferably
i~ o~es hav~g st~ong polaritiesO AmoT~g ~e solvents,
hyd~Qphilic solvents m~y b~ us~d i~ a m~xture with
20 ~a er. The reaction is prefera~ly carried out i~
aro~d neutral medium, Whe~ ~ne compou~d (Ic) or ~e
eompo~m~ (IV) is used i~ a f~ee fo~m~ the reaction is
preferably conduc ,ed in the presence o a base, for
example, i:~o~ga:nic base surh as alkali metal
~ydroxid~ ? alkall metal carbona e " alkall me~al bicarbo~ate
organic base su h as trial.kyl~mine, a~d the like. 1~.
r~ac1:ion ~empera~ure is :llo~ eritical, a~d ehe reaetio~
i5 usually earried ou~ at am~ emperat~re, Imder
warming or under slightly heating~
e present reac~io~ lud~s , ~ithln i~s SCQpe, t~e
~ase t~ protec~ed ~2r~0~ ~Ollp i~3 co~erted to ~ree
02r~0x;~r group d~lng t~e cour~e ~ the reactio~
Pr~cess 4
__
Th~ object compound (If) OT ~ salt ~hereof c~ be
~; pTepared by sub~cti:~g. ~he -compo~ d ~Ie3 .or a- sa~t .thereo~ - :
~o eliminatioD~ reaction of the p~otectilJe group OI amino~
- ~2 ~
Suitable sal~ of the compou!ld (Ie3 may i~clude a
meL~l salt, ~onium salt~ org~ic amine salt ~d
ehe like as aoreme~:Lti o:ned .
T~e pre~e~t elimi~Lation reac~io~ is carTied ou. i~
5 acco~darLce with a conve~tional method such as hydrolysis;
~educ~ion; a method by reacti~g ~he compound (Ie~
wherein the pretec~ive g~o~p i.5 acyl g~oup with imino- -
haloge~ting agent alld ehen wit~ iminue~herifying agent9
~ d, if necessa~9 subjecti~g the resu1ting compound to
1~ ~ydrolysis; or the like. Th~ hydr~lysis may ;~clude a
m~thod us~g aIl aeid or base or hydra2i~e and the lik~.
- These methods may be selected depe~di~g o:~ th~ k~ of
the protectilre groups to be elimiIlated.
Amo~g these methods, hydrolysis UsiDg ~ acid is
o~e o the common aDd preferable~ method or eliminating
th~ protecti~e gTOUp 5uch as substituted or lmsubstituted
alkoxycarbo~yl ~e .g. " t-pe~tyloxycarbo~yl, t-butoxy-
- ca~onyl, etc.~, alkanoyl ~e~g~, formylS etc.),
cycloalkoxyca~bonyl, subs .ituted or ~ subs~ituted
:20 aralkoxycar~ox~l ~e.g~, be~zyloxycarbor.yl~ substi~uted
be~zyloxycaTbonyl~ ~tC1) ~ subs-~itut~d phe~ylthio,
substituted aralkylidene ~ substituted alkrlidene 9
subs~ u~ed cycloalkylidene, ar~lower)alkyl (e.g.,
ben7yl, ~CTi~yl, e~c.) or ~:he like.
~5 Suitable acid may iDclud~ a~ organic or aD
i~Lo~g~ic acid, for exam~3le, :Eormic acid, ~rifluoro-.
a ~tic acid, ben~e~Lesulfonic acid9 p-tolue~esulfo~ic
ac~ d, h~rdrochloric acid a:cld ~ preferable
acid is ~for example ~ ormic acid~ ~ri ! luoroacetic acid~
~ydrochloric acid~ e~c, The acid suitab~e for ~e
reactio~ ca~ be selected accordiD~g to the kiIld of
pTo~ee~ive group to be elim;nat~d. ~ne~ he Qlimination
re c~io~L is co~ducted wi~h the acid, it c~n be carTied
ou~ ~rL the presence o~ absence 9~ a solYent~ Sui~able
~i solven~ may i~clude a co~en~ional orga~ie sol~re~t,
water or a mix~cure ~.he~eof. ~en ~Ti11lo~oacetic -aci~
~ 33 --
is used~ the eli;millat~ reactlo::L may preferably be
carTied ou~ in the presence o arLisole~
The hyd:rolysis us~g hyclra~ine is commonly applied
for elimiIlating the protecti~re gTOUp 3 ~or exaDLple,
succinyl or phthaloyl.
The hydrolysi5 wieh a bé~se is preferably applied
for eliminating ar.yl group3, i.or exaDIple, haloalk2Doyl
te.g., dichloroace~yl9 trifluoroacetyl5 etc.~ e~c.
S~ able base may include, :E~or example, all inorganic
~0 base such as alkali metal ~ydroxide ~e.g., sodium
- hydroxide, potassium hydroxid~, e~c.3, alkali~e
- ear~h metal hydroxide te.g.~ mag~ s;um hydroxide,
--- calcium hydroxide, etc.)~ allcali me~al carbonate (e.~,
sodiwn caTbo~:Late , poi:assium carbonate , et~ .~, alkal~e
1~ ea~th metal carbonate ~e .g. 9 m~gnesium carbo~a-l e, calcium
carbona-e, ete.), alkali metal bic ~bor~ate (e.g. j sodium
- bicarbo~ate~ potassium bica~onat~, etc.), aLt;ali
me~al ace~a e ~e-.g . ~ sodium ace~ate, po~assium aceta~
etc ~ alkali:~Le ~arth metal ph~sphate ~e . g ., magilesium
phosphate, calc~ m phosphate, etc.), alkali me~al
hyd~ogen phospha~e (e.g., d:~sodium ~ydroge~ phospha~e,
dipotassium hydroge~L pho5phat~" etc.~ " o~ ~he like
and a~ organic base such as trialkylamine (P O g ~ ~
trime~hylami:lle, t~iethy:Lami~e, etc.), picol~e, N-methyl-
pyrrolidine, N-methylmorphol~e ~ 1, 5 -diaza~icyclo [4, 3, O ~ -
~on-S-e~ 4-~iazablcyclo~2,2,2~o~ane, 1,5-diazabi~
cyclo~J4"0~ cLdece~ ur the like~ The hydrolysis
us~g a base is ofte~ c rTied out ~ wa~er, a co~ventioIIa
org~nic sol~Jen~ or a mixture i:hereof.
~U Amo~g ~he pro~ectiYe g~oup ~ the acyl g~u? caII be
ge~rally elimina~ed by hydrolysis as men~iQ~ed abo~e
or b~ t:he o~eI co~ve~tiQnal hydrolysisO In case
that the acyl g~oup is halogen substi~uted-alko.Yycarbo~yl
or 8-quinolyloxycarbonyl, they are eliminated by
3~ ~reati~g with a hea~ me~al such as cQpperj 2inc ~r
~che like~
- 34 -
The reductive elimi~ation is generally applied
fol~ elimina~ing the protective~ group ~ for example 9
haloalXoxycarbonyl ~e.g., tric:hloroethoxycarboIlyl etc.),
substituted o~ unsubstituted aralkoxycarbonyl (e . g .
benz~loxycarbonyl, substitu~ecl benzyloxycarbonyl etc.),
Z-pyridylmethoxycarbonyl, e~c, Sui~able reductio~ may
in~lude, ~or example" ~eduction wi~h ~L alkali m~tal
borohydride (e,g., sodium boTs~hyd~ide9 et~ d th~o
like .
:10 l~e reactio~ t~p~rature is ~ot critical a~d may
be sui~ably selected in accord~ce wi~h ~he kind of
- the pTotective group o the amino group a:c~d ~he
elimina~ior~ method as mentio~ed above" and ~he present
reaction ls preferably car~ied ou~ ~Lnder a mild
1~ co~di~io~ such as under cboling, aL ambien~ t~mpera.ure
or slightly ele~a~ed tempera~u~e.
The prese~t ~eactio~ includes, within its scope, -
the cas~s that the protected caTboxy group for R ~nd/or
R3 is tra~sformed into the free carboxy gTOUp in the
~0 course of th~ elimina~ion ~eac~ioII as men~ioned above
or ill the post-treatme~t of ~he reac~ion mixtuTe or
reaction p~oduct.
Plocess 5 - -
~ he ob~ect compoulld (I~ or a salt ~hereo~ ca~ be
prepare~ by ~ e~ g the compou~d ~ Qr a ~alt t~ere
to elimi~atlon re~ction OI t~e protectii~e gxoup of amino.
Suit2bl~ 3 lt ~ tha compo~nd (Ii.)ca~ be re~errea to
the one~ 2empli~ied Ior ~he compou~d (II).
The pre~nt ~limi~atiorL reactlon can be carried out
3~ ac~ordinæ ~ ta~tlall;y the ~ame ma~er a~ that o:~
The pre~;exLt reaction ~ncludes~, with:~n lt~ ~cope9
the case tE:Lat; pr~Gectcd amino(lower3a~ beg~g t.he ~ub~
~titue~t OIl heterocyclicthio~lo~e~ lky~ ~or ~4 :L9 t3:'an~1
. 3~. ~ormed int;:3 a~ino(lower)alkyl.
~ 3~ --
Proce89 6- -
__ .
. ~he ob~ec~ compound ~ r a salt thereo~ c~ e
prepare~ by ~ub j ecting the compound ( I~) or a ~alt
thereoP to eliml~ation rePction o-~ the protectl~e group
o~ carboxg~
~uitable ~ 1; 0~ the compoulld ~Ik) ~ be re~erred to
the one~ as e~empli~led ~or the compou:~ld (II ) ~,
The prese~t elimi~ati orl reaction ca~ be ca~ied out
aceord~ t~ ~ubsta:tlti~ly l;he same m~er as tha~ o~
~he p:rese~ reac~ion ~clud~ J Nithi:rl itis ~cope, the
ca~e thU~ protsct;ed amino(lo~r3alkyl bP~ng the su~stituent
-- - - on hete~oc~clicthi~(~ower1alkyl ~or ~iL4 ~ tra~sforme~ ~t~
ami~o ( low~r) alky~ ,D
i5 ~
- ~he ~b~ec~ compou~d (I~) e~ be prepared by subject1rLg
th~ omp~d (Im) or a 9alt thereo~ to e~te~ icati~.
~uitabl~ 9al1; 0~ the compourL~ (Im) ca:tl be re~errea tc~
the one~ a~ e~:empli~ied ~or the compcu~d (II~
~Le ~re~0~t rea~iorl ~a~ be carr~ ed out by reacting
the eompou~d ~Im) or a ~alt thereo~ ~rith esteri~rin~ agent.
~uitable e~er:i~g age~t ma~ be a compou~d oi the
wherei~ R8 a2ld :~: are eaeh aa de~ed abo~e.
~he present reaction is u~ually carried out in a
so1~e~t ~uch a~ dimet~l~orm~mide~ pyrl di~e, he:~amethyl-
pho~phoric triamiae ~r a~ other ~l~e~t which does ~o~
adve:~el y ai~es~t t~e r~act~on.
In case tha~ the compound (Im) i~ used i~ a fo~m of
3~ ~see acid, I;he reactlon i9 pre~erab:ty carried out i~ the
pre~e~ce s~ a base a~ mentio~ed a~o~eQ,
~e reactlon ~em~era~re ~ s :sot s~ritical and the
reaction :Ls p~eferab~y carr:ied out under c~ol~g~ a !
ambie:t temperature or under wa~ng
~32~
- 36 -
Process 8
The object compound (Ih) or a salt thereof can be prepared
by subjecting the canp~und lIg) or a salt thereof to elimination
reaction of the prot~ctive group of hydroxy.
Suitable salt of the conpcund (Ig) can be referred
to the ones as exemplified for the canpcund (II).
The present elemination reaction can be carried out
according to substantially tne same manner as -that of Process 4.
Process 9
me object ccm~ound (Ip) or a salt thereof can be prepared
by subjecting the co~pound (Io) or a salt thereof to dehydration
reaction.
The present reaction is preferably carried out by
reacting the c~npound (Io) or a salt thereof with dehydrating agent.
Suitable dehydrating agent may include an acid such as
alkanoic acid which may be substituted with halogen (e.g. pivalic
acid, trifluoroace-tic acid, etc.), arenesulfonic acid (e.g.,
toluenesulfonic acid, etc.) or the like; or its halide (e~g.,
trifluoroacetyl chloride, tosyl c~oride, pivaloyl chloride,
phosphorus oxychloride, etc.); or its symmetrical acid anhydride;
unsymnetrical muxed acid anhydride; a reactive derivative of
diketene or the like; florisil; Girard reagent T; ethyl(carboxysulf-
amoyl); a ylide ccmpound (e.g., an intramolecular salt of
triethylamm~nium lly~roxide, etc.); and the like.
T~le present reaction may preferably be carried out in
the presence of a baseD
~7~
The preferable ba5e includes an inorganic base
such as metal hydroxide ~e~g. sodium hydroxide,
pot~ssium hydro~ide, etc~), metal carbonate ~e.g.
sodium carbonate, po~assium carbonate~ magnesium
carbonate, etc.), metal bicarbonate (e.g. sodium
bicarbonate, potassium bicarbonate, e~c.), organic
base such as tertiary amine (e.g~ trimethyl amine,
triethyl amine, pyridine, e~c.), alkali me~al alkoxide
~e.g~ sodium methoxidP) sodi~ ethoxide, etc.~ -~
Th~ re~c~ion is usually carried out in a
co~ve~tio~al solvent such as ~n alco~ol, :tetr~hydrofura~
dime~hy~formamidej shloTo~orm, methylene chloride or
any otner sol~ent which does not adversely influe~ce
~he reaction, ~nder cooling or at an ambie~ or
somewhat elevated temperature.
a~Q~
~e ob~ee~ compound (Ir) or a ~alt ther~oi ca~ be
p~ep~r~d by ~ub~ec~g the compoun~ ~Iq) or a ~a~t
the~eoi to i~trod~tion rea~t~o~ o~ the pr~ect~e grou~
o~ amino~, -
~ui~able ~alt oi the comp~und ~Iq) c~n be re~err~d
ta the o~e~ a~ e~empl~ied ior t~e compou~d (II3.
The prese~t r~act ~ can be carr~ed ou~ a~cord~ng
to ~ubs~a~t~ally t~e ~ame manner a~ t~at o~
The prepara~iorl for prepar~g the start~g
compou~Ld ~III) are expla~ed below i~ de1:ail.
Prep arati O~
The c~ou~d (YII) ca~l be prepared by re~c~i~g
the compou:~d ~Y~ or a salt t}aereof with halogenating
agent a~d the compolmd (VI I .
Suitable h~loge~atiIlg agent to be used irL ehe
p~esent reactio~ may :inclul~e bromi~e, chloriIle nd
the like~,
. The prese~ rea~tio~ is preerabl~r carried ou~:
i~ the pre5ence o a base such ~s an i~org3~ic base or
arL orgaslic base, -for examplet alkali metal ca~bonateg
al~ali metal alkoxide ~ ~ri~lkylamille or the like O The
prese~t reactio~ is usually c rried ou~ in a so~ven~
such as i~:L alcohol ~.g., methaIl~l, eth~ol, etc.3 or
a;~y o~hèr sol~ent whi.ch does ~ot 2dv~rsely afect ~h~
reac~io~.- lhe reactio~ temper~ure is ~ot cri~ical
an~ ~he reac~io~ is usually carried out u~d~r cooling
- or a~ ambieD.t temperature~ this reac~io~, R6 of the
compou~d ~Y~ m y ~e cu~rert~d in~o o~her protective
g~Ollp o car~oxy accordi~g to r~actioll co~ditio~s a~d
ki~as o:E ~he pro~ective g~oup a~d i~ is ~cluded
~ri hin ~he s ope o ~he pr~se~: reactiorL.
.-.. O
3~
3~ ~
3~ 6
PreParatio~ ~2)
_ . _
l'he compound (VIII) cc-Ln b prepared by subjecting
the co~po~nd ~VII) to introduc~ion reaction of the
protecti~e group o amino.
The p~sent process ccm be carried out i~ a
conveIltional m~nTler and when the protective group o:E
am~o to be intloduced iIltO the amino group is acyl,
th reaction ca~ be carried out ill subs~an~ially the
5ame ma~er BS th~t: of Pros:ess_1. Accordingly, the
detailed explanation ~herefor is to ~e ~eferred ,,o
s~i~ P~o~ess lr
~r~ t~
The compound (X) can be prepaTed by reactlng the
compound ~YIII) with the compouDd ~IX~.
This proces5 is usually carried out in ~he presence of
base such as an alkali metal hydride ~e . g . ~ sodium
hydride, potassium hydride, etc.), an alkaline ear~n
me~al hydrlde ~e.g., c:21cium hyd~ide, etc.~ and ~he
like, and usually carTied out in a solYenc such as di-
. methylformamide or any oth~r solve~t which does not
adversely afert the reaction. The reactio~ temperature
is not criticai a~d th~ reactio~ is usually carried out
under coaling, at ambient tempera~ure or under warming,
P~eparation ~4~
-
- 'rhP compouIld ~XI~ ca~ be prepared by reacti~g the
compou~d ~X~ wi*h an acid and/or acid aihydride such
as ac~tic acid and/or acetic a~hyd~ideu The reaction
of ~his process can preferably be carried ou~ in ~he
prese~ce of alkali metal perhaloate te.g~, sodium
perchlora~e~ sodium perlodate, potassillm perchlorate,
etc.~, alkaline ear~h metal pe~chloratc ~e.gO, magnes~um
peTchlQTate, calcium perchlorate, eLc.) alld ~he like,
alld an ac:id such as an orgaIlic acid teOg~ ~ ~ormic acid,
~5 e~o . ~ QT a~ inorganic asid (e~g~, hydrochloric acid) .
;
The reactio~L temperature is not cri~cical and che
reaction is usually c~rriecl out under warmi~g.
Pre~earations (5) and (7)
The pTeparation (5) and ~7~ can be carried ou~
in a conventiollal manne:r as shown in P~ocess 2 or 4
In ~he prepara~io~ ~5), aocording to reaction
o~ditions3 there may be obtain~d ~he produc'c haYing
Rla ~EIa) ur the produc~ havl~ig amino in~tead of Rla (~:tb~
~d they are subseque~tly reacted with the compound (XII)
lQ or a salt ~hereof to give the compo~d (IIIa) or (IIIb) 3
respectively~ as shown in repa 1.
Suitable salt of the compound ~XII) is a convelltional
acid sal~ such as aIl ino~ganic acid salt (e .g. 9
hydrochloride, e*c.) and an or~g~nic acid salt
~e.g., p-toluenesulfonic acid sal etc.). Whe~ sal~
o said compound (XII) is used i~ this process, the
reac~io:ll is usually carried out i~ the presence of a
base such as an alkal metal hydroxide ~e . g ., sodium
hydroxide, pot ssium hydroxide, etc~q The reac~ion
is usually carried out in a solvent such ~s water9 a~
alcohol ~e .g ., me~hanol, ~ ol 9 et:c .) or any other
solvent which does no~ adversely affec~ the reaction.
The reaction ~emper~ure is not critical and ~he
reaction is usually carried out at ambie~t ~empera~cura.
~)
The compouIld (IIId) can be prepared by subjec~i~g
the compo~d (IIIc) to introduc~ion reac~io~ o:f the
3~ pro~ective group o hydroxy group~
The p~esent process c~n be carried ou~ in a con-
ven'Liana:l manner and when ~he pro-ec~ive gT5Up to be
introduced iIl~o the hydroxy g~oup is acyl." the :reaction
ca~ be carried out in substaIltially the same ma~er as
~hat o Process 1.
_ .
...
4~ B;~
In ca~e *hat th~ pro ective group ~o be i~troduced
is ar (lower) alXyl ~ the pIesent reaction is car~ied out
~y reacting the compound ~IIIc) with the compound of
~he f ormul a:
S R~
wherein R ~ is ar(lower)alk~l and ~y is an acid re~idue~
Suitable acid residue may }nclude a residue of an
acid such as an ~norgallic acid, f~r exa~Lple, hydro-
h~loge~ic acid ~e.g., hydrochloric acid, hydTobromic
1~ acid, etc.~ ~ sulfuric ac.id or the like, OT an orgaDic
acid9 ~or example~ lower alkanesulfonic acid ~e.g.,
methanesul:follic acid, ethanesulfonic acid~etc.) "
arenesulfonic acid ~e . g . ~ benzellesulfonic acid, p-
toluenesulfonic acid" etc.) or the like. Th~ presen~
reaction is preferably car~ied out in the pTes~nce o.
a base as mentioned above and usually carTied ou~c in
a solvent such as dimethylformamide or ~he like.
The reaction temperature is not cTitical and the reaction
is usual~y carTied out under cooling 7 at ambient
~emperature or under warming,
The compound (:~r ) can be prepaTed by reac~in~
~ rompound(~III)~ith ~ compound (~IY)o
The reaction is pre:E~rably carried out in the
presence of a base as exempli:fied in Process 1 in
case that X is an acid residue and in the presence
of a condensing agent, for example~ one fo~med by
triphenylphosphine and diethyl azoormate in case
3 that X is hydroxy, respectively.
_ The ~eaction is usually carried out in a sol-
ven~ such as acetonitrile, dime~hylformamide,
~etrahydrofuran or any o~her solvents which do no~
adv~rsely influence the reaction. .The reaction
temperature is nst critical and the reaction is
-
...
32~
~ 42
usually carried out f~om coo:!ing to hea.ing Tound
a boiling point of the solvellt used.
~9~
The compound (~ ) OT a salt the~eof c~Ln be
p~epared by subjecting a compound ~ o eliminat-
ion ~eaction of the amino pro~ectiYe gr~up.
This eliminatioIl reactiOn of the amino
protec:tive g~oup of the compound ~ be carried
ou~ in a simila~ ~nanner to tha* of afoTementioned
~o ~Pro ce s s 4 .
Suitable solYents include wa~er~ ethanol,
chlorofo~m, d~iethyl ether and the like. The react-
iDn temperatUTe i5 not critical and the ~eaction is
usually carried out unde~ wa~ming or heating.
1~ ~he preserLt rea~t~o~ includ~r w~ th~n ~ ~cope9
the ~3e t~at protect~d &m~no group i~ R i~ con~
~e:~ed i~to free am~lQ group~
l'r cr~t ~ 1~.
The comp~ d (~ ~r a salt thereoi ~a~ be prepared
~20 ~ subject~g t~e oompou~d ~:~) 3r a ~alt thereo~ to
introducti~ react:~on of the pro~ecti~e group of aminol,
~he p:re~ent reactlon can be cas:rie~ ou~ accordi~g
to ~ub~ta~ti ally th~ same man~er a~ tha~
I:n cas~ tha~ protec:ti~e group ~s be ~l;r~duced i5
2~ lower ~ o~l grOUp9 thi8 r~actlo~ i~ pre~e~
~sd ~ re~ct~g the comp~nd ~ with a com- -
pawDd of the :f~la;
12 '
R~
W~le~ ~ R12 ~8 lower alko~cycar~y} ~d 1~ ar;~lD
~he compo~d (~II ~ or a ~alt t~:Lere~I caD be
- prep~a ~ ~ub~e~::ng l;~ e ~ompou~d ~:3 or a
8al-.. there~I t~ d~t~ reaetlo:a ~ the 8U~
~tlt~aertt o~ hydro~ up.
- 4~
In CaBe ~at substituerlt to be i~troduced ls aryl
which may be 6ubstitu~ed with suit&ble sub~tituent(s) 9
the prese~t reaction i6 conducted by reacting the
c~mp~und (~I) or a ~alt the~o~ with a compou~d of
the fo~m~la~
R2i ~)2 R2i . ~ ~) (~)
Wh2re~n R2i i8 argl which may be sub~3tituted with
~uitable ~3ub~3~ituent(s)~ ~2 i~3 halogen and Y i8 an
acid re~id~e~
Sultable acid rPsidue may include hPlo~en~ toluene-
~ul~onylogy, re~id~e of ~ul~uric acid a~d the likeO
The present rea~tio~ ~s ~sually. carr~ed aut ~n
a 801ve~t Q~Ch a~ ~lcohl(~g~ methanol~ ethanol~
etc.), water9 mi~e~ ~ol~ent thereof~ or any other
~ ~olve~t which does not adversel~ a~fec~ the reactio~
~nd pre~e~ably carried out ~n tke ~e~ence o~ a ba6e~
The reactlo~ temperature i8 not critisal a~d
~e reaction iB u~ally ca~ried ou~ ~nder cooli~g~
at ambie~t ~emp~ature or under ~arm~-~g~
I~ case ~at ~b~tituent to be in~rod~ed 1~
c~clo~l~yl which may ~e s~ba~tuted with ~uitable
substituent(s)~ the reaction iB carried out by reacti~
the c~mp~u~d (~XI) or a Balt thereo~ with a compound
of the ~orm~la:
R~-Y ~g3~1)
~herein R2~ i9 cycloalkyl which may be 6ub~t~tuted w~th
suita~le substi~ue~t(~ and ~ i~ a6 de~ined abo~e~
~his reactio~ i~ carried o~t ~ccordi~g to ~ubstan-
tial~y th~ same manner as t~at o~ ~3o~ 5ha~_~
~a. 1
~ , .
~he co~pound (~ n ) or P 9 lt thereof can be
prepared by subjectlng t~e comp~und ~III) or a ~alt
thereo~ to cycli~atio~ reaetion~
~ .
3~8
- 4~ _
The ~resellt reac~iorl i~ usuE~lly carried out in
a solvent such as a1CQh1 (e~gO ~ methanol~ ethanol9 etc- )
or the like~
~his reaction ig c~rried out in the presence o~
dehydrating agent such as magneslum salfa~e 9 acià
a~hydride (e.,g" " acetic aIlhydride, etc. ) or the like~
~he reaction temperature i8 not critical and it
i6 ~ually car~ie~ ~t ~mder warming or heati~ or
a~ ambi e~t t emp~ræ~re .
1~ ~
The compound (X:EVI ) or ~ ~alt thereo-~ ca~ be
prepared by rea~ting th~ compound ~:~V) Wit~L ~lg3 ~r
s lt thereo~. v
Suitable ~al-t o~ 5 may be alkæli metal ~lt.
The reac~tion ls usua l ly carried o~t i~ a ~olve~t
~uch a~ waterF dio~ane, mixed solve~t thereo~ or any
other or~e which doe~ not adver~ely a~fect the reactiorLc
Th2 reactio:~l temperature 1~ not critlc~l ~d the
reaction i~ u~aally carr~ed out under heati~gl,
~
~e compou~d (~II) or a ~alt thereQY ca~ be
prepared by su-~ecting t~e eom~ound (~VI~ or ~ ~al-t
the~eoI t~ eli~rZa~lo~ r~action of the protective
group o~ a2ino~
T~e preserlt reactio~ i~ carrled out according to
- ~ubs~a~tiall;y the 6~me manner E~ tha~ o~
~ ' .
The comp~und ~VIII) or a ~alt t~:Lereof can be
prepared b~ ~u~ject:5:ng the compound (~VII ~ or a
~alt t~ereo:E to i2ltrod~Cti~ reacti~ o~ the pr~tec~
tive group of a3ci:~IoD
The pre~ent reactioIl I B ca~led out ~ccordi:llg to
substantially the æ~e manner a~ that of ~,
3~
~ 45 ~ L8;~
In ~he aoTemen'Lioned reactio~s ~d/or i~ the
pos~ ~reatment Or ~he reac~iDns oi: ~he present inventio~,
the aoremen~io~ed tau~omeric isomers may occasio~ally
be tra~lsformed into ~che o the r tau~omeric isomers and
such case is also included i~ the scope of the present
inven~ion .
In- case thBt the ob ject comDound (I~ is obtaiDed
i~ a form of i:he free acid a~ 4 positioIL and~or in
case tha~ the object compou~d ~I) has free amino group~
1~ it may be optionally tra:~sformed into its pharmaceutic 1-
ly acceptable salt a~ aoreme~L~îoned 1~y a co~ve~tional
me thod .
I'he ob j ect compouIld (I~ and pharmaceu~ieally
acceptable salt thereof o ~che preser~t invention are
all ~Lolrel compounds which exhibi~ high an~ibac.erial
a ~ y, inhibi~ing ~he growth o a wide v~rie.y sf
pathoge~ic microorgallisms i~cluding Gram-posi~ive a~d
~ram-:~ega~ive bact:eria and are usef~ as a~cibacteria
a ge~s~
~0
2~
A~
Now, in order to show the u ility of ~he obj ect
compouIld (I), wi~h regard ~o some represe:nta-ive
compouIlds of this înventio~ he tes~ da~ OIl ~he in
vi.ro anti-bac~erial ac~ y are shown in the ollo~i~g.
Test Compou~ds
(1) 7_{2-C~clopentylo~yimino~2-~5-amin~ 1,2~4~thiadiazol-
3~yl)acetamido~3 cephem 4~carbo~ylic aci~ ~8~n isomer)
.(2) 7-~2-Cyclcpen~ylo~yimlno-2 ~5-amino-1~2 9 4~thiadiazol-
3 yl)acetamido]-3-(793,4~th~adia~ol-2-yl~thiomethyl-3-
cephem-4-ca~bo~ylic ac~d t~ isomer~
(3) 7{ ~-t2-~yclope~te~ yl)o~imino--2 (5~mino-1~2,4-
th~ad~azol-3-yl)a~e~amid~-3-cephem-4 c~rboxylic acid
(~yrL i~omer)
~4) 7~2-(2~C~clopente~ yl)o~ ~ o-2-(5~amino~ 4
~h~adiaz~ y~)acetamidD]-3~(1~3~4Dthladia~ol~2-yl)thio-
meth~l 3 cephem-4 carbo~ylic acld ( 5yn i~mer~
~5) 7-~2-t2-Cyclohe~en~ o~y~mino-2~5~amino-1,2~4-
t~iadiazol-3~yl~ace~amido~-3~ ,4-thladiazol-2-yl~th~omethyl
~ cephem 4 car~ox~lic acid gsyn ~som~r)
(6~ 7-~2 ~4J~hlorophe~o~y ~ o) 2 (5i;amino 1,2y4-t~iadiazol
3-yl)acet~ldo~ thl~dia~ol 2~1~thiom~thyl~ cephe~
4-carb~lic acld t 9~n i~omer3
t7) 7-t2~11ylo~ no-2-(5- m~o_l,2~4~h~adiazol ~-yl)
acet~mido3-3 (1-allyl lE-~etra~ol 5-yl)thiomethyl 3;
cephem-4-carbo~lic ac~d ~ 9y~ isomer)
(83 7 ~2~ar~o~m~t~oxyimlno 2-(5-amino~ 9 2 j4~thiad~azol-
~yl)a~et~m~d~3-3~1 (2~ oeth~13 lE~tetrazol~5-yl~thio~
meth~ cephem 4~car~o~1ic acid ( 9yn isomer)
t9) 7-~2~ Carboxyethoxylmino~-2 ~5~ami~o~2~4-th1adiazol-
~-yl)a~e~am~do~-3~ 3 aminopropyl)~lH-tetrazol-5-yl]thi~
methyl 3-~ep~em~4~carboxylic acid ( B~ omer~
(10) 7~r2-Cyclopentylo~lmin~2 ~5-amin~-1j2~4 thiad~azol-
3 yl)acetamido~-3-(~etrazolo~1~5-b~pyrIdazi~-6~yl ) t~i omethylO
3-cephem~4~art~o~1ic ac~d ~syn isomer)
-
~ ~5b~
7~2~clope~tylo~cylm:Lrlo-2-(5 am~o 1~294
thiadiazol_3--yl)Qce~a~id~--~e~.hem ~ neth;~1]~
car~a~oylpyrid~am-4-car~o~yla~e ~ 30mer~
Test Me~hod
I~ ~ritTo a~tibactPTial acti~îty was deteTmi:~ed by
.he two-fold a~ar-pla~e d~lution me~od as d~scribed
below .
~e loopful o~ L ove~igh~ culture o each tes~
strain in Trypticase-soy broth ~10~ riable cclls per m~.
wax st~eaked OIl heart i~Lfusio~ agar (HI- agar)
rontai~ing gTad~d concentratio~s of test coounds, and
mi~imal inhibitoTy co~cen~atio~ (MIC~ was expres~ed in
~5 terms o ~lg/~l. af~er i~cubatioIL at 37C for 20 hoursO
~0
3~
45c
_ _ ___ . _ ~3
z ~S~, ~ ~: n C~ ;~ ~ ~
i--~ tD ;~ I_ Q
, P~ 3 Z pl
lD
. ~ ____
~d O ' O O ~-
~ ~ a~ ~D ~_
.' IJ ~3 ~ O ~
o a ~ --a ~
Y ~ O S f~
~Sl ~ _~J ~J 1~
~D CD ~D
J O
, , IJ a~ ~ CD
L~
~71 ~ . ~ ~ ~D 3
~,a ~ ~,a ~
~ ~1 ~d ~ C~ t~
. ~1 CO ~Sl .
. ~
. I:n ;. ~ ~ . .
'~' V O '',0 ~
~ ~ ~ ~n ~ ~ ~
~ ~ cr~ CL
, C~ ~ ~ ;~ ~
_ul ~ ~J cr~ ~_
_ _ _.
45d
.
rOT .herap~u+ic admiI~is cIatiDn~ the ob jPct compou~d
~I) o . .he presen, inver~tion is used in ~he . orm o~
conventioIIal pharmaoeutical prepaTa~ion which ont~ins
s id com~ounds, as aTl ac Live ingredient, in ac~ixture
with 2 phaTinzceutically ac~ep~ bl e c~rriers such as B
org~ic or ino~g~ic solid ~ liquid excipien1: which is
su~table fo~ o~al, par~n-ceral o~ ex~e~al administration.
The pharmaceuti~al pTepara~iuns m2y be in solid from such
2;, capsule, tablet~ dragee" o:intmen~ or suppos~tory, or
in liquid form such as solution, suspe:~sion" ~r e~ulsion.
- If needed, there may be included in *he abore p~epaTations
auxiliary sU~staIlc:es ,, 5 ~abili ~ ing agents ~ wet~ing OT
emulsiying agen ~ s, bufers a~d the ot:he~ commonly u~ed
additive s .
1~ Whi~ e ~he dos age of the compounds may ~rary -from
æld also depe~d upon the age J ~onditioT~s of ~he patient;
a ki:cLd o:f dise2se ~ a lcind of the compound (I) ~o be
a~Flied3 etc,,, ~ - erage single dose of a~ut 50 mg.,
100 mg., 250 :ng, a~d ~00 mg. o the o~ ject co~poun~
~I~ o:E ~e p~ese~Lt in.~,-e:ntion h~s proved ~to be ef~ectiYe
i~ trea~ing dise2ses :ulfected by pathogenic bacteria.
I~ general ~ daily dose be~ween 5 mg O a~d about
3,000 mg. o~ e~en ;nore may be administered ~o a
patienL . ' - ,,
~i T}12 ollowillg Prepara~ions a~d Ex3mples aTe
given :Eor ~h~ purpos~ of illus~rating ~he present
;~v~ i o~: - -
. .
PTe~aration 1
tl~ A mixture o N-hydroxyphthalimide ~.15 g),
tTiethylamine ~5.05 g), N,N-dimethylformamide ~60 ml)
. and l-bromo-2-cyclohexene ~8.05 g) was s~irred for
3.5 hours at room temperature, The reac~ion mixtuTe
5 was poured into water (300 ml). The pTecipitated
crystals we~e cQl~ ected by filtra~ion, washed suc-
cessi~rely with wa~r and Il-hexane nd then dried to
give N- ~2-cyclohexen-l-ylo~y)phthalimide (9.8 g).
mp 87~C, -1
I.R. (NujolJ*: 1770, 1770, 1610 cm
N.M~,R. (d6-DMSO,~) : 1.50-2.17 ~6H, m), ;
4.60-4.77 ~lH~ m3; 5.73-6.27 t2H, m),
7 gO (4H t S')
~2~ A mixture of N-hydroxyphthalimide (52.16 g),
1~ b~omocycloheptane (62.41 g)~ dimethylsulfoxide
~385 ml) and pota~sium caTbonate (44.16 g) were
s~i~red for 74 hours a~ 70~C. The reaction mixture
¦ was cooled und~ ice-cooling and added to iCe-Wat~T
(1.5 Q). The precipita~es were ~ollect*d by filtr t-
ion, washed with ic~-water ~x2) ~nd ~hen dried ~o
give N-(cy~loheptyloxy)phthalimide (63 g~, mp llO
to 112~C.
N~MoR~ ~d~-DMSO,~) : 1.57 (8H~ m~ 90 (4H9 m),
4~0 ~lHJ m), 7~93 ~4H, 5)~
t3) A mixture of N-hydrsxyphthalimide (58.2 g) ~
j l-chloro-2 cyclopentene t36.9 g), ~iethylamine
C53~9 g~ i~ aretonitrile (370 ml) was ~rea*ed in
similaT manners ~o those of P~epaTations 1-~1) and
1-~2) to give N-t2-cyclopen~en-1-yloxy~phthalimide
~56.5 g)
I.R. ~Nujol~ : 1780, 1730~ 1610 cm l
N.M.R, (d6-DMSO,~) : 7.SZ (4H~ s), 6~Z8 (lH,m),
~:........................... 6.D0 (lH~ m~, 5.4~ ~lH~ m)~ 2.9-l.9
~4H 3 m)
*tr~d~E~k
:
~ y~
~e~a`ratio-n
A mixtur~ o N-Ccycloheptyloxy)phtnalimid~
(2.59 g~ 9 hydrazine hyd~ate ~0.45 g~ in ethanol tl2 ml~
was refluxed for 5 minutes.
- The reaction mlx~ure was cooled
and filtered to give the filtrate con~aining
cyclohep~yloxyami~e.
.~,~ .
~1~ A mixtu~e of N-(2-cyclopenten-l-yloxy)-
phthalimide (~2.9 g~ and hydrazine h~drat~ (4.75 g~
i~ e~hanol (115 ml) was ~efluxed for 5 minu~esO
The reactivn mix~ure was ~iltered. The filtrate
coIltaining (2 = cyclopenten-l-yl~ oxyaDIi~e was add~d
~o a solution of sodium 2-~5-formamido-1~,4- _
- Lhiadia ol-3-yl)glyoxyla~e ~22.4 g) in water. The
mixture was adjus~:ed ~o pH 2 with 10% hydrochloric
acid, stirred for 2 hours ~nd then concentratedO ~he
co~ce:~trate was adjusted to pEI 1 with 10% hydrochloric
acia. Th.e precipi~a~es.were collected by il~ation
and d~ied to giv~ 2-(2-cyclopenten-1-yl~oxyimi~o-2^
(S-form~mido-1,2,4-~hiadi~ol-3-yl)ac~ic acid ~syn
isome~)~20.0 g~ 9 mp 150C (dec.~.
I.R. (Nujol) : 3400, 3100, 1720, 1690, 1540 cm
2~ N.M.R. ~d6-DMSO, ~3 : 1.80-2.50 ~4H, m)~ 5.30-
5~50 ~lH~ m), 5.83 6~30 ~2H~ m~g 8.90
(1~9 5)
~2~ A mix~uTe o N-~2-~yclohex~n-1-yloxy~-
phthalimide (7.29 g), hydra~ine hydra~e (1.5 g) in
ethanol ~40 ml~ was re1uxed for 5 minutes. The
reac~ion mix~uTe was cooled a~d fil~ered ~o gi~e
~he il~Tate containing (2-cyclohexen-1-yl)-
oxyzmine (filtrate A). On ~he o~he~ hand, a
mix~ure o S-me~hyl.2-~5-formamido-1~2~4-thladia_ol-
3~yl~th~.oglyoxy~at~ (6.93 g) in lN~aqueous solu*ion
of ~odium hydroxide C~ ml) was s~irre~ for 3Q
mi~utes at ~oom tempera~lre. Th~ reaction mixture
containing sodi~m 2-~5-formamido-1,2~4-thiadiazol-
3-y~)glyoxylate was ad~u;ted to pH 7 with 10%
. hydrochloric acid and theTeto was added the filtrat~
A and then the pH was adjusted $o 3 wi~h 10%
hydrochloric acid. The mix~ure was s~irred for 3
hsuTs at ~oom temp~Tature. The reac~ion mix~ure -~as
concen~ra~ed and to the co~centra~2 was added.e~hyl
- 10 ace~a~e. The mixtur~ was adjusted to pH 1 with
- 10% hydrochloric acid, The pr~cipitates wer~
collected by ~iltTation to giv~ 2~2-cyclohexen-1-
~ yl~oxyimi~o-2-(5~formamido-1,2,4-thiadia~ol-3-yl~-
ace~ic acid (syn isomer)~2~5 g~. O~ the other
.. 1~ hand9 ~he e~hyl ace~a~e layer was separa~d from
the filtrate and e~aporated. The Tesidue was
tri~ura~ed with diethyl ether to give the same
object compound ~1.5 g)~ To~al yield : 4.0 g,
m~ 190 ~o 1~2C ~dec~.
I.R. tNujol) : 35~.0, 3400, 3200~ ~500~ 1690
1590~ 1540 cm
N~MoR~ ~d~DMSO~ 1.5-2.3 ~6~9 m3~ 4.73-5.0
(lH~ m), 5.76-6.~3 ~2H, m)~ 8.97 (lH, s)~
13.~0 (lH, broad s)
(3) ~o a solution of s~dium hydroxide ~11.2 g) in water
(140 ml~ was added ~-me~hyl 2-~5-formamido-1,2~4O
thiadiazol-3 yl)thioglyoxyla~e (27 g) a~ 10C and
~he mix~ure was stirred foT 30 m~u~es a~ 20~.
. The reaction mixture con~aining sodium 2-(5-fo~mamiao-
3~ 1,2~4~thiadiazol-3-yl~glyoxyla~e was cooled, ~djusted
to pH 7 with 10% ~ydr~chlorlc acid a~d there~o was
added a solution of cyclopen~yloxyamine ~15.3 ) in
ethanol ~150m~)~ The mix~ure was adjus~ed ~o pH 3
with 10~ hydrochloric acid~ and stîrred for 1.5 hours,
The reaction mix~ure was adjus~ed to pH 7 with a~ -
aqueolls solution of sodiwn bicarbona~e and then
evaporated to remove Pthanol. The residue ~as
washed with ethyl acetate. To the aqueous layer
was added ethyl acetate and ~he mixture was adjusted
ts pH l with 10~ hydrochloric acid. The precipitates
were collected by filt~a1:ion to giYe 2-cyclopen*yloxy-
imino-2-(5-ormamido~ "4-thiadia7O1-3-yl)acetic
acid (syn isomer~(3.99 g). The filtra~e was
extracted with e~hyl acetate and ~he extract was
dried over magnesium sulfa~e and ~hen concentra~ed.
The p~ecipita~es were.coll~c~ced by fil~ration and
washed with diethyl ether ~o give ~he same objec~ ~ ~
- - compound (801 gl- To~al yield: 12D1)9 g~ Illp I80 ~-
to 185C (dec. ~ . .
-15 I.R. ~Nujol): 31309 3040, 2680; 2610, 252û,
17?.0, 1690 " 1~6~, 1600, 1550 ~cm 1
N.M.R. (dfj-DMSO, ~) : 1O33-2O1 0 (8H, m) "
4.67-5.0 (1~, m), 8.88 (lH~ s) ~ 13.50
- ~lH~ s)
(4~ The follo~ing compound was obtain~d according to
similar ma~ners *o ~hose of Prepara~ion~ 3(1) ~o
3~3~.
2-Cyclohep~yloxyimino-2-(5~ormamido-1,2,4-
thi~diazol-3-yl)acetic acid ~syn isome~).
N~M.R. ~d6~DMS0, ~ 1.50 (8H~ m)~ 1.80
(4H, m3, 4.37 (lH~ m) 3 8.81 t1H, s)~ ~
9.88 (lHa s3
=~ . .
~ ~ :tur~ o~ 2 ~2 cyclope~Lte~ l) oxyim:L~o.-2 - (5-
formamido-1,2,4-~hiadia~ol-3-yl)acetic acid (syn isomer~
(~0.0 g) and -~N aqueous solution o sodium hydroxide
(200 ml~ was s~irred for an hour a~ 50 to 55C~ The
reaction mixture was cooled) adjusted to pH 7 with 10~
hydrochloric acid a~d ~hereto was added e~hyl acetate.
The mixture was adjus~ed to pH l-wi~h 10% hydrochloric
5~
- acid znd extracted ~ith ethyl ace~ate. The ext~act
was washed ~ith a satu~ated aaueous solution of
sodium chloride, dried over :magnesium sulfate and
e~aporated. Th~ residue was pulverized with di-
;sopropyl ether to give 2-(2-cyclopenten-1-yl)oxyimino-
2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn
isomer), mp 150~C ~dec.).
I.R. (Nujol) : 3300, 31509 1710, 1620, 1520 cm 1
N.M.R. ~d~-DMSO, ~ : 1.80-2.50 (4H, m), 5~30-5.50
~lH, m~, 5.83-6.30 ~2~, m), 8.20 (2H9-s)
~ . .
The follo~ing compounds were obtained accordin~ ~b -
a similar manner to ~hat of Preparation 4.
(l) 2-(2-Cyclohexen-l-yl)oxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetic acid (sy.n isome~ mp 173C.
I.R. (Nujol~ : 3400, 33009 3200, 17203 1620)
16009 1520 cm~l
N.M.R. ~d6-DMSO, o) : 1.50-2.17 ~6H, m), 4.53-
4.83 ~lH; m), 5.57-6.13 (2H, m)~ 8.18
t2Hp s)
C2) 2-Cyclopen~yloxyimino-2~ amino-1~2,4-thiadiazol-
3-yl~acetic acid (syn isomer), mp 160 to 165C ~dec.).
I.R. ~Nujol) : 34709 32909 3200, 2400, 1715,
. 1515, 1600, 1520 cm~l
N.M.R. (d6-DMSOg ~) O 1.17 2.10 ~8H, m),
4.60-4.97 (lH9 m) 9 8.~2 ~2H9 s)
(3~ 2-Cyclohep~yloxyimino-2-(5-amino-1~2,4-thiadiazol
a-yl)ace~ic acid (syn isomer)p mp 116 to 119C (dec.~.
I.R. ~Nujol~ : 3250 a 3200 ~ 1650 ) 1600 9 1520,
1400~ 12603 1150, lO00, g20,
720 cm~~
(1~ A solution of 4-(3 aminopropyl)morpholine (122.6 g)
i~ dioxane (520 ml) was added to a solution of 97%
sodium hydroxide t35.1 g~ in water t420 ml) under O~C
,
:
51
and the~eto ~as added drop~ise carbon disulfide
~4.71 g) over a period of 0.5 hour at 0 to 5C.
The mix~ure was stirred flDr an hour at the same
tempera~u~e and ~here~o was added methyl iodide
S (12Q.65 g~ over a period of 0.5 hour at 0 to 5C.
The resulting mixture was stirred fOT 2 hours at
the same ~emperature. The precipi~a~es were
collec~ed by filtration, washed with wa~e~ ~X2)
and dried ~o give a pale yellow powder of 4-~3
{N-methyl~hio(thiocaTbonyl)amino }proprl ] mo~pholine
(174.55 g3. ____ _.
N.M.R. (d6-DMSO9 ~ : 1.73 (2H, m)~ 2.3 (6H, m),
2.48 ~3~, s), 3.2-3.9 (6H, m~, 9.91
(lH, broad s)5 ~2) To a solution of 4-[3-{N-methylthio(~hiocarbonyl)-
ami~o}propyl3morpholine (152 g) i~ dioxane (430 ml)
was added a solution of sodium azide ~42.25 g) in
wa~er (290 ml~. The r~sulting mixtu~e was Tefluxea
for 2 hours. The reaction mix~ure was evaporated,0 - adjus~ed to pH 8 and washed-wi~h diethyl ether.
The aqueous layer was adjusted to pH 5 and coQled.
The p~ecipi~ates were ~ollected by fil~ation,
washed with ice-water (X2) and then dried to gi~e
whi~e c~ys~als of 1-(3-morpholinQpropyl~-lH-tetrazole-
~5 5-thiol (116 g~, mp 210 to 212C ~dec.~.
I~R. (Nujol) : 3550, 3500~ 23509 1610a 1410~
1360 3 12~0 9 1190, 1130, 1090,
- 10503 990~ 880y 825~ 785 cm 1
N.M.R. ~d6-~MSO, ~) : 2.14 (2Ha m), 2,99 ~2H~
*, J=7Hz), 3.09 (4H, m~, 3.79 ~4H, m~,
4.24 (~H3 t, J=7Hz~
PrePar at i ol_
(1) The following com~ound was ob~ained according to
a similar ma~ner ~o that of Preparation 6 ~1) .
1- ~3-{N-Methylthio ~thi:oca~onyl) amino}p~opyl3 -
piperidine,~hite powder, mp 74 to 76C.
I.R. (Nujol) : 345-0,. 3150? 1670! 156D, 1410
134G,, 1315, 125~9 1030, 1000,
950, 880, 860, 800, 750 cm 1
(2) The following compound was obtained accoTdin~ to
a similaT manner to ~hat of Preparation 6~2~.
1~(3-Piperidinopropyl)-lH-~e~razole-5-thiol~ mp 142
to 144~C tdec.)~
I.R. tNujol) : 3500J-3350, 24507 1635~ 1360,
~Z~0, 1~00, 11~5~ 1120, 11~0
1~859 1070, 1000~ 9~5~ 950,
810 cm~l -
N.M.R~ ~d6-DMSO~ 3-lo9 ~6H, m), 2.20
(2H, m), 3.07 (2H, t, Jo7Hz) 3 3.17
lS ~4H, m)~ 4.~4 (2H~ t~ J-7Hz)
~1~ To a mixture ~ tetrabutyla3n~snillim bromide
~3,22 g) in met~lene chloride (300 ml~ w~s added
ethyl chloroforma~e ~108. 5 g) at -20C. To the
mixture was added a solution of sodium cyanide
~49 g) iII watçr t200 ml) o~er a peTiod of 15 minu~es
a~ -lD ~o -13C and ~he ~esul1:ing mixture was stirred
for a minute at -13C. The organic layer was
separated from the reaction mixture, dried over
magIlesium sulf~e arld allow~d to warm to room
~mpe~a~ureO The me~hyl~ne chloride îayer was
separated by decanta~ion a~d the insoluble material ~L~
washed wi~h methylene chloride. The combined
met~ylene chlo~ide layers ~370 ml) were dis~illed
at a~mospheric pressure ~o give a solution containing
ethyl cyanofo~ma~e (335 ml) 9 bp 42 ~o 117~.
t~) A solution of hydrogen chloride ~32.5 g~ in ~
ethanol ~34.5 g~ was cooled at -lO~C and added to
a solution obtai~ed in Prepa~ation 8(13 ~335 ml)
contai~ing ethyl cyanoforma~e prec.ool d to -lO~C.
,
53 118Z41i0
The res~llting solution was st-irred for 6 hours at
-5 to 5~C, cooled to -10C and *hereto was added
methylene chloride (400 ml). To the mixture were
dropwise added a solution of triethylamine ~85 . 8 g)
in methylene chloride (80 ml3 and water (200 ml~ at
-5 ~o 0C. The methyleIle chloride layer ~as
separatPd9 washed with wa.~er (200 ml x 2) ~ aried
over m~g~esium sulfate an.d evaporated ~o gi~e the
product ~112 g) c~ntainin.g 78 ,. 8~ of ethyl 2-imino-
lû 2-ethoxyacetate. This product was puri~ied by
dis~illa~ion (bp 80 to B8~C/ 40 mmHg) *o gi~e pure
product ~ -
t3~ A mixture of ethyl 2 imino-2-ethoxyacetate (60 g)
(pUTl~y 78. 8%) and ammonium chloride (17.4 g) in
me~hanol (180 ml~ was stirred fOT 3 hours at room
temperature and cooled to 15 ~o ~10C. To the
resultillg mixture containing l-methoxycar~onyl-
formamidine ~ydTochloTide weTe dropwis e added
b~omi~ 51.2 g) over a period o 10 mi~utes~,
t~iethylamlne (71~1 g~ Pver period of 3D minutes
and a solution oX potassium ~hiocyanate ~31. 0 g~
i~ methanol (150 ml~ over a period of 30 miIlu~es.
The resultillg mixture was s~irTed at 10 ~o -SC
for 15 minutes and a~ 0 to 5~C for an additional
~5 1.5 hours. Precipitates were collected by
filtsation ~ washed wi~h methanol aTld there~o
was add~d cold water (200 ml~. The mixture was
s~irred a~d th~ p~ecipitates were collec~ed by
filtTa~ion~ w~shed with cold water and dTied ~o
give methyl 5-amino-lgZ,4-thiadiazole 3-carboxylate
t32.~ g~-
(4) To a solution uf e~chyl cyanoformate (25. 0 g) in
me~hylene chloride (55 ml) was added 43 . 5% ethanolic.
solution of hydrogell chloride tl6 ~ 8 g3 wi~h stirrin~
a~ 3C. The mix~ure was s~irred ~or 5 hours at 3
to. 5~C and allo~Led to stand over nigh~ at-.-5 to -3C.
To the` resulting mixt:ure ~e:Te added methylene
chloride (120 ml) at ~elow 6C and a solution of
trie~hylamine (20~2 g) in methylene chloride
(20 ml) oveI~ a period of 30 minutes at below 6C.
The mixtuTe was stirred for 40 minutes and thereto
was added wa~er t40 ml) a't below 6~C. The resulting
mixture was stirred for 'S minu*es and ~he methylene
chloride layer was separated, dried oveT magnesium
sulfa~e a~d then evaporated. After the addition
o diisopropyl ~ther (40 ml~ to th~ residue"
inso luble ma'cerial was separated by iltra~ion and
washed with diisopropyl etheT (l o ml) . The filtTate
and washing were combined and ~hell evapora~ed to give
a pale yellow oil of el:hyl 2-imino 2-e~hoxyaceta~e
(26.7 g). A mix~ure of the oil (26.2 g) obtained
above9 ammonium chloride t6.4~ g) in methanol ~90 ml)
was stirred for 2 hOUTS at room ~emperatur~ and
thereto was added diisopropyl ether t450 ml). The
mixture was ice-cooled a~d ~hen stirred fo~ 30
minutes. Precipi~ates were collect~d by iltration
~o give a white powder of l-methoxycarboIlylfQr~aam}dine
hydrochloride tl3 . 8 g), mp 150 to 155C tdeo.)
I~R, ~Nujol~: 3350^3050~ 1780, 1710; 1695,
2~ 1~909 1270, 1070~ 980, 800 cm~~
N~M~lRo ~d~-DMSO" ~) : 3.97 (3H" s~ ~ 9~,5 ~4H~
bToad s~
~5~ To.a solwtion of l-methoxycarbonylformamidine
hydrochloride (7.6 g~ in me~hanol (55 ml) was
aO dropwise added brom~ne ~.8 g; over a peTiod of 5
minutes at -5 ~o ~C. To ~he mixture WeTe added
triethylamine ~11.1 g) over a period of 10 minutes
and a solution o potassium thiocyanate ~503 g) in
methanol ~30 ml) o~sr a period of 2-~ minutes at -5
to 0C. The mix~ure was s~ir~d or 1.5 hours at
O ~o 5C, Precipita~es we~e collec~ed: by filtration,
was~ed with meth nol (11 ml), dried and ~chereta was
added water (15 . 5 ml) . The mixture was stirred for
30 minutes and preclpitates were collected by
filtratiorl, washed with w~ater ~5 ml x 3) and dried
to give a whi*e powder of methyl S-amino-192~4-
thiadiazole-3-carboxyla~e! (6 . 3 g) .
(6) A mixture of e~hyl 2-i.mino 2-ethoxyacetate
(360~ g3, ammoalium bromicLe (21.2 g~ in methanol
(18~ ml) was stirred :EOT 4 houTs a~ room tempera~ure
and thereto was added diisopropyl ether ~oo ml~
with s~:irring. The mlxtuTe was allowed to sta~a
for 30 mirlu*es. Precipitates were remove~ - by
f iltratian, _ . ........ . .. _. -
~0
.
- ~ To ~he filtTate W~L5 added diisoprspyl
e~her t200 ml~ and ~he m x~ure was allowed to stand
-. foI 10 minutes. Precipit~tes were co:Llec~ed by
2~ fil~ration ~o give a white powder of 1-
methoxycarbonylformamidine hydrobTomide (16.1 g).
The ilt~ate was
co~centra~ed to ~he volume of about 150 ml.
To *he co~centrate was added diisopropyl e~her
(200 ml) and th~ mixture was allowed to stand fo~
30 minu1:es. Pr~cipi~a~es were collected by
filtra~-lo~ to give a white powde~ o ' the same
~11. 6 g) .. To~al yield : 27 ~ 7 g .
I.R. (Nujol): 33~0~3150, 1780" 1710, 169û,
12~ 7û, 1û60 9 9 ~0 ~ ~50 9
800~ 730 cm 1
N,M~R~ ~d6-DMSO, ~) : 3.91 (3H, s), 11~0
. (4H, br~ad s)
(7) A mixture of ethyl Z-imino-2-ethoxyacatate
(18,1 g) 3 ammonium chloride (5~8 g~ in ethanol
~90 ml) was stirred fOT 6 hours at Toom *emperature.
I~soluble ma*erials were separa~ed ~y filtration
and washed with e~hanol. The filtrate and washing
were combined and evapo~ated. To the resîdual oil
wa~ addPd ace~one (50 ~1). The precipi~ates were
collec*ed by filtTation and washed wi~h ace~one
~10 ml x 2~ to give a whi~e powder of 1-
ethoxycar`bonylformamidine hydrochloride (1.2 g~.
The filt~ate and washing were combined and .
e~aporated. The residue was pulve~i~ed with -
ace~one ~30 ml), collected by fil~ra~ion~ washed
successi~ely with ace~one, methylene chloride and
diisopTopyl ether ~o give a whi~e powder of th0
5~ma ~7 ~ 3 g~ ~ Total yield : 8.5 g.
IrR~ (Nujol~ : 3400-31009 1770~ 1730-1680~
1650~ 1300-~Z609 112~ 1010,
860, 760 cm`
2~
32
o 57
Preparation of Methyl 5-ami~o-1,2~4-thiadiazole-
3-carboxylate.
To a solution of l-etho~ycarbonylformamidin~0
5 hydrobromide ~16.6 g.) in absolute methanol ~84 ml)
was added a solu~ion of sodi~m (1.93 g)
,
in a~solu~e methanol (4~ ml) a~ 0C. To the mixture
w~re added alternately bromine ~12.8 ~) and a solution
lD of sodi~m (1.93 g) in ~bsolute methanol (4~ ml) a~
- - 0C a~d then to the suspe~sîon was added potassium- ~
thiocyanate ~8.1 g) in absolu~e me~hanol (lQ0 ml~. -
The reaction mix~ure was s~irred for an hour at 0 ~C
and for an additional 6 hours at ambient temperature.
The mix~ure was filtered ~hrough cellulose powder and
- ~he . iltrate was evapora~ed to d:ryness . The residue
was dissolYed in a mixture of ethyl ace~ate and water"
and therl the e~hyl acetate layer was separated a~d
driea over ~nhydrous magnesium sulfate. ~e solvent
was ~rAporated and the residue was tri~:ura~ed with
diethyl ether ~o give ~he ti~le compound (9~D g~ 3 mp.
~02 to ~05C.
I.R. ~Nujol) : 3400, 3250, 310Q, 1710,
1610, 1540 cm 1
N.M.R. ~d6~DMS0)
: 3.85 ~3~, s)p 8.25 (2H9 s)
Prepa~atlon of Methyl 5-ormamido-1,2,4-
~hiadiazole ~-carboxyla~e.
To a mixtur~ of formic acid (33 g) and acetic
anhydride (22 g) was added methyl 5-amino-1,2~4-
.hiadiazole-3-carboxylate (6.2 g) 3 and then the
mix~ure was s~irred or 2 days at ambien* temperature.
The reactioIl mix~ure was concentra~ed under reduced
pressure and *he residue was tri~u~a~ed with a mixture
4~i~
. 5~3
of diethyl ether and n-hexa~e to give ~he title
compound (7 , 2 g), mp . 210 to 215C .
I.R. ~Nujol): 31û0, 17:20~ 1680 cm 1
N .M . R . ~d6 -DMSO)
~: 3.90 (3H9 s) ~ 8.85 (lH, s)
Pr~para~ion of 5-Formamido-3- (?-methylthio-2-
m~thylsulinylacety~ 4-~hiadia~ole.
~o a mixture of m~hyl 5-fsrmamido-1, 2 ,4 -
thiadiazole-3-carbo~ylate (9.2 g) and methyl methyl-
- thiomethyl sulfoxide ~-6.1 g) in N,N-dime~hylformamide
~100 ml)~was added 50% sodium hydride ~?~l g? with
cooling in an ice-ba~h. The mixture was stirred foT
a~ houl ~ ~mbien~ temperature and for an addi~ional
one hour a~ 40C, After cooling to ambient tempera-
ture, me~hyle~e chloride ~300 ml) was added to the
reaction mixture 3 ~nd ~he resulting pTecipitates
we~e collected by filtration and washed with
methyl~ne chlorid~. Th~ pr~cipi~ate~ were added to
20 a s$irred mix~ure of hydrochloric acid ~14.7 ml),
ice-wat~r ~200 ml) and methylene chloride (200 ml~.
An i~soluble ma~erial was filtered off ~d ~he
methylene chloride layer was separated from the
filtra~e. l'he solution was d~i0d over anhydrous
magllesium sulfa~e, evaporated and ~he ~esidue was
tril:urated wi~h diel:hyl e~ch~r ~o give the ti~le
compouIld ~4.5 g~, mp. 130 to 132~C.
I .R.. (Nuj ol) : 3100 ~ 1680, 1670 cm 1
N.M.R~ ~d6-DMS0)
~: 2-~2 } ~3H, 2s)
2 .2~
2.68 } ~2H~ 2s)
2.85
i$
5.70 } ~1~, 2s)
s .sa
. 8.86 ~lH, s)
ar~ 2
Preparation of S-methyl (5-formamido-1,2,4-
thiadiazol-3-yl)thioglyoxylate.
A mix~ure of 5-formamido-3-~2-methylthio-2-
me~hylsulfinylacetyl)-1~2~4-thiadiazole (0.8S g) and
sodium perioda~e (0.2 g) in glacial acetic acid
~10 ml) was stirred for. 45 minutes at 70~. The
reac~io~ mixture was evaporated and the residue was
dissolved in a mixture of e~hyl acetate and wa~er.
The mixture was adjusted to pH 7 with an aqueous
1~ solution o-E sodium bicarbonate and treated with an
aqueous solution of sodium thiosulfate. The orga~ic
layer was separated~ dried over anhydruus magnesium
sulfat~ and evapora~ed ~o dry~ess. The ~esidue was
triturated with a mixture of di~thyl ether and
pet~oleum ether to give th~ title compound (280 mg),
mp. 186 to lB7G~
I.R. (Nujol) : 3100, 1680, 1660 cm
N.M.R. (d6-DMSO) .-
~ : 2.55 ~3H~ s~, 8.95 (lH, s~
23
3a
~5
~-8;~
, .
.
}~ ''
A mix~ure of 5-formamido-3-(2-methylthio-2-
Z5 methylsul~inylace~3rl)-1,~,4-thiadiazole ~10 g) and
sod um perioda~e (2~0 g~ in glacial ace~ic acid
(50 ml) was sti~red or 50 minukes at 70 C . The sol-
ven~ was evapo~at~d alld the ~esidue was washed with
n hexa~e. To the residue ~as added lN aqueous
3~ solution of sodium hydroxîde ~160 ml ) and the mixture
was s~irred for an hou~ at ambien~ temperature. To
the reac~ion mixture was added oall ylhydroxylamille
hydrochloTi.de ~4"~1g) alld the solutio~ was adjus~ed
~o pH 3 *o 4 with lû~ hyd~ochloric ac~ d a~d then
35 stirred for an hour ~ mbien~ ~empera~ure. Afte~
&~1
~L '";
an insoluble ma~erial was filteTed o~f, the filtrate
was washed wi~h ethyl ace~a~e, adjusted ~o pH 1 wi~h
10% hydrorhloric acid and extracted with ethyl acetate~
The extract was dried over ma.gnes ium sulf ate and
evapoTated o dryness. The Iesidue was triturated
with a mixture of diethyl ether and diisopropyl ethe~
to give ~- allylo~imlno~2~(5-*ormam$do-1,2~4~tkiadia~ol_
3-yl)a~etic acid (~yn i~omer)(5.6g), mp 169-to 172 C(dec~)~
T.R. (Nujol) : 3130~ 25009 1720, 1690~ 1590, 1550 cm 1
N.M.R, ~d~^DMS0~
: 4.,79 ~ d7 J=6Hz~, 5.1~5~6(~, m~ ,, 5.,8--
6"4(~7 m) ? 8.88t~)
15 ~
The following compounds were obtained ~ccording
~o a similar manner to that of Preparation
3D
tl~ 2-Benzyloxyimino-2-~5-oImamido-1,294-thiadiazol-
3-yl)ace~ic acid ~s~n isomer), mp. 90 ~o 95~C tdec.).
I.R. ~Nujol3 : 1720, 1680, i590, 1550, 1530 cm 1
N.M.R. (d6-DMS0)
~ : 5028 ~2H~ s), 7.37 (5H, s); 8.83 tlH, s)
(~ 2-(2-Propynyloxyimino)-2 ~5-formamido-1~2,4-
~hiadiazol^3-yl)acetir acid (syn isomer), mp. 150 to
155~C (dec.)~. .
Nujol) : 3570, 3360~ 3260, 3120~ 1720,
1670, 1550, 1530 cm~
N.M.R. (d -DMS0~
. ~ :- 3.55 (lH~ t, J-2Hz), 4.88 (ZH,-~,
J-2Hz3, 8.85 ~lH~ s~
~3~ 2-(2-Phenoxye hoxyimino~-2-(5-formamido-1~2 J4-
thiadiazol-3-yl)acetic acid (syn isomer) 9 mp. 147 to
1~0C (dec.~.
IoR~ ~Nujol~ : 3200, 17.40, 1720~ 1640,
1590 9 1530 cm
NoM~ (d~-DMSO~
: 4.~4.7 (4H, m), 6.7-7.5 (5H, m~, -
` 8.83 ~lH3 5~
~4) 2-Hydroxyim~no~2-~5-formamido-1~2~4-thiadiazol-
3-yl)acetic acid (syn isome~, mp. 240 to 241G ~deci~.
I.R. CNujol) : 3550, 346Q, lS65~ 1635, 1560 cm
Z~ ]5
A solu~ion of S-me~hyl (S-ormamido-1,2,4-
~hiadiazol 3-yl)~hioglyoxyl~e ~6.64 g3 in lN aqueous
solution o sodium hydroxide (80 ml~ was adjusted ~o
pH 8.~ wi~h 10% hydrochloric acid and stirrad for 30
minutes at ambien~ temperature. On the o~her hand9
a mixture of N-(2,2~2-trifluoroethoxy)phthalimide
~3
(8 . 78 g) and hydrazine hydrate (1. 7 g) in ethanol
(40 ml) was refluxed or 5 minutes and then cooled
in an ice bath. A resul~ing pre.ipi~a~es were
fil ~eTed off and wash~d wi~h ethanol . The filtrate
5 and the washings were combined a~d the combined
solution con~aining 0- (2 "2 ,Z-trifluoroethyl)hydroxyl-
amin~ was added ~o the abov2 aqueous solu~io~_ The
mix~ure was adjusted to. pH 3 ~o 4 with 10% hydro-
chloric acid and stirred for 1. 5 hou~s a~c ambient
temperatureO ~ solu~ion was neutralized with all ~
- aqueous solutio~ of sodi~ bicarbonate, concen~rated ~
to half volume in vacuo and wa~hed wi~h e~hyl acetate. ~ ~
The aqueous solution was aridified with 10% hydro- ~
chloric acid and extracted wi~h ethyl ace~ate. The
lS ex~ract was dried over magnesium sulfa~e " evapoTa~ed
to dryness and the resi~u was triturated with di-
isop~opyl ether to giv~ 2- ~, 2 ,2-~:rifluoroethoxyimino) -
;2- (5 -fs)rmalllido-l a2 a4 thiadia201-3-yl~ acetic acid
~syn isomer) t2 .46 g~ 3 mp. 18D ~o 185C (decO) .
N.M.R~ (d6-DMS0~ -
ô: 4 ~80 a~d 5.07 ~2H~ ABq, 3=9Hz) "
8.85 (lH, s~
2~ The following compounds were ob~ained according
~o a similar manne~ to ~hat of Prepara~ion 15 ~,
~1) 2-Methylthiomethoxyimino 20 ~5-ormamido-1~2 a~-
~hiadia~ol-3-yl~a~etic acid (syn isomer), mp. 146
to 148 C ~dec . ) .
3~ I .R. (Nujol~ : 3300 7 2600 g 2550, 1730 ~ 170S,
16B0 ~ 1600 ~ 1530 cm~~
NoM~R~ (d~,-DMS0)
~: 2.23 ~3H, s), S~40 ~2H3 s~, 8.B7 (~I" s~
~2) 2- (2 Methylthio thoxyimino) -2- (5-form~ido
35 1,2,4-~hiadiLa ol-3-yl)are~ic acid (SyD isomeT).
I.R. (Nujol) : 3230 a 1720 ~ 1690 ~ 1590
- 1520 cm 1
N ~MoR ~ ~d6 -DMSO )
~ : 2.17 ~3H~ s), 2.82 (2H, t9 J=7Hz),
4.42 ~2H; t~ J=7Hz), ~87 ~lH, s)
~3) ~-Phenoxyimino-2-(5-formamido-1,2,4-
thiadiazol-3-yl)acetic acid (syn isomer), mp. 145
to 147C ~dec.).
I.R. CNujol) ; 3130~ 1720 3 1690 ~ 1585~ 1550 cm 1
N.M~R. (d6-D~SO~
~ : 7.0-7~6.~5H~ m~ 8.8~ ~lH, s)
- ~ (4) 2-~2-(2-Hexyloxy~thoxy)e*hoxyimino~-2-(5- - -~ formamido-192,4-~hiadia~ol-3-yl)acetic acid (syn - -:
isomer). - -
li I.R.(CHCQ3) : 34~0, 3180, 1740, 1700, 1600-,: - -
153~, 14S0 rm 1
N.M.R. (ds-DM~O)
: 0.~7 (3H~ ~, J=5Hz) 9 0 .87-1.73 (8H~
m), 3.20-3.90 t8H, m), 4.23-4.53
~ ~2H, m), 8.. 84 (lH~ s~, 13,55 ~lH,
broad s~
(5) 2-Trityloxyimi~o-2-(~-formamido-1,2,4^thiadiazol-
3 yl)acetic acid ~an~i isomer), mp. 188 to 190C
(dec.). ~~
I.R. ~Nujol~ o~ 3150~ ~620 9 ~ 600 ~ 1540 cm 1
N.M~R. ~d6-DMS~)
: 7~00 ~15H, s)~ 8.92 ~1HJ S)
Preparatio~ 17
A mixture of S-methyl ~formamido-l ,~ ~4-thia-
30 diazol-3-yl)thioglyoxylate (6 g) aDd an aqueous
501UtiOIl (5û ml) o sodium hydroxide (4.2 g~ was
s~irred for ~an hou~ at 50 ~o 55 C . The mixture was
cooled to ambient ~emperature a:nd adj us~ed ~o pH 7
wi~h 10% hydrochloric acid. ~ ~he o~her haIld3 a
35 mix~ar~ of N ~e~hoxy~arbo~ylme~hoxy) ph~h~limide
~12.9 g) and hy~razine hydrate ~2.08 g) in eth nol (60 ml~
~as re~luxed for 5 minutes and cooled in an ice bath. A
resul~ing precipit~e was filt:ered off and washed with
e~hanol. The fil~ra~e ~nd the washings we~e combined and
the combined solution containi.ng O- ~ethoxyca~bonylmethyl)- -
hydroxylamine w 5 added to the above aqueous solution. l~e
mixture w~s adjusted to pH 3 1:o 4 with 10% hydrochloric acid
and stirred for 1.5 hou~:s at ambient temperature. The solut-
ion was neutrali~ed with an aqueous solution o~ sodium bi
ca~bonate, concentrated to ha:Lf ~olwne in ~acuo and washed
wi~h ethyl acetate~ The aqueous solution was acidified with
10% hydrochloric ~cid and extracted with e~hyl acetate. I~e
- extrac~ was dried o~er magnesium sulfate, ~vaporated to dry-
ness and the residue was tritllra~ed with diisopropyl ether
- 15 ~o give 2-e~hoxycarbonylmechoxyimino-2-~5-amino-1,2,4-thia-
diazol-3-yl)acetic acid (syn isomeT)~1.8 g), mp.l35 to 140C
~dec.)~
I.R. ~Nujol): 3500,3330,321072670,2S50,1740,1610,1540 cm
N.M.R. (d6 DMSO3
- ~: 1.24 ~3H9t9 J=7~Iz) D 4~14 (2H,q~ J=7Hz),
- 4,80 (2H, s), 8.15 ~2Ha broad s)
Pr~
The following compolmds were ob~ained according ~o a
similar mamleT to ~ha~ of Preparation 17 .
2~ ~1) Z-5yanomethoxyimino-2~5-amino-1,2,4-thiadiazol-3-yl3-
ace~ic acid ~syn isomer), mp.130 ~o ï3~C (dec.~.
I.R, ~Nujol): 335û~3150,173051630, 1540 cm 1
N~MoR~ ~d6-DMSO)
ô . 5.17 ~2H9 s), 8. 28 ~2H3 bTOad 5)
(2) 2- ~l-Ethoxycarbonyl-l-methylethoxyimino~ -2- (5-amino-
1,2,4-thiadiazot-3-yl)ace~ic acid ~syn isomer) ~ mp.l65
to 168C ~dec . ) .
I.R. (Nujol): 34$093350,3240,1750,17;0,1630,1530 cm l
N~M o R~ (d6-DMSO)
~: 1.18 ~3H"tjJ~7Hz) 9 1~ 50 ~6H,s~, 4.15
(2H, qj J~7Hz) 9 8.23 ~2H9 broad s)
..
(3) 2-(~,N-Diethylcarbamoylmethoxyimino)-2-(5-amino-l,
2,4-~hiadiazol-3-yl)acetic acid ~syn isomer), mp. 150
to 155C. (dec.).
I.R. (~;ujol) ~3400,3150?:L745,1635,1610,1595,1535 cm l
N.M.R. ~d6-DMSO)
: 1.03 (3H,t,J=7H~), l,lO (3H, t, J-7H ),
3.28 ~4H, q, J=7Hz) 3 4O90 ~2~,s),
8 . 23 C2H j brl3ad S~
(4~ 2-Mesylmethoxyimino-~-(5-amino-19 2 ,4-thiadia~ol-3-
yl)acetic acid (sy~ isomer).
- I.R. ~Nujol): 3450, 3400, 3270, 2600, 2460, 1735,
164Q, 1620~ 1530 cm l
N.M.R. (d6-DMS0)
~ : 3.00(3H3 s~ 5.38 (2H,s), 8.2~ (2H, broad s)
The fo:Llowing compounds were obtained according to
a similar ~anner to that of Preparation 4 .
~;7
~1) 2-Allyl~xyimino-2- (5-amino-1,2 ,4-thiadiazol-3-
yl)ace~ic acid (syn isomer~, mp. 93 to 959C (dec.).
I.R. ~Nujol) . 3430, 3100, 1710, 1615,1525 cm 1
N.M.R. (d~-DMSO)
~: 4.72 (2H5 d, J=6Hz), 5.1-S.5 ~H~ m),
5.7-6~3 ~lH, m) " 8.17 ~lH, broad 5)
(2~ 2-B~nzyloxyimiIlo-~- (5-amino-1,2 ,4-~hiadiazol-3-
yl3acetic acid (syn isomeT), mp.l58 ~o 160C ~dec.).
I .R. ~Nujol~ : 3430 ~ 3380, 3260 " 1730 3
1640, 1610, 1535 cm 1
.M.R. (d6-~MSO)
~: 5.22 (2~1, s) " 7.33 (5H, s~ ~ 8.17 (2Hg
.b~oad s)
(~) 2- ~2-Propynyloxyimino~ -2- (5-ami~o-1,~ ~4-
~hiadiazol-3-yl~ acetic acid ~syn is~mer), mp . 155 ~o
1~7 ~C (dec . ) .
I.R, {Nujol): 3500, 3~10, 3160, 2600, 248aS
1745, 1610, 1535 cm~
N~M.R. ~d6-DMSO)
~: 3.53 (lH, t, J~2Hz~, 4.87 ~2H, d,
J-2Hz~, 8.23 ~2H, broad 5)
~4~ 2- ~2 -Phenoxyethoxyi~ o) -2- ~5 -amirlo-l ,;2 ,4-
3S ~hi~diazol~3-yl~acetic acid (Syll isomer) D mp. ï50
..` ~8
to 153C (dec. ) .
I.R. (Nujol): 3470, 3300? 31iO~ 2550, 1750,
1620, 1600, 1540, 1500 cm 1
N.M.R. (d6-DMSO)
~,, 5~: 4.D-4.7 (4H, m)3 6.7w7~5 (5H, m),
8 . 20 (2H~ broad s~
t5) 2- (~,2,2-Trifluoroethoxyimlno)~ (5-amino-
1>2,4-thiadiazol-3-yl) acetic acid ~SyTl isomer), mp.
140 ~:o 143C ~dec. ) .
10I.R. (Nujol): 3450~ 3350, 3260, 1745, 1670,
-: 1645, 1615, 1515 cm
N.M,R. (d6-DMSO)
: ~ : 4 . 72 and 40 9S ~XH, ABq, J=3Hz) 3
8 . 25 ~2H, broad s)
(6) 2-Me~hylthi~me~hoxyimino-2- (5~amino -1,2,4-
thiadiazol-3-yl)acetic acid ~syn isomer~, mp. 140 to
143C (dec . ) q
I"R. ~Nujol): 3500, 3300, 3150; 267û~ 2580,
1740, 1615, 1605, 1$30 cm 1
N~M~Ro (d6-DMSO ~ .
~5 : 2. 22 ~3H, s), 5. 33 ~?Hs s), 8. 20
~ 2H, broad s)
~7) 2 ~2 Me~hyl~hiuethoxyimino)-2- (5-~mino-1,2,4-
thiadiazol-3-yl)acetic acid ~syn isomer), mp. 140
to143~ dec. ) .
- I.R. tNujol): 3430, 3340, 3230, Z650, Z45û,
172Q~ 161U, 1520 cm
NoM~R~ (d6-DMSO)
2. 08 ~3H, s) 7 2. 72 ~2H, t3 J=7Hz),
4~ 28 t7H, t, Jo7Hz), 8.17 (2H9
broad s)
t 8 ) 2 - Phenoxyimino ^ 2 - ~ 5 - amino -1, 2, 4 ~ thi adiazol -
3 yl)acetic acid ~syn isomer) r mp. 145 to 147~C ~dec.) .
I.R. ~Nujol): 33505~ 31709 ~500, 1730, 1719,
1645, 1630, 1595" 1535 cm l
r ~i9 ...
N.M.R. (d~-DMS0)
~ : 7.0~7.5 (SH~ m), 8.30 ~2H, broad s)
(~ 3 2-~2-(2 Hexyloxyethoxy)ethoxyimino~-2-~5 amino-
1,2,4-th;adia7.ol-3-yl)acetic: acid (syn isomer).
I.R. ~CHCQ3) : 3350, 3230, 2600, 2500, 1730,
1620~ 15~0, 1460 cm
N.M.R. (d6-DMSO)
: 0.87 C3H, t:, J~5Hz), 0.87-1.73 (8H,
m) 7 3.20-3.90 (8H, m), 4.13-4.47 (2H,
m), 8.17 (2H, broad s3
~lO) 2-T~i~yloxyimino-2-~5-amino-l,Z,4-thiadiazol-3-yl)-
acetic acid (syn isomer) 7 mp. 173 to 174DC (decO~.
I.R~ ~Nujol) : 3450, 1735~ 162Q~ 1540 cm 1
N.M.R~ ~d~-DMS0)
. ~ : 7.35 tl5H~ s), 8.22 ~2H, s)
~11) Z-TTi~yloxyimi~o-2-~5-amino-1~2,4-thiadiazol-3-
yl3acetic acid (anti isomer), mp. 17D to 171C.
I~R. (~ujol~ ~ 3300, 315p J 1680, 163~ 3 152D cm 1
N.M.R. (d6-DMS0)
~ : 7.33 ~15Hg s), 8.13 (2H, s~
-P ~ti ~D ~ ~ '
A mix~ure o 2-hydroxyimino-2-~5-~ormamido-1,2~4-
~hiadiazol-3-yl)acetic acld ~syn isomer)~3O3 g) and
dichloroacetyl chloride ~9~0 g~ in me~hylene chloride
(50 ml) wa~stirred for 6.5 hours a~ ambient temperature.
A resul~ing precipita~es weTe filtered and dissolved
in e~hyl ac~tate~ Af~er removing of an insoluble sub-
stance by iltration~ *~e filtrate was ~vaporated to_
d~yness. The resid~e was tri~urated wi~h diisopropyl
e~her to give 2-dichloroacetoxyimino-2-(5-~ormamido^
1~2~4-~hiacliazol-3-yl~acetic acid ~syn isomer)(2.3 g)
mp~ 123~C.
I.R. (Nujol) : 31sa; 1790, 1690, 1550 cm 1
21
_.
To a mixture of 2-hyd~oxyimino ~-(5-formamido-
1,2,4-~hi~dia~ol-3-yl3acetic acid (syn is~mer)(9.5 g)
and dimethylformamide (80 ml) was added with stirring
a~ ambient tempera~ure trityl chloride ~22.8 g), and
triethylamine (4.1 g) was gradually added there~o
S afte~ 3 minutes stirring. The resulting mixture was
stirred fo~ lO minutes and ethyl aceta~e ~250 ml) was
added there~o, The mixture was washed three times
with water and with a saturated aqueous solution of
sodium chloride, dried over magnesium sulfate and
collcentrated. To the residue were added an aqueous
solution of sodium bica~bonate ~50 ml) and diisopropyl
ether ~100 ml). Precipi~ates were collected by fil- -
tration and 1:he aqueous layer in ~he fil trate was
separated. The collected precipitates were suspended
in the separated aqueous layer and ethyl acetate was
added there~o. The mi~ture was adjusted ~o pH 2 with
10% hydrochloric aci d and ext~acted with ethyl acetate.
The ex~ract was dried oYer magnesium sulfate and
concent~ted in ~acuo~ The residue was washed with
hexane ~o give 2-t~ityloxyimino-2-~5-fo~mamido-1,2,4
~thiadia~ol-3-yl3acetic acid (syn isomer) ~17.1 g) 7 mp.
175 to 176C ~dec.)~ :
I.R. (Nujol): 3180, 30709 1700, 1600, 1540 crn 1
N . M. R. ~d6 - DMS0~
~ : 7;35 (15H, s), 8.83 (lH~ s), 13.52 ~lH,
brs~ad s )
3û
3~
~2
7~
1 o
Preparation 22
~1~ A solution of N~ (3-aminopropyl)acetamide ~146 g)
in dioxa~e (710 ml) was added to a solution of 97~i
sodium hydroxide ~52 g) in water ~620 ml) and then
- carbon disulfide (96 g) was added dropwise *hereto
over 35 minutes at 1 to 3C. The mixture was stirred
2$ foT 1 hour at 0 to 2~C. To the mixture containing
sodium N-(3-acetamidopropyl)dithiocarbama~e was added
dropwise methyl iodide ~779 g) over 35 minutes at
O to ~C i~nd ~hen the resul~ing mix~ure was stirred
for 3 hours at the same ~emperature, Dioxane w~s dis-
tilled off in racuo from the reac~ion mix~ure and theresidue was extracted ~ith ethyl acetate (300 ml)
200 ml x 4~. The extrac~s were dried over magnesium
sulfa~e iand concen~rated in vacuo to gi~e oil of
methyl N- ~3-iacetamidopropyl)dithiocarbamate ~193.18 g) .
- 35 ~2~ A mlx~ure of a solu~io~ of methyl N- ~3-
7~
acetamidopropyl)di*hiocarbamate tl93 g) in dioxane
(610 ml) and a solution of sodium azide ~79.42 g)
i~ water ~5~ ml) was refluxed under stirring for
4 hours. Dioxzne was distilled off and the remaining aqueous
layer wa~ washed with diethyl ether (150 m~ x 2),
adjusted to pH 1 with 170 5% hydrochloric acid, and
coo~d in ~n ice bath~ ~ecipitat2~ were collected by
fil~ration and washed with ice-water to give whi~e
powd~r of 1-~3-acetamidopropyl3-lH-te~razol-5v~hiol
(91.7~ g), ~p. 152 to 154~
N.M.R. (d6-DMS0)
: 1.87 (3H, s), ~.97 (2H, m)~ 3.17
~2H, m), 4.28 (2Hs t, J=7Hz)g
7.9 ~lH, brozd s), 15.0 (lH, broad s)
(3) A mixture of l-(3-ace~amidopropyl)-lH-tetrazole-
5-thiol ~8i g3 and 6N hydrochloric acid (1 Q~ was
refluxed fOT 75 minutes under stirring. The reaction
mixture was concentrated in ~acuo and precipita~es
- were collected by filt~a*ion and washed with hexane
20 and diethyl ether to give 1-~3-aminopropyl)-lH-
t~razole-5-thiol hydrochloride (67.15 g)v
N.M.R~ ~D2O7
: 2~45 (2H, m), 3.23 ~2H, t, J=7Hz),
4.50 ~2H, t~ J=7Hz)
~43 A solution of 2-t-butoxycarbonyloxyimino-2-
phenyl~ce~oni~rile (12~3 g) in dioxane ~30 ml) was
added under ce-cooling to a ~tirred solution of
1-(3-aminopropyl~-lH-te~razole-5-thiol hydrochloride
~9 s 78 ~ ancl triethylamine (ll o 1 g~ in a mix*ure of
30 dioxane ~25 ml~ and water (25 ml) ,~ and then ~he
resulting mixture was stirred o.r 1. 75 hours at
ambien~ ~emperature. Dioxane was distilled of and
~o the residue were added diethyl ether and a small
amount of w~ter. ~er shaking,1:he aqueous layer
35 was separated and ~he organic layer was ex~Tacted
~ - ~3
twice with 10~ potassi~m ca~bonate. Th~ ~xtracts
combined with the separated aqueous layer were
washed three ~imes with diethyl ether, adjusted to
pH 1 with hydrochloric acid ,and extracted wi~h
diethyl etherO The extract ~as was~ed with water,
dried and evaporated in vacuo. The residual oil
(10.92 g) was pulverized wi~h diisopropyl ether to
give 1- [ 3- ~N- t-butoxycarbony:lamino) propyl ] ~ lH-
tet~azole-5-thiol (9. 6 g), mp. 75 to 77C.
lU I.R. (Nujol): 3380, 32603 1650, 1530~ 1170,
1050 cm
N .M. R. (CDCQ3)
fi : 1.50 . (9H, s) 9 2.14 ~2H, m), 3.25
(2H, m), 4,3g ~2H, t, J=7Hz),
4~9-6O7 (lH, broad3
~0
~2
Ex amp l e
To a cold solution of phosphorus pentachloride
~450 mg) in methylene chlor:ide ~10 ml~ was added
2 - (4 - chlorophenoxyimino~ - 2 - ~5 - amino - 19 ;~!, 4 -~hiadia ol -
3-yl)acetic acid (syn isomer) (650 mg) at -15C and
the mixture was stirred for 30 minutes at the sam~
temperature~ 0n the other hand, a mixture of 7-amino-
3-~1,374-thiadiazol-~-yl)th:iomethyl-3-cephem-4
carboxylir acid (785 mg) and tTime~hylsilylacetamide
~2.1 g) in methylene chloride (10 ml) was warmed to
make a clear solution and ~hen cooled to -20C. The
solution was added to the abotJe ac~i~rated mixture at
-20C and ~he mixture was stiTred or 40 minu~es a~
-15C. The reaction mix~ule was poured into cold
15 aqueous solu~ion of sodium bicarbon~e t~0 ml) and
stirred at ambient tempera~ure for 30 minutes.
Methylene chloride was distilled o~f and ethyl acetate
was added *o the residual aqueous solution. The mix-
~ule was a~ju5ted ~o pH 3 or 4 with la% hydrochlo~ic
acid and extrac~ed wi~h ethyl acetate. The ext~act
was dried over magnesium sulfate, treated with an
a;-ti~ra~ed chaTcoal and evapora~ed ~o dryness. The
residue was t~itu~a~ed with diethyl e~her and ~e-
precipi~ated f~om a mixed 501vent o:E ace~one and
diethyl e~her. Precipitates were dissolved in an
aqueous solu~lon of sodium bicarbona~e and ~he solu~ion
was adjus~ed ~o pH 1 or 2 wi~h 10% hydrochloric acid
to giYe precipitates. The precipi~ates wer~ collected
by filtration and washed with water to give 7-[2-~4-
chlorophenoxyimi~o)~ 5-amino-19294-~hiadiazol--3-yl)^
acetamidoJ-3 (1~3~4-~hiadiazol-2-yl)thiomethyl-3
cephem-4-carboxylic acid ~syn isomer)~0.35 g~ mp 150
to 155C (dec.~.
I.R~ ~Nujol) : 3300, 3~00 9 17709 1670~ 1620,
1520 cm 1
~, ~5
N.M.R. ~d6-DMSOp~ : 3~o7 (2H, broad s),
4.~7 and 4.50 (2H9 ABq, J=14Hz~
5017 (lH, d, J=4H2), 5.80 (lH, dd,
J~4 and 8H~ 7.00-7.50 ~4H, m)~
8.~2 (2H~ s), 9~50 ~lH, s)~ 9.80
~lH, d, J=~Hz).
To a cold solution oi.' phosphorus pentachloride
(1.04 ~ me~hylene chlo~i.de ~5 ml) was added
2-~4-fluorophenoxyimino~-2-(~-amino-1,2,4-~hiadiazol-
3-yl)ace~ic acid (syn isome~)(l.4 g) a~ -15C and
~he mix~ure was stir~ed for 30 minu~es a~ ~he same
tempe~a~ur~. On the other hand, a mixture of 7-amino-
3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (1.55 g) and trimethylsilylacetamide
(5 g3 in methylene chloride (25 ml) was warmed to
make a clear solutio~ and then cooled to -15C.
The solution was added to the above acti~ated mixture
a~d the mix~ure was stirred for l hour a~ 0 t~ 5C~
Th~ reac~ion mix~ure was concentrated and to ~he
- residue were ~ddsd e~hyl acetate and water. After
ilteri~g off an insoluble material, ~he e~hyl aceta~e
laye~ was pou~ed into an aqueous solution o sodium
bicaTbona~e, The aqueous l~yer was.separa~ed out,
adjus~ed ~o p~ 4 wi~h 10% hydrochloric acid after
addition-of e~hyl ace~a~e and ex~rac~ed with ethyl
; ce*a~e. The extract was dried over magn~sium sulfate
~nd ev porated ~o a volume of about 10 ml, Precipi-
ta~s were collec~ed by filtration, washed with ethyl
acetate and die~hyl ether and dri~d ~o give 7-[2-~4-
1uorophe~oxyimino)-2-(5-amino l,Z~4-thiadiazol-3-
yl)-acetamido]-3-~1,3,4-thiadiaæol-2-yl)thiomethyl-
3-oephem-4-car~oxylic acid (syn isomer)~l.2 g),
mp 140 ~o 145C (dec.).
I,R,. ~Nujol~ : 3330, 3200~ 1770~ 16809 1620g
1520 cm~l
7_ ~
N.M.R. (d6-DM50,~) : 3.57 and 3.80 (2H, ABq,
J=18Hz) ~ 4r27 and 4~57 (2H, ABq, J=13Hz)~
5.20 (lH, d~ J-4Hz), 5087 (lH) dd, J=4
and 8Hz~ 7.17-'7.3 ~4H~ m), 8.20 (2H, s),
9.50 ~lH9 s~, 9.83 ~lH, d, J=8H~)
To a cold solution o phosphoTus pentachloride
~2.08 g) in methylene chloride (S0 ml) was added a~
-15~C 2-phenoxyimino-2-tS-amino-1,2,4-thiadiazol-3-
yl)acctic arid (syn isomer)~2.64 g) and ~he mix~urewas s~irred for 30 minutes at the same temperature.
On th~ ather hand, a mix~u~e of 4-nitrobenzyl 7-amino-
3-cephem-4-carboxyla~e ~3.35 g~ and ~rimethylsilyl-
acetamide ~1~ g~ in me~hylene chloride (50 ml) was
warmed ~o make a clear solu~ion and then cooled to
-15C. The solutlon was added to $he above activated
mixture and the mixture Wa5 stirred for 0.5 hour at
0 to 5C. The ~eac~ion miæture was pou~ed into cold
aqueous solu.ion (700 ml) of sodium bic rbo~a~e (5.9 g~
The me~hylene chloride layer was dried uver magnesium
sulfate and evapora~ed to dryness. The residue was
pulv~rized with diethyl e*her. Th~ resulting powder
was coll~cted by fi~tration and dried ~o give 4-
~i~robenzyl 7-~2-phenoxyimino-2 ~5-amino-1,2,4-
~hiadiazo~-3-yl~ace~amido]-3-cephem-4-ca~boxylate
~sy~ isome~)~S.l g~, mp 140 to 145C tdec.)~
I.R. (Nujol) : 3300~ 17753 1720, 16809 162~,
1600 9 1590 ~ 1520 cm~~
N.M.R. (d~-DMS0,~) : 3060 (2H, broad s),
5.23 ~H~ d, J=4Hz)~ 504~ ~H~ s),
6.00 (lH, dd; J=4 and ~Hz)~ 6~67 (lH, *9
J-4Hz~3 7~0-7.50 {5H~ m~ 7.73 (2H, d~
J-8Hz), 8.27 (2H9 d~ J-8Hz~ 8.30 ~2H~ s),
~097 ~lH, d9 J-8Hz)
5
~7
Exam~le 4
The following compounds were obtained according
to similar manne~s to those of Examples l to 3, 5 a~d
7 to 12.
tl) 7-~2-phenoxyimin~-2-~5-amino-l~2~4-thiadia
3-yl~ace~amido3-3-(1-ca;rboxyme*hyl-lH-tetTazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isome~), mp 175 to 180L (dec.
~ Nujol~ : 3400, 3200, l770, 1700~ 1660
1620, 1580, 1510 cm 1
N.M.R. (d6-D~SO9~ : 3.70 (2H, b~oad s) 9 4.23
and 4.50 ~2H9 ABq, J=l~Hz), 5.17 tlH~ d,
J=4Hz), 5.30 (2H9 s), 5.89 ~lH, dd, J=4
and 8Hz3, 7.0-7.5 ~SH, m~, 8.~2 ~lH~ s),
9.83 tlH, d, J=8Hz)
(~) 7-L 2 Phenoxyimino-2-(S-amino-192,4-thiaaiazol-
3-yl~acetamido~ 3~tl-allyl-lH-tetTazol~5-yl)-
thiome~hyl-3-cephem-4-carboxylic acld.~syn isomer~,
mp 145 to 150C (dec,)
I.R~ (Nujol) : 3450, 3350~ 3180, 1780, 1710,
1680, 1610~ l5gO, 1510 ~m~l
N.M.R. td6-DMSO~ 3.70 ~2H, broad s) 9 4.28
and 4.4~ ~2H, ABq; J~13Hz)~ 4.83-5.1a
(2H, m), 5.18 (lH, d9 J-4Hæ), 5.20-5~43
(~H~ m), 5.g3 (lH~ dd, J-4 and 8H~,
5~67-6.30 (1~, m)~ 7.0-7.57 ~5H~ m~;
8.30 ~2H, s), g~9~ tlH, d, J=8Hz)
; t3~ 7-~2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-
3-yl)ace~.amido]-3-~1-methyl-lH-tetrazol-5-yl)-
thiomethyl 3-cephem~4-carboxylic acid (syn isomer3 a
mp 155 to 158C ~dec~)
I.R. ~Nujol) : 3400, 3300j 3Z00, 1770, 1720;
1680, 1620 9 1590~ 1~20 cm l
N..M.R. (d6-DMSO,~) : 3~77 t2H, broad s3~ 3.95
(3H~ s), 4.33 (2H~ bro~d s~ 5
~8
~.27 (lH, d, J-4Hz)~ 5.93 ~lH~ dd9
J=4 and 8H~), 7.0-7.67 (5H, m),--
8.37 (2H, s), 10.0 (lH, d, J=8H~)
(4) 7-[~-Phenoxyimino-2-(S-amino-17 274 -~hiadiazol-
3-yl)acetamido~cephal~spo~anic acid ~syn isomer3,
mp 150 to 155C (dec.)
. (Nujol) : 3450, 3350~ 3180, 17759 1710,
168~1~ 1610,.1580, 1515 c~-l
. N.M.~ (d6-DM5O~ 2.03 (3H~ s3~ 3.62 ~2H,
broad s), 4477 and 5.03 (2H, ABq,
- J-14Hz), 5.28 ~lH, d9 J=4H~), 5.97 (lH,
dd3 J=4 and 8Hz), 7.0-7.6i (5H~ m),
8.37 ~H, s), 9.97 ~lH~ d; J=8Hz)
(5) 7-[~ -Methoxy-S-ni~rophenoxyimino)-2~
amino-1,2,4-thiadiazol-3-yl)acetamido]-3~ .3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
- acid (syn ~somer~ 9 mp 160 to 169C (dec.)
T.R. (Nujol) : 3380/ 322.0, 3100~ 178D, 16gO7
~~ 16~0g 16~0, 152~ 9 134~ 80,
2D 1085, 1065~ ~20, 750 cm 1
~ N.M~R. ~d~-DMSO,~ ; 3.71 (2~9 m), 3.98 (3~, s3 3 '
. 4.25 a~d 4.66 (2H, ABq, Jsl4Hz), 5.23
(lH, d~ J=5Hz), 5.~4 (lH, ~d, J-5 and
~ 9Hz~, 7.33 (lH, d, J-8Hz~9 8.10 ~lH, d,
: 25 J-8Hz); 8.19 (lH7 s), 8.34 (2H, b~oad s),
9.58 (lH, s~, 9.87 ~lH~ d~ J=9Hz~
(6) 7-~2-(4-Fluo~ophenoxyimino~-2-(5~ami~o-1,2,4-
thiadiazol-3-yl)ace~amido~-3-ttetrazolo~1,5-b~-
pyrida~in-6-yl)thiome~hyl 3-cephem-4-ca~boxylic
acid (syn isomer)~ mp 125 to 130C (dec,).
- I,R~ (Nujol) : 33Q0~ 31gO, 1770, 1670, 1615,
1520, 14g5 cm~~
N.M,R. ~d6-DMS0,~) : 3.80 ~2H, broaa s),
4.30 and 4.65 ~2H, ~Bq, J=13Hz),
5.27 ~lH, d~ J-5Hz)~
.
- ~9
~.95 ~lH, dd, J=5 and 8Hz), 7.25 (2H, s),
7.35 (2H9 s)~ 7.BO ~lH, d9 J-lOHz),
8.37 (2H9 broad s), 8.62 ~lH, d, J=lOH~),
9.9Z ~lH, d, J=8Hz)
~7) 4-Ni~roben~yl 7-[2-~4-fluo~ophenoxyimino)-2-
~5-amino-1,?,4-thiadiazol-3-yl)acetamido]-3-cephem-
4-carboxyla~e ~syn isomer~, mp 135 to 140~C tdec.3.
IoR~ (Nujol3 : 3300~ 3200, 1770, 1720, 1680
1625 ~ 1605 1 1500 9 1495 cm~
N.M~R. (d6-DMSO,~) : 3.45-307~ ~2H~ m),
5.15 (lH3d, J~5H_), 5.35 ~2H~ s),
5A92 (1~ ad> J-5 and 8Hz3, 6.58
(lH, t, Jz4H7), 7.08 ~2H~ s) 9 7.18 ~2H,
s), 7.60 ~2H~ d, J-8Hz~, 8.13 ~2H; d,
lS J=BH2)9 8.17 ~2H9 b~oad s), 9.75 ~lH, d,
J=8H~)
(B~ 7-[2-(4-Chlorophenoxyimino3-2-~5 amino-1,2,4-
thiadiazol-3-yl)acetamido~-3-(5-hydroxym~thyl-1 9 3,4-
- ~hiaaia~ol-2-yl)thiomsthyl-3-c~phem-4-carboxylic
acid (syn isomer), mp 135 to 140C ~dec.).
- I.R. ~Nujol) : 3450~ 3280~ 3180p 1760~ 1720,
1660 3 1620~ 09 1~20, 1480 c~ 1
N.M.R. ~d6 DMSa,~) 3.72 ~2H, broad s), 4.27
and 4~S5 ~2H~ ABq~ J-13H 3, 4.BO (2H, s),
S.22 ~lH~ d~ J=5Hz3, 5.88 ~lH, dd9 J=5
a~d 8~z), 7.25 (2H~ d~ J=gH~)~ 7.42 (2H~
d3 J~9Hz)~ 8~23 ~ZHo br~ad s)~
3.~5 tlH, d, J-8H~)
~9) 7-~2~4-Chlorophe~oxyimino)-2-t5 amino-1/2,4-
30 thiadiazol-3-yl)~ce~amido~3-(1-carboxrmethyl-1~-
~e~razol-~5-yl)~hiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp 135 ~o 140~C ~d~c.).
I.R. (Nujol) : 3400~ ~2~05 31709 1765, 1700,
1680, l~S~, 1615, 15~Q~ 151~,
1480 cm 1
r ~3 0 ':
N.M.R. (d6-DMSO~ 3.?0 t2H, broad s~
4.27 and 4.48 ~2H, ABq, J=l~Hz),
5.22 ~lH, dj J=5Hz), 5.30 (~H, s),
5.93 (lH9 dd, J=5 and 8Hz), 7.35 (2H,
d9 J=9Hz), 7.48 (2H, d, J=9Hz), 8.37
~2H, b~oad s), 9.97 tlH~ d~ J-8Hz)
(10~ 7-l2-(4-Chlorophenoxyimino)-2-~5-amino-1,2,4-
~hiadiazol-3-yl~ace~amido]-2-me~hyl-3-cephem-4-
ca~boxylic acid ~syn isamer), mp 150 to 155C (dec.).
I.R. (Nujol3 : 3400, 3270, 3180, 17709 1620,
1580, 1520, 1480 cm 1
N.M.R~ (d6-DMSO,~) : 1.45 (3H, d~.J~7Hz) 7
.. 3.60-4.10 (lH, m), 5.20 tl~, d, J=5Hz),
5.~0 tlH, dd, J=5 and 8Hz), 6~62 tlH,
lS d, J-6Hz), 7.35 t2HI d, J=9Hz), 7.48
(2H~ d, J-9Hz), 8.03-8.73 t2HI m),
; 9.97 tlH., d, J=8Hz)
(11) 4-Ni robenzyl 7-~2-(4-Chlorophe~oxyimino3-2~t5
am~no-1~,4-thiadiazol-3-yl)acetamido~-3-cephem-4-
, 20 ca~boxylate (syn isomer~, mp 15~ to 160C ~dec.).
I,R. (Nujol) : 3300, 31803 1770p 172U, 1680
1625 9 1600~ 1580, 1520, 1480 cm~~
N~MoR~ ~d6-DMSO9~) : 3.62 t2H~ broad s), 5.18
tl~, ~, J-5~z), ~.38 (2H~ s~, 5.95 (lH,
Z5 dd, J-5 and 8Hz), 6.63 ~lH, ~, J=4Hz~,
7.2~ ~2H, d, Jz9H2)~ 7.38 (2H, d, J-9Hz),
; 7.65 (XH, dg Jo8H~), 8.20 (2H, d, J~8Hz) 9
8.23 (2H, broad s), 9.85 ~lH, d, J=8Hz)
(1~) 7-~2-~4-ChloTophenoxyimlno)-2-~5-amino -1 7 2,4-
~hiadiazol-3-yl3acetamido]-3~ 2-hydroxyethyl)-
lH~ ra~ol-~-yl~thiomethyl-3-cephem-4-caTboxyli
- acid ~syn isomer~ 9 mp 120 to 125~C (dec.).
I~R. ~Nujol) : 3400, 3300a 3180~ 1765~ 1670,
1615, 1580~ 15~0~ 1480 cm 1
N.M.R. (d6-DMSO~3 : 3.50-3.93 ~4Hs m) 7
..
4.12-4.48 ~4H~ m), S.18 (lH, d, J-SHz),
5.88 (lH, dd, J=5 and 8Hz), 7.28 (2H~
d, J=9Hz), 7.45 (2H, dJ J=9Hz), 8.30
~2H~ broad s)~ 9.94 (lH~ d, J=8Hz)
(13) 7-[2-(3,4-Dichlorophenoxyimino)-2-~5-amino-
1j2,4-thiadiazol-3-yl)acetamido]cephalosporanic
acid ~syn isomeT~5 decomposed by 200~Co
I.R. (Nujol~ : 3600, ~400~ 1770~ 1720, 1680,
1530, 1250, 11~0, 970 cm~l
N~M~Ro (d6-DMS0~ 2.03 ~3H, s)~ 3.60 ~2H,m),
4.65 and 5.0~ ~2H~ ABq~ J=15Hz), 5~2~
(lH~ d, 3=SHz), 5.97 ~lH,-dd, J-~ and
- 8Hz~ 7~13-7O 77 ~3Hr m~, 8.35 ~2H, m),
9.90 (lH, d9 J-8Hz~
(14) 7-~2-(3~4~Dichlorophenoxyimino~ 5-ami~o-
- 1~2,4-thiadiazol~3-yl)acetamido]-3-(1,3~4-
thiadiazol-2-yl)~hiome~hyl-3-cephem-4-carboxylic
acid ~syn isomer) 3 decomposed by 160C.
I.R. (Nujol) : 330~, 3200~ i770, 16809 1620,
15209 1250, 1205~ lO~0 cm l
N.M.~ (d6-DMS0~3.: 3.77 ~2H, m~, 4D28
and 4.68 ~2H, ABq~ J-14Hz), ~.37
~lH~ d9 J=SHz), 5.97 (lH~ dd9 J=5 and
. 8Hz), 7.1~-7.8~ (3H9 m~, 8.36 (2H, s),
9.50 (lH, s), 9.93 (lH, d, J=8Hz)
4-Nitrobenzyl 7-~2-(3-*riFluorome~hyl-
phenoxyimino)-2 ~-amino-1,2~4-thiadia~ol-3-yl)~
acetamido~-3-cephem-4-carboxyla~ tsyn isomer),
mp 136 to 140~C (de
I.R. ~NuJol3 : 3370, 32003 17809 1730,
: 1~90~ 16~0, 1630~ ~61Qj ~20 9
14S~ 25~ 12gO9 1160~ ~259
975, ~07 740 ~m~l
N.M.R- (d6~DMSO,~) : 3~7 (2H, m), ~,22
tlH~ ~9 J=5Hz~, 5,37 t2H~ s~
~32
5.~9 (lH, dd~ J=5 and 8H7); 6.63
~lH~ m), 7.50 ~4H, b~oad a) J 7.66
f2H, d~ J=9Hz),
8.20 (2H, d, J=9Hz), 9.89 (lH, d,J-8Hz)
6) 7-~2-~3-TrifluoTo:methylphe~oxyimino)-Z-(S-
amino-192~4-thiadiazol-3-yl~acetamido]-3-(1,3,4-
thi~dia2O1-~-yl)thiomethyl-3-cephem-4-ca~boxylic
acid ~syn isomer~ decomposecl by 164C.
; I.R, ~Nujol~ : 3300, 31~0, 1765~ 1670, 161D9
1~20 9 132~, 1165, 1120 9 1060
930~ 790? 7D0 cm
N~M.R. ~d6-DMSO9~) : 3.73 (2H, mj, 4.23 and
~ 5.63 t2H~ ~Bq, J=14Hæ), 5927 (lH, d,
J-5Hz), 5~93 ~lH, dd, J-S and ~Hz),
7.55 (4H, broad s), 8.34 (2H, b~oad s~,
9.60 ~lH, s~ J 9 . 99 (lH3 d, J=8Hz)
~173 7-[2-~3 EthoxycaTbonylphenoxyimino~-2-(5-
amino-1,294-thiadiazol-3-yl)acetamido]-3-(1,3 7 4-
thiadiazol-2-yl3~hiomethyl-3-ceph~m 4-carboxylic
acid (syn isomer), d~composed by 162~C.
I~R. ~Nujol~ : 3350~31S0, 1770) 1720-1650, .-
1620, 15~3, 1290~ 1270, ll~0,
1~6~) 900, 760 cm 1
N.M.R. (d~-DMSO,~ : 1.32 ~3H, t, J 7Hz),
Z5 3.71 ~2~ m), 4.25 and 4O60 ~2H, ABq,
J=14Hz)~ 4.3~ ~2H, q, 3~7Hz), 5.23
~lH~ d; J~H~ 5,73 ~lH~ dd9 J=5 ~nd
8Hz), 7.40-7.g5 ~4H~ m3, 3.67 (~H,
broad s~, 9.5g ~lH~ s) 7 9~98 (lH9 d~
J~8~1z)
~18~ 7 - ~2 ~ ~4-Pluorophenoxyimino) - 2~ (S-amino-l 3 ~ 94-
thiadiazol-3-y~acetamido~ -3- [1- ~-hydroxyethyl~-
lH-tetrazol-S yl]~hiomethy~-3-c~phem-~-carboxylic
acid ~syn isomer) 9 mp 14~ to 150C ~dec.).
I.R~ CNujol~: 33U0, 3~0, 1770, 16709 16~0
1520 cm~
~2
83
N.M.R. (d6-DMS0,~) : 3.50-3.83 ~4H, m),
4.0-4.53 (4H, m), 5.13 (lH, d, J=4Hz~
~83 (lH, dd7 J=4 and 8Hz~, 7.12 (2H,
s~, 7.23 (2H, s), 8.18 (2H, s), 9.77
(lH, d9 J~8Hz)
(19) 7-~2-(4-Fluorophenoxyimino)-2-~5-amino-1,2,4-
~hiadia~ol-3-yl~ac~tam:ido~-3-(1-carboxyme~hyl-lH-
tetrazol-5-yl)thiometh~yl-3-cephem-4-ca~boxylic acid
(syn isomer~, mp lS0 to 155~C (dec~)0
: 10 I.R~ (Nujol) : 3300~ 3200, 17707 1720,
1670~ 1620, 15209 1500 cm 1
N~M.R. (d6-~MS0,~ : 3.57 (2H~ ~road s),
4.27 and 4.53 ~2H~ ABq~ J=14Hz), - -
5~23 ~lH, d~ J=8H2~, 5.37 (2H; s) 9
5.93 (lH, ddg J=4 and ~Hz~, 7.25
(2H, s~, 7.37 ~2H~ s)~ 8.32 (2H, s) 7
9.92 (lH, d, J=8Hz~ -
~) 7~t~-~4-FluoTophenoxyimino)-2-(5^amino-1~2,~-
~hiadiazol-3-yl~acetamido]-3-C2-carboxymethyl-3-
oxo-2,3-dihydTo 192,4-~ria~olo[4~3-b]pyrida7in-6-
yl~hiom~hyl 3-cephem-4-carboxylic acid ~sy~
isomer)l mp 165 to 170C (d~c.).
I.R~ ~Nujal3 : 3300, 32~0~ 1770, 1710, 1620)
1540, 15Z0; 1500 cm 1
N.M.R7 (d6-DMS0~ 3.67 and 3.90 (~H9 ~Bq,
J-18Hz), 4.13 and 4.37 62H~ ABq, J-13Hz3
4.73 ~2H, s), 5.23 ~lHs d; J-4Hz~,
5~90 (lH, dd, J=4 and 8Hz~, 7.08 ~lH, d,
J~lOHz3 r 7.17 (2H~ s~ ~, 7.28 ~2H~ s~ 7
7. 7i! (lH7 d5 3=lOHz) ~ B . 23 (2Hg s) ~,
9. 83 (lH~ d~ J=8Hz~
(~13 7~2-(4-Fluorophe~oxyimino~-2-~5-amino-1,2,4-
hiadiazol-3-yl)acetamid~-3~ (2-carboxyethyl~-
lH-~e~razol 5 yl]~hiomethyl-3-cephem-4-carboxylic
: 35 acid (syn isome~, mp 140 ~o 145~C (d~o.3.
~s
I.R. (Nujol): 3300, ~200" 1770, 1700,
1620, 1520, 15DD cm 1
N.M.R. (dj,-DMSO,~): 2.90 ~2H, t, J-6Hz),
3.70 ~2E~, broad s), 4~40 (2H, t 9
J=6H~) ~ 4.27' and 4.47 (~H~ ABq, J-13Hz),
5 .17 ~lH, d, J=4Hz), 5 . 87 ~lH, dd~
J-4 and 8Hz), 7.15 (2H, s~, 7,25 ~2H, s) "
8O;22 (2H~ s), g~83 (lH9 d, J~SHz~
~2~ 7-[2-~4 Pluorophenoxyimino~ 2-t~-amino-192~4-
lû ~adiazol -3 -yl~ acetamido~ -3 - ~1 -a:llyl -lH-te~razul -
5-yl~hl:omethyl-3-cephem-4-carboxylic acid (syn
isnmer~ ~ mp 145 to 1509C ~d~c..3 .
~- I.R. (Nujol3: 3450, 33509 31509 1780,
1705, 1670, 1610, 1510 cm l
N.M.R. (d6-DMSO,~): 3~66 and 3.84 (2H, ABq9
J-~8H~, 4 . 30 ~nd 4, 50 ~2H" .4Bq 9 J=14Hz) 3
5 . 00 ~2H, d" J=51Hz), 5 . 24 ~lH9 d5 J=4Hz)
5~20-So40 ~2H, m), 5.96 (lH5 dd3 ~-4
and 8Hz)" 5.80~6.20 ~lH, m?, 7.28 ~2H" s),
7.34 (~H, s), 8.32 (2H, s) 9 9.96 (lH, d~
J--8HZ)
(233 7~ C~~ (4-Flu~rophenoxyimino3 -2- (5-amirlo-1,2,4-
thi~diazol 3-yl)acetamido~cephalosporaIlic acid
CsYn isomer) 3 m~ 156 to 161C (dec.) .
I~,R~ (Nujol): 3450, 3300, 3~00g 17709 173D~
1680 9 1610 ~ 1510 ,, 1500 cm~l
N~.M.~7 (d6-I~MS0,~ : 2O04 (3H, s3, 3O52 and
3,68 (2H, ABqa J2:L8H~) ~ 4.74 arld
$.02 ~;2H9 ABq, J-14Hz~, 5O2~ ~lH, d,
J~4H7), 5.9¢ ~lH9 dd~ J~4 and 8Hz3 1
7~5 ~2H, s~ ~ 7.34 (2Ha s~ 9 8.30 (2H, s) "
9.94 (1~, ~, J=~z~
~24) 7-[2-PhenoxyimiIlo-2 tS-amino-~ ,2,4-thiadia7O1-
3-yl~ ace~amido~ -3- (te~razolo El ~ 5-b~pyridazin-6-yl~ -
~hiomethyl-3-cephem-4 earboxylic acid (syn isome~),
mp 175 *o 180~C (dec ~ ~ ~
- I.R. ~Nujol) : 3300, 3~00, 1775, 1680?
1615, 1585, 1520 cm 1
(253 7-~2-Phenoxyimino-2-~5-aminv-1,2,4~hiadiazol-
3-yl)ace~amido]-3-[1-~2-(N-t-bu~oxycarbonylamino)-
ethyl}-lH-te~r~zol-5-yl~thiomethyl-3-cephem-4-
carboxylic acid (syn is~mer)~ mp 150 ~o 155~C (dec.).
I.R. (Nujol~ : 3300, 32003 1770, 1680, 1620,
lS90, 15~0 cm 1
~?6) 7-~2-~3-Trifluoromelthylphenoxyimino)-2-(5-
amino-1~2,4-~hiadiazol-3-yl)ace~amido~-3-cephem-
4-carboxylic acid (syn isomer~, which is decomposed
by 193C.
Nujol) : 34~0, 3320, 3200, 1770, 17109
16659 1630~ 156~9 lSl~, 13259
11709 1110~ 940 cm~l .
(27~ 7-~2-Phenoxyimino-2-t5-amino-19294-thiadia~ol-
3-yl)ace~amido3-3-cephem-4-earboxylic acid (syn
isomeT) J mp 168 ~o 170C ~dec.~
I.R. ~Nu~ol3 : 3400, 3200~ 1780, 1660,
16~0~ 1600, 1590, 1~40 cm 1
- (28~ 7-~2-(4-Chlorophenoxyimino)-2-~5-amino-1,294-
~hiadiazol-3-yl~ace~amldo]-3-cephem-4-carboxylic
acid (syn isomer~.mp 145 to 153C ~dec.).
I.R~ (Nujol~ : 3400~ 3260, 3~B0~ 1775) 1675,
1625, 1600, 15X0~ 1480 cm 1
(29~ 7-~2-(4-Pluorophenoxyimino)-2-~5-amino-1,2,4-
thi~diazol-3-yl)acetamid~]-3-cephem~4-carboxylic
~cid ~sy~ isomer) 9 mp 130 ~o 135C (dec.).
I ~Ro (Nujol~ : 3400~ 3270~ 3180~ 1765, 1675,
1~05~ 1500 cm~
~30) 7~E2-Phenoxyimino-2-(s-amino-l~2~4-~hiadia
3-yl3ace~amido~ (2-aminoe~hyl)-lH-~e~razol-
5-ylJtllivm~thyl-3-cephem-4-caTboxylic acid (syn
isomer)~ mp 180 ~o 185C ~dec.).
I.R.(Nu~sl):33003 32S0, 17609 1670, 1620, 1590
1520 cm~l
2~
Exam~le S
To a cold solution of phosphor~s pentachloride
~Z.U~g)in me~hylene chloride (45 ml) was added
2-(t-butoxycarbonylmetho.~imino)-2-(5-amino-1,2,4-
~hiadiazol-3-yl)acetic acid (syn isomer) (2.51 g) at
-17C and ~he mixture was stirred for S0 minu*es at
the same tempera~ure~ On ~he other hand, a mixture
of 7-amino-3-(tetra~olo~:LpS-b]pyridazin-6-yl~-
~hiomethyl-3-cephem-4 carboxy1ic acid (3.34 g) and
t~imethylsilylacetamide ~1~ g) in methylene chloride
~45 ml) was warmed ~o mak~ a clear solution and then
cooled to -20C. The so`Lution was added to ~he above-
. activated mixture and ~he mixture was stirred for 1 -
hour at -10 to -15C. The reaction mixture was
15 e~raporated and to ~he residue we~e added ethyl acetate
and an aqueous solution of sodium bicarbonate, The
aqueous layer was separated out, adjusted to pH 3 to
4 wi*h 10% hydrochloric arid and ex~racted wi~h ethyl
aceta~. The ~xtract was dried over magnesium sulfate
20 and ~Yaporated u~de~ reduc~d pressure. The residue
- was tri~u~ated with die~hyl ether to give 7-~2-(t-
bu~oxy~aTbonylmethoxyimino) - 2 - ~ 5 - amino -1, 2, 4 -
$hiadiazol-3 -yl) acetamido~ -3 - (tetrazoïo ~1 g ~-b,:-.
pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid
~syn isomer) (2.4 g), mp L25 to 130C (dec.) .
I.R. ~Nujol): 340û, 3300~ 3180, 1770, 1720,
1680 ~ 162~ ~ 1525 cm~l
N~M.R. (d6-DMS0,~) : 1.47 ~9Hg s~ g 3.73 (2H,
broad s), 4.28 and 4.60 (2H, ABq,
J~13Hz3, 4.65 (2H, s), 5.18 (lH, d,
J-SHz) g 5.87 ~lH~ dd, J=5 and 8Hz),
7.78 ~lH~ d, J=lOHz), 8.17 (2H, broad s),
8.62 (lH, d, J=lOH~), 9~55 (lH~ dy J=8Hz3
The following compounds were obtained acrording
;
~7 .
to similar ma~ners to those o~ Examples 1 ~o ~,-5 an~
7 to 1~
(1) 7-~2-{3-(N-t-Bu*oxyc2rbonylamino)propoxyimi~o}-
2^(5-amino-17 ~ ,4-thiadiaz91-3-yl~acetamido~-3-
methyl-3-cephem 4-carboxylic acid (syn isomer), mp
114 to 119C (dec.).
N.M~R~ (d6-DMSO,~) : 1.40 ~9H~ s), 1.74 ~3H, s),
1.80 ~H,.m)~ 3.00 (4H; m), 4.14 (2H, m),
S.10 (lH, d~ J=~Hz~, 5.72 (lH, dd9 J35
and 8H~) 3 6.70 ~lH~ broad s~, 8.10 (2H3
.
broad s~, 9.44 ~lH~ d, J-8H~ ~
. .
~2) 4-Ni~robenzyl 7- ~2-t3- (N-~-bu~oxycarbonylamino?- ~ ~
~ ~ p~opoxyimino}-2-(S-amino-132,4-thiadiazol-3-yl)ace~-
amido]-3-chlors-3-cephem-4-carboxylate (syn isomer),
mp 91 to 100C ~dec.).
N.M.R, (d~-DMSO~D2O,~) : 1.3B ~gH~ s), 1,8~
- t2H, m)~ 3~06 ~2H, m~, 3.7-4.3 ~4Hr m~,
5~33 (lH9 ds J=5H~), 5.49 ~2~, s) ? 5-95
~ (lH, d~ J~5Hz), 7.74 ~2H, d~ J=9Hz)~
; 20 8.92 ~2H, d, ~9Hz)
~ ~3) 7-~2-{3-~N-t-Bu~oxycar~o~ylamino)propoxyimino}-
- 2-(5-amino~1,2,4-thiadia2O1-3-yl)ace~mido]-3~
: {2-(N-t-butoxyc~rbonylamino)e~hyl~-lH-te~razol-S-yl~-
. ~hiomethyl-~ cephem-4-carboxylic acid (syn isomer)~
mp 107 ~o 112C ~dec.).
N~MoR~ (d6-DMSO~D~O,~ : 1O32 ~H9 s3 D 1- 34
~9HD 5) 3 1.80 ~2H~ m), 3.10 ~2H, m)~
3.30 (2~, m~9 3.70 ~H9 m), 4.0-4.5 ~6H,
m) 7 5~13 (lH, d~ JaSHz~, 5~83 tlH, dg
J=SHz).
{4) 4-Ni~obenzyl 7-~2-allyloxyimino-2-~5-amino-
1,2,4-~hiadiazol-3-yl)a~etamido3-3-cephem-4-
~arboxyla~e ~syn isomer), mp 125 *o 130C (dec.).
I.R. {Nujol~ : 33~0~ 1770~ 1720~ 1680, 1630,
1610 9 15~0 cm~l
B8
N.M.R. (d~-DMSO,~) : 3.60 (2H, broad 5),
4.57-4.83 (ZH~ m) 9 5.17 (lH, d, J=4Hz)~
5.0-5.35 (2H, m), 5.40 (2H, s), 5.93
(lH, dd~ J=4 and 8H~), 5.87~6.17 (lH, m),
~ 5 6.63 ~lH, t, J=3Hz), 7.70 (2H, d, J=9Hz),
8.10 (2H, s), 8.23 ~H, d, J=9Hz),
9.57 (lH, d, J=8H~)
(5) 7-~2-(2,~2-Tri1uo~oethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3~ acetam$do~oephalos~oranic acid
(syn isomer~, mp 185 to 195C (dec.).
IoR~ (Nujol) : 3470, 3330, 3210, 3060, 1770p
17359 1700, ~7~9 1620, 1555, --
1520 cm~l - -
- N.M.R. (d~-DMSO,~) : 2.30 (3H, s), 3.53 (2H, - - -
broad s), 4.65 and 4.87 ~2H, A~q, J=9Hz3,-
4.70 and 4.93 ~2H, ABq, J=13Hz3, 5.1-2
(lH, d~ J=SH~), 5.7B ~lH, dd, J=5 and
8Hz) 3 8.12 ~2H~ broad s3~ 9.~2 (lH, ~,
J-8HZ)
~6) 7-~2-~2,2,2-Tr~1uoroethnxyimino~-2-~5-amino-
1~2,4-~hiadiazol-3-yl)ace~amido]-3~ allyl-lH-
tetrazol-5~yl~thiome~hyl-3-c~phem-4-caTboxylic acid
~syn isomer)~ mp 125 to 130~C (d~c.~.
I.R. tNujol) : 3300, 32003 1770, 1680,
1620 7 1520 cm~
N.M.R. ~d~-~MSO,~) : 3.68 ~2H~ broad s)~
4.30 a~d 4.40 (2H, ABq, J-13Hz), 4.68
and 4.92 (2H9 ABq, J~9Hz), 4~87-SolO
(2H) m); 5.15 ~lH, d9 J35Hz) 9 5017-5.47
(2H, m~, 5.83 ~lH~ dd~ 3=5 and 8Hz~,
.67-6.27 (lH, m), 8.2~ (2H, broad s) 3
.77 (lH, d, 3=8H~)
~7) 7-~2-(~,2~-Tri~luoroe~hoxyimino)-2-t5-amino-
1,2,4-~hiadiazol-3-yl)acetamido]-3-(1-methyl-lH-
te~razol-5-yl)thiomethyl~3 c~phem-4-carb~xylic acid
~39
(syn isom~), mp 145 ~o 150C (dec.j.
I.R. ~Nujol~ : 3300, ;200, 1770, 1680, 1620,
1525 cm l
NcM.R. ~d~-DMSO,~) : 3.70 (2H~ broad s), 3.95
(3H, s), 4.32 (2H, ~road s), 4,68 and
4.92 ~2H~ ABq~ J=9H~ 3 ~.15 (lH, d, ~=5Hz~,
5.85 (lH, dd, J=5 and 8Hz), 8.2~ (2H, broad
s), 9.75 ~lH, d, Ja8H~3
(8) 7-~2 ~2-~N-t-Butoxycarbonylamino~e~hoxyimino}-
2-~5-amino-1,2j4-thiadiazol-3-yl)acetamido] 2-
methyl-3-cephem-4-ca~bo~ylic acid ~syn isome~, mp
, 215 to 220C ~d~c.).
`~ ~ I.R. (Nujol) : 3230, 3150, 1775, 16~0, 1620, - -
1525 cm
~ 15 N.M.R. (d~-DMSO~D20,~) : 1.37 (9H, s), 1043 (3H,
d~ J-7Hz), 3O0-3.5 (2H~ m), 4.0-4.4 (2H,
m), 5.10 (lH, d, J~4~5Hz~ 9 5.8-6.1 (lH9 m)g
6.53 ~lH3 d, J-6.9Hz~ ,
. ~9~ 7-~2-{~-~N-*-Butoxycarbonylami~o)ethoxyimino}-
2~ amino-1,2j4-thiadiazsl-3-yl3ace~amido~-3-[l
~ {2-tN-S-bu~oxycarbonylamino)ethyl}-lH-~etra~ol-5-
~ . yl}thiome~hyl-3-cephem-4-carboxy}ic acid ~syn
isomer), mp 181 to 186C ~dec.).
I.R. ~Nujol~ : 3320~1780, 1680, 1620, 1520
~165 ~ 1
. N.M.R~ ~d6-DMSO~D2O~ 1,32 (18H9 s), 3,D7
; 3.~2 (4H, m), 3O7 ~2H9 broad s~ 9 4.0-4.5
~6Hg m) 9 5.1S (lH, d~ J=4~5Hz); 5.85 (lH,
d~ J~4 . 5Hz), ~. 23 (2H3 broad s)
llO) 7 ~2-Trityloxyimino-2- (S-amino-1"294-
thiadi.azol-3-yl)acetamido] -3- ~5-m~thyl-1,3,4-
thiadi. a~ol - 2 ~ yl ) thiome thyl 3 ~ cephem- 4 ~ carboxyl ic
aci~ (syn isomer), mp 147 to 161 C ~dec . ) .
I . ~. (Nuj ol) : 34Z0 3 178Q, 1680, 1615 ) 15~5 cm
N~M.R~ ~d6-DMSO~DzO~ .2.72 ~3H, s) ~
2~
3.73 ~2H, broad s), 4.30 and 4.67 (2H9
ABq3 3--14H~), 5.35 ~lHg d, J=5.OHz),
6315 (lH, dg J=S.OH~), 7.50 ~15H, s)
(11~ 7-~2-{2-(N-t-Butoxycarbonylamino)ethoxyimino}-
2-(5-amino-1,2,4-thiadiazol^3-yl)ace~amido]-3~
caTboxymethyl-lH-tetrazol-5-yl)thiom~thyl-3-cephem-
4-carboxylic acid ~s~n isumer), mp 105C (dec.).
I.R. ~Nujol) : 3305, 3160~ 1770,1670, 1520,
1245 cm 1
N.M.R. td~-DMSO~D209~) : 1.37 (9H, 5)9 3.0-3.5
~2H~ m), 3~7~ (~H~ broad s), 3.9-4.3
~2H, m), 4.1-4.6 t2H) m) 5 5.13 ~lH, d9.
J34.5Hz)~ 5.33 ~2H3 s), 5.7-6.0 (lH, m~
(12) 7-~-tt-Butoxycarbonylme~hoxyimino)-2-(S-amino-
1,2,4-thiadiazol-3-yl3acetamido~^3-~1~3,4-thiadiazol-
2-yl~*hiome~hyl-3-cephem-4-carboxylic acid (syn
isomer), mp 140 to 145C (dec.~ -
I.R. ~Nujol) : 3300, 3175~ 1770, 17205 1680,
- 1620 9 1520 c~ 1
N.M.R. (d6-DMSO,~) : 1.50 t~H, s)~ 3,73 ~2H,
- broad s), 4.33 and 4.58 (2H, ABq9 J=
13Hz) 3 4.65 ~2H, s)9 5017 (1H9 d7 J~4Hz)~
5.85 (lH, dd, J=4 a~d 8Hz), 8318 (2H, s),
. 9.50 ~lH, d, J=8Hz), 9.53 (lH, s)
~13) 7-~2-~t Butoxycarbonylm~thoxyimino)-2-~S-amino- v
1,2~4-~hiadiazol-3-yl~acetamido]cephalospora~ic acid
(sy~ isomer), mp 125 to 130~ (dec.).
I.R. ~Nujol~ : 33DO, 3200, 17709 1720, 1680,
16~0~ lS20 cm~l
N.M.R. ~d~-DMSO~ 1350 (9H, s), 2.10
(3~ s)~ 3.62 (2H~ broad s), 4~68 (ZH,
5)D 4.77 and 5.1)3 (2HD ABq~ J=13HZ),
S . ZO (1H~ d~ 3~-4HZ) ~ 5~ 88 ~1H~ dd~
J=4 and 8Hz) 7 8.1~ (2H, s), 9.55 ~lH,d~
J=BHz~
(14) 7~ t-Butoxycarbonylmethoxyimino)-2-~5-amino-
19 2,4-thiadia701-3-yl)acetamido]-3-(l-allyl-lH-
tetrazol-5-yl)thiomethyl--3-cephem-4-carboxylic acid
~syn isom r)~ mp 130 to :L35~C ~dec.).
I.R. ~Nujol) : 3400, 3280, 3180, 1770~ 1720,
168Q, 1620, 1520 cm~
N~M.R. (d6-DMS~,~3 : 1.42 (9H9 s), 3.67 ~2H~
broad s3, 4.27 and 4.43 (2H, ABq,
J~13Hz)~ 4.62 (2H, s), 4.87-5.07 (2H,
m)~ 5.10 tlH, d9 J=5H~ 5.13-5.43 ~2H,
m), ~.82 tlH, dd~ 3~5 and 8Hz~, 5.60- -
6.20 (1~, m); 8.10 ~2H, broad s),
9.~7 ~1~3 ~ J~8~
(1~3 7-l2-(t-Bu~oxycarbonylmethoxyimino)-2-~5-amino-
1,2,4-~hiadiazol~3-yl)acet~mido~-3-[~-~2-~N-t- - -
butoxyca~bonylamino)ethyl}-lH-~etrazol-5-yl3-
thiomethyl-3-c~phem-4-carboxylic acid tsy~ isomeT),
mp llO to llSC (dec.).
I~R~ ~Nujol~ : 3300g 3200, 1775, 16~0,
1620~ 1~20 cm=l
N.M~R~ (d~DMS09~3 : 1.32 ~9H~ s), 1.42 (~H,s3 9
3.33 (2H3 ~road s), 3.53-3.80 ~2H, m)~
4.13-4.47 (4H, m), 4,58 ~2H3 s), 5.~8
~lH~ d~ Jz5Hz~, S.78 (lH, dd, 3=5 and
8Hz)~ 8.07 (2H9 broad s)~ 9.45 (lH, d~
J-8Hz)
~1~) 7-~2~ Bu~oxycarbonylmethoxyimino~-2-(5-amino-
1,2,4-~hiadiazol-3-yl)ace~amido~-3-~1-phenyl-lH-
te~razol-5-yl)thiom~thyl-3-cephem-4-ca~boxylic acid
(syn isomer3~ mp 135 to 140C tdec.).
I.R. (Nujol) , 3400, 3300, 3200~ 1775, 172D~
168~, 1620~ 1525, 1500 cm 1
N.M,~. (d6~DMSO,~) : 1.43 (9H, s); 3,70 (~H,
broad s), 4.32 and 4.S7 (2H, ABq,
J~13Hz); 4.65 ~2H~ s)~ 5.12 (lH~ a~
J=5Hz)~ 5.85 (lH, dd, J~5 and BHz),
7.67 (SH9 ~) 9 8,17 (2H, broad s),
9.50 ~lH, d, J=8Hz)
(17) 7-~2-~3-(N-t-Butoxyc:arbonylamino)propoxyimino}-
~--t5-amino-1,2,4-thiadiazQl-3-y~)ace~amido]-2-~. '
methyl-3-cephem-4-carboxylic acid (syn isomer), mp
133 to 146~C ~dec.).
I.R. (Nujol) : 3280~ 31709 1775? 1685,
1670, 16259 1520 cm~l
N-M-R~ (d6-DMSO~D2Q9~ 4~ ~9H, 5~) 1,45
~3H, d, 3-7Hg), 1.56-2.06 (2H, m39
3.03 (2H5 ~g J-7Hz~, 3~1-4~1 (lH, m)~
4.23 (2H, t, J-7Hz), 5.13 ~lH~ d, J-5Hz),
5.97 (lH, d~ Ja5Hz)~ 6.65 ~lH, d,
J=6.5Hz)
(18~ 7-~-Allyloxyimino-2-(5-amino-1,2~4-~hiadiazol-.
3-yl)acetamido3-3-~1 allyl-lH-~etrazol-5-yl~-
thiomethyl-3 cephem-4-c~rboxylic acid (syn isomer3
mp 150 to 155C ~dec.).
I.R. ~Nujol) : 3300, 3200~ 1775~ 1670,
1620, 1520 cm~~
: ~19~ 7-~2-Allyloxy~mi~o-2-~5-amino-19 2~4-~hiadiazol-
3-yl3ace~amido~-3-~etra~olo~l a ~-b]py~idazln-6-yl)-
~hiomethyl-3-cephem-4-carboxylic acid ~syn isomer)~
mp 180 ~o 18~C ~d~c.3.
I.R. ~Nujol~ : 3300~ 3200~ 1770~ 1670,
~620, 1525 c~ 1
(20) 7-[2-~2~2,2-Trifluoroethoxyimino)-~ -amino-
1,2,4-~hiadiazol-3-yl)acetamido]-3~ {2-(N-t-
butoxycarbonylamino)e~hyl}-lH-tetrazol-5^yl]thio-
methyl-3-cephem-4-carboxylic acid (sy~ isomer) 3
powder.
(21~ 7-~ 2,~,2-Tri1uoroethoxyimino)-2-~5-amino-
1,234-thiadiazol-3-yl)acetamido]-3-(5-aminom~thyl~
1,3,4-~hiadia~ol-Z-yl)thiomethyl-3-cephem-4
carboxylic acid ~syn isomer), mp 150 *o. 155C
~dec.).
I.R. ~Nujol) : 330Q, 3180, 17607 1670,
1610, 1520 cm 1
(22) 7~ 2,2,2-TrifluoToethoxyimino~-2-(5-aming-
1,294~thiadiazol-3-yl~a.cetamido]-3- ~e~ra7010[1,5-
b3pyridazin-6-yl)~hiome~hyl-3-cephem-4-carboxylic
acid (syn isomer),-mp 1.65 to 170C (dec.).
I~Ro ~Mujol) : 3420~ 3300, 3190, 1773,
170S, ~670~ 162t)" 1525 cm~l
t23) 7-~2-~3-(N-~-Butoxycarbonylamino~propoxyimino}-
2-~5-amino~1~2~4-thladia~ol-3-yl3ace~amido3-3-
~ chloro~3-ceph~m-4-caIboxrli~ acid ~syn isomer),
mp 111 to llS~C tdec.).
I.R. ~Nu~ol) : 3300-31003 1780, 1690-1660,
1520, 1270 cm~l -
~24~ 7-[2-Allyloxyimino~2-(5~amino-1,234-~hiadiazol- -
3-yl)acetamido~-3-cephem-4-carboxyllc acid ~syn
isomerj, mp 160 t~ 16~C tdec.).
~25) 7- [~- (3-~minopropoxyimino)-2-(5-amino-1,294-
~hiadiazol-3-yl)acetamido~-3-tl-(2-ami~oethyl)-
lH-~etTazol 5-yl~thiome~hyl-3-cephem^4-carboxylic
acid tsy~ isomer), mp 184 ~o 196C ~dec.).
I.R~ ~Nujol) : 3400-3100, 1760~ 1660, 1610,
~5 l5Z0, 1170, 1060~ lOlD cm
~26) 7-~2-~2-~minoethoxyimi~o)-Z-(5 amino-1,2,4-
~hiadiazol-3-yl)acet~mido~v3-(l-carboxymethyl-lH-
te~azol 5-yl)~hiome~hyl-3-cephem-4-ca~boxylic
acid tsyn isomer)~ ~p lgO to 198C ~dec.~.
I.R. (Nujol) : 32509 3160, 1760) 1650,
1615, 1~22~ 1020 em~l
(27) 7-~2-Carboxymethoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido] -3- ~1,3 ,4-~hiadiazol-
2-yl)thiomethyl-3- cephem-4-carboxylic acid ~syn
isomer), mp 170 ~o 175C ~dec~
9~ :
I.R. (Nujol) : 3250~ 3150~ 1770, 1710,
1680, 1610, 15~0 cm 1
~28) 7-l2-Carboxymethoxyimino~ 5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-(1-allyl-lH-tetrazol-
5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer), mp 145 to 150~C ~dec~).
I.R. ~ujol~ : 3400, 3300~ 3?00, 176S,
. 17~0~ 16809 16~0, 1520 cm 1
~29) 7-~2-CarboxymethoxyiminD-2-(5-amino-1,2j4-
thiadiazol-3-yl)acetamido~cephalosporanic acid
(syn isomer), mp 160 ~o 165C (dec.).
I.R. (Nujol) : 3300, 3200, 17709 17203
. 1680, 1~20 cm~1 ~ ~
~30~ 7-[2-~2-Aminoethoxyimino~-2-(5-Pmino-1,294-
thiadiazol-3-yl)acetamido~-2-methyl-3-cephem-4-
carboxylic acid (syn isomer), mp 190 ~o 195~C
(dec,~,
I~R3 ~Nujol) : 3300~ 3150, 176Q, 1660,
lS759 1520, 1400 cm 1
~ 20 ~31~ 7- L2~ (3-Aminopropoxyimino)-2-(~-amino-1,234-
- ~ ~hiadiazol-3-yl~acetamido~-2-me~hyl-3-ceph~m-4-
~ carboxylic acid ~syn isomer), mp 182 ~o 187~C
~deG.) .
I.R. ~Nujol) : 32603 3150, 1758, 1660~
1616, 1575 3 1520, 1400 cm 1
; (32) 7-~2-Carboxymethoxyimino-2-~5-amino-lp2J4-
~hiadiazol -3-yl) ace~amido3 - 3 - (~e~razolo ~1, 5~
pyridazln-6-yl)thiomethyl-3-cephem-D.-carboxylic
acid (syn isomer)~ mp 170 ~o 17~C (dec,).
I~R. (Nujol) : 34009 3300, 3180, 1765,
1720 9 1680, 161~ 20 cm 1
~33~ 7 - ~2 - ~3-Aminopropoxyimillo) -2 - (5-amino-1 " 2 ,4-
~hiadiazol~3-yl~ace~amido]-3-m~thyl-3-cephem-4-
carbo~y~ic acid (syn isomer)g mp 175 ~o 195C
~dec.'~. .
~2
~5
I.R. (Nujol) : 3300-3100, 1770-1740~
166~, 1620, 1570, 15209 1280,
1110, ~ 60~ 1020 cm 1
(343 7~ 3-Aminopropoxyimino)-2-(5-amino-1,2,4
~hiadiazol-3-yl)ace~amidLo~-3-chloro-3-cephem-4-
carboxylic acid (syn isomel), mp 190 to 205C tdec.).
I.R. (Nujol3 : 340CI-3150, 1760, 1660,
.1~3CI-~59~ 20, 1340,
1170, 1030 cm
(35~ 7~ 2-Aminoethoxyimino)-2-(5-amino-1,2,4-
~iadiazol-3-yl~cetamido]-3-~1-(2-aminoethyl~-lH-
~etrazol-5-yl3*hiomethyl-3-cephem-4-ca~boxylic acld-
(syn isome~ mp 182 ~o 187C tdec.).
I.R. (Nujol) : 3350~ 3150, 1760, 1660,
16259 1565, 1520 cm~l
t36) 7-l2-Carboxymethoxyimino-2-t5-amino-1~2,4-
thiadiazol-3-yl~acetamido]-3-[1-t2-aminoethyl)-lH-
tet~azol-5-yl]~hiome~hyl-3-cep}1em-4-carboxylic acid
(syn isomer~ 3 mp 18S *o 190C ~dec.).
I.R. ~Nujol~ , 32509 1755, 1660, 1590s 1520 cm 1
~37) 7~[2-(2,29~-Trifluoroe~hoxyimino)-2-~5-amino-
1,2,4-thiadiazol-3-yl~ace~amidoJ 3~ 2-
aminoe~hyl)-lH-~trazol-5-yl]~hiomethyl-3-cephem-
4-carboxylic acid (~yn isomer), mp 185 ~o 190C
~5- (dec.).
I~R~ ~NU3O1) : 33Q0, 3170~ 17609 1670,
~615, 1500 cm~l
(38) 7-[2~Ca~boxymethoxyimino~ 5-amino-1,2~4-
thiadia~ol-3 yl~acetamidoJ-3~ phenyl-lH-tetTazol-
5-y~)~hiom~hyl-3-c~yhem-4-carboxylic acid (syn
isome~) 9 mp 155 ~o 160C (dec~).
I,.R. (~u3ol~ 3400, 3300, 3180, 1765, 1720,
16~ 615, 15Z05 1495 cm l
~39) 7-E2 Hydroxyimino-2-~5-~mino-1,2,4-thiadiazol-
3~ 3-yl3acetam do~-3-(5-methyl-1~3,4-~hiadiaæol-2 yl~-
o
thio~ethyl-3~cephem-4-caIboYylic acid ~syn isomer~,
mp 153 to 162C ~dec~)
I~R. (Nujol) : 3260, 3160~ 1763, 1665
16t)8, 1520 cm
~40) Pivalsyloxymethyl 7-[2-hydroxyimino-2-(5-
~mino-1,2~4-thiadiazol-3-yl)acetamido]-3-t5-methyl-
1,3,4-~hiadi~zol-2-yl)l:hiomethyl-3-cephem-4-
carboxyla~e ~syn isomer), mp 132 to 135C ~dec.).
~.R. ~Nu~ol) : 3270, 3160~ 1775; 1745,
1675, 1610~ 1520, 1115 cm~
xam~le 7
.
To a cold solution of phosphorus pentachloride
~2.5 g) in me~hylene chloride t60 ml) was added 2-~2-
oyclopenten-l-y'l~xyimino-2-t5-amino-1,294-thiadiazo~-
3-yl)acetic acid ~syn isomer)(~.54 g~ a~ -15C and the
mixture was sti~red for 45 minutes a~ *he same tem-.
peTa~ure. O~ the o~her hand9 a mixture of 7-amino-3-
(1,3,4-th;adiazol-2 yl)~hiomethyl 3-cephem-4-carboxylic
acid (4.0 g~ and trim~hylsilylace~amide ~12 g) in
methylene chloride (60 ml) was w rmed to make a clear
~501ution and ~hen cooled to -15C. The solution was
added to the above ac*i~a~ed mix~ure and the mixture
was stirred ~or 0~5 hou~ a~ ~ to -5C. The r~ac*ion
mix~ure was poured into cold aqueous solu~ion (150 ml)
of sodium bicarbonate ~7.1 g) and stirred at ambie~t
tempera~ure for 15 mi~utes~ The aqueous layer was
separa~ed out and added to ethyl ace~a~e. The mix~ure
was ad~us*ed to pH 3 with 10~ hydrochloTic acid and
then il~ered. The e~hyl ace~a~e layer was separa~ed
30 from the flltra~e~ was}led wi~h a saturated aqueous
solution of sodi~am chlorideg dried over magnesium
su~fate and evaporated to drynessO The residue was
triturated with diethyl etheT a~d precipitates were
collected by filt~ation and then dried to gi~e a c~ude
product ~1. 8 g) ~ This produc~ was dîssolved in aTl
~7
aqueous solu~ion of sodiu~ bicarbona~e and the
solu~ion was adjusted to pH 3 with 10~ hydrochloric
acidO Precipi~a~es were collec~ed by fil~ration,
washed wi~h water and then dTied to give 7-~2-(2-
cyclopenten-1-yl)oxyimino-2-~5 ~mino-1,~,4-thiadiazol-
3-yl~acetamido~-3 ~1,3,4-thiadiazol-2-yl~thiomethyl-3-
cephem-4-carboxylic acid (syn isomer)~l~4 g~g mp 155
~o 1~0C.
I.R. ~Nujol) : 3300~ 3200, 1770, 1670, 1620,
15~0 ~In 1
N,M~R. (d~-DMSO,~) : 2.0-2.50 (4H~ m~ 3.70 t2Hy
broad s), 4.30 and 4.57 (2H; ABq, ~=13Hz),
5.13 (lH, d9 J=4Hz), 5.27-5.43 (lH~ m~,
5.80 (lH, dd, J=4 and 8Hz)g 5.83-6.20
(2H3 m), 8.08 (~H3 s), 9.45 (lH, d,J=8Hz)~
9.50 ~lH, s)O
To a cold solution of phosphorus pentachloride
: ~2~ g) in methylene chloride ~60 ml) was added 2-(2-
cyclopen~en-1-yl~oxyimino-2-(5-amino-1,2,4-~hiadiazol-
~ 3-yl)aceti a~ id :~syn. i,somer3 (2D54 g) ~t -15C and
*he mix~ure was stirred for 30 minutes at the same
tempera~ure~ On ~he other hand~ a mixtu~e o 7-amino-
- 3-cephem-4-caTboxylic acid ~2.2 g) and trimehylsilyl-
ac~tamide tll g) in me~hyle~e chloride (60 ml) ~as
warmed to make a clear ~olution and ~hen cooled ~o
-l5~C. To ~he solution was added ~he above activated
mixture and the mix~ure was s~irred or 20 minu~es
at 5C. The reac~ion mixture was poured in~o cold
a~ueous solution (150 ml) of sodium bica~bonate ~7 g~
~d s~irred a~ ambien~ ~emperature fOT an hour.
The aqueous layer was sepa~ated out and added ~o
ethyl zcetate. The mix~ure was adjus~ed ~o pH 3 wi~h
10% hyd~ochloric acid and ex~rac~ed wi~h e~hyl ace~a~e.
~he extloact was washed with a saturated aqueous
28~0.
solution of sodium chloTide, dried over magnesium
sulfate and e~aporated to dIyness. Precipitated
crystals were collected ~y filt~a~ion~ washed succes-
sively with ethyl ace~ate and diethyl ethe~ to give a
crude product ~1.5 g~. This product was dissol~ed in
an aqueous solution of sodium bicarbona~e and the pH
was adjusted to 2 with dil. hydrochloric acid.
Precipitates were coll~c~ed by ~ Ta~ion, washed with
wa~e~ and *hen dried. The obtained product (1.2 g)
was dissolved in aqueous ace~ons 3 treated wi~h ac~i-
vated charcoal and then eraporated. The precipit~tes
were coll~cted by filtTa~ion~ washed with water and
dried to gi~e 7-[2-~2-cyclopenten-1-yl~oxyimino-2-(5-
amino-1,2,4-thiadiazol-3-yl)acetamido~-3-cephem-4-
carboxylic acid ~syn isomer)~0.93 g)~ mp 180 to 185C
tdec. ) .
I.R. (Nujol) : 3500, 3430~ 3300, 3200, 17~0-j 1690,
1660~ 1640, 1620r 158~ 1510 ~m 1
N~MoR~ (d6-DMSO7~ 87-2~50 ~4H~ m), 3.60 (2H,
~0 broad s), 5.07 (lH9 d~ J=8Hz3, 5.27-5.50
~ ~lH~ m), 5.80 (lH, dd, J~4 and 8Hz3,
5.~7-6.23 ~2~; m~, 6.47 (lH~ b~oad s~,
8.10 ~2H, s), 9.47 ~lH, d, J=8Hz)
To a cold so7utio~ of phosphsrus pen~achloride
~1.25 g3 in methyle~e chloride t30 ml) wa~ added 2-(2-
cyclohexen-~-yl)oxyimino-2-~5-amino-1,2,4-~hiadia~ol-
3~yl)acetic acid (syn isomer)(1.34 g~ at -15C and
~he mixture was stirred for 30 minu~es at ~he same
~emperature. On the other hand, a mixture of 7-amino-
3~ 334-~hiadiazol-2-yl~hiomethyl-3-cephem-4-
carboxylic acid ~1.98 g3 and trimethylsilylace~amide
~6 g) in me~hylene chloride ~30 ml) was warmed to
make a clear solu~ion and ~hen cooled ~o -15C. Th~
solutio~ was added to the abo~e ac~ivated mixture and
~he mix~u~e ~as stirred fo~ 0.5 hour at O ~o 5C.
The Teac~ion mixture was poured into cold aqueous
solution tlOO ml) of sodium bicarbon~te (4.03 g) and
stirred at ambient temp~rature for 30 minutes. The
aqueous layer was separated, adQed to ethyl acetate,
adjustea to pH 4 with 10% hydrochloric acid and
extracted with ethyl acetate. The extract was dried
ove~ magnesium sulfate and evaporated to dryness.
Th~ ~esidue was ~riturat~ed with diethyl ether, col-
lected by filtration ~nd dried to gi~e a crudeproduct (400 mg). This product was dissolved in an
aqueous solution of sodium bicarbona~e a~d the pH was
adjusted ~o 2 with hydrochloric acid. Precipitatec
were collected by iltration, washed with water and
~hen dTied to give 7- [?- ~2-cyclohexen-1-yl)oxyimino-
2-(5-amino-1,294-thiadiazol-3-yl)ace~amido]-3-tl,394-
thiadiazol-2-yl )thiomethyl-3-cephem-4-ca~boxylic acid
(syn isomer~ (250 mg) . mp 150 to 1~5C (dec.) ~
I.R. ~Nujol): 3300, 318Q~ 1770, 166û9 $620,
1~20 cm~l
.M.R. (d~-DMSO,~ 2~17 (6Ha m3,
370 t2~I9 broad s~ " 4033 and 4.'j8
t2H9 ABq, J=14Hz), 4 . 67-4. B3 tlH, m),
5 .17 ~lH, d, J=4Hæ), 5. 83 (lH, dd, J-4
and 8Hz) 5.60-6~12 ~2H, m), 8.1S ~2H, s)
9 . 53 ~lH, d~ J=8Hz~, 9. 93 ~lH, s)
To a cold solution of phosphorus pentachloride
tl~ 50 g) in methylene chloride (30 ml) was ~dded 2- (2-
30 cyclohexen-l-yl) oxyimino- 2 - ~5 -amino-l, 2, 4 -thia~iazol-
3-y~)ace~ . acid ~syn isomer) ~1.61 g~ at -15C.
The mixture was s~irred ~or 30 minutes at -13 to
-10C and evaporated and ~hen ~o the residue was
added tetrzhydrofuran ~20 ml)~ On ~he other hand,
3~ a mixture o 7-amino-3-~etrazolo~l~S-b~pyridazin-
3~ ~L 8~ L~
6-yl~hiome~hyl-3-cephem-4-ca~boxylio acid (2.86 g~,
sodium bicarbona~e ~2.52 g), ~a~e~ ~80 ml) and
ace~one ~45 ml) was cooled to 5 ~o 10C. To the
solution was added the abo~e activated mixture,
The mixture was stirred for 20 mi~utes at 5 to 10C,
allowed to warm to room ~emperature and then evapo-
rated. To ~he residue W2S added ethyl aceta~e and
~he mixture was adjus~ed to pH 2 wi~h 10~ hyd~ochloric
acid and ~hen extracted with ethyl aceta~e. The
extrac~ was treated with ac~ivated cha~coal (D.S g)~
dried over magnesium sulfate and then e~aporated.
The Tesidue was ~riturated with die~hyl ether, csl-
lected by filtratio~ to gi~e a crude product (2.37 g).
This produc~ was dissolved in an aqueous solution of. 15 sodium bicarbonate and the pH was adjus$ed to 2 with
hydrochloric acid. Precipitates were collected by
-filtr~tion ~o give 7-~2-~2-cycloh~xen-l-yl30xyimino-
2-(5-amino-L,2,4-~hiadiazol-3-yl)acetamido]-3-
~et~azolo~1,5-b~pyridazin-~-yl)~hiom~thyl-3-cephem-
~0 4-carboxylic acid (syn isomeT)~2.28 g). mp 170 to
175C tdec,).
I.R. ~Nu~ol) : 3400, 33009 3180, 16~0, 1620,
1520 cm 1 .
~oM~R~ ~d6-DMSOy~ 40-2~20 (6H, m) a
. 3.73 (2H, b~oad s)~ 4.27 and 4.65
(2H9 ~Bq, J=13Hz~, 4,6S-4.88 ~lH, m~,
5.18 (lH, d3 J=5Hz), 5.80 ~lH, dd, J=5
and 8Hz) 9 5.78-~.0~ (2H9 m~, 7.~0 ~lH, dg
J~lOHz), 8.17 (2H, broad s), 8.60 (lH, d,
J=lOH~3~ 9.5S (lH, d, J=8Hz)
~_Ll
To a cold solution o phosphorus pentachloride
~1.5 g~ in methylelole chloTide ~30 ml) was added 2-
cyclopentyloxyimino~2-~5-amino- 1 9 2~4thiadia~ol-3-
yl~ace~ic acid ~syn isome~)~1.37 g) a~ -15C and . . .
the mixture was stirred for 30 minu~es a~ -13 t9
-10C. On the other hand, a mixturP of 7-amino-3-
(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (2~18 g) and ~rimethylsilylace~amide
(6 g) in methylene chloricle (30 ml) was warmed to
make a clear solution and then cooled to -20~C.
The solu~ion was added to the above activa~ed mixture
and the mixture was s~irred for 0.5 hour at -10C.
The reactio~ mix~ure w~s poured in~o a cold saturated
aqueous solutio~ (60 ml) of sodium bicarbona~e and
stirred at ambient temperature for 30 minu~es. The
aqueous layeI was separated out, added ~o ethyl .
ace~at ~ adjus~ed ~o pH 2 to 3 wi~h 10% hydTochlQric
~cid ~nd extracted wi~h ethyl ace~ate. Th~ ext~ac.t
15 was dried over magnesium sulfate and e~porated ~o
-- d~yness. The residue ~as washed with diethyl to~her- :
- to give a crude produc~ (2.62 g3. This product was
dissolved in an aqueol7s solu~ion o:E sodium bicarbonate
a~d the pH was adjusted ~co 2 with hydrochloric acid.
20 P~ecipitates were collected by filtration to give
7 - ~2 - cyclopentylsxyimiIlo - 2 - ~5 - amino- 1, 2, 4- thiadiazol -
3-yl)acetamido]-3-(1~3~4-thiadiazol-2-yl)~hiome~hyl-
3-cephem-4 carboxylic acid (syn is~mer)(2.22 g~. mp
14 0 to 14 5 J C (dec.).
I.R. (Nujoï): 3400, 3300, 3200, 1770, 1670,
1620; 1S2~
N~ Ro (d~,-DMS0,~) : 1.33-2.10 (8~1, m),
3 . 72 ~2Ht broad s), 4. 33 and 4. 58
(2H~ A~q, J=13Hz~, 4~ 60-4. 90 (lH, m),
5.17 (l~H9 d7 J=5Hz), 5. 82 (lH~ dd,
J~5 and 8Hz), 8.15 (2H, s)~ 9.52 ~lH,
dD J=8Hz) a 9.58 ~lH~ s)
12
To a cold solution of phosphorus pentachloride
35 (1.~5 g) in methylene chloride ~25 ml3 was addPd
~32
2-cyclopentyloxyimino-2-~5-amino-1,2 9 4 thiadiazol-
3-yl)acetic acid (syn isomer)~l.2R g3 at -15C and
the mixture was stir~ed for 30 minu~es a~ -13 to
-lO~C. O~ the other hand, a mixture of 7-amino-3-
cephem-4-carboxylic acid ~1.1 g), and ~rimethylsilyl-
acetamide (5.5 g) in methylene chloride (25 ml~ was
warmed to make a clear solution and ~hen cooled to
-15C. The solutîon was added to ~he above ac~ivated
mixture and the mixture was stirred fo~ 0.5 houI at
-10C. The reac~i~n mixture was poured into a
saturated aqueous solution ~55 ml) of sodium
bicarbonate and stirred at ambient ~empe~ture foT 30
minutes and ~hen evapora~ed to remove methylene --
~ chloride. The residue was washed with ethyl ~ceta~e
and to ~he aqueous layer was added ethyl ace~ate.
- The mixtur~ was adjusted to pH 3 with 10% hydrochloris
acid a~d ex~racted with e~hyl ace~e. The extract
was dried o~e~ magnesium sulfate, t~ated with
activat~d charcoal (1.0 g) and ~hen evapora~ed. The
residue was washed with diethyl e~her ~o give a cTude
produc~ ~1.03 g). This pToduc~ was dissolYed in an
aqu~ous solution of sodium bicarboIlate and the~ol~t~on
was adjusted ~o pH 3 wi~h 10% hydrochloric acid.
Precipita~es were collec~ed ~y fil~ration ~u give
25 7-[2-cyclopentyloxyimino-~-(5-amino-1,2 9 4-thiadiazol-
3-yl)ace~a~idoJ-3-cephem-4-carboxylic acid ~syn
isomer~B60 mg). mp 170 ~o 175C.
I.R. ~Nuiol) : 3520, 34209 33209 3220, 3160, 17709
16859 1~559 1635~ 16259 1570,
1505 cm 1
N~M.R. ~d6-DMSO,~) : 1.33-2.07 (8H, m3, 3.43-3.77
~2H, m3, 4.63-4.93 (lH~ m) 3 5.15 (lH~ d,
3=~Hz), 5,90 (lH~ dd, ~-5 and 8Hz3~
6.43-6.67 ~lH, m), ~.23 (2H9 broad s) 3
9.63 (lH, d3 J=8Hz)
:L~3
ExamPle 13
~.
The following compounds were obtained according
to similar manners to tho~e of Examples 1 to 3, ~ and
7 ~ 12.
(1) 7-[2-(2-Cyclopenten-l-yl)oxyimino-Z-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido]cephalosporanic acid
(syn isomer). mp 154 to 159C ~dec.).
I.R. (Nujol) 3300, 1770~ 1720~ 1670, 16209
1520 c~ 1
N.M.R. td6-DMS0,~) : 2.0 ~3H, s), 2.0-2.40
~4H~ m), 3.5~ (2H, broad s), 4.70 and
- 4.~7 (2~, ABq, Jal4Hz), 5.~ (lH, d,
- . - Jo4Hz~, 5.27-5.40 ~lH, m)~ 5.82 ~lH, dd,
J-4 and 8Hz), 5.83-6.17 ~2H, m?;
1~ 8.13 (2H9 s~, 9.50 (lH, d~ J=8Hz)
(2) 7-~2-(2~Cyclopenten-l-yl)oxyimino-2-(5-amino-
1,2~4-~hiadiazol-3-yl~acPtamidoj-3-~1-methyl-lH- -
te~razol-~-yl~thiomethyl-3-cephem-4-carboxylic acid
~syn isomer). mp 155 to 160C ~dec~).
I.R. (Nujol) : 3300, 1770, 1670, 16207 1520 cm 1
N.M.R. (d6-DMS0,~) . 1.90-2~30 ~4H, m), 3.62
~2H, bToad s), 3.88 ~3H~ s), 4.25 ~2H7
broad s), 5.07 (lH~ d, J~4Hz)~ 5.20-5.40
(lH, m), ~.80 ~lH9 dd, J=4 and 8H~),
5.83-6.17 ~2H, m), 8.08 ~2H, s), 9.47
~lH, d~ Js8Hz)
~3) 7-~2-~2-Cyclspen*e~ yl)oxyimino-2-~5-ami~o-
1~2,4-thiadiazol-3-yl)ace*amido]-3-(1-carboxymethyl-
lH-te~razol-5-yl)~hiomethyl-3-cephem-4-carboxylic
acid (syn isomer). mp 155 ~o 160C ~dec.~.
I.R~ (Nujol~ : 3300~ 3200, 1770, 1720, 1670
1620~ 15Z0 cm~l
N.M.R. (d~-DMS0~ 1.83-2.50 (4H3 m~ 3067
(2H, broad s), 4.27 and 4.48 (2H, A~q,
J-14H~), 5.17 (lH~ d, J-4Hz~,
5,30 (2H, s), 5,27-5.50 (lH, m),
5 . 82 ~2H, dd, J=4 ~nd SHz), 5 . 83-6. 20
(2H, m), 8.17 ~2H, s), 9.50 (lH, d,
J-8Hz)
5(4) 7- [2- ~2-Cyclopenten-:l-yl)oxyimino-2- (5-amino-
1,2,4-thiadiazol-3-yl)acetamîdo]-3-[1-(2-carboxyethyl)-
lH-te~razol-5-yl~thiom~t:hyl-3-cephem-4-ca~boxylic
acid ~syn isomer~. mp 150 to 155~C (dec.).
I.R. (Nujol) : 33007 3200, 1770, 1720, 16709
13 16209 1520 cm~l
N~M.R. ~d6-DMS0,~) : 1.30-2.50 ~4H~ m), 2.97
(2H, tj J=6Hz), 3.73 (2H, broad s),
4.30 ~nd 4.50 ~2H~ ABq9 J=14Hz~
- - 4.~2 (~H, t, J=6Hz), 5.20 tlH, d, J=~Hz),
5.30-5.57 (lH, m), 5.90 ~lH, dd, J=4 and
Hz), 5~93-6.33 (2H, m), 8.33 ~2H, s),
9~77 (lH., d, J=8Hz)
~5) 7- ~2- (2-Cyclopenten-l-yl)oxyimino-2- (5-amino-
1j294-thiadiazol-3-yl)acetamido~-3-~l-allyl-lH-
tetrazoi-$-yl)thîomethyl-3-cephem-4-carboxylic acid
(syn isomer). mp 160 to ~65C tdec.).
I.R. (Nujol) : 3300, 1770, 1670~ 162o~ 15~0 cm 1
N~MoR~ td~-DMSOj~) : 1.93-2.33 ~4H~ m), 3.60
- ~2H, b~oad s), 4.22 and 4.37 (2H, ABq,
~=13Hz), 4.83-~.0 (2H, m), 5.0-5.40 ~4H,
m), 5.60-6.17 ~4H3 m), 8007 ~2H, s)~
. 9.47 ~lH, d, Jc~Hz~
(~) 7- ~2- ~Z-Cyclopenten-l-yl)oxyimillo-2- (5-amino-
li2~4-thiadiazol-3-yl)acetamido-3- ~etra~010~195-
b~py~ida~in-6-yl)~hiome~hyl-3-cephem-4-carboxylic .
acid (syn isomer). mp 170 to 175C (dec.).
I.R. (Nujol) : 3400~ 3300~ 3190~ 1770, 1670,
161~, 1520 c~~~
N.M.R. ~d6-DMS09~ 1.90-2.43 (4H~ m~, 3.68
(2H, b~oad s) 3 4.2~ and 4.58 (2H9 ABq,
~5
Jal3Hz~, 5.10 (lH, d, J-5Hz) 9 5~20-5.47
~lH, m)~ 5.78 (lH, dd, J=5 and 8Hz),
5.80-6.20 ~2H9 m), 7.75 (lH~ d, J=lOHz),
. 8.13 ~2H, broad s), 8.55 (lH, d, J=~OHz3,
9.52 ~lH, d, J=8H~)
(7) 7-~2-(Z-Cyclopenten-l-yl)oxyimino-2-~S-amino-
1~2!4-thiadiazol-3-yl)acetamido~-3-[l {2-(N-t-
~t oxycarbonylamino)ethyl}lH-tetrazol-S-yl]-
........... .... ..th~methyl-3-cephem-4-carboxylic acid (syn isomer).
~p 95 to lOO~C (dec.).
~ I.R. (Nujol~ : 33ao9 3190, l770~ 1680g 1620,
1520 cm~~
~ N.M,R. (d6-DMSO,~) : 1.40 t9H, s)~ 2.07-2.50
(4H, m)~ 3.30-3.57 (2H, m)~ 3.67-3.87
lS ~2H9 m), 4.27-4.57 (4H, m), 5.17 (lH,
d, J=SHz), 5.23-5~57 ~lH, m)g 5.70-
6,30 (3H, m) 7 8.17 (2H9 b~oad s) f
9.53 ~lH, d, J=8Hz)
(8) 7-L2-.~2-Cyclohexen-l-yl)oxyimino-2-(5-amlno-
1J2~4-~hiadiazol-3-yl)acetamido] 3-cephem-4-
- carboxylic acid (syn.isomer), mp 175 ~o 180C (dec.).
I.R~ tNujol) : 3300, 3200, 1770, 1670, 16309
1520 cm 1
N~M.R. ~d6-DMSO,~) : 1.50-2.13 ~6H, m),
3063 t2~, broad s~ 3 4 . 60-4~83 (lH, m~
5.12 (lH~ d, J=4H~), 5.77-6.0 ~3H, m) 3
6.50 (lH9 t~ 3=3Hz39 8.15 (2H, s),
9.~S ~lH, d3 J-8Hz)
(9) 7-[2-~2-Cyclohexen-l-yl~oxyimino-~-(5-amino-
~0 192,4-thiadiazol-3-yl)acetamido]cephalosporanic
~cid ~sy~ isomer). mp 160 to 165C (dec.),
I~R. ~Nujol) : 33009 3200~ 1775~ 17209 1670
16?0, 1520 cm l
N.M.R~ ~d6-~MSO,~) : 1.50-~.10 (6H, m) 3
2.07 (3H, s), 3.60 (2H, broad s),
~2~
4.67-4.83 (lH, m) 9 4.77 ~nd 5.03
(2H~ ABq, J~14Hz~, 5,17 (lH, d, J=4Hz),
5.77-6.10 ~3H, m) 3 8.17 (2H, s), 9.60
. (lH, d~ J-8Hz)
(10) 7-[2-~-Cyclohexen-l-yl)oxyimino-2-(5-amino-
i 1,~,4-thiadia701-3-yl~ce~amido]-3-~l-methyl-lH-
tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer~. mp 170 to 173~C (dec.).
I.R. ~Nujol) : 33!;0, 3250~ 178~, 1680, 1620,
lD 1520 cm 1
N.M.R. ~d6-DMS0,~) : 1.50-~.17 (6H, m),
- 3.16 (2H, broad s), 3.93 ~3H, s~ 3
4.30 (2H~ broad s3, 4.55-4.80 ~lH, m),
- S~10 (lH, d, J=4H2), 5.80 (lH, dd,
~: 15 J~4 and 8Hz), 5.80-S.93 (2H, m) 9
8.08 (2H~ s), 9.5D ~lH~ d, J=8Hz)
(11) 7- ~2- (Z-Cyclohexen-l-yl)oxyimino-2- (5-amino-
- 1,2,4-thiadiazol-3-yl)acetamido3-3-(1-
carbox~methyl lH-tet~azol-5-yl)~hiomethyl-3- - - -
cephem-4-carboxylic acid ~syn isomer3~ mp 17~0 ~o
175C (dec.~. .
I.R, ~Nujol~ : 3300, 32009 177G, 1720, 16509
1~20, 15~0 Gm 1
.
N,M.R~ ~d6-DMS09~) : 1.50-2.27 (6H, m~,
3.75 (2H9 b~oad s) 9 4030 and 4.55
~ ~2H, ABq, J~14Hz3, 4,67-4.83 (lH, m)S
z 5.17 ~lH, d~ J-4H~)~ S.37 ~2H, s)~
6.17-5.77 (3H9 m~, 8~18 (2H, s),
9.57 (lH, d~ J-8Hz~
: ~ . 30 ~12) 7-[2-(2-Cyclohexen-l-yl)oxyimino-2~5-amino-
1,2,4-thiadia~ol-3-yl)acetamido] ~3- ~ 2-
carboxyethyl)-lH-tetT~zol-S-yl]thiomethyl-3-cephem-
4-carboxrlic acid ~syn isomer). mp 165 to 170C.
I.R. tNuJol~ : 3300, 320~ 1770~ 1720, 1670
l~Z0~ 1520 cm 1
N.M~R. (d6 DMSO,~ .50~ 7 (6H7 m),
3,77 ~2H, b~Oad S)g 4.37 and 4.50
~ZH, ABq, ~=14HZ), 4.53 (2H, t7 J=6HZ),
4.67-4.93 ~1H, m) 7 5.23 ~1H~ d) J=4HZ3,
5~93 (1H, dd, J=4 and 8HZ)~ 5.97-6.17
(2H, m)~ 8.70 (~, S~, 9~80 (1H, d,
J=8HZ)
~13) 7-~2-~2-CYC1OheXen-1-Y1)OXYiminO-2-~5-aminO-
1,294-thiadiaZO1-3-Y1)aCetamidO3-3-(1-a11Y1-1H-
tetTaZO1-5-Y1)thiOmethY1-3-CePhem-4-Ca~bOXY1iC aCid
(SYn iSOme~). mP 160 ~O 165C ~deC.).
NU~Q1) : 330~, 3200, 1780, 1680, 1620
L~;20 cm~1
N.M.R. (d~-DMSO,~ : 1.50-2.16 (6H, m),
3 ~ 66 (2H, broad s~, 4 . 25 and 4 . 43
(2H, ABq, J-14Hz), 4, 55-4. 80 ~lH, m~,
4.93-5.0 (2sl3 m) 9 5.10 (lH, d, J=4Hz), . - - .
5.20-5.37 (ZH9 m), 5.67-6~20 (4H" m~,
8 . 08 (2H, s) 9 9 . 50 (lH, d, J=8H~)
(14) 7-~2-~2-Cyclohexen-l-yl)oxyimino-2-~5-amiIIo-
1,294 ~hiadiazol-3-yl)acetamido~-3-~1-{3-(N-~-
butoxycarbonylamino)propyl}-lH-te*razol-5-yl3-
thiomethyl-3-cephem-4-carboxylic acid (syn isome~
mp 100 to lO~C (dec.).
2~ I.R~ ~Nujol) : 3300, 3170, 1770, 1670, 16209
'1520 cm 1
N.M~R.(d6-DMS0~ 1.37 (9H3 s)9 1.50-2.~0
~8H, m); 2~2 (2H~ t~ 3=6Hz) 9 3.68 (2H~
broad s), 4.07-4.47 ~4H, m~, 4.53-4,83
~lH9 m),~5.10 (lH~ d, J=5Hz) J ~.80 ~lH.,
dd, J=S and 8Hz~ 5.70-5.93 ~2H, m~,
B.10 ~2H, broad s~, 9.47 (lH~ d~ J=8Hz)
(15) 7-~2-Cyclopentyloxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)ac~amido~cephalosporanic acid
~syn isome~), mp 140 ~o 145~C (dec.),
o ~
~o~ ~
I . R. (Nuj ol): 3480 , 3370 , 3250 , 1785 ,
1~309 1680, 1630, 1530 cm 1
N.M.R. (d6-DMSO, ~ 3-2 .17 (8H, m),
2. 03 (3H, s), 3. 57 (2H, broad s~,
4.60-4.90 ~lH, m), 4.73 and 4.97 (2H,
AB~D J=13Hz), 5.1S tlH~ d; J=5Hz),
5. 80 (lH, dd, J=5 and 8Hz), 8 .10 (2H,
broad s), 9.47 ~lH, d, J=8Hz)
(16) 7- ~2-Cycl~pentyloxyimino-2- ~5-amino-192~4-
.' 10 ~hiadiazol-3-yl)ace$amido]-3-~l~methyl-lH-~etrazol
5-yl)thiomethyl-3-cep.hem-4-carboxylic acid (syn
isom~r3. mp 14S to 150C ~d~c.),
'- I.R~ (Nujol~ : 3400,3290~ 3180~ 1770, 1670,
1620, 1520 cm~l
N.M.R. ~d6-DMSO,~) : 1.33-2.07 t8H, m),
3.70 ~2H, b~oad s), 3.93 (3H, s),
: 4.32 (2H, broad s)~ 4.10-4.90 ~lH~ m) J
5~12 (lH, d, J=5Hz)g 5.78 (lH~ dd,
J=~ ~nd 8Hz) 9 8~10 ~2H, broad s),
9.47 ~lH, dJ J-8Hz~ .
(17) 7-~2-Cyclopentyloxyimino-2-(5-amino-1,2,4-
thiadiazsl-3-yl)acetamido~-3~(1-carboxymethyl-
lH-tetrazol-5-yl~t:hioDlsthrl-3-cephem-4-
carboxylic acid ~syn isomer)~ mp 15~-160C tdec.).
I.R. (Nujol) : 3400, 3290, 3180, 1765, 1720,
1670, 16~0~ 152~
~d6 DMSO,~ : 1O27-2O07 ~8H m)
3.70 ~2H~ broad s~, 4.28 a~d 4O53
~2H, ABq~ J-13Hz~, 4.70-4.93 ~lH~ m)~
5.17 (lH, d, JsSH~), 5.33 (2H, s),
5.85 (lH, dd, 3~5 and 8Hz), 8.23 (2H,
broad s~, 9. 60 ~lH~ d~ 3=8Hzj
(18) 7-l2-Cyolopen~cyloxyimino-2~ amino-1,2,4-
~hiadiazol ~-yl~ace~amido]-3-~1-allyl-lH-tetrazol-
35 5-yl)~hiomethyl--3-cephem-4-carboxylic ~cid ~syn
2~
isomer). mp 135 to 140~C ~dec.~.
I.R. (Nujol) : 3400, 3300; 3190, 1770, 1670,
16~0, 1520 cm 1
N.M.R. (d~-DMSO,~) : 1.30-2.10 ~8H, m), 3.73
j ~2H, broad s), 4.3~ and 4.5Q ~2H~ ABq,
J=13Hz), 4.60-4.30 (lH, m), 4.83-5.17
~2H, m)~ ~.17 ~lH, d, J=5Hz), 5.17-5.50
~2H, m~ 5.87 (lH, dda J~5 and 8Hz),
5.67-6.33 (lH, m)~ 8.20 ~2H, broad s)~
9.60 ~lH, d, J-8H~)
(19) 7-~2-Cyclopentyloxyimino-2-~5-amino-1,~,4-
thiadiazol-3-y~)acetamido~-3-(te~razQlo~1,5-b~-
pyridazin-6-yl)thiome~hyl-3-cephem-4-carboxylic
acid (syn isome~). mp 160 to 16$C [dec.)~
Ro ~Nujol) : 3570~ 3440, 3320, 3180, 17757
1710 9 1660 ~ 1620 ~ 1580 ~ 1540
1520 c m~l
N.M.R. (d6-DMSO,~) : 1.40-2.03 (8H, m),
3.78 (2H, broad s~, 4.27 and 4.65
~2H, ABq, J=13H~, 4.67-4.93 ~lH, m)~
5=20 (lH3 d~ J-5Hz)~ 5=87 (lH, dd,
3=5 and 8Hz3, 7.78 ~lH, d, J-lOHz~,
8015 (2H, broad s)~ 8.58 (lH, d~ J=lOHz),
9.53 (lH3 d, J=8Hz)
(203 7-[2-Cyclopentyloxyimino-2-(5-amino-1,2 J 4-
~hiadiazol-3-yl)acetamido~-3-[1-~2-methoxyca~bonyl-
ethyl~-lH-~e~razol-S-yl~thiomethyl-3-cephem-4-
carbo~yLic acid ~syn isomer). mp 125 ~o 130~C (dec.).
I.R. (Nujol3 : 3480; 3370, 32509 1780, 1740,
16~5~ 1625, 1530 cm
N.M.R. ~d6-DMSO~ ~ : 1.30-2=07 C8H, m),
2.80-3.20 (2H~ m~ 9 3.58 (3H, s)~
3.67 ~2H~ b~o~d s), 4.20-4.70 (4H, m),
4.60-4.90 (lH, m), 5.1~ (lH, d, J-5Hz),
5.78 (lH, dd7 J-5 and 8H~ 9 8.07 ~2H,
8~
broad s), 9.43 (lH, d, J=8H7)
(21) 7-L2-Cyclopen*yloxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl~acetamido3-3-~4-methyl-5-oxo-6-
hydroxy-4,5-dihydro-1J2,4-tria7in-3-yl)-
thiome~hyl - 3 - c eph em- 4 - carb oxyl i c ac id ( syn
isomer). pale yellow powder. mp 195 to 199C
tdec . 3 .
IoR~ (Nujol): 33009 32û0, 1770, 1710-1670,
1590~ 15~!09 1240~ 1170~ 10909
l 000 ~ 720 cm~l
~22) 7-[2-Cy~lohep~yloxyimino-2-(5-ami~o-1,2,4-
thiadia~ol-3-yl~acetamido~-3-~1?3,4~hiadiazol-
2 -yl~ ~hiome~hyl - 3 - cephem- 4 - carboxyl ic ac id ~ 5yn - - -
isome~ . white powder. mp 150 to 154C (dec, ) .
I.R~ ~Nujol~ : 3300, 3200? 17709 1670, 1620,
1520~ 1400, 1240, 1160, 106~ 9
1000 cm~l
, N.M.R. ~d~-DMS3,~) : 1.50 (8H, m), 1.82
^~ (4H, m3, 3.54 and 3.76 ~2H, ABq~
J~20Hz), 4.32 (lH, m), 4.24 and 4.60
(2H, ABq, J=14Hz) 7 5.10 ~lH~ d, J-SHz)~
~ S.74 ~lH? dd~ J=5 and 8Hz~) 8.02 ~2Xg
m), 9.48 ~lH, s), ~.~8 ~ d, ~8Hz~
~23) 7-[2^Cyclohep~ylo~yimino-2-(5 amino-1,2,4-
~5 ~hiadiazol-3-yl)acetamidoJ-3-cephem-4 carboxylic
acid tsyn isomer). white p~wde~. mp 170 to 175~C
(d~c.).
I.R. (Nujol) : 3400, 3300~ 32Q0, 1770, 1670,
16~0 9 15Z0, 1280 ? 1240, 1160,
la~0~ g30~ 730 cm 1
N.M.R. (d6-DMSO~ 1.50 (8H, m), 1.85 (4H~
- m~g 3.60 ~2H~ m~, 4.0-4.50 ~lH, m),
5.13 tlH~ d, ~-5Hz)~ 5.87 (lH, dd~
: J-S and 8Hz), 6.50 (lH, m), 8,13
; 35 (2H, m3~ 9.37 (lH~ d3 J-8Hz)
~24) N-[7-{2-Cyclopentyloxyimino-2-~5-amino-1,2,4-
thiadia7ol 3-yl)acetamido}-3-cephem-3-ylmethyl]-
4-carbamoylpyridinium-4-carboxylate (syn isomer).
mp 230 to 235C ~dec.).
I.R, (Nujol) : 3300, 3200~ 1770) 1680, 1610,
1560, lS~0~ 1510 cm~l
(2S) 7-~2-Cyclopentyloxyimino-2-(5-amino-1,2,4-
thiadiaæol-3-rl~acetamidoj-3 [1-{3-(N-~-
butoxycarbonylamino)p~opyl}-lH-tetrazol-5-yl3-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer~.
pale ~ruwn powder.
I.R. (Nujol) : 3300y 1770, 1670; 1520, 1240,
iOa 100() ~m 1
- ~26) 7 ~2~ yc~opentyloxyimino-2-(5-amino-192y4-` -~
thiadiazol 3-yl)acetamido~-3~ 2 3 4-thiadia~ol-
5-yl)thiomethyl-3- ceph~m- 4-- carboxylic acid ~syn
isomer~. mp 175 ~o 178C (dec.).
I.R~ (Nujol~ : 3300~ 3200, 177~, 1680
. 1620, 1525 cm 1
~27~ 7-~2-Cyclopen~yloxyimino-2-~5~amino~1,2,4-
~hiadiazol-3-yl~acetam~do~-3-[1-(3-morpholinopropyl)-
tetrazol-5-yl]~hlomethyl~3-cephem-4-ca~boxylic
acid ~syn isomer3~ mp 183 to 188C (dec.).
I.R. (Nujol) 3300~150, 1770/ 1670, 1610,
~5 1530 cm~l
~2B) 7-l2-~2-Cyclopenten-l-yl)oxyimino-2-(5-amino-
,4-thiadiazol-3~yl3acetamido~-3-~ 2-
~minoethyl)-lH-tetrazol-5 yl~thiomethyl-3-c~phem-
4-ca~boxylic acid (syn isomer), mp 175 to 180C
3Q (dec~).
I.R. (Nujol3 : 340Q9 3300~ 3170y 1760,
1665 9 1610, 1~20 cm 1
(~9~ 7-[2-Cyclopentyloxyimino-2-~5-amino 1,2,4-
thiadiazol-3-yl)acetamido~-3-~ 3-aminopropyl)-
lH-~e~razol-5 yl]thiomethyl-3-cep}l~m-4-ca~boxylic
f~
acid (syn isomer). white powde~. mp 195 to l99~C
(dec.).
I.R. (Nujol) : 3300, 3150~ 1760, 1660,
1620, 1520, 1280, 1180, 1000 cm 1
(30) 7-~-(2-Cyclohexen-l-yl)oxyimino-2-(5-amino-
192,4-thiadiazol-3-yl)acetamido~-3-~ aminopropyl)-
lH-tetra~ol-S-yl]~hiomethyl-3-cephem-4-carboxylic
acid ~syn isomer). mp 185 to 190C ~dec.).
I.R. ~Nujol~ : 3?80, 3150, 17609 1665,
1620, 1520 cm~l
(31) 7-~2-Cyclopentyloxyimino-2-tS-amino'1,2~4-
*hiadiazol-3-yl)acetamido~-3-~ 3-pi~eridinopropyI)-
lH-tetrazol-5-yl~thiome~hyl-3-cephem-4-car~oxylic
acid ~syn isome~). mp 230C (dec.).
I.R. (Nujol) : 3300, 3200~ 1770, 16709
1600~ 1520 cm~
EY~Y~
A mix~ure of 7-~2-phenoxyimino-2-~5-amino-l,Z~4-
thiadiazol-3-yl)acetamido]cephalospo~anic acid ~syn
isomer)(3.5 g~, te~razolo~l~5-b~pyTidazine-6-thiol
~1.35 g~ and sodium ~ica~bonate (1.1 g) in pH 6.8
phosphate buffer solu~ion (130 ml) ~as s~irred fo~ 2
- hou~s at 70~C. The r~ac~ion mixture was cooled in an
ice bath, mixed with ethyl acetate and adjusted to pH 3 .
?5 with 10~ hydroch~o~ic acid. ~n insoluble mateTial was
il*eTed o~f and th~ filtra~e was ~x~racted with ethyl
aceta~e. The ex~Tact was dried over magnesium sul~ate
and evaporated to dryness. The residue was t~i~urated
with diethyl etheT to give 7-[2-phenoxyimino-Z-~5-
ami~o~l,2,4-thiadiazol-3-yl)ace~amido3-3-~e~ra7O1O-.
~ b3pyridazin-5-yl)~hiome~hyl-3-:cephem-4-carboxylic
acid (syn isomer~ ~0.7 g) ~ mp 175 ~o 180C (dec.).
I~RG (Nujol) : 3300~ 32009 1775, 1680, 1615,
L585 ~ 1~;ZO CIII-1
3~ N.M.R~ (d6-DMSO,~) : 3O77 (2H~ broad 5) Ç
4~23 and 4.63 ~2H, ABq, J=13Hæ),
5.23 ~lH, d, J~4H7) 9 5.93 (lH, dd,
J=.4 and 8Hz), 7.00-7.50 (5H~ m),
7.77 (lH, d, J=lOHz), 8.30 (2H, s),
S 8.60 (lH, d, J=lOHz~, 9.85 (lH, d, J=8Hz)
Exam~le lS
A mixture 0~ 7- L 2-phenoxyimino-2-~S-amino-192,4-
thiadiazol-3-yl)acetamidoJcephalosporanic acid
(syn isomer)(4.0 g~ 9 ~ 2- (N-t-butoxycarbonylamino)-
ethyl3-lH-tet~azole-5-~hiol ~2.4~ g~ a~d sodium
bicarbonate ~1.3 g) inp~ 6.8phosphate buffer solution
(150 ml) was stirred for 1.5 hours at 70C.
The reaction mixture was cooled in an ice bath~ mixed
with ethyl acetate and adjusted to pH 3 with 10~
hydrochloric acid. An insoluble ma~crial was filteTed
off and the the filtlate was extracted with ethyl acetate.
-The ex*ract was dried over magnesium sulfate and
e~apoTated to dryness. ~he residue was tritu~ated
wi~h diethyl etheT to give 7-l2-phencxyimino-2-~5-amino-
;20 - 172,4-~hia~iazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxy-
carbonylamino)ethyl}-lH-t~trazol-5-yl~thiomethyl-3-
cephem-4-carboxylic acid ~syn isomer~ 4 g),mp 150
to 155C ~dec.).
I~R. ~Nujol) : 3300, 32009 1770; 1680~ 1620,
- lS90, 1520 cm 1
N.M.R. (d6-DMSO~ 1.27 ~9H, s), 3.3-3.5
(2H, m3, 3.70 t2H, broad s)9 4.3-4.6
(4H, m) 9 5.1~ ~lH, d, J=4H~) t 5.90
. ~lH, dd, J~4 and 8H~), 7.0-705 ~SH, m~,
~8 (~H, s), 9.88 (lH9 d, J=8Hz)
__ 16
A mîxture of 7-l2-allyloxyimino-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamldo~cephalosporanic acid (syn
isomer)~3.3 g), 1-allyl-lH-tetraæole-5-thiol ~1.4 g~
and sodium bicarbonate ~1.3 g~ in pH 6.8 phospha~e
_. _ . . . . _ . . , .. . . ~ . _ . _ . . .. _
buffer solution (~lO ml) was stir~ed 2 hours at 70C.
The reaction mixture was cooled in an ice bath, mixed
wi~h ethyl,acetate and adjusted LO pH Z with 10%
hydrochloric acid. An insoluble material was filtered
J 5 off and the filtrate was extracted with ethyl acetate,
The ext~act was dried over magnesium sulfate and
evaporated to dryness. The residue was triturated with
diethyl ether to give 7-~2-allyloxyimino-2-(5-amino-
1,294-thiadiazol-3-yl)acetclmido] 3-(l-allyl-lH-tetra201-
lû 5-yl~thiomethyl-3-cephem-4- ca~boxylic acid (syn isomer}
- t2.l g) ,mp 150 to 155C ~dec.) .
I.R. (Nujol): 3~00, 3200, 1779, 1670, 16Z0;
1520 cm 1
N.M.R. ~d6-I3MSO, ô) : 3 . 68 (2H, broad s), 4 . 28 and
4.45 (2H, ABq, J=13Hz), 4~60-4.83 (2H, m3,
4.93-5.07 (?H, m), 5.12 (lH, d~ J=4Hz),
5 .17-5 . 57 (4H, m), 5 . 83 (lH, dd, J=4 and ~Hz) 9,
5077-6.37 (2H, m~, 8.22 ~2H, 5)7 9.67
(lH, d, J~8Hz)
:' ~0 ~
A mixtu~e of 7- [2-cyclopent~loxyimino-2- t5-amino-
1,2,4-thiadiazol-3-yl3acetamido3ceph~1Osporanic acid
(syn isDmer) ~5~1 g) ~ sodium hica~bonate (84~ mg), water
(50 ml), po~assium ~hiocyanate (24 . 3 g~ and
isonico~inamide (1. 83 g) was stirred for 22 hours at
50 to ~5C. The reaction mixture was ooled and addea
t~ ethyl ceta~e. The mixture was adjusted ~:o pH 2
with 10% hydrochloric acid and iltered. The aqueous
layer was sepaTated :Erom ~che filJcrate, washed wi~h
e~hyl aceta~:e and evaporated~ The residue was
su~jected to colu~n chromatography ~non-ionic adsorption
resin, Diaion HP20 prepared by Mitsubishi Chemical
: Indus~ries) and the column was washed with wa~er (0.~ ~)
a~d~hen ~:Luted with 30% aqueous methanol (0.7 Q).
The eluates eo~aining th object compvu~ were collected5
.. ` ~:L~ ''
washed with ethyl acetate and then evaporated.
The Iesidue was lyophilized to give N-~7-{2-
cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-
yl)acetamido}-3-cephem-3-ylmethyl3-4`-carbamoyl-
pyridinium-4-carboxylate ~yn isomer)(l.O g), mp 230
~o 235C ~dec.~.
I.R. (Nujol~ : 3300, 3~00~ 1770, 1680, 1610,
1S60, 1520, 1510 cm~l
N.M.R. (d6-DMSO9 ~) : 1.30-l.9S tBH, m), 3~15
and 3~50 (2H, ABq, J=18Hz), 5.60-5.75
~lH, m), ~06 ~lH, d, J=4Hz), 5.30 and
5.65 (2H, ABq, J-14Hæ), 5.70 (lH, dd,
J=4 and 8Hz), 8.12 (2H, s~, 8.45 (2H,
d, J=6Hz), 9.42 ~2H, d; J=6H~), 9.50
(lH~ d, J=8Hz~
Exam~le 1~
The following compounds were obtained according
to similar mann~rs to those of Examples 14 to 17.
(1) 7-~^Allyloxyimino-2-t5-amino-1,2~4-thiadiazol-
- 3-yl)acetamido]-3-(~etrazolo~1,5-b~pyrida~ 6- --
yl~hiom~thyl-3-cephem-4-carboxylic ~cid tsyn isQ~er),
mp 180 to 185C ~dec.)~
I.R. (Nujol) : 3300, 3200, 1770, 1670,
1620p 1525 c~ 1
~S N~M.R. ~d6-DMSO9 ~ : 3.73 ~2H, hroad s),
4~27 and 4063 ~2H, ABq~ J=14Hz~,
4.50-4.g3 (2H, m) 9 5.18 (lH9 d, J=4Hz),
5.23-5~53 ~2H,.m), 5~83 tlH3 dd, J=4
and 8H~) 9 5.87-6.33 ~lH~ m), 7.82 ~lH,
d, J=lOHz), 8.20 (2H9 s)~ 8~6~ (lH, d,
J=lOHz~, 9.68 ~lH, d, J=8Hz~
(2) 7-~2-(2~2~2-TIifluoroethoxyimino)-2-(5-amino-
1?2,4-thiadiazol-3-yl)ace amidoJ-3-Ll-{2-(N-~-
butoxycar~onylamino)ethyl}-lH-tetra~ol-5-yl]~hiomethyl-
3-cephem-4-car~oxylic aci~syn isomer) 9 powder.
(3) 7-~2-(2,~12-Trifluoroethoxyimino~-2-t5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-~5-zminomethyl-
1,3,4-thiadia~ol-2-~l)thiome~hyl-3-cephem-4-
carboxylic ~cid (s.y~ isomer), mp -15~-to 155~C (dec.).
I.R. (Nujol) : 3300~ 3180, 17~0 3 1670,
1610~ 1520 cm 1
N.M.R. (d6-DMSO, ~) : 3.60 (2H, broad s)~
4.05 a~d 4.28 (2H~ A~q, J-13Hz),
4.57 ~2H, s) 9 4.73 and 4.95 (2H, ABq,
J~9Hz), S.07 (lH, d, Js5Hz~, 5.73 (lH~
dd, J-5 and 8Hz), 8.17 (2H; b~oad s)g
9.63 ~lH~ d~ J-8Hz)
(4) 7-[2-~2,2,2-TrifluoToethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamîdo]-3-(tetrazolo~1,5-b]-
~yridazin-6~yl)*hiomet~y-1-3-cephem-4-caIboxylic zcid
(syn isomer), mp 165 to 170C ~dec.~.
.I.R. (Nujol~ : 3420, 3300, 3190, 1770,
. 1705, 1670~ 1620~ 1525 cm~l
N.M.R. ~d6-DMSO, ~) : 3.~D and 3.80 (2H ABq Jal8Hz)
4.57-4an~ ~a~i4t ~ ~2~q ~B ~ ~
J-5Hz3tS.82 ~lH,ddJJ~5 and BH2)37.72 ~lH,d,
J=lOHz)~ 8.17 (2H, bro~d s)~ 8.55 ~lH~ d,
J=lOHz)~ 9.6~ ~lH, d, J=8~z)
~5) 7-~2-Cyclopentyloxyimino-2.-~5-amino-1j2,4
thiadiazol-3-yl)acetamidoJ-3-~1-{3-tN-t-
butoxycarbo~yl~mino)propyl}-lH-tetrazol-5-yl~-
~hiome~hyl-3-cephem-4 carboxyl-ic acid (syn isomer),
pale b~own powder.
I.R. ~Nujol3 : 3300~ 1770, 1670, 15209 1240,
1160, 1000 cm-l
N.M.R. (d6-DMSO~ 1.33 (9H, s), 1.40-2.07
(lOH~ m), 2.95 (2H~ m~, 3.63 (2H~ m),
4.0-4.43 (4H, m~ 4.70 (lH, m), 5.07
(lH, d, J=SHz) 9 5.73 (1~ dd, J-5 and
3~ 8Hz), 6.80 (lH~ m~, 8.~7 (2H~ m3 9
9.89 (lH~ d, J-8Hz~
o~
(6) 7-~2-Cyclopentyloxyimino-~-(5-amino-1,2,4-
thiadiazol-3-yl)ace~amido]-3-(l,Z,4-thiadiazol-S-
~ yl)thiomethyl-3--cephem--4-ca~boxylic acid (syn isomer),
i mp 175 ~o 178C ~dec.~.
I.R. (Nujol3 : 3300~ 3200, 1775, 1680, 16Z0,
. 1525 cm~l
N.M.R. (d6-DMS09 ~ : 1.50~2.00 ~8H, m),
; 3.67 (2H, broad s~, 4.34 and 4.60
~2H, .4Bq, J-14Hz), 4.67-4.83 ~lH~ m~,
5.17 (lH, d, J~4Hz), 5.82 ~lH, dd,
~ J-4 a~d 8Hz), 8.12 (2H, s); 8.73 (lH~ s),
: - 3.S0 ~lH, d, J=8Hz)
(7) 7-[2-Cyclopen~yloxyimino-2-~5-amino-192,4-
thiadiazol-3-yl)acetamido]-3~[1-~3-morpholinopropyl)-
: 15- lH-tetra201-5-yl]thiomethyl-3-cephem-4-carboxylic
- acid ~syn isomeT), mp 183 to 188C ~dec.).
- I.R. ~Nujol) : 3300, 3150, 1770, 1670, 1610,
1530 cm~l .
N.M.R. ~d6-DMSO, ~ : 1.50-1.90 (8H, m~ 9
- 2.00-2.27 (2H~ m), ~.5G-2.83 (6H, m~,
3.50-3.83 (6H, m~, 4.23-4.53 ~4H, m)~
4.70-4.86 (lH,~ 5.13 (lH, d, J=4Hz~,
5.80 (lH, dd, J-4 and 8Hz), 8.13
~2H, s), 9.50 (lH~ d, Jo8Hz)
(8, 7-~2-~2-Gyclopen~en-l-yl)oxyimino-2-~5-amino-
172,4-~hiadiazol-3-yl)acetamidoJ-3-(1,3~4-thiadiazol-
2-yl)thiome~hyl-3-cephem-4-carboxylic acid (syn
isomeT~1.4 g), mp lSS ~o 160C.
I~R. ~Nujol) : 3300~ 3200~ 1770~ 16709 1620
1520 cm-l ~
(93 7-~2-(2-Cyclopenten-l-yl)oxyimino-2-~5-amino-
1~2,4-1:hiadiazol-3-yl)acetamidoJ-3-(l-methyl-lH-
~etrazol-S-yl)~hiome~hyl-3-cephem-4-carboxylic acid
~syn isomsr)7 mp 155 to 160C (dec.).
3S I~ .(Nujo~ : 3300~ 1770, 1670, 16207 lS20 cm 1
` ` ~ li 8
(10) 7-~2-(2-Cyclopenten-l-yl)oxyimino~Z-(5-amino-
1~2,4-thiadiazol-3-yl~acetamido~-3 (l-carboxymethyl-
lH-tetr~zol-S~yl)thiomethyl-3-cephem-4-ca~boxylic
acid tsyn isomer), mp 155 to 160C ~dec.).
I.R. (Nujol~ : 3300, 3200, 1770, 1720~ 1670,
162D~ 1520 cm 1
(11) 7-~2-~2-Cyclopenten-l-yl)oxyimino 2-(S-amino-
1,2,4-thiadia2Ol-3-yl)acetamido]-3-rl-(2-
carboxye~hyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-
lD 4-carboxylic acid ~syn isomer), mp 15p to 155~C (dec.3_
I.R. (Nujol) : 3300, ~200~ 1770, 1720 9 1670,
16~0) 1520 cm~~
(12) 7-[2-~2-Cyclopen~en-l-yl)oxyimino-2-(5-amino-
19 2,4-~hiadiazol-3-yl)acetamido]-3-~1-allyl-lH-
lS tetTazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
~syn isome~3, mp 160 to 165C Cdec.).
I.R. (Nujol) : 3300, 1770, 167Q, 1620, 1520 cm 1
(13~ 7-[2-~2-Cyclopenten-l-yl)oxyimino-2-~5-amino-
4-thiadiazol-3-yl)acetamido-3-(tetr zolo[l,5-b]-
~0 - pyridazin-6-yl~thiome~hyl-3-cephem-4-carboxylic
acid (sy~ isomer) 9 mp 170 to 175C tdec.3;
I.R. (Nujol) : 3400, 3300, 3190~ 1770, 1670,
lS15, 1520 cm~
~14) 7-~2-~2-Cyclopen~en-l-yl)o~yimino-2-(5-amino-
1,2,4~thiadiazol-3-yl)a6etamido]-3~ {2-(N-t-
butoxycarbonylamino)ethyl}-lH-tetrazol-5-yl]-
thiomethyl-3-cephem-4-ca~boxylic arid (syn isomer),
mp 95 to lOO~C (dec.3.
I~R. (Nujol) : 3300, 3190, 1770~ 1680, 1620
15~0 cm~l
(15) 7~2-~2-Cyclopenten-l-yl)oxyimino-2-~5-amino-
1)~,4-thiadiazol-3-yl)acetamido~-3-El-(2-aminoethy~-
lH-~etra201-5-yl~thiomethyl-3-cephem-4-rarboxylic
a~id ('syn isomer)~ mp 175 to 180~C.
3S I.R. (Nujol~ : 3400~ 3300, 3170~ 1760~ lS65
li824~
1610, 1520 ~
(16) 7- ~2- ~2-Cyclohexen-l-yl)oxyimino-2- ~5-amino-
192,4-~hiadi~ol-3-yl)acetamido]-3-(1,3,4-thiadiazol-
2-yl)thiome~hyl-3-cephem-4-carboxylic acid (syn
isomer), mp 150 to 155C ~dec.).
I.R. tNujol~ : 3300, 3180, 1770, 1660,
1~20, 1S20 cm-l
(17) 7-[2-~2-Cyclohexen-l-yl)oxrimino-2-~5-amino-
1,~,4-thiadiazol-3-yl~acetamidoJ-3-(tetrazolo~l,S-b]-
pyridazin-6-yl)~hi~me~hyl-3-cephem-4-carboxylic
acid ~syn isomer) , mp 170 ~o 175C (dec.).
I~Ro ~Nujol) : 3400, 3300~ 3180, 1670, 1620
1520 cm 1
(18) 7-[2-(2-Cyclohexer.-1 yl)oxyimino-2-(5-amino-
1,2~4-thiadi2zol-3-yl)acetamido]-3-(l-me~hyl-lH-
tetrazol-5-y~ )thiomethyl-3-cephem-4-caTboxylic acid
(syn isomer) 7 mp 170 ~o 173~C (dec.)
I.R. (Nujol~: 33~0, 3~50, 1780, 16809 16~0
lS20 cm 1
~ (19~ 7- [2- (2-Cyclohexen-l-yl)oxyimino-2- (5-amino-
1,2,4-thiadiazsl-3-yl)acetamido3 -3- (l-carboxymethyl-
lH-tetrazol-S yl)thiome~hyl-3-cephem-4-carboxylic
acid (syn isomer), mp 170 to 175 C (dec ~ ) .
I.R. ~Nujol) : 3300, 3200y 1770~ 17~0, 1650,
2~ 1620 9 1520 cm~l
~20~ 7-~ 2-Cyclohexen-l-yl)oxyimino-2-(S-amino-
1,2,4-~hiadi zol-3-yl)acetamidoJ-3-~1-(2^
carboxyethyl) -lH-te~razol-5-yl}~hiome~hyl-3-cephem-
4-carboxylic acid (syn isome~3 9 mp 165 ~co 170C.
I.R. (Nujol): 33009 3200~ 1770, 1720, 1670,
1620, 1520 cm 1 --
(~1) 7-~2-~2-Cyclohexen-l-yl)oxyimino-2-~5-amino-
1,2,4-thiadi~zol-3-yl)acetamidoJ-3-~1-allyl-lH-
~etrazol-5-yl~thiomethyl-3-cephem 4-c~rboxylic acid
`:; 35 (syn isDmer), mp 160 ~o 165C (dec.).
~2~
I.R. (Nujol) : 3300, 3200, 1780, 1680
1670, 1520 cm~l
~2~ 7-~2-t2-Cyclohexen-l-yl~oxyimino-2^(5-amino-
lJ2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-
butoxycarbonylamino)propyl} -lH-tetrazsl-5-yl]-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 100 to 105C (dec.).
I.R. ~Nujol) : 3300~ 3170~ 1770, 1670,
1620, 15~Q cm~l
(23) 7-~2-(2-Cyclohexen-l-yl)oxyimino-2-~5-amino^
1~274-thiadiazol-3 yl)acetamido]-3-~1-(3-
aminopropyl)-lH-~e~razol-5-yl]*hiome~hyl-3-cephem-
4-carboxylic acid ~syn isomer~, mp 185 to 190C
(d~c.).
I.R. (Nujol) : 3Z80~ 3150, 17609 1665,
16209 1520 cm 1
(24~ 7-~Z-Cyclopentyloxyimino 2-~S-aminQ 1,2,4-
thiadiazol-3-yl)ace~amidoJ-3-(1,3,4-~hiadiazol-
2-yl)thiome~hyl-3-cephem-4-carboxylic acid (syn
- isomer), mp 140 to 145~C ~dec.).
I.~. (Nujol) : 34001 330Q, 3200, 1770, 1670,
1620, ~25 cm~~
(25) 7-~2-Cyclopen~yloxyimino-2-(5-amino-1,2,4-
~hiadiazol-3-yl~ace~amido~ -3- (l-methyl-ïH-~et~azol-
5-yl)~hiomethyl-3-cephem-4 carboxylic acid ~syn
isom~r)~ mp 145 to 150C (d~c.~.
I.R. (Nujol) : 3400, 3290, 31803 1770, 1670,
1620 ? 1520 ~m
(26~ 7-~2-Cyclopen~yloxyimino-2-~5-amino-1,2,4-
thiadia~ol-3-yl)acetamido]-3-~1-carboxymethyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem~4-carboxylic acid
~syn isome~) 7 mp 155 to 160C (dec.).
I.R. ~Nujol) : 3400~ 3290J 3180~ 1765, 1720,
167~ 1620~ 1520 cm 1
(27) ,7-l2-Cyclopentyloxyimino-2-~S-amino-1,2,4-
~2~
thiadiazol-3-yl)ace~amido]-3-~1-allyl-lH-tetrazol-
5-yl)thiomethyl-3-cephe~m-4-carboxylic acid (syn
isomer); mp 13~ to 140C ~dec.).
I.R. (Nujol) : 3400g 3300, 3190, 1770, 1670,
1620~ 1520 cm 1
(28~ 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-
thiadiazol-3-yl)aceta~ido~-3-(te~razolo~l,S-b3-
p~ridazin-6~yl)thiomethyl-3-cephem-4-carboxylic
ac d (syn isome~), mp 160 ~o 165~C (dec.3.
I.R. ~Nujol) : 3570, 34409 3320, 3180, 1775,
1710, 1660, 1620, 1580, 1540,
1~20 cm 1
(29) 7-~2-Cyclopentyloxyimino-2-(5-amino-1~2,4-
thiadiazol-3-yl)acetamido~-3-~1-(3-aminopropyl~-
1~ lH-'cetlazol-S-yl]~hiomethyl-3-cephem-4-carboxylic
acid (sy~ isomer), white powder, mp 195 to 199C
tdec.).
I.R. ~Nujol) : 3300, 3150~ 1760~ 1660, 1620,
1520, 128Q9 1180, 1000 cm 1
~~30) 7-~2-Cyclopentyloxyimino-2-(~-amino-1,2,4--
~hiadiazol-3-yl~ace~amido]-3-~ 2-
methoxycarbonylethyl)-lH-tetra~ol-5-yl~hiomethyl-
3-cephem-4-carboxylic acid (sy~ isomer), mp 125 to
130C (dec.).
~S I.R. ~Nujol~ : 3480~ 3370~ 325D~ 1780, 1740,
1685, 1625, 1530 cm~l
(31) 7 r2-Cyclopentyloxyimino-2-~5-amino-1,2 7 4-
thiadiazol-3-yl~acetamido~-3-(4-methyl-5-oxo-6-
hyd~oxy-4,5-dihydro-1,2,4-t~iazin-3-yl~thiomethyl-
3D 3-cephem-4-carboxylic acid ~syn isomer), yellow
powder, mp 135 to l99~C (dec.3.
I.R. ~Nu~ol) : 3300, 3200, 1770, 1710-1670~
159~, 152~, 1240 J 1170, 1090 7
10009 720 ~m 1
N.M.R~ (d~-DMSO, ~) : 1.3-2.1 t8H, m)g 3.32
.
~1 22 ~
~3H~ s), 3.66 ~2H, m), 4.11 ~2H, m),
4.76 ~lH, m)~ 5.16 (lH~ d, ~=5Hz),
5.83 (lH~ dd, J=5 and 8Hz), 8.13
~2H, bruad s), 9.50 (1~ d, J=8Hz),
12.50 (lH, brozd s)
(32) 7-r2-Cycloheptyloxyimino-?-(S-amino-1,2,4-
. thiadia~ol-3-yl)ace~amidoJ-3-(1,3 3 4-~hiadia~ol-
2-yl~hiomethyl-3-cephem-4-carboxylic acid ~syn
isomer)g white powder, mp 150 to 154 ~ (dec~)~
I.R. (Nujol) : 3~00, 3200, 1770, 1670, 16?09
1520~ 1~005 12~0, 1160, 1060,
1000 cm~l
(33) 7-~2-Cyclopentyloxyimino-2-~5-amino-1~2~4-
~hiadiazol-3-yl)acetamido]-3-~ 3-piperidinopropyl)-
lH-~etrazol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer)~ mp 230C (dec.~.
I,R. (Nujol) : 3300~ 3200~ 17~0, 1670, 1600,
- 1520 cm ~
N.M..R. (d5-DMSO, ~) : 1.3 2.0 (6H, m), 2.10-2.3
- . ~2H, m)~ 2.73~3.10 ~6H~ m)9 3.57 (~HD
broad s), 4.10-4.5~ ~4H, m), 4.60-4.~0
(lH3 m), 5.00 tlH~ d; J=4Hz), 5.67
(lH, dd~ J=4 and 8Hz), 9.06 ~2H, s)g
9.37 (lH, d, Jz8Hz)
2~ e~
A soll~tion of 4-ni*robe~zyl 7-~2-(3
trifluorome~hylphenoxyimino)-2 ~5-amino-1,2,4`
thiadiazol-3-yl)acetamido3-3-cephem~4-carboxyla~e
~syn isomer) ~4.4 g) in mixture of tetrahydrofuran
3Q ~80 ml) ~ water (50 ml) and acetic acid ~4.4 ml~ was
hydrogenated over 10% palladium-charcoal ~2.2. g~ at
atmospheric pressure at room temperature for 3 hours.
The catalyst was filtered and wa~hed~ with ~etrahydrofuran~
- The fil*rate and washing were combin2d and the~
evapo~ated. To ~he res idue w~re added e~hyl acetate
.... . . _ . _ . _ . . . . . _ . .. .. , .. , .. . ~, _, _ = .. . _ . .. . ...... . . . .. . . .. . . . .
. .
and an aqueous solution of sodium bicarbonate so that
the pH was adjusted to 8. The aqueous layer was
separated, adjusted to pH 1 to 2, and extracted with
ethyl acetate. The extTact was washed successively
S with water and an aqueous solu~ion o~ sodium chloride,
~reated with activated charcoal, dried over magnesium
sulate and then evaporated. The residue was washed
with diethyl ether to gi~e a yellow powder ~1.0 g)~
Water ~10 ml) was added to this crude produc~ and the
mixture was stir~ed for 30 minutes. The prscipitates
were collected by filtration, washed with water and
dried under reduced pressuTe to give a yellow powder of
7-~2-~3-trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-
thiadia~ol-3-yl)acetamido~-3-cephem-4~carboxylic acid
(syn isomer)(l.0 g), decomposed by 193C.
I.R. (Nujol~ : 3450, 3320, 32009 1770, 1710,
- 166~ 1630, 1~60, 1515~ 1325,
1170 9 1110 ~ 940 cm~l
N.M.R. ~d6-DMS0, ~) : 3.63-~2H, m), 5.~1 (lH, d,
- J=5Hz), 5.94 (lH, dd, J=5 and 8Hz)~ 6.48
(lH~ m), 7.53 ~4H, broad s), 8.27 (2H,
b~oad s), 9.87 (lH, d9 J=8Hz~
~ ' .
A solution of 4-nitrobenzyl 7-[2-phenoxyimino-2-
(5~amino-1,2,4-thiadiazol-3-yl)acetamido~-3-cephem-4-
carboxylate (srn isomer3~4.5 g) in a mixture o
te~rahydrofuran (45 ml~ and water (20 ml) was
hydrogenated over 10% palladium-charcoal e2.5 g) for
3 hours at atmospheric pressure at room temperature.
The catalyst was filtered and the ~iltrate was
evaporated. To the residue was added ethyl acetate
and the mixture was adjusted to pH 8 with an aqueous
sol~tio~ of sodium bicarbonate. The aqueous layer
was sepaTated and ~here~o was added ethyl ace~ate,
a~d t~en the pH was adjusted ~o 3 with ~ydrochlori~
.
$~
~2
acid. The resulting mi~ture ~as ex*racted ~ith ethyl
acetate and .he extract w~s washed with water, dried
over magnes ium sulfate and then e~7aporated to give
7 - ~ 2 - phenoxy imino - 2 - ( 5 - amino - l ~ 2, 4 - thiadi az ol - 3 -yl) -
5 acetamido]-3-cephem-4-caTboxylic acid (syn isomer)
(1.4 g), mp 168 to 170C ~dec~)O
I.R. ~Nujol): 3400, 3200, 1780, 16609 1620,
1~00, 1590, 1540 cm 1
N.M.R. (DMSO-d6, ~) : .3.58 (2H, broad s), 5.15
(lH, d, J=4Hz) ~ 5.90 (lH~ dd" J=4 and
8Hz), 6.47 (lH9 t, J=3Hz), 6.97-7.60
~5H, m), 8.27 (2H, s), 9.9~ (lH~ d, J=8Hz)
The following compsunds were obtained according
- 15 to similar manners to those of Examples 19 and 20.
- ~1) 7-12-{3-~N-~-Bu~.cxycarbonylamino)propoxyimino}-
2-~5-amino-1,2,4-thiadiaz~1-3-yl)ace*amido3-3-chloro-
3-cephem-4- a~boxylic acid ~syn isomer).
I.R. ~I~ujol~: 3300-3100, 1780~ 1690-î650,
1520, 127Q cm ~
2 ) 7 - [ 2 - ( 4 - Chlo~ophenoxyimino) - 2 - t 5 - ~nino -1, 2 ~ 4 -
thiadiazol -3-yl) acetamido~ -3-cephem-4-GaTboxylic
acid (syn isomer), mp 145 to 150C (dec.).
I.R. ~Nujol): 34007 32607 3180, 1775, 1675
1625, 1600 g 15Z0, 1480 cm 1
N.M.R. ~d6-DMSO" ~ ~: 3.63 (2H, l~road s),
5.Z0 (lH~ d, J-5Hz) 7 5.93 ~lH, dd,
J-5 and 8Hz~, 6.52 (lH9 t, J=4Hz),
7~33 (2H, d, J=9Hz), 7.47 (~H, d,
3Q J=9Hz3, 8.32 (2H, broad s), 9.90
(lH" d" J=8Hz)
3) 7 - ~2 - ( 4 -Fluorophenoxyimino) - 2 - ( 5 - amino- 1, 2, 4-
thiadiazol-3-yl) acetamido3 -3-cephem-4^carboxylic
acid (syn isomeT), mp 130 to 135~C ~dec.~.
3~ I.R~ ~Nujol): 3400, 3270~ 31809 1765, 1675,
_ _ _ _ . . . . . ., . . _ , . . . .. .. . ~ . . . _ . .. , . . . . . ..... _ _ .. . .
~25
1605, 1500 cm l
N.M.R~ (d~-DMSOg ~) : 3~63 ~2H, Droad s),
5.22 (lH9 d, J-5Hz), 5.97 ~lH, ddJ
J=5 and 8Hz), 6.53 ~lH, t, J=4Hz),
7.25 ~H, s), 7.37 ~2H~ s), 8.30
(2H9 broad s), 9.gO (lH, d, J=8Hz)
~4) 7-l2-Allyloxyimino-2-~5-amino-1,2,4-thiadiazol-
3-yl)acetamido3-3-cephem-4-carboxylic acid (syn
isomer)~ mp 160 to 165DC (dec.),
10 N~M.R. (d6 DMSO~ 3.~3 (2Hg d~ J=4Hz~,
4O60-~77 ~2H, m), 5.07 (lH, d, J=4Hz),
- 5.0-5.50 ~2H~ m)~ 5.83 ~lH~ dd, J=4 and
8H~)/ 5.70-6.23 (lH, m), 6.4~UH3 t.~.
J-4Hz), 8.13 (2H~ s) 9 9. 57 ~lH, ~, J=8H7.~
~5) 7 ~2-(2-Cyclopenten-l-yl)oxyimino-~-(5-amino- -
1,2,4-thiadiazol-3-yl)a~etamido]-3-(1,3S4-~hiadiazol-
2-yl~thiomethyl-3-cephem-4-carboxylic acid tsyn
isomer), mp 155 ~o 160C.
l~R. (Nujol3 : 3300, 3200~ 1770, 1$70, 1620,
2~ . 1520 -1
(6~ 7-[2-~2-Cyclopenten-l-yl~oxyimino-2-~5-amino^
1,2,4-thi diazol-3-yl)acetamido]-3-cephem-4-caTboxylic
acid (sy~ isome~) , mp 180 to 185C (dec.)~
I.R~ ~Nujol) : 3500, 3430 9 3300~ 3200, 1770,
?5. 1690~ 1660, 1640~ 1620p 1580,
1510 cm 1
(7) 7-~2-~2-Cyclopente~ yl)oxyimi~o-2-t~-amino-
4~thiadiazol-3-yl)acetamido]cephalosporanic acid
tsYn isomer)g mp 154 to lS9C (dec,).
I.R~ (Nujol) : 3300~ 17709 1720~ 1670, 1620,
1520 cm~l
(8, 7~ (2-Cyflopente~-l-yl)oxyimino-2-(5-amino-1,2,4-
thiadiazol~3-yl)acetamido]-3-(1-me~hyl-lH-tetrazol-5-
yl~hiome~hyl-3-cephem-4-carboxylic acid ~syn isom~r~,
mp 15'j ~o 160C (dec.).
4~.
~2~
I.R. ~Nujol) : 3300, 1770, 1670, 1620, 1520 cm 1
t9) 7-~2-(2-Cyclopenten-l-yl)oxyimino-2-~5-amino-
1j2,4-thiadiazol-3-yl)acPt~mido]-3~ carboxymethyl-
lH-tetrazol-5-yl)thiome*hyl-3-cephem-4-carboxylic
~d (syn isomer), mp 155 to 160~C (dec.).
I.R. ~Nujol) : 3300, 3200, 1770, 1720, 1670,
1620, 15~0 cm~l
~10) 7- [2- (2-Cyclopenten-l-yl)oxyi~ino-~- (5-amino-
~,2,4-thiadiazol-3-yl)acetamido]-3~ 2-
carboxyethyl)~lH-tetrazol-5-yl3thiomethyl-3-cephem-
4-carboxylic acid (syn isomeT~ mp 15~ to l~S~C (dec.
- ~ I.R. (Nujol~ : 3300, 3200, 1770, 17~0, 1670,
1620, 1520 cm-l
- (11) 7-[2-~-Cyclopenten-l-yl30xyimiIlo-2-(5-amiIlo-
1,294-thiadia~ol-3-yl)acetamido~-3-(l-allyl-lH-
tetr~zol-~-yl)thiomethyl-3-cephem-4-ca~boxylic acid
- (syn isomer), mp 160 to 165~C ~dec,).
I.R. (Nujol) : 3300~ 1770, 1670, 1620, 1520 cm I
~12) 7- ~2- (2-Cyclopenten-l-yl)oxyimino 2- ~5-amino-
- 1, 2 " 4 -thiadiazol- 3-yl) acetamido- 3 - ~tetrazolo [1, 5 -b~ -
: pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer~, mp 170 ~o 175C ~dec.)~
I.R. (Nujol~ : 3400, 3300, 3190, 1770, 1670,
1615, 1520 cm~l
2a ~13) 7-~2-(2-Cyclopenten-l-yl~oxyimino-2-(5-amino-
1~2,4-thiadiazbl-3-yl~acetamido3-3- ~1-{2-~N-t-
butoxycarbonylamino~e~hyl}-lH-te~razol-5-yl3-
thiomethyl-3-cephem-4-carboxylic acid (syn isomerj~
mp 95 ~o lOO~C ~dec~).
33 I.R. (Nujol) : 3300~ 31909 1770, 1580, 162DJ
1520 cm ~
~14) 7-~2-(2-Cyclopent2n-l-yl~oxyimino-2-(5-amino-
ly~4-thiadiazol-3-yl~ac~tamido]-3-~1-(2-aminoethyl)-
lH-~e~:razol-5-y:l~*hiomethyl-3-c~phem-4-caTboxylic
acid ~syn isomer~, mp 175 to 180C ~dec.).
..... , .... _ ,, . . _, . ~ . _ ~ ... , .. . . , .. ... ,,_ _ . _ , . ,, , _ . .. .
I O R. (Nuj ol): 3400 " 3300, 3170, 1760 ~ 1665
161Q, 1520 cm ~
(15) 7- ~2- ~2-Cyclohexen- l-yl)oxyimino-2- (5-amino-
1,~,4-thiadiazol-3-yl)aLcetamido]-3-~1,3,4-thiadiazol-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
- isomer), mp 150 to 155~'C ~dec.3.
- I.R. ~Nujol): 3300, 3180~ 1770, 1660, 1620,
lS~!û cm 1
(16) 7 - ~2 - (2 - Cyclohexen- 1-~1) oxyimino- 2 - (5 ~ ami~o-
~ lO lJ2~4-thiadiazol-3-yl)ac~tamido~-3-cephem-4-::
carboxylic acid C~yn isomer), mp 175 to 180C (dec.) r . _
- I.R. (Nujol): 33009 32003 1770, 1670, 1630~ . .
1520 cm 1
(17) 7-~2-~2-Cyclohexen-l-yl)oxyimino-2-(5-amino-
-15 1, ~f 4-thiadiazol-3-yl~acetamido]-3-(tetrazolo ~1J5
pyridazin-6-yl)thiomethyl-3-ce~hem-4-c~rboxylic
acid (syn isvmer) , mp 17~ to 175C ~dec.).
I.R. ~Nujol): 34ûO, 33ûO; 3180, 16'70, 16203,
: 1520 cm 1
(18) 7-~2-(2-Cyclohexen-l-yl)oxyimino-2-(5-amino-
1~2,4-thiadiazol-3-yl)acetamido]cephalosporanic
acid (syn isomer), mp 160 to 165~C (dec.).
I . R. (Nuj ol): 3300, 32no 9 1775, 1720 9 1670,
1620, 1520 cm 1
Cl9~ 7 ~ ~2-(2-Cyclohexen-l-yl~oxyimino-2-~5-aminQ-
192~4-thiadia~ol-3-yl)ace~amido]-3-~l-methyl-lH-
~etra~ol-5-yl~thiomethyl-3-cephem-4-carboxylic
acid tSYn isomer) 9 mp 170 to 173~C (dec.).
I.R. ~Nujol): 3350, 3250, ï780, 1680,
1620, 15~0 c~ ~
(20) 7-[2-~2-Cyclohexen-l-yl)oxyimino-2-(5-amino-
1~2,4--thiadiazol 3-yl)acetamido]-3-(1-carbQxymethyl-
lH-tetrazol-~-yl)thiomethyl-3-cephem-4-carboxylio
acid ~syn isomer~ 9 mp 170 to 175C ~dec.).
X.R. ~Nujol) : 3300, 32009 1770~ 17209 1650
;
~28
16203 1520 cm 1
(21) 7~~7-~2-Cyclohexen-.l-yl)oxyimino-2-(5-amino-
192,4-thiadiazol-3-yl3acetamido~ -3-rl-(Z-
carboxyethyl)~lH-tetrazol-5-yl~thiomethyl-3-cephem-
4-carboxylic acid (syn :isomPr), mp 165 to 170~C.
I D R. ~Nujol) : 3300, 3200, 1770, 1720, 1670,
1520 cm 1
~223 7-~2-t2-Cyclohexen-l-yl)oxyimi~o 2-(5-amino-
- 1~2,4-thiadia~ol-3-yl)acetamidQ~-3-(1-allyl-lH-
tetrazol-5-yl~thiome~hyl-3-cephem 4-carboxy~ ic acid - -
(syn isomer), mp 160 to 165C ~decO). --
- I.R~ (Nu~ol): 33ûO9 320û, 1780~ 1680~ 16~0,- -
1520 cm 1
~23~ 7-~2-(2-Cyclohexen-l-yl~oxyimino-~-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-[1-~3-(N-t-
butoxycarbonylamino~propyl~-lH-te~ra201-S-ylJ-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer)~
mp 100 to 105C ~dec.~.
I,R~ iNujol) : 3300, 3170, 1770; 16~0, 1620,
- 1520 cm ~ ¦
~24~ 7-~2-(2-Cyclohexen-l-yl)oxyimino-2-(5-amino-
1~2,4-thiadiazol-3-yl)acetamido~-3-[1-(3-
nopropy~-lH-tetrazol-5-yl~thiomethyl-3-cephem-4-
c rboxylic aeid (syn isomer), mp 185 ~o l90~C (dec.).
I.R, ~Nujol) : 32803 3150, 1760, 1665, 1620
1520 cm -
~25) 7-~2-CyclopentyloxyiminQ-2-~5-amino-1,2~4- 1
~hiadiazol-3-yl)~cetamidoJ-3-~1~3~4-~hiadiazol-2- !
yl)thiomethyl-3~cephem-4-carboxylic acid tsyn isomer),
mp 140 to 145C tdec.). '.
I.R. ~Nujol) : 3400, 330G, 3200, 1770~ 1670,
1620 9 1525 cm~l
(26) 7-~2-Cyclopentyloxy;mino~ 5-amino-1,2,4-
~hiadia2sl-3-yl~ace~amido~-3-cephem-4-carboxylic
acid ~syn ~somer), mp 170 ~o 175~C.
~2~
I.R. ~Nujol)~ :. 33~0, 3~20, 3.32Q? 3.~20, 3I60,
17,7D, 1685, 1655g 1635, 16~5,
15.70, 1505 cm 1
~27) 7-~2-Cyclopentyloxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl~acetamido]cephalosporanic acid
(syn isomer), mp 140 ~o 145C ~dec.).
I.R. ~Nujol~ : 3480, 33707 3250, 1785, 1730,
16E~0, 16303 15~0 cm 1
(28) 7- [2-Cyclopentyloxyimino-2- ~5-amino-1~2~4-
thiad~azol-3-yl)acetamido]-3-~l^methyl-lH-tetrazol-
S-yl3thiomethyl-3-Gephem-4-carboxylic acid ~syn
isomer), mp 145 ~o 150C (dec.).
I.R. (Nujol~ : 3400, 329Q9 3180~ 1770g 1670,
16~0, ~520 c~ 1 . -
lS ~29~ . 7-~2-Cyclopentyloxyimino-2-(S-amlnc-1,2,4- . .
~hiadiazol-3-yl)ace~amido~-3-(1-carbox~methyl-lH- ..
te~r~zol-5-yl)t~iomethyl-3-cephem-4-carboxylic acid
~syn isomer) D mp 155 to 160C (d~c.).
Nujol~ : 3400, 32gO9 3180, 1765~ 1720
~0 - 1670, 16~09 ~520 ~ 1
~30) 7-~2-Cyclopentylnxyimi~o-2-~5-amino-1,2,4-
khiadiazol-3-yl).ace~amido3-3-.(1-allyl-lH-te~ra~ol-
5-yl)thiomethyl-3-cephem-4-caTboxylic acid ~syn
isomer)~ mp 135 to 140C ~dec.~.
I.R~ (Nu~ol) : 3400, 3300p 31~0, 1770, 1670,
1620; 1520 cm 1
(31~ 7- [2-Cyclopentyloxyimino-2- (5-amino~ ,4-
thiadiazol-3-yl)acetamido~-3-l~etrazolo[1,5-bJ-
pyridazi~-6-yl)~hiom~thyl-3-cephem-4~carboxylic
acid (syn isom~r); mp 160 ~o 165C ~dec.~.
I.R. (Nujol) : 3570, 3440~ 3320; 3180, 1775,
1710~ 1663, 1620g 1~80~ 1540
1520 cm~l
~3~ 7-~2-CyclQpentyloxyimino-2~5-amin~ 2,4-
~hiadiazol-3-yl)acetamido]-3-[1-{3-~N-t-
~2~&
1 1 3 ~
butoxycaIbonylamino)propyl}-lH-te:~ra, l-S-ylJ-
thiomethyl-3-cephem-4-carbQxylic acid (syn i~omer~,
pale br~wn powder.
I.R. ~Nujol) : 3300, 1770, 1670, 1520, 12409
1160, 1000 cm~l
~33) 7-~2-Cyclopentyloxyimino-2-(S-amino-1~2,4-
~hiadia~ol-3-yl)acetamido3 73- ~1 (3-2millOprOpy~ H-
~etrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid
~syn isomer), white powder~ mp 195 ~o 199C (dec.).
I.R. ~Nujol) : 33~0, 3150, 1760~ 1660a 1620
1520 9 1280~ 1180, 1000 cm~
(34) 7-[2-Cyc~opentyloxyimino 2-(5-amino-1,2~4-
thiadiazcl-3-yl)acetamido~-3~ 2--:-
methoxycarbonyle~hyl)-lH-tetrazol-5~yl]-
lS thiomeghyl-3-cephem-4-carboxylic acid (syn isomer~,
mp 125 to 130C (dec.~.
i I~Ro ~Nujol~ : 3480~ 3370S 3250, 178Q~ 1740,
1685, 1625, 1530 cm 1
(353 7- ~Z-Cyclopentyloxyimino-2- ~5-amino-1"2,4-
- ~hiadiazol-3 yl~acetamido~ -3- (4-methyl-5-oxo-6-
hyd~oxy-4~5-dihydro-1,2,4-~riazin-3-yl)~hiom~thyl-
3-cephem-4-carboxylic acid (syn isomer), yellow
powder~ mp 195 to 199C (dec.)~
~ I.R~ ~Nujol) : 3300, 3200~ 177Q, 1710-16703
; 25 15909 1~20, 1240, 1170, 1~90,
lOOO ~ 7~a cm 1
(~6) N-~7-{2-Cyclopentyloxyimino-2~$-amino-1,2,4-
thiadiazol-3-yl)ace~amido}-3-cephem-3-ylmethyl3-
; 4'-carbamoylpyridinium-4-carboxylate ~yn isomer~,
mp ~30 to ~3SC ~dec.),
I.R. (Nujol~ : 33~0, 3200, 1770, 1680, 1610
1560, 1520, 1510 cm~l
(37~ 7-~2-Cyclopentyloxyimino-2 (5-amino-1~2,4-
thiadiazol-3-yl) acet~mido]-3-~lp2 9 4-thiadia~ol-5-
yl~hiome~hyl-3-cephem-4-carboxylic acid ~syn isomer)~
~31
mp i75 to 178C (dec.).
I.R. ~Nujsl~ : 3300, 3~0S 1775, 1680, 1620,
15i'5 cm~l
(38) 7-~2-Cyclopentyloxyimino-2-(5-amino-1~2,4-
thiadia~ol-3-yl)ace~amido~-3-~1-(3-molpholinopropyl)
lH-te~razol-5-yl3thiomethyl-3-cephem-4-carboxylic
~cid (syn isomer) 9- mp 183 ~o 188C (dec~3.
I.R. (Nujol) : 33130, 3150, 1770, 1670, 1610,
1~30 cm
t39~ 7-L2-CyclohPp~yloxyimino-2-(5-amino-1,2,4-
. . thiadiazol-3-yl)acetamido]-3-(19 3~4-~hiadiazol-2-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer~ J white powder, mp 15Q to 154C (dec.).
I.R. (Nujol) : 3300) 3200~ 1770, 1~70,-162Q~ -
- 15 . 152~, 1400 9 1240, 116~, 1060,
. 1OOO cm
(40~ 7-~2-Cyclohep~yloxyimino-2- ~S-amino~1,2,4-
~hiadla~ol-3-yl~acetamido]-3-cephèm-4-carboxylic
acid (syn isomer), white powder, mp 170 to 175C
20 - ~decr).
I.R. (Nujol~ : 3400, 3300, 3200, 1770, 1670,
16~0, 15209 1280, 1~40, 1160
000 J 9BOg 730 cm 1
(41) 7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4--~.
thiad~azol-3-yl)acetamidoJ-3~ 3-piperidinopropyl~-
lH-*etrazol-5-yl]~hiomethyl-3-cephem-4-carboxyli~
acid (syn isomer~ ) mp 230~C (dec.~ .
I.R. Nujol: 3300" 3200~ 1770, 1570, 1600
1520 cm
3~ ~
A solution of 7~2-phenoxyimino-2-(5-amino-192,4-
~hi adi az o 1- 3 yl ) ac et a~nido J - 3 - [ 1- { 2 - (N - t -
butoxycalbonylami~o)e~hyl}-lH-te~razol-S-ylJ;
thiomethyl-3-cephem-4-carboxylic acid tsy~ isome~
(1.4 g) i.n foTmic acid ~14 ml) was sti~red at ambient
132
te~peratuxe for 3 hollrs and evaporated ~o dryness.
The residue was diss-olYed i:n a mixture o~ ethyl acetate
and an aqueous solution of sodium bicarbonate and
adjusted to pH 2 with 10% hydrochloric acid.
The aqueous layer was sepaTated ou~ 9 washed with ethyl
acetate and concentrated to remove ethyl acetate.
The aqueous Solution was su'bjected to column chromato-
graphy on Diaion HP-20 Tesi:n (TTademaTk: pTepa~ed by
Mitsubishi Chemical Industries L*d.). A~er the
column was washed with wa~eT, elution ~s carried out
- wi*h 50~ aqueous methanol. The eluen~ was eYaporated
to Temove methanol under reduced pressure and ~he
resul~ant aqueous solu~ion was lyophili~ed ~o ~ive
7-~2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol 3-yl~-
acetamido]-3~ 2-aminoethyl3-lH-tetrazol-S-yl]-
thiomethyl-3-cephe~-4-c~rboxylic acid (syn isomer~
(0.3 g), mp 180 to 185~C (dec.).
I.R. (Nujol~ : 3300~ 3250, 1760, 1670, 1620,
1590 3' 1520 cm~l
~ N~MoR~ td6-DMSOg ~;) 3~40 (2H~ broad s~ 3~60
~ZH, broad s), 4.23 ~2H, broad s), 4.60
(2H~ broad s), 5013 (lH, dJ J=4Hz~ 5.83
~lH~ dd~ J=4 and 8Hz) a 7.0-7,S ~5H9 m),
8.33 (2H~ s~ 9.90 (lH, d, J-8Hz)
~5
A solution of 7-[2-{3-~N-t-butoxycarbonylamino)-
propoxyimino}-2-(5-amino-lJ2J4-thiadia~.ol-3-yl)-
acetamido]-3-~1 {2-~N-t-butoxyca~bonylamino)ethyl}-
lH-~etrazol-S-yl]thiome~hyl-3-cephem-4-carboxylic
acid tsyn isomer)(4.0 g) in--formic acid ~40 ml) was
stiIred for 2~5 hours at ambien~ ~emperature.
The Teaction mixture was evaporated and dried under
reduced pressure to give oil. To ~he oil were added
water ~40 ml~ a~d 1~ hydrochloric acid (5 ml~ to give
clea~ solu~ion. The solution was subjec~ed to column
chromato~raphy on Diaion HP-20 resin (Trademark:
prepare~ by Mitsubishi Chemical IndustTies Ltd.) and
eluted successively with wateI and 5% aqueous methanol
to give 7-[2-~3-aminopropoxyimino)-2-(5-amino-1,2,4-
thi~diazol-3-yl)acetamido]-3~ (2-aminoethyl)-lH-
tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid
tSyn isomer)(Q.95 g),-mp 184 to 196C (dec.~.
Nujol) : 3400-3100, 1760~ 1660, ~610,
15209 1170~ 1060, 1010 cm l
N-M-~ (d~-DMSO ~ D2O~ lo9 (~H, m), 2.8
(2H~ m)~ 3.3 (2H, m), 3.5 (2H, m)~. 4.1
(4H, m)~ 4.5 ~2H, m~, 4.90 ~lH~ d, J=5Hz),
5.56 (l~ d~ J-5Hz)
Example 24
lS A solutio~ of 7-E2-{2-~N-t butoxycarbonylamino)-
ethoxyimino~-2 ~5-amino-1,~,4-thiadiazol-3-yl)a~etamido]-
3 (l-carboxymethyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-
4^carboxylic acid ~syn isomeT)~1.9 g) in formic acid
(28 ml) was s~irred for 2 hours at ambient temperature.
~ The reactisn mixture was post-trea~ed i~ a onventional
- manner to gi~e 7-~2-(2-aminoethoxyimino~-2-(5-~mino-
1,2,4-thiadiazol-3-yl)acetamido]-3~ carboxymethyl-
. lH-tetrazol-5-yl)thiomethyl 3-cephem-4-carboxylic acid
~syn isomer)(0.55 g), mp l90 to 198~C ~dec.).
I.R. (Nujol) : 3250, 3160, 176Q9 1650~ 1615,
1522 a 1020 cm ~
N~M.R. (DC~ 3.~1 ~2H7 broad 5), 3.28-3.65
-~2H, m~,~4.35 ~2H, broad s~p 4.4~-4.78
(2H, m), 5.25 ~lH, d, J-4~5Hz)y 5.42
- ~2H~ s), 5.88 ~lH, d~ J=4.5Hz)
ExamPle 25
A mixture of 7-[Z-(2-cyclopenten-1-yl~oxyimi~o-2-
~5-~mino-1,2,4-thiadiazol-3-yl)acetamido] 3-~1-{2-(N-
t-bu~oxycarbonylaminoethyl}-lH-$et~azol-5-yl3~hiomethyl-
3-rephem-4~carboxylic acid (syn isomeT)(~.5 g3 and
~34
formic acid (i5 ml) was stirred for 2 hours at room
temperature. The reaction mixtuTe was evapo~ated
and the residue was washed successively with diethyl
ether and acetone, The washed residue (2.65 g) was
added to an aqueous solution of sodium bicarbonate
(60 ml.). The mixtuTe was stir~ed and then fil~ered
to separate insoluble materials. To th~ filt~ate
was added e~hyl acetate and. the mixture was adjus~ed
to pH 3 with 3~ hydrochloric acid and then the aqueous
~ 10 ~ayer was separated. On the o~her hand~o the
fil*ered materials ob~ained abo~e were added water and
ethyl ace~ate. The mixture was adjusted to pH 3 with
10~ hydrochloric acid and then the aqueous layer was
separated. The separated aqueous layers were combined~
adjusted to pH 2 with 10% hydrochloric acid,--washe~
with ethyl acetate an~ evaporated to remove ethyl
ace~ate. The residua was subjected to column chToma~o-
graphy ~non ionic adsorption resin 9 Diaion HP-20 prepared
by Mitsubishi Chemical Industries), elu~ing with wa~er,
~0 30% methanol, 50~ me~hanol and 100% metha~ol.
The fractions con~ai~ing the object compound were -
collected~ evaporated and then lyophilized to give
7- [2 ~2~cyclopenten-1-yl)oxyimino-2- t5-amino~ ,4-
thiadiazol- 3-yl3 acetamido] - 3- [1- (2- aminoe~hyl) -lH-
Z5 ~e~razol-~-yl)~hiomethyl-3-cephem~4-carboxylic acid
(sy~ isomer)~580 mg)p mp 175 to 180C ~dec.).
I 7 R~ (Nujol~ : 3400~ 3300, 3170 9 1760, 1665,
1610~ 1520 cm~l
N.M.R. (d6-DMSO~ 1.87-2.5~ (4H, m)) 3.27-3.73
~4H, m), 4.13-4.37 (2H, m)~ 4.57-4.80
(~H3 m), 5.03 (lH, d, J-SHz), 5.27-5.53
(lH, m), 5.70 (lH, d9 J=5Hz~, 5.85-6.27
(2H, m~
E~ __6
-
~5 The following compounds were obtained according to
~3~
similar manners t~ those of Examples 22 to 25.
(1) 7 I2- ~2-Amino~thoxy:imino) -2-(5-amino~ ,4-
thiadiazol - 3 -yl) ace~amido] - 2 -methyl - 3 -cephem-4 -
carboxylic acid (syn isomer), mp 190 to 195C
~dec . ) .
I.R. (Nujol): 33009 3150, 1760, 1660, 1575,
.152a, 1400 ~m 1
N.M. R. fD2O~DCR ~ 55 (3H9 d.9 J-7H~),
3.5 ~2H3 t, J-4.6Hz); 3.7-4v2 (lH,
4.67 (2H, t, J~4.6Hz), 5,27 (lH, d,
Ja4.5Hz), 6.03 (lH, d, J~4.5Hz),
6.90 (lH, dJ J=6H~)
(2) 7-E2-(3-Aminop~opoxyimino)-2-(5-amino-1,2,4-
~hiadiazol-3-yl)acetamidoJ-2-methyl-3-cephem-4-
ca~boxylic acid (syn isomer) 9 mp 182 to 187~C
- (dec, ~ .
I . R3 ~Nuj ol): 3260 , 3150 " 1758 3 ï660 " 1616 ,
,. 1575, 1520, 1400 cm~l
N.M.R. ~DCQ:D20, ~ .5~ (3H, d, J=6.5Hz) 9
- 20 - 1.93-2.S0 ~H, m), 3.25 (2H, t9 J=7Hz),
3.70-4.15 (lH, m~, 4~5 (2H, t, J-6Hz),
5.Z3 (lH3 d~ J=4.5HZ) ~ 6.0S (lH, d,
J-4. 5H~, 6. 88 (lH9 d, J=6Hz)
( 3 ) 7 - ~ 2 - ( 3 - Aminoprop oxyimino) - 2 - ( S ~ amino -1, 2, 4 -
thiadi2zol 3-yl)acetamido~-3-methyl-3-cephem-4-
carboxylic acid (sy~ is~m~r3 ~ mp 175 to 195C
(dec. ) ~
IoR~ tNujol) 3300O 3100~ 1770- L74()~ 16~iOg
1620 ~ 1570, 1520, 1280 9 1170 9
1060 9 1020 cm~ 1
N.M~R. (d~,-DMSO~I:2O, ô) ~ 7 (3H, s), 1.9
(2H9 m), 2.9 t2H, m), 3. 2 (2H9 m) 9
4.2 (2H, m) y 4.93 (lH, d, J35Hz)
5 . 6n ~lH, d, J35Hz) . . -~
35 (4) 7- ~2- (3-Aminopropoxyimino) -2- (5-amino ~1,2,4-
-. ~3~
thiadiazol-3-yl)ace*~mido~^3-chloro-3-cephem-4
carboxylic acid (5yn isomeT~ J mp 190 ~o 205C
(d~c,).
I.R. ~Nujol~ : 34al0-3150~ 1760, 1660,
S 1630-15909 15Z0, ;~40, 1170,
1030 cm 1
N.M.R. ~d6-DMSO, ~) : 2.00 ~2~, m) J 2.90
(~H, m)~ 3.33 and 3.83 ~2H~ ABq~
J=16Hz~, 4.20 (2~, m), S.09 (lH,
d, J-SHz~ ~.60 (lH9 m), 8.lS ~H,
~), gO50 ~lH, m)
(5) 7-~2-~2-Aminoethoxyimino)-2-~5-amino-1,2,4-
thiadiazol-3-yl~acetamido~-3-[1-(2-aminoethyl)-
lH-tetraæol-S-yl3thiomethyl-3-cephem-4-carboxylic
acid (syn isomer); mp 182 to 187C ~d~c.).
IoR~ ~Nujol) : 3350~ 3150, 1760, 1660~ 1625,
1565 9 15~ cm 1
N.M.R. ~d6-DMSO9 ~ : 3.~-3.9 ~6H, m),
4.0594.32 ~2H, ~Bq~ J-14Hz)~ 4~4-5.Q
~4H9. m), 5.22 (llH, d, 3=4.5Hz)
~6~ 7-~2-(2 9 2 J 2-Trifluoroethoxyimino)-2-(5-amino-
17 2 9 4-thiadiazol-3--yl)acetamido]-3~ 2-
aminoe~hyl}-lH-tetrazol-S-yl~.hiomethyl-3-cephem-
4-carboxylic acid tsyn isome~, mp 185 to 190C
(dec.3~
I.R. ~Nujol) : 3300, 31707 1760~ 16~0, 1615
1500 cm~~
N.M.R, (d6-9MSO, ~ : 3.17-3~83 (4H, m~,
4.28 (2H9 broad s), 4.47-4.93 ~4H, m3,
S.10 (lH~ d, J-5Hz), 5.73 (lH, dd,
3=5 and 8Hz), 8.20 (2H9 broad s~g
9.65 ~lH, d, J-8Hz)
~7) 7 C2-Cyclopentyloxyimino-2-~5-amino-132~4-
thiadiazol-3 yl)acetamido~-3-[1-~3-aminopropyl)-
lH-~trazol-5-yl]~hiome*hyl-3~cephem-4-carboxylic
acid (syn isomeT), white powder, mp l9S ~o. 193C
~dec.).
I~R. (Nujol) : 3300; 3150, 1760, 1660, 1620,
1520~ 1280, 1180, 1000 cm 1
N.M.R. (d6 DMSO, ~) : 1.70 (8H, m), 2.20
~2H, m)~ 2.87 (2H, m), 3.57 (2H, m),
4.03-4.~60 (4H, m)~ 4.70 ~lH, m~ 3
S.00 (lH, dJ J=SHz), 5.63 (lH, dd9
J=S and 8Hz~, 8~10 ~2H~ m), 9.40
(lH, d, J-8~z~
(8) 7-~2-~2-Cyclohexen-l-yl3Oxyimino-2-~S-amino-
lp2~4-~hîadia~ol-3-yl)~cetamido]-3~ t3-
aminopropyl~-lH-tetrazol-5-yl]thiomethyl-3-
cephem-4-carboxylic acid (syn isomer3 a mp 185 to
190C (dec.).
I~R. (Nujol~ : 3280, ~150, 1760, 1665, 1520,
1520 cm
N.M.R. (d~-DMSO~ 1.47^2.30 ~8H, m),
~.73-3.13 (2H~ m~, 3.63 (2H9 broad s),
- 4.17 4.60 ~4H9 m), 4.60-4.90 ~lH~ m;,
5.03 (lH, d, J~5Hz)~ 5O73 ~lH, ddg
J=S and 8H~), 5.75-5.99 (2H, m),
. 8.13 (2H~ broad s~g 9.43 (lH~ d~ J=BHz)
A mlx*ure of 7-l2-t-butox)rcarbonylm~thoxyimino-
2-~5-ami~o-1,2,4-~hiadiazol-3-yl)ac~tamido]-3-
(1"3,4-thiadiazGl-2-yl)thiome~hyl-3-cephem-4-
carb~xy1i.c acid (5yn isome~ ~1, 6 g . ) ~ ~rifluoroacetic
ac~ d (~0 ml7 and anisole t~ ml) was stirred :L~or 30
minu~es a~ ambient tempe~ature~ The ~eaction mlx-
ture was e~aporated and the residue was pulv rized
with die~.hyl ether" collected by fil~ra*ion and then
dried, The obtained product ~1.6 g) was dissol~ed
in an aqueous solu~ion of sodium bicarbonate~ washed
wi~h e~hyl ac~ta~e and ~hen added ~o e~hyl acetate.
B2
`3 8
Th~ mi~ure was adjusted to pH 2 ~ith lN hydrochloric
~oid and extrac~ed with ethyl acetate. The extract was
washed with a satura~ed aqu~ ous solution of sodium
chloride, dried over magnes:ium sulfa~e and the~ evaporated.
5 The residue was pulveri~ed with diethyl ether 3 collected
by fil~ration and dried to give 7-[2-caTboxym~thoxyimino-
2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-
~hiadiazol-2-yl~hiomethyl-'3-ceph~m-4-carboxylic acid
~syn isomer)(0.52 g~ mp 170 to 17SC (dec.).
I.R. (Nujol~ : 3250, 31509 1770, 1710, 1680,
lSlO, 1520 cm~l .
N~MoR~ (d6-DMSOg~3 : 3.~7 (2H, broad s~, 4.55
(2H~ ABq, J=13Hz3, 4.63 (2H, s) 9 5~12
(lH~ d, J-4Hz), 5.80 (lH, dd, J-4 and
8Hz~ 8.15 (2H, s), 9.55 ~lH, d, J=BHz~,
9 . 5~ , s)
The following compounds were obtain~d according
to a similar manner to tha~ of Example 27.
(l~ 7-[2-Carboxymethoxyimino-2 (5-amino-1,2,4-
~ thiadiazol-3-yl)acetamido]-3-(1-a~lyl lH-~etra~ol-
5-yl)~hiome~hyl-3-cephem~4-carboxylic acid ~syn
isomer) 9 mp 145 to 150C (dec~).
I.R, ~Nujol) : 3400, 3300, 32D0 9 1765, 1720,
~5 1680, 1620, 1520 cm~l
N.M.R. (d6-DMSO~) : 3O70 (2H, broad s) 9
4O30 and 4.47 (2H, ABq, 3=13Hz)1
4.68 ~2H9 s)7 4.83-5015 ~2H, m), 5.15
(lH, d, J=5Hz) 7 5.17-5.50 ~2H~ m),
5.~5 ~lH, dd7 J-5 and 8H~), 5.60-6~20
~lH9 m~ 8~13 (~H, broad s~ 9.53 (lH,
dl J-~Hz)
~2) 7-[2-Carboxyme~hoxyimino-2-~5-amino 1~2,4-
~hiadiazol-3-yl~acetamido~cephalosporanic acid
(syn isomer3, mp 160 ~o 165~ (dec.).
I.R. (Nujol) : 3300, 3200, 1770, 1720,
1680, 152Q.cm 1
N.M.R. ~d~-DMSO,~) : i!.10 ~3H, s)~ 3.60 (2H,
broad s) 9 4.70 (2H, s~, 4.77 ~d 5.03
(2H9 ABq~ J-14Hz), 5.20 (lH, d, J=4Hz),
5.8~ ~lH, dd~ J=4 and 8Hz) 9 B.18 (2H, s~,
9.57 ~lH, d, J 8Hz)
(3) 7-[2~Ca~boxymethoxyimino-Z-(5-am.ino-1~2,4-
thiadiazol-3 yl~ a~e~amido~ -3- ~te-tra7010 ~1, 5-b~-
pyridazin-~-yl~thiome~hyl-3-cephem-4-carboxylic
acid ~syn isomer3S mp 170 to 175C tdec.).
~Ro ~Nujol) : 3400 9 3300~ 3~80~ 1765, 1720;
1680~ 1615~ 1520 cm 1
NoM~R~ ~d6-DMSO~ 3.75 ~2H~ broad s),
4.28 and 4,60 ~2~, ABq, J=13Hz)~
4.67 t2H, s)~ 5.17 (lH~ d~ J 5Hz~,
5,87 ~lH, dd, J=5 and 8Hz), 7.77
~lH~ d, J=lOHz), 8.17 ~2H, broad s) 3
B.6Q ~lHp d, J-lOHz)~ 9.57 (lH~ d,J=8Hz)
~4) 7-~2-Ca~box~ethoxyimino-~-(5-amino-1,~,4-
~hiadiazol-3-yl)asetamido~-3~ 2-aminoethyl)-lH-
tetrazol-5-yl~thiomethyl-3-cephem~4-carboxylic
acid ~sy~ isome~), mp 185 ~o 190C (dec.).
: I.R. ~Nujol) : 3250, 1755, 1660, 1590~ 1520 cm 1
N.M.R. ~d6-3MSO,~ : 3.23 3.67 (4H, m),
4.07 ~nd 4.35 ~2H9 ABq, J=13Hz),
4.~3-4.80 ~4H, m~, 5.03 ~lH, d, 3=5Hz),
5.70 ~lH, dd~ J~5 and 8Hz), 8.15 t2H,
. broad s), 11.03 ~lH~ d, J=8Hz)
~5) 7-[2-Carboxyme~hoxylmino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido3-3-~1-phenyl-lH-
tetrazol-5-yl~thiomethyl-3-cephem-4-carboxylic
acid (syn iSOmeT), mp 155 to 160C (dec.~.
I.R. ~Nujol) : 3400, 3300~ 3180, 176~, 1720,
1680, 16159 1S20p 1495 cm 1
N.M.R, ~d6-DMSO,~) : 3.65 (2H, b~oad s),
4.~8 and 4.52 ~2H, ABq~ J=13Hz),
4.63 (2H, s), 5.07 (lH, d, J=5Hz),
5.80 (lH, dld, J=5 and 8Hz), 7.63
(SH, s); 8.:10 (2H, broad s), 9.47
(lH, d~ J-8Hz)
A mixture of 7-[2-~rityloxyimino-2-(5-amino-
192,4~hiadiazol-3-yljace~amido~-3 ~5-methyl-1,3,4-
thiadiazol-2-yl~hiomethyl-3-cephem-4 carboxylic-acid
(syn isomer)~.5 g3, conc.hydrochloric acid ~4,5 ml)
~d methanol ~45 ml~ was s~irred for 7 hours at
ambient tempera~ure. Methanol was distill0d of
fTOm the reaction mixture and the residue wa~
adjusted to pH 5 by adding ethyl acetate and an
- aqueous solutio~ of sodium bicaTbo~ate. To the
separa~ed aqueous layer was added ~thyl aceta~e and
the mixtuTe was adjusted ~o pH 2 wi~h lD% hydrochloric
acid. The separated ethyl acetate layer was dried
over magnesi~m sulfa~e and evaporated in vacuo to a
- vol~me of 10 mlO Precipita*es w~re collected by
filtration, wash~d with ethyl aceta~e and die~hyl
ether and dried ~o give 7~ hydroxyimino~2-{5
. amino ~2,4-~hiadiazol-3-yl)ace~amido]-3-(5-methyl-
1,3,4-~hiadiazol-2^yl)~hiome~hyl-3-cephem-4-carboxylic
acid ~syn isomer) ~1.4 g)J mp 153 ~o 162DC ~dec.).
Nujol) : 3Z60~ 31609 1763, 1665~ 160B,
15~0 cm ~
f ~M~R~ ~d6-~M~0~ . 2~67 ~3H, s3~ 3.67 (~H,
~ broad s)~ 4.23 and 4.53 C2H, A~q, J=13Hi)~
i.12 ~lH, d~ J=4.5H~, 5.8~ (lH~ dd,
J=4,5 and 8.5H~, 7.98 ~2H, broad s3
9.37 ~lH, d7 J=8.5Hz~
Exam~ 0
; 35 A solution of 7-~2 hydroxyimino-2-(5-amino-1,2,4-
,
thiadiazol-3-yl)acetamido]-3-~5-methyl-1,3,4-
thiadia~ol~2-yl)thiomethyl-3-cephem-4-carboxylic aci~
(syn isomel) (257.3 mg) and sodium bicarbonate (42 mg)
in water ~7 0 ml~ was lyophi.lized. The obtained pro-
duct was dissolved in N,N-cLimethylformamide (5 ml)
and to ~he solution was added a solution of iodomethyl
pi~alate (14205 mg~ in N,N-dimethylormamide ~-ml~~
with s~iTring and ~he stirring was continued for 20
minutes. The reaotion mixt:ure was washed with wate~
(x3) 7 dried over magnesium sulfate and evapora~ced.
The residue was pulverized with diethyl ether ~o give
pivaloyloxyme~hyl 7- E2-hydroxyimino-2- (5-amino-1,2,4-
thiadia701-3-yl3ace~amido] -3- (5-me~hyl-1,3 94
thi adiaz o l - 2 - yl ) thi ome~hyl - 3 - cephem - 4 carb oxy l at e
(syn isomer) t240 mg), mp 132 to 135~C (dec.) .
I.R. (Nujol): 3~70, 3160~ 1775, 1745, 1675,
- 1610~ 1520, 1115 cm 1
N.M.R. ~d6-DMS0"~): l.û9 ~9H, s~, 2.70 ~3H, s),
3,66 and 3.82 ~2H, ABq~ J=15Hz39 4.18
and 4. 58 (~H, ABq~ J-14Hz~, 5~ 20 ~lH, d7
Jo40 SH~) D 5~ 80-6. 2 (3H" m), B. 04 t2H,
broad s) j 9.47 ~lH, d9 J=7.5Hz)
~xamDle 31
The following compounds were obtained according
to a similar manner ~o ~hat of Example 30.
~1) 4-Ni~robenzyl 7- ~2- ~4-chlo~ophenoxyimino) -2-
~5-amino-1,2~4-~hiadia7.ol-3-yl)acetamido~-3-cephem-
4-~arboxylate (syn isumer), mp 155 ~o 160C (dec.).
I~R. ~Nujol) : 3300, 318OD 1770, 1720, 1680,
1625, 1600~ 15809 1520, 1480 cm 1
~2) 4-N~ obenzyl 7-~2-ph~noxyimin~-2-(5 amino-
1,2,4-thiadiazol-3-yl)acetamido~-3-cephem-4-
ca~boxy:late ~syn isomer)~ mp ~4D ~o 145C (dec.).
l.R. ~Nujol~ : 3300, 1775, 1720, 1680~ 1625,
1600, 15~û~ 152û cm 1
(3~ 4-Nit~oben~yl 7- L2- (3-trifluoromethylphenoxyimino) -
2-(5-amino-1~2 3 4-thiadiazol-3-yl)acetamido3-3-
cephem-4-carboxylate (syn isomer), mp 136 to 140C
(dec.).
I.R. ~Nujol) : 33709 3200, 1780, 17309 1690,
1680, 1630, 1610~ 1520, 1~50,
13~J 1280, 11~0, 1125, 975,
850~ 740 cm~l
(4) 4-NitTobe~yl 7-[~-~4-fluorophenoxyimino)-2-
(5-amino-1,2J4-thiad.iazol-3-yl)acetamido~ 3-cephem-
4-carboxyla~e (syn isomer), mp 135 ~o 140C (dec.)~
I.R. (Nujol~ : 3~00, 32~0, 1770, li~0, 1680,
16~5, 1605, 1500, 1495 cm~l~
~53 4^Nitrob~zyl 7-l2-~3-~N-t-butoxycarbonyiamino)-
1$ propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)-
acetamido3-3-chloro~3-cephem-4-caTboxyla*e ~Syll
isom~), mp 91 to 100C (dec.),
N.M.R. (d6-DMSO~D~O9~) : 1,38 ~9H, s3, 1.80 ~2H,m)~
. ~.06 t2H, m)g 37-4 3 t4H~ m), 5.33 ~lH,
d, J-5Hz)g 5.49 ~2H, s)~ 5.95 (lH~ d,
~ J=5Hz), 7O74 (2H, d~ J~9Hz), 8.92 (2H,
d~ J-~Hz)
(6~ 4-Ni~robenzrl 7-[2-allyloxyimino-2-(5-amino-
1,294-thiadiazol-~-yl~acetamido]-3-cephem 4- -
carboxylate (syn isomer)~ mp 125 ~o 130C [dec~.
I.R. ~Nujol) : 3~00, 177D~ 1720, 1680, 1630,
1610 9 1520 cm~
~3
_ 2
A mixture o 2-allyloxyimino-2-(5-amino~ ,4-
thiadiazol-3-yl)acetic acid (syn isomer)(l.37 g)
and phosphorus oxychloride (3.67 g) in me~hylane -
chloride (30 ml~ was s~irred for 2 hours at ambien~
tempera~ure and then cooled to -12 ~o -15C.
To the cold mîx*ure was added dimethylformamid~
~244 ml) and the mixture was sti~red or 45 minu~es
at 8~ ~o -lQC. ~n the other hand, a mix~ure of
20 ~ 7-amino-3- (1 9 3,4-thiadia~ol-2-yl~hlome~hyl-3-
cephem-4-carbo~ylic acid (2.9 g) and trimethyl~-.
silylacetamide (8 g) in me~hylene chloride (40 ml)
was warmed to maXe a solution. The solution was
ooled *o -25C ~nd added to the above activated
~5 mixture, The reac~ion mix~u~e was stirred for ~0
minutes a~ -8 *o -10C a~d poured into a cold
aqueous solution of sodium bicarbonate. The mixture
was s~irred for 30 minutes ~* ambient temperature
and the aqueous layer was separated out.
The aqueous soluti~n was adjus~ed to pH l wi~h 10%
hydrochloric acid and extrac~ed with ethyl ~cetate.
- The extract ~as dried ove~ magnesium sulf t~ and
evapora~ed to dryness. The residue was tritura~ed
with diethyl ether ~o give a crude 7-~2-allyloxy.
imino-2 ~5-amino-1,2,4-thi2dia~ol 3-yl)acetamido~-
$~)
3 (1,3~4-~hiadiazol-2-yl)thiome~hyl-~ cephem-4-
carboxylic acid ~syn isomer~(2.1 g). The crude
product was dissolved in an aqueous solution of
sodium bicarbonatP and rep~ecipitated with an
addition of 10% hydrochlori.c acid to give pure
object compound ~lolS g)~ mp 138 to 140~C ~dec.)
I. R. (Nujol) : 33503 3230, 1780, 1680,
1620, 1530 cm 1
N.M.R. (d6-DMSO~ 3.63 ~2H, broad s),
4.27 and 4,52 t2H, ABq9 J=14Hz) 9 4.5 -
... 4.8 (2~ m~ 5.10 (lH, d~ J=5Hz), 5~0-
5.5 (2H7 m~, 5.78 ~lH, dd, J=5 ~nd 9Hz~,
5.7 - 6.3 ~lH, m~, 8~0g ~2H, broad s),
9.48 ~lH~ s)~ ~.S3 (lH, d~ J=9Hz)
~ _3
A mix~ure of 2-(292,2-~rifluoroethoxyimino)-2-
(5-ami~o-1~2,4-thiadiazol-3-yl)acetic acid (syn
isomer)~l.62 g) and phosphorus oxychloride ~3.67 g)
in methylene chloride (30 ml) was s~ir~d for 1.5
hours at ambient ~emperature and then oooled ~o -12
~o-15~C. To ~he cold mixture was added dimethyl-
ormamide (2.4 ml) and the mixture W8S stirred for -
45 minutes at -8 to -10C. On ~he other hand, a
mixture o~ 7-amino-3-~1,3,4-thiadiazol-2-yl)thio-
me~hyl-3-cephem-4-carboxylic acid ~2.9 g) and
trime~hylsilylace~amide ~8 g~ i~ methylene chloride
(40 ml) was warmed $o maXe a solu~io~ The solution
was coolecl to -Z5~C and ~dded ~o ~he above activa~ed
mixture. The reaction mixture was stirrad for 30
minutes at: ~10C and poured into a cold aqueous
sslution of sodium bicarbona~e. The mixture was
stirred or 30 minutes at ambien~ temperature and
the aqueous layer was separated out. The aqueous
solution was adjusted ~o pH 2 wi~h 10% hydrochloric
3S a id and extracted with ethyl ac~ta~e. The extract -
i~
was dried over magnesium sulfate and evaporated to
dryness. The residue wa~ ~riturated wi~h diethyl
etheT to gi~e a crude 7-~2-(2,2,2-trifluo~oe~hoxy-
imino)-2-~5-amino~ ,4-thiadi~zol-3-yl)aceta~.ido]-
- 5 3-(19 3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn iSomer)(2.45 g). The crude
product was di5solved }n an aqueous solution of
sodium bicarbonate ~nd reprecipitated with an addi-
tion of 10~ hydrochlo~ic acid ~o give pure ob]ect
1~ compound tl.42 g). mp 153 ~;o 158C (dec.~.
I. R. (Nujol~ : 3350, 3250, 17809 1680~ 1625 cm 1
N.M.R.(d6-DMSO~ 3.70 ~2H, broad s~, 4.33
and 4.58 (2H, ABq, J=13Hz), 4 70 and 4.32
t2H, ABq, J=9Hz), 5.17 (lH, d, J=SHz),
5.82 (lH, dd3 J 5 ~nd 8Hz)~ 8.18 (2H,
broad s), 9.55 (lH, s), 9~70 ~lH, d, J=8Hz~
~.~.8~
A mixture of dimethylformamide (6 ml) and
phosphorus oxychloride ~918 mg) was stirred for 30
minu~es at ambien~ temperature. Methylene chloride
(6 ml) was added th~re~o and then 2-dichloroacetoxy-
imino-2-(S-formamido-~J294-thiadiazol-3-yl)acetic
acid tsyn`isomer~(l.6 g)~iwas added thereto a~ -~Q to
-25C. The ~ix~ure was stirred for 30 minutes at
--10 ~o -15~C. To ~he ~esulting mix~ure was added
at -10 to -153C a solution of 7-amino-3-~1,3,4-
thiadia701-2-yl)thiomethyl-3-cephem-4-carboxylic ~cid
(2.0 g) and ~Timethylsilylacetamide (6 g) in methylene
chloride ~30 ml), and the mixture was stirred for
33 minutes at -S to -15C. Me~hylene chloride was
evaporated from ~he reaction mix~ure and to the
residue were added ice-water and ethyl ace~ate. The
resulting mixture containing 7-[2-dichloroace~oxy-
imino-2-(~-formamido-19 294-thiadiazol-3-yl)-
- 30 acetamido~-3-~1~3 94 -thiadiazol-2-yl)thiomethyl-3-
`~ cephem-4-carboxylic acid ~syn iSomer) was adjusted
to pH 5 with an aqueous solution o sodium bicarbonate.
An aqueous layer was separated and ethyl acetate was
~dded there~o. The mix~ure was adjusted ~o pH 2
with 10% hydrochloric acid and an insoluble substance
o
~4~
was filtered off. The filtrate was ex~racted th~ee
times with ethyl acet~te. The extracts were dTied
over magnesium sulfate and evaporated. The residue
was tritura*ed with diethyl ether and precipitates
were collec~ed by filtration and washed with diethyl
ether to give 7-[2-hydroxyimino-2-~S-formamido 1,2,4-
thiadiazol-3~yl)acetamido~-3-(1,3,4-thiadia~ol-2-yl~-
thiomethyl-3-cephem-4-caTboxylic acid ~syn lsomer~
(0.9 g). mp 155 to 160C tdec.)
. I. R. ~Nujol) : 32003 1780, 1680, 1520 cm
N.M.R~ (d6-DMS0~ ~) 3.67 (2H, broad s), 4.27
and 4.73 ~2H, A~q~ J=13Hz), 5.13 (lH,
dl J=4Hz) J 5.83 (lH, dd, J-4 and 8H~),
8.BQ (lH, s), 9.50 (lHJ d, J=8Hz),
9.53 (lH,-s), 12.22 (lH, s)
Example 35
The following compounds were ob~ained acco~ding
to similar manners to those of Examples 32 to 34t
(l~ 7-[2-(2-Propyn~loxyimino~-2-(5-amino-
1,2,4-thiadiazol-3-yl)acotamido]-3-~1,3"4-thiadiazol-
~-yl)~hio:me~hyl-3-cephem-4 carboxylic acid (syn
isomeT). mp 140 to 145C ~dec.)
~fl~8
I. R. (Nujol) : 3330, 3250, 1780, 1680,
16~0~ 1530 cm 1
N.M.R, ~d6-DMSOp ~) : 3.47 ~lH~ tj J=2Hz),
3.67 ~2H, broad s), 4.28 and 4.53
~2H, ABq~ J-13Hz), 4.77 ~2H, d, J-2Hz),
5.12 ~lH, dg J=5Hz), 5.78 ~lH9 dd,
J~5 and 8Hz)9 8.13 ~2H9 broad s)~
9.55 (lH~ 5)9 9067 ~lH, d, J=8Hz)
(2~ 7-[2-Benzyloxyimino-2-~5-amino~1~2,4-
~ ~hiadia~ol-3~yl)ac~tamido~-3-(1 9 3,4 *hiadiazol-2-yl~-
; *hiome~hyl-~-cephem-4-carboxylic acid ~syn isomer).
mp 130 to 13~C ~dec.~
I. R. ~Nujol) : 33609 3250, 1780, 1680,
1625, 1530 cm 1
. 15 N.M.R. (d6-DMS0, ~) : 3.63 ~2H9 broad s3, --~
: 4~35 and 4~5~ (2H, ABqg J~13Hz~,
5.13 ~ d, J=5Hz), 5.23 (2H; s),
S.80 ~lH, dd, J~5 a~d 8Hz~ 7.3
~5H~ s~, 8.13 (2H, broad s~5 9-57 ~lH) s~
- 9.63 (lH, d, J=8Hz)
~3 ) 7- E~--&~ Phenoxye*hoxyimino~ -2- ~5-amiTlo- .
1,2,4-thiadiazol-3-yl~acetamido]-3-~1,3,4-thiadia~ol-
2-yl~hiomethyl-3-cephem-4-carboxylic acid ~syn
isomer). mp 163 ~o 167C.(d~c,).
I. R. ~Nujol) . 3350~ 32S0~ 17803 1680) 16309
1600 9 153D, 1500 cm 1
N.M.R. (d6-DMS0~ 3.30 and 3.60 ~2H~ ABq3
: J-18Hz3, 4.0-4,70(6H7 m), 5.10 (lH, d,
J=4H2); 5.93 (lH, dd, J=4 ~nd 8Hz),
6~7~7~5 (SH, m)~ 8.13 ~2~I, s3~ 9050 ~lH~
s), 9,57 (lH, d~ J=~Hz~
(4 ) 7 - ~2~ Me*hylthiomethoxyimino-2- ~5-amino-
1"2"4-thiadiazol-3-yl~acetamido~-3~(1,3 3 4
thiadiazol-2-yl)thiome~hyl-3-cephem-4-earboxylic
3$ acid ~syn isom~r). mp 168-to 170C (dec.)
I. R. (Nujol) : 3350, 3250~ 1780, 1680, 1620,
1530 cm 1
N.M.R. (d~-DMS0, ~) : 2.17 (3H, s~, 3.65 (2H,
broad s)~ 4.30 ~nd. 4.57 (2H, ABq,
J-14Hz), 5.12 (lH, d9 J=4Hz~, 5.20 (2H,
s), 5.80 ~lH, dd, J=4 ~nd 8Hz), 8.~7
(2~, 5) ? 9-53 (lH, s), 9.62 (lH, d,
J-8Hz3
l5~ 7-~2-(2-Methylthioethoxyimino)-2-(~-amino-
1,2,4-~hiadia201-3-y~)acetamido]-3-~1,3,4-thiadiazol-
2-yl)thiomethyl-3-cephem-4-carboxylic ~cid (syn
isom0~). mp 125 to 130C (dec.)
I. R. (Nujol) : 3350, 3250~ 1780~ 1680~ 1625, - - I
1530 cm~l . l;
N.M.R. (d6-DMS09 ~) : 2.08 ~3H9 s)~ 2.72 (2Hy
~, J=7Hz~, 3.68 (2H, broad s), 4.28
- ~2H, t9 J~7Hz~ 4.30 and 4.55 ~2H, ABq,
J~13Hz), 5.13 (lH~ d, J=SHz~, 5082 (lH,
dd~ J=5 and 8H~)l 8.15 (2H, broa~ s~,
9.52 ~lH, d, J~Hx), 9.53 ~lHg s)
(6~ 7-[2-ph~noxyimino-2-~5-amino-lj?y4-
~hiadiazol-3yl~acetamido~ -3-~lp3,4-thiadia~ol-2-yl) -
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
mp 145 to 1~0C (dac.)
I j, R. ~Nujol) : 3350 ~ 3230, 1780, 1680, 1620,
lS90, 1530 ~m 1
N.M~R. Id6-DMS0, ~) : 3 1~ 70 (2H, broad s),
4 .30 and 4.60 (2H" ABq, J-14}Iz) p 5.23
(lHp d, J-~Hz)9 5.92 ~lH~ dd~ J-5 and
3~ 8H.~), 7~0-7.6 ~5~; m), 8.30 (~H~ broad
!5), 9.52 (lH~ s~, 9.83 (lH, d, J-8Hz)
~) 7-~2- ~yanomethoxyimino-2-~5-ami~o-1~2~4-
~hiadiazol~3-y:L~acetamido~-3-tl,3,4-~hiadiazol-2-yl)-
thiomethyl-3-cephem-4~carboxylic acid ~sy~ isomer).
mp 10~ to lliD~C (dec.)
. ~ .
-
~5~
I. R. (Nujol) : 3350, 3250~ 1780) 1680
1620, 1530 cm~l
N.M.R. Cd6-DMSO~ ~3 : 3.6 and ~.76 C2H, ABq,
J=18~z~, 4.3 and 4.56 (2H, ~Bq, J~13H~),
5.12 ~2H7 s) 9 5.:14 (lH~ dg J=5Hz~,
5.80 (1H J dd, Js~ and 8Hz~, 8.20 (2H,
broad s), 9.52 (lH9 s), 9.78 (lH, d,
J38~z)
~8~ 7-~2-~N,N-Diethylcarbamoyl)me~hoxyimino-2-
~S amin~-1,2,4-thiadiazol 3-yl3ace~amido] 3-(1,3,4-
thiadiazol-2-yl)thiom~hyl-3-cephem-4-caI~boxylic
acid (syn isome~). mp 175 to 180C (dec.3
I. R. (Nujol3: 34~0, 3310; 3200, 177~ 1740,
1680, 1630; 1610, 1515.cm
N.M.R. (d6-DMSO, ~) : 1.00 (3H7 *, J=7Hz~
1,0~ t3H, *~ J=7Hz), 3027 ~4H, q3 J=7Hz~,
3.62 and 3,7Z ~H, ABq~ J-18Hz), 4.33
and 4.55 (2H, ABq, Jsl4Hz~ 9 4.B8 (2H, s),
5015 (1~, d, J=5Hz) 3 5.83 ~lH9 dd,
J-5 ~nd 9Hz3, ~.13 (2H, b~oad s), ~.5
. ~lH~ s~ 9.62 ~lH~ d, J-9Hz)
(9 ) 7~ Ethoxycarbonyl-l-methyle~hoxyimino~-
7 - ~5 -amino-1,2~4-~hiadiazol'~3-yl)ace~amido~-3-(1,3~4-
thiadiazol-Z-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer). mp 130 *o 135C (dec.)
I. R. (Nujol) : 3360, 3~40~ 1780~ 17303 1690,
1630~ 1530 cm l
N.M.R. (d6-DM5O~ ~) : 1.18 (3H, t, J-7Hz)s
1.50 (6H, s), 3.72 (ZH, broad s~,
3~ 4.13 (2H9 q3 J=7Hz), 4.33 and 4.58 ~2H9
ABq, J=13H~ 5.18 (lH; dj J-5Hz),
5.85 (lH, dd~ J=S a~d 8Hz), 8.18 ~2H,
bToad s), 9.48 (lH, d~ J=8H~), 9.57 (lH,
s)
~lQ) 7-~Z-Ethoxycarbonylme~hoxyimino 2~
~5~
amino-1,2,4-thiadiazol-3-yl)acetamido]-3-~1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-ca~boxylic
acid ~syn isomer) mp 120 to 12-C ~dec.)
I. R. ~Nujol) : 3370, 32iO, 1780 9 1690,
1625, 1530 cm 1
N.M.R. ~d6-DMS0, ~ : 1.23 (3H, t, J=7Hz),
3.7~ ~2H9 broad s), 4.20 (2H, ~, J=7H2),
4.35 and 4.58 (2H, ~B~ J=13Hz), 4.78
~2H, s), 5.17 (lH9 dg J=5Hz), 5.83 (lH,
10 dd, J=S and 8Hz), 8 2Q (2H, bruad s),
9.58 (lH, d~ J=~Hz),-9.60 tlH, s)
~5
~ Ll ) 7- ~2 -Hydroxyimino- 2 - (5 - formamido- 1, 2, 4 -
~hi~diazol-3-yl~ acetamido~ -3- (1 ,3,4-thiadiazol-2-
yl )thiome~hyl-3-cephem-4-carboxylic acid ~SyTl isomer) .
mp 155 to 160~C ~dec.~
I. R, ~Nujol): 3200, 1780, 16~0, 1620 cm 1
(12) 7-[2-{2~(2-Hexyloxyethoxy~ethoxyimino}-
2-(5-amino-l J 2~4-~hiadiazol-3-yl)ace.~mi:do.~:3~(.1,3,~
th: adia~ol-2~yl)thlom~th~1-3 cephem-4-carboxylic acid
tsyn isomer) . mp 100 to 105DC (dec. )
I.R. ~Nujol): 3340) 3210, 1785, 1685, 1~209
1525 cm
N.M.R. ~df;-- DMSO, ~) : 0,87 ~3H~ t, J-5Hz) ~
0.87-1.73 (8H, m), 3.10-3.93 (lOH, m),
4.10-4.47 (~H" m), 4030 and~4.58 (2H,
ABq, J=13Hz), 5.17 (lH, d, J=5Hz) 3
5.83 ~lH, dd, J=5 and 8Hz), 8.12 (2H,
broad s) 3 3.55 (lH3 d9 J=8Hz) a 9.57 (lH~ s)
(1~) 7-~2-Mesylmethoxyimino-2-(5-amino-1~2~4-
thiadiazol-3-yl~ace~amido]-3-~1,3,4-thiadiazol-Z-yl)-
-thiomethyl-3-cephem-4-c~boxylic acid (syn isomer).
~p 16~ to 167~ c.
I~R. (Nujol~ : 3360, 3230, 1780~ 1690, 1620
1530 cm~
~.M~R. (d~-DMSO, ~) 3,02 (3H, s~ 3.7Z (2H,
broad s)~ 4.3.~ and 4.57 (2H~ ABq, J=13Hz)9
5,15 (lH, d, J~5Hz), 5.30 ~2H~ s),
5,83 ~lH, dd9 J-5 and 8H~)~ B~20 ~2H 9
broad s~ 9.55 (lH~ s), 9.78 ~lH~ d,
J-8Hz)
(14) 7 ~2~Tri~yloxyimino 2-(5-amino-1~2,4
thiadiazol-3-yl)acetamido3-3-~l-methyl lH tetra~ol-
5~yl)thiomethyl-3-cephem-4-carboxylic acid ~syn
isomer) l mp 163 to 167C ~dec~ )
I.R. tliu~ol3: 3480, 335û, 3250o 1785~ ï6~0,
1620, 1530 c ml
~3
N.M.R. ~d6-DMSO, ~) : 3.64 a~nd 3.7~ t2H3 ABq,
J=18~), 3.90 ~3El3 s), 4.24 and 4.38
. (2H, ABq, J=14Hz), 5.18 tlH, d, J34Hz),
5.98 (lH, dd, J=4 and 8Hz)g 7.30 (15H, s),
S 8.08 (2H~ s), 9.~34 ~lH, d, J=8Hz)
(15) 7-E2-Trltyloxyim:ino-2-(S-amino-1~2~4-
~hiadia~ol-3-yl)acetamido~-3-(1,3,4-thiadia~ol-2-yl)-
thiomethyl-3-cephem-~-carbux~ylic acid fsyn isomer)~
mp 175 ~o 178~C ~dec.)
10I.R. ~Nujol) : 3450, 3350, 3200j 1790, 1690,.
- 1620y 1530 cm~l -
~ N.M.R. ~d6-DMSO, ~ : 3.73 (7.H, broad s)-, 4.33
and 4.63 (2H~ ABq, J~13Hz~, 5.10 (lH, d,
J=4Hz)g 6.03 (lH9 dd, J=4 and 8H2),.
157.37 (lSH, s), 8.13 (2H, s), 9.60 (lH, s),
9.87 (lH, d~ J=8Hz)
~1~ 7-~2-Allyloxyimino-2-~5-ami~o-192,4-
~hiadiazol-3-yl~ace~amido~cephalosporanic acid ~syn
Isomer). mp 131 to 133C tdec.)
- 20 -I.R. ~Nu~ol~ : 3350, 3240, 17~0~ 17303 168Q,
1530 9 1240 cm~
N.M~R. ~d6 DMSO, ~) : 2.~7 t3~, s), 3757 t2H~
broad s), 4.5-5.~ (2H~ m), 4.7 (2H,
broad s), 5.1-5.6 (2H~ m~, 5.15 ~lH, d,
~ 2$ J~4Hz3, 5.6-6.4 ~lH, m~, 5.84 ~lH, dd,
J~4.S and 9Hz~ 8,13 (2H, broad s)~
9.67 (lH~ d, ~-9Hz)
(17~ 7~ Allyloxyimino-2-(5-amino-172 9 4-
thiadiazol-3-yl)ace~amido~-3-(l~methyl^lH-*etr zol-
5-yl)thismethyl-3-cephem-4-carboxylic acid (syn
isomer)O mp 154 to 156C (dec.~
I.R~ ~Nujol~ : 3380, 3245, 1780, 1680, 16259
1527 cm 1
N.M.R. ~d6-DMSO7 ~) : 3.53 and 3~77 (2Hg .~Bq,
J~14Hz)g 3.90 ~3H, s), 4.~7 ~2H9 broad ~)~
405-4.8 ~2H, m), 5.0-5.~ (~H9 m),
5.15 (lH, d~ J=4~,~Hzj, 5.5-6.3 ~lH, m),
5.85 (lH, ddl J=4.5 and 9Hz), 7,23
~2H, b~oad s), 9"77 ~lH, d, J=9Hz)
~18) 7-[2-Trityloxyimino-2~5-amino~ ,4-
thiadiazol-3-yl)acetamido]-3- ~1,3,4-thiadiazol-2-
yl3thiomethyl-3-cephem. 4-carboxylic acid (anti
isomer), mp 165 to 170C (dec.)
I.R. ~N~Ijol~ : 3350, 3200, 1785~ 1690~ 1620,
151~ cm~-L
N.M.R, (d6 DMS0, ~3 : 3.70 (2H~ broad s)~ _
4.33 and 4.60 (ZH, ABq, J=13Hz),
5.10 (lH, d, J=4H7.), 5.73 ~lH, dd~
J=4 and 8H~), 7.33 ~15H? s) 9 8.17
~lH, d, J-8Hz)~ 8.23 (2H, s), 9~60
(lH, s)
`` ~l9) 7-~2 Allyloxyimino-2 ~5-amino-1,2a4-
thiadiazo~-3-yl)ace~amido]-3-(5-aminome~hyl-1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxyIic
acid ~syn isomer). mp 161 to 164C (dec.)
I~R. (Nujol3 : 3350, 3220, 1770, 1670~ 1620,
15~5 cm l
(20) 7-[2-Allyloxyimino-2-~S~amino-1,2,4-
thiadi~zol-3-yl)acetamido]-3~ 2-(N~-butoxy
carbonylamino)e~hyl~-lH-~e~razo~-5-yl~thiome~hyl-
3-c~phem-4-ca~boxylic acid (syn isomer). powder.
~21) 7-[~-AilyloxyiminQ-2 t5-amino-1,X,4- ~
~ C2~4~i~
~hiadiazol-3-yl)ace~amido~-3~ 2-aminoethyl)-lH-
~etrazol-5-yl~thiome~hyl~3-c:ephem-4-carboxylic acid
(syn isomer). mp 165 to 169''C tdec.)
I.R, (Nujol) : 3350, 3200, 1768, 1670, 1610,
1522 cm 1
(22) 7-[2-Hydroxyimillo-2-(S-amino-1,2~4-
thiadiazol-3-yl)acetamido]-3-~1-methyl-lH-te~azol-
5-yl)thiomethyl-3~cephem-4-c:arboxylic acid ~syn
isomer). mp 165 to 170C (de~c.)
I.R. (Nujol) : 3350, 3250, 1780, 1680, 1620,
1530 cm~l 1 .
~ - ~3) 7-~2-Hydroxyimino-2-(5-amino-1,2,4- - ~
thiadiazol-3-yl~acetamido]-3-~1,3 3 4~thiadiazol-2-
yl)thiomethyl~3 cephem-4-carboxylic acid (syn
lS isomer). mp 170 to 175C ~dec.)
I.R. (Nu~ol) : 3480, 3350~ 177V, 16~0, 16209
. 1530 cm
t243 7-~?-~ydroxyimino-2-~5-amino-1~2~4w
thiadiazol-3-yl)acetamido~-3~1,3,4~thiadiaxol-2-
- 20 - yl)thiome~hyl-3-cephem 4~carboxylic acid ta~ti
isomer). mp 155 ~o 160C (dec.~
I3R. (Nujol~ : 3350, 3250, 1780, 1680, 1620,
1520 cm~
.
~ E~
.
The following compounds wer~ obtained accord-
ing to similar manners.to those of Examples14 tol7 .
(lJ . 7-~2-HydToxyimino 2-~S-formamido-1~2,4-
thiadia~ol~3-yl)ace~amido3-. ~~.
_ . .~ 3-(1,3,4-t~i~diazol-2 yl~hiomethyl~
3~cephem~4-carboxylic acid (syn isomer). mp 155 to
160C ~d~c.)
I.R. ~Nujol) 3200, 17809 1680, 1620 cm 1
~2 3 7-[20Allyloxyimino-2~5-amino-1,2,4-
~hiadiazol-3-yl)ac~amido]~3 ~1,3~4-~hiadiazol-2-yl)-
thiome~hyl~3-ceph m-4~carboxy1ic acld (syn isomer).
mp 138 to 140C ~tec.) ~
I.R~ (Nujol~: 335~,323071780al6gOal620,1530 cm 1
~.) 7~2-~2,2,2~Trifluoroethoxyimino)-2-
~5~amino-1,2~4-~hiadiazol-3-yl~acetamido]-3~(1,394-
thiadia~ol-2-yl)~hiome~hyl-3-cephem-4-carboxylic
acid (syn i somer) ~ mp 153 to 158~C. -
I.R. ~Nujol) : 3350? 3250~1780~1680~1625 cm 1
Z5 -
~5~i
(4~ 7-[2-~2 Propyny:loxyimino?-2~-5-amino-
1,2,4-thiadiazol-3-yl)acet`amido]-3-~1,3,4-~hiadiazol-
2-yl)th-omethyl-;-cephem-4-c;~r~oxylic acid (syn
isomer). mp 140 to 145C (dec.)
I.R. ~Nujol) : 3330, 3250, 1780, 1~80, 1620,
1533 cm 1
(5) 7-[2-Benzyloxyimino-2-tS-ami~o-1,2,4-
~hiadiazol-3-yl)ace~amido]~3 ~1,394-thiadiazo~-2-yl)-
thiomethyl-3-ceyhem-4-carboxylic acid (syn isom~r).
mp 130.to 135C (dec.)
I.R~ ~Nujol~ : 33609 3250, 1780~ 1680, 16259
1530 cm~l
6) 7-[2-(2~rPhènoxyethoxyimino)-2-{5-amino-
1,2,4-thiadiazol 3-yl)acetamido]-3-(1,3~4-
thiadiazol-~-yl)thiomethyl-3-cephem~4-carboxylio
acid (syn isomer~. mp 163 ~o 167C (dec.)
I.R. ~Nujol~ : 33509 3250, 1i80g 16809 1630,
1600 9 1530, l5U0 cm~l
(7 ) 7~[2^Methylthiome~hoxyimino-2-~5-
-amino-l 7 294-thiadi~zol-3-yI)ace~amido~-3- (1 9 3,4-
~hiadia~ol-2-yl~hiome~hyl-3~cephem-4-carboxylic
acid (syn isomer3. mp 168 to 170C (dec.)
IoR~ (Nujol) : 33509 3250, 17~09 1680, 1620,
1530 -1
(8 ) 7~ 2-Methyl~hioethoxyimino~-2-~5-
amino-192,4-~hiadiazol-3-yl3acetamido~-3~ 394-
~hiadiazol-~-yl)~hiome~hyl 3-cephem-4-carboxylic
acid tsy~ isomer)O mp 12~ ~o 130C (dec.)
I~R, ~Nujol) : 3350, 32507 1780~ 1680, 16~5,
1530 cm 1
(9 3 7-~2-Phenoxyimino-2-(5-~mino-1,2,4-
thiadiazol-3 yl)ace~amido]-3-(1,3,4-th adiazol-2-
yl)thiomethyl~3-cephem-4-carboxylic acid ~s~n
isomer). mp 145 ~o 150C (dec.)
I.R~ ~Nujol) : 33509 3230, 1780~ 1580~ 16207 1590,
1530 ~m~l
4~
(lO) 7-~2-Cyanomethoxyimino~2-~5-amino-
1~2,4-thiadia~ol-3-yl~acetamido~-3-~1,3J4-~hiadiazol-
2-yl~thiomethyl-3-cephem-4-caTboxylic acid (syn
isomer). mp 105 to 110C (dec.)
I.R. (Nujol) : 3350, 3250~ 1780, 1680, 1620,
1530 c~ 1
~li) 7-[2-~N~N-~Diethylcarbamoyl)methoxyimino-
2-~-amino-1,2~4~thiadiazol-3-yl)acetamido]-3-
(1~3,4-tlliadiPzol-2-yl)~hiom~thyl-3-cephem-4-
carboxylic acid ~syn isomer). mp 175 ~o 180C (dec.)
I.R. (Nujolj : 3480, 331Q, 3200, 1775~ 1?40,
168Q, 1630~ 1610~ 1515 cm~
~2) 7-[2-~1-Ethoxycarbonyl-l-me~hylethoxy-
imino)-~A (5-ami~o-1~2 9 4-thiadiazol-3-yl)acetamido3-
3~1,3,4-thiadiazol-2-yl~thiomethyl-3-cephem-4-
carboxylic acid (syn isomer)~ mp 130 to 135C ~dec.
IoR~ (Nujol~ : 3360, 3240, 1780, 17307 1690,
L639 9 153() cm~
~1~ 7-~2-Ethoxycarbonylmethoxyimino-2~
~ amino-1~2~4~thiadiazol-3-yl3ace~amido]-3-(1~3,4-
thiadiazol-2-yl)thiome*hyl-3-cephem-4-ca~boxylic
acid (syn isomer~. mp 120 to 125C (dec.)
I~R. (Nujol) : 3370~ 3250~ 1780~ 1690, 1625
1530 cm 1
2~
~.~8~
~ 14) 7-~2~{2-(2-Hexy~.oxyethoxy)ethoxyimino}.
2-(5-amino-1,2~4~thiadia201 3-yl)acetamidoJ-3-(1,3,
4-thiadiazol~2-yl)thiomethyl-3-cephem-4~carboxylio
acid (syn isom~T). mp 100 to 105C ~dec.
.10 I.R. ~Nujol) : 33409 3~10, 1785, 1685~ 1620
J 1525 c~ 1
(15) 7~[2-Mesylmethoxyimino-2-(5-amino-
1,2~4-thiadiazol 3-yl)acetamido]-3-(193,4-thiadiazol-
2-yl)~hiomethyl~3~cephem-4-carboxylic acid (syn
isomer). mp 164 to 167C (dec.)
I~R. (Nujol3 : 3360, 3230D 17807 1690~ 1620,
. 1530 cm~l
(16). 7 ~2~Trîtyloxyiminv~ S-amino-1~2,4-
- thiadiazol~3-yl~acetamido3 3~ methyl-lH-te~razol-
5 yl)thiome~hyl-3-cephem-4-carboxylic acid (syn
isomer). mp 163 ~o 167C (dec.)
I.R. ~Nujol) 3480, 3350~ 3250~ 1785, 1690,
1620 3 1530 cm 1
(17) 7- r2 -Trityloxyimino-2-~5~amino~ 94-
~hiadiazol-3~yl)acetamidoJ-3-tl, 3,4 thiadi azol-2-
yl)~hiomethy~-3-cephem-4-ca~boxylic a~id ~syn
isomer)~ mp 175 ~o 178~C ~dec.)
I.R. ~ujol~ : 345~ 3350, 3200, 1790, lfi909
~6209 ~530 c~ 1
(183 7-~2-Allyloxyimino-2 ~5-amino-1~2,4-
~hiadia201-3-yl)acetamido~-3~ me~hyl-lH-~etrazol-
~-yl3~hiome~hyl-3-c~phem~4-carboxylic aoid (syn
isomer). mp 154 o 156~C (dec~)
I.R. (Nujol) : 3380~ 32459 1780, 1680~ 1625,
1527 cm ~
~v~
(19) 7-[~-Trityloxyim:ino-2 ~S-amino 1?2,4-
thiadi~zol~-3-yl)acetamido~-3~193,4-thiadiazol-~-
yl~thiometh~l-3-cephem-4-car~oxylic acid ~anti
isomer~. mp 165 to 170C (de~
I.R~ (Nujol) : 3350~3200~ 1785, 1690, 1620,
1515 cm L
~20) 7-[2-Allyloxyimi:no-2-~5-amino-l~2~4
~hiadiazol-3-yl)acetamido~-3-(S-aminome~hyl-1,3,4-
thiadia~ol 2-yl3thiomethyl-3-cephem-4-carboxylic acid
~syn is~mer). mp lfil to 164~C td~C.)
I.R. ~Nujol~ : 3350, 32~Q, 1770, 1670, 1620,
1525 cm 1
N.M.R. ~d6-DMSO~D2O~ 3.6 t2Hs broad s~,
4.35 a~d 4.58 (2H, ABq3 J=15Hz), 4.2-
4,8 (4H~ m?, 5.0-5.5 ~2H, m)~ 5~05 ~lH,
d~ J-5Hz~ 5.75 ~lH, d~ J-SHz), 5.7-
6.4 (lH, m)
~21J 7-~2-Allyloxyimino-2-~-5-ami~o-192~4-
~hiadiazol~3-yl)acetamido~-3~ {2~(N-t butoxy-
2a carbo~ylamino~ethyl}~lH~tetrazol-S yl]~hiomethyl-
3~cephe~ 4-zarboxylic acid ~syn isomer)O powde~.
(22~ 7-~2 Ailyloxyimino-2-~S-amino-1,2~4-
thiadia~ol-3-yl)acetamido~-3-~1~(2-aminoe~hrl~-lH-
te~a~ol-5-yl]~hiome~hyl-3-cephem-4-carboxylic
a~id tsyn isomer~. mp 165 ~o 169C ~dec.)
~ I.R. (Nujol3 : 3350,3200,1768,1670,1610,1522 cm
t23) 7-~2-Hydroxyimino-2-(S-~mino-1~2,4-
~hiadiazol-~-yl)acetamido~ 3~ methyl-lH-~etrazol-
5-yl~thiomethyl-3-cephem-4 carboxylic acid (syn
3~ isomer)~ mp 165 ~o 170C (dec~)
I~R~ ~Nujol~ : 335073250, 1780,168091620~1530 cm 1
(24) 7 ~2 Hydroxyimino-2-(S-amino-1,2,4-
thiadiazol-3-yl)~ce~amido]~3-(1,3,4~hiadiazol2-
yl)thiom~hyl~3-c~ph~m~4-carbo~ylic acid ~syn iSOmeT).
mp 170 to 175~C ~dec.)
11~2~~
I.R, (Nujol) : 3480~3350,1770,16~0,1620,1530 cm 1
l25J 7-~2-Hydroxyimino-2-~5-amino-1,2,4-
~thiadiazol-3-yl)acetamido]-3-~1,3,4-thiadia~ol-2-yl)-
~hiomethyl-;-cephem-4 carboxyl:ic acid (anti isomer).
mp 155 to 160C ~dec~)
I~R. (Nujol) : 3350,3250,1780,16~0~162091520 cm 1
The ~ollowing compounds were obtained according
to similaT mannerstothose of Example3 22 to 25.
tl) 7~ Allyloxyimino-2-(5-amino~i,2,4-
thiadiazol-3-yl~acetamido~-3-(5-aminomethyl-1,3,4
thiadiazol-2-yl~thiomethyl-3-cephem~4-carboxyliE acid
(syn isomer). mp 161 to 164C ~dec )
I.R, ~Nujol) : 3~50~ 3220, 1770, 1670, 1620,
lS2~ cm 1
(2.) 7-~2-Allyloxyimino-2-~5-a~ino-1,2,4-
thiadiazol-X-yl)acetamido]-3r[1-(2-aminoethyl)-lH-
tetra,ol-5-yl]thiomethyl-3 cephem-4-ca~boxylic acid
- (syn isomer~ mp 165 to 169C (dec.)
I.R. ~Nujol) : 3350, 3200, 1768, 16709 1610,
1522 cm
N~M.R. ~d~-DMSO+D2~ 3.41 (2H, broad s),
3.60 (2H9 broad s~, 4.3-5.0 ~4H, m),
5.05 ~lH, d, J=4.5~z), 5~73 (lH, d9
. J=4.5Hz)~ 4.9-5.6 (2H, m)~ 5.7-6~4 (lH, m)
B~
.. .
~o
.~
A mixture o~ 7-l2-trityloxyimino-Z-(5-amino-
1,2,4-th;adia~ol-3-yl)acetamido]-3-~1,3,4-thiadia~ol-
2 yl)thiomethyl-3-cephem-4-carboxylic acid {syn
isomer)(0.95 g), co~c.hydrochloric acid (0.6 ml)
and methanol ~10 ml) was stiT~ed for 7 houls a~
~mbie~t tempe~aturea Methanol was distilled of
from the ~eaction mixture and the ~esidue was
adjusted to pH 5 by adding ethyl acetate and an
3~ aqueous solution of sodium bicarbonate. To the
separated aqueous laye~ was added ethyl acetate an~
the mixture was adjusted to pH 2 with 1~% hydrochloric
. . acid. The separ~ted ethyl acetate layer was d.ied
over magnesilLm sulfate and evaporated in vacuo to a
vo~ume of 10 ml~ Precipitates were collected by
:" .
i63
filtrati~n~ washed with e~hyl aceta~e and diethyl
e~h~r and dried to gi~e 7-~2-hydroxyimino-2 ~5-
amino-1,294.-thiadiazol-3-~l)acPtamido]-3-(1,3,4- ~
thiadiazol-2-yl)thiome~hyl-~5-c~phem-4-caTboxylic
S acid ~sy~ isomer)~0.3 g). mp 170 to 175C (dec.)
I.R. (Nujol~ : 3480~ 3~550, 1770, 1690, 1620,
1530 cm~l
~ N.M.R. (d6-DMS0~ 3.61 and 3O73 (2H9 ABq9
J=~ ~ ~94.30 ancL 4.~7 ~2H, ABqg J313H~),
5.13 (lH~ d~ J=4Hz3, 5,83 (lHj dd~
J34 and 8Hz), 8.03 ~2Hg s)~ 9.40 ~lH, -
dD J~8Hz), 9.S7 (lH~ s~, 11.93 ~lH, s)
The ~ollowing compounds were obtalned acco~ding
~ ~o a similar manner ~o ~ha~ of Example38 a
(1) 7-~2-Hydroxyimino-2-~5 amino-19294-
thiadiazol-3-yl~acetamido]-3~ methyl-lH-t~t~azol-
S-yl)~hiomethyl-3-cephem-4-carboxylic acid (sy~
isomer3. mp 165 to 170C ~dec.~
I.R. (Nujol~ : 33~0, 32S0, 1780V 1680, 1620~ -
1530 cm-l
N.~ d~-DMSO, ~) : 3.70 (2H, broad s),
3.Q7 (3H~ s); 4.33 ~2H, broad s),
5.13 (lH9 d~ J-4Hz)~ S.83 (lH, dd9
J-4 and 8Hz) 9 8.03 ~2H~ s~9 9.43 ~lH, d~
3~8Hz), 11~93 (lH~ s)
~2~ 7-~2~Hyclroxyimino 2 (5-amino-1,2,4-
thiadiazol-3-yl)acet~mido~-3~(1/3~4~hiadiazol-2~yl)
thiomethyl-3-cephem~4~carboxylic acid (a~ti isomer3.
mp 155 ~o 160C (dec.)
I.R. (Nujol3 . 3350~ 3250g 17~0, 1680, 1620,
1520 cm 1
N~M.R. ~d~-DMS0, ~) ~ 3O70 ~2H, broad s)~
4.35 and 4.53 ~2H, ABq, J~13Hz), 5.13
~lH, d, Jo4Hz)~ 5.73 ~7.H, dd, Jr 4 and 8Hz~g
8.03 (2Hjs), 8.92 (lHg d, J=8H~3,9.53 ~lH) s)
J~
A mixture of phosphorus pentachloTide (1.89 g)
and me~hylene chloride ~2~ ml) was stirred for 15
minutes at ambient temperature. 2~ Butoxysarbonyl-
S ethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic
acid ~syn isomer)(2.2 g) was added thel~eto at -15C
and the mixture was stirred for 30 minutes at -10 to
-15C. A solution of 7-amino-3-cephem-4-carboxylic
acid ~1.4 g~ and trimethylsilylacetamide (8.4 g) in
methylene chloride (20 ml~ was added ~hereto at -20C
and the ~ixture was stirred for 30 minu*es at -10 to
-15C and for 30 minutes at 0 to 5C. Me~hylene chloride
- was distilled off from the reaction mixture and to the
residue were added ethyl acetate and a small amoun~ of
w~er. The ~esulting solution was poured into an
aqueous solution ~f sodium bicarbonate and the aqueous
lay~r was sepaIated. To the aqueous layer was added
ethyl aceta~, and the mixture was acidified wi~h 6N
hydrochloric acid and then twice ~xtracted with ethyl
~ce~ate. The ext~act was washed wi~h wa~er, dried over
magnesium sulf~te, treated with an activated charcoal
and concentTated. The ~esidue w~s triturated with
di~sopropyl ether and precipitates were coll~cted by
filtration to gi~e pale yellow powder of 7- ~2- (1-~-
bu.oxycarbonylethoxyimino)-2-~5-amino-1;2,4-thiadiazol-
3-yl)acetamido]-3-cephem-4-carboxylic acid ~syn isomer)
(2.5 g~ which is decomposed by 250~C.
IR ~Nujol) : 3400, 3250a 3150~ 17709 17209 1680,
1~10, 1520l 1290, 12~0, 1150, 9~0,
740 cm 1
NMR ~DMSO-d6, ~ : 1.50 (12H, b~oad 5) 9 3.63
~2H, m), 4.73 (lH, q9 J=7Hz)~ 5.17 ~lH, d,
J-5Hz~ 7 5.92 tlH~ dd9 J=5 and 8Hz)~ 6.53
(lH, m), 8.17 (2H, m), 9.4 and 9.6 (lH, d, J=8Hz)
. . . .
~Z~~
~;3
Example 41
The following compounds were obtained according
to similar manners to those of Examples 1 to 3, 5, 7
to 12 9 32 to 34 and 40.
s
(1) 7-~2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-
thiadiazol~3-yl)acetamido]-3-(1-allyl-lH-*etrazol-
5-yl)thiomethyl-3-cephe:m-4-caTboxylic acid (syn
isomer), mp 120 to 25~C ~dec.~.
IR (Nujol) : 3290, 31~0, 1770~ 1680, 1615,
1580, 1520, 1480 cm l
NMR (DMSO-d6, ~) : 3.73 (2H, b~oad s)~ 4.40
(2H, bToad s3, 5.17 (IH, d, J=5Hz),
4q87~5~20 (2H, m~ 9 5.20-5.60 (2H, m),
lS 5.90 (lH, dd9 J=5 and 8Hz), 5.60-6.30
(lH, m3, 7.32 ~2Hg d, J=9H~)~ 7.48 !2H,
d,.J-9Hz) 9 8.32 t2H, broad s3, 9.90
(lH, d9 J=8Hz~
~2) 7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-
thiadiazol 3-yl)acetamido]-3~ methyl-lH-tetrazol-
5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer~ 9 mp 130 to 135C (dec.).
IR (Nujol) : 3400~ 3300, 3280, 1770, 1670
1615, 158.0, 1520, 1480 cm 1
NMR (DMS0-d6, ~) : 3,72 ~2H, br~ad s) 9 3.92
(3H, s), 4.32 ~2H, broad s)~ 5.18 (lH, d7 `
J~SHz~, 5.87 (lH, dd, J=5 and &Hz) 9 7.25
t2H, d9 J=9Hz3, 7.42 (2H, d, J=9Hz), 8.25
(2H, broad s), 9.B5 (lH, d9 J=8Hz)
~3) 7-l2-(4-Chlorophenoxyimino)-2-~5-amino-1,2~4-
thiadiazol-3-yl)acetamido3cephalosporanic acid
(s~n isom~r), mp 120 *o 125C ~dec.).
1~8?~
IR ~Nujol) : 3400, 3300, 3190, 1770, 1720,
1650, 1620, 1580, 1520 9 1480 cm
NMR (DMSO-d6, ~) : 2.02 (3H, s) 7 3.58 ~2H,
broad s), 4.75 a:nd 4.9S (2H~ ABq, J=13Hz),
S.22 (lH, d, J=5Hz), 5.87 (lH, dd, J=5 and
8Hz) 3 7.27 (2H, d, J=9Hz), 7.42 (2H9 d,
J=9Hz), 8.28 (2H, broad s3, 9.85 (lH9 d,
J=8HZ)
(4) 7-~2-~4-Chl~rophen~xyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)a~e~amido~-3-~1-f2-carboxyethyl~-
lH-te~razol-5-yl]thiome~hyl-3-cephem-4-carboxylic
acid ~syn isomer), mp 135 to ~40C ~dec.).
IR (Nujol3 : 3400, 3270, 3190, 1770, 1680,
1620, 15859 15209 1480 cm 1
NMR ~DMSO-d~ 2.70-3.10 ~2H7 m3, 3.70
(2H~ broad s), 4.10-4.60 (4H7 m3, 5.20.
~lH~ d, J-SHz), 5.87 ~lH9 dd, J=S and 8Hz),
` 7,28 (2H, d, J-9Hz) 9 7045 ~2H, d, J=9Hz),
8.30 (2H~ broad s~, 9.85 ~lH, d, J=8Hz3
(~) 7-~2-t4-Chlorophenoxyimino3-2-(S-amino-1,2~4-
thiadiazol^3-yl)acetamido~-3-[2-carboxymethyl-3-
oxo-Z,3-dihydro-1,2,4-triazolo~4,3-b]pyTidazin-
6-yl]~hiomethyl-3-cephem-4-carboxylic acid ~syn
isomer) 9 mp 140 ~o o45C ~dec.~.
I~ ~Nujol) : 3400, 3300, 3190 9 17$5, 1700,
1620, 1580, 1540, 1520, 1480 cm
NMR ~DMSO-d6, ~3 : 3080 (2H7 broad s), 4028
t2~ broad s) 7 4.73 (2H; s), 5.27 (lH, d,
J=5H~ .90 ~lH, ddS J=S and 8Hz), 7 ol2
(lH, ~ J=lOH~)~ 7.32 ~2H, d, J=9Hz), 7~47
(2H, d) J-9Hz), 7.72 ~lH, d, J=lOHz), 8.30
~2H, broad s~ 9.g2 (1~, d, 3=8Hz)
( 6 ) 7 - [ 2 - ~ 4 - Chl orophenoxy imino ~ - 2 - ( 5 - amino -1, 2, 4 -
thiadia~ol - 3 -yl) acetamido~ - 3 - (tetrazolo - ~1, 5 -b~ -
pyridaz in - 6 - yl ~ thiomethrl - 3 - cephem- 4 - caTboxyl ic
acid (syn isumer), mp 140 to 145C ~dec.).
IR ~Nujol) : 33509 3;240, 1780, 1685, 1625,
1530, 1490 cm 1
NMR (DMSO-d6, ~) : 3.70 ~2H~ broad s), 4.22
and 4.62 (2H, ABq, J-13Hz), 5.22 (lH, d,
J=5Hz), 5.93 (lH, dd, J=5 and B~z~, 7.27
(2H, d~ J=9Hz), 7.42 (2H, d, J=9H~), 7.73
(lH, d, J=9Hz)~ 8.28 ~2H, bToad s), 8.59
(lH, d, J-9Hz)g 9.87 (lH, d, Ja8Hz)
(7) 7-[2~ t-Butoxycarbonylbenzyloxyimino)-2-(S-
amino-1,2,4-thiadia~ol-3-yl)acetami.do~-3-(1,3,4-
~hiadiazol-2-yl.)thiomethyl-3-cephem-4-carboxylic
acid (syn isome~), mp lOS to 110C (dec.).
IR ~Nujol) : 3400~ 3300, 3180, 1780~ 17209
1680) 1620, 1520 cm 1
Z0 NMR ~DMSO-d6, ~ : 1.40 (9H, s), 3.50-3.83
(2H, m), 4.37 and 4.60 (2H, ABq, J=13Hz),
5.10 and 5.18 (lH, d, J=5Hz), 5.63 (lH, s),
5.67-~0 (lH, m), 7.47 (5H, s), 8.20 (2H,
broad s), 9.62 tl/2H, s~ 9 9. 64 tl/2H, s),
9.47-9.77 (lH~ ~)
t8~ 7-~2-~-t-ButoxycaTbonylbenzyloxyimino)-2-(5
amino-1,2,4-thiadiazol-3-yl)acetamido~-3-cephem-
4-carboxylic acid (syn isome~), mp 90 to 95C
~dec.).
IR ~Nujol) : 3400, 3380~ 3230, 1780, 1730,
1685, 1635, 1530 cm 1
N~IR (DMSO-d6, ~) : 1.38 (9H, s), 3~60 (2H~
broad s), 5.0-5.20 (lH, m), 5.63 (lH, s~,
$~
,
5.72-6.03 ~lH, m3, o.37-6.67 (lH3 m), 7.47
~5H, ~), 8.18 (2H, broad s), 9.~3-9.70
~lH, m~
(9) 7-~2~ t-Butoxycarbonylbenzyloxyimino)-2-~5-
amino-1,2,4-thiadiazol-3-yl)acetamido~-3-~ 2-
tN-t-butoxycarbonylamlno)ethyl}-lH-tetrazol-5-yl]-
thiomethyl-3-ceph-em-4-carboxylic acid (syn isomer)~
mp 105 to 1~0C (dec.)~
IR ~Nujol~ : 33609 3220, 17$5, 1690, 1625,
1525 cm~l .
NMR ~DMSO-d6, ~) : 1.38 (18H, s) 7 3.17-3.87
(4H, m~, 4~17-4.65 ~4H~ m), 5.0-5.28
(1~9 m), 5.12 ~lH, s), 5.58-6.0 (lH, m),
7.47 (5H, ~), 8.17 ~2H, broad S)9 3.45-9.75
(lH, m~
(10) 7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4~
thiadi~zol-3-yl3acetamido] -3- El- (2-carboxye~hyl)-
lH tetrazol-5-yl~thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 125 ~o 130C ~dec.).
IR (Nujol3 : 3400, 3260, 31909 2580, 1765,
1713, 1670, 1620, 1520 cm 1
NMR ~DMSO-d6~ ~3 : 2.92 ~2H, t, J=6Hz3, 3.47
(lH, t~ J-2Hz)~ 3.67 (2H, brDad s),
4~17-4.60 ~4H, m) 3 4.77 ~2H9 d, J=2Hz),
5.08 ~lH, d, J=5Hz), 5.77 (lH~ dd3 J=5 and
8Hz), 8.08 ~2H, broad s)5 9.57 (lH, d, J=8Hz3
3~ (11) 7-~2-(2-Propynyloxyimino3-2-~5-amino-1,2 54-
thiadiazol-3-yl)acetamido~cephalosporanic acid
~syn isomer~.
IR ~Nujol) : ~400~ 3270, 31803 17709 1720,
1655 7 1520 cm 1
4~
t
NMR ~DMS0-d~ 1.98 (3H, s), 2.45 (lH, t,
J=2Hz), 3.48 ~2H, broad s), 4.72 ~2H, d,
J~2Hz), 4.67 and 4.92 ~2H, ABq, J=13Hz),
5.08 (lH, d, J=l5Hz~ 9 5.77 (lH, dd, J=5 and
8Hz)g 8.07 (2H, broad s), 9.55 (lH, d, J=8Hz)
(12~ 7-~2-t-Butoxycarbonylmethoxyimino-2-(5-amino-
152~4-thiadiazol-~-yl)acetamidoJ-3-cephem-4-
carboxylic acid ~syn i.somer), mp 165 *o 170C
td~C ) -
IR ~Nujol) : 3350, 3250~ 3180t 1790, 1720,
1660, 1630, 1620~ 1520 cm 1
NMR (DMSO-d5, ~) : 1.40 ~9H, s), 3.57 (2H,
broad s), 4.60 (2H, s) 9 5.07 (lH, d9
- 15 J=4Hz), 5.83 (lH, dd, J~4 and 8Hz), 6.47
~lH, broad s)~ 8.13 ~2H, s) 9 9. SC tlH, d,
J~8~Z)
.
~13) 7-~2-tThiolan-l,l-dioxide-3-yl)oxyimino-2-(5-
; 20 amino-1,2,4-~hiadiazol-3-yl)acetamido3-3-(1,3,4-
!~ thiadiazo~ yl)thlomethyl-3-cephem-4-carb~xylic
acid (Syll isomer), mp 173 to 175C ~dec.)~
IR ~Nuj ol) : 3300, 3200, 1770 7 1570, 1620 9
` - 1520 cm 1
NMR (DMS0-d6" ~) : 2.30-2.50 ~2H, m) 9 3.0-3.57
t4H; m), 3.70 t2H~ broad s), 4.33 and 4.~7
(2H, ABq" J~13Hz), 5.0-5.1~ (lH, m), 5.ï7
(lH, d, J=4Hz), 5.83 ~lH, dd, J=4 and 8Hz)
8.23 ~2H, s), 9.60 ~lHI s), 9.67 ~lH~ d,
J=8H~)
~14) 7-~2-Allyloxyimino 2-(5-amins 192,4-thiadiazol-
3 yl)acetamido3-3-~1-carboxymethyl-lH-tetrazol-
5-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn
~,
&
~ ~ 7~
iSOmer3~ mP 140 tO 14SnC ~deC.).
IR (NUjO1) : 3303, 3200, 1770, 1720, 16707
1620, 15~0 Cm 1
NMR ~DMSO~d6, ~) : 3.63 ~2H, bTOad S~, 4.23
and 4.43 ~2H, ABq, J=14HZ), 4.60-4.73
(2H9 m), 5.10 (1H, d, J=4HZ~, 5~30 ~2H, S),
5~07Sa50 ~2H, m), 5.67-6.20 (2H, m), 8.15
(2H~ S~, 9.63 ~1H, d, JY8HZ)
(15) 7-~2-(2-P~OPYnY1OXYiminO)-2-t~-aminO-1~2~4-
thiadiaZO1-3-Y1)aCetamidO~-3-~1-Ca~bOXYmethY1-
lH-~e~Tazol-5-yl)'chiomethyl-3-cephem-4-carbo}cylic
aCid ~SYn iSOm~r), mP 135 ~O 140C ~deC.).
IR (NUjO1) : 3250~ 3150~ 1770, 1720, 1670,
1620~ 1520 Cm 1
NMR ~DMSO-d69 ~) : 3.47 (1H, t, J=2H7), 3.63
(2H~ bTOad S), 4.22 and 4.43 (2H3 ABq,
J-14HZ), 5.07 (1H, d, 3-4HZ), 5.28 ~2H, S) 7
5,80 ~1H, dd9 3=4 and 8HZ~ 9 8.15 ~,H, S~,
9.S3 ~1H, d, J=8HZ~
(16) 7-~2-A11Y1OXYiminO-2-(5-am1nO-1~294 ~hiadiaZO1-
3-Y1)aCe~amidO~-3-~1-t2-CarbOXYethY1)-1H-tetraZO1
5-Y1~thiOmethY1-3-CePhem-4-CarbOXY~iC aCid ~SYn
iSOmer)~ mP 140 tO 145~C (deC.).
IR (NUjO13 : 3300, 3200, 1770, 1720/ 1670,
1620~ 15Z0 Cm 1
N~ DMSO d6, ~) : 2.87 ~2HJ t~ J=6HZ), 3.63
(2H, brOad 5), 4.37 (2H, t9 J=6HZ), 4.20
and 4.47 ~2H, ~Bq, J~14HZ), 4.57-4.67
(2H~ m) ~ 5.07 ~lH~ d~ J=4HZ), 5.10-5.43
(2H, m)9 5.67-6.13 (2H9 m), 8.10 ~2H, S),
9.58 ~1H, d, J 8HZ~
~ z~
~7~
(17) 7-[2-~t-Butoxycarbonylmethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido] 3-[1-t2-
carboxyethyl)-lH-tetra:~ol-5-yl]thiomethyl-3-
cephem-4-carboxylic ac:id tsyn isomer), mp 150 to
155C ~dec.).
IR (Nujol) : 3300, 3200, 1770, 1720~ 1700,
1620, :1520 cm 1
NMR (DMSO-d6~ 1.5~ (9H, s~, 3.00 (2H~ ~,
J=6Hz), 3.73 ~2Hy broad s), 4.43 (2H,
broad s), 4~50 (2H, t, J-6Hz~, 4.67 ~2H,
s~, 5.17 ~lH~ d, J=4Hz), 5.8~ (lH, dd,
J=4 and ~Hz), 8.lB (2H, s), 9.53 (lH, d~
J=8Hz)
~18) 7-[2-~t-Butoxycarbonylmeihoxyimino~-2~5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-[1-~3-~4-
methyl-l-piperazinyl)propyl ~.IE;tetraæol-5-yl~
thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 220 to 225C ~dec.).
IR tNujol) : 3300~ 1700, 1680, 1605, 1520 cm 1
NM~ (DMSO-d6, ~) : 1.40 (9H, s~, 1.9~-2.10
t2H, m~, 2.38-2.50 (4H3 m)~ 2.60 (3H~ s),
2.gS-3.10 ~6H, m~ 3,52 and 3.65 ~2H, ABq,
J 16Hz) 7 4.20-4~40 ~4H, m), 4~60 t2H, s~,
5.06 ~lH9 d, J-4Hz~, 5.70 (lH, dd, J=4 and
8Hz), 8.12 (2H, s~, 9.44 (lH, d, J=8Hz),
~19) 7-[2-~1-t-Butoxycarbonyl-2 -methylpropoxyimino) - 2 -
~5-amino ~,2,4-thiadiaz~1-3 yl)acetamido]-
cephalosporanic acid ~syn isomer), mp 130 to 140C
(dec.~.
IR (Nujol) : 3400, 3300, 3200, 1780~ 1720-1680,
1620, 1520, 1460, 1370, 1230, 1150
1030, 730 cm 1
~2
NMR ~DMSO-d6, ~) : 1.03 (6H, d, J=7Hz), 1.43
(gH, s), 2.03 ~3H, s)) 1.9-2.2 (lH, m),
3.6 ~2H, m), 4.26 and 4.34 (lH9 d, J=6Hz),
4.68 ~nd S.05 (2~, ABq, J-13Hz~, 5019
(lH, d, J 5H7.), 5. 87 ~lH, dd, J=S and
8Hz~, 8.10 (2H, broad s), 9.48 ~lH, d,
J= 8Hz )
(20) 7-[2-(1-~-Butoxyca~bonylpropoxyimino~-2-(5-amino-
2,4-thiadiazol 3-yl)acetamido3-3~(1,3,4-
thiadi~zol-~-yl~thiomathyl-3-cephem-4-carboxylic
acid (syn isomer), mp 101 to 105C ~dec.3.
IR (Nujol) : 3300~ 3150, 1770, 1720, 1620,
1520~ 1450~ 1370, 12509 1150,
lS 1010, 900~ 840, 720 cm 1
NMR (DMSO-d6, ~3 o 0.93 (3H~ t, J=7Hz), 1.42
(9H~ s)~ 1.8 (2H, m), 3O7 (2H, m~ 4.6
-. t3H~ m), 5.18 (lH9 d, J=5Hz)~ 5.87 ~lH,
dd~ J-5 a~d BHz), 8.20 ~2H9 broad s), 9.S
(lH, m~, 9058 ~lH, s)
.
(Z1) 7- ~2- ~1-t-Bu'coxycarbonylpropoxyimino) -2- (5 amino~
1~ 2, 4-thiadiazol -3-yl) acetamidoJ cephalospo~anic
acid (syn isomer), mp 95 to 105C (dec.).
IR ~Nujo~ 3400,3300" 3200, 1780, 1720;
1620, 11 530, 1230~ 1150~ 1010,
890, 840 3 740 cm 1
N~IR (DMSO-d6, ~) : O.9S (3H, t7 J=7Hz), 1.39
~9H,, s); 1.8 (2H~ m~, 2~02 (3H9 s), 3~.5
(2H, m~ J~ 4.47 ~lH, m) ~ 4.67 and 5.03
~2H, ABq~ J=13Hz), S.:l4 ~lH~ d, J=5H~)
5.83 (lH, dd, J-5 and 8Hz), 8.07 (2H,
broad s); 9.37 and 9.43 (lH, d, J-8Hz~
L~
~22) 7-[Z~ Butoxycarbo:nylethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido~-3-(1,3,4-~
thiadiazol-2-yl3thiomethyl-3-cephem-4-carboxylic
. acid ~syn isomer3, mp 120 to 128DC ~dec.).
IR (Nujvl) : 3280, 3180, 1770~ 1720, 1680,
16203 1520, 12~0, 1~50, 1000,
740 9 720 cm 1
NMR ~DMSO~d6, ~) : 1.4 (12H~ m), 3.76 ~2H, m~,
4.30 and 4.67 (2H, ABq, J313Hz), 4r70
~lH, q, J=7Hz), 5.22 (lH, dy J=5Hz3, 5.88
~ dd3 J=5 and 8Hz3, 8.20 ~2H, b~oad s)~
- 9.47 (lH/ m), 9.60 (lH9 s3
(23) 7-~2-(1-t-Butoxy~arbonylethoxyimino) 2-(5-amino-
1,294-thiadia~ol-3-yl)acetamido~cephalosporanic
acid (syn isomeT)., mp 138 to 145C ~dec.).
IR (Nujol) : 32B0, 3180, 17gO, 1720, 1680,
1620, 1520, 1230 9 1150, 840 cm 1
NMR (DMSO~d~g ~ : 1.47 (12H, m~ 9 2.07 ~3H, s),
~Z0 3.58 (2H7 m)~ 4.5-5.1 ~3H, m3, 5.19 ~lH, d,
J=5Hz), 5.87 ~lH, dd9 J=5 and 8Hz) 7 8.10
(ZH, b~oad s), 9.~0 a~d 9.50 (lH, d7 J-8Hz)
(24) 7-[2-(1-Methrl-l-t-~utoxycarbonylethoxyimino)-2-
.25 ~5-amino-132,4-~hiadiazol-3-yl)acetamido~-3-(1,3,4-
thiadiazol-2-yl)thiom~thyl-3~cephem 4-carboxylic
acid (syn isomer), mp 115 to 120C ~dec.3.
IR (Nujol) : 3280, 3170, 1780, 1720, 1680,
1520, 1140, 390, 750 cm 1
~R (DMSO-d6, ~) : 1.40 ~9H9 sj, 1.46 ~6H~ s),
3.7 (2Hj m), 4~26 and 4~63 ~2H, ABq~
3=13Hz), 5~18 (lH3 d, J=5Hz), 5~83 ~lH, dd,
J=5 and 8Hz3, 8.13 (2H, broad s), 9.40
(lH~ d~ J-8Hz), 9.53 ~lH, s)
~25) 7-[2-(1-t-Butoxyca~bonyl-l-cyclopen~yloxyiminc)-
2-~5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-
~1,3,~-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid tsyn isomer), mp 140 to 143~C
~dec.).
IR ~Nujol) : 3300 9 .3180, 1770, 1720-1670y
162~, :152~, 1245, 1150, 1060,
595~ 840 cm~l
MMR (DMS0-d6, ~) : 1.40 ~9H, S)9 1.8 (4H, m),
2.1 (4H3 m), 3.7 ~2H~ m), 4.27 and 4.68
~2HD ABq9 ~=13Hz3, 5.18 ~lH,-d7 J=5Hz~
5.85 (lH, dd~ J=5 and 8Hz)~ 8.1 (2H,
broad s), 9.39 (lH, d, J-8Hz), 9.53
(lH, s)
~26) 7-~2-(1-Me~hyl-l-.t-butoxycarbonylethox~-imino)-
2-(5-amino-1,2,4-thiadiazol-3-yl~acetamino~-
cephalospo~anic acid ~syn isome~), mp 135 to
1408C (dec.).
IR (Nujol) : 3400p 3300, 318U, 1780~ 1720,
1690, 162~, ~540, 1300~ ~220,
1140, 1030, 9909 840, 740 cm 1
NMR (DMS0-d6, ~) : 1.57 (9Hp s), 1.62 ~6H, s),
- 2~03 (3H, s), 3.57 ~2H, m), 4.69 and 5.06
~2H, ABq, J=13Hz~, 5.19 ~lH, d, J=5Hz3,
5.89 ~lH, dd, J=5 and 8Hz~ 8.21 ~2H~
broad s), 9.32 (lH, d~ J=8Hz)
t27) 7-~2~ t-Butoxycarbonyl-l-cyclopentyloxyimino)-
2-(5-amino-1~2,4-thiadiazol-3-yl)acetamido]-
cephalosporanic acid tsyn isomer) 9 mp 98 to 102~C
(dec.).
IR (Nujol) : 3~SOp 3230, 1790~ 1730, 1630,
1530, 1340~ 1160, 1070~ 1040, lOOOcm 1
35 .
NMR (DMS0-d6, ~) : 1.47 (9H, s), 1.80 (4H, m),
2.10 ~4H, m), 2.13 t3H, s), 3.60 (2H, m),
4.73 and 5.1 (,2H, ABq, J=14Hz), 5.22 (lH,
d, J=5Hz), 5.88 (lH, dd, J=S and 8Hæ)7 8.15
(2H, m~ 9 9.43 ~lH, d, J=8Hz)
(28) 7-~2-~1-Methyl-l-t-butoxycarbonylethoxyimino)-
2-(5-amino-1,2l4-~hialliazol-3-yl)acetamido]-3-
[1-~2-~N-t^buto~ycarbonylamino~ethyl}-lH-tetrazol-
5-yl]~hiomethyl-3-ce~hem-4-carboxylic acid (syn
isomer), mp 96 to 100C ~dec.).
IR ~Nujol) : 3300, 315~ 1780, 1680, 1570,
1240, 1160, 990 cm~l
NMR ~DMSO-d6, ~) : 1.45 ~18H9 s)~ 1.52 ~6H~ s),
3.33 ~2H, m) 5 3.~7 (2H~ m~p 4.30 (4H, m),
5.10 (lH, d, J=5Hz) g 5.~5 (lH~ dd~ J=5 and
8Hz) ~ 5~92 ~lH, m), 8.13 (2H, m), 9.40
(lH, d, J=8Hz)
(29) 7-[2-~1-Methyl-l-t-butoxycarbonyle~hoxyimino)-
2- ~5-amino-1,2,4-thiadiazol-3-yl)acetamido~ -3-
cephem-4-carboxylic acid (syn isomer) 9 which is
- decomposed by 215C.
IR (Nuj ol): 3400 , . 3300 , 3150 y 1780 J 1710 3
2~ 1690, 1620, 1520, 1240~ 1140,
380 cm ~
NMR ~DMSO-d6, ~) : 1.40 (9H, s~; 1.47 ~6H, s~,
3.60 (2H, m)~ 5.17 (l}I, d, J=5Hz), 5.92
(lH, dd, J-S and 8Hz), 6.50 (lH, m), 8.22
~2H, m)~ 9~50 (lH~ d, J28Hz)
~'
~30) 7- [2- (1-t-Butoxycarbonyle~hoxyimino~-2-~5-amino-
192)4-thiadiazol-3-yl)acetamido] -3- ~1 allyl-lH-
tetr~zol-5-yl)~hiomethyl-3-cephem-4-carbo~ylic
' ;'
- ~7~
acid ~syn isomer), mp 96 to 100C (dec.~.
IR ~Nujol) : 3300, 3150, 1780, 1720, 1680,
16~0, 1~20~ 1~40~ 115~ 9 1090
1000 c~
NMR ~DMS0-d6, ~) : 1.40 ~12H, broad s), 3.67
~2H, m~ 4~2 anld 4.50 (2H~ ABq, J=13Hz),
4~67{1~a Cl.~ J-S]Hz) ~ 4.93 (2H~ lll) ~ 5.07
(~H, d~ J=5Hz), 5.13-5.37 (2H9 m)~ 5.83
(lH, dd~ J=5 and ~Hz3, 5.8~-~.22 ~lH, m),
8.10 ~2H, broad s~, 9.40 and 9.52 (lH~
d) J~8Hz)
(31) 7-[2-(l-phenylethoxyimino)-2-~s-amino-l~2~4-
thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-
2-yl)thiomethyl-3-cephem- 4 - carboxylic acid (syn
isomer), which is decomposed by 175C.
IR ~Nujol) : 34009 32509 3150~ 1750, 1650,
1610, 15209 140~, 1240, 11~0,
1060, lOOQ~ 700 cm l
NMR (DMS0-d6, ~) : 1.57 (3H~ d, J=8Hz~, 3.73
(2Hj m), 4.32 and 4~72 (2H, ABq, J=13Hz),
5.22 ~lH, d9 J=5Hz), 5.3-5.5 (lH, m)~ 5.93
(2H3 dd, J-5 and 8Hz), 7.36 (5H, m3, 8.13
- (2H, m~, 9.57 (lH; s), 9.72 (lH, d, J=8Hz~
(32) 7-~2-(3~4-Dichlorophenoxyimino)-~-(5 amino-1,294-
thiadiazol-3-yl)acetamido3~3-cephem-4 carboxylic
acid (syn isomer~, which is decomposed by 210~C.
IR ~Nu~ol) : 3450, 3300, 3200, 1760, 1660,
1560, 12909 ~210, 10009 970,
g-~o, 730 cm 1
NMR (DMSO-d6, ~) : 3.63 ~2H~ m) 9 5.17 (lH, d,
J=5H~)9 5.91 ~lH9 dd, J=5 and 8Hz~, 6.~1
~lH9 m), 7.13-7.73 ~3H, m)~
&~
t ~1 7 7
8.28 (2H, broad s), 9.87 (lH, d, J=8Hz)
(33) 7-[2-(p-Tolyloxyimino)-2-(5-amino-1,2,4-thiadiazol-
3-yl)acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic ~cid (syn isomer), which is
decomposed by 15QC~ which i~ a mixt~re w~ oly~-isomer.
IR (Nujol) : 3350, 3250, 1780 3 1680~ 1630,
1~30, :1510, 1230, 1050, 910,
820 cm 1
NMR (DMS0-d6, ~) : 2.23 (l/5H9 s), 2.27 (9/5H,
5) 9 .3-7~ t2H, m~, 4.21 and 4.61 (2H9 ABq,
J=13Hz), 5.23 (lH, d3 J-5Hz), 5.90 (lH, m),
7.16 (4H, m3, 8.~3 ~2H, m), 9.56 (lH~ s),
9.86 ~lH, d, J=8H~)
(34) 7-[2-(3-TTifluoTomethylphenoxyimino)-2-(5-amino-
1~2,4-~hiadiazol-3-yl)acetamido]-3-(1-allyl-lH-
tetrazol-5-yl~thiomethyl-3-cephem-4-carboxylic ,~
acid (syn isomer~, which is decomposed by 155C.
IR (Nujol) : 3300, 3200, 1770, 1680, 1620,
1520, 1320, 1160~ 1120, 1060,
980, 930; 700 cm 1
NMR (D~SO-d6, ~) : 3.S6 and 3.82 ~2H, ABq,
~=18Hz), 4.20 and 4.60 ~2H, ABq, ~=14Hz),
4.95 (2H, m), S.18 (lH, d9 J=5Hz),
5.12-5.24 t2H, m~, 5.92 ~lH, dd~ J=5 and
8Hz3, 5,72-6.12 tlH9 m), 7~50 (4H~ m),
8.26 (2H, m) 9 9.84 (lH, d, J=8Hz)
(35) 7-~2-(3-TrifluoTomethylphenoxyimino)-2-~5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid tsyn isomer), which is decomposed by 170C.
IR (Nujol) : 3~00, 3200, 1770j 1680~ 1620,
,
~1~24~
1520, 1320~ 1160, 1120, 1060,
930, 790, 700 cm 1
NMR (DMS0-d6, ~) : 3.77 (2H9 m)9 3.97 ~3H, s),
4.37 (2H9 m), 5.;27 (lH, dD J=5Hz), S.95
~lH, dd, J=5 and 8Hz), 7.60 ~4H, m39 8.33
(2HI m), 9.37 (lH, d3 J-8H~
~36) 7-[2-~4-Pluorophenoxyim:ino) 2-~5-amino-1,2,4-
.~hiadiazol-3-yl)ac~tamido]-3-~1-me~hyl-lH-tetrazol-
5-yl3thiomethyl-3-cephem-~-carboxylic acid ~sy~
isomer), which is d~composed by 170C.
IR ~Nujol) : 3450~ 3350, 3200, 1780, 1710,
1680, 1610, 1510 3 1590, lZ40 J
12039 1170, 1090, 9909 910, 840 cm 1
NMR ~DMSO-d~ ~) : 3.73 ~2H, m) 9 3.93 ~3H, s),
4.33 (2H~ m), 5.23 (lH, d, 3-5Hz), S.gO
~lH, dd, J-5 and gH~), 7.17-7.28 ~4H, m),
8.37 (2H, m). 9.87 ~lH, d, J=8Hz)
(37) 7-[2-(2,4-Dichlorophenoxyimlno~-2-~S-amino-192,4-
~hiadiazol-3-yl)ace~amido]~3-cephem-4-carboxylic
acid (syn isomer), which is decomposed by 240C.
IR (Nujol3 : 32509 1l70, 1660, 16209 1540,
15~0, 1280, 1230, 1100, 1050,
970, 920, 810, 750 cm~l
NMR (DMSO-d~ 3.56 (2H~ m~, 5.11 ~lH, d9
J=5Hz), 5.91 ~lHa dd~ J=S and 8Hz), 6.47
~lH, m~, 7.47-7.63 (3H3 m~, 8.21 (2Ha m),
9.81 tlH, d, J-8Hæ)
(38) 7~ 2~4-Dichlorophen3xyimino)-2-~5-amino-1,2,4-
thiadia~ol-3-yl)acetamido3-3-(1,3,4-~hiadiazol-
2-yl~hiomethyl-3-cephem-4-carboxylic acid (syn
isomer~, which is decomposed by 165C.
.
--
IR (Nujol): 3300~ 3200l 1770~ 1680, 16Z0,
1 5 2 0, 1 2 5 0 3 1 2 3 0, 1 1 0 0, 1 0 6 0,
960, 910, 810 cm
NMR tDMSO-d6, ~) : 3.71 ~2H~ m), 4~23 and 4.67
~2H9 ABq, Jal4Hz), 5 . 25 (lH, d, J=5Hz),
5.93 ~lH, dd, J-5 and 8Hz), 7.5D-7~67
~3H, m), 8 . 25 (2H, ,m), 9 . 57 ~lH, s3,
9, 38 ~lH9 d, J=8Hz)
lû ~3~) 7-~2-~2-Cyclopenten-l-yloxyimino)-2-~5-amino-1g2;4-
thiadiazol-3-yl)ace~amido3-3-me~hyl 3-csphem-4-
ra~boxylic acid ~syn isomer~, mp 165 to 21BC
~dec . ) .
IR ~Nuj ol) : 3350, 3250, 3140 9 3050 " 1750,
17059 1665, 1625, 1550, 1535 cm
NMR ~DMSO-d6~g2O~ 1.6-2.6 ~4H~ m~, 2.00
(3H9 s~, 3O0-3.9 ~2H, m), 5.0S (lH7 d,
J=4.5Hz), 5.2-5.5 ~lH, m~ 9 5O70 (lH~ d,
J-4.5Hz~ 5.7-6.3 ~2H! m)
ZO
~40) 7-l2-Cyclopentyloxyimino-2-~5 amino-1,2~4-
thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-
carboxylic acid (syn isomer), mp 170 to 212C
: ~dec.).
IR (Nujol~: 3350, 31203 30S09 17507 1705,
1668, 1625, 1556, 1534 cm ~
NMR (DMSO-d6~D2O, ~) : 1.3-2.2 (BH, m3, 2.03
(3H9 s), 3.0-3.9 (2H, m) 9 4.77 (lH, broad
s3, S.10 ~lH, d, J=4.5H~), 5.73 (lH, d,
3=4.5~
~41) 7-l2-~2-Cyclohexen-l-y1Oxyimino3-2-(5-amino-
13 2,4-thiadiazol-3-yl)acetamido~-3-methyl-3-
cephem-4~carboxylic acid (syn isome~ 9 mp 180 to
~,
--
205C (dec.).
IR ~Nujol) : 3340, 3250, 3120~ 3050, 1750,
1705, :1665, 1625, 1535 cm 1
NMR ~DMS0-d6+D2O, ~) : 1.3-2.4 ~6H9 m), 2.03
t3H, s), 3.1-3.'7 ~2H, m), 4.70 (lH, broad
s), 5.10 ~lH, dg J=4.5H~), S.73 (lH, d,
J=4.5Hz), 5~7-6.0 ~2H, m~
(4~) 7-[2- (2-Cyclopenten-l-yloxyimino) -~- (5-amino-
1,2~4-thiadiazol-3-yl)afetamido3-2-methyl~3-
cephem-4-carboxylic acid (syn i~omer3, mp 142
to 148~C ~dec.).
IR (Nujol) : 33Q0, 3200, 1775, 16509 1630,
1525 cm 1
NMR ~DMSO-d~D20~ 1.41 ~3H, d, J=7.5H~) 9
1.~-2.6 ~4H, m)g 3.5-4.1 t1H, m), 5.16
(lH~ d, J-4.5Hz)~ 5.Z-5.5 ~lH~ m), 5.6-6.4
~3H9 m3, 6,62 ~lH7 d9 J-6Hz)
20 ~43) 7~2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-
~-(5-amino-1~2,4-~hiadiazol-3-yl)acetamids~-3-
3~4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer).
I~ (Nujol) : 3200, 3163, 1773, 1685, 1620 cm 1
- 25 NMR (DMSO-~ +D2O, ~ : 1.41 (9H, s), 1.6-2.1
(2H, m), 2O8-3.3 (2H, m), 3~75 (2H) broad
. s39 4.0 4.5 (2H, m~ 4.35 and 4.65 ~2H,
: ABq9 J-14Hz)s 5.20 (lH, d, J=5Hz), 5.83
~lH, d3 Ja5Hz)3 9.58 ~lH, s)
~44~ 7-[2-{3-(N-t-Butoxycarbonylam;no)propoxyimino}-
2-~5-amino-1,2,4-thiadia7.ol-3-yl)acetamido~-3-
~ 2-hydroxy2thyl~-lH-~etrazol-5-rl~thiome~hyl-
: 3-cephem-4-carboxylic acid ~syn isomer).
,, .
IR ~ujol~ : 3200, 3160, 1775, 1720j 1700,
1675, 16~0 cm 1
NMR ~DMS0-d6~D20, ~) : 1.37 ~9H, s), 1.5-1.9
~2H, m), 2.~-3.;7 t2H, m), 3~4-3.9 ~4H, m),
3.g-4.4 (6H, m), 5.10 (lH, d, J=5Hz),
5.30 (lH, d, J=5Hz)
~45) 7-~2-{3-~N-t-ButoxycaTbonylamino)pTopoxyimino}-
2-~5-amino-~,2~4-thiad:iazol-3-yl)acetamido]-3-
~5-methyl-1~3~4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylic ac:id ~syn isomer).
IR (Nujol) o 3300, 3150, 1775, 1710, 1700,
1670, 1650, 1620 cm~l
NMR (DMS0-d6lD20p ~) : 1.40 (9H, s), 1.6-2.1
(2H9 m), 2.71 t3H; s), 2.9-3.3 ~2H, m),
3.71 t2H, broad s), 4.0-4.8 (4Hs m), 5.18
(lH~ d, Jo4.5Hz~ ~ 5.88 (lH, d~ J=4j5Hz)
~46) 7-[2-~3-~N~t ~utoxycarbonylamino)propoxyimino}-
2Q 2-~5-amino-1,2,4-thiadiazol-3-yl)acetamido~-3-
(l~methyl-lH-tetrazol-5-yl~thiomethyl-3-cephem-4-
carboxylic acid ~syn isomer), mp 81 to ll9~C
~dec.).
IR ~Nujol~ : 3300, 3180, 1773, 1715, 1700,
1670, 1620 cm 1
NMR ~DMS0-d6~D2O, ~) : 1.35 ~9H9 s)~ 1-5-2-0
~2H, m3, 2.7-3.~ ~2H, m)~ 3.68 ~2Hg broad
, S) 7 3.9-4~5 ~4H, m), 3.92 (3H, s); 5.12
(lH, d5 J~4.5Hz), 5.83 (lH, d, J=4.5Hz)
(47~ 7-[2-{4-(N-t-Butoxycarbonylaminomethyl)-
benzyloxyimino}-~-(5-amino-1,2,4-thiadiazol-3-
yl)acetamido~-3-methyl-3-cephem-4 carboxylic acid
(syn iso~er)~
, ,
~ ~,2~
IR (Nujol) : 3300~ 3170, 1760, 1680 cm 1
N~iR ~DMSO-d6, ~) : 1.65 (9H, s)~ 2.0 (3H, s),
3,4 (2H, m), 4.14 ~2H, d; J-6Hz), 5.1
(lH3 da J=4.5Hz), 5. 2 (2H, s) ~ 5 . 75
1 5 ~lH, dd, J=4.5 and 8Hz)
~48) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-
thiadiazol-3-yl)aceta:mido]-3-hydroxycepham-4-
carboxylic acid ~syn isomer), mp 169 to 173C
(d~c,3.
IR (Nujol) : 3440~ 32509 1750, 1660, 1520,
14VO, 1240, 1060 ? 990 ~ 720 cm 1
NMR (DMSO-d6, ~) : 1.7 t8H, m), 2.77 (lH, m)~
3.0-3.5 (lH, m)) 3.7-4.1 (lH, s), 4.43
(lH, d~ J=6Hz), 4.73 (lH9 m), 5.16 (lH,
d, J=5Hz), 5.47 (lHr dd9 J-5 and 8Hz),
8.02 (2Hs broad s), 9033 ~lH, d, J=8Hz)
(49~ 7-L2-{1-(Cycloh~xyloxycarbonyl)eth~xyimino~-2-
~5-amino-1,2,4-~hiadiazol-3-yl)acetamido~-3-
cephem-4-carboxylic acid (syn isomer), mp 160
to 163C (dec.).
IR (Nujol) : 3420, 3300, 3180, 1775, 1720l
1685, 1610,- 152~ 1290, 1230,
1040, 980, 740 cm 1
NMR (DMSO-d5, ~ 50 (3H, d, J=6Hz~,
1.0-2.1 ~lOH, m~, 3.62 ~2H, m)~ 4.80
(lH, q, J=6Hz), 4.6~5.0 ~lH, m), 5.15
~lH, d, J=5Hz), 5.90 ~lH9 dd, J~5 and
; 3Q 8Hz), 6.50 (lHI m), 8.13 ~2H, broad s),
9.39 (I~2H, d9 J-8Hæ), 9~53 (1/2H, d,
J=8HZ)
.
; (50~ 7-[2-(1-t-Butoxyca~bonyl-l-cyclopentyloxyimino)-
, 35
~.~@~
2-~5-amino-1,2,4-thiadiazol-3-yl~acetamido]-3-
cephem-4-carboxylic acid (syn isomer), mp 165
~o 169C (dec.).
IR (Nujol) : 34009 3300, 3200~ 1770~ 1710,
1680, 1610~ 1520~ 1290, 1240,
llS0, 1000, ~70, 740 cm 1
NMR (DMSO-d6, ~) : 1 42 (9H, s), 1.77 (4H, m),
2.05 (4H, ~n), 3.60 (2H, m)~ 5.13 ~lH, d,
J-5Hz~, 5.87 (lH, dd, J~5 and 8Hz), 6.47
~lH~ m), 8.13 (2H, m), 9.33 (lH, d, J=8Hz)
(Sl) 7-~2-Carboxyrnethoxyimino-2-(5-amino-1,2p4-
thiadiazol-3-yl)acetamido3-3~ 2-(N,N-
: dimethylamino)ethyl}-lH-tetrazol-5-yl]thiomethyl-
3-cephem-4-carboxylic acid ~syn isomer~, mp 170
to 173C ~dec.).
IR (Nujol) 3400, 3~80, 3150~ 1760, 16659
- 1610, 1520 cm 1
20 ~523 7-~2-Carboxymethoxyimino-2-~5-amino-1,2~4-
thiadia~ol-3-yl~acetamido~-3-[1-{3-~N,N-
dimethylamino)propyl}-lH-tetrazol~5-yl3thiomethyl-
3-cephem-4-carboxylic acid ~syn isomer), mp 170
to 175C ~dec.~.
IR ~Nujol) : 3400~ 3280, 3160, 1760, 16659
161Q, 1520 cm 1
(53~ 7-[2-(2-Propynyloxyimino)-2-(5 amino-1,2,4-
thiadiazol-3-yl)acetamido~-3-[1-{3-(~-t-
butoxycarbonylamino)propyl}-lH-tetraz31-5-yl3-
thiomethyl-3-cephem-4-carboxylic acid ~syn isomer),
rnp 85 to 90C ~dec.).
IR (Nujol) : 3400~ 3290, 3~00, 1770~ 1680,
1620~ 1520 cm
~54~ 7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-~ 3-(N-t-
butoxycarbonylamino)propyl}-lH-~etrazol-5-yl]-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 185 to 190C tdec.).
IR (Nujol) : 3300, 3200, 1770, 1680, 1620,
1520 cm~l
(55) 7-l2-(~,2,2-Trifluoroethoxyimino~-2-(5-amino-
1,2,4-thiadiazol-3-yl~ace~amido]-3-(1-ca~boxrmethyl-
lH-tetrazol-S-yl~thiomethyl-3-cephem-4-carboxylic
acid ~syn isomeT), mp 130 to 132C (dec.~.
IR ~Nujol) : 3300, 3200) 1770~ 1720, 1670,
1620, 1~2~ c~ 1
C56) 7-[2~ arboxy-2-methylpropoxyimino)-2-~5-amino-
192,4-thiadiazol-3-yl)acetamido]-3-~1-{3.(N-t-
butoxycarbonylamino)propyl}-lH-te~razol-5-yl]-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 192 to 195C (dec.).
IR (Nujol~ : 3400-3200, 1780, 168Q~ 15Z0,
1450, 1~60~ 1240~ 1160~ 1520
1020, 73O c~-l
2 5 ~ ~ 57 ~ 7 - ~2 - (1 - Carboxypropoxyimino~ - 2 - (5 - amino^l ~ 2, 4 -
thiadiazol- 3-yl) ace~amido] - 3- [1- { 3 - (N-t-
butoxyca~bonylamino)propyl~-lH-tetrazol-5-rl~-
thiomethyl-3-cephem-4-carboxylic acid ~syn isomeT~
mp 185 to 192C (dec.).
3G IR ~Nujol) : 3300,3200, 1770 a 1680, 1620,
~520, ~450, 1360, 1250; 1160,
1000, 730-710 cm 1
~58) 7-[2-{3-(N-t-Butoxyca~bonylamino~propoxyimino}-
3~
~8~
2-~5-amino-1,2,4^thiadiazol-3-yl)acetamido] 3-
[1-{3-~N-t-butoxycarbonylamino)propyl}-lH-tetrazol-
S-yl]thiomethyl-3-cep~hem-4-carboxylic acid (syn
. isomer).
J 5 IR ~Nujol) : 3300, 3150, 1775, 1715, 1675
16509 1615 cm 1
~59) 7-[2-~l-Carboxyet~oxyimino)-2-(5-amino-1~294-
: thiadiazol-3-yl)acetamido~-3-~1-{3-(N-t-
butoxycarbonylamino)pr~pyl}~.lH-tetrazol-5-yl]-
thiomethyl-3-cephem-4-carboxylic acid (syn
isomer~, mp 110 to 115C (dec.).
IR (Nujol) : 33009 3200, 1770, 1630, 1600,
1520~ 1250, lO00, 720 cm 1
: 15
(60) 7-~2-(1-Ca~boxy-l-cyclopentyloxyimino)-2-(S-
amino-1~2,4-thiadiazol-3-yl)2cetamldo~-3-~1-{3-
~N-t-butoxycaTbonylamino~propyl}-lH-tetrazol-5
yl]thi~methyl-3-cephem-4-carboxylic acid ~syn
isomer), mp 200 ~o 205C (dec.~.
IR (Nujol) : 3300, 3200, 1770, 1680, 1520,
1250, 1160, 1000 cm~l
(61) 7-[2-Carboxymethoxyimino-2^(5-amino-1,2,4-
thiadiazol-3 yl)acetamido~-3-[1-~3-morpholinopropyl)-
lH-te~razol-5-ylJthiomethyl-3-cephem-4-carboxylic
: ~cid (syn isomer), mp 190 to 194~C (dec~)O
IR (Nujol) 3300, 3200p 1770p 1680p 1610~
15309 124~, 1180, 1090, 1060,
- 30 880, 760 cm
J
~62) 7-[2-(1-Carboxy-l-methylethoxyimino)-2-(5-amino-
1,2,4-thiadiazol~3-yl)acetamidoJ-3-~1-{3-(N-t-
butoxycarbonylamino)propyl}-lH-te-trazol-5-yl~-
3S
~6
thiomethyl-3-cephem-4-carboxylic acid (syn
isomer~ .
IR ~Nujol) : 3300, 315Q7 17707 16809 1520,
1240 9 1160, ~90 cm 1
S
~63) 7-~2-Carboxymethoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-(4-me~hyl-5-oxo-6-
hydroxy-4~5-dihydro-1~2,4-triazin-3-yl)thiomethyl-
3-cephem-4-carboxylic acdd (syn isomer), mp 210
to 214C ~dec.~O
IR ~Nujol) : 3250, 3180, 17~0, 17.20-16607
1590~ 1520, 1~403 l~gO, ~050,
720 cm l
(64) 7-E2-Carboxymethoxyimino-2-(5-amino-1,2,4-
thiadi~olw3-yl)acetamido]-3-[1-~4-(N-t-
butoxycarbonylamino~bu*yl}-lH-tetrazol-S-yl]-
thiomethyl-3-cephem-4-carboxylic acid ~syn
isomer).
IR (Nujol) : 3300~ 3200~ 1770, 1680, 1620,
1520, 1240~ 116~, 1090~ ~060,
890 cm 1
(65~ 7-[2-Carboxymethoxyimino-2-(S-amino-1,2,4-
thiadiazol-3-yl)acetamido3-3-[1-~3-
piperidinop~opyl)-lH-tetrazol-5-yl]thiomethyl-
3-cephem-4-carboxylic acid (syn isomer), mp 223
to 228C (dec.).
IR ~Nujol~ : 33009 32007 1770, 1670 9 1610,
1520 cm 1
~66~ 7-[2-carboxymethoxyimino-2-(5-amino-l92~4-
thiad:iazol 3-yl)acetamido]-3-~1-carboxymethyl-
lH ~etrazol-5-yl)thiomethy~-3-cephem-4-carboxylic
~5
`~,
4~
acid (syn isomer), mp 170 to 175C (dec.)~
IR (Nujol) : 3300~ 3200, 1765~ 1720, 1660,
1620 9 1520 cm 1
t67) 7-[2-Carboxymethoxyimino-?-(5-amino-1,2~4-
thiadiazol-3-yl)acetamido]-3-~1-{6-(N-t-
butoxycaTbonylamino)hexyl}-lH-tetrazol-5-yl]-
thiomethyl-3-cep~em-4-carboxylic acid (syn isomer),
pale yellow powder.
(SSl 7-~2~ Carboxye~hoxyimino~-2 (5- amino- 1 ~2~4
: thiadiazol-3-yl)acetamido~-3-[5-~N-t-
butoxycarbonylamino~me~hyl-1,3,4-thiadiazol-2-
yl~hiomethyl-3-cephem-4-carboxylic acid (syn
isome~), mp 210 to 215C (dec.).
IR ~Nujol) : 3300, 1770, 1680, 1620, 1520,
1240, 1140 cm 1
(69~ 7~2-~2-Propynyloxyimino)-2-(5-amino-1,2,4-
: 20 ~hiadiazol-3-yl)ace~amido~-3-[1-~3-aminopropyl)-
'. lH-tetrazol-5-yl]thiome~hyl-3-cephem-4-car~oxylic
acid (syn isomer), mp 165 ~o 170C tdec.).
IR (Nujol) : 3450, 3300, 3210, 1770, 1570,
1620~ 1525 cm~
~5
; ~70) 7-C2-Carboxymethoxyimino-2-~5-amino-1~2,4-
~hiadiazol-~-yl)acetamido]-3-~l-t3-aminopTopyl)-
lH~tetrazol-5-yl]thiomethyl-3-cephem-4-caTboxylic
acid (syn isomer), mp 195 ~o 200C ~dec~.
IR (Nujol~ : 3150, 1750p 1660, 1640; 1520 cm l
(71~ 7-[2-(1-Carboxy-2-methylpropoxyimino)-2-~5-
amino-1~2,4-thiadiazol-3-yl)acetamido3-3-~ 3-
aminop~opyl~-lH-tetTa7.ol-5-yl]thiomethyl-3-
&~3
q ~
cephem-4-carboxylic acid (syn isomer), mp 183 to
189C ~dec.)O
IR (Nujol) : 3400-3100, 3150~ 1770, 1670,
1620~ 1520, 1380~ 128~ 1230,
1180, llO0, 1020, 900, 730 cm~
~72) 7- ~2-(1-Carboxypr~poxyimino)-2-(S-am1no-1,2,4-
thiadiazol-3-yl)a~e~amido~-3-[1-(3-aminopropyl3-
lH-tetrazol-S-yl~thiomethyl-3-cephem-4-carboxylic
acid ~syn isome~), mp 183 to 188~C (dec.).
IR (NUjO1): 3400-3150, 1770J 16~09 1620,
1530~ 1380~ 1280, 1230, llB0,
1100, 1050, 1010 7 730 cm ~
(73~ 7-[2-~1-Ca~boxye~hoxyimino)-2-~5-amino-1,2,4-
~hiadiaæol-3-yl~acetamido~ 3-[1-~3-aminopropyl~-
lH-tetrazol-5-ylJthiomethyl-3-cephem-4-carboxylic
acid ~syn isomer)~ mp 185 to 1~8C (dec.3.
IR ~Nujol) : 3300, 3150~ 1750, 1660, 1620
1520~ 1230, 1000, 720 cm~l
~74~ 7-[2-Carboxymethoxyimino~ 5-amino-lJ2,4-
thiadiazol-3-yl)~cetamido]-3 ~1-(4-aminobutyl)-
lH-tet~azol-5-yl~thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer), mp 191 to 194C ~dec.).
IR ~Nujol) : 3300, 31509 1760, 1670~ 1620
1520, 1230~ 1170, 105~ 8gO,
740~ 720 cm~l
(75~ 7-[2~ Carboxy-l-methylethoxyimino)-2-(5-amino-
1~2,4-thiadiazol-3-yl)acetamido~-3-[1-(3-
aminop~opyl~-lH-tetrazol-5-yl~thiomethyl-3-cephem-
4-carboxylic acid (syn isomeT), mp 200 to 203C
(dec.).
~2
~89
IR (Nujol) : 3300, 3150, 1760, 1660, 1620,
1520~ 1160, 990 cm 1
(76~ 7-[2-(1-Ca~boxy-l-cyclopentyloxyimino)-2-~5-amino-
1,2~4-thiadiazol-3-yl)acetamido]-3-[1-(3-
aminopropyl)-lH-tetra~ol-S-yl~thiome~hyl-3-cephem-
4-carboxylic acid (syn isomer), mp 202 to 205~C
(dec.),
IR ~Nujol~ : 3300, 3200) 1760, 1660, 1620,
1520, 1180, 1060, 1000~ 730 cm 1
~77) 7-[2-(1-Carboxye~hoxyimino)-2-(5-amino~ ,4-
thiadiazol-3-yl)acetamido~-3-~5-aminome~hyl-
1,3,4-thiadia~ol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid ~syr~ isomer)~ mp 207 to 210C
~dec.).
IR ~Nujol) : 3300, 3150, i760, 1660~ 1620,
1520, 12309 1170; 1090~ 1060,
1040, ggo ~-1
:~0
(78) 7-[2-Carboxym~thoxyimino-2-(5-amino-1,2,4-
thiadiazol-3 -rl ) acetamido~-3~1-(6-aminohexyl)-
lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer), mp 185 to 188C (dec.).
2~ ~R (Nujol) 3300~ 3200~ 1760, 1670) 1620,
1520, 1240~ 118~, 1060 c~ 1
~79) 7-[2-~3-Aminopropoxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-(1,3,4-th;adiazol-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer), mp 165 to 183C (dec.).
IR ~Nujol) : 3150, 1765, 1660~ ~630, 1570 9
1520 cm~
~5~
(80) 7-[2-~3-Aminopropoxyimino)-2-~5-amino-1,2,4-
thiadiazol-3-yl)ace~amido]-3-[1-(2-hydroxye~hyl)-
lH-tetrazol 5-yl]~hiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 170 to 185~C (dec.).
S IR ~u3O1) : 3140 9 1760~ 1660, 1610, 1580,
1520 cm 1
(81) 7-~2-(3-Aminop~opoxyimi.no)-2-~5-amino- 19 2,4-
thiadiazol-3-yl)acetamido~-3-(5-methyl-1~3,4-
thiadiazol-2-yl)thiom~thyl-3-cephem-4-carboxylic
acid (syn isumer), mp 192 to 195C ~dec,).
I~ ~Nujol) : 32~0, 3140, 1760 9 1640, 1520,
1585j 1525 cm 1
(82) 7-[2-(3-~minop~opoxyimino)-2-(S-amino-1,2,4-
thiadiazol-3-yl)a~etamido3-3-~1-methyl-lH-tetrazol-
5-yl~thiomethyl-3-cephem-4-carboxylic acid ~yn
isomer) 3 mp 180 to 184C ~dec.).
IR ~Nujol~ : 31S0, 1760, 1660J 1590 cm l
(833 7-~2-(4-Aminomethylbenzyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl~acetamido]-3-methyl-3-
cephem-4-carboxylic acid ormate ~syn isomer),
mp 230 to 240C (dec.).
IR (Nujol) : 1750 cm l
.
~84~ 7-[2-~3-Aminop~opoxyimino~-2-~5-amino-192,4-
thiadiaæol-3-yl~acetamido]-3-[1-(3-aminopropyl)-
lH-te1:razol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid (syn isomer~.
IR ~Nujol) : 3300, 3150, 1760, 16603 1607,
1595, 15~0 cm 1
~85~ 7-[2-~a-Carboxyb~nzyloxyimino)-2-~5-amino-1~2,4-
~hiadiazol-3-yl~acetamido~-3-(1,3,4-thiadiazol-
2-yl)~hiomethyl-3-cephem-4-carboxylic acid (syn
isomer), mp 150 to 155C (dec.).
IR ~Nujol) : 3400, 3290, 31609 2500, 1770,
17203 1615, 1520 cm 1
(86) 7-[2-(-Carboxyben~yloxyimino~-2-~5-amino-1,2 3 4-
- thiadiazol-3-yl)acetamido~-3-cephem-4-carboxylic
acid ~syn isomeT), mp 170 to 175C (dec.~.
; 10 IR tNujol) : 3400, 3280~ 3160, 2600, 1770
1720, 1670, 1625~ 1520 cm~
~87) 7-[~ -Carboxybenzyloxyimino)-2-C5-amino-
1,2,4-thiadiazol-3-yl)acet~mido~-3-~ 2-
: 15 aminoethyl)-lH-tetrazol-S-yl]thiomethyl-3-sephem-
4-ca~boxylic acid ts~ isomer~ mp 190 to 195C
~dec.).
IR (Nujol) : 3400~ 330G, 3150, 1765, 1670,
.16109 1520 cm 1
2~
~88~ 7-~2-Carboxymethoxyimi~o-2-~$-amino-1l2,4-
:. thiadiazol-3-yl)ace~amido~-3-cephem-4-carboxylic
acid (syn isomer), mp 180 to 185C (dec.~.
IR (Nujol) 3350~ 3250, 1770, 1720, 16809
~5 1630, 1530 cm ~
~89~ 7-~2-Ca~boxymethoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl~acetamido~-3-[1-~3-~4-methyl-1-
: pipera~inyl)propyl} lH tetrazol-5 yl3thiomethyl-
3-cephem-4-ca~boxylic acid tsyn isomer~, mp 185
to l90~C (dec.~O
IR (Nujol~ : 3300 3 1760, l6705 16009 1520 cm 1
; (90) 7-E2-tl-Carboxy-~-methylpropoxyimino)-2-(5-amino-
~5
1,2,4-thiadiazol-3-yl)acetamido~-cephalosporanic
acid (syn isomer~.
IR (Nujol) 3400-3150, 1770, 1730-1670,
17~0, ~ 0, 1460, 1370, 123~,
1030, 730 cm l
~91) 7-~2-(1-Carboxypropoxy:imino)-2-t5-amino-1,2,4-
thi~diazol-3-yl)acetam:ido3-3-(1,3,4-thiadiazol-
2-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn
isomer), mp 153 to 158'DC (dec.).
IR (Nujol) : 3300,3180, 1770, 172.0~16709
1620~ 1520, 1220, 1060, 1000,
. 900p 730 cm 1
(92) 7-~2-tl-Carboxypropoxyimino~-2-~5~amino-1,2,4-
thiadiazol-3-yl)acetamido~cephalosporanic acid
(syn isome~)~ mp 115 to 120C (dec.).
IR (Nujol) : 34009 33009 3200, 1770, 1720-1670,
16~.0, 1520, 1230, 1030-1010, 8909
~o 740-720 cm 1
~93~ 7-[2-(l-Carboxyethoxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido~-3~ 3,4-thiadiazol-
2-yl)thiomethyl-3-cephem-4-carboxylic acid tSyn
isomer) 3 mp l65 to 168C (dec.).
IR (Nujol) : 3400-32009 1770~ 1710, 1670,
1620, 1520~ 1230, ~170, 100~,
gO0, 720 cm~
~94) 7-[~-(1-Carboxy-l-me~hyle~hoxyimino)-2-(5-
amino-192~4-thiadiazol-3-yl)acetamido]-3-tl~3,4-
thiadia~ol 2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 164 to 167~ C (dec.).
IR ~Nujol~ : 3300, 3200, 2800-2300, 1770,
3~
~3
1720-1660, 16~0 9 1520, 1160, 1060,
990, 800 cm 1
~95) 7- [2-~1-Carboxy-l-cycl.opentylo~yimino~-2-(5-
amino-1,2~4-thiadiazol.-3-yl)acetamido~-3-(1,3,4-
thiadiazol-2-yl)thiome~thyl-3-cephem-4-carboxylic
acid ~syn isomer), mp 165 to 16~C (dec.).
IR (Nujol) : ~3009 3180, 1770, 1720-1660,
1620, 1520; 1240 9 1180, ~060 3
1000, 720 cm 1
~96) 7-[2-(1-Carboxy-l-methylethoxyimino)-2-t5-amino-
1,2,4-thiadiazol-3-yl3acetamido]-3-cephem-4-
carboxylic acid (syn isomer), mp 215 to 220C
(dec.).
IR ~Nujol~ : ~400, 32509 3200; 1770, 1670,
1520, 1290, 1240, 11~0, 1000,
-1
, 980, 740 cm
. .
;~ 20 ~97~ 7-~2-(1-Carboxyethoxyimino)-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-(1-allyl-lH-tetrazol-
5-yl) hiomethyl-3-cephem-4-carboxylic acid (syn
isomer), which is decomposed by 180C.
- IR (Nujol) : 3300, 3150, lY70, 1680, 1610,
2~ 1520, 126~a 1100; 1040, 1~00 cm~
(98) 7-[2-~1-Carboxyethoxyimino)-2-~5-amino-1~2,4-
ol-3-yl)acet~mido] ~-cephem-4-carboxyli~
acid ~syn isomer)~ mp 230 to 235C (dec.~.
3~) IR tNujol): 3400a 32503 3151), 1760, 1720,
1660, 1610~ 1550, 1290, 124~,
1170, 970, 740 cm 1
~9~) 7-[2~ Carboxy-l-cyclopentyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-
carboxylic acid tsyn isomer), mp 212 to 217~C
~dec.).
IR (Nujol) : 3300 9 3200~ 1770, 1670, 1620,
S 152~ ].280, 1240, 1180, 1000,
970, 7';0 cm 1
~100) 7-~2-(1-Carboxyethoxyimino)-2-~5-amino-1,2,4-
thiadiazol-3-yl~acetamido3cephalospo~anic acid
(syn i~omeT).
IR (Nujol) : 3300, 3200, 1770, 1710, 1670
15209 1230, 1040 cm 1
(101) 7-[2-(1-Carboxy^l-methylethoxyimino)-2-~S-amino-
lS 1,294-thiadiazol-3-yl)acetamido~-3-[1-(2-aminoethyl~-
lH-tetra7O1-5-yl~thiomethyl-3-cephem-4-carboxylic
acid (syn isomer)~ mp 195 to 200C (dec.).
IR (Nujol~ : 3150~ 17603 1670, 1620, 1520,
1170, 990 cm~
(102) 7-[2-Cyclopentyloxyimino-2-~5-aminv-1~2,4-
~hiadiazol-3-yl)acetamido~-3-[1^{3-(4-methyl-1-
piper~zinyl)propyl}-lH-tetrazol-5-yl]thiomethyl-
- 3-cephem-4-carboxylic acid (syn isomer), mp 175
~o 180~C (dec.~. ,
IR (Nujol~ : 33U0, 1770, 1650~ 1610~ 1520 cm 1
NMR tDMSO-d~ 1.50-1.80 (8H~ m), 1~80-2.10
(2H, m~, 2.30-2.50 (4H9 m~, 2.60 ~3H, s) 9
2.8-3.~ t6H, m~ 3.~0 ~2H9 broad s),
4,30-4.50 ~4H~ m), 4~67-4.83 tlH, m)9 5.10
(lH, d9 J=4Hz), 5.77 (lH~ dd, J-4 and 8Hz) 9
8.17 ~2H, s), 9.50 (lH~ d, J=8Hz)
~ 3
(103) 7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-
thiadiazol-3~yl)acetamido]-3-carbamoyloxymethyl-
3-cephem-4-carboxylic acid (syn isomer), mp 175
to 180C (dec.~.
IR (Nujol) : 3400, 3300~ 3180, 1770, 1710,
1670, 1620, 1520 cm~l
NMR ~DMSO-d6, ~ : 1.40-2.0 (8H, m~, 3.53
(2H~ broad s), 4~67 and 4.85 (2H, ABq,
J=13Hz)s 4.67-5.07 (lH9 m~, 5.15 (lHl
d, J-5Hz)~ 5.78 ~lH, dd, J=5 and 8Hz),
6,55 (2H, broad S~g 8.08 t2H, broad s),
9.45 (lH~ d, J=8Hz)
(104) 7-[2-(2-Cyclopen~en-l-yloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-carbamoyloxy-
methyl-3-cephem-4-carboxylic acid (syn isomer)
mp 165 to 170C (dec.).
IR ~Nujol) : 3400, 3300, 3180~ 1770, 1710,
1670, 1615~ 1520 cm 1
NMR (DMSO-d6) 8) : 1.97-2~47 ~4H~ m),
3.50 ~2HJ broad s) 3 4.65 and 4.85 ~2H,
A~q~ J=13HZ~, 5.12 (1H, d9 J=5HZ),
5.17-5.50 ~lH, m), 5.67-6.27 (3H, m),
6.55 ~2H, broad s), 8.10 (2H, broad s)~
9.47 (lH, d, J=8Hz)
tlO5) 7-~2-Cyclopentyloxyimi~o 2-~5-amino-1,2,4-
thiad;azol-3-yl)ace~amido]-2~m~thyl-3-cephem-4-
carboxylic acid tsyn isomer).
IR ~Nujol) : 3420g 3400, 3270~ 3180, 2430,
1790) 17759 1690, 1675~ 1640,
1615, 1600, 1495 cm 1
NMR (DMSO-d6, ~) : 1.43 (3H, d, J-7Hz),
1.5-~.1 (8H, m~, 3,73 (lHI q~ J=7Hz~,
~6
4.5-4.9 (.lH, m), 5.07 (lH, d, J=5Hz~,
5.84 ~lH3 cLd, J=5 and 9Hz) 9 6.50 ~lH,
d, J-6Hz), 8.02 ~2H, broad s), 9.38
! ( lH, d, J=5lHz)
1 5
~106~ 7-[2-(2-Oxo-3-*etrahLydrofuryloxyimino~-2-(5-
amino-1,2,4-thiadiazol-3-yl~acetamido~-3-(1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer~ 9 mp 165 to 170C (dec.~.
IR ~Nujol~ : 33009 3200, 17701 1680, 1620,
1525 cm~l
NMR ~DMSO~d~ .27-2~70 (2H, m),
3,70 (2H, broad s) 9 4.17-4.73 (4H, m)~
5.15 (lH~ d, J=4Hz3, 5.18 ~lH, t~ J=7Hz),
- 15 5.83 (lHs dd, J=4 and 8Hz~ 8.13 ~2H,
broad s), 9.50 (lH3 5) ~ 9.60 (lH, d,
J=8Hz~
~107) 7-[2-~2-Oxo-3-tetrahydrofuryloxyimino)-2-~5-
amino-1,2,4-thiadiazol-3-yl)acetamido]-3-
cephem-4-carboxylic acid (SyIl isomeT), mp 175
to 180C (dec.).
IR ~Nujoi) : 3300, 3200, 1775~ 1670, 15~0,
1530 cm 1
NMR ~DMS0-d6, ~) : 2.35-2.67 (2H, m),
3.57 (2H, broad s), 4.17-4.50 (2H, m)~
5.07 (lH, d, J=4Hz); 5~15 ~lHp t, J-8Hz~,
5~82 ~lH, dd3 J=4 and 8Hz), 6.43 ~lH,
~9 ~=5Hz)9 8.17 (2Hp broad s~, s.6n
~lH, d, J=8~z)
~10~) 7-[2~ Cyclohexyloxycarbonylethoxyimino) -2-
(5-amino-192,4-thiadiazol-3-yl~acet~nido]-3-
Ll-{3-(N-t-butoxycarbonylamino~propyl}-lH-
tetrazol-5-yl3thiomethyl-3-cephem-4-carboxylic
acid (syn isomer) ? mp 145 to 150C (dec.).
IR (Nujol) : 3400-3250~ 1780~ 1680, 16207
1520, 12~0, 1220, 1160, 1100
1000, 740~ 720 cm~l
NMR (DMSO-d6, ~) : 1.0-2.3 ~15H, m), 1.40
(9H~ s) 9 3.0 ~2H, m) 9 3.7 (2H, m) 3
4,3 (4H, m~, 4.5-5.0 ~lH, m~, 4.77 ~lH,
q, J=7Hz), 5.13 (lH, d, JaSHz3, 5.86
(lH, m) 3 6.83 ~lH, m), 8.12 (~H, broad
s)~ 9.37 ~1/2H, d, J=8Hz)., 9.Sl tl/2H~
d, J=8Hz~
(109) 7-[2-(1-Benzyloxycarbonylethoxyimino)-2-(5-
amino-1,2~4-thiadiazol-3-yl)acetamido]-3-
cephem-4~carboxylic acid (syn isomer), mp 177
~o 180C ~decO).
IR (Nujol) : 3400, 3300, 3700, 1770, 1730,
16~0, 1610 9 lS2~, 1240, 1160,
1040~ 980, 740 cm 1
NMR (DMSO-d67 ~ : 1.47 ~3H, d, J=7Hz),
3.57 (2H~ m), 4.88 ~lH, q, J=7Hz)~
5.10 (lH9 d, J=5Hz)9 5.18 ~2H~ 5) 9
5.87 (lH, dd, J-5 and 8Hæ), 6.45 (lH~
m~, 7.31 (5H, broad s), 8.10 ~2H,
broad s) 3 9.40 and 9.55 (lH, d, J-8Hz)
~110~ 7-[2-~1-Benzyloxycarbonylethoxyimino)-2-(5-
amino-1,2,4-thiadiazol-3-yl)acetamido]-3
~(N-~-bu~oxycaTbonylamino)propyl~-lH-
~etrazol-5~yl]*hiomethyl-3-cephem-4-carboxylic
acid (syn isomer)~ mp 113 to 117C (dec.).
IR (Nujol) : 3300, 3200, 1780, 1680, 1620,
1520, 1250, 1160~ 1100, 1040
1000, 740~ 700 cm 1
NMR (DMSO-d6, ~) : 1.43 ~9H, s), 1.53
(3H, d, J=6Hz), 2.0 (2H, m), 3.03 ~2H,
m)~ 3.70 ~2H, m), 4.10-4.67 ~4H, m),
4.88 (lH9 q, J-6Hz), 5.10 (lH, d,
J=5H~) 9 5.17 (2H, s), 5.80 (lH, dd7
J=5 and 8Hz), 6.53 ~lH, m)9 7.30 (5H,
s), 8.10 ~2Hs broad s), 9.40 and
9.55 (lH, d, J=8Hz)
(111) 7-[2-~1-Butoxycarbonrlethoxyimino~ (5-amino-
1,2,4-thiadiaz~1-3-yl)acetamido]-3-cephem-4~
carboxylic acid (syn isomer)g mp 147 to 151C
~dec.)~
IR (Nujol) : 3400, 3300, 3200, 1770, 1720,
168OJ 1610, 1520, 1~80, 1235,
1155, 1045, 980, 740 cm~l
NMR ~DMSO-d6, ~) : 0.87 (3H, t, J=6H~),
1.46 ~3H, d, J=7Hz)~ 0~8-1.8 ~4H, m),
3.6 (2H9 m), 4.08 (2H, t~ J=6Hz),
4.74 ~lH, q, J=7~z~, 5.08 (lH) d,
J~5Hz~, 5.83 (lH3 dd, J=5 and 8Hz),
~.4 (lH, m), 8.37 (2~, broad s),
9.39 and 9.44 (lH, d, J=6Hz)
2S
(112~ 7-[2~1-ButoxycaTbonylethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido~-3^~1-{3-(N-
t-bu~oxycar~onylamino)propyl} - lH-tetrazol~5-
yl~thiomethyl-3-cephem-4-carboxylic acid (syn
isom~r~l, mp 149 to 155C (dec.).
IR (Nujol) : 3300, 3200, 1780, 1700,
1520, 15~0, 1250, 1160,
00 7 1040, 1000, 740) 720 cm 1
~2
~99
NMR (DMSO-d6,~) : 0.26 (3H, t, J=7Hz),1.4Q(9H,s~
1.0-1 7 (4H, m), 1.43 (3H, d, J=7Hz),
107-2.3 ~2H, m), 3.0 t2H, m), 3.7 (2H,
m), 4.0-4.5 (6H, m), 4.77 (lH, q9 J=7Hz),
5.15 tlH, d, J=6Hz), 5.8 ~lH, m)9 6.9
(lH, m), 8.13 (2H, broad s), 9.5 (lH~ m~
(113) 7-[2-(2-D-Phenylglycylaminoethoxyimino)-2-
~5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-
methyl-3-cephem-4-caIboxylic acid ~syn isomer);
mp Z04 to 222C (dec.).
IR (Nujol) : 3~609 3150, 17609 1665, 1616,
1512, 1400, 1045 cm 1
lS ~114) 7-[2-(3-D-Phenylglycylaminopropoxyimino)-2-(S-
amino-1,2,4-thiadiazol-3-yl)~cetamido]-2-methyl-
3-cephem-4-carboxylic acid (syn isomer)~ mp 203
to 231C (dec,),
IR (Nujol) : 3280~ 1170, 1760, 1660, 1600,
1520, 1400 cm 1
NMR (D2O~DCl,~) : 1.47 (3H, d, J=7.5Hz),
1.7-2.3 ~2H, m), 3.40 (2H, *, J=7Hz),
3188 ~lH, q, J=7.5Hz), 4.33 ~2H, t,
J=6Hz~, 5,18 ~lH, d, J=4 5Hz), 5.20
(lH, s), 5.g5 ~lH, d, J=4,5Hz), 6.90
(lH, d, J=6 0Hz), 7.57 ~SH~ s)
(115) 7-[2~ Cyclohexyloxycarbonylethoxyimino)-2-t5-
amino-1~2,4-thiadi~zol-3~yl)acetamido]-3-[1-
~3-aminopropyl)-lH-tetrazol-5-yl]thiomethyl-3-
cephem-4-ca~boxylic acid (syn isomer), mp 175
~o 178C (decO~.
XR ~Nujol) o 3400-32G0~ 1765, 1680, 1610,
15~0, 12~0g llU0, 1000,
2~
890~ 790 cm~l.
NMR (DMSO-d6,~) : 0.9-2.0 (13H, m),
2.2 (2H9 m), 2.9 (~H, m)~ 3.6 (2Hp m~,
4,0-5.1 (5H, m), 4.76 ~lH, q, J=7Hz),
5.03 (lH, d, J=5Hz), 5.77 (lH, m),
8.17 (2H, broad s), 9.45 ~lH~ m)~
(116) 7-[2-(l-Benzylo~ycalbonylethoxyimino)-2-(S-
amino-1,2,4-thiadiazol-3-yl~acetamido]-3-[1-
~3-aminopropyl)~lH-*etrazol-S-yl~thiomethyl 3-
cephem-4-ca~boxylic acid (syn isomer), mp 16Z
to 166C (dec.).
IR (Nujol) : 3300~ 3200, 1760, 1680, 1620,
1520, 1100, 1040, lO00, 740 cm 1
NMR ~DMSO-d6,~) : 1.47 (3H, d, J=6Hz),
2.23 (2H, m ), 2.90 ~H, m~, 3.60 ~2H,
m), 4.43 ~4H, m), 4.90 ~1~, q, J=6Hz)~
5 07 ~lHp d, J=SHz), 5.20 ~2Hp s),
I . 5.77 ~lH, m), 7.43 ~SH, s)~ 8.23 t2H,
' 20 m), 9.57 (lH9 m)
~ . ,
(117) 7-[~ Butoxycarbonylethoxyimino) 2-~5-amino-
1,Z~4-thiadiazol-3-yl)acetamido]-3-[1-~3-
aminopropyl)-lH-tetrazol-5-yl]thiomethyl-3-
cephem-4-carboxylic acid ~syn isomer), mp 158
to 163C (dec )
IR ~Nujol) : 3400~320Q, 1770p 16B0, 1610~
1530, 13009 1290, 1050~ 10~0,
1000, 960~ 900, 790, 740
720 cm~l
) Pivaloyloxymethyl 7-~2-~3-aminopropoxyimino)-
Z-~5-amino-1,2,~-thiadiazol-3-yl)ace~amido]-Z-
methyl - 3 - cephem- 4 - carboxylate hydrochloride
(syn isomer), mp 91 to 156C (dec.~.
,
i
IR ~Nujol): 3150, 1780, 1745, 1670,
1625, 1525 cm 1
(119~ Pivaloyloxymethyl 7- E2-(3-aminopropoxyimino)-
2-~5-amino-1J2,4-thiadiazol-3-yl)acetamido]-
3~ methyl-lH-tetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylate hydrochloride (syn isomer) 9
mp 110 to 125C tdec ).
IR (Nujol): 178û9 1745, 16703 1625, 1525 cm 1
- (120) Pivaloyloxymethyl 7- ~2-~3-aminopropoxyimino3-
2-~5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-
(5-methyl-1,3,4-~hiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylate hydrochloride (syn isomer)g
mp 88 to 153C ~decO).
IR (Nujol): 2150, 1780, 1745, 1650, 1625,
1525 cm 1
NMR ~DMSO-d6lD20~ 1.16 (9H, s), 1 6-
2.~ ~2H~ m3, 2,6-3.1 (2H, m), 2.68
(3H, s), 3 76 (2H, broad s), 4.20 and
4~53 (2H, ABq, J=18Hz) I 4924 ~2H, broad
5~1~ 5.18 ~lH, d, J=4.5Hz), 5 6-6.0 (3H9m)
(121) Pivaloyloxymethyl 7 ~2- (3-aminopropoxyimino)-
2-(5-amino-1,2,4-thiadiazol~3-yl)acetamido]-3-
2-hydroxyethyl~-lH-tetrazoi-5-yl]thiomethyl-
3~cephem-4-carboxylate hydrochloride ~syn isomer),
mp 150 to 175C ~dec.).
IR ~Nujol): 3150, 1780, 1740, 1670, 1630,
1520 cm 1
(122) Pivaloyloxymethyl 7-~2- ~3-aminopropoxyimino3-
2-~5-amino-1,2,4-thiadiazol-3-yl3acetamido]-3-
~193,4-thiadiazol-2-yl)thiomethyl-3-cephe~l-4-
2Q~
caTboxylate hydrochloride (syn isomer), mp
96 to 155C ~dec.).
IR (Nujol) : 3300, 3150, 1775, 1730,
1670, 1625, 1530 cm 1
s
~123) Pivaloyloxymethyl 7-[2-(4 aminomethylbenzyloxyimino)-
2-(5-amino-19 294-thiadiazol-3-yl)acetami~o~-3-
methyl-3-cephem.4-carboxylate hydrochl3ride
(syn isomer), mp lS0 to 168C (dec.).
IR (Nujol) : 1780~ 1745~ 1670, 1628 cm 1
~124) Pivaloyloxymethyl 7-~2-~allyloxyimino-2-(5-
amino-lg2,4-thiadlazol-3-yl~acetamido~-3-[1-(2-
aminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-
4-carboxylate formate (syn isomer) 3 mp 9S to 105C
~dec.)~
IR ~Nujol) : 1790, 1735, 1452, 1370, 1118,
990 cm 1
NMR (DMSO d6~D2O,~) : 1.2 (9H~ s) 9 3-2-
3,35 (2H9 m), 3,7 ~2H, broad s~,
4.2-4~6 ~2H~ m)~ 4 1-4.6 (2H~ m),
4.7 (2H, broad s3~ 4,8-5.2 (lH, m~,
5.25 (lH, d, J=4.5Hz)~ 5.45 (2~, m~,
5.7-6.25 (2H, m), 5.8 ~lH, d7 J=4.5Hz)
(125) l-Acetoxyethyl 7-[2-cyclopentyloxyimino -2-(5-
: amino-l 3 2,4-thiadiazol-3-yl)acetamido]-2-methyl-
3-cephem-4-carboxylate (syn isomer).
IR (Nujol) : 3400g 3310, 3150, 1780, 1770,
1750, 167S cm l
(126) l-Isobutyryloxyethyl 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-
2-methyl-3-cepllem-4-carboxylate (syn isomer),
amorphous powder.
IR (Nujol~: 3400, 3300, 3170, 1780,
1745, 16759 1620, 1525 cm 1
NMR (DMSO-d6,~) : 1.08 (6H, d, J=7Hz),
1.2-2.2 ~14H, m)3 2.2-2.9 (lH, m),
3.88 (lH, q, J=7Hz~,
4.6-5,0 ~lH, m), 5,12 ~lH, d, J=4.5Hz),
5. 90 . ~lH, cld9 J=4.5 and 8Hz),
6.63 (lH3 d, J=7Hz), 8.06 ~2H~ broad s),
9.43 ~lH~ d, J-8Hz)
(1~7) l^Acetoxypropyl 7-~2-(2-cyclopenten-1-yloxylmino)-
2- (5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-
methyl-3-cephem-4-carboxylate ~syn isomer), mp
110 to 128C tdec.)
IR (Nujol): 3400, 328û, 3150, 1780, 1750,
1730, 1620 cm 1
~128) 1-~2-Azidoe~hoxycarbonyloxy~ethyl 7-~2-~2-
cyclopenten-1-yloxyimino)-2-(5-amino-lg2,4-
thiadiazol-3-yl)acetamido~-2-methyl-3-cephem-
4-carboxylate (syn isomer), mp 85 to lOGC (dec.).
IR ~Nu~ol) : 3310, 2200 9 1760-1785, 1680 cm 1
N~iR (DMSO-d6.D20,~) : 1.48 ~3H, d, J=6Hz),
1~5 ~3H, d, J=4.5H~3, 2.0-2.5 ~4H) m3,
305-4.1 (lH, m), 3.63 ~2H, ~" J=4Hz~, ~
4.30 ~2H9 t, J=4Hæ), 5~16 (lH" d,
J=4 5Hz), 5.2-5.45 ~lH, m), 5 7-5.2
(2H, m)~ 6-6.2 (l~t, m), 6.5-6~8 (lH, m),
6.7 ~lHg d, J=6Hz)
~129) l-Ethoxycarbonyloxyethyl 7-~2-(2-cyclopenten-
l-yloxyimino)-2-(5-amino-1,2~4-thiadiazol-3-
5
~2
~4
yl)ace~amido]-2-methyl-3-cephem-4-carboxylate
tSYn isomer).
IR (Nujol) : 3420-3300, 3150, 1780, 1760,
1675, 1620 cm 1
(130) Pivaloyloxymethyl 7-[2-{3-(N-t-butoxycarbonyl-
amino)propo~yimino}-2-(S-amino-1,2,4-thiadiazol-
3-yl)acetamido] 2-methyl-3-cephem-4-carboxylate
(syn isomer)~ powderg mp 66 to 75C (dec ).
IR (Nujol~ : 3300, 1780, 1745, 1680, 1620 cm 1
(131) Pivaloyloxymethyl 7-[2-{3-~N-t-butoxycarbonyl-
amino)propoxyimino}-~-(5-amino-~,2,4-thiadiazol-
3-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)-
thiomethyl-3 cephem-4-carboxylate (syn isome~),
powder.
IR (~ujol) : 3300, 1780, 1745, 1680, 1620 cm~
: 20
(132~ Pivaloyloxymethyl 7-[2-{3-~N t-butoxycarbonyl-
amino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-
3-yl)acetamido]-3- (5-methyl 1,3~4-thiadiazol-
2-yl)thiomethyl-3-cephem-4-carboxylate (syn
isomer~.
IR ~Nujol~ : 3300~ 3150, 17839 1745, 1675,
1615 cm 1
NMR ~DMSO-d6~D2O,~ : 1c15 ~9H, s), 1-37
~9H~ s), 1.5-2.0 (2H~ m)~ 2.65 (3H, s),
2.8-3.2 ~2H, m), 3.5-3.8 (2H, m),
3.9-4.3 ~2H, m) 9 4.16 and 4.53 (2H,
ABq, J-13Hz), 5.17 ~lH, d, J=4.5H~),
5.6-6,0 (3H, m)
~ - -
(133) Pivaloyloxymethyl 7-[2-{3-~N-~-butoxycarbonyl-
amino)propoxyimino~-2-(5-amino-1~2~4-thiadi2zol-
3-yl)acetamidoJ-3-[:1-(2-hydroxyethy ~ lH-
tetraz 31- 5 - yl ]thiomethyl-3-cephem-4-carboxylate
~syn isomer), powder, mp 88 to 101C (dec.).
IR (Nujol) : 3300, 1780, 1750, 1675, 1620 cm 1
(134) Pivaloyloxymethyl 7-[2-{3-(N-~-butoxycarbonyl-
amino)propoxyimino}-2-~5-amino 1,2,4 thiadiazol-
; 3-yl)acetamido]-3-~1,334-~hiadiazol-2-yl~-
thiomethyl-3-cephem-4-carboxylate ~syn isomer),
p~wder 5 mp 71 to 84C (dec~,
IR (Nujol) : 3300, 178~, 1745, 1680, 1615 cm~
(1353 Pivaloyloxymethyl 7-[2-(2 cyclohe~e~ 103~imino~
2-(5-amino-1,2,4-thiadiazol-3-yl~acetamido]-
~: cephalosporanate ~syn lsomer), mp 93 to 101C
(dec.~.
IR (Nujol) : 3400, 3300, 3180, 1780, 1740,
1675~ 1615, 1525 cm 1
~i35~ Phthalid-3-yl ester of 7-~2-(2 cyclope~te~
l-yloxyimino)-2-~5-amino-1~2,4-thiadiazol r 3_
yl)acetamido~-2-me*hyl-3-cephem-4-carboxylic
acid (syn isomer), mp 131 to 144~C (dec.)O
IR (Nujol) : 3420, 3210, 3150, 1780,
1740~ 16759 1620, 1525 cm
(137~ Pivaloyloxymethyl 7-[2-~2-cyclopenten-1-
yloxyimino)-2-(5-amino-132y~-thiadiazol~3-
~6
yl)acetamido]-2-methyl-3-cephem-4-carboxylate
(syn isomer~ mp 111 to 124C (dec.).
IR (Nujol) : 3400, 33003 3270, 1775~
1740, 1670, 1620/ 1520 cm 1
~138) l-Benzoyloxyethyl 7-l2-(2-cyclopenten-1-
yloxyimino)-2-~5-amino-1,2,4-thiadiazol-3-yl)-
acetamido]-2-methyl-3-cephem-4-carboxylate
~syn isomer) 9 mp 132 to 137C (dec.).
IR (Nujol) : 3400, 3300, 3160, 1~80, 1738,
16S0; 1620 cm~l
NMR (D~S0-d6~DzO~) : 1.43 t3H, d, J=7Hz),
1~62 ~3H, dg J=5Hz), 1.7-2.4 ~4H, m),
3.84 ~lH, q9 J=7Hz), 5.0
5.4 (lH, m), 5.13 (lH, d, J=4.5Hæ),
5,6-6.3 (3H; m), 6.70 (lH, d, J=6Hz),
7~16 ~lH, q, J=5Hz),
7.3-8~2 (5H, m~
~139) Pivaloyloxymethyl 7-[2-{4-(N-t-butoxycarbonyl-
amino)methylbenzyloxyimino}-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamidQ3-3-methyl-3-cephem-
4-carboxylate tsyn isomer), powder.
IR (Nujol) : 3300, 1780, 1750, 1680 cm 1
~5
~140) Pivaloyloxymethyl 7-~2-al~yloxyimino-2-(5-
amino-1,2,4-thiadia~ol-3-yl) acetamido 3 - 3- ~1-
{2-~N- t-butoxycarbonylamino)ethyI~lH-tetr~zol-
5-yl~thiomethyl-3-cephem-4-carboxylate (syn
30isomer), powder.
IR (Nujol) : 3300, 1780~ 1750~ 1680 cm 1
(141) 7-[2~{2-~N ~ -t-Butoxycarbonyl)-D-phenylglycyl-
amino)ethoxyimino}-2-(5-amino-1, 2 ,4-thiadiazol-
3-yl)acetamido]-2-methyl-3-cephem-4 carboxylic
acid ~syn isomer), mp 77 to 91C (dec.~.
I~ (Nujol) : 3300, 3160, 1775, 1680, 1660p
1630, 1525 cm 1
NMR tDMSO-d6,~ : 1.37 ~9H/ s), 1.40 (3H, d,
J=8Hz), 3.1--4.2 (5H, m), S,08 ~lH, d,
J=405Hz), 5~,10 (lH, d, J=8Hz), 5.90 (lH,
dd~ J-4.5 and 9Hz~, 6.S3 ~lH, d, J=7.5Hz),
7.32 ~5H, s~, 8.13 (2H, broad s) 9
9.48 tlH, dl, J=9Hz)
~142) 7-[2-{3-(N-(2-~1-amino-1-cyclohexyl)acetyl)-
amino)propoxyimino}-2-~5-amino-1,2,4^thiadiazol-
3-yl~acetamido]-2-methyl-3-cephem-4-carboxylic
acid (syn isomer), mp 198 to 224C ~dec.).
IR (Nujol) : 3250p 3150, 1760, 1640,1580
1520 cm 1
~143~ 7-[2-{3-~N-~N-~-Bu~oxycarbonyl-D-
~phenylglycylamino)propoxyimino}~2-~5-amino-
1,2 9 4-thiadiazol-3-yl)acetamido]-2-methyl-3-
cephem-4-carboxylic acid (syn isomer).
IR (Nujol) : 3300, 3200, 1775p 1700, 1650,
1525 cm 1
NMR ~DMS0-d6l-D~ 1.3-1.6 (12H, m),
1.6-2.0 (2H, m), 2.8-3.4 ~2H7 m) 7
3.~2 (lH9 q~ J=7.5Hz), 3.9-4~3 ~2H3 m),
5.05 (lH, d, J=40SHz), 5.g3 ~lH, d,
J=4.5Hz), 6.48 ~lH, d, J=~Hz).
Exam~le 42
A mixture of 7-~2-~l-t-butoxycarbonylethoxyimino)-
2-~5-amino-1~234-thiadiazol 3-yl)acetamido]-
cephalosporanic acid (syn isomer)~5.7 g), 1-[3-(N-t-
S butoxycarbonylamino)propyl~-lH-tetrazole-S-thiol ~3.9 g)
and sodium bicarbonate (2.5 g) in pH 6.8 phosphate
buffer solution (150 ml) was stirred for 4.6 hours at
70C. The reaction mixture was ice-cooled and washed
few times with ethyl acetate. Ethyl acetate was added
to an aqueous layer9 and the mixture was acidified with
hydrochloric acid and extracted with ethyl ace~ate.
The extract was successively washed with water and an
aqueous solution of sodium chloride, dried over magne-
sium sulf te and then evaporated, The residue was
lS triturated with diethyl ether and precipitates were
collected by filtration to give brown powder of 7-~2-
~l-ca~boxyethoxyimino)-2-(S-amino 1,2,4-thiadiazol-3-
yl)acetamido]-3-[1-~3-(N-t-butoxycarbonylamino)propyl}-
lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid
20 ~syn isomer)~3.5 g), mp llO to 115~C (dec.).
I~R. (Nujol) : 3300~ 3200, 1770, 16809 1600,
15209 12509 1000) 720 cm~l
N.M.R. (DMSO-d6~D2O,~ .4 ~12H, m) 9 2.02 (2H, m),
2.98 (2H~ ~ J=~Hz), 3070 ~2H, m),
4.1-4.5 (4H, m)~ 4.70 (lH, q, J=7Hz)~
5.13 ~lH, d, J=5Hz), 5.85 (lH, d, J=5Hz)
The following compounds were obtained according
' 30 to similar manners to *hose of Examples 14 to 17 and
4~.
(1) 7-[2-~4-Chlorophenoxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-tl-allyl-lH-tetrazol-
5-yl)thiomethyl-3-cephem-4~carboxylic acid (syn
~ 2~
_
isomer), mp 120 to 125C (dec.).
IR (~ujol) : 3290, 3180, 1770, 1680, 1615,
1580, 1520, 1480 cm 1
.~
:(2) 7-~2-(4-ChlorQphenoxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl3acetamido]-3-(l^methyl-lH-
`: tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer~, ~p 130 to 135C (dec.).
: IR (Nujolj : 34009 3300, 3280, 1770, 1670,
1615~ 1580, 1520, 1480 cm 1
.
~3) 7-~2-~4-Chlorophenoxyimino-2-~5-amino-1~2,4-
thiadiazol-3-yl)acetamido~-3-~1-C2-carboxyethyl)-
lH-tetrazol^5-yl]thiomethyl-3-cephem-4-carboxylic
: 15 acid (syn isomer3 3 mp 135 to 140C ~dec.).
IR (Nujol3 : 34009 3270, 3190, 1770, 1680,
1620, 1585, 15207 1480 cm 1
~4) 7-~2-(4-Chlorophenoxyimino~-2-~5~amino-1,2-
: 20 4-thiadiazol-3-yl)acetamido]-3-[2-caTboxymethyl-
- 3-oxo-293-dihydro-1,2,4-triazolo[4y3-b]py~ida~in-
6-yl]thiomethyl-3-cephem-4-carboxylic acid ~syn
isome~), mp 140 to 145C (dec,).
IR ~Nujol) : 3400y 3300~ 31907 1765, 1700,
1620, 1580, 1540, 1520, 1480 cm 1
(5) 7-~-(4-Chlorophenoxyimino)-2-~5-amino-19 2,4-
thladiazol-3-yl)acetamido~ tetrazolo~1,5-b~-
: pyridazin-6-yl)thiomethyl-3-ceph~m-4-carboxylic
acld (syn isomer), mp 140 to 145C (dec,).
IR ~Nujol) : 3350~ 32403 17S0, 16859 1625,
1530, 1490 cm~l
~6) 7-[2-~a-~-Butoxycarbonylbenzyloxyimino)-2-~5-
.
~s ~
amino-13 2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
~cid (syn isomer), mp 105 to 110C (dec.).
IR (Nujol) : 3400, 3300, 3180, 1780, 1720,
S 1680, 1620, 1520 cm 1
(7) 7-L2-~-t-Butoxycarbony:lbanzyloxyimino)-2-(5-
amino-l~Z,4-thiadiazol-3-yl)acetamido]-3 [1-{2-
~N-t-butoxycarbonylamino)ethyl}-lH-tetrazol-5-yl]-
thiomet~yl-3-cephem-4--carboxylic acid ~syn isomer),
mp 105 to 110C ~dec.).
IR ~Nujol3 : 3360, 3220~ 1785, 1690, 1625,
1525 cm~l :
~8~ 7- [2-(2-Propynyloxyimino~-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido~-3-~1-(2-carboxyethyl)-
lH-tetrazol 5-yl]thiomethyl-3-cephem-4-carboxylic
acid (syn isomer~, mp 125 ~o 130~C (dec.~.
IR (Nujol~ : 3400, 3250~ 3190, 2580, 1765,
1710, 1670; 1620, 1520 cm~
t9~ 7- [2-~Thiolan-lJl-dioxide-3~yl)oxyimino-2 ~S
: amino-1,2,4-thiadiazol-3-yl)acetamido]-3~(1,3,4- !
thiadiazol-2-yl)thiomethyl-3-~ephem-4-carboxylic
: 25 acid (syn isomer), mp 170 to 175C (dec.).
IR ~Nujol) : 3300, 3200, 1770, 1670, 1620,
1520 cm~
(10) 7-[Z-Allyloxyimino-2-~5-amino-1,2~4-thiadiazol-
3-yl~ace*amido]-3-(1-carboxymethyl-lH-tetrazol-
5-yl~thiomethyl-3-cephem-4-ca~boxylic acid ~syn
isomer), mp 140 to 145C (dec,~.
IR (Nujol~ : 3~00, 3200, 1770, 17207 1670,
1620, i520 cm 1
(11) 7-~2- ~2-pTopynylQxyimino)-2-(5-amino-l~274-
thiadiazol-3-yl)acetamido]-3~(1-carboxymethyl-
lH-tetrazol-5-yl)thioml~thyl-3-cephem-4-carboxylic
acid ~syn isomer), mp :135 to 140C (dec.).
IR ~Nujol) : 3250~ 3150, 1770, 1720, 1670,
1620, 1520 cm 1
(12) 7-~2-Allyloxyimino-2-(5-amino-1~2~4-thiadiazol-
3-yl)acetamido~-3~ 2^carboxyethyl)-lH-tetrazol-
5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn
isomer) 9 mp 140 ~o 145C (dec.)O
IR (Nujol) 3300, 3200, 1770, 1720~ 1670,
1620, 1520 cm 1
(13) 7-[2-~t-Butoxycarbonylmethoxyimino)-2-(5-amino-
1,2 9 4-thiadiazol-3-yl)acetamido]-3-~ 2-
carboxyethyl~-lH-tetrazol-5-yl]thiomethyl-3-
cephem-4-c~rboxylic acid ~syn isomer), mp 150
to 155C (dec.~.
IR ~Nujol) : 3300, 3200, 1770p 1720~ 1700,
1620, 1520 cm 1
~14) 7-[2-(t-Butoxycarbonylmethoxyimino)-2-~5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-~1-{3-(4-
r 25 methyl-1-piperazinyl)propyl}-1~-tetrazol-5-yl]-
thiomethyl-3-cephem-4-carboxylic acid ~syn isomer),
mp 22Q to 225C (dec.~.
IR (Nujol) : 3300, 1700, 1680~ 1605, 1520 cm 1
(15) 7-~2-~1-t-Butoxycarbonylpropoxyimino)-2-(5-
amino-1,2,4-thiadiazol-3-yl)acetamido]-~-tl,374-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer~, mp 101 to 105~C ~dec.).
2~L2
IR ~ujol) : 3300, 3150, 1770, 1720, 1620,
15~0, 1450, 1370, 1250, 1150,
1010, 90D, 840, 7~0 cm 1
..
S (16) 7-[2-(1-t-Butoxycarbonylethoxyimino)-2-(5-
amino-1,2,4-~hiadiazol-3-yl~acetamido]-3-~1,3,4-
thiadiazol-2-yl)~hiomethyl-3-cephem-4-carboxylic
acid ~syn isomer); mp 120 to 128C (dec~).
IR (Nujol) : 3280, 3180, 1770~ 1720, 1680,
1~ 16~0, 15209 1240, 11509 10~0,
740, 720 cm 1
(17) 7-[~-(1-Methyl-l-t-butoxycarbonylethoxyimino)-
2-(5-amino-1,2,4-thiadiazol-3-yl)acetam;do]-3-
(1~334-thiadiazol-2-yl)thiomethyi-3-cephem-4-
ca~boxylic acid (syn isomer), mp 115 to 120C
~d~c.).
IR (Nujol) : 32809 3170; 1780, 1720, I680
1520, 1140~ 990, 750 cm~
~18) 7-[2-~1-t-Rutoxycarbonyl-l-cyclopentyloxyimino)-
2-t5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-
~1,3,4~thiadiazol-2-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), mp 140 to 143C
(dec.).
IR ~Nujol) : 3300, 3180, 1770~ 1720-1670,
1620, 1520~ 12~5, 1150, 10609
9953 840 cm 1
~19) 7-~2~ Methyl-l-t-Butoxycarbonylethoxyimino)-
2-~5-amino-1,2,4-thiadiazol-3-yl)acetamido3-
3-[1-~2-~N-t-butoxycarbonylamino)ethyl}-lH-
tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer), mp 96 to 100C ~dec ).
~:13
IR ~Nujol) : 3300, 3150, 1780, 1680, 1570,
1240, 1160 3 390 cm 1
(20) 7-~2-~1-t-Butoxycarbony:Lethoxyimino)-2-~5-amino-
1,~,4-thiadiazol~3-yl)acetamido]-3-~1-allyl-lH-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 96 to 100C (dec.).
IR ~Nujol) : 3300, 315Q, 17803 1720, 16~0,
1620, 1520~ 1240, llS0, 1090,
1000 cm 1
~21) 7-[2-(1 Phenylethoxyimino)-2-~5-amino-1,294-
thiadiazol-3-yl~cetamido~-3-~1,3,4-thiadiazol-2-
yl)thiomethyl-3-cephem-4-carboxylic acid ~syn isomer),
which is decomposed by 175C.
IR ~Nujol~ : 3400, 3250, 31509 1750, 1650,
1610, 1520; 1400 D 1~40, 1160,
1060, 1000, 700 cm 1
-20 ~22) 7 L2-(p-Tolyloxyimino~-2-(5-amino-lp2,4~thiadiazol-
3-yl)acetamidoJ-3-(1,3,4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn ;somer), which is
~ecomposed by 150C~ which 1~ a mi~t~re wlth o tolyl i~omer~
IR (Nujol) : 3350~ 3250, 1780S 1680, 1630,
1530, 1510, 1230, lOS0, 910,
820 cm~l
~23) 7- L2- (3-Trifluoromethylphenoxyimino)-2-(5-amino-
1,~,4-*hiadiazol-3-yl)acet~mido~-3-(1-allyl-lH-
tet~azol-5-yl)thiome~hyl-3-cephem-4-carboxylic
acid (syn isomer), which is decomposed by 155Cf
IR ~Nujol) : 3300~ 3200g 1770, 1680~ 1620l
15~0, 1320~ 1160, ~120, 1060g
980, 930, 700 cm 1
~2
~1~
(24) 7-[2-~3-Trifluoromethylphenoxyimino)-2-~5-
amino-1,2,4-thiadiazo]L-3-yl)acetamido]-3-(1-
methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-
carboxylic acid (syn isomer), which is decomposed
by 170~C.
IR ~Nujol) : 3300; 3200, 1770, 1680, 1620t
152(), 1320~ 1160, 1120, 1060,
' 930~1 7909 700 cm 1
(253 ~7-[2-~4~Fluorophenoxyimino3-2-~5-amino-172,4-
thiadiazol-3-yl~acetamido]-3-~1-methyl-lH-tet~azol-
5-yl)~hiomethyl-3-cephem-4-carboxylic acid (syn
isomer3, which is decomposed by 170~C~
IR (Nujol) : 3450, 3350, 3200, 1780, 171Q~
1680 9 161~, 1510, 1590 9 1240 9
1~00, 117~ 1090, 9909 9107
840 cm 1
~26) 7-[2-(2,4-Dichlorophenoxyimino~-2-(5-amino-1,2,4-
thiadiazol-3-yl)aGetamido]-3-{1,3 9 4-thiadiazol-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer~ 3 which is decomposed by 165C.
IR ~Nujsl~: 3300, 320(), 1770, 1680~ 1620,
15~0, 1250, 1230, 1100, 1060,
~5 960 ,, 910 9 810 CM
.
~27) 7-~2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-
~-(5-amino-1,2,4-thiadiazol-3-yl~ acetamido~ -3 -
(-1,3,4-thiadiazol-2-~l)thiomethyl-3-cephem~4-
ca~boxylic acid ~syn isomeT).
IR ~Nujol~: 3200~ 3160, 1773, ï685~ 1620 cm 1
~28~ 7- ~2 {3 (N-t-Butoxycarbony:lamino)propo:cyimino~-2-
~ 5 - aTnino - 1 9 2,4-thiad;azol-3-yl~acetamido~-3-[1-(2-
2~;
hydroxyethyl)-lH-tetrazol-5-yl]thiomethyl^3-
cephem-4-carboxylic acid ~syn isomer~.
~R (Nujol~ : 3200, 3160, 1775, 1720, 1700,
i 1675, 1620 cm l
(29) 7-~2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-
. 2`(5-amino-1,2,4-thiadiazol-3 yl)acetamido]-3-(5-
methyl-1,3,4-thia~iazol-2-yl)thiomethyl-3-cephem-
- 4-ca~boxylic acid ~Syll isomer~.
IR ~Nujol) : 3300, 3150, 1775, 1710, 1700,
1670, 1650~ 1620 cm 1
(30~ 7-[2-{3-(N-t-Bu~oxycarbonylamino)propoxyimino}-
2-~5-amino-1,2,4-thiadiazol-3-yl)acetamido3-3-
lS ~l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid. (syn isomer~, mp 8~ to ll9~C
~dec.).
IR ~Nujol) : 3300, 3180 9 1773, 1715 9 1700 9
1670, 1620 cm 1
20
(31) 7-~2-Carboxymethoxyimino-2-(5-amino-1~2,4-
~' thiadiazol-3-yl)ac2tamido]-3-[1-{2-(N9N-
dimethylamino)ethyl}-lH-t~trazol-5-yl~thiomethyl-
3-cephem-4-carboxylic acid ~syn isome~), mp 170
to 173C (dec.).
IR ~Nujol~ : 3400~ 3280, 3150, 1760, 1665,
~61a, 1520 cm l
: NMR ~DMSO-d~D2O, ~) : 2.53 ~6H, s), 3.07-3.37
~2H, m), 3.50-3.77 ~2H9 m), 4~10-4.37
~0 (2H, m~, 4.43-4.83 t4H, m), 5~10 ~lH, dt
J=5Hz)~ 5.80 (lH, d3 J=5Hæ)
t32~ 7-~2-Carboxymethuxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido~ 1-{3-(N,N^
2~
dimethylamino)propyl}-lH-te~razol-5-yl]thiomethyl-
3-ceph~m-4-carboxylic acid ~syn isomer), mp 170
to 175C (dec.).
IR ~Nujol) : 3400" 3280, 3160, 1760, 1665,
1610" 1520 cm 1
~IR (DMSO-d6, ~) , 2.10-2.43 ~2H~ m), 2.70
~6H3 s) 9 2.92 3.28 (2H, m), 3.45-3.80
(2H, m), 4.17-4.80 ~6H, m), 5.10 ~lH, d,
J=5Hz3~ 5.84 ~lH, dd, J=5 and 8Hz~, 8.15
(2H; bToad s), 10.1 ~lH, d, J=8Hz)
(33~ 7-[2-(2-P~opynyloxyimino~-2~(5-amino-1,?.,4-
thiadiazol-3-yl~acetamido]-3-[1-{3-(N-t-
butoxycarbonylamino)propyl}-lH-tetrazol-5-yl~-
thi~methyl-3-cephem-4-carboxylic acid (syn isomer),
mp 85 to 90C ~dec.),
IR ~Nujol3 : 3400, 3290, 3200p 1770, 1680,
1620, 15Z0 cm 1
NMR ~DMSO~d6, ~) : 1.40 t9H, s), 1.77-2.17
(2H, m), 2.78-3.23 ~2H3 m)~ 3.50 (lH~ t,
J-2Hz), 3,73 ~2H, broad s), 4.07-4,53
(4H~ m), 4.~2 (2Hg d~ J=2Hz3 9 5.15 (lH,
d, J=5Hz), 5.85 ~lH, dd, J=S and 8Hz~,
8~17 (2H, broad s), 9.65 ~lH~ d, J=8Hz~
! 25
~34) 7-[2-Carboxymethoxyimino-2-~5-amino-1,2,4-
thiadia2O1-3-yl)acetamido]-3-[1-{3-(N-t-
butoxycarbonylamino)propyl}-lH-t~trazol-5-yl]-
thiomethyl-3-oephem-4-carboxylic acid ~syn
isomer), mp 185 ~o 190C (dec.).
:[R (Nujol) : 3300, 3200; 1770, 1680~ 1620,
1520 cm 1
NMR ~DMS0-d6, ~ 1.33 (9H, s), 1.67-2.12
~2H, m3, 2.77-3.07 (2H, m),
0
3 . 63 t2H9 broad s), 4 . 07-4 . 43 (4H, m),
4.60 (2H, s), 5.05 ~lH, d, J=4H7), 5.77
(lH, dd~ J=4 and 8Hz), 8 . 08 ~2H, s),
9~47 (lH, d, J=8Hz)
(35) 7-[2-(2J292-T~ifluoroelthoxyimino)-2-(5-amino-
1,2p4-thiadiazol-3-yl)acet2mido]-3-(l-
ca~boxymethyl-lH-~etra;zol-5-yl) thiom~thyl-3-
cephem-4-carboxylic ac:id (syn isomer), mp 130 to
132C ~dec.).
IR (Nujol) : 3300, 3200, 1770, 1720, 1670,
1620, 1520 cm~l
MMR (~MSO-d6 ~) : 3.73 (2H, b~oad s), 4.30
and 4.53 ~2H, ABq, J=14Hz), 4.73 and
4.97 (2H, ABq, J=8Hz), 5.10 (lH, d,
J=4Hz) 7 -5.35 ~2H, s3, 5.87 ~lH, dd,
J=4 and 8Hz), 8.23 ~2Hj s) J 9 . 80 (lH,
d, J=8Hz)
(36) 7- ~2- (1-Carboxy-2-methylpropoxyimino) -2- (5-amino-
1,2~4-~hiadiazol-3-yl)acetamido]-3-~1-{3-(N~t-
butoxycarbonylamino)propyl}-lH-tetrazol-5-yl~-
thiomethyl-3-cephem-4-carboxylic acid (syn
isome~), mp 192 to 195C (dec.).
~5 IR ~Nujol) : 3400-3200, 1780, 1680~ 1520,
1450 9 1360, 1240, 11~0, 1020 9
730 cm~l
NMR (DMSO-d6, ~) : 0.98 (6H, d, J=7Hz),
1~38 ~9H~ s), 1.8-2.2 (3H, m), 2.8-3.2
(2H, m), 3.7 (2H, m), 4.1-4.7 ~5H, m),
5~12 (lH, d, J=5Hz), 5.7-6.9 tlH, m),
6~7-6.9 (lH, m), 8.03 (2H, b~oad s),
g.42 (lH, d7 J=8Hz)
-
2~
~37~ 7-[2-(1-Carboxypropoxyi.mino)-2-(5-amino-1,2,4-
thiadia~ol-3-yl)acetamido~-3-[1-{3-(N-t-
butoxycarbonylamino)pl opyl} -lH-te~razol-5-yl~ -
thiomethyl-3-cephem-4-c:arboxylic acid (syn isomer),
mp 185 to 192C (dec.).
IR ~Nuj ol) : 3300 J 3200 3 1770, 1680, 1620,
1520, 14509 1360, 1250, 1160,
lG00, 730-710 cm 1
NMR (DMSO-d6~ 1.08 (3H, t, J-7Hz), 1.35
0 (9H, s), 1.6-2.1 (4H5 m) 9 2,6-3.1 (2H, m),
3.7 ~2H, m), 4.1-4.6 (5~, m), 5.10 (lH,
d, J=6Hz3, 5.Bl ~lH, dd~ J=5 and 8Hz),
6~8 (lH, m), 8.10 (2H, broad s), 9.45
and 9.47 (lH, d, J=8Hz)
(38) 7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-
2-(5-amino 1,2,4-thiadiazol-3-yl)acetamido]-3-
- [1-{3-~N-t-butoxycarbonylamino)propyl}-lH-tetrazol-
5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn
isomer).
IR (Nujol) : 3300, 3150, 1775, 1715, 1675,
1650, 1615 cm~l
NMR ~DMSO-d6~2O~ 1.37 (18H? s), 1.5-2.1
(4H~ m), 2.7-3.3 ~4Hs m)9 3.5-3.9 (2H9 m),
~25 3.9~4.5 ~6H, m), 5.13 ~lH, d, J=4.5Hz)~
5.83 (lH, d, J=4;5HZ)
~39) 7-[2-~1 Carboxyethoxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido~-3-[1-{3 ~N-t-
butoxycarbonylamino)propyl}-lH-tetra701-5-yl~-
thiomethyl-3-cephem-4-carboxylic acid (syn isomeT) 3
mp 110 to 115C (dec.).
IR (Nujol) : 3300 9 32009 1770, 1680, 1600,
1520, 1250~ 1000, 720 cm 1
~ ~ f~ ~
~9
NM~ (DMS0-d6-tD2O, ~) : 1.4 ~12H, m), 2.02
(2H9 m~, 2.98 ~2H, t, J~6Hz), 3.70
~2H, m), 4.1-4.5 (4H,-m~, 4.70 (lH, q,
Ja7Hz), 5.13 (lH, d9 J=5Hz), 5.85 ~lH,
d, J-5Hz)
~40) 7-[2-(1-Carboxy-l-cyclopentyloxyimino)-2-~5-
amino-1,2,4-t~ia~iazol-3-yl)acstamido]-3-[1-{3-
(N-t-butoxycarbonylamino)propyl}-l~S-tetra~ol-S-
yl~thiomethyl-3-cephem-4-caTboxylic acid ~syn
isomer~, mp 200 ~o 205C ~dec.~.
IR (Nujol) 33009 3200~ 1770, 1680, 1520
1250, 1160, 1000 cm~l
MMR (DMS0-d~ 1.38 ~9H, s), 1.68 ~4H~ m~,
2.0 (6H, m), 2.96 ~2H~ m), 3,70 (2H, m3,
4.26 ~4H, m~, 5.12 (lH, d, J-5Hz), 5.82
~lH~ dd, J=5 and 8Hz) 9 6~86 (lH, m)~
8.14 ~2H, m), 9.40 (lH, d, J~Hz)
~41) 7- ~2-Ca~boxyme~hoxyimino-2-(5-amino-1,254-
thiadiazol-3-yl~ acetamido~ ~3~ (3-morpholillopropyl~ -
lH-tet~azol-5-yl3~hiomethyl~3-cephem-4-carboxylic
acid (syn isomer) 9 mp 190 to 194C ~dec~.
IR (Nujol) : 3300, 3200, 1770~ 1680, 1610,
1530, 1240, 11809 1090, 1060,
88Q, 760 c~
~R (DMS0-d6p ~) : 2.17 (2H~ m3, 2,63 ~6H, m~
3.67 (6Hp m), 4.37 (4H, m)~ 4.67 (2H~
broad s~, 5.15 ~lH, d~ J-SHz), 5.83 (lH,
dd~ J=5 and 8}lz), 8.17 (2H, m)p 9.73
~lH, d, Ja8Hz~
(42~ 7-~Z~ Carboxy-l-m-ethyle~hoxyimino~-2-(5-amino-
1,2,4-thiadi.azol-3-yl)acetamido]-3-~1-{3-(N-t-
~8~
butoxycarbonylamino)propyl}-lH-tetrazol-5-yl]-
thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
IR ~Nujol) : 3300, 3150, 1770, 1680, 1520
12qO, 1160 9 990 C~ 1
NMR ~DMS0-d6, ~) : 1.45 (15H, broad s), 2.0
~2H, m), 3.0 (2H, m)~ 3.77 ~2H, m),
4,10-4.40 (4H, m); 5.20 (lH, d3 J=5Hz),
5,87 (lH~ dd~ 3-5 and ~Hz), 6.87 (lH, m),
8.20 (2H, broad s) 9 9.47 (lH9 dg J=8Hz)
(43) 7-[2-Carboxyme~hoxyimino-~-~S-amino-1,2 9 4-
thiadiazol-3-yl~acetamido]-3-~4-me~hyl-5-oxo-6-
hydroxy-495-dihydro-1,2,4-triazin-3-yl)thiomethyl-
3-cephem-4-carboxylic acid tsyn iSOmeT) ~ mp 210 to
214C tdec.).
IR (Nujol~ : 3250, 3180, 1760~ 1720-16609
1590, 1520, 12~0~ lOgO, 1050,
720 cm 1
NMR (DMSO-d6~20~ 3.30 (3H, s~ 9 3.65
(2H, m), 4.10 ~2H, m) 9 4.65 (2H, broad s),
5.11 (lH, d, J=5Hz)~ 5.82 (lH; dd, ~=5 and
8Hz~ ! '
(44) 7-[2-Carboxymethoxyimino-2-t5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-[1-{4-~N-t-
butoxycarbonylamino)butyl}-lH-tetrazol-5 yl~-
~hiom~thyl 3-cephem-4-carboxylic acid (syn isomer).
IR ~Nujol) 3300, 32007 1770, 1680g 1620,
1~20~ 124~ 9 1160, 1090, 1060,
890 cm
~R ~DMSO-d6~ ~3 : 1.0-2.0 ~4H, m), 1.33
~9H, s~, 2.90 (2H, m~, 3.66 t2H, m) 9
4.0-4.5 (4H, m~ 3 4.62 ~2H, broad s),
5.10 (lH, d, 3=5Hz~,
., .
2~L
5~80 (lH, dd, J=5 and 8H~), 6.75 ~lH, m)~
8.13 ~2H~ broacl s)> 9.55 ~lH, d, J=8Hz)
(4S) 7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-
thiadiazol - 3 -yl~ acetamido] -3 - [1- (3 -piperidinopropyl) -
lH-tetrazol-S^yl]thiome~thyl-3-cephem-4-carboxylic c
acid ~syn isomer), mp 2:23 to 228C (dec.).
IR ~Nujol) : 33Q0, 3200, 1770, 1670, 1610,
1520 cm~l
NMR (DMSO-d63 ~) : 1.30-1.83 t6H, m) 9 2.1-2.3
~2Ha m), 2~8-3.3 t6H, m), ~.60 (2H, bToad
5) ~ 4~0-4.50 (4H9 m~, 4~60 ~2HJ s), 5.06 .
(lH, d, J=4Hz), 5.B0 ~lH~ dd, J=4 ~nd 8H~),
8.15 (2H~ s~, lO.l (lH, d, J=8Hz)
1~
(46) 7-[2-Carboxyme~hoxyimino-2~(5-amino-1,2~4-
- thiadiazol-3-yl~acetamido]-3-(1-ca~boxymethyl-lH-
~etrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), ~p 170 to 175C (dec.~. -
rR (Nujol) : 3300, 32003 1765~ 17209 1660,
1620 J 1520 cm l
NMR (DMSO d~ 3.67 t2H, broad s~, 4.27
and 4.47 ~ZH, ABq, J=13Hz), 4.67 ~2H, s~,
5.13 ~lH, d~ J=4Hz~ 5.33 ~2H, s)l 5.87
(lH~ dd~ J=4 and 8Hz)g 8.20 ~2H~ s)~
9.60 ~lH~ d, J=8Hz)
( 4 7 ~ 7 - [ 2 - Carboxymethoxyimino - 2 - ( S - amino - l, ~ 9 4-
thiadiazol-3-yl)acetamido]-3-~ 6-(N-t-
butoxycarbonylamino)hexyl~-lH-tetrazol-5-yl]-
thiomethyl-3-c~phem-4-carboxylic acid ~syn isomer)~
pale yellow powder.
(48~ 7-~2-~l~Carboxyethoxyimino)~2-t5 amino-1,2,4-
3~
%~
~22
~hiadiazol-3-yl~ace*aDIido~-3-[5-~N-t-
butoxyca~bonylamino)me~hyl-1,3,4-thiadiazol-2-
yl]thiomethyl-3-cephem-4-carboxylic acid (syn
;somer~, mp 210 to 21'iC (dec.).
IR ~Nujol) : 3300J 1770, 1680, 1620, 1520,
1~4C), 1140 cm l
NMR (DMSO-d5, ~) : 1.43 (12H, broad s),
3.70 ~2H, m),, 4,27-4.87 (SH, m~, 5.70
~lH, d, J~5HZ:) t 5.87 ~lH, dd, J-5 and
8Hz), 7.70 ~lH~ m), 8.17 (2H, broad s~,
9.50 ~lH, d, J=8Hz)
(49~ 7-[2-~2-Propynyloxyimino)~ S-amino-192,4-
thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl~-
1H-tetrazol-5-yl~thiomethyl-3-Cephem-4^CarboXyliC
acid ~syn isomer3., mp 165 *o 170C ~dec.).
TR (Nujol~ : 3450, 3300, 3210, 1770, 1670,
16ZOj 1525 cm 1
~50~ 7-[2-Carboxymethoxyimino-2-t5-amlno-1,2,4-
~hiadiazol-3-yl)acetamido~-3-[1-(3-aminopropyl~-
lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxyllc
acid (syn isomer)~ mp 195 to ~00C (dec.~
IR (Nujol) : 3150, 1760, 1660, 16409 1520 cm 1
( 51) 7 - [ 2 ^ ( 1- Carboxy - 2 -methylpropoxyimino ~ - 2 - ~5-amino-
1,2,4-thiadiazol-3-yl)acetamido] -3- {1- t3-
amin~propyl~-lH-tet~a~ol-5-yl~thlomethyl-3-cephem-
4-carboxylic acid (syn isomer) 9 mp 183 to 18~C
(dec.~.
IR ~Nujol) : 3400-3100, 3150, 1770, 1670,
16209 1520~ 1380, 1280~ 1230,
1180 ~ 1100 3 1020 ~ 900 ~ 730 cm 1
~23
t52) 7- [2- (l-Carboxypropoxyimino) -2~ (5-amino-1, 2 9 4- -
thiadiazol-3-yl)acetamido]-3-~1-(3-aminopropyl)-
lH-~etrazol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer), mp 183 to 188C ~dec.).
IR (Nujol) : 3400-3150, 1770, 1670, 1620,
1530, 1380, 1280, 1230, 1180,
1100, 1050, 1010, 730 cm 1
(533 7-[2-~1-Carboxyethoxyimino)-2-(5-amino~ ,4-
~hiadiazol-3-yl)acetamido]-3-[1-~3-aminopropyl)-
lH-~trazol-5-yl~thiomethyl-3-cQphem-4-carboxylic
acid ~syn isomer~, mp 185 to 188~ (dec.~.
IR (Nujol) : 3300, 3150, 1760, 1660, 1620
1520, 1230, 1000, 720 cm 1
1 5
(54) 7-~2-Carboxymethoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-~1-(4-aminobutyl)-
lH-te~razol-5-yl~thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer3~ mp 191 ~o lg4C ~dec.).
IR ~Nujol) : 33ao, 31S0, 1760, 1670, 1620,
1520, 1230, 1170 D 1050, 890;
740, 720 cm~l
(55~ 7-~2-(1-Carboxy-l-methylethoxyimino)-2-~5-amino-
1,2,4-thiadiazol-3-yl)acetamidoJ-3-~ 3-
aminopropyl3 lH-te~ra~ol-5-yl]~hiomethyl-3-cephem-
4-carboxylic acid ~syn isomer), mp 200 ~o 203C
(dec.).
IR (Nujol) : 33003 31509 1760, 1660, 1620,
1520~ 1160, 990 cm l
(56) 7-[2-(1-Ca~boxy-l~cyclopen~yloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl~ace~amido~-3-~1-(3-
aminopropy~)-lH-tetra~ol-5-yl~thiomethyl-~-cephem-
5
--
2~
4-carboxylic acid (syn i.somer), mp 202 ~o 205~C
(dec.).
IR (Nujol) : 3300, 3200, 1760, 1660, 1620,
1520, 1180, 1060, 10003 730 cm 1
(57) 7-~2-(1-Carboxyethoxyimino)-2-~S-amino-1~2,4
thiadiazol-3-yl~ac~tamido~-3-(5-aminomethyl~1,3,4-
thiadiazol-2-yl)~hiomethyl-3-cephem-4-ca~boxylic
acid (syn isomer), mp 207 to 210~C Cdec.).
IR ~Nujol) : 3300, 3150~ 1760, 1660, 1620,
152D, 1230, 1170,.1090~ 1060,
1040~ 990 cm 1
(58~ 7-[2-Carboxymethoxyimino 2-(5-amino-1,2~4-
thiadiazol-3-yl)acetamidol-3-[1-~6-aminohexyl)-
lH-tetrazol-5-yl].thiomethyl-3-cephem-4-carboxylic
acid (syn isomer~ mp 185 to 188C (dec.).
IR ~Nujol) : 3300~ 3200, 1760~ 1670 7 1620,
1520~ 1240, 1180, 1060 cm~
~59) 7-~2-(3-Aminopropoxyimino) 2-(5~amino-1,2~4-
thiadiazol-3-yl)acetamido]-3-(1,3~4-thiadiazol-
2-yl)thiomethyl-3-ceph~m-4-carboxylic acid (syn
isomer), mp 165 to 183C (dec.).
IR (Nujol) : 3150, 1765, 1660, 1630, 1570,
1520 cm~l
(60) 7-[2-~3-Aminopropoxyimino~-2-(5-amino-1~2,4-
thiadiazol-3-yl)ac~t~mido]-3-~1-(2-hyd~oxyethyl~-
lH-~e~razol-5-yl~hiomethyl-3-cephem-4-carboxylic
acid (s~n isomer), mp 170 to 185C (dec.).
IR (Nujol~ : 3140, 1750, 1660l 1610, 1580
~520 cm~
225
~61) 7-[~-~3-Aminopropoxyimino)-~-~5-amino-1,2,4-
thiadiazol-3-yl)acetamiclo]-3-(5-methyl-1,3,4~
thiadiazol-2-yl)thiomethyl-3-cephem-4-ca~boxylic
acid (syn isomer) 9 mp 1'32 to 195C (dec.).
IR (Nujol) 3250, 3140, 1760, 16409 1620,
` 1585, 1525 cm 1
(62) 7-[2-~3-.~minoprop~xyimiIlo)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamiclo]-3-(1-methyl -lH-tetrazol -
5-yl)thiome~hyl-3-cephem-4-carboxylic acid ~syn
isome~), ~p 180 to 184C ~dec.).
IR (Nujol~ : 3160) 1760, 1660, 1590 cm 1
~63) 7-L2-~3-Aminopropoxyimino)-2-~5-amino-1,2,4-
thiadiazol^3-yl)acetamido]-3-[1-(3-aminoRTopyl3-
lH-tetTazol-5-yl]thiomethyl-3 cephem-4-carboxylic
acid (syn isomeT).
IR ~Nuj ol~ : 3300 9 3150 ~ 176û, 1660, 1607,
1595~ 1520 cm~
(64~ 7-~2-~a-Carboxybenzyloxyimino)-2-~5-amino 1,2,4-
thiadiazol-3-yl)2cetamido~-3-~1~3,4-~hiadiazol-
2-yl3thiomethyl-3~cephem-4-carboxylic acid ~syn
isomer), mp 150 to 155C (dec.~.
IR (Nujol) : 3400) 3290, 3160, 2500, 1770,
1720, 1615, 1520 cm 1
~65) 7-[2~ Carboxybenzyloxyimino~-2-~S-amino-1,2,4-
thiadiaæol-3-yl~ace~amido]-3-[1~-~2-aminoe~hyl)-
lH-~etrazol-S-yl~hiome~hyl-3-cephem-4-carboxylic
acid ~syn isome~), mp 190 to,195C (dec.).
IR ~Nujol) : 3400, 3300~ 3150, 1765, 1670,
1610, 1520 cm 1
22~
~66) 7-~2-Carboxymethoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-~1-{3-(4 methyl-l-
piperazinyl)propyl}-lH-tetT zol-5-yl]thiomethyl-
3-cephem-4-carboxylic acid (syn isomer~, mp 185
to 190C (dec.).
IR ~Nujol) : 3300, 1760, 1670, 1600, 1520 cm 1
(67) 7-[2-(l-Carboxypropoxyimino)-2-(5-amino-192,4-
thiadiazol-3-yl~acetamido~-3-(1~3,4-thiadiazol-
2-yl)thiomethyl-3-cepheTn-4-carboxylic acid (syn
isomer)~ mp 153 to 158C (dec.).
IR (Nujol) : 3300, 3180, 1770, 1720-1670,
1620, 1520, 1220, 1060, 1000
900, 730 cm 1
~68) 7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn
isomer~, mp 165 ~o 168C (dec.~
IR (Nujol) : 3400-32009 17709 1710, 1670,
1620, 1520~ 1230, 1~70, lO00,
- 9OO, 7~Q c~-l
- (69) 7-[2-(l-Carboxy-l-methylethoxyimino)-2-(5-amino-
~ 19 2 9 4-thiadiazol-3-yl)acetamido]-3-(1~3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid (syn isomer), mp 164 to 167C ~dec.).
IR ~Nujol) : 3300, 3200, 2800-2300, 1770,
1720-1660 9 1~20, 1520, 1160,
1060, 990, 800 cm 1
(70) 7-~2-(1-C~rboxy-l-cyclopentyloxyimino)-2-(5-amino-
132,4-thiadiazo`1-3~yl)acetamido~-3-(1~3,4-thiadiazol-
2-yl~thiomethyl-3^cephem-4-earboxylic acid ~syn
~7
isomer), mp 165 to 169C (dec.).
IR ~Nujol3 : 3300, 3180, 1770, 1720-1660p
1620, 1520, 12~09 1180, 10609
1000, 720 cm~l
C71) 7-[2-(1-Carboxyethoxyim:ino)-2-~5-amino-1,2,4-
thiadiazol-3-yl~acetamido]-3~ allyl-lH-tetrazol-
5-yl)thiomethyl-3 cepheJn-4-carboxylic acid (syn
isomer~, which is decomposed by 180C.
IR (Nujol) : 33009 3150, 1770, 1680, 1610~
15~0~ 1~60, 1100, 1040~ 10~0 c~ 1
(72) 7-[2-tl-Carboxy-l-methylethoxyimino)-2-(5-amino-
1~2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-
aminoethyl,)-lH-tetrazol-5-yl~hiomethyl-3-cephem-
4-carboxylic acid ~syn isomer), mp 195 to 200C
~d~c.).
IR (Nujol~ : 3150, 1~60~ 16709 16209 1520,
11709 990 cm 1
~73) 7-~2-Cyclopentyloxyimino-~-(5-amino-1~2D4-
~hiadiazol-3-yl)ace~amido3-3-[1~ (4-methyl-1-
piperazinyl)propyl} -lH-tetrazol-5-yl~-thiomethyl-
3-cephem-4 carboxylic acid (syn isomer), mp 175-
~5 ~o 180C ~dec.).
IR ~Nujol) : 3300, 1770, 1650, 1610, 1520 cm 1
(?4) 7 ~2~ oxo-3-tetrahydrofuryloxyimino)-2-(5-
amino-:L,2,4-thiadiazol-3-yl)acetam;do] -3-~1~3~4-
thiadiazol-2-yl~thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer), mp 165 to 170C (dec.).
IR ~Nujol) : 3300, 3200~ 1770, 1680, 16209
1525 cm 1
- ~8~
(75) 7-~2-(1-Cyclohexyloxycarbonylethoxyimino)-2-(5-
amino-1,2,4-thiadiazol-5-yl)acetamido]-3-[1-~3-
(N-t-butoxyca~bonylamino)propyl}-lH-tetrazol-5-
yl]thiomethyl-3-cephem-4-carboxylic acid (syn
isome~)~ mp 145 to 150C (dec.~.
IR (Nujol) : 3400-;250, 1780~ 1680, 1620,
1520, 1240, 1220, 11~0, 1100,
1000, 740, 720 cm 1
(~6) 7-[2-(1-Benzyloxycarbonylethoxyimino)-2-~S-
amino-1,2,4-thiadiazol-3-yl)acetamido~-3^~1 ~
3-(N-t-bu~oxycarbonylamino~propy ~lH-tetrazol-
5-yl3thiomsthyl-3-cephem 4-carboxylic ~cid ~syn
isome~), mp 113 to 117C (dec.).
IR (Nujol) : 3300, 3200, 1780, 1680, 1620,
1520, 1250, 1160, 1100, 1040
000 9 740, 700 cm 1
t77) 7-[2-~1-Bu~oxycarbonylethoxyimino~-2-~5-amino-
2D 1,2,4-thiadia~ol-3-yl)acet~mido~-3-~1-{3-(N-t-
butoxycarbonylamlno~propyl}-lH-tetrazul-S-yl~-
thiomethyl-3^cephem-4-carbvxylic acid (syn isomer~,
mp 149 to 155C ~dec.).
IR (Nujol) : 3300, 3200~ 17803 1700, 1620,
~ 1520, 1250, 1160p 1100, 1040,
1000, 740, 720 cm 1
(7~) 7-[2-~1-Cyclohexyloxycarbonylethoxyimino)-2-(5-
amino-1~2,4-thiadiazol-3-yl)acetamido3-3-~1-(3-
aminopropyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-
4-carboxylic ~cid ~syn isomer), mp ~75 to 178Co
~dec.~
IR ~ujol) : 3400-3200g 1765, 1680, 1610,
1520~ 1~20~ 1100~ 1000, ~9~ 5
3~ .
2 2 9
790 cm 1
(79) 7-[2-(1-Benzyloxycarbonyletnoxyimino)-2-(5-amino-
1,2~4-thiadiazol-3-yl)alcetamido]-3-[1-(3-
aminopropyl)-lH tetrazo:l-5-yl]-thiomethyl-3-
cephem-4-carboxylic acid (syn isomer), mp 162 to
166C ~dec.~
IR ~Nujol) : 3300, 3200, 1760, 1680, 1620,
1520, 1100, 1040, 1000, 740 cm 1
(80) 7-[2-~l-Butoxycarbonylethoxyimino)-~-~5-amino-
1,2,4-thiadiazol-3-yl3acetamido]-3-[1-(3-
aminop.opyl)-lH-tetrazol-5-yl3thiomethyl-3-
cephem-4~carboxylic acid (syn isomer~ ? mp 158 to
1~3C (dec.).
IR (Nujol) :.3400-3200, 17703 1680~ 1610,
1530, 1300,.12909 1050, 1040,
1000, 960, 900, 7909 740, 7~0 cm~
(81) Pivalvyloxymethyl 7-[Z-(3-aminopropoxyimino)-2-
(5~amino-1~2,4-thiadiazol-3-yl)ac~tamido~-3-~1-
m~hyl-lH-tetrazol 5-yl~thiome~hyl-3-cephem-4-
ca~boxylate hydrochloride ~syn isomer)~ mp 110
to 125C (dec.~
IR (Nujol) : 1780, 1745~ 1670, 1625, 1525 cm 1
(82) Pi~aloyloxymethyl 7-~2-~3-aminopropoxyimino)-2-
~5-amino-1j2~4-*hiadiazol-3-yl)acetamido] 3-~5-
methyl-1j3 3 4-thiadiazol-2-yl)khiomethyl-3-cephem-
4-carboxylate hydrochloride (syn isomer), mp 88
to 153~C (decO).
I~ ~Nujol~ : 2150) 1780, 1745/ 16509 1625,
1525 cm~l
~83~ Pivaloyloxymethyl 7-~2-(3-aminopropoxyimino)-2-
(5-amino-1,2,4-thiadia~ol-3-yl~acetamido~-3
23~
(2-hydroxyethyl)-lH-tetrazol-5-yl3thiome~hyl-
3-cephem-4-carboxylate hydrochloride (syn isomer),
mp 150 to 175C ~dec.).
IR (Nujol~ : 3150, 1780, 1740, 1670, 1630
S 1520 cm 1
~84) Pivaloyloxymethyl 7-~2-(3-aminopropoxyimino)-2-
~5-amino-1,2,4-thiadiazol-3-yl)acetamido~-3-
(1,3,4-thiadiazol-2-yl~thiomethyl-3-cephem-4-
ca~boxylate hydrochloride ~syn isomer), mp 96 to
155C (dec.~.
IR (Nujol) : 33009 3150, 1775, 1730~ 1670,
1625; 1530 cm 1
~85) Pivaloyloxymethyl 7-[Z-allyloxyimino-2-(5-amino-
1,2~4-thiadiaæol-3-yl)acetamido]-3-[1 ~-~minoethyl~-
lH-tetrazol-5-yl3thiomethyl-3-cephem-4-carboxylate
formate (syn isomer), mp 95 to 105C (dec.).
IR ~Nujol~ : 17sn~ 17359 1~529 1370, 1118
990 cm 1
(86) Pivaloyloxyme~hyl 7-[2-{3-(N-~-butoxycarbonyl-
amino)propoxyimino}-2~(5-amino-1,2,4-thiadiazol-
3-yl)acetamido]-3-~1-methyl-lH~tetrazol-5-yl)-
- 25 thiomethyl-3-cephem-4-carboxylate ~syn isomer),
powder.
IR (Nujol~ : 3300, 1780, 1745, 1680, 1620 cm
~87~ Pivaloyloxymethyl 7-[2-{3-(N-t-butoxycarbonyl-
amino~propoxrimirlo}-2-~5-amino-1,2,4-thiadiazol-
3-yl)acetamido]-3-(5-methyl-193,4-thiadiazol-2-
yl)thiomethyl-3-cephem-4-carboxylate (syn isomer)~
IR ~Nujol) : 3300y 3150, 1783l 1745, 16759
~Z4
~3~
161S cm 1
~88) Pivaloyloxymethyl 7-[2-{3-(N ~-butoxycarbonyl-
amino)propoxyimino}-2-(S-amino-1,2 3 4-thiadiazol-
3-yl)acetamido~-3-~ 2-hydroxyethyl)-lH-
~etrazol-S-yl]~h iomethyl - 3 - c ephem~4-carboxylate
(syn isomer)~ powder, mp 88 to 101C (dec.).
IR ~Nujol) :: 3300, 1780, 1750, ~675, 1620 cm~
lQ
~89~ Pivaloyloxymethyl 7-~2-{3-(N-t-buto~ycarbonyl-
~ amino)propoxyimino}-2-~5-amino-1~2,4-thiadiazol-
:- - 3-yl)acetamido~-3-(1,394-thiadia701-2-yl~thiomethyl-
3-cephem 4-caTb~xylate ~syn lsom~r), powde~, mp
71 to 84C ~decO).
IR (Nujol) :. 3300, 1780, 1745, 16~0, 1615 cm 1
- ~90) Pivaloyloxyme~hyl 7-~2~allyloxyimi~o-2-(5-amino-
1,2~4-thiadiazol-3-yl)acetamido~-3-~1-{2-tN-~-
butoxycarbonylami~o)ethyl~-lH-tetrazol-5-yl]-
thiome~hyl-3-ceph~m-4-carboxyla~e (syn isomer~,
po~der~
IR ~Nujol~ : 3300~ 1780~ 1750, 1680 cm 1
(91) 7-~2 - (4~Chlorop~e~ox~imI~ 3o2~ 5-~in~ 1~2~4O
thiadiazoI~ ce~amido~ 3~4 thisdiazol-
2~yl)thiom~*h~1-3 cep~em~4~carbo~ .c ac~a ~yn
i~mer)~ mp I50 t~ 15~C t~ecO)~
I~R. tNujol) : 3~no, ~200, 1770, 1670~ 1620
1~20 cm 1
~92) 7~r2~g4 FI~orophe~oæyim~no)~2~5~amlno~192~4_
thi~i zo~ 3~y~acetam~do~3 (1~,4-thladiaæol-
2~yI3t:~iomet~yl~3-cephem-4-car~ lic acid (~
isomer~ mp 140 to 145 CD(aec.)~
~5
~3~
I.R~ ~Nujol): 3aOO, 3200, 1770, 16809 1620~ -
15~0 ~m 1
~9~ 7~ Phenoxylmino~2~ 2~i~0-1, 2,4-thiadiazol-
3-yl~ ace~mido] -3- ~l-carbc~x)rm~thyl-lH-tetrazol ~ 5-
yl~ ~hiomethyl-3-cephem-4-carbox~lic acid ~syn
isom~r~ s m~ 175 to 180~C ( dec . 3 .
- I.R~ ~Nujol~: 3400~ 3~00, 1770, 1700~ 1660,
: 16~0, 1580 ~ 1510
(~4) 7- ~2-Phe:sloxyim:i~o-2- ~ o~ ,4-th~adia201-
- 10 3^yl)acetamido~3~ allyl-lH-~etrazol~5-yl)~
~hio:me~hyl-3~cephem~4~earboxylic acîdr ~sy~ is~mer) 9
mp 14S to 1~0C ~dec. 3 . . ~
I.,R~. (Nu~ ol) : 3450 9 335û, 3180 ,~ 1780, 17iO ~ -
1680 " 16:10 ~ l~Q0 7 1 .0 C~
~ 3 7 ~ ~ 2 - Phenoxy~i~o - 2 ~ ami:llo -l ~ 2 9 4 - thiadi ~ ~ ol - - - ~
3-yl3~cet~ido~-30(1 methy~-lH~ razol~5-yl)-
~hiome~yl-3~cephem~4-carl~oa~ylic acid ~sy~ isomer),
mp 1~5 to 158C: ~dec~.~
I.R., ~Nu~ol~: 3400~ 330~, 3200, 1770, 17~0,
_ 1680, 162~7 lS~û, 15~0
~g6) 7 - ~ 2 - C 2 -Methoxy - S -~i~r~phe~oxyimi~o ) - 2 ~ 5 ~
ami~ L, 2 D 4-~hiadia~ol-3-yl) ac~tam~do3 -3- ~193 y 4-
thiadiaO~ol-~-yl~thiome~hyl-3-cephem 4-carboxylic
acid ~sy;l isomer~ 9 mp 160 to 169~C ~decO~
~5 I~R~` (Nujol~: 3380, 3~2~ 310Q, 17807 16909
~6~ , 152Q, 1340 ~ 1280,
1085g 1065, 8Z0) 750 cm 1
(g7~ 7~2-(4-Flusrop}le~oxyimino)-2~ amino-17~,4-
~hiadia~ol-3-yl3aee~amido~ -3~tetrazolo~1,5-~]-
pyrida i~ 6 yl) thiomethyl-3Ocephem-4-carbQxylic
ac~ a ~sy~ isoIaer~, mp 125 to 130~C ~dec~ ~ .
X.~ uj~13: 3~00" 3190~ ~770~ 1670, 1615
152G " 1495 cm 1
%~
23 ~3
- (~8) 7- ~2- (4-~lorophe~ox~imino~ -2- (5^amillo~
-- ~hiadia2Ql 3-yl)acetalaidoJ-3-~5-hydroxyme~hyrl-l,3,~-
~hiadiazol -~ -yl) ~hiomethyl-~ -cephsm-4-carboxyl~ c
acid ~sy~ isomer; ~ mp l35 ~o l40C ~dec.~ . -
- I~Rc ~NUJ ol) : 34~iO, 3280, 3l80 " 1760, 17Z0,
1~609 1620, 1530J 15~0, 1480 C
- ~9~ 7 ~ 4~lorophe:rloxyi~ina)-~ ami~l4~ 4-
thiadi 201-3-yl) ac~amido~ -3- (l-ca~boæy~e~hyl-lH-
te~:raz o l - ~ -yl ) Shiome~hrl - 3 - ceph~m~ 4 - ca~ oxylic acid
~sys~ isomar) 9 Dl~t 135 ~o l40C ~dec~,) . -
Nujol) ~ 3400" 3250~ 3l709 1765, l100,
16BO, 1~50 Y 1615 9 15~0, 1510
~480
- - ~00) 7- ~2-~4-Ch~OrOP~e~OXYim~ Z~ ~5-ami~0-1,2,4-
Shiadia201 3-Yt~aCe~ dO]-3~ (Z~hYdrOXYeehY1~-
1H-tet~aZO1~-Y1lthiOmethY1~J-C2Phem-4 C~rbOXY1iC
- aCid ~SYn iSOmer~, m~ 120 tO 125C (deC.). ~
Io~R~ (NUjO1~: 340U9 3;00~ 3180" 1765, 1670,
1615, 1580". 1$20~ ~480 Cm 1
~01~ 7~ 3 9 4-Dichlorophenoxyimi~o)- 2~S~ O-
13,2~4~ adiaZO1~3-Y1~ aC~tamidOt -3~ ~1 ,3~4~
thi~dia~OI- 2 -Y1~ th10methY1-3 ~C~PhPm-4 -Ca~bOXY11C
acid (sy~ isomerl 9 d~eCo~po5ed bY 160~Cr
I~R ~NUjO1): 3300J a200, 1770, 1680~ 16205
lS20, l250 9 lZ05, 10~
7 ~Z-(3-Trifluoromethylphen~xyimi~o~-2-(5-
ami~o-IJ~,4 ~hia~iazol-3-yl)acetamidoJ 3-~l,3,~-
~hiad~azol-2-yl3thiome~hyl-3-cephem-4-carboxylic
~o acid (sy~ isomer~, deco~posed by l64C.
I;R. ~Nu~ol) : 3300~ 31807 l76S~ l670, ~610,
~5~ 9 13~0, 116~, 112Q, 106~ 7
g;0~ 79Q 9 700 r~ 1
3~
~3
- ~ lo~ 7- E2- ~3-E~ho~carbo~ylpheno~yimins~ -2-
o -1, 2 ~ 4 - hi adiazo 1- 3 -yl) ac e~amido ~ - 3 - ~1, 3 ~ 4 -
~hi adia~ ol ~ ~ -yl~ thiom~thyl - ~ - ceph~m 4 - carboxyl ~c
acid (Sy~L isomeT), deco~n3?osed by 16ZDC.
Nuj ol) o 33$0-3150 7 1770 9 17~0-1660 )
16~0~ 1520, 1290, lZ70, ïlO0,
10~0 y 900 ~ 7~
~4~ 7 - ~2 - ~4~Flllorophe$~oxyimi~o3 - 2~ ~5-amino -1 9 2 ~ 4-
~adi~ol 3 -yl) ac~amislo~ - 3 ~ ^hydroxyethyl) -
:~0 1~ razol- 5 ~yl~ ~hiome~hyl-; cephem~ car~oxylic
acïd ~sy~ isome~3 9 m~ 14~ to 150C (decO) .
I.R. (Nujo~ 3300, 32~0, 17709 1670, 1610
1~0 cm~
~105) 7~ (4~Flu~Tophe:!loxyimino~ -2- ~5~ o-1,2~4
1~ ~hiadiazol-3~yl~ acetamido~ ca boxymethyl-lH
~e~ra201-5-yl~ thiomethylo3-ceph~m-4-carb~xylic acia
yD isomer~D mp 150 to i~S~C ~dec.)~
1 ~Ro ~Nu~ ol) : 3300 ,, 3200 ~ 177~ 9 17~0,
1670, t620; I5~0, 1~00 cm
L06~ 7-~2-~4~ uoTophe~loxyimi~o)o2~ amino 1~ 4 ~
~h~adiazol-3~ yl~ acetam do~ -3- E2-carboxymethyl-~- -
oxo-273-dihya~o-l,Z,~-triazolo~4,3-b~pyridazi
ylJthiomethyl-3-cephem-4-earboxylic acid ~sy~
isomer), m~ 16~ to 170C (d~c o ) ~
~5 I .R. ~N~j ol~ : 330~, a~00 " 1770, 1710, 16Z0,
1540 y 1~20 9 l!iOO em ~
~0~ 2~4-P1uorophe~oxyimi~o)-~-tS ~mino-1,2,4-
~hiadia~ol3-rl~acetamidoJ^3~ 2-car~oxyethyl3-
et~azol-S~yl~h ome~hyl~3 cephem-4-carboxylic
acid tSy~ isomer~, mp 140 ~o 145~C ~d~c~)o
I9R. (Nujol) : 3300~ 3~00~ 1770~ 1700,
~20, 15~0, ~5~0 em ~
3~
~35
~108) 7~ 4 Fluo~ e~oxy.Lmino) -2- (5-ami:~o~' ,2,4-
t~adiazol-3-yl) acetamido l -3~ ally7 -lH-te~razol-
- 5~yl~thiome~hyl-3~ceph~m-l4-car~o~ l ic acid ~s~
isomes~, mp 145 o l~O~C (dec.). . ~
I.R~ ~Nujol): 34509 33509 31sn, 17~0,
17059 1670y 16109 1~10 cm 1
93 7 ~~2-Phenoxyimi~o-2-(~;-ami~o-l "2,4-~iadiazo~
3-yl)ac~tamido3~3~ 2-ami~oe~hyï~-lH~tetrazol-
yl~ thiomethyl-3~ceph~m-4-carboxylic acid ~sy~
~:1 isom~r~, mp 180 to 185~ tdee.), . .
I l>Ro ~Nujol):3300" 3250, 1760 J 1610g 1620, 1590,
15Z0 cm 1
-- (L10) '7~2~ o~:ycarbQ:~y~set~æy~m~no~ 2~(5~o 11,2~4_
thiadiazol ^3 -yl) acetamldo~ - 3 - ~e ~ra2010 ~l, 5 b~ ~
15 - py~idazirL-6-yl)thiQmethyl-3-cepheDl-4-casboxylic acid
~syn isom~r) ~, m~ 125 to 13QC (dec~O- -
I.R. ~Nuj ol~ : 3400 9 3300, 31B0, ï77û, 17~0,
1680, 1 620, 15~5 cm~1
~:~1) 7- ~2-{3- ~N-t Butoxycarbo~ o~propoxyimino}
~G 2 ~ am~o -1, 2 9 4 - thia~iazol - 3 ^yl) ac~tam~do 3 - 3 - [1-
~2- tN-t-bu~oxycarbonylami~o~ ~ hyl~ -lH ~e~razol-5 -yl~ -
thiomstlly~ -3-cephem-4-carboxylic acid ~SyTl isomer)
- mp 10 7 ~o 112 C ~d~c
7 - ~ 2 - ~ 2 9 2, :2 - Trif luoro ethoxyimino ) - 2 - t 5 - ami;lo -
4~th~adia~ol-3-yl)ace~amido~3-~1-allylwlH~
~tra2Ol-~-yl~thiome~yl-3-ceph~m-4-carboxyllc acid
tsy~ isomer), mp 125 ~o 130~e ~dec~ ) .
IoR~ ~Nujol): 3300~ ;200a~ 177û, 1680,
1~0 ~ 15;20 cm~l
~o ~ 7- ~2- ~2 " Z " 2 -Tri11loroethoxyimi~o~ 2 ~ ami~o-
1, 2, 4-th~2Ldiazol-3-yl~ ace~amldo~ 3- tl-me~h~}-lH-
~e~razol-; -yl) thiom@thyl-3 cephem 4-carboxylic acid
~sy~ isomer~ " mp 145 ~o 150C tdec.) ~
Nujol~ ~ 33ûO, 3200~ ~770~ 168U, 1~20;
~5 15~5 ~-1
~3~
~14) 7~ {~-(N~t-~utoxyc~rbonylami~)e~ho ~ imi~o}--
2-~5-~mino-I,2,4-thiadiazol-3~yl)~ce~amidoJ-3~
{2-~N-~bu~o.Yycarbo~ylami~o~ethyl} lH-te~ra~ol-~-
yl~hio~ethyl 3-cephem-4 carboxylic acid ~syn
isomer), mp 1~1 ~o 186C ~dec,).
I~R. ~Nujol) : 33Z0,178Q, 1680, 1620, 1520,
1165 ~1-l
~I5) 7-~2-Trityloxyimino-? ~5~amino-1,2,4-
thladiazol-3-yl~acçtamiclo~-3~5 me~hyl-1,3,4-
- la thia~i ~ol-2~yl)~hiomethyl-3-cephem-4-carboxylic
~ acid ~syn isom~r), mp 147 ~o 151~C ~dec.~, -
~ T.R. ~Nujol~ : 3420D 1780~ 1680~ 1615~ 1525 Cm 1
6~ 7-~ {2-t~-t-Butoxycarbanyl~mi~o)et~oxrimino~-.
(5- ~ ~o^1,2~4-thiadiazol-3-yl)ace~amido~-3~
15- `ca~boxymethyl-~H-t~tr~zol-5-yl~hiomethyl-3-eephem-
- 4-carboxylic acid (sy~ isomer)~ mp -105C ~dec.).
I.R~ ~Nu~ol) ~ 3305~ 316U~ 1770,1670, 1~0
-1~45 an~l
L7~ 7- E2- ~t-Bu~oxyearbo~ylme~hoxyîmi~o) -2o ~5~ o-
192~4-thiadia201~3~yl)acetamido~ ~3-~1,3,4-thiadlazol-
~-yl)thiome~hyl-3-cephem-4-car~oxylic acid ~sy~
isomer~ mp 140 to 1455C (d~c~
~ tNU~ol) : 3300, 3175, 17703 1120~ 1680
. ~B~0, l~Z0 ~m-l
2s ~ 7- L2 ~ Butoxyc rbonylmeth~xyimi~o~ 2-(5-amin~-
lj2,4~hiadiazQl-3-yl~acetamldoJ-3~ allrl-lH-
tetr~ol-5-yl)thi~met~yl-3~cephem~4-ca~boxylic acid
~sy~ ~s~mer)~ mp 130 to 135C ~decO~.
I.R~ .~Nujol) : 3400~ ;280, 31~0, 17703 1720,
1680, ~62~ 15~ om-l
!
;
.
237
~1~9) 7~ [2~ (t-Butaxycarbonylmethoxyimillo) -2- (5~amino-
192g4-thiadia~o1-3 yl~ace~amido~ -3- [1~2- (N-t
buto~ycar~o~ylamirlo) ethyl} -lH-tet~azol ~ -yl~ ^
~hiome~hyl-3-cephemo4-car~oxylic acid ~5~ isOlner),
~p 110 ~o 11~C (de~ ) .
I.,R. ~Nu~ol): 3300~ 3200, 1775, 1680
. 1620 1 15~0 ~Q
~120~ 7~ [2~ Butoxycarbo~y:Lme~hoxyi ino~ (S~ o-
lgZ~ hiadi ~ol-3-yl3acs~amido~3-(l-phenyl~
~e~razo 1- 5-y~) ~h~ ome~yl- 3 - cephem- 4 -caTboxylic acid
~sy~ isomer), mp 1~5 to 140C (dec.
I.R~ ~Nuj ol~ O 3400 ~ 3300, 3200, 1775 ~ 1720
16~, lÇ20, 1525, 1500 cm l
~l~ 7 ~ Aminoprop oxyimi~o J - 2 - ( 5 - ami~o ~ , 4 - -
- - 15 thia~iazol~3-yl~ ace~:mida~ -3~ (2-amin~thyl) - -
etra201- 5 -ylJ thiome~hyl - 3 -cephem^ 4~carboxylic
acid (sy~ isoDler~ 9 m~ 184 ~o 196C ~dec.~ .
I . R. ~u; ol) : 3400 -3100, 1760, 1660 " 1610,
lS20 ~ 117~, 1060 ~ 1010 ~m
- 20 ~1~23 7 ~2- ~2~ o~hoxyimi~o~-2~ ~S a~in~-I,2~4-
- t}~iadia201-3 ~yl3 ac~tamido~ 3~ ca~boxyme~hyl-lH-
~etra~ol-5~y}~hiome~hyl-~c~phem-4-caTboxylic
acid ~sy~ ~somer~, mp lgO to 198~C ~d~c~)~
I.R~ ~Nu~ol~: 3Z50~ 3160; 1760,, 16~0,
~ 1615 ~ 1522 9 lU20 cm l
(12~3 7 ~ Ca~b o~e~choxyimi~o ~ 2 C ~ - ami~o -1, 2, 4 -
thia ia~ol-3-yl)ac~amido3 3-(lp~ j4-~hiadiazol-
2 yl) ~:hiom~hrl-3-c~ph~m4-carboxylic acid ~sy~
somer), ~r~p 1 70 ~o 175C (dec.~ .
I .R. ~Nuj ol~ ~ 32~0 " 3150 " 1770 " 1710,
1680, 16~ ~ 1520 ~m 1
~L24) 7 - ~ Z Carbo:cymethoxyimins - 2 ~ ami~o -l, 2, 4-
~hladia~ 3-yl) acetamido~ -3 ~l-allyl~lH t~ ra~ol-
. ~-yl)~hî~im~thyl-3 cephem-4-carb~xylic cid ~syn
~5
~3~
isomer), ~p 14S to 150C (d~c.).
I.R~ (Nujol3: 34007 3~00, 3~00? 1765,
. 17~D, 1680, 1620~ 1520 cm 1
5) 7 ~-Car~ox~e~ho~imi~o-2- (5~amirLo~ ,4-
t:hiadia~ol~a-rl3 ace~amido~ -3- ~etrazolo ~1 " S-b3 -
pyridazi~G-yl) ~hiom~.yl-3 cephem-4 carboxyliG
acid ~5y~l som~r), mp 170 ~o 175C (dec.3.
I.R. ~NujoI~: 3400, 33003 3180~ 1765,
- 1720~ 1680, 1615, 1520 cm 1
1~ ~2C~ 7 - t2 - ~2 -Aminoeshoxyimi~o) ~ amino ^19 2 ~ 4-
thia~iazo1-3-y1~ac~amido3-3~ 2-aminoethyl)-lH-
~ e~ra~ol-5 yl~hiomethyl-3-cephem-4-car~oxylic aei~ - :
- ~ ~syn isom~r~, mp 182 to 1879C ~dec~)s
R. ~Nujol) : 3350, 3150, 1160) 1660,
2~ 653 152~
. . . ~7~ 7-~2-Carboacymethcxyimino-2-t~-ami~o~1J294- , ...- 2hiadia~ol-3-yl) ac~amido~ ~3 ~ oethy1) ~
~e~Orazol-5~yl3 ~hiomethyl-3-ceph~m-4-carboxylic acid
(SyR isomer3 9 m:p }85 t~ l90~ dec~)
I.~ ujQ1): 3251~; 17~;5D ~66~; 1590, }~20 ~
~128) ~ ~2 - ~2 9 2 ~ 2~'rr~ fluaroethoxy~:mino) -~ (5 amino- -
192,4~h~adi 201 3-yl)ace~ o~ 3~ 2-
a;ni~oe~hyl~-lH-te~azol-S-yl~hlo;nethyl-3-cephem-
4-carboxylic acid ~sy~ isomer) ~ mp 185 ~o 190C
~d~c~ );
~R~ (Nat~ ol) : 33~0, 3170 ~ 1760 ~ 1670
:~6155, 1500 m-l
~g~ 7 - ~2 -Carbo~yme~hoxy~ o ~ 5- amino -1, 2`, 4 -
~h adiazol-3-yl)ace~amido]-3~ p~enyl-lH ~etra~Ool-
S -yl) ~hiom0~hyl - 3 - c ephem - 4 ~car~oxy lic aci d ( s~rn
~somer) 9 Dlp 15~ ~o 160~C ~d~e
IoR~ CNujol) ~ 34009 3300, 31~0, 176i, 177.0
1~680 g 16 l.5 p 1520 ~t L49~; cm~
3~i
2`3~
~ ~Q~ 7 - L ~ -Hydroxyimi~o ~ 7 - ~ i - ami;Lo -1, 2, 4 - ~hiadia~ o l -
3oyl~ acetamido~ -3 ~ ~5 -me~hyl-1, 3, 4 -thiadiazo1- ~-yl) -
thiom~thyl - 3 -cephem-4-carboxylic acid (SyTi isomer~,
~p lS~ to 1~2~C ~dec.~ -
I~R. ~Nu~ ol) : 3260, 316Q ~ 1763, 1665,
1608 " 1520 cm 1
l~t.) PiYa1Oyloxyme~h~l 7- ~2-hydroxy~mino-2~
ami~o-l ,2, 4-~hiadia~ol-3-yl) ace~amido~ -3- ~S-me ~hyl-
1~3~4-~hiadia~ol-2-yl~hiomet~yl~3-c~phem-4-
car~ox~la~e ~sy~ is~mer), mp 132 ~o 13.~C ~dee.~.
I ,,R. ~Nu~ ol) : 327û 3 31~, 1775 3 1745,
- ~ : 1675, l6la~ 15Z~, lllS cm~
~0
~0
Example 44
A solution of 7-[2~ carboxyethoxyimino)-2-(5-
amino-l,~ hiadia~ol-3-yl)acetamido~-3-[1-{3-(N-t-
butoxycarbonylamino)propyl}-lH-te~razol-S-yl]thiomethyl-
3-eephem-4-carboxylic acid (syn isomer)(3.4 g) in formic
acid (34 ml~ was stirred for 2 hours at ambient tempe-
rature. The reaction mixturE: was post-treated in a
conventional manner to give 7-~2-(1-carboxyethoxyimino)-
2-(5-amino-1,2~4-thiadiazol-~i-yl)acetamido]-3-[1-~3-
aminopropyl)-lH-tetrazol-5-yl~thiomethyl-3-cephem-4-
ca~boxylic acid ~syn isomer)~l.l g~, mp 185 to 188C
(dec.).
IR (Nujol) : 3300, 3150, 1760, 1660, 1620, 1520,
1230, 1000, 720 cm 1
NMR (DMSO-d6~D2O, ~) : 1.48 (3H, d, J-7Hz), 2.3
(2H, m), 2.9 ~2H, m), 3.6 ~2H, m)~ 4.1-5.0
~4H9 m), 4.70 ~lH3 q, J=7Hz); 5.10 (lH3 d~
J-5Hz), 5.85 (lH, m)
.
~0 ~
A solution of pivaloyloxymethyl 7-[2-{3-~N-t-
butoxycarbonylamino)propoxyimino~-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido~-3-(1,334-thiadiazol-2-yl)-
thiomethyl-3-cephem-4-carboxylate (syn isomeT)~Z.7 g),
anisole ~24 drops) and 0.6N hydrochloric acid (26.6 ml~
in dioxane (18 ml~ was stirred for 30 minutes at ambient
temperature. An insoluble material was collected by
decantation, and dissolved in water. The aqueous solu-
tion was washed twice with athyl acetate and then
lyophilized to give pivaloyloxymethyl 7-[2-~3-
aminapropoxyimino)-2-(5~amino-1,2,4 thiadiazol-3-yl)-
acetamido]-3- ~193 ,4-thiadiazol-2-yl)thiomethyl-3-cephem-
4-carboxylate hydrochloride (syn isomer)(l.8 g) 9 mp
90 to 155C (dec,).
IR ~Nujol) : .~300, 3150, 1775, 1730~ 1670, 1625,
1530 cm 1
N~ ~DMS0-d~D2O, ~) : 1.20 (9H, s), 1.9-2 5
~2H, m), 2.9-3.5 ~2H, m), 3.78 ~2Hp broad s),
4.27 and 4.63 (2H, ABq, J=14Hz), 4.2-4.8
(2H, m), 5.25 ~lH, d, J=2.5Hz), 5.6-6.1
(3H, m), 9.42 ~lH, s)
The following compounds were obtained aceording to
siDIilar manners to those of Examples 22 to 25, 44 and 45.
(1) 7-[~-~2-Propynyloxyimino)-2-~5-amino-1,2,4-
thiadiazol-3-yl~acetamido]-3-[1-(3-aminop~opyl)-
lH-tetrazol-5-yl~thiomethyl-3-cephem-4-carboxylic
acid (syn isomer~, mp 165 to 170~C (dec.).
IR ~Nujol) : 3450, 3300, 3210, 1770, 1670, -
1620 9 1525 cm
NMR ~DMSO-d63 ~ : 1.90-2,37 (2H5 m~, 2.67-3.03
(2H, m), 3.47 ~lH~ ~, J=2~z~ 9 3.37 3.53
(2H, m) 9 3.93-4.60 (4H9 m), 4.75 ~2H, d,
J-2Hz)~ 5.0 ~lH, d, J=SHz), 5.68 (lH, dd,
J=5 and 8Hz) J 8.12 ~2H, broad s), 9.S0
~lH,.d1 J-8Hæ)
~5
(2) 7-~2-Carboxymethoxyimino-2-(5-amino-172,4-
thiadiazol-3-yl)acetamido~-3-[1-(3-aminopropyl)-
lH-tetrazol-5-yl~hiomethyl-3-cephem-4-carboxylic
acid ~syn isomer), mp l9S to 200~C (dec.).
IR ~Nujol) : 3150, 1760, 1660, 16409 1520 cm 1
NMR (DMSO-d6, ~) ~ 2.0-2.30 (2H3 m~9 2.73-3.0
(2H, m), 3.60 (2H~ broad s), 4. 20-4.50
~4H, m~, 4.60 (2H, s)~ 5.08 (lH, d, J~4Hz),
S.83 (lH, dd7 J=4 and 8Hz~, 8.23 ~2H~ s) 9
6~
lC.20 (lH, d, J=8H~)
(3) 7-l2-~1-Carboxy-2-methy:lpropoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-~1-(3-
aminopropyl)-lH-tetrazo:l-g-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn :isomer), mp 183 to 189C
(dec.).
IR (Nujol) : 3400-3100, 3150, 1770, 1670,
1620, 1.520, 13B0, 1280~ 1230~
1180, 1:100, 1020, 9U0, ~30 cm 1
MMR (DMSO-d~D20, ~3 : 0.98 (6H~ d, J=7E~z)~ 2,2
(3H9 m), 3.6 ~2H, m), 3.9 ~2Hg m), 4.3
(SH, m3, 5.06 (lH, d, J=5Hz) 9 5.70 ~1/2H,
d, JaSHz), 5.82 ~l/?.H, d, J~5Hz)
~4~ 7-~2-~1-Carboxypropoxyimino)-2-~5-amino-1,2~4-
t.hiadiazol-3-yl)acetamidoJ-3-~1-(3-aminopropyl)-
lH-tetrazol-5-yl]~hiome~hyl-3-cephem-4-carboxylic
acid (syn isome~), mp 183 to 188C (dec.).
IR (Nujol) : 3400-315Q9 1770, 1~70, 1620,
1530, 13~0, 12~0, 1230, 11~0,
1100, 1050, 1010, 730 cm ~
NMR (DMSO-d6, ~) : 0.98 (3H, t~ J=7Hz), 1.7-2.3
(4H, m)~ 2.7-3.1 (2H; m)9 3.4-3.7 (2H~ m)J
4.2-4~8 (5H, m), 5.07 (lH, d~ J=5Hz),
5.6-5.9 ~lH, m3, 8.13 (2H, broad s31 10.08
(lH~ m)
~5~ 7-[2-Carboxymeth~xyimino-2-~5-amino-1,2,4-
3Q thiadiazol-3-yl)acetamido~-3-[1-(4-aminobutyl)-
l~-tetrazol-5 yl]thiomethyl-3-cephem 4-carboxylic
acid ~syn isomer), mp 191 to 194C (dec.).
IR (Nu~ol) : 3300, 3150, 1760, 1670, 1620,
15~0, 1230, 1170 7 1050~ 8gO,
24~
740, 720 cm 1
NMR (DMSO-d6~D2O, ~) : 1.2-2.1 ~4H~ m), 2.80
(2H~ t, J=6Hz), 3.6 (2H, m), 4.3 (4H9 m)~
4.60 (2H, broad s), 5.10 ~lH, d, J=5Hz),
5.82 (lH, d3 J='iHz)
~6) 7-[2-(1-Carboxy-l-methylethoxyimi~o)-2-(S-amino-
192,4-thiadiazol-3-yl)acetamido~-3-~ 3-
aminopropyl)-lH-tetrazol-S~yl]thicmethyl-3-cephem-
4-carboxylic acid (syn isomer); mp Z00 to 203C
- (dec.~.
IR ~Nujol) 3300, 3150, 17~0, 16609 1620
152Q, il60, 990 cm 1
NMR (DMSO-d6~ 1.50 ~6H, s), 2.20 (2H, m~,
2.90 (2H, m), 3.60 (2H, m), 4.30 ~4H, m~,
5.10 (lH, dJ J=SHz), 5.83 (lH, m), 8.20
(2Hr broad s), 9.B7 (lH, d, J=8Hz~
(7~ 7-~2-(1-Carboxy-l-cyclopentyloxyimino)-2-(5-amino-
192,4-thiadiazol-3-yl~acetamido]-3-[1-~3-
ami~opropyl~-lH-tetrazol-5-yl]thiomethyl-3-cephem-
carbQxylic acid (syn isomer), mp 202 to 2D5~C
~dec.).
IR ~Nujol3 : 3300, 3200~ 1760, 1660, 1620,
, ~ 1520, 1180) 10609 10009 730 cm 1
: NMR ~DMSO-d6, ~ : 1.70 (4H, m), 2.10 (6H, m~,
2.90 ~2H, m), 3.11 and 3.60 (2H, ABq, J=18H~
4.40 (4~1, m), 5.08 (lH, d~ J-5H~), s.sn
~lH, dd9 J=5 and 8Hz), 8.Z3 (2H, m) 9 9.78
~lH, m)
~8) 7-~Z~ Carboxyethoxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido~-3-~5-aminomethyl-1,3~4-
~hiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
.
2~
acid (syn isomer), mp '~07 to 210C ~d~c,).
IR ~Nujol~ : 33Q0~ 3150, 1760, 1660, 1620,
1520, :L2303 1170, l~90, 1060,
1040, 990 cm 1
NMR (DMSO-d6+D2O, ~`) : 1.43 (3H, d, J=SHz), 3.60
(2H, m), 4.0-4.'33 ~5H, m), S~OS and S.lS
~lH, d, J=SH2), 5.70 ~lH, m), 8.1 (2H, broad
â) ~ 9. 5 ~ d, J=8H~)
(9) 7-~2-Carboxymethoxyimino-2-~5-amino-1,2 9 4 - thiadiazol-
3-yl)acetamido]-3-[1-t6-aminohexyl)-lH-tetrazol-5-yl]-
~hiomethyl-3 cephem-4-c~Tboxylic acid ~syn isomer),
mp lBS to 188~C ~dec.).
IR (Nujol) : 3300, 3200~ 1760, 1670~ 1620
1520, 1240~ 1180, 1060 cm~l
NMR (DMSO-d6, ~ : 1.10-1,57 (6H7 m)j 1.57-1.97
~2H, m), 2~70 ~2H, m), 3.83 (2H, m~, 4.27
(4H, m)~ 4.57 (2H5 broad s), 5.03 ~lH, d~
J=5Hz~, 5.72 ~lH~ dd, J=5 and 8H~), B.13
(2H5 m), 9.80 ~lH~ d, J=8Hz)
(10) 7-[2-~3-Aminop~opoxyimino)-~-(5-amino-lJ2~4-
thiadiazol-3-yl~acetæmido~-3-(1,3,4-thiadiazol-2-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn
: 25 isomPr), mp 165 to 183C (de~c.~.
IR (Nujol) : 3150~ 1765a 1660~ 1630a 1570,
1520 cm~l
MMR {DMSO-d6+D2O~ 1.6-2.3 (ZH~ m), 2.6-3.2
(2H~ m~l 3.2-3.7 ~2H9 m), 3.9-4~7 C4H, m),
4.97 ~lH~ d~ J=4~5Hz~ ~ 5.68 (lH~ d~ J=4.5Hz)
9. 50 (lH~ S)
7- [2 ~3-Aminopropoxyimino)-2-(5-amino-1,2,4-
thiadia7.ol-3-yl)acetamido]-3-[1-~2-hydToxyethyl)-
2~L:3
lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid (syn isomer~, mp 17Q to 185C (dec.).
IR (Nujol) : 3140, 1760, 1660 ! 1610, 1580,
1520 cm 1
~MR (DMSO-d~D~0, ~) : 1.6-Z.4 ~2H~ m)~ 2.7-3.
(2H3 m)~ 3.3-3.9 (4H, m3, 3.9-4.7 (6H, m)g
4.97 (lH, d, J=4.5Hz)) 5.67 (lH, d9 J=5Hz)
(12) 7-[2-t3-AminopTopoxyimino)-2-(5-~mino-1,2,4-
thiadiazol-3-yl)acetamido~-3~(5-me*hyl-1,3,4-
thiadia~ol-2-yl)thlomethyl-3-cephem-g carboxylic
acid (syn ~isomer), mp 192 ~o 195C (dec.).
IR (Nujol) : 3250, 3140~ 1760, 1640, 1620,
1585, 1525 cm 1
NMR (D2O~DCl, ~) : 2.0-3.4 (2H3 m), 3.00 (3H, s),
3.2Z (2H, ~, J=7H5), 3.74 and 3.92 (2H, ABq,
J-18Hz), 4.36 ~nd 4.53 ~2H, ABq, J-14Hz)3
4.54 ~2H~ t, J=7Hz)~ 5.28 ~lH, d, J-4.5Hz),
5.82 (lH~ d, J=4.5Hz)
~1~) 7-~2-~3-Aminopropoxyimino~-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3~ methyl-lH-tet~azol-
5-yl~thiomethyl-3-cephem-4-carboxylic acid (syn
isomer), mp 180 to 184C (dec.~.
IR ~Nujol) : 3160, 17607 1660, lS90 cm
NMR ~D20+DC19 ~) : 1.9-2.4 ~2HJ m~ 3 3.20
(3H, t~ J=8Hz), 3.80 ~2H1 broad s~, 4.02
~3H, s), 4.22 (2H, broad s), 4.52 (2H3 t,
J=6Hz),`5.25 (lH, d9 J-5H~, 5.85 ~lH3 d7
3~ J=5Hz)
~14~ 7 - E 2-~4-Aminomethylbenzyloxyimino)-2-~5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-
cephem-4-carboxylic acid formate (syn isomer~,
:~8
~4
mp 230 to ~40C (dec.).
IR (Nujol) : 1750 cm 1
NMR (DMS0-d6~D20, ~) : 1.86 (3H, s), 3.25
(2H, m), 3.97 (2H9 5) ~ 4.94 (lH, d, J=4.5Hz),
S 5.16 ~2H, s), 5.6 (lH, d3 J=4.5Hz), 7.35
(4H, s), 8.20 (lH, s)
~lS) 7-L2-~3-Aminopropoxyimino)-2-~5-amino-1~2,~-
thiadiazol-3-yl)acetamido]-3-[1-~3-aminopropyl)-
~H-tetrazol-5-yl~thiomethyl-3-cephem-4-carboxylic
acid (syn isomer).
IR ~Nujol) : 3300~ 3150, 1760 9 1660, 1607,
1595, 1520 cm~l
N~IR ~DMS0-d6~D20, 8) : 2.0-2.7 ~4H, m3, 3.0-3O5
(4H, m) 3 3.4-4.0 (2H9 m) 9 4.0-4.9 ~6H, m),
5.20 (lH, d9 J=4.5Hz), 5.81 (lH, d~ J=4.5H~
(~OE) 7-~2-~2-D-Phenylglycylaminoethoxyimino3-2-(5-
~mino-1~2,4-thiadiazol-3-yl)acetamido~-2-methyl-
3-cephem-4-carboxylic acid ~syn isomer), mp 204
~o 2~2C ~dec.).
IR ~Nujol~ : 32609 31503 1760, 1665, 1615,
- 1512, 1400p 1045 cm~
N~IR (DMSO-d~*D20,~ 43 ~3H, d, J=7Hz)~
3.13-4.45 ~SH, m)9 4.98 ~lH9 s), 5.02 (lH9
dg J=4.5Hz)9 5.85 (lH, d, J=4O5Hz), 6027
(lH9 d, J=6H73, 7.43 (5H7 S)
~173 7-[2-~3-D-Phenylglycylaminopropoxyimino)-2-(5-
amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-
3-cephem-4-carboxylic acid ~syn isomer~ mp 203
~o 231C ~dec,),
IR (Nujol) : 3280, 11709 17609 16609 1600,
15209.1400 cm~
~4~
NMR ~D20~DCl,~) : 1.47 (3H, d, J=7.5Hz) 7
1.7-2.3 (2H, m), 3,40 (2X, t, J=7H7),
3~88 ~lH, q, J=7.5Hz), 4.33 (2H, t, J=6Hz),
5.18 (lH, d, J=4.5Hz), 5.20 (lH, s),
5.95 (lH, dt J=4.5Hz), 6.90 (lH, d, J=6.0Hz),
7.57 (5H, s)
(18) 7-~2 (1-Cyclohex~loxycaTbonylethoxyimino)-2-(5-
amino-1~2~4-thiadiazol-3-yl)acetamido~-3-[1-
(3-aminopropyl)-lH-tetrazol-5-yl]thiomethyl-3-
cephem-4-carbox~lic acid (syn isomer), mp 175
~o 178C (dec.)~
IR (Nujol) : 3400-3200, 1765~ 1680a 1610~
1520, 1220, 1100, 1000, 890,
790 cm 1
~IR (~MSO-d~ 0,9-2.0 (13H, m)~ 2.2 ~2H, m)~
2.9 (2H9 m~, 3,6 (2H, m) 9 4.0-5.1 (5H, m),
4.76 ~lHs q, J=7Hz), 5.03 (lH, d, J=5Hz),
5.77 (lH, m), 8.17 (2Hs broad s), 9.45
(lH 9 m)
(19) 7- ~2 (l-Benzyloxycarbonylethoxyimino) -2 ~ ~5-
amino-1,2,4-thiadiazol-3-yl)acetamido~ 3- ~1- (3-
aminopropyl)-lH~tetrazol-S-yl~thiomethyl 3-
cephem-4-carboxylic acid ~syn is~mer), mp 162 to
166C (decO).
IR (Nujol~ : 3300, 3200, 17609 1680, 1620,
1520, 1100, 1040, lO00, 740 cm l
NMR (DMSO-d6,~) : 1047 ~3H~ d, J=6Hz), 2.23
~2H, m~, 2,90 (2H, m~ 9 3.60 ~2H, m),
4.43 (4H, m), 4.90 (lH, q, J=6Hz)~
5.07 (lH~ d, J=5Hz), 5.20 ~2H~ s)~ 5.77
(lH, m), 7.43 ~5H~ s) 7 8.23 (2H, m),
9,57 (lH, m)
` 35
,
~8
(20) 7-[2-(1-Bu~o,Yycarbonylethoxyimino~-2-(5-amino-
1,2,4-thiadia~ol-3-y:l)acetamido~-3-[1-(3-
aminopropyl)-lH-tet~azol-5-yl]thiomethyl-3-
cephem-4-carboxylic acid (syn isomer), mp 158
to 163C ~dec.).
IR (Nujol~ : 3400-3200, 1770, 1680, 1610,
1530 a 1300, 1290 9 1050, 1040,
.1000, 960~ 900, 790, 740, 720 cm 1
NMR (DMSO-d6,~) : 0.85 ~3H, t, J-6Hz~,
1~1-1.8 (4H, m), 1~43 t3H, d9 J=6Hz),
1.9-2.4 (2H, m)~ Z.7-3.1 ~2H~ m),
3.5 ~2H, m~, 3.9-4.4 (2H, m), 4.10 (2H,
t, J-6Hz), 4.3-4.6 (2H, m), 4.78 (lH, q9
J=7Hz~, 5.02 (lH, d, J=5Hz)9 5.7 (lH, m),
8.2 (2H9 broad s)~ 10.1 (lH~ m)
(21) Pi~aloyloxymethyl 7- [2- (3-aminopropoxyimino)-
2-(5-amino-1,2,4-thiadiazo~-3-yl)acetamîdo]-2-
methyl-3-cephem^4-carboxylate hydrochloride
~syn isomer~, mp 91 to 156G ~dec.).
IR (Nujol~ : 3150~ 1780, 174S, 1670, 1525,
1525 cm 1
~R (DMSO-d6-~D2O,~) : 1.13 (9H, s), 1.43 (3H~
d, J=7Hz), 1.7-2.3 l2H, m~ 7 2.5-3.2 (2H,
m) a 3.5-4.S (3H, m), 5.10 (lH, d, J=5Hz)~
5.6-6,1 (3H9 m), 6.63 (lHg d, J=7Hz)
(22) Pivaloyloxymethyl 7~-[Z-~3-aminopropoxyimino)-
~-(5-amino-1,2~4-thiadiazol-3-yl)ace~amido]-3-
~0 ~1-methyl-lH-tetrazol-5-yl)thiome~hyl-3-cephem-
4-carboxylate hydrochloride (syn isomer~, mp
llO to 125C (decO).
IR (Nujol) : 1780, 1745; 1670, 1625, 1525 cm l
. .N~iR (DMSO~d~+D2O,~ 13 (9H, s),
2~
1.7-2.3 (2H, m), 2.6-3.2 (2H~ m),
3.75 (2H9 broad s), 3.90 (3H~ s),
4-0-4.7 t4H, Tn) ~ 5.12 ~lH, d, J=4.5Hz),
5.6-6.1 ~3H, m~
233 Pivalsyloxymethyl 7-[2-(3-aminopropoxyimino)-
2-(5-amino-1j2,4-thiadiazol-3-yl)acetamido~-3-
(5-methyl-19 3,4-thiadiazol-2-yl)thiomethyl-3-
cephem-4-carboxylate hydrochloride ~syn isomer),
mp 88 to 153C (dec.~. .
IR (Nujol): 2150, 1780~ 1745, lS50, 1625,
1 5 2 5 cm 1
NMR ~DMSO-d6~D20,~) : 1.16 (9H, s~ 6-2
(2H, m), 2.6-3.1 (2H9 m~, 2.68 (3H, s3,
3,76 ~2H~ broad s), 4.20 and 4.53-~2H,
ABq~ J=18Hz), 4.24 ~2~, broad s), 5.1
~lH, d~ J=4.5Hz) 3 5.6 600 (3H, m)
~24) Pivaloyloxymethyl 7-[2-~3-aminopropoxyimin~-
2 ~5^amino-172;4-thiadiazol-3-yl)acetamido~-
3~ (2-hydroxyethyl~-lH-tetra~ol-5-yl]thiomethyl-
3-cephem 4-carboxylate hydrochloride (syn lsomer)~
mp 150 to 175~C (dec.).
IR ~Nujol) : 3150, 1780, 1740, 1670, 1630,
1520 cm
NMR (DM~O-d6~D2O,~ : 1,20 ~9H, s~, 1.7-2.3
~2H, m), 2.6-3.2 (2H~ m), 3.5-4.0 (4H9 m),
4.0-4.6 (6H, m), 5.17 (lH9 d, J=5Hz),
5.6-6.1 (3H, m)
(25~ Pivaloyloxymethyl 7- [2- (4-aminomethylbenzyloxy-
imino~ 2- (5-amino-1,2J4-thiadiazol-3-yl)acetamido]-
3-methyl-3-cephem-4-carbo.~yla~.e hydrochloride
~syn isomer), mp 160 to 168C ~dec.)~
~5
-~82
~50
IR (Nujol) : 1780~ 1745, 1670, 1628 cm 1
(26) Pivaloyloxymethyl 7-l2-allyloxyimino-2-(5-amino-
1,2,4-thiadiazol-3-y])acetamidoJ-3-[1-(2-
aminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-
cephem-4-carboxylate formate (syn isomer), mp
95 ~o 105C (dec.).
IR ~Nujol) :.1790) 1735, 1452, 1370, 1118,
990 cm 1
MMR ~DMSO-d6+D20,~ : 1.2 ~9H, s), 3.2-3.35 (
(2H, m)p 3.7 (2H, broad s), 4.2-4.6 ~2H,
m)~ 4.1-4.6 ~2HJ m3, 4O7 (2H, broad s),
4.8-5,2 (lH, m~, 5.25 ~lH, d, J=4.5~z),
5~45 (2H, m), 5.7-6.25 (2H, m), 5.8 (lH~
d~ J=4.SHz)
~2
25i
Exam~l~ 47
_ _ _
A mixture of 7-[2~ t-butoxycarbonylethoxyimino)-
2-~5-amino-1,2,4-thiadiazol-3-yl)acetamido3-3-cephem-4-
carboxylic acid ~syn lsomer~2.35 g), trifluoToacetic
S acid (16 ml) and anisole (3 ml) was stirred for 40
minutes at ambient temperature. The reaction mixture
was evaporated and the residue was triturated with
diisopropyl ether and w~shed with diisop~opyl e~her to
give white powder o 7-[2-(1-carboxyethoxyimino)-2-
(S-~mino-1,2~4-thiadiazol-3-yl)acetamido]-3-cephem-4-
carb~xylic acid (syn isomer)~2.3 g~. The.powder
t2~3~) ~a9 r~preci~i~a~ed ~rom a m~ure o~
~ :: sodium bicarbona~e (0044 g) in water ~50 ml~ and
precipitates were collected ~y filtTation and washed
~5 with wa~e~ to give pale brown powder of the same com-
pound ~l.l g), mp 230 to 235~C (dec.).
IR ~Nujol) : 3400~ 3250, 3150, 1760, 1720,
1660, 1610, 1550, lZ90 7 1240,
1170; 970, 740 cm ~
N~R ~DMS0-d6, ~ : 1.46 ~3H, d, J=8Hz) 9 3.46
(ZH, m), 4 72 (lH, q, J=7Hz)~ 5.15 ~1~, d, --
J-5Hz), 5.58 ~lH, dd, J-5 and 8Hz), 6.50
(lH, m)g 8.20 (2H, m) 9 9.40 and 9.57
(lH, d, J=8Hz)
A mixture of 7-~2-~-t-butoxycarbonylbenzyloxyimino~-
2-(5-amino-1~2,4-~hiadi~zol-3-yl)acetamido3-3-[1-{2-~N-
¦ t-butoxyca~bonylamino)ethyl}-lH-tetrazol-S-yl3thiomethyl-
30 I 3-cephem~4- carboxylic acld (syn isomer~ ~3~0 g), tri-
fluoroacet:Lc acid ~30 ml) and anisole ~6 ml) was stirred
I for :~ hour at ambient tempera~ure. rhe reaction mixture
was post-t:reated in a conventional manner to gi~e 7- IZ-
(~-carboxybenzyloxyimino)-2-(5 -amino- l ~ 2, 4-thiadiazol -
3-yl)acetamido]-3-[1-~2-aminoethyl)-lH-tetrazol-5-yl]-
~%~
thiomethyl-3-cephem-4-carboxylic acid ~syn .isomer)
~1.16 g), mp 190 to 195C (dec.).
IR ~Nujol) : 3400, 3:300, 3150 3 1765, 1670,
1610, 1520 cm 1
S NMR (DMS0-d6, ~) : 3.10-3.77 ~4H, m)~ 4.13-4.37
~2H, m), 4.40-4.'77 (2H; m3~ 5.0-5.23 ~lH, m),
5.57 ~1/2H, s), .5.65 rl/2H, s3, 5.53-5.93
(lH~ m), 7~27-7.,B0 (5H~ m), 8.28 (2H, b~oad s)
1~ ~xample 49
The following compounds were ob~ained according to
similar manners to thsse of Examples 27, 47 and 48.
(1) 7-[2-~-Carboxybenzyloxyimino)-2-(5-amino-1,2,4-
lS thiadiazol-3-yl)acetamido]-3-(1,394-thiadiazol-2-
yl)thiomethyl-3-cephem-4-ca~boxylic acid (syn
isomer~, mp lS0 to 155C (dec.).
IR ~Nujol) : 3400, 3290, 3160, 2500, 1770,
172Q, 1615, 1520 cm 1
NMR ~DMS0-d6, ~) : 3.12-3.~8 (ZH, m), 4.08-4.68
(ZHg m~, 5.04 (1/2H, d, J-5Hz), 5.10 (1/2H,
: d, J=SHz) 3 5.6Z ~lH, s)~ 5.S4-5.88 (lH, m),
7.12-7.68 (5H, m), 8.14 (2H~ broad s), 9.52
(1/2H, s), 9.54 (1/2H, s), 9.36-9.72
(lH~ m)
t2) 7-~2-~-Carboxybenzyloxyimino~2-tS-amino 1~2~4-
thiadiazol-3^yl)acetamido~-3-cephem-4-carboxylic
acid (syn isome~), mp 170 to 175C (dec.).
IR (Nujol~ : 3400, 3280, 3160, 2600, 1770,
1720, 1670~ 1625, 1520 cm 1
NMR ~DMS0-d6, ~) : 3.24-3.68 (2H, m~, 5.02
(l/~H, d, J=5Hz), 5.08 (1/2H, d, J=5Hz),
S.64 ~lH, s~, 5.68-5.96 ~1~3 m~,
~7
6.28-6.60 ~lH, m), 7.16-7.64 (5H, m)~ 8.16
(2H, broad s), 9.54 ~1/2Hp d, J=8Hz), 9.62
~1/2H, d, J~8Hz)
(3) 7-[2-CarboxymethoxyiminD-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetami~do] -3-cephem-4-carboxylic
acid (syn isomer), mp 180 to 185C (dec.).
IR ~Nujol) : 3~50, 3250~ 1770, 1720, 1680,
1630~ 1530 ~m 1
NMR (DMS0-d6, ~) : 3.53 (2H, d, J=3Hz), 4~63
(2H, s), 5.07 (lH, d, J=4Hz) 3 .5.85 (lH, dd,
~=4 and 8Hz) 9 6.45 (lH, t~ J=3H~), B.13
~2H~ S)1 9.50 (lH, d~ J=8Hz)
~4) 7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-
~hiadiazol-3-yl)acetamido3-3-[1-{3-(4-methyl-1-
pipera~inyl)propyl}-lH-tetrazol-5-yl]th;omethyl-
3-cephem-4-carboxylic acid tsyn isomer), mp 1~5 to
190C (dec.~.
IR ~Nujol) : 3300~ 1760, 1670, 1600, 1520 cm 1
MMR (~MSO~d~ 1.80-2.10 ~2H9 m), 2.30-2 50
~4Hg m~, 2.60 (3H, s~ 2.8-3.3 [6H, m), 3.60
(2H, broad s), 4.20-4.50 (4H~ m), 4.60 ~2H, s~,
5.10 (lH, d, J=4Hz), 5.83 (lH3 dd~ J=4 and 8Hz~,
~ 8.15 (2H, s), 10.17 (lH, d, J=8Hz)
-
(5) 7- ~2 ~1-Carboxy-2-methylpropoxyimino~-2-~5-amino-
1,2j4-thiadiazol-3-yl~acetamido] -cephalosporanic
acid ~syn isomer~.
IR (Nujol) : 3400-3150, 1770g 1730-1670, 1720,
1620, 1460, 1370~ 1230, 10~0,
730 cm~l
NMR (DMS0-d6, ~) : 0~97 (6H, d, J=7H2)~ 2.03
~3H, s), 1.9-2.3 (lH, m)l 3~6 (2Hr m),
,:.,
2~4
4.27 and 4.35 ~lH, d, J-6Hz), 4.65 and 5.02
~2H, ABq9 Jal3Hz), 5.15 ~lH, d, J=5Hz),
5.7-6.0 (lH, m~, 8.03 (2H, broad s)> 9.42
(lH, d, J=8Hz)
~6~ 7-[2-(1-Carboxypropoxyimino)-2-(5-amino-1,2~4-
thiadiazol-3-yl)acetamido-3-~1,3,4-thiadiazol-2-yl~-
thiomethyl-3-cephem-4-carboxylic acid ~syn isomer),
mp 153 to 158C (dec~)~
IR (Nujol) . 33003 3180, 1770, 1720-1670,
1620a 1520, 1220, 1060 9 1000
900, 730 cm~
NMR ~DMSO-d63 ~) : 0~97 ~3H, tg J-7Hz), 1.83
(2H, m), 3.56 and 3.80 (2H? ABq, J=18H~,
4.25 and 4.55 (2Hg ABq, J=14Hz)~ 4.52
(lH~ t, J=7-Hz~, 5.14 (lH, d, J-5Hz), 5.82
(lH7 dd, J=S and 8Hz~, 8.1 (2H, broad s),
9.46 ~lH, d~ J=8Hz), 9.52 (lH, s)
~0 (7~ 7-~2-(l-(:arboxypropoxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido]cephalosporanic acid
~syn isomer3, mp 115 to 120~C (dec.)O
IR (Nujol) : 34007 33no, 3200g 1770, 1720-1670,
1620, 1520, 1230, 1030-1010~ 890,
~-740-720 cm 1
NMR (DMSO-d6, ~) : 1.07 (3H, t, J-6Hz), 1.8
(2H~ m); 2.00 (3H, s); 3.5 (2H~ m~, 4.63
and 5.02 (2H, ABq~ J-14Hz), 4.5 tlH, m~,
5.14 t2H, d~ J=5Hz), So84 (lH, dd, J-5
and 9Hz3, 8.11 (2H3 broad s~ 9.5 (lH3 m)
(8) 7-~2-(1 Carboxyethoxyimino)-2-~5-amino-172 34-
thiadiazol-3-yl)acetamido~-3-~173,4-thiadiazol-2-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer))
~53
mp 165 to 168C (dec.).
IR (Nujol) : 3400-3200, 1770, 1710, 1670,
1620, 1'i20, 1230, 1170, 1000,
900~ 720 cm~1
N~R (DMSO-d6, ~ 43 (3H, d, J=7Hz), 3.7
(2H, m), 4.23 ancL 4.50 (2H, ABq, J=14Hz),
4.68 ~lH, ~, J=7Hz), 5.15 ~lH, d, J=5Hz),
5.83 (lH, dd, J='; and 8Hz), 8.1 (2H,
broad s), 9.3-9.6 ~lH, m) 9 9.50 (lH, s~
1~
(9) 7-~2-~1-Carboxy-1-methy1ethoxyimino)-2-~5-amino-
1,2>4-thiadiazo1-3-y1~a~etamido]-3-~1,3,4-
thiadiazo1-2-y1)thiomethy1-3-cephem-4-carboxy1ic
acid (syn isom~), mp 164 to 167~C (dec.~.
IR (Nujol) : 3300, 3200, 2800-2300, 1770,
1720-16609 1620, 1520, 1160,
1060, 990, 800 cm~l
NMR (DMSO-d6~ 1.47 (6H, s), 3.53 and 3.87
~2H, ABq, J~20Hz), 4.24 and 4.63 (2H, ABq,
J-14Hz)~ S.17 (lH~ d, J=5H~), 5.83 (lH,
dd, J=S and 8Hz), 8.2 (2H, broad s)5 9-44
tlH, d, J=8Hz), 9.50 ~lH, s)
~lQ) 7-[2-~1-Carboxy-l-cyclopentyloxyimino)-2-~S-amino-
1,2~4-thiadiazol-3-yl)acetamido]-3-(1,3,4-
thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic
acid ~syn isomer), mp 165 to 16gC ~dec.~
IR (Nujol) : 3300, 31B0, 1770, 1720-1660,
1620, 1520 9 12~0 9 1180, 1060,
1000~ 720 cm~l
NMR ~DMSO-d6, ~) : 1.8 (4H) m), 2.1 ~4H9 m),
3.7 (ZH, m) 9 4.30 and 4.68 (2H, ABq, J=13Hz),
.5.20 (lH, d, J-SHz), 5.87 (lH, dd, J=5 and
8Hz)~ 8.3 ~2H~ broad s), 9.48 (~H, d, J-8Hz),
~5
~8
2~;~
9.60 ~lH, s)
(ll) 7-[2-(1-Carboxy-l-methylethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)ac:etamido]-3-cephem-4-
carboxylic acid (syn isomer), mp 215 to 220C
(dec.).
IR ~Nujol) : 3400, 3i'50, 3200, 1770, 1670,
1~20, 1~'90, 1240, llfiO, 1000,
980~ 740 cm 1
NMR ~DMSO d6, ~) : 1057 (6H, s), 3.70 ~2H, m),
5~22 (lH, a, J=5Hz), 5.97 (lH, dd, J=5 and
8Hz), 6.58 (lH, m), 8.25 (2H, broad s),
9.52 ~lH, d, J=8H~)
lS (12) 7-[2-~1-Carboxyethoxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamido~-3-~1-allyl-lH-tetrazàl-
5-yl)thiomethyl~3-cephem-4-carboxylic acid (syn
isomer)~ which is decomposed by 180C~
IR ~Nujol) : 3300, 3150, 1770, 1680, 1610,
15209 1260, 1100, 1040, 1000 cm 1
NMR ~DMSO-d6, ~) : 1.46 (3H9 d, J=8Hz), 3.50
and 3.74 ~2H, ABq, J=18Hz~ 9 4.2 and 4.46
(2H, ABq, J=14Hz), 4.72 (lH, q, J=8Hz),
- 4.98 (2H, m), ~.12 (lH9 d7 J=SHz), 5.2-5.36
z5~ ~2H, m), 5.76-6.1 (3H, m), 8.12 ~2H~ m),
9~48 and 9.56 (lH, d, J=8Hz)
~13) 7-[2-(1-Carboxy-l-cyclopentyloxyimino~-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido~-3-cephem-4-
carboxylic acid (syn isomer), mp 212 ~o 217~C (dec.).
IR (Nujol) : 3300, 3200, 1770, 1670, 1~20,
1520, lZ80, 1240~ 1180, 10009
970~ 730 cm l
NMR (DMSO-d6, ~) : 1.70 (4H, m) 9 2.30 (4H, m~ 9
~ç;~
3 60 (2H, m), 5.10 (lH, d, J=5Hz~ 5.87
~lH, dd, J~5 and 8Hz3, 6.47 (lH, m), 8.20
(2H, m); 9.50 (lH, d, J=8H~)
~14) 7-[2-~1-Carboxyethoxyimino)-2-~5-amino-1,2,4-
thiadiazol-3-yl)acetamicIo]cephalosporanic acid
(syn isomer).
IR ~Nujol) : 3~00, 3200, 1770~ 1710, 1670
15209 12~30, 1040 cm 1
NMR (DMSO-d6, ~) : 1.47 (3H, d, J=8Hz), 2.03
(3H, s3, 3.58 (2H, m), 4.13-5.00 ~lH, m~
4.68 and $.03 ~2H, ABq, J=8Hz~, 5.26 ~lH,
d, J=5Hæ)l 5.87 (lH~ dd, J=5 and 8Hz3,
8.15 ~2H, broad s~, 9.42 and 9O55 (lH9 d9
lS J-8Hz)
(15) 7 [2~ CaTboxy-l-methylethoxyimino)-2-~5-amino-
1~2,4-~hiadiazol-3-yl)acetamido-3- Ll- ~2^aminoethyl)-
lH-tetTazol-5-yl~thiomethyl-3-cephem-4-caTboxylic
acid ~syn isomer~, mp 195 to 200C ~dec.).
IR ~Nujol~ : 3150, 1760, 16709 1620, 15209 --
117Q, 990 cm 1
NMR (DMSO-d6~D~09 ~) : l.S0 (6H, s~ 3.27
(2H9 m), 3.60 ~2H, m), 4.17 (2H, m); 4.57
(2H, m)) 5.10 (lH, d, J~5Hz)) 5.80 (lH, d~
J=~Hz~
. 30
- 2~g
Ex~mple 50
Pivaloyl chloride (66 mg) was added at ambient
~emperature to a stiTred solution of 7-[2-
cyclopentyloxyimino-2-~5-amino-1,2,4-thiadiazol-3-yl~-
acetami~o]-3-hydroxy-ceph~m-4-carboxylic acid (syn
isomer)(ll5 mg) in tetrahydrofu~an (1.5 ml). Sodium
acetate (32 mg) was added thereto ~fter 5 minutes and
it was stirred ~or 10 h.ours at ambient t~mperature.
The ~eaction mixtuTe was evaporated and to the residue
were added ethyl acetate and diluted aquoues solution
of sodiu~ bicarbonate. To the aqueous laye~ was added
ethyl acet~tc and the mixture was adjusted to pH 1 to
2 with hydrochloric acid and extracted. The extract
was ~ashed witn water and an aqueous solution of sodium
chloride, dried over magnesium sulfate and evaporated.
The residue was tri~urated with die~hyl eth0r to give
white powde~ of 7-~2-cyclopentyloxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido~-3-cephem-4-carboxylic
acid Csyn isomer)~70 mg~, mp 170 ~o 175C (dec.).
I~ ~Nujol) : 3520, 3420, 33209 3220, 3150,
177~, 1685, 1655, 1635 9 1625,
1570, 1505 cm 1
NMR (DMSO-d~ 1.33-2.07 (8HJ m), 3.43-3.77
~2H, m), 4.60-4.J3 ~lH, m), 5.15 (lH, d,
J=5Hz)g 5.90 ~lH, dd9 J=5 and 8Hz), 6.43-6.67
~lH, m), 8.23 ~2H9 broad s~, 9.63 ~lH, d,
J=8Hz)
Example 51
The following compounds were obtained acco~ding to
a similar manner to that of Example 50.
(l) 7-[2-(c~-t-Butoxycarbonylbenzyloxyimino)-2 (5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic
acid (syn isomer), mp 90 to 95C (dec.).
IR ~Nujol) : 3400J 3380~ 3230, 1780, 1730,
1685, 1635~ 1530 cm~l
(2) 7-[2-t-Butoxycarbonylmethoxyimino-2-~S-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-cephem~4-carboxylic
acid (syn isomer), mp 16'i to 170C (dec.)~
IR (Nujol) o 3~.50, 32'iO, 3180, 1790, 1720,
1660, 1530~ 1620, 1520 cm 1
(3) 7-~2-~1-M~*hyl-l-t-butoxycarbonylethoxyimino)-2-
(5-amino-1,2 9 4 - thiadiazol-3-yl)acetamido~-3-cephem-
4-carboxylic acid ~syn isomer), which is decomposed
by 215C,
IR (Nujol) : 3400, 3300, 3150, 1780, 1710,
1~90, 1620, 1520, 1240, 11~0,
980 cm~l
(4) 7-~2-~1-t-Butoxrcarbonylethoxyimino)-2-~5-amino-
1,2,4 thiadi~zol-3-yl)acetamido~-3-cephem-4-
carboxylic acid (syn isomer~ which is decomposed
by 250C.
IR (Nujol~ : 3400, 32rO9 3150~ 1770, 1720,
1680, 1610~ 1520, 1290, 1240,
~ 115Q, 980, 7~0 ~ 1
(5) 7-[2-~3~4-Dichlorophenoxyimino)-2-~5-amino-1,2 94-
thiadiazo~-3-yl)acetamido~-3-cephem-4-oarboxylic
acid ~syn isomeT~, which is decomposed by 210C.
IR ~Nujol): 3450, 3300~ 3200 9 1760, 1660~
15~0, 1~90, 1210~ 1~00 3 970,
940, 730 cm~
(6) 7-[2-~2~4-Dichlorophenoxyimillo)-2-~5-amino-1,2,4
2~
thiadiazol-3-yl)acetamido~-3-cephem-4-carboxylic
acid (syn isomer)~ which is decomposed by 240C.
IR (Nujol) : 3250, 1770, 1660, 1620, 1540,
1520, 12~0, 1230, 1100, 1050,
970, 920, 810, 750 cm 1
~7) 7-~Z-{l-(Cyclohexyloxycarbonyl)ethoxyimino~-2-(5-
amino-1,2~4-thiadiazol-3-yl~acetamido~-3-cephem-4-
carboxylic acid (syn isomer), mp 160 to 163~C ~dec.~O
IR (Nujol) : 3420~ 3300, 3180~ 1775y 1720,
1~85, 1~1OJ ~520, 12~0, 1230,
1040, 980, 740 cm 1
(8) 7-[2-~1-t-Butoxycarbonyl-l-cyclopentyloxyimino)-
2- (5 -2mi~0- 1, 2,4-thiad.iazol-3-yl)ac~tamido3-3-
cephem-4-carboxylic acid (syn isomer), mp 165 to
169C (dec.3.
IR (Nujol) : 3400, 3300, 3200~ 1770, 1710,
168~) 1610, 1520, 1290S 1240,
1150S 1000~ g709 740 cm 1
(9) 7- [2 - (ct-Carboxybe}lzyloxyimino) -2- ~5 -amino-l, 2, 4-
thiadiazol-3-yljacetamido3-3-cephem-4-carboxylic
acid (syn isomer)~ mp 170 ~o 175C (dec.).
IR ~Nujol) : 3400, 3280~ 3160, 2600~1770,
1720, 1670, 1625, 1520 cm 1
(10~ 7-~2-Carboxymethoxyimino-2-~5-amino-1,2,4-
thi~diazol-3-yl)acetamido~-3-cephem-4~ca~boxylic
acid (syn isomer), mp 180 to 185~C ~dec.).
IR (Nujol): 3350, 3250, 1770, 1720, 1680
1630, 1530 cm~l
(11~ 7-~2-(1-Carboxy-l-methylethoxyimino)~2-(5-amino-
1,2r4-thiadiazol-3-yl)acetamido]-3-cephem-4-
carboxylic acid ~syn isomer), mp 215 to 220C
(dec.).
IR ~Nujol) : 3400, 32.50, 3200, 1770, 1670,
S 1520, 12!30, 1240, 11~09 1000,
~80; 740 cm '
~17.) 7-~2-(l-Carboxyethoxyimino)-2-(5-amino-192,4-
thiadiazol-3-yl~acetamido]-3-cephem-4-carboxylic
acid ~syn i~omer)~ mp 230 to 235aC (dec.).
In ~Nujol) : 34003 32S0, 3150, 1760, 1720,
1~60, 1610, 1550, 1~90, 1~40,
1170, 970, 740 cm 1
15 (ls) 7-[2-(1-Carboxy-l-cyclopentyloxyimino) 2-(5-
amino-1,294-thiadiazol-3-yl)acetamido]-3-cephem-
4-carboxylic acid ~syn isomer), mp 212 to 217C
(d~c.).
IR ~Nujol) : 3300, 32003 1770, 1670, 16~0,
15Z0, 1280~ 1~40, 11~0, 1000,
970, 730 cm~l
(14) 7-~2-(2-Oxo-3-tetrahydrofuryloxyimino~-2^~5-amino-
132,4-thiadiazol-3-yl)acetamido]-3-cephem-4-
2S carboxylic acid ~syn isome~) 9 mp 175 to 180C
(dec.).
IR ~Nujol) : 33009 3200, 1775~ 1670, 1620
1530 cm~~
30 (15) 7-~2-(1-Benzyloxycarbonylethoxyimino~-2-~5-amino-
l,2J4-thiadiazol-3-yl)acetamido]-3 cephem-4-
carboxylic acid ~syn isomer), mp 177 to 180C ~dec.).
IR (Nujol) : 3400~ 33009 3200, 17709 1730,
lS8~ 3 1610~ 1520~ 1240 9 1160
262
10403 980, 740 cm 1
(16~ 7-[~-(1-Butoxycarbonylethoxyimino)-2-(S-amino-
1,2,4-thiadiazol-3-yl)acetamido~-3-cephem-4-
carboxylic acid tsyn isome~), mp 147 to 151C
(dec.).
IR (Nujol) : 3400 9 3300, 3200 7 1770, 1720,
1~80p 1610, 15~, 1280, ~235,
1155, 1045, 980, 740 cm~l
- 10 (1~ 4-~itr~en~yl 7~2^phen~xy~mi~u-2-~S amino~ ,4-
iadiazol~3-yl~at:~tamido]-3 cephem~4.-c~Tboxyla~e
ts~ isom~) , mp 14û to t 45~C ~d~c. ~ .
I.R. ~Nu~ol): 33009 177~ 1720, 1~80, 1625,
- 1600; ~5~0, lSZ~ cm 1
~18) 4-Ni~oben~yl 7- ~Z~ ~4-fluoropherloxylmi~o) ~2-
- ~S~a~ino-1, 2, 4~th$adia2O1-3-yl~ c~tamid4~ -3-cephem-
4-car~oxylate ~ L isome~) ~ m~ 135 tQ ~40~ (dec.) .
r~,R~ (Nu~ol~: ~300, 3200, 17~0~. 17~0~ 1680
1625, 16û5 ~ 1500 ~ 14~5 cm~
Z (19) 4-Nitrobe~yl. 7- ~2- ~4-chlo~Gp~e~oxyimino) -2
a~no~ 4-~hiadiazol-3~y~ ~ ac~amidoJ -3 c~ph~m-4
car~oxyla~e (5~ isomer3 9 m~J 155 to 160C ~dec.~ .
I.R. CNu~ 330Q7 ;180, 1770~ 17209 lÇ80,
16~ 00 " lS~û, 15~0 ~ 1480 c~ 1
(2~) 4-Nitro~nzyl 7- E2O ~3-~rifluorome~hyl-
phe~oxyimino) o 2 - ~ S ~ o-1, 2 7 4 '' t~ia~iazol-3-yl)
a etam~do~-3-c ph~m~4~czLrboxylate ~~sy~ isomer~
~p 136 ~ ~4Q~ c.~. .
I .R., ~Nu~ ol) : ~370 9 i20Q, 7 780 9 1730, ~-
~690a 168l~ 16303 1610, 1520,
1450~ 1~25, 12~0 3 1160" 1125
975, 850~ 74~ ~m-
:,
~63
~ ) 7 - ~ 2 - ~3 - Trif luoromethylphe:cloxyimi:l:Lo ) ^ 2 - ( 5 -
- amino-1~7 ,4-~hiadla~ol-3-yl ~ acetamido] -3~c~phem~
4-car~o~lic ac~d ~Syll isomer~ 9 which i5 decompose~
by 193 C .
I~R. (Nujol) ~ 3450, 3320, 3200, 1770~ 17109
1565 ~, 1630 ~ 1560, 1515 1 13Z5,
1170, 1110, 94G cm 1
7- [2-P:h~noxyimi~o-2- ~S-a:mino-1~2,4- I:hiadia
3-yl)acetam~do~-3~cephem-4-carboxylic cid ~5yIl
is~mer), mp 16B ~o 170~t. ~d~c. 3 .
I,,R. (Nujol3: 3400,, 3200, 178~, .1660,,
- - -. 1~20 ~ 1~00, 159~ 3 1~4~
(~ 2-(4~Ch~orophe~oxyimi~o)-~ ~S-ami~o-l,Z~4-
~hiadiazol-3-yl~ace, ~ do~ cephem~4-earboxylic.
acia (sy~ isomer~3,mp 14!; i:o 150~C (d~rl.~. .
I.R~ ~NU3O1~: 3400,. 3260~ 3180, 1775, 1675, :
16~5 j 1600, 1520, 1480 cm 1
(2 ~ 7 ~ ~2 ~ ~4Fluorophe~oxyimillo) - 2~ am:~o -l ~ ~ 9 4
thiadiazol^3~yl) acetami~o~ -~ocephem-4-carboxyl~c:
~ cid (Syil. ;somer~, mp 13û ~ 13~C ~de~").
I.R. -~Nujol): 34Q0~ 3270, 3180~. 1765" 1675,
- ~605~ ~.50~
( 25~ 4-Ni~robenzyl 7- ~Z~allylsxyimino Z ~5~ o-
1 ) 2 ,4-thiadizzol --3-yl) acetamido~ - 3~ceph~m-4-
~5 car~oxylate (~y~ isomer), mp 1~5 to 130qC ~dec.).
- I~R~ ~Nujol~: 33ûO~ ;L770~ 1720, 1~80~ 16309
1610, 1520 cm~~
~2~ ~ 7 ~ Allyloxyîmi~o - ~ - ( 5 - ami~o - 1, 2 3 4~hiadiaz o l o
3~yl) acet:~id~ -3-cephem-4-carboxylic acid ~sy~
isomer) ~ mp 160 ~o 165C ~d~c.~ r
3~
:~8~
- t2~? 7- ~- (2~yclopenten-1-yl~oxy~i~:Lo-2- (5- -
ami~o~ adia~ol-3-yl3 ace~amido~ cephem-4- - -
carboxylic acid ~Sy;l isomer) . mp 180 ~o 18-5C
(d~
I .R. tNU; ol) : 3500 9 3430 ~ 3~00, 3200, 1770, 16~0
1~60~ ~640, 162û, 1580, 1510 cm 1
t28~ 7- ~2-C~clope:~Ltyloxyimi~o--2- ~5~amino-1,2 ,4-thiadia~ol-
3-yl) acetamido] ~3-c~phem~4-carboxylic acid ~Sy
isomer~ 170 1:~ 1 75C.
lD IoR~ (Nu~ 3520 " 3420 ~ 3320 9 3220, 3160 9177'0 "
1585 D 1655 ~ 1635 9- 1625 ~ 1570
l~iO!i a~
9~ 7- ~ 2~y lohexell-1-yl)oxyimi~lo-2- (~-amino- -
19 2, 4~thiadiazol- 3 -yl~ ace~amido~ -3 ~cephem- 4-
1~ carboxylic cid tsy~ isom~r). mp 17S to 18ûC (dec.~O
I.R., ~Nujol) : 3300 j 3200" 1770, 1670, 16;0,
~ i 2 0 ~
(30 ) 7~ {2-cyclohep ~yloxyimino-2- ~5~ o-19 2, 4-
thiaaia~ol-3-yl) ace~amido~ -3-cephem-4-ca~boxyllc
acid ~sy~ isomer). whi~ powder~ mp 17D to 1-75C
- (dec. ) "
l.R. (Nujol~: 34009 3;009 3200" 1770, 1670,
16~0, 15~0, 12~) 1240, ~160,
1000, 98~ ~ 730 n 1
~5
,.~
6~
Exam~le 52
The ~ollowing compounds were obtained according
to a sim~lar manner to that of Example 30.
(l~ l-Acetoxyethyl 7-[2-cyclopentyloxyimino-2-(5-
amino 1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-
3-cephem-4-carboxylate (syn isomer).
IR ~Nujol) : 3400, 3310,~ 31S0, 17~0, 1750,
1675 cm l
NMR ~DMSO-d6, ~ : l.Z-1.6 ~6H3 m) 3 1.5~2.1
(8H, m3, 2.07 (3H, s), 3.6-4,1 (lH9 m),
4.6-5.0 (lH, m), 5.17 (lH, d, J=4.5Hz),
5O95 (lH~ dd, J=4.5 and 8Hz), 6.67 (lH,
d, J=6Hz), 6.90 (lH, q, J=5~z), 8.12
(2H9 broad s), 9.45 (lH~ d, J=8Hz)
(2~ l-Isobu~yryloxyethyl 7-~2-cyclopentyloxyimino-2-
~5-amino-1,294-thiadiazol-3-yl)acetamido]-2-
methyl-3-cephem-4-carboxylate (syn isomer),
morphous powder.
IR ~Nujol) : 3400, 3300~ 3170, 1780, 1745,
1675, 1620, 1525 cm ~
NMR (DMSO-d6, ~) : 1.08 (6H, d, J=7Hz~,
1.2-2.2 ~14H, m), 2.2-2.9 ~lH, m),
Z5 3,88 (lH, q, J=7Hz), 4.6-5.0 (1~, m),
5.12 (lH9 d9 J=4.5Hz)9 5.9~
(lH, dd, J=4.5 and 8Hz), 6.63 (lH~ d,
J=7H~), 8.06 (2H~ broad s~9 9.43 (lH,
d, J-8Hæ)
~0
(3) l-Acetoxypropyl 7-~2-~2-cyclopenten-l-yloxyimino)-
Z-(5-amino-1,2t4~thiadiazol-3-yl)aoetamido]-2-
methyl-3-cephem-4-carboxylate (syn isomer)9 mp
110 to 128C (dec.).
IR ~Nujol) : 3400, 3280~ 3150, 1780, 1750,
1730, 16?0 cm 1
NMR (DMS0-d6+D20, ~) : 0.92 (3~, t, J=7.5H~),
1.42 (3H, d, J=7Hz~, 1.8-2.5 ~4H, m)~
1.5-2.3 ~2H, m)> 2.05 ~3H> s), 3.6-4.1
(lH, m), 5.10 (lH, d, J=4.5Hz), 5.1-5.5
~lH, m), 5.7-6.3 (3H, m), 6.4-6.9 (2H~ m)
~4) 1-~2-Azidoe~hoxycarbonyloxy3~hyl 7-[2-(2~
cyclopent~n-1-yloxyimino)-2-~5-amino-1,2~4-
~hiadiazol-3-yl)ace~amido~-2-methyl-3-cephem-
4-carboxyla~e (syn isomer), mp 85 ~o lOO~C ~dec.)~.
IR ~Nujol~ : 3310, 2200,L760-1785, 1680 cm 1
NMR ~DMS0-d6~D20, ~) : 1.48 ~3H7 d, J=6Hz~,
lS 1.5 (3H, d~ J=4.5Hz), 2.0-2.5 ~4H9 m),
3.5-4.1 (lH, m), 3.63 (2H, t, J-4Hz),
4.30 ~2H9 t, J=4Hz), 5.16 ~lH, d, J=4.5Hz),
5.2-5.45 ~lH, m), 5.7-6.2 ~2H9 m), 6-6.2
(IH, m), 6.6-6.8 ~lH, m3, 6.7 ~lH~ d,-J=6Hz~
2~
~5) l-~thoxyca~bonyloxyethyl 7-~2-(2-cyclopent~n-1-
yloxyimino)-2-(S-amino-172,4-thiadiazol-3-yl~-
acetamido3-2-methyl-3-cephem-4-carboxylate ~syn
isomer).
IR (Nujol) : 3420 9 3300 9 3150 3 L780, 1760
1675, 1620 cm
NMR (DMSO-d6~DzO~ 1.23 ~3H, t9 3=8~z),
1.42 (3H, d~ J=7Hz), 1088 (3Hg d, J=5Hz),
i 1.8-2.5 ~4H, m), 3.6-4.1 ~lH~ m),
4.19 ~2H, q, J~8Hz), 5.18 (lH, d, J=5H7.)9
5.2-5.6 (lH, m), 5.9-6.3 (2H, m), 5.95
~:LH, d, J=5Hz), 6.8 ~lH, d3 J=7H~),
6~83 (lH, q9 J=5Hz)
~6) Pivaloyloxymethyl 7-~2-{3-~N-t-bu~oxycarbonylamino)-
propoxyimino}-2-(5-amino-192,4-~hiadia701-3-yl)-
acetamido~-2-methyl-3-cephem-4-carboxylate (syn
isome~), powder9 mp 66 to 75C (dec.).
IR tNujol) : 3300, 1780, 1745 r 1680 ~ 1620 cm 1
(7~ Pivaloyloxymethyl 7-[2-~3-~N-t-butoxycarbonyl-
amino)propoxyimino}-2-t5-amino~ ,4-thiadiazol-
3-yl)acetamido]-3-~1-methyl-lH-tetrazol-5-yl)-
thiomethyl-3-cephem-4-carboxylate (syn isomer)~
powder.
IR (Nujol) : 3300, 1780, 1745, 1680, 1620 cm 1
(8) Pi~aloyloxymethyl 7- ~- {3-(N-t-butoxycarbonyl-
~mino)propoxyimino}-2-(5-amino-lj2,4-thiadiazol-
3-yl~acetamido~-3-(S-methyl-lJ3~4-thiadiazol-2-
yl)thiomethyl-3-cephem-4-carboxylate ~syn isomer~.
IR ~Nujol) : 3300, 3150, 1783, 1745, 1675,
1615 cm 1
NM~ ~DMS0-d6~D20, ~) : 1.15 ~9Hs s~, 1.37
(9H, s~ 7 1.5-2.0 ~2H, m), 2.65 (3H, s) 9
2.8-3.2 (2H~ m), 3.5-3.8 ~2H~ m), 3.9-4.3
(2H, m), 4.16 and 4.S3 t2H3 ABq, J=13Hz),
5.17 (lH, d, J=4.5Hz~, 5.6-6.0 ~3H~ m)
(9) Piv~loyloxymethyl 7-~2-~3-(N-t-butoxyca~bonyl.
amino)propoxyimino}-~-~S-amino-1,~j4-~hiadiazol-
3-yl)acetamido]-3-[1-t2-hydroxyethy~-lH-*etrazol-
5-yl]thiomethyl-3-cephem-4-carboxylate ~syn isomer),
powder, mp 88 to 101C (dec.).
IR (Nujol~ 3300, 1780, 1750, 1675~ 1620 cm~
-- --
~10) PivaloyloxyDIethyl-7-[2-{3-(N-t-butoxycarbonyl-
amino)propoxyimino}-2-(5-amino-1~2,4-thiadiazol-
3-yl)acetamido~-3-~1,3,4-thiadiazol-2-yl)-
~hiomethyl-3-rephem-4-carboxylate (syn isomer),
powder, mp 71 to 84C (dec.~.
IR (Nujol)' 3300, 1780, 1745, 1680, 1615 cm~l
(11) PivalGyloxymethyl 7-[2-(2-cyclohexen-1-yloxyimino)-
2-(5-amino-1~2,4-thiadîazol-3-yl)acstamido]-
cephalosporana~e ~syn isomer~9 mp 9~ to 101C
~dec.).
IR ~Nujol) : 3400, 3300, 3180, 1780, 1740,
1675, 1615, 1525 cm 1
NMR ~DMSO-d6~20, ~ 13 (9H~ s) 7 1-4-2-2
(6H, m), 2,02 (3H~ s~, 3.58 (2H, s)~
4 5~-4t93 tlHJ m), 4u68 and 4.90 ~2H,
ABq~ J~13.5Hz~ 5.18 ~lH, d, J=4.5Hz),
5.6 6.2 ~5H, m~
Z)~ht~alid-3-yl ester of 7-~2-~2-cyclopenten-1-
yloxyimino)-2-~5-amlno-1,2,4-~hiadiazol-3-yl)-
acetamido~-2-methyl-3-cephem-4-carboxylic acid
(syn isomer), mp 131 to 144C (dec.)~ -
IR (Nujol) : 3420, 3210, 3150, 1780, 1740,
1675~ 1620, 1525 cm~l
NMR ~M~-d6~D~b, ~) : 1.45 (3H, d, J=7Hz),.
l.g-2.5 ~4HJ m), 5.13 (lH~ d9 J~4.5Hz),
5D2-5~5 (lH, m), 5.7-6.3 ~3H~ m~9 6.75
(1/2H, d~ J=6Hz), 6.77 (1~2H, d, J=6Hz),
7.6Z (1/2H, s~, 7.65 (1/2H, s)9 7.83
(4H, broad s)
(13) Pivaloyloxymethyl 7-[2-(2-cyclopenten-1-
--
2~9
yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)-
acetamido]-Z-methyl-3-cephem-4-carboxylate (syn
isomer~, mp lll to 124C (dec.).
IR ~Nujol) : 3400, 3300, 32703 1775, 1740,
S 1670, 1620, 1520 cm 1
NMR ~DMSO-d6+D2O, ~) : 1.17 ~9H, s), 1.45
~3H3 d, J=7Hz), 1.9-2.4 ~4H, m~, 3.7-4.0
(lH~ m), 5;1-5.$ (lH, m~, 5.13 (lH, d,
J-4.5Hz)~ 5.7-6.3 (5H, m~, 6~65 (lH, d9
J=7H~)
(14~ l-Ben~oyloxyethyl 7-~2-(2-cyclopenten-l-
yloxyimino)-2 (5-amino-1,2,4-~hiadiazol-3-yl)-
acetamido]-2-methyl-~-cephem-4-carboxylate tsyn
isomeT)~ mp 132 to 137C (dec.).
IR (Nujol) : 3400, 3300, 3160, 1780, 1738,
1680; 1620 cm 1
NMR (DMSO-d6~D2O, ~) : 1.43 (3H, d, J=7Hz),
1.62 (3H, d, J=5Hz), 1.7-2~4 (4H, m) 9
3. 84 ~lH9 qJ J=7Hz), 5-0-5-4
~lH, m~, 5.l3 (lH, ~, J=4.5Hz), 5.6-6.3
(3H, m), 6.70 (lH, d, J-6Hz),
7 ~6 ~1~, q, J=5Hz), 7.3-8.2 (5H, m)
(15) Pivaloyloxymethyl 7-~2-{4-(N-t-butoxycarbonyl-
ami~o)methylbenzyloxyimino}-2-(S-amino-1,2,4-
thiadiazol-3-yl)acetamido]-3-m~thyl-3-cephem-
4-carboxylate (syn isomer), powder.
IR ~Nujol~ : 3300, 1780, 1750, 1680 cm l
(16~ Pivaloyloxymethyl 7-~2-allyloxyimino-2-(5 amino-
1,2,4-thiadiazol-3-yl)acetamido3-3-[1-~2-(N-t-
butoxycarbonylamino)e*hyl}-lH-tetrazol-S-yl]-
thiomethyl-3-cephem-4-carboxylate (syn isomer3,
3S
.
~7~
powder .
IR ~Nujol): 3300, 1780~ 1750, 1680 cm 1
ZO
~7~
Example 53
A solution of 2-~1-amino-l-cyclohexyl)ace~yl
chloride hydro~hloride (127.2 mg) in methylene chloride
(2 ml) was dropwise added oveT 5 minutes to a stirred
solution o 7-[2-(3-amino-propoxyimino)-2-(5-amino-
1,~,4-~hiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-
car~oxylic acid ~syn isomer)(132 mg) and bis(trimethyl-
silyl)acetamide (0~6 ml) in imethylene chloride (6 ml)
at -30C and then the mix~re was stirred for 30 minutes
at -30 to -35C. The stirring was continued after
addition o a saturat~d aqueous solution of sodium
bicarbonate and the reaction mixture was post-tIeated
in a conventional manner to give 7-[2-~3-(N-(2~
amino-l-cyclohexyl)acetyl)amino)propoxyimino}-2-(5-
amino~ 94-thiadiazol-3-yl)acetamido]-2-~ethyl-3-
cephem-4-carboxylic acid (syn isomer)~85 mg), mp 198 -
2249C (dec.).
IR (Nujol) : 325Q9 3150, 1760, 1640, 1580,
1520 cm
ZO NMR (D20~DCl, ~) : 1.0-2.2 (15H, m), 2.65 (2H, s)~
3.1-3.6 ~2H, m) J 3.6-4.1 (lH9 m), 4.1-4.6
(2H, m), 5.0-5.3 (lH, m), 5.95 (lH, d~
J=4.5Hz), 6.82 (lH, d, J--6Hz)
Exa~ple 54
The following compounds we~e obtained according
to a similar manner ~o that of Example 53.
~1) 7-[2-~2-(N-~N-t-Butoxycarbonyl)-D-phenylglycylamino)-
ethoxyimino~2-(5-amino-1j2,4-thiadia~ol-3-yl)-
acetamido]-2-methyl-3-cephem-4-carboxylic acid
~syn isome~), mp 77 to 91~C (dec.).
IR ~Nujol~ o 3300, 3160, 1775, 1680, 1660,
1630, 15?5 cm 1
~72
NMR ~DMS0-d6, ~) : 1.37 (9H, s), 1.40 (3H, d,
J=8Hz), 3.1-4.2 (5H, m), 5.08 (lH, dg
J-4.5Hz), S.10 ~lH, d, J=8Hz), 5.90 (lH3
dd9 J-4~5 and 9Hz,l, 6.53 (lH, d, J=7.SHz),
7.32 ~5H, s), 8.1~5 (2H, broad s), 9.48
(lH, d, J-~Hz)
~2) 7-[2-{3-~N ~N-t-B~toxycarbonyl)-D-phenylglycyl-
amino)propoxyimino}-2-~ amino-1~2,4-thiadiazol-
3-yl)ace~amidoJ-2-methyl-3-cephem-4-carboxylic
acid ~syn isomer).
IR ~Nujol) : 3300, 3200, 17757 1700, 1650,
1525 cm~l
NMR ~DMSO-d6~D20, ~) : 1.3-1.6 ~12H, m), 1.5-2.0
(2H, m), 2.8-3.4 ~2H~ m), 3.82 (lH, q,
J-7.5Hz), 3.9-4.3 (ZH, m), 5.05 (lH, d,
J=4.5Hz), 5.83 (lH, d, J=4,5Hz), 6.48
(lH, d~ J=6Hz)
2~
;2~Ç~
~73
Preparation 23
Potassi~m iodate (20.0 g) was added at ambient
temperature to ~ stirred solution of iodine (7.7 g) in
conc. sulfuric acid (70 ml), and the mixture was stirred
for 1.5 hours at 35 to 40C. Acetic anhyd~ide (30 ml)
was added the~eto under lO~C over 0.5 hour and then
1,2-dichlorobenzene (44.69 g} was added thereto under
10C over 0.5 houT. The m xture was stirred for 1 hour
a~ the same temperature and then ~tirre~ ~or 19 hour~ at
ambient ~emperature. The reaction mixture was poured
into ice-water (500 ml) and washed with diethyl ethe~. To
th~ aqueous layer was added an aqueous solu~ion (50 ml)
of sodium chlo~ide t8.9 g) and precipitates were collected
by filt~ation and washed with ice-water to give 3,4,3',4'-
~etrachlorodiphenyliodonium chloride (58 g~ mp 183 to
186C (dec.~.
IR ~Nujol) : 1555, 1450, 1250, 1210, 1170,
1125, 1030 cm~
The ollowing compounds were obtained according to
a similar manner to that of Preparation 23.
(1) 3~3'-Di(trifluoromethyl)diphenyliodonium chloride.
IR (Nujol~ : 3600-3200, 1600, 1420, 1320, 1310,
1~90, 1170, 1120, 1095, 1085, 1055,
800, 700) 685 cm~l
~23 3,3 7 -DiccLTboxydiphenyliodonium bromide
IR ~Nujol) : 3400 9 1700, 1290, 1250, 1210 9
1170, 10509 750 cm 1
(3) 3, 3 ' -D:L tethoxycarbonyl)diphenyliodonium bromide,
~p 154 to ~S7C.
- -
~74
IR (Nujol) : 1730, 1295, 1280, 1255, 1110,
1020, 750 cm 1
Pl~eparation 25
The follo~ing compounds were obtained according
to similar manners to those of Prepa~ations 1-(1) and
1-(2)-
(1) N-(3-Phthalimidopropoxy~phthalimide 3 mp 168 to 170C.
IR (Nujol) : 1790, 1770, 1730~ 1710~ 139a,
1060, 725~ 705 cm 1
(2~ N-(l-Cyc~ohexyloxycarbonylethoxy)phthalimide 3 mp
50 to 54~.
NMR (d6-DMSO, ~ : 1.51 ~3H9 d, J=7Hz~, 0.9-2.1
(lOH~ m); 4.7 (lHI m), 4.8Z (lH, q, J=7Hz~,
7.87 (4~, 5)
~3~ N-~-t-Bu~oxycarbonylbenzyloxy)phthalimide.
(4) N~ t-Bu*oxycarbonyl-2-methylpropoxy~phthalimide,
mp 84 to 87C.
IR (Nujol) : 1790, 1730~ 1360, 11609 1140,
1000, 880, 780, 700 ~m 1
~5
~S) N-~l-t-Butoxyc~rbonylpropoxy)pht}lalimide, mp 49 *o
~2C.
NMR (d6-~MSO~ 1.02 (3H, t~ J=7Hz), 1.40
(9H, s), 1.9 (2H, m)~ 4.55 (lH, t, J=6Hz~,
7.82 (4H, s)
~6) N-(l-t-Bu~oxyca~bonylethoxy)phthalimide, mp 80 to
~2C.
NMR ~d~-DMS3, ~) : 1042 (9H, s),
6~
1.48 ~3H, d9 J=7Hz), 4.72 (lH, q, J-7Hz),
7,86 ~4H, s)
(7) N-(l-t-Butoxycarbollyl-l-methylethoxy)phthalimide,
mp 96 ~o 100C.
MMR (d6-DMSO, ~) : 1.42 (9H~ s~, 1.48 (6H, s),
7.87 (4H, s)
(8) N-(l-Butoxycarbonyle~h~xy)phthalimide, mp 48 to
53C.
IR (Nujol) : 1755, 1720, 1210~ 1140, 1110,
1080~ 8753 695 cm~l
~9~ N-(l-Benzyloxycarbonylethoxy)phthalimide, mp 65
~5 to 68C.
IR (Nujol) : 1790~ 1740, 1450, 1210, 1190,
1110, 1080, 980, 8~0~ 735, 70a ~m~
(10~ N-(2-Oxo-3-te~rahydrofuryloxy)ph~halimide, mp 140
to 1~29Co
IR (Nujol) : 17B5, 1760, 1720, 1605~ 1215,
1185, 870, 695 cm~
Preparation 26
The following compounds were obtained according .
to a similar manner to that of Prepara~ion 2.
(1~ 3-Aminopropoxyamine dihydrochloride
NMR (D20, ~) : 2.20 ~2H~ m), 3.27 ~2H~ t,
J=7Hz), 4.33 (2H, t, J=6Hz)
~2) l-Phenylethoxyamine
~3) 1-t-Butoxycarbonyl-2-methylpropoxyamine
-- ` --
2 7 ~
t4) ~-t-Butoxycarbonylbenzylt)xyamine
(5) l-Bu~oxycarbonylethoxyam:ine
Preparation 27
The following comiounds were obtained according
to a similar manner to that of Preparat;on 17.
.
(1) 2-(t-Butoxycarbonylmethoxyimino)-2-t5-amino-1,2,4-
thiadiazol-3-yl.~acetic acid ~syn isome~) 3 mp 150
to 155C ~dec.).
IR (Nujol) : 3420~ 3230~ 3100, 17253 1610~ -
1530 cm 1
N~IR ~DMS0-d6, ~3 : 1.45 (9H, s~, 4.70 ~2H, s),
8.12 ~2H, broad s)
(2) 2-(1-Cyclohexyloxycarbonylethoxyimino)-2-~5-amino-
1J2~4-thiadiazol-3-yl)acetic acid ~syn isomer),
mp 175 to 180C (dec.)~
IR (Nujol) : 338Q, 32609 3170, 1720, 1610,
1520, 1220, 990, 710 cm 1
MMR ~d6-DM50, ~ : 0.9-2.1 ~13H, m), 4.7 ~lH, m),
~.85 ~lH, q, J~6Hz), 8.13 (2H, broad s)
~3~ 2-~Thiolan-l,l-dioxide-3-yloxyimino)~2-(5-amino-
192,4-thiadiazol-3-yl)acetic aci* (syn isomer),
mp 200 to 205C ~dec.).
IR (Nujol) : 3300, 1720, 1620, 1530 cm 1
NMR ~d6-DMSO, ~) : 2.20-2.50 (2H, m), 3.00-3.50
~4H, m), 5,00-5.27 (~H~ m~, 8.20 (2H, s3
~4) 2-~-t-~utoxycarbonylbenzyloxyimino)-2-~5-amino-
1,2~4-thiadiazol-3-yl~acetic acid (syn isomer),
mp 155 to 160C ~dec.).
-- ^
I~ (Nujol) : 3440, 3350, 3250, 1750~ 1730,
1640, 1535 cm l
NMR (d6-DMSO, ~) : 1.37 ~9H7 5) ~ 5~67 ~lH, s),
7.45 (5H, s), B.25 ~2H, broad s)
~5) 2~ t-Butoxyca~bonyl-2-methylpropoxyimino)-2-~5-
amino-1~2,4-thiadiazol-3-yl)acetic acid ~syn isomer),
mp 158 to 152C (d~c.).
IR ~Nujol) : 3600, 3400, 1~4n9 1720, 1630 cm l
MMR ~d6-DMS0, ~) : 0.95 (6H, d9 Je7Hz), 1~8-2~4
(lH9 m), 4.33 ~lH, d9 J=6Hæ)g 8.13 (2H,
broad s)
(6) 2-~1-t-Butoxycarbonylpropoxyimino)-2-(5-amlno-
1,2,4-thiadia7O1-3-yl)acetîc acid (syn isomer), mp
152 to 155C (dec.).
MMR ~d~-~MSO~ 0.34 (3H, t, J-7Hz), 1.42
(9H~ ~9 1.80 (2H9 m) 9 4.Sl (lH, t, J=6Hz),
8.16 (2H, braad s)
~0
(7) 2-(1-t-Bu*oxycarbonylethoxyimino)-~-(5-amino-1,2~4-
thiadiazol-3-yl)acetic acid ~syn isomer3, mp 155 to
156~C (dec.).
IR ~Nujol) : 3400, 3300, 3200, 1720, 171Q,
1620, 1520 cm 1
NhiR ~d6-DM~O, ~ : 1. 2-lo 7 ~ 2H~ m) ~ 4 ~ 7?
~lH, q9 J~7Hz), 8.2 (2H, broad s)
(33 2-(1-t-Butoxycarbonyl-l-methylethoxyimino)-2-~5-
amino-1,2,4-thiadiazol-3-yl3acetic acid ~syn isomer),
~p 180 to 181C (dec.).
IR (Nujol) : 3400~ 3300, 3200, 1745, 1715,
16303 1530 cm~l
N~R (d6-DMS0~ ~3 : 1.38 (9H, s), 1.43 (6H~ s3,
4~;~
~8
8.15 ~2H, broad s)
~9) 2-(1-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetic acid (syn isomer), mp 120
~o 123C (dec.).
IR (Nujol) : 3400, 3300, 3200, 1725, 1615,
1510) 1410~ 1210, 1170, 1135,
11-009 1040, 330, B70, 720 cm 1
NMR ~DMSO-d6, ~) : 0.85 ~3H, t, J=6Hz), 1.43
(3H, d, J-7Hz), 1.0-1.7 ~4H, m), 4.12
~2H, t, J=6Hz)g 4.85 (lHI q; ~=7Hz)~
8.04 ~2H, broad ~)
~10) 2-(1-Benzyloxycarbonylethoxyimino)-2-~5-amino-
1,2,4-thiadiazol-3-yl)acetic acid ~syn isomer),
mp 129 to 133C tdec ).
IR ~Nujol) : 3300~ 3200, 17209 16209 1530 cm 1
NMR (DMSO-d~, ~) : 1.45 (3H, d, J=6Hz), 4.97
(lH, ~, J=6Hz), 5.18 (2H, s), 7.~1 (5H, s)~
8.17 t2H, broad s3
The following compounds were o`btained according
to a similar manner to that of Preparation 15.
~5
~1) 2-(Thiolan-l,l-dioxide-3-yloxyimino)-2-(5-
ormamido-1,2,4-thiadia~ol-3-yl)acetic acid (syn
isomer)~ mp ~14C ~dec.)~
IR ~Nujol) : 3200, 172Q, 1680, 1600, 1530 cm 1
NMR ~DMSO-d6, ~) : 2.30 2.S0 (2H, m3 9 2.90-3.83
(4H, m), 5.10-5.50 (lH, m)~ 8.92 tlH~ s)
(2) 2~ Phenylethoxyimino)-2-~5-formamido-1,2~4-
thiadi~zol-3-yl)acetic acid (syn isomer3, mp 1745
279
to 175C (dec.).
IR (Nujol) : 3100, 1720, 1690, 1550 cm 1
NMR (d6-DMSO, ~) : 1.58 (3H, d, J=6Hz),
5.44 (lH) q, J=6Hz), 7.32 (5H, m),
8.78 (lH, m), 13.34 (lH, broad s)
Preparation 29
To the aqueous solution containing sodium 2-(3-
aminopropoxyimino)-2-t5-form~mido-1,2,4-~hiadia~ol-3-
10 yl) aceta~e (syn isorner), which was pTepared by a similarmanne~ to that of Preparation 15, were added triethylamine
~20 g) and a solution of 2-~-butoxycarbonyloxyimino-2-
phenylacetorli~ril~ (27 g) in dioxane ~270 ml) and ~he
mixture was stirred at ambient temperature for 2 hours.
15 After evaporation of dioxane, the aqueous solution ~.~as
adjusted to pH 6 with 10% hyd~ochloric acid and washed
with ethyl ace~ate. To the aqueo~s layer was added
ethyl acetate and the mixture was adjusted to pH 3 with
10% hydrochloric acid. The o~ganic layer was washed with
~rine, dried over magnesium sulfate and ev~porated to
dryness. The ~esidue was ~riturated with diisopropyl
ether to give 2-[3-(N-t-butoxycarbonylamino)propoxyimino]-
2-(5-formamids 132,4-thiadiazol-3-yl)acetie acid ~syn
isomer)~l4.2 g), mp 115-117C (dec.~
IR (Nujol~ : 3320, 3150l 17409 16~09 1560-1530,
14~0, 12307 1143, 1040, 1030, 890 cm 1
NMR (DMSO-d69 ~) : 1.47 (9H, s), 1.97 (2H, m),
3.10 t2Hg t, J=7Hz), 4.30 (2Hg t9 J~7Hz),
8.80 (lH, s)
~L^r~ ~0
The following compounds were obtained ascording to
simil~r manners to those of Preparations 13 and 29.
~l) 2-~2-(N-t-Butoxycarbonylamino)ethoxyimino]-2-
~5-~ormamido-1,294-thiadiazol-3-yl)aretic acid
(syn isomer)~ mp 139 to 154C (dec.).
IR (Nujol) : 3400 9 3:L50, 1748, 1700, 1690,
1540 cm 1
NMR ~DMSO-d6+D20, ~) : 1.45 (~H, s) J 3-40
(2H, t, J=6Hz), 4.32 (2Hg t, J=6Hz),
8.07 (lH~ s~
~2~ 2-[4-~N-t-Butoxycarbony:Laminomethyl~benzyloxyimino-
2;~5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn
isomer)~
IR ~Nujol) : 3300, 31509 1700 cm 1
NMR (DMSO-d6, ~) : 1.65 (9H, s), 4~12 (2H, d,
J=5.5Hz) 9 5.19 (2H, s), 7.21 (4H, s)
Th~ following compounds were obtained according to
a s;milar manner to *hat of Prep~ration 4.
(1) 2-[2-~N-t-Butoxycarbonylamin~)ethoxyimi~o]-2-~5-
amino-1,2,4-thiadiazol-3-rl)acetic acid (syn isomer),
mp 172-177C tdec.).
IR ~Nujol) : 3300, 3140, 1738~ 16S0, 1628,
15g5, 1550, 1527, 1285, 1245,
1165, 1120 cm l
NMR ~VMSO-d6~D~0, ~) : 1.42 (9H, 5)9 3.35 t2H~ t~
J-6Hz), 4.22 (2H~ t, J=6Hz)
3Q ~2) 2-[3-(N-t-Butoxycarbonylamino)propoxyimino3-2-~5-
amino-1,2,4-thiadiazol-3-yl)acetic acid (syn
isomer).
IR (Nujol) : 3300, 3150, 2600-2400, 1720-1S60,
16?.0~ lS30~ 1250~ 11609 1030, 720 cm
2~
NMR ~DMS0-d6, ~) : 1.33 (9H, s), l.B2 ~2H, m),
3.03 ~2H, m), 4.17 ~2H, ~, J-6Hz), 6.73
(lH, broad s), 8.13 (2H, broad s)
S (3~ 2-~4-Chlorophenoxyimi~o)-2-~5-amino-1,294-
thiadiazol-3-yl)acetic acid (syn isomer) 9 mp 150-
155C (dec.).
IR ~Nujnl) : 3300, 3200~ 1710, 1640, 1580,
1530 cm~l
NMR ~DMSO-d6, ~ : 7.37 (2H, d, J=9Hz)~ 7.67
(2H, d7 J=9Hz), 8~50 ~2H, bro~d s~
~4) 2-~4-Fluorophenoxyimino)-2-~5-amino-1 J 2,4-thiadia~ol-
3-yl)acetic acid (syn isome~), mp 140-145C (dec.).
IR ~Nujol) : 3450, 3300, 3200, 1730, 1630,
1530, 150Q cm~l
NMR ~DMS0-d~ 7.17 (2H, s~, 7.27 ~2H, s),
8.27 (2H, s~
20 ~5) 2-Cl-t-~u*oxycarbonyl-l-cyclopent~loxyimino-2-~5-
amino-192,4-thi~diazol-3-yl)ace~ic acid tsyn isomer),
mp 174-175C (dec.).
IR (Nujol) : 3400, 3300, 3200, 1745, 1715,
1630, 1530 cm ~
NMR ~d6-DMS0~ 37 (3H, s)9 1.65 (4H9 m),
1.97 ~4H, m3, 8.17 (2H3 broad s~
(6) 2-~1-Phenylethoxyimino)-2-(5-amino-1~2,4-thiadiazol-
3-yl)acetic acid ~syn isomeT), mp 103-107C ~dec~).
- 30 IR tNujol) : 3250, 3150~ 1710j 1610, 1520 cm 1
NMR (d6-DMS0, ~) : 1. 57 (3H9 d, J=6Hz~, 5.42
~lH, q, J~6Hz), 7.40 (5Hl m), 8.20 ~2H, m)
~8~
Preparation 32
To a solution of 2-hydroxyimino-2-t5-formamido-
1,2,4-~hiadiazol-3-yl)acetic ~cid ~syn isomer~(7.2 g3
in an aqueous methanolic sodium hydroxide prepar~d from
methanol (83.7 ml) and lN aqueous solu~ion of sodium
hydroxide (83.7 ml) was added 4,4'-difluorodiphenyl-
iodonium chloride (11.8 g) and the mixture was sti~red
at ambient temperatu~e or an hour. The resulting oily
su~stance was removed by deca.ntation and ~he solution
ln was concentrated und~T reduced pressure ~o remo~e
methanol. The a~ueous solution was acidified with 10%
hydTochloric acid and extracted with ethyl aceta~e.
The ~xtract was washed with water9 dried over magnesium
sulfate and evaporated to dryness. The residue was
tri~ura~ed wi~h diisopropyl e~her to give 2-(4-
fluorophenoxyimino)-2-~5-formamido-1,2,4-thiadiazol-3-
yl)acetic acid (syn isomer!(6.0 g)~ mp 130-135C (decO).
IR (Nujol) : 3100, 3050, 1730, 1690~ 1530,
1500 cm~l
NMR (DMS0-d6, ~) : 7.77 (2H, s), 7.27 (2H, s),
8.83 (lH, s), 13.43 (lH, s)
The following compouns were obtained by a similar
manner to that of Prepara~ion 32.
~1) 2-~4 Chlorophenoxyimino)-2-(5-0rmamido-11294-
thiadiazol-3-yl)acetic acid ~syn isomer)~ mp 155
~o 160C (dec.).
IR ~NU3O1) : 31~0, 1725~ 1690, 15S09 1530 cm 1
NMR (DMS0-d6, ~) : 7.30 ~2Hg d, J=9Hz)7 7.57
(2H, d, J=9Hz), 9.0 (lH~ s)
(2) 2-(2-Methoxy-5-nitrophenoxyimino)-2-(5-amino-1,2,4-
~3
thiadiazol-3-yl~ace~ic acid (syn isomer), mp 125
to 128C (dec.).
IR (Nujol) : 34009 3280, 17409 1720, 1690,
16~0, 1590, 1510, 1~40~ 1275,
970, 720 cm~l
NMR (DMS0-d6, ~) : 3.93 ~3H~ s), 7.27 ~lH, d,
J=8Hz), 8.01 ~lH, d, J=8Hz), 8,07 ~lH, s),
8.30 (2H, broad s)
10 . ~ D 3 -
The following compound was ob~ained ~y a similar
manner to tha~ of Prepar~tion 21.
2~ t-Butoxycarbonyl-l-cyclopentyloxyimino)-2-(5-
formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)~
mp 140 to 141C (decO).
IR ~Nujol) : 3550~ 1730, 1670, 1550, 1540,
12809 1255, 1150, 980, 720 cm 1
NMR ~DMSO-d63 ~) : 1.48 (9~, s), 1.83 ~4~, m),
.03 (4H, m)~ 8.87 ~lH3 s)~ 13.6 ~lH~ broad s3
~5
_ eparation 35
The following compounds were obtained according
to a similar manner to that of Preparation 32 by using
~-hydroxyimino-2-~5-amino-1,2,4-thiadiazol-3-yl)acetic
5 acid (syn isomer) as a starting compound, which was
prepared by a similar manner to that of Prep~ration 4.
~1) 2-~0-and P-Tolyloxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetic acid ~syn isomer).
NMR ~d6-DklS0,~): 2.20 (lH, s), 2.27 ~2H, s),
6.97 7.43 (4H, m), 80 33 ~2H, bs)
(2) 2- (3,4-Dichlorophenoxyimino) - 2 ~5 -amino-l,2,4 -
thiadiazol-3-yl~acetic acid (syn isomer), mp
177 to 178~
IR (Nujol): 330û, 1710, 1625, 1585, 1530,
1300, 1210, 1120, 980 cm 1
NMR (DMSO-d6~ 6~83-7.73 ~3H3 m) 9
8c38 (2H, broad s)
(3) 2-(3-Trifluoromethylphenoxyimino)-2- ~5-amino- -
1,2,4-thiadiazol-3-yl)acetic acid ~syn isomer),
mp 167 to 163C (dec.).
IR ~Nujol) . 3250, 1645, 1620, 1590, 1450,
- 25 1320, 1170, 1140, ~010, 995,
B45, 730 cm 1
NMR (DMSO-d63~): 7.63 (4H, m), 8.44 (2H,
broad s)
30 (4) 2- ~3-E~hoxycarbonylphenoxyimino)-2-~S~amirlo-
1,294-thiadiazol-3~yl)acetic acid (syn isomer);
mp 161 ~o 164 C ~dec . ) .
IR (Nujol): 3400, 330û, 3180g 1755, 1720,
1690, 1630, 1590, :l545" 1~10,
1290, ~275, 9709 900, 755 cm 1
~2~
NMR ~DMSO-d~ 1.36 ~iH, t, J-7Hz),
4,40 (12H, q, J=7Y.z~, 7.4-8.0 (3H, m),
8.5 (2H, broad s~
(5) 2-(3-Carboxyphenoxyiminc))~2-(5-amino~1,2,4-
thiadiazol-3-yl)acetic ~acid (syn isomer), mp 186
to 188~C (dec.).
IR ~Nujol) : 3420, 3150, 1735~ 1690~ 1620,
1580, 1265, 1200, 1000, 980 3
760 cm ~
NMR ~DMSO-d69~ : 7.3-B.0 (4H, m3~ 8.30 (2H,
broad s~
~6) 2-Phenoxyimino-2-(5-amino-1~2,4~thiadiazol^3-yl)-
acetic acid ~SyIl isomer), mp 145 to 147C ~dec.).
IR (Nujol) : 3~50, 3173~ 2500, 1730~ 1710,
. 16459 1630, 1595, 1535 cm 1
NMR tDMSO-d~,~) : 7.0-7.5 ~5H, m), 8.30 (2H,
broad s)
. Pr~l~a
S-Methyl ~5-formamido-1~2~4-thiadiazol-3-yl~-
thioglyoxylate (64.8 g) and 1-carboxy-3-hydroxypropoxy-
amine, which was prepared by re~luxing a mixture of
N-~2-oxo-3-tetrahydrofuryloxy)phthalimide (65.0 g), .
conc, hydrochloric acid (50 ml) and water (200 ml) for
1 hourS were treated according to a similar manner to
that of Prepa~a~ion 17 ~o gi~e 2-(l-carboxy-3-hydroxy-
propoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic
acid (syn isomer~(33.2 g)g mp 186 to 188C ~dec.).
IR (Nujol) : 3400, 3250~ 3100, 1710, 1620
1540 cm 1
NMR (DMSO~d6~ 1.73-2.10 ~2H, m), 3.50 (2H,
t, J=6Hz), 4.73 ~lH, t~ J=6Hz), 8.13 (2H, s)
3S
,
2~
Preparation 37
To a solution of 2~ c:arDoxy-3-hydToxypropo.~yimino)-
2-~5-amino-1,2~4-thiadiazol-3-yl)acetic acid (syn isomer)
(33.0 g) in methanol (2.8 Q) we-;e added anhydrous
magnesium su~fate (120 g) and acetic anhydride (60 g).
The mixture was stirred at ambient temperature for 30
minutes, filtered and the ~iltra~e was evaporated to
dryness. The residue-was triturated in acetone (200
ml) and ethyl acetate (1 Q) was added theretoO The
mixture was s~irred at ambient temperatuTe for 1 hour
and the precipitates were collected by filtration and
washed with ethyl acetate.
The precipitates were dissolved in water (200 ml) and
then ethyl acetate ~500 ml)~ acetone (200 ml) and 6N
hydrochloric acid (40 ml) were added thereto
An organic layer was separated out and the aqueous
laye~ was extracted with ethyl acetate. The organic
layers were combined, dried over anhydrous magnesium
sulfate and evaporated to dryness. The residue was
tri~urated in diethyl ether, filtered and washed with
diisopropyl ether to give 2-~2-oxo-3-
tetrahydrofuryloxyimino)-2-~5-amino-1,2,4-thiadiazol-
3-yl)acetic acid (syn isomer)(26.5 g), mp 185-187C
~dec.).
IR ~ujol) : 3400~ 33U0, 3200, 1775, 1730,
1640, 1605p 1535 cm 1
NMR (d6-DMS09~) 2.27-2.70 (2H, m~, 4.17-4.50
(2H, m), 5,27 (lH7 ~ J=8Hz), 8.22 (2H, s)
3 ~E~
~13 The following compound was obtained by a similar
manner to that of PrepaTation 22-(1).
Methyl N-~6-acetamidohexyl)dithiocarbamate
NMR (D~IS0-d6,~3 : 1.33 (8H, broad s)p 1.80
- -
~7
(3H, s), 2.50 ~3H, s), 3.07 (2H, m),
3.53 ~2H3 m), 7.77 (lH, m), 9.80 ~lH, m)
(2) The following compoundc; were obtained by a similar
manner to tha~ of Preparation 22-(2).
~a) 1-(4-Acetamidobutyl)-lH-tetrazole-5-thiol
I R (Nujol) :- 3300j, 1620, 1560, 1520 cm 1
NMR (d~-DMSO,~) : 1.23-l.g3 (4H9 m), 1.77 (3H,
s), 3.10 (2H, m), 4,23 (2H, m), 7.80 (lH,
broad s)
~b) 1-(6-Acetamidohexyl)-lH-tetrazole-S-thiol 9 oil.
(3) The following compounds were obtained by a similar
manner to that o Preparation 22-(3).
~a) 1-(4-Aminobutyl)-lH-tetrazole-5-thiol hydrochloride5
white` powder.
(b) 1-(6-Aminohexyl)-lH-tetrazole-5-thio~ hydrochlor~d~;
red oil.
(4) The following compounds were obtained by a similar
manner to that of Preparation 22-(4).
(a) 1-[4-(N-t-Butoxycarbonylamino)butyl]-lH-tetrazole-
5-thiol, mp 107-108.5C.
IR ~Nujol~ : 3200, 1640, 1520 cm 1
MMR ~dh-DMSO,~) : 1.37 (9H~ s~, 1.38-2~1 ~4H~
m~, 2.97 ~2H, m), 4.23 ~2H5 m)~ 6.73 ~lH,
broad s)
(b) 1-~6-(N-t-Butoxycarbonylamino~hexyl3-lH-tetrazole-
3~
5-thio~, oil.
NMR ~d6-DMS0,~) : 1.40 (15H, m), 1.77 (2H, m),
2.93 (2H; m), ~.20 (2H, m), 6,70 (lH~bro~d s~
PreParation
3~ _
-- 5 (1) To the olution of ~-(3-bromopropyl) phthal ~ide
(402 g) in ac3~0ne (~.5 Q) were added l-met~ylpiperazirAe
(225 g) and potas5ium carbonat~ (41; ~)O The resulting
~ixture was refllIxed wi~h stirri~g for 3.5 hou~s. The
reaction mixtura was cooled and _hen filtered. The filter
~o caXe was wash d with acetone (500 mQ)~ ~he iltrate and
- washing were combined and e~aporated under reduced
- ~ressure~ The remaining starting ma~rial~in the residnal
~ -- oil w~r~ az~otropically r.~mov~d with bP~zene ~o give an
oil of N-~3-(4-me~hyl~l piper~zI~yl~propyl3pht:~a~Lmide
(502 g)~ I~Ro (~ilm) : 1770~1700 cm-
(2) l~o a ~olutio~ O~ N-r~-(4-methyl-l~p~perazi~
propyl~ph~halimide
(502 g) i~ ethanol (3.0~) was add~d 1~0% hy~razine hydrate
(187.6 g~. The nesul~ing ~ixtl~re was refluxPd Wit~l s~ivi~g
~or 1.5 hours. ~he reaction mi~ture was rooled a~l~ t;le~
filtered. Tlie fil~er cak~ was wash2d with eth~ol (1 Q~.
ThQ fil~rate and washing were combined a~d e~aporated, und~r
reduced pressure. l~he residuzl oil was distilled under
r~uced pressure to give 3-(4-methYl-l- piper-~zinyl)
2~ propylamine (146.6 g~, bp 34~mEg~127 to 128~C.
(3) To a s~lu~ion o potassium hydruxide (57.3 g) in
me~a~ol (250 mQ3 was added 3 (4-methyl-l~piperazinyl)
pr~pylamine (146 gj a~d thereto was added c~xbon disulid~
(70.6 g~ with stirring under ice cooling ovex a period of
3~ 40 minutes. The resulting mixture was stirred for 3.5
hours under ice cooling. The reaction mixture was evaporated
~nder reduced pressure. The residu~l oil was dissolved in
water ~4Q0 m~) and washed with diethyl ether ~ice. The
washed a~ueous lay~r was ice-cooled and there~o was added
methyl iodide (132.1 g) with stirringO The resulting mixture
~8~
~9
was stirred for 2 hours under ice cooling, and ext; acted
with ethyl acetate ~400 mQ x 3) and chloroform (400 mQ x 2).
The extracts were combined, dried over magnesium sulfate
and then evaporated under r~duced pressure to give methyl
N-[3-(4-methyl-1-peperazinyl)propyl]dithiocarbama~e (139.3 g).
Thus obtained product was used directly in the next
step reaction without further purification.
(4) To a solution o methyl N-[3-(4-methyl-l~piperazinyl)
propyl dithiocarbamate obtained in Pxeparation ~9(3)
.10 (139.3 g) in a mixture of water (420 mQ) and ethanol (280 mQ)
wa3 added sodi~n azide (47, 6 g) . The~ res~Llting mixture was
ref luxed ~ith stirriny or 3 hours. The reaction mixture
was concentrated ~nder reduced prossure. T~e concentrate
was washed successi~ely with ethyl acetate and diethyl
ether and then evaporated. To the residue was added
ethanol and the mixtu~ was filtered. The filtrate was
evaporated under reduced pressure~ and to the residual oil
was added 6N hydrochloric acid. The mixture was evaporated
under reduced pre~sure. The residue was recrystallized
from isopropyl alcohol containing water to give 1-~3-(4-
methyl-l-piperazinyl~propyl]-lH~tetrazole-5-thiol
dihydrochloride(48.1 g), mp 239 to 243C.
N.M.R. (D20, ~): 2.3-2.8 (2H, m), 3.07 (3H, s!
3.3-~3.7 (2H, m), 3~75 (8H, s), 4.42 (2H, t,J =
6~Iz?.
35 .
~3~
Exam~le 55
The rollowing compound was obtained according to
a similar manner to that of Example 40, 42 or 47.
7-~2-CaTboxymethoxyimino-2-~5-amino-1,2,4-thiadiazol-
3-yl)ac~tamido]-3-~1-(2-carboxyethyl~-lH-tetrazol-5-
yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
mp 215 to 220C (dec.).
IR (Nu~ol) : 3300, 32009 1770, 1720, 1$80,
1620, 1520 cm ~
NMR ~DMSO-d~ 2~93 (2H, t~ J=6Hz), 3.67
~2H, broad s) J 4.33 ~2H7 bToad s), 4.43
(2H~ t, J=6Hz)~ 4.67 ~2H~ s); 5.10 (lH,
d, J=4Hz), 5.83 (lH~ dd, J=4 and 8Hz),
8013 ~2H, s~, 9.50 ~lH, d, J=8Hz)
2~
3rJ
- 291 --
Example 56
The follcwing cc~ounds were obtained according to a similar
manner to that of EXample 30, 40, 42, 44r 45, 47, or 48.
(1) 7-(2-(2-oxo-3-tetrahydro~uu~71Oxyimino)-2-(5-amino-1,2,4-~hia-
diazol-3-yl)acetamido)-3-~1-(3-(n-t-butoxyc~rbonylamino)-propyl)-lh-
tetrazol-5-yl)-thiomethyl-3-cephem-4-carbo~ylic acid(syn iscmer),
MP 130 to 135C (Dec.).
IR (Nujol): 3300, 3200, 1780r 1680, 1620, 1525 C~l
(2) 7-(2-(2-oxo-3-tetrahydrofuryloxyi~ino)-2-(5-amino-1,2,4-thia-
di~zol-3-yl)acetamido)-3-(1-(3-aminoprop~ lh-tetrazol-5-yl)thio-
met~yl-3-cephem-4-carboxylic acid(syn isomer),
r~ 210 to 215C (Dec.).
IR ~Nujol~: 33Q0, 3200, 1770, 1670, 1620, 1525 ~1-1
(3) 7-(2-(1-methyl-1-car'~oxyethoxyimino)-2-(5-am mo-1,2,4-t~ia-
diazol-3-yl)acetamido)cephalosporanic acid(syn isomer~.
210 to 220C (Dec.).
IR ~Nujol): 3400, 3300, 3200, 1770, 1720, 1700 1670, 1620,
1520, 1230, 1150, 1060, 1020, 995, 975, 920 740
720 CM-l
(4) Pivaloyloxymethyl 7-(2-cyclopen-tyloxyimino-2~(5-arnino-1,2,4,-
thiadiazol-3-~vl~ace-~amldo)-2-me-thyl-3-cepherll-4-carboxylate(syn isomer),
amorphous po~der.
IR (Nujol): 3450, 3360, 3200, 1790, 1750, 1680, 1625, 1530 CM-l
(5) 7-(2-~1 methyl-1-t-butoxycarbonylethoxyimino)-2-(5-aminc~1,2,4-
thiadiazol-3-yl)acetamido)-3-(1-(3-arninopropyl)-Lh-tetrazol-5-yl)thio-
methyl-3-cephem-4-carboxylic acid (s~n isom~r).
198 to 203C(Dec.).
IR (Nujol): 3450-3300, 3200, 1770, 1680, 1600-1615, 1525, 1140,
990, 970, 750, 720 ~1
- 292 -
(6? 7-(2-~l-carboxyethoxyimlno)-2-~5-amino-l~2~4-thiadiazol-3-yl)
acetamido)-3~t5-(2-(n-t-b~ltoxycarbonylamino)ethyl)-1,3,4,-thiadiazol-
2-yl)thiomethyl-3-cepllem-4- OE boxylic acid(syn isomer),
~P 202 to 204C(Dec.).
IR (Nujol): 3350, 3200, 1780, 1680, 1620, 1520, 1250, 1170, 1100,
1050, 1000 CM-l
(7) 7-(2-(l-carboxyethoxyimino)-2-(5-amlno~l~2t4-thiadiazol-3-yl)
acetamido)-3-(5-(2-aminoethyl)-1,3,4-thiadiazol-2-yl)-thiometllyl-
3-cephemr4-carboxylic acid(syn isomer),
MP 200 to 204C(Dec.).
IR (2~jol): 3350, 3200, 1770, 1680, 1620, 1520, 1240, 1180, 1100,
1060, 10~0, 1000 CM-l
(8) N-(7-(2-cyclopent~n-1-yl-oxyimino)-2-(5-amuno-1,2,4-thiadiazol-
3-yl)acetamido)-3-cephem-3ylmethyl?-4-'carbamoyl-pyridinium-4-car~
oxylate(syn iscmer?
~P 155 to 160C(Dec.).
IR (Nujol): 3300, 3150, 1770, 1675, 1610, 1560, 1520 CM-1
(9) N-(7-(2~(1-m thyl-1-carboxyethoxyir~no)-2-(S-amuno-1,2,4-tllia-
diazol-3-yl)acetamido)-3-cephen~3-ylmethyl)-4'-carbamoyl-pyridinium-
4-carboxylate (syn isomer).
180 to 185C(Dec.).
IR (Nu~ol): 3300, 1770, 1680, 1620, 1560, 1520 C~-l
In this specification, the expression "such as" means "for
exar~plel', and is not intended to be construed as limiting.
