CA1337522C

CA1337522C - Syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for the preparation thereof

Info

Publication number: CA1337522C
Application number: CA000272430A
Authority: CA
Inventors: Takao Takaya; Takashi Masugi; Hisashi Takasugi; Hiromu Kochi
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Astellas Pharma Inc
Priority date: 1976-04-12
Filing date: 1977-02-23
Publication date: 1995-11-07
Anticipated expiration: 2012-11-07
Also published as: ES485063A1; MX4985E; SE8304465D0; DK75077A; IE45597B1; DK162391C; ATA138477A; SE7701964L; DE2707565A1; AT358728B; HU177441B; SE457351B; NL191259B; AR227864A1; NL191259C; ES457191A1; FR2348219B1; CH643557A5; FR2348219A1; ES485064A1

Abstract

Novel syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds are provided of the formula:

in which R1 is a group of the formula: wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkyl-amino; a group of the formula: wherein R7 is amino, pro-tected amino, hydroxy or lower alkyl; or a group of the formula:

Description

SYN-ISO~ER OF 3,7-DISUB~TITITTFD-3-C~PIIE~-4-C~RBOYYIIC
ACID CO~IPOUNDS AND PROCESSES FOR T~IE PREP~R~TI~N THEREO~
The present invention relates to new syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof. More particularly, it relates to new syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable sa]ts thereof wllicll have antibacterial activities and to processe.s for the preparation thereof, to pharmaceutical composition comprising the same, and to a method of using the s~me therapeutic-ally in the treatment o infectious diseases in human being and animals.
Accordingly, it is one object of the present invention to provide syn-isomer of 3,7-disubstituted-3-cephem-4-carboxyli-acid compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathog~nic kacterja.
Another object of the present invention is to provide processes for the preparation of syn-isomcr of 3;7-disubsti~liced-3-cephem-4-carboxylic acid compounds and ~harmaceutically acceptable salts thereof.
A ~urther object of the present invention is to provide pharmaceutical composition comprising, as active ingredicnts, said syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic zcid compounds and pharmaceutically acceptable salts thereof.
Still furthcr object of the present invention is to provide a method or the treatment of infectious diseases caused by pathogenic bacteria in hum3n being and animals.
The ol~ject syn-isom~r of 3,7-disubstituted-3-cephenl-4-carbo~ylic acid com~ounds are novel and can be represcnted by the following formula (1):

Rl- C-CONI~ ~ S ~
N oR2 ~ N ~ R4 (I) in which Rl is a group of the formula:
R5 ~ wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lo~er alkoxy, acyloxy, acyl-amino or di(lower)alkylamino;
a group of the ~ormula:
R7 N ~ wherein R7 is amino, protected amino, hydroxy or lower alkyl; or a group of the formula:
R8 ~ wherein R8 is lower alkyl and R9 is imino, protected R S
imino or oxo;
R2 is an aliphatic hydrocarbon group which may have suitable substituent(s);
R3 is carboxy or protected carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl or a heterocyclic-thiomethyl group which may have suitable sulstituent(s);
or R3 and R4 are linked together to form -COOCH2-.
With regard to the present invcntion, it is to be noted that this invention is characterized ~y providing syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds, which is represented by the formula (I), and the said syn-isomer can be represented by the partial structure of the formula: R C CO in their molecules, while the corresponding N-OR
anti-isomer is represented by the partia] structure of the formula : Rl-C-CO-Accordingly, in the following detailed explanations of this invention in this specification and claims, it is to be under-stood that the syn-isomers of the objcct compounds as well as the starting compounds of this invention are represented by the partial structure of the formula: -C-CO- in their molecules, N-O-provided that, in case that it is convenient for thc explanation of this invention to express both of the syn-isomer and anti-isomer by one general formula, they are represented by the partial structure of the formula: -C-CO-N~
o The objcct compounds of the presellt invention (I) are novel compounds and can be prepared by the Proccsses 1 to 8 as mentioned below.
Process 1 ~ ~ R4 ~ Rl-C-COOH ~ Rl-C-CONH ~ ~
R3 N_oR2 N-OR2o R

(II) (III) (I) or it6 reactive derivative or its reactive or a salt thereofat the amino group or a derivative at salt thereof the carboxy group or a salt thereof Process 2 Rla c CONH S
N oR2 ~ ~ R -~ R b-C-CONH

~ m~n~tion of the protective group of the amino (or imino) (IV) (Ia) or a salt thereof or a salt thereof Process 3 Acylation of the hydroxy group } C-CONH- S RSa HO N-OR O ~ ~ R6a ~ 1 2 ~ ~ R4 (V) (Ib) or a salt thereof or a salt thereof Process 4 Elimination of the protective group 1 S of the carboxy R -C-CONH , 2011 2 ~ N ~ R4 ~ Rl C CONH

(Va) tIC) or a salt thereof or a salt thereof Process 5 ~ n~tion of the 1 S protective group R -C-CONH ' ~ of the amino N-OR2 O~ - ~ ~ CH2-OCONH-R a_ Rl-CH-CONH ~ S~
R3 N-OR2 o~N ~ CH2-OCONH2 (Vb ) or a salt thereof (Id) or a salt thereof Process 6 Rl-C-CONH ~ S Rl-C-CONH S
N oR2 ~ N ~ CH2-R4b+ R4C^ SH ~ N oR2 ~ ~ H2 s R4c s (VC) (Vd) (Ie) or a salt thereof or its reactive or a salt thereof derivativ~ at the mercapto group ., .. , ...... ~
--- Process 7 R -C-CONH ~ S ~ Acid Rl-C-CONI-I ~ S

N_oR2 o ~ ~ CH2OH ~ O ~ 1 2 R CO- O

(Ve~ (If) or a salt thereof or a salt thereof Process 8 Rl-C-CONH ~ S~ Oxidation R -C-CONH l,S~
N-OR2o N ~ C~2H - ~ oR2o ~ N ~ CHO

(ve) (Ig) or a salt thereof or a salt thereof - - wherein Rl, R2, R3, R4 and R5 are each as defined above;
Rla is a group of the formula:
R7a ~ in which R7a is protected amino; or a group of the formula ~ 3 in which R8 is as defined abovc and R9a is protected R9a S
imino;

Rlb is a group of the formula:
N

~ S ~
a group of the formula:

R - ~ in which R8 is as defined above;
S

HN
RSa is hydrogen, halogen, nitro, lower alkoxy or acyloxy;
R6a is acyloxy;
R2a is protected carboxy(lower)alkyl;
R2b is carboxy(lower)alkyl; R4a is a protective group of amino;
R4b is a group which can be substituted by a group R4C-S-wherein R4c is a heterocyclic group which may have suitable substituent(s); and R4c is as defincd above.
Among the starting compounds, the starting compound (III), including the corresponding anti-isomer are novel and can be prepared by the processes which are illustrated by the following scheme.
RS ~ (VII) R ~ COCH3 (VI) (VIII) RSC RSC
R6b ~ COCH Oxidation ~ COCOOIi (IX) (X) iii) R5C Elimination R5c R10O~ COCOOH HO COCOOH

S (XI ) ( X I I ) (iV) R5 R2 ONH2 ( XIV ) or a 5 R6 3 ~ cocooH salt thereof R6 ~ IC!-COOH

oR2 (XIII) tIIIa) (2) (i) R5 NH2OH or a salt R5 ~3COCOOH thereof ~ C-COOII

HO HO N
OH
(XV) tXVI) (ii) ~O~ Alkylation R ~3c-cooR8 oR2c ~R2d (XVI I ) (XVI I I ) Hydro lys i s RS d ~ C- COOH

~R2d (IIIb) t3) RS Acylation Rsa HO ~ C-COOH R6a ~ C-COOH

OR oR2 tXIX) tIIIC) t4) ti) Nitrosation CH2 C~CH2~Z ~ XCH2Co c z R b-C-NH2 txx) OH ) R7C-~s ~ N
OH
(XXI) (XXIII) liminatin, R7 ~ ~ I

OH

tXXIIIa) tii) 7 ~ N ~ C Z Alkylation 7 ~ ~ jCI-Z
OH OR2e tXXIV) tXXV) Elimination 7d ~N ~ C-COOH
S N
OR e tIIId) Al~ylation Halogenation CH3-CO-C-Z ~ CH3CO-C-Z X-CH2CO-~-Z
N N N
OH ~R2e ~R2e (XXVI) (XXVII) (XXVIII) R7b- C-NH2 (XXII) R7 ~ ~11 Elimination , R7C ~ ~ 11 OR2e OR2e tXXIX) (IIIe) (6) (i) Amino-protecting H2N ~ ~ CH2 - Z ) R7a, ~_ CH2 - Z

tXXX~ (XXXI) (ii) Oxidation HydrQlysis RlC-C~2-z -~ RlC-CO-Z ~ R -C-Z
(XXXII) (XXXIII) N
0~
/ (XXIII~) ~ / R20-NH2 or a salt ~ ~ (XIV) thereof lc ~/ RlC-C- Z

\ R -ON112(XIv~ ~/ N
- (XXXIV) \ thereof.~ oR2 ~ ~ (XXXV) NH2H RlC c cOOH
or a salt thereo N
Rlc c cOOH oR2 Il N (IIIf) (XXXVI) (iii) N Alkylation R8 N 8 OH OR2e (XXXVII) (XXXVIII) ydrolysis R8 N ~ C-COOH
R9a~ S~ 11 ~R2e (IIIg) (7) Amino-protecting ~ S~ 11 agent , R7a~ ~ C Za ~N 2 ~ 2 OR OR
(XXXIX) (IIIh) in which R2, RS, R6, R5a, R6a, R7a, R8 and R9a are each as defined above;
R5b is halogen;
Y is an acid rèsidue;
R10 is ar(lower)alkyl;
RSc is hydrogen, halogen or nitro;
R6b is lower alkoxy, ar(lower)alkoxy or acylamino;
R2C is hydrogen, lower alkyl or lower alkenyl;
R5d is hydrogen, halogen, nitro, hydroxy or lower alkoxy;
X is halogen;
Z is protected carboxy;
R7b is lower alkyl, amino or lower alkoxy;
R c is lower alkyl, amino or hydroxy;

1 337~22 R7d is lower alkyl;
R2e is lower alkyl;
RlC is a group of the formula:
R7 ~ ~ in which R7 is as defined above, or S
a g~roup of the formula:

1 ~~ in which R8 and R9 are each as defined above;

R2d is lower alkyl or lower alkenyl; and Za is carboxy or protected carboxy.
The other starting compounds( I~r), tv), (Va)-(Vc) and (Ve) are all novel compounds and can be prepared by the aore-said Processes ] to 8.
Regarding the object com~ounds of the formulae (I), (Ia) and (IC)-(Ig) J and the starting compounds of the formulae (III), (IIIe), (IIIf), (IIIh), (IV), (Va)-(Vc), (Ve), (XXIII)-~XXIIIb), (XXIX)-(XXXVII) and (XXXIX), it is to be understood that said object and starting compounds include tautomeric isomers relating to their thiazole groups. That is, in case that the group represented by the formula:
N
R7e ~ ~ (wherein R7e is amino, protected amino or hydroxy) in the formula of said object and starting compounds take the formula: 7e ~ ~ (A) (R is as defined above), said group of the frmUla R7e ~ ~ can be also alternatively represented by its tautomeric formula: 7f 0~ ~ (B) (wherein R7f is imino9 protected imino or oxo). That is, both o the said groups (A) and (B) are in the state of equilibrium as so-colled 1. 1 -- ~,, , . . . ..

- tautomeric forms which can be represented by the following equilibrium:

7e l 5~ R7 (~) (B) (wherein R7e and R7f are each as defined above).
These types of tautomerism between 2-amino- and 2-hydroxythiazole compounds and 2-imino-or 2-oxo-thiazoline compounds as stated above have been well known in the literature, and it is obvious to a person skilled in arts that both of the tautomeric isomers are equilibrated and easily convertible reciprocally, and accordingly it is to be understood that such isomers are included within the same category of the compound per se. Accordingly, the both of t:he tautomeric for~s of the object compounds (I), (Ia) and (IC)-(Ig), and the starting compounds (III), (IIIe), (IIIf), (IIIh), (IV), (Va)-(Vc), (Ve), (XYIII)-(XXIIIb), (XXIX)-(XXXVII) and (XXXIX) ar.e clearly included within the scope of the present invention. In the present specification, claims and examples, the object and starting compounds including the group of such tautomeric isomers are represented by using one of the expressions therefor, that is the formula~ " only for the convenient sake.
R7e S -(A) Furthermore, regarding the object compounds (I), (Ia)~
(Ic) and (Ig), and the starting compounds (II), (IV), tv) and (Va), the compounds wherein R3 is carboxy and R4 is formyl can be also regarded as substantially same compounds as the compounds wherein R3 and R4 are linked together to form a group of the 1 337~22 formula: -COOCH(OH)- , i.e. so-called intramolecular hcmiacylal type compounds, and accordingly both of them are understood to be included within the same category of the compound per se and therefore within the scope o~ the present invention.
Suitable pharmaceutically acceptahle sait of ~.e object syn-isomer o~ 3,7-disubstituted-3-cel)hem-4-carboxylic acid compounds (I) are conventional non-toxic salts and may include an inorganic salt, for example, a mctal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), ammonium salt etc., an organic salt, for exa~ple, an organic amine salt (e.~., trime~hylamine salt, triethylamine salt, ethanolamine salt, diethanolamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylene-diamine salt, etc.) etc., an organic acid salt (e.g., acetate, maleate, tartrate, methanesul~onate, benzenesulfonate, toluene-sulfonate, etc.), an inor~anic acid salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), or a sal~ wit~l an amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.~, and the like.
In thte above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the prcsent invention intend to include within the scope thereof are explained in details as follows.
The te.~m "lo-~er" is intended to mean 1 to 6 carbon -atom(s), unless otherwise provided.
Aliphatic hydrocarbon group is intcnded to mean straight or branched aliphatic hydrocarbon having 1 to 6 carbon a~om(s) and may include lower alkyl, lower alkenyl and the like. ~nd said aliphatic hydrocarbon grotlp may have 1 to 2 suitable ~ substituent(s) such as carboxy, protected carboxy, arylthio, lower alkylthio, aryl, acyloxy, lower alkoxy, aryloxy, a heterocyclic group or the-like.
Suitable halogen may include chlorinè, bromine, fluorine and iodine Suitable lower alkoxy and lower alkoxy moiety in the term "ar(lower)alkoxy" may include one which may be branched, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like, and preferably one having 1 to 4 carbon atom(s), and more preferably one having 1 to 2 carbon atom(s).
Suitable protected amino may include an acylamino and amino group substituted by a conventional protective group other than the acyl group such as benzyl or the like.
- 15 Suitable lower alkyl and lower alkyl moiety in the terms "lower alkylthio", "carboxy(lower)alkyl", "protected carboxy(lower)alkyl", "ar(lower)alkyl" and "di(lower)alkylamirlo"
may include one which may be branched, for cxample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl~pentylJ hexyl and the like, and preferably one having 1 to 4 carbon atom(s), and more preferably one having 1 to 2 carbon atom(s).
Suitable protected imino may include an acylimino and imino group substituted by a conventional protective group other than the acyl group such as benzyl and the like.
Suitable protected carboxy and protected carboxy moiety in the term "protected carboxy(lower~alkyl" may include esterified carboxy in which said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, l-cyclopropylethyl . - 14 -ester, etc.), whcrein lower alkyl moiety may be prefer~bly one having 1 to 4 carbon atom(s); lower alkenyl ester (e.g., vinyl ester, allyl ester etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc ); mono(or di or tri)-halo(lower)-alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymcthyl ester, 2-acetoxy-ethyl ester, 2-propionyloxyethyl ester, etc.);
lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl es.er, 2-mesylethyl ester etc.);
ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., bcnzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phellethyl ester, trityl ester, diphenylmet}lyl ester, bis(methoxyphenyl)-methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiarybutylben~yl ester, etc.);
aryl ester whicll may have one or more suitable substituent(s (e.g., phenyl ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.), and the like.
Preferable example of protected carboxy may be lower alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxy-carbonyl, etc.) having 2 to 7 carbon atoms, pre~erably one having 2 to 5 carbon atoms.
~ Suitable aryl and aryl moiety in the terms "ar(lower)-alkyl", "ar(lower)alkoxy", "arylthio" and "aryloxy" may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl and the like, wherein said aryl group may have 1 to 3 suitable substituent(s) t 337522 such as halogen (e.g., chlorine, bromine, iodine or fluorine), hydroxy, and the like.
Suitable heterocyclic group and heterocyclic moiety in the term "a heterocyclicthiomethyl group which may have suitable substituent(s)" means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
And, es~ecially preferable heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4~-1-1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.)~ tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc;
saturated 3 to 8-membered (preferably 5 to 6 membered) hetero-monocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;
unsaturated 3-to 8-membered (preferab~y 5 to 6 membered) hetero-monocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.;
saturated 3 to 8-membered (preferably 5 to 6 membered) hetero-monocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, ben~oxadiazolyl, etc.;
unsaturated 3 to 8-membered (preferably 5 to 6 membered) hetero-monocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom~s), for example~thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyi, etc.), etc;
saturated 3 to 8-membered (preferably 5 to 6 membered) hetero-monocyclic group containing 1 to 2 sulfur atomts) and 1 to 3 nitrogen atom(s~, for example, thiazolidinyl, etc.;
unsaturated 3 to 8 membered (preferably 5 to 6 membered) heteromonocyclic grou~ containing a sulf~r atom, for example, thienyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulf-lr atom(s) and 1 to 3 nitrogen atom(s), for example, benzothia~olyl, benzothiadi~zolyl, etc. and the like;
wherein said heterocyclic group may have 1 to 2 suitable substituent(s) such as lower alkyl (e.g., methyl, ethyl, propyl, isopro~yl, butyl, isobutyl, pcntyl, cyclopentyl, hexyl, cyclohexyl, etc.), preferably one having 1 to 4 carbon atom(s); lower alkenyl (e.g., vinyl, allyl, butenyl, etc.);
aryl (e.g., phenyl, tolyl, etc.); halogen (e.g., chlorine, bromine, iodine or fluorine); amino; di(lower)alkylamino(lower)-alkyl (e.g. dimethylaminomethyl, dimethylaminoethyl, diethyl-aminopropy], ~iethylaminobutyl, etc.), pIeferably one having 3 to 6 carbon atoms; or the like.
Suitable ~ower alkenyl is one having 2 to 6 carbon atoms and may include, for example, vinyl, al]yl, isopropenyl, l-propenyl, 2-butenyl, 3-pentenyl and the like, and preferably one having 2 to 4 carbon atoms.
Suitable acyl moiety in the terms "acylaminO", "acyl-imino", "acyloxy" and "acyloxymethyl" as mentioned zbove may include carbamoyl, aliphatic acyl gro~p and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.), preferably one ha~Ting 1 to 4 carbon atom~s), more preferably one having 1 to 2 carbon atom(s);
lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g., methoxy-carbonyl, ethoxycarbonyl, propoxycarbonyl, l-cyclopropylethoxy-carbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.), preferably one having 3 to 6 carbon atoms;
lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.), preferably one having 1 to 4 carbon atom(s), more preferably one having 1 to 2 carbon atom(s);
arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.);
aroyl (e.g., benzoyl, toluoyl, naphthoyl, phtllaloyl, indancarbonyl, --- etc.);
ar(lower)alkanoyl ~e.g., phenylacetyl, phenylpropionyl, etc.);
ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxy-carbonyl, etc.); and the like.
The acyl moiety as stated above may have 1 to 3 suitable substituent(s) such as halogen (e.g., chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, etc.), lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl - ]8 -.,, - - ., .. A

1 33~5~2 ~e.g., vinyl, allyl etc.~, acyl such as halo(lower)alkanoyl (e.g., chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoro-acetyl, etc.), aryl (e.g., phenyl, tolyl, etc.), or the like.
Suitable examples of the acyl having said subs`tituent(s) may be mono(or di or tri)halo(lower)alkanoyl (e.g., tri1uoroacetyl, trichloroacetyl, etc.), preferably one having 2 to 4 carbon atoms;
mono(or di or tri)halo(lo~er)alkanoylcarbamoyl (e.g., trichloro acetylcarbamoyl, etc.), preferably onc having 3 to 4 carbon atoms; or the like.
Suitable protective group of amino for R4a may include acyl such as halo(lower)alkanoyl (e.g., chloroacetyl, dichloro-acetyl, trichloroacetyl, trifluoroacetyl, etc.), preferably one having 2 to 3 carbon atoms, or the like.
Suitable acid residue may include a residue of an acid such as an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, etc.) or an organic acid (e.g., methancsulfonic acid, bcnzenesulfonic acid, p-toluenesulfonic acid, etc.).
Sui~able example of a group which can be substituted by a group R4C-S- may include an acid residue such as halogen, azido or acyloxy wherein said halogen and acyl moiety of said acyloxy are the same ones as aforementioned.
Among the suitable examples of each of the groups of the object compounds as explained and illustrated above, the prefered examples thereof are illustrated as follows.
Preferable example of R5 may be hydrogen halogen (preferably chlorine~ or nitro;
preferable example of R6 may be hydroxy, lower alkoxy (preferab ~ Cl-C4, more preferably Cl-C2), acyloxy[preferably lower alkanoyloxy (preferably Cl-C4, more preferably Cl-C2) or carbamoyloxy], acylamino [preferably lower alkanesulfonyl-amino (prefcrably Cl-C4, more preferably (Cl-C2)J or di(lower)-alkylamino (whcrein the alkyl moiety is prefexably Cl-C4, more preferably Cl-C2);
preferable example of R7 may be amino, protected amino such as acylamino [prcferably lower alkancsulfonylamino (preferably Cl-C4, more preferably Cl-C2), trihalo(lower)alkanoylamino (preferably Cl-C4, morc preferably Cl-C2) lower alkoxycarbonylamino (pre~erably C2-C7, more ~referably C3-C6) or lower alkanoylar,lino (preferably Cl-C4, more preferably Cl-C2)], hydroxy or lower alkyl (preferably Cl-C4, more preferably Cl-C2);
preferable example of R8 is Cl-C4 lower alkyl, more prcferably Cl-C2 lowcr alkyl;
preferable example of R9 may be protected imino such as acylimino [preferably lowcr alkanesulfonylimino (prcferably Cl-C4, more preferably Cl-C2)];
preferable example of R2 may be lower alkyl (preferably Cl-C4, more preferably Cl-C2, most ~referably Cl), lower alkenyl, ar(lower)alkenyl [more prcferably phenyl(lower)alkenylJ, carboxy(lower)alkyl, protccted carboxy(lower)alkyl [more prcfcrably lowcr alkoxycarbonyl (prcferably C3-C6) (lower)alkyl], arylthio-(lowcr)alkyl [rnore ~refcrably phenylthio(lower)alkyl], ar(lower)-alkyl [more preferably phcnyl(]ower)alkyl] w}lich may have halogen (prefcrably brominc) and hydroxy, thienyl(lower)alkyl or aryloxytlower)alkyl [more preferably phcnoxy(lower)alkyl] which may ha~e hydroxy, in which alkcnyl and alkenyl moiety is C2-C6, prefcrably C2-C4, and alXyl moiety is prefcrably Cl-C4, more preferably Cl-C2;

1 337~22 preferable example of R3 may be carboxy;
preferable example of R4 may be acyloxymethyl~preferably lower alkanoyloxymethyl (in which alkanoyl moiety is preferably Cl-C4, more preferably Cl-C2, most preferably C2, i.e. acetyl) or carbamoyloxymethyl which may have trihalo(lower)al~anoyl (in which trihalo mOietyis preferably-trichloroand alkanoyl moiety is prefcrably C2-C~ , hydroxymcthyl, formyl, tetrazolyl-thiomethyl which may have lower alkyl (preferably Cl-C4, more preferably Cl-C2) or di(lower)alkylamino(lower)alkyl (in which alkyl moiety is preferably Cl-C4, more prc~crably Cl-C2), triazolylthiomethyl which may have lower ~lkyl (prcerably Cl-C4, more preferably Cl-C2) or thiadiazol)~lthiomethyl which may have lower alkyl (preferably Cl-C4, more preferably Cl-C2);
or R3 and R4 are linked together to form -COOCH2-The various processes for preparing the object compounds of the present invention are explained in details in the following.
Process 1:
The object compound (I) or a salt thercof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group or a salt thereof, which is a fundamental method for preparing the object compound (I) Suitable reactive derivative at the amino group of the compound (II) may include conventional reactive derivative used in amidation, for example, a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(t~imethylsilyl)acetamide, trimethylsilylacetamide or the like.
Suitable salt of the compound (II) may i.nclude an acid 1 ~37522 addition salt such as an organic acid salt (e.g., acetate, maleate, tartrate, benzenesulfonate, toluenesul~onate, etc.) or an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); a salt with an inorganic base such as an alkali metal salt (e.g., sodium salt, potassiu.m sal~, etc . ), .-an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.) or ammonium salt; a salt with an organic base (e.g., triethylamine salt, pyridine salt, etc.); and the like.
Suitable reactive derivative at the carboxy group of the compound (III) may include conventional one used in amidation.
The salts of the compound (III~ may be salts with an inorganic base such as an alkali metal salts (e.g., sodium or potassium salt), or an alkaline earth metal salt (e.g., calcium or magnesium salt), a salt with an organic base such as trimcthyl-amine, triethylamine, pyridine, a salt with an acid (e.g., hydrochloric acid or hydrobromic acid) or the like.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylfor~a~ide, pyridine or any other organic solvent which does not adversely influence to the reaction.
Among these solvents, hydrophilic solvents may be used in a mixture with water.
The present reaction is preferably carried out in the presence of a condensing agent such as so-called Vilsmeier reagent, for example, (chloromethylene)-dimethylammonium ohloride produced by the reaction of dimethylformamide with thionyl chloride or phosgene, a compound produced by the reaction of dimethylformamide with phosphorus oxychloride, etc., or the like.

,~

- 1 337~22 The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal bicarbonate, alkali metal carbonate, alkali metal acetate, tri-(lower)alkylamine, pyridine, N-(lower)-alkylmorphorine, N,N-di(lower)alkylbenzylamine, N,N-di(lower)-alkylaniline as exemplified below, or the like. When the base or the condensing agent is in liquid, it can be used also as a solvent. The reaction temperature is not critical, and the reaction is usually carried out under cooling or at ambient temperature.
In the present reaction, it is to be noted that, in case that the starting compound (III) is reacted with the compound (II) or its reactive derivative at the amino group or a salt thereof in the presence of, for example, phosphorus pentachloride, thionyl chloride, etc., only the corresponding anti-isomer to the object compound (I) or a mixture of the corresponding anti-isomer and syn-isomer is always given as an object compound even if the compound (III), i.e, syn-isomer is used as a staring compound. It is of course to be noted that the reaction of the corresponding anti-isomer to the starting compound (III) with the compound (II) can never produce the object compound (I) of the present invention, i.e, syn-isomer. It may be understood that such tendency and singularity of the reaction as mentioned above is due to the fact that the less stable syn-isomer tends to isomerize partially or wholly to the corresponding more stable anti-isomer in the course of the reaction, for example, in so-called activation step of the compound (III) so that the isomerized compound, i.e, the anti-isomer corresponding to the object compound (I) can be produced as an object compound.

Accordingly, in order to obtain the object compound (I), i.e., syn-isomer selectively and in high yield, it is necessary to use the starting compound (III), i.e., syn-isomer and to select a suitable reaction condition. That is, the S object compound (I), i.e., syn-isomer can be obtained selectively and in high yield by conducting the reaction, for example, in the presence of a Vilsmeier reagent as mentione~ above etc. and under around neutral condition.
Especially, in case that the starting compound (III) wherein Rl is a group of ~he formula: ~N ~ is used, the ob~ect compound (I),i.e., syn-isomer can be obtained selectively and in high yield by conducting the present reaction of the corresponding starting compound (III), i.e., syn-isomer with the compound (II), for example, in the presence of a Vilsmeier reagent produced by the reaction of dimethylformamide witl~ phosphorus oxychloride and under around neutral condition.
And, in this case, it is to be noted that particularly good results can be achieved by conducting the reaction in the presence of more than two molar equivalents of phosphorus oxychloride to each amount of the said starting compound (III), i.e., syn-isomer and dimethylf^rlnamide as shown in the working examples.
Further, in this case, it is to be also noted that good results can be achieved by conducting an activation step of thc starting compound (III), i.e., syn^isomer in the presence of a silyl compound [e.g. bis(trimethylsilyl)acetamide, trimethylsilylacet-amide, etc.] and the like.
With regard to the reaction of the compound (II) with the compound (III), it is to be noted that;
when the compound (II) wherein R4 is carbamoyloxymethyl group having acyl group is used as a starting compound, there may be obtained occasionally either the object compound (I) wherein R4 is carbamoyloxymethyl group having acyl group or free carbamoyloxy-methyl group according to reaction conditions;
when the compound (II) wherein R4 is hydroxymethyl group is used as a starting compound, there may be obtained occasionally the object compound (I~ wherein R3 and R4 are linked together to form -COOC~12- ;
and ~urther the protected carboxy group or salts in the compound (II) may be converted in~o free carboxy group; in the course of thc rcaction or in post-treatment. Thcse cases are also included within the scope of the present invention.
As clear from the explanation as stated above, it is to be understood that the Process 1 is a fundamental and the most advantageous method for preparing the object compound (I), i.e.
syn-isomer.
Process 2:
The object compound (Ia) or a salt thereof can be prepared by subjecting the compound (IV) or a salt thereof te elimination reaction of the protective group of the amino or imino.
Suitable salt of the compound (IV) may include a metal salt, ammonium salt, an organic amine salt and the like as aforementioned.
The present elimination reaction is carried out in accordance with a conventional method such as hydrolysis; reduction;
a method by reacting the compound (IV) wherein the protective group is acyl group with iminohalogenating agent and then with iminoetherifying agent, and, if necessary, subjecting the resulting compound to hydrolysis; or the like.

The hydrolysis may include a method usin~ an acid or base or hydrazine and the like. These methods may be selected depending on the kind of the protective groups to be eliminated.
Among these methods, hydrolysis using an acid is one of the common and preferable method for eliminating the protective groups such as substituted or unsubstituted alkoxy-carbonyl (e.g., t-pentyloxycarbonyl, etc.), alkanoyl (e.g., formyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl, substituted benzyloxy-carbonyl, etc.), substituted p}lenylthio, substituted aralkyli~.ene, substitutcd alkylidene, substituted cycloalkylidene, or the like.
Suitable acid may include an organic or an inorganic acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroch]oric acid and the like, and pre-ferable acid is an acid which can be easily removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, for example, formic acid, trifluoroacetic acid, hydrochloric acid, etc. The acid suitable for the reaction can be selected according to the kind of protective group to be eliminated. When the elimination reaction is conducted with the acid, it can be carried out in the presence or absence of a solvent. Suitable solvent may include an organic solvent, water or a mixed solvent thereof. ~hen trifluoroacetic acid is used, the elimination reaction may be preferably carried out in the presence of anisole.
The hydrolysis using hydrazine is commonly applied for eliminating the protective group, for example, succinyl or phthaloyl.
The hydrolysis with a base is preferably applied for eliminating acyl group, for example, haloalkanoyl (e.g., trifluoroacetyl, etc.) etc Suitahle base may include, for example, an inorganic base such as alkali meta] hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g., n;agnesium carbonatc, calcium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acctate (e.g., sodium acetate, potassium acetate, etc.), alkaline carth metal phosphate (e.g., magnesium phosphate, calcium p}lospllate, etc.), alkali metal hydrogcn phosphatc (e.g., disodium llydrogen pJlosph~te, dipotassium hydrogen phosp}late, etc.), or the like, and an organic base such as trialkylamine (e.g., trimethylamine, trieth)~laminc, etc.), picoline, N-methyl-pyrrolidine, N-methylmorpholinc, 1,5-diazabicyclo[4,3,0Jnon-5-ene, 1,4-diazabicyclo[2,2,2]octanc, 1,5-diazabicyclo[5,4,0]undccene-5 or the like. The hydrolysis using a base is often c~rried out in water or a hydrophilic organic solvent or a mixed solvent thereof.
Among the protectivc groups, the acyl group can be - - generally eliminate~ by hydrolysis as mentioned above or by the other conventional hydrolysis. In case that the acyl group is halogen substituted-alkoxycarbonyl or 8-quinolyloxycarbonyl, they are eliminated by treating with a heavy metal such as copper, zinc or the like.
The reductive elimination is gencrally applied for eliminating the protective group, for examp]e, haloalkoxycarbonyl (e.g., trich]oroethoxycarbollyl etc.), substituted or unsubstitllted aralkoxycarbonyl (e.g., benzyloxycarhonyl, substituted benzyloxy-carbonyl etc.), 2-pyridylmcthoxycarbonyl, ctc. Suitable reduction may include, for example, reduction with an alkali metal borohydride (e.g., sodium borohydridc, etc.) and the like.
Suitable iminohalogenating agent use~d in a ~ethod as mentioned above may include phosphorus trichloride, phosphorlls pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, phosgene and the like.
The reaction temperature is not critical, and the reac~ion is usually carried out at ambient temperature or under cooling.
Suitable iminoetherifying age]lt reacted Wit}l thus obtaincd reaction prodtlct may include an alcohol, metal alkoxide and the like. Suitable alcohol may include alkanol (e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, etc.) which may be substituted with alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.). Suitable meLal alkoxide may include alkali metal alkoxide (e.g., sodium alkoxide, potassium alkoxicle, etc.), alkalinc earth metal alkoxide (e.g., calcium alkoxide, barium alkoxide, etc.) and the like. The reaction temperature is not critical, and the reaction is usually carried Ollt under cooling or at ambient temperature.
Thus obtained product is, if necessary, subjected to hydrolysis. The hydrolysis can be readily carried out by pouring the reaction mixture obtained above into water, but there may be previously added a hydrophilic solvent (e.g., methanol, ethanol, etc.), a base (e.g., alkali metal bicarbonate, trialkylamine, etc.) or an acid (e.g., diluted hydrochloric acid , acetic acid, etc.) to the water.

The reaction temperature is not critical and may be - ~8 -suitably selected in accordance with the kind of the protective group of the amino group and the elimination method as mentioned above, and the present reaction is prcferably carried out under a mild condition such as under cooling, at ambient tempe-rature or slightly elevated temperature.
The present invention includes, within its scope, the cases that the protected carboxy is trans~ormed into the ~ree carboxy group; that when the compound tIV) wherein R4 is carbamoyl-oxymethyl group having acyl grup is used as the starting compound, there may be obtained occasionally either the object compound (Ia) wherein R4 is carbamoyloxymethyl group havin~ acyl gI'OUp or free carbamoyloxymethyl group according to reaction conditions;
and that when the compound (IV) wherein R4 is acyloxymethyl group is used as the starting compound, there may be obtained occasional-ly the object compound (Ia) wherein R3 and R4 are linked together to form -COOC~l2- according to reaction conditions;
in the course of the reaction or in post-treatMent.
Process 3:
The object compound tIb) or a salt thereof can be prepared by acylating the hydroxy group of the compound (V) or a salt thereof.
Suitable salt of the compound (V) can also be referred to the ones exemplified for thc compound (IV).
The acylating agent to be used for the present reaction may include an aliphatic, aromatic and heterocyclic carboxylic acid, and the corresponding sulfonic acid and thio acid which have aforesaid acyl group as their acyl moieties, and reactive derivatives of the above-mcntioned acids. Suitable rcactive derivative of the above-mentioned acids may include an acid halide, an acid anhydride, an activated amide, an activated ester, ... .

and the like. Suitable example may be an acid chloride;
an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric aci~, dibcnzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyi-carbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazolc, dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ((CII3)2N = C~-) ester, vinyl ester, propargyl estcr, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazophcnyl ester, phenyl thio-ester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester], or an ester with N,N-dimethylhydroxylam-:ne, 1-hydroxy-2-(lH)-pyridone, N-hydroxysuccinilllide, N-hydroxy-phthalimide or l-hydroxy-~-chloro-lH-benzotriazole, and the like.
These reactive derivatives can be optionally selccted from them according to the kind of the acylating agent to be used.
The acylating agent may further include aliphatic, aromatic or heterocyclic isocyanate or isothiocyanate (e.g., methyl isocyanate, phcnyl ;socyanate, trichloroacetyl isocyanate, methyl isothiocyanate, etc.) and haloformate (e.g., ethyl chloroformate, benzyl chloroformate, etc.). In this case, for example, whcn trichloroacetyl isocyanate is used as an acylating agent, trichloroacetylcarbamoyl group is introduced as acyl group and said group may be converted to carbamoyl gTOUp by treating with base, and when ethyl chloroformate is used as an acylating agent, ethoxycarhonyl group is introduced as acyl group.
The present reaction is carried out according to similar reaction conditions to those of aforesaid reaction of the compound (II) with thc compound (III), and is preferably carried out in the presence of a base. In the reaction of the compound (V) with an acylating agent, the protected carboxy group or salts in the compound (V) may be converted into free carboxy group in the course of the reaction or in post-treatment;
and when the compound (V) wherein R4 is carbamoyloxymethyl group ,, .. , ... ~ ~_ , having acyl group is used as the starting compound, there may be obtained occasionally either the object compound (Ib) wherein R4 is carbamoyloxymethyl group having acyl group or free carbamoyloxy-methyl group according to reaction conditions in the course of the reaction or in post-treatment. These cases are also included in the scope of the present invention.
Process 4:
The object compound (Ic) or a salt thereof can be prepared by subjecting the compound (Va) or a salt thereof to elimination rcaction of the protective group of the carboxy.
Suitable salt of the compound (Va) can be referred to the ones exemplified for the compound (IV).
The present elimination reaction is carried out in accordance with a conventional method such as hydrolysis .. ..
or the like. The hydrolysis may include a method using an acid or base and the like. These methods may be selected depending on kind of the protcctive groups to be eliminated.
The hydrolysis using an acid is one of the most common and preferable methods for eliminating the protective groups such as phenyl(lower)al~yl, substituted phenyl(lower)alkyl, lower alkyl, substituted lower alkyl, or the likc. Suitable acid may include inorganic or organic acid, for exa~ple, formic acid~
trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and the like. The present reaction m~y be carried out in the presence o~ anisole. The acid suitablc for the reaction can be selected according to the protec~ive group to be eliminated and other factors.
The hydrolysis using an acid may be carried out in the presence of a solvent, such as an organic solvent, water or a mixed solvent thereof.
The reaction temperature is not critical and may be suitably selected in accordance with the kind of thc protectivc group and the elimination method, and the present reaction is preferably carried out under a mild condition such as under cooling, at ambient temperature or slightly warming.
The present invention includes, within its scope, the cases that the protected carboxy group for R3 is transformed into the free carboxy group; that the protected amino group is transformed into the free amino group; that the protected imino group is transformed into the free imino group; that the acyloxy group is transformed into the hydroxy group; and/or that the carbamoyloxymethyl group having acyl group is transormed into the free carbamoyloxymethyl group; during the reaction or post-treating in the present reaction.
Process 5:
, . . . . ~ .. . .
The object compound (Id) or a salt thereof can be prepared by subjecting the compound (Vb) or a salt thereo to elimination reaction of the protective group of the amino.

Suitable salt of the compound (Vb) can be referred to the ones exemplified for the compound (IV).
The present elimination reaction may include an elimination method using a base, for example, an inorganic base s such as an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.) or alkali mctal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an organic base such as an alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, etc.), a trialkylamine (e.g., trimethylamine, triethylamine, etc.), triethanolaminc, ~',N-dimethylaniline, N,N-dimethylbenzylamine, N-methylmorpholine or pyridine; and an elimination reaction using basic alumina, basic ion exchange resin, acid (e.g., trifluoroacetic acid, trifluoroacetic acid-anisole, etc.). The prescnt elimination reaction is usually carried out in water, hydrophilic solvent or a mixture thereof. The reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or under cooling.
The present invention includes, within its scope, the cases that the protected carboxy group or salts in the compound (Vb) may be converted into free carboxy group, and that the protected amino and/or imino group may be converted into the free amino and/or imino group, respectively in the course of the reaction or in post-treatment.
Process 6:
The object compound (Ie) or a salt thereof can be prepared by reacting the compound (Vc) or a salt thereof with the compound (Vd) or its reactive derivative at the mercapto group.

Suitablc salt o the compound (Vc) can be referred to the ones exemplified for the compound (IV).
The suitable reactive derivativc at the mercapto group of the compound (Vd) may include a metal salt ~such as alkaii metal salts (e.g., sodium salt, potassium salt, etc.) or the like.
The present reaction may be carried out in a solven~
such as water, acetone, chloroform, nitrobcnzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethylsulfoxide, or any other solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydro-philic solvents may be used in a mixture ~ith water. The reaction is preerably carried out in weekly basic or around neutral condition. When the compound (Vc) and or the thiol compound (Vd) is used in a free form, the reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, organic base StlC]l as trialkylamine, pyridine, and the like. The reaction temperaturc is not critical, and the reaction is usually carried out at ambient temperature or under warming. The reaction product can be isolated from the reaction mixture by conventional methods.
The reaction of the compound (Vc) with the compound (Vd) includes, within its scope, the cases that the protected carboxy group or salts in the compound (Vc) may be converted into free carboxy group; that the protected amino and/or imino group may be converted into free amino and/or imino group;
and that the acyloxy group may be converted into hydroxy group;
respectively in the course of the reaction or in post-treatment.

Process 7:
The object compound (If) or a salt thereof can be prepared by treating the compound ~Ve) or a salt thereof with an acid.
s Suitable salt of the compound (Ve) can be refcrred to the ones exemplified for the compound (IV).
Suitable acid to bc used in the present reaction may include an inorganic acid (e.g., hydrochloric acid, hydrobromic ....
acid, sulfuric acid, ctc.) or an organic acid (e.g., or~.ic acid, acetic acid, etc.).
The prescnt reaction is usually carried out in a sol~ent such as water, acetonc, acetic acid or any other solvent which does not advcrsely influence the reaction. Among these solvents hydrophi]ic solvcnts can be used as a mixture with water.
The reaction tem~erature is not critical and the reactioJI is preferably carried out under cooling to warming.
Process ~:
The object compound (Ig) or a salt thereof can be prepared by oxidizing the compound (Ve) or a salt thereof.
Suitable oxidizing agent used in the present reaction may include Jones reagent being used by a combination of sulfuric acid and chromium trioxide, manganese dioxide, a reagent being used by a combination of dimethylsulfoxide and N,N'-dicyclohexyl-carbodiimide etc., and the like.
The present reaction is usually carried out in a solvent such as water, acetone, dimethylformamide or any other solvent which does not adversely affect the reaction. These solvents may be used as a mixture thereof.
The reaction temperature is not critical and the reaction is preferably carried out under cooling or around ambient temperature Processes for ~reparing the starting compound (III) i.e., syn-isomer and anti-isomer thereof used for References are explained in details as follows.
(A) Process of (VI)+(VII) -~ ~VIII) [Scheme (l)(i)~
The compound (VIII) can be prepared by reacting the compound (VI) with the compound (VII).
The present reaction is usually carried GUt in a solvent such as water, eth.~llol, acetone, ether, dimethylformamide or any other solvent which does not adversely influence the present reaction. The reaction is preferably carried ou~ in the presence of a base such as an inorganic base or an organic base as aforementioned. The reaction tenlperature is not critical and the reaction is usually carried out under cooling to under heating of boiling point of the solvent.
(B) Processes of (IX) ~ (X) [Scheme (l)(ii)] and (XXXII) ~XXXIII) [Scheme (6)(ii)]
The compounds (X) and (XXXIII) can be prepared by oxidizing the comp~unds (IX) and (XXXII), respectively.
The present oxidation reaction is conducted by a conventional method which is applied for the transformation of so-called activated methylene group into carbonyl group. That is, the present oxidation is conducted by a conventional n~ethod such as oxidation by using a conventional oxidizing agent such as selenium dioxide, potassium permanganate or tile like. The present oxidation is usually carried out in a solvent which does not adversely influence the reaction, for example, water, dioxane, pyridine, tetrahydrofuran, and the like.
The reaction temperature is not critical and the reaction is preferably carried out under warming to heating.
(C) Process of (XI)~(XII) [Scheme (1) tii.i)~

The compound (XII) can be prepared by subjecting the compound (XI) to elimination reaction of the ar(lower)alkyl group.
The prescnt elimination method may include all conventional methods used in the elil~ination reaction of the ar(lower)alkyl group, for exampie, hydrolysis, reduction, etc.
The hydrolysis using acid is one of the most pre-ferable method and the acid to be used may include an inorganic acid (e.g., hydrochloric acid, hydrobromic acid~
etc.), an organic acid (e.g., formic acid, acetic acid, trifluoroacetic acid, etc.) and a mixture thereof. The pre-sent reaction can be carried out in a solvent such as water, an organic solvent or a mixture thereof or without solvent.
The reaction temperature is not critical and the reaction is preferably carried out undcr warming to heating.
(D) Processes of (XIII)+(~.IV) ~ (IIIa) [Scheme (1) (iv)], (XXXIII)~(XIV) ~ (XXXV) [Scheme (6) (ii)~ and ~XXXIV)+(XIV) + (IIIf) [Scheme (6) (ii)]
The compounds (IIIa), (XXXV) and (IIIf) can be pre-pared by reacting the compounds (XIII), (XXXIII) and (XXXIV) with the compound (XIV) or a salt thereof, respectively.
Suitable salt of the compound (XIV) may include an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate, etc.), an organic acid salt (e.g., acetate, p-toluenesulfonate, etc.) and the like.
The present reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol, ethanol, etc.), a mixture thcreof or any other solvent which does not adversely influence the present reaction.
The present reaction, in case that the compound (XIV) is used in its salt form, is preferably carried ou~
in the presence of a base, for example, an inorganic base such as alkali metal (e.g., sodium, potassium, etc.), alkaline earth metal (e.g., magnesium, calciùm, etc.), tile hydroxide or carbonate or bicarbonat~ thereof or the like, and an organic base such as alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, etc.), trialkylamine (e.g., trimethylamine, triethylamine, etc.), N,N-dialkylami3le (e.g., N,N-dimethylaniline, etc.), N,N-dialkylbenzylamine (e.g., N,N-dimethylbenzylamine, etc.), pyridine or the li~e.
The reaction tempcrature is not critical and the reaction is usually carried out under cooling to heating.
In the present reaction, the mixture of syn- and anti-isomers of the compound (IIIa), (XXXV) or (IIIf) may be obtained according to reaction conditions etc., and in such case, both isomers may be resolved by conventional manners from the mixture. For example, the mixture is firstly esterified and the resulting esters are resolv~d, for example, by chromatography into each isomer. The resolved each isomer of esters is hydrolyzed by a conventional method to give the corresponding syn- or anti-carboxylic acid.
In order to obtain syn-isomer of the compound (IIIa), (XXXV) or ~IIIf) selectively and in high yield the present reaction is preferably carried out around neutral condition.
(E) Processes of (XV) ~(XVI) [Scheme (2) (i)] and (XXXIV) + ~XXXVI) [Schme (6) (ii)]
The compounds (XVI) and (XXXVI) can be prepared by reacting the compounds (XV) and (XXXIV) with hydroxylamine or a salt thereof, respectively.
Suitable salt of hydroxylamine can be referred to the ones exemplified for the compound (XIV).
The reaction conditions of the present reaction can also be referred to the ones exemplified for t.he pro-cesses of tXIII)+(XIV) ~(IIIa), (XXXIII)+(XIV) ~ (XXXV) and (XXXIV)+(XIV~ ~(IIIf) as mentioned in aforement oned (D).
(F) Processes of (XVII) ~ (XVIII~ [Scheme (2) (ii)~, (XXIV) ~(XXV) [Scheme (4) (ii)]
(XXVI) +(XXVII) [Scheme (5)] and (XXXVII) ~ (XXXVIII) LScheme (6) (iii)]
The compounds (XVIII), (XXV), (XXVII) and (XXXV~
can be prepared by alkylating the compounds (XVII), (XXIV~, (XXVI) and (XXXVII), respectively.
The alkylating agent to be used in the prcsent alkylation reaction may include di(lower)alkyl sulfate (e.g., dimethyl sulfate, diethyl sulfate, etc.), diazo(lower)alkane (e.g., diazomethane, diazoethane, etc.), lower alkyl halide (e.g., methyl iodide, ethyl iodide, etc.), lower alkyl sul-fonate (e.g., methyl p-toluenesulfonate, etc.),~ and the like.
The reaction using di(lower)alkyl sulfate, lower alkyl halide or lower alkyl sulfonate is usually carried out in a solvent such as water, acetone, ethanol, ether, dimethylformamide or any other solvent which does not adversely influence the reaction.
The present reaction is preferably carried out in the presence of a base such as an inorganic base or an organic base as aforementioned.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating around boiling point of the solvent.
The rcaction using diazoalkane is usually carried - 3~ -out in a solvent such as ether, tetrahydrofuran or the like.
The reaction temperature is not critical and tne -~ reaction is usually carried out under cooling or at ambient temperature.
(G) Processes of (XVIII) ~ (IIIb) [Scheme (2) (ii)l and (XXXVIII) ~ (IIIg) [Scheme (6) (iii)]

The compounds (IIIb) and (IIIg) can be prepared by subjecting the compounds (XVIII) and (XXXVIII) to hydrolysis, respectively.
The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an inorganic base and an organic base such as an alkali metal (e.g., sodium, potassium, etc.?, an alkaline earth metal (e.g., magnesium, calcium, etc.), the hydroxide or carbonate or bicarbonate thereof, trialkylamine (e.g., trimethylamine, - triethylamine, etc.), picoline, 1,5-diazabicyclo[4,3,01non-5-ene, 1,4-diazabicyclo-[2,2,2]octane, 1,5-diazabicyclo[5,4,0]-undecene-5, or the like.
Suitable acid may include an organic acid (e.g., formic acid, acetic acid, ~ropionic acid, trifluoroacetic acid, etc.) and an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).
The reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol, ethanol, etc.), a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can also be used as the solvent.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

(H) Process of (XIX) + (IIIC) ~Scheme (3)]
The compound (IIIC) can be prepared by subjecting the compound (XIX) to acylation.
The acylating agent to be used for the present reaction and the reaction conditions of the present reaction can be referred to the ones exemplified for Process 3.
(I) Process of (XX) ~ (XXI) [Scheme (4) (i)~
The compound (XXI) can be prepared by subjecting the compound (XX) to nitrosation.
The nitrosating agent to be used for the present reaction may include conventional agent which give C-nitroso compound by reacting with activated methylene group, such as nitrous acid, alkali metal nitrite (e.g., sodium nitrite, etc.), lower alkyl nitrite (e.g., isopentyl nitrite, t-butyl nitrite, etc.) or the like.
In case that salt of nitrous acid is used as nitrosating agent, the present reaction is usually carried , out in the pr_sence of an acid such as an inorganic acid or an organic acid (e.g., hydrochloric acid, acetic acid, etc.) In case that ester of nitrous acid is used, the present reaction is preferably carried out in the presencc of a strong base such as alkali metal alkoxide or the like.
The present reaction is usually carried out in a solvent such as water, acetic acid, benzene, alcohol te.g., ethanol, methanol, etc.) or any other solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient -~ temperature.

(J) Processes of (XXI)+(XXII) ~(XXIII) [Scheme (4) (i)]
and (XXVIII)+(XXII) ~(XXIX) [Scheme ~5)~
The compounds (XXIII~ and (XXIX) can be prepared by reacting the compounds (XXI) and ~XXVIII) with the compound (XXII), respectively.
The present reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanoi, ethanol, etc.), benzene, dimethylacetamide, dimethyl~ormamidc, tetrahydrofuran, a mixture thereof or an~ other solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is usually carried out from ambient temperature to under heating around the boiling pOillt of the solven~.
In ordcr to obtain syn-isomer of thc compound (XXIII) or (XXIX) selectively and in high yield, it is necessary to use syn-isomer of the starting compound (XXI) or (XXVIII) and the present reaction is preferably carried out aroun~ neutral condition in the presence of a base as aforement~oned.
Preferable example of base may be week base such as alka~
metal acetate (e.g., sodium acetate, potassium acetate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.) or the like.
(K~ Processes of (XXIII) ~ (XXIIIa) [Scheme (4) (i)], 2S (XXV? ~ (IIId) [Scheme (4) (ii)], (XXIX) ~ (IIIe) [Scheme (5)], (XXXIII) ~(XXXIV) [Scheme (6) (ii)~
and (XXXV) ~(IIIf) [Scheme (6) (ii)]
The compounds (XXIIIa), (IIId), (IIIe), (XXXIV) and (IIIf) can be prepared by subjecting the compounds (XXIII), (XXV), (XXIX), (XXXIII) and (XXXV) to elimination reaction of the protective group of the carboxy, respectively.
; In the present elimination reaction, conventional methods used in the elimination reaction of the protected carboxy, for example, hydrolysis etc. can be `applicable.
When the protective group is an ester, it can be eliminaLed by hydrolysis.
The present hydrolysis is carried out according to similar manners to those of processes (XVIII) ~(IIIb) and (XXXVIII) ~ (IIIg) as mentioned in aforesaid (G).
(L) Process of (XXVII) ~(XXVIII) [Schcme (5)]
The compound (XXVIII) can be prepared by halogenating the compound (XXVII).
The halogenating agent to be used in the prescnt reaction may include a conventional halogellating agent used in halogenation of so-called activated methylene group such as halogen (e.g., bromine, chlorine, etc.),sulfuryl halide (e.g., sulfuryl chloride, etc.), hypohalitc (e.g., hypochlorous acid, hypobromous acid, sodium hypochlorite, etc.), N-halogenated-imide (e.~., N-bromosuccinimide, N-bromophthalimide, N-chlorosuccinimide, etc.) and the like.
The present reaction is usually carried out in a solvent such as an organic acid (e.g., formic acid, acetic acid, propionic acid, etc.), carbon tetrachloride or any other solvent which does not adversely in~lucnce the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling~at ambiellt tem-perature, under warming or heating.
(M) Processes of (XXX) ~ (XXXI) [Scheme t6) (i)~ and (XXXIX)~ (IIIh) [Scheme (7)]
The compound (XX-XI) can be prepared by reacting the compound (XXX) or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent and the compound (IIIh) can be prepared by reacting the compound (XXXIX) or its reactive derivative at the amin`o group or a salt thereof with an amino-protecting agent.
Suitable reacti~e derivative at the amino group of the compound (XXX) or ~XXXIX) and suitable salt of the compound (XXX) or (XXXIX) may include the same ones as illustrated in the explanations of the reactive dcrivative at the amino group o~
the compound (II) and salt of the compound (II), respecti~ely.
Suitable amino-protecting agent may include acylating agent which may include an aliphatic, aromatic and heterocyelic carboxylic acid, and the corresponding sul~onic acid, haloformic acid ester, isocyanic acid ester and carbamic acid, and the corresponding thio acid thereof, and the reactive derivative of the above acids.
Suitable reactive derivative of the above acids may include the same ones as illustrated in the cxplanation of Process 3 The example of the protective group (e.g. acyl group) to be introduced into the amino group in the compound (XXX) or (XXXIX) by the above amino-protecting agent (e.g.
acylating agent) may be the same protecting group (e.g., acyl group) as illustrated in the explanation of the protective group moiety (e.g., acyl moiety) in the term "acylamino".
The present amino-protecting reaction is carried out in a similar manner as illustrated in thc reaction of the compound (II) with the compound (III) (Process 1).
; (N) Process of (XXIIIb) ~ (XXXIII) [Scheme (6) (ii)l The compound (XXXIII) can be prepared by subjecting the compound (XXIIIb) to hydrolysis.

The present hydrolysis is carried out in the presence of alkali metal bisulfite (e.g., sodium bisulfite, etc.) titanium trichloride, inorganic or organic acid such as hydrohalogenic acid (e.g., hydrochloric acid, hydrobromic acid, etc.), formic acid, nitrous acid or the like. Hydrohalogenic acid is preferably used in a combination of aldehyde (e.g., formaldehyde, etc.).
The present reaction is usually carried out in a solvent such as water, aqueous alcohol (e.g., aqueous methanol, aqueous ethanol, etc.), water-acetic acid or any other solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is usually carried out at ambient temperature, under warming or heating.
In the present reaction, protected carboxy group may be occasionally transformed into free carboxy group. l`his case is also included in the scope of the present invention.
In the aforementioned reactions and/or the post-treating of the reactions of the present inventio~i, the afore-mentioned tautomeric isomers may be occasionally transformed into the other tautomeric isomers and such case is also included in the scope of the present invention.
In case that the object compound (I) is obtained in a form of the free acid at 4 position and/or in case that the object compound (I) has free amino group, it may be transformed into its pharmaceutically acceptable salt as aforementioned by a conventional method.
The object compound (I) and pharmaceutically acceptable salt thereof of the present invention are all novel compounds which exhibit high antibacterial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative bacteria and are useful as antibacterial agents. Particularly, it is to be noted that the object compound (I), i.e., syn^isomer has much higher S antibacterial activities than the corresponding anti-iso.ner to the compound (I), and accordingly the object compound (I), i.e., syn-isomer is characterized by having much superiority to the corresponding anti-isomer ln the therapeutic vaiue.
Now, in order to show the utility of the object compound (I), with regard to some representative compounds of this invention, there are shown thc test data on the in vitro anti-bacterial activity, the test data on in vivo, i.e. the protecting effect against experimental in~ections and the acute toxicity in the following. Additionally, there are also shown the comparative test ~ata on in vitro antibacterial activities relating to the corresponding anti-isomer to the object compound (I) for the reference's sake in the following.
Test compounds tl) 7-[2-Methoxyimino-2-~3 hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3~
methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (4) 7-~2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]^3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (5) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-(i,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic aci~ ~syn isomer) (6) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetarllido~-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (7) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (8) 7-[2-Methoxyinlino-2-(2-amino-1,3-thiazol-4-yl)ace~atnido]-cephalosporanic acid (syn isomer) (9) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-cephalosporanic acid (anti isomer) (10) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acet-amido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (11) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acet-amido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carbo-xylic acid (anti isomer) (12) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acet-amido)cephalosporanic acid (syn isomer) (13) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (14) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamidol-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (15) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (16) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(S-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-~ 47 -carboxylic acid (syn isomer) (17) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido~-3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (18) 7-~2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) 1. In vitro antibacterial activity:
Test Method 10 In vitro antibacterial activity was determined by the two-fold agar-plate dilution method as described beloli.
One loopful o an overnight culture of each test strain in Trypticase-soy broth (108 viable cells per ml.) was streaked on heart infusion agar (HI-agar) containing graded concentrations of antibiotics, and the minimal inhi-bitory concentration (MIC) was expressed in terms of ~g/ml.
after incubation at 37C for 20 hours.

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As clearly seen from the above test results, the object compounds (I) of the present invention, i.e., syn-isomers have much higher antibacterial activity as compared with the corresponding anti-isomers thereof.
2. Protecting effect against experimental infections in mice:
Test Method Male ICR strain mice aged 4 weeks, each weighing 20-23 g were used in groups of 8 mice. The test bacteria were cultured overnight at 37C on IlI-agar and then suspended in 2.5 - 5~ mucin solution to obtain the suspension correspond-ing to each challenge cells. Mice were inoculated intra-peritoneally with O.S ml of the suspension. A solution containing each test compounds was given subcutaneously to the mice in various dosage one hour after challenge. The ED50 values were calculated from the number of surviving mice for each dosage after one week of observation.

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- 3. Acute Toxicity in Mice:
The same strain mice as aforesaid protecting test against experimental infections were used in groups of 10 mice.
Test compound ~) (2 g) was administered intràvenously to said mice. All mice survived ~ithou. showing any disorder after one week observation.
~or therapeutic administration, the objec~ compound (I) of the present invention is uscd in the form of conver.tional pharmaceutical preparation t~hich contains said compound, ~s an active ingredient, in admixturc Wit}l a ph.-rmaccuticall~
acceptable carriers such as an organic or inorganic soli~l or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparations may be in solid form SUC}I as capsule, tablet, dragee, ointmcnt or suppository, or in liquid form such as solution, suspension, or emulsion. If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and the other cominonly used additives.
While the dosage of the compounds may vary from and also depend upon the age, conditions of the paticnt, a kind of disease, a kind of the compound (I) to be applied, etc., an average single dose of about 50 mg., 100 mg., 250 mg., and 500 mg. of the object compound (I) of the present invention has proved to be e fective in treating diseases infected by pathogenic bacteria.
In general, amounts between 1 mg. and about 1000 mg.
or even more niay be administered to a patient.
The follo~lng examples are givcn for the purpose of illustrating the present invention:-- 53 - ,.
, ~

ExamPle 1 A mixture of dimethylformamide (2.81 g.) and phosphorus oxychloride (5.36 g.) was warmed at 40C for 1 hour. After cooling, methylene chloride (60 ml.) was added thereto and distilled off. To the residue was added dry ethyl acetate (50 ml.). Then, 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (6.83 g.) was added thereto at 5C with stirring under ice-cooling. The resultant mixture was then stirred for 50 minutes at the same temperature.
On the other hand, 7-amino-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (11.5 g.) and bis(trimethylsilyl)acetamide (28.4 g.) were dissolved in dry ethyl acetate (150 ml.) and stirred under cooling, to which was at a time added the above obtained solution at -40C. After stirring for 2 hours at -30 to -20C, a saturated sodium chloride aqueous solution (100 ml.) was added at -20C to the reaction mixture. The mixture was stirred for 5 minutes. The precipitates were filtered off and ethyl acetate layer in the filtrate was separated. The aqueous layer was extracted twice with ethyl acetate (50 ml.). Ethyl acetate layer separated from the filtrate and the extracts were combined. The combined ethyl acetate solution was washed with a saturated sodium chloride aqueous solution (50 ml.). To the ethyl acetate layer was added activated charcoal and the mixture was stirred for 5 minutes and filtered. Water (100 ml.) was added to the filtrate and the resulting mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated, and washed with methylene chloride. After the aqueous layer was separated, methylene chloride was removed from the aqueous layer by bubbling of nitrogen gas under ice-cooling. After filtration, the aqueous layer was adjusted ' ~;;r ~ - 54 -to pH 2 with 10% hydrochloric acid with stirring and ice-cooling.
Precipitating crystals were collected by filtration, washel -~ with water and dried to give 7-[2-methoxyimino-2-(3-hydroxy-phenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-y~l)thiomethyl-3-S cephem-4-carboxylic acid (syn isomer) (11.3 g.).
I.R. spectrum (Nujol) 3250, 1770, 1725, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.76 (lH, d, J=8Hz) 6.7-7.40 (4H, m) 5.86 (lH, dd, J=5,8Hz) 5.18 (lH, d, J=5Hz) 4.34 (2~1, ABq, J=13Hz) - 3.92 (6H, s) 3.72 (2H, ABq, J=17Hz) Example 2 A mixture of dimethylformamide (1.41 g.) and phosphorus oxychloride (2.95 g.) was warmed for 1 hour at 40C. After cooling, methylene chloride (30 ml.) was added thereto and distilled off. To the residue was added dry ethyl acetate ~20 ml.). 2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (3.4 g.) was added thereto with stirring and ice-cooling and the mixture was stirred for 30 minutes under ice-cooling. On the other hand, 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid ~4.8 g.) was dissolved in a solution of trimethylsilylacetamide (27.5 g.) in dry ethyl acetate (70 ml.). To the solution was at a time added the above obtained solution at -30C and the mixture was stirred for 1.5 hours at -30 to -10C. A saturated sodium chloride aqueous solution was added to the reaction mixture at -20C. The ethyl acetate ~ a~k ~ - 2 ~ 337522 layer was separated and the aqueous layer was extracted with ethyl acetate. Two ethyl acetate layers were combinea, ~ashed with a sodium chloride aqueous solution and treated with activated charcoal. After filtration, water (100 ml.) was added to the S filtrate and the mixture was adjusted to pH 7 with a sodium bicarbonate aqueous solution. The aqueous layer was separated and ethyl acetate was added thereto. The mix~ure was adjusted to pH 5 with 10% hydrochloric acid and the aqueous layer was separated. Ethyl acetate was added thereto and the mixture was adjusted to pH 2 with 10% hydrochloric acid. The e~nyl acetate layer was separated and the aqueous layer was further extracted with ethyl acetate. Two ethyl acetate layers were combined, washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diisopropyl ether.
The powder was collected by filtration and dried to give 7-~2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyl-oxyme~hyl-3-cephem-4-carboxylic acid (syn isomer) (3.26 g.).
I.R. spectrum (Nujol) 3500-3200, 1765, 1720, 1655 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.64 (lH, d, J=8Hz) 6.70-7.20 (4H, m) 6.78 (2H, s) 5.92 (lH, dd, J=5,8Hz) 5.16 (lH, d, J=5H~
4.73 (2H, ABq, J=13Hz) 3.91 (3~l, s) s- y ~ 3.72 (2H, ABqJ J=17Hz) ~r ~ - 3 7-[2-Methoxyimino-2-(3-hydroxyphenyl~acetamido~-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.98 g.) was suspended in water (15 ml.) and dissolved by adding sodium bicarbonate (0.35 g.) with stirring at ambient temperature.
The solution was lyophilized and dried to give sodium 7-[2-methoxy-imino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate (syn isomer) (1.9 g.).
I.R. spectrum (Nujol) 3300, 1765, 1715, 1665 cm~
N.M.R. spectrum (D2O, ~) ppm 6.83-7.60 (4H, m) 5.85 tlH, d, J=SHz) 5.17 (lH, d, J=SHz) 4.77 (2H, ABq, J=13Hz) lS 4.03 (3H, s) 3.48 (2H, ABq, J=18Hz) Example 3 A mixture of dry dimethylformamide (0.18 g.) and phosphorus oxychloride (0.38 g.) was stirred for 30 minutes at 40C. Dry methylene chloride (15 ml.) was added thereto and distilled off under reduced pressure. To the residue was added dry ethyl acetate (lS ml.) and 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (0.53 g.) was added thereto with stirring at -20C. The mixture was stirred fGr 1 hour below -10C. On the other hand, a mixture of 7-amino-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (1 g.), trimethylsilylacetamide (S g.) and dry ethyl acetate (25 ml.) was stirred for 1 hour at ambient temperature.
To this solution was dropwise added the above obtained solution with stirring below -10 and the resulting mixture was stirred ~ -4 ~ 337522 . .
for 2 hours at the same temperature. Water (50 ml.) and ethyl acetate (50 ml.) were added to the reaction mixture at -20C and the mixture was shaken. The organic layer contzining 7-[2-methoxyimino-2-(3-chloro-4-hydroxyphenyl~)acetamido~-3-tri-chloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic ac~d (syn isomer) was adjusted to pH 7.0 by adding water (S0 ml.) and sodium bicarbonate and the mixture was stirred for 2 hours at ambient temperature. Ethyl acetate (S0 ml.) was added to the aqueous layer and the mixture was adjusted to pH S.0 with 10% hydrochloric acid. The aqueous layer was separated, adjusted to pH 2.0 with 10~ hydrochloric acid and extracted with ethyl acetate (S0 ml.). The extract was washed with ice-water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was lS thoroughly washed with ether, collected by filtration and dried to give 7-[2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid tsyn isomcr) (0.3 g.)-I.R. spectrum (Nujol) 3450, 3300, 1770, 1730, 1715, 1660, 1650, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.72 (lH, d, J=8Hz) 7.48 (lH, d, J=2Hz) 7.40 (lH, dd, J=2,8Hz) 6.98 (lH, d, J=8Hz) 6.60 (2H, s) 5.70 (lH, q, J=SHz) 5.20 (lH, d, J=SHz) 4.74 (2H, ABq, J=13Hz) 3.90 (3H, s) 3.50 (2H, ABq~ J=18Hz) -58- ~ ~ 5 ~ 337522 Example 4 2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (1.1 g.) and 7-amino-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (2.35 g.) were reacted and post-treated according to a similar manner to that of Example 3 to give 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g.). This compound is identified with the compound obtained in Example 2 by I.R. and N.M.R. spectra.
Example 5 (a) 2-t-Butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxy-phenyl)acetic acid (syn isomer)(lg.) and 7-amino-3-(1-~ethyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1 g.) were reacted according to similar manners to those of Examples 1 and 2 to gi~e powder of 7-[2-t-butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g.).
(b) The powder obtained in Example 5(a) (1.5 g.) was added to a mixture of anisole (1.5 ml.) and trifluoroacetic acid (6 ml.) and the resulting mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was adjusted to pH 8 by adding a sodium bicarbonate aqueous solution (50 ml.), ethyl acetate (50 ml.) and sodium bicarbonate under ice-cooling. The aqueous layer was separated, adjusted to pH 5.0 with 10% hydro-chloric acid and washed with ethyl acetate (50 ml.). The aqueous layer was further adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate (100 ml.). The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was dissolved in pH 5.0 acetate buffer and subjected to column ~ _ 6 chromatography on Woelm neutral alumina (trade mark: made by ICN Company) using pH 5.0 acetate buffer as developing solvent.
The eluate was adjusted to pH 2.0 with 10% hydrochloric acid under ice-cooling. Precipitating materia~s were collected by filtration, washed with water and dried to give 7-~2-carboxy-methoxyimino-2-(3-chloro-4^hydroxyphenyl)acetamido]-3-(;-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g.), mp 145 to 148C (dec.).
I.R. spectrum (Nujol) 3400, 3200-3300, 2500-2600, 1780, 1720, 1670, 1600 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 7.50 (lH, d, J=2Hz) 7.45 (lH, d~,J=2,8Hz) 7.10 (lH, d, J=8Hz) 5.90 (lH, q, J=5Hz) S,22 (lH, d, J=5Hz) 4.70 (2H, s) 4.35 (2H, ABqJ J=13Hz) 3.95 (3H, s) ,~
-~ 3.75 (2H, ABq, J=18Hz) Example 6 (a) 2-(1-t-Butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2 g.) and 7-amino-3-(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (2 g.) were reacted according to similar manners to those of Examples 1 and 2 to give powder of 7-[2-(1-t-butoxycarbonyl-ethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.6 g.).
~ - 7 (b) The powder obtained in Example 6(a) (3.6 g.), anisole (4 ml.) and trifluoroacetic acid (16 ml.) were reacted according to a similar manner to that of Example 5(b) to give yel,ow powder of 7-[2-(1-carboxyethoxyimino)-2-(3-chloro-4-~ydroxyphenyl)acet-S amido]-3~ methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g.), mp 147 to 151C (dec.).

I.R. spectrum (Nujol) 3500, 3250, 2500-2600, 1780, 1730, 1660, 1630, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.62 (lH, d, J=8Hz) 7.46 (lH, d, J=2Hz) 7.34 (lH, dd, J~2,8Hz) 7.04 (lH, d, J=8Hz) 5.90 (lH, q, J=SHz) 5.22 (lH, d, J=SHz) 4.73 (lH, q, J=6Hz) 4.33 (2H, ABq, J=13Hz) 4.00 (3H, s) 3.73 (2H, ABq, J=18Hz) 1.37 (3H, d, J=6Hz) Example 7 The following compounds were obtained according to similar manners to those of Examples 1 and 2 (1) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-~-(4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn ~
isomer). ~`
I.R. spectrum (Nujol) 3250, 1775, 1710, 1665 cm~l `

~ - 8 N.M.R. spectrum (d6-DMSO, ~) ppm 9.67 (lH, d, J=8Hz) 8.40 tlH, s~
6.70-7.43 (4H, m) 5.82 (lH, dd, J~5,8Hz) 5.13 (lH, d, J=5Hz) 4.18 (2H, ABqJ J=13Hz) 3 90 (3H, s) 3 67 (2H, broad s) (2) 7-[2-Methoxyimino-2-~3-hydroxyphcnyl)acetamidol-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.78 (lH, d, J=8Hz) 9.55 (lH, s) 6.70-7.40 (4H, m) 5.89 (lH, dd, J=5,8Hz) 5.22 (lH, d, J=5Hz) 4.46 (2H, ABq, J=13Hz) 3.92 (3H, s) 3.76 (2H, ABq, J=18Hz) (3) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(5-methyl-1,3,4-tniadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.72(1H, d, J=8 Hz~
6.62-7.40(4H, m) S.94 (lH, dd, J-5,8Hz) 5.18 (lH, d, J=SHz) 4.18 (2H, ABq, J=13Hz) 3.8g (3H, s) S 3.70 (2H, ABq, J=17Hz) 2.65 (3H, s) (4) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-cephalosporanic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1785, 1740, 1720 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.78 (lH, d, J=8Hz) 6.86-7.36 (4H, m) S.86 (lH, dd, J=5,8Hz) lS 5.18 (lH, d, J=5Hz) 4.84 (2H, ABq, J=13Hz) E - lO

~ 337522 3.98 (3H, s) 3.54 (2H, ABq~ J=17Hz) 2.00 (3H, s) . ~-- ~
(5) 7-[2-Methoxyimino-2-t3-methoxyphenyl)acetamido~-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.78 (lH, d, J=8Hz) 6.95-7.54 (4H, m) 5.94 (lH, dd, J=5,8Hz) 5.18 (lH, d, J=SHz) 4.12 (2H, ABq~ J=13Hz) 3.92 (6H, s) 3.76 (3H, s) 3.72 (2H, ABq, J=18Hz) (6) 7-[2-Methoxyimino-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J~8Hz) 7.44 (2H, d, J=8Hz) 6.84 (2H, d, J=8Hz) 5.86 (lH, dd, J=5,8Hz) 5.18 (lH, d, J=5Hz) 4.34 (2H, ABq, J-13Hz) 3.93 (3H, s) 3.87 (3H, s) 3.74 (2H, ABq, J=18Hz) (7) 7-[2-Methoxyimino-2-(3-chloro-4-hydroxyphenyi)acetami~o]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxyiic S acid tsyn isomer), mp 145 to 148C (dec).
I.R. spectrum (Nujol) 3500, 3250, 2500-2600, 1780, 1720, 1655, 1625, 1600 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 10.80 (lH, broad s) 9.68 (lH, d, J=2Hz) 7.46 tlH, d, J-2Hz) 7.32 tlH, q, J=2,8Hz) 7.00 tlH, d, J=8Hz) lS 5.80 (lH, q, J=5Hz) 5.16 tlH, d, J=SHz) 4.28 (2H, ABq, J=13Hz) 3.92 (3H, s) 3.87 (3H, s) ~ .. ,~.. ~ .
3.72 (2H, ABq, J=18Hz) t8) 7-[2-Methoxyimino-2-(3-chloro-4-methoxyphenyl)acet-amido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 143 to 145C (dec.).
I.R. spectrum (Nujol) 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.76 (lH, d, J=8Hz) 7.56 (lH, d, J=2Hz) 7.48 (lH, dd, J~2,8Hz) 7.22 (lH, d, J=8Hz) ~-12 ~ 337522 5.84 (lH, q, J-SHz) 5.18 (lH, d, J=5Hz) 4.27 (2H, ABq, J=13Hz) 3.90 (6H, s) 3.88 (3H, s) 3.70 (2H, ABq, J=18Hz) t 9) 7-[2-Methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetamido~-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 149 to 152C (dec.).
I.R. spectrum (Nujol) 3400-3450, 3200, 2500-2600, 1780, 1720, 1660, 1620, 1600, 1535, 1350 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.72 (lH, d, J=8Hz) 7.97 (lH, d, J=2Hz) 7.72 (lH, dd, J=2,8Hz) 7.21 (lH, d, J-8Hz) 5.82 (lH, q, J=5Hz) 5.16 (lH, d, J=5Hz) 4.3 (2H, ABq~ J=13Hz) 3.92 (3H, s) 3.87 (3H, s) 3.72 (2H, ABq~ Jsl8Hz) ~O) 7-[2-Allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acet-amido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic ac;d (syn isomer), mp 163 to 165C (dec.).
I.R. spectrum (Nujol) 3200-3300, 2500-2600, 1780, 1720, 1670, 1600 cm~

N.M.R. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 7.40 (lH, d, J=2Hz) 7.30 (lH, dd, J=2,8Hz) 6.95 (lH, d, J=8Hz) 5.80 (2H, m) 5.30 (2H, d, J=8Hz) S.10 (lH, d, J=SHz) 4.60 (2H, d, J=SHz) 4.27 (2H, ABq, J=13Hz) 3.85 (3H, s) 3.65 (2H, ABq, J=18Hz) (1~ 7-~2-Allyloxyimino-2-(3-hydroxyphenyl)acetamido]~3-(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic lS acid (syn isomer), mp 149 to 152C (dec.).
I.R. spectrum (Nujol) 3250-3350, 2550-2600, 1780, 1730, 1670, 1650, 1600 cm~l N.M.R. spectrum ~d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 7.2-6.8 (4H, m) 6.1-5.8 (2H, m) 5.35 (2H, d, J=8Hz) 5.17 (lH, d, J=SHz) 4.7 (2H, d, J=SHz) 4.17 (2H, ABq, J=13Hz) 3.93 (3H, s) 3.75 (2H, ABq, J-18Hz) (1~ Sodium 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-cephalosporanate (syn isomer).

I.R. spectrum (Nujol~
3250, 1765, 1730, 1665 cm 1 N.M.R. spectrum (D2O, ~) ppm 6.83-7.13 (4H, m) 5.83 (lH, d, J=5Hz) 5.17 (lH, d, J=5Hz) 4.82 (2H, ABq, J=13Hz) 4.03 (3H, s) 3.50 (2H, ABq, J=17Hz) 2.1 (31~, s) (13) 7-[2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(4-hydroxy-phenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem--4-carboxylic acid (syn isomer), powder.
I.R. spectrum (Nujol) 3150, 1780, 1720, 1670 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.60 (lH, d, J=8Hz) 6.72-7.52 (7H, m) 5.80 (lH, dd, J=4,8Hz) 5.15 (lH, d, J=4Hz) 5.00 (2H, s) 4.28 (2H, ABq, J=13Hz) 3.90 (3H, s) 3.65 (2H, ABq, J=18Hz) (14) 7-[2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyl)acet-amido~-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), powder.
I.R. spectrum (Nujol) 3200-3300, 1780, 1720, 1660 cm 1 ~ - 15 N.M.R. spectrum td6-DMSO, ~) ppm 9.77 (lH, d, J=8Hz) 6.7-7.7 (7H, m) 5.83 (lH, dd, J=5,8Hz) S 5.29 (2H, s) 5.15 (lH, d, J=SHz) 4.3 (2H, ABq, J=13Hz) 3.92 (3~, s) 3.72 (2H, ABq, J=18Hz) (15) 7-[2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic -~````~~~ acid (syn isomer), colorless powder, mp 153 to 156C (dec.).
I.R. spectrum (Nujol) 3450, 3250, 2550-2600, 1780, 1725, 1665, 1630, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.71 (lH, d, J-8Hz) 7.50 (lH, d, J=2Hz) 7.36 (lH, dd, J=2,8Hz) 7.03 (lH, d, J=8Hz) 5.83 (lH, q, J=SHz) 5.17 (lH, d, J=SHz) 4.33 (2H, ABq, J=13Hz) 4.17 (2H, q, J=7Hz) 3.97 (3H, s) -- - 3.73 (2H, ABq, J=18Hz) 1.25 (3H, t, J=7Hz) (16) 7-~2-Allyloxyimino-2-(3-methoxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), powder, mp 135 to 138C (dec.) ~ - 16 I.R. spectrum (Nujol) 3300, 2600, 1785, 1730, 1670, 1645, 1600 c,n 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.82 (lH, d, J=8Hz) S 7.0-7.45 (4H, m) 5.8-6.2 (2H, m) 5.36 (2H, t, J=lOHz) 5.21 (lH, d, J=SHz) 4.72 (2H, d, J=SHz) 4.36 (2H, ABq, J=13Hz) 3.95 (3H, s) 3.91 (3H, s) 3.87 (2H, ABq, J=18Hz) (17) 7-[2-Ethoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), yellow powder, mp 145 to 148C (dec.).
I.R. spectrum (Nujol) 3450, 3250, 2500-2600, 1775, 1720, 1665, 1620, 1600 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 6.8-7.4 (4H, m) S.90 (lH, q, JsSHZ) 5.20 (lH, d, J=SHz) 4.36 (2H, ABq, J=13Hz) 4.20 (2H, q, J=7Hz) 4.00 (3H, s) 3.76 (2H, ABq, J=18Hz) 1.33 (3H, t, J=7Hz) (18) 7-[2-Ethoxyimino-2-(3-methoxyphenyl)acetamido]^3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), pale yellow powder, mp 140 to 143C (dec.j.
I.R. spectrum (Nujol) S 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm 1 N.M.R. spectrum (d6-~MSO, ~) ppm 9.71 (lH, d, J=8Hz) 6.9-7.5 ~4H, m) 5.90 (lH, q, J=5Hz) 5.17 (lH, d, J=5Hz) 4.33 ~2H, ABq, J=13Hz) 4.20 (2H, q, J=7Hz) 3.95 ~3H, s) 3.85 (3H, s) lS 3.75 ~2H, AB~, J=18Hz) 1.30 (3H, t, J=7Hz) (19) 7-[2-Allyloxyimino-2-~3-chloro-4-methoxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid tsyn isomer), pale yellow powder, mp 153 to 156C (dec ).
I.R. spectrum ~Nujol) 3250, 2600, 1780, 1720, 1670, 1645, 1630, 1600 cm 1 N.M.~. spectrum ~d6-DMSO, ~) ppm 9.65 (lH, d, J=8Hz) 7.27 (lH, d, J=2Hz) 7.20 (lH, dd, J=2,8Hz) 7.09 (lH, d, J=8Hz) 5.85-6.15 (2H, m) S.lS (2H, t, J=9Hz) S.OS (lH, d, J=SHz) 4.60 (2H, d, J=SHz) _71_ E - 18 3 95 (3H, s) 3.90 (3H, s) 3.47 (2H, ABq, J=18Hz) (20) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido~-3-carbamoyloxymethyl-3-cephem-4-carboxylic acîd (syn isomer).
I.R. spectrum (Nujol) 3450, 3250, 1765, 1710, 1655, 1530 crn N.M.R. spectrum (d6-DMSO, ~) ppm : 9.77 (lri ~ d, J=8Hz) 7.6 -7.1 (4H, m) 6.56 (2H, s) 5.83 (lH, dd, J=4,8Hz) 5.20 (lH, d, J=4Hz) 4.76 (2H, ABq, J=13Hz) 3.94 (3H, s) 3.55 (2H, broad s) 2.28 (3H, s) (21) 7-[2-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyi-3-cephem^4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3300, 1760, 1660, 1600, 1580, 1520 cm 1 .... , . ~, - N.M.R. spectrum (d6-DMSO, ~) ppm : 9.7 (lH, d, J=8Hz) 7.7 - 6.7 (9H, m) 5.8 - 5.4 (3H, broad s) 5.06 (lH, d, J=5Hz) 4.33 (2H, broad s) 3.9 (3H, s) 3.56 (2H, bro~d s) ~ - 19 (22) 7-[2-Methoxyimino-2-(3-mesylaminophenyl)acetamidoj-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 155 C (dec.).
I.R. spectrum (Nujol) 3300, 1780, 1730, 1670 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.98 (lH, s) 9.81 (lH, d, J=9Hz) 9.62 (lH, s) 5.90 (lH, dd, J=S, 9Hz) 5.24 (lH, d, J=SHz) 4.49 (2H, ABq, J=14Hz) 3.98 (3H, s) 3.77 (2H, broad s) 2.96 (3H, s) (2~) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido~-3-(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3450, 3300, 3200, 17~0, 1725, 1670 1620, 1590, 1520 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.77 (lH, d, J=7Hz) 7.6 -6.8 (6H, m) 5.83 ~lH, dd, J=4, 7Hz) 5.17 (lH, d, J=4Hz) 4.31 (2H, ABq, J=14Hz) 3.96 (6H, s) 3.72 (2H, broad s) 3o ~- 20 (24) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1735, 1675 cm 1 N.M.R. spectrum ~d6-DMSO, ~) ppm 9.81 (lH, d, J=8Hz) 9.62 (lH, s) 6.7 - 7.58 ~4H, m) 5.87 (lH, dd, J=5, 8Hz) 5.2 (lH, d, J=SHz) 4.25, 4.63 (2H, ABq, J=14Hz) 3.9 (3H, s) 3.7 (2H, broad s) (25) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamidoJ-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 178Q, 1740, 1720, 1680 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.86 (lH, d, J=8Hz) 9.61 (lH, s) 7.00 - 7.65(4H, m) 5.84 (lH, dd, J=S, 8Hz) 5.2 (lH, d, J=5Hz) 4.25, 4.63 (2H, ABq, J=14Hz) 3.92 ~3H, s) 3.53, 3.86 (2H, ABq, J=19Hz) 2.3 (3H, s) 3o i 337522 ~26) 7-[2-(3-Phenylallyloxyimino)-2-(3-hydroxyphenylj-acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 138 to 142C (dec.) I.R. spectrum (Nujol) 3300 - 3400, Z600, 1780, 1720, 1665, 1600 cm 1 N.~.R. spectrum (d6-~MSO, ~) ppm 9.80 (lH, d, J=8Hz) 6.4 - 7.4 (llH, m) 5.8S (lH, dd, J=S, 8Hz) 5.20 ~lH, d, J=SHz) 4.83 (2H, d, J=SHz) 4.32 (2H, ABq, J=lSHz) ` 3.95 (3H, s~
3.68 (2H, ABq, J=18Hz) (27) 7-[2-Methoxyimino-2-(4-dimethylaminophenyl)acetamidoj-3-~1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 88C (dec.).
I.R. spectrum (Nujol) 3250, 1780, 1730, 1680, 1610 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.63 (lH, d, J=8Hz) 7.40 (2H, d, J=8Hz) 6.73 (2H, d, J=8Hz) 5.83 (lH, dd, J=S, 8Hz) 5.17 (lH, d, J=5Hz) 4.33 (2H, ABq, J=13Hz) 3.97 (3H, s) 3.87 (3H, s) ~;
3.73 (2H, broad s) 3.00 (6H, s) I '33752 Z
.. .. ... . . . . ..
(28) 7-r2-Methoxyimino-2-(3-hydroxyphenyl)acetamid 3 3-3-ri-(2-dimethylaminoethyl)-I~-tetrazol-5-yl~thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I. R~ spectrum ( NUJ ol) 1765 c2-l N. M. R. spectrum (d6-3MSO, ~) ppm 9.67 (1~, d, J=9Hz) 6.72-7.36 (4H, m) 5.78 (lH, dd, J=5, 9 Hz) 5.12 (lH, d, J=5 Hz~
4.55 (2H, broad s) 4.30 ~2H, broad s) 3.gO (3H, s) 3.40-3.80 (2H, m) 3.14 ~2H, broad 8 ) 2.48 (6H, s) (29) 7-[2-{2-(2-Hydroxyphenoxy)ethoxyimino~-2-(3-hydro~yphenyl)-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiometnyl-3-cephem-4-carboxylic acid (syn isomer).
I. R. spectrum (Nujol) 3270, 1780, 1725, 1670, 1560 cm 1 N. M. R. spectrum (d6-DiISO,~ ) ppm6.5-7.4 (8H, m) 5.86(1H, dd, J=5, 8Hz) 5.14(lH, d, J=5Hz) .0-4.6 (5H, m) 3.92(3H, s) 3.52, 3.70(2H, ABq, J=7Hz) E_23 Example 8 A mixture of dimethylformamide (0.73g) and phosphorus .oxychloride (1.6g) was warmed for 30 minutes zt 40C. Benzene was added thereto and the mixture was concent~ated. The residue was suspended in ethyl acetate (20 ml) and 2-methoxyimino-2-(3-hydroxyphenyl) acetic acid (syn isomer) (1.9Sg) was added thereto at -lS to -5C, after which the resulting mixture was stirred for 30 minutes at the same temperature. On the other hand, a solution of sodium hydroxide (0.9g) in water (5 ml) was dropwise added at 0 to 5C over 25 minutes to a suspension of 7-aminocephalosporanic acid (2.7g) in water (12.Sml) an1 the mixture was stirred for 5 minutes, after which acetone (20 ml) was added thereto. To the resulting mixture containing sodium 7-amino-3-hydroxymethyl-3-cephem-4-carboxylate was dropwise added at 0 to 5C over 3 minutes the above obtained ethyl aceta~e solution keeping the pH value at 7.5 to 8.5 by adding triethyl-amine. After stirring for 30 minutes, the organic solvents were distilled off The aqueous layer was washed with ethyl acetate (20ml), adjusted to pH 2.0 with hydrochloric acid ard extracted with ethyl acetate (60ml) at 0 to 3C. The aqueous layer was further extracted with ethyl acetate (30ml). The combined ethyl acetate extracts were washed with a saturated aqueous solution of sodium chloride and dried. The solvent was distilled off and the residue was pulverized with diisopropyl ether to give a mixture of 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid'syn isomer)(I) and 6-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]-furo-[3,4-d][1,31thiazine-1,7(4H)-dione(syn isomer)~II) (2.64 g).
3o I.R. spectrum of (I) (Nujol) 3250, 1785, 1755, 1660, 1600, 1570, 1540 cm~
N.M.R. spectrum of (I) (d6-DMSO, ~) ppm 9.83 (lH, d, J=8~1z) 7.~ - 6.75 (4H, m) 5.8 (lH, dd, J=5,8~z) 5.21 (lH, d, J=5Hz) 4.3 (2H, broad s) 3.95 (3H, s) 3.63 (2H, broad s) I.R. spectrum of (II) (Nujol) 3250, 1785, 1755, 1660, 1600, 1570, 1540 cm~
N.M.R. spectrum of (II) (d6-DMSO, ~) ppm 9.83 (lH, d, J=8Hz) 7.5 - 6.75 (4H, m) 6.02 (lH, dd, J=S, 8Hz) 5.21 (lH, d, J=SHz) 5.07 (2H, broad s) 3.95 (3H, s) 3.84 (2H, broad s) Example 9 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.23 g) was dissolved in pyridine (1 ml) with stirring and ice-cooling, and acetyl chloride (0.082 g) was added thereto.
The mixture w~s stirred for 40 minutes under ice-cooling.
The reaction mixture was poured-into ice-water, acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After treating with activated ~- 25 charcoal, it was filtered and the filtrate was concentrated.
The residue was pulverized with diisopropyl ether to gi~e a mixture of 7-[2-methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) and 7-[2-methoxyimino-2-(3-acetoxyphenyl)acetamido3-3-carbamoyloxy-methyl-2-cephem-4-carboxylic acid ( syn isomer ) (0.18 g ).
N.M.R. spectrum (d6-DMS0, ~) ppm : 9.82 (lH, d, J=8Hz) 9.77 (lH, d, J=8Hz) 7.6-7.1 (8H, m) 6.60 (lH, s) 6.56 (2H, s) 5.83 (lH, dd, J=4, 8Hz) 5.60 (lH, dd, J=4,8Hz) 5.24 (lH, d, J=4Hz) 5.20 (lH, d, J=4Hz) 4.84 ~lH, s) 4.76 (2H, ABq, J=13Hz) 4.56 (2H, broad s) 3.94 (6H, s) 3.55 (2H, broad s) 2.28 (6H, s ~0 ~_26 ~ 33 7522 Example lO
The following compounds were obtained according ~o a similar manner to that of Example 9.
~1) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamidoJ-3-(1J3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxyii~c acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1740, 1720, 1680 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.86 (lH, d, J=8Hz) 9.61 (lH, s) 7.00 - 7.65 (4H, m) 5.84 (lH, dd, J=5, 8Hz) 5.2 (lH, d, J=5Hz) 4.25, 4.63 (2H, ABq, J=14Hz) 3.92 (3Hf s) 3.53, 3.86 (~H, ABq, J=19Hz) 2.3 (3H, s) (2) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R spectrum (N~jol) 3450, 3300, 3200, 1780, 1725, 1670, 1620, 1590, 1520 cm~l N.M.R. spectrum (d6-DMSO, ~) 2S ppm 9.77 (lH, d, J=7Hz) 7.6 - 6.8 (6H, m) 5.83 (lH, dd, J=4, 7Hz) 5.17 (lH, d, Js4Hz) 4.31 (2H, ABq, J=14Hz) 3.96 (6H, s) 3.72 (2H, broad s) (3) 7-[2-Methoxyimino-2-(3-carbamoyl-oxyphenyl)acetamidol- -3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1735, 1675 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.81 (lH, d, J=8Hz) 9.62 (lH, s) 6.7 - 7.58 (4H, m) 5.87 (1~, dd, J=S, 8Hz) 5.2 (lH, d, J=SHz) - ~ 4.25, 4.63 (2H, ABq, J=14Hz) 3.9 (3H, s) 3.7 (2H, broad s) Example 11 Phosphorus oxychloride (0.26 g.) was added under ice-cooling to dimethylformamide (0.15 g.) and the mixture was warmed at 40C for 1 hour. Ethyl acetate (l.S ml.) was added thereto and to the mixture was at a time added 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid (syn isomer) (0.3 g.) with s~irring and ice-cooling, after which the resulting mixture was stirred for 20 minutes. at 0 to 5C. On the other hand, bis(trimethyl-silyl)acetamide (1.2 g.) was added to a suspension of 7-amino-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (0.53 g.) in ethyl acetate (7 ml.) and the mixture was stirred at ambient temperature. To this solution was dropwise added the above obtained ethyl acetate solution at -20C
and the mixture was stirred for 2 hours at -10 to-20C. Water ~O (20 ml.) was added to the reaction mixture below -25C and -81- ~- 28 ethyl acetate (20 ml.) was added thereto, after ~-hich the mixture was stirred. An insoluble material was filtered off anG the ethyl acetate layer was separated. Water ~15 ml.) w~s aaded to the ethyl acetate iayer and the mixture was adjusted to ~H 7.5 with a saturated aqueous solution of sodium bicarbonate. lhe aqueous layer was separated, washed with methylene chio-.^ide and methylene chloride in tlle aqueous layer was removea by bu~bling of nitrogen gas. The aqueous solution was adjusted to pH 2.2 with 10% hydrochloric acid and precipitates were collected by fil~ration and dried to give 7-~2-methoxyimino-2-(2-methyl-l,3-thiazol-4-yl)acetamido~-3-(1-methyl-lH-tetrazol-S-yl)thiometnyl-3-cephem-4-carboxylic acid (syn isomer) (0.28 g.).
I.R. spectrum (Nujol) 1780, 1710, 1675 cm 1 N.M.R. spectrum (d6-DMSO, ~) PPm 9.65 (lH, d, J=lOHz) 7.66 (lH, s) 5.81 (lH, dd, J=S,lOHz) 5.15 (lH, d, J=SHz) 4.31 (2H, ABq, J=13Hz) 3.93 (3~1, s) 3.90 (3H, s) 3.70 (2H, ABq, J=16Hz) 2.65 (3H, s) .

Example 12 Phosphorus oxychloride (0.89 g.) and d,y dimet..yl-formamide (0.44 g.) were mixed under ice-cooling and ther.
warmed for 30 minutes at 40C. Dry methylene chloride (20 ml.) was added thereto and then distilled off. To the residue were added dry ethyl acetate (10 ml.) and then 2-methoxyimir.o-2-~2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yljacetic acid (syn isomer) (1.8 g.~ with stirring and ice-cooling. The mixture was stirred for 40 minutes at the same tempera~ure to give ciear solution. On the other hand, trimethylsilylacetamide (6.36 g.) was added to a suspension of 7-aminocephalosporanic acid (1.65 g.) in dry ethyl acetate (25 ml.) with stirrin~ at ambient tempcra~ure, after which the mixture was stirred for 1 hour tO give a clear solution. To this solution was at a time added the above-obtained ethyl acetate solution with stirring at -20 to -25C, and the resulting mixture was stirred for 2 hours at the same temperature. Water (30 ml.) was added to the reaction mixture at the same temperature, and then the mixture was stirred for 5 minutes at ambient temperature. The ethyl acetate layer was separated, and the aqueous layer was further extracted wi~h ethyl acetate. The ethyl acetate layerS werecombined and water ~0 ml.) was added thereto. The mixture was adjusted tG pH 7.5 with sodium bicarbonate, and the aqueous layer was separated.
Ethyl acetate (40 ml.) was added to the aqueous layer, and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid with stirring and ice-cooling. The ethyl acetate layer was separated, and the aqueous layer was further extracted twice with ethyl acetate (30 ml.). The ethyl acetate layers were combined, washed with an aqueous solution of sodium chloride and treated with acti~ated charcoal. The solvent was distilled off to give 7-~2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamidol cephalosporanic acid (syn isomer) (3.05 g.), mp 205C (dec.).
I.R. spectrum (Nujol~
325G, 1790, 1735, 1680, 1650 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.8 (lH, d, J=8Hz) 7.55 ~iH, s) 5.88 (11~, dd, J=5,8Hz) 5.25 (lH, d, J=5Hz) 4.8 (2H, ABq, J=1311z) 3.95 ~3H, s) 3.59 (2H, broad s) 2..03 (3~1, s) Example 13 Phosphorus oxychloride (2.0 g.) was at a time added at 5 to 10C to a suspension of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl) acetic acid (syn isomer) (2 g.) in dry ethyl acetate (20 ml.). After stirring for 20 minutes at 7 to 10C, bis-(trimethylsilyl) acetamide (0.4 g.) was addeà thereto at the same temperature. After stirring for 10 minutes at 7 to 10C, phosphorus oxychloride (2.0 g.) was dropwise added there~o at the same temperature. The resulting mixture was stirred for iO
minutes at 7 to 10C, and dry dimethylformamide (0.8 g.) was dropwise added thereto at the same temperature. The mixture was stirred for 30 minutes at 7 to 10C to give a clear solution.
On the other hand, trimethylsilylacetamide (7.35 g.) was added to a suspension of 7-aminocephalosporanic acid (2.45 g.) in dry ethyl acetate (8 ml.), after which the mixture was stirred at ~0 40C to give a clear solution. To this solution was at a time ~ - 3 added the above-obtained ethyl acetate solution at -15C, and the resulting mixture was stirred for 1 hour at -lG to -15C. The reaction mixture was cooled to -30C, and water (80 ml.~ was added thereto. The aqueous layer was separated, adjustea to pH 4.5 with sodium bicarbonate and subjected to column chromato-graphy on Diaion HP-20 resin (Trademark: prepared by Mitsubishi Chemical Industries Ltd.) using 25% aqueous soiution of isopropyi alcohol C as an eluent. The eluate was lyophilized to give 7-L2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido~cephalosporanic acid tsyn isomer) (1.8 g.), mp 227C (dec.).
I . R. spectrum (Nujol) 3300-3350, 1780, 1740, 167G cm 1 N.M.R. spectrum ~d6-DMSO, ~) ppm 9.6 (lH, d, J=8Hz) 6.8 (lH, s) 5.8 ~lH, dd, J=5,8Hz) 5.2 (lH, d, J=5Hz) 4.87 (2H, ABq~ J=13Hz) 3.89 (3H, s) 3.6 (2H, broad s) 2.08 (3~, s) Example 14 Phosphorus oxychloride (3.8 g.) was dropwise added at 5 to 8C to a suspension of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (4.0 g.) in dry ethyl acetate (40 ml.). After stirring for 30 minutes around 5C, bis(tri-methylsilyl)acetamide (0.86 g.) was added thereto at the same temperature. After stirring for 10 minutes at the same temperature, phosphorus oxychloride (3 . 8 g. ) was dropwise added thereto at 5 to 8C, after which the mixture was stirred for 30 minutes at the same temperature. Dry dimethylformamide (1.6 g.) was dropwise added thereto at 5 to 7C, after which the resulting mixture was stirred for 30 minutes at the same temperature to give a clear solution. On the other hand, S sodium acetate (3.3 g.) was added to a solution of 7-amino-ce~halosporanic acid (2.7 g.) in an aqueous solution (20 ml.) of sodium bicarbonate (1.7 g.), and then acetone (20 ml.) was added thereto. To this solution was dropwise added the above-obtained ethyl acetate solution with stirring at 0 to 5C keeping the pH of this solution at 7.0 to 7.5 by 20% aqueous solution of sodium carbonate. The mixture was stirred for 1 hour at the same temperature. An insoluble material was filtered off, and the aqueous layer in the filtrate was separated. The aqueous layer was concentrated under reduced pressure to remove the organic solvents, adjusted to pH 4.5 with sodium bicarbonate and subjected to column chromatography on Diaion HP-20 resin (Trademark: prepared by Mitsubishi Chemical Industries Ltd.) using 25% aqueous solution of isopropyl alcohol as an eluent.
The eluate was lyophilized to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer) (2.8 g.). This compound was identified with the compound obtained in Example 13 by I.R. and N.M.R. spectra.

~ - 33 Example 15 The following compounds were obtained according to similar manners to those of Examples llto 14 .
(~ 7-[2-Methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1718, 1675 cm~
N.M.R. spectrum (d6-D~ISO, ~) ppm 9.80 (lH, d, J=8Hz) 7.08 (iH, s) 5.80 (lH, dd, J=5,8Hz) 5.18 (lH, d, J=5Hz) 4.34 (2H, ABq, J=13Hz) 3.99 (3H, s) 3.96 (3H, s) 3.72 (2H, ABq, J=17Hz) 3.66 (3H, s) 2.98 (3H, s) (2) 7-[2-Methoxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)-acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3300-3150, 1780, 1710, 1670 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.84 (lH, d, J=8Hz) 6.97 (lH, s) 5.76 (lH, dd, J=5,8Hz) 5.12 (lH, d, J=5Hz) 4.33 (211, AB , J=13Hz) ~-~4 3.93 (6H, s) 3.74 (2H, ABq, J=17Hz) 2.96 (3H, s) (~ 7-[2-Methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 1780, 1665 cm l N.M.R. spectrum (d6-DMS0, ~) ppm 11.67 (lH, s) 9.83 (lH, d, J=8Hz) 6.61 (1~, s) 5.80 (lH, dd, J=5.5,8Hz) 5.17 (lH, d, J=5.5Hz) 4.37 (2H, broad s) 4.00 (3H, s) 3.96 (3H, s) 3.75 (2H, broad s) (4) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 1790, 1730, 1660 cm l N.M.R. spectrum (d6-DMSO, ~) ppm 9.73 (lH, d, J=8Hz) 7.53 (lH, s) 5.83 (lH, dd, J=5,8Hz) 5.15 (lH, d, J=5Hz) 4.33 (2H, broad s) 3.g3 (6H, s) 3.72 (2H, broad s) ~-~5 (5) 7-~2-Methoxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamidoj-3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3200, 1780, 1720, 1680 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.65 (lH, d, J=8Hz) 7.28 (lH, s) 5.80 (lli, dd, J=5,8Hz) 5.16 (lil, d, J=5Hz) 4.38 (211, ABq, J=13Hz) 3.86 (31i, s) 3.70 (2H, ABq, J=17Hz) 2.66 (3H, s) 1.78 (2H, q, J=8Hz) 1.44 (6H, s) 0.88 (3H, t, J=8Hz) (6) 7-[2-Allyloxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)-acetamidol-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-20 carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3100-3300, 1780, 1720, 1675 cm 1 N.M.R. spectrum (d6-D~ISO, ~) ppm 9.90 (lH, d, J=8Hz) 7.00 (lH, s) 6.07-5.63 (2H, m) 5.43 (2H, d, J=8Hz) 5.18 (lH, d, J=5Hz) 4.70 (2H, d, J=SHz) 4.37 (2H, broad s) ~- 36 3.98 (3H, s) 3.75 (2H, broad s) 3.00 (3H, s) ( 7) 7-[2-Allyloxyimino-2-(2-t~pentyloxycarbonylamino-i,3-thiazol-4-yl)acetamido3-3-(1-methyl-lH-tetrazol-5-yl).niomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1720, 1678, 1625 cm~
N.M.R. spectrum (d6-DMSO,~) ppm ; 9.74 (lH, d, J=8Hz) 7.31 (lH, s) 6.28 - 5.76 (2H, m) 5.28 (2h, dd, J=8, 16Hz) 5.18 (lH, d, J=5Hz) 4.66 (2H, d, J=SHz) 4.36 (2H, ABq, J=13Hz) 3.96 (3H, s) 3.74 (2H, ABq, Jz17Hz) 1.80 (2H, q, J=8Hz) 1.45 (6H, s) 0.89 (3H, t, J=8Hz) ( 8) 7-[2-Methoxyimino-2-(2-amino-1,3-~hiazol-4-yl)acetfimidoi-3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3200, 1765, 1600 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm : 9.Sl (lH, d, J=8.5Hz) 7.22 (2H, broad s) 6.72 (lH, s) 5.59 (lH, dd, J=5, 8.5Hz) 5.00 (lH, d, J=SHz) ~ 337522 4.35 (2H, ABq, J=12Hz) 3 90 (3H, s) 3.81 (3H, s) 3.55 (2H, ABq, Jsl8Hz) S ( 9) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazoi-4-yl)acetamido~-3-(S-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4 carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3400-3150, 1770, 1670, 1625 cm^
N.M.R. spectrum (d6-DMSO, ~) - ppm : 9.66 (lH, d, J=8Hz) 7.34 (2H, broad s) 6.76 (lH, s) 5.78 (2H, dd, J=5~8Hz) lS 5.16 (lH, d, J=SHz) 4.40 (2H, ABq, J=14Hz) 3.85 (3H, s) 3.70 (2H, ABq, J=17Hz) 2.68 (3H, s) (lO) 7-[2-Allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3100-3400, 1775, 1660, 1625 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm : 9.70 (lH, d, J=8Hz) 6.80 (lH, s) 6.30-5.60 (2H, m) 5.24 (2H, dd, J=8,16Hz) 5.15 (lH, d, J=5Hz) ~ - ~8 4.63 (2H, d, J=SHz) 4.32 (2H, ABq, J=12Hz) 3.94 (3H, s) 3.70 (2H, ABq, J=17Hz) ~1 ) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145 to 147~C (dec.).
I . R. spectrum (Nujol) 3150 - 3400, 1780, 1725, 1680, 1640 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 12.58 (lH, broad s) 9.70 (lH, d, J=8Hz) 9.58 (l~i, s) 8.50 (lH, s) 7.40 (lH, s) 5.82 (lH, dd, J=5,8Hz) 5.17 (lH, d, J=5Hz) 4.43 (2H, ABq, J=13Hz) 3.88 (3H, s) 3.70 (2H, broad s) (~2) 7-[2-Methoxyimino-2-(2-acetamido-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 171 to 173C (dec.).
I.R. spectrum (Nujol) 3500, 3250, 1780, 1720, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.65 (lH, d, J=8Hz) 7.3 (lH, s) 5.8 (lH, dd, J=5, 8Hz) 5.15 (lH, d, J-SHz) l 331522 4.35 (2H, broad s) 3.97 (3H, s) 3.9 (3H, s) 3.75 (2H, broad s) 2.15 (3H, s) ~) 7-[2-Methoxyimino-2 {2-(2,2,2-trifluoroacetamldo)-~,3-thiazol-4-yl}acetamido]-cephalosporanic acid (syn isomer), mp 205C (dec.), I.R. spectrum (Nujol) 3250, 1790, 1735, 1680, 1650 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.8 (lH, d, J=8Hz) 7.55 (lH, s) 5.88 (lH, dd, J~5, 8Hz) 5.25 (lH, d, JzSHz) 4.8 (2H, ABq, J=13~z) 3.95 (3H, s) 3 59 (2H, broad s) 2.03 (3H, s) (14) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3 thiazol-4-yl}acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
l.R. spectrum (Nujol) 3500, 3200, 1785, 1700, 1660 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.75 (lH, d, J=8Hz) 8.4 (2H, m) 7.53 (1~l, s) 6.6 (lH, m) 6.20 (lH, d, J=5Hz) 1 ~37 522 5.83 (lH, m) 4.77 ~2H, ABq, Js14Hz) 3.91 (3H, s) 3.55 (2H, m) (1~ 7-[2-Methoxyimino-2-t2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3200, 1780, 1720, 1650 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.81 (lH, d, J=8Hz) 9.6 (lH, m) 9.57 (lH, s) 7.56 (lH, s) 5.83 (lH, dd, J=5, 8Hz) 5.20 (lH, d, J=SHz) 4.47 (2H, ABq, J=14Hz) 3.96 (3H, s) 3.72 (2H, ABq, J=18Hz) (16) 7-~2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido~-3-hydroxymeth;1-3-cephem-4-carboxylic acid (syn isomer), mp 260 to 270C (dec.).
I.R. spectrum (Nujol) 3370, 3270, 1765, 1660, 1610, 1590, 1550 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.58 (lH, d, J-8Hz) 6.76 (lH, s) 5.75 (lH, dd, J=5, 8Hz) ~ - 41 5.12 tlH, d, J~5Hz) 4.27 (2H, broad s) 3.85 (3H, s) 3.57 (ZH, broad s) (17) 7-[2-Methoxyimino-2-(2-amino-l~3-thiazol-4-yl)acetamid cephalosporanic acid (syn isomer), mp 227C (dec.).
I.R. spectrum (Nujol) 3300 - 3350, 1780, 1740, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.6 ~lH, d, J=8Hz) 6.8 (lH, s) 5.8 (lH, dd, J=5, 8Hz) 5.2 (lH, d, J=5Hz) 4.87 (2H, ABq, J=13Hz) 3.89 (3H, s) 3.6 (2H, broad s) 2.08 (3H, s) (18) 7-[2-Methoxyimino-2-(2-amino-l~3-thiazol-4-yl)acetamid 3-carbamoyloxymethyl-3-cepham-4-carboxylic acid (syn isomer), mp 210 to 220C (dec.).
I.R. spectrum (Nujol) 3250, 1765, 1650 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.64 (lH, d, J=8Hz) 7.4 (2H, m) ~ - 42 ... .. .

1 3375~2 6.79 -(lH, s) 6.60 (2H, m) 5.77 (lH, dd, J=5, 8Hz) 5.16 (lH, d, J=5Hzl 4.75 (2H, ABq, J=12Hz) 3.87 (3H, s) 3.53 t2H, ABq, J=18Hz) (l9) 7-[2-Methoxyimino-2-(2-amino-l~3-thiazol-4-yl)acetamido]
3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 172 to 175C (dec.).
I.R. spectrum (Nujol) 3300, 1770, 1665 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.80 (lH, d, J=8Hz) 9.63 (lH, s) 6.95 (lH, s) 6.8 (2H, m) 5.82 (lH, dd, J=5, 8Hz) 5.22 (lH, d, J=5Hz) 4.48 (2H, ABq, J=lSHz) 3.97 (3H, s) 3.76 (2H, ABq, J=18Hz) (20) 7-[2-Methoxyimino-2-(2-amino-l~3-thiazol-4-yl)acetamido]
3-(4-methyl-4~-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 185C (dec.).
I.R. spectrum (Nujol) 3150 - 3350, 1770, 1710, 1660, 1630 cm 1 N.M.R. spectrum (d6-DMS0, ~) ppm 9.61 (lH, d, J=8Hz) 8.69 (lH, s) 1 33?522 6.73 (lH, s) 5.72 (lH, dd, J=4, 8Hz) 5.1 (lH, d, J=4Hz) 4.1 (2H, ABq, J=13Hz) 3.87 (3H, s) 3.65 (2H, broad s) 3.s9 (3H, s) (21) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido~-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 155 to 160C (dec.).
I.R. spectrum (Nujol) 3250, 1780, 1730, 1660, 1585, 1520 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.76 (lH, d, J=8Hz) 7.57 (lH, s) 5.80 (lH, dd, J=4, 8Hz) 5.15 (lH, d, J=4Hz) 4.29 (2~l, s) 3.93 (3H, s) 3.60 (2H, s) (22) 6-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a, 6-dihydro-3H,7H-azeto~2,1-b]furo[3,4-d]Ll,3]thiazine-1,7~4H)-dione (syn isomer), mp 210 to 215C (dec.).
I.R. spectrum (Nujol) 3270, 1780, 1740, 1655, 1610, 1525 c~,-N.M.R. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 7.26 (2H, broad s) 6.77 (lH, s) 5.93 (lH, dd, J=5, 8Hz) S.16 (lH, d, J=SHz) S.OS (2H, broad s) - . 3.85 (3H, s) 3. 81 (2H, broad s) ~23) 7-~2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-[1-(2-dimethylaminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 1765 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.56 ~lH, d, J=8Hz) 6.75 ~lH, s) 5.75 (lH, m) L0 5.10 (lH, d, J=4Hz) 4.58 (2H, broad s) 4.32 (2H, broad s) 3.82 (3H, s) 3.68 (2H, broad s) ., .. ~.~, L5 3.20 (2H, broad s) 2.50 (6H, s) (24) 7-~2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-acetamido]cephalosporanic acid (syn isomer).
I.R. spectrum (Nujol) '0 3280, 1785, 1740, 1700, 1650 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 12.68 (lH, broad s) 9.68 (lH, d, J=8Hz) 8.54 (lH, s) '5 7-45 (lH, s) 5.86 (lH, dd, J=5,8Hz) 5.20 (lH, d, J=5Hz) 4.90 (2H, ABq, J=8Hz) 3.61 (3H, broad s) ~0 2.06 (3H, s) _99_ 1 3375~2 (25) 7-[2-Methoxyimino-2-(2-ethoxycarbonylamino-i,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. specetum (Nujol) S 3200, 1775, 1720, 1680, 1660 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 11.9 (lH, m) 9.70 (lH, d, J=lOHz) 9.55 (lH, s) .0 7.31 (lH, s) 5.80 (lH, dd, J=5,10Hz) 5.18 (lH, d,J=5Hz) 4.44 (2H, ABq, J=16Hz) 4.22 (2H, q, J=7Hz) 3.89 (3H, s) 3.72 (2H, ABq~ J=16Hz) 1.23 (3H, t, J=7Hz) ~6) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido~-3-formyl-3-cephem-4-carboxylic acid 0 (syn isomer) [or this compound can be represented as 3-hycroxy-6-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-Sa,6-dihydro-3H,7H-azeto[2,1-b]furo~3,4-d~[1,3]-thiazine-1,7(4H)dione (syn isomer)].
.R. spectrum (Nujol) ~S 3150, 1790, 1720, 1655, 1560, 1500 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 9.88 (lH, d, J=8Hz) 7.60 (lH, s) ~0 6.30 (lH, d, J=6Hz) 6.05 tlH, dd, J=5,8Hz) 5.23 (lH, d, J=SHz) 3.96 (3H, s) 3.80 (2H, broad s) (27) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yI)-acetamido~-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3200-3300, 2600, 1780, 1720, ~ 1690, 1675 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 12.60 (lH, broad s) 9.70 (lH, d, J=8Hz) 8.50 (lH, s) L5 7.44 (lH, s) 5.88 (lH, dd, J=5,8Hz) S.l9 (lH, d, J=SHz) .25 (2H, ABq~ J=13Hz) 3.95 (3H, s) ,0 3.85 (3H, s) 3.65 (2H, ABq~ J=18Hz) (28) 7-~2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-acetamido~-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
!5 I.R. spectrum (Nujol) 3300, 1780, 1705, 1680 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 12.50 (lH, broad s) 9.67 (lH, d, J=8Hz) 8.50 (lH, s) t 337522 7.43 (lH, s) 6.58 (2H, broad s) 5.80 (lH, dd, J=5,8Hz) 5.16 (lH, d, J=SHz) 4.78 t2H, ABq~ J=14Hz) 3.95 (3H, s) 3.57 (2H, ABq~ J=18Hz) ~ - 49 -102_ 1 33752~

Example 16 A solution of 7-[2-methoxyimino-2-{2-(2,2,2-trifluoro-acetamido)-1,3-thiazol-4-yl}acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g.) S in a 0.1 N aqueous solution of sodium hydroxide (10.5 mi.) was warmed at 45C for 6 hours. Water (15 ml.) and ethy; ace~ate (30 ml.) were added to the reaction mixture and the resulting mixture was adjusted to pH 3.5 with 10~ hydrocnloric acid.
The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 5.0 with an aqueous solution of sodium bicarbonate.
The aqueous solution was subjected to column chromatography on Amberlite XAD-2 (20 ml.)(prepared by Rohm ~ Haas Co.) using 10~
ethanol as developing solvent. The eluate containing object compound was collected and lyophilized to give 7-L2-methoxyimino-lS 2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer~ (0.12 g.).
I.R. spectrum (Nujol) 3200, 1765, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.Sl (lH, d, J=8.SHz) 7.22 (2H, broad s) 6.72 (lH, s) S.S9 (lH, dd, J=5,8.5Hz) S.00 (lH, d, J=SHz) 4.35 (2H, ABq, J=12Hz) 3.90 (3H, s) 3.81 t3H, s) -- 3.55 (2H, ABq, J=l~Hz) ~ II,qale~qri~

Example 17 Trifluoroacetic acid (3 ml) was added ~nder ice-cooling to 7-[2-methoxyimino-2-~2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido~-3-(5-methyl-1,3,4-thiadiazoi-2-yl)-S thiomethyi-3-cephem-4-carboxylic acid (syn isomer) (0.5 g) and the mixture was stirred for 30 minutes at ambient temperatuïe.
~o the mixture was added ether and precipitating powder was collected by filtration and dissolved in a mixture of water (20 ml) and an lN aqueous solution of sodium hydroxide to adjust to pH 12 to 13. The solution was adjusted to pH 4.6 with lGgo hydrochloric acid, washed with ethyl acetate ar.d methylene chloride. Excess methylene chloride in the aqueous layer was thoroughly removed by bubbling of nitrogen gas. The aqueous layer was adjusted to pH 2 with stirring and ice-cooling to lS precipitate powder. The powder was collected by filtration and dried to give 7-~2-methoxyimino-2-(2-amino~1,3-thiazoi-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3 cephem-4-carboxylic acid (syn isomer) (0.128 g) I. R. spectrum (Nujol) 3400-3150, 1770, 1670, 1625 cm~
N.M.R. spect~um (d6-DMSO, ~) ppm : 9.66 (lH, d, J~8Hz) 7 34 (2H, broad s) 6.76 (lH, s) 5.78 (2H, dd, J=5, 8Hz) 5~16 (lH, d, J~SHz) 4,40 (2H, ABq, J 14Hz) 3 85 (3H, s) 3 70 (2H, ABq, J-17Hz) 2.68 (3H, s) ~ - 51 Example 18 Trifluoroacetic acid (4 ml.) and anisole (2 ml.) were added under ice-cooling to 7-[2-allyloxyimino -2-(2-t-penty-loxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syr.
isomer) (0.9 g.) and the mixture was stirred for 40 minutes at ambient temperature. The reaction mixture was post-treated according to a similar manner to that of Example 17 to give 7-[2-allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido'-3-(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.425 g.).
I.R. spectrum (Nujol~
3100-3400, 1775, 1660, 1625 c~
N.M.R. spectrum (d6-DMS0, ~) ppm : 9.70 (lH, d, J=8Hz) 6.80 (lH, s) 6.30 - 5.60 (2H, m) 5.24 (2H, dd, J=8, 16Hz) 5.15 (lH, d, J=5Hz) 4.63 (2H, d, J=5Hz) 4.32 (2H, ABq, J=12Hz) 3.94 (3H, s) 3.70 (2H, ABq, J=17Hz) Example l9 Disodium hydrogen phosphate (0.26 g) was added to a suspension of 7-[2-methoxyimino-2-{2-(2,2,2-trifluoro-acetamido)-1,3-thiazol-4-yl~acetamido~cephalosporanic acid(syn isomer) (1 g) in water (15 ml). A saturated aqueous solution of disodium hydrogen phosphate was further added thereto to adjust the pH value of the mixture at 6. The resulting mixture was stirred for 23 hours at ambient temperature.
The reaction mixture was adjusted to pH 4 under ice-cooting with 10~ hydrochloric acid, washed with ethyl acetate and adjusted to pH 2.5 with 10~ hydrochloric acid.
Precipitating crystals were collected by filtration, washea with cold water and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer)(0.18 g), mp 227C (dec.).
I.R. spectrum (Nujol~
3300 - 3350, 1780, 1740, 1670 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.6 (lH, d, J=8Hz) 6.8 (lH, s) 5.8 (lH, dd, J=5, 8Hz~
i 5.2 (lH, d, J=SHz) 4.87 (2H, ABq, J=13H2) 3.89 (3H, s) 3.6 (2H, broad s) ....
2.08 (3H, s) Example 20 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(syn isomer)(2~g) was suspended in a sol~tion of sodium acetate trihydrate (74.8 g) in water (230 ml) and the suspension was stirred for lS hours at ambient temperature.
The reaction mixture was adjusted to pH S.0 with conc.
hydrochloric acid and insoluble material was filtered off.
The filtrate was adjusted to pH 2.5 and precipitating o crystals were collected by filtration and dried to give 7-~- 53 [2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl~acetamido]-3-(l, 3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (14 g), mp 172 to 175C (dec.).
I.R. spectrum (Nujol) 3300, 1770, 1665 cm 1 N.M.R. spectrum (d6-DMS0, ~) ppm 9.80 ~lH, d, J=8Hz) 9.63 (lH, s) 6.95 (lH, s) 6.8 (2H, m) 5.82 (lH, dd, J=5, 8Hz) 5.22 (lH, d, J=5Hz) 4.48 (2H, ABq, J=15Hz) 3.97 (3H, s) 3.76 (2H, ABq, J=18Hz) ~ - 54 Example 21 7-[2-Methoxyimino-2-{2-~2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido~-3-carbamoyloxymethyi-3-cephem-4-carbaxylic acid (syn isomer) (3.5 g.) was suspended in a sc~~u~ion OI sodium S acetate trihydrate (12.2 g.) in water ~30 ml.). Tne mixture was stirred for lS hours at ambient temperature. The reaction mixture was saturated with sodium chloride and adjusted to pH S.0 with conc. hydrochloric acid with stirring and ice-cooling.
Precipitatin~ insoluble material was filtcred of. The ;il~rate 0 was adjusted to pH 3.0 with conc. hydrochloric acid and furtn~r adjusted to pH l.S with 10~ hydrochloric acid. Precipitates were collected by filtration and dried to give 7-[2-metho~yimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) ~2.1 g.), mp 210 to 220C
(dec-)-I.R. spectrum (Nujol) 3250, 1765, 1650 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 9.64 (lH, d, J=8Hz) 0 7.4 (2H, m) 6.79 (lH, s) 6.60 ~2H, m) 5.77 ~lH, dd, J=5,8Hz) 5.16 (lH, d, J=SHz) 4.75 (2H, ABq~ J=12Hz) 3.87 ~3H, s) 3.53 ~2H, ABq~ J=18Hz) Example 22 Conc. hydrochloric acid ~10.4 ml.) was added with D stirring at ambient temperature to a sus~ension of 7-[2-methoxy-imino-2-t2-formamido-1,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer) ~48.35 g.) in methanol (725 Ml.). Afte.
stirring for 3 hours at ambient temperature, tne reaction mixture was adjusted to pH 4.5 with a~ueous solution of ar.lmonia and methanol was distilled off. To the residue was added wa~er (100 ml.). The mixture was adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate, and insolubie ma~erial was collected by filtration to give 6-~2-methoxyimino-2-(2-am no-i,3-thiazo--4-yl)acetamido]-Sa,6-dihydro-3H,7H-azeto[2,1-b]furo~3,4-d~Ll,3~-thiazine-1,7(4H)dione (syn isomer) (6.5 g.). The filtrate was adjusted to pH 4.5 with acetic acid, adsorbed by Diaion H?-20 resin (Trademark: prepered by Mitsubishi Chemica~ Industries Ltd.) (600 ml.), washed with water (2 Q.) and then eluted with 25%
aqueous solution of isopropyl alcohol. Eluates containing the L5 ob~ect compounds were collected and cooled after addition of isopropyl alcohol (1/3 volume of the eluates). Precipitates were collected by filtration, washed with isopropyl alcohol and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)-acetamido]cephalosporanic acid (syn isomer~ (10.4 g.). The '0 mother liquor was concentrated under reduced pressure until crystals began to precipitate. To the residue was added isopropyl alcohol (2/3 volume of the residue). The mixture was cooled and precipitates were collected by ~iltration to give the same object compound (5.8 g.). Total yield (16.2 g.).
!5 This compound was identified with the compound obtained in the ~oregoing Examples by I.R. and N.M.R. spectra.
Example 2~
7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-iO carboxylic acid (syn isomer) (10.8 g.) was added to methanol ~ - 56 (200 ml.), and phosphorus oxychloride (7.2 g.) was dropwise added thereto with stirring and ice-cooling at 2 to 9C. After stirring for 1.5 hours at the same temperature, the reaction mixture was concentrated under reduced pressure on a water bath of 25 to 28C to the volume of 100 ml. To the residue was added ether (300 ml.) with stirring and ice-cooling Precipitates were collected by filtration and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (12.3 g.).
This powder (12.3 g.) was suspended in water (100 ml.) and dissolved by adjusting pH of the suspension to 7.5 by addition of a saturated aqueous solution of sodium bicarbonate. To the solution was added ethyl acetate (100 ml.), and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with cold water and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (6.1 g.). The aqueous layer in the mother liquor was separated and stirred under cooling after addition of sodium chloride.
Precipitates were collected by filtration to give the same object compound (3.8 g.). Total yield (9.9 g.).
This compound was identified with the compound obtained in the foregoing Examples by I.R. and N.M.R. spectra.

~ -- 110 --Example24 The following compounds were obtained according to similar manners to those of Examples 16to 23.
(1) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamidG}-3-hydroxymethyl-3-cephem-4-carboxylic acid (~yn isomer), mp 260 to 270C (dec.).
I.R. spectrum (~ujol) 3370, 3270, 1765 , 1~60, 1610, 1590, 1550 c~-N.M.R. spectrum (d6-DMSO, ~) ppm 9.58 (lH, d, J-81iz) 6.76 ~lH, s) 5.75 ~lH, dd, J=5, 8Hz) 5.12 (lH, d, J=5~fz) 4.27 (2H, broad s) 3.85 (3H, s) 3.57 (2H, broad s) 3o ~ - 58 ~2) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido~-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 210 to 220 C (dec.3.
I.R. spectrum (Nujol 3250, 1765, 1650 c~
N.M.R. spectrum ~d6-DMS0, ~) ppm 9.64 (lH, d, J=8Hz) 7.4 (2H, m) 6.79 ~, s) IO 6.60 ~2H, m) 5.77 (lH, dd, J=5, 8Hz) 5.16 (1~, d, J=5Hz) 4.75 (2H, ABq, J=12Hz) 3.87 ~3H, s) 3.53 (2H, ABq, J=18Hz) -- ~) 7-[2-Methoxyimino-2-(2-amino-],3-thiazol-4-yl)ace~amido'-3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 185C (dec.).
I.R. spectrum (~'ujol) 3150 - 3350, 1770, I710, 1660, 1630 cm 1 N.M.R. spectrum (d6-DMS0, ~) ppm 9.61 (lH, d, J=8Hz) 8.69 (1~l, s) 6.73 (lH. s) 5.72 (lH, dd, J=4, 8Hz) 5.1 (lH, d, J=4Hz) 4.1 (2H, ABq, J=13Hz) 3.87 (3H, s) 3.65 (2H, broad s) ~O 3.59 (3H, s) ~-5g (4) 6-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4,-d][l,3]thiazine-1,7(4H)-dione (syn isomer), mp 210 to 215C (dec.).
I.R. spectrum (Nujol) 3270, 1780, 1740,1655,1610,1525 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 7.26 (2H, broad s) 6.77 (lH, s) 5.93 (lH, dd, J=5, 8Hz) 5.16 (lH, d, J=5Hz) 5.05 ~2H, broad s) 3.85 (3H, s) 3.81 (2H, broad s) (5) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-[1-(2-dimethylaminoethyl)-lH-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 1765 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 9.56 (lH, d, J=8Hz) 6.75 (lH, s) 5.75 (lH, m) 5.10 (lH, d, J=4Hz) 4.58 (2H, broad s) 4.32 (2H, broad s) 3.82 (3H, s) 3.68 (2H, broad s) 3.20 (2H, broad s) 2.50 (6H, s) '~jif i~, Example 25 1 337J22 A suspension of 7-~2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]cephalosporanic acid (syn isomer) (2.76 g) and 4-methyl-4H-1,2,4-triazole-3-thiol (0.63 g) in pH 6.4 phcsphate buffer solution (50 ml) was adjusted to pH 6.4 with sodium bicarbonate and stirred for 6 hours at 65 to 70C. The reaction mixture was cooled and ethyl acetate was added thereto. The mixture was adjusted to pH 5 with 10~ hydrochloric acid and washed with ethyl acetate.
The aqueous layer was treated with activated charcoal and adjusted to pl-l 2.7 with 10% hydrochloric acid with stirring and ice-cooling. Precipitating crystals were collected by filtration, washed with cold water and dried to give 7-~2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-~4-methyl-4H-1,2,4-triazol-3-yl)thiomethyi-3-cephem-4-carboxylic acid (syn isomer) (0.7 g)J mp 185C ~dec.).
I.R. spectrum (NuJol) 31aO - 3350, 1770, 1710, 1660, i630 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.61 (lH, d, J=8Hz) 8.69 (lH, s) 6.73 (lH, s) 5.72 ~lH, dd, J=4, 8Hz) 5.1 (~H, d, J=4}-~z) 4.1 (2H, ABq, J=i3Hz) 3.87 (3H, s) 3.59 (3H, s) 3.65 (2H, broad s) Example 26 The following compounds were obtained according to a similar manner to that of Example 25~

1 ~752Z

(1) 7-[2-Methoxyimino-2-(2-methy~ 3-thiazol-4-yl)acetamid 3-(1-methyl-lH-tetrazoi-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 1780, 1710, 1675 cm i N.M.R. spectrum (d6-DMSO, ~) ppm 9.65 (lH, d, J=lOHz) 7.66 (1~, s) 5.81 ~iH, dd, J=5, lOHz) 5.15 (lH, d, J=5Hz) 4.31 ~2H~ ABq, J=13Hz) 3.93 (3H, s) 3.90 ~3H, s) 3.70 (2H, ABq, J=16Hz) 2.65 (3H, s) ~2~ 7-[2-Methoxyimino-2-(2-mesylimino-3-methyl-2~3-dihydr 1,3-thiazol-4-yl)acetamido]-3-~1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R~ spectrum (Nujol) 3250, 1780, 1718, 1675 cm~l - N.M.R. spectrum (d6-DMSO, ~) ppm 9.80 (i}~, d, J=8Hz) 7.08 (1~l, s) 5.80 (-H, dd, J=5, 8Hz) 5.18 (lH, d, J=5Hz) 4.34 (2H, ABq, J=13Hz) 3.99 (3H, s) 3.96 (3H, s) 3.72 (2H, ABq, J=17Hz) 3.66 ~3H, s) 2.98 (3H, s) ~3J 7-~2-Methoxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)-acet-amido~-3-(l-methyl-lH-tetrazol-s-yl)thiomethyl-3-cephem-4^
carboxylic acid (syn isomer).
~5 I.R. spectrum (Nujol) 3300 - 3150, 1780, 1710, 1670 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.84 (iH, d, J=8Hz) 6.97 (lH, s) 5.76 (lH, dd, J=S, 8Hz) 5.12 ~lH, d, J=5Hz) 4.33 (2H, ABq, J=131-lz) 3.93 (6H, s) 3.74 (2H, ABq, J=17Hz) 2.96 (3H, s) (4) 7-[2-Methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetamido~-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 1780, 1665 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 11.67 (lH, s) 9.83 (lH, d, J=8Hz) 6.61 (lH, s) 5.80 (lH, dd, J=5.5, 8Hz) 5.17 (lH, d, J=5.5Hz) 4.37 (2H, broad s) 4.00 (3H, s) 3.96 (3H, s) 3.75 (2H, broad s) (5) 7-~2-Allyloxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)-acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem 4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) ;

3100 - 3300, 1780, 1720, 1675 cm 1 N.M.R. spectrum (d6DMS0, ~) ppm 9.90 (lH, d, J=8Hz) 7.00 (lH, s) S 6.07 - 5.63(2H, m) 5.43 (2H, d, J=8Hz) 5.18 (lH, d, J=5Hz) - -~ 4.70 (2H, d, J=SHz) 4,37 (2H, broad s) 3.98 (3H, s) 3.75 (2H, broad s) 3.00 (3H, s) ( 6J 7-[2-Methoxyimino-2-t2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic lS acid (syn isomer).
I.R. spectrum (Nujol) 3200, 1765, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm: 8.51 (l~l, d, J=8.5Hi) 7.22 (2H, broad s) 6.72 (lH, s) S.S9 (lH, dd, J=5, 8.5Hz) 5.00 (lH, d, J=5Hz) 4.35 (2H, ABq, J=12Hz) 3.90 (3H, s) 3.81 (3H, s) 3.55 (2H~ ABq, J=18Hz) ( 7) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(S-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3400 - 3150, 1770, 1670, 1625 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.66 (lH, d, J=8Hz) 7.34 (2H, broad s) 6.76 (lH, s) 5.78 (2H, dd, J=5, 8Hz) 5.16 (lH, d, J=5Hz) 4.40 (2H, ABq, J=14Hz) 3.85 (3H, s) 3.70 (2H, ABq, J=17Hz) 2.68 (3H, s) (8) 7-[2-Allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3100 - 3400, 1775, 1660, 1625 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 6.80 (lH, s) 6.30 - 5.60(2H, m) 5.24 (2H, dd, J=8, 16Hz) 5.15 (lH, d, J=5Hz) 4.63 (2H, d, J=5Hz) 4.32 (2H, ABq, J=12Hz) 3.94 (3H, s) 3.70 (2H, ABq, J+17Hz) (9) 7-[2-Methoxyimino -2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145 to 147C
(dec.).

, ~, ~: 1337S2~
:
I.R. spectrum (Nujol) 3150 - 3400, 1780, 1725, 1680, 1640 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 12.58 (lH, broad s) 9.70 (lH, d, J=8Hz) 9.58 (lH, s) 8.50 (lH, s) 7.40 (lH, s) 5.82 (lH, dd, J=S, 8Hz) 5.17 (lH, d, J=5Hz) 4.43 (2H, ABq, J=13Hz) 3.88 (3H, s) 3.70 (2H, broad s) (1~ 7-[2-Methoxyimino-2-(2-acetamido-1,3-thiazol-4-yl)-acetamido~-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 171 to 173C (dec.).
I.R. spectrum (Nujol) 3500, 3250, 1780, 1720, 1670 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.65 (lH, d, J=8Hz) 7.3 (lH, s) 5.8 (lH, dd, J=5, 8Hz) 5.15 (lH, d, J=5Hz) . 4.35 (2H, broad s) 3.97 (3H, s) 3.9 (3H, s) 3.75 (2H, broad s) 2.15 (3H, s) ~0 l/q 3~5Z~
. . . . ..
(11) 7-~2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 172 to 175C (dec.).
I.R. spectrum (Nujol) 3300, 1770, 1665 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.80 (lH, d, J=8Hz) 9.63 (1~l, s) 6.95 (1~, s) 6.8 (2H, m) 5.82 (lH, dd, J=5, 8Hz) 5.22 (lH, d, J=5Hz) 4.48 (2H, ABq, J=15Hz) 3 97 (3H, s) 3.76 (2H, ABq, J=18Hz) 3o (12) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-~1-(2-dimethylaminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 1765 cm l N.M.R. spectrum (d6-DMSO, ~) ppm 9.56 (lH, d, J=8Hz) 6.75 (lH, s) 5.75 (lH, m) 5.10 (lH, d, J=4Hz) 4.58 (2H, broad s) 4.32 (2H, broad s) 3.82 (3~1, s) 3.68 (2H, broad s) 3.20 (2H, broad s) 2.50 (6H, s) (13) 7-~2-Methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3200, 1775, 1720, 1680, 1660 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 11.9 (lH, m) 9.70 (lH, d, J=lOHz) 9.55 (lH, s) 7.31 (lH, s) 5.80 (lH, dd, J=5,10Hz) 4.44 (2H, ABq~ J=16Hz) 4.22 (2H, q, J=7Hz) 3.89 ~3H, s) 3.72 (2H, ABq~ J-16Hz) 1.23 (3H, t, J=7Hz) (14) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-acetamidol-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3200-3300, 2600, 1780, 1720, 1690, 1675 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 12.60 (lH, broad s) 9.70 ~lH, d, J=8Hz) 8.50 (lH, s) 7.44 (lH, s) 5.88 (lH, dd, J=5,8Hz) 5.19 (lH, d, J=5Hz) 4.25 (2H, ABq, J=13Hz) 3 95 (3H, s) 3.85 (3H, s) 3.65 (2H, ABq, J=18Hz) 1 3375~2 (15) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxyiic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1770, 1725, 1670 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 9.76 (lH, d, J=8H2) 6.7-7.40 (4H, m) 5.86 (lH, dd, J=5, 8Hz) 5.18 (lH, d, J=SHz) 4.34 (2H, ABq, J=1;3Hz) 3.92 (6H, s) 3.72 (2H, ABq, J=17Hz) ~6) 7-[2-t-Butoxycarbonylmethoxyimino-2-(3-chloro-4-S hydroxyphenyl)acetamido]-3-(1-methyl-lH-tetra,ol-S-yl)thio-methyl-3-cephem-4-carboxylic acid (syn isomer), powder.
~7) 7-[2-Carboxy-methoxyimino-2-(3-chloro-4-hydroXyphenyl)acetamid 3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145 to 148C (dec.).
~0 I. R. spectrum (Nujol) 3400, 3200 - 3300, 2500 - 2600, 1780, 1720, 1670, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 7.50 (lH, d, J=2Hz) 7.45 (lH, dd,J=2, 8Hz) 7.10 (lH, d, J=8Hz) 5.90 (lH, q, J=5Hz) 5.22 (lH, d, J=SHz) 4.70 (2H, s) 4.35 (2H, ABq, J=13Hz) 3.95 (3H, s) 3.75 (2H, ABq, J=1811z) (18 ~-t2~ t-Butoxycarbonylethoxyimino )-2-(3-chloro-4-hydroxyphenyl)acetamido~-3-(1-methyl-lH-tetrazoi-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer), powder.
~9) 7-[2-(1-Carboxyethoxyimino)-2-(3-chloro-4-hydroxyphenyl)-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer),mp 147 to 151C (dec.).
I.R. spectrum (Nujol) 3500, 3250, 2500 - 2600, 17~0, 1730, 1660, 1630, 1600 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.62 (lH, d, J=8Hz) 7.46 (lH, d, J=2Hz) 7-34 tlH, dd, J=2, 8Hz) 7.04 (lH, d, J=8Hz) 5.90 (lH, q, J=5Hz) 5.22 (lH, d, J=5Hz) 4.73 (lH, q, J=6Hz) -- 4.33 (2H, ABq, J=13Hz) 4.00 (3H, s) 3.73 (2H, ABq, J=1811z) 1.37 (3H, d, J=6Hz) (20) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1775, 1710, 1665 cm~

N.~.R. spectrum (d6-DMSO, ~) ppm 9.67 (lH, d, J=8Hz) 8.40 tlH, s) 6.70-7.43 ~4H, m) 5.82 (lH, dd, J=5, 8Hz) 5.13 (lH, d, J=5Hz) 4.18 (2H, ABq, J=13Hz) 3.90 (3H, s) 3.67 (2H, broad s) (21) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiometllyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.78 (lH, d, J=8Hz) 9.55 (lH, s) 6.70-7.40 (4H, m) 5.89 (lH, dd, J=5, 8Hz) 5.22 (lH, d, J=SHz) 4~46 (2H, ABq, J=13Hz) 3.92 (3H, s) 3.76 (2H, ABq, J=18Hz~
(22~ 7-[2-~iethoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(S-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.72 (lH, d, J=8Hz) 6.G2-7.40 (4H, m) 5.94 (lH, dd, J=S, 8Hz~
5.18 (lH, d, J-5Hz) 4.18 (2H, ABq, J=13Hz) 3.89 (3H, s) 3.70 (2H, ABq, J=17Hz) 2.65 (3H, s) t2~ 7-[2-Methoxyimino-2-(3-methoxyphenyl)acetamidGî-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 10(syn isomer).
I . R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.78 (lH, d, J=8Hz) 6.95-7.54 (4H, m) 5.94 (lH, dd, J=5, 8Hz) ~ - 73 ~ 337522 5.18 (lH, d, J=5Hz) 4.12 (2H, ABq, J=13Hz) 3.92 (6H, s) 3.76 (3H, s) 3.72 (2H, ABq, J=18Hz) (24) 7-[2-Methoxyimino-2-(4-hydroxyphenyl)acetamido]-3-(i-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 10(syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 7.44 (2H, d, J=8Hz) 6.84 (2H, d, J=8Hz) 5.86 (lH, dd, J=5, 8Hz) 5.18 (lH, d, J=5Hz) 4.34 (2H, ABq, J=13Hz) 3'93 (3H, s) 3.87 (3H, s) 3.74 (2H, ABq, J=18Hz) (25) 7-[2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3~ methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145 to 148C (dec.).

I.R. spectrum (Nujol) 3500, 3250, 2500-2600, 1780, 1720, 165S, 1625, 1600 cm N.M.R. spectrum (d6-DMSO, ~) ppm 10.80 (lH, broad s) 9.68 (lH, d, J=2Hz) 7.46 (lH, d, J=2Hz) 7.32 (lH, q, J=2, 8Hz) 7.00 (lH, d, J=8Hz) 5.80 (lH, q, J=5Hz) - 5.16 (lH, d, J=SHz) 4.28 (2H, ABq, J=13Hz) 3 92 (3H, s) lS 3.87 (3H, s) 3.72 (2H, ABq, J=18Hz) (26) 7-[2-Methoxyimino-2-(3-chloro-4-methoxyphenyl)acet-amido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 143 to 145C (dec.).
I.R. spectrum (~ujol) 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.76 (lH, d, J=8Hz) 7.56 (lH, d, J=2Hz) 7.48 (lH, dd, J=2, 8Hz) t ~37522 7.22 (l~, d, J=8Hz) 5.84 (lH, q, J=SHz) 5.18 (lH, d, J=5Hz) 4.27 (2H, ABq, J=13Hz~
3.90 (6H, s) 3.88 (3H, s) 3.70 (2H, ABq, J=18Hz) ~27) 7-[2-Methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 149 to 152C (dec.).
I.R. spectrum (Nujol) 3400 - 3450, 3200, 2500 - 2600, 1780, 1720, 1660, 1620, 1600, 1535, 1350 cm N.M.R. spectrum (d6-DMSO, ~) lS ppm 9.72 (lH, d, J=8Hz) 7.97 (lH, d, J=2Hz) 7.72 (lH, dd, J=2, 8Hz) 7.21 (lH, d, J=8Hz) 5.82 (lH, q, J=5Hz) 5.16 (lH, d, J=5Hz) 4.3 (2H, ABq, J=13Hz) 3.92 (3H, s) 3.87 (3H, s) 3.72 (2H, ABq, J=18Hz) (28) 7-[2-Allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acet-amido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 163 to 165C (dec.).
I.R. spectrum (Nujol) 3200-3300, 2500-2600, 1780, 1720, 1670, 1600 cm~l N.M.R. spectrum (d6-DMSO, 6) ppm 9.70 tlH, d, J=8Hz) 7.40 (lH, d, J=2Hz) 7.30 (lH, dd, J=2, 8Hz) 6.95 (lH, d, J=8Hz) 5.80 (2H, m) 5.30 (2H, d, J=8Hz) 5.10 (lH, d, J=5Hz) 4.60 (2H, d, J=5Hz) 4.27 (2H, ABq, J=13Hz) 3.85 (3H, s~
3.65 (2H, ABq, J=18Hz) (29) 7-[2-Allyloxyimino-2-(3-hydroxyphenyl)acetamido]-3-(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 149 to 152C ( dec.), I.R. spectrum (Nujol) 3250 - 3350, 2550 - 2600, 1780, 1730, 1670, 1650, 1600 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 7.2 - 6.8 (4H, m) 6.1 - 5.8 (2H, m) S.35 (2H, d, J=8Hz) 5.17 (lH, d, J=SHz) 4.7 (2H, d, J=5Hz) 4.17 (2H, ABq, J=13Hz) 3.93 (3H, s) 3.75 (2H, ABq, J=18Hz) ~O) 7-[2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(4-hydroxy-phenyl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), powder.
I.R. spectrum (Nujol) 3150, 1780, 1720, 1670 cm 1 N.M.R. spectrum ~d6-DMSO, ~) S ppm 9.60 (lH, d, J=8Hz~) 6.72 - 7.52(7H, m) 5.80 (lH, dd, Jz4, 8Hz) 5.15 (lH, d, J=4Hz) 5.00 (2H, s) 4.28 (2H, ABq, J=13Hz) 3.90 (3H, s) 3.65 (2H, ABq, J=18Hz) (311 7-[2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyl)acet-amido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-lS carboxylic acid (syn isomer), powder.
I.R. spectrum (Nujol) 3200 - 3300, 1780, 1720, 1660 cm N.M.R. spectrum (d6-DMS0, ~) ppm 9.77 (lH, d, J=8Hz) 6.7 7.7 (7H, m) 5.83 (lH, dd, J=5, 8Hz) 5.29 (2H, s) 5.15 (lH, d, J=SHz) 4.3 (2H, ABq, J=13Hz) 3.92 (3H, s) 3.72 t2H, ABq, J=18Hz) t32) 7-[2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), colorless powder, mp 153 to 156C (dec.) ~ 337522 I.R. spectrum (Nujol) 3450, 3250, 2550 - 2600, 1780, 1725, 1665, 1630, 1600 cm~
N.M.R. spectrum (d6-DMSO,~) ppm 9.71 (lH, d, J=8Hz~) 7.50 (lH, d, J=2Hz) 7.36 tlH, dd, J=2, 8Hz) 7.03 (lH, d, J=8Hz) 5.83 (lH, q, J=5Hz) 5.17 (lH, d, J=5Hz) 4.33 (2H, ABq, J=13Hz) 4.17 (2H, q, J=7Hz) 3.97 (3H, s) 3.73 (2H, ABq, J=18Hz) 1.25 (3H, t, J=7Hz) (33) 7-[2-Allyloxyimino-2-(3-methoxyphcnyl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), powder, mp 135 to 138C (dec.).
I.R. spectrum (Nujol) 3300, 2600, 1785, 1730, 1670, 1645, 1600 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.82 (lH, d, J=8Hz) 7.0 - 7.45 (4H, m) 5.8 - 6.2 (2H, m) 5.36 (2H, t, J=lOHz) 5.21 (lH, d, J=5Hz) 4.72 (2H, d, J=5Hz) 4.36 (2H, ABq, J=13Hz) 3.95 (3H, s) 3.91 (3H, s) -132_ 3.87 (2H, ABq, J=18Hz) ~4) 7-[2-Ethoxyimino-2-(3-hydroxyphenyl)acetamido~-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), yellow powder, mp 145 to 148C (dec.~.
S I.R. spectrum (Nujol) 3450, 3250, 2500 - 2600, 1775, 1720, 1665, 1620, 1600 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 6.8-7.4 (4H, m) 5.90 (lH, q, J=5Hz) 5.20 (lH, d, J=SHz) 4.36 ~2H, ABq, J=13Hz) 4.20 (2H, q, J=7Hz) lS 4.00 (3H, s) 3.76 ~2H, ABq, J=18Hz) - 1.33 (3H, t, J=7Hz) ~5) 7-[2-Ethoxyimino-2-(3-methoxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), pale yellow powder, mp 140 to 143C (dec.).
I.R. spectrum (Nujol) 3300, 2500 - 2600, 1785, 1730, 1670, 1630, 1600 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 9.71 (lH, d, J=8Hz) 6.9 - 7.5 (4H, m) 5.90 tlH, q, J=SHz) 5.17 (lH, d, J=SHz) 4.33 (2H, ABq, J=13Hz) 4.20 (2H, q, J=7Hz) 3.95 (3H, s) 3.85 (3H, s) 3.75 (2H, ABq, J=18Hz) 1.30 (3H, t, J=7Hz) (36) 7-[2-Allyloxyimino-2-~3-chloro-4-methoxyphenyl)acetamido]-3~ methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), pale yellow powder, mp 153 to 156C (dec.).
I.R. spectrum (Nujol) 3250, 2600, 1780, 1720, 1670, 1645, 1630, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.65 (lH, d, J=8Hz) 7.27 (lH, d, J=2E~z) 7.20 (lH, dd, J=2, 8Hz) lS 7.09 (lH, d, J=8Hz) 5.85 - 6.15(2H, m) S.lS (2H, t, J=9Hz) S.OS (lH, d, J=SHz) 4.60 (2H, d, J=SHz) 4.15 (2H, ABq, J=13Hz) 3.95 (3H, s) 3.90 (3H, s) 3.47 (2H, ABq, J=18Hz) (37) 7-[2-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)-acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3300, 1760, 1660, 1600, 1580, 1520 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.7 (lH, d, J=8Hz) t }37522 7.7 - 6.7 (9H, m) 5.8 - 5.4 (3H, broad s) 5.06 (IH, d, J=SH2) 4.33 (2H, broad s) 3.9 (3H, s) 3.S6 (2H, broad s) (38) 7-[2-Methoxyimino-2-(3-mesylaminophenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 155C (dec.).
I.R. spectrum (Nujol) 3300, 1780, 173~, 1670 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 9.98 (lH, s) 9.81 (lH, d, J=9Hz) lS 9.62 (lH, s) S.90 (lH, dd, J-5,9Hz) 5.24 (lH, d, J=SHz) 4.49 (2H, ABq, J=14Hz) 3.98 (3H, s) 3.77 (2H, broad s) 2.96 (3H, s) (39) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3450, 3300, 3200, 1780, 1725, 1670, 1620, 1590, 1520 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.77 (lH, d, J=7Hz) 7.6 - 6.8 (6H, m) E-~2 5.83 (lH, dd, J=4, 7Hz) 5.17 ~lH, d, J=4Hz) 4.31 (2H, ABq, J=14Hz) 3.96 (6H, s) 3.72 (2H, broad s) (40) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiome$hyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1780, 1735, 1675, cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.81 (lH, d, J=8Hz) 9.62 (lH, s) 6.7 - 7.58 (4H, m) 5.8 (lH, dd, J=5, 8Hz) 5.2 (lH, d, J=SHz) 4.25, 4.63(2H, ABq, J=14Hz) 3.9 (3H, s) 3.7 (2H, broad s) (4~ 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acld (syn isomer).
I.R. spectrum (Nujol) ~ S0, 1780, 1740, 1720, 1680 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.86 (lH, d, J=8Hz) 9~61 (lH, s) 7.00-7.65 (4H, m) 5.84 (lH, dd, J=5, 8Hz) 5.2 (lH, d, J=SHz) 4.25-4.63 (2H, ABq, J=14Hz) 3.92 (3H, s) 3.53, 3.86 (2H, ABq, J=19Hz) 2.3 (3H, s) (42) 7-[2-(3-Phenylallyloxyimino)-2-(3-hydroxypheny')acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic - S acid (syn isomer), mp 138 to 142C (dec.).
I.R. spectrum (Nujol) 3300 - 3400, 2600, 1780, 1720, 1665, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.80 (lH, d, J=8Hz) 6.4 - 7.4 (llH, m) 5.85 (lH, dd, J=5, 8Hz) 5.20 (lH, d, J=SHz) 4.83 (2H, d, J=SHz) 4.32 (2H, ABq, J=lSHz) 3.95 (3H, s) 3.68 (2H, ABq, J=18Hz) (43)7-[2-Methoxyimino-2-(4-dimethylaminophenyl)acetamido]-3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephe~-4-carboxylic acid (syn isomer), mp 88C (dec.).
I.R. spectrum (Nujol) 3250, 1780, 1730, 1680, 1610 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.63 (lH, d, J=8Hz) 7.40 (2H, d, J=8Hz) 6.73 (2H, d, J=8Hz) 5.83 (lH, dd, J=5, 8Hz) 5.17 (lH, d, J=SHz) 4.33 (2H, ABq, J=13Hz) 3.97 (3H, s) 3.87 t3H, s) 3.73 (2H, broad s) 3.00 (6H, s) (44) 7-~2-Methoxyimino-2-(3-hydroxyphenyl)acetamido] -3-r ;-(2-dimethylaminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I. R. spectrum (Nujol) 1765 cm~l N. M. R. spectrum (d6-DMS0, ~) ~ 10 ppm 9.67 (lH, d, J=9Hz) 6.72-7.36 (4H, m) 5.78 (lH, dd, J=5, 9Hz) 5.12 (lH, d, J=5Hz) 4.55 (2H, broad s) 4.~0 (2H, broad s) 3.90 (3H, ~) 3.40-3.80 (2H, m) 3.14 (2H, broad s) 2.48 (6H, s) (45) 7-[2-~2-(2-Hydroxyphenoxy)ethoxyimino~-2-(3-hydroxyphenyl)-- acetamido~-3-(1-~ethyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I. R. spectrum (~ujol) 3~70, 1780, 1725, 1670, 1560 cm~
N. M. R. spectrum (d6-DMSO,~ ) ppm 6.5-7.4 (8H, m) 5.86(1H, dd, J=5, 8Hz) 5.14(1H, d, J=5Hz) 4.0-4.6 (6H, m) 3.92(3H, s) ~.52, 3.70(2H, ABq~ J=7Hz) ,, .. .... , .. ~ .

Example 27 A solution of 7-~2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid tsyn isomer) (0.3 g) in a mixture of acetone (3 ml) and water (1.5 ml) was adjusted to pH 2 with 6N hydrochloric acid and stirred for 4 hours at ambient temperature. After the acetone was distilled off, to the residue was added water (1 ml).
The mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and ice-cooled for 1 hour.
Precipitating crystals were collected by filtration, washed with water and dried to give 6-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazine-1,7(4H)-dione (syn isomer)(0.23g), mp 210 to 215 C(dec.).
I.R. spectrum (Nujol) 3270, 1780, 1740, 1655, 1610, 1525 cm 1 N.M.~. spectrum (d6-DMSO, ~) ppm 9.70 (lH, d, J=8Hz) 7.26 (2H, broad s) 6.77 (lH, s) 5 93 (lH, dd, J=S, 8Hz) 5.16 (lH, d, J=5Hz) 5.05 (2H, broad s) 3.85 (3H, s) 3.81 (2H, broad s) 3o E- ~6 Example 28 The following compound was obtained according to a similar manner to that of Example 27 .
6-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido] -5a,6-dihydro-3H~7H-azeto[2~l-b]furo[3~4-d][l~3]thiazine-l~7(4H) dione(syn isomer), I.R. spectrum (Nujol) 3250, 1785, 1755, 1660, 1600, 1570, 1540 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 9.83 (lH, d, J=8Hz) 7.5 - 6.75 (4H, m) 6.02 (lH, dd, J=5, 8Hz) 5.21 (lH, d, J=5Hz) 5.07 (2H, broad s) 3.95 (3H, s) 3.84 (2H, broad s) ~0 Example 29 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-hydroxymethyl-3-cephem-4-car~oxylic acid tsyn isomer) (1.0 g.) was dissolved in a mixture of dimethyl-formamide (6 ml.) and acetone (30 ml.). Jones reagent (1.25 ml.), which was prepared from conc. sulfuric acid (0.28 ml.), chromium trioxide (0.33 g.) and water (0.9 ml.), was dropwise added thereto over 2 minutes with stirring and cooling at 0 to 2C.
After stirring for 20 minutes at the same tempera'ure, the reaction mixture was poured into ice-water (50 ml.). After acetone was distilled off, the residue was twice extracted with ethyl acetate (50 ml.). The extracts were washed with a saturated aqueous solut,on of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diisopropyl ether to give 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}-acetamido]-3-formyl-3-cephem-4-carboxylic acid (syn isomer) [or this compound can be represented as 3-hydroxy-6-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazoi-4-yl}acetamido]-Sa,6-dihydro-3H, 7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)dione (syn isomer)]
~0.56 g.).
I.R. spectrum (Nujol) 3150, 1790, 1720, 1655, 1560, 1500 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.88 (lH, d, J=8Hz) 7.60 (lH, s) 6.30 (lH, d, J=6Hz) 6.05 (lH, dd, J=5,8Hz) 5.23 (lH, d, J=SHz) 3.96 (3H, s) 3.80 (2H, broad s) Example 30 The following compounds were obtained by conducting S elimination reaction of protective group of amino on carbamoyl group according to a similar manner to that of Example 3.
(1) 7-[2-Methoxyimino-2-t2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 210 to 220C (dec.).
I.R. spectrum (Nujol) 3250, 1765, 1650 cm l ,,, .. , ~ . ._~
- N.M.R. spectrum (d6-DMSO, ~) ppm 9.64 (lH, d, J=8Hz) 7.4 (2H, m) 6.79 (lH, s) 6.60 (2H, m) 5.77 (lH, dd, J=5,8Hz) 5.16 (lH, d, J=SHz) ` 4.75 (2H, ABq, J=12Hz) 3.87 (3H, s) 3.53 (2H, ABq, J=18Hz) (2) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-acetamido~-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. spectrum (Nujol) - 3300, 1780, 1705, 1680 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 12.50 (lH, broad s) 9.67 (lH, d, J=8Hz) 8.50 (lH, s) -142_ 7.43 (lH, s) 6.58 (2H, broad s) 5.80 tlH, dd, J=5,8Hz) 5.16 (lH, d, J=SHz) S 4.78 (2H, ABq, J=14Hz) 3.95 (3H, s) 3.57 (2H, ABq, J=18Hz) . , ~ , . .

Reference 1 Phosphorus pentachloride (3.3 g.) was added under ice-cooling to a suspension of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.5 g.) in methylene chloride S (30 ml.) and the mixture was stirred for 30 minutes at ambient temperature. Methylene chloride was distilled off under reduced pressure and acetone was added to the residue to give a suspension.
On the other hand, a suspension of 7-amino-3-(1-methyl-lH-tetra-zol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.2 g.) in an aqueous solution of sodium bicarbonate (0.76 g. in 50 ml. of water) was stirred for 10 minutes and acetone (50 ml.) was added thereto to give a solution. To the solution was dropwise added the above obtained suspension containing acid chloride with stirring and ice-cooling and keeping the solution at pH 7.5 lS to 8.5 with a 20% aqueous solution of sodium carbonate. The mixture was stirred for 1 hour at 3 to 5C and pH 8Ø Acetone was distilled off under reduced pressure and the residue was adjusted to pH 7.4 with ~ saturated aqueous solution of sodium bicarbonate and further adjusted to pH 4.5 with 10~ hydrochloric acid with stirring and ice-cooling. Precipitates were filtered off and the filtrate was saturated with sodium chloride, adjusted to pH 2.5 with 10~ hydrochloric acid and stirred for 1 hour. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1 methyl lH tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers) (0.95 g-)-I.R. spectrum (Nujol) 3400, 1775, 1710, 1670, 1630 cm 1 ~ - 91 N.M.R. spectrum (d6-D~SO, ~) ppm 9.85 (lH, d, J=8Hz) 9.50 (lH, d, J=8Hz) 7.58 (lH, s) 6.87 (lH, s) 6.65 (4H, broad s) 5.77 (2H, m) 5.15 (2H, d, J=5Hz) 4.35 (4H, broad s) 4.06 (6H, s) 3.97 (6H, s) 3.75 (4H, broad s) Reference 2 A suspension of phosphorus pentachloride (1.7 g.) in methylene chloride (20 ml.) was changed to a solution by stLrring for 2 hours at ambient temperature. 2-~ethoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (0.8 g.) was added thereto at a time at ambient temperature and the mixture was stirred. Methylene chloride was distilled off under reduced pressure and the residue was dissolved in acetone (20 ml.). On the other hand, 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1.0 g.) was suspended in a solution of sodium bicarbonate (0.59 g.) in water (20 ml.) and dissolved by adding acetone (10 ml.). To this solution was dropwise added the above obtained solution containing acid chloride with stirring and ice-cooling and keeping the solution at pH 7.5 to 8.5 with a 20~ aqueous solution of sodium carbonate. After stirring for 1 hour at pH 8 under ice-cooling, an insoluble material was filtered off. Acetone was distilled off under reduced pressure from the filtrate and an insoluble material was filtered off. The filtrate was adjusted to pH 2.5 with 10~
hydrochloric acid. Precipitates were collected by filtration and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers) (0.4 g.). The fil~-rate was saturated with sodium chloride and stirred under ice-cooling to give precipitates. The precipitates were collected by filtration and dried to give the same object compound (C.3 g ).
Total yield (0.7 g.).
I.R. spectrum (Nu3ol) 3400, 1775, 1705 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 9.71 (lH, d, J=8Hz) 9.42 (lH, d, J=8Hz) 7.70 (lH, s) 7.40 (4H, broad s) 7.00 (1l~, s) 6.61 (4H, s) 5.76 (2H, m) 5.16 (21T, d, J=4,5Hz) 4.76 (4H, ABq, J=12Hz) 3.98 (3H, s) 3.89 (3H, s) 3.53 (4H, ABq~ J=18Hz) Reference 3 A mixture of dimethylformamide (0.22 g.) and phospllorus oxychloride (0.46 g.) was warmed for 1 hour at 40C. The mixture was dissolved in dry methylene chloride (20 ml.) and 2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetic acid (anti isomer) (0.73 g.) was added thereto with stirring and ice-cooling, after which the resulting mixture was stirred for 1.5 hours under ice-cooling. On the other hand, 7-amino^3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (0.82 g.) was dissolved in a so~ution of bis-(trimethylsilyl)acetamide (1.5 g.) in dry methylene c'iloride (20 ml.). To this solution was added at -30C the above obtained methylene chloride solution, after which the mixture was stirred for 2 hours at -5 to -20C. After distilling off . . .
methylene chloride at low temperature, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and water (SO ml.) was added thereto. The resulting mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the aqueous layer was separated. The aqueous layer was adjusted to pH 1.5, saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate.
The solvent was distilled off and the residue was pulverized by a mixture of diisopropyl ether and ether. The powder was collected by filtration and dried to give 7-[2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (1.0 g.). This powder (1.0 g.) was suspended in water (30 ml.) and dissolved by adjusting to p~-l 6 by an aqueous solution of sodium bicarbonate. After removing the solvent by bubbling of nitrogen gas, the aqueous solution was lyophilized to give sodium 7-[2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate tanti isomer) (0.98 g ) . .

I.R. spectrum (KBr) 1760, 1675 cm~l N.M.R. spectrum (D2O, ~) ppm 8.05 (lH, s) 5.76 (lH, d, J=5Hz) 5.16 (lH, d, J=5Hz) 4.14 (2H, ABq~ J=13Hz) 4.10 (31~, s) 4.02 (3H, s) 3.52 ~2H, ABq, J=17Hz) 3.45 (3H, s) 3.24 (3H, s) Re~erence 4 The following compounds were obtained according to a similar manner to.that of Reference 3.
(1) 7-t2-Methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetamido]-3^(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid tanti isomer).
I.R. spectrum (Nujol) ~ 1790, 1720, 1680 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 9.53 (lH, d, J=8Hz) 8.27 (1~l, s) 5.83 (lH, dd, J=5.5, 8Hz) 5.15 (lH, d, J=5.SHz) 4.30 (2H, ABqJ J=14Hz) 4.00 (3H, s) 3.93 (3H, s) 3.70 (2H, AB~, J=16Hz) 2.65 (3H, s) ~ 95 (2) 7-[2-~lethoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer).
I.R. spectrum (Nujol) 3400, 1775, 1670 cm~l N.M.R. spectrum (d6-DMS0, ~) ppm 9.44 (lH, d, J=8Hz) 7.71 (1ll, s) 6.40 (2H, broad s) 5.77 (lH, dd, J=5,8Hz) 5.13 (lH, d, J=5Hz) 4.31 (2H, broad s) 4.00 (3H, s) 3.95 (3H, s) 3.70 (2H, broad s) 3o ( ~) 7-t2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-cephalosporanic acid (anti isomer).
I.R. spectrum (Nujol) 3400-3100, 1780, 1730, 1675 cm 1 N.M.R. spectrum (d6-D,~SO, ~) ppm 9.43 (lH, d, J=8l-lz~
9.16 (2H, broad s) 7.73 (i~l, s) 5.82 (11l, dd, J-5,8Hz) 5.18 (lH, d, J=5Hz) 4.90 (2H, ABq, J=13Hz) 4.03 (3'i, 5) 3.60 (2i-l, broad s) 2.07 (3ll, s) ( 4) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer), mp 152C (dec.).
I.R. spectrum (Nujol) 3300 - 3100, 1775, 1720, 1670, 1630 cm 1 2Q N.M.R. spectrum (d6-DMSO, ~) ppm 12.63 (lH, broad s) 9.66 (lH, s) 9.57 (lH, d, J=8Hz) 8.50 (lH, s) 8.07 (lH, s) 5.75 (lH, dd, J=5,8Hz) 5.15 (lH, d, J=SHz) 4.27 (2H, ABq, J=13~z) 4.00 ~3H, s) ~O 3.70 (2H, broad s) ~~97 ~150-(5) 7-[2-Methoxyimino-2-(3-hydroxyphc11yl)acetamido]-3-(l-- `~~ methyl-lH-tetlazol^S-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer).
I.R. spectrum (Nujol) 3350, 1780, 1726, 16&0 cm l N.M.R. spectrum (d6-D~5SO, ~) ppm9.24 (l1-~, d, J=8Hz) 7.36-7.lO
} (411, m) 7.00-6.74 5.70 (l1{, dd, J=5,8ilz) 5.13 (lH, d, J=SHz) 4.34 (21l, ABq, J=1311z) 3.95 (61i, s) 3.72 (21-1, ABq, J=l711z) . .

3o ~ - ~8 :.

Preparation of the startin~ com~ounds to be used for the afore-mentione~ Exam~les and References Preparation 1 A mixture of 3-chloro-4-hydroxyacetophenone (11.9 g.), benzyl chloride (9.35 g.), potassium carbonate ~14.5 g.) and dimethylformamide (60 ml.) was stirred for 1 hour a~ 100C.
The reaction mixture was poured into water ~150 ml.~ and extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution an~ dried over magnesium sulfate.
After distilling off the sol~-ent, the residue (18 g.) was recrystal-lized from ethanol (160 ml.) to give 3-chloro-4-benzyloxyaceto-phenone tl3.2 g.), mp 110 to 112C.
Preparation 2 1) Selenium dioxide powder (12.6 g.) was added over lO
minutes to a solution of 3-chloro-4-benzyloxyacetophenone (19.7 g.) in dry pyridine (100 ml.) with stirring at 100C, and the mixture was stirred for 3 hours at the same temperature.
Precipitating selenium was filtered off and the filtrate was concentrated. The residue was dissolved in water (150 ml.) and the solution was washed with ether. The aqueous solution was acidified under cooling with conc. hydrochloric acid and extracted with ether. The extract was washed with a sodium chloride aqueous solution, dried over magnesium sulfate and concentrated to give 2-(3-chloro-4-benzyloxyphenyl)glyoxylic acid (15.9 g.), mp 134 to 135C.
2) The following compounds were obtained according to a similar manner to that of Preparation 2-1).
~1) 2-(3-Nitro-4-benzyloxyphenyl)glyoxylic acid, mp 161 , . . .~ .. ~
to 164C.
(2) 2-(3-Chloro-4-methoxyphenyl)glyoxylic acid, mp 81 to 82C.
I.R. spectrum (Nujol) 2500-2600, 1715, 1670, 1600 cm 1 E - ~9 -152_ (3) 2-(3-Mesylaminophenyl)glyoxylic acid, mp 66 to 68C.
I.R. spectrum (Nu~ol) 3560, 3250, 1720, 1670 cm 1 Preparation 3 1) A mixture of 2-(3-nitro-4-benzyloxyphenyl)glyoxylic acid ~30 g.), conc. hydrochloric acid (90 ml.) and acetic acid (120 ml.) was stirred for 3 hours at 100C. To tne reaction mixture was added under cooling ice-water (600 ml.) ana the mixture was extracted with ethyl acetate. The extract was washed with ice-water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from a mixture of benzene: ether: petroleum ether (2:1:4). The crystals were collected by filtration, washed with benzene and dried under reduced pressure to give 2-(3-nitro-4-hydroxyphenyl)glyoxylic acid (19.0 g.), mp 139 to 140.5C.
2) The following compound was obtained according to a similar manner to that of Preparation 3-1).
(1) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid, mp 114 to 116C.
Preparation 4 2-(3-Hydroxyphenyl)glyoxylic acid (3.32 g.) and lN-methanol solution of hydroxylamine (45 ml.) were refluxed with stirring for 25 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in lN-aqueous solution of sodium hydroxide (70 ml.~. An aqueous solution was washed with ether, acidified with dil. hydrochloric acid and then extracted with ethyl acetate. The extract was washed, dried and treated with an activated charcoal. The solvent was distilled off to give 2-hydroxyimino-2-(3-hydroxy-phenyl)acetic acid (a mixture of syn and anti isomers) (2.9 g.).

E -lOO

I.R. s~ectrum (Nujol) 3200, 1700 cm 1 Preparation 5 l)(a) Phenolphthalein indicator (3 drops) was added to a solution of O-methylhydroxylamine hydrochloride (5.5 g.) in dry methanol (60 ml.). To the solution was dropwise added with stirring at ambient temperature lN methanol solution of sodium methoxide (65 ml.) until the color of thc solution was changed to purplisll red. O-Methylhydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirrcd for 30 minutes at ambient temperature. After precipitating sodium chloride was filtered off, 2-(3-hydroxyphenyl)glyoxylic acid (9.85 g.) was added to the filtrate and the mixture was refluxed for 30 minutes. After methanol was distilled off at low temperature, a saturated sodium chloride aqueous solution was added to the residue. The mixture was adjusted to pH 1 with lOPo hydrochloric acid and extracted with ether (300 ml.). The extract was dried over magnesium sulfate. Ether was distilled off at low temperature to give 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (a mixturc of syn and anti isomers).
(b) This material was dissolved in ether (60 ml.) and a solution of diazomethane in ether was gradually added thereto under ice-cooling until the color of the mixture was changed to yellow. Acetic acid was immediately added thereto and the mixture was washed with a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ether was distilled off to give oily residue (10.8 g.). The oily residue was subjected to column chromatograph~on silica gel (165 g.) using a mixture of benzene E lOl and ethyl acetate (9 : 1) as developing solvent. Firs~ly the eluate containing syn isomer was eluted and the eluate was collected and concentrated to give oily methyi 2-methoxyimino-2-(3-hydroxyphenyl)acetate (syn isomer) (7.9 g.). The oil S was allowed to stand to give crystals, mp 39.5 to 40.5C.
I.R. spectrum (Nujol) 3450, 1730 cm 1 N.M.R. spectrum (CDCQ3, ~) ppm 6.7 - 7.42 (4H, m) 3.98 (311, s) 3.92 (3H, s) After the eluate containing syn isomer was eluted, then the eluate containing anti isomer was eluted. The eluate was collected and concentrated to gi~e methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (anti isomer) (l.S g.). This material was recrystallized from a mixture of benzene and petroleum ether to give crystals, mp 96 to 98C.
I.R. spectrum (Nujol) 3350, 1715 cm 1 N.M.R. spectrum (CDCQ3, ~) ppm 7.12 - 7.40 (lH, m) 6.96 - 7.02 (3H, m) 3.99 (3H, s) 3.~4 (3H, s) (c) A 2N aqueoùs solution of sodium hydroxide (40 ml.) was added with stirring at ambient temperature to a suspension of methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (syn isomer) (7.55 g.) in water (70 ml.) and the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was adjusted to pH 6.5 with 10% hydrochloric acid, subjected to ~ 337522 salting-out and washed with ether (60 ml.). The aqueous layer was adjusted to pH 1 with conc. hydrochloric acid and extracted once with 100 ml. of and twice with 60 ml. of ether.
The extract was washed twice with a saturated sodium chloride aqueous solution (60 ml.) and dried over magnesium sulfate.
Ether was distilled off to give oil. Benzene was added thereto and removed (twice) to give crystals of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (6.44 g.), mp 98 to 101C (dec.).
I . R. spectrum (Nujol) 3370, 1720 cm 1 An aqueous solution of 2N sodium hydroxide (8 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (anti isomer) (1.56 g.) in methanol (30 ml.). After stirring for 3 hours at the same temperature, methanol was distilled off. To the residue was added water and the mixture was washed with ether.
The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, subjected to salting^out and extracted with ether. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. Ether was distilled off to give crystals of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (anti isomer) (1.07 g.). The crystals were recrystallized from a mixture of petroleum ether and ether to give crystals (0.7 g.), mp 99 to 101C (dec.).
I.~. spectrum ~Nujol) 3350, 1690 cm 1 2)(a) Phenolphthalein indicator (3 drops) was added to a solution of 0-methylhydroxylamine hydrochloride ( 3.7 g.) in dry methanol (45 ml.). To the solution was dropwise added with stirring at ambient temperature lN methanol solution of sodium methoxide (39 ml.) until the color of the solution was changed to purplish red. O-Methylhydroxylamine hydrochloride was added thereto by small portions until the solution was S changed to colorless solution. The mixture was stirred for 30 minutes at ambient temperature. After precipitating sodium chloride was filtered off, 2-(4-hydroxyphenyl)glyoxylic acid (6.56 g.) was added to the filtrate and the mixture was stirred for 1 hour at ambient temperature. After methanol was distilled off at low temperature, a saturated sodium chloride aqueous solution was added to the residue. The mixture was adjusted to pH 1 with 10% hydrochloric acid, subjected to salting-out and extracted with ether. The extract was dried over magnesium sulfate. Ether was distilled lS off at low temperature to give 2-methoxyimino-2-(4-hydroxyphenyl)-acetic acid (syn isomer).
(b) This material was dissolved in ether (S0 ml.) and a solution of diazomethane in ether was gradually added thereto under ice-cooling until the color of the mixture was changed to yellow. Acetic acid was immediately added thereto and the mixture was washed with a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ether was distilled off to give oily residue (8 g.). The oily residue was subjected to column chromat~graphy on silica gel using a mixture of ben~ene and ethyl acetate (9 : 1) as developing solvent to give methyl 2-methoxyimino-2-(4-hydroxyphenyl)acetate (syn isomer) (6.39 g.).
I.R. spectrum (Nujol) `
3350, 1720 cm 1 N.M.R. spectrum (CDC~3, ~) ppm 7.40 (2H, d, J=8Hz) 6.80 (2H, d, J=8Hz) 3.96 (3H, s) 3.92 (3H, s) (c) A 2N aqueous solution of sodium hydroxide (11 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(4-hydroxyphenyl)acetate (Syll isomer) ,, . . . ~ .~
-- ` (2.1 g.) in methanol (30 ml.) and the mixture was stirred for 18 hours at ambient temperature. The reaction mixture was adjusted to pH 7 with 10% hydrochloric acid and methanol was removed. To the residue was added water and the mixture was washed with ether. The aqueous layer was adjusted to p~ 1 with 10% hydrochloric acid, subjected to salting-out and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate.
Ethyl acetate was distilled off to give crystals of 2-methoxyimino-2-(4-hydroxyphenyl)acetic acid (syn isomer) (1.5 g.).
I.R. spectrum (Nujol) 3150, 1700 cm 1 3)(a) Phenolphthalein indicator (2 drops) was added to a solution of O-methylhydroxylamine hydrochloride (2.74 g.) in dry methanol (30 ml.). To the solution was dropwise added with stirring at ambient temperature lN methanol solution of sodium methoxide until the color of the solution was changed to purplish red. O-Methylhydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirred for 1 hour at ambient temperature. After precipitating sodium chloride was filtered off, 2-(3-nitro-4-hydroxyphenyl)glyoxylic acid (6.75 g.) was added to the filtrate and the mixture was stirred for 1 hour at ambient temperature. After methanol was distilled off at 35C, a saturated sodium chloride aqueous solution was added to the residue. The mi~xture was adjusted to pH 1 with 10% hydrochloric acid and extracted with ether.
The extract was dried over magnesium sulfate. Ether was distilled off at 35C under reduced pressure to give yellow crystals o~ 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.).
(b) This material was dissolved in a mixture of tetra-hydrofuran (15 ml.) and ether (100 ml.) and a solution o~
diazomethane in ether was gradually added thereto at ambient temperature until the color of the mixture was changed to yellow. Acetic acid was immediately added thereto and the lS mixture was concentrated to dryness at 35C under reduced pressure. The residue was dissolved in a mixed solvent of ethyl acetate and benzene (1 : 9) and subjected to column chromatography on silica gel using the same mixed solvent as developing solvent. The eluate containing syn isomer was collected and concentrated to give methyl 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetate (syn isomer) (3.7 g.), mp 93 to 95C.
I.R. spectrum (Nujol) ~ 3300, 1745, 1630, 1535, 1350 cm 1 N.M.R. spectrum (GDCQ3, ~) ppm 10.87 (lH, s) 8.22 (lH, d, J=2Hz) 7.86 (lH, dd, J=2,8Hz) 7 20 (lH, d, J=8Hz) 4.03 (3H, s) 3.9s (3H, s) ~ -106 (c) A 2N aqueous solution of sodium hydroxide (14 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetate (syn isomer) (3.5 g.) in methanol (70 ml.) and the mixture was stirred S for 60 hours at ambient temperature. The reaction mixture was concentrated to dryness at 40C under reduced pressure and the residue was dissolved in water. The solution was washed with ethyl acetate, adjusted to pH 1 with 10~ hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract was back-extracted with a saturated sodium bicarbonate aqueous solution. The aqueous extract was adjustcd to pH 1 with conc. hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract was washed with ice-water and dried over magnesium sulfate. The solvent was concen-trated to dryness at 40C under reduced pressure to give yellow crystals of 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetic acid (syn isomer) (3.2 g.), mp 142 to 143C (dec.).
I . R. spectrum (Nujol) 3300, 2500 - 2600, 1710, 1630, 1600, 1535, 1375 cm 1 N.M.R. spectrum (CDCQ3, ~) ppm 10.67 (2H, s) 8.33 (lH, d, J=2Hz) 7.95 (lH, dd, J=2,8Hz) 7.22 (lH, d, J=8Hz) 4.13 (3H, s) 4)(a) 2-(3^Chloro-4-hydroxyphenyl)glyoxylic acid (6.45 g.) and O-methylhydroxylamine hydrochloride (2.74 g.) were reacted according to a similar manner to that of Preparation 5-3)(a) to give oil of 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)-acetic acid (a mixture of syn and anti isomers) (7 g.).

(b) 2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.) ar,d diazomethane (1.5 g.) were reacted and the product was purified by column chromatography according to a similar manner to that of Prepa-ration 5-3)(b) to give crystals of methyl 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetate (syn isomer) (3.0 g.).
I.R. spectrum (Film) 3450, 1735, 1605, 1600 cm 1 N.M.R. spectrum (CDCQ3, ~) ppm 7.55 (lH, d, J=2Hz) 7.37 (lH, dd, J-2,8Hz) 6.95 (lH, d, J=8Hz) 6.12 (1~l, s) 3.97 (3H, s) 3.91 (3~, s) (c) Methyl 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)-acetate (syn isomer) (2.6 g.) and a 2N aqueous solution of sodium hydroxide (10.6 ml.) were treated according to a similar manner to that of Preparation S-3)(c) to give 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.4 g.), mp 147 to 150C (dec.).
I.R. spectrum (Nujol) 3500, 2500 - 2600, 1745, 1610, 1600 cm 1 N.~l.R. spectrum (CDC~3, ~) ppm 8.40 (2H, broad s) 7.65 (lH, d, J=2Hz) 7.40 (lH, dd, J=2,8Hz) 7.00 (lH, d, J-8Hz) 4.Q7 (3H, s) S) 2-(3-Hydroxyphenyl)glyoxylic acid (2.0 g.) and O-allyl-hydroxylamine hydrochloride (1.7 g.) were reacted according to a similar manner to that of Prep~ration S-2)(a) to give oil of - 2-allyloxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) s (2.7 g.).
I.R. spectrum (Film) 3350, 2550-2600, 1720, 1645, 1600 cm~l 6) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2 g.) and O-allylhydroxylamine hydrochloride (1.1 g.) were reacted according to a similar manner to that of Preparation 5-2)(a) to give oil of 2-allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.5 g.).
I R. spectrum (Film) 3450, 2600, 1730, 1700, 1650, 1610, 1600 cm 1 lS N.M.R. spectrum (d6-D~SO, ~) ppm 9.5 - lO.S (2H, broad s) 7.52 (lH, d, J~2Hz) 7.42 (lH, dd, J=2,8Hz) 7.12 (lH, d, J=8Hz) 6.0 (lH, m) 5.40 (2H, t, J=8Hz) . .
4.70 (2H, d, J=SHz) 7) A mixture of 2-(3-chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.), O-t-butoxycarbonylmethylhydroxylamine (1.62 g.) and methanol (20 ml.) was adjusted to pH 5 to 6 by adding an lN methanol solution of sodium methoxide and stirred for 3 hours at ambient temperature. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in an lN aqueous solution of sodium hydroxide to adjust ~o pl~ 7Ø
The aqueous solution was washed with ether, adjusted to pH 2.0 E - lO9 with 10~ hydrochloric acid under ice-cooling and extracted with ether. The extract was washed with water and dried over magnesium sulfate. The solution was concentrated to dryness under reduced pressure to give crystals of 2-t-butoxycarbonyl-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) .. ...
~2.6 g.), mp 116 to 118C (dec.).
I.R. spectrum (Nujol) 3250, 2600, 1735, 1690, 1670, 1610, 1590 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 11.00 (2H, broad s) 7.50 (lH, d, J=2Hz) 7.40 (lH, dd, J=2,8Hz) 7.08 (lH, d, J=8Hz) 4.68 (2H, s) 1.45 (9~, s) 8)(a)Potassium carbonate (49.7 g.) and dimethyl sulfate (45.4 g.) were added to a solution of 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (18.1 g.) in dry acetone (250 ml.) and the mixture was refluxed with stirring for 8.5 hours. After acetone was distilled off, the residue was dissolved in water and extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution ànd dried over magnesium sulfa~e. The sol~ent was distilled off to give oil (24 g.). The oil was subjected to column chromatography on silica gel using benzene as developing solvent. ~irstly the eluate containing syn isomer was eluted and the eluate was collected and concentrated to give oil of methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate (syn isomer) (9.2 g.).

E - llO

I.R. spectrum (Film) 1738 cm 1 N.M.R. spectrum (CDC~3, ~) ppm 7.47 - 6.77 (4H, m) 4.00 (3H, s) 3.92 (3H, s) 3.82 (3H, s) After the eluate containing syn isomer was eluted, then the eluate containing anti isomer was eluted. The eluate was collected and concentrated to give methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate (anti isomer) (3.9 g.), mp 66 to 68C.
This substance was recrystallized from petroleum ether to give prisms, mp 65 to 65.5C.
I . R. spectrum (Nujol) 1720 cm~l N.M.R. spectrum (CDCQ3, ~) ppm 7.14 - 7.44 tlH, m) 6.80 - 7.04 (3H, m) 4.02 (3H, s) 3.84 (3H, s) 3.76 (3H, s) (b) Methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate (syn isomer) (1.6 g.) and a 2N aqueous solution of sodium hydroxide (4 ml.) were treated according to a similar manner to that of Preparation 5-3) (c) to give oil of 2-methoxyimino-2-(3-methoxyphenyl)acetic acid (syn isomer) (1.23 g.).
I.R. spectrum (Film) 1735 cm~l Methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate (anti isomer) (1.6 g.) and a 2N aqueous solution of sodium , . . . , ~

hydroxide (4 ml.) were treated according to a similar manner to that of Preparation 5-3)(c) to give colorless prisms of 2-methoxy-imino-2-(3-methoxyphenyl)acetic acid (anti isomer) (1.3 g.), mp 97 to 98C.
I.R. spectrum (Nujol) 1695 cm~l 9)(a) A solution of diazomethane in ether was added at ambient temperature to a solution of 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (7 g.) in dry ether (50 ml.) until the color of the mixture was changed to yellow.
Acetic acid ~a~ immediately added thereto and the reaction mixture was concentrated to dryness at 35C under reduced pressure. The residue was subjected to column chromatography cn silica gel (120 g.) using a mixture of benzene and ethyl acetate lS (9 : 1) as a developing solvent. The first eluate was collected and concentrated at 40C under reduced pressure to give oil of methyl 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetate (syn isomer) (3.1 g.).
I.R. spectrum (Film) 2850, 1735, 1610, 1600, 1250 cm 1 N.M.R. spectrum (CDCQ3, ~) ppm 7.57 (lH, d, J=2Hz) 7.37 (lH, dd, J=2,8Hz) 6.87 (lH, d, J=8Hz) 3.97 (31i, s) 3.91 (3~, s) 3.88 (3H, s) (b) Methyl 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)-acetate (syn isomer) (2.7 g.) and a 2N aqueous solution of sodium hydroxide (10.6 ml.) were treated according to a simila~

-165_ manner to that of Preparation 5-3) (c) to give crystals of 2-methoxyimino-2-~3-chloro-4-methoxyphenyl)acetic acid (syn isomer) (2.6 g.), mp 133 to 135C (dec.).
I.R. spectrum (Nujol) S 2500-2600, 1745, 1610, 1600 cm 1 N.M.R. spectrum (CDC~3, ~) ppm 9.95 (1ll, broad s) 7.72 (1~, d, J=2Hz) 7.50 (1~l, dd, J=2,811z) 6.92 (1}l, d, J=8Hz) 4.08 (3~1, s) 3.95 (3~1, s) lO)(a)A solution of 2-bromopropionyl bromide (25 g.) in dry chloroform (50 ml.) was dropwise added with stirring and ice-cooling to a solution of N,N-dimethylaniline (24 g.) in t-butanol (11 g.) and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into 6N sulfuric acid (150 ml.) and extracted with ether. The extract was in turn washed with 6N sulfuric acid, water, a 10~ potassium carbon1te aqueous solution and water and dried over magnesium sulfate.
The solvent was distilled off to give oil of t-butyl 2-bromo-propionate (21 g.).
(b) This oil (21 g.) was added with stirrin~ at ambient temperature to a mixture of N-hydroxyphthalimide (16.3 g.), triethylamine (24 g.), dimethylformamide (20 ml.) and dimethyl-sulfoxide (20 ml.) and the resulting mixture was stirred for 4 hours at ambient tempera~ure. The reaction mixture was poured into water (800 ml.) and precipitating materials were collected by filtration, washed with water and dried to give t-butyl 2-pht}lalimidoxypropiollate (22.7 g.).

E

(c) This compound (22.7 g.) was dissolved in methylene chloride (200 ml.). A solution of 10~ hydrazine hydrate (9 ml.) in methanol (20 ml.) was added thereto and the mixture was stirred for 2 hours at ambient temperature. Precipitating materials were dissolved by adding 5N aqueous solution of ammonia and the aqueous layer was extracted with methylene chloride.
Two methylene chloride layers were combined and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give oil of 0~ t-butoxycarbonylethyl)hydroxylamine (13.5 g.~.
I.R. spectrum (~ilm) 3350, 3250, 1745 cm 1 (d) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.) and O-(l-t-butoxycarbonylethyl)hydroxylamine (3.2 g.) were reacted according to a similar manner to that of Preparation 5-7) to give 2-(1-t-butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (3.3 g.), mp i48 to 151C.
I.R. spectrum (Nujol) 3450, 2500-2600, 1725, 1690, 1620, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 7.46 (1~-1, d, J=2Hz) 7.33 (lH, dd, J=2,81-lz) 7.07 (lH, d, J=8Hz) 4.67 (lH, q, J=6Hz) l.S0 (12H, s) 11) Phenolphthalein indicator (3 drops) was added to a solution o O-methylhydroxylamine hydrochloride (8.8 g.) in dry methanol (60 ml.). To the solution was dropwise added with stirring at ambient temperature lN methanol solution of sodium methoxide (105 ml.) until the color of the solution was changed to pale pink. O-Methylhydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The pH value of the solution was 8.0 to 8.5. The mixture was stirred for 30 minutes at ambient temperature.
S- After precipitating sodium chloride was filtered off, 2-(3-hydroxyphenyl)glyoxylic acid (16.6 g.) was added to the filtrate and the mixture was stirred for 1 hour at ambient temlperature.
After methanol was distilled off at low temperature,water was added to the residue. The mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate, washed with ether, adjusted to pll 1 with 10% hydrochloric acid, subjected to salting-out and extracted with ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ether was distilled off and the operation that benzene was added to the residue and distilled off was repeated twice to give crystals of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (14.8 g.). This compound was identified with the compound obtained in Preparation 5-l)(c) by I.R. spectrum.
12) A solution of 2-(3-methoxyphenyl)glyoxylic acid (1.8 g.) in an aqueous solution of sodium bicarbonate was adjusted to pH 7Ø On the other hand, a solution of O-ethylhydroxyl-amine hydrochloride (1.4 g.) in water (20 ml.) was adjusted to pH 7.0 with sodium bicarbonate. Two solutions were combined ~ 25 together, adjusted to pH 5.5 with 10% hydrochloric acid and stirred overnight at ambient temperature. The reaction mixture was adjusted to pH 7.5 with sodiu~n bicarbonate and washed with ethyl acetate. The aqueous layer was adjusted to pH 1.0 with conc. hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract was washed with ice-water and dried over magnesium sulfate. The sol~ent was distilled off under reduced pTessure to give oil of 2-ethoxyimino-2-(3-methoxyphenyl)acetic acid (syn isomer) (2.2 g.).
I.R. spectrum (Film) 2600, 1735, 1700, 1610, 1600 cm~l 13) The following compounds were obtained according to similar manners to those of Preparation 5-5) to 5^7) and 5-10) to 5-12).
(1) 2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid tSYn isomer), oil.
I.R. spectrum (Film) 3450, 2250-2600, 1700-1720, 1610, 1600 cm 1 t2) 2-Ethoxyimino-2-~3-hydroxyphenyl)acetic acid (syn isomer) oil.
I.R. spectrum (Film) 3400, 2600, 1700-1730, 1605, 1600 cm 1 (3) 2-(3-Hydroxy-4^bromobenzyloxyimino)-2-(4-hydroxyphcnyl)-acetic acid (syn isomer), colorless powder.
I.R. spectrum (Nujol) 3500, 3200, 1700 cm 1 N.M.R. spectrum (d6-acetone, ~) ppm 6.68-8.05 (7H, m) 5.15 (2H, s) (4) 2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyl)acetic acid (syn isomer), powder.
I.R. spectrum (Nujol) 1705 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 6.7-7.7 (7H, m) 5.2~ (2H, s) (S) 2-Allyloxyimino-2-(3-methoxyphenyl)acetic acid (syn isomer), oil.
I.R. spectrum (Film) 3050-3100, 2600, 1730, 1645, 1610, 1600 cm~
N.M.R. spectrum (d6DMSO, ~) ppm 7.00-7.50 (4H, m) 5.80-6.30 (lH, m) 5.33 (2H, t, J=9Hz) 4.70 (2H, d, J=SHz) 3.82 (3H, s) (6) 2-Allyloxyimino-2-(3-chloro^4-methoxyphenyl)acetic acid (syn isomer), pale yellow oil.
I.R. spectrum (Film) 3100, 2600, 1710-1730) 1645, 1610, 1600 cm 1 lS N.M.R. spectrum (d6-DMSO, ~) ppm 7.63 (lH, d, J=2Hz) 7.50 (lH, dd, J=2,8Hz) 7.23 (lH, d, J=8Hz) 5.9-6.3 (lH, m) 5.33 (2H, t, J=9Hz) 4.73 (2H, d, J=5Hz) 3.91 (3H, s) ~7) 2-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer), oil.
I.R. spectrum ( Film ) 3300, 1730 cm 1 N.M.R. spectrum (CDCQ3, ~) -ppm : 6.8 - 7.7 (9H, m) 5.54 (2H, s) ~0 ~ -1]7 (8) 2-Methoxyimina-2-(3-mesylaminophenyl) acetic acid (syn isomer), mp .28C (dec,).
I.R. spectrum (Nujol) 3300, 1740 cm~l (9) 2-(3-Phenylallyloxyimino)-2-(3-hydroxyphenyl)acetic acid (syn isomer), mp 115 to 116C.
I.R. spectrum (Nujol) 3400, 1725 cm 1 ~10) 2-Methoxyimino-2-(4-dimethylamino-phenyl)acetic acid (syn isomer), mp 88 to 89C (dec.).
I.R. spectrum (Nujol) 2700 - 2100, 1720, 1660, 1612, 1590 cm~l 14) Acetyl chloride (4.1 g.) was added with stirring and ice-cooling to a solution of 2-methoxyimino-2-(3-hydroxyphenyl)-acetic acid (syn isomer) (S g.) in pyridine (20 ml.) and the mixture was stirred for 50 minutes at ambient temperature.
The reaction mixture was poured into ice-water, adjusted to pH 2.1 and extracted three times with ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was thoroughly removed under reduced pressure to give 2-methoxyimino-2-(3-acetoxyphenyl)acetic acid (syn isomer) (6.1 g.).
I.R. spectrum (Film) 3500, 2950, 1760, 1735, 1605, 1575, 1485, 1440, 1425, 1370 cm~l N.M.R. spectrum (CDCQ3, ~) ppm7.94 (lH, s) 7.6-7.0 (4H, m) 4.05 (3H, s) 2.30 (3H, s) ~ 331522 ~S) Trichloroacetyl isocyanate (70 ml) was dropwise added over 6 minutes at ambient temperature to a solution of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (40g) in dry dioxane (200 ml), and the resulting mixture was stirred for S hours at ambient temperature. Dioxane was distilled off and to the residue were added ethyl acetate (200 mlJ and by small portions water (200 ml) under ice-cooling. The mixture containing trichloroacetylcarbamoyl 2-methoxyimino-2-(3-trichloroacetylcarbamoyloxyphenyl)acetate was stirred for 5 hours at ambient temperature keeping the pH value of the mixture at 6.0 to 6.4 by adding an aqueous solution of sodium bicarbonate. The resulting mixture was wahsed twice with ethyl acetate. The aqueous layer was adjusted to pH2 with a 10~ hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed twice with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and precipi-tating crystals were collected by filtration to give colorless crystals of 2-methoxyimino-2-(3-carbamoyloxyphenyl~acetic acid (syn isomer) (lSg), mp 163C (dec.). The same compound (5.4g) was obtained from the mother liquor.
I.R. spectrum (Nu~ol) 3480, 3360, 1730, 1660 cm~
N M.R. spectrum (d6-DMSO, ~) ppm 3.97 (3H, s), 7.16 (2H, broad s), 7.1 - 7.7 (4H, m), 9.7 (lH, broad s) -172_ ~ 337522 Preparation 6 1) A solution of sodium nitrite (12.4 g.) in water (150 ml.) was dropwise added with stirring at S to 7C to a solution of ethyl 4-bromoacetoacetate (30 g.) in acetic acid (200 ml.) and the mixture was stirred for 2 hours at 10C. ~ater (200 ml.) was added to the reaction mixture and the resultant mixture was extracted with ether (S00 ml.). The extract was washed twice with water (200 ml.) and with a sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure to give yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoaceto-acetate (a mixture of syn and anti isomers) (32.6 g.).
I.R. spectrum (Film) 3350, 1740, 1710, 1620 cm 1 N.M.R. spectrum (CDCQ3, ~) ppm 8.75 (2H, broad s) 4.35 (8H, m) 1.35 (6H, m~
2) Pulverized potassium carbonate (160 g.) was added to a solution of ethyl 2-hydroxyiminoacetoacetate (a mixture of .. . .. ~

syn and anti isomers) (152 g.) in acetone (500 ml.). Dimethyl sulfate (130 g.) was dropwise added thereto with stirring over 1 hour at 45 to 50C and the mixture was stirred for 2 hours.
An insoluble material was filtered off and the filtrate was S concentrated under reduced pressure. The filtered insoluble material was dissolved in water (500 ml.) and this solution was added to the residue. The mixture was extracted twice with ethyl acetate (300 ml.). The extract was washed twice with water (200 ml.) and with a saturated sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to give colorless oil of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (145.3 g.), bp 55 to 64C/O.S mm Hg.
I.R. spectrum (Film) 1745, 1695, 1600 cm~
N.M.R. spectrum (CDCQ3, ~) ppm 4.33 (4H, q, J=811z) 4.08 (3H, s) 3.95 (3H, s) 2.40 (31~, s) 1.63 (3H, s) 1.33 (6H, t, J=8Hz) 3) Bromine (100 g.) was dropwise addcd over 40 minutes under reflux to a solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (100 g.) in a mixture of carbon tetrachloride (300 ml.) and acetic acid (300 ml.). The mixture was stirred at 70 to 80C until the evolution of hydrogen bromide ceased. The reaction mixture was washed twice with water (300 ml.), a sodium bicarbonate aqueous solution E ~121 and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solution was treated with activated charcoal (2 g.) and concentrated under reduced pressure to give ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (120.8 g.).
I.R. spectrum (Film) 1740, 1705, 1600 cm 1 N.M.R. spectrum (CDCQ3, ~) ppm 4.17-4.54 (8H, m) 4.15 (3~, s) 4.13 (31-l, s) 1.33 (6H, t, J=8~-lz) 4) A mixture of selenium dioxide (11.1 g.), dioxane (250 ml.) and water (5 ml.) was stirred for 15 minutes at 110 to 115C to give yellow solution. Ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)acetate (26.4 g) was added thereto with stirring at the same temperature. After stirring for 1 hour, the reaction mixture was decanted with heating and cooled to precipitate yellow crystals. The crystals were collected by filtration, washed with dioxane and ether and dried to give ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate (23.5 g.).
I.R. spectrum (Nujol) 3300, 1718, 1682 cm 1 S) Ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylatc (13.9 g.) was added with stirring at ambient temperature to a solution of sodium hydroxide (5.0 g.) in water (150 ml.). The mixture was stirred for 1 hour at ambient temperature, adjusted to pH 7 with conc. hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to p~l 0.5 with conc.
hydrochloric acid to precipitate yellow crystals. The crystals 1 3375~2 were collected by filtration, washed with water and dried to give 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylic acid (10.16 g.).
I.R. spectrum (Nujol) 3350, 1725, 1650 cm~l 6) To a solution of ethyl 2-(2-amino-1,3-thlazol-4-yl)-acetate (14 g.) in a mixture of pyridine (40 g.~ and methylene chloride (300 ml.) was gradually added diethyl ether solution of t-pentyl chloroformate (70 ml.) containing 0.35 mole o t-pentyl chloroformate over 10 minutes at -20C Witll stirring, and the mixture was stirred for 2 hours at the same temperature and further stirred for 0.5 hour at 0C. ~fter the reaction, the reaction mixture was poured into water (200 ml.), and then the organic layer was separated. The organic layer was washed with 2N hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water in turn and then dried over magnesium sulfate.
The sol~ent was distilled off from the organic layer to give dark brown oil of ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate (12 g.).
I.R. spectrum (liquid) 1667, 1660 tC0) cm 1 N.M.R. spectrum (CDC~3,~) ppm 3.75 (2H, s) 6.75 ~lH, s) 7) Ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)-acetate (0.3 g.) and selenium dioxide (0.11 g.) were treated according to a similar manner to that of Preparation 6-4) to give brown oil of ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (0.22 g.).
I.R. spectrum (liquid) 1720, 1690 (C0) cm 1 N.M.R. spectrum (CICQ3,~) ppm 8.3 (lH, s) 8) Ethyl 2-(2-t-~entyloxy,carbonylamino-1,3-thiazol-4-yl)-glyoxylate ~2.8 g.) and a solution of sodium~hydroxidc (0.54 g.) S in water (20 ml.) were treated according to a simiiar manner to that of Preparation 6-S) to give brown powder of 2-(2-t-pentyloxy-carbonylamino-1,3-thiazol-4-yl)glyoxylic acid (1.75 g.).
I.R. spectrum (Nujol) 1730, 1680 (C0) cm~l N.M.R. spectrum (d6-dimethylsulfoxide, ~) ppm 8.4 (lH, s) 9) A mixture of ethyl 2-hydroxyimino-2-(2-amino-1, 3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (0.37g), ethanol (5 ml), water (5 ml) and sodium bisulfite ",",,,,,,~ lS (0.72 g) was stirred for 12 hours at 65 to 70C. The reaction mixture was concentrated and water (10 ml) was added to the residue. The resulting mixture was subjected to salting-out and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give yellow crystals of ethyl 2-(2-amino-1,3-thiazol-4-yl)-glyoxylate (0.18 g), mp 115 to 120C.
I.R. spectrum (Nujol) 3420, 3250, 3120, 1730, 1665, 1612 cm 1 E - 12¢

10) Sulfuryl chloride (235 ml.) was dropwise added over 20 minutes with stirring and ice-cooling to a solution of ethyl 2-methoxyiminoacetoacetate (syn isomer) (500 g.) in acetic acid (500 ml.), and the mixture was stirred overnight under cooling with water. Nitrogen gas was introduced to the reaction mixture for 2 hours, and the resulting mixture was poured into water (2.5 Q). After extracting with methylene chlGride (500 ml.) and twice with methylene chloride (200 ml.), the extracts were combined. The combined extracts were washed with a saturated aqueous solution of sodium chloride, and adjusted to pH 6.5 by adding water (800 ml.) and sodium bicarbonate. Methylene chloride layer was separated, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (559 g.).
I.R. spectrum (Film) 1735, 1705 cm 1 ~ - 125 Preparation 7 1) A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (22.0 g.), thioacetamide (7.5 g.) and benzene (100 ml.) was refluxed for 3 hours. After cooling triethylamine (10 g.) was added thereto and the mixture was stirred for 1 hour. An insoluble material ~as filtered off and the filtrate was concentrated under reduced pressure to give ethyl 2-hydroxyimino-2-(2-methyl-1,3^thiazol-4-yl)acetatc (a mixture of syn and anti isomers) (8.6 g.). This substance was subjected to column chromatography on silica gel (80 g.) using benzene as developing solvent. Firstly the eluate containing anti isomer was eluted, collected and concentrated to give ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (2.5 g.), mp 90 to 92C.
I.R. spectrum (Nujol) 1720 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 12.55 (lH, s) 8.25 (lH, s) 4.27 (2H, q, J-7Hz) 2.63 (3H, s) 1.25 (3H, t, J-7Hz) After the eluate containing anti isomer was eluted, the eluate containing syn isomer was eluted, collected and concentrated to give ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer) (0.5 g.), mp 134 to 136C.
I.R. spectrum (Nujol) 1720 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 11.81 (lH, s) 7.81 (lH, s) 4.35 (2l~, q, J=7Hz) 2.70 (3H, s) 1.30 (3H, t, J-7Hz) 2) Phenolphthalein indicator (3 drops) was added to a solution of hydroxylamine hydrochloride (4.2 g.) in dry methanol (60 ml.). To the solution was dropwise added with stirring at ambient temperature lN methanol solution of sodium methoxide (60 ml.) until the color of the solution was changed to purplish red. Hydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirred for 30 minutes at ambient temperature. After precipitating sodium chloride was filtered off, 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylic acid (12.5 g.) was added to the filtrate and the mixture was refluxed with stirring for l S hours. The reaction mixture was cooled to precipitate crystals. The crystals were collected by filtration and dried to give crude 2-hydroxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid (a mixture of syn and anti isomers) (5.5 g.). The filtrate was concentrated to the volume of 1/4 and ether was added thereto. Precipitating crystals were collected by filtration, washed with ether and dried to give the same compound (8.78 g.). Total yield (14.3 g.).
3) A mixture of ethyl 2-hydroxyimino-4-~romoacetoac~ta~e (a mixture of syn and anti isomers) (2.4g) and thiourea (0.76 g) in ethanol (lS ml) was stirred for 1 hour at 60C.
Ethanol was distilled off under reduced pressure and ~ater was added to the residue. The resultant mixture was adjusted to pH 1.0 and washed with ethyl acetate. The aqueous layer was adjusted to pH 4.5 with triethylamine and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected-to column chromatography on silica gel using a mixture of ethyl acetate and benzene (1:3) as developing solvent. Tl~e eluates containing syn isomer were collected and conce~trated to give ethyl 2-hydroxyimino-2-(2-amino-1, 3-thiazol-4-yl)acetate tSYn isomer) (0 3 g) I.R. spectrum (Nujol) 3450, 3300, 3200, 1725, 1620 cm~
N.M.R. spectrur.l (CDCQ3, ~) ppm : 7.65 (lH, s) 5.33 (2H, broad s) 4.40 (2H, q, J-7.5Hz) 1.38 (3H, t, J=7.5~z) After the eluates containing syn isomerswere collected, the eluates containing a mixture of syn and anti isomers were collected and concentrated to give ethyl 2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (0.3 g.).
I.R. spectrum ~Nujol) 3400, 3300, 3200, 1715, 162~0 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm : 12.42 (lH, broad s) 11.55 tlH, s) 7.52 (1~, s) 7.12 (4H, broad s) 6.83 (1ll, s) 4.23 (4H, m) 1.26 (6H, m) 4) A solution of ethyl 2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (1.1 g) in an lN aqueous solution of sodium hydroxide (15 ml) was allowed to stand for 2 hours at ambient temperature.
The reaction mixture was adjusted to pH 3.5 with 10%
hydrochloric acid and precipitating crystals were collected by filtration, washed with acetone and dried to give 2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (a mixture of syn and anti isomers) (0.52 g), mp lS4 to 186C
(dec.).
I.R. spectrum (Nujol) 3200, 1670, 1530 cm~

-182_ 1 33752~

Preparation 8 l) Thioacetamide (3.8 g.) was added to a solution of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (12.6 g.) in ethanol (S0 ml.) and the mixture was stirred for S hours at 50C. Ethanol was distilled off under reduced pressure and water was added to the residue.
The resulting mixture was extracted with ethyl acetate. The extract was in turn washed with water, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (9.0 g.~.
2) A mixture of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (7.6 g.), O-ethyl thio-carbamate (3.0 g.) and dimethylacetamide (5 ml.) was stirred for 3 hours at 50C. Ethyl acetate (50 ml.) was added to the reaction mixture and the resulting mixture was washed with water and with a satura~ed sodium chloride aqueous solution and dried over magnesium sulfate. Ethyl acetate was distilled off to give crystalline residue. The residue was washed with diisopropyl ether to give ethyl 2-methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thlazol-4-yl)acetate (syn isomer) (2.35 g.).
I.R. spectrum (Nujol) 3200, 1735, 1680, 1650 cm 1 3o N.M.R. spectrum (CDCe3, ~) ppm 9.13 (lH, broad s) 6.37 (lH, s) 4.40 (2H, q, J=6Hz) 4.01 (3H, s) 1.38 (3H, t, J=6Hz) The mother liquor of diisopropyl ether was concentrated and the residue was subjected to column chromatography on silica gel (70 g.) using a mixture of benzene and ethyl acetate (9 : 1) as developing solvent. The eluate containing syn isomer was collected and concentrated to further give the above obtained syn isomer (0.65 g.). Total yield (3.0 g.).
Thereafter a mixture of benzene and ethyl acetate (5:1) was used as developing solvent. The eluate containing anti isomer was collected and concentrated to give ethyl 2-methoxyimino-2-(2-oxo-2,3-dihydro-1, 3-thiazol-4-yl)acetate (anti isomer) (0.26 g.).
I.R. spectrum (Nujol) 3250, 3200, 1720, 1690 cm~
N.M.R. spectrum (CDCe3, ~) ppm 9.90 (lH, broad s) 7.30 (lH, s) 4.40 (2H, q, J=6Hz) 4.03 (3H, s) 1.38 (3H, t, J=6Hz) 3~ A solution of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (17.4 g.) and thiourea (5.4 g.) in ethanol (100 ml.) was refluxed for 4 hours. The reaction mixture was allowed to stand and cooled in refrigerator to precipitate crystals. The crystals were collected by filtration, washed with ethanol and dried to give ethyl 2-methoxyimino-2-(2 ~7, amino-1,3-thiazol-4-yl)acetate hydrobromide (anti isomer) (9.5 g ). The filtrate and the washings were put together and concentrated under reduced pressure. Water (lO0 ml.) was added to the residue and the mixture was washed with ether.
The aqueous layer was alkalized with a 28% a~ueous solution of ammonia and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give crystalline substance of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (5.2 g.).
I.R. spectrum (Nujol) 3400, 3300, 3150, 1725, 1630, 1559 cm 1 N.M.R. spectrum (CDC~3, ~) ppm 6.72 (1l~, s) 5.91 (2H, broad s) 4.38 (2H, q, J:7Hz) 4.03 (3H, s) 1.38 (3H, t, J-7Hz) The above obtained ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)dcetate hydrobromide (anti isomer) (9.5 g.) was suspended in ethyl acetate (200 ml.) and triethylamine (4.0 g.) was added thereto. After stirring for 1 hour at ambient temperature, an insoluble material waS filtered off and the filtrate was concentrated under reduced pressure to give crystal-line substance of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (anti isomer) (6.15 g.).
I.R. spectrum (Nujol) 3450, 3250, 3150, 1730, 1620 cm 1 E ~ 132 N.M.R. spectrum (CDCQ3. ~) ppm 7.50 (1'1~, s) 5.60 (2~l, broad s) 4.35 (2H, q, J=7Hz) 4.08 (3~-l, s) 1.33 (3H, t, J-7Hz) 4) Phenolphthalein indicator (3 drops) was added to a solution of 0-methyl-hydroxylamine hydrochloride (-.25 g.) in dry methanol (15 ml.). To the solution was dropwise added with stirring at ambient temperature lN methanol solution of sodium methoxide (13 ml.) until the color of the solution was changed to purplish red. 0-Methylhydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirred for 30 minutes at ambient temperature. After precipitating sodium chloride was filtered off, ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate (3.8 g.) was added to the filtrate and the mixture was refluxed with stirring for 2 hours. After methanol was distilled off, the residue was dissolved in ethyl acetate. An insoluble material was filtered off and the filtrate was concentrated. The residue was subjected to column chromatography on silica gel using a mixture of benzene and ethyl acetate (9:1) as developing solvent. The eluate containing syn isomer was collected and concentrated to give ethyl 2-methoxyimino-2-t2-mesylamino-1,3-thiazol-4-yl)acetate (syn isomer) (2.8 g.).
I.R. spectrum (Nujol) 1725 cm N.M.R. spectrum (CDCQ3,~) ppm 6.76 (1~l, s) 4.44 (2H, q, J 7Hz) 4.04 (311, s) 3.04 (3H, s) 1.37 (3H, t, J-7Hz) . ~ . .
5) Pulverized potassium carbonate (0.33 g.) was suspended in a solution of ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer) (0.5 g.) in acetone (20 ml-.).
A solution of dimethyl sulfate (0.3 g.) in acetone (5 ml.) was dropwise added thereto with stirring at 40 to 45C. After stirring for 2 hours at the same temperature, an insoluble material was filtered off. The filtrate was concentrated and water was added to the residue. The resulting mixture was extracted with ethyl acetate. The extract was in turn washed with water, a sodium bicarbonate aqueous solution and a lS saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give pale yellow oil of ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer) (0.5 g.).
I.R. spectrum (Film) 1740, 1710, 1595 cm 1 N.M.R. spectrum (CDCQ3, ~) ppm 7.40 (lH, s) 4.25 (2H, q, J~7Hz) 4 03 (3H, s) 2.73 (3~i, s) 1.38 (3H, t, J~7Hz) 6) 2-Hydroxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)-acetic acid (a mixture of syn and anti isomeTs) (14.3 g.) obtained in Preparation 7-2) was suspended in dry acetone (300 ml.).
To the suspension were added potassium carbonate (22.8 g.) and E -1~4 dimethyl sulfate (20.8 g.). The mixture was refluxed with stirring for 9 hours. Acetone was distilled off rom the reaction mixture and water was added to the residue. The resulting mixture was extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous soiution and dried over magnesium sulfate. The solvent was distilled off to give oil (13 g.). The oil was subjected to column chromatography on silica gel using a mixture of benzene and ethyl acetate (9:1) as developing solvent. Firstly the eluate containing anti isomer was eluted, collected and concentrated. The residual oil (2.4 g.) was triturated under cooling to crystallize. The crystals were collected by filtration by adding petroleum ether to give methyl 2-methoxy-imino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)-acetate (anti isomer) (2.1 g.).
~ . . .
I.R. spectrum (Nujol) 1740 cm~l N.M.R. spectrum (CDCQ3, ~) ppm 7.90 (lH, s) 4.10 (3H, s) 3.90 (3H, s) 3.47 (3H, s) 3.07 (3H, s) After the eluate containing anti isomer was eluted, the eluate containing syn isomer was eluted, collected and concentrated to give crystals of methyl 2-methoxyimino-2-(2-- mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetate (syn isomer) (5.5 g.).
I.R. spectrum (Nujol) 1740 cm 1 E -1~5 N.M.R. spectrum (CDC~3, ~) ppm 6.72 (1ll, s) 4.05 (3H, s) 3.92 (3H, s) 3.72 (3H, s) 3.01 (3H, s) 7) The following compound was obtained according to a similar manner to that of Preparation 8-4).
Ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer).
I.R. spectrum (Nujol) 3400, 3300, 3150, 1725, 1630, 1559 cm 1 N.M.R. spectrum (CDCQ3, ~) ppm : 6.72 (lH, s) 5.91 (2~l, broad s) 4.38 (2H, q, J-7Hz) 4.03 (3H, s) 1.38 (3H, t, J-7Hz) 8 ) A mixture of acetic anhydride (6.1g) and formic acid (2 8g) was stirred for 2 hours at 50C. The resulting mixture was cooled and ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)-acetate (syn isomer) (4.6g) was added thereto at 15C. After the mixture was stirred for 3.5 hours at ambient temperature, cooled water (100 ml) was added thereto. The resulting mixture was extracted with ethyl acetate (200 ml). The extract was washed with water and then with a saturated aqueous solution of sodium bicarbonate until the washing was changed to weakly alkaline solution. The extract was further washed with a satu-rated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was washed with diisopropyl ether, collected by filtration and dried to gi~e ethyl 2-methoxyimino-2-(Z-fornlamido-1,3-thiazol-4-yl)acetate (syn isomer) (4.22g), mp 122 to 124~C
(dec.).
I.R. spectrum (Nujol) 3150, 1728, 1700 cm 1 N.M.R. spectrum (CDC13, ~) ppm 12.58 (lH, broad s), 8.95(1H, s), 7.i7 (lH, s), 4.42 (2H, q, J=8Hz), 4.00 (3H, s), 1.3~ (3H, t, JC8Hz) 9) Pyridine (3g.) was added to a solution of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (6.5 g.) in a mixture of ethyl acetate (60 ml.) and dimethylfor~m-amide (20 ml.). To the solution was dropwise added with stirring at 4C ethyl chloroformate (8 g.). After ad~ing water (50 ml.) to the reaction mixture, the organic layer wasseparated, washed with water and then with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (120 g.) using a mixture of ether and petroleum ether (5:2) as ~--an eluent to give ethyl 2-methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazol-4-yl)acetate (syn isomer) (5.4 g.).
N.M.R. spectrum (CDCQ3, ~) ppm 9.36 (lH, broad s) 7.10 (lH, s) 4.00-4.66 (4H, m) 4.00 (3H, s) 1.20-1.60 (6H, m) ~-137 ;~ 1 337522 10) Ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (50 g.) was added over 3 minutes with stirring at ambient temper-ature to a solution of thiourea (18.4 g.) and sodium acetate (19.8 g.) in a mixture of methanol (250 ml.) and water ~Z50 ml.).
After stirring for 35 minutes at 40 to 45C, the reaction mixture was cooled with ice and adjusted to pH 6.3 with a saturated aqueous solution of sodium bicarbonate. After stirring for 30 minutes at the same temperature, precipitates were collected by filtration, washed with water (200 ml.) and then with diisopropyl ether (100 ml.), and dried to give colorless crystals of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (37.8 g.), mp 161 to 162C.
I.R. spectrum (Nujol) 3400, 3300, 3150, 1725, 1630, 1559 cm~
; N.~l.R. spectrum (CDC~3, ~) ppm 6.72 (lH, s) 5.91 (2H, broad s) 4.38 (2H, q, J=7Hz) 4.03 (3H, s) 1.38 (3H, t, J=7Hz) 37~22 11) Ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)-acetate (anti isomer) (0.3 g.) and dimethyl sulfate (G.18 g.) were reacted according to a similar manner to that of Preparation 8-5) to give pale yellow oil of ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (0.27 g.).
I.R. spectrum (Film) 1750, 1605 cm 1 N.M.R. spectrum (CDCQ3, ~) ppm 8.07 (lH, s) 4.41 (2H, q, J~7Hz) 4.13 (3~, s) 2.75 (3H, s) 1.40 (3H, t, J~7Hz) 12~ The following compound was obtained according to a similar manner to that of Preparation 8-8).
ethyl 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetate (anti isomer), mp 96 to 99C (dec.).
I.R. spectrum (Nujol) 3150, 1740, 1650, 1600 cm~
N.M.R. spectrum (CDC13, ~) ppm 11.20 (lH, broad s), 8.60 (lH, s), 7.90 (lH, s), 4.32 (2H, q, J=8Hz), 4.13 (3H, s), 1.32 (3H, t, J-8Hz) ~0 Preparation 9 1) Ethanol (10 ml.) was added to a suspension of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) t2.2 g.) in a lN aqueous solution of sodium ~ydroxide (12 ml.) and the mixture was stirred for 15 hours at ambient temperature.
The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid and ethanol was distilled off under reduced pressure. The residual aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with 10~ hydrochloric acid and stirred under ice-cooling LO to precipitate crystals. The crystals were collected by filtration, washed with acetone and recrystallized from ethanol to give colorless needles of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.1 g.).
I.R. spectrum (Nujol) 3150, 1670, 1610, 1585 cm~
N.M.R. spectrum (d6-D~ISO, ~) ppm 7.20 (211, broad s) 6.85 (lH, s) 3.83 (3H, s) 2) lN-Aqueous solution of sodium hydroxide (1.5 ml.) was added to a solution of ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer) (0.3 g.) in ethanol (5 ml.) and the resulting mixture was stirred for 2 hours at 40C.
The reaction mixture was adjusted to pH 7.0 with 10~ hydrochloric acid, concentrated under reduced pressure, adjusted to pH l.S
with 10% hydrochloric acid and extracted with ethyl acetate.
The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off to give crystalline substance of 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid (syn isomer) (0.14 g.).
I.R. spectrum (Nujol) 1730 cm~l -N.M.R. spectrum (d6-DMSO, ~) - ppm 7.80 (lH, s) 3.85 (3H, s) 2.62 (3H, s) 3 ) The following compounds wcre obtained according to similar manners to those of Preparation 9-1) to 9~).
(1) 2-Methoxyimino-2-(Z-oxo-2,3-dihydro-1,3-thiazol-4-yl)-acetic acid (syn isomer).
I.R. spectrum (Nujol) 3250, 1710, 1650 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 10.61 (lH, broad s) 6.73 (lH, s) 0 3.95 (3H, s) (2) 2-Methoxyimino-Z-(2-mesylamino-1,3-thiazol-4-yl)-acetic acid (syn isomer).
I.R. spectrum (Nujol) 3150, 1720 cm~l ?5 N.M.R. spectrum (d6-DMSO, ~) ppm 7.17 (lH, s) 3.93 (3H, s) 3,02 (3H, s) (3) 2-Methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetic acid (syn isomer).
I.R. Spectrum (Nujol) 1730 cm~l (4) 2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)aceti.c acid (syn isomer), mp 152C (dec.).
I.R. spect~um (Nujol) 3200, 2800 - 2100, 1950, 1600 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 8.60 (lH, s) 7.62 (lH, s) 3.98 (lH, s) (5~ 2-Methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazol-4-yl)acetic aoid (syn isomer).
I. R. s~ectrum (Nujol) 3200, 1730, 1710, 1690, 15iO cm~
N. M. R. spectrum (d6-DMSO, ~) ppm 12.16 (lH, broad s) 7.50 (lH, g) 7.20 (lH, broad s) 4.25 (2E, q, J=7Hz) 3.93 (3H, s) 1.25 (3H, t, J=7Hz) , ~0 4 ) Pyridine (5 ml.) was added to a suspension of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (2.0 g.) in ethyl acetate (20 ml.). A solution o~ bis(2,2,2-trifluoroacetic)anhydride (2.5 g.) in ethyl acetate (3 ml.) was dropwise added thereto with stirring at 5 to 7C and the mixture was stirred for 30 minutes at 3 to 5C. Water (30 ml.) was added to the reaction mixture and the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate and two ethyl acetate layers were combined toge~her, washed with-water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 2-methoxyimino-2-[2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl]acetic acid (syn isomer) (0.72 g.).
I.R. spectrum (Nùjol) 1725, 1590 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 7.68 (lH, s) 3.91 (3H,s) 5 ) The following compound was obtained according to a similar manner to that of Preparation 9 - 4).
2-Methoxyimino-2-(2-acetamido-1,3-thiazol-4-yl)acetic acid (syn isomer), mp 184 to 185C (dec.).
I.R. spectrum (Nujol) 3200, 3050, 1695, 1600 cm 1 6) Phenolphthalein indicator (3 drops) was added tO a solution of O-allyl-hydroxylamine hydrochloride (0.84 g.) in dry methanol (10 ml.). To the solution was dropwise added with stirring at ambient temperature lN methanol solution of ~O sodium methoxide (6 ml.) until the color of the solution was - ~ 337522 ., . "
changed to pale pink. O-Allylhydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirred for 30 minutes at ambient temperature. After precipitating sodium chloride was filtered off, 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid (2.0 g.) was added to the filtrate and the mixture was stirred for 1 hour at ambient temperature.
After methanol was distilled off at low temperature, the residue was dissolved in an lN aqueous solution of sodium hydroxide.
LO The solution was washed with ether and ethyl acetate was added thereto. The mixture was adjusted to pH 1.5 with phosphoric acid and extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. Ethyl acetate was distilled off and the residue was washed with diisopropyl ether, collected by filtration and dried to give 2-allyloxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetic acid (syn isome~) (1.62 g.).
I.R. spectrum (Nujol) 3200, 1712 cm 1 N.M.R. spectrum (d6-DMSO, ~) ppm 7.40 (lH, s) 6.24-5.76 (lH, m) 5.26 (2H,dd, J=9, lO~z) 4.65 (2H, d, J=5Hz) 1.78 (2H, q, J=8Hz) 1.44 (6H, s) 0.88 (3H, t, J=8Hz) 7) The following compounds were obtained according to a similar manner to that of Preparation 9-6).
(1) 2-Methoxyimino-2-(2-t-pentyloxycarbony'amino-1,3-~ ~` . 1 337522 ,, thiazol-4-yl)acetic acid (syn isomer).
I.R. spectrum (Nujol) 3200, 1712 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 7.40 (lH, s) 3.88 (3H, s) 1.77 (2H, q, J~8Hz) 1.44 (6~1, s) 0.88 (3H, t, J~8Hz) O (2) 2-Allyloxyimino-2-(2-mesylamino^1,3-thiazol-4-yl)-acetic acid (syn isomer).
I.R. spectrum (Nujol) 3150, 1710, 1605 cm 1 (~) 2-Met~loxyimino-2-(2-amino-~,~-thiazol-4-yl)acetic acid (syn iso~er).
I.R. ~pectrum (Nujol) 3150, 1670, 1610, 1585 cm 1 N.M.R. spectrum (d6-DMSO,~ ) ppm 7.20 (2H, broad 5 ) 6.85 (lH, s) ~.83 (3H, s) 8) Ethyl 2-methoxyimino^2-(2-amino-1,3-thiazol-4-yl)acetate hydrobromide (anti isomer) (15.5 g.) was dissolved in a solution of sodium hydroxide (4.4 g.) in water (150 ml.) and the resulting solution was stirred for 1 hour at ambient temperature. An insoluble material was filtered off and the filtrate was adjusted to pH 5.0 to precipitate crystals. The crystals were collected by filtration and dried to give 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (anti isomer) (8.0 g.).
I.R. spectrum (Nujol) ~ 145 i 3150, 1655, 1595, 1550 cm~
N.M.R. spectrum (d6-DMSO, ~) ppm 7.53 (lH, s) 7.23 (2H, broad s) 3.99 (3~, s) ~) The ollowing compounds were obtained according to similar manner to that of Preparation 9-8).
(1) 2-Methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid (anti isomer) I.R. spectrum (Nujol) 1730, 1590 cm~l N.M.R. spectrum (d6-DMSO, ~) ppm 8.10 (1l~, s) 4.00 (3H, s) 2.65 (3H, s) ) 2-Methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetic acid (anti isomer).
I.R. spectrum (Nujol) 1730 cm 1 ~) 2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid tanti isomer), mp 156 to 158C (dec.).
I.R. spectrum (Nujol) 3200, 2700 - 2100, 1690, 1590, 1560 cm~
N,M.R. spectrum (d6-DM~O,~) ppm8.05 (IH, s) 4.02 (3H, 8) ~0 ~.. ~7. .

t ~- 1 337522 The expression "such as" employed in the specification means "for example" and is not intended to be construed as limit-ing the values which it qualifies.

-~6~

;:

SUPPLEME~T~RY DISCLOSURE
This disclosure and the Principal Disclosure are concerned with new syn-isomers of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof.
In addition this disclosure is particularly con-cerned with compounds of formula (I), as defined in the Principal Disclosure, in which the aliphatic hydrocarbon group R is a cyclic aliphatic hydrocarbon, particularly a cyclo(lower) alkyl group, more particularly a cyclo(lower)-alkyl group of 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
especially preferred are cyclo(lower)alkyl groups of 5 to 6 carbon atoms.
Compounds of formula (I) in which R2 is a cyclic aliphatic hydrocarbon group can be prepared in accordance with any of processes l to 8 described in the Principal Disclosure.
The invention is further illustrated by reference to the following Examples, illustrating the invention in particular and preferred embodiments, it will be evident that variation of the Examples, such as in the starting materials, in accordance with the invention will result in the production of different compounds (I), of the invention .

PreParation of the Startinq ComPounds Preparation S.D. 1 (1) 1-Allyl-lH-tetrazole-5-thiol (21.3 g) was added at 76 to 78C to a solution of sodium bicarbonate (10.6 g) in water (220 ml). Sodium 7-(5-amino-5-carboxyvaleramido)cephalosporanate (54.9 g) was added thereto over 15 minutes and the mixture was stirred for 80 minutes at 76 to 78C. The reaction mixture was adjusted to pH 3.0 with 6N hydrochloric acid under ice-cooling and filtered. The filtrate was subjected to column chromatography on non-ionic adsorption resin "Diaion HP-20" (Trademark:
prepared by Mitsubishi Chemical Industries Ltd.) and eluted with 30% aqueous solution of isopropyl alcohol. The eluate was adjusted to pH 6.5 with 28% aqueous solution of ammonia, concentrated and lyo,Philized to give ammonium 7-(5-amino-5-carboxy-valeramido)-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (21.7 g).
I.R. (Nujol) : 3175, 1760, 1590 cm~l N.M.R. (d6-DMSO, ~) : 1.23-2.42 (6H, m), 3.12 - 3.97 (3H, m), 4.37 (2H, broad s), 4.80-5.15 (3H, m), 5.15-5.51 (2H, m), 5.51-6.25 (2H, m), 8.77 (lH, d, J=8Hz) (2) N,N-Dimethylaniline (18.2 ml) was added to a mixture of ammonium 7-(5-amino-5-carboxyvaler-amido)-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (10.0 g), trimethylsilyl chloride (20.9 ml) and methylene chloride (75 ml), and the mixture was stirred under reflux for 2.5 hours. Phosphorus pentachloride (5.83 g) was added thereto at -30 to -35C and the mixture was stirred for 2 hours at the same temperature. 2-Ethoxy-ethanol (38 ml) was added dropwise thereto at the same temperature and the mixture was stirred for 1 _ hour at the same temperature. Water (80 ml) was added thereto at -5 to -10C over 10 minutes and the resulting mixture was stirred for 5 minutes at the same temperature. The aqueous layer was separated and adjusted to pH 4.2 with 28% aqueous solution of ammonia. Precipitates were collected by filtration, washed with 70% aqueous acetone (40 ml) and methanol (40 ml), and dried to give 7-amino-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4.1 g).
I.R. (Nujol) : 3150, 1800, 1610, 1530 cm~l N.M.R. (d6-DMSO, ~) : 3.65 (2H, ABq, J=18Hz), 4.33 (2H, ABq, J=13Hz), 6.38-4.70 (7H, m) PreParation S.D. 2 (1) Ethyl 2-hydroxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (126.4 g), formic acid (81:3 g) and acetic anhydride (180 g) were treated in a similar manner to that of Preparation 9-4) to give ethyl 2-hydroxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (109.6 g).

`- V,`
~ ; - 204 -I.R. (Nujol) : 3320, 3140, 3050, 1710, 1555 cm~l N.M.R. (d6-DMSO, ~) : 1.30 (3H, t, J=7Hz, 4.33 (2H,q, J=7Hz), 7.54 (lH, s), 8.54 (lH, s), 11.98 (lH, s), 12.58 (lH, s) (2) A mixture of chloromethylthiomethane (7.97 g), powdered potassium iodide (15.1 g) and acetone (79 ml) was stirred at ambient temperature for an hour, the resulting mixture was filtered and wa~hed with a small amount of acetone. The washings and the filtrate were combined and added to a stirred suspension of ethyl 2-hydroxyimino-2-(2-formamidothiazol-4-yl) acetate (syn isomer) (17.5 g) and powdered potassium carbonate (15.5 g) in acetone (300 ml). The mixture was stirred at ambient temperature for 3 hours, filtered and washed with acetone. The washings and the filtrate were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium chloride twice, dried over magnesium sulfate and concentrated in vacuo. The oily residue was subjected to column chromatography on silica gel and eluted with chloroform to give ethyl 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (2.4 g), mp. 130 to 131C.
I.R. (Nujol) : 3160, 3125, 3050, 1740, 1695 cm~l N.M.R. (d6-DMSO, ~) : 1.32 (3H, t, J=7Hz), 2.22 (3H, s), 4.38 (2H, q, J=7Hz), 5.33 (2H, s), 7.67 (lH, s), 8.56 (lH, s) .,~

. - 205 -(3) A mixture of ethyl 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (2.4 g), lN aqueous sodium hydroxide (23.8 ml) and methanol (19.8 ml) was stirred at 30C for 2.5 hours. The resultant solution was adjusted to pH 7 with 10%
hydrochloric acid and methanol was distilled off in vacuo. The aqueous solution was adjusted to pH 1, with 10% hydrochloric acid under ice cooling, and extracted with ethyl acetate three times. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1 13 g), mp. 157C
(dec.).
I.R. (Nujol) : 3210, 3160, 3075, 1700, 1555 cm~l N.M.R. (d6-DMSO, ~) : 2.24 (3H, s), 5.31 (2H, s), 7.61 (lH, s), 8.57 (lH, s), 12.73 (lH, s) Preparation S.D. 3 The following compounds were obtained according to similar manners to those of the foregoing Prepara-tions.
(1) 2-Isopropoxyimino-2-(2-formamidothiazo~-4-yl)-acetic acid (syn isomer), mp. 168 to 169C (dec.).
I.R. (Nujol) : 3200, 3130, 1710, 1600, 1560 cm~

(2) 2-Butoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer).
I.R. (Nujol) : 3350, 3160, 3050, 1700, 1680, 1570 cm~

(3) 2-Hexyloxyimino-2-(2-formamidothiazol-4-yl) acetic acid (syn isomer), mp. 115 to 116C (dec.).
I.R. (Nujol) : 3170, 3070, 1720, 1700, 1660 cm~l N.M.R. (d6-DMSO, ~) : 0.6-2.1 (llH, m), 4.15 (2H, t, J=6Hz), 7.53 (lH, s), 8.56 (lH, s), 12.69 (lH, s) (4) 2-(2-Formyloxyethoxy)imino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer).
I.R. (Nujol) : 3200, 1710, 1690 cm~l (5) 2-Benzyloxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer).
I.R. (Nujol) : 3330, 3200, 3100, 1660 1590 cm~l (6) 2-Ethoxycarbonylmethoxyimino-2-(2-formamido-thiazol-4-yl)acetic acid (syn isomer), mp. 110C, (dec.) I.R. (Nujol) : 3150, 1740, 1670, 1550 cm~l (7) 2-t-Butoxycarbonylmethoxyimino-2-(2-formamido-thiazol-4-yl)acetic acid (syn isomer), mp. 117C
(dec.) I.R. (Nujol) : 3180, 3140, 1750, 1690, 1630 cm~l (8) 2-(3-Isoxazolyl)methoxyimino-2-(2-formamido-thiazol-4-yl)acetic acid (syn isomer), mp. 110C
(dec.).
I.R. (Nujol) : 3270, 3130, 1680, 1540 cm~

5~
~'~` X - 207 -(9) 2-ethoxycarbonylmethoxyimino-2-~2-aminothizol-4-yl)acetic acid (syn isomer), I.R. (Nujol) : 3170, 1720, 1660, 1620 cm~
N.M.R. (d6-DMSO, ~) : 1.27 (3H, t, J=7Hz), 4.25 (2H, q, J=Hz), 4.77 (2H, s), 6.96 (lH, s) . .
(10) 2-(2-Ethoxyethoxy)imino-2-2-formamidothiazol-4-yl)acetic acid (syn isomer).
I.R. (Nujol) : 3350, 3140, 1740, 1700 cm~

, ~.
~ - 207a -Pre~ar~tio~ ~.~.4 The solution of 4-bromo-3-hydroxybenzyloxyamine phosphate (17.4 g.~ in water ~200 ml.) a~a e.hanol (200 ml.) was stirred at room temperature and adjusted to pH 7.0 w}th sodium bicarbonate. 2-(2-Fo~amido-thiazol-4-yl~glyoxylic acid (10.0 g.) was added to the solution ~nd the resulting suspension was adjus.ed to pH 4.0 to 4.5. After stirring the solution at - room temperature for 2 hours, ethanol was removed ~rom the resultant solution in va~uo.
Ethyl acetate was added to aqueous residue and adjus.ed to p~ 2.5 with 10~ hydrochloric acid. The ethyl acetat~ 12yer was separatea, wasned wit~ water and : dried over ~agnesium sulfate. ~he solution W2s con- --_ 15 ce~tra.ed in vacuo to give 2-(2-fo~mamidothiazol-4-yl)-2-(4-bromo-3-hyaroxybe~zyloxyimino)~cetlc acid (sy~ isomer, 14.8 g.).

Nu~ol 3350, 3150, 172Q, 168 , N.M.R. & (DMSO-d6, ppm) : 5.1~ (2H, m), 6.8 (lH, dd, 3=8Hz, 2Hz), 7.02 (lH, d, J=2Hz), - - - 7.5 ~lH, d, Jz8Hz), 7.58 (lH, s)~
- 8.58 (lH, s), 10.3; (lH, broad s), 25 - 12.7 (lH, broad s)-.

.

.

P`reparation ~,D. 5 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40.0 g.), 4-fluorobenzyl chloride (43.6 g.), N,N-dimethyl ormamide (60.0 ml), potassium carbonate (52.0 g.) and ethyl acetate (60.0 ml.) were treated i~
- ~ conventional manner to give ethyl 2-(4-fluoroben-yloxyimino)-3-oxobutyrate ~syn isomer, 64.4 g.~.

~0 ~.R. (Film): 3000, 2940, 1730, 1690, 1600 cm 1 N-M-R- (DMSO-d6, ~3: 1.21 (3H, t, J=7.0Hz), 2.34 (3H,. s), 4.26 (2~I, q, J=7.0Hz~, 5.32 (2H, s~, 6.97-7.73 (4H, m).
(2) Ethyl 2-~4-fluorobenzyloxyimino)-3-oxobu~yrate (syn isomer, 64.0 g.) and sulfuryl chloride (35.6 g.) and acetic acid (70.0 ml.) were treated in a similar manner to that of Preparation 6 -lO) to give ethyl 20 2-~4-fluorobenzyloxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 29.55 g.).

I.R. ~Film) : 1720, 1600 c;n 1 N.M.R. (DMSO-d6, ô) : 1.20 (3H, t, J=7.0Hz), 4.28 (2~, q, J=7.OHz), 4.87 (2H, s), 5.36 ~2H, s), 7.00-7.75 (4H, m).

(3) Ethyl 2- (4-fluoroben2yloxyimino)-3-oxo-4^
chlorobutyrate (syn isomer, 29.0 g.), thiourea ~8.8 g.?' sodium acetate ~7.9 g.), water ~72.5 ml .), tetrahydro-furan ~60 ml.) and ethanol (72.5 ml.) were t~eated in a similar manner to that of Preparation 8-io) to gi~e ethyl 2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-35 4-yl)acetate (syn isomer, 28.0 g.).
.

_ 209 --I.R. ~Nujol) : 3450, 315~, 3100, 1710, 1620 cm 1 N.M.R. ~DMS0-d6, ~ : 1.23 ~3H, t, J=7.0H~), 4.30 (2H, q, J=7Hz), 5.15 (2H, s), 6.90 ~lH, s), 6.95-7.60 (4H, m) (4) Eth- 2-(4-fluorobenzyloxyim~no)-2-(2-~minathiazol-4-yl)acetate (syn isomer, 25.5 g), l-methylimidazole (1.3 g), lN sodium hydroxide solution (118.3 ml.), methanol (250 ml.) and tetrahydrofur2n (2~0 mL) were treated in a similar manner to that of - 10 Preparation ~- 1) to give 2-(4-fluorobenzyloxyimino)-- 2-~2-aminothiazol-4-yl)acetic acid ~syn isomer, 22.11 g.)~
I.R. (Nujol) : 3650, 3450, 3300, 3150, 1630 cm 1 N.M.R. (DM~O-d6, ~) : 5.16 ~2H, s), ~.88 (lH, s), 7.04-7.66 (4H, m) --- (5) 2- ~4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl)acetic acid (syn isomer, 23.4 g.), bis-(trimethylsilyl~acetamide (32.2 g.), 2-,2,2-trifluoro-acetic anhydride (49.9 g.) and dry ethyl acetate ~234 ml.) were tIeated in a similar m~nner to that of Preparationq~to give 2-~4-fluoroben7yloxyimino)-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl~ac~tic - acid (sy~ isomer, 18.9 g.), mp. 180 to 182C.

-25 I.R. (Nujol) : 3200, 3150, 1730 cm l .
- - N.M.R. (DMS0-d6, ~) : 5.2~ (2H, s), 7.02-7.60-- - (4H, m), 7.72 (lH, s).
.
- -30 --Pre~aration ~.D. 6 (1-) The following comDound ~2S obtained b~
reacting et~yl 2-hydroxyimino-;-o~obutyrate ~syn is~mer) with3,4-dichloro~en~yl chloridein a cnn-~entiona~ ~nner~
: -, ~ , - 210 -Ethyl 2-(3,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn isomer), oil.

I.R. (Film) : 1730, 1690, 1600, 1470, 1400, 1370, 1310, 1240, 1130, 1080, 1010 cm~l N.M.R. (CCI4, ~) : 1.30 (3H, t, J=6Hz), 2.30 (3H, s), 4.30 (2H, q, J=6Hz), 4.47 (2H, s), 7.00-7.53 (3H, m) (2) The following compound was obtained according to a similar manner to that of Preparation 6-10.

Ethyl 2-(3,4-dichlorobenzyloxyimino)-3-oxo-4-chlorobutyrate (syn isomer), oil.

I.R. (Film) :1740, 1710, 1590, 1470, 1400, 1370, 1320, 1260, 1200, 1130, 1010 cm~l N.M.R. (CCI4, ~) : 1.37 (3H, t, J=6Hz), 4.23 (2H, q, J=6Hz), 4.43 (2H,s), 5.27 (2H, s), 7.10-7.60 (3H, m) (3) The following compound was obtained according to a similar manner to that of Preparation 8-10.

Ethyl 2-(3,4-dichlorobenzyloxyimino)-2-(2-amino-thiazol-4-yl)acetate (syn isomer).

3~ I.R. (Nujol) : 3460, 1720, 1600, 1540, 1460, 1390, 1260, 1180, 1020, 1010, 880, 810 cm~l N.M.R. (DMSO-d6, ~) : 1.25 (3H, t, J=7Hz), 4.30 (2H, q, J=7Hz), 5.17 (2H, s), 6.93 (lH, s), 7.27-7.73 (3H, m) ., ~ ~ ~ - 211 -(4) The following compound was obtained according to a similar manner to that of Preparation 9-1.

2-(3,4-dichlorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer).

I.R. (Nujol) : 3430, 1660, 1590, 1400, 1010 cm~l N.M.R. (DMSO-d6, ~) : 5.23 (2H, s), 6.93 (lH, s), 7.30-7.77 (3H, m) (5) The following compound was obtained according to a similar manner to that of Preparation 9-4.

2-(3,4-dichlorobenzyloxyimino)-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer).

I.R. (Nujol) : 1720, 1580, 1300, 1260, 1200, 1160, 1150 cm~1 N.M.R. (DMSO-d6, ~) : 5.40 (2H, s), 7.47-7.93 (4H, m) ,~. %

Preparation S.D. 7 To a suspension of N-(cinnamyloxy)phthalimide (21.0 g) in ethanol (200 ml) was added hydrazine hydrate (8.3 g) at 60C and the mixture was stirred for 1.5 hours at the same temperature. To the mixture were added conc. hydrochloric acid (22 ml) and water (220 ml) and the resulting mixture was filtered. The filtrate was concentrated to give precipitates, which were filtered off. The filtrate was adjusted to pH 7.0 and to the solution containing 0-cinnamyl hydroxylamine were added ethanol (300 ml) and 2-(2-formamidothiazol-4-yl)glyoxylic acid (10.0 g). The mixture was stirred for 2 hours at pH 4.0 to 4.5. The reaction mixture was concentrated and adjusted to pH 2.0 after addition of ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 2-cinnamyl-oxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (8.6 g.) I.R. (Nujol) : 3400-3100, 1700, 1550 cm~l N.M.R. (DMSO-d6, ~) : 4.85 (2H, d, J=5Hz), 6.2-6.93 (2H, m), 7.2-7.72 (5H, m), 7.6 (lH, s), 8.57 (lH, s), 12.7 (lH, broad s).

Example S.D. 1 2-Allyloxyimino-2-(2-formamidothiazol-4-yl)-acetic acid (syn isomer) (0.80 g) and dry ethyl acetate (10 ml) were added at 0 to 5C with stirring to a suspension of Vilsmeier reagent prepared from dry dimethylformamide (0.25 g) and phosphorus oxychloride (0.528 g) in dry ethyl acetate (0.75 ml) by conventional method, and the resulting mixture was stirred for 30 minutes at the same temperature to give a yellow solution. The solution was added at -10C
with stirring to a solution of 7-amino-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.11 g) and trimethylsilylacetamide (2.96 g) in dry ethyl acetate (15 ml), and the mixture was stirred for 1.5 hours at the same temperature. After addition of water (15 ml) to the reaction mixture, the ethyl acetate layer was separated and extracted with an aqueous solution of sodium bicarbonate (30 ml). The aqueous extract was acidified to pH 2.0 with 10%
hydrochloric acid and extracted with ethyl acetate (150 ml). The extract was washed with water, dried and evaporated. The residue was pulverized with diisopropyl ether to give colorless powder of 7-[2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.48 g).

I.R. (Nujol) : 3180, 1775, 1665 cm~l N.M.R. (d6-DMSO, ~) : 9.68 (lH, d, J=8Hz), 8.51 (lH, s), 7.40 (lH, s), 5.60-6.33 (3H, m), 4.85-5.57 (7H, m), 4.27-4.77 (4H, m), 3.70 (2H, ABq, J=18Hz) ExamPle S.D.2 The Vilsmeier reagent was prepared from dry dimethylformamide (0.4 g), phosphorus oxychloride (0.9 g) and dry ethyl acetate (1.6 ml) by the conventional method. Dry ethyl acetate (18 ml) was added thereto and then 2-ethoxyimino-2-(2-formamidothiazol-4-yl)-acetic acid (syn isomer) (1.3 g) was added thereto at 0C. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was added under -10C to a stirred solution of 7-amino-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g) and trimethylsilylacetamide (4.6 g) in dry ethyl acetate (36 ml), and the mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added water (30 ml). The ethyl acetate layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate (pH 7.5). The aqueous layer was washed three times with ethyl acetate and adjusted to pH 2.0 with conc. hydrochloric acid after addition of ethyl acetate (100 ml). The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with an activated charcoal and concentrated to dryness to give 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.56 g).
I.R. (Nujol): 3200, 1765, 1665 cm~l N.M.R. (d6-DMSO, ~) : 1.26 (3H, t, J=7.0Hz), 3.68 (2H, m), 4.18 (2H, q, J=7.0Hz), 4.36 (2H, ABq, J=14.OHz~, 4.75-5 57 (5H, m), 5.68-6.40 (2H, m), 7.37 (lH, s), 8.48 (lH, s), 9.60 (lH, d, J=8.OHz) ~;r Y ~ - 215 -~r~ ~

Example S.D.3 The Vilsmeier reagent was prepared from dry dimethylformamide (0.209 g), phosphorus oxychloride (0.434 g) and dry ethyl acetate (0.75 ml) by the conventional method. Dry tetrahydrofuran (6.5 ml) was added thereto and then 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (0.65 g) was added thereto at 0C. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was dropwise added at -5 to 0C to a stirred solution of 7-amino-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (1.25 g) in a mixture of water (10 ml) and acetone (10 ml) keeping the pH at 7.5 by triethylamine, and the mixture was stirred for 30 minutes at the same temperature at pH
7.5. To the reaction mixture was added ethyl acetate (60 ml) and the mixture was adjusted to pH 2.5 with 10%
hydrochloric acid. Insoluble material was filtered off and the filtrate was extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diethyl ether to give yellowish powder of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1003 g).
I.R. (Nujol): 3250, 3200, 1780, 1670, 1540 cm~l N.M.R. (d6-DMSO, ~) : 2.23 (3H, s), 3.72 (2H, s), 4.38 (2H, ABq, J=14Hz), 4.8-5.6 (7H, m) 5.7-6.4 (2H, m), 7.48 (lH, s), 8.55 (lH, s), 9.75 (lH, d, J=8Hz), 12.69 (lH, broad s) Example S.D.4 The Vilsmeier reagent was prepared from dry dimethylformamide (0.74 g), phosphorus oxychloride (1.56 g) and dry ethyl acetate (2.0 ml) by the con-ventional method. Dry tetrahydrofuran (15 ml) was added thereto and then 2-(3-isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.50 g) was added thereto at 0C. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was added dropwise at -5 to 0C to a stirred solution of 7-amino-3-(1-allyl-lH-tetrazol-5-yl) , .. ,~

thiomethyl-3-cephem-4-carboxylic acid (2.34 g) in a mixture of water (11.5 ml) and acetone (11.5 ml) keeping the pH at 7.5 by triethylamine, and the mixture was stirred for 30 minutes at the same temperature at pH 7.5. To the reaction mixture was added ethyl acetate (60 ml) and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid. Insoluble material was filtered off and the filtrate was extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diethyl ether to give yellowish powder of 7-[2-(3-isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.15 g).
I.R. (Nujol): 3250, 1780, 1670, 1550 cm~
N.M.R. (d6-DMSO, ~): 3.72 (2H, s), 4.40 (2H, ABq, J=14Hz), 4.8-5.6 (7H, m), 5.6-6.5 (2H, m), 6.67 (lH, d, J=2Hz), 7.50 (lH, s), 8.56 (lH, s), 8.92 (lH, d, J=2Hz), 9.80 (lH, d, J=8Hz), 12.72 (lH, broad s) Example S.D.5 Phosphorus oxychloride (1.0 g) was added at a time to suspension of 2-benzyloxyimino-2-(2-amino-thiazol-4-yl)acetic acid (syn isomer) (1.4 g) in dry tetrahydrofuran (14 ml) at 2C and the mixture was stirred for 15 minutes at 2 to 4C. Trimethylsilyl-acetamide (1.0 g) was added dropwise thereto and the resulting mixture was stirred for 20 minutes at 2 to 6C. Phosphorus oxychloride (1.0 g) was added thereto and the mixture was stirred for 20 minutes. Dry dimethylformamide (0.5 g) was added thereto at a time at 4 to 6C and the mixture was stirred for 1 hour to give a clear solution. On the other hand, trimethyl-silylacetamide (5.3 g) was added to a stirred suspension of 7-amino-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g) in dry ethyl acetate (27 ml) and the solution was stirred for 30 minutes at 40C. To this solution was added the above-obtained tetrahydrofuran solution at a time at -30C, and the resulting mixture was stirred for 1 hour at -5 to -20C. To the reaction mixture were added water (30 ml) and ethyl acetate (20 ml). An organic layer was separated and extracted with an aqueous solution of sodium bicarbonate. The extract was adjusted to pH 3.0 with 10~ hydrochloric acid.
Precipitates were collected by filtration, washed with water to give 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.85 g).
I.R. (Nujol): 3350, 3230, 1780, 1675, 1635 cm~l N.M.R. (d6-DMSO, ~) : 3.67 (2H, m), 4.40 (2H, ABq, J=15.OHz), 4.85-5.56 (6H, m), 5.62-6.45 (2H, m), 6.77 (lH, s), 7.01-7.65 (7H, m), 9.71 (lH, d, J=8Hz) ExamPle S.D.6 The Vilsmeier reagent was prepared from dry dimethylformaminde (0.44 g), phosphorus oxychloride (0.9 g) and dry ethyl acetate (1.0 ml) by the conventional method. Dry ethyl acetate (20 ml) was added thereto and then 2-methoxyimino-2-(2-formamidothiazol-4-yl)-acetic acid (syn isomer) (1.1 g) was added thereto at -5 to 10C. The mixture was stirred for 10 minutes at the same temperature. The resulting mixture was dropwise added at O to 5C and pH
6.5 to 7.5 with stirring to a solution of 7-amino-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (2.12 g) and sodium bicarbonate (2 g) ~ 1 337522 in a mixture of water (20 ml) and acetone (20 ml), and the mixture was stirred for 20 minutes at the same temperature. The aqueous layer was separated and acetone was evaporated. The aqueous layer was adjusted under ice-cooling and stirring to pH 3.0 with 10%
hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.94 g).
I.R. (Nujol) : 3200, 1780, 1680, 1550 cm~
N.M.R. (d6-DMSO, ~) : 3.72 (2H, broad s), 3.93 (3H, s), 4.20 (2H, broad s), 4.65 (2H, m), 4.72-5.43 (3H, m), 5.55-6.45 (2H, m), 7.43 (lH, s), 8.55 (lH, s), 8.65 (lH, s), 9.68 (lH, d, J=8Hz), 12.82 (lH, m) Example S.D.7 The following compounds were obtained according to similar manner to those of Examples S.D.l to S.D.6.
(1) 7-[2-Isopropoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), I.R. (Nujol) : 3220, 1780, 1670 cm~l N.M.R. (d6-DMSO, ~) : 1.20 (3H, s), 1.32 (3H, s), 3.70 (2H, broad s), 4.07-4.87 (3H, m), 4.93-5.50 (4H, m), 5.67-6.23 (2H, m), 7.40 (lH, s), 8.50 (lH, s) 9.58 (lH, d, J=8Hz) (2) 7-[2-Butoxyimino-2-(2-formamidothiazol-4-yl)- acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1780, 1695, 1675, 1655 cm~l ~,, i 337522 _ N.M.R. (d6-DMSO, ~) : 0.88 (3H, m), 1.10-2.01 (4H, m), 3.71 (2H, m), 4.14 (2H, t, J=7.OHz), 4.38 (2H, ABq, J=14.OHz), 4.83-5.51 (5H, m), 5.63-6.40 (2H, m), 7.42 (lH, s), 8.56 (lH, s), 9.65 (lH, d, J=9.OHz) (3) 7-[2-Hexyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3175, 1780, 1757, 1684, 1640 cm~l N.M.R. (d6-DMSO, ~) : 0.84 (3H, m), 1.06-2.03 (8H, m), 3.73 (2H, m), 4.14 (2H, t, J=6.OHz), 4.40 (2H, ABq, J=14.OHz), 4.85-5.52 (5H, m), 5.75-6.45 (2H, m), 6.97 (lH, broad s), 7.41 (lH, s), 8.54 (lH, s), 9.63 (lH, d, J=8.OHz) (4) 7-[2-(2-Formyloxyethoxy)imino-2-(2-formamido-thiazol-4-yl)acetamido-3-(l-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3265, 1780, 1720, 1680 cm~l N.M.R. (d6-DMSO, ~) : 3.74 (2H, m), 4.13-4.70 (6H, m), 4.85-5.53 (5H, m), 5.70-6.42 (2H, m), 7.48 (lH, s), 8.26 (lH, s), 8.56 (lH, s), 9.69 (lH, d, J=9.OHz) (5) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-formamido-thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3500, 3280, 1780, 1735, 1690 cm~l N.M.R. (d6-DMSO, ~) : 1.24 (3H, t, J=7Hz), 3.74 (2H, s), 4.20 (2H, q, J=7Hz), 4.42 (2H, s), 4.77 (2H, s), 4.5-5.6 (5H, m), 5.7-6.4 (3H, m), 7.50 i (lH, s), 8.57 (lH, s), 9.68 (lH, d, J=8Hz), 12.69 (lH, broad s) (6) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-formamido-thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3250, 1780, 1720, 1680, 1540 cm~l N.M.R. (d6-DMSO, ~) : 1.44 (9H, s), 3.71 (2H, ABq, J=18Hz), 4.37 (2H, ABq, J=14Hz), 4.62 (2H, s), 4.8-5.4 (5H, m), 5.5-6.4 (2H, m), 7.46 (lH, s), 8.52 (lH, s), 9.58 (lH, d, J=8Hz), 12.60 (lH, broad s) (7) 7-[2-Ethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 1780, 1675, 1635 cm~l (8) 7-[2-Isopropoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3250, 1780, 1675, 1630 cm~l (9) 7-[2-Butoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1672 cm~l (10) 7-[2-Hexyloxyimino-2-(aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3240, 1780, 1675, 1630 cm~l (11) 7-[2-Allyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3210, 1788, 1675 cm~

_. ~
~ - 222 --(12) 7-[2-Ethoxycarbonylmethoxyimino-2-l2-amino-thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 3230, 1780, 1680, 1630 cm~l (13) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3330, 1780, 1730, 1680, 1630 cm~l (14) 7-[2-Methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3270, 1760, 1650, 1520 cm~
(15) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3300, 1770, 1660, 1530 cm~l (16) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1680, 1630 cm~l (17) 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thio-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 1775, 1670, 1530 cm~l (18) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-(2,2,2-trifluoroacetamido)thiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3250, 3170, 1780, 1720, 1650 cm~

:,; ~.
: ~.

-N.M.R. (DMSO-d6, ~) : 3.64 (2H, m), 4.34 (2H, ABq, J=14Hz), 4.79-5.44 (7H, m), 5.65-6.27 (2H, m), 6.95-7.61 (4H, m), 7.51 (lH, s), 9.83 (lH, d, J=8Hz) 5 (19) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamino]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 157 to 161C (dec.).
I.R. (Nujol) : 3500, 1770, 1660, 1630, 1600 cm~l (20) 7-[2-(3,4-Dichlorobenzyloxyimino)-2-(2-(2,2,2-trifluoroacetamido)thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 1770, 1650 cm~l N.M.R. (DMSO-d6, ~) : 3.72 (2H, m), 4.40 (2H, m), 5.00-5.43 (7H, m), 5.73-6.60 (2H, m), 7.30-7.77 (4H, m), 9.90 (lH, d, J=8Hz) (21) 7-[2-(3,4-Dichlorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamino]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 155 to 175C (dec.).
I.R. (Nujol) : 1770, 1660-1620, 1450 cm~

ExamPle S.D.8 Conc. hydrochloric acid (0.33 g) was added to a solution of 7-[2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.30 g) in methanol (13 ml) and the mixture was stirred for 4.5 hours at ambient temperature. The solvent was dis-tilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate (25 ml). The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 2.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give color-less powder of 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.95 g).
I.R. (Nujol) : 3350, 3210, 1778, 1675 cm~l N.M.R. (d6-DMSO, ~) : 3.68 (2H, ABq, J=18Hz), 4.40-4.71 (4H, m), 4.80-5.45 (7H, m), 5.64-6.24 (3H, m), 6.74 (lH, s), 7.35 (2H, broad s), 9.62 (lH, d, J=8Hz) -~; - - 225 -- ~r ~0 ExamPle S.D. 9 Conc. hydrochloric acid (0.9 g) was added at ambient temperature to a solution of 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-. ~, tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.4 g) in a mixture of methanol (16.8 ml) and tetrahydrofuran (4.8 ml) and the mixture was stirred for 3 hours at 30C. The solvent was distilled off under reduced pressure and the residue was dis-solved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate and adjusted to pH 2.8 with conc.hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-ethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.72 g).
I.R. (Nujol) : 3350, 1780, 1675, 1635 cm~l N.M.R. (d6-DMSO, ~) : 1.24 (3H, t, J=7.3Hz), 3.71 (2H, m), 4.13 (2H, q, J=7.3Hz), 4.37 (2H, ABq, J=13.5Hz), 4.80-5.53 (5H, m), 5.64-6.45 (2H, m), 6.77 (lH, s), 7.25 (2H, broad s), 9.62 (lH, d, J=8.OHz) r:
'` X - 227 -~ , Example S.D.10 A mixture of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.95 g), conc.hydrochloric acid (0.324 g), methanol (9.5 ml) and tetrahydrofuran (2 ml) was stirred for 2 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.78 g).
I.R. (Nujol) : 3270, 1760, 1650, 1520 cm~
N.M.R. (d6-DMSO, ~) : 2.21 (3H, s), 3.72 (2H, s), 4.38 (2H, ABq, J=14Hz), 4.8-5.6 (7H, m), 5.7-6.4 (2H, m), 6.80 (lH, s), 7.26 (2H, broad s), 9.66 (lH, d, J=8Hz) Example S.D.ll A mixture of 7-[2-(3-isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g), conc.hydrochloric acid (0.497 g), methanol (15 ml) and tetrahydrofuran (3 ml) was stirred for 2 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution - 1 33752~
was washed with ethyl acetate (25 ml) and adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-(3-isoxazolyl)methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.65 g).
I.R. (Nujol) : 3300, 1770, 1660, 1530 cm~l N.M.R. (d6-DMSO, ~) : 3.71 (2H, s), 4.40 (2H, d, J=14Hz), 4.8-5.6 (7H, m), 5.6-6.5 (2H, m), 6.62 (lH, d, J=2Hz), 6.83 (lH, s), 7.29 (2H, broad s), 8.92 (lH, d, J=2Hz), 9.73 (lH, d, J=8Hz) Example S.D.12 A mixture of 7-~2-methoxyimino-2-(2-form-amido-thiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g), conc.hydrochloric acid (0.3 ml), methanol (7 ml) and tetrahydrofuran (7 ml) was stirred for 4.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 2.0 with 10%
hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g).
I.R. (Nujol) : 3350, 1775, 1670, 1530 cm~
N.M.R. (d6-DMSO, ~) : 3.65 (2H, broad s), 3.83 (3H, s), 4.15 (2H, broad s), 4.58 (2H, m), 4.77-5.5 (3H, m), 5.58-6.33 (2H, m), 6.73 (lH, s), 8.60 (lH, s), 9.58 (lH, d, J=8Hz) ~X

Example S.D.13 The following compounds were obtained accord-ing to similar manner to those of Examples S.D.8 to S.D.12 (1) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3230, 1780, 1675, 1635 cm~l (2) 7-[2-Isopropoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3250, 1780, 1675, 1630 cm~l N-M-R- (d6-DMso~ ~) : 1-20 (3H, s), 1.30 (3H, s), 3.70 (2H, broad s), 4.30 (3H, m), 4.97-5.40 (4H, m), 5.63-6.27 (2H, m), 6.70 (lH, s), 9.55 (lH, d, J=8Hz) (3) 7-[2-Butoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1672 cm~l N.M.R. (d6-DMSO, ~) : 0.91 (3H, t, J=6.0Hz), 1.18-1.96 (4H, m), 3.73 (2H, m), 3.87-4.73 (4H, m), 4.83-5.57 (5H, m), 5.63-6.40 (2H, m), 6.74 (lH, s), 7.20 (2H, broad s), 9.55 (lH, d, J=8.OHz) (4) 7-[2-Hexyloxyinino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3240, 1780, 1675, 1630 cm~l N.M.R. (d6-DMSO, ~) : 0.85 (3H, m), 1.00-2.00 (8H, m), 3.68 (2H, m), 4.05 (2H, m), 4.37 (2H, m), 4.80-5.47 (5H, m), 5.60--6.47 (2H, m), 6.69 (lH, s), 7.20 (2H, broad s), 9.50 (lH, d, J=8.0Hz) (5) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) I.R. (Nujol) : 3360, 3230, 1780, 1680, 1630 cm~l N.M.R. (d6-DMSO, ~) : 1.21 (3H, t, J=7Hz), 3.68 (2H, s), 4.14 (2H, q, J=7Hz), 4.38 (2H, s), 4.66 (2H, s), 4.8-5.5 (5H, m), 5.6-6.4 (3H, m), 6.80 (lH, s), 7.20 (2H, broad s), 9.48 (lH, d, J=8Hz) (6) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3330, 1780, 1730, 1680, 1630 cm~l N.M.R. (d6-DMSO, ~) : 1.43 (9H, s), 3.67 (2H, s), 4.37 (2H, ABq, J=14Hz), 4.56 (2H, s), 4.8-5.5 (5H, m), 5.6-6.4 (2H, m), 6.78 (lH, s), 7.20 (2H, broad s), 9.43 (lH, d, J=8Hz) (7) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)-acetamido-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1680, 1630 cm~
(8) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-amino-thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 157 to 161C (dec.).
I.R. (Nujol) : 3500, 1770, 1660, 1630, 1600 cm~l N.M.R. (DMSO-d6, ~) : 3.69 (2H, m), 4.39 (2H, ABq, J=14Hz), 4.75-5.48 (7H, m) 5.63-.,--~ - 231 -6.57 (2H, m), 6.76 (lH, s), 6.86-7.76 (4H, m), 9.67 (lH, d, J=8Hz) (9) 7-[2-(3,4-Dichlorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 155 to 175C (dec.).
I.R. (Nujol) : 1770, 1660-1620, 1450 cm~
N.M.R. (DMSO-d6, ~) : 3.63 (2H, m), 4.33 (2H, m), 4.93-5.37 (7H, m), 5.67-6.40 (2H, m), 6.73 (lH, s), 7.10-7.70 (3H, m), 9.73 (lH, d, J=8Hz) ExamPle S.D.14 Trifluoracetic acid (20 ml) was added under ice-cooling to a stirred suspension of 7-[2-t-butoxy-carbonylmethoxyimino-2-(2-aminothiazol-4-yl)acet-amido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.05 g) in anisole (2 ml), and the resultant mixture was stirred for 2 hours at ambient temperature. The reaction mixture was con-centrated under reduced pressure and diethyl ether wasadded thereto. Precipitates were collected by filtration, washed with diethyl ether, dried and dissolved in an aqueous solution of sodium bicarbonate.
An insoluble material was filtered off and the filtrate was adjusted to pH 3.2 with conc.hydorchloric acid.
Precipitates were collected by filtration, washed with water and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 30 (0.8 g).
I.R. (Nujol) : 3360, 1780, 1680, 1630 cm~l N.M.R. (d6-DMSO, ~) : 3.68 (2H, ABq, J=19Hz), 4.36 (2H, ABq, J=14Hz), 4.60 (2H, s), 4.60-6.2 (7H, m), 6.80 (lH, s), 7.24 (2H, broad s), 9.51 (lH, d, J=9Hz) ~;

ExamPle S.D.15 To a solution of 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]cephalosporanic acid (syn isomer) (4.8 g) in pH 6.4 phosphate buffer solution (100 ml) was added 1-allyl-lH-tetrazole-5-thiol (2.1 g) and then the mixture was stirred for 2 hours at 55 to 60C. The reaction mixture was cooled and adjusted to pH 3.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g).
I.R. (Nujol) : 3350, 3210, 1778, 1675 cm~l N.M.R. (DMSO-d6, ~) : 3.68 (2H, ABq, J=18Hz), 4.40-4.71 (4H, m), 4.80-5.45 (7H, m), 5.64-6.24 (3H, m), 6.74 (lH, s), 7.35 (2H, broad s), 9.62 (lH, d, J=8Hz) ExamPle S.D.16 The following compounds were obtained according to a similar manner to that of Example S.D.15.
(1) 7-[2-Allyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3180, 1775, 1665 cm~l (2) 7-~2-Ethoxyimino-2-(2-formamidothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1765, 1665 cm~

- ~ 337522 (3) 7-[2-Methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3250, 3200, 1780, 1670, 1540 cm~l (4) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3250, 1780, 1670, 1550 cm~l (5) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3230, 1780, 1675, 1635 cm~l (6) 7-[2-Methoxyimino-2-(2-formamidothiazol-4-yl)-acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1780, 1680, 1550 cm~l (7) 7-[2-Isopropoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

. X - 234 -~..

-I.R. (Nujol) : 3220, 1780, 1670 cm~l (8~ 7-[2-Bitoxyimino-2-(2-formamidothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1780, 1695, 1675, 1655 cm~l (9) 7-[2-Hexyloxyimino-2-(2-formamidothiazol-4-yl)-acetamido]-3(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3175, 1780, 1757, 1684, 1640 cm~l (10) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3500, 3280, 1780, 1735, 1690 cm~l (11) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3250, 1780, 1720, 1680, 1540 cm~l (12) 7-[2-Ethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 1780, 1675, 1635 cm~

(13) 7-[2-Isopropoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3250, 1780, 1675, 1630 cm~l (14) 7-[2-Butoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1672 cm~l (15) 7-[2-Hexyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3240, 1780, 1675, 1630 cm~l (16) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 3230, 1780, 1680, 1630 cm~l (17) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3330, 1780, 1730, 1680, 1630 cm~l (18) 7-[2-Methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3270, 1760, 1650, 1520 cm~
(19) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3300, 1770, 1660, 1530 cm~l (20) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 1780, 1680, 1630 cm~l (21) 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) :3350, 1775, 1670, 1530 cm 1 (22) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 157 to 161C (dec.).
I.R. (Nujol) : 3500, 1770, 1660, 1630, 1600 cm~

(23) 7-[2-(3,4-Dichlorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 155 to 175C ~dec).
I.R. (Nujol) : 1770, 1660-1620, 1450 cm~

~'- X-~- - 238 -ExamPle S.D.17 The Vilsmeier reagent was prepared from dry dimethylformamide (0.139 g.), phosphorus oxychloride (0.290 g.) and dry tetrahydrofuran (1.0 ml.) by the conventional method. Dry tetrahydrofuran (3.0 ml.) was added thereto and then 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (0.4 g.) was added thereto at -5 to 0C. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was dropwise added at -5 to 0C to a stirred solution of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (0.725 g.) in a mixture of water (7 ml.) and acetone (7 ml.) keeping the pH at 7.5 to 8.5 by triethylamine and the mixture was stirred for 30 minutes at the same temperature at pH 7.5 to 8.5.
Acetone was removed from the reaction mixture. To the residue was added ethyl acetate and water and the mixture was adjusted to pH 2.0 with 10% hydrochloric acid. Insoluble material was filtered off and the filtrate was extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diethyl ether to give 7-[2-methyl-thiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.64 g.).
I.R. (Nujol) : 3230, 1780, 1680, 1550 cm~l N.M.R. (d6-DMS0, ~) : 2.22 (3H, s), 3.72 (2H, ABq, J=18Hz), 4.44 (2H, ABq, J=14Hz), 5.18 (lH, d, J=5Hz), 5.23 (2H, s), 5.84 (lH, d,d, J=5 and 9Hz), 7.46 (lH, s), 8.52 (lH, s), 9.54 (lH, s), 9.74 (lH, d, J=9Hz), 12.64 (lH, broad s) ExamPle S.D.18 Phosphorus oxychloride (2.3 g.) was added at a time to a suspension of 2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (3.4 g.) in dry tetrahydrofuran (30 ml.) at -3C and the mixture was stirred for 20 minutes at the same temperature. Tri-methylsilylacetamide (2.4 g.) and tetrahydrofuran (5 ml.) were added dropwise thereto and the resulting mixture was stirred for 20 minutes at the same temperature. Phosphorus oxychloride (2.3 g.) was added thereto and the mixture was stirred for 30 minutes at 0 to 3C. Dry dimethylformamide (1.1 g.) was added thereto at a time at 0 to 3C and the mixture was stirred for 1 hour at the same temperature to give a clear solution. On the other hand, trimethylsilyl-acetamide (12.7 g.) was added to a stirred suspension of 7-amino-3-~1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (4.0 g.) in dry ethyl acetate (60 ml.) and the solution was stirred for 1 hour at ambient temperature. To this stirred solution was added the above-obtained tetrahydrofuran solution at a time at -20C, and the resulting mixture was stirred for 2 hours at -5 to -15C. To the reaction mixture were added a saturated aqueous solution of sodium chloride (50 ml.).
An organic layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate (pH
7.0). The extract was washed with ethyl acetate, treated with an activated charcoal and adjusted to pH
4.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give powder of 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.03 g.).

._.

I.R. (Nujol) : 3320, 3200, 1770, 1670, 1610 cm~l N.M.R. (d6-DMSO, ~) : 3.59 (2H, ABq, J=18.OHz), 4.47 (2H, ABq, J=12.OHz), 5.09 (lH, d, J=4.OHz), 5.15 (2H, s), 5.73 (lH, d,d, J=4.0 and 8.0Hz), 6.74 (lH, s), 7.36 (5H, m), 9.56 (lH, s), 9.69 (lH, d, J=8.0Hz) ExamPle S.D.l9 The Vilsmeier reagent was prepared from dry dimethylformamide (0.667 g.), phosphorus oxychloride (1.40 g.) and dry ethyl acetate (4 ml.) by the conventional method. Dry ethyl acetate (16 ml.) was added thereto and then 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (2 g.) was added thereto at 0C. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was added dropwise at -15C to a stirred solution of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (3.01 g.) and trimethyl-silylacetamide (9.6 g.) in dry ethyl acetate (30 ml.), and the mixture was stirred for 50 minutes at -15 to -5C. To the reaction mixture was added water (50 ml.).
An insoluble material was filtered off and the filtrate was extracted twice with ethyl acetate. The extracts were washed twice with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diethyl ether and the powder was collected by filtration and dried to give 7-[2-t-butoxycarbonylmethoxyimino-2-t2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thia-diazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.67 g.).

X. - 241 -~_t 1 337522 I.R. (Nujol) : 3225, 1780, 1725, 1685, 1550 cm~l N.M.R. (d6-DMSO, ~) : 1.38 (9H, s), 3.64 (2H, ABq, J=17Hz), 4.38 (2H, ABq, J=14Hz), 4.56 (2H, s), 5.12 (lH, d, J=5Hz), 5.77 (lH, d,d, J=5 and 9Hz), 7.38 (lH, s), 8.47 (lH, s), 9.49 (lH, s), 9.54 (lH, d, J=9Hz), 12.57 (lH, broad s) Example S.D.20 The following compounds were obtained accord-ing to similar manners to those of Examples S.D.17 to 19 .
(1) 7-[2-Methylthiomethoxyimino-2-(2-formamido-thiazol-4-yl)acetamido]-3-~1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3250, 1780, 1675, 1550 cm~l N.M.R. (d6-DMSO, ~) : 2.22 (3H, s), 3.72 (2H, ABq, J=19Hz), 3.96 (3H, s), 4.33 (2H, ABq, J=14Hz), 5.17 (lH, d, J=5Hz), 5.26 (2H, s), 5.85 (lH, d,d, J=5 and 8Hz), 7.48 (lH, s), 8.54 (lH, s), 9.78 (lH, d, J=8Hz), 12.64 (lH, s) (2) 7-[2-(2-Ethoxyethoxy)imino-2-(2-formamido-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3500, 3200, 1780, 1720, 1680 cm~l N.M.R. (d6-DMSO, ~) : 1.13 (3H, t, J=7Hz), 3.2~4.0 (6H, m), 4.30 (2H, t, J=4Hz), 4.50 (2H, ABq, J=13Hz), 5.23 (lH, d, J=5Hz), 5.87 (lH, d,d, J=5 and 8Hz), Xl.

7.48 (lH, s), 8.58 (lH, s), 9.60 (lH, s), 9.70 (lH, d, J=8Hz) (3) 7-[2-(2-Formyloxyethoxy)imino-2-(2-formamido-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 1770, 1710, 1670 cm 1 N.M.R. (d6-DMSO, ~) : 3.50 (2H, m), 4.10~4.60 (4H, m), 4.79 (2H, m), 5.16 (lH, d, J=5.0Hz), 5.81 (lH, d,d, J=5.0 and 8.0Hz), 6.58 (2H, broad s), 7.47 (lH, s), 8.28 (lH, s), 8.55 (lH, s) (4) 7-[2-(2-Formyloxyethoxy)imino-2-(2-formamido-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3160, 1775, 1710, 1670 cm~
N.M.R. (d6-DMSO, ~) : 3.71 (2H, ABq, J=18.0Hz~, 3.96 (3H, s), 4.00~4.54 (6H, m), 5.16 (lH, d, J=4.5Hz), 5.84 (lH, d,d, J=4.5 and 9.0Hz), 7.45 (lH, s), 8.24 (lH, s), 8.53 (lH, s), 9.70 (lH, d, J=9.OHz) (5) 7-[2-(2-Formyloxyethoxy)imino-2-(2-formamido-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thio-methyl-3-cephem-4-carboxylic acid (syn isomer).

-I.R. (Nujol) : 3180, 1775, 1673 cm~l N.M.R. (d6-DMSO, ~) : 3.75 (2H, m), 4.25~4.65 (6H, m), 5.22 (lH, d, J=5.0Hz), 5.88 (lH, d,d, J=5.0 and 9.0Hz), 7.49 (lH, s), 8.26 (lH, s), 8.57 (lH, s), 9.59 (lH, s), 9.71 (lH, d, J=9.OHz) (6) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-form-amido-hiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3250, 1775, 1720, 1680, 1540 cm~l N.M.R. (d6-DMSO, ~) : 1.22 (3H, t, J=7Hz), 3.74 (2H, s), 4.20 (2H, q, J=7Hz), 4.77 (2H, s), 5.22 (lH, d, J=5Hz), 5.88 (lH, d,d, J=5 and 8Hz), 7.51 (lH, s), 8.58 (lH, s), 9.63 (lH, s), g.70 (lH, d, J=8Hz), 12.68 (lH, broad s) (7) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-form-amidothiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3250, 1780, 1725, 1680, 1540 cm~l N-M-R- (d6-DMSO, ~) : 1.22 (3H, t, J=7Hz), 3.73 (2H, s), 3.97 (3H, s), 4.18 (2H, q, J=7Hz), 4.35 (2H, ABq, J=14Hz), 4.76 (2H, s), 5.18 (lH, d, J=5Hz), 5.86 (lH, d,d, J=5 and 9Hz), 7.48 (lH, s), 8.56 (lH, s), 9.67 (lH, d, J=9Hz), 12.69 (lH, broad s) (8) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3180, 1785, 1725, 1690, 1550 cm~l N-M-R- (d6-DMSO, ~) : 1.45 (9H, s), 3.72 (2H, ABq, J=17Hz), 3.96 (3H, s), 4.33 (2H, ABq, J=14Hz), 4.64 (2H, s), 5.17 (lH, d, J=5Hz), 5.84 (lH, d,d, J=5 and 9Hz), 7.46 (lH, s), 8.52 (lH, s), 9.62 (lH, d, J=9Hz), 12.61 (lH, broad s) 1 v, ~ ~b~ - 245 -t 337522 -(9) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-hexyl-lH-tetrazol-5-yl)thiomehtyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3250, 1780, 1680, 1633 cm~l N.M.R. (d6-DMSO, ~) : 0.86 (3H, m), 0.97~1.53 (6H, m), 1.53~2.10 (2H, m), 3.70 (2H, m), 4.10~4.77 (4H, m), 5.00~5.50 (3H, m), 5.85 (lH, d,d, J=5.0 and 8.OHz), 6.80 (lH, s), 6.98~7.63 (7H, m), 9.71 (lH, d, J=8.OHz) (10) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-form-amidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1775, 1675, 1540 cm~
N.M.R. (d6-DMSO, ~) : 3.72 (2H, s), 4.45 (2H, ABq, J=13Hz), 5.18 (lH, d, J=5Hz), 5.30 (2H, s), 5.96 (lH, d,d, J=5 and X

8Hz), 6.67 (lH, d, J=2Hz), 7.50 (lH, s), 8.55 (lH, s), 8.90 (lH, d, J=2Hz), 9.58 (lH, s), 9.79 (lH, d, J=8Hz), 12.69 (lH, s) (11) 7-[2-Methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3340, 3200, 1775, 1670 cm~l (12) 7-[2-Methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3300, 1770, 1670, 1530 cm~l (13) 7-[2-(2-Ethoxyethoxy)imino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3160, 3100, 1780, 1670, 1630 cm~l (14) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-amino-thiazol 4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3220, 1780, 1680, 1630 cm~l (15) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3230, 3100, 1780, 1680, 1630 cm~l (16) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. tNujol) : 3300, 1775, 1730, 1675, 1630 cm~

X` - 247 -(17) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3340, 3200, 1775, 1675, 1630 cm~l (18) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3230, 3110, 1775, 1675 cm~l (19) 7-[2-Carboxymethoxyimino-2-(2-formamido-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3200, 1780, 1720, 1680, 1545 cm~l (20) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3360, 3240, 3100, 1780, 1680, 1635 cm~l X

(Z~) 7-~2-~t-Butoxycarbonylmethoxyimino)-2-(2-- ~ fo~mamidothia201-4-yl)acetamido]-3-~lH-tetra ol-5-yl)-1~ thiomethyl-3-cephem-4-carboxyllc acid (syn isomer).

. r~ R. (Nujol) : 31tO, 1770, 17ZO, 1670 cm 1 - N.M.R. ~DMSO-d6, ~) : 1.44 (9H, s), 3.68 (2H, m), ~ 4.33 ~2H, AB~, J=12.0Hz), 4.6~ (2H, s), 5.16 (lH, d, J=5.OHz), 5.82 ~lH, dd, J=;.O and 8.0H~), 7.43 (lH, s), 8.51 (lH, s), 9.56 ~lH, d, J=8.0Hz) - (22-) -7-[2-(4-Fluorobenzyloxyimino)-2-{2-(2,2,2-. trifluoroacetamido)~hiazol-4-yl}acetamido~-3-(1-methyl-- l~-tet~azol-5-yl)-thiomethyl-;-cephem-4-c~rboxylic acid (syn isomer).

-I.-~. (Nujol)- : 3370, 3180, 1760, 1710, 1680, -3~ - 1650 cm ~
N.M.R. (DMSO-d6, ~) : 3.68 (2H, m), 3.92 ~3H, s), 4.32 (2H, m), 5.03-5.35 (3'~, m), 5.83 (lH, dd, J=5 and 8Hz), 6.99-7.70 (4H, m), 7.54 (lH, s), 3~ 9.87 (lH, d, Js8Hz) --1 33~522 C2~) 7-~2-E~hoxycarDonylmethoxyimino-2-(2-formamido-thiazol-i-yl) acetamido ] - 3-ClH-tetrazol-5;yl) t~Liomethyi -3-cephem-4-car~oxylic acid Csyn isome ), mp 112 to 125C
(de~.).

I. R. (Nujol) : 3250, 1770, 1730 ? 1680 cm 1 N.M.R. (DMSO-d6, ~) : 1.20 (3H, t, J=8Hz), 3.71 (2H, m), 4.07 (2H, q, J=8Hz), 4.36 (2H, m), 4.77 (2H, m~, 5.20 ~lH, d, J=SHz), 5.88 (lH, dd, --J=S and 8Hz), 7.50 (lH, s), 8.57 (lH, s), g.67 (lH, d, J=8Hz), 12.38 ~lH, broad s) .
(2~-) 7-~2-Benzyloxyimino-2-~2-aminothiazol-4-yl~-IS acetamido~-3-(lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 172 to 174C (dec.).

I. R. (Nujol) : 3250, 3150, 1`77Q, 1620 cm 1 N.M.R. (DMSO-d6, ~) : 3.67 ~2H, m), 4.33 C2H, m), 5.08-5.36 ~3H, m), 5.83 (lH, dd, - J=4 and 8Hz), 6.88 (lH, s), 7.3~ (5H, s), 9.73 ~lH, d, J=8Hz) (25) 7-[2-(4-Fluorobenzyloxyimino)-2-{2-~2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syrl iso~er). -I. R. (Nujol) : 3200, 177Q, 1720, 1650 cm 1 N.M.R. (DMSO-d6, ô) : 3.73 (2H, ABq, Jz18Hz), 4.49 (2H, ABq, J=14Hz), 5.03-5.46 ~3H, m), 5.88 (lH, dd, J=4 and 8Hz), 7.03-7.84 (4H, m), 7.59 ~lH, s), 9.60 (lH, s), 9.88 (lH, d, J=8Hz) 3~

(2~ 7-~2-Cinnamyloxyimino-2-(2-formamidothiazol-4-yl)acetamido~-3-(1,3,4-thiadiazol-2-yl)thiome;~yl-3-cephem-4-carboxylic acid ~syn isomer).

I. R. (Nujol) : 3400-3100, 1780, 1680, 1540 cm 1 N.M.R. (DMSO-d6, ~) : 3.67 ~2H, m), 4.45 (2H, ABq, J=14Hz), 4.83 (2H, d, J=5Hz), 5.18 (lH, d, J=SHz), 5.87 (lH, dd, J=5 and 8Hz~, 6.65 (lH, s~, 6.12-7.0 (2H, m), 7.1-7.7 ~5H, m), 8.S3 (lH, s), 9.57 (lH, s), 9.73 (lH, d, J=8Hz), 12.6 ClH, broad s) - (27) 7-~2-(4-Fluorobenzyloxyimino)-2-{2-(2,2,2- -trifluoroacetamido)thiazol-4-yl}acetamido~-3-(lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid - (syn isomer).

I. R. (Nujol) : 3200, 1780, 1730, 1660 cm 1 (2~ 7-~2-(4-Fluorobenzyloxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido3-cephalos-~ poranic acid (syn isomer).-I. R. (Nujol) : 3250, 1780, 1730, 166Q, 1630 cm N.M.R. (DMSO-d6, ~) : 2.07 (3H, s), 3.59 (2H, m), 4.90 (2H, ABq, J=14Hz), 5.13-5.46 (3H, m), 5.90 ~lH, dd, J=5 and 8Hz), 7.30-7.77 (4H, m), 7.58 (lH, s), ;~ 9.68 (lH, d, J=4.0Hz) (2g) 7-[2-(3,4-Dichlorobenzylo.xyimino)-2-{2-(2,2,2-trifluoroacetami-do)thiazol-4-yl}acetamido~-cephalospora-nic acid (syn isomer).

~ 251 -I. R. ~Nujol) : 1780, 1730, 1650 cm 1 N~M.R. ~DMSO-d6, ~) . 2.03 ~3H, s), 3.57 ~2H, m~, 4.87 ~2H, ABq, J=12Hz), 5.17-5.23 ~3H, m}, 5.~7 (tH, dd, J=6 and 8Hz), S 7.33-7.73 (4H, m), g.87 tlH, d, J=gHz~

(3O) 7-[2-~3-Hydroxy-4-bromobenzyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido~-3-(1,3,4-thiadiazol-: 2-yl)thiomethyl-3-cephem-4-carboxyllc acid (syn isomer).
~ I. R. (Nujol) : 3400-310~, 1780, 1680, 1540 cm 1 N.M.R. (DMSO-d6, ~) : 3.7 (2H, broad s~, 4.45 (2H, AB~, J-13~z), 5.13 (lH, d, J=~Hz), 5.18 (2H, s), 5.8Z ~lH, dd, J=S an~ 8Hz), -1~ 6.97 ~lH, d, J=2Hz), 7.4 ~lH, s), i.45 (l~,.d, J=8Hz), 8.5 (lH, s), - 9.68 (1~, d, J=8Hz), 12.6 (lH, broad s) :

~0 --- - - . .

- t~) 7-~2-(t-Butoxycarbonylmethoxyimino)-2-(2-aminothi~zol-4-yl)acetamido~-3-(lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

- --I-. R. (Nujol) : 3280, ~200, 1770, 1670, 1630 cm 1 (32) 7-[2-(4 -Fluoroben~yloxyimino) - 2 - (2 -aminothia~ol-4-yl)acetami~o~-3-(1-methyl-lH-tetra~ol-5-yl)-thiomethyl-3-cephem-4-ca~boxylic acid (syn isomer).

I. R. (Nujol) : 330a, 32ao, 177Q, 166Q, 162a, 160~-(3~ 7-[2-Ethoxycarbonylmethoxyimino-2-~2-aminothiazol-4-yl)acetamido~-3-(lH-tetra2O1-5-yl)thiomethyl-3-cepnem-4-carboxylic acid (syn isomer), m? 168 to 185C ~dec.~.

I. R. ~Nujol) : 3250, 1765, 1670, 1625 cm 1 (~4 7-~2-(¢-Fluorobenzyloxyimino)-2-~2-aminothiazol-4-yl)acetamido3-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-ceph~m-4-carboxylic acid (syn isomer), mp 145 to 14gC
(dec.).

1'- - I. R. (Nujol) : 3250, 1765, 1650 cm 1 1~5 ) 7- ~2-Cinnamyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1,3,~-thiadiazol-2-yl-~thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
~0 I. R. ~Nujol) : 3350-3100, 1760, 1650, 1620, 1520 cm 1 ~6) 7-~2-(4-Fluorobenzyloxyimino)-2-~2-aminothiazol-4-yl)acetamido~-3-(lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I. R. (Nujol) : 3300, 3200, 1770, 1660, 1630, 1600 cm 1 ~7 ) 7-[2-(4-Fluoroben~yloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-cephalosporanic acid ~syn isomer), mp 185 to 192CC (dec.~.

I. R. (Nujol) : 3380, 3250, 1780, 1700, 1650 cm 1 (~ 7-~2-C3,4-Dichlorobenzyloxyimino)-2-C2-- aminothiazol-4-yi)ace.amido~cephalosporanic acid ~syn isomer), mp 2Q0 to 205C ~dec.).

3 I. R. ~Nujol) : 1730, 16¢0, 160Q, 1230, 1020 cm (~g) 7-[2-(;-Hydroxy-4-bromobenzyloxyimino)-2-(2-~minothiazol-4-yl~acetamido]-3-(1,3,4-thiadiazol-2-yl~thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I. R. (Nujol) : 3400-3100, 1760, 1660, 1620, 1520 cm~l (40) 7-r2-Carboxymethoxyimino-2-(2-aminothiazol-4--15 yl)acetamido]-3-(lH-tetrazol-5-yl)thiomethyl-3-cep~em-4-carboxylic acid ~syn isomer), mp 178 to 190C (dec.) I. R. (Nujol) : 3300, 3280, 1770, 1670, 1630 cm 1 ~C -----.

-. . ; . -3~

_ 254 -Example S.D.21 A mixture of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.58 g.), conc. hydrochloric acid (0.405 g.), methanol (8.7 ml.) and tetrahydrofuran (5 ml.) was stirred for 2 hours and 10 minutes at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous solution of sodium hydroxide (pH 7~8.5). An insoluble material was filtered off and the filtrate was adjusted to pH 3.4 with 10% hydrochloric acid under ice-cooling and stirred for 30 minutes. Precipitates were collected by filtration, washed with water and dried to ~ive 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-y - 255 -1 33~52~
(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.4 g.).
I.R. (Nujol) : 3340, 3200, 1775, 1670 cm~
N.M.R. (d6-DMSO, ~) : 2.23 (3H, s), 3.74 (2H, s), 4.48 (2H, ABq, J=13Hz), 5.20 (lH, d, J=5Hz), 5.24 (2H, s), 5.83 (lH, d,d, J=5 and 9Hz), 6.83 (lH, s), 7.28 (2H, broad s), 9.62 (lH, s), 9.68 (lH, d, J=9Hz) ExamPle S.D.22 A mixture of 7-[2-t-butoxycarbonylmethoxy-imino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.3 g.), conc. hydrochloric acid (3.74 g.) and methanol (35 ml.) was stirred for 2 hours and 40 minutes at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous solution of sodium hydroxide (pH 7~8). The aqueous solution was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring and stirred for 30 minutes. Precipitates were collected by filtration, washed with water and dried to give 7-[2-t-butoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g.).
I.R. (Nujol) : 3300, 1775, 1730, 1675, 1630 cm~l N.M.R. (d6-DMSO, ~) : 1.46 (9H, s), 3.67 (2H, s), 4.42 (2H, ABq, J=14Hz), 4.55 (2H, s), 5.16 (lH, d, J=5Hz), 5.78 (lH, d,d, J=5 and 9Hz), 6.77 (lH, s), 7.21 (2H, s), 9.43 (lH, d, J=9Hz), 9.52 (lH, s) ~X

-~ 1 337522 ExamPle ~.~ 23 To a s~irred solution of sodium æcetate (2.7 g) in water ~46 ml) was added 7^[2-~4-1uorobenzyloxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}-acet~mido]-S 3-(1,;,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxyl~c acid (syn isomer) ~2.3 g) and the mixture w~s stirred for 20.5 hours at ambient temperature.
The reaction mixture w~s adjusted to pH 5.0 with 10%
hydrochloric acid af~er addition of ethyl acetate and the resulting mixture was shaken. The a~ueous layer was separated, w~shed twice with ethyl acetate and adjusted to pH 3.0 with 10% hydrochloric acid.
Precipitates were collected by .iltration, washed with water an~ dried to give 7-~2-(4-fluoro~enzyloxyimino~-1; - 2-~2-aminothiazol-4-yl)acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn isomer) (1.82 g), mp 145 to 149C (dec.).

I. R. (Nujol) : 3250, 1765, 1650 cm N.M.R. (DMSO-d6, ~) : 3.73 ~2H, ABq, 3=18Hz), 4.48 (2H, ABq, J=14Hz), S.Ql-5.3g (3H, m), 5.85 ~lH, dd, J=4 and 8Hz), 6.83 (lH, s), 7.02-7.75 (4H, m), 9.63 (lH, s), 9.75 ~lH, d, J=8Hz) .

3~

_ 257 -Example S.D.24 The following compounds were obtained accord-ing to similar manners to those of Examples S.D.21 to 23.
(1) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. ~Nujol) : 3320, 3200, 1770, 1670, 1610 cm~l (2) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-hexyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3250, 1780, 1680, 1633 cm~l (3) 7-[2-Methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thio-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3300, 1770, 1670, 1530 cm~
N.M.R. (d6-DMSO, ~) : 2.20 (3H, s), 3.72 (2H, s), 3.97 (3H, s), 4.36 (2H, s), 5.17 (lH, d, J=5Hz), d~
J~ ~ - 258 -~ ,~, .

-5.22(2H, s), 5.82 (lH, d,d, J=5 and 8Hz), 6.82 (lH, s), 7.28 (2H, broad s), 9.60 (lH, d, J=8Hz) (4) 7-[2-(2-Ethoxyethoxy)imino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3160, 3100, 1780, 1670, 1630 cm~l N.M.R. (d6-DMSO, ~) : 1.08 (3H, t, J=7Hz), 3.45 (2H, q, J=7Hz), 3.5~3.90 (4H, m), 4.20 (2H, t, J=4Hz), 4.47 (2H, ABq, J=13Hz), 5.17 (lH, d, J=5Hz), 5.80 (lH, d,d, J=5 and 8Hz), 6.77 (lH, s), 9.55 (lH, s), 9.55 (lH, d, J=8Hz) (5) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3220, 1780, 1680, 1630 cm~l N.M.R. (d6-DMSO, ~) : 1.23 (3H, t, J=7Hz), 3.70 (2H, s), 3.97 (3H, s), 4.16 (2H, q, J=7Hz), 4.35 (2H, s), 4.69 (2H, s), 5.15 (lH, d, J=5Hz), 5.80 (lH, d,d, J=5 and 9Hz), 6.81 (lH, s), 7.24 (2H, broad s), 9.54 (lH, d, J=9Hz) (6) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3230, 3100, 1780, 1680, 1630 cm~l X

N.M.R. (d6-DMSO, ~) : 1.21 (3H, t, J=7Hz), 3.72 (2H, ABq, J=18Hz), 4.18 (2H, q, J=7Hz), 4.70 (2H, s), 5.20 (lH, d, J=5Hz), 5.84 (lH, d,d, J=5 and 8Hz), 6.84 (lH, s), 7.26 (2H, broad s), 9.56 (lH, d, J=8Hz), 9.60 (lH, s) (7) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3340, 3200, 1775, 1675, 1630 cm~l N.M.R. (d6-DMSO, ~) : 3.68 (2H, s), 3.94 (3H, s), 4.32 (2H, ABq, J=14Hz), 4.70 (2H, s), 5.14 (lH, d, J=5Hz), 5.78 (lH, d,d, J=5 and 9Hz), 6.81 (lH, s), 7.1 (2H, broad s), 9.59 (lH, d, J=9Hz) (8) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350, 3230, 3110, 1775, 1675 cm~l N.M.R. (d6-DMSO, ~) : 3.71 (2H, ABq, J=18Hz), 4.46 (2H, ABq, J=14Hz), 5.17 (lH, d, J=5Hz), 5.27 (2H, s), 5.82 (lH, d,d, J=5 and 8Hz), 6.66 (lH, s), 6.83 (lH, s), 7.30 (2H, broad s), 8.87 (lH, s), 9.57 (lH, s), 9.75 (lH, d, J=8Hz) (9) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-30 yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3360, 3240, 3100, 1780, 1680, 1635 cm~

~0) 7-~2-Ben~yloxyimino-2-C2-aminothiazol-4-yl)-.. . . . . .
acetamidoJ-3-(lH-tetrazol-S-yl? t~iomethyl-3-cep~em-4-carboxylic 2cid (syn isomer~, mp ~72 to 174~ (dec.).

S I. R. ~Nujol) : 3250, 3150, 1770, 1620 cm 1 .. .i,~; .

: . - .
- : .

~0 ' .
(11) 7-~2-(t-Butoxycarbonylmethoxyimino~-2-(2-aminothiaz~l-4-yl)acetamido]-~-(lH-tet azol-S-yl)- -- thiomethyl-3-cephem-4-carboxylic acid (sy~ isomer).

I. R. (Nujol) : 3280, 3200, 1770, 1670-, 1630 cm 1 - . .
7-[2-(4-Fluoroben~yloxyimino)-2-~2-aminothiazol-4-yl)acetam~do~ -3- (l-methyl-lH-tetrazol-S-yl~-thiomethyl-~-cephem-4-carboxylic ~cid (syn isomer).
r. R. (Nujol) : 3300, 3200, 1770, 1660, 1620, - 1600 cm 1 N.M.R. (DMSO-d6, ~) : 3.67 ~2H, m), 3.94 ~3H, s), - 4.3Z (2H, m), 4.98-5.36 (3H, m), 3~ ~.78 (lH, dd, J=S and 8Hz), 6.72 (lH, s), _ 261 --6.95-7.65 (4H, m), 9.65 (lH, d, J=8Hz) (13) 7-2[2-Ethoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-(lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 168 to 185C
(dec.).
I.R. (Nujol) : 3250, 1765, 1670, 1625 cm~
N.M.R. (d6-DMSO, ~) : 1.21 (3H, t, J=7Hz), 3.70 (2H, broad s), 4.18 (2H, q, J=7Hz), 4.31 (2H, m), 4.72 (2H, broad s), 5.17 (lH, d, J=4Hz), 5.82 (lH, dd, J=4 and 7Hz), 6.83 (lH, s), 7.17 (2H, broad s), 9.57 (lH, d, J=7Hz) (14) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-amino-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145 to 149C (dec).
I.R. (Nujol) : 3250, 1765, 1650 cm~l (15) 7-[2-Cinnamyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-1(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3350-3100, 1760, 1650, 1620, 1520 cm~l N.M.R. (DMSO-d6, ~) : 3.47-3.97 (2H, m), 4.47 (2H, ABq, J=14Hz), 4.8 (2H, d, J=5Hz), 5.18 (lH, d, J=5Hz), 5.83 (lH, dd, J=5 and 8Hz), 6.83 (lH, s), 6.1-7.0 (2H, m), 7.08-7.72 (5H, m), 9.6 (lH, s), 9.72 (lH, d, J=8Hz) (16) 7-~2-(4-Fluorobenzyloxyimino)-2-(2-amino-thiazol-~: V

_.

4-yl)acetamido]-3- (lH-tetra~ol-5-yl~thiomethyl-3-cephem-4-carboxylic acid Csyn isomer).
.
I. R. ~Nujol) : 330a, 3200, 1770, 1660, 1630, 1600 cm 1 N.M.R. ~DMSO-d6, ~) : 3.69 (2H, ABa, 3=18Hz), 4. 35 (2H, ABq, J=15Hz), 4.93-5 .43 ~3H, m), 5 . 81 (lH, dd, J-5 and 8Hz), 6 . 80 ~lH, s), 6 .96-7. 70 ~4H, m~, 9. 73 (lH, d, J=8Hz) (:L7) 7- ~2- ~4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl)acetamido]cephalosporanic acid (sy~ isomer), mp 185 to 192C (dec.).

I. R. (NU3O1): 3380, ;250, 1780, 1700, 1650 cm N.M.R. (DMSO-d6, ~) : 2.Q2 (3H, s), 3.53 (2H, m), 4.84 (2H, ABq, J=13Hz), 5.13 (2H, s), 5.40 (lH, d, J=4Hz), 5. 79 (lH, dd, J=4 and 8Hz), 6 . 73 (lH, s), Z0 6.96-7.63 (4H, m), 9.62 (lH, d, J=8Hz) C~8) 7~ [2- (3,4-Dichlorobenzyloxyimino)-2-(2-amino-thiazol-4-yl)acetamido] cephalosporanic acid- ~syn isomer), mp 200 to 205C ~dec.).
2~
I. R. (Nujol): 1730, 1640, 16û0, 1230, 1020 cm 1 - N.M.R. (DMSO-d6, ~) : 2.00 (3H, s~, -3.30 (2H, ABq, J=18Hz), 4 . 68-5 . 12 ~5H, m), 5 .60 (lH, dd, J=6 and 8Hz), 6. 72 (lH, s), 3a 7. 3Z- 7. 64 (3H, m), 9 . 60 (lH, d, J=8Hz) ( 1~3 7- [2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl3-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
3~

_ 263 --3~52~ .
- I. R. (Nujol): 3400-31Q0, 17~0, 1660, 1620, 1520 cm N.M.R. ~DMSO-d6? ~) : 3.72 C2H, broad s)~
4.47 (2H, ABq, J=14Hz), S.l (lH, d, J=5Hz), 5.22 (2H, s~, 5.83 ~lH, dd, J=5 and 8Hz), 6.85 (lH, s), 6.87 ~lH, dd, J-2 and 8Hz), 7.08 (lH, d, J=2Hz), 7.52 (lH, d, J=8Hz), 9.67 (lH, s), 9.77 ~lH, d, J=8Hz) - (~O ) 7-t2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 178 to 180C (dec.).-- I. R. ~Nujol): 3300, 3280, 1770, 1670, 1630 cm 1 -, ~ 20 -~ -2~ -;~

.

_ 264 -ExamPle S.D.25 Trifluoroacetic acid (4 ml.) was added under ice-cooling to a stirred suspension of 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.0 g.) in anisole (1 ml.), and the resultant mixture was stirred for 70 minutes at ambient temperature. The reaction mixture was concentrated under reduced pressure and diethyl ether was added thereto. Precipitates were collected by filtration, washed with diethyl ether, dried, suspended in water (10 ml.) and then dissolved in a 10% aqueous solution of sodium hydroxide (pH 7-7.5). The solution was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring and stirred for 30 minutes under ice-cooling. Precipitates were collected by filtration, washed with water and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.75 g.).
I.R. (Nujol) : 3360, 3240, 3100, 1780, 1680, 1635 cm~l N.M.R. (d6-DMSO, ~) : 3.68 (2H, s), 4.46 (2H, ABq, J=15Hz), 4.61 (2H, s), 5.17 (lH, d, J=5Hz), 5.82 (lH, d,d, J=5 and 9Hz), 6.83 (lH, s), 7.23 (2H, broad s), 9.50 (lH, d, J=9Hz), 9.53 (lH, s) ExamPle S.D.26 The following compounds were obtained accord-ing to a similar manner to that of Example S.D.25.

_,_ (1) 7-[2-Carboxymethoxyimino-2-(2-formamido-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3200, 1780, 1720, 1680, 1545 cm~l N.M.R. (d6-DMSO, ~) : 3.72 (2H, ABq, J=16Hz), 3.96 (3H, s), 4.35 (2H, ABq, J=14Hz), 4.67 (2H, s), 5.17 (lH, d, J=5Hz), 5.86 (lH, d,d, J=5 and 9Hz), 7.47 (lH, s), 8.52 (lH, s), 9.64 (lH, d, J=9Hz), 12.64 (lH, broad s) (2) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3340, 3200, 1775, 1675, 1630 cm~l (3) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 178 to 180C (dec.).
I.R. (Nujol) : 3300, 3280, 1770, 1670, 1630 cm~l N.M.R. (DMSO d6, ~) : 3.69 (2H, m), 4.32 (2H, ABq, J=14Hz), 4.60 (2H, m), 5.14 (lH, d, J=5Hz), 5.79 (lH, d,d, J=5 and 8Hz), 6.79 (lH, s), 9.47 (lH, d, J=8Hz) ~ ~r ~.

Ex-ample ~);27 7-~2-(4-Fluorobenzyloxyimino)-2-~2-aminot~iazol-4-yl)acetamido]cephalosporanic acid ~syn isomer) (1.1 g) and 1,3,4-thiadiazole-2-thiol ~0.2~ g) were added to a S stirred solution of sodium ~icarbonate (0.34 g) in pH
6.8 phosphate buffer ~30 ml) and the mixture was stirred for 3 hours at 60 .o 65C. The reaction mixture was cooled and adjusted to pH 3 with 10% hydrochloric acid.
Precipitates were collected by filtration, washed with water and dried to gi~e 7-~2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acet~amido~-3-(1,3,4-thiadiazol-2- --yl)thiomethyl-~-cephem-4-carboxylic acid (syn isome~) (0.45 g), mp 145 to 149C ~dec.).
-1~ I. R. (Nujol) : 3250, 1765, 1650 cm 1 N.M.R. (DMSO-d6, ô) : 3.73 ~2H, 4Bq, J=18Hz), 4.48 (2H, ABq, J-14Hz), 5.01-5.39 (;H, m), 5.85 (lH, dd, J=4 and 8~z), 6.83 (lH, s), 7.02-7.7~ (4H, m), 9.63 (lH, s), 9.75 (lH, d, Jz8Hz) mT-le ~ 2~ -The following compounds were obtained according to a similar manner to that of Example ~.D.27, ~1~ 7-t2-Methylthiomethoxyimino-2-(2-.ormamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I. R. (Nujol~: 3230, 1780, 1680, 1550 cm 1 (2) 7-t2-Benzyloxyimino-Z-(2-aminothiazol-4-yl)-acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomet~yl-3-cephem-3S 4-carboxylic acid (SyIl isomer).

_ 267 -I. R. (Nujol) : 332Q, 320~, 1770; 1670, 1610 cm 1 (3) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-forma2ido-thiazol-4-yl)acetamido]-3-~1,3,4-thiadia7O1-2-y~-S thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I. R. (Nujol) : 3225, 1780, 1725, 1685, 1550 cm 1 (4) 7-[2-Methylthiomethoxyimino-2-~2-formamidothiazol-- 4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I. R. (Nujol) : 3250, 1780, 1675, 1550 cm 1 1~ (5) 7-~2-(2-Ethoxyethoxy)imino-2-(2-formamidothiazol-4-yl)acetamidoJ-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

.
I. R. (Nujol) : 3500, 3200, 1780, 1720, 1680 cm 1 (6) 7-~2-Ethoxycar~onylmethoxyimino-2-(2-formamido-thiazol-4-yl)ace.amido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic æcid (syn isomer).

2S I. R. (Nujol) ; 3250, 1775, 1720, 1680t 1540 cm 1 - (7) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-formamido-thiazol-4-yl)acetamido]-3-~1-methyl-lH-tetrazQl-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I. R. (Nujol) : 3250, 1780t 1725, 1680, 154~ cm 1 ~8) 7-~2-t-ButDxycarbonylmethoxyimino-2-(2-formamido-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetr~ol-5-yl)-3~ thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

- _ 268 -I. R. CNujoll . 318~, 1785, 1725, 1690, 1~50 cm l -(9) 7-~2-Benzyloxyimino-2-~2-aminothiazol-4-yl)-acetamido~-3-(1-hexyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn isomer).

I. R. (Nujol) : 3350, 3250, 1780, 1680, 163a cm 1 ~10) 7-[2-(3-Isoxazolyl)methoxyimino-2-~2-formamido-thiazol-4-yl)acetamid~1-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I. R. (Nujol) : 3200, 1775, 1675, 1540 cm 1 (11) 7-~2-Methylthiomethoxyimino-~-(2-aminothiazol-4-yl)acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethy}-3-;cephem-4-carboxylic acid ~syn isomer).

I. R. ~Nujol) : 3340, 3200, 1775, 167~ cm 1 ~12) 7-~2-Methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido~-3-(1-methyl-lH-tetrazol-S-yl)thiome.hyl-3-cephem-4-carboxylic acid ~syn isomer).

I. R. ~Nujol) : 3300, 177G, 1670, 153B cm 1 ~13) 7-[2-(2-Ethoxyethoxy)imino-2-(2-aminothiazol-- 4-yl)acetamido]-3~ ,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn isomer).
I. R. ~Nujol) : 3160, 3100, 1780, 1670, 1630 cm 1 (14~ 7-~2-Ethoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)ace;amido~-3-tl-methyl-lH-tetrazol-5-yl~-thiomethyl-3-cephem-4-carboxylic acid ~syn isomer).

_ 269 -I. R. (Nujol) : 3350, 322Q, 17~, 168Q~163Q cm..l (lS) 7-[2-Ethoxycarbonylmethoxyimino-2-C2-aminothiazol-4-yl)acetamido]-3-~1,3,4-thiadiazol-2-yl)-t~iomethyl-3-S cephem-4-carboxyllc acid (s~ isomer).

I. R. (Nujol) : 3a50, 3230, 3100, 1780, 1680, 1630 cm 1 (16) 7-[2-t-Butoxyc2rbonylmethoxyimino-2-(2-amino-thia ol-4-yl)acetamido~-3-~1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

. I.. R. ~Nujol~ : 3300, 1775~ 1730, 1675, 1630 cm I
(17) 7-~2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido~-3-~1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic.acid (syn isomer).

I. R. ~Nujol) : 3340, 3200, 1775, 1675, 1630 cm 1 (18~ 7-~2-~3-Isoxazolyl)methoxyimino-2-~2-amino-thiazol-4-yl)acetamidoJ-3-~1,3,4-thiadiazol-2-yl3-thiomethyl-3-cephem-4-c~rboxylic acid ~syn isomer).
~
- I. R. ~Nujol) : 3350, 3230, 3110, 1-775, 1675 cm 1 .

(19) 7-~2-Carboxymethoxyimino-2-~2-formamidothiazol-4-yl)acetamido]-;-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I. R. (Nu~ol) : 3200, 1780, 1720, 1680, 1545 cm 1 (20) 7-[2-Carboxymethoxyimino-2-~2-aminothiazol-4-yl)acetamido~-3-~1,3,4-thiadiazol-2-yl)thiomethyl-3-~' ~3 .

` - 1 337522 .

cephem-4-cærboxylic acid Csyn isomer).

. .
I. R. (Nujol) : 3360, 3240, 3100, 1780, 1680, 1635 cm 1 .5 (21) 7-[2-(t-Butoxycarbonylmethoxyimino)-2-~2-formamidothiazol-4-yl)acetamido]-3-(lH-.etrazol-S-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

- 10 I. R. ~Nujol) : 3170, 1770, 1720, 1670 cm 1 (22) 7-~2-Ethoxycarbonylmethoxyimino-2-(2-formamido-thizzol-4-yl)acetamido]-3-(lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic-acid ~syn isomer), mp 112 to 125C
(dec.).

I. R. (Nujol) : 3250, 1770, 1730, 1680 cm 1 (23) 7-~2-Benzyloxyimino-2-~2-aminothiazol-4-yl)-acetamido]-3-(lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 172 to 174C (dec.).

I. R. (Nujol) : 3250, 3150, 1770, 1620 cm 1 (24) 7-~2-Cinnamyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3~ ,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I. R. ~Nujol) : 3400-;100, 1780, 1680, 1540 cm - (25) 7-~2-~3-Hydroxy-4-bromobenzyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(l~3~4-thiadiazol-2 yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I. R. (Nujol) : 3400-3100, 1780, 1680, 1540 cm 1 ~i _ 271 -t 337522 (26) 7-[2-(t-Butoxycarbonylmethoxyimino)-2-~2--10 aminothiazol-4-yl)acetamido]-3-(lH-tetrazol-5-yl)-thiomethyi-3-cephem-4-carboxylic acid ~syn isomer).
.
I. R. ~Nujol) : 3280, 3200, 1770, 1670, 1630 cm 1 t2~) 7-[2-(4-Fluorobenzyloxyimino~-2-(2-aminothiazol-- 4-yl)acetamido3-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-- 3-cephem-4-carboxylic acid ~syn isomer). :-:- - -.
I. R. ~Nujol) : 3300, 3200, 1770, 1660, 16Z0, ~ - 1600 cm I

(28) 7-~2-Ethoxycarbonylmethoxyimino-2-(2-amino.hiazol-4-yl)acetamido~-3-(lH-~etrazol-S-yl)thiomethyl-;-c~phem-4-carboxylic acid ~syn isomer), mp 168 to 185C (dec.).--- - I. R. (Nujol) : 3250, 1765, 1670, 1625 cm 1 ~-(2g) 7-t2-clnnamyloxyimino-2-~2-aminothiazol-4-yl)-acetamido]-3-~1,3,4-thiadiazol-2-yl)thiomethyl-~-cephem-4-carboxylic acid ~syn isomer).

I. R. ~Nujol) : 335~-3100, 1760, 1650, 16Z0, - - , ,' . ' ~O) 7-t2-(4-Fluorobenzyloxyimino)-2-(2-aminothiazol-_ 272 --1 33;7522 - 4-yl)acetamido~-3-~lH-tetra7O1-5-yl)thiomethyl-3-cephem-- . 4-carboxylic acid Csyn isomer).

. .
I. R. ~Nujol) : 3300, 3200, 1770, 1660, 1630, 160Q cm-l .
(3~ 7-~Z-(3-Hydroxy-4-bromo~enzyloxyimino)-2-~Z-aminothia7O1-4.-yl)acetamido~-3-~1,3,4-`t~iadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
- I. R. (Nujol) : 3400-310.0, 1760, 1660, 16Z0, 1520 cm~l .~ (3~ 7-t2-Carboxymethoxyimino-2-~2- minothiazol-4--I~ yl)acet~mido~-3-(}H-tetrazol-S-yl)thiomethyl-3-cephem-4-car~oxylic acid (syn isomer), mp 178 to 180~ (dec.).

I. R. ~Nujol) : 3300, 3280, 1770, 1670, 1630 cm 1 ~0 2~ . .
'- ' - -' ;O

-3~ .
. - 273 - -Exam~le ~ ~2q 1 337522 Phosphorus oxychloride (974 mg) was added dropwise over 3 minutes at -5 to -10C to a solution of dimethylformamide ~464 mg) in tetrahydrofuran ~â ml).
S Tetrahydrofuran (12 ml) was added thereto and ~rter 10 minu.es, 2-cyclopentyloxyimino-2-~2-formamido-thiazol-4-yl)acetic acid ~syn isomer)(1.5 g) ~as added thereto at -5 to -10~C. The mixture was stirred for 10 minutes to give ~ clear solution. On the other 1-0 hand, 7-amino-3-~,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.27 g) was dissolved under stirring in a solution of triethylamine (1.3 g) in 50~ aqueous acetone (2a ml).
- To the solution was added dropwise with st;rring the tetrahydrofuran solution obtained above at 0 to 5C
and at pH 6.5 to 7.5. After-stirring for 30 minutes a, the same temperature, the reaction mixture ~as poured in.o a mixture of ~-ater and ethyl acetate and adjusted to pH 3.0 with 10% hydrochloric acid. After filterrirg off an insoluble material, the filtrate was twice extracted with ethyl acetate. The extracts - were washed 3 times with a saturated a~ueous solution of sodium chloride and dried over magnesium sulfate.
The solvent was distilled off and the residue was triturated with diethyl ether, collected by filtration and d,ied to give 7-[2-cyclopentyloxyimino-2-(2-formamidothiazol-4-yl)acetamidol-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer~(2.8 g).
1. R. (Nujol) : 3240, 3180, 1780, 1670, 1540 cm - 274 _ ` t 337522 N.M.R. ~DMSO-d6, ô~ : 1.2-2.3 (8H, m), 3.72 (2H, s), 4.45 ~2H, A~q, J=14Hz), 4.74 ~lH, -' broad s), 5.17 (lH, d, J=SHz), 5.82 (lH, dd, J=S and 8Hz), 7.36 (lH, s), 8.56 ~lH, s~, 9.52 ~lH, s), 9.55 (lH, d, J=8H ), 12.56 ~lH, broad s) Exam~le S ~30 The following compounds were obtained according to a similar manner to that of Example ~ ~ 29 ~1) 7-[2-Cyclopentyloxyimino-2-{2-~2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido~cephalosporanic acid (syn isomer), powder.

~2) 7-[2-Cyclopentyloxyimino-2-(2-aminothiazol-4-yl)-- 15 acetamidolcephalosporanic acid ~syn isomer).
I.R. ~Nujol~ : 3270, 1760, 1650 cm 1 N.M.R. ~D~ISO-d6,~) : 1.27-2.17 (8H, m), 2.04 ~3H, s), 3.58 ~2H, m), 4.74 ~lH, m), 4.87 (2H, ABq, J=13.0Hz~, 5.17 (lH, d, J=4.0Hz), 5.82 (lH, dd, J=4.0 and 8.0Hz), 6.74 (lH, s), 9.54 (lH, d, 3=8.0H7).

(3) 7-~2-Cyclopentyloxyimino-2-(2-formamidothia201-4-yl)acetamido~-3-(lH tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol) : 3150, 1770, 1660 cm 1 N.~.R. (D~SO-d6,o~ : 1.37-2.33 ~8~, m), 3.75 (2H, m), 4.38 (2H, ABq, J=14.0Hz), 4.7~ (lH, m), 5.21 (lH, d, J=S.OHz), 5.88 (lH, dd, J=S.O and 8.0Hz), 1 _ - 275 -7.42 (lH, s), 8.56 (lH, s), 9.62 (lH, d, J=8.OHz) ~4) 7-~2-Cyclopentylo~yimino-2-(2-aminothiazol-4-yl)-S acetamido~-3-(lH-tetrazol-S-yl)thiomethyl-a-cephem-4-czrbo~ylic acid (syn isomer), mp 185 to 190C (dec.).
I.R. (~ujol) : 3260, 1760, 1640 cm 1 N.M.R. (DMSO-d6,~) : 1.17-2.30 (8H, m), 3.71 (2H, ABq, J=18.0Hz), 4.32 (2H, ABq, J=13.0Hz), 4.68 (lH, m), 5.14 (lH, d, J=4.0Hz), 5.76 tlH, dd, J=4.0 and 8.0Hz), 6.71 (lH, s), 9.SO (lH, d, J=8.0Hz) ~S} 7-[2-Cyclopentyloxyimino-2-{2-(2,2,2-lS trifluoroacetamido)thiazol-4-yl}acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Mujol) : a200, 1780, 1720, 1680, 1625 cm 1 N.M.R. ~DMSO-d6,~) : 1.34-2.23 (8H, m), 3.77 ~2H, m), 3.98 ~3H, s), 4.;6 (2~, m), 4.78 (lH, m), 5.21 (1~, d, J=4.0Hz), 5.87 (lH, dd, J=4.0 and 8.0Hz), 7.52 (lH, s), 9.71 ~lH, d, J=8.0Hz) (6) 7-~2-Cyclopentyloxyimino-2-(2-aminothia:ol-4-yl)-acetamido~-3-(1-me.hyl-lH-tetrazol-S-y~)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 152 to 154C
(dec.).
I.R. ~Nu3ol) : 3aOO, ;200, 1770, 1660, 1620 cm 1 N.M.R. (D~ISO-d6,~) : 1.28-2.11 (8H, m), .

~ 337522 - 3.74 (2H, m), 3.97 ~3H, s~, 4.35 (ZH, m), 4.72 (lH, m), 5.17 (lH, d, J=S.OHz), 5.80 (lH, dd, J=S.O and 8.0Hz), 6.74 (lH, s), 9.54 (lH, d, J=8.0Hz) (7) 7-[2-Cyclopentyloxyimino-2-(2 -2mi nothiazol-4-yl)acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn isomer~.
I.R. (Nujol) . 3260, 1760, 1645, 1520 cm 1 N.M.R. (DMSO-d6,~) : 1.2-2.3 ~8H, m), 3.69 ~2H, s), 4.43 ~2H, ABq, J=14Hz), 4.66 ~lH, broad s), 5.12 ~lH, d, J=SHz), 5.73 ~lH, dd, J=5 and 8Hz), 6.67 (lH, s), 7.17 (2H, broad s), 9.43 ~lH, d, J=8Hz), 9.Sl (lH, s) Example ~ 31 Conc. hydrochloric acid (1.8 gJ was added to a solution af 7-~2-cyclopentyloxyimino-2-(2-formamidothia~ol-4-yl)acetamido~-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.7 g) in methanol (27 ml) and the mixture was stirred for 2 hours at ambient tempera.ure. An insolu-ble material was filtered off and ;he filtrate was concen~ra;ed to dryness under reduced pressure and the residue was triturated with diethyl ether and dried to give 7-[2-cyclopentylo~yimino-2-~2-amino~hia_ol-4-yl)acetamido]-3-~1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carbo~ylic acid hydrochloride (syn isomer)(2.9 g). The powder (2.9 g) was dissol~ed ~ 277 _ - ~ 1 337522 ~ in an aqueous solution of sodium hydroxide to adjust pH 7.5. The solution was adjusted to pH 3.0 and ~' pTecipitates were collected by filtration and washed with water to give 7-[2-cyclopentylo~yimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,~,~-.hiadia ol-2-yl)thi~methyl-~-cephem-4-carbo~ylic acid (syn isomer) ~1.95 g)-I.R. (Nujol~ 3260, 1760, 1645, 1520 cm 1 N-M-R- ~DMS0-d6,~) : 1.2-2.3 ~8H, m), 3.69 (2H, s~, 4.43 ~2H, ABqr J=14Hz), 4.66 (lH, broad s~, 5.12 (lH, d, J=SH~), 5.73 (lH, dd, J=S and 8Hz), 6.67 ~lH, s), 7.17 (2H, broad s), 9.43 ~lH, d, J=8Hz), 9.51 (1~, s) Example ~ 32 7-[2-~yclopentyloxyimino-2-{2-(2,2,2-;rifluoroacetamido)thiazol-4-yl}acetamido]-3-(1-methyl-lH-tetra70l-;-yl)thiomethyl-3-cephem-4-carboYylic acid (syn isomer)(2.~ g) was added to a - solution of sodium acetate trihyd!rate (5.8 g) in water ~25 ml), and tetrahydrofuran ~8.0 ml) was added thereto to give clear so1ution. The solution-was stirred for 16 hours at ambient temperature.
To the reaction mixture were added water and ethyl acetate and the mi~ture was adjus.ed to pH 6.2 with a saturated aqueous solution of sodium bicarbonate.
The separated aqueous layer was washed twice with ethyl acetate and adjusted to pH 3.0 with 10% hydro-- ~ chloric acid. PIecipitates were collected by , _ 2Z8 -~.
filtration, wasned with water and dried under reduced pTessure to give 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido~-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.63 g), mp 152 to 154CC ~dec.).
I.R. (Nujol) : 3300, 3200, 1770, 1660, 1620 cm 1 N.M.R. (DMSO-d6,~) : 1.28-2.11 (8H, m), 3.74 (2H, m), 3.97 (3H, s), 4.35 (2H, m), 4.72 (lH, m), 5.17 (lH, d, J=5.0Hz), 5.80 ~lH, dd, J=5.0 and 8.0Hz), 6.74 (lH, s), 9.54 (lH, d, J=8.0Hz) Exam~le S~33 The following compounds were ob~ained according to similar manners to those of Examples ~iD 31 o~d 32.
(1) 7-~2-Cyclopentyloxyimino-2-(2-aminothiazol-4-yl)ace.amido~cep'nalosporanic acid (syn isomer).
I.R. (Nu~ol) : 3270, 1760, 165~ cm 1 ~.M.R. (DMSO-d6,~) : 1.27-2.17 (8H, m~, 2 . 04 (3H, s), 3.58 (2H, m), 4.74 (1~, m), 4.87 (2H, ABq, J=13.0Hz), 5.17 (lH, d, Jz4.0Hz), 5.82 (lH, dd, J=4.0 and 8.0Hz) - 6.74 (lH, s), 9. 54 ~lH, d, J=8.OHz) 25 (2) 7- [2-Cyclopentyloxyimino-2- (Z-aminothia~ol-4-yl)ace.amido~-3-(1~-tet.azol-5-yl3thiomethyi-3-cephem-4-carbo~ylic ~cid (syn isomer), mp 18~ to 190C ~dec.).
I.~. (Nu301) : 3260, 1760, 1640 cm 1 N.M R. ~DMSO-d6,~) : 1.17-2.30 (8H, m), ..~
3.71 (2H, ABq, J=18Hz), 4.32 (2H, ABq, J=13.0H~, 4.68 (lH, m), 5.14 (lH, d, 3=4.OH7), 5.76 (lH, dd, J=4.0 and 8.OHz), 6.71 (lH, s), 9.50 (1~, d, J=8.0Hz) (3) 7-~2-Cyclo entylo~imino-2-(2-a~inothi~zol-4-yl)-acetamido]-3-(1-allyl-IH-tetrazol-5-yl)thiometh~1-3-cephem-4-carbox~lic acid (syn isomer), mp 140 ~o ~45 ~(dec.).
I R (~ujol): 3300, 1770, 1660, 1620 cm ~
N M R (d6-DMSO,~ 6-2.26(8~, n), 3.73 (2H, m), 4.41(2H, ABq, J=14Hz), 4.68(1H, m), 4.89-5.52(5H, m), 5.62-6.43(2~, m), 6.73(1~, s), 9.51(1H,d, J=8Hz) E~ample S. D. 34 - -The following compound was obtained according t~
a s;~ r manner to that of E~ample S.D. 29 or Example S.D. ~1.
7-[2-Cyclohe~yloxyimino-2-(2-aminothiazol-4-yl)acet-amido~¢ephalos~oranic acid (syn isomer).
I P~ (~ujol): 3400-3200, 1780, 1740, 1670, 1630, 1530 cm 1 N M R (d6-DMSO,~): 9.~6 (lH, d,J=8Hz), 6.72 (lH, s), 5.76 (lH, ad, J=5 and 8 Hz), 5.10 (LH, d, J=5Hz), 1.84 (2H, ABq~ J=13Hz), 4000 (lH, m), 3,50 (2~, broad s), 2.00 (3H, s), 1.00-2.00 (lOH, m) ~ 337522 PreParation S.D.8 The following compounds were obtained in any of a similar manner to those of aforesaid Preparations.
(1) Ethyl 2-cyclopentyloxyimino-3-oxobutyrate (syn isomer), oil.
I.R. Film : 1740, 1670, 1495, 1430 cm~
max N.M.R. ~(CC14, ppm) : 1.32 (3H, t, J=7Hz), 1.4-2.2 (8H, m), 2.33 (3H, s), 4.27 (2H, q, J=7Hz), 4.87 (lH, m) (2) Ethyl 4-chloro-2-cyclopentyloxyimino-3-oxobutyrate (syn isomer), oil.
I.R. Film : 1735, 1750, 1465, 1435 cm 1 max N.M.R. ~(CC14, ppm) : 1.33 (3H, t, J=7Hz), 1.3-2.4 (8H, m), 4.28 (2H, q, J=7Hz) 4.46 (2H, s~, 4.86 (lH, s) (3) Ethyl 2-(2-aminothaizol-4-yl)-2-cyclopentyloxyiminoacetate (syn isomer), mp. 134 -136C.
I.R. Nujol : 3490, 3450, 3250, 3120, 1735, ~max 1540, 1460 cm~l N.M.R. ~(DMSO-d6) : 1.25 (3H, t, J=7Hz), 1.62 (8H, broad s), 4.27 (2H, q, J=7Hz), 4.70 (lH, m), 6.85 (lH, s), 7.20 (2H, s) (4) 2-(2-Aminothiazol-4-yl)-2-cyclopentyloxy-iminoacetic acid (syn isomer), mp. 186C (dec.).
I.R. Nujol : 3330, 3120, 1635, 1450 cm~
max N.M.R. ~(DMSO-d6) : 1.1-2.2 (8H, m), 4.68 (lH, m), 6.81 (lH, S), 7.18 (2H, broad s).

'~ X

l5) 2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-cyclopentyloxyiminoacetic acid (syn isomer).
I.R. Nujol : 3200, 3130, 1720, 1590, 1580 cm~
max N.M.R. ~(DMSO-d6) : 1.34-2.22 (8H, m), 4.81 (lH, m), 7.71 (lH, s) (6) 2-Allyloxyimino-2-(2-formamidothiazol-4-yl)-acetic acid (syn isomer).
I.R. (Nujol) : 3110, 1730, 1660, 1540 cm~l N.M.R. (d6-DMSO, ~) : 4.70 (2H, m), 4.13-5.60 (2H, m), 5.73-6.27 (lH, m), 7.57 (lH, s), 8.35 (lH, s) (7) To acetic anhydride (32 g.) was added formic acid (14.4 g.) under ice-cooling and stirred at 40 to 45C for an hour. 2-(2-Aminothiazol-4-yl)-2-cyclo-pentyloxyiminoacetic acid (syn isomer, 20 g.) and tetrahydrofuran (100 ml.) were added to the solution under ice-cooling and stirred at 35C for 3 hours.
After the solution was concentrated in vacuo, the residue was pulverized with diisopropyl ether, and dried over phosphorus pentoxide to give 2-(2-formamidothiazol-4-yl)-2-cyclopentyloxyiminoacetic acid (syn isomer, 9 04 g ?, mp. 158C (dec.).
I.R. Nujol : 3100, 1730, 1695, 1685, 1550, max 1495 cm~l N.M.R. ~(DMSO-d6) : 1.2-2.3 (8H, m), 4.77 (lH, quintet, J=4Hz), 7.93 (lH, s), 9.37 (lH, s).
Preparation S.D.9 The following compound was obtained in any of a similar manner to those of aforesaid Preparations. 2-Cyclohexyloxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer), mp 148C (dec.).

Claims

1. A process for preparing syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds of the formula:

in which R1 is a group of the formula wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkyl-amino;
a group of the formula:

wherein R7 is amino, protected amino, hydroxy or lower alkyl; or a group of the formula:

wherein R8 is lower alkyl and R9 is imino, protected imino or oxo;
R2 is an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, aryl which may have halogen or halogen and hydroxy, acyloxy, lower alkoxy, aryloxy substituted with hydroxy, thienyl and isoxazolyl;
R3 is carboxy or protected carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl or a heterocyclic-thiomethyl group which may have lower alkyl, lower alkenyl or di(lower)alkylamino(lower)-alkyl; or R3 and R4 are linked together to form -COOCH2-, with the proviso that R4 is not 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl or 5-methyl-1,3,4,-thiadiazol-2-ylthiomethyl, when R1 is 2-amino-1,3-thiazol-4-yl, R2 is methyl and R3 is carboxy, or pharmaceutically acceptable salts thereof, which comprises a) reacting a compound of the formula:

wherein R3 and R4 are each as defined above, or its reactive derivative at the amino group or a salt thereof, with a substituted acetic acid of the formula:
wherein R1 and R2 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof, with the proviso that 1) R4 is not acetoxymethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl or 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl and R2 is methyl,

2) R4 is not acetoxymethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl and R2 is ethyl, and

3) R4 is not acetoxymethyl or 1-methyl-1H-tetrazol-5-ylthiomethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl and R2 is allyl, or b) subjecting a compound of the formula:

wherein R2, R3 and R4 are each as defined above and R1a is a group of the formula:

in which R7a is protected amino; or a group of the formula:

in which R8 is as defined above and R9a is protected imino; or a salt thereof, to an elimination reaction of the protective group of the amino or imino by hydrolysis, reduction or a method by reacting it with an iminohalogenating agent and an imino-etherifying agent, to give a compound of the formula:

wherein R2, R3 and R4 are each as defined above and R1b is a group of the formula:

or a group of the formula:

in which R8 is lower alkyl; with the proviso that 1) R4 is not acetoxymethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl or 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino-1,3-thiazol-

4-yl and R2 is methyl, 2) R4 is not acetoxymethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino-1,3-thiazol-4-yl and R2 is ethyl, and 3) R4 is not acetoxymethyl or 1-methyl-1H-tetrazol-5-ylthiomethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino-1,3-thiazol-4-yl and R2 is allyl, or pharmaceutically acceptable salts thereof; or c) reacting a compound of the formula:

wherein R2, R3 and R4 are each as defined above and R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy, or a salt thereof, with a compound of the formula:
R-OH
wherein R is acyl or reactive derivative thereof, or with an isocyanate or with an isothiocyanate or with a haloformate, to give a compound of the formula:

wherein R5a is hydrogen, halogen, nitro, lower alkoxy or acyloxy; R6a is acyloxy;
and R2, R3 and R4 are each as defined above, or pharmaceutically acceptable salts thereof; or d) subjecting a compound of the formula:

wherein R1, R3 and R4 are each as defined above and R2a is a protected carboxy-(lower)-alkyl, or a salt thereof, to an elimination reaction of the protective group of the carboxy by hydrolysis, to give a compound of the formula:

wherein R1, R3 and R4 are each as defined above and R2b is carboxy-(lower)-alkyl; or pharmaceutically acceptable salts thereof; or e) subjecting a compound of the formula:

wherein R1, R2 and R3 are each as defined above and R4a is a protective group of amino, or a salt thereof, to an elimination reaction of the protective group of the amino using a base, an acid, a basic alumina or a basic ion exchange resin, to give a compound of the formula:

wherein R1, R2 and R3 are each as defined above, or pharmaceutically acceptable salts thereof; or f) reacting a compound of the formula:

wherein R1, R2 and R3 are each as defined above and R4b is a group which can be substituted by a group R4c-S- wherein R4c is a heterocyclic group which may have lower alkyl, lower alkenyl or di-(lower)-alkylamino(lower)alkyl, or a salt thereof, with a compound of the formula:
R4c - SH
wherein R4c is as defined above or its reactive derivative at the mercapto group, to give a compound of the formula:

wherein R1, R2, R3 and R4c are each as defined above, with the proviso that R4c is not 1-methyl-IH-tetrazol-5-yl, 1-(2-dimethylaminoethyl)-1H-tetrazol-

5-yl or 5-methyl-1,3,4-thiadiazol-2-yl, when R1 is 2-amino-1,3-thiazol-4-yl, R2 is methyl and R4b is acetoxy, or pharmaceutically acceptable salts thereof; or g) treating a compound of the formula wherein R1 and R2 are each as defined above and R3 is carboxy or protected carboxy, or a salt thereof, with an acid, to give a compound of the formula:

wherein R1 and R2 are each as defined above, or pharmaceutically acceptable salts thereof; or h) oxidizing a compound of the formula:

wherein R1, R2 and R3 are each as defined above or a salt thereof, to give a compound of the formula:

wherein R1, R2 and R3 are each as defined above, or pharmaceutically acceptable salts thereof; and if desired, converting the resulting compounds defined above to pharmaceutically acceptable salts thereof.

2. A process for preparing syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds of the formula:

in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino;
a group of the formula:

wherein R7 is amino, protected amino, hydroxy or lower alkyl; or a group of the formula:

wherein R8 is lower alkyl and R9 is imino, protected imino or oxo;
R2 is an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, aryl which may have halogen or halogen and hydroxy, acyloxy, lower alkoxy, aryloxy substituted with hydroxy, thienyl and isoxazolyl;
R3 is carboxy or protected carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl or a heterocyclic-thiomethyl group which may have lower alkyl lower alkenyl or di(lower)-alkylamino-(lower)alkyl;
R3 and R4 are linked together to form -COOCH2-, or pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula:

wherein R3 and R4 are each as defined above, or its reactive derivative at the amino group or a salt thereof, with a substituted acetic acid of the formula:

wherein R1 and R2 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof, with the proviso that 1) R4 is not acetoxymethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-(2-dimethylaminoethyl)1H-tetrazol-5-ylthiomethyl or 5-methyl-1,3,4-thia-diazol-2-ylthiomethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl and R2 is methyl, 2) R4 is not acetoxymethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl and R2 is ethyl, and 3) R4 is not acetoxymethyl or 1-methyl-1H-tetrazol-5-ylthiomethyl, when R1 is 2-amino-1,3-thiazol-4-yl- or 2-(protected amino)-1,3-thiazol-4-yl and R2 is allyl.

3. A process according to claim 2, wherein the reaction is carried out in the presence of a condensing agent.

4. A process according to claim 3, wherein the condensing agent is a Vilsmeier reagent.

5. A process according to claim 4, wherein the reaction is carried out in the presence of a Vilsmeier reagent produced by the reaction of phosphorus oxychloride with dimethylformamide, and under around neutral condition.

6. A process according to claim 5, wherein is a group of the formula:

and the reaction is carried out in the presence of a Vilsmeier reagent produced by the reaction of phosphorus oxychloride with dimethylformamide, and under around neutral condition, wherein more than two molar equivalents of the phosphorus oxychloride are used for each amount of the substituted acetic acid and dimethylformamide.

7. A process according to claim 2, in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen or nitro and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)-alkylamino; a group of the formula:

wherein R7 is amino, protected amino, hydroxy or lower alkyl; or a group of the formula wherein R8 is lower alkyl and R9 is a protected imino;
R2 is a lower alkyl or lower alkenyl, each of which may have 1 to 2 substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, lower alkoxy, acyloxy, aryloxy substituted with one hydroxy, aryl which may have one halogen or one halogen and one hydroxy, isoxazolyl and thienyl;
R3 is carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl, or a heterocyclicthiomethyl group which may have 1 to 2 substituent(s) selected from the group consisting of lower alkyl, lower alkenyl and di(lower)-alkylamino-(lower)-alkyl; or R3 and R4 are linked together to form -COOCH2-.

8. A process according to claim 7, in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen or nitro and R6 is hydroxy, lower alkoxy, lower alkanoyloxy, carbamoyloxy, lower alkanesulfonylamino or di-(lower)-alkylamino; and R4 is lower alkanoyloxymethyl, carbamoyloxymethyl which may have one trihalo(lower)-alkanoyl, hydroxymethyl, tetra-zolylthiomethyl which may have one substituent selected from the group consisting of lower alkyl and di(lower)alkylamino(lower)-alkyl, thiadiazolyl-thiomethyl which may have one lower alkyl, or triazolylthiomethyl; or R3 and R4 are linked together to form -COOCH2.

9. A process according to claim 8, wherein R2 is lower alkyl which may have one substituent selected from the group consisting of carboxy, lower alkoxycarbonyl, phenylthio, phenoxy having one hydroxy, phenyl having one halogen and one hydroxy, and thienyl, or lower alkenyl which may have one phenyl.

10. A process according to claim 9, wherein R1 is 3-hydroxyphenyl, 3-chloro-4-hydroxy-phenyl, 3-methoxyphenyl, 4-hydroxyphenyl, 3-chloro-4-methoxy-phenyl, 3-nitro-4-hydroxyphenyl, 3-acetoxyphenyl, 3-mesylaminophenyl, 3-carbamoyloxy-phenyl or 4-dimethylaminophenyl;
R2 is methyl, ethyl, allyl, carboxymethyl, t-butoxycarbonylmethyl, 1-carboxyethyl, 1-t-butoxy-carbonylethyl, 3-hydroxy-4-bromobenzyl, 2-thienyl-methyl, phenylthiomethyl, cinnamyl or 2-(2-hydroxyphenoxy)-ethyl; and R4 is acetoxymethyl, carbamoyloxymethyl, trichloroacetyl-carbamoyloxymethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 4H-1,2,4-triazol-3-ylthio-methyl, 1,3,4-thiadiazol-2-ylthiomethyl, 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl, 1-[2-dimethylamino-ethyl]-1H-tetrazol-5-ylthiomethyl or hydroxymethyl;
or R3 and R4 are linked together to form -COOCH2-.

11. A process according to claim 7, in which R1 is a group of the formula:

wherein R7 is amino, lower alkanoylamino, halo(lower)alkanoylamino, lower alkanesulfonylamino, lower alkoxycarbonylamino, hydroxy or lower alkyl;
and R4 is lower alkanoyloxymethyl, carbamoyl-oxymethyl, hydroxymethyl, formyl, tetrazolyl-thiomethyl which may have one lower alkyl, lower alkenyl or di(lower)alkylamino(lower)alkyl, thiadia-zolylthiomethyl which may have one lower alkyl or triazolylthiomethyl which may have one lower alkyl or lower alkenyl; or R3 and R4 are linked together to form -COOCH2-.

12. A process according to claim 11, wherein R7 is amino R2 is lower alkyl or lower alkenyl, and R4 is lower alkanoyloxymethyl, carbamoyloxymethyl, tetrazolylthlomethyl which may have one lower alkyl or lower alkenyl, or thiadiazolylthiomethyl which may have one lower alkyl.

13. A process according to claim 11, wherein R7 is amino, formamido, acetamido, trifluoroacetamido, mesylamino, ethoxycarbonylamino, hydroxy or methyl;
R2 is methyl; and R4 is hydroxymethyl, formyl, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl-thiomethyl, 4-methyl-4H-1,2,4-triazol-3-yl-thio-methyl; or R3 and R4 are linked together to form -COOCH2-.

14. A process according to claim 12, wherein R2 is methyl and R4 is carbamoyloxymethyl.

15. A process according to claim 12, wherein R2 is methyl and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

16. A process for preparing a compound of the formula:

in which R1b is a group of the formula:

or a group of the formula:

in which R8 is lower alkyl;
R2 is an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower akylthio, aryl which may have halogen or halogen and hydroxy, acyloxy, lower alkoxy, aryloxy substituted with hydroxy, thienyl and isoxazolyl;
R3 is carboxy or protected carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl or a heterocyclicthiomethyl group which may have lower alkyl, lower alkenyl or di-(lower)alkylamino(lower)alkyl; or R3 and R4 are linked together to form -COOCH2-, or pharmaceutically acceptable salts thereof, which comprises subjecting a compound of the formula:

wherein R2, R3 and R4 are each as defined as above and R1a is a group of the formula:

in which R7a is protected amino; or a group of the formula:

in which R8 is as defined above and R9a is a protected imino; or a salt thereof, to an elimination reaction of the protective group of the amino or imino by hydrolysis, reduction or a method by reacting it with an iminohalogenating agent and an iminoetherifying agent, with the proviso that 1) R4 is not acetoxymethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl or 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino-1,3-thiazol-4-yl and R2 is methyl, 2) R4 is not acetoxymethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino-1,3-thiazol-4-yl and R2 is ethyl, and 3) R4 is not acetoxymethyl or 1-methyl-1H-tetrazol-5-ylthiomethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino-1,3-thiazol-4-yl and R2 is allyl.

17. A process according to claim 16, wherein R2 is a lower alkyl, or a lower alkenyl, each of which may have 1 to 2 substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, lower alkoxy, acyloxy, aryloxy substituted with one hydroxy, aryl which may have one halogen or one halogen and one hydroxy, isoxazolyl and thienyl;
R3 is carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl, or a heterocyclicthiomethyl group which may have 1 to 2 substituent(s) selected from the group consisting of lower alkyl, lower alkenyl and di(lower)-alkylamino-(lower)-alkyl; or R3 and R4 are linked together to form -COOCH2-.

18. A process according to claim 17, in which R1a is a group of the formula:

wherein R7a is a lower alkanoylamino, halo(lower)alkanoylamino or lower alkoxycarbonyl-amino;
R1b is a group of the formula:

and R4 is lower alkanoyloxymethyl, carbamoyl-oxymethyl, hydroxymethyl, formyl, tetrazolyl-thiomethyl which may have one lower alkyl lower alkenyl or di(lower)alkylamino(lower)alkyl, thiadiazolylthiomethyl which may have one lower alkyl or triazolylthiomethyl which may have one lower alkyl or lower alkenyl; or R3 and R4 are linked together to form -COOCH2-.

19. A process according to claim 18, wherein R2 is a lower alkyl or lower alkenyl, and R4 is a lower alkanoyloxymethyl, carbamoyloxymethyl, tetrazolylthiomethyl which may have one lower alkyl or lower alkenyl, or thiadiazolylthiomethyl which may have one lower alkyl.

20. A process according to claim 18, wherein R7a is a formamido, acetamido, trifluoroacetamido or ethoxycarbonylamino R2 is methyl; and R4 is hydroxymethyl, formyl, 1-(2-dimethyl-aminoethyl)-1H-tetrazol-5-ylthiomethyl, 4-methyl-4H-1,2,4-triazol-3-ylthiomethyl; or R3 and R4 are linked together to form -COOCH2-.

21. A process according to claim 19, wherein R7a is trifluoroacetamido, R2 is methyl, and R4 is carbamoyloxymethyl.

22. A process according to claim 19, wherein R7a is formamido, R2 is methyl and R4 is carbamoyloxymethyl.

23. A process according to claim 19, wherein R7a is trifluoroacetamido, R2 is methyl, and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

24. A process according to claim 19, wherein R7a is formamido, R2 is methyl, and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

25. A process for preparing a compound of the formula:

wherein R5a is hydrogen, halogen, nitro, lower alkoxy or acyloxy;
R6a is acyloxy;
R2 is an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, aryl which may have halogen or halogen and hydroxy, acyloxy, lower alkoxy, aryloxy substituted with hydroxy, thienyl and isoxazolyl;
R3 is carboxy or protected carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl or a heterocyclicthiomethyl group which may have lower alkyl, lower alkenyl or di(lower)alkylamino(lower)-alkyl; or R3 and R4 are linked together to form -COOCH2-, or pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula wherein R2, R3 and R4 are each as defined above and R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy, or a salt thereof, with a compound of the formula:

R-OH

wherein R is acyl or a reactive derivative thereof, or with an isocyanate or with an isothiocyanate or with a haloformate.

26. A process according to claim 25, wherein R5 is hydrogen, halogen or nitro;
R5a is hydrogen, halogen or nitro;
R6a is acyloxy;
R2 is lower alkyl or lower alkenyl, each of which may have 1 to 2 substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, lower alkoxy, acyloxy, aryloxy substituted with one hydroxy, aryl which may have one halogen or one halogen and one hydroxy, isoxazolyl and thienyl;
R3 is carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl, or a heterocyclicthiomethyl group which may have 1 to 2 substituent(s) selected from the group consisting of lower alkyl, lower alkenyl and di(lower)-alkylamino-(lower)-alkyl; or R3 and R4 are linked together to form -COOCH2-.

27. A process according to claim 26, wherein R5 and R5a are each hydrogen, R6a is lower alkanoyloxy or carbamoyloxy, R2 is lower alkyl, and R4 is carbamoyloxymethyl, thiadiazolyl-thiomethyl or tetrazolylthiomethyl which may have one lower alkyl.

28. A process according to claim 27, wherein R6a is acetoxy or carbamoyloxy, R2 is methyl and R4 is carbamoyloxymethyl, 1,3,4-thiadiazol-2-ylthiomethyl or 1-methyl-1H-tetrazol-5-ylthio-methyl.

29. A process according to claim 28, wherein R6a is 3-acetoxy and R4 is carbamoyloxymethyl.

30. A process according to claim 28, wherein R6a is 3-acetoxy and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

31. A process according to claim 28, wherein R6a is 3-carbamoyloxy and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

32. A process according to claim 28, wherein R6a is 3-carbamoyloxy and R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl.

33. A process for preparing a compound of the formula:

in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino;
a group of the formula:

wherein R7 is amino, protected amino, hydroxy or lower alkyl; or a group of the formula:

wherein R8 is lower alkyl and R9 is imino, protected imino or oxo;
R2b is carboxy-(lower)-alkyl;
R3 is carboxy or protected carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl or a heterocyclicthiomethyl group which may have lower alkyl, lower alkenyl or di(lower)alkylamino(lower)-alkyl or R3 and R4 are linked together to form -COOCH2-, or pharmaceutically acceptable salts thereof, which comprises subjecting a compound of the formula:

wherein R1, R3 and R4 are each as defined above and R2a is protected carboxy-(lower)-alkyl, or a salt thereof, to an elimination reaction of the protective group of the carboxy by hydrolysis.

34. A process according to claim 33, wherein R1 is a group of the formula:

wherein R5 is halogen and R6 is hydroxy;
R2a is lower alkoxycarbonyl(lower)alkyl;
R3 is carboxy; and R4 is tetrazolylthiomethyl which may have one lower alkyl.

35. A process according to claim 34, wherein R5 is chlorine, R6 is hydroxy, R2a is t-butoxycarbonylmethyl or 1-t-butoxy-carbonylethyl, R2b is carboxymethyl or 1-carboxyethyl and R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl.

36. A process for preparing a compound of the formula:

in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy, and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino;
a group of the formula:

wherein R7 is amino, protected amino, hydroxy or lower alkyl; or a group of the formula:

wherein R8 is lower alkyl and R9 is imino, protected imino or oxo;
R2 is an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, aryl which may have halogen or halogen and hydroxy, acyloxy, lower alkoxy, aryloxy substituted with hydroxy, thienyl and isoxazolyl; and R3 is carboxy or protected carboxy; or pharmaceutically acceptable salts thereof, which comprises subjecting a compound of the formula:

wherein R1, R2 and R3 are each as defined above and R4 is a protective group of amino, or a salt thereof, to an elimination reaction of the protective group of the amino using a base, an acid, a basic alumina or a basic ion exchange resin.

37. A process according to claim 36, in which R1 is a group of the formula:

wherein R5 is hydrogen or halogen and R6 is hydroxy or lower alkanoyloxy; or a group of the formula:

wherein R7 is amino or protected amino R2 is lower alkyl;

R3 is carboxy; and R4a is halo(lower)alkanoyl.

38. A process according to claim 37, wherein R1 is a group of the formula:

wherein R5 is hydrogen or chlorine and R6 is hydroxy or acetoxy, R2 is methyl and R4 is trichloroacetyl.

39. A process according to claim 37, wherein R1 is a group of the formula:

wherein R7 is amino, formamido or tri-fluoroacetamido, R2 is methyl and R4a is trichloroacetyl.

40. A process according to claim 38, wherein R5 is hydrogen and R6 is 3-hydroxy.

41. A process according to claim 38, wherein R5 is hydrogen and R6 is 3-acetoxy.

42. A process according to claim 38, wherein R5 is 3-chlorine and R6 is 4-hydroxy.

43. A process according to claim 39, wherein R7 is amino.

44. A process according to claim 39, wherein R7 is formamido.

45. A process according to claim 39, wherein R7 is trifluoroacetamido.

46. A process for preparing a compound of the formula:

in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino;
a group of the formula:

wherein R7 is amino, protected amino, hydroxy or lower alkyl; or a group of the formula:

wherein R8 is a lower alkyl and R9 is imino, protected imino or oxo;
R2 is an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, aryl which may have halogen or halogen and hydroxy, acyloxy, lower alkoxy, aryloxy substituted with hydroxy, thienyl and isoxazolyl;
R3 is carboxy or protected carboxy; and R4 is a heterocyclic group which may have lower alkyl, lower alkenyl or di(lower)-alkylamino(lower)alkyl;
or a pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula:

wherein R1, R2 and R3 are each as defined above and R4b is a group which can be substituted by a group R4c-S- wherein R4c is as defined above, or a salt thereof, with a compound of the formula:
R4c - SH
wherein R4c is as defined above or its reactive derivative at the mercapto group, with the proviso that R4c is not 1-methyl-IH-tetrazol-5-yl, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl or 5-methyl-1,3,4-thiadiazol-2-yl, when R1 is 2-amino-1,3-thiazol-4-yl, R2 is methyl and R4b is acetoxy.

47. A process according to claim 46, in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen, or nitro, and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino;
a group of the formula:

wherein R7 is amino, protected amino, hydroxy or lower alkyl; or a group of the formula:

wherein R8 is lower alkyl and R9 is a protected imino;
R2 is a lower alkyl or lower alkenyl, each of which may have 1 to 2 substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, lower alkoxy, acyloxy, aryloxy substituted with one hydroxy, aryl which may have one halogen or one halogen and one hydroxy, isoxazolyl and thienyl;

R3 is carboxy; and R4b is acyloxy; and R4c is a heterocyclic group which may have 1 to 2 substituent(s) selected from the group consisting of lower alkyl, lower alkenyl and di(lower)-alkylamino-(lower)-alkyl.

48. A process according to claim 47, in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen or nitro and R6 is hydroxy, lower alkoxy, lower alkanoyloxy, carbamoyloxy, lower alkanesulfonylamino or di-(lower)-alkylamino; R4b is lower alkanoyloxy and R4c is tetrazolyl which may have one substituent selected from the group consisting of lower alkyl, lower alkenyl and di-(lower)alkylamino(lower)-alkyl, thiadiazolyl which may have one lower alkyl, or triazolyl.

49. A process according to claim 48, wherein R2 is lower alkyl which may have one substituent selected from the group consisting of carboxy, lower alkoxycarbonyl, phenylthio, phenoxy having one hydroxy, phenyl having one halogen and one hydroxy, and thienyl, or lower alkenyl which may have one phenyl.

50. A process according to claim 49, wherein R1 is 3-hydroxyphenyl, 3-chioro-4-hydroxy-phenyl, 3-methoxyphenyl, 4-hydroxyphenyl, 3-chloro-4-methoxy-phenyl, 3-nitro-4-hydroxyphenyl, 3-acetoxyphenyl, 3-mesylaminophenyl, 3-carbamoyloxy-phenyl or 4-dimethylaminophenyl;
R2 is methyl, ethyl, allyl, carboxymethyl, t-butoxycarbonylmethyl, 1-carboxyethyl, 1-t-butoxy-carbonylethyl, 3-hydroxy-4-bromobenzyl, 2-thienyl-methyl, phenylthiomethyl, cinnamyl or 2-(2-hydroxyphenoxy)-ethyl;
R4b is acetoxy; and R4c is 1-methyl-1H-tetrazol-5-yl, 4H-1,2,4-triazol-3-yl, 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 1-[2-dimethylaminoethyl]-1H-tetra-zol-5-yl.

51. A process according to claim 47, in which R1 is a group of the formula:

wherein R7 is amino, lower alkanoylamino, lower alkanesulfonylamino, lower alkoxycarbonylamino, hydroxy or lower alkyl;
R4b is lower alkanoyloxy and R4c is a tetrazolyl which may have one lower alkyl, lower alkenyl or di(lower)alkylamino(lower)-alkyl, thiadiazolyl which may have one lower alkyl or triazolyl which may have one lower alkyl or lower alkenyl.

52. A process according to claim 51, wherein R7 is amino, R2 is lower alkyl or alkenyl, and R4b is lower alkanoyloxy, and R4c is tetrazolyl which may hav one lower alkyl or lower alkenyl, or thiadiazolyl which may have one lower alkyl.

53. A process according to claim 51, wherein R7 is amino formamido, acetamido, mesylamino, ethoxycarbonylamino, hydroxy or methyl;
R2 is methyl;
R4b is acetoxy and R4c is 1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl or 4-methyl-4H-1,2,4-triazol-3-yl.

54. A process according to claim 52, wherein R2 is methyl, R4b is acetoxy and R4c is 1,3,4--thiadiazol-2-yl.

55. A process according to claim 52, wherein R2 is allyl, R4b is acetoxy and R4c is 1-methyl-1H-tetrazol-5-yl.

56. A process for preparing a compound of the formula:

in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino;

a group of the formula:

wherein R7 is amino, protected amino, hydroxy or lower alkyl, or a group of the formula:

wherein R8 is lower alkyl and R9 is imino, protected imino or oxo; and R2 is an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, aryl which may have halogen or halogen and hydroxy, acyloxy, lower alkoxy, aryloxy substituted with hydroxy, thienyl and isoxazolyl;
or pharmaceutically acceptable salts thereof, which comprises treating a compound of the formula:

wherein R1 and R2 are each as defined above and R3 is a carboxy or protected carboxy, or a salt thereof, with an acid.

57. A process according to claim 56, wherein R1 is a group of the formula:

or a group of the formula:

R2 is lower alkyl and R3 is carboxy.

58. A process for preparing a compound of the formula:

in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino;
a group of the formula:

wherein R7 is amino, protected amino, hydroxy or lower alkyl, or a group of the formula:

wherein R8 is lower alkyl and R9 is imino, protected imino or oxo;
R2 is an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, aryl which may have halogen or halogen and hydroxy, acyloxy, lower alkoxy, aryloxy substituted with hydroxy, thienyl and isoxazolyl; and R3 is carboxy or protected carboxy; or pharmaceutically acceptable salts thereof, which comprises oxidizing a compound of the formula:

wherein R1, R2 and R3 are each as defined above or a salt thereof.

59. A process according to claim 58 wherein R1 is a group of the formula:

wherein R7 is halo(lower)alkanoylamino, R2 is lower alkyl and R3 is carboxy.

60. A process according to claim 59, wherein R7 is a trifluoroacetamido and R2 is methyl.

61. A compound of the formula:

wherein R1, R2, R3 and R4 are each as defined in claim 1, with the proviso that 1) R4 is not acetoxymethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-(2-dimethylamino-ethyl)-1H-tetrazol-5-ylthiomethyl or 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl, R2 is methyl, and R3 is carboxy, 2) R4 is not acetoxymethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1, 3-thiazol-4-yl, R2 is ethyl and R3 is carboxy, 3) R4 is not acetoxymethyl or 1-methyl-1H-tetrazol-5-ylthiomethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl R2 is allyl, and R3 is carboxy, or pharmaceutically acceptable salts thereof.

62. A compound of the formula:

wherein R1, R2, R3 and R4 are each as defined in claim 2, with the proviso that 1) R4 is not acetoxymethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl or 5-methyl-1,3,4-thia-diazol-2-ylthiomethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl and R2 is methyl, 2) R4 is not acetoxymethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl and R2 is ethyl, and 3) R4 is not acetoxymethyl or 1-methyl-1H-tetrazol-5-ylthiomethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl and R2 is allyl, or pharmaceutically acceptable salts thereof.

63. A compound of the formula:

(I) wherein R1 is and R2, R3 and R4 are each as defined in claim 2, or pharmaceutically acceptable salts thereof.

64. A compound of the formula:

(I) wherein R1, R2, R3 and R4 are each as defined in claim 7, or pharmaceutically acceptable salts thereof.

65. A compound of the formula (I) wherein R1, R2, R3 and R4 are each as defined in claim 8, or pharmaceutically acceptable salts thereof.

66. A compound of the formula:

(I) wherein R1, R2, R3 and R4 are each as defined in claim 9, or pharmaceutically acceptable salts thereof.

67. A compound of the formula:

(I) wherein R1, R2, R3 and R4 are each as defined in claim 10, or pharmaceutically acceptable salts thereof.

68. A compound of the formula:

(I) wherein R1, R2, R3 and R4 are each as defined in claim 11, or pharmaceutically acceptable salts thereof.

69. A compound of the formula:

(I) wherein R1, R2, R3 and R4 are each as defined in claim 12, or pharmaceutically acceptable salts thereof.

70. A compound of the formula:

(I) wherein R1, R2, R3 and R4 are each as defined in claim 13, or pharmaceutically acceptable salts thereof.

71. 7-[2-methoxyimino-2-(2-amino-1, 3-thiazol-4-yl)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

72. 7-[2-methoxyimino-2-(2-amino-1, 3-thiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

73. A compound of the formula:

(Ia) wherein R1b, R2, R3 and R4 are each as defined in claim 16, with the proviso that 1) R4 is not acetoxymethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl or 5-methyl-1,3,4-thia-diazol-2-ylthiomethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino-1,3-thiazol-4-yl and R2 is methyl, 2) R4 is not acetoxymethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino-1,3-thiazol-4-yl and R2 is ethyl, and 3) R4 is not acetoxymethyl or 1-methyl-1H-tetrazol-5-ylthiomethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino-1,3-thiazol-4-yl and R2 is allyl, or pharmaceutically acceptable salts thereof.

74. A compound of the formula:

(Ia) wherein R1b, R2, R3 and R4 are each as defined in claim 17, or pharmaceutically acceptable salts thereof.

75. A compound of the formula:

(Ia) wherein R1b, R2, R3 and R4 are each as defined in claim 18, or pharmaceutically acceptable salts thereof.

76. A compound of the formula:

(Ia) wherein R1b, R2, R3 and R4 are each as defined in claim 19, or pharmaceutically acceptable salts thereof.

77. A compound of the formula:

(Ia) wherein R1b, R2, R3 and R4 are each as defined in claim 20, or pharmaceutically acceptable salts thereof.

78. A compound of the formula:

(Ib) wherein R2, R3, R4, R5a and R6a are each as defined in claim 25, or pharmaceutically acceptable salts thereof.

79. A compound of the formula:

(Ib) wherein R2, R3, R4, R5a and R6a are each as defined in claim 26, or pharmaceutically acceptable salts thereof.

80. A compound of the formula:

(Ib) wherein R2, R3, R4, R5a and R6a are each as defined in claim 27, or pharmaceutically acceptable salts thereof.

81. A compound of the formula:

(Ib) wherein R2 R3, R4, R5a and R6a are each as defined in claim 28, or pharmaceutically acceptable salts thereof.

82. 7-[2-methoxyimino-2-(3-acetoxyphenyl)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxyl-ic acid (syn isomer) or pharmaceutically acceptable salts thereof.

83. 7-[2-methoxyimino-2-(3-acetoxyphenyl)-acetamido]-3-(1,3,4,-thiadiazol-2-yl-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

84. 7-[2-methoxyimino-2-(3-carbamoyloxyphenyl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable satls thereof.

85. 7-[2-methoxyimino-2-(3-carbamoyloxyphenyl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically salts thereof.

86. A compound of formula:

(Ic) wherein R1, R2b, R3 and R4 are each as defined in claim 33, or pharmaceutically acceptable salts thereof.

87. A compound of formula:

(Ic) wherein R1, R2b, R3 and R4 are each as defined in claim 34, or pharmaceutically acceptable salts thereof.

88. A compound of formula:

(Ic) wherein R1, R2b, R3 and R4 are each as defined in claim 35, or pharmaceutically acceptable salts thereof.

89. A compound of formula:

(Id) wherein R1, R2, and R3 are each as defined in claim 36, or pharmaceutically acceptable salts thereof.

90. A compound of formula:

(Id) wherein R1, R2, and R3 are each as defined in claim 37, or pharmaceutically acceptable salts thereof.

91. A compound of formula:

(Id) wherein R1, R2, and R3 are each as defined in claim 38, or pharmaceutically acceptable salts thereof.

92. A compound of formula:

(Id) wherein R1, R2, and R3 are each as defined in claim 39, or pharmaceutically acceptable salts thereof.

93. 7-[2-methoxyimino-2-(3-hydroxyphenyl)-ace-tamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

94. 7-[2-methoxyimino-2-(3-acetoxyphenyl)-ace-tamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

95. 7-[2-methoxyimino-2-(3-chloro-4-hydroxy-phenyl)acetamido]3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

96. 7-[2-methoxyimino-2-(2-formamido-1, 3-thia-zol-4-yl)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

97. 7-[2-methoxyimino-2-{2-(2,2,2-trifluoro-acetamido)-1,3-thiazol-4-yl}-acetamido]-3-carbamoyl-oxymethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

98. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 46, or pharmaceutically acceptable salts thereof.

99. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 47, or pharmaceutically acceptable salts thereof.

100. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 48, or pharmaceutically acceptable salts thereof.

101. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 49, or pharmaceutically acceptable salts thereof.

102. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 50, or pharmaceutically acceptable salts thereof.

103. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 51, or pharmaceutically acceptable salts thereof.

104. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 52, or pharmaceutically acceptable salts thereof.

105. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 53, or pharmaceutically acceptable salts thereof.

106. 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)-thio-methyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

107. A compound of the formula:

(If) wherein R1 and R2 are each as defined in claim 56, or pharmaceutically acceptable salts thereof.

108. A compound of the formula:

(If) wherein R1 and R2 are each as defined in claim 57, or pharmaceutically acceptable salts thereof.

109. A compound of the formula:

(Ig) wherein R1, R2 and R3 are each as defined in claim 58, or pharmaceutically acceptable salts thereof.

110. A compound of the formula:

(Ig) wherein R1, R2 and R3 are each as defined in claim 59, or pharmaceutically acceptable salts thereof.

111. 7-[2-methoxyimino-2-{2-(2,2,2-trifluoro-acetamido)-1,3-thiazol-4-yl} acetamido]-3-formyl-3-cephem-4-carboxylic acid (syn isomer), which can be also represented as 3-hydroxy-6-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1, 3-thiazol-4-yl}-acetamido]-5a, 6-dihydro-3H, 7H-azeto[2,1-b]furo-[3,4-d]-[1,3]-thiazine-1,7-(4H)-dione (syn isomer) or pharmaceutically acceptable salts thereof.

112. A process for the preparation of a cephalosporin of the formula:

(II) which comprises reacting an acid of the formula:

wherein the amino group is optionally protected, or a reactive derivative thereof, with an 7-aminocephalosporin of the formula:

or a salt thereof.

113. A compound of the formula (II) as defined in claim 112.

114. A process for the preparation of a cephalosporin of the formula:

II) which comprises reacting a compound of the formula:

or a salt thereof, with 1-mercapto-1,3,4,-thiadiazole.

115. A process for the preparation of a cephalosporin of the formula:

(XV) which comprises reacting an acid of the formula:

wherein the amino group is optionally protected, or a reactive derivative thereof, with an 7-aminocephalosporin derivative of the formula:

or a salt thereof.

116. A compound of the formula (XV) as defined in claim 115.

117. A process for the preparation of a cephalosporin of the formula:

(XV) which comprises reacting a compound of the formula:

or a salt thereof, with 5-mercapto-1-methyl-1,3,4-triazole.

118. A process for the preparation of a cephalosporin of the formula:

(XXVIII) which comprises reacting an acid of the formula:

wherein the amino group is optionally protected, or a reactive derivative thereof, with an 7-aminocephalosporin derivative of the formula:

or a salt thereof.

119. A compound of the formula (XXVIII) as defined in claim 118.

120. Process for the preparation of (CXX) wherein A represents hydrogen, an alkali metal and alkaline-earth metal or an organic nitrogen base, by reacting the acid:

wherein the NH2 group may be protected by standard procedure, or a reactive derivative thereof, with the lactam wherein A is as defined above, or low alkyl.

121. Compounds of the formula CXX, as defined in claim 120.

122. Process for the preparation of:

(CXXI) wherein a compound of the formula:

wherein R1 and R2 represent easily hydro-lyzable protecting group, and one of R1 or R2 may also represent hydrogen, is hydrolyzed, thereby removing the protecting groups.

123. Process for the preparation of:

(CXXII) wherein A represents hydrogen, an alkali metal, an alkaline-earth metal or an organic nitrogen base, by reacting in which NH2 may be protected by standard procedure, and functional derivatives thereof, with the lactam wherein A is as defined above or low alkyl.

124. Compounds of the formula CXXII as defined in claim 123.

125. Process for the preparation of:

(CXX) wherein A represents hydrogen, an alkali metal, an alkaline-earth metal, or an organic nitrogen base, by reacting (CXXII) wherein the group NH2 may be protected by standard procedure, and A is as defined above or low alkyl, with an isocyanate R2NCO wherein R2 is an easily removable group.

126. A compound of the formula:

wherein R7g is amino or protected amino, R2f is carboxy(lower)alkyl or protected carboxy(lower)alkyl, and Za is carboxy or protected carboxy, or a salt thereof.

127. A compound of claim 126, wherein R7g is amino, R2f is carboxymethyl, and Za is carboxy.

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE

128. A process for preparing syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds of the formula:

in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino;
a group of the formula:

wherein R7 is amino, protected amino, hydroxy or lower alkyl;
or a group of the formula:

wherein R8 is lower alkyl and R9 is imino, protected imino or oxo;
R2 is an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, aryl which may have halogen or halogen and hydroxy, acyloxy, lower alkoxy, aryloxy substituted with hydroxy, thienyl and isoxazolyl;
R3 is carboxy or protected carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl or a heterocyclic-thiomethyl group which may have lower alkyl lower alkenyl or di(lower)-alkylamino-(lower)alkyl;
R3 and R4 are linked together to form -COOCH2-, or pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula:

wherein R3 and R4 are each as defined above, or its reactive derivative at the amino group or a salt thereof, with a substituted acetic acid of the formula:

wherein R1 and R2 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof, with the proviso that 1) R4 is not acetoxymethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-(2-dimethylaminoethyl)1H-tetrazol-5-ylthio-methyl or 5-methyl-1,3,4-thia-diazol-2-ylthiomethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl and R2 is methyl, 2) R4 is not acetoxymethyl, when R1 is 2-amino-1,3-thiazol-4-yl or 2-(protected amino)-1,3-thiazol-4-yl and R2 is ethyl, and 3) R4 is not acetoxymethyl or 1-methyl-1H-tetrazol-5-ylthiomethyl, when R1 is 2-amino-1,3-thiazol-4-yl- or 2-(protected amino)-1,3-thiazol-4-yl and R2 is allyl.

129. A process according to claim 12, wherein R2 is lower alkenyl and R4 is tetrazolylthiomethyl substituted with one lower alkenyl.

130. A process according to claim 129, wherein R2 is allyl and R4 is 1-allyl-1H-tetrazol-5-ylthiomethyl.

131. A process according to claim 11, wherein R7 is amino, R2 is methylthiomethyl and R4 is 1-allyl-1H-tetrazol-5-ylthiomethyl.

132. A process according to claim 11, wherein R7 is amino, R2 is 4-fluorobenzyl and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

133. A process according to claim 11, wherein R7 is amino, R2 is ethoxycarbonylmethyl and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

134. A process according to claim 11, wherein R7 is amino, R2 is carboxymethyl and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

135. A process according to claim 128, wherein R2 is cyclo(lower)alkyl.

136. A process according to claim 135, wherein said cyclo(lower)alkyl is of 3 to 6 carbon atoms.

137. A process according to claim 136, wherein R1 is a group of the formula:

wherein R7 is amino, R2 is cyclohexyl, R3 is carboxy and R4 is acetoxymethyl.

138. A process according to claim 136, wherein R1 is a group of the formula:

wherein R7 is amino, R2 is cyclopentyl and R3 is carboxy.

139. A process according to claim 138, wherein R4 is acetoxymethyl.

140. A process according to claim 138, wherein R4 is 1H-tetrazol-5-ylthiomethyl.

141. A process according to claim 138, wherein R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl.

142. A process according to claim 138, wherein R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

143. A process according to claim 138, wherein R4 is 1-allyl-1H-tetrazol-5-ylthiomethyl.

144. A process according to claim 16, wherein R7a is lower alkanoylamino, R2 is lower alkenyl and R4 is tetrazolylthiomethyl substituted with one lower alkenyl.

145. A process according to claim 144, wherein R7a is formamido, R2 is allyl and R4 is 1-allyl-1H-tetrazol-5-ylthiomethyl.

146. A process according to claim 18, wherein R7a is formamido, R2 is methylthiomethyl and R4 is 1-allyl-1H-tetrazol-5-ylthiomethyl.

147. A process according to claim 18, wherein R7a is trifluoroacetamido, R2 is 4-fluorobenzyl and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

148. A process according to claim 18, wherein R7a is formamido, R2 is ethoxycarbonylmethyl and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

149. A process according to claim 18, wherein R7a is formamido, R2 is carboxymethyl and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

150. A process for preparing a compound of the formula:

in which R1b is a group of the formula:

or a group of the formula:

in which R8 is a lower alkyl;
R2 is an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituent(s) selected from the group consisting of a carboxy, protected carboxy, arylthio, lower akylthio, aryl which may have halogen or halogen and hydroxy, acyloxy, lower alkoxy, aryloxy substituted with hydroxy, thienyl and isoxazolyl;
R3 is carboxy or protected carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl or a hetercyclicthiomethyl group which may have lower alkyl, lower alkenyl or di-(lower)alkylamino(lower)alkyl; or R3 and R4 are linked together to form -COOCH2-, or pharmaceutically acceptable salts thereof, which comprises subjecting a compound of the formula:

wherein R2, R3 and R4 are each as defined as above and R1a is a group of the formula:

in which R7a is protected amino; or a group of the formula:

in which R8 is as defined above and R9a is a protected imino;
or a salt thereof, to an elimination reaction of the protective group of the amino or imino by hydrolysis, reduction or a method by reacting it with an iminohalogenating agent and an iminoetherifying agent, with the proviso that 1) R4 is not acetoxymethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthio-ethyl or 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino-1,3-thiazol-4-yl and R2 is methyl, 2) R4 is not acetoxymethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino 1,3-thiazol-4-yl and R2 is ethyl, and 3) R4 is not acetoxymethyl or 1-methyl-1H-tetrazol-5-ylthiomethyl, when R1a is 2-protected amino-1,3-thiazol-4-yl, R1b is 2-amino-1,3-thiazol-4yl and R2 is allyl.

151. A process according to claim 150, wherein R2 is cyclo(lower)alkyl.

152. A process according to claim 151, wherein said cyclo(lower)alkyl is of 3 to 6 carbon atoms.

153. A process according to claim 152, wherein R1a is a group of the formula:

wherein R7a is formamido or trifluoroacetamido, R1b is a group of the formula R2 is cyclopentyl, and R3 is carboxy.

154. A process according to claim 153, wherein R7a is trifluoroacetamido and R4 is acetoxymethyl.

155. A process according to claim 153, wherein R7a is formamido and R4 is 1H-tetrazol-5-ylthiomethyl.

156. A process according to claim 153, wherein R7a is trifluoroacetamido and R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl.

157. A process according to claim 153, wherein R7a is formamido and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

158. A process according to claim 153, wherein R7a is trifluoroacetamido and R4 is 1-allyl-1H-tetrazol-5-ylthiomethyl.

159. A process according to claim 33, wherein R1 is a group of the formula:

wherein R7 is amino, R2b is carboxymethyl, R2a is t-butoxycarbonylmethyl, R3 is carboxy and R4 is 1,3,4-thiadiazol-2-ylthiomethyl.

160. A process according to claim 52, wherein R2 is lower alkenyl and R4c is tetrazolyl substituted with one lower alkenyl.

161. A process according to claim 160, wherein R2 is allyl, R4b is acetoxy and R4c is 1-allyl-1H-tetrazol-5-yl.

162. A process according to claim 51, wherein R7 is amino, R2 is methylthiomethyl, R4b is acetoxy and R4c is 1-allyl-1H-tetrazol-5-yl.

163. A process according to claim 51, wherein R7 is amino, R2 is 4-fluorobenzyl, R4b is acetoxy and R4c is 1,3,4-thiadiazol-2-yl.

164. A process according to claim 51, wherein R7 is amino, R2 is ethoxycarbonylmethyl, R4b is acetoxy and R4c is 1,3,4-thiadiazol-2-yl.

165. A process according to claim 51, wherein R7 is amino, R2 is carboxymethyl, R4b is acetoxy and R4c is 1,3,4-thiadiazol-2-yl.

166. A process for preparing a compound of the formula:

in which R1 is a group of the formula:

wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino;
a group of the formula:

wherein R7 is amino, protected amino, hydroxy or lower alkyl;
or a group of the formula:

wherein R8 is a lower alkyl and R9 is imino, protected imino or oxo;
R2 is an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituent(s) selected from the group consisting of carboxy, protected carboxy, arylthio, lower alkylthio, aryl which may have halogen or halogen and hydroxy, acyloxy, lower alkoxy, aryloxy substituted with hydroxy, thienyl and isoxazolyl;
R3 is carboxy or protected carboxy; and R4 is a heterocyclic group which may have lower alkyl, lower alkenyl or di(lower)-alkylamino(lower)alkyl;
or a pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula:

wherein R1, R2 and R3 are each as defined above and R4b is a group which can be substituted by a group R4c-S- wherein R4c is as defined above, or a salt thereof, with a compound of the formula:
R4c - SH
wherein R4c is as defined above or its reactive derivative at the mercapto group, with the proviso that R4c is not 1-methyl-1H-tetrazol-5-yl, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl or 5-methyl-1,3,4-thiadiazol-2-yl, when R1 is 2-amino-1,3-thiazol -4-yl, R2 is methyl and R4b is acetoxy.

167. A process according to claim 166, wherein R2 is cyclo(lower)alkyl.

168. A process according to claim 167, wherein said cyclo(lower)alkyl is of 3 to 6 carbon atoms.

169. A process according to claim 168, wherein R1 is a group of the formula:

R2 is cyclopentyl, R3 is carboxy, R4b is acetoxy and R4c is 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1,3,4-thiadiazol-2-yl or 1-allyl-1H-tetrazol-5-yl.

170. A process according to claim 169, wherein R4c is 1H-tetrazol-5-yl.

171. A process according to claim 169, wherein R4c is 1-methyl-1H-tetrazol-5-yl.

172. A process according to claim 169, wherein R4c is 1,3,4-thiadiazol-2-yl.

173. A process according to claim 169, wherein R4c is 1-allyl-1H-tetrazol-5-yl.

174. A compound of the formula (I) wherein R1, R2, R3 and R4 are each as defined in claim 129, or pharmaceutically acceptable salts thereof.

175. 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl) acetamido]-3-(1-allyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

176. 7-[2-methylthiomethoxyimino-2-(2-amino-thiazol-4-yl)-acetamido]-3-(1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

177. 7-[2-(4-fluorobenzyloxyimino)-2(2-amino-thiazol-4-yl) acetamido]-3-(1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

178. 7-[2-ethoxycarbonylmethoxyimino-2-(2-amino-thiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

179. 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl) thiomethyl 3-cephem-4-carboxylic acid (syn isomer or pharmaceutically acceptable salts thereof.

180. A compound of the formula:

(I) as defined in claim 62, wherein R1, R3 and R4 are each as defined in claim 135 and R2 is cyclo(lower)alkyl, or pharmaceutically acceptable salts thereof.

181. A compound of the formula:

(I) wherein R1, R2, R3 and R4 are each as defined in claim 139, or pharmaceutically acceptable salts thereof.

182. 7-[2-cyclohexyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-cephalosporanic acid (syn isomer) or pharmaceutically acceptable salts thereof.

183. A compound of the formula:

(I) wherein R1, R2, R3 and R4 are each as defined in claim 138, or pharmaceutically acceptable salts thereof.

184. 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-cephalosporanic acid (syn isomer) or pharmaceutically acceptable salts thereof.

185. 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

186. 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl) thio-methyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically acceptable salts thereof.

187. 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically salts thereof.

188. 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)-thio-methyl-3-cephem-4-carboxylic acid (syn isomer) or pharmaceutically salts thereof.

189. A compound of the formula:

(Ia) wherein R1b, R2, R3 and R4 are each as defined in claim 136, or pharmaceutically acceptable salts thereof.

190. A compound of the formula:

Ia wherein R1b, R2, R3 and R4 are each a defined in claim 151, or pharmaceutically acceptable salts thereof.

191. A compound of the formula:

Ia wherein R1b, R2, R3 and R4 are each a defined in claim 152, or pharmaceutically acceptable salts thereof.

192. A compound of the formula:

Ia wherein R1b, R2, R3 and R4 are each a defined in claim 153, or pharmaceutically acceptable salts thereof.

193. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 160, or pharmaceutically acceptable salts thereof.

194. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 167, or pharmaceutically acceptable salts thereof.

195. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 168, or pharmaceutically acceptable salts thereof.

196. A compound of the formula:

(Ie) wherein R1, R2, R3 and R4c are each as defined in claim 169, or pharmaceutically acceptable salts thereof.