CA1146553A - Intermediates for cephalosporanic acid derivatives and processes for their preparation - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Intermediates of the formula:
wherein R1 is hydrogen, amino or a protected amino group, and R1 are each hydrogen, halogen, lower alkoxy or aryl-thio, R14 is carboxy or a protected carboxy group, X is lower alkylene or a group of the formula:

Description

~4~;SSS3 This invention relates to novel intermediates and processes for their preparation.
This application is a division of Canadian Patent Application Serial Number 316,120, filed November 10, 1978.
The novel intermediates of the invention are use-ful in the preparation of novel cephalosporanic acid deri-vatives and pharmaceutically acceptable salts thereof. The novel cephalosporanic acid derivatives and pharmaceutically acceptable salts thereof, have anti-bacterial activities, and can be employed in pharmaceutical compositions, and in a method for the therapeutic treatment of infectious diseases caused by pathogenic bacteria in human beings and animals.
In particular the novel cephalosporanic acid derivatives and pharmaceutically acceptable salts thereof, are highly active against a number of pathogenic bacteria.
In accordance with one aspect of the invention there i~ provided a new intermediate of the formula:

R~ R
Rl ~--X- R14 wherein Ral is hydrogen, amino or a protected amino group, Rb and RCl are each hydrogen, halogen, lower alkoxy or arylthio, R14 is carboxy or a protected carboxy group, X is lower alkylene or a group of the formula:
--C--N

o-R6 in which R6 is hydrogen or an organic residue which may have S-l ~ ~ .

:

Ei5~3 suitable substituent(s), and Z is N or CH, or a salt thereof.
In another aspect of the invention there is pro-vided a process for preparing a new intermediate, as defined above which comprises (l) reacting a compound of the formula R

Ra ~ N ~

wherein Rl, Rl, Rl, Rl4 and Z are each as defined above, or a salt thereof, with a compound of the formula:
R -O~H2 wherein R6 is as defined above, or a salt thereof, to give a compound of the formula:
Rb Rl ~- C~R14 wherein Ral, Rb, RCl, R6, Rl4 and Z are each as defined above;
or (2) reacting a compound of the formula: --R~; Rl ' Rl ~ ~ cH2-~l4 wherein Ra, Rb, Rl, Rl4 and z are each as defined above, or a salt thereof, with a nitrosating agent to give ~ compound of the formula:

RI R

a t\~

wherein Rl, Rb, RCl, Rl4 and Z are each as defined above or (3) reacting a compound of the formula:

S-la . Rb Rc R~ C~-Rl4 wherein Ral, Rb, Rl, R14 and z are each as defined above, or a salt thereof, with a substituting agent capable for substituting a hydrogen atom of the hydroxy by R6 group, in which R is an organic residue which may have suitable substituent(s), to give a compound of the formula:

q~ .
Rl ~N ~ ~~R14 o-R6 -wherein Ral, Rb, RCl, R , R14 and Z are each as defined above, or a salt thereof; or (4) reacting a compound of the formula:

. Rl--~ h R14 wherein Rl, R6 and R14 are each as defined above, or a salt thereof, with halogenating agent to give a compound of the formula:

R15 ~R8 Rl ~ C_R14.

- o-R6 wherein R8 is halogen, R15 is hydrogen or halogen, and Ra~

R6 and R14 are each as defined above, or a salt thereof, or (5) subjecting a compound of the formula:

R~; 1 Rl t~ X - Rl 4 ~herein Ra is a protected amino group, and Rb, Rc, R , X

S-lb . .

11~65S3 --- and z are each as defined above, or a salt thereof, to elimination of the amino-protective group to give a compound of the formula:

R~ Rc H2Nt~ X-R14 wherein Rb, Rl, R14, X and z are each as defined above, or a salt thereof: or (6) reacting a compound of the formula:

Rb Rl H2N~ X-R14 wherein ~b~ Rl~ R14~ X and Z are each as defined above, or a salt thereof with an amino protective agent to give a compound of the formula:

Rl Rl ' Rl t~ ~ X-R14 wherein Ral , ~ . RCl. R14, X and Z are each as defined above, or a salt thereof.
The desired cephalosporanic acid derivatives can be S-lc 1~465~i3 represented by the following general formula (I) :-Rl-X-CONH ~ ~ R (I) wherein Rl is a group of the formula :
Rb Rc Ra ~ , in which Ra is hydrogen, amino or N a protected amino group, Rb and Rc are each hydrogen, halogen, lower alkoxy or ~ arylthio, and Z is N or CH, R2 is hydrogen or lower alkoxy, R3 is hydrogen or lower alkyl, R4 is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkoxy, lower alkanoyloxymethyl, lower alkanoylthiomethyl, or heter0cyclic-thiomethyl which may have suitable substituent(s), R5 is carboxy or its derivative, and X is lower alkylene or a group of the formula:
-C- in which R6 is hydrogen or an organic residue which may have ~_R6 suitable substituent(s), and non-toxic, pharmaceutically acceptable salts thereof.
In the object compounds (I) and the corresponding . starting compounds (III) of Process 1 mentioned below, the partial structure represented by the formula:
nl ol Rl_~_ C,--5~3 is to be understood to include both of the geometrical structures represented by the formula:

and R6 -O- ' (A) syn form (A') anti form Accordingly, with regard to the compounds having the above mentioned partial structure, the compounds having the geometrical structure shown by the formula (A) are referred to as "syn isomer" and the other com-pounds having the alternative one shown by the formula(A'~ as "anti isomer" in this specification.
Suitable pharmaceutically acceptable salts of the ob~ect compounds (I~ are conventional non-toxic salts and may include an inorganic salt, for example, a metal salt such as an alkali metal salt (e.g., sodium salt, potassium ~alt, etc.) and an alkaline earth metal salt ~e.g., calcium salt, magnesium salt, etc.), and an ammonium salt etc.; an organic salt, for exampie, an organic amine salt (e.g., trimethylamine salt, triethyl-amine salt, pyridine salt, picoline salt, dicyclohexyl-amine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanol-amine salt, tris(hydroxymethylamino)methane $alt, etc.) etc.; an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); an inorganic acid addition salt (e.g., hydro-chloride, hydrobromide, sulfate, phosphate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.), and the like.

According to the presentdisclo~ure, the object compounds (I) and the pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated .by the following schemes.
Process 1:

H 2N+~S 'rR

Rs - or its reactive derivative at the amino group or a salt there-.of . Rl--X-COOH (~) . ~
.. . . ' or its reactive derivative at the carboxy group or a salt thereof -R2 ..

o~
.30 R5 or a salt thereof - ~-4 i553 Process 2 :

R --X-CONN~N4 ( Ia) or a salt thereof Elimination reaction of the amino-protective group Rln-x-coNH ~ I ~ R (Ib) ~0 ..
or ~ salt thereof ' /

' S-S

114~iS~i3 Process 3 :

R - XCONH ~ ~ 3 (Ic) ~ N ~ a Rs or a salt thereof ¦ Elimination reaction of the amino-protective group -. ' in Ra ~-X - CONH ~ -R4 (Id) ~ N~
.,20 Rs or a salt thereof ~5 ll~G5~3 Process 4 :

. .
S R~
- R1_XCONH ~ S ~ R3 (Ie) R
R~
or a salt thereof Elimin~.tion reaction of the carboxy-protective group R1-X - CONH ~ ~ R3 (If) (~ >~
~OOH
. or a salt thereof ~ -7 :

j53 Process 5:

Rl-X^CONH ~ S R3 (I ) N ~ CH2-Y g or a salt thereof ¦ H-R7 (IV) or a reactive derivative thereof Rl-X-CONH ~ S r R3 (Ih) R

or a salt thereof h i Rl R2 R3 R4, R5 and x are each as defined above, and Rl is a group of the formula:
R ~ Rl Rl'Z ~ , in which Ra is a protected amino group, and ~ J Rl and Z are each as defined above, Rl is a group of the formula:
Rl H2N t~ in which Rb, Rl and Z are N each as defined above, R4 is heterocyclic-thiomethyl having a protected . amino(lower)alkyl group, Rg is heterocyclic-thiomethyl having a amino-(lower)alkyl group, S ~3 ~ 3 R5 is a protected carboxy group, R~ is heterocyclic-thio which.may have suitable substituents, and Y is a conventional group which is capable to be replaced by the residue (-R7) of the compound of the formula: HR7 in which R7 is as defined above.
Some of the starting compound (m) in Pxocess l are novel and can be prepared, for example, from the known compounds (A-l), (B-l), (c-la) and (n-la) by the ProcesseS A t Qas illustrated by the following reaction schemes or a similar manner thereto.
The compounds (A-l),(B-l), (C-la) and (D-la) are disclosed, for example, in the following literatures.

Compound (A-l):

H2N - C- COOC2Hs (Journal of Organic IiH Chemistry, Vol.27, page 2C 3608) Compound (B-l):

C2HsO- CH = CH-C-OC2Hs(Journal of the American IIH Chemical Society, Vol.69, page 2657 ~1949)) Compound (C-la) ~ (Chemical Abstract Vol.54, H2N ~ N ~ COOCH3 6709) ~L~4~3 ~ COOCH3 (Chemical Abstract Vol.52, H2 ~ ~ 7313g) COOCH3 ~Chemical Abstract Vol.53, ~ 7162c).

H 2 ~N3

2 (Journal fur Praktische ~ Chemie Reihe 4, Vol.13, - ~N ~ COOCH3 page 58, 1961) Compound (D-la) OH

H2N ~ CH2COOC2H5 (Abstracts of the 9th . Congress of Heterocyclic Chemistry, page 146, Fukuoka, Japan, 1976) ~ 5 3 Process A:

H N-C-R9 ~ ~ ~
2 NH + CH2=C-CN ~ H2N-~ N ~ R9 or a salt thereof or a salt thereof ~A-l) (A-2) (A-3) Process B~
H2N-C-R9 ~ R10-OCH=CH-C-OR10 ~ H2N~N,~R9 NH NH
o~ a salt thereof or a salt thereof or a salt thereof (B-l) ~A-l) (B-2) Process C:
H2N ~ C2 ~ _CH2COOH

or a salt thereof . or a salt thereof (C~ -2) Proc~ss D:

I Halogenating ~

H2N ~ ~ CH2-R9Agent H2N ~N J CH2 R
or a salt thereof or a salt thereof (D-l) (D-2 Process E

R8 Dehalogenative - ~ CH R9 Rcduction 1, ~ N 9 (E-l) (E-2) S -ll 114~5~;3 Process F:
R8 Rl 1 N 14 Nucleophile or ~ N
H N t~ ~t--X -R ~ H2N t t-X -R14 2 N~ 1 a salt thereof N~
or a salt thereof or a salt thereof ~F-l) (F-2) Process G: .
2 Introduction of 12 Rl a carboxy- R
1 Z ~ protective group Rl Z ~ H -R9 Ra-~N ~ CH2COOH ~ a t~N ~ C 2 or a salt thereof or a salt thereof (G-l) (G-2) Process H:

1' Z~ ~ 9 R ScH2soR 1~ Z~ SOR10 R -t ~ - R R -+ ~ -COCH
. a ~N~ ~ a ~N' ~sRlo (H-l) (H-2) Process I:
Acid and/or acid anhydride Ra t~ ~ COCH~ 10 a ~N~
(H-2) (I-l) Process J:
l Rl Elimination ofRl Rl b~ /c the carboxy- b c 1' Z~ g protective group 1' Z ~
30Ra t~N ~ X2 R ~ Ra t~ ~ X2-COOH

(J-l) .or a salt thereof (J-2 S -~2 .

5~;3 Process K:

Rb Rc Introduction of Rb Rl ~ an amino- l' Z ~ 13 H2N ~ ~ R13 protective group Ra ~ N ~ R

(K-l) (K-2) Process L:

Rl Rl g OxidationRl R
Rla ~ ~ CH2 ~ Ra-~ N

(L-l) (L-2) 15Process M:

Ra ~ CO-Rl4 Z R~ Rl4 20or its hydrate,thereof ~R6 or a salt thereof -~
(M-l) or a salt thereof (M-2) Process N:
Rl Rlc Elimination of Rb R
/ the amino- \~_ /
~ X3-R14 pgrrotective H2Nt ~3-R14 or a salt thereof or a salt ~hereof (N-l) (N-2) Process 0:

~ Rc Nitrosation 1 Z ~ 14 Ra t'N CH2-R14 - ~ Ra t~N ~N-R
(0-2) ~H

114fi553 Process P: :

~ Rl Substitution of z ~ f Rl t ~ C-R14 hydrogen to R ~ Rl t~ ~ C-R14 N N ':i OH o-R6 or a salt thereof or a salt thereof (P-l) (P-2) Process Q:
R15 R8 .
14 Halogenation~ R1 ~ C R14 Ra t~N ~ C-R . a t N ~ ll N N
o-R6 ~_R6 or a salt thereof OT a salt thereof (Q-l) (Q-2) wherein Rla , Rb, Rc, R6 and Z are each as deined above, and R6 is an organic residue which may have suitable substituent(s), .
R8 is halogen, R is a protected carboxy group, R10 is lower alkyl, Rll is lower alkoxy or arylthio, R12 is hydrogen or lower alkyl, -R13 is a protected carboxy group, or a group of the formula X4 R14 or -C-R14 o-R6 in which X4 is lower alkylene, . ..

iS53 R6 is as defined above and R14 is as defined below, R14 is carboxy or a protected carboxy group, R15 is hydrogen or halogen, Xl is lower alkylene or a group of the formula:
C in which R6 is as ~l N defined above, f o R6 X2 is lower alkylene, or a group of the formula:
-C0- or -C-N
o-R6 in which R6 is as defined above, and X3 is a group of the formula : f -C0- or -C-N
~ O-R6, in which R6 is as defined above.

In the above and subsequent description of the present specification, suitable examples and illustra-tion of the various definitions which the present dis-clo~ure intends to include within the scope thereof are ~14~5~3 explainea in detail as follows.
The term "lower" is intended to mean a group hav-ing 1 to 6 carbon atoms, unless otherwise provided.

Suitable "protective group" in the terms "a pro-tected amino group" and "a protected amino(lower)-alkyl group" may inclu~e an acyl and the other conven-ticnal protective group such as ar(lower)alkyl (e.g., benzyl, trityl, diphenylmethyl, etc.), substituted phenylthio (e.g. 2-nitrophenylthio, etc.), substituted aralkylidene (e.g. 4-nitrobenzylidene, etc.), substituted alkylidene ~e.g. l-methoxycarbonyl-2-propylidene, etc.), substituted lower cycloalkylidene (e.g. 2-ethoxycarbonyl-cyclohexylidene, etc.), and the like. And suitable 1~ acyl group may be the ones derived from carboxylic, sulfonic or carbamic ac d, and more particularly sub-stituted or unsubstituted carbamoyl, aliphatic acyl, and acyl having an aromatic ring (referred to as aroma-tic acyl) or he~erocyclic ring (referred to as hetero-cyclic acyl.) Sui~able examples of the aliphatic acyl may be lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.);
lower cycloalkanecarbonyl (e.g. cyclopentanecarbonyl, cyclohexanecarbonyl, etc.);
lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbon-yl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxy-carbonyl, hexyloxycarbonyl, etc.); lower cycloalkyl-(lower)alkoxycarbonyl (e.g., l-cyclo~ropylethoxycarbony, etc.); lower alkoxyalkahoyl (e.g., methoxyacetyl, etho-xyacetyl, methoxypropionyl, etc.); and lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, pro-panesulfonyl, butanesulfonyl, etc.).
Suitable examples of the aromatic acyl may be ar-4~5~3 (lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl~
phenethyloxycarbonyl, etc.);
arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.); and aroyl (e;g., benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl, etc.), Suitable examples of the heterocyclic acyl may be heterocyclic(lower)alkanoyl (e.g., thienylacetyl, furylacetyl, pyrrolylacetyl, thiadiazolylacetyl, tetra-zolylacetyl, piperazinylacetyi, etc.); heterocyclic-oxycarbonyl (e.g. 8-quinolyloxycarbonyl, etc.);
heterocycliccarbonyl (e.g., thenoyl, furoyl, nicotinoyl, isonicotinoyl, pyrrolecarbonyl, pyrrolidinecarbonyl, tetrahydropyrancarbonyl, etc.); heter~cyclic-(lower) alkoxycarbonyl (e.g. 2-pyridylmethoxycarbonyl, etc.).
Suitable substituted or unsubstituted carbamoyl may include carbamoyl, lower alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), arylcarbamoyl ~e.g., phenylcarbamoyl, etc.), ar(lower)alkylcarbamoyl (e.g., benzylcarbamoyl, tritylcarbamoyl,-etc.), lower alkanoylcarbamoyl (e.g., formylcarbamoyl, acetylcarbamoyl, etc.), mono(or di or tri)halo(lower)alkanoylcarbamoyl (e.g., chloroacetylcarbamoyl, trichloroacetylcarbamoyl, etc.), and the like.
The "acyl" as stated above may optionally have 1 to 3 suitable substituent~s) such as halogen (e.g., chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoXy, lower alkyl, lower alkenyl, acyl[preferable mono~or di or tri)halo(lower)alkanoyl (e.g., chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc.)], aryl (e.g., phenyl, tolyl, etc.), or the like.
Preferable examples of said "protective group" in the term~ "a protected amino group" and "a protected amino~lower)alkyl group" are acyl, and more preferably ~ -17 lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc,), mono(or di or tri)halo(lower)-alkanoyl (e.g., chloro-acetyl, dichloroacetyl, trichloroacetyl, tri~luoroacetyl, etc.) and lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.).

Suitable "lower alkyl" may include straight or branched saturated aliphatic hydrocarbon residue such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, and the like, and preferably one having 1 to 4 carbon atoms.
Suitable "organic residue which may have suitable substituent(s)" may include : .
lower alkyl (e.g., methyl, ethyl, propyl, isopro-pyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.);
mono~or di or tri)halo(lower)alkyl (e.g., chloro-methyl, dichloromethyl, trichloromethyl, bromomethyl!
chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, trifluoroethyl, etc.);
lower alkenyl (e.g., vinyl, l-propenyl, allyl, l-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.);
lower alkynyl (e.g., ethynyl, l-propynyl, propargyl, l-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.);
aryl (e.g., phenyl, tolyl, xylyl, cumenyl, naphthyl, etc.);
ar(lower?alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.); and the like.
halo(lower)alkanoyl(e.g. chloroacetyl, dichloroacetyl, etc.); and the like.

S'-18 i~4~;SS3 suitable "lower alkoxy" may be straight or branched and include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, neopentyloxy, hexyloxy and the like, and preferably on~ having 1 to 4 carbon atoms.

Suitable "halogen'' may be chlorine, bromine, iodine or fluorine.

Suiiable "lower al~anoyloxylmethyl" may include acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, isovaleryloxy-methyl, pivaloyloxymethyl, hexanoyloxymethyl and the like.
Suitable "lower alkanoylthiomethyl" may include acetylthiomethyl, propionylthiomethyl, butyrylthiomethyl, isobutyrylthiomethyl, vaierylthiqmethyl, isovalerylthio-methyl, pivaloylthiomethyl, hexanoylthiomethyl, and the ~0 like.

Suitable "heterocyclic moiety" in the terms "hetero-cyclicthiomethyl which may have suitable substituent(s)"
and "heterocyclic-thio ~;lich may have suitable substitu-ent(s)" may be one containing at least one hetero atomselected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or poly-cyclic heterocyclic group, and preferable heterocyclic group may be ~-containing heterocyclic group such as unsaturated 3 to 6 membered heteromonocyclic group con-taining 1 to 4 nitrogen atoms, for example, pyrrolyl, pyr-rolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2~-tetrazolyl, S ~9 -.

- ~ 6 5 ~ 3 ete.), etc.;
saturated 3 to 6-membered heteromonocyclic group con-taining 1 to 4 nitrogen atoms ~e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.);
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[l,5-b]pyridazinyl, etc.), etc.;
unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 6-membered heteromonocyclic group con-taining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms ~e.g., morpholinyl, etc.);
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., benzoxazolyl, benzoxadiazolyl, etc.); ~
unsaturated 3 to 6-membered heteromonocyclic group con-taining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, or example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), etc.;
saturated 3 to 6-membered heteromonocyclic group con-taining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.);
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like;
wherein said heterocyclic grou~ may have 1 to 4 suitable substituents selected from lower alkyl or lower cyclo-alkyl le.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, etc.);

~ '20 - .

11~65S3 lower alkenyl (e;g. vinyl, allyl, l or 2 or 3-propenyl, l or 2 or 3 or 4-butenyl, l or 2 or i or 4 or 5-pentenyl, etc.); amino(lower)alkyl (e.g., aminomethyl, 2-amino-ethyl, 2-aminopropyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, etc.); a protected amino-(lower)alkyl group such as lower alkoxycarbonylamino-(lower)alkyl (e.g. tert-butoxycarbonylaminomethyl, etc.);
carboxy(lower)alkyl (e.g., carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 4-carboxykutyl, 5-carboxypentyl,6 -carboxyhexyl, etc.); sulfo(lower)alkyl ~e.g., sulfomethyl, 2-sulfoethyl, 2-sulfopropyl, 3-sulfopropyl, 4-sulfobutyl, 5-sulfopentyl, 6-sulfohexyl, etc.); phenyl which may have l to 3 halogen atom(s) (e.g. phenyl, 2 or 3 or 4-chlorophenyl, 2 or 3 or 4-lS bromophenyl, etc.); and lower alkylamino(Iower)alkyl (~.g., N-methylaminomethyl, N,N-dimethylaminomethyl, 2-(N-methylamino)ethyl, 2-(N,N-dimetbylamino)ethyl, 2-(N-methyl-N-ethylamino)ethyl, 3-(N-methylamino)propyl,

3-(N,N-dimethylamino)propyl, 3-(N,N-diethylamino)propyl,

4-(N'methylamino)butyl , 4-(N,N-dimethylamino)butyl, 4-(N-methyl-N-ethylamino)butyl, 5-(N-methylamino)pentyl,

5-(N,N-dimethylamino)pentyl, 6-(N,N-diethylamino)hexyl,

6-(N,N-dimethylamino)hexyl, etc.).
And prefera~le examples of said "heterocyclic moiety" are:
thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1;3,4-t~iadiazolyl, 1,2,5-thiadiazolyl, etc.) which may have a substituent selected from the groups consisting of lower alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), amino(lower)alkyl (e.g., aminomethyl, aminoethyl, aminopropyl, etc.) and lower alkoxycarbonylamino(lower)alkyl (e.g., methoxycarbonyl-aminomethyl, tert-butoxycarbonylaminomethyl, ethoxy-carbonylaminoethyl, etc.);
oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3, 4-.i 4~S~3 oxadiazolyl, 1,2;5-oxadiazolyl, etc.) which may have halophenyl(e.g., 2-chlorophenyl,4-chlorophenyl,4-bromophenyl,etc.), tetrazolyl(e.g., lH-tetrazolyl, 2H-tetrazolyl,) which may have a substituent selected from the groups consisting of lower alkyl ~e.g., methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), carboxy(lower)-alkyl(e.g., carboxymethyl, carboxyethyl, carboxypropyl, etc.) and lower alkenyl te.g., vinyl, allyl, etc.);
pyrazinyl; and tetrazolopyridazinyl (e.g., tetrazolo[l,5-b]pyrid-azinyl, etc.).
"Heterocyclic" moiety in the terms "heterocyclic-thiomethyl having a protected amino(lower)alkyl group"
and "heterocyclic-thiomethyl having an amino(lower)-alkyl group" may be the same as exemplified-above, and .thus defined heterocyclic moiety is preferably lower alkoxycarbonylamino(lower)alkylthiadiazolyl and amino (lower)alkylthiadiazolyl as aforementioned, respective-ly.
Suitable "lower alkylene" may include methylene,ethylene, trimethylene, l-methylethylene, etc:, pre-ferably one having 1 to 3 carbon atoms, more preferably one having 1 to 2 carbon atoms and the most preferably methylene.
Suitable "carboxy derivative" includes protected carboxy such as esterified carboxy. And suitable examples of 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 ester, etc.);
lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.);
lower alkynyl ester ~e.g., ethynyl ester, propynyl - S-~2 65~3 ester, etc.);
lower alkoxyalkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, l-ethoxyethyl ester, etc.);
lower alkylthioalkyl ester ~e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.);
mono~or di or tri)-halo~lower)alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
lower alkanoyloxy(iower)alkyl ester (e.g., acetoxy-methylester, proionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.);
lower alkanesulfonyl(lower)alkyl ester ~e.g., mesyl-methyl ester, 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., benzyl ester, 4-methoxybenzyl ester, 4-nitro-benzyl ester, phenethyl ester, trityl ester, diphenyl-methyl ester, bis~methoxyphenyl)methy~l ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.);
aryl ester which may have one or more suitable substi-tuent(s) such as substituted or unsubstituted phenyl ester ~e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri (lower)alkyl silyl ester;
lower alkylthioester (e.g. methylthioester, ethylthio-ester, etc.) and the like.
Suitable "a protected carboxy group" may include e~terified carboxy aA aforementioned.
Suitable "a conventional group which is capable s - 2 3 to be replaced by the residue (-R7) of the compound of the formula: HR7" in the symbol Y may include halogen ~e.g., chlorine, bromine, etc.), azido9 acyloxy such as lower alkanoyloxy (e.g., formyloxy, acetoxy, propionyloxy, butyryloxy, etc.), and the like.
Suitable "arylthio" may include phenylthio, tolylthio, xylylthio, mesitylthio, naphthylthio and the like.
The processes for preparing the object compounds (I) are explained in detail in the following.

Process 1:
The object compound (I) or a salt thereof can be prepared by reacting a 7-aminocephalosporanic acid derivative (II) or its reactive derivative at the amino group or a salt thereof with a carboxylic acid (III) or its reactive derivative at the carboxy group or a salt thereof.
As to the starting compounds to be used in this ~rocess, the 7-aminocephalosporanic acid derivatives (II) have been publicly known and can be prepared by the method known to the art in the cephalosporin fielt, and the carboxylic acid (III) can be prepared according to a manner as disclosed in Processes A to Q-Suitable reactive derivative at the amino group of the compound (II) may include a conventional reactive derivative used in amidation reaction, for example, a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide, trimethylsilylacetamide, etc.; isocyanato, isothiocyanato, etc.; Schiff's base or its tautomeric enamine type isomer formed by the reaction of the amino group with a carbonyl compound such as an aldehyde compound te.g., acetaldehyde, isopentaldehyde, benzaldehyde, salicylaldehyde, phenylacetaldehyde, p-nitrobenzalde-hyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, hydroxynaphthoaldehyde, furfural, thiophenecarbo- I
aldehyde, etc.) or a ketone compound (e.g., acetone, methyl ethyl ketone, .' / ~

/ .

~-- 11465~3 methyl isobutyl ~etone, acetylacetone, ethyl aceto-acetate, etc.), and the like.
Suitable derivatives at the carboxy group of the compound (~) and suitable salts of the compound (~) are to be referred to the ones exemplified for the compound (I).
Suitable reactive derivatives at the carboxy group of the compound (m) may include, for example, an acid halide, an acid anhydride, an activated amide, an activated ester, and the like, and preferably an acid chloride and acid bromide;
a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g., methyl carbonate, ethyl carbonate, propyl carbonate, etc.), aliphatic carboxylic acid ~e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethyl~utyric acid, trichloro- !
acetic acid, etc.), aromatic carboxylic acid ~e.g., benzoic acid, etc.); a symmetrical acid anhydride;
an activated acid amide with a heterocyclic compound contained imino function such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole f an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethylaminomethyl ester, vinyl ester, propar~yl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl-phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidinylester~ 8-quinolyl thioester, or an ester with a N-hydroxy compound such as N,N-dimethylhydroxylamine, 1-hydroxy-2-(lH)-pyridone, N-hydroxySUccinimide, s -2s 11~6SS3 N-hydroxyphthalimide, l~hydroxybenzotriazole, l-hydroxy-6-chlorobenzotriazole, etc.), and the' like.
The suitable reactive derivative can optionally be -selected from the above according to the kind of the ?
compound ~m) to be used practically.
Suitable salts of the compound (m) may include a salt with an i~organic base such as an alkali metal salt (e.g., sodium or potassium salt), an alkaline earth metal salt (e.g., calcium or magnesium saltj, a salt with an organic base such as trimethylamine, triethylamine, an acid addition salt (e.g., hydro-chloride), and the like.
The reaction is usually carried out in a con-ventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. Among these solvents, hydrophilic solvents 20 ~ may be used in a mixture with water. The reaction can be usually carried out under cooling.
When the carboxylic acid ~m) is used in a form of the free acid or salt in this reaction, the reaction is preferably carried out in the presence of a condens-ing agent such as a carbodiimide compound (e.g., N,N'-dicyclohexylcarbodiimide~ N-cyclohexyl-Nl-morpholino-ethylcarbodiimide, N-cyclohexyl-N'-(4-diethylamino-cyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,N'-' diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylamino-propyl)carbodiimide, etc.), a ketenimine compound (e.g.,N,N'-carbonylbis(2-methylimidazole), pentamethylene-ketene-N-cyclohexylimine, diphenylketene-N-cyclohexyli-mine, etc.); an olefinic or acetylenic ether compounds (e.g., ethoxyacetylene), ~-chlorovinylethyl ether, a sulfonic acid ester of N-hydroxybenzotriazole derivative S !27 .

e~ ~ ~

(e.g., l-(4-chlorobenzenesulfonyloxy)-6-chloro-lH
benzotriazole, etc.), a phosphorus compound (e.g., trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorus trichlo-S ride, triphenylphosphine, etc.), thionyl chloride,oxalyl chloride, N-ethyl-benzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3 -sulfonate, a reagent (referred to as so-called"Vilsmeier reagent") formed by the reaction o an amide compound such as dimethylformamide, diethylacetamide , N-methylformamide or the like wlth a halogen compound such as thionyl chloride, phosphoryl chloride, phosgene or the like. '~
Process 2~
The object compound (Ib) or a salt thereof can be lS prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of the amino-protective group.
' The elimination reaction is carried out by a con-ventional method such as hydrolysis, reduction or the like.
These methods may be selected depending on the kind of the protecting group to be eliminated.
The hydrolysis may include a method being conducted in the presence of an acid (referred to as acidic hydroly-sis hereinafter), base (referred to as basic hydrolysishereinafter), hydrazine, or the like.
Among these methods, acidic hydrolysis is one of the common and preferable method for eliminating the protective group'such as substituted or unsubstituted alkoxycarbonyl'(e.g., t-butoxycarbonyl, t-pentyloxy-carbonyl, trichloroethoxycarbonyl, etc.), substituted or unsubstituted alkanoyl (e.g., formyl, etc.) lower cycloalkoxycarbonyl, substituted or unsubstituted ar (lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, sub-stituted henzyloxycarbonyl, etc.), ar(lower)alkyl (e.g., 4~53 benzyl, trityl, etc.), substituted phenylthio, sub-stituted aralkylidene, substituted alkylidene, sub-stituted lower cycloalkylidene, or the like.
Suitable acid for the hydrolysis includes an organic or an inorganic acid, for example, formic acid, tri-fluoroacetic acid, benzenesulfonic acid, p-toluene-sulfonic acid, h~drochloric acid and the like.
Preferable acid is one which can easily be removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, for ex- i ample, 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, and the elimination reaction can be carried out in the presence or absence of a solvent.
Suitable solvent includes a conventional organic sol-vent, water or a mixture thereof. When the hydrolysis is carried out in the presence of trifluoroacetic acid, the reaction may be preferably carried out in the presence of anisole.
The basic hydrolysis is preferable applied for eliminating the protective group such as haloalkanoyl ~e.g., trifluoroacetyl, etc.), etc. Suitable base in-cludes, for example, an inorganic base such as alkali metal 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 carbonte, etc.), alkaline earth metal carbonate (e.g., magnesium carbonte, calcium carbonate, etc.), alkali meta~ bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal phosphate (e.g., magnesium phosphate, calcium phosphate, eta.), alkali metal hydrogen phosphate (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the S -2~ , 11~6553 f !
like, and an organic base such as alkali metal acetate ~e.g., sodium acetate, potassium acetate, etc.), alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium propoxide, etc.), trialkylamine (e.g., trimethyl- j 5amine, triethylamine, etc.), picoline, N-methylpyrroli-dine, N-methylmorpholine, 1,5-diazabicyclol4,3,0]-5-nonene, l,4-diazabicyclol2,2,2]octane, 1,5-diaza~icyclo [5,4,0]-5-undecene or the like. The basic hydrolysis is often carried out in water or a hydrophilic or 10moistened organic solvent or a mixture thereof.
The hydrolysis using hydrazine is commonly applied for eliminating the protective group such as succinyl or phthaloyl.
The protecting group can generally be eliminated 15by hydrolysis as mentioned above or by the other con-ventional hydrolysis. In case that the protective group is halo(lower)alkoxycarbonyl or 8~quinolyloxy-carbonyl, they are eliminated preferably by treating with a heavy metal such as copper, zinc or the like.
The reductive elimination is generally applied for eliminating the protective group such as halo(lower) alkoxycarbonyl (e.g., trichloroethoxycarbonyl etc.), substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl, substituted benzyloxycarbonyl e~c.), 2-pyridylmethoxycarbonyl, benzyl, etc. Suitable re-duction may include, for example, reduction with an ?
alkali metal borohydride (e.g., sodium borohydride, etc.) and the like.
The rea,ction temperature is not critical and may be suitably selected in accordance with the kind of the protective group to be eliminated and the method to be applied, and the present reaction is prefera~ly carried out under a mild condition such as under cool-ing, at ambient temperature or slightly elevated temper-ature.

1, 5 ~; 3 r Process 3:
The object compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to elimination reaction of the amino-protective group in Ra.
The present reaction is carrled out by conventional method, such as hydrolysis, reduction or the like.
The method of hydrolysis and reduction and the reaction conditions (e.g. reaction temperature, solvent, etc.) are substantially the same as those illustrated for the elimination of the protective group of the protected amino group for Ra of the compound (Ia) in the above Process 2 and therefore are to be referred to said ex-planation.
Process 4:
The object compound (If) can be prepared by sub-jecting the compound ~Ie) to elimination reaction of a carboxy-protective group.
The present reaction is carried out by conventional method, such as hydrolysis, reductio~ or the like.
The methods of hydrolysis and reduction and the reaction condi~ions ~e.g., reaction temperature, solvent, etc.) are substantially the same as those illustrated for the elimination of the protective group of the protected amino group for Ra of the compound (Ia) in the Process 2 and therefore are to be referred to said explanation.
Process 5:
The object compound ~Ih) or a salt thereof can be prepared by reacting the compound ~Ig) or a salt there-of with ~he compound ~IV) or its reactive derivativeat the mercapto group.
Suitable reactive derivative at the mercapto group of the compound (IV) may include a metal salt such as an alkali metal salt ~e.g., sodium salt, potassium salt, etc.) an alkaline earth metal salt ~e.g., magne-. . S-~l . .

., ' ' ~
, ~14~553 sium salt, etc.) and the like.
The reaction may be preferably carried out in a solvent such as water, acetone, chloroform, nitro-benzene, N,N-dimethylformamide, methanol, ethanol, dimethylsulfoxide, or any other organic solvents, which do not adversely influence the reaction and an optional mixture thereof, preferably in a rather high polar solvents. The reaction is preferably carried out in around neutral condition. When the compound (Ig) OT the compound -(IV) is used in a free form, the reaction is preferably conducted in the presence of a base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, trialkylamine or the like. The reaction is usually carried out at ambient temperature or slightly elevated temperature.
The present invention may include, within its scope, the cases that the protected amino group and/or the derivative at the carboxy group are transformed into the corresponding free amino group and/or carboxy group during the reaction or post-treatment in the processes as explained above.
The object compounds (I) obtained according to the processes 1-5 as explained above can be used without any isolation in the subsequent processes.
Processes A to Q for preparing the starting compounds are explained in detail as follows.
Process A:
The compound (A-3) or a salt thereof can be prepared by reacting the compound tA-l) or a salt thereof with the compound (A-2).
The present reaction is usually carried out in the presence of a base as aforementioned in Proces$ 2 in a conventional solvent which does not adversely influence the reaction.

... . ~ . . ~ . . .. .

~ ~16~;~3 The reaction temperature is not critical and the reaction can be carried out under cooling or at ambient temperature. r Process B: !
The compound (B-2) or a salt thereof can be prepared by reacting the compound (A-l) or a salt thereof with the compound (B-l) or a salt thereof.
The present reaction is substantially the same as Process A, and accordingly the reaction conditions (e.g. a base, reaction temperature, solvent, etc.) can be referred to those of Process A.
- Process C:
The compound (C-2) or a salt thereof can be prepared by reacting the compound (C-l) or a salt thereof with carbon dioxide.
The present reaction is usually carried out in the presence of a base such as alkyl lithium ~e.g.
butyl lithium, etc.) or the like in a conventional solvent which does not adversely in fluence the reaction.
The reaction temperature is not critical and the reaction can be carried out under cooling or at ambient temperature.
Process D:
The compound ~D-2) or a salt thereof can be prepared by reacting the compound (D-l) or a salt thereof with an halogenating agent.
Suitable halogenating agent may include a conventional one used for halogenation of hydroxy group such as phosphorus compound (e.g., phosphoryl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, etc.) or the like.
The present reaction is usually carried out in a conventional ~olvent which does not adversely ~1~6~3 ~, influence the reaction.
The reaction temperature is not critical and the reaction can be carried out under warming to heating.
Process E: ¦
_ The compound ~E-2) can be prepared by subjecting a compound (E-l) to dehalogenative reduction. The dehalogenative reduction to be used in this process is a conventional one such as a catalytic reduction (e.g., palladium on carbon, palladium black, spongy palladium, etc.) and the like.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out at ambient temperature.
- Process F:
The compound (F-2) or a salt thereof can be prepared by reacting the compound (F-l) or a salt thereof with a nucleophile selected from alkanol and arenethiol or a salt thereof.
The present reaction is usually carried out ~
in the presence of a base as aforementioned in -Process 2 in a conventional solvent which does not adversely influence the reaction.
Z5 The reaction temperature is not critical and the reaction can be caTried out under cooling or at ambient temperature.
Process G:
The compound (G-2) or a salt thereof can be prepared by reacting the compound (G-l) or a salt thereof with a carboxy protective agent.
Suitable agent to be used in this reaction may include conventional ones such as lower alkyl halide (e-g- methYliodide, etc.) di(lower)alkylsulfate (e.g. dimethylsulfate, etc.), diazo(lower)alkane s - 34 - ~ ~465~

(e.g. diazomethane, etc.), lower alkanol te.g. methanol, ethanol, etc.) or the like.
The present reaction is usually carried out in the presence of an acid as aforementioned in Process 2 in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out under cooling to heating.
Process H: ¦
The compound ~H-2) can be prepared by reacting the compound ~H-l) with a compound of the formula:
Rl OScH2soRl . . . I
The present reaction is usually carried out in the presence of a base as afoTementioned Process 2 in a conventional solvent which does not adversely influence the reaction. ~;
The reaction temperature is not critical and the reaction can be carTied out under cooling to under heating.
Process I:
The compound ((I-l) can be prepared by reacting the compound (H-2) with an acid and/or acid anhydride such as acetic acid and/or acetic anhydride. The reaction can preferably be carried out in the presence of alkali metal perchlorate (e.g. sodium perchlorate, potassium perchlorate, etc.~, alkaline earth metal perchlorate (e.g., magnesium perchlorate, calcium perchlorate, etc.) and the like, and an acid such as an organic carboxylic acid (e.g., formic acid, etc.).
The reaction temperature is not critical and the reaction is pTeferably carTied out under ~arming to heating.
PTocess J:
The compound (J-2) or a salt thereof can be ~ - 3 5 . .

... ~. . .
.

1~46~S3 prepared by subjecting the compound (J-l) to elimination reaction of the carboxy-protective group.
The present reaction can be carried out in substantially the same manner as that of Process 4.
Accordingly, the detailed explanation therefor is to be referred to said Process 4.
Process K
The compound (K-2) or a salt thereof can be prepared by reacting the compound (K-l) or a salt thereof with an amino-protective agent. When the amino-protective agent is acylating agent, the reaction can be carried out in substantially the same manner as that of Process 1. Accordingly, the detailed explanation therefor is to be referred to lS said Process 1.
Process L:
The compound (L-2) can be prepared by oxidizing the compound (L-l).
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 method such as oxidation by using selenium dioxide or the like.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is preferably carried out under warming to heating.
Process M:
The compound (M-2) or a salt thereof can be prepared by reacting the compound (M-l) or its hydrate or a salt thereof with a compound of the formula:

R6-ONH2 or a salt thereof.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, and when a salt of the compound of the formula: R6-ONH2 is used in the reaction, the reaction is preferably carried out in a presence of a base as aforementioned in Process 2.
The reaction temperature is not critical and the reaction can be carried out at ambient temperature.
Process N:
The compound (N-2) or a salt thereof can be prepared by subjecting the compound ~N-l) or a salt thereof to elimination reaction of the amino-protective group.
The present reaction can be carried out in substantially the same manner as that of Process 2.
Accordingly, the detailed explanation therefor is to be referred to said Process 2.
Process 0:
The compound (0-2) or a salt thereof can be prepared by reacting the compound (0-1) or a salt ~, thereof with a nitrosating agent.
Suitable nitrosating agent may include a conventional one such as alkali metal nitrite ~e.g., sodium nitrite, potassium nitrite, etc.) and the like.
The present reaction is usually carried out in a conventional solvent which does not adversely - --influence the reaction.
The reaction temperature is not critical and the reaction is preferably carried out under cooling or at ambient temperature.
Process P:
The compound (P-2) or a salt thereof can be prepared by reacting the compound (P-l) or a salt - ~ 4 ~ ~ 3 thereof with a substituting agent capable for substituting a hydrogen atom of the hydroxy in the compound (P-l) by R6 group.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
When the substituting agent is diazo compound, the reaction can be carried out under cooling or at ambient temperature.
Process Q:
The compound (Q-2) or a salt there of can be prepared by reacting the compound (Q-l) or a salt thereof with a halogenating agent.
Suitable halogenating agent may include a conventional one used for halogenation of an aromatic ring such as chlorine, bromine and the like.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out at ambi~nt temperature.

It is to be noted that, in the aforementioned reactions and/or the post-treatment of the reaction mixture, the aforementioned geometric isomer may be occasionally transformed into the other geometric isomer and such case is also included.

In case that the objec~ compound (I) haye a free carboxy group at 4 position and/or a free amino group for Ra~ it may be transformed into its pharma-ceutically acceptable salt by a conventional method.
All of the object compounds (I) and nontoxic pharmaceutically acceptable salt thereof of the present invention are novel and 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. Now, in order to show the utility of the object compounds (I), the test data on the in vitro antibacterial activity of some representative compounds (I) are shown in the following.
In vitro antibacterial activity:
Test Method In vitro antibacterial activity was determined by the two-fold agar-plate dilution method as desc~ibed below.
One loopful of an overnight culture of each test strain in Trypticase-soy broth (approximately 106 variable cells per ml.) was streaked onh~ infusion agar (HI-agar) containing graded concentrations of antibiotics, and the minimal inhibitory concent~ation (MIC) was expressed in terminal of ~g/ml after incubation at 37C for 20 hours.

Test compounds No. 1 7-[2-~4-Aminopyrimidin-2-yl)-2-ethoxyimino-acetamidol-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
No. 2 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-l(~-allyl-lH-te*razol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
No. 3 7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-ca~boxylic acid (syn isomer).
No. 4 7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
No. 5 7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-.., ~1~65~;3 trifluoroethoxyimino)acetamido]-3-[(1-carboxy-methyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
No. 6 7-[2-(6-aminopyridin-2-yl)-2-methoxyimino-acetamidoJ-3-(l-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
No. 7 7-[2-(6-aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-ceyhem-4-carboxylic acid.
No. 8 7-~2-(6-aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
No. 9 7-[2-(6-aminopyridin-2-yl)-2-methoxyimino-acetamido]cephalosporanic acid ~syn isomer).
No.10 7-l2-(2-aminopyrimidin-4-yl)-2-methoxyimino-lS acetamido]-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid.
No.ll 7-[2-(4-aminopyrimidin-2-yl)-2-methoxy-iminoacetamido]-3-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer). t No,12 7-[2-allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
No.13 7-[2-(6-aminopyridin-2-yl)-2-propargyloxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
No.14 7-[2-(6-aminopyridin-2-yl)-2-ethoxy-iminoacetamidoJ-2-methyl-3-cephem-4-carboxylic acid (syn isomer).

I

Test Results MIC (~g/ml.) Micro- Proteus Pseudomonas organisms \ vulgaris IAM 1025aeruglnosa ~, Compound No. . .
1 < 0.025 < 1.56 2 < 0.025 6.25.
_ 3 0.05 < 1.56 4 < 0.025 < 1,56 3 .
0.025 <.1.56 .
. . 6 < 0.025 < 1.56 _ lS 7 < 0,025 6.25 8 0.05 .3.13 _ 9 . _ 0.025 _ 1.56 ~
_ ., . 10 0.2 6.25 . I.
11 < 0.025 < 1.56 J
= .S
12 0.05 c 1.56 13 0.05 < 1.56 :
.
14 0.05 c 1.56 .

For therapeutic administration, the object compounds (I) and pharmaceutically acceptable salt thereof are used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical ~ ~6~53 preparations may be in solid form such as capsule, tablet, dragee, ointment 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 commonly used additives. I
While the dosage of the compounds may vary from and also depend upon the age, conditions of the patient, a kind of disease, a kind of the compounds (I) to be applied, etc. In general, amounts between 1 mg. and about 2000 mg. or even more per t day may be administered to a patient. An average single dose of about 50 mg., 100 mg., 250 mg., and 500 mg. of the object compounds (I) of the present invention may be used in treating diseases infected by pathogenic bacteria.
The following examples are given for the purpose of illustration.

~L~ 4~S~ii3 Example 1 (1) Phosphoryl chloride (0.998 g.) was added to N,N-dimethylformamide (S ml.) and stirred at 40C for 30 minutes. To the solution was added a solution of 2-(6-formamidopyridin-2-yl)-2-m0thoxyiminoacetic acid tsyn isomer) (1.125 g.) in N,N-dimethylformamide (5 ml.) at -15C, and stirred at -10 to -8C for 50 minutes [solution A].
On the other hand, 7-amino-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (2.007 g.) and trimethylsilylacetamide (7.22 g.) were dissol~ed in methylene chloride (20 ml.) at 40C and cooled. To the cool solution was added the above solution A at -Z0 to -15C and stirred at the same temperature for 40 minutes. The resultant solution was poured into - 15 a solution of a saturated aqueous solution of sodium bicarbonate (30 ml.) and water (40 ml.) under ice cooling. The aqueous layer was separated, washed with ethyl acetate, and then ethyl acetate (50 ml.) was added to the aqueous layer. The solution was adjusted to pH 3 wit~ 10~ hydrochloric acid, and extracted with ethyl acetate twice. The extract was washed with water and concentrated to a small amount under reduced pressure. The appeared precipitates were collected by filtration, washed with ethyl acetate and dried to give 7-[2-(6- -fo~mamidop-yridin-2-yl)-2-me*hoxyiminoacetamido~-3 methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (873 mg.). The same product (lZ6 mg.) was recovered from the mother liquor.
Total yield was 999 mg.
I.R. ~ NUa~ol : 3280, 1785, 1728, 1673, 1454, 1053 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.62, 3.76 ~ZH, AB-q, J=18Hz), 3~90 (3H, s), 3.94 (3H, - s), 4.24, 4.~5 (2H, AB-q, J=16Hz), - *trademark E- ~

i5~3 5.16 (lH, d, J=5Hz), 5.85 ~lH, dd, J=SHz~8Hz)~ 7.50 tlH, d? J=8Hz),

7.80 (lH, t, J=8Hz), 8.00 (0.3H, broad s), 6.88 (0.7H, broad d, J=8Hz), 9.28 (0.7H, broad d, J=lOHz), 8.28 (0.3H, broad s), 9.50 (lH, broad d, J=8Hz), 10.7 (lH, m, J=lOHz) (2) A mixture of N,N-dimethylformamide t3 ml.) and phosphoryl chloride (460 mg.) was stirred at 37 to 40C for 30 minutes. To the solution were added methylene chloride (3 ml.) and 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid ~669 mg.) at -20 to -25C and stirred at -10 to -15C for one hour.
A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (670 mg.) and trimethylsilylacetamide (2 g.) in methylene chloride (200 ml.) was added to the above solution at -10 to -15C, and then stirred i~
at the same temperature for 30 minutes. After the solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue.
The ethyl acetate layer was separated, washed with an aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, dried o~er magnesium sulfate and then concentrated f under reduced pressure. The residue was triturated with diethyl ether to give 4-nitrobenzyl 7-[2-~6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (730 mg.), mp. 195 to 200C (dec.).
I.R. v NUaJol : 3350, 3200, 1790, 1725, 1690, 1660 cm The following compounds were prepared in substantially the same manner as those of Example 1-(1) and (2).
(3) 7-[2-(6-Formamidopyridin-2-yl)-2-methoxyimino-E~

:

~i 4~5S3 acetamido]-3-~1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn isa~), mp. 167 to 169C (dec.).
I.R. v Nma~l : 3270, 1780, 1670, 1455, 1370, 1252, 1052 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.65, 3.7~ (2H, AB-q, J=18Hz), 3.97 (3H, s), 4.30, 4.57 (2H, AB-q, J=12Hz), 5.22 (lH, d, J=5Hz), 5.93 ~lH, dd, Js5Hz, 8Hz), 6.57 (lH, bToad d, J=7Hz), 7.58 (lH, d, J=7Hz), 7.90 (lH, t, J=7Hz), 9.3 - 9.8 (2H, m), 9.63 (lH, s), 10.62, 10.70 (lH, m) (4) 7-[2-(6-Formamidopyridin-2-yl)-2-methoxyimino-acetamido]-3-(5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 178 to 186C (dec.).
I.R. v mU~ol : 3280, 1785, 1720-1660 (broad), 1457, 1255, 1162, 1052 cm 1 N.M.R. ~ ppm (DMSO-d6) : 1.40 (9H, s), 3.63, 3.78 (2H, AB-q, J=18Hz), 3.98 (3H, s), 4.1-4.7 (4H, m), 5.~1 (lH, d, J~4.5Hz), 5.89 (lH, dd, J=4.5Hz, 8Hz), 6.2-8.2(4H, m), 8.33 (0.3H, broad s), 9.35 (0.7H, broad d, J=lOHz), 9.55 (lH, broad d, J=8Hz), 10.5-10.8 (lH, m) (5) 7-[2-(6-Formamidopyridin-2-yl)-2-methoxyimino-acetamido]cephalosporanic acid (syn isomer),mp. 191 to 193C (dec.).
I.R. ~ Nu~ol : 3250, 1780, 1725, 1665, 1240, 1053 cm N.M.R. ~ ppm (DMSO-d6) : 2.03 (3H, s), 3.53, 3.62 (2H, AB-q, J=17Hz), 3.97 (3H, s), 4.70, 5.02 (2H, AB-q, J=~ Hz), 5.18 (lH, d, J=5Hz), 5.88 (lH, dd, J=5Hz, ~5 E-~

~1~65~3 8Hz), 6.90 (lH, broad d, J=7Hz), 7.53 (lH, d, J=7Hz), 7.82 (lH, t, J=7Hz), 9~3 (lH, broad d, J=9Hz), 9.54 (lH, d, J-8Hz), 10.6 (lH, m).
(6) 4-Nitrobenzyl 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxy-late (syn isomer), mp. 162 to 168C (dec.).
I.R. v NmUa~ol : 3200, 1780, 1735, 1690-1660, 1040 cm N.M.R. ~ ppm (DMSO-d6) : 3.70, 4.10 (2H, AB-q, J=18Hz), 3.93 (3H, s), 5.32 (lH, d, J=5Hz), 5 45 (2H, s)~ 5.98 (lH, dd, J=5Hz, 8Hz), 6.9 (lH, m), 7.50 (lH, d, J=8Hz), 7.57 (2H, d, J=8Hz), 7.83 (lH, m), 8.26 (2H, d, J=8Hz), 9.30 (lH, m), 9.69 (lH, d, J=8Hz), 10.70 (lH, m).
(7) 4-Nitrobenzyl 7-[2-(6-formamidopyridin-2-yl)-2-i~ethoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylate. -~
I.R. v Nua~ol : 3700 3000, 1780, 1710-1640, 1050, 1010, 640 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.7 (2H, broad s), 3.84 (3H, s), 3.99 (3H, s), 5.25 (lH, d, J=5Hz), 5.36 (2H, s), 5.77 (lH, dd, J=5Hz, 8Hz), 6.9 (lH, m), 7.52 (lH, d, J=8Hz), 7.67 (2H, d, J=8Hz), 7.8 (lH, m), 8.22 ~2H, d, J=8Hz~, 9.3 (lH, m), 9.52 (lH, d, J=8Hz), 10.7 (lH, m)

(8) Benzhydryl 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-7-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer), mp. 145 to 150C (dec.).
I.R. v mUx 1 : 3230, 1780, 1725, 1680 cm 1 ~ ~ - E - ~

N.M.R. ~ ppm (acetone-d6) : 3.59 (3H, s), 3.63, 3.73 (2H, AB-q, J=18Hz), 3.83 (3H, s), 3.96 (3H, s), 4.23, 4.43 (2H, AB-q, J=13Hz), 5.10 (lH, s), 6.86 (lH, s~, 7.16-7.80 (13H, m)

(9) 7-[2-(6-Formamidopyridin-2-yl)-2-methoxyimino-acetamido~-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 198 to 202C (dec.).
I.R. v mU~ol : 3380-3070, 1790, 1735, 1670 cm 1 N.M.R. ~ ppm (DMSO-d6) : 1.47 (3H, d, J=7Hz~, 3.5-4.2 (lH, m), 4.00 (3H, s), 5.20 (lHj d, J=5Hz), 6.05 (lH, dd, J=5Hz, 8Hz),, 6.67 (lH, d, J=6Hz), 6.9-8.7 (3H, m).

(10) 7-[2-(6-Formamidopyridin-2-yl)-2-methoxyimino-acetamido)-3-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 225 to 225.5C tdec.).
I.R. v maU~ol : 3400, 3250, 3220, 1773, 1730, 1680-1650, 1560, 1260, 1160, 1050 cm~l N.M.R. ~ ppm (DMSO-d6) : 2.02 (3H, s), 3.3, 3.6 (2H, AB-q, J=18Hz), 3.96 (3H, s), 5.13 (lH, d, J=4.5Hz), 5.78 (lH, dd, J=4.5Hz, 8Hz), 6.9-8.3 (3H, m), 9.3-9.5 (2H, m), 10.55 (lH, m)

(11) 7-[2-(6-Trifluoroacetamidopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanic acid (syn isomer), mp. 151 to 155C.
I.R. v mUa~ol : ~ 3260, 1775, 1730, 1690-1670, 1380, 1160, 1040 cm 1 N.M.R. ~ ppm (DMSO-d6) : 2.00 (3H, s), 3.5 (2H, broad s), 3.g8 (3H, s), 4.67, 5.03 (2H, AB-q, J=12Hz), 5.18 (lH, d, J=5Hz), 5.88 (lH, dd, J=5Hz, 8Hz), 4 7 ~ - 5 ~ ~46SS3 7.5-8.0 (3H, m), 9.51 (lH, d, J=8Hz), 11.63 (lH, m)

(12) 7-[2-~6-Formamidopyridin-2-yl)-2-methoxyimino-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 185 to 190C (dec.).
I.R. v NmUxol : 3200, 1790, 1700, 1665 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.60, 3.42 (2H, AB-~
J=18Hz), 3.98 (3H, s), 4.64, 4.92 ~2H, AB-q, J=12Hz~, 5.20 (lH, d, J=4Hz~, 5.90 (lH, dd, J=4Hz, 9Hz), 6.50 (2H, s), 6.8-8.U (3H, s~ J 9.58 (lH, d, J=9Hz)

(13) 7-[2-(2-Formamidopyrimidin-4-yl)-2-methoxyimino-15 acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, mp. 138 to 155~dec.).
I.R. v mUjxol : 3300, 1787, 1565, 1408, 1043 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.63, 3.76 (2H, AB-q, J~18Hz), 3.92 (3H, s), 4.02 (3H, -~ s), 4.24, 4.35 (2H, AB-q, J=12Hz), 5.16 (lH, d, J=5Hz), 5.86 (lH, dd, J=5Hz, 9Hz), 7.47 ~lH, d, J=6Hz), 8.63 (lH, d, J=6Hz), 9.37 (lH, d, J=lOHz), 9.60 (lH, d, J=9Hz), 11.00 (lH, d, J=lOHz)

(14) 7-[2-(6-Formamidopyridin-2-yl)-2-ethoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 150 bo 155C (dec.).
I.R. v maUxol : 3200, 1780, 1700, 1660 cm 1 N.M.R. ~ ppm (DMSO-d6) : 1.30 (3H, t, J=7Hz), 3.65, 3.80 (2H, AB-q, J=16Hz), 3.95 (3H, s), 4.25 (2H, q, J=7Hz), 4.28 (2H, broad s), 5.18 (lH, d, J=SHz), 5.90 (lH, dd, J=SHz, 9Hz~, 6.8-8.2 (3H, m), 9.4 (2H, m), 10.6 (lH, broad d) 48 . E~6 ~1 '16553 .

(15~ A solution of pivaloyl chloride (1.07 g.~ in methylene chloride (3 ml.) was added to a solution of 2-(6-Formamidopyridin-2-yl)acetic acid (1.6 g~) and 1,5-diazabicyclo[5,4,0]und~e-5(1.35 g.) in methylene chloride (25 ml.) at -20 to -25C, and stirred at the same temperature for one hour [solution A]. On the other hand, a solution of 7-amino-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.24 g.) and 1,5-diazabicyclo[5,4,0~ndecene-5 (1.35 g.) in methylene chloride (60 ml.~ was stirred at room temperature for 10 minutes. To the solution was added the above solution A at -20 to -25C and stirred at the same temperature for 1.5 hours. After removing the solvent from the resultant solution, ethyl acetate, water and sodium bicarbonate were added to the residue. The aqueous layer was separated and washed with ethyl acetate. Ethyl acetate (300 ml.) was added to the aqueous solution, adjusted to pH 2 to 3 with 5~ hydrochloric acid, and then shaken sufficiently. The ethyl acetate layer was separated, washed with water and concentrated under reduced pressure to give 7 12-(6-formamidopyridin-2-yl)-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.2 g.).
I.R. v mUa~ol : 3320, 1782, 1690 (broad) cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.68 (4H, broad s), 3 93 (3H, s), 4.33 (2H, broad s), 5.10 (lH, d, J=5Hz), 5.72 (lH, dd, J=5Hz, 9Hz), 6.8, 7.8 (lH~, 7.10 (lH, d, J=8Hz), 7.73 (lH, t, J=8Hz), 9.10 (lH, d, J=9Hz), 8.33, 9.37 (lH, broad s), 10.55 (lH, broad d, J=7Hz) (16) A solution of phosphoryl chloride (2.14 g.) in N,N-dimethylformamide (14 ml.) was stirred at 37 to ~9 E-7 11~6S53 40C for 30 minutes. To the solution were added methylene chloride (14 ml.) and 2^t6-formamidopyridin-2^yl)-2-dichloroacetoxyiminoacetic acid ~ isar~r) (4.48 g.) at -20 to -25C and stirred at -10 to -15C for 30 minutes [solution A]. On the other hand, 7-amino-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4.6 g.) was dissolved in a solution of trimethylsilyl-acetamide (14 g.) in methylene chloride ~150 ml.) at 40C, and cooled to -10 to -15C. The solution was added to the above solution A at -10 to -15C and stirred at the same temperature for 30 minutes.
After removing methylene chloride ~om the resultant solution under reduced pressure, ice water and ethyl acetate were added to the residue, and adjusted to pH 4 with an aqueous solution of sodium bicarbonate.
The aqueous layer was separated, washed with ethyl acetate, adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sul-fate and concentrated under reduced pressure. The residue was triturated with diethyl ether. l~e precipitates were collected by filtration, washed with diethyl ether and dired to give 7-[Z-t6-formamidopyridin-2-yl)-Z5 2-hydroxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (5.0 g.), mp. 110 to 115C.
I.R. v NmUa~ol: 3240, 1780, 1700, 1660 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.73 (2H, broad s), 4.00 (3H, s), 4.35 (2H, broad s), 5.20 (lH, d, J=4Hz), 5.93 (lH, dd, J-9Hz, 4Hz), 6.83-8.0 (3H, m), 9.45 (lH, d, J=9Hz~

~0 E ~ 8 .

11 4~ 3 Example 2 (1) Conc. hydrochloric acid (127.4 mg.) was dropwise added to a suspension of 7-[2-(6-formamido-pyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 930 mg.) in methanol (15 ml.) and stirred at room temperature for 40 minutes. After methanol was removed under reduced pressure from the resultant solution, water ~100 ml.) was added to the residue and the solid substance was dissolved by adding 10~ hydrochloric acid. After the insoluble material was filtered out, the filtrate was adjusted to pH 3 with an aqueous sodium bicarbonate. The solution was purified by column chromatography on lS macroporous, non-ionic adsorption resin "Diaion HP-20"
(Trademark, manufactured by Mitsubishi Chemical Industries Ltd.), with an eluent of aqueous methanol.
The eluate was lyophilized to give 7-[2-(6-amino-pyridin-2-yl)-2-methoxyiminoacetamido~-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-~-cephem-4-carboxylic acid tsyn isomer) (605 mg.), mp. 150 to 154C.
I.R. v NmU~ol : 3360, 3220, 1780, 1670, 1620, 1585, 1544, 1042 cm N.M.R. ~ ppm (DMS0-d6) : 3.73 (2H, broad s), 3.75 (3H, s), 3.78 (3H, s), 4.30 and 4.37 (2H, AB-q, J=12Hz), 5.17 (lH, d, J=SHz), 5.85 (lH, dd, J=5Hz, 9Hz), 6~53 (lH, d, J=8Hz), 6.93 (lH, d, J=8Hz), 7.48 (lH, t, J=8Hz), 9.52 (lH, d, J=9Hz) (2) A solution of 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (2.3 g.) in methanolic hydrochloric acid (12 ml., containing hydrochloric acid 6 mmol) was stirred at room temperature for one hour. To the resultant ~1 solution was added diethyl ether, and the precipitates were collected by filtration and dissolved in a mixture of methanol (50 ml.) and water (10 ml.). The solution was adjusted to pH 3 with an aqueous solution of sodium bicarbonate, treated with activated charcoal (1 g.) and concentrated to a volu~e of about 20 ml.
The precipitating crystals were collected by filtration, washed with water and dried to give 7-l2-(6^amino-pyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (1.12 g.), mp. 215 to 220C (dec.).
The mother liqunr and washings were combined and concentrated under reduced pressure. The appeared precipitates were collected by filtration, washed with water and dried to give the same object compound (0.36 g.). Total yield 1.48 g I.R. v NmUaxol : 3300, 1785, 1730, 1670 cm l N.M.R. ~ ppm (DMSO-d6) 3.64 (2H, broad s), 4.06 (3H, s), 5.18 (lH, dd, J=4Hz, 8Hz), 5.85 (lH, dd, J=4Hz, 8Hz), 20~ 6.52 (lH, broad t), 6.78 (lH, d, J=8Hz), 7.19 (lH, d, Jz9Hz), 7.92 (lH, dd, J=8Hz, 9Hz), 10.0 (lH, d, J=8Hz) The following compounds were prepared in substantially the same manner as those of Examples 2-(1) and (2).
(3) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 152 to 156C (dec.).
I.R. v NmUaxol : 3400, 3230, 1780, 1670, 1622, 1590, 1550, 1050 cm~
N.M.R. ~ ppm (DMSO-d6) : 3.67, 3.73 (2H, AB-q, J=18Hz), 3.33 (3H, s), 4.30, 4.55 (2H, AB-q, J=14Hz), 5.13 (lH, d, J=4Hz), 5.82 (lH, dd, - 1~4~i5i53 J=4Hz, 8Hz), 6.50 (lH, d, J=8Hz), 6.88 (lH, d, J=8Hz), 7.45 (lH, t, J=8Hz), 9.50 (lH, d, J=8Hz), 9.57 (lH, s) (4) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-caTboxymethyl-lH-tetrazol-5-yl~-thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 169 to 177C (dec. ~ .
I.R. v mUxol : 3380, 3220, 1780, 1670, 1620, ) 1050 cm N.M.R. ~ ppm (DMSO-d6 + D2O) : 3.67, 3.80 (2H, AB-q, J=14Hz), 3.98 (3H, s), 4.27J 4.50 (2H, AB-49 J=14Hz), 5.18 (lH, d, J=5Hz), 5.33 (2H, s), 5.88 (lH, d, J=5Hz) J 6.65 (lH, d, J=8Hz), 6.97 (lH, d, J=8Hz), 7.60 ~lH, t, J=8Hz) (5) 7-[2-(6-Aminopyridin-2-yl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-' carboxylic acid (syn isomer), mp. 188 to 193C (dec. ) .
I.R. v Nmaxl : 3600-3080, 1763, 1698, 1663 cm 1 N.M.R. ~ ppm (D2O ~ DCQ) : 3.83 (2H, s), 4.03 (2H, s), 4.15 (3H, s), 4.20, 4.43 (2H, AB-q, J=14Hz), 5.27 (lH, d, J=SHz), 5.73 (lH, d, J=5Hz), 6.93 (lH, d, J=8Hz), 7.07 (lH, d, J=9Hz), 7.98 ~lH, dd, J=8Hz, 9Hz~
(6) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid hydro-chloride (syn isarner), yellow pawder, Ir~. 170 to 220C (dec.).
I.R. v mUaxol : 3300-3100, 1780, 1710, 1660, 1610, 1540, 1370 cm N.M.R. ~ ppm ~DMSO-d6) : 3.57 4.13 (2H, AB-q, J=18Hz), 4.13 (3H, s), 5.37 (lH, d, J=4.5Hz), 5.88 (~H, dd, J=4.5Hz, 8Hz), ~3 E- ~

1~4~S3 6.77 ~lH, d, J=8Hz), 7.21 (lH, d, J=9Hz), 7.97 (lH, dd, J=8Hz, 9Hz), 8.0-9.3 (2H, m), 10.07 (lH, d, J=8Hz) (7) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacet-amido]-3-methoxy-3-cephem-4-carboxylic acid, mp. 175 to 182^~dec.).
I.R. v NUxol : 3300, 1775, 1700-1650, 1045 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.62 (2H, broad s), - 3.75 (3H, s), 3.96 ~3H, s), 5.15 tlH, d, J=4.5Hz), 5.60 (lH, dd, J=4.5Hz, 8Hz), 6.70 (lH, d, J=8Hz), 6.85 (lH, d, J=8Hz), 7.56 (lH, t, J=8Hz), lS 9.53 (lH, d, J=8Hz) (8) 7-12-(,6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-7-methoxy-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 165 to 170C (dec.).
I.R. v Nma~l : 3300, 1780, 1700, 1680 cm 1 N.M.R. ~ ppm ~D2O + NaHCO3) : 3.72, 3.58 (2H, AB-q, J=17Hz), 3.64 (3H, s), 3.98 t3H, s), 4.04 (3H, s), 4.24, 4.06 ~2H, AB-q, J=13Hz), 5.20 tlH, s), 6.74 (lHJ d, J-8Hz), 7.10 (lH, d, J=8Hz~, 7.56 (lH, t, J=8Hz) (9) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacet-amido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 199 to 205~C (dec.).
I.R. ~ NmUxol : 3400-3100, 1780, 1730, 1665, 1550, 1295, 1258, 1050 cm N.M.R. ~ ppm (DMSO-d6) : 1.48 (3H, d, J=9Hz), 3.7-4.2 (lH, m), 4.10 (3H, s), 5.20 (lH, d, J=SHz), E- ~2 ~ L4655~

5.92 (lH, dd, J=9Hz, 5Hz), 6.62 (lH, d, J=6Hz), 6.78 (lH, d, J=8Hz), 7.27 (lH, d, J=9Hz), 8.00 (lH, dd, J=8Hz, 9Hz), S 10.00 (lH, d, J=9Hz) (10) 7-[2-t6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer), mp. 195 to 198C (dec.).
I,R. v NmUa~ol : 3100, 1780, 1682, 1668, 1260, 1050 cm 1 - N.M.R. ~ ppm (DMSO-d6) : 2.07 (3H, s), 3.35, 3.70 (2H, AB-q, J=18Hz), 4.11 (3H, s), 5.18 (lH, d, J=4.5Hz), 5.77 (lH, dd, J=~.5Hz, 8Hz), 6.80 (lH, d, J=8Hz), 7.20 (lH, d, J=9Hz), 7.98 (lH, dd, J=8Hz, 9Hz), 9.95 (lH, d, J=8Hz), 6-9.3 (2H, m) (11) 7-[2-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido]-3-(i-methyl-lH-tetrazol-5-yl)thiomethyl-3- -~
cephem-4-carboxylic acid(syn is~), mp. 165 to 170C (dec.).
I.R. v NmUa~ol : 3300, 1760, 1680 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.68 (2H, broad s), 3.93 (3H, s), 4.30 (2H, broad s), 5.13 (lH, d, J=4Hz), 5.83 (lH, dd, J=4Hz, 9Hz), 6.48 (lH, d, J=8Hz), 6.93 (lH, d, J=8Hz), 7.43 (lH, t, J=8Hz), 9.37 (lH, d, J=9Hz) (12) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp. l90 to 195C (dec.).
I.R. v mU~ol : 3400, 1780, 1720, 1670 cm l N.M.R. ~ ppm (DMSO-d6) : 3.60, 3.44 (2H, AB-q, J=17Hz), 3.88 (3H, s), 4.62, 4.88 (2H, AB-q, J=13Hz), 5~ E' 13 6~i3 5.13 (lH, d, J=4Hz), 5.80 (lH, dd, J=4Hz, 9Hz), 6.48 ~lH, d, J=8Hz), 6.88 (lH, d, J=8Hz), 7.42 (lH, t, J=8Hz~, 9.44 (lH, d, J=9Hz) (13) 7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, mp. 181 to 182.5C (dec.).
I.R. v NUxol : 3440, 3320, 1790, 1693, 16603 1630~ 1525, 1043 cm N.M.R. ~ ppm (DMSO-d6) : 3.68 (2H, broad s), 3.90 (3H, s), 3.93 (3H, s), 4.25, 4.33 (2H, AB-q, J=14Hz), 5.12 (lH, d, J=5Hz), 5.82 (lH, dd, J=5Hz, 8Hz), 6.85 (lH, d, J=5Hz), 8.27 (lH, d, J=5Hz), 9.50 (lH, d, J=8Hz) (14) 7-[2-(6-Aminopyridin-2-yl)-2-ethoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-ZO 3-cephem-4-carboxylic acid (syn isomer), mp. 165 bD 170C (dec.).
I.R. v NmaUxol : 3380, 3240, 1780, 1670 cm 1 N.M.R. ~ ppm (DMSO-d6) : 1.28 (3H, t, J=7Hz), 3.64, 3.76 (2H, AB-q, J=18Hz), 3.95 (3H, s), 4.18 (2H, q, J=7Hz), 4.24, 4.38 (2H, AB-q, J=14Hz), 5.15 (lH, d, J=5Hz~, 5.84 (lH, dd, J=5Hz, 8Hz), 6.50 (lH, d, J=8Hz), 6.90 (lH, d, J=8Hz), 7.43 (lH, t, J=8Hz), 9.46 (lH, d, J=8Hz)

(15) 7-[2-(6-Trifluoroacetamidopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanic acid (syn isomer)(380 mg.) was added to a solution of sodium acetate (857 mg.) in water (6 ml.), and stirred at room temperature for

16 hours. The resultant solution was washed with ~ E- )4 ethyl acetate (5 ml.),-adjusted to pH 4 with 10%
hydrochloric acid and washed with ethyl acetate.
The solution was concentrated under reduced pressure to 2/3 of the initial volume, and subjected to S column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20" (Trademark:
manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 10% isopropyl alcohol. The eluate was lyophilized to give 7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanic acid (syn i~x~)~130 mg.), pale yellow powder, mp. 155 to 161C (dec.).
I.R. v Nmaxl : 3350-3220, 1780, 1740, 1680-1655, 1380, 1040 cm~l N.M.R. ~ ppm (DMSO-d6) : 2.00 (2H, s), 3.5 (2H, lS broad s), 3.88 (3H, s), 4.67, 5.04 (2H, AB-q, J=12Hz), S.lS (lH, d, J=SHz), 5.83 (lH, dd, J=SHz, 8Hz), 6.45 tlH, d, J=8Hz), 6.88 (lH, d, J=8Hz), 7.43 (lH, t, J=8Hz), 9.4 (lH, d, J=8Hz) ;

- ~7 E ~L5 .~ .

;S~;3 Example 3 A solution of 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(5-t-butoxycarbonylamino-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn iso~)(1.12 g.) in 98% formic acid (11 ml.) was stirred at room temperature for 2 hours. Methanol (20 ml.) and conc. hydrochloric acid (0.3 ml.) were added to the resultant solution and then stirred at room temperature for 30 minutes. After the reaction mixture was concentrated in vacuo, water (25 ml.) was added to the residue, and then the solution was adjusted to pH 3 to 4 with a saturated aqueous solution of sodium bicarbonate. The solution was subjected to column chromatography on macroporous, non-lS ionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.) with an eluent of aqueous methanol. The eluate was concentrated under reduced pressure and lyophilized to give 7-[2-(6-aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.48 g.), mp. 248 to 251C (dec.).
I.R. ~ Nma~l : 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.53 (2H, broad s), 3.88 (3H, s), 4.35 (4H, broad s), 5.05 (lH, d, J=SHz), 5.75 (lH, dd, J=5Hz, 8Hz), 6.48 (lH, d, J=8Hz), 6.88 (lH, d, J=8Hz), 7.43 (lH, t, J=8Hz) - E- 1~

114~ 3 , Example 4 (1) 10~ Palladium on carbon (216 mg.) was added to a solution of 4-nitrobenzyl 7-[2-(6-formamido- }
pyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-S carboxylate (540 mg.) in tetrahydrofuran (10 ml.), methanol (5 ml.), ace~ic acid (0.075 ml.), and water (0.75 ml.). The mixture was subjected to ?
catalytic reduction at ambient temperature under ordinary pressure for 5 hours, and then allowed to stand overnight. After filtered off the catalyst, the filtrate was concentrated under reduced pressure.
Ethyl acetate and an aqueous solution of sodium bicarbonate were added to the residue, and the aqueous layer was separated. The solution was adjusted to lS pH 2 with 10% hydrochloric acid. The appeared precipitates were collected by filtration, washed with water and dried to give 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (300 mg.), mp. 202 to 204C (dec.).
I.R. v maUxol : 3250, 3200, 1780, 17210, 1660 cm 1 N.M.R. ~ ppm (DMSO-d6 ~ D2O) : 3.56 (2H, broad d), 3.96 (3H, s), 5.13 (lH, d, J~5Hz), 5.91 (lH, d, J=SHz), 6.46 (lH, m), 6.85-8.00 (3H, m) (2) A mixture of 4-nitrobenzyl 7-[2-(6-formamido-pyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn i~r)(l.43 g.), 10% palladium on carbon (0.8 g.), methanol (30 ml.) and tetrahydrafuran (60 ml.) was subjected to catalytic reduction at ambient temperature under ordinary pressure for 4 hours.
After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue, and the aqueous layer was separated. The aqueous layer was adjusted to pH 6, E - l 7 .. ~. .. : , ... ......... . ... . ~ , 11 ~65S3 washed with ethyl acetate, and then adjusted to pH 1 to Z. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. Diethyl ether (30 ml.) was added to the 'residue, stirred for one hour, and then the precipitates were collected by filtration to give 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic'acid ~syn isomer)(6~0 mg.), brownish yellow powder, mp.' 200 to 204C (dec.).
I.R. ~ mU~ol : 3225, 1780, 1730, 1680-1650, ' 1550 cm N.M.R. ~ ppm (DMSO-d6) : 3.65, 4.08 ~2H, AB-q, J=18Hz), 4.00 (3H, s), 5.30 tlH, d, J=4.5Hz), 5.98 (lH, dd, J=~Hz, 4.5Hz), 6.97 (lH, d, J=8Hz), 7.53 (lH, d, J=8Hz), 7.87 (lH, t, J=8Hz), 9.35 (lH, m), 9.63 (lH, d, J=8Hz), 10.63 (lH, m) The following compounds were prepared in substantially the same manner as that of Example 4-(1) 'and t2).
t3) 7-[2-t6-Formamidopyridin-2-yl)-2-methoxyimino-acetamido]-3-methoxy-3-cephem-4-carboxylic acid, mp. 173 to 175C (dec.).
I.R. v NmUa~ol : 3300, 1770, 1720-1660, 1040, 810, 620 cm N.M.R. ~ ppm tDMSO-d6) : 3.61 (2H, broad s), 3.73 (3H, s), 3.95 ~3H, s~, 5-14 tlH, d, J=5Hz), 5.66 tlH, dd, J=5Hz, 8Hz), 6.9 ~lH, m)~
7.48 tlH, d, J=8Hz), 7.80 (lH, dd, J=8Hz, 9Hz), 9.3 (lH, m), 9.42 (lH, d, J=8Hz), 10.5 (lH, m) ~v E~ 18 4 ~S ~ 3 (4) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v mUxol : 3360, 3220, 1780, 1670, 1620, 1585, 1544, 1042 cm 1 ~5) 7-[2-~6-aminopyridin-2-yl)-2-methoxyimina-acetamido]-3-cephem-4-carboxylic acid.
I.R. v Naxl : 3300, 1785, 1730, 1670 cm 1 ~6) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-~1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NaU~ol : 3400, 3230, 1780, 1670, 1622, . 1590, 1550, 1050 cm 1 (7) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUa~jxol : 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm 1 (8) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-carboxymethyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUxol : 3380, 3220, 1780, 1670, 1620, 1050 cm 1 (9) 7-~2-(6-Aminopyridin-2-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v maUxol : 3600-3080, 1763, 1698, 1663 cm 1 (10) .7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid hydrochloride (syn isomer).
I.R. v Nmaxl : 3300-3100, 1780, 1710, 1660, 1610, 1540, 1370 cm (11) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-methoxy-3-cephem-4-carboxylic acid.
I.R. v mUxol : 3300, 1775, 1700-1650, 1045 cm 1 ~ ~65~3 ~123 7-[2-( 6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-7-methoxy-3-~1-methyl-lH-tetrazol-S-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v mUaxol : 3300, 1780, 1700, 1680 cm 1 ~13) 7-[2-~6-Aminopyridin-2-yl)-2-methoxyim~no-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn iso~).
I.R. v mUxol : 3400-3100, 1780, 1730, 1665, 1550, 1295, 1258, 1050 cm (14) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer).
I R. v NmUxol : 3100, 1780, 1682, 166~, 1260, 1050 cm~
(15) 7-[2-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. ~ Nmaxl : 3300, 1760, 1680 cm 1 (16) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v Nmaxl : 3400, 1780, 1720, 1670 cm 1

(17) 7-[2-(2-Aminopyrimidin-4-yl)-2-me~hoxyimino-acetamido]-3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
I.R. v mUxol : 3440, 3320, 1790, 1693, 1660, 1630, 1525, 1043 cm

(18) 7-[Z-(6-Aminopyridin-2-yl)-2-ethoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUxol : 3380, 3240, 1780, 1670 cm 1

(19) 7-[2-(6-Aminopyridin-2-yl)-Z-methoxyimino-acetamido]cephalosporanic acid (syn isomer).
I.R. v NmUxol : 3350-3220, 1780, 1740, 1680-1655, 1380, 1040 cm

(20) 7-[2-(4-AminopyTimidin-2-yl)-2-~2 E-20 ~ 5 ~ 3 methoxyiminoacetamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (a mixture of syn and anti isomer).
I.R. v NmUajxol : 3380, 3220, 1780, 1700-1620, 1240, 1040 cm 1

(21) 7-[2-Allyloxyimino-2-~6-aminopyridin-2-yl)-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v majxl : 3380, 3310, 1780, 1670, 1620 cm 1

(22) 7-~2-(6-Aminopyridin-2-yl)-2-propargyloxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NUaxol : 3270, 1765, 1690 J 1665, 1620, 1580, 1530 cm~l

(23) 7-[2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride.
I.R. v NUaxo : 3300-3100, 1785, 1660, 1390, 1050 cm~l

(24) 7-[2-(4-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid tsyn isomer).
I.R. v mUJol : 3400, 3230, 1778, 1650, 1600, 1380, 1050 cm 1

(25) 7-[2-(6-Aminopyridin-2-yl)-2-propoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. ~ mUaxol : 3400, 3250, 1780, 1670, 1625, 1590, 1550 cm 1

(26) 7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. ~ mU~ol : 3380, 3240, 1780, 1670, 1620 cm 1

(27) 7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-3 ~-21 ~S3 cephem-4-carboxylic acid (syn isomer).
I.R. v Nm~axl : 3370, 3220, 1780, 1670, 1620 cm 1 - (28) 7-[2-(2-Aminopyridin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. ~ NmUxol 3200, 1775, 1670, 1600, 1560 cm 1 (29) 7-~2-(6-Aminopyridin-2-yl)-2-ethoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUaxol : 3350, 3150, 1795, 1730, 1670 cm 1 (30) 7-[2-(6-Aminopyridin-2-yl)-2-propoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NUxol : 3340, 3150, 1780, 1735, 1670 cm 1 (31j 7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUajxol : 3350, 3150, 1795, 1735, 1670 cm 1 (32) 7-[2-(6-Aminopyridin-2-yl)-2-butoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v mUa~ol : 3350, 3200, 1775, 1670, 1620, - 1585, 1540 cm 1 (33) 7-~2-(6-Aminopyridin-2-yl)-2-butoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v maUxol : 3400, 3120, 1785, 1660 cm 1 (34) 7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v mU~ol : 3300, 1785, 1735, 1660 cm 1 (35) 7-[2-Allyloxyimino-2-(6-aminopyridin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer) .
I.R. ~ NmaUxol : 3350, 3150, 1795, 1735, 1670 cm 1 64 ~-2~' 1~465~3 (36) 7-[2-~6-Aminopyridin-2-yl)-2-propargyloxy-iminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v mUxol : 3350, 1780, 1670 cm 1 (37) 7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoro-ethoxyimino)acetamido]-3-(1-methyl-lH-tetrazol-5-ylthio-methyl~-3-cephem-4-carboxylic acid (syn isomer).
I.R. v mUaxol : 3400, 1780, 1690 cm 1 (38) 7-[2-(6-Aminopyridin-2-yl)-2-phenoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn - isomer).
I.R. v NmUaxol : 3200, 1760, 1690, 1670 cm 1 (39) 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUaxol : 3380, 3Z20, 1780, 1680, 1630, 1590, 1550 cm~l (40) 7-[2-(6-Aminopyridin-3-yl3-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (anti isomer).
I.R. - v mUxol : 3350, 3200, 1780, 1680, 1630, 1520 cm (41) 7-[Z-(6-Amino-3-chloropyridin-2-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride (syn isomer).
I.R. v NmUaxol : 3350-3100, 1790, 1670J 1550, 1380, 1235, 1040 cm (42) 7-[2-(6-Amino-3,5-dichloropyridin-2-yl)-2-mqthoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUaxol : 3300, 1785, 1730, 1660, 1545, 1380, 1235, 1045 cm~l (43) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 164-171C
(dec.).

6~ E- ~3 ~1 4~iS~-3 (44) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(S-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 161-167C
(dec.).
(45) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]cephalosporanic acid (syn isomer), mp. 149-159C (dec.).

~ _ 5 ~

li ~6~53 Example 5 (1) A solution of 7-[2~-formamidopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanic acld (syn isomer) (2.10 g.) and disodium 2-(5-sulfido-lH-tetrazol-l-yl)acetate (2.70 g) in water (40 ml.) was adjusted to pH 7 with sodium bicarbonate, and stirred at 65~C for 6 hours at p~ 7 to 7.4. The resultant solution was washed with ethyl acetate, adjusted to pH 2.5 with 10% hydrochloric acid and stirred. The precipitates were collected by fil-tration, washed with water and diethyl ether in turnto give 7-[2-~formamidopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-carboxymethyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.27 g.), mp. 166 to 168C tdec.).
I R v Nu~ol : 3300, 1782, 1737, 1670 ~broad), 1577, 1247, 1053 cm 1 N.M.R. ~ppm (DMSO-d6) : 3.60, 3.72 (2H, AB-q, J=18Hz), 3.92 (3H, s), 4.23, 4.45 ~2H, AB-q, J=13Hz), 5.12 ~lH, d, J=5Hz), 5.28 (2H, s), 5.83 (lH, dd, J=5Hz, 8Hz), 6.88 (lH, broad d, J=8Hz), 7.50 (lH, d, J=8Hz), 7.83 (lH, t, J=8Hz), 9.32 (lH, broad d, J=8Hz), 9.55 (lH, broad d, J=8Hz), 10.5 - 10.8 (lH, m).

The following compounds were prepared in sub-stantially the same manner as that of Example 5-(1).
(23 7-[2-~6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. vmUaxol : 3360, 3220, 1780, 1670, 1620, 1585, 1544, 1042 cm~
(3) 7-[2-(6-Aminopyridin-2-yl)-2-67 E~

5~3 methoxyiminoacetamido]-3-~1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid ~syn isomer).

I.R. v mUJol : 3400, 3230, 1780, 1670, 1622, 1590, lS50, 1050 cm 1 .

~4) 7-[2-~6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v Nu~ol : 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm (5) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-carboxymethyl-lH-tetrazol-5-yl)- .
thiomethyl-3-cephem-4-carboxylic acid tsyn isomer).

I.R. ~ Na~l : 3380, 3220, 1780, 1670, 1620, lOS0 cm ~l (6) 7-[2-(6-Aminopyridin-2-yl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v NaUxol : 3600-3080, 1763, 1698, 1663 cm 1 (7) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-7-methoxy-3-(l~methyl-lH-tetrazol-5-yl)thio methyl-3-cephem-4-carboxylic acid (syn isomer) I.R. v NUaxol : 3300, 1780, 1700,1680 cm (8) 7-[2-(6-Aminopyridin-Z-yl)-2-hydroxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

68 E~

1~6553 I.R. v mUxol : 3300, 1760, 1680 cm 1 (9) 7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyiminoacetamido3-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid.

I.R. v Nma~l : 3440, 3320, 1790, 1693, 1660, 1630, 1525, 1043 cm~
(10) 7-[2-(6-Aminopyridin-2-yl}2-ethoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v ma~l : 3380, 3240, 1780, 1670 cm 1 (11) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (a mixture of syn and anti isomer).

I.R. v mUaxol : 3380, 3220, 1780, 1700-1620, 1240,1040 cm (12) 7-[2-(Allyloxyimino-2-(6-aminopyridin-2-yl)-acetamidol-3-(1-methyl-lH-tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid (syn isomer).

I.R. v mUaxQl : 3380, 3310, 1780, 1670, 1620 cm 1 (13) 7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v Nujol 3270, 1765, 1690, 1665, 1620, max 1580, 1530 cm~l E~

~ 3 (14) 7-[2-(2-Amino-6-chloropyri~idin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride I.R. v mUa~ol : 3300-3100, 1785, 1660, 1390, 1050 cm (15) 7-[2-(4-Aminopyridin-2-yl)-2-methoxymino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid tsyn isomer).

I.R. v NmUaxol : 3400, 3230, 1778, 1650, 1600, 1380, 1050 cm 1 (16) 7-12-(6-Aminopyridin-2-yl)-2-propoxyi~ino-- acetamido]i~-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).

I.R. v mU~ol : 3400, 3250, 1780, 1670, 1625, ~ 1590, 1550 cm (17) 7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v mUa~ol : 3380, 3240, 1780, 1670, 1620 cm 1 (18) 7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).

I.R. v maUxol : 3370, 3220, 1780, 1670, 1620 cm 1 (19) 7-[2-(2-Aminopyridin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-E- ;'8 ~ 6S ~ 3 3-cephem-4-carboxylic acid (syn isomer).

I.R. v NUaxol : 3200, 1775, 1670, 1600, 1560 cm 1 (20) 7-[2-(6-Aminopyridin-2-yl)-2-butoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-- 3-cephem-4-carboxylic acid (syn isomer).

I.R. v NmUjxol : 3350, 3200, 1775, 1670, 1620, 1585, 1540 cm~

(21) 7-[2-(~-Aminopyridin-2-yl)-2-(2,2,2-trifluoro-ethoxyimino)acetamido]-3-~1-methyl-lH-tetr.~zol-5-ylthio-methyl~-3-cephem-4-carboxylic acid (syn isomer)~
I.R. v NmUxol : 3400, 1780, 1690 cm 1 (22) 7-12-(6-Aminopyridin-3-yl)-2-metho.xyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).

I.R. v mUxol 3380, 3220, 1780, 1680, 1630, 1590, 1550 cm (23) 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid (anti isomer).

I.R. ~ ma~l : 3350, 3200, 1780, 1680, 1630, I520 cm (24) 7-[2-(6-Amino-3-chloropyridin-2-yl)-2-methoxy-iminoacetamido]-3-tl-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride (syn isomer).

E- ~9 I.R. v maxl : 3350-3100, 1790, 1670, 1550, 1380, 1235) 1040 cm~l (25) 7-~2-(6-Amino-3,5-dichloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol- 5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).

I.R. v mU~ol : 3300~ 1785, 1730, 1660, 1545, 1380, 1235, 1045 cm~l (26) 7-[2-(4-Aminopyri~idin-2-yl)-2-methoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic ~cid (syn isomer), mp 164 -171C ~dec.).

(27) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer), mp 161-167C (dec.).

.

.

6 ~ ~ 3 Example 6 To phosphoryl chloride t2.6 g.) was added N,N-dimethylformamide (4 ml.) and the mixture was stirred at 40 to 50C for 30 minutes, and then methylene chloride (20 ml.) was added thereto. To this mixture was added 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (1.9 g.~ under cooling at -20 to -15C with stirring, and the stirring was continued at the same temperature for 30 minutes.
On the other hand, 7-amino-3-~1-methyl~lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and trimethyl-silylacetamide ~11 g.~ were added to methylene chloride (66 ml.) and the mixture was stirred at ambient temperature for an hour, and to this solution was added all at once lS the above activated solution of 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid under ~ooling at ~20C.with stirring, and the stirring was continued at the same temperature for an hour and at ambient temperature for additional an hour.
The reaction mixture was concentrated under reduced pressure and then ethyl acetate and an aqueous solution of sodium bicarbonate were added to adjust the solution to pH 7 to 8.
After the aqueous layer was separated out, a proper quantity of ethyl acetate was added thereto. The mixture was adjusted to pH 1 to 2 with dilute hydrochloric acid and then salted out. The ethyl acetate layer was separated out, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate, and then evaporated to dryness under reduced pressure. The resultant foamy substance was pulverized in ethyl e~her, collected by filtration and then dried to give 7-[2-(4-formamidopyrimidin-' ':

11~6~;~i3 2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t2.9 g.). Thus obtained product (0.6 g.) was dissolved in a mixed solution of methanol and ethyl acetate (5 ml.)(2:1 by volume), and S the solution was poured into ethyl ether (40 ml.) and then the mixture was allowed to stand for a while. The precipitates were collected by filtration to give purified pale-yellowish powder of 7-[2-~4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetTazol-S-ylthio-methyl)-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers) (O.S g.).
I.R. v NmaU~ol : 3300, 1785, 1650-1730, 1570, 1240, 1175, 1040, 720 cm N.M.R. ~ppm (DMSO-d6) : 3.70 (2H, m) lS 3.92 (3H, s) 3.92 (s) } (3H) 3.99 (5) 4.20 and 4.30 (2H, ABq, J=15Hz) 5.05 (d, J=5Hz) } tlH) 5.15 (d, J=SHz) 5.60 (m) } (lH) 5.80 (d,d, J=5Hz, 9Hz) 6.90-7.60 (lH, m) 8.61 (lH, d, J=5Hz) 8.76 (d, J-9Hz) } (lH) 9.51 (d, J=9Hz) 11.10 (lH, broad s) Example 7 To phosphoryl chloride (1.6 g.) was added N,N-dimethylformamide (8 ml.) and the mixture was stirred at :

ll'lfiS~i3 40C for 30 minutes. To this mixture was added a solution of 2-allyloxyimino-2-(6-formamidopyridin-2-yl)acetic acid (syn isomer) (2.0 g.) in N,N-dimethylformamide (8 ml.) under cooling at -15C with stirring and the stirring was continued at -10 to -8C for an hour.
On the other hand, 7-amino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.2 g.) and trimethylsilylacetamide (11.5 g.) were added to methylene chloride (35 ml.), and the mixture was stirred at 30C
till it became a solution and then cooled to -i~C.
To this solution was added the above obtained N,N-dimethylformamide solution under cooling at -15C with stirring, and the stirring was continued at the same temperature for an hour After the reaction mixture was poured into an aqueous solution (80 ml.) of sodium bicarbonate (3.2 g.), the aqueous layer ~as separated out, washed with ethyl acetate. To the aqueous solution was added ethyl acetate and the mixture was adjusted to pH 3 to 4 with 5% hydrochloric acid. The ethyl acetate layer was separated out and the remaining aqueous solution was extracted twice with ethyl acetate. The ethyl acetate solution and these extracts were combined together, ~
dried and then evaporated to dryness under reduced pressure.
The residue was crystallized from water, collected by filtration and then dried to give 7-[2-allyloxyimino-2-(6-formamidopyridin-2-yl)acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.81 g.), mp. 132 - 135C (dec.) I.R. v Nma~l : 3300, 1785, 1670, 1580, 1545 cm 1 3C N.M.R. ~ ppm [ace~one-d6 and D2O~: 3.~3 (2H, broad s), E~33 ~4t~5~3 4.00 ~3H, s), 4.43 (2H, broad s), 4.70-4.87 (2H, m), 5.27 (lH, d, J=5Hz), 5.13-5.60 (2H, m), 5.83-6.27 (2H, m), 7.00-8.00(3H, m) ExamPle 8-(l) To phosphoryl chloride (1.61 g.) was added N,N-dimethylformamide (8 ml.) and the mixture was stirred at 40C for 30 minutes. To this mixture was added a solution of 2-(6-formamidopyridin-2-yl)-2-propargyloxyiminoacetic acid (syn isomer) (2.0 g.) in N,N-dimethylformamide (8 ml.) under cooling at -15C with stirring, and the stirring was continued at -10 to -8C for 40 minutes.
On the other hand, 7-amino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid lS (3-.25 g.) and trimethylsilylacetamide (10.5 g.) were added to methylene chloride (40 ml.), and the mixture was stirred at 30C till it became a solution.
To the solution was added the above obtained N,N-dimethylformaide mixture under cooling at -15C with stirring, and the stirring was continued at the same temperature for an hour. After the reaction mixture was poured into an aqueous solution ~80 ml.) of sodium bicarbonate (4.0 g.), the aqueous layer was separated out.
The remaining methylene chloride solution was extracted with an aqueous solution of sodium bicarbonate~ Thus obtained aqueous layer and extract were combined together, and adjusted to pH 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, dried and then evaporated to dryness under reduced pressure. The residue was pulverized in water, collected by filtTation and then dried to give 7-[2-t6-formamidopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-~1-methyl-lH-tetrazol- S-ylthiomethyl)-3-cephem-4-carboxylic acid tSyn isomerj (2.41 g.), mp. 123 - 125C (dec.) I.R. ~ NmaUixol : 3300, 1780, 167P, 1575, 1540 cm 1 N.M.R. ~ ppm (acetone-d6 and D2O~ : 3.07 (lH, tJ J=2Hz), 3.83 (2H, s), 4.00 (3H, s), 4.43 ~2H, s), 4.87 (2H, d, J=2Hz), 5.27 (lH, d, J=5Hz)~ 6.07 (lH, d, J=SHz), 7.00-8.07 (3H, m~
The following compounds were obtained according to similar manners to those of Examples 6 to 8-(1).
(2~ 7-[2-(Z-Pormamidopyridin-4-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 138-140C (dec.).
I.R. v Nma~l : 3250, 1780, 1680, 1610, 1550 cm 1 N.M.R. ~ ppm (~MS0-d6) : 3.73 (2H, broad s), 3.97 (3H, s~, 4.03 (3H, s), 4.40 (2H, broad s), 5.23 (lH, d, JzSHz), 5.90 ~lH, d,d, J=5Hz, 8Hz), 7.13-8.53 (3H, m), 9.87 (lH, d, J=8Hz), 10.73 (lH, d, J=6Hz) (3) 7-[2-(4-Formamidopyridin-2-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 160-166C ~dec.).
I.R. v mU~ol: 3300~ 1780, 1690, 1590, 1520, 1380, 1040 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.70 (2H, m), 3.95 (6H, s), 4.32 ~2H, broad s), 5.15 (lH, d, J=4.5 Hz) 5.85 (lH, d,d, J=4.5 Hz, 8.0 Hz), .~ ..
77 ~- ~5 ~1 ~65~;3 8.10-8.50 (4H, m), 9.52 (lH, d, J=8Hz) (4) 7-[2-(6-Chloro-2-formamidopyrimidin-4-yl~-2-methoxyiminoacetamido]-3-(1 methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (syn and anti mixture).
I.R. v ma~l : 3200-3300, 1780, 1700, 1680, 1550, 1380, 1040 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.75 (2H, m) 3.98 (3H, s) 4.01 (3H, s) 4.35 (2H, m) 5.20 (lH, d, J=405H~) 5.90 (lH, m) 6.80 (s) } (lH) 6.90 (s) 9.41 (d, J=BHz) 9.69 (d, J=8Hz) 9.45 (lH, d, J=lOHz) 11.05 (d, J=lOHz) 11.43 (d, J=lOHz) (5) 7-[2-(3-Chloro-6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer), mp.
165-172C (dec.).
I.R. v ma~l : 3300, 1790, 1710, 1670, 1645, 1370, 1270, 1050, 725 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.68 (2H, m), 3.94 (3H, s), 3.98 (3H, s), 4.20, 4.38 (2H, ABq, J=14Hz), 5.14 (lH, d, J=4.5Hz), 5.82 (lH, d,d, J=4.5Hz, 8Hz), 6.90 (lH, m), 7.94 (lH, d, J=8Hz), 65 ~ ~

9.22 (lH, m)~ 9.52 (lH, d, J=8Hz), 10.72 (lH, d, J=8Hz) (6) 7-[2-(3,5-Dichloro-6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-S-ylthio-methyl)-3-cephem-4-carboxylic acid ~syn isomer), mp. 149-155CC (dec.~.
I.R. v NUxol : 3250, 1785, 1705, 1688, 1665, 1420, 1255, 1200, 1073, 1050 cm 1 N.M.R. ~ ppm ~DMSO-d6) : 3.70 (2H, m), 3.95 (3H, s), 4.01 t3H, s), 4.33 (2H, broad s), 5.17 (lH, d, J=4.5Hz), 5.87 (lH, d,d, J=4.5Hz, 8Hz), 8.31 (lH, s), 9.18 (lH, d, J=8Hz), 9.57 (lH, d, J=8Hz), 10.65 (lH, d, J=8Hz) lS (7) 7-[2-Ethoxyimino-2-(6-formamidopyridin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 183-186C (dec.).
I.R. ~ Nu~ol : 3350, 3300, 1790, 1730, 1670 cm 1 N.M.R. ~ ppm (DMSO-d6) : 1.25 (3H, t, J=7Hz), 1.40 (3H, d, J=7Hz), 3.75 (lH, m), 4.15 (2H, q, J=7Hz), 5.10 (lH, d, J=4Hz), 5.90 (lH, d,d, J=8Hz, 4Hz), 6.50 (1~, d, J=6Hz), 6.70-8.20 (3H, m) (8) 7-[Z-(6~Formamidopyridin-2-yl)-2-propoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NuJol : 3300, 1785, 1680, 1580, 1550 cm 1 N.M.R. ~ ppm (acetone-d6 and D2O) : 0.96 ~3H, t, J=7Hz), 1.64-1.84 (2H, m), 3.72, 3.82 (2H, ABq, J=18Hz), 7 ~ '. 7 6 5 ~ ~
3.96 (3H, s), 4.16 (2H, t, J=7Hz), 4.40 (2H, broad s), 5.20 (lH, d, J=5Hz), 6.00 (lH, d, J=5Hz), 5.88-8.20 (3H, m) (9) 7-[2-Isopropoxyimino-2-(6-foTmamidopyridin-2-yl)acetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v Nma~l : 3300, 1785, 1680, 1580, 1540 cm 1 N.M.R. ~ ppm (acetone-d6 and D20) : 1.32 (6H, d, J-6Hz), 3.76, 3.88 (2H, ABq~ J=18Hz), 3.98 (3H, s), 4.40 (2H, broad s), 4.36-4.64 (lH, m), 5.24 (lH, d, J=SHz), 6.04 (lH, d, J=5Hz), 6.92-8.20 (3H, m) lS ~ 7-~2-(6-Formamidopyridin-2-yl)-2-propoxylmino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 145-150C (dec.) I.R. v Nu~ol : 3300, 1790, 1680 cm 1 N.M.R. ~ ppm (DMS0-d6) : 0.95 (3H, t, J=8Hz), 1.45 (3H, d, J=7Hz), 1.40-1.90 (2H, m), 3.83 (lH, m), 4.17 (2H, t, J=6Hz), 5.17 (lH, d, J=4Hz), 6.00 (lH, d,d, J=4Hz, 8Hz), 6.58 (lH, d, J=6Hz), 6.80-8.20 (3H, m) (ll) 7-[2-Isopropoxyimino-2-(6-formamidopyridin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp 160-163C.
I.R. v Nmajxl : 3300, 1790, 1735, 1670 cm 1 N.M.R. ~ ppm (DMS0-d6) .: 1.30 (6H, d, J=611z), 1.45 (3H, d, J=7Hz), 3.80 (lH, m), ~ E~ ~8 ~ ~ 4 6~

4.45 (lH, m), 5.15 (lH, d, J=4Hz), 6.00 (lH, d,d, J=4Hz, 8Hz), 6.58 ~lH. d, J=6Hz), 6.80-8.20 (3H, m) (12) 7-[~-Butoxyimino-2-(6-formamidopyridin-2-yl)-5acetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 153-155~C (dec.).
I.R. v NaU~ol : 3300, 1785, 1670, 1580, 1550 cm 1 N.M.R. 6 ppm (acetone-d6 and D20) : 0.80-1-07 t3H, m), - 1.23-1.83 (4H, m), 3.83 (2H, broad s), 3.97 (3H, s), 4.23 (2H, t, J=6Hz), 4.43 ~2H, broad s), 5.27 (lH, d, J=5Hz), 6.10 (lH, d, J=5Hz), 6.97-8.00 (3H, m) tl3) 7-[2-(6-Formamidopyridin-2-yl)-2-isobutoxyimino-15 acetamido~-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 118-120C (dec.).
I.R. v NuJol : 3500, 3300, 1785, 1680, 1580, 1550 cm~
N.M.R. ~ ppm (DMSO-d6) : 0.93 (6H, d, J=6Hz), 1.77-2.17 (lH, m), 3.70 (2H, broad s), .20 3.93 (3H, s), 4.00 (2H, d, J=6Hz), 4.33 (2H, broad s), 5.18 (lH, d, J=SHz), 5.90 (lH, d,d, J=SHz, 9Hz), 6.83-8.00 (3H, m) (14) 7-[2-Butoxyimino-2-(6-formamidopyridin-2-yl)-25acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp.155-160C ~dec.).
I.R. v maUJol : 3300, 1790, 1680 cm 1 N.M.R. ~ ppm (DMSO-d6) : 0.83-1.83 (lOH, m), 3.67-4.00 (lH, m~, 4.27 (3H, t, J=4Hz), 5.22 (lH, d, J=4Hz), 6.03 (lH, d,d, J=4Hz, 8Hz), ~ L ~9 6 5 ~ ~

6.62 (lH, d, J=6Hz), 7.00-8.50 (3H, m) ~ 15) 7- [2- (6-Formamidopyridin-2-yl)-2-isobutoxy-iminoacetami do]-2-me thyl - 3 - ceph em- 4 - carboxyli c aci d (syn isomer), mp. 152-154C (dec.).
I R ~ Nu~ol 3300, 1790, 1675 cm N.M.R. ~ ppm ~DMSO-d6) : 0.90 (6H, d, J=6Hz), 1.42 (3H, d~ J=6Hz), 2.00 ~lH, m), 3.80 (lH, m), 3.90 (2H, d, J=6Hz), 5.10 (lH, d, J=4Hz), 5.95 (lH, d,d, J=4Hz, 8Hz), 6.50 ~lH, d, J=6Hz), 6.80-8.20 (3H, m) (16) 7-[2-Allyloxyimino-2-(6-formamidopyridin-2-yl3-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer~
mp. 128-132C (dec.).
I.R. v Nu~ol 3300, 1790, 1730, 1670 cm N.M.R. ~ ppm (DMS0-d6) : 1.45 (3H, d, J=7Hz), 3.85 (lH, m), 4.70 (2H, d, J-5Hz), 5.20 (lH, d, J=4Hz), 5.20-5.50 t2H, m~, 5.80-6.20 (lHJ m~, 6.00 (lH, d,d, J=4Hz, 8Hz), 6.60 (lH, d, J=6Hz), 6.80-8.20 (3H, m) (17) 7-~2-~6-Formamidopyridin-2-yl)-2-propargyloxy-iminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 134-137C (dec.).
I.R. ~ Nma~l 3300, 1790, 1730, 1670 cm N.M.R. ~ ppm (DMS0-d6) : 1.45 (3H, d, J=7Hz), 3.50 tlH, t, J=2Hz), 3.80 (lH, m), 4.85 (2H, d, J=2Hz), 5.15 (lH, d, J=4Hz), 6.00 (lH, d,d, J=4Hz, 8Hz), ~2 E-40 ~ 465~
6.58 (lH, d, J-6Hz), 6.80-8.20 ~3H, m) ~18) 7-[2-(2,2,2-Trifluoroethoxyimino)-2-~6-formamidopyridin-2-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 165-170~C (dec.).
I.R. v NmU~ol : 3300, 1790, 1690 cm 1 N.M.R. ~ ppm (DMS0-d6) : 3.70 (2H, broad s) 9 3.93 (3H, s), 4.32 (2H, broad s), 4-70. 4.95 t2H, ABq, J=9Hz), 5.15 (lH, d, J-4Hz), 5.88 (lH, d,d, J=4Hz, 8Hz), 7.00-8.00 (3H, m), 9.33 (lH, m), 9.67 (lH, d, J-8Hz), 10.60 ~lH, m~
(19) 7-12-(6-Formamidopyridin-2-yl)-2-phenoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 150-155C (dec.).
I.R. v Nma~l : 3250, 1780, 1720, 1650 cm 1 N.M.R. ~ ppm (DMS0-d6) : 1.50 (3H, d, J=7Hz), 3.90 (lH, m), 5.25 (lH, d, J=4Hz), 6.10 (lH, d,d, J=4Hz, 8Hz), 6.60 (lH, d, J-6Hz), 7.0-8.2 (8H, m), 9.86 (lH, d, J=8Hz~, 10.73 (lH, d, J=8Hz) (20) 7-[2-(6-Formamidopyridin-3-yl)-2-methoxyimino-acetamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v mU~ol : 3250, 1780, 1680, 1250, 1175, 1035 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.75 (2H, broad s), ~; ~ 4 ~3 -6~
3.98 (6H, s), 4.35 (2H, broad s), 5.22 ~lH, d, J=5Hz), 5.87 (lH, d,d, J=5Hz, 8Hz), 7.8-8.5 (3H, m~, 9.83 (lH, d, J=8Hz), 10.87 (lH, d, J=7Hz) (21) 7~[2-(6-Formamidopyridin-3-yl)-2-methoxyimino-acetamido]-3-(l-methyl-lH-tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid ~anti isomer).
I.R. v NmaU~ol: 3300, 1780, 1680-1710, 1600, 1240, 1050 cm~l N.M.R. ~ ppm (DMSO-d6) : 3.74 (2H, broad s~, 3.96 (3H, s), 4.00 (3H, s), 4.00, 4.28 (2H, A8q, J=13Hz), 5.16 (lH, d, J=SHz), 5.72 (lH, d,d, J=5Hz, 8Hz), 7.80-8.50 (3H, m), 9.28 (lH, d, J=8Hz), 10.80 (lH, d, J=6Hz) ~le 9 (1) Phosphoryl chloride (500 mg.) was added dropwise to a suspension of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (250 mg.) in ethyl acecate ~5 ml.) at 0 to 6C with stirring and the stirring was continued at the same temperature for 45 minutes.
To this solution was added dropwise N,N-dimethylformamide (0.7 ml.) over a period of 6 minutes at 0 to 6DC with stirring, and che stirring was continued at the same temperature for 40 minutes. To the resultant solution was added all at once a solution of 7-amino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (365 mg.) and trimethylsilylacetamide ~1.5 g.) in ethyl ~ 4 1~: -42 , . :

65 ~ ~

acetate (7 ml.) under cooling at -20C, and the mixture was stirred at 0 to 6C for an hour. The reaction mixture was poured into water (20 ml.) and adjusted to pH 4 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated out and the remaining organic layer was extracted with water. The aqueous layers were-combined together and the ethyl acetate remained in the aqueous solution was removed therefrom undeT reduced pressure. The aqueous solution was subjected to column chromatogTaphy on a non-ionic adsorption resin, "Diaion HP-20" (Trade Mark, manufactured by Mitsubishi Chemical Industry Ltd.) t20 ml.). After the column was washed with water, elution was carried out with 5-10~ aqueous methanol tlO0 ml.), 20% aqueous methanol (lS0 ml.) and 20 to 30% aqueous methanol (150 ml.) in turn, and the fractions containing the desired compound were collected and evaporated to dryness under reduced pressure. The resultant residue was lyophilizedto give 7-t2-(4-amino-pyrimidin-2-yl)-2-methoxyiminoacetamido]-3-tl-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid -(sy~ isomer) (110 mg.), mp. 155 to 158C.
I.R. v NaUJol : 3380, 3220, 1780, 1630-1690, 1590, 1040, 840 cm 1 N.M.R. ~ ppm (DMS0-d6) : 3.65 (2H, m), 3.94 (3H, s), 4.32 (2H, broad s), 5.11 (lH, d, J-5Hz), 5.80 (lH, d,d, J=5Hz, 8Hz), ; 6.44 (lH, d, J=6Hz), 7.04 (2H, broad s~, 8.10 (lH, d, J=6Hz), 9.43 (lH, d, J=8Hz) The following compounds were obtained according ~ ~ 6~3 to similar manner to that of Example 9-(13.
(2) 7-[2-Allyloxyimino-2-(6-aminopyridin-2-yl)-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 149-151C
(dec.).
~3) 7-[2-(6-Aminopyridin-2-yl)-2-propargyloxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid tsyn isomer), mp. 163-165C
(dec.).
(4) 7-[2-(2-Aminopyridin-4-yl)-2-methoxyimino-acetamido~-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 175-177C
(dec.).
(5) 7-~2-(4-Aminopyridin-2-yl)-2-methoxyimino-lS acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl~3-cephem-4-carboxylic acid (syn isomer), mp. 163-167C
(dec.).
(6) 7-[2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid hydrochloride, mp. 170-180C.
(7) 7-[2-(6-Amino-3-chloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-S-ylthio-methyl)-3-cephem-4-carboxylic acid hydrochloride (syn isomer), mp. 155-160C (dec.).
(8) 7-[2-(6-Amino-3,5-dichloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer), mp.
139-144C (dec.).
(9) 7-[2-(6-Aminopyridin-Z-yl)-2-ethoxyiminoacetamido]-~ E-44 5~

2-methyl-3-cephem-4-carboxylic acid (syn iisomer), mp.
190-195C (dec.).
(10) 7-[2-(6-Aminopyridin-2-yl)-2-propoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer~j 138-140C tdec.).
~1) 7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyimino-acetamido]-3-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3 cephem-4-carboxylic acid (syn isomer3, mp. 149-151C
(dec.~.
(12) 7-[2-(6-Aminopyridin-2-yl)-2-propoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 190-195C (dec.).
(13) 7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyimino~
acetamido]-2-methyl-3-cephem~4-carboxylic acid (syn isomer), mp. 185-188C (dec.).
(14) 7-[2-(6-Aminopyridin-2-yl)-2-butoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 108-110C ~dec.).
(15) 7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 140-142C (dec.~.
(16) 7~[2-(6-Amir.opyridin-2-yl)-2-butoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp.
200-205C (dec.).
(17) 7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 175-180C (dec.).
(18) 7-[2-Allyloxyimino-2-(6-aminopyrydin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 168-173C (dec.).
8~ ~- 45 .

(19) 7-[2-(6-~ in-2-yl)-2-propargyloxy-iminoaceta~ido]~2-methyl-3-cephem-4-carboxylic acid (syn isomer~, mp. 165-170C ~dec.).
(20) 7-[2-(6-Aminopyridin-2-yl)-?-(2,2,2-trifluoro-S ethoxyiminoacetamido3-3-~1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (syn lsomer), mp.
165-170C (dec.).
(21) 7-[2-(6-Aminopyridin-2-yl)-2-phenoxyimino-acetamido~-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 145-147C (dec.).
ti2) 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 165-167C ~dec.).
(23) 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (anti isomer), mp. 153-155C (dec.).
(24) 7-[2-(4-Aminopyrimidin-2-yl)--2-methoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 164-171C (dec.).
I R ~ Nu~ol : 3380, 3220, 1780, 1620-1690, 1585, 1540, 1250, 1060, 1040, 89S, 830, 720 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.73 (2H, broad s), 3.95 (3H, s), 4.28, 4.65 (2H, ABq, J=13Hz), 5.18 (lH, d, J=5Hz), 5.87 (lH, d, d, J=5Hz, 8Hz), 6.48 (lH, d, J=7Hz), 7.05 (2H, broad s), 8.15 (lH, d, J=7Hz), 9.47 (lH, d, J=8Hz), 9.63 (lH, s) (2S) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 161-167C (dec.).

8 8 ~ ~ 4 b -- I.R. ~ ma~ 1 : 3380, 3220, 1780, 1620-1690, 1585, 1250, 1045, 840, 720 cm 1 N.M.R. ~ppm (DMSO-d6) : 2.70 (3H, s), 3.70 (2H, broad s), 3.97 (3H, s), 4.21, 4.58 (2H, ABq, J=13Hz), 5.22 (lH, d, J=5Hz), 5.81 (lH, d, d, J=5Hz, 8Hz), 6.47 (lH, d, J=7Hz), 7.05 (2H, broad s), 8.i2 (lH, d, J=7Hz), 9.47 (lH, a, J=8Hz) - (26) 7-[2-~4~Aminopyrimidin-~-yl)-2-methoxyimino-acetamido]cephalosporanic acid (syn isomer), mp 149-159C (dec.).
I.R. ~ NaU~ol : 3370, 3220, 1780, 1730, 1630-1680, 1040, 725 cm N.M.R. ~ ppm (DMSO-d6) : 2.03 (3H, s), 3.36, 3.62 ~2H, ABq, J=18Hzl, 3.93 (3H, s), 4.7, 5.0 ~2H, ABq, J=12Hz), 5.10 (lH, d, J=4.5Hz), 5.77 (lH, d, d, J=4.5Hz, 8.0Hz), 6.43 (lH, d, J=6.0HZ), 8.10 (lH, d, J=6.OHz), 9.40 (lH, d, J=8.OHz) ~9 6~ ~3 (27) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-~etrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v mUaxol : 3360, 3220, 1780, 1670, 1620, 1585, 1544, 1042 cm~l ~28) 7-(2-(6-Aminopyridin-2-yl)-2-methoximino-acetamido]-3-cephem-4-carboxylic acid.
I.R. v ma~l : 3300, 1785, 1730, 1670 cm 1 (29) 7-[2-(6-Aminopyridin-2-yl)-2-methoximino-acetamido]-3-(1,3,4-~hiadiazol-2-yl~thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v maxl : 3400, 3230, 1780, 1670, 1622, 1590, 1550, 1050 cm~l ~30) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v mUaxol : 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm 1 (31) 7-[2-(6-Aminopyridin-2-yl)-2-methoximino-acetamido]-3-(1-carboxymethyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v mUa~ol : 3380, 3220, 1780, 1670, 1620, 1050 cm (32) 7-[2-(6-Aminopyridin-2-yl)acetamido]-3-9 ~ ~ - 4 ~

s~
~l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) I.R. v maxl : 3600 3080, 1763, 1698, 1663 cm 1 (33) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid hydrochloride ~syn isomer).

I.R. v maxl : 3300-3100, 1780, 1710, 1660, - 1610, 1540, 1370 cm (34~ 7-~2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-methoxy-3-cephem-4-carboxylic acid.
I.R. v mUxol : 3300, 1775, 1700-1650, 1045 cm 1 (35) 7-[2-(6-Aminopyridin-2-yl)-2-me~hoxyimino-acetamido]-7-methoxy-3-(1-methyl-lH-tetrazol-5-yl)-thiometh~l-3-cephem-4-carboxylic acid (syn isomer).

I.R. v NUxol : 3300, 1780, 1700, 1680 cm 1 (36) 7-12-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid.(syn isomer).

I.R. v NmU~ol : 3400-3100, 1780, 1730, 1665, 1550, 1295, 1258, 1050 cm~l (37) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer).

I.R. v mUaxo : 3100, 1780, 1682, 1668, 1260, 1050 cm 9~ E-~J

6S ~ ~

~38) 7-[2-(6-Aminopyridin-2-yl)-2-hydroximino-acetamido]-3-~1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)~

I.R. v mUJol : 3300, 1760, 1680 cm 1 (39) 7-[2~(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid ~syn isomer).
I.R. v mUxol : 3400, 1780, 1720, 1670 cm 1 (40) 7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.

I.R. v Nmaxl : 3440, 3320, 1790, 1693, 1660, 1630, 1525, 1043 cm~l (41~ 7-[2-(6-Aminopyridin-2-yl)-2-et~axyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v NaJl : 3380, 3240, 1780, 1670 cm 1 (42) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]cephalosporanic acid (syn isomer).

I.R. v mUa]ol : 3350-3220, 1780, 1740, 1680-1655, 1380, 1040 cm 1 9 2 E ~ 50 ~ ~655~ .
.

Example 10 Conc.hydrochloric acid (0.36 ml) was added to a solution of 7-[2-(4-formamidopyrimidin-2-yl)-2--methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (1.9 g) in methanol (38 ml), and the mixture was stirred at ambient temperature for 5.5 hours. The reaction mixture was concentrated, and the concentrate was diluted with water and then washed with ethyl acetate.
After the ethyl acetate in the aqueous solution was remoYed by distillation, the aqueous solution was subjected to column chromatography on a macroporous, non-ionic adsorption resin, "Diaion HP-20" (Trade mark, manufactured by Mitsubishi Chemical Industries Ltd.) (110 ml). Elution was carried out with water (400 ml), iS~i~

10% aqueous methanol tlOO ml.), 20% aqueous methanol (200 ml.) and then 30% aqueous methanol (2 Q.), and the fractions containing the desired compound were collected. The combined fractions were e~aporated to dryness under reduced pressure to give powders tl- g.) of 7-[2-t4-aminopyrimidin-:. 2-yl)-2-methoxyiminoacetamido]-3-tl-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (a mixture of syn and anti isomer), mp. 150-160C tdec.).
I.R. ~, NaU~l: 3380, 3220, 1780, 1620-1700, 1240, 1040 cm 1 N.M.R. ~ ppm tDMSO-d6) : 3.72 (2H, broad s), 3.98 ~6H, s) 4.34 (2H, broad s) 5.08 (d, J=4H) } (lH) 5.15 (d, J=4Hz) ;. .
5.60-6.00 ~lH, m) 6.45 (lH, d, J=6Hz) 7.00 (2H, m) 8.12 (lHs d, J=6Hz) 8.87 (d, J=8Hz) 9.43 (d, J=8Hz) Example ii Conc. hydrochloric acid tO.31 ml.) was added to a solution of 7-[2-allyloxyimino-2-(6-formamidopyridin-2-yl)acetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.75 g.) in methanol (7 ml.), and the mixture was stirred at ambient temperature for 30 minutes. The methanol was remo~ed by distillation from the reaction mixture, and the remaining aqueous solution was diluted with water (80 ml.) 9 ~ E - 52 ...
:

~1 4L6S~33 and then adjusted to pH 2-3 with an aqueous solution of sodium bicarbonate. The aqueous solution was subjected to column chromatography on a macroporous, non-ionic adsorption resin "Diaion HP-20" (Trade Mark, manufactured S by Mitsubishi Chemical Industries Ltd.) (50 ml.). After the column was washed with water ~1 Q.), elution was carried out with 50% aqueous methanol (lQ.) and fractions containing the desired compound we~e collected. The methanol was removed by distillation from the combined fractions under reduced pressure and the resultant aqueous solution was lyophilized to give 7-[2-allyloxyimino-2-(6-aminopyridin-2-yl)a~etamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem^4-carboxylic acid (syn isomer) (1.13 g.), mp. 149-151C (dec.).
I.R. ~ mU~ol: 3380, 3310, 1780, 1670, 1620 cm 1 N.M.R. ~ ppm (DMS0-d6) : 3.70 (2H, broad s), 3.93 (3H, s), 4.33 ~2H, broad s), 4.67 (2H, d, J=5Hz), 5.17-5.57 t2H, m), 5.10 (lH, d, J=5Hz), 5.80 (lH, d,d, J=5Hz, 9Hz3, 5.83-6.27 (lH, m), 6.50 (lH, d, J=8Hz), 6.90 (lH, d, J=8Hz), 7.43 (lH, t, J=8Hz), 9.47 (lH, d, J=9Hz) E'xample~2 Conc. Hydrochloric acid (0.43 ml.~ was added to a solution of 7-[2-(6-formamidopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (2,35 g.) in methanol ~15 ml.), and the mixture was stirred 9~ E~

~ 3~ 3 at ambient temperature for 30 minutes. The methanol was removed by distillation under reduced pressure from the reaction mixture, and the remaining aqueous solution was diluted with water (100 ml.) and then adjusted to pH 2 with an aqueous solution of sodium bicarbonate. The precipitating crystals were collected by filtration, washed with water and then dried to give 7-[2-(6-aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.05 g.), mp. 163-16SC ~dec.).
I.R. v ma~xl: 3270, 1765, 1690, 1665, 1620, 1580, 1530 cm l ; N.M.R. ~ ppm (DMSO-d6j : 3.48 (lH, t, J=2Hz), 3.62, 3.76 (2H, ABq, J-18Hz), 3.90 (3H, s), 4.26, 4.34 (2H, ABq, J=13Hz), 4.76 (2H, d, J-2Hz~, 5.12 (lH, d, J=5Hz), 5.80 (1H, d,d, J=5Hz, 9Hz), 6.52 tlH, d, J=8Hz), 6.88 (lH, d, J-8Hz), 7.42 tlH, t, Jz8Hz), 9.54 (lH, d, J=9Hz) ExamPle 13~
Conc. hydrochloric acid (242 mg.) was added to a solution of 7-[2-(6-chloro-2-formamidopyrimidin-4-yl)-2S 2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthi-methyl)-3-cephem-4-carboxylic acid tl.2 g.) in methanol (12 ml.), and the mixture was stirred at ambient temperature for 5 hours. The reaction mixture was evaporated to dryness under reduced pressure to give a foamy residue, which was pulverized with ethyl ether. This powder tl.l g.) ~6~3 ....
was dissolved in methanol t6 ml.), and to ethyl ether ~50 ml.) was added dropwise the methanol solution. The precipitates were collected by filtration and then dried to gi~e 7-[2-(2-amino-6-chloropyrimidin-4-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride ~0.95 g.).
I.R. v ma~l : 3100-3300, 1785, 1660, 1390, 1050 cm 1 N.M.R. ~ ppm (DMS0-d6) : 3.75 (2H, m), 3.95 (3H, s), 4.00 (3H, s), 4.24, 4.40 (2H, ABq, J~14Hz), 5.18 (lH, d, J=4.5Hz), 5.79 (lH, d,d, J=4.5Hz, 8.0Hz), 6.28 (lH, s), 8.00-10.00 ~2H, broad s), 9.96 (lH, d, J=8Hz) The following compounds were obtained according to simila~ manners to those of ExampleslO and 13-(l).
(2) 7-[2-(4-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 163-167C (dec.~.
I.R. v mU~ol: 3400, 3230, 1778, 1650, 1600, 1380, 1050 cm 1 N.M.R. ~ ppm (DMS0-d6 a~d D2O) : 3.64 (2H, m), 3.97 (6H, s), 4.32 (2H, broad s), 5.12 (lH, d, J=4.5Hzi), 5.80 ~lH, d,d, J=4.5Hz, 8Hz)~ 6.60 (lH, d,d, J=2Hz, 7Hz), 6.97 tlH, d, J=2Hz), 8.00 (lH, d, J=7Hz), 9.52 (lH, d, J=8Hz) (3) 7-[2-t6-Aminopyridin-2-yl)-2-propoxyiminoacetamido]-3-tl-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid tsyn isomer), mp. 138-140~C (dec.).

~1~6~33 ... .

I.R. v mUaxol: 3400, 3250, 1780, 1670, 1625, 1590, 1550 cm~l N.M.R. ~ ppm (DMS0-d6~ : 0.9 (3H, t, J=8Hz), 1.67 (2H, m,, 3.7 t2H, broad s), 3.93 (3H, s), 4.07 ~2H, t~ J=8Hz), 4.30 ~2H, broad s), 5.13 (lH, d, J=5Hz), 5.83 (lH, d,d, J=5Hz, 9Hz), 6.50 (lH, d, J=8Hz), 6.90 (lH, d, J=BHz) 3 7.47 (lH, t, J=8Hz), 9.30 (lH, d, J=9Hz) (4) 7-~2-(6-Aminopyridin-2-yl)-2-isopropoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 149-151C
(dec.).
I.R. v NaU~ol: 3380, 3240, 1780, 1670, 1620 cm 1 N.M.R. ~ ppm (DMS0-d6): 1.27 (6H, d, J=6Hz), 3.70 (2H, broad s), 3.97 (3H, s), 4.33 (2H, broad s), 4.35 (lH, m), 5.17 (lH, d, J=5Hz), 5.87 (lH, d,d, J=5Hz, 9Hz), 6.50 (lH, d, J=8Hz), 6.93 (lH, d, J=8Hz), 7.47 (lH, t, J-8Hz), 9.43 (lH, d, J=9Hz) (5) 7-~2-(6-Aminopyridin-2-yl)-2-isobutoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 140-142C (dec.).
I-R- ~ NmUa~l 3370, 3220, 1780, 1670, 1620 cm 1 N.M.R. ~ ppm (DMS0-d6) : 0.88 (6H, d, J=7Hz), 1.96 (lH, m), 3.68 (2H, broad s), 3.88 (2H, d, J=7Hz), 3.92 (3H, s), 4.Z4, 4.36 (2H, ABq, J=13Hz), 98 E-~6 ~1 4~:i533 5.12 (lH, d, J=5Hz), 5.84 (lH, d,d, J=5Hz9 9Hz), 6.48 (lH, d, J=8Hz), 6.88 (lH, d, J=8Hz), 7.40 (lH, t, J=8Hz), 9.44 (lH, d, J=gHz) (6) 7-[2-(2-Aminopyridin-4-yl)-2-methoxyimino-acetamido]-3~ methyl-lH-tetrazol^5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 175-177C (dec.).
I.R. v mUJol: 3200, 1775, 1670, 1600, 1560 cm l N.M.R. ~ ppm (D.~SO-d6) : 3.73 (2H, broad s), 3.98 (6H, s), 4.35 (2H, broad s), 5.18 (lH, d, J=5Hz), 5.83 (lH, d,d, J=5Hz, 8Hz~, 6.67-6.80 (2H, m), 8.00 (lH, d, J=6Hz), 9.79 (lH, d, J=8Hz) t7) 7-[2-(6-Aminopyridin-2-yl)-2-ethoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 190-195C (dec.).
I.R. v mUJol: 3350~ 3150, 1795, 1730, 1670 cm 1 N.M.R. ~ ppm (DMSO-d6) : 1~33 (3H, t, J=7Hz), 1.43 (3H, d, J=7Hz), 3.90 (lH, m), 4.35 (2H, q, J=7Hz), 5.17 (lH, d, J=4Hz), 5.92 (lH, d,d, J=4Hz, 8Hz), 6.58 (lH, d, J=6Hz), 6.73 (lH, d, J=7Hz), 7.17 (lH, d, J=8Hz), 7.95 (lH, d,d, J=7Hz, 8Hz), 9.93 (lH, d, J-8Hz) (8) 7-[2-(6-Aminopyridin-2-yl)-2-propoxyiminoacet-amido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 190-195C (dec.).
I.R. v NmaUjxol: 33409 3150, 1780, 1735, 1670 cm 1 ~9 E- ~

~1~6~i3 N.M.R. ~ ppm tDMso-d6) : 0.85 (3H, t, J=8Hz), 1.40 (3H, d, J=7Hz), 1.70 ~2H, m), 3.80 (lH, m), 4.15 (2H, t, J=6Hz~, 5.10 (lH, d, J=4Hz), 5.90 (lH, d,d, J=4Hz, 8Hz), 6.54 (lH, d, J=6Hz), 6.74 ~lH, d, J~7Hz), 6.85 (lH, d, J=7Hz), 7.68 (lH, t, J=7Hz), 9.68 (lH, d, J=8Hz) (9) 7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 185-188~C (dec.).
I.R. v NmU~ol 3350, 3150, 1795, 1735, 1670 cm 1 N.M.R. ~ ppm (DMSO-d6): 1.37 (6H, d, J=6Hz), 1.47 (3H, d, J=6Hz), 3.92 (lH, m), 4.58 (lH, m), 5.20 (lH, d, J=4Hzj, 5.93 (lH, d,d, J=4Hz, 8Hz~, 6.60 (lH, d, J=6Hz), 6.77 (lH, d, J=7Hz), 7.08 (lH, d, J-8Hz), 7.90 (lH, d,d, J=7Hz, 8Hz), 9.87 (lH, d, J=8Hz) (10) 7-~2-(6-Aminopyridin-2-yl)-2-butoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid tsyn isomer), mp. 108-110C (dec.).
I.R. v NaUxol: 3350, 3200, 1775, 1670, 1620, 1585, 1540 cm 1 N.M.R. ~ ppm (DMSO-d6) : 0.90 (3H, t, J=7Hz), 1.80-1.16 (4H, m), 3.70 (2H, broad s), 3.92 (3H, s), 4.16 (2H, t, J=7Hz), 4.30 ~2H, broad s), 5.14 (lH, d, J=5Hz), 5.78 (lH, d,d, J=5Hz, 9Hz) 9 ~0 S~3 6.58 (lH, d, J=8Hz), 6.86 ~lH, d, J=8Hz), 7.48 (lH, t, J=8Hz), 9.50 (lH, d, J=9Hz) tll~ 7-[2-(6-Aminopyridin-2-yl)-2-butoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid tsyn iSOmeT)~
mp. 290-2~5C (dec.~.
I.R. ~ maxl: 3400~ 3120, 1785, 1660 cm~l N.M.R. ~ ppm (DMSO-d6): 0.90 ~3H, t, J=7Hz), 1.45 (3H, d, J=6Hz), 1.20-1.80 ~4H, m), 3.85 (lH, m~, 4.25 t2H) t, J=6Hz), 5.12 (lH, d, J=SHz), 5.90 (lH, d,d, J=5Hz, 8Hz), 6.56 (lH, d~ J=5Hz), 6.70 (lH, d, J=7Hz), 7.05 (lH, d, J=7Hz), 7.82 (lH, t, J=7Hz), 9.80 (lH, d, J=8Hz) ~r (12) 7-[2-(6-Aminopyridi~-2-yl)-2-isobutoxyimino-acetamido~-2-methyl-3-cephem-4-carboxylic acid tsyn isomer), mp. 175-180C (dec.).
I.R. v NUaxol: 3300, 1785, 1735, 1660 cm 1 N.M.R. ~ ppm (DMSO-d6) : 0.95 (6H, d, J=6Hz), 1.48 (3H, d, J=7Hz3, 2.08 (lH, m), 3.92 (lH, m), 4.08 (2H~ d, J=7Hz), 5.20 (lH, d, J=4Hz), 5.95 (lH, d,d, J=4Hz, 8Hz), 6.62 (lH, d, J=6Hz), 6.80 (lH, d, J=7Hz), 7.07 (lH, d, J=8Hz), 7.88 (lH, d,d, J=7Hz, 8Hz~, 9.87 (lH, d, J=8Hz~
(13) 7-[2-Allyloxyimino-2-(6-aminopyridin-2-yl)-acetamido~-2-methyl-3-cephem-4-carboxylic acid (syn isomer), 101 E~3 mp. 168-173C (dec.).
I.R. v maU~ol: 3350, 3150, 1795, 1735, 1670 cm 1 N.M.R. ~ ppm (DMSO-d6) : 1.47 ~3H, d, J=7Hz), 3.90 (lH, m), 4.83 (2H, d, J=5Hz)9 5.20 (lH, d, J=4Hz), 5.23-5.66 (2H, m), 5.95 (lH, d,d, J=4Hz, 8Hz), 5.83-6.30 (lH, m), 6.50 ~lH, d, J=6Hz), 6.77 ~lH, d, J=7Hz), 7.10 rlH, d, J=7Hz~, 7.93 (lH, t, J=7Hz), 9.93 (lH, d, J=8Hz) ~14) 7-[2-(6-Aminopyridin-2-yl)-2-propargyloxy-iminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 165-170C ~dec.).
I.R. ~ NmaUixol: 3350j 17~0, 1670 cm 1 lS N.M.R. ~ ppm ~DMS0-d6) : 1.47 (3H, d, J=7Hz), 3.58 (2H, t, J=2Hz), 3.87 (lH, m), 4.88 (lH, d, J=2Hz), 5.17 (lH, d, J=4Hz), 5.93 (lH, d,d, J=4Hz, 8Hz), 6.58 (lH, d, J=6Hz), 6.66 (lH, d, - J=8Hz), 6.70 ~lH, d, J=8Hz) 9 7.68 (lH, t, J=8Hz), 9~77 (lH, d, J=8Hz) (15~ 7-[2-(6-Aminopyriain-2-yl)-2-(2,2,2-trifluolo-ethoxyimino)acetamido]-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer), mp.
165-170C (dec.~.
I.~. v Nu~ol 3400, 1780, 1690 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.7Z (2H, broad s), 3.95 ~3H, s), 4.32 (2H, broad s), 4.66, 4.92 (2H, ABq, J=9Hz), ~ ~2 ~-60 5.17 (lH, d, J=4Hz), 5.83 ~lH, d,d, J=4Hz, 8Hz), 6.32 (lH, d, J=8Hz), 6.90 (lH, d, J=8Hz), 7.55 (lH, t, J=8Hz), 9.68 (lH, d, J=8Hz) (16) 7-[2-(6-Aminopyridin-2-yl)-2-phenoxyimino-acetamido~-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
mp. 145-147~C (dec.).
I.R. ~ Najxl: 3200, 1760, 1690, 1670 cm l N.M.R. ~ ppm (DMSO-d6) : 1.50 (3H, d, J=7Hz), - 3.9~ (lH, m), 5.23 (lH, 'd, 3=4Hz), 6.05 (lH, d,d, J=4Hz, 8Hz), 6.60 (lH, d, J=6Hz), 6.73 (lH, d, J=7.5Hz), 7.13 (lH, d, J=7.5Hz), 7.00-7.50 (5H, m), 7.63 (lH, d, J=7.5Hz), 9.88 (lH, d, J=8Hz) (17) 7-[2-(6-A]ninopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl''-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid tsyn isomer), mp. 165-167C (dec.).
I.R. ~ maU~ol: 3380, 3220, 1780, 1680, 1630, 1590, 1550 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.75 (2H, broad s), 3.90 (3H, s), 3.97 (3H, s), 4.35 (2H, broad s), 5.17 (lH, d, J=5Hz), 5.82 (lH, d,d, J=5Hz, 8Hz), 6.57 (lH, d, J=9Hz), 7.67 (lH, d,d, J=2Hz, 9Hz), 8.03 (lH, d, J=2Hz), 9.73 (lH, d, J=8Hz) (18) 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(l-me~hyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (anti isomer), mp 153-155~C (dec.).

~ ~3 E ~ ~1 i3 I.R. ~ mUxol: 3350- 3200, 1780, 1680, 1630, 1520 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.73 (2H, broad s), 3.97 (6H, s), 4.35 (2H, broad s), 5.17 ~lH, d, J=5Hz), 5.72 (lH, d,d, J=5Hz, 8Hz), 6.62 (lH, d, J=9Hz), 7.75 (lH, d,d, J=2Hz, 9Hz), 8.25 (lH, d, J=2Hz), 9.25 (lH, d, J=8Hz) (19) 7-~2-(6-Amino-3-chloropyridin-2-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl3-3-cephem-4-carboxylic acid hydrochloride (syn isomer), mp. 155-160C ~dec.).
I.R. v mu~ol 3100-3350, 1790, 1670, lSSO, 1380, 1235,1040 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.70 (2H, m), 3.94 (3H, s), lS 4.03 (3H, s), 4.21, 4.37 (2H, A~q9 J=14Hz), 5.14 (lH, d9 J=4.5Hz), 5.80 tlH, d,d, J=4.5Hz, 8Hz), 6.97 (lH, d, J=lOHz), 7.80 (lH, d, J=lOHz), 7.50-9.00 (2H, m), 9.70 (lH, d, J=8Hz) (20) 7-[2-(6-Amino-3,5-dichloropyridin-2-yl)-2-methoxyiminoacetamidoJ-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer), mp.
139-144C (dec.).
I.R. v ma~l: 3300, 1785, 1730, 1660, 1545, 1380, 1235, 1045 cm~l N.M.R. ~ ppm (DMSO-d6) : 3 73 (ZH, m), 3.98 (6H, s), 4.35 (2H, broad s) 9 5.17 (lH, d, - J=4.5-Hz), 5.81 (lH, d,d, J=4.5Hz, 8Hz), 7.87 (lH, s), 7.50-8.20 (2H, m), 9.43 (lH, d, J=8Hz) 1 0 4 E - h ,_ (21) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-~1,3,4-thiadiazol-2-ylthiomethYl)-3-Cephem-4-carboxylic acid (syn isomer), mp 164 - 171C (dec.).
(22) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer~, mp 161~167C (dec.).
(2~) 7-[2-(4-Aminopyrimidin-2-.yl)-2-methoXyiminoacetam_do]-cephalosporanic acid ~syn isomer), mp 149-159C (dec.).

~!-1 ~ 3 E-~

i3 Example 14 (1) A mixture of N,N-dimethyl fonnamide (12mQ) and phosphoryl chloride (1.84g) was stirred for 30 minutes at ambient temperature. To the mixture were added methylene chloride (12mQ) and 2-ethoxyimino-2-(4-formamidopyrimidin-2-yl~acetic acid (syn isomer) tl.91g) at -5 to 0C, and then the reaction mixture was stirred for an hour at the same temperature.
On the other hand, a mixture of 7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid ~4.36g) and trimethylsilyl acetamide (12g) in methylene chloride (i20mQ) was warmed to make a clear solution.
lS The solution was cooled to -10C and added to the activated acid solution obtained above.
The reaction mixture was stirred for 40 minutes at 0C, and then poured into a cold aqueous solution of sodium bicarbonate. The aqueous layer was separated out, adjusted to pH 2 with 10~ hydrochloric acid and extract-ed with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness.
The residue was triturated with diethyl ether to give an amorphous precipitate (3.6g) of 7-~2-ethoxyimino-2-(4-formamidopyrimidin-2-yl~acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-Farboxylic acid (syn isomer).

I.R.v Nm~xl: 3250, 1780, 1660, 1570cm~~.
N.M.R. ~ppm (~MSO-d6): 1~30 (3H,t,J=7Hz), 3.72 (2H, board s), 4.27 (2H,q,J=7Hz), 4.30, 4.57 (2H,A~q,J=13Hz), 5.18 (lH,d,J=5Hz), 5.88 (lH, dd, J=5Hz, 8Hz), 7.1-7.5 (lH,m), 8.67 (lH,d,J=6Hz), 8.9-9.2 E~

11 465~3 (lH,m), 9.45 (lH,d,J=8Hz), 9.52 (lH,s), 11.10 (lH,d,J=7Hz).
The following compounds were obtained according to the similar manner to that of Example 14-(1).
(2) 7-[2-(4-Formamidopyrimidin-2-yl)-2-propoxyi-minoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyll-3-cephem-4-carboxylic acid (syn isomer), mp 170 -175C (dec.).

I.R.~ Nm~ 3250, 3100, 1780, 1710, 1670, 1615, 1580cm~~.
N.M.R. ~ppm (DMSO-d6): 0.93 (3H,t,J=7Hz), 1.4-1.9 ~2H,m), 3.72 (2H,broad s), 4.20 (2H,t,J=7Hz), 4.33, 4.58 (2H, ~Bq, J=13Hz), 5.20 ~lH,d,J=6Hz), 5.92 (lH, d,d,J=5Hz,8Hz), 7.0 -7.7 (lH,m), 8.67 (lH,d,J=6Hz), 8.8-9.2 ~lH,m), 9.47 (lH,d,J=8Hz), g.53 (lH,s), 11.23 (lH,d,J=6Hz).

(3) 7-[2-Allyloxyimino-2-(4-formamidopyrimidin-2-yl)acetamidol-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 130-133C
(dec.).
I.R.~Nmal : 3250, 1780, 1720, 1660, 1570cm~
N.M.R. ~ppm (DMSO-d6): 3.73 (2H,broad s), 4.80 (2H,d,J=5Hz), 5.20 (lH,d, J=5Hz), 5.1-5.6 (2H, m), 5.90 (lH,d,d,J=5Hz, 8Hz?, 5.7-6.3 (lH, m), 7.0-8.7 (lH,m), 8.68 (IH,d, J=6Hz), 8.8-9.3 (lH,m), 9.53 (lH, d,J=8Hz), 9.57 (lH,s), 11.23 (lH, d, J=6Hz).
(4) 7-[2-Benzyloxyimino-2-(4-formamidopyrimidin-2-~ 0 7 E ~ ~ ~

yl)acetamido]-3-(1,3,4-thiadiazol 2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 143-145C (dec.).
I.R.vNmaxl : 3300, 178S, 1720, 1670, 1575cm-1.
N.M.R. ~ppm (DMSO-d6): 3.63 (2H, broad s), 4.28, 4.52 (2H,ABq,J=13Hz), 5.13 (lH,d,J=5Hz), 5.27 (2H,s), 5.85(1H,d,d,J=5Hz,8Hz), 7.32 (5H,s), 7.2-7.6 (lH,m), 8.60 (lH,d,J=6Hz), 8.8-9.2 (lH,m), 9.52 (lH,s), 9.55 (lH,d,J=8H7), 11.30 (lH,d,J=6Hz).
(5) 7-[2-(6-Formamidopyridin-2-yl)-2-methoxyimino-acetamido~-3-11-allyl-lH-tetrazol-5-yl)thiomethyl]
-3-cephem-4-carboxylic acid (syn isomer).
I.R.VNuaxl : 3300, 1785, 1700-1670, 1580, 1380, 1260, 815cm~~.
N.M.R. ~ppm (DMSO-d6): 3.72 (2H, broad s), 3.95 (3H,s), 4.20, 4.50 (2H, ABq, J=13Hz), 4.9-6.6(7H,m), 6.85-g.42(5H,m), 10.5(1H,m).
(6) 7-12-(2,2,2-Trifluoroethoxyimino)-2-(6-formamidopyridin-2-yl)acetamido]cephalosporanic acid (syn isomer), which starts to decompose at 120C.
I.R.v max : 3310, 1788, 1718, 1673 cm~~.
N~M.R. ~ppm (DMSO-d~): 2.00 (3H,s), 3.53 (2H, broad s), 4.5-5.0 (4H,m), 5.15 (lH,d,J=5Hz~, 5.88 (lH,d,d, J=SHz, 81~z), 6.7-8.1 (3H,m), 9.27 (lH,broad d, J=lOHz), 9.62 [lH,d,J=8Hz), 10.40-10.85 (lH, m).
(7) 7-[2-Allyloxyimino-2-(6-formamidopyridin-2-yl) acetamido]-3-(5-tert-butoxycarbonylaminomethyl-l~ -~ 08 ~6 65~3 3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer~, mp. 170-180C (dec.) I.R.v m~xl : 3300, 1788, 1720-1680 cm~l.
N.M.R. ~ppm (DMSO-d6): 1.43 (9H,s), 3.72 ~2H, broad s~, 4.1-4.9 (6H,m), 5.1 -6.3 (5H,m), 6.75 - 8.1 (3H,m), 9.1-9.5 (lH,m), 9.58 (lH,d,J=g~z), ~0.4-10.8 (lH,m).
(8) 7-~2-(6-Formamidopyridin-2-yl)-2-propargyloxyi-minoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer~, mpl52-156C
tdec.).
I.~.vNU~ : 3300, 1780, 1~70, 1580cm 1.
N.M.R. ~ppm (DMSO-d6): 3.5 (lH,m), 3.7 (2H,m~, 4.25, 4.62 (2H,ABq,J=13Hz), 4.8 (2H,m), 5.17(1H,d,J=4.5Hz), 6.22 (lH,d,d,J=4.5Hz,8Hz), 7.0-9.4 (2H, m), 7.5 (lH,d,J=7Hz), 7.85 (lH,t, J=7Hz), 9.57(1H,s), 9.4-9.5 (lH, 2~ m), 10.6 (lH,m).
(9) 7-[2-(4-Formamidopyrimidin-2-yl)-2-methoxyimino acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R.vNm~xl : 3250, 1780, 1710, 1680, 1570cm ~.
(10) 7-[2-(4-Formamidopyrimidin-2-yl)-2-methoxyimino acetamido]cephalosporanic acid (syn isomer), mp 150-154~C (dec.).
I.R.vNm~xl : 3250, 1780, 1700, 1670, 1590cm~l.
N.M~R.~ppm (DMSO-d6): 2.05 (3H,s), 3.58 (2H, broad s), 4.00 (3H,s), 4.73, 5.00 (2H,ABq,J~13Hz), 5.20 (lH,d,J=4Hz), 5.90 (lH,d,d,J=4Hz,8Hz), 7.40 (lH, broad s), 8.68 (lH,d,J=5Hz), 9.07 ~lH,broad s), 9.53 (lH,d,J=8Hz), 1~.23 (lH,d,J=8Hz).

.

~1 ~65~3 ~11) A mixture of N,N-dimethylformamide ~14m~) and phosphoryl chloride (2.5g) was stirred for 30 minut-es at 40C. To the mixture were added methylene chlaxide (14mQ) and 2-(2,2-dichloroacetoxyimino)-2-(6-formamidopyridin-2-yl)acetic acid (syn isomer) (5.3g) at -20C, and then the reaction mixture was ~tirred for 30 minutes at -15 to -10C.
On the other hand, a mixture of 7-amino-3-1( 1-hexyl-lH-tetrazol-5-yl)thiomethyl~-3-cephem-~-carboxylic acid (5.89g) and trimethylsilyl acet-amide t16g) in methylene chloride (150mQ) was warm-ed to make a clear solution. The solution was cooled to -15C and added all at once to the activat-ed acid solution prepared above. The reaction mix-ture was stirred for 30 minutes at -15 to 0C and ~or additional 30 minutes at ambient temperature.
The solvent was removed by distillation from the reaction mixture under reduced pressure to give a residue, to which ethyl acetate ~50mQ) and water (lOOmQ) were added, and then the mixed solution was adjusted to pH 3 with an aqueous solution of sodium bicarbonate. The organic layer was sepaxat-ed out, washed two times with an aqueous solution of sodium chloride and dried over magnesium sul-fate, and then evaporated to dryness to give a brownish-oil. This oil was washed three times with diethyl ether (70mQ) and triturated with diisopropyl ether to give a powder of 7-[2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetamido]-3 ~ hexyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer), mp 74 - 84C (dec.).
I.R.~Nm~Xi : 3300, 1785, 1700-1675~ i580, 1380, 1260, 810cm~1.
N.M.R.~ppm (DMSO-d6) : 0.8-1.8 (llH,m), 3.7 ~S (2H,m), 4.3 (4H,m), 5.18 (lH,d, 1~ E ~

J=4.5Hz), 5.95 (lH,d,d,J=4.5Hz, 8Hz), 7.5-9.43 (5H,m), 10.6 (lH,m).
The following compound was obtained according to the similar manner to that of Example 14- ~11).
~12) 7-~2-(6-Formamidopyridin-2-yl)-2-hydroxyimino-acetamido]-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer), mp 88-91C
~dec.).
I.R.v maxl : 3300- 17a5, 1700-1660, 1580, 1380 r 1260, 815cm~l.
N.M.R.~ppm (DMSO-d6) : 3.63 (2H, broad s), 4.13, 4.43 (2H, ABq,J~13Hz), 4.93 (2H,m), 5.0-5.2 (lH,m~, 5.25 (2H,m), 5.67-6.16 (ZH,m), 6.38-8.08 (3H,m), 9.3 (lH,d, 3-8Hz), 10.55 (lH,m).
(13) A mixture of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid dihydrate (syn isomer) ' (1.62g) and phosphoryl chloride (4.3g) in methylene chloride (lOmQ) was stirred for 30 minutes at O
to 5C. To the above mixture was added dropwise N,N-dimethylformamide (5.3mQ) and the resultant mixture was stirred for 30 minutes at O to 5C.
On the other hand, a mixture of 7-amino-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.5g~ and trimethylsilyl acet-amide (lOg) in methylene chloxide (35mQ) was warm-ed to make a clear solution. The solution was cooled to -5C and added to the activated acid solution obtained above.
The reaction mixture was stirred for 30 minutes at 5 to 10C and for additional 30 minutes at ambient temperature and then poured into a cold aqueous solution of sodium bicarbonate. The aqueous layer was separated out, adjusted to pH 3 with 10~

E - ~ 3 ~ 3~ ~

hydrochloric acid, washed with ethyl acetate and then subjected to column chromatography over ' nonionic adsorption resin, "Diaion HP20" (Trade Mark, manufactured by Mitsubishi Chemical Industries Ltd~ (70mQ). The column was washed with water and eluted with 30% aqueous methanol. The eluent con-taininy a desired compound was evaporated to re-move the methanol under reduced pressure and then lyophilized to give 7-[2-(4-aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.58g), mp 151-156C (dec.).
I.R.vNmaxl . 3370, 3220, 1780, 1680 ~ 1640cm ~.
N.M.R.~ppm (DMSO-d6) : 3.7 (2H,m), 3.95 (3H, s), 4.23, 4.48 (2H,ABq,J=13Hz), 4.8-5.4(5H,m), 5.7-6.2 (2H,m), 6.~5 (lH,d,J=7Hz), 7.05 (2H, -' broad s), 8.10 (lH,d,J=7Hz), 2n 9.45 (lH,d,J=8Hz).
(14) A mixture of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (2.32g) and phosphoryl chloride (4.6g) in methylene chloride '~15mQ) was stirred for 30 minutes at 3C. To the mixture was added dropwise a solution of N,N-dimethylformamide (3.OmQ) in methylene chloride (15mQ) and stirred for 40 minutes at 3C.
A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (3.02g) and trimethylsilyl acetamide (15g) in methylene chloride ~60mQ) was cooled to -5C and added to the activated acid solution obtained above. The mixture was stirred for 30 minutes at 3 to 5C and for additional 30 minutes at ambient temperature. The solvent was evaporated to dryness and the residue was dissolved in ethyl t~ ?' acetate (200mQ). The solution was washed with an aqueous solution of sodium bicarbonate and water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was washed with diethyl ether to give 4-nitrobenzyl 7-12-(4-amino-pyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (3.1g) as a powder, mp 125-131C (dec.) I.R.vNm~xl : 3500, 3400, 3250, 1790, 1720, 1690, 1640, 1525, 1040, 855, 740cm~l .
The followin~ compounds were obtained accord-ing to the similar manner to those of Examples 1-(13) and (14).
tl5) 7-[2-(4-aminopyrimidin-2-yl)-2-methoxyimino acstamido]-2-methyl-3-cephem-4-carb4xylic acid (syn isomer), mp 175-181"C (dec.).
.R.VNmaXl 3400, 3300, 1780, 1665, 1635, 1590 cm~l.
N.M.R.~ppm (DMSO~d6) : 1.45 (3H,d,J=7Hz), 3.78 (lH,d,J=7Hz), 3.95 (3H,s), 5.10 (lH,d,J=4.5Hz), 5.93 tlH, d,d,J~4.5Hz,8Hz), 6.45 (lH,d, J=7Hz~, 6.57 (lH,d,J=6Hz), 7.05 (2H, broad s), 8.10 (lH,d, J=6Hz), 9.41 (lH,d,J=8Hz).
(16) 7-~2-(4-Aminopyrimidin-2-yl)-2-methoxyimino acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer), mp 169~175C (dec.).
I.R.VNU~xl : 3350, 3210, 1765, 1680-1630, 1580, 1375, 1040, 920, 720cm~l.
N.M.R.~ppm (DMSO-d6~ : 2~03 (3H,s), 3.25, 3.66 (2H, ABq, J=18Hz), 3.95 (3H,s), 5.0~ (lH,d,J=4.5Hz), 5.76 (lH,d,d,J=4.5Hz,8.0Hz), 1~3 E- 7~

i i3 6.43 (lH,d,J=7Hz), 7.03~2H, - broad s), 8.10 (lH,d,J=7Hz), 9.37 (lH,d,J=8.OHz~
(17~ 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-carbomoyloxymethyl-3-cephem-4-carboxy-lic acid (syn isomer), mp 200-204C (dec.).
I.R.vNUjl : 3370, 3200, 1775, 1710, 1670-1630, 1400, 1320, 1040, 985, 720cm~l.
N.M.R.~ppm (DMSO-d6) 0 3.38, 3.61 (2H,ABq,J=
18Hz), 3.94 (3H,s), 4.62, 4.90 -~ (2H,ABq,J=13Hz~, 5.15(1H,d,J=
; 4.5Hz), 5.80 tlH,d,d,J=4.5Hz,8.0Hz), 6.44 (lH,d,J=7.0Hz~, 6.58 (2H,s), 7.03 (2H,broad s), 8.10 (lH,d,J=7.0Hz),-9.41 (lH, d,J~8.0Hz).
(18) 7-t2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-acetylthiomethyl-3-cephem-4-carboxylic acid ~syn isomer), mp 168-173C (dec.).~
I.R.VNmixl : 3400, 3240, 1780, 1680-1630cm~~.
N.M.R.~ppm (DMSO-d6) : 2.33 (3H,s), 3.2, 3.7 (2H, ABq,J=18Hz), 3.92 (3H,s), 3.9-4.2 (2H,m), 5.10 (lH,d,J-4.5Hz), 5.78 (lH,d,d,J=4.5Hz,8Hz), 6.40 (lH,d,;J=6Hz),7.02 (2H,broad s~, 8.08 (lH,d,J=6Hz), 9.37 (lH, d,J=8Hz).
~19) 4-Nitrobenzyl 7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxy-late (syn isomer), mp 100-108C (dec.).
I.R.VNm~ol : 3370, 3210, 1780, 1740, 1680, 1630, 1520, 1375, 1350, 1220, ; 1040, 850, 735cm~~.
N.M.R.~ppm (DMSO-d6) : 3.75, 4.07 (2H,ABq, 35 J=18Hz), 3.93 (3H,s), 5.30 (lH, 65~3 d,J=4.5Hz), 5.45 (2H,s), 5.95 (lH,d,d,J=4.5Hz,8.OHz), 6.42 (lH,d,J=7.0Hz), 7.06 (2H, broad s), 7.68 (2H,d,J=8.0H2), 8.22 (2H,d,J=8.0Hz), 8.08 ~lH,d,J=
7.0Hz), 9.53 (lH,d,J=8.0Hz).
(20) soaium 7-12-(4-Aminopyrimidin-2-yl)-2~methoxy iminoacetamido]-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl]-3-cephem-4-carboxylate (syn isomer), mp 211-221C (dec.).
I.R.vNmaxl : 3370, 3220, 1765, 1670-1600, 1400, 1090, 1040, 835, 728cm~l.
N.M.R. ~ppm (DMSO-d6): 3.3-3.7 (2H,m), 3.90 (3H,s), 4.4 (2H,m), 5.00 (lH,d, J=4.5Hz), 5.6 (lH,m), 6.45 (lH, d,J=7Hz), 7.05 (2H,broad s), 7.5 -8.1 (4H,m), 8.10 (lH,d,J=7Hz), 9.3 (lH,m).
(21) '7-[2-l4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isom-er), mp 173-178C (dec.).
I.R.VNm~xol : 3400, 3280, 1780, 1680, 1630, 1575, 1530, 138~, 1040, 900, 800 cm~l.
N.M.R.~ppm (DMSO-d~) : 3.72 (2H,broad s), 4.00 (3H,s), 4.28, 4.63 (2H, ABq, J=13Hz), 5.17 (lH,d,J=4.5Hz), 5.85 (lH,d,d,J=4.5Hz, 8.OHz~, 6.50 (lH,s), 7.4 (2H,broad s), 9.50 (lH,d,J=8.0Hz), 9.58 (lH,s).
(22) 7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-O cephem-4-carboxylic acid (syn isomer).
I.R.VNmaxol : 3350, 3250, 1780, 1660, 1585cm~~.

~3~ L~73 6.~

(23) 7-[2-t4-Aminopyrimidin-2-yl)-2-propoxyimino-acetamido]-3-~1,3,4-thiadia7ol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer~.
I~R~VNmaXl: 3375, 3225, 1780l 1660, 1590, 1540cm~l.
(243 7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl) acetamido3-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R.VNmaXl: 3380, 3230, 1780, 1660, 1585, 1540cm ~.
(25) 7-l2-t4-Aminopyrimidin-2-yl)-2-benzyloxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R.vNmaxl: 3370, 3230, 1780, 1660, 1590, '~
1540cm ~.
(26) 7-~2-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido]-3-[(1-hexyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
I.R.vNmaxl: 3200, 1780, 1670, 1620, 810, 725cm 1.
(27) 7-[2-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido]-3-[1 allyl-lH-tetrazol-5-yl)~hiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
I.R.VNmaXl: 3350, 3200, 1775, 1665, 1620, 1250, 990, 805cm~~

(28) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-[1-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
I.R.VNmaxol: 3380, 3240, 1780, 1670, 1620cm ~.

(29) 7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoro ethoxyimino)acetamido3-3-[(l~carboxymethyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
I-R-VNUjl 3440, 3320, 1778, 1688, 1665, 1623, 1552 cm~l.

7 4;

~ 6.~

(30) 7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyi- {
minoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl~-3-cephem-4-carboxylic acid (syn isomer).
I.R.vNUjl : 3300, 3200, 2160, 1775, 1735, max 1670, 1630, 1085, 1025cm~~.

(31) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamidol-3-cephem-4-carboxylic acid (syn isomer).
I.~.v~m~xl : 3380, 3240, 1780, 1680-1630, 1585, 1378, 1040, 985, 725cm~1.
(32~ 7-12-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid - (syn isomer).
I.R.VNuiol : 3460, 3400, 3260, 1773, 1680-1650, 1620, 1570, 1380, 1270, 1095, r 1040, 860cm~l.
(33~ 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(pyrazin-2-ylthiomethyl)-3-cephem-4-caroxylic acid (syn isomer).
I.R.VNm~xl : 3350, 3250, 1780, 1~60, 1590cm~l.

(34) 7-[Z-(4-Aminopyrimidin-2-yl)-2-methoxyimino acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R.VNmaXl : 3350, 1770, ]660, 1530cm 1. !
~35) 7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, mp 161 - 163C (dec.).
I.R. ~mUa~ 1 3400, 3250, 1780, 1675, 1620, 1580, 1380, 1040 cm N.M.R. ~ppm(DMSO-d6): 3.73(2H, broad s), 3.83(3H,s), 3.97(3H,s), 4.27,4,63(2H, ABq,J=13Hz), 5.17(1H,d,J=4.5HZ), 5-73 (lH,s), 5.87(1H,d,d,J=4.5Hz,8Hz), 6.77 (2H,broad s), 9.45(lH,m), 9.57(lH,s).
(36) 7-[2-(4-Amino 6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)-11 ~ 7 E ~ 75 : .

~6~
thiomethyl-3-cephem-4-carboxylic acid, mp 148 -160C(dec.).
I.R. ~ Nujol 3370, 3250, 1780, 1680, 1630, 1570, 750, 722 cm N.M.R. ~ ppm(DMSO-d6~: 3.7t2H,m), 3,95 (3H,s), 4.28,4.60(2H,ABq,J=13Hz), 5.16 (lH!d,J=4.5Hz), 5.8(2H,m), 6.98(2H, broad s), 7.60(5H,s), 9.47(lH,d,J=8Hz), 9.59 (lH,s).

., k ~

~ ~6~

Example 15 tl) A solution of 7-[2-ethoxyimino-2-(4-formamidopyri-midin-2-yl~acet~mido]-3-l1,3,4-thiadiazol-2-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer) (3.9?g) and concentrated hydrochloric acid ~0.73mQ) in methenol (80mQ) was stirred for 1.5 hours at ambient temperature. ~he solvent was evaporated to dryness and the residue was dissolved in water (lOOmQ). The aqueous solution was washed with ethyl acetate and adjusted to pH 3 with an aqueous solution of sodium bicarbonate and then subjected to column chromatography over nonionic adsorption resin, "Diaion HP 20". The column was washed with water and eluted with 50% aqueous methanol.
The eluent containing a desired compound was eva-porated to remove the methanol and then lyophilized to give 7-[2-(4-aminopyrimidin-2-yl)-2-ethoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.75g), mp 155-160C (dec.). .
I.R.~Nm~Xl : 3350, 3250, 1780, 1660, 1585cm~l.
N.M.R.~ppm (DMSO-d~) : 1.27 (3H,t,J=7Hz), 3.72 (2H, broad s), 4.22 (2H,q, J=7Hz), 4.33, 4.58 (2H,ABq, J=13Hz), 5.17 (lH,d,J-5Hz), 5.87 ~5 (lH,dd,J=5 ~z, and 8 Hz), 6.45 (lH,d,J=6Hz), 7.03 (2H, broad s), 8.12 (lH,d,J=6Hz), 9.37 (lH,d, J=8Hz~, 9.57 (lH,s).
The following compounds were obtained according to 30 the ~imilar manner to that of Example 15-(1).
(2) 7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 145-150C
(dec.).
I.R.VNmaxl : 3375, 322S, 1780, 1660, 1590, 119 L- 7i ~ ~ 655~

1540cm~l.
N.M.R.~ppm (DMSO-d6) : 0.90 (3H~t,J=7Hz), 1.4-1.8 (2H,m), 3.58, 3.74 (2H, ABq,J=18Hzj, 4.08 (2H,t,J-7Hz), 4.26, 4.54 (2H, ABq,J=13Hz), 5.12 (lH,d,J=5Hz), 5.80 (lH,d,d, J=5Hz,8Hz), 6.40(1H,d,J=6Hz), 7.00 (2H,s), 8.06 (lH,d,J=6Hz), 9.36 (lH,d,J=8Hz), 9.52 (lH,s).
~3) 7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl) acetamido~-3-~1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 150-153C
(dec.).
f~R~NUaxl : 3380, 3230, 1780, 1660, 1585, 1540cm~1.
N.M.R.~ppm (DMSO-d6) : 3.7 (2H,broad s), 4.30, 4.57 (2H,ABq,J-13Hz), 4.68 (2H,d,J=5Hz), 5.13 (lH,d, ' J=5Hz), 5.0-5.6 (2H,m), 5.85 ~ (lH,d,d,J=5Hz,8Hz), 5.7-6.2(1H,m), 6.42 (iH~d~J=6Hz)~ 7.02 (2H, broad s), 8.10 (lH,d,J=6Hz), 9.43 (lH,d,J=8Hz), 9.57 (lH,s).
~4) 7-[2-(4-Aminopyrimidin-2-yl)-2-benzyloxyimino-acetamidol-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 145-150C
(d~c.).
I.R.vNmaxl : 3370, 3230, 1780, 1660, 1590, 1540cm-1.
N.M.R.~ppm (DMSO-d6) : 3.6 (2H,broad s), 4.33, 4.57 (2H, ABq,J=13Hz), 5.15 (lH, d,J=5Hz), 5.28 (2H,s), 5.87 (lB, d,d,J=5Hz,8Hz), 6.47 (lH,d,J-6Hz), 7.0-7.3 (2H,m), 7.40 (5H,s), 8.13 (lH,d,J~6Hz),9.55 (lH,d,J=8Hz), ~2~ E~7~

~1 ~6S~

9.60 (lH,s).
(5) 7-[2-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido]-3-[(1-hexyl-lH-tetrazol-5-yl)thiomethyl]
-3-cephem-4-carboxylic acid (syn isomer), mp 148-153C (dec.).
I.R.vNmaxl : 3200, 1780, 1670, 1620, 810, 725cm~ l .
N.M.R.~ppm (DMSO-d 6 ): 0.8-1.8 (llH,m), 3.73 (2H, broad s), 4.4 (4H,m), 5.17 (lH,d,J=4.5Hz), 5.87 (lH, d,d,J=4.5Hz,8Hz), 6.63 (lH,d,J=
8Hz), 6.88 (lH,d,J=8Hz), 7.53 (lH,t,J=8Hz), 9.45 (lH,d,J=8Hz).
~6) 7-[2-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido]-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 168-171C (dec.).
I.R.vNm~xl : 3350, 3200, 1775, 1665, 1620, ! ~r 1250, 990, 805cm~l.
N.M.R.~ppm (DMSO-d6) : 3.75 (2H, broad s), 4.20, 4.52 (2H,ABq,J=14Hz), 5.0 (2H,m), 5.06 (lH,d,J=4.5Hz), 5.3 ~2H,m), 5.8-5.9 (2H,m), 6.65 ~lH,d,J=8Hz), 6.91 (lH,d,J=8Hz), 7-50 SlH,t,J=8Hz), 9.4 (lH,d, J=8Hz).
(7) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid ~syn isomer), mp 148-149C (dec.).
I~R~VNmaxl : 3380, 3240, 1780, 1670, 1620cm~~.
N.M.R.~ppm (DMSO-d6): 3.73(2H,broad s), 3.93 j (3H,s), 4.21, 4.54 (2ff~ABq~J~l4~z)~ 5.0 (2H,m), 5.15 (lH,d,J-4.5Hz), 5.3 (2H,m), 5.8 (lH,m), 5.85 (lH,d,d,J=4.5Hz,8Hz), 6.51 (lH,d,J=8Hz), 12~ E-73 6~ 3 6.91 (lH,d,J=8Hz), 7.48 (lH,t, J-8Hz), 9.5 (lH,d,J=8Hz).
(8) 7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoro e~hoxyimino)acetamido]-3-[(1-carboxymethyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer), mp 178C (dec.).
I.R.VNuaol : 3440, 3320, 1778, 1688, 1665 1623, 1552cm~2.
N.M.R.~ppm (DMSO-d6) : 3.60,3.74 (2H,ABq, J=19Hz), 4.22,4.48 (2H,ABq,J=
14Hz), 4.68, 4.84 (2H,ABq,J=9Hz), 5.12 (lH,d,J-5Hz), 5.30 (2H,s~, 5.83 (lH,d,d,J=5Hz,8Hz)~ 6.56 (lH,d,J=8Hz), 6.90 (lH,d,J=8Hz), 7.48 (lH,t,J=8Hz), 9~66 (lH,d, 3=8Hz).
~9) 7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyi-minoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 168-175C (dec.).
I.R.vNM~l : 3300, 3200, 2160, 1775, 1735, 1670, 1630, 1085, 1025cm-1.
N.M.R.~ppm (DMSO-d6) : 3.6 (3H,m), 4.30, 4.60 (2H,ABq,J=13Hz), 5.00 (2H,s), 5.22 (lH,d,J=4.5Hz), 5.83 ~lH, d,d,J=4.5Hz,8.0Hz), 6.80 (lH,d, J=6Hz), 7.16 (lH,d,J=6Hz), 7.90 (lH,t,J=6Hz), 9.60 (lH,s), 10.01 (lH,d,J=8Hz).
(10) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl3-3-cephem-4-carboxylic acid (syn isomer).
I-R-~Nm~xl : 3370, 3220, 1780, 1680-1640cm-1.
(11) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer).

~22 E-80 ~.~ 4~3 I~R.vNU~xl : 3380, 3240, 1780, 1680-1630, 1585, 1378, 1040, 985, 725cm~1.
~12~ 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino acetamido~-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R.VNm~xl : 3400, 3300, 1780, 1665, 1635, 1590cm~~.
(13) 7-t2-~4-Aminopyrimidin-2-yl)-2-methoxyimino acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer~.
I~R~VNmaxl : 3350, 3210, 1765, 1680-1630, 1580,-1375, 1040, 920, 720cm~l.
(14) 7-[2-(4-Aminopyimidin-2-yl)-2-methoxyimino-acetamidol-3-carbamoyloxymethyl-3-cepyem-4-carboxylic acid (syn isomer).
I.R.vNmaxl : 3370, 3200, 1775, 1710, 16?0-1630, 1400, 1320, 1040, 985, 720cm ~.
(15) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-'acetylthiomethyl-3-cephem-4-carboxylic acid (syn isomer) ~
I.R.v maxl : 3400, 3240, 1780, 1680-1630cm ~.
(16) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer).
I.R.VNmaxl : 3460, 3400, 3260, 1773, 1680-1650, 1620, 1570, 1380, 1270, 1095, 1040, 860 cm~l.
~17) Sodium 7-~2-(4-Aminopyrimidin-2-yl~-2-methoxy-iminoacetamido]-3-[5-(4-chlorophenyl)-1,3,4-oxadia-zol-2-ylthiomethyl]-3-cephem-4-carboxylate (syn isomer).
I.R.vNmaxl : 3370, 3220, 1765, 1670-1600, 1400, 1090, 1040, 835, 728cm~~.
(18) 7-t2-(4-Amino-6-chloropyimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-12~
~ - 8i 11 ~65~3 ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I~R~VNuaxl : 3400, 3280, 1780, 1680, 1630, 1575, 1530, 1380, 1040, 900, 800cm~l.
(19) 7-t2-(4-Aminopy~imidin-2-yl~-2-methoxyimino-acetamido~-3-(pyrazin-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R.vNU~xl : 3350, 3250, 1780, 1660, 15gOcm~~.
(20) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido~-3-(tetrazolo~l,5-b]pyridazin-6-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R.VNmaXl : 3350, 1770, 1660, 1530cm 1.
(21) 7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thio-methyl-3-cephem-4-carboxylic acid.
I.R. ~ max 1 3400, 3250, 1780, 1675, 1620, 1580, 1380, 1O40 cm (22) 7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid.
I.R. Jmax 1 3370, 3250, 1780, 1680, 1630, 1570, 750, 722 cm 1 12~
~ .~.,.

6~

Example 16 A solutio~ of 7-12-allyloxyimino-2-(6-formamidopyridin-2-yl)acetamido]-3-(5-tert-butoxycarbonylaminomethyl-1~3~4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (sym isomer) (2.7g) in formic acid (27mQ) was stirred for 2 hours at ambient temperature and evaporat-ed to dryness. To the residue were added methanol (50mQ) and concentrated hydrochloric acid (0.82g)~ and the mixture was stirred for an hour at ambient temper-at~re. The solvent was evaporated and the residue was dissolved in water (50mQ), adjusted to pH 4 to 5 with an aqueous solution of sodium bicarbonate, treated with an activated charcoal and then subjected to column chromatography over nonionic adsorption resin, "Diaion HP 20" ~80mQ). The column was washed with water and eluted with 50% aqueous methanol. The eluent contain-ing a desired compound was evaporated to remove the methanol and then lyophilized to give 7-12-allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(S-aminomethyl-1,3, 4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid ~0 ~syn isomer) (0.6g), mp 180C (dec.).
I.R.~Nm~Xl : 3400, 3250, 1770, 1670, 1620cm~1.
N.M.R.~ppm (DMSO-d6~D2O): 3.63 (2H, broad s), 4.2-4.8 (6H,m), 4.8-6.3 15H,m), 6.53 (lH,d,J=8Hz), 6.90 (lH,d,J=8Hz), 7.47 (lH,t,J=8Hz).

~2 E~

~ ~65~

Example 17 (1) A mixture o 4~nitrobenzyl 7-12-'(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (3.0g) and 10% palladium on carbon (1.5g) in 50~ aqueous tetrahydrofuran (9OmQ) was stirred under hydrogen atmosphere for 3 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated to half of the original volume. The remaining aqueous solution was diluted with water (lOOmQ), washed with ethyl acetate, adjusted to pH 3 with 10% ' hydrochloric acid and subjected to column chromato-graphy over nonionic adsorption resin, "Diaion HP20".
The column was washed with water and eluted with 10% methanol. The eluent containing a desired compound was evaporated to remove the methanol in vacuo and then lyophilized to give 7-[2-(4-amino-pyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) (750 mg), mp 191-197C ~dec.). -' I.R.vNmaxl : 3380, 3240, 1780, 1680-1630, 1585, 1378, 1040, 985, 725cm~~.
N.M.R.~ppm (DMSO-d6) : 3.6 (2H,m), 4.00 (3H, s1, 5.13 tlH,d,J=4.5HZ), 5.91 ~lH,dd,J=4.5Hz,8Hz), 6.50(1H,d, J=7Hz), 6.6 (lH ,m), 7.03 (2H, broad s), 8.17 (lH,d,J=7Hz), 9.47 (lH,d,J=8Hz).
The following compounds were obtained according to the similar manner to that of Example 17-(1).
(2) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer), mp 200-205C (dec.).
I.R.VNujol ; 3460, 3400, 3260, 1773, 1680-1650, max 1620, 1570, 1380, 1270, 1095, 1040, 860cm~l.

12~ E-~4 ~ 6,~?~

N.M.R.~ppm (DMSO-d6) : 3.60, 4.03 (2H,ABq, J=18Hz), 3.95 (3H,s), 5.25 (l~,d,J=4.5Hz3, 5.85 (lH,d,d, J-4.5Hz, 8.0Hz), 6.43 (lH,d,J=
7Hz), 7.03 (2H, broad s), 8.11 (lH,d,J=7.0Xz), 9.50 (lH,d,J=
8.OHz).
(3) 7-12-(4~Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[1-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
I.R.vNu~ol : 3370, 3220, 1780, 1680-1640cm~l.
(4) 7-12-(4-~ninopyrimidin-2-yl)-2-methoxyimino-- acetamido~-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R.V~m~l : 3400, 3300, 1780, 1665, 1635, L59Ocm~l.
(5) 7-[2-(4-~ninopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid ' ~syn isomer).
I~R~VNm~Xl ; 3350, 3210, 1765, 1680-1630, 1580, i375, 1040, 920, 720cm-1.
(6) 7-~2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido~-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R.VNmaxl : 3370, 3200, 1775, 1710, 1670-1630, 1400, 1320, 1040, 985, 720cm~l.
(7) 7-[2-(4~Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-acetylthiomethyl-3-cephem-4-carboxylic acid (sym isomer).
I.R.vNmaxl : 3400, 3240, 1780, 1680-1630cm~1.
(8) Sodium 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxy iminoacetamido]-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl]-3-cephem-4-carboxylate (sym isomer).

~L27 3i;5~3 I.R.VNm~xl : 3370, 3220, 1765, 1670-1600/
1400, 1090, 1040~ 835, 728cm~l.
(9) 7-[2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. ~Nujol 3400, 3280, 1780, 1680, 1630, 1575, 1530, 13gO, 1040, 900, 800cm~l.
(10) 7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyimino-acetamidol-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. ~Nmaxl: 3350, 3250, 1780, 1660, 1585cm~~.
~11) 7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v~maxl: 3375, 3225, 1780, 1660, 1590, 1540cm~~.
(12) 7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl) acetamido~-3-(1,3,4-thiadiazol-2-ylthiometyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNm~Xl: 3380, 3230, 1780, 1660, 1585, 1540cm- 1 .
(13) 7-[2-(4-Aminopyrimidin-2-y])-2-~enzyloxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNmaxl: 3370, 3230, 1780, 1660, 1590, 154Ocm~l.
(14) 7-12-(6-Aminopyridin-2-yl)-2-hYdroxyimino-acetamido]-3-l(l-hexyl-lH-tetrazol-5-yl)thiomethyl]-3-ceplem-4-carboxylic acid (syn isomer).
I.R. vNmaxl: 3200, 1780, 1670, 1620, 810, 725cm~l.
(15) 7-[2-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido]-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl]-128 E-~?6 . .

3-cephem-4-carboxylic acid (sym isomer).
I.R. vNmaXl : 3350, 32U0, 1775, 1665, 1620, 1250, 990, 805cm~l.
~16) '7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido~-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNmjl : 3380, 3240, 1780, 1670, 1620cm~
(17) 7-12-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoro ethoxyimino)acetamido]-3-1(1-carboxymethyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-'carboxylic acid (syn isomer).
I.R. v~U~xol : 3440, 3320, 1778, 1688, 1665, 1623, 1552cm~~.
(18) 7-[2-(6-Aminopyridin-2-yl)-2-propagyloxyimino acetamido~-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNUiol : 3300, 3200, 2160, 1775, 1735, max 1670, 1630, 1085, 1025cm-1.
(19) 7-[2-(4-Am'inopyrimidin-2-yl)-2-methoxyimino-acetamidol-3-(pyrazin-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNm¦l : 3350, 3250, 1780, 1660, 1590cm~l. ' ~20) 7-12-4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthiome-thyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. ~Nm¦xl : 3350, 1770, 1660, 1530cm~l.
(21) 7-[2-(4-Amino-6-me~hoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[1,3,4-thiadiazol-2-yl)- ' thiomethyl-3-cephem-4-carboxylic acid.
I.R. ~Nmaxl : 3400, 3250, 1780, 1675, 1620, 1580, 1'380, 1040cm~l.
(22) 7-[2-(4-Amino-6~phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid.

129 E-~, ..

~ 1 ~6553 I.R. J Nm~l: 3370, 3250, 1780, 1680, 1570, 750, 722cm (23) Benzhydryl 7- [2-(6-formamidopyridin-2-yl)-2-methoximinoacetamido]-7-methoxy-3-(1-methyl-lH-tetrazol-5-yl)~hiomethyl-3-cephem-4-carboxylate -(1.1 g) was added to a cooled mixture of trifluoro-acetic acid (10 ml) and anisole (2 ml), and stirred under ice cooling for 30 minutes. After removing the solvent ~rom the resultant solution, the residue was triturated with diethyl ether. The precipitates were collected by filtracion and washed with diethyl ether to give 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-7-methoxy-3-~1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid lS (900 mg), mp 124 to 128C tdec.).

I.R. v NmUxol: 3400-3200, 1780, 1700, 1670 cm 1 N.M.R. ~ ppm (aceton-d6) : 3.59 (3H, s), 3.63, , 3.76 (2H, AB-q, J=18Hz), 4.00 (6H, s), 4.36 (2H, broad s), 5.13 (lH, s), 6.90-8.10 (3H, m).

~3 E -~

~1 4655~

Example 18 ~1) A mixture of 7-[2-(2,2,2-trifluoroethoxyimino)-2-~6-formamidopyridin-2-yl)acetamido]cephalosporanic acid (4.7g), disodium salt of 2-(5-mercapto-lH-tetrazol-l-yl~acetic acid (2.3g) and sodium bicarbo-S nate (0.72g) in phosphate buffer (pH6.4, 150mQ) was stirred for 3 hours at 60 to 65C and then for 2 hours with an additional disodium salt of 2-(S-mercapto-lH-tetrazol-l-yl)acetic acid (0.88g) at the same temperature. The reaction mixture was cooled in an ice bat~, adjusted to pH4.5 with 10%
hydrochloric acid and washed with ethyl acetate.
The aqueoussolution was acidified to pH 1 with 10~
hydrochloric acid and extracted with ethyl acetate.
The extract was washed with water, dried over - !
anhydrous magnesium sulfate and evaporated to dry-ness. The residue was triturated with diethyl ether and washed with the same solvent to give crude 7-12-~2,2,2-trifluoroethoxyimino)-2-(6-formamido-pyridin-2-yl)acetamido]-3-[(1-carboxymethyl-lH-tetra-zol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer) (2.3g).
This compound was identified by transforming it to 7-t2-~2~2~2-trifluoroethoxyimino)-2-(6-amino-pyridin-2-yl)acetamido]-3-[(1-carboxymethyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid ~syn isomer) according to the similar manner to that of Example 2-~8).
I.R. ~Nmal : 3440, 3320, 1778, 1688, 1665, 1623, 1552cm~l.
The following compound was obtained according to the similar manner to that of Example 18-(1).
~2) 7-[2-~4-Formamidopyximidin-2-yl)-2-methoxyimino acetamido]-3-~tetrazolo[1,5-b]pyridazin-6-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer), mp 170-175C ~dec.).

13~

~65~;~

I.R. vNuj1 : 3250, 1780, 1710, 1680, 1570cm~l.
max.
N.M.R.~ppm (DMSO-d6): 3.76 (2H,broad, s), 4.00 (3H,s), 4.Z7, 4.63 (2H, ABq,J=14~z), 5.20 (lH,d,J=4Hz), 5.90 (lH,d,d,J=4Hz,8Hz),7.43 (lH, broad s~, 7.77 (lH,d,J=
lOHz), 8.58 (lH,d,J=lOHz), 8.70 (lH,d,J=4~z), 9.10 (lH,broad s), 9.55 (lH,d,J=8Hz).
(3) A mixture of 7-12-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido~-3-acetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2.8g), 2-mercatopyra-zine (0~853g) and sodium bicarbonte (1.48g) in phosphate buffer (pH 6.86, 120mQ) was stirred for 3 hours at 70C. The reaction mixture was cooled ; in an ice bath and adjusted to pH2 with 10% hy-drochloric acid. A resultant solid was filtered and the filtrate was washed three times with ethyl acetate. The solid was dissolved in a mixture of ethyl acetate, acetone and water, and then the aqueous layer was separated out. The filtrate and ; the aqueous layer were combined, concentrated in vacuo to remcve acetone and ethyl acetate and,then sub~ected to column chromatography over nonionic adsorption resin, "Diaion HP 20".
The column was washed with water and 20% aqueous methanol and eluted with 50% aqueous methanol.
The eluent was evaporated to remove the methanol in vacuo and then lyophilized to give 7-[2-(4-amino-pyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(pyrazin-2-yl-thiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (0.9~), mp 175-180C (dec.).
I.R. ~NUaol : 3350, 3250, 1780, 1660, 1590cm-~.
N.M.R.~ppm (DMSO-d6~: 3.55,3.73(2H,ABq,J=18Hz), 4.00 (3H,s), 4.10, 4.62 (2H,ABq, ~ ~1 ~ t) ~ 0 ~ 1 46S5;~

J=13Hz) 5.17 (lH,d,J=4Hz), 5.83 (lH,d,d,J=4Hz,8Hz~, 6.48 ~lH,d,J=6Hz), 7.10 (2H,s), 8.15 (lH,d,J=6Hz), 8.30-8.67 (3H,m), 9.45 (lH,d,J=8Hz) The following compounds were obtained according to the similar manner to that o~ Example 5-(3~. ~
(4) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-- acetamido]-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl]
; 10 -3-cephem-4-carboxylic acid (syn isomer) I.R. vNUiol : 3370, 3220, 1780, 1680-1640cm~~.
max (5) Sodium 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxy-iminoacetamido]-3-[5-(4-chlorophenyl)-1,3,4-oxa-diazol-2-ylthiomethyl]-3-cephem-4-carboxylate (syn isomer).
- I.R. vNUiol : 3370, 3220, 1765, 1670-1600, max 1400, 1090, 1040, 835, 728cm~l.
(6) 7-12-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2- -~
ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNmal : 3400, i280, 1780, 1680, 1630, 1575, lS30, 1380, 1040, 900, 800cm 1.
(7) 7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (~yn isomer).
I.R. VNuiol : 3350, 3250, 1780, 1660, 1585cm~l.
(8) 7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyiminoace-tamidol-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNmaxl : 3375, 3225, 1780, 1660, 1590, 1540Cm-l.
(9) 7-[2-Allyloxyimino-2-(4-amin~pyrimidin-2-yl) acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
.
~ E-9~

.

;

.
.

.

655;~

I.R. vNm~Xl : 3380, 3230, 1780, 1660, 1585, 1540cm l.
(10)7-[2-(4-Aminopyrimidin-2-yl)-2-benzyloY~yimino-acetaMidol-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNU~ol : 3370, 3230r 1780, 1660, 1590, 1540cm~l.
(11)7-12-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido]-3 [(1-hexyl-1~-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic-acid (syn isome~).
I.R. vNujol : 3200, 1780, 1670, 1620, 810, 725cm~l .
(12)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamino]-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNU~l 3350, 3200, 1775, 1665r 1620, 1250, 990, 805cm~~.
~13~7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl3-3-cephem-4-carboxylic acid (syn isomer).
I-R. vNmaxl : 3380, 3240, 1780, 1670, 1629cm~
(14)7-[2-(6-Aminopyridin-2-yl)-2-~2,2r2-trifluoro ethoxyimino)acetamido]-3-[(1-carboxymethyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid ~syn isomer).
I.R. vNm~xl : 3440, 3320, 1778, 1688, 1665, 1623, 1552cm~~.
(15)7-[2-~6-Aminopyridin-2-yl)-2-propargyloxyimino-acetamido]-3-~lr3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNm~Xl : 3300, 3200, 2160, 1775r 1735r 1670, 1630, 1085, 1025cm~l.
~16)7-[2-~4-Aminopyrimidin-2-yl)-2-metnoxyimino-acetamido]-3-~tetrazolo[1,5-b]pyridazin-6-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer), 13~ E-'l2 6~

mp 200-203C (dec.).
I.R. vNUiol : 3350, 1770, 1660, 1530cm 1.
N.M.R. ~ppm (DMSO-d6) : 3.63, 3.77 (2H,ABq, J=18Hz), 3.~3 (3H,s), 4.23, 4.60 (2H,ABq,J=14~z), 5.12(1H,d,J=4Hz), 5.85 (iH,d,dtJ=4Hz,8Hz), 6.45 ~lH,d,J=6Hz), 7.10 l2H,s), 7.75 (lH,d,J=lOHz), 8.12 (lH,d,J=6Hz), 8.60 (lH,d,J=lOHz), 9.43(1H,d, ~ J=8Hz).
(17) 7-[2-~4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid.
I;R. ~Nmaxl 3400, 3250, 1780, 1675l 1620, 1580, 1380, 1040cm (18) 7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid.
~ I.R. ~Nmaxl : 3370, 3250, 1780, 1680, 1630, 1570, 750, 722cm 13~ E-~3 55~

Example 19 7-~2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[1-(2-tert-butoxyc~rbonylaminoethyl)-lH-te~razol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained by reacting 7-amino-3-[1~
O ~2-tert-butoxycarbonylaminoethyl)-lH-tetrazol-5-yl3-thiomethyl-3-cephem-4-carboxylic acid, which can be prepared from 7-aminocephalosporanic acid and 1-(2-tert-butoxycarbonylaminoethyl)-lH-tetrazole-5-thiol, with 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) in substantially the same manner as that of Example 14-(1).
Ph~sical constant of 7-amino-3-~l-(2-tert-butoxycarbonylaminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid:
mp 185 - ~89C (dec.) ( I.R. v mU~ol : 3420, 3200,1810, 1700, 16Z0, 1525, 1290, 1175 cm - N.M.R. Cppm (NaHCO3+D2O) : 1.33 ~9H, s), 3.3-3 9 (4H, m), 4.20, 4.40 (2H, ABq, J=13Hz), 4.5-4.9 (2H, m), 5.10 (lH, d, J=5Hz), 5.51 (lH, d, J=5Hz) 13~

--- ~1465~;~

Physical constant of 7-[2-(4-aminopyrimidin-2-yl)_ 2-methoxyiminoacetamido]-3-~l-(2-tert-butoxy-carbonylaminoethyl)-lH-t~trazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid tsyn isomer);
I.R. v Nua~ol : 3400, 3220, 1790, 1720-1640, 1530, 126b, 1175, 1055, 725 cm~

N.~.R. ~ppm tDMSO-d6+D2O? : 1.66 t9H, s), 3-0-3-7 t2H, m), 3.7 t2H~ m), 4.12 (3H, s), 4.4 (4H, m), S.l9 (lH, d, . J=5Hz), 5.86 tlH, d, J=5Hz3, 6.90 (lH, d~ J=7Hz~, 8.23 tlH, d, J=7Hz) Example 20 - - 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamidoJ-3-[1~(2-aminoethyl)-lH-tetrazol-5 yl]
thiomethyl-3-cephem-4-carboxylic acid tsyn isomer~
was bbtained from the object compound in Ex~mnl~ 19 in substantia~ly the same manner as that,of Example 3, mp 183-195C (dec.~

I R ~ Nu~ol 3400, 3220, 1770, 1660, 1630, 1590, 1540, 1180, 1040 cm N M R ~ ppm tDMSO-d6lD2O) f 3.1-3.8 t4H~ m)t 3 99 (3H, s), 4.3-(2H, m3, 4.7 (2H, m), --5.12 (lH, d, J=5Hz~, 5.82 (lH, d, J=5Hz), 6.61 (lH, d, J=7Hz), 8.28 (lH, d, J=7Hz).

.. . .
,. . . .
: . - .-;
,;, ' ', .
' 1 3 7 . E-95 . ' , .
' , .: :

Preparation of the starting compounds ~1465 -~~ Preparation 1 (1) A 15% n-hexane solution (636 g.) of n-butyllithium was added to a solution of 6-amino-2-methylpyridine (64.8 g.) in tetrahydrofuran ~500 ml.) at -20 to -30C over one hour, and stirred at -8 to -lO~C for 30 minutes. To the solution was added trimethylsilylchloride (161.7 g.) at -15 to -5C
over 40 minlltes, and the resultant solution was stirred at room temperature overnight. The solution was filtered through by a column packed with silica gel (180 g.), washed with tetrahydrofuran and then the filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation to give 6-~N,N-bis(trimethylsilyl)-amino-2-methylpyridine (117.6 g.j, b.p. 95 to 97C/5-6 mm.
N-M-R- ~ppm (C~Q4) : 0.13 tl8H~ s)~ 2.35 ~3H, s), 6.43 (lH, d, J=8Hz), 6.60 (lH, d, J=8Hz), 7.25 (lH, t, J=8Hz) (2) A 15% n-hexane solution (338.6 g.) of n-butyllithium was dropwise added to a solution of 6-1N,N-bis(trimethylsilyl)amino]-2-methylpyridine ~100 g.) in anhydrous tetrahydrofuran (300 ml.) at -20 to -30C over one hour and the solution was stirred at 20 to 23C for one hour. The resultant solution was added in small portions to crushed dry ice (1 kg.) under stirring, and stirred till a room temperature. After removing tetrahydrofuran from the solution under reduced pressure, absolute ethanol (1 ~) was added to the residue. 30% Bthanol solution (660 ml.) -of hydrochloric acid was dropwise added to the solution at -5 to -10C, and further hydrogen chloride gas was bubbled at 0 to 5C for 3Q minutes and then the solution was stirred at 10C overnight. After removing ethanol from the resultant solution, the residue was dissolved in water, ~ 38 p_ i ~6553 and washed with ethyl acetate 3 times. The solution was adjusted to pH 7 to 8 with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give the cTude product (54 g.) The product was purified by column chromatography on silica gel (1 kg.) with an - eluent tethyl acetate ~ benzene) to give ethyl 2-(6-aminopyridin-2-yl)acetate (30.2 g.), mp 66 to 68C.
I.R. ~ mUa~ol : 3430, 3340, 3200, 1730, 1645, 1480, 1190 cm 1 N.M.R. ~ppm (CDCQ3) : 1.25 (3H, t, J=6Hz), 3.67 (2H, s), 4.20 (2H, q, J=6Hz), 5.33 ~2H, broad s), 6.43 (lH, d, J=8Hz), 6.62 (lH, d, J=8Hz), 7.40 (lH, t, J=8Hz).

~.
~3) Acetic anhydride ~16.6 ml.) and 98% formic acid t7.32 ml.) were mixed at room temperature and stirred at S0 to 66C for 30 minutes. The solution was dropwise added to a solution of ethyl 2-(6-aminopyridin-2-yl)acetate (26.5 g.) in ethyl acetate (250 ml.) at 20 to 23C over 30 minutes, and stirred at the same temperature for one hour. Cool water was added to the resultant solution and shaked sufficiently. The ethyl acetate layer was separated, washed with water, an aqueous solution of sodium bicarbonate and water in turn, dried and concentrated under reduced pressure to give ethyl 2-(~-formamidopyridin-2-yl)acetate (28 g.), mp 35 to 38~C.

: ~39 .

N O~ l 4 65 5 3 I. R. v mu~ : 3250, 3100, 1738, 1690, 1580, 1460, 1305, 1277 cm 1 N.M.R. ~ppm (DMS0-d6) : 1.17 (3H, t, J=8Hz), 3.75 (2H, s), 4.08 (2H, q, J=8Hz), 6.85 (0.5H, bToad d, J=8Hz~, 7.95 (0.5H, broad s), 7.08 (lH, d, J=8Hz), 7.73 (lH, t, J=8Hz), 8.33 (0.5H, broad s), 9.25 tO-5H, broad d), 10.58 (lH, broad s).

~4) To a solution of ethyl 2-(6-~ormamidopyridin-2-yl)acetate (26 g.) in dioxane (260 ml.) was added selenium dioxide (16.65 g.) in small portions at 85 to 90C over one hour and stirred at the same temperature for one hour.
After cooling the resultant solution the dioxane layer was separated and concentrated under reduced pressure and then : the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and treated with activated charcoal and then concentrated ~der ' reduced pressure. The residue was triturated with die~hyl ether to give ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (14.3 g.), mp 124 to 126C.

I. R. ~NmUaxol : 3220, 3100, 1737, 1720, 1690, 1273, 1233 cm N.M.R. ~ppm (DMS0-d6) : 1.34 (3H, t, J=8Hz), 4.44 (2H, q, J=8Hz), 7.33 (0.65H, broad s), 7.8 - 8.2 (0.35H), 7.84 (lH, d, J=8Hz), 8.09 (lH, t, J=8Hz?, 8.44 (0.35H, broad s), 9.22 (0.65H, broad s), 10.85 (lH, broad s).

1~ p ~14~i5S3 (5) 2N Sodium hydroxide solution [solvent:water ~1 part) ~ ethanol (4 parts~] ~14.87 ml.) was added to a solution of ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (6.00 g.~ in ethanol (180 ml.~ at room temperature and stirred at the same temperature for 20 minutes.
Methoxyamine hydrochloride (2.71 g.) was added to the resultant solution, stirred at room temperature for 1.5 hours and then concentrated to a small volume under re-duced pressure. The precipitates were collected by fil-teration washed with ethyl acetate and water, dissolved in methanol and then treated with aotivated charcoal. The solution was concentrated under reduced pressure and then the precipitates were colle~ted by filtration to give 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (3.63 g.), mp 170 to 171C (dec.).

I. R. ~ NUa~ol 3230, 3132, 1745; 1680~ 1575 1450, 1320? 1208, 1032 cm~l N.M.R. ~ppm (DMSO-d6) : 3.70 (3H, s), 6.90 (0.6H, broad d), 7.9 tO.4H, broad s), 7.10 (lH, d, J=8Hz), 7.75 (lH, t, J=8Hz), 8.38 i (0.4H, broad s), 9.25 (0.6H, broad d), : 10.58 (lH, broad d).

(6) To a solution of ethyl 2-(6-formamidopyridin-2-yl)acetate (4.4 g.) in ethanol (44 ml.) was added 2N sodium hydroxide solution [solvent:water tl part) + ethanol (4 parts] (15.9 ml.) at 18 to 20C over 30 min~tes, and then the solution was stirred at room temperatUTe for one hour.
After lN hydrochloric acid (31~7 ml.) was added to the 1~ p-4 : . .

~146553 solution, the solution was concentrated under reduced pressureS The residue was extracted with hot ethyl acetate t500 ml.) and the extract was concentrated under reduced pressure. The residue was washed with ethyl acetate to give 2-(~-formamidopyridin-2-yl)acetic acid (2.5 g.), mp 125 to 126C tdec.).

I.R. v maxl : 3270, 1720, 1655, 1575, 1460 cm~l N.M.R. ~ppm (DMSO-d6~D2O) : 3.70 (2H, s), c 6.9 and 7.9 (lH, m), 7.10 (lH~ d, J=8Hz), 7.75 (lH, t, Jz8Hz), 9.25 and 8.38 (lH, broad s).

(7) A suspension of 2~6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (1.5 g.) and conc.hydrochloric acid ~ tO.77 g.~ in methanol (30 ml.) was stirred at room tem-t perature for 45 minutes. After concentrating the resultant solution under reduced pressure, the residue was washed with diethyl ether. The precipitates were collected by filtration to give 2-(6-aminopyridin-2-yl)-2-methoxyimino-acetic acid hydrochloride (1.63 g.), mp 100 to 105C.

t I. R. v mua~ol 3400 3150, 1730, 1670 7 1245, 1050, 803 cm 1 N.M.R. ~ppm (DMSO-d6) : 4.13 t3H, s), 6.89 (lH, d, J=8Hz), 7.22 (lH, d, J=8.5Hz~, 7.95 (lH, dd, J-8.5Hz, 8Hz).

~8~ Bis(trimethylsilyl)~cetamide (1.61 g.) was added I k2 ' p ~ ~4~i~53 to a stirred-suspension of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride ~410 mg.~ in ethyl acetate (5 ml.) all at once, and stirTed at 40C for 50 minutes. Trifluoroacetic anhydride (1.3 g.) was dropped into the solution at -10 to -5~C over 30 minutes, and then the soiution was stirred at the same temperature for 3 hours. Ethyl acetate ~10 ml.) and.water (3 ml.) were added to the resultant solution. The solution was washed with water and a saturated aqueous solution of sodium bicarbonate in turn, dried over magnesium sulfate, and concentrated under reduced pressure to gi~e 2-t6-trifluoroacetamidopyridin-2-yl)-2-methoxyiminoacetic acid ' t470 mg.), mp 194 to 195C.

I. R. v NUa~ol : 3350, 1680-1670, 1600, 1380, 1040, 850, 810 cm 1 (9) lN Sodium 'hydroxide (27.5 ml.) was added to a stirred solution of ethyl 2-t6-formamidopyridin-2-ylj-glyoxylate t5.55 g.) in ethanol tlO0 ml.) at room temperature, and the solution was stirred at the same temperature for 30 minutes. To the solution was added hydroxylamine hydrochloride (1.9 g.~ all at once, and the solution was stirred at room temperature for 2 h~urs. After removing ethanol from the resultant solution under reduced pressure, ethylacetate was added to the residue, and then the solut-ion was adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 2 with 10% hydrochloric acid. The precipitates were col'lected by filtration, wash'ed with water and dried to ~43 p- ~

~ L146SS3 give 2-(6-formamidopyTidin-2-yl)-2-hydroxyiminoacetic acid (3.6 g.), mp 190 to 192C (dec.).

I. R. v NUa~ol : 3120, 1700, 1665, 1620 cm 1 s ; (10) A mixture of 2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid (3.6 g.), dichloroacetyl chloride (7.6 g.) and methylene chloride (100 ml.) was stirred at room temperature for 5 hours. The precipitates were col-lected by filtration, washed with diethyl ether and dried to give 2-t6-formamidopyridin-2-yl)-2-dichloroacetoxyimino-acetic acid (4.6 g.), mp 88 to 90~C.

I. R. ~ NmUa~ol : 1800, 1720, 1620 cm 1 Preparation 2 (1) A mixture of acetic anh~ydride (32.7 g.) and formic acid (16.2 g.) was stirred at 50 to 60C for 30 minutes. The solution was added to a suspension of methyl 2-(2-aminopyrimidin-4-yl)acetate (17.93 g.) in ethyl acetate (300 ml.) at room temperature over 10 minutes, and the solution was stirred at room temperature for 3 hours.
After removing the insoluble substance by filtration, water !' (300 ml.) was added to the filtrate, and then the mixture ~5 was adjusted to pH 7 with sodium bicarbonate. The aqueous layer was separated and extracted with ethyl acetate. The extract and the organic layer were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal, and then concentrated under reduced pressure. The residue was ~ ~655;~
triturated with diethyl ether to give methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.62 g.), mp 103 to 107~

I.R. v NUa~ol : 3000-3400~ (multiple), 1740, 1703, 1600, 1567 cm N.M.R. ~ppm (DMSO-d6) : ~.70 (3H, s), 3.90 (2H, - s), 7.25 (lH, d, J=SHz), 8.60 ~lH, d, Jz5Hz), 9.43 ~lH, d, J=lOHz), 11.07 (lH, broad d, J=lOHz) (2) Selenium oxide ~9.92 g.) was added to a solution of methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.52 g.) in dioxane (200 ml.) at 90 to 95C orer 20 minutes, and lS stirred at the same temperature for an houT. After cool-ing the resultant solutivn, the solution was filtered -. through a column packed with silica gel t20 g.), washed with dioxane and concentrated under reduced pressure.
The residue was dissolved in acetone and filtered, and then the filtrate was concentrated wldeT reduced pressure.
The residue was triturated with chloroform to give a crude product (8.2 g.). The product was added to ethyl acetate, heated and an insoluble material was filtered out. The filtrate was cooled, and the precipitates were collected by filtration to give methyl 2-(2-formamido-pyrimidin-4-yl)glyoxylate (5.55 g.). The product was recTystallized from ethyl acetate (saturated with water) to give mono hydrate thereof, mp 143 to 144C.
Anal. Calcd. for C8H7 N304-H20 1~ p- 8 ~146553 C H N
Calcd. 42 30 3.99 18.50 found 42.22 3 95 18.34 I. R. v NmUaxol : 3270, 3200, 1750, 1710, 1597, 1585, 1416, 1233 cm 1 .~.M.R. ~ppm (DMSO-d6) : 3.65 ~3H, s), 7.30 (2H, s~ J
7.40 (lH, d, J=5Hz), 8.63 (lH, dp J=5Hz), 9.33 (lH, d, J=lOHz), 10.95 (lH, bd7 J=lOHz).

(3) 4N sodium hydroxide (10.85 ml.) was added to a solution of methyl 2-(2-formamidopyrimidin-4-yl)glyoxylate mono hydrate (4.55 g.~ in methanol (60 ml.), and the solut-ion was stirred for an hour.
To the solution was added methoxylamine hyd~ochloride (1.82 g.) little by little, and the solution was stirred at room temperature for 30 minutes, and then under ice cooling for 30 minutes. The precipitates were collected by filtration, and dissolved in water. The insoluble substance was fil-tered out. The filtrate was adjusted to pH 1 with 10%
hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and concentrated under reduced pressure.
The precipitates were collected by filtration to give 2-(2-formamidopyrimidin-4-yl)-2-methoxyiminoacetic acid tO.63 ?.5 g.). The methanol solution obtained above was concentrated under reduced pressure, and the residue was dissolved in water. The aqueous solution was treated with activated charcoal, adjusted to pH 1 with 10% hydrochloric acid and e.xtracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and . P-9 3 1~6553 concentraced under reduced pressure. The precipitates were collected by filtration to give the same object compound (0.73 g.), total yield 1.36 g, mp 180 to 182C (dec.).
I. R. ~ma~ : 3300-2400 (multiple), 1750, 1670, ~~ 1590, 1573, 1408, 1240, 1048 cm 1 N.M.R. ~ppm (DMSO-d6) : 4.00 (3H, s3, 7.47 (lH, d, J=5Hz), 8.60 (LH, d, J=5Hz), 9.23 (lH, d, J=lOHz), 11.02 (lH, broad d, J=lOHz).
Preparation 3 tl) 1~ Sodium hydroxide solution (~.5 ml.) was adde~ to a stirred solution of ethyl 2-(6-formamidopyridin-2-yl)-glyoxylate (1.9 g.) in ethanol (30 ml.) at room temperature and stirred at the same temperature for 30 minutes. After adding ethoxylamine hydrochloride (912 mg.) to the solution, the solution was stirred at room temperature for 4 hours.
The resultant solution was concentrated under reduced pres-sure, and ethyl acetate and an aqueous solution of sodium bicarbonate were added to the residue. The aqueous layer was separated and ethyl acetate was added to the solution. The solution was adjusted to pH 1 with 10% hydrochloric acid.
The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated under reduced p essure. The resi-due was triturated with a mixture of diethyl ether and petroleum ether to give 2-(6-formamidopyridin-2-yl)-2-ethyoxyiminoacetic acid (920 mg.), mp. 155 to 156C (dec.).
I. R.~ maxl : 3250, 1740, 1650 cm 1 N.M.R. Oppm (DMSO-d6) : 1.3 (3H, t, J=7Hz), 4.3 (2H, q, J=7Hz), 6.8-8.2 (3H,m), 9.4 (lH, broad d), 10.5 (lH, broad d) 1~7 ~ ~ ~ 6 S 53 Preparation 4 (1) A mixture of formic acid t20 g.) and acetic anhydride ~41.3 g.) was stirred for 30 minutes at 50C and thereto was added methyl 4-amino-2-pyridinecarboxylate (11 g.) at ambient temperature, and then the mixture was stirred for 2 hours at 70-75C. After the removal of the solvent from the reaction mixture, the residue was recrystallized from ethanol (160 ml.) to give a pale yeIlow powder of methyl 4~formamido-2-pyridinecarboxylate (8.3 g.~, mp. 185 to 186.5C.
I.R. v mUa~ol: 3200-3300, 1690, 1675, 1585, 1570, 1495, 1420, 1260, 990, 860, 840 cm 1 (2) To a mixture of methyl 4-formamido-2-pyridine-carboxylate (9.9 g.), methyl methylthiomethyl sulfoxide ~6.82 g.) and N,N-dimethylformamide (200 ml.) was added 50% sodium hydride (7.92 g.) with stirring at ~0C and the stirring was continued for further 10.5 hours at 45C.
After the removal of N,N-dimethylformamide from the reaction mixture, to the residue was added a cold mixture of ethyl acetate and diluted hydrochloric acid. The ethyl acetate layer was separated and the remaining aqueous layer was further extracted with ethyl acetate. The combined extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and the solvent was distilled off. The residue (6.0 g.) was washed with a mixture of ethyl acetate and diethyl ether, collected by filtration and then dried to give the brownish yellow powder of 4-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine 1 4 ~ P - ~ i ' ~

~.~46~i;53 (1.96 g.), mp. 132 to 132.SC. After the concentration of the filtrate, the precipitates were collected by iltration,washed with diethyl ether and then dried to give the same compound (1.11 g.). Total yield : 3.07 g.
I.R. v NUa~ol: 3200-3225, 1680, 1580, 1290, 1170, 1020, 845 cm 1 (3) ~fter stirring a mixture of acetic anhydride (14 ml.) and formic acid (136 ml.) for 10 minutes at 40 to 50C, 4-formamido-2-~2-methanesulfinyl-2-methylthio-acetyl)pyridine (3.7 g.) was added thereto, and then the stirring was continued at 65C for 30 minutes. To the mixture was added sodium periodate (0.872 g.), and the mixture was stirred for 15 minutes. After the removal of the solvent from the reaction mixture, the residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium bicarbonate, aqueous sodium thiosulfate and water successively, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was washed with diethyl ether, collected by filtration and then dried to give a pale yellow powder of S-methy~ 2- (4-formamidopyridin -2-yl)-thioglyoxylate (1.96 g.), mp. 145 to 148C.
I.R. ~ NUa~ol: 3150-3300, 1690, 1670, 1585> 1570, 1500, 1420, 1265, 990, 860, 835, 745 cm 1 (4~ A mixture of S-methyl 2-(4-formamidopyridin-2-yl)thioglyoxylate (1.07 g.), methanol (20 ml.) and lN
aqueous solution of sodium hydroxide (5.7 ml.) was stirred for 50 minutes at ambient temperature to give a solutions containing 2-(4-formamidopyridin-2-yl)glyoxylic acid.
p j ~ ' J 14655~
.

To the solution was added O-methylhydroxylamine hydrochloride (43~ mg.), and the mixture was stirred for an hour at ambient temperature. After the removal of the solvent from the reac~ion mixture, to the residue was added water (5 ml.), and the mixture was washed with ethyl acetate and then water was distilled off. The remaining water in the residue was azeotropically removed with ethanol and benzene in turn to give a pale brown powder of 2-(4-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (960 mg.).
N.M.R. ~ ppm tDMSO-d6+D2O):3.93 t3H, s)j 7.6 (lH, broad) 8.1 (broad s) } (lH) . 8.55 (broad s) 8.45 (lH, broad s) Preparation 5 (l) A mixture of formic acid (559.3 g.) and acetic anhydride (1033.4 g.) was stirred for 30 minutes at 40 to 50C and thereto was added methyl 6-amino-2-pyridinecarboxylate (616 g.) at 40C, and then the mixture was stirred for 1 hour at 80~C. After the removal of the solvent from the reaction mixture, the residue was dissolved in a mixture of benzene and n-hexane and then filtered. Thus obtained precipitates were recrystallized from benzene t2 Q.) to give methyl 6-formamido-2-pyridinecarboxylate (647.8 g.), mp. 134 to 136C.

- o li9 P- l3 ~46S~;~
Element analysis:
C N H
Calcd (%) 53.33 4.48 15~55 Found (%) 53.37 4.40 15.58 I.R. ~ NaU~o~ 3200,1740, 1700cm 1 (2) To a mixture of methyl 6-formamido-2-pyridinecarboxylate (435.7 g.), methyl methylthiomethyl sulfoxide (300 g.) and N,N-dimethylfoTmamide ~2.2 Q.) was added 50~ sodium hydride (348 g.) with stirring under ice-cooling, and the mixture was stirred for 30 minutes at ambient temperature. To the reaction mixture was added benzene ~4.4 Q.) under ice-cooling and the precipitates were collected by filtration. The pre-cipitates were a~ded to a mixture of methylene chloride (3 ~.), iC9 (2 kg.) and concentrated hydrochloric acid (730 ml.). The mixture was adjusted to pH 7 with sodium bicarbonate and then extracted with methylene chloride. The extract was dried over magnesium sulfate and the solvent was distilled off. The residue was crystallize~l in diethyl ether, collected by filtration and then dried to give 6-formami~1O-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine ~430 g.), mp. 130 to 132CC.
I.R. maUixol: 3250, 3150, 3050, 17]0, 1690, 1600, 1510 cm 1 ~L1465~;~

N.M.R. ~ ppm (d6-acetone + D20) : Z.30 (3H, s), 2.88 ~3H, s), 6.00 (lH, s), . 7.7-8.2 (3H, m) (3) A mixture of 6-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine (424 g.), sodium periodate (100 g ) in acetic acid (2 1 Q.) was stirred for 30 minutes at 70~C. After the removal of the solvent from the reaction mixture, to the residue were added water (5 Q.) and sodium thiosulfate (116 g.), and then the mixture was adjusted to pH 7 with sodium bicarbonate. The precipitates were collected by filtration, washed with water and then dried to give S-methyl 2-(6-formamidopyridin-2-yl)thioglyoxylate (246.4 g.), mp. 163 to 165~C. Further, the same compound (12 g.) was obtained from the aqueous layer by extraction with ~thyl acetate.

I.R. ~ maUjxol : 3250, 3150, 3080, 1700, 1670, 1595, 1580, 1510 cm 1 N.M.R. ~ ppm (acetone-d6 ~ D2O) : 2.57 (3H, s), 7.77 - 8.27 (3H, m) (4)-a) A mixture of S-methyl 2-(6-formamidopyridin-2-yl)thioglyoxylate (4.48 g.), methanol (20 ml.) and lN
aqueous solution of sodium hydroxide (20 ml.) was stirred for 50 minutes at ar,lbient temperature to give a solution containing 2-(6-formamidopyridin-2-yl)glyoxylic acid.
To the solution was added 0-propylhydroxylamine hydrochloride 1 a 2 146S5~
t2.23 g.), and the mixture was stirred for 35 minutes at the same temperature. The reaction mixture was adjusted to pH 7 with ~ydrochloric acid and the methanol was distilled off. The remaining aqueous mixture was washed with ethyl acetate, and ethyl acetate was added thereto and then adjusted to pH 1 with 10~ hydrochloric acid.
The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate, treated with activated charcoal and then the solvent was distilled off. Thus obtained product was washed with a mixture of diethyl ether and diisopropyl ether and then dried to give 2-(6-formamidopyridin-2-yl)-2-propoxyiminoacetic acid (syn isomer) (1.76 g.), mp. 140 to 142C (dec.).
I.R. ~ Naxl: 3250, 3100, 2600, 1755, 1670, 1620, 1580 cm N.M.R. ~ ppm (acetone-d6 ~ D20) : 0.96 (3H, t~
J=7Hz), 1.56-1.84 (2H, m), 4.2 ~2H, t, J=7Hz), 7.0-8.32 (3H, m) Similarly,the following compounds were obtained.
(4)-b) 2-(6-Formamidopyridin-2-yl)-2-(2,2,2-trifluoro-~ ethoxyimino)acetic acid (syn isomer), mp. 183 to 184C
; (dec.) 1 25 I.R. ~ mUa~ol: 3220, 1760, 1680 cm 1 j N.M.R. ~ ppm (DMS0-d6) : 4.78, 5.07 (2H, ABq, j J=9Hz), 7.0-8.2 (3H, m), ¦ 9.0-9.3 (lH, m), 10.76 (lH, m) I (4)-c) 2-(6-Formamidopyridin-2-yl)-2-isopropoxy-, 30 iminoacetic acid (syn isomer), mp. 140 to 150C (dec.).
~ ~ 3 P ~

~465S~
I.R. v Nujol 3300, 2600, 1750, 1670, 1620, 1580, 1510 cm 1 N.M.R. ~ ppm (acetone-d6 ~ D2O) : 1.3 (6H, d, J=6Hz), 4.36-4.64 (lH, m), S.92-8.28 (3H, m) ' (4)-d) ~-Allyloxyimino-2-(6-for~amidopyridin-2-yl3 acetic acid (syn isomer), mp. 140C (dec.).
I.R. v Nax : 3250, 3100, 2600~ 1760, 1670, - 1620, 1580 cm 1 N.M.R. ~ ppm (acetone-d6 + D2O) : 4.67-4.9 (2H, m), 5.17-5.6 (2H, m), 5.B-6.52 (lH, m), 7.0-8.33 (3H, m) (4)-e) 2-(6-Formamidopyridin-2-yl)-2-propargyloxy-iminoacetic acid (syn isomer), mp. 145 to 150C (dec.).
I.R. v mUa~ol: 3350- 3250, 3100, 2600, 1755, 1685, 1620, 1580, 1510 cm N.M.R. ~ ppm (acetone-d6 + D20) : 3.04 (lH, t, J=2Hz), 4.88 (2H, d, J=2Hz), 7.0-8.28 (3H, m) (4)-f~ 2-Butoxyimino-2-(6-formamidopyridin-Z-yl)-acetic acid (syn isomer), mp. 129 to 131C (dec.).
I.R. v mUx 1 3150, 1755, 1670 cm 1 N.M.R.~ ppm (DMSO-d6) : 0.7-1.9 (7H, m), 4.20 (2H, t, J=6Hz), 7.0-8.1 (3H, m), 10.7 (lH, broad d) (4)-g) 2-Isobutoxyimino-2-(6-formamidopyridin-2-yl)-acetic acid (syn isomer), mp. 153 to 155C (dec.).
I.R. v maxl: 3250, 3150, 1750, 1680, 1620, 1580 cm 1 N.M.R. ~ ppm (acetone-d6 ~ D2O): 0.96 (6H, d, J=6}1z)~
1.88 2.16 (lH, m), 4.0 (2H, d, J=6Hz), 7.0-8 28 (3H, m) ~ 5 ~ r ~ 465~3 (4)-h) 2-(6-Formamidopyridin-2-yl)-2-phenoxyimino-acetic acid (syn isomer), mp. 148 to 150C (dec.) I.R. v mNUxl: 1730, 1660, 1560 cm 1 N.M.R. ~ ppm (DMSO-d6) : 6.80-8.2 (8H, m), 10.80 (lH, d, J=8Hz) Preparation 6 (1) Methyl 6-formamido-3-pyridinecarboxylate~
mp. 218 to 220C was obtained accoTding to the similar manner to that of the ~reparation 4-(l).
I.R. ~ NUa~ol: 3100, 3020, 1710, 1605, 1540 cm~
N.M.R. ~ ppm (DMSO-d6 + D2O) : 3-84 (3H, s), 8.12-8.84 (3H, m) (2) 2-Formamido-5-(2-methanesulfinyl-2-methylthio-acetyl)pyridine, mp. 125 to 127C was obtained according to the similar manner to that of Preparation 4-(2) I.R. v max : 3200, 1710, 1660, 1600, 1545 cm 1 (3) S-Methyl 2-(6-formamidopyridin-3-yl)thioglyoxylate, mp. 152 to 154C was obtained according to the similar manner to that of the Preparation ~-(3) by using acetic acid instead of acetic anhydride and formic acid.
I.R. v max : 3250, 3150, 3050, 1730, 1680~ 1600, 1590, 1510 cm 1 N.M.R. ~ ppm (acetone-d6 + D2O) : 2.47 (3H, s), 8.35-9.17 (3H, m) ~4) A mixture of S-methyl 2-(6-formamidopyridin-3-yl~thioglyoxylate (13 g.), methanol (50 ml.), lN aqueous solution of sodium hydroxide C58 ml.) and water (150 ml.) was stirred at ambient temperature for 30 minutes.
To the mixture was added O-methylhydroxylamine hydrochloride (4.85 g.) and then stirred for an hour. The reaction ~1 ~ 6~ ~ 3 mixture was adjusted to pH 7 with an aqueous solution o~
sodium ~icarbonate, and the methanol was removed by distillation under reduced pressure. The remaining aqueous solution was washed with ethyl acetate and thereto was added ethyl acetate. The Tesultant mixture was adjusted to pH 2 with 10% hydrochloric acid and theret~
was added sodium chloride, and the mixture was stirred for a while, The precipitateswere collected by filtration washed with diisopropyl ether and then dried to give 2-(2-for~amidopyridin-3-yl)-2-methoxyiminoacetic acid tsyn isomer) t2.0 g.), mp. lS9 to 161C (dec.).
I.R. v mUxol: 1735, 1665, 1590, 1550 cm 1 N.M.R. ~ ppm (DMS0-d6) : 4.0D (3H, s), 7.8-8.5 (3EI, m), 10.87 (lH, d, J=6Hz) lS On the other hand, the ethyl acetate layer W?s separated from the filtrate and the remaining aqueous layer was further extracted with ethyl acetate.
The ethyl acetate layers were combined together, dried over magnesium sulfate and then the-solvent was distilled off to give powder of 2-(6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (a mixture of syn and anti isomers).
Thus obtained powder was dissolved in an aqueous solution of sodium bicarbonate and then adjusted to pH 2 to 3 with 10~ hydrochloric acid. The precipitates were collected by filtration and then dried to gi~e 2-(6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid tanti isOmeT~ (1.45 g.), mp. 168 to 170C tdec.).
I.R. v NUaxol: 1705, 1605, 1535 cm 1 N.M.R. ~ ppm tDMSO-d6.) : 4.00 t3H, s), 7.8-8.5 t3H, m), 10.80 tlH, d, J=7Hz) S5~
Further, the mother liquor was adjusted to pH 3 to 4 with an aqueous solution of sodium bicarbonate.
The resultant solution was washed with ethyl acetate, adjusted to pH 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was dried over magnesium sulfate and then the solvent was distilled off to give further 2-(6-formamidopyridin-3-yl)-2-methoxyimlnoacetic acid (syn isomer) (2.5 g.).
- Preparation 7 (1) Methyl 2-formamido-4-pyridine mp. 196 to 197C was obtained according to the similar manner to that of the Preparation4 -(1).
I.R. v maU~ol: 3100, 1740, 1710, 1580, 1540 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.92 (3H, s), 7.48-8.6 (3H, m) (2) 2-Formamido-4-(2-methanesulfinyl-2-methyl-thioacetyl)pyridine, mp. 123 to 125C was obtained according to the similar manner to that of the Preparation 4-~2).
I.R. v mNU~ol: 3150, 3050~ 1690, 1610, 1565 cm 1 (3~ S-Methyl 2-(2-formamidopyridin-4-yl)thio-glyoxylate, mp. 165 to 167C was obtained according to the ~imilar manner to that of the Preparation 4-(3) by using acetic acid instead of acetic anhydride and formic acid.
I.R. v maU~ol: 3250, 3100, 1710, 1680, 1610, 1565, 1520 cm 1 N.M.R. ~ ppm (CDCQ3 + D20) : 2.48 (3H, s~, 7.5-8.6 (3H, m) (4) 2-(2-Formamidopyridin-4-yl)-2-methoxyiminoacetic acid (syn isomer), mp. 170 to 172CC (dec.) was obtained 1~7 P~

;553 according to the similar manner to that of the Preparation 4-(4) via 2-t2-formamidopyridin-4-yl)-glyoxylic acid.
I.R. v mNUa~ol: 2500, 1710, 1640, 1615, 1600, 1520 cm 1 N.M.R. ~ ppm (DMSO-d6 ~ D2O) : 4.02 (3H, s), 7.0-8.6 (3H, m~
PreParation 8 tl) A mixture of ethyl 2-(4-amino-6-hydroxy-pyrimidin-2-yl)acetate (15.8 g.) and phosphoryl chloride (75 ml.) was stirred for 4 hours under heating at 80 to 90C. The resultant solution was allowed to cool and phosphoryl chloride was distilled off. The remaining oily substance was poured into a mixtu~e of ice-water (200 ml.) and ethyl acetate (200 ml.). The resultant mixture was neutralized with an aqueous solution of ammonia and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then the solvent was distilled off. The resultant residue was washed with diisopropyl ether and then dried to give pale brown crystals of ethyl 2-~4-amino-6-chloro-pyrimidin-2-yl)acetate (8.1 g.), mp. 127 to 128C.
I.R. ~ mU~ol: 3250-3400, 1700, 1650, 1520-1580, 1320, 1160-1210, 860, 840 cm 1 (2) Ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)-acetate ~oil) was obtained according to the similar manner to that of the Preparation 4~
I.R. v malm : 2800-3600, 1680-1730, 1560, 1140-1190, 1020 cm 1 N.M.R. ~ ppm (CDCQ3) : 1.30 (3H, t, J=8Hz), - ~5~ P~

: .
' ' : - ' 6 5 ~ ~
3.92 (2H, s), 4.23 (2H, q, J=8Hz), 8.3-9.3 (lH, broad), 9.4-10.4 (2H, broad) t3) To a solution of ethyl 2-(6-chloro-4-formamido-pyrimidin-2-yl)acetate (2.3 g.) and sodium acetate (0.93 g.) in 80~ ethanol (50 ml.) was added 10~ palladium on carbon (0.2 g.), and the mixture was stirred under a hydrogen atmosphere for 8 hours at ambient temperature. The reaction mixture was filtered and the filtrate was c~oncentrated. To the residue were added ethyl acetate and a small amount of water and the ethyl acetate layer was separated. The remaining aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined together, washed with water and dried over magnesium sulfate and then the solvent was distilled off. Thus obtained oily substance (2.2 g.) was purified by column chromatography on silica gel (40 g.) using a mixture of benzene and ethyl acetate as an eluent to give a pale brown solid of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (1.3 g.), mp. 80 to 93C.
I.R. v NUa~ol : 1710, 1670, 1530, 1310, 1170, 840 cm 1 N.M.R. ~ ppm (CDCQ3~: 1.23 (3H, t, J=8Hz), 3.78 t2H, s), 4.33 (2H, q, J=8Hz), 6.5-8.3 tlH, broad), 8 37 (lH, d, J-5Hz), 9.15 (lH, broad s), 9.45 (lH, broad s) (4) To a solution of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (7.0 g.)in acetic acid t34 ml.) was added dropwise a solution of sodium nitrite (4.1 ~.) in wateT
(12 ml.) over a 15 minutes period with stirring at 10C, ~ ~ 9 P ~

~4655;~
and the stirring was continued at the same temperature for an hour and at ambient temperature for another an hour.
After cooling the reaction mixture in an ice bath, water t50 ml.) was added thereto. The precipitates were collected by filtration and washed successively with water and diethyl e*her and then dried to give a quantitative yield of a powder of ethyl 2-t4-formamidopyrimidin-2-yl) 2-hydroxyiminoacetate, mp. 164 to 180C (dec.).
N.M.R.~ ppm (DMSO-d6): 1.30 (3H, t, J=8Hz), 4.40 (2H, q, J=8Hz), 7.5 (lH, broad), 8.73 tlH, d, J=6Hz), 9.05 (lH, broad s) (5) Ethyl 2-(4-formamidopyrimidin-2-yl)-2-hydroxyiminoacetate (7.0 g.) was dissolved in dioxane (200 ml.) under heating and the resultant solution was cooled to ambient temperature in an ice bath, and then thereto was added a solution of diazomethane in diethyl ether with stirring until complete consumption of the starting materials. The reaction mixture was concentrated to give a brown oil, which was purified by column chromato~raphy on silica gel (140 g.) using benzene as an developing solvent and a mixture of benzene and ethyl acetate (3:1) as an eluent to give a pale brown semisolid of ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxy-iminoacetate (4.4 g.).
I.R. vmaxm : 3500-3600 (shoulder), 2900-3400, 1680-1740, 1560, 1500, 1250, 1020, 840 cm 1 N.M.R. ~ppm (CDC~3): 1.40 (3H, t, J=8Hz), 4.17 (3H, s~, 4.47 (2Hs q, J=8Hz), 7.5-8.6 (lH, broad), ~0 P- 23 .; .
, .

~ .

8.73 (lH, d, J=6Hz), 8.9 (lH, broad) (6) A mixture of ethyl 2-~4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (4.3 g.) and lON aqueous solution of sodium hydroxide (6.1 ml.) in ethanol ~100 ml.) was - stirred for 3 hours at ambient temperature. To the reaction mixture was gradually added concentrated hydrochloric acid with stirring, whereby said mixture was adjusted to pH 3. The pTecipitates were collected by filtration and washed successively with ethanol and diethyl ether and then dried to give white crystals of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid.
I.R. ~ tNUjol): 2500-3300, 1550-1650, 1240, 1000-1040 cm N.M.R. ~ ppm (D2O-NaHCO3) : 4.0S t3H, s), 6.67 tlH, d, J=6Hz), 8.18 tlH, d, J=6Hz) The filtrate ahd washings are combined together and the solvonts were distilled off. The residue was pulverized in diethyl ether, collected by filtration and then dried to give further ths same compound.
(7) 2-~4-Formamidopyrimidin-2-yl)-2-methoxyimino-acetic acid tbrown powder), mp. 64 to 70C (dec.) was obtained according to the similar manner to that of the Preparation 4-(1).
N.M.R. ~ ppm (DMS0-d6): 4.02 (3H, s), 7.1-7.9 (lH, broad) 8.73 (lH, d, J=6Hz), 8.9 (lH, broad) ~1 p .
,' ~ . .

- . ~1 4655;~

Preparation 9 (1) A mixture of ethyl 2-(4-formamidopyrimidin-2_ yl)acetate (2.95 g.), selenium dioxide ~1.73 g.) in dimethylsulfoxide (30 ml.) was stirred under heating at 50 to 52C for an hour and at 70 to 72C for another 0.5 hours. The reaction mixture was cooled to amb;ent temperature and filtered, and then the filtered precipitates were washed with ethyl acetate. The filtrate and washings were combined together and concentrated to the volume of about S ml. under reduced pressure below 100C. The residue was poured into water (S0 ml.), and the mixture was stirred for 10 minutes.
The resultant mixture was filtered and the filtered precipitates were washed with water. The filtrate and washings were combined together and adjusted to pH 7 with an aqueous~ solution of sodium bicarbonate. The mixture was washed with ethyl acetate and saturated with sodium chloride and then extracted with a mixture of ethyl acetate and ethanol (2:1). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then the solvent was distilled off to give a deep yellow oil of a mixture o ethyl 2-t4-formamidopyrimidin-2-yl)glyoxylate and its monohydrate, i.e. ethyl 2-(4-formamidopyrimidin-2-yl)-2,2-dihydroxyacetate (2.4 g.).
(2) A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (2~95 g.), selenium dioxide (1.87 g.) and N,N-dimethyl formamide (15 ml.) was stirred for an hour under heating at 70C. The reaction mixture was cooled to ambient temperature and filteled and then the filtered lB~ p ~5 ~i46SX3 precipitates were washed with a small amount of N,N-dimethylformamide. The filtrate and washings were combined together and the solvent was distilled off.
The residue was poured into water (60 ml.) and the ~esulting mix*ure was stirred for lO minutes~ The mixture was adjusted to pH 6 to 7 with an aqueous solution of sodium bicarbonate and filtered to separate insoluble substances, w~ich were washed with water. The filtrate and washings were combined together and washed successively with diethyl ether and ethyl acetate. The aqueous mixture was saturated with sodium chloride and then extracted with a mixtur2 of chloroform and ethanol (l:l) (60 ml. x 4). The extract was dried over magnesium sulfate and the solvent was distilled off. The resulting oily substance (2.2 g.) was dissolved in ethyl acetate (10 ml.) and subjected to column chromatography on silica gel (15 g.) using ethyl acetat~ as an eluent. The eluates containing the desired compound were collected and then the solvent was distilled off. The resulting oily substance (1.5 g.) was dissolved in a small amount of ethyl acetate and then crystallized from diisopropyl ether to give pale yellow crystals of a mixture of ethyl 2-(4-formamidopyrimidin-2-yl)-glyoxylate and its monohydrate, i.e. ethyl 2-(4-formamido-pyrimidin-2-yl)-2,2-dihydroxyacetate (0.6 g.), mp. 74 to 78C.
I.R. v mNUaxol: 3200-3400, 1755, 1690-1710, 1595, 1580, 12~0, 1250, 1215, 1135, llO0, 1030, 850 cm~l N.M.R. ~ ppm ~DMSO-d6) : 1.16 (1.8H, t, J=7Hz), 1.26 (1.2H, t, J=7Hz), 4.10 (1.2H,q,J=7Rz) ~63 P-~

~146553 4.42 t0.8H, q, J=7HzJ, 6.97 (1.2H, broad s), 7.0-7.8 (lH, m), 8.64 (0.6H~ d, J=6Hz), 8.90 (0.4H, d, J=6Hz), 8.8-9.6 (lH, m), 11.15 (lH, broad s) (3) A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)glyoxylate and its monohydrate obtained in Preparation 6-(1) was dissolved in ethanol (30 ml.~ and thereto was added dropwise lN ethanol solution of potassium hydroxide (11 ml.) under ice-cooling with stirr;ng, and then stirring was continued for 2 hours at ambient temperature.
The reaction mixture was filtered and the filtered precipitates were washed successively with a small amount of ethanol and diethyl ether and then dried to give a brown powder of potassium 2-(4-aminoprimidin-2-yl)-glyoxylate (0.4 g.). The filtrate and washings were combined together and concentrated to the'volume of about 15 ml, and to the residue was added diethyl ether (20 ml.~. The precipitates were collected by filtration and washed successively with a small amount of ethanol and diethyl ether to give further a pale brown powder of a mixture of potassium 2-(4-aminopyrimidin-2-y1)-glyoxylate and its monohydrate (0.8 g.).
Total yield : 1.2 g.
~5 I.R. v mNa~l : 3380, 3200, 1715, 1665, 1600, , 1245, 940, 750 cm 1 ; N.M.R. ~ ppm (D2O): 6.54 (d, J=6Hz) , 6.74 (d; J=6Hz) ! 8.13 (d, J=6Hz) } (lH) 3~ 8.24 (d, J=6Hz) p - ~7 .

-~14~SS3 (4) To a solution of O-methylhydroxylamine hydro-chloride (0.25 g.) in methano] (6 ml.) was added a mixture of potassium 2-(4-aminopyrimidin-2-yl)glyoxylate and its monohydrate with stirring at ambient temperature, and the mixture was stirred for 4 hours. The reaction mixture was allowed to stand overnight at ambient temperature, filteredJ and the filtered pTecipitztes were washed with ethanol. After the filtra e and washings were combined together, the solvents were distilled off.
The resultant oily substance was pulverized in acetone (15 ml.) and collected by filtration. Thus obtained powder was washed successively with acetone and diethyl ether and then dried to give a pale brown powder of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (290 mg.).
I.R. v mUJol: 3100-3400, 2500-2900, 1540-1660, 1250, 990-1040 cm 1 N.M.R. ~ ppm (D2O+NaHCO3): 4;05 (3H, s), 6.63 (lH, d, J=6Hz), 8.13 (lH, d, J=6Hz) Preparation lo j (1) Methyl 2-(2-formamido-6-chloropyrimidin-4-yl)acetate (crystal) was obtained according to the similar manner to that of the Preparation 4-(1).
I.R. v mUJol: 3200, 3140, 1730, 1700, 1540-1580, 1500, 1420, 1380, 1350, 1270, 1240, 1140, 840, 770, 740 cm 1 (2) Methyl 2-(2-formamido-6-chloropyrimidin-4-yl) 2-hydroxyiminoacetate, mp. llO to 112C was obtained according to the similar manner to that of the Preparation ~-(4). ~ ~ ~ p _~ ~

~146553 I.R. v NuJol 3200, 1740, 1700, 1675, 1570, 1560, 1380, 1270, 124~, 1180, 1045, 860, 810, 750 cm 1 N.M.R. ~ ppm (DMSO-d6): 3.90 (3H, s), 7.57 ~lH, s) 9.23 (lH, d, J=9Hz), 11.40 ~lH, d, J=9Hz), 13.28 (lH, s) (3) Methyl 2-(2-formamido-6-chloropyrimidin-4-yl~-2-methoxyiminoacetate (powder), mp. 165 to 17205C was obtained according to the similar manner to that of the Preparation 8-(S).
I.R. v mU~ol: 3150, 1750, 1700, 1670, 1645, 1420, 13B0, 1270, 1250, 1040, 955, 795, 735 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.93 and 4.14 (6H, s), 7.59 (lH, s), 9.26 (lH, d, J=9Hz), 11.50 (lH, d, J=9Hz) (4) 2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxy-iminoacetic acid (powder) was obtained according to the similar manner to that of the Preparation 8-(6).
I.R. v mUaxol: 3350, 3200, 1695-1740, 1660, 1365, 1030 cm 1 N.M.R.~ ppm tDMSO-d6 + D2O): 3.80 ~3H, s), 6.16 (s) } (lH) 6.77 (5) ~5) 2-(2-Formamido-6-chloropyTimidin-4-yl)-2-methoxyiminoacetic acid (powder), mp. 138 to 142C (dec.) was obtained according to the similar manner to that of Preparation 4-(1).
I.R. v maxl: 3400, 3325, 3200, 1740, 1695, 1670, 3~ 1550, 1385, 1250, 1040, 820 cm 1 ~6~ P-2~

~6553 N.M.R. ~ ppm (DMS0-d6) ; 4.05 (3H, s) 6.87 (5)1 (lH) 6.g3 (s) 9.38 (lH, d, J=9H~) 11.11 (lH, d, J=9Hz) Prep_ration 11 (1) A 15% n-hexane solution (636 g.) of n-butyl-lithium was added to a solution of 2-amino-6-methylpyridin (64.8 g.) in tetrahydrofuran (500 ml.) at -20 to -30C
over one hour, and stirred at -8 to -10C for 30 minutes.
To the solution was added trimethylsilylchloride ~161.7 g.) at -15 to -5C over 40 minutes, and the resultant solution was stirr~d at room temperature o~eTnight. The solution was filtered through by a column packed with silica gel (180 g.), washed with tetrahydrofuran and then the filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation to give a 2-[N,N-bis(trimethylsilyl)amino]-6-methylpyridine (117.6 g.), b.p. 9S to 97C/5-6 mmHg.
N.M.R. ~ppm (CC~4): 0.13 ~18H, s), 2.35 (3H, s), 6.43 ~lH, d, J=8Hz), 6.60 ~lH, d, J=8Hz), 7.25 (lH, t, J-8Hz) (2) A 15% n-hexane solution ~338.6 g.) of n-butyllithium was dropwise added to a solution of 2-[N,N-bis(trimethylsilyl)amino]-6--methylpyridine (100 g.) in anhydrous tetrahydrofuran (300 ml.) at -20 to -30C over one hour and the solution was stirred at 20 to 23C for one hour. The resultant solution ~as added in small portions to crushed dry ice (1 kg.) under stirring, and - 30 stirred till a room temperature. After removing P - 3 ~) 114655~
tetrahydrofuran ~rom the solution under reduced pressure, absolute ethanol (1 Q.) was added to the residue.
30% Ethanol solution (660 ml.) of hydrochloric acid was dropwisc added to the solution at -5 to -10C, and further hydrogen chloride gas was bubbled at 0 to 5C for 30 minutes and then the solution was stirred at 10C overnigh~
After removing ethanol from the resultant solution, the residue was dissolved in water, and washed with ethyl acetate 3 times. The solution was adjusted to pH 7 to 8 with sodium bicarbonate and extracted with ethyl acetate.
The ethyl acetate extract was washed with a saturated aqueous solution of sudium chloride, dried and concentrated under reduced pressure to give the crude product ~54 g.~. The product was purified by column chromatography on silica gel (1 k~.) with an eluent (cthyl acetate + benzene) to give ethyl 2-(6-aminopyridin-2-yl)acetate (30.2 g.), mp. 66 to 68~C~
I.R. v maJl: 3430- 3340, 3200, 1730, 1645, 1480, 1190 cm N.M.R. ~ ppm (CDCQ3): 1.25 (3H, t, J=6Hz), 3.67 (2H, s), 4.20 (2H, q, J=6Hz), 5.33 (2H, broad s), 6.43 (lH, d, J=8Hz), 6.62 (lH, d, J=8Hz), 7.40 (lH, t, J=8Hz~
(3) Ethyl 2-(6-formamidopyridin-2-yl)acetate, mp. 35 to 38C was obtained according to the similar manner to that of the Preparation 4-(1).
1, I.R. v mUaJol: 3250, 3100, 1738, 1690, 1580, j 1460, ~305, 1277 cm 1 , 30 N.M.R. ~ ppm (DMSO-d6): 1.17 (3H, t, J=8Hz), ~8 P-31 ~L146SS~

3,7s (2H, s), 4.08 (2H, q, J=8Hz), 6.85 ~0.5H, broad d, J=8}1z), 7.95 tO.5H, broad s), 7.08 (lH, d, J=8Hz)~ 7.73 (lH, t, J=8Hz), 8.33 (0.5H, broad s)~ 9.25 ~0.5H, broad d), 10.58 (lH, broad s).
~4) To a solution of ethyl 2-(6-formamidopyridin-2-yl)aceta~e (26 g.) in dioxane (260 ml.) was added selenium dioxide ~16.65 g.) in small portions at 85 to 90C o~er one hour and stirTed at the same temperature for one hour. After cooling the resultant solution the dioxane layer was separated and concentrated under reduced pressure and then the residue was dissolved in ethyl acetate. The solution was washed with water, dried lS ~ver magnesium sulate and treated with activated charcoal and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give ethyl 2-~6-formamidopyridin-2-yl)glyoxy~ate (14.3 g.), mp. 124 to 126C.
I.R. ~ NUa~ol: 3220, 3100, 1737, 1720, 1690, 1273, 1233 cm 1 N.M.R. ~ ppm (DMSO-d6): 1.34 (3H, t, J=8Hz), 4.44 ~2H, q, J=8Hz), 7.33 (0.65H, broad s), 7.8-8.2 (0.35H), 7.84 (lH, d, J=8Hz), 8.09 ~lH, t, J=8Hz), 8.44 (0.35H, broad s), 9.22 ~0.65H, broad s), 10.85 (lH, broad s) (5) 2-(6-Formamidopyridin-2-yl)-2-methoxyimino-acetic acid (syn isomer), mp. 170 to 171C (dec.) was obtained according to the similar manner to that of the ~ P-3~
.J

- 11 46S5;~
Preparation ~-(4) via 2-(6-formamidopyridin-2-yl) glyoxylic acid.
I.R. v Naxl: 3230, 3132, 1745, 1680, 1575, 1450, 1320, 1208, 1032 cm 1 N.M.R. ~ p~pm (DMSO-d6): 3.70 (3H, s), 6.9U (0.6H, broad d), 7.9 (0.4H, broad s), 7.10 ~lH, d, J=8Hz), 7.7S (lH, t, J=8Hz), 8.38 (0.4H, broad s), 9.25 (0.6H, broad d), 10.58 (lH, broad d) - (6) A mixture of 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) t5.0 g.) and concentrated hydrochloric acid (2.34 g.) in methanol (50 ml.) was stirred for 40 minutes at ambient temperatuTe.
After the removal o methanol from the reaction mixture under reduced pressure, the residue was pulverized in diethyl ether, collected by filtration and then dried to give a pale brown powder of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (syn isomer~ (5.2 g.).
N.M.R. ~ ppm (DMSO-d6 + D20): 4.10 (3H, s), 6.84 tlH, d, J=7Hz), 7.23 (lH, d, J=lOHz), 7.99 (lH, dd, J=7Hz, lOHz) (7) To a mixture of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (syn isomer~, acetic acid (350 ml.) and water (10 ml.) was introduced chloride gas for 1.5 hours, After the removal of the excess of the chlorine gas by bubbling air into the reaction mixture, the solvent was distilled off. The residue was pulverized in diethyl ether and collected by filtration. After the addition of water and ethyl acetate to the resultant ~7~ P-33 s~
powder (9.8 g.), the aqueous layer was separated and washed with ethyl acetate. The ethyl acetate layer and washings WeTe combined together, and further extracted with water.
The aqueous laye~s were combined together and adjusted to pH 4 with lN aqueous solution of sodium hydroxide, and then the solvent was distilled off under reduced pressure.
The remaining water in the residue was azeotropically removed with benzene three times to yield brownish powder which was dried in a desiccator to give 2-(6-amino-3-chloropyridin-2-yl)-2-methoxyiminoacetic acid tsyn isomer) (3-27 g ?
N.M.R. ~ ppm (DMSO-d6 ~ D2O): 3.81 ~3H, s), 6.50 (lH, d, J=9Hz), 7.48 (lH, d, J=9Hz) Further the remaining ethyl acetate layer was dried over magnesium sulfate and the solvent was distilled off. The residue was washed with diethyl ether and then dried to give 2-(6-amino-3,5-dichloropyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (2.4 g.), mp. 139 to 144C.
N.M.R. ~ ppm (DMSO-d6): 3.96 (3H, s), 6.2-7 1 (2H, broad), 7.83 (lH, s) (8)-a) 2-(3-Chloro-6-formamidopyridin-2-yl)-2-metnoxyiminoacetic acid (syn isomer) (powder), mp. 151 to 154C was obtained according to the similar manner to that of the Preparation 4-(1).
I.R. v Nuxol 3200, 1740, 1680, 1580, 1290, 1250, 1140, 1050, 840 cm 1 (8~-b) 2-(3,5-Dichloro 6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (powder), ~7~ p ~

~14~5~3 -mp. 164 to 165C was obtained according to the similar manner to that of the Preparation 4-(1), I.R. ~ Nu~ol: 3250, 2300-2600, 1712, 1565, 1410, 1250, 1035 cm 1 N.M.R. ~ ppm (DMSO): 4.02 ~3H, s.), 8.29 (lH, s), 9,05 (lH, d, J=lOHz)~ 10.77 (lH, d, J=lOHz) , ' 30 ~7~ P-3~

~1~6S53 Preparation 12 To a solution of ethyl 3-e~oxyacrylimidate hydro-chloride (4.0g) and l-ethoxycarbonylformamidine hydro-bromide (4.4g) in methanol (1-lOmQ~ was added dropwise a solution of sodium metal (lg) in methanol (llOmQ~ at 0C. The reaction mixture was stirred for an hour at O to 5C and for additional 4 hours at ambient temper-ature. The solution was evaporated to dryness and theresidue was dissolved in a mixture of ethyl acetate and an aqueous solution of sodium chloride. The organic layer was separated out and the aqueous layer was ex-tracted with ethyl acetate five times. All organic layers were combined, dri~d over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethylether to give methyl 4-amino-pyrimidine-2-carboxylate (1.33g), which was recrystalliz-ed from ethyl acetate, mp. 140-142.5C.
I.R. vNmaxl : 3450, 3300, 3180, 1730, 1630, 1585, 15~0cm~l.
N.M.R.~ppm (DMSO-d6) : 3.81 (3H,S), 6.54 (lH,d,J=
6Hz), 7.23 (2H,S), 8.16 (lH,d,J=
6Hz).

Preparation 13 (1) To a solution of 2-chloroacrylonitrile (437mg) and l-ethoxycarbonylformamidine hydrobromide ~985mg) in ethanol (5m~) was added dropwise triethylamine (l.Olg) at 0C. The reaction mixture was stirred for 4 hours at ambient temperature and evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and water,and extracted with ethyl acetate three times. ~he combined extracts were dried over anhydrGus magnesium sulfate and !

~.

1 3L 7 3 p ~

11 ~6553 evaporated to dryness. The residue was triturat-ed with diethyl ether to give ethyl 4-aminopyrimidine-2-carboxylate (480mg), which was recrystallized from a mixture of ethyl acetate and benzene, mp.
101-104C.
I.R. vNmaxl : 3450, 3300, 3180, 1730, 1630, 1580, 154Ocm~~.
N.M.R.~ppm (DMSO-d6) : 1.30 (3H,t,J=7Hz), ; 4.30 (2H,q,J=7Hz), 6.60 (lH,d, J=6Hz), 7.31 (2H, S), 8.20 (lH, d, J=6Hz).

The following compound was obtained according to the similar manner to that of Preparationl3-(1) by us-ing triethylamine or sodium carbonate as a base.
(2~ Methyl 4-aminopyrimidine-2-carboxylate.
I.R. vNmaxl : 3450, 3300, 3180, 1730, 1630, 1585, 1540cm~'.

20 Preparation 1A
(1) A mixture of formic acid ~lOOg) and acetic anhydride (204g) was stirred for half an hour at ambient temperature. To the solution was added ethyl 4-aminopyrimidine-2-carboxylate ~30g) and the mixture was stirred for 1.5 hours at 70 to 75C and then evaporated to dryness. The residue was triturated with ethanol, collected by filtration and washed with ethanol to give ethyl 4-formamido-pyrimidine-2-carboxylate (20.0g), mp 205-206C.
I.R. vNm~Xl : 3100, 1720, 1630, 1570, 1520cm 1.
N.~$.R. ~ppm (DMSO-d~) : 1.37 (3H,t,J=7~z), 4.40 (2H,q,J=7Hz), 7.73 (lH, broad s), 8.83 (lH, d,J=4Hz), 9.00 (lH,broad s), 11.40 (lH, 3~ broad s) ~ 7 ~ ?~

~i465S3 The following compound was obtained according to the similar manner to that of Preparation 14-(1).
~2) Methyl 4-formamidopyrimidine-2-carboxylate, mp 234~236C.
I.R. vNmaxl : 3100, 1735, 1710, 1640, 1570, 1530, 1510cm~l.
N.M.R. ~ppm (DMSO-d6) : 3.93 t3H,s), 7.73 (lH, broad s), 8.82 (lH,d,J=5Hz), 9 00 (lH, broad s), 11.40 (lH, broad s) Prep~ration 15 (1) To a solution of methyl 4-formamidopyrimidine-2-carboxylate (1.3g) and methyl methylthiomethyl sulfoxide (0.89g) in N,N-dimethylformamide (lOmQ) was added 50~ sodium hydride (l.Og) at 10C under stirring and the stirring was continued for 1.5 hours at ambient temperature. The mixture was cooled in an ice bath and thereto ~as added methy-lene chloride (30 mQ).
The precipitate which w;ls collected by filtration was added portionwise to a mixture of methylene chloride (50m~), ice water and concentrated hydro-chloric acid (2.lmQ) under stirring. The methylene chloride layer was separated out and the aqueous layer was extracted with methylene chloride.
The combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness.
The residue was triturated with diethyl ether, filtered and washed with ~iethyl ether to give 4-formamido-2-(2-methanesulfinyl-2-methylthioacetyl) pyrimidine (1.2g).
I.R. vNmaxl : 1690, 1560, 1450, 1370cm-~.
N M.R. ~ppm (DMSO-d6) : ~ 230 (s)}(3H)' ~7 '~

~146553 2 93 ~s)}(3H)r ~ 07 (s)}(lH)~
7.67 (lH, broad s), 8.92 ~lH,d,J=5Hz), 9.17 (lH, broad s), 11.40 (lH, broad 5) The same compound as the object compound of ~re-parationl~ll) was obtained from the following compound according to the similar manner thereto.
(2) Ethyl 4-formamidopyrimidine-2-carboxylate.

Preparation 16 A mixture of formic acid (4.82g) and acetic anhyd-ride (9.7g) was stirred for half an hour at ambient temperature.
To the solution was added 4-formamido-2-~2-methanesul-finyl-2-methylthioacety~pyrimidine (2.6g) and the mix-ture was stirred for 1.5 hours at 50C and then for an hour with an addition of sodium periodate (610mg) at the same temperature. The mixture was evaporated to dry-ness ~nd the residue was dissolved in a mixture of ethyl acetate (50m~) and an aqueous solution (20mQ) of sodium chloride. The organic layer was separated out and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness. The residue (2.0g) was subjected to column chromatography over silica gel (13g) using a mixture of ethyl acetate and benzene (1:1 by volume) as an eluent.
The fractions containing a desired compound were collect-ed, evaporated to dryness and crystallized from a small , 30 amount of ethyl acetate to give pure product of S-methyl ¦ 4-formamidopyrimidine-2-thioglyoxylate (840mg), mp 112-s 114C-' I.R. v max ; 3480, 3380, 1715, 1680, 1585cm-~.
¦ N.M.R. ~ppm (DMSO-d6) : 2.17 ~3H,s), 7.20 (lH, ~ 35 broad s), 8.12 (lH,d,J=6Hz), 9.17 (lH, broad s), ., .
'I ~ 7 ~t~ p~
._.

~1 ~6553 11.08 (lH,d,J=7Hz~.

Preparation 17 ~1) To a suspension of S-methyl 4-formamidopyri-midine-2-thioglyoxylate (3.0g) in water (26mQ) was added dropwise lN aqueous solution (12m~) of sodium hydroxide at ambient temperature and the mixture was stirred for half an hour at the same temperature.
To the solution was added an aqueous solution of ethoxyamine prepared by ethoxyamine hydrochloride (1.3g), water ~lOmQ) and sodium bicarbonate (1.12g)~
The reaction mixture was stirred for half an hour at ambient temperature and adjusted to pH 4 with lN hydrochloric acid (l.SmQ). The solution was - stirred for 10 minutes at ambient temperature and ad~usted to pH 3 with lN hy~rochloric acid and then washed with ethyl acetate. The aqueous layer was salted out, adjusted to pH 1 with 10% hydro-chloric acid and extracted with ethyl acetate.
The extract was dried over magnesium sulfate and evaporated to dryness. The crystallized residue was washed with n-hexane to give Z-ethoxyimino-2-(4-formamidopyrimidin-2-yl)acetic acid (syn isomer) t2-22g), mp. 13o-l35oc(dec.).
I.R. vNm~Xl . 3250, 1720, 1630, 1605, 1570cm~l.
N.M.R. ~ppm (DMSO-d6) : 1.28 (3H,t,J=7Hz), 4.32 (2H,q,J=7Hz), 7.4-7.7 (lH, m), 8.72 (lH,d,J=6Hz), 8.8-9.1 (lH,m), 11.37 (lH,d,J=6Hz).
The following compounds were obtained according to the similar manner to that of Preparation 17-(1).
(2) 2-(4-Formamidopyrimidin-2-yl)-2-methoxyimino-acetic acid (syn isomer), mp. 165-166C (dec.).
I.R. vNUiol . 3400, 3250, 3150, 1740, 1700, max ls70cm~~-~77 p-4i?

~L146SS3 N.M.R. ~ppm (DMSO~d6) : 4.00 ~3H,s), 7.53 ~lH, broad s), 8.72 (lH,d~
J~6~z), 8.87 (lH,broad s), 11.23 (lH,d,J=6Hz).
(3~ 2-(4-Formamidopyrimidin-2-yl)-2-propoxyimino-- acetic acid ~syn isomer), mp 145-148C (dec.).
I.R. vNmaxl : 3150, 3100, 3050, 1750, 1690, 1615, 1570, 1540cm~1.
(4) 2-Allyloxyimino-2-(4-formamidopyrimidin-2-yl) acetic acid (syn isomer~, mp 120-122C (dec.).
I.R. vNm~xl : 3250, 3100, 1710, 1630, 1570, 1515cm~1.
~5) 2-Benzyloxyimino-2-(4-formamidopyrimidin-2-yl)acetic acid ~syn isomer), mp 75-77C.
I.R. vNUaxl : 3250, 3050, 1720, 1630, 1570 cm~l.

Preparation 18 A mixture of ethyl 2-(6-chloro-4-~formamidopyrimidin-2-yl)acetate (24.3g) and selenium dioxide (16.65g) in N,N-dimethylformamide (243mQ) was stirred for an hour at 70 to 75C. The precipitated solid was filtered off, and the filtrate was concentrated in vacuo.
The residue was dissolved in ethyl acetate (500mQ), washed with water and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diiscpropyl ether to give a powder of ethyl 6-chloro-4-formamidopyrimidin-2-ylglyoxylate (17.74g).
This product (lg) was recrystallized from ethyl acetate (lOmQ) to afford the purified product (570mg), mp 114-117C.
I.R. vNujol : 3400, 3230-3100, 1760, 1720-1680, max 1580-1550, 1250, 1200, 850, 730cm~~.

~ 7~ p~i ~146553 .
Preparation 19 To a mixture of ethyl 6-chloro-4-formamidopyrimidin-2-ylglyoxylate (10.6g) and methoxyamine hydrochloride (3.34g) in ethanol (200mQ) was added an aqueous solution (60mQ) of sodium bicarbonate ~3.36g) and the mixture was stirred for 2 hours at ambient temperature.
After evaporation of the solvent, the residue was dis-solved in ethyl acetate. The solution was washed with - water, dried over anhydrous magnesium sulfate and evaporated to give oily product (10.8g).
This product was subjected to column chromatography over silica gel (118g) using benzene as an eluent.
The fractions contained a desired compound were collect-ed, and evaporated, and the resultant oily product (5.6g) was crystallized from diethyl ether to give ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)-2-methoxy~-minoacetic acid (syn isomer), mp. 116-ll9~C.
I.R. v~maxl : 3400, 1750, 1725, 1665, 1495, 1270, ~ 1030cm~~.
N.M.R. ~ppm (CDCQ3) : 1.35 (3H,t,J=7Hz), 4.09 (3H, s), 4.40 (2H,q,J=7Hz), 6.5-8.3(1H, broad), 8.3-9.0 (lH,broad), 9.2 (lH, broad s).

; 25 Preparation 30 A mixture of ethyl 2-(4-formamidopyrimidine-2-yl) acetate (50.0g) and selenium dioxide ~31.87g) in N,N-dimethylformamide (240mQ) was stirred for an hour at 70 to 75C and cooled to ambient temperature.
The precipitated solid was fil~ered off and the filt-rate was evaporated in vacuo to give an oily product.
The oil was added to water (750mQ) under stirring, ad-justing to pH7 with an aqueous solution of sodium bicarbonate. The precipitated yellow substance was filtered off and washed with water. ~he filtrate and , ~ 7 9 p ~d ~

~1465~3 washings were combined and thereto was added methoxya-mine hydrochloride (19.95g). The mixture was adjust-ed to pH4 with an aqueous solution of sodium bicarbo-nate and stirred for 3 hours at ambient temperature.
- 5 The a~ueous reaction mixture was extracted with ethyl acetate and the extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to give ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer~ (31g) as a brownish oil.
N.M.R. ~ppm (CDCQ3) : 1.36 (3H,t,J=7Hz), 4.12 (3~,s), 4.42 (2H,q,J=7Hz), 6.5-8.2 (lH, broad), 8.66 (lH,d,J=6Hz), 8.8 -10.0 (2H, broad) Preparation 21 (1) To a solution of ethyl 2-~4-formamidopyrimi-din-2-yl~-2-methoxyiminoacetic acid (syn isomer) (30.8g) in ethanol (308mQ) was added lN alcoholic solution (550mQ) of potassium hydroxide and the mixture was stirred for 3.5 hours at ambient temperature. The reaction mixture was cooled in an ice bath and adjusted to pH 3 with concentrat-ed hydrochloric acid (53mQ~. The resultant solid was filtered and washed with ethanol (60m~, water ~lOOmQ), acetone (lOOmQ) to give a crude product (28.8g). This product (lg) was recrystallized from water (lOmQ) to give a purified product of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (dihydrate,syn isomer) (0.4g), mp. 178-183C (dec.).
The following compound was obtained according to the similar manner to that of Preparation 21-(1).
(2) 2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyi-minoacetic acid (syn isomer).

~ p~

~4f~5S3 I.R. vNm~Xl: 3480, 3380, 3200, 1640, 1610-1580, 1530, 1040, 720cm~l.
N.M.R. ~ppm (D20) : 4.10 (3H,s), 6.76 (lH,s).

Preparation 22 To a solution of ethyl 2-(4-chloro-6-formamido-pyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (17g) in ethanol (255mQ) was added dropwise phosphoryl chloride ~14.7g) under cooling in an ice bath.
The mixture was stirred for 1.5 hours at ambient temper-ature and evaporated to dryness.
The residue was dissolved in a mixture of ethyl aceta~e and water and adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The organic layer was separated out, dried over anhydrous magnesium sulfate and eva-porated to dryness. The residue was triturated with n-hexane to give ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (9.99g), mp 136-142C.
I.R. vmBx : 3500~ 3330, 3200, 1735, 1640, 1575, 1535, 1040cm~~.
N.M.R. ~ppm (DMSO-d6) : 1.30 (3H,t,J=7Hz), 4.03 (3H,s), 4.30 (2H,q,J=7Hz), 6.53 (lH,s), 7.5 (2H, broad s) 1~1 p_~

S~

Preparation 23 (1) To a solution of ethyl 2-(4-amino-6-chloropyrimidin-2-yl)acetate (21.5 g) in methanol (200 ml) was added a solution of sodium metal (7.25 g) in methanol (130 ml) and the mixture was refluxed for 3.5 hours.
The reaction mixture was cooled in an ice-salt bath and saturated with dry hydrogen chloride and then allowed to stand overnight at ambient temperature.
The mixture was evaporated to dryness and the residue was dissolved in a mi~ture of ethyl acetate and a cold aqueous solution of sodium bicarbonate.
The organic layer was separated out, washed with water, dried over anhydrous magnesium sulfate ~d and evaporated to give methyl 2-(4-amino-6-methoxy-pyrimidin-2-yl)acetate (14.2 g), mp 91-94~.

I.R.~maXl : 3480, 3390, 3210, 1738, 1660, .l 1600cm 1 N.M.R. ~ppm (DMSO-d6): 3.66 (5H, s) , 3.82(3H, s), 5.68 (lH, s), 6.66 (2H, broad s).

(2) To a solution of thiophenol (2.55 g) in N,N-dimethyl-formamide (20 ml) was added 50 % sodium hydride (1.1 g) under cooling in an ice bath and the mixture was stirred for 20 minutes at 0C to 5C. To the mixture was added ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (2.0 g) and the mixture was stirred for 6 hours at ambient temperature.
The resultant mixture was poured into cold water, adjusted to pH 7 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was subjected to column chromatography on silica gel (50 g) using a mixture of chloroform and ethyl acetate (3:1 by valume) as an eluent. The fractions containing the object product were collected and evaporated to give ethyl 2-(4-amino-6-phenylthio-pyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (460 mg~, mp 154-156C

I.R.~mUx 1 : 3450, 3280, 3160, 1720, 1620, 1550, 1520, 1300, 1040, 1025, 700cm 1 N.M.R. ~ppm (CDC13): 1.34 (3H, t, J=7Hz), 4.05 (3H, s), 4.27 (2H, q, J=7Hz) 5.2 (2H, broad s), 5.84 (lH, s), 7.2-7.7 (5H, m).

Preparation 24 2~
Methyl 2-(4-formamido-6-methoxypyridin-2-yl)acetate (13.9 g) was obtained by reacting methyl 2-(4-amino-6-methoxypyrimidin-2-yl)acetate (14 g) with formic acid (14.7 g) and acetic anhydride (30.4 g) accarding to the similar manner to that of Preparation 14-(1), mp 61-63C.

N.M.R. ~ppm (DMSO-d6): 3.73 (3H, s), 3.87 (2H, ¦ s), 3.96 (3H, s), 6.1-7.8 (lH, ¦ broad), 8.1-9.8 (lH, broad), ¦ 30 10.87 (lH, d, J=6Hz).

I Preparation 25 ¦ Methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)-2-', 35 methoxyiminoacetate (syn isomer) (12.47 g) was obtained 183 P-~o by reacting methyl 2-(4-formamido-6-methoxypyrimidi~
2-yl)acetate (12.24 g) with selenium dioxide (6.94 g) and then methoxyamine hydrochloride (4.51 g) according to the semilar manner to that of Prepara-tion 20, I.R.~ maxm : 3300, 1750, 1720, 1660, 1590, 1565, 1210, 1035cm Preparation 26 (1~ 2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyimino-acetic acid (syn isomer) (8.22 g) was obtained by reacting methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (12.0 g) with lN ethanolic solution (187 ml) of potassium hydroxide according to the similar manner to that of Preparation 21, mp 127-129C (dec.).

I.R- ~ mUax : 3420, 3380, 1650, 1615, 1590, 1250, 1050, 1025cm N.M.R. ~ppm (DMSO-d6 + D20): 3.78 (3H,s ), 3.95 (3H,s ), 5.78 (lH,s ) (2) 2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxy-iminoacetic acid (syn isomer) (130 mg) was obtained t by reacting ethyl 2-(4-amino-6-phenylthiopyrimidin-2-yl)-2-methoxyimino-acetate (syn isomer) (247 mg) with lN aqueous solution (1.8 ml) of sodium hydroxide according to the similar manner to that of Preparation 21, mp 136-138C (dec.).

i I.R. ~mUaxol : 3300, 1650, 1600, 1560, 1150, 1 35 1040, 750cm 1, SUPPLEMENTARY DISCLOSURE
This disclosure and the Principal Disclosure are concerned with novel cephalosporanic acid derivatives, pharmaceutically acceptable salts thereof, and their preparation, The derivativeq are represented by the formula (I), as defined in the Principal Disclosure~
The following examples present further illustration:

1~
S.D. 1 ~L~ 4655;~

Example S.D. 1 (1) Methylene chloride (15 ml) was added to a Vilsmeier reagent, which was prepared by phosphoryl chloride ~0.75 g) and N,N-dimethylformamide (0.75 ml) in a conventional manner.
To this mixture was added 2-(4-formamiaopyrimidin-2-yl)-2-phenoxyiminoacetic acid (syn isomer) (1.0 g) at -20C, followed by stirring at -15 to -13C for half an hour. To this solution was added a solution of 7-amino-3-(1,3,4-thiadiazol-2-ylthio-methyl)-3-cephem-4-carboxylic acid (1.27 g) and trimethyls1lyl-acetamide (4.6 g) in methylene chloride ~14 ml) at -20C with stirring, and the stirring was continued at -15 to -13C or half an hour and at ambient temperature for additional half an hour. The reaction mixture was evaporated to give a residue, to which et~yl acetate and then an aqueous solution of sodium bicar~onate were added. To the separated aqueous solution was added ethyl acetate and then adjusted to pN 1 to 2 with hydro-chloric acid.

After addition of a small amount of acetone, the organic layer was separated, washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate, and then evaporated.
The residue was pulverized with diethyl ether to give 7-[2-(4-fonnar!lidopyrimidin-2-yl)-2-phenoxyiminoacetamldo]-3-(1,3,4-thiadiazol-2-ylthiomethyl3-3-cephem-4-carboxylic acid (syn isomer) (1.45 g).

I.R. v maU~ : 1780, 1710, 1660, 1570, 1210, 1060, 1000, 760 cm S.D. 2 ., .

~46S53 ;
N.M.R. ~ppm (DMSO-d6): 3.73 (2H, m), 4.27, 4.67 (2H, ABq, J=12Hz), 5.27 (lH, d, J=5Hz), 5.97 (lH, dd, J=5Hz, 8Hz), 6.9-7.6 (5H, m), 7.7-8.2 (lH, m), 8.77 (lH, d, J--6Hz), 9.10 (lH, m), 9.54 (lH, s), 9.83 (lH, d, J=8EIz), 11.10 (lH, d, J=7Hz) .
(2) 7-[2-(4-Formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido~-10 3-tl- (2-tert~butoxycarbonylaminoethyl)-lH-tetrazol-5-ylthio-methyl]-3-cephem-4-carboxylic acid (syn isomer) (1.8 g) was obtained by reacting 7-amino-3-[1-(2-tert-butoxycarbonylamino-ethyl)-lH~tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (2.12 g) with an activated acid prepared from 2-(4-formamido-15 pyrimidin-2-yl)-2-phenoxyiminoacetic acid (syn isomer) (1.1 g~, phosphoryl chloride (0.83 g) and N,N-dimethylformamide (0.8 ml), in substantially the same manner as that of Example 1-(1).

I.R. v maUxol : 3300-3100, 1770, 1715-1660, 1570, 1250, 1210, 1160, 990, 850, 760 cm 1 N.M.R. ~ppm (DMSO-d6): 1.25 (9H, s), 3.23 (2H, m), 3.70 (2H, m), 4.27 (4H, m), 5.17 (lH, d, J=5Hz), 5.90 (lH, m), 6.8~7.6 (5H, ; 25 m), 7.90 (lH, m), 8.73 (lH, d, J=
6Hz~, 9.83 (lH, d, J=8Hz), 11.20 (lH, d, J=7Hz) S.D 3 Example S.D 2 (1) A solution of 7-[2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.40 g) and coc.
hydrochloric acid (0.23 ml) in methanol (20 ml) was stirred at ambient temperature for 1.5 hours.
The reaction mixture was poured into diethyl ether ~150 ml) with stirring, followed by the precipitates were collected by filtration, washed with diethyl ether and dried to give a pale yellow powder (1.2 g). To this powder was added water (6 ml) and the suspension was stirred for 20 minutes. The remaining powder was collected by filtration, washed with water and then dried in vaccuo to give a pale yellow powder (0.96 g) of hydrochloric acid salt of 7-[2-(4-aminopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-(1,3,4-thiadiazol-2~ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 155-161C (dec.~.

I.R. ~ mUxol : 3300, 3160, 1770, 1650, 1580, 1200, 1060, 1000, 980, 760 cm ¦ N.M.R. ~ppm (D~SO-d6 + D2O): 3.76 (2H, m), 4.11, 4.64 (2H, f ABq, J=13Hz), 5.28 (lH, d, I J=5Hz), 5.95 (lH, d, J=5Hz), ~ 25 6.73 (lH, d, J=6Hz), 7.0-7.6 ¦ (5H, m), 8.30 (lH, d, J=6Hz), :! 9.63 (lH, s) S.D 4 , 30 ' ' ' ' ' : :

~L1465~3 :;
(2) A solution of formic acid salt of 7-[2-(4-formamido-pyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-[1-(2-aminoethyl)-lH-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer) (1.5 g) and conc. hydrochloric acid (0.45 ml) in methanol (20 ml) was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated till the precipitates appeared therein, and to the concentrate was added water (double volume of said concentrate).
The aqueous solution was chromatographed on non-ionic adsorption resin "Diaion HP-20" (Trade Mark: maker Mitsubishi Chemical Industries Ltd.) (60 ml) with 20 ~ aqueous methanol (500 ml), 30 % aqueous methanol (300 ml) and then 60 % aqueous methanol (500 ml) as an eluent, and the fractior.s-containing a desired compound were collected. These fractions were concentrated to a ~olume of ~50 ml and the concentrate was lyophilized to give a pale yellow powaer (0.55 g) of 7-12-(4-aminopyrimidin-2-yl)-2-phenoxy-iminoacetamido]-3-11-(2-aminoethyl)-lH-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer), mp 217-227 C (dec.).

I.R. v NaU~ol : 3300, 3160, 1760, 1660, 1620, 1580, 1200, 980, 950, 760 cm 1 N.M.R. ~ppm (DMSO-d6 + D20): 3.1-3.8 (4H, m), 4.27 (2H, m), 4.69 (2H, m), 5.17 (lH, d, J=5Hz), 5.87 (lH, d, J=5Hz), 6.60 (lH, d, J=6Hz), 7.0-7.7 (5H, m), 8.27 (lH, d, J=6Hz) S.D. 5 ~9 Example S.D,3 To 7-[2-(4-formamidopyrimidin-2-yl)-2-phenoxyimino-acetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-lH-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer) (1.7 g) was added formic acid (17 ml) and the solution was stirred at ambient temperature for 4 hours. After the reaction mixture was evaporated, the residue was pulverized with ethyl acetate to give a brown powder (1.5 g) of formic acid salt of 7-12-(4-formamid~pyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-tl-(2-aminoethyl)-lH-tetrazol-s-ylthiomethyl~-3-cephem-4 carboxylic acid (syn isomer).

I.R. v maUxol : 3200, 1770, 1710,-1660, 1570, 1210, 990 760 cm 1 . . .

., .
' 20 S.D.6 -~146SS3 . ...
Preparation S.D.l To a suspension of S-methyl (4-formamidopyrimidin-2-yl)-thioglyoxylate (6.7 g) in water (60 ml) was added dropwise lN aqueous solution of sodium hydroxide (26.8 ml) over a period of 15 minutes with stirring, and the stirring was continued at ambient temperature for 20 minutes.
On the other hand, an ethanolic solution (50 ml) of N-phenoxyphthalimide (9.26 g) and hydrazine monohydrate (1.84 g) was refluxed under heating for 5 minutes and the precipitates were removed by filtration. The resultant solution was added to the aqueous solution obtained above, followed by stirring for 5 minutes. After adjusting to pH 3 to 4 with 6N hydrochloric acid, the stirring was continued at ambient temperature for additional 3 hours. The ethanol was removed by evaporation from the reaction mixture, and the remaining aqueous solution was adjusted to pH 7 to 8 with 5 % aqueous solution of sodium bicarbonate and then washed with ethyl acetate. To the aqueous solution was added ethyl acetate and then adjusted to pH 1 to 2 with hydrochloric acid. The separated ethyl acetate layer was washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was pulverized with diisopropyl ether to give a brownish powder (2.2 g) of 2-(4-formamido-pyrimidin-2-yl)-2-phenoxyiminoacetic acid (syn isomer), mp 131-133 ~C (dec.).

I.R. v maU~ 1 : 3150, 1740, 1680, 1660, 1575, 1540, 1440, 1310, 1205, 980, 760 cm l s.D- 7 .:

~L~46S5~

N.M.R. ~ppm (DMSO-d6): 7.1-7.9 ~5H, m), 8.15 (lH, m), 8.97 (lH, d, J=6Hz~, 9.23 (lH, m), 11.57 (lH, d, J-6Hz) S.D. 8

Claims (190)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for preparing a compound of the formula :
(V) wherein R? is hydrogen, amino or a protected amino group, R? and R? are each hydrogen, halogen, lower alkoxy or arylthio, R14 is carboxy or a protected carboxy group, X is lower alkylene or a group of the formula :
in which R5 is hydrogen or an organic residue which may have suitable substituent(s), and Z is N or CH, or a salt thereof which comprises :
(1) reacting a compound of the formula :
(Va) wherein R?, R? R?, R14 and Z are each as defined above, or a salt thereof, with a compound of the formula :
R6 - ONH2 (VI) wherein R6 is as defined above, or a salt thereof, to give a compound of the formula :
(Vb) wherein R?, R?, R?, R6, R14 and Z are each as defined above; or (2) reacting a compound of the formula :
(Vc) wherein R?, R?, R?, R14 and Z are each as defined above, or a salt thereof, with a nitrosating agent to give a compound of the formula :
(Vd) wherein R?, R?, R?, R14 and Z are each as defined above; or (3) reacting a compound of the formula :
(Vd) wherein R?, R?, R?, R14 and Z are each as defined above, or a salt thereof, with a substituting agent capable for substituting a hydrogen atom of the hydroxy by R6 group, in which R6 is an organic residue which may have suitable substituent(s) to give a compound of the formula :
(Ve) wherein R?, R?, R?, R6 , R14 and Z are each as defined above, or a salt thereof; or (4) reacting a compound of the formula :
(Vf) wherein R?, R6 and R14 are each as defined above, or a salt thereof, with halogenating agent to give a compound of the formula :
(Vg) wherein R8 is halogen, R15 is hydrogen or halogen, and R?, R6 and R14 are each as defined above, or a salt thereof; or (5) subjecting a compound of the formula :
(Vh) wherein R?' is a protected amino group, and R?, R?, R14, X and Z are each as defined above, or a salt thereof, to elimination of the amino-protective group to give a compound of the formula :
(Vi) wherein R?, R?, R14, X and Z are each as defined above, or a salt thereof; or (6) reacting a compound of the formula ;
(Vi) wherein R?, R?, R14, X and Z are each as defined above, or a salt thereof with an amino protective agent to give a compound of the formula :
(Vh) wherein R? , R?, R?, R14, X and Z are each as defined above, or a salt thereof.

2. A process for preparing syn isomer of a compound of the formula :
(Vj) wherein R? is hydrogen, amino or a protected amino group, R? and R? are each hydrogen, halogen, lower alkoxy or arylthio, R6 is hydrogen or an organic residue which may have suitable substituent(s), R14 is carboxy or a protected carboxy group, and Z is N or CH, or a salt thereof which comprises :
reacting a compound of the formula :
(Va) wherein R?, R?, R?, R14 and Z are each as defined above, or a salt thereof, with a compound of the formula :
R6 - ONH2 (VI) wherein R6 is as defined above, or a salt thereof.

3. A process according to claim 2, wherein R? is amino or acylamino, R? and R? are each hydrogen, halogen or lower alkoxy, R6 is hydrogen lower alkyl, trihalo(lower)-alkyl, lower alkenyl, lower alkynyl, phenyl or phenyl(lower)alkyl, R14 is carboxy or an esterified carboxy group, and Z is N or CH.

4 A process according to claim 3, wherein R? is amino or lower alkanoylamino, and R14 is carboxy or lower alkoxycarbonyl.

5. A process according to claim 4, wherein a group of the formula :
is a group of the formula :
, in which R? is lower alkanoylamino, R6 is hydrogen, lower alkyl, trihalo(lower)-alkyl, lower alkenyl, lower alkynyl or phenyl-, and R14 is carboxy.

6. A process according to claim 5, wherein R? is formamido, and R6 is hydrogen.

7. A process according to claim 5, wherein R6 is lower alkyl.

8. A process according to claim 7, wherein R? is formamido, and R6 is methyl,

9. A process according to claim 7, wherein R? is formamido, and R6 is ethyl.

10. A process according to claim 7, wherein R? is formamido, and R6 is isopropyl.

11. A process according to claim 7, wherein R? is formamido, and R6 is propyl.

12. A process according to claim 7, wherein R? is formamido, and R6 is butyl.

13. A process according to claim 7, wherein R? is formamido, and R6 is isobutyl.

14. A process according to claim 5, wherein R6 is trihalo(lower)alkyl.

15. A process according to claim 14, wherein R? is formamido, and R6 is 2,2,2-trifluoroethyl.

16. A process according to claim 5, wherein R6 is lower alkenyl.

17. A process according to claim 16, wherein R? is formamido, and R is allyl.

18. A process according to claim 5, wherein R6 is lower alkynyl.

19. A process according to claim 18, wherein R? is formamido, and R6 is propargyl.

20. A process according to claim 5, wherein R? is formamido, and R is phenyl.

21. A process according to claim 4, wherein a group of the formula :
is a group of the formula :
, in which R? is lower alkanoylamino, R6 is lower alkyl, and R14 is carboxy.

22. A process according to claim 21, wherein R? is formamido, and R6 is methyl.

23. A process according to claim 4, wherein a group of the formula : is a group of the formula :
, in which R? is lower alkanoylamino, R6 is lower alkyl, and R14 is carboxy.

24. A process according to claim 23, wherein R? is formamido, and R is methyl.

25. A process according to claim 4, wherein a group of the formula : is a group of the formula :
, in which R? is lower alkanoylamino, R6 is lower alkyl, and R14 is carboxy.

26. A process according to claim 25, wherein R? is formamido, and R6 is methyl.

27. A process according to claim 4, wherein a group of the formula : is a group of the formula :

, in which R? is amino or lower alkanoylamino, R? is hydrogen, halogen or lower alkoxy, and R6 is lower alkyl, lower alkenyl,phenyl,or phenyl(lower)alkyl.

28. A process according to claim 27, wherein R? is hydrogen, R6 is lower alkyl, and R14 is carboxy.

29. A process according to claim 28, wherein R? is amino, and R6 is methyl.

30, A process according to claim 28, wherein R? is formamido, and R6 is methyl.

31. A process according to claim 28, wherein R? is formamido, and R6 is ethyl.

32. A process according to claim 28, wherein R? is formamido, and R6 is propyl.

33. A process according to claim 27, wherein R? is lower alkanoylamino, R? is hydrogen, R6 is lower alkenyl, and R14 is carboxy.

34. A process according to claim 33, wherein R? is formamido, and R6 is allyl.

35. A process according to claim 27, wherein R? is lower alkanoylamino, R? is hydrogen, R6 is phenyl(lower)alkyl, and R14 is carboxy.

36. A process according to claim 35, wherein R? is formamido, and R6 is benzyl.

37. A process according to claim 27, wherein R? is lower alkanoylamino, R? is hydrogen, R6 is lower alkyl, and R14 is lower alkoxycarbonyl.

38. A process according to claim 37, wherein R? is formamido, R6 is methyl, and R14 is ethoxycarbonyl.

39. A process according to claim 27, wherein R? is lower alkanoylamino, R? is halogen, R6 is lower alkyl, and R14 is lower alkoxycarbonyl.

40. A process according to claim 39, wherein R? is formamido, R? is chloro, R6 is methyl, and R14 is ethoxycarbonyl.

41. A process according to claim 27, wherein R? is lower alkanoylamino, R? is lower alkoxy, R6 is lower alkyl, and R14 is lower alkoxycarbonyl.

42. A process according to claim 41, wherein R? is formamido, R? is methoxy, R6 is methyl, and R14 is methoxycarbonyl.

43. A process according to claim 4, wherein a group of the formula :
is a group of the formula :
, in which R? is lower alkanoylamino, R6 is lower alkyl, and R14 is carboxy.

44. A process according to claim 43, wherein R? is formamido, and R6 is methyl.

45. A process for preparing syn isomer of a compound of the formula :
(Vk) wherein R? is hydrogen, amino or a protected amino group, R? and R? are each hydrogen, halogen, lower alkoxy or arylthio, R14 is carboxy or a protected carboxy group, and Z is N or CH, or a salt thereof which comprises :
reacting a compound of the formula :
(Vc) wherein R?, R?, R?, R14 and Z are each as defined above, or a salt thereof, with a nitrosating agent.

46. A process according to claim 45, wherein R? is acylamino, R? and R? are each hydrogen or halogen, and R14 is an esterified carboxy group.

47. A process according to claim 46, wherein R? is lower alkanoylamino, and R14 is lower alkoxycarbonyl.

48. A process according to claim 47, wherein a group of the formula :
is a group of the formula :
, in which R? is lower alkanoylamino.

49. A process according to claim 48, wherein R? is formamido, and R14 is ethoxycarbonyl.

50. A process according to claim 47, wherein a group of the formula :
is a group of the formula :
, in which R? is lower alkanoylamino and R? is halogen.

51. A process according to claim 50, wherein R? is formamido, R? is chloro, and R14 is methoxycarbonyl.

52. A process for preparing syn isomer of a compound of the formula :
(V?) wherein R? is hydrogen, amino or a protected amino group, R? and R? are each hydrogen, halogen, lower alkoxy or arylthio, R14 is carboxy or a protected carboxy group, R6' is an organic residue which may have suitable substituent(s), and Z is N or CH, or a salt thereof which comprises :
reacting syn isomer of a compound of the formula :
(Vk) wherein R?, R?, R?, R14 and Z are each as defined above, or a salt thereof, with a substituting agent capable for substituting a hydrogen atom of the hydroxy by R6' group, in which R6' is as defined above.

53. A process according to claim 52, wherein R? is acylamino, R? and R? are each hydrogen or halogen, R14 is carboxy or an esterified carboxy group, and R6' is lower alkyl or halo(lower)alkanoyl.

54. A process according to claim 53, wherein R? is lower alkanoylamino, and R14 is carboxy or lower alkoxycarbonyl.

55. A process according to claim 54, wherein a group of the formula :
is a group of the formula :
, in which R? is lower alkanoylamino, R14 is carboxy, and R6' is halo(lower)alkanoyl.

56. A process according to claim 55, wherein R? is formamido, and R6' is dichloroacetyl.

57. A process according to claim 54, wherein a group of the formula :
is a group of the formula .
, in which R? is lower alkanoylamino, R14 is lower alkoxycarbonyl, and R6' is lower alkyl.

58. A process according to claim 57, wherein R? is formamido, R14 is ethoxycarbonyl, and R6' is methyl.

59. A process according to claim 54, wherein a group of the formula :
is a group of the formula :
, in which R? is lower alkanoylamino and R? is halogen, R14 is lower alkoxycarbonyl, and R6 is lower alkyl.

60. A process according to claim 59, wherein R? is formamido, R? is chloro, R14 is methoxycarbonyl, and R6 is methyl.

61. A process for preparing syn isomer of a compound of the formula :
(Vm) wherein R? is hydrogen, amino or a protected amino group, R14 is carboxy or a protected carboxy group, R6 is hydrogen or an organic residue which may have suitable substituent(s), R8 is halogen, and R15 is hydrogen or halogen, or a salt thereof which comprises :
reacting syn isomer of a compound of the formula :
(Vn) wherein R?, R6 and R14 are each as defined above, or a salt thereof, with halogenating agent.

62. A process according to claim 61, wherein R? is amino, R14 is carboxy, and R6 is lower alkyl.

63. A process according to claim 62, wherein a group of the formula :
is a group of the formula :
, in which R? is amino, R15 is hydrogen or halogen, R8 is halogen, and a group of the formula :
is a group of the formula :
, in which R? is as defined above.

64. A process according to claim 63, wherein R6 is methyl, R8 is chloro, and R15 is chloro.

65. A process according to claim 63, wherein R6 is methyl, R8 is chloro, and R15 is hydrogen.

66. A process for preparing a compound of the formula :
(Vi) R? and R? are each hydrogen, halogen, lower alkoxy or arylthio, R14 is carboxy or a protected carboxy group, X is lower alkylene or a group of the formula :
in which R6 is hydrogen or an organic residue which may have suitable substituent(s), and Z is N or CH, or a salt thereof which comprises :
subjecting a compound of the formula :

(Vh) wherein R? is a protected amino group, and R?, R?, R14, X and Z are each as defined above, or a salt thereof, to elimination of the amino-protective group.

67. A process according to claim 66, wherein a group of the formula : -X-R14 is a group of the formula : , wherein -OR6 is in syn position and R6 is lower alkyl, R14 is carboxy or an esterified carboxy group, R? is acylamino.

68. A process according to claim 67, wherein a group of the formula :
is a group of the formula :
a group of the formula : a group of the formula :
in which R?' is lower alkanoylamino, and R14 is carboxy.

69. A process according to claim 68, wherein R? is formamido, and R6 is methyl.

70. A process according to claim 67, wherein a group of the formula :
is a group of the formula :
, in which R? is halogen, a group of the formula :
is a group of the formula :
, in which R? is lower alkanoylamino, R? is as defined above, and R14 is carboxy or lower alkoxycarbonyl.

71. A process according to claim 70, wherein R? is formamido, R? is chloro, R6 is methyl, R14 of the starting compound is methoxycarbonyl, and R14 of the object compound is carboxy.

72. A process according to claim 67, wherein a group of the formula :
is a group of the formula :
, in which R? is hydrogen, halogen or lower alkoxy, a group of the formula :
is a group of the formula :
, in which R? is lower alkanoylamino, R? is as defined above, and R14 is carboxy or lower alkoxycarbonyl.

73. A process according to claim 72, wherein R? is formamido, R? is hydrogen, R6 is methyl, R14 of the starting compound is ethoxycarbonyl, and R14 of the object compound is carboxy.

74. A process according to claim 72, wherein R?' is formamido, R? is chloro, R6 is methyl, R14 of the starting compound is ethoxycarbonyl, and R14 of the object compound is carboxy.

75. A process according to claim 72, wherein R?' is formamido, R? is chloro, R6 is methyl, and R14 is ethoxycarbonyl.

76. A process according to claim 72, wherein R?' is formamido, R? is methoxy, R6 is methyl, R14 of the starting compound is methoxycarbonyl, and R14 of the object compound is carboxy.

77. A process for preparing a compound of the formula :
(Vh) wherein R? is a protected amino group, R? and R? are each hydrogen, halogen, lower alkoxy or arylthio, R14 is carboxy or a protected carboxy group, X is lower alkylene or a group of the formula :
in which R6 is hydrogen or an organic residue which may have suitable substituent(s), and Z is N or CH, or a salt thereof which comprises :
reacting a compound of the formula :
(Vi) wherein R?, R?, R14, X and Z are each as defined above, or a salt thereof with an amino protective agent.

78. A process according to claim 77, wherein R? is acylamino, R? and R? are each hydrogen, halogen, lower alkoxy, R14 is carboxy or an esterified carboxy group, and X is lower alkylene or a group of the formula :
, in which R6 is lower alkyl.

79. A process according to claim 78, wherein a group of the formula :

is a group of the formula :
, in which R? is lower alkanoylamino, a group of the formula :
is a group of the formula :
, R14 is lower alkoxycarbonyl, and X is lower alkylene.

80. A process according to claim 79, wherein R? is formamido, R14 is ethoxycarbonyl, and X is methylene.

81. A process according to claim 78, wherein a group of the formula :
is a group of the formula :
, in which R?' is lower alkanoylamino or trihalo(lower)alkanoylamino, R? and R? are each hydrogen or halogen, a group of the formula :
is a group of the formula :
, in which R? and R? are each as defined above, and a group of the formula : -X-R14 is a group of the formula : , wherein -O-R6 is in syn position, R6 is lower alkyl and R14 is carboxy.

82. A process according to claim 81, wherein R? is trifluoroacetamido, R? and R? are both hydrogen, and R6 is methyl.

83. A process according to claim 81, wherein R? is formamido, R? is hydrogen, R? is chloro, and R6 is methyl.

84. A process according to claim 81, wherein R?' is formamido, R? is chloro, R? is chloro, and R6 is methyl.

85. A process according to claim 78, wherein a group of the formula :

is a group of the formula :

, in which R?' is lower alkanoylamino, R? is hydrogen or halogen, a group of the formula :

is a group of the formula :

, in which R? is as defined above, R14 is lower alkoxycarbonyl, and X is lower alkylene.

86. A process according to claim 85, wherein R?' is formamido, R? is hydrogen, R14 is methoxycarbonyl, and X is methylene.

87. A process according to claim 85, wherein is formamido, is chloro, R14 is methoxycarbonyl, and X is methylene.

88. A process according to claim 78, wherein a group of the formula :

is a group of the formula :

, in which is lower alkanoylamino, is halogen;
a group of the formula :

is a group of the formula :

, in which is as defined above, and a group of the formula : -X-R14 is a group of the formula : , wherein -O-R6 is in syn position, R6 is lower alkyl and R14 is carboxy.

89. A process according to claim 88, wherein is formamido, is chloro, and is methyl.

90. A process according to claim 78, wherein a group of the formula :

is a group of the formula :

, in which is lower alkanoylamino, is halogen or lower alkoxy, a group of the formula :

is a group of the formula :

, in which is as defined above, R14 is lower alkoxycarbonyl, and X is lower alkylene.

91. A process according to claim 90, wherein is formamido, is chloro, R14 is ethoxycarbonyl, and X is methylene.

92. A process according to claim 90, wherein is formamido, is methoxy, R14 is methoxycarbonyl, and X is methylene.

93. A process according to claim 78, wherein the object compound is syn isomer of a compound of the formula :

, in which is lower alkanoylamino and R6 is lower alkyl, and the starting compound is syn isomer of a compound of the formula :

, in which R6 is as defined above.

94. A process according to claim 93, wherein is formamido, and R6 is methyl.

95. A compound of the formula :

(V) wherein R?, R?, R?, R14, X and Z are each as defined in claim 1, or a salt thereof, whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.

96. A compound of the formula :
(Vj) wherein R?, R?, R?, R6, R14 and Z are each as defined in claim 2, or a salt thereof, whenever prepared by the process of claim 2, or by an obvious chemical equivalent thereof.

97. A compound of the formula (Vj), as defined in claim 2, wherein R?, R?, R?, R6, R14 and Z are each as defined in claim 3, or a salt thereof, whenever prepared by the process of claim 3, or by an obvious chemical equivalent thereof.

98. A compound of the formula (Vj), as defined in claim 2, wherein R?, R?, R?, R6, R14 and Z are each as defined in claim 4, or a salt thereof, whenever prepared by the process of claim 4, or by an obvious chemical equivalent thereof.

99. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6, R14 and Z are each as defined in claim 5, or a salt thereof, whenever prepared by the process of claim 5, or by an obvious chemical equivalent thereof.

100. 2-(6-Formamidopyridin-2-yl)-2-hydroxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 6, or by an obvious chemical equivalent thereof.

101. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6, R14 and Z are each as defined in claim 7, or a salt thereof, whenever prepared by the process of claim 7, or by an obvious chemical equivalent thereof.

102. Z-(6-Formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 8, or by an obvious chemical equivalent thereof.

103. 2-(6-Formamidopyridin-2-yl)-2-ethoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 9, or by an obvious chemical equivalent thereof.

104. 2-(6-Formamidopyridin-2-yl)-2-isopropoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 10, or by an obvious chemical equivalent thereof.

105. 2-(6-Formamidopyridin-2-yl)-2-propoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 11, or by an obvious chemical equivalent thereof.

106. 2-Butoxyimino-2-(6-formamidopyridin-2-yl)acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 12, or by an obvious chemical equivalent thereof.

107. 2-Isobutoxyimino-2-(6-formamidopyridin-2-yl)acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 13, or by an obvious chemical equivalent thereof.

108. A compound of the formula (Vj), as defined in claim 2, wherein R?, R?, R?, R6, R14 and Z are each as defined in claim 14, or a salt thereof, whenever prepared by the process of claim 14, or by an obvious chemical equivalent thereof.

109. 2-(6-Formamidopyridin-2-yl)-2-(2,2,2-trifluoro-ethoxyimino)acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 15, or by an obvious chemical equivalent thereof.

110. A compound of the formula (Vj), as defined in claim 2, wherein R?, R?, R?, R6, R14 and Z are each as defined in claim 16, or a salt thereof, whenever prepared by the process of claim 16, or by an obvious chemical equivalent thereof.

111. 2-Allyloxyimino-2-(6-formamidopyridin-2-yl)acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 17, or by an obvious chemical equivalent thereof.

112. A compound of the formula (Vj), as defined in claim 2, wherein R?, R?, R?, R6, R14 and Z are each as defined in claim 18, or a salt thereof, whenever prepared by the process of claim 18, or by an obvious chemical equivalent thereof.

113. 2-(6-Formamidopyridin-2-yl)-2-propargyloxy-iminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 19, or by an obvious chemical equivalent thereof.

114. 2-(6-Formamidopyridin-2-yl)-2-phenoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 20, or by an obvious chemical equivalent thereof.

115. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6, R14 and Z are each as defined in claim 21, or a salt thereof, whenever prepared by the process of claim 21, or by an obvious chemical equivalent thereof.

116. 2-(4-Formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 22, or by an obvious chemical equivalent thereof.

117. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6, R14 and Z are each as defined in claim 23, or a salt thereof, whenever prepared by the process of claim 23, or by an obvious chemical equivalent thereof.

118. 2-(6-Formamidopyridin-3-yl)-2-methoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 24, or by an obvious chemical equivalent thereof.

119. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6, R14 and Z are each as defined in claim 25, or a salt thereof, whenever prepared by the process of claim 25, or by an obvious chemical equivalent thereof.

120. 2-(2-Formamidopyrimidin-4-yl)-2-methoxyiminoacetic acid, (syn isomer), or a salt thereof, whenever prepared by the process of claim 26, or by an obvious chemical equivalent thereof.

121. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6, R14 and Z are each as defined in claim 27, or a salt thereof, whenever prepared by the process of claim 27, or by an obvious chemical equivalent thereof.

122. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6, R14 and Z are each as defined in claim 28, or a salt thereof, whenever prepared by the process of claim 28, or by an obvious chemical equivalent thereof.

123. 2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 29, or by an obvious chemical equivalent thereof.

124. 2-(4-Formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 30, or by an obvious chemical equivalent thereof.

125. 2-Ethoxyimino-2-(4-formamidopyrimidin-2-yl)acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 31, or by an obvious chemical equivalent thereof.

126. 2-(4-Formamidopyrimidin-2-yl)-2-propoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 32, or by an obvious chemical equivalent thereof.

127. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6 R14 and Z are each as defined in claim 33, or a salt thereof, whenever prepared by the process of claim 33, or by an obvious chemical equivalent thereof.

128. 2-Allyloxyimino-2-(4-formamidopyrimidin-2-yl)-acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 34, or by an obvious chemical equivalent thereof.

129. A compound of the formula (Vj), as defined in claim 2, wherein Ra, Rb, Rc, R6, R14 and Z are each as defined in claim 35, or a salt thereof, whenever prepared by the process of claim 35, or by an obvious chemical equivalent thereof.

130. 2-Benzyloxyimino-2-(4-formamidopyrimidin-2-yl)-acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 36, or by an obvious chemical equivalent thereof.

131. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6, R14 and Z are each as defined in claim 37, or a salt thereof, whenever prepaTed by the process of claim 37, or by an obvious chemical equivalent thereof.

132. Ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyimino-acetate (syn isomer), or a salt thereof, whenever prepared by the process of claim 38, or by an obvious chemical equivalent thereof.

133. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6, R14 and Z are each as defined in claim 39, or a salt thereof, whenever prepared by the process of claim 39, or by an obvious chemical equivalent thereof.

134. Ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)-2-methoxy-iminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 40, or by an obvious chemical equivalent thereof.

135. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6, R14 and Z are each as defined in claim 41, or a salt thereof, whenever prepared by the process of claim 41, or by an obvious chemical equivalent thereof.

136. Methyl Z-(4-formamido-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer),or a salt thereof, whenever prepared by the process of claim 42, or by an obvious chemical equivalent thereof.

137. A compound of the formula (Vj), as defined in claim 2, wherein , , , R6, R14 and Z are each as defined in claim 43, or a salt thereof, whenever prepared by the process of claim 43, or by an obvious chemical equivalent thereof.

138. 2-(2-Formamidopyridin-4-yl)-2-methoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 44, or by an obvious chemical equivalent thereof.

139. A compound of the formula :

(Vk) wherein , , , R14 and Z are each as defined in claim 45, or a salt thereof, whenever prepared by the process of claim 45, or by an obvious chemical equivalent thereof.

140. A compound of the formula (Vk), as defined in claim 45, wherein , , , R14 and Z are each as defined in claim 46, or a salt thereof, whenever prepared by the process of claim 46, or by an obvious chemical equivalent thereof.

141. A compound of the formula (Vk), as defined in claim 45, wherein , , , R14 and Z are each as defined in claim 47, or a salt thereof, whenever prepared by the process of claim 47, or by an obvious chemical equivalent thereof.

142. A compound of the formula (Vk), as defined in claim 45, wherein , , , R14 and Z are each as defined in claim 48, or a salt thereof, whenever prepared by the process of claim 48, or by an obvious chemical equivalent thereof.

143. Ethyl 2-(4-formamidopyrimidin-2-yl)-2-hydroxyimino-acetate (syn isomer), or a salt thereof, whenever prepared by the process of claim 49, or by an obvious chemical equivalent thereof.

144. A compound of the formula (Vk), as defined in claim 45, wherein , , , R14 and Z are each as defined in claim 50, or a salt thereof, whenever prepared by the process of claim 50, or by an obvious chemical equivalent thereof.

145. Methyl 2-(2-formamido-6-chloropyrimidin-4-yl)-2-hydroxyiminoacetate (syn isomer), or a salt thereof, whenever prepared by the process of claim 51, or by an obvious chemical equivalent thereof.

146. A compound of the formula :

(V?) wherein , , , R6', R14 and Z are each as defined in claim 52, or a salt thereof, whenever prepared by the process of claim 52, or by an obvious chemical equivalent thereof.

147. A compound of the formula (V?), as defined in claim 52, wherein , , , R6', R14 and Z are each as defined in claim 53, or a salt thereof, whenever prepared by the process of claim 53, or by an obvious chemical equivalent thereof.

148. A compound of the formula (V?), as defined in claim 52, wherein , , , R6', R14 and Z are each as defined in claim 54, or a salt thereof, whenever prepared by the process of claim 54, or by an obvious chemical equivalent thereof.

149. A compound of the formula (V?), as defined in claim 52, wherein , , , R6, R14 and Z are each as defined in claim 55, or a salt thereof, whenever prepared by the process of claim 55, or by an obvious chemical equivalent thereof.

150. 2-(6-Formamidopyridin-2-yl)-2-dichloroacetoxyimino-acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 56, or by an obvious chemical equivalent thereof.

151. A compound of the formula (V?), as defined in claim 52, wherein , , , R6', R14 and Z are each as defined in claim 57, or a salt thereof, whenever prepared by the process of claim 57, or by an obvious chemical equivalent thereof.

152. Ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxy-iminoacetate (syn isomer), or a salt thereof, whenever prepared by the process of claim 58, or by an obvious chemical equivalent thereof.

153. A compound of the formula (V?), as defined in claim 52, wherein , , , R6', R14 and Z are each as defined in claim 59, or a salt thereof, whenever prepared by the process of claim 59, or by an obvious chemical equivalent thereof.

154. Methyl 2-(2-formamido-6-chloropyrimidin-4-yl)-2-methoxyiminoacetate (syn isomer), or a salt thereof, whenever prepared by the process of claim 60, or by an obvious chemical equivalent thereof.

155. A compound of the formula :

(Vm) wherein , R6, R8, R14 and Rl5 are each as defined in claim 61, or a salt thereof whenever prepared by the process of claim 61, or by an obvious chemical equivalent thereof.

156. A compound of the formula (Vm), as defined in claim 61, wherein , R6, R8, R14 and R15 are each as defined in claim 62, or a salt thereof, whenever prepared by the process of claim 62, or by an obvious chemical equivalent thereof.

157. A compound of the formula (Vm), as defined in claim 61, wherein , R6, R8, R14 and R15 are each as defined in claim 63, or a salt thereof, whenever prepared by the process of claim 63, or by an obvious chemical equivalent thereof.

158. 2-(6-Amino-3,5-dichloropyridin-2-yl)-2-methoxyimino-acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 64, or by an obvious chemical equivalent thereof.

159. 2-(6-Amino-3-chloropyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 65, or by an obvious chemical equivalent thereof.

160. A compound of the formula :

(Vi) wherein , , R14, X and Z are each as defined in claim 66, or a salt thereof, whenever prepared by the process of claim 66, or by an obvious chemical equivalent thereof.

161. A compound of the formula (Vi), as defined in claim 66, wherein , , R14, X and Z are each as defined in claim 67, or a salt thereof, whenever prepared by the process of claim 67, or by an obvious chemical equivalent thereof.

162. A compound of the formula (Vi), as defined in claim 66, wherein , , R14, X and Z are each as defined in claim 68, or a salt thereof, whenever prepared by the process of claim 68, or by an obvious chemical equivalent thereof.

163. 2-(6-Aminopyridin-2-yl)-2-methoxyimino acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 69, or by an obvious chemical equivalent thereof.

164. A compound of the formula (Vi), as defined in claim 66, wherein , , R14, X and Z are each as defined in claim 70, or a salt thereof, whenever prepared by the process of claim 70, or by an obvious chemical equivalent thereof.

165. 2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 71, or by an obvious chemical equivalent thereof.

166. A compound of the formula (Vi), as defined in claim 66, wherein , , R14, X and Z are each as defined in claim 72, or a salt thereof, whenever prepared by the process of claim 72, or by an obvious chemical equivalent thereof.

167. 2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer3, or a salt thereof, whenever prepared by the process of claim 73, or by an obvious chemical equivalent thereof.

168. 2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyimino-acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 74, or by an obvious chemical equivalent thereof.

169. Ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer), or a salt thereof, whenever prepared by the process of claim 75, or by an obvious chemical equivalent thereof.

170. 2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyimino-acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 76, or by an obvious chemical equivalent thereof.

171. A compound of the formula :

(Vh) wherein , , , R14, X and Z are each as defined in claim 77, or a salt thereof, whenever prepared by the process of claim 77, or by an obvious chemical equivalent thereof.

172. A compound of the formula (Vh), as defined in claim 77, wherein , , , R14, X and Z are each as defined in claim 78, or a salt thereof, whenever prepared by the process of claim 78, or by an obvious chemical equivalent thereof.

173. A compound of the formula (Vh), as defined in claim 77, wherein , , , R14, X and Z are each as defined in claim 79, or a salt thereof, whenever prepared by the process of claim 79, or by an obvious chemical equivalent thereof.

174. Ethyl 2-(6-formamidopyridin-2-yl)acetate, or a salt thereof, whenever prepared by the process of claim 80, or by an obvious chemical equivalent thereof.

175. A compound of the formula (Vh), as defined in claim 77, wherein , , , R14, X and Z are each as defined in claim 81, or a salt thereof, whenever prepared by the process of claim 81, or by an obvious chemical equivalent thereof.

176. 2-(6-Trifluoroacetamidopyridin-2-yl)-2-methoxyimino-acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 82, or by an obvious chemical equivalent thereof.

177. 2-(3-Chloro-6-formamidopyridin-2-yl)-2-methoxyimino-acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 83, or by an obvious chemical equivalent thereof.

178. 2-(3,5-Dichloro-6-formamidopyridin-2-yl)-2-methoxyimino-acetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 84, or by an obvious chemical equivalent thereof.

179. A compound of the formula (Vh), as defined in claim 77, wherein R?, R?, R?, R14, X and Z are each as defined in claim 85, or a salt thereof, whenever prepared by the process of claim 85, or by an obvious chemical equivalent thereof.

180. Methyl 2-(2-formamidopyrimidin-4-yl)acetate, or a salt thereof, whenever prepared by the process of claim 86, or by an obvious chemical equivalent thereof.

181. Methyl 2-(2-formamido-6-chloropyrimidin-4-yl)-acetate, or a salt thereof, whenever prepared by the process of claim 87, or by an obvious chemical equivalent thereof.

182. A compound of the formula (Vh), as defined in claim 77, wherein R?', R?, R?, R14, X and Z are each as defined in claim 88, or a salt thereof, whenever prepared by the process of claim 88, or by an obvious chemical equivalent thereof.

183. 2-(2-Formamido-6-chloropyrimidin-4-yl)-2-methoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 89, or by an obvious chemical equivalent thereof.

184. A compound of the formula (Vh), as defined in claim 77, wherein , , , R14, X and Z are each as defined in claim 90, or a salt thereof, whenever prepared by the process of claim 90, or by an obvious chemical equivalent thereof.

185. Ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)acetate, or a salt thereof, whenever prepared by the process of claim 91, or by an obvious chemical equivalent thereof.

186. Methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)-acetate, or a salt chereof, whenever prepared by the process of claim 92, or by an obvious chemical equivalent thereof.

187. A compound of the formula (Vh), as defined in claim 77, wherein , , , R14, X and Z are each as defined in claim 93, or a salt thereof, whenever prepared by the process of claim 93, or by an obvious chemical equivalent thereof.

188. 2-(4-Formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 94, or by an obvious chemical equivalent thereof.

Claims supported by the supplementary disclosure.

189. A process according to claim 27, wherein is formamido, is hydrogen, R6 is phenyl, and R14 is carboxy.

190. 2-(4-Formamidopyrimidin-2-yl)-2-phenoxyiminoacetic acid (syn isomer), or a salt thereof, whenever prepared by the process of claim 189, or by an obvious chemical equivalent thereof.