CH638532A5 - METHOD FOR PRODUCING THE SYN-ISOMERS OF 3,7-DISUBSTITUTED 3-CEPHEM-4-CARBONIC ACIDS. - Google Patents

Description

The invention relates to processes for the preparation of new syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acids and their pharmaceutically acceptable salts which have antibacterial activity, in particular against pathogenic bacteria.

3-cephem compounds were already known from British Patent No. 1,399,086, the 7-position of which was substituted by an (x- (hydroxyimino) -acetamido group etherified on the hydroxyimino group. Also known from British Patent No. 1 389 1943 cephem compounds, the 7-position of which bears an a- (hydroxyimino or acyloxyimino) acylamido group.

The new compounds of the cephemcarboxylic acid series obtainable according to the invention correspond to the following formula:

C-CONH

in which mean:

R1 is a group of the formula

5

R

6

R

wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 hydroxy, lower alkoxy, acyloxy, acyl

represent amino or di (lower) alkylamino; a group of the formula wherein R7 is amino, protected amino, hydroxy or lower alkyl; or a group of the formula

R% 4U r9 ^ X

S

wherein R8 is lower alkyl and R "imino, protected imino or oxo;

R2 is an aliphatic hydrocarbon group that may have one or more substituents;

R3 carboxy or protected carboxy; and R4 acyloxymethyl, hydroxymethyl, formyl or a heterocyclic thiomethyl group, which may have one or more substituents;

or wherein R3 and R4 can be linked to form -COOCH2-.

It should be noted that the invention relates to a process for the preparation of the syn isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds, which is represented by the formula (I) given above and also by the Substructure of the formula

R1_C-CO-

II p

N-OR

can be represented in their molecules, while the corresponding anti-isomer is represented by the partial structure of the formula

R1_C-CO-? "

R O-N

can be represented.

Accordingly, it applies that in the following detailed explanations of the invention, both in the description and in the claims, the syn isomers of the compounds and the starting compounds used according to the invention due to the partial structure of the formula

-C-CO-

TI

R-O-

are represented in their molecules, with the proviso that when it is expedient for the explanation of the invention to express both the syn isomer and the anti isomer by a general formula, they by the partial structure of the formula

-c-co-

n?

0

1

can be displayed.

The compounds of formula I are new; they are made by the processes described below.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

638 532

4th

Procedure 1

h2n

.S.

J— Nv ^ J-R o T *

RJ

+ R -C-COOH

"2 N-ORz

R -C CONH

"2

N-OR

(II)

Procedure 2

(HI)

or its silyl derivative on or its reactive

Amino group or a salt derivative on the carboxy group thereof or a salt thereof

• (I)

rla-C-CONH ~ i f S

" 1

n-OR

2 ^ 0

N

R

Rlb-C-C0NII-

R *

/

N-OR2

Elimination of the amino or imino protecting group

(IV)

or a salt of it

N R, 3rd

Method 5, 5

K

YVc-

ho

CONH

n-or

Acylation of the hydroxy group sn r5a

4 6

R

N-OR

(V)

or a salt of it

Procedure H

r1-C-CONH-II

, 2a r

n-or l Y-N

0

Elimination of

Carboxy protection

group

R

+ R -C-CONH-

R *

Ï

N-OR '

2 B

0

<V

or a salt of it

0

-N ^ £

R

r *

(Ib)

r

N

R

R

(Ic)

Procedure 5

r -c-conh n-or2 0 '

Elimination of the amino protective group

^ -ch2-oconh-r

4a

(Vb)

or a salt of it

Procedure 6

r -c-conh

«2

N-OR

(Id)

638 532

'"P" L.

n ch2-oconh2

r -c-c0nh-

n-or2 o

■ ch2oh

Acid r *

or a salt thereof r -c-conh-

II-or

0

f

■ N

ch.

c0-0 cif)

wherein R1, R2, R3, R4 and R5 each have the meanings given above;

Rla is a group of the formula or a group of the formula

,8th

r

7a N

Rl

4-

hn

• n-

X

sr r8-N

wherein R7a represents protected amino, or a group of 35

Formula p wherein R8 is as defined above;

R5a is hydrogen, halogen, nitro, lower alkoxy or acyloxy;

R6a acyloxy;

40 R2a protected carboxy (lower) alkyl; R2b carboxy- (lower) alkyl;

wherein R8 is as defined above and R9a protected imino R4a is an amino protecting group.

K -JM; i

R "

poses;

RIb a group of the formula

N-pi

«2n J-

Among the starting compounds, the starting compounds of the formula (III), including the corresponding 45 anti-isomers, are new compounds and they can be prepared by processes which can be represented by the following reaction scheme:

(1) (i)

R5b "HO

(vi)

co ch.

r10- y (vii)

P5b

^ COCH,

R ^ V ^ 3

(viii)

(ü)

R

5c r

(ix)

co ch.

R

5c

oxidation

R

c0c00h

(x)

638 532

(iü)

R ** C T3V * • Î ^ C

t elimination - ^ - -

Y \ COCOOH COCOOH

R10O HO

(XI) CXII)

(iv)

5 R2-ONH2 (XIV) or 5

-f \ COCOOH a salt thereof | c. C0QH

r6 y \ = J r6 -A = r / II

N

5 2

OR

(XIII) (IIIa)

(2) (i).

r5 NH2OH or an R5

^ yCOCOOHSalZ daV ° n ► ^ O -! '000 "

HO HO N

l

OH

(XV) (XVI)

(ü)

R .cooh alkylÌerunS R V ^ Vc-COOR8

~ 8 '

HO R 0 N

N $

& «"

(XVII) Cxvni)

n5d

Hydrolys e R, * ■ £ Vc-COOH

R8O ~ il 5

OR2d

C "V

7

638 532

(3)

RVV C-COOH ACyllerUn? "V *

C-COOH

H0 N R N

§ 2 ^ 2

OR OR

(xix)

(inc)

(4) CD

Nitrosation

X-CH2-CO-CH2-Z

(xx)

xci-uco-c-z z II

N

OH-

R7b-C-NH,

m RMsTf oh

(xxi)

(xxiii)

N — r-C-COOH elimination n-] c ff \\ I

* R ~ \ c / N

s 5

Oh

(xxi na)

(ii)

^ jr AikYiieruns' * 7Aijt

^ ^ 2e

OH ORZe

(xxiv) (xxv)

N-tv— C-COOH

Elimination 7r1 for \\

- "H

Sx N

L2e ci "d)

638 532

(5)

Alkylation: halogenation ch - CO-C-Z - 5- 'CH, CO-C-Z> - X-CH7CO-C-Z

Ol, -J II ^ il n

3rd

oh (xxvi) R7b-C-NH "

N

5 2e OR

(xxvii)

n s

(xxii)

N-

-c-z

-> R

7K

Q / N

S 5

OR

Elimination unp :) p7c // y

2e

OR

(xxviii)

C-COOH II

N

5 2e OR

2e

(6) (i)

H,

(xxix)

* H "0"

(ine)

Amino protective agent

S

(xxx)

ch2-z

- R7a- ^ ~ ^ r ch2 "z

(ii)

r1c-ch2-z

(XXXII)

Oxidation s-

(xxxi)

lc hydrolysis lc r -co-z <r -c-z

(XXXIII)

rlc-cocooh (xxxiv)

N

3rd

OH

(xxiiib)

2nd

r o-nh2 or a 'salt thereof (xiv)

rlc-c-z r -onh2 (xiv) g7

JLj or an a 'salt thereof ^

I.

nh20h

R1c-c-cooh

I.

N

5 2

OR (xxxv)

or a salt thereof rlc-c-cooh «

N

3rd

OH

I.

n

§ 2 OR

(IIIf)

(XXXVI)

9

638 532

Alkylation R ^ m -> r

1N A C-COOR

«Ü ± jtyj-j-eiuxig r7H 3" «" C00H 'R9a ^

5 6 2e i or n

5

Oh

(xxxvii) (xxxviii)

Hydrolysis r.

n

R9a Â,

C-COOH

n §

or

2e

(7)

dHg)

(XXXIX)

H2Nt <3 îf "Za n

5 2

or

Amino protective agent

■>

R7ai3-

(mt)

C-Z. Il 'n

5 2 or wherein R2, R5, R6, R5a, R6a, R7a, R8 and R9a each have the meanings given above in which R8 and R9 each have the meanings given above;

R5b halogen;

Y is an acid residue;

R10 ar (lower) alkyl;

R5c is hydrogen, halogen or nitro; R6b lower alkoxy, Ar (lower) alkoxy or acylamino; R2c is hydrogen, lower alkyl or lower alkenyl; R5d is hydrogen, halogen, nitro, hydroxy or lower alkoxy;

X halogen;

Zprotected carboxy;

R7b lower alkyl, amino or lower alkoxy;

R7c lower alkyl, amino or hydroxy;

R7d lower alkyl;

R2e lower alkyl;

Rlc is a group of the formula r

7 "Gr in which R7 has the meanings given above, or a group of the formula r ^ - n - \

to have;

R2d lower alkyl or lower alkenyl; and

Za mean carboxy or protected carboxy.

The other starting compounds (IV), (V), (Va), (Vb) 45 and (Ve) are also all new compounds and can be prepared by processes 1 to 8 given above.

With regard to the compounds of the formulas (I), (Ia) and (Ic) to (If) and the starting compounds of the formulas (III), (IIIe), see (Ulf), (IIIh), (IV), (Va), (V „), (Ve), (XXIII) - (XXIIIb), (XXIX) to (XXXVII) and (XXXIX) it should be noted that the compounds obtainable according to the invention and the starting compounds also the tautomeric isomers with respect to their thiazole groups include. That is, if the group of the formula r74 ~ T-

60

wherein R7e represents amino, protected amino or hydroxy, in the formula of the compounds obtainable according to the invention and the starting compounds of the formula

65

n-

r

7eJlst

(A)

638 532

10th

where R7e has the meanings given above, this group of the formula can also be represented by its tautomeric formula

(B)

wherein R7f represents imino, protected imino or oxo. This means that both groups (A) and (B) exist in the equilibrium state as so-called tautomeric forms, which can be represented by the following equilibrium:

n

R

7e

J.J

(A)

hn ~

R7fAS

-t "

(B)

wherein R7e and R7f each have the meanings given above.

These types of tautomerism between 2-amino and 2-hydro-xythiazole compounds and 2-imino or 2-oxothiazoline compounds, as indicated above, are known in the literature and it will be readily apparent to those skilled in the art that both tautomeric isomers are in equilibrium with one another and are easily convertible into one another, and consequently the compounds obtainable according to the invention also include these isomers. Accordingly, both tautomeric forms of the compounds (I), (Ia) and (Ic) - (If) and the starting compounds (III), (IIIe), (IIIf), (IIIh), (IV), (Va) - ( VC), (Ve), (XXIII) to (XXIIIb), (XXIX) to (XXXVII) and (XXXIX) clearly within the scope of the present invention. In the description as well as in the examples and in the claims, the compounds obtainable according to the invention and the starting compounds which comprise (contain) the group of these tautomeric isomers are subsequently described for the sake of simplicity by using one of the terms therefor, i.e. through the formula

R

7e

N

4cj "

CA)

represents.

In addition, in the case of the compounds (I), (Ia) to (Ic) and (If) and the starting compounds (II), (IV), (V) and (Va), the compounds in which R3 is carboxy and R4 is formyl, also be regarded as practically the same compounds as the compounds in which R3 and R4 are connected to one another to form a group of the formula -COOCH (OH) -, ie so-called intramolecular hemiacylal compounds, and accordingly they belong to the same category of compounds and therefore belong within the scope of the present invention.

Examples of suitable pharmaceutically acceptable salts of the syn isomers of 3,7-disubstituted-3-cephem-4 ~ carboxylic acid compounds (I) are conventional non-toxic salts and may include an inorganic salt such as e.g. a metal salt such as an alkali metal salt (e.g. a sodium, potassium salt and the like) and an alkaline earth metal salt (e.g. a calcium, magnesium salt and the like), an ammonium salt 5 and the like, an organic salt (e.g. an organic amine salt (such as a trimethylamine, Triethylamine, ethanolamine, diethanolamine, pyridine, picoline, dicyclohexylamine, N, N'-dibenzylethylenediamine salt and the like) and the like, an organic acid salt (e.g. an acetate, maleate, io tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate and the like), an inorganic acid salt (e.g., a hydrochloride, hydrobromide, sulfate, phosphate, and the like) or a salt with an amino acid (e.g., arginine, aspartic acid, glutamic acid, and the like), etc. The following are some suitable examples and explanations of the various definitions that are used.

Unless otherwise stated, the term “low” as used here means that a group designated 20 contains 1 to 6 carbon atoms.

The term "aliphatic hydrocarbon group" as used herein means an unbranched (straight) or branched aliphatic hydrocarbon group, preferably having 1 to 6 carbon atoms, and this term can include lower alkyl, lower alkenyl and the like. This aliphatic hydrocarbon group may have 1 to 2 suitable substituents, e.g. Carboxy, protected car-boxy, arylthio, lower alkylthio, aryl, acyloxy, lower alkoxy, aryloxy, heterocyclic groups or the like.

A suitable halogen is e.g. Chlorine, bromine, fluorine and iodine.

A suitable lower alkoxy and a suitable lower alkoxy radical in the expression "Ar (lower) alkoxy" can be one which can be branched, such as 35 e.g. Methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like, and preferably it is one having 1 to 4 carbon atoms, especially 1 to 2 carbon atoms.

40 A suitable protected amino may include an acylamino and an amino group that are substituted by a conventional protecting group other than the acyl group, e.g. Benzyl or the like.

A suitable lower alkyl and a suitable lower-alkyl group in the terms «lower alkylthio», «carboxy- (lower) -alkyl», «protected carboxy (lower) alkyl», «ar (lower) -alkyl» and «di (lower) alkylamino may include one that may be branched, such as Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like, preferably one with 1 to 4 carbon atoms, in particular one with 1 to 2 carbon atoms.

A suitable protected imino may include an acyl imino and an imino group which are protected by a conventional protecting group other than the acyl group, e.g. Benzyl and the like.

A suitable protected carboxy and a suitable protected carboxy radical in the expression "protected carboxy (lower) alkyl" may include esterified carboxy, wherein the ester may be one of the following: e.g. a lower alkyl ester (such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, 1-cyclopropyl ethyl ester and the like), the lower alkyl radical preferably containing 1 to 4 carbon atoms 65; a lower alkenyl ester (e.g. a vinyl ester, allyl ester and the like); a lower alkynyl ester (e.g. an ethynyl ester, propynyl ester and the like); a mono (or di or tri) halogen (low) alkyl ester (e.g. a 2-iodoethyl

11 638 532

esters, 2,2,2-trichloroethyl ester and the like); one-membered) heteromonocyclic group which contains 1 to 2 sulfur, a lower alkanoyloxy (lower) alkyl ester (for example an acetatome and 1 to 3 nitrogen atoms, for example thiazolyl, oxymethyl ester, propionyloxymethyl ester, butyryloxymethylthiadiazolyl (such as 1,2,4-thiadiazolyl 1,3,4-thiadiazolyl, 1,2,5-ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexa-thiadiazolyl and the like) and the like; noyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl 5 a saturated 3- to 8-membered (preferably 5- to 6-membered ester and the like);) heteromonocyclic group which contains 1 to 2 sulfur atoms, a lower alkanesulfonyl (lower) alkyl ester (for example a mesyl and 1 to 3 nitrogen atoms, such as, for example, thiazolidinyl and methyl ester, 2-mesylethyl ester and the like) ; the like;

an Ar (lower) alkyl ester, e.g. a phenyl (lower) alkyl- an unsaturated 3 to 8-membered (preferably 5 to ester, the one or more suitable substituent having one or more o-membered) heteromonocyclic group which can contain a sulfur atom (such as, for example, a benzyl ester, 4-methoxybenzyl ester) , contains, such as thienyl and the like;

4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylme- an unsaturated condensed heterocyclic group which contains thylester, bis- (methoxyphenyl) methyl ester, 3,4-dimethoxybene 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as ethyl ester, 4-hydroxy 3,5-di-tert-butylbenzyl ester and the like, for example Benzothiazolyl, benzothiadiazolyl and the like and chen); 15 like; wherein the heterocyclic group 1 to 2 is an aryl ester which may have one or more suitable substituent substituents, e.g. Lower alkyl (such as Metten can have (such as a phenyl ester, tolyl ester, tert.-hyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclo-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester and pentyl, hexyl, cyclohexyl and the like), preferably one of the like) and the like. those with 1 to 4 carbon atoms; Lower alkenyl (like

A preferred example of protected carboxy can be vinyl, allyl, butenyl and the like);

Lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbo-aryl (e.g. phenyltolyl and the like); halogen (such as nyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, chlorine, bromine, iodine or fluorine); amino; di (lower) alkylamino

t-Pentyloxycarbonyl, hexyloxycarbonyl and the like) with 2 (lower) -alkyl (such as dimethylaminomethyl, dimethylamino to 7 carbon atoms, preferably with 2 to 5 carbon-ethyl, diethylaminopropyl, diethylaminobutyl and the like atoms. 25 chen), preferably one with 3 to 6 carbon atoms

A suitable aryl and aryl residue in the clothes or the like.

press «Ar (lower) alkyl», «Ar (lower) alkoxy», «Arylthio» A suitable lower alkenyl includes one with and «Aryloxy» can e.g. be phenyl, tolyl, xylyl, mesityl, 2 to 6 carbon atoms, and these can be, for example, cumenyl, naphthyl and the like, the aryl group 1 being, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-butene to 3 Can have substituents, such as Halogen (such as 30 nyl, 3-pentenyl and the like, preferably around such chlorine, bromine, iodine or fluorine), hydroxy and the like. with 2 to 4 carbon atoms.

Under a suitable heterocyclic group and a suitable acyl radicals in the terms "acylamino", suitable heterocyclic radical in the terms "heterocy-" acylimino "," acyloxy "and" acyloxymethyl ", as described above clical thiomethyl group, which mentions one or more substituents have been, for example Carbamoyl, which may have an aliphatic, is a saturated or unsaturated, monocyte acyl group and an acyl group which contains an aromatic clic or polycyclic heterocyclic group to form a ring or heterocyclic ring. Suitable examples of the hen containing at least one heteroatom, e.g. an acid acyl are lower alkanoyl (such as formyl, acetyl, propionyl,

Substance, sulfur, nitrogen atom and the like. A particularly butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, piva or the preferred heterocyclic group is e.g. one of the nachloyl and the like), preferably one with 1 to 4 Koh-heterocyclic groups: an unsaturated 40 atoms, in particular one with 1 to 2 carbons, 3 to 8-membered (preferably 5 to 6-membered) hetero- atoms; Lower alkoxycarbonyl with 2 to 7 carbon monocyclic groups containing 1 to 4 nitrogen atoms (such as methoxycarbonyl, ethoxycarbonyl, propoxycarbo-e.g. pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its nyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, but- N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. oxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentylo-

4H-1, 2,4-triazolyl, 1H-1, 2,3-triazolyl, 2H-1, 2,3-triazolyl and 45 xycarbonyl, hexyloxycarbonyl and the like), preferably the like), tetrazolyl (e.g. 1H-tetrazolyl, 2H -Tetrazolyl and one with 3 to 6 carbon atoms; lower alkane sulfo - or the like) and the like; nyl (such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfone

a saturated 3- to 8-membered (preferably 5- to 6-membered fonyl, butanesulfonyl and the like), preferably a sol) heteromonocyclic group which contains 1 to 4 nitrogen atoms with 1 to 4 carbon atoms, in particular one, such as Pyrrolidinyl, imidazolidinyl, piperidino, pipe-50 having 1 to 2 carbon atoms; Arenesulfonyl (such as benzenesulfonazinyl and the like; nyl, tosyl and the like); Aroyl (such as benzoyl, toluoyl,

an unsaturated condensed heterocyclic group, the naphthoyl, phthaloyl, indancarbonyl and the like); Contains 1 to 4 nitrogen atoms, e.g. Indolyl, isoindolyl, ar (lower) alkanoyl (such as phenylacetyl, phenylpropionyl and

Indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, the like); Ar (lower) alkoxycarbonyl (such as benzyloxycarbo-benzotriazolyl and the like; 55 nyl, phenethyloxycarbonyl and the like) and the like.

an unsaturated 3- to 8-membered (preferably 5- to The above-mentioned acyl radical can contain 1 to 3 suitable substituents

member) heteromonocyclic group which have 1 to 2 oxygen tuents, such as Halogen (such as chlorine, bromine, iodine atoms and 1 to 3 nitrogen atoms, such as oxazolyl, or fluorine), hydroxy, cyano, nitro, lower alkoxy (such as met-isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1, 3,4-oxadiazohoxy, ethoxy, propoxy, isopropoxy and the like), low-lyl, 1,2,5-oxadiazolyl and the like) and the like; 60 alkyl (such as methyl, ethyl, propyl, isopropyl, butyl and the like

a saturated 3- to 8-membered (preferably 5- to 6-membered), lower alkenyl (such as vinyl, allyl and the like), acyl, Rige) heteromonocyclic group containing 1 to 2 oxygen atoms such as e.g. Halogen (lower) alkanoyl (such as chloroacetyl, dichloro and contains 1 to 3 nitrogen atoms such as morpholinyl and acetyl, trichloroacetyl, trifluoroacetyl and the like), aryl the like; (such as phenyl, tolyl and the like) and the like. Suitable

an unsaturated condensed heterocyclic group containing 65 examples of the acyl with the substituent (s) may contain 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as its mono (or di or tri) halogen (lower) alkanoyl (e.g. tri- e.g. benzoxazolyl, benzoxadiazolyl and the like; fluoroacetyl, trichloroacetyl and the like), preferably an unsaturated 3 to 8-membered (preferably 5-to those having 2 to 4 carbon atoms: mono (or di- or

638 532 12

Tri) halogen (lower) alkanoylcarbamoyl (such as Trichlorace- the alkanoyl group preferably has 2 to 3 carbon atoms on tylcarbamoyl and the like), preferably one having 3], hydroxymethyl, formyl, tetrazolylthiomethyl which has up to 4 carbon atoms or the like. may have lower alkyl (preferably 1 to 4, in particular

Suitable amino protecting groups for R4a include e.g. their 1 to 2 carbon atoms) or di (lower) alkyl acyl, such as halogen (lower) alkanoyl (for example chloroacetyl, dichloro-5 amino (lower) alkyl (in which the alkyl radical is preferably 1 to 4, acetyl, trichloroacetyl, trifluoroacetyl and the like ), Preferably 1 to 2 carbon atoms in particular), triazolylthio-wise one with 2 to 3 carbon atoms or the like methyl, which may have lower alkyl (preferably 1 to 4, in particular 1 to 2 carbon atoms) or thiadia-

Suitable acid residues include e.g. a residue of a zolylthiomethyl, which may have lower alkyl (preferably

Acid such as an inorganic acid (such as water of chlorine, with 1 to 4, in particular 1 to 2, carbon atoms); Substance acid, hydrobromic acid, hydroiodic acid, Schwe- or R3 and R4 can be linked together under Feisäure and the like) or an organic acid (such as formation of -COOCH2-.

Methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid The various processes for the preparation of

and the same). Position of the compounds obtainable according to the invention in

Under the appropriate examples for each of the groups of the 15 individual explained in more detail.

Compounds obtainable according to the invention, as explained and explained above, are described below as process 1

some preferred examples are given: Compound (I) or a pharmaceutically acceptable salt

Preferred examples of R5 may be hydrogen, halo of which is produced by reacting the compound (II) gene (preferably chlorine) or nitro; 20 or a silyl derivative on the amino group or a salt preferred examples of R6 can be hydroxy, lower thereof with the compound (III) or a reactive alkoxy (preferably one with 1 to 4, in particular 1 to derivative on the carboxy group or a salt thereof, where it is 2 carbon atoms), acyloxy [preferably lower alkanoyl - this process is a basic process for the Her-oxy (preferably one with 1 to 4, in particular 1 to 2 position of the compound (I).

Carbon atoms) or carbamoyloxy], acylamino [preferred 25 the silyl derivative on the amino group of the compound (II), such as lower alkanesulfonylamino (preferably one used in the amidation and in the reaction of those having 1 to 4, in particular 1 to 2, carbon atoms)] or compound (II) with a silyl compound is, for example

Di (lower) alkylamino (in which the alkyl radical preferably contains 1 to bis (trimethylsilyl) acetamide, trimethylsilylacetamide or der-4, in particular 1 to 2 carbon atoms); same.

preferred examples of R7 can be amino, protected. A suitable salt for the compound (II) can e.g. its amino, such as acylamino [preferably lower alkanesulfonyl- an acid addition salt, e.g. an organic acid salt (such as an amino (preferably one having 1 to 4, especially 1 to acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate and 2 carbon atoms), trihalogen (lower) alkanoylamino the like) or an inorganic acid salt (such as a

(preferably one with 1 to 4, in particular 1 to 2 carbon hydrochloride, hydrobromide, sulfate, phosphate and the like-atom atoms), lower alkoxycarbonylamino (preferably 35 chen); a salt with an inorganic base, e.g. an alka - one with 2 to 7, in particular 3 to 6 carbon atoms) limetal salt (such as a sodium salt, potassium salt and the like or lower alkanoylamino (preferably one with 1 to 6)), an alkaline earth metal salt (such as a calcium salt, Magne-4, in particular 1 to 2 carbon atoms)], hydroxy or silicon salt and the like) or an ammonium salt; a salt of trigalkyl (preferably one with 1 to 4, especially 1 with an organic base (e.g. a triethylamine salt, pyridine to 2 carbon atoms); 40 salt and the like) and the like.

preferred examples of R8 are Ci-C4-lower alkyl, especially a suitable reactive derivative on the carboxy

special Ci-Cî lower alkyl; group of compound (III) can e.g. a conventional preferred example of R9 may be its protected imino, derivative as used in the amidation such as acylimino [preferably lower alkanesulfonylimino (pre- The salts of compound (III) may be salts with 1 to 4 , in particular 1 to 2 carbons with an inorganic base, such as atoms around an alkali metal salt)]; (like a sodium or potassium salt) or an alkaline earth

preferred examples of R2 can be lower alkyl (primary salt (such as a calcium or magnesium salt), a salt with preferably one with 1 to 4, in particular 1 to 2, especially an organic base, such as trimethylamine, triethylamine,

preferably with 1 carbon atom), lower alkenyl, pyridine, a salt with an acid (such as hydrochloric acid

Ar (low) alkenyl [particularly preferably phenyl (low) alkane-50 or hydrobromic acid) or the like, nyl], carboxy (lower) alkyl, protected carboxy (low) alkyl The reaction is usually carried out in a conventional [especially preferably lower alkoxycarbonyl (preferably a solvent such as water, acetone, dioxane, acetonitrile, chloro-such with 3 to 6 carbon atoms) - (lower) alkyl], arylroform, methylene chloride, ethylene chloride, tetrahydrofuran, thio (lower) alkyl [especially preferably phenylthio (lower ethyl acetate, N, N-dimethylformamide, pyridine or any

rig) alkyl], Ar (lower) alkyl [particularly preferably phenyl (lower 55 other organic solvent which affects the reaction rig) alkyl], which does not adversely affect halogen (preferably bromine) and hydroxy. Among these, thienyl (lower) alkyl or aryloxy (lower) alkyl solvents, the hydrophilic solvents can be used in [particularly preferred phenoxy (lower) alkyl], the hydroxy, in the form of a mixture with water.

The reaction according to the invention is preferably carried out in preferably 2 to 4 carbon atoms, and the alkyl radical is preferably in the presence of a condensing agent, e.g. one contains 1 to 4, in particular 1 to 2, carbon atoms; named Vilsmeier reagent, e.g. (Chloromethylene) dimet — a preferred example of R3 can be carboxy; hyl-ammonium chloride, which is used in the implementation of dimethyl

preferred examples of R4 may be acyloxymethylformamide formed with thionyl chloride or phosgene, a [preferably lower alkanoyloxymethyl (wherein the alkanoyl compound formed by reacting dimethylformamide with the balance preferably 1 to 4, especially 1 to 2, especially before 6s phosphorus oxychloride , and the like, or which contains 2 carbon atoms, such as acetyl) or carbam-like.

oyloxymethyl, which may have trihalo (lower) alkanoyl The reaction can also be in the presence of an inorganic (where the trihalo is preferably the trichloro and see or an organic base such as an alkali metal)

13

638 532

hydroxides, an alkali metal bicarbonate, an alkali metal carbonate, an alkali metal acetate, of tri (lower) alkyl amine, pyridine, N- (lower) alkyl morpholine, N, N-di- (lower rig) alkylbenzylamine, N, N-di- (lower) alkylaniline, as exemplified below, or the like. If the base or condensing agent is liquid, it can also be used as a solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.

It should be noted that in the reaction of the present invention, when the starting compound (III) is reacted with the compound (II) or a reactive derivative on the amino group or a salt thereof in the presence of, for example, phosphorus pentachloride, thionyl chloride and the like, only that corresponding anti-isomers to the compound (I) or a mixture of the corresponding anti-isomer and the syn isomer is given as the compound obtainable according to the invention, even if the compound (III), ie the syn isomer is used as the starting compound. Of course, when the corresponding anti-isomer is prepared from the starting compound (III) and the compound (II), the compound (I), i.e. the syn isomer can be formed. It is believed that this tendency and uniqueness of the above-mentioned reaction is due to the fact that the less stable syn isomer has a tendency to partially or completely increase in the course of the reaction, for example in a so-called activation step of the compound (III) the corresponding more stable anti-isomer to isomerize so that the isomerized compound, ie that anti-isomers corresponding to compound (I) can be formed.

For the selective preparation of compound (I), i.e. of the syn isomer, the starting compound (III), i.e. the syn isomer can be used and suitable reaction conditions must be selected. That is, compound (I), i.e. the syn isomer can be obtained selectively and in high yield if the reaction is carried out, for example, in the presence of a Vilsmeier reagent, as mentioned above and the like, and under approximately neutral conditions. Especially when the starting compound (III), i.e. such a compound is used in which R1 is a group of the formula n

H2N-ts can compound (I), i.e. the syn isomer can be obtained selectively and in high yield by carrying out the reaction of the corresponding starting compound (III), i.e. of the syn isomer, with the compound (II), for example in the presence of a Vilsmeier reagent which has been prepared by reacting dimethylformamide with phosphorus oxychloride, and is carried out under approximately neutral conditions. In this case it should be noted that particularly good results can be achieved by carrying out the reaction in the presence of more than two molar equivalents of phosphorus oxychloride, in each case based on the amount of the starting compound (III), i.e. of the syn isomer, and dimethylformamide, as described in the exemplary embodiments. In addition, good results can be achieved in this case if the starting compound (III), i.e. subjecting the syn isomer to activation in the presence of a silyl compound (e.g., bis (trimethylsilyl) acetamide, trimethylsilylacetamide and the like) and the like.

Regarding the reaction of the compound (II) with the compound (III), the following should be noted:

When the compound (II) in which R4 is a carbamoyloxy-methyl group with an acyl group is used as the starting compound, depending on the reaction conditions, the compound (I) in which R4 is a carbamoyloxy-5 methyl group with an acyl group or the free one may occasionally be used Carbamoyloxymethyl group can be obtained;

when the compound (II) in which R4 denotes the hydroxymethyl group is used as the starting compound,

can occasionally be obtained the compound (I) wherein R3 and R4 are linked to form -COOCH2-;

in addition, the protected carboxy group or the salts in the compound (II) can be converted into the free carboxy group in the course of the reaction or in an aftertreatment. These cases also fall within the scope of the present invention.

As can be seen from the explanation given above,

Process 1 represents a fundamental and the most advantageous process for the preparation of compound (I), i.e. of the Syn-Iso-20 meren.

Procedure 2

The compound (Ia) or a salt thereof is prepared by subjecting the compound (IV) or a salt thereof to an elimination reaction to remove the amino or imino protecting group. Examples of suitable salts of the compound (IV) are a metal salt, an ammonium salt, an organic amine salt and the like as mentioned above.

The elimination reaction according to the invention is carried out by a customary process, for example by hydrolysis, reduction, by a process by reacting the compound (IV) in which the protective group is an acyl group, with an imino halogenating agent and then 35 with an imino etherifying agent and, if necessary, the resulting is obtained Subjected to hydrolysis or the like.

Hydrolysis can be a process using an acid or a base or hydrazine and the like. These methods can be selected depending on the type of protecting groups to be eliminated. Among these methods, hydrolysis using an acid is one of the common and preferred methods for protecting group elimination, e.g. substituted or unsubstituted alkoxycarbonyl (such as t-pentyloxycarbonyl and the like), alkanoyl (such as formyl and the like), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (such as benzyloxycarbonyl, substituted benzyloxycarbonyl and the like), substituted phenylthio, substituted aralkyli-50 den , substituted alkylidene, substituted cycloalkylidene or the like. Examples of suitable acids are an organic or an inorganic acid, such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and a preferred acid is an acid which can be obtained in a conventional manner, for example by distillation under reduced pressure, can be easily removed from the reaction mixture, such as Formic acid, trifluoroacetic acid, hydrochloric acid and the like. The acid suitable for the reaction can be selected depending on the type of protective group to be elieo mined. If the elimination reaction is carried out with the acid, it can be carried out in the presence or in the absence of a solvent. Suitable solvents include an organic solvent, water, or a mixture thereof. 65 If trifluoroacetic acid is used, the elimination reaction can preferably be carried out in the presence of anisole.

The hydrolysis using hydrazine is used in the

638 532 14

Rule for eliminating a protecting group, such as Succinyl) or an acid (such as dilute hydrochloric acid, or phthaloyl. Hydrolysis with a base will become acetic acid and the like) may be added to the water, preferably for the elimination of an acyl group, e.g. The reaction temperature is not critical, and it can be

Halogenalkanoyl (such as trifluoroacetyl and the like) and - according to the type of protective group for the amino group and the same used. Suitable bases include e.g. a 5 the elimination method mentioned in a suitable inorganic base, such as an alkali metal hydroxide (such as sodium manner, and the inventive reagent, potassium hydroxide and the like), an alkaline earth ion is preferably used under mild conditions, for example tall hydroxide (such as magnesium hydroxide , Calcium hydroxide and wise under cooling, at ambient temperature or the like), an alkali metal carbonate (such as sodium carbonate, slightly elevated temperature).

Potassium carbonate and the like), an alkaline earth metal carbonate. The present invention also encompasses the cases (such as magnesium carbonate, calcium carbonate and the like) where the protected carboxy group is converted into the free carboxy-an alkali metal bicarbonate (such as sodium bicarbonate, potassium bi- group), in which case when the compound carbonate and the like), an alkali metal acetate (such as sodium (IV) wherein R4 is the carbamoyloxymethyl group with a umacetate, potassium acetate and the like), an alkaline earth metal acyl group is used as a starting compound, phosphate (such as magnesium phosphate, Calcium phosphate and this is, depending on the reaction conditions, occasionally the same as the invention), an alkali metal hydrogen phosphate (such as disodium compound (Ia), in which R4 is the carbamoyloxymethyl hydrogen phosphate, dipotassium hydrogen phosphate and the like group with an acyl group, or the free carbachine) , or the like, and an organic base, e.g. B. a moyloxymethyl group can be obtained; and those

Trialkylamine (such as trimethylamine, triethylamine and the like, in which when the compound (IV) wherein R4 is an acyl-chen), picoline, N-methylpyrrolidine, N-methylmorpholine, 20 oxymethyl group, 1,5-diazabicyclo is used as the starting compound [4,3,0] non-5-ene, 1,4-diazabicyclo [2,2,2] octane, depending on the reaction conditions, the invented 2,5-diazabicyclo [5,4,0] undecen-5 or the like. The compound (Ia) according to the invention can be obtained, in which R3

Hydrolysis using a base is often carried out in water and R4 are linked together to form or in a hydrophilic organic solvent or in -COOCH2-, during the course of the reaction or on a mixture thereof. 25 after-treatment.

Among the protecting groups, the acyl group can generally be obtained by hydrolysis as above or by Method 3

another conventional hydrolysis can be eliminated. The compound (Ib) or a salt thereof is produced

When the acyl group is halogen-substituted by acylation of the hydroxy group of the compound (V) or

Alkoxycarbonyl or 8-quinolyloxycarbonyl is 30 of a salt thereof. As a suitable salt of the compound (V)

these can be eliminated by treatment with a heavy metal such as copper, such as that exemplified by zinc or the like. The reductive elimi compound (IV) has been given.

Nation is generally used for the elimination of acylating agents for the inventive

Protecting group, e.g. Haloalkoxycarbonyl (such as trichloro reaction can include ali-ethoxycarbonyl and the like), substituted or unsubstituted, aromatic and heterocyclic carboxylic acid and tuned aralkoxycarbonyl (such as benzyloxycarbonyl, substituted- the corresponding sulfonic acid and thioic acid, which are acyl- tes benzyloxycarbonyl and the like), 2-pyridylmethoxycar- rests have the above acyl group, and the reac-bonyl and the like applied. A suitable reduction-capable derivative of the above acids. Too suitable e.g. be the reduction with an alkali metal borohydride reactive derivatives of the above acids (such as sodium borohydride and the like), and the like include an acid halide, an acid anhydride, an activated same. Amide, an activated ester and the like. Suitable subsidies

Suitable iminohalogenating agents used in one game are an acid chloride, an acid azide, a mixed acid process such as the one mentioned above, reanhydride with an acid such as substituted phosphoric acid include phosphorus trichloride, phosphorus pentachloride, phosphoric (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenyl tribromide, phosphorus pentabromide, phosphorus oxychloride, thio- 'phosphoric acid, dibenzylphosphoric acid, halogenated phosphonyl chloride, phosgene and the like. The reaction temperature (phosphoric acid and the like), dialkylphosphoric acid is not critical, and the reaction is usually carried out with sulphurous acid, thiosulphuric acid, Sulfuric acid, alkyl

Ambient temperature or under cooling. Carbonic acid, an aliphatic carboxylic acid (such as pivalin-suitable imino etherification agents, which are reacted with the resulting acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or the reaction product, can include 50 trichloroacetic acid and the like) or an aromatic alcohol, a metal alkylate ( Metal alkoxide) and the like carboxylic acid (such as benzoic acid and the like); a symmetrical one. Suitable alcohols may include an alkanol acid anhydride; an activated amide with imidazole, 4-sub- (such as methanol, ethanol, propanol, isopropanol, butanol, substituted imidazole, dimethylpyrazole, triazole or tetrazole;

t-butanol and the like), which may be substituted by or an activated ester (such as cyanomethyl ester, methoxymet alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy 55 hylester, dimethyliminomethyl (CH3) 2N + = CH -) - ester, vinyl -and the same). Suitable metal alkylates (metal alkoxy ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl-den) may include an alkali metal alkylate (such as sodium ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl alkylate, potassium alkylate and the like), an alkaline earth metal alphenyl ester, Phenylazophenyl esters, phenylthioesters,

kylate (such as calcium alkylate, barium alkylate and the like) and p-nitrophenylthioester, p-cresylthioester, carboxymethylthio-like. The reaction temperature is not critical, and 60 esters, pyranyl esters, pyridyl esters, piperidyl esters, 8-quinolylthio - the reaction is usually carried out with cooling or with esters] or an ester with N, N-dimethylhydroxylamine,

Ambient temperature. l-hydroxy-2- (lH) -pyridone, N-hydroxysuccinimide, N-hydro-

If necessary, the product obtained is subjected to xyphthalimide or 1-hydroxy-6-chloro-1H-benzotriazole and hydrolysis. The hydrolysis can easily resemble the same. These reactive derivatives can be carried out as desired by pouring the reaction obtained above into water, depending on the type of acylating agent to be used, but a hydrophilic one can be selected beforehand.

Solvents (such as methanol, ethanol and the like), suitable acylating agents may also include

Base (such as alkali metal bicarbonate, trialkylamine and the like an aliphatic, aromatic or heterocyclic isocyanate

15 638 532

or isothiocyanate (e.g. methyl isocyanate, phenyl isocyanate, lung in the context of the inventive reaction

Trichloroacetyl isocyanate, methyl isothiocyanate and the like) protected carboxy group for R3 is converted into the free carboxy group and a halogen formate (such as ethyl chloroformate, benzyl chloro; in which the protected amino group is in formate and the like). In this case, for example, the free amino group is converted; where when the trichloroacetyl isocyanate protected as the acylating agent 5 is used to convert the imino group protected to the free imino group, the trichloroacetylcarbamoyl group is used as the acyl group; where the acyloxy group is introduced into the hydroxy group and this group can be converted by treatment; and / or in which the carbamoyloxymet is converted into the carbamoyl group with a base, hylgruppe with an acyl group is converted into the free carbamoyloxymet and if ethyl chloroformate is used as the acylating agent.

, the ethoxycarbonyl group can be introduced as the acyl group. Procedure 5

The reaction according to the invention is prepared under similar methods. The compound (Id) or a salt thereof is prepared

Reaction conditions as for the above-mentioned reaction by using the compound (Vb) or a salt thereof, an elution of the compound (II) with the compound (III), are carried out, and it is preferably carried out in The present is subject. Suitable salts for the compound (Vb) are e.g. a base. When the compound is reacted the same as that exemplified above for the compound (IV) (V) with an acylating agent, the protected carbo- can be given.

xygruppe or the salts in the compound (V) in the course of the in the inventive elimination reaction it can

Implementation or during an aftertreatment into the free are an elimination process that is carried out to convert carboxy group; 20 is made using a base such as e.g. an inorganic

when the compound (V) in which R4 is the carbamoyloxymet base, such as an alkali metal hydroxide (e.g. sodium ethyl group with an acyl group, as the starting compound hydroxide, potassium hydroxide and the like) of an alkali metal compound, can be used depending on the reaction conditions tall bicarbonate (such as sodium bicarbonate, potassium bicarbonate in the course of the reaction or in the after-treatment and the like) or an alkali metal carbonate (such as sodium occasionally the compound (Ib) wherein R4 is the carbamoyloxy-25-carbonate, potassium carbonate and the like) having an organomethyl group. means an acyl group, or see the free base, such as an alkali metal alkylate (alkoxide) (such as carbamoyloxymethyl group. These cases are sodium methylate, sodium ethylate and the like), one gene also within the scope of the present invention. Trialkylamines (such as timethylamine, triethylamine and the like), of triethanolamine, N, N-dimethylaniline,

Method 4 30 N, N-dimethylbenzylamine, N-methylmorpholine or pyridine,

The compound (Ic) or a salt thereof is prepared or an elimination reaction by using the compound (Va) or a salt thereof of an elite of basic alumina, a basic ion exchange reaction to remove the carboxy protecting group shear resin, one Acid (such as trifluoroacetic acid, trifluoroacetic acid-subjects. Examples of suitable salts of the compound (Va) acid, anisole and the like) is carried out. The inventions are the same as those given above for the compound (IV). The elimination reaction according to the invention is generally given in Was-haft. water, in a hydrophilic solvent or in a

The elimination reaction according to the invention is carried out after a mixture thereof. The reaction temperature is not critical in a conventional method, for example by hydro, and the reaction is preferably carried out by lysis or the like. During hydrolysis it can be carried out at ambient temperature or under cooling.

is a method using 40 The present invention also includes the cases where acid or base and the like are carried out. those during the course of the reaction or during follow-up

These methods can be selected depending on the nature of the protected carboxy group or salts in the eliminating protecting groups. bond (Vb) can be converted to the free carboxy group. Hydrolysis using an acid is one of the can, and the cases where the protected amino and / or most common and most preferred methods for the 45 or imino group are each in the free amino and / or imino elimination of protective groups, such as Phenyl (low) group is (are) converted.

alkyl, substituted phenyl (lower) alkyl, lower alkyl, substituted lower alkyl or the like. Appropriate acids Procedure 6

may include inorganic or organic acids, e.g. The compound (If) or a salt thereof is prepared from formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluene-50 by treating the compound (Ve) or a salt thereof from sulfonic acid, hydrochloric acid and the like. It creates an acid. Suitable salts for the compound (processing) according to the invention may include in the presence of anisole e.g. those as listed above for compound (IV). The acid suitable for the reaction can be given in examples.

Dependence on the protective group to be eliminated and in acids which are suitable for use in the reaction according to the invention.

Dependence on other factors can be selected. The 55 tion that can be used include inorganic hydrolysis using an acid can in the presence of acid (such as hydrochloric acid, hydrobromic acid,

a solvent such as e.g. an organic solvent, sulfuric acid and the like) or an organic acid, in the presence of water or a mixture thereof (such as formic acid, acetic acid and the like).

be performed. The reaction according to the invention is generally described in

The reaction temperature is not critical and can be carried out in a solvent such as water, acetone, acetic acid or, depending on the nature of the protective agent, or any other solvent which does not adversely affect the reaction group and the elimination process used . These can be selected and the reaction according to the invention is pre-solvents. The hydrophilic solvents can preferably be used under mild conditions, for example in the form of a mixture with water.

Cooling, at ambient temperature or inadequate 65 The reaction temperature is not critical, and the conversion heating is carried out. tongue is preferably under cooling to heating

The present invention also includes the cases when performed.

those during the implementation or during the aftertreatment. The processes for producing the

638 532 16

Starting compound (III), i.e. of the syn isomer and the antigen) or in a mixture thereof or in any other isomer thereof, which are used as reference examples, their solvent which does not deleteriously explain the reaction. flows, performed.

The reaction is carried out in the event that the compound (XIV)

A) Process (VI) + (VII) - (VIII) [Reaction scheme (1) (i)] 5 is used in the form of its salt, preferably in counter-The compound (VIII) can be prepared by a base, e.g. an inorganic base, e.g. one

Reaction of the compound (VI) with the compound (VII). Alkali metal (such as sodium, potassium and the like), one

The reaction is usually carried out in a solvent such as alkaline earth metal (such as magnesium, calcium and the like), water, ethanol, acetone, ether, dimethylformamide or in a hydroxide or carbonate or bicarbonate thereof or any other solvent which the reaction io the like and in the presence of an organic base, such as not adversely affected. The reaction is carried out by an alkali metal alkylate (such as sodium methylate, sodium preferably in the presence of a base such as an inorganic ethylate and the like), a trialkylamine (such as trimethyl base or an organic base as mentioned above, amine, triethylamine and the like) , performed by N, N-dialkylamine. The reaction temperature is not critical and (such as N, N-dimethylaniline and the like, N, N-dialkylbenzyl) the reaction is usually carried out with cooling to under-15 amine (such as N, N-dimethylbenzylamine and the like), pyridine to the boiling point of the solvent, or the like.

B) Process (IX) - (X) [Reaction Scheme (1) (ii) J and The reaction temperature is not critical, and the reaction

(XXXII) - (XXXIII) [Reaction scheme (6) (ii)] is usually carried out with cooling to under heating-The compounds (X) and (XXXIII) can be passed through oxy-.

dation of the compounds (IX) or (XXXII) 20 In the reaction, a mixture of the syn- and the. The oxidation reaction is carried out using a conventional anti-isomer of the compound (IIIa), (XXXV) or (IIIf) which is used for the conversions, depending on the reaction conditions used, so-called activated methylene group in a Car and the like, and in such a case both iso-bonyl group can be used. That is, the reaction will be separated from the mixture in a conventional manner using a conventional method, for example. For example, the mixture is first referenced by oxidation using a conventional ester and the esters obtained are broken down, in the case of oxidizing agents such as selenium dioxide, potassium permanganate, for example by chromatography in each isomer. Any or the like. The oxidation is in the isomer obtained, the ester is after a conventional

Usually carried out in a solvent which hydrolyzes the reactive processes, whereby the corresponding ion is not adversely affected, e.g. in water, dioxane, pyri- 30 syn or anti-carboxylic acid.

din, tetrahydrofuran and the like. The reaction temperature for the selective production of the syn isomer of the

The structure is not critical and the reaction is preferably carried out with high yield (IIIa), (XXXV) or (IIIf) with heating. The reaction is preferably carried out under approximately neutral conditions.

C) Process (XI) - (XII) [Reaction scheme (1) (iii)] 35

Compound (XII) can be prepared by E) Process (XV) - * (XVI) [Reaction Scheme (2) (i)] and Compound (XI) an Elimination Reaction to Remove (XXXIV) - (XXXVI) [ Reaction scheme (6) (ii)]

Ar (lower) alkyl group. The compounds (XVI) and (XXXVI) can be produced

The elimination process includes all conventional ones by reacting the compounds (XV) and processes used for the elimination of the Ar (lower) alkyl group 40 (XXXIV) each with hydroxylamine or a salt thereof, e.g. the hydrolysis, the reduction and the - Suitable salts for hydroxylamine are for example the same. some as exemplified above for compound (XIV)

Hydrolysis using an acid is one that has been reported.

most preferred methods and acids that can be used. The reaction conditions of the reaction may also include an inorganic acid (such as 45 if the same as that for methods (XIII) + hydrochloric acid, hydrobromic acid and the like ( XIV) - Illa), (XXX) + (XIV) - ■ (XXXV) and (XXXIV) +

chen), an organic acid (such as formic acid, acetic acid, (XIV) - (IIIf) exemplified in the above (d) -trifluoroacetic acid and the like), and a mixture thereof. have been used.

The reaction can be carried out in a solvent such as water, in an organic solvent or in a mixture 50 F) Process (XVII) - (XVIII) [reaction scheme (2) (ii)], thereof or without solvent. The (XXIV) - (XXV) [Reaction scheme (4) (ii)], (XXVI) - * •

Reaction temperature is not critical, and the reaction (XXVII) [Reaction Scheme (5)] and (XXXVII) - (XXXVIII) is preferably carried out with heating to heating- [Reaction Scheme (6) (iii)]

guided. The compounds (XVIII), (XXV), (XXVII) and

55 (XXXVIII) can be prepared by alkylation of the

D) Process (XIII) + (XIV) - (IIIa) [Reaction scheme (1) Compounds (XVII), (XXIV), (XXVI) and (XXXVII).

(iv)], (XXXIII) + (XIV) - (XXXV) [Reaction Scheme (6) (ii)] Examples of alkylating agents which are used in the alkylation

and (XXXIV) + (XIV) - »(IIIf) [Reaction scheme (6) (ii)] action can be used are di (lower) alkyl sulfate

The compounds (IIIa), (XXXV) and (IIIf) can be prepared (such as dimethyl sulfate, diethyl sulfate and the like),

are prepared by reacting the compounds (XIII), 60 diazo (lower) alkane (such as diazomethane, diazoethane and the

(XXXIII) and (XXXIV) each with the compound (XIV) or the like), a lower alkyl halide (such as methyl iodide, ethyl-a salt thereof. To suitable salts for the compound iodide and the like), a lower alkyl sulfonate (such as methyl-p- ( XIV) include an inorganic acid salt (such as a toluenesulfonate and the like) and the like.

Hydrochloride, hydrobromide, sulfate, and the like) or a The reaction carried out using a di (lower organic acid salt (such as an acetate, p-toluenesulfonate 65 rig) alkyl sulfate, a lower alkyl halide or a never and the like) and the like. drigalkyl sulfonate is usually carried out in

The reaction is usually carried out in a solvent such as a solvent such as water, acetone, ethanol, ether, water, an alcohol (such as methanol, ethanol and the like, dimethylformamide or in any other solvent).

17th

638 532

tel, which does not adversely affect the reaction.

The reaction is preferably carried out in the presence of a base, e.g. an inorganic base or an organic base as mentioned above. The reaction temperature is not critical and the reaction is usually carried out with cooling to heating to about the boiling point of the solvent.

The reaction, which is carried out using diazoalkane, is usually carried out in a solvent such as ether, tetrahydrofuran or the like. The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.

G) Process (XVIII) - (Illb) [Reaction Scheme (2) (ii)] and (XXXVIII) - Illg) [Reaction Scheme (6) (iii)]

Compounds (IIIb) and (IIIg) can be prepared by subjecting compounds (XVIII) and (XXXVIII) to hydrolysis.

The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases can include an inorganic base and an organic base, e.g. an alkali metal (such as sodium, potassium and the like), an alkaline earth metal (such as magnesium, calcium and the like), the hydroxide or carbonate or bicarbonate thereof, a trialkylamine (such as trimethylamine, triethylamine and the like), picoline, 1,5-diazabicyclo [4 , 3,0] non-5-ene, 1,4-diazabicyclo [2,2,2] octane, 1,5-diazabicyclo [5,4,0] undecene-5 or the like.

Suitable acids may include an organic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like) and an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like).

The reaction is usually carried out in a solvent such as water, an alcohol (such as methanol, ethanol and the like), a mixture thereof or in any other solvent which does not adversely affect the reaction. A liquid base or a liquid acid can also be used as the solvent.

The reaction temperature is not critical, and the reaction is usually carried out with cooling to heating.

H) Process (XIX) - (IIIC) [Reaction Scheme (3)]

Compound (IIIC) can be prepared by subjecting compound (XIX) to acylation. Examples of acylating agents that can be used for the reaction and the reaction conditions that can be used in the reaction are e.g. those as exemplified above for Method 3.

I) Process (XX) - (XXXI) [Reaction Scheme (4) (i)]

Compound (XXI) can be prepared by subjecting compound (XX) to nitrosation.

Examples of nitrosating agents that can be used in the reaction are conventional agents that give C-nitroso compounds when reacted with an activated methylene group, e.g. Nitrous acid, an alkali metal nitrite (such as sodium nitrite and the like), a lower alkyl nitrite (such as isopentyl nitrite, t-butyl nitrite and the like) or the like.

When a nitrous acid salt is used as the nitrosating agent, the reaction is usually carried out in the presence of an acid, e.g. an inorganic acid or an organic acid (such as hydrochloric acid, acetic acid and the like). If an ester of nitrous acid is used, the reaction is preferably carried out in the presence of a strong base, e.g. an alkali metal alkylate or the like.

The reaction is usually carried out in a solvent such as water, acetic acid, benzene, an alcohol (such as ethanol, methanol and the like) or in any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.

10th

J) Process (XXI) + (XXII) - (XXIII) [Reaction Scheme (4) (i)] and (XXVIII) + (XXII) - (XXIX) [Reaction Scheme (5)]

The compounds (XXIII) and (XXIX) can be prepared by reacting the compounds (XXI) and 15 (XXVIII) with the compound (XXII), respectively.

The reaction is usually carried out in a solvent such as water, in an alcohol (such as methanol, ethanol and the like), in benzene, dimethylacetamide, dimethylformamide, tetrahydrofuran, a mixture thereof or in any other solvent which does not adversely affect the reaction , carried out. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature with heating to about the boiling point of the solvent.

25 To selectively prepare the syn isomer of compound (XXIII) or (XXIX) in high yield, the syn isomer of the starting compound (XXI) or (XXVIII) must be used, and the reaction is preferably carried out under about neutral conditions in the presence of a base , as mentioned above, 30. Preferred examples of usable bases are a weak base such as an alkali metal acetate (e.g. sodium acetate, potassium acetate and the like), an alkali metal bicarbonate (such as sodium bicarbonate, potassium bicarbonate and the like), an alkali metal carbonate (such as sodium carbonate, 35 potassium carbonate and the like) or the like.

K) Process (XXIII) - (XXIIIj [Reaction Scheme (4) (i)], (XXV) - (nid) [Reaction Scheme (4) (ii)], (XXIX) - (IIIe) [Reaction Scheme (5)], (XXXIII) - (XXXIV) [Reaction Scheme (6) (ii)] and (XXXV) - (IIIf) [Reaction Scheme (6) (ii)] Compounds (XXIIIa), (IIId), (IIIe), (XXXIV) and (IIIf) can be prepared by subjecting Compounds (XXIII), (XXV), (XXIX), (XXXIII) and (XXXV) to an elimination reaction to remove the carboxy-protecting group.

In the elimination reaction, conventional methods such as those used for the elimination of the protecting group, such as hydrolysis and the like, can be used. If the protective group is an ester, it can be eliminated by hydrolysis. The hydrolysis is carried out in a similar manner to processes (XVIII) - (IIIb) and (XXXVIII) - (IIIg) as described in section (G) above.

55 L) Process (XXVII) - (XXVIII) [Reaction Scheme (5)]

The compound (XXVIII) can be prepared by halogenating the compound (XXVII).

Examples of halogenating agents which can be used in the reaction are a conventional halogenating agent such as is used in the halogenation of the so-called activated methylene group, e.g. Halogen (such as bromine, chlorine and the like), sulfuryl halide (such as sulfuryl chloride and the like), hypohalite (such as hypochlorous acid, sub-bromine acid, sodium hypochlorite and the like), 65 N-halogenated imide (such as N-bromosuccinimide, N-bromophthalic -mid, N-chlorosuccinimide and the like) and the like.

The reaction is usually carried out in a solvent such as e.g. in an organic solvent (such as formic acid,

638 532 18

Acetic acid, propionic acid and the like), in carbon tetrachloride - if the compound (I) is in the form of the free acid in the fuel or in any other solvent which is obtained in the 4-position and / or if the compound (I) does not adversely affect the reaction influenced, performed. Having a free amino group, it can be after a konven reaction temperature is not critical, and the conversion process to its pharmaceutically acceptable salt, will usually be converted under cooling, at ambient temperature, 5 as indicated above.

with heating or with heating. Compound (I) and its pharmaceutically acceptable

Salts are all new compounds which have a high anti-M) process (XXX) - [reaction scheme (6) (i)] and (XXXIX) bacterial activity, the growth of a large - (IIIh) [reaction scheme (7)] Includes number of pathogenic microorganisms

The compound (XXXI) can be prepared by inhibiting gram-positive and gram-negative bacteria, and reacting the compound (XXX) or a reactive one is useful as an antibacterial agent. In particular, a derivative thereof on the amino group or a salt thereof is pointed out that the compound (I), i.e. the syn isomer, much with an amino protective agent, and the compound (IIIh) can have higher antibacterial activities than that correspondingly produced by converting the compound (XXXIX) corresponding anti isomer to the compound (I) and, accordingly, or a reactive derivative of which at the amino- 15 is the compound (I), ie the syn isomer, thereby group or a salt thereof with an amino protective agent. characterized that they in the corresponding anti-isomer in

Examples of suitable reactive derivatives in which their therapeutic value is far superior.

Amino group of the compound (XXX) or (XXXIX) and suitable. In order to demonstrate the usefulness of the compound (I) by means of some nete salts of the compound (XXX) or (XXXIX), the representative representatives will be as follows in the explanations of the reactive test results relating to the antibacterial activity in gene derivative on the amino group of the compound (II) or in vitro and the test results in vivo, ie the protective action of salt of the compound (II) has been given by way of example, against experimental infections, and the acute toxicity. Suitable amino protective agents include an acylation agent. In addition, some mediators, such as an aliphatic, aromatic and heterocyclic identical test data of the antibacterial activities in vitro for see carboxylic acid and the corresponding sulfonic acid, a 25 the corresponding anti-isomer of the compound (I) for ver-halogenoformic acid ester, an isocyanic acid ester and the carb- the same.

amic acid and the corresponding thioic acid thereof and the reactive derivatives of the above acids. Tested connections

Suitable reactive derivatives of the above- (1) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3-benic acids may include the same as those described above for the 30 carbamoyloxymethyl-3-cephem-4 -carboxylic acid (syn isomer) Explanation of method 3 has been given by way of example (2) 7- [2-methoxyimino-2- (3-hydroxyhenyl) acetamido] -3- (l-

are. An example of the protective group (e.g. the acyl group), methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid which is in the amino group in the compound (XXX) or (Syn-Isomeres)

(XXXIX) by the amino protection agent given above (e.g. (3) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3- (l-

the acylating agent) is to be introduced, the same 35 methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid protective group (e.g. acyl group) as described in the explanation (anti-isomer)

tion of the protective group residue (e.g. the acyl residue) in which Aus (4) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3-pressure "Acylamino" has been specified. (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn

The amino protection reaction is carried out in a similar manner to that of isomeres)

the reaction of compound (II) with compound (III) 40 (β) 7- [2-methoxyimino-2- (3-acetoxyphenyl) acetamido] -3- (Method 1) was carried out. (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn

Isomeres)

N) Method (XXIIIb) ^ (XXXIII) [Reaction Scheme (6) (ii)] (6) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acet-

The compound (XXXIII) can be prepared by amido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 hydrolysis of the compound (XXIIIb). 45 carboxylic acid (Syn-Isomeres)

The hydrolysis is carried out in the presence of an alkali metal bisul- (7) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acet-

fits (such as sodium bisulfite and the like) of titanium trichloride, amido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-an inorganic or organic acid such as a halocarboxylic acid (anti -Isomeres)

hydrochloric acid (e.g. hydrochloric acid, hydrobromic (8) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acet-

acid and the like), formic acid, nitrous acid 50 amidoj-eephalosporanic acid (Syn-isomeres)

or the like. A hydrohalic acid (9) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acet-

is preferably used in combination with an aldehyde (such as amidoj-eephalosporanic acid (anti-isomer)

Formaldehyde and the like) applied. (10) 7- [2-methoxyimino-2- (2-formamido-l, 3-thiazole-4-

The reaction is usually carried out in a solvent such as yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-water, an aqueous alcohol (for example in aqueous methanol, 55 carboxylic acid (Syn-Isomeres)

aqueous ethanol and the like), in water / acetic acid (11) 7- [2-methoxyimino-2- (2-formamido-l, 3-thiazole-4-

or in any other solvent which does not adversely affect the reactyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-ion. The reaction carboxylic acid (anti-isomer)

temperature is not critical and the reaction is carried out in the (12) 7- [2-methoxyimino-2- (2-formamido-l, 3-thiazole-4-

Usually at ambient temperature, with heating or under 6o yl) acetamido] cephalosporanic acid (Syn-Isomeres)

Heating done. (13) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acet-

In the reaction, the protected carboxy group gelamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (can be converted into the free carboxy group.

This case is also within the scope of the present invention. (14) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acet-In the above-mentioned reactions and / or in the after- 6.5 amido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carbon, the above-mentioned tautomeric isomeric acid (Syn-Isomeres)

occasionally converted into the other tautomeric isomers (15) 7- [2-methoxyimino-2- (2-amino-1,3,3-thiazol-4-yl) acet. amido] -3-hydroymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

19th

638 532

(16) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (5-methyl-l, 3,4-thiadiazol-2-yl ) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

(17) 7- [2-Methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (4-methyl-4H-l, 2,4-triazol-3 -yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

(18) 7- [2-methoxyimino-2- [2- (2,2,2-trifluoroacetamido) -l, 3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-car- bonic acid (Syn-Isomeres)

1. Antibacterial activity in vitro

Test method: The antibacterial activity in vitro was determined according to the double agar plate dilution method described below.

5 A platinum loop from an overnight culture of each test strain in a trypticase soy broth (108 viable cells per ml) was spread on cardiac infusion agar (HI agar) containing graded concentrations of antibiotics and the minimum inhibitory concentration (MIC) , expressed in 10 lig / ml, was determined after incubation at 37 ° C. for 20 hours

Test results

Test bacteria MIC (| ig / ml)

Test connections

(i) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17 ) (18)

Escherichia 1.56 1.56 50 3.13 12.5 0.20 12.5 0.10 3.13 0.78 12.5 1.56 1.56 0.10 0.78 0.39 0.20 3.13 coli NIHJ JC-2

Klebsiella 0.39 0.39 6.25 0.78 0.78 0.10 6.25 0.10 1.56 1.56 3.13 1.56 0.05 0.20 0.05 0.10 0.20 0.05

pneumoniae

417

Proteus 0.78 0.78 25 0.78 1.56 0.10 3.13 0.05 0.78 0.39 "3.13 0.78 0.025 0.10 0.10 0.39 0.39 0.025 mirabilis 525

As is clear from the test results given above, the compounds (I), i.e. the syn isomers, have a much higher antibacterial activity than their corresponding anti isomers.

2. Protection against experimental infections in mice

Test Procedure: 4 week old ICR strain male mice each weighing 20-23 g were used in groups of 8 mice. The test bacteria were

cultivated overnight at 37 ° C. on a HI agar and then suspended in a 2.5 to 5% strength mucin solution, the suspension corresponding to the respective vaccine cells being obtained 3o. The mice were inoculated intraperitoneally with 0.5 ml of the suspension. A solution containing each test compound was administered subcutaneously in various doses to the mice 1 hour after vaccination. The ED 50 values were calculated from the number of surviving mice at each 35 dose after 1 week of observation.

Test results

Protective effect against experimental infections in mice

Test bacteria

Vaccination

MIC of the strain used (| xg / ml)

EDso (S.C.) (mg / mouse)

cells /

viable

Test connections

Test connections

mouse

Cells / ml

(8) (14) (5)

(4)

CET *

(8) (14) (5)

(4)

CET

Escherichia

6x 106

108

0.2 ^ 0.03 0.78

0.78

12.5

coli 29

106

5 = 0.03 5 = 0.03 0.39

0.78

3.13

<0.005 <0.005 0.081

0.111

1,402

CET: 7- (2-thienyl) acetamidocephalosporanic acid

Test bacteria vaccination MIC of the strain used (µg / ml) EDso (S.C.) (mg / mouse)

cells / viable test compounds test compounds

Mouse cells / ml (13) (12) cefuroxime (13) (12) cefuroxime

Serratia mar- l.OxlO6 108 2 5 200 400

cesens 4 106; ä 0.025 6.25 50 <0.156 0.018 4,329

* Cefuroxime: 7- [2-methoxyimino-2- (2-furyl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

Test bacteria inoculation MIC of the strain used (µg / ml) EDso (S.C.) (mg / mouse) cells / viable test compounds Test compounds mouse cells / ml (6) Cefuroxime (6) Cefuroxime

Escherichia 3.5 xlO4 108 coli 100 106

1.56 May 12

0.2 12.5 0.023 1,158

638 532

20th

Test bacteria

Vaccine cells / mouse

MIC of the strain used (jig / ml) EDso (S.C.) (mg / mouse) viable test compounds test compounds cells / ml (2) (1) CEZ Na * (2) (1) CEZ Na

Escherichia coli 29

5.5 x 105

108 106

0.78 0.39 3.13

^ 0.1 0.2 - 0.78 0.386 0.079 0.182

* CEZ Na: sodium 7- [2- (l H-tetrazol-1-yl) acetamido] -3- (5-methyl-l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 carboxylate

3.) Acute toxicity in mice

The same strain of mice was used as in the above protection test against experimental infections in groups of 10 mice. 2 g of the test compound (8) was administered intravenously to the mice. After weeks of observation, all mice survived without showing any disturbance.

For therapeutic administration, compound (I) is preferably used in the form of a conventional pharmaceutical preparation which contains this compound as an active ingredient, optionally in admixture with pharmaceutically acceptable carriers, such as e.g. an organic or inorganic solid, or with a liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations can be in solid form, for example in the form of capsules, tablets, dragées, ointments or suppositories, or in liquid form, for example in the form of solutions, suspensions or emulsions. If necessary, auxiliary substances, stabilizers, wetting agents or emulsifying agents, buffers and other commonly used additives can also be incorporated into the preparations mentioned above.

The dosage of the compounds may vary and also depend on the age, the condition of the patient, the type of disease, the type of compound (I) administered and the like, an average single dose of approximately 50 mg, approximately 100 mg, approximately 250 mg and about 500 mg of the compound (I) according to the invention has proven to be effective for the treatment of diseases caused by pathogenic bacteria. In general, amounts between about 1 mg and about 1000 mg or even larger amounts can be administered to a patient.

The invention is illustrated by the following examples.

example 1

A mixture of 2.81 g of dimethylformamide and 5.36 g of phosphorus oxychloride was heated to 40 ° C for 1 hour. After cooling, 60 ml of methylene chloride were added and distilled off. 50 ml of dry ethyl acetate were added to the residue. Then 6.83 g of 2-methoxy-imino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres) were added at 5 ° C. with stirring and with ice cooling. The resulting mixture was then stirred at the same temperature for 50 minutes. On the other hand, 11.5 g of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and 28.4 g of bis (trimethylsilyl) acetamide were dissolved in 150 ml of tricky ethyl acetate and stirred with ice cooling, then the solution obtained above was added all at once at -40 ° C. After stirring at -30 to -20 ° C for 2 hours, 100 ml of a saturated sodium chloride aqueous solution was added to the reaction mixture at -20 ° C. The mixture was stirred for 5 minutes. The precipitates were filtered off and the ethyl acetate layer in the filtrate was separated. The aqueous layer was extracted twice with 50 ml of ethyl acetate. The ethyl acetate layer was separated from the filtrate and the extracts were combined. The combined ethyl acetate solution was washed with 50 ml of a saturated 15 aqueous sodium chloride solution. Activated carbon was added to the ethyl acetate layer and the mixture was stirred for 5 minutes and filtered. 100 ml of water were added to the filtrate and the resulting mixture was adjusted to pH 7 with an aqueous sodium carbonate solution 20. The aqueous layer was separated and washed with methylene chloride. After the aqueous layer was separated, the methylene chloride was removed from the aqueous layer by passing nitrogen gas under ice cooling. After filtering, the aqueous layer was adjusted to pH 2 with 10% hydrochloric acid with stirring and with ice cooling. The precipitated crystals were collected by filtration, washed with water and dried, 11.3 g of 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1 H-tetrazole- 5-30 yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) was obtained.

IR spectrum (Nujol): 3250.1770, 1725, 1670 cm "1.

NMR spectrum (de-DMSO, 5): ppm9.76 (lH, d, J = 8Hz), 6.7-7.40 (4H, m), 5.86 (1H, dd, J = 5.8Hz), 5.18 (1H, d, J = 5Hz), 4.34 (2H, ABq, J = 13Hz), 3.92 (6H, s), 3.72 (2H, ABq, J = 17Hz).

35

Example 2

A mixture of 1.41 g of dimethylformamide and 2.95 g of phosphorus oxychloride was heated to 40 ° C for 1 hour. After cooling, 30 ml of methylene chloride were added and distilled off. 20 ml of dry ethyl acetate were added to the residue. 3.4 g of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres) were added with stirring and with ice cooling. and the mixture was stirred under ice-cooling for 30 minutes, on the other hand, 4.8 g of 45 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid was dissolved in a solution of 27.5 g of trimethylsilylacetamide in 70 ml of dry ethyl acetate. To the solution was added the solution obtained above at -30 ° C at a time, and the mixture was stirred at -30 to -10 ° C for 1.5 hours. To the reaction mixture became a saturated sodium chloride aqueous solution at -20 ° C The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate, two layers of ethyl acetate were combined, washed with an aqueous sodium chloride solution 55, and treated with activated carbon after filtering 100 ml of water was added to the filtrate, and the mixture was adjusted to pH 7 with an aqueous sodium bicarbonate solution. The aqueous layer was separated and ethyl acetate was added. The mixture was adjusted to pH 5 with 60 10% hydrochloric acid and the aqueous layer was separated. Ethyl acetate was added and the mixture was adjusted to pH 2 with 10% hydrochloric acid. The ethyl acetate layer was separated and the aqueous layer was further extracted with ethyl acetate 65. The two ethyl acetate layers were combined, washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was treated with diisopropane.

21st

638 532

Pyl ether powdered. The powder was collected by filtration and dried to obtain 3.26 g of 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres).

IR spectrum (Nujol): 3500-3200.1765, 1720.1655 cm "1 s

N.M.R. spectrum (d6-DMSO, 5); ppm 9.64 (1H, d, J = 8Hz), 6.70-7.20 (4H, m), 6.78 (2H, s), 5.92 (1H, dd, J = 5Hz), 5.16 (1H, d) = 5 Hz, 4.73 (2H, ABq, J = 13Hz), 3.91 (3H, s), 3.72 (2H, ABq, J = 17Hz).

1.98 g of 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3-10 carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer) were suspended in 15 ml of water and by adding 0. 35 g of sodium bicarbonate dissolved with stirring at ambient temperature. The solution was lyophilized and dried,

to obtain 1.9 g of sodium 7- [2-methoxyimino-2- (3-hydroxyphe-15 nyl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylate (Syn-Isomeres).

IR spectrum (Nujol): 3300.1765.1715.1665 cm "1

N.M.R. spectrum (D20.8); ppm 6.83-7.60 (4H, m), 5.85 (1H, d, J = 5Hz), 5.17 (1H, d, J = 5Hz), 4.77 (2H, ABq, J = 13Hz), 20 4.03 (3H, s) , 3.48 (2H, ABq, J = 18Hz).

Example 3

A mixture of 0.18 g dry dimethylformamide and 0.38 g phosphorus oxychloride was stirred at 25 40 ° C for 30 minutes. 15 ml of dry methylene chloride were added and distilled off under reduced pressure. 15 ml of dry ethyl acetate were added to the residue and 0.53 g of 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetic acid (Syn-Isomeres) were added with stirring at -20 ° C. The mixture was stirred below -10 ° C for 1 hour. On the other hand, a mixture of 1 g of 7-amino-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid, 5 g of trimethylsilylacetamide and 25 ml of dry ethyl acetate was stirred at ambient temperature for 1 hour. To this solution, the solution obtained above was added dropwise with stirring below -10 ° C, and the resulting mixture was stirred at the same temperature for 2 hours. 50 ml of water and 50 ml of ethyl acetate were added to the reaction mixture at -20 ° C. and the mixture was shaken. 40 The organic layer containing 7- [2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) aceta-mido] -3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) was removed by adding 50 ml of water and sodium bicarbonate were adjusted to pH 7.0 and the mixture was stirred at 45 ambient temperature for 2 hours. 50 ml of ethyl acetate was added to the aqueous layer and the mixture was adjusted to pH 5.0 with 10% hydrochloric acid. The aqueous layer was separated, adjusted to pH 2.0 with 10% hydrochloric acid and extracted with 50 ml of ethyl acetate. The extract was washed with ice water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was washed thoroughly with ether, collected by filtration and dried, giving 0.3 g of 7- [2-methoxyimino-2- (3-chloro-4-55 hydroxyphenyl) acetamido] -3-carbamoyloxymethyl-3-cephem -4-carboxylic acid (Syn-Isomeres) was obtained.

IR spectrum (Nujol): 3450.3300, 1770, 1730, 1715, 1660, 1650, 1600 cm-1

N.M.R. spectrum (de-DMSO, 8); ppm 9.72 (1H, d, J = 8Hz), eo 7.48 (1H, d, J = 2Hz), 7.40 (1H, dd, J = 2.8Hz), 6.98 (1H, d, J = 8Hz), 6.60 ( 2H, s), 5.70 (1H, q, J = 5Hz), 5.20 (1H, d, J = 5Hz), 4.74 (2H, ABq, J = 13Hz), 3.90 (3H, s), 3.50 (2H, ABq , J = 18Hz).

Example 4

1.1 g of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres) and 2.35 g of 7-amino-3-trichloroacetylcarbamoyloxy-methyl-3-cephem-4-carboxylic acid were reacted with one another.

65

and aftertreated in a similar manner as in Example 3, 0.5 g of 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido ido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid ( Syn-Isomeres). This compound was identified with the compound obtained in Example 3 by its IR and NMR spectra.

Example 5

a) 1 g of 2-t-butoxycarbonylmethoxyimino-2- (3-chloro-4-hydro-xyphenyl) acetic acid (Syn-Isomeres) and 1 g of 7-amino-3- (1-methyl-1 H-tetrazole-5 -yl) thiomethyl-3-cephem-4-carboxylic acid were reacted with one another in a similar manner as in Examples 1 and 2, 1.5 g of 7- [2-t-butoxycarbonylmethoxyimino-2- (3-chloro- 4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained in the form of a powder.

b) 1.5 g of the powder obtained in Example 5 (a) was added to a mixture of 1.5 ml of anisole and 6 ml of trifluoroacetic acid and the resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was adjusted to pH 8 by adding 50 ml of an aqueous sodium bicarbonate solution, 50 ml of ethyl acetate and sodium bicarbonate with ice cooling. The aqueous layer was separated, adjusted to pH 5.0 with 10% hydrochloric acid and washed with 50 ml of ethyl acetate. The aqueous layer was further adjusted to pH 2.0 with 10% hydrochloric acid and extracted with 100 ml of ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was dissolved in a pH 5.0 acetate buffer and on Woelm neutral alumina (trademark of a product of ICN Company) using a pH 5.0 acetate buffer as a developing solvent of a column chromatography subject. The eluate was adjusted to pH 2.0 with 10% hydrochloric acid with ice cooling. The precipitating materials were collected by filtration, washed with water and dried, giving 0.5 g of 7- [2-carboxymethoxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido] -3- (l-methyl -lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), mp 145 to 148 ° C (dec.).

IR spectrum (Nujol): 3400.3200-3300.2500-2600.1780, 1720, 1670, 1600 cm-1

N.M.R. Spectrum (dó-DMSO, 8); ppm 9.70 (1H, d, J = 8Hz), 7.50 (1H, d, J = 2Hz), 7.45 (1H, dd, J = 2.8Hz), 7.10 (1H, d, J = 8Hz), 5.90 (1H , q, J = 5Hz), 5.22 (1H, d, J = 5Hz), 4.70 (2H, s), 4.35 (2H, ABq, J = 13Hz), 3.95 (3H, s), 3.75 (2H, ABq, J = 18Hz)

Example 6

a) 2 g of 2- (l-t-butoxycarbonylethoxyimino) -2- (3-chloro-4-hydrodyphenyl) acetic acid (syn isomer) and 2 g of 7-amino-3-

(1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid was reacted with one another in a similar manner to that in Examples 1 and 2, giving 3.6 g of 7- [2- (according to -Butoxycarbo-nyläthoxyimino) -2- (3-chloro-4-hydroxyphenyl) -acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres ) in the form of a powder.

b) 3.6 g of the powder obtained in Example 6 (a), 4 ml of anisole and 16 ml of trifluoroacetic acid were reacted with one another in a similar manner as in Example 5 (b), giving 2.0 g of 7- [2- (l -Carboxyethoxyimino) -2- (3-chloro-4-hydroxyphenyl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) , Mp 147 to 151 ° C (dec.), In the form of a yellow powder.

IR spectrum (Nujol): 3500.3250.2500-2600.1780.1737, 1660.1630.1600 cm- '

N.M.R. spectrum (d «-DMSO, ô); ppm 9.62 (IH, d, J = 8Hz),

638 532

22

7.46 (1 H, d, J = 2Hz), 7.34 (1 H, dd, J = 2.8Hz), 7.04 (1H, d, J = 8Hz), 5.90 (1H, q, J = 5Hz), 5.22 ( 1H, d, J = 5Hz), 4.73 (1H, q, J = 6Hz), 4.33 (2H, ABq, J = 13Hz), 4.00 (3H, s), 3.73 (2H, ABq, J = 18Hz), 1.37 (3H, d, J = 6Hz)

Example 7

The following compounds were obtained in a similar manner to that in Examples 1 and 2:

(1) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3- (4H-1,2,4-triazoI-3-yI) thiomethyl-3-cephem-4-carboxylic acid (syn isomer )

IR spectrum (Nujol): 3250.1775.1710.1665 cm- 'NMR spectrum (dò-DMSO, ô); ppm 9.67 (IH, d, J = 8Hz), 8.40 (IH, s), 6.70-7.43 (4H, m), 5.82 (1H, dd, J = 5.8Hz), 5.13 (1H, d, J = 5Hz), 4.18 (2H, ABq, J = 13Hz), 3.90 (3H, s), 3.67 (2H, wide s)

(2) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3-

(l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol): 3250, 1780, 1720, 1670 cm- 'N.M.R. spectrum (de-DMSO, ô); ppm 9.78 (1H, d, J = 8Hz), 9.55 (1 H, s), 6.70-7.40 (4H, m), 5.89 (1H, dd, J = 5.8Hz), 5.22 (1 H, d, J = 5Hz), 4.46 (2H, ABq, J = 13Hz), 3.92 (3H, s), 3.76 (2H, ABq, J = 18Hz)

(3) 7- [2-Methoxyimino-2- (3-hydroxyphenyl) acetamido] -3- (5-methyl-l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn isomer).

I.R. spectrum (Nujol): 3250.1780, 1720.1670 cm- 'N.M.R. spectrum (de-DMSO, 8); ppm 9.72 (1H, d, J = 8Hz), 6.62-7.40 (4H, m), 5.94 (1H, dd, J = 5.8Hz), 5.18 (1H, d, J = 5Hz), 4.18 (2H, ABq , J = 13Hz), 3.89 (3H, s), 3.70 (2H, ABq, J = 17Hz), 2.65 (3 H, s)

(4) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamodo] cephafosporanic acid (Syn-Isomeres).

IR spectrum (Nujol): 3250, 1785, 1740, 1720 cm * 1 NMR spectrum (ds-DMSO, B); ppm 9.78 (1H, d, J = 8Hz), 6.86-7.36 (4H, m), 5.86 (1H, dd, J = 5.8Hz), 5.18 (1H, d, J = 5Hz), 4.84 (2H, ABq, J = 13Hz), 3.98 (3H, s), 3.54 (2H, ABq, J = 17Hz ), 2.00 (3H, s)

(5) 7- [2-methoxyimino-2- (3-methoxyphenyl7acetamido] -3-

(1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres).

IR spectrum (Nujol): 3250.1780.1720.1670 cm 'NMR spectrum (dó-DMSO, ô); ppm 9.78 (1H, d, J = 8Hz), 6.95-7.54 (4H, m), 5.94 (1H, dd, J = 5.8Hz), 5.18 (1H, d, J = 5Hz), 4.12 (2H, ABq, J = 13Hz), 3.92 (6H, s), 3.76 (3H, s), 3.72 ( 2H, ABq, J = 18Hz)

(6) 7- [2-methoxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. spectrum (Nujol): 3250.1780.1720.1670 cm- N.M.R. spectrum (de-DMSO, 8); ppm 9.70 (1H, d, J = 8Hz), 7.44 (2H, d, J = 8Hz), 6.84 (2H, d, J = 8Hz), 5.86 (1H, dd, J = 5.8Hz), 5.18 (1H , d, J = 5Hz), 4.34 (2H, ABq, J = 13Hz), 3.93 (3H, s), 3.87 (3H, s), 3.74 (2H, ABq, J = 18Hz)

(7) 7- [2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (Syn-Isomeres) F. 145-148 ° C (dec.)

I.R. spectrum (Nujol): 3500.3250.2500-2600.1780.1720, 1655.1625.1600 cm- '

Nuclear Magnetic Resonance Spectrum (dô-DMSO, 8); ppm 10.80 (1H, broad), 9.68 (1H, d, J = 2Hz), 7.46 (1H, d, J = 2Hz), 7.32 (1H, q, J = 2 , 8Hz), 7.00 (1H, d, J = 8Hz), 5.80 (1H, q, J = 5Hz), 5.16 (1H,

d, J = 5Hz), 4.28 (2H, ABq, J = 13Hz), 3.92 (3H, s), 3.87 (3H, s), 3.72 (2H, ABq, J = 18Hz)

(8) 7- [2-methoxyimino-2- (3-chloro-4-methoxyphenyl) aceta-5 mido] -3- (1-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4- car-bonic acid (Syn-Isomeres) F. 143-145 ° C (dec.)

I.R. spectrum (Nujol): 3300,2500-2600,1785,1730,1670, 1630,1600 cm- '

N.M.R. spectrum (ds-DMSO, 8); ppm 9.76 (1H, d, J = 8Hz), io 7.56 (1H, d, J = 2Hz), 7.48 (IH, dd, J = 2.8Hz), 7.22 (1H, d, J = 8Hz), 5.84 ( 1H, q, J = 5Hz), 5.18 (1H, d, J = 5Hz), 4.27 (2H, ABq, J = 13Hz), 3.90 (6H, s), 3.88 (3H, s), 3.70 (2H, ABq , J = 18Hz)

15 (9) 7- [2-Methoxyimino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3- (1-methyl-l H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (Syn-Isomeres) F. 149-152 ° C (dec.)

I.R. spectrum (Nujol): 3400-3450,3200,2500-2600,1780, 1720,1660,1620,1600,1535,1350 cm- '20 N.M.R. spectrum (ds-DMSO, 8); ppm 9.72 (1H, d, J = 8Hz), 7.97 (1H, d, J = 2Hz), 7.72 (1H, dd, J = 2.8Hz), 7.21 (1H, d, J = 8Hz), 5.82 (1H , q, J = 5Hz), 5.16 (1H, d, J = 5Hz), 4.3 (2H, ABq, J = 13Hz), 3.92 (3H, s), 3.87 (3H, s), 3.72 (2H, ABq, J = 18Hz)

25th

(10) 7 - [- 2-Allyloxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (Syn-Isomeres) F. 163-165 ° C (dec.)

I.R. spectrum (Nujol): 3200-3300,2500-2600,1780,1720, 30 1670.1600 cm "'

N.M.R. spectrum (ds-DMSO, 8); ppm 9.70 (1H, d, J = 8Hz), 7.40 (1H, d, J = 2Hz), 7.30 (1H, dd, J = 2.8Hz), 6.95 (1H, d, J = 8Hz), 5.80 (2H , m), 5.30 (2H, d, J = 8Hz), 5.10 (1H, d, J = 5Hz), 4.60 (2H, d, J = 5Hz), 4.27 (2H, ABq, J = 13Hz), 3.85 35 (3H, s), 3.65 (2H, ABq, J = 18Hz)

(11) 7- [2-Allyloxyimino-2- (3-hydroxyimino-2- (3-hydroxyphenyl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem- 4-carboxylic acid (Syn-Isomeres) F. 149-152 ° C (dec.)

40 I.R. spectrum (Nujol): 3250-3350, 2550-2600,1780,1730, 1670,1650,1600 cm- '

N.M.R. spectrum (de-DMSO, 8); ppm 9.70 (1H, d, J = 8Hz), 7.2-6.8 (4H, m), 6.1-5.8 (2H, m), 5.35 (2H, d, J = 8Hz), 5.17 (1H, d, J = 5Hz ), 4.7 (2H, d, J = 5Hz), 4.17 (2H, ABq, J = 13Hz), 3.93 45 (3H, s), 3.75 (2H, ABq, J = 18Hz)

(12) Sodium 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] cephalosporanate (Syn-Isomeres).

I.R. spectrum (Nujol): 3250.1765.1730.1665 cm- 'so N.M.R. spectrum (D20.8); ppm 6.83-7.13 (4H, m), 5.83 (1 H, d, J = 5Hz), 5.17 (1 H, d, J = 5Hz), 4.82 (2H, ABq, J = 13Hz), 4.03 (3 H, s), 3.50 (2H, ABq, J = 17Hz), 2.1 (3H, s)

(13) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (4-hydro-55 xyphenyl) acetamido] -3- (l-methyl-l H-tetrazoI-5-yI) thiomethyI-3 -cephem-4-carboxylic acid (Syn-Isomeres), powder.

I.R. spectrum (Nujol): 3150.1780.1720.1670 cm- '

Nuclear Magnetic Resonance Spectrum (ds-DMSO, ô); ppm 9.60 (1H, d, J = 8Hz), 6.72-7.52 (7H, m), 5.80 (1H, dd, J = 4.8Hz), 5.15 (1H, d , J = 4Hz), 60 5.00 (2H, s), 4.28 (2H, ABq, J = 13Hz), 3.90 (3H, s), 3.65 (2H, ABq, J = 18Hz)

(14) 7- [2- (2-Thienylmethoxyimino) -2- (4-hydroxyphenyl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-654-carboxylic acid ( Syn-Isomeres), powder.

I.R. spectrum (Nujol): 3200-3300,1780,1720,1660 cm- '

N.M.R. spectrum (de-DMSO, 8); ppm 9.77 (1H, d, J = 8Hz), 6.7-7.7 (7H, m), 5.83 (1H, dd, J = 5.8Hz), 5.29 (2H, s), 5.15 (1H,

23

638 532

d, J = 5Hz), 4.3 (2H, ABq, J = 13Hz), 3.92 (3H, s), 3.72 (2H, ABq, J = 18Hz)

(15) 7- [2-ethoxyimino-2- (3-chloro-4-hydroxyphenyl) aceta-m ido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -car-bonic acid (Syn-Isomeres), liquid powder, melting point 153-156 ° C (dec.)

I.R. spectrum (Nujol): 3450.3250.2550-2600.1780, 1725, 1665.1630.1600 cm- '

N.M.R. spectrum (d6-DMSO, ô); ppm 9.71 (1H, d, J = 8Hz), 7.50 (1H, d, J = 2Hz), 7.36 (1H, dd, J = 2.8Hz), 7.03 (1H, d, J = 8Hz), 5.83 ( 1H, q, J = 5Hz), 5.17 (1H, d, J = 5Hz), 4.33 (2H, ABq, J = 13Hz), 4.17 (2H, q, J = 7Hz), 3.97 (3H, s), 3.73 (2H, ABq, J = 18Hz), 1.25 (3 H, t, J = 7Hz)

(16) 7- [2-Allyloxyimino-2- (3-methoxyphenyl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) , Powder, mp 135-138 ° C (dec.)

I.R. spectrum (Nujol): 3300.2600, 1785, 1730, 1670, 1645, 1600 cm-1

NMR spectrum (de-DMSO, S); ppm 9.82 (1 H, d, J = 8Hz), 7.0-7.45 (4H, m), 5.8-6.2 (2H, m), 5.36 (2H, t, J = 10Hz), 5.21 (1 H, d, J = 5Hz), 4.72 (2H, d, J = 5Hz), 4.36 (2H, ABq, J = 13Hz), 3.95 (3H, s), 3.91 (3H, s) , 3.87 (2H, ABq, J = 18Hz)

(17) 7- [2-ethoxyimino-2- (3-hydroxyphenyl) acetamido] -3- (l-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) , yellow powder, mp 145-148 ° C (dec.)

I.R. spectrum (Nujol): 3450.3250.2500-2600.1775, 1720, 1665, 1620, 1600 cm "i

N.M.R. spectrum (de-DMSO, 8); ppm 9.70 (1H, d, J = 8Hz),

6.8-7.4 (4H, m), 5.90 (1H, q, J = 5Hz), 5.20 (1H, d, J = 5Hz), 4.36 (2H, ABq, J = 13Hz), 4.20 (2H, q, J = 7Hz), 4.00 (3H, s), 3.76 (2H, ABq, J = 18Hz), 1.33 (3H, t, J = 7Hz)

(18) 7- [2-ethoxyimino-2- (3-methoxyphenyl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), pale yellow powder, mp 140-143 ° C (dec.)

I.R. spectrum (Nujol): 3300.2500-2600, 1785, 1730, 1670, 1630, 1600 cm-1

N.M.R. spectrum (de-DMSO, S); ppm 9.71 (1H, d, J = 8Hz),

6.9-7.5 (4H, m), 5.90 (1H, q, J = 5Hz), 5.17 (1H, d, J = 5Hz), 4.33 (2H, ABq, J = 13Hz), 4.20 (2H, q, J = 7Hz), 3.95 (3H, s), 3.85 (3H, s), 3.75 (2H, ABq, J = 18Hz), 1.30 (3H, t, J = 7Hz)

(19) 7- [2-Allyloxyimino-2- (3-chloro-4-methoxyphenyl) acetamid ido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer), pale yellow powder, mp 153-156 ° C (dec.)

I.R. spectrum (Nujol): 3250.2600, 1780.1720.1670, 1645, 1630.1600 cm "1

N.M.R. spectrum (dó-DMSO, 8); ppm 9.65 (1H, d, J = 8Hz), 7.27 (1H, d, J = 2Hz), 7.20 (1H, dd, J = 2.8Hz), 7.09 (1H, d, J = 8Hz), 5.85-6.15 (2H, m), 5.15 (2H, t, J = 9Hz), 5.05 (1H, d, J = 5Hz), 4.60 (2H, d, J = 5Hz), 4.15 (2H, ABq, J = 13Hz), 3.95 (3H, s), 3.90 (3H, s), 3.47 (2H, ABq, J = 18Hz)

(20) 7- [2-Methoxyimino-2- (3-acetoxyphenyl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol): 3450.3250.1765.1710.1655.1530 cm "'

Nuclear Magnetic Resonance Spectrum (do-DMSO, 8); ppm 9.77 (1H, d, J = 8Hz), 7.6-7.1 (4H, m), 6.56 (2H, s), 5.83 (1H, dd, J = 4.8Hz ), 5.20 (1H, d, J = 4Hz), 4.76 (2H, ABq, J = 13Hz), 3.94 (3H, s), 3.55 (2H, broad s), 2.28 (3H, s)

(21) 7- [2-Phenylthiomethoxyimino-2- (3-hydroxyphenyl) acetamido] -3- (l-methyl-l H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer )

I.R. spectrum (Nujol): 3300.1760, 1660.1600, 1580.1520 cm- '

N.M.R. spectrum (dô-DMSO, 8); ppm 9.7 (1H, d, J = 8Hz), 7.7-6.7 (9H, m), 5.8-5.4 (3H, broad s), 5.06 (1H, d, J = 5Hz), 4.33 (2H, broad s), 3.9 (3H, s), 3.56 (2H, broad s)

(22) 7- [2-Methoxyimino-2- (3-mesylaminophenyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomeres) F. 155 ° C (dec.)

I.R. spectrum (Nujol): 3300.1780, 1730.1670 cm- '

Nuclear Magnetic Resonance Spectrum (ds-DMSO, 8); ppm 9.98 (1H, s), 9.81 (1 H, d, J = 9Hz), 9.62 (1 H, s), 5.90 (1H, dd, J = 5.9Hz ), 5.24 (1H, d, J = 5Hz), 4.49 (2H, ABq, J = 14Hz), 3.98 (3H, s), 3.77 (2H, broad s), 2.96 (3H, s)

(23) 7- [2-Methoxyimino-2- (3-carbamoyloxyphenyl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- Isomeres)

I.R. spectrum (Nujol): 3450,3300,3200,1780,1725,1670, 1620,1590, 1520 cm "'

N.M.R. spectrum (d6-DMSO, 8); ppm 9.77 (1H, d, J = 7Hz), 7.6-6.8 (6H, m), 5.83 (1H, dd, J = 4.7Hz), 5.17 (1H, d, J = 4Hz), 4.31 (2H, ABq , J = 14Hz), 3.96 (6H, s), 3.72 (2H, broad s)

(24) 7- [2-methoxyimino-2- (3-carbamoyloxyphenyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, ( Syn isomeres)

I.R. spectrum (Nujol): 3250, 1780, 1735, 1675 cm- '

Nuclear Magnetic Resonance Spectrum (d6-DMSO, 8); ppm 9.81 (1H, d, J = 8Hz), 9.62 (1H, s), 6.7-7.58 (4H, m), 5.87 (1H, dd, J = 5, 8Hz ), 5.2 (1H, d, J = 5Hz), 4.25,4.63 (2H, ABq, J = 14Hz), 3.9 (3H, s), 3.7 (2H,

wide s)

(25) 7- [2-methoxyimino-2- (3-acetoxyphenyl) acetamido] -3-

(1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. spectrum (Nujol): 3250.1780.1740.1720.1680 cm- '

Nuclear Magnetic Resonance Spectrum (Ds-DMSO, 8); ppm 9.86 (1H, d, J = 8Hz), 9.61 (1H, s), 7.00-7.65 (4H, m), 5.84 (1H, dd, J = 5, 8Hz ), 5.2 (1H, d, J = 5Hz), 4.25,4.63 (2H, ABq, J = 14Hz), 3.92 (3H, s), 3.53, 3.86 (2H, ABq, J = 19Hz), 2.3 (3H, s)

(26) 7- [2- (3-Phenylallyloxyimino) -2- (3-hydroxyphenyl) ~ acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) F. 138-142 ° C (dec.)

I.R. spectrum (Nujol): 3300-3400,2600,1780,1720,1665, 1600 cm- '

N.M.R. spectrum (d «-DMSO, 8); ppm 9.80 (1H, d, J = 8Hz), 6.4-7.4 (11H, m), 5.85 (1H, dd, J = 5.8Hz), 5.20 (1H, d, J = 5Hz), 4.83 (2H, d , J = 5Hz), 4.32 (2H, ABq, J = 15Hz), 3.95 (3H, s), 3.68 (2H, AB ,, J = 18Hz)

(27) 7- [2-methoxyimino-2- (4-dimethylaminophenyl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- Isomeres), mp 88 ° C (dec.)

I.R. spectrum (Nujol): 3250.1780.1730, 1680.1610 cm- '

N.M.R. spectrum (de-DMSO, 8); ppm 9.63 (1H, d, J = 8Hz), 7.40 (2H, d, J = 8Hz), 6.73 (2H, d, J = 8Hz), 5.83 (1H, dd, J = 5, 8Hz), 5.17 (1H , d, J = 5Hz), 4.33 (2H, ABq, J = 13Hz), 3.97 (3H, s), 3.87 (3H, s), 3.73 (2H, broad s), 3.00 (6H, s)

(28) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3- [1 - (2-dimethylaminoethyl) -1 H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid ( Syn isomeres)

I.R. spectrum (Nujol): 1765 cm- '

N.M.R. spectrum (de-DMSO, 8); ppm 9.67 (1H, d, J = 9Hz), 6.72-7.36 (4H, m), 5.78 (1H, dd, J = 5.9Hz), 5.12 (1H, d, J = 5Hz), 4.55 (2H, broad s), 4.30 (2H, broad s), 3.90 (3H, s), 3.40-3.80 (2H, m), 3.14 (2H, broad s), 2.48 (6H, s)

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

638 532

24th

(29) 7- [2- {2- (2-Hydroxyphenoxy) ethoxyimino] -2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-l H-tetrazol-5-yl) thiomethyl- 3-cephem-4-carboxylic acid (Syn-Isomeres)

I.R. spectrum (Nujol): 3270.1780.1725.1670.1560 cm "1

Nuclear Magnetic Resonance Spectrum (dó-DMSO, Ô); ppm 6.5-7.4 (8H, m), 5.86 (1H, dd, J = 5, 8Hz), 5.14 (1H, d, J = 5Hz), 4.0-4.6 (6H , m), 3.92 (3H, s), 3.52,3.70 (2H, ABq, J = 7Hz)

Example 8

A mixture of 0.73 g dimethylformamide and 1.6 g phosphorus oxychloride was heated to 40 ° C for 30 minutes. Benzene was added and the mixture was concentrated. The residue was suspended in 20 ml of ethyl acetate and 1.95 g of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres) was added at -15 to -5 ° C, after which the resulting mixture became 30 Stirred at the same temperature for minutes. On the other hand, a solution of 0.9 g of sodium hydroxide in 5 ml of water was added dropwise over a period of 25 minutes at 0 to 5 ° C. to a suspension of 2.7 g of 7-aminocephalosporanic acid in 12.5 ml of water, and the mixture became 5 minutes long stirred, then 20 ml acetone was added. To the resulting mixture, which contained sodium 7-amino-3-hydroxymethyl-3-cephem-4-carboxylate, the ethyl acetate solution obtained above was added dropwise over a period of 3 minutes at 0 to 5 ° C., the pH value was kept at 7.5 to 8.5 by adding triethylamine. After stirring for 30 minutes, the organic solvents were distilled off. The aqueous layer was washed with 20 ml of ethyl acetate, adjusted to pH 2.0 with hydrochloric acid and extracted at 0 to 3 ° C. with 60 ml of ethyl acetate. The aqueous layer was further extracted with 30 ml of ethyl acetate. The combined ethyl acetate extracts were washed with a saturated aqueous sodium chloride solution and dried. The solvent was distilled off and the residue was pulverized with diisopropyl ether, giving 2.64 g of a mixture of 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3-hydroxymethyl-3-cephem-4 -carboxylic acid (syn isomer) (I) and 6- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -5a, 6-dihydro-3H, 7H-aceto [2, lb] furo [3, 4-d] [1,3] thiazine-1,7 (4H) dione (Syn-Isomeres) (II)

received.

IR spectrum of (I) (Nujol): 3250.1785, 1755, 1660, 1600, 1570, 1540 cm "1

N.M.R. spectrum of (I) (d «-DMSO, 5); ppm 9.83 (1H, d, J = 8Hz), 7.5-6.75 (4H, m), 5.8 (1H, dd, J = 5.8Hz), 5.21 (1H, d, J = 5Hz), 4.3 (2H, broad s), 3.95 (3H, s), 3.63 (2H, broad s)

I.R. spectrum of (II) (Nujol): 3250.1785,1755.1660, 1600.1570.1540 cm "1

N.M.R. spectrum of (II) (ds-DMSO, 5); ppm 9.83 (1H, d, J = 8Hz), 7.5-6.75 (4H, m), 6.02 (1H, dd, J = 5, 8Hz), 5.21 (1H, d, J = 5Hz), 5.07 (2H, broad s), 3.95 (3H, s), 3.84 (2H, broad s)

Example 9

0.23 g of 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) were dissolved in 1 ml of pyridine with stirring and with ice-cooling and it 0.082 g of acetyl chloride was added. The mixture was stirred under ice cooling for 40 minutes. The reaction mixture was poured into ice water, acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After the treatment with activated carbon, the mixture was filtered and the filtrate was concentrated. The residue was pulverized with diisopropyl ether, 0.18 g of a mixture of 7- [2-methoxyimino-2- (3-acetoxyphenyl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn- Isomeres) and 7- [2-methoxyimino-2- (3-acetoxyphenyl) -acet-

amido] -3-carbamoyloxymethyl-2-cephem-4-carboxylic acid (Syn-Isomeres). N.M.R. spectrum

N.M.R. spectrum (da-DMSO, S); ppm 9.82 (1H, d, J = 8Hz), 9.77 (1H, d, J = 8Hz), 7.6-7.1 (8H, m), 6.60 (1H, s), 6.56 (2H, s), 5 5.83 (1H , dd, J = 4.8Hz), 5.60 (1H, dd, J = 4.8Hz), 5.24 (1H, d, J = 4Hz), 5.20 (IH, d, J = 4Hz), 4.84 (1H, s ), 4.76 (2H, ABq, J = 13Hz), 4.56 (2H, broad s), 3.94 (6H, s), 3.55 (2H, broad s), 2.28 (6H, s)

Example 10

The compounds shown below were obtained in a similar manner as in Example 9.

(1) 7- [2-methoxyimino-2- (3-acetoxyphenyl) acetamido] -3-

(1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-15 isomer)

I.R. spectrum (Nujol): 3250.1780.1740.1720.1680 cm- '

N.M.R. spectrum (ds-DMSO, 8); ppm 9.86 (1H, d, J = 8Hz),

9.61 (1H, s), 7.00-7.65 (4H, m), 5.84 (1H, dd, J = 5.8Hz), 5.2 (1H, d, J = 5Hz), 4.25.4.63 (2H, ABq, J = 14Hz), 3.92 (3H, s), 3.53,3.86

20 (2H, ABq, J = 19Hz), 2.3 (3H, s)

(2) 7- [2-methoxyimino-2- (3-carbamoyloxyphenyl) acetamido] -3- (1-methyl-l H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- Isomeres)

25 I.R. spectrum (Nujol): 3450.3300.3200.1780.1725.1670, 1620.1590.1520 cm "'

N.M.R. spectrum (do-DMSO, 5); ppm 9.77 (1H, d, J = 7Hz), 7.6-6.8 (6H, m), 5.83 (1H, dd, J = 4.7Hz), 5.17 (1H, d, J = 4Hz), 4.31 (2H, AB ,, J = 14Hz), 3.96 (6H, s), 3.72 (2H, broad s)

30th

(3) 7- [2-Methoxyimino-2- (3-carbamoyl-oxyphenyl) aceta-mido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn isomer)

I.R. spectrum (Nujol): 3250.1780.1735.1675 cm-1 N.M.R. spectrum (d6-DMSQ, 8); ppm 9.81 (lH, d, J = 8Hz),

9.62 (1H, s), 6.7-7.58 (4H, m), 5.87 (1H, dd, J = 5.8Hz), 5.2 (1H, d, J = 5Hz), 4.25.4.63 (2H, ABq, J = 14Hz), 3.9 (3H, s), 3.7 (2H, broad s)

40 Example 11

0.26 g of phosphorus oxychloride was added to 0.15 g of dimethylformamide while cooling with ice, and the mixture was heated at 40 ° C for 1 hour. 1.5 ml of ethyl acetate were added and 0.3 g of 45 2-methoxyimino-2- (2-methyl-l, 3-thiazol-4-yl) acetic acid (Syn-Isomeres) was added to the mixture in one portion with stirring and added while cooling with ice, then the resulting mixture was stirred at 0 to 5 ° C for 20 minutes. On the other hand, 1.2 g of bis- (trimethylsilyl) acetamide were added to a suspension of 0.53 g of 7-amino-3- (1-met-50 hyl-1H-tetrazol-5-yl) thiomethyl-3-cephem- 4-carboxylic acid in 7 ml of ethyl acetate was added and the mixture was stirred at ambient temperature. To this solution, the ethyl acetate solution obtained above was added dropwise at -20 ° C., and the. Mixture was stirred at -10 to -20 ° C for 2 hours. 55 ml of water was added to the reaction mixture below -25 ° C and then 20 ml of ethyl acetate was added, then the mixture was stirred. An insoluble material was filtered off and the ethyl acetate layer was separated. 15 ml of 60 water were added to the ethyl acetate layer and the mixture was adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate solution. The aqueous layer was separated, washed with methylene chloride, and the methylene chloride in the aqueous layer was removed by passing nitrogen gas. The aqueous solution was adjusted to pH 2.2 with 10% hydrochloric acid, and the precipitates were collected by filtration and dried to give 0.28 g of 7- [2-methoxy-imino-2- (2-methyl -l, 3-thiazol-4-yl) acetamido] -3- (l-methyl-lH-

25 638 532

tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isome- added the ethyl acetate solution obtained above at -15 ° C, res). and the resulting mixture was kept at -10 to 1 hour

IR spectrum (Nujol): 1780.1710.1675cm "1-15 ° C. The reaction mixture was brought to -30 ° C.

N.M.R. spectrum (d6-DMSO, 8); ppm 9.65 (1H, d, cooled and 80 ml of water were added. The aqueous

J = 10Hz), 7.66 (1H, s), 5.81 (1H, dd, J = 5.10Hz), 5.15 (1H, d, 5 layers were separated, with sodium bicarbonate to pH 4.5 J = 5Hz), 4.31 ( 2H, ABq, J = 13Hz), 3.93 (3H, s), 3.90 (3H, s), 3.70 and a column chromatography on a diaion (2H, ABq, J = 16Hz), 2.65 (3H, s) HP-20 Resin (trademark for a product of Mitsu bishi Chemical Industries Ltd.) using an example 12 25% aqueous isopropyl alcohol solution as eluent.

Subjected to 0.89 g of phosphorus oxychloride and 0.44 g of dry dimethyl 10 tel The eluate was lyophilized, 1.8 g of formamide were mixed with ice-cooling, and 7- [2-methoxyimino-2- (2-amino-l, 3-thiazole-4-l) acetone then 40 for 30 minutes ° C warmed. 20 ml of trokamido] cephalosporanic acid (Syn-Isomeres), mp 227 ° C. (dec.),. Ken methylene chloride was added and then was distilled off.

liert. 10 ml of dry ethyl acetate IR spectrum (Nujol): 3300-3350.1780.1740.1670 cm "1 were added to the residue

and then 1.8 g of 2-methoxyimino-2- [2- (2,2,2-trifluoroacet- '5 NMR spectrum (do-DMSO, 8); ppm 9.6 (1H, d, J = 8Hz), amido ) -l, 3-thiazol-4-yl] acetic acid (Syn-Isomeres) with stirring 6.8 (1H, s), 5.8 (1H, dd, J = 5.8Hz), 5.2 (1H, d, J = 5Hz) , 4.87 (2H, and added while cooling with ice. The mixture became 40 ABq, J = 13Hz), 3.89 (3H, s), 3.6 (2H, broad s), 2.08 (3H, s)

Stirred at the same temperature for minutes to obtain a clear solution. On the other hand, 6.36 g of Example 14

Trimethylsilylacetamide to a suspension of 1.65 g of 7-ami-20 3.8 g of phosphorus oxychloride were at 5 to 8 ° C to a nocephalosporanic acid in 25 ml of dry ethyl acetate with a suspension of 4.0 g of 2-methoxyimino-2- (2- Amino-l, 3-thiazole-4 stirring at ambient temperature was added, then yl) acetic acid (Syn-Isomeres) in 40 ml of dry ethyl acetate, the mixture was stirred for 1 hour, a clear one being added dropwise. After stirring for 30 minutes at about 5 ° C

Solution received. The above 0.86 g of bis (trimethylsilyl) acetamide obtained at the same temperature at the same temperature was added to this solution all at once with stirring at -20 to -25 ° C 25. After stirring for 10 minutes at the same temperature and the resulting mixture was stirred for 2 hours, 3.8 g of phosphorus oxychloride were stirred at 5 to 8 ° C. at the same temperature. To the reaction dropwise, then the mixture was stirred at the same for 30 minutes at the same temperature, 30 ml of water at the same temperature. 1.6 g of dry dimet were added and then the mixture was added dropwise at 5 to 7 ° C. for 5 minutes at umhylformamide, after which the temperature at which it was raised was stirred. The ethyl acetate layer was separated mixture for 30 minutes at the same temperature, and the aqueous layer was further stirred with ethyl acetate to obtain a clear solution. On the other hand, extracted. The ethyl acetate layers were combined, 3.3 g of sodium acetate were combined to a solution of 2.7 g of 7-amine, and 50 ml of water were added. The mixture of nocephalosporanic acid in an aqueous solution (20 ml) was adjusted to pH 7.5 with sodium bicarbonate and the 1.7 g of sodium bicarbonate was added, and then 20 ml of aqueous layer was separated. 40 ml of ethyl acetate-35 acetone were added. To this solution, the above-obtained tat was added to the aqueous layer, and the mixture of ethyl acetate solution was added dropwise with stirring at 0 to 5 ° C,

was adjusted with 10% hydrochloric acid with stirring and the pH of this solution was adjusted to pH 2.5 with a 20% aqueous solution with ice cooling. The ethyl acetate layer of sodium carbonate solution was kept at 7.0 to 7.5. It was separated and the aqueous layer was extracted twice with 50 ml of ethyl acetate for 1 hour at the same temperature. The ethyl acetate layers were stirred. An insoluble material was filtered off, and the combined one with an aqueous sodium chloride aqueous layer in the filtrate was separated. The aqueous rid solution is washed and treated with activated carbon. The layer was concentrated under reduced pressure to give the

Solvent was distilled off, removing 3.05 g of organic solvent with sodium bicarbo-

7- [2-methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -1,3-thiazole-4-nate adjusted to pH 4.5 and a column chromatography on yllacet-amidoj-eephalosporanic acid (syn -Isomeres), 45 a Diaion HP-20 resin (trademark for a product of

F.2050 C (dec.). Mitsubishi Chemical Industries Ltd.) using

IR spectrum (Nujol): 3250.1790, 1735, 1680, 1650 cm-1 of a 25% aqueous isopropyl alcohol solution as Eluie N.M.R. spectrum (ds-DMSO, 8); ppm subjected to 9.8 (1H, d, J = 8Hz). The eluate was lyophilized, whereby 7.55 (1H, s), 5.88 (1H, dd, J = 5.8 Hz), 5.25 (1H, d, J = 5 Hz), 4.8 and 2.8 g7- [2-methoxyimino-2 - (2-amino-l, 3-thiazol-4-yl) acet- (2H, ABq, J = 13Hz), 3.95 (3H, s), 3.59 (2H, broad s), 2.03 (3H, s) 50 amido] cephalosporanic acid (Syn-Isomeres). This compound was identified with the compound obtained in Example 13 by Example 13 by IR and NMR spectra.

2.0 g of phosphorus oxychloride were suddenly at 5 to 10 ° C to a suspension of 2 g of 2-methoxyimino-2- (2-amino-l, 3 Example 15

thiazol-4-yl) acetic acid (Syn-Isomeres) in 20 ml of dry 55 The compounds listed below were added to ethyl acetate. After stirring for 20 minutes in a 7 to similar manner as in Examples 11 to 14 obtained. At 10 ° C., 0.4 g of bis (trimethylsilyl) acetamide was added at the same (1) 7- [2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihy temperature. After 1 minute Stirring at 7 to dro-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazole-5-10 ° C., 2.0 g of phosphorus oxychloride were used in the same temyl) thiomethyl -3-cephem-4-carboxylic acid (Syn-Isomeres).

temperature dropped. The resulting mixture was stirred for 10 60 I.R. spectrum (Nujol): 3250.1780.1718.1675 cm-1 minutes at 7 to 10 ° C, and at the same temperature N.M.R. spectrum (de-DMSO, 8); ppm 9.80 (1H, d, J = 8Hz), temperature 0.8 g of dry dimethylformamide were added dropwise. 7.08 (1H, s), 5.80 (1H, dd, J = 5.8Hz), 5.18 (1H, d, J = 5Hz), 4.34 The mixture was stirred at 7 to 10 ° C for 30 minutes, (2H, ABq , J = 13Hz), 3.99 (3H, s), 3.96 (3H, s), 3.72 (2H, ABq, giving a clear solution. On the other hand, 7.35 J = 17Hz), 3.66 (3H, s), 2.98 (3H, s)

g trimethylsilylacetamide to a suspension of 2.45 g 7-ami-65

Nocephalosporanic acid in 8 ml of dry ethyl acetate - (2) 7- [2-methoxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) -

ben, then the mixture was stirred at 40 ° C with Bil-acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-solution of a clear solution. 4-carboxylic acid (Syn-Isomeres) was suddenly added to this solution.

638 532

26

IR spectrum (Nujol): 3300-3150.1780.1710.1670 cm "1 NMR spectrum (d6-DMSO, 5); ppm 9.84 (1H, d, J = 8Hz), 6.97 (1 H, s), 5.76 (1H, dd, J = 5.8Hz), 5.12 (1H, d, J = 5Hz), 4.33 (2H, ABq, J = 13Hz), 3.93 (6H, s), 3.74 (2H, ABq, J = 17Hz), 2.96 (3H, s)

(3) 7- [2-methoxyimino-2- (2-oxo-2,3-dihydro-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazole-5- yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

IR spectrum (Nujol): 1780.1665 cm "1 NMR spectrum (ds-DMSO, 8); ppm 11.67 (1H, s), 9.83 (1H, d, J = 8Hz), 6.61 (1H, s), 5.80 (1H, dd, J = 5.5.8Hz), 5.17 (1H, d, J = 5.5Hz), 4.37 (2H, broad s), 4.00 (3H, s), 3.96 (3H, s), 3.75 (2H , wide s)

(4) 7- [2-Methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -l, 3-thiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5 -yl) thiomet-hyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

IR spectrum (Nujol): 1790.1730.1660 cm "1 NMR spectrum (ds-DMSO, 8); ppm 9.73 (IH, d, J = 8Hz), 7.53 (1H, s), 5.83 (1H, dd , J = 5.8Hz), 5.15 (1H, d, J = 5Hz), 4.33 (2H, broad s), 3.93 (6H, s), 3.72 (2H, broad s)

(5) 7- [2-Methoxyimino-2- (2-t-pentyloxycarbonylamino-l, 3-thiazol-4-yl) acetamido] -3- (5-methyl-l, 3,4-thiadiazol-2-yl ) -thio-methyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

IR spectrum (Nujol): 3200.1780.1720.1680 cm "1 NMR spectrum (ds-DMSO, 8); ppm 9.65 (1H, d, J = 8Hz), 7.28 (1H, s), 5.80 (1H , dd, J = 5.8Hz), 5.16 (1H, d, J = 5Hz), 4.38 (2H, ABq, J = 13Hz), 3.86 (3H, s), 3.70 (2H, ABq, J = 17Hz), 2.66 (3H, s), 1.78 (2H, q, J = 8Hz), 1.44 (6H, s), 0.88 (3H, t, J = 8Hz)

(6) 7- [2-Allyloxyimino-2- (2-mesy] amino-1,3-thiazoI-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid (Syn-Isomeres)

IR spectrum (Nujol): 3100-3300, 1780, 1720, 1675 cm "1 NMR spectrum (de-DMSO, 8); ppm 9.90 (1H, d, J = 8Hz), 7.00 (1H, s), 6.07 -5.63 (2H, m), 5.43 (2H, d, J = 8Hz), 5.18 (IH, d J = 5Hz), 4.70 (2H, d, J = 5Hz), 4.37 (2H, broad s), 3.98 ( 3H, s), 3.75 (2H, broad s), 3.00 (3H, s)

(7) 7- [2-Allyloxyimino-2- (2-t-pentyloxycarbonylamino-l, 3-thiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid (Syn-Isomeres)

IR spectrum (Nujol): 3250.1780.1720.1678.1625 cm "1 NMR spectrum (de-DMSO, 8); ppm 9.74 (1H, d, J = 8Hz), 7.31 (1H, s), 6.28 -5.76 (2H, m), 5.28 (2H, dd, J = 8.16Hz), 5.18 (1H, d, J = 5Hz), 4.66 (2H, d, J = 5Hz), 4.36 (2H, ABq, J = 13Hz), 3.96 (3H, s), 3.74 (2H, ABq, J = 17Hz), 1.80 (2H, q, J = 8Hz), 1.45 (6H, s, 0.89 (3H, t, J = 8Hz)

(8) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (Syn-Isomeres)

IR spectrum (Nujol): 3200.1765.1600 cm "1 NMR spectrum (dó-DMSO, 8); ppm: 9.51 (1H, d, J = 8.5Hz), 7.22 (2H, broad s), 6.72 (1H, s), 5.59 (1H, dd, J = 5, 8.5Hz), 5.00 (1H, d, J = 5Hz), 4.35 (2H, ABq, J = 12Hz), 3.90 (3H, s), 3.81 (3H, s), 3.55 (2H, ABq, J = 18Hz)

(9) 7- [2-Methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (5-methyl-l, 3,4-thiadiazol-2-yl ) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

IR spectrum (Nujol): 3400-3150.1770,1670.1625 cm "1 NMR spectrum (d6-DMSO, 8); ppm 9.66 (1H, d, J = 8Hz), 7.34 (2H, broad s), 6.76 (1H, s), 5.78 (2H, dd, J = 5.8Hz), 5.16 (1H, d, J = 5Hz), 4.40 (2H, ABq, J = 14Hz), 3.85 (3H, s), 3.70 (2H, ABq, J = I7Hz), 2.68 (3H, s)

(10) 7- [2-Allyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (l-methyl-l H-tetrazol-5-yl) thiomethyl- 3-cephem-4-carboxylic acid (Syn-Isomeres)

IR spectrum (Nujol): 3100-3400, 1775, 1660, 1625 cm "1 5 NMR spectrum (ds-DMSO, 8); ppm 9.70 (1H, d, J = 8Hz), 6.80 (1H, s), 6.30-5.60 (2H, m), 5.24 (2H, dd, J = 8.16Hz), 5.15 (IH, d, J = 5Hz), 4.63 (2H, d, J = 5Hz), 4.32 (2H, ABq, J = 12Hz), 3.94 (3H, s), 3.70 (2H, ABq, J = 17Hz)

io (11) 7- [2-Methoxyimino-2- (2-formamido-l, 3-thiazol-4-y]) acetamido] -3- (1,3,4-thiadiazol-2-y]) thiomethyl- 3-cephem-4-carboxylic acid (Syn-Isomeres), mp 145-147 ° C (dec.)

I.R. spectrum (Nujol): 3150-3400, 1780, 1725, 1680, 1640 cm "1

15 N.M.R. spectrum (ds-DMSO, 8); ppm 12.58 (1H, broad s), 9.70 (1H, d, J = 8Hz), 9.58 (1H, s), 8.50 (1H, s), 7.40 (1H, s), 5.82 (1H, dd, J = 5 , 8Hz), 5.17 (1H, d, J = 5Hz), 4.43 (2H, ABq, J = 13 Hz), 3.88 (3H, s), 3.70 (2H, broad s)

20 (12) 7- [2-Methoxyimino-2- (2-acetamido-l, 3-thiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (Syn-Isomeres), mp 171-173 ° C (dec.)

IR spectrum (Nujol): 3500.3250, 1780.1720.1670 cm "1 NMR spectrum (de-DMSO, 8); ppm 9.65 (1H, d, J = 8Hz), 25 7.3 (1H, s), 5.8 (1H, dd, J = 5, 8Hz), 5.15 (1H, d, J = 5Hz), 4.35 (2H, broad), 3.97 (3H, s), 3.9 (3H, s), 3.75 (2H, broad ), 2.15 (3H, s)

(I3) 7- [2-methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -l, 3-30 thiazol-4-yl) acetamido] cephalosporanoic acid (Syn-Isomeres), mp 205 ° C (dec.)

IR spectrum (Nujol): 3250.1790.1735.1680.1650 cm-1 NMR spectrum (ds-DMSO, 8); ppm 9.8 (1H, d, J = 8Hz), 7.55 (1H, s), 5.88 (1H, dd, J = 5.8Hz), 5.25 (1H, d, J = 5Hz), 4.8 35 (2H, AB ,, J = 13Hz), 3.95 (3H, s), 3.59 (2H, broad), 2.03 (3H, s)

(14) 7- [2-Methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -l, 3-thiazol-4-yllacetamido] -3-carbamoyloxymethyl-3-cephem-4-car-bonic acid ( Syn isomeres)

40 IR spectrum (Nujol): 3500.3200.1785.1700.1660 cm "1 NMR spectrum (d6-DMSO, 8); ppm 9.75 (1H, d, J = 8Hz), 8.4 (2H, m), 7.53 (1H, s), 6.6 (1H, m), 6.20 (1H, d, J = 5Hz), 5.83 (1H, m), 4.77 (2H, ABq, J = 14Hz), 3.91 (3H, s), 3.55 (2H, m)

45 (15) 7- [2-methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -1, 3-thiazol-4-yl} acetamido] -3- (1,3,4-thiadiazole- 2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

IR spectrum (Nujol): 3200.1780.1720.1650 cm "1 NMR spectrum (de-DMSO, 8); ppm 9.81 (1H, d, J = 8Hz), so 9.6 (1H, m), 9.57 ( 1H, s), 7.56 (1H, s), 5.83 (1H, dd, J = 5.8Hz), 5.20 (1H, d, J = 5Hz), 4.47 (2H, ABq, J = 14Hz), 3.96 (3H , s), 3.72 (2H, ABq, J = 18Hz)

(16) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acet-55 amido] -3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer), F. 260-270 ° C (dec.)

I.R. spectrum (Nujol): 3370.3270, 1765, 1660, 1610, 1590, 1550 cm "1

N.M.R. spectrum (ds-DMSO, 8); ppm 9.58 (1H, d, J = 8Hz), 60 6.76 (1H, s), 5.75 (1H, dd, J = 5.8Hz), 5.12 (1H, d, J = 5Hz), 4.27 (2H, broad see ), 3.85 (3H, s), 3.57 (2H, broad s)

(17) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] cephalosporanic acid (Syn-Isomeres), mp 227 ° C (dec.)

es IR spectrum (Nujol): 3300-3350,1780,1740,1670 cm "1 NMR spectrum (de-DMSO, 8); ppm 9.6 (1H, d, J = 8Hz), 6.8 (1H, s), 5.8 (1H, dd, J = 5.8Hz), 5.2 (1H, d, J = 5Hz), 4.87 (2H, ABq, J = 13Hz), 3.89 (3H, s), 3.6 (2H, broad s), 2.08 (3H, s)

27th

638 532

(18) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), F . 210-220 ° C (dec.)

I.R. spectrum (Nujol): 3250.1765.1650 cm-1

N.M.R. spectrum (ds-DMSO, 8); ppm 9.64 (1H, d, J = 8Hz), 7.4 (2H, m), 6.79 (1H, s), 6.60 (2H, m), 5.77 (1H, dd, J = 5.8Hz), 5.16 (1H, d, J = 5Hz), 4.75 (2H, ABq, J = 12Hz), 3.87 (3H, s), 3.53 (2H, ABq, J = 18Hz)

(19) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido ido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl- 3-cephem-4-carboxylic acid (Syn-Isomeres), mp 172-175 ° C (dec.)

I.R. spectrum (Nujol): 3300.1770.1665 cm-1

N.M.R. spectrum (de-DMSO, 8); ppm 9.80 (1H, d, J = 8Hz), 9.63 (1H, s), 6.95 (1H, s), 6.8 (2H, m), 5.82 (1H, dd, J = 5.8Hz), 5.22 (1H , d, J = 5Hz), 4.48 (2H, ABq, J = 15Hz), 3.97 (3H, s), 3.76 (2H, ABq, J = 18Hz)

(20) 7- [2-Methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (4-methyl-4H-l, 2,4-triazol-3 -yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), mp 185 ° C (dec.)

I.R. spectrum (Nujol): 3150-3350,1770,1710,1660,1630 cm "'

N.M.R. spectrum (ds-DMSO, 8); ppm 9.61 (1H, d, J = 8Hz), 8.69 (1H, s), 6.73 (1H, s), 5.72 (1H, dd, J = 4.8Hz), 5.1 (1H, d, J = 4Hz), 4.1 (2H, ABq, J = 13Hz), 3.87 (3H, s), 3.65 (2H, broad), 3.59 (3 H, s)

(21) 7- [2-methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -1, 3-thiazol-4-yl} acetamido] -3-hydroxymethyl-3-cephem-4-carbon- acid (Syn-Isomeres), mp 155-160 ° C (dec.)

I.R. spectrum (Nujol): 3250, 1780, 1730, 1660, 1585, 1520 cm-1

N.M.R. spectrum (de-DMSO, 8); ppm 9.76 (1H, d, J = 8Hz), 7.57 (1H, s), 5.80 (1H, dd, J = 4.8Hz), 5.15 (1H, d, J = 4Hz), 4.29 (2H, s), 3.93 (3H, s), 3.60 (2H, s)

(22) 6- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) aceta-mido] -5a, 6-dihydro-3H, 7H-aceto [2, lb] furo [ 3,4-d] [1,3] thiazine-1,7 (4H) -dione (Syn-Isomeres), mp 210-215 ° C (dec.)

I.R. spectrum (Nujol): 3270.1780.1740.1655.1610.1525 cm "'

N.M.R. spectrum (ds-DMSO, 8); ppm 9.70 (1H, d, J = 8Hz), 7.26 (2H, broad s), 6.77 (1H, s), 5.93 (1H, dd, J = 5.8Hz), 5.16 (1H, d, J = 5Hz) , 5.05 (2H, broad), 3.85 (3H, broad), 3.81 (2H, broad)

(23) 7- [2-Methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- [l- (2-dimethylaminoethyl) -lH-tetrazol-5-yl ] thiomet-hyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

I.R. spectrum (Nujol): 1765 cm "'

N.M.R. spectrum (ds-DMSO, 8); ppm 9.56 (1H, d, J = 8Hz), 6.75 (1H, s), 5.75 (1H, m), 5.10 (1H, d, J = 4Hz), 4.58 (2H, broad s), 4.32 (2H, broad s), 3.82 (3H, s), 3.68 (2H, wide s), 3.20 (2H, wide s), 2.50 (6H, s)

(24) 7- [2-methoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetamido] cephalosporanic acid (Syn-Isomeres)

I.R. spectrum (Nujol): 3280.1785.1740.1700.1650 cm "'

NMR spectrum (de-DMSO, 8); ppm 12.68 (1H, broad), 9.68 (1H, d, J = 8Hz), 8.54 (1H, s), 7.45 (1H, s), 5.86 (1H, dd, J = 5.8Hz), 5.20 (1H, d, J = 5Hz), 4.90 (2H, ABq, J = 8Hz), 3.16 (3H, broad s), 2.06 (3H, s)

(25) 7- [2-Methoxyimino-2- (2-ethoxycarbonylamino-1,3-thia-zol-4-yl) acetamido] -3- (1,3-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (Syn-Isomeres)

I.R. spectrum (Nujol): 3200.1775, 1720, 1680, 1660 cm- '

N.M.R. spectrum (d <s-DMSO, 8); ppm 11.9 (1H, m), 9.70

(1 H, d, J = 10Hz), 9.55 (1 H, s), 7.31 (1 H, s), 5.80 (1 H, dd, J = 5.10Hz), 5.18 (1H, d, J = 5Hz ), 4.44 (2H, ABq, J = 16Hz), 4.22 (2H, q, J = 7Hz), 3.89 (3H, s), 3.72 (2H, ABq, J = 16Hz), 1.23 (3H, t, J = 7Hz)

(26) 7- [2-Methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yllacetamido] -3-formyl-3-cephem-4-carboxylic acid (syn- Isomeres) [this compound can also be referred to as

3-Hydroxy-6- [2-methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -I, 3-thiazol-4-yllacetamido] -5a, 6-dihydro-3H, 7H-azeto [2 , lb] furo [3,4-d] [1,3] thiazine-1,7 (4H) dione (Syn-Isomeres)]

I.R. spectrum (Nujol): 3150.1790.1720, 1655.1560.1500 cm-1

N.M.R. spectrum (do-DMSO, 8); ppm 9.88 (1H, d, J = 8Hz), 7.60 (1H, s), 6.30 (1H, d, J = 6Hz), 6.05 (1H, dd, J = 5.8Hz), 5.23 (1H, d, J = 5Hz), 3.96 (3H, s), 3.80 (2H, broad)

(27) 7- [2-methoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3- cephem-

4-carboxylic acid (Syn-Isomeres)

I.R. spectrum (Nujol): 3200-3300,2600,1780,1720,1690, 1675 cm- '

NMR spectrum (ds-DMSO, 8); ppm 12.60 (1H, broad), 9.70 (1H, d, J = 8Hz), 8.50 (1H, s), 7.44 (1H, s), 5.88 (1H, dd, J = 5.8Hz), 5.19 (1H, d, J = 5Hz), 4.25 (2H, ABq, J = 13Hz), 3.95 (3H, s), 3.85 (3H, s), 3.65 (2H, ABq, J = 18Hz)

(28) 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. spectrum (Nujol): 3300, 1780, 1705, 1680 cm- '

N.M.R. spectrum (ds-DMSO, 8); ppm 12.50 (1H, broad s), 9.67 (1H, d, J = 8Hz), 8.50 (1H, s), 7.43 (1H, s), 6.58 (2H, broad s), 5.80 (1H, dd, J = 5.8Hz), 5.16 (1H, d, J = 5Hz), 4.78 (2H, ABq, J = 14Hz), 3.95 (3H, s), 3.57 (2H, ABq, J = 18Hz)

Example 16

A solution of 0.3 g of 7- [2- (methoxyimino-2- {2- (2,2,2-tri-fluoroacetamido) -1, 3-thiazol-4-yUacetamido] -3- (l-methyl-1H -tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isome-res) in 10.5 ml of an aqueous 0.1N sodium hydroxide solution was heated at 45 ° C. for 6 hours ml of water and 30 ml of ethyl acetate were added and the resulting mixture was adjusted to pH 3.5 with 10% hydrochloric acid, the aqueous layer was separated, washed with ethyl acetate and adjusted to pH 5.0 with an aqueous sodium bicarbonate solution was subjected to column chromatography on Amberlite XAD-2 (20 ml) (a product of Rohm &

Haas Co.) using 10% ethanol as the developing solvent. The eluate containing the desired compound was collected and lyophilized, 0.12 g of 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (1-methyl -1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) was obtained.

I.R. spectrum (Nujol): 3200.1765.1600 cm "'

N.M.R. spectrum (dó-DMSO, 8); ppm 9.51 (1H, d, J = 8.5Hz), 7.22 (2H, broad s), 6.72 (1H, s), 5.59 (1H, dd, J = 5.8Hz), 5.00 (1H, d, J = 5Hz), 4.35 (2H, ABq, J = 12Hz), 3.90 (3H, s), 3.81 (3H, s), 3.55 (2H, ABq, J = 18Hz)

Example 17

3 ml of trifluoroacetic acids were cooled to 0.5 g of 7- [2-methoxyimino-2- (2-t-pentyloxycarbonylamino-l, 3-thiazol-4-yl) acetamido] -3- (5-methyl-l, 3 , 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) was added and the mixture was stirred at ambient temperature for 30 minutes. Ether was added to the mixture, from 5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

638532

28

falling powder was collected by filtration and dissolved in a mixture of 20 ml of water and an aqueous in sodium hydroxide solution to adjust to pH 12 to 13. The solution was adjusted to pH 4.6 with 10% hydrochloric acid, washed with ethyl acetate and methylene chloride. The excess methylene chloride in the aqueous layer was thoroughly removed by introducing nitrogen gas. The aqueous layer was adjusted to pH 2 with stirring and with ice cooling, whereby a powder precipitated. The powder was collected by filtration and dried,

where 0.128 g of 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (5-methyl-l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres).

I.R. spectrum (Nujol): 3400-3150, 1770, 1670, 1625 cm-; ppm 9.66 (1H, d, J = 8Hz), 7.34 (2H, broad s), 6.76 (1H, s), 5.78 (2H, dd, J = 5.8Hz), 5.16 (1H, d, J = 5Hz ), 4.40 (2H, ABq, J = 14Hz), 3.85 (3H, s), 3.70 (2H, ABq, J = 17Hz), 2.68 (3H, s)

Example 18

4 ml of trifluoroacetic acid and 2 ml of anisole were added to 0.9 g of 7- [2-allyloxyimino-2- (2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl) acetamido] -3- (1 -methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) was added and the mixture was stirred for 40 minutes at ambient temperature. The reaction mixture was post-treated in a manner similar to that in Example 17, 0.425 g of 7- [2-allyloxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (1-methyl- 1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres).

I.R. spectrum (Nujol): 3100-3400,1775,1660,1625 cm'1

N.M.R. spectrum (dô-DMSO, ô); ppm 9.70 (IH, d, J = 8Hz), 6.80 (IH, s), 6.30-5.60 (2H, m), 5.24 (2H, dd, J = 8.16Hz), 5.15 (1H, d, J = 5Hz ), 4.63 (2H, d, J = 5Hz), 4.32 (2H, ABq, J = 12Hz), 3.94 (3H, s), 3.70 (2H, ABq, J = 17Hz)

Example 19

0.26 g of disodium hydrogenphosphate were added to a suspension of 1 g of 7- [2-methoxyimino-2-12- (2,2,2-trifluoroacet-amido) -l, 3-thiazol-4-yllacetamido] cephalosporanic acid (Syn-Isomeres) in 15 ml of water added. In addition, a saturated aqueous disodium hydrogen phosphate solution was added to adjust the pH of the mixture to 6. The resulting mixture was stirred at ambient temperature for 23 hours. The reaction mixture was adjusted to pH 4 with ice-cooling with 10% hydrochloric acid, washed with ethyl acetate and adjusted to pH 2.5 with 10% hydrochloric acid. The precipitated crystals were collected by filtration, washed with cold water and dried, whereby 0.18 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] cephalosporanic acid (Syn -Isomeres), mp 227 ° C (dec.).

1st spectrum (Nujol): 3300-3350,1780,1740,1670 cm- '

N.M.R. spectrum (d6-DMSO, ô); ppm 9.6 (1H, d, J = 8Hz),

6.8 (1H, s), 5.8 (1H, dd, J = 5.8Hz), 5.2 (1H, d, J = 5Hz), 4.87 (2H, ABq, J = 13Hz), 3.89 (3H, s), 3.6 (2H, broad s), 2.08 (3H, s)

Example 20

23 g 7- [2-methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -l, 3-thiazoI-4-yl) acetamido] -3- (1,3,4-thiadiazol-2- yl) -thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) was suspended in a solution of 74.8 g of sodium acetate trihydrate in 230 ml of water and the suspension was stirred for 15 hours at ambient temperature. The reaction mixture was adjusted to pH 5.0 with concentrated hydrochloric acid and the insoluble material was filtered off. The filtrate was adjusted to pH 2.5 and the precipitated crystals were collected by filtration and dried to give 14 g of 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido ] -3-

(l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), mp 172 to 175 ° C (dec.).

I.R. spectrum (Nujol): 3300.1770.1665 cm-1

N.M.R. spectrum (de-DMSO, S); ppm 9.80 (1H, d, J = 8Hz), 5 9.63 (1H, s), 6.95 (1H, s), 6.8 (2H, m), 5.82 (1H, dd, J = 5.8Hz), 5.22 (1H , d, J = 5Hz), 4.48 (2H, ABq, J = 15Hz), 3.97 (3H, s), 3.76 (2H, ABq, J = 18Hz)

Example 21

to 3.5 g of 7- [2-methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -1, 3-thiazol-4-yllacetamido] -3-carbamoyloxymethyl-3-cephem-4-car- bonic acid (Syn-Isomeres) were suspended in a solution of 12.2 g sodium acetate trihydrate in 30 ml water. The mixture was stirred at ambient temperature for 15 hours. The reaction mixture was saturated with sodium chloride and adjusted to pH 5.0 with concentrated hydrochloric acid with stirring and with ice cooling. The insoluble material which precipitated was filtered off. The filtrate was adjusted to pH 3.0 with concentrated hydrochloric acid and further adjusted to pH 1.5 with 10% hydrochloric acid. The precipitates were collected by filtration and dried, giving 2.1 g of 7- [2-methoxy-mino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxy-methyl- 3-cephem-4-carboxylic acid (Syn-Isomeres), mp 210 to 25 220 C (dec.).

I.R. spectrum (Nujol): 3250.1765.1650 cm-1

N.M.R. spectrum (de-DMSO, 5); ppm 9.64 (1H, d, J = 8Hz), 7.4 (2H, m), 6.79 (1H, s), 6.60 (2H, m), 5.77 (1H, dd, J = 5.8Hz), 5.16 (1H, d, J = 5Hz), 4.75 (2H, ABq, J = 12Hz), 3.87 (3H, s), 3.53 3o (2H, ABq, J = 18Hz)

Example 22

10.4 ml of concentrated hydrochloric acid was added to a suspension of 35 48.35 g of 7- [2-methoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetamido] cephalosporanic acid (syn- Isomeres) in 725 ml of methanol. After stirring for 3 hours at ambient temperature, the reaction mixture was adjusted to pH 4.5 with an aqueous ammonia solution and the methanol 40 was distilled off. 100 ml of water were added to the residue. The mixture was adjusted to pH 6.5 with an aqueous sodium bicarbonate solution and the insoluble material was collected by filtration, whereby 6.5 g of 6- [2-methoxyimino-2- (2-amino-1,3-thiazole -4-yl) acetamido] -45 5a, 6-dihydro-3H, 7H-aceto [2, lb] furo [3,4-d] [1,3] thiazine-1,7, (4H) dione (syn- Isomeres). The filtrate was adjusted to pH 4.5 with acetic acid, adsorbed on Diaion HP-20 resin (trademark for a product of Mitsubishi Chemical Industries Ltd.) (600 ml), washed with 21 water and then with a 25% aqueous isopropyl alcohol solution eluted. The eluates containing the desired compounds were collected and cooled after the addition of isopropyl alcohol (one third the volume of the eluates). The precipitates were collected by filtration, washed with isopro-55 pyl alcohol and dried, giving 10.4 g of 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] cephalo- sporanoic acid (Syn-Isomeres) was obtained. The mother liquor was concentrated under reduced pressure until crystals started to precipitate. Isopropyl alcohol was added to the residue (% of the volume of the residue). The mixture was cooled and the precipitates were collected by filtration to give 5.8 g of the desired compound. The overall yield was 16.2 g. This compound was identified with the compound obtained in the above examples by IR-65 and N.M.R. spectra.

Example 23

10.8 g 7- [2-methoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) -

29

638 532

acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-car-bonic acid (Syn-Isomeres) were added to 200 ml of methanol and with stirring and with ice cooling at 2-9 ° C 7.2 g of phosphorus oxychloride were added dropwise. After stirring for 1.5 hours at the same temperature, the reaction mixture was concentrated under reduced pressure on a water bath from 25 to 28 ° C. to a volume of 100 ml. 300 ml of ether were added to the residue with stirring and with ice cooling. The precipitates were collected by filtration and dried to give 12.3 g of 7- [2-methoxy-imino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (1,3 , 4-thiadia-zol-2-yl) thiomethyl-3-cephem-4-carboxylic acid hydrochloride (Syn-Isomeres). 12.3 g of this powder were suspended in 100 ml of water and dissolved by adjusting the pH of the suspension to 7.5 by adding a saturated aqueous sodium bicarbonate solution. To the solution was added 100 ml of ethyl acetate and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with cold water and dried, giving 6.1 g of 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3 - (l, 3,4-thiadia-zol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres). The aqueous layer in the mother liquor was separated and stirred with cooling after the addition of sodium chloride. The precipitates were collected by filtration to give 3.8 g of the same desired compound. The overall yield was 9.9 g. This compound was identified with the compound obtained in the above examples by I.R. and N.M.R. spectra.

Example 24

The compounds shown below were obtained in a similar manner as in Examples 16 to 23.

(1) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylic acid (Syn-Isome-res) , Mp 260-270 ° C (dec).

I.R. spectrum (Nujol): 3370.3270, 1765, 1660, 1610, 1590, 1550 cm-1

N.M.R. spectrum (ds-DMSO, 8); ppm 9.58 (1H, d, J = 8Hz), 6.76 (1H, s), 5.75 (1H, dd, J = 5.8Hz), 5.12 (1H, d, J = 5Hz), 4.27 (2H, broad s) , 3.85 (3H, s), 3.57 (2H, broad s)

(2) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), F . 210-220 ° C (dec.)

I.R. spectrum (Nujol): 3250.1765.1650 cm-1

N.M.R. spectrum (ds-DMSO, 8); ppm 9.64 (1H, d, J = 8Hz), 7.4 (2H, m), 6.79 (1H, s), 6.60 (2H, m), 5.77 (1H, dd, J = 5.8Hz), 5.16 (1H, d, J = 5Hz), 4.75 (2H, ABq, J = 12Hz), 3.87 (3H, s), 3.53 (2H, ABq, J = 18Hz)

(3) 7- [2-Methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (4-methyl-4H-l, 2,4-triazol-3 -yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), mp 185 ° C (dec.)

I.R. spectrum (Nujol): 3150-3350, 1770, 1710, 1660, 1630 cm-1

N.M.R. spectrum (ds-DMSO, 8); ppm 9.61 (1H, d, J = 8Hz), 8.69 (1H, s), 6.73 (1H, s), 5.72 (1H, dd, J = 4.8Hz), 5.1 (1H, d, J = 4Hz), 4.1 (2H, ABq, J = 13Hz), 3.87 (3H, s), 3.65 (2H, broad s), 3.59 63H, s)

(4) 6- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -5a, 6-dihydro-3H, 7H-aceto [2, lb] furo [ 3,4-d] [1,3] thiazine-1,7 (4H) -dione (Syn-Isomeres), mp 210-215 ° C (dec.)

I.R. spectrum (Nujol): 3270.1780.1740.1655.1610.1525 cm-1

N.M. R. spectrum (dô-DMSO, 8); ppm 9.70 (1H, d, J = 8Hz), 7.26 (2H, broad s), 6.77 (1H, s), 5.93 (1H, dd, J = 5.8Hz), 5.16 (1H, d, J = 5Hz) , 5.05 (2H, broad s), 3.85 (3H, broad), 3.81 (2H, broad broad)

(5) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) aceta-mido] -3- [l- (2-dimethylaminoethyl) -lH-tetrazol-5-yl ] thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

I.R. spectrum (Nujol): 1765 cm-1

N.M.R. spectrum (do-DMSO, 8); ppm 9.56 (1H, d, J = 8Hz), 6.75 (1H, s), 5.75 (1H, m), 5.10 (1H, d, J = 4Hz), 4.58 (2H, broad s), 4.32 (2H, broad s), 3.82 (3H, s), 3.68 (2H, wide s), 3.20 (2H, wide s), 2.50 (6H, s)

Example 25

A solution of 0.3 g of 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylic acid (syn- Isomeres) in a mixture of 3 ml acetone and 1.5 ml water was adjusted to pH 2 with 6N hydrochloric acid and stirred for 4 hours at ambient temperature. After the acetone was distilled off, 1 ml of water was added to the residue. The mixture was adjusted to pH 7 with a saturated aqueous sodium bicarbonate solution and ice-cooled for 1 hour. The precipitated crystals were collected by filtration, washed with water and dried, giving 0.23 g of 6- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -5a, 6 -dihydro-3H, 7H-aceto [2, lb] furo [3,4-d] [1,3] thiazine-1,7, (4H) dione (Syn-Isomeres), mp 210 to 215 ° C (dec .), received.

IR spectrum (Nujol): 3270.1780.1740.1655.1610.1525 cm-1

N.M.R. spectrum (dó-DMSO, 8); ppm 9.70 (1H, d, J = 8Hz), 7.26 (2H, broad s), 6.77 (1H, s), 5.93 (1H, dd, J = 5, 8Hz), 5.16 (1H, d, J = 5Hz) , 5.05 (2H, broad s), 3.85 (3H, broad), 3.81 (2H, broad broad)

Example 26

The following compound was obtained in a similar manner as in Example 25.

6- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -5a, 6-dihydro-3H, 7H-aceto [2, lb] furo [3,4-d] [1,3] thiazine-l, 7 (4H) -dione (Syn-Isomeres)

I.R. spectrum (Nujol): 3250, 1785, 1755, 1660, 1600, 1570, 1540 cm-1

N.M.R. spectrum (da-DMSO, 8); ppm 9.83 (1H, d, J = 8Hz), 7.5-6.75 (4H, m), 6.02 (1H, dd, J = 5.8Hz), 5.21 (1H, d, J = 5Hz), 5.07 (2H, broad s), 3.95 (3H, s), 3.84 (2H, broad s)

Example 27

The compounds shown below were obtained by performing an amino protecting group elimination reaction on the carbamoyl group in a similar manner as in Example 3.

(1) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer), F . 210-220 ° C (dec.)

I.R. spectrum (Nujol): 3250.1765.1650 cm-1

N.M.R. spectrum (dé-DMSO, 8); ppm 9.64 (1H, d, J = 8Hz), 7.4 (2H, m), 6.79 (1H, s), 6.60 (2H, m), 5.77 (1H, dd, J = 5.8Hz), 5.16 (1H, d, J = 5Hz), 4.75 (2H, ABq, J = 12Hz), 3.87 (3H, s), 3.53 (2H, ABq, J = 18Hz)

(2) 7- [2-methoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. spectrum (Nujol): 3300.1780, 1705, 1680 cm-1

N.M.R. spectrum (ds-DMSO, 8); ppm 12.50 (1H, broad s), 9.67 (1H, d, J = 8Hz), 8.50 (1H, s), 7.43 (1H, s), 6.58 (2H, broad), 5.80 (1H, dd, J = 5 , 8Hz), 5.16 (1H, d, J = 5Hz), 4.78 (2H, ABq, J = 14Hz), 3.95 (3H, s), 3.57 (2H, ABq, J = 18Hz)

Reference Example 1

3.3 g of phosphorus pentachloride were added to a suspension of 1.5 g of 2-methoxyimino-2- (2-amino-l, 3-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

638 532 30

thiazoI-4-yl) acetic acid (Syn-Isomeres) in 30 ml methylene chloride - reference example 3

rid, and the mixture was stirred for 30 minutes with a mixture of 0.22 g dimethylformamide and 0.46 g

Ambient temperature stirred. The methylene chloride was heated to 40 ° C for 1 hour, distilled off under reduced pressure and to the residue. The mixture was added in 20 ml of dry methylene chloride, acetone was added to form a suspension. 5, and 0.73 g of 2-methoxyimino-2- (2-mesylimino-on the other hand, a suspension of 2.2 g of 7-amino-3- (l-3-methyl-2,3-dihydro-l , 3-thiazol-4-yl) acetic acid (anti-isome-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in res) added with stirring and with ice-cooling, then an aqueous solution of 0.76 g of sodium bicarbonate and 50, the mixture obtained was stirred under ice-cooling ml of water for 10 minutes for 1.5 hours, and 50 ml of acetic acid was stirred. On the other hand, 0.82 g of 7-amino-3- (l-methyl clay was added to form a solution. To the solution io 1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in one was the suspension obtained above , which kept the acid chloride solution of 1.5 g of bis (trimethylsilyl) acetamide in 20 ml dry, added dropwise with stirring and with ice cooling, the methylene chloride being dissolved. To this solution, when dissolved with a 20% aqueous sodium carbonate solution at -30 ° C, was added the methylene chloride solution obtained above, which was kept at pH 7.5 to 8.5. The mixture became 1 then the mixture was kept at -5 to -0 ° C for 2 hours

Stirred at 3 to 5 ° C and pH 8.0 for one hour. The acetone 15 stirred. After distilling off methylene chloride at tie was distilled off under reduced pressure, and the reflux temperature, water was added to the residue, a saturated aqueous sodium bicarbo was added, and the mixture was extracted with ethyl acetate. The nat solution was adjusted to pH 7.4 and with a 10% chlorine extract was further seen with aqueous sodium chloride solution, hydrochloric acid with stirring and with ice cooling, and 50 ml of water were added. The obtained pH adjusted to 4.5. The precipitates were filtered off, the mixture was mixed with an aqueous sodium bicarbonate solution and the filtrate was saturated with sodium chloride, adjusted to pH 7, and the aqueous layer was separated.

10% hydrochloric acid adjusted to pH 2.5 and 1 The aqueous layer was adjusted to pH 1.5, with Na

Stirred for an hour. The precipitates were saturated with filtrium chloride and extracted with ethyl acetate. The ren collected, washed with water and dried, extract being washed with an aqueous sodium chloride solution, 0.95 g of 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) ace- 25 see and dried over magnesium sulfate. The solvent mit-tamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-tel was distilled off and the residue was washed with a carboxylic acid (a mixture of the syn- and anti- Isomers) was obtained. Powdered mixture of diisopropyl ether and ether. The Pul I.R. spectrum (Nujol): 3400.1775.1710.1670.1630 cm-1 ver was collected by filtration and dried, with N.M.R. spectrum (dô-DMSO, ô); ppm 9.85 (1H, d, J = 8Hz), 1.0 g of 7- [2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-9.50 (1H, d, J = 8Hz), 7.58 (1H, s), 6.87 (1H, s), 6.65 (4H, broad), 30 dihydro-l, 3-thiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5- 5.77 (2H, m), 5.15 (2H, d, J = 5Hz), 4.35 (4H, broad), 4.06 (6H, yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer), s), 3.97 (6H, s), 3.75 (4H, broad s) 1.0 g of this powder was suspended in 30 ml of water and dissolved by adjusting to pH 6 with an aqueous sodium bicarbonate solution reference example 2. After removing the solvent

A suspension of 1.7 g of phosphorus pentachloride in 20 ml of 35 by passing nitrogen gas through it, the aqueous solution of methylene chloride was stirred by stirring for 2 hours, converting 0.98 g of sodium 7- [2-methoxyimino-2 exercise temperature into a Solution converted. 0.8 g (2-mesylimino-3-methyl-2,3-dihydro-l, 3-thiazol-4-yl) aceta-2-methoxyimino-2- (2-amino-l, 3-thiazole- 4-yl) acetic acid (syn-mido) -3- (1-methyl-l H-tetrazol-5-yl) thiomethyl-3-cephem-4-car-isomer) boxylate (anti-isomer) added all at once at ambient temperature received.

and the mixture was stirred. Under reduced pressure 40 I.R. spectrum (KBr): 1760.1675 cm-1, methylene chloride was distilled off and the residue became N.M.R. spectrum (D20.8); ppm 8.05 (1H, s), 5.76 (1H, d, dissolved in 20 ml acetone. On the other hand, 1.0 g of 7-amino-3-car-J = 5Hz), 5.16 (1H, d, J = 5Hz), 4.14 (2H, ABq, J = 13Hz), 4.10 bamoyloxymethyl-3-cephem-4-carboxylic acid in a solution (3H, s), 4.02 (3H, s), 3.52 (2H, ABq, J = 17Hz), 3.45 ( 3H, s), 3.24 of 0.59 g sodium bicarbonate suspended in 20 ml water and (3H, s)

dissolved by adding 10 ml of acetone. To this solution was 45 the above-obtained solution containing the acid chloride under Reference Example 4

Stir and while cooling with ice, added dropwise, whereby the solution The following compounds were obtained in a manner similar to that in Reference Example 3 with a 20% aqueous sodium carbonate solution at pH.

7.5 to 8.5 was held. After stirring for 1 hour at pH 8 (1) 7- [2-methoxyimino-2- (2-methyl-l, 3-thiazol-4-yl) acet-

an insoluble material was filtered off under ice cooling. 50 amido] -3- (l-methyl-l H-tetrazol-5-yl) thiomethyl-3-cephem-4-

The acetone was carboxylic acid (anti-isomer) from the filtrate under reduced pressure.

distilled off and an insoluble material was filtered off. I.R. spectrum (Nujol): 1790.1720.1680 cm-1

The filtrate was adjusted to pH N.M.R. spectrum (de-DMSO, S) with 10% hydrochloric acid; ppm 9.53 (1H, d, J = 8Hz),

2.5 set. The precipitates were filtered by filtering 8.27 (1H, s), 5.83 (1H, dd, J = 5.5Hz), 5.15 (1H, d, J = 5.5Hz), 4.30

collected and dried, giving 0.4g 7- [2-methoxyi-55 (2H, ABq, J = 14Hz), 4.00 (3H, s), 3.93 (3H, s), 3.70 (2H, ABq,

mino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3-carbamoyloxy- J = 16Hz), 2.65 (3H, s)

methyl-3-cephem-4-carboxylic acid (a mixture of syn and

Anti-isomers). The filtrate was treated with sodium chloride (2) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acet-

saturated and stirred with ice-cooling, whereby NiederamidoJ-3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-beat was obtained. The precipitates were filtered by filtering 60 carboxylic acid (anti-isomer)

collected and dried, giving 0.3 g of the same I.R. spectrum (Nujol): 3400.1775.1670 cm-1

desired compound, the overall yield was N.M.R. spectrum (de-DMSO, 5); ppm 9.44 (1H, d, J = 8Hz),

0.7 g. 7.71 (1H, s), 6.40 (2H, broad s), 5.77 (1H, dd, J = 5.8Hz), 5.13 (1H,

I.R. spectrum (Nujol): 3400.1775.1705 cm-1 d, J = 5Hz), 4.31 (2H, broad), 4.00 (3H, s), 3.95 (3H, s), 3.70 (2H,

N.M.R. spectrum (de-DMSO, 8); ppm 9.71 (1H, d, J = 8Hz), 65 wide s)

9.42 (1H, d, J = 8Hz), 7.70 (1H, s), 7.40 (4H, broad), 7.00 (1H, s),

6.61 (4H, s), 5.76 (2H, m), 5.16 (2H, d, J = 4.5Hz), 4.76 (4H, ABq, (3) 7- [2-methoxyimino-2- (2-amino- l, 3-thiazol-4-yl) acet-J = 12Hz), 3.98 (3H, s), 3.89 (3H, s), 3.53 (4H, ABq, J = I8Hz) amidoj-eephalosporanic acid (anti-isomer)

31

638 532

IR spectrum (Nujol): 3400-3100.1780.1730.1675 cm "1, NMR spectrum (de-DMSO, 8); ppm 9.43 (1H, d, J = 8Hz), 9.16 (2H, broad s) , 7.73 (1H, s), 5.82 (1H, dd, J = 5.8Hz), 5.18 (1H, d, J = 5Hz), 4.90 (2H, ABq, J = 13Hz), 4.03 (3H, s) , 3.60 (2H, broad s), 2.07 (3H, s)

(4) 7- [2-methoxyimino-2- (2-formamido-1,3, -thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4-carboxylic acid (anti-isomer) F. 152 ° C (dec.)

I.R. spectrum (Nujol): 3300-3100,1775,1720,1670,1630 cm-1

NMR spectrum (dó-DMSO, 8); ppm 12.63 (1H, broad), 9.66 (1H, s), 9.57 (1H, d, J = 8Hz), 8.50 (1H, s), 8.07 (1H, s) , 5.75 (1H, dd, J = 5.8Hz), 5.15 (1H, d, J = 5Hz), 4.27 (2H, ABq, J = 13Hz), 4.00 (3H, s), 3.70 (2H, broad s)

(5) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3- (l-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer)

I.R. spectrum (Nujol): 3350.1780.1726.1680 cm "'

N.M.R. spectrum (d "-DMSO, 8); ppm 9.24 (1H, d, J = 8Hz), 7.36-7.10.7.00-6.74 (4H, m), 5.70 (1H, dd, J = 5.8Hz), 5.13 (1H, d, J = 5Hz), 4.34 (2H, ABq, J = 13Hz), 3.95 (6H, s), 3.72 (2H, ABq, J = 17Hz)

The preparation of the starting compounds used in the examples and reference examples mentioned above is explained in more detail in the preparation examples below.

Production Example 1

A mixture of 11.9 g of 3-chloro-4-hydroxyacetophenone, 9.35 g of benzyl chloride, 14.5 g of potassium carbonate and 60 ml of dimethylformamide was stirred at 100 ° C for 1 hour. The reaction mixture was poured into 150 ml of water and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. After the solvent was distilled off, the residue (18 g) was recrystallized from 160 ml of ethanol to obtain 13.2 g of 3-chloro-4-benzyloxyacetophenone, mp 110 to 112 ° C.

Production Example 2

1.) 12.6 g of selenium dioxide powder were added over a period of 10 minutes to a solution of 19.7 g of 3-chloro-4-benzyl-oxyacetophenone in 100 ml of dry pyridine with stirring at 100 ° C., and the mixture was 3 Stirred at the same temperature for hours. The precipitated selenium was filtered off and the filtrate was concentrated. The residue was dissolved in 150 ml of water and the solution was washed with ether. The aqueous solution was acidified while cooling with concentrated hydrochloric acid and extracted with ether. The extract was washed with an aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to give 15.9 g of 2- (3-chloro-4-benzyloxy-phenyl) glyoxylic acid, mp 134-135 ° C.

2.) The compounds shown below were obtained in a similar manner to that in Preparation Example 2- (1):

(1) 2- (3-nitro-4-benzyloxyphenyl) glyoxylic acid, mp 161-164 ° C.

(2) 2- (3-chloro-4-methoxyphenyl) glyoxylic acid, mp 81-82 ° C.

I.R. spectrum (Nujol): 2500-2600, 1715, 1670, 1600 cm "1

(3) 2- (3-Mesylaminophenyl) glyoxylic acid, mp 66-68 ° C.

I.R. spectrum (Nujol): 3560.3250.1720.1670 cm-1

Production Example 3

1.) A mixture of 30 g of 2- (3-nitro-4-benzyloxyphenyl) glyoxylic acid, 90 ml of concentrated hydrochloric acid and

120 ml of acetic acid was stirred at 100 ° C for 3 hours. To the reaction mixture was added 600 ml of ice water while cooling, and the mixture was extracted with ethyl acetate. The extract was washed with ice water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from a benzene / ether / petroleum ether (2/1/4) mixture. The crystals were collected by filtration, washed with benzene and dried under reduced pressure to give 19.0 g of 2- (3-nitro-4-hydroxyphenyl) glyoxylic acid, mp 139 to 140.5 ° C.

2.) The following compound was obtained in a similar manner as in Preparation Example 3 (1): 2- (3-chloro-4-hydroxyphenyl) glyoxylic acid, mp 114 to 116 ° C.

15

Production Example 4

3.32 g of 2- (3-hydroxyphenyl) glyoxylic acid and 45 ml of a 1N methanol solution of hydroxylamine were heated under reflux with stirring for 25 minutes. The reaction mixture 20 was concentrated under reduced pressure. The residue was dissolved in 70 ml of a 1N aqueous sodium hydroxide solution. The aqueous solution was washed with ether, acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extract was washed, dried and treated with activated carbon. The solvent was distilled off to obtain 2.9 g of 2-hydroxyimino-2- (3-hydroxyphenyl) acetic acid (a mixture of the syn and anti isomers). I.R. spectrum (Nujol): 3200.1700 cm-1

3o Production example 5

1.) a) 3 drops of phenolphthalein indicator were added to a solution of 5.5 g of O-methylhydroxylamine hydrochloride in 60 ml of dry methanol. 65 ml of a 1N methanol solution of sodium methylate were added dropwise to the solution with stirring at ambient temperature until the color of the solution turned purple. O-Methylhydroxylamine hydrochloride was added in small portions until the solution became colorless. The mixture was stirred at ambient temperature for 30 minutes. After filtering off the precipitated sodium chloride, 9.85 g of 2- (3-hydroxyphenyl) glyoxylic acid was added to the filtrate and the mixture was heated under reflux for 30 minutes. After the methanol was distilled off at low temperature,

a saturated aqueous sodium chloride solution was added to the residue. The mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with 300 ml of ether. The extract was dried over magnesium sulfate. The ether was distilled off at low temperature, whereby 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (in the form of a mixture of the syn and anti isomers)

received.

b) This material was dissolved in 60 ml of ether and a solution of diazomethane in ether was slowly added while cooling with ice until the color of the mixture turned yellow. Immediately thereafter, acetic acid was added, and the mixture was washed with an aqueous sodium bicarbonate solution and an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The ether was distilled off to obtain 10.8 g of an oily residue. 60 The oily residue was subjected to column chromatography on silica gel (165 g) using a benzene / ethyl acetate (9/1) mixture as the developing solvent. First, the eluate containing the syn isomer was eluted, and the eluate was collected and concentrated to obtain 7.9 g of 65 oily methyl 2-methoxyimino-2- (3-hydroxyphenyl) acetate (syn isomer). The oil was left to give crystals, mp 39.5 to 40.5 ° C. I.R. spectrum (Nujol): 3450.1730 cm-1

638 532

32

N.M.R. spectrum (CDCh, ô); ppm 6.7-7.42 (4H, m), 3.98 (3H, s), 3.92 (3 H, s)

After the eluate containing the syn isomer was eluted, the eluate containing the anti-isomer was eluted. The eluate was collected and concentrated to give 1.5 g of methyl 2-methoxyimino-2- (3-hydroxyphenyl) acetate (anti-isomer). This material was recrystallized from a benzene / petroleum ether mixture to give crystals, mp 96 to 98 ° C. IR spectrum (Nujol): 3350.1715 cm-1 NMR spectrum (CDCh, 8); ppm 7.12-7.40 (1H, m), 6.96-7.02 (3H, m), 3.99 (3H, s), 3.84 ( 3H, s)

c) 40 ml of a 2 N aqueous sodium hydroxide solution were added with stirring at ambient temperature to a suspension of 7.55 g of methyl 2-methoxyimino-2- (3-hydroxyphenyl) acetate (Syn-Isomeres) in 70 ml of water and the Mixture was stirred at ambient temperature for 1 hour. The reaction mixture was adjusted to pH 6.5 with 10% hydrochloric acid, salted out and washed with 60 ml of ether. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and extracted once with 100 ml and twice with 60 ml ether. The extract was washed twice with 60 ml of a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The ether was distilled off to obtain an oil. Benzene was added and removed again (twice), giving 6.44 g of crystals of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres), melting point 98 to 101 ° C. (dec.), received. I.R. spectrum (Nujol): 3370.1720 cm-1

8 ml of an aqueous 2N sodium hydroxide solution were added with stirring at ambient temperature to a solution of 1.56 g of methyl 2-methoxyimino-2- (3-hydroxyphenyl) acetate (anti-isomer) in 30 ml of methanol. After stirring for 3 hours at the same temperature, the methanol was distilled off. Water was added to the residue and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, salted out and extracted with ether. The extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The ether was distilled off to obtain 1.07 g of crystals of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (anti-isomer). The crystals were recrystallized from a petroleum ether / ether mixture, giving 0.7 g of crystals, mp 99-101 ° C (dec.). I.R. spectrum (Nujol): 3350.1690 cm-1

2.) a) 3 drops of phenolphthalein indicator were added to a solution of 3.7 g of O-methylhydroxylamine hydrochloride in 45 ml of dry methanol. 39 ml of a 1N methanol solution of sodium methylate was added dropwise to the solution with stirring at ambient temperature until the color of the solution turned purple. O-Methylhydro-xylamine hydrochloride was added in small portions until the solution became colorless. The mixture was stirred at ambient temperature for 30 minutes. After filtering off the precipitated sodium chloride, 6.56 g of 2- (4-hydroxyphenyl) glyoxylic acid was added to the filtrate and the mixture was stirred at ambient temperature for 1 hour. After the methanol was distilled off at a low temperature, a saturated aqueous sodium chloride solution was added to the residue. The mixture was adjusted to pH 1 with 10% hydrochloric acid, salted out and extracted with ether. The extract was dried over magnesium sulfate. The ether was distilled off at a low temperature to obtain 2-methoxyimino-2- (4-hydroxyphenyl) acetic acid (Syn-Isomeres).

b) This material was dissolved in 50 ml of ether and a solution of diazomethane in ether was slowly added while cooling with ice until the color of the mixture turned yellow. Immediately afterwards, acetic acid was added, and the

Mixture was washed with an aqueous sodium bicarbonate solution under a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The ether was distilled off to obtain 8 g of an oily residue. 5 The oily residue was subjected to column chromatography on silica gel using a benzene / ethyl acetate (9/1) mixture as a developing solvent to obtain 6.39 g of methyl 2-methoxyimino-2- (4-hydroxyphenyl) acetate (syn- Isomeres).

io I.R. spectrum (Nujol): 3350, 1720 cm-1

N.M.R. spectrum (CDCh, 5); ppm 7.40 (2H, d, J = 8Hz), 6.80 (2H, d, J = 8Hz), 3.96 (3H, s), 3.92 (3H, s)

c) 11 ml of a 2 N aqueous sodium hydroxide solution was added with stirring at ambient temperature to a solution 15 of 2.1 g of methyl 2-methoxyimino-2- (4-hydroxyphenyl) acetate (Syn-Isomeres) in 30 ml of methanol, and the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was adjusted to pH 7 with 10% hydrochloric acid and the methanol was removed. Water was added to the residue and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, salted out and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The ethyl acetate was distilled off to obtain 1.5 g of crystals of 2-methoxyimino-2- (4-hydroxyphenyl) acetic acid (Syn-Isomeres). I.R. spectrum (Nujol): 3150.1700 cm-1 3.) a) 2 drops of phenolphthalein indicator were added to a 30 solution of 2.74 g of O-methylhydroxylamine hydrochloride in 30 ml of dry methanol. A 1N methanol solution of sodium methylate was added dropwise to the solution with stirring at ambient temperature until the color of the solution turned purple. 0-Met-35-hydroxylamine hydrochloride was added in small portions until the solution became colorless. The mixture was stirred at ambient temperature for 1 hour. After filtering off the precipitated sodium chloride, 6.75 g of 2- (3-nitro-4-hydroxyphenyl) glyoxylic acid was added to the filtrate and the mixture was stirred at ambient temperature for 1 hour. After the methanol was distilled off at 35 ° C., a saturated aqueous sodium chloride solution was added to the residue. The mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with ether. The extract 45 was dried over magnesium sulfate. The ether was distilled off under reduced pressure at 35 ° C to obtain 7 g of yellow crystals of 2-methoxyimino-2- (3-nitro-4-hydroxyphenyl) acetic acid (a mixture of the syn and anti isomers).

so b) This material was dissolved in a mixture of 15 ml of tetrahydrofuran and 100 ml of ether and a solution of diazomethane in ether was slowly added at ambient temperature until the color of the mixture turned yellow. Immediately thereafter acetic acid was added and the mixture was concentrated to dryness at 35 ° C under reduced pressure. The residue was dissolved in an ethyl acetate / benzene (1/9) solvent mixture and subjected to column chromatography on silica gel 60 using the same solvent mixture as the developing solvent. The eluate containing the syn isomer was collected and concentrated, giving 3.7 g of methyl 2-methoxy-imino-2- (3-nitro-4-hydroxyphenyl) acetate (Syn-Isomeres), mp 93 to 95 ° C, received.

I.R. spectrum (Nujol): 3300.1745, 1630.1535, 1350 cm-1 65 N.M.R. spectrum (CDCh, 8); ppm 10.87 (1H, s), 8.22 (1H, d, J = 2Hz), 7.86 (1H, dd, J = 2.8Hz), 7.20 (1H, d, J = 8Hz), 4.03 (3H, s), 3.95 (3H, s)

c) 14 ml of a 2 N aqueous sodium hydroxide solution

33

638 532

added to a solution of 3.5 g of methyl 2-methoxyimino-2- (3-nitro-4-hydroxyphenyl) acetate (syn-isomer) in 70 ml of methanol while stirring at ambient temperature and the mixture was stirred for 60 hours Ambient temperature stirred. The reaction mixture was concentrated to dryness under reduced pressure at 40 ° C and the residue was dissolved in water. The solution was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid with ice-cooling and extracted with ethyl acetate. The extract was back extracted with a saturated aqueous sodium bicarbonate solution. The aqueous extract was adjusted to pH 1 with concentrated hydrochloric acid with ice cooling and extracted with ethyl acetate. The extract was washed with ice water and dried over magnesium sulfate. The solvent was evaporated to dryness under reduced pressure at 40 ° C., 3.2 g of yellow crystals of 2-methoxyimino-2- (3-nitro-4-hydroxyphenyl) acetic acid (Syn-Isomeres), mp 142 to 143 ° C (dec.).

I.R. spectrum (Nujol): 3300.2500-2600, 1710.1630.1600, 1535.1375 cm- '

N.M.R. spectrum (CDCh, 5); ppm 10.67 (2H, s), 8.33 (1H, d, J = 2Hz), 7.95 (1H, dd, J = 2.8Hz), 7.22 (1H, d, J = 8Hz), 4.13 (3H.s)

4.) a) 6.45 g of 2- (3-chloro-4-hydroxyphenyl) glyoxylic acid and 2.74 g of O-methylhydroxylamine hydrochloride were reacted with each other in a similar manner to Production Example 5 (3) (a) to form 7 g 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetic acid (mixture of syn and anti isomers) in the form of an oil.

b) 7 g of 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetic acid (mixture of the syn and anti isomers) and 1.5 g of diazomethane were reacted with one another and the product was prepared in a manner similar to in Production Example 5 (3) (b) purified by column chromatography to obtain 3.0 g of crystals of methyl 2-methoxyimino-2- (3-chloro-4-hydroxy-phenyl) acetate (Syn-Isomeres).

I.R. spectrum (film): 3450.1735.1605.1600 cm- '

N.M.R. spectrum (CDCh, Ô); ppm 7.55 (1H, d, J = 2Hz), 7.37 (1H, dd, J = 2.8Hz), 6.95 (1H, d, J = 8Hz), 6.12 (1H, s), 3.97 (3H, s), 3.91 (3H, s)

c) 2.6 g of methyl 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetate (Syn-Isomeres) and 10.6 ml of a 2N aqueous sodium hydroxide solution were prepared in a similar manner to that in the preparation example 5 (3) (c) treated, 2.4 g of 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetic acid (Syn-Isome-res), mp 147 to 150 ° C (dec .), received.

I.R. spectrum (Nujol): 3500.2500-2600.1745.1610.1600 cm- '

N.M.R. spectrum (CDCh, 8); ppm 8.40 (2H, broad s), 7.65 (1H, d, J = 2Hz), 7.40 (1H, dd, J = 2.8Hz), 7.00 (1H, d, J = 8Hz), 4.07 (3H, s)

5.) 2.0 g of 2- (3-hydroxyphenyl) glyoxylic acid and 1.7 g of 0-allyl-hydroxylamine hydrochloride were reacted with each other in a similar manner as in Production Example 5 (2) (a) to form 2.7 g 2 -Allyloxyimino-2- (3-hydroxyphenyl) acetic acid (syn isomer) in the form of an oil.

I.R. spectrum (film): 3350.2550-2600.1720.1645.1600 cm- '

6.) 2 g of 2- (3-chloro-4-hydroxyhenyl) glyoxylic acid and 1.1 g of O-allylhydroxylamine hydrochloride were reacted with each other in a similar manner to Production Example 5 (2) (a) to form 2.5 g of 2- Allyloxyimino-2- (3-chloro-4-hydroxy-phenyl) acetic acid (syn isomer) in the form of an oil.

I.R. spectrum (film): 3450.2600, 1730, 1700, 1650, 1610, 1600 cm- '

N.M.R. spectrum (ds-DMSO, 8); ppm 9.5-10.5 (2H, broad s), 7.52 (1H, d, J = 2Hz), 7.42 (1H, dd, J = 2.8Hz), 7.12 (1H, d, J = 8Hz), 6.0 (1H, m), 5.40 (2H, t, J = 8Hz), 4.70 (2H, d, J = 5Hz)

7.) A mixture of 2.0 g of 2- (3-chloro-4-hydroxyphenyl) glyoxylic acid, 1.62 g of ot-butoxycarbonylmethylhydroxylamine and 20 ml of methanol was adjusted to pH 5-6 with the addition of a 1N methanol solution of sodium methylate and 3

Stirred at ambient temperature for 5 hours. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in a 1N aqueous sodium hydroxide solution to adjust to pH 7.0. The aqueous solution was washed with ether, adjusted to pH 2.0 with 10% strength hydrochloric acid with ice cooling and extracted with ether. The extract was washed with water and dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure,

to obtain 2.6 g of crystals of 2-t-butoxycarbonylmethoxy-15 imino-2- (3-chloro-4-hydroxyphenyl) acetic acid (Syn-Isomeres), mp 116 to 118 ° C (dec.).

I.R. spectrum (Nujol): 3250.2600.1735.1690.1670.1610, 1590 cm- '

N.M.R. spectrum (ds-DMSO, 8); ppm 11.00 (2H, broad s), 20 7.50 (1H, d, J = 2Hz), 7.40 (1H, dd, J = 2.8Hz), 7.08 (1H, d, J = 8Hz), 4.68 (2H, s ), 1.45 (9H, s)

8.) (a) 49.7 g of potassium carbonate and 45.4 g of dimethyl sulfate became a solution of 18.1 g of 2-hydroxyimino-2- (3-hydro-xyphenyl) acetic acid (a mixture of the syn and anti isomes -

25 ren) in 250 ml of dry acetone was added and the mixture was refluxed with stirring for 8.5 hours. After the acetone was distilled off, the residue was dissolved in water and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off to obtain 24 g of oil. The oil was subjected to column chromatography on silica gel using benzene as a developing solvent. First, the eluate containing the syn isomer was eluted, and the 35 eluate was collected and concentrated to give 9.2 g of methyl 2-methoxyimino-2- (3-methoxyphenyl) acetate (syn isomer) in the form of an oil received.

I.R. spectrum (film): 1738 cm- '

N.M.R. spectrum (CDCh, 8); ppm 7.47-6.77 (4H, m), 4.00 40 (3H, s), 3.92 (3H, s), 3.82 (3H, s)

After the eluate containing the syn isomer was eluted, the eluate containing the anti-isomer was eluted. The eluate was collected and concentrated to give 3.9 g of methyl 2-methoxyimino-2- (3-methoxyphenyl) acetate 45 (anti-isomer), mp 66-68 ° C. This substance was recrystallized from petroleum ether to give prisms, mp 65 to 65.5 ° C.

I.R. spectrum (Nujol): 1720 cm-1

N.M.R. spectrum (CDCh, 8); ppm 7.14-7.44 (1 H, m), 6.80-50 7.04 (3H, m), 4.02 (3H, s), 3.84 (3H, s), 3.76 (3H, s)

b) 1.6 g of methyl 2-methoxyimino-2- (3-methoxyphenyl) acetate (Syn-Isomeres) and 4 ml of an aqueous 2N sodium hydroxide solution were treated in a manner similar to that in Preparation Example 5 (3) (c), to obtain 1.23 g of 2-methoxyimino-2-55 (3-methoxyphenyl) acetic acid (Syn-Isomeres) in the form of an oil.

I.R. spectrum (film): 1735 cm- '

1.6 g of methyl 2-methoxyimino-2- (3-methoxyphenyl) acetate (anti-isomer) and 4 ml of a 2N aqueous solution of sodium hydro-6oxide were treated in a similar manner to that in Preparation 5 (3) (c) , whereby 1.3 g of 2-methoxyimino-2- (3-methoxyphenyl) acetic acid (anti-isomer), mp 97 to 98 ° C., were obtained in the form of colorless prisms.

I.R. spectrum (Nujol): 1695 cm- '

65 9.) (a) A solution of diazomethane in ether at room temperature became a solution of 7 g 2-methoxy-imino-2- (3-chloro-4-hydroxyphenyl) acetic acid (Syn-Isomeres) in 50 ml dry ether added until the color of the mixture

638 532

34

turned yellow. Immediately afterwards, acetic acid was added and the reaction mixture was concentrated to dryness under reduced pressure at 35 ° C. The residue was subjected to column chromatography on silica gel (120 g) using a benzene / ethyl acetate (9/1) mixture as a developing solvent. The first eluate was collected and concentrated under reduced pressure at 40 ° C to give 3.1 g of methyl 2-methoxyimino-2- (3-chloro-4-methoxyphenyl) acetate (syn isomer) in the form of an oil.

I.R. spectrum (film): 2850.1735.1610.1600.1250 cm- '

N.M.R. spectrum (CDCh, 8); ppm 7.57 (1H, d, J = 2Hz), 7.37 (1H, dd, J = 2.8Hz), 6.87 (1H, d, J = 8Hz), 3.97 (3H, s), 3.91 (3H, s), 3.88 (3H, s)

b) 2.7 g of methyl 2-methoxyimino-2- (3-chloro-4-methoxyphenyl) acetate (Syn-Isomeres) and 10.6 ml of an aqueous 2N sodium hydroxide solution were prepared in a manner similar to that in the preparation example 5 (3) (c) treated, wherein 2.6 g of crystals of 2-methoxyimino-2- (3-chloro-4-methoxyphenyl) acetic acid (Syn-Isomeres), mp 133 to 135 ° C (dec .), received.

I.R. spectrum (Nujol)

2500-2600, 1745.1610.1600 cm "1 NMR spectrum (CDCh, 8), ppm 9.95 (1H, broad s), 7.72 (1H, d, J = 2Hz), 7.50 (1H, dd, J = 2 , 8Hz), 6.92 (1H, d, J = 8Hz), 4.08 (3H, s), 3.95 (3H, s).

10. (a) A solution of 25 g of 2-bromopropionyl bromide in 50 ml of dry chloroform was added dropwise with stirring and with ice-cooling to a solution of 24 g of N, N-dimethylaniline in 11 g of t-butanol and the mixture was added for 2 hours Reflux heated. After cooling, the reaction mixture was poured into 150 ml of 6N sulfuric acid and extracted with ether. The extract was washed successively with 6N sulfuric acid, water, a 10% aqueous potassium carbonate solution and water and dried over magnesium sulfate. The solvent was distilled off to obtain 21 g of t-butyl 2-bromopropionate in the form of an oil.

b) 21 g of this oil were added with stirring at ambient temperature to a mixture of 16.3 g of N-hydroxyphthalimide, 24 g of triethylamine, 20 ml of dimethylformamide and 20 ml of dimethyl sulfoxide, and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured into 800 ml of water and the precipitating materials were collected by filtration, washed with water and dried to obtain 22.7 g of t-butyl-2-phthalimidopropionate.

c) 22.7 g of this compound were dissolved in 200 ml of methylene chloride. A solution of 9 ml of 10% hydrazine hydrate in 20 ml of methanol was added and the mixture was stirred at ambient temperature for 2 hours. The precipitated materials were dissolved by adding an aqueous 5N ammonia solution and the aqueous layer was extracted with methylene chloride. Two layers of methylene chloride were combined and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 13.5 gO- (l-t-butoxycarbonylethyl) hydroxylamine in the form of an oil.

IR spectrum (film) 3350.3250, 1745 cm "1

d) 2.0 g of 2- (3-chloro-4-hydroxyphenyl) glyoxylic acid and 3.2 g of 0- (lt-butoxycarbonylethyl) hydroxylamine were reacted with one another in a manner similar to that in Preparation Example 5 (7), 3 g of 2- (lt-butoxycarbonylethoxyimino) -2- (3-chloro-4-hydroxyphenyl) acetic acid (Syn-Isomeres), mp 148 to 151 ° C, was obtained.

IR spectrum (Nujol)

3450.2500-2600, 1725.1690.1620.1600 cm "1 NMR spectrum (dö-DMSO, 8), ppm 7.46 (1H, d, J = 2Hz), 7.33 (1H, dd, J = 2.8Hz ), 7.07 (1H, d, J = 8Hz), 4.67 (1H, q, J = 6Hz), 1.50 (12H, s)

11.3 drops of phenolphthalein indicator were added to a solution of 8.8 g of O-methylhydroxylamine hydrochloride in 60 ml of dry methanol. 105 ml of a 1N methanol 5 solution of sodium methylate were added dropwise to the solution with stirring at ambient temperature until the color of the solution became pale pink. 0-Methyl-hydroxylamine hydrochloride was added in small portions until the solution became colorless. The pH of the solution was 8.0 to 8.5. The mixture was stirred at ambient temperature for 30 minutes. After filtering off the precipitated sodium chloride, 16.6 g of 2- (3-hydroxyphenyl) glyoxylic acid was added to the filtrate and the mixture was stirred at ambient temperature for 1 hour. After the methanol was distilled off at low temperature, water was added to the residue. The mixture was adjusted to pH 7 with an aqueous sodium bicarbonate solution, washed with ether, adjusted to pH 1 with 10% hydrochloric acid, salted out and extracted with ether. The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The ether was distilled off and the process of adding benzene to the residue and distilling off was repeated twice, to give 14.8 g of crystals of 2-methoxyimino-2- (3-hydroxy-phenyl) acetic acid (Syn-Isomeres) received. This compound 25 was identified with the compound obtained in Production Example 5 (1) (c) by the IR spectrum.

12. A solution of 1.8 g2- (3-methoxyphenyl) glyoxylic acid in an aqueous sodium bicarbonate solution was adjusted to pH 7.0. On the other hand, a solution of 1.4 g of 0-ethyl-30-hydroxylamine hydrochloride in 20 ml of water was adjusted to pH 7.0 with sodium bicarbonate. Both solutions were combined, adjusted to pH 5.5 with 10% hydrochloric acid and stirred overnight at ambient temperature. The reaction mixture was adjusted to pH 7.5 35 with sodium bicarbonate and washed with ethyl acetate. The aqueous layer was adjusted to pH 1.0 with concentrated hydrochloric acid under ice cooling and extracted with ethyl acetate. The extract was washed with ice water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.2 g of 2-ethoxy-imino-2- (3-methoxyphenyl) acetic acid (syn isomer) in the form of an oil.

I.R. spectrum (film)

2600,1735,1700,1610,1600 cm-1 45 13.) The compounds given below were obtained in a manner similar to that in Preparation Examples 5 (5) to 5 (7) and 5 (10) to 5 (12):

(I) 2-ethoxyimino-2- (3-chloro-4-hydroxyphenyl) acetic acid (Syn-Isomeres), oil 50 I.R. spectrum (film): 3450.2250-2600.1700-1720.1610, 1600 cm "1

(2) 2-ethoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres), oil

I.R. spectrum (film): 3400,2600,1700-1730,1605,

55 1600 cm "'

(3) 2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (4-hydroxyphenyl) acetic acid (Syn-Isomeres), colorless powder.

I.R. spectrum (Nujol): 3500.3200.1700 cm "1

N.M.R. spectrum (de-acetone, 8); ppm 6.68-8.05 (7H, m), 60 5.15 (2H, s)

(4) 2- (2-ThienyImethoxyimino) -2- (4-hydroxyphenyI) acetic acid (Syn-Isomeres), powder.

I.R. spectrum (Nujol): 1705 cm- '

N.M.R. spectrum (dc-DMSO, 8); ppm 6.7-7.7 (7H, m), 5.28 es (2H, s)

(5) 2-Allyloxyimino-2- (3-methoxyphenyl) acetic acid (Syn-Isomeres), oil

I.R. spectrum (film): 3050-3100,2600,1730,1645,1610, 1600 cm- '

35

638 532

N.M.R. spectrum (ds-DMSO, ô); ppm 7.00-7.50 (4H, m), 5.80-6.30 (1 H, m), 5.33 (2H, t, J = 9Hz), 4.70 (2H, d, J = 5Hz), 3.82 (3 H, s)

(6) 2-Allyloxyimino-2- (3-chloro-4-methoxyphenyl) acetic acid (Syn-Isomeres), pale yellow oil

I.R. spectrum (film): 3100.2600, 1710-1730, 1645, 1610, 1600 cm-1

N.M.R. spectrum (ds-DMSO, 8); ppm 7.63 (IH, d, J = 2Hz), 7.50 (IH, dd, J = 2.8Hz), 7.23 (IH, d, J = 8Hz), 5.9-6.3 (IH, m), 5.33 (2H, t , J = 9Hz), 4.73 (2H, d, J = 5Hz), 3.91 (3H, s)

(7) 2-phenylthiomethoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres), oil

I.R. spectrum (film): 3300.1730 cm-1

N.M.R. spectrum (CDCh, 8); ppm 6.8-7.7 (9H, m), 5.54 (2H, s)

(8) 2-Methoxyimino-2- (3-mesylaminophenyl) acetic acid (Syn-Isomeres), mp 128 ° C (dec.).

I.R. spectrum (Nujol): 3300.1740 cm-1

(9) 2- (3-Phenylallyloxyimino) -2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres), mp 115-116 ° C

I.R. spectrum (Nujol): 3400.1725 cm-1

(10) 2-methoxyimino-2- (4-dimethylamino-phenyl) acetic acid (Syn-Isomeres), mp 88-89 ° C (dec.)

I.R. spectrum (Nujol): 2700-2100,1720, 1660,1612, 1590 cm- '

14.) 4.1 g of acetyl chloride were added with stirring and with ice cooling to a solution of 5 g of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres) in 20 ml of pyridine and the mixture was stirred for 50 minutes Ambient temperature stirred. The reaction mixture was poured into ice water, adjusted to pH 2.1 and extracted 3 times with ether. The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed thoroughly under reduced pressure to obtain 6.1 g of 2-methoxyimino-2- (3-acetoxyhenyl) acetic acid (Syn-Isomeres).

I.R. spectrum (film): 3500.2950, 1760, 1735, 1605, 1575, 1485, 1440, 1425, 1370 cm "1

N.M.R. spectrum (CDCh, 8); ppm 7.94 (1H, s), 7.6-7.0 (4H, m), 4.05 (3H, s), 2.30 (3H, s)

15.) 70 ml of trichloroacetyl isocyanate were added dropwise over a period of 6 minutes at ambient temperature to a solution of 40 g of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres) in 200 ml of dry dioxane and the mixture obtained was stirred at ambient temperature for 5 hours. The dioxane was distilled off and to the residue were added 200 ml of ethyl acetate and 200 ml of water in small portions with ice cooling. The mixture containing trichloroacetylcarbamoyl-2-methoxyimino-2- (3-trichloroacetylcarbamoyloxyphenyl) acetate was stirred at ambient temperature for 5 hours while maintaining the pH of the mixture at 6.0 to 6.4 by adding an aqueous sodium bicarbonate solution . The resulting mixture was washed twice with ethyl acetate. The aqueous layer was adjusted to pH 2 with a 10% hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the precipitated crystals were collected by filtration, whereby 15 g of colorless crystals of 2-methoxyimino-2- (3-carbamoyloxyphenyl) acetic acid (Syn-Isomeres), mp 163 ° C. (dec.), Were obtained.

5.4 g of the same compound were obtained from the mother liquor.

I.R. spectrum (Nujol): 3480.3360.1730.1660 cm-1

N.M.R. spectrum (de-DMSO, 8); ppm 3.97 (3H, s), 7.16 (2H, broad), 7.1-7.7 (4H, m), 9.7 (1H, broad s)

Production Example 6

1.) A solution of 12.4 g of sodium nitrite in 150 ml of water was added dropwise with stirring at 5 to 7 ° C. to a solution of 30 g of ethyl 4-bromoacetoacetate in 200 ml of acetic acid and the mixture was s for 2 hours at 10 ° C stirred. 200 ml of water was added to the reaction mixture, and the resulting mixture was extracted with 500 ml of ether. The extract was washed twice with 200 ml of water and with 200 ml of an aqueous sodium chloride solution and dried over 10 mg magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 32.6 g of yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of the syn and anti isomers).

1st spectrum (film): 3350, 1740, 1710, 1620 cm-1

15 N.M.R. spectrum (CDCh, 8); ppm 8.75 (2H, broad s), 4.35 (8H, m), 1.35 (6H, m)

2.) 160 g of powdered potassium carbonate was added to a solution of 152 g of ethyl 2-hydroxyiminoacetoacetate (a mixture of the syn and anti isomers) in 500 ml of acetone.

Give 20. With stirring, 130 g of dimethyl sulfate were added dropwise at 45 to 50 ° C. over a period of 1 hour and the mixture was stirred for 2 hours. An insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The insoluble material 25 filtered off was dissolved in 500 ml of water and this solution was added to the residue. The mixture was extracted twice with 300 ml of ethyl acetate. The extract was washed twice with 200 ml of water and with 200 ml of a saturated aqueous sodium chloride solution and dried over magnesium sulfate 30. The solvent was distilled under reduced pressure to give 145.3 g of a colorless oil of ethyl 2-methoxyiminoacetoacetate (a mixture of the syn and anti isomers), bp 55-64 ° C / 0.5 mm Hg .

1 I.R. spectrum (film): 1745, 1695, 1600 cm-1 35 N.M.R. spectrum (CDCh, 8); ppm 4.33 (4H, q, J = 8Hz), 4.08 (3H, s), 3.95 (3H, s), 2.40 (3H, s), 1.63 (3H, s), 1.33 (6H, t, J = 8Hz)

3.) 100 g of bromine were refluxed over a period of 40 minutes to a solution of 100 g of ethyl 2-metho

40 xyiminoacetoacetate (a mixture of the syn and anti isomers) was added dropwise in a mixture of 300 ml of carbon tetrachloride and 300 ml of acetic acid. The mixture was stirred at 70 to 80 ° C until the evolution of hydrogen bromide ceased. The reaction mixture was washed twice with 300 ml of 45 water, an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solution was treated with 2 g of activated carbon and concentrated under reduced pressure to give 120.8 g of ethyl 2-methoxyimino-4-bromoace-50 toacetate (a mixture of the syn and anti isomers).

I.R. spectrum (film): 1740.1705.1600 cm-1

N.M.R. spectrum (CDCh, 8); ppm 4.17-4.54 (8H, m), 4.15 (3H, s), 4.13 (3H, s), 1.33 (6H, t, J = 8Hz)

4.) A mixture of 11.1 g of selenium dioxide, 250 ml of dioxane 55 and 5 ml of water were at 110 to 115 ° C for 15 minutes

stirred to obtain a yellow solution. 26.4 g of ethyl 2- (2-mesylamino-l, 3-thiazol-4-yl) acetate were added with stirring at the same temperature. After stirring for 1 hour, the reaction mixture was decanted with heating and cooled, whereby yellow crystals precipitated. The crystals were collected by filtration, washed with dioxane and ether and dried to obtain 23.5 g of ethyl 2- (2-mesylamino-l, 3-thiazol-4-yl) glyoxylate.

IR spectrum (Nujol): 3300.1718.1682 cm-1 65 5.) 13.9 g of ethyl 2- (2-mesylamino-l, 3-thiazol-4-yl) glyoxylate became a with stirring at ambient temperature Solution of 5.0 g of sodium hydroxide in 150 ml of water was added. The mixture was left at ambient temperature for 1 hour.

638 532 36

rature stirred, washed with concentrated hydrochloric acid to pH rid solution and dried over magnesium sulfate. 7 adjusted and washed with ethyl acetate. The aqueous The solvent was distilled off, and 559 g was obtained

Layer was concentrated with hydrochloric acid on ethyl 2-methoxyimino-4-chloroacetoacetate (Syn-Isomeres). pH adjusted 0.5, whereby yellow crystals precipitated. Crystals I.R. spectrum (film): 1735.1705 cm-1 was collected by filtration, washed with water and dried to give 10.16 g2- (2-mesylamino-l, 3-thiazole-4-Preparation Example 7

yl) received glyoxylic acid. 1.) A mixture of 22.0 g of ethyl 2-hydroxyimino-4-

IR spectrum (nujol) bromo-acetoacetate (a mixture of the syn and anti isomers),

3350.1725.1650 cm-1 7.5 g thioacetamide and 100 ml benzene was added for 3 hours

6.) To a solution of 14 g of ethyl 2- (2-amino-l, 3-thiazol-4-io under reflux. After cooling, 10 g of yl) acetate in a mixture of 40 g of pyridine and 300 ml Methyl triethylamine was added, and the mixture was lench chloride for 1 hour, 70 ml of a diethyl ether solution was slowly stirred for a long time. An insoluble material was concentrated, with t-pentyl chloroformate, the 0.35 mol of t-pentyl chloroformate being obtained from 8.6 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazole-4-over) a period of 10 minutes at -20 ° C under yl) acetate (a mixture of the syn and anti isomers). Stirring was added and the mixture was stirred for 2 hours. This substance was stirred using benzene as the same temperature and stirring solvent was further column chromatographed on silica at 0 ° C for 0.5 hours. After the reaction, the reaction microgel (80 g) was subjected). First the anti-isomer mixture was poured into 200 ml of water, and then the organo-containing eluate was eluted, collected and concentrated, whereby the layer was separated. After 2.5 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate, the organic layer was treated with 2N hydrochloric acid, water, a 5% strength 20 (anti Isomeres), mp 90 to 92 ° C, was obtained.

aqueous sodium bicarbonate solution and water washed I.R. spectrum (Nujol): 1720 cm-1

and then dried over magnesium sulfate. The Solvent with N.M.R. spectrum (do-DMSO, 6); ppm 12.55 (1H, s), 8.25

tel was distilled off from the organic layer, whereby (1H, s), 4.27 (2H, q, J = 7Hz), 2.63 (3H, s), 1.25 (3H, t, J = 7Hz) 12 g of a dark brown oil of Ethyl 2- (2-t-pentyloxycarbo-) After the eluate containing the anti-isomer eluted, nylamino-1,3-thiazol-4-yl) acetate was obtained. 25, the eluate containing the syn isomer became

I.R. spectrum (liquid): 1667.1660 (CO) cm-1 eluted, collected and concentrated, using 0.5 g of ethyl-2

N.M.R. spectrum (CDCh, 8); ppm 3.75 (2H, s), 6.75 (1H, s) hydroxyimino-2- (2-methyl-l, 3-thiazol-4-yl) acetate (Syn-Isome-

7.) 0.3 g of ethyl 2- (2-t-penteneoxycarbonylamino-l, 3-thiazole-4-res), mp 134 to 136 ° C, was obtained.

yl) acetate and 0.11 g of selenium dioxide were obtained in a similar manner to the I.R. spectrum (Nujol): 1720 cm-1

in Preparation 6 (4) treated to form 30 N.M.R. spectrum (de-DMSO, 8); ppm 11.81 (lH, s), 7.81 0.22 g ethyl 2- (2-t-pentyloxycarbonylamino-l, 3-thiazol-4- (1 H, s), 4.35 (2H, q, J = 7Hz), 2.70 (3H, s), 1.30 (3H, t, J = 7Hz)

yöglyoxylate in the form of a brown oil. 2.) 3 drops of phenolphthalein indicator became one

I.R. spectrum (liquid): 1720.1690 (CO) cm-1 solution of 4.2 g hydroxylaminohydrochloride in 60 ml dry

N.M.R. spectrum (CDCh, 8); ppm 8.3 (1H, s) nem methanol added. The solution was stirred

8.) 2.8 g of ethyl 2- (2-t-pentyloxycarbonylamino-l, 3-thiazole-4- 35 ren at ambient temperature 60 ml of a 1N methanol solution yl) glyoxyIate and a solution of 0.54 g of sodium hydroxide in 20 of sodium methylate was added dropwise until the color of the solution became pure-ml of water in a manner similar to that in the preparation purple. Hydroxylaminhy Example 6 (5) was treated in small portions to give 1.75 g of 2- (2-t-pentyl hydrochloride) until the solution became colorless. The oxyearbonylamino-1,3-thiazol-4-yl) Glyoxylic acid in the form of a mixture was brown powder for 30 minutes at ambient temperature. «Oh moved. After filtering off the precipitated sodium chloride

I.R. spectrum (Nujol): 1730.1680 (CO) cm-1 rids, 12.5 g2- (2-mesylamino-l, 3-thiazol-4-yl) glyoxyl-

N.M.R. spectrum (dô-dimethyl sulfoxide, 8); ppm 8.4 (1H, s) acid was added to the filtrate and the mixture became 1.5

9.) A mixture of 0.37 g of ethyl 2-hydroxyimino-2- (heated under reflux for 2 hours with stirring. The Reak-amino-1,3-thiazol-4-yl) acetate (a mixture of Syn The mixture was cooled and the anti-ionization mixture was cooled, whereby crystals precipitated out (the isomers), 5 ml of ethanol, 5 ml of water and 0.72 g of sodium bisulfite crystals were collected by filtration and dried, and the mixture was fit at 65 to 70 ° C. for 12 hours touched. The reaction was concentrated to 5.5 g of crude 2-hydroxyimino-2- (2-mesylamino-1,3-mixture), and 10 ml of water thiazol-4-yl) acetic acid (a mixture of Syn and Anti -Isome- was added to the residue, and the resulting mixture was obtained. The filtrate was salted to a quarter of its volume and extracted with ethyl acetate. The extract was concentrated and ether was added. The precipitated crystals were dried over magnesium sulfate and concentrated, 50 stalls were collected by filtration, washed with ether, 0.18 g of yellow crystals of ethyl 2- (2-amino-l, 3-thiazol-4- and dried, Obtaining 8.78 g of the same compound yDglyoxylate, mp 115 to 120 ° C. The overall yield was 14.3 g.

I.R. spectrum (Nujol): 3420.3250.3120.1730.1665.1612 3.) A mixture of 2.4 g of ethyl 2-hydroxyimino-4-bromo

cm-i acetoacetate (a mixture of the syn and anti isomers) and 0.76

10.) 235 ml of sulfuryl chloride were added over a period of 55 g of thiourea in 15 ml of ethanol was stirred for 1 hour at 60 ° C. for 20 minutes with stirring and with ice cooling. Under reduced pressure, ethanol was distilled off solution of 500 g of ethyl 2-methoxyiminoacetoacetate (syn-isolated and water was added to the residue. The meres) in 500 ml of acetic acid, and the mixture obtained was brought to pH 1, Set to 0 and stirred with ethyl under cooling with water overnight. Washed lacetate for 2 hours. The aqueous layer was triethyl-long, nitrogen gas was introduced into the reaction mixture, eo amine was adjusted to pH 4.5 and extracted with ethyl acetate. The and the resulting mixture was poured into 2.51 water extract was extracted with water and a saturated aqueous. After extraction, washed with 500 ml of methylene chloride and sodium chloride solution and dried over magnesium sulfate, which was extracted twice with 200 ml of methylene chloride. The solvent was reduced, the extracts were combined. The combined pressure was distilled off, and the residue was washed using extracts, washed with a saturated aqueous sodium chloride solution of an ethyl acetate / benzene (1/3) mixture as a developing solution, and by adding 800 ml of water and a solvent of column chromatography adjusted to pH 6.5 on silica gel sodium bicarbonate. Subjected to the methylene chloride. The eluates containing the syn isomer were separated, collected with an aqueous sodium chloride and concentrated, giving 0.3 g of ethyl 2-hydroxy

37 638 532

imino-2- (2-amino-l, 3-thiazol-4-yl) acetate (Syn-Isomeres). (IH, s), 4.40 (2H, q, J = 6Hz), 4.03 (3H, s), 1.38 (3H, t, J = 6Hz) IR spectrum (Nujol): 3450.3300.3200.1725.1620 cm-1 3.) A solution of 17.4 g of ethyl 2-methoxyimino-4-bromo

N.M.R. spectrum (CDCh, S); ppm 7.65 (1 H, s), 5.33 (2H, acetoacetate (a mixture of the syn and anti isomers) and 5.4 broad s), 4.40 (2H, q, J = 7.5Hz), 1.38 (3H, t, J = 7.5Hz) g of thiourea in 100 ml of ethanol was under for 4 hours

After the eluates containing the syn isomer are heated to reflux. The reaction mixture was left to stand, the mixture of the syn- and antisees was cooled and cooled in a refrigerator, eluates containing crystals of isomers being collected and evaporated to give a precipitate. The crystals were collected by filtration, washed with 0.3 g of ethyl 2-hydroxyimino-2- (2-amino-l, 3-thiazol-4-yl) ethanol and dried to give 9.5 g of ethyl 2-acetate (a mixture of the syn and anti isomers). methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetate hydrobromide

I.R. spectrum (Nujol): 3400.3300.3200.1715.1620cm-1 to (anti-isomer). The filtrate and washings became N.M.R. spectrum (de-DMSO, ô); ppm 12.42 (1H, broad s), the combined and concentrated under reduced pressure. To 11.55 (1H, s), 7.52 (1H, s), 7.12 (4H, broad), 6.83 (1H, s), 4.23 the residue was added 100 ml of water and the (4H, m), 1.26 (6H, m) mixture was washed with ether. The aqueous layer

4.) A solution of 1.1 g of ethyl 2-hydroxyimino-2- (2- was alkaline with a 20% aqueous ammonia solution amino-1,3-thiazol-4-yl) acetate (a mixture of Syn and Anti 15 and extracted with ethyl acetate The extract was washed with isomers) in 15 ml of an aqueous 1N sodium hydroxide solution, water and a saturated aqueous sodium chloride solution, washed for 2 hours at ambient temperature and dried over magnesium sulfate. That sen. The reaction mixture was distilled off with 10% hydrochloric acid solvent under reduced pressure, acidic acid was adjusted to pH 3.5 and the precipitated crystals, 5.2 g of ethyl 2-methoxyimino-2- (2-amino-l, 3- thiazole were collected by filtration, washed with acetone, and 20 4-yI) acetate (Syn-Isomeres) was dried in the form of a crystalline substance, whereby 0.52 g of 2-hydroxyimino-2- (2-amino-l, 3- was obtained .

thiazol-4-yl) acetic acid (a mixture of the Syn and Anti-Isome I.R. spectrum (Nujol): 3400,3300,3150,1725,1630,1559

ren), mp 184 to 186 ° C (dec.). cm-1

I.R. spectrum (Nujol): 3200.1670.1530 cm-1 N.M.R. spectrum (CDCh, 8); ppm 6.72 (1H, s), 5.91 (2H,

25 broad s), 4.38 (2H, q, J = 7Hz), 4.03 (3H, s), 1.38 (3H, t, J = 7Hz) Production Example 8 9.5 g of the ethyl 2-methoxyimino-2- obtained above (2-

1.) 3.8 g of thioacetamide were added to a solution of 12.6 g of amino-1,3-thiazol-4-yl) acetate hydrobromide (anti-isomer) ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of which were in 200 ml of ethyl acetate, and 4.0 g of syn and anti-isomers) in 50 ml of ethanol were added, and the triethylamine was added. After stirring for 1 hour with reverse mixing, the mixture was stirred at 50 ° C. for 5 hours. The ethanol at 30 ° C was filtered off an insoluble material, was distilled off under reduced pressure, and to which and the filtrate was concentrated under reduced pressure, residue was added to water. The resulting mixture was extracted with 6.15 g of ethyl 2-methoxyimino-2- (2-amino-l, 3-thia) with ethyl acetate. The extract became post-azole-4-yl) acetate (anti-isomer ) in the form of a crystalline subander with water, an aqueous sodium bicarbonate solution.

and a saturated aqueous sodium chloride solution with a 35 I.R. spectrum (Nujol): 3450.3250.3150, 1730.1620cm-1 and dried over magnesium sulfate. The Solvent N.M.R. spectrum (CDCh, 8); ppm 7.50 (1H, s), 5.60 (2H, tel was distilled off under reduced pressure, using broad s), 4.35 (2H, q, J = 7Hz), 4.08 (3H, s), 1.33 (3H, t, J = 7Hz) 9.0 g of ethyl 2-methoxyimino-2- (2-methyl-l, 3-thiazol-4-yl) acetate 4.) 3 drops of phenolphthalein indicator became one (a mixture of Syn and Anti -Isomers) was obtained. Solution of 1.25 g of O-methylhydroxylamine hydrochloride in 15 ml

2.) A mixture of 7.6 g of ethyl-2-methoxyimino-4-bromo- •>> dry methanol was added. To the solution was added under acetoacetate (a mixture of the syn and anti-isomers), 3.0 g of stirring At ambient temperature, 13 ml of 1N methanol-O-ethylthiocarbamate and 5 ml of dimethylacetamide were added dropwise with sodium methylate until the color of the solution was stirred for hours at 50 ° C. The reaction mixture turned purple. In small portions, O-methylhydro- 50 ml of ethyl acetate was added and the resulting xylamine hydrochloride was added until the solution became colorless, and the mixture was washed with water and with a saturated aqueous solution of sodium chloride for 30 minutes and stirred over magnesium sulfate filtering off the precipitated Na

fat dried. The ethyl acetate was distilled off to obtain trium chloride, 3.8 g of ethyl 2- (2-mesylamino-1,3-thiazole-a crystalline residue was obtained. The residue was added to the filtrate with 4-yl) glyoxylate and the mixture Washed diisopropyl ether, heating 2.35 g of ethyl 2-metho under reflux with stirring for 2 hours. xyimino-2- (2-oxo-2,3-dihydro-l, 3-thiazol-4-yl) acetate (syn-iso-so After the methanol had been distilled off, the residue meres) was obtained. dissolved in ethyl acetate. An insoluble material was filtered off

I.R. spectrum (Nujol): 3200.1735.1680.1650 cm-1 and the filtrate was concentrated. The residue was under

N.M.R. spectrum (CDCh, 8); ppm 9.13 (1H, broad s), 6.37 Use of a benzene / ethyl acetate (9 / l) mixture as (IH, s), 4.40 (2H, q, J = 6Hz), 4.01 (3H, s), 1.38 (3H , t, J = 6Hz) Development solvent by column chromatography on the diisopropyl ether mother liquor was concentrated and subjected to the silica gel. The eluate residue containing the syn isomer was collected using a benzene / ethyl acetate and concentrated to give 2.8 g of ethyl 2-met (9/1) mixture as a developing solvent of an acid oxyimino-2- (2 -Mesylamino-l, 3-thiazol-4-yl) acetate (Syn-Isome-Lenchromatographie on silica gel (70 g). That the res) received.

Eluate containing syn isomers was collected and an I.R. spectrum (Nujol): 1725 cm-1

concentrated, with a further 0.65 g of the syn isomer 60 N.M.R. spectrum obtained above (CDCh, 8); ppm 6.76 (1 H, s), 4.44 (2H, q). The overall yield was 3.0 g. Thereafter J = 7Hz), 4.04 (3H, s), 3.04 (3H, s), 1.37 (3H, t, J = 7Hz)

was used as the developing solvent a benzene / ethyl acetate 5.) 0.33 g of powdered potassium carbonate were in a

(5/1) mixture used. The solution of 0.5 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thia eluate containing the anti-isomer was collected and concentrated to give 0.26 g of ethyl-zol-4-yl ) acetate (Syn-Isomeres) suspended in 20 ml acetone. 2-methoxyimino-2- (2-oxo-2,3-dihydro-l, 3-thiazol-4-yl) acetate 65 A solution of 0.3 g (anti-isomer) was stirred at 40 to 45 ° C. received. Dimethyl sulfate added dropwise in 5 ml of acetone. After 2 hours

I.R. spectrum (Nujol): 3250.3200.1720.1690 cm-1 stirring at the same temperature became insoluble

N.M.R. spectrum (CDCh, 8); ppm 9.90 (1H, broad s), 7.30 material filtered off. The filtrate was concentrated and it was

638 532

38

Water was added to the residue. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with water, an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, giving 0.5 g of ethyl 2-methoxyimino-2- (2-methyl-l, 3-thiazol-4-yl) acetate (syn isomer) in the form of a pale yellow oil.

I.R. spectrum (film): 1740.1710.1595 cm "1

N.M.R. spectrum (CDCh, 5); ppm 7.40 (1H, s), 4.25 (2H, q, io J = 7Hz), 4.03 (3H, s), 2.73 (3H, s), 1.38 (3H, t, J = 7Hz)

6.) 14.3 g of the 2-hydroxyimino-2- (2-mesylamino-l, 3-thiazol-4-yl) acetic acid (a mixture of the syn and anti isomers) obtained in Preparation Example 7 (2) suspended in 300 ml of dry acetone. 22.8 g of potassium carbonate and 20.8 g of dimethyl sulfate were added to the suspension. The mixture was refluxed with stirring for 9 hours. The acetone was distilled off from the reaction mixture and water was added to the residue. The resulting mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off to obtain 13 g of an oil. The oil was subjected to silica gel column chromatography using a benzene / ethyl acetate (9/1) mixture as a developing solvent. First, the eluate containing the anti-isomer was eluted, collected and concentrated. The remaining oil (2.4 g) was ground with cooling to crystallize. The crystals were collected by filtration by adding petroleum ether to give 2.1 g of methyl 2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-l, 3-thiazole-4- yl) acetate (anti-isomer).

I.R. spectrum (Nujol): 1740 cm-1

N.M.R. spectrum (CDCh, 8); ppm 7.90 (1H, s), 4.10. (3H, s), 3.90 (3H, s), 3.47 (3H, s), 3.07 (3H, s)

After the eluate containing the anti-isomer was eluted, the eluate containing the syn-isomer was eluted, collected, and concentrated to give 5.5 g of crystals of methyl 2-methoxyimino-2- (2-mesylimino-3-methyl) -2,3-dihydro-l, 3-thiazol-4-yl) acetate (Syn-Isomeres) was obtained. 40

I.R. spectrum (Nujol): 1740 cm-1

N.M.R. spectrum (CDCh, 8); ppm 6.72 (1H, s), 4.05 (3H, s), 3.92 (3H, s), 3.72 (3H, s), 3.01 (3H, s)

7.) The following compound was obtained in a similar manner as in Preparation Example 8 (4): 45 ethyl-2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetate (syn isomer )

I.R. spectrum (Nujol): 3400.3300.3150.1725.1630.1559 cm-1

N.M.R. spectrum (CDCh, 8); ppm 6.72 (1H, s), 5.91 (2H, 50 wide s), 4.38 (2H, q, J = 7Hz), 4.03 (3H, s), 1.38 (3H, t, J = 7Hz)

8.) A mixture of 6.1 g of acetic anhydride and 2.8 g of formic acid was stirred at 50 ° C for 2 hours. The resulting mixture was cooled and 4.6 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate 55 (Syn-Isomeres) was added at 15 ° C. After the mixture was stirred at ambient temperature for 3.5 hours

100 ml of chilled water are added. The resulting mixture was extracted with 200 ml of ethyl acetate. The extract was washed with water and then with a saturated aqueous sodium bicarbonate solution until the wash water was slightly alkaline. The extract was further washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was washed with diisopropyl ether 65, collected by filtration and dried to give 4.22 g of ethyl 2-methoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetate ( Syn-Isomeres) mp 122 to 124 ° C (dec.).

I.R. spectrum (Nujol): 3150, 1728, 1700 cm-1

N.M.R. spectrum (CDCh, 8); ppm 12.58 (1H, broad), 8.95

(1 H, s), 7.17 (1H, s), 4.42 (2H, q, J = 8Hz), 4.00 (3H, s), 1.37 (3H, t, J = 8Hz)

9.) 3 g of pyridine were added to a solution of 6.5 g of ethyl-2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Syn-Isomeres) in a mixture of 60 ml Ethyl acetate and 20 ml of dimethylformamide were added. 8 g of ethyl chloroformate were added dropwise to the solution while stirring at 4 ° C. After adding 50 ml of water to the reaction mixture, the organic layer was separated, washed with water and then with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (120 g) using an ether / petroleum ether (5/2) mixture as the eluent to give 5.4 g of ethyl 2-methoxyimino-2- (2-ethoxycarbonylamino -l, 3-thiazol-4-yl) acetate (Syn-Isomeres).

N.M.R. spectrum (CDCh, 8); ppm 9.36 (1H, broad), 7.10 (1H, s), 4.00-4.66 (4H, m), 4.00 (3H, s), 1.20-1.60 (6H, m)

10.) 50 g of ethyl 2-methoxyimino-4-chloroacetoacetate (Syn-Isomeres) were added over a period of 3 minutes with stirring at ambient temperature to a solution of 18.4 g of thiourea and 19.8 g of sodium acetate in a mixture of 250 ml of methanol and 250 ml of water were added. After stirring at 40 to 45 ° C. for 35 minutes, the reaction mixture was cooled with ice and adjusted to pH 6.3 with a saturated aqueous sodium bicarbonate solution. After stirring at the same temperature for 30 minutes, the precipitates were collected by filtration, washed with 200 ml of water and then with 100 ml of diisopropyl ether and dried to give 37.8 g of ethyl 2-methoxyimino-2- (2-amino-l, 3-thiazole -4-yl) acetate (Syn-Isomeres), mp 161 to 162 ° C, in the form of colorless crystals.

35 I.R. spectrum (Nujol): 3400.3300.3150.1725.1630.1559 cm-1

N.M.R. spectrum (CDCh, 8); ppm 6.72 (1H, s), 5.91 (2H, broad s), 4.38 (2H, q, J = 7Hz), 4.03 (3H, s), 1.38 (3H, t, J = 7Hz)

II.) 0.3 g of ethyl 2-hydroxyimino-2- (2-methyl-l, 3-thiazol-4-40 yl) acetate (anti-isomer) and 0.18 g of dimethyl sulfate were added

in a manner similar to that in Preparation 8 (5), with 0.27 g of ethyl 2-methoxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (anti-isomer) in the form of a pale yellow oil.

I.R. spectrum (film): 1750.1605 cm-1

N.M.R. spectrum (CDCh, 8); ppm 8.07 (1H, s), 4.41 (2H, q, J = 7Hz), 4.13 (3H, s), 2.75 (3H, s), 1.40 (3H, t, J = 7Hz)

12.) The following compound was obtained in a similar manner as in Preparation Example 8 (8): Ethyl-2-methoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetate (anti-isomer) , F. 96 to 99 ° C (dec.)

I.R. spectrum (Nujol): 3150.1740.1650.1600 cm-1

N.M.R. spectrum (CDCh, 8); ppm 11.20 (1H, broad), 8.60 (1H, s), 7.90 (1H, s), 4.32 (2H, q, J = 8Hz), 4.13 (3H, s), 1.32 (3H, t, J = 8Hz)

Production Example 9

1.) 10 ml of ethanol were added to a suspension of 2.2 g of ethyl-2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Syn-Isomeres) in 12 ml of an aqueous 1 n Sodium hydroxide solution was added and the mixture was stirred at ambient temperature for 15 hours. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid and the ethanol was distilled off under reduced pressure. The remaining aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acid and stirred with ice-cooling, whereby crystals precipitated. The crystals were collected by filtration, with Ace-.

39

638 532

washed clay and recrystallized from ethanol to give 1.1 g of 2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetic acid (Syn-Isomeres) in the form of colorless needles.

1st R. spectrum (Nujol): 3150, 1670, 1610, 1585 cm-1 N.M.R. spectrum (ds-DMSO, ô); ppm 7.20 (2H, broad s),

6.85 (1H, s), 3.83 (3H, s)

2.) 1.5 ml of an aqueous 1N sodium hydroxide solution were added to a solution of 0.3 g of ethyl 2-methoxyimino-2- (2-methyl-l, 3-thiazol-4-yl) acetate (syn- Isomeres) in 5 ml of ethanol was added, and the resulting mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid, concentrated under reduced pressure, adjusted to pH 1.5 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off to obtain 0.14 g of a crystalline substance from 2-methoxyimino-2- (2-methyl-l, 3-thiazol-4-yl) acetic acid (Syn-Isomeres).

I.R. spectrum (Nujol): 1730 cm-1 N.M.R. spectrum (d6-DMSO, 5); ppm 7.80 (1H, s), 3.85 (3H, s), 2.62 (3H, s)

3.) The compounds shown below were obtained in a similar manner as in Production Example 9 (1) to 9 (2):

(1) 2-methoxyimino-2- (2-oxo-2,3-dihydro-l, 3-thiazol-4-yl) acetic acid (syn isomer)

I.R. spectrum (Nujol): 3250.1710.1650 cm-1 N.M.R. spectrum (ds-DMSO, 8); ppm 10.61 (1H, broad), 6.73 (1H, s), 3.95 (3H, s)

(2) 2-methoxyimino-2- (2-mesylamino-l, 3-thiazol-4-yl) acetic acid (syn isomer)

I.R. spectrum (Nujol): 3150.1720 cm-1 N.M.R. spectrum (ds-DMSO, 8); ppm 7.17 (1H, s), 3.93 (3H, s), 3.02 (3H, s)

(3) 2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl) acetic acid (syn isomer)

I.R. spectrum (Nujol): 1730 cm-1

(4) 2-methoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetic acid (Syn Isomer), mp 152 ° C (dee.)

I.R. spectrum (Nujol): 3200, 2800-2100, 1950, 1600 cm-1 N.M.R. spectrum (ds-DMSO, 8); ppm 8.60 (1H, s), 7.62 (1H, s), 3.98 (1H, s)

(5) 2-methoxyimino-2- (2-thoxycarbonylamino-l, 3-thiazol-4-yl) acetic acid (syn isomer)

I.R. spectrum (Nujol): 3200.1730.1710.1690.1570 cm-1 N.M.R. spectrum (dó-DMSO, 8); ppm 12.16 (1H, broad), 7.50 (1H, s), 7.20 (1H, broad), 4.25 (2H, q, J = 7Hz), 3.93 (3H, s), 1.25 (3H, t, J = 7Hz)

4.) 5 ml of pyridine were added to a suspension of 2.0 g of 2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetic acid (Syn-Isomeres) in 20 ml of ethyl acetate. With stirring, a solution of 2.5 g of bis (2,2,2-trifluoroacetic acid) anhydride in 3 ml of ethyl acetate was added dropwise at 5 to 7 ° C, and the mixture was stirred at 3 to 5 ° C for 30 minutes . 30 ml of water was added to the reaction mixture and the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate, and two layers of ethyl acetate were combined, washed with water and a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.72 g of 2-methoxyimino-2- [2- (2,2,2-trifluoroacetamido) -l, 3-thiazol-4-yl] acetic acid (Syn-Isomeres) .

I.R. spectrum (Nujol): 1725.1590 cm-1 N.M.R. spectrum (ds-DMSO, 8); ppm 7.68 (1H, s), 3.91 (3H, s)

5.) The connection specified below was opened

similar manner as obtained in Preparation 9 (4): 2-methoxyimino-2- (2-acetamido-l, 3-thiazol-4-yl) acetic acid (Syn-Isomeres), mp 184 to 185 ° C (dec. )

I.R. spectrum (Nujol): 3200.3050, 1695.1600 cm-1 5 6.) 3 drops of phenolphthalein indicator were added to a solution of 0.84 g of O-allylhydroxylamine hydrochloride in 10 ml of dry methanol. 6 ml of a 1N methanol solution of sodium methylate was added dropwise to the solution with stirring at ambient temperature until the color of the solution became pale pink. O-allylhydroxylamine hydrochloride was added in small portions until the solution became colorless. The mixture was stirred at ambient temperature for 30 minutes. After the precipitated sodium chloride was filtered off, 2.0 g of 2- (2-c-pentyloxycarbonyla-15 mino-l, 3-thiazol-4-yl) glyoxylic acid was added to the filtrate and the mixture was stirred at ambient temperature for 1 hour touched. After the methanol was distilled off at a low temperature, the residue was dissolved in an aqueous 1N sodium hydroxide solution. The solution was washed with 20 ether and ethyl acetate was added. The mixture was adjusted to pH 1.5 with phosphoric acid and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The ethyl acetate was distilled off and the residue was washed with diisopropyl ether, collected by filtration and dried to give 1.62 g of 2-allylo-xyimino-2- (2-t-pentyloxycarbonylamino-l, 3-thiazol-4-yl) acetic acid (Syn-Isomeres).

IR spectrum (Nujol): 3200.1712 cm-1 30 NMR spectrum (dó-DMSO, 8); ppm 7.40 (1H, s), 6.24-5.76 (1H, m), 5.26 (2H, dd, J = 9.10Hz), 4.65 (2H, d, J = 5Hz), 1.78 (2H, q, J = 8Hz), 1.44 (6H, s), 0.88 (3H, t, J = 8Hz)

7.) The compounds shown below were obtained in a similar manner to that in Preparation Example 9 (6).

35 th:

(1) 2-methoxyimino-2- (2-t-pentyloxycarbonylamino-l, 3-thiazol-4-yl) acetic acid (Syn-Isomeres)

IR spectrum (Nujol): 3200.1712 cm-1 NMR spectrum (ds-DMSO, 8); ppm 7.40 (1H, s), 3.88 40 (3H, s), 1.77 (2H, q, J = 8Hz) , 1.44 (6H, s), 0.88 (3H, t, J = 8Hz) (2) 2-allyloxyimino-2- (2-mesylamino-l, 3-thiazol-4-yl) -acetic acid (syn-isomer )

IR spectrum (Nujol): 3150, 1710, 1605 cm-1 (3) methoxyimino-2- (zamino-l, 3- + thiazol-4-yl) acetic acid (Syn-Isomeres) 45 IR spectrum (Nnjol ): 3150.1670.1610.1585 cm-1

N.M.R. spectrum (ds-DMSO, 8); ppm 7.20 (2H, broad s), 6.85 (1H, s), 3.83 (3H, s)

8.) 15.5 g of ethyl-2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetate hydrobromide (anti-isomer) were dissolved in a solution

50 of 4.4 g of sodium hydroxide was dissolved in 150 ml of water, and the solution obtained was stirred at ambient temperature for 1 hour. An insoluble material was filtered off and the filtrate was adjusted to pH 5.0, whereby crystals precipitated. The crystals were collected by filtration 55 and dried to give 8.0 g of 2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetic acid (anti-isomer). I.R. spectrum (Nujol): 3150.1655, 1595.1550 cm-1 N.M.R. spectrum (ds-DMSO, 8); ppm 7.53 (1H, s), 7.23 (2H, broad), 3.99 (3H, s)

60 9.) The compounds shown below were obtained in a similar manner as in Preparation Example 9 (8):

(1) 2-methoxyimino-2- (2-methyl-l, 3-thiazol-4-yl) acetic acid (anti-isomer)

65 I.R. spectrum (Nujol): 1730.1590 cm-1

N.M.R. spectrum (ds-DMSO, 8); ppm 8.10 (1H, s), 4.00 (3H, s), 2.65 (3H, s)

(2) 2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-

638 532

40

1,3-thiazol-4-yl) acetic acid (anti-isomer)

I.R. spectrum (Nujol): 1730 cm-1

(3) 2-methoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetic acid (anti-isomer), mp 156-158 ° C (dec.)

I.R. spectrum (Nujol): 3200.2700-2100.1690.1590.1560 cm-1

N.M.R. spectrum (ds-DMSO, 8); ppm 8.05 (1H, s), 4.02 (3H, s)

Production Example 10

To a solution of 30 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid and 12.6 g of sodium bicarbonate in 1300 ml of water was added 19.8 g of allyloxyamine hydrochloride and the mixture was stirred at ambient temperature at pH 6 for 7 hours touched. 500 ml of ethyl acetate was added to the reaction mixture. After the mixture was adjusted to pH 1.9 with 10% hydrochloric acid, the ethyl acetate layer was separated. The ethyl acetate layer was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off. The residue was pulverized in diisopropyl ether, collected by filtration, and then dried to obtain 25.3 g of 2-allyloxyimino-2- (2-formamidothiazol-4 ~ yl) acetic acid (Syn-Isomeres).

I.R. (Nujol): 3110.1730.1660.1540 cm-1

N.M.R. (ds-DMSO, 8): 4.70 (2H, m), 5.13-5.60 (2H, m), 5.73-6.27 (1H, m), 7.57 (1H, s), 8.35 (1H, s)

Production Example 11

1.) 35.2 g of sulfuryl chloride were added all at once to a stirred solution of 48.9 g of ethyl 2-ethoxyimino-3-oxobutyrate (Syn-Isomeres) in 49 ml of acetic acid at room temperature, and stirring was carried out at the same temperature Continued for 1 hour. After the solution thus obtained was added to 200 ml of water, the solution was extracted with methylene chloride. The extract was washed with a saturated aqueous sodium chloride solution, neutralized with an aqueous sodium bicarbonate solution and washed with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure to obtain 53.8 g of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer) in the form of a pale yellow oil.

2.) A mixture of 38.7 g of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate, 13.2 g of thiourea, 14.3 g of sodium acetate, 95 ml of methanol and 95 ml of water was stirred at 48 ° C. for 40 minutes . After the resulting solution was adjusted to pH 6.5 with an aqueous sodium bicarbonate solution, the precipitates which appeared were collected by filtration and washed with diisopropyl ether, whereby 14.7 g of ethyl 2-ethoxyimino-2- (2-aminothiazol-4 -yl) acetate (Syn-Isomeres), mp 130 to 131 ° C, was obtained.

I.R. (Nujol): 3450.3275.3125.1715.1620 cm-1

3.) 5 g of ethyl-2-ethoxyimino-2- (2-aminothiazol-4-yl) acetate (Syn-Isomeres) was added to a mixture of 45.9 ml of 1N sodium hydroxide and 30 ml of ethanol, and it became 5 Stirred at room temperature for hours. After the ethanol had been removed from the resulting solution under reduced pressure, the residue was dissolved in 60 ml of water and adjusted to pH 2.0 with 10% hydrochloric acid. The solution was subjected to salting-out, and the precipitates were collected by filtration and dried to obtain 2.9 g of 2-ethoxyimino-2- (2-aminothiazol-4-ylylacetic acid (Syn-Isomeres).

I.R. (Nujol): 3625.3225 (shoulder), 3100.1650.1615 cm- "

N.M.R. (ds-DMSO, 8) 1.20 (3H, t, J = 7Hz), 4.09 (2H, q, J = 7Hz), 6.82 (1 H, s), 7.24 (2H, broad s)

4.) 100 g of 2-ethoxyimino-2- (2-aminothiazol-4-yl) acetic acid (Syn-Isomeres), 85.5 g of formic acid and 190.1 g of acetic anhydride were prepared in the same manner as in Preparation Example 9 (4th ) treated to obtain 99.1 g of 2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (Syn-Isomeres).

I.R. (Nujol): 3200.3140.3050.1700 cm "1 s NMR (ds-DMSO, 8) 1.18 (3H, t, J = 6Hz), 4.22 (2H, q, J = 6Hz), 7.56 (1H, s ), 8.56 (1H, s), 12.62 (1H, broad)

Production Example 12

The following compounds were prepared in a similar manner as in Preparation Examples 10 tons and 11:

(1) 2-isopropoxyimino-2- (2-formamidothiazol-4-yl) -acetic acid (Syn-Isomeres), mp 168-169 ° C (dec.)

I.R. (Nujol): 3200.3130.1710.1600.1560 cm "1

(2) 2-butoxyimino-2- (2-formamidothiazol-4-yl) acetic acid 15 (syn isomer)

I.R. (Nujol): 3350.3160.3050.1700.1680.1570 cm "1 _

(3) 2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (Syn-Isomeres), mp 115-116 ° C (dec.)

I.R. (Nujol): 3170,3070,1720,1700,1660 cm- '20 N.M.R. (ds-DMSO, 8) 0.6-2.1 (11H, m), 4.15 (2H, t, J = 6Hz), 7.53 (1H, s), 8.56 (1H, s), 12.69 (1H, s)

(4) 2-Pentyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (Syn-Isomeres), mp 176 ° C (dec.)

I.R. (Nujol): 3160.1655.1620.1460 cm- '25 N.M.R. (ds-DMSO, 8) 7.20 (2H, s), 6.82 (1H, s), 4.07 (2H, t, J = 6Hz), 0.6-2.2 (9H, m)

(5) 2-Propoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (Syn-Isomeres), mp 164 ° C (dec.)

I.R. (Nujol): 3200.3120.3050, 1700, 1550 cm "1 30 (6) 2-pentyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (Syn-Isomeres), mp 125 ° C (dec. )

I.R. (Nujol): 3200.3140.1700.1565 cm- '

(7) 2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (Syn-Isomeres), mp 187 ° C (dec.) 35 (8) 2-hexyloxyimino-2- (2-aminothiazol-4 -yl) acetic acid (Syn-Isomeres), mp 174 ° C (dec.)

I.R. (Nujol): 1660.1625, 1425 cm "'

(9) 2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetic acid (Syn-Isomeres), mp 151 ° C (dec.) 40 (10) 2-isobutoxyimino-2- (2-aminothiazol-4 -yl) acetic acid (Syn-Isomeres), mp 122-124 ° C

(11) 2-Propoxyimino-2- (2-aminothiazol-4-yl) acetic acid (Syn-Isomeres), mp 161 ° C (dec.)

(12) 2-isobutoxyimino-2- (2-formamidothiazol-4-yl) -acetic acid-45 acid (Syn-Isomeres), mp 163 ° C (dec.)

Production Example 13

1.) 500 ml of water were added to 490.0 g of hexylamine and a solution of 193.6 g of sodium hydroxide in 700 ml of water was added while cooling with ice and with stirring. 367.8 g of carbon disulfide were added dropwise at 2 to 10 ° C. over a period of 2 hours, and 687.3 g of methyl iodide were then added dropwise at 0 to 5 ° C. over a period of 1 hour. The resulting mixture was stirred at the same temperature for 55 minutes and at ambient temperature for 2 hours. The reaction mixture was extracted with 1.51 diethyl ether. The extract was washed with 300 ml of a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated to give 60,825.5 g of methyl N-hexyldithiocarbamate in the form of an oil.

I.R. (Film): 3225.2960.2935.2860 cm "'

N.M.R. (CDCh, 8) 0.86 (3H, t, J = 5.0Hz), 1.10-1.90 (8H, m), 2.58 (3H, s), 3.72 (2H, m)

65 2.) 155.9 g of sodium azide and 0.81 of water were added with stirring to a solution of 430 g of methyl N-hexyldithiocarbamate in 1.71 of ethanol, and the resulting mixture was kept at 90 ° C. for 3.5 hours heated under reflux. The

41 638 532

Ethanol was distilled off from the reaction mixture and filtered, collected, washed with diethyl ether and dried.

the residue was washed with 11 diethyl ether, with Konnet, whereby 7.7 g of benzhydryl-7- (2-phenylacet-

centered hydrochloric acid adjusted to pH 2.0 and amido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-

extracted with 11 diethyl ether. The extract was obtained with water 4-carboxylate-1-oxide.

washed, dried over magnesium sulfate and concentrated, 5 I.R. (Nujol): 3280, 1790, 1700, 1650, 1600, 1530 cm-1

where 431.3 g of l-hexyl-1H-tetrazole-5-thiol in the form of a 3.) 3.2 g of phosphorus trichloride were at -40 ° C to a

Got oil. stirred solution of 7.6 g of benzhydryl-7- (2-phenylacetamido) -

I.R. (film): 3110.2960.2930.2860 cm-1 3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-carbo-

N.M.R. (CDCh, 5) 0.91 (3H, t, J = 5.0Hz), 1.10-1.65 (6H, xylate-1 oxide in 50 ml dimethylformamide added and the m), 1.97 (2H, m), 4.33 (2H, t, J = 7.0 Hz) 10 mixture was stirred at -20 to -40 ° C for 1 hour. The

3.) To 150.0 g of 7-aminocephalosporanic acid, 31 of a reaction mixture were poured into chilled water. The

0.2 M phosphate buffer solution was added, the precipitates by dissolving were collected by filtration, washed with water of 62.1 g of sodium biphosphate dihydrate and 25.5 g of disodium, and dried to give 5.0 g of benzhydryl-7- (2-

hydrogenphosphate had been prepared in 31 water, and phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -

the resulting mixture was obtained with an aqueous 2 n '5 3-cephem-4-carboxylate.

Sodium carbonate solution adjusted to pH 6.5. To the I.R. (Nujol): 3280.3190.1780.1730.1710.1660.1620.1600,

154.6 g of l-hexyl-1H-tetrazole-5-thiol was added to the mixture 1540 cm-1

ben, and the resulting mixture was N.M.R. (ds-DMSO, 8) 3.56 (2H, s), 3.64 (2H, s), 4.86 (2H,

at 60 to 65 ° C and at a pH of 6.0 to 6.5 under ABq, J = 12Hz), 5.I4 (1H, d, J = 5Hz), 5.76 (1H, d, d, J = 5 and

Introducing nitrogen gas stirred. The reaction mixture 20 8Hz), 6.95 (1 H, s), 7.00-7.70 (19H, m), 9.10 (1 H, d, J = 8Hz),

was treated with concentrated hydrochloric acid under ice cooling 1 o.OO (2H, s)

adjusted to pH 3.5. The precipitates were collected by 4.) 1.9 g of pyridine were collected to a solution of 4.93 g of Phos filtering and washed with water and phorpentachloride in 50 ml of methylene chloride was added at 5 ° C.

41 methanol and 400 ml concentrated hydrochloric acid, and the suspension was stirred for 30 minutes

admitted. The mixture was stirred for 2 hours and stirring temperature. To the reaction mixture, an insoluble material was filtered off. The filtrate was 5.0 g of benzhydryl-7- (2-phenylacetamido) -3- [N- (3-chlorophe-

treated with activated carbon and treated with a 28% aqueous nyI) carbamoyloxymethyl] -3-cephem-4-carboxylate at 5 ° C

Ammonia solution adjusted to pH 3.5. The precipitates give and it was stirred for 1.5 hours at 5-7 ° C, collected by filtration, successively with water, to form a homogeneous solution. To get the above

Washed acetone and diethyl ether and dried, whereby 30 NEN solution, which had been cooled to -30 ° C, 8

116.38 g of 7-amino-3- (l-hexyl-1H-tetrazol-5-yl) thiomethyl-mi methanol are added. After the solution for 1 hour

3-cephem-4-carboxylic acid was obtained in the form of a powder. Was stirred at -10 to -20 ° C, 5 ml of water

I.R. (Nujol): 1803.1620.1350 cm-1 was added and stirring was continued at 0 to for 30 minutes

N.M.R. (ds-DMSO, 8) 0.95 (3H, t, J = 6.5Hz), 1.26 (6H, m), 5 ° c continued. After removing the solvent under

1.80 (2H, m), 3.65 (2H, ABq, J = 18Hz), 4.00-4.50 (4H, m), 4.79 35 reduced pressure, 80 ml water and 100 ml diet hy

(1H, d, J = 6.0Hz), 4.95 (1H, d, J = 6.0Hz) ether added to the residue and the oil-containing aqueous layer was separated. That contains the oil

Preparation Example 14 aqueous solution was with a 20% aqueous

283.0 g of 7-aminocephalosporanic acid and 225.0 g of 1-propyl sodium carbonate solution are adjusted to pH 8.0 and treated with ethyl

1 H-tetrazole-5-thiol was extracted in a similar manner to that in the acetate. The extracts were saturated with a

Position example (3) in 5.51 of a 0.2 M phosphate buffer solution, aqueous sodium chloride solution, treated with magnesium, 125.0 g of 7-amino-3- (l-propyl-1H-tetrazole sulfate) being dried and concentrated under reduced pressure.

5-yl) thiomethyl-3-cephem-4-carboxylic acid was obtained. The residue was pulverized with diisopropyl ether, whereby

I.R. (Nujol): 3300.1795.1610 cm-1 and 2.2 g of benzhydryl-7-amino-3- [N- (3-chlorophenyl) carbamoy-

N.M.R. (dó-DMSO, 8) 0.91 (3H, t, J = 7.5 Hz), 1.60-2.28 (2H, 45 loxymethyl] -3-cephem-4-carboxylate.

m), 3.63 (2H, ABq, J = 18.0Hz), 3.98-4.58 (4H, m), 5.08 (1H, d, IR (Nujol): 3410.3360.1760, 1700.1650, 1595.1520 cm -1

J = 5.0Hz), 5.49 (1H, d, J = 5.0Hz) N.M.R. (ds-DMSO, 8) 3.60 (2H, broad), 4.80 (lH, d,

J = 5Hz), 4.83 (2H, ABq, J = 13Hz), 5.05 (IH, d, J = 5Hz), 6.93

Preparation 15 (1H, s), 6.90-7.70 (14H, m), 9.97 (1H, s)

1.) 3.7 g of 3-chlorophenyl isocyanate were at ambient 50

temperature to a solution of 10.3 g of benzhydryl-7- (2-phenyl preparation example 16

acetamide) -3-hydroxymethyl-3-cephem-4-carboxylate in one The compounds given below were based on

Mixture of 200 ml of tetrahydrofuran and 2.4 g of triethylamine was added in a manner similar to that in Preparation 15, and the mixture was stirred for 1 hour. The manufactured:

55 (1) benzhydryl-7-amino-3- (N-phenylcarbamoyloxymethyl) -

narrowed. The residue was dissolved in 200 ml of ethyl acetate and 3-cephem-4-carboxylate the solution was sequentially washed with 10% hydrogen chloride I.R. (Nujol): 3420.3380.1770, 1725, 1660, 1600.1530 cm-1

acid, a saturated aqueous sodium bicarbonate solution N.M.R. (ds-DMSO, 8) 3.65 (2H, broad s), 4.83 (2H, ABq,

and a saturated aqueous sodium chloride solution - J = 13Hz), 4.90 (1H, d, J = 5Hz), 5.10 (1H, d, J = 5Hz), 7.00 (1H,

see, giving a solution which was a mixture of 60 s), 6.83-7.73 (15H, m), 9.78 (1 H, s)

Benzhydryl-7- (2-phenylacetamide) -3- [N- (3-chlorophenyl) carba- (2) benzhydryl-7-amino-4- (4-nitrobenzoyloxymethyl) -3-

moyloxymethyl] -3-cephem-4-carboxylate and benzhydryl-7- (2-cephem-4-carboxylate hydrochloride phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -2- I.R. (Nujol): 3400.3350.1770.1720.1630.1600.1540 cm-1

cephem-4-carboxylate contained. N.M.R. (ds-DMSO, 8): 3.74 (2H, broad s), 4.72-5.32 (4H, m),

2.) To the ethyl acetate solution obtained above was a solution of at 7 65 6.92 (1H, s), 7.0-7.64 (10H, m), 8.12 (2H, d, J = 9Hz), 8.32 (2H, to 10 ° C) 5.2 g 3-chloroperbenzoic acid in ethyl d, J = 9Hz)

Acetate was added dropwise and the mixture was stirred at the same temperature for 1 hour. The rainfall was through

638 532

42

Example 28

3.0 g of 2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (Syn-Isomeres) and 40 ml of dry ethyl acetate were added at 0 to 5 ° C. with stirring to a suspension of a Vilsmeier reagent, the was conventionally prepared from 1.0 g of dry dimethylformamide and 2.1 g of phosphorus oxychloride in 4.0 ml of dry ethyl acetate, and the resulting mixture was stirred at the same temperature for 30 minutes. The solution became at -10 ° C with stirring to a solution of 3.7 g of 7-amino-3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, 10.3 g of trimethylsilyl acetamide and 6.8 g of bis (trimethylsilyl) acetamide in 80 ml of dry ethyl acetate were added and the mixture was stirred at the same temperature for 1.5 hours. After adding 50 ml of water to the reaction mixture, an insoluble material was filtered off, the ethyl acetate layer in the filtrate was separated and extracted with 50 ml of an aqueous sodium bicarbonate solution. The aqueous extract was washed with ethyl acetate and acidified to pH 2.0 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed with water and dried, giving 2.3 g of 7- [2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained in the form of a powder.

I.R. (Nujol): 3250.1780.1680 cm "1

N.M.R. (ds-DMSO, 8) 1.31 (3H, t, J = 7.0Hz), 3.77 (2H, m), 4.28 (2H, q, J = 7.0Hz), 4.43 (2H, ABq, J = 13, 0Hz), 5.18 (1H, d, J = 5.4Hz), 5.84 (1H, d, d, J = 5.4 and 9.8Hz), 7.42 (1H, s), 8.53 (1 H, s), 9.57 (1H, s), 9.66 (1H, d, J = 9.8Hz)

Example 29

The Vilsmeier reagent was prepared in a conventional manner from 1.0 g of dry dimethylformamide, 4 ml of dry ethyl acetate and 2.1 g of phosphorus oxychloride. Then 45 ml of dry ethyl acetate and 2.85 g of 2-methoxy-imino-2- (2-formamidothiazol-4-yl) acetic acid (Syn-Isomeres) were added. This solution was added at -10 ° C to a stirred solution prepared by stirring 1 hour at 40 ° C of a mixture of 4.5 g of 7-amino-3- (1-hexyl-1H-tetrazole-5 -yl) thiomethyl-3-cephem-4-carboxylic acid, 10.4 g of trimethylsilylacetamide and 90 ml of dry ethyl acetate, and the resulting mixture was stirred at -5 to -10 ° C for 1.5 hours. 50 ml of water was added to the reaction mixture and the ethyl acetate layer was separated. 40 ml of water was added and the mixture was adjusted to pH 7.0 with a saturated aqueous sodium bicarbonate solution. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried under reduced pressure, whereby 6.18 g of 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l- hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained in the form of a powder.

I.R. (Nujol): 3250.1777.1680 cm "1

N.M.R. (ds-DMSO, 8) 0.85 (3H, t, J = 5.5Hz), 1.65 (6H, m), 2.78 (2H, m), 3.72 (2H, m), 3.93 (3H, s), 4.07- 4.59 (4H, m), 5.17 (1H, d, J = 5.0Hz), 5.83 (1H, d, d, J = 5.0.8.2Hz), 7.46 (1H, s), 9.56 (IH, s), 9.70 (IH, d, J = 8.2Hz)

Example 30

0.92 g of phosphorus oxychloride was added dropwise over 3 minutes at -5 to -10 ° C to a solution of 0.44 g of dimethylformamide in 2 ml of ethyl acetate. 20 ml of ethyl acetate was added and after 10 minutes 1.29 g of 2-isopropoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres) at -5 to -10 ° C added. The mixture was stirred for 10 minutes to give a clear solution. On the other hand, 1.37 g of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid was dissolved with stirring in a solution of 1.68 g of sodium bicarbonate in 30 ml of water, and then 20 ml of acetone was added. The ethyl acetate solution obtained above was added dropwise to the solution with stirring at 0 to 5 ° C. and at a pH of 6.5 to 7.5. After stirring at the same temperature for 20 minutes, the aqueous layer was separated and the acetone was distilled off. The remaining aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid with ice cooling and with stirring. The precipitates were collected by filtration, washed with water and dried, giving 1,5g7- [2-isopropoxyimino-2- (2-formamido-l, 3-thia-zol-4-yl) acetamido] -3-carbamoyloxymethyl- 3-cephem-4-carbon-15 acid (Syn-Isomeres) was obtained.

I.R. (Nujol): 3450.3250.1780.1710.1690.1650 cm "1

N.M.R. (d6-DMSO, 8) 9.63 (1H, d, J = 8Hz), 8.53 (IH. sì. 7.43 (IH, s), 6.60 (IH, s), 5.83 (IH, dd, J = 5.8Hz) , 5.20 (IH, d, J = 5Hz), 4.77 (2H, ABq, J = 14Hz), 4.40 (IH, m), 3.57 (2H, broad 20 s), 1.27 (6H, d, J = 6Hz)

Example 31

0.05 g of water was added to a suspension of 1.0 g of 2-allyl-oxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetic acid (Syn-Isomeres)

25 in 10 ml of tetrahydrofuran added. At 0 to 5 ° C, 0.84 g of phosphorus oxychloride was added and the mixture was stirred at the same temperature for 20 minutes. 0.66 g of trimethylsilylacetamide was added and the mixture was stirred at the same temperature for 20 minutes. 0.66 g of trimethylsilylacetamide was added and the mixture was stirred at the same temperature for 20 minutes, then 0.84 g of phosphorus oxychloride was added, the resulting mixture was stirred at 0 to 5 ° C. for 20 minutes, then 0.45 g of dimethylformamide was added and the resulting mixture was stirred at the same temperature for 1 hour. The solution thus obtained was added dropwise at -5 to 5 ° C. and at a pH of 7.0 to 8.0 to a solution which had been prepared by adding 15 ml of acetone and 15 ml of tetrahydrofuran to a solution of 1.45 g of 7-amino-3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in a mixture of 0.42 g of sodium bicarbonate and 10 ml of water. The resulting mixture was stirred under ice cooling for 2 hours while keeping the pH of the mixture at 7.0 to 8.0, and then the pH was adjusted to 7.5.

The insoluble material was filtered off and the filtrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 6.0 and the organic solvent in the aqueous layer was distilled off under reduced pressure. The remaining aqueous layer was adjusted to pH 4.0 and an insoluble material was filtered off. The filtrate was adjusted to pH 3.0 and the precipitates were collected by filtration and dried to give 1.5 g7- [2-allyloxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3-55 (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) was obtained.

1st row (Nujol): 3350.1780.1680.1630 cm "1

N.M.R. (de-DMSO, 8) 9.63 (1H, d, J = 8Hz), 9.57 (1H, s), 7.23 (2H, m), 6.77) 1H, s), 6.10 (1H, m), 5.83 (1H, dd, J = 5, 8Hz), 5.43 60 1H, m), 5.25 (1H, m), 5.17 (1H, d, J = 5Hz), 4.61 (2H, m), 4.47 (2H, ABq, J = 14Hz ), 3.72 (2H, m)

Example 32

0.1 ml of water was added to a suspension of 2.0 g of 2-hexyloxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetic acid (Syn-Isomeres) in 20 ml of tetrahydrofuran. At 0 to 5 ° C, 1.4 g of phosphorus oxychloride was added and the mixture was at the same temperature for 20 minutes

43

638 532

touched. 1.3 g of trimethylsilylacetamide were added and the mixture was stirred at the same temperature for 20 minutes, then 1.4 g of phosphorus oxychloride were added, the resulting mixture was stirred at 0 to 5 ° C. for 20 minutes, it became 0 , 75 g of dimethylformamide 3 were added, and the resulting mixture was stirred at the same temperature for 1 hour. The solution obtained was suddenly at -20 ° C to a solution of 3.3 g of 7-amino-3- (1 Hl, 2,3-triazol-5-yl) thiomethyl-3-cephem-4-car-bonic acid added in a mixture of 30 ml of tetrahydrofuran and 6.8 io g of trimethylsilylacetamide. The resulting mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was post-treated in a manner similar to that in the above examples, 1.5 g of 7- [2-hexyloxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- being (1 Hl, 2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres).

I.R. (Nujol): 3100.1780, 1630 cm "1

N.M.R. (ds-DMSO, ô> 10.17 (IH, d, J = 8Hz), 8.17 (2H, m), 7.97 (IH, s), 7.25 (IH, m), 6.70 (IH, s), 5.73 (IH, dd, J = 5.8Hz), 20 5.13 (IH, d, J = 5Hz), 3.97 (2H, m), 3.60 (2H, m), 1.25 (8H, m), 0.83 (3H, m)

acetate extracted. The ethyl acetate layers were combined and 20 ml of water was added. The resulting mixture was adjusted to about pH 6 with sodium bicarbonate. The aqueous layer was separated and 25 ml of ethyl acetate was added. The mixture was adjusted to pH 2.5 with ice cooling and with stirring with 10% hydrochloric acid. The ethyl acetate layer was separated and the aqueous layer was further extracted with 15 ml and 10 ml of ethyl acetate. The ethyl acetate layers were combined, washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, treated with activated carbon and evaporated under reduced pressure to give crystals, which were dried under reduced pressure to give 1.15 g of 7- [2-methoxyimino -2- {2- (2,2,2-trifluoroacetamido) -l, 3-thiazol-4-yllacetamido] -3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3250.1790.1730.1650 cm "1 NMR (dó-DMSO, ô) 9.95 (IH, d, J = 8Hz), 7.92-8.16 (2H, m), 7.4-7.84 (3H, m) , 7.6 (1H, s), 5.92 (1H, dd, J = 5.8Hz), 5.26 (1H, d, J = 5Hz), 5.18 (2H, ABq, J = 13Hz), 3.96 (3H, s), 3.76 (2H, broad s)

Example 33

0.92 g of phosphorus oxychloride was added dropwise over a period of 3 minutes at -5 to -10 ° C to a solution of 0.44 g of dimethylformamide in 2 ml of ethyl acetate. 20 ml of ethyl acetate was added and after 10 minutes 1.29 g of 2-isopropoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetic acid (Syn-Isomeres) at -5 to -10 ° C. added. The mixture was stirred for 10 minutes to give a clear solution. On the other hand, 1.64 g of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid was dissolved with stirring in a solution of 1.68 g of sodium bicarbonate in 30 ml of water and then 20 ml of acetone was added. The ethyl acetate solution obtained above was added dropwise to the solution with stirring at 0 to 5 ° C. and at a pH of 6.5 to 7.5. After stirring at the same temperature for 20 minutes, the aqueous layer was separated and the acetone was distilled off. The remaining aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid with ice cooling and with stirring. The precipitates were collected by filtration, washed with water and dried to give 1.7 g of 7- [2-isopropoxyimino-2- (2-form

amido-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres).

1st row (Nujol): 3500.3300.1780.1730.1680 cm "1

N.M.R. (ds-DMSO, 8) 9.62 (1H, d, J = 8Hz), 8.53 (1H, s), 7.40 (1H, s), 5.83 (1H, dd, J = 5.8Hz), 5.17 (1H, d , J = 5Hz), 4.17 (2H, m), 3.97 (3H, s), 3.73 (2H, broad), 1.27 (6H, d, J = 6Hz)

Example 34

0.51 g of phosphorus oxychloride was added dropwise over a period of 5 minutes at 5 ° C. to a solution of 0.24 g of dimethylformamide in 1 ml of dry ethyl acetate. After crystal precipitation, the mixture was stirred at 10 ° C for 30 minutes, then 9 ml of dry ethyl acetate and 0.89 g of 2-methoxyimino-2- [2- (2,2,2-trifluoroacet-amido) -l, 3-thiazol-4-yl] acetic acid (Syn-Isomeres) at -10 to -5 ° C stirred. The solution obtained was added dropwise over a period of 5 minutes at −15 ° C. to a solution of 1.0 g of 7-amino-3-benzoyloxymethyl-3-cephem-4-carboxylic acid and 3.2 g of trimethylsilylacetamide in 10 ml of dry ethyl acetate , then the resulting mixture was stirred at -10 to -15 ° C for 1 hour. 10 ml of water was added to the reaction mixture and the ethyl acetate layer was separated. The aqueous layer was washed with a further 10 ml of ethyl

Example 35

25 0.56 g of phosphorus oxychloride were at once below 5 ° C to a mixture of 0.6 g of 2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetic acid (Syn-Isomeres) and 6 ml of dry ethyl acetate was added and the mixture was stirred at 4-6 ° C for 20 minutes. At the same temperature, 0.3 g of bis (trimethylsilyl) acetamide was added all at once, and the mixture was stirred at the same temperature for 10 minutes. To the obtained mixture, 0.56 g of phosphorus oxychloride was added all at once, and the mixture was stirred at the same temperature for 30 minutes, then 0.24 g of dimethylformamide was added dropwise, and the obtained mixture was at 4 to 6 ° for 30 minutes C stirred. The solution obtained was suddenly stirred at - 15 ° C to a solution of 1.1 g of 7-amino-3- (4-nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid and 3.5 g of trimethylsi-40 lylacetamide in 20 ml of dry ethyl acetate, and the resulting mixture was stirred at -5 to -10 ° C for 2 hours. The reaction mixture was adjusted to pH 7 to 7.5 at 0 ° C. with a saturated aqueous sodium bicarbonate solution, stirred at pH 7 below 5 ° C. for 1 hour, adjusted to 45 pH 2.5 and filtered. The organic layer in the filtrate was separated and 20 ml of water was added. The mixture was adjusted to pH 6.5 with sodium bicarbonate. The aqueous layer was separated and washed with diethyl ether. The solvent remaining in the aqueous layer was removed by introducing nitrogen gas, and the aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling. The precipitates were collected by filtration, washed with water and dried, giving 0.7 g of 7- [2-methoxyi-55 mino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3 - (4-nitroben-zoyl) oxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), mp 151 to 163 ° C (dec.), In the form of a pale yellow powder.

I.R. (Nujol) -. 3250-3350, 2500-2600, 1780, 1725, 1680, 1650, 1600, 1535, 1350 cm "'

60 N.M.R. (ds-DMSO, Ô) 9.68 (1H, d, J = 8Hz), 8.5 (4H, m), 7.28 (2H, s), 6.80 (1H, s), 5.88 (1H, dd, J = 5, 8Hz ), 5.24 (1H, d, J = 5Hz), 5.20 (2H, ABq, J = 13Hz), 3.82 (3H, s), 3.72 (2H, ABq, J = 18Hz)

65 Example 36

The following compounds were prepared in a manner similar to Examples 28 to 35:

(1) 7- [2-isopropoxyimino-2- (2-formamidothiazol-4-yl) -acet-

638 532

44

amido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3300.3050, 1777, 1727, 1672 cm- 'N.M.R. (ds-DMSO, 8): 1.28 (6H, d, J = 6Hz), 3.75 (2H, broad s), 4.43 (3H, m), 4.8-5.6 (1H), 5.90 (1H, d, d, J = 5 and 8Hz), 7.45 (1 H, s), 8.58 (1H, broad s), 9.60 (1 H, s), 9.77 (1H, d, J = 8Hz), 12.80 (1H, broad s)

(2) 7- [2-pentyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4- carbonic acid (Syn-Isomeres)

I.R. (Nujol): 3300, 3250, 1785, 1680 cm- '

N.M.R. (ds-DMSO, 8): 0.6-1.9 (9H, m), 3.72 (2H, broad s), 4.11 (2H, t, J = 6Hz), 4.47 (2H, ABq, J = 13Hz), 5.18 (1H , d, J = 5Hz), 5.82 (1H, d, d, J = 5 and 8Hz), 7.41 (1H, s), 8.53 (1H, s), 9.57 (1 H, s), 9.64 (1 H, d, J = 8 Hz), 12.65 (1 H, s)

(3) 7- [2-Butoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-l H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3300.2550-2600.1775,1710.1690.1670.1645 cm- '

N.M.R. (ds-DMSO, 8): 0.90 (3H, m), 1.2-1.8 (4H, m), 3.70 (2H, ABq, J = 18Hz), 3.94 (3H, s), 4.12 (2H, m), 4.32 (2H, ABq, J = 13Hz), 5.16 (1H, d, J = 5Hz), 5.80 (1H, d, d, J = 5 and 8Hz), 7.37 (1H, s), 8.50 (IH, s), 9.62 (IH, d, J = 8Hz), 12.6 (1H, s)

(4) 7- [2-Methoxyimino-2- (20-formamidothiazol-4-yl) acetamido] -3- (1-propyl-l H-tetrazol-5-yl) thiomethyl-3-cephem-4 -car-bonic acid (Syn-Isomeres)

I.R. (Nujol): 3180.1775.1665 cm "'

N.M.R. (ds-DMSO, 8) 0.85 (3H, t, J = 8.0Hz), 1.82 (2H, m), 3.69 (2H, m), 3.88 (3H, s), 4.06-4.66 (4H, m), 5.13 (IH, d, J = 5.0Hz), 5.81 (IH, d, d, J = 5.0 and 8.0 Hz), 7.42 (IH, s), 8.52 (IH, s), 9.65 (IH , d, J = 8.0Hz)

(5) 7- [2-Allyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 -car-bonic acid (Syn-Isomeres)

I.R. (Nujol): 3180.1775, 1670 cm- '

N.M.R. (ds-DMSO, 8) 0.87 (3H, t, J = 8.0Hz), 1.65 (2H, m), 3.73 (2H, ABq, J = 16.0Hz), 4.00-4.53 (4H, m), 4.69 (2H, d, J = 5.0Hz), 5.00-5.68 (3H, m), 5.68-6.36 (2H, m), 7.45 (IH, s), 8.56 (IH, s), 9.72 (IH, d, J = 8.0Hz)

(6) 7- [2-isopropoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4- car-bonic acid (Syn-Isomeres)

I.R. (Nujol): 3175.1780.1670 cm- '

N.M.R. (ds-DMSO, 8): 0.66 (3H, t, J = 5.0Hz, 1.05-1.57 (6H, m), 1.92 (2H, m), 3.77 (2H, m), 4.10-4.72 (5H, m ), 5.24 (1H, d, J = 5.0Hz), 5.90 (IH, d, d, J = 5.0 and 8.4Hz), 7.43 (IH, s), 8.56 (IH, s), 9.64 ( IH, d, J = 8.4Hz)

(7) 7- [2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -car-bonic acid (Syn-Isomeres)

I.R. (Nujol): 3175.1785.1642 cm "'

N.M.R. (ds-DMSO, 8): 0.86 (6H, m), 1.00-1.57 (12H, m), 1.57-2.07 (4H, m), 3.75 (2H, m), 3.97-4.60 (8H, m), 5.18 (IH, d. J = 5.2Hz), 5.85 (IH, d, d, J = 5.2 and 8.4Hz), 7.41 (IH, s), 8.56 (1 H, s), 9.65 (1H, d , J = 8.4Hz)

(8) 7- [2-Allyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -car-bonic acid (Syn-Isomeres)

I.R. (Nujol): 3180.1780.1680 cm "'

N.M.R. (ds-DMSO, 8): 0.64-1.97 (1 IH, m), 3.68 (2H, ABq, J = 18Hz), 4.30 (4H, m), 4.64 (2H, m), 5.00-5.46 (3H, m ), 5.56-6.24 (2H, m), 7.37 (IH, s), 8.48 (IH, s), 9.67 (IH, d, J = 8Hz), 5.92 (IH, d, d, J = 5 and 8Hz) , 6.78 (IH, s), 6.88 (4H, s), 6.95 (IH, s), 7.04-7.64 (10H, m), 9.64 (1H, d, J = 8Hz)

(9) Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-pivaloyloxymethyl-3-cephem-4-carboxylate (syn - (-) isomer)

LR. (Nujol): 3300.1780.1725, 1680, 1620.1530 cm- '"NMR (ds-DMSO, 8) 1.13 (9H, s), 3.62 (2H, broad), 3.88 (3H, s), 4.86 (2H , ABq, J = 14Hz), 5.26 (IH, d, J = 5Hz), 5.96 (IH, d, d, J = 5 and 8Hz), 6.80 (IH, s), 6.98 (IH, s), 7.12- 7.68 (10H, 5 m), 9.73 (IH, d, J = 8Hz)

(10) Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-carboxylate (syn isomer )

I.R. (Nujol): 3300.1770.1720.1670.1600.1530 cm "'io NMR (ds-DMSO, 8): 3.70 (2H, broad), 3.90 (3H, s), 4.90 (2H, AB ,, J = 13Hz), 5.27 (IH, d, J = 5Hz), 5.93 (IH, d, d, J = 5 and 8 Hz), 6.80 (IH, s), 6.97 (IH, s), 6.87-7.77 (14H , m), 9.60 (IH, d, J = 8Hz), 10.00 (lH, s)

(11) Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazole-4-

15 yl) acetamido] -3- (N-phenylcarbamoyloxymethyl) -3-cephem-4-carboxylate (Syn-Isomeres)

I.R. (Nujol): 3300.1780.1720.1675.1600.1530.1500 cm "'NMR (ds-DMSO, 8): 3.63 (2H, broad s), 3.80 (3H, s), 4.80 (2H, AB, , J = 13Hz), 5.20 (IH, d, J = 5Hz), 5.86 (IH, d, d, J = 5 and 20 8Hz), 6.73 (IH, s), 6.93 (IH, s), 6.83-7.67 (15H, m), 9.57 (IH, d, J = 8Hz), 9.73 (IH, s)

(12) 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomeres)

25 LR. (Nujol): 3300.1775.1660 cm "'

(13) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4- carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3325.1774.1656 cm "'30 (14) 7- [2-pentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3350.3200.1775.1675 cm "'

(15) 7- [2-Butoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-35 (l-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid

(Syn isomer)

I.R. (Nujol): 3350.3250.2550-2600.1780.1770.1670.1630 cm "'

(16) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] - • <o 3- (1-propyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carbon-

acid (Syn-Isomeres)

I.R. (Nujol): 3350.1780.1670.1630 cm "'

(17) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-propyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carbon-

45 acid (Syn-Isomeres)

I.R. (Nujol): 3340.3230, 1780.1680.1630 cm "'

(18) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( Syn isomeres)

so I.R. (Nujol): 3350.3230.1777.1675.1627 cm "'

(19) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4- car-bonic acid (Syn-Isomeres)

I.R. (Nujol): 3320.1780.1675.1630 cm "'55 (20) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-hexyl-1H -tetrazol-5-yl) thiomethyl-3-cephem-4-car-bonic acid (Syn-Isomeres)

I.R. (Nujol): 3350.3230.1765.1670.1615 cm "'

(21) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -60 3- (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carbon -

acid hydrochloride (Syn-Isomeres)

I.R. (Nujol): 3240.1780.1720.1675 cm "'

(22) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-car-

65 bonic acid (Syn-Isomeres)

I.R. (Nujol): 3320.1780.1710.1680.1600.1540 cm "'

(23) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-pivaloyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)

45

638 532

I.R. (Nujol): 3300.1780.1720.1670.1540 cm- '

(24) Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-nitrobenzoyloxymethyl) -3-cephem-4-carboxylate (syn isomer)

I.R. (Nujol): 3300.1780.1720.1670.1600.1520 cm -1 s

N.M.R. (dö-DMSO, S): 3.43 (2H, broad s), 3.92 (3H, s), 5.08 (2H, ABq, J = 13 Hz), 5.2 (IH, d, J = 5Hz), 6.00 (IH, d, d, J = 5 and 8Hz), 6.83 (IH, s), 7.00 (IH, s), 7.10-7.80 (10H, m), 8.15 (2H, d, J = 9Hz), 8.38 (2H, d , J = 9Hz), 9.73 (IH, d, J = 8Hz)

(25) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] - io 3- (N-phenylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3300.1780.1710.1670.1600 cm- '

(26) 7- [2-Isobutoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] cephalosporanic acid (Syn-Isomeres)

I.R. (Nujol): 3400-3200,1780,1740,1660,1630,1540 cm- 'N.M.R. (dö-DMSO, Ô) 9.56 (IH, d, J = 8Hz), 6.72 (IH, s), 5.78 (IH, dd, J = 5.8Hz), 5.14 (IH, d, J = 5Hz), 4.83 (2H, ABq, J = 14Hz), 3.82 (2H, d, J = 7Hz), 3.54 (2H, ABq, J = 17Hz), 2.02 (3H, s), 1.98 (IH, m), 0.88 (6H, d, J = 7Hz) 20

(27) 7- [2-Propoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3400-3200,1780,1670,1630,1535 cm- 'N.M.R. (ds-DMSO, 8) 9.57 (IH, d, J = 8Hz), 6.72 (IH, s), 5.7725 (IH, dd, J = 5.8Hz), 5.13 (IH, d, J = 5Hz), 4.30 (2H, ABq, J = 14Hz), 4.02 (2H, t, J = 7Hz), 3.93 (3H, s), 3.69 (2H, ABq, J = 18Hz), 1.64 (2H, m), 0.90 (3H, t, J = 7Hz)

(28) 7- [2-Pentyloxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl -3-cephem-4- 30 carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3300.1770.1660.1630 cm- '

N.M.R. (dö-DMSO, 8) 9.52 (IH, d, J = 8Hz), 7.20 (2H, m), 6.68 (IH, s), 5.74 (IH, dd, J = 4.8Hz), 5.10 (IH, d , J = 4Hz), 4.30 (2H, AB ,, J = 13Hz), 4.02 (2H, t, J = 6Hz), 3.90 (3H, s), 3.66 (2H, 35 ABq, J = 18Hz), 1.60 ( 2H, m), 1.30 (4H, m), 0.82 (3H, t, J = 6Hz)

(29) 7- [2-Hexyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3350.3250.1780.1670.1630 cm "'40

N.M.R. (dö-DMSO, 8) 10.25 (IH, d, J = 5Hz), 7.25 (2H, m), 6.73 (IH, s), 5.77 (IH, dd, J = 5.8Hz), 5.13 (IH, d , J = 5Hz), 4.17 (2H, m), 3.91 (3H, s), 3.67 (2H, m), 1.33 (8H, m), 0.83 (3H, m)

(30) 7- [2-ethoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid 45 (syn-isomer)

I.R. (Nujol): 3500.3300.1780.1710.1660 cm- 'N.M.R. (de-DMSO, 8) 9.67 (IH, d, J = 8Hz), 8.53 (IH, s), 7.43 (IH, s), 6.58 (IH, s), 5.87 (IH, dd, J = 5.8Hz ), 5.23 (IH, d, J = 5Hz), 4.80 (2H, ABq, J = 13Hz), 4.23 (2H, q, J = 7Hz), 3.57 so (2H, broad s), 1.3 (3H, t, J = 7Hz)

(31) 7- [2-ethoxyimino-2- (2-amino-l, 3-thiazol-4-yl) -acet-amido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. (Nujol): 3300.3200.1780.1720.1660 cm- '55

N.M.R. (dö-DMSO, 8) 9.58 (IH, d, J = 8Hz), 7.33 (IH, broad s), 6.77 (IH, s), 6.58 (IH, s), 5.83 (IH, dd, J = 4, 8Hz), 5.20 (IH, d, J = 4Hz), 4.77 (2H, ABq, J = 12Hz), 4.16 (2H, q, J = 7Hz), 3.53 (2H, broad s), 1.23 (3H, t, J = 7Hz)

(32) 7- [2-propoxyimino-2- (2-formamido-l, 3-thiazol-4- 60 yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. (Nujol): 3250,3200,1780,1700,1660,1525 cm "'NMR (ds-DMSO, 8) 9.62 (IH, d, J = 8Hz), 8.50 (IH, s), 7.43 (IH, s) , 6.57 (2H, broad), 5.84 (IH, dd, J = 5.8Hz), 5.18 (IH, d, es J = 5Hz), 4.58 (2H, ABq, J = 13Hz), 4.08 (2H, t, J = 7Hz), 3.54 (2H, AB ,, J = 18Hz), 1.68 (2H, m), 0.92 (3H, t, J = 7Hz)

(33) 7- [2-isobutoxyimino-2- (2-formamido-l, 3-thiazole-4-

yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3450,3300,1780,1710, 1680,1610 cm- 'N.M.R. (de-DMSO, 8)

9.6 (IH, d, J = 8Hz), 8.5 (IH, s), 7.18 (IH, s), 6.6 (2H, broad), 5.8 (IH, dd, J = 5.8Hz), 5.15 (IH, d , J = 5Hz), 4.76 (2H, ABq,) = 13Hz), 3.84 (2H, d,) = 6Hz), 3.5 (2H, ABq, J = 18Hz), 2.04 (IH, m), 0.88 (6H, d, (6Hz)

(34) 7- [2-isobutoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. (Nujol): 3300.1770.1730.1660 cm "1 NMR (do-DMSO, 8) 9.55 (IH, d, J = 9Hz), 7.27 (2H, broad s), 6.73 (IH, s), 6.60 ( IH, broad), 5.83 (IH, dd, J = 5.9Hz), 5.20 (IH, d, J = 5Hz), 4.80 (2H, ABq, J = 12Hz), 3.87 (2H, d, J = 7Hz) , 3.53 (2H, ABq, J = 18Hz), 0.90 (6H, d, J = 7Hz)

(35) 7- [2-Allyloxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. (Nujol): 3300.1770.1720.1660.1630 cm- 'N.M.R. (dö-DMSO, 8) 9.82 (IH, d, J = 8Hz), 7.20 (2H, m), 6.92 (IH, s), 6.7 (2H, m), 6.0 (IH, m), 5.80 (IH, dd, J = 5.8Hz), 5.40 (IH, m), 5.22 (IH, m), 5.13 (IH, d, J = 5Hz), 4.70 (2H, ABq, J = 14Hz), 4.65 (2H, m ), 3.50 (2H, ABq, J = 16Hz)

(36) 7- [2-Propoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carbon-acid (Syn-Isomeres)

I.R. (Nujol): 3400-3200.1780, 1670, 1625, 1540 cm "'NMR (ds-DMSO, 8) 9.50 (IH, s), 9.50 (IH, d, J = 8Hz), 6.68 (IH, s) , 5.74 (IH, dd, J = 5.8Hz), 5.12 (IH, d, J = 5Hz), 4.40 (2H, AB ,, J = 14Hz), 3.98 (2H, t, J = 7Hz), 3.66 ( 2H, ABq, J = 17Hz), 1.62 (2H, m), 0.87 (3H, t, J = 7Hz)

(37) 7- [2-ethoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (1Hl, 2,3-triazol-5-yl) thiomethyl-3 -cephem-4-car-bonic acid (Syn-Isomeres)

I.R. (Nujol): 3500.3200.1780.1670.1620 cm- 'N.M.R. (dö-DMSO, 8) 9.64 (IH, d, J = 8Hz), 8.5 (IH, s), 7.9 (IH, s), 7.4 (IH, s), 5.76 (IH, dd, J = 4, 8Hz) ), 5.14 (IH, d, J = 4Hz), 4.1 (2H, q, J = 7Hz), 3.92 (2H, ABq, J = 13Hz), 3.58 (2H, ABq, J = 18Hz), 1.26 (6H, t, J = 7Hz)

(38) 7- [2-ethoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (lH-l, 2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3350.3150.1770.1670 cm- '

N.M.R. (dö-DMSO, 8) 9.56 (IH, d, J = 9Hz), 7.92 (IH, s), 7.28 (IH, m), 6.75 (IH, s), 5.75 (IH, dd, J = 5.9Hz ), 5.06 (IH, d, J = 5Hz), 4.05 (2H, q, J = 7Hz), 3.9 (2H, m), 3.64 (2H, ABq, J = 17Hz), 1.24 (3H, t, J = 7Hz)

(39) 7- [2-Propoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetamido] -3- (lH-l, 2,3-triazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3300-3100,1780,1680,1650,1550 cm- 'N.M.R. (do-DMSO, 8) 9.62 (IH, d, J = 8Hz), 8.50 (IH, s), 7.92 (IH, s), 7.38 (IH, s), 5.78 (IH, dd, J = 5.8Hz ), 5.15 (IH, d, J = 5Hz), 4.20-3.70 (4H, m), 3.65 (2H, ABq, J = 17Hz), 1.66 (1H, m), 0.90 (3H, t, J = 7Hz)

(40) 7- [2-Propoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1 H-1,2,3-triazol-5-yl ) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3400-3100,1770, 1670,1630, 1530 cm- 'N.M.R. (d6-DMSO, 8) 9.58 (IH, d, J = 8Hz), 7.97 (IH, s), 6.77 (IH, s), 5.78 (IH, dd, J = 5.8Hz), 5.18 (IH, d , J = 5Hz), 4.23-3.76 (4H, m) 3.67 (2H, broad s), 1.67 (2H, m), 0.93 (3H, t, J = 7Hz)

(41) 7- [2-Isopropoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3- (1H-l, 2,3-triazol-5-yl) thiomethyl -3-cephem-4-carbon-acid (Syn-Isomeres)

"I.R. (Nujol): 3300.3150.1780.1670.1640 cm "1

N.M.R. (dö-DMSO, 8) 9.50 (IH, d, J = 9Hz), 7.97 (IH, s), 6.73

638 532

46

(IH, s), 5.77 (IH, dd, J = 5.9Hz), 5.17 (IH, d, J = 5Hz), 4.33 (IH, m), 4.0 (2H, ABq, J = I3Hz), 3.67 ( 2H, ABq, J = 18Hz), 1.23 (6H, d, J = 6Hz)

(42) 7- [2-isobutoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1 H-1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)

I.R. (Nujol): 3470.3320.3200.3160.1770.1660 cm "1

N.M.R. (dó-DMSO, 5) 9.57 (IH, d, J = 9Hz), 7.97 (IH, s), 7.22 (2H, broad s), 6.75 (IH, s), 5.77 (IH, dd, J = 5, 9Hz), 5.18 (IH, d, J = 5Hz), 4.03 (2H, ABq, J = 12Hz), 3.88 (2H, d, J = 6Hz), 3.70 (2H, ABq, J = 18Hz), 2.0 (IH , m), 0.92 (6H, d, J = 6Hz)

(43) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3300.3200.1780.1720.1640 cm "1

(44) 7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -

3-carbamoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride (Syn-Isomeres)

I.R. (Nujol): 3350.3200, 1770.1720.1665.1630.1550 cm- '

(45) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn isomer)

I.R. (Nujol): 3330.3250.1780.1680 cm- '

(46) 7- [2-methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -1, 3-thiazol-4-yllacetamido] -3- (4-nitrobenzoyl) oxymethyl-3-cephem-

4-carboxylic acid (Syn-Isomeres), pale yellow powder.

I.R. (Nujol): 3200.2500-2600.1785,1720.1680.1650.1600, 1525.1355 cm- '

N.M.R. (dó-DMSO, S) 9.80 (IH, d, J = 8Hz), 8.4 (4H, m), 7.60 (1H, s), 5.78 (1H, dd, J = 5.8Hz), 5.25 (1H, d , J = 5Hz), 5.15 (2H, ABq, J = 13Hz), 3.94 (3H, s), 3.75 (2H, ABq, J = 18Hz)

(47) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3300.1780.1720.1680 cm- '

N.M.R. (dó-DMSO, ô) 9.63 (1H, d, J = 8Hz), 7.87-8.1 (2H, m), 7.48-7.75 (3H, m), 6.75 (1H, s), 5.83 (1H, dd, J = 5.8Hz), 5.19 (1H, d, J = 5Hz), 5.15 (2H, ABq, J = 13Hz), 3.83 (3H, s), 3.72 (2H, broad s)

(48) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-phenylacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3350,3300,1780,1710,1660,1542,1535,1460, 1400,1380,1320,1280,1260,1240,1130,1115,1065,1042,965, 720 cm- '

N.M.R. (d6-DMSO, ô) 7.33 (5H, s), 7.23 (2H, broad), 6.78 (1H, s), 5.81 (1H, dd, J = 4.8Hz), 5.16 (1H, d, J = 4Hz ), 4.78 and 5.06 (2H, AB ,, J = 8Hz), 3.9 (3H, s), 3.73 (2H, s), 3.5 (2H, broad)

(49) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3-hexanoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3350.3300, 1780, 1700, 1660, 1535, 1460, 1400, 1375, 1340, 1315, 1280, 1255, 1045 cm "1

N.M.R. (dó-DMSO, ô) 9.63 (1H, d, J = 8Hz), 7.24 (2H, broad s), 6.76 (1H, s), 5.81 (1H, dd, J = 4.8Hz), 5.17 (1H, d,) = 4Hz), 4.75 and 5.03 (2H, ABq, J = 12Hz), 3.84 (3H, s), 3.45 and 3.67 (2H, ABq, J = 18Hz), 2.32 (2H, t, J = 8Hz) , 1-1.7 (6H, m), 0.85 (3H, t, J = 3Hz)

(50) 7- [2-methoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) acetamido] -3- (2-benzothiazolyl) thiomethyl-3-cephem-4-carboxylic acid ( Syn isomeres)

I.R. (Nujol): 3200.1780.1680.1620.1545, 1460.1435.1385, 1040.1000 cm "'

N.M.R. (dó-DMSO, 8) 9.7 (IH, d,) = 8Hz), 8.53 (IH, s), 7.66-8.16 (2H, m), 7.16-7.66 (3H, m), 5.83 (1H, dd, J = 5.8Hz), 5.18 (1H, d, J = 5Hz), 4.23 and 4.81 (2H, ABq, J = 15Hz), 3.93 (3H, s), 3.73 (2H, broad s)

Example 37

0.85 g of concentrated hydrochloric acid was cooled with ice to a stirred solution of 2.3 g of 7- [2-ethoxyimino-2- (2-formamidothiazoI-4-yl) acetamido] -3- (l, 3,4-thiadia-

5 zol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) was added in a mixture of 23 ml of methanol and 23 ml of tetrahydrofuran, and the mixture was stirred at ambient temperature for 2.5 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous sodium bicarbonate solution (pH 7.0). The aqueous solution was washed with ethyl acetate and adjusted to pH 3.5 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed with water and dried, giving 15 1.865 g of 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol- 2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained in the form of a powder.

1st row (Nujol): 3300.1775.1660 cm- '

N.M.R. (dó-DMSO, 8) 1.67 (3H, t, J = 7.6 Hz), 3.75 (2H, m), 20 4.16 (2H, q, J = 7.6Hz), 4.48 (2H, ABq, J = 13.6Hz), 5.18 (IH, d, J = 5.2Hz), 5.83 (IH, d, d, J = 5.2 and 8.0Hz), 6.79 (IH, s), 7.38 (2H, broad s ), 9.63 (IH, s), 9.63 (IH, d, J = 8.0Hz)

Example 38

25 2.1 g of concentrated hydrochloric acid were cooled with ice and with stirring to a solution of 6.0 g of 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l-hexyl-1H) -tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) in 60 ml of methanol was added and the mixture was stirred at ambient temperature for 4 hours. The solvent was removed from the reaction mixture and 50 g of ethyl acetate was added. The mixture was adjusted to pH 7.0 with a saturated aqueous sodium bicarbonate solution. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 3.5 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed with water and dried under reduced pressure, giving 4.62 g of 7- [2-methoxyimino-2- (2-aminothiazol-4-40 yl) acetamido] -3- (l-hexyl -lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) was obtained.

I.R. (Nujol): 3350.3230.1777.1675.1627 cm "'

N.M.R. (dó-DMSO, 8) 0.82 (3H, t, J = 5.0Hz), 1.23 (6H, m), 1.80 (2H, m), 3.69 (2H, m), 3.85 (3H, s), 4.05- 4.63 (4H, m), 5.12 45 (IH, d, J = 5.0Hz), 5.75 (IH, d, d, J = 5.0.8.6Hz), 6.76 (IH, s), 7.23 (2H , wide s), 9.59 (IH, d, J = 8.6Hz)

Example 39

1 ml of concentrated hydrochloric acid was added to a solution of 1.3 g of 7- [2-isopropoxyimino-2- (2-formamido-l, 3-thiazol-4-yl) -acetamido] -3-carbamoyloxymethyl-3-cephem-4 -carboxylic acid (Syn-Isomeres) added in a mixture of 10 ml of tetrahydrofuran and 10 ml of methanol. The mixture was stirred at ambient temperature for 3.5 hours and then concentrated to dryness. Water was added to the residue and sodium bicarbonate was added to the mixture to form a solution. The solution was adjusted to pH 3.0 with concentrated hydrochloric acid with ice cooling. The precipitates were collected by filtration 60, washed with water and dried, yielding 0.25 g of 7- [2-isopropoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3 -carbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) was obtained.

I.R. (Nujol): 3300,3200,1780, 1720,1640 cm "'es NMR (dó-DMSO, 8) 9.48 (IH, d, J = 8Hz), 7.24 (2H, broad s), 6.7 (IH, s) , 6.54 (IH, s), 5.75 (IH, dd, J = 5.8Hz), 5.16 (IH, d, J = 5Hz), 4.72 (2H, ABq, J = 13Hz), 4.3 (1H, m), 3.5 (2H, broad s), 1.22 (6H, d, J = 6Hz)

47 638 532

Example 40 s), 4.37 (3H, m), 5.15 (IH, d, J = 5Hz), 5.77 (IH, d, d, J = 5 and

0.5 g 7- [2-propoxyimino-2- (2-formamido-l, 3-thiazole-4- 8Hz), 6.70 (1H, s), 7.20, (2H, m), 9.50 (1H, d, J = 8Hz), 9.55 (1H, yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid s)

(Syn-Isomeres) were suspended in 15 ml of methanol. To the (2) 7- [2-pentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -

To the suspension were added 0.2 ml of concentrated hydrochloric acid 5 3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, and the mixture was stirred for 2 hours at

exercise temperature stirred. The reaction mixture was I.R. (Nujol): 3350.3200.1775.1675cm-1

concentrated and the residue was washed with tetrahydrofuran - N.M.R. (ds-DMSO, 8) 0.62-2.0 (9H, m), 3.72 (2H, broad s),

see, collected by filtration and dried, leaving 4.06 (2H, t, J = 6Hz), 4.45 (2H, ABq, J = 13Hz), 5.17 (IH, d, 0.4g 7- [2-propoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] - io J = 5Hz), 5.78 (IH, d, d, J = 5 and 8Hz), 6.73 (IH, s), 7.2 (2H, s), 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride 9.5 (1H, d, J = 8Hz), 9.55 (1 H, s)

(Syn-Isomeres) received. (3) 7- [2-butoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-

1st row (Nujol): 3350,3200,1770,1720,1665,1630,1550 cm-1 (1-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid N.M.R. (ds-DMSO, 8) 9.82 (IH, d, J = 8Hz), 6.98 (IH, s), 5.80 (Syn-Isomeres)

(IH, dd, J = 5.8Hz), 5.22 (IH, d, J = 5Hz), 4.80 (2H, ABq, is I.R. (Nujol): 3350.3250,2550-2600,1780,1700,1670,1630

J = 14Hz), 4.15 (2H, t, J = 7Hz), 3.58 (2H, broad s), 1.72 (2H, m), cm "1

0.92 (3H, t, J = 7Hz) N.M.R. (ds-DMSO, 8) 1.0 (3H, m), 1.2-1.7 (4H, m), 3.77

(2H, ABq, J = 19Hz), 3.95 (3H, s), 4.15 (2H, m), 4.33 (2H, ABq, example41 J = 13Hz), 5.20 (IH, d, J = 5Hz), 5.82 (IH , d, d, J = 5.8 Hz), 6.73

1 ml of concentrated hydrochloric acid became 20 (1 H, s), 9.56 (1H, d, J = 8Hz)

Solution of 1.5 g 7- [2-isopropoxyimino-2- (2-formamido-l, 3- (4) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-

thiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomet- (1-propyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid hyl-3-cephem-4-carboxylic acid (Syn-Isomeres) in a mixture (Syn-Isomeres)

added from 12 ml of tetrahydrofuran and 12 ml of methanol. The I.R. (Nujol): 3350.1780.1670.1630 cm-1 mixture was stirred at ambient temperature 25 N.M.R. for 3.5 hours. (dó-DMSO, 8) 0.87 (3H, t, J = 7.0Hz), 1.84 (2H, m), stirred and then evaporated to dryness. Water was added to the residue 3.73 (2H, broad), 3.89 (3H, s), 4.06-4.72 (4H, m), 5.14 (IH, d, and sodium-J = 5.0Hz), 5.80 (1H, d, d, J = 5.0 and 8.0Hz), 6.78 (1H, s), 7.23 bicarbonate added to form a solution. The solution (2H, broad s), 9.59 (1H, d, J = 8.0Hz)

was concentrated with hydrochloric acid under ice cooling- (5) 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-

adjusted to pH 3.0. The precipitates were collected by 30 (1-propyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid filtering, washed with water and dried, (Syn-Isomeres)

whereiman0.8g7- [2-isopropoxyimino-2- (2-amino-l, 3-thiazole-4- IR (Nujol): 3340, 3230, 1780, 1680, 1630 cm-1 yI) -acetamido] -3- ( 1-methyl-1 H-tetrazol-5-yl) thiomethyl-3 NMR (dö-DMSO, 8) 0.86 (3H, t, J = 7.0Hz), 1.83 (2H, m),

cephem-4-carboxylic acid (Syn-Isomeres) was obtained. 3.71 (2H, broad), 4.05-4.80 (6H, m), 5.01-5.53 (3H, m),

I.R. (Nujol): 3330.3250,1780,1680cm-1 35 5.63-6.42 (2H, m), 6.75 (lH, s), 7.20 (2H, broad), 9.59 (lH, d,

N.M.R. (ds-DMSO, 8) 9.50 (IH, d, J = 8Hz), 6.70 (IH, s), 5.83 J = 8.2Hz)

(IH, dd, J = 5.8Hz), 5.17 (IH, d, J = 5Hz), 4.33 (2H, broad), 3.97 (6) 7- [2-isopropoxyimino-2- (2-aminothiazole-4- yl) -acet-

(3H, s), 3.71 (2H, broad s), 1.25 (6H, d, J = 6Hz) amido] -3- (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-3- car-

bonic acid (Syn-Isomeres)

Example 42 40 I.R. (Nujol): 3320.1780.1675.1630 cm-1

A solution of 1.1 g7- [2-methoxyimino-2-f2- (2,2,2-tri-NMR (ds-DMSO, 8): 0.84 (3H, t, J = 6.0Hz), 1.00- 1.50

fluoroacetamido) -l, 3-thiazol-4-yl (acetamido] -3-benzoyloxymet- (12H, m), 1.80 (2H, m), 3.72 (2H, ABq, J = 17.0Hz), 4.10-4.60 hyl -3-cephem-4-carboxylic acid (Syn-Isomeres) in 4 ml acetone (5H, m), 5.15 (IH, d, J = 5.0Hz), 5.81 (IH, d, d, J = 5.0, 8.0 Hz), at ambient temperature became a solution of 2.4 g 6.77 (IH, s), 9.59 (IH, d, J = 8.0 Hz)

Sodium acetate trihydrate water was added and the mixture 45 (7) 7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] was left to stand at room temperature for 3 hours. The 3- (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid acetone was distilled off under reduced pressure and it (Syn-Isomeres)

10 ml of water was added. The resulting mixture was I.R. (Nujol): 3350.3230.1765.1670.1615 cm-1 with 10% hydrochloric acid with ice cooling to pH N.M.R. (ds-DMSO, 8) 0.84 (6H, m), 1.26 (12H, m), 1.70 (4H,

2.5 set. The precipitates were collected by filtration 50 m), 3.20-4.60 (8H, m), 5.40 (IH, d, J = 5.0 Hz), 5.68 (IH, d, d), washed with water and under reduced J = 5 , 0, 8.0Hz), 6.72 (IH, s), 7.23 (2H, broad s), 9.49 (IH, d,

Pressure dried, giving 0.62 g of 7- [2-methoxyimino-2- (2 J = 8.0 Hz)

amino-1,3-thiazol-4-yl) acetamido] -3-benzoyloxymethyl-3- (8) 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-

cephem-4-carboxylic acid (Syn-Isomeres) was obtained. (1 -hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid-

I.R. (Nujol): 3300.1780, 1720, 1680cm-1 55 hydrochloride (Syn-Isomeres)

N.M.R. (ds-DMSO, 8) 9.63 (1H, d, J = 8Hz), 7.87-8.1 (2H, I.R. (Nujol): 3240.1780.1720.1675 cm-1

m), 7.48-7.75 (3H, m), 6.75 (IH, s), 5.83 (IH, dd, J = 5.8Hz), 5.19 N.M.R. (ds-DMSO, 8): 0.63-2.13 (1 IH, m), 3.73 (2H, ABq, (IH, d, J = 5Hz), 5.15 (2H, ABq, J = 13Hz), 3.83 (3H, s ), 3.72 (2H, J = 18Hz), 4.08-4.90 (6H, m), 5.10-6.30 (5H, m), 6.94 (IH, s), broad s) 7.93 (2H, broad s), 9.80 (IH , d, J = 8Hz)

60 (9) 7- [2-Methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acet example 43 amido] -3- (4-nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid

The following compounds were prepared in (Syn-Isomeres), pale yellow powder, mp 151-163 ° C (dec.) In the same manner as in Examples 37 to 42: I.R. (Nujol): 3250-3350,2500-2600,1780,1725,1680,1650,

(l) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) -acet- 1600.1535.1350 cm-1

imido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carbon- 65 N.M.R. (ds-DMSO, 8) 9.68 (IH, d, J = 8Hz), 8.5 (4H, m), 7.28> acid (Syn-Isomeres) (2H, s), 6.80 (IH, s), 5.88 (IH, dd, J = 5.8Hz), 5.24 (IH, d,

I.R. (Nujol): 3325.1774.1656cm-1 J = 5Hz), 5.20 (2H, ABq, J = 13Hz), 3.82 (3H, s), 3.72 (2H, ABq,

N.M.R. (ds-DMSO, 8) 1.22 (6H, d, J = 6Hz), 3.70 (2H, broad J = 18Hz)

638 532

(10) 7- [2-methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) acetamido] -3-phenylacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3350, 3300, 1780,1710,1660,1542,1535,1460, 1400,1380,1320,1280,1260,1240,1130,1115,1065,1042,965, 720 cm-!

N.M.R. (dó-DMSO, ô) 7.33 (5H, s), 7.23 (2H, broad s), 6.78 (1H, s), 5.81 (1H, dd, J = 4.8Hz), 5.16 (1H, d, J = 4Hz), 4.78 and 5.06 (2H, ABq, J = 8Hz), 3.9 (3H, s), 3.73 (2H, S), 3.5 (2H, broad)

(11) 7- [2-Methoxyimino-2- (2-amino-l, 3-thiazol-4-yl) aceta-mido] -3-hexanoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Iso-meres)

I.R. (Nujol): 3350,3300,1780,1700,1660,1535,1460,1400, 1375,1340, 1315, 1280,1255,1045 cm- '

N.M.R. (ds-DMSO, 8) 9.63 (1H, d, J = 8Hz), 7.24 (2H, broad s), 6.76 (1 H, s), 5.81 (1 H, dd, J = 4.8Hz), 5.17 ( 1 H, d, J = 4Hz), 4.75 and 5.03 (2H, ABq, J = 12Hz), 3.84 (3H, s), 3.45 and 3.67 (2H, ABq, J = 18Hz), 2.32 (2H, t, J = 8Hz), 1-1.7 (6H, m), 0.85 (3 H, t, J = 3Hz)

Preparation of the starting compounds preparation 17

(1) 21 3 g of l-allyl-1H-tetrazole-5-thiol were added at 76 to 78 ° C to a solution of 10.6 g of sodium bicarbonate in 220 ml of water. Then 54.9 g of 7- (5-amino-5-carboxy-valeramido) cephalosporaic acid sodium were added over the course of 15 minutes and the mixture was stirred at 76 to 78 ° C. for 80 minutes. The reaction mixture was adjusted to pH 3.0 by adding 6N hydrochloric acid under ice cooling and then filtered. The filtrate was subjected to column chromatography on a nonionic adsorption resin (Diaion HP-20 »(trademark of Mitsubishi Chemical Industries Ltd.) and eluted with a 30% aqueous solution of isopropyl alcohol. The eluate was added to a mixture by adding 28% aqueous ammonia solution The pH was adjusted to 6.5, then concentrated and lyophilized, giving 21.7 g of 7- (5-amino-5-carboxyvaleramido) -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl -3-cephem-4-carbonsau-res ammonium was obtained.

I.R. (Nujol): 3175, 1760.1590 cm "1

N.M.R. (dô-DMSO, 5): 1.23-2.42 (6H, m), 3.12-3.97 (3H, m), 4.37 (2H, broad s), 4.80-5.15 (3H, m), 5.15-5.51 (2H, m ), 5.51-6.25 (2H, m), 8.77 (IH, d, J = 8Hz)

(2) 8.12 ml of N, N-dimethylaniline was added to a mixture of 10.0 g of ammonium-7- (5-amino-5-carboxyvaleramido) -3- (l-allyl-1 H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylate, 20.9 ml of trimethylsilyl chloride and 75 ml of methylene chloride were added. Then the mixture was heated to boiling under reflux for 2Vi hours with stirring. 5.83 g of phosphorus pentachloride were then added at a temperature of from -30 ° C. to -35 ° C. and the mixture was stirred at the same temperature for 2 hours. Then 38 ml of 2-ethoxyethanol were added dropwise at the temperature just mentioned and the mixture was stirred at the same temperature for 1 hour. Then 80 ml of water were added at a temperature of -5 ° C to -10 ° C within 10 minutes and the resulting mixture was stirred at the same temperature for 5 minutes. The aqueous layer was separated and its pH was adjusted to 4.2 by adding 28% aqueous ammonia solution. The precipitate was collected by filtration, washed with 40 ml of a 70% aqueous acetone solution and 40 ml of methanol and dried, giving 4.1 g of 7-amino-3- (l-allyl-1H-tetrazol-5-yl) - thiomethyl-3-cephem-4-carboxylic acid was obtained.

I.R. (Nujol): 3150,1800,1610,1530 cm-1

N.M.R. (ds-DMSO, 5): 3.65 (2H, ABq, J = 18Hz), 4.33 (2H, ABq, J = 13Hz), 6.38-4.70 (7H, m).

Preparation 18

(1) 126.4 g of 2-hydroxyimino-2- (2-aminothiazol-4-yl) -acetic acid ethyl ester (syn isomer), 81.3 g of formic acid and 180 g of acetic anhydride were prepared in a similar manner to that described in s Preparation 9-4 has been treated, giving 109.6 g of 2-hydroxyimino-2- (2-formamidothiazol-4-yl) acetic acid ethyl ester (syn isomer).

I.R. (Nujol): 3320.3140.3050.1710.1555 cm "1

N.M.R. (ds-DMSO, 5): 1.30 (3H, t, J = 7Hz), 4.33 (2H, q, io J = 7Hz), 7.54 (IH, s), 8.54 (lH, s), 11.98 (IH, s ), 12.58 (IH, s)

(2) A mixture of 7.97 g of chloromethylthiomethane, 15.1 g of powdered potassium iodide and 79 ml of acetone was stirred at room temperature for 1 hour, and the resulting mixture was then filtered and washed with a little acetone.

15 Then the washing water and the filtrate were combined and put into a suspension of 17.5 g of 2-hydroxyimino-2- (2-formamido-thiazol-4-yl) ethyl acetate (syn isomer) and 15.5 g of powdered potassium carbonate in 300 ml of acetone stirred in. The mixture was then stirred for 3 hours at room temperature 20, filtered and washed with acetone. Then the washing water and the filtrate were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The oily residue thus obtained was subjected to column chromatography over silica gel, eluting with chloroform. In this way, 2.4 g of 2-methyl-thiomethoxyimino-2- (2-formamidothiazol-4-yl) -acetic acid ethyl ester (syn isomer) were obtained, melting point 130 to 131 ° C. 30 I.R. (Nujol): 3160.3125.3050.1740.1695 cm "1

N.M.R. (ds-DMSO, 5): 1.32 (3H, t, J = 7Hz), 2.22 (3H, s), 4.38 (2H, q, J = 7Hz), 5.33 (2H, s), 7.67 (IH, s) , 8.56 (IH, s).

(3) A mixture of 2.4 g of 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) ethyl acetate (syn isomer), 23.8

35 ml of aqueous sodium hydroxide solution and 19.8 ml of methanol were stirred at 30 ° C for 2 Vi hours. The solution thus obtained was then adjusted to a pH of 7 by adding 10% hydrochloric acid and the methanol was then distilled off under vacuum. The pH of the aqueous solution was adjusted to 1 by adding 10% hydrochloric acid while cooling with ice, and this solution was then extracted three times with ethyl acetate. The extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo, 45 whereupon 1.13 g of 2-methylthiomethoxyimino-2- (2-formamido-dothiazol-4-yl) acetic acid (syn isomer), Melting point 157 ° C (decomposition).

I.R. (Nujol): 3210.3160.3075, 1700.1555 cm "1

N.M.R. (ds-DMSO, Ô): 2.24 (3H, s), 5.31 (2H, s), 7.61 (IH, s), so 8.57 (IH, s), 12.73 (IH, s).

Preparation 19

The following connections were made when working in a manner similar to that described in the preceding 55 preparations.

(1) 2-isopropoxyimino-2- (2-formamidothiazol-4-yl) acetic acid, mp. 168 to 169 ° C (decomposition) (syn isomer)

I.R. (Nujol): 3200.3130.1710.1600.1560 cm- '

(2) 2-Butoxyimino-2- (2-formamidothiazol-4-yl) acetic acid 60 (syn isomer)

I.R. (Nujol): 3350.3160, 3050, 1700, 1680, 1570 cm-1.

(3) 2 l-hexyloxyimino-2- (2-formamidothiazol-4-yl) -acetic acid (syn isomer), mp. 115 to 116 ° C (decomposition)

I.R. (Nujol): 3170,3070,1720,1700,1660 cm-1 es N.M.R. (ds-DMSO, 5): 0.6-2.1 (11H, m), 4.15 (2H, t, J = 6Hz), 7.53 (IH, s), 8.56 (IH, s), 12.69 (IH, s)

(4) 2- (2-formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer)

49

638 532

I.R. (Nujol): 3200.1710.1690 cm- '

(5) 2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer)

I.R. (Nujol): 3330.3200.3100.1660.1590 cm "1

(6) 2-ethoxycarbonylmethoxyimino-2- (2-formamidothiazole-4-yl) acetic acid (syn isomer), mp. 112 ° C (decomposition)

I.R. (Nujol): 3150.1740.1670.1550 cm- '

(7) 2-tert-butoxycarbonylmethoxyimino-2- (2-formamido-4-yl) acetic acid (syn isomer), mp. 117 ° C. (decomposition)

I.R. (Nujol): 3180.3140, 1750.1690.1630cm- 'io

(8) 2- (3-isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp. 110 ° C (decomposition)

I.R. (Nujol): 3270.3130.1680.1540 cm- '

(9) 2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer)

I.R. (Nujol): 3170, 1720, 1660, 1620 cm "'

N.M.R. (ds-DMSO, 8): 1.27 (3H, t, J = 7Hz), 4.25 (2H, q, J = 7Hz), 4.77 (2H, s), 6.96 (IH, s)

(10) 2- (2-ethoxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) 20

I.R. (Nujol): 3350.3140.1740.1700 cm- »

Preparation 20

A solution of 17.4 g of 4-bromo-3-hydroxybenzyloxyamine phosphate in 200 ml of water and 200 ml of ethanol was stirred at room temperature and its pH was adjusted to 7.0 using sodium bicarbonate. Then 10.0 g of 2- (2-formamidothiazol-4-yl) -glyoxylic acid were added to the solution,

whereupon the resulting suspension was adjusted to a pH of 4.0 to 4.5. After the solution had been stirred for 2 hours at room temperature, the ethanol was removed from the solution obtained in vacuo. Ethyl acetate was then added to the aqueous residue and the pH was adjusted to 2.5 using 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate. The solution was finally concentrated in vacuo to give 14.8 g of 2- (2-formamidothiazol-4-yl) -2- (4-bromo-3-hydroxybenzyloxyimino) acetic acid (Syn-Iso-mer).

I.R. YNu'o'max "-3350.3150.1720.1680.1570cm- '40

N.M.R. 8 (DMSO-ds, ppm): 5.13 (2H, m), 6.8 (IH, dd, J = 8Hz, 2Hz), 7.02 (IH, d, J = 2Hz), 7.5 (IH, d, J = 8Hz) , 7.58 (IH, s), 8.58 (IH, s), 10.35 (IH, breitess), 12.7 (IH, broad s).

Preparation 21 45

(1) 40.0 g of 2-hydroxyimino-3-oxobutyric acid ethyl ester (syn isomer), 43.6 g of 4-fluorobenzyl chloride, 60.0 g of N, N-dimethylformamide, 52.0 g of potassium carbonate and 60.0 ml Ethyl acetate was treated in the usual manner to obtain 64.4 g of ethyl 2- (4-fluorobenzyl-oxyimino) -3-oxobutyrate (syn isomer). 50

I.R. (Film): 3000.2940.1730.1690.1600 cm- '

N.M.R. (DMSO-dó, ô): 1.21 (3H, t, J = 7.0Hz), 2.34 (3H, s), 4.26 (2H, q, J = 7.0Hz), 5.32 (2H, s), 6.97- 7.73 (4H, m).

(2) 64.0 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxobutyrate (syn isomer), 35.6 g of sulfuryl chloride and 70.0 ml of acetic acid 55 were treated in a similar manner to that of Preparation 11-1, with 29.55 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer) were obtained.

I.R. (Film): 1720.1600 cm- '

N.M.R. (DMSO-dó, Ô) 1.20 (3H, t, J = 7.0Hz), 4.28 (2H, q, eo J = 7.0Hz), 4.87 (2H, s), 5.36 (2H, s), 7.00- 7.75 (4H, m).

(3) 29.0 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxo-4-chlorobutter (syn isomer), 8.8 g of thiourea, 7.9 g of sodium acetate, 72.5 ml of water, 60 ml of tetrahydrofuran and 72.5

ml of ethanol were treated in a similar manner to preparation 65 11- (2), 28.0 g of 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) -acetic acid ethyl ester (syn isomer)

received.

I.R. (Nujol): 3450.3150.3100, 1710.1620 cm- 'N.M.R. (DMSO-da, Ô) 1.23 (3H, t, J = 7.0Hz), 4.30 (2H, q, J = 7Hz), 5.15 (2H, s), 6.90 (IH, s), 6.95-7.60 (4H , m).

(4) 25.5 g of ethyl 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn isomer), 1.3 g of 1-methylimidazole, 118.3 ml In sodium hydroxide solution, 52 ml of methanol and 200 ml of tetrahydrofuran were treated in a similar manner to that of preparation 11- (3), giving 22.11 g of 2- (4-fluorobenzyloxy-imino) -2- (2-aminothiazol-4 -yl) acetic acid (syn isomer) was obtained.

I.R. (Nujol): 3650.3450.3300.3150.1630 cm "'N.M.R. (DMSO-ds, Ô) 5.16 (2H, s), 6.88 (IH, s), 7.04-7.66 (4H, m)

(5) 23.4 g of 2- (fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn isomer), 32.2 g of bis (trimethylsilyl) acetamide, 49.9 g of 2, 2,2-Trifluoroacetic anhydride and 234 ml of dry ethyl acetate were treated in a similar manner to that of preparation 9- (4), with 18.9 g of 2- (4-fluorobenzyloxyimino) -2- [2- (2,2,2- trifluoroacetamido) thiazol-4-yl] acetic acid (syn isomer), melting point 180 to 182 ° C, was obtained.

I.R. (Nujol): 3200, 3150, 1730 cm- '

N.M.R. (DMSO-ds, 8) 5.25 (2H, s), 7.02-7.60 (4H, m), 7.72 (lH, s)

Preparation 22

(1) The reaction of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) with 3,4-dichlorobenzyl chloride in a conventional manner gave ethyl 2- (3,4-dichlorobenzyloxyimino) -3- oxobutyrate (syn isomer), oil.

I.R. (Film): 1730.1690,1600.1470,1400,1370,1310,1240, 1130,1080,1010 cm- '

N.M.R. (CCU, 8) 1.30 (3H, t, J = 6Hz), 2.30 (3H, s), 4.30 (2H, q, J = 6Hz), 4.47 (2H, s), 7.00-7.53 (3H, m).

(2) Working according to preparation 11- (1), ethyl-2- (3,4-dichlorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer), oil was obtained.

I.R. (Film): 1740.1710.1590.1470.1400.1370.1320.1260, 1200.1130.1010 cm "'

N.M.R. (CCU, Ô) 1.37 (3H, J = 6Hz), 4.23 (2H, q, J = 6Hz), 4.43 (2H, s), 5.27 (2H, s), 7.10-7.60 (3H, m).

(3) When working in a similar way to the preparation

11- (2) gave ethyl 2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn isomer)

I.R. (Nujol): 3460.1720.1600.1540.1460.1390.1260.1180, 1020.1010.880.810 cm- '

N.M.R. (DMSO-de, 8) 1.25 (3H, t, J = 7Hz), 4.30 (2H, q, J = 7Hz), 5.17 (2H, s), 6.93 (IH, s), 7.27-7.73 (3H, m ).

(4) When working in a similar way to the preparation

11- (3) gave 2- (3,4-dichlorobenzyloxyimino) -2- (2-ami-nothiazol-4-yl) acetic acid (syn isomer)

I.R. (Nujol): 3430.1660.1590.1400.1010 cm- 'N.M.R. (DMSO-de, 8) 5.23 (2H, s), 6.93 (IH, s), 7.30-7.77 (3H, m).

(5) Working in a similar manner to preparation 9- (4) gave 2- (3,4-dichlorobenzyloxyimino) -2- [2- (2,2,2-trifluoroacetamido) thiazol-4-yl] acetic acid (syn isomer).

I.R. (Nujol): 1720.1580,1300,1260,1200,1160,1150 cm- 'N.M.R. (DMSO-de, 8) 5.40 (2H, s), 7.47-7.93 (4H, m).

Preparation 23

8.3 g of hydrazine hydrate were added at 60 ° C. to a suspension of 21.0 g of N- (cinnamyloxy) phthalimide in 200 ml of ethanol, and the mixture was stirred at this temperature for 1 vi hours. The mixture was then mixed with 22 ml of concentrated hydrochloric acid and with 220 ml of water and then filtered. The filtrate was concentrated to give a precipitate, which was filtered off. Then the filtrate was adjusted to a pH of 7.0 and the solution containing 0-cinnamylhydroxylamine with 300 ml of ethanol

638 532

50

and 10.0 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid were added. The mixture thus obtained was stirred at pH 4.0 to 4.5 for 2 hours. The reaction mixture was then concentrated and its pH was adjusted to 2.0 after the addition of ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to give 8.6 g of 2-cinnamyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

I.R. (Nujol): 3400-3100.1700.1550 cm- '">

N.M.R. (DMSO-d «, Ô) 4.85 (2H, d, J = 5Hz), 6.2-6.93 (2H, m), 7.2-7.72 (5H, m), 7.6 (IH, s), 8.57 (IH, s) , 12.7 (IH, broad s)

Example 44 is

0.80 g of 2-allyloxyimino-2- (2-formamidothiazol-4-yI) acetic acid and 10 ml of dry ethyl acetate were, with stirring at 0 to 5 ° C., a suspension of a Vilsmeier reagent, prepared from 0.25 g of dry dimethylformamide and 0.528 g of phosphorus oxychloride in 0.75 ml of dry ethyl acetate were added. The mixture thus obtained was stirred at the same temperature for 30 minutes to obtain a yellow solution. This solution was then at -10 ° C with stirring a solution of 1.11 g of 7-amino-3 (l-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and 2.96 g 25 trimethylsilylacetamide in 15 ml of dry ethyl acetate were added and the mixture was stirred at the same temperature for 1½ hours. 15 ml of water were then added to the reaction mixture, and the ethyl acetate layer was separated off and extracted with 30 ml of an aqueous sodium bicarbonate solution 30. The aqueous extract was acidified to pH 2.0 using 10% hydrochloric acid and extracted with 150 ml of ethyl acetate. The extract was washed with water, dried and evaporated. The residue was converted into a powder with diisopropyl ether, giving 1.48 g of 35 powder which consisted of 7- [2-allyloxyimino-2- (2-formamido-dothiazol-4-yl) acetamido] -3- (l -allyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

1st row (Nujol): 3180.1775.1665 cm "'

N.M.R. (ds-DMSO, ô) 9.68 (IH, d, J = 8Hz), 8.51 (IH, s), 7.4040 (IH, s), 5.60-6.33 (3H, m), 4.85-5.57 (7H, m), 4.27-4.77 (4H, m), 3.70 (2H, ABq, J = 18Hz).

Example 45

The Vilsmeier reagent was prepared in a manner known per se from 0.4 g of dry dimethylformamide, 0.9 g of phosphorus oxychloride and 1.6 ml of dry ethyl acetate. Then 18 ml of dry ethyl acetate and then 1.3 g of 2-ethoxy-imino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) were added at 0 ° C. The mixture was stirred at the same temperature for 50 minutes. The mixture was then at a temperature of -10 ° C in a solution of 1.8 g of 7-amino-3- (l-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and 4.6 g of trimethylsilylacetamide are stirred into 36 ml of dry ethyl acetate and the mixture is stirred for a further 55 hours at the same temperature. The reaction mixture was then mixed with 30 ml of water. The ethyl acetate layer was separated and extracted with a saturated aqueous sodium bicarbonate solution (pH 7.5). The aqueous layer was washed three times with ethyl acetate and its pH was adjusted to 2.0 by adding concentrated hydrochloric acid after the addition of 100 ml of ethyl acetate. The ethyl acetate layer was separated, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, treated with activated carbon and evaporated to dryness 65, 2.56 g of 7- [2-ethoxyimino-2- (2-formamido-dothiazoI-4-yI ) -acetamido] -3- (l-allyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3200.1765.1665 cm "'

N.M.R. (ds-DMSO, 5) 1.26 (3H, t, J = 7.0Hz), 3.68 (2H, m), 4.18 (2H, q, J = 7.0Hz), 4.36 (2H, ABq, J = 14, 0Hz), 4.75-5.57 (5H, m), 5.68-6.40 (2H, m), 7.37 (IH, s), 8.48 (IH, s), 9.60 (IH, d, J = 8.0Hz).

Example 46

The Vilsmeier reagent was prepared in a manner known per se from 0.209 g of dry dimethylformamide, 0.434 g of phosphorus oxychloride and 0.75 ml of dry ethyl acetate. Then 6.5 ml of dry tetrahydrofuran and then 0.65 g of 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) were added to this reagent at 0 ° C. The resulting mixture was stirred at the same temperature for 30 minutes. Then it was added dropwise at -5 ° C to 0 ° C in a solution of 1.25 g of 7-amino-3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid in a mixture of 10 ml of water and 10 ml of acetone with the addition of triethylamine and maintaining a pH of 7.5 and the mixture was then stirred for 30 minutes at the same temperature and the pH just mentioned. The reaction mixture was then mixed with 60 ml of ethyl acetate and the pH was then adjusted to 2.5 by adding 10% hydrochloric acid. The insolubles were filtered off and the filtrate was extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off and the residue was converted into a yellowish powder using diethyl ether, 1.03 g of 7- [2-methylthiomethoxyimino-2- (2-formamidothia-zol-4-yl) acetamido] -3- (1 -allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3250.3200.1780.1670.1540 cm "'

N.M.R. (ds-DMSO, 5) 2.23 (3H, s), 3.72 (2H, s), 4.38 (2H, ABq, J = 14Hz), 4.8-5.6 (7H, m), 5.7-6.4 (2H, m), 7.48 (IH, s), 8.55 (IH, s), 9.75 (IH, d, J = 8Hz), 12.69 (IH, broad s).

Example 47

The Vilsmeier reagent was prepared in a manner known per se from 0.74 g of dry dimethylformamide, 1.56 g of phosphorus oxychloride and 2.0 ml of dry ethyl acetate. Then it was mixed with 15 ml of dry tetrahydrofuran and then at 0 ° C. with 1.50 g of 2- (3-isoxazolyl) methoxyimino-2- (2-formamidothia-zol-4-yl) acetic acid (syn isomer) . The mixture was then stirred at the same temperature for 30 minutes. The mixture thus obtained was added dropwise at a temperature of -5 ° C to 0 ° C in a solution of 2.34 g of 7-amino-3- (l-allyl-1H-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid was stirred into a mixture of 11.5 ml of water and 11.5 ml of acetone while maintaining a pH of 7.5 which had been set by adding triethylamine, and the mixture was then stirred at the same temperature and at the same pH stirred for 30 minutes. The reaction mixture was then mixed with 60 ml of ethyl acetate and the pH was adjusted to 2.5 by adding 10% hydrochloric acid. The insoluble matter was filtered off and the filtrate extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was converted into a yellowish powder with diethyl ether, 2.15 g of 7- [2- (3-isoxazolyl) methoxyimino-2- (2-formamidothia-zol-4-yl) acetamido] -3- (l-allyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained.

I.R. (Nujol): 3250.1780.1670.1550 cm- '

N.M.R. (dó-DMSO, 5): 3.72 (2H, s), 4.40 (2H, ABq, J = 14Hz), 4.8-5.6 (7H, m), 5.6-6.5 (2H, m), 6.67 (IH, d, J = 2Hz), 7.50 (IH,

51

638 532

s), 8.56 (IH, s), 8.92 (IH, d, J = 2Hz), 9.80 (IH, d, J = 8Hz), 12.72 (IH, broad s).

Example 48

1.0 g of phosphorus oxychloride was immediately suspended in a suspension of 1.4 g of 2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer) in 14 ml of dry tetrahydrofuran at 2 ° C. added and the mixture stirred for 15 minutes at a temperature of 2 to 4 ° C. Then 1.0 g of trimethylsilylacetamide was added dropwise and the resulting mixture was stirred at 2 to 6 ° C. for 20 minutes. Then 1.0 g of phosphorus oxychloride was added and the mixture was stirred for 20 minutes. Then 0.5 g of dry dimethylformamide was immediately added at a temperature of 4 to 6 ° C. and the mixture was stirred for 1 hour, giving a clear solution. On the other hand, 5.3 g of trimethylsilylacetamide were suspended in a suspension of 1.8 g of 7-amino

3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid was stirred into 27 ml of dry ethyl acetate and the solution was stirred at 40 ° C. for 30 minutes. This solution was then added directly to the tetrahydrofuran solution obtained as described above at -30 ° C. and the resulting mixture was stirred at -5 ° C. to -20 ° C. for 1 hour. Then 30 ml of water and 20 ml of ethyl acetate were added to the reaction mixture. The separated organic layer was extracted with an aqueous sodium bicarbonate solution. The extract was adjusted to a pH of 3.0 by adding 10% hydrochloric acid. The precipitate was collected by filtration and washed with water, 0.85 g of 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) - 30 acetamido] -3- (1 -allyl-1 H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained.

I.R. (Nujol): 3350.3230.1780.1675.1635 cm "1

N.M.R. (ds-DMSO, Ô) 3.67 (2H, m), 4.40 (2H, ABq,

J = 15.0Hz), 4.85-5.56 (6H, m), 5.62-6.45 (2H, m), 6.77 (IH, s), 35 7.01-7.65 (7H, m), 9.71 (IH, d, J = 8Hz)

Example 49

The Vilsmeier reagent was prepared in a manner known per se from 0.44 g of dry dimethylformamide, 0.9 g of phosphorus oxychloride and 1.0 ml of dry 40 ethyl acetate. Then 20 ml of dry ethyl acetate and then 1.1 g of 2-methoxy-imino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) were added at a temperature of -50 ° C to -10 ° C. The mixture was stirred at this temperature for 45 minutes. Then it was added dropwise at 0 to 5 ° C and at a pH of 6.5 to 7.5 in a solution of 2.12 g of 7-amino-3- (4-allyl-4H-l, 2.4 -triazol-3-yl) -thiomethyl-3-cephem-

4-carboxylic acid and 2 g of sodium bicarbonate are stirred into a mixture of 20 ml of water and 20 ml of acetone and the mixture is stirred at this temperature for 20 minutes. The aqueous layer was separated and the acetone evaporated. The aqueous layer was adjusted to a pH of 3.0 with ice cooling and stirring by adding 10% hydrochloric acid. The precipitate was collected by filtration, washed with water and dried,

being 0.94 g

7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (4-allyl-4H-l, 2,4-triazol-3-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer). 60

I.R. (Nujol): 3200.1780.1680.1550 cm- '.

N.M.R. (ds-DMSO, Ô) 3.72 (2H, broad s), 3.93 (3H, s), 4.20 (2H, broad s), 4.65 (2H, m), 4.72-5.43 (3H, m), 5.55-6.45 ( 2H, m), 7.43 (IH, s), 8.55 (IH, s), 8.65 (IH, s), 9.68 (IH, d, J = 8Hz), 12.82 (IH, m). 65

Example 50

When working in a manner similar to that in Examples 44

up to 49 you can make the following connections:

(1) 7- [2-isopropoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem- 4-car-bonic acid (syn isomer).

I.R. (Nujol): 3220.1780, 1670 cm- '.

N.M.R. (ds-DMSO, ô) 1.20 (3H, s), 1.32 (3H, s), 3.70 (2H, broad s), 4.07-4.87 (3H, m), 4.93-5.50 (4H, m), 5.67-6.23 (2H, m), 7.40 (1H, s), 8.50 (1H, s), 9.58 (1H, d, J = 8Hz).

(2) 7- [2-butoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem- 4-car-bonic acid (syn isomer).

I.R. (Nujol): 3200.1780.1695.1675.1655 cm- '.

N.M.R. (ds-DMSO, Ô) 0.88 (3H, m), 1.10-2.01 (3.71 (2H, m), 4.14 (2H, t, J = 7.0Hz), 4.38 (2H, ABq, J = 14, 0Hz), 4.38-5.51 (5H, m), 5.63-6.40 (2H, m), 7.42 (1H, s), 8.56 (1H, s), 9.65 (1H, d, J = 9.0Hz).

(3) 7- [2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem- 4-car-bonic acid (syn isomer).

I.R. (Nujol): 3175, 1780, 1757, 1684, 1640 cm- '.

N.M.R. (ds-DMSO, ô) 0.84 (3H, m), 1.06-2.03 (8H, m), 3.73 (2H, m), 4.14 (2H, t, J = 6.0Hz), 4.40 (2H, ABq, J = 14.0Hz), 4.85-

5.52 (5H, m), 5.75-6.45 (2H, m), 6.97 (IH, broad s), 7.41 (1H, s), 8.54 (1H, s), 9.63 (1H, d, J = 8.0Hz) .

(4) 7- [2- (2-formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl- 3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3265.1780.1720.1680 cmr '.

N.M.R. (ds-DMSO, 8) 3.74 (2H, m), 4.13-4.70 (6H, m), 4.85-

5.53 (5H, m), 5.70-6.42 (2H, m), 7.48 (1H, s), 8.26 (1H, s), 8.56 (1H, s), 9.69 (1H, d, J = 9.0Hz).

(5) 7- [2-ethoxycarbonylmethoxyimino-2- (2-formamido-thiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer).

I.R. (Nujol): 3500, 3280, 1780, 1735, 1690 cm- '.

N.M.R. (ds-DMSO, 8) 1.24 (3H, t, J = 7Hz), 3.74 (2H, s), 4.20 (2H, q, J = 7Hz), 4.42 (2H, s), 4.77 (2H, s), 4.5-5.6 (5H, m), 5.7-6.4 (3H, m), 7.50 (1H, s), 8.57 (1H, s), 9.68 (IH, d, J = 8Hz), 12.69 (1 H, broad s ).

(6) 7- [2-tert-Butoxycarbonylmethoxyimino-2- (2-formamido-dothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-ethyl -3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3250.1780.1720.1680.1540 cm- '.

N.M.R. (ds-DMSO, 8) 1.44 (9H, s), 3.71 (2H, ABq, J = 18Hz), 4.37 (2H, ABq, J = 14Hz), 4.62 (2H, s), 4.8-5.4 (5H, m ), 5.5-6.4 (2H, m), 7.46 (1H, s), 8.52 (1H, s), 9.58 (1H, d, J = 8Hz), 12.60 (IH, broad s).

(7) 7- [2-Ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-allyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn isomer).

I.R. (Nujol): 3350.1780.1675.1635 cm- '.

(8) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem- 4-car-bonic acid (syn isomer).

I.R. (Nujol): 3350.3250.1780.1675.1630 cm- '.

(9) 7- [2-Butoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-l H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer).

I.R. (Nujol): 3360.1780.1672 cm "'.

(10) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem- 4-car-bonic acid (syn isomer).

I.R. (Nujol): 3350.3240.1780.1675.1630 cm "'.

(11) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer).

I.R. (Nujol): 3350.3210.1778.1675 cm "'.

(12) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazole-

638 532

52

4-yl) acetamido] -3- (l-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-cabonic acid (syn isomer).

I.R. (Nujol). -3360.3230, 1780.1680.1630 cm- '.

(13) 7- [2-tert-Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3330, 1780, 1730, 1680, 1630 cm- '.

(14) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 ~ carboxylic acid (syn isomer).

I.R. (Nujol): 3270.1760.1650.1520 cm- '.

(15) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-allyl-l H-tetrazol-5-yl) thiomethyl- 3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300.1770.1660.1530 cm- '.

(16) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-allyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn isomer).

I.R. (Nujol): 3360.1780.1680.1630 cm- '.

(17) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-allyl-4H-l, 2,4-triazol-3-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350.1775.1670.1530 cm- '.

(18) 7- [2- (4-fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacetamido) thiazol-4-yl) acetamido] -3- (l-allyl-lH- tetrazol-5-yl) thio-methyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3250.3170.1780.1720.1650 cm- '.

N.M.R. (DMSO-dó) 3.64 (2H, m), 4.34 (2H, ABq, J14Hz), 4.79-5.44 (7H, m), 5.65-6.27 (2H, m), 6.95-7.61 (4H, m), 7.51 ( 1H, s), 9.83 (1 H, d, J = 8Hz).

(19) 7- [2- (4-Fluorobenzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer), melting point 157 to 161 ° C (decomposition).

I.R. (Nujol): 3500.1770.1660.1630.1600 cm- '.

(20) 7- [2- (3,4-dichlorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacetamido) thiazol-4-yl} acetamido] -3- (l-allyl- 1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 1770, 1650 cm "'.

N.M.R. (DMSO-de, ô) 3.72 (2H, m), 4.40 62H, m), 5.00-5.43 (7H, m), 5.73-6.60 (2H, m), 7.30-7.77 (4H, m), 9.90 (1H , d, J = 8Hz).

(21) 7- [2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (l-allyl-lH-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer), melting point 155 to 175 ° C (decomposition).

I.R. (Nujol): 1770.1660.1620.1450 cm- '.

Example 51

0.33 g of concentrated hydrochloric acid was added to a solution of 1.30 g of 7- [2-allyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazole-5- yl) -thiomethyl-3-cephem-4-car-bonic acid (syn isomer) in 13 ml of methanol was added and the mixture was stirred at room temperature for 414 hours. The solvent was then distilled off under reduced pressure and the residue was dissolved in 25 ml of a saturated aqueous sodium bicarbonate solution. This aqueous solution was washed with 25 ml of ethyl acetate and its pH was adjusted to 2.0 by adding 10% hydrochloric acid. The precipitate was collected by filtration, washed with water and dried, giving 0.95 g of a colorless powder consisting of 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 - (l-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

1st row (Nujol): 3350.3210.1778.1675 cm- '.

N.M.R. (dö-DMSO, 8): 3.68 (2H, ABq, J = 18Hz), 4.40-4.71 (4H, m), 4.80-5.45 (7H, m), 5.64-6.24 (3H, m), 6.74 (IH, s), 7.35 (2H, broad s), 9.62 (IH, d, J = 8Hz).

Example 52

0.9 g of concentrated hydrochloric acid was added at room temperature to a solution of 2.4 g of 7- [2-ethoxyimino-2- (2-formamido-thiazol-4-yl) -acetamido] -3- (l-allyl-lH-tetrazol-5 -yl) -thiomethyl-

5 3-cephem-4-carboxylic acid (syn isomer) in a mixture of 16.8 ml of methanol and 4.8 ml of tetrahydrofuran was added and the mixture was stirred at 30 ° C. for 3 hours. Then the solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous sodium bicarbonate solution. The aqueous solution was washed with ethyl acetate and the pH was adjusted to 2.8 by adding concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water and dried, giving 1.72 g of 7- [2-ethoxyimino-2- (2-aminothia-15 zol-4-yl) acetamido] -3- (1-allyl -1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

1st row (Nujol): 3350.1780.1675.1635 cm- '.

N.M.R. (ds-DMSO, 8) 1.24 (3H, t, J = 7.3Hz), 3.71 (2H, m), 4.13 (2H, q, J = 7.3Hz), 4.37 (2H, ABq, J = 13, 5Hz), 4.80-5.53 20 (5H, m), 5.64-6.45 (2H, m), 6.77 (IH, s), 7.25 (2H, broad s), 9.62 (IH, d, J = 8.0Hz).

Example 53

A mixture of 0.95 g of 7- [2-methylthiomethoxyimino-2- (2-25 formamidothiazol-4-yl) acetamido] -3- (l-allyl-lH-tetrazol-5-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer), 0.324 g of concentrated hydrochloric acid, 9.5 ml of methanol and 2 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Then the solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous sodium bicarbonate solution. The aqueous solution was washed with 25 ml of ethyl acetate and the pH was adjusted to 1.5 by adding 10% hydrochloric acid. The precipitate was collected by filtration, water washed with water and dried to give 0.78 g of 7- [2-methylthiomethoxyxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l -allyl-1 H-tetra-zol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3270.1760.1650.1520 cm "'. 40 NMR (do-DMSO, 8) 2.21 (3H, s), 3.72 (2H, s), 4.38 (2H, ABq, J = 14Hz), 4.8 -5.6 (7H, m), 5.7-6.4 (2H, m), 6.80 (IH, s), 7.26 (2H, broad s), 9.66 (IH, d, J = 8Hz).

Example 54

45 A mixture of 1.5 g of 7- [2- (3-isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l-allyl-lH-tetrazol-5-yl ) -thiomethyI-3-cephem-4-carboxylic acid (syn isomer), 0.497 g. concentrated hydrochloric acid, 15 ml methanol and 3 ml tetrahydrofuran were stirred for 2 hours at room temperature. Then the solvent was distilled off under reduced pressure and the residue was dissolved in an aqueous saturated sodium bicarbonate solution. The aqueous solution was washed with 25 ml of ethyl acetate and the pH was adjusted to 1.5 by adding 10% hydrochloric acid. The precipitate was collected by filtration, washed with water and dried, giving 0.65 g of 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] - 3- (l-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

60 I.R. (Nujol): 3300.1770.1660.1530 cm- '.

N.M.R. (dö-DMSO, 8): 3.71 (2H, s), 4.40 (2H, d, J = 14Hz), 4.8-5.6 (7H, m), 5.6-6.5 (2H, m), 6.62 (IH, d, J = 2Hz), 6.83 (IH, s), 7.29 (2H, broad s), 8.92 (IH, d, J = 2Hz), 9.73 (IH, d, J = 8Hz).

65

Example 55

A mixture of 0.9 g of 7- [2-methoxyimino-2- (2-formamido-dothiazol-4-yl) acetamido] -3- (4-allyl-4H-l, 2,4-triazol-3- yl) -thio-

53

638 532

methyl-3-cephem-4-carboxylic acid (syn isomer) and 0.3 ml of concentrated hydrochloric acid, 7 ml of methanol and 7 ml of tetrahydrofuran were stirred at room temperature for 4½ hours. The solvent was then distilled off under reduced pressure and the residue was dissolved in an aqueous saturated sodium bicarbonate solution. The aqueous solution was washed with 25 ml of ethyl acetate and its pH was adjusted to 2.0 by adding 10% hydrochloric acid. The precipitate was collected by filtration, washed with water and dried, yielding 0.5 g of 7- [2-methoxyimino-2- (2-io aminothiazol-4-yl) acetamido] -3- (4-allyl-4H -l, 2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350.1775.1670.1530 cm "1.

N.M.R. (dö-DMSO, S) 3.65 (2H, broad s), 3.83 (3H, s), 4.15 (2H, broad s), 4.58 (2H, m), 4.77-5.5 (3H, m), 5.58-6.33 ( 2H, is m), 6.73 (IH, s), 8.60 (IH, s), 9.58 (IH, d, J = 8Hz).

Example 56

The following compounds were obtained by operating in a similar manner to Examples 51 to 55. 20th

(1) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer).

I.R. (Nujol): 3350.3230.1780.1675.1635 cm "1.

(2) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) -acet- 25 amido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem -4-car-bonic acid (syn isomer).

I.R. (Nujol): 3350.3250.1780.1675.1630 cm "1.

N.M.R. (ds-DMSO, 8) 1.20 (3H, s), 1.30 (3H, s), 3.70 (2H, broad s), 4.30 (3H, m), 4.97-5.40 (4H, m), 5.63-6.27 (2H , m), 30 6.70 (1H, s), 9.55 (1H, d, J = 8Hz).

(3) 7- [2-butoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer).

I.R. (Nujol): 3360.1780.1672 cm "1.35

N.M.R. (ds-DMSO, 8) 0.91 (3H, t, J = 6.0Hz), 1.18-1.96 (4H, m), 3.73 (2H, m), 3.87-4.73 (4 H, m). 4.83-5.57 (5H, m), 5.63-6.40 (2H, m), 6.74 (1H, s), 7.20 (2H, broad s), 9.55 (1H, d, J = 8.0Hz).

(4) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] - 40 3- (l-allyl-l H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer).

I.R. (Nujol): 3350.3240.1780.1675.1630 cm "1.

N.M.R. (ds-DMSO, 8) 0.85 (3H, m), 1.00-2.00 (8H, m), 3.68 (2H, m), 4.05 (2H, m), 4.37 (2H, m), 4.80-5.47 (5H, m), 5.60-45 6.47 (2H, m), 6.69 (1H, s), 7.20 (2H, broad s), 9.50 (1H, d, J = 8.0Hz).

(5) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-allyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn isomer). 50

I.R. (Nujol): 3360.3230.1780.1680.1630 cm "1.

N.M.R. (ds-DMSO, 8) 1.21 (3H, t, J = 7Hz), 3.68 (2H, s), 4.14 (2H, q, J = 7Hz), 4.38 (2H, s), 4.66 (2H, s), 4.8-5.5 (5H, m), 5.6-6.4 (3H, m), 6.80 (1H, s), 7.20 (2H, broad s), 9.48 (1H, d, J = 8Hz). 55

(6) 7- [2-tert-Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3330.1780.1730.1680.1630 cm "1.

N.M.R. (ds-DMSO, 8) 1.43 (9H, s), 3.67 (2H, s), 4.37 (2H, eo ABq, J = 14Hz), 4.56 (2H, s), 4.8-5.5 (5H, m), 5.6 -6.4 (2H, m), 6.78 (1H, s), 7.20 (2H, broad s), 9.43 (1H, d, J = 8Hz).

(7) 7- [2-Carboxy methoxy imino-2- (2-aminothiazol-4-yl) acetamido-3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem -4-car-bonic acid (syn isomer). 65

I.R. (Nujol): 3360, 1780, 1680, 1630 cm "1.

(8) 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3- cephem-4-

carboxylic acid (syn isomer), melting point 157 to 161 ° C (decomposition).

I.R. (Nujol): 3500.1770.1660.1630.1600 cm "1.

N.M.R. (DMSO-ds, 8) 3.69 (2H, m), 4.39 (2H, ABq, J = 14Hz), 4.75-5.48 (7H, m), 5.63-6.57 (2H, m), 6.76 (1H, s), 6.86-7.76 (4H, m), 9.67 (1H, d, J = 8Hz).

(9) 7- [2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl- 3-cephem-4-carboxylic acid (syn isomer), melting point 155 to 175 ° C (decomposition).

I.R. (Nujol): 1770, 1660, 1620, 1450 cm "1.

N.M.R. (DMSO-ds, 8): 3.63 (2H, m), 4.33 (2H, m), 4.93-5.37 (7H, m), 5.67-6.40 (2H, m), 6.73 (1H, s), 7.10-7.70 (3H, m), 9.73 <1H, d, J = 8Hz).

Example 57

20 ml of trifluoroacetic acid were cooled with ice in a suspension of 2.05 g of 7- [2-tert-butoxycarbonylmethoxyimino-2- (2-aininothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazole -5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer) stirred in 2 ml of anisole and the resulting mixture was stirred at room temperature for 2 hours. Then the reaction mixture was concentrated under reduced pressure and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether, dried and dissolved in an aqueous sodium bicarbonate solution. The insoluble constituents were filtered off and the filtrate was adjusted to a pH of 3.2 by adding concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water and dried, whereby 0.8 g of 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) -acet-amido] -3- (1-allyl- 1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-car-bonic acid (syn isomer) was obtained.

I.R. (Nujol): 3360.1780.1680.1630 cm "1.

N.M.R. (Ds-DMSO, 8) 3.68 (2H, ABq, J = 19Hz), 4.36 (2H, ABq, J = 14Hz), 4.60 (2H, s), 4.60-6.2 (7H, m), 6.80 (IH, s ), 7.24 (2H, broad s), 9.51 (IH, d, J = 9Hz).

Example 58

The Vilsmeier reagent was prepared in a manner known per se from 0.139 g of dry dimethylformamide, 0.290 g of phosphorus oxychloride and 1.0 ml of dry tetrahydrofuran. Then 3.01 dry tetrahydrofuran and then 0.4 g of 2-methylthiomethoxyimino-2- (2-formamidothia-zol-4-yl) acetic acid (syn isomer) were added at a temperature of -5 ° C to 0 ° C . The mixture was stirred at this temperature for 30 minutes. Then it was added dropwise at a temperature of -5 to 0 ° C in a solution of 0.725 g of 7-amino-3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in a mixture of 7 ml of water and 7 ml of acetone while maintaining a pH of 7.5 to 8.5, which was done by adding triethylamine, added dropwise and the mixture was stirred for 30 minutes at this temperature and said pH . The acetone was then removed from the reaction mixture. Ethyl acetate and water were added to the residue, and the mixture was adjusted to a pH of 2.0 by adding 10% hydrochloric acid. The insoluble matter was filtered off and the filtrate extracted twice with ethyl acetate. The combined extracts were washed twice with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off and the residue was converted into a powder using diethyl ether, 0.64 g of 7- [2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3) 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained.

I.R. (Nujol): 3230.1780.1680.1550 cm "1.

N.M.R. (ds-DMSO, 8) 2.22 (3H, s), 3.72 (2H, ABq, J = 18Hz),

638 532

54

4.44 (2H, Aß ,, J = 14Hz), 5.18 (IH, d, J = 5Hz), 5.23 (2H, s), 5.84 (IH, d, d, J = 5 and 9Hz), 7.46 (1H, s ), 8.52 (1H, s), 9.54 (1H, s), 9.74 (1 H, d, J = 9Hz), 12.64 (1 H, broad s).

Example 59

2.3 g of phosphorus oxychloride were immediately added 3.4 g of a suspension of 2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer) in 30 ml of dry tetrahydrofuran at -3 ° C and the mixture stirred at the same temperature for 20 minutes. Then 2.4 g of trimethylsilylacetamide and 5 ml of tetrahydrofuran were added dropwise, and the resulting mixture was stirred at the same temperature for 20 minutes. 2.3 g of phosphorus oxychloride were then added and the mixture was stirred at 0 to 3 ° C. for 30 minutes. Then 1.1 g of dry dimethylformamide were immediately added at a temperature of 0 to 3 ° C. and the mixture was stirred at the temperature mentioned for 1 hour, a clear solution being obtained. On the other hand, 12.7 g of trimethylsilylacetamide were stirred with a suspension of 4.0 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-car-bonic acid in 60 ml dry ethyl acetate was added and the solution was then stirred at room temperature for 1 hour. Then the tetrahydrofuran solution obtained according to the above information was always added directly at -20.degree. C. and the resulting mixture was stirred at -5.degree. The reaction mixture was then mixed with 50 ml of a saturated aqueous sodium chloride solution. An organic layer separated out, which was extracted with a saturated aqueous sodium bicarbonate solution (pH 7.0). The extract was washed with ethyl acetate, treated with activated carbon and the pH was adjusted to 4.5 by adding 10% hydrochloric acid. The precipitate was collected by filtration, washed with water and dried, whereby 1.03 g of a powder consisting of 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1 , 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3320.3200.1770.1670.1610 cm- '.

N.M.R. (dö-DMSO, 5) 3.59 (2H, ABq, J = 18.0Hz), 4.47 (2H, AB ,, J = 12.0Hz), 5.09 (IH, d, J = 4.0Hz), 5.15 (2H , s), 5.73 (IH, d, d, J = 4.0 and 8.0Hz), 6.74 (IH, s), 7.36 (5H, m), 9.56 (IH, s), 9.69 (IH, d, J = 8.0 Hz).

Example 60

The Vilsmeier reagent was prepared in a manner known per se from 0.667 g of dry dimethylformamide, 1.40 g of phosphorus oxychloride and 4 ml of dry ethyl acetate.

Then 16 ml of dry ethyl acetate and then 2 g of 2-tert-butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) were added at 0 ° C. The mixture was stirred at this temperature for 30 minutes. Then it was added dropwise at -15 ° C to a solution of 3.01 g of 7-amino-3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid and 9.6 g of trimethylsilylacetamide is stirred into 30 ml of dry ethyl acetate and the mixture is stirred for a further 50 minutes at -15 ° C. to -5 ° C. The reaction mixture was then mixed with 50 ml of water. The insoluble matter was filtered off and the filtrate extracted twice with ethyl acetate. The extracts were washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was converted into a powder with diethyl ether. This powder was collected by filtration and dried, giving 2.67 g of 7- [2-tert-butoxycarbonylmethoxyimino-2- (2-formamidothiazo-l-4-yl) acet]

amido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carbon-

acid (syn isomer).

I.R. (Nujol): 3225.1780.1725.1685.1550 cm-1.

N.M.R. (Ds-DMSO, 5) 1.38 (9H, s), 3.64 (2H, ABq, J = 17Hz), 4.38 (2H, ABq, J = 14Hz), 4.56 (2H, s), 5.12 (IH, d, J = 5Hz), 5.77 5 (IH, d, d, J = 5 and 9Hz), 7.38 (IH, s), 8.47 (IH, s), 9.49 (IH, s), 9.54 (IH, d, J = 9Hz ), 12.57 (IH, broad s).

Example 61

When working in a similar way as in Beilo 58 to 60 above, the following compounds were obtained.

(1) 7- [2-Methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn isomer).

I.R. (Nujol): 3250.1780.1675.1550 cm-1. 15 N.M.R. (ds-DMSO, 8) 2.22 (3H, s), 3.72 (2H, ABq, J = 19Hz), 3.96 (3H, s), 4.33 (2H, ABq, J = 14Hz), 5.17 (IH, d, J = 5Hz), 5.26 (2H, s), 5.85 (IH, d, d, J = 5 and 8Hz), 7.48 (IH, s), 8.54 (IH, s), 9.78 (IH, d, J = 8Hz) , 12.64 (IH, s).

(2) 7- [2- (2-ethoxyethoxy) imino-2- (2-formamidothiazol-4-20 yI) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl- 3-cephem-4-

carboxylic acid (syn isomer).

I.R. (Nujol): 3500.3200.1780.1720.1680 cm- '.

N.M.R. (ds-DMSO, 8) 1.13 (3H, t, J = 7Hz), 3.2-4.0 (6H, m), 4.30 (2H, t, J = 4Hz), 4.50 (2H, ABq, J = 13Hz), 5.23 (IH, d, 25 J = 5Hz), 5.87 (IH, d, d, J = 5 and 8Hz), 7.48 (IH, s), 8.58 (IH, s), 9.60 (IH, s), 9.70 (IH , d, J = 8Hz).

(3) 7- [2- (2-Formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

so I.R. (Nujol): 1770.1710.1670 cm "1.

N.M.R. (ds-DMSO, 8) 3.50 (2H, m), 4.10-4.60 (4H, m), 4.79 (2H, m), 5.16 (IH, d, J = 5.0Hz), 5.81 (IH, d, d , J = 5.0 and 8.0Hz), 6.58 (2H, broad s), 7.47 (IH, s), 8.28 (IH, s), 8.55 (IH, s).

(4) 7- [2- (2-formyloxyethoxy) imino-2- (2-formamidothiazol-35 4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl- 3-

cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3160.1775.1710.1670 cm- '.

N.M.R. (ds-DMSO, 8) 3.71 (2H, ABq, J = 18.0Hz), 3.96 (3H, s), 4.00-4.54 (6H, m), 5.16 (IH, d, J = 4.5Hz), 5.84 (IH, d, d, 40 J = 4.5 and 9.0Hz), 7.45 (IH, s), 8.24 (IH, s), 8.53 (IH, s), 9.70 (IH, d, J = 9, 0Hz).

(5) 7- [2- (2-Formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer).

45 I.R. (Nujol): 3180.1775.1673 cm "1.

N.M.R. (Ds-DMSO, 8) 3.75 (2H, m), 4.25-4.65 (6H, m), 5.22 (IH, d, J = 5.0Hz), 5.88 (IH, d, d, J = 5.0 and 9.0Hz), 7.49 (IH, s), 8.26 (IH, s), 8.57 (IH, s), 9.59 (IH, s), 9.71 (IH, d, J = 9.0Hz).

so (6) 7- [2-ethoxycarbonylmethoxyimino-2- (2-formamidothia-zol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer).

I.R. (Nujol): 3250.1775.1720.1680.1540 cm-1.

N.M.R. (ds-DMSO, 8) 1.22 (3H, t, J = 7Hz), 3.74 (2H, s), 4.20 55 (2H, q, J = 7Hz), 4.77 (2H, s), 5.22 (IH, d, J = 5Hz), 5.88 (IH, d, d, J = 5 and 8 Hz), 7.51 (IH, s), 8.58 (IH, s), 9.63 (IH, s), 9.70 (IH, d, J = 8Hz), 12.68 (IH, broad s).

(7) 7- [2-ethoxycarbonylmethoxyimino-2- (2-formamidothia-zol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-

60 cephem-4-carboxylic acid (syn isomer).

LR. (Nujol): 3250.1780.1725.1680.1540 cm-1.

N.M.R. (ds-DMSO, 8) 1.22 (3H, t, J = 7Hz), 3.73 (2H, s), 3.97 (3H, s), 4.18 (2H, q, J = 7Hz), 4.35 (2H, ABq, J = 14Hz), 4.76 (2H, s), 5.18 (IH, d, J = 5Hz), 5.86 (IH, d, d, J = 5 and 9Hz), 7.48 (IH, es s), 8.56 (IH, s ), 9.67 (IH, d, J = 9Hz), 12.69 (IH, broad s).

(8) 7- [2-tert-Butoxycarbonylmethoxyimino-2- (2-formamido-dothiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thio-methyl- 3-cephem-4-carboxylic acid (syn isomer).

55 638 532

I.R. (Nujol): 3180, 1785, 1725, 1690, 1550 cm- '. J = 8.0 Hz).

N.M.R. (dó-DMSO, S): 1.45 (9H, s), 3.72 (2H, ABq, J = 17Hz), (22) 7- [2- (4-fluorobenzyloxyimino) -2- {2- (2,2, 2-trifluoroacet

3.96 (3H, s), 4.33 (2H, ABq, J = 14Hz), 4.64 (2H, s), 5.17 (IH, d, amido) -thiazol-4-yll-acetamido] -3- (1-methyl- l H-tetrazol-5-yl) -

J = 5Hz), 5.84 (IH, d, d, J = 5 and 9Hz), 7.46 (IH, s), 8.52 (IH, s), thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

9.62 (IH, d, J = 9Hz), 12.61 (IH, broad s). 5 I.R. (Nujol): 3370.3180, 1760.1710.1680.1650 cm- '.

(9) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] - N.M.R. (DMSO-dó, ô) 3.68 (2H, m), 3.92 (3H, s), 4.32 (2H,

3- (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carbon-m), 5.03-5.35 (3H, m), 5.83 (IH, dd, J = 5 and 8Hz) , 6.99-7.70 acid (syn isomer). (4H, m), 7.54 (1H, s), 9.87 (1H, d, J = 8Hz).

I.R. (Nujol): 3350.3250.1780.1680.1633 cm- '. (23) 7- [ethoxycarbonylmethoxyimino-2- (2-formamidothia-

N.M.R. (dó-DMSO, 8) 0.86 (3H, m), 0.97 ~ 1.53 (6H, m), io zol-4-yl) -acetamido] -3- (lH-tetrazol-5-yl) -thiomethyl-3- cephem-

1.53 ~ 2.10 (2H, m), 3.70 (2H, m), 4.10 ~ 4.77 (4H, m), 5.00-5.50 4-carboxylic acid (syn isomer), melting point 112 to 125 ° C (decomp

(3H, m), 5.85 (IH, d, d, J = 5.0 and 8.0Hz), 6.80 (1H, s), 6.98 ~ 7.63 settlement).

(7H, m), 9.71 (1H, d, J = 8.0Hz). I.R. (Nujol): 3250.1770.1730.1680 cm "'.

(10) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-formamidothia NMR (DMSO-ds, 8) 1.20 (3H, t, J = 8Hz), 3.71 (2H, m), zol -4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3- is 4.07 (2H, q, J = 8Hz), 4.36 (2H, m), 4.77 ( 2H, m), 5.20 (1H, d, cephem-4-carboxylic acid (syn isomer). J = 5Hz), 5.88 (IH, dd, J = 5 and 8Hz), 7.50 (1H, s), 8.57 (1H , s),

I.R. (Nujol): 3200.1775.1675.1540 cm- '. 9.67 (1H, d, J = 8Hz), 12.38 (IH, broad s).

N.M.R. (ds-DMSO, 8) 3.72 (2H, s), 4.45 (2H, ABq, J = 13Hz), (24) 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) -acet-

5.18 (1H, d, J = 5Hz), 5.30 (2H, s), 5.96 (IH, d, d, J = 5 and 8Hz), amido] -3- (1H-tetrazol-5-yl) thiomethyl- 3-cephem-4-carbon

6.67 (1H, d, J = 2Hz), 7.50 (1H, s), 8.55 (1H, s), 8.90 (1H, d, 20 acid (syn isomer), melting point 172 to 174 ° C (decomposition).

J = 2Hz), 9.58 (1H, s), 9.79 (1H, d, J = 8Hz), 12.69 (1H, s). I.R. (Nujol): 3250.3150, 1770, 1620 cm- '.

(11) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) - N.M.R. (DMSO-ds) 3.67 (2H, m), 4.33 (2H, m), 5.08-5.36 acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-car - (3H, m), 5.83 (IH, dd, J = 4 and 8Hz), 6.88 (1H, s), 7.39 (5H, s), bonic acid (syn isomer). 9.73 (1H, d, J = 8Hz).

I.R. (Nujol): 3340.3200, 1775, 1670 cm- '25 (25) 7- [2- (4-fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacet-

(12) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) amido) thiazol-4-yll-acetamido] -3- (l, 3,4-thiadiazol-2-yl) - thio-acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-methyl-3-cephem-4-carboxylic acid (syn isomer).

4-carboxylic acid (syn isomer). I.R. (Nujol): 3200.1770.1720.1650 cm "'.

I.R. (Nujol): 3300.1770.1670.1530 cm- '. N.M.R. (DMSO-ds, 8) 3.73 (2H, ABq, J = 18Hz), 4.49 (2H,

(13) 7- [2- (2-ethoxyethoxy) imino-2- (2-aminothiazol-4-yl) - 30 ABq, J = 14Hz), 5.03-5.46 (3H, m), 5.88 (IH, dd , J = 4 and 8Hz), acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-car- 7.03-7.84 (4H, m), 7.59 (1H, s ), 9.60 (1H, s), 9.88 (1H, d,

bonic acid (syn isomer). J = 8Hz).

I.R. (Nujol): 3160.3100.1780.1670.1630cm- '. (26) 7- [2-Cinnamyloxyimino-2- (2-formamidothiazol-4-yl) -

(14) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazole acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-car-

4-yl) acetamido] -3- (l-methyl-1H-tetrazol-5-yl) thiomethyl-3- 35 bonic acid (syn isomer).

cephem-4-carboxylic acid (syn isomer). I.R. (Nujol): 3400-3100, 1780, 1680, 1540 cm- '.

I.R. (Nujol): 3350.3220.1780.1680.1630 cm- '. N.M.R. (DMSO-ds, 8) 3.67 (2H, m), 4.45 (2H, ABq,

(15) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazole- J = 14Hz), 4.83 (2H, d, J = 5Hz), 5.18 (1H, d, J = 5Hz), 5.87 (1H,

4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-dd, J = 5 and 8Hz), 6.65 (1H, s), 6.12-7.0 ( 2H, m), 7.1-7.7 (5H,

4-carboxylic acid (syn isomer). 40 m), 8.53 (1H, s), 9.57 (1H, s), 9.73 (1H, d, J = 8Hz), 12.6 (1H,

I.R. (Nujol): 3350.3230.3100.1780.1680.1630cm- '. broad).

(16) 7- [2-tert-Butoxycarbonylmethoxyimino-2- (2-amino- (27) 7- [2- (4-fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacet-

thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-amido) thiazol-4-yl} acetamido] -3- (1 H-tetrazole -5-yl) -thiomet-

cephem-4-carboxylic acid (syn isomer). hyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300.1775.1730.1675.1630cm- '. 45 I.R. (Nujol): 3200.1780.1730.1660cm-1.

(17) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) - (28) 7- [2- (4-fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacet-

acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) -thiomethyl-3-cephem-amido) -thiazol-4-ylî-acetamido] -cephelosporanoic acid (syn-iso-

4-carboxylic acid (syn isomer). mer).

I.R. (Nujol): 3340, 3200, 1775, 1675, 1630 cm "1st I.R. (Nujol): 3250, 1780, 1730, 1660, 1630 cm- '.

(18) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazole-4- 50 NMR (DMSO-dó, 8) 2.07 (3H, s), 3.59 (2H, m), 4.90 ( 2H,

yl) -acetamido] -3- (l, 3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4- ABq, J = 14Hz), 5.13-5.46 (3H, m), 5.90 (IH, dd, J = 5 and 8Hz),

carboxylic acid (syn isomer). 7.30-7.77 (4H, m), 7.58 (1H, s), 9.68 (1H, d, J = 4.0Hz).

I.R. (Nujol): 3350.3230, 3110, 1775, 1675 cm "'. (29) 7- [2- (3,4-dichlorobenzyloxyimino) -2- {2- (2,2,2-trifluoro-

(19) 7- [2-Carboxymethoxyimino-2- (2-formamidothiazol-4-acetamido) -thiazol-4-yll-acetamido] -cephelosporanoic acid (syn-

yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-55 isomer).

cephem-4-carboxylic acid (syn isomer). I.R. (Nujol): 1780.1730.1650 cm "'.

I.R. (Nujol): 3200.1780.1720.1680.1545 cm "'. N.M.R. (DMSO-dó, 8) 2.03 (3H, s), 3.57 (2H, m), 4.87 (2H,

(20) 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) - ABq, J = 12Hz), 5.17-5.23 (3H, m), 5.87 (IH, dd, J = 6 and 8Hz) , acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-car-7.33-7.73 (4H, m), 9.87 (1H, d, J = 8Hz).

bonic acid (syn isomer). 60 (30) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-formami-

I.R. (Nujol): 3360.3240.3100.1780.1680.1635 cm "'. Dothiazol-4-yl) -acetamido] -3- (l, 3,4-thiadiazol-2-yl) -thiomethyl-

(21) 7- [2- (tert-Butoxycarbonylmethoxyimino) -2- (2-forma- 3-cephem-4-carboxylic acid (syn isomer). Midothiazol-4-yl) -acetamido] -3- (lH- tetrazol-5-yl) thiomethyl-3 IR (Nujol): 3400-3100.1780.1680.1540 cm- '. cephem-4-carboxylic acid (syn isomer). N.M.R. (DMSO-dó, 8) 3.7 (2H, broad s), 4.45 (2H, ABq,

I.R. (Nujol): 3170.1770.1720.1670 cm- '. es J = 13Hz), 5.13 (1H, d, J = 5Hz), 5.18 (2H, s), 5.82 (1H, dd, J = 5

N.M.R. (DMSO-dó, 8) 1.44 (9H, s), 3.68 (2H, m), 4.33 (2H, and 8Hz), 6.97 (1H, d, J = 2Hz), 7.4 (1H, s), 7.45 (1H , d, J = 8Hz),

ABq, J = 12.0Hz), 4.63 (2H, s), 5.16 (1H, d, J = 5.0Hz), 5.82 (1H, 8.5 (1H, s), 9.68 (1H, d, J = 8Hz) , 12.6 (IH, broad s),

dd, J = 5.0 and 8.0Hz), 7.43 (1H, s), 8.51 (1H, s), 9.56 (1H, d, (31) 7- [2- (tert-butoxycarbonylmethoxyimino) -2- (2-amino

638 532

56

thiazol-4-yI) acetamido] -3- (1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3280.3200.1770.1670.1630 cm- '.

(32) 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazoI-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300.3200.1770.1660.1620.1600 cm "1.

(33) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-y]) acetamido] -3- (1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer), melting point 168 to 185 ° C (decomposition).

I.R. (Nujol): 3250.1765.1670.1625 cm- '.

(34) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-car-bonic acid (syn isomer), melting point 145 to 149 ° C (decomposition).

I.R. (Nujol): 3250.1765.1650 cm "1.

(35) 7- [2-Cinnamyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carbon acid (syn isomer).

I.R. (Nujol): 3350-3100, 1760, 1650, 1620, 1520 cm "'.

(36) 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1 H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer).

I.R. (Nujol): 3300.3200.1770.1660.1630.1600 cm "'.

(37) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] cephalosporanic acid (syn isomer), melting point

185 to 192 ° C (decomposition).

I.R. (Nujol): 3380.3250.1780.1700.1650 cm "1.

(38) 7- [2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] cephalosporanic acid (syn isomer), melting point 200 to 205 ° C (decomposition).

I.R. (Nujol): 1730.1640.1600.1230.1020 cm- '.

(39) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3400-3100, 1760, 1660, 1620, 1520 cm "'.

(40) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( Syn isomer), melting point 178 to 180 ° C (decomposition).

I.R. (Nujol): 3300.3280.1770.1670.1630 cm "'.

Example 62

A mixture of 0.58 g of 7- [2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer), 0.405 g concentrated hydrochloric acid, 8.7 ml methanol and 5 ml tetrahydrofuran was stirred for 135 minutes at room temperature. Then the solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous sodium hydroxide solution (pH 7 to 8.5). The insoluble constituents were filtered off and the filtrate was adjusted to a pH of 3.4 by adding 10% hydrochloric acid with ice cooling and stirring for 30 minutes. The precipitate was collected by filtration, washed with water and dried, giving 0.4 g of 7- [2-methylthio-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3 4-thia-diazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3340.3200.1775.1670 cm "'.

N.M.R. (ds-DMSO, ô) 2.23 (3H, s), 3.74 (2H, s), 4.48 (2H, ABq, J = 13Hz), 5.20 (IH, d, J = 5Hz), 5.24 (2H, s), 5.83 (IH, d, d, J = 5 and 9Hz), 6.83 (IH, s), 7.28 (2H, broad s), 9.62 (IH, s), 9.68 (IH, d, J = 9Hz).

Example 63

A mixture of 2.3 g of 7- [2-tert-butoxycarbonylmethoxy-imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4-thiadia-

zol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), 3.74 g of concentrated hydrochloric acid and 35 ml of methanol were stirred at room temperature for 160 minutes. Then the solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous sodium hydroxide solution (pH 7 to 8). The aqueous solution was adjusted to a pH of 3.0 by adding 10% hydrochloric acid with ice cooling and stirring and stirred for 30 minutes. The precipitate was collected by filtration, washed io with water and dried, giving 1.1 g of 7- [2-tert-butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-car-bonic acid (syn isomer) was obtained.

LR. (Nujol): 3300.1775.1730.1675.1630 cm "1.15 NMR (ds-DMSO, 8) 1.46 (9H, s), 3.67 (2H, s), 4.42 (2H, AB ,, J = 14Hz ), 4.55 (2H, s), 5.16 (IH, d, J = 5Hz), 5.78 (IH, d, d, J = 5 and 9Hz), 6.77 (IH, s), 7.21 (2H, s), 9.43 (IH, d, J = 9Hz), 9.52 (IH, s).

20 Example 64

A solution of 2.7 g of sodium acetate in 46 ml of water was mixed with 2.3 g of 7- [2- (4-fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacetamido) thiazole-4- with stirring. yl} -acetamido] -3- (l, 3,4-thia-diazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 25 were added and the mixture was stirred at room temperature for 20% hours . Ethyl acetate was then added to the reaction mixture, and the pH was then adjusted to 5.0 by adding 10% hydrochloric acid. The mixture was shaken. The aqueous layer was separated, washed twice with ethyl acetate and its pH was adjusted to 3.0 using 10% hydrochloric acid. The precipitate was collected by filtration, washed with water and dried, giving 1.82 g of 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothia-zol-4-yl) acetamido] -3- ( l, 3,4-thiadiazol-2-yl) thiomethyl-3-35 cephem-4-carboxylic acid (syn isomer), melting point 145 to 149 ° C (decomposition).

LR. (Nujol): 3250, 1765.1650 cm "1.

N.M.R. (DMSO-ds, 8) 3.73 (2H, ABq, J = 18Hz), 4.48 (2H, ABq, J = 14Hz), 5.01-5.39 (3H, m), 5.85 (IH, dd, J = 4 and 8Hz ), 4o 6.83 (IH, s), 7.02-7.75 (4H, m), 9.63 (IH, s), 9.75 (IH, d,

J = 8Hz).

Example 65

Working in a similar manner as in Examples 62 45 to 64, the following compounds were obtained.

(l) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn isomer).

I.R. (Nujol): 3320.3200.1770.1670.1610 cm "1, so (2) 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -

3- (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

LR. (Nujol): 3350.3250.1780.1680.1633 cm "1.

(3) 7- [2-methylthiomethoxyimino-2- (2-aminothiazol ~ 4-yl) -55 acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-

4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300.1770.1670.1530 cm "1.

N.M.R. (ds-DMSO, 8) 2.20 (3H, s), 3.72 (2H, s), 3.97 (3H, s), 4.36 (2H, s), 5.17 (IH, d, J = 5Hz), 5.22 (2H, s), 5.82 (IH, d, d, J = 5 60 and 8Hz), 6.82 (IH, s), 7.28 (2H, br. s), 9.60 (IH, d, J = 8Hz).

(4) 7- [2- (2-ethoxyethoxy) imino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-car-bonic acid (syn isomer).

I.R. (Nujol): 3160.3100.1780.1670.1630 cm "1st es NMR (ds-DMSO, 8) 1.08 (3H, t, J = 7Hz), 3.45 (2H, q, J = 7Hz), 3.5- 3.90 (4H, m), 4.20 (2H, t, J = 4Hz), 4.47 (2H, ABq, J = 13Hz), 5.17 (IH, d, J = 5Hz), 5.80 (IH, dd, J = 5 and 8Hz), 6.77 (IH, s), 9.55 (IH, s), 9.55 (IH, d, J = 8Hz).

57 638 532

(5) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4- ir (nujol): 3350-3100,1760,1650,1620,1520 cm "1. Yl) -acetamido] -3- (l- methyl-1H-tetrazol-5-yl) thiomethyl-3 NMR (DMSO-dö, S) 3.47-3.97 (2H, m), 4.47 (2H, ABq, cephem-4-carboxylic acid (syn isomer). J = 14Hz), 4.8 (2H, d, J = 5Hz), 5.18 (IH, d, J = 5Hz), 5.83 (IH, dd,

I.R. (Nujol): 3350.3220.1780.1680.1630cm-1. J = 5und8Hz), 6.83 (IH, s), 6.1-7.0 (2H, m), 7.08-7.72 (5H, m),

N.M.R. (dö-DMSO, 5): 1.23 (3H, t, J = 7Hz), 3.70 (2H, s), s 9.6 (IH, s), 9.72 (IH, d, J = 8Hz).

3.97 (3H, s), 4.16 (2H, q, J = 7Hz), 4.35 (2H, s), 4.69 (2H, s), 5.15 (16) 7- [2- (4-fluorobenzyloxyimino) -2- ( 2-aminothiazol-4-yl) -

(1H, d, J = 5Hz), 5.80 (IH, dd, J = 5 and 9Hz), 6.81 (IH, s), 7.24 acetamido] -3- (lH-tetrazol-5-yl) thiomethyl-3- cephem-4-carbon

(2H, widest), 9.54 (IH, d, J = 9Hz). acid (syn isomer).

(6) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazole-4- IR (Nujol): 3300,3200,1770,1660, 1630,1600 cm-1. Yl) -acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 to NMR (DMSO-dö, 5) 3.69 (2H, ABq, J = 18Hz), 4.35 (2H, carboxylic acid (syn isomer). ABq, J = 15Hz), 4.93-5.43 (3H, m), 5.81 (IH, dd , J = 5 and 8Hz),

I.R. (Nujol): 3350.3230.3100.1780.1680.1630 cm- '. 6.80 (lH, s), 6.96-7.70 (4H, m), 9.73 (lH, d, J = 8Hz). N.M.R. (dó-DMSO, S) 1.21 (3H, t, J = 7Hz), 3.72 (2H, ABq, (17) 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) -

J = 18Hz), 4.18 (2H, q, J = 7Hz), 4.70 (2H, s), 5.20 (IH, d, acetamido] -cephalosporanic acid (syn isomer), melting point J = 5Hz), 5.84 (IH, dd , J = 5 and 8Hz), 6.84 (IH, s), 7.26 (2H, is 185 to 192 ° C (decomposition).

broad s), 9.56 (lH, d, J = 8Hz), 9.60 (lH, s). I.R. (Nujol): 3380.3250.1780.1790.1650 cm- '.

(7) 7- [2-Carboxymethoxyimino-2- (2-ammothiazol-4-yl) -acet- N.M.R. (DMSO-ds, 8) 2.02 (3H, s), 3.53 (2H, m), 4.84 (2H, amido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem -4- ABq, J = 13Hz), 5.13 (2H, s), 5.40 (IH, d, J = 4Hz), 5.79 (IH, dd, carboxylic acid (syn isomer). J = 4 and 8Hz), 6.73 (IH , s), 6.96-7.63 (4H, m), 9.62 (IH, d,

I.R. (Nujol): 3340.3200.1775.1675.1630 cm- '. 20 J = 8Hz).

N.M.R. (dö-DMSO, ô) 3.68 (2H, s), 3.94 (3H, s), 4.32 (2H, (18) 7- [2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-

ABq, J = 14Hz), 4.70 (2H, s), 5.14 (IH, d, J = 5Hz), 5.78 (IH, dd, yl) -acetamido] -cephalosporanoic acid (syn isomer), enamel J = 5 and 9Hz), 6.81 (IH, s), 7.1 (2H, broad s), 9.59 (IH, d, point 200 to 205 ° C (decomposition).

J = 9Hz). I.R. (Nujol): 1730.1640.1600.1230.1020 cm- '.

(8) 7- [2- (3-Isoxazolyl) methoxyimino-2- (2-aminothiazole-4- 25 NMR (DMSO-dö, Ô) 2.00 (3H, s), 3.30 (2H, ABq, J = 18Hz ), yl) -acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4- 4.68-5.12 (5H, m), 5.60 (IH, dd, J = 6 and 8Hz), 6.72 (IH, s), carboxylic acid (syn isomer). 7.32-7.64 (3H, m), 9.60 (IH, d, J = 8Hz).

I.R. (Nujol): 3350.3230.3110, 1775.1675 cm-1. (19) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-amino-

N.M.R. (ds-DMSO, 8) 3.71 (2H, ABq, J = 18Hz), 4.46 (2H, thiazol-4-yl) -acetamido] -3- (l, 3,4-thiadiazol-2-yl) -thiomethyl- 3-ABq, J = 14Hz), 5.17 (IH, d, J = 5Hz), 5.27 (2H, s), 5.82 (IH, dd, 30 cephem-4-carboxylic acid (syn isomer).

J = 5 and 8Hz), 6.66 (lH, s), 6.83 (lH, s), 7.30 (2H, broad s), 8.87 I.R. (Nujol): 3400-3100,1760,1660,1620, 1520cm- '. (IH, s), 9.57 (IH, s), 9.75 (IH, d, J = 8Hz). N.M.R. (DMSO-ds 8) 3.72 (2H, broad s), 4.47 (2H, ABq,

(9) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) -acet- J = 14Hz), 5.1 (IH, d, J = 5Hz), 5.22 (2H, s), 5.83 (IH , dd, J = 5 amido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carbon and 8 Hz), 6.85 (IH, s), 6.87 (IH, dd, J = 2 and 8Hz), 7.08 (IH, d, acidic (syn isomer). 35 J = 2Hz), 7.52 (IH, d, J = 8Hz), 9.67 (IH, s), 9.77 (IH, d, J = 8Hz).

I.R. (Nujol): 3360.3240.3100.1780.1680.1635 cm "'.

(10) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acet- (20) 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) -

amido] -3- (1 H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carbon-acetamido] -3- (1 H-tetrazol-5-yl) -thiomethyl-3-cephem-4- carbonic acid (syn isomer), melting point 172 to 174 ° C (decomposition), acid (syn isomer), melting point 178 to 180 ° C (decomposition). I.R. (Nujol): 3250.3150.1770.1620cm "'. 40 I.R. (Nujol): 3300.3280.1770.1670.1630cm-'.

(11) 7- [2- (tert-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1 H-tetrazol-5-yl) thiomethyl-3 example 66

cephem-4-carboxylic acid (syn isomer). 4 ml of trifluoroacetic acid were ice-cooled in a

I.R. (Nujol): 3280.3200.1770.1670.1630 cm-1. Suspension of 1.0 g of 7- [2-tert-butoxycarbonylmethoxyimino-2-

(12) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) - 45 (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazole -2-yl) -thio-acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) -thiomethyl-3-cephem-methyl-3-cephem-4-carboxylic acid (syn isomer) in 1 ml of anisole 4-carboxylic acid (syn isomer). stirred in and the mixture obtained for 70 minutes

I.R. (Nujol): 3300,3200,1770,1660,1620,1600 cm "'. Stirred at room temperature. Then the reaction was

N.M.R. (DMSO-dö, 8) 3.67 (2H, m), 3.94 (3H, s), 4.32 (2H, mixed concentrated under reduced pressure and diethyl ether m), 4.98-5.36 (3H, m), 5.78 (IH, dd, J = 5 and 8Hz), 6.72 (IH, s), 50 added. The precipitate was filtered by filtering a total of 6.95-7.65 (4H, m), 9.65 (IH, d, J = 8Hz). melt, washed with diethyl ether, dried, in 10 ml of water

(13) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazole- suspended and then in a 10% aqueous sodium hy-4-yi) acetamido] -3- (1 H-tetrazol-5-yl) thiomethyl -3-cephem-4-hydroxide solution (pH 7 to 7.5) dissolved. The solution was by means of carboxylic acid (syn isomer), melting point 168 to 185 ° C (Zer- 10 ° / oiger hydrochloric acid with ice cooling and stirring to a sediment). 55 pH adjusted to 3.0 and under ice for 30 minutes

I.R. (Nujol): 3250.1765.1670.1625 cm ~ '. cooling stirred. The precipitate was filtered

N.M.R. (DMSO-dö, 8) 1.21 (3H, t, J = 7Hz), 3.70 (2H, broad collected, washed with water and dried, using s), 4.18 (2H, q, J = 7Hz), 4.31 (2H , m), 4.72 (2H, broad s), 5.17 0.75 g 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) -acet- (1H, d, J = 4Hz), 5.82 ( IH, dd, J = 4 and 7 Hz), 6.83 (IH, s), 7.17 amido] -3- (l, 3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carbon- ( 2H, broad s), 9.57 (IH, d, J = 7Hz). 60 acid (syn isomer) was obtained.

(14) 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) - I.R. (Nujol): 3360.3240.3100.1780.1680.1635 cm- '. acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-car- N.M.R. (dö-DMSO, 8) 3.68 (2H, s), 4.46 (2H, ABq, J = 15Hz), bonic acid (syn isomer), melting point 145 to 149 ° C (decomp. 4.61 (2H, s), 5.17 ( IH, d, J = 5Hz), 5.82 (IH, dd, J = 5 and 9Hz), tongue). 6.83 (IH, s), 7.23 (2H, broad s), 9.50 (IH, d, J = 9Hz), 9.53

I.R. (Nujol): 3250.1765.1650 cm- ». it (IH, s).

(15) 7- [2-Cinnamyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carbon- Example 67

acid (syn isomer). When working according to example 66 above, the

638 532 58

produce the following compounds: amido] -3- (l-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-

(1) 7- [2-carboxymethoxyimino-2- (2-formamidothiazole-4-carboxylic acid (syn isomer). Yl) acetamido] -3- (l-methyl-lH-tetrazoI-5-yl) -thiomethyl- 3- IR (Nujol): 3340.3200, 1775, 1675, 1630 cm-1.

cephem-4-carboxylic acid (syn isomer). (3) 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acet-

I.R. (Nujol): 3200.1780.1720.1680.1545 cm-1. 5 amido] -3-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid

N.M.R. (De-DMSO, 8) 3.72 (2H, ABq, J = 16Hz), 3.96 (3H, s), (syn isomer), melting point 178 to 180 ° C (decomposition). 4.33 (2H, ABq, J = 14Hz), 4.67 (2H, s), 5.17 (lH, d, J = 5Hz), 5.86 I.R. (Nujol): 3300.3280, 1770, 1670, 1630cm-1.

(1 H, dd, J = 5 and 9Hz), 7.47 (IH, s), 8.52 (IH, s), 9.64 (IH, d, NMR (DMSO-d6.8) 3.69 (2H, m), 4.32 ( 2H, ABq,

J = 9Hz), 12.64 (IH, broad s). J = 14Hz), 4.60 (2H, m), 5.14 (IH, d, J = 5Hz), 5.79 (IH, d d, J = 5

(2) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) aceto and 8Hz), 6.79 (IH, s), 9.47 (IH, d, J = 8Hz).

Claims (10)

638 532 2. The method according to claim 1, characterized in that that the reaction is carried out in the presence of a condensing agent. 2nd PATENT CLAIMS 1. Process for the preparation of the syn isomers of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds of the general formula R1-j-CONH ^ 'i-OR2 y-N O' ■ R (X) in which mean: R1 is a group of the formula 3rd 638 532 C-CONH HO N-OR ' wherein R2 to R5 have the meanings given in claim 1, or a salt thereof acylated. 3. The method according to claim 2, characterized in 4. The method according to claim 3, characterized in that the reaction in the presence of a Vilsmeier reagent, which is carried out by reacting phosphorus oxychloride with dimethylform io amide has been prepared, and is carried out under approximately neutral conditions. 5. The method according to claim 4, characterized in that R1 represents a group of the formula 15 h2N. r » \ s / R wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di (lower) alkylamino; a group of the formula R and that the reaction is carried out in the presence of a Vilsmeier reagent produced by reacting phosphorus oxychloride with dimethylformamide and under approximately neutral conditions, the phosphorus oxychloride in an amount of more than 2 molar equivalents based on that respective amount of the substituted acetic acid 25 and the dimethylformamide is used. 5 that a Vilsmeier reagent is used as the condensing agent. 6. The method according to claim 1 for the preparation of a compound of formula I, wherein R1 is a group of the formula: wherein R7 represents amino, protected amino, hydroxy or lower alkyl; or a group of the formula 30 H2N R 7. The method according to claim 1 for the preparation of a compound of the formula: wherein R3 and R4 have the meanings given above, or a silyl derivative thereof on the amino group or a salt thereof with a substituted acetic acid of the formula (III) 55 60 R- 5a R 6a-A =. ; -C0NIi N-0R h2n. n- "k Practice) s / wherein R1 and R2 each have the meanings given above, or a reactive derivative thereof on the car-boxy group or a salt thereof. wherein R5a is hydrogen, halogen, nitro, lower alkoxy or acyloxy and R6a is acyloxy and R2, R3 and R4 have the meanings given in claim 65, and their pharmaceutically acceptable salts, characterized in that the hydroxyl group of a compound of the formula: 8. The method according to claim 1 for the preparation of a compound of the formula I in which R 2 is carboxy (lower) alkyl, or its pharmaceutically acceptable salts, characterized in that a compound of the formula I in which R 2 is protected carboxy (lower) alkyl is obtained , or a salt thereof is subjected to an elimination reaction to remove the carboxy protecting group. 8th -N " (II) wherein R8 is lower alkyl and R9 represents protected imino, 50 or a salt thereof undergoes an elimination reaction to remove the amino or imino protecting group. 8th or R ~ rT- HN- R " N- r means in which R8 represents lower alkyl or a pharmaceutically acceptable salt thereof, characterized in that a compound of the formula I obtained in which R1 is a group of the formula: wherein Rs are lower alkyl and R9 is imino, protected imino or oxo; R2 is an aliphatic hydrocarbon group that may have one or more substituents; R3 carboxy or protected carboxy; and R4 acyloxymethyl, hydroxymethyl, formyl or a heterocyclic thiomethyl group, which may have one or more substituents; or in which R3 and R4 can be linked to form -COOCH2-, and their pharmaceutically acceptable salts, characterized in that a compound of the general formula R ' 40 No. wherein R7 represents protected amino or denotes a group of the formula: 45 R R- 9. The method according to claim 1 for the preparation of a compound of the formula I in which R4 is a group of the formula -CH2OCONH2, or a pharmaceutically acceptable salt thereof, characterized in that a compound of the formula I in which R4 is a group of the formula - CH2-OCONH-R4a means, wherein R4a means an amino protecting group, or a salt thereof undergoes an elimination reaction to remove the amino protecting group. 10. The method according to claim 1 for the preparation of a compound of formula I, wherein R3 and R4 together form the group -CH2OCO-, or their pharmaceutically acceptable salts, characterized in that one obtains a compound of formula I, wherein R4 is hydroxymethyl, or a salt thereof with an acid.