CH657135A5 - CEPHALOSPORINE AND THEIR SALTS. - Google Patents

Description

The present invention relates to new cephalosporins, processes for making these cephalosporins and an antibacterial agent containing these cephalosporins.

Studies have been carried out with the aim of finding compounds which have a broad spectrum of antibacterial activity, show an excellent antibacterial activity against gram-positive and gram-negative bacteria, are resistant to bacteria-produced β-lactamase, have a low toxicity, at the same time when administered orally or parenterally are well absorbable and have an excellent therapeutic effect on diseases of humans and animals. It was found

that cephalosporins, which are characterized in that a substituted or unsubstituted 2,3-dioxo-l, 2,3,4-te-trahydropyrazinyl-, 2-oxo-l, 2-dihydropyrazinyl-, 3,6-di-oxo -1,2,3,6- tetrahydropyridazinyl- or 6-oxo-l, 6-dihydro-pyridazinyl group is bound by a carbon-nitrogen bond to the exomethylene group in the 3-position of the Ce-phem ring and a group of Formula:

HlJZ

a-co-r4

,8th

° l / °

-nvw o

10th

or is where R6 is hydrogen, hydroxyl, nitro, carba-15 moyl, thiocarbamoyl, sulfamoyl or a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl -, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxy-2o carbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclesulfonyl -, Dialkylcarbamoyl-, Alkylthiocarbamoyl-, Dialkyl-thiocarbamoyl-, Acylcarbamoyl-, Acylthiocarbamoyl-, Al-kylsulfonylcarbamoyl-, Arylsulfonylcarbamoyl-, Alkylsulfo-25 nylthiocarbamoyon-, Arylsulfoyl-, Arylsulfonyl- -, Cycloalkylmethylenamino-, Arylmethylenamino-, Heterocyclusmethylenamino- or heterocyclic group or a group of the formula:

30th

35

-N:

, R16

■ r17

\

wherein A, R4 and R5 have the meanings given below, are attached to the amino group in the 7-position, have the above-mentioned excellent properties.

The aim of the invention is to provide new cephalosporins with the above-mentioned characteristic chemical structural features, which have a broad antibacterial activity spectrum, are resistant to bacteria-produced β-lactamase, have a low toxicity and are well absorbed when administered orally or parenterally and have an excellent therapeutic effect on diseases of humans and animals.

Another object of the invention is to provide a process for the preparation of these new cephalosporins.

Another object of the invention is to provide an antibacterial agent containing these cephalosporins.

The invention therefore relates to new cephalosporins of the formula:

where R16 and R17, which are the same or different, each represent hydrogen or an alkyl group or R16 and R17 together with the adjacent nitrogen atom form a ring, furthermore R7, R8, R9, R10, R1 ', R14 and 40 R15, which are the same or different, each represent hydrogen, a halogen atom or a substituted or unsubstituted alkyl, aralkyl or aryl group and R13 represents hydrogen, a halogen atom, carboxyl, sulfo, carbamoyl or thiocarbamoyl or a substituted or unsubstituted 45 alkyl, aralkyl -, aryl-, alkoxy-, alkylthio-, acyl-, alkoxy-carbonyl-, cycloalkyloxycarbonyl-, acyloxycarbonyl-, aral-kyloxycarbonyl-, alkylsulfonyl-, cycloalkylsulfonyl-, arylsulfonyl-, heterocyclusulfonyl-, alkylcarbamoyl-, dialkylcarbylcarbamoyl , Dialkylthiocarbamoyl, so acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl or arylsulfonylthiocarbamoyl group;

R3 represents hydrogen or an alkoxy group;

R4 represents hydrogen or a halogen atom; 55 R5 represents hydrogen or a protected or unprotected amino group; and

A for a group of the formula -CH2- or a group of the formula:

60

-c-

-a-conh ch2r

(I)

coor or their salts, wherein

R1 represents hydrogen or a carboxyl protecting group; R2 for a group of the formula:

or '

18th

65, where R18 is hydrogen, a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic group or a hydroxyl protecting group or a group of the formula:

657 135

u / R19 -P

\ r20

where R19 and R20, which are the same or different, each represent hydroxyl or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group, and wherein the bond means that the compound is a syn isomer or can be an anti-isomer or a mixture thereof.

The invention is explained in more detail below.

In this specification, unless otherwise specified, the terms used have the following meanings: The term "alkyl" means an unbranched or branched alkyl group having 1 to 14 carbon atoms and includes e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, dodecyl, lauryl and the like; the term "alkoxy" means -O-alkyl, wherein the alkyl group is as defined above; the term "lower alkyl" means a straight or branched alkyl group having 1 to 5 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like; the term "lower alkoxy" means -O-lower alkyl, wherein the lower alkyl group is as defined above; the term "acyl" means formyl, an alkanoyl group having 2 to 5 carbon atoms, which includes, for example, acetyl, propionyl, isovaleryl, pivaloyl, pentanecarbonyl and the like, a cycloalkanecarbonyl group having 5 to 8 carbon atoms in the cycloalkane radical, e.g. Cyclopentylcarbonyl, cyclohexylcarbonyl and the like, an aryl group e.g. Benzoyl, toluoyl, 2-naphthoyl and the like and a heterocycle carbonyl group e.g. Thenoyl, 3-furoyl, nicotinoyl and the like; the term "acyloxy" means -O-acyl, wherein the acyl group is as defined above; the term "alkylthio" means -S-alkyl, wherein the alkyl group is as defined above; the term "alkenyl" means alkenyl having 2 to 10 carbon atoms and includes e.g. Vinyl, allyl, isopropenyl, 2-pentenyl, butenyl and the like; the term "alkynyl" means alkynyl having 2 to 10 carbon atoms and includes e.g. Ethynyl, 2-propynyl and the like; the term "cycloalkyl" means cycloalkyl of 3 to 7 carbon atoms and includes e.g. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; the term "alkadienyl" means alkadienyl having 4 to 10 carbon atoms and includes e.g. 1,3-butadienyl, 1,4-hexadienyl and the like; the term "cycloalkenyl" means cycloalkenyl of 5 to 7 carbon atoms and includes e.g. Cycloptenyl, cyclohexenyl and the like; the term "cyclo-alkadienyl" means cycloalkadienyl of 5 to 7 carbon atoms and includes e.g. Cyclopentadienyl, cyclo-hexadienyl and the like; the term "aryl" includes e.g. Phenyl, naphthyl, indanyl and the like; the term "aralkyl" includes e.g. Benzyl, phenylethyl, 4-methyl-benzyl, naphthylmethyl and the like; the term "heterocyclic group" means a heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur, and includes e.g. Furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl, 4- (5-methyl) 2-pyrol (2-pyrrolinyl), N-methylpiperidinyl, quinolyl, phenazinyl, 1,3-benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, phthalidyl, coumarinyl and the like; the term "heterocyclic alkyl" means a group consisting of a heterocyclic group defined above and one defined above

Alkyl group; and the term "halogen atom" includes e.g. Fluorine, chlorine, bromine and iodine.

The Svmbol R1 in the formulas in this specification represents hydrogen or a carboxyl protecting group, and the carboxyl protecting group includes those which are conventionally used in the fields of penicillins and cephalosporins, for example ester-forming groups, by catalytic hydrogenation, chemical reduction or treatment other mild conditions, an ester-forming group that can be easily removed in a living body, or an organic silyl-containing group, an organic phosphorus-containing group or an organic tin-containing group or the like, which can be removed by treatment with water or can be easily removed from an alcohol, and various other well-known ester-forming groups.

Of these protecting groups, the following are preferred:

(a) alkyl groups, e.g. Alkyl of 1 to 4 carbon 20 atoms;

(b) Substituted lower alkyl groups in which at least one of the substituents is selected from halogen atoms or nitro, acyl, alkoxy, oxo, cyano, hydroxyl, cy-cloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl -,

25 alkoxycarbonyl-, 5-alkyl-2-oxo-l, 3-dioxol-4-yl-, 1-indanyl, 2-indanyl-, furyl-, pyridyl-, 4-imidazolyl-, phthalimi-do- , Succinimido, azetidino, aziridino, pyrrolidino, pipe-ridino, morpholino, thiomorpholino, N-lower alkylpipe-razino, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxa-30 zolyl, isoxazol -, thiadiazolyl, oxadiazolyl, thiatriazo-lyl, oxatriazolyl, triazolyl, tetrazolyl, quinolyl, phenazinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, coumarinyl, 2,5-dimethylpyrrolidino 1,4,5,6-tetra-hydropyrimidinyl-, 4-methylpiperidino-, 2,6-dimethylpiperi-35 dino-, 4- (5-methyl-2-pyrrolinyl) -, 4- (2-pyrrolinyl) -, N-methylpiperidinyl, 1,3-benzodioxolanyl, alkylamino, dialkylamino, acyloxy, acylthio, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, alkenyloxy, aryloxy, aralkyloxy, cycloalkyloxy , Cycloalkenyloxy, heterocy-40 clusoxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, H heterocycloxycarbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, heterocycleoxycarbonyl or 45 alkylanilino groups or alkylanilino groups which are substituted by a halogen atom, a lower alkyl group or a lower alkoxy group

(c) cycloalkyl groups, lower alkyl-substituted cycloalkyl groups or (2,2-di-lower alkyl-1,3-dioxol-4-yl) -me-

50 ethyl groups,

(d) alkenyl groups,

(e) alkynyl groups,

(f) phenyl groups, substituted phenyl groups, in which at least one of the substituents from the above in paragraph (b)

55 specifically named substituents is selected, or aryl groups, such as groups of the formula:

60

-et where -Y1- for -CH = CH-O-, -CH = CH-S-, -CH2CH2S-, -CH = N-CH = N-, -CH = CH-CH = CH-, -CO- CH = 65 CH-CO- or -CO-CO-CH = CH-, or substituted derivatives thereof, in which the substituents are selected from those specifically mentioned in paragraph (b) above, or groups of the formula:

-O:

wherein -Y2- represents a lower alkylene group, such as - (CH2) 3- or - (CH2) 4-, or a substituted derivative thereof, in which the substituents are selected from those specifically mentioned in paragraph (b) above,

(g) aralkyl groups such as benzyl or substituted benzyl groups, wherein at least one of the substituents is selected from those specifically mentioned in paragraph (b) above;

(h) heterocyclic groups or substituted heterocyclic groups, wherein at least one of the substituents is selected from those specifically mentioned in paragraph (b) above;

(i) indanyl or phthalidyl groups or substituted derivatives thereof, in which the substituents are methyl groups or halogen atoms, tetrahydronaphthyl groups or substituted derivatives thereof, in which the substituents are methyl groups or halogen atoms, trityl, cholesteryl, bicyclo- [4,4,0] - decyl or the like,

© Phthalidylidene lower alkyl groups or substituted derivatives thereof, wherein the substituents are halogen atoms or lower alkyl groups.

The carboxyl protecting groups mentioned above are typical examples, and the carboxyl protecting group can also be selected from other protecting groups described in the following literature: US Pat. Nos. 3,499,909,3,573,296 and 3,641,018; DE-OS No. 2 301 014.2 253 287 and 2 337 105.

Of these carboxyl protecting groups, preferred are: diphenylmethyl, 5-lower alkyl-2-oxol, 3-dioxol-4-yl-lower alkyl groups, acyloxyalkyl groups, acylthioalkyl groups, phthalidyl groups, indanyl groups, phenyl groups, substituted or unsubstituted phthalidylidene lower alkyl groups or those groups which are in can be easily removed from a living body, such as groups of the formula:

-CH (CH2) mOR21, -CHOCOOR21 and -CH (CH2) mCOOR21

I.

R22

R22

I.

R23

7 657135

wherein R21 is a known substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group, R22 is hydrogen or a known substituted or unsubstituted alkyl, alkenyl, aryl, 5 aralkyl, alicyclic or heterocyclic group and R23 denotes hydrogen, a halogen atom or a known substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclic group or a group of the formula - (CH2) nCOOR2! means, where R21 has the meaning io above and n stands for 0.1 or 2, and where m stands for 0.1 or 2.

Specifically, the following can be used: 5-lower alkyl-2-oxo-1,3-dioxol-4-ylmethyl groups, such as 5-methyl-2-oxo-1,3-di-oxol-4-ylmethyl, 5-ethyl-2- oxo-l, 3-dioxol-4-ylmethyl, i5 5-propyl-2-oxol, 3-dioxol-4-ylmethyl and the like; Acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxyethyl, 1-pivaloyloxy-n-propyl and the like; Acylthioalkyl groups such as acetylthiomethyl, piva-loylthiomethyl, benzoylthiomethyl, p-chlorobenzoylthiomethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1-benzoylthioethyl, l- (p-chlorobenzoylthio) ethyl and the like; Alkoxymethyl groups such as methoxymethyl, ethoxymethyl, pro-25 poxymethyl, isopropoxymethyl, n-butyloxymethyl and the like; Alkoxycarbonyloxyalkyl groups, such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, n-butoxycarbonyloxoxymethyl, tert.-butoxycarbonyloxymethyl, 1-metho-30xycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxyoxyoxy, 1-propoxyoxyoxy, 1-propoxyoxyoxy, 1-propoxyoxyoxy, 1-propoxyoxyoxy, 1-propoxyoxyoxy, 1-propoxyoxyoxy .-Butoxycarbonyloxyethyl, 1-n-butoxycarbonyloxyethyl and the like; Alkoxycarbonylmethyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl and the like; 35 phthalidyl groups; Indanyl groups; Phthalidylidene alkyl groups such as 2- (phthalidylidene) ethyl, 2- (5-fluorophthalidylidene) ethyl, 2- (6-chlorophthalidylidene) ethyl, 2- (6-methoxy-xphthalidylidene) ethyl and the like; etc.

R2 stands for a group of the formula:

40

OO R

M 6 \

-n n-r,

-n vV S *

, 11

or wherein R6 is hydrogen, hydroxyl, nitro, carbamoyl, thiocarbamoyl, sulfamoyl or a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl *, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, Alkoxy-, alkylthio-, acyloxy-, cycloalkyloxy-, aryloxy-, alkoxycarbonyl-, cycloalkyloxycarbonyl-, acyloxycarbonyl-, aralkyloxycarbonyl-, alkylsulfonyl-, cycloalkylsulfonyl-, arylsulfonyl-, heterocyclusulfonyl-, alkylcarbamoyoyl-, dialkylcarbyloyl-, dialkylcarbyloyl-, dialkylcarbyloyl-, dialkylcarbyloyl-, dialkylcarbyloyl-, dialkylcarbyloyl-, dialkylcarbyl- moyl-, acylcarbamoyl-, acylthiocarbamoyl-, alkylsulfonyl-carbamoyl-, arylsulfonylcarbamoyl-, alkylsulfonylthiocar-bamoyl-, arylsulfonylthiocarbamoyl-, alkylsulfamoyl-, dialkylsulfamoyi-methylamino-methamyl-methamyl-methamyl-methamyl-methamyl-methylene-methylene-methamyl-methylene-methylene-methylene-methylene-methamyl-methoxy-methyl-cyclo-methyl-methoxy-methyl-cyclo-methyl-methoxy-methyl-cyclo-methoxy-methyl-methoxy-methyl-cyclo-methyl-methoxy-methyl-methoxy-methyl- or a group of the formula:

, R20

-No

\ r'7

50, wherein R16 and R17, which are the same or different, each represent hydrogen or an alkyl group or R16 and R17 together with the adjacent nitrogen atom form a ring, furthermore R7, R8, R9, R10, R11, R12, R14 and R15 , which are the same or different, each represent hydrogen, a halogen atom or a substituted or unsubstituted alkyl, aralkyl or aryl group and R13 represents hydrogen, a halogen atom, carboxyl, sulfo, carbamoyl, thiocarbamoyl or a substituted or unsubstituted alkyl -, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxy-60 carbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclesulfonyl, alkylcarbamoyl , Dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarba-65 moyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarba-moylthonyl or arylsulfonyl group. In each of the groups mentioned above as the meanings of R6 and R13, the term “cycloalkyloxy” stands for —O-cycloalkyl,

657 135

the expression «aryloxy» for -O-aryl, the expression «alkoxycarbonyl» for

-C-O-alkyl II O

the term "cycloalkyloxycarbonyl" for -C-O-cycloalkyl O

the expression "acyloxycarbonyl" for

-C-O-acyl II O

the expression «aralkyloxycarbonyl» for

-C-O-aralkyl II O

the term "alkylsulfonyl" for -S02-alkyl, the term "cycloalkylsulfonyl" for SO2 cycloalkyl, the term "arylsulfonyl" for SO2 aryl, the term "heterocycle sulfonyl" for SO2 heterocycle, the term "alkylcarbamoyl" for

C-NH-alkyl II O

the expression «dialkylcarbamoyl» for

10th

15

20th

the expression "acylthiocarbamoyl" for

-C-NH acyl

II p

5

the expression «alkylsulfonylcarbamoyl» for

-C-NH-SOralkyl

II O

the expression «arylsulfonylcarbamoyl» for

-C-NH-S02-Aryl II O

the expression «alkylsulfonylthiocarbamoyl» for

-C-NH-SO2 alkyl

II p

the expression «arylsulfonylthiocarbamoyl» for

-C-NH-S02 aryl

; II

S

the expression "alkylsulfamoyl" for SO2-NH-alkyl, the expression "dialkylsulfamoyl" for

30th

/ Alkyl

-so2-n <;

-C-N Ii O

Alkyl \ alkyl the expression «alkylthiocarbamoyl» for

-C NH alkyl

II p

the expression «dialkylthiocarbamoyl» for

Alkyl

/

-C-N <il \ alkyl S

the expression "acylcarbamoyl" for

-C-NH-Acyl O

\ Alkyl

35 the expression «alkoxythiocarbonyl» for

-C-O-alkyl

II p

4o the term "alkylideneamino" for -N = CH-alkyl, the term "cycloalkylmethylenamino" for -N = CH-cycloalkyl, the term "arylmethylenamino" for -N = CH-aryl and the term "heterocyclomethyleneamino" for -N = CH heterocycle.

45 The group of the formula:

-N:

r16 /

"R17

50

55

wherein R16 and R17 have the above meanings, includes amino groups, alkylamino groups of the formula -NH-alkyl, dialkylamino groups of the formula:

Alkyl

-n <f \ alkyl and groups of the formulas:

/ ~ A /

-N o, -N

\ / V

NH, -N N-alkyl, -N

-g "o- • -O-

657 135

/ = \ / = \ / - ^ v / == ^ / / N?

- »w0. - »wS, -» wS02. - »J -. - »J

or

/ n = n

The substituents for the above-mentioned various groups include halogen atoms, alkyl groups, aralkyl groups, aryl groups, alkenyl groups, hydroxyl groups, oxo groups, alkoxy groups, alkylthio groups, nitro groups, cyano groups, amino groups, acyl groups, acyloxy groups, carboxyl groups, carbamoyl groups, sulfo groups , Sulfamoyl groups, alkylamino groups of the formula -NH-alkyl, dialkylamino groups of the formula:

-N

Alkyl

\

Alkyl

Acylamino groups of the formula -NH-acyl, alkoxycarbonyl groups of the formula:

-C-O-alkyl II O

Acylalkyl groups such as acetylmethyl, propionylmethyl and the like, aminoalkyl groups such as aminomethyl, aminoethyl and the like, N-alkylaminoalkyl groups such as N-methylaminomethyl, N-methylaminoethyl and the like, N, N-dialkylaminoalkyl groups such as N, N-dimethylamino-methyl, N, N-dimethylaminoethyl and the like, hydroxy alkyl groups such as hydroxymethyl, hydroxyethyl and the like, hydroxyiminoalkyl groups such as hydroxyimino methyl, hydroxyiminoethyl and the like, alkoxyalkyl groups such as methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and the like, carboxyalkyl groups such as carboxymethyl Carboxyethyl and the like, alkoxycarbonylalkyl groups such as methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl and the like, aralkyloxycarbonylalkyl groups such as benzyloxycarbonylmethyl, benzyloxycarbonylethyl and the like, sulfoalkyl groups such as sulfomethyl, sulfoethyl and the like, sulfamoylalkylamrappen ylethyl and the like, carbamoylalkyl groups such as carbamoylmethyl, carbamoylethyl and the like, carbamoylalkenyl groups such as carbamoylallyl and the like, N-hydroxycarbamoylalkyl groups such as N-hydroxy-carbamoylmethyl, N-hydroxycarbamoylethyl and the like, groups of the formula:

-c = c-r24 / \

V

where R24 represents a lower alkyl group, etc. The above-mentioned various groups which can be represented by R6, R7, R8, R9, R10, R ", R12, R13, R14 and R'5 can be represented by at least one of the above Of the above-mentioned substituents, hydroxyl groups, amino groups and carboxyl groups may be protected by a suitable protective group which is usually available in this field The hydroxyl protective groups include all hydroxyl protective groups which can usually be used, such as easily removable ones Acyl groups, e.g. benzyloxycarbonyl, 4-nitrobenzyl

carbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) -10 benzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, tert.-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, Diphenylmethoxycarbonyl, 2,2,2-tri-chloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-fur-furyloxycarbonyl, 1-adamantyloxycarbonyl, 1-cyclo-15 propylethoxycarbonyl, 8-quinolyloxycarbonyl, formyl, acetyl, chloroacetyl, benzoyl, trifluoroacetyl and the same; Alkylsulfonyl groups such as methanesulfonyl, ethanesulfonyl and the like; Arylsulfonyl groups such as phenylsulfonyl, toluenesulfonyl and the like; 20 benzyl, diphenylmethyl, trityl, methoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-nitrophenylthio, 2,4-dinotrophenylthio and the like.

In addition, the amino protecting groups include all commonly used amino protecting groups, such as easily removable acyl groups, e.g. 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, 4-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, acetyl, mono-, di- and tri-chloroacetyl, trifluoroacetyl, formyl, tert-amyloxycarbonyl, tert-butoxycarbo-30 nyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, pyridine-l-oxide-2 - yl-methoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycar-35-bonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and the like; easily removable groups, e.g. Trityl,

0-nitrophenylsulfonyl, 2,4-dinitrophenylthio, 2-hydroxy-benzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l-

40 naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, l-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, l-acetyl-2-propylidene,

1-benzoyl-2-propylidene, l- [N- (2-methoxyphenyl) carbamoyl] -2-propylidene, l- [N- (4-methoxyphenyl) carbamoyl]

45 -2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene, 4-nitrofurfurylidene and the like; Di- or trialkylsilyl and the like. Furthermore, the carboxyl protecting groups include all commonly used carboxyl protecting groups, and there are cases where the carboxyl group is protected by such a group as methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, benzyl, Diphenylmethyl, trityl, 4-nitrobenzyl, 4-methoxy-benzyl, benzoylmethyl, acetylmethyl, 4-nitrobenzoylmethyl, 55 p-bromobenzoylmethyl, 4-methanesulfonylbenzoylmethyl, phthalimidomethyl, 2,2,2-trichlorethyl, l, l-l-dimethyl-2-methyl -penyl, 1,1-dimethylpropyl, acetoxymethyl, propionyloxy-methyl, pivaloyloxymethyl, 3-methyl-3-butinyl, succinimido-domethyl, 1-cyclopropylethyl, methylthiomethyl, phenyl-6o thiomethyl, dimethylaminomethyl, quinoline-l-oxide-2- yl-methyl, pyridine-l-oxide-2-ylmethyl, bis (p-methoxyphenyl) methyl and the like in which the carboxyl group is protected by a non-metal compound such as titanium tetrachloride and in which the carboxyl group is protected by a silylverbin-65 tion, such as dimethylchlorosilane, is protected, as in the u Japanese Unexamined Patent Application No. 7 037/71 and Unexamined Dutch Patent Application No. 71 05 259.

657 135

R5 represents hydrogen or a protected or unprotected amino group, and these amino protecting groups include many groups commonly used in the penicillin and cephalosporin field, specifically all of the amino protecting groups mentioned above in connection with R2.

A represents a group of the formula -CH2- or a group of the formula:

-c-

II

n or18

wherein R18 represents hydrogen, a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic group or a hydroxyl protecting group or a group of the formula:

10th

O

, R19

\ r20

1-5

where R19 and R20, which are the same or different, each represent hydroxyl or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group, and the bond means that the compound is a syn isomer or can be an io anti-isomer or a mixture thereof. The hydroxyl protecting groups mentioned include the hydroxyl protecting groups mentioned in connection with R2. In addition, the above-mentioned various groups represented by R18 may be substituted by at least one substituent selected from halogen atoms, oxo groups, cyano groups, hydroxyl groups, alkoxy groups, amino groups, alkylamino groups, dialkylamino groups, heterocyclic groups and groups of the formula:

-coor

-CO <r26 '

r25 © / R25

ne W y

R26, -nhcor and _p / R27 \

OR

25th

or '

26

wherein R 'has the above meaning and R25, R26 and R27, which are the same or different, each represent hydrogen, an alkyl group, an aralkyl group or an aryl group. Of these substituents, the hydroxyl group, the amino group and the carboxyl group can be protected by the hydroxyl protecting groups and the amino protecting groups mentioned in connection with R2 or the carboxyl protecting groups mentioned in connection with R1.

The oximes of the formula:

-c-

or '

18th

include syn and anti isomers and mixtures thereof.

From the groups of the formula:

If the group -CH2R2 in formula I is a group of the formula:

0

30th

o o

\ -A

ch - n n-r6 or

2 w

R1 ^ —N

35 means in which R6, R10, Ru and R12 have the above meanings, there are tautomers when R6 and R10 are each hydrogen, and these tautomers are also encompassed by the invention and are represented by the following equilibrium formulas:

40

o p o oh

(- ___

-ch2-n nh

-ch - n n

2 W

45

JK

in the individual formulas in this patent there are tautomers when R5 is a protected or unprotected amino group, and these tautomers are encompassed by the invention and are represented by the following equilibrium formulas:

-he

* 5a

M

50

-ch - n.

-ch2-n.

wherein R4 and R5 have the meanings above and R5a means a protected or unprotected imino group. In the above formulas, the imino protecting groups for group R5a include those groups used in the field of penicillins and cephalosporins, specifically the same groups as the monovalent groups among the above amino protecting groups mentioned in connection with R2.

The salts of the compounds of formula I include salts on the basic group and salts on the acidic group, 55 of which are well known in the penicillin and cephalosporin art. The salts on the basic group include salts with mineral acids such as hydrochloric acid, nitric acid, sulfuric acid and the like; Salts with organic carboxylic acids such as oxalic acid, succinic acid, formic acid, 60 trichloroacetic acid, trifluoroacetic acid and the like; and salts with sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2,4,6-trimethylbenzenesulfonic acid), naphthalene-1-sulfonic acid, naphthalene-2-sulfone -65 acid, phenylmethanesulfonic acid, benzene-l, 3-disulfonic acid, toluene-3,5-disulfonic acid, naphthalene-l, 5-disulfonic acid, naphthalene-2,6-disulfonic acid, naphthalene-2,7-disulfonic acid, benzene-l, 3,5-trisulfonic acid, benzene-1,2,4-trisulfonic acid,

11

657 135

Naphthalene-1,3,5-trisulfonic acid and the like. The salts on the acidic group include salts with alkali metals such as sodium, potassium and the like; Salts with alkaline earth metals such as calcium, magnesium and the like; Ammonium salts; and salts with nitrogen-containing organic bases, such as procaine, dibenzylamine, N-benzyl-ß-phenylethylamine, 1-ephenamine, N, N-dibenzylethylene diamine, triethylamine, trimethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N- Methylmorpholine, diethylamine, di-cyclohexylamine and the like.

The invention encompasses all optical isomers and the racemic compounds of cephalosporins of the formula I and their salts and likewise all crystal forms and hydrates of the compounds mentioned. More specific are preferred examples of compounds of formula I oximes, wherein A is a group of the formula:

-c-

18th

-N

/ R1 V

in which R16 and R17 have the above meanings, furthermore groups of the formula:

"A

r10 0

\ A -K

II

-N. JkR12

wherein R10, Rn and R12, which are the same or different, each represent hydrogen, a halogen atom or an alkyl group, and groups of the formula:

or '

represents, in particular the syn isomers thereof, in which R18 is preferably an alkyl group, in particular methyl or ethyl, or a substituted alkyl group, in particular a group of the formula:

CH3

I.

-CH2COOR 'or-C-COOR1

!

CH3

where R1 has the meaning given above.

Preferred examples of R2 are groups of the formula:

,

-n n-r \ = /

wherein R6 is hydrogen, a substituted or unsubstituted lower alkyl group or a group of the formula:

wherein R7, R8 and R9, which are the same or different, each represent hydrogen or an alkyl group, or groups of the formula:

wherein R13, R14 and R15, which are the same or different, each represent hydrogen or an alkyl group.

Next, the pharmacological effects on some typical compounds of Formula I are shown:

1) Antibacterial activity (Table 1)

According to the standard method of the Japan Society of Chemo-therapy [Chemotherapy, Volume 23, Pages 1 and 2 (1976)]

15, a bacterial solution obtained by growing in heart infusion broth (manufactured by Eiken Kagaku) at 37 ° C for 20 hours was inoculated onto a heart infusion agar containing an active ingredient and grown at 37 ° C for 20 hours, after which the growth of the bacteria was observed

20 was used to determine the minimum concentration at which the growth of the bacteria was inhibited as MIC (| xg / ml). The amount of bacteria inoculated was 104 cells / plate (106 cells / ml). The MIC values of the following test compounds are given in Table 1.

25 (A) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- | [l- (2,3-dioxo-1,2,3, 4-tetrahydropyrazinyl)] methyl} -A3-cephem-4-car-bonic acid,

(B) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl)

30 -2- (syn) -methoxyiminoacetamido] -3- {[l- (4-methyl-2,3-

dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -A3-cephem-4-carboxylic acid,

(C) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- j [l- (4-ethyl-2,3-di-

35 oxo-l, 2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem-4-carboxylic acid,

(D) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- | [l- (4-isopropyl-2,3-dioxo-l, 2, 3,4-tetrahydropyrazinyl)] methyl} -A3-ce-

40 phem-4-carboxylic acid,

(E) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- {[l- (4-dimethylamino-2,3-dioxo-1,2, 3,4-tetrahydropyrazinyl)] - methyl] A3-ce-phem-4-carboxylic acid,

(F) 7- [2- (2-aminothiazol-4-yl) -2- (syn) -carboxymethoxyiminoacetamido] -3- ([1- (2,3-dioxo-1,2,3,4- tetrahydropyrazinyl)] methyl} -A3-cephem-4-carboxylic acid,

(G) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) - carboxymethoxyiminoacetamido] -3-1 [1- (4-me-

50 thyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazinyl)] -methyl} -A3-cephem-4-carboxylic acid,

(H) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -carboxymethoxyiminoacetamido] -3- {[l- (4-ethyl-2,3-dioxo -1,2, 3,4-tetrahydropyrazinyl)] methyl} -A3-ce-

55 phem-4-carboxylic acid,

(I) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -carboxymethoxyiminoacetamido] -3- | [l- (4-dimethylamino-2,3-dioxo -1, 2,3,4-tetrahydropyrazinyl)] -methyl} -A3-cephem-4-carboxylic acid,

60 (J) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- [[1- (2-oxo-l, 2-dihy-dropyrazinyl)] -methyl} - A3-cephem-4-carboxylic acid,

(K) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- {[1- (3,6-dioxo-l, 2,

65 3,6-tetrahydropyridazinyl)] methyl} -A3-cephem-4-car-bonic acid,

(L) formic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -carboxymethoxyiminoacetamido] -3- {[1- (3,6-dio-

45

657 135

xo-l, 2,3,6-tetrahydropyridazinyl)] -methyl | - A3-cephem-4-carboxylic acid,

(M) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) - methoxyiminoacetamido] -3- {[1- (3-methyl-6-oxo-1,6-dihydropyridazinyl) ] -methyl | - À3-cephem-4-car-bonic acid and

(N) formic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -carboxymethoxyiminoacetamido] -3- j [l- (3-methyl-6-oxo-l, 6-dihydropyridazinyl) ] -methyl} -À3-cephem-4-car-bonic acid.

Table 1

Antibacterial activity

Organism connection

A

B

C.

D

E

E. coli NIHJ

<0.1

<0.1

<0.1

<0.1

go, i

E. coliTK-3 *

<0.1

<0.1

S0.1

^ 0.1

^ 0.1

Kl.pneumoniae Y-50

<0.1

<0.1

<0.1

<0.1

^ 0.1

Kl.pneumoniae Y-41

<0.1

<0.1

<0.1

<0.1

<0.1

Kl. Pneumoniae Y-4 *

<0.1

0.2

^ 0.1

0.39

^ 0.1

Ser. marcescens W-134

<0.1

<0.1

S 0.1

^ 0.1

^ 0.1

Ser. marcescens IID620

<0.1

<0.1

^ 0.1

^ 0.1

^ 0.1

Per. morganii T-216

<0.1

^ 0.1

go, i

<0.1

<0.1

Per. mirabilis T-lll

<0.1

^ 0.1

go, i

0.2

go, i

Per. vulgaris GN76 **

<0.1

0.2

1.56

0.39

1.56

Cit. freundii N-7

0.39

1.56

0.78

1.56

0.78

Ps. Aeruginosa GN918 **

12.5

25th

6.25

-

-

MIC ((ig / ml

F

G

H

I.

J

K

L

M

N

go, i

<0.1

: g0, l

^ 0.1

^ 0.1

<0.1

^ 0.1

^ 0.1

<0.1

<0.1

0.2

<0.1

go, i

0.2

0.2

0.78

0.2

0.2

^ 0.1

0.2

0.2

0.2

^ 0.1

^ 0.1

0.78

0.2

0.39

0.39

^ 0.1

<0.1

0.2

-

-

-

-

-

0.2

0.2

0.2

0.39

-

-

-

-

-

<0.1

^ 0.1

^ 0.1

<0.1

0.39

<0.1

<0.1

0.78 ^ 0.1

^ 0.1

â0, l

^ 0.1

<0.1

<0.1

^ 0.1

1.56

0.2

<0.1

go, i go, i

<0.1

: g0, l go.i go, i

<0.1

0.2

^ 0.1

go, i

^ 0.1

^ 0.1

= S0.1

0.2

^ 0.1

^ 0.1

0.2

<0.1

^ 0.1

^ 0.1

^ 0.1

^ 0.1

0.78

^ 0.1

^ 0.1

0.2

^ 0.1

0.78

1.56

1.56

1.56

0.78

0.78

3.13

0.78

0.78

-

-

6.25

12.5

-

-

-

-

-

* Penicillinase-producing strain ** Cephalosporinase-producing strain

2) Urinary excretion

A test compound was orally administered to mice (ICR, male, 4 weeks old) in an amount of 1 mg / mouse, and urinary excretion was determined. The results obtained are shown in Table 2.

In the test compounds (No. 1 and No. 2), the ester group in a living body is easily removed, whereby the compounds are converted into the corresponding free carboxylic acids

25th

be transferred. The excretion in the urine was therefore measured by quantitative determination of the free carboxylic acids excreted in the urine.

Method of administration: A test compound suspended in 0.5% CMC (carboxy-30 methyl cellulose) was administered orally.

Quantitative determination method: The amount of free carboxylic acid was determined by biological value determination (a paper disk method) using the test organisms mentioned in Table 35 2.

Table 2

"N-n c-conh-i — f svi n ^ s-l 1! (syn

\ 0 1 1

0rl8 coor-1-

Connection Testorga- certification

No. R18 R1 R2 nism formation in

Urine * (%)

1 -CH3 -CH2OCOC (CH3) 3 Kl.pneumo- 15.9 ± 1.6

R niae ATCC

0 10031

X3

2 -CH3 -CH2OCOC (CH3) 3 do. 20.4 ± 3.7

—N "

Ö

3 -CH2COOH -H do. 10.4 ± 1.1

* 0 to 6 hours, one group; 5 mice (mean ± standard deviation)

3) Acute toxicity

The LD50 values of the following test compounds were 3 g / kg or more when the compounds were administered intravenously to mice (ICR, male, body weight 20 to 24 g).

Sodium-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxy-iminoacetamido] -3-1 [1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl )] -methyl} -A3-cephem-4-carboxylate,

Sodium-7- [2- (2-aminothiazol-4-yl) -2- (syn) - methoxy-iminoacetamido] -3- j [1- (4-methyl-2,3-dioxo-1,2,3 , 4-tetrahydropyrazinyl)] -methyl} A3-cephem-4-carboxylate,

13 657135

Sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxy-iminoacetamido] -3- {[1- (3,6-dioxo-l, 2,3,4-tetrahydropyri -dazinyl)] -methyl) - A3-cephem-4-carboxylate and

Sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxy-5iminoacetamido] -3- {[1- (3-methyl-6-oxo-l, 6-dihydropyri-dazinyl )] -methyl} - A3 cephem-4-carboxylate.

Next, the manufacturing processes will be described.

The connections in accordance with the expiry date can be produced using the following methods:

15

Production route 1

ch2R

29

[ii]

r> 28:

coor1 or a salt thereof

[Ill-a] 1 ', [iii-b] 2) [III-cl3),

, n. -a-cooh

HI

S R

[v]

or a salt thereof or a reactive derivative thereof ^

(Acylation)

c n -_. a ~ conh_j—>

CH2R

coor "1- [i]

or a salt thereof or a salt thereof, /

(Conversion reaction in the ^ xch2coch2cooh [vi]

or a salt thereof or a reactive ■

capable «D.rlvat X (:" 5C0C "OTH

3 position)

h2ncr-

[XII]

2s: s coor!

[IV]

or a salt before it, or a reactive derivative thereof on the amino group thereof.

(Acylation)

[IX]

or a salt of it

3 ^ Uy ^ ch coor1

(Ring closure)

-R-

n ^. ^. ch2conh

(Nitrosation)

HJ

■ Nn ^ CH2R

i

* (Continuation)

coorl [Ia]

or a salt of it

135

14

Production route 1 (continued)

11

XCH2COCCOOH

OH

[VII]

XCH_COCCONH-j-f S>

/ \ W

"'COOR1

(Acylation)

CH2R

or a salt of it

[X]

H-NCR

or a salt or a reactive, capable derivative "

of which XCH-COCCOOH

28:

[VIII]

1 (etherification or final) phosphorylation)

N

or '

18a

F3

(Ring-

H-NCR 2 n

[XII]

[XII]

R3

or a salt thereof * * 2 'Cî ^ r2 or a reactive r = F derivative thereof

! ^ <3 XCH-COCCONH-j-1

(Acylation)

J

Lisa, cooî

CH2R ': COORl

(Ring closure)

or a salt thereof or a reactive derivative thereof on the amino group

_ N_, COCOOH

[XIII]

or a salt thereof or a reactive

[XI]

or a salt of it

R3 i

(Ac;

capable derivative N coconh4—

COC

-ch2r-

COOR1

. N ^ -CCONH-i-Y'SNt

■ -gQ 0U ^ CH2E

nnlS rnnrcl

OR

or a salt of it

COORl [Ib]

'blf cLu-vvq

(Oxiralnation)

hjnor18 [xv]

or a salt of it

[XIV]

or a salt of it

Footnote: 1) Formula [Ill-a] is

2) Formula [Ill-b] is

6

HN N-R

W "8

\

HN

3) Formula [III-c]

4) Formula [IH-d] is

Production route 2 r3

r30-conh-; ^ sn

Htr \ [xvi]

^ -N ^ y '^ ch2X COORl or a Salt; from that

(3-position conversion reaction)

"10 0

\

-V "

o R13

Vf

HN NR [Ill-a]

s = y or a salt thereof

15

657 135

Production route 2 (continued)

30: ^ p

R -CONH-V-f p NR6

COOR

R30-CONH- | -Y'S ^ ° - \ //

J-N ^ - CH2N NR6

COOR1

[XVII]

R

5 wherein R4, R5 and A have the above meanings; X represents a halogen atom; > Z means> S or> S-> 0, and the dotted line in the ring means a double bond between the 2 and 3 positions or between the 3 and 4 positions.

A further detailed explanation is given below. R28 stands for amino, a group of the formula:

15

R31 R32

C = C-NH-

R33

or a salt of it

(Conversion to û3 cephem)

R 3 ° —CONH —i ~ f S ^ | ^

NR6 [XVIII]

or a group of the formula:

20th

R3 \

/ C = N-,

r55

and the group of the formula:

O "|

COORl or a salt thereof

(Deacylation)

R31 R32

/

C = C-NH-I

R33

30 includes the group of the formula:

R31

R32

^ CH-C = N-

35

R33

v-fr5! Y?

/ NnA

CH2N NO

[XIX]

COOR

or a salt of it

In the above formulas, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R18, A and the bond have the meanings above; R18a has the same meanings as R18 with the exception of a hydrogen atom; R28 stands for amino or a group of the formula:

R \

> c = c-nh-R32 I

R33

wherein R31, R32 and R33, which are the same or different, each represent hydrogen or an organic radical not participating in the reaction, or a group of the formula:

R34s

\

R35

C = N-

wherein R34 and R35, which are the same or different, each represent hydrogen or an organic radical not participating in the reaction; R29 represents a substituted or unsubstituted acyloxy or carbamoyloxy group; R30 means benzyl, phenoxymethyl or a group of the formula:

which is an isomer of it. The organic radicals not participating in the reaction, which are represented by R31, R32, R33, R34 and R35, comprise radicals which are well known to the person skilled in the art, specifically specifically substituted or unsubstituted aliphatic radicals, alicyclic radicals, aromatic radicals, aromatic-aliphatic radicals Residues, heterocyclic residues, acyl groups and the like. The following groups are particularly included:

45 (1) Aliphatic residues: alkyl groups; Alkenyl groups;

(2) alicyclic residues: cycloalkyl groups; Cycloalkenyl-grappen;

(3) aromatic residues: aryl groups;

(4) aromatic aliphatic residues: aralkyl groups; see (5) heterocyclic radicals: heterocyclic groups;

(6) acyl groups: acyl groups that can be derived from organic carboxylic acids, including aliphatic carboxylic acids, alicyclic carboxylic acids and alicycloaliphatic carboxylic acids; and which includes aromatic-ali-55 phatic carboxylic acids, aromatic-oxyaliphatic carboxylic acids, aromatic-thioaliphatic carboxylic acids, heterocyclic-aliphatic carboxylic acids, heterocyclic-oxyaliphatic carboxylic acids and heterocyclic-thioaliphatic carboxylic acids, in which an aromatic radical or group 60 is one is bonded to an aliphatic carboxylic acid directly or via an oxygen or sulfur atom; organic carboxylic acids in which an aromatic radical, an aliphatic group or an alicyclic group is bonded to the carbonyl group via an oxygen, nitrogen or sulfur atom; aromatic carboxylic acids; heterocyclic carboxylic acids; and the same.

The above aliphatic carboxylic acids include formic acid, acetic acid, propionic acid, butanoic acid, isobutane

657135 16

acid, pentanoic acid, methoxyacetic acid, methylthioacetic acid -> S, but also compounds in which> Z represents acid, acrylic acid, crotonic acid and the like; the above> S-> 0 is used as starting materials, alicyclic carboxylic acids include cyclohexanoic acid and, in the latter case, the grouping> S-> 0 may be similar; and the above alicycloaliphatic carboxylic acid during the reaction or in a post-treatment step in> S ren include cyclopentane acetic acid, cyclohexane acetic acid, 5.

Cyclohexane propionic acid, cyclohexadiene acetic acid and the- When the 2,3-dioxo-1,2,3-4-tetrahydropyrazine the same as. with III-a, the 2-oxo-l, 2-dihydropyrazine of the formula III-b,

The aromatic radicals in the above-mentioned organ- the 3,6-dioxo-1,2,3,6-tetrahydropyridazine of the formula III-c see carboxylic acids include phenyl, naphthyl and der- or the 6-oxo-1,6-dihydropyridazine of the formula Ill-d, the same in. io the reaction is used as a reaction partner, a

Any of the groups bearing these organic carboxylic acid or acidic group as a substituent can form them by a substituent such as a halogen compound, if necessary in the form of the corresponding atom, hydroxyl, a protected hydroxyl group, an alkyl salt in the reaction be used. In this case, grappe, an alkoxy group, an acyl group, nitro, amino, the salts on the basic groups and the salts include a protected amino group, carboxyl or a protected group on the acidic group, those related to carboxyl group may be further substituted. mentioned with the salts of the compounds of formula I.

To the substituted or unsubstituted acyloxy and were.

Carbamoyloxy groups represented by R29 also include the salts of the compounds of formulas II and IV alkanoyloxy groups such as acetoxy, propionyloxy, Bu- include salts on the basic groups and on the acidic tyryloxy and the like; Alkenoyloxy groups such as acrylo groups, and these salts include those used together, and the like; Aroyloxy groups such as benzoyloxy associated with the salts of the compounds of formula I er-naphthoyloxy and the like; and carbamoyloxy. These were believed. The salts of the compounds of the formula II groups can be isolated by one or more substituents and can be isolated beforehand and then used, but they can also be prepared in situ, such as halogen atoms, nitro groups, amino groups, alkylynes.

grappes, alkoxy groups, alkylthio groups, acyloxy groups- 25 As acids or complex compounds of acids used in the reaction, pen, acylamino groups, hydroxyl groups, carboxylgrap- are e.g. Protonic columns, sulfamoyl groups, carbamoyl groups, alkoxycarbons, Lewis acids and complex compounds of Lewis acid-nylcarbamoyl groups, aroylcarbamoyl groups, alkoxycars mentioned. Protonic acids include sulfuric acid, bonylsulfamoylgrappen, arylgrappen, carbamoyloxygrup-sulfonic acids and superacids (superacids means syrups and the like), which are stronger than 100% sulfuric acid, and this term may include some of the above-mentioned substituents for R29 of the above sulfuric acids, the hydroxyl group, the amino group, the carboxyl group and sulfonic acids). More specifically, the protonic acids and the like belong to protective groups which usually use sulfuric acids such as sulfuric acid itself, chlorosulfur, and the protecting groups include acid, fluorosulfuric acid and the like, sulfonic acids, specifically those hydroxyl protective groups, amino- 35 e.g. Alkyl mono- or di-sulfonic acids, such as methane sulfone protective groups and carboxyl protective groups, which have been mentioned above in relation to acid, trifluoromethane sulfonic acid and the like, aryl mo-related to R2. no, di or tri sulfonic acids such as p-toluenesulfonic acid and the like, super acids such as perchloric acid, magic acid (a) conversion reaction in the 3-position. (FS03H-SbF5), FS03H-AsF5, CF3S03H-SbF5, HF-BF3,

In the 7-position a substituted or unsubstituted Ami- 40 H2S04-S03 and the like.

nograppe and a substituted methyl group in the 3-position The Lewis acids include e.g. Boron trifluoride and the bearing cephemcarboxylic acid of formula IV or their complex compounds of Lewis acids include complex

Salts can be prepared in high yield with high purity using compounds of boron trifluoride with dialkyl ethers, such as the di-use of an industrially easily processable ethyl ether, di-n-propyl ether, di-n-butyl ether and the like, by using a 2, 3-dioxo-1,2,3,4-techen 45; with amines such as ethylamine, n-propylamine, n-butyl-trahydropyrazine of the formula III-a, a 2-oxo-l, 2-dihydropyamine, triethanolamine and the like; with esters such as ethyl-razin of formula III-b, a 3,6-dioxo-l, 2,3,6-tetrahydropyriformate, ethyl acetate and the like; with aliphatic acid dazin of the formula III-c or a 6-oxo-1,6-dihydropyridazine, such as acetic acid, propionic acid and the like; and with the formula III-d or a salt thereof with a cephalosponitrile such as acetonitrile, propionitrile and the like, ranic acid of the formula II or a salt thereof in the presence of the reaction. The reaction is preferably carried out in the presence of an organic acid or a complex compound Acidic solvent. The organi-sets used and then, if desired, the protecting group removed, see solvents include all organic solvents which protect the carboxyl group or the compound obtained, which are inert with respect to the reaction, for example Niehl salt. Furthermore, the above-mentioned 2,3-dioxotroalkane such as nitromethane, nitroethane, nitropropane and 1,2,3,4-tetrahydropyrazine can be prepared by the method or the like; organic carboxylic acids, such as formic acid, are described in the Journal of Chemical Society, Perkin I, acetic acid, trifluoroacetic acid, dichloroacetic acid, propion-

Pp. 1888-1890 (1975). acid and the like; Ketones, such as acetone, methyl ethyl

Furthermore, the substituent on the amino group in the clay, methyl isobutyl ketone and the like; Ethers, such as di-7-position, if necessary in a conventional manner, demethyl ether, diisopropyl ether, dioxane, tetrahydrofuran,

be removed to connect with an unsubstituted 60 ethylene glycol dimethyl ether, anisole, dimethyl cellosolve and amino group in the 7-position. According to this procedure; Esters such as ethyl formate, diethyl carbonate, and the like can not only use the A3 cephem compounds, thylacetate, ethyl acetate, ethyl chloroacetate, butyl acetate, but also the A3 cephem compounds as starting compounds; Nitriles such as acetonitrile, butyronitrile and the like bonds are used, and when the A2 cephems; and sulfolanes, such as sulfolane itself and the like, can be used as starting compounds, “These solvents can be used in a mixture with one another, the A2 cephem obtained as the reaction product can be used. Furthermore, these organic solder bonds can also be converted into A3 cephem compounds. Compounds formed by solvents and Lewis acids cannot only be compounds in which> Z for gene are used as solvents. It is sufficient that the

17 657 135

Amount of acid or complex compound of acid containing N, N-dimethylacetamide; Acetone; Water; and mixtures is used, the amount of the compound of formula II thereof.

or its salt is at least equimolar, and the amount In this case, the compound of formula III-a can be varied depending on the conditions in question. or their salt, preferably in an amount of about 1.0 to in particular, the use is in a ratio of 2 5 2.0 moles per mole of the compound of formula XVI or hers to 10 moles per mole of the compound of formula II or its salt used. The reaction is generally preferred for a salt. When the complex compound of the acid is used at a temperature of 0 to 50 ° C for 30 minutes to 10 hours, it can be used by itself as a solvent.

and two or more such complex compounds. The mixture of an A2 and an A3 Ce thus obtained

can be used in a mixture with each other. 10 phem connection, i.e. the compounds of formula XVII

It is sufficient that the amount of 2,3-dioxo-l, 2,3,4-tetrahy- or their salts can easily be incorporated into the A3-cephem compound dropyrazine of the formula III-a, at 2-oxo-l, 2- dihydropyrazine can be converted to produce a compound of the formula XVIII of the formula III-b, 3,6-dioxo-l, 2,3,6-tetrahydropyridazine or a salt thereof, which is then represented by the formula III-c or on 6-oxo-1,6-dihydropyridazine from the deacylation into the compound of the formula XIX, using the formula III-d or a salt thereof, at least equimolar. This conversion reaction and deacylation-the amount of the compound of formula II or its salt is, reaction are in the field of penicillins and cephalospo-and in particular the use is known in a lot of rine and are described in Journal of Organic Chemistry, ca. 1, 0 to 5.0 moles per mole preferred. Vol. 35, No. 7, pp. 2430-2433 (1970) and «Cephalosporins and

This reaction is usually carried out at 0 to 80 ° C, Penicillins (by Flynn, Academic Press), pp. 56-64, and ends in 10 minutes to 30 hours. The 20 described.

The presence of water in the reaction system can cause undesirable side reactions, such as lactonization of the output. If the substituents of the 2,3-dioxo-l, 2,3,4-tetrahy starting material or the products and cleavage of the β-lac dropyrazine of the formula III -a, the 2-oxo-l, 2-dihydropyrazine tamringes, so that it is desirable to use the system of the formula IH-b, the 3,6-dioxo-l, 2,3,6-tetrahydropyridazine under anhydrous conditions to keep. In order to meet these requirements of the formula III-c or the 6-oxo-1,6-dihydropyridazine, it is sufficient to give the reaction system a suitable formula III-d or its salts, which are used in the reaction as reactants. To add a suitable dehydrating agent, for example, a cation partner, substituted by a hydroxyl group, phosphorus compound such as phosphorus pentoxide, polyphos- an amino group, a carboxyl group or the like, phosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus, these groups can be reacted with phoroxychloride or the like; An organic silylie- 30 protecting agents mentioned above can be used as protective agents, such as N, 0-bis- (trimethylsilyl) acetamide, trimethyl and, after the reaction has ended, a conventional thylsilylacetamide, trimethylchlorosilane, dimethyldichlorosilane removal reaction can be subjected to the or the like; to obtain an organic acid chloride such as acetyl desired compound.

chloride, p-toluenesulfonyl chloride or the like; an acid- The compound of formula IV or XIX may require requisite anhydride, such as acetic anhydride, trifluoroacetic acid, if necessary also by a conventional method on the drid or the like; Protect an inorganic drain with carboxyl group or convert it into a salt, such as anhydrous magnesium sulfate, anhydrous calcium to obtain the desired compound. A ver chloride, a molecular sieve, calcium carbide or the like. Compound of formula IV, wherein R28 stands for amino, can also be converted into a reaction using a conventional method when a compound of formula II, wherein R1 stands for a 40-capable derivative of the amino group or the compound of the carboxyl protecting group, is used as starting material, formula XIX As mentioned below, in some cases a compound of formula IV, wherein R1 is hydrogen, can be obtained directly from the reaction, or it can be obtained by removing the protective (b) acylation grappe in a conventional manner . 45 If a compound of formula V, VI, VII, VIII or

Next, the conversion reaction in the 3-position XIII or a salt thereof or a reactive derivative described in Production Route 2 will be explained. thereof with a compound of the formula IV or a salt The halogenated compound of the formula XVI can be prepared by using it or a reactive derivative of the amino process which is converted into tetrahedron let group, a compound of the formula I, ters, No. 40, pp. 3991-3994 (1974) and Tetrahedron Letters, so IX, X, XI or XIV or a salt thereof.

No. 40, pp. 3915-3918 (1981). The salts of the compounds of formula V, VI, VII, VIII

The compound of formula XVII or a salt thereof and XIII include salts on the basic group or on which can be prepared by reacting a halogenated acid group, which specifically includes those related to the compound of formula XVI or a salt thereof with the salts of the compounds of the For-a 2,3-dioxo-l, 2,3,4-tetrahydropyrazine of the formula III-a ss mei I have been mentioned.

or a salt thereof in the presence of a base. The reactive derivatives on the amino group of sen include alkali metal carbonates, e.g. Sodium carbonate, compounds of formula IV include all derivatives, the häu-potassium carbonate or the like; Alkali metal hydrogen carbon used in the acylation, for example a bonate, e.g. Sodium hydrogen carbonate, potassium hydrogen car isocyanate; a Schiff base, which is implemented by a bonat and the like; Alkali metal hydroxides, e.g. Na 60 compound of formula IV or a salt with a carbohydrate hydroxide, potassium hydroxide and the like; nitrogen nyl compound such as an aldehyde, a ketone or the containing organic bases, e.g. Triethylamine, pyridine, N, N-like, is produced (of the type of ketimines or their iso-dimethylaniline and the like. Mere, namely of the type of enamines); a silyl derivative, a

The 3-position conversion is usually carried out in a phosphorus derivative or a tin derivative, which is carried out by reaction with a suitable solvent. The solvent of a compound of Formula IV or a salt thereof includes halogenated hydrocarbons such as chloroform, a silyl compound such as bis (trimethylsilyl) acetamide, tri-methylene chloride and the like; Ethers such as tetrahydromethylsilylacetamide, trimethylsilyl chloride or the like, furan, dioxane and the like; N, N-dimethylformamide; a phosphorus compound, such as phosphorus trichloride,

:

657 135 18

. Q [- o \ to obtain a salt thereof, a 4-halo-3-oxobutyryl

\> cl, pel, halide, which is obtained by reacting diketene with a

j / 'chj - ^ - 0 / logen, such as chlorine or bromine, is obtained [Journal of the

Chemical Society, 97, 1987 (1910)], according to a customary method

- o 5 method with a compound of formula IV or a salt l pei, (ch3ch20) 2pc1, (ch3ch2) 2pci thereof. Reaction conditions and reaction

0 / drive, which are known to the expert, can for this

,,, ■,. . ... Reaction. The salts of the compounds or the like, or a tin compound such as, T, uvi ••, •,. , ,,,

tr- u- \ c / -i a a 1 • u t a of formula IX can easily be done by a conventional method

(C4HnhSnCl or the like.,. 1U,, ",,, c,

tv w • 4. a v u- j j e] n are produced; the salts include the same salts,

The reactive derivatives of the compounds of form 10. 0 ... ', Jf. . c. °,.

nr vi wwt jvm c ■ n c- u i as described above in connection with the salts of the verb

mel V, VI, VII, VIII and XIII specifically include acid halo,, ^ n. 0,. ,,. ,.

nides, acid anhydrides, mixed acid anhydrides, active sauces ^ orms were given. Although the connection

■ a 1 c *,, e-u- f, -1, • j, fertilize formula IX or its salts isolated and purified reamide, active esters and reactive derivatives by? , ... , r r <••• j- ut-

IT. ,,. j, r, ö. ', they can also be used without insulation lur the

Implementation of the death formula VI, VI, Vm se se de de reaction.

and XIII can be obtained with a Vilsmeier reagent. The A,,, ■,, ut

... c, ..,, •, r- ■ c .. u In addition, the compounds of the formula V, VI,

mixed acid anhydrides include mixed acid anhydrides or their Sa] ze ^ reactive dride with a monoalkyl carbonate, such as Monoethylcarbo- derivatives yorz ^ an M of ca! Mol 4 meh.

nat, monoisobutyl carbonate and the like, and mixed rer Q ^ ol of the compound of formula IV or their

Acid anhydrides with a lower alkanoic acid, which by the salt or their reactive derivative on the amino

logen can be substituted, such as Pivahnsure, Tnchloressig- .j »o t» • -a -u v uu ■ ■

..,, "• w o- 'a c m group used. The reaction is usually carried out at an acidic or the like. The acidic acid amides include N-temperature ranging from -50 to +40 ° C. The

Acylsaccharins, N-Acylimidazole N-Acylbenzoylamide reaction time is usually 10 minutes to 48

N, N -dicyclohexyl-N-acylureas, N-acylsulfonamides hours and the like. The active esters include cyanomethyl-p ^ ner can the compounds of formula I, IX, X, XI

esters, substituted phenyl esters, substituted benzyl esters, sub- and ^ where Rl is a carboxyl protecting group,

s 1 uier e ìeny it did not come out. by a conventional method in the compounds of the formula

As obtained by reaction with a Vilsmeier reagent, j Ix x XI or XIV in which Rl stands for hydrogen, or a reactive derivative includes those which are obtained; in a similar manner, the th can be reacted with a Vilsmeier reagent to give compounds of the formula I, IX, X, XI and XIV, where R> is that by reacting an acid amide, such as N, N-dimethyl water stole? Compounds of the formula I, IX, X,

formamide, N, N-dimethylacetamide or the like, with an XI xjy where Ri is a carboxyl protecting group,

halogenating agents such as phosgene, thionyl chloride or their salts are converted; and the salts of the

Phosphorus chloride, phosphorus tribromide, phosphorus oxychloride of the formef., IX, x, XI and XIV can be used in the nd, phosphorus pentachloride, chloromethyl chloroformate,. ° t. , ... c .. V -,,

1 1 i.i j a a 1 • V u 1 * ■ a 35 corresponding free acid forms.

Oxalyl chloride or the like is obtained. 1. ■, • A, •, -,

«R a- v u- j a r 1 v xtt \ ttt T7TTT j If R1, R- and R- in this acylation reaction m be

If the compounds of formula V, VI, VII, VIII and ,,. , .. "3 ,,, ..,.

VTTT. .,. T ~ t. 0 e. ". active groups to the reaction, they can

XIII each in the form of a free acid or a salt ver, n, ... . .

J. , -,. . ,. Appropriate condensing agent is also used in groups before the reaction, ••, CU * U-K. A A a-a 4. * 7 a V a - «i t.- xt \ i / a- u. • communal protection groups are protected, and that turns. The condensing agents include N, N -disubsti- c,. , .. r. a d w u u. •. g ~ \ * a "* A ■ tvt \ t '-r» - 11. 1 1! j - a io Protective groups can also be removed after the reaction by a tuned carbodumide, such as N, N ^ lcyclohexykarbodnmid; usual method.

Azo id compounds ^ vie N, N -Thiony diimidazole; Water drainage- The waste obtained by the method mentioned above

Cleaving agents, such as N-ethoxycarbonyl-2-ethoxy-l, 2-dihy-bind of the formula I and their salts can be

Straw poppy, phosphorus oxychloride, alkoxyacetylenes and conventional methods can be isolated.

same; 2-halopyndinium salts, such as 2-chloropyridimum

methyl iodide and 2-fluoropyridinium methyl iodide; and der- /, M.f dykes (c) mtrosierung

6 'A,. ,. j r,. To a compound of formula X or a salt thereof

This acylation reaction is usually carried out in a solvent suitable for a compound of the formula IX or a salt thereof in the presence or absence of a solvent which is subsequently obtained using a nitrosating agent

Base executed. With regard to the 5Q, the connection of the form! IX or their salt implemented.

Reaction inert solvents are used, for example. The reaction is usually carried out in a solvent.

As a solution, a hydrogenated hydrocarbon, such as chloroform, can be used in relation to the reaction.

Methylene chloride or the like; a ^ ether such as tetrahedronic solution (water), such as water, acetic acid, benzene, meth-

furan dioxane or the like; N N-dimethylformamide; anol Etha ^ oU jetrahydrofuran or the like used

N.M-dimethylacetaimd; Acetone; Water; or a mixture 55. Preferred examples of nitrosating agents are thereof. As bases, inorganic bases such as alkane-nitric acid and their derivatives, for example nitrosyl

a hydroxyde, alkahmetal oil hydrogen carbonate, alkane-} ^ like nitros lchloride> nitrosyl bromide and the like

tall carbonates, alkali metal acetates or the like; tertiary ch ° alkali metal nitrites, such as sodium nitrite, potassium nitrite LTtthy ^ mm'T "ethykmin, Tnbutylamm, Pyd de and aikyl nitrites, such as butyl nitrite, pentyl

ndin, N-methylpiperidine, N-methylmorphohn, Lutidm Col- 60 ni ^ d corpses. w ^ nn a salt of nitrous acid as hdm or the like; or secondary wet nurse, such as Dicyclohe-Niîrosiera s ° medium is used, the reaction xylamm, dieihylamine or the like is carried out; used wemen. preferably in the presence of an inorganic or organic

^ Compounds of the formula IX and their salts which mix acid, such as acidic acid, sulfuric acid, formic acid, es-

the compounds of the formulas Ia and Ibundderen salts acidic or the like. If an alkyl nitrite as Ni

v can be used using the following 65 agents, the reaction is carried out

Procedure are made. preferably in the presence of a strong base such as one

To use alkali metal alcoholate or the like using a compound of formula IV. The reaction or a salt thereof is a compound of formula IX or is usually carried out at a temperature in the range of -15

19 657135

up to + 30 ° C, and the reaction time is set. Although it is not essential, a homely 10 minutes to 10 hours. Adding the salts of the compound binding agent, the reaction fertilizing formula X can easily proceed according to a usual method - sometimes smooth, if one produces an acid binding agent in one method; the salts comprise the same amount such that the cephalosporin skeleton does not

Salts as affected above in connection with the salts of FIG. 5. To the acid- used for the reaction

Compounds of formula I have been mentioned. Although the binding agents include inorganic and organic ba

Compounds of the formula X or their salts obtained, such as alkali metal hydroxides, alkali metal hydrogen carbo-

Well-known methods are used to isolate and purify nate, triethylamine, pyridine, N, N-dimethylaniline and the like.

can, they can also be used without insulation for the same. The reaction will usually be used at a temperature sending reaction. 10 from 0 to 100 C. The thioformamide or the

Thiourea is usually used in an amount of approximately 1 mole

(d) etherification and phosphorylation up to several moles per mole of the compound of formula IX, X To use a compound of formula XI or a salt thereof or XI or its salt. The reaction time is

from a compound of formula X or a salt thereof for 1 to 48 hours, preferably 1 to 10 hours. Furthermore, the compound of the formula X or its salt is obtained in the case of the compounds of the formula Ia or Ib in the etherification reaction or in a phosphorylation reaction, protecting the carboxyl group and removing the carbo-

tion subjected. xyl protective group or the transfer of the product into one

The etherification reaction and the phosphorylation salt can be carried out by a conventional method, and the reaction can be carried out by a conventional method to convert the compound into the corresponding desired compound as described in Japanese Unexamined Publication 20. If R1, R2 and R5 in the formulas la or Ib

Patent Applications No. 137,988 / 78,105,689 / 80,149,295 / 80 containing reaction groups that are active in the reaction, and the like have been described. expediently these groups before the reaction by a

For example, the alkylation can be protected according to a conventional protective group, and the protective

Method. The reaction is generally carried out after the reaction using a conventional method.

can be removed at a temperature of - 20 to + 60 ° C. The desired

and is finished in 5 minutes to 10 hours. Compounds of the formula la or Ib or their salts can be

A solvent can be isolated with respect to the reaction by a conventional method.

first solvent, e.g. Tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene chloride, ethyl acetate, Bu- (f) oxime formation tylacetate, N, N-dimethylformamide, N, N-dimethylacetamide, 30 The compounds of formula Ib or their salts

Water or a mixture thereof can be used. obtained by using a compound of formula XIV or

As alkylating agents e.g. Niederalkylhaloge- their salt with a compound of formula XV or a salt nide, such as methyl iodide, methyl bromide, ethyl iodide, ethylbro- reacted. The salts of the compounds of formula XV mid or the like, dimethyl sulfate, diethyl sulfate, diazo- include hydrochloride, hydrobromide, sulfate and the-methane, diazoethane, methyl p-toluenesulfonate or the like. This reaction will usually not only be used in one way. When an alkylating agent other than diazomethane and solvents such as water, an alcohol, N, N-dimethyl-diazoethane is used in acetamide or the like, but also in other solvents, the reaction is carried out in the presence of an alkali metal car- Reaction are inert, or carried out in carbonates such as sodium carbonate, potassium carbonate or mixtures thereof. The reaction is carried out at the same; an alkali metal hydroxide such as sodium hydro temperature from 0 to 100 ° C, preferably in the range of 10x, potassium hydroxide or the like; or an organic up to 50 ° C. The reaction time is ordinary base, such as triethylamine, pyridine, N, N-dimethylaniline, for 10 minutes to 48 hours. The connections of the Foroder or the like; executed. with XV or its salts in an amount of about 1 mole. The salts of the compounds of the formula XI can be obtained from one to several moles per mole of the compound of the formula XIV if easily by a customary method; using the 4S or its salt. Although the salts of the verbin salts comprise the same salts as can be used alone in connection with the formula XV above for the reaction in connection with the salts of the compounds of the formula I, they can also be used in Presence of one fancies. Base, e.g. an inorganic base, such as a further protective groups can be introduced and removed by a conventional alkali metal hydroxide (for example sodium hydroxide, Ka method, whereby a verium hydroxide or the like), an alkaline earth metal hydroxide bond into a corresponding desired compound (for example magnesium hydroxide, calcium hydroxide or can be conducted. The like), an alkali metal carbonate (for example Na-

Although the compounds of the formula XI obtained in this way can be isolated from triumearbonate, potassium carbonate or the like), an alkaline earth metal or their salts by a customary method and can be purified from potassium metal carbonate (for example magnesium carbonate, Cal), they can also be used without isolation for 55 cium carbonate or the like), an alkali metal hydrogen-the subsequent reaction can be used. carbonai (e.g. sodium bicarbonate, potash

umhydrogencarbonate or the like), an alkaline earth metal

(e) ring-closing reaction phosphate (for example magnesium phosphate, calcium — the compounds according to the invention of the formula la phosphate or the like), an alkali metal hydrogen phosphate

or Ib or their salts can be obtained by umphosphate (for example disodium hydrogen phosphate, dipotassium

setting of a compound of formula IX, X or XI or ih-hydrogen phosphate or the like) or an alkali metal

salts with thioformamide or a thiourea of acetate (for example sodium acetate, potassium acetate or the like

Formula XII. This reaction is usually carried out in a solvent or an organic base such as a trialkylamine solvent. As a solvent, one can be used in relation to (for example trimethylamine, triethylamine or the like

solvent inert to the reaction, for example washing), picoline, N-methylpyrrolidine, N-methylmorpholine,

water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, 1,5-diazabicyclo- [4,3,0] - 5-ones, 1,4-diazabicyclo- [2,2,2] -

N, N-dimethylformamide, N, N-dimethylacetamide or N-octane, 1,5-diazabicyclo- [5,4,0] - 7-undecene or the like.

Methylpyridone alone or in a mixture with one another. The compounds of the formula Ib or their compounds thus obtained

657 135 20

Salts can be conventionally subjected to conversion (finally, dropping solutions), suppositories or the like of R1, and can also be isolated using a method if the above-mentioned medicament is used in a customary manner. form is processed, diluents and / or

Additives, for example carriers, such as starch, lactose, sugar,

(g) alkoxylation s calcium phosphate, calcium carbonate or the like; Binding

The compounds of the formula IV in which R3 is an alkoxy agent, such as gum arabic, starch, microcrystalline cellulose

group means, from the compounds of the formula loose, carboxymethyl cellulose, hydroxypropyl cellulose or

IV, wherein R3 is hydrogen, by means of the like known per se; Lubricants such as talc, magnesium stearate or

Methods are synthesized, for example by means of the like; and disintegrants, such as carboxymethyl calcium,

driving used in the Journal of Synthetic Organic Chemistry, Jaio Talc, or the like,

pan, 35, 563-574 (1977). If the compounds of the formula I or their salts

Furthermore, the compounds of the formula I, Ia, Ib, IX can be administered, the dosage, the administration

X, XI and XIV, in which R3 denotes an alkoxy group, are persistent and the method of administration is varied depending on the corresponding compounds of I, Ia, Ib, IX, X, XI and the symptoms of the patient, and generally

or XIV, in which R3 stands for hydrogen, in known manner it is sufficient for them to be produced orally or parenterally in adults in an adult manner, for example by means of the measurement of a dose of about 50 to 5000 mg in 1 to 4 Servings per method to be administered in the unexamined Japanese Pa day.

24 888/79 and 103 889/79 described. The invention will now be described with reference to examples. and examples explained.

The compounds of formula I thus obtained or their 20th

Salts can be in the form of the free acid or in the form of a reference example 1

pharmaceutically acceptable salt or ester for (1) a solution of 20.0 g of ethyl N- (2,2-diethoxyethyl) -

For the treatment of bacterial infections and the oxamate in 60 ml of ethanol is treated with 6.1 ml of a 70 wt .-%

Protection against bacterial infections in humans and aqueous ethylamine solution and the mixture thereon

Animals are administered. The compounds are preferably reacted for 2 hours at room temperature for 1 hour. Parenterally, in the form of a free acid or a finished reaction, the precipitated crystals are collected by pharmaceutically acceptable salt or orally in the form of a filter and recrystallized from ethanol, with pharmaceutically acceptable ester being administered. 17.0 g (yield: 85.1%) of N-ethyl-N '- (2,2-diethoxy-

If it is sufficient for the compound to be given a dosage form of ethyl) -oxamide with a melting point of 131 to 132 ° C.,

processed, usually for cephalosporin drugs - 30 IR (KBr), cm ~ 1: vc = 0 1650

Mente is used, for example tablets, capsules, in a similar manner, the following table

Powder, fine granules, granules, syrups, injections (create 3 shown compounds.

Table 3

(CH3CH20) 2CHCH2NHC0C0NHR6

Compound solvent

R6 for the environmental

stallization

-H -CH3

- (CH2) 2CH3

-ck

/

ch3

xch3 - (ch2) 3ch3

- (ch2) 4ch3 - (ch2) 5ch3 - (ch2) 7ch3 - (ch2) „ch3

-CH2—

Ethyl acetate

Ethanol

acetone

Acetone n-hexane n-hexane n-hexane n-hexane n-hexane n-hexane

Ethanol n-hexane

Mp (° C)

141-142 135-136 84- 85

111-112 92-93 87- 88 110-111 83- 84

IR (KBr), cm- ': Vc = 0

1650.1635

1645

1645

145-146 1650.1635

1645 1650 1650 1645 1645

154-155 1640

113-114 1655

21st

657 135

Table 3 (continued) (CH3CH20) 2CHCH2NHC0C0NHR6

Connection R6

-ch2ch2oh

: h3: h3

och 3rd

-ch2 ^ o) -och.

Solvents for recrystallization

Ethanol ethanol

M.p. IR (KBr), cm ~ 1: (° C) vc = 0

118-119 -157-158 1645

128-129 1655

(2) A solution of 17.0 g of N-ethanol-N'- (2,2-diethoxy) is collected on crystals by filtration. The crystals of ethyl) -oxamide, obtained according to paragraph (1) above, are dissolved in 85 ml recrystallized from methanol, 6.8 g (0.05 ml of concentrated hydrochloric acid are added from acetic acid. 20% loot: 61.8%) of 4-ethyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazine the mixture is obtained for 30 minutes from melting point 173 to 174 ° C.

river heated to boiling. When the reaction has ended, the IR (KBr), cm-1: vc = 0 1680-1620 solvent is distilled off under reduced pressure. The table in the table below can be removed in a similar manner, and 70 ml of acetone can be added to the residue, which is shown in FIG Make connections.

Table 4

Connection R6

-h -ch3

- (ch2) 2ch3

ch3

-ch (

ch3

- (ch2) 3ch3 - (ch2) 4ch3 - (ch2) 5ch3 - (ch2) 7ch3 - (ch2) „ch3

^ ï>

^ «HN N-R6

w

Solvents for recrystallization

Ethanol acetone

acetone

Mp (° C)

> 280

220-231

182-183

IR (KBr), cm-1: vc-o

1680-1640 1690-1635 1680-1640

215-219 1680.1625

acetone

149-150

1680, 1640

acetone

171-172

1685, 1660, 1620

acetone

141-142

1685, 1660, 1620

acetone

145-146

1670, 1635

Ethanol

145-146

1660, 1625

acetone

254-255

1670, 1635

-CH2- ^ o) acetic acid

-CH2CH2OCOCH3 methanol .CH3

-N ^ ethanol

CH3

225 1665.1635

178-180 1720.1675.1625 229-230 1700-1625

OCH 3

-ch2 - ^) - och3

175-176

1740-1620

657 135 22

(3) a suspension of 5.2 g of 4- (2,4-dimethoxybenzyl) -2,3-dioxo-l, 2,3,4-tetrahydropyrazine, obtained according to paragraph (2) above, in 26 ml of N, 4.1 g of potassium carbonate are added to N-dimethylformamide, and the mixture is stirred at room temperature for 30 minutes. 5.8 g of 4-bromomethyl-5-methyl-1,3-dioxol-2-one are then added, and the mixture is reacted at 50 to 60 ° C. for 3 hours. The reaction mixture is then introduced into a mixed solvent of 200 ml of ethyl acetate and 200 ml of water and the organic layer is separated off, washed with 100 ml of water and dried over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure and the residue is purified by column chromatography (Wako Silica Gel C-200, eluent chloroform), 4.9 g (yield: 66.0%) of l- (2, 4-Dimethoxybenzyl) -4- (5-methyl-2-oxo-l, 3-dioxo-4-yl) methyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazine, melting point 154 to 156 ° C receives.

IR (KBr), cm "1: vc = 0 1820.1675.1630

The compounds shown in Table 5 below can be prepared in a similar manner.

Table 5

Connection R6

IT "

wc "3 vf

CH30- ^ O / ~ CH2 ~ N N_-r6

Mp (° C) IR (KBr), cm "1: vc = o

188-190

1775, 1700, 1650

-CH2OCOC (CH3) 3 100-101 1750, 1690, 1660,

1640

-CH2COOC (CH3) 3 105-106

1740, 1690, 1650

Table 6

s connection R6

W.

hn n-r6 \ = /

M.p. (C) IR (KBr), cm-1: Vc = 0

> 270

-CH2OCOC (CH3) 3 166-167

1790, 1775, 1730, 1690

1740, 1700, 1660

-chicooh

282 (decomposition) 1730, 1670-1630

(5) A solution of 2.6 g of l-carboxymethyl-2,3-dioxo, 1,2,3,4-tetrahydropyrazine in 13 ml of N, N-dimethylacetamide is mixed with 3.9 g of diphenyldiazomethane at room temperature and the mixture is kept for 10 minutes implemented. The reaction mixture is then introduced into a solvent mixture of 25 ml of ethyl acetate and 25 ml of water and the mixture is stirred for 15 minutes. The crystals thus precipitated are collected by filtration and then washed first with 10 ml of ethyl acetate and then with 10 ml of 25 diethyl ether, 2.9 g (yield: 80.4%) of l-diphenylmethyloxycarbonylmethyl-2,3-dioxo-1, 2,3,4-trahydroyprazine with a melting point of 97 to 98 ° C. IR (KBr), cm-1: vc = 0 1750.1675.1645

30 Example 1

(1) A solution of 10 ml of ethyl acetate containing 2.71 g of boron trifluoride is mixed with 2.72 g of 7-aminocephalosporanic acid (hereinafter referred to as 7-ACA) and 1.54 g of 4-ethyl-2,3- dioxo-1,2,3,4-tetrahydropyrazine was added, whereupon the mixture was reacted for 16 hours at room temperature. When the reaction has ended, the reaction mixture is introduced into 50 ml of methanol with cooling, and 3.16 g of pyridine are added dropwise. The precipitated crystals are collected by filtration, 40 are sufficiently washed with 30 ml of methanol and dried, whereby 3.10 g (yield: 88.1%) of 7-amino-3 {[l- (4-ethyl-2,3- dioxo-1,2,3,4-tetrahydropyrazinyl)] -methyl J-A3-cephem-4-carboxylic acid from melting point 191 to 195 ° C. with decomposition.

45 IR (KBr), cm "1: vc = 0 1795.1670.1620 NMR (CF3COOD), 8 values:

1.44 (3H, t, J = 7Hz,> nch2 so 3.69 (2H, bs, C2-H),

jh3)

4.08 (2H, q, J = 7Hz,

(4) In a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole, 3.7 g of l- (2,4-dimethoxy-benzyl) -4- (5-methyl-2-oxo-l, 3-dioxol-4- yl) -methyl-2,3-di-oxo-1,2,3,4-tetrahydropyrazine, obtained according to paragraph (3) above, and the mixture thus obtained is reacted at a temperature of 50 to 60 ° C. for 2 hours . The solvent is then removed by distillation under reduced pressure and 30 ml of diethyl ether are added to the residue. Then the crystals formed are collected by filtration, whereby 2.0 g (yield: 90.9%) of 4- (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl-2,3 -dioxo -1,2,3,4-te-trahydropyrazine with a melting point of 225 to 226 ° C.

IR (KBr), cm "1: vc = 0 1825.1805.1725.1690.1670

The compounds shown in Table 6 below can be prepared in a similar manner.

: nch2ch3)

5,14,5,51 (2H, ABq, J = 15Hz, s

),

5.48 (2H, s, C6-H, C7-H),

60 6.74.7.00 (2H, ABq, J = 6Hz,

)

h h

(2) The reaction to be carried out at the 3-position mentioned in paragraph (1) above is carried out under the reaction conditions shown in Table 7 below, whereby the 7-amino-3- {[1- (4-ethyl -2,3- dioxo-1,2,3,4-tetrahydropyrazinyl)] -methyl j- A3-cephem-4-car-bonic acid is obtained in the yields shown in Table 7.

23

657 135

Table 7

Source material

No. 7-ACA cio solvent acid or complex reaction amount hnn-ch ch medium combination of acid conditions (yield)

2 3

1 2.72 g 1.54 g sulfolane 10 ml boron trifluoride 2.71 g room temperature 2 2.6 g

Hours (73.9%)

2 2.72 g 1.54 g nitromethane boron trifluoride diethyl room temperature 16 2.85 g

14 ml ether complex 5.7 g hours (81.0%)

(3) In a similar way as set out in paragraph (1) above, after the reaction has ended at the 3-digit position, the table 8 shown below is poured into ice water and the pH is adjusted using a level Receive connections. (In this case, the 28% by weight aqueous ammonia solution is obtained from ice-cooling desired compounds by setting the lung to 3.5.)

Table 8

CH2-R2

cooh

No.

connection

R2

Mp CC)

IR (KBr), cm VC = 0

-1

NMR (d, -DMSO) j S values:

0 .0 -N N (CH-) cCH0

\ - / 25 3

189.5-191.0

(Decomposition)

1800, 1680

5

1620

0.87 (3H, t, J = 6Hz,> N (CH2) 5CH3),

1.05-1.49 (8H, m, ^ NCH2 (CH2) 4CH3),

3.44 (2H, bs, C2-H), 3.55-3.88

(2H, in,> NCH2 (CH2) 4CH3), 4.44,

5.05 (2H, ABq, J = 15Hz, Sv]),

CH_ -

4.88 (1H, d, J = 5Hz, Cg-H), 5.06 (1H, d, J = 5Hz, C7-H), 6.71 (2H,

S '>

O O

) —Ì

-N N (CH-) -, CH,

\ = y 2 7

191.5-192.5

(Decomposition)

1800, 1680

5

1620

0.87 (3H, t, J = 6Hz,> N (CH2) 7CH3),

1.03-1.50 (12h, m,> nch2 (ch2) gch3)

3.40 (2H, bs, C2-H), 3.52-3.86

(2H, ia,> NCH2 (CH2) gCH3), 4.43,

5.04 (2H, ABq, J = 15Hz, Svj),

^ ch2-

4.86 (1H, d, J = 6Hz, Cg-H), 5.04 C1H, d, J = 6Hz, C7-H), 6.69 (2H,

s,)

H H

657 135

24th

Table 8 (continued)

o o

-n ^ n (ch2) 4ch3

196-199

(Decomposition)

1800, 1678, 1630

0.91 (3H, t, J = 7Hz,} N (CH2) 4CH3), 1.10-1.95 (6H, m,> NCH2 (CH2) 3CH3), 3.63 (2H, bs, C2- H), 3.77 (2H, t,

J = 7Hz,> NCH2 (CH2) 3CH3), 4.34,

- S-,

4.82 (2H, ABq, J = 15Hz, 1),

ch2-

5.32 (2H, bs, Cg-H, C? -H),

6.76 (2H, bs,)

h h

> 200

3.72 (2H, bs, C2-H), 5.41,

1790, 1655, 1630, 1600

5.72 (2H, ABq, J = 15Hz,

Svi

A

),

CH.

5.47 (2H, s, Cg-H, C? -H), 7.58 (2H, s,)

Measured in CF3COOH

(4) The reaction shown in paragraph (1) above to give 7-amino-3 {[1- (3,6-dioxo-l, 2,3,6-tetrahydro-at the 3-position is described under the of the following Table 9 3S pyridazinyl)] -methyl 1 - A3-cephem-4-carboxylic acid in the reaction conditions shown in, where the following Table 9 yields.

Table 9

No starting material

7-ACA

2.0 g

2.72 g

Painting

acid-

hydrazine

0.91g

1.23 g

solvent

Tri-fluor acetic acid 10 ml

Sulfolan 10 ml

Acid or complex compound of the acid

Boron trifluoride-diethyl ether complex 4.17 g

Boron trifluoride 2.71g

(5) In a similar manner as in paragraph (1) above, the crude crystals mentioned in Table 10 are obtained.

Reaction conditions

Amount (yield)

Room temperature 1.72 g 16 hours (72.3%)

Room temperature 3 hours

2.75 g (84.9%)

Table 10

25th

657 135

No.

Connection r2

1

Vf

-n n-h

2nd

V «0

-n n-ch,

v = y 3

3rd

0 0

y-i

-n n-ch-ch-ch - \ - / 2 2 3

4th

o, 0

y-Ì ^ ch3

-n n-chcf w ^ ch3 ■

5

VY

-n n (ch -), ch,

6

° v P

^ ~~ J ~~ \

7

Vf

-n n (chk) mch, \ / <5 ix j

8th

Vf

-n n-ch-ch.ococh-n '22 3

9

10th

-n n-nc w \ ch3

11

ch,

4th

657 135

26

Table 10 (continued)

0 * 2

Comment:

The compounds shown under numbers 10, 11, 12, 13, 14 and 15 are obtained by reaction using sulfolane as a solvent.

* 1: This compound is obtained by introducing the reaction mixture into methanol, filtering off the insoluble components and adding pyridine to the filtrate.

* 2: This illustration is given because it is not clear whether the chlorine atom is at the 4- or 5-position and whether it is a single compound or a mixture. (The same information applies to the representations shown in the following tables).

* 3: This means that the product consists of a mixture of a compound substituted in the 4-position and a compound substituted in the 5-position.

(In the following tables, the same references refer to the same meanings).

Example 2

A suspension of 3.0 g of 7-amino-3- | [l- (4-ethyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazinyl)] -methyl 1 -A3-ce-

45 phem-4-carboxylic acid, obtained according to example 1- (1) above, in 30 ml of methanol is mixed with 1.62 g of p-toluenesulfonic acid monohydrate in order to obtain a solution which is then slowly mixed with 5 , 0 g of diphenyldiazomethane is added, whereupon the mixture obtained is reacted for 15 minutes at room temperature. When the reaction has ended, the solvent is removed by distillation under reduced pressure and the residue thus obtained is dissolved in a solvent mixture of 20 ml of ethyl acetate and 20 ml of water. The solution is then adjusted to a pH of 7.0 by adding 55 sodium hydrogen carbonate. The organic layer is then separated off and dried over anhydrous magnesium sulfate and the solvent is removed by distillation under reduced pressure. The residue is purified by column chromatography 6o (Wako Silica Gel C-200, eluent: benzene: ethyl acetate = 1: 4 volume ratio), 3.1 g (yield 70.3%) of diphenylmethyl-7-amino-3- { [1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] - methyl) -A3-ce-phem-4-carboxylate with a melting point of 183 to 186 ° C (decomposition at 65 ) receives.

IR (KBr), cm-1: vc = 0 1765.1730.1680.1630 The compounds shown in Table 11 below are obtained in a similar manner.

27th

657 135

Table 11

m,

o 'T ch2r cooch (<^ o)

COOCH (\ 0 / '2

connection

M.p. ("cl

IR (KBr), cm "1: vc = Q

R2

0 O

^ 4

-n nh V = /

129-130 (decomposition)

1765, 1725, 1690, 1630

0 0 ^^

-N N-CH,

\ = / 3

127-128

(Decomposition)

1770, 1725, 1690, 1640

0 O

") —K

-n n (ch,), ch, \ —y 2 2 3

169-171

(Decomposition)

1765, 1730, 1685, 1635

O O

.ch -N NCHCT

w ch3

179-180.5

(Decomposition)

1760, 1720, 1685, 1635

° \ p

-n n (ch -), ch, \ = / 2 3 3

180-189

(Decomposition)

1760, 1725, 1680, 1630

0, 0

-n n (ch,). ch, 'y ..-, / 4 4 J

185-194

(Decomposition)

1765, 1730, 1685, 1630

Q .0} - ^

-N N (CH_), -CH,

\ - - / Ä D J

170-174

(Decomposition)

1765, 1730, 1685, 1635

o, p

-N N (CH_)., CH, 2 7 3

186-188

(Decomposition)

1765, 1730, 1685, 1635

° x 0

-N N (CH.,) ... CH, \ / 2 11 J

164-172

(Decomposition)

1765, 1730, 1685, 1635

W A- \

165-168

(Decomposition)

1765, 1725, 1680, 1625

0 0

/ ~ \

"NV = / N_CH2" \ 0 /

155-160

[Decomposition)

1770, 1725, 1680, 1630

657 135 28

Table 11 (continued)

° v, 0

-N NCH2CH2OCOCH3

146-148

[Decomposition)

1770, 1725, 1678, 1623

0, 0

IM: CH -N N-NC ° CH3

172-175

1760, 1720, 1680, 1630

N

V

0

82-85

(Decomposition)

1775, 1720, 1650

V

108-114

(Decomposition)

1765, 1725, 1650

$

0

132-135 (decomposition)

1780, 1730, 1665

178-181

(Decomposition)

1780, 1730, 1660

0 0

HN'li-CH, HN'li

V * V-

0 0

137-139

(Decomposition)

1780, 1730, 1660

CH,

it?

O

90-93

(Decomposition)

1770, 1720, 1660

CH-CH, <>

O

138-143 (decomposition)

1770, 1720, 1660

Example 3

4.9 g of diphenylmethyl-7-amino-3- [l- (2,3-dioxo-l, 2,3,4-tetrahydropyrazinyl) - me- are dissolved in a solvent mixture of 25 ml of trifluoroacetic acid and 10 ml of anisole. thyl-A3-cephem-4-carboxylate, whereupon the solution is reacted for 2 hours at room temperature. When the reaction has ended, the solvent is removed by distillation under reduced pressure and 50 ml of diethyl ether are added to the residue, whereupon the crystals formed are collected by filtration. The crystals are washed sufficiently with 40 ml of diethyl ether and dried thereupon, 4.25 g (yield: 97.0%) of trifluoroacetic acid salt of 7-amino-3- j [l- (2,3-dioxo-1, 2,3,4-tetrahydropyrazinyl)] - methyl j-A3-cephem-4-carboxylic acid from melting point 105 to 106 ° C (decomposition).

IR (KBr), cm-1: vc = 0 1780.1700-1630 55 NMR (CF3COOD), 5 values:

3.27 (2H, bs, C2-H),

5.14, 5.52 (2H, ABq, J = 15Hz, S) -CH _ j,

60 -

5.44 (2H, S, C6-H, Ct-H),

6,78,6,98 (2H, ABq, J = 6Hz,

65

The compounds shown in Table 12 below are obtained in a similar manner.

29

657 135

Table 12

cf3cooh- h2n-p-j ^ ^ rT

0 COOH

CH2 "R

connection

Mp (° G)

IR (KBr), cm "1: VC = 0

((dg-DMSO + CF COOD) * 1 '

NMR I (CF3COOD 3) * 2)) S values: \ (d g-DMSO + D) * 3,

0, 0

m

-N N-CH, \ = /

10 9-110 (decomposition)

1795, 1680, 1635

3.36 (3H, s,> NCH3), 3.50 (2H, bs, C2-H), 4.53, 5.11 (2H, ABq, J = 15Hz, S "ì),

5.06 (1H, d, J = 5Hz, Cg-H), 5.17 (1H, d,

J = 5Hz, C_-H), 6.73 (2H, bs,) = ^

H H

* 3

O, p

-N N (CH2) 2CH3

152-155 (decomposition)

1780, 1675, 1635

0.91 (3H, t, J = 7HZ,> N (CH2) 2CH3), 1.35-2.08 (2H, m, ^ NCH2CH2CH3), 3.52 (2H, bs, C2-H), 3 , 77 (2H, t, J = 7Hz, ^ nch2CH2CH3),

4.31, 4.86 (2H, ABq, J = 15Hz, Ì),

CHg-

5.35 (2H, bs, Cg-H, C? -H), 6.73 (2H, bs,

H )

H H * 1

° v P

M

-N N-CH '

/ CH3

\

CH_

L59.5-161.5

(Decomposition)

1780, 1680 p

1620

1.46 (6H, d, J = 7Hz,> NCHC ^ C ^ 3),

C5l

3.70 (2H, bs, C, -H),

/ CH3

4.77-5.60 (3H, m,> NCH <, j),

^ CH.-

3 _2

5.46 (2H, bs, C, -H, C ..- H),

/

6.82, 7.04 (2H, ABq, J = 6Hz, v = /

H H

° \ P

m

-N N- (CH.), CH, S— / 2 3 3

158-162

(Decomposition)

1780, 1675, 1635

0.92 (3H, t, J = 7Hz,> N (CH2) 3CH3), 1.10-1.90 (4H, m,> NCH2 (CH ^) 2CH3), 3.62 (2H, bs, C2 -H),

3.75 (2H, t, J = 7Hz,> NCH2 (CH2) 2CH3),

4.56, 5.18 (2H, ABq, J = 15Hz,

5.29 (2H, s, Cg-H, C? -H), 6.70 (2H, bs,)

1 "

<^ ch3-

H H

*1

135

30th

Table 12 (continued)

-n n-

167-169

(Decomposition)

1780, 1680

s

1620

HHH

1.15-2.35 (10H, m,),

3.69 (2H, bs, C2-H),

4.47-5.07 (1H, m, 7Q),

5.21-5.54 (2H, m, S]),

CV

5.47 (2H, s, Cg-H, C? -H),

6.81-6.98 (2H, ABq, 'J = 6Hz,)

H H

* 2

0, 0

"ÎL = / N ~ (CH2) HCH3

138-143 (decomposition)

1775, 1675, 1635

0.89 (3H, t, J = 7HZ,> NCH2 (CH2) 1QCH3), 1.02-1.85 (20H, m, ^> NCH2 (CH2) 10CH3), 3.63 (2H, bs, C2 -H),

3.76 (2H, t, J = 7Hz, ^> NCH2 (CH2) 1QCH3), 4.57, 5.21 (2H, ABq, J = 15Hz,),

C ^ f

5.32 (2H, bs, Cg-H, C7 ~ H), 6.67 (2H, bs,)

H H

*1

O O

-N NCH-CH-OCOCH, V— / i A J

86-91

(Decomposition)

1780, 1725, 1675, 1635

2.03 (3H, s, -OCOCH3), 3.59 (2H, bs, C2-H),

3.86-4.54 (4H, m, ^> NCH2CH20-),

4.57, 5.16 (2H, ABq, J = 15Hz, S> 1),

11

5.28 (2H, bs, Cg-H, C? -H),

6.81 (2H, bs, y = ^>

H H

*1

Q, 0

m: / CH

-n n-n-f "* = / CH.

158-160 (decomposition)

1780, 1680

s

1630

3.34 (6H, s, -N /),

CH3

3.72 (2H, bs, C2-H),

5.12, 5.50 (2H, ABq, J = 15Hz,),

^ CHj-

5.49 {2H, s, Cg-H, C? -H),

7.15 (2H, bs,)

* 2 ~ -

Table 12 (continued)

31

657 135

N

V

119-122

(Decomposition)

1780,

1675 '

*

1640

3.89 (2H, bs, C2-H), 5.26, 5.62 (2H, ABq, J = 15Hz, S ~ 1), 5.52 (2H, s, Cg-H, C? -H ),

C ^ 2 ~

7.93, 8.69 (2H, ABq, J = 5Hz, T ~),

^ H

8.88 (1H, s, yH)

* 2

0

*

CH,

241-243

(Decomposition)

1800, 1660, 1600

2.58 (3H, s, -CH3), 3.73 (2H, bs, C2 ~ H), 5.50 (2H, bs, C2-H), 5.51, 5.93 (2H, ABq, J = 15Hz,),

cv

7.52, 7.79 (2H, ABq, J = 10Hz, ^ ~)

* 2

'0

*

1.36 (3H, t, J = 7Hz, -CH2CH3), 2.90 (2H,

CH2CH3 0

219-222 (decomposition)

1800, 1660, 1600

q, J = 7Hz, -CH2CH3), 3.69 (2H, bs, C2 ~ H), 5.47 (2H, bs, Cg-H, C? -H), 5.48, 5.90 (2H , ABq, J = 15Hz, S-,), 7.48, 7.76 (2H, ABq,

AH7-

vH -

J = 10Hz, iï)

* 2

*

3.70 (2H, bs, C2-H), 5.34, 5.79 (2H, ABq,

1 - 1 - ci

"r

0

> 200

1795, 1640, 1600

J = 16Hz, S>), 5.47 (2H, s, Cg-H, C-j-H),

^ CH, -7.59 (1H, s, ^ -H)

* 2

0 *

2.42 (1.5H, s, -CH3 x 0.5), 2.50 (1.5H, s,

IIN jT 'CH3

V

0

> 200

1795, 1640, 1600

-CH3 x 0.5), 3.73 (2H, bs, C2 ~ H), 5.52 (2H, s, Cg-H, C? -H), 5.63 (2H, bs,),

7.38 (0.5H, s, ^ -H x 0.5), 7.60 (0.5H,

+

s, "^ -H x 0.5)

0

II

* 2

TIi

"N ¥ \

Ï CH3

657 135

Table 12 (continued)

32

**

O 0

H

—U NH

\ = y

139-140 (decomposition)

1780, 1710, 1690

S

1620

3.46 (2H, bs, C2-H), 4.47, 5.07 (2H, ABq, J = 15Hz,), 5.04 (1H, d, J = 5Hz,

AcHg "

Cg-H), 5.20 (1H, d, J = 5Hz, C? -H), 6.34,

6.59 (2H, ABq, J = 6Hz,) = ()

H H

* 3

**

0 0

H

-N N-CH,

\ = / 3

152-155

(Decomposition)

1780, 1690, 1660, 1620

3.35 (3H, s,> NCH3), 3.48 (2H, bs, C2 ~ ü), 4.50, 5.12 (2H, ABq, J = 15Hz, S-.),

^ CH2-

4.87 (1H, d, J = 5Hz, Cg-H), 5.03 (1H, d,

J = 5Hz, C7-H), 6.70 (2H, bs,) = <)

H H

* 3

Comment:

* = Free connection; the desired compounds are obtained by reaction in a solvent mixture of trifluoroacetic acid and anisole, subsequent removal of the solvent, dissolving the residue in water and adjusting the pH to 3.5 with the aid of 28% aqueous ammonia solution.

** = free connection; obtained by treating the trifluoroacetic acid salt with pyridine in methanol.

Example 4

To a suspension of 5.0 g of 7-amino-3-j [1- (3-methyl-6-oxo-1,6-dihydropyridazinyl)] methyl 1 -A3-cephem-4-carboxylic acid in 15 ml of acetone 2.36 g of 1,8-diazabi-cyclo- [5,4,0] -7-undecene and 4.51 g of pivaloyloxymethyl iodide are added at 10 to 15 ° C., and the mixture is reacted for 30 minutes. After the reaction has ended, the reaction mixture is introduced into a solvent mixture of 50 ml of water and 50 ml of ethyl acetate and the organic layer is separated off, washed with water and then dried over anhydrous magnesium sulfate. 10 ml of a solution containing 1.40 g of oxalic acid in ethyl acetate are then added, and the crystals formed are collected by filtration and washed with ethyl acetate. In this way, 4.59 g (yield: 56.2%) of oxalic acid salt of pivaloyloxymethyl-7-amino-3-1 [1- (3-methyl-6-oxo-1,6-dihydropyridazinyl)] - methyl) -A3-cephem-4-car-boxylates melting point 145 to 147 ° C (decomposition).

IR (KBr), cm-1: vc = Q 1790, 1750, 1660

NMR (d6-DMSO), S values:

1.21 (9H, s, -CH3 x 3).

2.29 (3H, s ,,> - CH3),

3.52 (2H, bs, C2-H),

S> -

4,94,5,33 (2H, ABq, J = 15Hz ,, ^ _CH _

5.14 (1H, d, J = 5Hz, C6-H),

5.76-6.23 (3H, m, C7 H, -0CH20-),

30 7,01,7,53 (2H, ABq, J = 10Hz ,, '

7.44 (3H, bs, -NH3®)

Example 5

35 (1) A solution of 2.69 g l- (5-methyl-2-oxo-1,3-di-oxol-4-yl) methyl-2,3-dioxo-1,2,3,4 -tetrahydropyrazine in 27 ml of N, N-dimethylformamide is mixed with 1.52 g of potassium carbonate and the resulting mixture is stirred for 20 minutes at room temperature. Then 4.70 g of tert-butyl-7-phenylacetamido-3-bromomethyl-A2-cephem-4-carboxylate are added under 40 ° ice cooling, and the mixture is reacted for 2 hours at room temperature. The reaction mixture is introduced into a solvent mixture of 200 ml of ethyl acetate and 150 ml of water and the 45 organic layer is separated off, washed with 150 ml of water and then dried over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure and the residue formed is dissolved in 100 ml of chloroform. This solution is then mixed with 2.45 g (degree of purity 70%) of m-chloroperbenzoic acid and the mixture is reacted for 1 hour at room temperature. The solvent is then removed by distillation under reduced pressure and the residue is mixed with 100 ml of ethyl acetate and 100 ml of water. The organic layer is separated, washed with 100 ml of water and then dried over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure and the residue formed is purified by column chromatography 60 (Wako Silica Gel C-200, eluent chloroform), 2.70 g (yield: 43.2%) of tert-butyl-7 -phenylacetamido-3- | [l- [4- (5-methyl-2-oxo-l, 3-dioxol-4-yl) - methyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazinyl] ] -methyl] - A3-cephem-4-carboxylate-l-oxide of melting point 65 1 35 to 136 C (decomposition).

IR (KBr), cm-1: vc = 0 1820.1790.1720.1685.1650 (2) 3.0 g of tert.- are dissolved in a solvent mixture of 12 ml of N, N-dimethylformamide and 6 ml of acetonitrile. Bu-

33

657 135

tyl-7-phenylacetamido-3-j [1- [4- (5-methyl-2-oxo-l, 3-dio-xol-4-yl) - methyl-2,3-dioxo-l, 2,3 , 4-tetrahydropyrazinyl]] - methyl) - A3-cephem-4-carboxylate-l-oxide. Then 1.0 g of stannous chloride and then 1.58 g of acetyl chloride are added to this solution while cooling with ice and the mixture is reacted for 30 minutes at room temperature. The solvent is then removed by distillation under reduced pressure and 50 ml of ethyl acetate and 50 ml of water are added to the residue, whereupon the resulting mixture is adjusted to a pH of 6.0 using sodium hydrogen carbonate. The organic layer is then separated off, washed with 50 ml of water and then dried over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure and the residue is purified by column chromatography (Wako Silica Gel C-200, eluent toluene: ethyl acetate = 3: 2 by volume), with 2.12 g (yield: 72.4%) .-Butyl-7-phenylacetamido-3 - ([l- [4- (5-methyl-2-oxo-l, 3-dioxol-4-yl) - methyl-2,3-dio-xol, 2 , 3,4-tetrahydropyrazinyl]] - methyl] - A3-cephem-4-car-boxylate of melting point 120 to 122 ° C (decomposition).

IR (KBr), cm-1: vc = 0 1820.1775.1715.1685.1645

NMR (CDC13), S values:

10th

15

1.58 (9H, s, -C (CH3) 3),

2.28 (3H, s, -CH3)

3,17,3,61 (2H, ABq, J = 18Hz, C2-H),

s 3.77 (2H, s ,, <0 / -ch2-),

4.53, 5.13 (2H, ABq, J = 15Hz ,, ^]

4.71 (2H, s ,,> NCH2-),

/ -ch2- '

5.03 (IH, d, J = 5Hz, C6-H),

5.93 (IH, dd, J = 5Hz, J = 8Hz, CV-H),

6.53.6.89 (2H, ABq, J = 6Hz ,,} = {* '

h h

7.32 - 7.51 (5H, m ,,

20 7.57 (IH, d, J = 8Hz, -CONH-)

In a manner similar to that described in paragraph (1) and paragraph (2) above, the compounds found in Table 13 below can be prepared.

25th

Table 13

<g ^ CH2CONH ^ Ç ^

cooc (ch3) 3

ch0n n-r6

2 \ = /

connection

Mp (° c)

IR (KBr),

dfi-DMSO *

NMR (CDC1 ** >> 8 values:

R6

cm ~ 1; vc = 0

1.52 (9H, s, -C (CH3) 3), 3.57 (4H, bs.

-r

180-183

(Decomposition)

1780, 1710, 1700, 1680, 1645

C2-H, @ -CH2 ~), 4.30, 5.12 (2H, ABq, J = 15Hz, S), 5.12 (IH, d, J = 5Hz, CH2-

Cg-H), 5.75 (IH, dd, J = 5Hz, J = 8Hz, C7 ~ H),

6.07, 6.54 (2H, ABq, J = 6Hz,) == <'),

H H

7.12-7.45 (5H, m, - (o)), 7.57-8.14 (5H, m, ^) '(IH, ä, J = 8Hz,

-CONH-)

*

657 135

Table 13 (continued)

34

1.21 (9H, s, -C (CH3) 3), 1.56 (9H, s,

-CH2OCOC (CH3) 3

105-108

(Decomposition)

1780, 1740, 1730, 1660

—C (CH3) 3), 3.22, 3.61 (2H, ABq, J = 18Hz, C2-H), 3.71 (2H, s, <g> -CH2-), 4.58, 5 , 11 (2H, ABq, J = 15Hz,), 5.03 (1H,

•OH,-

d, J = 5Hz, Cg-H), 5.81 (2H, s, ^ NCH2 ~),

5.93 (1H, dd, J = 5Hz, J = 9Hz, C7 ~ H), 6.55,

6.88 (2H, ABq, J = 7Hz,) = (), 7.14 (1H,

H H

d, J = 9Hz, -CONH-), 7.43 (5H, 3, - (5))

• kit

1.53 (9H, s, -C (CH3) 3), 3.27 (2H, bs,

-CH2COOCH (^ (5)) 2

124-129

(Decomposition)

1770, 1730, 1685, 1650

C2-H), 3.61 (2H, s, (Ö} -CH2-), 4.54 (2H, s,> NCH2-), 4.91 (2H, bs,),

• 2 ^ CH2-

5.18 (1H, d, J = 5Hz, Cg-H), 5.86 (1H, dd,

J = 5Hz, J = 8Hz, C7-H), 6.12, 6.59 (2H, ABq,

J = 6Hz, y = Ci, 6.88 (1H, s, -CH <-), H H X

6.96-7.47 (15R, m, - ^) x 3), 7.95 (1H,

d, J = 8Hz, -CONH-)

**

(3) 2.0 g of tert-butyl-7-phenylacetamido-3- | [1- (4- (5-methyl-2-oxo-l, 3-dioxol-4-yl) is dissolved in 30 ml of anhydrous methylene chloride ) -methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl]] - methyl 1 -A3-cephem-4-carboxylate, then this solution is mixed with 1.59 g of N, N-dimethylaniline and then with 0.57 g of trimethylsilyl chloride was added and the resulting mixture was stirred at room temperature for 1 hour, then the reaction mixture was cooled to -40 ° C. and then 0.89 g of phosphorus pentachloride was added, and the mixture was then stirred for 21 hours at a temperature of - 30 ° C. to -20 ° C. The reaction mixture is then cooled to a temperature of -40 ° C., 5.2 g of anhydrous methanol are then added, and the reaction is continued for 1 hour while cooling with ice 20 ml of water are added and the mixture is stirred for a further 30 minutes, after which the reaction mixture is adjusted to a pH of 0.5 using 6N hydrochloric acid d then the watery

Layer separated. This aqueous layer is now with

50 ml of ethyl acetate are added and the mixture is adjusted to a pH of 6.5 with sodium hydrogen carbonate. The organic layer is separated, washed with 50 ml of water and then dried over anhydrous magnesium sulfate. Then the solvent is obtained by distillation

45 removed under reduced pressure and 50 ml of diethyl ether were added to the residue. The crystals are collected by filtration. In this way, 1.05 g (yield: 64.8%) of tert-butyl-7-amino-3- {[1- (4- (5-methyl-2-oxo-1,3-dioxol- 4-yl) -methyl-2,3-dioxo-l, 2,3,4-tetrahydropy-50 razinyl]] - methyl] -A3-cephem-4-carboxylate, melting point 185 to 188 ° C (decomposition).

IR (KBr), cm-1: vc = 01820.1765.1705.1690.1635 NMR (CDC13 + d6-DMSO), 8 values:

1.52 (9H, s, -C (CH3) 3), 2.24 (3H, s, -CH3),

55 3.46 (2H, bs, Qr-H), 4.35.5.08 (2H, ABq,

J = 15Hz, S "1) r

^ CH2-

4.76-5.09 (4H, m,> NCH2-, Q-H, C7-H),

The compounds shown in Table 14 can be prepared in a similar manner.

35

657 135

Table 14

it m ^ S ^ 0 0

2 L x 6

> -N ^ -CH0N N-R6

T 2w

C00C (CH3) 3

connection

Mp (° C)

XR (KBr), cm "1: VC = 0

d -DMSO *

NMR (CDC1 **) s S values:

R6

IT

111-113 (decomposition)

1780, 1710, 1690, 1650

1.50 (9H, s, -C (CH3) 3), 3.48 (2H, bs, C2 "H), 4.28, 5.07 (2H, ABq, J = 15Hz,),

CH2-

4.82 (1H, d, J = 5Hz, Cg-H), 5.03 (1H, d, J = 5Hz, C? -H), 6.08, 6.55 (2H, ABq, J = 6Hz , ^) i 7.58-8.12 (5H, m, ^

-CH2OCOC (CH3) 3 ***

(Hydrochloride)

132-134

(Decomposition)

1775, 1740, 1715, 1695, 1640

1.17 (9H, s, -C (CH3) 3), 1.53 (9H, s, -C (CH3) 3), 3.67 (2H, bs, C2 ~ H), 4.41, 5 , 13 (2H, ABq, J = 15Hz,),

^ CH2-

5.30 (2H, s,> NCH2-), 5.75 (2H, bs, Cg-H,

C - H), 6.80 (2H, bs,) / = ()

H H

*

-ch2cooch (<o)) 2

160-163 (decomposition)

1780, 1760, 1715, 1690, 1650

1.54 (9H, s, -C (CH3) 3), 1.74 (2H, bs, -NH2), 3.05, 3.48 (2H, ABq, Js = 18Hz, C2 ~ H),

4.40, 4.99 (2H, ABq, J = 15Hz,),

CH ^ -

4.55 (2H, s,> NCH2-), 4.65 (1H, d, J = 5Hz,

Cg-H), 4.84 (1H, d, J = 5Hz, C? -H), 6.09,

6.62 (2H, ABq, J = 6Hz, \ => (), 6.85 (1H,

H H

s, -CH <^), 7.17-7.31 (ÎOH, m, x 2)

**

*** The imino ether compound is poured into water and the separated chlorohydrate is isolated.

Example 6

(1) 2.29 g of 2- (2-formamidothiazol-4-yl) -2- (syn) -methoxyiminoacetic acid are dissolved in 2.29 ml of N, N-dimethylacetamide and 4.58 ml of acetonitrile and the solution thus obtained is added dropwise 1.62 g of phosphorus oxychloride are added and the mixture is reacted for 1 hour at a temperature of -5 ° C to 0 ° C. Then this reaction mixture with 5.18 g of diphenylmethyl-7-amino-3- {[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] - methyl j-A3-cephem -4-carboxylate and added for 1 hour

- 5 ° C to 0 C implemented. After the 60 reaction has ended, the reaction mixture is introduced into a solvent mixture of 80 ml of water and 80 ml of ethyl acetate and the resulting solution is adjusted to a pH of 6.5 using sodium hydrogen carbonate. The organic layer is then separated off and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and 60 ml of diethyl ether are added to the residue. The crystals formed are then collected by filtration, whereby

657135 36

6.05 g (yield: 83.0%) of diphenylmethyl-7- [2- (2-form-amidothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3 - {[l- (4- ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] - methyl} -A3-cephem-4-carboxylate from melting point 165 to 168 ° C. s

IR (KBr), cm "1: vc = 0 1780.1720.1680.1640 NMR (d6-DMSO), 5 values:

; n-ch2chì),

1.18 (3H, t, J = 7Hz ,,

3.59 (2H, bs, C2-H), 3.72 (2H, q, J = 7Hz,> n-ch2ch3), 3.97 (3H, s, -OCH3),

15

4.42.5.04 (2H, ABq, J = 15Hz,

),

ch2-

5.30 (IH, d, J = 5Hz, Q-H),

6.02 (1H, dd, J = 5Hz, J = 8Hz, Cr-H),

6,50,6,62 (2H, ABq, J = 6Hz „> = /

h ä

),

7.04 (1H, s, -ch <),

N — 77—

7.17-7.82 (llH, m, - <Ö> * 2,> »

s h

8.63 (IH, s, HCO-),

9.89 (IH, d, J = 8Hz, -CONH-),

12.68 (IH, bs, HCONH-)

The connections shown in the following tables 20, 15, 16 and 17 can be made in a similar manner.

Table 15

hconh-

J

fJL

-conh

■ r4 n.

ch2r

Still,

cooch ((o)) 2 (syn-isoraer)

connection

Mp (° c)

IR (KBr), cm-1:

vc = o

R2

R4

u

-N N-CH,

\ = / 3

H

120-125

(Decomposition)

1780, 1720, 1680-1640

0.0 yy /

-N N- (CH.). CH, 2 4 3

H

■ 154-156

(Decomposition)

1785, 1720, 1685, 1645

O O

M

-N N (CH_) cCH,.

\ / Z D J

H

131-136

(Decomposition)

1783, 1725, 1680, 1645

OO

-Q, (CH2) 7CH3

H

180-182

(Decomposition)

1780, 1720, 1680-1640

u

-N N- (CH _) ,, CII,

r- / JLX J

H

158-166 (decomposition university »)

1780, 1725, 1675, 1640

H

- \ J ~ CH2- {O)

H

126-138

1785, 1725, 1685, 1650

Table 15 (continued)

37

657 135

0, 0

} -K

-n n-ch_ch, \ - / 2 3

Br

142

(Decomposition)

1780, 1720, 1675, 1640

0

V

0

H

171-173

(Decomposition)

1780, 1720, 1690-1650

ch-0

H

148-151

(Decomposition)

1780, 1730, 1690, 1660

ch3

ch3

r j "V

0

H

191-195

(Decomposition)

1775, 1720, 1670

Table 16

? h3 n-ry-c-conh — i — rs "i ch ^ -c-oconh- ^ J J J iX ¥ 2

CH3 \ 0 1 / —v OR C00CH <(Q)

(syn-isomer)

connection

IR (KBr), cm "1:

vc = o

R2

Rl8

Mp (° c)

U

-n nh \ = /

-ch3

176-179

(Decomposition)

1780, 1720, 1680, 1640

0 0

y-i

- ^ - m2) 2cn2

"CHS

152-155

(Decomposition)

1780, 1720, 1680, 1640

0 0

M / ch

-n nchc ^ \ CH3

-ch3

158-160

(Decomposition)

1780, 1720, 1680, 1640

o o h - * (

-nwn- (ch2) 3ch3

-ch3

166-167

(Decomposition)

1780, 1720, 1685, 1645

657 135

38

Table 16 (continued)

o 0

_y \

-nwn- ^ h}

-ch3

162-165

(ZflTiCtKUriR)

1780, 1720, 1680, 1640

U

-n n-chocho0c0tt \ —✓ 2 2

"ch3

[3rd

145-147

(Decomposition)

1780, 1720, 1682, 1640

o 0.

M

-N_N- (CH2) 7CH3

-ch3

138-144

(Decomposition)

1780, 1715, 1690, 1620

W / ch3

-n n-tk w h3

-ch3

88-90

1780, 1720, 1690-1620

o 0

M

-n n-ch_ch, - / 2 3

-ch2c i 131

3 (decomposition)

1786, 1723, 1684, 1645

ch-ch,

i 2 3

.0

II

0

-ch3

118-120

(Decomposition)

1780, 1720, 1660

0

hn ^ V

O

-ch3

190-192

(Decomposition)

ì780, 1720, 1665

0

hn ^ vch,

V

0

'4-,

0

"ch3

183-185

(Decomposition)

1780, 1720, 1670

O

1

-ch,

128-131

(Decomposition)

1780, 1720, 1680, 1660

39 657135

Table 17

ch,

I N-ii-c '

CH, CH, C-OCONH-e '| (

3 2 | s-u ph \

3 ochj cooc (ch3) 3

(syn isomer)

connection

Mp (° C)

IR (KBr), cm-1: VC = 0

R2

w

-N N — CH ^ ctCH,

2r \ 3

° Y °

0

141-143

(Decomposition).

1815, 1775, 1710, 1680, 1640

O 0

M / ° v ° -NWN \ _y

154-156

(Decomposition)

1775, 1710, 1700, 1680, 1650

O 0

-N N-CH-OCOC (CH,) n 2 3 3

85-88

(Decomposition)

1785, 1730, 1715, 1660

O O

-N_N-CH2COOCH ((o)) 2

144-146

(Decomposition)

1775, 1745, 1715, 1690, 1650

(2) A solution of 6.05 g diphenylmethyl-7- [2- (2-formamidothiazol-4-yl) -2- (syn) - methoxyiminoacetamido] -3 | [l- (4-ethyl-2,3- dioxo-l, 2,3,4-tetrahydropyrazinyl)] -methyl) -A3-cephem-4-carboxylate in 31 ml of methanol is mixed with 0.5 ml of concentrated hydrochloric acid and the mixture for 2 hours at 35 ° C. Implemented. When the reaction is complete, the solvent is removed by distillation under reduced pressure. This residue is then mixed with 100 ml of ethyl acetate and 100 ml of water and the resulting solution is adjusted to a pH of 6.0 by adding sodium bicarbonate. The organic layer is then separated off and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and 50 ml of diethyl ether are added to the residue. The crystals formed are collected by filtration, 5.1 g (yield: 87.7%) of diphenyl-methyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) - methoxyimino-acetamido ] -3-1 [1- (4-ethyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazinyl)] methyl) -E3-cephem-4-carboxylate, melting point 165-167 ° C receives.

IR (KBr), cm-1: vc = 0 1780.1720.1680.1640

NMR (d6-DMSO), Ô values:

1.18 (3H, t, J = 7Hz,> n-ch2ch3),

40

3.55 (2H, bs, C2-H),

3.75 (2H, q, J = 7Hz,> n-ch2ch3),

45

3.90 (3H, s, -OCH3),

4.41, 5.02 (2H, ABq, J = 15Hz, S \),

<# s * -ch2-

50

5.26 (IH, d, J = 5Hz, C6-H),

6.01 (1H, dd, J = 5Hz, J = 8Hz, Q-H),

6.52.6.65 (2H, ABq, J = 6Hz, \ = / ''

55 H H

6.88 (IH, s, N.X.

s h

7.07 (IH, s, -ch <),

60

7.15-7.84 (10H, m, - @ x2),

9.81 (IH, d, J = 8Hz, -CONH-)

The compounds given in Table 18 can be prepared in a similar manner.

: 657 135

40

Table 18

n-r c-conh t — s p

HHl7î o ^ Q ^ ch2r2

\> CH3 COOCH ((5)) 2

(syn-ïsonian)

connection

IR (KBr), cm 1:

vc = o

R2

R4

Mp (° c)

u

-n n-ch,

H

158-166 (decomposition)

1780, 1720, 1680, 1640

o o

M:

-n = J- (ch2) 4ch3

H

151-156

(Decomposition)

1780, 1720, 1680, 1640

0 0

-n n— (ch_) cch, \ - / 2 = 3

H

150-156

(Decomposition)

1780, 1720, 1680, 1640

0 0

M

-n n- (ch _),., ch,

\ / 2. XX o h

168-175

(Decomposition)

1775, 1723, 1685, 1640

0 p h ~ (/ ~ \

-n = ncH2- ^ Oj)

H

161-166

1780, 1720, 1680, 1640

0 O

M

-n nch0ch-2 3

t

Br

146

(Decomposition)

1780, 1720, 1680, 1640

-O

0

H

175-178

(Decomposition)

1780, 1720, 1685 -1660

X3

0

H

146-148

(Decomposition)

1780, 1720, 1660

(3) 5.1 g of diphenylmethyl-7 [2- (2-aminothiazol-4-yl) -2- (syn) - are dissolved in a solvent mixture of 25.5 ml of trifluoroacetic acid and 7.86 g of anisole methoxyimino-acetamido] -3 j [l- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] -methyl j-A3-cephem-4-carboxylate, after which the solution was dissolved Hours at room temperature. When the reaction is complete, the solvent is removed by distillation under reduced pressure. This residue is then mixed with 40 ml of diethyl ether 65 and the crystals formed are collected by filtration, whereby 4.3 g (yield 91.1%) of trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) - 2- (syn) - methoxy-iminoacetamido] -3-i [l- (4-ethyl-2,3-dioxo-l, 2,3,4-tetrahy-

dropyrazinyl)] - methyl} -A3-cephem-4-carboxylic acid from melting point 155 to 157 ° C (decomposition). IR (KBr), cm-1: vc = 01775.1710-1630 NMR (d6-DMSO), 5 values:

1.21 (3H, t, J = 7Hz,> n-ch2ch3),

3.52 (2H, bs, C2-H), 3.73 (2H, q, J = 7Hz,

3.96 (3H, s, -OCH3),> n-ch2ch3),

4,44,5,12 (2H, ABq, J = 15Hz,> <

j ~ c h2-

41

657 135

5.21 (IH, d, J = 5Hz, Q-H, 5.83 (1H, dd, J = 5Hz, J = 8Hz, Ct-H),

5.86 (3H, bs -NH3® 6.71 (2H, bs,

H H

),

6.95 (IH, s,), 9.90 (1 H, d, J = 8Hz, -CONH-)

n

S H

The compounds listed in Tables 19 and 20 below can be prepared in a similar manner.

Table 19

cf, cooh.h, n-f ^. II j ns rq n

-conh

7Ç-

ch2-r2

och

COOH (s yn-1sorner)

connection

IR (KBr), cm "^: v

C = 0

NMR (dg-DMSO), S-T .. * erte:

R2

R4

Mp (° C)

3.34 (3H, s,> N-CH3), 3.51 (2H, bs, C2 ~ H),

0 0

} ~ i

-N N-CH, vw 3

H

95-102

1773, 1670, 1660, 1640

4.00 (3H, s, -OCH3), 4.52, 4.90 (2H,

(Decomposition)

ABq, J = 15Hz, S> | ), 5.25 (IH, d,

y CH, -

J = 5Hz, Cg-H),

5.90 (IH, dd, J = 5Hz, J = 8Hz, C? -H),

6.68 (2H, bs, V = <), 6.99 (IH, s, NT),

SS si

9.85 (IH, d, J = 8Hz, -CONH-)

0.86 (3H, t, J = 7Hz,> N- (CH2) 4CH3), 1.05-

0 0

M

"iLJ '- (CH2) 4CH3

H

115-125 (decomposition)

1770, 1670, 1660, 1635

1.85 (6H, m,> N-CH2 (CH2) 3CH3), 3.53 (2H, bs, C2-H), 3.73 (2H, t, J = 7Hz,

> N-CH2 (CH2) 3CH3), 3.93 (3H, s, -OCH3), 4.40, 5.05 (2H, ABq, J = 15Hz, Svi),

J-CH2-

5.20 (IH, d, J = 5Hz, Cg-H),

5.86 (IH, dd, J = 5Hz, J = 8Hz, C7 "H), 6.68

(2H, bs,> = <), 6.95 (IH, s, NTT),

S S sAH

9.85 (IH, d, J = 8Hz, -CONH-)

135

Table 19 (continued)

42

o o

-nwn- (ch2) 5ch h

155-160 (decomposition)

1770, 1670, 1655, 1630

0.87 (3H, t, J = 7Hz,> N- {CH2) 5CH3), 1.04-1.85 (8H, m,> NCH2 (CH2) 4CH3), 3.53 (2H, bs, C2 -H), 3.77 (2H, t, J = 7Hz,> NCH2 (CH2) 4CH3), 3.97 (3H, s, -OCH3), 4.47, 5.13 (2H, ABq, J = 15Hz, Ss]),

X- ch2-

5.23 (1H, d, J = 5Hz, Cg-H), 5.82 (1H, dd,

J = 5Hz, J = 8Hz, C? -H), 6.44 (3H, bs,

-NH3®), 6.70 (2H, bs,) o (), 6.95 (1H, s,

H H

), 9.85 (IH, d, J = 8Hz, -CONH-)

S H

O O -nwn- (ch2) llch3

140-147

(Decomposition)

1770,

1675

1635

0.87 (3H, t, J = 7Hz,> N- (CH2) l; LCH3), 1.04-1.84 (20H, m,> NCH2 (CH2) 10CH3), 3.51 (2H, bs , C2-H), 3.72 (2H, t, J = 7Hz,> NCH2 (CH2) 1QCH3), 3.92 (3H, s, -OCH3), 4.45, 5.05 (2H, ABq, J = 15Hz,

X

),

ch2-

5.20 (IH, d, J = 5Hz, Cg-H), 5.80 (IH, dd,

J = 5Hz, J = 8Hz, C? -H), 6.15 (3H, bs,

-NH, ®), 6.67 (2H, bs,> = (), 6.88 (IH,

H H

s, Nu), 9.75 (IH, d, J = 8Hz, -CONH-) S H

O O

-0 "CH2 <ô)

130-135 (decomposition)

1770, 1670, 1635

3.52 (2H, bs, C2-H), 3.91 (3H, s, -OCH3),

4.41, 4.98 (2H, ABq, J = 15Hz,.),

j-CHj-

4.95 (2H, s, -CH ^ - ^ O)), 5.19 (IH, d, J = 5Hz, Cg-H), 5.82 (IH, dd, J = 5Hz, J = 8Hz, C? —H), 6.15 (3H, bs, -NH3®), 6.68 (2H, bs, y => (), 6.90 (IH, s, Nl ~), 7.35 (5H ,

s s g H

bs,), 9.75 (IH, d, J = 8Hz, -CONH-)

O O

IMI

-NwNCH2CH3

Br

147

(Decomposition)

1775, 1680, 1640

1.21 (3H, t, J = 7Hz,> NCH2CH3), 3.50 (2H, bs, C2-H), 3.81 (2H, q, J = 7Hz,> NCH2CH3),

3.91 (3H, s, -OCH3), 4.42, 5.10 (2H, ABq,

J = 15Hz

'I

), 5.19 (IH, d, J = 5Hz,

ch2-

43

657 135

Table 19 (continued)

: g-H), 5.95 (lHf dd, J = 5Hz, J = 8Hz, C? -H),

5.67 (2H, bs,), 9.64 (1H, d, J = 8Hz, H H

-CONH-)

3.34 (2H, bs, C2-H), 3.89 (3H, S, -OCH3),

• 0

-v

H

195-198

(Decomposition)

1775, 1710,

1690?

1630

4.99 (2H, bs, ^ 1), 5.12 (IH, d, J = 5Hz, J-CH ^ -

Cg-H), 5.75 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.84 (IH, s,), 6.89, 7.10 (2H, ABq,

0

S H J = 10Hz,),

9.70 (1H, d, J = 8Hz, -CONH-)

2.31 (3H, s,) - CH3), 3.44 (2H, bs, C2 ~ H),

1770,

3.96 (3H, S, -OCH3), 4.98, 5.40 (2H, ABq,

CH-

4th

H

188-189

(Decomposition)

1710, 1680;

1630 ■

J = 15Hz, S "1), 5.23 (1H, d, J = 5Hz, j-CH ^ -

Cg-H), 5.88 (IH, dd, J = 5Hz, J = 8Hz, C? -H),

0

6.17 (3H, bs, -NH3®), 6.95 (IH, s, ^),

s ä

7.00, 7.50 (2H, ABq, J = lQHz, Xh 5 '9.87 (IH, d, J = 8Hz, -CONH-)

2.22 (3H, s, -CH3), 3.46 (2H, 'bs, Cj-H),

0 0

u

-N N-CHr7 = rCH, S = / 2M 3

V

0

H

151-154 (decomposition)

1820, 1775, 1685, 1640

3.90 (3H, s, -OCH3), 4.42, 5.05 (2H, ABq,

J = 15Hz, Sni), 4.78 (2H, s,> NCH2-), j-CH ^ -

5.18 (IH, d, J = 5Hz, Cg-H), 5.80 (IH, dd,

J = 5Hz, J = 8Hz, C - H), 6.64 (2H, s,) = ('),

H H

6.84 (IH, s,), 9.78 (IH, d, J = 8Hz, S H

-CONH-)

135

Table 19 (continued)

44

3.59 (2H, bs, C2-H), 3.99 (3H, s, -OCH3),

0 0

M / ° v -NwN-O = 0

H

175-180 (decomposition)

1770,

1700?

1630

4.48, 5.19 (2H, ABq, J = 15Hz, S-j),

5.27 (IH, d, J = 5Hz, Cg-H), 5.94 (IH, dd,

J = 5Hz, J = 8Hz, Cy-H), 6.15, 6.68 (2H, ABq.

J = 6Hz, y = i), 6.99, (IH, s, NY), H H J1 - - S - "- H

7.66-8.19 (5H, m,.. 4 ^ 0), 9.92 (IH, d, J = 8Hz, -CONH-)

O 0} - {

-N N-CH.OCOC (Cl 2

H i3) 3

108-110 "(decomposition).

1780, 1730, 1690, 1650

1.18 (9H, s, -C (CH3) 3), 3.54 (2H, bs, C-j-H),

3.98 (3H, s, -OCH,), 4.49, 5.17 (2H, ABq,

s.

J = 15Hz, I), 5.29 (IH, d, J = 5Hz,

S ~ Cn_2 ~

Cg-H), 5.77 (2H, s,> NCH2-), 5.90 (IH, dd, J = 5Hz, J = 8Hz, C? -H),

6.79 (2H, bs, 7.02 (IH, s ,,), ~ ~ S H

9.99 (IH, d, J = 8Hz, -CONH-)

3.51 (2H, bs', C2-H), 3.96 (3H, s, -OCH3),

0 0

-N ^ -CH.COOH s = / 2

H

161-166 (decomposition)

1770, 1680, 1640

4.52, 5.15 (2H, ABq, J = 15Hz,),

4.54 (2H, s,> NCH2-), 5.27 (IH, d, J = 5Hz, Cg-H), 5.88 (IH, dd, J = 5Hz, J = 8Hz, C? -H ), 6.75 (2H, s,) CD {), 6.98 (IH, s,),

S. S

9.92 (IH, d, J = 8Hz, -CONH-)

45

657 135

Table 20

N-rr-C CONH-

cf3cooh-h2n-

S "N

V18

ch2-r "

COOH (Syr. Isoreer)

connection

, 18th

Mp (° c)

IR (KBr),

cm_1: VC = 0

NMR (dg-DMSO), 6 values:

O 0 -N N- (CH2) 2CH3

-CH.

1S5-167

(Decomposition

1770,

1710?

1630

0.90 (3H, t, J = 7Hz,> N-CH2CH2CH3), 1.32-2.01 (2H, m,> NCH2CH2CH3), 3.53 (2H, bs, C2-H), 3.73 (2H, t, J = 7Hz,> N-CH2CH2CH3), 3.96 (3H, s, -OCH3), 4.48, 5.14 (2H, ABq,

J = 15Hz

'X

), 5.14 (IH, d, J = 5Hz,

ch2-

Cg-H), 5.91 (IH, dd, J = 5Hz, J = 8Hz, C? -H),

6.24 (3H, bs, -NH, ®), 6.69 (2H, bs,> CD () J H H

6.92 (IH, s, N ^) '9.82 (IH, d, J = 8Hz, -CONH-)

S H

o O

M / 3

• N N-CH

-ch3

-CH.

160-162 (decomposition)

1770,

1710?

1630

1.25 (6H, d, J = 7Hz,> N-CH (CH3) 2), 3.48 (2H

bs, C2-H), 3.93 (3H, s, -OCH3), 4.44, 5.08 (2H, ABq, J = 15Hz,), 4.64-5.12 (IH,

3-ch.

m,> N-CH (CH3) 2), 5.21 (IH, d, J = 5Hz, Cg-H) 5} 86 (IH, dd, J = 5Hz, J = 8Hz, C? -H), 6.36 (3H, bs, -NH3®), 6.72 (2H, bs, £ = <),

H H

6.91 (IH, s,), 9.79 (IH, d, J = 8Hz,

S H

-CONH-)

O O

• Ö (CH2) 3CH3

-CH,

155-157 (decomposition)

1775, 1710,

1680>

1630

0.89 (3H, t, J = 7Hz,> N (CH2) 3CH3), 1.03-1.93 (4H, m,> N-CH2 (CH2) 2CH3), 3.49 (2H, bs, C2-H), 3.74 (2H, t, J = 7Hz,> NCH2 (CH2) 2CH3), 3.92 (3H, s, -OCH3),

4.41, 5.11 (2H, ABq, J = 15Hz,

),

ch2-

5.21 (IH, d, J = 5Hz, 'Cg-H), 5.81 (IH, dd,

J = 5Hz, J = 8Hz, C_-H), 6.65 (2H, bs,) C = D (),

• • 'H H

6.87 (IH, s, 7.26 (3H, bs, -NH3®),

S H

9.81 (IH, d, J = 8Hz, -CONH-)

135

Table 20 (continued)

46

o o

-ö® — ®

-CH,

175-177

(Decomposition)

1770,

1710>

1630

0.86-2.06 (10H, m,> N

(2H, bs, C2-H), 3.87 (3H, s, -OCH3), 4.20-4.71 (IH, m,> N jQ) / 4.36, 5.11 H

(2H, ABq, J = 15Hz, S-v), 5.14 (3H, bs,

-NH3®), 5.23 (IH, d, J = 5Hz, Cg-H), 5.76

(IH, dd, J = 5Hz, J = 8Hz, C? -H), 6.62 (2H,

bs, \), 6, 80 (IH, s, ^ ~ |), H H A.

- ~ S H

9.66 (IH, d, J = 8Hz, -CONH-)

-n ^ jUch2) 2ococh3

O O

-CH.

105-107

(Decomposition)

1770, 1720, 1710;

1630

1.97 (3H, s, -OCOCH3), 3.44 (2H, bs, C2-H), 3.80-4.42 (4H, m,> NCH2CH20-), 3.91. (3H, s, -OCH3), 4.41, 5.04 (2H, ABq, J = 15Hz,

JcH), 5.15 (IH, d, J = 5Hz, Cg-H), 5.79

(IH, dd, J = 5Hz, J = 8Hz, C? -H), 6.59 (2H, bs,

> = <), 6.88 (IH, s, NT ~), 7.38 (3H, bs, H H

S H

©,

-NH3W), 9.75 (IH, d, J = 8Hz, -CONH-)

O O

■ yja

NwN (CH2) 7CH3

■ CH,

131-135

(Decomposition)

1775, 1670, 1660, 1640

0.88 (3H, t, J = 7Hz,> N (CH2) 7CH3), 1.05-1.85 (12H, m,> NCH2 (CH2) gCH5), 3.53 (2H, bs, C2- H), 3.73 (2H, t, J = 7Hz,

> NCH2 (CH2) gCH3), 3.96 (3H, s, -OCH3),

ïz. S]) t ■ J- CH_-

4.48, 5.13 (2H, ABq, J = 15Hz,

5.25 (IH, d, J = 5Hz, Cg-H), 5.88 (IH, dd,

J = 5Hz, J = 8Hz, C? -H), 6.72 (2H, bs,.

> == <), 6.98 (IH, s, N "T> '7.21 (3H, bs, H H

- S H

-NH3®), 9.93 (IH, d, J = 8Hz, -CONH-)

Table 20 (continued)

47

657 135

O P fU

M / 3 -N N-N

w xch3

-ch.

179-181

(Decomposition)

1770, 1710, 1680;

1620

2.86 (6H, s, -N'C ^ 3), 3.51 (2H, bs, C, -H), 3 2

3.93 (3H, s, -0CH3), 4.42, 5.07 (2H, ABq, J = 15Hz, Svl), 5.22 (IH, d, J = 5Hz,

> CiV

Cg-H), 5.96 (IH, dd, J = 5Hz, J = 8Hz, C? -H),

6.57, 6.72 (2H, ABq, J = 6Hz,> = (), 6.90 (lit.

H H

s, 7.44 (3H, bs, -NH.®), 9.80 (IH,

S H

d, J = 8Hz, -CONH-)

0 0

M

-N N-CH "CH,> - / 2 3

| -CH2CH3

169-174

(Decomposition)

1775, 1645

1.20 (3H, t, J = 7Hz,> NCH2CH3), 1.29 (3H, t, J = 7Hz, -OCH2CH3), 3.52 (2H, bs, Cj-H), 3.47 (2H , q, J = 7Hz,> N-CH2CH3), 4.26 (2H, q, J = 7Hz, -OCH2CH3), 4.45, 5.13 (2H, ABq,

J = 15Hz,

l

), 5.26 (IH, d, J = 5HZ,

ch2-

Cg-H), 5.90 (IH, dd, J = 5Hz, J = 8Hz, C7 ~ H),

6.70 (2H, bs, Z ^), 6.95 (IH, s, nt ~), H H

S H

9.86 (IH, d, J = 8Hz, -CONH-)

ch2CH3

-ch.

153-156

(Decomposition)

1780, 1720, 1690; 1630

1.17 (3H, t, J = 7Hz, CH3CH2-), 2.64 (2H, q, J = 7Hz, CH3CH2-), 3.46 (2H, bs, C2 ~ H), 3.96 (3H , s, -OCH3), 4.96, 5.40 (2H, ABq, J = 15Hz, S "1), 5.23 (IH, d, J = 5Hz,

y ch2-

Cg-H), 5.88 (IH, dd, J = 5Hz, J = 8Hz, C? -H), 6.95, 7.19 (2H, ABq, J = 10Hz, '

6.97 (IH, s, NJ ^ "), S H

7.59 (3H, bs, -NH3®), 9.90 (IH, d, J = 8Hz, -CONH-)

657 135 48

Table 20 (continued)

0

»

2.05 (1.5H, s, -CH3xO.5), 2.07 (1.5H, s

™ ìtch3

-CH3xO, 5), 3.34 (2H, bs, C2 ~ H), 3.87 (3H,

V

0

"CH3

> 200

1770, 1710, 1665

s, -0CH3), 4.97 (2H, bs, S "|),

> Cf2 "

+ n

5.09 (IH, d, J = 5Hz, Cg-H), 5.73 (IH, dd,

A

-NY ^ "CH3

J = 5Hz, J = 8Hz, C? -H), 6.77 (0.5H, s, ^ - H

x 0.5), 6.80 (IH, s, 6> 94 (° i5H /

S H

0

s, yHxOt5), 7.75 (3H, bs, -NH3®), 9.67 (IH, d, J = 8Hz, -CONH-)

3.43 (2H, bs, C2-H), 3.87 (3H, s, -OCH3),

4.51, 5.65 (2H, ABq, J = 15Hz, Svl),

1770,

J-ch2-

-Q

O

-ch3

144-147

(Decomposition)

1680

5

1640

5.14 (IH, d, J = 5Hz, Cg-H), 5.78 (IH, dd,

J = 5Hz, J = 8Hz, C? -H), 6.80 (IH, s,),

S H

7.31, 7.57 (2H, ABq, J = 5Hz, ^ -),

7.98 (IH, s, yh), 9.66 (IH, d, J = 8Hz, -CONH-)

3.40 (2H, bs, C2-H), 3.90 (3H, s, -OCH3),

0

1775,

4.87, 5.24 (2H, ABq, J = 15Hz, S> |),

V "01

A

-CH3

> 200

1710, 1665

1630

X CHj-

5.06 (IH, d, J = 5Hz, Cg-H), 5.78 (IH, dd,

u

J = 5Hz, J = 8Hz, C? -H), 6.84 (IH, s, N ^ "),

s ü

7.44 (IH, s, ^ H), 9.69 (IH, d, J = 8Hz, -CONH-)

3.50 (2H, bs, C2-H), 3.95 (3H, s, -OCH3),

0 0

4.47, 5.15 (2H, ABq, J = 15Hz, S> |),

M

-N NH \ /

-CH3

168-170

1770, 1710)

1630

J-ch2-

(Decomposition)

5.24 (IH, d, J = 5Hz, Cg-H), 5.85 (IH, dd,

J = 5Hz, J = 8Hz, C7-H), 6.46, 6.62, (2H, ABq,

J = 6Hz,) = (), 6.94 (IH, s, KT "), 7.03 'H H

- - S H (3H, bs, -NH®), 9.85 (IH, d, J = 8Hz, -CONH-)

49

657 135

(4) In 30 ml of water, 6.35 g of trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) - methoxyiminoacet-amido] -3- {[1- (2,3 -dioxo-l, 2,3,4-tetrahydropyrazinyl)] methyl} - A3-cephem-4-carboxylic acid dissolved and the resulting solution adjusted to a pH of 7.4 using sodium hydrogen carbonate. This solution is then purified by passing it through an Amberlite XAD-2 column, 4.7 g (yield: 86.6%) of sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) - methoxyimino-acetamido] -3- | [l- (2,3-dioxo-l, 2,3,4-tetrahydropyrazinyl)] - methyl] - A3-cephem-4-carboxylate, melting point 200 ° C or higher.

IR (KBr), cm "vc = 0 1763,1670,1650-1620 The following compounds can be prepared in a similar manner:

Sodium-7- [2- (2-aminothiazol-4-yl) -2- (syn) - methoxy-iminoacetamido] -3- j [1- (4-methyl-2,3-dioxo-1,2,3 , 4-tetra-hydropyrazinyl)] - methyl] - A3-cephem-4-carboxylate. Melting point 190 to 195 ° C (decomposition).

IR (KBr), cm-1: vc = 0 1760.1670.1650.1630 sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) - methoxy-iminoacetamido] -3- | [1- (3,6-dioxo-l, 2,3,6-tetrahydropyri-dazinyl)] methyl) -A3-cephem-4-carboxylate.

Sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) - methoxy-iminoacetamido] -3- {[1- (3-methyl-6-oxo-l, 6-dihydropyri-dazinyl )] methyl) - A3 cephem-4-carboxylate.

Example 7

(1) A solution of 3 g of 2- (2-tritylaminothiazol-4-yl) -2- (syn) - tert-butoxycarbonylmethoxyiminoacetic acid in 15 ml of N, N-dimethylacetamide is added dropwise with 0.93 g of phosphorous oxychloride to one Temperature of -10 ° C was added and the mixture was then reacted for 1 hour at a temperature of -5 ° C to 0 ° C. This solution is then added dropwise to a solution of 19.4 ml of anhydrous methyl chloride which contains 1.94 g of 7-amino-3-y [1- (4-ethyl-2,3-dioxo-1,2,3,4- tetrahydropyrazinyl)] -methyl) - A3-cephem-4-carboxylic acid and 2.25 g bis- (trimethylsilyl) -acetamide contains, at - 5 ° C to 0 ° C, given. After the dropwise addition has ended, the mixture is reacted at the same temperature for 30 minutes and then for 30 minutes at 0 to 10 ° C. When the reaction has ended, the methylene chloride is removed by distillation under reduced pressure and the residue is mixed with a solvent mixture of 100 ml of saturated aqueous sodium chloride solution and 100 ml of acetonitrile. Then the organic layer is separated and washed twice with 50 ml of a saturated aqueous sodium chloride solution, after which the solvent is removed by distillation under reduced pressure. The resulting residue is dissolved in 50 ml of methanol, whereupon 1 g of diphenyldiazomethane is added to the solution at a temperature of 5 to 10 ° C. Then the mixture is reacted at the same temperature for 30 minutes. After the reaction has ended, the solvent is removed by io distillation under reduced pressure. The residue is purified by column chromatography (Wako Si-lica Gel C-200, eluent benzokethylacetate = 3: 1), 1.6 g (yield: 27.8%) of diphenylmethyl-7- [2- (2-tritylaminothiazole- 4-yl) -2- (syn) - tert-butoxycarbonylme-15 thoxyiminoacetamido] -3- {[l- (4-ethyl-2,3-dioxo-l, 2,3,4-te-trahydropyrazinyl)] -methyl) -A3-cephem-4-carboxylate of melting point 98 to 100 ° C (decomposition).

IR (KBr), cm-1: vc = 0 1780.1720.1680.1630 NMR (d6-DMSO), 5 values:

20 1.17 (3H, t, J = 7Hz,> nch2ch3),

1.44 (9H, s, -C (CH3) 3), 3.62 (2H, bs, C2-H),

25th

3.74 (2H, q, J = 7Hz,> n-ch2ch3),

O

II

4.55 (2H, s, -OCH2C ~),

30 4.51.5.16 (2H, ABq, J = 15Hz,),

^ CV

5.27 (IH, d, J = 5Hz, C6-H), 5.87 (IH, dd, J = 5Hz, 35 J = 8Hz, C / -H),

6.55 (2H, bs, 6.80 (IH, s, -CH <),

H H

N -jp

4o 6.97 (ih, s, A), 7.05-7.67 (25H, m, - / ô) x5), s h w

8.86 (IH, bs, (0) 3C-NH-),

9.54 (IH, d, J = 8Hz, -CONH-)

45 The compounds listed in Tables 21 and 22 can be prepared in a similar manner.

Table 21

(<o) '3cIKJ

jN -ri— CCONH

T II

H 'S' N O

\

(syn isomer)

connection

M.p. ("e)

IR (KBr), cm "1: vc = 0

R2

R18

O O

M

-N N-CH.CH, \ - / 2 3

CH,

1 3

-C-COOC (CH3) 3 CH3

118-120

(Decomposition)

1780, 1720, 1690-1640

O O

M

-N N-H

\ = /

-CH2COOC (CH3) 3

155-156

(Decomposition)

1780, 1720, 1680, 1640

135

Table 21 (continued)

50

o o y ~ i

-N N-CH,

\ = ^ 3

-CH2COOC (CH3) 3

125-127

(Decomposition)

1785, 1725, 1690, 1645

0 0

M. / CH -N N-N 'x—' CH3

-CH2COOC (CH3) 3

151-154

(Decomposition)

1780, 1725, 1685, 1640

■ Ô

0

-CH2COOC (CH3) 3

126-130

(Decomposition)

1780, 1725, 1690-1660

CH,

-0

0

-CH2COOC (CH3) 3

118-120

(Decomposition)

1780, 1720, 1660

Table 22

^ .Nv_-CC0NH. r ^ Sv>

'©' ^ TOÌ 0J-ÇL <= 2 »2

\ COOC (CH,) - OCH2COOC (CH3) 3 y j

connection

Mp (° c)

IR (KBr), cm "1: vc = Q

R2

0. p

'Hi

-NwN-CH2-y = y-cH3

V

0

133-135

(Decomposition)

1820, 1780, 1720, 1690, 1650

0 0

r ^ <y *

w <°> .. ..

164-167

(Decomposition)

1785, 1730, 1710, 1690, 1660

0 .0 -N N-CH2pC0C (CH3) 3

135-138

(Decomposition)

1785, 1740, 1730, 1710, 1680, 1660

o, fi

^ f / - \

-N N-CH2C00CH (> 2nd

152-154 (decomposition)

1785, 1750, 1720, 1690, 1655

51

657 135

(2) 1.6 g of diphenylmethyl-7- [2- (2-tritylaminothiazol-4-yl) -2- (syn) -tert.-butoxycarbonyl- is dissolved in a solvent mixture of 8 ml of trifluoroacetic acid and 3 ml of anisole. methoxyiminoacetamido] -3- | [l- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] - methyl 1 -A3-cephem-4-carboxylate, followed by this solution during 1 hour at room temperature. When the reaction is complete, the solvent is removed by distillation under reduced pressure. 10 ml of diethyl ether are added to the residue, and the crystals are collected by filtration. The crystals obtained are then dissolved in 20 ml of a 50% strength by weight aqueous formic acid solution and the solution is reacted at a temperature of 45 to 55 ° C. for 1 hour. After the reaction was completed, the precipitated crystals were collected by filtration and the solvent was removed by distillation under reduced pressure. The resulting residue is mixed with 10 ml of ethyl acetate and the crystals formed are collected by filtration. The crystals are then sufficiently washed with 10 ml of ethyl acetate and dried, 0.7 g (yield: 80.7%) of 7- [2- (2-aminothiazol-4-yl) -2- (syn) - carboxymethoxyimino-acetamido] -3- | [l- (4-ethyl-2,3-dioxo-l, 2,3,4-tetrahydropy-

razinyl)] - methyl | - A3-cephem-4-carboxylic acid from melting point 139 to 140 ° C (decomposition).

IR (KBr), cm-1: vc = 0 1775.1695.1680.1635 NMR (d6-DMSOï values:

1.22 (3H, t, J = 7Hz,> nch2ch3), 3.53 (2H, bs, C2-H), 3.74 (2H, q, J = 7Hz,> nch2ch3), 4.70 (2H , s, -OCHjCO-),

10 4.45, 5.10 (2H, ABq, J = 15Hz,), s

15

),

ch2-

5.23 (IH, d, J = 5Hz, C6-H),

5.90 (1H, dd, J = 5Hz, J = 8Hz, Cr-H),

6.69 (2H, bs,) = (), 6.94 (IH, s, N-n-.

H H ''

S H

9.70 (IH, d, J = 8 Hz, -CONH-)

The compounds shown in Table 23 below can be prepared in a similar manner.

Table 23

.N —n— c CONH —i — f -

'<T I.

\ R18

-ch2-r-

COOH

(syn isomer)

connection

"18th

M.p. CO

IR (KBr), cm ~ 1: VC = Ol

NMR (dg-DMSO), «values:

*1

w

-n nch-ch, \ - / 2 3

ch,

I 3

-c-cooh

I.

ch,

165-166 (decomposition)

1775, 1705, 1690

S

1620

1.22 (3H, t, J = 7Hz,> NCH2CHa),

1.53 (6H, s, CH,),

I -

-C-COOH

I.

CH3

3.54 (2H, bs, C2-H), 3.75 (2H, q, J = 7Hz,> NCH2CH3), 4.49, 5.16 (2H, ABq, J = 15Hz, S-n),

a

CHj-

5.27 (IH, d, J = 5Hz, Cg-H), 6.01

(IH, dd, J = 5Hz, J = 8Hz, Cy-H),

6.72 (2H, bs, V ^), 6.96 H H

(IH, S, N -jT—), 9.64 (IH ,. d,

S ^ H J = 8Hz, -CONH-)

135

Table 23 (continued)

52

o o

-N NH

-CHjCOOH

182-183

(Decomposition)

1770, 1690, 1670, 1640

O O

M

-n n-ch-,

-ch2cooh

88-91

(Decomposition)

3.44 (2H, bs, C2-H), 4.42,

5.00 (2H, ABq, J = 15Hz, S

1

),

ch2-

4.60 (2H, bs, -OCH2COOH),

5.19 (IH, d, J = 5Hz, Cg-H),

5j84 (IH, dd, J = 5Hz, J = 8Hz,

C7-H), 6.52 (2H, ABq, J = 6Hz,

/ \) t 6.82 (IH, s, Ntj—), H H sJla

9.56 (IH, d, J = 8Hz, -CONH-)

1770, 1680, 1660, 1630

3.34 (3H, s,> NCH3), 3.41 (2H, bs, C2-H), 4.45, 5.02 (2H, ABq,

J = 15Hz, S

), 4.67 (2H,

CH2-

bs, -OCH2COOH), 5.16 (IH, d,

J = 5Hz, ■ Cg-H), 5.84 (IH, dd,

J = 5Hz, J = 8Hz, C? -H), 6.60 (2H,

bs,) c =! () / 6.97 (IH, s, N-jp), S £ sJls

9.75 (IH, d, J = 8Hz, -CONH-)

*1

O O

M / H

-N N-N (

\ = /

CH,

-ch2cooh

155-158

(Decomposition)

1770, 1710, 1670, 1630

/ CH3

2.85 (6H, s, -N <-), 3.49 (2H, \

CH.

bs, C2-H), 4.43, 4.98 (2H, ABq, J = 15Hz, S.), 4.65 (2H, s,

ch2-

-OCH2CO-), 5.15 (IH, d, J = 5Hz, Cg-H), 5.79 (IH, dd, J = 5Hz, J = 8Hz, C? -H), 6.61 (IH, bs,> == <), 6.91 (IH, s, N — r),

S- s 1h

9.65 (IH, d, J = 8Hz, -CONH-)

O O

M

-N N -CH2 "J = ^ CH3

V

-CH2COOH

151-154

(Decomposition)

1820, 1770, 1680, 1640

2.22 (3H, s, -CH3), 3.50 (2H, bs, C2-H), 4.70 (2H, s,> NCH2-), 4.85 (4H, bs, -OCH2CO-, ),

■ K

CHj-

5.27 (IH, d, J = 5Hz, Cg-H),

5.94 (IH, dd, J = 5Kz, J = 8Hz,

C -H), 6.75 (2H, s, y = ^),

H H

6.97 (IH, s, SIH), 9.81 (IH, d, J = 8Hz, -CONH-)

Table 23 (continued)

53

657

o o

-ch2cooh

137-140

(Decomposition)

1785, 1720, 1690, 1640

3.75 (2H, bs, C2-H), 4.47, 5.13 (2H, ABq, J = .l5Hz,),

^ CH, -

4.74 (2H, s, -OCH2CO-), '5.13 (IH,

a, J = 5Hz, Cg-H), 5.97 (IH, dd,

J = 5Hz, J = 8Hz, C7-H), 6.12, 6.66

(2H, ABq, J = 6Hz, y = (), 7.05 H H

(IH, s, sXhK 7.61-8.25 (5H, m,

^ Î ^ O), 8.84 (IH, d, J = 8Hz, -CONH-)

O O

-n n-ch, ococ (ch.), \ - / * ■ j j ch2cooh

178-183

(Decomposition)

1790, 1730, 1690, 1650

1.17 (9H, s, -C (CH3) 3), 3.72 (2H, bs, C2-H), 4.46, 5.20 (2H, ABq, J = 15Hz, S-,), 4.70 (2H,

CH, -

1

s, -OCH2CO-), 5.03 (IH, d, J = 5Hz, Cg-H), 5.73 (2H, s,> NCH2-), 6.06 (IH, dd, J = 5Hz, J = 8Hz, C7-H), 6.73 (2H, bs, ^ == ^ '),

7.05 (IH, s, g ^ ljj) 'd, J = 8Hz, -CONH-)

87 (IH,

28

O O

y ~ {

-n n-ch, cooh W / 2

-ch2cooh

135-142

(Decomposition)

1780, 1720, 1680, 1635

3.73 (2H, bs, C2-H), 4.48, 5, (2H, ABq, J = 15Hz,), 4.54

^ ch2-

(2H, s,> NCH2-), 4.73 (2H, s, -OCH2CO-), 5.10 (IH, d, J = 5Hz, Cg-H), 6.07 (IH, dd, J = 5Hz, J = 8Hz, C? -H), 6.74 (2H, bs,

> - \), 7.05 (IH, s, N-ii—),

H H

saw'

8.89 (IH, d, J = 8Hz, -CONH-)

657 135

54

Table 23 (continued)

* 2

hn

I.

0

Y

-CH2COOH

190-193

(Decomposition)

1770, 1710, 1660, 1630

3.34 (2H, bs, C2-H), 4.63 (2H, s, -OCH2CO-), 4.98 (2H, bs, S>,), 5.10 (IH, d, J = 5Hz ,

CV

Cg-H), 5.77 (IH, dd, J = 5Hz, J = 8Hz, C? -H), 6.83 (IH, s, Ny), 6.85, 7.11 (2H, ABq,

J = 10Hz, Jj— ", 9.51 (IH, i.e.

J = 8Hz, -CONH-)

-ch2cooh

194-197

(Decomposition)

1770, 1710, 1690

s

1630

2.28 (3H, s,> - CH3), 3.43 (2H,

bs, C2-H), 4.73 (2H, s,

-OCH2CO-), 5.14 (IH, d, J = 5Hz, Cg-H), 5.23 (2H, bs,),

X

VCH2 "

5.88 (IH, dd, J = 5Hz, J = 8Hz, C7-H), 6.96, 7.46 (2H, ABq, J = 10Hz, ^ jj-H), 7.01 (IH, s ,

Ny), 7.80 (3H, bs, -NH3 ©), S AH

9.76 (IH, d, J = 8Hz, -CONH-)

* 1 trifluoroacetic acid salt (to purify the product obtained by the above process, it is converted into a diphenylethyl ester in a manner known per se and then subjected to de-esterification using trifluoroacetic acid, giving a trifluoroacetic acid salt).

* 2 formate

Example 8

(1) To a solution of 1.68 g of diketene in 8.40 ml of anhydrous methylene chloride is added dropwise a solution of 2.08 g of bromine in 6.25 ml of anhydrous methylene chloride with stirring at -30 ° C and then this mixture is left for React for 30 minutes at a temperature of - 30 to -20 ° C. The reaction mixture thus obtained is then added dropwise at -30 ° C or less to a solution of 50 ml of anhydrous methylene chloride containing 5.20 g of diphenylmethyl-7-amino-3- {[l- (4-ethyl-2,3-dioxo -l, 2,3,4-tetra-hydropyrazinyl)] - methyl) -A3-cephem-4-carboxylate and 4.08 g bis- (trimethylsilyl) - acetamide contains added.

After the dropwise addition has ended, the mixture is reacted for 30 minutes at a temperature of -30 to -20 ° C. and then for 1 hour at a temperature of 0 to 10 ° C. After the reaction has ended, the solvent is removed by distillation under reduced pressure and the residue thus obtained is dissolved in 50 ml of ethyl acetate and 40 ml of water. The organic layer is then separated off, washed with 40 ml of water and then with 40 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure. The resulting residue is mixed with 50 ml of diisopropyl ether, and the crystals which precipitate are then collected by filtration, 5.85 g (yield: 85.6%) of diphenyl-methyl-7- (4-bromo-3-oxobutyramido) -3- {[1- (4-ethyl-2,3-55 dioxo-1,2,3,4-tetrahydropyrazinyl)] - methyl j -A3-cephem-4-carboxylate, melting point 138 to 142 ° C (decomposition ) receives.

IR (KBr), cm-1: vc = o 1778.1720.1680.1640 NMR (d6-DMSO), 5 values:

60

1.22 (3H, t, J = 7Hz, ^ nch2ch3), 3.40 (2H, bs, C2-H), 3.85 (2H, q, J = 7Hz,> nch2ch3), 3.87 (2H bs

65 BrCH ^ COCCH? -),

4.18 (2H, bs, BrCH2CO ~),

4,47,4,96 (2H, ABq, J = 15Hz,), S \),

J-ch2—

5.04 (IH, d, J = 5Hz, C6-H), 5.90 (IH, dd, J = 5Hz, J = 8Hz, Cj-H),

\ / 1

6.15, 6.50 (2H, ABq, J = 6Hz, h h '

6.98 (IH, s, -ch <), 7.40 (10H, bs, - © x 2),

8.55 (IH, d, J = 8Hz, -CONH-)

The following connection can be made in a similar way:

4.09 g (yield: 62.6%) diphenylmethyl-7- (4-bromo-3-oxo-butyramido) -3- j [l- (3,6-dioxo-1,2,3,6-tetrahydropyri -dazinyl)] -methyl j- A3 cephem-4-carboxylate with a melting point of 124 to 126 ° C (decomposition).

IR (KBr), cm "1: vc = 0 1780.1725.1660

NMR (d6-DMSO), 8 values:

55 657135

5.11 (IH, d, J = 5Hz, C6-H), 5.80-6.15 (IH, m, Q-H), 6.13.6.52 (2H, ABq, J = 6Hz,),

H n

7.02 (lH, s, -ch <), 7.41 (10H, bs, - <5) x2),

9.20 (IH, d, J = 8Hz, -CONH-)

In a similar way, the following connection is obtained:

4.71 g (yield 75.1%) diphenylmethyl-7- (4-bromo-2-hydroxyimino-3-oxobutyramido) -3- {[1- (3,6-dioxo-1,2,3,6- tetrahydropyridazinyl)] -methyl] -A3-cephem-4-car-boxylate, melting point 138 to 141 ° C (decomposition). IR (KBr), cm-1: vc = 0 1780.1720.1660 NMR (d6-DMSO), 8 values:

O

O

II

3.46 (2H, bs, C2-H), 4.62 (2H, 4.96 (2H, bs, s

3.49 (4H, bs, C2-H, -CCH2C-),

O

II

4.52 (2H, s, BrCH2C-),

),

ch2-

20th

5.06 (IH, bs, s »

> '5.26 (IH, d, J = 5Hz, C6-H), w

5.18 (IH, d, J = 5Hz, C6-H), 5.93 (IH, dd, J = 5Hz, J = 8Hz, Cr-H),

6,89,7,13 (2H, ABq, J = 10Hz,),>,

6.96 (IH, s, -ch <), 7.13-7.72 (10H, m, - {Ô> x 2), 9.45 (lH, d, J = 8Hz, -CONH-), 13.36 (1H, s, = N-OH)

30th

(3) In 12 ml of N, N-dimethylacetamide, 3.00 g of the diphenylmethyl-7- (4-bromo-2-hydroxyimino-3-oxobutyramido) obtained according to paragraph (2) above are dissolved -3- {[1- ( 4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] -methyl] - A3-ce-35 phem-4-carboxylate and 0.42 g of thiourea, followed by the resulting solution for 3 hours implement at room temperature. When the reaction has ended, the reaction mixture is poured into a solvent mixture consisting of 120 ml of water and 240 ml of ethyl acetate. The mixture is then adjusted to a pH of 7.0 by means of sodium hydrogen carbonate, whereupon the organic layer is separated off and washed with 50 ml of water and then with 50 ml of a saturated aqueous sodium chloride mixture for 2 hours at room temperature . After drying the organic to implement. After the reaction is complete, the 45 layer is poured over anhydrous magnesium sulfate, the Lö reaction mixture is poured into 500 ml of water, the solvent being removed by distillation under reduced pressure

Eliminate crystals. These crystals are removed by filtration. The residue is then collected with 20 ml of diethyl ether, washed with water in sufficient quantities, and the crystals formed are filtered off and dried. The crystals are then collected in 10 ml of chlorine, 2.10 g (yield: 72.3%) of diphenyl-roform being dissolved and then by column chromatography-50-methyl-7- [2- (2-aminothiazol-4-yl ) -2- (syn) -hydroximino-phie (Wako Silica Gel C-200, eluent = mixture acetamido] -3- ((l- (4-ethyl-2,3-dioxo-l, 2,3,4- tetrahydropy-of benzene and ethyl acetate = 2: 1 by volume)) -razinyl)] - methyl i-A3-cephem-4-carboxylate from the mixture, with 3.15 g (yield: 54.9%) of diphenylmethyl-7- point 137 to 140 ° C (decomposition).

JLch ^ -

5.90 (IH, dd, J = 5Hz, J = 8Hz, c7-H),

7.01.7.25 (2H, ABq, J = 10Hz,),

7.09 (IH, s, -ch <) f 7.24-7.91 (10H, m, x 2),

9.34 (IH, d, J = 10Hz, -CONH-)

(2) To a solution of 5.50 g of diphenylmethyl-7- (4-bromo-3-oxobutyramido) -3- {[1 - (4-ethyl-2,3-dioxo-1,2,3,4- tetrahydropyrazinyl) - methyl) -A3-cephem-4-carboxylate in 30 ml of acetic acid is added dropwise to a solution of 5 ml of water containing 0.74 g of sodium nitrite with ice-cooling within 1 hour, whereupon the

(4-bromo-2-hydroxyimino-3-oxobutyramido) -3- {[l- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl] -A3-cephem- 4-carboxylate of melting point 127 to 132 ° C (decomposition).

IR (KBr), cm-1: vc = 0 1778.1720.1680.1635 NMR (CDC13), 5 values:

1.26 (3H, t, J = 7Hz,> nch2ckì), 3.47 (2H, bs, C2-H),

3.81 (2H, q, J = 7Hz,> nch2ch3), 4.52 (2H, s, BrCHjCO-),

4,53,4,78 (2H, ABq, J = 15Hz,), s-,),

55

60

IR (KBr), cm-1: vc = 0 1778.1720.1680.1640 NMR (d6-DMSO), 5 values:

1.19 (3H, t, J = 7Hz,> nch2ch3), 3.48 (2H, bs, C2-H), 3.68 (2H, q, J = 7Hz,),

4.46, 5.04 (2H, ABq, J = 15Hz, s

),

5.28 (IH, d, J = 5Hz, C6-H), 5.97 (IH, dd, J = 5Hz, 65 J = 8Hz, Cr-H),

Ì

6.57.6.75 (2H, ABq, J = 6Hz;

ch2-

, M

H

657 135

56

6.79 (IH, s, "X1, 7.07 (1H, s, -ch <),

s h

7.53 (ÌOH, bs, ./pS x 2), 9.70 (IH, d, J = 8Hz, -CONH-) W

(4) 2.00 g of diphenyl-methyl-7 [2- (2-aminothiazol-4-yl) -2- (syn) - hydroxyimino- is dissolved in a solvent mixture of 10.0 ml of trifluoroacetic acid and 2.0 ml of anisole. acetamido] -3- {[l- (4-ethyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazinyl)] - methyl j- A3-cephem-4-carboxylate, obtained according to paragraph (3) above , whereupon the solution thus obtained is reacted for 2 hours at room temperature. After the reaction has ended, the solvent is removed by distillation under reduced pressure and 15 ml of diethyl ether are added to the residue, whereupon the crystals formed are collected by filtration. The crystals are then sufficiently washed with 10 ml of diethyl ether and dried thereupon, 1.62 g (yield: 87.6%) of the trifluoroacetic acid salt of 7- [2- (2-ami-nothiazol-4-yl) - 2- (syn) - hydroxyiminoacetamido] -3 - {[l- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -A3-cephem-4-carboxylic acid, melting point 112 to 118 ° C (decomposition) is obtained.

IR (KBr), cm "1: vc = 0 1780.1680.1620

NMR (d6-DMSO), 8 values:

1.19 (3H, t, J = 7Hz,> n-ch2ch3), 3.47 (2H, bs, C2-H),

3.72 (2H, q, J = 7Hz,> nch2ch3),

4.45-6.70 (4H, m, Sv), Q-H, Ct-H),

^ -ch2-

5.10 (IH, d, J = 5Hz, Q-H), 6.05 (IH, dd, J = 5Hz, J = 8Hz, Cr-H),

H1,

6,38,6,73 (2H, ABq, J = 6Hz,

h h

6.98 (IH, s, -ch <") / 7.32 (10H, bs, x2),

9.18 (IH, d, J = 8Hz, -CONH-) 10 Similarly, the following connection is obtained:

1.70 g (yield: 24.5%) diphenylmethyl-7- [4-bromo-2- (syn) -methoxyimino-3-oxobutylamido] -3- {[l- (3,6-dioxo-1,2 , 3,6-tetrahydropyridazinyl)] - methyl) - A3-cephem-4-car-15 boxylate, melting point 145 to 148 ° C (decomposition). IR (KBr), cm-1: vc = Q 1780, 1730, 1660 NMR (d6-DMSO), 5 values:

3.49 (2H, bs, C2-H, 4.03 (3H, s, -OCH3),

20 4.60 (2H, s, BrCH2CO-), 5.02 (2H, bs, s ^

),

^ CH2-

25th

30th

5.30 (IH, d, J = 5Hz, Q-H),

6.02 (IH, dd, J = 5Hz, J = 8Hz, Cj-H),

6.92.7.16 (2H, ABq, J = 10Hz,) /

6.99 (lH, s, -ch <), 7.17-7.78 (10H, m, x 2),

6.59-6.83 (3H, m, y = (■ NJ | ^]

h h s -

Example 9

(1) A solution of 7.1 g diphenylmethyl-7- (4-bromo-2-hydroxyimino-3-oxobutylamido) -3- {[l- (4-ethyl-2,3-dioxo-1,2,3 , 4-tetrahydropyrazinyl)] -methyl) -A3-cephem-4-carboxylate in 70 ml of anhydrous methylene chloride is slowly mixed with a solution of diazomethane in diethyl ether at a temperature of - 5 to 0 ° C and the resulting solution at reacted at the same temperature for 30 minutes. After the removal of the di-azomethane has been observed, the solvent is removed by distillation under reduced pressure. The residue thus obtained is purified by column chromatography (Wako Silica Gel C-200, eluent: mixture of benzene and ethyl acetate in a volume ratio of 3: 1), 2.32 g (yield: 32.0%) of di-phenylmethyl 7- [4-bromo-2- (syn) - methoxyimino-3-oxobutylamido] -3 {[l- (4-ethyl-2,3-dioxo -1,2,3,4-tetrahydropyrazinyl) ] -methyl) -A3-cephem-4-carboxylate with a melting point of 135 to 140 ° C (decomposition).

IR (KBr), cm-1: vc = 0 1778.1720.1682.1638

NMR (CDC13), 5 values:

1.25 (3H, t, J = 7Hz,> nch2ch ^), 3.4g (2H, bs, C2-H),

3.84 (2H, q, J = 7Hz,> nch2ch3), 4.00 (3H, s, -OCH3),

4.10 (2H, s, BrCI ^ CO-), 4.48, 4.67 (2H, ABq, J = 15Hz,

),

ch2-

10.16 (IH, d, J = 8Hz, -CONH-)

(2) In 14 ml of N, N-dimethylacetamide, 2.3 g of di-phenylmethyl-7- [4-bromo-2- (syn) - methoxyimino-3-oxobutyl-amido] - 3 - {[l- ( 4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazi-35 nyl)] - methyl] - A3-cephem-4-carboxylate and 0.32 g of thiourea and the resulting solution is left for 3 hours react at room temperature. After the reaction has ended, the reaction mixture is poured into a solvent mixture of 50 ml of water and 150 ml of ethyl acetate. 4o Sodium bicarbonate is then added to adjust the mixture to a pH of 6.7, after which the organic layer is separated off. The aqueous layer is then extracted twice with 100 ml of ethyl acetate each time. The combined organic layer is washed with water 45 and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue is then mixed with 20 ml of diethyl ether and the crystals are collected by filtration, whereby 1.92 g (yield: 86.3%) so diphenylmethyl-7- [2- (2-aminothiazol-4-yl) - 2- (syn) -metho-xyiminoacetamido] -3-) [1- (4-ethyl-2,3-dioxo-l, 2,3,4-tetra-hydropyrazinyl)] - methyl) - A3-cephem-4 carboxylate with a melting point of 165 to 167 ° C.

55 IR (KBr), cm-1: vc = 0 1780.1720.1680.1640

The following compound is obtained in a similar manner: Diphenylmethyl-7- [2- (2-aminothiazol-4-yl) - 2- (syn) -me-thoxyiminoacetamido] -3- | [l- (3,6-dioxo- l, 2,3,6-tetrahydro-pyridazinyl)] - methyl) - A3-cephem-4-carboxylate; Melt-60 point 175 to 178 C (decomposition).

IR (KBr), cm-1: vc = 0 1780.1720.1685-1660

The same ring closure reaction as described above 65 is repeated and then the reaction mentioned in Example 6- (3) or in Example 7- (2) is carried out, adding the compounds listed in Tables 24, 25 and 26 reached.

57

657

Table 24

/ N-ir-C- CONH 1 f-S ^

CP3COOH.H2N-y ^ ^ * ^^ 2

OCH, COOH

(syn isomer)

r2

r2

r2

Vf

-N N-CH,

w 3

CH,

✓s

1

-v

0

o, P} -%

-N N-CH.COOH

w 2

0 0

w

-nwn "(ch2) 4ch3

CH3 *

cV '

• ■ -v

0

0 0 y ^

-N N (CH,), CH, \ / 2 2 3

r2

r2

o, o y ~~ <

-N NCH, CH, 0C0CH_

\ = / 22 3

0 0 HN irCH, HN

1 3 + 1

-N -N -CH,

V Y

0. 0

y— <

-NwN- (CH2) 7CH3

-0

0 0

y- ^

-N N- (CH,) cCH, \ / 2 5 3

0 0

M "

-N NCH, C = C-CH,

w 2 / \ 3

0 0

Y

0 0

M / CH

-N N-CH J w ^ CH3

q. 0

M

"îl <ch2> l1ch3

0 0

} ~ i _yO o

0 0

M

-NWN (CH2) 3CH3

0 0

-nwn-ch2- (o)

0 0

M

-N ^ -CH20C0C (CH3) 3

0 0

(/ - \ wh \ /

657 135

Table 24 (continued)

Q, o

M / CH3 -N N-N

W ^ CH3

0

/ V

HN]

1

"Y

0

• Cl

0 0

) - {-N NCH-CH,

w 2 3

O .0

y ~ i

-N NH

w

CH CH

"O

n

-V

b

0

* Hydrochloride.

Table 25

q, N-n C CONH—, TSvl

-

\ R18 COOH

(syn isomer)

r2

r5

00

- n nch.ch,

w 2 3

nh2-

-chjcooh

0 o

- n nch0ch-, \ - / 2 3

cf3c00h-nh2-

ch,

1 3

-c-cooh

1

ch3

o 0

Vf

- n nh \ = /

nh2-

-ch2c00h o 0 —n nch,

cf3cooh-nh2-

-chjcooh

59

Table 25 (continued)

657 135

0 0

M / -CH3 - n n-n xch3

cf3cooh-nh2 "

-ch2cooh

0

A,

hn

1

n

V

0

hc00h-nh2-

-ch2cooh ch.

1

- n

Y

0

1

hcoöh-nh2-

-ch2cooh

0v / °

M r

—N nch, c = c-ch-

w y \ -

V

0

nh2-

-ch2cooh

0 0

IM ", 0yjO

-n n-o ^

w <°>

nh2-

-ch2cooh

0 0 —n ^ ~~ ^ jch_ococ (ch

3 »3 NH2-

-ch2cooh o o

- n nch-cooh w / 2

nh2-

-ch2cooh

0 o y ~ (

—N nch-ch, \ J 2 3

hcooh-nh2-

-ch2coo- (o)

0 0

y— ^

-n ^ jch 2ck3

hcooh-nh2-

-ch2c00 - ^ - ^

0 0

—N nch..ch, w 2 3

hcooh-nh2-

-ch2cooch2ch3

657 135

60

Table 26

n "tî c— conh, \

v-fJT I

^ OCH, O I 1

coor

(syn isomer)

r1

r2

-chococ (ch,),

1

ch3

P ■

—N nch-ch,

w 2 3

-chococ (ch3) 3

ch3

0., 0

—N nch, y = / 3

-chococ (ch,), | 3 3

ch3

°, P

y-i

-n n- (ch _). ch, \ / 2 4 3

-chococ (ch,),

1

ch3

V-?

-n n- (ch,) qch, 2 5 3

-chococ (ch,),

1 y j ch3

0, Q -nwn (ch2) 7ch3

-chococ (ch,),

1

ch3

ov .0

-nwn (ch2) i; lch3

-ch2ococ (ch3) 3

° v / °

m:

-n ^ 1ch2ch3

-chocooc (ch,), | 3 3

ch3

° h °

—N nch-ch,

2 3

61

657 135

Table 26 (continued)

0 0

-N NCH-CH - \ - / 2 3

- <CH2} 3CH3

V ^ °

—N NCH-CH,

S / 2 3

-CH, C = C-CH,

J \

V

O

Ov, 0

J - ^ (

—N NCH-CH, \ / 2 3

-CH2OCOC (CH3) 3

CHo

1 year

-P

0

-CH2OCOC (CH3) 3

CH,

"V

0

-CH2OCOC (CH3) 3

vs

-NV

0

-CH2OCOC (CH3) 3

f ^ N

-v

0

-CHOCOC (CH,),

1

CH3

CH,

-V

0

-CH2OCOC (CH3) 3

0, 0

M / ° w °

-N N- <Y

w ¥

The physical properties, namely the melting points, infrared and nuclear magnetic resonance spectra, of the above compounds are the same as those obtained in Examples 6, 7, 11 and 12.

657 135

62

Example 10

(1) To a suspension of 2.2 g2- (2-formamidothia-zol-4-yl) glyoxylic acid in 11 ml of N, N-dimethylacetamide is added dropwise 1.8 g of phosphorus oxychloride at a temperature of -20 ° C and allows the resulting mixture to react at the same temperature for 2 hours. The reaction mixture is then treated with a solution of 26 ml of methylene chloride containing 5.2 g of diphenylmethyl-7-amino-3- {[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) ] -methyl j- A3 cephem-4-carboxylate, added at -30 to -20 ° C. After the dropwise addition has ended, the mixture is reacted at the same temperature for 1 hour. When the reaction has ended, 70 ml of water and 50 ml of methylene chloride are added, and sodium hydrogen carbonate is then added in order to adjust the mixture to a pH of 6.5. Then the insoluble matter is removed by filtration. The organic layer is then separated off, washed with 100 ml of water and then with 10 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure. The residue is purified by column chromatography (Wako Silica Gel C-200, eluent: chloroform: methanol = 20: 1 volume ratio), 1.4 g (yield: 20.0%) of di-phenylmethyl-7- [2- ( 2-formamidothiazol-4-yl) glyoxylami-do] -3- j [l- (4-ethyl-2,3-dioxo -1,2,3,4-tetrahydropyrazinyl)] - ethyl} -A3-cephem-4 carboxylate of melting point 140 to 145 ° C (decomposition).

IR (KBr), cm "1: 5C = 0 1780.1720.1680.1670.1640

NMR (d6-DMSO), 6 values:

1.20 (3H, t, J = 7Hz,> nch2ch3),

3.50 (2H, bs, QrH), 3.69 (2H, q, J = 7Hz, ^ CH ^ CHj),

4.40.5.00 (2H, ABq, J = 15Hz,), s. ),

Xch ^ -

5.30 (IH, d, J = 5Hz, Q-H), 6.00 (IH, dd, J = 5Hz, J = 9Hz, Q-H),

6,50,6,62 (2H, ABq, J = 5Hz,), H ^ H> '

7.04 (IH, s, -chC), 7.30 (10H, bs, - ^ 5) x 2),

8.64 (IH, s, N-yy-), 8.81 (IH, s, HCONH-),

s h

10.20 (IH, d, J = 9Hz, -CONH-), 12.90 (IH, bs, HCONH-)

In a similar manner, 0.09 g (yield: 19.2%) of diphenylmethyl-7- [2- (2-formamidothiazol-4-yl) -glyoxyl-

amido] -3- {[1- (3,6-dioxo-l, 2,3,6-tetrahydropyridazinyl)] - methyll -A3-cephem-4-carboxylate, melting point 153 to 154 ° C (decomposition).

IR (KBr), cm-1: vc = 0 1780.1725.1690.1665 5 NMR (CDCI3 + d6-DMSO), 5 values:

3.42 (2H, bs, C2-H), 4.96-5.40 (3H, m, s ^ 'C6-H),

X-CH2-

10 5.95 (IH, dd, J = 5Hz, J = 8Hz, Cy-H),

H

6.72-7.78 (13H, m, -ci <, ^ ~, x2),

8.66 (IH, s,, n "FT), 8.73 (IH, s, HCO-), 15 sAH

9.86 (IH, d, J = 8Hz, -CONH-)

(2) A solution of 7.0 g diphenylmethyl-7- [2- (2-form-amidothiazol-4-yl) glyoxylamido] -3- j [l- (4-ethyl-2,3-di-20 oxo-1,2,3,4-tetrahydropyrazinyl)] -methyl} -A3-cephem-4-carboxylate in 35 ml of N, N-dimethylacetamide is mixed with 1.7 g of methoxyamine hydrochloride while cooling with ice and the resulting mixture for 3 hours 15 to 20 ° C implemented. After the reaction has ended, the reaction mixture is poured into a solvent mixture of 250 ml of water and 250 ml of ethyl acetate and the organic layer is separated off, washed first with 250 ml of water and then with 250 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure. 50 ml of diethyl ether are then added to the residue, and the crystals formed are collected by filtration, 6.1 g (yield: 83.7%) of diphenylmethyl-7- [2- (2-formamidothiazol-4-yl) - 2- (syn) -35 methoxyiminoacetamido] -3 - {[1- (4-ethyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazinyl)] -methyl J-A3 cephem-4-carboxylate from Receives melting point 165 to 168 ° C.

IR (KBr), cm-1: vc = 0 1780.1720.1680.1640

Diphenylmethyl-7-40 [2- (2-formamidothiazol-4-yl) -2- (syn) - methoxyiminoacetamido] -3 {[1- (3,6-dioxo-l, 2,3 , 6-tetrahydropyridazinyl)] - methyl j-A3-cephem-4-carboxylate of melting point 171 to 173 ° C (decomposition).

The same oximation reaction as the above leads with 45 subsequent reaction according to the information in Example 6- (2), (3) and / or Example 7- (2) to the following compound and to the compounds mentioned in Tables 27, 28 and 29 :

Trifluoroacetic acid salt of 7- [2- (2-amino-5-bromothiazol-50 4-yl) -2- (syn) - methoxyiminoacetamido] -3-1 [1- (4-ethyl-2,3-dioxo- 1, 2,3,4-tetrahydropyrazinyl)] methyl j-A3-ce-phem-4-carboxylic acid; Melting point 147 ° C (decomposition).

IR (KBr), cm "1: vc = 0 1775.1680.1640

63

657

Table 27

(syn isomer)

R2

R2

R2

K

-N N-CH,

w 3

A

V

0

0, 0

-N N-CH.COOH

W 2

0 0

V- /

-N ^ N- (CH2) 4CH3

CH, *

ch'nÀ

-v

0

0 0

y ^

-N N (CH,) _ CH, W 2 2 3

R2

R2

0 «0) ~ <

—N NCH, CH, OCOCH,

• w 22 3

0 0

X A

HN ^ TfCH, HN n

1 3 + 1

-N - N. -CH,

V Y

0 0> - <

-NwN- (CH2) 7CH3

-Ç

0 0 -N N- (CH.) KCH-

\ / 25 3

0 0

M

-N NCH_C = C-CH,

w 2 / \ 3

0 0

Y

0 O

M / CH3

-N N-CH N = / v-CH3

° M °

-NJ'- <CH2> 11CH3

0 0

X _ / V> °

0 0 ^^

~ IW / (CH2) 3CH3

0 0

r- \

-NwN-CH2- (O)

0 0 y ^

—N N-CH-OCOC (CH.) - \ = s / 3 3

o o

/ - \ VI /

657 135

Table 27 (continued)

64

0 0

y-i / ch3

-n n-n v ^ ch3

0

hn j

1

-n ^ 0

-cl

0 0

m

-n nch-ch,

w 2 3

ol, 0> - <

-n nh w

ch-ch,

fi

■ A

-v

0

n

0

Footnote: Hydrochloride

Table 28

c / N "il c CONH —i f ^ ^

^ sF S.

\ R18 COOH

(syn isomer)

r2

r5

00

W

- w nch-ch,

\ = / 2 3

nh2-

-ch2c00h

0 0

Vf

- n nch-ch ", \ - / 2 3

■ cf3c00h-nh2-

T3

-c-cooh

1

ch3

0 0

Vf

- n nh nh2-

-ch2cooh

0 0

Vf

—Nn,

cf3c00h-nh2-

-ch2c00h

65

657 135

Table 28 (continued)

° v 0

H / ch3

- n n-n y

W \

xch3

cf3c00h-nh2-

-ch2cooh

0

A,

hn

1

n

V

0

hcooh.nh2-

-ch2cooh ch.

-!

V

0

1

hcooh-nh2-

-ch2cooh

° x y °

M

—N nch, c = c-ch-

w y \ -

V

nh2-

-ch2cooh

0 0

w ©

nh2-

-ch2cboh

0 0

—N ^ ^ nch-ococ (ch w 2

3> 3 nh2-

-ch2cooh o o

Vf

—N nch-cooh w / 2

nh2-

-ch2cooh

0 0

Vf

—N nch-ch, \ '2 3

hc00h-nh2-

-ch2coo-0

0 0

Vf

-nwjch2ch3

hcooh-nh2-

-ch2c00 - ^ - ^

0 0

Vf

—N nch-ch,

W 2 3

hcooh-nh2-

-ch2cooch2ch3

657 135

Table 29

66

.n-fi c— conh

H2N-fs] J "TIJLch ^

xoch, o | ,

j coor

(syn isomer)

r1

r2

-chococ (ch,) -

1

ch3

0 o h ~ Ì

—N nch_ch,

2 3

-chococ (ch,),

! 3rd

ch3

0, 0

f ~ {

—N nch, y = / 3

-chococ (ch,),

1

ch3

o, 0

-n n- (ch,). ch, \ / 2 4 3

-chococ (ch.),

1 3 3

CH3

W

-n n- (ch_) cch, 2 5 3

-chococ (ch,),

1 y y

CH3

w

-n n (ch,) -jch, '■> / 2 7 3

-chococ (ch3) 3

ch3

ov a -hwh «ch2,11ch3

-ch2ococ (ch3) 3

O". ,O

-il = / ch2ch3

-chocooc (ch,),

1

ch3

0 .0 -n nch-ch,

v f 2 3

67

Table 29 (continued)

657 135

(§4

O

H-

0 p

7 ~ i

-n nch-ch,

\ = / 2 3

- (ch2) 3ch3

Vf

—N nch.ch, N / 2 3

—Ch_c = c-ch_

2 / \ 3

V

0

0 0

—N nch-ch, S— / 2 3

-ch2ococ (ch3) 3

çh3

-0

0

-ch2ococ (ci ^) 3

ch, CH3 A

. -v

0

-ch2ococ (ch3) 3

0

~ nt

0

-ch2ococ (ch3) 3

"V

0

-chococ (ch,),

1

ch3

ch, §

0

-ch2ococ (ch3) 3

0V .0

M 7oV / o

-N N- <

W ©

* Hydrochloride

The physical properties, namely the melting points, infrared and magnetic nuclear magnetic resonance spectra, of the above compounds are the same as those obtained according to Examples 6, 7, 11 and 12.

657 135

68

Example U 3.73 (2H, q, J = 7Hz, ^ nch ^ ch 3),

(1) 7.29 g of diphenylmethyl-7- 3.91 (3H, s, -OCH3) are dissolved in a solvent mixture of 37 ml of trifluoroacetic acid and 10.8 g of anisole,

[2- (2-formamidothiazol-4-yl) -2- (syn) - methoxyiminoacet-sjf amido] -3- {[l- (4-ethyl-2,3-dioxo -1,2,3,4- tetrahydropyrazi- 5 4.42.4.95 (2H, ABq, J = 15Hz,), ^

nyl)] -methyl) -A3-cephem-4-carboxylate, whereupon the solution obtained in this way ^> - ch2 is reacted for 2 hours at room temperature. After completion of the implementation, the 5.21 (IH, d, J = 5Hz, Q-H), 5.89 (IH, dd, J = 5Hz,

Solvent by distillation under reduced pressure J = 8Hz, c7-H),

away. The resulting residue is mixed with 50 ml of diethyl-10 n -n—

ether is added, and the crystals formed are replaced by 6.65 (2H, bs, 7.46 (1H, s, 11) '

Filter collected, washed with 50 ml of diethyl ether in a sufficient amount and dried, 5.2 g (yield: 92.4%) of 7- [2- (2-formamidothiazol-4-yl) -2- ( syn) - me- 8.59 (IH, s, HCONH-), 9.77 (IH, d, J = 8Hz, -CONH-), thoxyiminoacetamido] -3- {[l- (4-ethyl-2, 3-dioxo-1,2,3,4-te-15

trahydropyrazinyl)] - methyl) - A3-cephem-4-carboxylic acid 12.58 (IH, bs, HCONH)

from melting point 155 to 158 ° C (decomposition). A similar manner is obtained in the table below

IR (KBr), cm-1: vc = 0 1775.1710.1675.1640 30 enumerated compounds.

NMR (d6-DMSO), 5 values:

20th

1.20 (3H, t, J = 7Hz,> nch2ch-J, 3.49 (2H, bs, Q-H),

Table 30

, 13-17-c conh 1

™ -u l ch2r2

\ 0ch3 cooh

(syn isomer)

connection

IR (KBrl m.p. (° C) 1 -1

; cm: vc = 0

R2

0 p

-N N-CH,

195-198

(Decomposition)

1775, 1720, 1680-1640

O 0 -NJJ- (CH2) 4CH3

122-125

(Decomposition)

1775, 1680, 1640

0, 0

M

-HJ- | CH2) 5CH3

165-170

(Decomposition)

1775, 1680, 1640

O 0

h-i rOy -N N (V-0

195-198

(Decomposition)

1775, 1685, 1650

0 0

-N N (CH_) -, CH, \ - / 2 7 3

155-158

(Decomposition)

1780, 1720, 1680-1640

H

-N N- (CH2) 1; ICH3

144-147

(Decomposition)

1778, 1685, 1660, 1645

69

657 135

Table 30 (continued)

T3

Q

0

186-188

(Decomposition)

1775, 1710, 1690, 1650

CH CH3

\ 3

v

218-221

(Decomposition)

1775, 1670, 1650

n

0

(2) To a solution of 5.63 g of 7- [2- (2-formamidothia crystals) are collected by filtration, whereby zol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- {[l - (4-ethyl- 5.5 g (yield: 79.6%) l-pivaloyloxyethyl-7- [2- (2-form-2,3-dioxo -1,2,3,4-tetrahydropyrazinyl)] - methyl j- A3-ce-amidothiazol-4-yl) -2- (syn) - methoxyiminoacetamido] -3-

phem-4-carboxylic acid in 25 ml of N, N-dimethylacetamide gives 25 ([1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] - me-man 1.52 g 1 , 8-diazabicyclo- [5,4,0] -7-undecene and 3.84 g of thylj-A3-cephem-4-carboxylate with a melting point of 140 to 1-pivaloyloxyethyl iodide while cooling with ice and leave this at 142 ° C.

React mixture for 30 minutes. Upon completion of IR (KBr), cm-1: vc = o 1780.1740.1680.1640

The reaction mixture is converted into a solvent. In a similar manner, the mixture of 100 ml of water and 100 ml of ethyl acetate shown in the table below can be poured. 30 31 Establish the connections listed. In this case, the organic layer is then separated off, and the compounds, as mentioned in Table 1, are washed with water and then dried over anhydrous magnesium sulfate using the same method as in Example 6- (1) sulfate . The solvent is produced by distillation with the difference, however, that instead of ion removal it is removed under reduced pressure and the resulting diphenylmethyl ester is used with the corresponding esters. 50 ml of diethyl ether were added to the residue. The resulting 35

Table 31

, n -ir- c conh -1—

HCOMM I I J Q-C „rP, 2

OCHj COOR '' - (syn isomer)

connection

Mp (° c)

IR (KBr), cm "1: vc = Q

R1

R2

-chococ (ch,),

1 3 3

CH3

o o

M

-n n-ch, W / J

182-188

(Decomposition)

1780, 1740, 1680-1640

-chococ (ch3) 3

ch3

0 0

Hi

-nwn (CH2) 4CH3

120-122

(Decomposition)

1783, 1740, 1680, 1640

-chococ (ch3) 3 ch3

0 0

M

-n n (ch2) 5ch3

108-115

1782, 1740, 1680, 1640

-chococ (ch,),

1 3 3

ch3

0 0

M

-n n (ch.) _ ch, \ - / 2 7 3

166-168

(Decomposition)

1780, 1740, 1680-1640

657 135

Table 31 (continued)

70

-CHOCOC (CH,),

1 3 3

CH3

0 O

M

-NwN- (CH2) llCH3

117-122

1785, 1745, 1685, 1645

-CH2OCOC (CH3) 3

0 0

-N N-CH.CH, \ - / Z. 3

158-160

1780, 1742, 1680, 1640

—CHOCOOCH-CH,

1 2 3

CH3

0 0

M

-N NCH-CH - \ - / 2 3

150-152

1780, 1760, 1680, 1640

*1

ir °

0 0

M

-N NCH-CH,

1 'A J

160-162

1780, 1680-1630

- + ca2) 3CB3

0 0 -N NCH2CH3

136-141

(Decomposition)

1780, 1720, 1680, 1640

-CH-C - CCH, 2 / x 3

0 0 \ c /

ii

0

0 0

M

-N N-CH-CH,> '2 3

165-168

(Decomposition)

1810, 1775, 1720, 1670, 1640

-CH2OCOC (CH3) 3

° p

M / \

193-195

(Decomposition)

1775, 1745, 1685, 1650

-CH2OCOC (CH3) 3

CH-

6

V

0

138-140.

(Decomposition)

1780, 1750, 1690, 1660

-CH2OCOC (CH3) 3

C ^ 3Ji3

N

V

0

158-164

(Decomposition)

1780, 1740, 1680-1640

* 1 diastereomer

(3) A solution of 5.5 g of l-pivaloyloxyethyl-7- [2- (2- 60 and 50 ml of water is added, whereupon the mixture is dissolved by formamidothiazol-4-yl) - 2- (syn) -methoxyiminoacetamido] - 3- Add sodium hydrogen carbonate to a pH value of j [1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] - me- of 6.0. Subsequently, the organic layer thyl) - A3-cephem-4-carboxylate, obtained in accordance with the above, is separated off and dried over anhydrous magnesium sulfate.

Set (2), in 27.5 ml of methanol, 1.13 ml of concentrated net are added, whereupon the solvent is removed by distillation

Hydrochloric acid was added, whereupon the reaction mixture was removed under reduced pressure. The residue is then with

Reacted for 2 hours at 35 ° C. After the reaction has ended, 45 ml of diethyl ether are added and the crystals are collected by filtration and the solvent is collected by distillation, reducing to 4.65 g (yield: 88.1%) of 1-pivaloyl.

removed pressure and the residue with 50 ml of ethyl acetate oxyethyl-7- [2- (2-aminothiazol-4-yl) - 2- (syn) -methoxyimino-

71

acetamido] -3- j [1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] - methyl i-A3-cephem-4-carboxylate, melting point 148 to 150 ° C receives.

IR (KBr), cm "1: vc = 0 1780.1740.1680.1640

NMR (d6 DMSO), 6 values:

0.90-1.39 (12H, m, -C (CH, k> nch2ch3),

1.52 (3H, d, J = 5Hz, -OCHO-), 3.52 (2H, bs, C2-H),

I.

CH3

3.76 (2H, q, J = 7Hz,> nch2ch3),

3.88 (3H, s, -och3),

4.38, 5.04 (2H, ABq, J = 15Hz, Ì

),

ch2-

657 135

5.21 (IH, d, J = 5Hz, Q-H), 5.87 (IH, dd, J = 5Hz, J = 8Hz, Q-H),

6.61 (2H, bs, ^ = <H] '6.78 (IH, s, "X 5 - - s H

7.04 (IH, q, J = 5Hz, -OCHO-), 7.22 (2H, bs, -NH2), CH3

10th

9.67 (IH. D, J = 8Hz, -CONH-)

The compounds mentioned in Table 15 32 below are obtained in a similar manner.

Table 32

■ N -n— C CONH

> <r y

r

-ch2-r '

-och.

COOR

(syn isomer)

Connection r!

r2

Mp (° c)

IR (KBr),

"-1.

c = o

NMR (dg-DMSO), S-V. values:

-chococ (ch,),

I J

ch-

o p

M

-n n — ch.,

198-201

(Decomposition)

1780, 1740, 1680

5

1640

1.19 (9H, s, -C (CH3) 3), 1.54 (3H, d, J = 5Hz, -OCHO-),

I.

C ^ 3

3.30 (3H, s,> N-CH3), 3.54 (2H, bs, C2-H), 3.88 (3H, s, -OCH3>, 4.40, 5.06 (2H, ABq , J = 15Hz, Sv), 5.24 (IH, d, J = 5Hz,

C ^ 2 ~

Cg-H), 5.91 (IH, dd, J = 5Hz,

J = 8Hz, C? -H), 6.46, 6.60 (2H,

ABq, J = 6Hz,> = <), 6.80 (IH, s, H H

"TT), 7.07 (IH, q, J = BTHz, -CH-),

S ^ H

I.

CH,

7.26 (2H, bs, -NH2), 9.74 (IH, d, J = 8Hz, -CONH-)

-CHOCOC (GH),

I J

CH-

O O

M

139-141

(Zer-

-n n- (ch0) after ^ settlement)

1783, 1740, 1680, 1640

0.87 (3H, t, J = 7Hz,> N (CH2) 4CH3), 1.18 (9H, s, -C (CH3) 3), 1.53 (3H, d, J = 5Hz, -CHO -),

ch

1.04-1.85 (6H, m,> NCH2 (CH2) 3CH3) 3.59 (2H, bs, C2-H), 3.72 (2H, t, J = 7Hz,> NCH2 (CH2) 3CH3 ), 3.91 (3H, s, -OCH3), 4.45, 5.08 (2H, ABq, J = 15H2, p.),

> ch2-

135

Table 32 (continued)

72

5.28 (IH, d, J = 5Hz, Cg-H), 5.92

(IH, dd, J = 5Hz, J = 8Hz, C? -H),

6.65 (2H, bs,> = <), 6.85 (IH, H H

s, X), 7.00 (IH, q, J = 5Hz, S H

-OCHO-), 9.82 (IH, d, J = 8Hz,

r ch3

-CONH-)

-chococ (ch,),

I 3 3

ch,

0 O

-n n (ch2) 5ch.

145-150 (decomposition)

1780, 1740, 1685, 1645

0.87 (3H, t, J = 7Hz,> N (CH2) 5CH3), 1.18 (9H, s, -C (CH3) 3),

1.03-1.79 (8H, m,> NCH2 (CH2) 4CH3), 1.53 (3H, d, J = 5Hz, -OCHO-),

CH,

3.60 (2H, bs, C2-H), 3.72 (2H, t, J = 7Hz,> NCH2 (CH2) 4CH3),

3.90 (3H, s, -OCH3), 4.41, 5.09 (2H, ABq, J = 15Hz, S),

5.25 (IH, d, J = 5Hz, Cg-H), 5.90

(IH, dd, J = 5Hz, J = 8Hz, C? -H),

6.63 (2H, bs, "> = <), 6.82 (ih, h h s, X) f 6.98 (IH, q, J = 5Hz, S H

-OCHO-), 9.75 (IH, d, J = 8Hz,

■ I

ch3

-CONH-)

-CHOCOC (CH,),

I 3 3

CH,

O O

• N =, N (CH2) 7CH3

170-172

(Decomposition)

1780, 1740, 1680, 1640

0.88 (3H, t, J = 8Hz,> N (CH2)? CH3), 1.02-1.43 (2IH, m, -C (CH3> 3,> NCH2 (CH2) gCH3), 1, 56 (3H, d,

73

657 135

Table 32 (continued)

J = 5Hz, -OCHO-), 3.38-3.83 (4H, CH,

m,> NCH2 (CH2) 6CH3, C2-H), 3.90 (3H, s, -OCH3), 4.43, 5.11 (2H, ABq, J = 15Hz, S-), 5.28

J-CH2-

(1H, d, J = 5Hz, Cg-H), 5.94 (IH,

dd, J = 5Hz, J = 8Hz, C7-H), 6.65

(2H, bs,> = <), 6.83 (IH, s, H H

"X '' 7.02 (1K, q, J = 5Hz,

s h

—Ocho-), 7.15 (2h, bs, -nh_),

r 2

ch3

9.70 (ih, d, j = 8hz, -conh-)

-CHOCOC (CH,),

I 3 3

CH,

O 0

M

153-158 (Zer-

N N (CH2) llCH3 settlement)

17 80, 1745, 1675, 1640

0.86 (3H, t, J = 7Hz,> N (CH2) l: LCH3), 1.18 (9H, s, -C (CH3) 3),

1.02-1.87 (20H, in,> NCH2 (CH2) 10CH3), 1.52 (3H, d, J = 5Hz, -OCHO-), 3.53 (2H, bs,

I.

. ch3

C2-H), 3.70 (2H, t, J = 7Hz,> NCH2 (CH2) 10CH3), 3.87 (3H, s, -OCH3), 4.38, 5.03 (2H, ABq, J = 15Hz,), 5.20 (IH, d,

ch2-

J = 5Hz, Cg-H), 5.85 (IH, dd, J = 5Hz, J = 8Hz, C7-H), 6.58 (2H, bs, X), 6.75 (IH, s, Nn ),

S S A

S H

7.01 (IH, q, J = 5Hz, -OCHO-),

r ch3

9.65 (IH, d, J = 8Hz, -CONH-)

657 135

Table 32 (continued)

74

-ch2ococ '(ch3) 3

0 0

M

-n n-ch-ch, 2 3

145-147

1780, 1740, 1675, 1640

1.01-1.35 (12H, m, -C (CH3) 3,> NCH2CH3), 3.47 (2H, bs, C2-H), 3.70 (2H, q, J = 7Hz,> KCH2CH3 ), 3.78 (3H, s, -OCH3), 4.30, 5.01 (2H, ABq, J = 15Hz, S),

CÜÄ ~

5.14 (IH, d, J = 5Hz, Cg-H), 5.67-

6.06 (3H, m, -0CH20-, C? -H),

6.55 (2H, bs,> = <) / 6.70 (IH, H H

s, X), 7.12 (2H, bs, —NH_), S H z

9.52 (IH, d, J = 8Hz, -CONH-)

-CHOCOOCH "CH,

I 2 3

CH,

O O

-lf ~~ 1> j-ch, ch, V — r 2 3

155-157

1780, 1760, 1680, 1640

1.23 (6H, t, J = 7Hz,> NCH2CH3, -OCH2CH3), 1.55 (3H, d, J = 5Hz, -OCHO-), 3.53 (2H, bs, C - H),

I ^

C ^ 3

3.76 (2H, q, J = 7Hz,> NCH2CH3),

3.86 (3H, s, -OCH3), 4.19 (2H, q, J = 7Hz, -OCH2CH3), 4.40,

5.05 (2H, ABq, J = 15Hz,),

5.21 (IH, d, J = 5Hz, Cg-H), 5.86 (IH, dd, J = 5Hz, J = 8Hz, C? -H), 6.52, 6.65 (2H, ABq , J = 6Hz, X), 6.74 (IH, s, X "),

H H S H

6.87 (IH, q, J = 5Hz, -OCHO-),

i ~

CH3

7.02 (2H, bs, -NH2), 9.65 (IH, d, J = 8Hz, -CONH-)

75

657 135

Table 32 (continued)

*1

Ä o ¥

* 2

0 O

M

-n nch-ch, 2 3

> 200

17 80, 1680, 1640

ch-

1.21 (3H, t, J = 7Hz,> NCH2CH3),

3.67 (2H, bs, C2-H), 3.81 (2H,

t, J = 7Hz,> NCH2CH3), 3.99 (3H, s,

-OCH3), 4.17-5.13 (5H, m, ^

-NH ©), 5.22 (IH, d, J = 5Hz, Cg-H),

5.83 (IH, dd, J = 5Hz, J = 8Hz,

C? -H), 6.95, 6.77 (2H, ABq,

J = 7Hz,> = <), 6.95 (0.5H, s,

H H

N '

s' H

X), 7.00 (0.5H, s, X ").

H

"J

s h

7.58-8.15 (5H, m,

),

ü- (0

H

9.87 (IH, d, J = 8Hz, -CONH-)

(ch2) 3ch3

-ch2c = cch3

V

O O

K

N NCH-CH - \ - / z J

139-144

(Decomposition)

1780, 1720, 1680, 1640

O O

! K

-n n-ch2ch3

0.63-1.85 (10H, m, -cooch2ch2ch2ch3,> nch2ch3),

3.55 (2H, bs, C2-H), 3.76 (2H, q, J = 7Hz,> NCH2CH3), 3.89 (3H, s, -OCH3), 4.30 (2H, t, J = 7Hz, -COOCH2CH2CH2CH3), 4.39, 5.12 (2H, ABq, J = 15Hz, p.),

C ^ 2 ~

5.25 (IH, d, J = 5Hz, Cg-H), 5.92

(IH, dd, J = 5Hz, J = 8Hz, C? -H),

6.68 (2h, bs,> = <), 6.82 (ih, h h s, X>, 7.28 (2H, bs, -NH-), S H Z

9.79 (IH, d, J = 8Hz, -CONH-)

17 3-175

(Decomposition)

1820, 17 80, 1730, 1680, 1640

1.19 (3H, t, J = 7Hz,> NCH2CH3),

2.20 (3H, s, -C = C-CH), 3.53

\ I —i

(2H, bs, C2-H), 3.73 (2H, q, J = 7Hz,> NCH2CH3), 3.84 (3H, s, -OCH3), 4.34, 5.06 (2H, ABq, J = 15Hz,), 5.09-5.30

CH ^ -

(3H, m, Cg-H, -OCH2Ç =), 5.87

(IH, dd, J = 5Hz, J = 8Hz, C? -H),

6.59 (2H, bs,> = <), 6.74 (IH, H H

s, X), 7.17 (2H, bs, -NH-), S H z

9.62 (IH, d, J = 8Hz, -CONH-)

657 135 76

Table 32 (continued)

1.24 (9H, s, -C (CH3) 3), 2.31 (3H,

CH-

s,)> - CH3), 3.40 (2H, bs, C2-H),

-CH2OCOC (CH3) 3

■ 0

0

141-142

(Decomposition)

1775, 1740, 1650

3.99 (3H, s, -0CH3), 5.01, 5.33 (2H, ABq, J = 15Hz, S-.),

Xcn2-

5.09 (IH, d, J = 5Hz, Cg-H), 5.61-6.14 (3H, m, -0CH20-, C? —H), 6.71 (2H, bs, -NH2) ,

6.77 (IH, s,), 6.86,

s £

7.24 (2H, ABq, J = 10Hz, s ^ H),

A,

9.34 (IH, d, J = 8Hz, -CONH-)

1.19 (9H, s, -C (CH3) 3), 2.27 (6H,

C "3 f" 3

s, y <CH3), 3.35 (2H, bs, C2-H),

-CH2OCOC (CH3) 3

V

156-159 (decomposition)

1775, 1740, 1670

S

1640

XCH3

3.86 (3H, s, -OCH3), 5.02, 5.40

ii 0

(2H, ABq, J = 15Hz,),

Xch2-

5.20 (IH, d, J = 5Hz, Cg-H), 5.70-6.14 (3H, m, C? —H, -0CH20-),

6.81 (IH, s, 7'26 <2H '

s p

m, -NH2), 7.98 (IH, s,> -H)

* 3

0

II

1.17 (9H, s, -C (CH3) 3), 3.43 (4H, bs, C2-H, -NH2), 3.85

-CH2OCOC (CH3) 3

0

0

151-153

(Decomposition)

1780, 1745, 1660

(3H, s, -OCH3), 4.75, 5.01 (2H, ABq, J = 15Hz,), 5.16

J-CHj-

(1H, d, J = 5Hz, Cg-H), 5.60-6.08 (3H, m, C? -H, -0CH20-), 6.77

(IH, s, '6.89, 7.12 (2H, S H

ABq, J = 10Hz, jj ^ S '' 9.62 (1H 'd, J = 8Hz, -CONH-)

77

657 135

Table 32 (continued)

* 3

1.24 (9H, S, -C (CH3) 3), 3.53 (2H, bs, C2-H), 4.06 (3H, s, -OCH3),

-ch2ococ (ch3) 3

N

0

134-137

(Decomposition)

1780, 1750, 1680

s

1650

4.70, 5.35 (2H, ABq, J = 15Hz,

), 5.25 (IH, d, J = 5Hz,

^ CHj-

Cg-H), 5.98-6.48 (5H, m, -0CH20-, C7-H, -NH2), 6.88

(IH, s, Nj-), 7.54, 7.70 (2H,

S ä

ABq, J = 5Hz, YH) '8.33 (1H' s

A «

—H), 8.59 (IH, d, J = 8Hz,

-CONH-)

(measured in CDC13>

* 3

CH,

1 3

1.18 (9H, s, -C (CH3) 3), 1.53 (3H, d, J = 6Hz, -OCHO-), 2.28 (3H, s,

1

CH3

-CHOCOC (CH),

1 y y

CH3

0

143-145

(Decomposition)

1780, 1740, 1655

•) ^ - CH3), 3.47 (4H, bs, C2-H, -NH2), 3.89 (3H, s, -OCH3), 4.91, 5.29 (2H, ABq, J = 15Hz ,),

J-CHz-

5.22 (IH, d, J = 5Hz, Cg-H), 5.88 (IH, dd, J = 5Hz, J = 8Hz,

Cy-H), 6.92 (IH, s, NJ ~> '

s s

6.93, 7.41 (2H, ABq, J = 10Hz,

"lf"), 6.96 (IH, q, J = 6Hz, -OCHO-), - ^ H | ~

CH3

9.74 (IH, d, J = 8Hz, -CONH-)

657 135

Table 32 (continued)

78

1.21 (9H, s, -C (CH3) 3, 3.65 (2H,

bs, C2-H), 3.93 (3H, s, -OCH-j),

-CH2OCOC (CH3) 3

O 0

} -i / ° \

-N N— (> 0

w ¥

154-160

(Decomposition)

1775, 1750, 1700, 1650

4.44, 5.14 (2H, ABq, J = 15Hz,

), 5.28 (IH, d, J = 5Hz,

Xq & j-

Cg-H), 5.78-6.76 (5H, m, C? -H,

-OCH-O-,) = K), 6.89 (IH, s, Z H H

X ") / 7.36 (2H, bs, NH--), 3 - H 7.72-8, 27 (5H, m, ^, - ^ °)),

9.81 (IH, d, J = 8Hz, -CONH-)

* 1 diastereomer

* 2 chlorohydrate (the salt is produced in a manner known per se).

* 3 The desired compound is produced by reacting the trifluoroacetic acid salt with a halide in the presence of 1,8-diazabicyclo- [5,4,0] - 7-undecene at a temperature between - 5 and 0 ° C.

(4) A solution of 1.05 g of 7- [2- (2-formamidothiazol-4-yl) -2- (syn) methoxyiminoacetamido] -3- ([l- (2,3-dimethyl-

6-oxol, 6-dihydropyrazinyl)] - methylj-A3-cephem-4-car-bonic acid, obtained according to paragraph (1) above, in 10 ml of methanol is mixed with 0.38 ml of concentrated hydrochloric acid and the mixture obtained during Implemented for 2 hours at 35 ° C. When the reaction is complete, the solvent is removed by distillation under reduced pressure. The residue is then mixed with 10 ml of diethyl ether, and the crystals are collected by filtration, giving 0.43 g (yield: 84.8%) of the chlorohydrate

7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetami-do] -3- | [l- (2,3-dimethyl-6-oxol, 6-dihydropyrazinyl)] -me-thyl j- A3-cephem-4-carboxylic acid of melting point 250 ° C or above.

IR (KBr), cm-1: vc = 0 1765.1660.1620

NMR (d6-DMSO), 5 values:

45

50

2.20 (6H, bs, -CH3 x 2), 3.18 (2H, bs, C2-H), 3.90 (3H, s, -OCH3),

4,94,5,24 (2H, ABq, J = 15Hz, S ~ ^ _Ch2-> '

5.10 (IH, d, J = 5Hz, C6-H), 5.78 (IH, dd, J = 5Hz, J = 8Hz, Ct-H),

6.89 (IH, s, g Xh> '7.82 (IH, s,> -h),

9.79 (1H, dd, J = 8Hz, -CONH-)

Example 12

(1) In a similar manner to Example 7- (1) above, the compounds shown in Table 33 below can be prepared from the starting materials shown below.

79

657 135

N-ir-C-COOH

\

Starting material (syn isomer)

OCH2COOR

NH.

T3Ô-

0, 0

CH..N N-CH_CH, / ^ -5

COOCH «g>) 2

^ tUÌ

/ N "n — Ç CONH

O'

V

0 o

M

.N V ^ NCH 2NWN-CH 2CH3

\

0CH2C00R

COOCH (<o)).

(desired compound, syn isomer)

Table 33

Desired connection

Mp (° c)

IR (KBr), cm "1: vc = 0

Rl

-®. -

127-130

(Decomposition)

1780, 1720, 1685, 1645

- <PP

127-130

(Decomposition)

1780, 17 20, 1685, 16 35

-CH2CH3

150-152

(Decomposition)

1780, 1720, 1680, 1645

(2) The compounds listed in Table 34 are obtained by reacting the above-mentioned compounds in a similar manner to that described in Example 7- (2).

135

Table 34

80

n-n-c conh 1 f ^ sv] <l_p hcooh.h2n- (j j ^ j_n1ach2n n-ch2ch3

\ 0 I

\, cooh och, coor z (Syr. isomer)

connection

R1

Mp (° C)

IR (KBr) cm 1: Vc = Q

NMR (dg-DMSO), 5 ", Hertel

- (ö)

123-125

(Decomposition)

1770, 1680, 1670, 1630

1.25 (3H, t, J = 7Hz,> NCH2CH3), 3.50 (2H, bs, C2-II), 3.76 (2H, q, J = 7Hz,> NCH2CH3), 5.03 (2H , s, -OCH2CO-), 4.50-5.00 (2H, m, S- ^), 5.20 (IH, d, J = 5Hz,

^ cv

C.-H), 5.90 (IH, dd, J = 5Hz, J = 9Hz,

O

C - H), 6.70 (2H, s,) = * (), 6.98 H H

(IH, s, T), 7.30 (5H, bs, - ((S)), S / H w

8.27 (IH, s, HCOOH), 9.80 (IH, d, J = 9Hz, -CONH-)

~ t§0

125-128

(Decomposition)

1770, 1680, 1670, 1635

1.25 (3H, t, J = 7Hz,> NCH2CH3), 2.00 (2H,

H H

'm, X> 2.80 (4H'm'

), 3.50 (2H, bs, C2-H),

H H

3.75 (2H, q, J = 7Hz,> NCH2CH3), 5.00 (2H, s, -OCH2CO-), 4.50-5.00 (2H, m, S \), 5.25 (IH d

J = 5Hz, Cg-H), 5.95 (IH, dd, J = 5Hz, J = 9Hz, C? —H), 6.70 (2H, s,), 6.96 (IH, s, N -ip),

H H

7.30 (3H, m.

H

H H

A

),

8.27 (IH, s, HCOOH),

9.80 (IH, d, J = 9Hz, -CONH-)

Table 34 (continued)

81

657 135

-CH2CH3

122-123

(Decomposition)

1770, 1720, 1670, 1640

1.22 (6H, t, J = 7Hz,> NCH2CH3, -OCH2CH3), 3.51 (2H, bs, C2-H)

3.76 (2H, q, J = 7Hz,> NCH2CH3), 4.18 (2H, q, J = 7Hz, -OCHjCH ^,

4.77 (2H, s, -OCH2CO-), 4.50-5.00 (2H, m, Sv,), 5.24 (IH, d,

'X

CH2-

J = 5Hz, Cg-H), 5.91 (IH, dd, J = 5Hz, J = 9Hz, C? -H), 6.69 (2H, s,

> t 6.96 (IH, s, N-n-),

ü fi) {

S 'H

8.27 (IH, s, HCOOH), 9.84 (IH, d, J = 9Hz, -CONH-)

Example 13 Dried magnesium sulfate. The solvent is through

(1) To a solution of 2.72 g of 2- (2-tert-amyloxycarbox) distillation under reduced pressure. The Rück-amidothiazol-4-yl) -acetic acid in 40 ml of anhydrous stand with 35 ml of diethyl ether are added, and the ethylene chloride formed is added 1.06 g of N-methylmorpholine and 3 "crystals are collected by filtration, the mixture then being cooled to 3.62 ° C. to - 35 ° C. Then g (yield: 90.5% ) Diphenylmethyl-7- [2- (2-tert.-amyl-man with 1.12 g of chlorocarbonic acid ethyl ester and leaves the oxycarboxamidothiazol-4-yl) -acetamido] -3- {[1- (4-ethyl-mixture a temperature of -35 to -25 ° C during 2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] -methyl) -A3-ce-11 ji hours, whereupon 5.18 g of diphenylmethyl-phem-4 carboxylate of melting point 152 to 154 ° C (Zer-7-amino-3- | [l- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyra-35 settlement) is obtained.

zinyl)] -methyl | - A3-cephem-4-carboxylate is added. Then IR (KBr), cm-1: vc = o 1780.1720.1685.1640

the reaction mixture is at -30 to for 1 hour. The following compound can be prepared in a similar manner.

—20 ° C. and then for 1 hour at a temperature: 6.15 g (yield: 82.7%) of diphenylmethyl-7- [2- (2-temperature from −10 to 10 ° C.). tert-amyloxycarboxamidothiazol-4-yl) -acetamido] -3 - {[1-ended reaction, the solvent is distilled by 40- (3,6-dioxo-l, 2,3,6-tetrahydropyridazinyl)] methyl) - A3 ce-tion removed under reduced pressure. The residue becomes phem-4-carboxylate; Melting point 136 to 139 ° C (then dissolved in 40 ml of ethyl acetate and 30 ml of water. The organization).

The niche layer is separated and again with 30 ml of water IR (KBr), cm-1: vc = o 1780.1720.1665

transferred. Then the mixture using sodium hydrogen (2) The compounds listed in Table 35 are

carbonate with ice cooling to a pH of 7.0 by obtaining the one in paragraph (1) above. The organic layer is separated off, reacted with 30 ml of compounds in the same manner as in Example water and then with 30 ml of a saturated aqueous 6- (3).

washed with sodium chloride solution and over anhydrous

COOH

connection

Mp (° c)

IR (KBr), cm "1: vc = 0

NMR (dg — DMSO), S value e:

R2

Vf

-N N—CH.CH,

\ / 2 3

109-115

(Decomposition)

1775, 1690, 1630

1.20 (3H, t, J = 7Hz,> NCH2CH3), 3.50 (2H, bs, C2-H), 3.61-3.81 (4H, m, ^ NCH2CH3, Nj-CH2 "), 4.47, 5.17 (2H, ABq, J = 15Hz,

657 135 82

Table 35 (continued)

), 5.21 (IH, d, J = 5Hz, Cg-H), 5.60-6.02 <3H, m, C? -H, j ^ 3 ^), 6.81 (IH,

s, N-n-), 9.24 (IH, d, J = 8Hz, -CONH-) S H

$

> 200

1770, 1710, 1670, 1630

.

3.43 (2H, bs, C2-H), 3.67 (2H, bs, N-jCH2 ~), 5.08 {2H, bs, Svj), 5.16 (IH, d, J = 5Hz,

AcH2-

II

0

Cg-H), 5.78 (IH, dd, J = 5Hz, J = 8Hz, C? -H),

6.76 (IH, s, NX) '7.01, 7.14 (2H, ABq, S nH

J = 10Hz,), 9.29 (IH, d, J = 8Hz, -CONH-)

Example 14

6.82 g of diphenylmethyl-7- (4-bromo-3-oxobutyramido) -3-} [1- (4-ethyl-2,3-dioxo-l, 2,3) is dissolved in 48 ml of N, N-dimethylacetamide , 4-tetrahydropyrazinyl)] -methyl] - A3-ce-phem-4-carboxylate and 1 g of thiourea and the mixture is allowed to react for 2 hours at room temperature. When the reaction has ended, the reaction mixture is poured into a solvent mixture of 500 ml of water and 500 ml of ethyl acetate and the mixture is adjusted to a pH of 6.7 by adding sodium hydrogen carbonate. The organic layer is separated and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue is then dissolved in 33 ml of trifluoroacetic acid and 8 ml of anisole, and the mixture is reacted for 1 hour at room temperature. When the reaction is complete, the solvent is removed by distillation under reduced pressure. 40 ml of diethyl ether are added to the residue, and the crystals formed are collected by filtration, giving 4.50 g (yield: 74.1%) of the trifluoroacetic acid salt of 7- [2- (2-aminothi-azol-4-yl ) -acetamido] -3-j [1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] -methyl} -A3-cephem-4-carboxylic acid, melting point 109-115 ° C (decomposition) is obtained.

The following compound can be prepared in a similar manner: Trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) acetamido] -3- | [l- (3,6-dioxo- 1,2,3,6 -tetrahydropyrida-zinyl)] -methyl j -A3-cephem-4-carboxylic acid with a melting point of 200 ° C. or above.

The physical properties, namely infrared and magnetic nuclear magnetic resonance values of this compound, are identical to those according to Example 13- (2).

35

Preparation Example 1 An aqueous sodium salt solution of 7- [2- (2-aminothi-azol-4-yl) -2- (syn) - methoxyiminoacetamido] -3 - [[1- (2,3-dioxo- 1,2,3 , 4- tetrahydropyrazinyl)] -methyl 1- A3-cephem-4-

40 carboxylic acid is treated in the usual way to obtain a freeze-dried and sterilized sodium salt. 1 g (potency) of this sodium salt is dissolved in 20 ml of physiological saline in order to obtain an injection solution.

45 Preparation example 2

1 g (potency) of the freeze-dried product obtained according to preparation example 1 above is dissolved in 4 ml of a 0.5% by weight /% aqueous lidocaine hydrochloride solution, a dilutable solution for injection being obtained.

50

Preparation example 3 1 g (potency) of the freeze-dried product obtained according to preparation example 1 is dissolved in 20 ml of a 5% glucose solution, whereby an injection solution is obtained.

The other compounds of the formula I can also be converted into the corresponding freeze-dried products (sodium salts) or into injection solutions by treating them in accordance with preparation examples 1 to 3.

C.

Claims (36)

657 135 PATENT CLAIMS 1. Cephalosporin derivatives of the formula: r- N n -a conh- r A coor ch2r (I) R5 represents hydrogen or a protected or unprotected amino group; and A for a group of the formula -CH2- or a group of the formula: 5 -c- ' II n * 18 or or their salts, wherein R1 represents hydrogen or a carboxyl protecting group; R2 for a group of the formula: 10th o o . 6 -n n — r , 7 rows v » where R18 is hydrogen, a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic group or a hydroxyl protecting group or a group of the formula: 15 O V t R13 ! rRl4 V 0 ^ <R15 \ , R19 R20 stands in what R6 represents hydrogen, hydroxyl, nitro, carbamoyl, thio-carbamoyl, sulfamoyl or a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl -, Al-koxy-, alkylthio-, acyloxy-, cycloalkyloxy-, aryloxy-, Al-koxycarbonyl-, cycloalkyloxycarbonyl-, acyloxycarbonyl-, aralkyloxycarbonyl-, alkylsulfonyl-, cycloalkylsulfonyl-, arylsulfonyl-, heterocyclusulfonl-, alkylcarbamoyl kylcarbamoyl-, Alkylthiocarbamoyl-, Dialkylthiocarbamo-yl, Acylcarbamoyl-, Acylthiocarbamoyl-, Alkylsulfonylcar-bamoyl-, Arylsulfonylcarbamoyl-, Alkylsulfonylthiocarba-moyl-, Ajylsulfonylthiocarbamoyl-, alkylsulfamoyl, dial-kylsulfamoyl-, alkoxythiocarbonyl, Alkylidenamino-, Cy-cloalkylmethylenamino -, Arylmethylenamino-, Heterocy-clusmethylenamino- or heterocyclic group or a group of the formula: 20 means wherein R19 and R20, which are the same or different, each represent hydroxyl or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group, and the bond - means that the compound is a syn -Isomer or an anti-isomer or a mixture thereof. 25 2. Cephalosporin derivatives or their salts according to claim 1, characterized in that R3 is hydrogen. 3. cephalosporin derivatives or their salts according to claim 1 or 2, characterized in that R4 is hydrogen. 30 4. cephalosporin derivatives or their salts according to one of claims 1 to 3, characterized in that R5 stands for amino. 5. cephalosporin derivatives or their salts according to any one of claims 1 to 4, characterized in that A for a 35 group of formula: -c- 40 L18 -n: / , r16 V7 where R16 and R17, which are the same or different, each represent hydrogen or an alkyl group or R16 and R17 together with the adjacent nitrogen atom form a ring, in which R7, R8, R9, R10, R11, R12, R14 and R15, which are the same or different, each represent hydrogen, a halogen atom or a substituted or unsubstituted alkyl, aralkyl or aryl group and R13 represents hydrogen, a halogen atom, carboxyl, sulfo, carbamoyl, thiocarbamoyl or a substituted or unsubstituted alkyl, Aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclesulfonyl, alkylcarbamoyl, dialkylcarbam , Alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl or arylsulfonylthiocarbamoyl group; R3 represents hydrogen or an alkoxy group; R4 represents hydrogen or a halogen atom; is in which R18 and the bond '- have the meanings given in claim 1. 6. cephalosporin derivatives or their salts according to claim 5, characterized in that R18 for a substituted 45 or unsubstituted alkyl group. 7. cephalosporin derivatives or their salts according to any one of claims 1 to 6, characterized in that A for a group of the formula: 50 _c_ il N \) CH3 55 (syn isomer) stands. 8. cephalosporin derivatives or their salts according to one of claims 1 to 6, characterized in that A for a group of the formula: 60 -C- II N \ 65 ochjcoor1 (syn isomer), in which R1 has the meaning given in claim 1. 657 135 9. Cephalosporin derivatives or their salts according to one of claims 1 to 6, characterized in that A for a group of the formula: -C-II N CH3 \ O-C-COOR1 I. ch3 (syn isomer), in which R1 has the meaning given in claim 1. 10. Cephalosporin derivatives or their salts according to one of claims 1 to 9, characterized in that R2 for a group of the formula: o, 0 ^ 6 -n n-r is where R6 has the meaning given in claim 1. 11. Cephalosporin derivatives or their salts according to claim 10, characterized in that R6 represents hydrogen, a heterocyclic group, a substituted alkyl, aralkyl or cycloalkyl group or a group of the formula: -N: R16 \ Rn stands, where R16 and Ri7 have the meanings given in claim 1. 12. Cephalosporin derivatives or their salts according to claim 10, characterized in that R6 represents hydrogen, a substituted or unsubstituted alkyl, aralkyl or cycloalkyl group or a group of the formula: -n: r16 R17 stands, wherein R16 and R17 have the meanings given in claim 1. 13. Cephalosporin derivatives or their salts according to one of claims 1 to 9, characterized in that R2 for a group of the formula ■ yi-. stands, wherein R7, R8 and R9 have the meanings given in claim 1. 14. Cephalosporin derivatives or their salts according to claim 13, characterized in that R7, R8 and R9, which are the same or different, each represent hydrogen or an alkyl group. 15. Cephalosporin derivatives or their salts according to one of claims 1 to 9, characterized in that R2 for a group of the formula: stands, wherein R10, R11 and R12 have the meanings given in claim 1. 16. Cephalosporin derivatives or their salts according to lo spruch 15, characterized in that R10, R11 and R12, which are the same or different, each represent hydrogen, a halogen atom or an alkyl group. 17. Cephalosporin derivatives or their salts according to one of claims 1 to 9, characterized in that R2 for i5 is a group of the formula: 20th 25, where R13, R14 and R15 have the meanings given in claim 1. 18. Cephalosporin derivatives or their salts according to claim 17, characterized in that R13, R14 and R15, which are the same or different, each represent hydrogen or an alkyl group. 19.7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-acetamido] -3- l [l- (2,3-dioxo-l, 2,3,4-tetrahydropyrazinyl)] -methyl | -A3-cephem-4-carboxylic acid, its esters or salts according to claim 1. 35 20.7- [2- (2-aminothiazol-4-yl) -2- (syn) -carboxymethoxy-iminoacetamido] -3- | [l- (2,3-dioxo-l, 2,3,4-tetrahydropyra- zinyl)] -methyl} -A3-cephem-4-carboxylic acid, its esters or salts according to claim 1. 21.7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-40 acetamido] -3-1 [1- (4-methyl-2,3-dioxo-1,2,3, 4-tetrahydro-pyrazinyl)] -methyl} -A3-cephem-4-carboxylic acid, its esters or salts according to Claim 1. 22.7- [2- (2-aminothiazol-4-yl) -2- (syn) -carboxymethoxy-iminoacetamido] -3- | [l- (4-methyl-2,3-dioxo -1,2,3,4 -tetra-45 hydropyrazinyl)] methyl) - A3-cephem-4-carboxylic acid, its esters or salts according to claim 1. 23.7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-acetamido] -3- {[l- (4-ethyl-2,3-dioxo-1,2,3,4 -tetrahydropy-razinyl)] -methyl 1- A3-cephem-4-carboxylic acid, its esters or salts according to claim 1. 24.7- [2- (2-aminothiazol-4-yl) -2- (syn) -carboxymethoxy-iminoacetamido] -3- {[l- (4-ethyl-2,3-dioxo-l, 2,3,4 -tetra-hydropyrazinyl)] -methyl} -A3-cephem-4-carboxylic acid, its esters or salts according to claim 1. 55 25.7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino- acetamido] -3- | [l- (4-isopropyl-2,3-dioxo-1,2,3,4-tetrahy-dropyrazinyl)] -methyl} -A3-cephem-4-carboxylic acid, its esters or salts according to Claim 1. 26.7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-60 acetamido] -3- j [l- (4-dimethylamino -2,3-dioxo-l, 2,3, 4-te-trahydropyrazinyl)] -methyl} - A3-cephem-4-carboxylic acid, its esters or salts according to Claim 1. 27.7- [2- (2-aminothiazol-4-yl) -2- (syn) carboxymethoxyiminoacetamido] -3- {[1- (4-dimethylamino-2,3-dioxo-651,2,3,4 -tetrahydropyrazinyl)] - methyl) -A3-cephem-4-car-bonic acid, its esters or salts according to claim 1. 28.7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-acetamido] -3- | [l- (2-oxo-l, 2-dihydropyrazinyl)] methyl) - 657 135 4th À3-cephem-4-carboxylic acid, its esters or salts according to claim 1. 29.7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-acetamido] -3- j [l- (3,6-dioxo-l, 2,3,6-tetrahydropyridazi-nyl )] -methyl) -A3-cephem-4-carboxylic acid, its esters or salts according to claim 1. 30.7- [2- (2-aminothiazol-4-yl) -2- (syn) -carboxymethoxy-iminoacetamido] -3- ([l- (3,6-dioxo-l, 2,3,6-tetrahydropyri-dazinyl )] -methyl) - A3-cephem-4-carboxylic acid, its esters or salts according to claim 1. 31.7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-acetamido] -3- j [l- (3-methyl-6-oxo-l, 6-dihydropyridazinyl)] -methyl) -A3-cephem-4-carboxylic acid, its esters or salts according to claim 1. 32.7- [2- (2-aminothiazol-4-yl) -2- (syn) - carboxymethoxy-iminoacetamido] -3- {[1- (3-methyl-6-oxo-l, 6-dihydropyri-dazinyl)] -methyl) - A3-cephem-4-carboxylic acid, its esters or salts according to claim 1. 33. A process for the preparation of cephalosporin derivatives of the formula (I) according to claim 1 and the salts of these compounds, characterized in that a compound of the formula: is, wherein R18 and the bond - have the meanings given in claim 1. 35. The method according to claim 33 or 34, characterized in that one carries out the reaction at a temperature s of -50 to +40 3C. 36. Process for the preparation of cephalosporin derivatives of the formula (I) according to claim 1 and the salts of these compounds, characterized in that a compound of the formula: 10th xch2c0-a-c0nh- .r CH2R coor .28. r ch2R coor or a salt thereof, wherein R28 is amino or a group of the formula: R31-R32 ' ~ C = C-NH- I. R33 wherein R31, R32 and R33, which are the same or different, each represent hydrogen or an organic radical not participating in the reaction, or a group of the formula: or a salt thereof, in which X represents a halogen atom and R1, R2, R3 and A have the above meanings, with a compound of the formula: H2NCR5 II S (XII) 2S wherein R5 has the meaning given above, and if desired converting the compound obtained into a salt. 37. Method according to claim 36, characterized in that A for a group of the formula: 30th -Olli N 18th stands, where R18 and the bond 35 have given meanings. which in claim 1 40 38. The method according to claim 36 or 37, characterized in that one carries out the reaction at a temperature of 0 to 100 CC. 39. Process for the preparation of cephalosporin derivatives of the formula: r34. R35 ' ? C = N- wherein R34 and R35, which are the same or different, each represent hydrogen or an organic radical not participating in the reaction, and R1, R2 and R3 have the above meanings, with a compound of the formula: a-cooh 45 -.- crr ^ V-v (Ib) OR 18th coor 50 in which the various symbols have the meanings given in claim 1 and the salts of these compounds, characterized in that a compound (V) of the formula: 55 or a reactive derivative thereof on the carboxyl group, in which R4, R5 and A have the above meanings, and if desired converting the compound obtained into a salt. 34. The method according to claim 33, characterized in that A for a group of the formula: -c- _ n — n coconh Holy * 60 n- ^ ch2r2 coor1 (XIV) 65 OR 18th or a salt thereof, in which R1, R2, R3, R4 and R5 have the above meanings, with a compound of the formula: H2NOR18 (XV) or a salt thereof, in which R18 has the above meaning, 657 135 reacted and the compound obtained, if desired, converted into a salt. 40. The method according to claim 39, characterized in that one carries out the reaction at a temperature of 0 to 100 ° C. 41. Pharmaceutical preparation which is useful for the treatment of bacterial infections in humans and animals, characterized in that it contains an antibacterially effective amount of a cephalosporin or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32 in combination with a pharmaceutically acceptable inert Contains diluent or carrier.