CH660010A5 - CEPH-3-EM-4-CARBONIC ACIDS WITH AN AMINOGROUP AND A SUBSTITUTED METHYLGROUP IN 7-POSITION OR IN 3 POSITION AND THEIR PRODUCTION PROCESS. - Google Patents

Description

The present invention relates to novel A3-cephem-4-carboxylic acids bearing a substituted or unsubstituted amino group in the 7-position and A3-cephem-4-carboxylic acids bearing a substituted methyl group 20, their salts and processes for their preparation.

These compounds correspond to the formula:

25th

30th

'Ph

(I)

ch2r coor in which R1, R2, R3 and R4 have the meanings given in claim 1.

The compounds of formula I and their salts are valuable intermediate products for the production of cephalosporins, which have a broad antibacterial spectrum, show excellent antibacterial activity against gram-positive and gram-negative bacteria, are resistant to bacterial-produced β-lactamase, and are low in toxicity 40, are readily absorbable when administered orally or parenterally, and have an excellent therapeutic effect on diseases in humans and animals.

The inventors have found that new compounds 45 of the formula II and their salts have the above-mentioned excellent therapeutic properties (Swiss Patent No. 657 135):

r-

50

C00H

in which R3 and R4 have the meanings given in claim 1 and R34 represents a substituted or unsubstituted acyloxy or carbamoyloxy group, or a salt thereof with a compound of the formula (purple), (Illb), (IIIc) or (Illd) in the presence of an acid or a complex compound of an acid, which protects the carboxyl group and, if desired, converts the product into a salt.

30. The method according to claim 29, characterized in that R3 is hydrogen.

31. The method according to claim 30, characterized in that a Lewis acid or a complex compound of a Lewis acid is used as the acid or complex compound of an acid.

.n-

-conh

, 22

coor

55

in which R1, R2 and R3 have the meanings already given,

R22 represents hydrogen or a halogen atom;

R23 represents hydrogen or a protected or unprotected-6o te amino group; and

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

65

-c-

II

n for OR

R24 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:

means where R25 and R26, which are the same or different, each represent hydroxyl or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group, and the bond / vt & means that the compound is a syn isomer or can be an anti-isomer or a mixture thereof.

The invention further relates to processes for the preparation of the aforementioned ceph-3-em-4-carboxylic acids and their salts.

Unless otherwise stated, the terms used in this description 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, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, hep-tyl, 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, pentane-carbonyl 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, toluo-yl, 2-naphthoyl and the like, and a heterocyclic carbonyl group e.g. Thenoyl, 3-Furoyl, Nicotino-yl 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. Cyclopentenyl, cyclo-hexenyl and the like; the term "cycloalkadienyl" means cycloalkadienyl of 5 to 7 carbon atoms and includes e.g. Cyclopentadienyl, cyclohexadienyl and the like; the term "aryl" includes e.g. Phenyl, naphthyl, indanyl and the like; the term "aralkyl" includes e.g. Benzyl, phenylethyl, 4-methylbenzyl, 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, isothia

5 660 010

zolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl, 4- (5-methyl-2-pyrrolinyl), 4- (2-pyrrolinyl), N-methylpiperidinyl, quinolyl, phenazinyl, 1,3-benzodioxolanyl, benzofu-5 ryl, benzothienyl, benzoxazolyl, benzothiazolyl, phthalidyl, coumarinyl and the like; the term "heterocyclusalkyl" means a group consisting of a heterocyclic group as defined above and an alkyl group as defined above; and the term "halogen atom" includes e.g. io fluorine, chlorine, bromine and iodine.

The symbol R1 in the formulas in this description represents hydrogen or a carboxyl protecting group; and the carboxyl protecting group includes those conventionally used in the fields of penicillins and cephalo-15 sporins, for example ester-forming groups which can be removed by catalytic hydrogenation, chemical reduction or treatment under other mild conditions, an ester-forming group which is easily in one 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 easily removed by treatment with water or an alcohol, and various other well-known ester-forming groups. 25 Of these protecting groups, the following are preferred:

(a) alkyl groups, e.g. Alkyl with 1 to 4 carbon 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, cycloalkyl, aryl, alkylthio, alkylsulfinyl, Alkylsulfonyl, alkoxycarbonyl, 5-alkyl-2-oxo-l, 3-dioxol-4-yl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4-imidazolyl, phthalimi- 35 do, succinimido, azetidino, aziridino, pyrrolidino, pi-peridino, morpholino, thiomorpholino, N-lower alkyl pi-perazino, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl -, Thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, quinolyl, 40 phenazinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, coumarinyl, 2,5-dimethylpyrrolidino , 4,5,6-tetrahydropyrimidinyl-, 4-methylpiperidino-, 2,6-dimethylpiperidino-, 4- (5-methyl-2-pyrrolinyl) -, 4- (2-pyrrolinyl) -, N-methylpiperidinyl-, 1 , 3-benzodioxolanyl, 45 alkylamino, dialkylamino, acyloxy, acylthio, acylamino, Dialkylaminocarbonyl-, alkoxycarbonylamino-, al-kenyloxy-, aryloxy-, aralkyloxy-, cycloalkyloxy-, cycloal-kenyloxy-, heterocyclusoxy-, alkoxycarbonyloxy-, alkenyl-oxycarbonyloxy-, aryloxycarbonyloxy-, aralkyloxycarbo-50-nyloxyoxyoxyyloxycarbyl-50oxycarbonyloxy-, oxycarboxy-alyloxy- oxycarboxy-50-nyloxy- oxycarbonyl nyl, aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, heterocycleoxycarbonyl or alkylanilino groups or alkylanilino groups which are substituted by a halogen atom, a Niederal-55 kylgruppe or a Niederalkoxygruppe,

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

(d) alkenyl groups,

so (e) alkynyl groups,

(f) phenyl groups, substituted phenyl groups, in which at least one of the substituents is selected from the substituents specifically mentioned in paragraph (b) above, or aryl groups, such as groups of the formula:

660 010

where -Y1- for -CH = CH-O-, -CH = CH-S-, -CH2CH2S-, -CH = N-CH = N-, -CH = CH-CH = CH-, -CO-CH = -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:

-CH (CH2) mOR27, -CHOCOOR27 and -CH (CH2) mCOOR27

R28

R28

R29

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, in which at least one of the substituents is selected from those specifically mentioned in paragraph (b) above,

(h) heterocyclic groups or substituted heterocyclic groups, in which 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,

(j) 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-oxo-1,3-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:

20th

O 0

y-i 5

-n n-r »

Vs wherein R27 is a known substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group, R28 is hydrogen or a known substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group Group and R29 is hydrogen, a halogen atom or a known substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclic group or a group of the formula ~ (CH2) nCOOR27, where R27 has the above meaning and n is 0 , 1 or 2, and wherein m is 0.1 or 2.

15 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, 5-propyl-2-oxo-1,3-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-25 loylthiomethyljbenzoylthiomethyl, p-chlorobenzoylthiomethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1-benzoylthioethyl, l- (p-chlorobenzoylthio) ethyl and the like Alkoxymethyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butyloxymethyl and 3o the like; Alkoxycarbonyloxyalkyl groups, such as methoxy-carbonyloxymethyl, ethoxycarbonyloxymethyl, propoxy-carbonyloxymethyl, isopropoxycarbonyloxymethyl, n-but-oxycarbonyloxymethyl, tert.-butoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 35 1-propoxyethylopropyloxyoxyyl, 1

1-tert-butoxycarbonyloxyethyl, 1-n-butoxycarbonyloxyethyl and the like; Alkoxycarbonylmethyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl and the like; Phthalidyl groups; Indanyl groups; Phthalidyli-

40 denalkyl groups, such as 2- (phthalidylidene) ethyl, 2- (5-fluorophthalidylidene) ethyl, 2- (6-chlorophthalidylidene) ethyl,

2- (6-methoxyphthalidylidene) ethyl and the like; etc.

R2 stands for a group of the formula:

45

or wherein R5 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, heterocyclesulfonyl, alkylcarbamoyl -, Dialkylcarbamoyl-, Alkylthiocarbamoyl-, Dialkyl-thiocarbamoyl-, Acylcarbamoyl-, Acylthiocarbamoyl-, Al-kylsulfonylcarbamoyl-, Arylsulfonylcarbamoyl-, Alkylsulfo-nylthiocarbamoyyl-, Arylsulfoyl-, Arylsulfonyl- , Cycloalkylmethylenamino, arylmethylenami-

55 no, heterocycle methyleneamino or heterocyclic group or a group of the formula:

-N;

60

/ Rl5

\ R16

stands, wherein R15 and R16, which are the same or different, each represent hydrogen or an alkyl group or R15 and R16 together with the adjacent nitrogen atom form a ring, wherein R6, R7, R8, R9, R10, R11, R13 and R14, which are the same or different, each represent hydrogen, a halogen atom or a substituted or unsubstituted alkyl, aralkyl or aryl group and R12 represents

660 010

-C-NH acyl

II O

Hydrogen, a halogen atom, carboxyl, sulfo, carbamoyl, the term "acylcarbamoyl" for thiocarbamoyl or a substituted or unsubstituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl -, Aral-kyloxycarbonyl-, alkylsulfonyl-, cycloalkylsulfonyl-, aryl- 5 sulfonyl-, heterocycle-sulfonyl-, alkylcarbamoyl-, dialkyl- the term “acylthiocarbamoyl” for carbamoyl-, alkylthiocarbamoyl-, dialkylthiocarbamyl

Acylcarbamoyl-, acylthiocarbamoyl-, alkylsulfonylcarb- -C-NH-acylamoyl-, arylsulfonylcarbamoyl-, alkylsulfonylthiocarbamo- 11

yl or arylsulfonylthiocarbamoyl group. In each of the io S

Groups mentioned above as meanings of R5 and R12 are the term "cycloalkyloxy" for -O-cycloalkyl, the term "alkylsulfonylcarbamoyl" for term "aryloxy" for -O-aryl, the term "alkoxy-carbonyl" for

15

-C-O-alkyl ii O

the expression «cycloalkyloxycarbonyl» for

-C-O-cycloalkyl O

the expression "acyloxycarbonyl" for

-C-O-acyl ii O

-C-NH-SO2-alkyl II O

the expression «arylsulfonylcarbamoyl» for

I.

-C-NH-SOrAryl

II O

25 the expression “alkylsulfonylthiocarbamoyl” for

-C -NH-SO2-alkyl

II p

30th

the expression «aralkyloxycarbonyl» for

-C-O-aralkyl

II O

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

-C-NH-alkyl ii O

the expression «dialkylcarbamoyl» for

35

the expression «arylsulfonylthiocarbamoyl» for

-C-NH-SOi aryl

II p

the term "alkylsulfamoyl" for -S02 NH-alkyl, the term "dialkylsulfamoyl" for

40

-soi-n

^ Alkyl v

Alkyl the expression «alkoxythiocarbonyl» for

1 -C -O-alkyl

II

-c-n: o

/ Alkyl \

Alkyl the expression «alkylthiocarbamoyl» for

-C-NH-alkyl ii s the term «dialkylthiocarbamoyl» for the term «alkylidenamino» for -N = CH-alkyl, the term «cycloalkylmethylenamino» for -N = CH-cycloalkyl, the term «arylmethylenamino» for - N = CH aryl and the expression "heterocycle methyleneamino" for -N = CH heterocycle.

The group of the formula:

55

/ R

n (

R'6

60 wherein R15 and R16 have the above meanings, includes amino groups, alkylamino groups of the formula - NH-alkyl, dialkylamino groups of the formula:

-c-n rXalkyl

Vlkyl

65

-N;

/ Alkyl

Vlkyl and groups of formulas:

660 010

- "G - -O

-n -n nh, - -n ^ Ü-alkyl, ~ Nf ^ | »" N,

-0 ,. -Q .. -c- -0 ° * - -O ■ ■ <] -

/ n = n -N |

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 of the formula -NH-alkyl, dialkylamino groups of the formula:

-N:

^ Alkyl "^ alkyl

Acylamine 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, hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl and the like, hydroxyiminoalkyl groups such as hydroxyiminomethyl, hydroxyiminoethyl and the like, alkoxy-alkyl groups such as methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and the like, carboxyalkyl groups such as carboxymethyl, carboxyethyl, and the like, alkoxy carbonylalkylgruppen, such as methoxycarbonylmethyl, metho-xycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonyl-ethyl, and the like, Aralkyloxycarbonylalkylgruppen as benzyloxycarbonylmethyl, benzyloxycarbonylethyl, and the like, sulfoalkyl groups such as sulfomethyl, sulfoethyl, and the like, Sulfamoylalkylgruppen as sulfamoyl methyl, sulfamic oylethyl 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-hydroxycarbamoylmethyl, N-hydroxycarbamoylethyl and the like, groups of the formula:

"* 0

-c = c-r 0

where R30 represents a lower alkyl group, etc. The above-mentioned various groups which can be represented by R5, R6, R7, R8, R9, R10, R ", R12, R13 and R14 can be represented by at least one of the above-mentioned substituents From the above-mentioned substituents, hydroxyl groups, amino groups and carboxyl groups may be protected by a suitable protecting group which is usually available in this field.25 The hydroxyl protecting groups include all hydroxyl protecting groups which can usually be used, such as easily removable acyl groups , e.g. benzyloxycarbonyl, 4-nitrobenzylcarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3o 4- (phenylazo) benzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, tert.-butocycarbonyl, 1, 1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamant yloxycarbonyl, 351-cyclopropylethoxycarbonyl, 8-quinolyloxycarbonyl, formyl, acetyl, chloroacetyl, benzoyl, trifluoroacetyl and the like; Alkylsulfonyl groups, e.g. methanesulfonyl, ethanesulfonyl and the like; Arylsulfonyl groups, for example phenylsulfonyl, toluenesulfonyl and the like-4o; Benzyl, diphenylmethyl, trityl, methoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-nitrophenylthio, 2,4-dinitrophenylthio and the like.

In addition, the amino protecting groups include all commonly used amino protecting groups such as 45 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-butoxycarbonyl, so 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 4- (4-methoxyphe-nylazo) benzyloxycarbonyl, pyridine-1-oxide-2 -ylmethoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-Cy-55 clopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and the like; easily removable groups, e.g. Trityl, o-nitrophenylsulfonyl, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylme-6o ethylene, 3-hydroxy-4-pyridylmethylene, 2-methoxycarbonyl-2 -propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-propylidene, l- [N- (2-methoxyphenyl) - carbamoyl] -2-propylidene, l- [N- (4-methoxyphenyl) carbamoyl] -2-propylidene, 65 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclophenylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocy- clohexylidene, 4-nitrofurfurylidene and the like; Di- or tri-alkylsilyl and the like. The carbo-

xyl protecting groups all commonly usable carboxyl protecting groups, and there are cases in which 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-methoxybenzyl, benzoylmethyl, acetylmethyl, 4-nitrobenzoylmethyl, p-bromobenzoylmethyl, 4-methanesulfonylbenzoylmethyl, phthalimidomethyl, 2,2,2-trichloroethyl, l, l-dimethyl-2-propenyl, 1,1- Dimethylpropyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 3-methyl-3-butinyl, succinimidomethyl, 1-cyclopropylethyl, methylthiomethyl, phenylthiomethyl, dimethylaminomethyl, quinolin-l-oxide-1-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 silyl compound such as dimethylchlorosilane such as published in the unchecked Japanese n Patent application No. 7 073/71 and the unexamined published Dutch patent application No. 71 05 259.

R4 stands for amino, a group of the formula:

R17 \

R18 '

C = C-NH-I

R19

or a group of the formula:

R20

> C = N-R2 '

and the group of the formula:

R17 ~

iC = C-NH-R18 "I

RI9

includes the group of the formula:

R17, R18 '

CH-C = N-I

R19

which is an isomer of it. The organic radicals not participating in the reaction, which are represented by R17, R18, R19, R20 and R21, comprise radicals which are well known to the person skilled in the art, specifically substituted or unsubstituted aliphatic radicals, alicyclic radicals, aromatic radicals, aromatic-aliphatic radicals, heterocyclic radicals Residues, acyl groups and the like. The following groups are particularly included:

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

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

(3) aromatic residues: aryl groups;

(4) aromatic aliphatic residues: aralkyl groups;

(5) heterocyclic groups: 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 to which also aromatic-aliphatic carboxylic acids, aromatic-oxyaliphatic carboxylic acids, aromatic-thioaliphatic carboxylic acids, hetero-

9 660 010

rocyclic-aliphatic carboxylic acids, heterocyclic-oxyaliphatic carboxylic acids and heterocyclic-thioaliphatic carboxylic acids, in which an aromatic radical or a heterocyclic group 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;

10 heterocyclic carboxylic acids; and the same.

The above aliphatic carboxylic acids include formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, methoxyacetic acid, methylthioacetic acid, acrylic acid, crotonic acid and the like; the above ali-15 cyclic carboxylic acids include cyclohexanoic acid and the like; and the above alicyclo-aliphatic carboxylic acids include cyclopentane acetic acid, cyclohexane acetic acid, cyclohexane propionic acid, cyclohexadiene acetic acid and the like.

20 The aromatic residues in the above-mentioned organic carboxylic acids include phenyl, naphthyl and the like.

Each of the groups constituting these organic carboxylic acids can be substituted by a substituent such as a halogen atom, hydroxyl, a protected hydroxyl group, an alkyl group, an alkoxy group, an acyl group, nitro, amino, a protected amino group, carboxyl or a protected carboxyl group , be further substituted.

R23 means hydrogen or a protected or unprotected amino group, and these amino protecting groups include many groups commonly used in the penicillins and cephalosporins field, specifically all of the amino protecting groups mentioned above in connection with R2.

35 A denotes a group of the formula -CH2- or a group of the formula:

-C-

40

N

I.

OR

2h

45 wherein R24 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:

50

O

II -P

R25

R26

55, where R25 and R26, which are the same or different, each represent hydroxyl or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group, and the bond 'w. means that the compound can be a syn isomer or an anti isomer or a mixture thereof. The 60 hydroxyl protecting groups mentioned include the hydroxyl protecting groups mentioned in connection with R2. In addition, the above-mentioned various groups represented by R24 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 :

\

660 010 10

1 / r © 31 ■ / or31

■ coor -con ^ -n ^ -r32 -nhcör and _p /

R ^ r33 t xOR3

wherein R1 has the above meaning and R31, R32 and R33, 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.

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

u

-ch, -n n-r 2 W.

5 or

O O

Hi

-ch - n nh 2 \ - /

-ch2-

, 10th

, ii o oh

V- /

■ -ch2-NJ

Oh

10th

15

where R5, R9, R10 and Ru have the above meanings, there are tautomers when R5 and R9 are each hydrogen, and these tautomers are also encompassed by the invention and represented by the following equilibrium formulas:

20th

25th

30th

-ch.

, 10th

11

35

40

The salts of the compounds of formulas I and II include salts on the basic group and salts on the acidic group, which are well known in the field of penicillins and cephalosporins. 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, 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

01-4-sulfonic acid, mesithylene sulfonic acid (2,4,6-trimethyl-benzenesulfonic acid), naphthalene-l-sulfonic acid, naphthalene

2-sulfonic acid, phenylmethanesulfonic acid, benzene-1,3-disulfonic acid, toluene-3,5-disulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, naphthalene-2,7-di- sulfonic acid, benzene-1,3,5-trisulfonic acid, benzene-1,2,4-trisulfonic acid, 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-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine 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.

The compounds according to the invention can be prepared by the following processes:

Production route 1

r-

, 34

COOR

Conversion reaction in the

CH2R 3 position

[IlI-a] 1) [III-bJ 2) [III-c] 3) [IH-d] 2.5

COOR-1

[IV] [III-c] [Ill-d] [I]

or a salt thereof or a salt thereof. or a salt of it

Pussnote: 1) Formula [Ill-a] is

2) Formula [Ill-b] is

11

660 010

3) Formula [III-c]

1)) Formula [III-d]

Production route 2 R3

R35-CONH 4-txS> h

Qj-NY ^ CH2X

[V]

COORl or a salt thereof

Conversion reaction in the 3-position u

HN NRJ [Ill-a] or a salt thereof

35:

R -CONH-f-

0v P

COOR

R 35-CONH - + - S S> ° \\ /?

L1 J_ ^ 5

CH2N NR-5 COOR1

or a salt of it

[VI]

Conversion to A ^ cephem

R55-CONH-j— ^

NR5 [VII]

oJ ~ K ^ J ~ CH2n

\ = /

COORl or a salt thereof

\ l deacylation

660 010

12

Production route 2 (continued)

R3 * ■

H2N4YS1 W 5 [vm,

J-Nv ^ -CH-N NR5 [vm]

O II COOR

or a salt of it.

In the above formulas, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 have the above meanings; R34 represents a substituted or unsubstituted acyloxy or carbamoyloxy group; R35 means benzyl or phenoxymethyl; and X represents a halogen atom.

The substituted or unsubstituted acyloxy and carbamoyloxy groups represented by R34 include alkanoyloxy groups such as acetoxy, propionyloxy, butyryloxy and the like; Alkenoyloxy groups such as acryloyloxy and the like; Aroyloxy groups such as benzo-yloxy, naphthoyloxy and the like; and carbamoyloxy. These groups can be replaced by one or more substituents, such as halogen atoms, nitro groups, amino groups, alkyl groups, alkoxy groups, alkylthio groups, acyloxy groups, acylamino groups, hydroxyl groups, carboxy groups, solfamoyl groups, carbamoyl groups, alkoxycarbonylcarbamoyl groups, aroylcarbamoyyl groups, aryloxy carbamoyl groups, aryloxy carbamyl groups, aryloxy carbamyl groups, aryloxy carbamyl groups, aryloxy carbamyl groups, aryloxy carbamyl groups, aryloxy carbamyl groups, aryloxy carbamoyl groups, aryloxy carbamyl groups, aryloxy carbamyl groups, aryloxy carbamyl groups, aryloxy carbamoyl groups, aryloxy carbamyl groups and aryloxy carbamyl groups, the like, be substituted.

Of the above-mentioned substituents for R34, the hydroxyl group, the amino group, the carboxyl group and the like may be protected by protecting groups which are commonly used, and the protecting groups specifically include those hydroxyl protecting groups, amino protecting groups and carboxyl protecting groups mentioned above in connection with R2.

(a) Conversion reaction in the 3-position.

First, the usual implementation at the 3 position, which is described in production route 1, is explained.

In the 7-position a substituted or unsubstituted amino group and in the 3-position a substituted methyl group-bearing cephemcarboxylic acid of the formula [I] or salts thereof can be prepared in high yield with high purity using an industrially easy to carry out process by using a 2,3 -Dioxo- 1,2,3,4-tetra-hydropyrazine of the formula Ill-a, a 2-oxo-1,2-dihydropyrazine of the formula Ill-b, a 3,6-dioxo-1,2,3 , 6-tetrahydropyridazine of the formula III-c or a 6-oxo-1,6-dihydropyridazine of the formula IH-d or a salt thereof with a cephalosporanic acid of the formula [IV] or a salt thereof in the presence of an acid or a complex compound an acid and then, if desired, the protective group is removed, the carboxyl group is protected or the compound obtained is converted into a salt. Furthermore, the above-mentioned 2,3-dioxo-1,2,3,4-tetrahydropyrazine can be produced by the method described in Journal of Chemical Society, Per-kin I, pp. 1888-1890 (1975).

Furthermore, the substituent on the amino group in the 7-position can be removed in a conventional manner to make a connection with an unsubstituted amino group in the 7-position.

If the 2,3-dioxo-1,2,3,4-tetrahydropyrazine of the formula III-a, the 2-oxo-1,2-dihydropyrazine of the formula III-b, the 3,6-dioxo-1,2, 3,6-tetrahydropyridazine of the formula III-c or the 6-oxo-1,6-dihydropyridazine of the formula IH-d, which are used in the reaction as reactants, has basic or acidic groups as a substituent, these compounds can be in the form of appropriate salt can be used in the reaction. In this case, the salts on the basic groups and the salts on the acidic groups include those mentioned in connection with the salts of the compounds of formula [I].

The salts of the compounds of the formula [IV] also include salts on the basic groups and on the acidic groups, and these salts include those mentioned in connection with the salts of the compounds of the formulas [I] and [II]. The salts of the compounds of formula II can be isolated beforehand and then used, but they can also be prepared in situ.

As acids or complex compounds of acids used in the reaction, e.g. Protonic acids, Lewis acids and complex compounds of Lewis acids mentioned. Protonic acids include sulfuric acid, sulfonic acids, and super acids (super acids means acids that are stronger than 100% sulfuric acid, and this term includes some of the above sulfuric acids and sulfonic acids). More specifically, the protonic acids include sulfuric acids such as sulfuric acid itself, chlorosulfuric acid, fluorosulfuric acid and the like, sulfonic acids e.g. Alkyl mono- or di-sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and the like, aryl mono-, di- or tri-sulfonic acids such as p-toluenesulfonic acid and the like, super acids such as perchloric acid, magic acids (FS03H-SbF5) , FS03H-AsF5, CF3S03H-SbF5, HF-BF3, H2S04-S03 and the like.

Lewis acids include e.g. Boron trifluoride, and the complex compounds of Lewis acids include complex compounds of boron trifluoride with dialkyl ethers such as diethyl ether, di-n-propyl ether, di-n-butyl ether and the like; with amines such as ethylamine, n-propylamine, n-butylamine, triethanolamine and the like; with esters such as ethyl formate, ethyl acetate and the like; with aliphatic acids such as acetic acid, propionic acid and the like; and with nitriles such as acetonitrile, propionitrile and the like.

The reaction is preferably carried out in the presence of an organic solvent. The organic solvents used include all organic solvents which are inert to the reaction, for example nitroalkanes such as nitromethane, nitroethane, nitropropane and the like; organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid, propionic acid and the like; Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; Ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, dimethyl cellosolve and the like; Esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, butyl acetate and the like; Nitriles such as acetonitrile, butyronitrile and the like; and sulfolanes, such as sulfolane itself and the like. These solvents can be used in a mixture with each other. Complex compounds formed from these organic solvents and Lewis acids can also be used as solvents. It suffices that the amount of the acid or complex compound of the acid used is at least equimolar to the amount of the compound of the formula II or its salt, and the amount can be varied depending on the conditions in question. In particular, use in a ratio of 2 to 10 moles per mole of the compound of formula [IV] or its salt is preferred. When the complex compound of the acid is used, it can be used alone as a solvent, and two or more such complex compounds

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

13

660 010

Bonds can be used in a mixture with each other. The 3-position conversion is usually in the. a suitable solvent. The solution

It is sufficient that the amount of 2,3-dioxo-1,2,3,4-tetra-agent includes halogenated hydrocarbons such as chloro-

hydropyrazine of the formula III-a, an 2-oxo-l, 2-dihydropyra-form, methylene chloride and the like; Ethers, such as tetrahedral

zin of formula III-b, on 3,6-dioxo-1,2,3,6-tetrahydropyri- 5-hydrofuran, dioxane and the like; N, N-dimethylform

dazin of the formula III-c or 6-oxo-l, 6-dihydropyridazine amide; N, N-dimethylacetamide; Acetone; Water; and Gemi-of the formula III-d or a salt thereof at least equimose thereof.

lar the amount of the compound of formula [IV] or its In this case, the compound of formula III-a

Salt, and in particular the use in one or its salt is preferably in an amount of about 1.0 to 2.0

Amount of about 1.0 to 5.0 moles per mole is preferred. 10 moles per mole of the compound of the formula [V] or its salt

This reaction is usually used at 0 to 80 ° C. The reaction is generally carried out in one and ends in 10 minutes to 30 hours. Temperature from 0 to 50 ° C for 30 minutes to 10 hours

The presence of water is carried out in the reaction system.

can undesirable side reactions such as lactonization. The mixture of an A2 and an A3

of the starting material or products and cleavage of the 15 phem compound, i.e. the compounds of the formula [VI]

ß-lactam ringes, so that it is desirable that the or their salts, can easily be incorporated into the A3 cephem compound

Keep system under anhydrous conditions. To be transferred to a compound of formula [VII]

To meet the requirement, it is sufficient to prepare the reaction system or a salt thereof, which can then be added by a suitable dewatering agent, for example deacylation into the compound of the formula [VIII]

se a phosphorus compound, such as phosphorus pentoxide, poly-20 leads. This conversion reaction and entaclylic

phosphoric acid, phosphorus pentachloride, phosphorus trichloride, reaction are in the field of penicillins and Ce

Phosphorus oxychloride or the like; an organic silylphosphorus are known and are described in Journal of Organic, such as N, 0-bis (trimethylsilyl) acetamide, Tri-Chemistry, Vol. 35, No. 7, pp. 2430-2433 (1970) and «Cepha -

methylsilylacetamide, trimethylchlorosilane, dimethyldichlorosporins and penicillins »(from Flynn, Academic Press), p.

silane or the like; an organic acid chloride as specifically described in 25 56-64.

Acetyl chloride, p-toluenesulfonyl chloride or the like; a If the substituents of 2,3-dioxo- 1,2,3,4-tetrahy-

Acid anhydride, such as acetic anhydride, trifluoroacetic acid - dropyrazine of the formula IH-a, of 2-oxo-l, 2-dihydropyra

anhydride or the like; an inorganic dewatering rate of the formula Ill-b, the 3,6-dioxo- 1,2,3,6-tetrahydropyri-

Means such as anhydrous magnesium sulfate, anhydrous addition of the formula III-c or 6-oxo-l, 6-dihydropyrida calcium chloride, a molecular sieve, calcium carbide or der- 30 interest of the formula IH-d or their salts, which in the reaction same. be used as reactants by a hydro-

The compounds of the formula [I] in which R3 denotes an alkoxyxyl group, an amino group, a carboxyl group or grappe can be substituted from the compounds of the formula the like, these groups can be substituted before

[I], in which R3 stands for hydrogen, by means of a reaction known per se with the aid of the protective groups mentioned above.

Processes are synthesized, for example, by means of the 35 and after completion of the reaction, a

Process which, in the Journal of Synthetic Organic Chemistry, is subjected to conventional removal reactions

Japan, 35, 563-574 (1977). to get the connection you want.

When a compound of the formula [IV] in which R1 The compound of the formula [I] or [VIII] may be required to have a carboxyl protecting group is also used as a starting material by a conventional method, a compound of the formula [I] wherein 40 carboxyl group is protected or salted-R1 is hydrogen by removing the protecting group to obtain the desired compound. A vérin can be obtained in a conventional manner. In some cases the bond of formula IV, in which R4 stands for amino, the carboxyl protecting group can also be split off by a conventional method into a derivative of the amino group capable of reacting during the reaction of the compounds of the formulas or the compound of (III ) and (IV). «Formula [VIII] can be transferred as mentioned below.

Next, the conversion reaction in the The invention will now be illustrated by reference examples

3-position, which is described in production route 2, and examples explained.

purifies.

The halogenated compound of formula [V] can according to reference example 1

the process prepared in Tetrahedron Let- 50 (l) A solution of 20.0 g of ethyl N- (2,2-diethoxyethyl) -

ters, No. 40, pp. 3991-3994 (1974) and Tetrahedron Letters, oxamate in 60 ml of ethanol is mixed with 6.1 ml of a 70 wt.

No. 40, pp. 3915-3918 (1981). % aqueous ethylamine solution and the mixture

The compound of the formula [IV] or a salt thereof then reacted for 1 hour at room temperature can be prepared by the reaction of a halogenated. After the completion of the reaction, the filled crystal compound of the formula [V] or a salt thereof is collected by filtration and recrystallized from ethanol, a 2,3-dioxo-1,2,3,4-tetrahydropyrazine of the formula III-a, where 17.0 g (yield: 85.1%) of N-ethyl-N '- (2, 2-di or a salt thereof in the presence of a base.Bathoxyethyl) -oxamide from melting point 131 to 132 ° C includes alkali metal carbonates, for example Sodium carbonate.

Potassium carbonate or the like; Alkali metal hydrogen car IR (KBr), cm-1: vc = o 1650

bonate, e.g. Sodium hydrogen carbonate, potassium hydrogen eo in a similar way, the in the following table-

carbonate and the like; Alkali metal hydroxides, e.g. Prepare all of the compounds shown, trium hydroxide, potassium hydroxide, and the like; nitrogenous organic bases, e.g. Triethylamine, pyridine,

N, N-dimethylaniline and the like.

65

660 010 14

Table 1

(ch3ch20) 2chch2nhc0c0nhr5

connection

Solvents for environmental (c)

stallization

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

r5

-H

Ethyl acetate

141-142

• 1650, 1635

-ch3

Ethanol

135-136

1645

- (CH2) 2CH3

acetone

84-85

1645

/ ch3 -ch ^

Acetone n-hexane

145-146

1650, 1635

- (ch2) 3ch3

n-hexane

111-112

1645

- (ch2) 4ch3

n-hexane

92-93

1650

- (ch2) 5ch3

n-hexane

87-88

1650

- (ch2) 7ch3

n-hexane

110-111

1645

.- (CH2) iich3

n-hexane

83-84

1645

Ethanol

154-155

1640

-ch2- <ö>

n-hexane

113-114

1655

-ch2ch2oh

Ethanol

118-119

-

/ cii3 ^ CH3

Ethanol

157-158

1645

och3

-CH2 ^^) - OCH3>

-

128-129

1655

(2) A solution of 17.0 g of N-ethyl-N '- (2,2-diethoxy-ethyl) -oxamide, obtained according to paragraph (1) above, in 85 ml of acetic acid is mixed with 0.05 ml of concentrated hydrochloric acid . The mixture is then heated to reflux for 30 minutes. When the reaction has ended, the solvent is removed by distillation under reduced pressure and 70 ml of acetone are added to the residue, whereupon crystals are collected by filtration. The crystals are recrystallized from methanol, 6.8 g (yield: 61.8%) of 4-ethyl-2,3-dioxo-l, 2,3,4-tetrahy-65 dropyrazine, melting point 173 to 174 ° C. receives. IR (KBr), cm-1: vc = o 1680-1620 The compounds shown in Table 4 below can be prepared in a similar manner.

Table 2

15

660 010

hn n-r5

W

connection

Solution Center] for the Umkri

M.p.

IR (KBrL cm 1:

R5

stallization

(° c)

* 00

-H

-

> 280

1680-1640

-ch3

Ethanol

220-231

1690-1635

- (ch2) 2ch3

acetone

182-183

1680-1640

-ch <ch3 ^ CH3

acetone

215-219

1680, 1625

- (ch2) 3cH3

acetone

149-150

1680, 1640

- (ch2) 4gh3

acetone

171-172

1685, 1660, 1620

• - <CH2> 5CH3

acetone

141-142

1685, 1660, 1620

7 (CH2) 7CH3

acetone

145-146

1670, 1635

- (CH2) iiCH3

Ethanol

145-146

1660, 1625

acetone

254-255

1670, 1635

-CH2- <0>

acetic acid

225

1665, 1635

-CH2CH2OCOCH3

Methanol

178-180

1720, 1675, 1625

-N <3

CH3

Ethanol

229-230

1700-1625

och 3 -ch2- <g) -och3

-

175-176

1740-1620

(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 then reacted at 50 to 60 ° C. for 3 hours. Then the reaction mixture is poured into a mixed solvent of 200 ml of ethyl acetate and 200 ml of water, and the organic layer is separated, 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-dioxol-4-yl) methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine of 65 melting point 154 to 156 ° C.

IR (KBr), cm-1: vc = 0 1820, 1675, 1630 The compounds shown in Table 3 below can be prepared in a similar manner.

660 010

Table 3

16

och3 0 0

CH3 ° - <^ - CH2-NM »-R5

connection

Mp (° c)

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

R5

188-190

1775, 1700, 1650

-CH2OCOC (CH3) 3

100-101

1750, 1690, 1660, 1640

-CH2COOC (CH3) 3

105-106

1740, 1690, 1650

(4) In a mixed solvent of 37 ml of Trifluores- 30 added. Then the resulting crystals are filtered

acetic acid and 10.8 g of anisole, 3.7 g of l- (2,4-dimethoxy- trieren) are collected, 2.0 g (yield: 90.9%) of 4- (5-

benzyl) - 4- (5-methyl-2-oxol, 3-dioxol-4-yl) - methyl-2,3-di-methyl-2-oxol, 3-dioxol-4-yl) - methyl-2,3-dioxo-1,2,3,4-

oxo-1,2,3,4-tetrahydropyrazine, obtained in accordance with the above tetrahydropyrazine, having a melting point of 225 to 226 ° C.,

set (3), and sets the mixture thus obtained for 2 hours IR (KBr), cm-1: vc = o 1825, 1805, 1725, 1690, 1670

around at a temperature of 50 to 60 ° C. 35 In a similar way, the following table

prepare the solvent by distillation under reduced le 4 represented compounds.

Pressure removed and the residue with 30 ml of diethyl ether

Table ■

w hn n-r5

connection

Mp (° C)

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

R5

_ / ° \ = o •

w

> 270

1790, 1775, 1730, 1690

-CH2OCOC (CH3) 3

166-167

1740, 1700, 1660

-CH2COOH

282

(Decomposition)

1730, 1670-1630

17th

660 010

(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 implemented during 10 minutes. 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 diethyl ether, 2.9 g (yield: 80.4%) of 1-diphenylmethyloxycarbonylmethyl-2,3-dioxo-1,2 , 3,4-trahydropyrazine with a melting point of 97 to 98 ° C.

IR (KBr), cm-1: vc = 0 1750.1675.1645

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-aminocephalospo-ranoic acid (hereinafter referred to as 7-ACA) and 1.54 g of 4-ethyl-2,3- dioxo-1,2,3,4-tetrahydropyrazine was added and 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, washed sufficiently with 30 ml of methanol and dried, whereby 3.10 g (yield: 88.1% 7-amino-3 - ([l- (4-ethyl-2,3-dioxo - 1,2,3,4-tetrahydropyraziny])] - methyl) -A3-cephem-4-carboxylic acid from melting point 191 s to 195 ° C with decomposition.

IR (KBr), cm- ': vc = 0 1795, 1670, 1620 NMR (CF3COOD), Ö values:

1.44 (3H, t, J = 7Hz,> NCH2CH3),

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

io 4.08 (2H, q, J = 7Hz,> NCH2CH3),

5.14, 5.51 (2H, ABq, J = 15Hz, S-,),

/ <

5.48 (2H, s, Q-H, C ^ H), i5 6.74, 7.00 (2H, ABq, J-6Hz,

-ch2-

\ = k)

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 5 below, whereby the 7-amino-3 - ([1- (4-ethyl-2 , 3-dioxo-l, 2,3,4-tetrahydropyrazinyl)] - methyl | -A3-cephem-4-car-bonic acid in the yields shown in Table 5.

Table 5

Source material

No. 7-ACA

Ok

"Hi

HNV_Ji ~ CH2CH3

1 2.72 g 1.54 g

2 2.72 g 1.54 g

Solution

Acid or

Reaction area

Quantity medium

Complex connection conditions

(Yield)

formation of acid

Sulfolan

Boron trifluoride

Room temperature

2.6 g

10 ml

2.71g for 2 hours

(73.9%)

Nitro

Boron trifluoride

Room temperature

2.85 g methane

Diethyl ether

16 hours

(81.0%)

14 ml

Complex 5.7 g

(3) In a similar manner as set out in paragraph (1) above, the compounds shown in Table 6 below are obtained. (In this case, the desired compounds are obtained by

After the reaction has ended, pour the 3-position solution into ice water and adjust the pH to 3.5 using a 28% strength by weight aqueous ammonia solution while cooling with ice.)

Table 6

h2nTY 1 2

0A-nY ^ CH2-R

cooh.

No.

connection

Mp (° C)

IR (KBr), cm "1:

NMR (dg-DMSO), S values:

R2

o n

o>

1

0

y-K

-N N (CH,) cCH, S = / 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, m, ^ NCH2 (CH2) 4CH3), 4.44, 5.05 (2H, ABq, J = 15Hz, Svl),

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

660 010

Table 6 (port setting)

18th

No.

connection

R2

Mp (eC)

IR (KBr), cm VC = 0

-1

NMR (dg-DMSO), S values:

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

H H

)

Vf

-N N (CH _), CH, \ / il 3

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) 6CH3), 3.40 (2H, bs, C2- H), 3.52-3.86 (2H, m,> NCH2 (CH2) gCH3), 4.43, 5.04 (2H, ABq, J = 15Hz, S> i),

A

ch2-

4.86 (1H, d, J = 6Hz, Cg-H), 5.04 (IH, d, J = 6Hz, C? -H), 6.69 (2H,

s »)

H H

w

-N N (CH.) .CH

\ = /

2 4 3

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, CgrH, C7 ~ H),

6.76 (2H, bs,)

H H

> 200

1790, 1655, 1630, 1600

3.72 (2H, bs, C2-H), 5.41, 5.72 (2H, ABq, J = 15Hz, Sv »

A

),

ch2-

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

Measured in CF3COOH

(4) The reaction 60 reproduced in paragraph (1) above to give 7-amino-3- j [l- (3,6-dioxo-1,2,3,6-tetrahydro-at the 3-position is under the pyridazinyl)] - methyl] -A3-cephem-4-carboxylic acid carried out in the reaction conditions given in Table 7 below, the yields shown in Table 7 below.

19th

660 010

Table 7

Source material

2.0 g 2.72 g

0.91g 1.23g

Solution

Acid or

Reaction area

Quantity medium

Complex connection conditions

(Yield)

formation of acid

Trifluoro

Boron trifluoride

Room temp

1.72 g acetic acid

Diethyl ether temperature

(72.3%)

10 ml

complex

16 hours

4.17 g

Sulfolan

Boron trifluoride

Room temp

2.75 g

10 ml

2.71g temperature

(84.9%)

3 hours

(5) In a similar manner as in paragraph (1) above, the crude crystals mentioned in Table 8 are obtained.

Table 8

COOH

No.

connection

K2

1

. Vf

-N N-H

2nd

Q 0 -N N-CH,

3rd

0 O

} —I

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

4th

° h ° ^ CH3

-N N-CHC.

W CH3 •

5

Vf

-N N (CH2) 3CH3 \. J

6

Q, 0

_r ~ \

-Nwn "vv

7

Vf

-N N (CH _) .. CH-

.y Z XX «3

660 010 20

Table 8 (continued)

8th

VC

-N N-CH ^ CH ^ OCOCH, y / 2 2 3

9

V? / -A

"N \ —7" CH2 ~ ^ /

10th

V ^ 5 / CH3

-N N-NC S = / ^ -CH3

11

CH,

4 "

12

CH-CH,

■ A

V

0

13

O * 2

HN \ ^ CI

Y

14

0 0 * 3

mVc "3» -S

V + -L / ch3

o 0

15

N

-9

0

16

CH,

V-.

-V

0

21st

660 010

Comment:

The compounds shown in 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 - {[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] - methyl) - A3-cephem-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 mono-

hydrate was added to obtain a solution, which was then slowly mixed with 5.0 g of diphenyldiazomethane, whereupon the resulting mixture was reacted for 15 minutes at room temperature. After 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 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 (Wako Silica Gel C-200, eluent: i5 benzene: ethyl acetate = 1: 4 by volume), 3.1 g (yield 70.3%) of diphenylmethyl-7-amino-3 - ([l - (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] - methyl) -A3-cephem-4-carboxylate from melting point 183 to 186 ° C (decomposition).

20 IR (KBr), cm "1: vc = 0 1765, 1730, 1680, 1630

The compounds shown in Table 9 below are obtained in a similar manner.

Table 9

25th

he T ch2r cooch (^ O ^) 2

connection

Mp. {»E)

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

R2

o o ^^

-n nh \ = /

129-130 (decomposition)

1765, 1725, 1690, 1630

o o ^^

-n n-ch,

\ = / 3

127-128 (decomposition)

1770, 1725, 1690, 1640

o 0

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

169-171 (decomposition)

1765, 1730, 1685, 1635

O O

ch

-n nchc w ch3

179-180.5 • (decomposition)

1760, 1720, 1685, 1635

660 010

22

Table 9 (continued)

V?

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

180-189 (decomposition)

1760, 1725, 1680, 1630

-N ^ CH ^ Ci ^ -

185-194 (decomposition)

1765, 1730, 1685, 1630

° v P

} —X

-N ^ N (CH2) 5CH3

170-174 (decomposition)

1765, 1730, 1685, 1635

Ov 0

f-ç

-N N (CH _) _ CH, \ / * / «5

186-188 (decomposition)

1765, 1730, 1685, 1635

Ov 0

"M:

-H = 3 »(CH2) 11CH3

164-172 (decomposition)

1765, 1730, 1685, 1635

165-168 (decomposition)

1765, 1725, 1680, 1625

0 ^ 0

- ^ - CH2- <Ö)

155-160 [decomposition)

1770, 1725, 1680, 1630

° s, 0

-N NCH_CH_OCOCH, \ - / 2 2 3

146-148 [decomposition)

1770, 1725, 1678, 1623

° v P

M: ^ CH

-N N-NC ^ CH3

172-175

1760, 1720, 1680, 1630

N

-V

0

82-85 •• (decomposition)

1775, 1720, 1650

V »V

108-114 (decomposition)

1765, 1725, 1650

l)

132-135 (decomposition)

1780, 1730, 1665

178-181 (decomposition)

1780, 1730, 1660

23

Table 9 (continued)

660 010

0 0 HN'Ti — CH, HN'ìì

V + V-

0 0

137-139 (decomposition)

1780, 1730, 1660

CH3 0

90-93 (decomposition)

1770, 1720, 1660

CH-CH, <»

0

138-143 (decomposition)

1770, 1720, 1660

Example 3

4.9 g of diphenylmethyl-7-amino-3- [l- (2,3-dioxol, 2,3,4-tetrahydropyrazinyl) methyl- are dissolved in a solvent mixture of 25 ml of trifluoroacetic acid and 10 ml of anisole. 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 sufficiently washed with 40 ml of diethyl ether and dried thereupon, 4.25 g (yield: 97.0%) of trifluoroacetic acid salt of 7-amino-3- | [l- (2,3-dioxo- 1,2,3,4-tetra

hydropyrazinyl)] - methyl | - A3-cephem-4-carboxylic acid from melting point 105 to 106 ° C (decomposition). IR (KBr), cm- ': vc = 0 1780, 1700-1630 NMR (CF3COOD), Ô values:

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

30 5.14, 5.52 (2H, ABq, J = 15Hz, S "l o,

/ /

5.44 (2H, s, C6-H, Ct-H), ~~

35 6.78, 6.98 (2H, ABq, J = 6Hz, "X, '

The compounds shown in Table 10 below are obtained in a similar manner.

Table 10

CF3COOH 'HjNW' N

J-hyL

CH2 "R

COOH

connection

Mp (° C)

IR (KBr), cm VC = 0

-I

/ (dg — DMSO + CF COOD) * 1 \ NMR ((cf3cood 3) * 2, S values: \ (dg-DMSO + D ^ O) * 3 / '

O O -n n-ch,

\ = / 3

109-110 (decomposition)

1795, 1680, 1635

3.36 (3H, s,> NCH3), 3.50 (2H, bs, C2-H),

4.53, 5.11 (2H, ABq, J = 15Hz,

),

CH.

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

J-SHz, C7-H), 6.73 (2H

* 3

, bs,) = ^

H H

Q, 0

-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, \),

^ CH2-

010

Table 10 (continued)

24th

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

) = <)

H H

*1

0, 0

m / CH

-N N-CH <\ = / XCH3

L59.5-161.5 (decomposition)

1780, 1680 5

1620

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

CH3

3.70 (2H, bs, C2-H),

/ CH3 Si 4.77-5.60 (3H, m,> NCH <J, \),

Xch3 ^ CHjf

5.46 (2H, bs, Cg-H, C7 ~ H),

6.82, 7.04 (2H, ABq, J = 6Hz, '

H H

* 2

° \ P

-N N- (CH2) 3CH3

158-162 (decomposition)

1780, 1675, 1635

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

3.75 (2H, t, J = 7Hz,> NCH2 (CH2) 2CH3), 4.56, 5.18 (2H, ABq, J = 15Hz, S>]),

-ch2-

5.29 (2H, s, Cg-H, C7 ~ H), 6.70 (2H, bs,)

H H

*1

ith «-H

-H '

-N

n ©

167-169 (decomposition)

1780, 1680

S

1620

1.15-2.35 (10H, m,

3.69 (2H, bs, C2-H), 4.47-5.07 (1H, m, 7 ©),

5.21-5.54 (2H, m, JL),

CHj-

5.47 (2H, s, Cg-H, C? -H), 6.81-6.98 (2H, ABq, 'J = 6Hz,

* 2

hO.

H H

Table 10 (continued)

25th

660 010

o o

Vf

-NN- (CH ^ uCHs

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) 10CH3), 4.57, 5.21 (2H, ABq, J = 15Hz,),

CÎLf

5.32 (2H, bs, Cg-H, C? -H), 6.67 (2H, bs,)

H H

*1

O O

-N NCH_CHo0C0CH.

2 2

86-91 (decomposition)

1780, 1725, 1675, 1635

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

3.86-4.54 (4H, m, ^ NCHgCHjO-),

4.57, 5.16 (2H, AB <J, J = 15Hz, S "1),

5.28 (2H, bs, Cg-H, C? -H), 6.81 (2H, bs, y = ^)

H H

*1

% -i ° / CH3 -N N-N '

nch,

158-160 (decomposition)

CH.

1780, 1680

5

1630

5.34 (6H, s, -n /),

CH,

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

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

<^ CH_-

-CH ^

5.49 (2H, s, Cg-H, C? -H), 7.15 (2H, bs,)

* 2 ~ ~

N

V

119-122 (decomposition)

1780, 1675 '

S

1640

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

7.93, 8.69 (2H, ABq, J = 5Hz, "Y),

H

8.88 (1H, s, yH)

* 2

241-243 (decomposition)

1800, 1660, 1600

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

A

ch2-

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

* 2

660 010

Table 10 (port setting).

26

ch2ch3

219-222 (decomposition)

1800, 1660, 1600

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

ÏH;

CH,

J = 10Hz, H) • H

* 2

> 200

1795, 1640, 1600

3.70 (2H, bs, C2-H) 5.34, 5.79 (2H, ABq, J = 16Hz, S>), 5.47 (2H, s, Cg-H, C? -H),

ch2-

7.59 (1H, s, H)

* 2

> 200

■ Ù

-r \

O CH3

1795, 1640, 1600

2.42 (1.5H, s, -CH3 x 0.5), 2.50 (1.5H; S, -CH3 x 0.5), 3.73 (2H, bs, C2 ~ H), '5 , 52 (2H, s, Cg-H, C? -H), 5.63 (2H, bs,),

1

^ CH--

7.38 (0.5H, s, ^ -H x 0.5), 7th, 60 (0.5H, s, ^ "H x 0.5)

* 2

O O

H

-V NH \ = /

139-140 (decomposition)

1780, 1710, 1690

S

1620

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

A

CH,

Cg-H), 5.20 (IH, d, J = 5Hz, C? -H), 6.34, 6.59 (2H, ABq, J = 6Hz,) f = ^)

H H

* 3

O O

H

-N N-CH,

152-155 (decomposition)

1780, 1690, 1660, 1620

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

chr '

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

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

H H

* 3

27th

660 010

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 - {[1- (3-methyl-6-oxol, 6-dihydropyridazinyl)] - methyl j-A3-cephem-4-carboxylic acid in 15 ml Acetone is added to 2.36 g of 1,8-diazabi-cyclo- [5,4,0] - 7-undecene and 4.51 g of pivaloyloxymethyl iodide at 10 to 15 ° C., whereupon 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 pivaloyloxymethal-7-amino-3 - ([l- (3-methyl-6-oxo-l, 6-dihydropyridazinyl)] - methyl] -A3-cephem- 4-carboxylate melting point 145 to 147 ° C

(7 (* rQPt711Tl

IR (KBr), cm-1: vc = 0 1790.1750, 1660

NMR (d6-DMSO), 5 values:

1.21 (9H, s, -CH3X3).

2.29 (3H, s, ^ CH3),

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

4.94, 5.33 (2H, ABq, J = 15Hz, N] '

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

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

7.01, 7.53 (2H, ABq, J = 10Hz,,

7.44 (3H, bs, -NH3®)

Example 5

(1) A solution of 2.69 g of l- (5-methyl-2-oxo-1,3-dio-xol-4-yl) - methyl-2,3-dioxo-1,2,3,4- 1.52 g of potassium carbonate is added to tetrahydropyrazine in 27 ml of N, N-dimethylformamide and the resulting mixture is stirred at room temperature for 20 minutes. Then, with ice cooling, 4.67 g of tert-butyl-7-phenylacet-amido-3-bromomethyl-A2-cephem-4-carboxylate are added, 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 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 (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 100 ml of ethyl acetate and 100 ml of water are added to the residue. 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 (Wako Silica Gel C-200, eluent chloroform), 2.70 g (yield: 43.2%) of tert-butyl-7- phenylacetamido-3- | [1- [4- (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazinyl ]] - methyl) -A3-cephem-4-carboxylate-1-oxide with a melting point of 135 to 136 ° C (decomposition).

IR (KBr), cm "1: vc = 0 1820, 1790, 1720, 1685, 1650

(2) 3.0 g of tert-butyl-7-phenylacetamido-3- | [l- [4- (5-methyl-2 -oxo-l, 3-dioxol-4-yl) - methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazi-nyl]] - methyl) - A3-cephem-4-carboxylate-1-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 volume ratio), 2.12 g (yield: 72.4% ) tert-Butyl-7-phenylacetamido-3- ([l- [4- (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl-2,3-dioxol , 2,3,4-tetrahydropyrazinyl]] - methyl | - A3-ce-phem-4-carboxylate from melting point 120 to 122 ° C (decomposition).

IR (KBr), cm ~ ': vc = 0 1820, 1775, 1715, 1685, 1645

NMR (CDC13), S values:

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

2.28 (3H, s, -CH3)

3.17, 3.61 (2H, ABq, J = 18Hz, C2-H),

3.77 (2H, s, <QhCH2-),

4.53, 5.13 (2H, ABq, J = 15Hz, ^ _ch _ X

4.71 (2H, s,> NCH, -), _

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

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

6.53, 6.89 (2H, ABq, J = 6Hz,} = {^

H H

7.32-7.51 (5H, m, - (Ô ^),

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 11 below can be prepared.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

660 010 28

Table 11

/ ÖVcH ^ CONH-r-r'Svl ^

CH-N N-R5

2 \ = /

CH2CONH -t — s> 1

• o ^ NT ^

COOC (CH3) 3

connection

Mp (oc)

IR (KBr), cm ^: V

C = 0

d, -DMSO *

NMR (CDCI3 **> '8-Werfce:

IT

180-183 (decomposition)

1780, 1710, 1700, 1680, 1645

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

C2 "H '© ~ ch2 ~)' 4i30 '5» 12 {2H' AB ^ '

J = 15Hz, Sv), 5.1-2 (1H, d, J = 5Hz,

^ cv

Cg-H), 5.75 (1H, dd, J = 5Hz, J = 8Hz, C? -H),

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

H H

7.12-7.45 (5H, m, - ^ O)), 7.57-8.14 (5H, H f

^, \ / 0), 9.14 (1H, d, J = 8Hz,

m, -C0NH-)

-ch2ococ (ch3) 3

105-108 (decomposition)

1780, 1740, 1730, 1660

1.21 (9H, s, -C (CH3) 3), 1.56 (9H, s, -C (CH3) 3), 3.22, 3.61 (2H, ABq, J = 18Hz, C2- .H), 3.71 (2H, s, © -CH2-), 4.58, 5.11 (2H, ABq, J = 15Hz, S ^,),. 5.03 (IH,

ch2-

а, J = 5Hz, Cg-H), 5.81 (2H, s, ^ = NCH2-), 5.93 (1H, dd, J = 5Hz, J = 9Hz, C? -H), 6.55 ,

б, 88 (2H, ABq, J = 7Hz,) = (), 7.14 (1H,

H H

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

-ch2cooch (^ 3)) 2

124-129 (decomposition)

1770, 1730, 1685, 1650

1.53 (9H, s, -C (CH3) 3), 3.27 (2H, bs, Cj-H), 3, * 61 (2H, s, <Ö) -CH2-), 4.54 ( 2H, s,> NCH2-), 4.91 (2H, bs,),

^ CV

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,), 6.88 (1H, s, -CH <*),

H H N

6 v96-7.47 (15R, m, x 3), 7.95 (1H,

d, J = 8Hz, -CONH-)

**

29

660 010

(3) 2.0 g of tert-butyl-7-phenylacetamido-3-J [l- [4-5-methyl-2-oxo-1,3-dioxol-4-yl) are dissolved in 30 ml of anhydrous methylene chloride. -methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazonyl]] - methyl) -A3-cephem-4-carboxylate. [Received according to paragraph (2) above.]

Then this solution is mixed with 1.59 g of N, N-dimethylaniline and then with 0.57 g of trimethylsilyl chloride, and the resulting mixture is stirred at room temperature for 1 hour. The reaction mixture is then cooled to -40 ° C and then 0.89 g of phosphorus pentachloride is added, after which the mixture is reacted for 2 t / 2 hours at a temperature of -30 ° C to -20 ° C. The reaction mixture is then cooled to a temperature of -40 ° C. and then 5.2 g of anhydrous methanol are added, whereupon the reaction is continued for 1 hour while cooling with ice. The reaction mixture is then mixed with 20 ml of water and stirred for a further 30 minutes. The reaction mixture is then adjusted to a pH of 0.5 using 6N hydrochloric acid, and the aqueous layer is then separated off. This aqueous layer is now mixed with 50 ml of ethyl acetate 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. The solvent is then removed by distillation under reduced pressure and 50 ml of diethyl ether are added to the residue. The crystals are collected by filtration. To this

In this way, 1.05 g (yield: 64.8%) of tert-butyl-7-amino-3 - ([l- [4- (5-methyl-2-oxol, 3-dioxol-4 -yl) -methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl]] - methyl j-A3-ce-phem-4-carboxylate with a melting point of 185 to 188 ° C. (decomposition).

io IR (KBr), cm "1: vc = 0 1820, 1765, 1705, 1690, 1635 NMR (CDCl3 + d6-DMSO), S values:

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

3.46 (2H, bs, C2-H), 4.35, 5.08 (2H, ABq,

i5 J = 15Hz, S1

^ ch2-

4.76-5.09 (4H, m,> NCH2-, C6-H, C ^ H),

6.74 (2H, s,

The compounds shown in Table 12 can be prepared in a similar manner.

20th

25th

Table 12

O 0

M

Y CH, N N-r5

he T 2 W COOC (CH3) 3

connection

Mp (° C)

IR (KBr), cm v

C = 0

d, -DMSO *

NMR (CDC13 6 "values:

"T

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, S-s.),

CH ^ -

4.82 (1H, d, J = 5Hz, Cg-H), 5.03 (IH, d, J = 5Hz, C7 "H), 6.08, 6.55 (2H, ABq, J = 6Hz,

w

H H ^ '7.58-8.3

12 (5H, m,, 1 ^ .0)

U

-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, S

),

ch2-

5.30 (2H, s,> NCH2-), 5.75 (2H, bs, Cg-H, C7-H), 6.80 (2H, bs, y = ()

h h

010 30

Table 12 (continued)

-ch2cooch (<o>).

160-163 (decomposition)

1780, 1760, 1715, 1690, 1650

1.54 (9H, s, -C (CH3) 3), 1.74 (2H, bs, -NHj), 3.05, 3.48 (2H, ABq, JS = 18Hz, C2-H), 4 , 40, 4.99 (2H, ABq, J = 15Hz,)

sx

CHj-

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,

s, -CH <^), 7.17-7.31 (10H, m, x 2)

Footnote:

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

Claims (29)

660 010 PATENT CLAIMS 1. In the 7-position a substituted or unsubstituted amino group and in the 3-position a A3-cephem-4-carboxylic acids carrying a substituted methyl group of the formula: (I) coor and their salts, wherein R1 represents hydrogen or a carboxyl protecting group; R2 for a group of the formula: 0 0 -N N-R or -n: R15 'R16 carbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyoy or arylsulfonylthiocarbam; 5 R3 represents hydrogen or an alkoxy group; and R4 for amino, a group of the formula: R \ > C = C-NH- 10 R'8 'in R19 wherein R17, R18 and R19, which are the same or different, each represent hydrogen or an organic radical, 15 or a group of the formula: R2 ^ R21- sc = N- 20th R5 represents hydrogen, hydroxyl, nitro, carbamoyl, thiocarbamoyl, sulfamoyl or a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cy-cloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, Acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclesulfonyl, alkylcarb amoyl-, dialkylcarbamoyl-, alkylthiocarbamoyl-, dialkylthiocarbamoyl-, acylcarbamoyl-, acylthiocarbamoyl-, alkyl-sulfonylcarbamoyl, alkylsulfonylthiocarbamoyoyl, alkylsulfonylthiocarbamoyoyl-, alkylsulfonyl Cycloalkylmethyleneamino, arylmethyleneamino, heterocyclemethyleneamino or heterocyclic group or a group of the formula: wherein R20 and R21, which are the same or different, each represent hydrogen or an organic radical. 2. A3-cephem-4-carboxylic acids or their salts according to claim 1, characterized in that R3 for hydrogen 25 stands. 3. A3-cephem-4-carboxylic acids or their salts according to claim 2, characterized in that R4 stands for amino. 4. Ä3-cephem-4-carboxylic acids or their salts according to claim 3, characterized in that R2 for a group 30 of the formula: O O x 5 35 is in which R5 has the meaning given in claim 1. 5. A3-cephem-4-carboxylic acids or their salts according to claim 4, characterized in that R5 for hydrogen, 40 is a heterocyclic group or a substituted or unsubstituted alkyl, aralkyl or cycloalkyl group or a group of the formula: 45 -N ' \ R! 6 stands, wherein R15 and R16, which are the same or different, each represent hydrogen or an alkyl group or R15 and R16 together with the adjacent nitrogen atom form a ring, wherein R6, R7, R8, R9, R10, R1 !, R13 and R14 , which are the same or different, each represent hydrogen, a halogen atom or a substituted or unsubstituted alkyl, aralkyl or aryl group and R12 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, cycloalkylsufonyl, arylsulfonyl, heterocyclesulfonyl, alkylcarbamoyl, dialkyl stands, wherein R15 and R16 have the meanings given in claim 1. 6. A3-cephem-4-carboxylic acids or their salts according to claim 5, characterized in that R5 represents a dialkylamino group or hydrogen or an alkyl, aralkyl or cycloalkyl group, optionally by an alkanoyloxy or carboxyl group or a group of For-55 mei: -c = or30 I \ : V O 60 65 wherein R30 is a lower alkyl group, is substituted. 7. A3-cephem-4-carboxylic acids or their salts according to claim 4, characterized in that R5 is hydrogen or a substituted or unsubstituted alkyl, aralkyl or cycloalkyl group or a group of the formula: 3rd 660 010 -N; \ r16 wherein R15 and R16 have the meanings given in claim 1. 8. A3-cephem-4-carboxylic acids or salts thereof according to claim 7, characterized in that R5 represents a dialkylamino group or hydrogen or an alkyl, aralkyl or cycloalkyl group which is optionally substituted by acyloxy. 9. A3-cephem-4-carboxylic acids or their salts according to claim 3, characterized in that R2 for a group of the formula: r6 r7 cook io or a salt thereof, in which R1, R3 and R4 have the meanings given above and R34 represents a substituted or unsubstituted acyloxy or carbamoyloxy group, with a compound of the formula: ■ v » 20th wherein R6, R7 and R8 have the meanings given in claim 1. 10. A3-cephem-4-carboxylic acids or their salts according to claim 9, characterized in that R6, R7 and R8, which are the same or different, each represent hydrogen or an alkyl group. 11. A3-cephem-4-carboxylic acids or their salts according to claim 3, characterized in that R2 for a group of the formula: 25th 30th H hnnr5, w (purple) R9- »ArE Ve 6 * 7 V » (Illb) hn, ; io • r11 or (iiic) wherein R9, R10 and R "have the meanings given in Claim 1. 12. A3-cephem-4-carboxylic acids or their salts according to claim 11, characterized in that R9, R10 and R ", which are the same or different, each represent hydrogen, a halogen atom or an alkyl group. 13. A3-cephem-4-carboxylic acids or their salts according to claim 3, characterized in that R2 for a group of the formula: wherein R12, R13 and R14 have the meanings given in claim 1. 14. A3-cephem-4-carboxylic acids or their salts according to claim 13, characterized in that R12, R13 and R14, which are the same or different, each represent hydrogen or an alkyl group. 15. A process for the preparation of A3-cephem-4-carboxylic acids of the formula I according to claim 1 and their salts, characterized in that a cephalosporanic acid of the formula: 35 or a salt thereof, wherein R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 have the above meanings, in the presence of an acid or a complex compound of an acid and, if desired, converting the product into a salt. 40 16. The method according to claim 15, characterized in that R3 is hydrogen. 17. The method according to claim 16, characterized in that the acid or complex compound of an acid is a Lewis acid or a complex compound of a Le- 45 white acid used. 18. The method according to claim 17, characterized in that boron trifluoride or a complex compound thereof is used as Lewis acid or complex compound of a Lewis acid. 19. Process according to one of claims 15 to 18, characterized in that the reaction is carried out in the presence of an organic solvent. 20. The method according to claim 19, characterized in that one is an organic solvent as an organic solvent 55 carboxylic acid, an ester, a nitroalkane or a sulfolane used. 21. The method according to any one of claims 15 to 20, characterized in that R34 stands for acetoxy. 22. Process for the preparation of A3-cephem-4-carbon 6o acids of the formula: COOH 660 010 4th in which R2, R3 and R4 have the meanings given in Claim 1, and their salts, characterized in that a cephalosporanic acid of the formula: coor in which R1 'represents a carboxyl protecting group, R3 and R4 have the meanings given in claim 1 and R34 represents a substituted or unsubstituted acyloxy or carbamoyloxy group, or a salt thereof with a compound of the formula (IIla) given in claim 15, ( Illb), (IIIc) or (Illd) in the presence of an acid or a complex compound of an acid, the protective group is removed and, if desired, the product is converted into a salt. 23. The method according to claim 22, characterized in that R3 is hydrogen. 24. The method according to claim 23, characterized in that a Lewis acid or a complex compound of a Lewis acid is used as the acid or complex compound of an acid. 25. The method according to claim 24, characterized in that boron trifluoride or a complex compound thereof is used as Lewis acid or complex compound of a Lewis acid. 26. The method according to any one of claims 22 to 25, characterized in that one carries out the reaction in the presence of an organic solvent. 27. The method according to claim 26, characterized in that an organic carboxylic acid, an ester, a nitroalkane or a sulfolane is used as the organized solvent. 28. The method according to any one of claims 22 to 27, characterized in that R34 stands for acetoxy. 29. A process for the preparation of A3-cephem-4-carboxylic acids of the formula I given above, in which R1 represents a carboxyl protecting group and R2, R3 and R4 have the meanings given in claim 1, and their salts, characterized in that a cephalosporanic acid of the formula: 32. The method according to claim 31, characterized in that boron trifluoride or a complex compound thereof is used as the Lewis acid or complex compound of a Lewis acid. s 33. The method according to any one of claims 29 to 32, characterized in that one carries out the reaction in the presence of an organic solvent. 34. The method according to claim 33, characterized in that an organic io carboxylic acid, an ester, a nitroalkane or a sulfolane is used as the organic solvent. 35. The method according to any one of claims 29 to 34, characterized in that R34 is acetoxy.