CEPHALOSPORIN DERIVATIVES

TRADUCTION NON-DISPONIBLE

English Abstract

Abstract of the Disclosure
A compound of the formula:
<IMG>
wherein W represents a halogen and Y represents an acetoxy group
or a group of formula -SR3 (where R3 is a nitrogen-containing
heterocyclic group), or a salt thereof, is found to be a
useful intermediate for the cephem compounds of the formula:
<IMG>
which have a broad antimicrobial spectrum and, in particular,
effective against gram-negative bacteria including Escherichia
coli, Klebsiella pneumoniae, Proteus vulgaris, Proteus morganii,
as well as gram positive ones, and thus may be used for anti-
microbial agents in therapeutical purposes.

Claims

The embodiments of the invention in which an ex-
clusive property or privilege is claimed are defined as follows:
1. A process for producing a compound of the
formula:
<IMG>
wherein W is a halogen atom and Y represents acetoxy or a
group of the formula -SR3, where R3 is a 5 or 6 membered ring
containing one to four nitrogens as hetero atoms which may be in
oxide form or, in addition to the nitrogen atom or atoms, one or
more other hetero atoms selected from the group consisting of
oxygen and sulfur, said ring being optionally substituted with
one or more of a lower alkyl, a lower alkoxyl; amino; mercapto;
hydroxyl; carboxyl; carbamoyl; a lower alkyl group substituted
with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo,
carbamoyl, mono-, di- or tri-(lower alkyl)amino, mono-, di- or
tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl,
acyloxy, or morpholinocarbonyl group; a mercapto group substituted
with a lower alkyl group or a lower alkyl group substituted with
a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl,
mono-, di-or tri-(lower alkyl)amino, mono-, di- or tri-(lower
alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or
morpholinocarbonyl group; an amino group substituted with a lower
alkyl, alkoxycarbonyl, acyl, carbamoyl, or lower alkylcarbamoyl
group, or a lower alkyl group substituted with a hydroxyl,
mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-,
di- or tri-(lower alkyl)amino, mono- or di-(lower alkyl)carbamoyl,
alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl
group, or a halogen atom; or a salt or ester thereof, which
22

comprises reacting a compound of the formula;
<IMG>
wherein Y has the same meaning as defined above, or a salt or
ester thereof, with a compound of the formula;
WCH2COCH2COW
wherein W has the same meaning as defined above.
2. A compound of the formula.
<IMG>
wherein W is a halogen and Y represents acetoxy or a group of
formula -SR3 where R3 is a 5 or 6 membered ring
containing one to four nitrogens as hetero atoms which may be in
oxide form or, in addition to the nitrogen atom or atoms, one or
more other hetero atoms selected from the group consisting of
oxygen and sulfur, said ring being optionally substituted with
one or more of a lower alkyl, a lower alkoxyl; amino; mercapto;
hydroxyl; carboxyl; carbamoyl; a lower alkyl group substituted
with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo,
carbamoyl, mono-, di-.or tri-(lower alkyl)amino, mono-, di- or
tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl,
acyloxy, or morpholinocarbonyl group; a mercapto group substituted
with a lower alkyl group or a lower alkyl group substituted with
a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl,
mono-, di-or tri-(lower alkyl)amino, mono-, di- or tri-(lower
alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or
morpholinocarbonyl group; an amino group substituted with a lower
23

alkyl, alkoxycarbonyl, acyl, carbamoyl, or lower alkylcarbamoyl
group, or a lower alkyl group substituted with a hydroxyl,
mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-
di - or tri-(lower alkyl) amino, mono- or di-(lower alkyl) car-
bamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpho-
linocarbonyl group, or a halogen atom; or a salt or ester there-
of, whenever prepared by the process of claim 1 or an obvious
chemical equivalent thereof.
3. A process as claimed in Claim 1, wherein the halo-
gen is chlorine or bromine.
4. A process as claimed in Claim 3, wherein Y repre-
sents an acetoxy group.
5. A process as claimed in Claim 3, wherein Y repre-
sents a group of formula -SR3, where R3 is a 5 or 6 membered
ring containing one to four nitrogens as hetero atoms which may
be in oxide form or, in addition to the nitrogen atom or atoms,
one or more other hetero atoms selected from the group consist-
ing of oxygen and sulfur, said ring being optionally substituted
with one or more of a lower alkyl, a lower alkoxyl; amino;
mercapto; hydroxyl; carboxyl; carbamoyl; a lower alkyl group
substituted with a hydroxyl, mercapto, amino, morpholino, car-
boxyl, sulfo, carbamoyl, mono-, di- or tri-(lower alkyl) amino,
mono-, di- or tri-(lower alkyl) carbamoyl, alkoxy, alkylthio,
alkylsulfonyl, acyloxy, or morpholinocarbonyl group; a mercapto
group substituted with a lower alkyl group or a lower alkyl group
substituted with a hydroxyl, mercapto, amino, morpholino, car-
boxyl, sulfo, carbamoyl, mono-, di-or -tri-(lower alkyl) amino,
mono-, di- or tri-(lower alkyl) carbamoyl, alkoxy, alkylthio,
alkylsulfonyl, acyloxy, or morpholinocarbonyl group; an amino
group substituted with a lower alkyl, alkoxycarbonyl, acyl,
carbamoyl, or lower alkylcarbamoyl group, or a lower alkyl
group substituted with a hydroxyl,
24

mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-,
di- or tri-(lower alkyl)amino, mono- or di-(lower alkyl)-
carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpho-
linocarbonyl group, or a halogen atom.
6. A process as claimed in Claim 5, wherein the ring
is selected from pyridyl, N-oxide-pyridyl, pyrimidyl, pyridazinyl,
N-oxide-pyridazinyl, pyrazolyl, diazolyl, triazolyl and tetra-
zolyl.
7. A process as claimed in Claim 5, wherein the ring
contains oxygen.
8. A process as claimed in Claim 7, wherein the ring
is oxadiazolyl.
9. A process as claimed in Claim 5, wherein the ring
contains sulfur.
10. A process as claimed in Claim 9, wherein the ring
is thiazolyl or thiadiazolyl.
11. A process as claimed in Claim 5, wherein the sub-
stituent of the substituted lower alkyl group is a hydroxyl,
mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-
di- or tri- lower alkylamino, mono-, or di- lower alkylcarbamoyl,
alkoxyl, alkylthio, alkylsulfonyl, acyloxy, or morpholino-
carbonyl group.
12. A process as claimed in Claim 5, wherein the sub-
stituent of the substituted mercapto group is a lower alkyl
group or a lower alkyl group substituted with a hydroxyl,
mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-,
di- or tri- lower alkylamino, mono- or di- tri- lower alkyl-
carbamoyl, alkoxyl, alkylthio, alkylsulfonyl, acyloxy, or
morpholinocarbonyl group.
13. A process as claimed in claim 5, wherein the sub-
stituent of the substituted amino group is a lower alkyl group,

an alkoxycarbonyl, an acyl, carbamoyl, a lower alkylcarbamoyl, or
a lower alkyl group substituted with a hydroxyl, mercapto, amino,
morpholino, carboxyl, sulfo, carbamoyl, mono-, di- or tri- lower
alkylamino, mono-, or di- lower alkylcarbamoyl, alkoxyl, alkylthio,
alkylsulfonyl, acyloxy, or morpholinocarbonyl group.
14. A process as claimed in Claim 5, wherein the
ring is triazolyl.
15. A process as claimed in Claim 5, wherein
the ring is tetrazolyl.
26

16. A process according to Claim 4 wherein 7-amino-
3-acetoxymethyl-3-cephem-4-carboxylic acid is reacted with a
compound of the formula WCH2COCH2COW whereln W is bromine or
chlorine; thereby to produce 7-(4-bromo or chloro-3-oxo-butyryla-
mido)-3-acetoxymethyl-3-cephem-4-carboxylic acid.
17. A process according to Claim 15 wherein 7-amino-3-
[1-(2-N,N-dimethylaminoethyl) tetrazol-5-yl] thiomethyl-3-cephem-
4-carboxylic acid is reacted with a compound of the formula
WCH2COCH2COW wherein W is bromine or chlorine, thereby to pro-
duce 7-(4-bromo or chloro-3-oxybutyrylamido)-3-[1-(2-N,N- di-
methylaminoethyl)tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid.
18. A process according to Claim 15 wherein 7-amino-
3-(1-carbamoylmethyl tetrazol-5-yl) thiomethyl-3-cephem-4-
carboxylic acid is reacted with a compound of the formula
WCH2COCH2COW wherein W is bromine or chlorine, thereby to pro-
duce 7-(4-bromo or chloro-3 oxobutyrylamido)-3-(1-carbamoylmethyl
tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.
19. A process according to Claim 15 wherein 7-amino-3-
(l-methyl-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
is reacted with a compound of the formula WCH2COCH2COW wherein
W is bromine or chlorine, thereby to produce 7-(4-bromo or
chloro-3-oxobutyrylamido)-3-(1-methyltetrazol-5-yl)thiomethyl-3-
cephem-4-carboxylic acid.
20. A process as claimed in Claim 5, wherein the ring
is thiazolyl.
21. A process according to Claim 20 wherein 7-amino-3-
(4-carboxylmethyl-1,3 thiazol-2-yl)-thiomethyl-3-cephem-4-car-
boxylic acid is reacted with a compound of the formula WCH2COCH2
COW wherein W is Br or C1, thereby to produce 7-(4-bromo or
chloro-3-oxobutyrylamido)-3-carboxyl-methyl-1,3-thiazol-2-yl)
thiomethyl-3-cephem-4-carboxylic acid.
27

22. A process as claimed in Claim 5 wherein the
ring is thiadiazolyl.
23 A process according to Claim 22 wherein
7-amino-3 (2-amino-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid is reacted with a compound of the formula
WCH2COCH2COW wherein W is Br or Cl, thereby to produce 7-(4-bromo
or chloro-3-oxobutyrylamido)-3-(2-amino-1,3,4-thiadiazol-5-yl)thio-
methyl-3-cephem-4-carboxylic acid.
24. A process according to Claim 22 wherein
7-amino-3-[2-(hydroxyl-ethylthio)-1,3,4-thiadiazol-5-yl[ thiomethyl-
3-cephem-4-carboxylic acid is reacted with a compound of the
formula WCH2COCH2COW wherein W is bromine or chlorine, thereby
to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-[2-hydroxyl-
ethylthio)-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid.
25. A process according to Claim 22 wherein
7-amino-3-[3-(2-acetoxyethylthio)-1,3,4-thiadiazol-5-yl)thio-
methyl-3-cephem 4-carboxylic acid is reacted with a compound of
the formula WCH2COCH2COW wherein W is bromine or chlorine
thereby to produce 7-(4-bromo or chloro-3-oxobutyryl-amido)-3-[2-
(2-acetoxyethylthio)-1,3,4-thiadiazol-5-yl] thiomethyl-3-cephem-
4-carboxylic acid.
26. A process according to Claim 22 wherein 7-
amino-3-[2-(N,N-dimethylaminomethylcarbonyl)amino-1,3,4-
thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid is
reacted with a compound of the formula WCH2COCH2COW wherein
W is bromine or chlorine, thereby to produce 7-(4-bromo or
chloro-3- oxobutyrylamido)-3-[2-(N,N-dimethylaminomethylcarbonyl)
amino-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic
acid.
27. A process according to Claim 22, wherein
7-amino-3-[2-(N,N-dimethylaminocarbonyl)methyl-1,3,4-thiadiazol-
5-yl]thiomethyl-3-cephem-4-carboxylic acid is reacted with a
28

compound of the formula WCH2COCH2COW wherein W is bromine or
chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyryl-
amido-3-[2-(N,N-dimethylaminocarbonyl)methyl-1,3,4-thiadiazol-
5-yl]thiomethyl-3-cephem-4-carboxylic acid.
28. A process according to Claim 22 wherein 7-
amino-3-[2-(2-N,N-dimethylaminoethyl)thio-1,3,4-thiadiazol-5-
yl]thiomethyl-3-cephem-4-carboxylic acid is reacted with a
compound of the formula WCH2COCH2COW wherein W is bromine or
chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-
3-[2-(2-N,N-dimethylaminoethyl)thio-1,3,4-thiadiazol-5-yl]thiomethyl-
3-cephem-4-carboxylic acid.
29. A process according to Claim 22 wherein 7-
amino-3-(2-carboxylmethyl -thio-1,3,4-thiadiazol-5-yl)
thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound
of the formula WCHCOCH2COW wherein W is bromine or chlorine, thereby
to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-carboxyl-
methylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid.
30. A process according to Claim 22 wherein 7-amino-3-(2-
ethoxycarbonylmethyl-thio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem,4-carboxylic
acid is reacted with a compound of the formula WCH2COCH2COW wherein W is bromine
or chlorine, thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-
ethoxycarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic ac:
31. A process according to Claim 22 wherein 7-
amino-3-(2-carbamoylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid is reacted with a compound of the
formula WCH2COCH2COW wherein W is bromine or chlorine, thereby
to produce 7-(4-bromo or chloro-3-oxybutyrylamido)-3-(2-carbamoyl-
methylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid.
32. A process according to Claim 22 wherein
7-amino-3-[2-(2-hydroxyethyl)amino-1,3,4-thiadiazol-5-yl]thio-
methyl-3-cephem-4-carboxylic acid is reacted with a compound of
the formula WCH2COCH2COW wherein W is bromine or chlorine thereby
29

to produce 7-4-bromo or chloro-3-oxybutyrylamido)-3-[2-2-hydro-
xyethyl) amino-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-car-
boxylic acid.
33. A process according to Claim 22 wherein 7-amino-3-
[2-(2-N,N-dimethylaminoethyl)amino-1,3,4-thiadiazol-5-yl]thio-
methyl-3-cephem-4-carboxylic acid is reacted with a compound of
the formula WCH2COCH2COW, thereby to produce 7-(4-bromo or chloro-
3-oxybutyrylamido-3-[2-(2-N,N-dimethylamino-ethyl)amino-1,3,4-
thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid.
34. A process according to Claim 22 wherein 7-amino-3-
(2-carboxymethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid is reacted with a compound of the formula WCH2
COCH2COW wherein W is bromine or chlorine, thereby to produce
7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-carboxymethyl-1,3,4-
thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
35. A process according to Claim 22 wherein 7-amino-3-
(2-carbamoylmethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid is reacted with a compound of the formula WCH2
COCH2COW wherein W is bromine or chlorine, thereby to produce
7-(4-bromo or chloro-3-oxobutyrylamido)-3-(2-carbamoylmethyl-1,
3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
36. A process according to Claim 22 wherein 7-amino-
3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid is reacted with a compound of the formula WCH2COCH2COW
wherein W is bromine or chlorine, thereby to produce 7-(4-bromo
or chloro-3-oxobutyrylamido)-3-(2-methyl-1,3,4-thiadiazol-5-yl)
thiomethyl-3-cephem-4-carboxylic acid.
37. A process according to Claim 22 wherein 7-amino-3-
(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic

acid is reacted with a compound of the formula WCH2COCH2COW
wherein W is bromine or chlorine,, thereby to produce 7-(4-bromo
or chloro-3-oxobutyrylamido)-3-(1,3,4-thiadiazol-2-yl)-thio-
methyl-3-cephem-4-carboxylic acid.
38. A process according to Claim 22 wherein
7-amino-3-(2-methylthiomethyl-1,3,4-thiadiazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid is reacted with a compound of the
formula WCH2COCH2COW wherein W is bromine or chlorine, thereby
to produce 7-(4-bromo or chloro-3 oxobutyrylamido)-3-(2-methyl-
thiomethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid.
39. A process according to Claim 22 wherein 7-
amino-3-(2-morpholinocarbonylmethylthio-1,3,4-thiadiazol-5-yl)
thiomethyl-3-cephem-4-carboxylic acid is reacted with a compound
of the formula WCH2COCH2COW wherein W is bromine or chlorine,
thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-
(2-morpholinocarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid.
40. A compound according to Claim 2 wherein
the halogen is chlorine or bromine, whenever prepared by the
process of Claim 3 or by an obvious chemical equivalent thereof.
31

41. A compound according to Claim 2 wherein the halogen
is chlorine or bromine and Y represents an acetoxy group,
whenever prepared by the process of Claim 4 or an obvious
chemical equivalent thereof.
42. A compound of the formula
<IMG>
wherein W is chlorine or bromine and Y represents a group of
formula -SR3 wherein R3 is a 5 or 6 membered ring containing
one to four nitrogens as hetero atoms which may be in
oxide form or, in addition to the nitrogen atom or atoms, one or-
more other hetero atoms selected from the group consisting-of
oxygen and sulfur, said ring being optionally substituted with
one or more of a lower alkyl, a lower alkoxyl; amino; mercapto;
hydroxyl; carboxyl; carbamoyl; a lower alkyl group substituted
with a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo,
carbamoyl, mono-, di- or tri-(lower aikyl)amino, mono-, di or
tri-(lower alkyl)carbamoyl, alkoxy, alkylthio, alkylsulfonyl,
acyloxy, or morpholinocarbonyl group; a mercapto group substituted
with a lower alkyl group or a lower alkyl group substituted with
a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl,
mono-, di-or tri-(lower alkyl)amino, mono-, di- or tri-(lower
alkyl)carbamoyl, alkoxy, alkyithio, alkylsulfonyl, acyloxy, or
morpholinocarbonyl group; an amino group substituted with a lower
alkyl, alkoxycarbonyl, acyl, carbamoyl, or lower alkylcarbamoyl
group, or a lower alkyl group substituted with a hydroxyl,
mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-,
di- or tri-(lower alkyl)amino, mono- or di-(lower alliyl)carbamoyl,
32

alkoxy, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl
group, or a halogen atom; whenever prepared by the process of
Claim 5 or an obvious chemical equivalent thereof.
43. A compound according to Claim 42, wherein the
ring is selected from pyridyl, N-oxide pyridyl, pyrimidyl,
pyridazinyl, N-oxide pyridazinyl, pyrazolyl, diazolyl, triazolyl
and tetrazolyl, whenever prepared by the process of Claim 6 or
an obvious chemical equivalent thereof.
44. A compound according to Claim 42, wherein the
ring contains oxygen, whenever prepared by the process of Claim 7
or an obvious chemical equivalent thereof.
45. A compound according to Claim 42, wherein the ring
is oxadiazolyl, whenever prepared by the process of Claim 8 or
an obvious chemical equivalent thereof.
46. A compound according to Claim 42, wherein the ring
contains sulfur, whenever prepared by the process of Claim 9 or
an obvious chemical equivalent thereof.
47. A compound according to Claim 42, wherein the ring
is thiazolyl or thiadiazolyl, whenever prepared by the process of
Claim 10 or an obvious chemical equivalent thereof.
48. A compound according to Claim 42, wherein the
substituent of the substituted lower alyl group is a hydroxyl,
mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, mono-
di- or tri- lower alkylamino, mono-, or di- lower alkylcarbamoyl,
alkoxyl, alkylthio, alkylsulfonyl, acyloxy, or morpholinocarbonyl
group, whenever prepared by the process of Claim 11 or an obvious
chemical equivalent thereof.
49. A compound according to Claim 42, wherein the
substituent of the substituted mercapto group is a lower alkyl
group or a lower alkyl group substituted with a hydroxyl, mercapto,
amino, morpholino, carboxyl, sulfo, carbamoyl, mono-, di or tri-
33

lower alkylamino, mono- or di- tri- lower alkylcarbamoyl, alkoxyl,
alkylthiol alkylsulfonyl, acyloxy, or morpholinocarbonyl group,
whenever prepared by the process of Claim 12 or an obvious
chemical equivalent thereof.
34

50. A compound according to claim 42, wherein
the substitute of the substituted amino group is a lower
alkyl group, an alkoxycarbonyl, an acyl, carbamoyl, a lower
alkylcarbamoyl, or a lower alkyl group substituted with
a hydroxyl, mercapto, amino, morpholino, carboxyl, sulfo,
carbamoyl, mono-, di- or tri-lower alkylamino, mono-,
or di- lower alkylcarbamoyl, alkoxyl, alkylthio, alkyl-
sulfonyl, acyloxy, or morpholinocarbonyl group, whenever
prepared or produced by the process of claim 13 or by an
obvious chemical equivalent thereof.
51. A compound according to claim 42, wherein
the ring is triazolyl, whenever prepared or produced by the
process of claim 14 or by an obvious chemical equivalent
thereof.
52. A compound according to claim 42, wherein
the ring is tetrazolyl, whenever prepared or produced by
the process of claim 15 or by an obvious chemical equivalent
thereof.
53. The compound, 7-(4-bromo or chloro-3-
oxobutyrylamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid,
whenever prepared or produced by the process of claim 16
or by an obvious chemical equivalent thereof.
54. The compound, 7-(4-bromo or chloro-3-
oxobutyryl amido)-3-[1-(2 N, N-dimethylaminoethyl)tetrazol-5-yl]-
thiomethyl-3-cephem-4-carboxylic acid, whenever prepared
or produced by the process of claim 17 or by an obvious
chemical equivalent thereof.
55. The compound, 7-(4-bromo or chloro-3-
oxobutyryl amido)-3-(1-carbamoylmethyltetrazol-5-yl)thio-
methyl-3 cephem-4-carboxylic acid, whenever prepared or
produced by the process of claim 18 or by an obvious chemical
equivalent thereof.

56. The compound, 7-(4-bromo or chloro-3-
oxobutyrylamido)-3-(1-methyl-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid whenever prepared or produced
by the process of claim 19 or by an obvious chemical equivalent
thereof.
57. A compound according to claim 42 wherein the
ring is thiazolyl, whenever prepared or produced by the
process of claim 20 or by an obvious chemical equivalent
thereof.
58. The compound 7-(4-bromo or chloro-3-
oxobutyrylamido)-3-(4-carboxylmethyl-1, 3-thlazol-2-yl)-
thiomethyl-3-cephem-4-carboxylic acid, whenever prepared or
produced by the process of claim 21 or by an obvious chemical
equivalent thereof.
59. A compound according to claim 42 wherein the
ring is thiadiazolyl, whenever prepared or produced by the
process of claim 22 or by an obvious chemical equivalent
thereof.
60. The compound 7-(4-bromo or chloro-3-oxo-
butyrylamido)-3-(2-amino-1, 3, 4-thiadiazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid, whenever prepared or produced
by the process of claim 23 or by an obvious chemical equivalent
thereof.
61. The compound 7-(4-bromo or chloro-3 oxo-
butyrylamido)-3-[2-(hydroxyethylthio)-1, 3, 4-thiadiazol-
5-yl]thiomethyl-3-cephem-4-carboxylic acid, whenever
prepared or produced by the process of claim 24 or by an
obvious chemical equivalent thereof.
62. The compound 7-(4-bromo or chloro-3-
oxobutyrylamido)-3[[2-(2-acetoxyethylthio)-1, 3, 4-thia-
diazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, whenever
prepared or produced by the process of claim 25 or by an
36

obvious chemical equivalent thereof.
63. The compound 7- (4-bromo or chloro-
3-oxobutyrylamido)-2-[2-(N, N-di-
methylaminomethylcarbonyl)amino-1, 3, 4-thiadiazol-5-yl]
thiomethyl-3-cephem-4-carboxylic acid, whenever
prepared or produced by the process of claim 26 or by
an obvious chemical equivalent thereof.
64. The compound 7-(4-bromo or chloro-3-oxobutyryl-
amido)-3-[2-(N, N-dimethylaminocarbonyl)methyl-1, 3, 4-
thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid,
whenever prepared or produced by the process of claim 27
or by an obvious chemical equivalent thereof.
65. The compound 7-(4-bromo or chloro-3-
oxobutyrylamido)-3-[2-(2-N, N-dimethylaminoethyl)thio-1,
3, 4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid,
whenever prepared or produced by the process of claim 28
or by an obvious chemical equivalent thereof.
66. The compound 7-(4-bromo or chloro-3
oxobutyrylamido)-3-(2-carboxylmethylthio-1, 3, 4-thiadiazol-
5-yl)thiomethyl-3-cephem-4-carboxylic acid, whenever prepared
or produced by the process of claim 29 or by an obvious
chemical equivalent thereof.
67. The compound 7-(4-bromo or chloro-3-oxo-
butyrylamido)-3-(2-ethoxycarbonylmethylthio-1, 3, 4-
thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, whenever
prepared or produced by the process of claim 30 or by an
obvious chemical equivalent thereof.
68. The compound 7-(4-bromo or chloro-3-oxo-
butyrylamido)-3-(2-carbamoylmethylthio-1, 3, 4-thiadiazol-
5-yl)thiomethyl-3-cephem-4-carboxylic acid, whenever prepared
or produced by the process of claim 31 or by an obvious
chemical equivalent thereof.
37

69. The compound 7-(4-bromo or chloro-3-oxo-
butyrylamido)-3-[2-(2-hydroxyethyl)amino-1, 3, 4-thiadiazol-
5-yl]thiomethyl-3-cephem-4-carboxylic acid, whenever prepared
or produced by the process of claim 32 or by an obvious
chemical equivalent thereof.
70. The compound 7-(4-bromo or chloro-3-oxo-
butyrylamido)-3-[2-(2-N, N-dimethylaminoethyl)amino-1,
3, 4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid,
whenever prepared or produced by the process of claim 33
or by an obvious chemical equivalent thereof.
71. The compound 7-(4-bromo or chloro-3-oxo-
butyrylamido)-3-(2-carboxymethyl-1, 3, 4-thiadiazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid, whenever prepared
or produced by the process of claim 34 or by an obvious
chemical equivalent thereof.
72. The compound 7-(4-bromo or chloro-3-oxo-
butyrylamido)-3-(2-carbamoylmethyl-1, 3, 4-thiadiazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid, whenever prepared
or produced by the process of claim 35 or by an obvious
chemical equivalent thereof.
73. The compound 7-(4-bromo or chloro-3-oxo-
butyrylamido)-3-(2-methyl-1, 3, 4-thiadiazol-5-yl)thio-
methyl-3-cephem-4-carboxylic acid, whenever prepared
or produced by the process of claim 36 or by an obvious
chemical equivalent thereof.
74. The compound 7-(4-bromo or chloro-3-
oxobutyrylamido)-3-(1, 3, 4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid, whenever prepared or produced by
the process of claim 37 or by an obvious chemical equivalent
thereof.
75. The compound 7-(4-bromo or chloro-3-oxo-
38

butyrylamido)-3-(2-methylthiomethyl-1, 3, 4-thiadiazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid, whenever prepared
or produced by the process of claim 38 or by an obvious
chemical equivalent thereof.
39

76 . The compound 7-(4-bromo or chloro-3-oxobutyryl-
amido)-3-(2-morpholinocarbonylmethylthio-1,3,4-thiadiazol-5-yl)
thiomethyl-3-cephem-4-carboxylic acid, whenever prepared by
the process of Claim 39 or by an obvious chemical equivalent
thereof.
77. A process according to Claim 22 wherein 7-
amino-3-(2-morpholinocarbonylmethyl-1,3,4-thiadiazol-5-yl)thio-
methyl-3-cephem-4-carboxylic acid, is reacted with a compound
of the formula WCH2COCH2COW wherein W is bromine or chlorine,
thereby to produce 7-(4-bromo or chloro-3-oxobutyrylamido)-3-
(2-morpholinocarbonylmethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3
cephem-4-carboxylic acid.
78. The compound 7-(4-bromo or chloro-3-oxobutyryl-
amido)-3-(2-morpholinocarbonylmethyl-1,3,4-thiadiazol-5-yl)thio-
methyl-3-cephem-4-carboxylic acid; whenever prepared by the
process of Claim 77 or by an obvious chemical equivalent thereof.

Description

5~7
This .invention relates to novel cephalosporin deriva-
tives having novel 7-acyl groups and preparations thereo~.
More particularly, this invention r~lates to 7-(4-halogeno-3-
~xobutyrylamido)cephalosporin derivatives of the formula:
WCEI2COCH2CONH ~ S ~ [VI ]
o ~LCH2Y
COOH
wherein W is a halogen and Y is an acetoxy group or a grou~ of
Pormula SR (where R3 is a n~trogen-containing heterocyclic
group), or a salt thereof and also relates to processes for
producing the same.
Heretofore~ studies on synthetic cephalosporin
derivatives have been directed to the conversion of 7-
aminocephalosporanic acid to various acyl derivatives at the
7-position or to derivatives at the 3-acetoxy group in order
to synthesize compounds having either a broad antibacterial
spectrum or a specific antibacterial spectxum. However,
these well-known cephalosporin derivatives are not yet
satisfactory in antimicrobi.al activities against a wide
variety of microorganisms. Hence, a compound has been sought
after which has a broad or antimicrobial spectrum and is
effective even at a lower concentration.
It has now been found that novel cephalosporin deri~a-
tives represented by the above formula [VI] are useful inter-
mediates for the production of 7-[2-(2-exo-substituted-4-
thiazolin-4-yl)acetamido]cephalosporin derivatives of the
formula:
~t,~

x~s
N ~il -- CH2coHN ~
R~ N~L C~ 2 Y [ I ]
COOH
wherein Rl is a hydrogen atom or an alkyl group; X is oxygen or a
sulfur atom or a group of formula NR2 (where R2 is hydrogen
or an alkvl gr~up, and in the case of an alkyl group, it may ~orm a ring
joined ~ith Rl), Y hasthe same meaning as defined above, or
a pharmaceutically acceptable salt thereof, ~ich have broader
antimicro~ial spectra as compared with those of known cephalo-
sporins. For example, the cephalosporin deriva-tives ~I~ are
desirable cephalosporin antibiotics, having a strong and
broad an_imicrobial spectrum especiaLly against such gram-
negative bacterla as Escherichia coli, Klebs_ella pneumoniae,
Proteus vulgaris and Pro_teus morganl , showing greater in-
hibitory activlty in comparison wlth known cephalosporins.
` Referring, now, to the above formula [VI], Y stands
:Eor an-acetc~ygroup or a group denoted by formula -SR3. R3
stands for a nltrogen-containing heterocyclic group containing
not less than one nitrogen whlch may be in the oxide form or,
in addition to nitrogen or nitrogens, such others as oxygen
or/and sulfur. The nitrogen-containing heterocyclic group
desirably has one to:four hetero atoms in its heterocyclic
ring and the ring maybe a 5 or 6 membered one. As such nitrogen-
containing heterocyclic group, there may be mentioned, among
others, pyridyl, N-oxido-pyridyl, pyrimidyl, pyridazinyl, N- `~
oxido-pyridazinyl, pyrazolyl, diazolyl, thiazolyl, 1,2,3-
thiadiazolyl, 1,2,4~thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-
thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-
oxadiaæolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl~

9~9~
lH-tetrazolyl, 2H-tetrazolyl and others. Each of these
nitrogen-containing heterocyclic groupS may be further sub-
stituted and, as the substituents, there may be mentioned
monovalent groups, for example, lower alkyls such as methyl,
ethyl, trifluoromethyl~ etc., lower alkoxyls such as methoxy,
ethoxy, etc., halogens such as chlorine, bromine, etc., amino,
mercapto, hydroxyl, carbamoyl, or carboxyl groups, etc. or a
substituted lower alkyl group, a substituted mercapto group,
or a mono- or di-substituted amino group, etc. The substituents
in the substituted lower alky] group may be hydroxyl, mercapto,
amino, morpholino, carboxyl, sulfo, carbamoyl,~alkoxycarbonyl,
mono-, di- or tri-lower alkylamino, mono- or dl-lower alkyl-
carbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, morpholino-
carbonyl groups, etc., wherein the acyloxy group is exemplified
by acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy,
phenylacetoxy, etc., the alkoxy group by methoxy, ethoxy,
propoxy, butoxy, isobutoxy, hexyloxy, octyloxy, decyloxy,
dodecyloxy, etc. r and others are the same meaning as hereir.-
before described. The substituent of the substituted mercapto
group may be a lower alkyl group or a substituted lower alkyl
group above mentioned. The substituents of the mono- or-di-
substituted amino group may be alower alkyl group, an alkoxy-
carbonyl, an acyl, carbamoyl, a lower alk~lcarbamoyl,oor a
substituted lower alkyl group mentioned above.
Specifically, use may be made of, for example, a
substituted lower alkyl group such as carboxymethyl, carbamoyl-
methyl, an N-lower alkylcarbamoylmethyl (e.g. N,N-dimethyl-
carbamoylmethyl), a hydroxy-lower alkyl (e.g. hydroxymethyl, 2-
hydroxyethyl), an acyloxy-lower alkyl (e.g. acetoxymethyl,
2-acetoxyethyl), an alkoxycarbonylmethyl (e.g. methoxycarbonyl-
methyl, hexyloxycarbonylmethyl, octyloxycarbonylmethyl), methyl-

257
thiomethyl, methylsulfonylmethyl, an N-lower alkylamino-lower
alkyl te.g. N,N-dimethylaminomethyl, N,N-dimeth~ylaminoethyl,
N,N,N-trimethylammoniumethyl), morpholinomethyl, etc., mono-
or dl-substituted amino groups such as a lower alkylamino
~e~g. methylamino), a sulfo-lower alkylamino ~e.g. 2-sulfo-
ethylamino), a hydroxy-lower alkylamino (e.g., hydroxyethyl-
amino), a lower alkylamino-lower alkylamino (e.g. 2-dimethyl-
amino-ethylamino, 2-trimethylammoniumethylamino), an acylamino
(e.g~ acetylamino), 2-dimethylaminoacetylamino, 2-trimethyl-
ammonium-acetylamino, a lower alkoxycarbonylamino (e.g.
methoxycacbonylamino), etc., a substituted mercapto group such
as methylthio, 2-hydroxyethylthio, a 2-acyloxyethylthio (e.g.
2-acetoxyethylthio, 2-phenylacetoxyethylthio, 2-caproyloxy-
ethylthio), carboxymethylthio, an alkoxycarbonylmethylthio
(e.g. methoxycarbonylmethylthio, hexyloxycarbonylmethylthio~,
carbamoylmethylthio, an N-lower alkylcarbamoylmethylthio (e.g.
N,N-dlmethylcarbamoylméthylthio), acetylmethylthio, an N-lower
alkylamino-lower alkylthio (e.g. 2-N,N-dimethylamino-ethylthio,
2-N,N,N-trimethylammonium-ethylthio), morpholinocarbonylmethyl-
thio, 2-sulfoethylthio, etc.
The 7-(4-halogeno-3-oxobutyrylamido)cephalosporin
derivatives ~q]of this invention may be used with its 4-carboxyl
group being free or after being made into a salt with a nontoxic
cation such as sodium, potassium or the like; a basic amino
acid such as arginine, ornithine, lysine, histidine or the like;
or a polyhydroxyalkylamine such as N-methylglucamine, diethanol-
amine, triethanolamine, tris-hydroxymethylaminomethane or the
like. The compounds [I] may also be used after it has been
converted to an ester derivative by esterification of its 4- !
carboxyl group, said ester derivatives being conducive to, for
instance, an increased blood level or/and a longer duration of
activity. As the ester residues of use for this purpose~ there
-- 5 --

~ 57
may be m~ntioned, for example, alkoxylmethyl and ~-alkox~ethyl
and other ~-alkoxy~subs~ituted methyl groups, e.g. methoxy-
methyl, ethoxymethyl, isopropoxymethyl, ~-methoxyethyl,
~-ethoxyethyl, etc ; alkylthio~e~hyl groups, e.g. methylthio-
methyl, ethylthiomethyl, isopropylthiomethyl, etc.; and acyloxy-
methyl and a-acyloxy-~-substituted methyl groups, e.g.
pivaloyloxymethyl, ~-acetoxybutyl, etc.
The present invention, in a broad aspect, resides in
a process for producing a compound o~ the formula:
L0
WcH2cocH2coNE~F~s ~
N ~ CH2Y
COOH
wherein W is a halogen atom and Y represents acetoxy or a group
of formula -SR3 (where R3 is a nitrogen-containing heterocyclic
group), or a salt or ester thereof, which comprises reacting
a compound o the formula:
H2N
O N ~ CH2Y
COOH
wherein Y is the same meanIng as defined above, or a salt or
ester thexeof, with a compound of the formula:
WCH2COCH2COW
wherein ~ is the same meaning as defined above.
In another broad aspect, this invention resides in a
compound of the formula
WCH~COCH2CONH ~ ~ S
~CH2Y [
~ ~ - 6 - .
..., .~si~,

;7
wherein W is a halogen atom and Y represents acetoxy or a
group of formula - SR (where R3 is a nitrogen-containing
heterocyclic group), or a salt thereof.
The cephalosporin derivatives [VI] of the present
invention may be allowed to react with a compound of the
formula:
NH
NH2-C-SH [VII]
or a salt thereof, to obtain a compound of the formula [II]
NH
NH2-c-sc~2coc~l2coNH ~ [II]
~O ~ N ~ CH2Y
~ COOH
wherein the symbol has the same meaning as above, or a salt
or an ester thereof, whlch is subjected to a ~ closure re-
action with elimination of water, to obtain cephalosporin
derivatives of the formula [I].
The 3-nitrogen-containing heterocyclic thiomethyl
compounds [VI] and [XII] are prepared by the reaction formulated
below;
.
NH ~ S j ~XII]
o~ N~o~L 2
COOH
;
i WCH2COCH2COW [XIV]
WCH2COCH2CONH ~ ~S
o~N~ CH2Y [VI~
COOH
-- 7 --

` ~L@~257
The amino compounds [XII] may be prepared by de-
acylating the reaction product of cephalosporin C and a
nitrogen-containing heterocyclic thiol of the formula [X];
R3SH wherein R3 ha~ the same meaning as above, or its salt,
or by reacting 7-protected aminocephalosporanic acid with
a nitrogen-containing heterocyclic thiol [X] and removing the
protecting group from the reaction product with the nomenclature
of similar compounds adopted by Chemical Abstracts. The
tautomeric isomers, however, are all included within the
scope of this invention.
The typical examples of 7-(4-halogeno-3-oxobutyrylamido)
cephalosporin derivatives ~1] thus obtained are 7-(4-chloro or
bromo-3-oxobutyrylamido)-3-(1,3,4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid, 7-(4-chloro or bromo-3-oxobutyryl-
amido)-3-(l~methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic
acid, 7-(4-chloro or bromo-3 oxobutyrylamido)-3-(1-ethyltetrazol-
5-yl)-thiomethyl-3-cephem-4-carboxylic acid, 7-(4-chloro or
I bromo-3-oxobutyrylam.ido)-3-(2-methyl-1,3,4-thiadiazol-~-yl)-
thiomethyl-3-cephem-4-carboxylic acid, 7-(4-chloro or bromo-3-
oxobutyrylamido -3-[2-(2-hydroxyethyl-
thio)-1,3,4~thiadiazol-5-yl]t~iomethyl-3-cephem-4-carboxylic
acid, 7-(4-chloro or bromo-3-oxobutyrylamido)-3-12-(N,N-di-
methylcarbamoylmethyl)-1,3,4-thiadiazol-5-yl]thiomethyl-3-
cephem-4-carboxylic acid, 7 (4-chloro or bromo-3-oxobutyryl-
amido)-3-[2-(2-acetoxyethylthio)-1,3,4-thiadiazol-5-yl]thio-
methyl-3-cephem-4-carboxylic acid, 7-(4-chloro or bromo-3-
oxobutyrylamido)-3-(2-carboxymethyl-1,3,4-thiadiazol-5-yl)-
thiomethyl-3-cephem-4-carboxylic acid, 7-(4 chloro or bromo-
3-oxobutyrylamido)-3-(2-carbamoylmethyl-1,3,4~thi.adiazol-5-
yl~thiomethyl-3-cephem-4-carboxylic acid, 7 (4-chloro or bromo-
3-oxobutyrylamido)-3-(2 carbamoylmethylthio-1,3,4-thiadiazol-
5-yl)thiomethyl-3-cephem-4-carhoxylic acid.
, ~ ~

i7
The present invention is illustrated in further
detail below with reference to examples, but it is to be
understood that the examples are solely for the purpose of
illustration and not to be construed as limitations of the
invention, and that many variations may be resorted to with-
out departing from the spirit and scope of the invention~
In this specification, "g", "mg.", "kg.", "ml.", "cm.", "ppm",
"H2", "MHz", "mol", "m mol", "mcg"~ "Calcd.", "DMSO", "nm"
and "decomp." are abbreviations of "gram", "milligram",
"kilogram", "milliliter", "centimeter", "part per million",
"Herz"j "mega Herz"~ "Mole", "milli-Mole", "microgram",
"Calculated", "dimethylsulfoxide", "Nano meter", and "decom-
posed", respectively. Resins named 'Amberlite"* are products
manufactured by Rohm & Haas Co. in U.S.A. All the temperatures
are uncorrected and the percentages are all on the weight
basis except specifically defined. The NMR spectra given
therein were measured using a Varian Model HA 100 (100 MHz) or
T60 (60 MHz) spectrometer with tetramethylsilane as the in-
ternal reference and all ~ values are in ppm. The sy~bol s
~0 stands for a singlet, d a doublet, t a triplet, q a quartet,
_ a multiplet, and J a coupling constant.
Reference ExamDle 1
Production of sodium 7-[2-(2-aminothiazol-4-yl)
acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate
In a mixture of 53 mQ. of water and 26.4 mQ. of
tetrahydrofuran are dissolved 0.442 g. of thiourea and 0.889 g.
of sodium hydrogen carbonate. Then, 2.3 g. of 7-(4-bromo-3-
* Trade~ark
g

9~i~57
oxobutyrylamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid iS
gradually added and dissolved. The mixture is stirred at room
temperature for 30 minutes, af~er which time it is concentrated
under reduced pressure to remove the tetrahydrofuran and further
to a final volume of 20 mQ. The residue is chromatographed on
a column of polystyrene r sin (~erlite X~2"*) and developed
with water. The fractions containing the desired product (with
good absorption of ultraviolet light at 254 m~) are pooled and
freeze-dried. The procedure gives the above-indicated compound.
Yield 1.305 g. (52.6 %)
IR(cm , KBr): 1767
UV~ max( in water): 256 nm(1.35 x 104)
NMR(~ in D2O): 2.15 (s, CH3CO), 3.39 & 3.69(ABq, J18Hz,
2-CH2), 3.62(s, CH2CO), 4.75 & 4.94(ABq,
J13Hz, 3-CH2), 5.15(d, J5Hz, 6-H), 5.71(d,
JSHz, 7-H), 6.52(s, thiazole 5-H)
Elemental analysis: Calcd. for C15H15N4O6S2Na 2H2O:
C, 38.29; H, 4.07; N, 11.91
Found: C, 38.41; H, 3.90; N, 11.72
Antibacterial spectra
-(mcg/mQ., agar diluti-on m~thod)
,
Strain of Product
microorganism of this Cephalor~dine Cephazolin
example
. . ~
S. aureus 209P <0.78 0.05 0.1
S. aureus 1840 1.56 0.39 1.56
E. coli NIHJ JC-21.56 6.25 1.56
K. pneumoniae DT<0.78 3.125 1.56
P. vulgaris Eb-57~0.78 ~100 50
.. _ _ ............. _ . ... _ _ ._ _
*,Trademark
-- 10 --

`~ 25~
Reference Example 2
Production of 7-[2-(2-aminothiazol-4-yl)acetamido]-
3-acetoxymethyl-3-cephem-4-carboxylic acid
III a mixture of 80 mQ. of water and 40 mQ. of
tetrahydrofuran are dissolved 0.602 g. of thiourea and 0.664 g.
of sodium hydrogen carbonate. Then, 3.085 g. of 7-(4-chloro-
3-oxobutyrylamido)-3-acetoxymethyl-3~cephem-4-carboxylic acid
is gradually added and dissolved. The mixture is stirred at
room temperature for 1 hour, after which time the te-trahydro-
furan is dlstilled off under reduced pressure. The residue
is allowed to stand at room temperature and the resulting
crystals are recovered by filtration. The filtrate is further
eoncentrated and allowed to stand, whereupon an additional
crop of crys-tals is obtained. These crystals are recovered
and combined with those previously harvested. The described
proeedure gives 2.703 g. (83%) of the above-indicated compound.
IR(cm , KBr): 1776
UV~ max(- in water): 256 nm(l.35 x 104)
NMR(~ in d6-DMSO): 2.01(s, CH3CO), 3.38(s, CH2CO),
3.40 & 3.63(ABq, J18Hz, 2-CH2), 4.68 & 4.98
(ABq, J13Hz, 3-CH2), 5.06(d, J5Hz, 6-H),
5.68(dd, J5 & 8Hz, 7-H), 6.23(s, thiazole 5-H),
6.90(broad s, NH2), 8.82(d, J8Hz, CONH),
9.20(broad s, COOH).
Referenee Example 3
Production of sodium 7-[2-(2-aminothiazol-4-yl)-
acetamido]-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylate
In a mixture of 10 mQ. of water and 10 mQ. of
tetrahydrofuran are dissolved 0.076 g. of thiourea and 0.084 g.
of sodium hydrogen carbonate. Then, 0.447 g. of powdery
-- 11 --

;7
7-(4-chloro-3-oxobutyrylamido~-3-~1-methyltetrazol-5-yl)thio-
methyl-3-cephem-4-car~oxylic acid is added and dissolved. The
reaction mixture iS allowed to stand at room temperature
overnight, after which it is concentrated under reduced pressure
to remove the tetrahydrofuran. To t~e residue is added 0.16 g.
of sodium hydrogen carbonate and the resultant mixture is
chromatographed on a column of polystyrene resin ("Amberlite
~21'*3 and developed with water~ The fractions containing
the desired product axe pooled and freeze-dried. The procedure
gives the above indicated compound. Yield 0.182 g.
IR(cm 1, KBr): 1763
w~ max( in water): 260 nm(1.48 x 104)
NMR~ in D20): 3.48 & 3.81(ABq, J17~z, 2-CH2), 3.63(s,
CH2CO), 4.06(s, tetrazolyl 1-CH3), 4.09 &
4.37td, J14Hz, 3-CH2), 5.13(d, J5Hz, 6-H),
5.68(d, J5Hz, 7-H), 6.52(s, thiazole 5-H)
Elemental analysis: Calcd. fox C16H15N8O4S3 2.5H2O
C, 33.54; H, 3.76i N, 20.92
Found : C, 33.80; H, 3.33; M, 19.86
Antibacterial spectra
~mcg/mQ., agar dilution method)
- -.
Strain of Product
microorganism - of this Cephaloridine Cephazolin
example
.. . . . . . _ . . . . . _
S. aureus 209P 0.39 0.05 0.1
S. aureus 1840 0.78 0.39 1.56
E. coli NIHJ JC-2 0.39 6.25 1.56
E. c _ 0-111 0.2 3.125 1.56
K. pneumoniae DT ~0.1 3.125 1.56
P. vulgaris Eb 58 0.39 12.5 6.25
P. morganii Eb 53 3.125 >100 100
.. ....... ..
* Trademark
- 12 -

57
Reference Example 4
Production of sodium 7-12-(2-aminothiazol-4-yl)-
acetamido]-3-(5-methyl-1,3~4-thiadiazol-2-yl)thiomethyl-3
cephem-4-carboxylate
In a mixture o~ 10 m~. of water and 10 m~O of
tetrahydrofuran are dissolved 0.076 g. of thiourea and
0.084 g. of sodium hydrogen carbonate. Then, 0.463 g. of
7-(4-chloro-3-oxobutyrylamido)-3-(5-methyl-1,3,4-thiadiazol-
2-yl)thiomethyl-3-cephem-4-carboxylic acid is added and
dissolved. The mixture is allowed to stand at room temperature
~vernightr after which it is concentrated under reduced pres-
sure to remove the tetrahydrofuran. To the residue is added
0.16 g. of sodium hydrogen carbonate and the mixture is
chromatographed on a column of polystyrene resin (Amberlite
XAD-2) and developed with water. The fractions containing
the desired product are pooled and freeze-dried.
IR(cm , KBr): 1763
NMR(~ in D2O): 2.76(s, thiadiazole 5-CH3), 3.42 & 3.79
tABq, J18Hz, 2-CH2), 3.62(s, CH2CO), 4.02 &
4.51(ABq, J14Hz, 3-CH2), 5.11 (d, J5Hz, 6-H),
5.68(d, J5Hz, 7-H), 6.50(s, thiazole 5-H)
Elemental analysis: Calcd. for Cl6Hl5N6o4s4Na-2.5H2o
C, 34.84; H, 3.65; N, 15.23
Found : C, 34.87; H, 3.47; N, 14.82
Elemental analysis: Calcd. for Cl7Hl9N~o6s2Na-l.5H2o
C, 41.71; H, 4.53; N, 11.45;
Found : C, 42.08; H, 4.98; N, 11.47
Example 1
The compounds listed in Tables 1 to 4 are prepared
by one or more of the following Methods 1 to 2.

2~ii7
Method l
(l) In 40 mQ . of water are dissolved 10.7 g. (7.30 m mol)
of 7-acetoacetamido~3-acetoxymethyl-3-cephem-4-carboxylic acid,
30 m mol of a nitrogen-containing heterocyclic thiol and 5.04
g. (60 m mol) of sodium hydrogen carbona~e and the solution
is adjusted at pH 7.0 with a lO ~ aqueous solution of sodium
hydroxide, followed by stirring for 4 hours at 60 - 65C.
After cooling, 2.31 g. (33 m mol) of hydroxylamine hydrochloride
is added to the reaction mixture and the mixture is adjusted
to pH 3.6 by adding N-hydrochloric acid, followed by standing
at room temperature for overnight. The precipitated crystals
of a 7~amino-3-(nitrogen-containing heterocyclic)-~hiomethyl-
3-cephem-4-carboxylic acid are collected by filtration, washed
with acetone and dried.
(2) A solution of 1.03 g. (13 m mol) of diketene in 5 mQ.
of methylene chloride is previously chilled to -30C and a
solution of 1.05 g (15 m mol) of chlorine in lO mQ. of carbon
tetrachloride or a solution of 2.24 g. (14 m mol) of bromine
in 5 mQ. of methylene chloride is added dropwise thereto.
Meanwhile, 10 m mol of a 7-amino-3-(nitrogen-containing heter-
ocyclic)thiomethyl-3-cephem-4-carboxylic acid and 2.02 g.
(20 m mol) of triethylamine are dissolved in 20 mQ. of methylene
chloride and the solution is chilled to -20~C. To this solution
is dropped rapidly the above-prepared reaction mixture. The
temperature rises in most cases to the neighborhood of 0C
caused by the exothermic reaction~ After the exothermic reaction
is subsided, the temperature is gradually increased to room
temperature. After stirring for 15 minutes, the reaction solu-
tion is added to a mixture of 150 mQ. of e-thyl acetate and lO0
mQ. of a lO % aqueous solution of phosphoric acid under
vigorous stirring. The organic layer is separated, washed with
- 14 ~

~g~;~57
water and dried, followed by the evaporation of the solvent.
To the residue is added ether and the mixture is allowed to
stand. The resulta~t preeipitate of a 7-(4-chloro or bromo-
3-oxobutyrylamido)-3-(nitrogen-eontalning heterocyelic)thio-
methyl-3-eephem-4-earboxylie acid is recovered by filtration
as powder.
Method 2
(1) A solution of 60 g. (0.2 mol) of 7-formamido-3-
aeetoxymethyl-3-eephem-4-carboxylie aeid, 0.2 mol of a nitrogen-
eontaining heterocyelic thiol and 33.6 g. (0.4 mol) of sodium
hydroger, earbonate dissolved in 200 mQ. of water is adjusted
to pH 7.0 by adding a 10 % aqueous solution of sodium hydroxide
and stirred for 4-5 hours at 60-65C, followed by addition of
500 mQ. of methanol. The mixture is eooled down with ice and
80 g. of concentrated sulfurie aeid is added thereto under
stirring and keeping the temperature not exceeding 30C,
followed by standing in ice-room overnight. The reaetion
mixture is diluted with 1000 mQ. of water and the mixed solu-
tion is shaken with ethyl aeetate (2 x 400 mQ.). The combined
aqueous layer is subjeeted to the filtration under suction
to remove undissolved materials and the filtrate is adjusted
to pH 3.8 by adding eoncentrated aqueous ammonia, followed by
standing at 0C for 3 hours. The preeipitated erystals are
eolleeted by filtration and washed with cold water (100 mQ.)
and then aeetone (300 mQ.), followed by drying to give 7-amino-
3-(nitrogen-eontaining heteroeyclie)thiomethyl-3-eephem-~-
earboxylie acid.
(2) The material obtained in above (1) is treated
in the similar manner as (2) of Method 1 to obtain 7-(4-ehloro
or bromo-3-oxobutyrylamido)-3-(nitrogen-eontaining heterocyclic)-
thiomethyl-3-eephem-4-carboxylic acid.
1 5 ~`r

~i7
Table 1
WcH2cocH2coNH ~ S ~ N N
N ~ CH2S ~ S ~ R
COOM
Compound No. I- R5 Method No.
_. I
¦ -NH2 H 2
I _ .. l
3 -NHCOOCH3 I H 21
__ ~ 1
2 2 H , H 2
,, .
-NHCOCH2N(CH3)2
6 -CH2CON(CH3)2 2
. .. .. _ ' , .
7 2 2 (CH3)2 2
, . I
...
8 -SCH2COOC2H5 2
~ 1 1 '
9 -SCH2CON O H
_ ____ _
-SCH2COOH H ~
. __ . . .. _ ~
-16 -

Compound No. R M l~let~od ~o.
_ . ~. _ _~ . -~
11 -SCH2CONH2 H 2
~ . -
12 ~NHCH2CH2OH . H 2
.__ _ . _
1 3 -NHCH 2 C H 2 N ( CH 3 ) 2 H 2
. __ . . . , . I
14 -CH2COOH H 21
-CH2COOCH3 H 1
_
16 -CH2CONH2 H 2
17 2 3 H 21
. _ .
18 1 -CH2SO2CH3 H 2
/ \ I 1
19 , -CH2CON f H 1 2
-SCH2CON (CH3) 2 2
-- 17 --

i7
Table 2
2 2 H
COOM R6
. _ .. . . ~ .. _
Compound No. R M M~thod No.
__ _ _. _........ _
21 -CH2CH2N(CH3)2 H 2
..
22 -CH2COUH2 E
.
Table 3
. _ . .
WCH2COCH2CONH I S~ ~ R7
o N ~L CH 2 S 1~ S ~i~
COOM
. .. ... _ .. ~
Compound No ~7 I M
. ~thod No
.~ _ _ _ _
23 -C~COO~ ~ 1
.
Table 4
WC~2COCH2CO~ f S~
N ~ CH2SR
. COOM
;~ Compound No.¦ R __ _ M ~e~xlNo.
24 N - N
N
CH3

3;~7
Example 2
Preparatlon of 7-(4 chloro-3-oxobutyrylamido)-3-
acetoxymethyl-3-cephem-4~carboxylic acid.
A solution of 4.4 g. of diketene in lO ml. of
methylene chloride is previously chilled to -35~C and 3.92 g.
of chlorine is passed into the solution. The reaction mixture
is stirred for 15 minutes. Meanwhile, 10.9 g. of 7-amino-
cephalosporanic acid and 8.1 g. of triethylamine are dis-
solved in 100 ml. of methylene chloride and the solution is
chilled to -30C. To this solution is added the above-pre-
pared reaction mixture under stirring and coollng so that the
temperature will not rise beyond -30C. Then, the temperature
of the mixture is gradually increased to room temperature
over a period of one hour, after which the solvent is distilled
off under reduced pressure. To the residue is added 100 ml.
of ethyl acetate and the mixture is shaken vigorously with
100 ml. of a 10% aqueous solution of phosphoric acid. The
water layer is taken, saturated with sodium chloride and
extracted three times with ethyl ace-tate. The ethyl acetate
layers are pooled, washed with a saturated aqueous solution
of sodium chloride, dehydrated and concentrated under reduced
pressure to a final volume of 20 ml. The concentrate is
allowed to stand in the cold and the resultant crystals are
recovered by filtration. The described procedure gives the
above-indicated compound.
Yield 6.3 g. Melting point: 135-140C (decomp.)
IR(cm , KBr): 1790, 1750, 1655 r
NMR(~ in d6-DMSO): 2.00(s,COCH3), 3.41 & 3.64(ABq,
J18Hz, 2-CH2), 3.56(s,COCH2CO), 4.50(s,ClCH2-),
4.67 & 5.00 (ABq, J13Hz, 3-CH2), 5-07(d, J4.5Hz
6-H), 5.66(dd, J4.5 & 8Hz, 7-H), 9.04(d, J8Hz,
CONH)
- 19 --
.

Elemental analysis: Calcd. for C14H15ClN2O7S :
C, 43.03; H, 3.87, N, 7.17
Found : C, 43.01; H, 3.89; N, 7.18
Example 3
.
Preparation of 7-(4-bromo-3-oxobutyrylamido)-
3-acetoxymethyl-3-cephem 4-carboxylic acid.
~ solution of 3.4 g. of diketene in 10 ml. of
methylene chloride is previously chilled to -30C and a
solution of 6.4 g. of bromine in 10 ml. of methylene chloride
is added dropwise. Meanwhile, 10.9 g. of 7-aminocephalosporanic
acid and 8.1 g. of triethylamine are dissolved in 100 ml. of
methylene chloride and the solution is chilled to -30C. To
this solution is added the above-prepared reaction mixture
under stirring and cooling so that the temperature of the
mixture will not exceed -30~C.
The temperature is gradually increased to room
temperature over a period of one hour, after which the solvent
is distilled off under reduced pressure. To the residue is
added 100 ml. of ethyl acetate and the mixture is shaken
vigorously with 100 ml. of a 10% aqueous solution of phos
phoric acid. The water layer is taken, saturated with sodium
chloride and extracted twice with ethyl acetate. The ethyl
acetate layers are pooled, washed with a saturated aqueous
solution of sodium chloride, dehydrated, treated with activated
carbon and concentrated to dryness under reduced pressure. To
the residue is added ether and the mixture is allowed to stand.
The resultant crystals are recovered by Eiltration
under suction. The procedure gives the above-indica-ted com-
pound. This product includes a quarter of a mole of e-thyl
acetate as the solvent of crystallization. Yield 8 grams.
IR(cm , KBr): 1780, 1735, 1650
- 20 -

NMR(~ in d6-DMSO): 2.O1~s,CH3CO), 3.54(m,2-CH2),
3.62(s,COCH2CO)~ 4.37(s,BrCH2CO), 4.67 & 5.01
(ABq, Jl4Hz, 3-CH2), 5.08(d, J4Hz, 6-H),
5.66(dd, J4 & 8Hz, 7-H), 9.04(d, J8Hz, CONH)
Elemental analysis: Calcd- for C14H15BrN2O7S 1/4 C4H~O2:
C, 39.40; H, 3.75; N, 6.13;
Found : C, 39.20; H, 3.63; N, 6.09