Method for production of cephalosporin compounds

A method for producing a compound of the formula; ##STR1## wherein R stands for a hydrogen atom, an acyl group or a protective group other than acyl groups, Q stands for a hydrogen atom or an ester residue, Y stands for the residue of a nucleophilic compound and the dotted line shows the double bond at 2- or 3- position of the cephem ring or a salt thereof, characterized by allowing a compound of the formula; ##STR2## [R, Q and the dotted line are of the same meaning as above] or a salt thereof to react with a nucleophilic compound or a salt thereof and a compound of the formula; ##STR3## wherein R.sup.1, R.sup.2, R.sup.3 independently stand for a hydrocarbon group having not more than 8 carbon atoms, or R.sup.1 and R.sup.2, R.sup.1 and R.sup.3 or R.sup.2 and R.sup.3 may be combined to form polymethylene group, according to which the end product [I] of high quality can be provided in a high yield by one reaction step by using the compound [III] of relatively low cost, thus the method of this invention is advantageous for mass-producing the compound [I] on an industrial scale from the compound [II] and a nucleophilic compound.

This invention relates to an industrially advantageous method for producing 
a compound of the formula 
##STR4## 
wherein R stands for hydrogen atom, an acyl group or a protective group 
other than acyl groups, Q stands for hydrogen atom or an ester residue, Y 
stands for the residue of a nucleophilic compound, and the dotted line 
shows the double bond at the 2- or 3-position (the compound [I] should be 
construed as including also a salt thereof and the same shall apply 
hereinafter), by using as starting materials a compound of the formula 
##STR5## 
wherein R, Q and the dotted line are of the same meaning as defined above 
(the compound [II] should be construed as including also a salt thereof 
and the same shall apply hereinafter), and a nucleophilic compound or a 
salt thereof. 
The compound [I] is important as an antibacterial compound or an 
intermediate for synthesizing antibacterial compounds, and methods of 
preparing the compound [I] have been studied and researched extensively. 
Industrially employable starting materials of cephem compounds are 
principally cephalosporin C (CPC) producible fermentatively or a 
3-acetoxymethyl cephem compound derived therefrom and deacetyl 
cephalosporin C (DCPC) or 3-hydroxymethyl cephem compound [II] producible 
by subjecting DCPC or CPC to chemical or enzymatic reaction. Heretofore 
compounds of [I] have been produced by substituting their acetoxy group or 
hydroxy group of them with a nucleophilic compound. However, for 
substituting a nucleophilic group for the acetoxy group of a 
3-acetoxymethyl cephem compound, due to relatively low reactivity of 
acetoxy group, heating or use of a large amount of an acid catalyst is 
required, and, therefore, lowering of the yield due to decomposition of 
the cephalosporin under such conditions as above is unavoidable and use of 
a large amount of strong acid requires some restrictions on industrial 
equipment or requires complicate after-treatment. On the other hand, 
methods which comprise substitution of a more reactive group for the 
hydroxy group of 3-hydroxymethyl cephem compound [II] followed by allowing 
the resultant compound to react with a nucleophilic compound have been 
studied. These methods are exemplified by: 
(1) a method which comprises substituting a halogeno group for the hydroxy 
group at the 3-position followed by allowing the resultant product to 
react with a nucleophilic substance (e.g. Belgian patent No. 719,710), 
(2) a method which comprises substituting a more reactive acyloxy group 
(e.g. acetoacetoxy group) compared with acetoxy group for the hydroxy 
group at 3-position followed by allowing the resultant product to react 
with a nucleophilic substance (e.g. British Patent No. 1544103), and 
(3) a method which comprises allowing a compound [II] to react with a 
nucleophilic compound and a cyclic phosphorus compound having the partial 
structure representable by the formula; 
##STR6## 
[wherein W, w.sup.1 stand for O, S, NH or a hydrocarbon-substituted amino 
group] in an organic solvent (e.g. British Patents Nos. 2108114 and 
2147900). 
In both methods (1) and (2), however, two reaction processes are required 
to be conducted separately resulting in increase of reaction steps in 
number and requiring a great deal of labour while lowering the overall 
yield. Besides, in the method (1), a side reaction forming a lactone ring 
with the carboxyl group at the 4-position and the hydroxyl group at the 
3-position during the halogenation of the hydroxyl group occurs easily, 
and, for preventing this, protection of the carboxyl group at 4-position 
by its esterification, for example, is essential. This esterification 
should naturally be followed by de-esterification, which makes the process 
more complicate. In the method (2), depending on the kinds of acyloxy 
group of 3-acyloxymethyl, better reactivity can be expected, but not 
sufficient, and, depending on the acylating agent employed, lactone ring 
formation is apt to occur as the side reaction resulting in lowering the 
yield. In the method (3), cyclic phosphorus compounds employed, which 
contain a double bond in the ring, are unstable against the moisture in 
the air and are easily hydrolized. Besides, the cyclic phosphorus 
compounds are relatively expensive, thus being less advantageous for mass 
production on an industrial scale. 
No fully satisfactory method for commercial production of the end product 
[I] employing a compound [II] and a nucleophilic compound has been found 
yet, and, in view of the great demand for the end product [I], an 
advantageous method has been desired. 
Circumstances being such as mentioned in the foregoing, the present 
inventors have conducted extensive studies on various methods of preparing 
the cephalosporin compound [I], resulting in finding that a compound [I] 
of high quality can be unexpectedly prepared in a high yield by a single 
step which comprises allowing a compound [II] obtained by subjecting DCPC 
or CPC producible in a high potency by fermentative cultivation to 
chemical or enzymatic reaction to react with a nucleophilic compound and a 
compound of the formula 
##STR7## 
[wherein R.sup.1, R.sup.2 and R.sup.3 each stand for a hydrocarbon group 
having not more than 8 carbon atoms, and R.sup.1 and R.sup.2, R.sup.1 and 
R.sup.3 or R.sup.2 and R.sup.3 may be combined to form a polymethylene 
group] which has never been used in the field of production of [II] from 
[I] and that, as the compound [III] is less expensive, the end product [I] 
can be prepared in a large amount on an industrial scale. Furthermore, it 
was also found that the process with use of the compound [III] has the 
following advantageous features from the view-point of industrial 
application. 
(1)the compound [III] is more stable particularly as compared with the 
cyclic phosphorus compound used in the known method (3) mentioned above, 
which facilitates the employment and handling of the compound [III]. 
(2) the ester-linkage of the phosphorous compound [III] is hydrolized, with 
the reaction proceeding, to produce corresponding alcohols as by-product, 
which are easily removed from the desired compound by e.g. distillation; 
(3) the compound [III] acts as a reducing agent and thus is capable of 
preventing the coloring of the product compound [I] due to oxidation; 
(4) the reaction with use of the compound [III] is mild and not exothermic, 
which enables the reaction very efficiently to be carried out at room 
temperature without heating and cooling. The present invention was 
completed on the basis of this finding. 
The present invention therefore relates to a method of preparing the 
compound [I], which is characterised by allowing a compound [II] to react 
with a nucleophilic compound and a compound [III]. 
In the above formulae, R stands for hydrogen atom, an acyl group or a 
protecting group other than acyl groups. The acyl group is well known in 
the .beta.-lactam antibiotic field and exemplified by known ones such as 
the acyl group substituted at the amino group at the 6-position of a 
penicillin derivative or the acyl group substituted at the amino group at 
the 7-position of a cephalosporin derivative. Specific examples of these 
acyl groups include those led by eliminating OH from carboxylic acid, 
which are further exemplified by groups representable by the formula 
R.sub.a --CO-- [IV] [wherein R.sup.a stands for hydrogen atom, alkyl*, 
phenyl* or heterocyclic* group], groups representable by the formula 
##STR8## 
[wherein R.sup.b stands for hydrogen, amino acid residue, a protective 
group of amino group or a group representable by the formula R.sup.d 
--(CH.sub.2)n.sub.1 --CO-- { wherein R.sup.d stands for a heterocyclic* 
group and n.sub.1 denotes an integer of 0 to 2}, and R.sup.c stands for 
alkyl, phenyl* and a heterocyclic* group], groups representable by the 
formula R.sup.3 --R.sup.f --CO-- [VI] [wherein R.sup.e stands for a group 
representable by the formula 
##STR9## 
{wherein R.sup.g stands alkyl*, a heterocyclic* group or phenyl* and 
R.sup.h stands for hydrogen, alkyl* or a group representable by the 
formula --R.sup.i --R.sup.j (wherein R.sup.i stands for alkylene or 
alkenylene* and R.sup.j stands for phenyl*, carboxyl or an ester or mono- 
or dialkylamino thereof, respectively), respectively}, and R.sup.f stands 
for a bond itself or a group representable by the formula 
##STR10## 
(wherein R.sup.k stands for alkyl, phenyl* or thiazolyl* group), 
respectively], a group representable by the formula [wherein R.sup.1 
stands for hydroxy, hydroxysulfonyloxy, carboxy, 
##STR11## 
ureido*, sulfamoyl*, sulfo or phenoxy* carbonylformyloxy, and R.sup.m 
stands for hydrogen, alkyl, alkoxy, halogen, nitro, hydroxy, 
respectively], and a group representable by the formula R.sup.n --R.sup.o 
--CH.sub.2 --CO-- [VIII] [wherein R.sup.n stands for cyano, phenyl*, 
phenoxy*, acyloxy, alkenyl* or heterocyclic* group, and R.sup.o stands for 
a bond itself or --S--, respectively], etc. As for the groups represented 
by the afore-mentioned symbols R.sup.a to R.sup.o as well as groups 
described throughout this specification, the following definition 
respectively shall apply with the number of carbon atoms, when 
particularly specified, varied accordingly, unless otherwise defined. When 
they are "optionally substituted ones", they are shown by attaching 
asterisk * on the right shoulder thereof. For instance, "optionally 
substituted alkyl" is shown by "alkyl*". In this case, the number of the 
substituents is not limited to one, but, depending on the groups to be 
substituted, 2 to several number of substitutents, preferably 2 to 8 
substitutents, more preferably 2 or 3 substituents, which may be the same 
or different from one another, may be attached. Preferable alkyl groups 
are straight-chain or branched lower ones having 1 to 6 carbon atoms, as 
exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 
tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc. Especially, 
"lower alkyl group" means such alkyl having 1 to 6 carbon atoms unless 
otherwise specified. Preferable alkenyl groups are straight-chain or 
branched lower alkenyl groups having 2 to 6 carbon atoms, as exemplified 
by vinyl, allyl, isopropenyl, 2-methallyl, 2-butenyl, 3-butenyl, etc. As 
heterocyclic groups are mentioned 5 to 8 membered ring containing 1 to 
several (preferably 1 to 4) hetero-atoms selected from among nitrogen atom 
(optionally oxides thereof), oxygen atom and sulfur atom, or condensed 
ring thereof, those having a bond itself at the carbon atom, which are 
exemplified by 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 
3-pyrrolidinyl, 2-, 3- or 4-pyridyl, N-oxido-2-, 3- or 4-pyridyl, 2-, 3- 
or 4-piperidinyl, 2-, 3or 4-pyranyl, 2-, 3- or 4-thiopyranyl, pyradinyl, 
2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl, 3-, 
4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 3- or 
4-pyridazinyl, N-oxido-3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 
N-oxido-2-, 4- or 5-pyrimidinyl, piperazinyl, 4- or 
5-(1,2,3-thiadiazolyl), 3- or 5-(1,3,4-thiadiazolyl), 1,3,4-thiadiazolyl, 
1,2,5-thiadiazolyl, 4- or 5 -(1,2,3-oxidiazolyl), 3- or 
5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3- or 
1,2,4-triazolyl, 1H or 2H-tetrazolyl, pyrido[2,3-d]pyrimidyl, 
benzopyranyl, 1,8-, 1,4-, 1,6-, 1,7-, 2,7- or 2,6-naphthylidyl, quinolyl, 
thieno[2,3-d]pyridyl, imidazo[1,2-a]pyridinium-1-yl, 
2,3-cyclopenteno-1-pyridinio, imidazo[1,5-a]pyridinium-2-yl, 
imidazo[1,2-b]pyridazinium-1-yl, etc., which are subjected to common use. 
Preferably alkoxy groups are straight-chain or branched lower alkoxy 
groups having 1 to 6 carbon atoms, which are exemplified by methoxy, 
ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 
tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, etc. As 
halogen are used fluorine, chlorine, bromine or iodine. As amino acid 
residue are exemplified glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, 
threonyl, cysteinyl, cystyl, methionyl, .alpha.- or .beta.-asparagyl, 
.alpha.- or .gamma.-glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl, 
tyrosyl, histidyl, triptophanyl, prolyl, etc. The aminoacid residues 
include not only the residues of D-amino acid but also those of L-amino 
acid. Preferable alkylene is lower alkylene having 1 to 3 carbon atoms, as 
exemplified by methylene, ethylene, propylene, isopropylene, etc. 
Preferably alkenylene is straight-chain or branched lower alkenylene 
having 2 to 4 carbon atoms, as exemplified by vinylene, propenylene, etc. 
As ester of carboxyl group are used lower alkyl ester having 1 to 6 carbon 
atoms, as exemplified by methyl ester, ethyl ester, propyl ester, n-butyl 
ester, isobutyl ester, tert-butyl ester, etc. As amino-protecting groups 
shown by R.sup.b are conveniently employed those which are used for this 
purpose in the field of synthesizing .beta.-lactam and peptide. More 
concretely stating, they are exemplified by aromatic acyl groups such as 
phthaloyl, toluoyl, naphthoyl, benzoyl, chlorobenzoyl, p-nitrobenzoyl, 
p-tert-butylbenzoyl, p-tert-butylbenzene-sulfonyl, benzenesulfonyl, 
toluenesulfonyl, phenylacetyl, etc., aliphatic acyl groups such as formyl, 
acetyl, propionyl, valeryl, caprylyl, n-decanoyl, acryloyl, pivaloyl, 
monochloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfonyl, 
ethanesulfonyl, camphorsulfonyl, trifluoroacetyl, maleyl, succinyl, etc., 
esterified carboxyl groups such as methoxycarbonyl, ethoxycarbonyl, 
t-butoxycarbonyl, isopropoxycarbonyl, 2-cyanoethoxycarbonyl, .beta., 
.beta., .beta.-trichloroethoxycarbonyl, 
.beta.-trimethylsilylethoxycarbonyl, .beta.-methylsulfonylethoxycarbonyl, 
benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 
diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, 
acetylmethyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, etc., 
substituted carbamoyl groups such as methylcarbamoyl, phenylcarbamoyl, 
naphthylcarbamoyl, etc.; further, e.g. trityl, 
1-methyl-2-ethoxycarbonylvinyl, 2,2-diethoxycarbonylvinyl, 
3-oxobute-1-en-1-yl, 2-nnitrophenylthio, benzylidene, 4-nitrobenzylidene, 
trialkylsilyl, benzyl, p-nitrobenzyl; phosphoryl groups such as 
diethylphosphoryl, dimethylphosphoryl, diphenylphosphoryl, 
di-isopropylphosphoryl, di-isobutylphosphoryl, dibutylphosphoryl, 
o-hydroxyphenylphosphoryl, methyl(o-hydroxyphenyl)phosphoryl, etc., 
phosphinyl groups such as diemthylphosphinyl, diphenylphosphinyl, etc., 
phosphonyl groups such as phenylphosphonyl, butylphosphonyl, etc., which 
are amino-protecting groups other than acyl groups. From among these 
protecting groups set forth above, any one can be optionally selected for 
the purpose of this invention. 
Among these optionally substituted groups alkyl, alkenyl and alkenylene may 
have 1 to 3 substituents such as cycloalkyl*, cycloalkenyl* aryl*, 
heterocyclic* group, alkoxycarbonyl, acyl, oxo, halogen, cyano, 
trifluoromethyl, hydroxy, alkoxy, aryl*oxy, acryloxy, carbamoyloxy, 
hydroxysulfonyloxy, alkylsulfonyloxy, aryl* sulfonyloxy, nitro, amino, 
carboxyl, aminocarbonyl, alkylthiocarbonyl, mercapto, alkylthio, 
aminoalkylthio, acylaminoalkylthio, aralykyl*thio, aryl*thio, 
heterocyclic*thio, quaternary ammonium*, alkenyl* etc. 
As substituted alkyl groups are employed those representable by, for 
example, the formula 
##STR12## 
[wherein n.sub.2 denotes an integer of 0pg,15 to 3, R.sup.p and R.sup.q 
independently stand for hydrogen atom, alkyl, cycloalkyl*, aralkyl*, 
aryl*, heterocyclic* group, alkoxycarbonyl, acyl, or R.sup.p and R.sup.q, 
taken together, stand for oxo, and R.sup.r stands for hydrogen atom, 
alkyl, cycloalkyl*, cycloalkenyl*, aryl*, heterocyclic* group halogen, 
cyano, hydroxy, alkoxy, aryl*oxy, acyloxy, carbamoyloxy, 
hydroxysulfonyloxy, alkylsulfonyloxy, aryl* sulfonyloxy, nitro, amino, 
carboxy, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, acyl, mercapto, 
alkylthio, aminoalkylthio, acylaminoalkylthio, aralkyl*thio, aryl*thio, 
heterocyclic* thio or quaternary ammonium*]. As the cycloalkyl groups are 
preferable those having 3 to 8 carbon atoms, and use is made of for 
example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 
adamantyl, etc. As the aryl groups use is made of, among other, phenyl, 
.alpha.-naphthyl, .beta.-naphthyl, biphenyl and anthryl, especially phenyl 
and naphthyl etc. being often used. As the aralkyl groups, use is made of, 
for example, benzyl, phenethyl, phenylpropyl or naphthylmethyl. As the 
acyl groups, use is made of, for example, formyl, alkylcarbonyl, aryl* 
carbonyl, aralkyl* carbonyl, heterocyclic* acetyl, especially, for 
example, acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, 
n-hexanoyl, benzoyl, 4-hydroxybenzoyl, 4-methoxybenzoyl, phenylacetyl, 
4-hydroxyphenylacetyl, 4-methoxyphenylacetyl, 2-thienylcarbonyl, 
2-furylcarbonyl, 2-, 4- or 5-thiazolylacetyl, 2- or 3-thienylacetyl, 2- or 
3-furylacetyl, 2-amino-4 or t-thiazolylacetyl, etc. As the quarternary 
ammonium group, use is made of, for example, pyridinium, quinolinium, etc. 
These quarternary ammonium group may form an intramolecular salt with a 
counter ion from an acid radical such as carboxylic group. As the 
cycloalkenyl group, use is made of, for example, 1-cyclopropenyl, 
1-cyclohexenyl, 1-cycloheptenyl, etc. having 3 to 8 carbon atoms. 
As the substituents of cycloalkyl*, cycloalkenyl*, aralkyl*, aryl*, 
heterocyclic* group and quaternary ammonium*, use is made of, for example, 
alkyl, alkoxy, alkenyl, aryl, aralkyl, mercaptio, alkylthio, arylthio, 
aralkylthio, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, hydroxy, oxo, 
thioxo, halogen, nitro, amino, cyano, carbamoyl, carboxy, acyl, acyloxy, 
acylamino, hydroxyalkyl, carboxyalkyl, halogenoalkyl, mono- or 
dialkylaminoalkyl, etc. 
As the substituents of pehnoxy*, use is made of such as those of aryl* 
described in the foregoing. Further, as the substituents of thiazolyl*, 
use is made of acylamino having 3 to 4 carbon atoms substituted with for 
example alkyl, alkoxy, halogen, hydroxy, amino, etc. As the substituents 
of heterocyclic* group, use may be made of phenyl substituted with for 
example alkyl, alkoxy, halogen, nitro, amino, etc. As the substituents of 
ureido*, use is made of, for example, sulfo, carbamoyl, sulfamoyl, 
amidino, alkyl having 1 to 3 carbon atoms, which are in a form of suitable 
salt with sodium, potassium, etc. As the substituents of sulfamoyl*, use 
is made of, for example, lower alkyl having 1 to 3 carbon atoms, amidino, 
etc. As the substituents of alkenylene*, use is made of, for example, 
carboxy, cyano, etc. 
The formula 
##STR13## 
stands for a syn-isomer representable by the formula 
##STR14## 
and an anti-isomer representable by the formula 
##STR15## 
or a mixture thereof. 
In the above-mentioned acyl group represented by R, concrete examples of 
the acyl group representable by the formula R.sup.a --CO-- are, among 
others, formyl, acetyl, hexanoyl, benzoyl, p-nitrobenzoyl, 
3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl-carbonyl, 
5-methyl-3phenyl-4-isoxazolylcarbonyl, and 
4-ethyl-2,3dioxo-1piperazinocarbonyl. 
As the practical examples of the acyl group representable by the formula 
##STR16## 
are mentioned D-alanyl, benzyl N.sup.a 
-carbobenzoxy-.gamma.-D-glutamyl-D-alanyl, D-phenylglycyl-D-alanyl, 
N-carbobenzoxy-D-alanyl, N-carbobenzoxy-D-phenylglycyl, 
D-alanyl-D-phenylglycyl, .gamma.-D-glutamyl-D-alanyl, 
2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-phenylacetyl, 
2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-4-(sulfoxyphenyl)acetyl, 
N-(4-ethyl-2,3-dioxo-1-piperazinocarbonyl)-D-alanyl, 
N-(4-ethyl-2,3-dithioxo-1piperazinocarbonyl)-D-phenylglycyl, 
2,2-bis-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)acetyl, 
2-(2-amino-4thiazolyl)-2-(4-ethyl-2,3-dioxo-1piperazinocarboxamido)acetyl, 
2-(4-hydroxy-6-methylnicotinamido)-2-phenylacetyl, 
2-(4-hydroxy-6-methylnicotinamido)-2-(4-hydroxyphenyl)acetyl, 
2-{5,8-dihydro-2-(4formyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6 
-carboxamido}-2-phenylacetyl, 
2-(3,5-dioxo-1,2,4-triazine-6-carboxamido)-2-(4-hydroxyphenyl)acetyl, 
2(3-furfurylideneamino-2-oxoimidazolidine-1-carboxamido)-2-phenylacetyl, 
2-(coumarin-3-carboxamido)-2-phenylacetyl, 
2-(4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxamido)-2-phenylacetyl, 
2-(4-hydroxy-7-trifluoromethylquinoline-3-carboxamido)-2-phenylacetyl, 
N-[2-(2-amino-4thiazolyl)acetyl]-D-phenylglycyl, 
2-(6-bromo-1-ethyl-1,4-dihydro-4-oxothieno[2,3 
-d]pyridine-3-carboxamido)-2-phenylacetyl, 
2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-thienylacetyl, 
2-(4-n-pentyl-2,3-dioxo-1-piperazinocarboxamido)-2-thienylacetyl, 
2-(4-n-octyl-2,3-dioxo-1-piper-azinocarboxamido)-2thienylacetyl, 
2-(4-cyclohexyl-2,3-dioxo-1piperazinocarboxamido)-2-thienylacetyl, 
2-[4-(2-phenylethyl)-2,3-dioxo-1-piperazinocarboxamido]-2-thienylacetyl, 
2-(3-methylsulfonyl-2-oxoimidazolidine-1-carboxamido)-2-phenylacetyl, 
2-(3-furfurylideneamino-2-oxoimidazolidine-1-carboxamido)-2-(4-hydroxyphen 
yl)acetyl, 
2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-(4-benzyloxyphenyl) 
acetyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-(4-methoxyphenyl)a 
cetyl, 2-(8-hydroxy-1,5-naphthyridine-7-carboxamido)-2-phenylacetyl, etc. 
As the concrete examples of the acyl group representable by the formula 
R.sup.3 --R.sup.f --CO--, are mentioned 
N-[2-(2-amino-4-thiazolyl)-2methoxyiminoacetyl]-D-alanyl, 
N-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl]-D-phenylglycyl, 
2-(2-amino-4-thiazolyl)-2-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido 
]acetyl, 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl, 
2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl,2-(2-amino-4-thiazolyl)-2-eth 
oxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetyl, 
2-(2-amino-4-thiazolyl)-2-butoxyiminoacetyl, 
2-(2-amino-4-thiazolyl)-2-benzyloxyiminoacetyl, 
2-(2-amino-4-thiazolyl)-2-allyloxyiminoacetyl, 
2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetyl, 
2-(2-amino-5-bromo-4-thiazolyl)-2-methoxyiminoacetyl, 
2-(2-amino-4-thiazolyl)-2-oxyiminoacetyl, 2-thienyl-2-methoxyiminoacetyl, 
2-furyl-2-methoxyiminoacetyl, 
2-(1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl, 
2-(1,2,4-thiadiazol-5-yl)-2-methoxyiminoacetyl, 
2-(1,3,4-thiadiazol-yl)-2-methoxyiminoacetyl, 
2-(4-hydroxyphenyl)-2-methoxyiminoacetyl, 2-phenyl-2-methoxyiminoacetyl, 
2-phenyl-2-oxyiminoacetyl, 
2-[4-(.gamma.-D-glutamyloxy)phenyl]-2-oxyiminoacetyl, 
2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-oxyiminoacetyl, etc. 
As concrete examples of the acyl group representable by the formula 
##STR17## 
are mentioned .alpha.-sulfophenylacetyl, .alpha.-carboxyphenylacetyl, 
.alpha.-hydroxyphenylacetyl, .alpha.-ureidophenylacetyl, 
.alpha.-sulfoureido-phenylacetyl, .alpha.-sulfamoylphenylacetyl, 
.alpha.-phenoxycarbonyl-phenylacetyl, 
.alpha.-(p-tolyloxycarbonyl)phenylacetyl, .alpha.-formyloxyphenylacetyl, 
etc. 
As concrete examples of the acyl group representable by the formula R.sup.n 
--R.sup.o --CH.sub.2 --CO--, are mentioned cyanoacetyl, acetoacetyl, 
phenylacetyl, phenoxyacetyl, 5-amino-5-carboxyvaleryl, 
5-oxo-5-carboxyvaleryl, 4-carboxybutyryl, trifluoromethylthioacetyl, 
cyanomethylthioacetyl, 1H-tetrazolyl-1-acetyl, thienylacetyl, 
2-(2-amino-4-thiazolyl) acetyl, 4-pyridylthioacetyl, 2-thienylthioacetyl, 
3,5-dichloro-1,4-dihydro-4oxopyridine-1-acetyl, 
.beta.-carboxyvinylthioacetyl, 2-(2-aminomethylphenyl)acetyl, etc. 
The above-mentioned amino group and/or carboxyl group and/or hydroxyl group 
of the above-mentioned acyl group may optionally be protected. 
As such amino-protecting groups are used groups similar to those 
representable by the afore-mentioned R.sup.b. As carboxyl-protecting 
groups, are used any ones usually employable for protecting carboxyl group 
in the fields of .beta.-lactam and organic chemistry. There are used, for 
example, ester residual groups and silyl groups, as more concretely 
exemplified by methyl, ethyl, n-propyl, isopropyl, tert-butyl, tert-amyl, 
benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, 1-indanyl, phenacyl, 
phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, 
acetoxymethyl, pivaloylmethyl, .beta.-methylsulfonyl, 
.beta.-trimethylsilylethyl, methylthiomethyl, trityl, 
.beta.,.beta.,.beta.-trichloroethyl, .beta.-iodoethyl, trimethylsilyl, 
dimethylsilyl, acetylmethyl, p-nitrobenzoylmethyl, p-mesylbenzoylmethyl, 
phthalimdomethyl, propionyloxymethyl, 1,1-dimethylpropyl, 
3-methyl-3-butenyl, succinimidomethyl, 3,5-di-tert-butyl-4-hydroxybenzyl, 
mesylmethyl, benzenesulfonylmethyl, phenylthiomethyl, dimethylaminoethyl, 
pyridine-1-oxide-2-methyl, methylsulfinylmethyl, 
bis(p-methoxyphenyl)methyl, 2-cyano,-1,1-dimethylethyl, etc. As 
hydroxyl-protecting groups, are used any ones usually exployable for 
protecting hydroxyl group in the fields of .beta.-lactam antibiotic, 
peptide and organic chemistry. They are, for example, ester residual 
groups such as acetyl, chloroacetyl, etc., esterified carboxyl groups such 
as .beta.,.beta.,.beta.-trichloroethoxycarbonyl, 
.beta.-trimethylsilylethoxycarbonyl, etc., ether residual groups such as 
tert-butyl, benzyl, p-nitrobenzyl, trityl, methylthiomethyl, 
.beta.-methoxyethoxymethyl, etc., silyl ether residual groups such as 
trimethylsilyl, tert-butyldimethylsilyl, etc., acetal residual groups such 
as 2-tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl, etc., etc. The 
above-mentioned protecting groups can be optionally selected like in the 
cases of amino group and carboxyl groups. 
As protecting groups other than the acyl groups representable by R, use is 
made of, for example, aminoprotecting groups other than acyl groups, as 
employed as amino-protecting group representable by the afore-mentioned 
R.sup.b. 
The symbol Q in the formulae [I] and [II] stands for hydrogen atom or an 
ester residual group. As the ester residual group representable by Q, use 
is made of, for example, C.sub.1-6 alkyl groups (e.g. methyl, ethyl, 
n-propyl, isopropyl, tert-butyl, tert-amyl, etc.), aralkyl* groups (e.g. 
benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, 
bis(p-methoxyphenyl)methyl, etc.), etc. 
The symbol Y in the formula [I] stands for the residual group of a 
nucleophilic compound. As the nucleophilic compound, use is made of, for 
example, one characterized by having nucleophilic nitrogen, carbon or 
sulfur, which has been widely described in various reports published so 
far concerning cephalosporin chemistry. For example, such reports 
published so far include the abovementioned British Patents Nos. 1544103, 
2108114 and 2147900 and Belgian Patent No. 719,710. These nucleophilic 
compounds which have been known and used in the field of cephalosporin 
chemistry can widely be employed in the present invention. 
The nucleophilic compound employable is exemplified by a sulfur 
nucleophilic compound, a nitrogen nucleophilic compound or a carbon 
nucleophilic compound. As the sulfur nucleophilic compounds (Y--H), a wide 
variety of known ones can be used. Among them, use is made of, for 
example, alkyl* thiol, allyl thiol, aryl* thiol, aralkyl* thiol, or a 
nitrogen-containing heterocyclic thiol having 1 to 5 nitrogen atoms having 
optionally having hetero-atoms other than nitrogen, selected from oxygen 
and sulfur. The nitrogen-containing heterocyclic thiol includes those 
having one to four substituents in the nucleus thereof. As such 
nitrogen-containing heterocyclic groups represented by Y, use is made of 
six-membered nitrogen-containing heterocyclic group e.g. pyridyl, 
N-oxidopyridyl, pyrimidyl, pyridazinyl, N-oxidopyridazinyl, triazinyl, 
quinazolinyl, etc. and condensed ring groups thereof, five-membered 
nitrogen-containing heterocyclic group e.g. imidazolyl, thiazolyl, 
thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, etc. and condensed ring 
groups thereof. As the substituents on these nitrogen-containing 
heterocyclic groups, use is made of, for example, hydroxyl group, amino 
group, carboxyl group, oxo group, carbamoyl group, lower alkyl group (e.g. 
methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, isobutyl, etc.), 
lower alkoxy group (e.g. methoxy, ethoxy, propoxy, butoxy, etc.), halogen 
atom (e.g. chlorine, bromine, etc.) or groups having various substituents 
through polyvalent groups such as C.sub.1-3 lower alkylene group, --S--, 
##STR18## 
etc. When the polyvalent groups are C.sub.1-3 lower alkylene groups, said 
substituents may be mono- or di-lower alkylamino group, morpholino group, 
carboxyl group, sulfo group, carbamoyl group, alkoxycarbonyl group, lower 
alkylcarbamoyl group, alkoxy group, alkylthio group, alkylsulfonyl group, 
acyloxy group, morpholinocarbonyl group, etc., while when the polyvalent 
groups are --S-- and 
##STR19## 
said substituents may be lower alkyl groups and lower alkylene groups 
having the above-mentioned substituents. When the polyvalent group is 
##STR20## 
an alkoxycarbonyl group, acyl group, carbamoyl group, lower alkylcarbamoyl 
group, etc. may further be bonded directly. Among these substituents on 
the nitrogencontaining heterocyclic groups more preferable examples are 
hydroxyl group, amino group, lower alkyl group mono- or di-lower 
alkylaminoalkyl group, sulfoalkyl groups. Use is concretely made of, for 
example, heterocyclic thiol such as pyridine thiol such as 
pyridine-2-thiol, pyrimidine thiol such as pyrimidine-2-thiol, 
methylpyridazine thiol, 
4,5-dihydro-6-hydroxy-4-methyl-1,2,4-triazine-3-thiol, 
2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazine-3-thiol, 
imidazolethiol (e.g. imidazole-2-thiol), 1,3,4-thiadiazole-5-thiol, 
1,2,3-thiadiazole-5-thiol, 2-methyl-1,3,4-thiadiazole-5-thiol, 
thiazolethiol, 5-methyl-1,3,4-oxadiazole-2-thiol, 
1,2,3-triazole-5-triazole-5-thiol, 1-methyltetrazole-5-thiol, 
1-(2-dimethylaminoethyl)tetrazole-5-thiol, 
1-(2-sulfoethyl)tetrazole-5-thiol, 1-sulfomethyltetrazole-5thiol, 
benzimidazolethiol, benzthiazolethiol, benzoxazolethiol, etc. Besides, use 
is made of aliphatic, aromatic thiol e.g. methane thiol, ethane thiol, 
thiophenol, etc., thiourea, thiourea derivatives e.g. N-methyl thiourea, 
etc., thioamide derivatives e.g. thioacetamide, thiobenzamide, etc., 
thodanate e.g. potassium rhodanide, etc., thiocarboxylic acids e.g. 
thiosalicylic, dithiocarboxylic acids etc., thiocarbonates e.g. potassium 
ethylxanthate, potassium piperidine dithiocarbamate, etc. Among these 
sulfur nucleophilic compounds, the nitrogen-containing heterocyclic thiols 
are preferably employed. These sulfur nucleophilic compounds can be used 
for the reaction in the free form or a form of salt with the base at the 
acid radical thereof or a form of salt with the acid at the basic radical 
thereof. As the nitrogen nucleophilic compounds, a wide variety of known 
ones can be used. Among them, there may be, for example, mentioned metal 
salts of azide ion, (e.g. sodium azide) secondary or tertiary aliphatic, 
aromatic, and aroma-aliphatic amines and nitrogen-containing heterocyclic 
compounds such as dialkylamine (e.g. dimethylamine, diethylamine, etc.), 
trialkylamine (e.g. triethylamine, etc.), pyridine bases (pyridine and 
alkylpyridines, etc.), and a 5- to 7-membered heterocyclic compounds 
having two to five hetero-atoms selected from the group consisting of 
sulfur oxygen and nitrogen, at least one of the hetero-atoms being 
nitrogen, such as pyrimidines, morpholines, purines, pyridazines, 
pyrazines, pyrazoles, imidazoles, triazoles and tetrazoles, condensed 
heterocyclic compounds in which two or more, preferably two to three, such 
heterocyclic rings are orthocondensed or ortho-peri-condensed, such as 
imidazopyridines, imidazopyridazines and cycloalkenopyridines. 
As preferable nitrogen nucleophilic compounds are employed those 
representable by the formula 
##STR21## 
[wherein n.sub.3 denotes an integer of 0 to 5, and R.sup.s (when n.sub.3 
is 2 to 5, R.sup.s' s may be the same as or different from each other, or 
they may form, together with carbon atoms they are attached to, a 5 to 
7-membered saturated or unsaturated condensed ring) stands for aliphatic 
group such as lower alkyl (methyl, ethyl, n-propyl, iso-propyl, etc.) 
etc., aryl group such as phenyl, etc., aroma-aliphatic group such as 
phenyl lower alkyl (benzyl, phenylethyl, etc.), etc. or alkoxymethyl such 
as methoxymethyl, ethoxymethyl, n-propoxymethyl, iso-propoxymethyl, etc., 
or acyloxymethyl such as alkanoyloxymethyl e.g. acetoxymethyl, etc., 
cyano, formyl, carbamoyl, acyloxy such as alkanoyloxy e.g. acetoxy, etc., 
esterified carboxy, alkoxy such as methoxy, ethoxy, n-propoxy, 
iso-propoxy, etc., aryloxy such as phenoxy, etc., aralkolxy such as 
benzyloxy, etc., alkylthio such as methylthio, ethylthio, etc., arylthio, 
aralkylthio, hydroxy, N-mono C.sub.1-6 lower alkylcarbamoyl such as 
N-methylcarbamoyl, N-ethylcarbamoyl, etc., N,N-di-lower alkyl carbamoyl 
such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, etc., N-(hydroxy 
lower alkyl)carbamoyl such as N-(hydroxymethyl)carbamoyl, 
N-(hydroxyethyl)-carbamoyl, etc., carboxy lower alkyl such as 
carboxymethyl, etc. or carbamoyl lower alkyl such as carbamoyl methyl, 
carbamoyl ethyl, etc.]. 
Among the substituents representable by R.sup.s mentioned above, more 
preferable examples are C.sub.1-6 alkyl, C.sub.2-7 alkoxymethyl cyano, 
formyl, carbamoyl, C.sub.1-6 alkyl and carbamoyl C.sub.1-6 alkyl. 
As further examples of preferable nitrogen nucleophilic compounds are 
employed those representable by the formula 
##STR22## 
[wherein R.sup.t and R.sup.u each stand for hydrogen atom or the group 
defined by R.sup.s, or R.sup.t and R.sup.u are bonded to each other and 
form, together with the carbon and nitrogen atoms they are each attached 
to, a saturated or unsaturated 5 to 7-membered heterocyclic ring having 
one to five hetero-atoms selected from among sulfur, oxygen and nitrogen, 
one to four of the hetero-atoms being nitrogen, which is exemplified by 
pyridine, pyridazine, pyrimidine, pyrazine, thiazole, oxazole, imidazole, 
tetrazole, triazole, thiadiazole, triazine, etc., then to form a condensed 
heterocyclic ring]. Specific embodiments are, for example, 
nitrogen-containing heteroxyclic compounds, such as pyridine, nicotinic 
acid, nicotinamide, isonicotinamide, pyridine-sulfonic acid, pyridylacetic 
acid, pyrazine, 2-carbamoyl pyrazine, pyrimidine imidazole, 1-methyl 
imidazole, 2,3-cyclopentenopyridine, methyl nicotinate, imidazo 
[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-b pyridazine, 
1-methylpyrrolidine, 2-(4-pyridyl)ethanesulfonic acid, 5-methyl tetrazole, 
etc. 
As the carbon nucleophilic compounds are employed, for example, inorganic 
cyanides (e.g. sodium cyanide), pyrroles and condensed pyrroles (e.g. 
indoles), etc. 
The dotted lines in the formulae [I]and [II]show that the double bond at 
the cephem ring is located at the 2-position 
##STR23## 
In the trivalent phosphorus compounds representable by the formula [III], 
R.sup.1, R.sup.2 and R.sup.3 respectively stand for hydrocarbon group 
whose carbon number is not more than 8, and any of the two of them may be 
combined to each other to form polymethylene group. As hydrocarbon groups 
shown by R.sup.1, R.sup.2 and R.sup.3 are mentioned, for example, alkyl* 
group, alkenyl* group, cycloalkyl* group, aryl* group, aralkyl* group, 
etc., whose carbon number is not more than 8. As preferable hydrocarbons 
shown by R.sup.1 are used, for example, C.sub.1-8 alkyl such as, C.sub.1-6 
alkyl mentioned above, heptyl, octyl, etc., C.sub.5-8 aralkyl e.g. benzyl, 
phenethyl, furfuryl, etc., C.sub.2-8 alkenyl e.g. allyl, 2-butenyl, 
3-butenyl, etc., and these C.sub.1-8 alkyl groups, C.sub.5-8 aralkyl 
groups and C.sub.2-8 alkenyl groups may have 1 to 3 substituents. As 
examples of those substituents are mentioned those described in the 
foregoing about the substituents of alkyl, aralkyl and alkenyl groups of 
R.sup.a to R.sup.o. As preferable examples of hydrocarbon groups 
representable by R.sup.2 and R.sup.3 are employed, for example, besides 
for example C.sub.1-8 alkyl groups, C.sub.5-8 aralkyl groups and C.sub.2-8 
alkenyl groups described in respect of R.sup.1, C.sub.5-10 aryl groups 
e.g. phenyl, naphthyl, furyl, etc. These C.sub.5-10 aryl groups may have 1 
to 3 substituents which are exemplified by those described in respect of 
R.sup.a to R.sup.o. In the compounds of the formula [III], any two of 
R.sup.1, R.sup.2, and R.sup.3 may be bonded to each other to form 
polymethylene group e.g. dimethylene, trimethylene, etc. As specific 
examples of such trivalent phosphorus compounds [III] are mentioned 
phosphorous triester, phosphonous acid diester, phosphinous acid ester, 
etc. The phosphorous triester was exemplified by trimethyl phosphite, 
triethyl phosphite, triisopropyl phosphite, tri-n-butyl phosphite, 
isooctyl phosphite, tris(2-ethylhexyl)phosphite, 
tris(2-chloroethyl)phosphite, etc., and those described on "Organic 
Phosphorus Compounds", Vol. 5, pp. 157 to 194 (1973). The phosphonous acid 
diester is exemplified by, besides phenyl phosphonous acid dimethylester, 
phenyl phosphonous acid diethylester, etc., those described on "Organic 
Phosphorus Compounds", Vol. 4, pp. 361 to 391 (1972). The phosphinous acid 
ester (phosphinite) is exemplified by, besides diethylphosphinic acid 
methylester, diphenylphosphinic acid ethylester, etc., those described on 
"Organic phosphorus Compounds" Vol. 4, pp.513 to 517 (1972). These pp. 
compound [ III] can be synthesized by a known method or by a method 
analogous to a known method, and they can be used for the method of this 
invention as isolated or they as the reaction mixture. Among the 
phosphorus compounds [III], the ones wherein R.sup.1, R.sup.2 and R.sup.3 
are independently C.sub.1-8 alkyl are preferred, and further, among them 
trimethyl phosphite, triethyl phosphite, triisopropyl phosphite or 
tri-n-butyl phosphite are preferable. Moreover, phosphorous acid triester 
such as trimethyl phosphite or, triethyl phosphite, for example, which is 
industrially produced as a flame retarder of plastic and wood and an 
additive for gasoline and paint, is readily available and can be used for 
advantageously especially for the present invention. In the method of this 
invention, the end product [I] can be produced by allowing a compound [II] 
to react with a nucleophilic compound and a trivalent phosphorus compound 
[III]. 
Compounds [II] include not only those whose acid radicals such as carboxyl 
group, sulfo group, etc. contained in R and Q are in the free form but 
also the salts thereof with non-toxic cation of sodium, potassium, etc., 
an organic amine e.g. triethylamine, tri-n-butylamine, di-n-butylamine, 
dicyclohexylamine, pyridine, collidine, 2, 6-lutidine, etc. And, when R 
and Q contain a basic group, a salt with an organic acid such as acetic 
acid, tartaric acid, methanesulfonic acid, etc., and a salt with an 
inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, 
phosphoric acid, etc. may be formed, and such salts as well as 
intramolecular salts formed by, for example a quaternary ammonium group 
contained in R or Y and its counter ion from an acid radical e.g. carboxyl 
group, are included in the starting compounds [II . The nucleophilic 
compounds can, depending on the kinds, take the form of salts preferably 
non-toxic salts, with a base or of salts, preferably non-toxic salts, with 
an acid, and both the salts are included in the materials of this 
invention. As these salts with bases and acids are used, for example, 
those described in respect of compounds [II]. 
The order of mixing a compound [II], a nucleophilic compound and a compound 
[III] is not especially limited, and, usually, in an organic solvent, a 
phosphorus compound [III] or an organic solvent solution thereof is added 
to a mixture of [II] and a nucleophilic compound, or, in an organic 
solvent, a compound [II] or an organic solvent solution thereof is added a 
mixture of a nucleophilic compound and a phosphorus compound. 
The molar ratios of a nucleophilic compound and a phosphorus compound [III] 
relative to a compound [II] are preferably 1.0 times or more, usually 1.0 
times to ten times, respectively. A nucleophilic compound or a phosphorus 
compound [III] per se can be used as a reaction solvent, but, usually, a 
nucleophilic compound is used in an amount of 1.0 to 10.0 times relative 
to a compound [II], preferably 1.0 to 5.0 times and a phosphorus compound 
is used in an amount of 1.0 to 5.0 times, preferably 1.0 to 3 .0 times 
relative to a compound [II]. 
Organic solvents to be employed for this reaction may be any ones which are 
inert to the reaction, which are exemplified by amides such as formamide, 
dimethylformamide, dimethylacetamide, etc., halogenated hydrocarbons such 
as chloroethane, isobutyl chloride, methylene chloride, chloroform, 
1,2-dichlorethane, carbon tetrachloride, 1,1,1-trichloroethane, 
1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, fluorobenzene, 
dichlorobenzene, etc., ethers such as diemthyl ether, diethyl ether, 
tetrahydrofuran, dioxane, etc., esters such as methyl acetate, ethyl 
acetate, isobutyl acetate, methyl propionate, ethylene carbonate, etc., 
nitriles such as acetonitrile, propionitrile, benzonitrile, etc., nitro 
compounds such as nitromethane, nitroethane, etc., ketones such as 
acetone, methyl ethyl ketone, etc., hydrocarbons such as benzene, toluene, 
mesitylene, etc., alcohols such as methanol, ethanol, propanol, butanol, 
etc., acids such as acetic acid, propionic acid, etc., etc. and these may 
be used as a suitable mixture. Especially, use of, for example, methylene 
chloride, acetonitrile, formamide, a mixture solvent of formamide and 
acetonitrile, a mixture solvent of methylene chloride and acetonitrile, a 
mixture solvent of methylene chloride and tetrahydrofuran, etc. brings 
about a favorable result. 
This reaction proceeds more promptly when an acid component is present in 
the reaction mixture. In the compound [II], when Q is hydrogen, i.e. when 
"--COOQ" is a carboxyl group, the reaction is usually completed in a short 
period of time due to its acidity, while when Q is ester residue, in the 
form of a salt with cation of sodium, potassium etc. or organic amine, and 
when the acidity of carboxyl group is neutralized due to a basic group 
such as amino group, etc. contained in the structure of the compound [II] 
or the nucleophilic compound, the reaction requires a relatively long 
period of time. In such cases, the reaction can be conducted by adding an 
acid so as to shorten the reaction time. As the acid to be used for such 
purpose may by any one which does not give unfavorable effects on the 
reaction, as exemplified by carboxylic acid such as formic acid, acetic 
acid, propionic acid, butyric acid, valeric acid, benzoic acid, etc., 
sulfonic acids such as methane sulfonic acid, benzene sulfonic acid, 
p-toluene sulfonic acid, etc., hydrogen halogenides such as hydrogen 
chloride, hydrogen bromide, etc., Lewis acids such as boron trifluoride, 
zinc chloride, aluminium chloride, etc., etc. Among them, carboxylic acids 
such as acetic acid are used especially preferably. The reaction 
temperature and time may be suitably selected depending on the kinds of 
compounds [II], nucleophilic compounds, phophorus compounds [III] and 
solvents. However, the reaction time is usually a minute to about ten 
hours. The reaction may be conducted in a broad temperature range from 
-20.degree. C. to 80.degree. C. In general, the reaction time can be 
shortened by raising the temperature, but the reaction is usually 
conducted at room temperature or under slight cooling (0 to 30.degree. C.) 
for the purpose of avoiding the decomposition of the cephalosporins due to 
heating. The reaction is usually completed under mild conditions, at 15 to 
30.degree. C. for several minutes to several hours. 
In the method of this invention, as the reaction proceeds, the 
ester-linkage of a phosphorus compound [III] is hydrolized to produce 
corresponding alcohols, and the reaction can be allowed to proceed while 
eliminating such alcohols by, for example, azeotropic distillation under 
reduced pressure with the organic solvent then employed. 
Cephalosporin compound [I] thus obtained can be isolated from the reaction 
mixture by for example, when desired, subjecting an excess amount of the 
phosphorus compound then employed to, for example, hydrolysis, followed by 
subjecting the resultant product to per se conventional means such as 
filtration, solvent extraction. pH change, phase transfer, salting out, 
crystallization, recrystallization, chromatography, etc. And, depending on 
the kinds of the acyl group shown by R, [I] can be led to 7-amino cephem 
compound (compound [I] where R is hydrogen atom), which is a useful 
intermediate for preparing an antibiotic substance, by adding to the 
reaction mixture, without isolating [I], dimethyl aniline, trimethyl silyl 
chloride, phosphorus pentachloride, methanol and water in sequence to 
thereby cleave the acyl group at 7-position by a known method or a method 
analogous to known method. When the object compound [I] is in the free 
form, it may be modified into a salt by per se conventional manner, which 
is included in the object compounds of the formula [I]. As the salts of 
the object compound [I], preferably non-toxic salts such ones as described 
in respect of the starting compound [II] are mentioned, which are, for 
example, salts at the acid radical with an alkali metal e.g. lithium, 
sodium, potassium, etc., an alkaline earth metal e.g. calcium, magnesium, 
etc. amines e.g. di-n-butylamine, dicyclohexylamine, diisobutylamine, 
di-tert-butylamine, triethylamine, pyridine, 2,6-lutidine, tributyl-amine, 
etc., and salts at the basic radical with a mineral acid e.g. hydrochloric 
acid, sulfuric acid, etc., an organic acid e.g. oxalic acid, acetic acid, 
formic acid, trichloroacetic acid, trifluoroacetic acid, etc., sulfonic 
acid e.g. methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic 
acid, camphor sulfonic acid, etc., phosphoric acid e.g methylphosphoric 
acid, dimethylphosphoric acid, diphenylphosphoric acid, etc., phosphonic 
acid e.g. phenylphosphonic acid, etc. 
Incidentally, the starting compounds [II] employable in the present 
invention can be prepared by, for example, a fermentative method [e.g. 
methods described on Nature Vol. 246, p.154 (1973), Japanese Patent 
Application Laid-Open No., 491/1974, etc.] or by subjecting the product 
obtained by the fermentative method to chemical or enzymatic treatment 
[e.g. methods described on Biochemical Journal Vol. 81, pp.591-596 
(1961)]. And, the nucleophilic compounds can be synthesized by a known 
method, e.g. a method described on, "Heterocyclic Compounds" compiled by 
Robert C. Elderfield, "The Chemistry of Heterocyclic Compounds", compiled 
by Weissberger et al., J. Heterocyclic Chemistry Vol. 15, p.1295 (1978), 
J. Pharmaceutical Sciences Vol. 51, pp. 862-864 (1962), Japanese Patent 
Application Laid-Open No. 231684/1985 or methods analogous thereto. 
The antibacterial compounds [I] wherein R is an acyl can be used as 
antibiotic substances having excellent antibiotic properties when used in 
accordance with known methods [e.g. methods described on Japanese Patent 
Applications Laid-Open No. 72286/1974, 48996/1977 and 1280/1978 etc.], and 
the compounds [I] can also be used as intermediates for antibiotic 
substances having excellent antibiotic potency. For example, a compound 
[I] embraces 7-[2-(2-imino-4-thiazolin-4yl) acetamido] compound [described 
on e.g. USP 4,080498, etc.] which can be obtained by first subjecting the 
compound [I] wherein R is for example a group of the formula 
##STR24## 
to a per se conventional method [e.g. Japanese Patent Application 
Publication Nos. 41-13862/1966 40899/1970, Laid-Open No. 34387/1972, USP 
3.632, 578, etc.] and to cleave the acyl group at 7-position, then 
allowing the resultant to react with 
4-halogeno-3-oxobutyrylamido-compound, followed by allowing the resultant 
to react with 4-halogeno-3-oxobutyrylamido-compound, followed by allowing 
the resultant to react with thiourea. All of the thus-obtained 
antibacterial compounds show excellent antibiotic properties, though the 
properties are somewhat different among them depending on the kinds of 
substituents at 3-position.

The following examples are intended to illustrate this invention in further 
detail and should by no means be construed as limiting the scope of the 
present invention. 
Symbols used in the examples are of the following meaning. 
s: singlet, br: broad, d: doublet, dd: double doublet, t: triplet, q: 
quartet, ABq: AB type quartet, m: multiplet, D.sub.2 O: deuterium oxide, 
%: weight %, TLC: thin layer chromatography, DMSO--d.sub.6 : dimethyl 
sulfoxide--d.sub.6, NaHCO.sub.3 : sodium hydrogencarbonate 
NMR (nuclear magnetic resonance spectrum) was, unless otherwise specified, 
shown in terms of the chemical shift values [.delta.(ppm)] obtained by 
using, as internal standards, tetramethylsilane (when DMSO--d.sub.6 was 
used as the solvent) or sodium 2,2-dimethyl-2-silapentane-5-sulfonate 
(when D.sub.2 O was used as the solvent). "Room temperature" means a 
temperature between about 5 and 35.degree. C. 
EXAMPLE 1 
To 5.03 g of 
7.beta.-D-5-carboxy-5-phthalimidovaleramido)-3-cephem-4-carboxylic acid 
were added 100 ml of tetra-hydrofuran-methylene chloride mixture solution 
(1:2,v/v), 1.74 g of 5-mercapto-1-methyl-1H-tetrazole and 2.3 ml of 
trimethyl phosphite in sequence. The reaction was allowed to proceed at 18 
to 22.degree. C. for 3.5 hours while stirring. To the reaction solution 
was added 30 ml of 1N HCl, and the mixture was stirred for 30 minutes, 
which was concentrated under reduced pressure to about 30 ml. To the 
concentrate was added 30 ml of methylene chloride, to which was added 1N 
NaOH to render the pH to 5.6, followed by separating the organic layer 
from the aqueous layer. To the aqueous layer was added 30 ml of 
tetrahydrofuran-methylene chloride mixture solution (1:1,v/v), whose pH 
was changed to 2.0 with 2N HCl, then the organic layer was separated. The 
aqueous layer was subjected to extraction with 30 ml of the same mixture 
solution. The organic layers were combined, washed with saturated aqueous 
saline solution and dried on anhydrous magnesium sulfate, followed by 
concentration under reduced pressure. The concentrate was poured into 300 
ml of ether and the precipitating matter was collected by filtration, 
washed with ether and dried to obtain 5.86 g (yield:97.4%) of 
7.beta.-D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-1H-tetrazol-5-yl) 
thiomethyl-3-cephem-4-carboxylic acid as white powder. 
IR(KBr): 3350,2950,1773,1713,1530 cm.sup.-1 
NMR(DMSO-d.sub.6): .delta.1.20-2.40(6H,m,--(CH.sub.2).sub.3 --), 
3.60(2H,br,2--CH.sub.2), 3.94(3H,s,--CH.sub.3),4.27(2H,br, 
3--CH.sub.2),4.27(1H,t,J.dbd.8 Hz, &gt;CH--),5.00(1H,d,J.dbd.5 Hz,C.sub.6 
--H),5.61(1H,dd,J.dbd.8.times.5 Hz,C.sub.7 --H),7.89(4H, s,C.sub.6 H.sub.4 
&lt;),8.76(1H,d,J.dbd.8 Hz,--CONH--)ppm 
EXAMPLE 2 
To 2.52 g of 
7.beta.-(D-5phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic 
acid were added 20 ml of methylene chloride, 0.99 g of 
5-mercapto-2-methyl-1,3,4-thiadiazole and 1.7 ml of triethyl phosphite in 
sequence. The mixture was stirred at room temperature for 3.0 hours. To 
this reaction solution was added 10 ml of 1N HCl, which was stirred for 30 
minutes at 20 to 25.degree. C.; the pH was adjusted to 6.0 with 1N NaOH, 
followed by separating into two layers. To the aqueous layer were added 20 
ml of tetrahydrofuran and 20 ml of methylene chloride; the pH was adjusted 
to 2.0 with 2N HCl, followed by separating into two layers. The aqueous 
layer was subjected to extraction with a mixture of 20 ml of 
tetrahydrofuran and 20 ml of methylene chloride. The organic layers were 
combined and dried on anhydrous magnesium sulfate, which was concentrated 
under educed pressure, followed by addition of 150 ml of ether. Resultant 
powder was collected by filtration, washed with ether, then dried under 
reduced pressure to obtain 2.87 g (yield: 92.9%) of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-(2-methyl-1,3,4-thiadiazol 
-5-yl) thiomethyl-3-cephem-4-carboxylic acid as white powder. 
IR(KBr): 3330,2920,1775,1715,1530 cm.sup.-1 
NMR(DMSO--d.sub.6): .delta.1.30-2.40(6H,m,--(CH.sub.2).sub.3 --), 
2.71(3H,s,--CH.sub.3),3.62(2H,ABq,J.dbd.18 Hz,2--CH.sub.2), 
4.37(2H,ABq,J.dbd.14 Hz,3--CH.sub.2),4.76(1H,t,J.dbd.7 Hz, 
&gt;CH--),5.07(1H,d,J.dbd.5 Hz,C.sub.6 --H),5.65(1H,dd,J.dbd.8.times.5 
Hz,C.sub.7 --H),7.92(4H,s,C.sub.6 H.sub.4 &lt;),8.81(1H,d,J.dbd. 
8 Hz,CONH)ppm 
EXAMPLE 3 
To 580 mg of dipotassium 
7.beta.-D-5-carboxy-5-phthalimidovaleramido)-3-hydroxylmethyl-3-cephem-4-c 
arboxylate were added 4.0 ml of glacial acetic acid, 151 mg of 
5-mercapto-1-methyl-1H-tetrazole and 0.50 ml of triethyl phosphite in 
sequence. The reaction was allowed to proceed at 25.+-.2.degree. C. for 30 
minutes under stirring. To the reaction solution was added 50 ml of ether, 
and then precipitating powder was collected by filtration, which was 
washed with ether, followed by drying under reduced pressure to obtain 
0.78 g of white powder. The powder was suspended in 8 ml of water, whose 
pH was adjusted to 2.0 with 4N HCl. Resultant precipitates were collected 
by filtration, washed with water and dried under reduced pressure to 
obtain 550 mg (yield: 91.4%) of 
7.beta.-(D-5-carboxy-5-phtalimidovaleramido)-3-(1-methyl-1H-tetrazol-5-yl) 
thiomethyl-3-cephem-4-carboxylic acid as white powder. IR and NMR spectra 
of this product were in agreement with those in Example 1. 
EXAMPLE 4 
In a mixture of 2.0 ml of formamide and 1.0 ml of acetonitrile was 
dissolved 232 mg of 5-mercapto-1-methyl-1H-tetrazole. To this solution 
were added 580 mg of dipotassium 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-c 
arboxylate and 0.50 ml of triethyl phosphite in sequence. The mixture 
solution was warmed to 30.degree. C. in about one minute. The reaction was 
allowed to proceed at 80.+-.3.degree. C. for 9 minutes under stirring. The 
reaction solution was cooled on an ice-water bath, to which was added 3 ml 
of 1N HCl. The mixture was stirred for 30 minutes, followed by 
concentration under reduced pressure. To the concentrate were added 20 ml 
of water, 10 ml of tetrahydrofuran and 10 ml of methylene chloride. The 
mixture was shaken and left standing to form two layers. The organic layer 
was separated, and the aqueous layer was subjected to extraction with a 
mixture of 10 ml of tetrahydrofuran and 10 ml of methylene chloride. The 
organic layers were combined, washed with 10 ml of water and dried over 
anhydrous magnesium sulfate, followed by concentration under reduced 
pressure. To the concentrate was added 50 ml of ether, then resultant 
precipitates were collected by filtration, followed by drying under 
reduced pressure to obtain 504 mg (yield: 83.8%) of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-1H-tetrazol-5-yl 
) thiomethyl-3-cephem-4-carboxylic acid as white powder. The IR and NMR 
spectra of this product were in agreement with those in Example 1. 
EXAMPLE 5 
In a mixture of 2.0 ml of formamide and 8.0 ml of acetonitrile was 
dissolved 0.522 g of 5-mercapto-1-methyl-1H-tetrazole. To the solution 
were added in sequence 1.43 g of 
7.beta.-(D-5-benzamido-5-carboxyvaleramido)-3-hydroxymethyl-3-cephem-4-car 
boxylic acid and 1.1 ml of trimethyl phosphite, and the mixture was stirred 
at 20 to 25.degree. C. for 60 minutes. To the reaction solution were added 
3 ml of 2N HCl and 50 ml of water, and the mixture was stirred for 30 
minutes, followed by concentration under reduced pressure. To the 
concentrate was added 40 ml of a mixture of tetrahydrofuran and methylene 
chloride (1:1,v/v), which was allowed to form two layers. The aqueous 
layer was separated and subjected to extraction with 20 ml of the same 
mixture. The organic layers were combined, washed with 15 ml of water and 
dried over anhydrous magnesium sulfate, followed by concentration under 
reduced pressure. To the concentrate was added ether, and resulting powder 
was collected by filtration, followed by drying under reduced pressure to 
give 1.62 g (yield: 93.8%) of 
7.beta.-(D-5-benzamido-5-carboxyvaleramido)-3(1-methyl-1H-tetrazol-5-yl) 
thiomethyl-3-cephem-4-carboxylic acid. 
IR(KBr): 3300,2950,1780,1720,1645, 1530 cm.sup.-1 
NMR(D.sub.2 O--NaHCO.sub.3): .delta.1.5-2.6(6H,m,--(CH.sub.2).sub.3), 
3.41(2H,ABq,J.dbd.17 Hz,2--CH.sub.2),4.00(3H,s,--CH.sub.3), 
4.15(2H,ABq,J.dbd.14 Hz,3--CH.sub.2),4.44(1H,br,&gt;CH--), 
5.20(1H,d,J.dbd.5 Hz,C.sub.6 --H),5.56(1H,d,J.dbd.5 Hz,C.sub.7 -- 
H),7.3-8.2(5H,m,C.sub.6 H.sub.5 --)ppm 
EXAMPLE 6 
To a mixture of 3.53 g of 
7-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxy 
lic acid ditriethylamine salt and 1.45 g of 
5-mercapto-1-methyl-1H-tetrazole were added in sequence 20 ml of 
acetonitrile and 4.66 g of tributyl phosphite. The reaction was allowed to 
proceed at 20 to 22.degree. C. for 60 minutes. To the reaction solution 
was added 70 ml of water, then most of the acetonitrile was distilled off 
under reduced pressure. To the residue was added 30 ml of methylene 
chloride, to which was added 1N NaOH to change the pH to 8.5 to allow the 
precipitates to be dissolved. To the solution was added 2N HCl to change 
the pH to 5.6, then the solution was made to form two layers. To the 
aqueous layer was added 60 ml of a mixture of tetrahydrofuran-methylene 
chloride (1:1,v/v), to which was added 2N HCl to change the pH to 2.0, 
then the solution was made to form two layers. The organic layer was 
separated, and the aqueous layer was subjected to extraction with 40 ml of 
the same mixture solvent. The organic layers were combined, washed with 20 
ml of water and dried over anhydrous magnesium sulfate, followed by 
concentration under reduced pressure. To the concentrate was added 140 ml 
of ether, and resulting precipitates were collected by filtration, then 
washed with ether, followed by drying under reduced pressure to obtain 
2.86 g (yield: 95.1%) of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-1H-tetrazol-5-yl 
) thiomethyl-3-cephem-4-carboxylic acid as white powder. The NMR spectrum 
of this product was in agreement with that in Example 1. 
EXAMPLE 7 
To 0.543 g of 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole 
hydrochloride were added 6.0 ml of formamide and 6.0 ml of acetonitrile to 
make a solution. The solution was added to 1.00 g of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-c 
arboxylic acid, followed by addition of 0.50 ml of trimethyl phosphite. The 
reaction was allowed to proceed at 20 to 25.degree. C. while stirring for 
2.0 hours. To the reaction solution were added 30 ml of acetonitrile and 
50 ml of ether to cause precipitation of a resinous substance. The 
supernatant was removed by decantation, and the resinous substance was 
washed with 20 ml of acetone. To the resultant were added in sequence 10 
ml of ethanol, 50 ml of ether and 2.5 ml of ether solution of hydrogen 
chloride (2 mol./l). The mixture was stirred, and the resulting powder was 
collected by filtration, washed with ether, and dried under reduced 
pressure to obtain 1.27 g (yield: 92.0%) of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-[1-(2-dimethylaminoethyl)- 
1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid hydrochloride as 
white powder. 
IR(KBR): 3140,3030,1773,1713,1530 cm.sup.-1 
NMR(DMSO--d.sub.6 --D.sub.20): .delta.1.3-2.4(6H,m, --(CH.sub.2).sub.3 
--),2.92(6H,s,--CH.sub.3 .times.2),3.5-3.9(4H,m,2--CH.sub.2 --CH.sub.2 
N&lt;),4.30(2H,br,3--CH.sub.2),4.5-4.9(3H, m,--CH.sub.2 CH.sub.2 
N&lt;and&gt;CH--),5.03(1H,d,j.dbd.5 Hz,C.sub.6 --H), 5.58(1H,d,J.dbd.5 
Hz,C.sub.7 --H),7.92(4H,s,C.sub.6 H.sub.5 --)ppm 
EXAMPLE 8 
To a solution of 1.31 g of 
7.beta.-(D-5-carboxy-5-phenoxycarbonylaminovaleramido)-3-hydroxymethyl-3-c 
ephem-4-carboxylic acid in a mixture solution of tetrahydrofuran (5.0 
ml)-methylene chloride (5.0 ml) was added 0.33 g of pyridine dissolved in 
2.0 ml of tetrahydrofuran, followed by addition of 0.70 ml of trimetyl 
phosphite. The resultant was stirred at 20 to 25.degree. C. for 2.0 hours. 
Precipitating powder was collected by filtration, which was washed with 10 
ml of tetrahydrofuran-methylene chloride mixture solution (1:1,v/v) and 10 
ml of methylene chloride. The resultant product was dissolved in 6.0 ml of 
acetonitrile-water (4:1,v/v). The solution was subjected to a silica gel 
chromatography, using acetonitrile-water (4:1) as the eluent. The eluate 
was subjected to TLC (developed with a solvent, acetonitrile 15:water 
5:99% formic acid 0.25, using silica gel plate 60F-254, manufactured by E. 
Merck, and detected with UV). Fractions showing a spot at Rf 0.27 were 
collected, concentrated under reduced pressure, followed by freeze-drying 
to obtain 1.21 g (yield: 82.3%) of 
7.beta.-(D-5-carboxyl-5-phenoxycarbonylaminovaleramido)-3-(1-pyridinio) 
methyl-3-cephem-4-carboxylate as white powder. 
IR(KBr): 3370,3040,1775,1725,1660, 1610 cm.sup.-1 
NMR(D.sub.2 O--NaHCO.sub.3): .delta.1.78(4H,br,--CH.sub.2 CH.sub.2 --), 
2.39(2H,br,CH.sub.2 CO),3.30(2H,ABq,J.dbd.18 Hz,2--CH.sub.2), 
4.02(1H,br,&gt;CH--),5.15(1H,d,J.dbd.5 Hz,C.sub.6 --H), 5.40(2H,ABq,J.dbd.14 
Hz,3--CH.sub.2),5.65(1H,d,J.dbd.5 Hz, C.sub.7 --H),7.1-7.6(5H,m,C.sub.6 
H.sub.5 --),7.8-9.0(5H,m, Pyridine)ppm 
EXAMPLE 9 
To 4.93 g of 
7.beta.-(D-5-carboxy-5-phenoxycarbonylaminovaleramido)-3-hydroxymethyl-3-c 
ephem-4-carboxylic acid were added 80 ml of tetrahydrofuran-methylene 
chloride mixture solution (1:2,v/v) and 1.74 g of 
5-mercapto-1-methyl-1H-tetrazole. The mixture was stirred for 5 minutes, 
to which was added 3.7 ml of trimethyl phosphite, followed by stirring at 
20 to 25.degree. C. for 3hours. To the reaction solution was added 21 ml 
of water, whose pH was rended to 2.0 with 4N HCl, which was made to form 
two layers. The aqueous layer was subjected to separation into two layers 
twice using a mixture of 10 ml of tetrahydrofuran and 20 ml of methylene 
chloride. The organic layers were combined, washed with aqueous saline, 
dried over anhydrous magnesium sulfate, followed by concentration under 
reduced pressure. To the concentrate was added ether, and the solid matter 
was crushed, then resulting powder was collected by filtration. Thus 
collected powdery product was washed with ether and subjected to drying 
under reduced pressure to obtain 5.23 g (yield: 88%) of 
7.beta.-(D-5-carboxy-5-phenoxycarbonylaminovaleramido)-3-(1-1H-tetrazol-5- 
yl) thiomethyl-3-cephem-4-carboxylic acid. 
IR(KBr): 3270,3020,2920,1780,1725, 1530 cm.sup.-1 
NMR(DMSO--d.sub.6): .delta.1.4-2.4(6H,m,--(CH.sub.2).sub.3), 
3.69(2H,br,2--CH.sub.2),3.94(3H,s,CH.sub.3),4.30(2H,br, 
3-CH.sub.2),5.05(1H,d,J.dbd.5 Hz,C.sub.6 --H),5.65(1H,q,J.dbd.5 .times.8 
Hz,C.sub.7 --H),6.9-7.6(5H,m,C.sub.6 H.sub.5 --),8.03(1H,d,J .dbd.8 
Hz,OCONH),8.83(1H,d,J.dbd.8 Hz,CONH)ppm 
EXAMPLE 10 
To 4.77 g of 
7.beta.-[D-5-(p-tert-butylbenzamido)-5-carboxyvaleramido]-3-hydroxymethyl- 
3-cephem-4-carboxylic acid were added 80 ml of tetrahydrofuran-methylene 
chloride mixture solution (1:2,v/v), 1.74 g of 
5-mercapto-1-methyl-1H-tetrazole and 4.15 g of triethyl phosphite. The 
mixture was stirred at 20 to 25.degree. C. for 3 hours, followed by 
subjecting to after-treatment similar to that in Example 9 to give 5.71 g 
(yield: 90%) of 7 
[D-5-(p-tert-butylbenzamido)-5-carboxyvaleramido]-3-(1-methyl-1H-tetrazol- 
5-yl) thiomethyl-3-cephem-4-carboxylic acid. 
IR(KBr): 3300,2960,1780,1725,1640, 1535 cm.sup.-1 
NMR(D.sub.2 O--NaHCO.sub.3): .delta.1.23(9H,s,CH.sub.3 .times.3),1.98 
(4H,br,--CH.sub.2 CH.sub.2 --),2.43(2H,br,CH.sub.2 CO),3.34(2H, 
ABq,J.dbd.17 Hz,2--CH.sub.2),4.00(3H,s,N--CH.sub.3),4.16(2H, ABq,J.dbd.14 
Hz,3--CH.sub.2),5.01(1H,d,J.dbd.5 Hz,C.sub.6 --H), 5.60(1H,d,J.dbd.5 
Hz,C.sub.7 --H), 7.65(4H,dd,J.dbd.8 Hz,--C.sub.6 H.sub.4 --)ppm 
EXAMPLE 11 
In a mixture of 2 ml of formamide and 4 ml of acetonitrile was dissolved 
633 mg of 2-carboxymethylthio-5-mercapto-1,3,4-thiadiazole at about 
40.degree. C. The solution was cooled to about 30.degree. C., to which 
were added in sequence 0.31 ml of trimethyl phosphite, 689 mg of 
tributylamine salt of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-c 
arboxylic acid and 0.20 ml of ether solution of hydrogen chloride 
(5mol./l). The mixture was stirred at 20 to 25.degree. C. for one hours, 
to which was added 20 ml of water. Acetonitrile was distilled off under 
educed pressure. To the residue was added 10 ml of tetrahydrofuran, whose 
pH was rendered to 2.6with 4N HCl. To the resultant was added 15 ml of 
methylene chloride to allow the mixture to form two layers. The aqueous 
layer was taken, to which were added 10 ml of tetrahydrofuran and 15 ml of 
methylene chloride, then resulting organic layer was separated. The 
organic layers were combined and washed with aqueous saline and dried over 
anhydrous magnesium sulfate, then the solvent was distilled off. The 
residue was subjected to a silica gel chromatography to obtain 580 mg 
(yield: 81%) of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-(2-carboxymethylthio-1,3,4 
-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid. 
IR(KBr): 3370,2950,1770,1710,1530, 1390 Cm.sup.-1 
NMR(DMSO--d.sub.6 --D.sub.2 O): .delta.1.3-2.4(6H,m, --(CH.sub.2).sub.3 
--),3.59(2H,br,2--CH.sub.2),4.10(2H,br,SCH.sub.2 
CO),4.23(2H,br,3--CH.sub.2),4.72(1H,t,J.dbd.7 Hz, &gt;CH--),5.00(1H,d,J.dbd.5 
Hz,C.sub.6 --H),5.57(1H,d,J.dbd.5Hz,C.sub.7 --H),7.90(4H,s,C.sub.6 H.sub.4 
&lt;)ppm 
EXAMPLE 12 
To a solution of 240 mg of 1-carboxymethyl-5-mercapto-1H-tetrazole in a 
mixture of 2 ml of formamide and 4 ml of acetonitrile was added 689 mg of 
tributylamine salt of 
7.beta.-(D-5-carboxyl-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4- 
carboxylic acid. To the solution were added in sequence 1.0 ml of 
tetrahydrofuran solution of hydrogen chloride (1 mol/l) and 0.30 ml of 
trimethyl phosphite. The mixture was stirred at 20 to 25.degree. C. for 2 
hours. To the reaction solution was added 20 ml of water, which was 
concentrated under reduced pressure to distill off acetonitrile. To the 
concentrate was added 10 ml of tetrahydrofuran, whose pH was adjusted to 
2.6 with 4N HCl, followed by separating by addition of 15 ml of methylene 
chloride. The organic layers were combined and washed with aqueous saline, 
dried over anhydrous magnesium sulfate, followed by concentration under 
reduced pressure. The concentrate was poured into ether, then resulting 
powder was collected by filtration, followed by drying under reduced 
pressure to obtain 507 mg (yield: 82%) of 
3-(1-carboxymethyl-1H-tetrazol-5-yl) 
thiomethyl-7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-cephem-4-carbox 
ylic acid. 
IR(KBr): 3300,2940,1770,1710,1530, 1390 cm.sup.-1 
NMR(DMSO--d.sub.6 --D.sub.2 O): .delta.1.3-2.4(6H,m, --(CH.sub.2).sub.3 
--),3.59(2H,br,2--CH.sub.2),4.10(2H,br,SCH.sub.2 
CO),4.23(2H,br,3--CH.sub.2),4.72(1H,t,J.dbd.7 Hz, &gt;CH--),5.00(1H,d,J.dbd.5 
Hz,C.sub.6 --H),5.57(1H,d,J.dbd.5 Hz,C.sub.7 --H),7.90(4H,s,C.sub.6 
H.sub.4 &lt;)ppm 
EXAMPLE 13 
To a solution of 265 mg of 4,6-dimethyl-2-mercapto-pyrimidine hydrochloride 
in a mixture of 3.5 ml of formamide and 4 ml of acetonitrile were added in 
sequence 0.31 ml of trimethyl phosphite and 689 mg of tributylamine salt 
of 7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem- 
4-carboxylic acid. The mixture was stirred at 20.about.25.degree. C. for 
1.5 hour, which was subjected to the same treatment as in Example 12 to 
obtain 573 mg (yield: 91%) of 
7.beta.-(D-5-carbyoxy-5-phthalimidovaleramido)-3-(4,6-dimethylpyrimidin-2- 
yl) thiomethyl-3-cephem-4-carboxylic acid. 
IR(KBr): 3260,2950,1775,1715,1580, 1530 cm.sup.-1 
NMR(DMSO--d.sub.6): .delta.1.3-2.3(6H,m,--(CH.sub.2).sub.3 --), 
2.35(6H,s,CH.sub.3 .times.2),3.55(2H,ABq,J.dbd.18 Hz,2--CH.sub.2), 
4.15(2H,ABq,J.dbd.14 Hz,3--CH.sub.2),4.78(1H,br,&gt;CH--), 4.99(1H,d,J.dbd.5 
Hz,C.sub.6 --H),5.56(1H,q,J.dbd.5.times.8 Hz, C.sub.7 
--H),6.93(1H,s,Pyrimidine),7.87(4H,s, C.sub.6 H.sub.4 &lt;),8.22(1H,d,J.dbd.8 
Hz,CONH)ppm 
EXAMPLE 14 
To 1.01 g of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-c 
arboxylic acid were added in sequence 10 ml of tetrahydrofuran, 15 ml of 
methylene chloride, 0.70 g of 2-ethoxycarbonylmethylthio 
-5-mercapto-1,3,4-thiadiazole and 0.70 g of triethyl phosphite. The 
mixture was stirred at 20 to 25.degree. C. for two hours. To the reaction 
solution was added 10 ml of water, whose pH was adjusted to 2.5 with 4N 
HCl to allow the mixture to form two layers. To the aqueous layer was 
added a mixture of 10 ml of tetrahydrofuran and 15 ml of methylene 
chloride, which was again allowed to form two layers. The organic layers 
were combined, washed with aqueous saline, dried over anhydrous magnesium 
sulfate, then concentrated under reduced pressure. To the concentrate was 
dissolved in a small volume of acetone, and the solution was poured into 
ether. Precipitating powdery product was collected by filtration and dried 
under reduced pressure to give 1.12 g (yield: 87%) of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-(2-ethoxycarbonylmethylthi 
o-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid. 
IR(KBr): 3300,2950,1775,1530, 1490 cm.sup.-1 
NMR(DMSO--D.sub.6): .delta.1.20(3H,t,CH.sub.3),1.4-2.4(6H, 
m,--(CH.sub.2).sub.3 --),3.62(2H,br,2--CH.sub.2),3.9-4.5(6H,m, 
COCH.sub.2,SCH.sub.2 CO,3--CH.sub.2),4.75(1H,t,J.dbd.7 Hz,&gt;CH--), 
5.06(1H,d,J.dbd.5 Hz,C.sub.6 --H),5.66(1H,br,C.sub.7 --H),7.90 
(4H,s,C.sub.6 H.sub.4 &lt;),8.33(1H,br,CONH)ppm 
EXAMPLE 15 
To 2.01 g of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-c 
arboxylic acid were added in sequence 4 ml of formamide, 4ml of 
acetonitrile, 0.95 g of pyridine and 1.5 ml of trimethyl phosphite. The 
mixture was stirred at 20 to 25.degree. C. for two hours. The reaction 
solution was cooled, and there were added 40 ml of acetonitrile and 20 ml 
of ether to cause precipitation of resinous matter. The supernatant was 
removed by decantation, and the resinous matter was washed twice with 10 
ml each portions of acetonitrile. To the resultant material was added 50 
ml of fresh acetonitrile and crushed to give homogeneous powder. The 
powder was collected by filtration, washed with acetonitrile, followed by 
drying under reduced pressure to give 1.90 g (yield: 84%) of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-(1-pyridinio) 
methyl-3-cephem-4-carboxylate. 
IR(KBR): 3420,3060,2950,1770,1710, 1390 cm.sup.-1 
NMR(D.sub.2 O--NaHCO.sub.3): .delta.1.30-2.60(6H,m, --(CH.sub.2).sub.3 
--),3.19(2H,ABq,J.dbd.18 Hz,2--CH.sub.2),5.90(1H, d,J.dbd.5 Hz,C.sub.6 
--H),5.47(2H,ABq,J.dbd.13 Hz,3--CH.sub.2), 5.61(1H,d,J.dbd.5 Hz,C.sub.7 
--H),7.80(4H,s,C.sub.6 H.sub.4 &lt;),8.0.about.9.1(5H,m,Pyridine)ppm 
EXAMPLE 16 
To 1.51. g of 
7.beta.-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-c 
arboxylic acid were added in sequence 6 ml of formamide, 1.10 g of 
isonicotinic acid amide and 6 ml of acetonitrile. To the solution was 
added, after stirring for 5 minutes, 0.75 ml of trimethyl phosphite. The 
mixture was stirred at 20 to 25.degree. C. for two hours, to which were 
added 40 ml of acetonitrile and 20 ml of ether, followed by cooling. 
Resulting resinous substance was separated and washed with acetonitrile 
and the product then dissolved in 20 ml of a mixture of water and 
acetonitrile (1:1,v/v), whose pH was changed to 6.0 with 1N NaOH, followed 
by concentration under reduced pressure. The concentrate was subjected to 
an XAD-2 (100 ml) column chromatography, eluting with water and a mixture 
of water and acetonitrile. Fractions containing the end-product were 
collected; the pH was adjusted to 6.0and the product was concentrated 
under reduced pressure, followed by freeze-drying to give sodium 
7.beta.-(D-5-carboxylate-5-phthalimidovaleramido)-3-(4-carbamoyl-1-pyridin 
io)-methyl-3-cephem-4 -carboxylate. 
IR(KBr): 3380,1765,1705,1610,1460, 1395 cm.sup.-1 
NMR(D.sub.2 O): .delta.1.4-2.6(6H,M,--(CH.sub.2).sub.3 --),3.26 
(2H,ABq,J.dbd.18 Hz,2--CH.sub.2),4.58(1H,t,J.dbd.7 Hz, 
&gt;CH--),5.11(1H,d,J.dbd.5 Hz,C.sub.6 --H),5.53(2H,ABq,J .dbd.13 
Hz,3--CH.sub.2),5.61(1H,d,J.dbd.5 Hz,C.sub.7 --H), 7.78(4H, s,C.sub.6 
H.sub.4 &lt;),8.42 & 9.16(4H, respectively d,J.dbd.7 Hz. Pyridine)ppm 
EXAMPLE 17 
In 6 ml of formamide was dissolved 1.43 g of 
7.beta.-(D-5-benzamido-5-carboxyvaleramido)-3-hydroxymethyl-3-cephem-4-car 
boxylic acid. To the solution were added in sequence 6 ml of acetonitrile, 
0.95 g of pyridine and 1.1 ml of trimethyl phosphite. The reaction was 
allowed to proceed at 20 to 25.degree. C. for two hours and there was 
added 60 ml of acetonitrile, followed by cooling. The supernatant was 
removed by decantation. The residual rubber-like substance was washed with 
acetonitrile, to which was added 20 ml of a mixture of water and 
acetonitrile (1:1,v/v), whose pH was adjusted to 6.0 with 1N NaOH. The 
resultant solution was concentrated under reduced pressure to distill off 
acetonitrile. The residue was subjected to an Amberlite XAD-2 (100 ml) 
column chromatography, eluting with water. The fractions containing the 
end product were combined and freeze-dried to give sodium 
7.beta.-(D-5-benzamido-5-carboxylate 
valeramido)-3-(1-pyridinio)methyl-3-cephem-4-carboxylate. 
IR(KBr): 3400,3050,1770,1610,1535, 1485 cm.sup.-1 
NMR(D.sub.2 O): .delta.1.50.about.2.60(6H,m,--(CH.sub.2).sub.3 --),3.19 
(2H,ABq,J.dbd.18 Hz,2--CH.sub.2),4.37(1H,br,&gt;CH--), 5.11(1H,d,J.dbd.5 
Hz,C.sub.6 --H),5.23(2H,ABq,J.dbd.14 Hz, 3--CH.sub.2),5.64(1H,d,J.dbd.5 
Hz,C.sub.7 --H),7.30 -9.10(10H, m,C.sub.6 H.sub.5 --and Pyridine)ppm 
EXAMPLE 18 
To 1.73 g of 
7.beta.-(D-5-carboxy-5-phenoxycarbonylaminovaleramido)-3-hydroxymethyl-3-c 
ephem-4-carboxylic acid were added 2 ml of formamide, 3 ml of acetonitrile 
and 0.85 g of isonicotinic acid amide. The mixture was stirred for 5 
minutes and there was added 1.1 ml of trimethyl phosphite, followed by 
stirring at 20 to 25.degree. C. for two hours. To the resultant mixture 
was added 1 ml of water and it was left standing for 10 minutes. To the 
reaction solution was added 10 ml of acetonitrile, which was subjected to 
a silica gel chromatography (using 60 g of silica gel), eluting with a 
mixture of water and acetonitrile (1:4,v/v). Fractions containing the end 
product were combined, whose pH was adjusted to 6.5 with 1N NaOH, followed 
by concentration under educed pressure and freeze-drying to give sodium 
7.beta.-(D-5-carboxylate-5-phenoxycarbonylaminovaleramido)-3-(4-carbamoyl- 
1-pyridinio) methyl-3-cephem-4-carboxylate. 
IR(KBr): 3400,1770,1725,1690,1610 cm.sup.-1 
NMR(D.sub.2 O): .delta.1.5.about.2.6(6H,m,--(CH.sub.2).sub.3 
--),3.35(2H,ABq,J.dbd.17 
Hz,2--CH.sub.2),4.02(1H,br,&gt;CH-),5.17(1H,d,J.dbd.5 Hz,C.sub.6 
--H),5.47(2H,ABq, 3--CH.sub.2),5.66(1H,d,J.dbd.5 Hz,C.sub.7 
--H),7.0-7.6(5H,m,C.sub.6 H.sub.5 --),8.32 and 9.11(4H,respectively 
d.J.dbd.8 Hz, pyridine)ppm 
EXAMPLE 19 
To a solution of 1.22 g of 1-(2-dimethylethyl)-5-mercapto-1H-tetrazole 
hydrochloride in a mixture of 5 ml of formamide and 4 ml of acetonitrile 
was added 1.93 g of triethyl phosphite, to which was added a solution of 
2.47 g of 
7.beta.-(D-5-carboxy-5-phenoxycarbonylaminovaleramido)-3-hydroxymethyl-3-c 
ephem-4-carboxylic acid in a mixture of 5 ml of formamide and 5 ml of 
acetonitrile. The whole mixture was stirred for 10 minutes and there was 
added 2 ml of water, followed by standing for 10 minutes. The resultant 
mixture was concentrated under reduced pressure to distill off 
acetonitrile. The residual solution was poured into 200 ml of cold water, 
and precipitates then formed were collected by filtration and washed with 
water, followed by dissolving in a mixture of acetonitrile and water 
(4:1,v/v). The solution was subjected to a column chromatography using 50 
g of silica gel, eluting with a mixture of acetonitrile and water 
(4:1,v/v). Fractions containing the end product were combined, 
concentrated under educed pressure and freeze-drying to give 
7.beta.-(D-5-carboxy-5-phenoxycarbonylaminovaleramido)-3-[1-(2 
-dimethylaminoethyl)-1H-tetrazol-5-yl]-thiomethyl-3-cephem-4-carboxylic 
acid. 
IR(KBr): 3300,1760,1725,1600,1530 cm.sup.-1 
NMR(D.sub.2 O--NaHCO.sub.3): .delta.1.81(4H,br,--CH.sub.2 CH.sub.2 --), 
2.40(2H,br,CH.sub.2 CO),2.63(6H,s,N(CH.sub.3).sub.2),3.31(2H, t,J.dbd.6 
Hz,CH.sub.2 N),3.56(2H,ABq,J.dbd.18 Hz,2--CH.sub.2), 
4.20(2H,br,3--CH.sub.2),5.07(1H,d,J.dbd.5 Hz,C.sub.6 --H), 
5.57(1H,d,J.dbd.5 Hz,C.sub.7 --H),7.0-7.6(5H,m,C.sub.6 H.sub.5 --) ppm 
EXAMPLE 20 
To 1.52 g of 
7.beta.-(D-5-benzyloxycarbonylamino-5-carboxyvaleramido)-3-hydroxymethyl-3 
-cephem-4-carboxylic acid was added 0.79 g of 
5-mercapto-2-methyl-1,3,4-thiadiazole dissolved in 2 ml of formamide and 8 
ml of acetonitrile. To the mixture was added 1.25 g of trimethyl 
phosphite, which was stirred at 20 to 25.degree. C. for 3 hours. To the 
reaction solution was added 15 ml of water, which was stirred for 10 
minutes, from which acetonitrile was distilled off under reduced pressure. 
To the residue was added 10 ml of tetrahydrofuran, whose pH was adjusted 
to 2.6 with 2N HCl, followed by addition of 15 ml methylene chloride to 
cause the mixture to form two layers. The aqueous layer was subjected to 
extraction twice more with a mixture of 6 ml of tetra hydrofuran and 9 ml 
of methylene chloride. The extracts were combined with the organic layer, 
which was washed with aqueous saline, dried over anhydrous magnesium 
sulfate, followed by concentration under reduced pressure. The concentrate 
was dissolved in a small volume of acetone, and the solution was poured 
into ether. Resulting precipitates were collected by filtration, washed 
with ether, followed by drying under reduced pressure to give 1.55 g 
(yield: 83%) of 
7.beta.-(D-5-benzyloxycarbonylamino-5-carboxyvaleramido)-3-(2-methyl-1,3,4 
-thiadiazol-5yl) thiomethyl-3-cephem-4-carboxylic acid. 
IR(KBr): 3280,2940,1775,1715,1530 cm.sup.-1 
NMR(DMSO--d.sub.6): .DELTA.1.65(4H,br,--CH.sub.2 CH.sub.2 
--),2.17(2H,br,CH.sub.2 CO),2.68(2H,s,CH.sub.3),3.63(2H,br,2--CH.sub.2), 
4.36(2H,ABq,J.dbd.14 Hz,3--(CH.sub.2),5.00(3H,br,CH.sub.2 OCO & C.sub.6 
--H & &gt;CH--),5.62(1H,br,C.sub.7 --H),7.33(6H,m, C.sub.6 H.sub.5 .sup.- & 
CONH),8.80(1H,br,CONH)ppm 
EXAMPLE 21 
To 1.34 g of 
7.beta.-(D-5-carboxy-5-ethoxycarbonylaminovaleramido)-3-hydroxymethyl-3-ce 
phem-4-carboxylic acid were added in sequence a solution of 0.70 g of 
5-mercapto-1-methyl-1H-tetrazole in a mixture of 2 ml of formamide and 8 
ml of acetonitrile then 1.25 g of triethyl phosphite, followed by stirring 
at 20 to 25.degree. C. for 3hours. The reaction solution was subjected to 
after-treatment in the same manner as in Example 20 to give 1.39 g (yield: 
85%) of 
7.beta.-(D-5-carboxy-5-ethoxycarbonylaminovaleramido)-3-(1-methyl-1H-tetra 
zol-5yl) thiomethyl-3-cephem-4-carboxylic acid. 
IR(KBr): 3350,2960,1777,1710,1530 cm .sup.-1 
NMR(DMSO--d.sub.6): .delta.1.16(3H,t,J.dbd.7 Hz,CH.sub.2 CH.sub.3), 
1.61(4H,br,--(CH.sub.2).sub.2 --),2.18(2H,br,Ch.sub.2 
CO),3.67(2H,br,2--CH.sub.2),3.93(3H,s,N--CH.sub.3),3.96(2H,q,J.dbd.7 
Hz,CH.sub.2 CH.sub.3),4.29(2H,br,3--CH.sub.2),5.04(1H,d,J.dbd.5Hz,C.sub.6 
--H),5.63(1H,q,J.dbd.8.times.5 Hz,C.sub.7 --H),7.26(1H,d, J.dbd.8 
Hz,OCONH),8.76(1H,d,J.dbd.8 Hz,CONH)ppm 
EXAMPLE 22 
In 4 ml of ethyl acetate were dissolved 418 mg of 
7.beta.-(D-5-diphenylmethyloxycarbonyl-5-phthalimidovaleramido)-3-hydroxym 
ethyl-3-cephem-4-carboxylic acid diphenyl methyl ester and 116 mg of 
5-mercapto-1-methyl-1H-tetrazole. To the solution was added 166 mg of 
triethyl phosphite, which was stirred at 20 to 25.degree. C. for one hour. 
To the reaction solution was added 1 ml of n-hexane. The mixture was 
subjected to a silica gel chromatography, eluting with a mixture of ethyl 
acetate and n-hexane (4:1,v/v). Fractions containing the end product were 
combined and concentrated under reduced pressure. To the concentrate was 
added ether, then precipitating powdery product was collected by 
filtration, followed by drying under reduced pressure to give 
diphenylmethyl 
7.beta.-(D-5-diphenylmethyloxycarbonyl-5-phthalimidovaleramido)-3-(1-methy 
l-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate. 
IR(KBr): 3350,3030,2930,1775,1715 cm.sup.-1 
NMR(DMSO--d.sub.6): .delta.1.30-2.40(6H,m,--(CH.sub.2).sub.3 --), 
3.68(2H,br,2--CH.sub.2),3.88(3H,s,N--CH.sub.3),4.24(2H, 
br,3--CH.sub.2),4.90-5.20(2H,m,C.sub.6 --H &gt;CH-),5.73(1H,q,J.dbd.5.times.8 
Hz),6.83 & 6.90(2H,s,--COOCH&lt;.times.2), 7.10-7.60(20H,m,C.sub.6 H.sub.5 
--.times.4),7.91(4H,s,C.sub.6 H.sub.4 &lt;), 8.87(1H,d,J.dbd.8 
Hz,--CONH--)ppm 
EXAMPLE 23 
To 477 mg of 
7.beta.-(D-5-benzamido-5-carboxyvaleramido)-3-hydroxymethyl-3-cephem-4-car 
boxylic acid and 114 mg of thiourea were added 1 ml of formamide and 3 ml 
of acetonitrile to make a solution, to which was added 248 mg of trimethyl 
phosphite. The mixture was stirred at 20 to 25.degree. C. for two hours. 
To the reaction mixture was added 50 ml of acetonitrile, then 
precipitating crystals were collected by filtration, washed with 
acetonitrile and dried to give 466 mg (yield: 87%) of 
7.beta.-(D-5-benzamido-5-carboxyvaleramido)-3-carbamimidoylthiomethyl-3-ce 
phem-4-carboxylic acid. 
IR(KBr): 3270,3050,1765,1645,1600,1580, 1535 cm.sup.-1 
NMR(D.sub.2 O--NaHCO.sub.3): .delta.1.5-2.6(6H,m, --(CH.sub.2).sub.3 
--),3.45(2H,s,2--CH.sub.2),3.6-4.6(3H,m,3--CH.sub.2 & 
&gt;CH--),5.07(1H,d,J.dbd.5 Hz,C.sub.6 --H),5.56(1H,d, J.dbd.5 Hz,C.sub.7 
--H),7.4-8.2(5H,m,C.sub.6 H.sub.5 --)ppm 
EXAMPLE 24 
To 582 mg of 
7.beta.-[2-(2-thienyl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic 
acid and 174 mg of 5-mercapto-1-methyl-1H-tetrazole was added 12 ml of 
ethyl acetate to make a solution. To the solution were added in sequence 
0.25 ml of trimethyl phosphite and 0.2 ml of ether solution of hydrogen 
chloride (5mol/l), and the mixture was stirred at 20 to 25.degree. C. for 
3hours. To the reaction solution was added 10 ml of water, whose pH was 
adjusted to 2 with 2N HCl, which was then allowed to form two layers. The 
aqueous layer was taken, to which was added 10 ml of ethyl acetate. The 
mixture was allowed to form two layers. The organic layers were combined 
and washed with 5 ml of aqueous saline, which was dried over anhydrous 
magnesium sulfate, which was then concentrated under reduced pressure. To 
the concentrate was added ether, then precipitating powdery product was 
collected by filtration, washed and dried to give 804 mg (yield: 89%) of 
3-(1-methyl-1H-tetrazol-5-yl) 
thiomethyl-7.beta.-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid. 
R(KBr): 1776,1734,1672 cm .sup.-1 
NMR(DMSO--d.sub.6): .delta.3.67(2H,ABq,J.dbd.18 Hz,2--CH.sub.2), 
3.73(2H,s,CH.sub.2 CO),3.92(3H,s,N--CH.sub.3),4.29(2H, ABq,J.dbd.13 
Hz,3--CH.sub.2),5.05(1H,d,J.dbd.5 Hz,C.sub.6 --H), 
5.66(1H,q,J.dbd.5.times.8 Hz,C.sub.7 --H),6.90 & 7.29(3H,Thienyl 
9.10(1H,d,J.dbd.8 Hz,CONH)ppm 
EXAMPLE 25 
Using 450 mg of triethylamine salt of 
7.beta.-(2-phenyl-acetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid, 
reaction and after-treatment were conducted in the same manner as in 
Example 24 to give 385 mg (yield: 86%) of 
3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7.beta.-(2-phenylacetamido)-3-ceph 
em-4-carboxylic acid. 
IR(KBr): 1780,1720,1668 cm.sup.-1 
NMR(DMSO--d.sub.6 --D.sub.2 O): .delta.3.56(2H,s,CH.sub.2 CO),3.69 
(2H,br,2--CH.sub.2),3.95(3H,s,N--CH.sub.3),4.27(2H,br, 
3-CH.sub.2),5.03(1H,d,J.dbd.4.5 Hz,C.sub.6 --H),5.63(1H,d,J.dbd.4.5 
Hz,C.sub.7 --H),7.30(5H,s,C.sub.6 H.sub.5 --)ppm 
EXAMPLE 26 
In a mixture of 4 ml of formamide and 4 ml of acetonitrole was suspended 
423 mg of sodium 
7.beta.-[2-(2-aminothiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carb 
oxylate.dihydrate. To the suspension were added in sequence 315 mg of 
1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole hydrochloride, 0.45 ml of 
trimethyl phosphite and 0.20 ml of ether solution of hydrogen chloride (5 
mol./l). The mixture was stirred at 20.about.25.degree. C. for 1.5 hour, 
and there was added 5 ml of water, followed by concentration under reduced 
pressure at 20 to 25.degree. C. To the concentrated solution was added 50 
ml of water, whose pH was adjusted to 5.8 with 1N NaOH, followed by 
subjecting the resultant to an Amberlite XAD-2 column chromatography, 
eluting with a mixture of water and acetone (4:1,v/v). Fractions 
containing the end product were combined, concentrated under reduced 
pressure and then freeze-dried to give 7.beta.-[ 2-(2-aminothiazol-4-yl) 
acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephe 
m-4-carboxylic acid. 
IR(KBr): 3320,1765,1670,1610 cm.sup.-1 
NMR(D.sub.2 O): 
.delta.3.30(6H,s,--N(CH.sub.3).sub.2),3.3.about.4.0(6H,M,CH.sub.2 CO & 
2--CH.sub.2 & --CH.sub.2 N&lt;),4.21(2H,br,3--CH.sub.2), 4.88(2H,t,J.dbd.6 
Hz,N--CH.sub.2),5.10(1H,d,J.dbd.5 Hz,C.sub.6 --H),5.63(1H,d,J.dbd.5 
Hz,C.sub.7 --H),6.50(1H,s,Thiazole)ppm 
EXAMPLE 27 
In 2 ml of acetonitrile was suspended 103 mg of 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-hydroxymet 
hyl-3-cephem-4 -carboxylic acid. To the suspension were added in sequence 
0.10 ml of pyridine, 0.21 ml of triethyl phosphite and 0.2 ml of acetic 
acid. The mixture was stirred at 20 to 25.degree. C. for 8 hours, followed 
by concentration under reduced pressure. To the concentrated solution was 
added 10 ml of tetrahydrofuran, then precipitating powdery product was 
collected by filtration, followed by concentration under reduced pressure 
to give 7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-(1 
-pyridinio)methyl-3-cephem-4-carboxylate. 
IR(KBr): 3350,1771,1660,1620 cm.sup.-1 
NMR(D.sub.2 O): .delta.3.18 & 3.65(2H,ABq,J.dbd.18 Hz, 
2--CH.sub.2),3.94(3H,s,OCH.sub.3),5.23(1H,d,J.dbd.5 Hz,C.sub.6 --H) ,5.30 
& 5.56(2H,ABq,J.dbd.15 Hz,3--CH.sub.2),5.80(1H,d, J.dbd.5 Hz,C.sub.7 
--H),6.19(1H,s,Thiazole),7.9.about.8.2 & 8.4-9.0(2H & 3H,m.Pyridine)ppm 
EXAMPLE 28 
In 2 ml of acetonitrile was suspended 103 mg of 
7.beta.-[20(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-hydroxymeth 
yl-3-cephem-4 -carboxylic acid. To the suspension were added in sequence 
0.15 ml of 2,3-cyclopentenopyridine, 0.21 ml of triethyl phosphite and 0.2 
ml of acetic acid. The mixture was stirred at 20 to 25.degree. C. for 5.5 
hours, and there was added further 0.1 ml of acetic acid. The stirring was 
conducted for further one hour, which was concentrated under reduced 
pressure. To the concentrated solution was added 10 ml of tetrahydrofuran, 
then resulting powdery product was collected by filtration, followed by 
drying under reduced pressure to give 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-(2,3-cyclo 
penteno-1 -pyridinio)-methyl-3-cephem-4-carboxylate. 
IR(KBr): 3350,1765,1665,1615 cm.sup.-1 
NMR(D.sub.2 O--NAHCO.sub.3): .delta.2.0.about.2.5(2H,m,--CH.sub.2 CH.sub.2 
CH.sub.2 --),3.0-3.5(4H,m,--CH.sub.2 CH.sub.2 CH.sub.2 --),3.16 & 3.46(2 
H,ABq,J.dbd.18 Hz,2--CH.sub.2),3.94(3H,s,OCH.sub.3),5.20(1H, d,J.dbd.5 
Hz,C.sub.6 --H),5.23 & 5.47(2H,ABq,J.dbd.17 Hz, 
3--CH.sub.2),5.79(1H,d,J.dbd.5 Hz,C.sub.7 --H),6.84(1H,s,Thiazole), 
7.5-7.8 & 8.05-8.55(1H & 2H,m,Pyridine)ppm 
EXAMPLE 29 
In 4 ml of acetonitrile was suspended 207 mg of 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-hydroxymet 
hyl-3-cephem-4 -carboxylic acid. To the suspension were added in sequence 
343 mg of methyl nicotinate, 0.43 ml of triethyl phosphite and 0.4 ml of 
acetic acid. The mixture was stirred at 20 to 25.degree. C. for 7 hours, 
and concentrated under reduced pressure. To the concentrated solution was 
added 10 ml of tetrahyudrofuran, then precipitating powdery product was 
collected by filtration, followed by drying under reduced pressure to give 
218 mg (yield: 82%) of 
7.beta.-[2-(2-aminothizol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-(3-methoxyc 
arbonyl-1 -pyridinio)methyl-3-cephem-4-carboxylate. 
IR(KBr): 3375,1770,1735,1665,1620 cm.sup.-1 
NMR(D.sub.2 O--NaHCO.sub.3): .delta.3.18 & 3.17(2H,ABq,J.dbd.18 
Hz,2--CH.sub.2),3.94(3H,s,NOCH.sub.3),4.01(3H,s, 
COOCH.sub.3),5.26(1H,d,J.dbd.5 Hz,C.sub.6 --H),5.34 & 5.69(2H, 
ABq,J.dbd.15 Hz,3--CH.sub.2),5.78(1H,d,J.dbd.5 Hz,C.sub.7 --H), 
6.81(1H,s,Thiazole),8.0-8.3 & 8.8-9.25(1H & 
2H,m,Pyridine),9.55(1H,br,Pyridine)ppm 
EXAMPLE 30 
In 4 ml of acetonitrile was suspended 207 mg of 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-hydroxymet 
hyl-3-cephem-4 -carboxylic acid. To the suspension were added in sequence 
0.25 ml of .alpha.-picoline, 0.43 ml of triethyl phosphite and 0.4 ml of 
acetic acid. The mixture was stirred at 20 to 25.degree. C. for 7 hours, 
and concentrated under reduced pressure. To the concentrated solution was 
added 10 ml of tetrahydrofuran, then precipitating powdery product was 
collected by filtration and dried under reduced pressure to give 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-(2-methyl- 
1-pyridinio) methyl-3-cephem-4-carboxylate. 
IR(KBr): 3350,1770,1660,1620 cm.sup.-1 
NMR(D.sub.2 O--NaHCO.sub.3): .delta.2.81(3H,s,CH.sub.3),3.17 & 
3.50(2H,ABq,J.dbd.18 Hz,2--CH.sub.2),3.95(3H,s,OCH.sub.3), 
5.22(1H,d,J.dbd.5 Hz,C.sub.6 --H),5.28 & 5.53(2H,ABq,J.dbd.17 
Hz,3--CH.sub.2),5.81(1H,d,J.dbd.5 Hz,C.sub.7 --H),6.90(1H,s, 
Thiazole),7.6-7.95 & 8.15-8.45 & 8.55-8.75(2H & 1H & 1H,m,Pyridine)ppm 
EXAMPLE 31 
In 1 ml of formamide were dissolved 207 mg of 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-hydroxymet 
hyl-3-cephem-4 -carboxylic acid and 183 mg of isonicotinic acid amide. To 
the solution were added in sequence 2 ml of acetonitrile, 0.43 ml of 
triethyl phosphite and 0.2 ml of acetic acid. The mixture was stirred at 
20 to 25.degree. C. for 3 hours, and was concentrated under educed 
pressure. The concentrated solution was gradually added dropwise to 50 ml 
of tetrahydrofuran, then precipitating powdery product was collected by 
filtration, followed by drying under reduced pressure to give 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-(4-carbamo 
yl-1-pyridinio) methyl-3-cephem-4-carboxylate. 
IR(KBr): 3250,3150,1765,1680,1615 cm .sup.-1 
NMR(D.sub.2 O--NaHCO.sub.3): .delta.3.21 & 3.70(2H,ABq,J.dbd.18 
Hz,2--CH.sub.2),3.95(3H,s,OCH.sub.3),5.26(1H,d,J.dbd.5 Hz, C.sub.6 
--H),5.37 & 5.67(2H,ABq,J.dbd.15 Hz,3--CH.sub.2),5.80(1H,d,J.dbd.5 
Hz,C.sub.7 --H),6.87(1H,s,Thiazole),8.31 & 9.08(respectively 2H,d,j.dbd.7 
Hz,Pyridine)ppm 
EXAMPLE 32 
In 1 ml of formamide were dissolved 413 mg of 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-hydroxymet 
hyl-3-cephem-4 -carboxylic acid and 0.36 g of imidazo[1,2-a] pyridine. To 
the solution were added in sequence 2 ml of acetonitrile, 0.86 ml of 
triethyl phosphite and 0.8 ml of acetic acid. The mixture was stirred at 
20 to 25.degree. C. for 14 hours, and concentrated under reduced pressure. 
The concentrated solution was gradually added dropwise to 70 ml of 
tetrahydrofuran, then precipitating powdery product was collected by 
filtration. The powdery product was dissolved in 20 ml of water, which was 
subjected to an Amberlite XAD-2 column chromatography, eluting with a 
mixture of water and acetonitrile (9:1,v/v). Fractions containing the end 
product were combined, concentrated under reduced pressure and 
freeze-dried to give 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-(imidazo[1 
,2 -a]pyridinium-1-yl)-methyl-3-cephem-4-carboxylate. 
IR(KBr): 3375,1765,1610 cm.sup.-1 
NMR(DMSO--d.sub.6): .delta.2.97 & 3.44(2H,ABq,J.dbd.17 Hz, 
2--CH.sub.2),3.77(3H,s,OCH.sub.3),4.97(1H,d,J.dbd.5 Hz, C.sub.6 --H),5.22 
& 5.35(2H,ABq,J.dbd.14 Hz,3--CH.sub.2),5.58(1H,dd,J.dbd.5.times.8 
Hz,C.sub.7 --H),6.65(1H,s,Thiazole). 7.13(2H,br,NH.sub.2),7.35-7.6 & 
7.8-8.1 & 8.25-8.7 & 8.8-8.95(1H & 1H & 3H & 1H,m,Imidazopyridine), 
9.41(1H,d,J.dbd.8 Hz,CONH)ppm 
EXAMPLE 33 
In 1 ml of formamide were dissolved 413 mg of 
7.beta.-[2-(2-aminothiazole-4-yl)-2-(Z)-methoxyiminoacetamido]-3-hydroxyme 
thyl-3-cephem-4 -carboxylic acid and 354 mg of imidazo[1.5-a]pyridine. To 
the solution were added 1 ml of acetonitrile and 0.86 ml of triethyl 
phosphite, and the mixture was stirred at 20 to 25.degree. C. for 10 
hours. The resultant product was treated by the manner of Example 32 to 
give 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-(imidazo 
[1,5-a]pyridinium-2-yl)methyl-3-cephem-4-carboxylate. 
IR(KBr): 3375,1765,1655,1610 cm.sup.-1 
NMR(DMSO--d.sub.6): .delta.3.13 & 3.45(2H,ABq,J.dbd.18 Hz, 
2--CH.sub.2),3.77(3H,s,OCH.sub.3),5.00(1H,d,J.dbd.5 Hz,C.sub.6 --H), 5.04 
& 5.51(2H,ABq,J.dbd.15 Hz,3--CH.sub.2),5.59(1H,dd, J.dbd.5.times.8 
Hz,C.sub.7 --H),6.66(1H,s,Thiazole),7.13(2H,br,NH.sub.2),6.9-7.4 & 7.7-7.9 
& 8.4-8.7(2H & 1H & 1H,m) & 8.47 .varies. 10.03(respectively 1H,br. 
Imidazopyridine),9.37(1H,d,J.dbd.8 Hz,CONH)ppm 
EXAMPLE 34 
In 1 ml of formamide were dissolved 413 mg of 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-hydroxymet 
hyl-3-cephem-4 -carboxylic acid and 357 mg of imidazo[1.2-b]pyridazine. To 
the solution were added 1 ml of formamide and 0.86 ml of triethyl 
phosphite. The mixture was stirred at 20 to 25.degree. C. for 5 hours, and 
treated in the manner of Example 32 to give 
7.beta.-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-(imidazo[1 
,2 -b]-pyridazinium-1-yl)methyl-3-cephem-4-carboxylate. 
IR(KBr): 3375,1765,1665,1610 cm.sup.-1 
NMR(DMSO--d.sub.6): .delta.3.30 & 3.48(2H,ABq,J.dbd.18 Hz, 
2--CH.sub.2),3.77(3H,s,OCH.sub.3),4.98(1H,d,J.dbd.5 Hz, C.sub.6 --H),5.25 
& 5.51(2H,ABq,J.dbd.14 Hz,3--CH.sub.2),5.59(1H,dd,J.dbd.5.times.8 
Hz,C.sub.7 --H),6.65(1H,s,Thiazole 
7.13(2H,br,NH.sub.2),7.90(1H,dd,J.dbd.4.times.9 Hz) & 8.37(2H,br) & 
8.99(1H,d,J.dbd.4 Hz) & 9.27(1H,d,J.dbd.9 Hz, Imidazopyridazine 
8.42(1H,d,J.dbd.8 Hz, CONH)ppm