Novel penicillins and cephalosporins and non-toxic salts thereof, which contain a mono- or di-oxo- or thioxo-piperazino(thio)carbonylamino group in molecule. These compounds are valuable antibacterial compounds for use in mammals including man. This disclosure relates to such compounds and a process for the preparation thereof.

Procedures for producing the compounds of the present invention are shown 
below with reference to examples. 
EXAMPLE 1 
(1) To a mixture comprising 2.5 g of 1-acetyl-3-oxo-piperazine, 3.45 g of 
triethylamine and 20 ml of anhydrous dioxane was added a solution of 3.71 
g of trimethylchlorosilane in 10 ml of anhydrous dioxane. The resulting 
mixture was refluxed for 17 hours and cooled to deposit triethylamine 
hydrochloride, which was then removed by filtration. The filtrate was 
dropped at -40.degree. to -30.degree. C. into a solution of 1.8 g of 
phosgene in 30 ml of anhydrous methylene chloride. After the dropping, the 
resulting mixture was elevated in temperature, and reacted at room 
temperature for 30 minutes. Subsequently, the excess phosgene and the 
solvent were removed by distillation under reduced pressure to obtain 3.5 
g of pale brown, oily 4-acetyl-2-oxo-1-piperazinocarbonyl chloride. 
IR (film) cm.sup.-1 : .nu..sub.C=0 1790, 1710, 1640. 
(2) A suspension of 1.0 g of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid in 20 ml of 
tetrahydrofuran containing 20% by volume of water was adjusted to a pH of 
8.0 to 8.5 by gradual addition of triethylamine with stirring, and then 
cooled to 0.degree. C. Into the thus treated suspension was dropped a 
solution of 900 mg of the aforesaid 4-acetyl-2-oxo-piperazinocarbonyl 
chloride in 5 ml of tetrahydrofuran at said temperature over a period of 
30 minutes. During this period, the pH of the suspension was maintained at 
7.5 to 8.0 by gradual addition of triethylamine. Subsequently, the 
temperature of resulting mixture was elevated to 5.degree. to 10.degree. 
C., and the mixture was reacted at said temperature for 1 hour while 
maintaining the pH thereof at 7.5 to 8.0 addition of triethylamine. After 
the reaction, the tetrahydrofuran was removed by reduced pressure 
distillation, and the residue was dissolved in a mixed solvent comprising 
30 ml of ethyl acetate and 10 ml of water. The resulting solution was 
adjusted to a pH of 1.5 to 2 by addition of dilute hydrochloric acid with 
ice-cooling, and then the organic layer was separated off. The aqueous 
layer was re-extracted with 20 ml of ethyl acetate, and the resulting 
organic layer was combined with the aforesaid organic layer. The combined 
organic layer was washed with water, dried over anhydrous magnesium 
sulfate, and then ice-cooled. Into this organic layer was dropped a 
solution of 470 mg of a sodium salt of 2-ethylhexonic acid in 20 ml of 
ethyl acetate to deposit white crystals. The deposited crystals were 
collected by filtration, washed with ethyl acetate and then dried to 
obtain 1.4 g of a sodium salt of 
6-[D(-)-.alpha.-(4-acetyl-2-oxo-1-piperazinocarbonylamino)phenylacetamido] 
penicillanic acid, m.p. 205.degree. C. (decomp.), yield 94%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1760 (lactam), 1600-1700 
(--COO.sup..crclbar., --CON&lt;). 
NMR: [(CD.sub.3).sub.2 SO+D.sub.2 O].tau. values: 2.73 (5H), 4.35 (1H), 
4.75 (2H), 5.75 (1H), 5.84 (2H), 6.42 (4H), 8.03 (3H), 8.52 (3H), 8.64 
(3H). 
The above-mentioned operation was repeated, except that the 
4-acetyl-2-oxo-1-piperazinocarbonyl chloride was replaced by each of the 
reactive derivatives of compounds of formula (III) shown in Table 8, to 
obtain the respective objective compounds as shown in Table 8. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 8 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
##STR276## 
##STR277## 
##STR278## 
##STR279## 
##STR280## 
##STR281## 
##STR282## 
##STR283## 
##STR284## 
##STR285## 
##STR286## 
##STR287## 
##STR288## 
##STR289## 
##STR290## 
##STR291## 
##STR292## 
##STR293## 
##STR294## 
##STR295## 
__________________________________________________________________________ 
EXAMPLE 2 
(1) Into a solution of 1.74 g of a sodium salt of 
D(-)-.alpha.-aminophenylacetic acid in 30 ml of tetrahydrofuran containing 
20% by volume of water which had been cooled to 0.degree. C., a solution 
of 2.5 g of 4-acetyl-2-oxo-1-piperazinocarbonyl chloride in 5 ml of 
tetrahydrofuran was dropped at said temperature over a period of 30 
minutes. During this period, the pH of the reaction solution was 
maintained at 11.0 to12.0 by gradual addition of a 10% aqueous sodium 
hydroxide solution. Subsequently, the temperature of the resulting mixed 
solution was elevated to 5.degree. to 10.degree. C., and the solution was 
reacted at room temperature for 2 hours while maintaining the pH thereof 
at 10.0 to 11.0 by addition of a 10% aqueous sodium hydroxide solution. 
After the reaction, the tetrahydrofuran was removed by reduced pressure 
distillation. The residue was dissolved in a mixed solvent comprising 20 
ml of water and 50 ml of ethyl acetate, and the resulting solution was 
adjusted to a pH of 1.0 to 1.5 by addition of dilute hydrochloric acid 
with ice-cooling. Subsequently, the organic layer was separated off, 
washed with water and then dried over anhydrous magnesium sulfate. To this 
organic layer, a solution of 1.66 g of a sodium salt of 2-ethylhexonic 
acid in 20 ml of ethyl acetate was added to deposit white crystals. The 
deposited crystals were collected by filtration, sufficiently washed with 
ethyl acetate and then dried to obtain 1.89 g of a sodium salt of 
D(-)-.alpha.-(4-acetyl-2-oxo-1-piperazinocarbonylamino)phenylacetic acid, 
m.p. 115.degree. C. (decomp.), yield 52%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=0 1690, 1650-1600. 
(2) To a suspension in 15 ml of anhydrous acetone of 833 mg of the 
above-mentioned sodium salt of 
D(-)-.alpha.-(4-acetyl-2-oxo-1-piperazinocarbonylamino)phenylacetic acid 
was added 10 mg of N-methylmorpholine. The resulting mixture was cooled to 
-20.degree. to -15.degree. C. and a solution of 286 mg of ethyl 
chlorocarbonate in 5 ml of anhydrous acetone was dropped into said mixture 
over a period of 5 minutes. Subsequently, the mixture was stirred at said 
temperature for 60 minutes. Into the thus treated mixture, a solution of 
646 mg of a triethylamine salt of 6-aminopenicillanic acid in 30 ml of 
anhydrous methylene chloride was dropped at -40.degree. to -30.degree. C. 
over a period of 10 minutes. Thereafter, the mixture was reacted with 
stirring at -30.degree. to -20.degree. C. for 60 minutes, at -20.degree. 
to 10.degree. C. for 30 minutes, and at -10.degree. to 0.degree. C. for 30 
minutes. After the reaction, the organic solvent was removed by reduced 
pressure distillation. The residue was dissolved in a mixed solvent 
comprising 50 ml of ethyl acetate and 20 ml of water, and the resulting 
solution was adjusted to a pH of 1.5 to 2.0 by addition of dilute 
hydrochloric acid with ice-cooling. Subsequently, the organic layer was 
separated off, sufficiently washed with water and then dried over 
anhydrous magnesium sulfate, and the ethyl acetate was removed by reduced 
pressure distillation. The residue was dissolved in 50 ml of acetone, and 
the resulting solution was mixed with a solution of 340 mg of a sodium 
salt of 2-ethylhexonic acid in 20 ml of acetone with ice-cooling to 
deposit white crystals. The deposited crystals were collected by 
filtration, sufficiently washed with acetone and then dried to obtain 1.16 
g of a sodium salt of 
6-[D(-)-.alpha.-(4-acetyl-2-oxo-1-piperazinocarbonylamino)phenylacetamido] 
penicillanic acid, m.p. 205.degree. C. (decomp.), yield 94%. 
EXAMPLE 3 
(1) To a mixture comprising 1.0 g of 1 -palmitoyl-3-oxo-piperazine, 0.6 g 
of triethylamine and 20 ml of anhydrous dioxane was added a solution of 
0.65 g of trimethylchlorosilane in 10 ml of anhydrous dioxane. The 
resulting mixture was refluxed for 16 hours and cooled to deposit 
triethylamine hydrochloride, which was then removed by filtration. The 
filtrate was dropped at -40.degree. to -30.degree. C. into a solution of 
0.6 g of phosgene in 30 ml of anhydrous methylene chloride. After the 
dropping, the temperature of the resulting mixture was elevated and the 
mixture was reacted at room temperature for 30 minutes. Subsequently, the 
excess phosgene and the solvent were removed by reduced pressure 
distillation to obtain 1.1 g of pale yellow, oily 
4-palmitoyl-2-oxo-1-piperazinocarbonyl chloride. 
IR (film) cm.sup.-1 : .nu..sub.C=0 1740, 1660, 1640. 
(2) A suspension of 1.0 g of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid in 20 ml of 
tetrahydrofuran containing 20% by volume of water was adjusted to a pH of 
8.0 to 8.5 by gradual addition of triethylamine with stirring, and then 
cooled to 0.degree. C. Into the thus treated suspension, a solution of 
1.27 g of the aforesaid palmitoyl-2-oxo-1-piperazinocarbonyl chloride in 5 
ml of tetrahydrofuran was dropped at said temperature over a period of 30 
minutes. During this period, the pH of the suspension was maintained at 
7.5 to 8.0 by gradual addition of treithylamine. Subsequently, the 
temperature of the resulting mixture was elevated to 5.degree. to 
10.degree. C., and the mixture was reacted at said temperature for 1 hour 
while maintaining the pH thereof at 7.5 to 8.0 by addition of 
triethylamine. After the reaction, the tetrahydrofuran was removed by 
reduced pressure distillation, and the residue was dissolved in a mixed 
solvent comprising 30 ml of ethyl acetate and 10 ml of water. The 
resulting solution was adjusted to a pH of 1.0 to 2.0 by addition of 
dilute hydrocloric acid with ice-cooling, and then the organic layer was 
separated off. The aqueous layer was re-extracted with 20 ml of ethyl 
acetate, and the resulting organic layer was combined with the aforesaid 
organic layer. The combined organic layer was washed with water, and dried 
over anhydrous magnesium sulfate. This organic layer was concentrated 
under reduced pressure to remove the solvent, and the concentrate was 
charged into 10 ml of diisopropyl ether to deposit crystals. Thereafter, 
the crystals were collected by filtration to obtain 1.65 g of white 
crystals of 
6-[D(-)-.alpha.-(4-palmitoyl-2-oxo-1-piperazinocarbonylamino)phenylacetami 
do]penicillanic acid, m.p. 121.degree.-123.degree. C. (decomp.), yield 80%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=0 1770 (lactam), 1730 (--COOH), 1660-1630 
(--CON&lt;). 
The above-mentioned operation was repeated, except that the 
4-palmitoyl-2-oxo-1-piperazinocarbonyl chloride was replaced by each of 
the reactive derivatives of compounds of formula (III) shown in Table 9, 
to obtain respective objective compounds as shown in Table 9. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 9 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
##STR296## 
##STR297## 
##STR298## 
##STR299## 
##STR300## 
##STR301## 
##STR302## 
##STR303## 
##STR304## 
##STR305## 
##STR306## 
##STR307## 
##STR308## 
##STR309## 
##STR310## 
##STR311## 
##STR312## 
##STR313## 
##STR314## 
##STR315## 
##STR316## 
##STR317## 
__________________________________________________________________________ 
EXAMPLE 4 
(1) To a solution of 6.4 g of 1-formyl-3-oxo-piperazine in 10 ml of 
anhydrous dimethylformamide was added 2.7 g of a sodium hydride (purity 
53%) with ice-cooling, and the resulting mixture was reacted at room 
temperature for 1 hour. Subsequently, the mixture was incorporated with 
7.1 g of methyl iodide and reacted for 10 hours. After the reaction, the 
dimethylformamide was removed by reduced pressure distillation to obtain 
1-formyl-4-methyl-3-oxo-piperazine. This piperazine was dissolved in 70 ml 
of a 50% aqueous actone solution containing 2.2 g of sodium hydroxide, and 
the resulting solution was reacted at room temperature for 3 hours. 
Thereafter, the solvent was removed by distillation under reduced 
pressure, and the residue was charged into acetone to deposit insolubles. 
The insolubles were separated by filtration, and the acetone was removed 
from the filtrate the distillation under reduced pressure. Subsequently, 
the residue was subjected to reduced pressure distillation to obtain 5.2 g 
of 1-methyl-2-oxo-piperazine, b.p. 104.degree. C./4 mmHg, yield 91%. 
(2) Into a solution of 1.9 g of phosgene in 20 ml of anhydrous dioxane was 
dropped at 10.degree. C. 20 ml of an anhydrous dioxane solution containing 
2.0 g of 1-methyl-2-oxo-piperazine and 1.95 g of triethylamine, upon which 
reaction took place to deposit white crystals of triathylamine 
hydrochloride. The deposited crystals were removed by filtration, and the 
filtrate was concentrated to dryness to obtain 3.0 g of pale yellow, oily 
4-methyl-3-oxo-1-piperazinocarbonyl chloride. 
IR (film) cm.sup.-1 : .nu..sub.C=0 1710, 1630. 
(3) A suspension of 4.0 g of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid in40 ml of 
tetrahydrofurna containing 20% by volume of water was adjusted to a pH of 
8.0 to 8.5 by gradual addition of triethylamine with stirring, and then 
cooled to 0.degree. C. Into the thus treated suspension, 10 ml of a 
tetrahydrofuran solution containing 2.2 g of the aforesaid 
4-methyl-3-oxo-1-piperazinocarbonyl chloride was dropped. During this 
period, the pH of the suspension was maintained at 7.5 to 8.5 by gradual 
addition of triethylamine. Subsequently, the resulting mixture was reacted 
at said temperature for 30 minutes, and the temperature thereof was 
elevated at 10.degree. to 15.degree. C., after which the mixture was 
further reacted at said temperature for 90 minutes while maintaining the 
pH thereof at 7.5 to 8.0 by addition of triethylamine. After the reaction, 
the tetrahydrofuran was removed by distillation under reduced pressure, 
and the residue was dissolved in 30 ml of water. The resulting solution 
was washed with ethyl acetate, and then the aqueous layer was separated 
off. This aqueous layer was ice-cooled and then adjusted to a pH of 1.5 by 
addition of dilute hydrochloric acid to deposit white crystals. The 
deposited crystals were collected by filtration, washed several times with 
a small amount of water, dried, and then dissolved in 100 ml of acetone. 
To the resulting solution was added 1.9 g of a sodium salt of 
2-ethylhexonic acid with ice-cooling to deposit white crystals, which were 
then collected by filtration to obtain 5.4 g of a sodium salt of 
6-[D(-)-.alpha.-(4-methyl-3-oxo-1-piperazinocarbonylamino)phenylacetamido] 
penicillanic acid, m.p. 195.degree. C. (decomp.), yield 92%. 
IR (KBr) cm.sup.-1 :.nu..sub.C=0 1760 (lactam), 1600-1660 
(--CON&lt;,--COO.crclbar.). 
NMR [(CD.sub.3).sub.2 SO+D.sub.2 O] .tau. values: 2.62 (5H), 4.48 (1H), 
4.56 (2H), 5.97 (3H), 6.63-6.39 (4H), 7.13 (3H), 8.46 (3H), 8.55 (3H). 
The above-mentioned operation was repeated, except that the 
4-methyl-3-oxo-1-piperazinocarbonyl chlordie was replaced by each of the 
reactive derivatives of compounds of formula (III) shown in Table 10, to 
obtain respective objective compounds as shown in Table 10. The structure 
of each objective compound was confirmed by IR and NMR. 
TABLE 10 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
##STR318## 
##STR319## 
##STR320## 
##STR321## 
##STR322## 
##STR323## 
##STR324## 
##STR325## 
##STR326## 
##STR327## 
##STR328## 
##STR329## 
##STR330## 
##STR331## 
##STR332## 
##STR333## 
##STR334## 
##STR335## 
##STR336## 
##STR337## 
##STR338## 
##STR339## 
##STR340## 
##STR341## 
##STR342## 
##STR343## 
##STR344## 
##STR345## 
##STR346## 
##STR347## 
##STR348## 
##STR349## 
##STR350## 
##STR351## 
__________________________________________________________________________ 
EXAMPLE 5 
(1) A solution of 1.0 g of a sodium salt of D(-)-.alpha.-aminophenyl acetic 
acid in 20 ml of tetrahydrofuran containing 20% by volume of water was 
cooled to 0.degree. to 5.degree. C. To this solution was added 1.2 g of 
2-methyl-3-oxo-1-piperazinocarbonyl chloride over a period of 10 minutes. 
During this period, the pH of the solution was maintained at 11.0 to 12.0 
by gradual addition of a 10% aqueous sodium hydroxide solution. The 
solution was reacted at said temperature for 1 hour, and the temperature 
thereof was elevated to 5.degree. to 10.degree. C., after which the 
mixture was further reacted at said temperature for 2 hours, while 
maintaining the pH thereof at 10.0 to 11.0 by addition of a 10% aqueous 
sodium hydroxide solution. After the reaction, tetrahydrofuran was removed 
by distillation under reduced pressure, and the residue was dissolved in a 
mixed solvent comprising 20 ml of water and 50 ml of ethyl acetate. The 
resulting solution was adjusted to a pH of 1.5 by addition of dilute 
hydrochloric acid with ice-cooling, and then the organic layer was 
separated off. The aqueous layer was further extracted with 50 ml of ethyl 
acetate, and the resulting organic layer was combined with the aforesaid 
organic layer. The combined organic layer was washed with water and then 
dried over anhydrous magnesium sulfate. To this organic layer was added 
0.9 g of a sodium salt of 2-ethylhexonic acid to deposit white crystals. 
The deposited crystals were collected by filtration and then dried to 
obtain 1.26 g of white crystals of a sodium salt of 
D(-)-.alpha.-(2-methyl-3-oxo-1-piperazinocarbonylamino)phenylacetic acid, 
m.p. 215.degree. C. (decomp.), yield 70%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1650-1590. 
(2) To a suspension in 15 ml of anhydrous acetone of 1.0 g of the 
above-mentioned sodium salt of 
D(-)-.alpha.-(2-methyl-3-oxo-1-piperazinocarbonylamino)-phenylacetic acid 
was added 10 mg of N-methylmorpholine. The resulting mixture was cooled to 
-20.degree. to -15.degree. C., and a solution of 380 mg of ethyl 
chlorocarbonate in 5 ml of anhydrous acetone was dropped into said mixture 
over a period of 5 minutes. Subsequently, the mixture was stirred at said 
temperature for 60 minutes, and then cooled to -40.degree. to -30.degree. 
C. Into the thus treated mixture was dropped a solution of 960 mg of a 
triethylamine salt of 6-aminopenicillanic acid in 10 ml of anhydrous 
methylene chloride over a period of 10 minutes. Thereafter, the mixture 
was reacted with stirring at -30.degree. to -20.degree. C. for 60 minutes, 
at -20.degree. to -10.degree. C. for 30 minutes, and at -10.degree. to 
-0.degree. C. for 30 minutes. After the reaction, the organic solvent was 
removed by distillation under reduced pressure. The residue was dissolved 
in a mixed solvent comprising 20 ml of water and 50 ml of ethyl acetate, 
and the resulting solution was adjusted to a pH of 1.5 by addition of 
dilute hydrochloric acid with ice-cooling. Subsequently, the organic layer 
was separated off, sufficiently washed with water and then dried over 
anhydrous magnesium sulfate. To this organic layer was added 0.5 g of a 
sodium salt of 2-ethylhexonic acid with ice-cooling to deposit white 
crystals. The deposited crystals were collected by filtration, and then 
dried to obtain 1.39 g of a sodium salt of 
6-[D(-)-.alpha.-(2-methyl-3-oxo-1-piperazinocarbonylamino)-phenylacetamido 
]penicillanic acid, m.p. 208.degree. C. (decomp.), yield 90%. 
In the same manner as above, 2.0 g of a sodium salt of 
6-[D(-)-.alpha.-(4-ethyl-3-oxo-1-piperazinocarbonylamino)propionamido]peni 
cillanic acid, m.p. 195.degree. C. (decomp.), yield 86%, was obtained from 
1.59 g of a sodium salt of 
D(-)-.alpha.-(4-ethyl-3-oxo-1piperazinocarbonylamino)propionic acid and 
1.59 g of a triethylamine salt of 6-aminopenicillanic acid. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1760 (lactam), 1680-1600 (--CON&lt;, 
--COO.sup..crclbar.). 
EXAMPLE 6 
(1) Into a solution of 0.5 g of phosgene in 10 ml of anhydrous dioxane was 
dropped at 10.degree. C. 10 ml of anhydrous dioxane containing 0.56 g of 
1-allyl-2-oxo-piperazine and 0.5 g of triethylamine, upon which reaction 
took place to deposit white crystals of triethylamine hydrochloride. 
Subsequently, the deposited crystals were collected by filtration, and the 
filtrate was concentrated to dryness to obtain 800 mg of pale yellow, oily 
4-allyl-3-oxo-1-piperazinocarbonyl chloride. 
IR (film) cm.sup.-1 : .nu..sub.C=O 1720, 1640. 
(2) A suspension of 1.4 g of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid in tetrahydrofuran 
containing 20% by volume of water was adjusted to a pH of 8.0 to 8.5 by 
gradual addition of triethylamine with stirring, and then cooled to 
0.degree. C. Into the thus treated suspension was dropped 10 ml of a 
tetrahydrofuran solution containing 800 mg of the aforesaid 
4-allyl-3-oxo-1-piperazinocarbonyl chloride. During this period, the pH of 
the suspension was maintained at 7.5 to 8.5 by gradual addition of 
triethylamine. Subsequently, the resulting mixture was reacted at said 
temperature for 30 minutes, and the temperature thereof was then elevated 
to 10.degree. to 15.degree. C., after which the mixture was further 
reacted at said temperature for 90 minutes while maintaining the pH 
thereof at 7.5 to 8.0 by addition of triethylamine. After the reaction, 
the tetrahydrofuran was removed by distillation under reduced pressure, 
and the residue was dissolved in 20 ml of water. The resulting solution 
was washed with ethyl acetate, and the aqueous layer was then separated 
off. This aqueous layer was ice-cooled and adjusted to a pH of 1.5 by 
addition of dilute hydrochloric acid to deposit white crystals. The 
deposited crystals were collected by filtration, sufficiently washed with 
water and then dried to obtain 1.8 g of 
6-[D(-)-.alpha.-(4-allyl-3-oxo-1-piperazinocarbonylamino)phenylacetamido]p 
enicillanic acid, m.p. 92.degree. C. (decomp.), yield 90%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1760 (lactum), 1720-1620 (--COOH, 
--CON&lt;). 
The above-mentioned operation was repeated, except that the 
4-allyl-3-oxo-1-piperazinocarbonyl chloride was replaced by each of the 
reactive derivatives of compounds of formula (III) shown in Table 11, to 
obtain respective objective compounds as shown in Table 11. The structure 
of each objective compound was confirmed by IR and NMR. 
TABLE 11 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
##STR352## 
##STR353## 
##STR354## 
##STR355## 
##STR356## 
##STR357## 
##STR358## 
##STR359## 
##STR360## 
##STR361## 
##STR362## 
##STR363## 
##STR364## 
##STR365## 
##STR366## 
##STR367## 
##STR368## 
##STR369## 
##STR370## 
##STR371## 
__________________________________________________________________________ 
EXAMPLE 7 
Using 0.63 g of 6-[D(-)-.alpha.-aminophenylacetamido]pencillanic acid and 
600 mg of a hydrochloride of 
4-(N-morpholinomethyl)-3-oxo-1-piperazinocarbonyl chloride, the same 
operation as in Example 6 was repeated to obtain 0.63 g of 
6-{D(-)-.alpha.-[4-(N-morpholinomethyl)-3-oxo-1-piperazinocarbonylamino]-p 
henylacetamido}penicillanic acid, m.p. 85.degree. C. (decomp.), yield 60%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O : 1770 (lactam), 1600-1680 
(--COO.sup..crclbar., --CON&lt;). 
EXAMPLE 8 
Using 5.0 g of a hydrochloride of pivaloyloxymethyl ester of 
6-[D(-)-.alpha.-aminophenylacetamido]-penicillanic acid and 1.94 g of 
2-methyl-3-oxo-1-piperazinocarbonyl chloride, the same operation as in 
Example 6 was repeated to obtain 5.2 g of a pivaloyloxymethyl ester of 
6-[D(-)-.alpha.-(2-methyl-3-oxo-1-piperazinocarbonylamino)phenylacetamido] 
-penicillanic acid, m.p. 140.degree. C. (decomp.), yield 80%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1740-1770 (lactam, ester) 1630-1670 
(--CON&lt;). 
EXAMPLE 9 
(1) Into a mixture comprising 8.0 g of 4-acetyl-2,5-dioxo-piperazine, 5.0 g 
of triethylamine and 100 ml of anhydrous tetrahydrofuran was dropped 6.0 g 
of trimethylchlorosilane with stirring at room temperature. After the 
dropping, the resulting mixture was reacted at said temperature for 2 
hours to deposit triethylamine hydrochloride. The deposited hydrochloride 
was separated by filtration, and the filtrate was dropped at 0.degree. to 
5.degree. C. into 100 ml of an anhydrous tetrahydrofuran solution 
containing 10.0 g of phosgene. After completion of the dropping, the 
resulting mixture was stirred at 10.degree. to 15.degree. C. for 3 hours 
to terminate the reaction. Subsequently, the tetrahydrofuran and the 
excess phosgene were removed by distillation under reduced pressure to 
obtain 11.0 g of oily 4-acetyl-2,5-dioxo-1-piperazinocarbonyl chloride. 
(2) A suspension of 17.5 g of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid in 200 ml of 
tetrahydrofuran containing 20% by volume of water was adjusted to a pH of 
8.0 to 8.5 by gradual addition of triethylamine with stirring at 
10.degree. to 15.degree. C. to form a homogeneous solution. Into this 
solution was dropped a solution of 11.0 g of the aforesaid 
4-acetyl-2,5-dioxo-1-piperazinocarbonyl chloride in 30 ml of 
tetrahydrofuran at 0.degree. C. over a period of 30 minutes. During this 
period, the pH of the reaction solution was maintained at 7.5 to 8.0 by 
gradual addition of triethylamine. Subsequently, the temperature of the 
resulting mixed solution was elevated to 5.degree. to 10.degree. C. and 
the solution was further reacted for 1 hour while maintaining the pH 
thereof at 7.5 to 8.0 by addition of triethylamine. After completion of 
the reaction, the tetrahydrofuran was removed by distillation under 
reduced pressure. To the residue was added 100 cc of N hydrochloric acid 
at 0.degree. to 10.degree. C., and the resulting mixture was stirred for 
30 minutes to deposit white crystals. The deposited crystals were 
collected by filtration, and again suspended in water. The resulting 
aqueous suspension was adjusted to a pH of 8.0 by gradual addition of 
triethylamine at 5.degree. to 10.degree. C., and then freed from 
insolubles by filtration. The filtrate was adjusted to a pH of 1.5 by 
gradual addition of N hydrochloric acid to deposit crystals. The deposited 
crystals were collected by filtration, washed with water and then dried to 
obtain 21.2 g of 
6-[D(-)-.alpha.-(4-acetyl-2,5-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]penicillanic acid, m.p. 162.degree.-164.degree. C. (decomp.), yield 
80%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1770 (lactam), 1730-1660 (--COOH, 
--CON&lt;). 
NMR ((CD.sub.3).sub.2 CO).tau. values: 0.23 (1H), 2.65 (5H), 4.26 (1H), 
4.33-4.63 (2H), 5.38 (4H), 5.68 (1H), 7.55 (3H), 8.47 (3H), 8.53 (3H). 
The above-mentioned operation was repeated, except that the 
4-acetyl-2,5-dioxo-1-piperazinocarbonyl chloride was replaced by each of 
the reactive derivatives of compounds of formula (III) shown in Table 12, 
to obtain respective objective compounds as shown in Table 12. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 12 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
D(-)- 
##STR372## 
##STR373## 
m.p. (decomp.) 88.degree. C., yield 60% 
D(-)- 
##STR374## 
##STR375## 
m.p. (decomp.) 179-181.degree. C., yield 83% 
D(-)- 
##STR376## 
##STR377## 
m.p. (decomp.) 88.degree. C., yield 82% 
D(-)- 
##STR378## 
##STR379## 
m.p. 214-215.degree. C., yield 89.6% 
D(-)- 
##STR380## 
##STR381## 
m.p. (decomp.) 176-181.degree. C., yield 84.4% 
D(-)- 
##STR382## 
##STR383## 
m.p. (decomp.) 148-151.degree. C., yield 92% 
D(-)- 
##STR384## 
##STR385## 
m.p. (decomp.) 95-100.degree. C., yield 91% 
D(-)- 
##STR386## 
##STR387## 
m.p. (decomp.) 120-125.degree. C., yield 92% 
D(-)- 
##STR388## 
##STR389## 
m.p. (decomp.) 147-149.degree. C., yield 
__________________________________________________________________________ 
89% 
EXAMPLE 10 
(1) A suspension of 8.0 g of D(-)-.alpha.-aminophenyl acetic acid in 80 ml 
of tetrahydrofuran was adjusted to a pH of 11.5 by gradual addition of a N 
sodium hydroxide solution with stirring to form a homogeneous solution. 
This solution was cooled to 0.degree. C., and 15 ml of a tetrahydrofuran 
solution containing 11 g of 4-acetyl-2,5-dioxo-1-piperazinocarbonyl 
chloride was dropped at said temperature into said solution over a period 
of 30 minutes. During this period, the pH of the reaction solution was 
maintained at 10.5 to 11.0 by gradual addition of a N sodium hydroxide 
solution. Subsequently, the temperature of the resulting mixed solution 
was elevated to 5.degree. to 10.degree. C., and the mixture was further 
reacted for 1 hour, upon which D(-)-.alpha.-aminophenylacetic acid 
deposited. After completion of the reaction, the deposited acid was 
separated by filtration, and the filtrate was concentrated under reduced 
pressure to remove tetrahydrofuran. The residue was dissolved in a mixed 
solvent comprising 10 ml of water and 80 ml of ethyl acetate, and the 
resulting solution was adjusted to a pH of 1.0 by addition of dilute 
hydrochloric acid with ice-cooling. Subsequently, the organic layer was 
separated off, dried over anhydrous magnesium sulfate, and then charged 
into 100 ml of an ethyl acetate solution containing 8.3 g of sodium 
2-ethylhexonate to deposit crystals. The deposited crystals were collected 
by filtration, washed with acetone, and then dried over P.sub.2 O.sub.5 to 
obtain 7.9 g of a sodium salt of 
D(-)-.alpha.-(4-acetyl-2,5-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid, m.p. 104.degree. C. (decomp.), yield 42%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1690-1650, 1600-1590. 
(2) To a suspension in 25 ml of anhydrous acetone of 1.75 g of the 
aforesaid sodium salt of 
D(-)-.alpha.-(4-acetyl-2,5-dioxo-1-piperazinocarbonylamino)phenyl acetic 
acid was added 20 mg of N-methylmorpholine, and the resulting mixture was 
cooled to -20.degree. to -15.degree. C. Into this mixture was dropped a 
solution of 0.57 g of ethyl chlorocarbonate in 5 ml of anhydrous acetone 
over a period of 5 minutes, and the mixture was stirred at said 
temperature for 60 minutes. Subsequently, a solution of 1.29 g of a 
triethylamine salt of 6-aminopenicillanic acid in 30 ml of anhydrous 
methylene chloride was dropped into said mixture at -40.degree. to 
-30.degree. C. over a period of 10 minutes. The temperature of the 
resulting mixture was elevated from -30.degree. C. to 0.degree. C., and 
the mixture was then reacted at said temperature for about 2 hours. After 
the reaction, the solvent was removed by distillation under reduced 
pressure. The residue was charged into 30 ml of water, and the resulting 
mixture was freed from insolubles by filtration with ice-cooling. The 
filtrate was adjustable to a pH of 1.5 to 2.0 by addition of dilute 
hydrochloric acid to deposit crystals. The deposited crystals were 
collected by filtration, sufficiently washed with water, and then dried to 
obtain 2.34 g of 
6-[D(-)-.alpha.-(4-acetyl-2,5-dioxo-piperazinocarbonylamino)phenylacetamid 
o]penicillanic acid, m.p. 162.degree.-164.degree. C. (decomp.), yield 90%. 
In the same manner as above, 530 mg of 
6-[D(-)-.alpha.-(4-benzyl-2,2-pentamethylene-3,5-dioxo-1-piperazinocarbony 
lamino)phenylacetamido]penicillanic acid, m.p. 95.degree.-100.degree. C., 
yield 82.68%, was obtained from 450 mg of 
D(-)-.alpha.-(4-benzyl-2,2-pentamethylene-3,5-dioxo-1-piperazinocarbonylam 
ino)phenylacetic acid and 320 mg of a triethylamine salt of 
6-aminopenicillanic acid. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1770 (lactam), 1700-1660 (--COOH, 
--CON&lt;). 
EXAMPLE 11 
(1) Into a mixture comprising 8 g of a diethyl ester of oxalic acid and 8 
ml of ethanol was dropped at room temperature 4.4 g of N-ethyl 
ethylenediamine. The resulting mixture was allowed to react for 3 hours, 
and then heated to remove the ethanol. Subsequently, the residue was 
recrystallized from 10 ml of dioxane to obtain 5.4 g of 
1-ethyl-2,3-dioxo-piperazine, m.p. 124.degree. C., yield 76.0%. 
(2) To a suspension of 0.71 g of the above-mentioned 
1-ethyl-2,3-dioxo-piperazine in 15 ml of anhydrous dioxane were added with 
stirring 0.70 g of trimethylsilyl chloride and 0.83 ml of triethylamine. 
The resulting mixture was stirred at room temperature for 20 hours to 
deposit triethylamine hydrochloride. This hydrochloride was separated by 
filtration, and the filtrate was dropped at 5.degree. to 10.degree. C. 
into a solution of 0.70 g of phosgene in 10 ml of anhydrous 
tetrahydrofuran. Subsequently, the resulting mixture was reacted at 
5.degree. to 10.degree. C. for 30 minutes and at room temperature for 2 
hours, and then the solvent was removed by distillation under reduced 
pressure to obtain 1.0 g of pale yellow crystals of 
4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1780, 1660. 
(3) A suspension of 1.75 g of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid in 50 ml of 
tetrahydrofuran containing 20% by volume of water was adjusted to a pH of 
8.0 to 8.5 by addition of triethylamine with stirring to form a solution. 
This solution was cooled to 0.degree. to 5.degree. C., and then 7 ml of an 
anhydrous tetrahydrofuran solution containing 1.0 g of the aforesaid 
4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was dropped into the 
solution. During this period, the pH of the reaction solution was 
maintained at 7.5 to 8.0 by gradual addition of triethylamine. The 
resulting mixed solution was reacted at said temperature for 30 minutes 
and then at 5.degree. to 10.degree. C. for 1 hour, while maintaining the 
pH thereof at 7.5 to 8.0. After the reaction, the tetrahydrofuran was 
removed by distillation under reduced pressure, and the residue was 
dissolved in 20 ml of water and then washed two times with 20 ml of ethyl 
acetate. To the aqueous layer was again added 50 ml of ethyl acetate, and 
the resulting mixture was adjusted to a pH of 1.5 by gradual addition of 
dilute hydrochloric acid with ice-cooling. Subsequently, the ethyl acetate 
layer was separated off, sufficiently washed with water, and then dried 
over anhydrous magnesium sulfate. Into the thus treated layer was dropped 
10 ml of an ethyl acetate solution containing 0.83 g of sodium 
2-ethylhexonate to deposit white crystals. The deposited crystals were 
collected by filtration, sufficiently washed with ethyl acetate, washed 
with diethyl ether, and then dried to obtain 2.4 g of a sodium salt of 
6-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]penicillanic acid, m.p. 183.degree.-185.degree. C. (decomp.), yield 89%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1765 (lactam), 1720-1670 (--CON&lt;), 1600 
(--COO.sup..crclbar.). 
NMR ((CD.sub.3).sub.2 SO+D.sub.2 O) .tau. values: 2.62 (5H), 4.31 (1H), 
4.50 (1H), 4.70 (1H), 6.05 (1H), 6.35-6.65 (6H), 8.49 (3H), 8.60 (3H), 
8.91 (3H). 
The above-mentioned operation was repeated, except that the 
4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by each of 
the reactive derivatives of compounds of formula (III) shown in Table 13, 
to obtain respective objective compounds as shown in Table 13. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 13 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
##STR390## 
##STR391## 
##STR392## 
##STR393## 
##STR394## 
##STR395## 
##STR396## 
##STR397## 
##STR398## 
##STR399## 
##STR400## 
##STR401## 
##STR402## 
##STR403## 
##STR404## 
##STR405## 
##STR406## 
##STR407## 
##STR408## 
##STR409## 
__________________________________________________________________________ 
EXAMPLE 12 
A suspension of 1.4 g of 6-[D(-)-.alpha.-aminophenylacetamido]penicillanic 
acid in 30 ml of tetrahydrofuran containing 20% by volume of water was 
adjusted to a pH of 8.0 to 8.5 by addition of triethylamine with stirring 
to form a solution. This solution was cooled to 0.degree. to 5.degree. C., 
and 10 ml of a tetrahydrofuran solution containing 1.2 g of 
4-n-pentyl-2,3-dioxo-1-piperazinocarbonyl chloride was dropped into said 
solution. During this period, the pH of the reaction solution was 
maintained at 7.5 to 8.5 by gradual addition of triethylamine. 
Subsequently, the resulting mixed solution was reacted at said temperature 
for 30 minutes and then at 10.degree. to 15.degree. C. for 90 minutes, 
while maintaining the pH thereof at 7.5 to 8.5. After the reaction, the 
tetrahydrofuran was removed by distillation under reduced pressure, and 
the residue was dissolved in 20 ml of water and then washed two times with 
20 ml of ethyl acetate. To the aqueous layer was further added 30 ml of 
ethyl acetate, and the resulting mixture was adjusted to a pH of 1.5 by 
addition of dilute hydrochloric acid with ice-cooling. Thereafter, the 
ethyl acetate layer was separated off, sufficiently washed with water, 
dried over magnesium sulfate, and then freed from the solvent by 
distillation under reduced pressure. The residue was crystallized by 
addition of diisopropyl ester to obtain 1.8 g of crystals of 
6-[D(-)-.alpha.-(4-n-pentyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacet 
amido]penicillanic acid, m.p. 96.degree. C. (decomp.), yield 80.5%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1770 (lactam), 1720-1660 (--CON&lt;, 
--COOH). 
NMR ((CD.sub.3).sub.2 SO+D.sub.2 O).tau. values: 2.62 (5H), 4.31 (1H), 
4.51-4.69 (2H), 6.04 (1H), 6.20-6.90 (6H), 8.50 (3H). 8.60 (3H), 8.75 
(6H), 8.90 (3H). 
The above-mentioned operation was repeated, except that the 
4-n-pentyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by each of 
the reactive derivatives of compounds of formula (III) shown in Table 14, 
to obtain respective objective compounds as shown in Table 14. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 14 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
D(-)- 
##STR410## 
##STR411## 
m.p. (decomp.) 107.degree. C., yield 89% 
D(-)- 
##STR412## 
##STR413## 
m.p. (decomp.) 92.degree. C., yield 88.5% 
D(-)- 
##STR414## 
##STR415## 
m.p. (decomp.) 95.degree. C., yield 79.8% 
D(-)- 
##STR416## 
##STR417## 
m.p. (decomp.) 80-82.degree. C., yield 
__________________________________________________________________________ 
95% 
EXAMPLE 13 
Using 1.7 g of a triethylamine salt of 
6-[D(-)-.alpha.-amino-p-hydroxyphenylacetamido]penicillanic acid and 0.7 g 
of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, the same operation as 
in Example 12 was repeated to obtain 1.2 g of a sodium salt of 
6-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyph 
enylacetamido]penicillanic acid, m.p. 170.degree.-172.degree. C. (decomp.), 
yield 75%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1760 (lactam), 1710-1660 (--CON&lt;), 1600 
(--COO.crclbar.). 
NMR ((CD.sub.3).sub.2 SO) .tau.values: 2.8-3.3 (4H), 4.45 (1H), 4.65 (2H), 
6.05 (1H), 6.2 (4H), 6.97 (3H), 8.48 (3H), 8.60 (3H). 
In the same manner as above, a sodium salt of 
6-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphe 
nylacetamido]penicillanic acid, m.p. 175.degree. C. (decomp.), yield 72%, 
was obtained from 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride and a 
triethylamine salt of 
6-[D(-)-.alpha.-amino-p-hydroxyphenylacetamido]penicillanic acid. 
EAMPLE 14 
To a solution of 0.8 g of a phthalide ester of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid in 10 ml of 
tetrahydrofuran was added 0.25 ml of triethylamine. Into the resulting 
mixture was dropped 0.32 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl 
chloride with ice-cooling, and the mixture was reacted at room temperature 
for 2 hours. After the reaction, the solvent was removed by distillation 
under reduced pressure. The residue was dissolved in a mixed solvent 
comprising 20 ml of ethyl acetate and 20 ml of water, and the resulting 
solution was adjusted to a pH of 2 by addition of dilute hydrochloric 
acid. Subsequently, the organic layer was separated off, washed with 
water, washed with a 2% aqueous sodium hydrogencarbonate solution, washed 
with water, dried over magnesium sulfate, and then concentrated to a 
liquid amount of about 2 ml. To the concentrate was added 20 ml of 
diisopropyl ether to deposit crystals, which were then collected to obtain 
0.95 g of crystals of a phthalide ester of 
6-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]penicillanic acid, m.p. 157.degree.-160.degree. C. (decomp.), yield 
90.0%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1780 (lactam), 1715 (ester), 1680 
(--CON&lt;). 
NMR (CD.sub.3l ).sub.2 CO+D.sub.2 O) .tau.values: 2.12 (4H), 2.40 (1H), 
2.58 (5H), 4.25-4.60 (3H), 5.45 (1H), 5.85-6.42 (4H), 6.90 (3H), 8.50 
(6H). 
The above-mentioned operation was repeated, except that the 
4-methyl-2,3dioxo-1-piperazinocarbonyl chloride was replaced by each of 
the reactive derivatives of compounds of formula (III) shown in Table 15, 
to obtain respective objective compounds as shown in Table 15. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 15 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
##STR418## 
##STR419## 
##STR420## 
##STR421## 
##STR422## 
##STR423## 
A solution of 0.86 g of a hydrochloride of methoxymethyl ester of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid in 15 ml of 
tetrahydrofuran containing 20% by volume of water was adjusted to a pH of 
8.0 to 8.5 by addition of triethylamine at 0.degree. to 5.degree. C. Into 
this solution, a solution of 0.38 g of 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride in 10 ml of 
tetrahydrofuran was dropped over a period of 10 minutes. During this 
period, the pH of the reaction solution was maintained at 7.5 to 8.0 by 
gradual addition of triethylamine. The resulting mixed solution was 
reacted for 30 minutes, while maintaining the pH thereof at 7.5 to 8.0. 
After completion of the reaction, the tetrahydrofuran was removed by 
distillation under reduced pressure. The residue was dissolved in a mixed 
solvent comprising 50 ml of water and 50 ml of ethyl acetate, and the 
resulting solution was adjusted to a pH of 1.5 by addition of dilute 
hydrochloric acid with ice-cooling. Subsequently, the organic layer was 
separated off, washed with water, dried over anhydrous magnesium sulfate, 
and then freed from the solvent by distillation under reduced pressure to 
form crystals. The thus formed crystals were washed with diethyl ether to 
obtain 0.9 g of a methoxymethyl ester of 
6-[D(-)-.alpha.-(4methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]penicillanic acid, m.p. 111.degree.-115.degree. C. (decomp.), yield 
82.5%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1780 (lactam), 1740 (ester), 1700-1660 
(--CON&lt;). 
NMR ((CD.sub.3).sub.2 CO) .tau. values: 0.15 (1H), 2.0 (1H), 2.67 (5H), 
4.3-4.5 (3H), 4.75 (2H), 5.7 (1H), 6.55 (4H), 6.97 (3H), 7.25 (3H), 8.84 
(3H), 8.60 (3H). 
The above-mentioned operation was repeated, except that the 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by each of 
the reactive derivatives of compounds of formula (III) shown in Table 16, 
to obtain respective objective compounds as shown in Table 16. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 16 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
D(-)- 
##STR424## 
##STR425## 
m.p. (decomp.) 83-85.degree. C., yield 80.2% 
D(-)- 
##STR426## 
##STR427## 
m.p. (decomp.) 78-80.degree. C., yield 80% 
D(-)- 
##STR428## 
##STR429## 
m.p. (decomp.) 93-95.degree. C., yield 82.5% 
D(-)- 
##STR430## 
##STR431## 
m.p. (decomp.) 70-74.degree. C., yield 
__________________________________________________________________________ 
74.4% 
EXAMPLE 16 
Using 1.5 g of a hydrochloride of pivaloyloxymethyl ester of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid and 0.6 g of 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, the same operation as in 
Example 15 was repeated to obtain a pivaloyloxymethyl ester of 
6-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]penicillanic acid, m.p. 108.degree.-111.degree. C. (decomp.), yield 
75%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1780 (lactam), 1750 (ester), 1710-1660 
(--CON&lt;). 
The above-mentioned operation was repeated, except that the 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by each of 
the reactive derivatives of compounds of formula (III) shown in Table 17, 
to obtain respective objective compounds as shown in Table 17. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 17 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
##STR432## 
##STR433## 
##STR434## 
##STR435## 
__________________________________________________________________________ 
EXAMPLE 17 
Using 0.81 g of a hydrochloride of 62-piperidinoethyl ester of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid and 0.3 g of 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, the same operation as in 
Example 15 was repeated to obtain 0.75 g of a .beta.-piperidinoethyl ester 
of 
6-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]penicillanic acid, m.p. 166.degree.-169.degree. C. (decomp.), yield 
78%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1780 (lactam), 1740 (ester), 1710-1670 
(--CON&lt;). 
NMR (CDCl.sub.3) .tau. values: 2.7 (5H), 4.3-4.6 (3H), 5.7 (1H), 5.75 (2H), 
6.0 (2H), 6.4 (2H), 6.9 (3H), 7.45 (2H), 7.6 (4H), 8.5 (12H). 
The above-mentioned operation was repeated, except that the 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by 
4-n-octyl-2,3-dioxo-1-piperazinocarbonyl chloride, to obtain a 
.beta.-piperidinoethyl ester of 
6-[D(-)-.alpha.-(4-n-octyl-2,3-dioxo-1-piperazinocarbonylamino)phenylaceta 
mido]penicillanic acid, m.p. 110.degree.-115.degree. C. (decomp.), yield 
73.58%. 
EXAMPLE 18 
Using 0.93 g of a hydrochloride of .beta.-morpholinoethyl ester of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid and 0.39 g of 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, the same operation as in 
Example 15 was repeated to obtain 0.8 g of a .beta.-morpholinoethyl ester 
of 
6-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]penicillanic acid, m.p. 150.degree.-153.degree. C. (decomp.), yield 
73%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1780 (lactam), 1740 (ester), 1710-1680 
(--CON&lt;). 
NMR (CDCl.sub.3) .tau. values: 2.55 (5H), 4.3-4.55 (3H), 5.6 (1H), 5.7 
(3H), 6.0 (2H), 6.3 (2H), 7.4 (2H), 7.5 (4H), 8.5 (6H). 
The above-mentioned operation was repeated, except that the 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by 
4-n-octyl-2,3-dioxo-1-piperazinocarbonyl chloride, to obtain a 
.beta.-morpholinoethyl ester of 
6-[D(-)-.alpha.-(4-n-octyl-2,3-dioxo-1-piperazinocarbonylamino)phenylaceta 
mido]penicillanic acid, m.p. 103.degree.-105.degree. C. (decomp.), yield 
70%. 
EXAMPLE 19 
(1) To a solution of 8.7 g of a sodium salt of D(-)-.alpha.-phenylglycine 
in 50 ml of water were added 50 ml of ethyl acetate and 5.05 g of 
triethylamine. To the resulting mixture was gradually added 9.5 g of 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride at 0.degree. to 5.degree. 
C. over a period of 15 minutes, and then the mixture was reacted at 
5.degree. to 15.degree. C. for 30 minutes. After the reaction, the aqueous 
layer was separated off, washed with diethyl ether, and then adjusted to a 
pH of 1.5 by addition of dilute hydrochloric acid to deposit crystals. The 
deposited crystals were collected by filtration, washed with water and 
dried to obtain 14.1 g of 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid, m.p. 138.degree.-141.degree. C. (decomp.), yield 87%. 
Recrystallization from hydrous butanol gave white crystals, m.p. 
140.degree.-142.degree. C. (decomp.). 
Elementary analysis (for C.sub.14 H.sub.15 N.sub.3 O.sub.5.H.sub.2 O): 
Calculated (%)--C: 52.01, H: 5.30, N: 13.00; Found (%)--C: 52.24, H: 5.32, 
N: 12.87. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1710, 1700, 1660. 
(2) Into a solution of 10 g of the above-mentioned 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid in 200 ml of acetone was dropped a solution of 5.2 g of a sodium salt 
of 2-ethylhexonic acid in 50 ml of acetone with stirring to deposit 
crystals. The deposited crystals were collected by filtration and then 
washed with acetone to obtain 9.6 g of a sodium salt of 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid, m.p. 165.degree. C. (decomp.), yield 95%. 
(3) To a suspension of 8.8 g of the above-mentioned sodium salt of 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperzinocarbonylamino) phenylacetic 
acid in 80 ml of methylene chloride was added 20 mg of N-methylmorpholine. 
Into the resulting mixture was dropped a solution of 3.1 g of ethyl 
chlorocarbonate in 20 ml of methylene chloride at -20.degree. to 
-15.degree. C. over a period of 5 minutes, and the mixture was reacted at 
said temperature for 1 hour. Into this reaction liquid was dropped a 
solution of 9.4 g of a triethylamine salt of 6-aminopenicillanic acid in 
40 ml of methylene chloride at -40.degree. to -30.degree. C. over a period 
of 10 minutes, and the resulting mixture was reacted at -40.degree. to 
-20.degree. C. over a period of 1 hour. After the reaction, the 
temperature of the reaction liquid was gradually elevated at 0.degree. C. 
over a period of 1 hour, and the mixture was then subjected to extraction 
with 100 ml of water. Subsequently, the aqueous layer was separated off, 
and the methylene chloride layer was further subjected to extraction with 
50 ml of water, and the resulting aqueous layer was combined with the 
aforesaid aqueous layer. The combined aqueous layer was adjusted to a pH 
of 2 addition of dilute hydrochloric acid with ice-cooling to deposit 
crystals. The deposited crystals were collected by filtration, 
sufficiently washed with water, dried and then dissolved in 200 ml of 
acetone. Into the resulting solution was dropped a solution of 4 g of a 
sodium salt of 2-ethylhexonic acid in 40 ml of acetone over a period of 10 
minutes to deposite crystals. The deposited crystals were collected by 
filtration, washed with acetone and then dried to obtain 11.4 g of a 
sodium salt of 
6-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]penicillanic acid, m.p. 170.degree. C. (decomp.), yield 80.8%. 
The above-mentioned operation was repeated, except that the 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid was replaced by each of the compounds of formula (V) shown in Table 
18, to obtain respective objective compounds as shown in Table 18. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 18 
__________________________________________________________________________ 
Compound of formula (V) Objective compound 
__________________________________________________________________________ 
##STR436## 
##STR437## 
##STR438## 
##STR439## 
##STR440## 
##STR441## 
__________________________________________________________________________ 
EXAMPLE 20 
(1) To a solution of 2.28 g of D(-)-.alpha.-amino-1,4-cyclohexadienylacetic 
acid in 15 ml of N NaOH were added 20 ml of ethyl acetate and 2.1 ml of 
triethylamine, and the resulting mixture was cooled to 0.degree. C. To 
this mixture was gradually added 1.69 g of 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride over a period of 10 
minutes. Subsequently, the mixture was reacted over 30 minutes with 
ice-cooling, and then the aqueous layer was separated off. To the aqueous 
layer was further added 20 ml of ethyl acetate. The resulting mixture was 
adjusted to a pH of 2 by addition of 2 N hydrochloric acid with 
ice-cooling, and the ethyl acetate layer was separated off. The organic 
layer was sufficiently washed with water, dried over anhydrous magnesium 
sulfate, freed from the solvent by distillation under reduced pressure and 
then incorporated with isopropyl alcohol to deposit crystals. The 
deposited crystals were collected by filtration to obtain 2.5 g of white 
crystals of D(-)-.alpha.-(4-methyl- 
2,3-dioxo-1-piperazinocarbonylamino)-1,4-cyclohexadienylacetic acid, m.p. 
140.degree.-145.degree. C. (decomp.), yield 74%. 
IR (KBr) cm.sup.-1 : .nu..sub.NH 3300, .nu..sub.C=O 1715, 1660. 
NMR (d.sub.6 -DMSO) .tau. values: 0.57 (1H, d), 4.26 (1H, s), 4.36 (2H, s), 
5.29 (1H, d), 6.07-6.18 (2H, m), 6.38-6.49 (2H, m), 7.05 (3H, s), 7.35 
(4H, s). 
(2) To a suspension of 0.45 g of the above-mentioned 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-1,4-cyclohexad 
ienylacetic acid in 15 ml of anhydrous methylene chloride was added 0.24 ml 
of N-methylmorpholine with stirring to form a solution. After cooling the 
solution of -10.degree. C., 3 ml of an anhydrous methylene chloride 
solution containing 0.24 g of ethyl chlorocarbonate was dropped into the 
solution, and the resulting mixture was reacted at said temperature for 90 
minutes. Subsequently, the reaction liquid was cooled to -20.degree. C., 
and 5 ml of a methylene chloride solution containing 0.70 g of a 
triethylamine salt of 6-aminopenicillanic acid and 0.31 of triethylamine 
was gradually dropped into the reaction liquid. The resulting mixture was 
reacted at -20.degree. C. for 1 hour, at -20.degree. to 0.degree. C. for 1 
hour, and at 0.degree. to 5.degree. C. for 1 hour. Thereafter, the 
reaction liquid was freed from the solvent by distillation under reduced 
pressure. The residue was dissolved in 10 ml of water and then washed with 
10 ml of ethyl acetate. The aqueous layer was again incorporated with 15 
ml of ethyl acetate, and then adjusted to a pH of 2.0 by addition of 2 N 
HCl with ice-cooling. Subsequently, the ethyl acetate layer was separated 
off, washed with water, dried over anhydrous magnesium sulfate, and freed 
from the solvent by distillation under reduced pressure to obtain 0.74 g 
of white crystals of 
6-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-1,4-cyclohe 
xadienylacetamido]penicillanic acid, m.p. 84.degree.-87.degree. C. 
(decomp.), yield 87%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1780 (lactam), 1730-1660 (--COOH, 
--CON&lt;). 
NMR (d.sub.6 -DMSO) .tau. values: 0.55 (1H, d), 0.95 (1H, d), 4.22 (1H, s), 
4.35 (2H, s), 4.41-4.61 (2H, s), 4.92 (1H, d), 5.75 (1H, s), 6.05 (2H, 
bs), 6.40 (2H, bs), 7.03 (3H, s), 7.35 (4H, s), 8.40 (3H, s), 8.52 (3H, 
s). 
The thus obtained product was adjusted to a pH of 7.0 by neutralization 
with an aqueous sodium hydrogencarbonate solution, and then subjected to 
filtration and freeze-drying to obtain a sodium salt thereof. 
The above-mentioned operation was repeated, except that the 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-1,4-cyclohexad 
ienylacetic acid was replaced by each of the compounds of formula (V) shown 
in Table 19, to obtain respective objective compounds as shown in Table 
19. The structure of each objective compound was confirmed by IR and NMR. 
TABLE 19 
__________________________________________________________________________ 
Compound of formula (V) Objective compound 
__________________________________________________________________________ 
##STR442## 
##STR443## 
##STR444## 
##STR445## 
##STR446## 
##STR447## 
__________________________________________________________________________ 
EXAMPLE 21 
(1) To a solution of 2.2 g of DL-.alpha.-amino-2-thienylacetic acid in 14 
ml of a N sodium hydroxide solution was added at 0.degree. C. 2.2 g of 
triethylamine. To the resulting mixture was further added 3.6 g of 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride little by little at said 
temperature. Subsequently, the mixture was reacted at 0.degree. C. for 30 
minutes, and then at room temperature for 30 minutes. After the reaction, 
the reaction liquid was adjusted to a pH of 1.0 by addition of dilute 
hydrochloric acid to deposit crystals. The deposited crystals were 
collected by filtration, washed with water and then dried to obtain 3.5 g 
of 
DL-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-2-thienylacetic 
acid, m.p. 214.degree.-215.degree. C. (decomp.), yield 80.5%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1710, 1680-1660. 
(2) Into a solution of 3.5 g of the above-mentioned 
DL-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-2-thienylacetic 
acid in 100 ml of acetone was dropped a solution of 1.86 g of a sodium 
salt of 2-ethylhexonic acid in 50 ml of acetone, upon which crystals were 
deposited. The deposited crystals were collected by filtration and then 
washed with acetone to obtain 3.5 g of a sodium salt of 
DL-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-2-thienylacetic 
acid, m.p. 175.degree.-176.degree. C. (decomp.). 
(3) To a suspension of 3.3 g of the above-mentioned sodium salt of 
DL-.alpha.-(4-methyl-2,3dioxo-1-piperazinocarbonylamino)-2-thienylacetic 
acid in 50 ml of methylene chloride was added 30 mg of N-methylmorpholine, 
and the resulting mixture was then cooled to -20.degree. to -15.degree. C. 
Into the resulting mixture was dropped a solution of 1.3 g of ethyl 
chlorocarbonate in 20 ml of methylene chloride over a period of 5 minutes, 
and the mixture was stirred at said temperature for 90 minutes. 
Subsequently, a solution of 3.3 g of a triethylamine salt of 
6-aminopenicillanic acid in 50 ml of methylene chloride was dropped into 
the mixture at -50.degree. to -40.degree. C. over a period of 20 minutes, 
and the resulting mixture was reacted with stirring at -40.degree. to 
-30.degree. C. for 30 minutes, at -30.degree. to -20.degree. C. for 30 
minutes, and then at -20.degree. to 0.degree. C. for 30 minutes. After the 
reaction, the solvent was removed by distillation under reduced pressure, 
and the residue was dissolved in water. The resulting aqueous solution was 
adjusted to a pH of 2.0 by addition of dilute hydrochloric acid with 
ice-cooling to deposit crystals. The deposited crystals were collected by 
filtration, sufficiently washed with water and then dried to obtain 4.1 g 
of 
6-[DL-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-2-thienylacet 
amido]penicillanic acid, m.p. 185.degree. C. (decomp.), yield 80.5%. 
IR (nujol) cm.sup.-1 : .nu..sub.C=O 1780 (lactam), 1715 (--COOH), 1685-1675 
(--CON&lt;). 
NMR ((CD.sub.3).sub.2 CO) .tau. values: 0.5 (1H), 1.8 (1H), 2.6 (1H), 
2.85-3.05 (2H), 4.0 (1H), 4.2-4.5 (2H), 5.7 (1H), 5.8-6.0 (2H), 6.2-6.4 
(2H), 6.95 (3H), 8.4 (3H), 8.45 (3H). 
The thus obtained product was adjusted to a pH of 7.0 by neutralization 
with an aqueous sodium hydrogencarbonate solution, and then subjected to 
filtration and freeze-drying to obtain a sodium salt thereof. 
The above-mentioned operation was repeated, except that the sodium salt of 
DL-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-2-thienylacetic 
acid was replaced by each of the compounds of formula (V) shown in Table 
20, to obtain respective objective compounds as shown in Table 20. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 20 
__________________________________________________________________________ 
Compound of formula (V) Objective compound 
__________________________________________________________________________ 
##STR448## 
##STR449## 
##STR450## 
##STR451## 
##STR452## 
##STR453## 
__________________________________________________________________________ 
EXAMPLE 22 
To a suspension of 0.9 g of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid in 30 ml of 
anhydrous ethyl acetate were added at 5.degree. to 10.degree. C. 0.55 g of 
triethylamine and 0.6 g of trimethylsilyl chloride. The resulting mixture 
was reacted at 15.degree. to 20.degree. C. for 3 hours to form 
trimethylsilylated 6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid. 
To this acid was then added 1 g of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl 
chloride, and the resulting mixture was reacted at 15.degree. to 
20.degree. C. for 2 hours. After the reaction, a deposited triethylamine 
hydrochloride was separated by filtration, and the filtrate was 
incorporated with 0.4 g of n-butanol to deposit crystals. The deposited 
crystals were collected by filtration to obtain 1.25 g of white crystals 
of 6-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacet 
amido]penicillanic acid. Into a solution of said crystals in 30 ml of 
tetrahydrofuran was dropped a solution of 0.38 g of a sodium salt of 
2-ethylhexonic acid in 10 ml of tetrahydrofuran, upon which white crystals 
were deposited. The deposited crystals were collected by filtration, 
sufficiently washed with tetrahydrofuran and then dried to obtain 1.25 g 
of a sodium salt of 
6-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]penicillanic acid, m.p. 183.degree.-185.degree. C. (decomp.), yield 90%. 
EXAMPLE 23 
To a suspension of 4 of a trihydrate of 
6-[D(-)-.alpha.-aminophenylacetamido]penicillanic acid in 40 ml of water 
was added 20 ml of ethyl acetate, and the resulting mixture was cooled to 
2.degree. C. Subsequently, the mixture was incorporated with 1.37 g of 
potassium carbonate, and then stirred at 2.degree. to 3.degree. C. for 2 
minutes. Thereafter, 1.89 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl 
chloride was added to the mixture at said temperature over a period of 10 
minutes, and the resulting mixture was reacted at said temperature for 15 
minutes. After the reaction, slight amounts of insolubles were separated 
by filtration, and the filtrate was charged into 80 ml of ethyl acetate. 
Into the resulting mixture was dropped 5 ml of 2 N HCl at 20.degree. to 
22.degree. C. over a period of 5 minutes, and the mixture was stirred at 
said temperature for 5 hours to deposit crystals. The deposited crystals 
were collected by filtration, washed two times with 4 ml of water, 
further washed two times with 4 ml of isopropanol, and then dried to 
obtain 4.0 g of a dihydrate of 
6-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]penicillanic acid, m.p. 156.degree.-157.degree. C. (decomp.), yield 
75.4%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1775, 1740, 1695, 1670. 
NMR (d.sub.6 -DMSO) .tau. values: 0.18 (1H, d), 0.77 (1H, d), 2.66 (5H, s), 
4.30 (1H, d), 4.40 (3H, br), 4.48 (1H, g), 4.65 (1H, d), 5.80 (1H, s), 
6.12 (2H, bs), 6.45 (2H, bs), 7.06 (3H, s), 8.48 (3H, s), 8.60 (3H, s). 
The above-mentioned operation was repeated, except that the 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by 
4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride, to obtain a monohydrate 
of 6-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacet 
amido]penicillanic acid, m.p. 154.degree.-156.degree. C. (decomp.), yield 
84.8%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1775, 1735, 1705, 1680, 1665. 
NMR (d.sub.6 -DMSO) .tau. values: 0.20 (1H, d), 0.76 (1H, d), 2.69 (5H, s), 
4.32 (1H, d), 4.53 (1H, q), 4.64 (1H, d), 5.00 (3H, br), 5.83 (1H, s), 
6.13 (2H, bs), 6.49 (2H, bs), 6.62 (2H, q), 8.44 (3H, s), 8.58 (3H, s), 
8.91 (3H, t). 
The thus obtained monohydrate was neutralized with an aqueous sodium 
hydrogencarbonate solution, and then subjected to filtration and 
freeze-drying to obtain a sodium salt of 
6-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]penicillanic acid. 
Further, a solution in 10 ml of nitromethane of 2 g of the aforesaid 
dihydrate of 
6-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]penicillanic acid was allowed to stand overnight to deposit crystals, 
which were then collected by filtration to obtain 2 g of a monohydrate of 
a nitromethane addition product of 
6-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]penicillanic acid, m.p. 128.degree.-130.degree. C. (decomp.), yield 
92.2%. 
Elementary analysis (for C.sub.22 H.sub.25 N.sub.5 O.sub.7 S.CH.sub.3 
NO.sub.2.H.sub.2 O): Calculated (%)--C: 47.42, H: 5.19, N: 14.43; Found 
(%)--C: 47.94, H; 5.13, N: 14.53. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1770, 1735, 1700, 1680. 
NMR (d.sub.6 -DMSO) .tau. values: 0.22 (1H, d), 0.80 (1H, d), 2.69 (5H, s), 
3.30 (3H, br), 4.30 (1H, d), 4.46-4.70 (2H), 5.67 (3H, s), 5.81 (1H, s), 
6.13 (2H, bs), 6.46 (2H, bs), 7.07 (3H, s), 8.45 (3H, s), 8.58 (3H, s). 
EXAMPLE 24 
To a suspension of 1.6 g of a trihydrate of D(-)-.alpha.-aminobenzyl 
penicillin in 20 ml of water was added at 2.degree. to 3.degree. C. 0.54 g 
of potassium carbonate, and the resulting mixture was stirred for 3 
minutes. To the mixture was gradually added 0.81 g of 
4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride at said temperature over a 
period of 10 minutes, and the mixture was reacted for 15 minutes. After 
the reaction, slight amounts of insolubles formed were separated by 
filtration, and the filtrate was charged into 10 ml of methyl n-propyl 
ketone. Into the resulting mixture was dropped 1.98 ml of 2 N HCl at 
15.degree. to 20.degree. C. over a period of 2 minutes, and the mixture 
was stirred at said temperature for 1 hour to deposit crystals. The 
deposited crystals were collected by filtration, washed two times with 2 
ml of water, further washed two times with 2 ml of methyl n-propyl ketone, 
and then dried to obtain 1.7 g of a monohydrate of 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)benzylpenicillin 
, m.p. 152.degree.-154.degree. C. (decomp.), yield 80.2%. 
The thus obtained product was neutralized with an aqueous sodium 
hydrogencarbonate solution, and then subjected to filtration and 
freeze-drying to obtain a sodium salt of the said product. 
EXAMPLE 25 
A suspension of 4.0 g of a monohydrate of 
7-[D(-)-.alpha.-aminophenylacetamido]-3-methyl-.DELTA..sup.3 
-cephem-4-carboxylic acid in 60 ml of tetrahydrofuran containing 20% by 
volume of water was adjusted to a pH of 8.0 to 8.5 by gradual addition of 
triethylamine with stirring to form a solution, which was then cooled to 
0.degree. C. To this solution were gradually added 2.5 g of crystals of 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride over a period of 10 
minutes. During this period, the pH of the reaction solution was 
maintained at 7.5 to 8.0 by gradual addition of triethylamine. 
Subsequently, the resulting mixture was reacted at 0.degree. to 5.degree. 
C. for 15 minutes while maintaining the pH thereof at 7.5 to 8.0. After 
the reaction, the reaction liquid was stirred together with 60 ml of 
diethyl ether and 70 ml of water, and then the aqueous layer was separated 
off. The thus obtained aqueous layer was washed with 30 ml of ethyl 
acetate, cooled to 0.degree. to 5.degree. C., and then adjusted to a pH of 
1.5 by addition of dilute hydrochloric acid to deposit white crystals. The 
deposited crystals were collected by filtration, sufficiently washed with 
water and then dried to obtain 4.7 g of white crystals of 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-methyl-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 
185.degree.-186.degree. C. (decomp.), yield 86%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1770-1760 (lactam), 1720-1660 (--CON&lt;, 
--COOH). 
NMR (d.sub.6 -DMSO) .tau. values: 0.1 (1H, d), 0.56 (1H, d), 2.62 (5H, s), 
4.26-4.37 (2H, dd), 5.05 (1H, d), 6.1 (2H, bs), 6.47 (2H, bs), 6.63 (2H, 
s), 7.05 (3H, s), 8.02 (3H, s). 
The above-mentioned operation was repeated, except that the 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by each of 
the reactive derivatives of compounds of formula (III) shown in Table 21, 
to obtain respective objective compounds as shown in Table 21. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 21 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
##STR454## 
##STR455## 
##STR456## 
##STR457## 
##STR458## 
##STR459## 
__________________________________________________________________________ 
EXAMPLE 26 
(1) To a solution of 0.92 g of 1-n-pentyl-2,3-dioxo-piperazine in 15 ml of 
anhydrous dioxane were added 1.1 ml of triethylamine and 1.08 g of 
trimethylsilyl chloride. The resulting mixture was stirred at room 
temperature for 20 hours to form triethylamine hydrochoride. This 
hydrochloride was separated by filtration, and the filtrate was dropped at 
0.degree. to 5.degree. C. into a solution of 0.6 g of phosgene in 10 ml of 
anhydrous tetrahydrofuran. Subsequently, the resulting mixture was reacted 
at 5.degree. to 10.degree. C. for 30 minutes and then at room temperature 
for 2 hours. Thereaafter, the solvent was removed by distillation under 
reduced pressure to obtain 1.21 g of pale yellow, oily 
4-n-pentyl-2,3-dioxo-1-piperazinocarbonyl chloride. 
IR (film) cm.sup.-1 : .nu..sub.C=O 1790, 1720-1665. 
(2) A suspension of 1.70 g of a monohydrate of 
7-[D(-)-.alpha.-aminophenylacetamido]-3-methyl-.DELTA..sup.3 
-cephem-4-carboxylic acid in 50 ml of tetrahydrofuran containing 20% by 
volume of water was adjusted to a pH of 8.0 to 8.5 by addition of 
triethylamine with stirring to form a solution. This solution was cooled 
to 0.degree. to 5.degree. C., and 7 ml of an anhydrous tetrahydrofuran 
solution containing 1.21 g of the 
4-n-pentyl-2,3-dioxo-1-piperazinocarbonyl chloride obtained in (1) was 
dropped into the solution. During this period, the pH of the solution was 
maintained at a pH of 7.5 to 8.0 by addition of triethylamine. 
Subsequently, the resulting mixed solution was reacted at 0.degree. to 
5.degree. C. for 1 hour and then at 5.degree. to 10.degree. C. for 2 hours 
while maintaining the pH thereof at 7.5 to 8.0. After the reaction, the 
tetrahydrofuran was removed by distillation under reduced pressure, and 
the residue was dissolved in 20 ml of water and then washed two times with 
20 ml of ethyl acetate. The aqueous layer was again charged with 40 ml of 
ethyl acetate, and then adjusted to a pH of 1.5 by gradual addition of 
dilute hydrochloric acid with ice-cooling. Subsequently, the ethyl acetate 
layer was separated off, washed with water, and then dried over anhydrous 
magnesium sulfate. Thereafter, 10 ml of an ethyl acetate solution 
containing 0.75 g of sodium 2-ethylhexonate was dropped into the layer at 
0.degree. to 5.degree. C. to deposite white crystals. The deposited 
crystals were collected by filtration, and washed with ethyl acetate and 
then with diethyl ether to obtain 1.95 g of a sodium salt of 
7-[D(-)-.alpha.-(4-n-pentyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacet 
amido]-3-methyl-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 
164.degree.-166.degree. C. (decomp.), yield 75 %. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1750 (lactam), 1720-1660 (--CON&lt;), 1590 
(--COO.sup..crclbar.). 
NMR (d.sub.6 -DMSO+D.sub.2 O) .tau. values: 2.58 (5H, s), 4.33 (1H, s), 
4.49 (1H, d), 5.17 (1H, d), 6.10 (2H, bs), 6.42-6.87 (6H, m), 8.09 (3H, 
s), 8.60-8.90 (6H, bs), 9.12 (3H, t). 
The above-mentioned operation was repeated, except that the 
4-n-pentyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by each of 
the reactive derivatives of compounds of formula (III) shown in Table 22, 
to obtain respective objective compounds as shown in Table 22. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 22 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
D(-)- 
##STR460## 
##STR461## 
m.p. (decomp.) 160.degree. C., yield 77.7% 
D(-)- 
##STR462## 
##STR463## 
m.p. (decomp.) 158.degree. C., yield 78% 
D(-)- 
##STR464## 
##STR465## 
m.p. (decomp.) 154.degree. C., yield 78% 
D(-)- 
##STR466## 
##STR467## 
m.p. (decomp.) 185-188.degree. C., yield 77% 
D(-)- 
##STR468## 
##STR469## 
m.p. (decomp.) 135-137.degree. C., yield 
__________________________________________________________________________ 
79.2% 
EXAMPLE 27 
Using 1.5 g of a hydrochloride of methoxymethyl ester of 
7-[D(-)-.alpha.-aminophenylacetamido]-3-methyl-.DELTA..sup.3 
-cephem-4-carboxylic acid and 0.65 g of 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, the same operation as in 
Example 25 was repeated to obtain 1.6 g of a methoxymethyl ester of 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-methyl-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 
146.degree.-148.degree. C. (decomp.,), yield 86%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1770 (lactam), 1710 (ester), 1680-1600 
(--CON&lt;). 
EXAMPLE 28 
To a suspension of 0.20 g of 
7-[D(-)-.alpha.-aminophenylacetamido]-3-acetoxymethyl-.DELTA..sup.3 
-cephem-4-carboxylic acid in 15 ml of anhydrous chloroform was added 0.17 
ml of triethylamine with stirring to form a solution, which was then 
cooled to 0.degree. C. To this solution was added 0.11 g of 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, and the resulting 
mixture was reacted at room temperature for 2 hours. After the reaction, 
the reaction liquid was evaporated under reduced pressure, and the residue 
was dissolved in 15 ml of water. The resulting solution was washed with 10 
ml of ethyl acetate. The aqueous layer was again charged with 20 ml of 
ethyl acetate, and then adjusted to a pH of 1.5 by addition of 2N 
hydrochloric acid with ice-cooling. Subsequently, the ethyl acetate layer 
was separated off, successively washed with water and a saturated aqueous 
sodium chloride solution, and then dried over magnesium sulfate. 
Thereafter, the solvent was removed by distillation under reduced pressure 
to obtain 0.22 g of white crystals of 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 
175.degree. C. (decomp.), yield 76%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1770 (lactam), 1720-1650 (--CON&lt;, 
--COOH). 
NMR (d.sub.6 -DMSO) .tau. values: 0.23 (1H, d), 0.63 (1H, d), 2.66 (5H, s), 
4.32 (1H, q), 4.43 (1H, d), 5.05 (1H, d), 5.21 (2H, q), 6.15 (2H, bs), 
6.40 (2H, bs), 6.57 (2H, bs), 7.0 (3H, s), 8.0 (3H, s). 
The above-mentioned operation was repeated, except that the 
4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by each of 
the reactive derivatives of compounds of formula (III) shown in Table 23, 
to obtain respective objective compounds as shown in Table 23. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 23 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
D(-)- 
##STR470## 
##STR471## 
m.p. (decomp.) 150.degree. C., yield 83.4% 
D(-)- 
##STR472## 
##STR473## 
m.p. (decomp.) 165.degree. C., yield 83% 
D(-)- 
##STR474## 
##STR475## 
m.p. (decomp.) 146.degree. C., yield 82% 
D(-)- 
##STR476## 
##STR477## 
m.p. (decomp.) 112.degree. C., yield 95% 
D(-)- 
##STR478## 
##STR479## 
m.p. (decomp.) 134.degree. C., yield 90.2% 
__________________________________________________________________________ 
The aforesaid 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 
175.degree. C. (decomp.) was recrystallized from hydrous acetone to obtain 
white crystals showing a melting point of 198.degree. to 200.degree. C. 
(decomp.) 
EXAMPLE 29 
(1) To a solution of 28.2 g of a sodium salt of D(-)-phenylglycine in 150 
ml of water were added 200 ml of ethyl acetate and 18.2 g of 
triethylamine, and the resulting mixture was cooled to 0.degree. C. To 
this mixture was added 34.3 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl 
chloride over a period of 15 minutes, and the mixture was reacted at 
5.degree. to 10.degree. C. for 15 minutes. Thereafter, the aqueous layer 
was separated off and adjusted to a pH of 0.5 by addition of 2N 
hydrochloric acid with ice-cooling to deposit crystals. The deposited 
crystals were collected by filtration and then dried to obtain 42 g of 
white crystals of 
D(-)-.alpha.(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid, m.p. 195.degree. C. (decomp.) 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1700, 1660. 
NMR (d.sub.6 -DMSO) .tau. values: 0.1 (1H, d), 2.65 (5H, s), 4.60 (1H, d), 
6.10 (2H, bs), 6.50 (2H, bs), 7.0 (3H, s). 
(2) To a suspension in 15 ml of anhydrous methylene chloride of 0.31 g of 
the 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic ac 
id obtained in the above-mentioned item (1) was added 0.11 g of 
N-methylmorpholine with stirring to form a solution, which was then cooled 
to -20.degree. C. To this solution was added 3 ml of an anhydrous 
methylene chloride solution containing 0.13 g of ethyl chlorocarbonate, 
and the resulting mixture was reacted at -10.degree. to 20.degree. C. for 
60 minutes to form a mixed acid anhydride. Into the thus formed acid 
anhydride was dropped a solution formed by adding 0.50 ml of triethylamine 
to a suspension in 5 ml of methanol of 0.41 g of 
7-amino-3-[2-(5-methyl-1,3,4-thiadiazoly)-thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid. After the dropping, the resulting mixture was 
reacted at -50.degree. to -30.degree. C. for 30 minutes, at -30.degree. to 
-20.degree. C. for 30 minutes, at -20.degree. to 0.degree. C. for 60 
minutes, and then at room temperature for 30 minutes. Thereafter, the 
reaction liquid was concentrated under reduced pressure, and the 
concentrate was dissolved in 10 ml of water, washed with 5 ml of ethyl 
acetate, again charged with 15 ml of ethyl acetate, and then adjusted to a 
pH of 1.5 by addition of 2N hydrochloric acid with ice-cooling. 
Subsequently, insolubles were separated by filtration, and the ethyl 
acetate layer was separated off, successively washed with water and a 
saturated sodium chloride solution, dried over magnesium sulfate, and then 
freed from the solvent by distillation under reduced pressure to obtain 
0.58 g of pale yellow crystals of 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-[2-(5-methyl-1,3,4-thiadiazolyl)-thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, m.p. 160.degree. C. (decomp.), yield 91%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1780 (lactam), 1650-1720 (--CON&lt;, 
--COOH). 
NMR (d.sub.6 -DMSO) .tau. values: 0.2 (1H, d), 0.6 (1H, d), 2.60 (5H, s), 
4.35 (1H, q), 4.40 (1H, d), 5.0 (1H, d), 5.70 (2H, q), 6.10 (2H, bs), 
6.25-6.55 (2H, 2H, bs), 7.0 (3H, s), 7.30 (3H, s). 
The above-mentioned operation was repeated, except that the 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid was replaced by each of the compounds of formula (V) shown in Table 
24, to obtain respective objective compounds as shown in Table 24. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 24 
__________________________________________________________________________ 
Compound of formula (V) 
Objective compound 
__________________________________________________________________________ 
D(-)- D(-)- 
##STR480## 
##STR481## 
m.p. (decomp.) 150.degree. C., yield 91% 
D(-)- D(-)- 
##STR482## 
##STR483## 
m.p. (decomp.) 147.degree. C., yield 85.4% 
D(-)- D(-)- 
##STR484## 
##STR485## 
m.p. (decomp.) 144.degree. C., yield 84.3% 
D(-)- D(-)- 
##STR486## 
##STR487## 
m.p. (decomp.) 167.degree. C., yield 
__________________________________________________________________________ 
93% 
EXAMPLE 30 
Using 0.3 g of 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid and 0.33 g of 
7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, the same operation as in Example 29 was 
repeated, to obtain 0.5 g of 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, m.p. 161.degree.-163.degree. C. (decomp.), 
yield 76%. 
IR (nujol) cm.sup.-1 : .nu..sub.C=O 1775 (lactam), 1720-1660 (--CON&lt;, 
--COOH). 
NMR (d.sub.6 -DMSO) .tau. values: 0.02 (1H, d), 0.34 (1H, d), 2.48 (5H, s), 
4.17 (1H, q), 4.26 (1H, d), 4.92 (1H, d), 5.66 (2H, s), 6.01 (5H, s), 6.35 
(4H, s), 7.0 (3H, s). 
The above-mentioned operation was repeated, except that the 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid was replaced by each of the compounds of formula (V) shown in Table 
25, to obtain respective objective compounds as shown in Table 25. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 25 
__________________________________________________________________________ 
Compound of formula (V) 
Objective compound 
__________________________________________________________________________ 
##STR488## 
##STR489## 
##STR490## 
##STR491## 
##STR492## 
##STR493## 
__________________________________________________________________________ 
*Anhydrous methylene chloride was substituted for the methanol used in 
Example 29. 
EXAMPLE 31 
Using 0.30 g of 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid and 0.34 g of 
7-amino-3-[5-(1,3,4-thiadiazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, the same operation as in Example 29 was 
repeated, to obtain 0.47 g of 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-[5-(1,3,4-thiadiazolyl)thiomethyl-.DELTA..sup.3 -cephem-4-carboxylic 
acid, m.p. 158.degree.-159.degree. C. (decomp.), yield 71.5 %. 
IR (nujol) cm.sup.-1 : .nu..sub.C=O 1775 (lactam), 1720-1660 (--CON&lt;, 
--COOH). 
The above-mentioned operation was repeated, except that the 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid was replaced by 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid, to obtain 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-[5-(1,3,4-thiadiazolyl)-thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, m.p. 123.degree. C. (decomp.), yield 64.5%. 
EXAMPLE 32 
Using 0.31 g of 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid and 0.39 g of 
7-amino-3-[2-(1-methyl-1,3,4-triazolyl)-thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, the same operation as in Example 29 was 
repeated, except that the methanol was replaced by anhydrous methylene 
chloride, to obtain 0.43 g of 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-[2-(1-methyl-1,3,4-triazolyl)-thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, yield 70%. 
IR (nujol) cm.sup.-1 : .nu..sub.C=O 1780 (lactam), 1720-1650 (--CON&lt;, 
--COOH). 
The above-mentioned operation was repeated, except that the 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid was replaced by each of the compounds of formula (V) shown in Table 
26, to obtain respective objective compounds as shown in Table 26. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 26 
__________________________________________________________________________ 
Compound of formula (V) 
Objective compound 
__________________________________________________________________________ 
##STR494## 
##STR495## 
##STR496## 
##STR497## 
__________________________________________________________________________ 
EXAMPLE 33 
The procedure of Example 29 was repeated, except that the 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid was replaced by each of the compounds of formula (V) shown in Table 
27, to obtain respective objective compounds shown in Table 27. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 27 
__________________________________________________________________________ 
Compound of formula (V) 
Objective compound 
__________________________________________________________________________ 
D(-)- D(-)- 
##STR498## 
##STR499## 
D(-)- D(-)- 
##STR500## 
##STR501## 
D(-)- D(-)- 
##STR502## 
##STR503## 
D(-)- D(-)- 
##STR504## 
##STR505## 
D(-)- D(-)- 
##STR506## 
##STR507## 
D(-)- D(-)- 
##STR508## 
##STR509## 
D(-)- D(-)- 
##STR510## 
##STR511## 
D(-)- D(-)- 
##STR512## 
##STR513## 
D(-)- D(-)- 
##STR514## 
##STR515## 
__________________________________________________________________________ 
EXAMPLE 34 
The procedure of Example 30 was repeated, except that the 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid was replaced by each of the compounds of formula (V) shown in Table 
28, to obtain respective objective compounds shown in Table 28. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 28 
__________________________________________________________________________ 
Compound of formula (V) 
Objective compound 
__________________________________________________________________________ 
D(-)- D(-)- 
##STR516## 
##STR517## 
D(-)- D(-)- 
##STR518## 
##STR519## 
D(-)- D(-)- 
##STR520## 
##STR521## 
D(-)- D(-)- 
##STR522## 
##STR523## 
D(-)- D(-)- 
##STR524## 
##STR525## 
D(-)- D(-)- 
##STR526## 
##STR527## 
D(-)- D(-)- 
##STR528## 
##STR529## 
D(-)- D(-)- 
##STR530## 
##STR531## 
D(-)- D(-)- 
##STR532## 
##STR533## 
__________________________________________________________________________ 
EXAMPLE 35 
(1) To a suspension of 0.9 g of D(-)-.alpha.-alanine in 15 ml of water was 
added 2.05 g of triethylamine to dissolve D(-)-.alpha.-alanine in water, 
and the resulting solution was cooled to 0.degree. C. To the solution was 
added 2.3 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride over 15 
minutes, after which reaction was effected for 30 minutes with 
ice-cooling. Dilute hydrochloric acid was then added to the reaction 
product to adjust the pH thereof to 2.0. The water was removed by 
distillation under reduced pressure, and 30 ml of acetone was added to the 
residue, after which insolubles were filtered off. To the resulting 
acetone solution was added 10 ml of an acetone solution of 1.6 g of a 
sodium salt of 2-ethylhexonic acid, and the deposited crystals were 
collected by filtration, and dried to obtain 2.1 g of a sodium salt of 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)propionic acid 
having a melting point of 115.degree.-8.degree. C. (decomp.), yield 
78.5%. 
IR (KBr) cm.sup.-1 :.nu..sub.C=O 1700, 1680, 1600 (--CON&lt;, --COO.sup.63). 
(2) In the same manner as in Example 32, 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)propionamido 
]-3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid was obtained from 
a sodium salt of 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)propionic acid 
and 7-amino-3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid. The 
thus obtained product was dissolved in 20 ml of acetone, and a solution of 
0.65 g of a sodium salt of 2-ethylhexonic acid in 5 ml of acetone was 
added to the resulting solution. The deposited crystals were collected by 
filtration and dried to obtain 1.2 g of sodium salt of 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)propionamido 
]-3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid having a melting 
point of 195.degree. C. (decomp.), yield 67.7%. 
IR (KBr) cm.sup.-1 ; .nu..sub.C=O 1780 (lactam), 1710-1660 (--CON-), 1600 
(--COO.sup..crclbar.). 
EXAMPLE 36 
In the same manner as in Example 32, 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonyl)-p-hydroxyphenyla 
cetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid was obtained from 
7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid and 
D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxypheny 
lacetic acid. 
Melting point (decomp.), 147.degree.-9.degree. C.; yield, 62.0%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1765 (lactam), 1720-1660 (--CON&lt;, 
--COOH). 
In the same manner as above, 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphe 
nylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, m.p. 188.degree.-190.degree. C. (decomp.), 
yield 80.7%, was obtained from 
7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid and 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphenyl 
acetic acid. 
EXAMPLE 37 
In the same manner as in Example 29, 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-azidomethyl-.DELTA..sup.3 -cephem-4-carboxylic acid was obtained 
from D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacet 
ic acid and 7-amino-3-azidomethyl-.DELTA..sup.3 -cephem-4-carboxylic acid. 
Melting point (decomp.), 185.degree.-8.degree. C.; yield, 68.0%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1775 (lactam), 1720-1660 (--CON&lt;, 
--COOH); .nu..sub.N.sbsb.3 2090. 
EXAMPLE 38 
In 10 ml of a phosphoric acid buffer solution of a pH of 6.3 was suspended 
0.57 g of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, and 0.07 g of 
sodium hydrogencarbonate was dissolved therein. To the solution was then 
added 0.12 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole to dissolve the 
latter in the former, and the solution was subjected to reaction for 24 
hours while maintaining the pH of the solution at 6.5-6.7 by using dilute 
hydrochloric acid and sodium hydrogencarbonate. After the reaction, the 
reaction liquid was cooled, and then adjusted to a pH of 5.0 by adding 
dilute hydrochloric acid. The reaction liquid was sufficiently washed with 
ethyl acetate, after which the aqueous layer was separated off and then 
adjusted to a pH of 1.5 by adding dilute hydrochloric acid thereto. The 
deposited crystals were collected by filtration and dried, after which the 
dried crystals were washed with ethyl acetate to obtain 0.40 g of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, m.p. 163.degree.-165.degree. C. (decomp.), 
yield 74.5%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1775 (lactam), 1720-1660 (--CON&lt;, 
--COOH). 
NMR (d.sub.6 -DMSO) .tau. values: 0.18 (1H, d), 0.55 (1H, d), 2.64 (5H, s), 
4.3 (1H, q), 4.4 (1H, d), 5.0 (1H, d), 5.75 (2H, s), 6.05 (5H, s), 6.3-6.8 
(6H), 8.92 (3H, t). 
In the same manner as above, the objective compounds shown in Table 29 were 
obtained from 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonyl)phenylacetamido]- 
3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid or 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid and the 
compounds of formula (VII) shown in Table 29. All the objective compounds 
were D(-) isomers, and the structure of each objective compound was 
confirmed by IR and NMR. 
TABLE 29 
__________________________________________________________________________ 
Compound of 
formula (VII) Objective compound 
__________________________________________________________________________ 
##STR534## 
##STR535## 
##STR536## 
##STR537## 
##STR538## 
##STR539## 
##STR540## 
##STR541## 
##STR542## 
##STR543## 
##STR544## 
##STR545## 
##STR546## 
##STR547## 
##STR548## 
##STR549## 
##STR550## 
##STR551## 
##STR552## 
##STR553## 
##STR554## 
##STR555## 
##STR556## 
##STR557## 
##STR558## 
##STR559## 
##STR560## 
##STR561## 
##STR562## 
##STR563## 
NaN.sub.3 
##STR564## 
##STR565## 
##STR566## 
##STR567## 
##STR568## 
##STR569## 
##STR570## 
__________________________________________________________________________ 
EXAMPLE 39 
In 10 ml of water was suspended 1.15 g of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, and 0.17 g of 
sodium hydrogencarbonate was then dissolved therein, after which 0.48 g of 
pyridine and 4.1 g of potassium thiocyanate were added thereto. The 
resulting mixture was subjected to reaction at 60.degree. C. for 5 hours 
while maintaining the pH of the mixture at 6.0 to 6.5 by adding dilute 
hydrochloric acid or sodium hydrogencarbonate. After the reaction, 20 ml 
of water was added to dilute the reaction mixture, which was then 
sufficiently washed with chloroform. The aqueous layer was then separated 
off and then adjusted to a pH of 1.5 by adding dilute hydrochloric acid. 
The deposited crystals were collected by filtration, dried, and then 
washed with acetone to obtain 1.04 g (yield, 79.6%) of a thiocyanic acid 
salt of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-pyridinomethyl-.DELTA..sup.3 -cephem- 4-carboxylic acid betaine 
having a melting point (decomp.) of 155.degree.-160.degree. C., said 
product having the formula, 
##STR571## 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1780 (lactam), 1720-1660 (--CON&lt;); 
.nu.SCN 2040. 
In the same manner as above, a thiocyanic acid salt of 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-pyridinomethyl-.DELTA..sup.3 -cephem-4-carboxylic acid betaine was 
obtained from 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-acetoxymethy-1-.DELTA..sup.3 -cephem-4-carboxylic acid and pyridine, 
said product having the formula, 
##STR572## 
Melting point (decomp.), 180.degree.-185.degree. C.; yield, 82.0%. 
In a conventional manner, the above two products were treated with an ion 
exchange resin to obtain the desired 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-pyridinomethyl-.DELTA..sup.3 -cephem-4 -carboxylic acid betaine and 
7-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetam 
ido]-3-pyridinomethyl-.DELTA..sup.3 -cephem-4-carboxylic acid betaine. 
EXAMPLE 40 
In 85 ml of anhydrous methanol was dissolved 1.5 g of a sodium salt of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-[2-(pyridyl-1-oxide)thiomethyl]-.DELTA..sup.3 -cephem-4-carboxylic 
acid. To the resulting solution was added 0.65 g of anhydrous cupric 
chloride, and the resulting mixture was stirred at room temperature for 15 
minutes and then subjected to reaction at 50.degree. C. for 14 hours. 
After the reaction, hydrogen sulfide gas was passed through the reaction 
solution with ice-cooling for 20 minutes. The resulting insolubles were 
filtered off, and the filtrate was concentrated under reduced pressure. To 
the residue was added 20 ml of a 5% aqueous sodium hydrogen-carbonate 
solution, and the insolubles were filtered off, after which dilute 
hydrochloric acid was added to the filtrate to adjust the pH to 6.5. The 
filtrate was then washed with 10-ml portions of ethyl acetate three times, 
after which the aqueous layer was separated off and then adjusted to a pH 
of 1.8 by adding dilute hydrochloric acid thereto. The thus deposited 
crystals were collected by filtration and then dried under reduced 
pressure and washed with 20 ml of an ethyl acetate-chloroform mixed 
solvent (1:1 by volume) to obtain 0.40 g of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-methoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 
162.degree.-6.degree. C. (decomp.), yield 30.5 %. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1770 (lactam), 1700 (--COOH), 1666 
(--CON&lt;). 
NMR (d.sub.6 -DMSO) .tau. values: 0.13 (1H, d), 0.53 (1H, d), 2.61 (5H, s), 
4.31 (1H, q), 4.41 (1H, d), 4.96 (1H, d), 5.82 (2H, s), 6.10 (2H bs), 6.33 
(2H, 2H, 2H, bs), 6.79 (3H, s), 8.89 (3H, t). 
EXAMPLE 41 
To a solution of 3.2 g of 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid in 20 ml of anhydrous methylene chloride and 5 ml of 
dimethylformamide was added 1.33 g of N,N-dimethylaniline. The resulting 
mixture was cooled to -15.degree. to -10.degree. C., and a solution of 
1.14 g of ethyl chlorocarbonate in 5 ml of anhydrous methylene chloride 
was dropped into said mixture over a period of 5 minutes. The mixture was 
reacted at said temperature for 60 minutes. 
On the other hand, to a suspension of 3.28 g of 
7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid in 65 ml of anhydrous acetonitrile was added 
3.04 g of N,O-bis(trimethylsilyl)acetamide to obtain a solution. The 
solution was cooled to -20.degree. C. and poured into the aforesaid 
reaction mixture. Subsequently, the mixture was reacted at -10.degree. C. 
to -5.degree. C. for 60 minutes, and at 5.degree. to 10.degree. C. for 60 
minutes. After the reaction, to the reaction mixture 5 ml of methanol was 
added and the mixture was freed from insolubles by filtration. Thereafter 
the solvent was removed by distillation under reduced pressure. The 
residue was dissolved in a mixed solvent comprising 100 ml of water and 50 
ml of ethyl acetate, and the resulting solution was adjusted to a pH of 
7.5 to 8.0 by addition of sodium hydrogencarbonate, after which the 
aqueous layer was added 80 ml of ethyl acetate and 20 ml of acetone, and 
the resulting solution was adjusted to a pH of 1.5 by addition of dilute 
hydrochloric acid. Subsequently, the organic layer was separated off, 
sufficiently washed with water and then the solvent was removed from ethyl 
acetate layer by distillation under reduced pressure. The residue was 
dissolved in 15 ml of acetone, and to this solution was added 60 ml of 
2-propanol with stirring to deposit white crystals. The deposited crystals 
were collected by filtration, sufficiently washed with 2-propanol and then 
dried to obtain 5.26 g of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, m.p. 163.degree.-165.degree. C. (decomp.), 
yield 83.6%. The structure of this compound was confirmed by IR and NMR. 
The above-mentioned operation was repeated except that the sodium salt of 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid was replaced by each of the reactive derivatives of compounds of 
formula (III) shown in Table 30, to obtain the respective objective 
compounds as shown in Table 30. The structure of each objective compound 
was confirmed by IR and NMR. 
TABLE 30 
__________________________________________________________________________ 
Reactive derivative of 
compound of formula (III) 
Objective compound 
__________________________________________________________________________ 
D(-)- D(-)- 
##STR573## 
##STR574## 
m.p. (decomp.) 161-163.degree. C., yield 85.8% 
D(-)- D(-)- 
##STR575## 
##STR576## 
m.p. (decomp.) 188-190.degree. C., yield 75.5% 
D(-)- D(-)- 
##STR577## 
##STR578## 
m.p. (decomp.) 162-165.degree. C., yield 74.0% 
D(-)- D(-)- 
##STR579## 
##STR580## 
m.p. (decomp.) 124-128.degree. C., yield 
__________________________________________________________________________ 
75.3% 
EXAMPLE 42 
Using 3.1 g of 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid and 3.0 g of 7-amino-3-[5-(1,2,3-triazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, the same operation as in Example 41 was 
repeated to obtain 4.5 g of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-[5-(1,2,3-triazolyl)thiomethyl]-.DELTA..sup.3 -cephem-4-carboxylic 
acid, m.p. 177.degree.-180.degree. C. (decomp.), yield 76.7%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1770 (lactom), 1703 (--COOH), 1680, 1667 
(--CON&lt;). 
EXAMPLE 43 
Using 1.5 g of 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphenyl 
acetic acid and 1.5 g of 
7-amino-3-[5-(2-methyl-1,3,4-thiadiazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, the same operation as in Example 41 was 
repeated to obtain 2.3 g of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphe 
nylacetamido]-3-[5-(2-methyl-1,3,4-thiadiazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, m.p. 172.degree.-177.degree. C. (decomp.), 
yield 77.7%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1780 (lactam), 1710 (--COOH), 1685, 1672 
(--CON&lt;). 
In the same manner as above, the objective compounds shown in Table 31 were 
obtained from 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid or 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphenyl 
acetic acid and the compounds of formula (IV) shown in Table 31. The 
structure of each objective compound was confirmed by IR and NMR. 
TABLE 31 
__________________________________________________________________________ 
Compound of formula (IV) 
Objective compound 
__________________________________________________________________________ 
D(-)- 
##STR581## 
##STR582## 
m.p. (decomp.) 171-175.degree. C., yield 72.5% 
D(-)- 
##STR583## 
##STR584## 
m.p. (decomp.) 156-160.degree. C., yield 73.1% 
D(-)- 
##STR585## 
##STR586## 
m.p. (decomp.) 163-165.degree. C., yield 67.4% 
D(-)- 
##STR587## 
##STR588## 
m.p. (decomp.) 159-161.degree. C., yield 68.0% 
D(-)- 
##STR589## 
##STR590## 
m.p. (decomp.) 183-185.degree. C., yield 77.7% 
D(-)- 
##STR591## 
##STR592## 
m.p. (decomp.) 167.degree. C., yield 82.0% 
D(-)- 
##STR593## 
##STR594## 
m.p. (decomp.) 168-174.degree. C., yield 
__________________________________________________________________________ 
65.0% 
EXAMPLE 44 
In a mixed solvent comprising 80 ml of water and 40 ml of ethyl acetate was 
suspended 4.0 g of 
7-[D(-)-.alpha.-aminophenylacetamido]-3-acetoxymethyl-.DELTA..sup.3 
-cephem-4-carboxylic acid, and 1.65 g of anhydrous potassium carbonate was 
then dissolved therein with ice-cooling. 
To this solution was added 7.3 g of 
4-(.alpha.-hydroxyethyl)-2,3-dioxo-1-piperazinocarbonyl chloride at 
0.degree. to 5.degree. C. over a period of 15 minutes, and the resulting 
mixture was reacted at 10.degree. to 15.degree. C. for 30 minutes. After 
the reaction, the aqueous layer was separated off, 100 ml of acetonitrile 
was added to the aqueous layer, and the resulting solution was adjusted to 
a pH of 1.5 by addition of dilute hydrochloric acid, and was saturated by 
sodium chloride. Subsequently, the acetonitrile layer was separated off, 
successively washed two times with 30 ml of saturated solution of sodium 
chloride and then dried by reduced pressure. The residue was dissolved in 
a mixed solvent comprising 50 ml of acetone and 10 ml of ethanol, and 
insolubles were separated off. Subsequently, 100 ml of isopropyl alcohol 
was added to the resulting solution, and then concentrated to a liquid 
amount of about two-thirds under reduced pressure. The deposited crystals 
were collected by filtration, washed with iso-propyl alcohol and then 
dried to obtain 4.5 g of 
7-[D(-)-.alpha.-4-(.beta.-hydroxyethyl)-2,3-dioxo-1-piperazinocarbonylamin 
ophenylacetamido]-3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, 
m.p. 142.degree.-144.degree. C. (decomp.), yield 76.3%. 
IR (KBr) cm.sup.-1 : .nu..sub.C=O 1770 (lactam), 1708 (--COOH), 1680, 1665 
(--CON&lt;). 
The above-mentioned procedure was repeated, except that the 
7-[D(-)-.alpha.-aminophenylacetamido]-3-acetoxymethyl-.DELTA..sup.3 
-cephem-4-carboxylic acid was replaced by each of the compounds of formula 
(II) shown in Table 32, to obtain the respective objective compounds as 
shown in Table 32. The structure of each objective compound was confirmed 
by IR and NMR. 
TABLE 32 
__________________________________________________________________________ 
Compound of formula (II) Objective compound 
__________________________________________________________________________ 
D(-)- 
##STR595## 
##STR596## 
m.p. (decomp.) 153-157.degree. C., yield 62.0% 
D(-)- 
##STR597## 
##STR598## 
m.p. (decomp.) 141-145.degree. C., yield 64.6% 
D(-)- 
##STR599## 
##STR600## 
m.p. (decomp.) 170-173.degree. C., yield 
__________________________________________________________________________ 
58.0% 
EXAMPLE 45 
(1) To a solution of 0.63 g of 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid in 10 ml of anhydrous methylene chloride were added 0.5 g of oxalyl 
chloride and a drop of N,N-dimethylformamide, and the resulting mixture 
was reacted at room temperature for 30 minutes. After the reaction, the 
solvent was removed by distillation under reduced pressure. The residue 
was washed with anhydrous benzene to obtain 0.6 g of 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetyl 
chloride, m.p. 112.degree.-116.degree. C. (decomp.), yield 88.8%. 
IR (KBr) cm.sup.-1 : .nu..sub.NH 3280; .nu..sub.C=O 1790, 1695. 
(2) To a suspension of 0.27 g of 7-aminocephalosporanic acid in 6 ml of 
anhydrous methanol was added 0.24 g of triethylamine. The resulting 
solution was cooled to -40.degree. C., and to the solution was added a 
solution of 5 ml of anhydrous methylene chloride containing 0.34 g of 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetyl 
chloride, and then the temperature of the reaction liquid was gradually 
elevated to room temperature over a period of 1 hour. After the reaction, 
the solvent was removed by distillation under reduced pressure. The 
residue was added to 20 ml of water, and the resulting solution was washed 
two times with 5 ml of ethyl acetate. To the aqueous layer was added 20 ml 
of ethyl acetate, and the solution was adjusted to a pH of 1.5 by addition 
of 2N hydrochloric acid with stirring. Subsequently, the organic layer was 
separated off, washed with saturated aqueous sodium chloride, dried over 
anhydrous magnesium sulfate, and then the solvent was removed by 
distillation under reduced pressure to obtain 453 mg of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 
165.degree.-166.degree. C. (decomp.), yield 79.0%. 
In the same manner as above, 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphe 
nylacetamido]-3-acetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 
168.degree.-174.degree. C. (decomp.), yield 72.3%, was obtained from 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonaylamino)-p-hydroxypheny 
lacetyl chloride and 7-aminocephalosporanic acid. 
EXAMPLE 46 
To a suspension of 2.16 g of 6-aminopenicillanic acid in 20 ml of methylene 
chloride was added 2.02 g of triethylamine. Into the resulting solution 
was added 3.4 g of 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetyl 
chloride at 10.degree. to 15.degree. C. and the resulting mixture was 
reacted at 10.degree. to 15.degree. C. for 2 hours. After the reaction, 
the solvent was removed by distillation under reduced pressure. The 
residue was added to 20 ml of water, and to the resulting solution was 
added 30 ml of ethyl acetate. The solution was adjusted to a pH of 2.5 by 
addition of 2N hydrochloric acid and was stirred over a period of 4 hours 
to deposit crystals. The deposited crystals were collected by filtration 
to obtain 4.4 g of 
6-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]penicillanic acid, m.p. 154.degree.-156.degree. C. (decomp.), yield 
82.2%. 
In the same manner as above, 
6-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphe 
nylacetamido]penicillanic acid m.p. 160.degree.-161.degree. C. (decomp.), 
yield 70.5%, was obtained from 6-aminopenicillanic acid and 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphenyl 
acetyl chloride. 
EXAMPLE 47 
Using 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic aci 
d and 7-amino-3-carbamoyl-oxymethyl-.DELTA..sup.3 -cephem-4-carboxylic 
acid, the same procedure as in Example 41 was repeated, to obtain 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-carbamoyloxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 
175.degree.-180.degree. C. (decomp.), yield 68.0%. 
IR (KBr) cm.sup.-1 : .nu..sub.NH.sbsb.2 3450, 3350; .nu..sub.CONH 3300; 
.nu..sub.C=O 1778, 1710, 1670. 
In the same manner as above, 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphe 
nylacetamido]-3-carbamoyloxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, 
m.p. 178.degree.-182.degree. C. (decomp.), yield 65.0%, was obtained from 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphenyl 
acetic acid and 7-amino-3-carbamoyloxymethyl-.DELTA..sup.3 
-cephem-4-carboxylic acid. 
EXAMPLE 48 
(1) To a solution of 0.32 g of 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid in 15 ml of methylene chloride was added 0.1 g of N-methylmorpholine. 
The resulting solution was cooled to -20.degree. C., and to the solution 
was added a solution of 0.11 g of ethyl chlorocarbonate in 2 ml of 
methylene chloride, and then the resulting solution was subjected to 
reaction at -10.degree. to -20.degree. C. for 1 hour. Subsequently, into 
the reaction liquid was dropped a solution of 0.44 g of a benzhydryl ester 
of 7-amino-3-carbamoyloxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid in 
5 ml of methylene chloride at -20.degree. C. After the dropping, the 
resulting solution was subjected to reaction at -10.degree. to -20.degree. 
C. for 1.5 hours, and the temperature was then elevated to room 
temperature. Thereafter, the solvent was removed by distillation under 
reduced pressure, and the residue was dissolved in 15 ml of ethyl acetate. 
Subsequently, the resulting solution was successively washed with 10 ml of 
water, with 5% (weight/weight) aqueous sodium hydrogencarbonate, and 
saturated aqueous sodium chloride, and then dried over anhydrous magnesium 
sulfate. The solvent was removed by distillation under reduced pressure. 
Subsequently, the residue was purified with a column chromatography 
(silica gel - chloroform), to obtain 0.53 g of benzhydryl ester of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-carbamoyloxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 
120.degree.-125.degree. C. (decomp.), yield 71.6%. 
IR (KBr) cm.sup.-1 : .nu..sub.NH.sbsb.2 3480, 3380; .nu..sub.CONH 3300; 
.nu..sub.C=O 1780, 1718, 1680. 
NMR (CDCl.sub.3) .tau. values: 0.1 (1H, d), 2.05 (1H, d), 2.64 (15H, bs), 
3.19 (1H, s), 4.20 (2H, m), 4.86 (1H, d), 5.20 (2H, s), 5.25 (2H, bs), 6.1 
(2H, m), 6.3-6.9 (6H, m), 8.9 (3H, t). 
(2) To a solution of 0.2 g of a benzhydryl ester of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-carbamoyloxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid in 5 ml of 
anisole was added 5 ml of trifluoroacetic acid while ice-cooling, and the 
resulting mixed solution was reacted for 30 minutes while ice-cooling. 
After the reaction, the solvent was removed by distillation under reduced 
pressure. Subsequently, the residue was dissolved in 15 ml of ethyl 
acetate, and to the resulting solution was added 10 ml of water, and then 
the resulting solution was adjusted to a pH of 7.5 by addition of sodium 
hydrogen-carbonate while stirring. Thereafter, the aqueous layer was 
separated off, added to 20 ml of ethyl acetate, and then adjusted to a pH 
of 2.0 by addition of 2N hydrochloric acid. Subsequently, the organic 
layer was separated off, successively washed with water and saturated 
aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. 
The solvent was removed by distillation under reduced pressure to deposit 
crylstals. Subsequently, the deposited crystals were collected by 
filtration to obtain 0.13 g of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-carbamoyloxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 
175.degree.-180.degree. C. (decomp.), yield 83.8%. 
IR (KBr) cm.sup.-1 : .nu..sub.NH.sbsb.2 3450, 3350; .nu..sub.CONH.sub.2 
3300; .nu..sub.C=O 1778, 1710, 1670. NMR (d.sub.6 -DNSO) .tau. values: 
0.15 (1H, d), 0.55 (1H, d), 2.60 (5H, b), 3.47 (2H, s), 4.28 (2H, m), 4.95 
(1H, d), 5.25 (2H, q), 6.10 (2H, m), 6.25-6.90 (6H, m), 8.9 (3H, t). 
EXAMPLE 49 
(1) To a solution of 0.32 g of 
D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetic 
acid in 15 ml of anhydrous methylene chloride was added 0.1 g of 
N-methylmorpholine. The resulting solution was cooled to -20.degree. C., 
and to the solution was added a solution of 0.11 g of ethyl 
chlorocarbonate in 1 ml of methylene chloride, and then the resulting 
mixed solution was reacted at -10.degree. to -20.degree. C. for 1 hour. 
Subsequently, into the reaction solution was dropped a solution of 0.46 g 
of .beta.,.beta.,.beta.-trichloroethyl ester of 
7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid in 5 ml of methylene chloride at -20.degree. C. 
After the dropping, the resulting mixed solution was reacted at 
-10.degree. to -20.degree. C. for 1 hour, and at room temperature for 30 
minutes. After the reaction, the solvent was removed by distillation under 
reduced pressure, and the residue was successively washed with 5% 
(weight/weight) aqueous sodium hydrogencarbonate, and with saturated 
aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. 
Subsequently, the solvent was removed by distillation under reduced 
pressure, the residue was purified with a column chromatography (silica 
gel-benzene-ethyl acetate) to obtain 0.53 g of 
.beta.,.beta.,.beta.-trichloroethyl ester of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, m.p. 125.degree.-135.degree. C. (decomp.), 
yield 69.6%. 
IR (KBr) cm.sup.-1 :.nu..sub.C=O 1780, 1715, 1680. 
(2) To a solution of 0.5 g of .beta.,.beta.,.beta.-trichloroethyl ester of 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid were added 0.5 g of zinc dust and 0.5 ml of 
acetic acid, and then the resulting mixture was reacted for 1.5 hours. 
After the reaction, the reaction liquid was subjected to sellaite 
filtration, the filtrate was freed from the solvent by distillation under 
reduced pressure. Thereafter, the residue was dissolved in 15 ml of water, 
and the resulting solution was adjusted to a pH of 1.5 by addition of 2N 
hydrochloric acid to deposit crystals. Subsequently, the deposited 
crystals were collected by filtration, dried and then washed with ethyl 
acetate to obtain 
7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami 
do]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA..sup.3 
-cephem-4-carboxylic acid, m.p. 163.degree.-165.degree. C. (decomp.), 
yield 82.1%.