4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative and process for producing 4-(1-carboxyalkyl)azetidin-2-one derivative using the same

A 4-(1,1-dialkoxycarbonylalkyl )azetidin-2-one derivative represented by formula (I): ##STR1## wherein R.sup.1 and R.sup.2 are identical or different and each represents an alkyl group, an alkenyl group, or an aralkyl group, R.sup.3 represents a lower alkyl group, R.sup.4 represents a hydrogen atom or a hydroxyl-protective group, and R.sup.5 represents a hydrogen atom or an amino-protective group, and a process for producing a 4-(1-carboxyalkyl)azetidin-2-one derivative represented by formula (II) useful as an intermediate for 1.beta.-alkylcarbapenem-type antibacterials: ##STR2## wherein R.sup.3 represents a lower alkyl group and R.sup.4 represents a hydrogen atom or a hydroxyl-protective group, which comprises de-esterifying and decarboxylating the derivative represented by formula (I), and in the case where an amino-protective group is present in the derivative of formula (I), eliminating the protective group from the derivative, are disclosed.

FIELD OF THE INVENTION 
The present invention relates to a novel 4-(1,1- 
dialkoxycarbonylalkyl)azetidin-2-one derivative and a process for 
producing, from the derivative, a 4-(1-carboxyalkyl)azetidin-2-one 
derivative which is useful as an intermediate for various 
1.beta.-alkylcarbapenem-type antibacterial agents. 
BACKGROUND OF THE INVENTION 
Carbapenem-type antibacterial agents are excellent antibacterials having 
strong antibacterial activity against a wide spectrum of bacteria ranging 
from gram-positive bacteria to gram-negative bacteria including 
Pseudomonas aeruginosa. Hence, new antibacterials of the carbapenem-type 
are being energetically developed in recent years. Although carbapenem 
derivatives having no substituent at the 1-position in the carbapenem 
backbone, such as thienamycin shown by formula (III): 
##STR3## 
have drawbacks that they are chemically unstable at high concentrations 
and that they are readily metabolized by dehydropeptidase I, incorporation 
of a .beta.-configuration alkyl group at the 1-position improves the 
stability of such carbapenem derivatives and enables the derivatives to be 
used alone without the necessity of addition of a dehydropeptidase 
inhibitor thereto. Therefore, efforts are currently being made to develop 
1.beta.-alkylcarbapenem-type antibacterials and also to develop methods of 
synthesizing 4-[(R)-1-carboxyalkyl]azetidin-2-one derivatives represented 
by formula (II.beta.): 
##STR4## 
(wherein R.sup.3 represents a lower alkyl group and R.sup.4 represents a 
hydrogen atom or a hydroxyl-protective group), which derivatives can be 
used as intermediates for such antibacterials. 
As synthetic methods for compounds (II.beta.) described above, many reports 
have been made. The most promising method of these is to alkylate a 
4-acetoxyazetidin-2-one derivative represented by formula (IV): 
##STR5## 
(wherein R.sup.4 has the meaning as defined above and Ac denotes an acetyl 
group) at the 4-position with any of various nucleophilic agents thereby 
to incorporate a side chain. With respect to this method, the following 
reports, for example, have been made: alkylation with a propionic acid 
ester enolate [C. U. Kim et al., Tetrahedron Lett., 28 (5) 507-510 (1987); 
T. Chiba et al., Chem. Lett., 1343-1346 (1985); and T. Shibata et al., 
Tetrahedron Lett., 26 (39) 4739-4742 (1985)]; alkylation with a 
propionimide enolate [Y. Nagao et al., J. Am. Chem. Soc., 108, 4673-4675 
(1986); Yoshimitsu Nagao, Kayak (Chemistry), 42 (3) 190-196 (1987); L. M. 
Fuentes et al., J. Am. Chem. Soc., 108, 4675-4676 (1986); R. Deziel et 
al., Tetrahedron Lett., 27 (47) 5687-5690 (1986); and Y. Ito et al., 
Tetrahedron Lett ., 28 (52) 6625-6628 (1987)]; and alkylation with a 
propionic acid thiol ester enolate [M. Endo, Can. J. Chem., 65, 2140-2145 
(1987); C. U. Kim et al., Tetrahedron Lett., 28 (5) 507-510 (1987); and A. 
Hartei et al., Can. J. Chem., 66, 1537-1539 (1988)]. 
Other methods for synthesizing compounds (II.beta.) include, for example, a 
method of alkylating compound (V) 
##STR6## 
(wherein R.sup.4 has the meaning as defined above) with lithium 
diisopropylamide [D. H. Shih et al., Heterocycles, 21 (1) 29-40 (1984)] 
and a method in which the exo-methylene group of compound (VI) 
##STR7## 
(wherein R.sup.4 has the meaning as defined above, R.sup.5 represents a 
hydrogen atom or an amino-protective group, and R.sup.6 represents. an 
alkyl group, a carboxyl group, or an alkoxycarbonyl group) is reduced by 
catalytic reduction or by asymmetric reduction using a specific catalyst 
[JP-A-58-26887 (corresponding to European Patent 71908B); C. U. Kim et 
al., Tetrahedron Lett., 28 (5) 507-510 (1987); T. Ohta et al., J. Org. 
Chem., 3176-3178 (1987); and T. Iimori et al., Tetrahedron Lett., 27 (19) 
2149-2152 (1986)]. (The term "JP-A" as used herein means an "unexamined 
published Japanese patent application".) These methods are reported in 
Yoshio Itoh et al., Yuki Gosei Kagaku (Chemistry of Organic Syntheses), 47 
(7) 606-618, "Synthesis of the 1.beta.-Methylcarbapenem Key 
Intermediates"(1989). 
According to these methods, compound (II.beta.) in most: cases is obtained 
in the form of compound (II) 
##STR8## 
(wherein R.sup.3 and R.sup.4 each has the meaning as defined above) which 
is a mixture, in a specific proportion, of the compound (II.beta.) and 
compound (II.alpha.) 
##STR9## 
(wherein R.sup.3 and R.sup.4 each has the meaning as defined above) which 
is a stereoisomer with the compound (II.beta.). This compound (II.alpha.) 
having an .alpha.-configuration alkyl group can be converted to the 
desired compound (II.beta.) having a .beta.-configuration alkyl group by 
isomerization, which may be conducted by the method disclosed, for 
example, in D. H. Shih et al., Heterocycles, 21 (1) 29-40 (1984). 
However, the above-described methods for synthesizing compounds (II) and 
(II.beta.) are disadvantageous in that special and expensive reagents are 
used, reaction temperature extremely low, or expensive or toxic metals are 
used as catalyst. Therefore, the above methods are unsuited for syntheses 
in large quantities and are not being practiced on an industrial scale. 
Hence, there has been a desire for development of process for efficiently 
producing compound (II), especially compound (II.beta.) which has a 
.beta.-configuration alkyl group and is more useful as an intermediate for 
1.beta.-alkylcarbapenem-type antibacterials. 
SUMMARY OF THE INVENTION 
Under these circumstances, the present inventors have conducted intensive 
studies. As a result, it has been found that a 
4-(1-carboxyalkyl)azetidin-2-one derivative can be produced efficiently 
when it is synthesized by a method in which a 
4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative having a structure 
in which a malonic acid derivative has been bonded to the azetidin-2-one 
backbone at the 4-position is first synthesized and this azetidin-2-one 
derivative is then de-esterified and decarboxylated and, in the case where 
an amino-protective group is present in the derivative, the protective 
group is eliminated. The present invention has been completed based on 
this finding. 
Accordingly, the present invention provides a 
4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative represented by 
formula (I): 
##STR10## 
wherein R.sup.1 and R.sup.2 are identical or different and each represents 
an alkyl group, an alkenyl group, or an aralkyl group, R.sup.3 represents 
a lower alkyl group, R.sup.4 represents a hydrogen atom or a 
hydroxyl-protective group, and R.sup.5 represents a hydrogen atom or an 
amino-protective group. 
The present invention further provides a process for producing a 
4-(1-carboxyalkyl)azetidin-2-one derivative represented by formula (II): 
##STR11## 
wherein R.sup.3 and R.sup.4 each has the meaning as defined above, which 
comprises de-esterifying and decarboxylating the derivative of formula 
(I), and in the case where an amino-protective group is present in the 
derivative of formula (I), eliminating the protective group from the 
derivative. 
DETAILED DESCRIPTION OF THE INVENTION 
The 4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative of the present 
invention is represented by formula (I) described above. 
Examples of the alkyl group of R.sup.1 and R.sup.2 in the formula include 
straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, 
isopropyl, n-butyl, and tert-butyl; and monocyclic or polycyclic alkyl 
groups such as cyclopentyl, cyclohexyl, menthyl, fenchyl, and bornyl. 
Examples of the alkenyl group of R.sup.1 and R.sup.2 include 
straight-chain or branched alkenyl groups such as vinyl, allyl, 2-butenyl, 
and 2-methyl-2-propenyl. Examples of the aralkyl group of R.sup.1 and 
R.sup.2 include benzyl and benzhydryl. Preferably, R.sup.1 and R.sup.2 are 
identical and each represents a 2-alkenyl group. 
The lower alkyl group of R.sup.3 is an alkyl group having 1 to 4 carbon 
atoms. Examples of the lower alkyl group include methyl, ethyl, and 
n-propyl. Of these, a methyl group is particularly preferred. 
Examples of the hydroxyl-protective group of R.sup.4 include 
tri-substituted silyl groups such as trimethylsilyil and 
tert-butyldimethylsilyl; acyl groups such as acetyl; and aralkyl groups 
such as benzyl. 
Examples of the amino-protective group of R.sup.5 include tri-substituted 
silyl groups such as trimethyisilyl, triethylsilyl, 
tert-butyldimethylsilyl, and methyldiphenyl-silyl; aralkyl groups which 
may have a substituent on the aromatic ring(s), such as benzyl, 
p-methoxybenzyl, p-tert-butylbenzyl, 3,4-dimethylbenzyl, phenethyl, and 
benzhydryl; and alkoxyalkyl groups such as tetrahydropyranyl and 
methoxymethyl. Of these groups, tri-substituted silyl groups are 
preferred. 
In the case where such 4-(1,1-dialkoxycarbonyl-alkyl)azetidin-2-one 
derivatives are represented by formula (I) in which R.sup.5 is a hydrogen 
atom (hereinafter referred to as "azetidin-2-one derivatives (Ia)"), these 
compounds can be produced according to, for example, the method proposed 
by R. Joyeau et al., J. Chem. Soc., Perkin Trans. I, 1899-1907 (1987); 
Tetrahedron Lett., 30 (3) 337-340 (1989) in which a malonic acid 
derivative (VII) is reacted with a 4-acetoxyazetidin-2-one derivative (IV) 
as shown by the following scheme: 
##STR12## 
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and Ac each has the meaning 
as defined above). 
Illustratively stated, a 4-acetoxyazetidin-2-one derivative (IV) is added 
to a solution of a malonic acid derivative (VII) which has been activated, 
for example, with an alkali metal such as potassium metal, sodium metal, 
or lithium metal, an alkali metal hydride such as sodium hydride, an alkyl 
alkali metal such as butyllithium, an alkali metal alkoxide such as 
potassium tert-butoxide, sodium ethoxide, or sodium methoxide, an alkali 
metal hydroxide such as potassium hydroxide or sodium hydroxide, an alkali 
metal carbonate such as potassium carbonate, or the like. The reactants in 
the resulting mixture are then allowed to react at a temperature of from 
-60.degree. to 40.degree. C., especially preferably at room temperature 
(20.degree.-30 .degree. C.), for a period of preferably from 0.5 to 15 
hours, more preferably from 2 to 5 hours thereby to produce the desired 
compound. Examples of the solvent for use in the above method include 
water; alcohols such as methanol and ethanol ethers such as diethyl ether, 
dioxane, and tetrahydrofuran; acetone; dimethylformamide; and mixed 
solvents consisting off water and one or more of such organic solvents. Of 
these, tetrahydrofuran is especially preferably used. The proportions of 
the reactant compounds are preferably such that the malonic acid 
derivative (VII) is used in an amount of about from 1 to 1.3 mol, 
particularly about 1.1 mol, per mol of the 4-acetoxyazetidin-2-one 
derivative (IV). The azetidin-2-one derivative (Ia) thus obtained can be 
purified by extraction washing, dehydration, and so forth, which may be 
conducted in an ordinary way, followed by recrystallization, column 
chromatography, etc. 
In the case where the 4-(1,1-dialkoxycarbonyl-alkyl)azetidin-2-one 
derivative of the present invention is represented by formula (I) in which 
R.sup.5 is an amino-protective group (hereinafter referred to as 
"azetidin-2-one derivative (Ib)"), this compound can be produced by 
obtaining an azetidin2-one derivative (Ia) in which R.sup.5 is a hydrogen 
atom, according to the method described above, and then incorporating an 
amino-protective group into the derivative (Ia) by an ordinary method. For 
instance, a tri-substituted silyl group can be incorporated into the 
derivative (Ia) as the amino-protective group by reacting the derivative 
(Ia) with a tri-substituted silyl chloride in a solvent such as 
N,N-dimethylformamide, acetonitrile, or tetrahydrofuran in the presence of 
a base such as triethylamine, diisopropylamine, or pyridine at -20.degree. 
to 30 .degree. C. for the night to a week, according to the method 
described in JP-A-58-26887 (corresponding to European Patent 71908B), and 
an aralkyl group or an alkoxyalkyl group can be incorporated by reacting 
the derivative (Ia) with R--X (wherein R represents an aralkyl group or an 
alkoxyalkyl group and X represents a halogen atom) in the above solvent in 
the presence of an alkali such as potassium hydroxide, sodium hydroxide, 
or sodium hydride at 0.degree. to 30 .degree. C. for 3 to 24 hours, 
according to the method proposed by D. Reuschling et al., Tetrahedron 
Lett., (7) 615-618 (1978). 
Further, according to the present invention, compound (I) thus obtained is 
de-esterified and decarboxylated by an ordinary method, whereby a 
4-(1-carboxyalkyl)azetidin-2-one derivative (II) can be obtained. 
##STR13## 
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 each has the 
meaning as defined above.) 
The de-esterification and decarboxylation reactions can, for example, be 
performed by hydrolysis and heating in an ordinary way. Illustratively 
stated, compound (I) is hydrolyzed in the presence of a base, such as 
sodium hydroxide, potassium hydroxide, or lithium hydroxide, and the 
hydrolyzate is then decarboxylated by heating it to 80.degree. to 
120.degree. C. In the case where R.sup.1 and R.sup.2 are an aralkyl group, 
the de-esterification may also be accomplished by hydrogenation which is 
conducted using palladium carbon in the presence of an amine. 
In the case where compound to be used as a raw material is represented by 
formula (I) in which R.sup.1 and R.sup.2 are a 2-alkenyl group, it is 
possible to carry out the de-esterification and decarboxylation reactions 
by the method described above. However, it is preferable that the 
de-esterification and decarboxylation reactions of such compound (I) be 
performed by reacting formic acid or an amine salt of formic acid with the 
compound (I) in the presence of a palladium compound; this is an 
application of, for example, the method proposed by J. Tsuji et al., 
Tetrahedron Lett., (7) 613-616 (1979). This method is preferred in that 
both de-esterification and decarboxylation can be carried out in a single 
step. As the palladium compound for use in the above method, any palladium 
compound may be employed as long as it is capable of generating zerovalent 
palladium, which is an active species, in the reaction system. Examples of 
such palladium compounds include divalent palladium compounds such as 
palladium acetate, palladium chloride, and palladium acetylacetonate; and 
zero valent palladium compounds such as tribenzylidenedipalladium and 
tetrakis(triphenylphosphine)palladium. Along with the palladium compound 
described above, a trialkylphosphine such as triethylphosphine or 
tributylphosphine, a triarylphosphine such as triphenylphosphine or 
tritolylphosphine, or the like is used as a compound to be a ligand. Due 
to the presence of both the palladium compound and the ligand compound, a 
complex is formed in the reaction system and functions as a catalyst to 
accelerate the reaction. This reaction may be conducted using a solvent, 
e.g., an ether such as 1,4-dioxane or tetrahydrofuran, toluene, or 
benzene, by heating the reaction mixture with refluxing for from 1 to 5 
hours. The proportions of the reactant compounds preferably are such that 
the amount of the palladium compound is about from 0.01 to 0.1 mol and the 
amount of formic acid or a formic acid amine salt is about from 3 to 15 
mol, per mol of the azetidin-2-one (I). 
In the case where the raw compound is azetidin-2-one derivatives (Ia) 
represented by formula (I) in which R.sup.5 is a hydrogen atom, the 
de-esterification and decarboxylation reactions of these compounds 
selectively yield .alpha.-alkyl isomers (II.alpha.) as compounds (II). 
Although the configuration for the alkyl group at the 1-position in the 
carbapenem backbone of each of the final desired compounds is 
.beta.-configuration, the .alpha.-alkyl isomers (II.alpha.) obtained can 
be converted to .beta.-alkyl isomers (II.beta.) by isomerizing the 
.alpha.-alkyl isomers according to the known method described above. 
On the other hand, in the case where the raw compound is azetidin-2-one 
derivatives (Ib) represented by formula (I) in which R.sup.5 is an 
amino-protective group, the desired compound (II) can be obtained by 
conducting the de-esterification and decarboxylation reactions as 
described above and then eliminating the amino-protective group. This 
process preferred because .beta.-alkyl isomer (II.beta.) is preferentially 
obtained as compound (II) and is, hence, of high value in industrial 
utilization thereof. The elimination reaction for the amino-protective 
group is conducted in different ways according to the kind of the 
protective group. For example, in the case where the protective group is a 
tri-substituted silyl group, the elimination may be accomplished by 
reacting an acid such as diluted hydrochloric acid or tetrabutylammonium 
fluoride. In the case where the protective group is benzyl, phenethyl, or 
benzhydryl group or the like which may have a substituent, the elimination 
may be carried out by reacting the de-esterified and decarboxylated 
compound with sodium metal in liquid ammonia by means of Birch's 
reduction. 
According to the present invention, a 4-(1-carboxyalkyl)azetidin-2-one 
derivative useful as an intermediate for l.beta.-alkylcarbapenem-type 
antibacterials can be produced efficiently.

The present invention will be explained below in more detail with reference 
to Examples, but the present invention is not construed as being limited 
thereto. 
For the following measurements, the instruments specified below were used. 
Melting point: 
Type MP-S3 (manufactured by Yanagimoto Shoji K. K., Japan) Mass spectrum 
(MS): 
M-80B mass spectrometer (ionization potential: 20 eV) (manufactured by 
Hitachi Ltd., Japan) 
Infrared absorption spectrum (IR): Type IR-810 (manufactured by JASCO Inc., 
Japan) 
.sup.1 H Nuclear magnetic resonance spectrum (.sup.1 H-NMR): Type AM-400 
(400 MHz) (manufactured by Bruker Inc.) Internal standard: 
tetramethylsilane 
EXAMPLE 1 
##STR14## 
(In the above scheme, Ac has the meaning as defined hereinabove and TBDMS 
denotes a tert-butyldimethylsilyl group. The same applies hereinafter.) 
In 50 ml of tetrahydrofuran was suspended 2.52 g (62.9 mmol) of 60% sodium 
hydride. While this suspension was kept being stirred at room temperature, 
a solution prepared by dissolving 11.88 g (60.0 mmol) of diallyl 
methylmalonate (VII-1) in 20 ml of tetrahydrofuran was added thereto 
dropwise over a period of 20 minutes. After the resulting mixture was 
further stirred for 2.5 hours, a solution prepared by dissolving 14.35 g 
(50.0 mmol) of a 4-acetoxyazetidin-2-one derivative (IV-1) in 30 ml of 
tetrahydrofuran was added thereto dropwise over a period of 15 minutes, 
and a reaction was allowed to proceed at room temperature for 15 hours. 
To the reaction mixture was added 30 ml of a saturated aqueous solution of 
ammonium chloride. After stirring and liquid separation, the 
tetrahydrofuran layer obtained was washed with saturated aqueous common 
salt solution and dehydrated with anhydrous magnesium sulfate. 
Subsequently, the solvent was removed by distillation to obtain 23.5 g of 
crude crystals. This crude product was then recrystallized using hexane, 
thereby obtaining 18.03 g (percent yield 85%) of an azetidin-2-one 
derivative (Ia-1) as white crystals. 
Melting point: 82.degree.-82.5.degree. C. MS (m/e): 426 (M.sup.+ +1), 410, 
368 IR (KBr) cm.sup.l : 1765, 1735 .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 
0.07 (s, 6H), 0.88 (s, 9H), 1.14 (d,J=6.3 Hz, 3H), 1.50 (s, 3H), 3.03 (m, 
1H), 4.19 (d,J=2.1 Hz, 1H), 4.21 (m, 1H), 4.64 (m, 4H), 5.27 (m, 2H), 5.34 
(m, 2H), 5.88 (m, 2H), 5.96 (broad s, 1H) 
EXAMPLE 2 
##STR15## 
Five ml of hexane was added to 1.12 g (28.0 mmol) of sodium hydride, 
subsequently the resulting mixture was stirred, and the hexane was then 
removed by decantation. This procedure was repeated several times to wash 
the sodium hydride. Thereafter, 20 ml of tetrahydrofuran was added to the 
sodium hydride. While this mixture was kept being stirred at room 
temperature, a solution prepared by dissolving 4.52 g (26.0 mmol) of 
diethyl methylmalonate (VII-2) in 20 ml of tetrahydrofuran was added 
thereto dropwise over a period of 15 minutes. After the resulting mixture 
was further stirred for minutes, a solution prepared by dissolving 5.74 g 
(20.0 mmol) of a 4-acetoxyazetidin-2-one derivative (IV-I) in 20 ml of 
tetrahydrofuran was added thereto dropwise over a period of 10 minutes, 
and a reaction was allowed to proceed at room temperature for 1 hour. 
To the reaction mixture was added 25 ml of a saturated aqueous solution of 
ammonium chloride. After stirring and liquid separation, the 
tetrahydrofuran layer obtained was washed with saturated aqueous common 
salt solution and dehydrated with anhydrous magnesium sulfate. 
Subsequently, the solvent was removed by distillation to obtain crude 
crystals. This crude product was then recrystallized using hexane, thereby 
obtaining 6.17 g (percent yield 77%) of an azetidin-2one derivative (Ia-2) 
as white crystals. 
Melting point: 100.5.degree.-101.degree. C. MS (m/e): 402 (M.sup.+ +1 ), 
386,344 IR (KBr) cm.sup.-1 : 1770, 1735 .sup.1 H-NMR (CDCl.sub.3) .delta. 
ppm: 0.07 (s, 6H), 0.88 (s, 9H), 1.14 (d, J=6.3 Hz, 3H), 1.26, 1.28 (2 
overlapping t, J=7.1 Hz, 6H), 1.46 (s, 3H), 3.01 (m, 1H), 4.15 (d, J=2.2 
Hz, 1H), 4.21 (m, 5H), 5.98 (broad s, 1H) 
EXAMPLE 3 
##STR16## 
(In the above scheme, Ph denotes a phenyl group. The same applies 
hereinafter.) 
In 5 ml of tetrahydrofuran was suspended 0.43 g (10.8 mmol) of 60% sodium 
hydride. While this suspension was kept being stirred at room temperature, 
a solution prepared by dissolving 3.13 g (10.5 mmol) of dibenzyl 
methylmalonate (VII-3) in 3 ml of tetrahydrofuran was added thereto 
dropwise over a period of 20 minutes. After the resulting mixture was 
further stirred at room temperature for 30 minutes, a solution prepared by 
dissolving 2.87 g (10.0 mmol) of a 4-acetoxyazetidin-2-one derivative 
(iV-1) in 5 ml of tetrahydrofuran was added thereto dropwise over a period 
of 15 minutes, and a reaction was allowed to proceed at room temperature 
for 1.5 hours. 
To the reaction mixture was added 15 ml of a saturated aqueous solution of 
ammonium chloride. After stirring, extraction was conducted using 20 ml of 
ethyl acetate. The ethyl acetate layer obtained was washed with water, 
subsequently dehydrated with anhydrous magnesium sulfate, and then 
concentrated, thereby to obtain an oily substance. This oily substance was 
purified by silica gel column chromatography (developing solvent; 
hexane:ethyl acetate=4:1 by volume), thereby obtaining 4.28 g (percent 
yield 82%) of an azetidin-2one derivative (Ia-3) as white crystals. 
Melting point: 93.degree.-93.5.degree. C. MS (m/e): 526 (M.sup.+ +1), 510, 
468 IR (KBr) cm.sup.-1 : 1770, 1735 .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 
0.06 (s, 6H), 0.87 (s, 9H), 1.09 (d, J=6.4 Hz, 3H), 1.50 (s, 3H), 3.03 (m, 
1H), 4.19 (m, 1H), 4.20 (d, J=2.1 Hz, 1H), 5.11 (m, 4H), 5.89 (broad s, 
1H), 7.23 (m, 4H), 7.32 (m, 6H) 
EXAMPLE 4 
##STR17## 
In 15 ml of tetrahydrofuran was suspended 2.17 g (54.3 mmol) of 60% sodium 
hydride. While this suspension was kept being stirred at room temperature, 
a solution prepared by dissolving 10.9 g (54.0 mmol) of tert-butyl ethyl 
methylmalonate (VII-4) in 20 ml of tetrahydrofuran was added thereto 
dropwise over a period of 1 hour. After the resulting mixture was further 
stirred at room temperature for 30 minutes, a solution prepared by 
dissolving 14.1 g (49.1 mmol) of a 4-acetoxyazetidin-2-one derivative 
(IV-1) in 30 ml of tetrahydrofuran was added thereto dropwise over a 
period of 20 minutes, and a reaction was allowed to proceed at room 
temperature overnight. 
To the reaction mixture was added 50 ml of a saturated aqueous solution of 
ammonium chloride. After stirring extraction was conducted using 50 ml of 
ethyl acetate. The ethyl acetate layer obtained was washed twice with 25 
ml of saturated aqueous common salt solution, subsequently dehydrated with 
anhydrous magnesium sulfate, and then filtered and concentrated, thereby 
to obtain a crude product. This crude product was purified by silica gel 
column chromatography (developing solvent; hexane:ethyl acetate=4:1 by 
volume), thereby obtaining 14.2 g (percent yield 67%) of an isomer mixture 
of azetidin-2-one derivatives (Ia-4) and (Ia-5) [isomer ratio 
(Ia-4):(Ia-5)=77:23 by mol] as white crystals. 
Melting point: 73.degree.-74.degree. C. MS (m/e): 414, 372 IR (KBr) 
cm.sup.-l : 1765, 1735 .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.07 (s, 
3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.15 (d, J=6.4Hz, 3H.times.23/100), 1.20 
(d, J=6.3 Hz, 3H.times.77/100), 1.27 (d, J=7.1 Hz, 3H.times.77/100), 1.29 
(d, J=7.1 Hz, 3H.times.23/100), 1.41 (s, 3H.times.23/100), 1.42 (s, 
3H.times.77/100), 1.45 (s, 9H.times.23/100), 1.47 (s, 9H.times.77/100), 
2.98 (m, 1H.times.23/100), 3.02 (m, 1H.times.77/100), 4.04 (d, J=2.1 Hz, 
1H.times.77/100), 4.09 (d, J=2.2 Hz, 1H.times. 23/100), 4.20 (m, 3H), 5.97 
(broad s, 1H) 
EXAMPLE 5 
##STR18## 
To 0.30 g (7.5 mmol) of 60% sodium hydride was added 3 ml of hexane. This 
mixture was stirred and the hexane was then removed by decantation. 
Thereafter, 3.5 ml of tetrahydrofuran was added to the sodium hydride. 
While the mixture was kept being stirred at room temperature, a solution 
prepared by dissolving 2.96 g (7.5 mmol) of di-l-menthyl methylmalonate 
(VII-5) in 5 ml of tetrahydrofuran was added thereto dropwise over a 
period of 15 minutes. After the resulting mixture was further stirred at 
room temperature for 30 minutes, a solution prepared by dissolving 2.01 g 
(7.0 mmol) of a 4-acetoxyazetidin-2-one derivative (IV-1) in 5 ml of 
tetrahydrofuran was added thereto dropwise over a period of 10 minutes, 
and a reaction was allowed to proceed at room temperature for 1 hour. 
To the reaction mixture was added 10 ml of a saturated aqueous solution of 
ammonium chloride. After stirring and liquid separation, the 
tetrahydrofuran layer was washed with saturated aqueous common salt 
solution and then dehydrated with anhydrous magnesium sulfate. 
Subsequently, the solvent was removed by distillation to obtain a crude 
product. This crude product was purified by silica gel column 
chromatography (developing solvent; hexane:ethyl acetate=8:1 by volume), 
thereby obtaining 2.94 g (percent yield 68%) of an azetidin-2-one 
derivative (Ia-6) which was colorless and had an oily consistency. 
MS (m/e): 622 (M.sup.+ +1), 564 IR (neat) cm.sup.-l : 1770, 1740, 1720 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.07 (s, 3H), 0.08 (s, 3H), 0.72 
(d, J=7.0 Hz, 3H), 0.77 (d, J=7.0 Hz, 3H), 0.88 (s, 9H), 0.91 (d, J=6.7 
Hz, 6H), 0.92 (d, J=6.5 Hz, 0.95 (m, 6H), 1.22 (d, J=6.3 Hz, 3H), 1.42 (m 
4H), 1.45 (s, 3H), 1.70 (m, 4H), 1.86 (m, 2H), 2.03 (m, 2H), 3.10 (m, 1H), 
4.06 (d, J=2.2 Hzr 1H), 4.22 (m, 1H), 4.73 (m, 2H), 5.91 (s, 1H) 
EXAMPLE 6 
##STR19## 
In 50 ml of tetrahydrofuran was suspended 2.92 g (73.0 mmol) of 60% sodium 
hydride. While this suspension was kept being stirred at room temperature, 
a solution prepared by dissolving 33.07 g (73.0 mmol) of diallyl 
n-propylmalonate (VII-6) in 50 ml of tetrahydrofuran was added thereto 
dropwise. After the resulting mixture was stirred for 2.5 hours, a 
solution prepared by dissolving 20.10 g (70.0 mmol) of a 
4-acetoxyazetidin-2-one derivative (IV-1) in 50 ml of tetrahydrofuran was 
added thereto dropwise over a period of 30 minutes, and a reaction was 
allowed to proceed at room temperature for 15 hours. 
To the reaction mixture was added 60 ml of a saturated aqueous solution of 
ammonium chloride. After stirring and liquid separation, the 
tetrahydrofuran layer obtained was washed with saturated aqueous common 
salt solution and dehydrated with anhydrous magnesium sulfate. 
Subsequently, the solvent was removed by distillation to obtain a crude 
product This crude product was purified by silica gel column 
chromatography (developing solvent; hexane:ethyl acetate=t10:1 by volume), 
thereby obtaining 26.32 g (percent yield 83%) of an azetidin-2-one 
derivative (Ia-7) as white crystals. 
Melting point: 47.degree.-48.degree. C. MS (m/e): 438, 396 IR (KBr) 
cm.sup.-1 : 1770, 1730 .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.07 (s, 
6H), 0.88 (S, 9H), 0.94 (t, J=7.3 Hz,3H), 1.17 (d, J=6.4 Hz, 3H), 1.25 (m, 
1H), 1.47 (m, 1H), 1.80 (ddd, J=4.4, 12.5, 14.0 Hz, 1H), 1.97 (ddd, J=4.6, 
12.7, 14.0 Hz, 1H) , 3.08 (m, 1H), 4.25 (m, 2H), 4.65 (m, 4H), 5.30 (m, 
4H), 5.88 (m, 3H) 
EXAMPLE 7 
##STR20## 
In 20 ml of N,N-dimethylformamide were dissolved 8.50 g (20.0 mmol) of the 
azetidin-2-one derivative (Ia-1) obtained in Example 1 and 6.04 g (40.0 
mmol) of tert-butyldimethylsilyl chloride. To this solution, a solution 
prepared by dissolving 6.06 g (60.0 mmol) of triethylamine in 5 ml of 
N,N-dimethylformamide was added dropwise at room temperature over a period 
of 15 minutes. After the resulting mixture was further stirred for 4 
hours, 0.12 g (1.0 mmol) of 4-N,N-dimethylaminopyridine was added thereto, 
and a reaction was allowed to proceed at room temperature for 6 days. 
The reaction mixture was concentrated under a reduced pressure. Thereafter, 
40 ml of water was added to the concentrate and extraction was conducted 
using 200 ml of diethyl ether. The diethyl ether layer obtained was washed 
with 30 ml of saturated aqueous common salt solution and then dehydrated 
with anhydrous magnesium sulfate. Subsequently, the solvent was removed by 
distillation to obtain a crude product. This crude product was purified by 
alumina column chromatography (developing solvent; hexane:ethyl 
acetate=from 9:1 to 8:2 by volume), thereby obtaining 8.02 g (percent 
yield 74%) of an azetidin-2-one derivative (Ib -1) which was colorless and 
had an oily consistency. 
MS (m/e): 540 (M.sup.+ +1), 524, 482 IR (neat) cm.sup.-1 : 1760, 1740 
.sup.1 H-NMR (CDCl .sub.3) .delta. ppm: 0.07 (s, 3H), 0.08 (s, 3H), 0.11 
(s, 3H), 0.29 (s, 3H), 0.89 (s, 9H), 0.96 (s, 9H), 1.22 (d, J=6.2 Hz, 3H), 
1.50 (s, 3H), 3.07 (dd, J=2.6, 6.8 Hz, 1H), 4.09 (m, 1H), 4.35 (d, J=2.6 
Hz, 1H), 4.64 (m, 4H), 5.30 (m, 4H), 5.90 (m, 2H) 
EXAMPLE 8 
##STR21## 
In 13 ml of N,N-dimethylformamide were dissolved 1.70 g (4.0 mmol) of the 
azetidin-2-one derivative (Ia-1) obtained in Example 1 and 1.12 g (4.8 
mmol) of methyldiphenylsilyl chloride. This solution was stirred in an ice 
bath. Thereto, a solution prepared by dissolving 0.48 g (4.8 mmol) of 
triethylamine in 2 ml of N,N-dimethylformamide was added dropwise over a 
period of 40 minutes. The resulting mixture was then allowed to stand 
overnight in a refrigerator. 
From the reaction mixture, the solvent was removed by distillation under a 
reduced pressure. Subsequently, 10 ml of water and 15 ml of ethyl acetate 
were added to the residue and extraction was conducted. The ethyl acetate 
layer obtained was dehydrated with anhydrous magnesium sulfate and the 
solvent was then removed by distillation, thereby to obtain an oily 
substance. This oily substance was purified by silica gel column 
chromatography (developing solvent; hexane:ethyl acetate =5:1 by volume), 
thereby obtaining 1.69 g (percent yield 68%) of an azetidin-2-one 
derivative (Ib-2) which was colorless and had an oily consistency. 
MS (m/e): 606,564,544 IR (neat) cm.sup.-1 : 1755, 1735 .sup.1 H-NMR 
(CDCl.sub.3) .delta. ppm: -0.02 (s, 3H), 0.06 (s, 3H), 0.82 (s, 3H), 0.88 
(s, 9H), 1.14 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 3.15 (m, 1H), 4.16 (m, 1H), 
4.32 (m, 4H), 4.43 (d, J=2.7 Hz, 1H), 5.18 (m, 4H), 5.71 (m, 2H), 7.47 (m, 
10H) 
EXAMPLE 9 
##STR22## 
In 25 ml of N,N-dimethylformamide were dissolved 2.87 g (6.7 mmol) of the 
azetidin-2-one derivative (Ia-1) obtained in Example 1 and 1.58 g (10.5 
mmol) of triethylsilyl chloride. This solution was stirred in an ice bath. 
Thereto, a solution prepared by dissolving 1.06 g (10.5 mmol) of 
triethylamine in 5 ml of N,N-dimethylformamide was added dropwise over a 
period of 20 minutes. The resulting mixture was then allowed to stand 
overnight in a refrigerator. 
From the reaction mixture, the solvent was removed by distillation under a 
reduced pressure. Subsequently, 15 ml of a saturated aqueous solution of 
sodium hydrogen carbonate and 25 ml of ethyl acetate were added to the 
residue and extraction was conducted. The ethyl acetate layer obtained was 
dehydrated with anhydrous magnesium sulfate and the solvent was then 
removed by distillation, thereby to obtain an oily substance. This oily 
substance was purified by alumina column chromatography (developing 
solvent; hexane:ethyl acetate =10:1 by volume), thereby obtaining 2.20 g 
(percent yield 61%) of an azetidin-2-one derivative (Ib-3) which was 
colorless and had an oily consistency. 
MS (m/e): 524,511, 482 IR (neat) cm.sup.-1 : 1750 .sup.1 H-NMR (CDC1B) 
.delta. ppm: 0.06 (s, 3H), 0.07 (s, 3H), 0.78 (m, 6H), 0.88 (s, 9H), 0.98 
(t, J=7.8 Hz, 9H), 1.26 (d, J=6.3 Hz, 3H), 1.49 (s, 3H), 3.05 (m, 1H), 
4.12 (m, 1H), 4.21 (d, J=2.6 Hz, 1H), 4.63 (m, 4H), 5.30 (m, 4H), 5.87 (m, 
2H) 
EXAMPLE 10 
##STR23## 
In 5 ml of N,N-dimethylformamide was suspended 0.19 g (4.8 mmol) of 60% 
sodium hydride. This suspension was cooled to 0.degree. C., and a solution 
prepared by dissolving 1.93 g (4.5 mmol) of the azetidin-2-one derivative 
(Ia-1) obtained in Example 1 in 5 ml of N,N-dimethylformamide was added 
thereto dropwise over a period of 10 minutes. After the resulting mixture 
was lo further stirred for 30 minutes, the temperature of the mixture was 
returned to room temperature. Subsequently, 0.58 g (4.6 mmol) of benzyl 
chloride was added thereto dropwise and a reaction was allowed to proceed 
for 4 hours. 
To the reaction mixture was added 5 ml of a saturated aqueous solution of 
ammonium chloride. Extraction was then conducted with 50 ml of diethyl 
ether. The diethyl ether layer obtained was dehydrated with anhydrous 
magnesium sulfate and the solvent was then removed by distillation, 
thereby to obtain a crude product. This crude product was purified by 
silica gel column chromatography (developing solvent; hexane:ethyl 
acetate=4:1 by volume), thereby obtaining 1.57 g (percent yield 68) of an 
azetidin-2-one derivative (Ib-4) which was colorless and had an oily 
consistency. 
MS (m/e): 516 (M.sup.+ +1), 500, 458 IR (neat) cm.sup.-1 : 1760, 1740 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: -0.01 (s, 3H), 0.05 (s, 3H), 0.85 
(s, 9H), 1.13 (d, J=6.3 Hz, 3H), 1.31 (s, 3H), 2.99 (m, 1H), 4.18 (m, 1H), 
4.23 (d, J=15.4 Hz, 1H), 4.31 (d, J=2.1 Hz, 1H), 4.57 (m, 5H), 5.28 (m, 
4H), 5.83 (m, 2H), 7.31 (m, 5H) 
EXAMPLE 11 
##STR24## 
Using 2.13 g (5.0 mmol) of the azetidin-2-one derivative (Ia-1) obtained in 
Example 1, 0.22 g (5.5 mmol) of 60% sodium hydride, and 1.25 g (5.5mmol) 
of p-tert-butylbenzyl bromide, N-benzylation was conducted in the same 
manner as in Example 10. Thus, 2.27 g (percent yield 79%) of an 
azetidin-2-one derivative (Ib-5) was obtained which was colorless and had 
an oily consistency. 
MS (m/e): 556, 514 IR (neat) cm.sup.-1 : 1765, 1740 .sup.1 H-NMR ( 
CDCl.sub.3) .delta. ppm: -0.06 (s, 3H), 0.03 (s, 3H), 0.84 (s, 9H), 1.13 
(d, J=6 . 3 Hz, 3H), 1.29 (s, 9H), 1.33 (s, 3H), 2.98 (dd, J=2.1, 4.5 Hz, 
1H), 4.13 (d, J=15.3 Hz, 1H), 4.14 (m, 1H), 4.35 (d, J=2.1 Hz, 1H), 4.52 
(m, 5H), 5.27 (m, 4H), 5.80 (m, 4H), 7.29 (m, 4H) 
EXAMPLE 12 
##STR25## 
Using 2.13 g (5.0 mmol) of the azetidin-2-one derivative (Ia-1) obtained in 
Example 1, 0.24 g (6.0 nmol) of sodium hydride, and 0.94 g (6.0 mmol) of 
p-methoxybenzyl chloride, N-benzylation was conducted in the same manner 
as in Example 10. Thus, 2.07 g (percent yield 76%) of an azetidin-2-one 
derivative (Ib-6) was obtained which was colorless and had an oily 
consistency. 
MS(m/e): 488 IR (neat) cm.sup.-1 : 1760, 1735 .sup.1 H-NMR (CDCl.sub.3) 
.delta. ppm: 0.01 (s, 3H), 0.05 (s, 3H), 0.85 (s, 9H), 1.13 (d, J=6 .3 Hz, 
3H ) , 1.30 (s, 3H), 2.98 (dd, J=2.1, 4.3 Hz, 1H), 3.79 (s, 3H), 4.16 (m, 
1H) , 4.18 (d, J=15.2 Hz, 1H), 4.37 (d, J=2.1 Hz, 1H), 4.43 (d, J=15.2 Hz, 
1H), 4.59 (m, 4H) , 5.28 (m, 4H), 5.82 (m, 2H), 6.83 (dd, J=2.1, 6.3 HZ, 
2H), 7.27 (dd, J=2.1, 6.3 Hz, 2H) 
EXAMPLE 13 
##STR26## 
Using 4.01 g (10.0 mmol) of the azetidin-2-one derivative (Ia-2) obtained 
in Example 2, 0.40 g (11.0 mmol) of sodium hydride, and 1.39 g (11.0 mmol) 
of benzyl chloride, N-benzylation was conducted in the same manner as in 
Example 10. Thus, 4.30 g (percent yield 88%) of an azetidin-2-one 
derivative (Ib-7) was obtained which was colorless and had an oily 
consistency. 
MS(m/e): 476,434 IR (neat) cm.sup.-1 : 1760, 1730 .sup.1 H-NMR (CDC13) 
.delta. ppm: 0.00 (s, 3H), 0.06 (s, 3H), 0.87 (s, 9H), 1.16 (d, J=6.3 Hz, 
3H), 1.20, 1.22 (2 overlapping t, J=7.3 Hz, 6H), 1.30 (s, 3H), 2.99 (dd, 
J=2.1, 4.5 Hz, 1H), 4.17 (m, 6H), 4.36 (d, J=2.1 Hz, 1H), 4.55 (d, J=15.3 
Hz, 1H), 7.31 (m, 5H) 
EXAMPLE 14 
##STR27## 
To 0.40 g (10.0 mmol) of 60% sodium hydride was added 5 ml of hexane. This 
mixture was stirred and the hexane was then removed by decantation. To the 
sodium hydride was added 25 ml of N,N-dimethylformamide. Subsequently, 
4.65 g (8.9 mmol) of the azetidin-2-one derivative (Ia-3) obtained in 
Example 3 was added thereto at room temperature. After the resulting 
mixture was further stirred at room temperature for 30 minutes, a solution 
prepared by dissolving 1.12 g (8.9 mmol) of benzyl chloride in 4 ml of 
N,N-dimethylformamide was added thereto dropwise over a period of 5 
minutes, and the mixture was kept being stirred overnight at room 
temperature. 
From the reaction mixture, the solvent was removed by distillation under a 
reduced pressure. Subsequently, 15 ml of a saturated aqueous solution of 
sodium hydrogen carbonate and 35 ml of ethyl acetate were added to the 
residue and extraction was conducted. The ethyl acetate layer obtained was 
dehydrated with anhydrous magnesium sulfate and the solvent was then 
removed by distillation, thereby to obtain an oily substance. This oily 
substance was purified by silica gel column chromatography (developing 
solvent; hexane:ethyl acetane=2:1 by volume), thereby obtaining 3.50 g 
(percent yield 64%) of an azetidin-2-one derivative (Ib-8) which was 
colorless and had an oily consistency. 
MS (m/e): 600, 558 IR (neat) cm.sup.-1 : 1760, 1730 .sup.1 H-NMR 
(CDCl.sub.3) .delta. ppm: -0.03 (s, 3H), 0.03 (s, 3H), 0.84 (s, 9H), 1.10 
(d, J=6.3 Hz, 3H), 1.30 (s, 3H), 3.00 (dd, J=2.1, 4.4 Hz, 1H), 4.12 (d, 
J=15.4 Hz, 1H), 4.15 (m, 1H), 4.37 (d, J=15.4 Hz, 1H), 4.40 (d, J=2.1 Hz, 
1H), 4.94 (d, J=12.2 Hz, 1H), 5.06 (m, 3H), 7.26 (m, 15H) 
EXAMPLE 15 
##STR28## 
In an argon stream, 4.8 mg (0.02 mmol) of palladium acetate was suspended 
in 2 ml of 1,4-dioxane, and a solution prepared by dissolving 52.0 mg (0.2 
mmol) of triphenylphosphine in 2 ml of 1,4-dioxane was added dropwise to 
the suspension. Subsequently, the resulting mixture was heated with 
refluxing and, further, a solution prepared by dissolving 0.85 g (2.0 
mmol) of the azetidin-2-one derivative (Ia-1) obtained in Example 1, 0.37 
g (7.9 mmol) of formic acid, and 0.81 g (8.0 mmol) of triethylamine in 6 
ml of 1,4-dioxane was added thereto dropwise. A reaction was then allowed 
to proceed for 3 hours. 
To the reaction mixture were added 10 ml of a 5% aqueous solution of sodium 
hydroxide and 10 ml of ethyl. acetate. After liquid separation, the 
aqueous layer was acidified with in hydrochloric acid and extraction was 
then conducted with 20 ml of ethyl acetate. The ethyl acetate layer 
obtained was dehydrated with anhydrous magnesium sulfate and the solvent 
was then removed by distillation, thereby obtaining 0.47 g (percent yield 
78%) of the desired compound, a 4-(1-carboxyethyl)-azetidin-2-one 
derivative (II-1), as white crystals. 
In the compound (II-1) thus obtained, the proportions of compound 
(II.alpha.-1) in which the methyl group at the wavy line in the formula 
showing the compound (II-1) was of the .alpha.-configuration and compound 
(II.beta.-1) in which that methyl group was of the .beta.-configuration 
were such that .alpha.:.beta.=85:15 (by mol). This structure determination 
was made by separating these isomers by means of high-performance liquid 
chromatography (HPLC) (column; Inertsil ODS, manufactured by GL Sciences 
Inc., Japan, developing solvent; acetonitrile:water:acetic acid =700:300:3 
by volume). 
Isomer (II.alpha.-1) 
Melting point: 168.degree.-170.degree. C. MS (m/e): 286, 244 IR (KBr ) 
cm.sup.-l : 1720 .sup.1 H-NMR (CDCl .sub.3) .delta. ppm: 0.07 (s, 3H), 
0.08 (s, 3H), 0.88 (s, 9H) 1.25 (2 overlapping d, J=6.2, 7.3 Hz, 6H), 2.56 
(qd, J=7.3, 9.8 Hz, 1H), 2.80 (dd, J=2.0, 5.3 Hz, 1H), 3.70 (dd, J=2.0, 
9.8 Hz, 1H), 4.19 (m, 1H), 6.67(broad s, 1H) 
Isomer (II.beta.-1) 
Melting point: 143.5.degree.--144.5.degree. C. MS (m/e): 286, 244 IR (KBr ) 
cm.sup.-l : 1720 .sup.1 H-NMR (CDCl .sub.3 ) .delta. ppm: 0.07 (s, 3H), 
0.08 (s, 3H), 0.87 (s, 9H), 1.20 (d, J=6.3 Hz, 3H), 1.27 (d, J=7.0 Hz, 
3H), 2.75 (qd, J=5.0, 7.0 Hz, 1H), 3.03 (dd, J=2.2, 4.3 Hz, 1H), 3.94 (dd, 
J=2.2, 5.0 Hz, 1H), 4.20 (qd, J=4.5, 6.3 Hz, 1H),6.25 (broad s, 1H) 
EXAMPLE 16 
##STR29## 
In a nitrogen atmosphere, a solution prepared by dissolving 746.0 mg (16.22 
mmol) of formic acid and 1,647.7 mg (16.31mmol) of triethylamine in 10 ml 
of 1,4-dioxane was added to a solution prepared by dissolving 9.0 mg (0.04 
mmol) palladium acetate and 53.0 mg (0.20mmol) of triphenylphosphine in 8 
ml of 1,4-dioxane, and this mixture was heated with refluxing. Thereto was 
added dropwise, over a period of 40 minutes, a solution prepared by 
dissolving 1,815.4 mg (4.01 mmol) of the azetidin-2-one derivative (Ia-7) 
obtained in Example 6 in 5 ml of 1,4-dioxane. The resulting mixture was 
kept being heated with refluxing for further 5 hours. 
The reaction mixture was cooled to room temperature, and extraction was 
conducted with 15 ml of diethyl ether and 20 ml of a 5% aqueous solution 
of sodium hydroxide. Subsequently, 2N hydrochloric acid was added to the 
alkaline layer to adjust it to pH 2, and extraction was conducted with two 
35 ml portions of ethyl acetate. The ethyl acetate layer obtained was 
washed with saturated aqueous common salt solution, subsequently 
dehydrated with anhydrous magnesium sulfate, and then filtered and 
concentrated, thereby obtaining 985.8 mg (percent yield 75%) of the 
desired compound, a 4-(1-carboxybutyl)azetidin-2-one derivative (II-2), as 
white crystals. 
In the compound (II-2) thus obtained, the proportions of compound 
(II.alpha.-2) in which the n-propyl group at the wavy line in the formula 
showing the compound (II-2) was of the .alpha.-configuration and compound 
(II.beta.-2) in which that n-propyl group was of the .beta.-configuration 
were such that .alpha.:.beta.=73:27 (by mol). This structure determination 
was made by separating these isomers by means of HPLC (conditions 
concerning the column ant developing solvent were the same as those in 
Example 15). 
.alpha.Isomer (II.alpha.-2) Melting point: 173.degree.-174.degree. C. MS 
(m/e): 314, 272 IR (KBr) cm.sup.-1 : 1720 .sup.1 H-NMR (CD.sub.3 OD) 
.delta. ppm: 0.08 (s, 3H), 0.10 (s, 3H), 0.90 (s, 9H) , 0.94 (t, J=7.2 Hz, 
3H), 1.23 (d, J=6.3 Hz, 3H), 1.40 (m, 2H), 1.60 (m, 2H), 2.47 (m, 1H), 
2.88 (dd, J=2.0, 4.3 Hz, 1H), 3.78 (dd, J=2.0, 8.7 Hz, 1H), 4.20 (qd, 
J=4.3, 6.3 Hz, 1H) 
.beta.Isomer (II.beta.-2 ) 
Melting point: 164.5.degree.-166.degree. C. MS (m/e): 314, 272 IR (KBr) 
cm.sup.-1 : 1720 .sup.1 H-NMR (CD.sub.3 OD ) .delta. ppm: 0.07 (s, 3H), 
0.08 (s, 3H), 0.89 (s, 9H) , 0.95 (t, J=7.2 Hz, 3H), 1.16 (d, J=6.4 Hz, 
3H), 1.45 (m, 3H), 1.64 (m, 1H), 2.48 (m, 1H), 3.01 (dd, J=2.0, 2.7 Hz, 
1H), 3.77 (dd, J=2.0, 8.4 Hz, 1H), 4.22 (qd, J=2.7, 6.4 Hz, 1H) 
EXAMPLE 17 
##STR30## 
In a nitrogen atmosphere, 0.56 g (12.0 mmol)of formic acid was added to a 
solution prepared by dissolving 4.5 mg (0.02 mmol) of palladium acetate 
and 10.5 mg (0.04 mmol) of triphenylphosphine in 2.5 ml of toluene, and 
this mixture was stirred with heating at 70.degree. C. To this reaction 
mixture was added dropwise, over a period of 15 minutes, a solution 
prepared by dissolving 0.54 g (1.0 mmol) of the azetidin-2-one derivative 
(Ib-1) obtained in Example 7 in 2 ml of toluene. The mixture was then kept 
being further stirred at 70.degree. C. for 3.5 hours. 
The reaction mixture was cooled to room temperature and ml of diethyl ether 
and 5 ml of 2N hydrochloric acid were added thereto. After the resulting 
mixture was stirred for 20 minutes, liquid separation was conducted. The 
diethyl ether layer was extracted with three 10 ml portions of a 5% 
aqueous solution of sodiumhydroxide. Thereafter, 2N hydrochloric acid was 
added to the aqueous layer to adjust it to pH 2 and extraction was 
conducted with two 20 ml portions of diethyl ether. The diethyl ether 
layer obtained was washed with saturated aqueous common salt solution, 
subsequently dehydrated with anhydrous magnesium sulfate, and then 
filtered and concentrated, thereby obtaining 0.23 g (percent yield 76%) of 
the desired compound (II-1). 
In the compound (II-1) thus obtained, the proportions of isomers were such 
that (II.alpha.-1):(II.beta.-1)=6:94 (by mol). 
EXAMPLE 18 
##STR31## 
In a nitrogen atmosphere, a solution prepared by dissolving 2.02 g (44.0 
mmol) of formic acid and 5.55 g (55.0 mmol) of triethylamine in 15 ml of 
tetrahydrofuran was added to a solution prepared by dissolving 24.8 mg 
(1.1 mmol) of palladium acetate and 57.6 mg (2.2 mmol) of 
triphenylphosphine in 15 ml of tetrahydrofuran, and this mixture was 
heated with refluxing. To this reaction mixture was added dropwise, over a 
period of 30 minutes, a solution prepared by dissolving 5.68 g (11.0 mmol) 
of the azetidin-2-one derivative (Ib-4) obtained in Example 10 in 20 ml of 
tetrahydrofuran. The resulting mixture was kept being stirred for further 
1.5 hours. 
The reaction mixture was cooled to room temperature and 80 ml of diethyl 
ether was added thereto. After liquid separation, the mixture was washed 
with 30 ml of saturated aqueous common salt solution and dehydrated with 
anhydrous magnesium sulfate. The solvent was then removed by distillation 
under a reduced pressure thereby to obtain 4.41 g of a crude product. 
Subsequently, 1.29 g (56.0 mmol) of sodium metal was added to 100 ml of 
liquid ammonia cooled to -60.degree. C. Immediately after the sodium had 
dissolved and the liquid had turned dark blue, a solution prepared by 
dissolving 4.41 g of the crude product obtained above in 20 ml of diethyl 
ether was added thereto dropwise over a period of 30 minutes. Cooling of 
the reactor was stopped, and the temperature of the reaction mixture was 
returned to room temperature over a period of one night while the reaction 
mixture was kept being stirred. To the resulting reaction mixture were 
added 50 ml of diethyl ether and 50 ml of water. This mixture was stirred 
and liquid separation was then conducted. To the aqueous layer obtained, 
an extract was added which had been obtained by extracting the diethyl 
ether layer with 20 ml of a 5% aqueous solution sodium hydroxide. 
Subsequently, the resulting mixture was adjusted to pH 2 with diluted 
hydrochloric acid. This mixture was extracted with 100 ml of diethyl 
ether, and the extract was washed with 30 ml of saturated aqueous common 
salt solution, subsequently dehydrated with anhydrous magnesium sulfate, 
and then filtered and concentrated, thereby obtaining 2.60 g (percent 
yield 77%) of the desired compound (II-1). 
In the compound (II-1) thus obtained, the proportions of isomers were such 
that (II.alpha.1):(II.beta.1)=31:69 (by mol). 
EXAMPLE 19 
##STR32## 
Using 1.09 g (2.0 mmol) of the azetidin-2-one derivative (Ib-6) obtained in 
Example 12, 9.0 mg (0.04 mmol) of palladium acetate, 21.0 mg (0.08 mmol) 
of triphenyiphosphine, 0.37 g (8.0 mmol) of formic acid, and 0.91 g (9.0 
mmol) of triethylamine, de-esterification and decarboxylation reactions 
were conducted in the same manner as in Example 18. Subsequently, 
debenzylation reaction was performed using 30 ml of liquid ammonia and 
0.24 g (10.0 mmol) of sodium metal. Thus, 0.48 g (percent yield 80%) of 
the desired compound was obtained. 
In the compound (II-1) thus obtained, the proportions of isomers were such 
that (II.alpha.-1):(II.beta.-1)=39:61 (by mol). 
EXAMPLE 20 
##STR33## 
In 30 ml of methanol were suspended 1.58 g (3.0 mmol) of the azetidin-2-one 
derivative (Ia-3) obtained in Example 3, 0.72 g (7.1 mmol) of 
triethylamine, and 0.3 g of 5% palladium carbon. Hydrogenation was then 
conducted at ordinary pressure. 
The palladium carbon was removed from the resulting reaction mixture by 
filtration. Thereafter, the methanol was removed by distillation under a 
reduced pressure, and 10 ml of a saturated aqueous solution of sodium 
hydrogen carbonate and 10 ml of ethyl acetate were added to the residue. 
This mixture was stirred and liquid separation was conducted. The aqueous 
layer was acidified with iN hydrochloric acid and the white solid thus 
formed was filtered off, washed with water, and then dried under a reduced 
pressure, thereby obtaining 0.54 g (percent yield 52%) of a dicarboxylic 
acid compound (VIIIa). 
Melting point: 110.degree.-111.degree. C. MS (m/e): 244, 200 IR (KBr) 
cm.sup.-1 : 1755, 1720 .sup.1 H-NMR (CD30D) .delta. ppm: 0.02 (s, 3H), 
0.04 (s, 3H), 0.86 (s, 9H), 1.13 (d, J=6.4 Hz, 3H), 1.33 (s, 3H), 3.01 
(dd, J=2.1, 2.7 Hz, 1H), 4.19 (d, J=2.1 Hz, 1H) 4.20 (m, 1H) 
EXAMPLE 21 
##STR34## 
In a mixture of 15 ml of ethanol and 5 ml water was dissolved 1.08 g (2.7 
mmol) of the azetidin-2-one derivative (Ia-2) obtained in Example 2. 
Thereto was added a solution prepared by dissolving 0.99 g (17.6 mmol) of 
potassium hydroxide in 3 ml of water. This mixture was kept being stirred 
for 5 hours with heating at 50.degree. C. 
The reaction mixture was cooled to room temperature and then poured into 30 
ml of water. The resulting mixture was acidified with 2N hydrochloric acid 
and the white solid thus formed was filtered off, washed with water, and 
then dried under a reduced pressure, thereby obtaining 0.63 g (percent 
yield 68%) of a dicarboxylic acid compound (VIIIa). 
EXAMPLE 22 
##STR35## 
In 2 ml of ethanol was dissolved 0.40 g (0.93 mmol) of the isomer mixture 
consisting of azetidin-2-one derivatives (Ia-4) and (Ia-5) obtained in 
Example 4. Thereto was added a solution prepared by dissolving 0.34 g (6.1 
mmol) of potassium hydroxide in 3 ml of water. This mixture was kept being 
stirred at 50.degree. C. for 2 days. 
The reaction mixture was concentrated under a reduced pressure and iN 
hydrochloric acid was then added thereto to adjust it to pH 2. Thereafter, 
the resulting mixture was further concentrated under a reduced pressure. 
To the solid thus obtained, 10 ml of diethyl ether was added. This mixture 
was stirred sufficiently and then filtered and concentrated, thereby 
obtaining 0.21 g (percent yield 66%) of a dicarboxylic acid compound 
(VIIIa). 
EXAMPLE 23 
##STR36## 
In a mixture of 10 ml of ethanol and 3 ml of water was dissolved 0.62 g 
(1.0 mmol) of the azetidin-2-one derivative (Ia-6) obtained in Example 5. 
Thereto was added a solution prepared by dissolving 0.38 g (6.8mmol) of 
potassium hydroxide in 3 ml of water. This mixture was kept being stirred 
at 50.degree. C. for 25 hours. 
The reaction mixture was cooled to room temperature and then poured into 30 
ml of water. Extraction was conducted with two 10 ml portions of diethyl 
ether. The aqueous layer obtained was acidified with 2N hydrochloric acid 
and extraction was conducted with two 15 ml portions of ethyl acetate. 
Subsequently, the extract was dehydrated with anhydrous magnesium sulfate 
and then filtered and dried under a reduced pressure, thereby obtaining 
0.18 g (percent yield 52%) of a dicarboxylic acid compound (VIIIa). 
EXAMPLE 24 
##STR37## 
To 2.40 g (4.9 mmol) of the azetidin-2-one derivative (Ib-7) obtained in 
Example 13 were added 5 ml of ethanol and 10 ml of water. Thereto was 
added, with stirring, a solution prepared by dissolving 1.10 g (19.6 mmol) 
of potassium hydroxide in 5 ml of water. This mixture was stirred 
overnight at room temperature. 
The resulting reaction mixture was poured into 50 ml of water and 1N 
hydrochloric acid was added thereto to adjust it to pH 7. Extraction was 
then conducted using 50 ml of diethyl ether. Thereafter, 1N hydrochloric 
acid was added to the extract until it became pH 1, and 50 ml of diethyl 
ether was then added thereto to conduct extraction. The diethyl ether 
layer obtained was washed with 15 ml of saturated aqueous common salt 
solution, subsequently dehydrated with anhydrous magnesium sulfate, and 
then filtered and concentrated, thereby obtaining 1.50 g (percent yield 
69%) of a dicarboxylic acid compound (VIIIb). 
Melting point: 128.degree.-129.degree. C. MS (m/e): 334,290 IR (KBr) 
cm.sup.-1 : 1750, 1730 .sup.1 H-NMR (CD.sub.3 OD) .delta. ppm: 0.01 (s, 
3H), 0.07 (s, 3H), 0.86 (s, 9H), 1.16 (d, J=6.4 Hz, 3H), 1.21 (s, 3H), 
3.04 (m, 1H), 4.21 (m, 1H), 4.30 (d, J=15.2 Hz, 1H), 4.45 (d, J=2.1 Hz, 
1H), 4.46 (d, J=15.2 Hz, 1H), 7.30 (m, 5H) 
EXAMPLE 25 
##STR38## 
In 15 ml of diethylene glycol dimethyl ether was dissolved 1.38 g (4.0 
mmol) of the dicarboxylic acid compound (VIIIa) obtained in Examples 20 to 
23. This solution was heated at 120.degree. C. for 3 hours. 
The reaction mixture was cooled to room temperature and extraction was then 
conducted using 20 ml of diethyl ether and 15 ml of a 5% aqueous solution 
of sodium hydroxide. Thereafter, the aqueous layer was washed with 10 ml 
of diethyl ether and then adjusted to pH 2 with 2N hydrochloric acid, and 
extraction was conducted using 30 ml of diethyl ether. The diethyl ether 
layer obtained was washed with 10 ml of saturated aqueous common salt 
solution, subsequently dehydrated with anhydrous magnesium sulfate, and 
then filtered and concentrated, thereby obtaining 0.97 g (percent yield 
80%) of the desired compound (II-1). 
In the compound (II-1) thus obtained, the proportions of isomers were such 
that (II.alpha.1):(II.beta.1)=90:10 (by mol). 
EXAMPLE 26 
##STR39## 
In the same manner as in Example 23, 0.87 g (2.0 mmol) of the dicarboxylic 
acid compound (VIIIb) obtained in Example 24 was heated to conduct 
decarboxylation reaction. Thereafter, debenzylation reaction was performed 
using liquid ammonia and sodium metal in the same manner as in Example 18, 
thereby obtaining 0.42 g (percent yield 70%) of the desired compound 
(II-1). 
In the compound (II-1) thus obtained, the proportions of isomers were such 
that (II.alpha.1):(II.beta.1)=28:72 by mol). 
While the invention has been described in detail and with reference to 
specific embodiments thereof, it will be apparent to one skilled in the 
art that various changes and modifications can be made therein without 
departing from the spirit and scope thereof.