JP2958835B2 - Method for producing 4- (1-carboxyalkyl) azetidin-2-one derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to 4- (1-alkylcarbapenem) antibacterial agents useful as synthetic intermediates.
The present invention relates to a method for producing a (1-carboxyalkyl) azetidin-2-one derivative.

[0002]

2. Description of the Related Art Carbapenem antibacterial agents are excellent antibacterial agents having strong antibacterial activity against a wide range of bacteria from Gram-positive bacteria to Gram-negative bacteria including Pseudomonas aeruginosa. In recent years, it has been actively developed. Equation (3)

[0003]

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Carbapenems which do not have a substituent at the 1-position of the carbapenem skeleton, such as thienamycin, are chemically unstable at high concentrations and are easily metabolized by renal dehydropeptidase. However, the introduction of a β-configuration alkyl group at the 1-position increases the stability and enables the use alone without blending a renal dehydropeptidase inhibitor. For this reason, 1
The development of β-alkylcarbapenem antibacterials has been focused on, and the synthetic formula (2β)

[0005]

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[0006] (wherein, R ³ represents a lower alkyl group, R ⁴
Represents a protecting group for a hydrogen atom or a hydroxyl group).
[(R) -1-carboxyalkyl] azetidine-2-
Development of a method for synthesizing on derivatives is also actively pursued.

Although many reports have been made on the method of synthesizing this compound (2β), the compound of the general formula (4)

[0008]

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(Wherein, R ⁴ has the same meaning as described above;
c represents an acetyl group), and the method of introducing a side chain by alkylating the 4-position of the 4-acetoxyazetidin-2-one derivative represented by the formula (1) with various nucleophiles is most expected. , Alkylation with propionate enolate [C. U. Kim et al .; Tetrahedr.
on Lett. , 28 (5) 507-510 (198
7), T. Chiba et al .; Chem. Lett. , 13
43-1346 (1985); Shibata et al .;
Tetrahedron Lett. , 26 (39) 4
739-4742 (1985)], alkylation of propionimide with an enolate [Y. Nagao et al .;
J. Am. Chem. Soc. , 108 , 4673-4
675 (1986), Nagamitsu Yoshimitsu; Chemistry, 42 (3) 19
0-196 (1987); M. Fuentes et al .;
J. Am. Chem. Soc. , 108 , 4675-4
676 (1986); Deziel et al; Tetra
hedron Lett. , 27 (47) 5687-5
690 (1986); Ito et al .; Tetrahed
ron Lett. , 28 (52) 6625-6628
(1987), alkylation with propionate thiol ester enolate [M. Endo; Can. J. Ch
em. , 65 , 2140-2145 (1987), C.I.
U. Kim et al; Tetrahedron Lett. ,
28 (5) 507-510 (1987); Mart
el et al; Can. J. Chem. , 66 , 1537-1
539 (1988)]. Other methods for synthesizing compound (2β) include, for example, compound (5)

[0010]

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(Wherein R ⁴ has the same meaning as described above) with lithium diisopropylamide [D. H. Shih et al .; Heterocycles,
21 (1) 29-40 (1984), compound (6)

[0012]

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[0013] (wherein, R ⁴ are as defined above, R ⁵
Represents a protecting group for a hydrogen atom or an amino group, and R ⁶ represents an alkyl group, a carboxy group or an alkoxycarbonyl group). No. 26887,
C. U. Kim et al; Tetrahedron Let
t. , 28 (5) 507-510 (1987); O
hta et al .; Org. Chem. , 52 , 3176
3178 (1987); Iimori et al .; Tetr
ahedron Lett. , 27 (19) 2149-
2152 (1986)], and a review article [Yoshio Ito et al .; Synthetic Organic Chemistry, 47 (7) 606-618 (198).
9)].

Compound (2β) obtained by these methods
Is most often the stereoisomer of the compound (2
α)

[0015]

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(Wherein R ³ and R ⁴ have the same meanings as described above) and a compound (2) mixed at a specific ratio

[0017]

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(Wherein R ³ and R ⁴ have the same meanings as described above). The compound (2α) having an alkyl group in α-configuration can be obtained, for example, from D.I. H. Shih et al .;
Heterocycles, 21 (1) 29-40 (1
If isomerization is carried out by the method described in No. 984),
Compounds having the desired alkyl group of β-configuration (2
β).

However, the above-mentioned methods for synthesizing the compound (2) and the compound (2β) use special and expensive reagents, have extremely low reaction temperatures, or use expensive metals or toxic metals as catalysts. For example, it is not a method suitable for mass synthesis, and is not actually manufactured on an industrial scale.

Accordingly, compound (2), particularly compound (2) having a β-configuration alkyl group, which is more useful as a synthetic intermediate for 1β-alkylcarbapenem-based antibacterial agents
Development of a method for efficiently producing β) has been desired.

[0021]

Under these circumstances, the present inventors have conducted intensive studies, and as a result, have found that a malonic acid derivative is bonded to the 4-position of the azetidin-2-one skeleton.
-Dialkoxycarbonylalkyl) azetidine-2-
The 4- (1-carboxyalkyl) azetidin-2-one derivative can be efficiently obtained by using an on derivative as a raw material, de-esterifying and de-carboxylating it, and deprotecting if an amino-protecting group is present. They found that they could be manufactured and completed the present invention.

That is, the present invention provides a compound represented by the general formula (1):

[0023]

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(Wherein R ¹ and R ² are the same or different,
Each represents an alkyl group, an alkenyl group or an aralkyl group; R ³ represents a lower alkyl group; R ⁴ represents a hydrogen atom or a hydroxyl protecting group; and R ⁵ represents a hydrogen atom or an amino group protecting group). A 4- (1,1-dialkoxycarbonylalkyl) azetidin-2-one derivative to be subjected to deesterification and decarboxylation and, if an amino-protecting group is present, to deprotection. 2)

[0025]

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(Wherein R ³ and R ⁴ have the same meanings as described above). A method for producing a 4- (1-carboxyalkyl) azetidin-2-one derivative represented by the formula:

In the present invention, 4
The-(1,1-dialkoxycarbonylalkyl) azetidin-2-one derivative is represented by the general formula (1). In the formula, examples of the alkyl group represented by R ¹ and R ² include methyl A linear or branched alkyl group such as a group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a tert-butyl group; a cyclopentyl group;
Monocyclic or polycyclic alkyl groups such as a cyclohexyl group, a mentyl group, a fentyl group, and a bornyl group are exemplified. Examples of the alkenyl group include a vinyl group, an allyl group,
A straight-chain or branched-chain alkenyl group such as a butenyl group and a 2-methyl-2-propenyl group can be mentioned, and examples of the aralkyl group include a benzyl group and a benzhydryl group. Examples of the lower alkyl group represented by R ³ include a methyl group, an ethyl group, and an n-propyl group. Examples of the protecting group for the hydroxyl group represented by R ⁴ include a trimethylsilyl group and a tert-butyldimethylsilyl group. A trisubstituted silyl group such as a group; an acyl group such as an acetyl group; an aralkyl group such as a benzyl group;
Examples of the protecting group for the amino group represented by R ⁵ include trisubstituted silyl groups such as trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group and methyldiphenylsilyl group; benzyl group, p-methoxybenzyl group, An aralkyl group which may have a substituent on an aromatic ring such as -tert-butylbenzyl group, 3,4-dimethylbenzyl group, phenethyl group, benzhydryl group;
Examples thereof include an alkoxyalkyl group such as a tetrahydropyranyl group and a methoxymethyl group.

When R ⁵ is a hydrogen atom in the general formula (1) (hereinafter referred to as “azetidin-2-one derivative (1a)”),
For example, R. Joyeau et al. [J. Chem. So
c. , Perkin Trans. I, 1899-19
07 (1987), Tetrahedron Let
t. , 30 (3) 337-340 (1989)] and a malonic acid derivative (7) is reacted with a 4-acetoxyazetidin-2-one derivative (4) according to the following formula.

[0029]

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Wherein R ¹ , R ² , R ³ , R ⁴ and Ac have the same meaning as described above.

Alkali metal such as potassium metal, sodium metal and lithium metal; alkali metal hydride such as sodium hydride; alkali metal alkylide such as butyl lithium; potassium-tert
Alkali metal alkoxides such as butyrate, sodium ethylate and sodium methylate; alkali metal hydroxides such as potassium hydroxide and sodium hydroxide; malonic acid derivatives activated with alkali metal carbonates such as potassium carbonate (7) A 4-acetoxyazetidin-2-one derivative (4) is added to the solution, and
C., particularly preferably at room temperature for 0.5 to 15 hours. Examples of the solvent used here include water; alcohols such as methanol and ethanol; ethers such as diethyl ether, dioxane and tetrahydrofuran; acetone; dimethylformamide; or a mixed solvent of water and these organic solvents. Among them, tetrahydrofuran is particularly preferably used. The ratio of the reaction compound is preferably about 1 to 1.3 mol of the malonic acid derivative (7) per 1 mol of the 4-acetoxyazetidin-2-one derivative (4). The obtained 4- (1,1-dialkoxycarbonylalkyl) azetidin-2-one derivative (1a) is subjected to extraction, washing, dehydration, etc. by a usual method, and then purified by recrystallization, column chromatography or the like. be able to.

In the general formula (1), when R ⁵ is a protecting group for an amino group (hereinafter referred to as “azetidin-2-one derivative (1b)”), R ⁵ is a hydrogen atom by the above-mentioned method. After obtaining a certain azetidin-2-one derivative (1a), it is produced by introducing an amino-protecting group by an ordinary method.

In the present invention, the desired 4- (1-carboxyalkyl) azetidin-2-one derivative is obtained by subjecting the thus obtained compound (1) to deesterification and decarboxylation by a conventional method. (2) can be obtained.

[0034]

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(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as described above)

This deesterification and decarboxylation reaction can be carried out, for example, by ordinary hydrolysis and heating reactions. That is, the compound (1) may be hydrolyzed in the presence of a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, and then decarbonated by heating to 80 to 120 ° C. When R ^{1 and} R ² are aralkyl groups, deesterification can also be performed by hydrogenation using palladium carbon in the presence of an amine.

When the compound (1) in which R ¹ and R ² are 2-alkenyl groups is used as a raw material, the deesterification and decarboxylation can be carried out by the above-mentioned methods. The method of Tsuji et al. [Tetrahe
drone Lett. , 20 (7) 613-616 (1
979)], the esterification and decarboxylation can be carried out in one step, preferably by reacting the compound (1) with formic acid or an amine salt of formic acid in the presence of a palladium compound. The palladium compound used here may be any as long as it can generate zero-valent palladium as an active species in the reaction system, and specifically, a divalent compound such as palladium acetate, palladium chloride, or palladium acetylacetonate. Palladium compounds; zero-valent palladium compounds such as tribenzylidene dipalladium and tetrakistriphenylphosphine palladium; and the like. Further, as ligands, trialkylphosphines such as triethylphosphine and tributylphosphine; triphenylphosphine and triphenylphosphine. When a triarylphosphine such as tolylphosphine is mixed, a complex is formed in the reaction system and acts as a catalyst to cause the reaction to proceed. This reaction is carried out by heating and refluxing for 1 to 5 hours using a solvent such as ethers such as 1,4-dioxane and tetrahydrofuran; toluene; benzene. The ratio of the reaction compound is about 0.01 to 1 mol of the palladium compound per 1 mol of azetidin-2-one (1).
It is preferably 0.1 mol, formic acid or about 3 to 15 mol of formic acid amine salt.

The starting compound is, in the general formula (1) ^{R 5}
Is an azetidin-2-one derivative (1a)
In the case of the compound (2) obtained by the deesterification / decarboxylation reaction, an α-alkyl compound (2α) can be selectively obtained. The configuration of the alkyl group at the 1-position of the carbapenem skeleton, which is the final product, is in the β-configuration. The obtained α-alkyl form (2α) is isomerized by the above-mentioned known method to give the β-alkyl form. (2β).

On the other hand, when R ⁵ is a protecting group for an amino group in the general formula (1) (hereinafter referred to as “azetidin-2-one derivative (1b)”), After performing the esterification and decarboxylation reaction, the target compound (2) can be obtained by removing the protecting group of the amino group. In this case, the obtained compound (2) is a β-alkyl Since the body (2β) is preferentially obtained, the industrial utility value is high, which is preferable. The elimination reaction of the protecting group for the amino group differs depending on the type of the protecting group. For example, when the protecting group is a trisubstituted silyl group, an acid such as dilute hydrochloric acid may be reacted. In the case where the protecting group is a benzyl group, a phenethyl group, a benzhydryl group or the like which may have a substituent, it may be reduced with birch and reacted with metallic sodium in liquid ammonia.

[0040]

Next, the present invention will be further described with reference to Reference Examples and Examples, but the present invention is not limited thereto. The following equipment was used for the following measurements. Melting point: MP-S3 type (Yanagimoto Shoji Co., Ltd.) Mass spectrum (MS): M-80B mass spectrometer (ionization voltage: 20 eV) (Hitachi Ltd.) Infrared absorption spectrum (IR): IR-810 type (Manufactured by JASCO Corporation) ¹ H nuclear magnetic resonance spectrum ( ¹ H-NMR): AM-40
0 type (400MH _z) (manufactured by Bruker) Internal standard substance: tetramethylsilane

Reference Example 1

[0042]

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(In the formula, Ac has the same meaning as described above.
BDMS represents a tert-butyldimethylsilyl group.
2.52 g (62.9 mmol) of 60% sodium hydride was suspended in 50 ml of tetrahydrofuran, and diallyl methylmalonate (7
-1) A solution obtained by dissolving 11.88 g (60.0 mmol) in 20 ml of tetrahydrofuran was added dropwise over 20 minutes. After further stirring for 2.5 hours, 14.35 g of the 4-acetoxyazetidin-2-one derivative (4-1) (5.
0.0mmol) in 30 ml of tetrahydrofuran was added dropwise over 15 minutes, and the reaction was continued at room temperature for 15 hours. 30 ml of saturated aqueous ammonium chloride solution
After stirring and liquid separation, the obtained tetrahydrofuran layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 23.5 g of crude crystals. Recrystallization was performed using hexane to obtain 18.03 g (yield: 85%) of azetidin-2-one derivative (1a-1) as white crystals. ^{Mp: 82-82.5 ℃ MS (m / e} ): 426 (M + +1), 410,368 IR (KBr) cm -1: 1765,1735 1 H-NMR δ (CDCl 3): 0.07 ( s, 6
H), 0.88 (s, 9H), 1.14 (d, J = 6.
3Hz, 3H), 1.50 (s, 3H), 3.03
(M, 1H), 4.19 (d, J = 2.1 Hz, 1
H), 4.21 (m, 1H), 4.64 (m, 4H),
5.27 (m, 2H), 5.34 (m, 2H), 5.8
8 (m, 2H), 5.96 (broad s, 1H)

Reference Example 2

[0045]

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1.12 g of 60% sodium hydride (2
8.0 mmol), 5 ml of hexane was added and stirred, and then the hexane was removed by a gradient method. After washing by repeating this procedure several times, 20 ml of tetrahydrofuran was added, and while stirring at room temperature, diethyl methylmalonate (7 ml) was added.
-2) A solution of 4.52 g (26.0 mmol) in 20 ml of tetrahydrofuran was added dropwise over 15 minutes. After further stirring for 30 minutes, 4-acetoxyazetidine-
5.74 g (20.0 mmol) of 2-one derivative (4-1)
Was added dropwise over 10 minutes, and the reaction was continued at room temperature for 1 hour. To the reaction mixture was added 25 ml of a saturated aqueous solution of ammonium chloride, and the mixture was stirred and separated. The obtained tetrahydrofuran layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain crude crystals. Recrystallization was performed using hexane, and 6.17 g of an azetidin-2-one derivative (1a-2) as white crystals was obtained.
(77% yield). Melting point: 100.5-101 ° C MS (m / e): 402 (M ⁺ +1), 386,344 IR (KBr) cm ^-1 : 1770,1735 ¹ H-NMR δ (CDCl ₃ ): 0.07 (s, 6H), 0.88 (s, 9H), 1.14 (d, J = 6.
3Hz, 3H), 1.26,1.28 (2overlapping t, J = 7.1Hz, 6H), 1.46
(s, 3H), 3.01 (m, 1H), 4.15 (d, J = 2.2Hz, 1H), 4.21 (m, 5H), 5.
98 (broad s, 1H)

Reference Example 3

[0048]

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(In the formula, Ph represents a phenyl group; the same applies hereinafter.) In 5 ml of tetrahydrofuran, 0.1% of 60% sodium hydride was added.
43 g (10.8 mmol) were suspended and, while stirring at room temperature, 3.13 g of dibenzyl methylmalonate (7-3)
A solution of (10.5 mmol) in 3 ml of tetrahydrofuran was added dropwise over 20 minutes. Further, after stirring at room temperature for 30 minutes, a solution of 2.87 g (10.0 mmol) of the 4-acetoxyazetidin-2-one derivative (4-1) dissolved in 5 ml of tetrahydrofuran was added dropwise over 15 minutes. The reaction was continued for 1.5 hours. To the reaction mixture was added 15 ml of a saturated aqueous solution of ammonium chloride, and the mixture was stirred.
Extraction was performed using ml. The obtained ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated to obtain an oily substance. This was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 4:
Purification according to 1) gave 4.28 g (82% yield) of azetidin-2-one derivative (1a-3) as white crystals. Melting point: 93-93.5 ° C MS (m / e): 526 (M ⁺ +1), 510,468 IR (KBr) cm ^-1 : 1770,1735 ¹ H-NMR δ (CDCl ₃ ): 0.06 (s, 6H), 0.87 (s, 9H), 1.09 (d, J = 6.
4Hz, 3H), 1.50 (s, 3H), 3.03 (m, 1H), 4.19 (m, 1H), 4.20 (d, J =
2.1Hz, 1H), 5.11 (m, 4H), 5.89 (broad s, 1H), 7.23 (m, 4H),
7.32 (m, 6H)

Reference Example 4

[0051]

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A suspension of 2.17 g (54.3 mmol) of 60% sodium hydride in 15 ml of tetrahydrofuran was added with 10.9 g (54.0 mmol) of tert-butylethyl methylmalonate (7-4) at room temperature while stirring. A solution dissolved in 20 ml of tetrahydrofuran was added dropwise over 1 hour. Furthermore, after stirring at room temperature for 30 minutes, 14.1 g of 4-acetoxyazetidin-2-one derivative (4-1) was obtained.
A solution of (49.1 mmol) dissolved in 30 ml of tetrahydrofuran was added dropwise over 20 minutes, and the reaction was continued at room temperature overnight. After adding 50 ml of a saturated aqueous solution of ammonium chloride to the reaction solution and stirring, extraction was performed using 50 ml of ethyl acetate.
The obtained ethyl acetate layer was washed twice with 25 ml of saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. This was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate =
4: 1) to give azetidine-2- white crystals.
An isomer mixture of the on derivatives (1a-4) and (1a-5) [mixing ratio (1a-4) :( 1a-5) = 77: 23]
14.2 g (67% yield) was obtained. Melting point: 73-74 ° C MS (m / e): 414,372 IR (KBr) cm ^-1 : 1765,1735 ¹ H-NMR δ (CDCl ₃ ): 0.07 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H)
1.15 (d, J = 6.4Hz, 3H × 23/100), 1.20 (d, J = 6.3Hz, 3H × 77/1
00), 1.27 (d, J = 7.1Hz, 3H × 77/100), 1.29 (d, J = 7.1Hz, 3H ×
23/100), 1.41 (s, 3H × 23/100), 1.42 (s, 3H × 77/100), 1.45
(s, 9H × 23/100), 1.47 (s, 9H × 77/100), 2.98 (m, 1H × 23/10
0), 3.02 (m, 1H × 77/100), 4.04 (d, J = 2.1Hz, 1H × 77/100),
4.09 (d, J = 2.2Hz, 1H × 23/100), 4.20 (m, 3H), 5.97 (broad
s, 1H)

Reference Example 5

[0054]

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0.30 g of 60% sodium hydride (7.
5 mmol), and 3 ml of hexane was added and stirred, and then hexane was removed by a gradient method. To this, tetrahydrofuran 3.
Add 5 ml, and stir at room temperature.
2.96 g (7.5 mmol) of (1) -menthyl (7-5)
Was dissolved dropwise in 5 ml of tetrahydrofuran over 15 minutes. After stirring at room temperature for 30 minutes,
1. Acetoxyazetidin-2-one derivative (4-1)
A solution of 01 g (7.0 mmol) in 5 ml of tetrahydrofuran was added dropwise over 10 minutes, and the reaction was continued at room temperature for 1 hour. 10 ml of a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred and separated. The tetrahydrofuran layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product. This was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 8: 1) to give azetidine-2 as a colorless oil.
2.94 g (68% yield) of the -one derivative (1a-6) was obtained. MS (m / e): 622 (M + +1), 564 IR (neat) cm -1: 1770,1740,1720 1 H-NMR δ (CDCl 3): 0.07 (s, 3H), 0.08 (s, 3H), 0.72 (d, J = 7.
0Hz, 3H), 0.77 (d, J = 7.0Hz, 3H), 0.88 (s, 9H), 0.91 (d, J = 6.7
Hz, 6H), 0.92 (d, J = 6.5Hz, 6H), 0.95 (m, 6H), 1.22 (d, J = 6.3H
z, 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 = 2.2Hz, 1H), 4.22 (m, 1H
H), 4.73 (m, 2H), 5.91 (s, 1H)

Reference Example 6

[0057]

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2.92 g (73.0 mmol) of 60% sodium hydride were suspended in 50 ml of tetrahydrofuran, and diallyl n-propylmalonate (7
-6) A solution of 33.07 g (73.0 mmol) in 50 ml of tetrahydrofuran was added dropwise. After stirring for 2.5 hours, a solution of 20.10 g (70.0 mmol) of the 4-acetoxyazetidin-2-one derivative (4-1) in 50 ml of tetrahydrofuran was added dropwise over 30 minutes.
The reaction was continued at room temperature for 15 hours. After adding 60 ml of a saturated aqueous solution of ammonium chloride to the reaction solution and stirring and separating the resulting solution, the obtained tetrahydrofuran layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product.
This was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 10: 1) to give an azetidin-2-one derivative (1a-) as white crystals.
7) 26.32 g (83% yield) was obtained. Melting point: 47-48 ° C MS (m / e): 438,396 IR (KBr) cm ^-1 : 1770,1730 ¹ H-NMR δ (CDCl ₃ ): 0.07 (s, 6H), 0.88 (s, 9H), 0.94 (t, J = 7.
3Hz, 3H), 1.17 (d, J = 6.4Hz, 3H), 1.25 (m, 1H), 1.47 (m, 1H),
1.80 (ddd, J = 4.4,12.5,14.0Hz, 1H), 1.97 (ddd, J = 4.6,12.
7,14.0Hz, 1H), 3.08 (m, 1H), 4.25 (m, 2H), 4.65 (m, 4H), 5.30
(m, 4H), 5.88 (m, 3H)

Reference Example 7

[0060]

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In 20 ml of N, N-dimethylformamide, the azetidin-2-one derivative (1a-
1) 8.50 g (20.0 mmol) and tert-butyldimethylsilyl chloride 6.04 g (40.0 mmol)
Was dissolved, and 6.06 g (60.0 mmol) of triethylamine was dissolved.
A solution of l) in 5 ml of N, N-dimethylformamide was added dropwise at room temperature over 15 minutes. After further stirring for 4 hours, 0.12 g of 4-N, N-dimethylaminopyridine
(1.0 mmol) was added and reacted at room temperature for 6 days. After the reaction solution was concentrated under reduced pressure, 40 ml of water was added and extraction was performed using 200 ml of diethyl ether. The obtained diethyl ether layer was washed with 30 ml of saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a crude product. This was purified by alumina camula chromatography (developing solvent; hexane: ethyl acetate = 9: 1 to 8: 2) to give a colorless oily azetidin-2-one derivative (1b
-1) 8.02 g (74% yield) was obtained. MS (m / e): 540 (M ⁺ +1), 524,482 IR (neat) cm ^-1 : 1760,1740 ¹ H-NMR δ (CDCl ₃ ): 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 = 6.2Hz, 3
H), 1.50 (s, 3H), 3.07 (dd, J = 2.6,6.8Hz, 1H), 4.09 (m, 1H),
4.35 (d, J = 2.6Hz, 1H), 4.64 (m, 4H), 5.30 (m, 4H), 5.90 (m, 2
H)

Reference Example 8

[0063]

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60 ml of 5 ml of N, N-dimethylformamide
0.19 g (4.8 mmol) of sodium hydride was cooled to 0 ° C., and the azetidine-2 obtained in Reference Example 1 was suspended in the suspension.
A solution obtained by dissolving 1.93 g (4.5 mmol) of the -one derivative (1a-1) in 5 ml of N, N-dimethylformamide was added to 1
It was added dropwise over 0 minutes. After further stirring for 30 minutes, the temperature was returned to room temperature, 0.58 g (4.6 mmol) of benzyl chloride was added dropwise, and the reaction was continued for 4 hours. To the reaction solution was added 5 ml of a saturated aqueous solution of ammonium chloride, and the mixture was extracted with 50 ml of diethyl ether. After the obtained diethyl ether layer was dehydrated with anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product. This was subjected to silica gel column chromatography (developing solvent;
Hexane: ethyl acetate = 4: 1) to give a colorless oily azetidin-2-one derivative (1b-2).
7 g (68% yield) were obtained. MS (m / e): 516 (M ⁺ +1), 500,458 IR (neat) cm ^-1 : 1760,1740 ¹ H-NMR δ (CDCl ₃ ): -0.01 (s, 3H), 0.05 (s, 3H) ), 0.85 (s, 9
H), 1.13 (d, J = 6.3Hz, 3H), 1.31 (s, 3H), 2.99 (m, 1H), 4.18
(m, 1H), 4.23 (d, J = 15.4Hz, 1H), 4.38 (d, J = 2.1Hz, 1H), 4.57
(m, 5H), 5.28 (m, 4H), 5.83 (m, 2H), 7.31 (m, 5H)

Reference Example 9

[0066]

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2.13 g (5.0 mmol) of the azetidin-2-one derivative (1a-1) obtained in Reference Example 1, 60%
0.24 g (6.0 mmol) of sodium hydride and p chloride
N-benzylation was carried out using 0.94 g (6.0 mmol) of -methoxybenzyl according to the above Reference Example 8 to give a colorless oily azetidin-2-one derivative (1b-3) 2.0
7 g (76% yield) were obtained. MS (m / e): 488 IR (neat) cm ^-1 : 1760,1735 ¹ H-NMR δ (CDCl ₃ ): 0.01 (s, 3H), 0.05 (s, 3H), 0.85 (s, 9H),
1.13 (d, J = 6.3Hz, 3H), 1.30 (s, 3H), 2.98 (dd, J = 2.1,4.3Hz,
1H), 3.79 (s, 3H), 4.16 (m, 1H), 4.18 (d, J = 15.2Hz, 1H), 4.37
(d, J = 2.1Hz, 1H), 4.43 (d, J = 15.2Hz, 1H), 4.59 (m, 4H), 5.28
(m, 4H), 5.82 (m, 2H), 6.83 (dd, J = 2.1,6.3Hz, 2H), 7.27 (dd,
(J = 2.1,6.3Hz, 2H)

Reference Example 10

[0069]

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The azetidin-2-one derivative (1a-2) obtained in Reference Example 2 (4.01 g, 10.0 mmol),
0.40 g of 60% sodium hydride (11.0 mmo
l) and 1.39 g (11.0 mmol) of benzyl chloride
Was subjected to N-benzylation according to the above Reference Example 8 to give a colorless oily azetidin-2-one derivative (1b-
4) 4.30 g (88% yield) was obtained. MS (m / e): 476,434 IR (neat) cm -1: 1760,1730 1 H-NMR δ (CDCl 3): 0.00 (s, 3
H), 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 (d
d, 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)

Embodiment 1

[0072]

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4.8 m of palladium acetate in a stream of argon
g (0.02 mmol) was suspended in 2 ml of 1,4-dioxane, and 52.0 mg of triphenylphosphine was added thereto.
(0.2 mmol) dissolved in 2 ml of 1,4-dioxane was added dropwise, and the mixture was heated under reflux, and then the azetidin-2-one derivative (1a-1) obtained in Reference Example 1 was added.
85 g (2.0 mmol), formic acid 0.37 g (8.0 m
mol) and 0.81 g (8.0 mm) of triethylamine.
ol) in 6 ml of 1,4-dioxane was added dropwise and reacted for 3 hours. 10 ml of a 5% aqueous solution of sodium hydroxide and 10 ml of ethyl acetate were added to the reaction solution, and the mixture was separated.
Extracted with l. After the obtained ethyl acetate layer was dehydrated with anhydrous magnesium sulfate, the solvent was distilled off, and the target compound 4- (1-carboxyethyl) -azetidine-2 was obtained as white crystals.
0.47 g (78% yield) of the -one derivative (2-1) was obtained. The formation ratio of the compound (2α-1) in which the methyl group of the wavy line in the formula of the obtained compound (2-1) is α-position and the compound (2β-1) in which the methyl group is β-position is α: β = 85: 15 and
These are high performance liquid chromatography (HPLC) (column: Inertsil ODS, manufactured by GL Sciences Inc., developing solvent: acetonitrile: water: acetic acid = 7)
00: 300: 3) and the structure was determined. α body (2α-1) mp: 168-170 ℃ MS (m / e ): 286,244 IR (KBr) cm -1: 1720 1 H-NMR δ (CDCl 3): 0.07 (s, 3
H), 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 (broads, 1H) β body (2β-1) mp: 143.5-144.5 ℃ MS (m / e ): 286,244 IR (KBr) cm -1: 1720 1 H-NMR δ (CDCl 3 ): 0.07 (s, 3
H), 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)

Embodiment 2

[0075]

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Under a nitrogen atmosphere, 9.0 mg of palladium acetate
(0.04 mmol) and triphenylphosphine 53.0
mg (0.20 mmol) in 8 ml of 1,4-dioxane was dissolved in a solution of 746.0 mg (16.22 mmol) of formic acid and 1647.7 mg (16.31 mmol) of triethylamine in 10 ml of 1,4-dioxane. In addition, the mixture was heated to reflux. In addition, azetidine-2- obtained in Reference Example 6
1815.4 mg (4.01 mmol) of the on derivative (1a-7)
A solution of l) dissolved in 5 ml of 1,4-dioxane was added dropwise over 40 minutes, and the mixture was further heated under reflux for 5 hours. The reaction solution was cooled to room temperature, extracted with 15 ml of diethyl ether and 20 ml of a 5% aqueous sodium hydroxide solution, adjusted to pH 2 by adding 2N hydrochloric acid to the alkaline layer, and extracted twice with 35 ml of ethyl acetate. The obtained ethyl acetate layer was washed with a saturated saline solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated to obtain the target compound 4- (1-carboxybutyl) -azetidin-2-one derivative (2) as white crystals. -2) 98
5.8 mg (75% yield) were obtained. The formation ratio of the compound (2α-2) in which the n-propyl group of the wavy line in the formula of the obtained compound (2-2) is α-position and the compound (2β-2) in which β-position is obtained is α: β = 73:27, which are HPLC
(The conditions of the column and the developing solvent were the same as in Example 1), and the structure was determined. α body (2α-2) mp: 173-174 ℃ MS (m / e ): 314,272 IR (KBr) cm -1: 1720 1 H-NMR δ (CD 3 OD): 0.08 (s, 3H), 0.10 ( s, 3H), 0.90 (s, 9H),
0.94 (t, J = 7.2Hz, 3H), 1.23 (d, J = 6.3Hz, 3H), 1.40 (m, 2H),
1.60 (m, 2H), 2.47 (m, 1H), 2.88 (dd, J = 2.0,4.3Hz, 1H), 3.78
(dd, J = 2.0,8.7Hz, 1H), 4.20 (qd, J = 4.3,6.3Hz, 1H) β-isomer (2β-2) Melting point: 164.5-166 ° C MS (m / e): 314,272 IR (KBr ^{) cm -1: 1720 1 H-} NMR δ (CD 3 OD): 0.07 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H),
0.95 (t, J = 7.2Hz, 3H), 1.16 (d, J = 6.4Hz, 3H), 1.45 (m, 3H),
1.64 (m, 1H), 2.48 (m, 1H), 3.01 (dd, J = 2.0,2.7Hz, 1H), 3.77
(dd, J = 2.0,8.4Hz, 1H), 4.22 (qd, J = 2.7,6.4Hz, 1H)

Embodiment 3

[0078]

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Under a nitrogen atmosphere, 4.5 mg of palladium acetate
(0.02 mmol) and 10.5 triphenylphosphine
0.56 g (12.0 mmol) of formic acid was added to a solution of mg (0.04 mmol) dissolved in 2.5 ml of toluene, and the mixture was heated and stirred at 70 ° C. 0.54 g (1.0 mm) of the azetidin-2-one derivative (1b-1) obtained in Reference Example 7 was added to the reaction solution.
ol) in 2 ml of toluene was added dropwise over 15 minutes, and stirring was continued at 70 ° C. for 3.5 hours. The reaction solution was cooled to room temperature, 15 ml of diethyl ether and 5 ml of 2N hydrochloric acid were added, and the mixture was stirred for 20 minutes and then separated. After the diethyl ether layer was extracted three times with 10 ml of a 5% aqueous sodium hydroxide solution, the aqueous layer was adjusted to pH 2 with 2N hydrochloric acid, and extracted twice with 20 ml of diethyl ether. The obtained diethyl ether layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 0.23 g of the desired compound (2-1) (yield: 76%).
The isomer generation ratio of the obtained compound (2-1) is as follows:
(2α-1): (2β-1) = 6: 94.

Embodiment 4

[0081]

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Under a nitrogen atmosphere, 24.8 mg of palladium acetate
(1.1 mmol) and 57.6 mg of triphenylphosphine
(2.2 mmol) in a solution of 15 ml of tetrahydrofuran was added a solution of 2.02 g (44.0 mmol) of formic acid and 5.55 g (55.0 mmol) of triethylamine in 15 ml of tetrahydrofuran, and the mixture was heated under reflux. A solution of 5.68 g (11.0 mmol) of the azetidin-2-one derivative (1b-2) obtained in Reference Example 8 in 20 ml of tetrahydrofuran was added dropwise to the reaction solution over 30 minutes.
Stirring was continued for another 1.5 hours. The reaction solution was cooled to room temperature, 80 ml of diethyl ether was added, and 30 ml of saturated saline was added.
After dehydration with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 4.41 g of a crude product. Then, -60 ° C
1.29 g (56.0 mmol) of metallic sodium was added to 100 ml of cooled liquid ammonia, and when the sodium dissolved and the solution turned dark blue, 4.41 g of the crude product obtained above was added to 20 ml of diethyl ether. Upon dissolution, the solution was added dropwise over 30 minutes. The cooling of the reaction vessel was stopped, and the temperature of the reaction solution was returned to room temperature overnight while stirring was continued. 50 ml of diethyl ether and 50 ml of water were added, followed by stirring and liquid separation. The obtained aqueous layer was combined with a solution obtained by extracting the diethyl ether layer with 20 ml of a 5% aqueous sodium hydroxide solution, and then adjusted to pH 2 with dilute hydrochloric acid. . This was extracted with 100 ml of diethyl ether, washed with 30 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, filtered and concentrated to obtain 2.60 g of the desired compound (2-1) (yield 77%). ) Got. The isomer generation ratio of the obtained compound (2-1) was (2α-1) :( 2β-1) = 31: 6.
Nine.

Embodiment 5

[0084]

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1.09 g (2.0 mmol) of the azetidin-2-one derivative (1b-3) obtained in Reference Example 9, 9.0 mg (0.04 mmol) of palladium acetate, and 21.0 mg (0.0 mg) of triphenylphosphine. 08 mmol),
After deesterification and decarboxylation were performed using 0.37 g (8.0 mmol) of formic acid and 0.91 g (9.0 mmol) of triethylamine according to the above reference example, 30 ml of liquid ammonia and 0.24 g of metal sodium (10.
0 mmol) to obtain 0.48 g of the desired compound (2-1) (yield: 80%). The isomer generation ratio of the obtained compound (2-1) was (2α-1) :( 2β-1) = 39: 61.

Embodiment 6

[0087]

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1.58 g (3.0 mmol) of the azetidin-2-one derivative (1a-3) obtained in Reference Example 3, 0.72 g (7.1 mmol) of triethylamine and 0.3 g of 5% palladium carbon were added to 30 ml of methanol. And hydrogenated at normal pressure. After removing palladium carbon by filtration, methanol was distilled off under 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, followed by stirring and liquid separation. The aqueous layer was acidified with 1N hydrochloric acid, the generated white solid was filtered off, washed with water, and dried under reduced pressure to obtain 0.54 g (52% yield) of a dicarboxylic acid compound (8a). Melting point: 110-111 ° C MS (m / e): 244,200 IR (KBr) cm ^-1 : 1755,1720 ¹ H-NMR δ (CD ₃ OD): 0.02 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H),
1.13 (d, J = 6.4Hz, 3H), 1.33 (s, 3H), 3.01 (dd, J = 2.1,2.7Hz,
1H), 4.19 (d, J = 2.1Hz, 1H), 4.20 (m, 1H)

Embodiment 7

[0090]

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1.08 g (2.7 mmol) of the azetidin-2-one derivative (1a-2) obtained in Reference Example 2 was dissolved in 15 ml of ethanol and 5 ml of water, and 0.99 g (17%) of potassium hydroxide was added thereto. (3.6 mmol) in 3 ml of water was added, and the mixture was heated to 50 ° C. and stirred for 5 hours. After the reaction solution was cooled to room temperature, it was poured into 30 ml of water, acidified with 2N hydrochloric acid, the resulting white solid was separated by filtration, washed with water, and dried under reduced pressure to obtain 0.63 g of the dicarboxylic acid compound (8a).
(68% yield).

Embodiment 8

[0093]

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An isomer mixture 0.4 of the azetidin-2-one derivative (1a-4) and (1a-5) obtained in Reference Example 4.
0 g (0.93 mmol) was dissolved in 2 ml of ethanol, and 0.34 g (6.1 mmol) of potassium hydroxide was added to 3 ml of water.
Was added and stirring was continued at 50 ° C. for 2 days. After the reaction solution was concentrated under reduced pressure, 1N hydrochloric acid was added to adjust the pH to 2, followed by further concentration under reduced pressure. 10 ml of diethyl ether was added to the obtained solid, and the mixture was thoroughly stirred, filtered and concentrated to obtain 0.21 g (yield: 66%) of a dicarboxylic acid compound (8a). Example 9

[0095]

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0.62 g (1.0 mmol) of the azetidin-2-one derivative (1a-6) obtained in Reference Example 5 was dissolved in 10 ml of ethanol and 3 ml of water, and 0.38 g of potassium hydroxide (6. 8 mmol) in 3 ml of water was added and stirring was continued at 50 ° C. for 25 hours. After the reaction solution was cooled to room temperature, it was poured into 30 ml of water, and diethyl ether 10
Extraction was performed twice with ml. The resulting aqueous layer was acidified with 2N hydrochloric acid, extracted twice with 15 ml of ethyl acetate, and then the extract was dehydrated with anhydrous magnesium sulfate, filtered and dried under reduced pressure to obtain a dicarboxylic acid compound (8a). .18g
(52% yield). Example 10

[0097]

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To 2.40 g (4.9 mmol) of the azetidin-2-one derivative (1b-4) obtained in Reference Example 10 were added 5 ml of ethanol and 10 ml of water, and 1.10 g of potassium hydroxide (19 (6 mmol) in 5 ml of water was added and stirred at room temperature overnight. This reaction solution is added to water 5
The mixture was poured into 0 ml, adjusted to pH 7 by adding 1N hydrochloric acid, and then extracted with 50 ml of diethyl ether. In addition, pH 1
After adding 1N hydrochloric acid until the mixture becomes
The resulting diethyl ether layer was washed with 15 ml of saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 1.50 g of the dicarboxylic acid compound (8b) (yield: 69). %). Melting point: 128-129 ° C MS (m / e): 334,290 IR (KBr) cm ^-1 : 1750, 1730 ¹ H-NMR δ (CD ₃ OD): 0.01 (s, 3H), 0.07 (s, 3H), 0.86 (s, 9H),
1.16 (d, J = 6.4Hz, 3H), 1.21 (s, 3H), 3.04 (m, 1H), 4.21 (m, 1
H), 4.30 (d, J = 15.2Hz, 1H), 4.45 (d, J = 2.1Hz, 1H), 4.46 (d, J
= 15.2Hz, 1H), 7.30 (m, 5H)

Embodiment 11

[0100]

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1.38 g (4.0 mmol) of the dicarboxylic acid compound (8a) obtained in Examples 6 to 9 were dissolved in 15 ml of diethylene glycol dimethyl ether.
Heated for hours. After the reaction solution was cooled to room temperature, 20 ml of diethyl ether and 15 ml of a 5% aqueous sodium hydroxide solution were used.
The aqueous layer was extracted with
After washing with 0 ml, the mixture was adjusted to pH 2 with 2N hydrochloric acid and extracted with 30 ml of diethyl ether. The obtained diethyl ether layer was washed with 10 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, filtered and concentrated to obtain 0.97 g (yield 80%) of the desired compound (2-1). Obtained. The isomer generation ratio of the obtained compound (2-1) was (2α-1) :( 2β-1) = 90: 10.

Embodiment 12

[0103]

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After subjecting 0.87 g (2.0 mmol) of the dicarboxylic acid compound (8b) obtained in Example 10 to a heat decarboxylation reaction according to Example 11, liquid ammonia and metallic sodium were added according to Example 4. Compound (2-1) 0.42
g (70% yield). In addition, the obtained compound (2-
The isomer formation ratio of 1) is (2α-1) :( 2β-1) =
28:72.

[0105]

According to the present invention, a 4- (1-carboxyalkyl) azetidin-2-one derivative useful as a synthetic intermediate for a 1β-alkylcarbapenem-based antibacterial agent can be efficiently produced.

Continuation of the front page (72) Inventor Hirohiko Kobayashi 5-36-31 Kamata, Ota-ku, Tokyo Takasago Incense Research Institute, Inc. (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 205 / 08 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A compound of the general formula (1) (Wherein R ¹ and R ² are the same or different and each represent an alkyl group, an alkenyl group or an aralkyl group, R ³ represents a lower alkyl group, R ⁴ represents a hydrogen atom or a protecting group for a hydroxyl group, ⁵ is a hydrogen atom or an amino-protecting group), and the 4- (1,1-dialkoxycarbonylalkyl) azetidin-2-one derivative is de-esterified and decarboxylated, and an amino-protecting group is present. In general, the compound is deprotected in the case of (Wherein R ³ and R ⁴ have the same meanings as described above), and a method for producing a 4- (1-carboxyalkyl) azetidin-2-one derivative represented by the formula: 2. The compound according to claim 1, wherein in the general formula (1), R ⁵ represents a protecting group for an amino group, and after the esterification and decarboxylation reaction, the protecting group for the amino group is eliminated. Manufacturing method. 3. In the general formula (1), R ¹ and R ² are 2
-An alkenyl group, wherein the deesterification and decarboxylation reactions are performed on an azetidin-2-one derivative represented by the general formula (1):
2. The process according to claim 1, wherein the reaction is carried out by reacting formic acid or an amine salt of formic acid in the presence of a palladium compound.