JPH05155850A - Azetidine-2-one derivative - Google Patents

Abstract

PURPOSE:To provide a new compound useful as an intermediate for synthesizing 1beta-alkylcarbapenem-based antibacterial agents. CONSTITUTION:A compound of formula I (R<1> and R<2> are each alkyl, alkenyl or aralkyl; R<3> is lower alkyl; R<4> is H or protected hydroxyl group; R<5> is H or protected amino), e.g. a compound of formula III (TBDMS is t- butyldimethylsilyl). The compound of the formula I can be obtained, for example, by reaction of a compound of formula III with a compound of formula IV in a solvent (e.g. THF) in the presence of a base such as sodium methylate.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an azetidin-2-one derivative useful as a synthetic intermediate for various 1β-alkylcarbapenem antibacterial agents.

[0002]

BACKGROUND OF THE INVENTION Carbapenem antibacterial agents are excellent antibacterial agents having a strong antibacterial activity against a wide range of bacteria ranging from Gram-positive bacteria to Gram-negative bacteria including Pseudomonas aeruginosa. In recent years, active development has been made. Formula (2)

[0003]

[Chemical 2]

Carbapenems such as thienamycin, which do not have a substituent at the 1-position of the carbapenem skeleton, are chemically unstable at high concentrations and are easily metabolized by renal dehydropeptidase. However, when a β-configured alkyl group is introduced into the 1-position, the stability is increased, and it can be used alone without compounding a renal dehydropeptidase inhibitor. For this reason, 1
Development of β-alkylcarbapenem antibacterial agents has been focused on, and the general formula (3β), which is a synthetic intermediate, has been developed.

[0005]

[Chemical 3]

(In the formula, R ³ represents a lower alkyl group, and R ⁴
Represents a hydrogen atom or a hydroxyl-protecting group) 4-
[(R) -1-Carboxyalkyl] azetidine-2-
The development of synthetic methods for on-derivatives is also actively carried out.

Many reports have been made as to the method of synthesizing this compound (3β), but in particular the general formula (4)

[0008]

[Chemical 4]

(Wherein R ⁴ has the same meaning as described above, and A 4
c represents an acetyl group), and a method of introducing a side chain by alkylating the 4-position of the 4-acetoxyazetidin-2-one derivative represented by various nucleophiles is most expected. Alkylation with propionate enolate [C. U. Kim et al .; Tetrahedr
on Lett. , 28 (5) 507-510 (198).
7), T. Chida et al .; Chem. Lett. , 13
43-1346 (1985), T.W. 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), Yoshimitsu Nagao; Chemistry, 42 (3) 19
0-196 (1987), L.A. M. Fuentes et al .;
J. Am. Chem. Soc. , 108 , 4675-4
676 (1986), R.I. Deziel et al .; Tetra
hedron Lett. , 27 (47) 5687-5.
690 (1986), Y. Ito et al .; Tetrahed
ron Lett. , 28 (52) 6625-6628.
(1987), alkylation with a propionic acid thiol ester enolate [M. Endo et al .; Can, J .; C
hem. , 65 , 2140-2145 (1987),
C. U. Kim et al .; Tetrahedron Let
t. , 28 (5) 507-510 (1987), A.A. M
artel et al .; Can. J. Chem. , 66 , 153
7-1539 (1988)] and the like have been reported. Other synthetic methods of compound (3β) include, for example, compound (5)

[0010]

[Chemical 5]

(Wherein R ⁴ has the same meaning as described above) is alkylated with lithium diisopropylamide [D. H. Shih, Heterocycles, 2
1 (1) 29-40 (1984), compound (6)

[0012]

[Chemical 6]

(In the formula, R ⁴ has the same meaning as described above, and R ⁵
Represents a hydrogen atom or a protecting group for an amino group, and R ⁶ represents an alkyl group, a carboxy group or an alkoxycarbonyl group), or asymmetric reduction by a specific catalyst [JP-A-58- 26887 publication,
C. U. Kim et al .; Tetrahedron Let
t. , 28 (5) 507-510 (1987), T.S. O
Hta et al .; Org. Chem. , 52 , 3176-
3178 (1987), T.S. Iimori et al .; Tetr
ahedron Lett. , 27 (19) 2149-
2152 (1986)], etc., and a review [Yoshio Ito et al .; Synthetic Organic Chemistry, 47 (7) 606-618 (198).
9)].

Compound (3β) obtained by these methods
Is a compound (3
α)

[0015]

[Chemical 7]

Compound (3) mixed with (in the formula, R ³ and R ⁴ have the same meanings as described above) in a specific ratio

[0017]

[Chemical 8]

(Wherein R ³ and R ⁴ have the same meanings as described above), the compound (3α) having an α-configured alkyl group can be obtained, for example, from D.I. H. Shih et al .;
Heterocycles, 21 (1) 29-40 (1
If the isomerization is carried out by the method described in 984),
A compound having a desired β-configuration alkyl group (3
β).

However, in the method of synthesizing the compound (3) and the compound (3β), a special and expensive reagent is used, a reaction temperature is extremely low, and an expensive metal or a toxic metal is used as a catalyst. However, it is not a method suitable for large-scale synthesis, and it has not been actually manufactured on an industrial scale.

Therefore, the compound (3), especially the compound (3 having an β-configured alkyl group, which is more useful as a synthetic intermediate for 1β-alkylcarbapenem antibacterial agents, is useful.
It was desired to develop a method for efficiently producing β).

[0021]

Under these circumstances, as a result of intensive studies by the present inventors, a compound in which a malonic acid derivative was bonded to the 4-position of an azetidin-2-one derivative was
They have found that they are useful as synthetic intermediates for compound (3) and compound (3β), and completed the present invention.

That is, the present invention has the general formula (1)

[0023]

[Chemical 9]

(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 group protecting group, and R ⁵ represents a hydrogen atom or an amino group protecting group) And an azetidin-2-one derivative.

The azetidin-2-one derivative of the present invention is represented by the above-mentioned general formula (1). In the formula, the alkyl group represented by R ¹ and R ² is, for example, a methyl group,
A linear or branched alkyl group such as an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a tert-butyl group; a single group such as a cyclopentyl group, a cyclohexyl group, a menthyl group, a fentyl group, and a bornyl group. Examples thereof include a cyclic or polycyclic alkyl group, and examples of the alkenyl group include a linear or branched alkenyl group such as a vinyl group, an allyl group, a 2-butenyl group, and a 2-methyl-2-propenyl group. Examples of the aralkyl group include a benzyl group and a benzhydryl group. Further, examples of the lower alkyl group represented by R ³ include a methyl group, ethyl group and n-propyl group, and examples of the protective group for the hydroxyl group represented by R ⁴ include a trimethylsilyl group,
A tri-substituted silyl group such as a tert-butyldimethylsilyl group; an acyl group such as an acetyl group; an aralkyl group such as a benzyl group. Examples of the amino group protecting group represented by R ⁵ include a trimethylsilyl group. , Triethylsilyl group, tert-butyldimethylsilyl group, trisubstituted silyl group such as methyldiphenylsilyl group; benzyl group, p-methoxybenzyl group, p-tert-butylbenzyl group, 3,4-dimethylbenzyl group, phenethyl group Group, an aralkyl group which may have a substituent on the aromatic ring such as a benzhydryl group; an alkoxyalkyl group such as a tetrahydropyranyl group and a methoxymethyl group.

These azetidin-2-one derivatives (1) are represented by the formula (1) in which R ⁵ is a hydrogen atom (hereinafter referred to as "azetidin-2-one derivative (1a)").
Is described in, for example, R.I. The method of Joyeau et al. [J. Chem. Soc. , Perkin Tran
s. I, 1899-1907 (1987), Tetra.
hedron Lett. , 30 (3) 337-340.
(1989)], the 4-acetoxyazetidin-2-one derivative (4) is reacted with the malonic acid derivative (7) according to the following formula.

[0027]

[Chemical 10]

(In the formulae, R ¹ , R ² , R ³ , R ⁴ and Ac have the same meanings as described above)

That is, alkali metals such as metal potassium, sodium metal and lithium; alkali metal hydrides such as sodium hydride; alkali metal alkylates such as butyl lithium; potassium-tert.
-Alkali metal alkoxides such as butyrate, sodium ethylate, 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) To the solution, 4-acetoxyazetidin-2-one derivative (4) was added, and -60 to 40
It is manufactured by reacting at 0 ° 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. However, 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) with respect to 1 mol of the 4-acetoxyazetidin-2-one derivative (4). The obtained azetidin-2-one derivative (1a) can be purified by recrystallization, column chromatography and the like after extraction, washing, dehydration and the like by a usual method.

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)), azetidine in which R ⁵ is a hydrogen atom is prepared by the method described above. After the 2-one derivative (1a) is obtained, it is produced by introducing an amino-protecting group by a conventional method.

The azetidin-2-one derivative (1) of the present invention thus obtained is subjected to deesterification and decarboxylation according to the following formula by a conventional method to give 4-
It can be a (1-carboxyalkyl) azetidin-2-one derivative (3).

[0032]

[Chemical 11]

(In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above.)

The deesterification and decarboxylation reactions 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 heated at 80 to 120 ° C. for decarboxylation.

When the azetidin-2-one derivative (1) in which R ¹ and R ² are 2-alkenyl groups is used as a raw material, the deesterification and decarboxylation reactions can be carried out by the above-mentioned method. , J. The method of Tsuji et al. [Tetrahedron Lett. , (7) 613
-616 (1979)], azetidine-2-
The on-derivative (1) is reacted with formic acid or an amine salt of formic acid for 1 to 5 hours under heating and reflux in the presence of a palladium compound and a compound serving as a ligand thereof to perform deesterification and decarboxylation. It can be carried out in one step and is preferred. The palladium compound used here may be any compound that can generate 0-valent palladium, which is an active species, in the reaction system. Specifically, it is a divalent palladium compound such as palladium acetate, palladium chloride, or palladium acetylacetonate. Palladium compounds; trivalent dilidene dipalladium, zero-valent palladium compounds such as tetrakistriphenylphosphine palladium and the like can be mentioned. As a ligand,
Examples thereof include trialkylphosphines such as triethylphosphine and tributylphosphine; and triarylphosphines such as triphenylphosphine and tritolylphosphine. Examples of the solvent used here include ethers such as 1,4-dioxane and tetrahydrofuran; toluene; benzene and the like.
The ratio of the reaction compound is about 0.01 to 0.3 mol of the palladium compound with respect to 1 mol of azetidin-2-one (1),
Formic acid or amine salt of formic acid is preferably about 3 to 15 mol.

The starting compound is R ⁵ in the general formula (1).
Is an azetidin-2-one derivative (1a)
In the case of, the α-alkyl compound (3α) is preferentially obtained as the compound (3) obtained by the deesterification / decarboxylation reaction. The configuration of the alkyl group at the 1-position of the carbapenem skeleton, which is the final target product, is β-configuration. The obtained α-alkyl compound (3α) is isomerized by the above-mentioned known method to obtain the β-alkyl compound. It can be (3β).

On the other hand, in the case where the starting compound is R ⁵ in the general formula (1) is a protecting group for an amino group (hereinafter, referred to as “azetidin-2-one derivative (1b)”), the above-mentioned removal is carried out. After carrying out the esterification and decarboxylation reaction, the target compound (3) can be obtained by removing the protective group of the amino group. In this case, the obtained compound (3) is a β-alkyl group. Since the body (3β) is preferentially obtained, it has a high industrial utility value, which is preferable. The elimination reaction of the protective group of the amino group varies depending on the type of the protective group, but when the protective group is a trisubstituted silyl group, a weak acid such as dilute hydrochloric acid may be reacted. When the protecting group is a benzyl group which may have a substituent, a phenethyl group or a benzhydryl group, it may be reacted with sodium metal in liquid ammonia by reduction of Birch.

[0038]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. The following equipment was used for the following measurements. Melting point: MP-S3 type (manufactured by Yanagimoto Corporation) Mass spectrum (MS): M-80B mass spectrometer (ionization voltage: 20 eV) (manufactured by Hitachi, Ltd.) Infrared absorption spectrum (IR): IR-810 type (Nippon Bunko Kogyo Co., Ltd.) ¹ H nuclear magnetic resonance spectrum ( ¹ H-NMR): AM-40
Type 0 (400 MHz) (Brooker) Internal standard substance: Tetramethylsilane

Example 1

[0040]

[Chemical 12]

(In the formula, Ac has the same meaning as described above, and T
BDMS represents a tert-butyldimethylsilyl group.
The same applies below) 2.52 g (62.9 mmol) of 60% sodium hydride was suspended in 50 ml of tetrahydrofuran, and diallyl methylmalonate (7-1) 11.88 was stirred with stirring at room temperature.
A solution of g (60.0 mmol) in 20 ml of tetrahydrofuran was added dropwise over 20 minutes. Further, after stirring for 2.5 hours, a solution of 14.35 g (50.0 mmol) of 4-acetoxyazetidin-2-one derivative (4-1) dissolved in 30 ml of tetrahydrofuran was added dropwise over 15 minutes at room temperature. The reaction was continued for 15 hours. After adding 30 ml of a saturated aqueous solution of ammonium chloride to the reaction mixture and stirring and separating the layers, the obtained tetrahydrofuran layer was washed with saturated brine and dehydrated with anhydrous magnesium sulfate, and the solvent was distilled off to give crude crystals.
5 g was obtained. Recrystallization was performed using hexane to give a white crystalline azetidin-2-one derivative (1a-1) 18.03.
g (yield 85%) was obtained. Melting point; 82-82.5 ° C MS (m / e): 426 (M ⁺ +1), 410,368 IR (KBr) cm ^-1 : 1765,1735 ¹ H-NMR δ (CDCl ₃ ): 0.07 (s, 6H), 0.88 (s, 9H), 1.14 (d, J = 6.
3Hz, 3H), 1.50 (s, 3H), 3.03 (m, 1H), 4.19 (d, J = 2.1,1H), 4.2
1 (m, 1H), 4.64 (m, 4H), 5.27 (m, 2H), 5.34 (m, 2H), 5.88 (m, 2
H), 5.96 (broad s, 1H)

Example 2

[0043]

[Chemical 13]

60% sodium hydride 1.12 g (2
After adding 5 ml of hexane to 8.0 mmol) and stirring, hexane was removed by a gradient method. After washing by repeating this procedure several times, 20 ml of tetrahydrofuran was added, and diethyl methylmalonate (7
-2) A solution of 4.52 g (26.0 mmol) dissolved in 20 ml of tetrahydrofuran was added dropwise over 15 minutes. After further stirring for 30 minutes, 4-acetoxyazetidine-
2-one derivative (4-1) 5.74 g (20.0 mmol)
Was added dropwise to 20 ml of tetrahydrofuran over 10 minutes, and the reaction was continued at room temperature for 1 hour. To the reaction solution was added 25 ml of a saturated aqueous solution of ammonium chloride, and the mixture was stirred and separated, then, the obtained tetrahydrofuran layer was washed with saturated brine and dehydrated with anhydrous magnesium sulfate, and the solvent was distilled off to obtain crude crystals. Recrystallization was performed using hexane, and 6.17 g of a white crystalline azetidin-2-one derivative (1a-2) was obtained.
(Yield 77%) was obtained. 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, 3H), 5.
98 (broad s, 1H)

Example 3

[0046]

[Chemical 14]

(In the formula, Ph represents a phenyl group. The same applies to the following.) 60 ml of 60% sodium hydride was added to 5 ml of tetrahydrofuran.
43 g (10.8 mmol) was suspended, and 3.13 g of dibenzyl methylmalonate (7-3) was stirred at room temperature.
A solution of (10.5 mmol) in 3 ml of tetrahydrofuran was added dropwise over 20 minutes. Furthermore, after stirring at room temperature for 30 minutes, a solution prepared by dissolving 2.87 g (10.0 mmol) of 4-acetoxyazetidin-2-one derivative (4-1) in 5 ml of tetrahydrofuran was added dropwise over 15 minutes, and at room temperature. The reaction was continued for 1.5 hours. After adding 15 ml of saturated aqueous ammonium chloride solution to the reaction mixture and stirring, ethyl acetate 20
Extraction was performed using ml. The obtained ethyl acetate layer was washed with water, dehydrated with 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 by 1) yielded 4.28 g (yield 82%) of white crystalline azetidin-2-one derivative (1a-3). 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)

Example 4

[0049]

[Chemical 15]

2.17 g (54.3 mmol) of 60% sodium hydride was suspended in 15 ml of tetrahydrofuran, and 10.9 g (54.0 mmol) of tert-butylethyl methylmalonate (7-4) was stirred with stirring at room temperature. A solution dissolved in 20 ml of tetrahydrofuran was added dropwise over 1 hour. Furthermore, after stirring for 30 minutes at room temperature, 14.1 g of 4-acetoxyazetidin-2-one derivative (4-1)
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 ammonium chloride aqueous solution to the reaction mixture 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, and then filtered and concentrated to obtain a crude product. This is subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate =
4: 1) to give white crystalline azetidine-2-
Isomeric mixture of on-derivatives (1a-4) and (1a-5) [mixing ratio (1a-4) :( 1a-5) = 77: 23]
14.2 g (yield 67%) 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 x 23/100), 1.47 (s, 9H x 77/100), 2.98 (m, 1H x 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)

Example 5

[0052]

[Chemical 16]

0.30 g of 60% sodium hydride (7.
After adding 3 ml of hexane to 5 mmol) and stirring, hexane was removed by a gradient method. Tetrahydrofuran 3.
Add 5 ml and stir at room temperature while stirring with methylmalonic acid di-
2.96 g (7.5 mmol) of (1) -menthyl (7-5)
Was dissolved in 5 ml of tetrahydrofuran and added dropwise over 15 minutes. Further, after stirring at room temperature for 30 minutes, 4-
Acetoxyazetidin-2-one derivative (4-1) 2.
A solution prepared by dissolving 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. After adding 10 ml of a saturated ammonium chloride aqueous solution to the reaction solution, stirring and separating the layers, 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 colorless oily azetidine-2.
2.94 g (yield 68%) 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, 1
H), 4.73 (m, 2H), 5.91 (s, 1H)

Example 6

[0055]

[Chemical 17]

2.92 g (73.0 mmol) of 60% sodium hydride was suspended in 50 ml of tetrahydrofuran, and diallyl n-propylmalonate (7
-6) A solution prepared by dissolving 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 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, stirring and separating the layers, the obtained tetrahydrofuran layer was washed with saturated brine and dehydrated with 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 a white crystalline azetidin-2-one derivative (1a-).
7) 26.32 g (yield 83%) 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, 2
H), 4.65 (m, 4H), 5.30 (m, 4H), 5.88 (m, 3H)

Example 7

[0058]

[Chemical 18]

20 ml of N, N-dimethylformamide was added to the azetidin-2-one derivative (1a-) obtained in Example 1.
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 mmo of triethylamine was dissolved.
A solution obtained by dissolving 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
(1.1 mmol) was added and reacted at room temperature for 6 days. The reaction solution was concentrated under reduced pressure, 40 ml of water was added, and the mixture was extracted with 200 ml of diethyl ether. The obtained diethyl ether layer was washed with 30 ml of saturated saline and then dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a crude product. This was purified by alumina kamura 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 (yield 74%) 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)

Example 8

[0061]

[Chemical 19]

The azetidin-2-one derivative (1a-obtained in Example 1) was added to 13 ml of N, N-dimethylformamide.
1) 1.70 g (4.0 mmol) and 1.12 g (4.8 mmol) of methyldiphenylsilyl chloride were dissolved and stirred in an ice bath. 0.48g of triethylamine
A solution of (4.8 mmol) dissolved in 2 ml of N, N-dimethylformamide was added dropwise over 40 minutes and left overnight in the refrigerator. The solvent of the reaction solution was distilled off under reduced pressure, and then 10 ml of water and 15 ml of ethyl acetate were added for extraction. The obtained ethyl acetate layer was dehydrated with anhydrous magnesium sulfate, and then the solvent was distilled off to obtain an oily substance. This was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 5: 1) to obtain 1.69 g (yield 68%) of a colorless oily azetidin-2-one derivative (1b-2). .. MS (m / e): 606,564,544 IR (neat) cm ^-1 : 1755,1735 ¹ H-NMR δ (CDCl ₃ ):-0.02 (s, 3H), 0.06 (s, 3H), 0.82 (s, 3
H), 0.88 (s, 9H), 1.14 (d, J = 6.3Hz, 3H), 1.25 (s, 3H), 3.15
(m, 1H), 4.16 (m, 1H), 4.32 (m, 4H), 4.43 (d, J = 2.7Hz, 1H), 5.
18 (m, 4H), 5.71 (m, 2H), 7.47 (m, 10H)

Example 9

[0064]

[Chemical 20]

25 ml of N, N-dimethylformamide was added to the azetidin-2-one derivative (1a-) obtained in Example 1.
1) 2.87 g (6.7 mmol) and 1.58 g (10.5 mmol) of triethylsilyl chloride were dissolved and stirred in an ice bath. To this, 1.06 g of triethylamine (1
A solution of 0.5 mmol) dissolved in 5 ml of N, N-dimethylformamide was added dropwise over 20 minutes, and the mixture was left overnight in the refrigerator. The solvent was distilled off from the reaction solution under reduced pressure, and then 15 ml of a saturated aqueous sodium hydrogen carbonate solution and 25 ml of ethyl acetate were added for extraction. The obtained ethyl acetate layer was dehydrated with anhydrous magnesium sulfate, and then the solvent was distilled off to obtain an oily substance. Alumina column chromatography (developing solvent; hexane:
Purification by ethyl acetate = 10: 1) gave 2.20 g (yield 61%) of colorless oily azetidin-2-one derivative (1b-3). MS (m / e): 524,511,482 IR (neat) cm ^-1 : 1750 ¹ H-NMR δ (CDCl ₃ ): 0.06 (s, 3H), 0.07 (s, 3H), 0.78 (m, 6H),
0.88 (s, 9H), 0.98 (t, J = 7.8Hz, 9H), 1.26 (d, J = 6.3Hz, 3H),
1.49 (s, 3H), 3.05 (m, 1H), 4.12 (m, 1H), 4.21 (d, J = 2.6Hz, 1
H), 4.63 (m, 4H), 5.30 (m, 4H), 5.87 (m, 2H)

Example 10

[0067]

[Chemical 21]

60 ml of 5 ml of N, N-dimethylformamide
0.19 g (4.8 mmol) of sodium hydride was suspended and cooled to 0 ° C. to obtain azetidine-2 obtained in Example 1.
A solution prepared by dissolving 1.93 g (4.5 mmol) of the -one derivative (1a-1) in 5 ml of N, N-dimethylformamide was prepared.
It was added dropwise over 0 minutes. After 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. 5 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with 50 ml of diethyl ether. The obtained diethyl ether layer was dehydrated with anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a crude product. This is subjected to silica gel column chromatography (developing solvent;
Hexane: ethyl acetate = 4: 1) to give a colorless oily azetidin-2-one derivative (1b-4) 1.5.
7 g (yield 68%) was 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), 4.31 (d, J = 2.1Hz, 1H), 4.57
(m, 5H), 5.28 (m, 4H), 5.83 (m, 2H), 7.31 (m, 5H)

Example 11

[0070]

[Chemical formula 22]

2.13 g (5.0 mmol) of the azetidin-2-one derivative (1a-1) obtained in Example 1, 60%
0.22 g (5.5 mmol) of sodium hydride and p-bromide
-Tert-butylbenzyl 1.25 g (5.5 mmol)
Was subjected to N-benzylation according to Example 10 above to give a colorless oily azetidin-2-one derivative (1b-
5) 2.27 g (yield 79%) was obtained. MS (m / e): 556,514 IR (neat) cm ^-1 : 1765,1740 ¹ H-NMR δ (CDCl ₃ ):-0.06 (s, 3H), 0.03 (s, 3H), 0.84 (s, 9
H), 1.13 (d, J = 6.3Hz, 3H), 1.29 (s, 9H), 1.33 (s, 3H), 2.98 (d
d, J = 2.1,4.5Hz, 1H), 4.13 (d, J = 15.3Hz, 1H), 4.14 (m, 1H),
4.35 (d, J = 2.1Hz, 1H), 4.52 (m, 5H), 5.27 (m, 4H), 5.80 (m, 4
H), 7.29 (m, 4H)

Example 12

[0073]

[Chemical formula 23]

2.13 g (5.0 mmol) of the azetidin-2-one derivative (1a-1) obtained in Example 1, 60%
0.24 g (6.0 mmol) of sodium hydride and p chloride
N-benzylation was carried out according to Example 10 above using 0.94 g (6.0 mmol) of -methoxybenzyl to give a colorless oily azetidin-2-one derivative (1b-6) .2.
07 g (yield 76%) was 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)

Example 13

[0076]

[Chemical formula 24]

4.01 g (10.0 mmol) of the azetidin-2-one derivative (1a-2) obtained in Example 1, 60
% Sodium hydride 0.40 g (11.0 mmol) and benzyl chloride 1.39 g (6.0 mmol) were used for N-benzylation according to the above-mentioned Example 10, and colorless oily azetidin-2-one derivative (1b). -7) 4.30 g (yield 88%) was obtained. MS (m / e): 476,434 IR (neat) cm ^-1 : 1760,1730 ¹ H-NMR δ (CDCl ₃ ): 0.00 (s, 3H), 0.06 (s, 3H), 0.87 (s, 9H),
1.16 (d, J = 6.3Hz, 3H), 1.20,1.22 (2overlapping t, J = 7.3H
z, 6H), 1.30 (s, 3H), 2.99 (dd, J = 2.1,4.5Hz, 1H), 4.17 (m, 6
H), 4.36 (d, J = 2.1Hz, 1H), 4.55 (d, J = 15.3Hz, 1H), 7.31 (m, 5
H)

Example 14

[0079]

[Chemical 25]

60% sodium hydride 0.40 g (1
After adding 5 ml of hexane to 0.0 mmol) and stirring, hexane was removed by a gradient method. After adding 25 ml of N, N-dimethylformamide thereto, 4.65 g (8.A) of the azetidin-2-one derivative (1a-3) obtained in Example 3 was obtained.
9 mmol) was added at room temperature. Furthermore, after stirring at room temperature for 30 minutes, 1.12 g (8.9 mmol) of benzyl chloride was added to N,
A solution of 4 ml of N-dimethylformamide was added dropwise over 5 minutes and stirring was continued overnight at room temperature. After distilling off the solvent from the reaction solution under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate 15
ml and 35 ml of ethyl acetate were added for extraction. The obtained ethyl acetate layer was dehydrated with anhydrous magnesium sulfate, and then the solvent was distilled off to obtain an oily substance. This was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 2:
Purification by 1) yielded 3.50 g (yield 64%) of azetidin-2-one derivative (1b-8) as a colorless oil. MS (m / e): 600,558 IR (neat) cm ^-1 : 1760,1730 ¹ H-NMR δ (CDCl ₃ ):-0.03 (s, 3H), 0.03 (s, 3H), 0.84 (s, 9
H), 1.10 (d, J = 6.3Hz, 3H), 1.30 (s, 3H), 3.00 (dd, J = 2.1,4.4
Hz, 1H), 4.12 (d, J = 15.4Hz, 1H), 4.15 (m, 1H), 4.37 (d, J = 15.
4Hz, 1H), 4.40 (d, J = 2.1Hz, 1H), 4.94 (d, J = 12.2Hz, 1H), 5.0
6 (m, 3H), 7.26 (m, 15H)

Reference Example 1

[0082]

[Chemical formula 26]

4.8 mg of palladium acetate under a stream of argon
(0.02 mmol) was suspended in 2 ml of 1,4-dioxane, and 52.0 mg (0.2
A solution of 2 mmol of 1,4-dioxane dissolved in 1,4-dioxane was added dropwise, followed by heating under reflux, and 0.85 g (2.0%) of the azetidin-2-one derivative (1a-1) obtained in Example 1.
mmol), 0.37 g (7.9 mmol) of formic acid and 0.81 g (8.0 mmol) of triethylamine dissolved in 6 ml of 1,4-dioxane were added dropwise and reacted for 3 hours. To the reaction mixture were added 5% aqueous sodium hydroxide solution (10 ml) and ethyl acetate (10 ml) for liquid separation. The aqueous layer was acidified with 1N hydrochloric acid and then extracted with 20 ml of ethyl acetate. The obtained ethyl acetate layer was dehydrated with anhydrous magnesium sulfate, and then the solvent was distilled off to give the target compound 4- (1-carboxyethyl) -azetidin-2-one derivative (3-1) 0.47 as white crystals.
g (yield 78%) was obtained. The obtained compound (3-
The compound (3α- in which the methyl group of the wavy line in the formula 1) is in the α-position
1) and the compound (3β-1) at the β-position have a production ratio of α: β
= 85:15, these are high performance liquid chromatography (HPLC) (column; Inertsil OD).
S, manufactured by GL Sciences Inc., developing solvent; acetonitrile: water: acetic acid = 700: 300: 3), and
The structure was determined. α-form (3α-1) Melting point: 168-170 ° C MS (m / e): 286,244 IR (KBr) cm ^-1 : 1720 ¹ H-NMR δ (CDCl ₃ ): 0.07 (s, 3H), 0.08 (s , 3H), 0.88 (s, 9H),
1.25 (2overlapping d, J = 6.2,7.3Hz, 6H), 2.56 (qd, J = 7.3,
9.8Hz, 1H), 2.80 (dd, J = 2.0,5.3Hz, 1H), 3.70 (dd, J = 2.0,9.
8Hz, 1H), 4.19 (m, 1H), 6.67 (broad s, 1H) β-body (3β-1) Melting point: 143.5-144.5 ° C MS (m / e): 286,244 IR (KBr) cm ^-1 : 1720 ¹ H-NMR δ (CDCl ₃ ): 0.07 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H),
1.20 (d, J = 6.3Hz, 3H), 1.27 (d, J = 7.0Hz, 3H), 2.75 (qd, J = 5.
0,7.0Hz, 1H), 3.03 (dd, J = 2.2,4.3Hz, 1H), 3.94 (dd, J = 2.2,
5.0Hz, 1H), 4.20 (qd, J = 4.5,6.3Hz, 1H), 6.25 (broad s, 1H)

Reference Example 2

[0085]

[Chemical 27]

9.0 mg of palladium acetate under nitrogen atmosphere
(0.04 mmol) and triphenylphosphine 53.0
To a solution prepared by dissolving mg (0.20 mmol) in 8 ml of 1,4-dioxane, a solution prepared by dissolving 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 was added. In addition, the mixture was heated to reflux. The azetidine-2-obtained in Example 6 was added to this.
On-derivative (1a-7) 1815.4 mg (4.01 mmo)
A solution prepared by dissolving l) in 5 ml of 1,4-dioxane was added dropwise over 40 minutes, and the mixture was heated under reflux for another 5 hours. The reaction mixture was cooled to room temperature, extracted with 15 ml of diethyl ether and 20 ml of 5% aqueous sodium hydroxide solution, the alkaline layer was adjusted to pH 2 with 2N hydrochloric acid, and extracted twice with 35 ml of ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give white crystals of the target compound 4- (1-carboxybutyl) -azetidin-2-one derivative (3 -2) 98
5.8 mg (75% yield) was obtained. In addition, the production ratio of the compound (3α-2) in which the n-propyl group in the wavy line in the formula of the obtained compound (3-2) is in the α position and the compound (3β-2) in which the β position is α: β = 73:27, these are HPLC
(The conditions of the column and the developing solvent are the same as those in Reference Example 1), and the structure was determined. α-form (3α-2) Melting point: 173-174 ° C 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-body (3β-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)

Reference Example 3

[0088]

[Chemical 28]

4.5 mg of palladium acetate under a nitrogen atmosphere
(0.02 mmol) and triphenylphosphine 10.5
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 with stirring at 70 ° C. 0.54 g (1.0 mm) of the azetidin-2-one derivative (1b-1) obtained in Example 7 was added to this reaction solution.
ol) dissolved in 2 ml of toluene was added dropwise over 15 minutes, and stirring was continued at 70 ° C. for 3.5 hours. The reaction mixture 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. 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 brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 0.23 g (yield 76%) of the desired compound (3-1).
The isomer production ratio of the obtained compound (3-1) is
(3α-1) :( 3β-1) = 6: 94.

Reference Example 4

[0091]

[Chemical 29]

Under a nitrogen atmosphere, 24.8 mg of palladium acetate
(1.1 mmol) and 57.6 mg of triphenylphosphine
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 was added to a solution of (2.2 mmol) in 15 ml of tetrahydrofuran, and the mixture was heated under reflux. A solution prepared by dissolving 5.68 g (11.0 mmol) of the azetidin-2-one derivative (1b-4) obtained in Example 10 in 20 ml of tetrahydrofuran was added dropwise to this reaction solution over 30 minutes, and further 1.5 hours. Stirring was continued. The reaction solution was cooled to room temperature, 80 ml of diethyl ether was added, and saturated saline solution was added.
After washing with 0 ml and dehydration with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 4.41 g of a crude product. Then, -6
To 100 ml of liquid ammonia cooled to 0 ° C, 1.29 g (56.0 mmol) of metallic sodium was added, and when sodium was dissolved and the liquid became deep blue, 4.41 g of the crude product obtained above was added to diethyl ether. It was dissolved in 20 ml and 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 continuing stirring. Diethyl ether (50 ml) and water (50 ml) were added and stirred, and then liquid separation was performed.
The extracts extracted with 20 ml of an aqueous solution of sodium hydroxide were combined and then adjusted to pH 2 with diluted hydrochloric acid. This was extracted with 100 ml of diethyl ether, washed with 30 ml of saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 2.60 g of the target compound (3-1) (yield 77%). ) Got. The isomer production ratio of the obtained compound (3-1) was (3α-1) :( 3β-1) = 31: 6.
It was 9.

Reference Example 5

[0094]

[Chemical 30]

1.09 g (2.0 mmol) of the azetidin-2-one derivative (1b-6) obtained in Example 12, 9.0 mg (0.04 mmol) of palladium acetate, and 21.0 mg (0.04 mmol) of triphenylphosphine. 08 mmol), formic acid 0.37 g
(8.0 mmol) and 0.91 g of triethylamine (9.
0 mmol) and deesterification according to Reference Example 3 above.
After carrying out the decarboxylation reaction, the debenzylation reaction was carried out using 30 ml of liquid ammonia and 0.24 g (10.0 mmol) of metallic sodium to obtain the target compound (3-1) 0.4
8 g (yield 80%) was obtained. The obtained compound (3
The isomer production ratio of -1) is (3α-1) :( 3β-1)
= 39:61.

Reference Example 6

[0097]

[Chemical 31]

1.58 g (3.0 mmol) of the azetidin-2-one derivative (1a-3) obtained in 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 suspended in and hydrogenated at normal pressure. After removing palladium carbon by filtration, methanol was distilled off under reduced pressure, 10 ml of a saturated aqueous sodium hydrogen carbonate solution and 10 ml of ethyl acetate were added to the residue, and the mixture was stirred and separated. The aqueous layer was acidified with 1N hydrochloric acid, the produced white solid was filtered off, washed with water and dried under reduced pressure to obtain 0.54 g of dicarboxylic acid compound (8a) (yield 52%). 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)

Reference Example 7

[0100]

[Chemical 32]

1.08 g (2.7 mmol) of the azetidin-2-one derivative (1a-2) obtained in Example 2 was dissolved in 15 ml of ethanol and 5 ml of water, and 0.99 g (17 g) of potassium hydroxide was added thereto. (6 mmol) in 3 ml of water was added, and the mixture was heated to 50 ° C. and stirred for 5 hours. The reaction solution was cooled to room temperature, poured into 30 ml of water, acidified with 2N hydrochloric acid, the white solid produced was filtered off, washed with water and dried under reduced pressure to give 0.63 g of dicarboxylic acid compound (8a).
(Yield 68%) was obtained.

Reference Example 8

[0103]

[Chemical 33]

Isomeric mixture of azetidin-2-one derivatives (1a-4) and (1a-5) obtained in Example 4 0.4
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.
The solution dissolved in was added, and stirring was continued at 50 ° C. for 2 days. The reaction solution was concentrated under reduced pressure, 1N hydrochloric acid was added to adjust the pH to 2, and further concentrated under reduced pressure. Diethyl ether (10 ml) was added to the obtained solid, and the mixture was well stirred, filtered and concentrated to obtain 0.21 g (yield 66%) of dicarboxylic acid compound (8a).

Reference Example 9

[0106]

[Chemical 34]

0.62 g (1.0 mmol) of the azetidin-2-one derivative (1a-6) obtained in Example 5 was dissolved in 10 ml of ethanol and 3 ml of water, and 0.38 g (6. A solution of 8 mmol) in 3 ml of water was added and stirring was continued at 50 ° C. for 25 hours. The reaction solution was cooled to room temperature and then poured into 30 ml of water, and diethyl ether 10 was added.
Extraction was performed twice with ml. The obtained aqueous layer was acidified with 2N hydrochloric acid, extracted twice with 15 ml of ethyl acetate, and then the extract was dehydrated over anhydrous magnesium sulfate, filtered and dried under reduced pressure to obtain dicarboxylic acid compound (8a) 0 .18 g
(Yield 52%) was obtained.

Reference Example 10

[0109]

[Chemical 35]

To 2.40 g (4.9 mmol) of the azetidin-2-one derivative (1b-7) obtained in Example 13 was added 5 ml of ethanol and 10 ml of water, and 1.10 g of potassium hydroxide (19 g) was added with stirring. (6 mmol) in 5 ml of water was added, and the mixture was stirred at room temperature overnight. This reaction solution is mixed with water 5
It was poured into 0 ml and adjusted to pH 7 with 1N hydrochloric acid, and then extracted with 50 ml of diethyl ether. Furthermore, pH 1
After adding 1N hydrochloric acid until
The mixture was added with ml and extracted, and the obtained diethyl ether layer was washed with 15 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1.50 g of dicarboxylic acid compound (8b) (yield 69 %) Was obtained. 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)

Reference Example 11

[0112]

[Chemical 36]

1.38 g (4.0 mmol) of the dicarboxylic acid compound (8a) obtained in Reference Examples 6 to 8 was dissolved in 15 ml of diethylene glycol dimethyl ether, and the mixture was stirred at 120 ° C. for 3 days.
Heated for hours. After cooling the reaction mixture to room temperature, 20 ml of diethyl ether and 15 ml of 5% aqueous sodium hydroxide solution.
Extraction was carried out with and the aqueous layer was further extracted with diethyl ether 1
After washing with 0 ml, the pH was adjusted to 2 with 2N hydrochloric acid, and extraction was performed with 30 ml of diethyl ether. The obtained diethyl ether layer was washed with 10 ml of saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 0.97 g (yield 80%) of the desired compound (3-1). Obtained. The isomer production ratio of the obtained compound (3-1) was (3α-1) :( 3β-1) = 90: 10.

Reference Example 12

[0115]

[Chemical 37]

0.87 g (2.0 mmol) of the dicarboxylic acid compound (8b) obtained in Reference Example 10 was heated and decarboxylated according to Reference Example 11, and then liquid ammonia and sodium metal were added according to Reference Example 4. Debenzylation reaction is carried out using the desired compound (3-1) 0.42
g (yield 70%) was obtained. The obtained compound (3-
The isomer production ratio of 1) is (3α-1) :( 3β-1) =
It was 28:72.

[0117]

By using the azetidin-2-one derivative of the present invention, a 4- (1-carboxyalkyl) -azetidin-2-one derivative, which is a synthetic intermediate of 1β-alkylcarbapenem antibacterial agents, can be efficiently produced. can do.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] September 25, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0009

[Correction method] Change

[Correction content]

(Wherein R ⁴ has the same meaning as described above, and A 4
c represents an acetyl group), and a method of introducing a side chain by alkylating the 4-position of the 4-acetoxyazetidin-2-one derivative represented by 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), T.W. 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), Yoshimitsu Nagao; Chemistry, 42 (3) 19
0-196 (1987), L.A. M. Fuentes et al .;
J. Am. Chem. Soc. , 108 , 4675-4
676 (1986), R.I. Deziel et al .; Tetra
hedron Lett. , 27 (47) 5687-5.
690 (1986), Y. Ito et al .; Tetrahed
ron Lett. , 28 (52) 6625-6628.
(1987), alkylation with a propionic acid 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), A.S. Mart
el et al .; Can. J. Chem. , 66 , 1537-1
539 (1988)] and the like have been reported. Other synthetic methods of compound (3β) include, for example, compound (5)

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0034

[Correction method] Change

[Correction content]

The deesterification and decarboxylation reactions 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 heated at 80 to 120 ° C. for decarboxylation. When R ¹ and R ² are aralkyl groups, deesterification can also be carried out by hydrogenation using palladium carbon in the presence of amine.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0077

[Correction method] Change

[Correction content]

4.01 g (10.0 mmol) of the azetidin-2-one derivative (1a-2) obtained in Example 2,
60% sodium hydride 0.40 g (11.0 mmo
1) and 1.39 g (6.0 mmol) of benzyl chloride were subjected to N-benzylation according to the above-mentioned Example 10 to give a colorless oily azetidin-2-one derivative (1b-).
7) 4.30 g (yield 88%) 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 = 2.1Hz, 1H), 4.
55 (d, J = 15.3 Hz, 1H), 7.31 (m,
5H)

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0095

[Correction method] Change

[Correction content]

1.09 g (2.0 mmol) of the azetidin-2-one derivative (1b-6) obtained in Example 12,
Palladium acetate 9.0 mg (0.04 mmol), triphenylphosphine 21.0 mg (0.08 mmo
1), 0.37 g (8.0 mmol) of formic acid and 0.91 g (9.0 mmol) of triethylamine, followed by deesterification and decarboxylation according to Reference Example 4,
Liquid ammonia 30 ml and metallic sodium 0.24 g
The debenzylation reaction was carried out using (10.0 mmol) to obtain the target compound (3-1) 0.48 g (yield 80
%) Was obtained. The isomer production ratio of the obtained compound (3-1) was (3α-1) :( 3β-1) = 39: 61.

[Procedure Amendment 5]

[Document name to be amended] Statement

[Name of item to be corrected] 0113

[Correction method] Change

[Correction content]

1.38 g (4.0 mmol) of the dicarboxylic acid compound (8a) obtained in Reference Examples 6 to 9 was dissolved in 15 ml of diethylene glycol dimethyl ether to give 120
Heated at ° C for 3 hours. The reaction solution was cooled to room temperature, extracted with 20 ml of diethyl ether and 15 ml of 5% aqueous sodium hydroxide solution, the aqueous layer was further washed with 10 ml of diethyl ether, adjusted to pH 2 with 2N hydrochloric acid, and 30 ml of diethyl ether was used. Was extracted.
The obtained diethyl ether layer was washed with 10 ml of saturated saline and then dehydrated with anhydrous magnesium sulfate, followed by filtration and concentration to obtain the desired compound (3-1) 0.9.
7 g (yield 80%) was obtained. The obtained compound (3
The isomer production ratio of -1) is (3α-1) :( 3β-1)
= 90:10.

Continued Front Page (72) Inventor Toyohiko Kobayashi 5-36-31 Kamata, Ota-ku, Tokyo Takasago International Corp.

Claims (1)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ and R ² are the same or different and 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 group-protecting group, and R ⁵ represents a hydrogen atom or an amino-protecting group), and is an azetidin-2-one derivative.