KR910003612B1 - Process for preparing 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives - Google Patents

Abstract

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Description

Method for preparing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative

The present invention provides a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having a hydroxyethyl group in a protected state of a hydroxyl group at a C3-position and an acetoxy group at a C4-position. It is about a method. The 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives are known as useful intermediates for preparing carbapenem β-lactam antibiotics and penem β-lactam antibiotics such as thienamycin. [See, eg. Tetrarahedron Letters, Reider et al., Vol. 23, p. 2293, 1982 and Chem. Pharm. Bull. Yoshida et al, 29, 2899. 1981]

As a method for synthesizing the 4-acetoxy-3-hydroxyethylazetidin-2-one derivative known to date, for example, a method for synthesizing from 6-aminophenicylanic acid (see Chem. Pharm. Bull. Yoshida et al. , Vol. 29, p. 2899, 1981), Synthesis from threonine (cf. tetrahedron, shiozaki et al., Vol. 39, p. 2399, 1983), Synthesis from aspartic acid (cf. tetrahedron Laters, Rider et al., Vol. 23, p. 2293, 1982) and methods of synthesis from metal oleates of β-hydroxybutyric acid (cf. chemistry, Nakai et al., 1927, 1984). However, these methods avoid the problem of using industrially unsuitable reagents such as mercury compounds such as mercury acetate or mercury sulfate and lead tetraacetate to introduce acetoxy groups to the C4-position of the β-lactam ring. I have it.

The inventors have found and patented a method of introducing an acetoxy group at the C4-position using an N-protected β-lactam compound having an O-protected hydroxyethyl group at the C3-position and a silylether group at the C4-position. (See Japanese Patent Laid-Open No. 18758/1986).

However, the method involves two steps, a first step of introducing a protecting group to N of β-lactam in advance, and another second step of removing the protecting group after introducing an acetoxy group into the C4-position. Rough

Therefore, the present inventors have found a method for introducing an acetoxy group directly into the C4-position without protecting the N of β-lactam, thereby completing the present invention.

According to the present invention, 4-acetic acid having the following general formula (II) characterized by reacting a β-lactam compound having the general formula (I) in an organic solvent in the presence of acetic anhydride and a low concentration of substituted pyridine Provided is a method for preparing a oxy-3-hydroxyethylazetidin-2-one derivative.

(Wherein R ¹ is a protecting group for a hydroxyl group, and R ² , R ³ and R ⁴ are lower alkyl groups, phenyl groups or aralkyl groups having 1 to 6 carbon atoms.)

As the inventors have disclosed in the prior application (Japanese Patent Laid-Open No. 1831/1986), the β-lactam compound (I) having a silyl ether group at the C4-position can be easily obtained according to the reaction scheme shown below. Can:

Examples of the O-protecting group of R ¹ representing the hydroxyethyl group present at the C3-position of the β-lactam compound (I) include a trialkylsilyl group having the following general formula (III):

Wherein R ⁵ , R ⁶ and R ⁷ are lower alkyl groups having 1 to 6 carbon atoms, and examples thereof include t-butyldimethylsilyl group, triisopropylsilyl group, isopropyldimethylsilyl group, isobutyldimethylsilyl group, 1, 2-dimethylpropyldimethylsilyl group, dimethyl-1, 1, 2-trimethyl-propylsilyl group, t-butyl group, benzyl group, trichloroethoxycarbonyl group, t-butoxycarbonyl group, p-nitrobenzyloxycarbonyl group, etc. Belongs. Of these, t-butyldimethylsilyl group, isopropyldimethylsilyl group and dimethyl-1,1,2-trimethylpropylsilyl group are most preferred because they are stable during the reaction process and can be selectively removed by acid treatment. . The groups R ² , R ³ and R ⁴ of the β-lactam compound having the general formula (I) are the same or different from each other, and are methyl, ethyl, isopropyl, isobutyl, t-butyl or 1, 1, 2-trimethylpropyl group. Aralkyl groups such as lower alkyl groups having 1 to 6 carbon atoms, phenyl groups, or benzyl groups, and p-nitrobenzyl groups. It is preferable that all of R ² , R ³ and R ⁴ are methyl groups.

A β-lactam compound (I) prepared as described above by reacting a β-lactam compound having the following general formula (I) in the presence of a low concentration of substituted pyridine in acetic anhydride and an organic solvent It is converted into a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having the formula (II).

(Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above.) In the above reaction, the concentration of substituted pyridine in the reaction system is an important factor to be considered in order to obtain the desired compound in sufficient yield. As a result, the most appropriate concentration should be determined.

As the substituted pyridine used in the present invention, 4-pyrrolidinopyridine or 4 as a substituted pyridine having a heterocyclic group containing a dialkylaminopyridine and a nitrogen atom as 4-dimethylaminopyridine or 4-dimethylaminopyridine as a substituent or 4 -Piperidinopyridine is preferred. The concentration of substituted pyridine in the reaction system is preferably 0.2 to 3% by weight. At this time, if less than 0.2% by weight, the reaction rate is lowered and side reactions of substrate decomposition occur seriously.

On the other hand, when the concentration is 3% by weight or more, the yield of the sub-product having the following general formula (IV) is increased, and the desired compound is not obtained in sufficient yield.

Wherein R ¹ is as defined above.

In the present invention, when the acetic anhydride is smaller than the substituted pyridine, the reaction rate is lowered, so that acetic anhydride is used in a larger amount than the substituted pyridine. Preferably, acetic anhydride is used in the reaction system in an amount of 10 to 50% by weight. As the reaction solvent, it is preferable to use halogenated hydrocarbons such as methylene chloride or carbon tetrachloride, hydrocarbons such as n-hexane, aromatic hydrocarbons such as toluene, ethyl acetate, tetrahydrofuran and tetrahydropyran. Pyridine, picoline, lutidine, diethyl ether, diglyme, dimethylformamide, acetone and the like can also be used as the reaction solvent.

In order to obtain the desired compound (II) in sufficient yield, the reaction is carried out at a low temperature within the range of 0 to -70 캜. It is preferable to carry out the reaction at a temperature in the range of -10 to -60 캜.

The reaction is carried out by dissolving β-lactam compound (I) having a silylether group in the C4-position in an organic solvent such as methylene chloride or toluene, cooling the mixture, and then replacing substituted acetic anhydride and 4-dimethylaminopyridine. This is done by adding pyridine all at once or in portions. The reaction is then advanced while observing with thin membrane chromatography and the reaction mixture is added to water when the starting material is extinguished or almost all is extinguished. The organic layer is washed with sodium bicarbonate and water and then dried over magnesium sulfate. The solvent is distilled off to collect crude crystals, and then recrystallized with n-hexane or the like to obtain the desired 4-acetoxy-3-hydroxyethylazetidin-2-one derivative. Alternatively, the reaction mixture obtained after evaporating the solvent may be column chromatographed to obtain 4-acetoxy-3-hydroxyethylazetidin-2-one derivative.

Further, as another method for obtaining a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (II) in high yield, a β-lactam compound having general formula (I) When the reaction is carried out in the presence of acetic anhydride and low concentration of substituted pyridine in an organic solvent, the addition of low concentration of water or acetic acid increases the yield of the target compound.

A β-lactam compound having the following general formula (II) is reacted by reacting a β-lactam compound having the general formula (I) with substituted pyridine and acetic anhydride in the presence of low use water or acetic acid in an organic solvent. Is converted to an acetoxy-3-hydroxy ethylazetidin-2-one derivative.

(Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above.) In the above-mentioned reaction, the concentration of water or acetic acid in the reaction solvent is important to obtain the desired compound in sufficient yield. As a factor, select and determine the most appropriate concentration.

The concentration of water in the reaction solvent is preferably 0.1 to 1.0% by volume, and the concentration of acetic acid is preferably 0.6 to 5.0% by volume. When the concentration of water or acetic acid is lower than the above-mentioned range, the yield of the sub-product having the following general formula (IV) is high.

Wherein, R ¹ is as defined above. On the other hand, when the concentration of water or acetic acid is higher than the above-mentioned range, side reaction of substrate decomposition occurs seriously. As a result, the desired compound cannot be obtained in sufficient yield.

Substituted pyridines used in the reaction of the present invention described above include, for example, dialkylaminopyridine such as 4-dimethylaminopyridine or 4-diethylaminopyridine, and a substituted heterocyclic group containing a nitrogen atom as a substituent. Preferred is 4-pyrrolidinopyridine or 4-piperidinopyridine as pyridine. The concentration of substituted pyridine in the reaction system is preferably within the range of 0.2 to 3% by weight.

In the present invention, when the amount of acetic anhydride is smaller than the substituted pyridine, the reaction rate is lowered, so that acetic anhydride is used in a larger amount than the substituted pyridine. Preferably, acetic anhydride is used in the reaction system in an amount of up to 10 to 50% by weight. As the reaction solvent, it is preferable to use halogenated hydrocarbons such as methylene chloride or carbon tetrachloride, hydrocarbons such as n-hexane, aromatic hydrocarbons such as toluene, ethyl acetate, tetrahydrofuran and tetrahydropyran. Alternatively, pyridine, picoline, lutidine, diethyl ether, diglyme, dimethylformamide, acetone and the like can also be used as the reaction solvent.

In order to obtain the desired compound (II) in sufficient yield, the reaction is carried out at a low temperature within the range of 0 to -70 캜. Preferably, the reaction is carried out at a temperature in the range of -10 ° C to -60 ° C.

The reaction is performed by dissolving β-lactam compound (I) having a silyl ether group in the C4-position in an organic solvent such as tetrahydrofuran or ethyl acetate, cooling the mixture, and then adding an appropriate amount of water or acetic acid, and then It is carried out by the addition of substituted pyridine such as acetic anhydride and 4-dimethylaminopyridine at once or in portions at temperatures. The reaction is then advanced while observing with thin membrane chromatography and the reaction mixture is added to water when the starting material is extinguished or almost extinguished. The organic layer was washed with sodium bicarbonate and water, and dried over magnesium sulfate. The solvent is distilled off to obtain crude crystals, and then recrystallized with n-hexane or the like to obtain the desired 4-acetoxy-3-hydroxyethylazetidin-2-one derivative. Alternatively, the crude crystals may be column chromatographed to obtain 4-acetoxy-3-hydroxyethylazetidin-2-one derivative.

The following describes the present invention in more detail by describing non-limiting examples. However, it will be appreciated that any modification or development is possible without departing from the scope and spirit of the present invention.

Example 1

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

(3R, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one (melting point: 95-96 ° C, [α] _D ²⁵ =- 9.5 ° (c = 1.0, CHCI ₃ )) 157 mg is dissolved in 0.9 ml of methylene chloride, and the mixture is cooled to -35 ° C. Then 544 mg of acetic anhydride and 20 mg of 4-dimethylaminopyridine (concentration: 1.05 wt%) are added, and the mixture is stirred at −35 ° C. for 1 day and night. After the reaction is complete, 5% aqueous NaHCO ₃ solution is added and the mixture is separated. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to yield 147 mg of a waxy solid.

The reaction mixture was subjected to high performance liquid column chromatography [column: YMC-pak (A-303 0DS), 4.6 × 250 mm, column temperature: 50 ° C., solvent: methanol / water = 7/3 (v / v), flow rate: 1 Ml / min, detection: 210 nm]; 72.5 mg of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one (Yield: 51.0%).

The reaction mixture is then dissolved in n-hexane and the insolubles are filtered off. The mixture was left to cool at −15 ° C. to yield 44 mg of white solid. The obtained solid was the desired (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one on the basis of the characteristics shown below. It was confirmed.

[α] _D ²⁵ = + 50 ° (c = 0.5, CHCI ₃ )

mp: 107-108 degreeC

¹ H-NMR (90 MHz, CDCL ₃ ), δ (ppm): 0.08 (6H, s), 0.84 (9H, s), 1.20 (3H, d), 2.10 (3H, s), 3.04 (1H, dd ), 4.12 (1H, m), 5.76 (1H, d), 6.73 (NH)

Example 2

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

After dissolving 156 mg of (3R, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one in 3.6 ml of toluene, the mixture was -35. Cool to ° C. Then 782 mg of acetic anhydride and 30 mg of 4-dimethylaminopyridine (concentration: 0.73 wt%) are added, and the mixture is stirred at −35 ° C. for 43 hours. After the reaction and the same treatment as in Example 1 were completed, the reaction mixture was analyzed by high-performance liquid chromatography used in Example 1, whereupon (3R, 4R) -4-acetoxy-3-[(R) -1 72 mg of -t-butyldimethylsilyloxyethyl] azetidin-2-one was observed (yield: 51.0%).

The reaction mixture was purified by silica-gel column chromatography (hexane: ethyl acetate = 10: 1) to give (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxy 65 mg of ethyl] azetidin-2-one were obtained in a needle body.

[Examples 3 to 13 and Comparative Examples]

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

Using (3R, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one as starting material, the conditions shown in Table 1 below The reaction was carried out in the process of Example 1 using different concentrations of 4-dimethylaminopyridine, 4-pyrrolidinopyridine or piperidinopyridine as substituted pyridine under (3R, 4R) -4-acetoxy 3-[(R) -1-t-butyldimethyl-silyloxyethyl] azetidin-2-one was obtained.

The yield was measured by analysis by high performance liquid chromatography used in Example 1.

The reaction conditions and the yield of the product are as shown in Table 1 below.

TABLE 1

EXAMPLE 14 AND 15

4-acetoxyazetidine as a starting material was subjected to the same process under the same conditions as in Example 1, using 4-alkylsilyloxyazetidin-2-one (compound (A)) shown in Table 2 below. 2-one (Compound (B)) was obtained.

The yield of compound (B) is as showing in Table 2 below.

TABLE 2

Example 16

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

After dissolving 157 mg of (3R, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one in 1.6 ml of tetrahydrofuran, the mixture was dissolved. Cool to -35 ° C. Subsequently, 0.005 ml of water (concentration: 0.31% by volume), 0.5 ml of acetic anhydride and 20 mg of 4-dimethylaminopyridine (concentration: 0.93% by weight) are added, and the mixture is stirred at -35 ° C for 22 hours. After the reaction was completed, ethylacetate and 5% aqueous NaHCO ₃ solution were added, and the mixture was separated. The organic layer was washed with water, and the solvent was distilled off under reduced pressure to collect 14 mg of solid.

The reaction mixture was subjected to high performance liquid column chromatography [column: YMC-pak (A-303 0DS), 4.6 × 250 mm, column temperature: 15 ° C., solvent: CH ₃ / water = 6/4 (v / v), flow rate: 1 ml / min, detection: 210 nm] (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one 99.5 mg (Yield: 70%) was obtained.

The reaction mixture is then dissolved in n-hexane and the insolubles are filtered off. The mixture was left to cool at −15 ° C. to yield 89 mg of white solid. The obtained solid was the desired (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one on the basis of the characteristics shown below. It was confirmed.

[α] _D ²⁵ = + 50 ° (c = 0.5, CHCI ₃ )

mp: 107-108 degreeC

¹ H-NMR (90 MHz, CDCl ₃ ), δ (ppm): 0.08 (6H, s), 0.84 (9H, s), 1.20 (3H, d), 2.10 (3H, s), 3.04 (1H, dd ), 4.12 (1H, m), 5.76 (1H, d), 6.78 (NH)

Example 17

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

156 mg of (3R, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one was dissolved in 1.6 ml of ethyl acetate, and the mixture was- Cool to 35 ° C. Subsequently, 0.005 ml of water (concentration: 0.31% by volume), 0.5 ml of acetic anhydride and 30 mg of 4-dimethylaminopyridine (concentration: 1.38% by weight) are added. The mixture is stirred at −35 ° C. for 21 hours. After completion of the reaction and the same treatment as in Example 16, it was analyzed by high performance liquid chromatography used in Example 16 to give (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethyl 85 mg (yield 60%) of silyloxyethyl] azetidin-2-one were collected. Recrystallization with n-hexane gave 76 mg of the above-mentioned compound as a needle.

Example 18

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

After dissolving 156 mg of (3R, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one in 1.6 ml of ethyl acetate, the mixture was- After cooling to 35 ° C., 0.03 ml of acetic acid (concentration: 1.84% by volume), 0.5 ml of acetic anhydride and 30 mg of 4-dimethylaminopyridine (concentration: 1.36% by weight) are added. The mixture is stirred at −35 ° C. for 21 hours. After completion of the reaction and the same treatment as in Example 16, the result was analyzed by high performance liquid chromatography used in Example 16 to obtain (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyl 83 mg (yield: 59%) of dimethylsilyloxyethyl] azetidin-2-one were collected.

Example 19

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

155 mg of (3R, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one was dissolved in 1.6 ml of tetrahydrofuran and the mixture was Cool to 35 ° C. Then 0.03 ml of acetic acid (concentration: 1.84% by volume), 0.5 ml of acetic anhydride and 20 mg of 4-dimethylaminopyridine (concentration: 0.92% by weight) are added. The mixture is stirred at −35 ° C. for 22 hours. After the same treatment as in Example 16, the result was analyzed by high performance liquid chromatography used in Example 16, and the results were (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyl. 84 mg (60% yield) of oxyethyl] azetidin-2-one were obtained.

Example 20

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

The process of Example 16 was repeated, but 0.01 mL (concentration: 0.62% by volume) was used instead of 0.005 mL of water. The concentration of 4-dimethylaminopyridine in the reaction system is 0.93% by weight.

The yield of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one obtained was 65%.

Example 21

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

The process of Example 16 was repeated, but instead of 0.005 mL of water, 0.006 mL of acetic acid (concentration: 3.6% by volume) was used. The concentration of 4-dimethylaminopyridine in the reaction system is 0.91% by weight.

The yield of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one obtained was 66%.

[Examples 22 to 24]

As a starting material, 4-acetoxyazetidine- was subjected to the same reaction and treatment as in Example 17, using 4-alkylsilyloxyazetidin-2-one (Compound (A)) shown in Table 3 below. 2-one (Compound (B)) was obtained.

The yield is as Table 3 below.

TABLE 3

Example 25

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

311.3 mg of (3R, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl-4-trimethylsilyloxy] azetidin-2-one is dissolved in 3.2 ml of pyridine and the mixture is -50 deg. Cool to Then 0.3 ml of acetic anhydride, 30 mg of 4-dimethylaminopyridine (concentration: 0.97 wt%) and 0.01 ml of water (concentration: 0.31 vol%) are added, and the mixture is stirred at -50 ° C for 18.5 hours. After the reaction is completed, hexane and a buffer solution of citric acid and sodium bicarbonate are added, and the mixture is separated.

The organic layer was washed with water, and the solvent was distilled off under reduced pressure to collect 294.9 mg of solid. The obtained solid was analyzed in the same manner as in Example 16, and the result was (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one. 180 mg (yield: 64%) were obtained.

[Examples 26 to 31]

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

The process in Example 16 was repeated, but instead of 1.6 ml of tetrahydrofuran, the solvent shown in Table 4 below was used at the specified amount.

The yield of the obtained (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one and the concentration of 4-dimethylaminopyridine are shown in the following table. It is as showing in 4.

TABLE 4

Example 32

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

After dissolving 300 mg of (3R, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one in 1 ml of tetrahydrofuran, the mixture was dissolved. Cool to -55 ° C. Subsequently, 0.005 ml of water (concentration: 0.5% by volume), 0.8 ml of acetic anhydride and 35 mg of 4-dimethylaminopyridine (concentration: 1.87% by weight) are added, and the mixture is stirred at -55 ° C for 69 hours. After the reaction was completed, 20 ml of ethyl acetate and 20 ml of 5% aqueous NaHCO ₃ solution were added and the mixture was separated. The organic layer was washed with water, dried over magnesium sulfate and the solvent was distilled off under reduced pressure to give 265 mg of a solid.

The reaction mixture was subjected to high performance liquid chromatography [column: YMC-pak (A-303 0DS), 4.6 x 250 mm; Column temperature: 15 ° C., solvent: CH ₃ CN / water = 6/4 (v / v), flow rate: 1 ml / min, detection: 210 nm]. As a result, (3R, 4R) -4-acetoxy 212 mg (yield: 78%) of 3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one were obtained.

Example 33

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

The process in Example 16 was repeated but no water was added. The concentration of 4-dimethylaminopyridine is 0.94% by weight.

The yield of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one obtained was 40%.

Example 34

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one].

The process in Example 17 was repeated but no water was added. The concentration of 4-dimethylaminopyridine is 1.38% by weight.

The yield of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxy] azetidin-2-one obtained was 40%.

Example 35

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxy] azetidin-2-one].

The process of Example 17 was repeated, but 0.005 ml of water (concentration: 3.03% by volume) was used instead of 0.005 ml of water. The concentration of 4-dimethylaminopyridine is 1.35% by weight.

The yield of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxy] azetidin-2-one obtained was 35%.

Example 36

[Preparation of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxy] azetidin-2-one].

The process of Example 19 was repeated, but 0.15 ml of acetic acid (concentration: 8.57% by volume) was used instead of 0.03 ml of acetic acid. The concentration of 4-dimethylaminopyridine is 1.29% by weight.

The yield of (3R, 4R) -4-acetoxy-3-[(R) -1- (t-butyldimethylsilyloxy) ethyl] azetidin-2-one obtained was 37%.

In addition to the components used in the above-described embodiments, the same results can be obtained by carrying out the reaction using other components exemplified in the specification.

Claims (15)

4-acetoxy-3-hydride having the general formula (II) characterized by reacting a β-lactam compound having the general formula (I) in the presence of acetic anhydride and a low concentration of substituted pyridine Process for the preparation of oxyethylazetidin-2-one derivatives.

(Wherein R ¹ is a protecting group for a hydroxyl group, and R ² , R ³ and R ⁴ are lower alkyl, phenyl or aralkyl groups of 1 to 6 carbons.) 4. The 4-acetoxy-3-hydroxyethylazetidine-containing general formula (II) according to claim 1, wherein the organic solvent described above contains at least one selected from the group consisting of water and acetic acid. Method for preparing 2-one derivative. The process for producing the 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (II) according to claim 1, wherein R ¹ is a group represented by the following general formula (III).

(Wherein R ⁵ , R ⁶ and R ⁷ are lower alkyl groups of 1 to 6 carbon atoms). The process for producing the 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (II) according to claim 1, wherein R ¹ is a t-butyldimethylsilyl group. The method for producing the 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (II) according to claim 1, wherein R ¹ is an isopropyldimethylsilyl group. 2. The 4-acetoxy-3-hydroxyethylazetidin-2-one derivative of formula (II) according to claim 1, wherein R ¹ is a dimethyl-1, 1, 2-trimethylpropylsilyl group. Manufacturing method. The process for producing the 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (II) according to claim 1, wherein R ² , R ³ and R ⁴ are methyl groups. The process for preparing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (II) according to claim 1, wherein the substituted pyridine is 4-dimethylaminopyridine. The process for preparing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (II) according to claim 1, wherein the substituted pyridine is 4-pyrrolidinopyridine. The process for preparing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (II) according to claim 1, wherein the substituted pyridine is 4-piperidinopyridine. 2. The 4-acetoxy-3-hydroxyethylazetidin-2-one derivative of formula (II) according to claim 1, wherein the concentration of the above-mentioned substituted pyridine in the reaction system is 0.2 to 3% by weight. Manufacturing method. The process for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (II) according to claim 2, wherein the concentration of water in the solvent is 0.1 to 1.0% by volume. The process for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (II) according to claim 2, wherein the concentration of acetic acid in the solvent is 0.6 to 5.0% by volume. The process for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (II) according to claim 1, wherein the organic solvent is tetrahydrofuran. The process for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having general formula (III) according to claim 1, wherein the organic solvent is pyridine.