JPH066570B2 - Process for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative.

In recent years, since the discovery of thienamycin, various carbapenems have been discovered and synthesized, and development is proceeding due to their excellent antibacterial activity, β-lactamase inhibitory action and the like. Further, penem, which is a skeletal analog thereof, has the same antibacterial activity and is being studied because it can be orally administered. In order to express these activities, 1 at the 6-position
It is important to have a -hydroxyethyl group. Further, as an important method for synthesizing these skeletons, a carbapenem by ring-closing the 4-position and the 1-position of a β-lactam compound,
The method of guiding to Penem is widely used.

Therefore, it has 1-hydroxyethyl or the one having its hydroxyl group protected at the 3-position, and has a leaving group, particularly an acetoxy group, which is easily substituted with carbon or a sulfur compound at the 4-position.
-Acetoxy-3-hydroxyethylazetidine-2-
The on-derivatives are known as important useful intermediates in carbapenem and penem synthesis reactions.

(Conventional Technology and Problems) Conventionally, as a method for synthesizing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative, a method for synthesizing from 4-aminopenicillanic acid [Yoshida et al., Chemical and Pharma Chemical Bulletin (Chem.Pharm.Bul
l.), 29, 2899 (1981)], a method of synthesizing from threonine [Shiozaki et al., tetrahedron
(Tetrahedron), 39, 2399 pages (1983)
)], A method for synthesizing from aspartic acid (Raider et al., Tetrahedron Lett.),
23, page 2393 (1982)] and the like are known. However, all of these methods have a drawback in that industrially unfavorable heavy metal compounds such as mercury acetate and lead tetraacetate are used for introducing an acetoxy group at the 4-position of the β-lactam ring. . Therefore, the inventor
As a result of continuous research to solve these drawbacks, silyl enol ethers were reacted with chlorosulfonyl isocyanate to give a novel 1-hydroxyethyl group having a hydroxyl group at the 3-position and a silyl ether at the 4-position. The inventors have found a method for producing a β-lactam compound (Japanese Patent Application No. 139797 in 1984), and have further found a simple method for converting the 4-position of this β-lactam compound into an acetoxy group, thereby completing the present invention. The details will be described below.

(Means and Solutions for Solving Problems) The present invention provides a compound represented by the general formula (I) (Wherein R ¹ represents a hydroxyl protecting group, R ² , R ³ and R ⁴ represent C _{1 to} C ₄ lower alkyl groups, phenyl groups or aralkyl groups, and R ⁵ represents an N protecting group). A general formula (II) characterized by reacting a β-lactam compound with acetyl nitrate and then removing the N protecting group, if necessary. (Wherein R ¹ is the same as above, R ⁶ represents hydrogen or a protecting group for N) and a method for producing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative.

The β-lactam compound represented by the general formula (I) has already been applied by the present inventors (Japanese Patent Application No. 139797 in 1984).
No. 3) A β-lactam compound (I ′) (R ¹ , R ² , R ³ and R ⁴ are the same as described above) which can be synthesized by a simple method as shown in the following reaction formula, and a N protecting group R ⁵ is added to the β-lactam compound (I ′). It is obtained by introducing.

This is an operation to be performed because the yield is generally higher when N is protected when acetyl nitrate is acted next. At this time, R ⁵ —X (X is a halogen) can be used as a reagent for introducing a protecting group. As R ⁵ -X, silyl chloride such as trimethylsilyl chloride, t-butyldimethylsilyl chloride, isopropyldimethylsilyl chloride, isobutyldimethylsilyl chloride, triisopropylsilyl chloride, or the like, Although oxalyl chloride and the like commonly used as N-protecting reagents for β-lactams can be used,
Trimethylsilyl chloride and t-butyldimethylsilyl chloride are preferred. In the reaction, compound (I ′) and R ⁵ —X are added to DMF, dichloromethane, THF in the presence of a base such as trimethylamine or imidazole.
The mixture is mixed in an inert organic solvent such as, and the treatment is completed at room temperature to the boiling point of the solvent for several hours to 1 day. The target β-lactam compound can be obtained by the usual operations such as evaporation of the solvent, extraction, and washing with water.
(I) is obtained.

The hydroxyl-protecting group R ¹ has the general formula (III) (In the formula, R ⁷ , R ⁸ and R ⁹ represent a C _{1 to} C ₄ lower alkyl group), for example, t-butyldimethylsilyl group, isopropyldimethylsilyl group, triisopropylsilyl group , Isobutyldimethylsilyl group and the like, and other t-butyl group, benzyl group, trichloroethoxycarbonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group and the like, but preferably during the reaction. To
A t-butyldimethylsilyl group or an isopropyldimethylsilyl group, which is more stable and can be selectively deprotected by acid treatment or the like, is preferable.

Further, the substituents R ² , R ³ and R ⁴ of the silyl ether at the 4-position of the β-lactam compound are C _{1 to} C ₄ lower alkyl groups such as methyl, ethyl, isopropyl, isobutyl and t-butyl,
The same or different groups can be selected from phenyl groups or aralkyl groups such as benzyl and p-nitrobenzyl groups, but R ² = R ³ = R ⁴ = methyl is preferred.

General formula (I) prepared as described above (In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as above) By reacting acetyl nitrate with the compound, the silyl ether at the 4-position can be converted to an acetoxy group. Then, if necessary, the protecting group of N is removed to give a compound of the general formula (II) (Wherein R ¹ is the same as above, R ⁶ is hydrogen or a protecting group for N). Acetyl nitrate is
According to a known method, fuming nitric acid or concentrated nitric acid is slowly added dropwise into acetic anhydride under cooling, preferably at 15 ° C or lower. At this time, it can be performed by diluting with an inert solvent such as a halogenated hydrocarbon. In addition, it is desirable to add concentrated sulfuric acid before dropping nitric acid as a reaction catalyst. When the solution of acetyl nitrate thus obtained is reacted with the compound (I), the reaction temperature is −70 ° C. to room temperature, preferably −40 ° C. to 0 ° C., with respect to the compound (I). Acetyl nitrate is 1 to 20 times mol, acetic anhydride is 1 to 100 times mol, concentrated sulfuric acid is 0.01 to
A 10-fold molar amount may be used. As the solvent, an inert one such as a halogenated hydrocarbon can be used, but usually the same one as that used to prepare acetyl nitrate may be used.
As the reaction operation, the solution of the compound (I) may be slowly added dropwise to the cooled acetyl nitrate solution, and when the compound (I) disappears, the reaction solution may be treated with a usual organic solvent and water. At this time, it is desirable to use alkaline water or a buffer solution at a low temperature so that the pH of the reaction solution does not become strongly acidic. Then, the solvent is distilled off to obtain a β-lactam compound having an acetoxy group at the 4-position, but a protecting group R ^{5 for} N
Type, the reaction, by the processing conditions, if R ⁵ is eliminated, or if the mixture of compounds compound and R ⁵ which R ⁵ is attached is eliminated can be obtained, or a compound that remains attached R ⁵ is May be obtained. If it is necessary to remove the protecting group of N from these, by performing the elimination operation by a conventional method, the compound of the general formula (II) (Wherein R ¹ and R ⁶ are the same as described above) can be obtained. Alternatively, when a carbapenem or penem compound is derived from these, a deprotection operation may be carried out as necessary to introduce an arbitrary protecting group, by a known method.

Regarding elimination of the protecting group of N, it is often desirable to eliminate only the protecting group of N without eliminating the protecting group R ¹ of the hydroxyethyl group at the 3-position. In this case,
Specifically, when the protecting group of N is a trialkylsilyl group, for example, t-butyldimethylsilyl group, tetrabutylammonium fluoride, tetrabutylammonium chloride or a combination reagent of tetramethylammonium chloride and potassium fluoride is used as THF or The reaction may be carried out in the presence of acetic acid using dichloromethane or the like as a solvent. In the case of an unstable trimethylsilyl group, a known amount of pyridinium p-toluenesulfonate is allowed to act in a THF-water solvent. Any method may be used.

The compound (II) thus obtained can be purified by crystallization from n-hexane or petroleum ether or by silica gel chromatography.

(Examples) Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 (3R, 4R) -4-acetoxy-3-[(R) -1-ter
t-Butyldimethylsilyloxyethyl] -azetidine-2
Synthesis of 3-one (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one (1.00 g) was dissolved in DMF (10 ml). After adding 1.05 g of triethylamine and 0.82 g of trimethylsilyl chloride and stirring at room temperature for 6 hours,
Diluted with hexane 60 ml, ice-cold while 5% NaHCO ₃ aqueous 6
0 ml was added. After separating the aqueous layer, the organic layer was mixed with 10% citric acid-5% NaHCO ₃ mixed solution (pH 4) 60 ml and saturated saline solution 60 ml.
After washing with × 2 and drying over anhydrous magnesium sulfate, the solvent was distilled off to give a pale yellow liquid (3R, 4
1.05 g of (R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-trimethylsilyloxy-1-trimethylsilylazetidin-2-one was obtained.

5.39 g of acetic anhydride was dissolved in 5 ml of 1,2-dichloroethane, 0.1 ml of concentrated sulfuric acid was added to the mixture while ice-cooled, and fuming nitric acid (specific gravity 1.
52) 0.8 ml was added dropwise. 0 hours after completion of dropping
After keeping at 10 ° C, it was cooled to -40 ° C (dry ice-acetone bath). In addition, (3R, 4R) -3-
[(R) -tert-butyldimethylsilyloxyethyl] -4
-Trimethylsilyloxy-1-trimethylsilylazetidin-2-one 1.05 g was added to 1,2-dichloroethane 2
A solution dissolved in 1 ml was added dropwise over 1 hour. After reacting as it was at -40 ° C for 3 hours, the reaction solution was poured at once into a mixed solution of 350 ml of hexane, 150 ml of ethyl acetate and 500 ml of a phosphate buffer solution (0.5 M) having a pH of 7.
After separating the aqueous layer, the organic layer was added to 5% NaHCO ₃ water (500 ml),
500 ml of 10% citric acid-5% NaHCO ₃ mixture (pH 4),
The extract was washed successively with 200 ml of saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off to give a pale yellow oily substance 0.62 g.
Got This is (3R, 4R) -4-acetoxy-3-
[(R) -1-tert-butyldimethylsilyloxyethyl]
-1-Trimethylsilylazetidin-2-one and (3
R, 4R) -4-acetoxy-3-[(R) -1-tert-
Butyldimethylsilyloxyethyl] -azetidine-2-
Since it was a mixture of ON (molar ratio 1: 2), THF3
It was dissolved in a mixed solution of 0 ml and water (15 ml), 30 mg of pyridium p-toluenesulfonate was added, and the mixture was stirred for 30 minutes. Hexane (350 ml) and ethyl acetate (150 ml) were added to the reaction solution, and the mixture was washed with 500 ml of water, 500 ml of 5% NaHCO _{3 and} 200 ml of saturated brine in that order, and the organic layer was evaporated to give (3R, 4R) -4-acetoxy as a pale yellow solid. -3-[(R) -1-ter
t-butyldimethylsilyloxyethyl] -azetidine-
0.33 g of 2-one was obtained. By recrystallizing this from n-hexane, the target β-lactam (3
R, 4R) -4-acetoxy-3-[(R) -1-tert-
Butyldimethylsilyloxyethyl] -azetidine-2-
0.27 g of ON was obtained as colorless needle crystals.

▲ [α] ²⁵ _D ▼ = + 50 ° (c = 0.5, CHCl ₃ ), mp. 107-108 ° C. ¹ H-NMR (90 MHz, CDCl ₃ ), δ (ppm): 0.08 (6H, s), 0.84 (9H, s), 1.20 (3H, d), 2.01 (3H, s), 3.04 (1H, dd), 4.12 (1H, m), 5.76 (1H, d), 6.78 (NH) Example 2 (3R, 4R) -4- Acetoxy-3-[(R) -1-ter
t-butyldimethylsilyloxyethyl] -azetidine-
Synthesis of 2-one Dissolve 5.39 g of acetic anhydride in 5 ml of 1,2-dichloroethane, add 0.1 ml of concentrated sulfuric acid into the ice-cooled solution, and add fuming nitric acid while keeping the liquid temperature at 10 to 15 ° C. (Specific gravity 1.
52) 0.8 ml was added dropwise. After completion of dropping, stirring was continued for 30 minutes as it was, and then the reaction solution was ice-cooled. In this
(3R, 4R) -3-synthesized in the same manner as in Example 1.
[(R) -1-tert-butyldimethylsilyloxyethyl]
A solution prepared by dissolving 0.93 g of -4-trimethylsilyloxy-1-trimethylsilylazetidin-2-one in 21 ml of 1,2-dichloroethane was added dropwise over about 1 hour. After continuing stirring for 3 hours, the reaction solution was mixed with 350 ml of hexane, 150 ml of ethyl acetate, and a phosphate buffer solution (0.5 M) having a pH of 500 (500 M).
Pour into the ml mixture at once. After separating the aqueous layer, the organic layer was added to 500 ml of 5% NaHCO ₃ water, 10% citric acid-
500 ml of 5% NaHCO ₃ mixed solution (pH 4), saturated saline solution 200
The extract was washed successively with ml, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 0.33 g of a pale yellow oily substance. This is n
Crystallization from -hexane gave 0.13 g of the desired β-lactam as colorless needle crystals. Each property was the same as the value shown in Example 1.

Example 3 (3R, 4R) -4-acetoxy-3-[(R) -1-ter
t-butyldimethylsilyloxyethyl] -azetidine-
Synthesis of 2-one (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one 1.00 g of dichloromethane 10 ml
Dissolved in 0.89 g of triethylamine and tert-
Butyldimethylsilyl chloride (0.61 g) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction, a 5% NaHCO ₃ aqueous solution was added to this solution, the aqueous layer was separated, and the organic layer was washed successively with dilute hydrochloric acid having a pH of 3 and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a brown liquid. This was subjected to silica gel chromatography (hexane: ether = 100:
Purified in 3), (3R, 4R) -3-[(R) -1-ter
0.80 g of t-butyldimethylsilyloxyethyl] -4-trimethylsilyloxy-1-tert-butyldimethylsilylazetidin-2-one was obtained as a colorless liquid.

2.70 g of acetic anhydride was dissolved in 2.5 ml of 1,2-dichloroethane, 0.05 ml of concentrated sulfuric acid was added to this while cooling with ice, and fuming nitric acid (specific gravity) was added while keeping the liquid temperature at 10 to 15 ° C. 1.52) 0.4 ml was slowly added dropwise. Then, the temperature was kept at 0 to 10 ° C for 30 minutes, and this was cooled to -40 ° C, and (3R, 4R) -3-[(R) -1-tert was added thereto.
-Butyldimethylsilyloxyethyl] -4-trimethylsilyloxy-1-tert-butyldimethylsilylazetidin-2-one 0.61 g was added to 1,2-dichloroethane 11 m.
What was melt | dissolved in l was dripped over 1 hour. 1 hour,-
After keeping at 40 ° C. and further reacting at −30 ° C. for 2 hours,
210 ml of hexane, 90 ml of ethyl acetate, pH 7
Was poured all at once into a mixture of 300 ml of phosphate buffer (0.5 M). After removing the water layer, the organic layer was washed with 5% NaHCO ₃ water,
The mixture was washed with 10% citric acid-5% NaHCO ₃ mixed solution (pH 4) and saturated saline in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 0.32 g of a pale yellow oily substance. This is subjected to silica gel chromatography (hexane: ether =
10: 1) to give (3R, 4R) -4-acetoxy-3-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-tert-butyldimethylsilylazetidine-2- 0.22 g of on was obtained as a colorless oil. This is dissolved in 20 ml of THF, 0.15 g of tetra-n-butylammonium fluoride and 0.07 g of acetic acid are added,
Stirred at room temperature for 1 hour. The solvent was distilled off and ethyl acetate 30
50 ml of 5% NaHCO ₃ water was added, the aqueous layer was separated, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the residue was recrystallized from n-hexane to obtain 0.13 g of the target β-lactam as colorless needle crystals. Each property was the same as the value shown in Example 1.

Example 4 (3R, 4R) -4-acetoxy-3-[(R) -1-isopropyldimethylsilyloxyethyl] azetidine-2
Synthesis of 3-one 3-[(R) -1-isopropyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one 1.50 g [(3R, 4R) body: (3S, 4S) body =
5: 1] was dissolved in 15 ml of dichloromethane, 0.65 g of triethylamine and 1.00 g of tert-butyldimethylsilyl chloride were added, and the mixture was stirred at room temperature for 14 hours. After diluting with 50 ml of dichloromethane, 50 ml of 5% NaHCO ₃ , pH 4
It was washed successively with diluted hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and 1.56 g of 3-[(R) -1-isopropyldimethylsilyloxyethyl] -4-trimethylsilyloxy-1-tert-butyldimethylsilylazetidin-2-one was obtained as a yellow oil. Obtained.

5.39 g of acetic anhydride was mixed with 5 ml of 1,2-dichloroethane, 0.2 ml of concentrated sulfuric acid was added thereto, and the mixture was cooled to an internal temperature of 1
The temperature was 0 to 15 ° C. While maintaining the temperature, 0.8 ml of fuming nitric acid (specific gravity 1.52) was added dropwise over about 1.5 hours, and stirring was continued for 2 hours. This is cooled to −80 ° C. and 3-[(R) -1-isopropyldimethylsilyloxyethyl] -4-trimethylsilyloxy-1-tert-butyldimethylsilylazetidin-2-one 1.56 g
Was added dropwise to 30 ml of 1,2-dichloroethane over about 1.5 hours, and stirring was continued for about 3 hours. The reaction solution
A mixture of 350 ml of hexane, 150 ml of ethyl acetate and 500 ml of a phosphate buffer (0.5 M) having a pH of 7 was poured all at once into an ice-cooled bath. After separating the aqueous layer, the organic layer was separated with 5% NaHCO ₃
300 ml of water, 10% citric acid-5% NaHCO ₃ mixture (pH
4) It was washed with 300 ml and saturated saline in this order and dried over anhydrous magnesium sulfate. The solvent was distilled off to give a yellow oily substance.
90 g were obtained. This 4-acetoxy-3-[(R) -1-
Isopropyldimethylsilyloxyethyl] -1-tert-
The oily material containing butyldimethylsilylazetidin-2-one was dissolved in 20 ml of dichloromethane as it was, and acetic acid of 0.
37g, tetramethylammonium chloride 0.34g,
0.13 g of potassium fluoride was added, and the mixture was stirred in a thick state. After reacting at room temperature for 8 hours, add 5% NaHC
After pouring into 100 ml of O ₃ water-80 ml of dichloromethane and stirring for a while, the aqueous layer was removed and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The obtained target β-lactam [(3R, 4R):
The pale yellow oil containing (3S, 4S) = 5: 1] was crystallized from hexane to give (3R, 4R) -form 0.21
g was obtained as colorless needles.

▲ [α] ²⁵ _D ▼ = + 54.2 ° (c = 0.5, CHCl ₃ ) mp. = 92 to 94 ° C ¹ H-NMR (90 MHz), CDCl ₃ ) δ (ppm): 0.04 (6H, s), 0.90 (7H), 1.23 (3H, d), 2.06 ( 3H, s), 3.13 (1H, dd), 4.13 (1H, m), 5.76 (1H, d), 6.40 (NH)

Claims (11)

[Claims] 1. A general formula (I) (In the formula, R ¹ is a hydroxyl-protecting group, R ² , R ³ and R ⁴ are C _{1 to} C ₄ lower alkyl groups, phenyl groups or aralkyl groups, and R ⁵ is N.
Acetyl nitrate is allowed to act on the β-lactam compound represented by the formula (4), and then the protecting group for N is eliminated, if necessary. (In the formula, R ¹ represents a hydroxyl-protecting group and R ⁶ represents hydrogen or N-protecting group.) A process for producing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative represented by the formula: 2. R ¹ is the general formula (III) (Wherein R ⁷ , R ⁸ and R ⁹ represent a C _{1 to} C ₄ lower alkyl group), and the production method according to claim 1. 3. The method according to claim 1, wherein R ¹ is a t-butyldimethylsilyl group. 4. The production method according to claim 1, wherein R ¹ is an isopropyldimethylsilyl group. ^5. The production method according to claim 1, wherein R ⁵ is a trimethylsilyl group. 6. The method according to claim 1, wherein R ⁵ is a t-butyldimethylsilyl group. 7. The method according to claim 1, wherein R ⁶ is hydrogen. 8. The process according to claim 1, wherein R ⁶ is a t-butyldimethylsilyl group. 9. The method according to claim 1, wherein R ⁶ is a trimethylsilyl group. 10. The method according to claim 1, wherein R ² , R ³ and R ⁴ are methyl groups. 11. A general formula (I ′) (Wherein R ¹ is a hydroxyl-protecting group, R ² , R ³ and R ⁴ are C _{1 to} C ₄ lower alkyl groups, phenyl groups, or aralkyl groups) and R ⁵ -X ( R ⁵ is a protecting group for N, and X is a halogen).
General formula (I) (Wherein R ¹ represents a hydroxyl-protecting group, R ² , R ³ and R ⁴ represent C _{1 to} C ₄ lower alkyl groups, phenyl groups or aralkyl groups, and R ⁵ represents an N protecting group). To produce a compound, and then reacting the compound (I) with acetyl nitrate, and then
If necessary, by removing the protecting group of N, the compound of the general formula (II) (In the formula, R ¹ represents a hydroxyl-protecting group, and R ⁶ represents hydrogen or N-protecting group.) A method for producing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative.