JPH0655717B2 - Process for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Field of the Invention The present invention has 4-acetoxy-3-hydroxyethyl having a hydroxyethyl group having a hydroxyl group protected at the 3-position and an acetoxy group at the 4-position. The present invention relates to a novel method for producing an azetidin-2-one derivative.

4-acetoxy-3-hydroxyethylazetin-2-
The on derivative is known to be useful as a carbapenem β-lactam antibiotic typified by thienamycin and a synthetic intermediate for a penem β-lactam antibiotic (for example, Raider et al., Tetrahedron Letters). 23, 2293 (1982), and Yoshida et al., Chemical and Pharmacy Bulletin (Chem, Pham, Bull,) 29, 2899 (1981).
Year)〕.

(Conventional Technology and Problems) Conventionally, a method for synthesizing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative from 6-aminopenicillanic acid [Yoshida et al., Chem, Pharm, Bul]
1, 29, 2899 (1981)], a method of synthesizing from threonine [Shiozaki et al., tetrahedron, 39.
Vol., 2399 (1983)], a method for synthesizing from aspartic acid [Raider et al., Tetrahedron Letters, 23, 2293 (1982)], and a method for synthesizing β-hydroxybutyric acid metal enolate [Nakai. Chemistry Letters, p. 1927 (1984)
Years)] etc. are known. However, in any method, in order to introduce an acetoxy group at the 4-position of the β-lactam ring, a mercury compound such as mercury acetate or mercury sulfate, or an industrially unfavorable reagent such as lead tetraacetate is used. It had some difficulties.

We have an O-protected hydroxyethyl group at the 3-position, a 4
A method for introducing an acetoxy group at the 4-position using a novel β-lactam compound having a silyl ether group at the position (N is unprotected) was found, and a patent application has already been filed (patent application No. 101856 in 1986). As a result of further detailed studies, the present inventors have found that the yield is improved by adding water or acetic acid in a certain amount in the above reaction, and arrived at 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 a C _{1 to} C ₆ lower alkyl group, a phenyl group or an aralkyl group) and an organic solvent is added to the β-lactam compound. 0.1 to 1.0 (v / v)% of water or 0.6 to 5.0
0.2 to 3% by weight of acetic anhydride in the presence of (v / v)% acetic acid, characterized by the general formula (II) (In the formula, R ₁ represents a hydroxyl-protecting group) 4
-Acetoxy-3-hydroxyethylazetidine-2-
The gist is a method for producing an on-derivative.

The β-lactam compound represented by the general formula (I) and having a silyl ether group at the 4-position can be prepared by the method of reaction formula I as already filed by the present inventors (Japanese Patent Laid-Open No. 61-18791). Can be easily acquired.

Reaction formula I: As R ₁ which is an O-protecting group for the hydroxyethyl group at the 3-position of the β-lactam compound (I), R ₁ is represented by the general formula (III) (In the formula, R ₅ , R ₆ and R ₇ represent a C _{1 to} C ₆ lower alkyl group)
A trialkylsilyl group represented by, for example, tert-butyldimethylsilyl group, triisopropylsilyl group, isopropyldimethylsilyl group, isoptyldimethylsilyl group, 1,2-dimethylpropyldimethylsilyl group, dimethyl-1,1,2- Examples thereof include a trimethylpropylsilyl group, and other t-butyl group, benzyl group, trichloroethoxycarbonyl group, tert-butoxycarbonyl group, p-nitrobenzyloxycarbonyl group, and the like, but it is preferable that it is more stable during the reaction and further acid. A tert-butyldimethylsilyl group, an isopropyldimethylsilyl group and a dimethyl-1,1,2-trimethylpropylsilyl group which can be selectively deprotected by the treatment are preferable. Also, β-lactam compounds
(I) R ₂ , R ₃ and R ₄ are each a C _{1 to} C ₆ lower alkyl group such as methyl, ethyl, isopropyl, isobutyl, tert-butyl, 1,1,2-trimethylpropyl, a phenyl group, or The same or different groups can be selected from aralkyl groups such as benzyl group and p-nitrobenzyl group, but preferably R ₂ =
Optimally R ₃ = R ₄ = methyl.

General formula (I) prepared as described above (Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as above), a substituted pyridine and acetic anhydride are added to the β-lactam compound in an organic solvent in the presence of low concentration water or acetic acid. The desired 4-acetoxy-3-hydroxyethylazetidine-
2-one derivative (II) (Wherein R ₁ is the same as above), and the concentration of water or acetic acid in the reaction system is an important factor for obtaining the compound (II) in a satisfactory yield. There is also an optimal concentration range. The preferred concentration of water or acetic acid in the reaction system is 0.1 to 1.0 (v / v)% in the case of water relative to the solvent used, and 0.6 to 5.0 (v / v) in the case of acetic acid.
v)% range is adopted. Below this, the following general formula
By-product represented by (IV) (In the formula, R ₁ is the same as the above), and when the concentration is high, side reactions of decomposition of the substrate increase, and the desired compound (II) cannot be obtained in a satisfactory yield.

Examples of the substituted pyridine used include dialkylaminopyridines such as 4-dimethylaminopyridine and 4-diethylaminopyridine, and substituted pyridines having a nitrogen-containing heterocyclic group such as 4-pyrrolidinopyridine and 4-piperidinopyridine as a substituent. Is preferred. The concentration of the substituted pyridine in the reaction system is preferably in the range of 0.2 to 3% by weight.

If the amount of acetic anhydride is smaller than that of the substituted pyridine, the reaction rate will decrease. Therefore, an excess amount of acetic anhydride may be used, and the concentration in the reaction system is preferably 10 to 50 wt%. Good.

The solvent used in the reaction is preferably a halogen-based solvent such as methylene chloride or carbon tetrachloride, a hydrocarbon such as n-hexane, an aromatic hydrocarbon such as toluene, ethyl acetate, tetrahydrofuran or tetrahydropyran. Further, a solvent such as pyridine, picoline, lutidine, diethyl ether, diglyme, dimethylformamide or acetone can be used.

By carrying out the reaction in the low temperature range of 0 ° C to -70 ° C, the desired compound (II) can be obtained in a satisfactory yield. Preferably, the reaction may be carried out under the temperature condition of -10 ° C to -60 ° C.

As a reaction operation, a β-lactam compound having a silyl ether group at the 4-position represented by the general formula (I) is dissolved in an organic solvent such as tetrahydrofuran or ethyl acetate, the solution is cooled, and water or acetic acid is added. An appropriate amount is added, and the reaction is carried out at this temperature by adding acetic anhydride and a substituted pyridine such as 4-dimethylaminopyridine all at once or in divided portions.
The reaction is carried out while checking the progress of the reaction by thin layer chromatography, and when the raw material disappears or a trace amount is reached, the reaction solution is poured into water. Next, the organic layer is washed with sodium hydrogen carbonate and water and then dried over magnesium sulfate. The solvent is distilled off and the obtained crude crystals are recrystallized with a solvent such as n-hexane to obtain the desired 4-acetoxy-3-hydroxyethylazetidin-2-one derivative. Also, from the reaction mixture obtained by distilling off the solvent, 4 by column chromatography.
-Acetoxy-3-hydroxyethylazetidine-2-
It is also possible to obtain an on derivative.

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

Example 1 (3R, 4R) -4-acetoxy-3-[(R-1-te
rt-Butyldimethylsilyloxyethyl] -azetidine-
Synthesis of 2-one (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one [mp 95-96 ° C., ▲ [α ] ²⁵ _D
▼ = −9.5 ° (c = 1.0, CHCl ₃ )] 157 mg was dissolved in 1.6 ml of tetrahydrofuran, and this was cooled to −35 ° C.
Then 0.005 ml of water and 0.5 ml of acetic anhydride were added, and 2 more
Add 0 mg of 4-dimethylaminopyridine to give -35
The mixture was stirred at 0 ° C for 22 hours. After the reaction, ethyl acetate and 5% NaHC
An aqueous solution of O ₃ was added thereto for liquid separation, the organic layer was washed with water, and the solvent was distilled off under reduced pressure to obtain 140 mg of a solid.

The reaction mixture was subjected to high performance liquid column chromatography (column YMC-pack (A-303 ODS) 4.6 × 250 m).
m, column temperature 15 ° C., solvent (CH ₃ CN: water = 6: 4 v / v)
When analyzed with a flow rate of 1 ml / min and detection of 210 nm), 99.5 mg of (3R, 4R) -4-acetoxy-3-[(R) -1-
tert-Butyldimethylsilyloxyethyl] azetidine-
2-one was produced (yield 70%).

Further, this reaction mixture was dissolved in n-hexane, and after insoluble matter was passed therethrough, it was left to cool at -15 ° C to obtain 89 mg of a white solid. From the following physical properties, the desired (3R, 4R) -4 was obtained.
-Acetoxy-3-[(R) -1-tert-butyldimethylsilyloxyethyl] azetidin-2-one was confirmed.

▲ [α] ²⁵ _D ▼ = + 50 ° (c = 0.5, CHCl ₃ ) mp = 107-108 ° C. ¹ Hnmr (90 MHz CDCl ₃ ), δ (ppm): 0.08 (6 H, s),
0.84 (9H, s), 1.20 (3H, d), 2.10 (3H,
s), 3.04 (1H, dd), 4.12 (1H, m), 5.76 (1
H, d), 6.78 (NH) Example 2 (3R, 4R) -4-acetoxy-3-[(R) -1-
Synthesis of tert-butyldimethylsilyloxyethyl] -azetidin-2-one (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidine-2- Dissolve 156 mg of ONE in 1.6 ml of ethyl acetate, cool to -35 ° C, then add 0.005 ml of water and 0.5 ml of acetic anhydride.
Was added, and further 30 mg of 4-dimethylaminopyridine was added, and the mixture was stirred at -35 ° C for 21 hours. After the reaction, the mixture was treated in the same manner as in Example 1 and analyzed by high performance liquid chromatography (3R, 4R) -4-acetoxy-3-[(R) -1-tert-butyldimethylsilyloxyethyl. ] 85 mg of azetidin-2-one was produced (yield 60%). By recrystallizing the reaction product from n-hexane, 76 mg of the above compound was obtained as needle crystals.

Example 3 (3R, 4R) -4-acetoxy-3-[(R) -1-
Synthesis of tert-butyldimethylsilyloxyethyl] -azetidin-2-one (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidine-2- Dissolve 156 mg of ONE in 1.6 ml of ethyl acetate, cool to -35 ° C, add 0.03 ml of acetic acid, 0.5 m of acetic anhydride.
1 was added, and further 30 mg of 4-dimethylaminopyridine was added, followed by stirring at -35 ° C for 21 hours. After the reaction
When treated by the same method as in Example 1 and analyzed by high performance liquid chromatography, (3R, 4R) -4-acetoxy-3-[(R) -1-tert-butyldimethylsilyloxyethyl] azetidine- 83 mg of 2-one was produced (yield 59%).

Example 4 (3R, 4R) -4-acetoxy-3-[(R) -1-
Synthesis of tert-butyldimethylsilyloxyethyl] -azetidin-2-one (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidine-2- 155mg of ON to 1.6m of tetrahydrofuran
It was dissolved in 1 and cooled to -35 °. Then acetic acid
0.03 ml, 0.5 ml acetic anhydride were added, and 20 mg of 4-
Dimethylaminopyridine was added, and the mixture was stirred at -35 ° C for 22 hours. After that, the same processing as in Example 1 is performed,
When analyzed by high performance liquid chromatography (3R,
84 mg of 4R) -4-acetoxy-3-[(R) -1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one was formed (yield 60%).

Example 5 (3R, 4R) -4-acetoxy-3-[(R) -1-
Synthesis of tert-butyldimethylsilyloxyethyl] -azetidin-2-one The same charging as in Example 1 was carried out, and an experiment was carried out in which only the addition of water was changed. The results are shown in Table 1. Processing and analysis were carried out as in Example 1.

Example 6 The reaction and treatment were carried out in the same manner as in Example 2 using various 4-alkylsilyloxyazetidin-2-ones (compound A) as starting materials to obtain 4-acetoxyazetidin-2-ones (compounds). The production yield of B) is shown in Table 2.

Example 7 (3R, 4R) -4-acetoxy-3-[(R) -1-
Synthesis of tert-butyldimethylsilyloxyethyl] -azetidin-2-one (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidine-2- Dissolve 311.3 mg of on in 3.2 ml of pyridine,
Cool to -50 ° C, then 0.3 ml of acetic anhydride and 30 mg of 4
-Dimethylaminopyridine and 10 µ of water were added, and the mixture was stirred at -50 ° C for 18.5 hours. After the reaction, hexane was added, a buffer solution consisting of citric acid and sodium hydrogen carbonate was added, the layers were separated, the organic layer was washed with water, and the solvent was distilled off under reduced pressure to obtain a solid (294.9 mg).

When analyzed in the same manner as in Example 1, (3R, 4R) -4-
180 mg of acetoxy-3-[(R) -1-tert-butyldimethylsilyloxyethyl] -acetidin-2-one
It was produced (yield 64%).

Example 8 (3R, 4R) -4-acetoxy-3-[(R) -1-
Synthesis of tert-butyldimethylsilyloxyethyl] -azetidin-2-one The following reactions were carried out in the same manner as in Example 1 except that the following various solvents were used instead of tetrahydrofuran in Example 1.

Example 9 (3R, 4R) -4-acetoxy-3-[(R) -1-
Synthesis of tert- (butyldimethylsilyloxy) ethyl] -azetidin-2-one (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxy) ethyl] -4-trimethylsilyloxyazetidine 2-one 300 mg tetrahydrofuran 1
It was dissolved in ml and cooled to -55 ° C. Then water 0.
005 ml and acetic anhydride 0.8 ml were added, 35 mg 4-dimethylaminopyridine was further added, and the mixture was stirred at -55 ° C for 69 hours. After the reaction, 20 ml of ethyl acetate and 5% NaHCO ₃ aqueous solution 2
0 ml was added, 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 obtain 265 mg of a solid.

The reaction mixture was subjected to high performance liquid column chromatography (column: YMC-pack (A-303 ODS) 4.6 × 25).
0 mm, temperature: 15 ° C solvent: CH ₃ CN: water = 6: 4 (v / v),
Flow rate: 1 ml / min, detection: 210 nm) 212 when analyzed
mg (3R, 4R) -4-acetoxy-3-[(R)-
1- (tert-Butyldimethylsilyloxy) ethyl] -azetidin-2-one had formed (yield 78%).

Reference Example Regarding Example 1 and Example 2, the same reaction was performed. At that time, the experiment was conducted by changing the amount of water or acetic acid. The results are shown in Table 3.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kiyo Watanabe 5-15-41 Matsugaoka, Akashi-shi, Hyogo (56) References JP 61-18758 (JP, A)

Claims (11)

[Claims] 1. A general formula (I) (In the formula, R ₁ is a hydroxyl-protecting group, and R ₂ , R ₃ and R ₄ are C
Lower alkyl group of ₁ -C _6, a phenyl group or an aralkyl group. ) To a β-lactam compound represented by
A general formula (II) characterized in that 0.2 to 3% by weight of substituted pyridine and acetic anhydride are allowed to act in the presence of ˜1.0 (v / v)% water or 0.6 to 5.0 (v / v)% acetic acid. II) (In the formula, R ₁ represents a hydroxyl-protecting group) 4
-Acetoxy-3-hydroxyethylazetidine-2-
Method for producing on-derivative. 2. R ₁ is a compound represented by the general formula (III) (Wherein R ₅ , R ₆ , and R ₇ represent a C _{1 to} C ₆ lower alkyl group), and the production method according to claim 1. 3. The production method according to claim 1, wherein R ₁ is a tert-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 ₁ is a dimethyl-1,1,2-trimethylpropylsilyl group. 6. The production method according to claim 1, wherein R ₂ , R ₃ and R ₄ are methyl groups. 7. The production method according to claim 1, wherein the substituted pyridine is 4-dimethylaminopyridine. 8. The process according to claim 1, wherein the substituted pyridine is 4-pyrrolidinopyridine. 9. The method according to claim 1, wherein the substituted pyridine is 4-piperidinopyridine. 10. The method according to claim 1, wherein the organic solvent is tetrahydrofuran. 11. The production method according to claim 1, wherein the organic solvent is pyridine.