JPH0751558B2 - Highly stereoselective synthesis of β-lactam derivatives - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for synthesizing a β-lactam derivative with high stereoselectivity.

[0002]

It is a well-known reaction that a β-lactam derivative can be efficiently synthesized by the reaction of an organic ester lithium enolate and an organic imine compound (reaction formula I). (Note) i-Pr ₂ NLi: lithium diisopropylamide (diisopropylamine and n-butyllithium (n-
BuLi) equivalent reaction) DJ Hart et al. (J. Am. Chem.
Soc ., 106, 4819-25 (1984)), when R ³ and R ⁴ are phenyl groups and the reaction solvent contains n-hexane,
It has been reported that the β-lactam produced is produced in a ratio of cis isomer 95% and trans isomer 5% with respect to the configurations of R ¹ and R ³ .

[0003]

DISCLOSURE OF THE INVENTION The present inventors have conducted various experiments and researches on a method for synthesizing a β-lactam derivative with high stereoselectivity, which is different from the conventional method for synthesizing a β-lactam derivative. As a result, the novel synthetic method of the present invention has been reached.

[0004]

Means for Solving the Problems In the above reaction formula I, the present inventors removed n-hexane from the reaction system and reacted in a polar solvent such as tetrahydrofuran to obtain only the trans isomer at a high yield ( It was found that 100%) can be synthesized.

The present inventors have also found that a cis isomer can be synthesized with a high stereoselectivity of 100% by using a compound in which an imine is coordinated with a trialkylaluminum as shown in the following reaction formula II.

The present invention relates to an organic ester lithium enola
In the synthesis of a β-lactam derivative by the reaction of an organic imine compound with an organic imine compound, a highly stereoselective β characterized by reacting in tetrahydrofuran using an imine having a trialkylaluminum coordinated as the above organic imine compound. -The gist is the synthetic method of lactam derivatives.

[0007]

In the practice of the present invention, the present inventor has tried to produce an organic imine compound even in the synthetic reaction of a β-lactam derivative by reacting a lithium enolate of β-hydroxybutyric acid having the same side chain as thienamycin with an organic imine compound. It was also found that the reaction with highly stereoselective reaction occurs when the one in which alkylaluminum is coordinated is used (Scheme III). At that time, it was also found that when Al (CH ₃ ) ₃ is used as AlR ₃ which is a ligand of an imine compound, natural thienamycin type αRS, 3SR, 4SR can be synthesized with a stereoselectivity as high as 85%.

The structure of natural thienamycin is as shown in the following formula (A).

The present inventors also used (R) -3- as a starting material.
It was also found that β-lactam (natural type) represented by the following formula (B) can be synthesized with a yield of 32% by the same method as above using the methyl ester of hydroxybutyric acid.

The above structure was confirmed by a Hitachi 250R type superconducting nuclear magnetic resonance apparatus.

[0011]

[Examples and effects of the invention]

(Example 1) 12 mmol of diisopropylamine under a nitrogen stream
N-BuLi (15% hexane solution) in 7 ml of n-hexane
12 mmol was added under ice cooling and stirred for 30 minutes. Then under reduced pressure
It was distilled off n- hexane, and cooled in tetrahydrofuran 5ml to _{-78 ℃, (CH 3) 2} CHCH 2 COOC 2 H
₅ or 10 mmol of CH ₃ CH ₂ COOC ₂ H ₅ was added to each 3
After adding within a minute, both of them as imines are C ₆ H ₅
CH = NC ₆ H ₅ 10 mmol of tetrahydrofuran and Table 1
And a tetrahydrofuran solution (5 mmol) of a mixture of 10 mmol of AlR ₃ shown in Table 2 was added. Therefore, remove the low temperature bath, gradually raise the temperature, return to room temperature after 2 hours, and then
It was hydrolyzed with aqueous NH Cl and the product was extracted with benzene.

Then, the benzene solvent is removed to remove the target β
-I got a lactam. This β-lactam yield and ci
The results of the s: trans ratio are shown in Tables 1 and 2.

[0013]

[Table 1]

[0014]

[Table 2]

Example 2 Lithium enolate of β-hydroxybutyric acid (a mixture of ethyl ester of β-hydroxybutyric acid and twice the molar amount of n-BuLi of the ester) was used as the lithium enolate of organic ester. The same procedure as in Example 1 was carried out to obtain the target β-lactam. The yield and cis: trans ratio are shown in Table 3.

[0016]

[Table 3]

(Example 3) Synthesis of β-lactam represented by the formula (C).

It is synthesized according to the following reaction formula IV. Under an argon stream, 24 mmol of n-BuLi (15% hexane solution) was added to a solution of 24 mmol of diisopropylamine in 7 ml of n-hexane under ice cooling, and the mixture was stirred for 30 minutes. N-Hexane was distilled off under reduced pressure, 5 ml of tetrahydrofuran was added, and the mixture was cooled to -78 ° C and β
10 ml of ethyl hydroxybutyrate was added. This was stirred for 30 minutes, was added s husband tetrahydrofuran 5ml of _{(CH 3) 3 Si-≡} -CH = N-Si (CH 3) 3 and AlR each 10mmol mixture destined for _3. After stirring at -78 ° C for about 2 hours, the mixture was further stirred at room temperature for 1 hour, hydrolyzed with 1N HCl aqueous solution and extracted with ethyl acetate. Remove the solvent under reduced pressure,
The residue was subjected to column chromatography (Wako-Gel C200
use. The solvent was n-hexane: ethyl acetate = 7: 3) to obtain the target β-lactam. The results are shown in Table 4.

[0019]

[Table 4]

Example 4 11 mmol of hexamethyldisilazane and 11 mmol of n-BuLi in place of diisopropylamine,
The reaction was carried out in the same manner as in Example 3 except that methyl β-hydroxybutyrate was used instead of ethyl β-hydroxybutyrate to obtain the desired β-lactam. The results are shown in Table 5.

[0021]

[Table 5]

Claims (1)

[Claims] 1. In the synthesis of a β-lactam derivative by the reaction of an organic ester lithium enolate and an organic imine compound, an imine coordinated with a trialkylaluminum is used as the above organic imine compound and reacted in tetrahydrofuran. Highly stereoselective β characterized by
-Synthesis of lactam derivatives.