JPS6365667B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an optically active epoxy succinate.

Optically active epoxy succinate esters are important as intermediates in the synthesis of certain physiologically active substances.

For example, (2S,3S)-epoxysuccinate ester inhibits the action of an enzyme (CANP) that shows abnormally high activity in the diseased muscles of patients with muscular dystrophy. Carboxyoxirane-2-carbonyl)-L-leucyl]
It is important as an intermediate in the synthesis of agmatine.

Conventionally, (2R,3R)-epoxysuccinic acid diester was produced by treating (2S,3S)-2-halo-3-hydroxysuccinic acid diester with a metal alcoholate, but the yield and purity were low. There has been a desire for a manufacturing method that is low in both and increases in both.

As a result of various studies, the present inventors have completed the present invention by discovering that by using a tertiary amine as a processing agent, the yield and purity of the target product can be significantly improved, and the reaction operation can be facilitated.

The present invention is based on the general formula (In the formula, R represents a substituent commonly used to protect a functional group, and X represents a halogen atom.) By treating a succinic acid derivative represented by the formula or its enantiomer with a tertiary amine, each of the general formula This is a method for producing an optically active epoxysuccinic acid ester represented by the formula (wherein R has the same meaning as above) or its enantiomer.

In the present invention, substituents commonly used to protect functional groups include methyl, ethyl, propyl, isopropyl,
These include alkyl groups such as butyl and tert-butyl, aryl groups such as phenyl, and aralkyl groups such as benzyl and phenethyl, and should be removed after achieving the purpose of protecting the functional group. In practice, it may be selected as appropriate depending on the conditions, but generally an alkyl group may be used.

The halogen atom includes a chlorine atom, a bromine atom, an iodine atom, etc., and a bromine atom is particularly preferred.

Tertiary amines include triethylamine, N-methylmorpholine, DBU (1,8-diazobicyclo(5,
4,0)-7-undecene) can be selected and used as appropriate, but triethylamine is preferably used from the viewpoint of cost and reaction operation.

The method of the present invention is carried out as follows.

That is, a succinic acid ester derivative represented by the general formula () and an equimolar to several times the molar amount of a tertiary amine are reacted in an inert solvent or in the absence of a solvent for several tens of minutes to several tens of hours under cooling or heating under reflux. An epoxy succinic acid ester represented by the general formula () is produced. In particular, one of the advantages of the method of the present invention is that the desired product can be produced almost quantitatively by simply leaving the reactant at room temperature overnight. The enantiomer of the epoxy succinate ester represented by the general formula () can be obtained by similarly treating the enantiomer of the succinate ester derivative represented by the general formula ().

The inert solvents used in the process of the present invention are wider than those used in conventional methods using metal alcoholates, and include hydrocarbons such as hexane and benzene, dichloromethane, 1,2-dichloroethane, and chlorobenzene. Halohydrocarbons, alcohols such as methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol, methyl cellosolve, ethers such as ethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, acetone, methyl isobutyl ketone, cyclohexanone Ketones such as, esters such as ethyl acetate, butyl acetate,
N,N-dimethylformamide, N-methyl-2
- Amides such as pyrrolidone, dimethyl sulfoxide, etc. may be used singly or in combination.

In the method of the present invention, the reaction operation is much easier than in conventional methods, and the yield and purity of the target product obtained are much better.

Next, the conventional method will be used as a reference example, and the method of the present invention will be shown as an example. By comparing the two, it will be shown that the present invention is superior, and the present invention will be specifically explained.

Reference example 1 (2S, 3S)-2- dissolved in 25 ml of ethanol in a sodium ethoxide solution prepared from 3.0 g (0.13 atomic equivalents) of metallic sodium and 80 ml of ethanol.
Diethyl bromo-3-hydroxysuccinate 29.6g
(0.11 mol) was added dropwise over 30 minutes at 0°C.
After further stirring for 1 hour at room temperature, 1.2 g of acetic acid was added and concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate.

The organic layer was washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate solution, and brine, and dried over anhydrous sodium sulfate. After distilling off ethyl acetate, distillation under reduced pressure,
15.7 g of a fraction (bp 115-124°C/7 mmHg) containing diethyl (2R, 3R)-epoxysuccinate as the main component was obtained.

This was purified by column chromatography (silica gel, benzene:acetone = 100:3).
TLC yielded 12.6 g (61% yield) of single diethyl epoxysuccinate.

[α] ²⁰ _D -95.4° (C = 1.0, = 10, Et ₂ O) Reference example 2 Ethanol was distilled off under reduced pressure from a sodium ethoxide solution prepared from 11.6 g (0.50 atomic equivalent) of metallic sodium and 190 ml of ethanol. A cake was formed, and 500 ml of ethyl ether was added to suspend it.
This was dissolved in 150ml of ethyl ether (2R,
112.7 g (0.42 mol) of diethyl 3R)-2-bromo-3-hydroxysuccinate was added dropwise at 0° C. over 1 hour. After further stirring for 3 hours, water was added and the organic layer was separated, washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate, and brine, and dried. After distilling off the ethyl ether, it was distilled under reduced pressure to obtain 47.0 g (yield 59.6%) of diethyl (2S,3S)-epoxysuccinate.

bp116-118℃/7mmHg [α] ²⁰ _D +87.2゜ (C = 1.0, = 10, Et ₂ O) A part of this was purified by column chromatography in the same manner as in Reference Example 1, and purified by TLC. The angle of optical rotation was as follows.

[α] ²⁰ _D +91.4° (C=1.0, =10, Et ₂ O).

Example 1 53.8 g (0.20 mol) of diethyl (2S, 3S)-2-bromo-3-hydroxysuccinate and 40.4 g (0.40 mol) of triethylamine were added at once to 500 ml of dichloromethane and left overnight at room temperature. Separate the precipitated triethylamine hydrobromide and dilute the solution with dilute hydrochloric acid.
It was washed successively with saline and dried. Dichloromethane was distilled off, and the optical rotation [α] ²⁰ _D −102.6° (C=1.0, =
10, Et ₂ O) 38.5 g of liquid was obtained. This was purified by column chromatography in the same manner as in Reference Example 1, and 35.3 g (yield 94%) of single diethyl (2R,3R)-epoxysuccinate was obtained by TLC.

[α] ²⁰ _D −107.4. (C=1.0, =10, Et ₂ O).

Example 2 53.8 g of diethyl (2R,3R)-2-bromo-3-hydroxysuccinate and 40.4 g of triethylamine were added at once to 500 ml of acetone and left overnight. Separate the precipitated triethylamine hydrobromide,
The liquid was concentrated, ethyl ether was added, washed with water, and dried. Thereafter, the same treatment as in Example 1 was carried out, followed by TLC.
Single (2S,3S)-diethyl epoxysuccinate
36.0g (yield 96%) was obtained.

[α] ²⁰ _D +108.5° (C=1.0, =10, Et ₂ O).

Claims (1)

[Claims] 1. General formula (In the formula, R represents a substituent commonly used to protect a functional group, and X represents a halogen atom.) By treating a succinic acid derivative represented by the formula or its enantiomer with a tertiary amine, each of the following formulas: (In the formula, R has the same meaning as above.) A method for producing an optically active epoxysuccinic acid ester or its enantiomer.