JPH0318630B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the following general formula () (In the formula, R ₁ represents an alkyl group.) The present invention relates to a novel method for producing an epoxysuccinic acid monoester represented by the following formula. The epoxysuccinic acid monoester represented by the formula () obtained by the method of the present invention is, for example, 3-[3-methyl-1-
{4-(2,3,4-trimethoxyphenylmethyl)piperazin-1-ylcarbonyl}butylcarbamoyl] It is a compound useful as an intermediate in the synthesis of oxirane-2-carboxylic acid ester. Conventionally, as a method for producing epoxysuccinic acid monoester, a method of semi-saponifying epoxysuccinic acid dialkyl ester is known (Japanese Patent Application Laid-open No. 31024/1983). However, according to this method, semi-saponified epoxysuccinic acid monoester is precipitated in the form of an alkali metal salt, but it is extremely difficult to precipitate this chemically active form, making the isolation procedure cumbersome. However, the alkali metal salt obtained in this way had to be further converted into a free acid form. Therefore, the present inventor conducted extensive research in an attempt to overcome these drawbacks, and as a result, discovered a method by which the desired epoxysuccinic acid monoester can be obtained in high yield from the reaction solution through extremely simple post-treatment operations. The method of the present invention is shown by the following reaction formula. (In the formula, R ₂ represents an ester residue that can be removed by catalytic reduction, and R ₁ has the above meaning.) That is, the present invention epoxidizes tartaric acid mixed ester () to produce epoxysuccinic acid mixed ester (). This is a method for producing epoxysuccinic acid monoester (2) by catalytic reduction. Tartaric acid mixed ester, which is a raw material for the method of the present invention, is, for example, tartaric acid monoalkyl ester [()
In the compound where R ₂ is a hydrogen atom], R ₂ OH
(R ₂ has the above meaning) or a reactive derivative thereof. The object compound of the present invention has four types of optically active forms depending on the two asymmetric carbon atoms, and the present invention includes any of these optically active forms and mixtures thereof. According to the present invention, these optically active substances are produced by using the corresponding optically active substances as epoxysuccinic acid mixed esters (). In the present invention, R ₁ is methyl, ethyl,
Examples of R ₂ include alkyl groups such as propyl, butyl, and tert-butyl, which can be removed by catalytic reduction such as benzyl, phenacyl, diphenylmethyl, and benzyloxymethyl groups. In the method of the present invention, the epoxidation of the tartaric acid mixed ester () is carried out by a method known per se. For example, first tartaric acid mixed ester ()
is reacted with triphenylphosphine and carbon tetrahalide (chlorine and bromine as halogens) to form a compound represented by the formula ( ). (In the formula, one of X ₁ and X ₂ is a hydroxyl group, the other is a chlorine atom or a bromine atom, and R ₁ and R ₂ have the above meanings.) This reaction is performed using hydrocarbons such as hexane and benzene, In an inert solvent such as halohydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, ethers such as ethyl ether, tetrahydrofuran, and dioxane, and esters such as ethyl acetate and butyl acetate, under cooling or heating under reflux, 1 to several Preferably it is carried out for 10 hours. Next, by treating the thus obtained compound of formula ( ) with a tertiary amine, epoxysuccinic acid mixed ester ( ) can be obtained in high yield. Catalytic reduction of epoxysuccinic acid mixed ester () is carried out in the presence of a metal catalyst such as commonly used palladium black, palladium on carbon, platinum oxide, etc. In other words, 1/ for compound ()
Using a metal catalyst in an amount of 500 to 1/10, the reaction is carried out in an inert solvent for several minutes to several tens of hours under cooling or heating under reflux. The hydrogen pressure is preferably normal pressure to several tens of atmospheres. A wider range of inert solvents can be used here than those used in conventional semi-saponification methods, such as hydrocarbons such as hexane and benzene, dichloromethane, 1,2-dichloroethane, etc. halohydrocarbons, methanol,
Alcohols such as ethanol, isopropyl alcohol, tertiary butyl alcohol, and methyl cellosolve, ethers such as ethyl ether, tetrahydrofuran, and dioxane, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate and butyl acetate, acetic acid, and propion. Acids such as acids, water, etc. are used singly or in combination. After removing the catalyst from the reaction solution thus obtained, the desired epoxysuccinic acid monoester () can be obtained in an almost quantitative yield by simply distilling off the solvent under reduced pressure. Therefore, isolation of the target product is extremely easy. Next, reference examples, working examples, and comparative examples will be given and explained. Reference example (2R, 3R)-monoethyl potassium tartrate 16
g (74 mmol), benzyl bromide 12.6 g (74 mmol) and 18-crown-678.0 mg (3 mmol) were added to 100 ml acetonitrile, and the mixture was heated under reflux for 4 hours. After the reaction, acetonitrile was distilled off under reduced pressure, 170 ml of ethyl acetate was added to the residue, and saturated brine was added.
Washed twice with 170 ml. Dry the organic layer (Na ₂ SO ₄ )
The solvent was then distilled off under reduced pressure to obtain 19.0 g (yield 96%) of (2R,3R)-monoethyl tartrate monobenzyl ester as a pale yellow oil. Example 1 (2R,3R)-monoethyl tartrate monobenzyl ester 5.36 g (20 mmol) triphenylphosphine 10.5 g (40 mmol), carbon tetrabromide 10.0 g
(30 mmol) in 40 ml of chloroform, 50
Stirred at ℃ for 4 hours. After evaporating the solvent under pressure, it was purified by column chromatography (silica gel, benzene:ethyl acetate = 25:1), and (2S,3R)-2-bromo-3-hydroxysuccinic acid monoethyl monobenzyl ester and (2R ,3S)-3-brome-
5.15 g (yield 78%) of a mixture of 2-hydroxysuccinic acid monoethyl monobenzyl ester was obtained. Further, this product was dissolved in 40 ml of dichloromethane, 2.0 g (20 mmol) of triethylamine was added, and the mixture was stirred at room temperature overnight. After separating the precipitated triethylamine hydrobromide, the liquid was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, benzene: ethyl acetate = 25:1) and TLC.
3.28 g (yield: 84%) of a single (2R,3R)-epoxysuccinic acid monoethyl monobenzyl ester was obtained as a colorless oil. IR〓neat (cm ^-1 ) 1750 (ester) 900 (epoxy) NMR (CDCl ₃ ): δ=1.28 (3H, t, J=7Hz, -C H ₃ ) 3.65−3.70 (2H, m,

[Formula]) 4.22 (2H, q, J = 7Hz, -O CH ₂ -) 5.20 (2H, s, -O CH ₂ ph) 7.34 (5H, s, - ph ) (2S, 3S)-Epoxysuccinic acid Monoethyl monobenzyl ester, (2R,3R)-epoxysuccinic acid monoethyl monophenacyl ester, and (2R,3R)-epoxysuccinic acid monoethyl monodiphenyl methyl ester were prepared in almost the same manner according to the above examples. Synthesized with high yield. Example 2 2.5 g (10 mmol) of (2R,3R)-epoxysuccinic acid monoethyl monobenzyl ester and 50 mg of palladium black were added to 10 ml of ethanol, and the mixture was stirred at room temperature under a hydrogen atmosphere for 20 hours. After passing the catalyst through Celite, ethanol was distilled off under reduced pressure and (2R,3R)-
1.56 g (yield 98%) of epoxysuccinic acid monoethyl ester was obtained as a colorless oil. of this
TLC, NMR, and IR were consistent with the compound obtained in the comparative example described below. [α] ²⁴ _D -93.8 (C = 1.0, l = 10, CHCl ₃ ) Example 3 2.5 g (10 mmol) of (2S, 3S)-epoxysuccinic acid monoethyl monobenzyl ester and 50 mg of palladium black were added to 10 ml of etal. , under hydrogen atmosphere,
Stirred at room temperature for 20 hours. After passing the catalyst through Celite, the ethanol was distilled off under reduced pressure to give (2S,3S)-epoxysuccinic acid monoethyl ester 1.53g (yield: 96%).
%) was obtained as a colorless oil. [α] ²⁴ _D +94.5 (C = 1.0, l = 10, CHCl ₃ ) Example 4 (2R, 3R)-epoxysuccinic acid monoethyl monophenacyl ester 1.0 g (3.6 mmol) palladium black 20 mg in ethanol 4 ml and stirred at room temperature for 2 hours under a hydrogen atmosphere. After passing the catalyst through Celite, ethanol was distilled off under reduced pressure, 20 ml of hexane was added to the residue, and after vigorous stirring, hexane was removed and further dried under reduced pressure to obtain 490 mg of (2R,3R)-epoxysuccinic acid monoethyl ester (yield). rate 85%)
was obtained as a colorless oil. NMR, IR of this
was consistent with the compound obtained in the comparative example. [α] ²⁴ _D -92.6 (C = 1.0, l = 10, CHCl ₃ ) Example 5 (2R, 3R)-epoxysuccinic acid monoethyl monodiphenyl methyl ester 890 mg (2.73 mmol) palladium black 20 mg in 5 ml of ethanol In addition,
The mixture was stirred at room temperature under a hydrogen atmosphere for 20 hours. After passing the catalyst through Celite, ethanol was distilled off under reduced pressure, 30 ml of hexane was added to the residue, and after vigorous stirring, the hexane was removed and further dried under reduced pressure to obtain 415 mg (2R, 3R)-epoxysuccinic acid monoethyl ester (yield: 95
%) was obtained as a colorless oil. TLC for this one,
IR and NMR were consistent with the compound obtained in the comparative example. [α] ²⁴ _D −93.5 (C=1.0, l=10, CHCl ₃ ) Comparative example Half saponification of (2R, 3R)-epoxysuccinic acid diethyl ester: (2R, 3R)-epoxysuccinic acid diethyl ester 5.0 g (26.8 mmol) in 25 ml of ethanol, 1.5 g (26.8 mmol) of potassium hydroxide
40 ml of an ethanol solution containing was added under ice cooling and stirred for 2 hours. At this time, cream-like fine crystals precipitated and were difficult to filtrate using normal methods, so pressure filtration was performed at approximately 5 atmospheres. Further, wash under pressure with a small amount of ethanol and ether (2R,
3.8 g of 3R)-epoxysuccinic acid monoethyl ester potassium salt was obtained. This product was dissolved in a small amount of water, made acidic by adding sulfuric acid, extracted twice with 30 ml of ethyl acetate, and the extracts were combined, washed with a small amount of saturated brine, and dried with sodium chloride. After separating the Glauber's salt, the solvent was distilled off under reduced pressure to obtain 2.9 g (yield 67%) of (2R, 3R)-epoxysuccinic acid monoethyl ester as a colorless oil.

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ is an alkyl group and R ₂ is an ester residue that can be removed by catalytic reduction.) (In the formula, R ₁ has the above-mentioned meaning.) A method for producing an epoxysuccinic acid monoester represented by the following. 2 General formula (In the formula, R ₁ is an alkyl group, and R ₂ is an ester residue that can be removed by catalytic reduction.) The tartaric acid mixed ester represented by the formula (wherein R ₁ and R ₂ have the above-mentioned meanings) and then catalytic reduction of the epoxysuccinic acid mixed ester (In the formula, R ₁ has the above-mentioned meaning.) A method for producing an epoxysuccinic acid monoester represented by the following.