KR920000694B1 - Process for producing dipeptides derivatives - Google Patents

Abstract

A method for preparing a dipeptide derivative of formula (I) comprises (a) condensing an aminoacid deriv. of formula (II) with a phenol deriv. of formula (III) to obtain arylester cpd., and (b) reacting the obtd. cpd. with L-proline sodium salt to form (I). In the formulas, X=O or S; Y=H, halo, NO2 or CN. Pref. the condensing-reaction is proceeded in the presence of dicyclohexyl carbodiimide as a condensing agent. Cpd. (I) is useful for the treatment of hypertension.

Description

Method for producing dipeptide derivatives

The present invention relates to a method for preparing a dipeptide derivative, and more particularly, to a method for preparing a dipeptide derivative useful for treating hypertension by using a new activator, aryl ester, as an intermediate.

In general, dipeptide derivatives are known to have a high blood pressure therapeutic effect. As a conventional method for preparing such a dipeptide derivative, the following three examples may be generally used.

First, as a method proposed in European Patent No. 12401 (1980), which is represented by the following reaction scheme.

However, in this method, NaCNBH ₃ used in the reduction reaction is an expensive product, and there is a considerable difficulty in manufacturing because the process of separating the desired isomers by chromatography in the purification process after the reaction is complicated.

Secondly, there is a method of using phosgene gas [Organic Preperations and Procedures int. 20 (2), 109 ~ 115,1988].

However, this method has a fatal disadvantage that it is very difficult to handle because it uses toxic phosgene gas.

Third, there is a method proposed in, for example, Japanese Patent Publication No. 62-48655 as a method of using hydrogen chloride gas and PCl ₅ , which is represented by the following reaction scheme.

However, it is pointed out that even in such a method, the use of expensive hydrogen chloride gas and PCl ₅ and the difficulty in handling thereof are also difficult.

Accordingly, the present invention is to prepare an intermediate having an activated ester group without using toxic gas or expensive raw materials as in the prior art, and reacted with L-proline to yield a high purity dipeptide derivative in an easy manner. Its purpose is to provide a method for manufacturing.

Hereinafter, the present invention will be described in detail.

The present invention provides a condensation reaction between the amino acid derivative represented by the following general formula (II) and the phenol derivative represented by the following general formula (III) in the preparation of a dipeptide derivative represented by the following general formula (I), which is useful as a therapeutic agent for hypertension. To prepare an aryl ester compound represented by the following general formula (IV), which is an intermediate, and then reacting the compound of the general formula (IV) with the L-proline sodium salt represented by the following general formula (V). It features.

In the above formulas, X represents an oxygen atom or a sulfur atom, and Y represents a hydrogen atom, a halogen atom, a nitric acid group (NO ₂ —) or a cyan group (-CN).

Referring to the present invention in more detail as follows.

The present invention is characterized in that the preparation of a dipeptide derivative, the preparation of a novel aryl ester compound represented by the general formula (IV) as an intermediate, and reacting it with the L-proline salt.

In order to prepare the intermediate compound as described above, the amino acid derivative of Formula (II) and the phenol derivative of Formula (III) are dissolved in triethylamine to form a condensation agent, dicyclohexylcarbodiimide (N, N-dicyclohexylcar-bodiimide). ) Condensation reaction in the presence.

When the L-proline sodium salt of the general formula (V) is reacted with the aryl ester compound which is the intermediate compound thus prepared, it is possible to prepare the dipeptide derivative of the general formula (I).

Such a manufacturing process of the present invention is represented by the following reaction scheme.

In the above formulas, X and Y are as described above, respectively.

As described above, in the present invention, when the aryl ester compound is used as an intermediate, the condensation reaction may be performed by so-called salt coupling, even if the carboxyl terminal of the amino component is not separately protected during the condensation reaction. The overall manufacturing process is simplified.

In addition, since the manufacturing process is thus simplified, the yield and purity can also be manufactured in high purity and high yield.

As described above, the present invention is a method for preparing a dipeptide using a novel aryl ester compound, which is an intermediate, and has a high purity and high yield even in a simple method without using toxic gas or expensive raw materials as in the prior art. The desired compound can be prepared.

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

Example 1

[Preparation of N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine-p-nitrophenyl ester]

10.0 g of N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine and 5 g of p-nitrophenyl are suspended in 150 ml of dichloromethane, and then 5 ml of triethylamine is added to give a clear solution. made. The solution was lowered to 0 ° C. and 7.5 g of dicyclohexylcarbodiimide was slowly added.

After stirring for 4 hours without further cooling the resulting white precipitate was filtered, the filtrate was washed three times with 0.1 N caustic soda (50 ml) again washed twice with water (50 ml) and dried This yielded 12.2 g of a pale yellow oil (yield: 85%).

Example 2

[Preparation of N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl-L-proline]

To 50 ml anhydrous ethanol solution in which 3.4 g of L-proline sodium was dissolved, 3.5 mg of triethylamine was added, followed by slowly adding 10 g of the compound prepared in Example 1 dissolved in 50 ml of dichloromethane at 0 ° C. After stirring for 2 hours at 0 ° C., 100 ml of water was added and distilled under reduced pressure to evaporate the organic solvent. The aqueous layer was adjusted to pH 4.2 with 6N hydrochloric acid, extracted twice with ethyl acetate (40 ml), and then saturated sodium chloride solution ( 20 ml) was washed twice and dried to give 8.6 g (yield: 91%) of a clear oil.

The obtained transparent oil was dissolved in 22.4 ml of acetonitrile and heated to 70 ° C., and this was added to a maleic acid (2.27 g, 1 equivalent) solution dissolved in 32 ml of 70 ° C. acetonitrile. Then, the mixed solution was stirred at 70 ° C. for 2 hours, and the resultant white precipitate was cooled and filtered to obtain 6.5 g of white precipitate. From the filtrate, 0.8 g of white precipitate was obtained again and recrystallized from acetonitrile. 8.0 g of maleic acid N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl-L-proline was obtained (m, p .; 145.5-147 ° C)

Example 3

[Preparation of N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine-thiophenylester]

Dissolve 10.0 g of N- [1 (S) -ethoxycarbonyl-3-phenipropyl] -L-alanine and 3.9 g of thiophenol in 100 ml of dimethylformamide, and then cool to -15 ° C. 7.43 g of dicyclohexylcarbodiimide was slowly added thereto, and the resultant precipitate was filtered after reacting at room temperature for 6 hours.

200 ml of ethyl acetate was mixed with the obtained filtrate, and then washed once with water (100 ml) and once with saturated sodium chloride (100 ml), dried over magnesium sulfate, and the solvent was blown off under reduced pressure to obtain 10.7 g of a clear oil. (Yield; 80%)

Example 4

[Preparation of maleic acid N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine-L-proline]

3.45 g of L-proline and 3.18 g of sodium carbonate were dissolved in 30 ml 1N sodium hydroxide, and 100 ml of water and 150 ml of acetone were added thereto. 7.62 g of the compound prepared in Example 3 dissolved in 150 ml acetone was added to the solution, followed by stirring at 0 ° C. for 30 minutes.

Then, the reaction solution was adjusted to pH = 2 with 6N hydrochloric acid, again adjusted to pH = 4.5 with 1N caustic soda, and acetone was blown off under reduced pressure. Then, the aqueous layer was bubbled with sodium chloride, extracted three times with ethyl acetate (150 ml), washed once with saturated sodium chloride solution (80 ml), and dried to obtain 7.1 g of a clear oil. The obtained transparent oil was dissolved in 28 ml of acetonitrile and heated to 70 ° C., and this was added to a maleic acid (2.6 g, 1 equivalent) solution dissolved in 40 ml of 70 ° C. acetonitrile. The mixed solution was stirred at 70 ° C. for 2 hours to cool the white precipitate, which was filtered and filtered to obtain 7.8 g of white precipitate. From the filtrate, 1.0 g of white precipitate was obtained and recrystallized from acetonitrile to give maleic acid N- [1 (S ) -Ethoxycarbonyl-3-phenylpropyl] -L-alanyl-L-proline 8.59 g (83%) was obtained (mp; 144.5-146.7 degreeC).

Comparative Example 1

[Preparation of N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl-L-proline]

A solution of 1.09 g of ethyl-2-oxo-phenylbutylate and 0.19 g of L-alanine-L-proline in 1: 1 ethanol-water solvent and 0.19 g of sodium-cyanoborohydride dissolved in ethanol-water. It is added dropwise over 2 hours at room temperature.

After the reaction, 2% pyridine-water was passed through DOWEX 50 (H ⁺ ) using an electric solvent and chromatographed again to obtain N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L, which is a desired isomer. Alanine-L-proline was obtained.

Comparative Example 2

[Preparation of maleic acid N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl-L-phthaloline]

2.5 g of N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine N-carboxy anhydride was dissolved in 25 ml of tetrahydrofuran, which was added to 15 ml of water and 1.23 g of sodium bicarbonate. -A solution of 1.4 g of proline was added slowly.

After stirring for 2.5 hours at room temperature, the organic solvent was distilled under reduced pressure, the pH was adjusted to 6.5 with 2N-HCl, extracted with dichloromethane two or more times, washed twice with water, dried over anhydrous magnesium sulfate, and colorless oil. 2.62 g (85%) were obtained.

Claims (2)

In preparing a dipeptide derivative represented by the following general formula (I) useful for treating hypertension, the amino acid derivative represented by the following general formula (II) and the phenol derivative represented by the following general formula (III) are condensation reactions. A dipeptide derivative characterized by preparing an aryl ester compound represented by the following general formula (IV), and then reacting the compound of the general formula (IV) with the L-proline sodium salt represented by the following general formula (V). Manufacturing method.

In the above formulas, X represents an oxygen atom or a sulfur atom, and Y represents a hydrogen atom, a halogen atom, a nitric acid group (NO ₂ —) or a cyan group (-CN). The method of claim 1, wherein the condensation reaction is carried out in the presence of dicyclohexylcarbodiimide as a condensation agent.