JPS62145100A - Novel production of alpha-aspartyl-phenylalanine ester - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a sweetening agent in high yield without producing a by-product, by catalytically reducing an N-protected- N-hydroxymethyl-alpha-aspartylphenylalanine ester with hydrogen gas in the presence of an aromatic primary amine. CONSTITUTION:An N-protected-N-hydroxymethyl-phenylalanine ester expressed by formula I (R represents organic group reductively substituted by H, preferably benzyloxycarbonyl; R' represents 1-4C alkyl) (example; N- benzyloxycarbonyl-N-hydroxymethyl-alpha-aspartyl-phenylalani-ne methyl ester, etc.) is catalytically reduced with hydrogen gas using a catalyst such as palladium-carbon, etc. (preferably at 0-40 deg.C, for 0.5-3hr) in the presence of preferably 0.5-1.5 equivalents aromatic primary amine (preferably aniline), usually in a solvent such as methanol to obtain the aimed compound expressed by formula II.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention provides a method for producing α-aspartyl-phenylalanine ester represented by the general formula (1) (wherein R1 represents a C1 to C4 alkyl group). Regarding.

α-Aspartyl-phenylalanine ester is a substance that is useful as a low-calorie sweetener and has attracted attention in recent years.

[Conventional technology]

α-[3-substituted-5-oxazolidinyl-] represented by general formula (n) (wherein R is the same as above)
(4)] - General formula (V) obtained by condensing acetic acid with a phenylalanine alkyl ester represented by the general formula ([) (wherein R and R' are the same as above) is the same as above.)
A method for producing α-aspartyl-phenylalanine ester kHmf represented by the general formula (1) by reducing a 75=n ester in a hydrogen atmosphere is already known (Japanese Patent Publication No. 4.8-812).

[Problem that the invention seeks to solve]

However, when the above method is examined in detail, compound (II)
When condensing with compound (l[), compound (v) is not obtained, but N-a-N- expressed by the general formula (It/) below is formed.
Hydroxymethyl-α-aspartyl-phenylalanine ester is formed, and the general formula (IV) is formed in the reduction step.
It has been found that the yield of the compound of the general formula (H) is low because the hydroxymethyl group of the compound is reduced to a methyl group to produce N-methyl-L-α-7spartyl-L-phenylalanine methyl ester as a by-product.

[Means for solving problems]

Therefore, the present inventors conducted intensive studies to improve the above method and make it a completed industrial manufacturing method.

General formula (IV) H20H (wherein, R represents an organic residue that is reductively substituted with hydrogen)
7 represents a C1-C4 alkyl group. ) expressed as N
-Hodoku-N-hydroxymethyl-α-aspartyl-phenylalanine ester in the presence of an aromatic primary amine,
When catalytically reduced with hydrogen gas, N-
The retained group and the hydroxyl methyl group are simultaneously removed without producing methyl-α-7subalterphenylalanine as a by-product, resulting in a high-quality product represented by the general formula (1) (wherein R' is the same as above). It has been found that α-aspartyl-phenylalanine ester can be obtained in high yield.

The present invention has been completed based on the above findings.

To explain the present invention in more detail, R in the compound (R/) may be any organic residue that can be reductively substituted with hydrogen among those used as a target group for an amine group in peptide synthesis.

benzyloxycarbonyl group, alkoxybenzikyFF dicarbonyl group such as p-methoxybenzyloxycarbonyl group, halogenbenzyloxycarbonyl group such as p-chlorobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, etc. Examples include substituted or unsubstituted benzyloxycarbonyl groups, with benzyloxycarbonyl groups being preferred. The asymmetric carbon beam in compound (M) may be any of D and DL, and a typical example of compound (R/) is N-benzyloxycarbonyl-N-hydroxymethyl-α-aspartyl-phenylalaninemethyl. Ester, N-benzyloxycarbonyl-N-hydroxymethyl-α-7subarthyl phenylalanine ether ester/l/, N-p-
Metquin benzyloxycarbonyl-N-hydroxymethyl-α-aspartyl-phenylalanine methyl ester, N-p-methoxybenzyloxycarbonyl-
N-Hydroxymethyl-aspartyl-phenylalanine ethyl ester, N-p-nitrobenzyl oxy7
Carbonyl-N-hydroxymethyl-α-aspartyl-phenylalanine methyl ester, N-p-nitropenzyloxycarbonyl-N-hydroxymethyl-α
-7 Spartyl-7enylalanine ethyl ester, N
-I) -10-chlorobenzyloxycarbonyl-N-hydroxymethyl-α-aspartyl-phenylalanine methyl ester and N-p-chlorobenzyloxycarbonyl-N-hydroxymethyl-α-asbaltyl-7 phenylalanine ethyl ester.

The reduction reaction of the present invention can be carried out in a solvent in the presence of an aromatic primary amine using a catalytic reduction catalyst under normal pressure or increased pressure.

The solvent used in the present invention may be any solvent as long as it does not adversely affect the reaction, such as methanol, ethanol,
Lower alcohols such as propatool.

Examples include ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, esters of methyl acetate, ethyl acetate, and propyl acetate, and mixed solvents of the above organic solvents and water, with methanol being particularly preferred.

The catalyst is not particularly limited as long as it is capable of catalytic reduction, but palladiums are preferred, particularly palladium-
Carbon and palladium black are preferred.

Specific representative examples of aromatic primary amines used in the present invention include 2. Alkyl-substituted anilines such as aniline, 0-toluidine, and 'p-toluidine, and o-chloroaniline.
m-chloroaniline, p-chloroaniline halogen-substituted aniline, 0-nitroaniline, m-nitroaniline, p-nitroaniline, 0-methoxyaniline,
Alcoquine anilines such as m-methoxyaniline and p-methoxyaniline may be mentioned, but aniline is preferred.

In addition, the amount used is 0.1 to 0.1 to compound (IV).
It may be 6 equivalents, preferably 0.5 to 1.5 equivalents.

The reaction temperature is not particularly limited as it varies depending on the solvent, but it is preferably carried out at -10°C to 80°C, preferably 0 to 40°C, and the reaction is completed in about 0.5 to 5 hours.

To isolate α-aspartyl-phenylalanine ester of general formula (I) from the reaction solution: 1. Add water to the reaction solution, heat it to dissolve the product, remove the catalyst, and then distill off the solvent under reduced pressure. and cool to crystallize, or add 6N hydrochloric acid to pH 1.
After adjusting the pH to 4.5 to 5.5 with aqueous ammonia and crystallizing it, the product can be dissolved and the catalyst sent to each house.

〔Effect of the invention〕

The product according to Example 1 and its production ratio and the existing method as a control (Example 3 of Japanese Patent Publication No. 1981-812, reduction temperature 2)
Table 1 shows the production ratios of the target product and by-products when the temperature was 5°C.

As is clear from this table, the control method produces many by-products, making it difficult to extract the target product in its pure form.
If it is not refined, it will not become a product.

In contrast, the method of the present invention produces no by-products at all.

Therefore, it has an extremely excellent effect in that a high quality product can be obtained at a high yield simply by crystallizing it from the reaction solution without going through a purification step.

〔Example〕

The present invention will be specifically explained below using Examples.

Example 1 L-N-α-aspartyl-L-phenylalanine methyl ester (1) (R'=CH3-)L-N-benzyloxycarbonyl-N-hydroxymethyl-α-aspartyl-L-phenylalanine methyl ester (V
l) mmol) and 0.247 (2.62 mmol) of aniline are dissolved in 50xl of 80% methanol-water.

5 Add palladium-carbon 0.151, internal temperature 0-5
Hydrogen gas was passed through the mixture for 2 hours while maintaining the temperature at ℃.

Next, the crystals were dissolved by heating to an internal temperature of 45 to 50°C to remove the catalyst, and the methanol was distilled off under reduced pressure to concentrate to 151 Lt. After cooling to 5 to 0°C, the compound ( 1) Crystal 0.95f of (R'= CH3-)
was obtained (yield 9B, 3t).

TIJC Rf value of the crystal obtained here (silica gel).

Developing solvent n-butanol/acetic acid/water = 4:1:1
).

The R, NMR, optical rotation, and melting point were the same as those of a separately synthesized standard product.

Example 2 In Example 1, the internal temperature was 20-25℃ instead of 0-5℃.
The reaction was carried out in the same manner as in Example 1 using a temperature of 0.94°C and crystals of compound (1) were obtained at 0.94°C. was obtained (yield: 97.5 cm).

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents an organic residue that is reductively substituted with hydrogen.
' represents an alkyl group of C_1 to C_4. ) is characterized by catalytic reduction of N-protected-N-hydroxymethyl-α-aspartyl-phenylalanine ester with hydrogen gas in the presence of an aromatic primary amine ▲Mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R' is the same as above.) A method for producing α-aspartyl-phenylalanine ester.