JPS62164692A - Novel production of alpha-aspartyl-phenylalanine ester - Google Patents

Abstract

PURPOSE:To otain the titled compound useful as a low-calorie sweetener in high yield, by treating an N-protected-N-hydroxymethyl-alpha-aspatyl-phenylalanine ester with formic acid (salt) in the presence of Pd catalyst. CONSTITUTION:An N-protected-N-hydroxymethyl-alpha-aspartyl-phenylalanine ester (e.g., N-benzyloxycarbonyl-N-hydroxymethyl-alpha-aspartyl-phenylalanine methyl ester, etc.,) shown by formula I (R is organic residue which is reductively replaced with H; R' is 1-4C alkyl) is treated with formic acid (salt) (preferably dissolved in a mixed solvent of water-methanol) in the presence of a palladium catalyst (preferably palladium-carbon) preferably at 10-40 deg.C for 0.5-3hr to give the aimed compound shown by formula II.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to an α-aspartyl-phenylalanine ester represented by the general formula (1) (wherein R' represents an alkyl group of 01 to C4). Regarding manufacturing methods.

α-Aspartyl-7enylalanine ester is a substance that is useful as a low-calorie sweetener and has attracted attention in recent years.

[Conventional technology]

As a method for obtaining α-aspartyl-phenylalanine ester, for example, N-protected-α-aspartyl-7enylalanine ester represented by the general formula (II) (wherein R is the same as above) is prepared in the presence of a palladium catalyst.

A method of reduction with formic acid is known (Japanese Unexamined Patent Application Publication No. 1983-1999).
No. 20260).

[Problem that the invention seeks to solve]

Currently, there are expectations for the development of a method for producing α-aspartyl-phenylalanine ester at low cost.

[Means for solving problems]

Therefore, the present inventors conducted various studies.

General formula (lit) (wherein, R is an organic residue that is reductively replaced with hydrogen, R
' represents a C1-C4 alkyl group. ) expressed as N
-protected-N-hydroquinemethyl-α-aspartyl-phenylalanine ester in the presence of a palladium catalyst,
Unfortunately, when formic acid or formate is used, the protecting group and the hydroxyl methyl group are removed at the same time, resulting in a high quality α represented by the general formula (1) (wherein R'' is the same as above). It has been found that -aspartyl-phenylalanine ester can be obtained in high yield.

The present invention has been completed through the above review.

To explain the present invention in more detail, R in the compound of general formula (U) may be any organic residue that can be reductively substituted with hydrogen among those used as protecting groups for amino groups in peptide synthesis.

For example, alkoxybenzyloxycarbonyl groups such as benzyloxycarbonyl group and p-methoxybenzyloxycarbonyl group, halogenobenzyloxycarbonyl group such as I)-chlorobenzyloxycarbonyl group,
Examples include substituted or unsubstituted benzyloxycarbonyl groups such as p-nitrobenzyloxycarbonyl group,
A benzylox7carbonyl group is preferred.

Compounds of general formula (11) include 1, for example, N-benzyloxycarbonyl-N-human axymethyl-α-aspartyl-phenylalanine methyl ester, N-benzyloxycarbonyl-N-hydroxymethyl-α-aspartyl-phenylalanine ether Ester, N-p
-methoxybenzyloxy7carbonyl-N-hydroxymethyl-α-aspartyl-phenylalanine methyl ester, N-p-methoxybenzyloxycarbonyl-
N-Hydroxymethyl-α-aspartyl-phenylalanine ethyl ester, N-p-nitrobenzyloxycarbonyl-N-hydroxymethyl-α-aspartyl-phenylalanine methyl ester, N-p-nitrobenzyloxycarbonyl-N-hydroquine Methyl-α
-Asharthyl-phenylalanine ethyl ester, N
-p-chlorobenzyloxycarbonyl-N-hydroxymethyl-α-aspartyl-phenylalanine methyl ester, N-p-chlorobenzyloxycarbonyl-
Examples include N-hydroxymethyl-α-asparter-phenylalanine ethyl ester.

Although the compound of general formula ([) has an asymmetric carbon.

In the present invention, any one of L integrated, D integrated, and DL integrated can be used.

As the solvent used in the present invention, any solvent may be used as long as it dissolves the compound of the general formula (l[l) and formic acid or a formate salt, and a mixed solvent of water and an organic solvent or an organic solvent alone may be used. Specific typical examples of solvents include water, alcohols such as methanol and ethanol,
Examples include ethers such as dioxane and tetrahydrofuran, ketones such as acetone and methyl ethyl ketone, esters such as methyl acetate and ethyl acetate, N,N-dimethylformamide, and dimethyl sulfoxide, but preferably a water-methanol mixed solvent.

The formic acid or ga salt used in the present invention has the general formula (
The amount may be 1 to 10 mol based on the compound of l[[).

More preferably, it is 1 to 5 mol. Formic acid and formate salts may be used alone or as a mixture, but preferably they are used as a mixture so that the pH of the reaction solution at the end of one reaction is 5.5 or less.

Specific representative examples of formates include alkali metal salts such as sodium formate and potassium formate, aliphatic amine salts such as ammonium formate, monomethylammonium formate, dimethylammonium formate, and trimethylammonium formate, pyridinium formate, picolinium formate, and pyrrole formate. % pyrrolidinium formate.

Ni-containing heterocyclic salts such as piperidinium formate, anilinium formate, N-methylanilinium formate, N, N- formate
Mention may be made of aromatic amine salts such as dimeteranilinium, with ammonium formate and anilinium formate being particularly preferred for industrial production.

In addition, in one reaction, the above-mentioned formate may be added as it is, or formic acid and a base corresponding to the above-mentioned formate may be separately administered to generate the formate in one reaction system. Corresponding bases include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, ammonia, and aliphatic amines such as monomethylamine, dimethylamine, and triethylamine.

Examples include pyridine, picoline, pyrrole, pyrrolidine, piperidine, aniline, N-methylaniline, and NN-dimethylaniline.

Palladium used as a catalyst may be palladium black or palladium-carbon, but palladium-carbon is used for industrial production.
Carbon is preferred, and its amount is 5 to 15% based on the compound of general formula ([1)].

The reaction temperature is not particularly limited as it varies depending on the solvent, but it is preferably carried out at -10 to 80°C, preferably 10 to 40°C, and the reaction is completed in about 0.5 to 3 hours.

To isolate α-aspartyl-phenylalanine ester from the reaction solution 1. Heat the reaction solution to dissolve the product and separate the catalyst, then cool and crystallize or adjust the pH to 1 to 2 with 6N hydrochloric acid. After dissolving the product and distributing the catalyst, the pH may be adjusted to 4.5 to 5.5 with 28 thiammonium water, crystallized, and then collected.

〔Effect of the invention〕

According to the method of the present invention, highly pure α-aspartyl-phenylalanine ester can be obtained in high yield, so the present invention is expected to be an inexpensive method for producing the compound.

〔Example〕

The present invention will be specifically explained below using Examples.

Example 1 L-N-penzyloxocarbonyl-N-hydroxymethyl-α-aspartyl-L-phenyla 5:7
Mef Jb z Stell (V) (R+CH2-0-
After dissolving 1-s t (3.28 mmol) in 17.6 m/m of methanol/water (10:1), 0.619 (13.12 mmol) of 98% formic acid and 0.619 (13.12 mmol) of aniline. 601 (6.06 mmol) and 5% palladium on carbon o, +sy were added and stirred at room temperature for 1 hour. Next, the reaction solution was adjusted to pH 2 to 2.5 with 6N hydrochloric acid to dissolve the crystals, and then the catalyst t-F was removed. 28% in F solution
Add ammonia water to adjust the pH to 4.5-5.5, and
Compound (1) was obtained by stirring at ~5°C for 1 hour and then filtering.
Crystals 1.112 were obtained (yield 99.4%). Rf value of TLC of the crystal obtained here (silica gel, developing solvent n -
Butanol/acetic acid/water: 4:1:1), engineering R, NMR.

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

Example 2 In Example 1, 0.41 p (6.06 mmol) of ammonium formate was used instead of aniline.

The reaction was carried out in the same manner as in Example 1 to obtain crystal 1 of compound CD.
．． 069 was obtained (yield 94.5≠).

Example 3 In Example 1, 0.61f (6.06 mmol) of triethylamine was used instead of aniline.

The reaction was carried out in the same manner as in Example 1 to obtain 0.731 i' of crystals of compound (1) (yield: 65.3 i').

Example 4 In Example 1, L-N-p- was used instead of L, -N-benzyloxycarbonyl-N-hydroxymethyl-α-aspartyl-L-phenylalanine methyl ester.
Using methoxybenzyloxycarbonyl-N-hydroquinemethyl-α-aspartyl-phenylalanine methyl ester (V) (5.2B mmol), a reaction was carried out in the same manner as in Example 1, and the compound (crystals o, q2? was obtained (yield 82.4%).

Example 5 A reaction was carried out in the same manner as in Example 1 for 4 hours except that aniline was used.
9 was obtained (yield: 86.3 cm).

Reference example L-N-benzyloxycarbonyl-N-human R'==
CH5-) Triethylamine 8.08p (80 mmol) containing mbenzene 55a/α-[5-benzyloxyl) and hyphenylalanine methyl ester hydrochloride (melon) (R'=
After adding and dissolving CH3-) 12-93 t (60 mmol), the mixture was stirred for 6 hours while maintaining the temperature at 45°C. Then, the mixture was extracted twice with 6°d of drained water to which Penzea 6 Gat was added. The aqueous layers were combined, adjusted to pH 2 with 10% hydrochloric acid, and extracted twice with 80ml of ethyl acetate.

The ethyl acetate layers were combined and washed once with 1% hydrochloric acid aaat and then six times with 10% brine at 7 amt. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain compound ([) 8.93 F. was obtained (yield 97.5%).

Patent Applicant Nippon Kayaku Co., Ltd. Procedural Amendment (Method) % Formula % 1. Indication of the case Patent Application No. 4251 of 1985 2. Name of the invention a - New method for producing aspartyl-phenylalanine ester 3. Make amendments Patent applicant: 11-2 Fujimi-chome, Chiyoda-ku, Tokyo (4081) Nippon Kayaku Co., Ltd. Representative Director and President Towa Itano 4, Agent: 11-2 Fujimi-chome, Chiyoda-ku, Tokyo (1986) March 25, 2015 6, Contents of amendment subject to amendment 1, Specification, on page 2 or between line 611 and line 2, “3
, "Detailed Description of the Invention".

that's all

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents an organic residue that is reductively replaced with hydrogen.
' represents an alkyl group of C_1 to C_4. ) is a general formula characterized by the action of formic acid or a formate salt in the presence of a palladium catalyst on N-protected-N-hydroxymethyl-α-aspartyl-phenylalanine ester ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R' is the same as above.) A method for producing α-aspartyl-phenylalanine ester represented by the following.