JPH06107632A - Process for producing N-maleoylphenylalanine alkyl ester - Google Patents

Abstract

(57) [Summary] [Structure] After reacting a phenylalanine derivative with maleic anhydride, an acid catalyst and an alcohol having 1 to 6 carbon atoms are added. Production method. According to the production method of the present invention, it is possible to efficiently obtain N-maleoylphenylalanine alkyl ester which is useful as a precursor for producing aspartame. Further, the present invention can provide an inexpensive precursor for aspartame production using maleic anhydride as a raw material instead of L-aspartic acid which requires selective introduction of a protecting group.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing N-maleoylphenylalanine alkyl ester, and more particularly to a method for producing N-maleoylphenylalanine alkyl ester useful as an aspartame precursor.

[0002]

The structure of aspartame is α-L-aspartyl-L-phenylalanine methyl ester.
Aspartame is known as an artificial sweetener for diet, and the demand for it has been increasing rapidly in recent years.

However, even though demand continues to grow, conventional manufacturing methods are still insufficient in terms of production efficiency and the like.
Since aspartame is a dipeptide, it has been conventionally produced based on the condensation of L-aspartic acid and L-phenylalanine methyl ester. However, in this case, it is necessary to selectively introduce a protective group into L-aspartic acid and remove the protective group after condensation, which causes an increase in manufacturing cost.

Therefore, it has been desired to develop a method for producing aspartame that does not use the condensation of such protected amino acid derivative.

On the other hand, N-maleoylphenylalanine alkyl ester is considered as an important precursor for the production of aspartame without condensation of amino acid derivatives, but no method for synthesizing it in high yield has been known so far. For example, Journal of Macromolecule Science, Chemistry, Vol. A11, pp. 491-506 (1977).
(Year) describes the production by thermal decomposition of malediamide obtained by the reaction of N-carbethoxymaleimide and phenylalanine methyl ester, but the yield is less than 10%.

[0006]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a method for obtaining a high yield of N-maleoylphenylalanine alkyl ester used as a precursor for the production of aspartame without condensation of amino acid derivatives. To do.

[0007]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that N-maleoyl phenylalanine alkyl ester can be efficiently produced by using a phenylalanine derivative and maleic anhydride as raw materials. They have found that they can be manufactured and have completed the present invention.

That is, the present invention is represented by the following general formula 3

[0009]

[Chemical 3] (In the formula, R represents hydrogen or an alkyl group having 1 to 6 carbon atoms.) After reacting a phenylalanine derivative with maleic anhydride, an acid catalyst and an alcohol having 1 to 6 carbon atoms are added. The following general formula 4 is characterized in that

[0010]

[Chemical 4] (In formula, R shows a C1-C6 alkyl group.) It concerns with the manufacturing method of N- maleoyl phenylalanine alkyl ester represented by these.

The N-maleoylphenylalanine alkyl ester obtained here can be converted into an N- (aminosuccinyl) phenylalanine alkyl ester with high yield and high selectivity by addition of ammonia, and further the N- (amino The succinyl) phenylalanine alkyl ester is a known method (European Patent No. 297560).
It can be converted to an aspartame derivative by the method described in Japanese Patent Publication No.

The present invention will be described in detail below.

In the production method of the present invention, the reaction of the phenylalanine derivative represented by the general formula 1 with maleic anhydride and the reaction mixture obtained in the step are carried out in the presence of an acid catalyst to obtain 1 carbon atom.
It is a method for producing N-maleoylphenylalanine alkyl ester by a continuous reaction by treating with an alcohol of 6 to 6.

R in the formula in the phenylalanine derivative represented by the general formula 3 represents hydrogen or an alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group and an ethyl group. Group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group,
Examples thereof include an n-hexyl group, and among these, a methyl group is particularly preferably used in the production of aspartame. In addition, the solid of the phenylalanine portion can have any of L-form, D-form, and DL-form. Therefore, specific examples of the phenylalanine derivative include, for example, L-phenylalanine, D-phenylalanine, DL-phenylalanine, L-phenylalanine methyl ester, D-phenylalanine methyl ester, DL-phenylalanine methyl ester, L-phenylalanine ethyl ester, L- Phenylalanine n
-Butyl ester, L-phenylalanine n-hexyl ester and the like can be mentioned.

The amount of maleic anhydride used relative to the phenylalanine derivative represented by the general formula 3 is 0.90 to 1.
10 equivalents, particularly 0.95 to 1.05 equivalents are preferred. A solvent is preferably used in the production method of the present invention. The solvent is not particularly limited as long as it is inert to the reaction, and specific examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as pentane, hexane and heptane, dichloromethane, chloroform and the like. And the ethers such as ethyl ether and tetrahydrofuran. The amount of these solvents used is preferably 0.1 to 60 parts by weight, and particularly preferably 0.5 to 40 parts by weight with respect to 1 part by weight of the phenylalanine derivative represented by the general formula 3.

The above reaction is suitably carried out under the following conditions.

Reaction temperature: -10 to 160 ° C, preferably 0 to 140 ° C Reaction time: 0.1 to 48 hours Reaction pressure: Normal pressure to increased pressure, preferably 1 to 4 atm Atmosphere: Under nitrogen or argon Then, an acid catalyst and an alcohol having 1 to 6 carbon atoms are added to the reaction mixture obtained in the above reaction. As the acid catalyst,
For example, sulfuric acid, toluenesulfonic acid, xylenesulfonic acid, trifluoromethanesulfonic acid, trifluoromethanebenzenesulfonic acid, phosphoric acid, 12-molybdophosphoric acid, 12-tungstophosphoric acid and the like can be preferably used. The amount of these acid catalysts used is 0.03 to the phenylalanine derivative represented by the general formula 3.
It is suitable to use 0.50 equivalent, preferably 0.05 to 0.40 equivalent. On the other hand, as the alcohol having 1 to 6 carbon atoms, for example, methanol, ethanol, n-propanol, n-butanol, isobutanol, n-hexanol or the like can be preferably used. The amount of the alcohol having 1 to 6 carbon atoms to be used is preferably 0.8 to 50 equivalents, particularly preferably 1 to 40 equivalents with respect to the phenylalanine derivative represented by the general formula 3. The reaction can be preferably carried out while the generated water and the alcohol having 1 to 6 carbon atoms used for charging are discharged from the system by reflux. The reflux liquid at that time can be withdrawn to the outside of the reaction system at an arbitrary ratio, but at that time, the same kind of solvent used for the charging as 0 to 10 times the volume of the withdrawn amount is supplied to the reaction liquid side. Is desirable. The solvent to be supplied may be continuously supplied or may be collectively supplied.

The reaction temperature of this reaction is 10 to 180 ° C, preferably 30 to 160 ° C. Further, it can be carried out while raising the temperature at a constant temperature and within the above temperature range. The reaction time is preferably 0.1 to 20 hours, and the reaction pressure is from reduced pressure to increased pressure, preferably 20 mmHg to 4 kg.
/ Cm ² , and is preferably performed in a nitrogen or argon atmosphere.

After completion of the reaction, the reaction mixture is washed with an aqueous solution of sodium hydrogen carbonate and the solvent is distilled off to isolate the N-maleoylphenylalanine alkyl ester represented by the general formula (4). Further, if necessary, it may be purified by recrystallization or the like.

In the production method, the general formula 3 which is a raw material is used.
The phenylalanine derivative represented by can be used as either the L-form or D-form optically active form or racemic form, but even if the optically active form is used, the target optically active N It can lead to maleoyl phenylalanine alkyl esters.

The N-maleoyl-phenylalanine alkyl ester represented by the general formula 4 thus produced by the method of the present invention is specifically N-maleoyl-L-phenylalanine methyl ester or N-maleoyl- DL-phenylalanine methyl ester, N-maleoyl-D-phenylalanine methyl ester, N-
Maleoyl-L-phenylalanine ethyl ester, N
-Maleoyl-L-phenylalanine n-butyl ester, N-Maleoyl-L-phenylalanine isobutyl ester, N-maleoyl-L-phenylalanine n-
A hexyl ester etc. can be mentioned.

[0022]

EXAMPLES Next, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

EXAMPLE In a nitrogen atmosphere, a glass atmospheric pressure reactor equipped with a stirrer was added with 5.00 g of L-phenylalanine methyl ester hydrochloride.
(23.2 mmol) was added and dissolved in 15 ml of water. To this solution, 0.93 g of sodium hydroxide dissolved in 5 ml of water was added at 0 ° C. with stirring. The mixture was extracted with ether, the ether solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4.10 g (22.9 mm) of L-phenylalanine methyl ester was added to the residue.
ol) was obtained.

2.26 g (23.0 mm) of maleic anhydride was placed in a glass atmospheric pressure reactor having a stirrer under a nitrogen atmosphere.
ol) was added and dissolved in 50 ml of toluene. To this solution was added a solution of 4.10 g (22.9 mmol) of L-phenylalanine methyl ester and 20 ml of toluene. After stirring at room temperature for 30 minutes, 12 ml of methanol and 0.29 ml of sulfuric acid were added. Heat and reflux under conditions that do not return to the reaction solution.
Reflux was continued for 0 minutes. During this period, 30 ml of reflux liquid was withdrawn.

Furthermore, the reaction was carried out for 2 hours under reflux conditions. During this period, 100 ml of toluene was supplied and 130 ml of the reflux liquid was extracted. After cooling, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The obtained toluene solution was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Vacuum-dried crystals of N-maleoyl-L-phenylalanine methyl ester 5.63
g (21.7 mmol, production yield 95%) was obtained, which was further purified by recrystallization from benzene: hexane = 1: 1. The melting point of the obtained N-maleoyl-L-phenylalanine methyl ester was 93 ° C., and the specific rotation was [α] _D ²⁴ = -128.7 ° (c 1.04, benzene).

[0026]

According to the production method of the present invention, aspartate
It is possible to efficiently obtain N-maleoylphenylalanine alkyl ester, which is useful as a precursor for the production of aluminum. Further, the present invention can provide an inexpensive precursor for aspartame production using maleic anhydride as a raw material instead of L-aspartic acid which requires selective introduction of a protecting group.

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Claims (1)

[Claims] 1. The following general formula 1 (In the formula, R represents hydrogen or an alkyl group having 1 to 6 carbon atoms.) After reacting a phenylalanine derivative with maleic anhydride, an acid catalyst and an alcohol having 1 to 6 carbon atoms are added. Characterized by the addition of the following general formula 2 (In formula, R shows a C1-C6 alkyl group.) The manufacturing method of N- maleoyl phenylalanine alkyl ester represented by these.