JPS61221199A - Production of n-formyl-alpha-l-aspartyl-l-phenylalanine methyl ester - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as an intermediate for producing sweetener because of high alpha-isomer ratio, by reacting formylaspartic anhydride with phenylalanine methyl ester using a specific method. CONSTITUTION:N-formyl-L-aspartic anhydride (A) is suspended or dissolved in an orgnaic solvent (preferably methylene chloride, etc.). L-phenylalanine methyl ester (B) is added to the organic solvent containing the component A in the presence of an organic sulfonic acid (e.g. p-toluenesulfonic acid) and the components A and B are made to react with each other preferably at -15-+30 deg.C to obtain the objective compound. The amount of the organic sulfonic acid is preferably 0.1-5wt% based on the component A, and that of the organic solvent is usually 2-100pts.wt. per 1pt.wt. of the component A to facilitate the reaction operation.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides N-formyl-α-L-aspartyl-L-
This invention relates to an improved method for producing phenylalanine methyl ester. N-formyl-α-ri-asbarthyl-L-
Phenylalanine methyl ester is an important compound as an intermediate for α-L-ascha/L/-r-/I/-L-phenylalanine methyl ester, which is used as a sweetener.

For example, according to JP-A-58-185545, N-formyl-α-L-aspartyl-L-phenylalanine methyl ester is deformylated by contacting it with highly concentrated hydrochloric acid in methanol. It is known that aspartyl-L niphenylalanine methyl ester can be produced.

(Prior art and its problems) By the way, in producing N-formyl-α-L-aspartyl-L-phenylalanine methyl ester from N-formyl-L-aspartic acid anhydride and L-phenylalanine methyl ester, In addition to the generally targeted N-formyl-α-L-aspartyl-L-phenylalanine methyl ester, N-formyl- where L-phenylalanine methyl ester is condensed with the carboxyl group at the β-position relative to the amino group of aspartic acid. β-Aspartyl-L-phenylalanine methyl ester is produced as a by-product. β-L-Aspartyl-L-phenylalanine methyl ester obtained from this β-isomer has no sweetening effect and rather exhibits a bitter taste. - In the reaction of aspartic acid anhydride and L-phenylalanine methyl ester, the by-product of β-isomer is suppressed as much as possible to improve the α-isomer production ratio, and the final α-L-aspartyl-L - There is a need to reduce the cost of producing phenylalanine methyl ester.

Conventionally, N-formyl-L-aspartic anhydride and L-
By reacting with phenylalanine methyl ester, N-
A method for producing formyl-α-L-aspartyl-L-phenylalanine methyl ester is disclosed in JP-A-46
-1370, JP-A-51-113841, JP-A-54-
Methods such as 17727 are known.

In the method of JP-A-46-1370, N-formyl-L-aspartic anhydride is added to an organic solvent containing L-phenylalanine methyl ester and reacted to form N-formyl-α-L-asnocrutyl- This is a method for obtaining L-phenylalanine methyl ester. However, this method has low selectivity to the α-isomer and generally produces 30 or more β-isomers in the reaction product, which is economically disadvantageous.

Furthermore, in the method of JP-A-51-115841, N-formyl-L-aspartic acid anhydride and L-phenylalanine lower alkyl ester are heated at 25°C for the purpose of improving the α-integral production ratio. By reacting in the presence of an organic acid with an acid dissociation constant of 10 or less, N-formyl-α-
L-asunocrutyl-L-phenylalanine lower alkyl ester is obtained.

In this method, the effect of selectivity towards the α-isomer is observed. However, this method usually involves the presence of an excess of organic acids (such as acetic acid) in the reaction system, which increases the solubility of the product and improves efficiency (N-formyl-α-L-aspartyl-L
- In order to obtain a phenylalanine lower alkyl ester, operations such as concentration are required, which has the drawback that the operations become complicated.

Furthermore, in the method of Japanese Patent Publication No. 54-17727, N-formyl-L-aspartic acid m-hydrate and L-phenylalanine methyl ester hydrochloride are mixed in an aqueous solvent to a pH of 7 to 9.
N-formyl-α-L-
Aspartyl-L-phenylalanine methyl ester is produced. This method improves the α-integral production ratio to about 85% compared to the previous production method in which the reaction is carried out in an organic solvent. However, although this method performs the reaction while adjusting the pH, it is conducted in an aqueous solvent and an alkali is used. It has the disadvantage that side reactions such as these tend to occur. Moreover, the reaction is conducted in a dilute solution and has poor volumetric efficiency.
In order to isolate L-phenylalanine methyl ester, operations such as concentration or extraction are required, which also has the drawback of complicating the operations.

Recently, a method has been disclosed in which the reaction is carried out in the presence of an ion exchange resin in an organic solvent (JP-A-59-212452). ester in an organic solvent in the presence of a cation exchange resin having a free sulfonic acid group, phosphoric acid group, or carboxylic acid group to produce N-formyl-α-L-aspartyl-L-phenylalanine methyl ester. Specifically, for example, N-formyl-L-aspartic anhydride and an ion exchange resin are suspended in ethyl acetate, and L-
A solution of phenylalanine methyl ester in ethyl acetate is added dropwise to react. After the reaction, the ion exchange resin is separated, and the N-formyl-L-aspartyl-L-phenylalanine methyl ester is precipitated by cooling the liquid and isolated by filtration. This method is
Compared to the conventional method, the α-isomer:β-isomer ratio is 85.
:15, and the selectivity to the α-isomer is relatively good. However, the ion exchange resin used in reaction 1 must be sufficiently dried beforehand, and the purpose of using the ion exchange resin is to It is necessary to separate it from objects and operation is complicated;
Furthermore, since an organic solvent that dissolves the target product is used in the reaction, if an organic solvent with high solubility is used,
It has drawbacks such as the need for complicated operations such as concentration.

As described above, each of the conventionally known methods for producing N-formyl-α-L-aspartyl-L-phenylalanine methyl ester has drawbacks, and the industrial production methods are not necessarily satisfactory.

(Means for Solving the Problems) The present inventors have discovered that in the reaction of N-formyl-L-aspartic acid anhydride and L-phenylalanine methyl ester, there is no drawback of the conventional method as described above, and α - High selectivity to isomers and high yield of N-formyl-α-
A method for producing L-aspartyl-L-phenylalanine methyl ester was intensively studied.

As a result, in the presence of an organic sulfonic acid in an organic solvent containing N-formyl-L-aspartic anhydride, L
- It was discovered that the α-isomer production ratio was significantly improved by adding and reacting phenylalanine methyl ester, and the present invention was completed.

That is, the present invention is characterized in that L-phenylalanine methyl ester is added and reacted in an organic solvent containing N-formyl-L-aspartic acid anhydride in the presence of an organic sulfonic acid. This is a method for producing -L-aspartyl-L-7 22-alanine methyl ester.

The L-aspartic anhydride used in the method of the present invention is L-
- It can be easily produced by reacting aspartic acid with formic acid in acetic anhydride.

Also, L-phenylalanine methyl ester.

It can be produced by esterifying L-phenylalanine in methanol in the presence of aqueous chloride by conventional methods.

The method of the present invention comprises: in an organic solvent containing N-formyl-L-aspartic anhydride in the presence of an organic sulfonic acid;
L-phenylalanine methyl ester is added and reacted. The organic solvent used is an organic solvent that is inert towards N-formyl-L-aspartic anhydride, and (a) -logenated hydrocarbon solvents, or esters such as fatty acid esters or phosphoric acid esters. A system solvent is preferred.

Specific examples include methylene chloride, ethylene chloride, trichloroethylene, and tetrachloroethylene as non-logenated hydrocarbon solvents, and ethyl acetate, butyl acetate, ethyl formate, propyl formate, and methyl propionate as fatty acid ester solvents. , or ethyl propionate, triethyl phosphate, phosphate ester solvents, etc.
Tri%-butyl phosphate and the like can be mentioned.

N-formyl-L-aspartic acid anhydride is contained in these organic solvents in a suspended or dissolved state.

The amount of these organic solvents to be used is not limited to specific circumstances, but due to the reaction operation, the amount of the raw material N-formyl-L
- Use in an amount of 2 to 100 times the weight of aspartic acid anhydride.

In the method of the present invention, N-formyl-L-aspartic acid anhydride and L-phenylalanine methyl ester are reacted in the presence of an organic sulfonic acid. Specific examples of the organic sulfonic acids used include aliphatic sulfonic acids and aromatic sulfonic acids.

The amount of these organic sulfonic acids to be used is not particularly limited, and is usually in the range of 0.05 to 10 wt%, preferably 0.1 to 5 wt%, based on L-aspartic anhydride. When the amount used is less than 0.05, selectivity to the α-isomer tends to decrease. Further, even if the amount exceeds 10 wt%, the selectivity of the α-isomer^ does not improve significantly.

To carry out the method of the present invention, first, N-formyl-L
- Aspartic anhydride is suspended or dissolved in an organic solvent, and then an organic sulfonic acid is added. After that, the reaction can be carried out by adding a solution of L-phenylalanine methyl ester in an organic solvent.

The reaction temperature is usually -50 to 50°C, preferably -11°C.
The temperature is 5-30°C.

The reaction time is usually α5 to 20 hours.

After the reaction, N-formyl-α-L-aspartyl-L-phenylalanine methyl ester generally precipitates in the reaction system, so it is easier to filter and wash the precipitate. -Formyl-α-L-
Aspartyl-L-phenylalanine methyl ester can be isolated.

(Actions and Effects) According to the method of the present invention, ■ compared to conventionally known methods, α
- Increasing the isomer production ratio; (1) In the reaction, L
- Since phenylalanine methyl ester is added, the raw material N-formyl-L-aspartic acid anhydride does not absorb moisture, and the reaction temperature is easy to control;
■Since N-formyl-α-L-aspartyl-L-phenyl alanine methyl ester is precipitated, it has selectivity to the α-isomer even under mild conditions compared to counter-injection. Industrially advantageous.

As described above, this method has various advantages and is a manufacturing method of high industrial value.

(Example) Hereinafter, the present invention will be explained in detail with reference to Examples.

Example 1 After adding and suspending 14.39 (11 morph) N-formyl-L-aspartic acid anhydride to 225 g of ethyl acetate,
Trifluoromethanesulfonic acid 0 under stirring at 20-25℃
．． Add 079. At the same temperature, 57.9.9% of an ethyl acetate solution containing 17.99% of L-phenylalanine methyl ester (1 mole of CL) was added dropwise over 1 hour.Furthermore, after stirring and reacting at the same temperature for 1 hour, the precipitated Filter and wash the crystals.

By drying, crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained.

Yield: 29.99C Yield: 92.9%/Phenylalanine Methyl Ester F Ta.

Example 2 The same procedure as in Example 1 was carried out except that the reaction temperature was changed. The results are shown in Table 1.

Table 1 Example 3 Example 11C was carried out in the same manner as in Example 1 except that the amount of trifluoromethanesulfonic acid used was changed. The results are shown in Table 2.

Table 2 Comparative Example 1 L-phenylalanine methyl ester 17.9.9 (0
, 1 mol) in 172.0 g of ethyl acetate solution containing 20 ~
While stirring at 25° C., 14.5 g (0.1 mol) of N-formyl-L-aspartic acid anhydride was added over 1 hour.

After reacting at the same temperature for 2 hours, the mixture was filtered, washed and dried at the same temperature to obtain crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester.

Yield 28.1! ! (Yield: 87.3% per phenylalanine methyl ester) The α-isomer:β-isomer ratio of the crystals obtained here was 6.
It was 7.7:52.5.

Comparative Example 2 After adding 14.5 g (0.1 mol) of N-formyl-L-aspartic acid anhydride to vinegar PZ #1431 and suspending it, L-phenylalanine methyl ester 17 was added under stirring at 20-25°C. A solution of 57.2.9 in ethyl acetate containing 0.99 (0.1 mol) was added dropwise over a period of 1 hour. After further reaction at the same temperature for 2 hours, N-formyl-α-L-aspartyl-
Crystals of L-phenylalanine methyl ester were obtained.

Yield: 28.5 g (Yield: 87.9%/1 phenyl methylesterne) The α-isomer:β-isomer ratio of the crystals obtained here was 7.
It was 7.0:23.0.

Example 4 After adding 14.5 g (0.1 mol) of ethyl acetate 225IIKN-formyl-L-aspartic anhydride and suspending, 0.0 g of methanesulfonic acid was added under stirring at -10 to -15°C.
7 Add fi. At the same temperature, 57.99 g of an ethyl acetate solution containing 17.9 g (0.1% L) of L-phenylalanine methyl ester was added dropwise over 1 hour. After further stirring and reacting at the same temperature for 1 hour, the temperature was raised to 25-30°C, and the precipitated crystals were filtered, washed, and dried by stirring at the same temperature for 1 hour. Aspartyl-
Crystals of L-phenylalanine methyl ester were obtained.

Yield: 28.0 g (yield: 87.0 g/1 phenylalanine methyl ester) The α-isomer:β-isomer ratio of the obtained crystals is a 3
．． 6:1 (It was 5.4.

Example 5 Example 4 was carried out in the same manner as in Example 4 except that the reaction temperature and the type of organic sulfonic acid were changed.

The results are shown in Table 3.

Example 5 The same procedure as in Example 4 was carried out except that the type of organic solvent was changed. The results are shown in Table 4.

Claims (1)

[Claims] 1) N-formyl-α from N-formyl-L-aspartic acid anhydride and L-phenylalanine methyl ester
- A method for producing L-aspartyl-L-phenylalanine methyl ester, in which L-phenylalanine methyl ester is added and reacted in the presence of an organic sulfonic acid in an organic solvent containing N-formyl-L-aspartic acid anhydride. N-formyl-α-
A method for producing L-aspartyl-L-phenylalanine methyl ester.