JPS61165354A - Production of racemic type n-acylphenylalanine - Google Patents

Abstract

PURPOSE:In heating N-acyl-D-phenylalanine, etc., as a raw material in an organic solvent, to obtain the titled compound useful as an essential component of a medicine for promoting nutrition, etc., by a simple operation in a short time, by carrying out the heating in the presence of a catalytic amount of a dehydrating agent. CONSTITUTION:N-Acyl-D-phenylalanine or N-acyl-L-phenylalanine is heated in the presence of a catalytic amount of a dehydrating agent (especially preferably acetic anhydride) in an aromatic hydrocarbon (preferably xylene) at >=130 deg.C, to give the titled compound. In order to obtain the titled compound from a reaction system, for example, after the reaction is over, the reaction solution is cooled while stirring, fine crystal is formed and dispersed in the solvent, so it is filtered. The amount of the dehydrating agent used is preferably 1-10wt% (0.02-0.2mol) based on the raw material N-acyl-D-phenylalanine.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention is important in the production of L-phenylalanine, which is used as an essential component of infusions or nutritional drinks, and as a raw material for the artificial sweetener aspartame. The present invention relates to a racemization method for racemic N-acylphenylalanine as an intermediate.

[Conventional technology]

L-phenylalanine is currently produced by fermentation or synthesis; in the latter, it is produced using a hydrolytic enzyme, acylase, in an aqueous solution of an alkali or ammonium salt of racemic N-acyl-DL-phenylalanine. A common method is to hydrolyze only N-acyl-L-phenylalanine and convert it into L-7 22-alanine.

On the other hand, unhydrolyzed N-acyl-D-phenylalanine is racemized into racemic N-acylphenylalanine and returned to the acylase hydrolysis step.

Conventionally, as a racemization method for N-acyl phenylalanine, the above-mentioned undesired optically active N-acyl-D-phenylalanine is separated by crystallization, and then the undesired optically active N-acyl-D-phenylalanine is separated by crystallization, and then the undesired optically active N-acyl-D-phenylalanine is separated by crystallization. A method of racemization in an organic solvent selected from the group consisting of sulfoxides (Japanese Patent Publication No. 51-18402), a method of adding acetic anhydride to N-acyl-D-amino acid crystals or an aqueous solution thereof, and heating the mixture (Japanese Patent Publication No. 51-18402). Kosho 56-351
No. 76), and a method of adding an aromatic hydrocarbon to N-acyl-D-amino acid crystals and heating them (Japanese Patent Application No. 172397/1987 filed by the present applicant) has been reported.

[Problem that the invention seeks to solve]

Among the conventional techniques, in the method of adding aromatic hydrocarbon to N-acyl-D-amino acid crystals and heating, the moisture in the system is reduced to 1
If the weight is 8% or more, there is a drawback that it takes several hours to complete racemization.

Furthermore, the method of adding acetic anhydride to N-acyl-D-amino acid crystals or an aqueous solution thereof and heating the mixture has the disadvantage that it is necessary to add a large amount of the χN-acyl acetic anhydride.

As a result of intensive research to solve this problem, the inventor of the present invention found that
The invention has been completed.

[Means to solve the problem]

The present invention provides N-acyl-D-phenylalanine or N-acyl-D-phenylalanine or
This is a method for producing racemic N-anruphenylalanine, which is characterized by adding a catalytic amount of a dehydrating agent to A/R-L-7 enylalanine and heating the mixture at 100'C or higher in the presence of an aromatic hydrocarbon.

In particular, the present invention hydrolyzes only N-acyl-L-phenylalanine in an aqueous solution of N-acyl-DL-phenylalanine salt in the presence of acylase, and extracts L-7 enylalanine and N-acyl-phenylalanine from this optically resolved solution. It is particularly effective for separating D-phenylalanine and racemizing crude crystals of N-acyl-D-phenylalanine. That is, the following relationship exists.

The crystals of N-acyl-D-phenylalanine recovered after acylase splitting contain water, organic acids, and a small amount of L.
- Contains phenylalanine, but the azeotrope of aromatic hydrocarbons, water, and organic acids can be removed from the reaction system by dispersing these crystals in an aromatic hydrocarbon solvent and heating them without any particular purification. , at this time, the temperature in the system is 100'
By adding a dehydrating agent at a temperature of C or higher, racemization rapidly progresses. Furthermore, by shortening the racemization time, side reactions such as hydrolysis of N-acyl-D-phenylalanine and racemization of L-phenylalanine are significantly suppressed.

The same applies to N-acyl-L-phenylalanine.

Examples of the acyl form include acetyl form, talolacetyl form, be/diyl form, etc., and acetyl form is industrially preferred.

Aromatic hydrocarbons are used as the bath medium. Specifically, benzene, toluene, ethylbenzene, xylenes, inpropylbenzene, mesitylene, etc. are used, and kiln is particularly preferably used.

Dehydrating agents include acetic anhydride, oxalic acid, sulfonic acid, etc.
Examples include organic compounds and inorganic compounds such as sulfuric acid, diline pentoxide, and anhydrous zinc chloride, but acetic anhydride is particularly preferred.

Furthermore, the amount of the dehydrating agent to be used is a catalytic amount, preferably 1 to 10% by weight (0.02 to 0.02% by weight) relative to N-acyl-D-phenylalanine or N-acyl-d-phenylalanine.
2 times the mole). When adding the dehydrating agent, the temperature in the system is 100℃.
It is desirable to carry out the process at a temperature of 120°C or higher, preferably 120°C or higher, in order to achieve the desired effect.

The reaction temperature needs to be 130°C or higher, and the reaction is carried out at normal pressure.
Pressurization may be used, and the air in the reactor may be replaced with an inert gas such as nitrogen gas.

The reaction time depends on the reaction temperature and the amount of dehydrating agent added, but at 138°C, for example, racemization is completed within 30 minutes.

By the above method, the racemization reaction of N-acyl-D-phenylalanine or N-acyl-L-phenylalanine proceeds easily, and the racemization reaction of N-acyl-D-phenylalanine or N-acyl-L-phenylalanine due to the coexisting moisture Side reactions such as hydrolysis of phenylalanine and racemization of L-phenylalanine or D-phenylalanine are significantly suppressed, and the racemization reaction can be completed within 60 minutes.

The racemization reaction is carried out under stirring, but after the reaction is complete,
When the reaction solution is cooled while stirring, the N-acyl-DL-phenylalanine melted in the reaction system becomes fine crystals and is dispersed in the aromatic hydrocarbon. Here, N-acyl-DL-phenylalanine can be recovered in a crystalline state by filtration, or N-acyl-DL-phenylalanine can be recovered in a crystalline state by adding an alkaline aqueous solution or aqueous ammonia to this dispersion.
Acyl-DL-phenylalanine can also be extracted into the aqueous layer and easily separated from the aromatic hydrocarbon layer and recovered.

Thus, another feature of the present invention is that racemized N-acyl-DL-phenylalanine can be easily recovered from the reaction system.

The racemized N-acyl-DL-phenylalanine obtained by the above method is again supplied to the enzymatic resolution step.

〔Example〕

Hereinafter, this will be explained in more detail with reference to Examples.

Example 1 (11N-acetyl-DL-phenylalanine chemical division N-7 cetyl-DL-phenylalanine 207# (-
1゜0 kmol) to water 1300 &! ? Add 130 g (0.55 mol) of cobalt chloride filtrate and hydroxide) Adjust to p) 17.0 using IJum, then add acylase (Ohno Pharmaceutical KIJ product > 6.5 x 107 units) and reacted at 37°C. When the phenylalanine produced was quantified by high-performance liquid chromatography, the reaction rate reached approximately 100 g in 21 hours. After the reaction, it was concentrated under reduced pressure to obtain L-phenylalanine 73A: g (0.44g). kilomol) was crystallized, and the specific light absorption was [α), = -34.6°
(C=2, water).

On the other hand, the result of analysis of the crystallized mother liquor of phenylalanine/
-acetyl-D-phenylalanine 1 (lj3/#
(0.50 kmol), L-phenylalanine 9# (
0.05 kmol).

(Isolation of 21N-acetyl-D-phenylalanine (1)
) by adding hydrochloric acid to the crystallization mother liquor of L-phenylalani/
The temperature was adjusted to H2 to obtain crystals of N-acetyl-D-phenylalanine. The specific rotation ft, degree H(αF3'
= 52.0° (C=2, xp/-/I/). This crystal contained 98 kg of N-acetyl-D-phenylalanine, 0.2 kg of L-phenylalanine, 1 otr-9 of water, and 0.5 kg of acetic acid.

(3) Racemization of N-acetyl-D-phenylalanine (experiment number 1).

Add 33 Q Icg of xylene to the crystals obtained in (2), remove water by azeotropic distillation with xylene, and boil the can at 130'C.
At that point, 2# of acetic anhydride (2.0% by weight to N-acetyl-D-phenylalanine) was added and heated at the boiling point of xylene (137-138°C) for 10 minutes (no water in the reaction system). .1% or less). After the reaction was completed, the mixture was cooled with stirring to crystallize N-acetyl-DL-phenylalanine and separate it from xylene. The specific luminous intensity is [α]9
°--〇, 6° (C=2.0, ethanol), and the racemization rate was 99.4%.

Example 2 (Experiment No. 2) In the step (3) of Example 1 (Experiment No. 1), the can part was 1
When the temperature reached 30°C, acetic anhydride 9.6 # (9,8
Weight s vs. u-acetyl-p-phenylalanine) was added and then heated for 1 minute under the boiling point of xylene. The racemization rate was 99.2%.

Example '5 (Experiment No. 3) In the step (3) of Example 1 (Experiment No. 1), the can part 1
When the temperature reached 35° C., 0.5 kg of acetic anhydride (0.5% by weight to N-acetyl-D-phenylalanine) was added, and the mixture was heated for 10 minutes at the boiling point of xylene. The racemization rate was 98.6%.

Example 4 (Experiment No. 4) In the same manner as in step (3) of Example 1 (Experiment No. 1) except that N-7 cetyl-D-phenylalanine crystals (water content 15.2% by weight) were used. Racemization reaction 10
It was carried out for minutes. The racemization rate was 99.0% Example 5 and Comparative Examples 1 to 2 (Experiment numbers 5 to 7) Example 1 except that the can part when adding acetic anhydride was changed as shown in Table 1.
The racemization reaction was carried out for 10 minutes in the same manner as in step (3) (experiment number 1).

Table 1 Example 6 (Experiment No. 8) The same procedure as in step (3) of Example 1 (Experiment No. 1) was carried out except that N-acetyl-L-phenylalanine crystals (water content 10.7%) were used. The racemization reaction was carried out for 10 minutes according to the method. The racemization rate was 99.6.

Examples 7 to 9 (Experiment No. 9 to 11) In the step (3) of Example 1 (Experiment No. 1), the racemization reaction was carried out using the compounds shown in Table 2 instead of acetic anhydride as a dehydrating agent. This was done for 10 minutes.

Table 2 Comparative Example 6 A racemization reaction was carried out for 10 minutes in the same manner as in step (3) of Example 1 (Experiment No. 1) without adding acetic anhydride. The racemization rate was 66.7%. The reaction was further continued for 6 hours. Racemization rate is 99.2%
Met.

Measurement method Moisture, ■Crystals: Measurement of loss on drying at 105°C for 6 hours.

■Solution: Based on Karl Huitscher method.

Determine the water content of the reaction system using ■ and ■ above.

Racemization rate [Effect of the invention] The present invention provides an excellent method for obtaining the desired substance in a short time and in high yield by a simple operation of adding a catalytic amount of a dehydrating agent to the conventional organic solvent heating method. It's a method.

Patent Applicant Denki Kagaku Kogyo Co., Ltd. Procedures Amendment Document February 13, 1985 1, Case Description 1985 Patent Application No. 5882 2, Title of Invention Process for Producing Racemic N-acylphenylalanine 3, Amendment Relationship with the case of a person who does the following Patent applicant address: 1-4-1 Yurakucho, Chiyoda-ku, Tokyo 0100
Column 5 of Detailed Description of the Invention in the Specification, Contents of Amendment

Claims (1)

[Claims] N-acyl-D-phenylalanine or N-acyl-
A method for producing racemic N-acylphenylalanine, which comprises adding a catalytic amount of a dehydrating agent to L-phenylalanine and heating the mixture at 130° C. or higher in the presence of an aromatic hydrocarbon.