JPH0237912B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing phenylalanine amino acids or esters thereof. More specifically, the present invention relates to a novel and extremely useful industrial production method for obtaining a phenylalanine amino acid or its ester from a phenylserine amino acid or its ester.

[Conventional technology]

Among the phenylalanine-based amino acids, phenylalanine is an amino acid that is useful as a component of pharmaceutical amino acid infusions and comprehensive amino acid preparations, and has recently attracted attention as an ingredient in the low-calorie sweetener aspartame. There is a particular need for inexpensive industrial production of this raw material, phenylalanine.

Furthermore, among the alanine-alanine amino acids, tyrosine is useful as an intermediate for pharmaceuticals.

There are the following methods for synthesizing the above-mentioned phenylalanine amino acids.

Wheeler-Hoffmann method Hydantoin () obtained from formaldehyde and potassium cyanide is condensed with benzaldehyde to produce benzalhydantoin (). This benzalhydantoin is reduced with red phosphorus and hydroiodic acid, and the resulting benzylhydantoin () is hydrolyzed with an alkali to obtain phenylalanine ().

Erlenmeyer method When azlactone () obtained by the condensation of acetylglycine (), which is obtained by acetylating glycine with glacial acetic acid and acetic anhydride, and benzaldehyde, is reduced using a Raney nickel catalyst in a sodium hydroxide solution, acetylphenylalanine () is obtained. When this is hydrolyzed in an aqueous hydrochloric acid solution, phenylalanine () is obtained.

Tyrosine can be obtained by condensing anisyl bromide () and ethyl acetamidomalonate () in the presence of sodium ethoxide and hydrolyzing the condensate ().

[Problems to be solved by the invention] Among the above conventional techniques, method (2) not only has a long and complicated synthesis route, but also requires highly toxic chemicals such as potassium cyanide as an auxiliary raw material, and is not always sufficient. It is difficult to say that this is a satisfactory industrial manufacturing method. In addition, method (2) also has a long synthetic route, which also poses a problem as an industrial production method. Furthermore, the method uses ethyl acetamidomalonate as a raw material, which is an expensive chemical and is problematic as an industrial production method from an economical point of view.

Therefore, the present invention provides that in water or alcohol medium,
The purpose of the present invention is to provide an industrially extremely useful phenylalanine amino acid using a phenylserine amino acid or its ester as a starting material, which is easily produced by reacting a corresponding benzaldehyde compound with glycine in the presence of an alkali. That is.

[Means and effects for solving problems]

According to the invention, the general formula (): [In formula (), R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are each the same or different and represent a hydrogen atom, a hydroxyl group, or an alkoxy group, and R ⁶ represents a hydrogen atom or an alkyl group. ] A phenylserine amino acid or its ester represented by is subjected to catalytic hydrogen reduction in the presence of at least one selected from perchloric acid, sulfuric acid, phosphoric acid, nitric acid, and a cation exchange resin and a noble metal catalyst. formula(): [In formula (), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as above. ] A method for producing a phenylalanine amino acid represented by the following is provided.

Among the compounds represented by the general formula (), specifically, phenylserine, p-hydroxyphenylserine, p-methoxyphenylserine, 3,4-
Dihydroxyphenylserine and ester derivatives thereof are exemplified as preferred application materials. A particularly preferred starting material is phenylserine, p
-Hydroxyphenylserine.

The phenylserine amino acid as a starting material used in the present invention can be easily obtained by reacting the corresponding benzaldehyde compound with glycine in the presence of an alkali in water or an alcoholic medium.

In the production method of the present invention, the compound represented by the general formula () is mixed with at least one selected from perchloric acid, sulfuric acid, phosphoric acid, nitric acid, and a cation exchange resin using an organic acid, water, or a mixture thereof as a medium. Catalytic hydrogen reduction in the presence of species and noble metal catalysts.

In the above reaction, the selection of perchloric acid, sulfuric acid, phosphoric acid, and nitric acid greatly affects the yield, and among them, perchloric acid and sulfuric acid are preferably used. The usage ratio (mole ratio) of phenylserine amino acid and mineral acid is phenylserine amino acid:mineral acid=1:
It is preferable to select from the range of 0.5 to 5, preferably 1:1 to 3.

Although both strongly acidic and weakly acidic types of cation exchange resins can be used, strongly acidic cation exchange resins for use in aqueous solutions are particularly suitable. Note that the resin is used in a free acid form (H type). The usage ratio (equivalent ratio) of phenylserine amino acids and strongly acidic cation exchange resin is:
Strongly acidic cation exchange resin = 1: range of 0.5 to 5,
Preferably, the ratio is selected from the range of 1:1 to 3.

Practically all catalysts known for cleaving benzyl O-bonds can be used as noble metal catalysts in the process according to the invention (Organic
(See Reactions, Vol. 5, pp. 264 et seq. (1953)). More specifically, suitable hydrogenation catalysts include elements of the 8th subgroup of the periodic table (white metal elements) (Ru, Rh, Pd, Os,
Ir, Pt), and palladium (Pd) is particularly preferred.
Metal catalysts are typically prepared using known support materials such as SiO ₂ , charcoal,
Attached to aluminum oxide silicate, BaSO ₄ etc. The supporting rate of the above noble metal catalyst is 0.5 to 5% by weight.
is appropriate. The catalyst is used in an amount of about 2 to 25% based on the weight of the raw phenylserine amino acid.

Examples of organic acids serving as catalysts include formic acid, acetic acid, propionic acid, butyric acid, and valeric acid, among which formic acid and acetic acid are preferably used.

Next, the reaction can be carried out sufficiently at normal pressure, but the reaction can also be carried out under hydrogen pressure of up to about 8 kg/cm ² G. Higher pressures generally have no benefit.

The reaction is carried out under heat. The temperature during the reaction is
It varies somewhat depending on the reaction pressure and the type of organic acid used as a catalyst, but when the reaction pressure is normal pressure, it is 50~
It is carried out in the range of 120°C, preferably in the range of 80-110°C. Further, the reaction time is required to be about 2 to 8 hours.

After the catalytic hydrogen reduction reaction is thus completed, the catalyst component is removed in accordance with a conventional method, and the reaction solution is concentrated, and the resulting crystals or liquid are dissolved in water.
When the pH of this aqueous solution is adjusted with an alkali (PH5-6), phenylalanine amino acids precipitate as crystals. Separately, this is dried to obtain a product.

If necessary, optional purification such as activated carbon treatment and recrystallization can be performed.

Next, the method of the present invention will be explained in more detail with reference to examples, but the method is not limited thereto. "%"
are based on weight unless otherwise specified.

〔Example〕

Example 1 In a 200 ml flask equipped with a stirrer and a thermometer, 6 g of phenylserine, 75 g of 80% formic acid, 60
8.3 g of % perchloric acid were fed. After purging the inside of the reaction vessel with nitrogen, 1 g of 0.5% palladium/carbon was supplied.
After the inside of the flask was again purged with nitrogen and further with hydrogen, the temperature was raised while supplying hydrogen and the reaction temperature was maintained at 90° C. to carry out the reaction. Hydrogen absorption stopped after 6 hours.

After the reaction was completed, the flask was cooled and the catalyst was separated from the reaction product liquid. The liquid was concentrated, and the concentrated residue was dissolved in 30 g of water, and the pH was adjusted to 5.5 with an alkali to precipitate white crystals of phenylalanine. The yield was 90 mol% based on phenylserine.

Further, when analyzed by thin layer chromatography after reconsolidation from water-ethanol, only one spot was found.

Example 2 30 g of phenylserine and 80% formic acid were placed in an electromagnetic induction rotating stirring type glass autoclave with an internal volume of 1000 ml.
375 g, 41 g of 60% perchloric acid were supplied. After purging the inside of the autoclave with nitrogen, 3 g of 0.5% palladium/carbon was supplied. After replacing the inside of the autoclave with nitrogen and hydrogen again, the temperature was raised to 110°C.
The total pressure was controlled to 5 kg/cm ² G using hydrogen, and the reaction was carried out while maintaining the above temperature and pressure while replenishing hydrogen. Hydrogen absorption stopped after 3 hours.

After the reaction was completed, the autoclave was cooled and the catalyst was separated from the reaction product liquid. The liquid was concentrated, the concentrated residue was dissolved in 150 g of water, and the pH was adjusted to 5.5 with an alkali to precipitate white crystals of phenylalanine. The yield was 93 mol% based on phenylserine.

Further, when analyzed by thin layer chromatography after reconsolidation from water-ethanol, only one spot was found.

Example 3 The same experiment as Example 1 was conducted except that 4.9 g of concentrated sulfuric acid was used instead of 60% perchloric acid. The yield of phenylalanine was 85 mol%.

Example 4 The same experiment as Example 2 was conducted except that glacial acetic acid was used instead of 80% formic acid. The yield of phenylalanine was 88 mol%.

Example 5 The same experiment as Example 2 was carried out, except that 110 g of a strongly acidic cation exchange resin (Amberlite IR-120, sulfonic acid type strong acid manufactured by Tokyo Organic Chemical Co., Ltd.) was used instead of 60% perchloric acid. I did it. The yield of phenylalanine was 83 mol%.

Example 6 1.45 g of p-hydroxyphenylserine was added to a 200 ml flask equipped with a stirrer and a thermometer.
100 g of 80% formic acid and 1.85 g of 60% perchloric acid were supplied.
After purging the inside of the reaction vessel with nitrogen, 0.36 g of 0.5% palladium/carbon was supplied. After the inside of the flask was again purged with nitrogen and further with hydrogen, the temperature was raised while supplying hydrogen and the reaction temperature was maintained at 90° C. to carry out the reaction. 5
After some time, hydrogen absorption stopped.

After the reaction was completed, the catalyst was separated from the reaction product liquid while still hot. The liquid was concentrated, the concentrated residue was dissolved in 300 g of water, and the pH was adjusted to 5.5 with an alkali to precipitate white crystals of tyrosine. The yield was 88 mol% based on p-hydroxyphenylserine.

Further, when analyzed by thin layer chromatography after reconsolidation from water-ethanol, only one spot was found.

Comparative Example 1 The same experiment as Example 2 was conducted without using 60% perchloric acid. PH the concentrated residue aqueous solution with alkali
When the solution adjusted to 5.5 was analyzed by thin layer chromatography, no phenylalanine was detected.

〔Effect of the invention〕

As mentioned above, in the production method of the present invention, phenylserine amino acids or their ester derivatives, which are easily produced industrially, are subjected to catalytic hydrogen reduction in the presence of a noble metal catalyst, thereby achieving high yield, low cost, and Phenylalanine amino acids can be easily produced. Phenylalanine amino acids are important as components of pharmaceutical amino acid infusions, comprehensive amino acid preparations, raw materials for the low-calorie sweetener aspartame, and intermediates for pharmaceuticals, and the significance of the present invention in providing an inexpensive industrial method for producing them is big.

Claims (1)

[Claims] 1 General formula (): [In formula (), R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are each the same or different and represent a hydrogen atom, a hydroxyl group, or an alkoxy group, and R ⁶ represents a hydrogen atom or an alkyl group. ] The phenylserine amino acid or its ester is subjected to catalytic hydrogen reduction in the presence of at least one selected from perchloric acid, sulfuric acid, phosphoric acid, nitric acid, and a cation exchange resin and a noble metal catalyst. formula(): [In formula (), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as above. ] A method for producing a phenylalanine amino acid or an ester thereof.