JPH0623149B2 - Method for producing high-purity N-acetyl-DL-amino acid - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a N-acetyl-DL-amino acid by hydrolyzing a hydantoin compound and subsequently acetylating it with acetic anhydride.

N-acetyl-DL-amino acid is useful as a feed additive itself, and can be L-amino acid or D-amino acid produced by enzymatic hydrolysis with acylase or the like. It is a useful intermediate.

Problems to be Solved by Prior Art and Invention As a method for obtaining a DL-amino acid aqueous solution by alkaline hydrolysis of a hydantoin compound, USP 24806
44, USP 2567920, etc.

USP 2480644 describes that 5-isopropylhydantoin is used in an amount of 3.3 times by mole sodium hydroxide under a N ₂ stream at atmospheric pressure and under reflux at 103 to 107 ° C.
There is a description that DL-valine is obtained by reacting for a time. Also U
According to the specification of SP 2557920, 5-
When (3-indolylmethyl) hydantoin or the like is reacted at a high temperature with 2 to 4 times the molar amount of sodium hydroxide or the like, the target product such as DL-tryptophan can be rapidly obtained in a high yield. The reduction is carried out at 140 to 300 ° C, preferably 150 ° C or higher.

In any case, in the hydrolysis reaction of the hydantoin compound, if the hydrolysis conditions are mild, especially when the reaction temperature is low, many intermediates remain, and when the hydrolysis temperature is high, tar formation is caused by a side reaction. Since DL-amino acid was not obtained in high yield, it was difficult to select the optimum hydrolysis reaction conditions.

The present invention is a method for obtaining an N-acetyl-DL-amino acid of formula (II) from a hydantoin compound of formula (I) according to the following formula: When the hydrolysis conditions are mild, the N-carbamyl-DL-amino acid of the intermediate of formula (III) remains, and when acetylated in an aqueous solution containing this, N-acetyl-DL-amino acid and N-carbamyl-DL -A reaction solution in which amino acids are present is obtained. Since both amino acid derivatives have extremely similar physical properties such as solubility, it is difficult to separate the two, and the latter contaminated N-acetyl-DL-amino acid can be obtained. N-Acetyl-containing N-carbamyl compound
When an acylase is allowed to act on a DL-amino acid for selective hydrolysis, the N-carbamyl compound remains as it is because it does not serve as a substrate for the acylase, and is accumulated particularly when one of the optically active substances is racemized and recycled. Extremely adversely affects quality and yield.

Means for Solving Problems In the above formula, N of the formula (III), which is a by-product in the hydrolysis step, is used.
The -carbamyl-DL-amino acid can be easily converted into the hydantoin compound of the formula (I) by performing a certain aging reaction under a specific acidic condition and at a specific reaction temperature or higher, and in the acetylation step, N-carbamyl-DL-
It was also found that even a small amount of amino acid is not affected at all in the acetylation reaction.

Therefore, N produced as a by-product in the hydrolysis process of hydantoin
-The carbamyl compound is obtained by acid precipitation after completion of the acetylation step.
The compound (II) is returned to the compound of formula (I) before isolation of the desired product, and at the time of isolation of the compound of formula (II), an organic solvent that dissolves only the hydantoin compound of formula (I) is used. It was found that if removed, a high-purity N-acetyl-DL-amino acid containing no N-carbamyl derivative can be obtained even if the hydrolysis reaction is carried out under mild conditions.

The present invention has been completed based on these findings.
That is, according to the present invention, a hydantoin compound is converted into a corresponding N by a hydrolysis reaction and an acetylation reaction.
When obtaining an acetyl-DL-amino acid, the reaction solution obtained by subsequently adding acetic anhydride to the acetylation reaction of the aqueous solution of the DL-amino acid obtained by alkaline hydrolysis of the hydantoin compound is adjusted to PH2 or lower and the temperature is adjusted to 40 to 40 ° C. By holding at 80 ° C., the N-carbamyl compound, which is a by-product at the time of hydrolysis of the contained hydantoin compound, is converted into a hydantoin compound, and then the obtained N-acetyl-DL-amino acid containing the hydantoin compound is cooled, A method for producing a high-purity N-acetyl-DL-amino acid, which comprises purifying using a ketone compound when crystallizing and isolating.

In the present invention, the hydantoin compound represented by the formula (I) (In the formula, R is a hydrogen atom, a lower alkyl group, a phenyl group,
A hydroxyphenyl group, a benzyl group, a hydroxybenzyl group, and a 3-indolylmethyl group. ), As specific examples, hydantoin, 5-methylhydantoin, 5-isopropylhydantoin, 5- (sec) butylhydantoin, 5- (iso) butylhydantoin, 5
-Phenylhydantoin, 5- (4-hydroxyphenyl) hydantoin, 5-benzylhydantoin, 5-
(4-hydroxybenzyl) hydantoin, 5- (3-
Methylindolyl) Hydantoin and the like.

Using these as raw materials, the corresponding N represented by the above formula (II)
Specific examples of -acetyl-DL-amino acid include N-acetyl-glycine, N-acetyl-DL-alanine and N.
-Acetyl-DL-valine, N-acetyl-DL-leucine, N-acetyl-DL-isoleucine, N-acetyl-DL-phenylglycine, N-acetyl-DL-4
-Hydroxyglycine, N-acetyl-DL-phenylalanine, N-acetyl-DL-tyrosine, N-acetyl-DL-tryptophan and the like are obtained in high quality and high yield.

In the alkali hydrolysis step of the hydantoin compound of the present invention, the alkali metal compound used is NaO.
Although H, KOH, Ca (OH) _{2 and the} like can be used, NaOH is most suitable, and the amount thereof is preferably 3 times or more the mole of the hydantoin compound. However, use in an amount of 4 times by mole or more is not preferable because a severe foaming phenomenon due to decomposition of Na ₂ CO ₃ or the like is observed in the acetylation step after hydrolysis, and finally the amount of salt such as NaCl increases.

Further, in the present invention, a slight increase in the amount of intermediate by-products of the N-carbamyl compound is not a problem, and therefore the atmospheric pressure is 100 to 110.
It is preferable to carry out hydrolysis under mild conditions of ℃ to suppress tar-like impurities. As the substrate concentration during hydrolysis, the concentration of the hydantoin compound should be 15-25w in the conventional method.
t.% is good.

The hydrolysis reaction mass thus obtained is usually P
It is an aqueous solution of H10 or more, and contains 85 to 95 mol% of DL-amino acid and 5 to 15 mol% of N-carbamyl compound with respect to the hydantoin compound.

In the present invention, acetic anhydride is directly added to the hydrolysis reaction solution, preferably 1.0% to the hydantoin compound.
The usual acetylation reaction is carried out by adding about 1.5 times the molar amount at about 40 ° C.

After completion of the acetylation reaction, an inorganic acid such as concentrated hydrochloric acid is added to adjust the pH to 2 or less, 40 to 80 ° C, preferably 45 to 80 ° C.
The temperature is maintained at 60 ° C. and the temperature is maintained for 2 hours or more to perform an aging reaction for converting the N-carbamyl compound in the acetylation reaction solution into the corresponding hydantoin compound. When PH is 2 or more and the reaction temperature is 40 ° C. or lower, complete conversion of the N-carbamyl compound to a hydantoin compound is impossible,
The N-carbamyl body remains in the reaction solution. Further, if the reaction temperature is 80 ° C. or higher, decomposition of acetyl groups tends to occur during heat retention, which is not preferable. Although the heat retention time depends on the temperature, it requires a time for converting the entire amount of the N-carbamyl compound, but if the heat retention is longer than necessary, N-acetyl-
Degradation of DL-amino acids also tends to occur, so that it is usually desirable for about 4 to 6 hours.

The acetylation reaction liquid thus heat-insulated is cooled to 10 ° C. or lower for crystallization separation, and ordinary crystallization is carried out to isolate crude N-acetyl-DL-amino acid crystals containing a hydantoin compound. .

During isolation, the contained hydantoin compound must be removed.This can be easily removed, for example, by washing the solid phase with a ketone compound such as acetone, dioxane, or methyl ethyl ketone as a solvent during solid-liquid separation. it can. These ketone compounds are good solvents for the hydantoin compound, but the N-acetyl-DL-amino acid does not dissolve, so that washing loss hardly occurs. Further, although the hydantoin compound can be removed to some extent by only washing with water, complete removal is difficult, and use of only water is not preferable. Usually, it is sufficient to use a ketone compound solvent in an amount of about 1 to 2 times the amount of crystals and to wash it.
Further, by washing with a solvent after washing, the hydantoin compound can be almost completely removed, and a high-purity N-acetyl-DL-amino acid can be obtained.

The solvent used for washing and sludging can be recovered and reused by ordinary means, and the hydantoin compound can of course be recovered and reused.

Hereinafter, the present invention will be described in detail with reference to examples. The analysis conditions of high performance liquid chromatography (HLC) in the examples are as follows.

Analytical conditions for high performance liquid chromatography Column: FinePak SIL C-18 from JASCO Corporation Column diameter x length 4.6 mm x 250 mm Detector: Ultraviolet spectrophotometer (wavelength 200 nm) from JASCO Corporation Mobile phase: Distilled water 900 ml + Phosphoric acid 1.8 g + Potassium phosphate 4.5 g + Methanol 100 ml Flow rate: 1 ml / min Retention time: DL-valine 3.8 min N-carbamyl-DL-valine 7.6 min Isopropylhydantoin 10.3 min N-acetyl-DL-valine 15.0 minutes Example isopropylhydantoin 96.2 g (0.676 mol) with 45% Na
176 g (2.028 mol) of OH aqueous solution and 106 g of water were added, and hydrolysis was carried out at 105 to 110 ° C. for 24 hours under normal pressure and reflux. The obtained reaction liquid was analyzed by HLC to find that DL-valine was 68.1 g (conversion rate 86%) and N-carbamyl-DL-
Valine 14.0 g (conversion rate 10%) and a slight peak of isopropyl hydantoin as a raw material were detected.

Subsequently, 103 g of acetic anhydride was added to this hydrolyzed liquid at 40 ° C. over 2 hours to complete the acetylation reaction.

The reaction solution was adjusted to 45 ° C., 140 g of concentrated hydrochloric acid was added dropwise over 2 hours to adjust to PH1, and the mixture was aged at the same temperature for 2 hours with stirring.

After completion of the aging, the mixture was cooled to 5 ° C., kept warm for 2 hours and crystallized.
87.0 g of a white crystalline substance was obtained.

This product had an HLC purity of 99.0% and no N-carbamyl-DL-valine peak was detected. The recovery rate in terms of purity was 80 mol% with respect to isopropylhydantoin.

Comparative Example Except that the aging reaction of the acetylation reaction solution was not carried out,
The hydrolysis reaction, acetylation reaction and acid precipitation crystallization were carried out in the same manner as in the examples.

That is, after the acetylation reaction completed liquid was cooled to 5 ° C., 140 g of concentrated hydrochloric acid was added dropwise over 2 hours to bring the pH to 1 or less and further kept at 5 ° C. for 2 hours for crystallization.

The crystals after washing were washed with water and dried to obtain 94.0 g of a white crystalline substance.
This product contained HLC purity of 92.3% and N-carbamyl-DL-valine of 6.8%. The recovery rate in terms of purity was 80 mol% with respect to isopropylhydantoin.

Claims (2)

[Claims] 1. When obtaining a corresponding N-acetyl-DL-amino acid from a hydantoin compound by an alkaline hydrolysis reaction and an acetylation reaction, a DL-amino acid aqueous solution obtained by alkaline hydrolysis of the hydantoin compound is continuously added. The N-carbamyl compound, which is a by-product at the time of hydrolysis of the contained hydantoin compound, was maintained by keeping the temperature at 40 to 80 ° C. in a reaction liquid obtained by adding acetic anhydride to carry out an acetylation reaction, at pH 2 or less, After conversion into a hydantoin compound, the obtained N-acetyl-DL-amino acid containing a hydantoin compound is cooled and crystallized to isolate the N-acetyl-DL-amino acid by purification using a ketone compound. Method for producing acetyl-DL-amino acid. 2. The method according to claim 1, wherein the hydrolysis reaction is carried out at 100 to 110 ° C.