JPS6236364A - Production of 5-benzylhydantion - Google Patents

Abstract

PURPOSE:To obtain in high yield the titled substance useful as a precursor raw material for a sweetener without using free ammonia and causing problems of acid treatment and coloring, by reacting a prussic acid compound and an ammonium slat with phenylacetaldehyde under a specific temperature condition and further carrying out the reaction under specific rise in temperature. CONSTITUTION:A prussic acid compound and one or more ammonium salts(preferably ammonium bicarbonate is used) selected from ammonium bicarbonate and ammonium carbamate in an aqueous medium are previously fed to a reactor, they are reacted with phenylacetaldehyde at 0-60 deg.C, preferably 10-50 deg.C while adding continuously phenylacetaldehyde and after the addition is over, the reaction is carried out by raising the reaction temeprature to <=120 deg.C, preferably 70-100 deg.C, to give the aimed compound. The amount of the prussic acid is preferably 1.0-1.2mol based on phenylacetaldehyde and the amount of ammonium bicarbonate is preferably 1.0-1.6mol.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a method for producing 5-benzylhydantoin.

5-penzylhydanhydantoin is an essential amino acid and is a precursor of L-phenylalanine, which is attracting attention as a raw material for sweeteners, and is an important compound especially as a substrate in the production of L-7 enylalanine by enzymatic methods. .

[Conventional technology]

Conventionally, it has been known that 5-benzylhydantoin is produced as one of the intermediates when producing DL-phenylalanine from phenylacetaldehyde F. 5-Benzylhydantoin is produced by mixing phenylacetaldehyp bisulfite, potassium cyanide, and ammonium carbonate in a molar ratio of 1:2:4, respectively, in an aqueous solution of 50 titanol.
A method of reacting at 5°C with a yield of about 40% is known.Also, it is possible to react at 5°C to obtain phenylacetaldehyde in a mixture of water and a hydrophilic organic solvent by adding more than the same mole of free ammonium ions, cyanide ions, and carbonate ions. A method has been proposed in which the yield is increased by treating the reaction solution with strong acidity (
(Special Publication No. 56-14110).

[Problem that the invention seeks to solve]

However, the former method for producing 5-benzylhydine has a low yield, and the latter method (1) uses a large excess of free ammonia, resulting in a large amount of ammonia after the reaction, and the cost of recovering it is high. (2) Since the highly reactive phenylacetaldehyde is charged at high temperature, colored substances are produced and the selectivity and yield of 5-pentylhydantoin are reduced. (3) The - of the reaction solution is changed from alkaline to strongly acidic. Problems arise with the material of the device, and (4) a large amount of salt is produced when changing the pH of the reaction solution from alkaline to strongly acidic.

The present inventors conducted extensive research to solve these problems, and as a result, they arrived at the present invention.

[Means for solving problems]

In the present invention, a cyanide compound and one or more ammonium salts selected from ammonium bicarbonate, ammonium carbonate, and ammonium carbamate are charged in advance into a reactor in an aqueous medium, and phenylacetaldehyde IS is produced at 0 to 60°C. React with continuous addition and then 120℃
This is a method for producing 5-penclhydantoin, which is characterized in that the reaction is carried out at elevated temperature.

The present invention will be explained in detail below.

The phenylacetaldehyde used in the present invention can be used as it is or as a sodium bisulfite addition salt.

Examples of the cyanide compound used include hydrogen cyanide, potassium cyanide, sodium cyanide, and ammonium cyanide. The amount used is at least equimolar to phenylacetaldehyde V, preferably 1.0 to 1.2 times the molar amount. Even if the amount of the cyanide compound exceeds 1.2 moles, no improvement in the reaction yield is observed, and rather problems such as coloring of 5-benzylhydantoin occur due to the increased amount.

Examples of the ammonium salt containing a carbonate group to be used include ammonium bicarbonate, ammonium carbonate, ammonium carbamate, and the like. Preferably, ammonium bicarbonate, which is industrially available and inexpensive, is used in an amount of 1.0 to 1.6 moles relative to phenylacetaldehyde.

Water is suitable as the reaction medium in the method of the present invention, and the amount used is such that the concentration of phenylacetaldehyde at the time of charging is 8 to 30% by weight (hereinafter, "H" is expressed by weight unless otherwise specified), preferably 1110 to 20% by weight. It is desirable to adjust the concentration to the desired concentration. A mixed solution of water and a hydrophilic organic solvent can also be used. The hydrophilic organic solvent is preferably a lower alcohol such as methanol, but is not particularly limited.

It is sufficient that the amount of the hydrophilic organic solvent used is less than 7.5 times the mole of phenylacetaldehyde.

Further, the pressure at which the raw materials and reaction medium are charged and reacted can be either normal pressure or increased pressure, and the reaction can be carried out under stirring conditions in either a patch system or a flow system.

There is no particular restriction on the time for continuously adding phenylacetaldehyde, but it is preferably about 15 minutes to 4 hours.

The reaction temperature is 0 to 60°C, preferably 10 to 50°C during the continuous addition of phenylacetaldehyde, and the reaction temperature is raised to 120°C or less, preferably 70°C to 100°C after the addition is complete. React with.

Crystals of 5-benzylhydantoin can be easily obtained from the reaction solution by neutralizing the reaction solution as it is or by concentrating a small amount and then neutralizing it, and filtering the precipitated crystals.

Further, as a matter of course, DL-phenylalanine can be obtained by adding an alkali or the like to the reaction solution and heating it to perform hydrolysis.

〔Example〕

The present invention will be specifically explained with examples, but the present invention is not limited thereto.

Example 1 In a 1j electromagnetic stirring type stainless steel autokunde,
Water 2099 Sodium cyanide 43.1.9 (0.88 mol) Ammonium bicarbonate 88.5.9 (1.12 mol)
and methanol 150I, and while stirring, 96% phenyla-7toaldehyde t-''100.9 (0,
80 mol) was added continuously over 60 minutes at 18°C. After the addition was completed, the temperature was raised to 80° C. in 1 hour, and the reaction was continued for 4 hours while maintaining the same temperature. A part of the reaction solution was transferred to a high performance liquid chromatograph (column, 4φ x 250m).
m, nucleocillool B o, i molar phosphate buffer' (pH 3,2): methanol-80:20
(v/v) flow rate 2.0ml 7 minutes, room temperature, UV (210
nm) Kaideka analysis revealed that the yield of 5-benzylhydantoin was 91.2 compared to phenylacetaldehyde.
%, other N-carbamylphenylalanine amide is 2.1%, and N-carbamylphenylalanine is 2.7%.
It was generating. The reaction solution was heated under reduced pressure (50-60°
G-, / 15'Omrtz H3) After removing methanol, the pH of the reaction solution was adjusted to 8.0 using a 36% aqueous hydrogen chloride solution. The precipitated crystals were filtered, dried, and analyzed to yield 160.4 g of crystals. This crystal was purified by recrystallization, elemental analysis, infrared absorption spectrum,
As a result of analysis by nuclear magnetic resonance spectroscopy, it was confirmed that it was 5-benzylhydantoin. Similarly, when the same crystal was analyzed by liquid chromatography, a single peak was obtained. Furthermore, when the same crystal was developed by thin layer chromatography (developing solvent: water: n-detanol: methanol 1:4:1), a single spot was obtained.

Comparative Reli 1 Same as Example 1, but when preparing Chiruga, add 25% ammonia aqueous solution to phenylacetaldehyde by 6 times the mole (1
When 63g) was added and analyzed under the same reaction conditions as Example 1, the yield of 5-benzylhydantoin was 82.8.
%, N-carbamylphenylalanine amide is 8.1%
, N-carbamylphenylalanine was 6.1%.

Comparative Example 2 Phenylacetaldehyde in Example 1 was heated to 80°C.
The reaction was carried out in the same manner as in Example 1 except for continuous addition at the stage where Carbamylphenylalanine is 2
．． It was 0%. The reaction solution was a dark brown liquid.

Example 2 Sodium cyanide 47.1 g (0.96 mol) Ammonium carbonate 92.49 (0.96 mol) Water 480 g 1
The mixture was charged into a stainless steel reactor No. 1, and bisulfite solder addition salt 179I (0.80 mol) of phenylacetaldehyde was continuously added thereto, and the reaction was carried out in the same manner as in Example 1. After the reaction was completed, the reaction solution was analyzed and found to be 89.8% of 5-benzylhydantoin, 3.2% of N-carbamylphenylalanine amide, and 0.6% of N-carbamylphenylalanine.
The yield was low.

Example 3 Using the same reaction procedure as in Example 1, instead of using ammonia bicarbonate, ammonia carbonate was charged at 1.1 times the mole of phenylacetaldehyde (84,51,0,88 moles), and phenylacetaldehyde was heated at 20°C. dripped.

After the dropwise addition was completed, the reaction temperature was raised to 80°C, and the reaction was continued at the same temperature for 4 hours. Analysis of the reaction solution revealed a yield of 91.6% 5-benzylhydantoin, 3.2% N-carbamylphenylalanine amide, and 2.1% N-carbamylphenylalaenka.

Comparative Example 6 The same reaction operation as in Example 3 was carried out, but 2
An aqueous solution of 5-thiammonia was prepared in a molar amount 4 times that of phenylacetaldehyde (218) and reacted at 80°C for 4 hours. Analysis of the reaction solution revealed that 5-benzylhydantoin was 75.9% and N-carbamylphenylalanine amide was 15.9%. 5%, N-carbamylphenylalanine 3.9
% yield.

Reference Example Without extracting the hydantoinization reaction solution of Example 3, caustic soda 9611 (2.4 mol) was added and hydrolysis was carried out at 145° C. for 11 hours.

After recovering ammonia, a by-product of hydrolysis, from the hydrolysis solution while heating, the reaction solution was analyzed by liquid chromatography, and DL-phenylalanine was found to be 163.2%.
The yield was 98.9% based on phenylacetaldehyde.

Example 4 Ammonium bicarbonate phenylacetal '
? 80°C using 1.6 times the mole (101g) against IS
The reaction was carried out for 14 hours. After the reaction was completed, analysis revealed that 5-benzylhydantoin was 90.7% and N-
Carbamylphenylalanine amide is 5-01, N-
Carbamylphenylalanine was obtained in a yield of 6.5 tons.

〔Effect of the invention〕

As explained above, according to the production method of the present invention, 5-benzylhydantoin can be obtained in high yield without using free ammonia, without problems such as coloring of the reaction solution, and without an acid treatment step. It's loud.

Patent Applicant Denki Kagaku Kogyo Co., Ltd. Procedural Amendment September 25, 1985 Director General of the Patent Office Michibe Uga 1, Indication of Case 1985 Patent Application No. 173292 2 Title of Invention 5 - Manufacture of Pencil Hydantoin Law 3, Relationship with the amendment person case Patent applicant Address: 1-4-1 Yurakucho, Chiyoda-ku, Tokyo Name (3)
29) Contents of amendment in Column 5 of Detailed Description of the Invention in Denki Kagaku Kogyo Co., Ltd. Specification (1) Page 1, line 14 of the specification is corrected to "5-benzylhydantointoino Jtr5-pencylhydantoin."

(2) Same page 2, line 9 r Vol 2677.3 J as f Vol.

773,” he corrected.

(3) On page 2, line 15, "Tokuko Showa No. 56-" is corrected to "Tokuko Showa No. 56-". ' (4) Same page 3, lines 6-5 ``(2) Reactivity...
...Delete up to ``.

(5) Same page 6, line 6 r (3) J to r (2) J
I am corrected.

(6) Same page 6, line 7 “Reactor” “Reactor”
I am corrected.

(7) Same page 6, line 8 r (4) J to r (3) J
(8) Page 6, lines 11 to 13 [The inventors...
...I have arrived. Jt, rThe present inventors have conducted intensive research to solve these problems, and by using excess free ammonia, N-carbamylphenylalanine amide, N-carbamylphenylalania, etc. We have found that by-products increase and the selectivity for 5-benzylhydantoin decreases, and that when highly reactive phenylacetaldehyde is charged at high temperatures, colored substances are produced and the yield and selectivity decrease. The invention provides a method for producing 5-pencylhydantoin that does not use excess free ammonia and has excellent yield and selectivity.''

(9) On page 5, line 9, "7.5 times the mole" is corrected to "2 times the weight."

α1 On page 6, in the 4th line, "filtration" is corrected to "filtration".

aυ On page 6, line 14, change “209 g of hydrocyanic acid” to “20 g of water.
9Ii, prussic acid,” he corrected.

(121, page 11, line 10 [Corrected as process Jtr process J.

(that's all)

Claims (1)

[Claims] (1) In an aqueous medium, a cyanide compound and one or more ammonium salts selected from ammonium bicarbonate and ammonium carbamate are charged in advance into a reactor, and 0 to 6
1. A method for producing 5-benzylhydantoin, which comprises reacting at 0°C while continuously adding phenylacetaldehyde, and then raising the temperature to 120°C or lower.