JP2871778B2 - Method for producing 5-arylhydantoins - Google Patents

Description

The present invention relates to a novel method for producing 5-arylhydantoins. 5-Arylhydantoins are useful for the synthesis of semi-synthetic penicillins and cephalosporins.
It is an important compound as a raw material for producing 2-arylglycines (for example, D-phenylglycine or Dp-hydroxyphenylglycine).

2. Description of the Related Art It is known that 5-arylhydantoins are classically synthesized by the reaction of a corresponding aryl aldehyde with ammonium carbonate and sodium cyanide by the Bucherer-Berg method. (Journal Feel Practice Chemie (J., Prak)
t., Chem.,), 1934, 140 , 291).

Also, a method of reacting glyoxylic acid, urea and phenol under acidic conditions (see Japanese Patent Publication No. 55-22474),
A method in which allantoin and phenol are simultaneously reacted (see Japanese Patent Publication No. 55-16582), a method in which hydroxymaldenic acid and urea are acidified (see Japanese Patent Publication No. 57-57033), and a method in which glyoxyl urea and phenol are reacted ( JP-A-54-128572), a method of reacting alloxanic acid with phenol (see JP-A-53-138558), and a method of reacting glyoxylic acid triureide with phenol (see JP-A-54-138559). ) And 5-
Many methods are known, such as a method of reacting hydroxyhydantoin with phenol (see JP-A-54-138560).

[Problems to be Solved by the Invention] However, hazardous sodium cyanide must be used in the production by the Bucherer-Burg process, and crude hydantoin cannot be obtained due to the oxidative side reaction of the phenol nucleus in alkaline conditions. There are problems such as the incorporation of a large amount of by-products and coloring of the produced hydantoin.

In addition, the method using raw materials such as glyoxylic acid, allantoin, 5-hydroxyhydantoin, maldenic acid, glyoxyl urea, alloxanic acid, and diglyoxylic acid triureide is expensive and not satisfactory.

[Means for Solving the Problems] The present inventors have made intensive studies to solve these problems, and as a result, completely novel 5-arylhydantoins using parabanic acid as a raw material which can be synthesized from inexpensive oxalic acid. Have found a method for synthesizing the present invention, and have completed the present invention.

That is, the present invention provides a reducing agent such as paravanic acid,
Reduction with a metal such as zinc, iron or magnesium or a Raney-based catalyst such as Raney nickel, the obtained reduction product and a compound of the general formula (I): (Wherein, R ¹ is a hydroxyl group or a lower alkoxy group, at least one of the para and / or ortho positions thereof is unsubstituted, and R ² and R ³ are each independently a hydrogen atom, a hydroxyl group, a lower alkoxy group. , A lower alkyl group, a halogen atom, an acylamino group or a nitro group) in an acidic aqueous medium to produce a 5-arylhydantoin.

[Example] This reaction is represented by the following formula.

In the above reaction, the reduction may be carried out in the same acidic aqueous medium as in the reaction with the aryl compound, or may be carried out in a different solvent from this reaction, for example, a lower alcohol. When the reaction is carried out in an acidic aqueous medium, the reduction of parabanic acid and the reaction with the aryl compound (I) can be carried out simultaneously and in parallel.

Hereinafter, the present invention will be described in detail. It is known that the raw material parabanic acid can be synthesized very easily and in high yield (76%) by, for example, the reaction of inexpensive diethyl oxalate with urea (Organic Synthesis (Org.
Syn. Coll. Vol. 4 , 744, (1963)). Parabanic acid used in the present invention does not necessarily need to be a purified product, and a crude product synthesized by the above method can be used as it is.

At least 1 reducing agent is used per 1 molar equivalent of parabanic acid.
Equivalent, the reducing agent is preferably 2-
10 equivalents are preferably used. The aryl compound (I) is at least 1 equivalent to 1 mol equivalent of parabanic acid.
Desirably, 1 to 2 molar equivalents are suitably used.

As the reducing agent in the production method of the present invention, a metal such as zinc, iron and magnesium or a Raney-based catalyst such as Raney nickel can be suitably used. When catalytic hydrogenation is carried out using a Raney-based catalyst such as Raney nickel, the amount used is preferably 5 to 200% (% by weight, the same applies hereinafter), especially 10 to 100% with respect to parabanic acid, and the hydrogen pressure is generally 1 to 100%. 10 kg / cm ² can be suitably used.

In this reaction, the presence of an acid effectively promotes the reaction. As the acid, it is appropriate to use a mineral acid such as hydrochloric acid or sulfuric acid, and the concentration of the acid in the reaction system is 0 to 12N.
Preferably, it is selected from the range of 0-7 stipulations. When magnesium is used as the reducing agent, the reduction proceeds under acidic conditions using the reaction substrate parabanic acid without using a mineral acid.

In the reduction reaction, the reaction temperature in a solvent such as water or lower alcohol is selected from the range of about 0 to 95 ° C, preferably about 0 to 40 ° C. ° C, then 50-90 ° C, preferably 50-70 ° C
It is desirable to raise the temperature to ° C. The reaction time is preferably 4 to 20 hours.

The reaction between the product obtained by the reduction reaction and the aryl compound (I) is carried out in a solvent such as water or a lower alcohol at a temperature of about 50 to 90 ° C, preferably about 50 to 70 ° C.
It is preferably performed for up to 20 hours. When the reaction is carried out in an acidic aqueous medium, the reduction of parabanic acid and the reaction with the aryl compound (I) are carried out simultaneously and at a temperature of about 0 to 95 ° C, preferably about 0 to 70 ° C. It is preferably carried out for 4 to 20 hours.

The isolation of the hydantoins formed is generally very easy. That is, the desired 5-arylhydantoin is generally poorly soluble in an acidic or neutral aqueous solution, and is easily precipitated by cooling the reaction solution during the reaction or after the completion of the reaction. . However, it is of course possible to increase the purity by an operation such as recrystallization if necessary. When a metal reducing agent is used, there is no problem since the metal is converted into a water-soluble hydrochloride or sulfate.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 1.14 g (10 mmol) of parabanic acid, 1.41 g of phenol
(15 mmol), 13.2 ml of water and 6.8 ml of 35% hydrochloric acid, 4 g (55 mmol) of zinc dust were mixed with stirring at room temperature, and the mixture was stirred for 20 hours. Add 6.8 ml of the same hydrochloric acid and add 60 ° C
For 17 hours. The resulting white precipitate is collected, washed with water and dried to give 5- (4-hydroxyphenyl) hydantoin
0.70 g was obtained (37% yield). The crystals had a melting point of 263 to 265 ° C., and the infrared absorption spectrum, NMR spectrum and Rf value of silica gel thin film chromatography were as follows.
This was completely identical with the standard synthesized by a known method described in Japanese Patent No. -22474 (Rf = 0.83, BuOH: CH ³ CO ₂ H: H ₂ O = 4: 1: 1).

Example 2 1.14 g (10 mmol) of parabanic acid, 1.41 g of phenol
(15 mmol), 13.2 ml of water and 6.8 ml of 35% hydrochloric acid were mixed, 4 g (72 mmol) of iron powder was mixed with stirring at room temperature, 13.6 ml of 35% hydrochloric acid was added, and the mixture was stirred at 60 ° C. for 4 hours. .
The reaction solution was diluted with a 50% aqueous methanol solution to produce 5-
When the amount of (4-hydroxyphenyl) hydantoin was determined by high performance liquid chromatography, 0.33 g (yield 1
7%).

In addition, the conditions of the high performance liquid chromatography used are as follows.

Model JASCO Corporation, High Performance Liquid Chromatograph
TRIROTAR Column YMC Corporation, YMC Packed Column A-303
S-5 120A ODS column Developing solvent 13% acetonitrile, pH2.5 Phosphate buffer Flow rate 0.6ml / min Detection 210nm UV detector Example 3 1.14 g (10 mmol) of parabanic acid, 1.41 g of phenol
(15 mmol) and 13.2 ml of water, and 1 g (41 mmol) of magnesium powder was added under ice cooling. Add hydrochloric acid 1 at 0 ° C
3.6 ml was added, and the mixture was stirred at 70 ° C. for 5 hours. The produced crystals were collected to obtain 0.62 g (yield 32%) of 5- (4-hydroxyphenyl) hydantoin as white crystals.

Example 4 1.00 g (88 mmol) of parabanic acid, 1 g of Raney nickel (R-210, manufactured by Nikko Rika Co., Ltd.), and 20 ml of methanol
Stir vigorously at 5 ° C. and add hydrogen at normal pressure. After adding about 150 ml of hydrogen, Raney nickel was removed by filtration,
The methanol was distilled off. 13.2 ml of water, 6.8 ml of hydrochloric acid and 1.41 g of phenol were added to the residue, and the mixture was stirred at 70 ° C for 15 hours.
The reaction solution was diluted with a 50% aqueous methanol solution to produce 5-
When the amount of (4-hydroxyphenyl) hydantoin was quantified by high performance liquid chromatography, 0.25 g (yield 1
5%).

[Effects of the Invention] According to the present invention, high-purity 5-arylhydantoins can be easily obtained by reducing parabanic acid using a reducing agent and reacting the aryl compound under heating. That is, the present invention provides a very effective method for producing D-arylglycine.

Claims (7)

(57) [Claims] 1. Reduction of parabanic acid, the reduction product obtained and a compound of the general formula (I): (Wherein, R ¹ is a hydroxyl group or a lower alkoxy group, at least one of the para and / or ortho positions thereof is unsubstituted, and R ² and R ³ are each independently a hydrogen atom, a hydroxyl group, a lower alkoxy group. A lower alkyl group, a halogen atom, an acylamino group or a nitro group) in an acidic aqueous medium. (Wherein R ¹ , R ² and R ³ are the same as described above)
A method for producing an arylhydantoin. 2. The method according to claim 1, wherein the reduction of parabanic acid is carried out using a metal selected from zinc, iron and magnesium as a reducing agent. 3. The process according to claim 1, wherein the reduction of parabanic acid and the reaction with the aryl compound represented by the general formula (I) are carried out simultaneously and in parallel. 4. The method according to claim 1, wherein the acidic aqueous medium is a hydrochloric acid or sulfuric acid acidic aqueous medium. 5. The process according to claim 1, wherein parabanic acid is catalytically hydrogenated with a Raney-based catalyst to reduce and then react with an aryl compound represented by the general formula (I). 6. The method according to claim 5, wherein Raney nickel is used as a catalyst. 7. The method according to claim 1, wherein phenol is used as the aryl compound.