JP2000219680A - Production of 5-arylhydantion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To readily produce the subject high-purity compound by reacting a specific alkyl oxoacetate with urea and a specified aryl compound in the presence of an acid. SOLUTION: An alkyl 2-oxoacetate represented by formula I (R1 is an alkyl) is reacted with urea in an amount of preferably 1.0-3.0 mol based on 1 mol of the alkyl 2-oxoacetate and an aryl compound represented by formula II (R2 is hydroxyl or a lower alkoxy; and R3 and R4 are each H, hydroxy or the like) (preferably phenol) in an amount of preferably 1.0-2.0 mol based on 1 mol of the alkyl 2-oxoacetate preferably in the presence of a 1-10 N acid (preferably hydrochloric acid or sulfuric acid), preferably in an aqueous medium at 60-95 deg.C to thereby produce the objective compound represented by formula III. The compound represented by formula I in a required amount may previously be added to a solution containing the urea and the compound represented by formula II or slowly added to the reactional system. The objective compound may be isolated by cooling the reactional liquid and carrying out the solid-liquid separation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel method for producing 5-arylhydantoins. 5-Allylhydantoins are important compounds as raw materials for producing D-2-arylglycines (eg, Dp-hydroxyphenylglycine) useful for the synthesis of semisynthetic penicillins and cephalosporins. is there.

[0002]

2. Description of the Related Art 5-Allylhydantoins are classically known as Bucherer-Bergs.
g), it is known to be synthesized by the reaction of the corresponding aryl aldehyde with ammonium carbonate and sodium cyanide (Jurnal Fil Practice Hemi- (J., Prakt. , Che
m. ), 1934 (140), 231).

A method of reacting glyoxylic acid, urea and phenol under acidic conditions (Japanese Patent Publication No. 55-2247)
No. 4), a method of reacting allantoin with phenol (see Japanese Patent Publication No. 55-16592), a method of reacting hydroxymandelic acid and urea with acidification (see Japanese Patent Publication No. 57-57033), glyoxyl. Method for reacting urea with phenol (Japanese Patent Application Laid-Open No. 54-12857)
No. 2), a method of reacting alloxanic acid with phenol (see JP-A-54-138558), and a method of reacting glyoxylic acid triureide with phenol (see JP-A-54-138559). Of phenol and 5-hydroxyhydantoin (see Japanese Patent Application Laid-Open No. 54-138560) and a method of reacting urea and phenol with methyl glyoxylate methyl hemiacetal (Japanese Patent Application Laid-Open No. 4-138560). Many methods are known.

[0004]

However, when manufacturing by the Buffer-Berg method, dangerous cyanide solution is used.
In addition, there is a problem that a large amount of by-products is mixed into the crude hydantoin due to an oxidative side reaction of the phenol nucleus in an alkaline state, and the generated hydantoin is colored.

[0005] Glyoxylic acid, allantoin, 5
-Hydroxyhydantoin, mandelic acid, glyoxylurea, alloxanic acid, diglyoxylic acid triureide,
The method using raw materials such as glyoxylic acid methyl ester methyl hemiacetal is not a satisfactory method because the raw materials are expensive or are difficult to obtain directly as industrial raw materials.

[0006]

The present inventors have conducted intensive studies to solve these problems, and as a result, they are manufactured from inexpensive ethylene glycol (JP-A-8-291107, JP-A-9-291107). A novel synthesis method of 5-arylhydantoins using 2-oxoacetic acid alkyl ester (glyoxylic acid alkyl ester) as a raw material has been found, and the present invention has been completed.

That is, the present invention provides a compound represented by the following general formula (4):

[0008]

Embedded image
(4) Wherein R 1 is an alkyl group, 2-oxoacetic acid alkyl ester, urea and general formula (5):

[0009]

Embedded image
(5) (Wherein R2 is a hydroxyl group or a lower alkoxy group, at least one of the para and / or ortho positions thereof is unsubstituted, and R3 and R4 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 the presence of an acid.

[0010]

Embedded image
(6) (Wherein R2, R3 and R4 are the same as described above)
The present invention relates to a method for producing allylhydantoins.

[0011]

DETAILED DESCRIPTION OF THE INVENTION It is known that the starting 2-oxoacetic acid alkyl ester used in the present invention can be produced continuously by gas-phase oxidation and subsequent esterification using inexpensive ethylene glycol as a starting material ( JP 8
-291107, JP-A-9-118650). For example, inexpensive 2-oxoacetic acid esters comprising a lower alkyl group in which the alkyl group of a 2-oxoacetic acid alkyl ester is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, etc. It can be used as a raw material of the present invention.

As the reaction medium, an aqueous medium is preferred, and it is most practical to use water. However, a mixed solvent such as water and alcohol or water and acetic acid can also be used.

This reaction is effectively promoted by the presence of an acid. As the acid, a mineral acid such as hydrochloric acid or sulfuric acid is suitably used, and the concentration of the acid in the reaction system can be selected from a range of 0.5 to 12N. As the acid concentration increases,
Although the yield of 5-arylhydantoins tends to be improved, use of an excessive amount of an acid may decompose the produced target product, so that it is preferably selected from the range of 1 to 10N.

At least 1.0 mole of urea is used per mole of 2-oxoacetic acid alkyl ester, and urea is decomposed in an acidic medium to form ammonia and CO ₂ , preferably 1.0 to 3.0 moles. Is preferably used. The aryl compound is at least 1.0 mole per mole of the 2-oxoacetic acid alkyl ester, and the use of an excess of phenol makes purification difficult. Is preferably used.

[0015] The reaction temperature is desirably 35 ° C or higher, more preferably a temperature of 60 to 95 ° C.

The alkyl 2-oxoacetate may be added in a necessary amount to a solution containing urea and an aryl compound in advance, or may be gradually added to the reaction system.

The isolation of the generated 5-arylhydantoins is generally very easy. That is, the target 5
-Allyl hydantoins are generally poorly soluble in acidic or neutral aqueous solutions, and are easily precipitated by cooling the reaction solution during or after the reaction, and may be separated into solid and liquid. If necessary, the purity can be increased by an operation such as recrystallization.

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

[0019]

EXAMPLES (Example 1) 32.0 g of phenol (0.3
4 mol), 38.9 g (0.65 mol) of urea, 100 parts of water
of 2-oxoacetic acid ethyl ester (23.1 g, 0.1 g) at 80 ° C. with stirring at 80 ° C.
23 mol) was added continuously over 10 hours. After the addition, the mixture was further heated and stirred at 80 ° C. for 10 hours. The reaction solution was cooled to 60 ° C., and the generated precipitate was filtered, washed with water and dried to obtain 23.9 g of 5- (4-hydroxyphenyl) hydantoin having a purity of 98% or more (yield: 55.0%). The obtained crystal showed a melting point of 263 to 265 ° C., and its infrared absorption spectrum, NMR spectrum, and Rf value of silica gel chromatography were completely identical to those of a sample synthesized by a known method described in JP-B-55-22474. (R
f = 0.83, BuOH: CH ₃ COOH: H ₂ O = 4:
1: 1). (Example 2) 32.0 g (0.34 mol) of phenol,
A mixture of 38.9 g (0.65 mol) of urea, 100 ml of water and 100 g of concentrated hydrochloric acid was stirred at 80 ° C. while
20.0 g of oxoacetic acid methyl ester (0.23 mol,
(The one synthesized by the method described in JP-B-4-66656) was added continuously over 10 hours. After the addition,
Further, heating and stirring were continued at 80 ° C. for 10 hours. Reaction solution 5
The mixture was diluted with a 0% aqueous methanol solution, and the amount of 5- (4-hydroxyphenyl) hydantoin produced was quantified by high performance liquid chromatography to find 28.8 g (66.0).
%) Was confirmed to be formed.

Model: LC-6A, manufactured by Shimadzu Corporation Column: ODS column manufactured by Nacalai Tesque Co., Ltd. Cosmosil (registered trademark) 5C18-AR-300 Eluent: pH 2.5 phosphoric acid containing 9.9 v / v% acetonitrile Buffer flow rate: 1.0 ml / min Detection: 210 nm (UV detector) Temperature: 35 ° C. Under these conditions, the retention time of 5- (4-hydroxyphenyl) hydantoin was 4.5 minutes. (Example 3) 32.0 g (0.34 mol) of phenol,
A mixture of 38.9 g (0.65 mol) of urea, 100 ml of water and 100 g of concentrated hydrochloric acid was stirred at 80 ° C. while
Oxoacetic acid ethyl ester 23.1 g (0.23 mol)
Was added all at once. After the addition, heating and stirring were continued at 80 ° C. for 16 hours. The reaction solution was diluted with a 50% aqueous methanol solution,
When the amount of generated 5- (4-hydroxyphenyl) hydantoin was determined by high performance liquid chromatography,
It was confirmed that 20.9 g (48.0%) was produced.

[0021]

According to the present invention, high-purity 5-arylhydantoin can be easily obtained by reacting an alkyl 2-oxoacetate with an aryl compound and urea by heating in the presence of an acid. Obtainable. That is, the present invention provides a method for producing an intermediate material which is extremely effective for producing D-arylglycine.

Claims (5)

[Claims] 1. General formula (1):
(1) (Wherein, R 1 is an alkyl group) represented by the formula (2):
(2) (Wherein R2 is a hydroxyl group or a lower alkoxy group, at least one of the para and / or ortho positions thereof is unsubstituted, and R3 and R4 are each independently a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower alkyl group. Wherein the aryl compound is a group, a halogen atom, an acylamino group or a nitro group) in the presence of an acid.
(3) (Wherein R1, R2, R3 and R4 are the same as described above). 2. The method according to claim 1, wherein the alkyl group of the 2-oxoacetic acid alkyl ester is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or an isobutyl group. 3. The method according to claim 1, wherein phenol is used as the aryl compound. 4. The method according to claim 1, wherein hydrochloric acid or sulfuric acid is used as the acid. 5. The method according to claim 1, wherein the reaction is carried out in an aqueous medium.
The production method according to 2, 3, or 4