JPH06135937A - Production of 5,5-disubstituted hydantoin - Google Patents

Abstract

PURPOSE:To produce a 5,5-disubstituted hydantoin in excellent operating characteristics, safety and economic efficiency by using an inexpensive raw material. CONSTITUTION:A 2-keto-carboxylic acid of formula I (R<1> is alkyl, aralkyl or aryl which may be replaced with OH, halogen, CN, CF3, 1-4C alkoxy or alkylmercapto; R' is H or 1-4C alkyl) is reacted with a urea of formula II (R<2> and R<3> are H, alkyl, aralkyl or aryl) and a compound of the formula Ar-H (Ar is aryl which may be replaced with OH, 1-4C alkoxy, halogen, 1-4C alkyl, alkylmercapto, CN, CF or their combination) in the presence of an acid, preferably a strong mineral acid at 60-100 deg.C to give a compound of formula III. In the reaction, an intermediate for formula IV is formed by the reaction between the compound of formula I and the compound of formula II and is reacted with a compound of the formula Ar-H.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula (IV):

[0002]

[Chemical 5]

(In the formula, R ¹ is a hydroxyl group, a halogen atom,
A cyano group, a trifluoromethyl group, an alkyl group which may be substituted with an alkoxy group having 1 to 4 carbon atoms or an alkylmercapto group, an aralkyl group or an aryl group,
R ² and R ³ are the same or different and each is a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, Ar is a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkylmercapto. Group, a cyano group, a trifluoromethyl group or an aryl group which may be substituted with a combination of these groups), a process for producing a 5,5-disubstituted hydantoin represented by The object is to industrially advantageously produce the important compounds.

[0004]

2. Description of the Prior Art 5,5-Disubstituted hydantoins are generally prepared by the Bucherer-Berg method of synthesizing hydantoins (Journal Feel Practic.
It can be synthesized from the corresponding ketone by a method known as J. Parkt. Chem. 1934, 140, 291.).

That is, it is known that a ketone can be obtained by heating a cyanide salt with ammonium carbonate in an alcoholic aqueous medium.

[0006]

[Problems to be Solved by the Invention] However, Bucher
In the er-Berg method, it is necessary to use a highly toxic and dangerous hydrocyanic acid salt, and there are problems in terms of operability and economy such as handling problems and waste liquid treatment problems.

Further, when producing hydantoin having a phenol group, there are problems that a large amount of by-products are mixed in due to an oxidative side reaction of the phenol nucleus in an alkaline condition and that the product is colored.

[0008]

SUMMARY OF THE INVENTION The present inventors have found that Bucherer
-Operability, safety, to overcome the problems in the Berg method,
As a result of repeated studies to establish an industrial production method of 5,5-disubstituted hydantoin excellent in economic efficiency, a highly efficient novel production method using 2-ketocarboxylic acids and urea and aryl compounds was found, and the present invention Was completed.

That is, the present invention has the general formula (I):

[0010]

[Chemical 6]

(In the formula, R ¹ is a hydroxyl group, a halogen atom,
A cyano group, a trifluoromethyl group, an alkyl group which may be substituted with an alkoxy group having 1 to 4 carbon atoms or an alkylmercapto group, an aralkyl group or an aryl group,
R'represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), a 2-ketocarboxylic acid represented by the general formula (II):

[0012]

[Chemical 7]

(In the formula, R ² and R ³ are the same or different and each represents a hydrogen atom, an alkyl group, an aralkyl group or an aryl group) and a urea represented by the general formula (III)
:

[0014]

[Chemical 8]

(In the formula, Ar is a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkylmercapto group, a cyano group, a trifluoromethyl group or a combination of these groups. An aryl compound which may be substituted) is reacted under heating in the presence of an acid to give a compound of the general formula (I
V):

[0016]

[Chemical 9]

The present invention relates to a method for producing a 5,5-disubstituted hydantoin represented by the formula (wherein R ¹ , R ² , R ³ and Ar are the same as above).

[0018]

EXAMPLES In the compounds represented by the general formulas (I) and (II) used in the method of the present invention, the alkyl groups represented by R ¹ , R ² and R ³ are linear groups having 1 to 10 carbon atoms. It is a branched chain alkyl group, specifically, a methyl group, an ethyl group,
Examples thereof include propyl group, isopropyl group, butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group and decyl group. The aralkyl group is an alkyl group having an aryl group, and specifically, phenylmethyl group, 2-phenylethyl group, 1-
Examples thereof include phenylethyl group and 1-phenylpropyl group. The aryl group is a substituted or unsubstituted phenyl group, naphthyl group or the like, and specific examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like. In addition, the number of carbon atoms that can be substituted with the group represented by R ¹ is 1
Examples of the alkoxy group of to 4 include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and an alkylmercapto group includes a methylmercapto group and an ethylmercapto group.

Examples of the alkyl group having 1 to 4 carbon atoms represented by R'include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and a t-butyl group.

In the compound represented by the general formula (III),
The aryl group represented by Ar is a substituted or unsubstituted phenyl group or a naphthyl group, and specifically, a phenyl group, a naphthyl group, a thienyl group, a benzofuryl group, an anthranyl group, a phenanthryl group, a pyrrole group,
Examples include frill groups. Further, the alkyl group having 1 to 4 carbon atoms which can be substituted with the aryl group is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a t-butyl group, and a halogen atom is fluorine, bromine, chlorine, Examples of iodine and alkoxy groups having 1 to 4 carbon atoms include methoxy group, ethoxy group, propoxy group, butoxy group, and examples of alkylmercapto group include methylmercapto group and ethylmercapto group.

In this reaction, the compound represented by the general formula (I) first reacts with the compound represented by the general formula (II) to produce an intermediate, which is then reacted with the compound represented by the general formula (III). Reacts.

In the reactions of the general formulas (I) and (II), the general formula (V):

[0023]

[Chemical 10]

It is considered that the ureidocarboxylic acid compound represented by the formula (3) is produced as an intermediate.

The reaction method in the present invention includes 2-ketocarboxylic acids (I), ureas (II) and aryl compounds.
A so-called one-pot reaction in which (III) is added at once and the intermediately formed ureidocarboxylic acid compound (V) is generated in situ in the reaction system and is reacted with the aryl compound (III) is also possible.

The 2-ketocarboxylic acids (I) and the ureas (II) are used in a ratio of 1: 3 to 3: 1 in consideration of their decomposition because both are slightly unstable under acid conditions. Selected from the range. Generally, the cheaper one is used in excess. For the same reason, the ratio of 2-ketocarboxylic acid (I) to aryl compound (III) and urea (II) to aryl compound (III) are 2
-It is necessary to use ketocarboxylic acids (I) and ureas (II) in a slight excess, and both are selected from the range of 3: 1 to 1: 1. The concentration of these reactants is not particularly limited, but is preferably 1% to 30%.

This reaction can be carried out in an aqueous medium or an organic solvent, but when the aryl compound represented by the general formula (III) is water-soluble, it is preferable to use an aqueous medium.

When this reaction is carried out in an aqueous medium,
Water is the most practical solvent, but water-alcohol,
An aqueous mixed solvent such as water-acetic acid can also be used.

This reaction is effectively promoted by acid. Inorganic and organic acids are used as the acid, but in practice, it is suitable to use a strong mineral acid such as hydrochloric acid or sulfuric acid.
The concentration of the strong mineral acid in the reaction system is preferably 2 N or more, but a range of 4 to 10 N is adopted to increase the reaction rate. The reaction temperature is preferably 40 ℃ or more, especially 60 ℃ ~ 100
A range of ° C is suitable. The reaction is completed in 0.5 to 30 hours, preferably 3 to 10 hours.

The hydantoin produced is hardly soluble in an acidic / neutral aqueous solution, and therefore the precipitate deposited after the reaction may be solid-liquid separated. However, it is of course possible to increase the purity by an operation such as recrystallization or column chromatography if necessary.

When the aryl compound represented by the general formula (III) is soluble in an organic solvent, an organic solvent may be used. In this case, benzene, toluene, xylene or a mixed solvent of these and acetic acid is preferably used as the reaction medium. It is preferable to use sulfuric acid as the acid. The acid concentration is selected from the range of 1 to 30%, preferably 3 to 15%. The other reaction conditions such as reaction temperature and reaction time are the same as in the case of the aqueous medium.

The formed hydantoin is easily precipitated by adding water after concentrating the reaction solution after the reaction is completed, so solid-liquid separation may be performed. However, it is of course possible to increase the purity by operations such as recrystallization and column chromatography, if necessary.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to such examples.

Example 1 10.0 g (0.106 mol) of phenol and 12.0 g (0.200 g of urea)
Mol), 42.0 ml of water and 27.0 ml of 36% hydrochloric acid were heated to 75 ° C. with stirring. Then, a mixture of 8.8 g (0.100 mol) of pyruvic acid and 13.0 ml of water was added over 3 hours, and the mixture was further heated and stirred at 75 ° C for 4 hours. The reaction solution was cooled to room temperature and then extracted with ethyl acetate. The obtained organic layer was concentrated under reduced pressure to remove the solvent. Then, carbon tetrachloride and petroleum ether were added, and the mixture was stirred and allowed to stand, and the supernatant was removed. Ethyl acetate was added to the residue, and a white precipitate formed was collected by filtration and dried to give 5- (4-hydroxyphenyl) -5-.
2.10 g (0.010 mol) of methylhydantoin was obtained.

Mp: 227-237 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ , δ): 1.6 (s, 3H), 6.6
~ 7.3 (q, 4H), 8.4 (s, 1H), 9.2 (s, 1H), 10.7 (s, 1H) Example 2 Phenol 8.00 g (0.085 mol) and urea 9.60 g (0.160)
Mol), 36.0 ml of water and 26.0 ml of 36% hydrochloric acid were heated to 90 ° C. with stirring. Then benzoylformic acid 12.80 g (0.
A mixture of (085 mol) and 10.0 ml of water was added over 5 hours, and the mixture was further heated and stirred at 90 ° C. for 15 hours. The reaction solution was cooled to room temperature, a white precipitate was collected by filtration, washed with ethanol and dried to obtain 19.69 g (0.073 mol) of 5- (4-hydroxyphenyl) -5-phenylhydantoin.

Mp: 306 to 310 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ , δ): 6.6 to 7.3 (q, 4H)
, 7.3 (s, 5H), 9.2 (s, 1H), 9.6 (s, 1H), 10.7 (s, 1H) Example 3 1.00 g (8.92 mmol) of p-fluorophenol and urea
A mixture of 1.25 g (20.8 mmol), 4.0 ml of water and 3.0 ml of 36% hydrochloric acid was heated to 90 ° C. with stirring. Then, a mixture of 1.34 g (8.93 mmol) of benzoylformic acid and 1.0 ml of water was added, and the mixture was further heated and stirred at 90 ° C. for 15 hours. The reaction solution was cooled to room temperature, the generated white precipitate was collected by filtration, washed with acetone and dried to give 1.54 g of 5- (5-fluoro-2-hydroxyphenyl) -5-phenylhydantoin (5.
38 mmol) was obtained.

Mp: 305 to 308 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ , δ): 6.2 to 6.4 (m, 1H)
, 6.6 to 7.3 (m, 2H), 7.3 to 7.8 (m, 5H), 8.6 (s, 1H)
, 10.1 (s, 1H), 10.8 (s, 1H) Example 4 1.00 g (8.92 mmol) of p-fluorophenol and urea
A mixture of 1.25 g (20.8 mmol), 4.0 ml of water and 3.0 ml of 36% hydrochloric acid was heated to 90 ° C. with stirring. Then pyruvic acid
Add a mixture of 0.79 g (8.97 mmol) and 1.0 ml of water,
Further, the mixture was heated and stirred at 90 ° C. for 8 hours. The reaction solution was cooled to room temperature, washed with benzene, and the obtained aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and then concentrated under reduced pressure to remove the solvent. Diethyl ether was added to the obtained concentrate, and a white precipitate formed was collected by filtration, washed with diethyl ether, and dried to give 5- (5-fluoro-2-hydroxyphenyl) -5-methylhydantoin 0.34 g (1.52 mmol ).

Mp: 230-240 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ + CDCL ₃ , δ): 1.6
(s, 3H), 6.5 to 7.2 (m, 3H), 7.8 (s, 1H), 9.8 (s, 1H)
, 10.6 (s, 1H) Example 5 2-methoxynaphthalene 7.8 g (0.05 mol), methyl pyruvate 5.0 g (0.05 mol), urea 3.0 g (0.05 mol)
Was dissolved in a solution of 50 ml of toluene, 5 ml of sulfuric acid and 50 ml of acetic acid.

Water was azeotropically removed from this solution by a Dean-Stark apparatus for 3 hours. After distilling off the solvent, add distilled water to 50
Add ml, neutralize the pH to 7 with sodium hydroxide, and add 100 ml.
It was extracted with ethyl acetate. The extract was dried over magnesium sulfate and then purified by silica gel chromatography (eluent hexane: acetone 5: 1) to give 5- (6
2.7 g of'-methoxy-2'-naphthyl) -5-methylhydantoin were obtained. Yield 20%.

Rf (silica gel, hexane: acetone =
1: 1) = 0.4 NMR (DMSO-d ₆ , δ): 10.74 (1H), 8.65 (1)
H), 7.8 to 8.0 (s, 3H), 7.83 (d, J = 6Hz, 1H), 7.30 (s, 1)
H), 7.16 (d, J = 6Hz, 1H), 3.87 (s, 3H), 1.75 (s, 3H) This compound is prepared from 2-acetyl-6-methoxynaphthalene according to the method described in JP-A-47-7215. (Synthesis from 2-acetyl-6-methoxynaphthalene using ammonium bicarbonate and potassium cyanide by the Bucherer-Burger method) 5- (6'-methoxy-2'-naphthyl) -5
-Methylhydantoin was in agreement with Rf and NMR.

[0041]

According to the present invention,

[0042]

[Chemical 11]

The 5,5-disubstituted hydantoin represented by the formula (wherein R ¹ , R ² , R ³ and Ar are the same as above) can be easily synthesized from an inexpensive raw material. Therefore, the present invention provides a method for industrially producing the compound, which is important as a drug / polymer stabilizer.

Claims (4)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ is a hydroxyl group, a halogen atom, a cyano group, a trifluoromethyl group, an alkyl group which may be substituted with an alkoxy group having 1 to 4 carbon atoms or an alkylmercapto group, an aralkyl group or an aryl group, R 1 ′ Represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), a 2-ketocarboxylic acid represented by the general formula (II): (In the formula, R ² and R ³ are the same or different and each represents a hydrogen atom, an alkyl group, an aralkyl group or an aryl group) and a urea represented by the general formula (III): (In the formula, Ar is a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms,
The presence of an acid represents an aryl compound represented by a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkylmercapto group, a cyano group, a trifluoromethyl group or an aryl group which may be substituted with a combination of these groups. General formula (IV) characterized by reacting under heating: (Wherein R ¹ , R ² , R ³ and Ar are the same as above), and a method for producing a 5,5-disubstituted hydantoin. 2. The method according to claim 1, wherein hydrochloric acid or sulfuric acid is used as the acid. 3. The method according to claim 1, wherein the reaction is carried out using an aqueous medium.
The manufacturing method described. 4. The method according to claim 1, wherein the reaction is carried out using benzene, toluene, xylene or a mixed solvent of these and acetic acid.