JP3137430B2 - Method for producing 5,5-disubstituted hydantoin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

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(Wherein R ¹ represents a hydroxyl group, a halogen atom,
A cyano group, a trifluoromethyl group, an alkyl group optionally 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 represents a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, and Ar represents a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, an alkyl group having 1 to 4 carbon atoms, alkyl mercapto. , A cyano group, a trifluoromethyl group or an aryl group which may be substituted by a combination of these groups). It is intended to produce the important compounds industrially advantageously.

[0004]

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

[0005] That is, it is known that a ketone can be obtained by reacting a cyanate with ammonium carbonate by heating in an alcoholic aqueous medium.

[0006]

SUMMARY OF THE INVENTION However, Bucher
In the er-Berg method, a highly toxic and dangerous cyanide must be used, which has problems in handling and economical aspects such as waste liquid treatment.

Further, when producing a 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 a phenol nucleus under alkaline conditions, and that the product is colored.

[0008]

Means for Solving the Problems The present inventors have proposed Bucherer
-Operability, safety, and
As a result of repeated studies to establish an industrial production method of a 5,5-disubstituted hydantoin which is excellent in economic efficiency, a novel production method using 2-ketocarboxylic acids, urea and an aryl compound with high efficiency was found. Was completed.

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

[0010]

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(Wherein R ¹ is a hydroxyl group, a halogen atom,
A cyano group, a trifluoromethyl group, an alkyl group optionally 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]

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

[0014]

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(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 represented by an aryl group which may be substituted) is reacted by heating in the presence of an acid.
V):

[0016]

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(Wherein R ¹ , R ² , R ³ and Ar are the same as described above).

[0018]

EXAMPLES In the compounds of 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 straight-chain alkyl groups having 1 to 10 carbon atoms. It is a branched alkyl group, specifically, a methyl group, an ethyl group,
Examples thereof include propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl groups. The aralkyl group is an alkyl group having an aryl group, and specifically, a phenylmethyl group, a 2-phenylethyl group,
Examples include a phenylethyl group and a 1-phenylpropyl group. The aryl group is a substituted or unsubstituted phenyl group, naphthyl group and the like, and specific examples include a phenyl group, a 1-naphthyl group and a 2-naphthyl group. Further, carbon atoms may be replaced by a group represented by R ¹ 1
Examples of the alkoxy groups (1) to (4) include a methoxy group, an ethoxy group, a propoxy group and a butoxy group, and examples of the alkylmercapto group include 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.

Further, in the compound represented by the general formula (III),
The aryl group represented by Ar is a substituted or unsubstituted phenyl group or 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,
And a furyl group. Further, as the alkyl group having 1 to 4 carbon atoms which can be substituted by the aryl group, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and halogen atoms such as fluorine, bromine, chlorine, Examples of iodine and an alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, a propoxy group and a butoxy group, and examples of the alkylmercapto group include a methylmercapto group and an ethylmercapto group.

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

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

[0023]

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It is considered that the ureidocarboxylic acid compound represented by the formula is formed 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 intermediate ureidocarboxylic acid compound (V) is reacted in situ in the reaction system with the aryl compound (III) is also possible.

The use ratio of the 2-ketocarboxylic acids (I) to the ureas (II) is slightly unstable under acid conditions, and therefore, the ratio is 1: 3 to 3: 1 in consideration of the decomposition of each. Is selected from the range. Generally, the inexpensive one is used excessively. The ratios of 2-ketocarboxylic acids (I) to aryl compounds (III) and ureas (II) to aryl compounds (III) are 2 for the same reason.
-It is necessary to use the ketocarboxylic acids (I) and the ureas (II) in a slight excess, both of which 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. However, 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 an acid. Inorganic and organic acids are used as the acid, but in practice it is appropriate 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 desirably 2N or more, but a range of 4 to 10N is employed to increase the reaction rate. The reaction temperature is preferably 40 ° C or higher, especially 60 ° C to 100 ° C.
A range of ° C is appropriate. The reaction is completed in 0.5 to 30 hours, preferably 3 to 10 hours.

Since the formed hydantoin is hardly soluble in an acidic / neutral aqueous solution, the precipitate deposited after completion of the reaction may be subjected to solid-liquid separation. However, it is of course possible to increase the purity by operations such as recrystallization and 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 suitably used as a reaction medium. Sulfuric acid is preferably used as the acid. The concentration of the acid is selected from the range of 1 to 30%, but is preferably in the range of 3 to 15%. Other reaction conditions such as reaction temperature and reaction time are the same as those for the aqueous medium.

The produced hydantoin is easily precipitated by adding water after concentrating the reaction solution after the completion of the reaction. 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 these examples.

Example 1 10.0 g (0.106 mol) of phenol and 12.0 g (0.200 mol) 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. After the reaction solution was cooled to room temperature, it was 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 the resulting white precipitate was collected by filtration, dried and dried to give 5- (4-hydroxyphenyl) -5-.
2.10 g (0.010 mol) of methylhydantoin were 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 8.00 g (0.085 mol) of phenol and 9.60 g (0.160 mol) of urea
Mol), 36.0 ml of water and 26.0 ml of 36% hydrochloric acid were heated to 90 ° C. with stirring. Then 12.80 g of benzoylformic acid (0.
[085 mol] and 10.0 ml of water were 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, the 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: 306-310 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ , δ): 6.6-7.3 (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. while 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, and the resulting white precipitate was collected by filtration, washed with acetone and dried, and 1.54 g of 5- (5-fluoro-2-hydroxyphenyl) -5-phenylhydantoin (5.
38 mmol).

Mp: 305-308 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ , δ): 6.2-6.4 (m, 1H)
, 6.6-7.3 (m, 2H), 7.3-7.8 (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. while 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. After cooling the reaction solution to room temperature, it was washed with benzene, and the obtained aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and 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, and 0.34 g (1.52 mmol) of 5- (5-fluoro-2-hydroxyphenyl) -5-methylhydantoin was obtained. ).

Mp: 230-240 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ + CDCL ₃ , δ): 1.6
(s, 3H), 6.5-7.2 (m, 3H), 7.8 (s, 1H), 9.8 (s, 1H)
Example 5 7.8 g (0.05 mol) of 2-methoxynaphthalene, 5.0 g (0.05 mol) of methyl pyruvate, 3.0 g (0.05 mol) of urea
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 the solution by a Dean-Stark apparatus for 3 hours. After distilling off the solvent, add distilled water
neutralized to pH 7 with sodium hydroxide and add 100 ml
Extracted with ethyl acetate. The extract was dried over magnesium sulfate and purified by silica gel chromatography (eluent: hexane: acetone 5: 1) to give 5- (6
'-Methoxy-2'-naphthyl) -5-methylhydantoin 2.7 g was obtained. Yield 20%.

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

[0041]

According to the present invention,

[0042]

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(Wherein R ¹ , R ² , R ³ and Ar are the same as described above), can be easily synthesized from inexpensive raw materials. Therefore, the present invention provides a method for industrially advantageously producing the compound which is important as a drug / polymer stabilizer.

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁷ , DB name) C07D 233/78 C07D 233/76 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] [Claim 1] General formula (I): (Wherein, R ¹ represents a hydroxyl group, a halogen atom, a cyano group, a trifluoromethyl group, an alkyl group optionally substituted by an alkoxy group having 1 to 4 carbon atoms or an alkylmercapto group, an aralkyl group or an aryl group, 'Represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), a 2-ketocarboxylic acid represented by the general formula (II): (Wherein R ² and R ³ are the same or different and represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group) and a urea represented by the general formula (III): (Wherein, 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 alkyl mercapto group, a cyano group, a trifluoromethyl group or an aryl group which may be substituted by 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 described above). 2. The method according to claim 1, wherein hydrochloric acid or sulfuric acid is used as the acid. 3. The reaction according to claim 1, wherein the reaction is carried out using an aqueous medium.
Production method as described. 4. The method according to claim 1, wherein the reaction is carried out using benzene, toluene, xylene or a mixed solvent of these with acetic acid.