JPH07300463A - Production of 5-alkoxyhydantoin compound - Google Patents

Abstract

PURPOSE:To safely, easily obtain in high yield the subject compound useful as an intermediate for medicines and agrochemicals by reaction of a specific hydantoin compound with an alcohol and chlorine in the presence of a specific catalyst. CONSTITUTION:The objective compound of formula III is obtained, (A) in the presence of a phase-transfer catalyst except those containing bromide ions iodide ions {e.g. a compound of formula I [R<4>, R<5>, R<6> and R<7> each is an alkyl, a (substituted) aralkyl or a heterocyclic group formed by combining R<4>, R<5> and R<6> together with the adjacent nitrogen atom; X<-> is an anion except bromide ion and iodide ion]}, by reaction of (B) a compound of formula II (R<1>, R<2> and R<3> each is H, an alkyl, an aryl or an aralkyl) with (C) a compound of formula ROH [R is a (cyclo)alkyl] and (C) chlorine. It is preferable that the amount of the component A to be used be 0.001-0.4mol per mol of the component B.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing 5-alkoxyhydantoins, which are intermediates useful for medicines, agricultural chemicals and the like.

[0002]

2. Description of the Related Art Conventionally, as a method for synthesizing 5-alkoxyhydantoins, hydantoins have been brominated in an acetic acid solvent to give 5-bromohydantoins.
A method of reacting bromhydantoins with alcohol to obtain the corresponding 5-alkoxyhydantoins (J. H.
etherocycl. Chem. , 7, 1289 (19
70)) is known. Then, as a method for solving the drawbacks of this method, halogenation of hydantoins and a reaction between a halide and an alcohol produced thereby by adding chlorine to hydantoins in an alcohol solvent in the presence of bromine and / or iodine. To obtain corresponding 5-alkoxyhydantoins
No. 330064) is known.

[0003]

However, bromine, iodine and chlorine used in the latter method are highly toxic and corrosive, and are substances that easily cause ulcers when they come into contact with the skin.
Further, bromine and iodine have extremely low permissible concentrations of 0.1 ppm or less. Therefore, when carrying out this method, in terms of safety in handling and reaction operation of these substances,
Furthermore, sufficient consideration must be given to the treatment of waste liquid containing bromine or iodine. Therefore, there is a demand for a method for producing 5-alkoxyhydantoins which is more excellent in safety and the like. It is an object of the present invention to provide a method for producing 5-alkoxyhydantoins with high yield, which is improved in safety in industrial practice.

[0004]

Means for Solving the Problems As a result of various studies to solve the above problems, the present inventors have found that when a hydantoin compound is reacted with alcohol and chlorine in the presence of a phase transfer catalyst which is easy to handle, The inventors have found that 5-alkoxyhydantoins can be obtained in good yield without using bromine and iodine, and completed the present invention.

That is, according to the present invention, hydantoins represented by the following general formula (1) are represented by the general formula (2): ROH [wherein R is
Represents an alkyl group or a cycloalkyl group. ] When producing a 5-alkoxyhydantoin represented by the following general formula (3) by reacting with an alcohol and chlorine represented by the formula, a phase transfer catalyst (however, a phase transfer catalyst containing a bromide ion or an iodide ion is excluded The present invention relates to a method for producing 5-alkoxyhydantoins, which comprises conducting the reaction in the presence of

General formula (1):

[Chemical 4] [In the formula, R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group. ] Hydantoins shown by.

General formula (3):

[Chemical 5] [In the formula, R ¹ , R ² , R ³ and R are the same as above. ] The 5-alkoxy hydantoins shown by these.

In the method of the present invention, the hydantoins of the general formula (1) are chlorinated to give a 5-
The reaction that produces chlorohydantoins, and this 5
It is presumed that the reaction in which the desired product, the 5-alkoxyhydantoins of the general formula (3), is produced from the chlorohydantoins and the alcohol of the general formula (2) is successively progressing rapidly.

General formula (5):

[Chemical 6] [In the formula, R ¹ , R ² and R ³ are the same as above. ] 5-chlorohydantoins shown by these.

Next, the present invention will be described in more detail. R ¹ in the general formulas (1), (3) and (5) of the present invention,
R ² and R ³ are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group. The alkyl group may be a linear alkyl group or a branched alkyl group. Specific examples of the alkyl group include a linear alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, Typical examples are branched alkyl groups having 1 to 6 carbon atoms such as tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group, and isohexyl group. The aryl group may be unsubstituted or may have a substituent, and specific examples thereof include a phenyl group, a 4-methylphenyl group, 2,
Typical examples are a 5-dimethylphenyl group, a naphthyl group, a 4-chlorophenyl group, and a 3,5-dichlorophenyl group. Typical examples of the aralkyl group are benzyl group and phenethyl group.

In the general formulas (2) and (3) of the present invention, R represents an alkyl group or a cycloalkyl group. As the alkyl group, those similar to the above are typical. The cycloalkyl group is a monovalent group derived from a cycloalkane having 3 to 6 carbon atoms, and is typically a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or the like. As is clear from these, the alkoxy of the present invention means a monovalent substituent formed by an alkyl group bonding with an oxygen atom, and a monovalent substituent formed by a cycloalkyl group bonding with an oxygen atom. Means a valent substituent.

The hydantoins of the general formula (1) include
Hydantoin, alkyl hydantoin, dialkyl hydantoin, trialkyl hydantoin, aryl hydantoin, aralkyl hydantoin, alkyl-aralkyl hydantoin, etc. are mentioned. Specific examples of the alkyl hydantoin include 1-methylhydantoin, 1-ethylhydantoin, 1-propylhydantoin, 1-butylhydantoin, 1-pentylhydantoin, 1-hexylhydantoin, and the like, 3-alkylhydantoin, 3-methylhydantoin, 3- 3-alkylhydantoin such as ethylhydantoin, 3-propylhydantoin, 3-butylhydantoin, 3-pentylhydantoin, 3-hexylhydantoin, 5-methylhydantoin, 5-ethylhydantoin, 5-propylhydantoin, 5-butylhydantoin, 5 Typical examples are 5-alkylhydantoins such as pentylhydantoin and 5-hexylhydantoin. Specific examples of dialkylhydantoin are:
1,3-dimethylhydantoin, 1,5-dimethylhydantoin, 3,5-dimethylhydantoin, 1,3-diethylhydantoin, 1,5-diethylhydantoin,
A typical example is 3,5-diethylhydantoin. Specific examples of trialkylhydantoins include 1,3,5
-Triethylhydantoin, 1,3,5-trimethylhydantoin and the like are typical. Specific examples of the arylhydantoin include 1-phenylhydantoin, 3-phenylhydantoin, 5-phenylhydantoin and 1-phenylhydantoin.
(4-methylphenyl) hydantoin, 3- (4-methylphenyl) hydantoin, 1- (1-naphthyl) hydantoin, 1- (2-naphthyl) hydantoin, 3-
(1-naphthyl) hydantoin, 3- (2-naphthyl)
Hydantoin, 1- (4-chlorophenyl) hydantoin, 3- (4-chlorophenyl) hydantoin, 1-
(3,5-Dichlorophenyl) hydantoin, 3-
A typical example is (3,5-dichlorophenyl) hydantoin. Specific examples of aralkyl hydrant in are 1
-Benzylhydantoin, 3-benzylhydantoin,
Benzylhydantoin such as 5-benzylhydantoin is typical. The hydantoins of the general formula (1) are not limited to these.

As the alcohol of the general formula (2) used in the present invention, for example, an alkyl alcohol having 1 to 6 carbon atoms,
Alternatively, a cycloalkyl alcohol having 3 to 6 carbon atoms can be used. Specific examples of the former include methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, s.
ec-butyl alcohol, tert-butyl alcohol, pentyl alcohol, isopentyl alcohol, neopentyl alcohol, hexyl alcohol and the like are typical, and specific examples of the latter include cyclopropyl alcohol, cyclobutyl alcohol, cyclopentyl alcohol, Cyclohexyl alcohol and the like are typical, but not limited to these.

In the present invention, a phase transfer catalyst (provided that
Excludes phase transfer catalysts containing bromide or iodide ions. It is important to react the hydantoins of general formula (1) with alcohol and chlorine in the presence of That is, the presence of the phase transfer catalyst makes it possible to increase the yield of the 5-alkoxyhydantoins of the general formula (3) and the production rate thereof, as compared with the absence thereof. A typical example of the phase transfer catalyst is a quaternary ammonium salt.

The quaternary ammonium salt has the general formula (4):

[Chemical 7] [Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and each represents an alkyl group or an optionally substituted aralkyl group,
Alternatively, R ⁴ , R ⁵ and R ⁶ together with the adjacent nitrogen atom represent a heterocyclic group. X ⁻ represents an anion (excluding bromide ion and iodide ion). ] The quaternary ammonium salt shown by these is mentioned.

Typical examples of the quaternary ammonium salt of the general formula (4) are quaternary ammonium chloride salt, quaternary ammonium hydrogensulfate salt and the like. Specific examples of the quaternary ammonium chloride salt include tetraalkylammonium chloride such as tetramethylammonium chloride, tetrabutylammonium chloride and trioctylmethylammonium chloride, aralkyl such as benzyltrimethylammonium chloride, benzyltriethylammonium chloride and benzyltributylammonium chloride. Trialkylammonium chloride, N-methylpyridinium chloride, N-butylpyridinium chloride, N-
N-alkylpyridinium chloride such as laurylpyridinium chloride, N-methyl-2-methylpyridinium chloride, N-butyl-2-methylpyridinium chloride, N-lauryl-2-methylpyridinium chloride,
N-alkyl-, such as N-methyl-4-methylpyridinium chloride, N-butyl-4-methylpyridinium chloride, N-lauryl-4-methylpyridinium chloride
Alkylpyridinium chloride, N-benzylpyridinium chloride, N- (p-chlorobenzyl) pyridinium chloride, N- (p-laurylbenzyl) pyridinium chloride and the like, which may be substituted, N-aralkylpyridinium chloride, N-benzyl-2- Methylpyridinium chloride, N- (p-chlorobenzyl) -2-methylpyridinium chloride, N- (p-laurylbenzyl)
-2-Methylpyridinium chloride, N-benzyl-4
-Methylpyridinium chloride, N- (p-chlorobenzyl) -4-methylpyridinium chloride, N- (p-
An optionally substituted N-aralkyl-alkylpyridinium chloride such as laurylbenzyl) -4-methylpyridinium chloride is typical. Specific examples of the hydrogen sulfate quaternary ammonium salt include tetramethylammonium hydrogensulfate, tetrabutylammonium hydrogensulfate, tetraalkylammonium hydrogensulfate such as trioctylmethylammonium hydrogensulfate, and the like. It is a thing.
The quaternary ammonium salt of the general formula (4) is not limited to these.

As a preferred example of the method of the present invention, a hydantoin of the general formula (1), a phase transfer catalyst and an alcohol are charged into a reactor and heated to a desired temperature with stirring.
Then, chlorine is introduced to start the reaction, and after the completion of chlorine introduction, stirring is continued at the same temperature to complete the reaction. When the reaction is carried out in this way, the yield of the desired 5-alkoxyhydantoins of the general formula (3) becomes better.

The amount of alcohol used is not particularly limited, but since alcohol is usually used also as a solvent, it is preferable to use alcohol in an excess amount relative to the theoretical amount. The theoretical amount of alcohol is 1 mol with respect to 1 mol of the hydantoins of the general formula (1).

The amount of the phase transfer catalyst used is preferably 0.001 to 0.4 mol, and more preferably 0.01 to 0.1 mol, relative to 1 mol of the hydantoins of the general formula (1).
When the amount of the phase transfer catalyst used is less than the above range, the reaction proceeds slowly and the yield of the 5-alkoxyhydantoins of the general formula (3) decreases. If it exceeds the above range, there is no particular problem, but it is economically disadvantageous.

Chlorine is a hydantoin 1 of the general formula (1).
The amount is preferably 0.8 to 1.5 mol, and more preferably 1.0 to 1.2 mol with respect to the mol, for about 1 to 10 hours to be introduced into the reaction solution. If the amount of chlorine introduced is less than the above range, the yield will decrease, and if it is more than that, it is uneconomical.

The reaction temperature may be a temperature at which the hydantoins of the general formula (1) are dissolved in alcohol, preferably 20 to 200 ° C.

After completion of the reaction, the reaction solution is cooled to around room temperature, water is added to dilute the solution, and the solution is further cooled to about 10 ° C. to precipitate crystals. The precipitated 5-alkoxyhydantoins of the general formula (3) can be obtained by filtering and drying the precipitated crystals.

The alkoxy OR of the 5-alkoxyhydantoins of the general formula (3) obtained as described above is derived from the alcohol of the general formula (2), and is the residue of the alcohol used in the reaction. RO is introduced at the 5-position of the hydantoins of general formula (1). 5-of the general formula (3)
Examples of the alkoxyhydantoins include those represented by the general formula (3)
1-alkyl (having 1 to 6 carbon atoms) -5, in which R of the alkoxy OR at the 5-position in is an alkyl group having 1 to 6 carbon atoms.
Alkoxyhydantoin, 1-phenyl-5-alkoxyhydantoin, 1-benzyl-5-alkoxyhydantoin, 3-alkyl (C1-6) -5-alkoxyhydantoin, 3-phenyl-5-alkoxyhydantoin, 3-benzyl- 5-alkoxyhydantoin,
5-alkyl (C1-6) -5-alkoxyhydantoin, 5-phenyl-5-alkoxyhydantoin,
5-benzyl-5-alkoxyhydantoin, 3- (4
-Chlorophenyl) -5-alkoxyhydantoin, 3
A typical example is-(3,5-dichlorophenyl) -5-alkoxyhydantoin. 5-of the general formula (3)
Alkoxyhydantoins are not limited to these.

[0024]

EXAMPLES The present invention will now be described in more detail by way of examples, which should not be construed as limiting the invention thereto. Example 1 190 g (1.0 mol) of 1-benzylhydantoin and 5.56 g (0.02 mol) of tetrabutylammonium chloride were placed in a glass four-necked flask having a capacity of 2000 ml.
And 760 g of ethyl alcohol were added, and the temperature was raised to 76 ° C. Chlorine gas 85. while maintaining the temperature at 74 to 78 ° C.
2 g (1.2 mol) was introduced over 2 hours, and after completion of chlorine introduction, the temperature was kept at the same temperature and aging was carried out for 1 hour. Then 50
The mixture was cooled to 0 ° C, 1000 g of water was added, further cooled to 10 ° C, and the precipitated crystals were filtered. The obtained crystals were dried under reduced pressure to give white crystals of 1-benzyl-
201.7 g of 5-ethoxyhydantoin (purity 99%,
A yield of 86.1%) was obtained.

Example 2 5.79 g of tetrabutylammonium chloride and 6.79 g of tetrabutylammonium hydrogensulfate
1-Benzyl-5-ethoxyhydantoin was produced in the same manner as in Example 1 except that (0.02 mol) was used. As a result, 158.5 g (purity 96.0%, yield 65.0%) of white crystals of 1-benzyl-5-ethoxyhydantoin were obtained.

Comparative Example 1-Benzyl-5 was prepared in the same manner as in Example 1 except that 5.56 g of tetrabutylammonium chloride was not used.
-Ethoxyhydantoin was prepared. As a result, white crystals of 1-benzyl-5-ethoxyhydantoin 1
70.2 g (purity 71.4%, yield 52.2%) was obtained.

[0027]

According to the method of the present invention, 5 of the general formula (3) is used without using bromine and iodine, which are highly toxic and corrosive, cause an ulcer on the skin, and have a low permissible concentration.
Since the alkoxyhydantoins can be produced in good yield, the method of the present invention is superior to the conventional method in terms of safety and the like, and the industrially very advantageous general formula (3)
It is a method for producing alkoxy hydantoins.

Claims (4)

[Claims] 1. A hydantoin represented by the following general formula (1) is represented by the general formula (2): ROH [wherein R represents an alkyl group or a cycloalkyl group. ] When producing a 5-alkoxyhydantoin represented by the following general formula (3) by reacting with an alcohol and chlorine represented by the formula, a phase transfer catalyst (however, a phase transfer catalyst containing a bromide ion or an iodide ion is excluded The method for producing 5-alkoxyhydantoins is characterized in that the reaction is carried out in the presence of General formula (1): [In the formula, R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group. ] Hydantoins shown by. General formula (3): [In the formula, R ¹ , R ² , R ³ and R are the same as above. ] The 5-alkoxy hydantoins shown by these. 2. The method of claim 1 wherein the phase transfer catalyst is a quaternary ammonium salt. 3. The quaternary ammonium salt is a quaternary ammonium salt represented by the following general formula (4).
Or the method described in 2. General formula (4): [Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and each represents an alkyl group or an optionally substituted aralkyl group,
Alternatively, R ⁴ , R ⁵ and R ⁶ together with the adjacent nitrogen atom represent a heterocyclic group. X ⁻ represents an anion (excluding bromide ion and iodide ion). ] The quaternary ammonium salt shown by these. 4. The method according to claim 1, 2 or 3, wherein the amount of the phase transfer catalyst used is 0.001 to 0.4 mol with respect to 1 mol of the hydantoins.