JP2001247549A - Method of producing 1-position substituted hydantoins - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of producing a 1-position substituted hydantoin inexpensively, safely and in a high yield. SOLUTION: This method of producing a 1-position substituted hydantoin is characterized by reacting a 3-(substituted aminomethyl)-hydantoin with a dialkyl sulfuric ester in an organic solvent in the presence of a base and then hydrolyzing the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel process for producing 1-substituted hydantoins, which are important intermediates as pharmaceutical raw materials such as anticancer agents.

[0002]

2. Description of the Related Art Conventionally, a method for producing 1-substituted hydantoins,
For example, as a method for producing 1,5,5-trimethylhydantoin, 3- (morpholinomethyl) -5,5-
Dimethylhydantoin is reacted with methyl iodide in the presence of sodium hydride in dimethylformamide (DMF) solvent dried over molecular sieves, followed by hydrolysis under alkaline conditions and then neutralization, There is known a method of extracting with ether, concentrating the ether, and recrystallization from benzene / petroleum ether (Helv. Chim. Acta, 75 (1992), 1251). In this method, the desired product is obtained in a yield of 29.6 mol% based on the starting material 5,5-dimethylhydantoin.

However, the above method uses isolated 3- (substituted aminomethyl) hydantoin, uses water-inhibiting sodium hydride, has a low boiling point, is highly flammable, and forms peroxide upon recovery. The use of diethyl ether, which is easy to use, and DMF, which is a polar solvent, requires drying and the recovery rate is low. In addition, the yield of the target product is low as described above. This is a method that is difficult to employ industrially in terms of.

[0004] As another method, after reacting methylamine and acetone cyanohydrin, the product is reacted with potassium cyanate and then treated with hydrochloric acid (J. Prakt. Chem., (2) ) 113 (1926), 256)
However, the yield is also very low in this method, which is not a practical method.

[0005]

As described above, in any of the conventionally known methods for producing 1-substituted hydantoins, it is difficult to obtain the desired product in high yield, or in addition to this, it is difficult to handle. It is also a method in which an aqueous substance or the like is used.

An object of the present invention is to eliminate the drawbacks in the production of these conventionally known 1-substituted hydantoins, and to provide a method for obtaining the desired product inexpensively, safely and in good yield. Things.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above object, and have found that 3- (substituted aminomethyl) -hydantoins can be converted to dialkyl sulfates in an organic solvent in the presence of a base. It is very effective to employ a method of reacting with esters and then hydrolyzing,
As a result, 1-substituted hydantoins can be inexpensively, safely,
Moreover, they have found that they can be obtained in high yield, and have completed the present invention.

That is, the present invention relates to a compound represented by the following formula (1):

Embedded image (Wherein, R ¹ and R ² represent a hydrogen atom or a carbon atom having 1 to 1
0 unsubstituted or optionally substituted alkyl group,
And represents an aryl group, an alkylidene group or an arylidene group, which may be the same as or different from each other, or may be linked. R ³ and R ^{4 each} represent a hydrogen atom or an unsubstituted or substituted alkyl group or aryl group having 1 to 10 carbon atoms, which may be the same or different, or may be linked. ) Is reacted with a 3- (substituted aminomethyl) -hydantoin represented by the following formula (2) in the presence of a base:

Embedded image (Wherein, R ⁵ represents an unsubstituted or optionally substituted alkyl group having 1 to 10 carbon atoms). Formula (3)

Embedded image (Wherein R ^1, R ² and R ⁵ are the same as defined above). A method for producing a 1-substituted hydantoin represented by the following formula (4): Chemical formula 10]

Embedded image (Wherein, R ¹ and R ² are the same as defined above) and a hydantoin represented by the following formula (5):

Embedded image (Wherein, R ³ and R ⁴ are the same as defined above), and formaldehyde or paraformaldehyde are reacted to give the following formula (1):

Embedded image (Wherein, R ¹ and R ² , and R ³ and R ⁴ are the same as defined above).
Hydantoins are produced, and the reaction mixture is reacted with a dialkyl sulfate represented by the formula (2) in the presence of a base, and then hydrolyzed. A method for producing a position-substituted hydantoin, comprising the steps of: producing a 3- (substituted aminomethyl) -hydantoin represented by the formula (1), and subjecting the produced liquid to azeotropic dehydration. The method according to any one of the above, wherein the organic solvent is a halogen-based solvent, and the method according to any one of the above, wherein the base is an alkali metal hydroxide. The method according to any one of the above, wherein the hydrolysis is performed under acidic conditions, and the produced 1-substituted hydantoins are crystallized from a hydrocarbon solvent. Do The method according to any one of the above, wherein the 1-substituted hydantoin represented by the formula (3) is 1,5,
4. The method according to any one of the above items, wherein the method is 5-trimethylhydantoin.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, R ¹ and R in a 3- (substituted aminomethyl) -hydantoin represented by the formula (1) and a hydantoin represented by the formula (4) used as raw materials ² is a hydrogen atom or a carbon atom having 1 to 10
Represents an unsubstituted or substituted alkyl group, aryl group, alkylidene group or arylidene group, which may be the same or different, or may be linked. Examples of these unsubstituted or optionally substituted alkyl groups include a methyl group, an ethyl group,
n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, chloromethyl group, methoxymethyl group, cyclohexyl group, benzyl group, p-hydroxybenzyl group and the like, and R ¹ and R ² are Examples of the linked one include a pentamethylene group.

Examples of the unsubstituted or substituted aryl group include a phenyl group, a 4-chlorophenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group and a 4-hydroxy-3-methoxyphenyl group. Examples of the unsubstituted or optionally substituted alkylidene group include an iso-propylidene group and an ethylidene group.
Furthermore, examples of the unsubstituted or substituted arylidene group include a benzylidene group and a p-hydroxybenzylidene group.

The formula (1) used in the present invention
(Substituted aminomethyl) -hydantoins, and formula (5)
R ³ and R ⁴ in the amines represented by are a hydrogen atom or an unsubstituted or substituted alkyl group or aryl group having 1 to 10 carbon atoms, which may be the same or different, Also, they may be connected.

In the present invention, 3-
The reaction of the (substituted aminomethyl) -hydantoins with the dialkyl sulfates represented by the formula (2) is carried out in an organic solvent and in the presence of a base.

The type of the organic solvent is not particularly limited, but examples thereof include halogen solvents such as dichloromethane, 1,2-dichloroethane and dichlorobenzene, ether solvents such as diethyl ether, tetrahydrofuran and anisole, and acetic acid. Ester solvents such as ethyl and butyl acetate; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; alcohol solvents such as methanol, ethanol and isopropyl alcohol; N, N-dimethylformamide, N, N-dimethylacetamide , N, N-dimethylimidazolidinone, dimethylsulfoxide, and aprotic polar solvents such as N-methylpyrrolidone. Among these, halogen solvents such as dichloromethane, 1,2-dichloroethane, and dichlorobenzene dissolve the target 1-substituted hydantoins well and separate from water. When it is obtained, it is a preferably used solvent. These solvents are usually represented by the formula (1)
5 to 5 for 3- (substituted aminomethyl) -hydantoins
It is used in a range of 0 mass times.

The base used in the present invention is a hydroxide or carbonate of an alkali metal or an alkaline earth metal, or an oxide of an alkaline earth metal, preferably an alkali metal hydroxide. In the present invention, by using these, a safe and sufficient effect can be obtained. Examples of the alkali metal hydroxide include potassium hydroxide and sodium hydroxide, and examples of the alkali metal carbonate include potassium carbonate, sodium carbonate, and sodium hydrogen carbonate. The amount of the base to be used is generally 1 to 5 moles, preferably 1.5 to 2.5 moles, per 3- (substituted aminomethyl) -hydantoins represented by the formula (1).

In the present invention, the dialkyl sulfates represented by the formula (2) are those wherein R ⁵ is an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms;
Such alkyl groups include methyl, ethyl, n-
Examples include a propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a methoxymethyl group, a chloromethyl group, and a benzyl group. Specific examples include dimethyl sulfate and diethyl sulfate.

In the present invention, the amount of the dialkyl sulfate used is not particularly limited, and the hydantoins represented by the formula (4) or the 3- (3) represented by the formula (1) are used.
(Substituted aminomethyl) -hydantoins are usually 0.1%.
8 to 2 moles, more preferably 0.9 to 1.2 moles.
The range is twice as high.

In the present invention, the 1-position alkylation of 3- (substituted aminomethyl) hydantoins is carried out, for example, in a mixture of 3- (substituted aminomethyl) hydantoins and an organic solvent.
This can be performed by adding a base and a dialkyl sulfate, but is not limited thereto.
Also, the order of addition is not particularly limited,
Usually, it is carried out by a method of adding a dialkyl sulfate after adding a base.

The reaction between the above-mentioned 3- (substituted aminomethyl) hydantoins and dialkyl sulfates is usually 5 to 10
Carried out at a temperature of 0 ° C, more preferably 10-60 ° C
It is. The reaction time is not fixed depending on the temperature and other conditions, but is usually in the range of 10 minutes to 3 hours, and the aging time is at most about 3 hours at most.

In the present invention, the starting materials are not only starting from the 3- (substituted aminomethyl) -hydantoins represented by the formula (1), but also starting from the hydantoins represented by the formula (4), This is converted to a compound of the formula (5)
To form 3- (substituted aminomethyl) -hydantoins by reacting with amines represented by the formula (1) and formaldehyde or paraformaldehyde, and reacting the reaction solution with dialkyl sulfates in the presence of a base. be able to.

Here, specific examples of the hydantoins represented by the formula (4) include unsubstituted hydantoin, 5-methylhydantoin, 5- (n-propyl) hydantoin, 5- (iso-propyl) hydantoin, -(sec-butyl) hydantoin, 5
-(iso-butyl) hydantoin, 5-methoxymethylhydantoin, 5,5-dimethylhydantoin, 5-ethyl-5-methylhydantoin, 5- (iso-propyl) -5-methylhydantoin, 5-benzylhydantoin, 5, 5-pentamethylene hydantoin, 5- (p-hydroxybenzyl) hydantoin,
5-phenylhydantoin, 5- (4-hydroxy-3-methoxyphenyl) hydantoin, 5,5-diphenylhydantoin, 5- (iso-propylidene) hydantoin, 5-benzylidenehydantoin, and 5- (p-hydroxybenzylidene)
Hydantoin etc. are mentioned.

The amines represented by the formula (5) include ammonia, methylamine, ethylamine, n-propylamine, iso-propylamine, dimethylamine, diethylamine, di (n-propyl) amine, di (isopropyl) amine. -Propyl) amine, methylethylamine, aniline, diphenylamine and the like. Examples of the amine in which R ³ and R ⁴ are linked are morpholine, piperidine, piperazine,
Examples include pyrrolidine and pyrrole.

In the reaction for producing 3- (substituted aminomethyl) -hydantoins at this time, the amount of the amines represented by the formula (5) is based on the amount of the hydantoins represented by the formula (4) It is usually in the range of 0.5 to 2 moles, preferably 0.9 to 1.1 moles.

As formaldehyde or paraformaldehyde used for producing the 3- (substituted aminomethyl) -hydantoins represented by the formula (1), when formaldehyde is used, those having a wide concentration range are used. For example, a 37% aqueous formaldehyde solution may be used. When paraformaldehyde is used, its molecular weight and concentration are not particularly limited.
Examples include paraformaldehyde crystals. The amount of the formaldehyde or paraformaldehyde to be used is usually 0.5 to 1.5 times, preferably 0.9 to 1.5 times the hydantoin represented by the formula (4) as the number of moles of (CH ₂ O) units. It is in the range of 1.1 times mol.

In the present invention, the hydantoins represented by the formula (4) are reacted with formaldehyde or paraformaldehyde and the amines represented by the formula (5) in an organic solvent to give a compound represented by the formula (1). As for the conditions for producing 3- (substituted aminomethyl) -hydantoins, the reaction can be carried out at a relatively wide range of reaction temperature, usually at 5 to 80 ° C. The reaction time is not fixed depending on conditions such as temperature, but is usually in the range of 30 minutes to 5 hours. Also, there is no particular restriction on the order of addition of the above raw materials,
As an example, there is a method in which a hydantoin represented by the formula (4) and formaldehyde or paraformaldehyde are mixed in the above-mentioned organic solvent, and an amine represented by the formula (5) is added dropwise thereto.

In the present invention, a 3- (substituted amino acid represented by the formula (1) is reacted by reacting a hydantoin represented by the formula (4), an amine represented by the formula (5), and formaldehyde or paraformaldehyde. In the case of producing methyl) -hydantoins, a dialkyl sulfate represented by the formula (2) may be reacted with this product solution, but it is also a preferable embodiment that the product solution is once subjected to azeotropic dehydration. . That is, in the case of performing the azeotropic dehydration operation of the product liquid, it is possible to easily maintain the dispersion of the product liquid in a more suitable state, and furthermore, it is possible to obtain the desired 1-substituted hydantoins in higher yield. Become.

In the present invention, the conditions for the azeotropic dehydration are not particularly limited.
After heating to about 100 ° C. to condense the vaporized components and separate them into two layers, an organic layer and an aqueous layer, the aqueous layer can be removed from the system. In this case, the pressure is not particularly limited, and may be normal pressure or reduced pressure.

In the present invention, the 3-
The hydantoin compound obtained by reacting (substituted aminomethyl) -hydantoins with the dialkyl sulfates represented by the formula (2) is then hydrolyzed to remove the 3-substituted aminomethyl group, The desired 1-substituted hydantoins are produced. The hydrolysis is usually performed by reacting an acid or an alkali with the reaction solution. However, in the present invention, the elimination of the 3-substituted aminomethyl group at this time is easier and more complete, and the desired product is obtained in a better yield. It is more preferable to carry out.

Examples of the acid used for the hydrolysis include strong acids such as hydrochloric acid and sulfuric acid.
The concentration is not particularly limited, but is usually 50% by mass.
It is preferable to use the following aqueous solutions. The amount of the acid used is preferably equal to or more than that of the base used before the hydrolysis, and when the reaction solution separates into an organic layer and an aqueous layer after the addition of the acid, the water is used. The pH of the layer is preferably 5 or less. More preferably, the pH is adjusted to 2 or less in order to complete the hydrolysis.

The temperature at the time of the hydrolysis and the subsequent aging temperature are usually 5 to 100 ° C., more preferably 1 to 100 ° C.
0-80 ° C. The aging time is optional, but usually 1
Within hours is enough.

In the present invention, when the reaction solution after the hydrolysis is a single phase without being separated into two layers of an organic layer and an aqueous layer, the reaction solution is usually concentrated to dryness, A hydrocarbon-based solvent is added thereto, and the insolubles are separated by filtration. Thereafter, crystallization and filtration of the hydrocarbon-based solvent by concentration and cooling of the concentrated solution are performed to obtain the desired 1-substituted hydantoins. It is possible. In this case, examples of the hydrocarbon-based solvent for crystallization include toluene and xylene.

When the reaction solution after the hydrolysis is separated into two layers of an organic layer and an aqueous layer, the product is extracted with an organic solvent, and then the extraction solvent is mixed with the hydrocarbon-based solvent. After substituting with a solvent, crystallization, cooling and filtration are performed to obtain the desired product.

The organic solvent used in the above extraction operation includes:
A solvent that can be separated from the aqueous layer, for example, a halogen-based solvent such as 1,2-dichloroethane and dichloromethane, an ester-based solvent such as ethyl acetate and butyl acetate,
Examples thereof include ketone solvents such as methyl isobutyl ketone. It is preferable to use the same extraction solvent and reaction solvent.

Further, the above-mentioned extraction solvent and the reaction solvent may be concentrated to dryness, or the above-mentioned hydrocarbon may be added to the extracted organic layer before or during concentration. Any of a method of adding a system solvent and removing an extraction solvent having a low boiling point and a reaction solvent by distillation may be used.

[0034]

EXAMPLES The method for producing 1-substituted hydantoins in the present invention will be described in more detail with reference to Examples.
In the following,% is based on mass unless otherwise specified, and the component analysis value in each step is obtained from the result of measurement by HPLC.

Example 1 In a reactor having an internal volume of 1 liter, under a nitrogen atmosphere, 45.9 g (0.20 mol) of 3-morpholinomethyl-5,5-dimethylhydantoin having a purity of 99% and 1,2 were added. -Dichloroethane (461.3 g) was added and stirred. At 20 ° C, 86
28.7 g (0.44 mol) of granular potassium hydroxide was added, followed by 28.0 g (0.22 g) of 99% dimethyl sulfuric acid.
2 mol) was added dropwise at 20 ° C. over 2 hours. Aging was performed at the same temperature for 2 hours. Then, 10% hydrochloric acid 16
4.0 g (0.45 mol) was added, and the mixture was stirred at 50 ° C. for 1 hour. After liquid separation, the aqueous layer was extracted with 1,2-dichloroethane. The pH of the aqueous layer was about 0.5. In the 1,2-dichloroethane layer, 1,5,5-trimethylhydantoin was added to 3-morpholinomethyl-5,5-dimethylhydantoin in an amount of 72%.
It was present in a mole% yield. In the aqueous layer, 1,5,5-trimethylhydantoin was present in a yield of 23 mol% based on 3-morpholinomethyl-5,5-dimethylhydantoin. Therefore, the reaction yield of 1,5,5-trimethylhydantoin is 5,5
It was 95 mol% based on 5-dimethylhydantoin.
Thereafter, magnesium sulfate was added to the 1,2-dichloroethane layer, dried, filtered, and concentrated.
Toluene was added, and the remaining 1,2-dichloroethane was distilled off with toluene and completely removed. This toluene dispersion was cooled to 10 ° C., filtered and washed with toluene to obtain white crystals of 1,5,5-trimethylhydantoin. This was dried and 19.3 g of 1,5,5-trimethylhydantoin crystals were obtained.
(0.136 mol). The extraction yield is 5,5-
The amount was 68 mol% based on dimethylhydantoin, and the purity was 98.5%.

Example 2 25.9 g of 99% pure 5,5-dimethylhydantoin was introduced into a 1-liter reactor with a nitrogen atmosphere.
(0.20 mol), 92% paraformaldehyde 6.9
g (0.21 mol), and 1,2-dichloroethane 46
1.3 g was added and stirred. Here is 99% morpholine 1
8.5 g (0.21 mol) was added dropwise at 40 ° C. over 30 minutes. Stirring was performed at the same temperature for 2 hours. After cooling to 20 ° C., 28.7 g (0.44 mol) of 86% granular potassium hydroxide were added, followed by 28.0 g of 99% dimethyl sulfuric acid.
(0.22 mol) was added dropwise at 20 ° C. over 2 hours. Aging was performed at the same temperature for 2 hours. Thereafter, 164.0 g (0.45 mol) of 10% aqueous hydrochloric acid was added, and the mixture was stirred at 50 ° C. for 1 hour. After liquid separation, the aqueous layer was extracted with 1,2-dichloroethane. The pH of the aqueous layer was about 0.5. The 1,2-dichloroethane layer contains 1,5,5-trimethylhydantoin
It was present in a yield of 62 mol%, based on 5,5-dimethylhydantoin. The aqueous layer contained 1,5,5-trimethylhydantoin in an amount of 21 mol% based on 5,5-dimethylhydantoin.
In yield. Therefore, the reaction yield of 1,5,5-trimethylhydantoin is 8 to 5,5-dimethylhydantoin.
3 mol%. Thereafter, magnesium sulfate was added to the 1,2-dichloroethane layer, dried, filtered, and 1,2-dichloroethane was concentrated and removed to dryness. Toluene was added, and the toluene dispersion was cooled to 10 ° C., filtered and washed with toluene to obtain 1,5,5-trimethylhydantoin white crystals.
This was dried and 1,5,5-trimethylhydantoin crystal 1
7.4 g (0.120 mol) were obtained. The extraction yield is
It was 60 mol% based on the starting material 5,5-dimethylhydantoin, and the purity was 98.0%.

Example 3 25.9 g of 99% pure 5,5-dimethylhydantoin was placed in a 1-liter reactor with a nitrogen atmosphere.
(0.20 mol), 92% paraformaldehyde 6.9
g (0.21 mol), and 1,2-dichloroethane 46
1.3 g was added and stirred. Here is 99% morpholine 1
8.5 g (0.21 mol) was added dropwise at 40 ° C. over 30 minutes. Stirring was performed at the same temperature for 2 hours. Then 80
Water was removed by azeotropic dehydration at -87 ° C. After cooling to 20 ° C., 28.7 g (0.4%) of 86% granular potassium hydroxide
4 mol) was added, followed by 28.0% dimethyl sulfate 28.0.
g (0.22 mol) was added dropwise at 20 ° C. over 2 hours. Aging was performed at the same temperature for 2 hours. Thereafter, 164.0 g (0.45 mol) of 10% hydrochloric acid was added, and the mixture was stirred at 50 ° C. for 1 hour. After liquid separation, the aqueous layer was extracted with 1,2-dichloroethane. The pH of the aqueous layer was about 0.5. 1,5-Dichloroethane layer contains 1,5-, 5-trimethylhydantoin
It was present in a yield of 67 mol% based on dimethylhydantoin. In the aqueous layer, 1,5,5-trimethylhydantoin was present in a yield of 24 mol% based on 5,5-dimethylhydantoin. Therefore, the reaction yield of 1,5,5-trimethylhydantoin is 91% relative to 5,5-dimethylhydantoin.
Mole%. Thereafter, magnesium sulfate was added to the 1,2-dichloroethane layer, dried and filtered, and 1,2-dichloroethane was concentrated and removed. Toluene is added and remaining
1,2-Dichloroethane was distilled off together with toluene. This toluene dispersion was cooled to 10 ° C., filtered and washed with toluene to obtain white crystals of 1,5,5-trimethylhydantoin.
This was dried and 1,5,5-trimethylhydantoin crystal 1
8.7 g (0.129 mol) were obtained. The extraction yield is
It was 65 mol% with respect to the starting material 5,5-dimethylhydantoin, and the purity was 98.2%.

Example 4 25.9 g of 99% pure 5,5-dimethylhydantoin was placed in a 1-liter reactor under a nitrogen atmosphere.
(0.20 mol), 92% paraformaldehyde 6.9
g (0.21 mol), and 1,2-dichloroethane 46
1.3 g was added and stirred. To this, 9.56 g (0.21 mol) of 99% dimethylamine was added dropwise at 6 ° C. over 30 minutes. The mixture was stirred at the same temperature for 2 hours and at 40 ° C. for 2 hours. Thereafter, water was removed by azeotropic dehydration at 80 to 87 ° C. After cooling to 20 ° C., 28.7 g (0.44 mol) of 86% granular potassium hydroxide were added, followed by 28.0 g (0.22 mol) of 99% dimethyl sulfuric acid at 20 ° C. over 2 hours. It was dropped. Aging was performed at the same temperature for 2 hours. Thereafter, 164.0 g (0.45 mol) of 10% aqueous hydrochloric acid was added, and the mixture was stirred at 50 ° C. for 1 hour. After liquid separation, the aqueous layer was extracted with 1,2-dichloroethane. The pH of the aqueous layer is
It was about 0.5. 1,5-Dichloroethane layer contains 1,5,5-
Trimethylhydantoin was present in a yield of 73 mol% based on 5,5-dimethylhydantoin. Also, the water layer
1,5,5-Trimethylhydantoin was present in a yield of 18 mol% based on 5,5-dimethylhydantoin. Therefore,
The reaction yield of 1,5,5-trimethylhydantoin was 91 mol% based on 5,5-dimethylhydantoin. afterwards,
Magnesium sulfate was added to the 1,2-dichloroethane layer, dried, filtered, and 1,2-dichloroethane was concentrated and removed. Toluene was added, and the remaining 1,2-dichloroethane was distilled off together with the toluene. This toluene dispersion was cooled to 10 ° C., filtered and washed with toluene to obtain white crystals of 1,5,5-trimethylhydantoin. This was dried to obtain 20.2 g (0.140 mol) of 1,5,5-trimethylhydantoin crystals. The removal yield was 70 mol% based on the starting material 5,5-dimethylhydantoin, and the purity was 98.3%.

Example 5 38.0 g of 5-benzylhydantoin having a purity of 99% was placed in a 1-liter reactor in a nitrogen atmosphere.
(0.20 mol), 17.0 g of 37% formalin (0.
21 mol), and 461.3 g of dichloromethane. Here, 18.5 g of 99% morpholine (0.2
1 mol) was added dropwise at 40 ° C. over 30 minutes. Stirring was performed at the same temperature for 2 hours. Thereafter, water was removed by azeotropic dehydration at 41 to 42 ° C. After cooling to 20 ° C., 18.1 g (0.44 mol) of 97% granular sodium hydroxide were added, followed by 34.3 g (0.22 mol) of 99% diethyl sulfuric acid.
Mol) was added dropwise at 20 ° C. over 2 hours. Aging was performed at the same temperature for 2 hours. Thereafter, 10% hydrochloric acid 164.
0 g (0.45 mol) was added, and the mixture was stirred at 50 ° C. for 1 hour. After liquid separation, the aqueous layer was extracted with dichloromethane. The pH of the aqueous layer was about 0.5. In the dichloromethane layer, 1-ethyl-5-benzylhydantoin was present in a yield of 65 mol% with respect to 5-benzylhydantoin. In the aqueous layer, 1-ethyl-5-benzylhydantoin was present in a yield of 25 mol% with respect to 5-benzylhydantoin. Therefore, the reaction yield of 1-ethyl-5-benzylhydantoin was 90 mol% based on 5-benzylhydantoin.
Met. Thereafter, dichloromethane was concentrated and removed. Toluene was added, and the remaining dichloromethane was distilled off together with the toluene. This toluene dispersion was cooled to 10 ° C., filtered and washed with toluene to obtain white crystals of 1-ethyl-5-benzylhydantoin. This is dried and 1-ethyl
26.7 g of crystals of -5-benzylhydantoin (0.12
0 mol). The removal yield was 60 mol% based on the starting material 5,5-dimethylhydantoin, and the purity was 98.1.
%Met.

Example 6 20.2 g (0.20 mol) of 99% pure hydantoin and 6.9 g (0.21 mol) of 92% paraformaldehyde were placed in a 1-liter reactor in a nitrogen atmosphere.
Mol), and N, N-dimethylimidazolidinone 260.
0 g was added and stirred. Here, 99% morpholine 18.5
g (0.21 mol) was added dropwise at 40 ° C. over 30 minutes. Stirring was performed at the same temperature for 2 hours. After cooling to 20 ° C,
86% granular potassium hydroxide 28.7 g (0.44 mol)
Was added, followed by 28.0 g of 99% dimethyl sulfate (0.
22 mol) was added dropwise at 20 ° C. over 2 hours. Aging was performed at the same temperature for 2 hours. Then, 10% hydrochloric acid 18
2.2 g (0.50 mol) was added, and the mixture was stirred at 50 ° C. for 1 hour. The pH of the solution was about 1. The reaction yield was 80 mol% with respect to the starting material hydantoin. The N, N-dimethylimidazolidinone was concentrated under reduced pressure, and after drying, toluene was added, the dissolved and insoluble components were separated by filtration, the dissolved toluene layer was concentrated, and then cooled to 10 ° C.
Filtration and toluene washing. The filter cake was dried, and 14.1 g (0.120 mol) of white crystals of 1-methylhydantoin were obtained.
I got The removal yield was 60 mol% with respect to the starting material 5,5-dimethylhydantoin, and the purity was 97.0%.

Comparative Example 1 3-morpholinomethyl-5,5-dimethylhydantoin
3 g (0.05 mol) and 70 ml of dried DMF were mixed. There 60% sodium hydride (including paraffin)
2.2 g were added, followed by methyl iodide. 15 at room temperature
After stirring for an hour, 100 ml of 3N-NaOH was added to carry out hydrolysis. After neutralization with concentrated hydrochloric acid, extraction was performed with diethyl ether. After concentrating the solvent, it was crystallized from a mixed solvent of benzene and petroleum ether to give 1,5,5-trimethylhydantoin in 2.1.
g, 3-morpholinomethyl-5,5-dimethylhydantoin was obtained at a yield of 29.6 mol%.

[0042]

As described above, according to the present invention, the desired 1-substituted hydantoins can be obtained with high purity and high yield without using any water-inhibiting sodium hydride or the like. It can be manufactured with a safer and simplified process.

Further, according to the present invention, from the hydantoins
By producing 3- (substituted aminomethyl) -hydantoins and using this reaction solution without isolation, it is possible to produce the desired 1-substituted hydantoins in a single pot. Is also a very useful method.

Claims (8)

[Claims] In an organic solvent, a compound represented by the following formula (1): (Wherein, R ¹ and R ² represent a hydrogen atom or a carbon atom having 1 to 1
0 unsubstituted or optionally substituted alkyl group,
And represents an aryl group, an alkylidene group or an arylidene group, which may be the same as or different from each other, or may be linked. R ³ and R ^{4 each} represent a hydrogen atom or an unsubstituted or substituted alkyl group or aryl group having 1 to 10 carbon atoms, which may be the same or different, or may be linked. The 3- (substituted aminomethyl) -hydantoins represented by the following formula (2) are reacted in the presence of a base with the following formula (2): (Wherein, R ⁵ represents an unsubstituted or optionally substituted alkyl group having 1 to 10 carbon atoms). Formula (3) [Formula 3] (Wherein R ^1, R ² and R ⁵ are the same as defined above). 2. In an organic solvent, a compound represented by the following formula (4): (Wherein R ¹ and R ² are the same as defined above), and the following formula (5): (Wherein R ³ and R ⁴ are the same as defined above), and formaldehyde or paraformaldehyde are reacted with each other to form a compound represented by the following formula (1): (Wherein, R ¹ and R ² , and R ³ and R ⁴ are the same as defined above).
Hydantoins are produced, and the reaction mixture is reacted with a dialkyl sulfate represented by the formula (2) in the presence of a base, and then hydrolyzed. Method for producing position-substituted hydantoins. 3. The method according to claim 2, wherein after producing the 3- (substituted aminomethyl) -hydantoins represented by the formula (1), the produced liquid is subjected to azeotropic dehydration. 4. The method according to claim 1, wherein the organic solvent is a halogen-based solvent. 5. The production method according to claim 1, wherein the base is an alkali metal hydroxide. 6. The method according to claim 1, wherein the hydrolysis is carried out under acidic conditions.
5. The production method according to any one of 5. 7. The produced 1-substituted hydantoins are crystallized from a hydrocarbon-based solvent.
7. The method according to any one of items 1 to 6, above. 8. The production method according to claim 1, wherein the 1-substituted hydantoin represented by the formula (3) is 1,5,5-trimethylhydantoin.