JPH0548227B2 - - Google Patents

Description

[Detailed Description of the Invention] A. Field of Industrial Application The present invention is based on the formula (1) (Here, R ₁ and R ₂ may be different or the same, and C _{1 to 4}
The present invention relates to a method for producing 5-alkylidenehydantoin represented by the following alkyl group. The above-mentioned 5-alkylidenehydantoin is attracting attention as a pharmaceutical product. α-ketocarboxylic acid,
It is an important intermediate for producing amino acids.

B. Prior Art Methods for obtaining 5-substituted hydantoins by condensing carbonyl compounds with hydantoins are known, but most of them involve reactions with aldehydes, and there are only a few examples of reactions with ketones. Furthermore, in these known methods, the reaction is carried out in an acetic acid solvent (J.Am.Chem.Soc., 45 , 369
(1911)) in anhydrous piperazine (Org.
Syn.Coll.Vol., 5 , 627), all of which use expensive organic solvents and are not industrially satisfactory.

C Means for solving the problems and effects of the invention The present invention is based on the formula (2) (Here, R ₁ and R ₂ may be different or the same,
Reacting a ketone represented by (representing a _C1-4 alkyl group) with hydantoin (2,4-imidazolidinedione) in the presence of an amino acid or a salt thereof in water or an aqueous solution in the pH range of 8 to 12. According to
The present invention provides a method for industrially producing 5-alkylidenehydantoin in free form. According to the present invention, 5-alkylidenehydantoin with good crystallinity can be obtained in a good yield within a relatively short reaction time in an aqueous solvent.

Specifically, the ketones that are raw materials of the present invention include acetone, methyl ethyl ketone, diethyl ketone,
These include methylpropylketone, methylisopropylketone, methylbutylketone, and methylisobutylketone.

Water is generally used as the reaction solvent in the present invention, but not only water but also a mixture of water and a water-soluble organic solvent such as methanol, ethanol, dioxane, etc. may be used as necessary. You can also do that.

Amino acids used include glutamic acid, aspartic acid, lysine, arginine, ornithine, glycine, α-alanine, leucine, isoleucine, valine, β-alanine, phenylalanine, tyrosine, dopa, phenylglycine, serine, threonine, and methionine. , taurine, etc., and their salts can be used alone or in combination. Salt forms include alkali metal salts such as sodium salts and potassium salts,
Alkaline earth metal salts such as calcium salts and mineral acid salts such as hydrochlorides and sulfates can be used. In addition, the amount used is 0.1 to 2 molar ratio to hydantoin,
Preferably, the molar ratio is 0.3 to 1. If it is used too little, the effect will be low, and even if it is used too much, the corresponding effect will not be obtained and it is not economical.

The pH during the reaction is preferably 8 to 12, preferably 9 to 10. Even if the amino acid is used in a neutral or acidic state, no effect is obtained, and it is necessary to adjust the pH of the reaction solution to the above-mentioned pH. Types of alkali used for pH preparation include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, and their carbonates, and alkaline earth metals such as magnesium hydroxide and calcium hydroxide. Metal hydroxides etc. can be used. When using acids for pH adjustment, mineral acids such as hydrochloric acid and sulfuric acid and organic acids such as formic acid and acetic acid can be used.

There are no strict restrictions on the reaction temperature and time, but it is usually 40-100°C, preferably 60-80°C.
°C for 1 to 10 hours, preferably 2 to 5 hours.

Since the reaction product 5-alkylidenehydantoin is sparingly soluble in water, it precipitates as crystals as the reaction progresses, so it can be removed by centrifugation or other methods.
It can be easily separated and recovered.

D. Examples The method of the present invention will be explained in more detail with reference to Examples below. However, these are merely examples for explanation, and the present invention is not limited to these examples in any way.

Example 1 A 500 ml separable flask equipped with a thermometer, reflux condenser, and stirrer was set in a constant temperature bath.

200ml of water, 50.0g of hydantoin (=0.50mol),
Acetone 58.0g (=1.00mol), glycine 37.5g
(=0.50mol), caustic soda 10.0g (=0.25mol)
was added, the temperature was raised, and the mixture was stirred at 60 to 65°C for 6 hours. During this time, the pH of the reaction solution was 9.8 to 9.6. After cooling to room temperature, the crystals were collected by centrifugation to obtain 64.5 g of 5-isopropylidenehydantoin. The yield was 92.1% based on hydantoin.

Example 2 In Example 1, 44.5g of alanine was substituted for glycine.
(=0.50mol) of acetone and methyl ethyl ketone
6 at 75-80℃ instead of 108.3g (=1.50mol)
Stir for hours. During this time, the pH of the reaction solution was 9.7 to 9.5. After cooling to room temperature, the crystals were collected by centrifugation to obtain 57.8 g of 5-secondary-butylidenehydantoin. The yield was 75% based on hydantoin.

Comparative Example 1 The same reaction as in Example 1 was carried out using 33.0 g of caustic soda. During this time, the pH of the reaction solution was 12.8.
It was ~12.0. After cooling, it was centrifuged to obtain 17.0 g of 5-isopropylidenehydantoin. The yield was 24.3% based on hydantoin.

Comparative Example 2 2.1g of caustic soda was used in Example 1, and the reaction was carried out in the same manner as in Example 1. During this time, the pH of the reaction solution was 7.5.
It was ~6.8. After cooling, it was centrifuged to obtain 7.5 g of 5-isopropylidenehydantoin. The yield was 10.7% based on hydantoin.

Claims (1)

[Claims] 1 formula (Here, R ₁ and R ₂ may be different or the same, and C _{1 to 4}
A formula characterized by reacting a ketone represented by (representing an alkyl group of A method for producing an alkylidenehydantoin represented by (wherein R ₁ and R ₂ are as described above).