WO2003033473A1

WO2003033473A1 - Novel 5-substituted hydantoin derivative and process for producing the same

Info

Publication number: WO2003033473A1
Application number: PCT/JP2002/010514
Authority: WO
Inventors: Kazuhiko Watabe; Nobuo Nagashima
Original assignee: Kaneka Corporation
Priority date: 2001-10-10
Filing date: 2002-10-10
Publication date: 2003-04-24
Also published as: JP2005104835A

Abstract

A process for producing a hydantoin derivative having a substituted propargyl group in the 5-position from an easily available 5-alkoxycarbonylhydantoin, etc. through a simple procedure; and a 5-substituted hydantoin derivative having a substituted propargyl group in the 5-position, which is an intermediate for an amino acid derivative. The process comprises introducing a substituted propargyl group into a 5-alkoxycarbonylhydantoin produced from an N-carbamoylaminomalonic diester derivative and a base, or comprises the substituted-propargyl introduction, followed by deesterification and decarboxylation. Thus, a 5-substituted hydantoin derivative having a substituted propargyl group in the 5-position can be efficiently produced.

Description

Specification

Novel 5-substituted hydantoin derivatives and production method thereof

The present invention relates to a 5-substituted hydantoin derivative, which is a synthetic intermediate of an amino acid derivative useful as an intermediate for pharmaceuticals and agricultural chemicals, a bioactive substance, etc., that is, a novel compound having a substituted propargyl group at the 5-position. The present invention relates to a 5-substituted hydantoin derivative and a method for producing the same. Background art

There are several known hydantoin derivatives substituted at the 5-position, which are intermediates in the synthesis of amino acid derivatives useful as intermediates for pharmaceuticals and agricultural chemicals and biologically active substances, and their production methods.

(-) The product obtained by reacting sodium salt of 5-ethoxycarbolhydantoin with 11-chloro-5- (chloromethinole) -12-methyl-14-to-n-benzene is treated with hydrochloric acid to give 5-position 5 A method for producing hydantoin substituted with a glolow 4-methyl-l2--to-benzyl group (J. Med. Chem., 34, 2906, (1991)).

(Ii) A method for producing 5:-! Aralkylhydantoin by condensing arylaldehyde and hydantoin to give 5-aralkylidenehydantoin (Am. Chem. J , 45, 368, (1 9 1 1)).

(3) A method of producing a 5-substituted hydantoin derivative by acid-treating a labamoyl-1-amino acid synthesized from an α-amino acid and a cyanic acid rim.

However, the method (1) described above includes 5-ethoxycarbonylhydantoin in which the 5-position is substituted with 5-chloro-4-methyl-12-nitrobenzyl group and hydantoin in which the 5-position is substituted with the substituent. Only the production method was reported, but no production method for other 5-substituted hydantoin derivatives was reported.

In the method (2), hydroiodic acid and red phosphorus are used in the reduction step. Since the reaction is a heating reaction under an acid 1 "raw condition, a side reaction at the triple bond portion becomes a problem when trying to be applied to the compound of the present invention having a triple bond. Although a production method in which the reduction step is carried out by catalytic reduction is known (Japanese Patent Application Laid-Open No. 5-255273), in the compound of the present invention having a triple bond, the triple bond is also easily reduced. Therefore, it cannot be applied to this compound.

Since the method (3) is generally a method for producing a 5-monosubstituted hydantoin derivative using an amino acid as a target compound as a starting material, it is not industrially valuable except in special cases.

As described above, each method has a problem to be solved as a method for producing a 5-substituted hydantoin derivative having a substituted propargyl group at the 5-position, and development of a simple production method has been desired. Summary of the Invention

In view of the above, the inventors of the present invention carried out substituted propargylation using a readily available 5-alkoxycarbonylhydantoin or the like as a raw material, and further performed deesterification and decarboxylation sequentially, thereby improving the efficiency. It has been found that a 5-substituted hydantoin derivative having a substituted propargyl group at the 5-position can be produced well.

That is, the present invention provides a compound represented by the general formula (1):

(Wherein, R ¹ is a cyclic or non-cyclic aralkyl group having 1 to 10 carbon atoms which may have a substituent, an aralkyl group having 7 to 10 carbon atoms which may have a substituent, or Represents an aryl group having 6 to 10 carbon atoms which may have a substituent (s). The cyclization of an N-potassium rubamoylaminomalonic acid diester derivative represented by the general formula (2)

(Wherein, R ¹ has the same meaning as described above.) Or an anion thereof, followed by the general formula (3)

X (3)

(Wherein, R ² is a hydrogen atom, a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, or an aralkyl group having 7 to 10 carbon atoms which may have a substituent. And X represents a leaving group.) A general formula (4) characterized by reacting with an alkyne derivative represented by the following formula:

(Wherein, R ¹ and R ² have the same meanings as described above.) A method for producing a 5-substituted hydantoin derivative represented by the formula:

Further, the present invention provides a compound represented by the following general formula (2):

(Wherein, R ¹ is a cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, an aralkyl group having 7 to 10 carbon atoms which may have a substituent, or Represents an aryl group having 6 to 10 carbon atoms which may have a substituent. General formula (3)

FT ヽ

(3)

(Wherein, R ² is a hydrogen atom, a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, or an aralkyl group having 7 to 10 carbon atoms which may have a substituent. And X represents a leaving group.) A general formula (4) characterized by reacting with an alkyne derivative represented by the formula) in the presence of a base.

Further, the present invention provides a compound represented by the following general formula (4):

(Wherein, R ¹ is a cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, an aralkyl group having 7 to 10 carbon atoms which may have a substituent, or Represents a aryl group having 6 to 10 carbon atoms which may have a substituent, and R ² represents a hydrogen atom, a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, or Represents an aralkyl group having 7 to 10 carbon atoms which may have a substituent.) A compound represented by the general formula (5), which is obtained by deesterification and then decarboxylation.

(Wherein, R ² has the same meaning as described above.) A method for producing a 5-substituted hydantoin derivative represented by the formula:

Furthermore, the present inventors have confirmed the usefulness of the 5-substituted hydantoin derivative represented by the general formula (4) and the 5-substituted hydantoin derivative represented by the general formula (5) in the production of α-substituted propargydarricin derivatives. The present invention relates to a compound represented by the general formula (4)

(Wherein, R ¹ is a cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, an aralkyl group having 7 to 10 carbon atoms which may have a substituent, or Represents a aryl group having 6 to 10 carbon atoms which may have a substituent; R ² represents a hydrogen atom; a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent; Or a aralkyl group having 7 to 10 carbon atoms, which may have a substituent. 5) -substituted hydantoin derivative represented by the following general formula (5):

(Wherein, R ² is a hydrogen atom, a cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, or a carbon atom having 7 to 10 carbon atoms which may have a substituent. Aral Kill Represents a group. ) A 5-substituted hydantoin derivative represented by Detailed Disclosure of the Invention

Hereinafter, the present invention will be described in detail.

The N-potassium rubamoylaminomalonic acid diester derivative represented by the general formula (1), which is a starting material of the present invention, can be easily obtained by, for example, reacting a cyanomatous acid rim with an aminomalonic acid diester. (See, for example, J. Am. Chem. Soc., Vol. 36, p. 345, (1991)). In the formula, R ¹ is a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, an aralkyl group having 7 to 10 carbon atoms which may have a substituent, or And represents an aryl group having 6 to 10 carbon atoms which may have a group.

The cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cycloalkyl group. Propyl, n-butyl, isobutyl, t-butyl, cycloptinole, n-pentynole, cyclopentyl, n-hexyl, cyclohexyl, n-octyl, n-decyl, etc. And preferably a methyl group or an ethyl group.

The aralkyl group having 7 to 10 carbon atoms which may have a substituent is not particularly limited, and examples thereof include a benzyl group, a p-hydroxybenzyl group, a p-methoxybenzyl group, and a p-alkyl group. Examples thereof include a dibenzobenole group, an o-hydroxybenzyl group, an o-methoxybenzyl group, an o-nitrobenzyl group, an 11-phenethyl group, and a 2-phenethyl group, and preferably a p-methyl group. It is a toxic benzyl group.

The aryl group having 6 to 10 carbon atoms which may have a substituent is not particularly limited, and examples thereof include phenyl, p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, and naphthyl. And a phenyl group.

In the present specification, the term “substituent” is not particularly limited as long as it does not adversely affect the reaction. Specifically, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, and a 6 alkoxy groups, C1-6 alkylthio groups, halogeno groups, nitro Groups, amino groups, cyano groups, carboxyl groups and the like. These may be in the form protected by known means, if necessary.

The above R ¹ is preferably a methyl group or an ethyl group.

In the first aspect of the present invention, the N-potassium rubamoylaminomalonic acid diester derivative represented by the above general formula (1) is cyclized in the presence of a base, and the compound represented by the general formula (2) or a compound thereof Ayuon is formed and subsequently reacted with an alkyne derivative represented by the general formula (3) to produce a 5-substituted hydantoin derivative represented by the general formula (4). First, the substituent in each compound will be described.

In the compound represented by the general formula (1), R ¹ is as described above, and in the compound represented by the general formula (2), R ¹ is the compound represented by the general formula (1) Since it is derived from R ¹ and does not change under the reaction conditions in the production process of the compound represented by the general formula (2), it is the same as described above. In the alkyne derivative represented by the general formula (3), R ² represents a hydrogen atom, a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, or a substituent. And represents an aralkyl group having 7 to 10 carbon atoms.

The cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropylinole group, and a cyclopropyl group. Group, n-butyl group, isobutyl group, t-butyl group, cyclobutyl group, n-pentyl group, cyclopentyl group, n-hexyl group, cyclohexyl group, n-octyl group, n-decyl group, etc. And preferably a methyl group or an ethyl group.

The aralkyl group having 7 to 10 carbon atoms which may have a substituent is not particularly limited. Examples thereof include a benzyl group, a ρ-hydroxybenzyl group, a ρ-methoxybenzino group, and a p-nitro group. Benzinole group, o-hydroxybenzinole group, o-methoxybenzyl group, o-nitrobenzinole group, 11-phenethyl group, 2-phenethyl group, etc., and preferably p- It is a methoxybenzyl group.

Preferred among the above-mentioned R ² groups are a hydrogen atom and a methyl group.

In the alkyne derivative represented by the general formula (3), X represents a leaving group, a halogen atom such as chlorine, bromine, and iodine; and an acetoxy group and a benzoyloxy group. Siloxy group; methanesulfoeroxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, benzenesulfonyloxy group, p-toluenesnorenolinoleoxy group; Substituted snolephonyloxy groups such as a oxy group and a p-ethoxybenzenesnolephonyloxy group; and substituted phosphoryloxy groups such as a dipheninolephosphoryloxy group. Preferable are a halogen atom and a substituted sulfoxy group, and more preferred is a methanesulfoninoleoxy group.

The 5-substituted hydantoin derivative represented by the general formula (4) is a novel compound whose usefulness in the production of α-substituted propargyldaricin derivatives has been confirmed by the present inventors. RR ² in the compound (4) is derived from RR ² in the compounds represented by the general formulas (1) and (3), and does not change under the reaction conditions in the production process of the compound (4) Therefore, it is as already explained above.

Next, each step of producing the compound represented by the general formula (4) from the compound represented by the general formula (1) will be described.

The compound represented by the general formula (1) is cyclized in the presence of a base, and is converted into the compound represented by the general formula (2) or its cation.

Examples of the base used in this reaction include organic lithium compounds such as methyllithium, n-butyllithium, t-butyllithium, and phenyllithium; 11-butynolemagnesium chloride, methinoremagnesium Grignard compounds such as promid; lithium amide, sodium amide, lithium diisopropyl amide, magnesium diisopropyl amide, lithium hexamethyl disilazide, sodium hexamethyl disilazide, potassium hexamethyl disilazide Alkali metal amide or alkaline earth metal amide; sodium methoxide, sodium methoxide, sodium-t-butoxide, lithium methoxide, lithium ethoxide, lithium-t-butoxide, potassium-t-butoxide, etc. Alkali metal hydride or alkaline earth metal hydride such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide Metal hydroxide such as magnesium hydroxide, calcium hydroxide, etc. Alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; triethylamine, diisopropylethylamine, DBU ( Organic tertiary amines such as 1,8-diazabicyclo [5,4,0] indene) can be mentioned. Among the above bases, alkali metal alkoxides, alkali metal hydrides, and alkaline earth metal hydrides are preferably used, and alkali metal alkoxides are particularly preferable.

The amount of the base used varies depending on the type of the base used, the type of the solvent and the reaction conditions, but is 1 to 3 times, preferably 1 to 2 times the molar amount of the compound represented by the general formula (1). The amount is doubled.

A solvent is usually used for the reaction, and examples of the reaction solvent include dichloromethane, chlorophonolem, dichloroethane, benzene, tonolene, getinoleatenole, methinolate t-petinoleatenole, tetrahydrofuran, and 1,4-hydrofuran. Dioxane, N,

N-dimethylfosolemamide, N-methylpyrrolidone, 1,3-dimethylimidazolidinone, dimethylsulfoxide, acetone, acetonitrile, ethyl acetate, mono-t-butynole acetate, t-butanol, s-butanol, isobutanol, n- Examples include butanol, isopropanol, n-propanol, ethanol, and methanol. The above solvents may be used alone or as a mixture. In this case, the mixing ratio is not particularly limited. Among the above solvents, preferred are alcohols, and particularly preferred is t-butanol.

The substrate concentration in the reaction is usually 20 w as the concentration of compound (1) in the solvent.

/ v% or less, but preferably 1 Ow / vo / o or less.

The reaction temperature can be selected from the range of 130 ° C. to the boiling point of the solvent used, and is preferably in the range of 0 ° C. to 100 ° C. The reaction time is usually from 30 minutes to 48 hours.

After completion of the reaction, the solvent is distilled off, if necessary, and then added to water, or after adding water, extracted with an organic solvent such as tonnolene, ethyl acetate, jeti / leiethenole, dichloromethane, or closphophore, and then extracted with water. Compound (2) can be obtained through operations such as washing and concentration. The obtained compound is analyzed by column chromatography and crystallization. Separation and purification, or may be used as is in the next step.

When an organic lithium compound, a Grignard compound, an alkali metal amide or an alkaline earth metal amide, an alkali metal alkoxide, an alkali metal hydride or an alkaline earth metal hydride is used as the base, the general formula (2) ) Can be isolated as the metal salt, and can be isolated and isolated (for example, J. Org. Chem., 29, 2003, (1964) The compound may be reacted with the compound represented by the general formula (3), or may be successively reacted with the compound represented by the general formula (3) without isolation.

The compound represented by the general formula (2) or its anion produced as described above is then reacted with an alkyne derivative represented by the general formula (3) to obtain a compound represented by the general formula (4). Is converted to a 5-substituted hydantoin derivative.

When the anion of the compound represented by the general formula (2) is isolated and reacted with the compound represented by the general formula (3), as a reaction solvent, for example, dichloromethane, chloroform honolem, dichloroethane, benzene, tonolene , Getinoleatenole, methinolate t-petinoleetegre, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone, 1,3-dimethylimidazolidinone, dimethyls / reoxide, a Setone, acetonitril, ethinole acetate, monobutyl acetate, t-butanol, s-butanoole, isobutanol, n-butanol, isopropanol, _n -propanol, ethanol, Methanol and the like can be mentioned. The above solvents may be used alone or as a mixture, and in this case, the mixing ratio is not particularly limited. Among the above solvents, preferred are alcohols and tetrahydrofuran, and particularly preferred is t-butanol.

When the anion of the compound represented by the general formula (2) is subsequently reacted with the compound represented by the general formula (3) without isolation, the reaction solvent is the same as the solvent used in the cyclization reaction described above. May be used as it is, or the reaction may be carried out with another solvent. Examples of the reaction solvent used in this case include dichloromethane, chloroform, dichloroethane, benzene, tonolene, getinoleatenole, methinoleone-t-butinoleatenoline, tetrahydrofuran, 1,4-dioxane, and N, N-dimethyl. Formamide, N-methinolepyrrolidone, 1,3-Dimethimidazolidinone, Dimethinoresnoreth Examples include foxide, acetone, acetonitrile, ethyl acetate, mono-t-butyl acetate, t-butanol, s-butanol, isobutanol, n-butanol, isopropanol, n-propanol, ethanol, and methanol. The above solvents may be used alone or as a mixture. In this case, the mixing ratio is not particularly limited. Among the above solvents, preferred are alcohols, and particularly preferred is t-butanol.

Alternatively, when the compound represented by the general formula (2) is reacted with the compound represented by the general formula (3), the reaction is performed in the presence of a new base. Examples of the base used in this case include, for example, organic lithium compounds such as methyllithium, n-butyllithium, t-butyllithium, and phenyllithium; grual compounds such as n-butylmagnesium chloride and methylmagnesium bromide; Metal amides such as lithium amide, sodium amide, lithium diisopropyl amide, magnesium diisopropyl amide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc. Alkaline earth metal amides; Alkali such as sodium methoxide, sodium methoxide, sodium-butoxide, lithium methoxide, lithium ethoxide, lithium-t-butoxide, potassium-t-butoxide Limetal alkoxides; lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc .; metal hydrides or lithium hydrides; lithium hydroxide, sodium hydroxide, potassium hydroxide Alkali metal hydroxides or alkaline earth metal hydroxides such as cesium hydroxide, magnesium hydroxide, calcium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; triethylamine, diisopropyl Organic tertiary amines such as ethylamine and DBU (1,8-diazabicyclo [5,4,0] indene). Among the above bases, alkali metal alkoxides, alkali metal hydrides, and alkaline earth metal hydrides are preferably used, and alkali metal alkoxides are particularly preferable.

The amount of the base used varies depending on the type of base used, the type of solvent and the reaction conditions, but it is preferably 1 to 3 times, preferably 1 to 3 times the molar amount of the compound represented by the general formula (2). ~ 2 times the molar amount.

In addition, a solvent is usually used for the reaction. Examples of the reaction solvent include dichloromethane, chlorophonorem, dichloroethane, benzene, tonolene, ethinoleatenole, methyl-t-butyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methinolepyrrolidone, 1,3-dimethylimidazolidinone, dimethylsulfoxide, acetone, acetonitrile, ethyl acetate, t-peptinole acetate, t-ptananol, s-butanol, iso Butanol, n-butanol, isopropanol, n-propanol, ethanol, methanol and the like. The above solvents may be used alone or as a mixture. In this case, the mixing ratio is not particularly limited. Among the above solvents, preferred are alcohols and tetrahydrofuran, and particularly preferred is t-butanol. Regardless of whether the compound represented by the general formula (2) or an anion thereof is used, the amount of the alkyne derivative represented by the general formula (3) may vary depending on the type of the alkyne derivative, the type of the solvent, and the amount of the reaction. Although it depends on the conditions, it is 0.5 to 3 moles, preferably 0.7 to 2 moles per mol of the compound represented by the general formula (2). The concentration of the toxin in the reaction is usually 20 wZv% or less, preferably 10 wZv% or less, as the concentration of the compound (2) with respect to the solvent.

The reaction temperature can be selected from the range of 30 ° C. to the boiling point of the solvent used, and is preferably in the range of 0 ° C. to 100 ° C. The reaction time is usually from 30 minutes to 48 hours.

After completion of the reaction, the solvent is distilled off, if necessary, and then added to water or, after adding water, extracted with an organic solvent such as tonnolene, ethinole diacid, detinoleate / dichloromethane, dichloromethane, and chloroform. Compound (4) can be obtained through operations such as washing and concentration. The obtained compound may be separated and purified by column chromatography and crystallization, or may be used as it is in the next step.

Next, a second embodiment of the present invention will be described. In this embodiment, a compound represented by the general formula (2) is reacted with an alkyne derivative represented by the general formula (3) in the presence of a base to form a 5-substituted hydantoin derivative represented by the general formula (4). To manufacture.

In the compound represented by the general formula (2) or the general formula (4), R represented by the general formula (3) or Represented X in compounds by formula (4) R ² in the compound represented by, and the general formula (3) are the same as those described in the section of the first aspect, the R ¹ group Preferred are a methyl group and an ethyl group, and preferred as the R ² group are a hydrogen atom and a methyl group. Preferred as the leaving group X is a halogen atom or a substituted sulfonyloxy group, and more preferred is a methanesulfonyloxy group. The reaction is carried out in the presence of a base. Examples of the base used include organic lithium compounds such as methyllithium, n-butyllithium, t-butylinolelithium, and fuel lithium; n-butylmagnesium chloride And daliary compounds such as methylmagnesium bromide; lithium salts such as lithium amide, sodium amide, lithium diisopropylamide, magnesium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide. Metal amide or earth metal amide; sodium methoxide, sodium ethoxide, sodium methoxide, lithium methoxide, lithium ethoxide, lithium-t-butoxide, potassium-t- Alkali metal alkoxides such as toxides; alkali metal hydrides or alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; lithium hydroxide, sodium hydroxide, water Alkali metal hydroxides or alkaline earth metal hydroxides such as lithium oxide, cesium hydroxide, magnesium hydroxide and calcium hydroxide; lithium metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; triethylamine; Organic tertiary amines such as disopropylethylamine and DBU (1,8-diazabicyclo [5,4,0] indene) can be mentioned. Among the above bases, alkali metal alkoxides, alkali metal hydrides and alkaline earth metal hydrides are preferably used, and alkali metal alkoxides are particularly preferable.

The amount of the base used depends on the type of base used, the type of solvent, and the reaction conditions, but it is 1 to 3 times the molar amount of the compound represented by the general formula (2), preferably 1 to 2 times. It is twice the molar amount.

The amount of the alkyne derivative represented by the general formula (3) varies depending on the type of the alkyne derivative, the type of the solvent, and the reaction conditions. The amount is 0.5 to 3 moles, preferably 0.7 to 2 moles per mole of the compound. A solvent is usually used for the reaction, and examples of the reaction solvent include dichloromethane, chloroform, dichloroethane, benzene, tonolene, gethylethene, methyl t-butyl ether, tetrahydrofuran, and 1,4-dioxane , N, N-dimethylformamide, N-methylpyrrolidone, 1,3-dimethylimidazolidinone, dimethylsulfoxide, acetone, acetonitrile, ethyl acetate, mono-t-butynole, t-butanol, s-butanol, Isobutanol, n-butanol, isopropanol, _n -propanol, ethanol, methanol, etc. The above-mentioned solvents may be used alone or in combination. There is no particular limitation on the mixing ratio. And tert-butanol, and the substrate concentration in the reaction is usually 20 wZv% or less as the concentration of the compound (2) relative to the solvent, but is preferably 10 wZ v ° / o or less.

After completion of the reaction, the solvent is distilled off, if necessary, and then added to water, or after adding water, extracted with an organic solvent such as toluene, ethyl acetate, getyl ether, dichloromethane, and chloroform. Compound (4) can be obtained through operations such as washing and concentration. The obtained compound may be separated and purified by column chromatography and crystallization, or may be used as it is in the next step.

Next, a third embodiment of the present invention will be described. In this embodiment, the 5-substituted hydantoin derivative represented by the general formula (4) is de-esterified and subsequently decarboxylated to produce the 5-substituted hydantoin derivative represented by the general formula (5). .

In the general formula (4), R ¹ is a cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, or a C 7 to 10 carbon atom which may have a substituent. Represents an arylalkyl group or an aryl group having 6 to 10 carbon atoms which may have a substituent, and R ² represents a hydrogen atom, a cyclic or non-cyclic group having 1 to 10 carbon atoms which may have a substituent. A cyclic alkyl group or an aralkyl group having 7 to 10 carbon atoms which may have a substituent; As described in detail in the section of the first embodiment of the present invention. Preferred as the R ¹ group is a methyl group or an ethyl group, and preferred as the R ² group is a hydrogen atom or a methyl group.

The 5-substituted hydantoin derivative represented by the general formula (5) is a novel compound that has been confirmed by the present inventors to be useful in the production of a monosubstituted propargylglycine derivative. In the formula, R ² is the same as defined in the general formula (4) because it does not change under the reaction conditions in the production process of the compound (5).

The reaction conditions for deesterifying compound (4) are not particularly limited, and the reaction can be performed under general deesterification conditions. Examples of the deesterification method include a method of removing an aryl ester by the action of a nucleophile such as carboxylic acid or morpholine in the presence of a palladium catalyst; 2,2,2-trichloroethyl ester in acetic acid and zinc in acetic acid. A method of reducing by use of 2-trimethylsilylethyl ester with hydrogen fluoride / tetrabutylammonium fluoride to remove the ρ-methoxybenzyl ester from DDQ (2 Oxidative removal using 1,5-dichloro-1,5-dicyanobenzoquinone) or CAN (cerium (IV) ammonium nitrate); removal of benzyl ester and t-butyl ester using oodotrimethylsilane Method for removing t-butyl ester using TFA (trifluoroacetic acid); esterification by acid or alkali hydrolysis It can be exemplified a method of removing the base. The method of removing an ester group by acid or alkali hydrolysis is preferable, and the method of removing the ester group by alkali hydrolysis is more preferable because it is inexpensive and can be applied to most kinds of ester groups.

Alkali metal used for alkaline hydrolysis includes metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide, magnesium hydroxide, calcium hydroxide, and the like. Examples thereof include alkaline earth metal hydroxides such as barium hydroxide and lithium metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate. Preferably, it is an alkali metal hydroxide, and more preferably, sodium hydroxide.

Acids used for acid hydrolysis include hydrochloric acid, sulfuric acid, nitric acid, and sulfuric acid. And inorganic acids such as perchloric acid and perchloric acid.

Examples of the reaction solvent for the deesterification include tetrahydrofuran, 1,4-dioxane, getyl ether, methyl-t-butyl ether, tonolen, benzene, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, Examples include dichloromethane, chlorohonolem, acetone, acetone, butanol, propanol, ethanol, methanol, and water. The above solvents may be used alone or as a mixture, and in this case, the mixing ratio is not particularly limited. Among the above solvents, preferred are tetrahydrofuran, ethanol, methanol and water.

The substrate concentration in the reaction is usually not more than 20 wZv%, preferably not more than 10 w / v ° / o, as the concentration of the compound (4) in the solvent.

The reaction temperature can be selected from the range of from 130 ° C. to the boiling point of the solvent used, and is preferably from 0 ° C. to 40 ° C. The reaction time is usually 30 minutes to 27 hours.

The product carboxylic acid may be isolated from the reaction solution obtained by the above-mentioned deesterification reaction, but usually the reaction solution can be used as it is in the next decarboxylation step.

The decarboxylation step can be easily performed by adding an acid to the deesterification reaction liquid to make the liquid acidic. Examples of the acid used include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, and methanesulfonic acid. Acids, more preferably hydrochloric acid.

When the product carboxylic acid is once isolated from the reaction solution obtained by the above-mentioned deesterification reaction and then subjected to the decarboxylation step, the reaction solvent may be, for example, dichloromethane, chlorophonolem, dichloroethane, benzene, tonolene, Detinole ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone, 1,3-dimethylimidazolidinone, dimethylsulfoxide, aceton, acetoetrile, ethyl acetate, acetic acid One t-butyl, t-butanol, s-butanol, isobutanol, n-butyl Tanol, isopropanol, _n -propanol, ethanol, methanol and the like can be mentioned. The above solvents may be used alone or as a mixture. In this case, the mixing ratio is not particularly limited. Among the above solvents, preferred are tetrahydrofuran, ethanol and methanol.

Further, when the product carboxylic acid is not isolated from the reaction solution obtained by the above-mentioned deesterification reaction and is used as it is in the next decarboxylation step, the reaction solvent is the above-mentioned deesterification reaction. The solvent used in step 1 may be used as it is, or the reaction may be performed by substituting another solvent. Examples of the reaction solvent used in this case include dichloromethane, chloroform, dichloroethane, benzene, tonoleene, ethynoleatenole, methinole-t_p-thinoleether, tetrahydrofuran, 1,4-dioxane, N, N— Dimethylformamide, N-methylpyrrolidone, 1,3-dimethinoreimidazolidinone, dimethylsnoreoxide, acetone, acetonitrile, ethyl acetate, t-butyl acetate, t-butanol, s-butanol, Isobutanol, n-butanol, isopropanol, n-propanol, ethanol, methanol, and the like can be given. The above solvents may be used alone or as a mixture. In this case, the mixing ratio is not particularly limited. Among the above solvents, preferred are tetrahydrofuran, ethanol and methanol.

The concentration of the substrate in the reaction is usually 20 w / v% or less, preferably 10 wZ v ° / o or less, as the concentration of the compound (4) in the solvent.

The reaction temperature can be selected from the range of 130 ° C. to the boiling point of the solvent used, and is preferably 0 ° C. to 60 ° C. The reaction time is usually 30 minutes to 24 hours. After completion of the reaction, if necessary, neutralize the reaction solution, evaporate the solvent, extract with an organic solvent such as ethyl acetate, toluene, dichloromethane, and chloroform, wash with water, and concentrate. Compound (5) can be obtained. The obtained compound (5) may be separated and purified by column chromatography and crystallization.

The 5-substituted hydantoin derivative represented by the general formula (4) according to the fourth embodiment of the present invention is a novel compound which has been confirmed by the present inventors to be useful in the production of monosubstituted propargylglycine derivatives, In the formula, R ¹ is a cyclic or non-cyclic alkyl group having ^{1 to 1} ° carbon atoms which may have a substituent, and 7 to 7 carbon atoms which may have a substituent. Represents an aralkyl group having 10 or an aryl group having 6 to 10 carbon atoms which may have a substituent.

The cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cycloalkyl group. Propyl, n-butyl, isobutyl, t-butyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, n-butyl, n-decyl, etc. And preferably a methynole group or an ethyl group.

The aralkyl group having 7 to 10 carbon atoms which may have a substituent is not particularly limited, and examples thereof include a benzyl group, a p-hydroxybenzyl group, a p-methoxybenzino group, and a p-nitro group. Benzinole group, o-hydroxybenzylinole group, o-methoxybenzinole group, o-nitrobenzinole group, 11-phenethyl group, 2-phenethinole group, etc., and preferably p- It is a methoxybenzyl group.

The aryl group having 6 to 10 carbon atoms which may have a substituent is not particularly limited, and examples thereof include a phenyl group, a p-methinolephenyl group, a p-methoxyphenyl group, a p-chlorophenyl group, and a naphthyl group. And a phenyl group is preferable.

R ² is a hydrogen atom, a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, or an aralkyl group having 7 to 10 carbon atoms which may have a substituent. Represents

The cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropynole. Group, n-butyl group, isobutyl group, t-butyl group, cyclobutyl group, n-pentyl group, cyclopentyl group, n-hexyl group, cyclohexyl group, n-octyl group, n-decyl group, etc. And preferably a methyl group or an ethyl group.

The aralkyl group having 7 to 10 carbon atoms which may have a substituent is not particularly limited. Examples thereof include a benzyl group, a —hydroxybenzyl group, a ρ-methoxybenzino group, and a p-nitro group. Benzinole group, o-hydroxybenzinole group, o-methoxybenzene Examples thereof include a jyl group, an o-ethoxybenzyl group, an 11-phenethyl group and a 2-phenethyl group, and a p-methoxybenzyl group is preferable.

In addition, the compound (4) has an asymmetric carbon atom, and any of an optically active compound and a racemic compound are included in the scope of the present invention.

Further, a 5-substituted hydantoin derivative represented by the general formula (5), which is the fifth embodiment of the present invention, is also a novel compound which has been confirmed by the present inventors to be useful in the production of α-substituted propargylglycine derivatives. Wherein R ² is a hydrogen atom, a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, or a carbon atom having 7 to 10 carbon atoms which may have a substituent. Represents an aralkyl group of 10.

The cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent is not particularly limited, and examples thereof include a methyl group, an ethyl group, an η-propyl group, an isopropyl group, and a cycloalkyl group. Propyl, 11-butyl, isobutyl, t-butyl, cyclobutynole, n-pentynole, cyclopentynole, n-hexynole, cyclohexyl, n-octyl, n-decyl And the like, and preferably a methyl group or an ethyl group.

The aralkyl group having 7 to 10 carbon atoms which may have a substituent is not particularly limited, and examples thereof include a benzyl group, a p-hydroxybenzyl group, a ρ-methoxybenzyl group, and a p- Examples thereof include nitrobenzyl group, o-hydroxybenzyl group, o-methoxybenzyl group, o-trobenzyl group, 1-phenethyl group, and 2-phenethyl group, and preferably p-methyl group. It is a toxic benzyl group.

Incidentally, the compound (5) has an asymmetric carbon atom, and any of an optically active compound and a racemic compound are included in the scope of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, 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) Preparation of 5- (2-pentinole) -1-5-ethoxycarbonylhydantoin Lithium methoxide (38 mg, lmmo 1) was added to a solution of tert-butanol (2.5 ml) of getyl N-force rubamoylaminomalonate (21.8 mg, 1 mmo 1) in a nitrogen stream. The mixture was heated under reflux for 1 hour, and a solution of 2-butynylmethanesulfonate (148 mg, lmmo 1) in t-butanol (1.5 m 1) was heated and refluxed for 13.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and 15 ml of ethyl acetate and 5 ml of 0.1 N hydrochloric acid were added to the residue to carry out liquid separation. The aqueous layer was extracted twice with 15 ml of ethyl acetate, and the whole organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtering off sodium sulfate, the filtrate was concentrated under reduced pressure to obtain a yellow oil (398.lmg). The content of this yellow oil was analyzed by high performance liquid chromatography (HP LC), and as a result, 5- (2-butynyl) -1-ethoxycarbonylhydantoin (173.6 mg, 0.796 mmo 1, yield 79.6%). (HPLC analysis conditions: Deve 1 osi 1 C 30— UG—5 (manufactured by Nomura Chemical Co., Ltd.) 4.6 mmX 25 Omm, mobile phase acetonitrile: water = 1: 3, flow rate—1.01 / ΧΆin , Detection wavelength 210 nm, column temperature 30 ° C)

^{.. X H-NMR (400MH} z, CD C 1 3) S i 3 0~1 3 2 (t, J = 7. 08H z, 3H), 1. 77~: L. 7 9 (t, J = 2.44, 3H), 2.8 1 to 3.09 (d, q, J = 2.44, 16.60, 2H), 4.27 to 4.34

(m, 2H), 6.23 (br, 1H), 8.51 (br, 1H)

FT-IR (cm— ¹ ) 3 26 9.7, 2 3 6 1.2, 1 7 8 2.4, 1 7 36.1, 1 54 1. 3, 1 508.5, 14 1 7. 9, 1 36 9.6, 1 2 5 3.9, 1 140.1, 1 06 1.0, 8 5 8. 4, 6 8 8.7, 6 36.6, 5 78.7, 4 16.7

Example 2 Production of 5- (2-butulyl) -1-5-ethoxycarbonylhydantoin

Under a stream of nitrogen, a solution of tert-butanol (2.5 ml) of tert-butanol (2.5 l) of tert-butanol (1 l 2 mg, lmmo 1) ) And heat to reflux for 3 hours, and add a solution of 2-butynylmethanesulfonate (148 mg, lmmo 1) in t-butanol (1.5 ml). And heated to reflux for 14.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and 15 ml of ethyl acetate and 5 ml of 0.1 N hydrochloric acid were added to the residue to carry out liquid separation. The aqueous layer was extracted twice with 15 ml of ethyl acetate, and the whole organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off sodium sulfate, the filtrate was concentrated under reduced pressure to obtain a yellow oily substance (298.2 mg). The content of this oil was analyzed by HP LC and found to contain 5- (2-butynyl) _5-ethoxycarbonylhydantoin (173.6 mg, 0.774 mmo1, yield 77.4%). Was.

(Example 3) Production of 5- (2-pentinole) -5-ethoxycarbonylhydantoin

Under a stream of nitrogen, add ethanol solution (1 20 ml) of N-potassium rubamoylaminomalonate (6.546 g, 30 mmo 1) in ethanol (1 ml) and add sodium methoxide (2 M solution in ethanol) 15 m 1 , 30 mmo 1) and stirred at 75 for 3 hours. The reaction solution was cooled to room temperature, filtered through a glass filter, and the crystals were washed three times with 5 ml of ethanol and three times with 5 ml of getyl ether, and then dried under vacuum to remove sodium 5-ethoxycarbonylhydantoin. White crystals of the salt (5.672 g) were obtained. The obtained sodium salt of 5-ethoxycarbolhydantoin (194 mg, 1 mmo 1) was suspended in toluene (1 ml) under a nitrogen stream, and the mixture was suspended at room temperature in 2-butylenolemethansnolefonate (148 mg, 1 mmo 1). Mmo 1) toluene (1 m 1) was added. After heating to 70 ° C and stirring for 5.5 hours, dimethylsulfoxide (0.2 ml) was added, and the mixture was further stirred for 3 hours. The reaction solution was cooled to room temperature, and 15 ml of ethyl acetate and 2 ml of a saturated aqueous solution of ammonium chloride were added thereto to carry out liquid separation. 2 ml of water was added to the aqueous layer, and extracted twice with 15 ml of ethyl acetate. All organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. After filtration of sodium sulfate, the filtrate was concentrated under reduced pressure and dried with a vacuum pump to obtain a yellow oil (257.6 mg). The content of this oil was analyzed by HP LC. As a result, it was found that 5- (2-butyl) -1-5-ethoxycarbo-norehydantoin (115 mg, 0.512 mmo1, yield 51) 2%). Example 4 Production of 5- (2-Petinole) -1-5-ethoxycarponylhydantoin

In a nitrogen stream, a suspension of sodium salt of 5-ethoxycarboehydantoin (194 mg, 1 mmol) in tetrahydrofuran (2 ml) prepared by the method described in Example 3 was added at room temperature to 2-butyl. A solution of methanesulfonate (148 mg, lmmo 1) in tetrahydrofuran (1 ml) was added. The mixture was heated under reflux for 17 hours, added with lml of tetrahydrofuran, and further heated under reflux for 23 hours. After cooling to room temperature, 20 ml of ethyl acetate and 5 ml of water were added to carry out liquid separation. The aqueous layer was adjusted to pH 1 by adding 1N hydrochloric acid, and extracted twice with 15 ml of ethyl acetate. All organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. After filtration of sodium sulfate, the filtrate was concentrated under reduced pressure and dried with a vacuum pump to obtain a yellow oil (336.5 mg). The content of this oily substance was analyzed by HP LC, and as a result, 5- (2-butynyl) -15-ethoxycanoleponizolehydantoin (140.8 mg, 0.628 mmol, yield 62.8) %).

Example 5 Production of 5- (2-Petit-Nole) _5-Ethoxycarpoelhydantoin

Under a stream of nitrogen, a suspension of sodium hydride (60% oil, 52 mg, 1.29 mmo 1) in tetrahydrofuran (lm l) was added at 18 ° C at 5- ° C with 5-ethoxycarbylhydantoin (222 mg, 1 A solution of 29 mmo 1) in tetrahydrofuran (1.5 ml) was added. After stirring at room temperature for 1 hour, add a solution of 2-butylmethanesnorrephonate (191 mg, 1.29 mmo 1) in tetrahydrofuran (lm 1) at the same temperature and stir for 3 hours. The mixture was heated to C and stirred for 22 hours. After cooling to room temperature, the reaction mixture was added with ethyl acetate (10 ml), a saturated aqueous solution of ammonium chloride (lml), and water (lml), stirred and separated. The aqueous layer was extracted with ethyl acetate (20 ml). The whole organic layer was washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. After filtration of sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent—n-hexane: ethyl acetate = 2: 1 to 1: 1) to give 5- (2-butynyl) ) One 5 _ ethoxycarponica Was obtained (121.9 mg, yield 42%).

(Example 6) Production of 5- (2-pentinole) -5-ethoxycarbonylhydantoin

Under a nitrogen stream, a solution of 5-ethoxycarbonylhydantoin (229 mg, 1.33 mMol) in ethanol (2.5 ml) was added to a solution of sodium ethoxide (2.5 ml) at room temperature.

2 mo 1 Z 1 ethanol solution, 0.67 ml) was added. After heating the reaction vessel to 50 ° C and stirring for 1 hour, 2-butynylmethanesulfonate (197 mg, 1.

A solution of 33 mmo1) in ethanol (1.5 ml) was added, and the mixture was heated under reflux for 3.5 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the residue for liquid separation, and the aqueous layer was extracted with ethyl acetate. All organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The sodium sulfate was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel gel column chromatography (developing solvent—n-hexane: ethyl acetate = 2: 11: 1) to give 5- (2— (Putinyl) 15-ethoxycalponylhydantoin (136.7 mg, yield 46%) was obtained.

Example 7 Production of 5- (2-butul) -1-5-ethoxycarbonylhydantoin

In a nitrogen stream, a solution of getyl N-force rubamoylaminomalonate (1.01 g, 5 mMol) in ethanol (2 Om1) was added at room temperature with sodium ethoxide (2 mol / l ethanol solution). , 2.5 ml) was added and the mixture was heated under reflux for 1.5 hours. After the reaction solution was cooled to room temperature, a solution of 2-butynylmethanesulfonate (741 mg, 5 mmo 1) in ethanol was added, and the mixture was stirred at room temperature for 1 hour, then heated to 60 ° C and stirred for 17 hours. . Ethanol was distilled off under reduced pressure, and 50 ml of ethyl acetate and 10 ml of water were added to the residue, followed by liquid separation. The aqueous layer was extracted with 40 ml of ethyl acetate, and the whole organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The sodium sulfate was filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oil (1.7712 g). The content of this oil was analyzed by HP LC and found to contain 5- (2-butynyl) -15-ethoxycarbonylhydantoin (572 mg, 2.55 mmo1, yield 51%). Was.

Example 8 Ethanol (20 ml) of N-canolebamoylaminomalonate getyl (1.091 g, 5 mMol) under a nitrogen stream of 5-ethoxyethoxycarbonyl 51- (2-propynyl) hydantoin ) To the solution was added sodium ethoxide (2.5 ml of a 2 mo 1/1 ethanol solution) at room temperature, and the mixture was heated to 60 ° C and stirred for 3.5 hours. A solution of 2-propynylmethanesulfonate (671 mg, 5 mmol) in ethanol (2 ml) was added while the temperature was maintained at 60 ° C, and the mixture was stirred for 19 hours. Ethanol was distilled off under reduced pressure, and to the residue were added 30 ml of ethyl acetate, 2 ml of a saturated aqueous solution of ammonium chloride and 10 ml of 7K, and the layers were separated. The aqueous layer was extracted twice with 20 ml of ethyl acetate, and the entire organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The sodium sulfate was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent—n-hexane: ethyl acetate = 3 _: 1 to 1 _: 1) to give 5-ethoxycarbonyl-5_. (2-Probul) Hydantoin (347 mg, yield 33%) was obtained.

'H-NMR (40 OMH z, DMS O— d 6) δ 1.26 ~: L. 30 (t, J = 7.33 Hz, 3H), 2.85-3.03 (d, q, J = 2.44, 1 7.09, 2 H), 3.10—3.1 2 (t, J = 2.44, 1 H) 4.25-4 3 3 (q, J = 7.33, 2 H), 8.64 (br, 1H)

FT—IR (cm— ¹ ) 3269.7, 236 1.2, 1 782.4, 1 7 3 61, 1 541.3, 1508.5, 1417.9, 1 369.6 1253. 9 1 140.1, 1061.0, 858.4, 688.7, 636, 578.7, 416.7

(Example 9) Production of 5- (2-butyl) hydantoin

5- (2-Petininole) 1-5-ethoxycanoleponinolehydantoin (105 mg, 0.468 mm. 1) in methanol (2 ml) at room temperature was added to a 1N aqueous sodium hydroxide solution (0.47 m l) was added and the mixture was stirred for 15.5 hours. 1 N hydrochloric acid (0. 47 ml), and the mixture was stirred, and methanol was distilled off under reduced pressure. 20 ml of ethyl acetate and 5 ml of water were added to the residue, and the mixture was separated. The aqueous layer was extracted twice with 20 ml of ethyl acetate. All the organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The sodium sulfate was filtered, the filtrate was concentrated, and dried with a vacuum pump to obtain a white solid (84.5 mg). The content of this white crystal was analyzed by HP LC, and as a result, it was found to contain 5- (2-butul) hydantoin (44.9 mg, 0.295 mmol, yield 63%).

^{X H-NMR (400MHz, CD} C 1 3 / DMS O- d 6) δ 1. 76 (s, 3 H), 2. 56~2. 63 (2 H), 3. 99~4. 02 (t , J = 4.89 Hz, 1 H), 7.69 (br, 1 H), 10.5 5 (br, 1 H)

FT—IR (cm— ¹ ) 3649.8, 3300.6, 2783.6, 1755.4, 1747.7, 1718.8, 1425.6, 1315.6, 1217.2, 1 1 88.3, 1095.7, 1022.4, 816.0, 785.1, 765.8, 671.3, 638.5, 59.2, 420.5

(Example 10) Production of 5- (2-propynyl) hydantoin

5 _Ethoxycanolebonyl mono 5- (2-propyninole) hydantoin (105 mg, 0.5 mmol) in tetrahydrofuran / water = 0.5 ml / 0.5 ml 1N sodium hydroxide at room temperature An aqueous solution (0.5 ml) was added and the mixture was stirred for 17 hours. Add 1N aqueous sodium hydroxide solution (0.2 ml) and stir for another 5 hours, then add 1N aqueous sodium hydroxide solution (0.2 ml) and stir for another 1.5 hours, then add 1N An aqueous sodium hydroxide solution (0.1 ml) was added, and the mixture was stirred for 1.5 hours. The reaction solution was adjusted to pH 4 with 1 N hydrochloric acid, 10 ml of ethyl acetate was added, and the mixture was stirred and separated. The aqueous layer was extracted twice with 10 ml of ethyl acetate, and the whole organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The sodium sulfate was filtered, the filtrate was concentrated, and dried with a vacuum pump to obtain white crystals (56 mg, yield 81%).

^ -NMR (400 MHz, CDC 13 / DMS O-d 6) 6 2.14 to 2.16 (t, J = 2.44 Hz, 1H), 2.65 to 2.69 (m, 2H), 4. 07— 4.10 (t, J = 4.89, 1H), 7, 58 (br, 1H), 10 5 1 (br, 1H)

FT—IR (cm— ¹ ) 3904.4, 38 54.2, 382.2, 3690 3, 3649.8, 3302.5, 1869.2 1 772.8, 1 716.9

1670.6, 1647.4, 1635.8, 1558.7, 1541.3, 1522.0, 1508.5, 1489.2, 1473.8, 15456.4, 1338.8, 1 31 9.5, 124.2, 1 1 90.2, 1 1 1 1.1, 101 8.5 Industrial availability

Since the present invention has the above-mentioned constitution, it is a synthetic intermediate of an amino acid derivative useful as an intermediate for pharmaceuticals and agricultural chemicals or a physiologically active substance from a readily available raw material such as 5-alkoxycarbonylhydantoin. 5-substituted hydantoin derivatives having a substituted propargyl group can be industrially advantageously produced.

Claims

Claims General formula (1)

0 C0 ₂ R,

义 J

Η ₂ Ν ', Ν', C0 ₂ R ¹

(Wherein, R ¹ is a cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, an aralkyl group having 7 to 10 carbon atoms which may have a substituent, or A C 6-: aryl group of L 0) is cyclized in the presence of a base to give a compound represented by the general formula (2):

X (3)

(Four) (Wherein, R ¹ and R ² have the same meanings as described above.) A method for producing a 5-substituted hydantoin derivative represented by the formula:

2. General formula (2)

(Wherein, R ¹ is a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, an aralkyl group having 7 to 10 carbon atoms which may have a substituent, or Represents an aryl group having 6 to 10 carbon atoms which may have a group represented by the general formula (3)

X (3)

(Wherein, R ² is a hydrogen atom, a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, or an aralkyl group having 7 to 10 carbon atoms which may have a substituent. And X represents a leaving group.) A general formula (4) characterized by reacting with an alkyne derivative represented by the formula (1) in the presence of a base.

3. The method according to claim ^{1, wherein} R ¹ is a methyl group or an ethyl group.

4. R ² is a manufacturing method for placing serial to any one of the ranges the first to third term according a hydrogen atom or a methyl group.

5. The production method according to any one of claims 1 to 4, wherein X is a halogen atom or a substituted sulfonyloxy group.

6. The production method according to claim 5, wherein the substituted sulfonyloxy group is a methanesulfonyloxy group.

7. General formula (4)

(Wherein, R ¹ is a cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, an aralkyl group having 7 to 10 carbon atoms which may have a substituent, or Represents a aryl group having 6 to 10 carbon atoms which may have a substituent; R ² represents a hydrogen atom; a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent; Or a aralkyl group having 7 to 10 carbon atoms which may have a substituent.) A compound represented by the general formula (5):

8. The production method according to claim 7, wherein the deesterification is carried out by hydrolysis.

9. The method according to claim 7, wherein R ¹ is a methyl group or an ethyl group.

10. The production method according to claim 7, wherein R ¹⁰ is a hydrogen atom or a methyl group. General formula (4)

(Wherein, R ¹ is a cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, an aralkyl group having 7 to 10 carbon atoms which may have a substituent, or Represents a aryl group having 6 to 10 carbon atoms which may have a substituent; R ² represents a hydrogen atom; a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent; Or a aralkyl group having 7 to 10 carbon atoms which may have a substituent.) A 5-substituted hydantoin derivative represented by the formula:

2. General formula (5)

(Wherein, R ² is a hydrogen atom, a cyclic or acyclic alkyl group having 1 to 10 carbon atoms which may have a substituent, or a carbon atom having 7 to 10 carbon atoms which may have a substituent. A 5-substituted hydantoin derivative represented by).

13. The compound according to claim 11, wherein R ¹ is a methyl group or an ethyl group.

1 4. R ² is The compound of any crab described range of the first 1 to 1 3 of claims is a hydrogen atom or a methyl group.