WO2003033473A1 - Nouveau derive d'hydantoine a substitution en position 5 et son procede de production - Google Patents

Nouveau derive d'hydantoine a substitution en position 5 et son procede de production Download PDF

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Publication number
WO2003033473A1
WO2003033473A1 PCT/JP2002/010514 JP0210514W WO03033473A1 WO 2003033473 A1 WO2003033473 A1 WO 2003033473A1 JP 0210514 W JP0210514 W JP 0210514W WO 03033473 A1 WO03033473 A1 WO 03033473A1
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group
substituent
carbon atoms
general formula
cyclic
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PCT/JP2002/010514
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Japanese (ja)
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Kazuhiko Watabe
Nobuo Nagashima
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Kaneka Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • 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
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a compound represented by the general formula (1):
  • 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).
  • 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.
  • X represents a leaving group.
  • 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.
  • 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.
  • X represents a leaving group.
  • 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 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.
  • 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 ⁇ -substituted propargydarricin derivatives.
  • the present invention relates to a compound represented by the general formula (4)
  • 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.
  • 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.
  • 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.
  • 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.
  • a methyl group an ethyl group, an n-propyl group, an isopropyl group, and a cycloalkyl group.
  • a methyl group or an ethyl group 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.
  • substituted 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.
  • R 1 is preferably a methyl group or an ethyl group.
  • 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).
  • the substituent in each compound will be described.
  • 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.
  • 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.
  • a methyl group or an ethyl group 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 ⁇ -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.
  • R 2 groups are a hydrogen atom and a methyl group.
  • X represents a leaving group, a halogen atom such as chlorine, bromine, and iodine; and an acetoxy group and a benzoyloxy group.
  • a halogen atom and a substituted sulfoxy group Preferable are a halogen atom and a substituted sulfoxy group, and more preferred is a methanesulf
  • the 5-substituted hydantoin derivative represented by the general formula (4) is a novel compound whose usefulness in the production of ⁇ -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.
  • 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.
  • organic lithium compounds such as methyllithium, n-butyllithium, t-butyllithium, and phenyllithium
  • 11-butynolemagnesium chloride
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • preferred are alcohols, and particularly preferred is t-butanol.
  • the reaction is performed in the presence of a new base.
  • 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).
  • 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.
  • a solvent is usually used for the reaction.
  • 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.
  • the mixing ratio is not particularly limited.
  • preferred are alcohols and tetrahydrofuran, and particularly preferred is t-butanol.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • alkali metal alkoxides, alkali metal hydrides and alkaline earth metal amide sodium meth
  • 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.
  • 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.
  • 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). .
  • 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.
  • R 2 represents a hydrogen atom, a cyclic or non-cyclic group having 1 to 10 carbon atoms which may have a substituent.
  • Preferred as the R 1 group is a methyl group or an ethyl group
  • 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.
  • 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.
  • 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.
  • metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide, magnesium hydroxide, calcium hydroxide, and the like.
  • alkaline earth metal hydroxides such as barium hydroxide and lithium metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate.
  • 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.
  • reaction solvent for the deesterification examples 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.
  • 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.
  • 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.
  • 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
  • t-butyl, t-butanol, s-butanol, isobutanol, n-butyl Tanol, isopropanol, n -propanol, ethanol, methanol and the like can be mentioned.
  • 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.
  • reaction solvent used in this case examples 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
  • 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
  • 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.
  • 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.
  • a methynole group or an ethyl group is 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.
  • 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.
  • 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.
  • a methyl group or an ethyl group isobutyl group, t-butyl group, cyclobutyl group, n-pentyl group, cyclopentyl group, n-hexyl group, cyclohexyl group, n-octyl 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 ⁇ -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.
  • 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.
  • 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 ⁇ -substituted propargylglycine derivatives.
  • 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.
  • 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 ⁇ -propyl group, an isopropyl group, and a cycloalkyl 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 ⁇ -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.
  • 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.
  • 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.
  • 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.
  • 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) %).
  • 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.
  • 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%).
  • 5- (2-butynyl) -15-ethoxycarbonylhydantoin 572 mg, 2.55 mmo1, yield 51%).
  • 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 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%).
  • the present invention 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.

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Abstract

L'invention concerne un procédé de production d'un dérivé d'hydantoïne présentant un groupe propargyle substitué dans la position 5, à partir de 5-alcoxycarbonylhydantoïne facilement disponible, etc., selon une procédure simple; et un dérivé d'hydantoïne à substitution en position 5 ayant un groupe propargyle substitué dans la position 5, lequel est un intermédiaire d'un dérivé d'acide aminé. Le procédé consiste à introduire un groupe propargyle substitué dans une 5-alcoxycarbonylhydantoïne produite à partir d'un dérivé de diester N-carbamoylaminomalonique et d'une base, ou il consiste en l'introduction de propargyle substitué, suivie d'une désestérification et d'une décarboxylation. Ainsi, un dérivé d'hydantoïne à substitution en position 5 ayant un groupe propargyle substitué dans la position 5 peut être produit efficacement.
PCT/JP2002/010514 2001-10-10 2002-10-10 Nouveau derive d'hydantoine a substitution en position 5 et son procede de production WO2003033473A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007040272A1 (fr) * 2005-10-06 2007-04-12 Kaneka Corporation Procédé pour la production d'un dérivé de d-(4-aminométhyl)phénylalanine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5346913A (en) * 1992-05-26 1994-09-13 Rohm And Haas Company N-iodopropargyl hydantoin compounds, compositions, preparation, and use as antimicrobial agents
US5883260A (en) * 1996-06-24 1999-03-16 Sumitomo Chemical Company, Limited Process for producing 1-substituted-hydantoins
WO2000040545A1 (fr) * 1999-01-07 2000-07-13 Aventis Cropscience Nouveau procede de preparation d'aminoacides chiraux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5346913A (en) * 1992-05-26 1994-09-13 Rohm And Haas Company N-iodopropargyl hydantoin compounds, compositions, preparation, and use as antimicrobial agents
US5883260A (en) * 1996-06-24 1999-03-16 Sumitomo Chemical Company, Limited Process for producing 1-substituted-hydantoins
WO2000040545A1 (fr) * 1999-01-07 2000-07-13 Aventis Cropscience Nouveau procede de preparation d'aminoacides chiraux

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007040272A1 (fr) * 2005-10-06 2007-04-12 Kaneka Corporation Procédé pour la production d'un dérivé de d-(4-aminométhyl)phénylalanine

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