JP2006131587A - Tyrosine glycoside, method for producing the same and use thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new tyrosine glycoside useful in many fields including a medicine, an agrochemical and a cosmetic material and to provide a method for producing the same and a use thereof. <P>SOLUTION: The tyrosine glycoside is produced by reacting a tyrosine derivative with pentaacetyl glucose in the presence of an acid catalyst. Then the new tyrosine derivative is obtained by deprotecting the part of a saccharide residue and, if necessary, converting a carboxylic acid ester part to a carboxylic acid. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a tyrosine glycoside useful in various fields including pharmaceuticals, agricultural chemicals, and cosmetic materials, a production method thereof, and use thereof.

  In recent years, useful compounds having physiological activity in which a phenolic hydroxyl group is glycosylated have attracted attention. For example, in the pharmaceutical field, a novel phlorizin glycoside (T-1095, etc.) that is expected as a novel therapeutic agent for diabetes by inhibiting reabsorption of sugar in the kidney has been reported (see Non-Patent Document 1). .) As cosmetic materials, arbutin in which glucose is glycosylated to hydroquinone (see Patent Document 1), a compound in which glucose is glycosylated to gallic acid (see Patent Document 2), etc. are found and widely used.

  In general, when a compound is glycosylated, expression of a specific physiological activity derived from sugar is expected, and water solubility and solubility are improved compared to the compound before glycosylation. It can also be expected to improve physical properties. Furthermore, it is believed that glycosylation of a toxic compound reduces the toxicity of the compound and improves biocompatibility.

  Thus, when the useful effects of glycosylation are widely known, it is strongly expected that more novel glycosides will be supplied stably and inexpensively from an industrial viewpoint. I came. For example, tyrosine is one of the essential amino acids contained in hair, etc. and is essential for living organisms, but tyrosine glycoside compounds are highly bioactive and highly biocompatible in many fields including pharmaceuticals, agricultural chemicals, and cosmetic materials. Sex is expected. However, there are few reports on glycosides of tyrosine and tyrosine derivatives.

On the other hand, when the glycoside is to be produced industrially, there are a problem of yield and a problem of isolation and purification of the target compound (see Non-Patent Document 2). Therefore, it is difficult to say that a method for stably and inexpensively producing a large number of new glycosides from an industrial point of view has been well established for more novel glycosides, and a more effective production method. Establishment of is desired.
JP-A-62-263194 WO2003 / 026598 J. Med. Chem. 1999, 42, 5311-5324 Insect. Biochem. 12 (4), 377-381, 1982

  An object of the present invention is to provide a novel tyrosine glycoside.

  The present inventors chemically modified the amino group of tyrosine methyl ester and then reacted with pentaacetylglucose in the presence of an acid catalyst to produce a glycosylated tyrosine derivative. The present inventors have found that a novel tyrosine glycoside can be produced by removing respective protecting groups of hydroxyl group, amino group and carboxyl group, and found that the tyrosine derivative has an antibacterial action, thereby completing the present invention.

  That is, the present invention relates to the general formula (1)

(Wherein R 1 represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 30 carbon atoms, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted heterocyclic group. ), A method for producing the compound, and a use thereof.

  ADVANTAGE OF THE INVENTION According to this invention, a novel tyrosine glycoside and its manufacturing method can be provided. The tyrosine glycoside is useful as an antibacterial agent.

  The compound of the present invention is a compound represented by the general formula (1) or an alkali metal or alkaline earth metal salt of the compound.

  In general formula (1), R1 is a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, an optionally substituted aralkyl group, an optionally substituted phenyl group, or an optionally substituted group. A good heterocyclic group is shown.

  “Unsubstituted or substituted alkyl group having 1 to 30 carbon atoms” means an alkyl in which any hydrogen atom of an unsubstituted alkyl group having 1 to 30 carbon atoms or an alkyl group having 1 to 30 carbon atoms is substituted with a substituent. Means a group. As the alkyl group, the alkyl group includes methyl, ethyl, isopropyl, tert-butyl, pentyl, hexyl, cyclohexyl, octyl, decyl, pentadecyl, heptadecyl, arachidyl, or allyl. Etc. In addition, the substituent of the alkyl group includes an alkoxy group such as a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or Mention may be made of halogen atoms such as fluorine, chlorine, bromine or iodine atoms.

  “Unsubstituted or substituted aralkyl group” means an unsubstituted aralkyl group or an aralkyl group in which any hydrogen atom of an aralkyl group is substituted with a substituent. Examples of the aralkyl group include a benzyl group, a naphthylmethyl group, a phenylethyl group, and a 9-fluorenylmethyl group. Examples of the substituent for the aralkyl group include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. An alkoxy group such as a group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom can be exemplified. .

  “Unsubstituted or substituted phenyl group” means an unsubstituted phenyl group or a phenyl group in which any hydrogen atom of the phenyl group is substituted with a substituent. Examples of the substituent of the phenyl group include an alkyl group such as a methyl group, a tert-butyl group or a benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. An alkoxy group such as a group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom can be exemplified. .

  The “unsubstituted or substituted heterocyclic group” means an unsubstituted heterocyclic group or a heterocyclic group in which any hydrogen atom of the heterocyclic group is substituted with a substituent. Examples of the heterocyclic group include tetrahydropyranyl group, tetrahydrofuranyl group, tetrahydrothienyl group, piperidyl group, morpholinyl group, piperazinyl group, pyrrolyl group, furyl group, thienyl group, pyridyl group, furfuryl group, tenenyl group, pyridylmethyl group, Examples thereof include a pyrimidyl group, a pyrazyl group, an imidazolyl group, an imidazolylmethyl group, an indolyl group, an indolylmethyl group, an isoquinolyl group, a quinolyl group, and a thiazolyl group. Examples of the substituent for the heterocyclic group include an alkyl group such as a methyl group, a tert-butyl group or a benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxy group. Examples include alkoxy groups such as ethoxy groups, phenoxy groups, nitro groups, amino groups, amide groups, carboxyl groups, alkoxycarbonyl groups, phenoxycarbonyl groups or halogen atoms such as fluorine atoms, chlorine atoms, bromine atoms or iodine atoms. it can.

  As shown below, the compound represented by the general formula (1) has an asymmetric carbon atom at the position where the nitrogen atom is bonded. As the compound represented by the general formula (1), for example, Formula (2)

(In the formula, R1 is synonymous with R1 in the general formula (1)).
R1 in the general formula (2) has the same meaning as R1 in the general formula (1).
The compound represented by the general formula (1) is represented by the general formula (3).

(Wherein R1 represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 30 carbon atoms, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted heterocyclic group, R2 represents an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, an unsubstituted or substituted aralkyl group, or an unsubstituted or substituted phenyl group. The compound represented by (3) is a synthetic intermediate of the compound represented by the general formula (1).

  In general formula (3), R1 is a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 30 carbon atoms, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted heterocyclic group. R2 represents an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, an unsubstituted or substituted aralkyl group, or an unsubstituted or substituted phenyl group.

  "Unsubstituted or substituted alkyl group having 1 to 30 carbon atoms", "unsubstituted or substituted aralkyl group", "unsubstituted or substituted phenyl group" and "unsubstituted" in R1 or R2 in the general formula (3) “Substituted heterocyclic group” has the same meaning as those described in the section for R1 in the general formula (1).

  The “unsubstituted or substituted alkyl group having 1 to 10 carbon atoms” in R2 in the general formula (3) is any hydrogen of an unsubstituted alkyl group having 1 to 10 carbon atoms or an alkyl group having 1 to 10 carbon atoms. It means an alkyl group in which an atom is substituted with a substituent. Examples of the unsubstituted alkyl group having 1 to 10 carbon atoms include methyl group, ethyl group, isopropyl group, tert-butyl group, pentyl group, hexyl group, cyclohexyl group, octyl group, decyl group, and allyl group. . In addition, the substituent of the alkyl group includes an alkoxy group such as a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or Mention may be made of halogen atoms such as fluorine, chlorine, bromine or iodine atoms.

Next, a method for producing the compound represented by the general formula (3) will be described.
General formula (4)

(Wherein R2 has the same meaning as R2 in formula (3)) or an acid salt thereof and R1-CO-X (wherein R1 is R1 in formula (3)). Wherein X is a halogen atom or O—CO—R1 (R1 is synonymous with R1 in the above general formula (3))) in the presence of a base to react with the general formula ( 5)

(Wherein R1 and R2 are synonymous with R1 and R2 in the general formula (3)), and then the compound represented by the general formula (5) and pentaacetylglucose are The reaction is carried out in the presence of an acid catalyst to give a general formula (6)

(Wherein R1 and R2 have the same meanings as R1 and R2 in the general formula (3)), and then on the glucose residue of the compound represented by the general formula (6) By deprotecting the acetyl group, a compound represented by the general formula (3) can be produced.
R2 in the general formula (4) has the same meaning as R2 in the general formula (3) according to claim 3.

  Although the compound represented by General formula (4) can obtain a commercial item, it can be easily manufactured from tyrosine by the well-known esterification method.

  The compound represented by the general formula (4) or an acid salt thereof and R1-CO-X (wherein R1 has the same meaning as R1 in the general formula (3) according to claim 3, and X is a halogen atom or The compound represented by O-CO-R1 (R1 is synonymous with R1 in the general formula (3) according to claim 3) is reacted in the presence of a base and is represented by the general formula (5). Compounds can be produced.

  Examples of the acid salt of the compound represented by the general formula (4) include inorganic acid salts such as hydrochloride, bromate, and sulfate, and organic acid salts such as p-toluenesulfonate and oxalate. Can be mentioned.

  In R1-CO-X, R1 has the same meaning as R1 in the general formula (3), and X represents a halogen atom or O-CO-R1. R1 has the same meaning as R1 in the general formula (3).

  Examples of R1-CO-X include acetic anhydride, propionic anhydride, benzoic anhydride, succinic anhydride, acetyl chloride, acetyl bromide, propionyl chloride, lauroyl chloride, palmitoyl chloride, stearoyl chloride and the like.

  The amount of R1-CO-X used for the compound represented by the general formula (4) is not particularly limited, but is preferably in the range of 1 to 3 equivalents.

  The base that can be used in producing the compound represented by the general formula (5) is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and carbonate. Inorganic bases such as sodium hydride, sodium metal, sodium hydride, sodium methoxide, sodium ethoxide, metal alkoxide bases such as potassium tert-butoxide, organometallic bases such as n-butyllithium and ethylmagnesium bromide, triethylamine, diisopropylethylamine And organic amine bases such as tributylamine, pyridine, N, N-dimethylaminopyridine, and 1,8-diazabicycloundecene.

  When producing the compound represented by the general formula (5), a reaction solvent is usually used. The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction. Examples thereof include water, alcoholic solvents such as methanol, ethanol and 2-propanol, hydrocarbon solvents such as toluene and hexane, chloroform and dichloromethane. And halogenated solvents such as ethyl acetate, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylimidazolidinone (DMI), tetrahydrofuran (THF), 1,4-dioxane or diethyl ether Can do. These reaction solvents can also be used as a mixed solvent at an arbitrary ratio, and for example, can be used in a two-phase method using toluene and water.

  Although there is no restriction | limiting in particular in the reaction temperature at the time of manufacturing the compound represented by General formula (5), Preferably it is the range from -20 degreeC to the boiling point of a solvent.

  R1 and R2 in the general formula (5) have the same meanings as R1 and R2 in the general formula (3).

  The compound represented by the general formula (6) can be produced by reacting the compound represented by the general formula (5) with pentaacetylglucose in the presence of an acid catalyst.

  The acid catalyst is not particularly limited, but examples include inorganic acid catalysts such as hydrochloric acid, sulfuric acid, phosphoric acid, and boric anhydride, organic acid catalysts such as P-toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, and trifluoride. Lewis acid catalysts such as boron chloride, tin (II) chloride, titanium (IV) chloride, zinc bromide, magnesium chloride, iron chloride, aluminum chloride, copper iodide, silver trifluoromethanesulfonate, titanium oxide, alumina oxide, oxidation Examples thereof include solid acid catalysts such as zinc and silica gel, heteropolyacid catalysts such as phosphomolybdic acid and phosphotungstic acid, and acidic resin catalysts such as Nafion and Amberlite IR-120B plus. Among these acid catalysts, boron trifluoride is a preferred catalyst.

  The amount of catalyst used can be in the range of 0.001 to 10 equivalents relative to the compound represented by the general formula (5), but is preferably in the range of 1 to 2 equivalents.

  Pentaacetylglucose can be used in the α-form, β-form, or a mixture of stereoisomers in an arbitrary ratio. However, the β body can obtain higher reactivity. The amount of pentaacetylglucose used is not particularly limited with respect to the compound represented by the general formula (5), but is preferably in the range of 0.5 to 5 equivalents, more preferably in the range of 1 to 2 equivalents. .

  When producing the compound represented by the general formula (6), a reaction solvent is usually used. The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction. However, hydrocarbon solvents such as toluene and hexane, halogen solvents such as chloroform, dichloromethane and 1,2-dichloroethane (EDC), ethyl acetate, and the like. N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylimidazolidinone (DMI), tetrahydrofuran (THF), 1,4-dioxane, diethyl ether and the like. These reaction solvents can also be used as a mixed solvent at an arbitrary ratio.

  Although there is no restriction | limiting in particular in the reaction temperature at the time of manufacturing the compound represented by General formula (6), Preferably it is the range from -20 degreeC to the boiling point of a solvent.

  R1 and R2 in the general formula (6) have the same meanings as R1 and R2 in the general formula (3).

  The compound represented by the general formula (1) can be produced by deprotecting the acetyl group on the glucose residue of the compound represented by the general formula (6).

  Examples of the method for deprotecting the acetyl group on the glucose residue of the compound represented by the general formula (6) include a method by transesterification using an alkali metal alkoxide in the presence of an alcoholic solvent.

  Usable alkali metal alkoxides include lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like. Moreover, the equivalent of alkali metal alkoxide can be used in a catalytic amount with respect to the reaction substrate. Preferably it is the range of 0.001-1 equivalent. As the reaction solvent, an alcoholic solvent such as methanol, ethanol, 2-propanol, tert-butanol or the like can be used alone or as a mixed solvent in an arbitrary ratio. Also, the above alcoholic solvents and hydrocarbon solvents such as toluene and hexane, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylimidazolidinone (DMI), tetrahydrofuran (THF), 1, 4 -It can also be used as a mixed solvent with dioxane or diethyl ether. Moreover, R2 of the carboxylic acid ester moiety of the general formula (3) can be obtained as an ester corresponding to the alcoholic solvent used as the reaction solvent. For example, if methanol is used as the alcoholic solvent, a methyl ester can be obtained. Although there is no restriction | limiting in particular in reaction temperature, Preferably it is the range from -20 degreeC to the boiling point of a solvent.

  Moreover, the compound represented by General formula (3) can remove the alkali metal used for reaction by using a cation exchange resin after completion | finish of reaction. The cation exchange resin is not particularly limited, and examples thereof include strongly acidic cation exchange resins such as Amberlite 120B plus.

  If the production example of the compound represented by the general formula (3) from the compound represented by the general formula (4) is shown, for example, the general formula (7)

(Wherein R2 is synonymous with R2 in the general formula (3)) or an acid salt thereof and R1-CO-X (wherein R1 is the general formula (3) of the above-mentioned claim 3) 3) Synonymous with R1 in 3), X is a halogen atom or O—CO—R1 (R1 is synonymous with R1 in General Formula (3) of claim 3))) Reaction in the presence of general formula (8)

(Wherein R1 and R2 have the same meanings as R1 and R2 in the general formula (3)), and then the compound represented by the general formula (8) and pentaacetylglucose The reaction is carried out in the presence of an acid catalyst (for example, boron trifluoride) to give the general formula (9)

(Wherein R1 and R2 have the same meanings as R1 and R2 in the general formula (3)), and then on the glucose residue of the compound represented by the general formula (9) By deprotecting the acetyl group of general formula (10)

(Wherein, R1 and R2 have the same meanings as R1 and R2 in the general formula (3)) can be produced.

  R2 in the general formula (7), the general formula (8), the general formula (9), and the general formula (10) has the same meaning as R2 in the general formula (3), and the general formula (8) and the general formula R1 in (9) and general formula (10) has the same meaning as R1 in general formula (3).

  Further, the general formula (11)

(Wherein R2 is synonymous with R2 in the general formula (3)) and pentaacetylglucose are reacted in the presence of boron trifluoride (BF3) to give a general formula (12)

(In the formula, R2 is synonymous with R2 in the general formula (3)), and then the acetyl group on the glucose residue of the compound represented by the general formula (12) is prepared. By deprotecting, general formula (13)

(Wherein R2 is synonymous with R2 in the general formula (3)).

  R2 in the general formula (11), the general formula (12), and the general formula (13) has the same meaning as R2 in the general formula (3).

  The compound represented by the general formula (1) can be produced by hydrolyzing the compound represented by the general formula (3) produced as described above.

  Examples of the hydrolysis method for producing the compound represented by the general formula (1) include a method using an alkali metal hydroxide or the like. Examples of the alkali metal hydroxide that can be used for the reaction include lithium hydroxide, sodium hydroxide, and potassium hydroxide. In order to complete the reaction, the equivalent amount of the alkali metal hydroxide is required to be 1 equivalent or more with respect to the compound of the general formula (3), but is preferably in the range of 1 to 3 equivalents. As the reaction solvent, an alcoholic solvent such as water, methanol, ethanol, 2-propanol or the like can be used alone or as a mixed solvent in an arbitrary ratio. In addition, the above solvents and hydrocarbon solvents such as toluene and hexane, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylimidazolidinone (DMI), tetrahydrofuran (THF), 1,4-dioxane Alternatively, it can be used as a mixed solvent with diethyl ether or the like. Although there is no restriction | limiting in particular in reaction temperature, Preferably it is the range from -20 degreeC to the boiling point of a solvent.

  Among the compounds represented by the general formula (1), a compound having a free carboxylic acid can be produced, for example, by using a cation exchange resin after the reaction and removing the alkali metal used in the reaction. It is. The cation exchange resin used in this case is not particularly limited, and examples thereof include strongly acidic cation exchange resins such as Amberlite 120B plus.

  Among the compounds represented by the general formula (1), the compound having an alkali metal or alkaline earth metal salt of a carboxylic acid is a free carboxylic acid among the compounds represented by the general formula (1). It can manufacture by processing the compound which has this with an alkali metal compound or an alkaline-earth metal compound.

  If the example of manufacture of the compound represented by General formula (1) by hydrolyzing the compound represented by General formula (3) is shown, for example, the compound represented by General formula (13) will be hydrolyzed. By doing so, N-carbobenzoxy-O-β-D-glucopyranosyl-L-tyrosine can be produced.

  Furthermore, O-β-D-glucopyranosyl-L-tyrosine can be produced by hydrogenolysis of N-carbobenzoxy-O-β-D-glucopyranosyl-L-tyrosine.

  The hydrocracking is performed in a hydrogen atmosphere. Although there is no restriction | limiting in particular in the catalyst which can be used for hydrocracking, For example, palladium-carbon, Raney nickel, etc. can be mentioned. There are no particular restrictions on the amount of catalyst used and the hydrogen pressure used. A reaction solvent is usually used for the hydrogenolysis. The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction, but water, alcoholic solvents such as methanol, ethanol and 2-propanol, hydrocarbon solvents such as toluene and hexane, ethyl acetate, N, N-dimethylformamide (DMF), dimethylimidazolidinone (DMI), tetrahydrofuran (THF), 1,4-dioxane, diethyl ether and the like can be mentioned. These reaction solvents can also be used as a mixed solvent at an arbitrary ratio.

  Although there is no restriction | limiting in particular in the reaction temperature at the time of hydrogenolysis, Preferably it is the range from -20 degreeC to the boiling point of a solvent.

  The compound represented by the general formula (1) produced by the above production method can be separated and recovered from the reaction mixture by known means such as gel filtration, silica gel column chromatography, or crystallization operation. it can.

  The compound represented by the general formula (1) includes rice blight fungus (Pellicularia sasakii), gray fungus fungus (Botrytis cinerea), apple spotted leaf fungus (Alternaria mali), and cucumber vine split fungus (Fusarium oxysporus f. Sp. Cucumerinum) was found to have antibacterial activity. Therefore, the bactericidal agent comprising the compound represented by the general formula (1) is useful for sterilizing these bacteria. Among the compounds represented by the general formula (1), N-acetyl-O-β-D-glucopyranosyl-L-tyrosine and O-β-D-glucopyranosyl-L-tyrosine are preferable compounds as a fungicide.

  Examples of the present invention will be described below, but the present invention is not limited by these.

Production of N-acetyl-O-β-D-glucopyranosyl-L-tyrosine methyl ester
[Production of N-acetyl-L-tyrosine methyl ester]

50.6 g of L-tyrosine methyl ester hydrochloride was suspended in 250 g of toluene and 50 g of methanol, 20.4 g of sodium bicarbonate was added thereto, and the mixture was stirred at room temperature for 30 minutes. 27.0 g of acetic anhydride was added dropwise, and the mixture was stirred at room temperature for 4 hours. 100 g of water was added, and the aqueous layer was separated. To the obtained aqueous layer, 50 g of 20% brine was added, and the target compound was extracted with 100 g of ethyl acetate. From the remaining aqueous layer, the target compound was extracted again with 50 g of ethyl acetate. The obtained ethyl acetate layer was concentrated under reduced pressure. To the resulting residue, 50 g of toluene was added, and the resulting white crystals were collected by filtration. Then, it dried at 40 degreeC under pressure reduction.
Yield: 49.5 g
Yield: 95%
Melting point: 122-124 ° C
¹ H-NMR (CDCl ₃ , 270 MHz) δ 6.94 (d, 2H, J = 8.6 Hz), 6.73 (d, 2H, 8.6 Hz), 6.52 (s, 1H), 6.02 (D, 1H, J = 7.9 Hz), 4.87 (ddd, 1H, J = 5.9, 6.1, 7.9 Hz), 3.74 (s, 3H), 3.09 (dd, 1H, J = 5.9, 14.2 Hz), 2.97 (dd, 1H, J = 6.1, 14.2 Hz), 1.99 (s, 3H)

[Production of N-acetyl-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -L-tyrosine methyl ester]

30.0 g of the N-acetyl-L-tyrosine methyl ester obtained above is dissolved in 300 g of 1,2, -dichloroethane, and 61.6 g of β-pentaacetylglucose and 21.5 g of boron trifluoride diethyl ether complex are added. Reaction was performed in the range of 35-45 degreeC for 4 hours. After completion of the reaction, the reaction yield was 81% by HPLC analysis. Subsequently, the reaction solution was cooled to 15 ° C. or lower, and a solution obtained by dissolving 50 g of sodium carbonate in 300 g of water was dropped. The organic layer was fractionated after stirring at 15 degrees C or less for 1 hour. After washing with 100 g of water, the organic layer was concentrated under reduced pressure. 180 g of ethyl acetate was added to the obtained residue, and the mixture was cooled and stirred at 0 to 10 ° C. for 30 minutes to crystallize the target compound. The obtained crystals were collected by filtration and subsequently dried at 40 ° C. under reduced pressure.
Yield: 51.3g
Yield: 72%
Melting point: 178-180 ° C
¹ H-NMR (CDCl ₃ , 270 MHz) δ 7.01 (d, 2H, J = 8.6 Hz), 6.90 (d, 2H, J = 8.6)
Hz), 5.89 (d, 1H, J = 7.6 Hz), 5.34-5.22 (m, 2H), 5.17 (t, 1H, J = 9.7 Hz), 5.07 ( d, 1H, J = 7.6 Hz), 4.86 (ddd, 1H, J = 5.3, 5.9, 7.6 Hz), 4.29 (dd, 1H, J = 5.3, 12. 5 Hz), 4.17 (dd, 1H, J = 2.3, 12.5 Hz), 3.86 (ddd, 1H, J = 2.3, 5.3, 9.7 Hz), 3.73 (s , 3H), 3.12 (dd, 1H, J = 5.9, 13.8 Hz), 3.05 (dd, 1H, J = 5.3, 13.8 Hz), 2.08, 2.07, 2.05, 2.04 and 1.99 (5s, each 3H)

[Production of N-acetyl-O-β-D-glucopyranosyl-L-tyrosine methyl ester]

35.0 g of N-acetyl-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -L-tyrosine methyl ester obtained above was suspended in 175 g of methanol, and 28 % Sodium methoxide methanol solution 1.2g was added and it stirred at room temperature for 1 hour. Subsequently, it was neutralized with 15 g of a strongly acidic resin (Amberlite 120B plus). After removing the resin by filtration, the filtrate was concentrated under reduced pressure and crystallized from 30 g of methanol. The target compound was collected by filtration and dried at 40 ° C. under reduced pressure.
Yield: 24.6g
Yield: Quantitative melting point: 170-172 ° C
¹ H-NMR (D ₂ O, 270 MHz) δ 7.17 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H, J = 8.3 Hz), 5.04 (d, 1H, J = 7.3 Hz), 4.60 (dd, 1 H, J = 5.9, 8.6 Hz), 3.88 (dd, 1 H, J =
2.0, 12.0 Hz), 3.73-3.67 (m, 1H), 3.67 (s, 3H), 3.60-3.51 (m, 3H),
3.44 (t, 1H, J = 9.2 Hz), 3.11 (dd, 1H, J = 5.9, 14.2 Hz), 2.92 (dd, 1H, J =
(8.6 Hz, 14.2 Hz)

Production of N-acetyl-O-β-D-glucopyranosyl-L-tyrosine

24.6 g of N-acetyl-O-β-D-glucopyranosyl-L-tyrosine methyl ester obtained in Example 1 was dissolved in 123 g of methanol, and 23.2 ml of 4N sodium hydroxide aqueous solution at a temperature of 0 to 10 ° C. Was dripped. The reaction solution was stirred at a temperature of 0 to 10 ° C. for 1 hour and then neutralized with 35 g of a strongly acidic resin (Amberlite 120B plus). After removing the resin by filtration, the filtrate was concentrated under reduced pressure, and 20 g of water was added to the residue, followed by concentration under reduced pressure. 15 g of water was added to the obtained residue, and the target compound was crystallized by cooling and stirring at 0 to 5 ° C. The obtained white crystals were collected by filtration and dried at 40 ° C. under reduced pressure.
Yield: 13.5g
Yield: 57%
Melting point: 215 ° C. (decomposition)
¹ H-NMR (D ₂ O, 270 MHz) δ 7.19 (d, 2H, J = 8.2 Hz), 7.03 (d, 2H, J = 8.2 Hz), 5.05 (d, 1H, J = 6.9 Hz), 4.56 (dd, 1 H, J = 5.3, 8.7 Hz), 3.88 (d, 1 H, J =
5.6 Hz), 3.69 (dd, 1H, J = 5.6, 12.5 Hz), 3.59-3.40 (m, 4H), 3.14 (dd,
1H, J = 5.3, 14.2 Hz), 2.93 (dd, 1H, J = 8.7, 14.2 Hz), 1.89 (s, 3H)

Production of N-stearoyl-O-β-D-glucopyranosyl-L-tyrosine methyl ester
[Production of N-stearoyl-L-tyrosine methyl ester]

A solution prepared by suspending 5.0 g of L-tyrosine methyl ester hydrochloride in 50 g of toluene and adding 4 g of sodium hydrogen carbonate dissolved in 25 g of water was added, followed by stirring at 0 to 10 ° C. for 15 minutes. Subsequently, 7.85 g of stearoyl chloride was added dropwise at 0 to 10 ° C. After completion of the addition, the reaction solution was warmed to room temperature and stirred for 8 hours. The target compound precipitated in the reaction solution was collected by filtration and washed successively with 20 g of toluene and 20 g of water. The obtained white crystals were dried at 40 ° C. under reduced pressure.
Yield: 9.65 g
Yield: 97%
Melting point: 104-106 ° C
¹ H-NMR (CDCl ₃ , 270 MHz) δ 6.96 (d, 2H, J = 8.6 Hz), 6.74 (d, 2H, J = 8.4)
Hz), 5.90 (d, 1H, J = 7.9 Hz), 5.72 (s, 1H), 4.89 (ddd, 1H, J = 5.6, 6.0,
7.9 Hz), 3.75 (s, 3H), 3.10 (dd, 1H, J = 5.6, 13.9 Hz), 3.00 (dd, 1H, J =
6.0 Hz), 2.18 (t, 2H, J = 7.2 Hz), 1.62-1.57 (m, 2H), 1.26 (s, 28H), 0.89 (t, 3H, J = 6.6Hz)

[Production of N-stearoyl-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -L-tyrosine methyl ester]

Dissolve 2.31 g of the N-stearoyl-L-tyrosine methyl ester obtained above in 35 g of 1,2-dichloroethane, add 2.44 g of β-pentaacetylglucose and 0.84 g of boron trifluoride diethyl ether complex, Reaction was performed in the range of 35-45 degreeC for 6 hours. After completion of the reaction, the reaction yield was 78% by HPLC analysis. Subsequently, the reaction solution was cooled to 15 ° C. or less, and 5 g of sodium carbonate dissolved in 30 g of water was added dropwise. The organic layer was fractionated after stirring at 15 degrees C or less for 1 hour. After washing with 20 g of water, the organic layer was concentrated under reduced pressure. 2 g of ethyl acetate and 2 g of hexane were added to the obtained residue, and the target compound was crystallized by cooling and stirring at 0 to 10 ° C. for 30 minutes. The obtained crystal was dried at 40 ° C. under reduced pressure.
Yield: 2.5g
Yield: 63%
Melting point: 109-111 ° C
¹ H-NMR (CDCl ₃ , 270 MHz) δ 7.01 (d, 2H, J = 8.6 Hz), 6.90 (d, 2H, J = 8.6)
Hz), 5.85 (d, 1H, J = 7.9 Hz), 5.30-5.13 (m, 3H), 5.06 (d, 1H, J = 7.6 Hz), 4.91- 4.86 (m, 1H), 4.30 (dd, 1H, J = 5.3, 12.2 Hz), 4.16 (dd, 1H, J = 2.3, 12.2 Hz), 3.89 -3.83 (m, 1H), 3.73 (s, 3H), 3.10-3.07 (m, 2H), 2.18 (t, 2H, J = 7.6 Hz), 2.08 , 2.07, 2.05 and 2.04 (4s, each 3H), 1.63-1.58 (m, 2H), 1.26 (s, 28H), 0.88 (t, 3H, J = 6) .6Hz)

[Production of N-stearoyl-O-β-D-glucopyranosyl-L-tyrosine methyl ester]

1.5 g of N-stearoyl-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -L-tyrosine methyl ester obtained in reaction 2 was dissolved in 20 g of methanol, The 0.2% 28% sodium methoxide methanol solution was added. The reaction solution was stirred at room temperature for 3 hours and quenched with 1.1 ml of 1N hydrochloric acid. 30 g of ethyl acetate and 30 g of water were added to the reaction solution, and the organic layer was separated.
The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain the desired amorphous residue.
Yield: 1.09 g
Yield: 92%
¹ H-NMR (DMSO-d6, 270 MHz) δ 8.21 (d, 1H, J = 7.6 Hz), 7.11 (d.2H, J =
8.6 Hz), 6.92 (d, 2 H, J = 8.6 Hz), 5.26 (d, 1 H, J = 4.6 Hz), 5.05 (d, 1 H, J = 4.3 Hz), 4.99 (d, 1H, J = 5.0 Hz), 4.79 (d, 1H, J = 7.3 Hz), 4.53 (t, 1H, J =
5.8 Hz), 4.39 (ddd, 1H, J = 5.8, 7.6, 9.2 Hz), 3.71-3.64 (m, 1H), 3.58 (s, 3H), 3.50-3.39 (m, 2H), 3.30-3.12 (m, 3H), 2.94 (dd, 1H, J = 5.8, 13.7 Hz), 2.81 (dd , 1H, J = 9.2, 13.7 Hz), 2.04 (t, 2H, J = 7.1 Hz), 1.46
1.35 (m, 2H), 1.24 (s, 28H), 0.85 (t, 3H, J = 6.6 Hz)

Production of N-stearoyl-O-β-D-glucopyranosyl-L-tyrosine

625 mg of N-stearoyl-O-β-D-glucopyranosyl-L-tyrosine methyl ester obtained in Example 3 was dissolved in 15 g of methanol, and 1 mL of 2N sodium hydroxide aqueous solution was added at room temperature. The reaction solution was stirred at room temperature for 1 hour and then treated with 1 g of a strongly acidic resin (Amberlite IR-120B plus). After the resin was filtered off, the filtrate was concentrated under reduced pressure to obtain the desired amorphous residue.
Yield: 610 mg
Yield: 100%
¹ H-NMR (DMSO-d6, 270 MHz) δ 8.03 (d, 1H, J = 7.9 Hz), 7.12 (d, 2H, J =
8.9 Hz), 6.91 (d, 2H, J = 8.9 Hz), 5.25 (d, 1H, J = 4.5 Hz), 5.05 (s, 1H),
4.99 (s, 1H), 4.79 (d, 1H, J = 7.3 Hz), 4.53 (t, 1H, J = 5.5 Hz), 4.35 (ddd,
1H, J = 4.9, 7.9, 9.2 Hz), 3.71-3.63 (m, 1H), 3.50-3.15 (m, 5H), 2.96 (dd, 1H) , J = 4.9 Hz, 13.9 Hz), 2.79 (dd, 1H, J-9.2, 13.9 Hz), 2.04 (t, 2H, J = 6.6 Hz), 1.45 1.35 (m, 2H), 1.23 (s, 28H), 0.85 (t, 3H, J = 6.6 Hz)

Production of N-carbobenzoxy-O-β-D-glucopyranosyl-L-tyrosine methyl ester
[Production of N-carbobenzoxy-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -L-tyrosine methyl ester]

40 g of N-carbobenzoxy-L-tyrosine methyl ester is dissolved in 600 g of 1,2-dicololoethane, and 58.9 g of β-pentaacetylglucose and 20.6 g of boron trifluoride diethyl ether complex are added. The reaction was carried out for 6 hours. After completion of the reaction, the reaction yield was 80% by HPLC analysis. Subsequently, the reaction solution was cooled to 15 ° C. or lower, and a solution obtained by dissolving 48 g of sodium carbonate in 430 g of water was added dropwise. The organic layer was fractionated after stirring at 15 degrees C or less for 1 hour. After washing twice with 300 g of 2% brine, the organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. 80 g of ethyl acetate and 80 g of hexane were added to the obtained residue, and the target compound was crystallized by cooling and stirring at 0 to 10 ° C. for 2 hours. The obtained crystals were collected by filtration and subsequently dried at 40 ° C. under reduced pressure.
Yield: 55g
Yield: 69%
Melting point: 110-112 ° C
¹ H-NMR (CDCl ₃ , 270 MHz) δ 7.39-7.29 (m, 5H), 7.01 (d, 2H, J = 8.6 Hz), 6.89 (d, 2H, J = 8. 6Hz), 5.33-5.03 (m, 6H), 5.04 (d, 1H, J = 7.5 Hz),
4.66-4.61 (m, 1H), 4.29 (dd, 1H, J = 5.3, 12.2 Hz), 4.16 (dd, 1H, J = 2.3 Hz), 3.87 -3.81 (m, 1H), 3.72 (s, 3H), 3.09-3.05 (m, 2H), 2.07, 2.06, 2.05 and 2.03 (4s, each 3H) )

[Production of N-carbobenzoxy-O-β-D-glucopyranosyl-L-tyrosine methyl ester]

45 g of N-carbobenzoxy-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -L-tyrosine methyl ester obtained above was suspended in 225 g of methanol and 28% Sodium methoxide methanol solution was added and stirred at room temperature for 2 hours. The reaction solution was treated with 44 g of a strongly acidic resin (Amberlite IR-120B plus), and then the resin was filtered off. The filtrate was concentrated under reduced pressure, 115 g of water was added to the resulting residue, and the mixture was stirred at room temperature for 30 minutes. Then, it cooled and stirred at 0-10 degreeC for 1 hour, and the target compound which precipitated was filtered. The obtained white crystals were dried at 40 ° C. under reduced pressure.
Yield: 31.9 g
Yield: 95%
Melting point: 172-174 ° C
¹ H-NMR (CD ₃ OD, 270 MHz) δ 7.36-7.28 (m, 5H), 7.11 (d, 2H, J = 8.6 Hz), 7.01 (d, 2H, J = 8) .6 Hz), 5.03 (s, 2H), 4.87 (d, 1H, J = 7.6 Hz), 4.40 (dd,
1H, J = 5.6, 8.9 Hz), 3.89 (d, 1H, J = 13.6 Hz), 3.73-3.62 (m, 1H), 3.69 (s, 3H), 3.47-3.38 (m, 4H), 3.09 (dd, 1H, J = 5.6, 14.0 Hz), 2.89 (dd,
1H, J = 8.9, 14.0 Hz)

Production of O-β-D-glucopyranosyl-L-tyrosine
[Production of N-carbobenzoxy-O-β-D-glucopyranosyl-L-tyrosine]

20.0 g of N-carbobenzoxy-O-β-D-glucopyranosyl-L-tyrosine methyl ester obtained in Example 5 was dissolved in 200 g of methanol, and 15.3 mL of 4N sodium hydroxide aqueous solution was added, and the mixture was brought to room temperature. And stirred for 1 hour. The reaction solution was treated with 44 g of a strongly acidic resin (Amberlite IR-120B plus), and then the resin was filtered off. The filtrate was concentrated under reduced pressure to obtain the target compound as an amorphous solid.
Yield: 19.0 g
Yield: 98%
¹ H-NMR (CD ₃ OD, 270 MHz) δ 7.32-7.29 (m, 5H), 7.13 (d, 2H, J = 8.6 Hz), 7.00 (d, 2H, J = 8) .6 Hz), 5.03 (s, 2H), 4.85-4.70 (m, 1H), 4.38 (dd, 1H, J = 5.0, 8.8 Hz), 3.88 (d , 1H, J = 11.9 Hz), 3.69 (dd, 1H, J = 4.0, 11.5 Hz), 3.46-3.41 (m, 4H), 3.13 (dd, 1H, J = 5.0, 13.8 Hz), 2.88 (dd, 1H, J = 8.8, 13.8 Hz)

[Production of O-β-D-glucopyranosyl-L-tyrosine]

19.0 g of N-carbobenzoxy-O-β-D-glucopyranosyl-L-tyrosine obtained above was dissolved in 200 g of methanol, and 3.0 g of 10% palladium-carbon catalyst (50% water-containing product) was added. The mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere (atmospheric pressure). After completion of the reaction, 1000 g of water was added, the precipitated target compound was dissolved, and the catalyst was filtered off using celite. The filtrate was concentrated under reduced pressure, and 15 g of water and 15 g of ethanol were added to the resulting residue, followed by stirring at 0 to 10 ° C. for crystallization. The obtained white crystals were collected by filtration and dried at 40 ° C. under reduced pressure.
Yield: 10.6 g
Yield: 77%
Melting point: 260 ° C (decomposition)
¹ H-NMR (D ₂ O, 270 MHz) δ 7.23 (d, 2H, J = 8.9 Hz), 7.08 (d, 2H, J = 8.9 Hz), 5.08 (d, 1H, J = 7.5 Hz), 3.94-3.85 (m, 2H), 3.70 (dd, 1H, J = 5.6, 12.2 Hz), 3.62-3.52 (m, 4H) 3.45 (t, 1H, J = 9.2 Hz), 3.20 (dd, 1H, J = 5.3)
14.4 Hz), 3.04 (dd, 1H, J = 7.9, 14.4 Hz)

Antibacterial tests were performed on the compounds obtained in Examples 2 and 6.
[Test method]
The cells were inoculated on a sterile petri dish containing a medium having a diameter of 9 cm, and an antibacterial test was performed at a sample concentration of 100 ppm at 25 ° C. The following pathogenic bacteria were implemented.
Rice blight fungus: Pellicularia sasakii (hereinafter abbreviated as “PS”)
Gray mold fungus: Botrytis cinerea (hereinafter abbreviated as “BC”)
Apple leaf spot fungus: Alternaria mali (hereinafter abbreviated as “AM”)
Cucumber vine split disease fungus: Fusarium oxysporus f. Sp. Cucumerinum (hereinafter abbreviated as “FO”)
Moreover, the inhibition rate was calculated | required with the following formula | equation.
Inhibition rate (%) = [(control hyphal elongation−treated hyphal elongation) / control hyphal elongation] × 100
[Test results]
Antibacterial activity was observed in the compounds described in Examples 2 and 6. The test results are shown in Table 1.

  The present invention is useful for providing a novel tyrosine glycoside. Moreover, since the novel tyrosine glycoside of the present invention has an antibacterial action, it is useful as a bactericidal agent.

Claims (9)

General formula (1)

(Wherein R 1 represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 30 carbon atoms, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted heterocyclic group. Or an alkali metal or alkaline earth metal salt of the compound. General formula (2)

(Wherein R1 is synonymous with R1 in general formula (1) according to claim 1). General formula (3)

(Wherein R1 represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 30 carbon atoms, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted heterocyclic group, R2 represents an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, an unsubstituted or substituted aralkyl group, or an unsubstituted or substituted phenyl group. General formula (4)

(Wherein R2 has the same meaning as R2 in formula (3) of claim 3) or an acid salt thereof and R1-CO-X (wherein R1 is defined in claim 3). A compound represented by the same formula as R1 in formula (3), wherein X is a halogen atom or O—CO—R1 (R1 is the same as R1 in formula (3) according to claim 3). Is reacted in the presence of a base to give a general formula (5)

(Wherein R1 and R2 have the same meanings as R1 and R2 in general formula (3) according to claim 3), and then a compound represented by general formula (5) By reacting pentaacetylglucose in the presence of an acid catalyst, the general formula (6)

(Wherein R1 and R2 have the same meanings as R1 and R2 in general formula (3) according to claim 3), and then the compound represented by general formula (6) is prepared. General formula (3) for deprotecting an acetyl group on a glucose residue

(Wherein R1 and R2 have the same meanings as R1 and R2 in general formula (3) according to claim 3). General formula (7)

(Wherein R2 has the same meaning as R2 in formula (3) of claim 3) or an acid salt thereof and R1-CO-X (wherein R1 is claim 3). In the general formula (3), and X is a halogen atom or O—CO—R1 (R1 is the same as R1 in the general formula (3) of claim 3). The compound is reacted in the presence of a base to give the general formula (8)

(Wherein R1 and R2 are synonymous with R1 and R2 in the general formula (3) according to claim 3), and then the compound represented by the general formula (8) By reacting pentaacetylglucose in the presence of an acid catalyst, the general formula (9)

(Wherein R1 and R2 are synonymous with R1 and R2 in the general formula (3) of claim 3), and then the compound represented by the general formula (9) Deprotecting the acetyl group on the glucose residue, general formula (10)

(Wherein R1 and R2 have the same meanings as R1 and R2 in general formula (3) according to claim 3). The production method according to claim 4 or 5, wherein the acid catalyst is boron trifluoride (BF3). Formula (11)

(Wherein R2 is synonymous with R2 in general formula (3) of claim 3) and pentaacetylglucose are reacted in the presence of boron trifluoride (BF3). (12)

(Wherein R2 is synonymous with R2 in general formula (3) according to claim 3), and then on the glucose residue of the compound represented by general formula (12). Deprotecting the acetyl group of general formula (13)

(Wherein R2 is synonymous with R2 in general formula (3) according to claim 3). The compound represented by the general formula (13) according to claim 7 is hydrolyzed to produce N-carbobenzoxy-O-β-D-glucopyranosyl-L-tyrosine, and then the N-carbobenzoxy- A method for producing O-β-D-glucopyranosyl-L-tyrosine, wherein hydrogenolysis of O-β-D-glucopyranosyl-L-tyrosine is further performed. General formula (1)

(Wherein R 1 represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 30 carbon atoms, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted heterocyclic group. Or a fungicide comprising an alkali metal or alkaline earth metal salt of the compound.