WO2001019777A1 - $G(a)-CETO ESTERS ET LEURS PROCEDES DE PREPARATION - Google Patents

$G(a)-CETO ESTERS ET LEURS PROCEDES DE PREPARATION Download PDF

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Publication number
WO2001019777A1
WO2001019777A1 PCT/JP2000/006301 JP0006301W WO0119777A1 WO 2001019777 A1 WO2001019777 A1 WO 2001019777A1 JP 0006301 W JP0006301 W JP 0006301W WO 0119777 A1 WO0119777 A1 WO 0119777A1
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compound
group
formula
salt
reaction
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PCT/JP2000/006301
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English (en)
Japanese (ja)
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Makoto Yamashita
Toshiaki Nagata
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Takeda Chemical Industries, Ltd.
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Priority to AU73132/00A priority Critical patent/AU7313200A/en
Publication of WO2001019777A1 publication Critical patent/WO2001019777A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids

Definitions

  • the present invention provides a method for producing an oxazolidinedion derivative or a salt thereof, which has a blood sugar and blood lipid lowering effect and is useful as a therapeutic agent for diabetes and the like, and an important raw material intermediate in the course of the process.
  • EP-A 0 6 1 2 7 4 3 and ⁇ ⁇ —AO 7 10 6 5 9 describe oxazolidinedione derivatives or their salts that are important as pharmaceuticals such as antidiabetic drugs, and their production methods. ing. These methods use an ester compound (eg, EP-A0) in which a hydroxyl group on a benzene ring of an ester compound (a compound represented by the following formula (II) or a salt thereof) is substituted with an expensive aromatic alkyl group. (A compound represented by the formula (IX-6) or a salt thereof) of 71059 is used as a starting compound.
  • Japanese Patent Application Laid-Open Nos. H10-12026 and H10-1262022 disclose a keketoester which is an alkyloxy substituted with a substituent on a benzene ring. No disclosure is made of ⁇ -ketoester in which the above substituent is a hydroxy group.
  • the present inventors have conducted intensive studies to solve the above problems, and as a result, for the first time, synthesized a novel ⁇ -ketoester (a compound represented by the following formula (I) or a salt thereof), When used as an intermediate for the synthesis of various drugs such as therapeutic agents, it is possible to unexpectedly obtain the desired product by using high-yield, high-purity and inexpensive raw materials. As a result, they found that an industrially advantageous production method could be provided, and based on these findings, completed the present invention.
  • a novel ⁇ -ketoester a compound represented by the following formula (I) or a salt thereof
  • R represents a hydrocarbon group.
  • R represents a hydrocarbon group.
  • salt thereof
  • R ′ represents a hydrocarbon group.
  • R'OOC-COOR [wherein, R represents a hydrocarbon group; R "represents a hydrogen atom or a hydrocarbon group.]
  • Formula (I) characterized in that the ester, its salt or its reactive derivative is condensed and then subjected to a decarboxylation reaction.
  • R and R ′ represent the same or different hydrocarbon groups.
  • the compound represented by the formula (I) or a salt thereof is subjected to a decarboxylation reaction.
  • R and R ′ are the same or different and represent a hydrocarbon group. ] Or a salt thereof;
  • R represents a hydrocarbon group.
  • R represents a hydrocarbon group.
  • R ′ represents a hydrocarbon group. And a salt thereof and a compound of the formula (III): R'OOC-COOR wherein R is a hydrocarbon group; R "is a hydrogen atom or a hydrocarbon group Is shown. And a salt or a reactive derivative thereof represented by the formula (IV)
  • R a is an optionally substituted heterocyclic group or an optionally substituted carbon hydrocarbon radical
  • R b is a hydrogen atom or a flicking 4 alkyl group
  • Y one CO-, -CH
  • examples of the hydrocarbon group represented by R or R ′ include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, and an aromatic-aliphatic hydrocarbon group.
  • aliphatic hydrocarbon group 1 to carbon atoms: L5 linear or branched aliphatic hydrocarbon group such as alkyl group, C 2 - 1 5 alkenyl group, C 2 - 1 5 alkynyl group And the like.
  • alkyl group examples include an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and Ethylpropyl, Examples include hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, and decyl. It is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or an ethyl group.
  • alkenyl group examples include alkenyl groups having 2 to 10 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl (allyl), 2-methyl-1-propenyl. , 2-methyl_2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- Pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.
  • alkynyl group examples include alkynyl groups having 2 to 10 carbon atoms such as ethynyl, 1-propynyl, 2-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.
  • the alicyclic hydrocarbon group, 3 carbon 12 saturated or alicyclic carbon hydrocarbon radical of unsaturated, e.g., C 3 ⁇ 2 cycloalkyl group, C 2 cycloalkenyl group, C 5 - 1 2 A cycloalkadienyl group;
  • cycloalkyl group examples include a cycloalkyl group having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [ 2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, and the like.
  • cycloalkenyl group examples include cycloalkenyl groups having 3 to 10 carbon atoms, such as 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, and 2-cyclohexene-11. —Yl, 3-cyclohexene-1 f1 and the like.
  • cycloalkadienyl group examples include cycloalkyl having 5 to 10 carbon atoms.
  • Lukadienyl groups include, for example, 2,4-cyclopentene-1-yl, 2,4-cyclohexene-1-yl, 2,5-cyclohexene-1-yl and the like.
  • aromatic hydrocarbon group examples include monocyclic or condensed polycyclic aromatic hydrocarbons having 6 to 16 carbon atoms (e.g., aryl groups and the like), for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, Biphenyl is preferred. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
  • aromatic monoaliphatic hydrocarbon group examples include phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl and 3-phenylpropyl, and naphthylalkyl having 11 to 13 carbon atoms. And, for example, ⁇ -naphthylmethyl, 1-naphthylethyl and the like.
  • the hydrocarbon group represented by R or R ' is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably methyl or ethyl.
  • the most preferred is 5- (4-hydroxyphenyl) -12-oxopentanoate or a salt thereof, or 5- (4-hydroxyphenyl) _ Methyl 2-oxopentanoate or a salt thereof.
  • the compound of the present invention represented by the formula (I) or a salt thereof (hereinafter sometimes referred to as compound (I).
  • compound (I) means a compound represented by the formula (II) or a salt thereof.
  • Compound (I) is obtained by combining compound ( ⁇ ) with a compound which can be produced by a method known per se.
  • the compound (IV) is obtained by condensing an oxalate, a salt thereof or a reactive derivative thereof represented by the formula (1), followed by decarboxylation by heating or the like.
  • Examples of the hydrocarbon group represented by R include the same as the hydrocarbon group represented by R.
  • R is preferably an alkyl group having 1 to 4 carbon atoms, more preferably Et al.
  • R and R may be the same or different, but are preferably the same.
  • Examples of the reactive derivative of the oxalate represented by the formula (III) include, for example, acid anhydride, acid halide (acid chloride, acid bromide), imidazolide or mixed Acid anhydrides (eg, anhydrides with methyl carbonate, anhydrides with ethyl carbonate, etc.) are examples.
  • QaOC-COOR [where Q a is desorbed A group (eg, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc., and R is as defined above.) And the like.
  • a group eg, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc., and R is as defined above.
  • reaction of the compound (II) with the oxalate represented by the formula (III), a salt thereof or a reactive derivative thereof is advantageously performed in a suitable solvent in the presence of a base.
  • the solvent examples include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; and acetylene, diisopropyl ether, dioxane, and tetrahydrofuran. Ethers; halogenated hydrocarbons such as formaldehyde, dichloromethane, and 1,1,2,2-tetrachloroethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide; dimethyl And sulfoxides such as sulfoxide.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • acetylene diisopropyl ether, diox
  • solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the solvent to be used is generally 1- to L00-fold (v / w), preferably 1- to 20-fold (vZw), relative to compound ( ⁇ ).
  • the solvent is preferably an alcohol such as ethanol.
  • Examples of the base include metal alkoxides such as sodium ethoxide, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide.
  • the amount of the base to be used is 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (II).
  • the base is preferably potassium tert-butoxide.
  • the amount of the oxalate represented by the formula (in) to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound ⁇ ).
  • the reaction temperature is usually from ⁇ 50 ° C. to 150 °, preferably from 110 ° C. (: up to 100 ° C.)
  • the reaction time is generally from 0.5 to 50 hours, preferably from 1 to 50 ° C.
  • the compound (IV) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound (IV) may be used in the next reaction as it is in the reaction mixture.
  • Compound (IV) is a novel compound, and in particular, a compound in which R and R 'are ethyl groups is useful as a synthetic intermediate.
  • Compound (I) can be produced by subjecting compound (IV) to a decarboxylation reaction.
  • This decarboxylation reaction is usually carried out by heating in a mixed solvent of water and a polar solvent such as hydrated dimethylformamide or hydrated dimethyl sulfoxide in the presence or absence of sodium chloride or lithium chloride.
  • the amount of sodium chloride or lithium chloride to be used is generally 0 to 5 molar equivalents, preferably 0 to 2 molar equivalents, relative to compound (IV).
  • the reaction temperature is usually 50 to 150, preferably 80 to 130.
  • the reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.
  • the compound (I) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • separation and purification means for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the solvent examples include alcohols such as methanol, ethanol, n-propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; getyl ether, diisopropyl ether, dioxane, tetrahydrofuran and the like. Ethers; amides such as ⁇ , ⁇ -dimethylformamide; sulfoxides such as dimethylsulfoxide; and esters such as acetic acid. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the solvent to be used is generally 1- to 100-fold (vZw), preferably 1- to 20-fold (vZw) the amount of 4-hydroxyphenylacetaldehyde.
  • Examples of the base include alkali metal salts such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and potassium hydroxide; amines such as pyridine, triethylamine, N, N-dimethylaniline; sodium hydride; Metal hydrides such as potassium hydride; metal alkoxides such as sodium ethoxide, sodium methoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • the amount of the base to be used is generally 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 4-hydroxyphenylacetaldehyde.
  • the amount of pyruvic acid to be used is generally 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 4-hydroxyphenylacetaldehyde.
  • This reaction is usually carried out at 150: to 150, preferably at _10 ° C to 100. It is.
  • the reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.
  • the compound (XII) is subjected to an esterification reaction to produce a compound (XIII).
  • This esterification reaction can be carried out by a method known per se, for example, compound (XII) and alcohols (R OH) [R has the same meaning as described above.
  • an acid for example, an acid anhydride, an acid halide (an acid chloride, an acid bromide), an imidazolide or a mixed acid anhydride (eg, For example, a method of appropriately reacting an anhydride with methyl carbonic acid, an anhydride with ethyl carbonic acid, etc.) with an alcohol (ROH) is used.
  • the amount of the alcohol (R ⁇ H) to be used is generally 1 to 100 molar equivalents, preferably 1 to 30 molar equivalents, relative to compound (XII).
  • the compound (XIII) is subjected to a reduction reaction to produce a compound (I).
  • This reduction reaction can be performed by a method known per se. Examples of the reduction reaction include reduction with a metal hydride, reduction with a metal hydride complex, reduction with diborane and substituted borane, catalytic hydrogenation, and the like.
  • the reduction reaction is performed by treating compound (XIII) with a reducing agent in an organic solvent that does not affect the reaction.
  • a reducing agent examples include alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.); metal hydride complex compounds such as lithium aluminum hydride; metal hydrides such as sodium hydride; organotin compounds ( Metal and metal salts such as nickel compounds and zinc compounds; catalytic reducing agents using a transition metal catalyst such as palladium, platinum, rhodium, ruthenium and iridium and hydrogen; and diborane.
  • the amount of the reducing agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XIII).
  • the solvent examples include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, diisopropyl ether, dioxane, and the like.
  • Ethers such as tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide.
  • These solvents are two kinds The above may be mixed and used at an appropriate ratio.
  • the amount of the solvent to be used is generally 1- to 100-fold (vZw), preferably 1- to 20-fold (vZw), relative to compound (XIII).
  • the reaction temperature is usually from ⁇ 20 ° C. to 150 ° C., preferably from 0 ° C. to 100 ° C.
  • the reaction time is generally 0.5 to 24 hours, preferably 1 to 12 hours.
  • the compound (I) thus obtained can be isolated and purified by a known separation and purification means such as concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • a known separation and purification means such as concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • -Compounds (XII) and (XIII) may be isolated and purified by known separation and purification means, or may be used as a reaction mixture in the next reaction.
  • R 2 represents an alkyl group having 1 to 4 carbon atoms.
  • Examples of the alkyl group having 1 to 4 carbon atoms represented by R 2 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.
  • phosphate ester (XIV) is the It is produced by brominating hydantoin and then reacting with a trialkyl phosphite according to the method described in Strey, Vol. 56, p. 6977, 1991.
  • This condensation reaction is performed in a solvent in the presence of a base.
  • the solvent examples include alcohols such as methanol, ethanol, n-propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; getyl ether, diisopropyl ether, dioxane, tetrahydrofuran and the like.
  • Ethers esters such as ethyl acetate and methyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide; dimethyl Sulfoxides such as sulfoxide; carboxylic acids such as acetic acid;
  • These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the solvent used is usually 1 to 100 times (v Zw) with respect to 4-hydroxyphenylpropionaldehyde, preferably:! 110 times (v Zw).
  • the base examples include metal salts such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, hydroxide hydroxide and the like; amines such as pyridine, triethylamine, and ⁇ , ⁇ -dimethylaniline; hydrogen Metal hydrides such as sodium hydride and potassium hydride; metal alkoxides such as sodium ethoxide, sodium methoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • the amount of the base to be used is generally 0.1 to 5 molar equivalents, preferably 0.5 to 2 molar equivalents, relative to 4-hydroxyphenylpropionaldehyde.
  • the amount of hydantoin or compound (XIV) to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to 4-hydroxyphenylpropionaldehyde.
  • the reaction temperature is generally 0: to 150, preferably 10 to 60 :.
  • the reaction time is generally 5 to 50 hours, preferably 1 to 24 hours.
  • the compound (XV) is subjected to a hydrolysis reaction to produce a compound (XVI).
  • This hydrolysis reaction is carried out in a water-containing solvent in the presence of potassium hydroxide or sodium hydroxide. Performed in the presence of a base.
  • the solvent to be used include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran.
  • Ethers of halogen halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachlorobenzene; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide And the like.
  • These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the solvent to be used is generally 1- to 100-fold (v / w), preferably 1- to 10-fold (v / w), relative to compound (XV).
  • the amount of the strong base to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XV).
  • the compound (I) thus obtained can be isolated and purified by a known separation and purification means such as concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compounds (XV) and (XVI) may be isolated and purified by known separation and purification means, or may be used as a reaction mixture in the next reaction.
  • X a is fluorine, chlorine, bromine, a halogen atom such as iodine. Of these, chlorine and bromine are preferred.
  • a compound (XVII) 4-hydroxyphenylpropionaldehyde is reduced To produce a compound (XVII).
  • the reduction reaction is performed in the same manner as the reduction reaction in the above-mentioned Method B.
  • the compound (XVHI) can be produced by subjecting the compound (XVII) to a halogenation reaction known per se (eg, chlorination with thionyl chloride, bromination with phosphorus tribromide, etc.).
  • the compound ( ⁇ ) is subjected to a Grignard reaction (for example, the method described in Synthesis Communications, Vol. 11, p. 943, 1981) to produce the compound (I). Can be.
  • a Grignard reaction for example, the method described in Synthesis Communications, Vol. 11, p. 943, 1981
  • the solvent aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as getyl ether, diisopropyl ether, dioxane and tetrahydrofuran are used. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the solvent to be used is generally 1 to 100 times (v Zw), preferably 1 to 20 times (v / w) based on 4-hydroxyphenylpropionaldehyde.
  • the reaction temperature is usually from 150 ° C. to 150, preferably from ⁇ 20 to 100.
  • the reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.
  • the compound (I) thus obtained can be isolated and purified by a known separation and purification means such as concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compounds (XVII) and (XVIII) may be isolated and purified by known separation and purification means, or may be used as a reaction mixture in the next reaction.
  • R 3 and R 4 are the same or different hydrocarbon groups; other symbols are as defined above.
  • Examples of the hydrocarbon group represented by R 3 or R 4 include the same as the hydrocarbon group represented by R, preferably an alkyl group having 1 to 4 carbon atoms.
  • 4-hydroxyphenylbutyronitrile and sulfide (XIX) are subjected to a condensation reaction to produce compound (XX), and then compound (XX) is treated with copper chloride to give compound (I). ) To manufacture.
  • the condensation reaction is performed in the same manner as the condensation reaction in the above-mentioned Method B.
  • the reaction between compound (XX) and copper chloride is carried out according to a method known per se (for example, the method described in Tetrahedron Res., Pp. 375, 1978).
  • Solvents used in this method include alcohols such as methanol, ethanol, n-propanolyl, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; getyl ether, diisopropyl ether, dioxane And ethers such as tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane, and 1,1,2,2-tetrachloromethane; amides such as N, N-dimethylformamide. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the solvent to be used is generally 1 to 100 times (v Zw), preferably 1 to 20 times (v Zw), relative to compound (XX).
  • the reaction temperature is usually from 120 to 150 :, preferably from 0 t to 100.
  • the reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.
  • the compound (I) thus obtained can be isolated and purified by a known separation and purification means such as concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound (XX) may be isolated and purified by a known separation and purification means, or may be used as a reaction mixture in the next reaction.
  • R 5 represents an alkyl group having 1 to 4 carbon atoms
  • R 7 represents a hydrogen atom, a substituted or unsubstituted silyl group, an alkyl group which may be substituted, or a cycloalkyl having 3 to 8 carbon atoms.
  • Q b is a leaving group, and other symbols are as defined above.
  • the alkyl group having 1 to 4 carbon atoms represented by R 5 for example methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec- heptyl, etc. tert- butyl.
  • Examples of the optionally substituted silyl group represented by R 7 include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like.
  • Examples of the optionally substituted alkyl group represented by R 7 include, for example, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl , Methylthiomethyl, phenylthiomethyl, phenacyl, cyclopropylmethyl, tert-butyl, benzyl, nitrobenzyl, 2,6-dimethylbenzyl, 4-methoxybenzyl, 2,6-dichlorobenzyl, 9-anthrylmethyl, 4-1 Picolyl, trityl and the like.
  • Examples of the cycloalkyl group having 3 to 8 carbon atoms represented by R 7 include, for example, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
  • one to three (preferably one) of carbon atoms as ring-constituting atoms may be substituted with an oxygen atom or a sulfur atom, and examples thereof include tetrahydrofuryl and tetrahydrofuryl. Vilanyl and the like.
  • the leaving group represented by Q b a halogen atom (e.g., fluorine, chlorine, bromine, iodine), methanesulfonyloxy O carboxymethyl, benzenesulfonyl O carboxymethyl, p- toluene sulfonyl O carboxymethyl and the like.
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine
  • compound (XXI) is reacted with compound (XXII) to produce compound (XXIII).
  • This reaction is performed in a suitable solvent in the presence of a base according to a conventional method.
  • the solvent examples include alcohols such as methanol, ethanol, n-propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; getyl ether, diisopropyl ether, dioxane, tetrahydrofuran and the like.
  • These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the solvent to be used is generally 1- to L00-fold (vZw), preferably 1- to 20-fold (vZw), relative to compound (XXI).
  • Examples of the base include alkali metal salts such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and potassium hydroxide; amines such as pyridine, triethylamine, N, N_dimethylaniline; sodium hydride; Metal hydrides such as potassium hydride; metal alkoxides such as sodium ethoxide, sodium methoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • the amount of these bases to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XXI).
  • the amount of compound (II) to be used is generally 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (XXI). You.
  • the reaction temperature is usually from ⁇ 50 ° C. to 150 ° C., preferably from ⁇ 10 ° C. to 100 ° C.
  • the reaction time is generally 0.5 to 30 hours, preferably 1 to 15 hours.
  • compound (XXIV) is produced by subjecting compound (II) to a reduction reaction. This reduction reaction is carried out according to a conventional method in a solvent, in the presence of a catalyst, in a hydrogen atmosphere of 0.1 to 5.1 MPa.
  • the solvent examples include alcohols such as methanol, ethanol, n-propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; getyl ether, diisopropyl ether, dioxane, tetrahydrofuran and the like. Ethers; halogenated hydrocarbons such as chloroform, dichloromethane, and 1,1,2,2-tetrachloromethane; esters such as ethyl acetate; acetic acid; N, N-dimethylformamide; Amides. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the solvent to be used is generally 1- to 100-fold (v Zw), preferably 1- to 20-fold (v / w), relative to compound (XXIII).
  • the catalyst examples include metals such as nickel compounds; transition metal catalysts such as palladium, platinum, rhodium, ruthenium, and iridium.
  • the reaction temperature is usually 0 to 150, preferably 10 to 120 ° C.
  • the reaction time is generally 0.5 to 100 hours, preferably 1 to 24 hours. .
  • the compound (XXIV) thus obtained is further subjected to a reduction reaction to produce a compound (XVIIa).
  • This reduction reaction can be performed by a method known per se. As such a method, for example, reduction with a metal hydride, reduction with a metal hydride complex compound, reduction with diborane and substituted borane, and the like are used.
  • the reduction reaction is carried out by treating compound (XXIV) with a reducing agent in an organic solvent that does not affect the reaction.
  • the reducing agent examples include alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.), metal hydrogen complex such as lithium aluminum hydride, diborane, etc., and among them, diisobutylaluminum hydride ⁇ Is preferred.
  • the amount of the reducing agent to be used is generally 1-10 mol equivalents, preferably 1-5 mol equivalents, relative to compound (XXIV).
  • the solvent examples include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; and getyl ether and diisopropyl alcohol.
  • Ethers such as ter, dioxane, and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloromethane; amides such as ⁇ , ⁇ -dimethylformamide; Is mentioned.
  • These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the solvent to be used is generally 1- to L00-fold (v / w), preferably 1- to 20-fold (v / w), relative to compound (XXIV).
  • the reaction temperature is usually from 120 to 150, preferably from 0 to 100.
  • the reaction time is generally 0.5 to 24 hours, preferably 1 to 12 hours.
  • Compound (XVIIa) are prepared by methods known per se, for example chlorinated by chloride Chioniru, phosphorus tribromide bromination or methanesulphonyl chloride according to Ri by the mesylation by, Q b is C l of each formula (XVIIIa), B r Or ⁇ a compound of SO 2 CH 3 can be produced.
  • the solvent examples include alcohols such as methanol, ethanol and n-propanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diisopropyl ether, dioxane and tetrahydrofuran; Halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide; sulfoxides such as dimethylsulfoxide; ketones such as acetone and 2-butaneone And the like. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as diisopropyl ether, dioxane and tetrahydrofuran
  • Halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane
  • amides such as N, N-dimethylformamide
  • the amount of the solvent to be used is generally 1- to 100-fold (v / w), preferably 1- to 20-fold (v / w), relative to compound (XVIIIa).
  • the amount of potassium cyanide or sodium cyanide to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XVIIIa).
  • the reaction temperature is generally 0 to 150 ° (: preferably 20 to 120 ° C.)
  • the reaction time is generally 0.5 to 30 hours, preferably 1 to 15 hours. is there.
  • compound (XXVI) is produced by subjecting compound (XXV) to a hydrolysis reaction.
  • This hydrolysis reaction is carried out in a water-containing solvent in the presence of an acid or a base, preferably in the presence of a mineral acid such as hydrochloric acid, sulfuric acid or nitric acid.
  • the solvent examples include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, diisopropyl ether, siloxane, and tetrahydrofuran.
  • Ethers such as chloroform, halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane and the like; esters such as ethyl acetate; acetic acid; amides such as N, N-dimethylformamide And sulfoxides such as dimethyl sulfoxide.
  • the amount of the solvent to be used is generally 1- to 100-fold (v Zw), preferably 1- to 20-fold (v Zw) with respect to compound (XXV).
  • the acid include mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid
  • examples of the base include potassium hydroxide or sodium hydroxide.
  • the amount of these acids or bases to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XXV).
  • Compound (Ila) is produced by subjecting compound (XXVI) to an esterification reaction. This reaction is carried out in the same manner as in the esterification reaction in Method B.
  • Compound (II) can be produced by subjecting compound (Ila) thus obtained to a deprotection reaction.
  • the deprotection reaction is performed according to a method known per se.
  • R 7 of compound (Ila) is benzyl
  • compound (II) is produced by treating in the same manner as in the reduction reaction (catalytic hydrogenation reaction) of compound (XIII) in method B.
  • 4-hydroxyphenylbutyronitrile can be produced by subjecting compound (XXV) to a deprotection reaction.
  • the compound (II) and 4-hydroxyphenylbutyrate obtained in this manner can be isolated by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. It can be purified.
  • the compounds (XXIII), (XXIV), (XVIIa), (XVIIIa), (XXV). (XXVI) and (Ila) may be isolated and purified by known separation and purification means, or The mixture may be used in the next reaction.
  • Compound (II) mentioned in Method A can also be produced from Compound (XXVI) according to Method G.
  • R 8 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; other symbols are as defined above.
  • a compound ( ⁇ ⁇ ) and a succinic anhydride or a compound ( ⁇ ) are first subjected to a Friedel-Crafts reaction to produce a compound (XXIX).
  • This reaction is carried out in a solvent in the presence of a Lewis acid according to a conventional method.
  • Lewis acid examples include aluminum chloride, titanium tetrachloride, antimony chloride, tin tetrachloride, zinc chloride, and iron chloride. Of these, aluminum chloride is preferred.
  • solvent examples include aromatic hydrocarbons such as nitrobenzene, benzene, toluene, and xylene; ethers such as getyl ether, diisopropyl ether, dioxane, tetrahydrofuran, and anisol; chloroform, dichloromethane; Halogenated hydrocarbons such as 1,1,2,2-tetrachlorobenzene; carbon disulfide; These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the solvent is preferably a halogenated hydrocarbon such as dichloromethane and anisol.
  • the amount of the solvent to be used is generally 1- to 100-fold (v / w), preferably 1- to 20-fold (vZw), relative to compound (XXVII).
  • the amount of succinic anhydride or compound (XXVIII) to be used is generally 5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (XXVII).
  • the amount of the Lewis acid to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XXVII).
  • the reaction temperature is from 120 ° C to 150 ° C, preferably from 0 to 100 ° C.
  • the reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.
  • the compound (XXIX) is subjected to a reduction reaction to produce a compound (lib).
  • This reaction can be performed by a method known per se. Examples of such a method include the method described in Organic Reactions, Vol. 4, p. 378, pp. 1948 (eg, reduction by the Oluf Kissner reaction), Organic Reactions, Vol. 1, p. , 1942 (eg, reduction by Clementen reaction), reduction with metal hydride complex, reduction with diborane and substituted borane, reduction with tritylsilane, catalytic hydrogenation, and the like.
  • the reduction reaction is carried out by treating compound (XXIX) with a reducing agent in a solvent that does not affect the reaction.
  • the reducing agent examples include hydrazine under basic conditions, zinc amalgam under acidic conditions; alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.), and metals such as diisobutylaluminum hydride. Hydrogen complex compounds; metal hydrides such as sodium hydride; organotin compounds (triphenyltin hydride etc.); metals and metal salts such as nickel compounds and zinc compounds; transitions such as palladium, platinum, rhodium, ruthenium and iridium Using metal catalyst and hydrogen Contact reducing agent and diborane.
  • alkali metal borohydride eg, sodium borohydride, lithium borohydride, etc.
  • metals such as diisobutylaluminum hydride.
  • Hydrogen complex compounds metal hydrides such as sodium hydride; organotin compounds (triphenyltin hydride etc.); metals and metal salts such as nickel compounds and zinc compounds; transitions
  • the amount of the reducing agent to be used is generally 1-10 molar equivalents, preferably 1-5 molar equivalents, relative to compound (XXIX).
  • the solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; and methyl ether, diisopropyl alcohol.
  • Ethers such as ter, dioxane, and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane; amides such as ⁇ , ⁇ -dimethylformamide; water And the like.
  • halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane
  • amides such as ⁇ , ⁇ -dimethylformamide
  • water And the like may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the solvent to be used is generally 1- to L00-fold (v / w) relative to the compound (XXIX), preferably:! Up to 20 times (v / w).
  • the reaction temperature is usually from ⁇ 20 to 200, preferably from 0 t: to 100.
  • the reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.
  • R 7 of the compound (lib) is a methyl group or an isopropyl group will be described below.
  • a compound (lie) is produced by subjecting a compound (lib) in which R 7 is a methyl group to a demethylation reaction.
  • the demethylation reaction is carried out in an aqueous solvent in the presence of an acid (eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid) and under heating.
  • the reaction temperature is usually 0 to 200: preferably 50 to 150.
  • the reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.
  • the demethylation reaction can also be performed by reacting with an alkylmercaptan (eg, ethyl mercaptan, dodecamercaptan, etc.) in a solvent in the presence of aluminum chloride or titanium tetrachloride.
  • alkylmercaptan eg, ethyl mercaptan, dodecamercaptan, etc.
  • the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran; chloroform, dichloromethane, 1,1,2,2. —Halogenated hydrocarbons such as tetrachloroethane and the like.
  • These solvents may be used by mixing two or more kinds in an appropriate ratio. May be used.
  • the amount of the solvent to be used is generally 1 to 100 times (V / w), preferably 1
  • the amount of aluminum chloride or titanium tetrachloride to be used is generally 1 to 20 molar equivalents, preferably 5 to 10 equivalents, relative to compound (lib).
  • the reaction temperature is usually -80 "C-100: preferably-50 ° C-50.
  • the reaction time is usually 5-50 hours, preferably 1-24 hours. .
  • the compound (lie) is produced by subjecting the compound (lib) in which R 7 is an isopropyl group to a deisopropylation reaction.
  • the deisopropylation reaction is performed by treating with a solvent such as aluminum chloride, titanium tetrachloride, titanium trichloride, boron trichloride, or silicon tetrachloride.
  • the solvent examples include halogenated hydrocarbons such as chloroform, dichloromethane, and 1,1,2,2-tetrachlorobenzene; nitriles such as acetonitrile. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the solvent to be used is generally 1 to 100 times (v Zw), preferably 1 to 20 times (v Zw), relative to the compound (lib).
  • the amount of aluminum chloride, titanium tetrachloride, titanium trichloride, boron trichloride, or manganese tetrachloride to be used is generally 1 to 20 molar equivalents, preferably 1 to 6 molar equivalents, relative to compound (lib). .
  • the reaction temperature is usually from 180 to 100, preferably from 150 to 8 Ot :.
  • the reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.
  • the compound (lie) in which R 8 is a hydrogen atom is subjected to an esterification reaction to produce a compound (II). Further, the compound (lie) in which R 8 is an alkyl group having 1 to 4 carbon atoms is subjected to a transesterification reaction, if necessary, to produce a compound (II). These reactions are carried out in the same manner as the esterification reaction in Method B.
  • the compound ( ⁇ ) thus obtained can be isolated and purified by a known separation and purification means such as concentration, (2) concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compounds (XXIX), (lib) and (lie) may be isolated and purified by known separation and purification means, or may be used as a reaction mixture in the next reaction.
  • 4-Hydroxyphenylpropionaldehyde used in Method C and Method D can be produced from compound (XXIVa) according to Method H.
  • compound (XXIVa) is subjected to a reduction reaction to produce compound (XVII).
  • This reaction is performed in the same manner as in the reduction reaction in the above-mentioned Method F.
  • the compound (XVII) is subjected to an oxidation reaction to produce 4-hydroxyphenylpropionaldehyde. This reaction is performed according to a known oxidation reaction.
  • Such reactions include, for example, Jones oxidation consisting of chromium oxide-pyridine sulphate, Collins oxidation using a chromium oxide pyridine complex, oxidation with pyridinium dichromate, and oxidation with pyridinium dichromate; Oxidation with activated dimethyl sulfoxide (activated DMSO), oxidation with oxoammonium salts, and the like. Of these, oxidation with activated DMSO is preferred.
  • Oxidation with activated DMSO is performed, for example, in a solvent in the presence of DMSO and an electrophilic reagent.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran; chromate form, dichloromethane, 1,1,2, Halogenated hydrocarbons such as 2-tetrachloroethane; amines such as pyridine; amides such as ⁇ , ⁇ -dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be used as a mixture of two or more at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran
  • chromate form dichloromethane, 1,1,2, Halogenated hydrocarbons such as 2-tetrachloroethane
  • the amount of the solvent to be used is generally 1 to 100 times (v / w), preferably 1 to 20 times (v / v), relative to compound (XVII).
  • the 4-hydroxyphenylpropionaldehyde thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. .
  • the compound (XVII) may be isolated and purified by a known separation and purification means, or may be used as a reaction mixture in the next reaction.
  • compound (XXX) is subjected to an oxidation reaction to produce compound (XXXI).
  • This reaction can be performed by a method known per se. Examples of such a method include oxidation with manganese dioxide, oxidation with chromic acid, and oxidation with dimethyl sulfoxide.
  • the oxidation reaction is performed by treating compound (XXX) with an oxidizing agent in an organic solvent that does not affect the reaction.
  • an oxidizing agent for oxidizing agents, Chromic anhydride or the like is used. Of these, manganese dioxide is preferred.
  • the amount of the oxidizing agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XXX).
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran; chromatoform, dichloromethane, 1,1,2,2-tetra Halogenated hydrocarbons such as chlorobenzene; sulfoxides such as dimethyl sulfoxide; and the like. These solvents may be used by mixing two or more kinds at an appropriate ratio.
  • the amount of the solvent to be used is generally 1 to 100 times (V / w), preferably 1 to 20 times (v Zw), relative to compound (XXX).
  • the reaction temperature is usually from 120 to 150, preferably from 0 to 100.
  • the reaction time is generally 0.5 to 24 hours, preferably 1 to 12 hours.
  • the 4-hydroxyphenylpropionaldehyde thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. .
  • the compounds (XXIIIa), (XXX), and (XXXI) may be isolated and purified by a known separation and purification method, or may be used as a reaction mixture in the next reaction.
  • Each compound (including compounds (1), (11), (III) and (V), etc.) in the above-mentioned Method A to Method I may form an appropriate salt as long as the reaction is not hindered.
  • Such salts include suitable salts with inorganic acids, organic acids, inorganic bases or organic bases.
  • Suitable examples of salts with inorganic or organic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, Examples include salts with malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
  • Preferable examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt.
  • salts of organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine. Salts with min and the like.
  • the compound (I) can be prepared by introducing an aromatic alkyl group into a hydroxyl group on the benzene ring E by a method known per se to obtain a compound as described in JP-A-10-120621 and JP-A-10-120. After synthesizing an ⁇ -ketoester compound or a salt thereof described in 62 as a starting compound, JP-A-10-12062 and JP-A-10-120
  • a oxazolidinedione derivative or a salt thereof can be derived according to the method described in AO7106959, and is useful as an intermediate for synthesizing the oxazolidinedione derivative or a salt thereof.
  • R a represents an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group
  • R b represents a hydrogen atom or a C i _ 4 alkyl group
  • Y represents —CO—,- CH
  • the heterocyclic group in the “optionally substituted heterocyclic group” represented by R a includes, as a ring-constituting atom, a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom.
  • a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom examples thereof include a 5- to 7-membered cyclic or fused ring group having 1 to 4 atoms.
  • the condensed ring include a condensed ring of such a 5- to 7-membered heterocyclic ring, a 6-membered ring containing 1 or 2 nitrogen atoms, a benzene ring or a 5-membered ring containing 1 sulfur atom.
  • heterocyclic group examples include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl Dinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl , 4-thiazolyl, 5-thiazolyl, 2-xoxazolyl, 4-oxoxazolyl, 5-xoxazolyl, 1,2,4-oxoxadiazo-l-u 5-yl, 1,2,4-triazo-l-u 3 1, 2, 3 — triazo- 4 yl, tetrazo 1-5-yl, benzimidazole 2-
  • hydrocarbon group in the “optionally substituted hydrocarbon group” for Ra examples include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic-aliphatic hydrocarbon group, and an araliphatic group.
  • an aliphatic hydrocarbon group having 1 to 8 carbon atoms is preferable.
  • the aliphatic hydrocarbon group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, hexyl and isohexyl.
  • C1-8 saturated aliphatic hydrocarbon groups such as xyl, heptyl and octyl (eg, alkyl groups, etc.); for example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-1pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2 , 4-hexagenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl 1, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexyn
  • an alicyclic hydrocarbon group having 3 to 7 carbon atoms is preferable.
  • the alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl (eg, cycloalkyl group) and 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl
  • an unsaturated alicyclic hydrocarbon group having 5 to 7 carbon atoms eg, cycloalkenyl group, cycloalkadienyl group, etc.
  • Examples of the alicyclic monoaliphatic hydrocarbon group include those in which the above alicyclic hydrocarbon group is bonded to an aliphatic hydrocarbon group (eg, a cycloalkyl-alkyl group, a cycloalkenyl monoalkyl group, etc.). Among them, an alicyclic monoaliphatic hydrocarbon group having 4 to 9 carbon atoms is preferable.
  • Examples of the alicyclic monoaliphatic hydrocarbon group include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclo Hexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl and the like.
  • the number of carbon atoms in the araliphatic hydrocarbon group to 13 araliphatic hydrocarbon groups are preferred.
  • the araliphatic hydrocarbon group include phenylalkyl having 7 to 9 carbon atoms, such as benzyl, phenyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and 1-phenylpropyl.
  • Examples thereof include naphthylalkyl having 11 to 13 carbon atoms, such as methyl, hynaphthylethyl, 3-naphthylmethyl, and ⁇ -naphthylethyl.
  • aromatic hydrocarbon group an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, aryl group, etc.) is preferable.
  • aromatic hydrocarbon group include phenyl, naph Chill ( ⁇ -naphthyl, / 3-naphthyl) and the like.
  • the hydrocarbon group and the heterocyclic group represented by Ra may have 1 to 5, preferably 1 to 3 substituents at any substitutable positions.
  • substituents include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic complex ring group, a non-aromatic heterocyclic group, a halogen atom, a nitro group, and a substituent.
  • Good amino group optionally substituted acyl group, optionally substituted hydroxyl group, optionally substituted thiol group, optionally esterified carboxyl group, amidino group, sorbamoyl group, Examples include a sulfamoyl group, a sulfo group, a cyano group, an azide group, and a nitroso group.
  • Examples of the aliphatic hydrocarbon group include a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, such as an alkyl group, an alkenyl group, and an alkynyl group.
  • Preferred examples of the alkyl group include an alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.
  • alkenyl group examples include alkenyl groups having 2 to 10 carbon atoms, for example, vinyl, aryl, isopropyl, 1-propenyl, 2-methyl-1-probenyl, 1-butenyl, 2-butenyl , 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-1hexenyl, Examples include 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.
  • alkynyl group examples include alkynyl groups having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,
  • alicyclic hydrocarbon group examples include a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group.
  • cycloalkyl group examples include a cycloalkyl group having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2 2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] noel, bicyclo [4.3.1] decyl.
  • cycloalkenyl group examples include cycloalkenyl groups having 3 to 10 carbon atoms, for example, 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, 2-cyclohexene-11-yl. And 3-cyclohexene-11%.
  • cycloalkadienyl group examples include cycloalkadienyl groups having 4 to 10 carbon atoms, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadiene-1-yl, 2 , 5-cyclohexadiene-1-yl and the like.
  • aryl group examples include an aryl group having 6 to 14 carbon atoms, such as phenyl, naphthyl (1-naphthyl, 2-naphthyl), anthryl, phenanthryl, and acenaphthylenyl.
  • aromatic heterocyclic group examples include, for example, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 3,4-oxaziazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, Aromatic monocyclic heterocyclic groups such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; for example, benzofuranyl, isobenzofuranyl, benzo [b] phenyl, indolyl, isoindolinyl, 1H-ind
  • non-aromatic heterocyclic group examples include, for example, oxilanyl, azetidinyl, oxenyl, cesyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydroviranyl, morpholinyl, thiomorpholin, piradizinyl, pyrrolidino, piperidino , Morpholino, and thiomorpholino.
  • halogen atoms also include fluorine, chlorine, bromine and iodine.
  • the substituted amino group includes an N-monosubstituted amino group and an N, N-disubstituted amino group.
  • substituent amino group for example, 10 alkyl group, C 2 - 10 alkenyl group, C 2 - 10 Al Kiniru group,, C 3 -.
  • An amino group having one or two substituents e.g., alkanoyl, benzoyl, nicotinyl
  • a substituent e.g., methylamino, dimethylamino, ethylamino, getylamino, dibutylamino, diarylamino, cyclohexylamino, phenylamino, N —Methyl-1-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinylamino, etc.
  • acyl group in the optionally substituted acyl group examples include, for example, an acyl group having 1 to 13 carbon atoms, for example, an alkanol group having 1 to 10 carbon atoms, and 3 to 10 carbon atoms. And a cycloalkanoyl group having 4 to 10 carbon atoms, a cycloalkenoyl group having 4 to 10 carbon atoms, and an aromatic carbonyl group having 6 to 12 carbon atoms.
  • alkanoyl group having 1 to 10 carbon atoms include, for example, formyl, acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, and octanol.
  • alkenoyl group having 3 to 10 carbon atoms include, for example, acryloyl, methacryloyl, crotonyl, isocrotonyl and the like.
  • cycloalkanoyl group having 4 to 10 carbon atoms include cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl and the like.
  • cycloalkenoyl group having 4 to 10 carbon atoms include 2-cyclohexenecarbonyl.
  • aromatic carbonyl group having 6 to 12 carbon atoms include benzoyl, naphthoyl, nicotinol and the like.
  • Examples of the substituent in the substituted acyl group include an alkyl group having 1 to 3 carbon atoms, for example, an alkoxy group having 1 to 3 carbon atoms, a halogen atom (eg, chlorine, fluorine, bromine, etc.), a nitro group, and a hydroxyl group. And an amino group.
  • examples of the substituted hydroxyl group include an alkoxy group, a cycloalkyloxy group, an alkenyloxy group, a cycloalkenyloxy group, an aralkyloxy group, an acyloxy group, and an aryloxy group. And the like.
  • alkoxy group examples include an alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy, neope And benzyloxy, hexyloxy, heptyloxy, nonyloxy and the like.
  • cycloalkyloxy group examples include a cycloalkyloxy group having 3 to 10 carbon atoms, such as cyclobutoxy, cyclopentyloxy, and cyclohexyl. Roxy and the like.
  • alkenyloxy group examples include alkenyloxy groups having 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy, and 3-hexenyloxy.
  • cycloalkenyloxy group examples include a cycloalkenyloxy group having 3 to 10 carbon atoms, such as 2-cyclopentenyloxy and 2-cyclohexenyloxy. '
  • a preferred example of an aralkyloxy group is carbon number? ⁇ 10 aralkyloxy groups, for example fenir ⁇ . ⁇ 4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.) and the like.
  • acyloxy group examples include an acyloxy group having 2 to 13 carbon atoms, and more preferably an alkanoyloxy group having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isoptyryloxy) Etc.).
  • aryloxy group examples include an aryloxy group having 6 to 14 carbon atoms, such as phenoxy and naphthyloxy.
  • the aryloxy group may have one or two substituents, and examples of such a substituent include a halogen atom (eg, chlorine, fluorine, bromine, etc.).
  • substituents examples include a halogen atom (eg, chlorine, fluorine, bromine, etc.).
  • substituted aryloxy group examples include 4-chlorophenoxy and the like.
  • examples of the substituted thiol group include an alkylthio group, a cycloalkylthio group, an alkenylthio group, a cycloalkenylthio group, an aralkylthio group, an acylthio group, and an arylthio group.
  • alkylthio group examples include an alkylthio group having 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, tert.-butylthio, pentylthio, and isobenzylthio. , Neopentylthio, hexylthio, heptylthio, nonylthio and the like.
  • cycloalkylthio group examples include cycloalkyl having 3 to 10 carbon atoms.
  • Ruthio group for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
  • alkenylthio group examples include a alkenylthio group having 2 to 10 carbon atoms, such as allylthio, crotylthio, 2-pentenylthio, and 3-hexenylthio.
  • cycloalkenylthio group examples include a cycloalkenylthio group having 3 to 10 carbon atoms, for example, 2-cyclopentenylthio, 2-cyclohexenylthio and the like.
  • aralkylthio group examples include carbon number? ⁇ 1 0 Ararukiruchio group, for example phenylene Lou C i _ 4 alkylthio (e.g., benzylthio, Fuenechiruchio, etc.) and the like.
  • acylthio group examples include an acylthio group having 2 to 13 carbon atoms, more preferably an alkanolthio group having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.).
  • arylthio group examples include an arylthio group having 6 to 14 carbon atoms, such as phenylthio and naphthylthio.
  • the arylthio group may have one or two substituents, and such substituents include, for example, nitrogen, and a halogen atom (eg, chlorine, fluorine, bromine, etc.).
  • substituents include, for example, nitrogen, and a halogen atom (eg, chlorine, fluorine, bromine, etc.).
  • substituted arylthio group examples include 4-chlorophenylthio and the like.
  • alkoxycarbonyl group examples include an alkoxy group having 2 to 5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxy group, butoxycarbonyl and the like.
  • aralkyloxycarbonyl group examples include an aralkyloxycarbonyl group having 8 to 10 carbon atoms, such as benzyloxycarbonyl.
  • Preferred examples of the aryloxycarbonyl group include an aryloxycarbonyl group having 7 to 15 carbon atoms, such as phenoxycarbonyl and p-tolyloxycarbonyl. Bonyl and the like.
  • the substituent in the hydrocarbon group and the heterocyclic group represented by R is preferably an alkyl group having 1 to 10 carbon atoms, an aromatic heterocyclic group, or an aryl group having 6 to 14 carbon atoms, more preferably Alkyl, frill, chenyl, phenyl and naphthyl.
  • the substituents on the hydrocarbon group and the heterocyclic group represented by Ra are more appropriate when they are an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group. May have one or more, preferably 1 to 3, such substituents.
  • Examples of such a substituent include an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, An alkynyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 14 carbon atoms, an aromatic heterocyclic group (eg, chenyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non- aromatic Hajime Tamaki (e.g., tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidino, piperazino, etc.), Ararukiru group, an amino group of 7 carbon atoms 9, N-mono- 4 alkylamino, N, N-di - C i _ 4 alkylamino group, ⁇ Shiruamino group having 2 to 8 carbon atoms (e.g.,
  • alkano Ashiru group e.g., 2 to 8 carbon atoms of 2 to 8 carbon atoms
  • N-mono- 4- alkyl rubamoyl group N, N-di- 4- alkyl rubamoyl group, sulfamoyl group, N-mono-alkylsulfamoyl group, N, N-diC i _ 4 alkylsulfamoyl group, propyloxyl group, alkoxycarbonyl group having 2 to 8 carbon atoms, hydroxyl group, alkoxy group having 1 to 4 carbon atoms, alkenyloxy group having 2 to 5 carbon atoms, carbon number 3 7 to 7 cycloalkyloxy groups, C7 to C9 aralkyloxy groups, C6 to C14 aryloxy groups, mercapto groups, C1 to C4 alkylthio groups, C7 to C7 9 aralkylthio groups
  • Ra is preferably an optionally substituted heterocyclic group.
  • R a is more preferably 0 Bok 3 alkyl, furyl, thienyl, from phenyl and naphthyl Pyridyl, oxazolyl or thiazolyl which may have 1 to 3 substituents selected.
  • Ra is particularly preferably 5-methyl-2-phenyl-1,3-thiazol-4-yl, 5-methyl-2-phenyl-1,3-oxazolu-1-yl or the like.
  • Examples of the alkyl group represented by R b and R c include those exemplified above for R 2 .
  • R b is preferably a hydrogen atom.
  • Y is - CO-, one CH (OH) - or - NRi2_ a indicates (Ri2 is an alkyl group which may be substituted), preferably _CH (OH) one or - - NRi 2.
  • examples of the alkyl group include the C i _ 4 alkyl groups exemplified as R 2 above.
  • the alkyl group may have 1 to 3 substituents. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine), C ⁇ 4 alkoxy (eg, Methoxy, ethoxy, propoxy, butoxy, t.-butoxy), hydroxy, nitro, dimethyl (eg, formyl, acetyl, propionyl) and the like.
  • a halogen atom eg, fluorine, chlorine, bromine, iodine
  • C ⁇ 4 alkoxy eg, Methoxy, ethoxy, propoxy, butoxy, t.-butoxy
  • hydroxy, nitro, dimethyl eg, formyl, acetyl, propionyl
  • n preferably 0.
  • leaving group for Q leaving groups exemplified for the aforementioned Q a. Of these, a halogen atom is preferable, and chlorine is particularly preferable.
  • Preferable examples of compound (VI) include 4- (chloromethyl) -1-methyl-2-phenyl-1,3-xazole, 4- (chloromethyl) -15-methyl-2-phenyl — 1, 3-thiazol and the like.
  • halogen atom represented by X examples include fluorine, chlorine, bromine, and iodine. Of these, chlorine and bromine are preferred.
  • R c is preferably methyl or ethyl, and more preferably ethyl.
  • Preferable examples of the compound (IX) include methyl chlorocarbonate, ethyl chlorocarbonate, propyl chlorocarbonate, isopropyl chlorocarbonate, methyl bromocarbonate, bromocarbon Ethyl acid, propyl bromocarbonate, isopropyl bromocarbonate, butyl bromocarbonate and the like. Of these, ethyl chlorocarbonate is preferred.
  • the compounds (V), (VII), (VIII), (X) and (XI) are preferably optically active forms.
  • Preferred examples of compound (VII) or a salt thereof include 2-hydroxy-5- [4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl] pentyl Ethyl acid or its salt, sodium 2-hydroxy-5- [4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl] pentenoate or And salts thereof.
  • ethyl (R) -2-hydroxy-5- [4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenylyl] pentanoate or a salt thereof ,
  • Examples of the salts of the compounds (V), (VI), (VII), (VIII), (X), and (XI) include those exemplified as the salts of each compound used in Method A and the like.
  • compound (1), (V), (VI), (VII), (VIII) (X) as a raw material and compound (XI) as a target compound are It may be used as a salt as described above.
  • the reduction reaction of compound (I) can be carried out in the same manner as in the reduction reaction of compound (XIII) in the above-mentioned Method B.
  • an optically active compound of the compound (V) can be produced by subjecting the compound (I) to an asymmetric reduction reaction.
  • asymmetric reduction reaction for example, a method using baker's yeast (eg,
  • a method using a chiral catalyst such as a ruthenium-phosphine complex (eg, Japanese Patent Application Laid-Open No. H10-12026, Japanese Patent Application Laid-Open No. H10-12062), etc. ) And the like.
  • a chiral catalyst such as a ruthenium-phosphine complex.
  • the method J and the method K described in detail below are preferable because the desired optically active substance can be obtained easily with high yield and high purity.
  • W is an optically active tertiary phosphine
  • M is Zn, Al, Ti or Sn
  • ⁇ is N (C 2 H 5 ) 3 , HN (C 2 H 5 ) 2 , H 2 N (C 2 H 5 ), CH 3 CO 2 or a halogen atom
  • X is N (C 2 H 5 ) 3 , HN (C 2 H 5 ) 2 or H 2 N (C 2 H 5 )
  • 1 Is 2 and h is 1 and k is 4 when M is Zn, k is 5 when M is A1, k is 6 when M is Ti or Sn
  • ⁇ is CH 3 C0 2 or a halogen atom, 1 is 1, h is 2, and k is 2 'when M is Zn, k is 3 when M is A1, k when M is Ti or Sn Is 4.
  • optically active tertiary phosphine represented by W is represented by the general formula (XXXIV)
  • ring G represents a benzene ring which may be hydrogenated
  • R 9 , Rio and each represent a hydrogen atom or a C 1-4 alkyl group which may be the same or different.
  • compound (XXXIV) examples include 2,2'-bis (diphenylphosphino) - ⁇ , ⁇ -binaphthyl; 2,2'-bis (di- ( ⁇ -tolyl) phosphino) - ⁇ , ⁇ -Binaphthyl; 2,2'-bis (di- (3,5-dimethylphenyl) phosphino) - ⁇ , ⁇ -binaphthyl; 2,2'-bis (diphenylphosphino) -5,5 ', 6,6' , 7,7 ', 8,8'-octane hydro- ⁇ , ⁇ -binaphthyl and the like.
  • Compound (XXXIV) is particularly preferably a compound in which ring G is a benzene ring and R 9 , Rio and Rii are hydrogen atoms, that is, 2,2′-bis (diphenylphosphino) - ⁇ , ⁇ - Binaphthyl and 2,2'-bis (di- (p-tolylyl) phosphino) -1,1'-binaphthyl.
  • the optically active tertiary phosphine represented by W has optical isomers of (R) and (S), which can be appropriately selected depending on the absolute configuration of the target compound. That is, to obtain the (R) -form target compound, use the (R) optically active tertiary phosphine.To obtain the (S) -form target compound, use the (S) optical compound. Active tertiary phosphine may be used.
  • examples of the halogen atom represented by ⁇ include fluorine, chlorine, bromine, and iodine, with chlorine being preferred.
  • compound ( ⁇ ) is, W compound (XXXIV), the ring G is a benzene ring, R9, Riq and RU are hydrogen atoms, M is Ti, X 1 is N (C 2 H 5) 3 or chlorine When X 1 is N (C 2 H 5 ) 3 , 1 is 2, h is 1, k force is 6, and when Xi is chlorine, 1 is 1, h is 2, and k is 4. Is mentioned.
  • the compound ( ⁇ ) is particularly preferably bis [ruthenium [2,2′-bis (diphenylphosphino) - ⁇ , ⁇ -binaphthyl] hexaclo-titanium] triethylamine.
  • Compound (XXXII) can be produced by a method known per se, for example, a method described in JP-A-64-68387, JP-A-3-255090, JP-A-4-139140, or a method analogous thereto.
  • X 2 is a halogen atom
  • T is optionally substituted benzene, a Asetoni Bok drills or
  • W is an optically active tertiary phosphine
  • Z is a halogen atom, C] 0 4, Indicate PF 6 , BPh 4 , BF 4 ;
  • Examples of d.4 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, tert.-butoxy and the like.
  • C 2 The 5 alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, cycloalkenyl, propoxy force Ruponiru, isopropoxycarbonyl, butoxycarbonyl two Le, isobutoxycarbonyl, sec- butoxide deer Lupo alkenyl, tert- butoxycarbonyl sulfonyl, and the like.
  • halogen atom those similar to the halogen atom represented by the above ⁇ are used.
  • benzene which may have a substituent represented by ⁇ include benzene, toluene, xylene, trimethylbenzene, hexamethylbenzene, ethylbenzene, tert.-butylbenzene, P-cymene, cumene And methyl benzoate, methyl benzoate, benzoyl, methyl anisol, benzene benzene, dichlorobenzene, trichlorobenzene, bromobenzene, fluorobenzene, and the like.
  • Preferred examples of the compound ( ⁇ ) include a compound in which T is benzene; W is a compound (XXXIV); ring G is a benzene ring; R 9 , R 10, and R 11 are hydrogen atoms; And the like.
  • the compound ( ⁇ ) is particularly preferably ruthenium chromatobenzene [2,2′-bis (diphenylphosphino) - ⁇ , ⁇ -binaphthyl] chloride.
  • Compound ( ⁇ ) can be prepared by a method known per se, for example, JP-A-2-191289 and JP-A-3-191289.
  • the Lewis acid is preferably titanium tetrachloride.
  • the reaction between compound ( ⁇ ) and a Lewis acid is usually performed in an organic solvent.
  • the organic solvent may be any as long as it does not inhibit the reaction. Specific examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, diisopropyl ether, tert.-butyl methyl ether, dioxane, and the like. Ethers such as tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,1,2,2-tetrachlorobenzene; These organic solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the organic solvent is preferably a halogenated hydrocarbon such as dichloromethane.
  • the amount of the organic solvent to be used is generally 1 to 100 times (v Zw), preferably 1 to 500 times (v Zw), relative to compound (XXXIII).
  • the reaction temperature is usually from ⁇ 20 to: I30 :, preferably from 0 to 50 t :.
  • the reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
  • the amount of the Lewis acid to be used is generally 0 :! to 5 moles, preferably 0.5 to 2 moles, relative to compound (II).
  • the compound (XXXII) in which X 1 is a halogen atom thus obtained can be purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, and the like. Further, a reaction solution containing the compound (XXXIII) and a Lewis acid may be used as the compound (II) in the reduction reaction of the compound (I).
  • the hydrogenation reaction of compound (I) is carried out by a method known per se in an organic solvent under a hydrogen pressure of usually 0.01 to: 2 MPa, preferably 0.01 to 5 MPa. This reaction is preferably performed in an inert gas such as argon or helium.
  • the organic solvent may be any as long as it does not inhibit the reaction.
  • Specific examples thereof include alcohols such as methanol, ethanol, n.-propanol and isopropanol; aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as getyl ether, diisopropyl ether, tert.-butyl methyl ether, dioxane, tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, chloroform, 1,1,2,2-tetrachloroethane, etc.
  • esters such as ethyl acetate and isopropyl acetate; acetic acid; and amides such as N, N-dimethylformamide.
  • These organic solvents may be used by mixing two or more kinds thereof at an appropriate ratio.
  • Organic solvent Is preferably an alcohol, and more preferably an alcohol having the same alkyl group as R in compound (I) (eg, ethanol and the like). Further, it is preferable to use the degassed and dehydrated organic solvent.
  • the amount of the organic solvent to be used is generally 1- to 1000-fold (v Zw), preferably 1- to 500-fold (v / w), relative to compound (I).
  • the reaction temperature is usually 0 to 150 ° C, preferably 5 to: 120 ° ⁇ , and more preferably 10 to 80. '
  • the reaction time is generally 0.5 to: 100 hours, preferably 1 to 50 hours, more preferably 5 to 30 hours.
  • the compound (V) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • protic acid examples include methanesulfonic acid, (-)-camphor-10-sulfonic acid, (+)-camphor-10-sulfonic acid, (+)-3-bromocampha-8-sulfonic acid, sulfuric acid, and ⁇ - Toluenesulfonic acid, perchloric acid (including silver (I) perchlorate), tetrafluoroboric acid (including silver (I) tetrafluoroborate), phosphoric acid, benzoic acid, hexafluorophosphate Acids (including silver (I) hexafluorophosphate).
  • the protonic acid is preferably (-)-camphor-10-sulfonic acid, (+)-camphor-10-sulfonic acid, p.toluenesulfonic acid, sulfuric acid, perchloric acid and the like.
  • Protic acids may be used as a mixture of two or more kinds at an appropriate ratio.
  • the amount of the protonic acid to be used is generally 0.1 to 100,000-fold mol, preferably 0.5 to 100-fold mol, relative to compound (XXXIII).
  • the compound (V) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Compound (V) is a novel compound, especially a compound in which R is an ethyl group. Things are useful.
  • reaction between compound (V) and compound (VI) is carried out, for example, in the presence of a base in a suitable solvent.
  • the base examples include alkali metal salts such as potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium hydrogen carbonate; amines such as pyridine, triethylamine, ⁇ , ⁇ -dimethylaniline; potassium hydride, sodium hydride, and the like.
  • the amount of the base to be used is preferably 1 to 5 molar equivalents relative to compound (V).
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; ketones such as acetone and 2-butanone; ⁇ , ⁇ -dimethylformamide and the like. Amides; sulfoxides such as dimethyl sulfoxide; and halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the solvent is preferably an amide such as ⁇ , ⁇ -dimethylformamide.
  • the amount of compound (VI) to be used is generally 1 to 5 molar equivalents, relative to compound (V).
  • the reaction temperature is usually from 150 to 150, preferably from -10 to 100.
  • the reaction time is generally 0.5 hour to 30 hours, preferably 1 hour to 10 hours.
  • the compound (VII) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • compound (VII) may be used in the next reaction as a reaction mixture.
  • the compound (VI) used in the above reaction can be produced according to a method known per se.
  • the compound ( ⁇ ) can be produced by subjecting the compound evil) to a hydrolysis reaction. This reaction is carried out in the same manner as in the hydrolysis reaction of compound (XV) in the above-mentioned Method C.
  • the compound (VIII) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Further, the compound ( ⁇ ) may be used in the next reaction as a reaction mixture.
  • a salt eg, sodium salt, potassium salt
  • a base eg, sodium hydroxide, potassium hydroxide
  • compound (VIII) is reacted with compound (IX) and ammonia to produce compound (X).
  • This reaction is carried out according to a method known per se, for example, a method described in JP-A-10-182623. This reaction is performed, for example, in an organic solvent in the presence of a base.
  • organic solvent examples include ethers such as getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran; esters such as ethyl acetate; ketones such as acetone and methyl ethyl ketone; chloroform, dichloromethane; -Halogenated hydrocarbons such as -dichloroethane and 1,1,2,2-tetrachloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; amines such as pyridine; ⁇ , ⁇ -dimethylformamide And amides such as dimethylacetamide; nitriles such as acetonitrile. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the solvent is preferably an ester such as ethyl acetate.
  • Examples of the base include amines such as pyridine, triethylamine, tri- ⁇ -butylamine, 1,8-diazabicyclo [5.4.0] indes-7-ene (DBU), and 4-dimethylaminopyridine. Of these, triethylamine and the like are preferred.
  • the amount of these bases to be used is preferably 2 to 10 equivalents to compound (VIII).
  • ammonia is usually used as an aqueous solution.
  • concentration of ammonia in the aqueous solution is, for example, 5 to 20%.
  • amount of compound (IX) to be used is generally 1 to 5 molar equivalents, relative to compound (VIII).
  • the reaction temperature is usually from ⁇ 60 to 100 ° (preferably, from ⁇ 20 ° C. to 50.
  • the reaction time is usually from about 0.5 to 30 hours, preferably from 1 to 10 hours.
  • the compound (X) thus obtained should be isolated and purified by known separation and purification means, for example, concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc.
  • the compound (X) may be used as a reaction mixture in the next reaction.
  • compound (XI) can be produced by subjecting compound (X) to a ring closure reaction.
  • This reaction is carried out according to a method known per se, for example, a method described in JP-A-10-182623. This reaction is carried out, for example, in an organic solvent in the presence of a base.
  • organic solvent examples include alcohols such as methanol, ethanol, propanol, and isopropanol; ethers such as getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran; esters such as ethyl acetate; and acetone and methyl ethyl ketone.
  • Ketones such as formaldehyde, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene Amines such as pyridine; amides such as ⁇ , ⁇ -dimethylformamide and dimethylacetamide; nitriles such as acetonitrile.
  • solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the solvent is preferably a nitrile such as acetonitrile.
  • Examples of the base include metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium ethoxide, sodium methoxide and potassium tert.-butoxide; pyridine, triethylamine, tri-n-butylamine, Examples thereof include amines such as 8-diazabicyclo [5.4.0] penta-7-ene (DBU) and 4-dimethylaminopyridine. Of these, amines such as 1,8-diazabicyclo [5.4.0] pendase-7-ene (DBU) are preferred.
  • the amount of the base to be used is preferably 1 to 10 equivalents to compound (X).
  • the reaction temperature is usually from ⁇ 50 to 100, preferably from 130 to 50.
  • the reaction time is usually 10 minutes to 20 hours, preferably 0.5 hours to 10 hours.
  • the compound (XI) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the thus-obtained compound (XI) or a salt thereof has an excellent pharmaceutical effect (eg, a blood glucose and blood lipid lowering effect).
  • an excellent pharmaceutical effect eg, a blood glucose and blood lipid lowering effect.
  • the method described in EP-A-612, 743, etc. Therefore it can be used.
  • room temperature indicates 1 to 30 ° C.
  • the solvent ratio indicates a volume ratio.
  • methanol and ethanol used in the asymmetric reduction reaction were refluxed, distilled and further degassed in the presence of magnesium methoxide or magnesium ethoxide.
  • a commercially available anhydrous solvent was degassed and used as necessary.
  • a commercially available dehydrated solvent was used as necessary.
  • the optical purity of the optically active substance was evaluated by the enantiomeric excess (% e.e.).
  • the enantiomeric excess was determined by the following formula using high performance liquid chromatography under the following conditions.
  • n-hexane / isopropanol 80/20 (v / v) or 90/10 (v / v)
  • the reaction solution was cooled, 880 ml of ethyl acetate was added, and 440 ml of 5% aqueous NaCl was added dropwise.
  • the aqueous layer was separated and washed once with acetate Echiru layer with 5% NaHCO 3 water 440 ml, 5% NaCl water 440 ml, 10% NaCl water 440 ml.
  • the ethyl acetate layer was concentrated to 477 g under reduced pressure, and then 367 ml of n-hexane and 146.6 g of silica gel were added.
  • the silica gel was removed by filtration and washed with 733 ml of ethyl acetate: n-hexane (1: 1). The combined filtrates were concentrated to 293 g under reduced pressure. 268 ml of n- hexane was added dropwise to the concentrated solution, and then seed crystals were inoculated and stirred at room temperature for 1.5 hours. After confirming the crystallization, 710 ml of n-hexane was further added dropwise over 1 hour, and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled with ice water and aged at 5 or less for 2 hours.
  • the precipitated crystals were collected by filtration and washed with 440 ml of ethyl acetate: n- hexane (1: 8). The mixture was dried under reduced pressure at 30 for 10 hours or more to give 113.94 g (69%) of the title compound as pale brown crystals.
  • the reaction solution was cooled to an internal temperature of 10: and ethyl ethyl acetate (100 ml) was added, and then water (60 ml) was added dropwise.
  • the aqueous layer was separated, and the ethyl acetate layer was washed once with water and saturated saline.
  • the residue was subjected to silica gel column chromatography (elution with ethyl acetate-II. Hexane), and the effective fraction was concentrated to obtain 0.39 g of the title compound as crystals. .
  • the amount of (R)-(-)-camphorsulfonic acid used is 0.0mg (0.0000mmol),
  • optically active phosphorus ligands ( ⁇ ⁇ ⁇ ), (R, R) -Me-DuPHOS, (S, S) -DIOP, (S, S) -BDPP, BPPM, (R) (S) -JOSIPHOS, (R) (S) -BPPFA, (R) (S) -BPPFOH, (R) (S) -PPFA, (R, R) -NORPHOS, (R) -PROPHOS, CARBOPHOS, (S) -NMDPP, ( When S) -QUINAP and BCPM (PPM) are used, the enantiomeric excess is 60 (R), 33 (R), 73 (R), 11 (R), 10 (S), 16 (S), respectively. , 10 (S), 10 (S), 79 (R), 38 (R), 3 (R), 4 (R), 32 (S), 6 (R)% ee.
  • the crystallization liquid was allowed to stand at 25 t: for 1 hour, and filtered. The residue was washed once with 4.3 L of acetonitrile-water (1: 2) and twice with 4.3 L of water, and dried under reduced pressure at 50 to give crude crystals (741.8 g, yield 95.8%, optical purity 99.6% ee). Obtained.
  • the crude crystals were dissolved at 70 in 8.89 L of ethanol-water (85:15).
  • Activated carbon (trade name: Shirasagi A) 37 g was added to the resulting solution, and the mixture was stirred for 15 minutes.
  • the peak ketoester of the present invention that is, the compound (I) or a salt thereof is useful as an intermediate for synthesizing various drugs such as an oxazolidinedione derivative or a salt thereof, such as an antidiabetic agent. This is an industrially advantageous production method that can obtain the target product at high efficiency, high purity and low cost.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés représentés par les formules générales (I), (IV) et (V) ou leurs sels, utiles en tant qu'intermédiaires de synthèse de médicaments, ainsi que procédés servant à préparer ces composés ou leurs sels, dans lesquels R et R' représentent chacun un groupe hydrocarbure.
PCT/JP2000/006301 1999-09-16 2000-09-14 $G(a)-CETO ESTERS ET LEURS PROCEDES DE PREPARATION WO2001019777A1 (fr)

Priority Applications (1)

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AU73132/00A AU7313200A (en) 1999-09-16 2000-09-14 Alpha-keto esters and processes for the preparation thereof

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JP11/262769 1999-09-16
JP26276999 1999-09-16

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006525331A (ja) * 2003-04-30 2006-11-09 ウェルスタット セラピューティクス コーポレイション 代謝障害の処置のための化合物
JP2010512391A (ja) * 2006-12-12 2010-04-22 マリンクロット インコーポレイテッド ジヒドロイソキノリンからのヘキサヒドロイソキノリンの調製
WO2015134357A1 (fr) * 2014-03-03 2015-09-11 Emory University Modulateurs du récepteur de l'insuline

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10182623A (ja) * 1996-12-26 1998-07-07 Takeda Chem Ind Ltd ２，４−オキサゾリジンジオン化合物の製造法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10182623A (ja) * 1996-12-26 1998-07-07 Takeda Chem Ind Ltd ２，４−オキサゾリジンジオン化合物の製造法

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Title
FERINGA BEN ET AL.: "Asymmetric phenol oxidation. Stereospecific and stereoselective oxidative coupling of a chiral tetrahedronaphthol", J. ORG. CHEM., vol. 46, no. 12, 1981, pages 2547 - 2557, XP002935192 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006525331A (ja) * 2003-04-30 2006-11-09 ウェルスタット セラピューティクス コーポレイション 代謝障害の処置のための化合物
JP4837557B2 (ja) * 2003-04-30 2011-12-14 ウェルスタット セラピューティクス コーポレイション 代謝障害の処置のための化合物
JP2010512391A (ja) * 2006-12-12 2010-04-22 マリンクロット インコーポレイテッド ジヒドロイソキノリンからのヘキサヒドロイソキノリンの調製
WO2015134357A1 (fr) * 2014-03-03 2015-09-11 Emory University Modulateurs du récepteur de l'insuline

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