WO2011024691A1 - Process for preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate - Google Patents

Process for preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate Download PDF

Info

Publication number
WO2011024691A1
WO2011024691A1 PCT/JP2010/063950 JP2010063950W WO2011024691A1 WO 2011024691 A1 WO2011024691 A1 WO 2011024691A1 JP 2010063950 W JP2010063950 W JP 2010063950W WO 2011024691 A1 WO2011024691 A1 WO 2011024691A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
amino
ethyl
ethenylcyclopropanecarboxylate
formula
Prior art date
Application number
PCT/JP2010/063950
Other languages
French (fr)
Japanese (ja)
Inventor
安岡順一
相川利昭
池本哲哉
Original Assignee
住友化学株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 住友化学株式会社 filed Critical 住友化学株式会社
Priority to CN2010800371923A priority Critical patent/CN102482200A/en
Publication of WO2011024691A1 publication Critical patent/WO2011024691A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/34—Preparation of optical isomers by separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a method for producing optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate or an acid addition salt thereof, and an intermediate used in the method.
  • a method for producing optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate is described in, for example, Journal of Organic Chemistry, Vol. 70, 5869-5879, 2005. There are known a method of optical resolution of a racemate of ethyl ethenylcyclopropanecarboxylate with di-p-toluoyl-D-tartaric acid and a method of optical resolution with an enzymatic reaction.
  • the optical purity of the obtained optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate is not as high as 50 to 55% ee, and the enzyme
  • the present invention provides a process for producing optically active ethyl 2-ethenylcyclopropanecarboxylate that solves the above problems. That is, the present invention provides the inventions described in the following [1] to [6].
  • [1] Formula (1) A mixture containing (1R, 2S) isomer and (1S, 2R) isomer of ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by formula (2)
  • Ar represents a phenyl group which may be substituted, and the substituents each have 1 to 3 independent alkyl groups having 1 to 12 carbon atoms, cycloalkyl groups having 3 to 12 carbon atoms, An alkoxy group having 1 to 12 carbon atoms, a cycloalkyloxy group having 3 to 12 carbon atoms, a halogen atom, a nitro group, a cyano group, or a trifluoromethyl group (* represents an asymmetric carbon).
  • Formula (3) comprising the step of decomposing a diastereomeric salt by treatment with an acid or base
  • a method for optical resolution of ethyl 1-amino-2-ethenylcyclopropanecarboxylate which comprises a step of reacting with an optically active tartranyl acid compound represented by the formula: [5] Ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate and formula (2)
  • Ar represents a phenyl group which may be substituted, and the substituents each have 1 to 3 independent alkyl groups having 1 to 12 carbon atoms, cycloalkyl groups having 3 to 12 carbon atoms, An alkoxy group having 1 to 12 carbon atoms, a cycloalkyloxy group having 3 to 12 carbon atoms, a halogen atom, a nitro group, a cyano group, or a trifluoromethyl group (* represents an asymmetric carbon).
  • a salt with an optically active tartranyl acid compound represented by the formula: [6] A salt of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate and (2S, 3S) -2′-chlorotalthranilic acid.
  • the mixture containing the (1R, 2S) isomer and (1S, 2R) isomer of ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by the formula (1) is usually (1R, 2S) isomerism. Racemate, which is an equimolar mixture of the isomer and the (1S, 2R) isomer, can be used, but a mixture rich in either isomer can also be used.
  • the isomer mixture (1) can be produced according to any known method. For example, it can be obtained by reacting N-phenylmethyleneglycine ethyl with 1,4-dibromo-2-butene in the presence of a base by the method described in Journal of Organic Chemistry, 70, 5869-5879, 2005.
  • the resulting ethyl 1- (N-phenylmethyleneamino) -2-ethenylcyclopropanecarboxylate can be produced by acid treatment or the like.
  • the isomer mixture (1) forms a salt with any acid other than the optically active tartlanyl acid compound represented by the formula (2) (hereinafter abbreviated as optically active tartlanyl acid compound (2)).
  • optically active tartlanyl acid compound (2) it is preferable to base-treat the salt before reacting with the optically active tartranyl acid compound (2).
  • examples of the alkyl group having 1 to 12 carbon atoms include a methyl group, an ethyl group, a propyl group, Examples thereof include isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group and dodecyl group; a cycloalkyl group having 3 to 12 carbon atoms Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group; examples of the alkoxy group having 1 to 12 carbon atoms include a
  • examples thereof include a xy group, a heptyloxy group, an octyloxy group, a nonyloxy group, a decyloxy group, an undecyloxy group, and a dodecyloxy group
  • examples of the cycloalkyloxy group having 3 to 12 carbon atoms include a cyclopropyloxy group and a cyclobutyl group.
  • the two asymmetric carbons represented by * are preferably both S configuration or both R configuration, and more preferably both S configuration.
  • the optical purity of the optically active tartranilic acid compound (2) is preferably 90% ee (hereinafter, ee represents an enantiomer excess), more preferably 95% ee, and still more preferably 98%. ee or higher, particularly preferably 99% ee or higher.
  • ee represents an enantiomer excess
  • the optically active tartranyl acid compound (2) a commercially available product can be used, or a product produced by the method described in JP2001-89431A can also be used.
  • the amount of the optically active tartranilic acid compound (2) used is not limited, but when a racemate is used as the isomer mixture (1), it is usually 0.5 mol times or more with respect to the isomer mixture (1).
  • the molar ratio is preferably 0.5 to 2 mol times, more preferably 0.9 to 1.5 mol times.
  • the reaction of the isomer mixture (1) and the optically active tartlanyl acid compound (2) is preferably performed in a solvent.
  • solvents include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, t-butylcyclohexane, petroleum ether and the like.
  • Aliphatic hydrocarbon solvent benzene, toluene, ethylbenzene, isopropylbenzene, t-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, ⁇ , ⁇ , ⁇ -trifluoromethylbenzene, 1,2-dichlorobenzene, 1, Aromatic solvents such as 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, di Such as chill ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, t-butyl methyl ether, cyclopentyl methyl ether,
  • Ether solvent methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, t-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, 2-hexanol, iso Hexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol mono Chill ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono t-butyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl Alcohol solvents such as ether, diethylene glycol monoisopropyl ether, diethylene glycol mono
  • the solvent is preferably a mixed solvent of an aromatic solvent and at least one solvent selected from the group consisting of a ketone solvent, an ester solvent, an alcohol solvent and an ether solvent, more preferably an aromatic solvent and a ketone solvent or an alcohol. It is a mixed solvent with a solvent, more preferably a mixed solvent of toluene and ethanol, a mixed solvent of toluene and 2-propanol, a mixed solvent of toluene and acetone, a mixed solvent of toluene and methyl ethyl ketone, particularly preferably It is a mixed solvent of toluene and 2-propanol.
  • the amount of the solvent used depends on the solvent used and the structure of the optically active tartlanic acid compound (2), but is preferably 1 to 50 L, more preferably 3 to 30 L with respect to 1 kg of the isomer mixture (1). is there.
  • the solvent and the isomer mixture (1) are mixed, and the optically active tartranyl acid compound (2) is added to the resulting mixture. It can also carry out by mixing a solvent and an optically active tartranilic acid compound (2), and can also carry out by adding an isomer mixture (1) to the obtained mixture.
  • the reaction temperature of the isomer mixture (1) and the optically active tartlanyl acid compound (2) is not limited, and is preferably 0 ° C. or higher and the boiling point of the solvent or lower.
  • One diastereomeric salt can be separated from the other diastereomeric salt by preferentially precipitating one diastereomeric salt in a solvent from the resulting mixture of diastereomeric salts. If no diastereomeric salt precipitation is observed from the mixture of diastereomeric salts in the solvent, after adding one of the previously prepared diastereomeric salts as seed crystals, the solution of the diastereomeric salt mixture is cooled. Thus, one diastereomeric salt can be preferentially precipitated.
  • the solution When precipitation of diastereomeric salt is observed, the solution may be cooled as it is, but in order to improve the optical purity of the diastereomeric salt to be precipitated, the solution is heated to dissolve the precipitate. It is preferable to preferentially precipitate one diastereomeric salt by cooling, and in the precipitation of the diastereomeric salt, one diastereomeric salt prepared in advance can be used as a seed crystal.
  • the optical purity of the seed crystal is preferably as high as possible, preferably 90% ee or more, more preferably 95% ee or more, still more preferably 98% ee or more, and particularly preferably 99% ee or more.
  • one diastereomeric salt can be taken out by performing solid-liquid separation treatment such as filtration or decantation. After the solid-liquid separation treatment, it is preferable to perform a washing treatment in terms of improving the optical purity of the diastereomeric salt.
  • the same solvent as described above with respect to the reaction between the isomer mixture (1) and the optically active tartranyl acid compound (2) can be used. It is preferable to perform a drying process after the cleaning process.
  • the drying treatment can be performed under normal pressure or reduced pressure, preferably in the range of 20 to 80 ° C.
  • the liquid resulting from the solid-liquid separation treatment contains the other diastereomeric salt, and the other diastereomeric salt can be extracted from the liquid phase by a conventional method. By purifying the diastereomeric salt, the optical purity can be further improved.
  • a recrystallization method is preferable as the purification treatment.
  • a method in which a diastereomeric salt is dissolved in a solvent and cooled to precipitate a purified diastereomeric salt, a diastereomeric salt is dissolved in a solvent, and a purified diastereomer is added dropwise by adding a poor solvent Purification can be carried out by a method of precipitating the dimer salt, a method of precipitating the diastereomeric salt by distilling off the solvent after dissolving the diastereomeric salt in a solvent, or a combination thereof.
  • one of the diastereomeric salts prepared in advance can be added as a seed crystal.
  • solvent used for the purification treatment examples include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, t-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1 -Hexanol, 2-hexanol, isohexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether , Ethylene glycol monobutyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono t-butyl ether, diethylene glycol mono Alcohol solvents such as chill ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monoiso
  • the amount of the solvent to be used can be appropriately adjusted depending on the solvent to be used, but is preferably a ratio of 1 to 10 L with respect to 1 kg of the diastereomeric salt.
  • the temperature at which the diastereomeric salt is dissolved is preferably 0 to 80 ° C.
  • Examples of the poor solvent include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, t-butylcyclohexane, petroleum ether, and the like.
  • Aliphatic hydrocarbon solvent benzene, toluene, ethylbenzene, isopropylbenzene, t-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, ⁇ , ⁇ , ⁇ -trifluoromethylbenzene, 1,2-dichlorobenzene, 1, Aromatic solvents such as 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, etc., preferably aliphatic hydrocarbon soluble, more preferably heptane.
  • the usage-amount of a poor solvent can be suitably adjusted with the precipitation degree of refinement
  • the purified diastereomeric salt is precipitated by cooling treatment, it is preferably cooled to 0 to 25 ° C., and the cooling temperature per hour is preferably 3 to 10 ° C.
  • the diastereomeric salt thus obtained is a novel compound, preferably an optically active tartlanic acid compound having an absolute configuration of (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate and (2S, 3S) A salt with (2), or a salt with ethyl (1S, 2R) -1-amino-2-ethenylcyclopropanecarboxylate and an optically active tartlanic acid compound (2) having an absolute configuration of (2R, 3R) More preferably a salt of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate and an optically active tartlanyl acid compound (2) having an absolute configuration of (2S, 3S), Preferably, a salt of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate and (2S, 3S) -2′-chlorotalthranilic
  • the optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by the formula (3) or an enantiomer thereof, or an acid thereof Addition salts can be obtained.
  • the optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by the formula (3) or an enantiomer thereof, or an acid addition salt thereof is abbreviated as an optically active amino compound (3).
  • the acid for treating the diastereomeric salt is generally one having higher acidity than the optically active tartranyl acid compound (2).
  • Such acid examples include mineral acids such as hydrochloric acid, phosphoric acid and sulfuric acid; p-toluenesulfonic acid And organic acids such as benzenesulfonic acid and camphorsulfonic acid.
  • the acid is preferably hydrochloric acid or sulfuric acid. These acids can be used alone or in combination with a solvent described later.
  • the usage-amount of an acid is 1 mol times or more normally with respect to a diastereomeric salt.
  • the acid treatment of the diastereomeric salt is usually performed in a solvent.
  • solvents examples include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, t-butylcyclohexane, petroleum ether and the like.
  • Aliphatic hydrocarbon solvent benzene, toluene, ethylbenzene, isopropylbenzene, t-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, ⁇ , ⁇ , ⁇ -trifluoromethylbenzene, 1,2-dichlorobenzene, 1, Aromatic solvents such as 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, di Such as chill ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, t-butyl methyl ether, cyclopentyl methyl ether,
  • Ether solvent methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, t-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, 2-hexanol, iso Hexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol mono Chill ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono t-butyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl Alcohol solvents such as ether, diethylene glycol monoisopropyl ether, diethylene glycol mono
  • the solvent is preferably a mixed solvent of an aromatic solvent and a ketone solvent or an alcohol solvent, more preferably a mixed solvent of an aromatic solvent and an alcohol solvent.
  • the amount of the solvent used is preferably 1 to 50 L, more preferably 3 to 30 L with respect to 1 kg of the diastereomeric salt.
  • the acid treatment of the diastereomeric salt can be performed, for example, by mixing a diastereomeric salt and a solvent and adding the acid thereto.
  • the treatment temperature is preferably 0 to 40 ° C, more preferably 0 to 30 ° C.
  • the treatment time is not limited and is preferably 1 minute to 24 hours.
  • the optically active amino compound (3) is precipitated as an acid addition salt in the mixture obtained by the acid treatment of the diastereomeric salt
  • the acid addition salt is separated into solid and liquid, for example, filtration or decantation.
  • the acid addition salt can be taken out.
  • the obtained mixture is, for example, concentrated, mixed with a solvent in which the salt is difficult to dissolve, or cooled.
  • the acid addition salt is precipitated, and the acid addition salt can be taken out by subjecting the precipitated acid addition salt to a solid-liquid separation treatment such as filtration or decantation.
  • the extracted acid addition salt can be purified, for example, by recrystallization or the like, or the optically active amino compound (3) can be extracted as a free base in the same manner as in the base treatment of a diastereomeric salt described later.
  • Specific examples of the acid addition salt include addition salts of hydrochloric acid, phosphoric acid, sulfuric acid, paratoluenesulfonic acid, benzenesulfonic acid and camphorsulfonic acid.
  • the filtrate obtained by the above-described solid-liquid separation treatment contains the optically active tartranyl acid compound (2).
  • the optically active tartranyl acid compound (2) is taken out from the filtrate by a conventional method and reused in the present invention. be able to.
  • Examples of the base used to treat the diastereomeric salt include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium methylate and sodium. Examples include alkali metal alcoholates such as ethylate, potassium methylate, and potassium ethylate; and amine compounds such as triethylamine and diethylamine.
  • the base is preferably an alkali metal hydroxide, more preferably sodium hydroxide.
  • the base can be used alone or in combination with a solvent described later.
  • the usage-amount of a base is 1 mol times or more normally with respect to a diastereomeric salt.
  • the base treatment of the diastereomeric salt is preferably performed in a solvent.
  • solvents examples include alcohol solvents such as methanol, ethanol, 2-propanol, 1-propanol, and 1-butanol; diethyl ether, t-butyl methyl ether, methyl isobutyl ether, diisopropyl ether, methyl cyclopentyl ether, 1, 2 -Ether solvents such as dimethoxymethane; aromatic solvents such as toluene, xylene and chlorobenzene; aliphatic hydrocarbon solvents such as hexane and cyclohexane; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate and t-butyl acetate Solvents; halogenated aliphatic hydrocarbon solvents such as dichloromethane; water; and mixtures thereof.
  • alcohol solvents such as methanol, ethanol, 2-propanol, 1-propano
  • the solvent is preferably an aromatic solvent, an alcohol solvent or water, or a mixed solvent thereof, more preferably toluene or water, or a mixed solvent thereof.
  • an inorganic base such as an alkali metal hydroxide or alkali metal carbonate
  • water alone or an organic solvent having low compatibility with water for example, the above ether solvents, aromatic solvents, aliphatic hydrocarbons
  • solvent, ketone solvent, ester solvent, halogenated hydrocarbon solvent water are more preferably used as a mixture.
  • the amount of the solvent used is preferably 1 to 50 L, more preferably 3 to 30 L with respect to 1 kg of the diastereomeric salt.
  • the base treatment of a diastereomeric salt can be performed, for example, by mixing a diastereomeric salt and a solvent and adding a base thereto.
  • the treatment temperature is preferably 0 to 60 ° C, more preferably 10 to 30 ° C.
  • the treatment time is not limited and is preferably 1 minute to 24 hours.
  • the base treatment of the diastereomeric salt can be performed, for example, by the following method. A base is added to the mixture of water and diastereomeric salt to make the aqueous layer of the mixture basic (preferably pH 8.5 or higher), and an organic solvent having low compatibility with water is added to the resulting mixture. By subjecting it to a liquid separation treatment, an organic layer containing the optically active amino compound (3) can be obtained.
  • the optically active amino compound (3) can be isolated as a free base.
  • an alkali metal alcoholate is used as the base and an alcohol solvent is used as the solvent, the alkali metal salt of the optically active tartranilic acid compound (2) can be precipitated. The precipitate is filtered off and the resulting solution is concentrated.
  • the optically active amino compound (3) can be isolated as a free base.
  • the obtained optically active amino compound (3) can be purified by subjecting it to purification treatment such as rectification and column chromatography.
  • the optically active amino compound (3) can be taken out as an acid addition salt with any acid.
  • the aqueous layer obtained by the liquid separation treatment contains the optically active tartranyl acid compound (2).
  • the optically active tartranyl acid compound (2) is taken out from the aqueous layer by a conventional method and reused in the present invention. be able to.
  • the optically active tartlanyl acid compound (2) can be taken out from the alkali metal salt of the optically active tartranyl acid compound (2) filtered out by the conventional method and reused in the present invention.
  • the optical purity of the optically active amino compound (3) thus obtained is preferably 80% ee or more, more preferably 95% ee or more, although it depends on the optical purity of the optically active tartranyl acid compound (2) used. Yes, more preferably 98% ee or more, particularly preferably 99% ee or more.
  • the obtained mixture was adjusted to 15 ° C., and a mixed solution of 31.5 g (311 mmol) of triethylamine and 15.9 g of toluene was dropped therein over 40 minutes. After completion of dropping, the mixture was stirred at 15 ° C. for 4 hours. The reaction mixture was cooled to 8 ° C. and 84 g of water was added dropwise. After completion of dropping, the mixture was stirred for 20 minutes, followed by liquid separation, and the obtained organic layer was washed with 57 g of 20% brine.
  • Reference example 2 Preparation of racemic ethyl 1-amino-2-ethenylcyclopropanecarboxylate 1,4-dibromo-2-butene 50.0 g (234 mmol), tert-butoxy lithium 44.4 g (purity 97%, 538 mmol), To a mixture of 0.041 g (0.47 mmol) of lithium bromide, 294 g of tert-butyl methyl ether was added, and the mixture was cooled to 10 ° C. while stirring.
  • the mixture was cooled to 15 ° C. with stirring, and 13.6 g of a 48% aqueous sodium hydroxide solution (164 mmol of sodium hydroxide) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 30 minutes, separated, and the organic layer was separated. Then, 73.3 g of toluene was poured into the obtained aqueous layer to perform re-extraction.
  • Example 1 Preparation of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate / (2S, 3S) -2′-chlorotaltranylate 187 g of toluene solution obtained in Reference Example 2 (1- Into pure amino (19.9 g, 128 mmol) of ethyl amino-2-ethenylcyclopropanecarboxylate, 8.0 g of 2-propanol was poured at room temperature and stirred.
  • optical purity of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate obtained by treatment with diethylamine was determined. Optical purity 88% ee.
  • Diastereomer salt ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate ⁇ (2S, 3S) -2′-chlorotaltranylate is treated with diethylamine to give (1R , 2S) -1-amino-2-ethenylcyclopropanecarboxylate ethyl ester.
  • optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate useful as a synthetic intermediate for antiviral drugs and the like can be efficiently produced with high optical purity.

Abstract

A process for the preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by formula (3), an enantiomer thereof, or acid addition salts of the same, which comprises a step of reacting a mixture containing the (1R, 2S) and (1S, 2R) isomers of ethyl 1-amino-2 -ethenylcyclopropanecarboxylate represented by formula (1) with an optically active tartranilic acid compound represented by general formula (2) to form a diastereomeric salt mixture, a step of separating one of the diastereomeric salts from the other thereof, and a step of treating each of the separated diastereomeric salts with either an acid or a base to decompose the diastereomeric salt. By this process, ethyl 1-amino-2 -ethenylcyclopropanecarboxylate with a high optical purity can be prepared efficiently.

Description

光学活性な１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの製造方法Process for producing optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate
　本発明は、光学活性な１−アミノ−２−エテニルシクロプロパンカルボン酸エチル又はその酸付加塩の製造方法、及びその製造方法に用いられる中間体に関する。 The present invention relates to a method for producing optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate or an acid addition salt thereof, and an intermediate used in the method.
　光学活性な１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの製造方法は、例えばＪｏｕｒｎａｌ　ｏｆ　Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ，第７０巻，５８６９−５８７９頁，２００５年に記載されており、１−アミノ−２−エテニルシクロプロパンカルボン酸エチルのラセミ体をジ−ｐ−トルオイル−Ｄ−酒石酸により光学分割する方法、及び酵素反応により光学分割する方法が知られている。
　しかしながら、ジ−ｐ−トルオイル−Ｄ−酒石酸による光学分割では、得られる光学活性な１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの光学純度が５０~５５％ｅｅと高くなく、また、酵素反応により光学分割は、１−アミノ−２−エテニルシクロプロパンカルボン酸エチルのアミノ基をｔ−ブトキシカルボニル基で保護する必要があり、工程数が増加するという問題と共に、酵素反応を完結させるまでに９日間を要し、しかもその間に反応混合物中へ酵素を補充する必要があるという問題があり、効率的な方法ではなかった。 A method for producing optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate is described in, for example, Journal of Organic Chemistry, Vol. 70, 5869-5879, 2005. There are known a method of optical resolution of a racemate of ethyl ethenylcyclopropanecarboxylate with di-p-toluoyl-D-tartaric acid and a method of optical resolution with an enzymatic reaction.
However, in the optical resolution with di-p-toluoyl-D-tartaric acid, the optical purity of the obtained optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate is not as high as 50 to 55% ee, and the enzyme In the optical resolution by the reaction, it is necessary to protect the amino group of ethyl 1-amino-2-ethenylcyclopropanecarboxylate with a t-butoxycarbonyl group, which increases the number of steps and completes the enzymatic reaction. It took 9 days to complete the process, and during that time, it was necessary to replenish the enzyme into the reaction mixture, which was not an efficient method.
　本発明は、上記問題を解消する光学活性な２−エテニルシクロプロパンカルボン酸エチルの製造方法を提供する。
　即ち、本発明は、下記〔１〕~〔６〕に記載される発明を提供するものである。
〔１〕式（１）
Figure JPOXMLDOC01-appb-I000007
で示される１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの（１Ｒ，２Ｓ）異性体と（１Ｓ，２Ｒ）異性体とを含む混合物と、式（２）
Figure JPOXMLDOC01-appb-I000008
（式中、Ａｒは置換されていてもよいフェニル基を表し、該置換基は、１~３個のそれぞれ独立した、炭素数１~１２のアルキル基、炭素数３~１２のシクロアルキル基、炭素数１~１２のアルコキシ基、炭素数３~１２のシクロアルキルオキシ基、ハロゲン原子、ニトロ基、シアノ基又はトリフルオロメチル基である。＊は不斉炭素を表す。）
で示される光学活性なタルトラニル酸化合物とを反応させ、ジアステレオマー塩の混合物を得る工程、一方のジアステレオマー塩を他方のジアステレオマー塩から分離する工程、及び分離したジアステレオマー塩を酸又は塩基で処理することにより、ジアステレオマー塩を分解する工程を含む式（３）
Figure JPOXMLDOC01-appb-I000009
で示される光学活性な１−アミノ−２−エテニルシクロプロパンカルボン酸エチル若しくはその鏡像異性体、又はそれらの酸付加塩の製造方法。
〔２〕Ａｒが２−クロロフェニル基である〔１〕に記載の製造方法。
〔３〕上記の光学活性なタルトラニル酸化合物における２つの不斉炭素が共にＳ配置である〔１〕又は〔２〕に記載の製造方法。
〔４〕式（１）
Figure JPOXMLDOC01-appb-I000010
で示される１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの（１Ｒ，２Ｓ）異性体と（１Ｓ，２Ｒ）異性体とを含む混合物と、式（２）
Figure JPOXMLDOC01-appb-I000011
（式中、Ａｒは置換されていてもよいフェニル基を表し、該置換基は、１~３個のそれぞれ独立した、炭素数１~１２のアルキル基、炭素数３~１２のシクロアルキル基、炭素数１~１２のアルコキシ基、炭素数３~１２のシクロアルキルオキシ基、ハロゲン原子、ニトロ基、シアノ基又はトリフルオロメチル基である。＊は不斉炭素を表す。）
で示される光学活性なタルトラニル酸化合物とを反応させる工程を含む１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの光学分割方法。
〔５〕（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチルと式（２）
Figure JPOXMLDOC01-appb-I000012
（式中、Ａｒは置換されていてもよいフェニル基を表し、該置換基は、１~３個のそれぞれ独立した、炭素数１~１２のアルキル基、炭素数３~１２のシクロアルキル基、炭素数１~１２のアルコキシ基、炭素数３~１２のシクロアルキルオキシ基、ハロゲン原子、ニトロ基、シアノ基又はトリフルオロメチル基である。＊は不斉炭素を表す。）
で示される光学活性なタルトラニル酸化合物との塩。
〔６〕（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチルと（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸との塩。 The present invention provides a process for producing optically active ethyl 2-ethenylcyclopropanecarboxylate that solves the above problems.
That is, the present invention provides the inventions described in the following [1] to [6].
[1] Formula (1)
Figure JPOXMLDOC01-appb-I000007
A mixture containing (1R, 2S) isomer and (1S, 2R) isomer of ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by formula (2)
Figure JPOXMLDOC01-appb-I000008
(In the formula, Ar represents a phenyl group which may be substituted, and the substituents each have 1 to 3 independent alkyl groups having 1 to 12 carbon atoms, cycloalkyl groups having 3 to 12 carbon atoms, An alkoxy group having 1 to 12 carbon atoms, a cycloalkyloxy group having 3 to 12 carbon atoms, a halogen atom, a nitro group, a cyano group, or a trifluoromethyl group (* represents an asymmetric carbon).
And a step of obtaining a mixture of diastereomeric salts, a step of separating one diastereomeric salt from the other diastereomeric salt, and a separated diastereomeric salt. Formula (3) comprising the step of decomposing a diastereomeric salt by treatment with an acid or base
Figure JPOXMLDOC01-appb-I000009
A process for producing an optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate or an enantiomer thereof, or an acid addition salt thereof.
[2] The production method according to [1], wherein Ar is a 2-chlorophenyl group.
[3] The production method according to [1] or [2], wherein the two asymmetric carbons in the optically active tartranyl acid compound are both in S configuration.
[4] Formula (1)
Figure JPOXMLDOC01-appb-I000010
A mixture containing (1R, 2S) isomer and (1S, 2R) isomer of ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by formula (2)
Figure JPOXMLDOC01-appb-I000011
(In the formula, Ar represents a phenyl group which may be substituted, and the substituents each have 1 to 3 independent alkyl groups having 1 to 12 carbon atoms, cycloalkyl groups having 3 to 12 carbon atoms, An alkoxy group having 1 to 12 carbon atoms, a cycloalkyloxy group having 3 to 12 carbon atoms, a halogen atom, a nitro group, a cyano group, or a trifluoromethyl group (* represents an asymmetric carbon).
A method for optical resolution of ethyl 1-amino-2-ethenylcyclopropanecarboxylate, which comprises a step of reacting with an optically active tartranyl acid compound represented by the formula:
[5] Ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate and formula (2)
Figure JPOXMLDOC01-appb-I000012
(In the formula, Ar represents a phenyl group which may be substituted, and the substituents each have 1 to 3 independent alkyl groups having 1 to 12 carbon atoms, cycloalkyl groups having 3 to 12 carbon atoms, An alkoxy group having 1 to 12 carbon atoms, a cycloalkyloxy group having 3 to 12 carbon atoms, a halogen atom, a nitro group, a cyano group, or a trifluoromethyl group (* represents an asymmetric carbon).
A salt with an optically active tartranyl acid compound represented by the formula:
[6] A salt of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate and (2S, 3S) -2′-chlorotalthranilic acid.
　以下、本発明について詳細に説明する。
　式（１）で示される１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの（１Ｒ，２Ｓ）異性体と（１Ｓ，２Ｒ）異性体とを含む混合物としては、通常（１Ｒ，２Ｓ）異性体と（１Ｓ，２Ｒ）異性体との等量混合物であるラセミ体が用いられるが、いずれか一方の異性体を多く含む混合物を用いることもできる。以下、式（１）で示される１−アミノ−２−エテニルシクロプロパン−１−カルボン酸エチルの（１Ｒ，２Ｓ）異性体と（１Ｓ，２Ｒ）異性体とを含む混合物を異性体混合物（１）と略記する。
　異性体混合物（１）は、任意の公知の方法に従って製造することができる。例えばＪｏｕｒｎａｌ　ｏｆ　Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ，第７０巻，５８６９−５８７９頁，２００５年に記載の方法により、塩基の存在下、Ｎ−フェニルメチレングリシンエチルと１，４−ジブロモ−２−ブテンとを反応させて得られる１−（Ｎ−フェニルメチレンアミノ）−２−エテニルシクロプロパンカルボン酸エチルを、酸処理するなどして製造することができる。異性体混合物（１）が、式（２）で示される光学活性なタルトラニル酸化合物（以下、光学活性タルトラニル酸化合物（２）と略記する。）以外の任意の酸と塩を形成している場合には、光学活性タルトラニル酸化合物（２）と反応させる前に、該塩を塩基処理することが好ましい。
　光学活性タルトラニル酸化合物（２）において、Ａｒで表される置換されていてもよいフェニル基の置換基のうち、炭素数１~１２のアルキル基としては、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔ−ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基が挙げられ；炭素数３~１２のシクロアルキル基としては、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基が挙げられ；炭素数１~１２のアルコキシ基としては、例えばメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ｔ−ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基、ヘプチルオキシ基、オクチルオキシ基、ノニルオキシ基、デシルオキシ基、ウンデシルオキシ基、ドデシルオキシ基が挙げられ；炭素数３~１２のシクロアルキルオキシ基としては、例えばシクロプロピルオキシ基、シクロブチルオキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基、シクロヘプチルオキシ基、シクロオクチルオキシ基が挙げられ；ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。Ａｒは、好ましくはフェニル基またはクロロフェニル基であり、より好ましくはクロロフェニル基であり、さらに好ましくは２−クロロフェニル基である。
　光学活性タルトラニル酸化合物（２）において、＊で表される２つの不斉炭素は、好ましくは共にＳ配置又は共にＲ配置であり、より好ましくは共にＳ配置である。
　光学活性タルトラニル酸化合物（２）の光学純度は、好ましくは９０％ｅｅ（以下、ｅｅは鏡像体過剰率を表す。）以上であり、より好ましくは９５％ｅｅ以上であり、さらに好ましくは９８％ｅｅ以上であり、特に好ましくは９９％ｅｅ以上である。
　光学活性タルトラニル酸化合物（２）は、市販のものを用いることもできるし、ＪＰ２００１−８９４３１Ａに記載の方法等により製造したものを用いることもできる。
　光学活性タルトラニル酸化合物（２）の使用量は限定されないが、異性体混合物（１）としてラセミ体を用いる場合は、異性体混合物（１）に対して、通常０．５モル倍以上であり、収率および経済性の観点から、０．５モル倍~２モル倍であることが好ましく、０．９モル倍~１．５モル倍であることがより好ましい。
　異性体混合物（１）と光学活性タルトラニル酸化合物（２）との反応は、溶媒中で行うことが好ましい。かかる溶媒としては、例えば、ペンタン、ヘキサン、イソヘキサン、ヘプタン、イソヘプタン、オクタン、イソオクタン、ノナン、イソノナン、デカン、イソデカン、ウンデカン、ドデカン、シクロペンタン、シクロヘキサン、メチルシクロヘキサン、ｔ−ブチルシクロヘキサン、石油エーテル等の脂肪族炭化水素溶媒；ベンゼン、トルエン、エチルベンゼン、イソプロピルベンゼン、ｔ−ブチルベンゼン、キシレン、メシチレン、モノクロロベンゼン、モノフルオロベンゼン、α，α，α−トリフルオロメチルベンゼン、１，２−ジクロロベンゼン、１，３−ジクロロベンゼン、１，２，３−トリクロロベンゼン、１，２，４−トリクロロベンゼン等の芳香族溶媒；テトラヒドロフラン、メチルテトラヒドロフラン、１，４−ジオキサン、ジエチルエーテル、ジプロピルエーテル、ジイソプロピルエーテル、ジブチルエーテル、ジペンチルエーテル、ジヘキシルエーテル、ジヘプチルエーテル、ジオクチルエーテル、ｔ−ブチルメチルエーテル、シクロペンチルメチルエーテル、１，２−ジメトキシエタン、ジエチレングリコールジメチルエーテル、アニソール、ジフェニルエーテル等のエーテル溶媒；メタノール、エタノール、１−プロパノール、２−プロパノール、１−ブタノール、イソブチルアルコール、ｔ−ブチルアルコール、１−ペンタノール、２−ペンタノール、イソペンチルアルコール、１−ヘキサノール、２−ヘキサノール、イソヘキシルアルコール、１−ヘプタノール、２−ヘプタノール、３−ヘプタノール、イソペプチルアルコール、エチレングリコールモノメチルエーテル、エチレングリコールモノエチルエーテル、エチレングリコールモノプロピルエーテル、エチレングリコールモノイソプロピルエーテル、エチレングリコールモノブチルエーテル、エチレングリコールモノイソブチルエーテル、エチレングリコールモノｔ−ブチルエーテル、ジエチレングリコールモノメチルエーテル、ジエチレングリコールモノエチルエーテル、ジエチレングリコールモノプロピルエーテル、ジエチレングリコールモノイソプロピルエーテル、ジエチレングリコールモノブチルエーテル、ジエチレングリコールモノイソブチルエーテル、ジエチレングリコールモノｔ−ブチルエーテル等のアルコール溶媒；アセトニトリル、プロピオニトリル、ベンゾニトリル等のニトリル溶媒；ジクロロメタン、クロロホルム、１，２−ジクロロエタン等の塩素化脂肪族炭化水素溶媒；酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル、酢酸イソブチル、酢酸ｔ−ブチル、酢酸アミル、酢酸イソアミル、酢酸ヘキシル、プロピオン酸メチル、プロピオン酸エチル、プロピオン酸プロピル、プロピオン酸イソプロピル等のエステル溶媒；アセトン、メチルエチルケトン、メチルプロピルケトン、メチルイソプロピルケトン、メチルブチルケトン、メチルイソブチルケトン、ジエチルケトン、シクロペンタノン、シクロヘキサノン等のケトン溶媒；ジメチルスルホキシド、スルホラン、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ，Ｎ−ジメチルプロピオンアミド、Ｎ−メチルピロリドン、γ−ブチロラクトン、炭酸ジメチル、炭酸ジエチル、エチレンカーボネート、プロピレンカーボネート、１，３−ジメチル−２−イミダゾリジノン、１，３−ジメチル−３，４，５，６−テトラヒドロ−２（１Ｈ）−ピリジノン等の非プロトン性極性溶媒；水；これらの混合物が挙げられる。溶媒は、好ましくは芳香族溶媒と、ケトン溶媒、エステル溶媒、アルコール溶媒及びエーテル溶媒からなる群から選ばれる少なくとも１つの溶媒との混合溶媒であり、より好ましくは芳香族溶媒と、ケトン溶媒又はアルコール溶媒との混合溶媒であり、さらに好ましくはトルエンとエタノールとの混合溶媒、トルエンと２−プロパノールとの混合溶媒、トルエンとアセトンとの混合溶媒、トルエンとメチルエチルケトンとの混合溶媒であり、特に好ましくはトルエンと２−プロパノールとの混合溶媒である。
　溶媒の使用量は、用いる溶媒及び光学活性タルトラニル酸化合物（２）の構造にもよるが、異性体混合物（１）１ｋｇに対して、好ましくは１~５０Ｌ、より好ましくは３~３０Ｌの割合である。
　異性体混合物（１）と光学活性タルトラニル酸化合物（２）との反応は、例えば、溶媒と異性体混合物（１）とを混合し、得られる混合物に光学活性タルトラニル酸化合物（２）を添加することにより行うこともできるし、溶媒と光学活性タルトラニル酸化合物（２）とを混合し、得られる混合物に異性体混合物（１）を添加することにより行うこともできる。
　異性体混合物（１）と光学活性タルトラニル酸化合物（２）との反応温度は限定されず、０℃以上、溶媒の沸点以下であることが好ましい。
　生成したジアステレオマー塩の混合物より溶媒中で一方のジアステレオマー塩を優先的に析出させることにより、他方のジアステレオマー塩から分離することができる。
　溶媒中のジアステレオマー塩の混合物からジアステレオマー塩の析出が認められない場合、予め調製した一方のジアステレオマー塩を種晶として添加した後に、ジアステレオマー塩の混合物の溶液を冷却することにより、一方のジアステレオマー塩を優先的に析出させることができる。
　ジアステレオマー塩の析出が認められる場合は、溶液をそのまま冷却してもよいが、析出するジアステレオマー塩の光学純度を向上させるためには、溶液を加熱して析出物を溶解させた後、冷却することにより、一方のジアステレオマー塩を優先的に析出させることが好ましく、かかるジアステレオマー塩の析出において、予め調製した一方のジアステレオマー塩を種晶として用いることもできる。種晶の光学純度は高い程よく、好ましくは９０％ｅｅ以上であり、より好ましくは９５％ｅｅ以上であり、さらに好ましくは９８％ｅｅ以上であり、特に好ましくは９９％ｅｅ以上である。
　ジアステレオマー塩の混合物の溶液を加熱する場合は、３０℃以上、溶媒の沸点以下に加熱することが好ましい。冷却処理としては、０~２５℃へ冷却することが好ましく、析出するジアステレオマー塩の光学純度を向上させるためには、徐々に冷却することが好ましい。
　一方のジアステレオマー塩を優先的に析出させた後に、例えば濾過やデカンテーション等の固液分離処理を施すことにより、一方のジアステレオマー塩を取り出すことができる。固液分離処理後には、ジアステレオマー塩の光学純度を向上させる点において、洗浄処理を施すことが好ましい。かかる洗浄処理には、異性体混合物（１）と光学活性タルトラニル酸化合物（２）との反応に関して上述した溶媒と同じ溶媒を用いることができる。洗浄処理の後、乾燥処理を行うことが好ましい。乾燥処理は、常圧若しくは減圧条件下で、好ましくは２０~８０℃の範囲で行うことができる。
　上記の固液分離処理した結果の液体には、他方のジアステレオマー塩が含まれており、液相から常法により、他方のジアステレオマー塩を取り出すこともできる。
　ジアステレオマー塩を精製処理することにより、光学純度をさらに向上させることもできる。
　精製処理としては、再結晶法が好ましい。例えば、ジアステレオマー塩を溶媒に溶解し、冷却して精製されたジアステレオマー塩を析出させる方法、ジアステレオマー塩を溶媒に溶解させた後、貧溶媒を滴下して精製されたジアステレオマー塩を析出させる方法、ジアステレオマー塩を溶媒に溶解させた後、溶媒を留去して精製されたジアステレオマー塩を析出させる方法、又はこれらの組み合わせにより、精製処理を行うことができる。精製処理において、予め調製した一方のジアステレオマー塩を種晶として添加することもできる。精製処理に用いられる溶媒としては、例えば、メタノール、エタノール、１−プロパノール、２−プロパノール、１−ブタノール、イソブチルアルコール、ｔ−ブチルアルコール、１−ペンタノール、２−ペンタノール、イソペンチルアルコール、１−ヘキサノール、２−ヘキサノール、イソヘキシルアルコール、１−ヘプタノール、２−ヘプタノール、３−ヘプタノール、イソペプチルアルコール、エチレングリコールモノメチルエーテル、エチレングリコールモノエチルエーテル、エチレングリコールモノプロピルエーテル、エチレングリコールモノイソプロピルエーテル、エチレングリコールモノブチルエーテル、エチレングリコールモノイソブチルエーテル、エチレングリコールモノｔ−ブチルエーテル、ジエチレングリコールモノメチルエーテル、ジエチレングリコールモノエチルエーテル、ジエチレングリコールモノプロピルエーテル、ジエチレングリコールモノイソプロピルエーテル、ジエチレングリコールモノブチルエーテル、ジエチレングリコールモノイソブチルエーテル、ジエチレングリコールモノｔ−ブチルエーテル等のアルコール溶媒；テトラヒドロフラン、メチルテトラヒドロフラン、１，４−ジオキサン等の環状のエーテル溶媒；水が挙げられ、好ましくはアルコール溶媒又は環状のエーテル溶媒であり、より好ましくはエタノール、２−プロパノール又はテトラヒドロフランである。溶媒の使用量は、用いる溶媒により適宜調節することができるが、ジアステレオマー塩１ｋｇに対して、好ましくは１~１０Ｌの割合である。ジアステレオマー塩を溶解させる温度は、好ましくは０~８０℃である。貧溶媒としては、例えば、ペンタン、ヘキサン、イソヘキサン、ヘプタン、イソヘプタン、オクタン、イソオクタン、ノナン、イソノナン、デカン、イソデカン、ウンデカン、ドデカン、シクロペンタン、シクロヘキサン、メチルシクロヘキサン、ｔ−ブチルシクロヘキサン、石油エーテル等の脂肪族炭化水素溶媒；ベンゼン、トルエン、エチルベンゼン、イソプロピルベンゼン、ｔ−ブチルベンゼン、キシレン、メシチレン、モノクロロベンゼン、モノフルオロベンゼン、α，α，α−トリフルオロメチルベンゼン、１，２−ジクロロベンゼン、１，３−ジクロロベンゼン、１，２，３−トリクロロベンゼン、１，２，４−トリクロロベンゼン等の芳香族溶媒が挙げられ、好ましくは脂肪族炭化水素溶であり、より好ましくはヘプタンである。貧溶媒の使用量は、精製ジアステレオマー塩の析出度合いにより適宜調節することができる。冷却処理により精製ジアステレオマー塩を析出させる場合は、０~２５℃に冷却することが好ましく、１時間あたりの冷却温度は３~１０℃であることが好ましい。
　かくして得られるジアステレオマー塩は新規化合物であり、好ましくは（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチルと（２Ｓ，３Ｓ）の絶対配置を有する光学活性タルトラニル酸化合物（２）との塩、又は（１Ｓ，２Ｒ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチルと（２Ｒ，３Ｒ）の絶対配置を有する光学活性タルトラニル酸化合物（２）との塩であり、より好ましくは（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチルと（２Ｓ，３Ｓ）の絶対配置を有する光学活性タルトラニル酸化合物（２）との塩であり、さらに好ましくは（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチルと（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸との塩である。
　得られたジアステレオマー塩を酸又は塩基で処理することにより、式（３）で示される光学活性な１−アミノ−２−エテニルシクロプロパンカルボン酸エチル若しくはその鏡像異性体、又はそれらの酸付加塩を得ることができる。以下、式（３）で示される光学活性な１−アミノ−２−エテニルシクロプロパンカルボン酸エチル若しくはその鏡像異性体、又はそれらの酸付加塩を、光学活性アミノ化合物（３）と略記することがある。
　ジアステレオマー塩を処理する酸は、一般に光学活性タルトラニル酸化合物（２）よりも酸性度の高いものであり、かかる酸としては、例えば塩酸、リン酸、硫酸等の鉱酸；パラトルエンスルホン酸、ベンゼンスルホン酸、カンファースルホン酸等の有機酸が挙げられる。酸は、好ましくは塩酸又は硫酸である。これらの酸は、単独で用いることもできるし、後述する溶媒と混合して用いることもできる。
　酸の使用量は、ジアステレオマー塩に対して、通常１モル倍以上である。
　ジアステレオマー塩の酸処理は、通常溶媒中で行われる。かかる溶媒としては、例えば、ペンタン、ヘキサン、イソヘキサン、ヘプタン、イソヘプタン、オクタン、イソオクタン、ノナン、イソノナン、デカン、イソデカン、ウンデカン、ドデカン、シクロペンタン、シクロヘキサン、メチルシクロヘキサン、ｔ−ブチルシクロヘキサン、石油エーテル等の脂肪族炭化水素溶媒；ベンゼン、トルエン、エチルベンゼン、イソプロピルベンゼン、ｔ−ブチルベンゼン、キシレン、メシチレン、モノクロロベンゼン、モノフルオロベンゼン、α，α，α−トリフルオロメチルベンゼン、１，２−ジクロロベンゼン、１，３−ジクロロベンゼン、１，２，３−トリクロロベンゼン、１，２，４−トリクロロベンゼン等の芳香族溶媒；テトラヒドロフラン、メチルテトラヒドロフラン、１，４−ジオキサン、ジエチルエーテル、ジプロピルエーテル、ジイソプロピルエーテル、ジブチルエーテル、ジペンチルエーテル、ジヘキシルエーテル、ジヘプチルエーテル、ジオクチルエーテル、ｔ−ブチルメチルエーテル、シクロペンチルメチルエーテル、１，２−ジメトキシエタン、ジエチレングリコールジメチルエーテル、アニソール、ジフェニルエーテル等のエーテル溶媒；メタノール、エタノール、１−プロパノール、２−プロパノール、１−ブタノール、イソブチルアルコール、ｔ−ブチルアルコール、１−ペンタノール、２−ペンタノール、イソペンチルアルコール、１−ヘキサノール、２−ヘキサノール、イソヘキシルアルコール、１−ヘプタノール、２−ヘプタノール、３−ヘプタノール、イソペプチルアルコール、エチレングリコールモノメチルエーテル、エチレングリコールモノエチルエーテル、エチレングリコールモノプロピルエーテル、エチレングリコールモノイソプロピルエーテル、エチレングリコールモノブチルエーテル、エチレングリコールモノイソブチルエーテル、エチレングリコールモノｔ−ブチルエーテル、ジエチレングリコールモノメチルエーテル、ジエチレングリコールモノエチルエーテル、ジエチレングリコールモノプロピルエーテル、ジエチレングリコールモノイソプロピルエーテル、ジエチレングリコールモノブチルエーテル、ジエチレングリコールモノイソブチルエーテル、ジエチレングリコールモノｔ−ブチルエーテル等のアルコール溶媒；アセトニトリル、プロピオニトリル、ベンゾニトリル等のニトリル溶媒；酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル、酢酸イソブチル、酢酸ｔ−ブチル、酢酸アミル、酢酸イソアミル等のエステル溶媒；アセトン、メチルエチルケトン、メチルイソプロピルケトン、メチルイソブチルケトン、シクロペンタノン、シクロヘキサノン等のケトン溶媒；ジクロロメタン、クロロホルム、１，２−ジクロロエタン等の塩素化脂肪族炭化水素溶媒；蟻酸、酢酸、プロピオン酸等のカルボン酸溶媒；水；これらの混合物が挙げられる。溶媒は、好ましくは芳香族溶媒と、ケトン溶媒又はアルコール溶媒との混合溶媒であり、より好ましくは芳香族溶媒とアルコール溶媒との混合溶媒である。溶媒の使用量は、ジアステレオマー塩１ｋｇに対し、好ましくは１~５０Ｌ、より好ましくは３~３０Ｌの割合である。
　ジアステレオマー塩の酸処理は、例えば、ジアステレオマー塩と溶媒とを混合し、そこへ酸を添加することにより行うことができる。処理温度は、好ましくは０~４０℃であり、より好ましくは０~３０℃である。処理時間は限定されず、好ましくは１分~２４時間である。
　ジアステレオマー塩の酸処理により得られた混合物中に、光学活性アミノ化合物（３）が酸付加塩として析出している場合は、該酸付加塩を、例えば濾過やデカンテーション等の固液分離処理に付すことにより、該酸付加塩を取り出すことができる。酸付加塩の析出が不十分である場合や、酸付加塩が析出していない場合は、得られた混合物を、例えば、濃縮処理、該塩を溶解し難い溶媒との混合処理、あるいは、冷却処理に付すことにより、酸付加塩を析出させ、析出した酸付加塩を、例えば濾過やデカンテーション等の固液分離処理に付すことにより、酸付加塩を取り出すことができる。取り出した酸付加塩は、例えば再結晶等により精製することもできるし、後述するジアステレオマー塩の塩基処理と同様にして、光学活性アミノ化合物（３）を遊離塩基として取り出すこともできる。
　酸付加塩の具体例としては、塩酸、リン酸、硫酸、パラトルエンスルホン酸、ベンゼンスルホン酸及びカンファースルホン酸の付加塩が挙げられる。
　上述した固液分離処理により得られる濾液には、光学活性タルトラニル酸化合物（２）が含まれており、該濾液から常法により光学活性タルトラニル酸化合物（２）を取り出し、本発明に再使用することができる。
　ジアステレオマー塩を処理するのに使用される塩基としては、例えば、水酸化カリウム、水酸化ナトリウム等のアルカリ金属水酸化物；炭酸ナトリウム、炭酸カリウム等のアルカリ金属炭酸塩；ナトリウムメチラート、ナトリウムエチラート、カリウムメチラート、カリウムエチラート等のアルカリ金属アルコラート；トリエチルアミン、ジエチルアミン等のアミン化合物が挙げられる。塩基は、アルカリ金属水酸化物が好ましく、水酸化ナトリウムがより好ましい。塩基は、単独で用いることもできるし、後述する溶媒と混合して用いることもできる。
　塩基の使用量は、ジアステレオマー塩に対して、通常１モル倍以上である。
　ジアステレオマー塩の塩基処理は、溶媒中で行われることが好ましい。かかる溶媒としては、例えば、メタノール、エタノール、２−プロパノール、１−プロパノール、１−ブタノール等のアルコール溶媒；ジエチルエーテル、ｔ−ブチルメチルエーテル、メチルイソブチルエーテル、ジイソプロピルエーテル、メチルシクロペンチルエーテル、１，２−ジメトキシメタン等のエーテル溶媒；トルエン、キシレン、クロロベンゼン等の芳香族溶媒；ヘキサン、シクロヘキサン等の脂肪族炭化水素溶媒；メチルエチルケトン、メチルイソブチルケトン等のケトン溶媒；酢酸エチル、酢酸ｔ−ブチル等のエステル溶媒；ジクロロメタン等のハロゲン化脂肪族炭化水素溶媒；水；これらの混合物が挙げられる。溶媒は、好ましくは芳香族溶媒、アルコール溶媒若しくは水、又はそれらの混合溶媒であり、より好ましくはトルエン若しくは水、又はそれらの混合溶媒である。塩基としてアルカリ金属水酸化物やアルカリ金属炭酸塩等の無機塩基を用いる場合は、水単独か又は水との相溶性が低い有機溶媒（例えば、上記のエーテル溶媒、芳香族溶媒、脂肪族炭化水素溶媒、ケトン溶媒、エステル溶媒、ハロゲン化炭化水素溶媒）と水とを混合して用いることがより好ましい。
　溶媒の使用量は、ジアステレオマー塩１ｋｇに対し、好ましくは１~５０Ｌ、より好ましくは３~３０Ｌの割合である。
　ジアステレオマー塩の塩基処理は、例えば、ジアステレオマー塩と溶媒とを混合し、そこへ塩基を添加することにより行うことができる。処理温度は、好ましくは０~６０℃であり、より好ましくは１０~３０℃である。処理時間は限定されず、好ましくは１分~２４時間である。
　ジアステレオマー塩の塩基処理は、具体的には、例えば下記の方法により行うことができる。
　水とジアステレオマー塩との混合物に塩基を加えて、混合物の水層を塩基性（好ましくはｐＨ８．５以上）とし、得られた混合物に、水との相溶性が低い有機溶媒を加え、分液処理に付すことにより、光学活性アミノ化合物（３）を含む有機層を得ることができる。有機層を、必要に応じて水洗処理に付した後、濃縮すれば、光学活性アミノ化合物（３）を遊離塩基として単離することができる。塩基としてアルカリ金属アルコラートを用い、溶媒としてアルコール溶媒を用いた場合は、光学活性タルトラニル酸化合物（２）のアルカリ金属塩を析出させることができ、この析出物を濾別して、得られた溶液を濃縮処理に付すことにより、光学活性アミノ化合物（３）を遊離塩基として単離することができる。得られた光学活性アミノ化合物（３）は、例えば精留、カラムクロマトグラフィー等の精製処理に付すことにより、精製することもできる。光学活性アミノ化合物（３）は、任意の酸との酸付加塩として取り出すこともできる。
　上記分液処理により得られる水層には、光学活性タルトラニル酸化合物（２）が含まれており、該水層から常法により光学活性タルトラニル酸化合物（２）を取り出し、本発明に再使用することができる。また、上記で濾別された光学活性タルトラニル酸化合物（２）のアルカリ金属塩から、常法により光学活性タルトラニル酸化合物（２）を取り出し、本発明に再使用することもできる。
　かくして得られる光学活性アミノ化合物（３）の光学純度は、用いた光学活性タルトラニル酸化合物（２）の光学純度にもよるが、好ましくは８０％ｅｅ以上であり、より好ましくは９５％ｅｅ以上であり、さらに好ましくは９８％ｅｅ以上であり、特に好ましくは９９％ｅｅ以上である。 Hereinafter, the present invention will be described in detail.
The mixture containing the (1R, 2S) isomer and (1S, 2R) isomer of ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by the formula (1) is usually (1R, 2S) isomerism. Racemate, which is an equimolar mixture of the isomer and the (1S, 2R) isomer, can be used, but a mixture rich in either isomer can also be used. Hereinafter, a mixture containing the (1R, 2S) isomer and the (1S, 2R) isomer of ethyl 1-amino-2-ethenylcyclopropane-1-carboxylate represented by the formula (1) is referred to as an isomer mixture ( Abbreviated as 1).
The isomer mixture (1) can be produced according to any known method. For example, it can be obtained by reacting N-phenylmethyleneglycine ethyl with 1,4-dibromo-2-butene in the presence of a base by the method described in Journal of Organic Chemistry, 70, 5869-5879, 2005. The resulting ethyl 1- (N-phenylmethyleneamino) -2-ethenylcyclopropanecarboxylate can be produced by acid treatment or the like. When the isomer mixture (1) forms a salt with any acid other than the optically active tartlanyl acid compound represented by the formula (2) (hereinafter abbreviated as optically active tartlanyl acid compound (2)). For this, it is preferable to base-treat the salt before reacting with the optically active tartranyl acid compound (2).
Among the substituents of the optionally substituted phenyl group represented by Ar in the optically active tartranilic acid compound (2), examples of the alkyl group having 1 to 12 carbon atoms include a methyl group, an ethyl group, a propyl group, Examples thereof include isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group and dodecyl group; a cycloalkyl group having 3 to 12 carbon atoms Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group; examples of the alkoxy group having 1 to 12 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, and an iso group. Propoxy group, butoxy group, isobutoxy group, t-butoxy group, pentyloxy group, hexyl Examples thereof include a xy group, a heptyloxy group, an octyloxy group, a nonyloxy group, a decyloxy group, an undecyloxy group, and a dodecyloxy group; examples of the cycloalkyloxy group having 3 to 12 carbon atoms include a cyclopropyloxy group and a cyclobutyl group. Examples thereof include an oxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclooctyloxy group; examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Ar is preferably a phenyl group or a chlorophenyl group, more preferably a chlorophenyl group, and still more preferably a 2-chlorophenyl group.
In the optically active tartranilic acid compound (2), the two asymmetric carbons represented by * are preferably both S configuration or both R configuration, and more preferably both S configuration.
The optical purity of the optically active tartranilic acid compound (2) is preferably 90% ee (hereinafter, ee represents an enantiomer excess), more preferably 95% ee, and still more preferably 98%. ee or higher, particularly preferably 99% ee or higher.
As the optically active tartranyl acid compound (2), a commercially available product can be used, or a product produced by the method described in JP2001-89431A can also be used.
The amount of the optically active tartranilic acid compound (2) used is not limited, but when a racemate is used as the isomer mixture (1), it is usually 0.5 mol times or more with respect to the isomer mixture (1). From the viewpoint of yield and economy, the molar ratio is preferably 0.5 to 2 mol times, more preferably 0.9 to 1.5 mol times.
The reaction of the isomer mixture (1) and the optically active tartlanyl acid compound (2) is preferably performed in a solvent. Examples of such solvents include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, t-butylcyclohexane, petroleum ether and the like. Aliphatic hydrocarbon solvent: benzene, toluene, ethylbenzene, isopropylbenzene, t-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, α, α, α-trifluoromethylbenzene, 1,2-dichlorobenzene, 1, Aromatic solvents such as 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, di Such as chill ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, anisole, diphenyl ether, etc. Ether solvent; methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, t-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, 2-hexanol, iso Hexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol mono Chill ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono t-butyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl Alcohol solvents such as ether, diethylene glycol monoisopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monoisobutyl ether, diethylene glycol mono t-butyl ether; nitrile solvents such as acetonitrile, propionitrile, benzonitrile; dichloromethane, chloroform Chlorinated aliphatic hydrocarbon solvents such as 1,2-dichloroethane; methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, t-butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, propionic acid Ester solvents such as methyl, ethyl propionate, propyl propionate, and isopropyl propionate; ketone solvents such as acetone, methyl ethyl ketone, methyl propyl ketone, methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone, diethyl ketone, cyclopentanone, and cyclohexanone Dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropionamide, N-methylpyrrolidone, γ-butyrolactone, dimethyl carbonate , Aprotic such as diethyl carbonate, ethylene carbonate, propylene carbonate, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyridinone Polar solvents; water; and mixtures thereof. The solvent is preferably a mixed solvent of an aromatic solvent and at least one solvent selected from the group consisting of a ketone solvent, an ester solvent, an alcohol solvent and an ether solvent, more preferably an aromatic solvent and a ketone solvent or an alcohol. It is a mixed solvent with a solvent, more preferably a mixed solvent of toluene and ethanol, a mixed solvent of toluene and 2-propanol, a mixed solvent of toluene and acetone, a mixed solvent of toluene and methyl ethyl ketone, particularly preferably It is a mixed solvent of toluene and 2-propanol.
The amount of the solvent used depends on the solvent used and the structure of the optically active tartlanic acid compound (2), but is preferably 1 to 50 L, more preferably 3 to 30 L with respect to 1 kg of the isomer mixture (1). is there.
In the reaction of the isomer mixture (1) and the optically active tartlanyl acid compound (2), for example, the solvent and the isomer mixture (1) are mixed, and the optically active tartranyl acid compound (2) is added to the resulting mixture. It can also carry out by mixing a solvent and an optically active tartranilic acid compound (2), and can also carry out by adding an isomer mixture (1) to the obtained mixture.
The reaction temperature of the isomer mixture (1) and the optically active tartlanyl acid compound (2) is not limited, and is preferably 0 ° C. or higher and the boiling point of the solvent or lower.
One diastereomeric salt can be separated from the other diastereomeric salt by preferentially precipitating one diastereomeric salt in a solvent from the resulting mixture of diastereomeric salts.
If no diastereomeric salt precipitation is observed from the mixture of diastereomeric salts in the solvent, after adding one of the previously prepared diastereomeric salts as seed crystals, the solution of the diastereomeric salt mixture is cooled. Thus, one diastereomeric salt can be preferentially precipitated.
When precipitation of diastereomeric salt is observed, the solution may be cooled as it is, but in order to improve the optical purity of the diastereomeric salt to be precipitated, the solution is heated to dissolve the precipitate. It is preferable to preferentially precipitate one diastereomeric salt by cooling, and in the precipitation of the diastereomeric salt, one diastereomeric salt prepared in advance can be used as a seed crystal. The optical purity of the seed crystal is preferably as high as possible, preferably 90% ee or more, more preferably 95% ee or more, still more preferably 98% ee or more, and particularly preferably 99% ee or more.
When heating a solution of a mixture of diastereomeric salts, it is preferably heated to 30 ° C. or higher and lower than the boiling point of the solvent. As the cooling treatment, cooling to 0 to 25 ° C. is preferable, and in order to improve the optical purity of the diastereomeric salt to be precipitated, it is preferable to gradually cool.
After preferentially precipitating one diastereomeric salt, for example, one diastereomeric salt can be taken out by performing solid-liquid separation treatment such as filtration or decantation. After the solid-liquid separation treatment, it is preferable to perform a washing treatment in terms of improving the optical purity of the diastereomeric salt. In the washing treatment, the same solvent as described above with respect to the reaction between the isomer mixture (1) and the optically active tartranyl acid compound (2) can be used. It is preferable to perform a drying process after the cleaning process. The drying treatment can be performed under normal pressure or reduced pressure, preferably in the range of 20 to 80 ° C.
The liquid resulting from the solid-liquid separation treatment contains the other diastereomeric salt, and the other diastereomeric salt can be extracted from the liquid phase by a conventional method.
By purifying the diastereomeric salt, the optical purity can be further improved.
A recrystallization method is preferable as the purification treatment. For example, a method in which a diastereomeric salt is dissolved in a solvent and cooled to precipitate a purified diastereomeric salt, a diastereomeric salt is dissolved in a solvent, and a purified diastereomer is added dropwise by adding a poor solvent. Purification can be carried out by a method of precipitating the dimer salt, a method of precipitating the diastereomeric salt by distilling off the solvent after dissolving the diastereomeric salt in a solvent, or a combination thereof. . In the purification treatment, one of the diastereomeric salts prepared in advance can be added as a seed crystal. Examples of the solvent used for the purification treatment include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, t-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1 -Hexanol, 2-hexanol, isohexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether , Ethylene glycol monobutyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono t-butyl ether, diethylene glycol mono Alcohol solvents such as chill ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monoisopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monoisobutyl ether, diethylene glycol mono t-butyl ether; cyclic solvents such as tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane Ether solvent; water is used, preferably an alcohol solvent or a cyclic ether solvent, more preferably ethanol, 2-propanol or tetrahydrofuran. The amount of the solvent to be used can be appropriately adjusted depending on the solvent to be used, but is preferably a ratio of 1 to 10 L with respect to 1 kg of the diastereomeric salt. The temperature at which the diastereomeric salt is dissolved is preferably 0 to 80 ° C. Examples of the poor solvent include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, t-butylcyclohexane, petroleum ether, and the like. Aliphatic hydrocarbon solvent: benzene, toluene, ethylbenzene, isopropylbenzene, t-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, α, α, α-trifluoromethylbenzene, 1,2-dichlorobenzene, 1, Aromatic solvents such as 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, etc., preferably aliphatic hydrocarbon soluble, more preferably heptane. The usage-amount of a poor solvent can be suitably adjusted with the precipitation degree of refinement | purification diastereomeric salt. When the purified diastereomeric salt is precipitated by cooling treatment, it is preferably cooled to 0 to 25 ° C., and the cooling temperature per hour is preferably 3 to 10 ° C.
The diastereomeric salt thus obtained is a novel compound, preferably an optically active tartlanic acid compound having an absolute configuration of (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate and (2S, 3S) A salt with (2), or a salt with ethyl (1S, 2R) -1-amino-2-ethenylcyclopropanecarboxylate and an optically active tartlanic acid compound (2) having an absolute configuration of (2R, 3R) More preferably a salt of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate and an optically active tartlanyl acid compound (2) having an absolute configuration of (2S, 3S), Preferably, a salt of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate and (2S, 3S) -2′-chlorotalthranilic acid It is.
By treating the obtained diastereomeric salt with an acid or a base, the optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by the formula (3) or an enantiomer thereof, or an acid thereof Addition salts can be obtained. Hereinafter, the optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by the formula (3) or an enantiomer thereof, or an acid addition salt thereof is abbreviated as an optically active amino compound (3). There is.
The acid for treating the diastereomeric salt is generally one having higher acidity than the optically active tartranyl acid compound (2). Examples of such acid include mineral acids such as hydrochloric acid, phosphoric acid and sulfuric acid; p-toluenesulfonic acid And organic acids such as benzenesulfonic acid and camphorsulfonic acid. The acid is preferably hydrochloric acid or sulfuric acid. These acids can be used alone or in combination with a solvent described later.
The usage-amount of an acid is 1 mol times or more normally with respect to a diastereomeric salt.
The acid treatment of the diastereomeric salt is usually performed in a solvent. Examples of such solvents include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, t-butylcyclohexane, petroleum ether and the like. Aliphatic hydrocarbon solvent: benzene, toluene, ethylbenzene, isopropylbenzene, t-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, α, α, α-trifluoromethylbenzene, 1,2-dichlorobenzene, 1, Aromatic solvents such as 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, di Such as chill ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, anisole, diphenyl ether, etc. Ether solvent; methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, t-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, 2-hexanol, iso Hexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol mono Chill ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono t-butyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl Alcohol solvents such as ether, diethylene glycol monoisopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monoisobutyl ether, diethylene glycol mono t-butyl ether; nitrile solvents such as acetonitrile, propionitrile, benzonitrile; ethyl acetate, propyl acetate, vinegar Ester solvents such as isopropyl acid, butyl acetate, isobutyl acetate, t-butyl acetate, amyl acetate, isoamyl acetate; ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopentanone, cyclohexanone; dichloromethane, chloroform, Examples thereof include chlorinated aliphatic hydrocarbon solvents such as 1,2-dichloroethane; carboxylic acid solvents such as formic acid, acetic acid and propionic acid; water; and mixtures thereof. The solvent is preferably a mixed solvent of an aromatic solvent and a ketone solvent or an alcohol solvent, more preferably a mixed solvent of an aromatic solvent and an alcohol solvent. The amount of the solvent used is preferably 1 to 50 L, more preferably 3 to 30 L with respect to 1 kg of the diastereomeric salt.
The acid treatment of the diastereomeric salt can be performed, for example, by mixing a diastereomeric salt and a solvent and adding the acid thereto. The treatment temperature is preferably 0 to 40 ° C, more preferably 0 to 30 ° C. The treatment time is not limited and is preferably 1 minute to 24 hours.
When the optically active amino compound (3) is precipitated as an acid addition salt in the mixture obtained by the acid treatment of the diastereomeric salt, the acid addition salt is separated into solid and liquid, for example, filtration or decantation. By subjecting to treatment, the acid addition salt can be taken out. When precipitation of the acid addition salt is insufficient or when the acid addition salt is not precipitated, the obtained mixture is, for example, concentrated, mixed with a solvent in which the salt is difficult to dissolve, or cooled. By subjecting to treatment, the acid addition salt is precipitated, and the acid addition salt can be taken out by subjecting the precipitated acid addition salt to a solid-liquid separation treatment such as filtration or decantation. The extracted acid addition salt can be purified, for example, by recrystallization or the like, or the optically active amino compound (3) can be extracted as a free base in the same manner as in the base treatment of a diastereomeric salt described later.
Specific examples of the acid addition salt include addition salts of hydrochloric acid, phosphoric acid, sulfuric acid, paratoluenesulfonic acid, benzenesulfonic acid and camphorsulfonic acid.
The filtrate obtained by the above-described solid-liquid separation treatment contains the optically active tartranyl acid compound (2). The optically active tartranyl acid compound (2) is taken out from the filtrate by a conventional method and reused in the present invention. be able to.
Examples of the base used to treat the diastereomeric salt include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium methylate and sodium. Examples include alkali metal alcoholates such as ethylate, potassium methylate, and potassium ethylate; and amine compounds such as triethylamine and diethylamine. The base is preferably an alkali metal hydroxide, more preferably sodium hydroxide. The base can be used alone or in combination with a solvent described later.
The usage-amount of a base is 1 mol times or more normally with respect to a diastereomeric salt.
The base treatment of the diastereomeric salt is preferably performed in a solvent. Examples of such solvents include alcohol solvents such as methanol, ethanol, 2-propanol, 1-propanol, and 1-butanol; diethyl ether, t-butyl methyl ether, methyl isobutyl ether, diisopropyl ether, methyl cyclopentyl ether, 1, 2 -Ether solvents such as dimethoxymethane; aromatic solvents such as toluene, xylene and chlorobenzene; aliphatic hydrocarbon solvents such as hexane and cyclohexane; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate and t-butyl acetate Solvents; halogenated aliphatic hydrocarbon solvents such as dichloromethane; water; and mixtures thereof. The solvent is preferably an aromatic solvent, an alcohol solvent or water, or a mixed solvent thereof, more preferably toluene or water, or a mixed solvent thereof. When an inorganic base such as an alkali metal hydroxide or alkali metal carbonate is used as the base, water alone or an organic solvent having low compatibility with water (for example, the above ether solvents, aromatic solvents, aliphatic hydrocarbons) (Solvent, ketone solvent, ester solvent, halogenated hydrocarbon solvent) and water are more preferably used as a mixture.
The amount of the solvent used is preferably 1 to 50 L, more preferably 3 to 30 L with respect to 1 kg of the diastereomeric salt.
The base treatment of a diastereomeric salt can be performed, for example, by mixing a diastereomeric salt and a solvent and adding a base thereto. The treatment temperature is preferably 0 to 60 ° C, more preferably 10 to 30 ° C. The treatment time is not limited and is preferably 1 minute to 24 hours.
Specifically, the base treatment of the diastereomeric salt can be performed, for example, by the following method.
A base is added to the mixture of water and diastereomeric salt to make the aqueous layer of the mixture basic (preferably pH 8.5 or higher), and an organic solvent having low compatibility with water is added to the resulting mixture. By subjecting it to a liquid separation treatment, an organic layer containing the optically active amino compound (3) can be obtained. If the organic layer is subjected to a washing treatment as necessary and then concentrated, the optically active amino compound (3) can be isolated as a free base. When an alkali metal alcoholate is used as the base and an alcohol solvent is used as the solvent, the alkali metal salt of the optically active tartranilic acid compound (2) can be precipitated. The precipitate is filtered off and the resulting solution is concentrated. By subjecting to treatment, the optically active amino compound (3) can be isolated as a free base. The obtained optically active amino compound (3) can be purified by subjecting it to purification treatment such as rectification and column chromatography. The optically active amino compound (3) can be taken out as an acid addition salt with any acid.
The aqueous layer obtained by the liquid separation treatment contains the optically active tartranyl acid compound (2). The optically active tartranyl acid compound (2) is taken out from the aqueous layer by a conventional method and reused in the present invention. be able to. In addition, the optically active tartlanyl acid compound (2) can be taken out from the alkali metal salt of the optically active tartranyl acid compound (2) filtered out by the conventional method and reused in the present invention.
The optical purity of the optically active amino compound (3) thus obtained is preferably 80% ee or more, more preferably 95% ee or more, although it depends on the optical purity of the optically active tartranyl acid compound (2) used. Yes, more preferably 98% ee or more, particularly preferably 99% ee or more.
　以下、実施例により本発明をさらに詳細に説明するが、本発明はこれら実施例により限定されるものではない。
参考例１
（Ｅ）−Ｎ−フェニルメチレングリシンエチルエステルの製造
　グリシンエチルエステル塩酸塩４１．４ｇ（２９７ｍｍｏｌ）とトルエン１２９ｇとを混合し、Ｎ−メチルピロリドン１９．５ｇを室温で加えた。得られた混合物にベンズアルデヒド３０．０ｇ（２８３ｍｍｏｌ）を滴下し、続いて、オルトギ酸トリメチル３１．５ｇ（２９７ｍｍｏｌ）を滴下した。滴下終了後、得られた混合物を１５℃に調整し、そこへトリエチルアミン３１．５ｇ（３１１ｍｍｏｌ）とトルエン１５．９ｇとの混合溶液を４０分かけて滴下した。滴下終了後、１５℃で４時間攪拌した。反応混合物を８℃まで冷却し、水８４ｇを滴下した。滴下終了後２０分攪拌した後、分液を行い、得られた有機層を２０％食塩水５７ｇで洗浄した。有機層を硫酸マグネシウムで乾燥した後、溶媒を減圧留去して（Ｅ）−Ｎ−フェニルメチレングリシンエチルエステルのトルエン溶液１２７ｇ（（Ｅ）−Ｎ−フェニルメチレングリシンエチルエステル純分５１．１ｇ、２６７ｍｍｏｌ）を得た。収率９５％。
参考例２
１−アミノ−２−エテニルシクロプロパンカルボン酸エチルのラセミ体の製造
　１，４−ジブロモ−２−ブテン５０．０ｇ（２３４ｍｍｏｌ）、ｔｅｒｔ−ブトシキリチウム４４．４ｇ（純度９７％，５３８ｍｍｏｌ）、臭化リチウム０．０４１ｇ（０．４７ｍｍｏｌ）の混合物にｔｅｒｔ−ブチルメチルエーテル２９４ｇを加え、攪拌を行いながら１０℃まで冷却をした。得られた混合物に、参考例１で得た（Ｅ）−Ｎ−フェニルメチレングリシンエチルエステルのトルエン溶液１２３ｇ（（Ｅ）−Ｎ−フェニルメチレングリシンエチルエステル純分４９．１ｇ，２５７ｍｍｏｌ）を４時間かけて滴下し、１０℃で１４時間反応させた。反応後、混合物に１０％塩化アンモニウム水溶液１００ｇを１０℃で滴下した。滴下終了後、２０分攪拌した後、分液を行い、得られた有機層を１０％塩化アンモニウム水溶液１００ｇで洗浄した。有機層に室温で水６７．５ｇを流入した後、３５％塩酸水溶液２４．４ｇを１時間かけて滴下し、３時間室温で攪拌した後、分液を行い、水層を分取した。一方、有機層に０．５％塩酸水溶液４２．６ｇを加え、再抽出を行った。得られた水層を合わせ、１−アミノ−２−エテニルシクロプロパンカルボン酸エチルのラセミ体を含む水溶液１９６ｇ（１−アミノ−２−エテニルシクロプロパンカルボン酸エチル純分２７．３ｇ、１９４ｍｍｏｌ）を得た。１，４−ジブロモ−２−ブテンからの収率８３％。
　得られた水溶液１９６ｇから１３１ｇ（１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの純分１８．２ｇ、１２９ｍｍｏｌ）を分取し、分取した水溶液にトルエン７３．３ｇを流入した。その混合物を攪拌しながら１５℃に冷却した後、４８％水酸化ナトリウム水溶液１３．６ｇ（水酸化ナトリウム１６４ｍｍｏｌ）を滴下した。滴下終了後、３０分攪拌し、分液を行い、有機層を分取した後に、得られた水層にトルエン７３．３ｇを流入して再抽出を行った。得られた有機層を合わせ、硫酸マグネシウムで乾燥し、１−アミノ−２−エテニルシクロプロパンカルボン酸エチルのラセミ体を含むトルエン溶液１８７ｇ（１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの純分１９．９ｇ、１２８ｍｍｏｌ）を得た。１，４−ジブロモ−２−ブテンからの収率８２％。
実施例１
（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸塩の製造
　参考例２で得られたトルエン溶液１８７ｇ（１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの純分１９．９ｇ、１２８ｍｍｏｌ）に室温で２−プロパノール８．０ｇを流入し、攪拌した。得られた混合物に（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸１７．５ｇ（６７．３ｍｍｏｌ、１−アミノ−２−エテニルシクロプロパンカルボン酸エチルに対して０．５２モル倍）を室温で添加し、光学純度９９％ｅｅ以上の（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸塩０．０１ｇを種晶として添加した後に３０分攪拌した。得られたスラリーに（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸１７．５ｇ（６７．３ｍｍｏｌ、１−アミノ−２−エテニルシクロプロパンカルボン酸エチルに対して０．５２モル倍）を室温で添加して、室温で２０時間攪拌した。得られた混合物を室温で濾過し、濾別された結晶をトルエン１０ｇと２−プロパノール０．５０ｇとの混合溶媒で洗浄した。洗浄した結晶を減圧乾燥して、（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸塩２４．２ｇ（５８．３ｍｍｏｌ）を得た。収率４６％。
　得られた（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸塩の一部を、下記の光学純度分析条件下、ジエチルアミンで処理して得た（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの光学純度を決定した。光学純度８８％ｅｅ。ジアステレオマー塩である（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸塩をジエチルアミン処理することにより、（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチルが得られる。
　得られた（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸塩２４．２ｇのうち１７．３ｇ（４１．７ｍｍｏｌ）を分取し、分取した結晶にエタノール３４．６ｇを室温で流入した後、６２℃まで加熱して結晶を溶解させた。得られた溶液を５８℃に冷却した後、光学純度９９％ｅｅ以上の（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸塩（光学純度＞９９％ｅｅ）を種晶として０．０１ｇ接種した後に２０分攪拌してスラリーとした。そのスラリーにヘプタン３４．６ｇを５７℃で２時間かけて滴下を行った。滴下完了後、１０℃／時間の冷却速度で４．５時間かけて１５℃まで冷却し、１５℃で１２時間攪拌した。得られたスラリーを１５℃で濾過し、濾別した結晶をエタノール８．６ｇとヘプタン８．６ｇとの混合溶媒で洗浄した。得られた結晶を減圧乾燥することによって、（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸塩を１４．０ｇ（３３．８ｍｍｏｌ）得た。再結晶収率８１％。１−アミノ−２−エテニルシクロプロパンカルボン酸エチルからの通算収率３７％。上記と同様の操作により、（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの光学純度を決定した。光学純度＞９９％ｅｅ。
＜光学純度分析条件＞
カラム：ＣＨＩＲＡＬＣＥＬ（登録商標）ＡＤ−ＲＨ（４．６×１５０ｍｍ，５μｍ）
移動相　：Ａ＝０．１％ジエチルアミン−水、Ｂ＝０．１％ジエチルアミン−メタノール、Ａ／Ｂ＝６０／４０
流量　　：０．７ｍｌ／分
検出器　：ＵＶ２１５ｎｍ
保持時間：（１Ｒ，２Ｓ）体＝６．７分、（１Ｓ，２Ｒ）体＝１０．８分
（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸塩
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δｐｐｍ：９．４２（１Ｈ，Ｓ），８．３６（１Ｈ，ｄｄ，Ｊ＝１．５，７．８Ｈｚ），７．５２（１Ｈ，ｄｄ，Ｊ＝１．５，８．３Ｈｚ），７．３９−７．３０（１Ｈ，ｍ），７．１６−７．０８（１Ｈ，ｍ），５．６４−５．５３（１Ｈ，ｍ），５．２２（１Ｈ，ｄｄ，Ｊ＝２．０，１７．１Ｈｚ），５．０２（１Ｈ，ｄｄ，Ｊ＝２．０，１０．３Ｈｚ），４．４６（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），４．３６（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），４．１３−４．０４（２Ｈ，ｍ），２．０３−１．９５（１Ｈ，ｍ），１．４３（１Ｈ，ｄｄ，Ｊ＝４．９，７．３Ｈｚ），１．３２（１Ｈ，ｄｄ，Ｊ＝４．９，９．３Ｈｚ），１．２０（３Ｈ，ｔ，Ｊ＝６．８Ｈｚ）
１３Ｃ−ＮＭＲ（ＤＭＳＯ−ｄ６，１００ＭＨｚ）δｐｐｍ：１７３．４，１７２．０，１７０．６，１３４．９，１３４．１，１２９．２，１２７．８，１２４．８，１２２．２，１２０．６，１１６．４，７３．５，７１．８，６０．６，４２．０，３４．０，２１．８，１４．２
融点：１２３．１℃
（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・ヘミ硫酸塩の製造
　再結晶により得られた（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸塩１２．７ｇ（３０．７ｍｍｏｌ）とトルエン３１．８ｇとを混合し、その混合物を１４℃に冷却した後、水酸化ナトリウム１．２９ｇを水５０．９ｇに溶解させた水溶液を滴下した。滴下終了後、得られた混合物に水６．４ｇを追加し、１３℃で３０分攪拌した後、分液を行い、有機層を分取した。得られた水層にトルエン２５．５ｇを流入し、再抽出を行った。得られた有機層を合わせ、その有機層を１０％炭酸ナトリウム水溶液１２．７ｇで洗浄し、洗浄した有機層を硫酸マグネシウムで乾燥した。有機層を１１℃に冷却して撹拌し、硫酸１．４５ｇ（１４．２ｍｍｏｌ）とシクロペンチルメチルエーテル１２．７ｇとの混合液をその有機層に３．５時間かけて滴下した。混合物を１１時間１０℃で攪拌した後、得られたスラリーを３℃まで冷却してさらに３．５時間撹拌した。スラリーを３℃で濾過し、濾別した結晶をトルエン６．４ｇとシクロペンチルメチルエーテル１．３ｇとの混合溶媒で洗浄した。得られた結晶を減圧乾燥することによって、（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチル・ヘミ硫酸塩を得た。収率９２％。上記と同様の操作により、（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの光学純度を決定した。光学純度＞９９％。
１Ｈ−ＮＭＲ（ＣＤ３ＯＤ，４００ＭＨｚ）δｐｐｍ：５．８８−５．７５（１Ｈ，ｍ），５．３８（１Ｈ，ｄｄ，Ｊ＝１．５，１７．１Ｈｚ），５．１７（１Ｈ，ｄｄ，Ｊ＝１．５，１０．３Ｈｚ），４．３２−４．２２（２Ｈ，ｑ，Ｊ＝６．８Ｈｚ），２．５６−２．４７（１Ｈ，ｍ），１．８６（１Ｈ，ｄｄ，Ｊ＝６．４，１０．２Ｈｚ），１．７０（１Ｈ，ｄｄ，Ｊ＝６．４，８．３Ｈｚ），１．３０（３Ｈ，ｔ，Ｊ＝６．８Ｈｚ）
１３Ｃ−ＮＭＲ（ＣＤ３ＯＤ，１００ＭＨｚ）δｐｐｍ：１６９．０，１３３．３，１１９．６，６３．５，４１．２，３１．６，２０．０，１４．５ EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these Examples.
Reference example 1
(E) Production of -N-phenylmethyleneglycine ethyl ester 41.4 g (297 mmol) of glycine ethyl ester hydrochloride and 129 g of toluene were mixed, and 19.5 g of N-methylpyrrolidone was added at room temperature. To the resulting mixture, 30.0 g (283 mmol) of benzaldehyde was added dropwise, followed by 31.5 g (297 mmol) of trimethyl orthoformate. After completion of the dropwise addition, the obtained mixture was adjusted to 15 ° C., and a mixed solution of 31.5 g (311 mmol) of triethylamine and 15.9 g of toluene was dropped therein over 40 minutes. After completion of dropping, the mixture was stirred at 15 ° C. for 4 hours. The reaction mixture was cooled to 8 ° C. and 84 g of water was added dropwise. After completion of dropping, the mixture was stirred for 20 minutes, followed by liquid separation, and the obtained organic layer was washed with 57 g of 20% brine. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure, and 127 g of a toluene solution of (E) -N-phenylmethyleneglycine ethyl ester (51.1 g of pure (E) -N-phenylmethyleneglycine ethyl ester, 267 mmol). Yield 95%.
Reference example 2
Preparation of racemic ethyl 1-amino-2-ethenylcyclopropanecarboxylate 1,4-dibromo-2-butene 50.0 g (234 mmol), tert-butoxy lithium 44.4 g (purity 97%, 538 mmol), To a mixture of 0.041 g (0.47 mmol) of lithium bromide, 294 g of tert-butyl methyl ether was added, and the mixture was cooled to 10 ° C. while stirring. To the obtained mixture, 123 g of toluene solution of (E) -N-phenylmethyleneglycine ethyl ester obtained in Reference Example 1 (49.1 g of pure (E) -N-phenylmethyleneglycine ethyl ester, 257 mmol) was added for 4 hours. The solution was added dropwise and reacted at 10 ° C. for 14 hours. After the reaction, 100 g of 10% aqueous ammonium chloride solution was added dropwise to the mixture at 10 ° C. After completion of the dropwise addition, the mixture was stirred for 20 minutes and then separated, and the obtained organic layer was washed with 100 g of a 10% aqueous ammonium chloride solution. After 67.5 g of water flowed into the organic layer at room temperature, 24.4 g of 35% aqueous hydrochloric acid solution was added dropwise over 1 hour and stirred for 3 hours at room temperature, followed by liquid separation to separate the aqueous layer. On the other hand, 42.6 g of 0.5% hydrochloric acid aqueous solution was added to the organic layer and re-extraction was performed. The obtained aqueous layers were combined and 196 g of an aqueous solution containing a racemate of ethyl 1-amino-2-ethenylcyclopropanecarboxylate (ethyl 1-amino-2-ethenylcyclopropanecarboxylate 27.3 g, 194 mmol) Got. 83% yield from 1,4-dibromo-2-butene.
131 g (pure 18.2 g, 129 mmol of ethyl 1-amino-2-ethenylcyclopropanecarboxylate) was collected from 196 g of the obtained aqueous solution, and 73.3 g of toluene was poured into the collected aqueous solution. The mixture was cooled to 15 ° C. with stirring, and 13.6 g of a 48% aqueous sodium hydroxide solution (164 mmol of sodium hydroxide) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 30 minutes, separated, and the organic layer was separated. Then, 73.3 g of toluene was poured into the obtained aqueous layer to perform re-extraction. The obtained organic layers were combined, dried over magnesium sulfate, and 187 g of a toluene solution containing a racemate of ethyl 1-amino-2-ethenylcyclopropanecarboxylate (in ethyl 1-amino-2-ethenylcyclopropanecarboxylate). Pure 19.9 g, 128 mmol) was obtained. 82% yield from 1,4-dibromo-2-butene.
Example 1
Preparation of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate / (2S, 3S) -2′-chlorotaltranylate 187 g of toluene solution obtained in Reference Example 2 (1- Into pure amino (19.9 g, 128 mmol) of ethyl amino-2-ethenylcyclopropanecarboxylate, 8.0 g of 2-propanol was poured at room temperature and stirred. To the resulting mixture, 17.5 g (67.3 mmol, 0.52 mol times with respect to ethyl 1-amino-2-ethenylcyclopropanecarboxylate) (2S, 3S) -2′-chlorotaltranyl acid was added. 0.01 g of (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate / (2S, 3S) -2′-chlorotaltranylate having an optical purity of 99% ee or higher added at room temperature Was added as a seed crystal and stirred for 30 minutes. 17.5 g (67.3 mmol, 0.52 mol times with respect to ethyl 1-amino-2-ethenylcyclopropanecarboxylate) (2S, 3S) -2′-chlorotalthranilic acid was added to the resulting slurry. It added at room temperature and stirred at room temperature for 20 hours. The obtained mixture was filtered at room temperature, and the separated crystals were washed with a mixed solvent of 10 g of toluene and 0.50 g of 2-propanol. The washed crystals were dried under reduced pressure to give ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate / (2S, 3S) -2′-chlorotaltranylate 24.2 g (58. 3 mmol) was obtained. Yield 46%.
A part of the obtained ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate / (2S, 3S) -2′-chlorotaltranylate was subjected to the following optical purity analysis conditions. The optical purity of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate obtained by treatment with diethylamine was determined. Optical purity 88% ee. Diastereomer salt ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate · (2S, 3S) -2′-chlorotaltranylate is treated with diethylamine to give (1R , 2S) -1-amino-2-ethenylcyclopropanecarboxylate ethyl ester.
Of the obtained ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate / (2S, 3S) -2′-chlorotaltranylate (24.2 g), 17.3 g (41.7 mmol) ), And 34.6 g of ethanol was poured into the collected crystals at room temperature, and then heated to 62 ° C. to dissolve the crystals. After cooling the obtained solution to 58 ° C., ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate / (2S, 3S) -2′-chlorotart having an optical purity of 99% ee or higher After inoculating 0.01 g of lanylate (optical purity> 99% ee) as a seed crystal, the mixture was stirred for 20 minutes to form a slurry. To the slurry, 34.6 g of heptane was added dropwise at 57 ° C. over 2 hours. After completion of dropping, the mixture was cooled to 15 ° C. over 4.5 hours at a cooling rate of 10 ° C./hour, and stirred at 15 ° C. for 12 hours. The obtained slurry was filtered at 15 ° C., and the separated crystals were washed with a mixed solvent of 8.6 g of ethanol and 8.6 g of heptane. The obtained crystals were dried under reduced pressure to obtain 14.0 g of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate / (2S, 3S) -2′-chlorotaltranylate. (33.8 mmol) was obtained. Recrystallization yield 81%. 37% overall yield from ethyl 1-amino-2-ethenylcyclopropanecarboxylate. The optical purity of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate was determined by the same operation as above. Optical purity> 99% ee.
<Optical purity analysis conditions>
Column: CHIRALCEL (registered trademark) AD-RH (4.6 × 150 mm, 5 μm)
Mobile phase: A = 0.1% diethylamine-water, B = 0.1% diethylamine-methanol, A / B = 60/40
Flow rate: 0.7 ml / min Detector: UV 215 nm
Retention time: (1R, 2S) isomer = 6.7 minutes, (1S, 2R) isomer = 10.8 minutes (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate / (2S, 3S ) -2'-chlorotaltranylate
1 H-NMR (DMSO-d 6 , 400 MHz) δ ppm: 9.42 (1H, S), 8.36 (1H, dd, J = 1.5, 7.8 Hz), 7.52 (1H, dd, J = 1.5, 8.3 Hz), 7.39-7.30 (1H, m), 7.16-7.08 (1H, m), 5.64-5.53 (1H, m), 5.22 (1H, dd, J = 2.0, 17.1 Hz), 5.02 (1H, dd, J = 2.0, 10.3 Hz), 4.46 (1H, d, J = 2. 0 Hz), 4.36 (1H, d, J = 2.0 Hz), 4.13-4.04 (2H, m), 2.03-1.95 (1H, m), 1.43 (1H, dd, J = 4.9, 7.3 Hz), 1.32 (1H, dd, J = 4.9, 9.3 Hz), 1.20 (3H, t, J = 6.8 Hz)
13 C-NMR (DMSO-d 6 , 100 MHz) δ ppm: 173.4, 172.0, 170.6, 134.9, 134.1, 129.2, 127.8, 124.8, 122.2, 120.6, 116.4, 73.5, 71.8, 60.6, 42.0, 34.0, 21.8, 14.2
Melting point: 123.1 ° C
Production of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate / hemisulfate ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate obtained by recrystallization -12.7 g (30.7 mmol) of (2S, 3S) -2'-chlorotaltranylate and 31.8 g of toluene were mixed, and the mixture was cooled to 14 ° C, and then 1.29 g of sodium hydroxide. An aqueous solution in which 50.9 g of water was dissolved was added dropwise. After completion of the dropwise addition, 6.4 g of water was added to the obtained mixture, and the mixture was stirred at 13 ° C. for 30 minutes, followed by liquid separation to separate the organic layer. To the obtained aqueous layer, 25.5 g of toluene was introduced to perform re-extraction. The obtained organic layers were combined, the organic layer was washed with 12.7 g of a 10% aqueous sodium carbonate solution, and the washed organic layer was dried over magnesium sulfate. The organic layer was cooled to 11 ° C. and stirred, and a mixture of 1.45 g (14.2 mmol) of sulfuric acid and 12.7 g of cyclopentylmethyl ether was added dropwise to the organic layer over 3.5 hours. After the mixture was stirred for 11 hours at 10 ° C., the resulting slurry was cooled to 3 ° C. and stirred for an additional 3.5 hours. The slurry was filtered at 3 ° C., and the separated crystals were washed with a mixed solvent of 6.4 g of toluene and 1.3 g of cyclopentyl methyl ether. The obtained crystals were dried under reduced pressure to obtain ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate / hemisulfate. Yield 92%. The optical purity of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate was determined by the same operation as above. Optical purity> 99%.
1 H-NMR (CD 3 OD, 400 MHz) δ ppm: 5.88-5.75 (1H, m), 5.38 (1H, dd, J = 1.5, 17.1 Hz), 5.17 (1H , Dd, J = 1.5, 10.3 Hz), 4.32-4.22 (2H, q, J = 6.8 Hz), 2.56-2.47 (1H, m), 1.86 ( 1H, dd, J = 6.4, 10.2 Hz), 1.70 (1H, dd, J = 6.4, 8.3 Hz), 1.30 (3H, t, J = 6.8 Hz)
13 C-NMR (CD 3 OD, 100 MHz) δ ppm: 169.0, 133.3, 119.6, 63.5, 41.2, 31.6, 20.0, 14.5
　本発明によれば、抗ウイルス薬の合成中間体等として有用な光学活性１−アミノ−２−エテニルシクロプロパンカルボン酸エチルを高い光学純度で効率的に製造できる。 According to the present invention, optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate useful as a synthetic intermediate for antiviral drugs and the like can be efficiently produced with high optical purity.

Claims (6)

  1. 　式（１）
    Figure JPOXMLDOC01-appb-I000001
    で示される１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの（１Ｒ，２Ｓ）異性体と（１Ｓ，２Ｒ）異性体とを含む混合物と、式（２）
    Figure JPOXMLDOC01-appb-I000002
    （式中、Ａｒは置換されていてもよいフェニル基を表し、該置換基は、１~３個のそれぞれ独立した、炭素数１~１２のアルキル基、炭素数３~１２のシクロアルキル基、炭素数１~１２のアルコキシル基、炭素数３~１２のシクロアルキルオキシ基、ハロゲン原子、ニトロ基、シアノ基又はトリフルオロメチル基である。＊は不斉炭素を表す。）
    で示される光学活性なタルトラニル酸化合物とを反応させ、ジアステレオマー塩の混合物を生成する工程と、一方のジアステレオマー塩を他方のジアステレオマー塩から分離する工程と、分離したジアステレオマー塩を酸又は塩基で処理することによりジアステレオマー塩を分解する工程とを含む式（３）
    Figure JPOXMLDOC01-appb-I000003
    で示される光学活性な１−アミノ−２−エテニルシクロプロパンカルボン酸エチル若しくはその鏡像異性体、又はそれらの酸付加塩の製造方法。     Formula (1)
    Figure JPOXMLDOC01-appb-I000001
    A mixture containing (1R, 2S) isomer and (1S, 2R) isomer of ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by formula (2)
    Figure JPOXMLDOC01-appb-I000002
    (In the formula, Ar represents a phenyl group which may be substituted, and the substituents each have 1 to 3 independent alkyl groups having 1 to 12 carbon atoms, cycloalkyl groups having 3 to 12 carbon atoms, An alkoxyl group having 1 to 12 carbon atoms, a cycloalkyloxy group having 3 to 12 carbon atoms, a halogen atom, a nitro group, a cyano group, or a trifluoromethyl group (* represents an asymmetric carbon).
    A diastereomer salt mixture, a diastereomer salt mixture, a diastereomer salt mixture, a diastereomer salt mixture, a diastereomer salt mixture; Decomposing the diastereomeric salt by treating the salt with an acid or base, and formula (3)
    Figure JPOXMLDOC01-appb-I000003
    A process for producing an optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate or an enantiomer thereof, or an acid addition salt thereof.
  2. 　Ａｒが２−クロロフェニル基である、請求項１に記載される製造方法。 The production method according to claim 1, wherein Ar is a 2-chlorophenyl group.
  3. 　光学活性なタルトラニル酸化合物における２つの不斉炭素がともにＳ配置である、請求項１又は２に記載される製造方法。 The production method according to claim 1 or 2, wherein both of the two asymmetric carbons in the optically active tartranilic acid compound are in S configuration.
  4. 　式（１）
    Figure JPOXMLDOC01-appb-I000004
    で示される１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの（１Ｒ，２Ｓ）異性体と（１Ｓ，２Ｒ）異性体とを含む混合物と、式（２）
    Figure JPOXMLDOC01-appb-I000005
    （式中、Ａｒは置換されていてもよいフェニル基を表し、該置換基は、１~３個のそれぞれ独立した、炭素数１~１２のアルキル基、炭素数３~１２のシクロアルキル基、炭素数１~１２のアルコキシル基、炭素数３~１２のシクロアルキルオキシ基、ハロゲン原子、ニトロ基、シアノ基又はトリフルオロメチル基である。＊は不斉炭素を表す。）
    で示される光学活性なタルトラニル酸化合物とを反応させる工程を含む１−アミノ−２−エテニルシクロプロパンカルボン酸エチルの光学分割方法。     Formula (1)
    Figure JPOXMLDOC01-appb-I000004
    A mixture containing (1R, 2S) isomer and (1S, 2R) isomer of ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by formula (2)
    Figure JPOXMLDOC01-appb-I000005
    (In the formula, Ar represents a phenyl group which may be substituted, and the substituents each have 1 to 3 independent alkyl groups having 1 to 12 carbon atoms, cycloalkyl groups having 3 to 12 carbon atoms, An alkoxyl group having 1 to 12 carbon atoms, a cycloalkyloxy group having 3 to 12 carbon atoms, a halogen atom, a nitro group, a cyano group, or a trifluoromethyl group (* represents an asymmetric carbon).
    A method for optical resolution of ethyl 1-amino-2-ethenylcyclopropanecarboxylate, which comprises a step of reacting with an optically active tartranyl acid compound represented by the formula:
  5. 　（１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパンカルボン酸エチルと式（２）
    Figure JPOXMLDOC01-appb-I000006
    （式中、Ａｒは置換されていてもよいフェニル基を表し、該置換基は、１~３個のそれぞれ独立した、炭素数１~１２のアルキル基、炭素数３~１２のシクロアルキル基、炭素数１~１２のアルコキシル基、炭素数３~１２のシクロアルキルオキシ基、ハロゲン原子、ニトロ基、シアノ基又はトリフルオロメチル基である。＊は不斉炭素を表す。）
    で示される光学活性なタルトラニル酸化合物との塩。     Ethyl (1R, 2S) -1-amino-2-ethenylcyclopropanecarboxylate and the formula (2)
    Figure JPOXMLDOC01-appb-I000006
    (In the formula, Ar represents a phenyl group which may be substituted, and the substituents each have 1 to 3 independent alkyl groups having 1 to 12 carbon atoms, cycloalkyl groups having 3 to 12 carbon atoms, An alkoxyl group having 1 to 12 carbon atoms, a cycloalkyloxy group having 3 to 12 carbon atoms, a halogen atom, a nitro group, a cyano group, or a trifluoromethyl group (* represents an asymmetric carbon).
    A salt with an optically active tartranyl acid compound represented by the formula:
  6. （１Ｒ，２Ｓ）−１−アミノ−２−エテニルシクロプロパン−１−カルボン酸エチルと（２Ｓ，３Ｓ）−２’−クロロタルトラニル酸との塩。 A salt of ethyl (1R, 2S) -1-amino-2-ethenylcyclopropane-1-carboxylate and (2S, 3S) -2'-chlorotalthranilic acid.
PCT/JP2010/063950 2009-08-25 2010-08-12 Process for preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate WO2011024691A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2010800371923A CN102482200A (en) 2009-08-25 2010-08-12 Process for preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009193914A JP5476859B2 (en) 2009-08-25 2009-08-25 Process for producing optically active ethyl 1-amino-2-ethenylcyclopropane-1-carboxylate or acid addition salt thereof, and intermediate used in the process
JP2009-193914 2009-08-25

Publications (1)

Publication Number Publication Date
WO2011024691A1 true WO2011024691A1 (en) 2011-03-03

Family

ID=43627797

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/063950 WO2011024691A1 (en) 2009-08-25 2010-08-12 Process for preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate

Country Status (3)

Country Link
JP (1) JP5476859B2 (en)
CN (1) CN102482200A (en)
WO (1) WO2011024691A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2684864A1 (en) * 2011-03-10 2014-01-15 Sumitomo Chemical Company Limited Method of producing optically active 1-amino-2-vinylcyclopropane carboxylic acid ester

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10218847A (en) * 1997-02-14 1998-08-18 Daito Kagaku Kk Production of tartranilic acid
JP2001089431A (en) * 1999-09-16 2001-04-03 Sumika Fine Chemicals Co Ltd Method of producing tertranilic acid
JP2001097933A (en) * 1999-09-28 2001-04-10 Toray Ind Inc Method for producing optically active 2- aminocyclohexanol derivative
JP2001131148A (en) * 1999-11-09 2001-05-15 Sumika Fine Chemicals Co Ltd Method for depositing diastereomer crystal
JP2002522557A (en) * 1998-08-10 2002-07-23 ベーリンガー インゲルハイム （カナダ） リミテッド Hepatitis C inhibitor peptide
JP2004051604A (en) * 2002-07-24 2004-02-19 Sumitomo Chem Co Ltd Production method of optically active 2-amino-2-(2-naphthyl)ethanols and intermediate thereof
JP2006282607A (en) * 2005-04-01 2006-10-19 Sumitomo Chemical Co Ltd Purification method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate
JP2006282605A (en) * 2005-04-01 2006-10-19 Sumitomo Chemical Co Ltd Preparation method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate and method for recovering optical resoluting agent
JP2006282606A (en) * 2005-04-01 2006-10-19 Sumitomo Chemical Co Ltd Method of crystallizing (3s,4r)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine(+)-2'-chlorotartranyl acid monohydrate

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10218847A (en) * 1997-02-14 1998-08-18 Daito Kagaku Kk Production of tartranilic acid
JP2002522557A (en) * 1998-08-10 2002-07-23 ベーリンガー インゲルハイム （カナダ） リミテッド Hepatitis C inhibitor peptide
JP2001089431A (en) * 1999-09-16 2001-04-03 Sumika Fine Chemicals Co Ltd Method of producing tertranilic acid
JP2001097933A (en) * 1999-09-28 2001-04-10 Toray Ind Inc Method for producing optically active 2- aminocyclohexanol derivative
JP2001131148A (en) * 1999-11-09 2001-05-15 Sumika Fine Chemicals Co Ltd Method for depositing diastereomer crystal
JP2004051604A (en) * 2002-07-24 2004-02-19 Sumitomo Chem Co Ltd Production method of optically active 2-amino-2-(2-naphthyl)ethanols and intermediate thereof
JP2006282607A (en) * 2005-04-01 2006-10-19 Sumitomo Chemical Co Ltd Purification method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate
JP2006282605A (en) * 2005-04-01 2006-10-19 Sumitomo Chemical Co Ltd Preparation method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate and method for recovering optical resoluting agent
JP2006282606A (en) * 2005-04-01 2006-10-19 Sumitomo Chemical Co Ltd Method of crystallizing (3s,4r)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine(+)-2'-chlorotartranyl acid monohydrate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PIERRE L. B. ET AL.: "Synthesis of (1R, 2S)-1-Amino-2-vinylcyclopropanecarboxylic Acid Vinyl-ACCA) Derivatives: Key Intermediates for the Preparation of Inhibitors of the Hepatitis C Virus NS3 Protease", J. ORG. CHEM., vol. 70, no. 15, 2005, pages 5869 - 5879, XP002686607, DOI: doi:10.1021/JO050468Q *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2684864A1 (en) * 2011-03-10 2014-01-15 Sumitomo Chemical Company Limited Method of producing optically active 1-amino-2-vinylcyclopropane carboxylic acid ester
EP2684864A4 (en) * 2011-03-10 2014-08-20 Sumitomo Chemical Co Method of producing optically active 1-amino-2-vinylcyclopropane carboxylic acid ester

Also Published As

Publication number Publication date
CN102482200A (en) 2012-05-30
JP2011046613A (en) 2011-03-10
JP5476859B2 (en) 2014-04-23

Similar Documents

Publication Publication Date Title
JP5387040B2 (en) Method for optical resolution of alkylpiperidin-3-ylcarbamate and intermediates thereof
JP4433156B2 (en) Process for producing optically active oxoheptenoic acid ester
US8742162B2 (en) Method for producing optically active 1-amino-2-vinylcyclopropanecarboxylic acid ester
JP2003522122A (en) Production of substituted piperidin-4-ones
US20160251311A1 (en) Process for the preparation of enantiomerically enriched 3-aminopiperidine
US20090326244A1 (en) Bisulfite purification of an alpha-keto amide
JP5476859B2 (en) Process for producing optically active ethyl 1-amino-2-ethenylcyclopropane-1-carboxylate or acid addition salt thereof, and intermediate used in the process
JP2003335756A (en) Method for producing aromatic aldehyde and chiral diol
JP2009256298A (en) Optical resolution method for piperidin-3-ylcarbamate compound, and its intermediate
JP4887720B2 (en) Process for producing optically active fluorinated benzyl alcohol
US9259723B2 (en) Quaternary ammonium salt
WO2012121068A1 (en) Method of producing optically active 1-amino-2-vinylcyclopropane carboxylic acid ester
WO2011004778A1 (en) Method for producing optically active compound
JP4126921B2 (en) Process for producing optically active β-phenylalanine derivative
KR101088488B1 (en) Method for preparing an optically active amlodipine
JP4109446B2 (en) Process for producing pure trans-2-[(α-methylbenzyl) amino] cyclopentanol as a diastereoisomer
JP2005097158A (en) Method for producing fluorine-containing organic compound
JP4193437B2 (en) Optically active carboxylic acids
JPH07258215A (en) Production of optically active 1-(4-chloropyridin-2-yl)-2-(pyridin-2-yl)ethylamine
JP5176452B2 (en) Process for producing optically active tetrahydropyranylglycine compound
JP2007023040A (en) Stereoselective synthesis of 3,4-disubstituted cyclopentanone and related compound
WO2010090341A1 (en) Method of manufacturing optically active trans-4-aminopiperidine-3-ol compound
JP2003238513A (en) Method for producing optically active 2- aminopentanenitrile salt
JP2004059492A (en) Method for producing optically active alpha-(2-aminophenyl)benzylamine
JP2002088057A (en) Method for producing optically active 3- hydroxypyrrolidine compounds

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080037192.3

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10811741

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2626/CHENP/2012

Country of ref document: IN

122 Ep: pct application non-entry in european phase

Ref document number: 10811741

Country of ref document: EP

Kind code of ref document: A1