WO2015194508A1 - Method for producing optically active substance - Google Patents

Method for producing optically active substance Download PDF

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Publication number
WO2015194508A1
WO2015194508A1 PCT/JP2015/067195 JP2015067195W WO2015194508A1 WO 2015194508 A1 WO2015194508 A1 WO 2015194508A1 JP 2015067195 W JP2015067195 W JP 2015067195W WO 2015194508 A1 WO2015194508 A1 WO 2015194508A1
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Prior art keywords
group
optionally substituted
substituent
formula
nmr
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PCT/JP2015/067195
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French (fr)
Japanese (ja)
Inventor
祐希 竹内
健裕 浅野
浩一 和田
和也 津崎
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第一ファインケミカル株式会社
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Priority to JP2016529335A priority Critical patent/JP6630667B2/en
Publication of WO2015194508A1 publication Critical patent/WO2015194508A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a method for producing an optically active substance.
  • the compound represented by the formula (Z) (hereinafter, also referred to as “compound (Z)”) is a compound in which an oxygen atom or a nitrogen atom is bonded to two consecutive carbon atoms, and at least in one molecule. Since it has two asymmetric carbons, there are multiple optical isomers.
  • the optically active compound (Z) is one of chemical structures widely used in the field of pharmaceutical or agricultural chemical development, and can also be used as a ligand for a transition metal catalyst used in an asymmetric reaction.
  • X represents —O— or —NR f —
  • Y represents —O—, —NR g — or —S—
  • R a , R b , R c , R d , R e , R f and R g each independently represent a hydrogen atom or an organic group, and an asterisk indicates that the carbon atom is an asymmetric carbon.
  • the compound (Z) includes, for example, 1,2-diol (when X and Y are both —O—), 1,2-aminoalcohol (where X is —O— and Y is —NH—). Or X is —NH— and Y is —O—), 1,2-diamine (when both X and Y are —NH—), 1,2-mercaptoalcohol (where X is -O- and Y is -S-), 1,2-mercaptoamine (when X is -NH- and Y is -S-).
  • optically active compounds Z
  • a method of obtaining an optically active compound (Z) by reacting a compound having an epoxide structure or an aziridine structure, which is readily available, with a nucleophile, and performing stereoselective ring opening has high atomic efficiency and is useful. is there.
  • an optically active compound (Z) by reacting a compound having an epoxide structure with a nucleophile
  • A a method of optically resolving a racemate (for example, Patent Documents 1 to 3, Non-patent Documents 1, 2)
  • B a method of introducing an asymmetric carbon at another position and separating the resulting diastereomers (for example, Patent Document 4, Non-Patent Document 3)
  • C Optically active catalyst
  • a method using an optically active acid as a resolving agent a method using a column chromatography using an optically active filler, and an enzyme derived from an animal or a microorganism are used. Methods are known.
  • Japanese Patent No. 4406483 Japanese Patent No. 4406482 US Pat. No. 5,981,267 JP-A-9-157258 JP 2003-206266 A JP 2011-83934 A
  • the target optically active compound (Z) can be produced in a short process, but in many cases, a metal catalyst or a strong acid catalyst is used as the optically active catalyst. Use. Therefore, in the methods (C) and (E), usable compounds or nucleophiles having a hetero-containing three-membered ring structure are limited, and an expensive metal catalyst recovery step is required.
  • an object of the present invention is to react a compound having an epoxide or aziridine with a nucleophile by a simple operation using an inexpensive and easily available catalyst, and convert the compound represented by the formula (3) into a steric form. It is to provide a method for selective and efficient production.
  • An optionally substituted C 6-10 aryl group, and the substituent is a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a C 1-4 alkoxy group, an amino group, an imino group.
  • a nitro group, a hydroxy group, an oxo group, a nitrile group, a mercapto group or a halogen atom, and R 2 and R 3 may be bonded to each other to form a compound represented by the formula (1b)) (Wherein X, R 1 and R 4 are the same as defined above, and R 7 represents a group formed by combining R 2 and R 3 with each other)
  • an optionally substituted C 3-6 cycloalkyl group an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-6 cycloalkenyl group, a substituted group A C 2-6 alkynyl group which may have a substituent or a C 6-10 aryl group which may have a substituent, wherein the substituent is a C 1-4 alkoxy group, a C 6-10 aryl group, amino A group, an imino group, a nitro group, a hydroxy group, an oxo group, a nitrile group, a mercapto group, or a halogen atom, and R 5 and R 6 are bonded to each other to form a compound represented by the formula (2a).
  • the compound represented by the formula (2) is water or sulfurized. Not in the original) (Wherein R 8 represents a group formed by combining R 5 and R 6 with each other) And a compound represented by the following: Formula (3): (Wherein X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above) The manufacturing method of the compound represented by Formula (3) including the process of obtaining the compound represented by these. [2] The production method according to claim 1, wherein the compound represented by the formula (1) is a compound represented by the formula (1c). (Wherein X and R 7 are the same as defined above) [3] The production method according to [1], wherein the compound represented by the formula (1) is a compound represented by the formula (1a).
  • X is —O— or —NR—
  • R is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, or a C 3-6 which may have a substituent.
  • An optionally substituted C 1-6 alkylsulfonyl group or a C 6-10 arylsulfonyl group, and R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted C 1-6 alkyl having group, an optionally substituted C 3-6 cycloalkyl group, a substituent Good C 2-6 alkenyl group
  • [5] The production method according to any one of [1] to [3], wherein Y is —O—.
  • [6] The production method according to any one of [1] to [3], wherein Y is —S—.
  • the processed plant product is a legume, cucurbitaceae, eggplant, urushiaceae, ginger, citrus, antaceae, sage, cruciferous, lotus, matabidae, rose, lily, gramineous
  • a compound represented by the formula (3) is obtained by reacting a compound having an epoxide structure or an aziridine structure with various nucleophiles by a simple operation using an inexpensive and easily available catalyst. Can be produced stereoselectively and efficiently.
  • the catalyst used in the present invention is an easily obtained plant processed product, and does not necessarily require recovery of the catalyst. Furthermore, the catalyst can be recovered and reused after completion of the reaction.
  • a compound represented by the formula (1) (hereinafter, also referred to as “compound (1)” or the like) and a compound (2) are reacted in the presence of a processed plant product to obtain a compound (3 ).
  • X is —O— or —NR—. That is, the compound (1) means a compound having an epoxide structure or a compound having an aziridine structure.
  • R is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 2-6 alkenyl.
  • a C 3-6 cycloalkenyl group which may have a substituent a C 2-6 alkynyl group which may have a substituent, a C 6-10 aryl group which may have a substituent, a substituent
  • R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkenyl A group, a C 2-6 alkynyl group or a C 6-10 aryl group.
  • the C 1-6 alkyl group means an alkyl group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkyl group include a methyl group, an ethyl group, a propan-1-yl group, a propan-2-yl group (isopropyl group), a butan-1-yl group, a butan-2-yl group, and pentane.
  • Examples include a 1-yl group, a pentan-2-yl group, a pentan-3-yl group, a hexane-1-yl group, a hexane-2-yl group, and a 3-hexyl group.
  • the C 3-6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms.
  • Examples of the C 3-6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • the C 2-6 alkenyl group means an alkenyl group having 2 to 6 carbon atoms.
  • Examples of the C 2-6 alkenyl group include a vinyl group, 1-propen-1-yl group, 2-propen-1-yl group, propen-2-yl group, 2-buten-1-yl group, 2- Buten-2-yl group, 3-buten-1-yl group, 2-penten-1-yl group, 3-penten-1-yl group, 2-hexen-1-yl group, 3-hexen-1-yl Groups, 4-hexen-1-yl group and 5-hexen-1-yl group.
  • the C 3-6 cycloalkenyl group means a cycloalkenyl group having 3 to 6 carbon atoms.
  • Examples of the C 3-6 cycloalkenyl group include a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.
  • the C 2-6 alkynyl group means an alkynyl group having 2 to 6 carbon atoms.
  • Examples of the C 2-6 alkynyl group include an ethynyl group, a propargyl group, and a 3-butyn-1-yl group.
  • the C 6-10 aryl group means an aryl group having 6 to 10 carbon atoms.
  • Examples of the C 6-10 aryl group include a phenyl group and a naphthyl group.
  • the C 1-6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkenyl group, C 3-6 cycloalkenyl group, C 2-6 alkynyl group and C 6-10 aryl group are each unsubstituted. Alternatively, it may have a substituent.
  • Substituents include C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, amino group, imino group, nitro group, hydroxy group, oxo group, nitrile group , A mercapto group or a halogen atom.
  • Examples of the C 1-4 alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, and a butoxy group.
  • Examples of the compound (1) include Cis-2,3-epoxybutane.
  • a compound having a thiirane structure in which X is —S— may be used.
  • 1,2-mercaptoamine, 1,2-mercaptoalcohol, and 1,2-dithiol can be obtained.
  • the compound (1) may be the compound (1b).
  • X, R 1 and R 4 are the same as defined above, and R 7 represents a group formed by combining R 2 and R 3 with each other.
  • X represents —O— or —NR—
  • R 7 represents a group formed by combining R 2 and R 3 with each other.
  • the groups R 2 and R 3 are bonded to each other to form, when R 2 or R 3 has a substituent, may be coupled to be connected via the substituent. That is, R 7 is not only a C 1-6 alkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group and a C 6-10 arylene group, but R 2 and R 3 are bonded via a substituent.
  • the aspect formed as above is also included.
  • a C 1-6 alkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group and a C 6-10 arylene group are respectively a C 1-6 alkyl group defined by the formula (1), a C 2-6 A group obtained by further removing one hydrogen atom from an alkenyl group, a C 2-6 alkynyl group and a C 6-10 aryl group.
  • R 2 and R 3 are bonded via a substituent includes, for example, a 2-oxapropylene group (—CH 2 OCH 2 —), a 3-oxapentylene group (—CH 2 CH 2 OCH 2 CH 2 —) and 3-oxopentylene group (—CH 2 CH 2 C ( ⁇ O) CH 2 CH 2 —).
  • Specific examples of the compound represented by the formula (1b) include 6-oxabicyclo [3.1.0] hexane, 7-oxabicyclo [4.1.0] heptane, 8-oxabicyclo [5.1. 0] octane and 3,6-dioxabicyclo [3.1.0] hexane.
  • Y is —O—, —NR 6 — or —S—. That is, the compound (2) means alcohol, amine or thiol. However, water and hydrogen sulfide are excluded from the range of the compound (2).
  • R 5 and R 6 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkenyl group, a C 2-6 An alkynyl group or a C 6-10 aryl group.
  • Examples of the C 1-6 alkyl group include a methyl group, an ethyl group, a propan-1-yl group, a propan-2-yl group (isopropyl group), a butan-1-yl group, a butan-2-yl group, and pentane.
  • Examples include a 1-yl group, a pentan-2-yl group, a pentan-3-yl group, a hexane-1-yl group, a hexane-2-yl group, and a 3-hexyl group.
  • Examples of the C 3-6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • Examples of the C 2-6 alkenyl group include a vinyl group, 1-propen-1-yl group, 2-propen-1-yl group, propen-2-yl group, 2-buten-1-yl group, 2- Buten-2-yl group, 3-buten-1-yl group, 2-penten-1-yl group, 3-penten-1-yl group, 2-hexen-1-yl group, 3-hexen-1-yl Groups, 4-hexen-1-yl group and 5-hexen-1-yl group.
  • Examples of the C 3-6 cycloalkenyl group include a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.
  • Examples of the C 2-6 alkynyl group include an ethynyl group, a propargyl group, and a 3-butyn-1-yl group.
  • Examples of the C 6-10 aryl group include a phenyl group and a naphthyl group.
  • the C 1-6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkenyl group, C 3-6 cycloalkenyl group, C 2-6 alkynyl group and C 6-10 aryl group are each unsubstituted. Alternatively, it may have a substituent.
  • substituents include C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 6-10 aryl group, C 1-4 alkoxy group, amino group, imino group, nitro group, hydroxy group Group, oxo group, nitrile group, mercapto group or halogen atom.
  • Examples of the C 1-4 alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, and a butoxy group.
  • the compound (2) include methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, phenol, ammonia, methylamine, Ethylamine, propylamine, 2-propylamine (isopropylamine), 2-pentylamine, 3-pentylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, tert-butylamine, allylamine, propargylamine, benzylamine, 2 -Phenylethylamine, aniline, dimethylamine, diethylamine, 3-methoxypropylamine, 3-ethoxypropylamine, methanethiol, ethanethiol, 1-propanethiol 2-propanethiol, include butanethiol.
  • the compound (2) may be the compound (2a).
  • R 8 represents a group formed by combining R 5 and R 6 with each other.
  • R 8 represents a group formed by combining R 5 and R 6 with each other.
  • the groups R 5 and R 6 are bonded to each other to form, when R 5 or R 6 has a substituent may be attached so as to be connected via the substituent. That is, R 8 is a C 1-6 alkylene group, a C 3-6 cycloalkylene group, a C 2-6 alkenylene group, a C 3-6 cycloalkenylene group, a C 2-6 alkynylene group and a C 6-10 arylene group only.
  • R 5 and R 6 are bonded via a substituent is also included.
  • C 1-6 alkylene group, C 3-6 cycloalkylene group, C 2-6 alkenylene group, C 3-6 cycloalkenylene group, C 2-6 alkynylene group and C 6-10 arylene group are each represented by the formula (2 And a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, and a C 6-10 aryl group defined in (1) above.
  • R 5 and R 6 are bonded via a substituent includes, for example, a 2-oxapropylene group (—CH 2 OCH 2 —), a 3-oxapentylene group (—CH 2 CH 2 OCH 2 CH 2 —) and a 3-oxopentylene group (—CH 2 CH 2 C ( ⁇ O) CH 2 CH 2 —).
  • the compound (2a) is pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, and thiomorpholine.
  • the amount of the compound (2) can be any amount in consideration of economy and recoverability. Such an amount is, for example, 0.01 to 100 equivalents, preferably 0.1 to 10 equivalents, more preferably 0.5 to 2 equivalents, relative to the number of moles of the compound (1).
  • the compound (3) is a compound represented by the formula (3), in which X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are Is the same as defined above.
  • the compound (3) includes the compounds (3a) to (3c).
  • the compound (3) examples include 1,2-diol (when X and Y are both —O—), 1,2-amino alcohol (when X is —O— and Y is —NH—). Or X is —NH— and Y is —O—), 1,2-diamine (when X and Y are both —NH—), 1,2-mercaptoalcohol (X is —O—). And Y is -S-) and 1,2-mercaptoamine (when X is -NH- and Y is -S-).
  • the processed plant product is a powder or extract obtained by processing a part of an edible plant.
  • the above “edible plant” means a plant generally known as a plant that a human can eat a part of.
  • the edible plant is, for example, a plant classified into cereals, beans, vegetables, fruits or potatoes, and part of the edible plant is the whole fruit, pulp, pericarp, stem, seed, germ, root, bulb and It can be appropriately selected from leaves.
  • edible plants include legumes (for example, soybeans, black beans, red kidney beans, peas), oleaceae (for example, olives), salamanders (for example, bananas), gramineae (for example, wheat), Cucurbitaceae (for example, pumpkin), solanaceae (for example, tomato, potato), urushiaceae (for example, pistachio, cashew nut), ginger (for example, turmeric), camellia (for example, tea), citrus (for example, Natsumikan) , Eggplant, flower bud, buntan), Amaryllidaceae (eg, garlic), celery family (eg, carrot), Brassicaceae (eg, radish), lotus family (eg, lotus root), matabidae (eg, kiwi), rose Plants of the family (eg apple) and leeks (eg leek) are mentioned.
  • legumes for example, soybeans, black beans, red kidney beans, peas
  • Edible plants include legumes (e.g., soybeans, black beans, red kidney beans, peas), camellia (e.g., tea), serpentaceae (e.g., carrots), matabidae (e.g., kiwi) and lily families (e.g., Preferably selected from the group consisting of leek).
  • a leek may be classified as a leek family.
  • processing means, if necessary, processing such as drying, heating, baking, roasting, oiling, fermenting, removing unnecessary parts, etc. It means to pulverize until it becomes or to extract components.
  • the processed plant product includes a powder obtained by extracting an extract of an edible plant and then pulverizing a dried product. Therefore, the tea may be green tea or black tea.
  • the soybean may be kinako or natto.
  • the plant processed product may be a commercially available product that has been processed into a powder or liquid state, or a product that has been processed in a processed state may be appropriately pulverized into a powder.
  • commercially available products include kina flour, defatted soybean flour (for example, Fujipro F (trade name, manufactured by Fuji Oil Co., Ltd.), Sunrich F (trade name, manufactured by Showa Sangyo Co., Ltd.), Soya Flower FT-N ( Nisshin Oilio Co., Ltd., trade name), Essan Meat Special (Ajinomoto Co., trade name), Toyotomi Soipro (J-Oil Mills Co., trade name), water-soluble soybean polysaccharide (for example, It is preferable to use a processed soybean product such as Soya Five S-DN (trade name, manufactured by Fuji Oil Co., Ltd.), and it is more preferable to use Kina Flour, Soya Flower FT-N or Soya Five S-DN.
  • the amount of the processed plant product any amount in consideration of economy and recoverability can be used.
  • the amount of such processed plant product is, for example, 0.01 to 100 times, preferably 0.1 to 10 times, and more preferably 0.1 to 10 times the mass of the compound represented by formula (1).
  • the amount is preferably 1 to 5 times.
  • the asymmetric ring-opening reaction according to the embodiment of the present invention may be performed in a solvent.
  • an organic solvent and water well known in organic synthetic chemistry can be used as long as the solvent does not react with compound (1) and compound (2).
  • organic solvents include aromatic hydrocarbons such as benzene, toluene, and xylene; hydrocarbons such as hexane, cyclohexane, and heptane; diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl tert-butyl ether, and cyclopentyl.
  • ethers such as methyl ether
  • esters such as ethyl acetate and butyl acetate
  • halogenated hydrocarbons such as dichloromethane and chloroform.
  • These solvents may be used alone or in combination of two or more.
  • the amount of the solvent that can be used in the asymmetric ring-opening reaction can be used in consideration of economic efficiency in either a single solvent or mixed solvent.
  • the amount of such a solvent is, for example, 0 to 100 times, preferably 0.5 to 50 times, more preferably 2 to 10 times the volume of the compound (1) by volume.
  • the content of water that can be used for the asymmetric ring-opening reaction can be 0.05 to 1 times the mass of water with respect to the catalyst, and 0.20 to 0.50 of water with respect to the catalyst. More preferably, it is in the range of double amount. Within such a range, the conversion rate of the reaction and the optical purity of the product are further improved.
  • the reaction temperature is preferably -20 ° C to 100 ° C, particularly preferably 30 ° C to 50 ° C.
  • the corresponding compound (3) can be obtained by filtering off the catalyst.
  • the catalyst recovered by filtration can be reused.
  • the reaction time can be reacted until a time when an arbitrary conversion rate considering economic efficiency is obtained.
  • a reaction time is, for example, 1 to 500 hours, preferably 1 to 100 hours, and more preferably 1 to 48 hours.
  • the compound (3) After completion of the reaction, the compound (3) can be obtained by filtering the catalyst.
  • the obtained compound (3) can also be easily purified by a conventional method such as crystallization or distillation.
  • Solvents that can be used for crystallization are not particularly limited as long as they are usually used in organic synthetic chemistry; hydrocarbons such as hexane, heptane, and cyclohexane; aromatic hydrocarbons such as toluene, benzene, and xylene; Ethers such as diisopropyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, and cyclopentyl methyl ether can be used, and these solvents may be used alone or in admixture of two or more.
  • the amount of the above-mentioned solvent can be set in consideration of economic efficiency in either case of a single solvent or a mixed solvent, and is 0.1 to 100 times by volume with respect to the mass of the compound (3).
  • the amount is preferably 0.5 to 50 times, more preferably 1 to 10 times.
  • the compound (3) obtained by the present invention can increase the optical purity by forming a salt with an inorganic acid or an organic acid usually used in organic synthetic chemistry.
  • the acid include inorganic acids such as hydrochloric acid, sulfuric acid, sulfurous acid, nitric acid, perchloric acid, chloric acid, iodic acid, and phosphoric acid; formic acid, acetic acid, lactic acid, oxalic acid, citric acid, maleic acid, fumaric acid, Organic acids such as benzoic acid, phthalic acid, salicylic acid, methanesulfonic acid, toluenesulfonic acid and the like can be mentioned.
  • a salt with an optically active acid may be formed.
  • the optically active acid include tartaric acid, malic acid, mandelic acid, phenylglycine and the like, and the acid may be substituted.
  • a solvent usually used in organic synthetic chemistry can be used in consideration of economy and recoverability.
  • the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; hydrocarbons such as hexane, cyclohexane and heptane; diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl tert-butyl ether, cyclopentyl methyl ether and the like.
  • Ethers such as ethyl acetate and butyl acetate; halogenated hydrocarbons such as dichloromethane and chloroform; alcohols such as methanol, ethanol and isopropanol; water and the like. More than one species may be mixed.
  • the amount of the solvent used when forming the salt can be used in an amount taking into consideration economic efficiency in either a single solvent or a mixed solvent.
  • the amount of the solvent is, for example, 0 to 100 times, preferably 0.5 to 50 times, more preferably 2 to 10 times the volume of the compound (1) by volume.
  • the compound (3) having a higher purity can be purified by a method well known to those skilled in the art.
  • Compound B When reacting Compound A and Compound B, Compound B can be reacted after reacting Compound A and a carbonylating reagent in advance as shown in the following formula (Eq.1).
  • the reaction product may be purified after reacting Compound A and the carbonylating reagent. [Wherein R represents a residue of the carbonylation reagent. ]
  • Reaction (i) can be carried out without solvent or in a solvent.
  • solvent examples include ethers such as dioxane, tetrahydrofuran, and diethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; methanol, Examples include alcohols such as ethanol and isopropanol; polar solvents such as N, N-dimethylformamide, acetone, dimethyl sulfoxide, acetonitrile, and water. These solvents may be used alone or in combination of two or more.
  • Examples of the carbonylation reagent include chloroformate such as phenyl chloroformate, carbonate such as diethyl carbonate, carbonyldiimidazole, phosgene, and triphosgene.
  • Reaction (i) is usually performed at ⁇ 20 to 150 ° C., preferably ⁇ 20 to 100 ° C.
  • Reaction (i) can be performed in the presence or absence of a basic compound.
  • basic compounds that can be used in the reaction (i) include inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium hydride; triethylamine, N, N-diisopropylethylamine, imidazole, An organic base such as pyridine can be used.
  • an additive may be further used in order to advance the reaction more efficiently.
  • additives include potassium iodide, sodium iodide, imidazole, 4-dimethylaminopyridine, 4-pyrrolidinopyridine and the like.
  • Reaction (ii) can be carried out without solvent or in a solvent.
  • the solvent that can be used in the reaction (ii) the solvents mentioned in the reaction (i) can be used.
  • the reaction (ii) is usually performed at ⁇ 20 to 150 ° C., preferably ⁇ 20 to 100 ° C.
  • Reaction (ii) can be performed in the presence or absence of a basic compound.
  • a basic compound that can be used in the reaction (ii)
  • the basic compounds mentioned in the reaction (i) can be used.
  • compound A may be reacted after reacting compound B and a carbonylating reagent in advance.
  • each step can be performed by the same method as in the case of formula (Eq.1). [Wherein R represents a residue of the carbonylation reagent. ]
  • the compound B used in the present invention may be a protected compound B.
  • the protected compound B one in which the 1-position of quinolinone is substituted with a protecting group can be used.
  • protecting groups include alkyl groups such as methoxymethyl group and benzyl group; substituted silyl groups such as triethylsilyl group and triphenylsilyl group; substituted acyl groups such as acetyl group and trifluoroacetyl group; Examples thereof include alkoxycarbonyl groups such as butoxycarbonyl group.
  • 6- (3-aminopropoxy) -quinoline substituted at the 2-position can also be used as the protected compound B.
  • the substituent of 6- (3-aminopropoxy) -quinoline substituted at the 2-position is, for example, a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom; an alkoxy group such as a methoxy group or a methoxymethoxy group; a benzyloxy group Arylalkyloxy groups such as acetoxy group, pivaloyloxy group and other acyloxy groups; triethylsilyloxy group and other silyloxy groups.
  • a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom
  • an alkoxy group such as a methoxy group or a methoxymethoxy group
  • a benzyloxy group Arylalkyloxy groups such as acetoxy group, pivaloy
  • the structural formula of the synthesized compound was determined by 1 H-NMR and 13 C-NMR spectra using tetramethylsilane as an internal standard.
  • the data described the chemical shift value ( ⁇ ) when TMS (tetramethylsilane) used as an internal standard was 0 ppm.
  • TMS tetramethylsilane
  • the “conversion rate” used in the specification is a value calculated based on the following formula. Specifically, the conversion rate calculation method is as follows. First, a small amount of a reaction solution is collected when the reaction between the compound (1) and the compound (2) is performed in the presence of the processed plant product. Next, the reaction solution collected using gas chromatography is measured to obtain the peak areas of compound (1) and compound (3). From the obtained peak areas, the molar ratio of the compound (1) and the compound (3) is calculated by the effective carbon number method (ECN), and is a value calculated based on the following formula.
  • ECN effective carbon number method
  • the effective carbon number method (ECN) is described in, for example, Gas Chromatography, Academic Press, New York, 1962, p207 and the Analytical Chemistry Handbook 5th edition (Seishiro Murata, edited by Japan Analytical Chemical Society, Maruzen Co., Ltd.) It is a method.
  • ECN effective carbon number of 7-oxabicyclo [4.1.0] heptane
  • heptane 5.00
  • 2-cyclopropylamino-1-cyclohexanol 7.50.
  • Conversion rate (%) 100 ⁇ number of moles of compound (3) / (number of moles of compound (1) + number of moles of compound (3))
  • BETADEX 120 (length: 30 m, inner diameter: 0.25 ⁇ m, manufactured by Supelco)
  • CP-CHIRASIL-DEX CB (length: 25 m, inner diameter: 0.25 mm, film thickness: 0.25 ⁇ m, manufactured by Varian)
  • racemic synthesis and analysis method for analysis are shown in the following reference examples.
  • Reference Example 2 synthesis of trans-2- (cyclopropylamino) cyclohexanol All operations were performed in the same manner as Reference Example 1 except that cyclopropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
  • Reference Example 15 synthesis of trans-2- (2-phenylethylamino) cyclohexanol All operations were performed in the same manner as Reference Example 1 except that 2-phenylethylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
  • Reference Example 17 synthesis of trans-2- (3-ethoxypropylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that 3-ethoxypropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
  • Reference Example 30 Synthesis of trans-4- (isopropylamino) -3-tetrahydrofuran-3-ol The same operation as in Reference Example 1 was conducted except that 3,6-dioxabicyclo [3.1.0] hexane was used as the epoxide.
  • Reference Example 33 Synthesis of trans-4- (allylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that allylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
  • Reference Example 41 synthesis of trans-4- (3-ethoxypropylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that 3-ethoxypropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
  • Reference Example 42 synthesis of trans-2- (isopropylamino) cycloheptanol The same operation as in Reference Example 1 was conducted except that 8-oxabicyclo [5.1.0] octane was used as the epoxide. The obtained crude product was used for analysis as it was.
  • Reference Example 51 The same procedure as in Reference Example 1 was conducted except that trans-3-cyclopropylamino-2-butanol Cis-2,3-epoxybutane and cyclopropylamine were used. The obtained crude product was used for analysis as it was. (Outer bath temperature 135-140 ° C, pressure 0.1mmHg) Analysis condition G Retention time 11.0 minutes, 11.3 minutes
  • Reference Example 54 trans-N-tosyl- (2- (2-phenylethylamino) cyclohexylamine) Reference Example except that 2-phenylethylamine was used in place of isopropylamine and 7-tosyl-7-azabicyclo [4.1.0] heptane was used in place of 7-oxabicyclo [4.1.0] heptane The same operation as in 1 was performed. The obtained crude product was used for analysis as it was.
  • the catalyst used in this example was obtained as follows.
  • the defatted soybean powder, pectin (citrus-derived), water-soluble soybean polysaccharide, pumpkin, lotus root, potato, carrot, wheat germ, and turmeric were processed into powder.
  • Unprocessed plant pieces such as kiwi, buntan, natsum, flower aubergine, garlic, soy, leek, pistachio, cashew nut, tea (tea, green tea), red kidney beans, peas, etc. are heated in a desiccator if necessary.
  • Examples 1 to 27 To a 5 mL test tube, 100 mg of the processed plant product described in Table 3 was weighed, and 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, 34 mg of cyclopropylamine, and 17 mg of water were added. Sealed and shaken in a 37 ° C. bath for 16 hours. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.
  • Examples 28-47 To a 5 mL test tube, 100 mg of the processed plant product described in Table 4 was weighed, and 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, 29 mg of isopropylamine, and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.
  • pumpkin powder made by Kodama Foods
  • Mashed Potato made by Miki Foods
  • Carrot Powder made by Kodama Foods
  • Tomato Powder made by Kodama Foods
  • Japanese radish “Dried radish grated” manufactured by Kodama Foods
  • “Loren powder” manufactured by Kodama Foods) as a lotus root was pulverized into a powder form, and pistachio was degreased and pulverized.
  • Example 28 to 47 compound (3) was obtained stereoselectively.
  • Examples 28 to 31, 33, 39, 43 and 46 were excellent in both conversion rate and stereoselectivity.
  • Examples 48-63 In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) was weighed, 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, compound (2) shown in Table 5 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.
  • Soya Five S-DN water-soluble soybean polysaccharide
  • Examples 77-88 In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) is weighed, 0.4 mL of toluene, 41 mg of 6-oxabicyclo [3.1.0] hexane, compound (2) shown in Table 7 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.
  • Soya Five S-DN water-soluble soybean polysaccharide
  • Examples 89-100 In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) is weighed, 0.4 mL of toluene, 42 mg of 3,6-dioxabicyclo [3.1.0] hexane, and the compounds described in Table 8 (2) 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.
  • Soya Five S-DN water-soluble soybean polysaccharide
  • Examples 101-108 In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) was weighed, 0.4 mL of toluene, 41 mg of 8-oxabicyclo [5.1.0] octane, compound (2) shown in Table 9 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.
  • Soya Five S-DN water-soluble soybean polysaccharide
  • Example 101-108 all gave compound (3) stereoselectively.
  • Example 107 was excellent in both conversion rate and stereoselectivity.
  • Example 109 In a 5 mL test tube, weigh 1.1 g of water-soluble soybean polysaccharide (Soya Five S-DN), 2.87 mL of toluene, 41 mg of Cis-2,3-epoxybutane, 1.2 equivalent of cyclopropylamine, and 390 mg of water. added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC. As a result, the conversion was 55% and the selectivity was 4% ee.
  • Soya Five S-DN water-soluble soybean polysaccharide
  • toluene 41 mg
  • Cis-2,3-epoxybutane 41 mg
  • cyclopropylamine 1.2 equivalent of cyclopropylamine
  • Examples 110-114 In a 1 L four-necked flask equipped with a stirrer and a thermometer, 70.0 g of processed soybean, 198 mL of toluene, 28.0 mL of water, 35.0 g of 7-oxabicyclo [4.1.0] heptane and 24. 4 g was added and stirred at 40 ° C. under a nitrogen atmosphere. Table 1 shows the processed soybean and reaction time used in each example. A small amount of the reaction solution was collected, and the conversion rate and selectivity at a predetermined reaction time were calculated using gas chromatography.
  • Examples 110 to 114 all gave compound (3) stereoselectively.
  • Examples 112 to 114 were excellent in both conversion rate and stereoselectivity.
  • Example 115 In a 5 mL test tube, weigh 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN), and add 0.4 mL of toluene, 100 mg of 7-oxabicyclo [4.1.0] heptane, 109 mg of 2-propanethiol, and 17 mg of water. added. Sealed and shaken in a 50 ° C. bath for 5 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC. As a result, the conversion rate was 7% and the selectivity rate was 72% ee.
  • Example 116 In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) was weighed, 0.4 mL of toluene, 100 mg of 7-tosyl-7-azabicyclo [4.1.0] heptane, 58 mg of 2-phenylethylamine, 17 mg of water was added. Sealed and shaken in a 50 ° C. bath for 5 days. After the reaction, the catalyst was filtered and the filtrate was concentrated to obtain 120 mg of a crude product of trans-N-tosyl (2- (2-phenylethylamino) cyclohexylamine). The crude yield was 81% and the selectivity was 4% ee.
  • the obtained filtrate was concentrated under reduced pressure, and 58.4 g (content 51.0 g, 64% ee, yield 92%) of (1R, 2R) -2- (cyclopropylamino) cyclohexanol was obtained as a crude product. Obtained.
  • the content was calculated based on the mass of the crude product by measuring the 1 H-NMR spectrum of the crude product and using the integral ratio of protons of 2- (cyclopropylamino) cyclohexanol and toluene. Value.
  • the obtained toluene layer was washed with 68 mL of water three times and concentrated under reduced pressure using a rotary evaporator to obtain 154.1 g (content 135.6 g) of a solid.
  • 154.1 g (content 135.6 g) of the solid and 407 mL of heptane add 154.1 g (content 135.6 g) of the solid and 407 mL of heptane, adjust the internal temperature to 25 ° C., add 135 mg of seed crystal B, and take 30 minutes. Left to stand. At this time, (1R, 2R) -2- (cyclopropylamino) cyclohexanol was used as seed crystal B.
  • the precipitated crystals were collected by filtration.
  • the obtained crystals were washed with 68 mL of heptane at 0 ° C. and dried under reduced pressure at room temperature to obtain 103.0 g (100% ee) of primary crystals of white (1R, 2R) -2- (cyclopropylamino) cyclohexanol. It was.
  • the filtrate was concentrated on a rotary evaporator under reduced pressure to obtain 11.0 g (100% ee) of secondary crystals in the same manner as when primary crystals were obtained.
  • the yield of was 42%.
  • Example 118 Synthesis of optically active trans-2- (isopropylamino) cyclohexanol
  • 14.4 g of Soya Five S-DN 36 mL of heptane, 4.3 mL of water, 7-oxabicyclo [4.1.0] 12 g of heptane and 8.7 g of isopropylamine were added, and the mixture was stirred at 40 ° C. for 49 hours under a nitrogen atmosphere.
  • Soya Five S-DN was filtered off using Nutsche and washed with 50 mL of heptane.
  • Example 119 Synthesis of optically active trans-2- (propargylamino) cyclohexanol Into a 50 mL four-necked flask equipped with a stirrer and a thermometer, 1.2 g of Soya Five S-DN, 3 mL of heptane, 0.36 mL of water, 7-oxabicyclo [4.1.0] Heptane (0.858 g) and propargylamine (0.407 g) were added, and the mixture was stirred at 40 ° C. for 6 days under a nitrogen atmosphere. Toluene 3 mL was added and stirred, and Soya Five S-DN was filtered off using Nutsche and washed with toluene 3 mL.
  • the obtained filtrate was concentrated under reduced pressure to obtain 1.19 g (45% ee, 91% yield) of optically active trans-2- (propargylamino) cyclohexanol as a crude product.
  • 1.19 g (45% ee) of the optically active trans-2- (propargylamino) cyclohexanol of the obtained crude product and 12 mL of ethanol were added, and the mixture was heated to 40 ° C. After the temperature was raised, 0.595 g of fumaric acid and 10 mg of seed crystals were added and allowed to stand for 30 minutes.
  • racemic trans-2- (propargylamino) cyclohexanol fumarate was used as a seed crystal.
  • the precipitated racemic trans-2- (propargylamino) cyclohexanol fumarate crystals were filtered off using Nutsche and washed with 1 mL of ethanol. The obtained filtrate was concentrated under reduced pressure using a rotary evaporator.
  • optically active trans-2- (propargylamino) cyclohexanol 10 mL of toluene, 1 mL of water and 0.480 g of potassium hydroxide were added to convert to a free form, and the toluene layer was separated.
  • the obtained toluene layer was washed with 1 mL of water three times and concentrated under reduced pressure using a rotary evaporator to obtain 0.440 g (90% ee) of optically active trans-2- (propargylamino) cyclohexanol.
  • the total yield at this time was 31%.

Abstract

　A method for producing a compound represented by formula (3), the method including a step for reacting a compound represented by formula (1): (in the formula, X is –O- or –NR-, R, R1, R2, R3, and R4 are each independently C1-6 alkyl groups or the like) and a compound represented by formula (2): (in the formula, Y is –O-, -NR6-, or –S-, R5 and R6 are each independently C1-6 alkyl groups or the like) in the presence of a processed plant product, and obtaining a compound represented by formula (3): (in the formula, X, Y, R1, R2, R3, R4, and R5 are defined in the same manner as above).

Description

光学活性体の製造方法Method for producing optically active substance
　本発明は、光学活性体の製造方法に関する。 The present invention relates to a method for producing an optically active substance.
　式（Ｚ）で表される化合物（以下、「化合物（Ｚ）」ともいう。）は、連続する２つの炭素原子に、それぞれ酸素原子または窒素原子が結合した化合物であり、１分子中に少なくとも２つの不斉炭素を有するため、複数の光学異性体が存在する。光学活性な化合物（Ｚ）は、医薬品または農薬の開発の分野において汎用される化学構造の１つであり、不斉反応で使用する遷移金属触媒のリガンドとしても使用できる。
Figure JPOXMLDOC01-appb-C000008
 　なお、式中、Ｘは－Ｏ－または－ＮＲｆ－を示し、Ｙは－Ｏ－、－ＮＲｇ－または－Ｓ－を示し、Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ、Ｒｅ、ＲｆおよびＲｇは、それぞれ独立に水素原子または有機基を示し、アスタリスクはその炭素原子が不斉炭素であることを示す。 The compound represented by the formula (Z) (hereinafter, also referred to as “compound (Z)”) is a compound in which an oxygen atom or a nitrogen atom is bonded to two consecutive carbon atoms, and at least in one molecule. Since it has two asymmetric carbons, there are multiple optical isomers. The optically active compound (Z) is one of chemical structures widely used in the field of pharmaceutical or agricultural chemical development, and can also be used as a ligand for a transition metal catalyst used in an asymmetric reaction.
Figure JPOXMLDOC01-appb-C000008
 In the formula, X represents —O— or —NR f —, Y represents —O—, —NR g — or —S—, and R a , R b , R c , R d , R e , R f and R g each independently represent a hydrogen atom or an organic group, and an asterisk indicates that the carbon atom is an asymmetric carbon.
　化合物（Ｚ）は、具体的には、例えば、１，２－ジオール（ＸおよびＹがともに－Ｏ－である場合）、１，２－アミノアルコール（Ｘが－Ｏ－かつＹが－ＮＨ－である場合、または、Ｘが－ＮＨ－かつＹが－Ｏ－である場合）、１，２－ジアミン（ＸおよびＹがともに－ＮＨ－である場合）、１，２－メルカプトアルコール（Ｘが－Ｏ－かつＹが－Ｓ－である場合）、１，２－メルカプトアミン（Ｘが－ＮＨ－かつＹが－Ｓ－である場合）である。 Specifically, the compound (Z) includes, for example, 1,2-diol (when X and Y are both —O—), 1,2-aminoalcohol (where X is —O— and Y is —NH—). Or X is —NH— and Y is —O—), 1,2-diamine (when both X and Y are —NH—), 1,2-mercaptoalcohol (where X is -O- and Y is -S-), 1,2-mercaptoamine (when X is -NH- and Y is -S-).
　現在までに、光学活性な化合物（Ｚ）の製造方法について、多くの検討が行われている。なかでも、入手が容易なエポキシド構造またはアジリジン構造を有する化合物に求核剤を反応させ、立体選択的に開環することにより光学活性な化合物（Ｚ）を得る方法は、原子効率が高く有用である。 To date, many studies have been made on methods for producing optically active compounds (Z). Among them, a method of obtaining an optically active compound (Z) by reacting a compound having an epoxide structure or an aziridine structure, which is readily available, with a nucleophile, and performing stereoselective ring opening has high atomic efficiency and is useful. is there.
　例えば、エポキシド構造を有する化合物に求核剤を反応させて、光学活性な化合物（Ｚ）を得る方法としては、（Ａ）ラセミ体を光学分割する方法（例えば、特許文献１～３、非特許文献１、２）、（Ｂ）他の位置に不斉炭素を導入し、生じたジアステレオマーを分離する方法（例えば、特許文献４、非特許文献３）、（Ｃ）光学活性な触媒の存在下でエポキシド構造を有する化合物と求核剤の不斉開環反応を行う方法（例えば、特許文献５、非特許文献４～６）等がある。特に、（Ａ）の方法としては、分割剤として光学活性な酸を用いる方法、光学活性な充填剤を利用したカラムクラマトグラフィーを用いて分離する方法、および動物または微生物に由来する酵素を利用する方法などが知られている。 For example, as a method of obtaining an optically active compound (Z) by reacting a compound having an epoxide structure with a nucleophile, (A) a method of optically resolving a racemate (for example, Patent Documents 1 to 3, Non-patent Documents 1, 2), (B) a method of introducing an asymmetric carbon at another position and separating the resulting diastereomers (for example, Patent Document 4, Non-Patent Document 3), (C) Optically active catalyst There are methods for performing an asymmetric ring-opening reaction between a compound having an epoxide structure and a nucleophile in the presence (for example, Patent Document 5, Non-Patent Documents 4 to 6). In particular, as the method (A), a method using an optically active acid as a resolving agent, a method using a column chromatography using an optically active filler, and an enzyme derived from an animal or a microorganism are used. Methods are known.
　また、アジリジン構造を有する化合物に求核剤を反応させて、化合物（Ｚ）を得る方法としては、（Ｄ）ラセミ体を光学分割する方法（例えば、特許文献６）、（Ｅ）光学活性な触媒の存在下でアジリジン構造を有する化合物と求核剤の不斉開環反応を行う方法（例えば、非特許文献７，８）等がある。 Further, as a method of obtaining a compound (Z) by reacting a compound having an aziridine structure with a nucleophile, (D) a method of optically resolving a racemate (for example, Patent Document 6), (E) an optically active compound There are methods for performing asymmetric ring-opening reaction between a compound having an aziridine structure and a nucleophile in the presence of a catalyst (for example, Non-Patent Documents 7 and 8).
特許第４４０６４８３号公報Japanese Patent No. 4406483 特許第４４０６４８２号公報Japanese Patent No. 4406482 米国特許第５９８１２６７号明細書US Pat. No. 5,981,267 特開平９－１５７２５８号公報JP-A-9-157258 特開２００３－２０６２６６号公報JP 2003-206266 A 特開２０１１－８３９３４号公報JP 2011-83934 A
　しかしながら、（Ａ）、（Ｂ）および（Ｄ）の方法では、理論上の収率が５０％を超えることはなく、製造物と同じ量の分割剤の使用、または、大容量カラムによる精製が必要となり、工業的に製造する方法としては問題がある。 However, in the methods (A), (B), and (D), the theoretical yield does not exceed 50%, and it is possible to use the same amount of resolving agent as the product or to purify by a large capacity column. There is a problem as an industrially produced method.
　一方、（Ｃ）および（Ｅ）の方法では、短工程で目的の光学活性な化合物（Ｚ）を製造することができるが、多くの場合、光学活性な触媒として金属触媒または強力な酸触媒を用いる。そのため、（Ｃ）および（Ｅ）の方法では、使用できる含ヘテロ３員環構造を有する化合物または求核剤が限定され、高価な金属触媒の回収工程が必要となる。 On the other hand, in the methods (C) and (E), the target optically active compound (Z) can be produced in a short process, but in many cases, a metal catalyst or a strong acid catalyst is used as the optically active catalyst. Use. Therefore, in the methods (C) and (E), usable compounds or nucleophiles having a hetero-containing three-membered ring structure are limited, and an expensive metal catalyst recovery step is required.
　したがって、本発明の目的は、安価で入手が容易な触媒を使用し、簡便な操作により、エポキシドまたはアジリジンを有する化合物と求核剤とを反応させ、式（３）で表される化合物を立体選択的かつ効率よく製造する方法を提供することである。 Accordingly, an object of the present invention is to react a compound having an epoxide or aziridine with a nucleophile by a simple operation using an inexpensive and easily available catalyst, and convert the compound represented by the formula (3) into a steric form. It is to provide a method for selective and efficient production.
　本発明は、以下の［１］～［９］を提供する。
［１］式（１）：
Figure JPOXMLDOC01-appb-C000009
 （式中、Ｘは、－Ｏ－または－ＮＲ－であり、Ｒは、水素原子、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ３－６シクロアルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ３－６シクロアルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよいＣ６－１０アリール基、置換基を有してもよいＣ１－６アルキルカルボニル基、置換基を有してもよいＣ６－１０アリールカルボニル基、置換基を有してもよいＣ１－６アルキルスルホニル基またはＣ６－１０アリールスルホニル基であり、Ｒ１、Ｒ２、Ｒ３およびＲ４は、それぞれ独立に、水素原子、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ３－６シクロアルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ３－６シクロアルケニル基、置換基を有してもよいＣ２－６アルキニル基または置換基を有してもよいＣ６－１０アリール基であり、前記置換基が、Ｃ１－４アルキル基、Ｃ２－４アルケニル基、Ｃ２－４アルキニル基、Ｃ１－４アルコキシ基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、また、Ｒ２およびＲ３が互いに結合して式（１ｂ）で表される化合物となっていてもよい）
Figure JPOXMLDOC01-appb-C000010
 （式中、Ｘ、Ｒ１およびＲ４は、前記定義と同一であり、Ｒ７は、Ｒ２およびＲ３が互いに結合して形成される基を示す）
で表される化合物と、
　式（２）：
Figure JPOXMLDOC01-appb-C000011
 （式中、Ｙは、－Ｏ－、－ＮＲ６－または－Ｓ－であり、Ｒ５およびＲ６は、それぞれ独立に、水素原子、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ３－６シクロアルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ３－６シクロアルケニル基、置換基を有してもよいＣ２－６アルキニル基または置換基を有してもよいＣ６－１０アリール基であり、前記置換基が、Ｃ１－４アルコキシ基、Ｃ６－１０アリール基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、また、Ｒ５およびＲ６が互いに結合して式（２ａ）で表される化合物となっていてもよく、ただし、式（２）で表される化合物は水または硫化水素ではない）
Figure JPOXMLDOC01-appb-C000012
 （式中、Ｒ８は、Ｒ５およびＲ６が互いに結合して形成される基を示す）
で表される化合物と、を植物加工物の存在下反応させ、
　式（３）：
Figure JPOXMLDOC01-appb-C000013
 （式中、Ｘ、Ｙ、Ｒ１、Ｒ２、Ｒ３、Ｒ４およびＲ５は、前記定義と同一である）
で表される化合物を得る工程を含む、式（３）で表される化合物の製造方法。
［２］前記式（１）で表される化合物が、式（１ｃ）で表される化合物である、請求項１に記載の製造方法。
Figure JPOXMLDOC01-appb-C000014
 （式中、ＸおよびＲ７は、前記定義と同一である）
［３］前記式（１）で表される化合物が、式（１ａ）で表される化合物である、［１］に記載の製造方法。
Figure JPOXMLDOC01-appb-C000015
 （式中、Ｘは、－Ｏ－または－ＮＲ－であり、Ｒは、水素原子、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ３－６シクロアルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ３－６シクロアルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよいＣ６－１０アリール基、置換基を有してもよいＣ１－６アルキルカルボニル基、置換基を有してもよいＣ６－１０アリールカルボニル基、置換基を有してもよいＣ１－６アルキルスルホニル基またはＣ６－１０アリールスルホニル基であり、Ｒ２およびＲ３は、それぞれ独立に、水素原子、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ３－６シクロアルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ３－６シクロアルケニル基、置換基を有してもよいＣ２－６アルキニル基または置換基を有してもよいＣ６－１０アリール基であり、前記置換基が、Ｃ１－４アルキル基、Ｃ２－４アルケニル基、Ｃ２－４アルキニル基、Ｃ１－４アルコキシ基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子を示す）
［４］Ｙが－ＮＲ６－である、［１］～［３］のいずれか一項に記載の製造方法。
［５］Ｙが－Ｏ－である、［１］～［３］のいずれか一項に記載の製造方法。
［６］Ｙが－Ｓ－である、［１］～［３］のいずれか一項に記載の製造方法。
［７］前記植物加工物が、マメ科、ウリ科、ナス科、ウルシ科、ショウガ科、ミカン科、ヒガンバナ科、セリ科、アブラナ科、ハス科、マタタビ科、バラ科、ユリ科、イネ科、モクセイ科、バショウ科、ツバキ科およびネギ科の植物からなる群から選択される植物を粉砕して調製される、［１］～［６］のいずれか一項に記載の製造方法。
［８］７－オキサビシクロ［４．１．０］ヘプタンおよびシクロプロピルアミンを、大豆加工物の存在下で反応させて（１Ｒ，２Ｒ）－２－シクロプロピルアミノ－１－シクロヘキサノールを得る工程を含む、（１Ｒ，２Ｒ）－２－シクロプロピルアミノ－１－シクロヘキサノールの製造方法。
［９］（１）　７－オキサビシクロ［４．１．０］ヘプタンおよびシクロプロピルアミンを、大豆加工物の存在下で反応させて（１Ｒ，２Ｒ）－２－シクロプロピルアミノ－１－シクロヘキサノールを得る工程と、
　（２ａ）　（１Ｒ，２Ｒ）－２－シクロプロピルアミノ－１－シクロヘキサノールとカルボニル化試薬を反応させた後に、さらに保護された若しくは保護されていない６－（３－アミノプロポキシ）－２（１Ｈ）－キノリノンとを反応させ、または、
　（２ｂ）　保護された若しくは保護されていない６－（３－アミノプロポキシ）－２（１Ｈ）－キノリノンとカルボニル化試薬を反応させた後に、さらに（１Ｒ，２Ｒ）－２－シクロプロピルアミノ－１－シクロヘキサノールを反応させ、
　保護された６－（３－アミノプロポキシ）－２（１Ｈ）－キノリノンを用いた場合は、さらに脱保護を行うことによって、
　（－）－６－〔３－〔３－シクロプロピル－３－〔（１Ｒ，２Ｒ）－２－ヒドロキシシクロヘキシル〕ウレイド〕－プロポキシ〕－２（１Ｈ）－キノリノンを得る工程と、
　を含む、（－）－６－〔３－〔３－シクロプロピル－３－〔（１Ｒ，２Ｒ）－２－ヒドロキシシクロヘキシル〕ウレイド〕－プロポキシ〕－２（１Ｈ）－キノリノンの製造方法。 The present invention provides the following [1] to [9].
[1] Formula (1):
Figure JPOXMLDOC01-appb-C000009
 (In the formula, X is —O— or —NR—, and R is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, or a C 3-6 which may have a substituent. A cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-6 cycloalkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-10 aryl group, an optionally substituted C 1-6 alkylcarbonyl group, an optionally substituted C 6-10 arylcarbonyl group, a substituent A C 1-6 alkylsulfonyl group or a C 6-10 arylsulfonyl group which may have, and each of R 1 , R 2 , R 3 and R 4 may independently have a hydrogen atom or a substituent. a C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, Yes which may have a substituent C 2-6 alkenyl group, an optionally substituted C 3-6 cycloalkenyl group, an optionally C 2-6 alkynyl group or a substituted group may have a substituent An optionally substituted C 6-10 aryl group, and the substituent is a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a C 1-4 alkoxy group, an amino group, an imino group. A nitro group, a hydroxy group, an oxo group, a nitrile group, a mercapto group or a halogen atom, and R 2 and R 3 may be bonded to each other to form a compound represented by the formula (1b))
Figure JPOXMLDOC01-appb-C000010
 (Wherein X, R 1 and R 4 are the same as defined above, and R 7 represents a group formed by combining R 2 and R 3 with each other)
A compound represented by
Formula (2):
Figure JPOXMLDOC01-appb-C000011
 (Wherein Y is —O—, —NR 6 — or —S—, and R 5 and R 6 are each independently a hydrogen atom or a C 1-6 alkyl group optionally having substituent (s). , an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-6 cycloalkenyl group, a substituted group A C 2-6 alkynyl group which may have a substituent or a C 6-10 aryl group which may have a substituent, wherein the substituent is a C 1-4 alkoxy group, a C 6-10 aryl group, amino A group, an imino group, a nitro group, a hydroxy group, an oxo group, a nitrile group, a mercapto group, or a halogen atom, and R 5 and R 6 are bonded to each other to form a compound represented by the formula (2a). However, the compound represented by the formula (2) is water or sulfurized. Not in the original)
Figure JPOXMLDOC01-appb-C000012
 (Wherein R 8 represents a group formed by combining R 5 and R 6 with each other)
And a compound represented by the following:
Formula (3):
Figure JPOXMLDOC01-appb-C000013
 (Wherein X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above)
The manufacturing method of the compound represented by Formula (3) including the process of obtaining the compound represented by these.
[2] The production method according to claim 1, wherein the compound represented by the formula (1) is a compound represented by the formula (1c).
Figure JPOXMLDOC01-appb-C000014
 (Wherein X and R 7 are the same as defined above)
[3] The production method according to [1], wherein the compound represented by the formula (1) is a compound represented by the formula (1a).
Figure JPOXMLDOC01-appb-C000015
 (In the formula, X is —O— or —NR—, and R is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, or a C 3-6 which may have a substituent. A cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-6 cycloalkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-10 aryl group, an optionally substituted C 1-6 alkylcarbonyl group, an optionally substituted C 6-10 arylcarbonyl group, a substituent An optionally substituted C 1-6 alkylsulfonyl group or a C 6-10 arylsulfonyl group, and R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted C 1-6 alkyl having group, an optionally substituted C 3-6 cycloalkyl group, a substituent Good C 2-6 alkenyl group, an optionally substituted C 3-6 cycloalkenyl group, which may have a good C 2-6 alkynyl group or a substituted group may have a substituent C 6- 10 aryl group, and the substituent is C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, amino group, imino group, nitro group, hydroxy group , Oxo group, nitrile group, mercapto group or halogen atom)
[4] The production method according to any one of [1] to [3], wherein Y is —NR 6 —.
[5] The production method according to any one of [1] to [3], wherein Y is —O—.
[6] The production method according to any one of [1] to [3], wherein Y is —S—.
[7] The processed plant product is a legume, cucurbitaceae, eggplant, urushiaceae, ginger, citrus, antaceae, sage, cruciferous, lotus, matabidae, rose, lily, gramineous The production method according to any one of [1] to [6], wherein the plant is prepared by pulverizing a plant selected from the group consisting of plants of the family Moleaceae, Salamoniaceae, Camelliaaceae and Alliumaceae.
[8] A step of reacting 7-oxabicyclo [4.1.0] heptane and cyclopropylamine in the presence of processed soybean so as to obtain (1R, 2R) -2-cyclopropylamino-1-cyclohexanol. A process for producing (1R, 2R) -2-cyclopropylamino-1-cyclohexanol.
[9] (1) 7-oxabicyclo [4.1.0] heptane and cyclopropylamine are reacted in the presence of processed soybean products to produce (1R, 2R) -2-cyclopropylamino-1-cyclohexanol Obtaining
(2a) After reacting (1R, 2R) -2-cyclopropylamino-1-cyclohexanol with a carbonylating reagent, further protected or unprotected 6- (3-aminopropoxy) -2 (1H ) -Reacting with quinolinone, or
(2b) After reacting protected or unprotected 6- (3-aminopropoxy) -2 (1H) -quinolinone with a carbonylating reagent, (1R, 2R) -2-cyclopropylamino-1 -Reacting cyclohexanol;
When protected 6- (3-aminopropoxy) -2 (1H) -quinolinone is used, by further deprotection,
Obtaining (−)-6- [3- [3-cyclopropyl-3-[(1R, 2R) -2-hydroxycyclohexyl] ureido] -propoxy] -2 (1H) -quinolinone;
(−)-6- [3- [3-Cyclopropyl-3-[(1R, 2R) -2-hydroxycyclohexyl] ureido] -propoxy] -2 (1H) -quinolinone.
　本発明によれば、安価で入手が容易な触媒を使用し、簡便な操作により、エポキシド構造またはアジリジン構造を有する化合物と種々の求核剤とを反応させ、式（３）で表される化合物を立体選択的かつ効率的に製造することができる。 According to the present invention, a compound represented by the formula (3) is obtained by reacting a compound having an epoxide structure or an aziridine structure with various nucleophiles by a simple operation using an inexpensive and easily available catalyst. Can be produced stereoselectively and efficiently.
　また、本発明で使用する触媒は、入手容易な植物加工物であり、必ずしも触媒の回収を必要としない。さらに、触媒は、反応終了後、回収して再利用することも可能である。 Further, the catalyst used in the present invention is an easily obtained plant processed product, and does not necessarily require recovery of the catalyst. Furthermore, the catalyst can be recovered and reused after completion of the reaction.
　以下、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
　本発明の一実施形態は、式（１）で表される化合物（以下、「化合物（１）」等ともいう。）と化合物（２）を植物加工物の存在下で反応させ、化合物（３）を得るものである。
Figure JPOXMLDOC01-appb-C000016
 In one embodiment of the present invention, a compound represented by the formula (1) (hereinafter, also referred to as “compound (1)” or the like) and a compound (2) are reacted in the presence of a processed plant product to obtain a compound (3 ).
Figure JPOXMLDOC01-appb-C000016
＜式（１）で表される化合物（化合物（１））＞
　式（１）において、Ｘは、－Ｏ－または－ＮＲ－である。すなわち、化合物（１）は、エポキシド構造を有する化合物またはアジリジン構造を有する化合物を意味する。
Figure JPOXMLDOC01-appb-C000017
 <Compound represented by Formula (1) (Compound (1))>
In the formula (1), X is —O— or —NR—. That is, the compound (1) means a compound having an epoxide structure or a compound having an aziridine structure.
Figure JPOXMLDOC01-appb-C000017
　Ｒは、水素原子、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ３－６シクロアルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ３－６シクロアルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよいＣ６－１０アリール基、置換基を有してもよいＣ１－６アルキルカルボニル基、置換基を有してもよいＣ６－１０アリールカルボニル基、置換基を有してもよいＣ１－６アルキルスルホニル基またはＣ６－１０アリールスルホニル基である。 R is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 2-6 alkenyl. Group, a C 3-6 cycloalkenyl group which may have a substituent, a C 2-6 alkynyl group which may have a substituent, a C 6-10 aryl group which may have a substituent, a substituent A C 1-6 alkylcarbonyl group which may have a substituent, a C 6-10 arylcarbonyl group which may have a substituent, a C 1-6 alkylsulfonyl group which may have a substituent or a C 6-10 An arylsulfonyl group.
　また、Ｒ１、Ｒ２、Ｒ３およびＲ４は、それぞれ独立に、水素原子、Ｃ１－６アルキル基、Ｃ３－６シクロアルキル基、Ｃ２－６アルケニル基、Ｃ３－６シクロアルケニル基、Ｃ２－６アルキニル基またはＣ６－１０アリール基である。 R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkenyl A group, a C 2-6 alkynyl group or a C 6-10 aryl group.
　Ｃ１－６アルキル基とは、炭素数１～６のアルキル基を意味する。Ｃ１－６アルキル基としては、例えば、メチル基、エチル基、プロパン－１－イル基、プロパン－２－イル基（イソプロピル基）、ブタン－１－イル基、ブタン－２－イル基、ペンタン－１－イル基、ペンタン－２－イル基、ペンタン－３－イル基、ヘキサン－１－イル基、ヘキサン－２－イル基および３－ヘキシル基が挙げられる。 The C 1-6 alkyl group means an alkyl group having 1 to 6 carbon atoms. Examples of the C 1-6 alkyl group include a methyl group, an ethyl group, a propan-1-yl group, a propan-2-yl group (isopropyl group), a butan-1-yl group, a butan-2-yl group, and pentane. Examples include a 1-yl group, a pentan-2-yl group, a pentan-3-yl group, a hexane-1-yl group, a hexane-2-yl group, and a 3-hexyl group.
　Ｃ３－６シクロアルキル基とは、炭素数３～６のシクロアルキル基を意味する。Ｃ３－６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、シクロヘキシル基が挙げられる。 The C 3-6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms. Examples of the C 3-6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
　Ｃ２－６アルケニル基とは、炭素数２～６のアルケニル基を意味する。Ｃ２－６アルケニル基としては、例えば、ビニル基、１－プロペン－１－イル基、２－プロペン－１－イル基、プロペン－２－イル基、２－ブテン－１－イル基、２－ブテン－２－イル基、３－ブテン－１－イル基、２－ペンテン－１－イル基、３－ペンテン－１－イル基、２－ヘキセン－１－イル基、３－ヘキセン－１－イル基、４－ヘキセン－１－イル基および５－ヘキセン－１－イル基が挙げられる。 The C 2-6 alkenyl group means an alkenyl group having 2 to 6 carbon atoms. Examples of the C 2-6 alkenyl group include a vinyl group, 1-propen-1-yl group, 2-propen-1-yl group, propen-2-yl group, 2-buten-1-yl group, 2- Buten-2-yl group, 3-buten-1-yl group, 2-penten-1-yl group, 3-penten-1-yl group, 2-hexen-1-yl group, 3-hexen-1-yl Groups, 4-hexen-1-yl group and 5-hexen-1-yl group.
　Ｃ３－６シクロアルケニル基とは、炭素数３～６のシクロアルケニル基を意味する。Ｃ３－６シクロアルケニル基としては、例えば、シクロブテニル基、シクロペンテニル基、シクロヘキセニル基が挙げられる。 The C 3-6 cycloalkenyl group means a cycloalkenyl group having 3 to 6 carbon atoms. Examples of the C 3-6 cycloalkenyl group include a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.
　Ｃ２－６アルキニル基とは、炭素数２～６のアルキニル基を意味する。Ｃ２－６アルキニル基としては、例えば、エチニル基、プロパルギル基および３－ブチン－１－イル基が挙げられる。 The C 2-6 alkynyl group means an alkynyl group having 2 to 6 carbon atoms. Examples of the C 2-6 alkynyl group include an ethynyl group, a propargyl group, and a 3-butyn-1-yl group.
　Ｃ６－１０アリール基とは、炭素数６～１０のアリール基を意味する。Ｃ６－１０アリール基としては、例えば、フェニル基およびナフチル基が挙げられる。 The C 6-10 aryl group means an aryl group having 6 to 10 carbon atoms. Examples of the C 6-10 aryl group include a phenyl group and a naphthyl group.
　Ｃ１－６アルキル基、Ｃ３－６シクロアルキル基、Ｃ２－６アルケニル基、Ｃ３－６シクロアルケニル基、Ｃ２－６アルキニル基およびＣ６－１０アリール基は、それぞれ無置換であっても、置換基を有していてもよい。置換基としては、Ｃ１－４アルキル基、Ｃ２－４アルケニル基、Ｃ２－４アルキニル基、Ｃ１－４アルコキシ基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子が挙げられる。Ｃ１－４アルコキシ基としては、例えば、メトキシ基、エトキシ基、プロピルオキシ基およびブトキシ基が挙げられる。 The C 1-6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkenyl group, C 3-6 cycloalkenyl group, C 2-6 alkynyl group and C 6-10 aryl group are each unsubstituted. Alternatively, it may have a substituent. Substituents include C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, amino group, imino group, nitro group, hydroxy group, oxo group, nitrile group , A mercapto group or a halogen atom. Examples of the C 1-4 alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, and a butoxy group.
　化合物（１）としては、例えば、Ｃｉｓ－２，３－エポキシブタンが挙げられる。 Examples of the compound (1) include Cis-2,3-epoxybutane.
　また、化合物（１）の代わりに、Ｘが－Ｓ－であるチイラン構造を有する化合物を用いてもよい。チイラン構造を有する化合物を用いた場合、１，２－メルカプトアミン、１，２－メルカプトアルコール、１，２－ジチオールを得ることができる。 Further, instead of the compound (1), a compound having a thiirane structure in which X is —S— may be used. When a compound having a thiirane structure is used, 1,2-mercaptoamine, 1,2-mercaptoalcohol, and 1,2-dithiol can be obtained.
　また、化合物（１）は、化合物（１ｂ）であってもよい。
Figure JPOXMLDOC01-appb-C000018
 　式中、Ｘ、Ｒ１およびＲ４は、上記定義と同一であり、Ｒ７は、Ｒ２およびＲ３が互いに結合して形成される基を示す。 In addition, the compound (1) may be the compound (1b).
Figure JPOXMLDOC01-appb-C000018
 In the formula, X, R 1 and R 4 are the same as defined above, and R 7 represents a group formed by combining R 2 and R 3 with each other.
　式（１ｂ）中、Ｘは、－Ｏ－または－ＮＲ－を示し、Ｒ７は、Ｒ２およびＲ３が互いに結合して形成される基を示す。Ｒ２およびＲ３が互いに結合して形成される基とは、Ｒ２またはＲ３が置換基を有している場合、当該置換基を介して接続されるように結合してもよい。すなわち、Ｒ７は、Ｃ１－６アルキレン基、Ｃ２－６アルケニレン基、Ｃ２－６アルキニレン基およびＣ６－１０アリーレン基だけでなく、Ｒ２とＲ３とが置換基を介して結合して形成される態様も包含する。 In formula (1b), X represents —O— or —NR—, and R 7 represents a group formed by combining R 2 and R 3 with each other. The groups R 2 and R 3 are bonded to each other to form, when R 2 or R 3 has a substituent, may be coupled to be connected via the substituent. That is, R 7 is not only a C 1-6 alkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group and a C 6-10 arylene group, but R 2 and R 3 are bonded via a substituent. The aspect formed as above is also included.
　Ｃ１－６アルキレン基、Ｃ２－６アルケニレン基、Ｃ２－６アルキニレン基およびＣ６－１０アリーレン基とは、それぞれ式（１）で定義されたＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基およびＣ６－１０アリール基からさらに水素原子を１つ除いてなる基である。 A C 1-6 alkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group and a C 6-10 arylene group are respectively a C 1-6 alkyl group defined by the formula (1), a C 2-6 A group obtained by further removing one hydrogen atom from an alkenyl group, a C 2-6 alkynyl group and a C 6-10 aryl group.
　Ｒ２とＲ３が置換基を介して結合して形成される態様とは、例えば、２－オキサプロピレン基（－ＣＨ２ＯＣＨ２－）、３－オキサペンチレン基（－ＣＨ２ＣＨ２ＯＣＨ２ＣＨ２－）、３－オキソペンチレン基（－ＣＨ２ＣＨ２Ｃ（＝Ｏ）ＣＨ２ＣＨ２－）が挙げられる。 The embodiment in which R 2 and R 3 are bonded via a substituent includes, for example, a 2-oxapropylene group (—CH 2 OCH 2 —), a 3-oxapentylene group (—CH 2 CH 2 OCH 2 CH 2 —) and 3-oxopentylene group (—CH 2 CH 2 C (═O) CH 2 CH 2 —).
　式（１ｂ）で表される化合物の具体例としては、６－オキサビシクロ［３．１．０］ヘキサン、７－オキサビシクロ［４．１．０］ヘプタン、８－オキサビシクロ［５．１．０］オクタンおよび３，６－ジオキサビシクロ［３．１．０］ヘキサンが挙げられる。 Specific examples of the compound represented by the formula (1b) include 6-oxabicyclo [3.1.0] hexane, 7-oxabicyclo [4.1.0] heptane, 8-oxabicyclo [5.1. 0] octane and 3,6-dioxabicyclo [3.1.0] hexane.
＜式（２）で表される化合物（化合物（２））＞
　式（２）において、Ｙは、－Ｏ－、－ＮＲ６－または－Ｓ－である。すなわち、化合物（２）は、アルコール、アミンまたはチオールを意味する。ただし、水および硫化水素は、化合物（２）の範囲から除かれる。
Figure JPOXMLDOC01-appb-C000019
 <Compound represented by formula (2) (compound (2))>
In the formula (2), Y is —O—, —NR 6 — or —S—. That is, the compound (2) means alcohol, amine or thiol. However, water and hydrogen sulfide are excluded from the range of the compound (2).
Figure JPOXMLDOC01-appb-C000019
　また、Ｒ５およびＲ６は、それぞれ独立に、水素原子、Ｃ１－６アルキル基、Ｃ３－６シクロアルキル基、Ｃ２－６アルケニル基、Ｃ３－６シクロアルケニル基、Ｃ２－６アルキニル基またはＣ６－１０アリール基である。 R 5 and R 6 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkenyl group, a C 2-6 An alkynyl group or a C 6-10 aryl group.
　Ｃ１－６アルキル基としては、例えば、メチル基、エチル基、プロパン－１－イル基、プロパン－２－イル基（イソプロピル基）、ブタン－１－イル基、ブタン－２－イル基、ペンタン－１－イル基、ペンタン－２－イル基、ペンタン－３－イル基、ヘキサン－１－イル基、ヘキサン－２－イル基および３－ヘキシル基が挙げられる。 Examples of the C 1-6 alkyl group include a methyl group, an ethyl group, a propan-1-yl group, a propan-2-yl group (isopropyl group), a butan-1-yl group, a butan-2-yl group, and pentane. Examples include a 1-yl group, a pentan-2-yl group, a pentan-3-yl group, a hexane-1-yl group, a hexane-2-yl group, and a 3-hexyl group.
　Ｃ３－６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、シクロヘキシル基が挙げられる。 Examples of the C 3-6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
　Ｃ２－６アルケニル基としては、例えば、ビニル基、１－プロペン－１－イル基、２－プロペン－１－イル基、プロペン－２－イル基、２－ブテン－１－イル基、２－ブテン－２－イル基、３－ブテン－１－イル基、２－ペンテン－１－イル基、３－ペンテン－１－イル基、２－ヘキセン－１－イル基、３－ヘキセン－１－イル基、４－ヘキセン－１－イル基および５－ヘキセン－１－イル基が挙げられる。 Examples of the C 2-6 alkenyl group include a vinyl group, 1-propen-1-yl group, 2-propen-1-yl group, propen-2-yl group, 2-buten-1-yl group, 2- Buten-2-yl group, 3-buten-1-yl group, 2-penten-1-yl group, 3-penten-1-yl group, 2-hexen-1-yl group, 3-hexen-1-yl Groups, 4-hexen-1-yl group and 5-hexen-1-yl group.
　Ｃ３－６シクロアルケニル基としては、例えば、シクロブテニル基、シクロペンテニル基、シクロヘキセニル基が挙げられる。 Examples of the C 3-6 cycloalkenyl group include a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.
　Ｃ２－６アルキニル基としては、例えば、エチニル基、プロパルギル基および３－ブチン－１－イル基が挙げられる。 Examples of the C 2-6 alkynyl group include an ethynyl group, a propargyl group, and a 3-butyn-1-yl group.
　Ｃ６－１０アリール基としては、例えば、フェニル基およびナフチル基が挙げられる。 Examples of the C 6-10 aryl group include a phenyl group and a naphthyl group.
　Ｃ１－６アルキル基、Ｃ３－６シクロアルキル基、Ｃ２－６アルケニル基、Ｃ３－６シクロアルケニル基、Ｃ２－６アルキニル基およびＣ６－１０アリール基は、それぞれ無置換であっても、置換基を有していてもよい。置換基としては、Ｃ１－４アルキル基、Ｃ２－４アルケニル基、Ｃ２－４アルキニル基、Ｃ６－１０アリール基、Ｃ１－４アルコキシ基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子が挙げられる。Ｃ１－４アルコキシ基としては、例えば、メトキシ基、エトキシ基、プロピルオキシ基およびブトキシ基が挙げられる。 The C 1-6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkenyl group, C 3-6 cycloalkenyl group, C 2-6 alkynyl group and C 6-10 aryl group are each unsubstituted. Alternatively, it may have a substituent. Examples of the substituent include C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 6-10 aryl group, C 1-4 alkoxy group, amino group, imino group, nitro group, hydroxy group Group, oxo group, nitrile group, mercapto group or halogen atom. Examples of the C 1-4 alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, and a butoxy group.
　化合物（２）の具体例としては、メタノール、エタノール、１－プロパノール、２－プロパノール（イソプロパノール）、１－ブタノール、２－ブタノール、１－ペンタノール、２－ペンタノール、フェノール、アンモニア、メチルアミン、エチルアミン、プロピルアミン、２－プロピルアミン（イソプロピルアミン）、２－ペンチルアミン、３－ペンチルアミン、シクロプロピルアミン、シクロブチルアミン、シクロペンチルアミン、シクロヘキシルアミン、ｔｅｒｔ－ブチルアミン、アリルアミン、プロパルギルアミン、ベンジルアミン、２－フェニルエチルアミン、アニリン、ジメチルアミン、ジエチルアミン、３－メトキシプロピルアミン、３－エトキシプロピルアミン、メタンチオール、エタンチオール、１－プロパンチオール、２－プロパンチオール、ブタンチオールが挙げられる。 Specific examples of the compound (2) include methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, phenol, ammonia, methylamine, Ethylamine, propylamine, 2-propylamine (isopropylamine), 2-pentylamine, 3-pentylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, tert-butylamine, allylamine, propargylamine, benzylamine, 2 -Phenylethylamine, aniline, dimethylamine, diethylamine, 3-methoxypropylamine, 3-ethoxypropylamine, methanethiol, ethanethiol, 1-propanethiol 2-propanethiol, include butanethiol.
　また、化合物（２）は、化合物（２ａ）であってもよい。
Figure JPOXMLDOC01-appb-C000020
 　式中、Ｒ８は、Ｒ５およびＲ６が互いに結合して形成される基を示す。 In addition, the compound (2) may be the compound (2a).
Figure JPOXMLDOC01-appb-C000020
 In the formula, R 8 represents a group formed by combining R 5 and R 6 with each other.
　式（２ａ）中、Ｒ８は、Ｒ５およびＲ６が互いに結合して形成される基を示す。Ｒ５およびＲ６が互いに結合して形成される基とは、Ｒ５またはＲ６が置換基を有している場合、当該置換基を介して接続されるように結合してもよい。すなわち、Ｒ８は、Ｃ１－６アルキレン基、Ｃ３－６シクロアルキレン基、Ｃ２－６アルケニレン基、Ｃ３－６シクロアルケニレン基、Ｃ２－６アルキニレン基およびＣ６－１０アリーレン基だけでなく、Ｒ５とＲ６が置換基を介して結合して形成される態様も包含する。 In formula (2a), R 8 represents a group formed by combining R 5 and R 6 with each other. The groups R 5 and R 6 are bonded to each other to form, when R 5 or R 6 has a substituent may be attached so as to be connected via the substituent. That is, R 8 is a C 1-6 alkylene group, a C 3-6 cycloalkylene group, a C 2-6 alkenylene group, a C 3-6 cycloalkenylene group, a C 2-6 alkynylene group and a C 6-10 arylene group only. In addition, an embodiment in which R 5 and R 6 are bonded via a substituent is also included.
　Ｃ１－６アルキレン基、Ｃ３－６シクロアルキレン基、Ｃ２－６アルケニレン基、Ｃ３－６シクロアルケニレン基、Ｃ２－６アルキニレン基およびＣ６－１０アリーレン基とは、それぞれ式（２）で定義されたＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基およびＣ６－１０アリール基からさらに水素原子を１つ除いてなる基である。 C 1-6 alkylene group, C 3-6 cycloalkylene group, C 2-6 alkenylene group, C 3-6 cycloalkenylene group, C 2-6 alkynylene group and C 6-10 arylene group are each represented by the formula (2 And a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, and a C 6-10 aryl group defined in (1) above.
　Ｒ５とＲ６が置換基を介して結合して形成される態様とは、例えば、２－オキサプロピレン基（－ＣＨ２ＯＣＨ２－）、３－オキサペンチレン基（－ＣＨ２ＣＨ２ＯＣＨ２ＣＨ２－）、３－オキソペンチレン基（－ＣＨ２ＣＨ２Ｃ（＝Ｏ）ＣＨ２ＣＨ２－）が挙げられる。 An embodiment in which R 5 and R 6 are bonded via a substituent includes, for example, a 2-oxapropylene group (—CH 2 OCH 2 —), a 3-oxapentylene group (—CH 2 CH 2 OCH 2 CH 2 —) and a 3-oxopentylene group (—CH 2 CH 2 C (═O) CH 2 CH 2 —).
　化合物（２ａ）の具体例としては、ピロリジン、ピペリジン、モルホリン、ピペラジン、ホモピペラジン、チオモルホリンである。 Specific examples of the compound (2a) are pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, and thiomorpholine.
　化合物（２）の量は、経済性、回収性を考慮した任意の量を用いることができる。このような量としては、例えば、化合物（１）のモル数に対して０．０１～１００当量、好ましくは０．１～１０当量、更に好ましくは０．５～２当量である。 The amount of the compound (2) can be any amount in consideration of economy and recoverability. Such an amount is, for example, 0.01 to 100 equivalents, preferably 0.1 to 10 equivalents, more preferably 0.5 to 2 equivalents, relative to the number of moles of the compound (1).
＜式（３）で表される化合物（化合物（３））＞
　化合物（３）とは、式（３）で表される化合物であり、式中、Ｘ、Ｙ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７およびＲ８は、上記定義と同一である。
Figure JPOXMLDOC01-appb-C000021
 <Compound represented by formula (3) (compound (3))>
The compound (3) is a compound represented by the formula (3), in which X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are Is the same as defined above.
Figure JPOXMLDOC01-appb-C000021
　また、化合物（１）が化合物（１ｂ）である場合、化合物（２）が化合物（２ａ）である場合を考慮すると、化合物（３）には化合物（３ａ）～（３ｃ）が包含される。
Figure JPOXMLDOC01-appb-C000022
 When the compound (1) is the compound (1b) and the case where the compound (2) is the compound (2a) is considered, the compound (3) includes the compounds (3a) to (3c).
Figure JPOXMLDOC01-appb-C000022
　化合物（３）の具体例としては、１，２－ジオール（ＸおよびＹがともに－Ｏ－である場合）、１，２－アミノアルコール（Ｘが－Ｏ－かつＹが－ＮＨ－である場合、または、Ｘが－ＮＨ－かつＹが－Ｏ－である場合）、１，２－ジアミン（ＸおよびＹがともに－ＮＨ－である場合）、１，２－メルカプトアルコール（Ｘが－Ｏ－かつＹが－Ｓ－である場合）、１，２－メルカプトアミン（Ｘが－ＮＨ－かつＹが－Ｓ－である場合）が挙げられる。 Specific examples of the compound (3) include 1,2-diol (when X and Y are both —O—), 1,2-amino alcohol (when X is —O— and Y is —NH—). Or X is —NH— and Y is —O—), 1,2-diamine (when X and Y are both —NH—), 1,2-mercaptoalcohol (X is —O—). And Y is -S-) and 1,2-mercaptoamine (when X is -NH- and Y is -S-).
＜植物加工物＞
　本明細書において、植物加工物とは、食用植物の一部を加工して得られる粉末または抽出物である。 <Processed plant products>
In the present specification, the processed plant product is a powder or extract obtained by processing a part of an edible plant.
　上記「食用植物」とは、ヒトがその一部を食べることができる植物として、一般的に知られた植物を意味する。食用植物としては、例えば、穀類、豆類、野菜、果物またはいも類に分類される植物であり、食用植物の一部とは、果実全体、果肉、果皮、茎、種子、胚芽、根、球根および葉から適宜選択することができる。食用植物としては、具体的には、マメ科（例えば、大豆、黒豆、赤インゲンマメ、エンドウマメ）、モクセイ科（例えば、オリーブ）、バショウ科（例えば、バナナ）、イネ科（例えば、小麦）、ウリ科（例えば、カボチャ）、ナス科（例えば、トマト、ジャガイモ）、ウルシ科（例えば、ピスタチオ、カシューナッツ）、ショウガ科（例えば、ウコン）、ツバキ科（例えば、茶）、ミカン科（例えば、ナツミカン、柚子、花柚子、ブンタン）、ヒガンバナ科（例えば、ニンニク）、セリ科（例えば、ニンジン）、アブラナ科（例えば、ダイコン）、ハス科（例えば、レンコン）、マタタビ科（例えば、キウイ）、バラ科（例えば、リンゴ）およびネギ科（例えば、ネギ）の植物が挙げられる。食用植物としては、マメ科（例えば、大豆、黒豆、赤インゲンマメ、エンドウマメ）、ツバキ科（例えば、茶）、セリ科（例えば、ニンジン）、マタタビ科（例えば、キウイ）およびユリ科（例えば、ネギ）からなる群から選択されることが好ましい。なお、ネギは、ネギ科として分類される場合もある。 The above “edible plant” means a plant generally known as a plant that a human can eat a part of. The edible plant is, for example, a plant classified into cereals, beans, vegetables, fruits or potatoes, and part of the edible plant is the whole fruit, pulp, pericarp, stem, seed, germ, root, bulb and It can be appropriately selected from leaves. Specific examples of edible plants include legumes (for example, soybeans, black beans, red kidney beans, peas), oleaceae (for example, olives), salamanders (for example, bananas), gramineae (for example, wheat), Cucurbitaceae (for example, pumpkin), solanaceae (for example, tomato, potato), urushiaceae (for example, pistachio, cashew nut), ginger (for example, turmeric), camellia (for example, tea), citrus (for example, Natsumikan) , Eggplant, flower bud, buntan), Amaryllidaceae (eg, garlic), celery family (eg, carrot), Brassicaceae (eg, radish), lotus family (eg, lotus root), matabidae (eg, kiwi), rose Plants of the family (eg apple) and leeks (eg leek) are mentioned. Edible plants include legumes (e.g., soybeans, black beans, red kidney beans, peas), camellia (e.g., tea), serpentaceae (e.g., carrots), matabidae (e.g., kiwi) and lily families (e.g., Preferably selected from the group consisting of leek). In addition, a leek may be classified as a leek family.
　上記「加工」とは、必要に応じて、乾燥する、加熱する、火であぶる、焙煎する、油であげる、発酵させる、不要な部位を除去する等の処理を行った後、粉末状になるまで粉砕すること、あるいは成分を抽出することを意味する。また、上記植物加工物には、食用植物のエキスを抽出した後、乾燥したものを粉砕して得られる粉末も包含される。したがって、上記茶は、緑茶であってもよく、紅茶であってもよい。また、上記大豆は、きな粉であってもよく、納豆であってもよい。 The above-mentioned “processing” means, if necessary, processing such as drying, heating, baking, roasting, oiling, fermenting, removing unnecessary parts, etc. It means to pulverize until it becomes or to extract components. In addition, the processed plant product includes a powder obtained by extracting an extract of an edible plant and then pulverizing a dried product. Therefore, the tea may be green tea or black tea. In addition, the soybean may be kinako or natto.
　植物加工物は、粉末状または液状に加工された状態で市販されたものを使用してもよく、加工された状態で市販されたものを適宜粉末状に粉砕して使用してもよい。市販されたものとしては、きな粉、脱脂大豆粉（例えば、フジプロＦ（不二製油（株）製、商品名）、サンリッチＦ（昭和産業（株）製、商品名）、ソーヤフラワーＦＴ－Ｎ（日清オイリオ（株）製、商品名）、エスサンミート特等（味の素（株）製、商品名）、豊年ソイプロ（Ｊ－オイルミルズ（株）製、商品名）、水溶性大豆多糖類（例えば、ソヤファイブＳ－ＤＮ（不二製油（株）製、商品名）等の大豆加工物を用いることが好ましく、きな粉、ソーヤフラワーＦＴ－ＮまたはソヤファイブＳ－ＤＮを用いることがより好ましい。 The plant processed product may be a commercially available product that has been processed into a powder or liquid state, or a product that has been processed in a processed state may be appropriately pulverized into a powder. Examples of commercially available products include kina flour, defatted soybean flour (for example, Fujipro F (trade name, manufactured by Fuji Oil Co., Ltd.), Sunrich F (trade name, manufactured by Showa Sangyo Co., Ltd.), Soya Flower FT-N ( Nisshin Oilio Co., Ltd., trade name), Essan Meat Special (Ajinomoto Co., trade name), Toyotomi Soipro (J-Oil Mills Co., trade name), water-soluble soybean polysaccharide (for example, It is preferable to use a processed soybean product such as Soya Five S-DN (trade name, manufactured by Fuji Oil Co., Ltd.), and it is more preferable to use Kina Flour, Soya Flower FT-N or Soya Five S-DN.
　植物加工物の量としては、経済性、回収性を考慮した任意の量を用いることができる。このような植物加工物の量としては、例えば、式（１）で表される化合物の質量に対して、質量比で０．０１～１００倍量、好ましくは０．１～１０倍量、更に好ましくは１～５倍量である。 As the amount of the processed plant product, any amount in consideration of economy and recoverability can be used. The amount of such processed plant product is, for example, 0.01 to 100 times, preferably 0.1 to 10 times, and more preferably 0.1 to 10 times the mass of the compound represented by formula (1). The amount is preferably 1 to 5 times.
＜不斉開環反応＞
　本発明の実施形態に係る不斉開環反応は、溶媒中で行ってもよい。溶媒中で行う場合は、化合物（１）および化合物（２）と反応しない溶媒であれば、通常、有機合成化学でよく知られた有機溶媒および水を使用することができる。このような有機溶媒としては、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ヘキサン、シクロヘキサン、ヘプタン等の炭化水素類；ジイソプロピルエーテル、テトラヒドロフラン、メチルｔｅｒｔ－ブチルエーテル、エチルｔｅｒｔ－ブチルエーテル、シクロペンチルメチルエーテル等のエーテル類；酢酸エチル、酢酸ブチル等のエステル類；ジクロロメタン、クロロホルム等のハロゲン化炭化水素類が挙げられる。また、これらの溶媒は、単独で使用してもよく、２種以上を混合して用いてもよい。２種以上を混合して用いる場合は、有機溶媒と水を混合して用いることが好ましく、回収性、安全性、経済性の面からトルエンまたはヘプタンと水との混合溶媒を用いることが特に好ましい。 <Asymmetric ring opening reaction>
The asymmetric ring-opening reaction according to the embodiment of the present invention may be performed in a solvent. When the reaction is carried out in a solvent, an organic solvent and water well known in organic synthetic chemistry can be used as long as the solvent does not react with compound (1) and compound (2). Examples of such organic solvents include aromatic hydrocarbons such as benzene, toluene, and xylene; hydrocarbons such as hexane, cyclohexane, and heptane; diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl tert-butyl ether, and cyclopentyl. Examples include ethers such as methyl ether; esters such as ethyl acetate and butyl acetate; and halogenated hydrocarbons such as dichloromethane and chloroform. These solvents may be used alone or in combination of two or more. When using a mixture of two or more, it is preferable to use a mixture of an organic solvent and water, and it is particularly preferable to use a mixed solvent of toluene or heptane and water from the viewpoint of recoverability, safety and economy. .
　不斉開環反応に使用できる溶媒の量は、単独溶媒、混合溶媒のいずれにおいても経済性を考慮した量で用いることができる。このような溶媒の量は、例えば、化合物（１）の質量に対して、容量比で０～１００倍量、好ましくは０．５～５０倍量、更に好ましくは２～１０倍量である。 The amount of the solvent that can be used in the asymmetric ring-opening reaction can be used in consideration of economic efficiency in either a single solvent or mixed solvent. The amount of such a solvent is, for example, 0 to 100 times, preferably 0.5 to 50 times, more preferably 2 to 10 times the volume of the compound (1) by volume.
　不斉開環反応に使用できる水の含量は、触媒に対して水を質量比で０．０５～１倍量の範囲とすることができ、触媒に対して水を０．２０～０．５０倍量の範囲であることが更に好ましい。このような範囲であれば、反応の変換率および生成物の光学純度がより向上する。 The content of water that can be used for the asymmetric ring-opening reaction can be 0.05 to 1 times the mass of water with respect to the catalyst, and 0.20 to 0.50 of water with respect to the catalyst. More preferably, it is in the range of double amount. Within such a range, the conversion rate of the reaction and the optical purity of the product are further improved.
　反応温度は－２０℃～１００℃が好ましく、特に３０℃～５０℃が好ましい。反応終了後、触媒をろ別することで、対応する化合物（３）を得ることができる。本発明の不斉開環反応を行う際に、ろ別によって回収された触媒を再利用することができる。 The reaction temperature is preferably -20 ° C to 100 ° C, particularly preferably 30 ° C to 50 ° C. After completion of the reaction, the corresponding compound (3) can be obtained by filtering off the catalyst. When carrying out the asymmetric ring-opening reaction of the present invention, the catalyst recovered by filtration can be reused.
　反応時間は、経済性を考慮した任意の変換率が得られる時間まで反応を行うことができる。このような反応時間としては、例えば、１～５００時間、好ましくは１～１００時間、更に好ましくは１～４８時間である。 The reaction time can be reacted until a time when an arbitrary conversion rate considering economic efficiency is obtained. Such a reaction time is, for example, 1 to 500 hours, preferably 1 to 100 hours, and more preferably 1 to 48 hours.
　反応終了後、触媒をろ別することで化合物（３）を得ることができる。得られた化合物（３）は、更に晶析、蒸留等の定法により、容易に精製することもできる。 After completion of the reaction, the compound (3) can be obtained by filtering the catalyst. The obtained compound (3) can also be easily purified by a conventional method such as crystallization or distillation.
　晶析に使用できる溶媒は、通常、有機合成化学で使用される溶媒であれば特に限定されず、ヘキサン、ヘプタン、シクロヘキサン等の炭化水素類；トルエン、ベンゼン、キシレン等の芳香族炭化水素類；ジイソプロピルエーテル、メチルｔｅｒｔ－ブチルエーテル、エチルｔｅｒｔ－ブチルエーテル、シクロペンチルメチルエーテル等のエーテル類などを用いることができ、これらの溶媒を単独または２種以上を混合して用いてもよい。 Solvents that can be used for crystallization are not particularly limited as long as they are usually used in organic synthetic chemistry; hydrocarbons such as hexane, heptane, and cyclohexane; aromatic hydrocarbons such as toluene, benzene, and xylene; Ethers such as diisopropyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, and cyclopentyl methyl ether can be used, and these solvents may be used alone or in admixture of two or more.
　上記溶媒の量は、単独溶媒、混合溶媒のいずれの場合においても、経済性を考慮した量とすることができ、化合物（３）の質量に対して、容量比で０．１～１００倍量、好ましくは０．５～５０倍量、さらに好ましくは１～１０倍量である。 The amount of the above-mentioned solvent can be set in consideration of economic efficiency in either case of a single solvent or a mixed solvent, and is 0.1 to 100 times by volume with respect to the mass of the compound (3). The amount is preferably 0.5 to 50 times, more preferably 1 to 10 times.
＜塩形成反応＞
　本発明により得られた化合物（３）は、有機合成化学で通常使用される無機酸または有機酸と、塩を形成することにより、光学純度を高めることができる。上記酸としては、例えば、塩酸、硫酸、亜硫酸、硝酸、過塩素酸、塩素酸、ヨウ素酸、リン酸等の無機酸；ギ酸、酢酸、乳酸、シュウ酸、クエン酸、マレイン酸、フマル酸、安息香酸、フタル酸、サリチル酸、メタンスルホン酸、トルエンスルホン酸等の有機酸が挙げられる。 <Salt formation reaction>
The compound (3) obtained by the present invention can increase the optical purity by forming a salt with an inorganic acid or an organic acid usually used in organic synthetic chemistry. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, sulfurous acid, nitric acid, perchloric acid, chloric acid, iodic acid, and phosphoric acid; formic acid, acetic acid, lactic acid, oxalic acid, citric acid, maleic acid, fumaric acid, Organic acids such as benzoic acid, phthalic acid, salicylic acid, methanesulfonic acid, toluenesulfonic acid and the like can be mentioned.
　化合物（３）の光学純度を高めるために、光学活性な酸との塩を形成させてもよい。上記光学活性な酸としては、例えば、酒石酸、リンゴ酸、マンデル酸、フェニルグリシン等が挙げられ、上記酸は置換されているものであってもよい。 In order to increase the optical purity of the compound (3), a salt with an optically active acid may be formed. Examples of the optically active acid include tartaric acid, malic acid, mandelic acid, phenylglycine and the like, and the acid may be substituted.
　塩を形成する際の溶媒としては経済性、回収性等を考慮して、有機合成化学で通常使用される溶媒を用いることができる。上記溶媒としては、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ヘキサン、シクロヘキサン、ヘプタン等の炭化水素類；ジイソプロピルエーテル、テトラヒドロフラン、メチルｔｅｒｔ－ブチルエーテル、エチルｔｅｒｔ－ブチルエーテル、シクロペンチルメチルエーテル等のエーテル類；酢酸エチル、酢酸ブチル等のエステル類；ジクロロメタン、クロロホルム等のハロゲン化炭化水素類；メタノール、エタノール、イソプロパノール等のアルコール類；水等を挙げることができ、これらの溶媒を単独または２種以上混合してもよい。 As a solvent for forming a salt, a solvent usually used in organic synthetic chemistry can be used in consideration of economy and recoverability. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; hydrocarbons such as hexane, cyclohexane and heptane; diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl tert-butyl ether, cyclopentyl methyl ether and the like. Ethers such as ethyl acetate and butyl acetate; halogenated hydrocarbons such as dichloromethane and chloroform; alcohols such as methanol, ethanol and isopropanol; water and the like. More than one species may be mixed.
　塩を形成する際に使用する溶媒の量は、単独溶媒、混合溶媒のいずれにおいても経済性を考慮した量で用いることができる。上記溶媒の量は、例えば、化合物（１）の質量に対して、容量比で０～１００倍量、好ましくは０．５～５０倍量、更に好ましくは２～１０倍量である。 The amount of the solvent used when forming the salt can be used in an amount taking into consideration economic efficiency in either a single solvent or a mixed solvent. The amount of the solvent is, for example, 0 to 100 times, preferably 0.5 to 50 times, more preferably 2 to 10 times the volume of the compound (1) by volume.
　塩形成反応において、より高純度の化合物（３）を得るために、当業者によく知られた方法により、精製することができる。 In the salt formation reaction, the compound (3) having a higher purity can be purified by a method well known to those skilled in the art.
＜医薬候補化合物への応用＞
　本発明で得られる（１Ｒ，２Ｒ）－２－シクロプロピルアミノ－１－シクロヘキサノール（以下、「化合物Ａ」ともいう。）は、６－（３－アミノプロポキシ）－２（１Ｈ）－キノリノン（以下、「化合物Ｂ」ともいう。）と反応させることにより、（－）－６－〔３－〔３－シクロプロピル－３－〔（１Ｒ，２Ｒ）－２－ヒドロキシシクロヘキシル〕ウレイド〕－プロポキシ〕－２（１Ｈ）－キノリノンを製造することができる。 <Application to drug candidate compounds>
(1R, 2R) -2-cyclopropylamino-1-cyclohexanol (hereinafter also referred to as “compound A”) obtained in the present invention is 6- (3-aminopropoxy) -2 (1H) -quinolinone ( Hereinafter, (−)-6- [3- [3-cyclopropyl-3-[(1R, 2R) -2-hydroxycyclohexyl] ureido] -propoxy] is reacted with “compound B”). -2 (1H) -quinolinone can be produced.
　（－）－６－〔３－〔３－シクロプロピル－３－〔（１Ｒ，２Ｒ）－２－ヒドロキシシクロヘキシル〕ウレイド〕－プロポキシ〕－２（１Ｈ）－キノリノンは、インビボ（ｉｎ　ｖｉｖｏ）での強い抗血栓作用および血管内皮肥厚抑制作用の２つの作用を有する物質であり、血小板凝集抑制作用、血小板塊解離作用、脳および末梢血管増加作用等を有している。したがって、（－）－６－〔３－〔３－シクロプロピル－３－〔（１Ｒ，２Ｒ）－２－ヒドロキシシクロヘキシル〕ウレイド〕－プロポキシ〕－２（１Ｈ）－キノリノンは、血栓性疾患や動脈硬化性疾患の治療および予防に有用である。 (−)-6- [3- [3-Cyclopropyl-3-[(1R, 2R) -2-hydroxycyclohexyl] ureido] -propoxy] -2 (1H) -quinolinone is obtained in vivo. It is a substance having two actions of a strong antithrombotic action and a vascular endothelial thickening inhibiting action, and has a platelet aggregation inhibiting action, a platelet mass dissociating action, a brain and peripheral blood vessel increasing action and the like. Therefore, (−)-6- [3- [3-cyclopropyl-3-[(1R, 2R) -2-hydroxycyclohexyl] ureido] -propoxy] -2 (1H) -quinolinone is useful for thrombotic diseases and arteries. Useful for the treatment and prevention of sclerotic diseases.
　化合物Ａおよび化合物Ｂから（－）－６－〔３－〔３－シクロプロピル－３－〔（１Ｒ，２Ｒ）－２－ヒドロキシシクロヘキシル〕ウレイド〕－プロポキシ〕－２（１Ｈ）－キノリノンを製造する方法としては、公知の方法を用いることができる。公知の方法とは、例えば、特許文献４に記載の方法である。 (-)-6- [3- [3-Cyclopropyl-3-[(1R, 2R) -2-hydroxycyclohexyl] ureido] -propoxy] -2 (1H) -quinolinone is produced from Compound A and Compound B. As the method, a known method can be used. A well-known method is a method of patent document 4, for example.
　化合物Ａおよび化合物Ｂを反応させる際には、下記式（Ｅｑ．１）のように、予め化合物Ａおよびカルボニル化試薬を反応させた後に、化合物Ｂを反応させることができる。化合物Ａおよびカルボニル化試薬を反応させた後に、反応生成物を精製してもよい。
Figure JPOXMLDOC01-appb-C000023
 ［式中、Ｒはカルボニル化試薬の残基を意味する。］ When reacting Compound A and Compound B, Compound B can be reacted after reacting Compound A and a carbonylating reagent in advance as shown in the following formula (Eq.1). The reaction product may be purified after reacting Compound A and the carbonylating reagent.
Figure JPOXMLDOC01-appb-C000023
 [Wherein R represents a residue of the carbonylation reagent. ]
　反応（ｉ）は、無溶媒または溶媒中で行うことができる。反応（ｉ）で使用できる溶媒としては、例えば、ジオキサン、テトラヒドロフラン、ジエチルエーテル等のエーテル類；ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジクロロメタン、クロロホルム等のハロゲン化炭化水素類；メタノール、エタノール、イソプロパノール等のアルコール類；Ｎ，Ｎ－ジメチルホルムアミド、アセトン、ジメチルスルホキシド、アセトニトリル、水等の極性溶媒が挙げられる。これらの溶媒は単独で用いてもよく、２種以上を混合して用いてもよい。 Reaction (i) can be carried out without solvent or in a solvent. Examples of the solvent that can be used in the reaction (i) include ethers such as dioxane, tetrahydrofuran, and diethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; methanol, Examples include alcohols such as ethanol and isopropanol; polar solvents such as N, N-dimethylformamide, acetone, dimethyl sulfoxide, acetonitrile, and water. These solvents may be used alone or in combination of two or more.
　上記カルボニル化試薬には、例えば、クロロぎ酸フェニル等のクロロぎ酸エステル、炭酸ジエチル等の炭酸エステル、カルボニルジイミダゾール、ホスゲン、トリホスゲンが挙げられる。 Examples of the carbonylation reagent include chloroformate such as phenyl chloroformate, carbonate such as diethyl carbonate, carbonyldiimidazole, phosgene, and triphosgene.
　反応（ｉ）は、通常、－２０～１５０℃で行われ、好ましくは－２０～１００℃である。 Reaction (i) is usually performed at −20 to 150 ° C., preferably −20 to 100 ° C.
　反応（ｉ）は、塩基性化合物の存在下または非存在下で行うことができる。反応（ｉ）で使用できる塩基性化合物としては、炭酸カリウム、炭酸ナトリウム、水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム、水素化ナトリウム等の無機塩基；トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、イミダゾール、ピリジン等の有機塩基などを用いることができる。 Reaction (i) can be performed in the presence or absence of a basic compound. Examples of basic compounds that can be used in the reaction (i) include inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium hydride; triethylamine, N, N-diisopropylethylamine, imidazole, An organic base such as pyridine can be used.
　反応（ｉ）には、反応をより効率よく進行させるために、さらに添加剤を使用してもよい。このような添加剤の例には、ヨウ化カリウム、ヨウ化ナトリウム、イミダゾール、４－ジメチルアミノピリジン、４－ピロリジノピリジン等が挙げられる。 In the reaction (i), an additive may be further used in order to advance the reaction more efficiently. Examples of such additives include potassium iodide, sodium iodide, imidazole, 4-dimethylaminopyridine, 4-pyrrolidinopyridine and the like.
　反応（ｉｉ）は、無溶媒または溶媒中で行うことができる。反応（ｉｉ）で使用できる溶媒には、反応（ｉ）で挙げた溶媒を使用することができる。 Reaction (ii) can be carried out without solvent or in a solvent. As the solvent that can be used in the reaction (ii), the solvents mentioned in the reaction (i) can be used.
　反応（ｉｉ）は、通常、－２０～１５０℃で行われ、好ましくは－２０～１００℃である。 The reaction (ii) is usually performed at −20 to 150 ° C., preferably −20 to 100 ° C.
　反応（ｉｉ）は、塩基性化合物の存在下または非存在下で行うことができる。反応（ｉｉ）で使用できる塩基性化合物には、反応（ｉ）で挙げた塩基性化合物を使用することができる。 Reaction (ii) can be performed in the presence or absence of a basic compound. As the basic compound that can be used in the reaction (ii), the basic compounds mentioned in the reaction (i) can be used.
　また、下記式（Ｅｑ．２）のように、予め化合物Ｂおよびカルボニル化試薬を反応させた後に、化合物Ａを反応させてもよい。この場合、各工程は式（Ｅｑ．１）のときと同様の方法により、行うことができる。
Figure JPOXMLDOC01-appb-C000024
 ［式中、Ｒはカルボニル化試薬の残基を意味する。］ Moreover, like the following formula (Eq.2), compound A may be reacted after reacting compound B and a carbonylating reagent in advance. In this case, each step can be performed by the same method as in the case of formula (Eq.1).
Figure JPOXMLDOC01-appb-C000024
 [Wherein R represents a residue of the carbonylation reagent. ]
　本発明に用いる化合物Ｂは、保護された化合物Ｂであってもよい。保護された化合物Ｂは、キノリノンの１位が保護基で置換されているものを用いることができる。このような保護基としては、例えば、メトキシメチル基、ベンジル基等のアルキル基；トリエチルシリル基、トリフェニルシリル基等の置換シリル基、アセチル基、トリフルオロアセチル基等の置換アシル基、ｔｅｒｔ－ブトキシカルボニル基等のアルコキシカルボニル基などが挙げられる。 The compound B used in the present invention may be a protected compound B. As the protected compound B, one in which the 1-position of quinolinone is substituted with a protecting group can be used. Examples of such protecting groups include alkyl groups such as methoxymethyl group and benzyl group; substituted silyl groups such as triethylsilyl group and triphenylsilyl group; substituted acyl groups such as acetyl group and trifluoroacetyl group; Examples thereof include alkoxycarbonyl groups such as butoxycarbonyl group.
　また、保護された化合物Ｂとして、２位が置換された６－（３－アミノプロポキシ）－キノリンを用いることもできる。２位が置換された６－（３－アミノプロポキシ）－キノリンの置換基は、例えば、フッ素原子、塩素原子、臭素原子等のハロゲン原子；メトキシ基、メトキシメトキシ基等のアルコキシ基；ベンジルオキシ基等のアリールアルキルオキシ基；アセトキシ基、ピバロイルオキシ基等のアシルオキシ基；トリエチルシリルオキシ基等のシリルオキシ基などが挙げられる。 Further, 6- (3-aminopropoxy) -quinoline substituted at the 2-position can also be used as the protected compound B. The substituent of 6- (3-aminopropoxy) -quinoline substituted at the 2-position is, for example, a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom; an alkoxy group such as a methoxy group or a methoxymethoxy group; a benzyloxy group Arylalkyloxy groups such as acetoxy group, pivaloyloxy group and other acyloxy groups; triethylsilyloxy group and other silyloxy groups.
　保護された化合物Ｂを反応に用いた場合、反応後に公知の方法によって脱保護し、（－）－６－〔３－〔３－シクロプロピル－３－〔（１Ｒ，２Ｒ）－２－ヒドロキシシクロヘキシル〕ウレイド〕－プロポキシ〕－２（１Ｈ）－キノリノンへと変換することもできる。このような脱保護の条件としては、プロテクティブ　グループス　イン　オーガニック　シンセシス（Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）、Ｊｏｈｎ　Ｗｉｌｅｙ　ａｎｄ　Ｓｏｎｓ刊（１９８０）に記載の方法を使用することができ、例えば、酸性条件、アルカリ性条件、水素添加が挙げられる。 When protected compound B is used in the reaction, it is deprotected by a known method after the reaction, and (−)-6- [3- [3-cyclopropyl-3-[(1R, 2R) -2-hydroxycyclohexyl] is used. It can also be converted to ureido] -propoxy] -2 (1H) -quinolinone. As such deprotection conditions, the methods described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980) can be used. For example, acidic conditions and alkaline conditions And hydrogenation.
　以下、本発明を実施例、参考例により具体的に説明するが、本発明はその要旨を超えない限り、以下の実施例に限定されるものではない。 Hereinafter, the present invention will be specifically described with reference to examples and reference examples. However, the present invention is not limited to the following examples unless it exceeds the gist.
　合成した化合物は、テトラメチルシランを内部標準とした１Ｈ－ＮＭＲおよび１３Ｃ－ＮＭＲスペクトルにより、その構造式を決定した。データは、内部標準として用いたＴＭＳ（テトラメチルシラン）を０ｐｐｍとしたときの化学シフト値（δ）を記載した。また、水酸基およびアミノ基等の幅広いピークの場合は、記載していない。 The structural formula of the synthesized compound was determined by 1 H-NMR and 13 C-NMR spectra using tetramethylsilane as an internal standard. The data described the chemical shift value (δ) when TMS (tetramethylsilane) used as an internal standard was 0 ppm. In addition, in the case of broad peaks such as a hydroxyl group and an amino group, it is not described.
　明細書中で用いられる「変換率」とは、下記式に基づいて算出した値である。変換率の算出方法は、具体的には、次のとおりである。まず、植物加工物の存在下、化合物（１）と化合物（２）との反応を行った際の反応液を少量採取する。次に、ガスクロマトグラフィーを用いて採取した反応液を測定し、化合物（１）および化合物（３）の各ピーク面積を得る。得られた各ピーク面積から、有効炭素数法（ＥＣＮ）によって化合物（１）と化合物（３）のモル比を算出し、下記式に基づいて算出した値である。なお、有効炭素数法（ＥＣＮ）とは、例えば、Ｇａｓ　Ｃｈｒｏｍａｔｏｇｒａｐｈｙ，Ａｃａｄｅｍｉｃ　Ｐｒｅｓｓ，ＮｅｗＹｏｒｋ，１９６２，ｐ２０７および分析化学便覧改訂５版（村田誠四郎、日本分析化学会編、丸善（株））に記載の方法である。例えば、７－オキサビシクロ［４．１．０］ヘプタンの有効炭素数は、５．００であり、２－シクロプロピルアミノ－１－シクロヘキサノールの有効炭素数は、７．５０である。
変換率（％）＝１００×化合物（３）のモル数／（化合物（１）のモル数＋化合物（３）のモル数） The “conversion rate” used in the specification is a value calculated based on the following formula. Specifically, the conversion rate calculation method is as follows. First, a small amount of a reaction solution is collected when the reaction between the compound (1) and the compound (2) is performed in the presence of the processed plant product. Next, the reaction solution collected using gas chromatography is measured to obtain the peak areas of compound (1) and compound (3). From the obtained peak areas, the molar ratio of the compound (1) and the compound (3) is calculated by the effective carbon number method (ECN), and is a value calculated based on the following formula. The effective carbon number method (ECN) is described in, for example, Gas Chromatography, Academic Press, New York, 1962, p207 and the Analytical Chemistry Handbook 5th edition (Seishiro Murata, edited by Japan Analytical Chemical Society, Maruzen Co., Ltd.) It is a method. For example, the effective carbon number of 7-oxabicyclo [4.1.0] heptane is 5.00, and the effective carbon number of 2-cyclopropylamino-1-cyclohexanol is 7.50.
Conversion rate (%) = 100 × number of moles of compound (3) / (number of moles of compound (1) + number of moles of compound (3))
　光学純度は、鏡像体過剰率（％ｅｅ）を算出して記載した。測定条件は以下のとおりである。 Optical purity was described by calculating the enantiomeric excess (% ee). The measurement conditions are as follows.
　「選択率（％ｅｅ）」は、特記しない限り、ガスクロマトグラフィー（ＧＣ）を用いて測定した後、ピーク面積の比から、下記式に基づいて計算した。すなわち、選択率が負の値の場合は、「短いＧＣ保持時間のピーク面積」の値が「長いＧＣ保持時間のピーク面積」の値より大きかったことを示す。なお、「選択率（Ｒ，Ｒ）％ｅｅ」と記載されている場合は、（Ｒ，Ｒ）体の選択率を示す。
選択率（％ｅｅ）＝１００×｛（保持時間が長いピークのピーク面積）－（保持時間が短いピークのピーク面積）｝／｛（保持時間が長いピークのピーク面積）＋（保持時間が短いピークのピーク面積）｝ The “selectivity (% ee)” was calculated based on the following formula from the ratio of peak areas after measurement using gas chromatography (GC) unless otherwise specified. That is, when the selectivity is a negative value, it indicates that the value of “peak area of short GC holding time” is larger than the value of “peak area of long GC holding time”. When “selectivity (R, R)% ee” is described, the selectivity for (R, R) isomers is indicated.
Selectivity (% ee) = 100 × {(peak area of peak with long retention time) − (peak area of peak with short retention time)} / {(peak area of peak with long retention time) + (short retention time) Peak area)}
分析条件
（１）ガスクロマトグラフィー法
　得られた化合物の分析条件は、表１に記載の条件で測定した。なお、全ての分析条件に共通する事項は、下記共通条件に記載のとおりである。
共通条件
キャリアガス：ヘリウム
検出器：水素炎イオン化検出器
圧力：９４ｋＰａ
気化室温度：２２０℃
検出器温度：３００℃
スプリット比：　１：１５０
注入量：０．５μＬ
サンプル前処理：試料約１ｍｇをジクロロメタンに溶解し、塩化トリメチルシランとトリエチルアミンを加え撹拌し、不溶物をろ過した。
カラム：
ＢＥＴＡＤＥＸ　１２０（長さ：３０ｍ、内径：０．２５μｍ、Ｓｕｐｅｌｃｏ社製）
ＣＰ－ＣＨＩＲＡＳＩＬ－ＤＥＸ　ＣＢ（長さ：２５ｍ、内径：０．２５ｍｍ、膜厚：０．２５μｍ、ＶＡＲＩＡＮ社製）
Figure JPOXMLDOC01-appb-T000025
 Analysis Conditions (1) Gas Chromatography Method The analysis conditions of the obtained compound were measured under the conditions described in Table 1. Items common to all analysis conditions are as described in the following common conditions.
Common conditions Carrier gas: Helium detector: Hydrogen flame ionization detector Pressure: 94 kPa
Vaporization chamber temperature: 220 ° C
Detector temperature: 300 ° C
Split ratio: 1: 150
Injection volume: 0.5 μL
Sample pretreatment: About 1 mg of a sample was dissolved in dichloromethane, trimethylsilane chloride and triethylamine were added and stirred, and insoluble matter was filtered off.
column:
BETADEX 120 (length: 30 m, inner diameter: 0.25 μm, manufactured by Supelco)
CP-CHIRASIL-DEX CB (length: 25 m, inner diameter: 0.25 mm, film thickness: 0.25 μm, manufactured by Varian)
Figure JPOXMLDOC01-appb-T000025
（２）液体クロマトグラフィー法
　得られた化合物の分析条件は、表２に記載の条件で測定した。なお、全ての分析条件に共通する事項は、下記共通条件に記載のとおりである。
共通条件
注入量：５μＬ
検出器：紫外吸光検出器（波長２５４ｎｍ）
カラム：
ＣＨＩＲＡＬＣＥＬ　ＯＢ－Ｈ（４．６×２５０ｍｍ、株式会社ダイセル製）
ＣＨＩＲＡＬＰＡＫ　ＡＳ－ＲＨ（４．６×１５０ｍｍ、株式会社ダイセル製）
ＣＨＩＲＡＬＣＥＬ　ＯＤ－Ｈ（４．６×２５０ｍｍ、株式会社ダイセル製）
Figure JPOXMLDOC01-appb-T000026
 (2) Liquid Chromatography Method The analysis conditions of the obtained compound were measured under the conditions described in Table 2. Items common to all analysis conditions are as described in the following common conditions.
Common condition injection volume: 5 μL
Detector: UV absorption detector (wavelength 254 nm)
column:
CHIRALCEL OB-H (4.6 × 250mm, manufactured by Daicel Corporation)
CHIRALPAK AS-RH (4.6 × 150mm, manufactured by Daicel Corporation)
CHIRALCEL OD-H (4.6 × 250mm, manufactured by Daicel Corporation)
Figure JPOXMLDOC01-appb-T000026
　分析の為のラセミ体合成と分析方法は、以下の参考例に示した。 The racemic synthesis and analysis method for analysis are shown in the following reference examples.
参考例１　ｔｒａｎｓ－２－（イソプロピルアミノ）シクロヘキサノール合成
　５０ｍＬナスフラスコに７－オキサビシクロ［４．１．０］ヘプタン　１．４５ｇとイソプロピルアミン０．８７ｇを量りとり、メタノール８ｍＬと水２ｍＬ、塩化リチウム０．１３ｇを加え、５０℃で４８時間反応した。反応後、減圧下に濃縮し、粗体を得た。粗体は柴田科学社製ガラスチューブオーブンＧＴＯ－２５０ＲＳ（クーゲルロール）で減圧蒸留し、ｔｒａｎｓ－２－（イソプロピルアミノ）シクロヘキサノールを１．２６ｇ得た。（外浴温度１３５－１４０℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．８２－０．９４（ｍ，１Ｈ），　１．００（ｄ，Ｊ＝６．３１Ｈｚ，３Ｈ），　１．０６（ｄ，Ｊ＝６．３１Ｈｚ，３Ｈ），　１．２０－１．３１（ｍ，３Ｈ），　１．６９－１．７３（ｍ，２Ｈ），　２．０６－２．１０（ｍ，２Ｈ），　２．１８－２．２６（ｍ，１Ｈ），　２．９６（ｓｅｐ，Ｊ＝６．３１Ｈｚ，１Ｈ），３．０９（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２２．７９（ＣＨ３），　２４．２８（ＣＨ２），　２４．７３（ＣＨ３），　２５．３６（ＣＨ２），　３１．２９（ＣＨ２），　３２．９８（ＣＨ２），　４５．０５（ＣＨ），　６０．６４（ＣＨ），　７３．８７（ＣＨ）
分析条件Ａ　保持時間　１２．９分、１３．２分 Reference Example 1 trans-2- (isopropylamino) cyclohexanol synthesis 1.45 g of 7-oxabicyclo [4.1.0] heptane and 0.87 g of isopropylamine were weighed into a 50 mL eggplant flask, 8 mL of methanol, 2 mL of water, and chloride. 0.13 g of lithium was added and reacted at 50 ° C. for 48 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was distilled under reduced pressure in a glass tube oven GTO-250RS (Kugel Roll) manufactured by Shibata Kagaku Co., Ltd. to obtain 1.26 g of trans-2- (isopropylamino) cyclohexanol. (Outer bath temperature 135-140 ° C, pressure 0.1mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.82-0.94 (m, 1H), 1.00 (d, J = 6.31 Hz, 3H), 1.06 (d, J = 6 .31 Hz, 3H), 1.20-1.31 (m, 3H), 1.69-1.73 (m, 2H), 2.06-2.10 (m, 2H), 2.18-2 .26 (m, 1H), 2.96 (sep, J = 6.31 Hz, 1H), 3.09 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 22.79 (CH3), 24.28 (CH2), 24.73 (CH3), 25.36 (CH2), 31.29 (CH2), 32. 98 (CH2), 45.05 (CH), 60.64 (CH), 73.87 (CH)
Analysis condition A Retention time 12.9 minutes, 13.2 minutes
参考例２　ｔｒａｎｓ－２－（シクロプロピルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、シクロプロピルアミンを用いる他は全て参考例１と同様に操作した。得られた粗体はそのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．１９－０．５５（ｍ、４Ｈ），０．９４－１．０７（ｍ，１Ｈ），１．１８－１．３０（ｍ，３Ｈ），１．７１－１．７６（ｍ，２Ｈ），２．００－２．０６（ｍ，１Ｈ），２．１９－２．３６（ｍ，３Ｈ），３．０６－３．１４（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　５．６９（ＣＨ２），７．２２（ＣＨ２），２４．１９（ＣＨ２），２４．８５（ＣＨ２），２７．５０（ＣＨ），３０．７１（ＣＨ２），３３．２６（ＣＨ２），６３．５４（ＣＨ），７２．９４（ＣＨ）
分析条件Ｂ　保持時間　（Ｓ，Ｓ）体：２６．９分、（Ｒ，Ｒ）体：２７．４分 Reference Example 2 synthesis of trans-2- (cyclopropylamino) cyclohexanol All operations were performed in the same manner as Reference Example 1 except that cyclopropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.19-0.55 (m, 4H), 0.94-1.07 (m, 1H), 1.18-1.30 (m, 3H) ), 1.71-1.76 (m, 2H), 2.00-2.06 (m, 1H), 2.19-2.36 (m, 3H), 3.06-3.14 (m , 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 5.69 (CH2), 7.22 (CH2), 24.19 (CH2), 24.85 (CH2), 27.50 (CH), 30. 71 (CH2), 33.26 (CH2), 63.54 (CH), 72.94 (CH)
Analysis condition B Retention time (S, S) isomer: 26.9 minutes, (R, R) isomer: 27.4 minutes
参考例３　ｔｒａｎｓ－２－（プロピルアミノ）シクロヘキサンノール合成
　イソプロピルアミンに代えて、プロピルアミンを用いる他は全て参考例１と同様に操作した。（外浴温度１１５－１２０℃、圧力０．２ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．９０－０．９９（ｍ，４Ｈ），１．２１－１．２９（ｍ，３Ｈ），１．４２－１．５５（ｍ，２Ｈ），１．７１－１．７３（ｍ，２Ｈ），２．０２－２．２２（ｍ，３Ｈ），２．３９－２．４７（ｍ，１Ｈ），２．７０－２．７９（ｍ，１Ｈ），３．１０－３．１８（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　１１．６９（ＣＨ３），２３．６０（ＣＨ２），２４．３９（ＣＨ２），２５．０３（ＣＨ２），３０．４３（ＣＨ２），３３．５２（ＣＨ２），４８．５４（ＣＨ２），６３．４７（ＣＨ），　７３．４６（ＣＨ）
分析条件Ｂ　保持時間　２０．０分、２０．３分 Reference Example 3 trans-2- (Propylamino) cyclohexaneanol synthesis All operations were performed in the same manner as Reference Example 1 except that propylamine was used instead of isopropylamine. (Outer bath temperature 115-120 ° C, pressure 0.2mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.90-0.99 (m, 4H), 1.21-1.29 (m, 3H), 1.42-1.55 (m, 2H) ), 1.71-1.73 (m, 2H), 2.02-2.22 (m, 3H), 2.39-2.47 (m, 1H), 2.70-2.79 (m , 1H), 3.10-3.18 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 11.69 (CH3), 23.60 (CH2), 24.39 (CH2), 25.03 (CH2), 30.43 (CH2), 33. 52 (CH2), 48.54 (CH2), 63.47 (CH), 73.46 (CH)
Analysis condition B Retention time 20.0 minutes, 20.3 minutes
参考例４　ｔｒａｎｓ－２－（３－ペンチルアミノ）シクロヘキサノール合成
　イソプロピルアミンに替えて、３－アミノペンタンを用いる他は全て参考例１と同様に操作した。（外浴温度１５０－１５５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．８３－０．９４（ｍ，７Ｈ），１．２０－１．５６（ｍ，７Ｈ），１．６９－１．７３（ｍ，２Ｈ），２．０５－２．０９（ｍ，２Ｈ），２．１４－２．２２（ｍ，１Ｈ），２．４４－２．５２（ｍ，１Ｈ），３．０２－３．１０（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　８．９９（ＣＨ３），１０．２６（ＣＨ３），２４．２８（ＣＨ２），２５．４０（ＣＨ２），２６．１９（ＣＨ２），２６．８９（ＣＨ２），３１．４１（ＣＨ２），３２．８９（ＣＨ２），５６．７６（ＣＨ），６１．１４（ＣＨ），７４．１２（ＣＨ）
分析条件Ｂ　保持時間　３０．３分、３１．３分 Reference Example 4 synthesis of trans-2- (3-pentylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that 3-aminopentane was used instead of isopropylamine. (Outer bath temperature 150-155 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.83-0.94 (m, 7H), 1.20-1.56 (m, 7H), 1.69-1.73 (m, 2H) ), 2.05 to 2.09 (m, 2H), 2.14 to 2.22 (m, 1H), 2.44 to 2.52 (m, 1H), 3.02 to 3.10 (m) , 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 8.99 (CH3), 10.26 (CH3), 24.28 (CH2), 25.40 (CH2), 26.19 (CH2), 26. 89 (CH2), 31.41 (CH2), 32.89 (CH2), 56.76 (CH), 61.14 (CH), 74.12 (CH)
Analysis condition B Retention time 30.3 minutes, 31.3 minutes
参考例５　ｔｒａｎｓ－２－（ｔｅｒｔ－ブチルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、ｔｅｒｔ－ブチルアミンを用いる他は全て参考例１と同様に操作した。（外浴温度１００－１０５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．９０－１．１９（ｍ，１Ｈ），１．１３（ｓ，９Ｈ），１．２４－１．３２（ｍ，３Ｈ），１．６７－１．７１（ｍ，２Ｈ），１．９８－２．０７（ｍ，２Ｈ），２．１９－２．２７（ｍ，１Ｈ），２．８９－２．９７（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２４．４７（ＣＨ２），２５．８８（ＣＨ２），３０．６３（ＣＨ３），３２．６４（ＣＨ２），３４．８８（ＣＨ２），５０．６８（Ｃ），５８．１３（ＣＨ），７４．３１（ＣＨ）
分析条件Ｂ　保持時間　１５．６分、１６．０分 Reference Example 5 synthesis of trans-2- (tert-butylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that tert-butylamine was used instead of isopropylamine. (Outer bath temperature 100-105 ° C, pressure 0.1mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.90-1.19 (m, 1H), 1.13 (s, 9H), 1.24-1.32 (m, 3H), 1. 67-1.1.7 (m, 2H), 1.98-2.07 (m, 2H), 2.19-2.27 (m, 1H), 2.89-2.97 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 24.47 (CH2), 25.88 (CH2), 30.63 (CH3), 32.64 (CH2), 34.88 (CH2), 50. 68 (C), 58.13 (CH), 74.31 (CH)
Analysis condition B retention time 15.6 minutes, 16.0 minutes
参考例６　ｔｒａｎｓ－２－（アリルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、アリルアミンを用いる他は全て参考例１と同様に操作した。得られた粗体はそのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．９２－１．０４（ｍ，１Ｈ），１．１９－１．３１（ｍ，３Ｈ），１．７０－１．７２（ｍ，２Ｈ），　１．９７－２．０７（ｍ，２Ｈ），２．２４－２．３２（ｍ，１Ｈ），３．１１－３．２６（ｍ，２Ｈ），３．３６－３．４２（ｍ，１Ｈ），５．０６－５．２２（ｍ，２Ｈ），５．８４－５．９７（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２４．２８（ＣＨ２），２４．７１（ＣＨ２），３０．０７（ＣＨ２），３３．６２（ＣＨ２），４９．１７（ＣＨ２），６２．６５（ＣＨ），７３．２７（ＣＨ），１１５．６１（ＣＨ２），１３６．８５（ＣＨ）
分析条件Ａ　保持時間　３４．８分、３５．２分 Reference Example 6 synthesis of trans-2- (allylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that allylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.92-1.04 (m, 1H), 1.19-1.31 (m, 3H), 1.70-1.72 (m, 2H) ), 1.97-2.07 (m, 2H), 2.24-2.32 (m, 1H), 3.11-3.26 (m, 2H), 3.36-3.42 (m) , 1H), 5.06-5.22 (m, 2H), 5.84-5.97 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 24.28 (CH2), 24.71 (CH2), 30.07 (CH2), 33.62 (CH2), 49.17 (CH2), 62. 65 (CH), 73.27 (CH), 115.61 (CH2), 136.85 (CH)
Analysis condition A Retention time 34.8 minutes, 35.2 minutes
参考例７　ｔｒａｎｓ－２－（プロパルギルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、プロパルギルアミンを用いる他は全て参考例１と同様に操作した。得られた粗体はそのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．９２－１．０５（ｍ，１Ｈ），１．２１－１．３８（ｍ，３Ｈ），１．６８－１．７３（ｍ，２Ｈ），１．９６－２．０８（ｍ，２Ｈ），２．２４（ｔ，Ｊ＝２．４０Ｈｚ，１Ｈ），２．４０－２．４８（ｍ，１Ｈ），３．２１－３．２９（ｍ，１Ｈ），３．４７（ｄｑ，Ｊ１＝１６．８２Ｈｚ，Ｊ２＝２．４０Ｈｚ，２Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２４．３１（ＣＨ２），２４．５６（ＣＨ２），２９．７９（ＣＨ２），３３．８０（ＣＨ２），３５．３５（ＣＨ２），６２．０１（ＣＨ），７１．３０（Ｃ），７３．６１（ＣＨ），８２．２２（ＣＨ）
分析条件Ｃ　保持時間　４７．１分、４７．６分 Reference Example 7 synthesis of trans-2- (propargylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that propargylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.92-1.05 (m, 1H), 1.21-1.38 (m, 3H), 1.68-1.73 (m, 2H) ), 1.96-2.08 (m, 2H), 2.24 (t, J = 2.40 Hz, 1H), 2.40-2.48 (m, 1H), 3.21-3.29 (M, 1H), 3.47 (dq, J1 = 16.82 Hz, J2 = 2.40 Hz, 2H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 24.31 (CH2), 24.56 (CH2), 29.79 (CH2), 33.80 (CH2), 35.35 (CH2), 62. 01 (CH), 71.30 (C), 73.61 (CH), 82.22 (CH)
Analysis condition C Retention time 47.1 minutes, 47.6 minutes
参考例８　ｔｒａｎｓ－２－（シクロペンチルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、シクロペンチルアミンを用いる他は全て参考例１と同様に操作した。（外浴温度１７０－１７５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．８７－０．９５（ｍ，１Ｈ），１．２０－１．３８（ｍ，５Ｈ），１．５０－１．８７（ｍ，８Ｈ），２．０１－２．２２（ｍ，３Ｈ），３．０１－３．０９（ｍ，１Ｈ），３．１９－３．２７（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）δ　２３．５９（ＣＨ２），２３．７９（ＣＨ２），２４．３１（ＣＨ２），２５．２７（ＣＨ２），３０．９１（ＣＨ２），３３．０８（ＣＨ２），３３．１２（ＣＨ２），３４．５９（ＣＨ２），５６．１４（ＣＨ），６１．８６（ＣＨ），７３．７５（ＣＨ）
分析条件Ｄ　保持時間　２４．７分、２５．１分 Reference Example 8 synthesis of trans-2- (cyclopentylamino) cyclohexanol All operations were performed in the same manner as Reference Example 1 except that cyclopentylamine was used instead of isopropylamine. (Outer bath temperature 170-175 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.87-0.95 (m, 1H), 1.20-1.38 (m, 5H), 1.50-1.87 (m, 8H) ), 2.01-2.22 (m, 3H), 3.01-3.09 (m, 1H), 3.19-3.27 (m, 1H)
13 C-NMR (75.45 MHz, CDCl3) δ 23.59 (CH2), 23.79 (CH2), 24.31 (CH2), 25.27 (CH2), 30.91 (CH2), 33.08 (CH2), 33.12 (CH2), 34.59 (CH2), 56.14 (CH), 61.86 (CH), 73.75 (CH)
Analysis condition D Retention time 24.7 minutes, 25.1 minutes
参考例９　ｔｒａｎｓ－２－（シクロヘキシルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、シクロヘキシルアミンを用いる他は全て参考例１と同様に操作した。（外浴温度１７０－１７５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．８３－１．０４（ｍ，２Ｈ），１．０８－１．３６（ｍ，７Ｈ），１．６２－１．７３（ｍ，６Ｈ），１．９０（ｄ，Ｊ＝１２．３２Ｈｚ，１Ｈ），１．９７－２．０８（ｍ，２Ｈ），２．２１－２．３０（ｍ，１Ｈ），２．５１－２．６０（ｍ，１Ｈ），３．０１－３．０９（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２４．２９（ＣＨ２），２４．５６（ＣＨ２），２５．０６（ＣＨ２），２５．２９（ＣＨ２），２６．００（ＣＨ２），３１．４７（ＣＨ２），３３．０４（ＣＨ２），３３．５０（ＣＨ２），３５．１９（ＣＨ２），５３．１８（ＣＨ），６０．２６（ＣＨ），７３．７７（ＣＨ）
分析条件Ｅ　保持時間　３１．４分、３１．９分 Reference Example 9 trans-2- (Cyclohexylamino) cyclohexanol synthesis All operations were performed in the same manner as Reference Example 1 except that cyclohexylamine was used instead of isopropylamine. (Outer bath temperature 170-175 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4MHz, CDCl 3) δ 0.83-1.04 (m, 2H), 1.08-1.36 (m, 7H), 1.62-1.73 (m, 6H ), 1.90 (d, J = 12.32 Hz, 1H), 1.97-2.08 (m, 2H), 2.21-2.30 (m, 1H), 2.51-2.60 (M, 1H), 3.01-3.09 (m, 1H)
13 C-NMR (75.45 MHz, CDCl3) δ 24.29 (CH2), 24.56 (CH2), 25.06 (CH2), 25.29 (CH2), 26.00 (CH2), 31.47 (CH2), 33.04 (CH2), 33.50 (CH2), 35.19 (CH2), 53.18 (CH), 60.26 (CH), 73.77 (CH)
Analysis condition E Retention time 31.4 minutes, 31.9 minutes
参考例１０　ｔｒａｎｓ－２－（ジメチルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、ジメチルアミンを用いる他は全て参考例１と同様に操作した。（外浴温度７０－７５℃、圧力０．２ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．０３－１．３１（ｍ，４Ｈ），１．６９－１．７８（ｍ，３Ｈ），２．０７－２．３３（ｍ，８Ｈ），３．２７－３．３５（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２０．１６（ＣＨ２），２３．９７（ＣＨ２），２５．１４（ＣＨ２），３３．０５（ＣＨ２），３９．９８（ＣＨ３），６９．１１（ＣＨ），６９．３６（ＣＨ）
分析条件Ｆ　保持時間　４６．５分、４７．１分 Reference Example 10 synthesis of trans-2- (dimethylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that dimethylamine was used instead of isopropylamine. (Outer bath temperature 70-75 ° C, pressure 0.2mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.03-1.31 (m, 4H), 1.69-1.78 (m, 3H), 2.07-2.33 (m, 8H) ), 3.27-3.35 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 20.16 (CH2), 23.97 (CH2), 25.14 (CH2), 33.05 (CH2), 39.98 (CH3), 69. 11 (CH), 69.36 (CH)
Analysis condition F Retention time 46.5 minutes, 47.1 minutes
参考例１１　ｔｒａｎｓ－２－（ジエチルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、ジエチルアミンを用いる他は全て参考例１と同様に操作した。（外浴温度８０－８５℃、圧力０．２ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．０４（ｔ，Ｊ＝６．９１Ｈｚ，６Ｈ），１．１３－１．３１（ｍ，４Ｈ），１．６９－１．７７（ｍ，３Ｈ），２．１０－２．１４（ｍ，１Ｈ），２．２６－２．４２（ｍ，３Ｈ），２．５７－２．６９（ｍ，２Ｈ），３．２６－３．３４（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　１４．５８（ＣＨ３），２２．６９（ＣＨ２），２４．０４（ＣＨ２），２５．６１（ＣＨ２），３３．０７（ＣＨ２），４３．０８（ＣＨ２），６６．０５（ＣＨ），６８．８９（ＣＨ）
分析条件Ｇ　保持時間　２９．７分、３０．６分 Reference Example 11 synthesis of trans-2- (diethylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that diethylamine was used instead of isopropylamine. (Outer bath temperature 80-85 ° C, pressure 0.2mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.04 (t, J = 6.91 Hz, 6H), 1.13-1.31 (m, 4H), 1.69-1.77 (m 3H), 2.10-2.14 (m, 1H), 2.26-2.42 (m, 3H), 2.57-2.69 (m, 2H), 3.26-3.34. (M, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 14.58 (CH3), 22.69 (CH2), 24.04 (CH2), 25.61 (CH2), 33.07 (CH2), 43. 08 (CH2), 66.05 (CH), 68.89 (CH)
Analysis condition G Retention time 29.7 minutes, 30.6 minutes
参考例１２　ｔｒａｎｓ－２－（１－ピロリジニル）シクロヘキサノール合成
　イソプロピルアミンに代えて、ピロリジンを用いる他は全て参考例１と同様に操作した。（外浴温度１００－１０５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．１７－１．２７（ｍ，４Ｈ），１．６９－１．７８（ｍ，７Ｈ），２．０５－２．１５（ｍ，１Ｈ），２．４２－２．５９（ｍ，３Ｈ），２．６４－２．７１（ｍ，２Ｈ），３．２９－３．３７（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２０．９９（ＣＨ２），２３．４３（ＣＨ２），２４．０３（ＣＨ２），２５．１６（ＣＨ２），３３．１３（ＣＨ２），４７．０３（ＣＨ２），６４．７８（ＣＨ），７０．５１（ＣＨ）
分析条件Ｈ　保持時間　２３．０分、２３．２分 Reference Example 12 trans-2- (1-Pyrrolidinyl) cyclohexanol synthesis All operations were performed in the same manner as Reference Example 1 except that pyrrolidine was used instead of isopropylamine. (Outer bath temperature 100-105 ° C, pressure 0.1mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.17-1.27 (m, 4H), 1.69-1.78 (m, 7H), 2.05-2.15 (m, 1H) ), 2.4-2.59 (m, 3H), 2.64-2.71 (m, 2H), 3.29-3.37 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 20.99 (CH2), 23.43 (CH2), 24.03 (CH2), 25.16 (CH2), 33.13 (CH2), 47. 03 (CH2), 64.78 (CH), 70.51 (CH)
Analysis condition H Retention time 23.0 minutes, 23.2 minutes
参考例１３　ｔｒａｎｓ－２－（１－ピペリジニル）シクロヘキサノール合成
　イソプロピルアミンに代えて、ピペリジンを用いる他は全て参考例１と同様に操作した。（外浴温度１０５－１１５℃、圧力０．２ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．１２－１．２６（ｍ，４Ｈ），１．４３－１．７９（ｍ，９Ｈ），２．１０－２．１７（ｍ，２Ｈ），２．３１－２．３４（ｍ，２Ｈ），２．６３－２．７０（ｍ，２Ｈ），３．３１－３．３９（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２２．０６（ＣＨ２），２４．０４（ＣＨ２），２４．７９（ＣＨ２），２５．５６（ＣＨ２），２６．６７（ＣＨ２），３３．１９（ＣＨ２），４９．６３（ＣＨ２），６８．４５（ＣＨ），７０．９３（ＣＨ）
分析条件Ｈ　保持時間　３５．６分、３５．８分 Reference Example 13 synthesis of trans-2- (1-piperidinyl) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that piperidine was used instead of isopropylamine. (Outer bath temperature 105-115 ° C, pressure 0.2mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.12-1.26 (m, 4H), 1.43-1.79 (m, 9H), 2.10-2.17 (m, 2H) ), 2.31-2.34 (m, 2H), 2.66-2.70 (m, 2H), 3.31-3.39 (m, 2H)
13 C-NMR (75.45 MHz, CDCl3) δ 22.06 (CH2), 24.04 (CH2), 24.79 (CH2), 25.56 (CH2), 26.67 (CH2), 33.19 (CH2), 49.63 (CH2), 68.45 (CH), 70.93 (CH)
Analysis condition H Retention time 35.6 minutes, 35.8 minutes
参考例１４　ｔｒａｎｓ－２－（フェニルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、アニリンを用いる他は全て参考例１と同様に操作した。得られた粗体はそのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．９８－１．１１（ｍ，１Ｈ），１．２４－１．４７（ｍ，３Ｈ），１．７０－１．７９（ｍ，２Ｈ），２．１０－２．１４（ｍ，２Ｈ），３．１０－３．１８（ｍ，１Ｈ），３．３１－３．３９（ｍ，１Ｈ），６．７０－６．７７（ｍ，３Ｈ），７．１５－７．２５（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２４．１５（ＣＨ２），２４．８２（ＣＨ２），３１．４２（ＣＨ２），３３．０９（ＣＨ２），５９．８９（ＣＨ），７４．２５（ＣＨ），１１４．１７（ＣＨ），１１８．０７（ＣＨ），１２９．１８（ＣＨ），１４７．７３（Ｃ）
分析条件α　保持時間　２７．５分、２９．７分 Reference Example 14 synthesis of trans-2- (phenylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that aniline was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.98-1.11 (m, 1H), 1.24-1.47 (m, 3H), 1.70-1.79 (m, 2H) ), 2.10-2.14 (m, 2H), 3.10-3.18 (m, 1H), 3.31-3.39 (m, 1H), 6.70-6.77 (m , 3H), 7.15-7.25 (m, 2H)
13 C-NMR (75.45MHz, CDCl3 ) δ 24.15 (CH2), 24.82 (CH2), 31.42 (CH2), 33.09 (CH2), 59.89 (CH), 74.25 (CH), 114.17 (CH), 118.07 (CH), 129.18 (CH), 147.73 (C)
Analysis condition α Retention time 27.5 minutes, 29.7 minutes
参考例１５　ｔｒａｎｓ－２－（２－フェニルエチルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、２－フェニルエチルアミンを用いる他は全て参考例１と同様に操作した。得られた粗体はそのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．８４－０．９６（ｍ，１Ｈ），１．１８－１．３２（ｍ，３Ｈ），１．６７－１．７１（ｍ，２Ｈ），１．９９－２．０７（ｍ，２Ｈ），２．１６－２．２５（ｍ，１Ｈ），２．７０－２．８６（ｍ，３Ｈ），３．００－３．１５（ｍ，２Ｈ），７．１８－７．３２（ｍ，５Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２４．２９（ＣＨ２），２５．１５（ＣＨ２），３０．５５（ＣＨ２），３３．２５（ＣＨ２），３７．０１（ＣＨ２），４７．８９（ＣＨ２），６３．５５（ＣＨ），７３．６２（ＣＨ），１２６．０６（ＣＨ），１２８．３６（ＣＨ），１２８．６３（ＣＨ），１４０．０６（Ｃ）
分析条件α　保持時間　２５．０分、３５．０分 Reference Example 15 synthesis of trans-2- (2-phenylethylamino) cyclohexanol All operations were performed in the same manner as Reference Example 1 except that 2-phenylethylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.84-0.96 (m, 1H), 1.18-1.32 (m, 3H), 1.67-1.71 (m, 2H) ), 1.99-2.07 (m, 2H), 2.16-2.25 (m, 1H), 2.70-2.86 (m, 3H), 3.00-3.15 (m) , 2H), 7.18-7.32 (m, 5H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 24.29 (CH2), 25.15 (CH2), 30.55 (CH2), 33.25 (CH2), 37.01 (CH2), 47. 89 (CH2), 63.55 (CH), 73.62 (CH), 126.06 (CH), 128.36 (CH), 128.63 (CH), 140.06 (C)
Analysis condition α Retention time 25.0 minutes, 35.0 minutes
参考例１６　ｔｒａｎｓ－２－（ベンジルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、ベンジルアミンを用いる他は全て参考例１と同様に操作した。（外浴温度１７５－１８０℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．９１－１．０５（ｍ，１Ｈ），１．１６－１．３５（ｍ，３Ｈ），１．７１－１．７４（ｍ，２Ｈ），２．０１－２．０７（ｍ，１Ｈ），２．１５－２．２１（ｍ，１Ｈ），２．２５－２．３３（ｍ，１Ｈ），３．１６－３．２４（ｍ，１Ｈ），３．６９（ｄ，Ｊ＝１２．９２Ｈｚ，１Ｈ），３．９６（ｄ，Ｊ＝１２．９２Ｈｚ，１Ｈ），７．２２－７．３６（ｍ，５Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２４．２５（ＣＨ２），２４．８５（ＣＨ２），３０．２０（ＣＨ２），３３．４０（ＣＨ２），５０．６８（ＣＨ２），６２．８９（ＣＨ），７３．４１（ＣＨ），１２６．８１（ＣＨ），１２７．９６（ＣＨ），１２８．２５（ＣＨ），１４０．３２（Ｃ）
分析条件α　保持時間　１６．９分、２６．９分 Reference Example 16 synthesis of trans-2- (benzylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that benzylamine was used instead of isopropylamine. (Outer bath temperature 175-180 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.91-1.05 (m, 1H), 1.16-1.35 (m, 3H), 1.71-1.74 (m, 2H) ), 2.01-2.07 (m, 1H), 2.15-2.21 (m, 1H), 2.25-2.33 (m, 1H), 3.16-3.24 (m , 1H), 3.69 (d, J = 12.92 Hz, 1H), 3.96 (d, J = 12.92 Hz, 1H), 7.22-7.36 (m, 5H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 24.25 (CH2), 24.85 (CH2), 30.20 (CH2), 33.40 (CH2), 50.68 (CH2), 62. 89 (CH), 73.41 (CH), 126.81 (CH), 127.96 (CH), 128.25 (CH), 140.32 (C)
Analysis condition α Retention time 16.9 minutes, 26.9 minutes
参考例１７　ｔｒａｎｓ－２－（３－エトキシプロピルアミノ）シクロヘキサノール合成
　イソプロピルアミンに代えて、３－エトキシプロピルアミンを用いる他は全て参考例１と同様に操作した。得られた粗体は、そのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．９１－１．０３（ｍ，１Ｈ），１．１５－１．３０（ｍ，６Ｈ），１．７０－１．７９（ｍ，４Ｈ），１．９９－２．０９（ｍ，２Ｈ），２．１７－２．２５（ｍ，１Ｈ），２．５２－２．６１（ｍ，１Ｈ），２．８２－２．９１（ｍ，１Ｈ），３．１４－３．２２（ｍ，１Ｈ），３．４３－３．５１（ｍ，４Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　１４．９８（ＣＨ３），２４．２６（ＣＨ２），２４．８６（ＣＨ２），３０．２１（ＣＨ２），３０．３３（ＣＨ２），３３．４２（ＣＨ２），４３．９０（ＣＨ２），６３．３５（ＣＨ），６５．９８（ＣＨ２），６８．８０（ＣＨ２），７３．２７（ＣＨ）
分析条件ＡＡ　保持時間　２５．６分、２５．８分 Reference Example 17 synthesis of trans-2- (3-ethoxypropylamino) cyclohexanol All operations were performed in the same manner as in Reference Example 1 except that 3-ethoxypropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.91-1.03 (m, 1H), 1.15-1.30 (m, 6H), 1.70-1.79 (m, 4H) ), 1.99-2.09 (m, 2H), 2.17-2.25 (m, 1H), 2.52-2.61 (m, 1H), 2.82-2.91 (m) , 1H), 3.14-3.22 (m, 1H), 3.43-3.51 (m, 4H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 14.98 (CH3), 24.26 (CH2), 24.86 (CH2), 30.21 (CH2), 30.33 (CH2), 33. 42 (CH2), 43.90 (CH2), 63.35 (CH), 65.98 (CH2), 68.80 (CH2), 73.27 (CH)
Analysis condition AA Retention time 25.6 minutes, 25.8 minutes
参考例１８　ｔｒａｎｓ－２－（イソプロピルアミノ）シクロペンタノール合成
　エポキシドとして６－オキサビシクロ［３．１．０］ヘキサンを用いる他は参考例１同様に操作した。（外浴温度９５－１００℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．０５－１．１０（ｍ、６Ｈ），１．２１－１．３１（ｍ、１Ｈ），１．４８－１．７８（ｍ、３Ｈ），１．８８－２．０８（ｍ、２Ｈ），２．６７－２．９５（ｍ、２Ｈ），３．７８－３．８５（ｍ、１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２０．０３（ＣＨ２），２２．４４（ＣＨ３），２３．８５（ＣＨ３），３０．４１（ＣＨ２），３２．１８（ＣＨ２），４７．０３（ＣＨ），６３．９０（ＣＨ），７７．７８（ＣＨ）
分析条件Ｉ　保持時間　１４．３分、１４．７分 Reference Example 18 synthesis of trans-2- (isopropylamino) cyclopentanol The same operation as in Reference Example 1 was conducted except that 6-oxabicyclo [3.1.0] hexane was used as the epoxide. (Outer bath temperature 95-100 ° C, pressure 0.1mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.05-1.10 (m, 6H), 1.21-1.31 (m, 1H), 1.48-1.78 (m, 3H ), 1.88-2.08 (m, 2H), 2.67-2.95 (m, 2H), 3.78-3.85 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 20.03 (CH2), 22.44 (CH3), 23.85 (CH3), 30.41 (CH2), 32.18 (CH2), 47. 03 (CH), 63.90 (CH), 77.78 (CH)
Analysis condition I Retention time 14.3 minutes, 14.7 minutes
参考例１９　ｔｒａｎｓ－２－（シクロプロピルアミノ）シクロペンタノール合成
　イソプロピルアミンに代えて、シクロプロピルアミン用いる他は全て参考例１８と同様に操作した。（外浴温度１０５－１１０℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．３１－０．５２（ｍ，４Ｈ），１．２７－１．４０（ｍ，１Ｈ），１．４８－１．７９（ｍ，３Ｈ），１．８８－１．９９（ｍ，１Ｈ），２．０３－２．１９（ｍ，２Ｈ），２．９０－２．９７（ｍ，１Ｈ），３．８５（ｑ，Ｊ＝６．３１Ｈｚ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　５．８９（ＣＨ２），６．４６（ＣＨ２），２０．０８（ＣＨ２），２９．３０（ＣＨ），３０．１３（ＣＨ２），３２．１２（ＣＨ２），６６．９５（ＣＨ），７７．２１（ＣＨ）
分析条件Ｊ　保持時間　１５．５分、１５．７分 Reference Example 19 synthesis of trans-2- (cyclopropylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that cyclopropylamine was used instead of isopropylamine. (Outer bath temperature 105-110 ° C, pressure 0.1mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.31-0.52 (m, 4H), 1.27-1.40 (m, 1H), 1.48-1.79 (m, 3H) ), 1.88-1.99 (m, 1H), 2.03-2.19 (m, 2H), 2.90-2.97 (m, 1H), 3.85 (q, J = 6) .31Hz, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 5.89 (CH2), 6.46 (CH2), 20.08 (CH2), 29.30 (CH), 30.13 (CH2), 32. 12 (CH2), 66.95 (CH), 77.21 (CH)
Analysis condition J Retention time 15.5 minutes, 15.7 minutes
参考例２０　ｔｒａｎｓ－２－（プロピルアミノ）シクロペンタノール合成
　イソプロピルアミンに代えて、プロピルアミン用いる他は全て参考例１８と同様に操作した。（外浴温度１００－１０５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．７１（ｔ，Ｊ＝７．５１Ｈｚ，３Ｈ），１．２２－１．３５（ｍ，１Ｈ），１．４５－１．７８（ｍ，５Ｈ），１．８８－２．１１（ｍ，２Ｈ），２．５０－２．６６（ｍ，２Ｈ），２．７８－２．８６（ｍ，１Ｈ），３．８５（ｑ，Ｊ＝６．６１Ｈｚ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　１１．６６（ＣＨ３），２０．１５（ＣＨ２），２３．２２（ＣＨ２），２９．９３（ＣＨ２），３２．５３（ＣＨ２），５０．４１（ＣＨ２），６６．５７（ＣＨ），７７．４３（ＣＨ）
分析条件Ｋ　保持時間　１７．３分、１７．６分 Reference Example 20 synthesis of trans-2- (propylamino) cyclopentanol The same operation as in Reference Example 18 was performed except that propylamine was used instead of isopropylamine. (Outer bath temperature 100-105 ° C, pressure 0.1mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.71 (t, J = 7.51 Hz, 3H), 1.22-1.35 (m, 1H), 1.45-1.78 (m , 5H), 1.88-2.11 (m, 2H), 2.50-2.66 (m, 2H), 2.78-2.86 (m, 1H), 3.85 (q, J = 6.61Hz, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 11.66 (CH 3 ), 20.15 (CH 2), 23.22 (CH 2), 29.93 (CH 2), 32.53 (CH 2), 50. 41 (CH2), 66.57 (CH), 77.43 (CH)
Analysis condition K Retention time 17.3 minutes, 17.6 minutes
参考例２１　ｔｒａｎｓ－２－（アリルアミノ）シクロペンタノール合成
　イソプロピルアミンに代えて、アリルアミン用いる他は全て参考例１８と同様に操作した。得られた粗体はそのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．２３－１．３６（ｍ，１Ｈ），１．４８－１．７８（ｍ，３Ｈ），１．８９－２．０６（ｍ，２Ｈ），２．８２－２．９０（ｍ，１Ｈ），３．１８－３．３４（ｍ，４Ｈ），３．８３－３．８９（ｍ，１Ｈ），５．１０（ｄ，Ｊ＝１０．２１Ｈｚ，１Ｈ），５．１８（ｄｄ，Ｊ１＝１７．１２Ｈｚ，Ｊ２＝１．５０Ｈｚ，１Ｈ），５．８５－５．９８（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２０．０２（ＣＨ２），２９．６７（ＣＨ２），３２．３８（ＣＨ２），５０．８７（ＣＨ２），６５．８１（ＣＨ），７７．３１（ＣＨ），１１５．９７（ＣＨ２），１３６．３１（ＣＨ）
分析条件Ｌ　保持時間　３２．９分、３４．０分 Reference Example 21 synthesis of trans-2- (allylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that allylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.23-1.36 (m, 1H), 1.48-1.78 (m, 3H), 1.89-2.06 (m, 2H) ), 2.82-2.90 (m, 1H), 3.18-3.34 (m, 4H), 3.83-3.89 (m, 1H), 5.10 (d, J = 10 .21 Hz, 1H), 5.18 (dd, J1 = 17.12 Hz, J2 = 1.50 Hz, 1H), 5.85-5.98 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 20.02 (CH2), 29.67 (CH2), 32.38 (CH2), 50.87 (CH2), 65.81 (CH), 77. 31 (CH), 115.97 (CH2), 136.31 (CH)
Analysis condition L Retention time 32.9 minutes, 34.0 minutes
参考例２２　ｔｒａｎｓ－２－（プロパルギルアミノ）シクロペンタノール合成
　イソプロピルアミンに代えて、プロパルギルアミン用いる他は全て参考例１８と同様に操作した。得られた粗体はそのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．２５－１．３７（ｍ，１Ｈ），１．５１－１．８１（ｍ，３Ｈ），１．８９－２．０７（ｍ，２Ｈ），２．２７－２．２９（ｍ，１Ｈ），３．０１－３．０８（ｍ，１Ｈ），３．３５－３．５４（ｍ，２Ｈ），３．８９（ｑ，Ｊ＝６．３１Ｈｚ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２０．１２（ＣＨ２），２９．３９（ＣＨ２），３２．４８（ＣＨ２），３６．５７（ＣＨ２），６４．９７（ＣＨ），７１．５０（Ｃ），７７．５３（ＣＨ），８１．８９（ＣＨ）
分析条件Ｍ　保持時間　４０．１分、４１．９分 Reference Example 22 synthesis of trans-2- (propargylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that propargylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.25-1.37 (m, 1H), 1.51-1.81 (m, 3H), 1.89-2.07 (m, 2H) ), 2.27-2.29 (m, 1H), 3.01-3.08 (m, 1H), 3.35-3.54 (m, 2H), 3.89 (q, J = 6) .31Hz, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 20.12 (CH2), 29.39 (CH2), 32.48 (CH2), 36.57 (CH2), 64.97 (CH), 71. 50 (C), 77.53 (CH), 81.89 (CH)
Analysis condition M Retention time 40.1 minutes, 41.9 minutes
参考例２３　ｔｒａｎｓ－２－（シクロペンチルアミノ）シクロペンタノール合成
　イソプロピルアミンに代えて、シクロペンチルアミン用いる他は全て参考例１８と同様に操作した。（外浴温度１６５－１７０℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．２２－１．３６（ｍ，３Ｈ），１．４７－１．７７（ｍ，７Ｈ），１．８２－２．０６（ｍ，４Ｈ），２．８２－２．８９（ｍ，１Ｈ），３．１１（ｑｕｉｎ，Ｊ＝７．２１Ｈｚ，１Ｈ），３．８１（ｑ，Ｊ＝６．９１Ｈｚ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　１９．８３（ＣＨ２），２３．５７（ＣＨ２），２３．６６（ＣＨ２），２９．９８（ＣＨ２），３２．１０（ＣＨ２），３２．６３（ＣＨ２），３３．６５（ＣＨ２），５８．３４（ＣＨ），６５．０１（ＣＨ），７７．２５（ＣＨ）
分析条件Ｎ　保持時間　２４．３分、２４．５分 Reference Example 23 synthesis of trans-2- (cyclopentylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that cyclopentylamine was used instead of isopropylamine. (Outer bath temperature 165-170 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.22-1.36 (m, 3H), 1.47-1.77 (m, 7H), 1.82-2.06 (m, 4H) ), 2.82-2.89 (m, 1H), 3.11 (quin, J = 7.21 Hz, 1H), 3.81 (q, J = 6.91 Hz, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 19.83 (CH2), 23.57 (CH2), 23.66 (CH2), 29.98 (CH2), 32.10 (CH2), 32. 63 (CH2), 33.65 (CH2), 58.34 (CH), 65.01 (CH), 77.25 (CH)
Analysis condition N Retention time 24.3 minutes, 24.5 minutes
参考例２４　ｔｒａｎｓ－２－（１－ピロリジニル）シクロペンタノール合成
　イソプロピルアミンに代えて、ピロリジン用いる他は全て参考例１８と同様に操作した。（外浴温度１２５－１３０℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．４６－１．８３（ｍ，８Ｈ），１．８６－２．００（ｍ，２Ｈ），２．４１－２．４８（ｍ，１Ｈ），２．５９－２．６１（ｍ，４Ｈ），４．０６－４．１２（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２１．３４（ＣＨ２），２２．９６（ＣＨ２），２９．７０（ＣＨ２），３４．５１（ＣＨ２），５２．４６（ＣＨ２），７３．１９（ＣＨ），７６．２８（ＣＨ）
分析条件Ｏ　保持時間　１９．９分、２０．３分 Reference Example 24 synthesis of trans-2- (1-pyrrolidinyl) cyclopentanol The same procedure as in Reference Example 18 was carried out except that pyrrolidine was used instead of isopropylamine. (Outer bath temperature 125-130 ° C, pressure 0.1mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.46-1.83 (m, 8H), 1.86-2.00 (m, 2H), 2.41-2.48 (m, 1H) ), 2.59-2.61 (m, 4H), 4.06-4.12 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 21.34 (CH2), 22.96 (CH2), 29.70 (CH2), 34.51 (CH2), 52.46 (CH2), 73. 19 (CH), 76.28 (CH)
Analysis condition O Retention time 19.9 minutes, 20.3 minutes
参考例２５　ｔｒａｎｓ－２－（１－ピペリジニル）シクロペンタノール合成
　イソプロピルアミンに代えて、ピペリジン用いる他は全て参考例１８と同様に操作した。（外浴温度１２５－１３０℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．４１－１．７５（ｍ，１０Ｈ），１．８０－１．９７（ｍ，２Ｈ），２．４８－２．５６（ｍ，５Ｈ），４．１０－４．１６（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２１．７１（ＣＨ２），２４．２９（ＣＨ２），２５．７６（ＣＨ２），２６．９２（ＣＨ２），３４．３６（ＣＨ２），５２．１４（ＣＨ２），７４．３８（ＣＨ），７５．１７（ＣＨ）
分析条件Ｎ　保持時間　２３．１分、２３．４分 Reference Example 25 synthesis of trans-2- (1-piperidinyl) cyclopentanol The same procedure as in Reference Example 18 was carried out except that piperidine was used instead of isopropylamine. (Outer bath temperature 125-130 ° C, pressure 0.1mmHg)
1 H-NMR (300.4MHz, CDCl 3) δ 1.41-1.75 (m, 10H), 1.80-1.97 (m, 2H), 2.48-2.56 (m, 5H ), 4.10-4.16 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 21.71 (CH2), 24.29 (CH2), 25.76 (CH2), 26.92 (CH2), 34.36 (CH2), 52. 14 (CH2), 74.38 (CH), 75.17 (CH)
Analysis condition N Retention time 23.1 minutes, 23.4 minutes
参考例２６　ｔｒａｎｓ－２－（フェニルアミノ）シクロペンタノール合成
　イソプロピルアミンに代えて、アニリン用いる他は全て参考例１８と同様に操作した。（外浴温度１６０－１６５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．２９－１．３８（ｍ，１Ｈ），１．４１－２．０２（ｍ，４Ｈ），２．１６－２．２８（ｍ，１Ｈ），３．５２－３．５８（ｍ，１Ｈ），３．９６－４．０１（ｍ，１Ｈ），６．６２－６．７３（ｍ，３Ｈ），７．０９－７．２１（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２０．８４（ＣＨ２），３０．９７（ＣＨ２），３２．６１（ＣＨ２），６１．９３（ＣＨ），７７．９７（ＣＨ），１１３．３０（ＣＨ），１１７．４２（ＣＨ），１２９．１７（ＣＨ），１４７．６４（Ｃ）
分析条件Ｐ　保持時間　５１．３分、５１．６分 Reference Example 26 synthesis of trans-2- (phenylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that aniline was used instead of isopropylamine. (Outer bath temperature 160-165 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.29-1.38 (m, 1H), 1.41-2.02 (m, 4H), 2.16-2.28 (m, 1H) ), 3.52-3.58 (m, 1H), 3.96-4.01 (m, 1H), 6.62-6.73 (m, 3H), 7.09-7.21 (m , 2H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 20.84 (CH2), 30.97 (CH2), 32.61 (CH2), 61.93 (CH), 77.97 (CH), 113. 30 (CH), 117.42 (CH), 129.17 (CH), 147.64 (C)
Analysis condition P Retention time 51.3 minutes, 51.6 minutes
参考例２７　ｔｒａｎｓ－２－（２－フェニルエチルアミノ）シクロペンタノール合成
　イソプロピルアミンに代えて、２－フェニルエチルアミン用いる他は全て参考例１８と同様に操作した。（外浴温度１６０－１６５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．１８－１．３１（ｍ，１Ｈ），１．４７－１．７６（ｍ，３Ｈ），１．８６－２．０４（ｍ，２Ｈ），２．７２－２．９６（ｍ，５Ｈ），３．８２（ｑ，Ｊ＝６．３１Ｈｚ，１Ｈ），７．１８－７．３０（ｍ，５Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２０．２４（ＣＨ２），３０．０２（ＣＨ２），３２．６３（ＣＨ２），３６．３２（ＣＨ２），４９．６３（ＣＨ２），６６．５０（ＣＨ），７７．６１（ＣＨ），１２６．０７（ＣＨ），１２８．３６（ＣＨ），１２８．５４（ＣＨ），１３９．６９（Ｃ）
分析条件α　保持時間　１３．６分、１８．３分 Reference Example 27 synthesis of trans-2- (2-phenylethylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that 2-phenylethylamine was used instead of isopropylamine. (Outer bath temperature 160-165 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.18-1.31 (m, 1H), 1.47-1.76 (m, 3H), 1.86-2.04 (m, 2H) ), 2.72-2.96 (m, 5H), 3.82 (q, J = 6.31 Hz, 1H), 7.18-7.30 (m, 5H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 20.24 (CH2), 30.02 (CH2), 32.63 (CH2), 36.32 (CH2), 49.63 (CH2), 66. 50 (CH), 77.61 (CH), 126.07 (CH), 128.36 (CH), 128.54 (CH), 139.69 (C)
Analysis condition α Retention time 13.6 minutes, 18.3 minutes
参考例２８　ｔｒａｎｓ－２－（ベンジルアミノ）シクロペンタノール合成
　イソプロピルアミンに代えて、ベンジルアミン用いる他は全て参考例１８と同様に操作した。（外浴温度１６０－１６５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．２３－１．３６（ｍ，１Ｈ），１．４３－１．５７（ｍ，１Ｈ），１．５９－１．７５（ｍ，２Ｈ），１．８４－２．０４（ｍ，２Ｈ），２．８１－２．８８（ｍ，１Ｈ），３．６６－３．８５（ｍ，３Ｈ），７．２０－７．３２（ｍ，５Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２０．２２（ＣＨ２），２９．９６（ＣＨ２），３２．４６（ＣＨ２），５２．４５（ＣＨ２），６６．０３（ＣＨ），７７．６９（ＣＨ），１２６．８８（ＣＨ），１２８．０７（ＣＨ），１２８．３０（ＣＨ），１４０．０４（Ｃ）
分析条件β　保持時間　３３．２分、３４．９分 Reference Example 28 synthesis of trans-2- (benzylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that benzylamine was used instead of isopropylamine. (Outer bath temperature 160-165 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.23-1.36 (m, 1H), 1.43-1.57 (m, 1H), 1.59-1.75 (m, 2H) ), 1.84-2.04 (m, 2H), 2.81-2.88 (m, 1H), 3.66-3.85 (m, 3H), 7.20-7.32 (m , 5H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 20.22 (CH2), 29.96 (CH2), 32.46 (CH2), 52.45 (CH2), 66.03 (CH), 77. 69 (CH), 126.88 (CH), 128.07 (CH), 128.30 (CH), 140.04 (C)
Analysis condition β retention time 33.2 minutes, 34.9 minutes
参考例２９　ｔｒａｎｓ－２－（３－エトキシプロピルアミノ）シクロペンタノール合成
　イソプロピルアミンに代えて、３－エトキシプロピルアミン用いる他は全て参考例１８と同様に操作した。得られた粗体は、そのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．１９（ｔ，Ｊ＝６．９１Ｈｚ，３Ｈ），１．２６－１．３６（ｍ，１Ｈ），１．４８－１．８１（ｍ，５Ｈ），１．８９－２．０７（ｍ，２Ｈ），２．６４－２．８６（ｍ，３Ｈ），３．３５－３．５１（ｍ，４Ｈ），３．８３－３．８９（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　１５．０１（ＣＨ３），２０．１８（ＣＨ２），２９．９０（ＣＨ２），２９．９９（ＣＨ２），３２．４８（ＣＨ２），４５．９１（ＣＨ２），６６．０２（ＣＨ２），６６．０４（ＣＨ），６８．９８（ＣＨ２），７７．４２（ＣＨ）
分析条件γ　保持時間　２３．６分、２４．７分 Reference Example 29 synthesis of trans-2- (3-ethoxypropylamino) cyclopentanol All operations were performed in the same manner as in Reference Example 18 except that 3-ethoxypropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.19 (t, J = 6.91 Hz, 3H), 1.26-1.36 (m, 1H), 1.48-1.81 (m , 5H), 1.89-2.07 (m, 2H), 2.64-2.86 (m, 3H), 3.35-3.51 (m, 4H), 3.83-3.89 (M, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 15.01 (CH3), 20.18 (CH2), 29.90 (CH2), 29.99 (CH2), 32.48 (CH2), 45. 91 (CH2), 66.02 (CH2), 66.04 (CH), 68.98 (CH2), 77.42 (CH)
Analysis condition γ Retention time 23.6 minutes, 24.7 minutes
参考例３０　ｔｒａｎｓ－４－（イソプロピルアミノ）－３－テトラヒドロフラン－３－オール合成
　エポキシドとして３，６－ジオキサビシクロ［３．１．０］ヘキサンを用いる他は参考例１同様に操作した。（外浴温度１２０－１２５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．０８（ｄ，Ｊ＝６．３１Ｈｚ，３Ｈ），１．０８（ｄ，Ｊ＝６．３１Ｈｚ，３Ｈ），２．８６（ｓｅｐ，Ｊ＝６．３１Ｈｚ，１Ｈ），３．２３－３．２６（ｍ，１Ｈ），３．５５（ｄｄ，Ｊ１＝９．０１Ｈｚ，Ｊ２＝３．９１Ｈｚ，１Ｈ），３．６２－３．６６（ｍ，１Ｈ），３．９８（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝５．１１Ｈｚ，１Ｈ），４．０５（ｄｄ，Ｊ１＝９．３１Ｈｚ，Ｊ２＝５．７１Ｈｚ，１Ｈ），４．１１－４．１５（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２２．４６（ＣＨ３），２３．１１（ＣＨ３），４６．７０（ＣＨ），６３．７３（ＣＨ），７２．１７（ＣＨ２），７３．６３（ＣＨ２），７６．３３（ＣＨ）
分析条件γ　保持時間　２５．５分、２５．７分 Reference Example 30 Synthesis of trans-4- (isopropylamino) -3-tetrahydrofuran-3-ol The same operation as in Reference Example 1 was conducted except that 3,6-dioxabicyclo [3.1.0] hexane was used as the epoxide. (Outer bath temperature 120-125 ° C, pressure 0.1mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.08 (d, J = 6.31 Hz, 3H), 1.08 (d, J = 6.31 Hz, 3H), 2.86 (sep, J = 6.31 Hz, 1H), 3.23-3.26 (m, 1H), 3.55 (dd, J1 = 9.01 Hz, J2 = 3.91 Hz, 1H), 3.62-3.66 ( m, 1H), 3.98 (dd, J1 = 9.61 Hz, J2 = 5.11 Hz, 1H), 4.05 (dd, J1 = 9.31 Hz, J2 = 5.71 Hz, 1H), 4.11 -4.15 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 22.46 (CH3), 23.11 (CH3), 46.70 (CH), 63.73 (CH), 72.17 (CH2), 73. 63 (CH2), 76.33 (CH)
Analysis condition γ Retention time 25.5 minutes, 25.7 minutes
参考例３１　ｔｒａｎｓ－４－（シクロプロピルアミノ）テトラヒドロフラン－３－オール合成
　イソプロピルアミンに代えて、シクロプロピルアミンを用いる他は全て参考例３０と同様に操作した。得られた粗体はそのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．４１－０．５３（ｍ，４Ｈ），　２．１２－２．１９（ｍ，１Ｈ），　３．２７－３．３１（ｍ，１Ｈ），　３．６１－３．６８（ｍ，２Ｈ），　３．９７（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝４．８１Ｈｚ，１Ｈ），４．０６（ｄｄ，Ｊ１＝９．０１Ｈｚ，Ｊ２＝５．４１Ｈｚ，１Ｈ），　４．２１（ｑ，Ｊ＝２．４０Ｈｚ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　６．１８（ＣＨ２），６．３５（ＣＨ２），２８．９３（ＣＨ），６６．５７（ＣＨ），７１．９０（ＣＨ２），７３．６２（ＣＨ２），７５．５９（ＣＨ）
分析条件γ　保持時間　２６．２分、２８．２分 Reference Example 31 synthesis of trans-4- (cyclopropylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that cyclopropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.41-0.53 (m, 4H), 2.12-2.19 (m, 1H), 3.27-3.31 (m, 1H) ), 3.61-3.68 (m, 2H), 3.97 (dd, J1 = 9.61 Hz, J2 = 4.81 Hz, 1H), 4.06 (dd, J1 = 9.01 Hz, J2 = 5.41 Hz, 1H), 4.21 (q, J = 2.40 Hz, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 6.18 (CH2), 6.35 (CH2), 28.93 (CH), 66.57 (CH), 71.90 (CH2), 73. 62 (CH2), 75.59 (CH)
Analysis condition γ Retention time 26.2 minutes, 28.2 minutes
参考例３２　ｔｒａｎｓ－４－（プロピルアミノ）テトラヒドロフラン－３－オール合成
　イソプロピルアミンに代えて、プロピルアミンを用いる他は全て参考例３０と同様に操作した。（外浴温度１５０－１５５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．９３（ｔ，Ｊ＝７．２１Ｈｚ，３Ｈ），１．５０（ｓｅｘｔ，Ｊ＝７．２１Ｈｚ，２Ｈ），２．５８（ｔ，Ｊ＝７．２１Ｈｚ，２Ｈ），３．１３－３．１５（ｍ，１Ｈ），３．５８（ｄｄ，Ｊ１＝９．３１Ｈｚ，Ｊ２＝３．６０Ｈｚ，１Ｈ），３．６５（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝２．７０Ｈｚ，１Ｈ），３．９９（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝４．８１Ｈｚ，１Ｈ），４．０５（ｄｄ，Ｊ１＝９．３１Ｈｚ，Ｊ２＝５．７１Ｈｚ，１Ｈ），４．１３－４．１４（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　１１．５４（ＣＨ３），２３．０２（ＣＨ２），４９．９６（ＣＨ２），６６．５２（ＣＨ），７１．９６（ＣＨ２），７３．８０（ＣＨ２），７５．９８（ＣＨ）
分析条件Ｑ　保持時間　１８．３分、１８．９分 Reference Example 32 Synthesis of trans-4- (propylamino) tetrahydrofuran-3-ol The same procedure as in Reference Example 30 was performed except that propylamine was used instead of isopropylamine. (Outer bath temperature 150-155 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.93 (t, J = 7.21 Hz, 3H), 1.50 (sext, J = 7.21 Hz, 2H), 2.58 (t, J = 7.21 Hz, 2H), 3.13-3.15 (m, 1H), 3.58 (dd, J1 = 9.31 Hz, J2 = 3.60 Hz, 1H), 3.65 (dd, J1 = 9.61 Hz, J2 = 2.70 Hz, 1H), 3.99 (dd, J1 = 9.61 Hz, J2 = 4.81 Hz, 1H), 4.05 (dd, J1 = 9.31 Hz, J2 = 5. 71 Hz, 1H), 4.13-4.14 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 11.54 (CH3), 23.02 (CH2), 49.96 (CH2), 66.52 (CH), 71.96 (CH2), 73. 80 (CH2), 75.98 (CH)
Analysis condition Q Retention time 18.3 minutes, 18.9 minutes
参考例３３　ｔｒａｎｓ－４－（アリルアミノ）テトラヒドロフラン－３－オール合成
　イソプロピルアミンに代えて、アリルアミンを用いる他は全て参考例３０と同様に操作した。得られた粗体はそのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　３．１７－３．２７（ｍ，３Ｈ），３．５６－３．６８（ｍ，２Ｈ），３．９５－４．０５（ｍ，２Ｈ），４．１０－４．１６（ｍ，１Ｈ）５．１１－５．２３（ｍ，２Ｈ），５．８１－５．９５（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　５０．３９（ＣＨ２），６５．５９（ＣＨ），７１．７８（ＣＨ２），７３．７０（ＣＨ２），７５．８６（ＣＨ），１１６．５８（ＣＨ２），１３５．６７（ＣＨ）
分析条件Ｒ　保持時間　２０．３分、２０．７分 Reference Example 33 Synthesis of trans-4- (allylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that allylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 3.17-3.27 (m, 3H), 3.56-3.68 (m, 2H), 3.95-4.05 (m, 2H) ), 4.10-4.16 (m, 1H) 5.11-5.23 (m, 2H), 5.81-5.95 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 50.39 (CH2), 65.59 (CH), 71.78 (CH2), 73.70 (CH2), 75.86 (CH), 116. 58 (CH2), 135.67 (CH)
Analysis condition R Retention time 20.3 minutes, 20.7 minutes
参考例３４　ｔｒａｎｓ－４－（プロパルギルアミノ）テトラヒドロフラン－３－オール合成
　イソプロピルアミンに代えて、プロパルギルアミンを用いる他は全て参考例３０と同様に操作した。得られた粗体はそのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　２．３１（ｓ，１Ｈ），３．３７－３．５２（ｍ，３Ｈ），３．５７－３．７２（ｍ，２Ｈ），３．９７－４．１８（ｍ，３Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　３６．２８（ＣＨ２），６４．８８（ＣＨ），７１．９４（ＣＨ２），７２．０７（Ｃ），７３．８７（ＣＨ２），７５．９７（ＣＨ），８１．４８（ＣＨ）
分析条件Ｓ　保持時間　２４．５分、２５．１分 Reference Example 34 synthesis of trans-4- (propargylamino) tetrahydrofuran-3-ol The procedure of Reference Example 30 was repeated except that propargylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 2.31 (s, 1H), 3.37-3.52 (m, 3H), 3.57-3.72 (m, 2H), 3. 97-4.18 (m, 3H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 36.28 (CH2), 64.88 (CH), 71.94 (CH2), 72.07 (C), 73.87 (CH2), 75. 97 (CH), 81.48 (CH)
Analysis condition S Retention time 24.5 minutes, 25.1 minutes
参考例３５　ｔｒａｎｓ－４－（シクロペンチルアミノ）テトラヒドロフラン－３－オール合成
　イソプロピルアミンに代えて、シクロペンチルアミンを用いる他は全て参考例３０と同様に操作した。（外浴温度１７０－１７５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．２２－１．３６（ｍ，２Ｈ），１．５３－１．７４（ｍ，４Ｈ），１．８７－１．９０（ｍ，２Ｈ），３．０６－３．２２（ｍ，２Ｈ），３．５６（ｄｄ，Ｊ１＝９．０１Ｈｚ，Ｊ２＝３．９１Ｈｚ，１Ｈ），３．６５（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝２．７０Ｈｚ，１Ｈ），３．９５－４．１５（ｍ，３Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２３．６７（ＣＨ２），３３．００（ＣＨ２），３３．３８（ＣＨ２），５８．１３（ＣＨ），６５．２７（ＣＨ），７２．３３（ＣＨ２），７３．７３（ＣＨ２），７６．３７（ＣＨ）
分析条件γ　保持時間　２８．５分、２８．７分 Reference Example 35 synthesis of trans-4- (cyclopentylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that cyclopentylamine was used instead of isopropylamine. (Outer bath temperature 170-175 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.22-1.36 (m, 2H), 1.53-1.74 (m, 4H), 1.87-1.90 (m, 2H) ), 3.06-3.22 (m, 2H), 3.56 (dd, J1 = 9.01 Hz, J2 = 3.91 Hz, 1H), 3.65 (dd, J1 = 9.61 Hz, J2 = 2.70 Hz, 1H), 3.95-4.15 (m, 3H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 23.67 (CH2), 33.00 (CH2), 33.38 (CH2), 58.13 (CH), 65.27 (CH), 72. 33 (CH2), 73.73 (CH2), 76.37 (CH)
Analysis condition γ Retention time 28.5 minutes, 28.7 minutes
参考例３６　ｔｒａｎｓ－４－（ジエチルアミノ）テトラヒドロフラン－３－オール合成
　イソプロピルアミンに代えて、ジエチルアミンを用いる他は全て参考例３０と同様に操作した。（外浴温度１１５－１２０℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．０５（ｔ，Ｊ＝７．２１Ｈｚ．６Ｈ），２．６２（ｑ，Ｊ＝７．２１Ｈｚ，４Ｈ），３．２１（ｄｔ，Ｊ１＝６．６１Ｈｚ，Ｊ２＝３．００Ｈｚ，１Ｈ），３．６１－３．６９（ｍ，２Ｈ），３．９３－４．０３（ｍ，２Ｈ），４．２７－４．３２（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　１１．５５（ＣＨ３），４３．９７（ＣＨ２），６９．５９（ＣＨ２），７０．３３（ＣＨ），７４．４８（ＣＨ），７４．７６（ＣＨ２）
分析条件Ｔ　保持時間　１５．８分、１６．１分 Reference Example 36 Synthesis of trans-4- (diethylamino) tetrahydrofuran-3-ol The same procedure as in Reference Example 30 was performed except that diethylamine was used instead of isopropylamine. (Outer bath temperature 115-120 ° C, pressure 0.1mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.05 (t, J = 7.21 Hz. 6H), 2.62 (q, J = 7.21 Hz, 4H), 3.21 (dt, J1 = 6.61 Hz, J2 = 3.00 Hz, 1H), 3.61-3.69 (m, 2H), 3.93-4.03 (m, 2H), 4.27-4.32 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 11.55 (CH3), 43.97 (CH2), 69.59 (CH2), 70.33 (CH), 74.48 (CH), 74. 76 (CH2)
Analysis condition T Retention time 15.8 minutes, 16.1 minutes
参考例３７　ｔｒａｎｓ－４－（１－ピペリジニル）テトラヒドロフラン－３－オール合成
　イソプロピルアミンに代えて、ピペリジンを用いる他は全て参考例３０と同様に操作した。（外浴温度１５０－１５５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．４７（ｄ，Ｊ＝４．８１Ｈｚ，２Ｈ），１．５６－１．６３（ｍ，４Ｈ），２．３４－２．４０（ｍ，２Ｈ），２．５４－２．５７（ｍ，２Ｈ），２．８１（ｄｔ，Ｊ１＝６．６１Ｈｚ，Ｊ２＝２．７０Ｈｚ，１Ｈ），３．６６－３．７１（ｍ，２Ｈ），３．９５（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝５．７１Ｈｚ，１Ｈ），４．０２（ｄｄ，Ｊ１＝９．０１Ｈｚ，Ｊ２＝７．２１Ｈｚ，１Ｈ），４．３２－４．３６（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２３．９９（ＣＨ２），２５．４８（ＣＨ２），５２．３９（ＣＨ２），６９．６３（ＣＨ２），７４．１１（ＣＨ），７４．９５（ＣＨ），７５．１３（ＣＨ２）
分析条件Ｕ　保持時間　１６．６分、１７．０分 Reference Example 37 Synthesis of trans-4- (1-piperidinyl) tetrahydrofuran-3-ol The same operation as in Reference Example 30 was conducted except that piperidine was used instead of isopropylamine. (Outer bath temperature 150-155 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.47 (d, J = 4.81 Hz, 2H), 1.56-1.63 (m, 4H), 2.34-2.40 (m , 2H), 2.54-2.57 (m, 2H), 2.81 (dt, J1 = 6.61 Hz, J2 = 2.70 Hz, 1H), 3.66-3.71 (m, 2H) 3.95 (dd, J1 = 9.61 Hz, J2 = 5.71 Hz, 1H), 4.02 (dd, J1 = 9.01 Hz, J2 = 7.21 Hz, 1H), 4.32-4.36 (M, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 23.99 (CH2), 25.48 (CH2), 52.39 (CH2), 69.63 (CH2), 74.11 (CH), 74. 95 (CH), 75.13 (CH2)
Analysis condition U Retention time 16.6 minutes, 17.0 minutes
参考例３８　ｔｒａｎｓ－４－（フェニルアミノ）テトラヒドロフラン－３－オール合成
　イソプロピルアミンに代えて、アニリンを用いる他は全て参考例３０と同様に操作した。（外浴温度１９５－２００℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤ３ＯＤ）　δ　３．６６－３．７８（ｍ，３Ｈ），３．９５（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝３．９１Ｈｚ，１Ｈ），４．１６－４．２１（ｍ，２Ｈ），６．６０－６．６８（ｍ，３Ｈ），７．０８－７．１３（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤ３ＯＤ）　δ　６２．６６（ＣＨ），７２．９６（ＣＨ２），７４．９５（ＣＨ２），７６．５２（ＣＨ），１１４．１１（ＣＨ），１１８．２４（ＣＨ），１３０．０７（ＣＨ），１４８．７２（Ｃ）
分析条件Ｖ　保持時間　５０．８分、５１．２分 Reference Example 38 synthesis of trans-4- (phenylamino) tetrahydrofuran-3-ol The same operation as in Reference Example 30 was performed except that aniline was used instead of isopropylamine. (Outer bath temperature 195-200 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CD 3 OD) δ 3.66-3.78 (m, 3H), 3.95 (dd, J1 = 9.61 Hz, J2 = 3.91 Hz, 1H), 4. 16-4.21 (m, 2H), 6.60-6.68 (m, 3H), 7.08-7.13 (m, 2H)
13 C-NMR (75.45 MHz, CD 3 OD) δ 62.66 (CH), 72.96 (CH2), 74.95 (CH2), 76.52 (CH), 114.11 (CH), 118 .24 (CH), 130.07 (CH), 148.72 (C)
Analysis condition V Retention time 50.8 minutes, 51.2 minutes
参考例３９　ｔｒａｎｓ－４－（２－フェニルエチルアミノ）テトラヒドロフラン－３－オール合成
　イソプロピルアミンに代えて、２－フェニルエチルアミンを用いる他は全て参考例３０と同様に操作した。（外浴温度１９０－１９５℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　２．７６－２．９０（ｍ，４Ｈ），３．１５（ｓ，１Ｈ），３．５１（ｄｄ，Ｊ１＝９．０１Ｈｚ，Ｊ２＝３．３０Ｈｚ，１Ｈ），３．６３（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝１．８０Ｈｚ，１Ｈ），３．９３（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝４．８１Ｈｚ，１Ｈ），４．００－４．０８（ｍ，２Ｈ），７．１７－７．３１（ｍ，５Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　３６．１７（ＣＨ２），４９．２８（ＣＨ２），６６．５６（ＣＨ），７２．１７（ＣＨ２），７３．９２（ＣＨ２），７６．２８（ＣＨ），１２６．２７（ＣＨ），１２８．４７（ＣＨ），１２８．５３（ＣＨ），１３９．３４（Ｃ）
分析条件γ　保持時間　２９．２分、２９．４分 Reference Example 39 Synthesis of trans-4- (2-phenylethylamino) tetrahydrofuran-3-ol The same procedure as in Reference Example 30 was performed except that 2-phenylethylamine was used instead of isopropylamine. (Outer bath temperature 190-195 ° C, pressure 0.1mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 2.76-2.90 (m, 4H), 3.15 (s, 1H), 3.51 (dd, J1 = 9.01 Hz, J2 = 3 .30 Hz, 1H), 3.63 (dd, J1 = 9.61 Hz, J2 = 1.80 Hz, 1H), 3.93 (dd, J1 = 9.61 Hz, J2 = 4.81 Hz, 1H), 4. 00-4.08 (m, 2H), 7.17-7.31 (m, 5H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 36.17 (CH2), 49.28 (CH2), 66.56 (CH), 72.17 (CH2), 73.92 (CH2), 76. 28 (CH), 126.27 (CH), 128.47 (CH), 128.53 (CH), 139.34 (C)
Analysis condition γ Retention time 29.2 minutes, 29.4 minutes
参考例４０　ｔｒａｎｓ－４－（ベンジルアミノ）テトラヒドロフラン－３－オール合成
　イソプロピルアミンに代えて、ベンジルアミンを用いる他は全て参考例３０と同様に操作した。（外浴温度１８５－１９０℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　３．１５（ｓ，１Ｈ），３．５４（ｄｄ，Ｊ１＝９．３１Ｈｚ，Ｊ２＝３．３０Ｈｚ，１Ｈ），３．６２（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝１．８０Ｈｚ，１Ｈ），３．７４（ｓ，２Ｈ），３．９４（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝４．５１Ｈｚ，１Ｈ），４．００（ｄｄ，Ｊ１＝９．３１Ｈｚ，Ｊ２＝５．７１Ｈｚ，１Ｈ），４．０８－４．１０（ｍ，１Ｈ），７．２２－７．３４（ｍ，５Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　５２．０３（ＣＨ２），６５．８２（ＣＨ），７２．０８（ＣＨ２），７３．８２（ＣＨ２），７６．１８（ＣＨ），１２７．１５（ＣＨ），１２８．０７（ＣＨ），１２８．４２（ＣＨ），１３９．３７（Ｃ）
分析条件γ　保持時間　２９．１分、２９．３分 Reference Example 40 Synthesis of trans-4- (benzylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that benzylamine was used instead of isopropylamine. (Outer bath temperature 185-190 ° C, pressure 0.1 mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 3.15 (s, 1H), 3.54 (dd, J1 = 9.31 Hz, J2 = 3.30 Hz, 1H), 3.62 (dd, J1 = 9.61 Hz, J2 = 1.80 Hz, 1H), 3.74 (s, 2H), 3.94 (dd, J1 = 9.61 Hz, J2 = 4.51 Hz, 1H), 4.00 (dd, J1 = 9.31 Hz, J2 = 5.71 Hz, 1H), 4.08-4.10 (m, 1H), 7.22-7.34 (m, 5H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 52.03 (CH2), 65.82 (CH), 72.08 (CH2), 73.82 (CH2), 76.18 (CH), 127. 15 (CH), 128.07 (CH), 128.42 (CH), 139.37 (C)
Analysis condition γ Retention time 29.1 minutes, 29.3 minutes
参考例４１　ｔｒａｎｓ－４－（３－エトキシプロピルアミノ）テトラヒドロフラン－３－オール合成
　イソプロピルアミンに代えて、３－エトキシプロピルアミンを用いる他は全て参考例３０と同様に操作した。得られた粗体は、そのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．１９（ｔ，Ｊ＝６．９１Ｈｚ，３Ｈ），１．７６（ｑｕｉｎ，Ｊ＝６．６１Ｈｚ，２Ｈ），２．６９－２．７３（ｍ，２Ｈ），３．１３－３．１７（ｍ，１Ｈ），３．４６－３．５１（ｍ，４Ｈ），３．５７（ｄｄ，Ｊ１＝９．０１Ｈｚ，Ｊ２＝３．３０Ｈｚ，１Ｈ），３．６６（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝２．４０Ｈｚ，１Ｈ），３．９８（ｄｄ，Ｊ１＝９．６１Ｈｚ，Ｊ２＝４．８１Ｈｚ，１Ｈ），４．０６（ｄｄ，Ｊ１＝９．０１Ｈｚ，Ｊ２＝５．４１Ｈｚ，１Ｈ），４．１４（ｑｕｉｎ，Ｊ＝２．４０Ｈｚ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　１４．９８（ＣＨ３），２９．７８（ＣＨ２），４５．７４（ＣＨ２），６６．０５（ＣＨ２），６６．５５（ＣＨ），６８．８９（ＣＨ２），７２．０８（ＣＨ２），７３．８４（ＣＨ２），７５．９１（ＣＨ）
分析条件ζ　保持時間　７．３分、９．１分 Reference Example 41 synthesis of trans-4- (3-ethoxypropylamino) tetrahydrofuran-3-ol All operations were performed in the same manner as in Reference Example 30 except that 3-ethoxypropylamine was used instead of isopropylamine. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.19 (t, J = 6.91 Hz, 3H), 1.76 (quin, J = 6.61 Hz, 2H), 2.69-2.73 (M, 2H), 3.13-3.17 (m, 1H), 3.46-3.51 (m, 4H), 3.57 (dd, J1 = 9.01 Hz, J2 = 3.30 Hz, 1H), 3.66 (dd, J1 = 9.61 Hz, J2 = 2.40 Hz, 1H), 3.98 (dd, J1 = 9.61 Hz, J2 = 4.81 Hz, 1H), 4.06 (dd , J1 = 9.01 Hz, J2 = 5.41 Hz, 1H), 4.14 (quin, J = 2.40 Hz, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 14.98 (CH3), 29.78 (CH2), 45.74 (CH2), 66.05 (CH2), 66.55 (CH), 68. 89 (CH2), 72.08 (CH2), 73.84 (CH2), 75.91 (CH)
Analysis condition ζ Retention time 7.3 minutes, 9.1 minutes
参考例４２　ｔｒａｎｓ－２－（イソプロピルアミノ）シクロヘプタノール合成
　エポキシドとして８－オキサビシクロ［５．１．０］オクタンを用いる他は参考例１同様に操作した。得られた粗体は、そのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．０２（ｄ，Ｊ＝６．０１Ｈｚ，３Ｈ），１．０６（ｄ，Ｊ＝６．０１Ｈｚ，３Ｈ），１．３６－１．７２（ｍ，８Ｈ），１．８８－２．０５（ｍ，２Ｈ），２．２３－２．３１（ｍ，１Ｈ），２．９４（ｓｅｐ，Ｊ＝６．０１Ｈｚ，１Ｈ），３．０８－３．１４（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２２．３５（ＣＨ３），２２．５６（ＣＨ２），２４．０７（ＣＨ３），２４．３８（ＣＨ２），２６．５０（ＣＨ２），３０．６９（ＣＨ２），３２．９６（ＣＨ２），４５．５６（ＣＨ），６２．５２（ＣＨ），７５．０９（ＣＨ）
分析条件Ｗ　保持時間　９．４分、９．５分 Reference Example 42 synthesis of trans-2- (isopropylamino) cycloheptanol The same operation as in Reference Example 1 was conducted except that 8-oxabicyclo [5.1.0] octane was used as the epoxide. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.02 (d, J = 6.01 Hz, 3H), 1.06 (d, J = 6.01 Hz, 3H), 1.36-1.72 (M, 8H), 1.88-2.05 (m, 2H), 2.23-2.31 (m, 1H), 2.94 (sep, J = 6.01 Hz, 1H), 3.08 -3.14 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 22.35 (CH3), 22.56 (CH2), 24.07 (CH3), 24.38 (CH2), 26.50 (CH2), 30. 69 (CH2), 32.96 (CH2), 45.56 (CH), 62.52 (CH), 75.09 (CH)
Analysis condition W Retention time 9.4 minutes, 9.5 minutes
参考例４３　ｔｒａｎｓ－２－（シクロプロピルアミノ）シクロヘプタノール合成
　イソプロピルアミンに代えて、シクロプロピルアミンを用いる他は全て参考例４２と同様に操作した。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．２２－０．５６（ｍ，４Ｈ），１．２１－１．３２（ｍ，１Ｈ），１．３９－１．７１（ｍ，７Ｈ），１．８９－１．９９（ｍ，１Ｈ），２．０７－２．１４（ｍ，１Ｈ），２．２１－２．２８（ｍ，１Ｈ），２．３３－２．４１（ｍ，１Ｈ），３．０６－３．１６（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　６．２０（ＣＨ２），７．１３（ＣＨ２），２２．０３（ＣＨ２），２３．７１（ＣＨ２），２６．５５（ＣＨ２），２７．６２（ＣＨ），　２９．９０（ＣＨ２），３２．７５（ＣＨ２），６５．７６（ＣＨ），７４．９０（ＣＨ）
分析条件γ　保持時間　２５．８分、３０．８分 Reference Example 43 synthesis of trans-2- (cyclopropylamino) cycloheptanol All operations were performed in the same manner as Reference Example 42 except that cyclopropylamine was used instead of isopropylamine.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.22-0.56 (m, 4H), 1.21-1.32 (m, 1H), 1.39-1.71 (m, 7H) ), 1.89-1.99 (m, 1H), 2.07-2.14 (m, 1H), 2.21-2.28 (m, 1H), 2.33-2.41 (m , 1H), 3.06-3.16 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 6.20 (CH2), 7.13 (CH2), 22.03 (CH2), 23.71 (CH2), 26.55 (CH2), 27. 62 (CH), 29.90 (CH2), 32.75 (CH2), 65.76 (CH), 74.90 (CH)
Analysis condition γ Retention time 25.8 minutes, 30.8 minutes
参考例４４　ｔｒａｎｓ－２－（２－フェニルエチルアミノ）シクロヘプタノール合成
　イソプロピルアミンに代えて、２－フェニルエチルアミンを用いる他は全て参考例４２と同様に操作した。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．０９－１．２０（ｍ，１Ｈ），１．３３－１．６７（ｍ，７Ｈ），１．８３－１．９８（ｍ，２Ｈ），２．２４（ｄｔ，Ｊ１＝９．３１Ｈｚ，Ｊ２＝２．７０Ｈｚ，１Ｈ），２．６７－３．０７（ｍ，５Ｈ），３．１３－３．２０（ｍ，１Ｈ），７．１５－７．２９（ｍ，５Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２１．９５（ＣＨ２），２３．８０（ＣＨ２），２６．５２（ＣＨ２），２９．２７（ＣＨ２），３３．２５（ＣＨ２），３６．５５（ＣＨ２），４７．９９（ＣＨ２），６５．３９（ＣＨ），７４．９６（ＣＨ），１２５．８３（ＣＨ），１２８．１１（ＣＨ），１２８．３４（ＣＨ），１３９．６５（Ｃ）
分析条件β　保持時間　９．７分、１２．４分 Reference Example 44 synthesis of trans-2- (2-phenylethylamino) cycloheptanol The same operation as in Reference Example 42 was performed except that 2-phenylethylamine was used instead of isopropylamine.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.09-1.20 (m, 1H), 1.33-1.67 (m, 7H), 1.83-1.98 (m, 2H) ), 2.24 (dt, J1 = 9.31 Hz, J2 = 2.70 Hz, 1H), 2.67-3.07 (m, 5H), 3.13-3.20 (m, 1H), 7 .15-7.29 (m, 5H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 21.95 (CH2), 23.80 (CH2), 26.52 (CH2), 29.27 (CH2), 33.25 (CH2), 36. 55 (CH2), 47.99 (CH2), 65.39 (CH), 74.96 (CH), 125.83 (CH), 128.11 (CH), 128.34 (CH), 139.65 (C)
Analysis condition β retention time 9.7 minutes, 12.4 minutes
参考例４５　ｔｒａｎｓ－２－（ベンジルアミノ）シクロヘプタノール合成
　イソプロピルアミンに代えて、ベンジルアミンを用いる他は全て参考例４２と同様に操作した。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．１７－１．３０（ｍ，１Ｈ），　１．３４－１．７２（ｍ，７Ｈ），　１．８９－２．０２（ｍ，２Ｈ），　２．３２（ｄｔ，Ｊ１＝９．３１Ｈｚ，Ｊ２＝３．００Ｈｚ，１Ｈ），　３．１９－３．２６（ｍ，１Ｈ），３．６４（ｄ，Ｊ＝１２．６２Ｈｚ，１Ｈ），３．９０（ｄ，Ｊ＝１２．６２Ｈｚ，１Ｈ），　７．１９－７．３０（ｍ，５Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２２．００（ＣＨ２），２３．８０（ＣＨ２），２６．６５（ＣＨ２），２９．１１（ＣＨ２），３３．３１（ＣＨ２），５０．８８（ＣＨ２），６４．９０（ＣＨ），７５．２２（ＣＨ），１２６．８１（ＣＨ），１２７．９７（ＣＨ），１２８．１９（ＣＨ），１３９．８９（Ｃ）
分析条件β　保持時間　８．１分、１０．１分 Reference Example 45 synthesis of trans-2- (benzylamino) cycloheptanol All operations were performed in the same manner as in Reference Example 42 except that benzylamine was used instead of isopropylamine.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.17-1.30 (m, 1H), 1.34-1.72 (m, 7H), 1.89-2.02 (m, 2H) ), 2.32 (dt, J1 = 9.31 Hz, J2 = 3.00 Hz, 1H), 3.19-3.26 (m, 1H), 3.64 (d, J = 12.62 Hz, 1H) , 3.90 (d, J = 12.62 Hz, 1H), 7.19-7.30 (m, 5H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 22.00 (CH2), 23.80 (CH2), 26.65 (CH2), 29.11 (CH2), 33.31 (CH2), 50. 88 (CH2), 64.90 (CH), 75.22 (CH), 126.81 (CH), 127.97 (CH), 128.19 (CH), 139.89 (C)
Analysis condition β Retention time 8.1 minutes, 10.1 minutes
参考例４６　ｔｒａｎｓ－２－（プロパルギルアミノ）シクロヘプタノール合成
　イソプロピルアミンに代えて、プロパルギルアミンを用いる他は全て参考例４２と同様に操作した。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．２０－１．３１（ｍ，１Ｈ），１．３４－１．７４（ｍ，７Ｈ），１．８１－１．９８（ｍ，２Ｈ），２．２１－２．２６（ｍ，１Ｈ），２．４４－２．５２（ｍ，１Ｈ），３．２６－３．３３（ｍ，１Ｈ），３．３８－３．５５（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２２．００（ＣＨ２），２３．５４（ＣＨ２），２６．７６（ＣＨ２），２８．６３（ＣＨ２），３３．６９（ＣＨ２），３５．６５（ＣＨ２），６４．４２（ＣＨ），７１．１０（Ｃ），７５．４１（ＣＨ），８２．０３（ＣＨ）
分析条件Ｘ　保持時間　２２．０分、２２．３分 Reference Example 46 synthesis of trans-2- (propargylamino) cycloheptanol All operations were performed in the same manner as in Reference Example 42 except that propargylamine was used instead of isopropylamine.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.20-1.31 (m, 1H), 1.34-1.74 (m, 7H), 1.81-1.98 (m, 2H) ), 2.21-2.26 (m, 1H), 2.44-2.52 (m, 1H), 3.26-3.33 (m, 1H), 3.38-3.55 (m , 2H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 22.00 (CH2), 23.54 (CH2), 26.76 (CH2), 28.63 (CH2), 33.69 (CH2), 35. 65 (CH2), 64.42 (CH), 71.10 (C), 75.41 (CH), 82.03 (CH)
Analysis condition X Retention time 22.0 minutes, 22.3 minutes
参考例４７　ｔｒａｎｓ－２－（シクロペンチルアミノ）シクロヘプタノール合成
　イソプロピルアミンに代えて、シクロペンチルアミンを用いる他は全て参考例４２と同様に操作した。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．１０－２．０５（ｍ，１８Ｈ），２．２３（ｄｔ，Ｊ１＝９．３１Ｈｚ，Ｊ２＝３．００Ｈｚ，１Ｈ），３．０７－３．１４（ｍ，１Ｈ），３．２２（ｑｕｉｎ，Ｊ＝６．０１Ｈｚ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２２．２８（ＣＨ２），２３．４７（ＣＨ２），２３．６９（ＣＨ２），２４．０３（ＣＨ２），２６．４９（ＣＨ２），３０．１５（ＣＨ２），３２．７７（ＣＨ２），３３．０３（ＣＨ２），３４．２６（ＣＨ２），５６．３３（ＣＨ），６３．６３（ＣＨ），７５．０９（ＣＨ）
分析条件Ｙ　保持時間　２１．０分、２１．２分 Reference Example 47 synthesis of trans-2- (cyclopentylamino) cycloheptanol All operations were performed in the same manner as Reference Example 42 except that cyclopentylamine was used instead of isopropylamine.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.10-2.05 (m, 18H), 2.23 (dt, J1 = 9.31 Hz, J2 = 3.00 Hz, 1H), 3.07 -3.14 (m, 1H), 3.22 (quin, J = 6.01 Hz, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 22.28 (CH2), 23.47 (CH2), 23.69 (CH2), 24.03 (CH2), 26.49 (CH2), 30. 15 (CH2), 32.77 (CH2), 33.03 (CH2), 34.26 (CH2), 56.33 (CH), 63.63 (CH), 75.09 (CH)
Analysis condition Y Retention time 21.0 minutes, 21.2 minutes
参考例４８　ｔｒａｎｓ－２－（ジエチルアミノ）シクロヘプタノール合成
　イソプロピルアミンに代えて、ジエチルアミンを用いる他は全て参考例４２と同様に操作した。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．０９（ｔ，Ｊ＝７．２１Ｈｚ，６Ｈ），１．１９－１．７８（ｍ，９Ｈ），２．０１－２．０９（ｍ，１Ｈ），２．３４－２．５２（ｍ，３Ｈ），２．６４－２．７６（ｍ，２Ｈ），３．３８－３．４５（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　１４．０８（ＣＨ３），２２．００（ＣＨ２），２２．４７（ＣＨ２），２４．７４（ＣＨ２），２６．９０（ＣＨ２），３３．５２（ＣＨ２），４３．５９（ＣＨ２），６７．３７（ＣＨ），７１．２７（ＣＨ）
分析条件Ｃ　保持時間　２１．０分、２１．２分 Reference Example 48 synthesis of trans-2- (diethylamino) cycloheptanol All operations were performed in the same manner as in Reference Example 42 except that diethylamine was used instead of isopropylamine.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.09 (t, J = 7.21 Hz, 6H), 1.19-1.78 (m, 9H), 2.01-2.09 (m , 1H), 2.34-2.52 (m, 3H), 2.64-2.76 (m, 2H), 3.38-3.45 (m, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 14.08 (CH3), 22.00 (CH2), 22.47 (CH2), 24.74 (CH2), 26.90 (CH2), 33. 52 (CH2), 43.59 (CH2), 67.37 (CH), 71.27 (CH)
Analysis condition C Retention time 21.0 minutes, 21.2 minutes
参考例４９　ｔｒａｎｓ－２－（１－ピペリジニル）シクロヘプタノール合成
　イソプロピルアミンに代えて、ピペリジンを用いる他は全て参考例４２と同様に操作した。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．１４－１．２６（ｍ，１Ｈ），１．３０－１．８３（ｍ，１４Ｈ），２．０１－２．０８（ｍ，１Ｈ），２．１４－２．２１（ｍ，１Ｈ），２．３１－２．３３（ｍ，２Ｈ），２．６０－２．６７（ｍ，２Ｈ），３．３３－３．４１（ｍ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２１．４６（ＣＨ２），２１．６７（ＣＨ２），２４．０２（ＣＨ２），２４．４０（ＣＨ２），２６．２２（ＣＨ２），２６．４４（ＣＨ２），３３．０３（ＣＨ２），４８．９６（ＣＨ２），７０．６０（ＣＨ），７１．８８（ＣＨ）
分析条件Ｚ　保持時間　２１．０分、２１．２分 Reference Example 49 synthesis of trans-2- (1-piperidinyl) cycloheptanol All operations were performed in the same manner as in Reference Example 42 except that piperidine was used instead of isopropylamine.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.14-1.26 (m, 1H), 1.30-1.83 (m, 14H), 2.01-2.08 (m, 1H) ), 2.14-2.21 (m, 1H), 2.31-2.33 (m, 2H), 2.60-2.67 (m, 2H), 3.33-3.41 (m) , 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 21.46 (CH2), 21.67 (CH2), 24.02 (CH2), 24.40 (CH2), 26.22 (CH2), 26. 44 (CH2), 33.03 (CH2), 48.96 (CH2), 70.60 (CH), 71.88 (CH)
Analysis condition Z Retention time 21.0 minutes, 21.2 minutes
参考例５０　ｔｒａｎｓ－２－アミノシクロヘキサノール
　ｔｒａｎｓ－２－アミノシクロヘキサン－１－オールは、シグマアルドリッチ社製のものをそのまま用いた。
分析条件Ａ　保持時間　（Ｓ，Ｓ）体：１８．３分、（Ｒ，Ｒ）体：１８．７分 Reference Example 50 trans-2-aminocyclohexanol The trans-2-aminocyclohexane-1-ol manufactured by Sigma-Aldrich was used as it was.
Analysis condition A Retention time (S, S) isomer: 18.3 minutes, (R, R) isomer: 18.7 minutes
参考例５１　ｔｒａｎｓ－３－シクロプロピルアミノ－２－ブタノール
　Ｃｉｓ－２，３－エポキシブタンとシクロプロピルアミンを用いる他は、参考例１と同様に操作した。得られた粗体は、そのまま分析に用いた。（外浴温度１３５－１４０℃、圧力０．１ｍｍＨｇ）
分析条件Ｇ　保持時間　１１．０分、１１．３分 Reference Example 51 The same procedure as in Reference Example 1 was conducted except that trans-3-cyclopropylamino-2-butanol Cis-2,3-epoxybutane and cyclopropylamine were used. The obtained crude product was used for analysis as it was. (Outer bath temperature 135-140 ° C, pressure 0.1mmHg)
Analysis condition G Retention time 11.0 minutes, 11.3 minutes
参考例５２　ｔｒａｎｓ－２－（２－プロピルチオ）シクロヘキサノール
　５０ｍＬナスフラスコに７－オキサビシクロ［４．１．０］ヘプタン　２．００ｇと２－プロパンチオール１．７０ｍＬを量りとり、メタノール８ｍＬと水２ｍＬ、トリエチルアミン２．８４ｍＬを加え、５０℃で２０時間反応した。反応後、減圧下に濃縮し、残渣３．１２ｇ得た。残渣１．００ｇを柴田科学社製ガラスチューブオーブンＧＴＯ－２５０ＲＳ（クーゲルロール）で減圧蒸留し、ｔｒａｎｓ－２－（２－プロピルチオ）シクロヘキサン－１－オールを０．７７ｇ得た。（外浴温度１４０－１５０℃、圧力０．１ｍｍＨｇ）
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．２０－１．５１（ｍ，４Ｈ），１．２９（ｄ，Ｊ＝６．６１Ｈｚ，３Ｈ），１．３０（ｄ，Ｊ＝６．６１Ｈｚ，３Ｈ），１．６８－１．７９（ｍ，２Ｈ），２．０７－２．１５（ｍ，２Ｈ），２．３８－２．４６（ｍ，１Ｈ），３．０３（ｓｅｐ．，Ｊ＝６．６１Ｈｚ，１Ｈ），３．２６（ｄｔ，Ｊ１＝４．５１Ｈｚ，Ｊ２＝９．９１Ｈｚ，１Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２４．２４（ＣＨ３），２４．３１（ＣＨ２），２４．３９（ＣＨ３），２６．２３（ＣＨ２），３３．６７（ＣＨ２），３４．０５（ＣＨ２），３５．０８（ＣＨ），５３．５８（ＣＨ），７２．５６（ＣＨ）
分析条件ＡＢ　保持時間　１７．６分，１８．８分 Reference Example 52 trans-2- (2-propylthio) cyclohexanol 50 mL of 7-oxabicyclo [4.1.0] heptane and 1.70 mL of 2-propanethiol were weighed into a 50 mL eggplant flask, 8 mL of methanol, and 2 mL of water. Then, 2.84 mL of triethylamine was added and reacted at 50 ° C. for 20 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 3.12 g of a residue. 1.00 g of the residue was distilled under reduced pressure using a glass tube oven GTO-250RS (Kugel Roll) manufactured by Shibata Kagaku Co., Ltd., to obtain 0.77 g of trans-2- (2-propylthio) cyclohexane-1-ol. (Outer bath temperature 140-150 ° C, pressure 0.1mmHg)
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.20-1.51 (m, 4H), 1.29 (d, J = 6.61 Hz, 3H), 1.30 (d, J = 6 .61 Hz, 3H), 1.68-1.79 (m, 2H), 2.07-2.15 (m, 2H), 2.38-2.46 (m, 1H), 3.03 (sep ., J = 6.61 Hz, 1H), 3.26 (dt, J1 = 4.51 Hz, J2 = 9.91 Hz, 1H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 24.24 (CH3), 24.31 (CH2), 24.39 (CH3), 26.23 (CH2), 33.67 (CH2), 34. 05 (CH2), 35.08 (CH), 53.58 (CH), 72.56 (CH)
Analysis condition AB Retention time 17.6 minutes, 18.8 minutes
参考例５３　７－トシル－７－アザビシクロ［４．１．０］ヘプタン
　温度計、攪拌子を設置した５０ｍＬ四つ口フラスコに２－アミノシクロヘキサノール１．００ｇ、ＴＨＦ１５ｍＬ，トリエチルアミン１．８１ｍＬを加え、氷冷し、内温３℃で塩化トシル１．７４ｇを加えた。この時内温は１０℃まで上昇した。氷冷下で３０分、室温（２６℃）で３０分攪拌した後、水２０ｍＬ、トルエン２０ｍＬを加えて分液し、トルエン層を水１０ｍＬで２回洗浄した。洗浄後のトルエン層を硫酸ナトリウムで乾燥し、ロータリーエバポレーターで減圧濃縮した。得られたオイルを真空ポンプで乾燥しｔｒａｎｓ－Ｎ－トシル－２－アミノシクロヘキサノール（結晶）を２．２７ｇ得た。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．１０－１．３０（ｍ，４Ｈ），１．５３－１．７６（ｍ，３Ｈ），２．００－２．０４（ｍ，１Ｈ），２．４３（ｓ，３Ｈ），２．６５（ｄ，Ｊ＝３．３０Ｈｚ，１Ｈ），２．８０－２．９０（ｍ，１Ｈ），３．２６－３．３５（ｍ，１Ｈ），４．９６（ｄ，Ｊ＝６．９１Ｈｚ，１Ｈ），７．３２（ｄ，Ｊ＝８．１１Ｈｚ，１Ｈ），７．８０（ｄ，Ｊ＝８．１１Ｈｚ，１Ｈ）
　温度計、攪拌子、塩化カルシウム管を設置した５０ｍＬ四つ口フラスコにｔｒａｎｓ－Ｎ－トシル－２－アミノシクロヘキサノール２．１７ｇ、トリフェニルホスフィン２．７５ｇ、ＴＨＦ２２ｍＬを加え、氷冷し、内温２℃でアゾジカルボン酸ジイソプロピル（９０．０＋％）２．１７ｇを滴下ロートを用いて１０分かけて滴下した。このとき内温は５℃まで上昇した。氷冷下で８０分、室温（２６℃）で６０分攪拌した後、水２０ｍＬ、酢酸エチル３０ｍＬを加えて分液し、酢酸エチル層をロータリーエバポレーターで減圧濃縮し、残渣７．２１ｇを得た。残渣をシリカゲル１４０ｇ、展開溶媒トルエン：酢酸エチル＝５：１を用いてカラムクロマトグラフィーを行い、７－トシル－７－アザビシクロ［４．１．０］ヘプタン１．３３ｇを得た。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　１．１５－１．２７（ｍ，２Ｈ），１．３５－１．４４（ｍ，２Ｈ），１．７９（ｔ，Ｊ＝５．１１Ｈｚ，４Ｈ），２．４４（ｓ，３Ｈ），２．９７－２．９８（ｍ，２Ｈ），７．３２（ｄ，Ｊ＝８．１１Ｈｚ，２Ｈ），７．８２（ｄ，Ｊ＝８．１１Ｈｚ，２Ｈ） Reference Example 53 7-tosyl-7-azabicyclo [4.1.0] heptane To a 50 mL four-necked flask equipped with a thermometer and a stirrer was added 1.00 g of 2-aminocyclohexanol, 15 mL of THF, and 1.81 mL of triethylamine. The mixture was ice-cooled and 1.74 g of tosyl chloride was added at an internal temperature of 3 ° C. At this time, the internal temperature rose to 10 ° C. After stirring for 30 minutes under ice cooling and 30 minutes at room temperature (26 ° C.), 20 mL of water and 20 mL of toluene were added for liquid separation, and the toluene layer was washed twice with 10 mL of water. The toluene layer after washing was dried over sodium sulfate and concentrated under reduced pressure using a rotary evaporator. The obtained oil was dried with a vacuum pump to obtain 2.27 g of trans-N-tosyl-2-aminocyclohexanol (crystal).
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.10-1.30 (m, 4H), 1.53-1.76 (m, 3H), 2.00-2.04 (m, 1H ), 2.43 (s, 3H), 2.65 (d, J = 3.30 Hz, 1H), 2.80-2.90 (m, 1H), 3.26-3.35 (m, 1H) ), 4.96 (d, J = 6.91 Hz, 1H), 7.32 (d, J = 8.11 Hz, 1H), 7.80 (d, J = 8.11 Hz, 1H)
To a 50 mL four-necked flask equipped with a thermometer, a stirrer, and a calcium chloride tube, add 2.17 g of trans-N-tosyl-2-aminocyclohexanol, 2.75 g of triphenylphosphine, and 22 mL of THF. At 2 ° C., 2.17 g of diisopropyl azodicarboxylate (90.0 +%) was added dropwise using a dropping funnel over 10 minutes. At this time, the internal temperature rose to 5 ° C. After stirring for 80 minutes under ice cooling and 60 minutes at room temperature (26 ° C.), 20 mL of water and 30 mL of ethyl acetate were added for liquid separation, and the ethyl acetate layer was concentrated under reduced pressure using a rotary evaporator to obtain 7.21 g of a residue. . The residue was subjected to column chromatography using 140 g of silica gel and a developing solvent toluene: ethyl acetate = 5: 1 to obtain 1.33 g of 7-tosyl-7-azabicyclo [4.1.0] heptane.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 1.15-1.27 (m, 2H), 1.35-1.44 (m, 2H), 1.79 (t, J = 5.11 Hz , 4H), 2.44 (s, 3H), 2.97-2.98 (m, 2H), 7.32 (d, J = 8.11 Hz, 2H), 7.82 (d, J = 8 .11Hz, 2H)
参考例５４　ｔｒａｎｓ－Ｎ－トシル－（２－（２－フェニルエチルアミノ）シクロヘキシルアミン）
　イソプロピルアミンに代えて、２－フェニルエチルアミンを、７－オキサビシクロ［４．１．０］ヘプタンに代えて、７－トシル－７－アザビシクロ［４．１．０］ヘプタンを用いる他はすべて参考例１と同様に操作した。得られた粗体はそのまま分析に用いた。
１Ｈ－ＮＭＲ（３００．４ＭＨｚ，ＣＤＣｌ３）　δ　０．８３－０．９４（ｍ，１Ｈ），１．０６－１．２５（ｍ，３Ｈ），１．５７－１．６３（ｍ，２Ｈ），１．９７－２．０７（ｍ，２Ｈ），２．１６－２．２４（ｍ，１Ｈ），２．３８（ｓ，３Ｈ），２．５４－２．６９（ｍ，４Ｈ），２．７８－２．８７（ｍ，１Ｈ），７．１３－７．３０（ｍ，７Ｈ），７．７０（ｄ，Ｊ＝８．１１Ｈｚ，２Ｈ）
１３Ｃ－ＮＭＲ（７５．４５ＭＨｚ，ＣＤＣｌ３）　δ　２１．２７（ＣＨ３），２４．２３（ＣＨ２），２４．４２（ＣＨ２），３０．８９（ＣＨ２），３２．３２（ＣＨ２），３６．４３（ＣＨ２），４６．９０（ＣＨ２），５７．０７（ＣＨ），６０．１１（ＣＨ），１２５．９２（ＣＨ），１２６．９７（ＣＨ），１２８．２２（ＣＨ），１２８．３９（ＣＨ），１２９．３５（ＣＨ），１３７．０９（Ｃ），１３９．６８（Ｃ），１４２．８９（Ｃ）
分析条件θ　保持時間：３７．２分、４０．６分 Reference Example 54 trans-N-tosyl- (2- (2-phenylethylamino) cyclohexylamine)
Reference Example except that 2-phenylethylamine was used in place of isopropylamine and 7-tosyl-7-azabicyclo [4.1.0] heptane was used in place of 7-oxabicyclo [4.1.0] heptane The same operation as in 1 was performed. The obtained crude product was used for analysis as it was.
1 H-NMR (300.4 MHz, CDCl 3 ) δ 0.83-0.94 (m, 1H), 1.06-1.25 (m, 3H), 1.57-1.63 (m, 2H) ), 1.97-2.07 (m, 2H), 2.16-2.24 (m, 1H), 2.38 (s, 3H), 2.54-2.69 (m, 4H), 2.78-2.87 (m, 1H), 7.13-7.30 (m, 7H), 7.70 (d, J = 8.11 Hz, 2H)
13 C-NMR (75.45 MHz, CDCl 3 ) δ 21.27 (CH3), 24.23 (CH2), 24.42 (CH2), 30.89 (CH2), 32.32 (CH2), 36. 43 (CH2), 46.90 (CH2), 57.07 (CH), 60.11 (CH), 125.92 (CH), 126.97 (CH), 128.22 (CH), 128.39 (CH), 129.35 (CH), 137.09 (C), 139.68 (C), 142.89 (C)
Analysis condition θ Retention time: 37.2 minutes, 40.6 minutes
＜触媒調製例＞
　本実施例で使用した触媒は、以下のようにして入手した。
　脱脂大豆粉、ペクチン（柑橘類由来）、水溶性大豆多糖類、カボチャ、レンコン、ジャガイモ、ニンジン、小麦胚芽、ウコンは、粉末状に加工されたものを入手した。
　キウイ、ブンタン、ナツミカン、花柚子、ニンニク、大豆、ネギ、ピスタチオ、カシューナッツ、茶（紅茶、緑茶）、赤インゲンマメ、エンドウマメなど加工していない植物片は、必要に応じて加温されたデシケーターで乾燥し、約５ｇを小型粉砕器“粉砕くん”（柴田化学器械工業社製、ＳＣＭ－４０Ａ）にて３０秒間粉砕した後、ヘキサン５０ｍＬを加えて分散させ、ヘキサンを除去した後、得られた粉末を減圧下乾燥した。 <Catalyst preparation example>
The catalyst used in this example was obtained as follows.
The defatted soybean powder, pectin (citrus-derived), water-soluble soybean polysaccharide, pumpkin, lotus root, potato, carrot, wheat germ, and turmeric were processed into powder.
Unprocessed plant pieces such as kiwi, buntan, natsum, flower aubergine, garlic, soy, leek, pistachio, cashew nut, tea (tea, green tea), red kidney beans, peas, etc. are heated in a desiccator if necessary. After drying, about 5 g was pulverized for 30 seconds with a small pulverizer “Crusher-kun” (SCM-40A, manufactured by Shibata Chemical Instruments Co., Ltd.), dispersed by adding 50 mL of hexane, and obtained after removing hexane. The powder was dried under reduced pressure.
＜実施例１～２７＞
　５ｍＬの試験管に、表３に記載の植物加工物１００ｍｇを量りとり、トルエン０．４ｍＬ、７－オキサビシクロ［４．１．０］ヘプタン４８ｍｇ、シクロプロピルアミン３４ｍｇ、水１７ｍｇを加えた。密閉し、３７℃の温浴で１６時間振とうした。反応後、触媒をろ過し、ＧＣにて変換率と選択率を測定した。なお、カボチャとして「パンプキンパウダー」（こだま食品製）、ジャガイモとして「マッシュポテト」（三木食品製）、ニンジンとして「キャロットパウダー」（こだま食品製）、トマトとして「トマトパウダー」（こだま食品製）、ダイコンとして「乾燥大根おろし」（こだま食品製）、レンコンとして「れんこんパウダー」（こだま食品製）を粉末状に粉砕して使用した。また、ピスタチオは、脱脂した後に粉砕したものを使用した。
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-T000028
 ＊：ペクチンとして、「ペクチン（柑橘類由来）」（関東化学製、Ｃａｔ　Ｎｏ．３２５３６－３２）を使用した。 <Examples 1 to 27>
To a 5 mL test tube, 100 mg of the processed plant product described in Table 3 was weighed, and 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, 34 mg of cyclopropylamine, and 17 mg of water were added. Sealed and shaken in a 37 ° C. bath for 16 hours. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC. Pumpkin powder (made by Kodama Foods) as pumpkin, Mashed Potato (made by Miki Foods) as potato, Carrot Powder (made by Kodama Foods) as carrot, Tomato Powder (made by Kodama Foods) as tomato, Japanese radish “Dried radish grated” (manufactured by Kodama Foods) and “renkon powder” (manufactured by Kodama Foods) were ground and used as lotus root. The pistachio used was degreased and then pulverized.
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-T000028
 *: “Pectin (derived from citrus fruits)” (Cat No. 32536-32, manufactured by Kanto Kagaku) was used as the pectin.
　結果を表３に示した。実施例１～２７では、立体選択的に化合物（３）が得られた。特に、実施例１，２，１１および１３は、変換率、立体選択性ともに優れていた。 The results are shown in Table 3. In Examples 1 to 27, compound (3) was obtained stereoselectively. In particular, Examples 1, 2, 11 and 13 were excellent in both conversion rate and stereoselectivity.
実施例２８～４７
　５ｍＬの試験管に、表４に記載の植物加工物１００ｍｇを量りとり、トルエン０．４ｍＬ、７－オキサビシクロ［４．１．０］ヘプタン４８ｍｇ、イソプロピルアミン２９ｍｇ、水１７ｍｇを加えた。密閉し、４０℃の温浴で６日間振とうした。反応後、触媒をろ過し、ＧＣにて変換率と選択率を測定した。なお、カボチャとして「パンプキンパウダー」（こだま食品製）、ジャガイモとして「マッシュポテト」（三木食品製）、ニンジンとして「キャロットパウダー」（こだま食品製）、トマトとして「トマトパウダー」（こだま食品製）、ダイコンとして「乾燥大根おろし」（こだま食品製）、レンコンとして「れんこんパウダー」（こだま食品製）を粉末状に粉砕して使用し、ピスタチオは、脱脂した後に粉砕したものを使用した。 Examples 28-47
To a 5 mL test tube, 100 mg of the processed plant product described in Table 4 was weighed, and 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, 29 mg of isopropylamine, and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC. Pumpkin powder (made by Kodama Foods) as pumpkin, Mashed Potato (made by Miki Foods) as potato, Carrot Powder (made by Kodama Foods) as carrot, Tomato Powder (made by Kodama Foods) as tomato, Japanese radish “Dried radish grated” (manufactured by Kodama Foods), “Loren powder” (manufactured by Kodama Foods) as a lotus root was pulverized into a powder form, and pistachio was degreased and pulverized.
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
　結果を表４に示した。実施例２８～４７では、立体選択的に化合物（３）が得られた。特に、実施例２８～３１，３３，３９，４３および４６は、変換率、立体選択性ともに優れていた。 The results are shown in Table 4. In Examples 28 to 47, compound (3) was obtained stereoselectively. In particular, Examples 28 to 31, 33, 39, 43 and 46 were excellent in both conversion rate and stereoselectivity.
実施例４８～６３
　５ｍＬの試験管に、水溶性大豆多糖類（ソヤファイブＳ―ＤＮ）１００ｍｇを量りとり、トルエン０．４ｍＬ、７－オキサビシクロ［４．１．０］ヘプタン４８ｍｇ、表５に記載の化合物（２）１．２当量、水１７ｍｇを加えた。密閉し、４０℃の温浴で６日間振とうした。反応後、触媒をろ過し、ＧＣにて変換率と選択率を測定した。 Examples 48-63
In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) was weighed, 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, compound (2) shown in Table 5 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
　結果を表５に示した。実施例４８～６３では、立体選択的に化合物（３）が収率よく得られた。 The results are shown in Table 5. In Examples 48 to 63, the compound (3) was obtained in good yield in a stereoselective manner.
実施例６４～７６
　５ｍＬの試験管に、ニンジン１００ｍｇを量りとり、トルエン０．４ｍＬ、７－オキサビシクロ［４．１．０］ヘプタン４８ｍｇ、表６に記載の化合物（２）１．２当量、水１７ｍｇを加えた。密閉し、４０℃の温浴で６日間振とうした。反応後、触媒をろ過し、ＧＣにて変換率と選択率を測定した。 Examples 64-76
To a 5 mL test tube, 100 mg of carrot was weighed, and 0.4 mL of toluene, 48 mg of 7-oxabicyclo [4.1.0] heptane, 1.2 equivalents of the compound (2) described in Table 6 and 17 mg of water were added. . Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
　結果を表６に示した。実施例６４～７６では、立体選択的に化合物（３）が得られた。特に、実施例６９および７５は、変換率、立体選択性ともに優れていた。 The results are shown in Table 6. In Examples 64-76, compound (3) was obtained stereoselectively. In particular, Examples 69 and 75 were excellent in both conversion rate and stereoselectivity.
実施例７７～８８
　５ｍＬの試験管に、水溶性大豆多糖類（ソヤファイブＳ―ＤＮ）１００ｍｇを量りとり、トルエン０．４ｍＬ、６－オキサビシクロ［３．１．０］ヘキサン４１ｍｇ、表７に記載の化合物（２）１．２当量、水１７ｍｇを加えた。密閉し、４０℃の温浴で６日間振とうした。反応後、触媒をろ過し、ＧＣにて変換率と選択率を測定した。 Examples 77-88
In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) is weighed, 0.4 mL of toluene, 41 mg of 6-oxabicyclo [3.1.0] hexane, compound (2) shown in Table 7 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
　結果を表７に示した。実施例７７～８８は全て、立体選択性、収率ともに優れていた。 The results are shown in Table 7. Examples 77 to 88 were all excellent in stereoselectivity and yield.
実施例８９～１００
　５ｍＬの試験管に、水溶性大豆多糖類（ソヤファイブＳ―ＤＮ）１００ｍｇを量りとり、トルエン０．４ｍＬ、３，６－ジオキサビシクロ［３．１．０］ヘキサン４２ｍｇ、表８に記載の化合物（２）１．２当量、水１７ｍｇを加えた。密閉し、４０℃の温浴で６日間振とうした。反応後、触媒をろ過し、ＧＣにて変換率と選択率を測定した。 Examples 89-100
In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) is weighed, 0.4 mL of toluene, 42 mg of 3,6-dioxabicyclo [3.1.0] hexane, and the compounds described in Table 8 (2) 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
　結果を表８に示した。実施例８９～１００は全て、立体選択性、収率ともに優れていた。 The results are shown in Table 8. Examples 89 to 100 were all excellent in stereoselectivity and yield.
実施例１０１～１０８
　５ｍＬの試験管に、水溶性大豆多糖類（ソヤファイブＳ－ＤＮ）１００ｍｇを量りとり、トルエン０．４ｍＬ、８－オキサビシクロ［５．１．０］オクタン４１ｍｇ、表９に記載の化合物（２）１．２当量、水１７ｍｇを加えた。密閉し、４０℃の温浴で６日間振とうした。反応後、触媒をろ過し、ＧＣにて変換率と選択率を測定した。 Examples 101-108
In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) was weighed, 0.4 mL of toluene, 41 mg of 8-oxabicyclo [5.1.0] octane, compound (2) shown in Table 9 1.2 equivalents and 17 mg of water were added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC.
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
　結果を表９に示した。実施例１０１～１０８は全て、立体選択的に化合物（３）を与えた。特に、実施例１０７は、変換率、立体選択性ともに優れていた。 The results are shown in Table 9. Examples 101-108 all gave compound (3) stereoselectively. In particular, Example 107 was excellent in both conversion rate and stereoselectivity.
実施例１０９
　５ｍＬの試験管に、水溶性大豆多糖類（ソヤファイブＳ－ＤＮ）１．１ｇを量りとり、トルエン２．８７ｍＬ、Ｃｉｓ－２，３－エポキシブタン４１ｍｇ、シクロプロピルアミン１．２当量、水３９０ｍｇを加えた。密閉し、４０℃の温浴で６日間振とうした。反応後、触媒をろ過し、ＧＣにて変換率と選択率を測定した。その結果、変換率５５％、選択率４％ｅｅであった。 Example 109
In a 5 mL test tube, weigh 1.1 g of water-soluble soybean polysaccharide (Soya Five S-DN), 2.87 mL of toluene, 41 mg of Cis-2,3-epoxybutane, 1.2 equivalent of cyclopropylamine, and 390 mg of water. added. Sealed and shaken in a 40 ° C. bath for 6 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC. As a result, the conversion was 55% and the selectivity was 4% ee.
実施例１１０～１１４
　攪拌機、温度計を装着した１Ｌ四つ口フラスコに、大豆加工物７０．０ｇ、トルエン１９８ｍＬ、水２８．０ｍＬ、７－オキサビシクロ［４．１．０］ヘプタン３５．０ｇおよびシクロプロピルアミン２４．４ｇを加え、窒素雰囲気下にて、４０℃で撹拌した。各実施例で使用した大豆加工物および反応時間を表１に示した。反応液を少量採取し、ガスクロマトグラフィーを用いて、所定の反応時間における変換率および選択率を算出した。 Examples 110-114
In a 1 L four-necked flask equipped with a stirrer and a thermometer, 70.0 g of processed soybean, 198 mL of toluene, 28.0 mL of water, 35.0 g of 7-oxabicyclo [4.1.0] heptane and 24. 4 g was added and stirred at 40 ° C. under a nitrogen atmosphere. Table 1 shows the processed soybean and reaction time used in each example. A small amount of the reaction solution was collected, and the conversion rate and selectivity at a predetermined reaction time were calculated using gas chromatography.
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
　結果を表１０に示した。実施例１１０～１１４は全て、立体選択的に化合物（３）を与えた。特に、実施例１１２～１１４は、変換率、立体選択性ともに優れていた。 The results are shown in Table 10. Examples 110 to 114 all gave compound (3) stereoselectively. In particular, Examples 112 to 114 were excellent in both conversion rate and stereoselectivity.
実施例１１５
　５ｍＬの試験管に、水溶性大豆多糖類（ソヤファイブＳ－ＤＮ）１００ｍｇを量りとり、トルエン０．４ｍＬ、７－オキサビシクロ［４．１．０］ヘプタン１００ｍｇ、２－プロパンチオール１０９ｍｇ、水１７ｍｇを加えた。密閉し、５０℃の温浴で５日間振とうした。反応後、触媒をろ過し、ＧＣにて変換率と選択率を測定した。その結果、変換率７％、選択率７２％ｅｅであった。 Example 115
In a 5 mL test tube, weigh 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN), and add 0.4 mL of toluene, 100 mg of 7-oxabicyclo [4.1.0] heptane, 109 mg of 2-propanethiol, and 17 mg of water. added. Sealed and shaken in a 50 ° C. bath for 5 days. After the reaction, the catalyst was filtered, and conversion and selectivity were measured by GC. As a result, the conversion rate was 7% and the selectivity rate was 72% ee.
実施例１１６
　５ｍＬの試験管に、水溶性大豆多糖類（ソヤファイブＳ－ＤＮ）１００ｍｇを量りとり、トルエン０．４ｍＬ、７－トシル－７－アザビシクロ［４．１．０］ヘプタン１００ｍｇ、２－フェニルエチルアミン５８ｍｇ、水１７ｍｇを加えた。密閉し、５０℃の温浴で５日間振とうした。反応後、触媒をろ過し、ろ液を濃縮し、ｔｒａｎｓ－Ｎ－トシル（２－（２－フェニルエチルアミノ）シクロヘキシルアミン）の粗体１２０ｍｇを得た。粗収率８１％、選択率４％ｅｅであった。 Example 116
In a 5 mL test tube, 100 mg of water-soluble soybean polysaccharide (Soya Five S-DN) was weighed, 0.4 mL of toluene, 100 mg of 7-tosyl-7-azabicyclo [4.1.0] heptane, 58 mg of 2-phenylethylamine, 17 mg of water was added. Sealed and shaken in a 50 ° C. bath for 5 days. After the reaction, the catalyst was filtered and the filtrate was concentrated to obtain 120 mg of a crude product of trans-N-tosyl (2- (2-phenylethylamino) cyclohexylamine). The crude yield was 81% and the selectivity was 4% ee.
実施例１１７　（１Ｒ，２Ｒ）－２－（シクロプロピルアミノ）シクロヘキサノールの合成
　攪拌機、温度計を装着した１Ｌ四つ口フラスコに、ソヤファイブＳ－ＤＮ７０．０ｇ、トルエン１９８ｍＬ、水２８．０ｍＬ、７－オキサビシクロ［４．１．０］ヘプタン３５．０ｇおよびシクロプロピルアミン２４．４ｇを加え、窒素雰囲気下にて、４０℃で２６時間撹拌した。ソヤファイブＳ－ＤＮを、ヌッチェを用いてろ別し、トルエン１４０ｍＬで洗浄した。得られたろ液を減圧下にて濃縮し、粗生成物として（１Ｒ，２Ｒ）－２－（シクロプロピルアミノ）シクロヘキサノール５８．４ｇ（含量５１．０ｇ、６４％ｅｅ、収率９２％）を得た。ここで、含量は、粗生成物の１Ｈ－ＮＭＲスペクトルを測定し、２－（シクロプロピルアミノ）シクロヘキサノールとトルエンとのプロトンの積分比を用いて、粗生成物の質量を基に算出した値である。
　攪拌機、温度計を装着した５Ｌ四つ口フラスコに、得られた粗生成物の（１Ｒ，２Ｒ）－２－（シクロプロピルアミノ）シクロヘキサノール３１７．５ｇ（含量２７２．４ｇ、６４％ｅｅ）とイソプロパノール２７２４ｍＬを加え、４０℃に昇温した後、フマル酸６１．１ｇと種晶Ａ１０ｍｇ、活性炭（精製白鷺（日本エンバイロケミカルズ社、商品名））２７．２ｇを加え、３０分間静置した。このとき、種晶Ａには、ラセミ体の２－シクロプロピルアミノシクロヘキサノールフマル酸塩を用いた。室温まで冷却し、さらに６０分間静置した後に、析出したラセミ体の２－（シクロプロピルアミノ）シクロヘキサノールフマル酸塩の結晶および活性炭を、ヌッチェを用いてろ別し、イソプロパノール２７２ｍＬで結晶を洗浄した。得られたろ液をロータリーエバポレーターで減圧下、濃縮した。得られた（１Ｒ，２Ｒ）－２－（シクロプロピルアミノ）シクロヘキサノールにトルエン１４９８ｍＬ、水３４．５ｍＬおよび水酸化カリウム４０．３ｇを加えて、フリー体に変換し、トルエン層を分離した。得られたトルエン層を水６８ｍＬで３回洗浄し、ロータリーエバポレーターを用いて減圧下にて濃縮し、固形物１５４．１ｇ（含量１３５．６ｇ）を得た。攪拌機、温度計を装着した１Ｌ四つ口フラスコに、当該固形物１５４．１ｇ（含量１３５．６ｇ）とヘプタン４０７ｍＬを加え、内温２５℃に調整し、種晶Ｂ１３５ｍｇを加え、３０分間かけて静置した。このとき、種晶Ｂには、（１Ｒ，２Ｒ）－２－（シクロプロピルアミノ）シクロヘキサノールを用いた。さらに、内温１０～１５℃で６０分間、０℃で６０分間静置した後、析出した結晶をろ取した。得られた結晶を０℃のヘプタン６８ｍＬで洗浄し、室温で減圧乾燥し、白色の（１Ｒ，２Ｒ）－２－（シクロプロピルアミノ）シクロヘキサノールの一次晶１０３．０ｇ（１００％ｅｅ）を得た。ろ液はロータリーエバポレーターで減圧下にて濃縮し、一次晶を得た時と同様の操作で二次晶１１．０ｇ（１００％ｅｅ）を得た。粗生成物の（１Ｒ，２Ｒ）－２－（シクロプロピルアミノ）シクロヘキサノールから、一次晶および二次晶を合わせた（１Ｒ，２Ｒ）－２－（シクロプロピルアミノ）シクロヘキサノールの結晶を得る工程の収率は４２％であった。 Example 117 Synthesis of (1R, 2R) -2- (cyclopropylamino) cyclohexanol Into a 1 L four-necked flask equipped with a stirrer and a thermometer, 70.0 g of Soya Five S-DN, 198 mL of toluene, 28.0 mL of water, 7 -35.0 g of oxabicyclo [4.1.0] heptane and 24.4 g of cyclopropylamine were added, and the mixture was stirred at 40 ° C for 26 hours under a nitrogen atmosphere. Soya Five S-DN was filtered off using Nutsche and washed with 140 mL of toluene. The obtained filtrate was concentrated under reduced pressure, and 58.4 g (content 51.0 g, 64% ee, yield 92%) of (1R, 2R) -2- (cyclopropylamino) cyclohexanol was obtained as a crude product. Obtained. Here, the content was calculated based on the mass of the crude product by measuring the 1 H-NMR spectrum of the crude product and using the integral ratio of protons of 2- (cyclopropylamino) cyclohexanol and toluene. Value.
In a 5 L four-necked flask equipped with a stirrer and a thermometer, 317.5 g (content 272.4 g, 64% ee) of (1R, 2R) -2- (cyclopropylamino) cyclohexanol of the obtained crude product was obtained. After adding 2724 mL of isopropanol and raising the temperature to 40 ° C., 61.1 g of fumaric acid, 10 mg of seed crystal A, and 27.2 g of activated carbon (refined birch (Nippon Enviro Chemicals, Inc., trade name)) were added and left for 30 minutes. At this time, racemic 2-cyclopropylaminocyclohexanol fumarate was used as seed crystal A. After cooling to room temperature and allowing to stand for another 60 minutes, the precipitated crystals of racemic 2- (cyclopropylamino) cyclohexanol fumarate and activated carbon were filtered off using Nutsche, and the crystals were washed with 272 mL of isopropanol. . The obtained filtrate was concentrated under reduced pressure using a rotary evaporator. To the obtained (1R, 2R) -2- (cyclopropylamino) cyclohexanol, 1498 mL of toluene, 34.5 mL of water and 40.3 g of potassium hydroxide were added to convert to a free form, and the toluene layer was separated. The obtained toluene layer was washed with 68 mL of water three times and concentrated under reduced pressure using a rotary evaporator to obtain 154.1 g (content 135.6 g) of a solid. To a 1 L four-necked flask equipped with a stirrer and a thermometer, add 154.1 g (content 135.6 g) of the solid and 407 mL of heptane, adjust the internal temperature to 25 ° C., add 135 mg of seed crystal B, and take 30 minutes. Left to stand. At this time, (1R, 2R) -2- (cyclopropylamino) cyclohexanol was used as seed crystal B. Further, after allowing to stand at an internal temperature of 10 to 15 ° C. for 60 minutes and at 0 ° C. for 60 minutes, the precipitated crystals were collected by filtration. The obtained crystals were washed with 68 mL of heptane at 0 ° C. and dried under reduced pressure at room temperature to obtain 103.0 g (100% ee) of primary crystals of white (1R, 2R) -2- (cyclopropylamino) cyclohexanol. It was. The filtrate was concentrated on a rotary evaporator under reduced pressure to obtain 11.0 g (100% ee) of secondary crystals in the same manner as when primary crystals were obtained. A step of obtaining crystals of (1R, 2R) -2- (cyclopropylamino) cyclohexanol, which is a combination of primary and secondary crystals, from the crude product (1R, 2R) -2- (cyclopropylamino) cyclohexanol. The yield of was 42%.
実施例１１８　光学活性ｔｒａｎｓ－２－（イソプロピルアミノ）シクロヘキサノールの合成
　攪拌機、温度計を装着した１Ｌ四つ口フラスコに、ソヤファイブＳ－ＤＮ１４．４ｇ、ヘプタン３６ｍＬ、水４．３ｍＬ、７－オキサビシクロ［４．１．０］ヘプタン１２ｇおよびイソプロピルアミン８．７ｇを加え、窒素雰囲気下にて、４０℃で４９時間撹拌した。ソヤファイブＳ－ＤＮを、ヌッチェを用いてろ別し、ヘプタン５０ｍＬで洗浄した。得られたろ液を減圧下にて濃縮し、再び３６ｍＬのヘプタンに溶解し、生じた結晶をろ過した。結晶を５ｍＬのヘプタンで洗浄し、母液を濃縮して、光学活性ｔｒａｎｓ－２－（イソプロピルアミノ）シクロヘキサノール１１ｇ（保持時間の長い異性体　８２％ｅｅ）を得た。 Example 118 Synthesis of optically active trans-2- (isopropylamino) cyclohexanol To a 1 L four-necked flask equipped with a stirrer and a thermometer, 14.4 g of Soya Five S-DN, 36 mL of heptane, 4.3 mL of water, 7-oxabicyclo [4.1.0] 12 g of heptane and 8.7 g of isopropylamine were added, and the mixture was stirred at 40 ° C. for 49 hours under a nitrogen atmosphere. Soya Five S-DN was filtered off using Nutsche and washed with 50 mL of heptane. The obtained filtrate was concentrated under reduced pressure, dissolved again in 36 mL of heptane, and the resulting crystals were filtered. The crystals were washed with 5 mL of heptane, and the mother liquor was concentrated to obtain 11 g of optically active trans-2- (isopropylamino) cyclohexanol (isomer 82% ee with a long retention time).
実施例１１９　光学活性ｔｒａｎｓ－２－（プロパルギルアミノ）シクロヘキサノールの合成
　攪拌機、温度計を装着した５０ｍＬ四つ口フラスコに、ソヤファイブＳ－ＤＮ１．２ｇ、ヘプタン３ｍＬ、水０．３６ｍＬ、７－オキサビシクロ［４．１．０］ヘプタン０．８５８ｇおよびプロパルギルアミン０．４０７ｇを加え、窒素雰囲気下にて、４０℃で６日間撹拌した。トルエン３ｍＬを加え攪拌し、ソヤファイブＳ－ＤＮを、ヌッチェを用いてろ別し、トルエン３ｍＬで洗浄した。得られたろ液を減圧下にて濃縮し、粗生成物として光学活性ｔｒａｎｓ－２－（プロパルギルアミノ）シクロヘキサノール１．１９ｇ（４５％ｅｅ、収率９１％）を得た。
　攪拌機、温度計を装着した５０ｍＬ四つ口フラスコに、得られた粗生成物の光学活性ｔｒａｎｓ－２－（プロパルギルアミノ）シクロヘキサノール１．１９ｇ（４５％ｅｅ）とエタノール１２ｍＬを加え、４０℃に昇温した後、フマル酸０．５９５ｇと種晶１０ｍｇを加え、３０分間静置した。このとき、種晶には、ラセミ体のｔｒａｎｓ－２－（プロパルギルアミノ）シクロヘキサノールフマル酸塩を用いた。室温まで冷却し、さらに６０分間静置した後に、析出したラセミ体のｔｒａｎｓ－２－（プロパルギルアミノ）シクロヘキサノールフマル酸塩の結晶を、ヌッチェを用いてろ別し、エタノール１ｍＬで結晶を洗浄した。得られたろ液をロータリーエバポレーターで減圧下、濃縮した。得られた光学活性ｔｒａｎｓ－２－（プロパルギルアミノ）シクロヘキサノールにトルエン１０ｍＬ、水１ｍＬおよび水酸化カリウム０．４８０ｇを加えて、フリー体に変換し、トルエン層を分離した。得られたトルエン層を水１ｍＬで３回洗浄し、ロータリーエバポレーターを用いて減圧下にて濃縮し、光学活性ｔｒａｎｓ－２－（プロパルギルアミノ）シクロヘキサノール０．４４０ｇ（９０％ｅｅ）を得た。この時の通算収率は３１％であった。 Example 119 Synthesis of optically active trans-2- (propargylamino) cyclohexanol Into a 50 mL four-necked flask equipped with a stirrer and a thermometer, 1.2 g of Soya Five S-DN, 3 mL of heptane, 0.36 mL of water, 7-oxabicyclo [4.1.0] Heptane (0.858 g) and propargylamine (0.407 g) were added, and the mixture was stirred at 40 ° C. for 6 days under a nitrogen atmosphere. Toluene 3 mL was added and stirred, and Soya Five S-DN was filtered off using Nutsche and washed with toluene 3 mL. The obtained filtrate was concentrated under reduced pressure to obtain 1.19 g (45% ee, 91% yield) of optically active trans-2- (propargylamino) cyclohexanol as a crude product.
To a 50 mL four-necked flask equipped with a stirrer and a thermometer, 1.19 g (45% ee) of the optically active trans-2- (propargylamino) cyclohexanol of the obtained crude product and 12 mL of ethanol were added, and the mixture was heated to 40 ° C. After the temperature was raised, 0.595 g of fumaric acid and 10 mg of seed crystals were added and allowed to stand for 30 minutes. At this time, racemic trans-2- (propargylamino) cyclohexanol fumarate was used as a seed crystal. After cooling to room temperature and allowing to stand for another 60 minutes, the precipitated racemic trans-2- (propargylamino) cyclohexanol fumarate crystals were filtered off using Nutsche and washed with 1 mL of ethanol. The obtained filtrate was concentrated under reduced pressure using a rotary evaporator. To the obtained optically active trans-2- (propargylamino) cyclohexanol, 10 mL of toluene, 1 mL of water and 0.480 g of potassium hydroxide were added to convert to a free form, and the toluene layer was separated. The obtained toluene layer was washed with 1 mL of water three times and concentrated under reduced pressure using a rotary evaporator to obtain 0.440 g (90% ee) of optically active trans-2- (propargylamino) cyclohexanol. The total yield at this time was 31%.

Claims (9)

  1. 　式（１）：
    Figure JPOXMLDOC01-appb-C000001
     （式中、Ｘは、－Ｏ－または－ＮＲ－であり、Ｒは、水素原子、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ３－６シクロアルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ３－６シクロアルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよいＣ６－１０アリール基、置換基を有してもよいＣ１－６アルキルカルボニル基、置換基を有してもよいＣ６－１０アリールカルボニル基、置換基を有してもよいＣ１－６アルキルスルホニル基またはＣ６－１０アリールスルホニル基であり、Ｒ１、Ｒ２、Ｒ３およびＲ４は、それぞれ独立に、水素原子、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ３－６シクロアルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ３－６シクロアルケニル基、置換基を有してもよいＣ２－６アルキニル基または置換基を有してもよいＣ６－１０アリール基であり、前記置換基が、Ｃ１－４アルキル基、Ｃ２－４アルケニル基、Ｃ２－４アルキニル基、Ｃ１－４アルコキシ基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、または、Ｒ２およびＲ３が互いに結合して式（１ｂ）で表される化合物となっていてもよい）
    Figure JPOXMLDOC01-appb-C000002
     （式中、Ｘ、Ｒ１およびＲ４は、前記定義と同一であり、Ｒ７は、Ｒ２およびＲ３が互いに結合して形成される基を示す）
    で表される化合物と、
    　式（２）：
    Figure JPOXMLDOC01-appb-C000003
     （式中、Ｙは、－Ｏ－、－ＮＲ６－または－Ｓ－であり、Ｒ５およびＲ６は、それぞれ独立に、水素原子、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ３－６シクロアルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ３－６シクロアルケニル基、置換基を有してもよいＣ２－６アルキニル基または置換基を有してもよいＣ６－１０アリール基であり、前記置換基が、Ｃ１－４アルコキシ基、Ｃ６－１０アリール基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子であり、または、Ｒ５およびＲ６が互いに結合して式（２ａ）で表される化合物であってもよく、ただし、式（２）で表される化合物は水または硫化水素ではない）
    Figure JPOXMLDOC01-appb-C000004
     （式中、Ｒ８は、Ｒ５およびＲ６が互いに結合して形成される基を示す）
    で表される化合物と、を植物加工物の存在下反応させ、
    　式（３）：
    Figure JPOXMLDOC01-appb-C000005
     （式中、Ｘ、Ｙ、Ｒ１、Ｒ２、Ｒ３、Ｒ４およびＲ５は、前記定義と同一である）
    で表される化合物を得る工程を含む、式（３）で表される化合物の製造方法。     Formula (1):
    Figure JPOXMLDOC01-appb-C000001
     (In the formula, X is —O— or —NR—, and R is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, or a C 3-6 which may have a substituent. A cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-6 cycloalkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-10 aryl group, an optionally substituted C 1-6 alkylcarbonyl group, an optionally substituted C 6-10 arylcarbonyl group, a substituent A C 1-6 alkylsulfonyl group or a C 6-10 arylsulfonyl group which may have, and each of R 1 , R 2 , R 3 and R 4 may independently have a hydrogen atom or a substituent. a C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, Yes which may have a substituent C 2-6 alkenyl group, an optionally substituted C 3-6 cycloalkenyl group, an optionally C 2-6 alkynyl group or a substituted group may have a substituent An optionally substituted C 6-10 aryl group, and the substituent is a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a C 1-4 alkoxy group, an amino group, an imino group. A nitro group, a hydroxy group, an oxo group, a nitrile group, a mercapto group or a halogen atom, or R 2 and R 3 may be bonded to each other to form a compound represented by the formula (1b))
    Figure JPOXMLDOC01-appb-C000002
     (Wherein X, R 1 and R 4 are the same as defined above, and R 7 represents a group formed by combining R 2 and R 3 with each other)
    A compound represented by
    Formula (2):
    Figure JPOXMLDOC01-appb-C000003
     (Wherein Y is —O—, —NR 6 — or —S—, and R 5 and R 6 are each independently a hydrogen atom or a C 1-6 alkyl group optionally having substituent (s). , an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-6 cycloalkenyl group, a substituted group A C 2-6 alkynyl group which may have a substituent or a C 6-10 aryl group which may have a substituent, wherein the substituent is a C 1-4 alkoxy group, a C 6-10 aryl group, amino Group, imino group, nitro group, hydroxy group, oxo group, nitrile group, mercapto group or halogen atom, or a compound represented by formula (2a) in which R 5 and R 6 are bonded to each other Well, however, the compound represented by the formula (2) is water or sulfide water Not)
    Figure JPOXMLDOC01-appb-C000004
     (Wherein R 8 represents a group formed by combining R 5 and R 6 with each other)
    And a compound represented by the following:
    Formula (3):
    Figure JPOXMLDOC01-appb-C000005
     (Wherein X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above)
    The manufacturing method of the compound represented by Formula (3) including the process of obtaining the compound represented by these.
  2. 　式（１）で表される化合物が、式（１ｃ）で表される化合物である、請求項１に記載の製造方法。
    Figure JPOXMLDOC01-appb-C000006
     （式中、ＸおよびＲ７は、前記定義と同一である）     The manufacturing method of Claim 1 whose compound represented by Formula (1) is a compound represented by Formula (1c).
    Figure JPOXMLDOC01-appb-C000006
     (Wherein X and R 7 are the same as defined above)
  3. 　式（１）で表される化合物が、式（１ａ）で表される化合物である、請求項１に記載の製造方法。
    Figure JPOXMLDOC01-appb-C000007
     （式中、Ｘは、－Ｏ－または－ＮＲ－であり、Ｒは、水素原子、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ３－６シクロアルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ３－６シクロアルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよいＣ６－１０アリール基、置換基を有してもよいＣ１－６アルキルカルボニル基、置換基を有してもよいＣ６－１０アリールカルボニル基、置換基を有してもよいＣ１－６アルキルスルホニル基またはＣ６－１０アリールスルホニル基であり、Ｒ２およびＲ３は、それぞれ独立に、水素原子、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ３－６シクロアルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ３－６シクロアルケニル基、置換基を有してもよいＣ２－６アルキニル基または置換基を有してもよいＣ６－１０アリール基であり、前記置換基が、Ｃ１－４アルキル基、Ｃ２－４アルケニル基、Ｃ２－４アルキニル基、Ｃ１－４アルコキシ基、アミノ基、イミノ基、ニトロ基、ヒドロキシ基、オキソ基、ニトリル基、メルカプト基またはハロゲン原子を示す）     The manufacturing method of Claim 1 whose compound represented by Formula (1) is a compound represented by Formula (1a).
    Figure JPOXMLDOC01-appb-C000007
     (In the formula, X is —O— or —NR—, and R is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, or a C 3-6 which may have a substituent. A cycloalkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-6 cycloalkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-10 aryl group, an optionally substituted C 1-6 alkylcarbonyl group, an optionally substituted C 6-10 arylcarbonyl group, a substituent An optionally substituted C 1-6 alkylsulfonyl group or a C 6-10 arylsulfonyl group, and R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted C 1-6 alkyl having group, an optionally substituted C 3-6 cycloalkyl group, a substituent Good C 2-6 alkenyl group, an optionally substituted C 3-6 cycloalkenyl group, which may have a good C 2-6 alkynyl group or a substituted group may have a substituent C 6- 10 aryl group, and the substituent is C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, amino group, imino group, nitro group, hydroxy group , Oxo group, nitrile group, mercapto group or halogen atom)
  4. 　Ｙが－ＮＲ６－である、請求項１～３のいずれか一項に記載の製造方法。 The production method according to any one of claims 1 to 3, wherein Y is -NR 6- .
  5. 　Ｙが－Ｏ－である、請求項１～３のいずれか一項に記載の製造方法。 The production method according to any one of claims 1 to 3, wherein Y is -O-.
  6. 　Ｙが－Ｓ－である、請求項１～３のいずれか一項に記載の製造方法。 The production method according to any one of claims 1 to 3, wherein Y is -S-.
  7. 　前記植物加工物が、マメ科、ウリ科、ナス科、ウルシ科、ショウガ科、ミカン科、ヒガンバナ科、セリ科、アブラナ科、ハス科、マタタビ科、バラ科、ユリ科、イネ科、モクセイ科、バショウ科、ツバキ科およびネギ科の植物から選択される植物を粉砕して調製される、請求項１～６のいずれか一項に記載の製造方法。 The plant processed product may be legume, cucurbitaceae, eggplant, urchinaceae, ginger, citrus, antaceae, cruciferous, cruciferous, lotus, matabidae, rose, lily, gramineous, oleaceae. The production method according to any one of claims 1 to 6, wherein the plant is prepared by pulverizing a plant selected from plants of the family Salamaceae, Camelliaaceae and Alliumaceae.
  8. 　７－オキサビシクロ［４．１．０］ヘプタンおよびシクロプロピルアミンを、大豆加工物の存在下で反応させて（１Ｒ，２Ｒ）－２－シクロプロピルアミノ－１－シクロヘキサノールを得る工程を含む、（１Ｒ，２Ｒ）－２－シクロプロピルアミノ－１－シクロヘキサノールの製造方法。 Reacting 7-oxabicyclo [4.1.0] heptane and cyclopropylamine in the presence of processed soybean to give (1R, 2R) -2-cyclopropylamino-1-cyclohexanol, A method for producing (1R, 2R) -2-cyclopropylamino-1-cyclohexanol.
  9. 　（１）　７－オキサビシクロ［４．１．０］ヘプタンおよびシクロプロピルアミンを、大豆加工物の存在下で反応させて（１Ｒ，２Ｒ）－２－シクロプロピルアミノ－１－シクロヘキサノールを得る工程と、
    　（２ａ）　（１Ｒ，２Ｒ）－２－シクロプロピルアミノ－１－シクロヘキサノールとカルボニル化試薬を反応させた後に、さらに保護された若しくは保護されていない６－（３－アミノプロポキシ）－２（１Ｈ）－キノリノンとを反応させ、または、
    　（２ｂ）　保護された若しくは保護されていない６－（３－アミノプロポキシ）－２（１Ｈ）－キノリノンとカルボニル化試薬を反応させた後に、さらに（１Ｒ，２Ｒ）－２－シクロプロピルアミノ－１－シクロヘキサノールを反応させ、
    　保護された６－（３－アミノプロポキシ）－２（１Ｈ）－キノリノンを用いた場合は、さらに脱保護を行うことによって、
    　（－）－６－〔３－〔３－シクロプロピル－３－〔（１Ｒ，２Ｒ）－２－ヒドロキシシクロヘキシル〕ウレイド〕－プロポキシ〕－２（１Ｈ）－キノリノンを得る工程と、
    　を含む、（－）－６－〔３－〔３－シクロプロピル－３－〔（１Ｒ，２Ｒ）－２－ヒドロキシシクロヘキシル〕ウレイド〕－プロポキシ〕－２（１Ｈ）－キノリノンの製造方法。     (1) A step of reacting 7-oxabicyclo [4.1.0] heptane and cyclopropylamine in the presence of processed soybean to obtain (1R, 2R) -2-cyclopropylamino-1-cyclohexanol. When,
    (2a) After reacting (1R, 2R) -2-cyclopropylamino-1-cyclohexanol with a carbonylating reagent, further protected or unprotected 6- (3-aminopropoxy) -2 (1H ) -Reacting with quinolinone, or
    (2b) After reacting protected or unprotected 6- (3-aminopropoxy) -2 (1H) -quinolinone with a carbonylating reagent, (1R, 2R) -2-cyclopropylamino-1 -Reacting cyclohexanol;
    When protected 6- (3-aminopropoxy) -2 (1H) -quinolinone is used, by further deprotection,
    Obtaining (−)-6- [3- [3-cyclopropyl-3-[(1R, 2R) -2-hydroxycyclohexyl] ureido] -propoxy] -2 (1H) -quinolinone;
    (−)-6- [3- [3-Cyclopropyl-3-[(1R, 2R) -2-hydroxycyclohexyl] ureido] -propoxy] -2 (1H) -quinolinone.
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