WO2015194508A1 - Procédé de production de substance optiquement active - Google Patents

Procédé de production de substance optiquement active 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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group
optionally substituted
substituent
formula
nmr
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Japanese (ja)
Inventor
祐希 竹内
健裕 浅野
浩一 和田
和也 津崎
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Kyowa Pharma Chemical Co Ltd
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Kyowa Pharma Chemical Co Ltd
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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%.

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Abstract

　L'invention concerne un procédé de production d'un composé représenté par la formule (3), le procédé comportant une étape consistant à faire réagir un composé représenté par la formule (1) : (dans la formule, X représente –O- ou –NR-, R, R1, R2, R3 et R4 représentent chacun indépendamment des groupes alkyle en C1-6 ou similaire) et un composé représenté par la formule (2) : (dans la formule, Y représente –O-, -NR6- ou –S-, R5 et R6 représentent chacun indépendamment des groupes alkyle en C1-6 ou similaire) en présence d'un produit végétal traité, et obtenir un composé représenté par la formule (3) : (dans la formule, X, Y, R1, R2, R3, R4, et R5 sont définis de la même manière que ci-dessus).
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JP2017104044A (ja) * 2015-12-09 2017-06-15 協和ファーマケミカル株式会社 触媒活性の向上方法
WO2021100852A1 (fr) 2019-11-21 2021-05-27 キリンホールディングス株式会社 Procédé de préparation d'un échantillon d'analyse structurale de cristal pour l'analyse structurale par un procédé d'éponge cristalline
WO2023191088A1 (fr) * 2022-03-31 2023-10-05 協和ファーマケミカル株式会社 Organocatalyseur d'origine végétale

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WO2021100852A1 (fr) 2019-11-21 2021-05-27 キリンホールディングス株式会社 Procédé de préparation d'un échantillon d'analyse structurale de cristal pour l'analyse structurale par un procédé d'éponge cristalline
WO2023191088A1 (fr) * 2022-03-31 2023-10-05 協和ファーマケミカル株式会社 Organocatalyseur d'origine végétale
JPWO2023191088A1 (fr) * 2022-03-31 2023-10-05
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