WO2017200184A1 - Novel chiral phase-transfer catalyst, and method for preparing α-amino acid by using same - Google Patents

Novel chiral phase-transfer catalyst, and method for preparing α-amino acid by using same Download PDF

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WO2017200184A1
WO2017200184A1 PCT/KR2017/001270 KR2017001270W WO2017200184A1 WO 2017200184 A1 WO2017200184 A1 WO 2017200184A1 KR 2017001270 W KR2017001270 W KR 2017001270W WO 2017200184 A1 WO2017200184 A1 WO 2017200184A1
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bis
methyl
dibromide
biphenyl
mmol
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PCT/KR2017/001270
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French (fr)
Korean (ko)
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남기평
이연지
임배근
우승아
오지인
손원경
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영남대학교 산학협력단
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Priority claimed from KR1020160160908A external-priority patent/KR101823271B1/en
Application filed by 영남대학교 산학협력단 filed Critical 영남대학교 산학협력단
Priority to EP17799542.0A priority Critical patent/EP3459947B1/en
Priority to US16/302,618 priority patent/US10696621B2/en
Priority to CN201780039350.0A priority patent/CN109689651B/en
Publication of WO2017200184A1 publication Critical patent/WO2017200184A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0239—Quaternary ammonium compounds
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/12—Polycyclic non-condensed hydrocarbons
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/44—Allylic alkylation, amination, alkoxylation or analogues
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/46—C-H or C-C activation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/001—General concepts, e.g. reviews, relating to catalyst systems and methods of making them, the concept being defined by a common material or method/theory
    • B01J2531/002—Materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/90—Catalytic systems characterized by the solvent or solvent system used
    • B01J2531/98—Phase-transfer catalysis in a mixed solvent system containing at least 2 immiscible solvents or solvent phases
    • B01J2531/985—Phase-transfer catalysis in a mixed solvent system containing at least 2 immiscible solvents or solvent phases in a water / organic solvent system

Definitions

  • the present invention relates to a novel asymmetric phase transfer catalyst and a method for preparing alpha-amino acid using the same.
  • Alpha-amino acids having optical activity and derivatives thereof are widely used in living organisms.
  • a method of synthesizing amino acids through a phase transfer reaction using a quaternary ammonium salt as a phase transfer catalyst is used. It is getting great attention recently.
  • the ammonium salt derived from chiral alkaloids as a catalyst, it becomes possible to asymmetrically synthesize alpha-amino acids having optical activity, and tetraalkylammonium derived from the chiral alkaloids, cinona alkaloids, by MJ O'Donnell.
  • the H.-G. Park research group [Park, H.-g .; Jeong, B.-S .; Yoo, M.-S .; Lee, J.-H .; Park, M.-k .; Lee, Y.-J .; Kim, M.-J .; Jew, S.-s. Angew. Chem. Int. Ed. 2002, 41, 3036.] developed the catalyst of the following C and asymmetrically synthesized alpha-amino acid by using it as a phase transfer catalyst, but also the reaction conditions for the production of alpha-amino acid were 5 mol% of catalyst and 5 equivalents of reagent. The reaction temperature has to be maintained at 0 ° C., which is still difficult for industrial applications.
  • the present invention has been made to solve the above problems, and the present inventors have diligently studied to find a novel material that can be used as an asymmetric phase transfer catalyst, and as a result, a small amount of catalyst, an equivalent of a reaction reagent, and a room temperature A novel asymmetric phase transfer catalyst derived from synacona alkaloids capable of reaction was identified, and the present invention was completed.
  • an object of the present invention is to provide a novel synacona alkaloid compound.
  • Another object of the present invention is to provide a novel use of the synacona alkaloid compound as an asymmetric phase transfer catalyst for the asymmetric synthesis of alpha-amino acids.
  • the present invention provides a synacona alkaloid compound represented by the following formula (1).
  • X represents CH 2 —, —C (OH) H—, —C ( ⁇ O) —, —O—, —S—, —S ( ⁇ O) — or —S (O 2 ) —;
  • R is or Represents
  • R 1 represents hydrogen, C 1 -C 10 alkyl or C 1 -C 5 alkoxy
  • R 2 represents vinyl or ethyl
  • R 3 represents hydrogen, C 1 -C 10 alkyl, allyl, C 5 -C 10 aryl, naphthalen-1-yl-methyl or anthracene-9-yl-methyl;
  • Y - is fluorine, chlorine, bromine, and a halogen anion selected from the group consisting of iodine, IO 4 -, ClO 4 - , R 4 SO 3 -, OTf - ( sulfonate trifluoromethyl) or HSO 4 - a Represent;
  • R 4 is C 1 -C 4 alkyl or C 5 -C 10 aryl.
  • the present invention the synthesis method of alpha-amino acid using the synacona alkaloid compound of the formula (1) as a asymmetric phase-transfer catalyst, alpha-amino acid comprising the synacona alkaloid compound as an active ingredient Synthetic compositions, and the use of the synacona alkaloid compounds for the synthesis of alpha-amino acids.
  • the amino acid synthesis reaction using the catalyst of the present invention may be carried out at 10 to 20 °C conditions, preferably, at a high temperature (20 °C) or close to room temperature to a high photochemical yield Can be.
  • the asymmetric phase transfer catalyst may be used in the range of 0.0005 to 0.012 equivalents or less with respect to 1 equivalent of the reactant, preferably, 0.01 equivalent (1.0% equivalent) or less based on 1 equivalent of the reactant It can be used to obtain a high photochemical yield.
  • novel syncona alkaloid compound according to the present invention can be synthesized through a relatively simple process, and when used as asymmetric phase transfer catalyst, it has a high optical yield under reaction conditions that are easy to apply industrially. Since the asymmetric synthesis of alpha-amino acids was possible, the novel syncona alkaloid compounds of the present invention may be utilized as core technologies in the field of synthesis and preparation of alpha-amino acids.
  • the present invention provides a synacona alkaloid compound represented by the following formula (1).
  • X represents CH 2 —, —C (OH) H—, —C ( ⁇ O) —, —O—, —S—, —S ( ⁇ O) — or —S (O 2 ) —;
  • R is or Represents
  • R 1 represents hydrogen, C 1 -C 10 alkyl or C 1 -C 5 alkoxy
  • R 2 represents vinyl or ethyl
  • R 3 represents hydrogen, C 1 -C 10 alkyl, allyl, C 5 -C 10 aryl, naphthalen-1-yl-methyl or anthracene-9-yl-methyl
  • Y - is a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine, IO 4 -, ClO 4 - , R 4 SO 3 -, OTf - or HSO 4 - represents
  • R 4 may be C 1 -C 4 alkyl or C 5 -C 10 aryl.
  • alkyl generally means linear and branched saturated hydrocarbon groups having the specified number of carbon atoms (eg, 1 to 10 carbon atoms).
  • alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl and the like.
  • Alkyl may be attached to the parent group or substrate at any ring atom unless the attachment would violate valence requirements.
  • Alkoxy means alkyl-O-, wherein alkyl is defined above. Examples of alkoxy groups include without limitation methoxy, ethoxy and the like. Alkoxy may be attached to a parent group or substrate at any ring atom if the attachment does not violate valence requirements. Likewise, an alkoxy group may include one or more non-hydrogen substituents unless the attachment would violate valence requirements.
  • Aryl refers to monovalent and divalent aromatic groups, respectively, including 5- and 6-membered monocyclic aromatic groups
  • heteroaryl refers to 5- and 6- containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. It refers to monovalent and divalent aromatic groups, respectively, including circular monocyclic aromatic groups.
  • Examples of monocyclic aryl groups and heteroaryl groups include, without limitation, phenyl, pyridinyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, Isoxoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and the like.
  • Aryl groups and heteroaryl groups also include bicyclic groups, tricyclic groups, etc., including fused 5- and 6-membered rings as defined above.
  • polycyclic aryl groups and heteroaryl groups include, without limitation, isoquinolinyl, naphthyl, bifenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzo Thiophenyl, quinolinyl, indolyl, benzofuranyl, furinyl, indolizinyl and the like.
  • the aryl group and heteroaryl group may be attached to the parent group or substrate at any ring atom as long as the attachment does not violate valence requirements.
  • aryl and heteroaryl groups may include one or more non-hydrogen substituents unless the substitution would violate valence requirements.
  • Non-hydrogen substituents of aryl and heteroaryl groups may also be substituted with additional non-hydrogen substituents.
  • R 1 represents hydrogen or C 1 -C 5 alkoxy
  • R 2 represents vinyl or ethyl
  • R 3 represents hydrogen, C 1 -C 10 alkyl, allyl or C 5 -C 10 aryl
  • Y ⁇ may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
  • R 1 represents hydrogen or methoxy
  • R 2 represents vinyl or ethyl
  • R 3 represents hydrogen or allyl
  • Y ⁇ may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
  • R 1 represents hydrogen or C 1 -C 5 alkoxy
  • R 2 represents vinyl or ethyl
  • R 3 is hydrogen, C 1 -C 10 alkyl, allyl, or represents C 5 -C 10 aryl
  • Y ⁇ may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
  • R 1 represents hydrogen or methoxy
  • R 2 represents vinyl or ethyl
  • R 3 represents hydrogen, allyl or benzyl
  • Y ⁇ may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
  • R 1 represents hydrogen or C 1 -C 5 alkoxy
  • R 2 represents vinyl or ethyl
  • R 3 represents hydrogen, C 1 -C 10 alkyl, allyl or C 5 -C 10 aryl
  • Y ⁇ may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
  • R 1 represents hydrogen
  • R 2 represents vinyl or ethyl
  • R 3 represents hydrogen or allyl
  • Y ⁇ may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
  • synacona alkaloid compound of Formula 1 according to the present invention can be prepared through several methods.
  • the compound represented by the general formula (2a) (-)-synconidine, (-)-hydrocinconidine, (-)-quinine or (-)-hydroquinine Bis (4- (bromomethyl) phenyl) methanone, bis (3,4 '-(bromomethyl) phenyl) methanone, bis (3- (bromomethyl) phenyl) methanone, bis (4- ( Bromomethyl) phenyl) methane, bis (4- (bromomethyl) phenyl) methanol, 4,4'-oxybis- (bromomethyl) benzene, bis (4- (bromomethyl) phenyl) sulfan, 4 Reacted with 4'-sulfinylbis- (bromomethyl) benzene or 4,4'-sulfonylbis- (bromomethyl) benzene to the following general formula 3, 5, 7, 9, 11, 13 or 15 Synthesized synacon
  • halogen compound such as various allyl halides, various benzyl halides, or alkyl halides having 1 to 10 carbon atoms under basic conditions, to general formula 4, 6, 8, 10, 12, 14 or 16 Synthesized synacona and alkaloid compounds can be synthesized.
  • (+)-synconin, (+)-hydrocinconin, (+)-quinidine or (+)-hydroquinidine which are the compounds represented by the general formula (2b) are bis (4 -(Bromomethyl) phenyl) methanone, bis (4- (bromomethyl) phenyl) methane, bis (4- (bromomethyl) phenyl) methanol, 4,4'-oxybis- (bromomethyl)
  • a halogen compound such as various allyl halides, various benzyl halides, or alkyl halides having 1 to 10 carbon atoms under basic conditions, to general formula 18, 20, 22, 24, 26, 28 or 30. Synthesized synacona and alkaloid compounds can be synthesized.
  • the present invention the synthesis method of alpha-amino acid using the synacona alkaloid compound of Formula 1 as the asymmetric phase-transfer catalyst, the alpha-amino acid comprising the synacona alkaloid compound as an active ingredient Synthetic compositions, and the use of the synacona alkaloid compounds for the synthesis of alpha-amino acids.
  • the overall reaction conditions are low temperature (-78 °C ⁇ -10 °C), at room temperature conditions, the binding between the ion pair weakens or the solvent is involved in the reaction, the optical purity is sharply lowered Since there are disadvantages, there are still difficulties in industrial applications.
  • the method for synthesizing alpha-amino acid using the synacona alkaloid compound of the present invention as a catalyst can exhibit a high optical yield only by applying a temperature of room temperature, a small amount of catalyst, and an almost equivalent amount of reagent.
  • the dimeric ammonium catalyst linked through the linker -X- of the present invention has elasticity and rotationality in a bent form, and thus It can be tuned to a more suitable structure and thus better catalyst efficacy, and similar resilience and rotational properties can be expected through the combination of -XX- or -X-X'- which can also be expected to improve catalytic function.
  • the linker -X- of the present invention has elasticity and rotationality in a bent form, and thus It can be tuned to a more suitable structure and thus better catalyst efficacy, and similar resilience and rotational properties can be expected through the combination of -XX- or -X-X'- which can also be expected to improve catalytic function.
  • preparing a compound of formula III by reacting a compound of formula I with a compound of formula I in the presence of the synacona alkaloid compound, ie, an asymmetric phase transfer catalyst; And it can provide a method for synthesizing alpha-amino acid, comprising the step of preparing a compound of formula IV by hydrolysis of the compound of formula III prepared in the above step in an acidic condition, which is to illustrate the method of preparing alpha-amino acid Only, if the synthesis method of amino acids having a specific chirality can be included without limitation.
  • R ' is C 2 -C 6 alkyl
  • R'' may be C 2 -C 6 alkyl or C 5 -C 10 aryl, etc., preferably R' is tert-butyl, alkyl, R '' May be benzyl, but is not limited thereto.
  • the step of reacting the compound of formula (I) with the compound of formula (II), may be carried out preferably at 10 to 20 °C, more preferably 13 to 17 °C, most preferably 15 °C conditions, the compound of Formula II, preferably It can be used in the range of 0.8 to 1.6 equivalents, more preferably 1.0 to 1.4 equivalents, most preferably 1.2 equivalents to 1 equivalent of Formula I compound, wherein the asymmetric phase transfer catalyst is preferably 0.0005 to 0.012 for 1 equivalent of Formula I compound It can be used in the equivalent range (0.05 to 1.2% equivalent), more preferably 0.009 to 0.011 (0.9 to 1.1% equivalent), most preferably 0.010 equivalent (1.0% equivalent), but is not limited thereto.
  • Example 20- 1 3 , 3'- Bis (O (9) -allylicindium-N-methyl) biphenyl ether Dibromide (10-1)
  • Example 27-1 3,3'- Bis (O (9) -allylicindium-N-methyl) biphenyl Sulfide Dibromide (12-1)
  • reaction mixture was cooled to room temperature, added dropwise to ether (20 mL) to precipitate a solid, and then filtered under reduced pressure.
  • the obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (150 mg) as a pale orange solid.
  • reaction mixture was cooled to room temperature, added dropwise to ether (40 mL) to precipitate a solid, and then filtered under reduced pressure.
  • ether 40 mL
  • the obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (253 mg) as a pale yellow solid.
  • (+)-Synconin [(+)-cinchonine] (144 mg, 0.49 mmol) in a 25 mL round bottom flask with bis ((4-bromomethyl) phenyl) methanone [bis (4- (bromomethyl) phenyl) methanone] (101 mg, 0.27 mmol) was added, and the mixture was stirred under reflux at 110 ° C. for 4 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (5 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (223 mg) as a pale yellow solid.
  • (+)-cinconine [(+)-cinchonine] (449 mg, 1.52 mmol) in bis (4- (bromomethyl) phenyl) methane [bis (4- (bromomethyl) phenyl) methane] ( 300 mg, 0.847 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 5 hours in a mixed solvent (4 mL) of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (468 mg) as a pink solid.
  • (+)-Quinidine [(+)-quinidine] (330 mg, 1.02 mmol) in a 25 mL round bottom flask with bis (4- (bromomethyl) phenyl) methane] ( 200 mg, 0.565 mmol) was added, and the mixture was stirred under reflux at 110 ° C. for 4 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (4 mL).
  • the reaction mixture was cooled to room temperature, added dropwise to ether (200 mL) to precipitate a solid, and then filtered under reduced pressure.
  • the obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (202 mg) as a pale yellow solid.
  • (+)-cinconin [(+)-cinchonine] (75.5 mg, 0.256 mmol) in bis (4- (bromomethyl) phenyl) methanol [bis (4- (bromomethyl) phenyl) methanol] (50 mg, 0.135 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 4 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (4 mL).
  • the reaction mixture was cooled to room temperature, added dropwise to ether (20 mL) to precipitate a solid, and then filtered under reduced pressure.
  • the obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the target product (53 mg) as a pale yellow solid.
  • (+)-Quinidine [(+)-quinidine] (328.0 mg, 1.01 mmol) in a 25 mL round bottom flask with 4,4'-oxybis (bromomethyl) benzene [4,4'-oxybis ((bromomethyl) benzene) (200 mg, 0.56 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 4 hours in a mixed solvent (3 mL) of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (636 mg) as an off-white solid.
  • the optical purity of the obtained target product was measured by asymmetric high performance liquid chromatography, in which the instrument operating conditions were as follows.
  • the monobenzyl ammonium catalysts of Comparative Examples 1 and 2 (10% equivalent) showed (S) -optical yield of approximately 80% ee, whereas the catalysts of the present invention were 1 High optical yields of 95-99% ee were shown under the conditions of% equivalent of catalyst and 1.2 equivalent of benzyl bromide.
  • the monobenzyl ammonium catalysts (10% equivalent) of Comparative Examples 3 and 4 showed an (R) -optical yield of approximately 70% ee, while the catalysts of the present invention were 1% equivalent of catalyst and 1.2 equivalents of benzyl. High optical yields, such as up to 95% ee, were shown in bromide conditions.
  • the catalyst of the present invention exhibits high optical yield with only a small amount of catalyst and almost equivalent amount of reagents, and can be manufactured by a simple process, and thus can be widely applied to the production of industrial alpha-amino acids. And it was found.

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Abstract

The present invention relates to a novel chiral phase-transfer catalyst, and a method for preparing an α-amino acid by using the same. According to the present invention, an α-amino acid could be chirally synthesized in a high yield under an easy industrially applicable reaction condition by using a novel cinchona alkaloid compound as a chiral phase-transfer catalyst, and thus the present invention can be used as a key technique of the α-amino acid synthesis and preparation field.

Description

신규한 비대칭 상 이동 촉매 및 이를 이용한 알파-아미노산의 제조방법 Novel asymmetric phase transfer catalyst and method for preparing alpha-amino acid using the same
본 발명은 신규한 비대칭 상 이동 촉매 및 이를 이용한 알파-아미노산의 제조방법에 관한 것이다.The present invention relates to a novel asymmetric phase transfer catalyst and a method for preparing alpha-amino acid using the same.
광학활성을 갖는 알파-아미노산 및 이들의 유도체는 생체에 널리 이용되는 물질로서, 이들을 대량 생산하기 위한 합성방법으로 4급 암모늄염을 상 이동 촉매로 사용하는, 상 이동 반응을 통한 아미노산을 합성하는 방법이 최근 큰 주목을 받고 있다. 특히, 키랄성 알칼로이드에서 유래된 암모늄염을 촉매로 사용함으로써 광학활성을 갖는 알파-아미노산의 비대칭 합성이 가능하게 되었으며, 오돈넬 (M. J. O'Donnell)에 의해서 키랄 알칼로이드인 신코나 알칼로이드에서 유래된 테트라알킬암모늄 할로겐화물인 하기 A의 화합물을 비대칭 촉매로 사용하는 알파-아미노산의 비대칭 합성방법이 최초로 발표된 바 있다 (O'Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353.). 그러나 하기 A의 화합물을 촉매로 활용한 반응에서, 알파-아미노산 생성물은 광학수율이 약 80% ee에 불과하여 대량 생산 측면에서 한계가 존재하였다. Alpha-amino acids having optical activity and derivatives thereof are widely used in living organisms. As a synthesis method for mass production thereof, a method of synthesizing amino acids through a phase transfer reaction using a quaternary ammonium salt as a phase transfer catalyst is used. It is getting great attention recently. In particular, by using the ammonium salt derived from chiral alkaloids as a catalyst, it becomes possible to asymmetrically synthesize alpha-amino acids having optical activity, and tetraalkylammonium derived from the chiral alkaloids, cinona alkaloids, by MJ O'Donnell. Asymmetric synthesis of alpha-amino acids using a halide compound of the following A as an asymmetric catalyst was first published (O'Donnell, MJ; Bennett, WD; Wu, SJ Am. Chem. Soc. 1989, 111, 2353.). However, in the reaction utilizing the compound of the following A as a catalyst, the alpha-amino acid product was limited in terms of mass production because the optical yield was only about 80% ee.
Figure PCTKR2017001270-appb-I000001
Figure PCTKR2017001270-appb-I000001
이후, 라이고 (B. Lygo) 연구 그룹 [Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595.]과 코리 (E. J. Corey) 연구 그룹 [Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.]은 신코나 알칼로이드 기반의 새로운 촉매인 하기 B의 화합물을 개발하고, 이를 상 이동 촉매로 이용한 알킬화 반응을 통해 비대칭 알파-아미노산을 합성하였으나, 이는 경제적인 면에서 생성물의 단가가 높다는 문제점이 있었으며, 알파-아미노산 합성을 위한 온도 조건이 -78℃이어서, 실제 공업적인 적용에 한계가 있었다.Later, the B. Lygo research group [Lygo, B .; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595.] and E. J. Corey Research Group [Corey, E. J .; Xu, F .; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.] developed a compound of the following B, a new catalyst based on syncona alkaloids and synthesized an asymmetric alpha-amino acid through alkylation reaction using this as a phase transfer catalyst. There was a problem that the high, and the temperature condition for the synthesis of alpha-amino acid is -78 ℃, there was a limit to the practical industrial applications.
Figure PCTKR2017001270-appb-I000002
Figure PCTKR2017001270-appb-I000002
또한, 박 (H.-G. Park) 연구 그룹 [Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-k.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-s. Angew. Chem. Int. Ed. 2002, 41, 3036.]은 하기 C의 촉매를 개발하고, 이를 상 이동 촉매로 활용하여 알파-아미노산을 비대칭 합성하였으나, 이 역시 알파-아미노산의 생성 반응 조건이 촉매량 5몰%와 반응시약 5 당량이며, 반응 온도를 0℃로 유지하여야 하는바, 여전히 공업적인 적용에 어려움이 있었다. In addition, the H.-G. Park research group [Park, H.-g .; Jeong, B.-S .; Yoo, M.-S .; Lee, J.-H .; Park, M.-k .; Lee, Y.-J .; Kim, M.-J .; Jew, S.-s. Angew. Chem. Int. Ed. 2002, 41, 3036.] developed the catalyst of the following C and asymmetrically synthesized alpha-amino acid by using it as a phase transfer catalyst, but also the reaction conditions for the production of alpha-amino acid were 5 mol% of catalyst and 5 equivalents of reagent. The reaction temperature has to be maintained at 0 ° C., which is still difficult for industrial applications.
Figure PCTKR2017001270-appb-I000003
Figure PCTKR2017001270-appb-I000003
이러한 배경하에서, 공업적인 적용이 용이한 반응 조건 하에서 높은 광학수율의 알파-아미노산을 비대칭적으로 합성할 수 있는, 신규한 비대칭 상 이동 촉매의 개발에 대한 연구가 활발히 진행되고 있으나, 아직은 미비한 실정이다. Under these circumstances, research on the development of a novel asymmetric phase transfer catalyst capable of asymmetrically synthesizing a high optical yield of alpha-amino acid under industrially easy reaction conditions has been actively conducted, but it is still insufficient. .
본 발명은 상기와 같은 문제점을 해결하기 위해 안출된 것으로서, 본 발명자들은 비대칭 상 이동 촉매로 사용 가능성이 있는 신규 물질을 발굴하고자 예의 연구한 결과, 적은 양의 촉매, 당량의 반응 시약, 및 실온에서의 반응이 가능한, 신코나 알칼로이드 유래의 신규 비대칭 상 이동 촉매를 확인하고, 본 발명을 완성하게 되었다.The present invention has been made to solve the above problems, and the present inventors have diligently studied to find a novel material that can be used as an asymmetric phase transfer catalyst, and as a result, a small amount of catalyst, an equivalent of a reaction reagent, and a room temperature A novel asymmetric phase transfer catalyst derived from synacona alkaloids capable of reaction was identified, and the present invention was completed.
이에, 본 발명의 목적은, 신규한 신코나 알칼로이드 화합물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a novel synacona alkaloid compound.
본 발명의 다른 목적은, 알파-아미노산의 비대칭 합성을 위한 비대칭 상 이동 촉매로서, 상기 신코나 알칼로이드 화합물의 신규 용도를 제공하는 것이다. Another object of the present invention is to provide a novel use of the synacona alkaloid compound as an asymmetric phase transfer catalyst for the asymmetric synthesis of alpha-amino acids.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.
상기와 같은 본 발명의 목적을 달성하기 위하여, 본 발명은, 하기 화학식 1로 표시되는 신코나 알칼로이드 화합물을 제공한다. In order to achieve the object of the present invention as described above, the present invention provides a synacona alkaloid compound represented by the following formula (1).
[화학식 1][Formula 1]
Figure PCTKR2017001270-appb-I000004
Figure PCTKR2017001270-appb-I000004
상기 화학식 1에서, In Chemical Formula 1,
X는 CH2-,-C(OH)H-, -C(=O)-, -O-, -S-, -S(=O)- 또는 -S(O2)-를 나타내고; X represents CH 2 —, —C (OH) H—, —C (═O) —, —O—, —S—, —S (═O) — or —S (O 2 ) —;
R은
Figure PCTKR2017001270-appb-I000005
또는
Figure PCTKR2017001270-appb-I000006
을 나타내고; R is
Figure PCTKR2017001270-appb-I000005
or
Figure PCTKR2017001270-appb-I000006
Represents;
상기 R1은 수소, C1-C10 알킬 또는 C1-C5 알콕시를 나타내고;R 1 represents hydrogen, C 1 -C 10 alkyl or C 1 -C 5 alkoxy;
상기 R2는 비닐 또는 에틸을 나타내고;R 2 represents vinyl or ethyl;
상기 R3는 수소, C1-C10 알킬, 알릴, C5-C10 아릴, 나프탈렌-1-일-메틸 또는 안트라센-9-일-메틸을 나타내고; R 3 represents hydrogen, C 1 -C 10 alkyl, allyl, C 5 -C 10 aryl, naphthalen-1-yl-methyl or anthracene-9-yl-methyl;
상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온, IO4 -, ClO4 - , R4SO3 -, OTf- (트리플루오로메탄설포네이트) 또는 HSO4 -를 나타내고; 및Wherein Y - is fluorine, chlorine, bromine, and a halogen anion selected from the group consisting of iodine, IO 4 -, ClO 4 - , R 4 SO 3 -, OTf - ( sulfonate trifluoromethyl) or HSO 4 - a Represent; And
상기 R4는 C1-C4 알킬 또는 C5-C10 아릴이다. R 4 is C 1 -C 4 alkyl or C 5 -C 10 aryl.
또한, 본 발명은, 상기 화학식 1의 신코나 알칼로이드 화합물을 비대칭 상 이동 촉매 (Chiral phase-transfer catalyst)로 이용하는 알파-아미노산의 합성방법, 상기 신코나 알칼로이드 화합물을 유효성분으로 포함하는, 알파-아미노산 합성용 조성물, 및 알파-아미노산의 합성을 위한 상기 신코나 알칼로이드 화합물의 용도를 제공한다. In addition, the present invention, the synthesis method of alpha-amino acid using the synacona alkaloid compound of the formula (1) as a asymmetric phase-transfer catalyst, alpha-amino acid comprising the synacona alkaloid compound as an active ingredient Synthetic compositions, and the use of the synacona alkaloid compounds for the synthesis of alpha-amino acids.
본 발명의 일 구현예로서, 본 발명의 촉매를 이용한 상기 아미노산 합성 반응은 10 내지 20℃ 조건에서 진행될 수 있으며, 바람직하게는, 상온 (20℃) 혹은 상온에 근접한 온도에서 높은 광화학적 수율로 진행될 수 있다.In one embodiment of the present invention, the amino acid synthesis reaction using the catalyst of the present invention may be carried out at 10 to 20 ℃ conditions, preferably, at a high temperature (20 ℃) or close to room temperature to a high photochemical yield Can be.
본 발명의 다른 구현예로서, 상기 비대칭 상 이동 촉매는 반응물 1 당량에 대해 0.0005 내지 0.012 당량 범위, 또는 그 이하로 사용할 수 있으며, 바람직하게는, 반응물 1 당량에 대해 0.01 당량(1.0% 당량) 이하로 사용하여 높은 광화학적 수율을 얻을 수 있다.In another embodiment of the present invention, the asymmetric phase transfer catalyst may be used in the range of 0.0005 to 0.012 equivalents or less with respect to 1 equivalent of the reactant, preferably, 0.01 equivalent (1.0% equivalent) or less based on 1 equivalent of the reactant It can be used to obtain a high photochemical yield.
본 발명에 따른 신규 신코나 알칼로이드 화합물은 비교적 간이한 공정을 통해 합성할 수 있으며, 이를 비대칭 상 이동 촉매 (Chiral phase-transfer catalyst)로 이용한 경우, 공업적인 적용이 용이한 반응 조건 하에서 높은 광학수율의 알파-아미노산을 비대칭적으로 합성할 수 있었는바, 본 발명의 신규 신코나 알칼로이드 화합물은 알파-아미노산의 합성 및 제조 분야의 핵심기술로 활용될 수 있을 것이다. The novel syncona alkaloid compound according to the present invention can be synthesized through a relatively simple process, and when used as asymmetric phase transfer catalyst, it has a high optical yield under reaction conditions that are easy to apply industrially. Since the asymmetric synthesis of alpha-amino acids was possible, the novel syncona alkaloid compounds of the present invention may be utilized as core technologies in the field of synthesis and preparation of alpha-amino acids.
이하, 본 발명을 상세히 설명하기로 한다. Hereinafter, the present invention will be described in detail.
본 발명은, 하기 화학식 1로 표시되는 신코나 알칼로이드 화합물을 제공한다. The present invention provides a synacona alkaloid compound represented by the following formula (1).
[화학식 1][Formula 1]
Figure PCTKR2017001270-appb-I000007
Figure PCTKR2017001270-appb-I000007
상기 화학식 1에서, In Chemical Formula 1,
X는 CH2-,-C(OH)H-, -C(=O)-, -O-, -S-, -S(=O)- 또는 -S(O2)-를 나타내고; X represents CH 2 —, —C (OH) H—, —C (═O) —, —O—, —S—, —S (═O) — or —S (O 2 ) —;
R은
Figure PCTKR2017001270-appb-I000008
또는
Figure PCTKR2017001270-appb-I000009
을 나타내고; R is
Figure PCTKR2017001270-appb-I000008
or
Figure PCTKR2017001270-appb-I000009
Represents;
상기 R1은 수소, C1-C10 알킬 또는 C1-C5 알콕시를 나타내고; 상기 R2는 비닐 또는 에틸을 나타내고; 상기 R3는 수소, C1-C10 알킬, 알릴, C5-C10 아릴, 나프탈렌-1-일-메틸 또는 안트라센-9-일-메틸을 나타내고; 상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온, IO4 -, ClO4 - , R4SO3 -, OTf- 또는 HSO4 -를 나타내고; 및 상기 R4는 C1-C4 알킬 또는 C5-C10 아릴일 수 있다. R 1 represents hydrogen, C 1 -C 10 alkyl or C 1 -C 5 alkoxy; R 2 represents vinyl or ethyl; R 3 represents hydrogen, C 1 -C 10 alkyl, allyl, C 5 -C 10 aryl, naphthalen-1-yl-methyl or anthracene-9-yl-methyl; Wherein Y - is a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine, IO 4 -, ClO 4 - , R 4 SO 3 -, OTf - or HSO 4 - represents; And R 4 may be C 1 -C 4 alkyl or C 5 -C 10 aryl.
여기서, "알킬"은 일반적으로 명시된 수의 탄소원자 (예컨대, 1 내지 10개의 탄소원자)를 갖는 선형 및 분지형 포화 탄화수소 기를 의미한다. 알킬기의 예는 제한 없이 메틸, 에틸, n-프로필, 이소프로필, n-부틸, sec-부틸, 이소부틸, tert-부틸, n-펜틸, n-헥실 및 n-헵틸 등을 포함한다. 알킬은 부착이 원자가 필요조건을 위반하지 않는다면 임의의 고리 원자에서 부모 기 (parent group) 또는 기재 (substrate)에 부착될 수 있다. Here, "alkyl" generally means linear and branched saturated hydrocarbon groups having the specified number of carbon atoms (eg, 1 to 10 carbon atoms). Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl and the like. Alkyl may be attached to the parent group or substrate at any ring atom unless the attachment would violate valence requirements.
"알콕시"는 알킬-O-를 의미하며, 여기에서 알킬은 상기 정의되어 있다. 알콕시 기의 예는 제한없이 메톡시, 에톡시 등을 포함한다. 알콕시는 부착이 원자가 필요조건을 위반하지 않는다면 임의의 고리 원자에서 부모 기(parent group) 또는 기재(substrate)에 부착될 수 있다. 마찬가지로, 알콕시기는 부착이 원자가 요구조건을 위반하지 않는다면 하나 이상의 비수소 치환기를 포함할 수 있다. "Alkoxy" means alkyl-O-, wherein alkyl is defined above. Examples of alkoxy groups include without limitation methoxy, ethoxy and the like. Alkoxy may be attached to a parent group or substrate at any ring atom if the attachment does not violate valence requirements. Likewise, an alkoxy group may include one or more non-hydrogen substituents unless the attachment would violate valence requirements.
"아릴"은 5- 및 6-원 일환 방향족 기를 포함한 각각 일가 및 이가 방향족 기를 말하며, "헤테로아릴"은 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 함유하는 5- 및 6-원 일환 방향족 기를 포함한 각각 일가 및 이가 방향족 기를 말한다. 일환 아릴기 및 헤테로아릴기의 예는 제한없이 페닐, 피리딘일, 퓨란일, 피롤릴, 티오펜일, 티아졸릴, 이소티아졸릴, 이미다졸릴, 트리아졸릴, 테트라졸릴, 피라졸릴, 옥사졸릴, 이소옥사졸릴, 피라진일, 피리다진일, 피리미딘일 등을 포함한다. 아릴기 및 헤테로아릴기는 또한 상기 정의된 융합된 5- 및 6-원 고리를 포함한 이환 기, 삼환 기 등을 포함한다. 다환 아릴기 및 헤테로아릴기의 예는 제한없이 이소퀴놀린일, 나프틸, 바이펜일, 안트라센일, 피렌일, 카바졸릴, 벤족사졸릴, 벤조다이옥사졸릴, 벤조티아졸릴, 벤조이미다졸릴, 벤조티오펜일, 퀸올린일, 인돌릴, 벤조퓨란일, 푸린일, 인돌리진일 등을 포함한다. 상기 아릴기 및 헤테로아릴기는 부착이 원자가 요구조건을 위반하지 않는다면 임의의 고리 원자에서 부모 기 또는 기재에 부착될 수 있다. 마찬가지로, 아릴기 및 헤테로아릴기는 치환이 원자가 요구조건을 위반하지 않는다면 하나 이상의 비-수소 치환기를 포함할 수 있다. 아릴기 및 헤테로아릴기의 비-수소 치환기는 또한 추가적인 비-수소 치환기로 치환될 수 있다. "Aryl" refers to monovalent and divalent aromatic groups, respectively, including 5- and 6-membered monocyclic aromatic groups, and "heteroaryl" refers to 5- and 6- containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. It refers to monovalent and divalent aromatic groups, respectively, including circular monocyclic aromatic groups. Examples of monocyclic aryl groups and heteroaryl groups include, without limitation, phenyl, pyridinyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, Isoxoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and the like. Aryl groups and heteroaryl groups also include bicyclic groups, tricyclic groups, etc., including fused 5- and 6-membered rings as defined above. Examples of polycyclic aryl groups and heteroaryl groups include, without limitation, isoquinolinyl, naphthyl, bifenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzo Thiophenyl, quinolinyl, indolyl, benzofuranyl, furinyl, indolizinyl and the like. The aryl group and heteroaryl group may be attached to the parent group or substrate at any ring atom as long as the attachment does not violate valence requirements. Likewise, aryl and heteroaryl groups may include one or more non-hydrogen substituents unless the substitution would violate valence requirements. Non-hydrogen substituents of aryl and heteroaryl groups may also be substituted with additional non-hydrogen substituents.
상기 화학식 1에서, X가 -CH2-, -C(OH)H- 또는 -C(=O)-인 경우, 바람직하게, 상기 R1은 수소 또는 C1-C5 알콕시를 나타내고; 상기 R2는 비닐 또는 에틸을 나타내고; 상기 R3는 수소, C1-C10 알킬, 알릴 또는 C5-C10 아릴을 나타내고; 및 상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온일 수 있고, In Formula 1, when X is —CH 2 —, —C (OH) H— or —C (═O) —, preferably, R 1 represents hydrogen or C 1 -C 5 alkoxy; R 2 represents vinyl or ethyl; R 3 represents hydrogen, C 1 -C 10 alkyl, allyl or C 5 -C 10 aryl; And Y − may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
보다 바람직하게, 상기 R1은 수소 또는 메톡시를 나타내고; 상기 R2는 비닐 또는 에틸을 나타내고; 상기 R3는 수소 또는 알릴을 나타내고; 및 상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온일 수 있으며,More preferably, R 1 represents hydrogen or methoxy; R 2 represents vinyl or ethyl; R 3 represents hydrogen or allyl; And Y − may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
가장 바람직하게는, 4,4'-비스(신코니디움-N-메틸)바이페닐 메타논 디브로마이드; 4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 메타논 디브로마이드; 4,4'-비스(히드로신코니디움-N-메틸)바이페닐 메타논 디브로마이드; 4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 메타논 디브로마이드; 3,4'-비스(신코니디움-N-메틸)바이페닐 메타논 디브로마이드; 3,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 메타논 디브로마이드; 3,3'-비스(신코니디움-N-메틸)바이페닐 메타논 디브로마이드; 3,3'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 메타논 디브로마이드; 4,4'-비스(신코니디움-N-메틸)바이페닐 메탄 디브로마이드; 4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 메탄 디브로마이드; 4,4'-비스(히드로신코니디움-N-메틸)바이페닐 메탄 디브로마이드; 4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 메탄 디브로마이드; 4,4'-비스(퀴니움-N-메틸)바이페닐 메탄 디브로마이드; 4,4'-비스(O(9)-알릴퀴니움-N-메틸)바이페닐 메탄 디브로마이드; 4,4'-비스(신코니디움-N-메틸)바이페닐 메탄올 디브로마이드; 4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 메탄올 디브로마이드; 4,4'-비스(히드로신코니디움-N-메틸)바이페닐 메탄올 디브로마이드; 4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 메탄올 디브로마이드; 4,4'-비스(신코니움-N-메틸)바이페닐 메타논 디브로마이드; 4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 메타논 디브로마이드; 4,4'-비스(신코니움-N-메틸)바이페닐 메탄 디브로마이드; 4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 메탄 디브로마이드; 4,4'-비스(퀴니디움-N-메틸)바이페닐 메탄 디브로마이드; 4,4'-비스(O(9)-알릴퀴니디움-N-메틸)바이페닐 메탄 디브로마이드; 4,4'-비스(신코니움-N-메틸)바이페닐 메탄올 디브로마이드; 또는 4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 메탄올 디브로마이드일 수 있으나, 이에 제한되는 것은 아니다. Most preferably, 4,4'-bis (cinconium-N-methyl) biphenyl metanon dibromide; 4,4'-bis (O (9) -allylicindium-N-methyl) biphenyl metanon dibromide; 4,4'-bis (hydrocinconium-N-methyl) biphenyl metanon dibromide; 4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl metanon dibromide; 3,4'-bis (cinconium-N-methyl) biphenyl metanon dibromide; 3,4'-bis (O (9) -allylicinium-N-methyl) biphenyl metanon dibromide; 3,3'-bis (cinconium-N-methyl) biphenyl metanon dibromide; 3,3'-bis (O (9) -allylconconium-N-methyl) biphenyl metanon dibromide; 4,4'-bis (cinconium-N-methyl) biphenyl methane dibromide; 4,4'-bis (O (9) -allylicindium-N-methyl) biphenyl methane dibromide; 4,4'-bis (hydrocinconium-N-methyl) biphenyl methane dibromide; 4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl methane dibromide; 4,4'-bis (quinium-N-methyl) biphenyl methane dibromide; 4,4'-bis (O (9) -allylquinium-N-methyl) biphenyl methane dibromide; 4,4'-bis (cinconium-N-methyl) biphenyl methanol dibromide; 4,4'-bis (O (9) -allylicindium-N-methyl) biphenyl methanol dibromide; 4,4'-bis (hydrocinconium-N-methyl) biphenyl methanol dibromide; 4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl methanol dibromide; 4,4'-bis (cinconium-N-methyl) biphenyl metanon dibromide; 4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl metanon dibromide; 4,4'-bis (cinconium-N-methyl) biphenyl methane dibromide; 4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl methane dibromide; 4,4'-bis (quinidium-N-methyl) biphenyl methane dibromide; 4,4'-bis (O (9) -allylquinidium-N-methyl) biphenyl methane dibromide; 4,4'-bis (cinconium-N-methyl) biphenyl methanol dibromide; Or 4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl methanol dibromide, but is not limited thereto.
또한, 상기 화학식 1에서, X가 -O-, -S- 또는 -S(=O)-인 경우, 바람직하게, In addition, in Formula 1, when X is -O-, -S- or -S (= O)-, preferably,
상기 R1은 수소 또는 C1-C5 알콕시를 나타내고; 상기 R2는 비닐 또는 에틸을 나타내고; 상기 R3는 수소, C1-C10 알킬, 알릴 또는 C5-C10 아릴을 나타내고; 및 상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온일 수 있고, R 1 represents hydrogen or C 1 -C 5 alkoxy; R 2 represents vinyl or ethyl; Wherein R 3 is hydrogen, C 1 -C 10 alkyl, allyl, or represents C 5 -C 10 aryl; And Y − may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
보다 바람직하게, 상기 R1은 수소 또는 메톡시를 나타내고; 상기 R2는 비닐 또는 에틸을 나타내고; 상기 R3는 수소, 알릴 또는 벤질을 나타내고; 및 상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온일 수 있으며,More preferably, the R 1 represents hydrogen or methoxy; R 2 represents vinyl or ethyl; R 3 represents hydrogen, allyl or benzyl; And Y − may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
가장 바람직하게는, 4,4'-비스(신코니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-비스(O(9)-벤질신코니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-비스(히드로신코니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-비스(퀴니움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-비스(O(9)-알릴퀴니움-N-메틸)바이페닐 에테르 디브로마이드; 3,3'-비스(신코니디움-N-메틸)바이페닐 에테르 디브로마이드; 3,3'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-비스(신코니디움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-비스(히드로신코니디움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-비스(퀴니움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-비스(O(9)-알릴퀴니움-N-메틸)바이페닐 티오에테르 디브로마이드; 3,3'-비스(신코니디움-N-메틸)바이페닐 설파이드 디브로마이드; 3,3'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 설파이드 디브로마이드; 4,4'-비스(신코니디움-N-메틸)바이페닐 설폭사이드 디브로마이드; 4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 설폭사이드 디브로마이드; 4,4'-비스(히드로신코니디움-N-메틸)바이페닐 설폭사이드 디브로마이드; 4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 설폭사이드 디브로마이드; 4,4'-비스(신코니움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-비스(퀴니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-비스(O(9)-알릴퀴니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-비스(신코니움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-비스(퀴니디움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-비스(신코니움-N-메틸)바이페닐 설폭사이드 디브로마이드; 또는 4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 설폭사이드 디브로마이드일 수 있으나, 이에 제한되는 것은 아니다. Most preferably, 4,4'-bis (cinconium-N-methyl) biphenyl ether dibromide; 4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl ether dibromide; 4,4'-bis (O (9) -benzylcinconium-N-methyl) biphenyl ether dibromide; 4,4'-bis (hydrocinconium-N-methyl) biphenyl ether dibromide; 4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl ether dibromide; 4,4'-bis (quinium-N-methyl) biphenyl ether dibromide; 4,4'-bis (O (9) -allylquinium-N-methyl) biphenyl ether dibromide; 3,3'-bis (cinconium-N-methyl) biphenyl ether dibromide; 3,3'-bis (O (9) -allylicinium-N-methyl) biphenyl ether dibromide; 4,4'-bis (cinconium-N-methyl) biphenyl thioether dibromide; 4,4'-bis (O (9) -allylicindium-N-methyl) biphenyl thioether dibromide; 4,4'-bis (hydrocinconium-N-methyl) biphenyl thioether dibromide; 4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl thioether dibromide; 4,4'-bis (quinium-N-methyl) biphenyl thioether dibromide; 4,4'-bis (O (9) -allylquinium-N-methyl) biphenyl thioether dibromide; 3,3'-bis (cinconium-N-methyl) biphenyl sulfide dibromide; 3,3'-bis (O (9) -allylicindium-N-methyl) biphenyl sulfide dibromide; 4,4'-bis (cinconium-N-methyl) biphenyl sulfoxide dibromide; 4,4'-bis (O (9) -allylicindium-N-methyl) biphenyl sulfoxide dibromide; 4,4'-bis (hydrocinconium-N-methyl) biphenyl sulfoxide dibromide; 4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl sulfoxide dibromide; 4,4'-bis (cinconium-N-methyl) biphenyl ether dibromide; 4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl ether dibromide; 4,4'-bis (quinidium-N-methyl) biphenyl ether dibromide; 4,4'-bis (O (9) -allylquinidium-N-methyl) biphenyl ether dibromide; 4,4'-bis (cinconium-N-methyl) biphenyl thioether dibromide; 4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl thioether dibromide; 4,4'-bis (quinidium-N-methyl) biphenyl thioether dibromide; 4,4'-bis (cinconium-N-methyl) biphenyl sulfoxide dibromide; Or 4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl sulfoxide dibromide, but is not limited thereto.
또한, 상기 화학식 1에서, X가 -S(O2)-인 경우, 바람직하게, 상기 R1은 수소 또는 C1-C5 알콕시를 나타내고; 상기 R2는 비닐 또는 에틸을 나타내고; 상기 R3는 수소, C1-C10 알킬, 알릴 또는 C5-C10 아릴을 나타내고; 및 상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온일 수 있고,In addition, in Formula 1, when X is -S (O 2 )-, preferably, R 1 represents hydrogen or C 1 -C 5 alkoxy; R 2 represents vinyl or ethyl; R 3 represents hydrogen, C 1 -C 10 alkyl, allyl or C 5 -C 10 aryl; And Y − may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
보다 바람직하게, 상기 R1은 수소를 나타내고; 상기 R2는 비닐 또는 에틸을 나타내고; 상기 R3는 수소 또는 알릴을 나타내고; 및 상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온일 수 있으며, More preferably, R 1 represents hydrogen; R 2 represents vinyl or ethyl; R 3 represents hydrogen or allyl; And Y − may be a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine,
가장 바람직하게는, 4,4'-비스(신코니디움-N-메틸)바이페닐 설폰 디브로마이드; 4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 설폰 디브로마이드; 4,4'-비스(히드로신코니디움-N-메틸)바이페닐 설폰 디브로마이드; 4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 설폰 디브로마이드; 4,4'-비스(신코니움-N-메틸)바이페닐 설폰 디브로마이드; 또는 4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 설폰 디브로마이드일 수 있으나 이에 제한되는 것은 아니다. Most preferably, 4,4'-bis (cinconium-N-methyl) biphenyl sulfone dibromide; 4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl sulfone dibromide; 4,4'-bis (hydrocinconium-N-methyl) biphenyl sulfone dibromide; 4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl sulfone dibromide; 4,4'-bis (cinconium-N-methyl) biphenyl sulfone dibromide; Or 4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl sulfone dibromide, but is not limited thereto.
한편, 본 발명에 따른 화학식 1의 신코나 알칼로이드 화합물은 몇몇의 방법을 통해 제조될 수 있다. On the other hand, the synacona alkaloid compound of Formula 1 according to the present invention can be prepared through several methods.
한 구체예에서, 반응식 2에 나타낸 바와 같이, 일반식 2a로 표시되는 화합물인 (-)-신코니딘, (-)-하이드로신코니딘, (-)-퀴닌 또는 (-)-하이드로퀴닌을 비스(4-(브로모메틸)페닐)메탄논, 비스(3,4'-(브로모메틸)페닐)메탄논, 비스(3-(브로모메틸)페닐)메탄논, 비스(4-(브로모메틸)페닐)메탄, 비스(4-(브로모메틸)페닐)메탄올, 4,4'-옥시비스-(브로모메틸)벤젠, 비스(4-(브로모메틸)페닐)설판, 4,4'-설피닐비스-(브로모메틸)벤젠 또는 4,4'-설포닐비스-(브로모메틸)벤젠과 반응시켜 하기 일반식 3, 5, 7, 9, 11, 13 또는 15로 표시되는 신코나 알칼로이드 화합물을 각각 합성할 수 있다. 또한, 상기 수득물을 염기 조건에서 각종 알릴계 할라이드, 각종 벤질계 할라이드 또는 탄소수 1-10개의 알킬할라이드 등과 같은 할로겐 화합물과 반응시켜 하기 일반식 4, 6, 8, 10, 12, 14 또는 16으로 표시되는 신코나 알칼로이드 화합물을 각각 합성할 수 있다.In one embodiment, as shown in Scheme 2, the compound represented by the general formula (2a) (-)-synconidine, (-)-hydrocinconidine, (-)-quinine or (-)-hydroquinine Bis (4- (bromomethyl) phenyl) methanone, bis (3,4 '-(bromomethyl) phenyl) methanone, bis (3- (bromomethyl) phenyl) methanone, bis (4- ( Bromomethyl) phenyl) methane, bis (4- (bromomethyl) phenyl) methanol, 4,4'-oxybis- (bromomethyl) benzene, bis (4- (bromomethyl) phenyl) sulfan, 4 Reacted with 4'-sulfinylbis- (bromomethyl) benzene or 4,4'-sulfonylbis- (bromomethyl) benzene to the following general formula 3, 5, 7, 9, 11, 13 or 15 Synthesized synacona and alkaloid compounds can be synthesized. Further, the obtained product is reacted with a halogen compound such as various allyl halides, various benzyl halides, or alkyl halides having 1 to 10 carbon atoms under basic conditions, to general formula 4, 6, 8, 10, 12, 14 or 16 Synthesized synacona and alkaloid compounds can be synthesized.
[반응식 2]Scheme 2
Figure PCTKR2017001270-appb-I000010
Figure PCTKR2017001270-appb-I000010
또한, 반응식 3에 나타낸 바와 같이, 일반식 2b로 표시되는 화합물인 (+)-신코닌, (+)-하이드로신코닌, (+)-퀴니딘 또는 (+)-하이드로퀴니딘을 비스(4-(브로모메틸)페닐)메탄논, 비스(4-(브로모메틸)페닐)메탄, 비스(4-(브로모메틸)페닐)메탄올, 4,4'-옥시비스-(브로모메틸)벤젠, 비스(4-(브로모메틸)페닐)설판, 4,4'-설피닐비스-(브로모메틸)벤젠 또는 4,4'-설포닐비스-(브로모메틸) 벤젠과 반응시켜 하기 일반식 17, 19, 21, 23, 25, 27 또는 29로 표시되는 신코나 알칼로이드 화합물을 각각 합성할 수 있다. 또한, 상기 수득물을 염기 조건에서 각종 알릴계 할라이드, 각종 벤질계 할라이드 또는 탄소수 1-10개의 알킬할라이드 등과 같은 할로겐 화합물과 반응시켜 하기 일반식 18, 20, 22, 24, 26, 28 또는 30으로 표시되는 신코나 알칼로이드 화합물을 각각 합성할 수 있다.In addition, as shown in Scheme 3, (+)-synconin, (+)-hydrocinconin, (+)-quinidine or (+)-hydroquinidine, which are the compounds represented by the general formula (2b), are bis (4 -(Bromomethyl) phenyl) methanone, bis (4- (bromomethyl) phenyl) methane, bis (4- (bromomethyl) phenyl) methanol, 4,4'-oxybis- (bromomethyl) By reacting with benzene, bis (4- (bromomethyl) phenyl) sulfan, 4,4'-sulfinylbis- (bromomethyl) benzene or 4,4'-sulfonylbis- (bromomethyl) benzene Cinco alkaloid compounds represented by general formula 17, 19, 21, 23, 25, 27 or 29 can be synthesize | combined, respectively. Further, the obtained product is reacted with a halogen compound such as various allyl halides, various benzyl halides, or alkyl halides having 1 to 10 carbon atoms under basic conditions, to general formula 18, 20, 22, 24, 26, 28 or 30. Synthesized synacona and alkaloid compounds can be synthesized.
[반응식 3]Scheme 3
Figure PCTKR2017001270-appb-I000011
Figure PCTKR2017001270-appb-I000011
본 발명의 일 시험예에서, 상기 반응식 2 및 3의 합성 전략에 따라 제조된 일반식 3 내지 30으로 표시되는 신코나 알칼로이드 화합물을 비대칭 상 이동 촉매로 사용하여 비대칭 알파-아미노산을 합성한 결과, 종래의 방법에 비해 개선된 반응 조건에서 반응이 진행되었으며, 기존의 모노 벤질 암모늄 촉매에 비해 광학수율 역시 현저하게 증진되었는바, 본 발명의 신규 신코나 알칼로이드 화합물은 알파-아미노산의 합성 및 제조 분야의 핵심기술로 활용될 수 있음을 확인할 수 있었다. In one test example of the present invention, as a result of synthesizing asymmetric alpha-amino acid using a synacona alkaloid compound represented by Formulas 3 to 30 prepared according to the synthesis strategies of Schemes 2 and 3 as an asymmetric phase transfer catalyst, The reaction proceeded under improved reaction conditions compared to the method of, and the optical yield was also significantly improved compared to the conventional mono benzyl ammonium catalyst, the novel syncona alkaloid compound of the present invention is the core of the synthesis and preparation of alpha-amino acid It could be confirmed that it can be used as a technology.
이에, 본 발명은, 상기 화학식 1의 신코나 알칼로이드 화합물을 비대칭 상 이동 촉매 (Chiral phase-transfer catalyst)로 이용하는 알파-아미노산의 합성방법, 상기 신코나 알칼로이드 화합물을 유효성분으로 포함하는, 알파-아미노산 합성용 조성물, 및 알파-아미노산의 합성을 위한 상기 신코나 알칼로이드 화합물의 용도를 제공한다. Thus, the present invention, the synthesis method of alpha-amino acid using the synacona alkaloid compound of Formula 1 as the asymmetric phase-transfer catalyst, the alpha-amino acid comprising the synacona alkaloid compound as an active ingredient Synthetic compositions, and the use of the synacona alkaloid compounds for the synthesis of alpha-amino acids.
대부분의 생물학적 반응은 비대칭성 반응으로서, 특정 키랄성(Chiral) 물질을 생성하는 반면, 인위적인 합성 반응에서는 일반적으로 라세미체 (Racemic mixture)가 생성되므로, 이후 분리 (Resolution) 단계를 거쳐야만 특정 키랄성 화합물을 수득할 수 있었다. 그러나 상기와 같은 종래의 방법은 라세미체의 특성상, 특정 키랄성 화합물의 수득율이 최대 50%에 불과하여 비효율적이라는 문제를 지니고 있었다. 이러한 비효율성을 해결하기 위한 수단 중 하나로서, 라세미체의 합성없이, 특정 키랄성을 갖는 물질을 합성할 수 있는 비대칭 상 이동 촉매에 대한 연구가 활발히 진행되고 있다. 이에 따라, Merk사의 연구진이 N-benzyl-chinconidium 상전이 촉매를 활용하여 phenylindanone의 메틸화 반응에서 최초로 비대칭적 합성에 성공한 이래, 다양한 비대칭 상 이동 촉매가 개발되고 있다. 그러나 종래의 비대칭 상 이동 촉매의 경우에는, 전반적인 반응 조건이 저온 (-78℃~-10℃)으로, 실온 조건에서는 이온쌍간 결합이 약해지거나 용매가 반응에 개입함으로써, 광학적 순도가 급격하게 낮아진다는 단점이 존재하므로, 여전히 공업적인 적용에 어려움을 겪고 있는 실정이다. Most biological reactions are asymmetric, producing specific chiral substances, whereas artificial synthetic reactions generally produce racemic mixtures, which require a subsequent resolution step to remove specific chiral compounds. Could be obtained. However, the conventional method as described above has the problem that the yield of a specific chiral compound is only 50%, which is inefficient due to the nature of the racemate. As one of means for solving such inefficiency, research on asymmetric phase transfer catalysts capable of synthesizing a material having a specific chirality without the synthesis of racemates is being actively conducted. Accordingly, since Merk's team succeeded in asymmetric synthesis for the first time in methylation of phenylindanone using N-benzyl-chinconidium phase transfer catalyst, various asymmetric phase transfer catalysts have been developed. However, in the case of the conventional asymmetric phase transfer catalyst, the overall reaction conditions are low temperature (-78 ℃ ~ -10 ℃), at room temperature conditions, the binding between the ion pair weakens or the solvent is involved in the reaction, the optical purity is sharply lowered Since there are disadvantages, there are still difficulties in industrial applications.
한편, 본 발명의 신코나 알칼로이드 화합물을 촉매로 이용한 알파-아미노산의 합성 방법은, 상기와 같이, 실온의 온도, 적은 촉매량, 및 거의 당량의 시약의 적용만으로도 높은 광학수율을 나타낼 수 있는바, 공업적인 적용에 용이하다. 또한, 기존 dimeric 촉매에서 링커로 활용된 벤젠 고리나 나프틸 고리와 달리, 본 발명의 링커 -X-를 통해 연결된 dimeric 암모니움 촉매는 굽은 형태로써 탄력성과 회전성을 가지며, 이를 통해 해당 촉매 반응에 더욱 적합한 구조로 조정이 가능하고 이로써 더 우수한 촉매 효능을 보여줄 수 있으며, -X-X- 혹은 -X-X'-의 조합을 통해서 유사한 탄력성과 회전성을 기대할 수 있으므로 이 또한 향상된 촉매 기능을 기대할 수 있다는 점에서 기술적 특징이 있다. On the other hand, the method for synthesizing alpha-amino acid using the synacona alkaloid compound of the present invention as a catalyst, as described above, can exhibit a high optical yield only by applying a temperature of room temperature, a small amount of catalyst, and an almost equivalent amount of reagent. Easy to apply In addition, unlike the benzene ring or naphthyl ring utilized as a linker in the conventional dimeric catalyst, the dimeric ammonium catalyst linked through the linker -X- of the present invention has elasticity and rotationality in a bent form, and thus It can be tuned to a more suitable structure and thus better catalyst efficacy, and similar resilience and rotational properties can be expected through the combination of -XX- or -X-X'- which can also be expected to improve catalytic function. There are technical features in this regard.
한 구체예에서, 반응식 1에 나타낸 바와 같이, 상기 신코나 알칼로이드 화합물, 즉, 비대칭 상 이동 촉매 존재 하에서, 화학식 Ⅰ 화합물과 화학식 Ⅱ 화합물을 반응시켜 화학식 Ⅲ 화합물을 제조하는 단계; 및 상기 단계에서 제조된 화학식 Ⅲ 화합물을 산성 조건에서 가수분해시켜 화학식 Ⅳ화합물을 제조하는 단계를 포함하는, 알파-아미노산의 합성방법을 제공할 수 있으나, 이는 알파-아미노산의 제조방법을 예시한 것에 불과하며, 특정 키랄성을 갖는 아미노산의 합성방법이라면 제한없이 포함될 수 있다.In one embodiment, as shown in Scheme 1, preparing a compound of formula III by reacting a compound of formula I with a compound of formula I in the presence of the synacona alkaloid compound, ie, an asymmetric phase transfer catalyst; And it can provide a method for synthesizing alpha-amino acid, comprising the step of preparing a compound of formula IV by hydrolysis of the compound of formula III prepared in the above step in an acidic condition, which is to illustrate the method of preparing alpha-amino acid Only, if the synthesis method of amino acids having a specific chirality can be included without limitation.
[반응식 1]Scheme 1
Figure PCTKR2017001270-appb-I000012
Figure PCTKR2017001270-appb-I000012
한편, 상기 반응식 1에서, R'는 C2-C6 알킬, R''는 C2-C6 알킬 또는 C5-C10 아릴 등일 수 있으며, 바람직하게 R'는 tert-부틸, 알킬, R''는 벤질일 수 있으나, 이에 제한되는 것은 아니다.On the other hand, in Scheme 1, R 'is C 2 -C 6 alkyl, R''may be C 2 -C 6 alkyl or C 5 -C 10 aryl, etc., preferably R' is tert-butyl, alkyl, R '' May be benzyl, but is not limited thereto.
또한, 상기 화학식 Ⅰ 화합물과 화학식 Ⅱ 화합물을 반응시키는 단계는, 바람직하게 10 내지 20℃, 보다 바람직하게 13 내지 17℃, 가장 바람직하게 15℃ 조건에서 진행될 수 있고, 상기 화학식 Ⅱ 화합물은, 바람직하게 화학식 Ⅰ 화합물 1 당량에 대해 0.8 내지 1.6 당량, 보다 바람직하게 1.0 내지 1.4 당량, 가장 바람직하게 1.2 당량 범위로 사용할 수 있으며, 상기 비대칭 상 이동 촉매는, 바람직하게 화학식 Ⅰ 화합물 1 당량에 대해 0.0005 내지 0.012 당량 범위(0.05 내지 1.2% 당량), 보다 바람직하게 0.009 내지 0.011(0.9 내지 1.1% 당량), 가장 바람직하게, 0.010 당량(1.0% 당량) 범위로 사용할 수 있으나, 이에 제한되는 것은 아니다. In addition, the step of reacting the compound of formula (I) with the compound of formula (II), may be carried out preferably at 10 to 20 ℃, more preferably 13 to 17 ℃, most preferably 15 ℃ conditions, the compound of Formula II, preferably It can be used in the range of 0.8 to 1.6 equivalents, more preferably 1.0 to 1.4 equivalents, most preferably 1.2 equivalents to 1 equivalent of Formula I compound, wherein the asymmetric phase transfer catalyst is preferably 0.0005 to 0.012 for 1 equivalent of Formula I compound It can be used in the equivalent range (0.05 to 1.2% equivalent), more preferably 0.009 to 0.011 (0.9 to 1.1% equivalent), most preferably 0.010 equivalent (1.0% equivalent), but is not limited thereto.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.
실시예Example 1. 4,4'- 1.4,4'- 비스(신코니디움-N-메틸)바이페닐Bis (syncondium-N-methyl) biphenyl 메타논Metanon 디브로마이드Dibromide (3) (3)
25mL 둥근바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (145 mg, 0.49mmol)와 비스((4-브로모메틸)페닐)메타논 [bis(4-(bromomethyl)phenyl)methanone] (100mg, 0.27mmol)을 넣고, 톨루엔 용매 (5mL) 중에서 4시간 동안 110℃에서 환류 교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (205 mg)을 연노랑색의 고체로 수득하였다. In a 25 mL round bottom flask, (-)-cinconidine [(-)-cinchonidine] (145 mg, 0.49 mmol) and bis ((4-bromomethyl) phenyl) methanone [bis (4- (bromomethyl) phenyl) methanone] (100 mg, 0.27 mmol) was added, and the mixture was stirred under reflux at 110 ° C. for 4 hours in toluene solvent (5 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (205 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.00 (d, J = 4.5 Hz, 2H), 8.35 (d, J = 8.4 Hz, 2H), 8.12 (dd, J = 8.3, 1.6 Hz, 2H), 7.99 (m, 8H), 7.94-7.71 (m, 6H), 6.82 (m, 2H), 6.60 (m, 2H), 5.80-5.62 (m, 2H), 5.35 (m, 2H), 5.20 (d, J = 17.3 Hz, 4H), 4.98 (d, J = 10.6 Hz, 2H), 4.38 (m, 2H), 4.15-3.94 (m, 2H), 3.87 (m, 2H), 3.41 (m, 2H), 3.17 (m, 2H), 2.72 (m, 2H), 2.13 (m, 4H), 2.03 (m, 2H), 1.85 (m, 2H), 1.40-1.21 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.00 (d, J = 4.5 Hz, 2H), 8.35 (d, J = 8.4 Hz, 2H), 8.12 (dd, J = 8.3, 1.6 Hz, 2H) , 7.99 (m, 8H), 7.94-7.71 (m, 6H), 6.82 (m, 2H), 6.60 (m, 2H), 5.80-5.62 (m, 2H), 5.35 (m, 2H), 5.20 (d , J = 17.3 Hz, 4H), 4.98 (d, J = 10.6 Hz, 2H), 4.38 (m, 2H), 4.15-3.94 (m, 2H), 3.87 (m, 2H), 3.41 (m, 2H) , 3.17 (m, 2H), 2.72 (m, 2H), 2.13 (m, 4H), 2.03 (m, 2H), 1.85 (m, 2H), 1.40-1.21 (m, 2H).
실시예Example 2. 4,4'- 2. 4,4'- 비스(O(9)-알릴신코니디움-N-메틸)바이페닐Bis (O (9) -allylicindium-N-methyl) biphenyl 메타논Metanon 디브로마이드Dibromide (4) (4)
실시예 1의 방법으로 얻은 화합물 3 (304mg, 0.31 mmol)을 디클로로메탄 (10 mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.35mL, 3.1mmol)과 알릴브로마이드 (0.16mL, 1.9mmol)를 넣고, 2시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 에틸 에테르 (50mL)에 적가하여 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (270 mg)을 연한 주황색의 고체로 수득하였다.Compound 3 (304 mg, 0.31 mmol) obtained by the method of Example 1 was suspended in dichloromethane (10 mL), and then 50% aqueous potassium hydroxide solution (0.35 mL, 3.1 mmol) and allyl bromide (0.16 mL, 1.9 mmol) were added. Put, and stirred at room temperature for 2 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The solid obtained by dropwise addition to ethyl ether (50 mL) was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (270 mg) as a pale orange solid.
1H NMR (300 MHz, Chloroform-d) δ 8.98 (m, 2H), 8.81 (d, J = 8.5 Hz, 2H), 8.20-8.10 (m, 6H), 7.86 (m, 4H), 7.83-7.69 (m, 6H), 6.73 (d, J = 11.5 Hz, 2H), 6.24 (m, 2H), 6.27-6.04 (m, 2H), 5.64-5.52 (m, 2H), 5.42 (m, 6H), 5.02 (m, 4H), 4.77 (d, J = 10.7 Hz, 2H), 4.64 (m, 2H), 4.29 (m, 4H), 4.13 (m, 2H), 3.58 (m, 2H), 3.44 (m, 2H), 2.71 (m, 2H), 2.12 (m, 4H), 1.99 (m, 4H), 1.41 (m, 2H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.98 (m, 2H), 8.81 (d, J = 8.5 Hz, 2H), 8.20-8.10 (m, 6H), 7.86 (m, 4H), 7.83-7.69 (m, 6H), 6.73 (d, J = 11.5 Hz, 2H), 6.24 (m, 2H), 6.27-6.04 (m, 2H), 5.64-5.52 (m, 2H), 5.42 (m, 6H), 5.02 (m, 4H), 4.77 (d, J = 10.7 Hz, 2H), 4.64 (m, 2H), 4.29 (m, 4H), 4.13 (m, 2H), 3.58 (m, 2H), 3.44 (m , 2H), 2.71 (m, 2H), 2.12 (m, 4H), 1.99 (m, 4H), 1.41 (m, 2H).
실시예Example 3. 4,4'- 3. 4,4'- 비스(히드로신코니디움-N-메틸)바이페닐Bis (hydrocinconium-N-methyl) biphenyl 메타논Metanon 디브로마이드Dibromide (3-1) (3-1)
25mL 둥근바닥 플라스크에 (-)-히드로신코니딘 [(-)-hydrocinchonidine] (292mg, 0.98mmol)와 비스(4-(브로모메틸)페닐) 메타논 [bis(4-(bromomethyl)phenyl)methanone] (200mg, 0.55mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 3 시간 동안 110℃ 에서 환류 교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압 여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (300mg)을 연노랑색의 고체로 수득하였다.(-)-Hydrocinconidine [(-)-hydrocinchonidine] (292 mg, 0.98 mmol) and bis (4- (bromomethyl) phenyl) methanone (bis (4- (bromomethyl) phenyl) in a 25 mL round bottom flask methanone] (200 mg, 0.55 mmol) was added, and the mixture was stirred under reflux at 110 ° C. for 3 hours in a mixed solvent of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (300 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.01 (d, J = 4.4 Hz, 2H), 8.36 (d, J = 8.6 Hz, 2H), 8.12 (d, J = 8.3 Hz, 2H), 8.05 (m, 6H), 7.82 (m, 4H), 7.71 (m, 4H), 6.79 (m, 2H), 6.60 (m, 2H), 5.39 (d, J = 12.2 Hz, 2H), 5.14 (d, J = 12.3 Hz, 2H), 4.43-4.36 (m, 2H), 4.06-3.95 (m, 2H), 3.58 (m, 2H), 3.42-3.20 (m, 4H), 2.10 (m, 4H), 2.00 (m, 2H), 1.77 (m, 4H), 1.35 (m, 2H), 1.20 (m, 4H), 0.73 (m, 6H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.01 (d, J = 4.4 Hz, 2H), 8.36 (d, J = 8.6 Hz, 2H), 8.12 (d, J = 8.3 Hz, 2H), 8.05 (m, 6H), 7.82 (m, 4H), 7.71 (m, 4H), 6.79 (m, 2H), 6.60 (m, 2H), 5.39 (d, J = 12.2 Hz, 2H), 5.14 (d, J = 12.3 Hz, 2H), 4.43-4.36 (m, 2H), 4.06-3.95 (m, 2H), 3.58 (m, 2H), 3.42-3.20 (m, 4H), 2.10 (m, 4H), 2.00 (m, 2H), 1.77 (m, 4H), 1.35 (m, 2H), 1.20 (m, 4H), 0.73 (m, 6H).
실시예Example 4. 4,4'- 4. 4,4'- 비스(O(9)-알릴히드로신코니디움Bis (O (9) -allylhydrocinconium -N--N- 메틸methyl )) 바이페닐Biphenyl 메타논Metanon 디브로마이드Dibromide (4-1) (4-1)
실시예 3의 방법으로 얻은 화합물 3-1 (200mg, 0.21mmol)을 디클로로메탄 (3mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 알릴브로마이드 (0.127mL, 1.46mmol)를 넣고, 3시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄 용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이 용액을 감압증류하여 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (144mg)을 연한 주황색의 고체로 수득하였다.Compound 3-1 (200 mg, 0.21 mmol) obtained by the method of Example 3 was suspended in dichloromethane (3 mL), followed by 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and allyl bromide (0.127 mL, 1.46 mmol). Was added, and stirred at room temperature for 3 hours. After diluting the reaction solution with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The solid obtained by distillation under reduced pressure was purified by column chromatography (dichloromethane / methanol) to obtain the target substance (144 mg) as a pale orange solid.
1H NMR (300 MHz, Chloroform-d) δ 8.99 (d, J = 4.5 Hz, 2H), 8.83 (d, J = 8.6 Hz, 2H), 8.14 (m, 4H), 8.12 (m, 2H), 7.82 (m, 2H), 7.79 (m, 4H), 7.75 (m, 4H), 6.51 (d, J = 11.9 Hz, 2H), 6.31 (m, 2H), 6.14 (m, 2H), 5.50 (m, 2H), 5.36 (m, 2H), 4.81 (d, J = 11.9 Hz, 2H), 4.70 (m, 4H), 4.41 (m, 2H), 4.33 (m, 2H), 4.08 (m, 2H), 3.46 (m, 2H), 3.32 (m, 2H), 2.27 (m, 4H), 2.11 (m, 2H), 2.05 (m, 4H), 1.47 (m, 4H), 1.33-1.19 (m, 2H), 0.78 (m, 6H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.99 (d, J = 4.5 Hz, 2H), 8.83 (d, J = 8.6 Hz, 2H), 8.14 (m, 4H), 8.12 (m, 2H), 7.82 (m, 2H), 7.79 (m, 4H), 7.75 (m, 4H), 6.51 (d, J = 11.9 Hz, 2H), 6.31 (m, 2H), 6.14 (m, 2H), 5.50 (m , 2H), 5.36 (m, 2H), 4.81 (d, J = 11.9 Hz, 2H), 4.70 (m, 4H), 4.41 (m, 2H), 4.33 (m, 2H), 4.08 (m, 2H) , 3.46 (m, 2H), 3.32 (m, 2H), 2.27 (m, 4H), 2.11 (m, 2H), 2.05 (m, 4H), 1.47 (m, 4H), 1.33-1.19 (m, 2H ), 0.78 (m, 6 H).
실시예Example 5. 3,4'- 5. 3,4'- 비스(신코니디움-N-메틸)바이페닐Bis (syncondium-N-methyl) biphenyl 메타논Metanon 디브로마이드Dibromide (3-2) (3-2)
25mL 둥근바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (432mg, 1.46mmol)에 (3-(브로모메틸)페닐) (4-(브로모메틸)페닐)메타논 [(3-(bromomethyl)phenyl)(4-(bromomethyl) phenyl)methanone)] (300mg, 0.815mmol)을 넣고, 에탄올: N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (4 mL) 중에서 5 시간 동안 110℃에서 환류 교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (200mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (238 mg)을 흰색의 고체로 수득하였다.To (-)-cinconidine [(-)-cinchonidine] (432 mg, 1.46 mmol) in a 25 mL round bottom flask (3- (bromomethyl) phenyl) (4- (bromomethyl) phenyl) methanone [( 3- (bromomethyl) phenyl) (4- (bromomethyl) phenyl) methanone)] (300mg, 0.815mmol) was added and ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) mixed solvent (4 mL At reflux at 110 ° C. for 5 hours. The reaction mixture was cooled to room temperature, added dropwise to ether (200 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (238 mg) as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (m, 2H), 8.41 - 8.28 (m, 3H), 8.06 (m, 4H), 7.94 (s, 4H), 7.89 - 7.69 (m, 7H), 6.85 - 6.72 (m, 2H), 6.57 (m, 2H), 5.72 - 5.55 (m, 2H), 5.39-5.01 (m, 6H), 4.9 -4.74 (m, 2H), 4.34 (m, 2H), 3.98 (m, 2H), 3.83 (m, 2H), 3.62 (m, 2H), 3.40 - 3.21 (m, 2H), 2.73 (m, 2H), 2.18-1.81 (m, 8H), 1.23 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (m, 2H), 8.41-8.28 (m, 3H), 8.06 (m, 4H), 7.94 (s, 4H), 7.89-7.69 (m, 7H ), 6.85-6.72 (m, 2H), 6.57 (m, 2H), 5.72-5.55 (m, 2H), 5.39-5.01 (m, 6H), 4.9 -4.74 (m, 2H), 4.34 (m, 2H) ), 3.98 (m, 2H), 3.83 (m, 2H), 3.62 (m, 2H), 3.40-3.21 (m, 2H), 2.73 (m, 2H), 2.18-1.81 (m, 8H), 1.23 ( m, 2H).
실시예Example 6. 3,4'- 6. 3,4'- 비스(O(9)-알릴신코니디움-N-메틸)바이페닐Bis (O (9) -allylicindium-N-methyl) biphenyl 메타논Metanon 디브로마이드Dibromide (4-2) (4-2)
실시예 5의 방법으로 얻은 화합물 3-2 (200mg, 0.209mmol)을 디클로로메탄 (4mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.23mmol)과 알릴브로마이드 (178mg, 1.46mmol)를 넣고, 4.5시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (162mg)을 연노랑색의 고체로 수득하였다.Compound 3-2 (200 mg, 0.209 mmol) obtained by the method of Example 5 was suspended in dichloromethane (4 mL), followed by 50% aqueous potassium hydroxide solution (0.25 mL, 2.23 mmol) and allyl bromide (178 mg, 1.46 mmol). The mixture was stirred at room temperature for 4.5 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. This was purified by column chromatography (dichloromethane / methanol) to give the desired product (162 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 9.06 - 8.87 (m, 1H), 8.86 - 8.70 (m, 1H), 8.14 (d, J = 8.8 Hz, 2H), 7.94 - 7.55 (m, 2H), 6.59 (t, J = 12.4 Hz, 2H), 6.35 - 5.97 (m, 4H), 5.70-5.49 (m, 2H), 5.48-5.34 (m, 6H), 5.01-4.78 (m, 4H), 4.33-4.20 (m, 4H), 4.08-3.96 (m, 2H), 3.72 (m, 1H), 3.43 (m, 1H), 3.08 (m, 1H), 2.91 (m, 1H), 2.71-2.43 (m, 2H), 2.27 - 1.96 (m, 4H), 1.89 (m, 4H), 1.39 (m, 2H). 1 H NMR (300 MHz, Chloroform- d ) δ 9.06-8.87 (m, 1H), 8.86-8.70 (m, 1H), 8.14 (d, J = 8.8 Hz, 2H), 7.94-7.55 (m, 2H) , 6.59 (t, J = 12.4 Hz, 2H), 6.35-5.97 (m, 4H), 5.70-5.49 (m, 2H), 5.48-5.34 (m, 6H), 5.01-4.78 (m, 4H), 4.33 -4.20 (m, 4H), 4.08-3.96 (m, 2H), 3.72 (m, 1H), 3.43 (m, 1H), 3.08 (m, 1H), 2.91 (m, 1H), 2.71-2.43 (m , 2H), 2.27-1.96 (m, 4H), 1.89 (m, 4H), 1.39 (m, 2H).
실시예Example 7. 3,3'- 7. 3,3'- 비스(신코니디움-N-메틸)바이페닐Bis (syncondium-N-methyl) biphenyl 메타논Metanon 디브로마이드Dibromide (3-3) (3-3)
25mL 둥근바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (456mg, 1.55mmol)에 비스(3-(브로모메틸)페닐)메타논 [bis(3-(bromomethyl)phenyl)methanone] (300 mg, 0.815 mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (4.5mL) 중에서 6.5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (20mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (225mg)을 연한 노랑색의 고체로 수득하였다.In a 25 mL round bottom flask, (-)-cinconidine [(-)-cinchonidine] (456 mg, 1.55 mmol) in bis (3- (bromomethyl) phenyl) methanone [bis (3- (bromomethyl) phenyl) methanone (300 mg, 0.815 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 6.5 hours in a mixed solvent (4.5 mL) of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2). The reaction mixture was cooled to room temperature, added dropwise to ether (20 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (225 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (d, J = 4.5 Hz, 2H), 8.34 (d, J = 8.7 Hz, 2H), 8.27 (s, 2H), 8.08 (d, J = 8.3 Hz, 4H), 7.97 (d, J = 7.7 Hz, 2H), 7.86 - 7.69 (m, 8H), 6.74 (d, J = 5.0 Hz, 2H), 6.56 (m, 2H), 5.70 - 5.59 (m, 2H), 5.41 (d, J = 14.5 Hz, 2H), 5.27 (m, 4H), 4.94 (d, J = 10.5 Hz, 2H), 4.34 (m, 2H), 3.97 - 3.89 (m, 4H), 3.49 (m, 2H), 3.30 (m, 2H), 2.74 (m, 2H), 2.09 (m, 4H), 1.99 (m, 2H), 1.87 (m, 2H), 1.28 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.34 (d, J = 8.7 Hz, 2H), 8.27 (s, 2H), 8.08 (d, J = 8.3 Hz, 4H), 7.97 (d, J = 7.7 Hz, 2H), 7.86-7.69 (m, 8H), 6.74 (d, J = 5.0 Hz, 2H), 6.56 (m, 2H), 5.70-5.59 ( m, 2H), 5.41 (d, J = 14.5 Hz, 2H), 5.27 (m, 4H), 4.94 (d, J = 10.5 Hz, 2H), 4.34 (m, 2H), 3.97-3.89 (m, 4H ), 3.49 (m, 2H), 3.30 (m, 2H), 2.74 (m, 2H), 2.09 (m, 4H), 1.99 (m, 2H), 1.87 (m, 2H), 1.28 (m, 2H) .
실시예Example 8. 3,3'- 8. 3,3'- 비스(O(9)-알릴신코니디움-N-메틸)바이페닐Bis (O (9) -allylicindium-N-methyl) biphenyl 메타논Metanon 디브로마이드Dibromide (4-3) (4-3)
실시예 7의 방법으로 얻은 화합물 3-3 (100mg, 0.105mmol)을 디클로로메탄 (1.7mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.15mL, 4.06mmol)과 알릴브로마이드 (88.50mg, 0.732mmol)를 넣고, 2.5시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (83mg)을 연한 노랑색의 고체로 수득하였다.Compound 3-3 (100 mg, 0.105 mmol) obtained by the method of Example 7 was suspended in dichloromethane (1.7 mL), followed by 50% aqueous potassium hydroxide solution (0.15 mL, 4.06 mmol) and allyl bromide (88.50 mg, 0.732 mmol). ) Was added and stirred at room temperature for 2.5 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the target product (83 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 8.96 (d, J = 4.5 Hz, 2H), 8.81 (d, J = 8.5 Hz, 2H), 8.50 (m, 2H), 8.12 (m, 4H), 7.84 (m, 4H), 7.74 (m, 2H), 7.69 - 7.52 (m, 4H), 6.47 (d, J = 12.1 Hz, 2H), 6.32 (m, 2H), 6.22 - 6.05 (m, 2H), 5.62 (m, 2H), 5.46 - 5.39 (m, 2H), 5.39 - 5.32 (m, 3H), 5.29 (m, 1H), 4.98 - 4.90 (m, 2H), 4.86 (m, 2H), 4.64 (d, J = 11.9 Hz, 2H), 4.52 (m, 2H), 4.42 - 4.28 (m, 2H), 4.23 (m, J = 5.6 Hz, 4H), 3.65 (d, J = 7.3 Hz, 2H), 3.58 - 3.43 (m, 2H), 2.81 (m, 2H), 2.22 - 2.03 (m, 8H), 1.50 - 1.36 (m, 2H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.96 (d, J = 4.5 Hz, 2H), 8.81 (d, J = 8.5 Hz, 2H), 8.50 (m, 2H), 8.12 (m, 4H), 7.84 (m, 4H), 7.74 (m, 2H), 7.69-7.52 (m, 4H), 6.47 (d, J = 12.1 Hz, 2H), 6.32 (m, 2H), 6.22-6.05 (m, 2H) , 5.62 (m, 2H), 5.46-5.39 (m, 2H), 5.39-5.32 (m, 3H), 5.29 (m, 1H), 4.98-4.90 (m, 2H), 4.86 (m, 2H), 4.64 (d, J = 11.9 Hz, 2H), 4.52 (m, 2H), 4.42-4.28 (m, 2H), 4.23 (m, J = 5.6 Hz, 4H), 3.65 (d, J = 7.3 Hz, 2H) , 3.58-3.43 (m, 2H), 2.81 (m, 2H), 2.22-2.03 (m, 8H), 1.50-1.36 (m, 2H).
실시예Example 9. 4,4'- 9. 4,4'- 비스(신코니디움-N-메틸)바이페닐Bis (syncondium-N-methyl) biphenyl 메탄  methane 디브로마이드Dibromide (5) (5)
25mL 둥근바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (449mg, 1.52mmol)에 비스(4-(브로모메틸)페닐) 메탄 [bis(4-(bromomethyl)phenyl)methane] (300mg, 0.847mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (4 mL) 중에서 3.5시간 동안 110℃ 에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피(디클로로메탄/메탄올)로 분리 정제하여 목적물 (352mg)을 연노랑색의 고체로 수득하였다.Bis (4- (bromomethyl) phenyl) methane [-(-)-cinchonidine] (449 mg, 1.52 mmol) in a 25 mL round bottom flask (300 mg, 0.847 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 3.5 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (4 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (352 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (d, J = 4.4 Hz, 2H), 8.31 (d, J = 8.5 Hz, 2H), 8.10 (dd, J = 8.4, 1.3 Hz, 2H), 7.88 - 7.65 (m, 10H), 7.49 (d, J = 8.1 Hz, 4H), 6.73 (d, J = 4.9 Hz, 2H), 6.55 (d, J = 4.9 Hz, 2H), 5.73 - 5.58 (m, 2H), 5.27 - 5.10 (m, 4H), 5.06 (d, J = 12.2 Hz, 2H), 4.95 (d, J = 10.5 Hz, 2H), 4.40 - 4.21 (m, 2H), 4.14 (s, 2H), 4.09 - 3.86 (m, 4H), 3.85 - 3.72 (m, 2H), 3.40 - 3.30 (m, 2H), 2.69 (d, J = 7.9 Hz, 2H), 2.16 - 1.94 (m, 6H), 1.91 - 1.74 (m, 2H), 1.37 - 1.20 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.4 Hz, 2H), 8.31 (d, J = 8.5 Hz, 2H), 8.10 (dd, J = 8.4, 1.3 Hz, 2H) , 7.88-7.65 (m, 10H), 7.49 (d, J = 8.1 Hz, 4H), 6.73 (d, J = 4.9 Hz, 2H), 6.55 (d, J = 4.9 Hz, 2H), 5.73-5.58 ( m, 2H), 5.27-5.10 (m, 4H), 5.06 (d, J = 12.2 Hz, 2H), 4.95 (d, J = 10.5 Hz, 2H), 4.40-4.21 (m, 2H), 4.14 (s , 2H), 4.09-3.86 (m, 4H), 3.85-3.72 (m, 2H), 3.40-3.30 (m, 2H), 2.69 (d, J = 7.9 Hz, 2H), 2.16-1.94 (m, 6H ), 1.91-1.74 (m, 2H), 1.37-1.20 (m, 2H).
실시예Example 10. 4,4'- 10. 4,4'- 비스(O(9)-알릴신코니디움-N-메틸)바이페닐Bis (O (9) -allylicindium-N-methyl) biphenyl 메탄  methane 디브로마이드Dibromide (6) (6)
실시예 9의 방법으로 얻은 화합물 5 (280mg, 0.297mmol)을 디클로로메탄 (7mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.35mL, 3.1mmol)과 알릴브로마이드 (254mg, 2.08mmol)를 넣고, 2.5시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이 용액을 감압증류하여 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (141.6mg)을 연노랑색의 고체로 수득하였다.Compound 5 (280 mg, 0.297 mmol) obtained by the method of Example 9 was suspended in dichloromethane (7 mL), and then 50% aqueous potassium hydroxide solution (0.35 mL, 3.1 mmol) and allyl bromide (254 mg, 2.08 mmol) were added thereto. Stir at room temperature for 2.5 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The solid obtained by distillation under reduced pressure was purified by column chromatography (dichloromethane / methanol) to obtain the target product (141.6 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 8.98 (d, J = 4.5 Hz, 2H), 8.82 (d, J = 8.5 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H), 8.02 - 7.41 (m, 10H), 7.34 - 7.23 (m, 4H), 6.47 (d, J = 11.8 Hz, 2H), 6.22 (m, 2H), 6.11 (m, 2H), 5.68 (m, 2H), 5.38 (m, 6H), 4.98 (m, 2H), 4.82 (d, J = 14.1 Hz, 2H), 4.65 (d, J = 12.1 Hz, 4H), 4.29 (m, 4H), 4.08 (s, 2H), 4.03 (m, 2H), 3.44 (m, 6.9 Hz, 2H), 3.26 (m, 2H), 2.68 (m, 2H), 2.16 - 2.07 (m, 6H), 1.92 (m, 2H), 1.40 (m, 2H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.82 (d, J = 8.5 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H), 8.02- 7.41 (m, 10H), 7.34-7.23 (m, 4H), 6.47 (d, J = 11.8 Hz, 2H), 6.22 (m, 2H), 6.11 (m, 2H), 5.68 (m, 2H), 5.38 (m, 6H), 4.98 (m, 2H), 4.82 (d, J = 14.1 Hz, 2H), 4.65 (d, J = 12.1 Hz, 4H), 4.29 (m, 4H), 4.08 (s, 2H) , 4.03 (m, 2H), 3.44 (m, 6.9 Hz, 2H), 3.26 (m, 2H), 2.68 (m, 2H), 2.16-2.07 (m, 6H), 1.92 (m, 2H), 1.40 ( m, 2H).
실시예Example 11. 4,4'- 11.4,4'- 비스(히드로신코니디움-N-메틸)바이페닐Bis (hydrocinconium-N-methyl) biphenyl 메탄  methane 디브로마이드Dibromide (5-1) (5-1)
25mL 둥근바닥 플라스크에 (-)-히드로신코니딘 [(-)-hydrocinchonidine] (452mg, 1.52mmol)에 비스(4-(브로모메틸)페닐) 메탄 [bis(4-(bromomethyl)phenyl)methane] (300mg, 0.847mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (5mL) 중에서 3.5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (495.7mg)을 연노랑색의 고체로 수득하였다.(-)-Hydrocinconidine [(-)-hydrocinchonidine] (452 mg, 1.52 mmol) in a 25 mL round bottom flask with bis (4- (bromomethyl) phenyl) methane [bis (4- (bromomethyl) phenyl) methane (300mg, 0.847mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 3.5 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (5 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (495.7 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (d, J = 4.5 Hz, 2H), 8.29 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 8.3 Hz, 2H), 7.89 - 7.76 (m, 4H), 7.75 - 7.57 (m, 6H), 7.48 (d, J = 8.1 Hz, 4H), 6.71 (m, 2H), 6.55 (m, 2H), 5.22 (d, J = 12.4 Hz, 2H), 4.94 (d, J = 12.3 Hz, 2H), 4.31 (m, 2H), 4.13 (s, 2H), 3.95 (m, 2H), 3.52 - 3.41 (m, 2H), 3.20 - 3.13 (m, 2H), 3.04 (t, J = 7.3 Hz, 2H), 2.14 - 2.00 (m, 4H), 1.97 - 1.88 (m, 2H), 1.84 - 1.67 (m, 4H), 1.42 - 1.28 (m, 2H), 1.17 (m, 4H), 0.69 (m, 6H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.29 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 8.3 Hz, 2H), 7.89 -7.76 (m, 4H), 7.75-7.57 (m, 6H), 7.48 (d, J = 8.1 Hz, 4H), 6.71 (m, 2H), 6.55 (m, 2H), 5.22 (d, J = 12.4 Hz, 2H), 4.94 (d, J = 12.3 Hz, 2H), 4.31 (m, 2H), 4.13 (s, 2H), 3.95 (m, 2H), 3.52-3.41 (m, 2H), 3.20-3.13 (m, 2H), 3.04 (t, J = 7.3 Hz, 2H), 2.14-2.00 (m, 4H), 1.97-1.88 (m, 2H), 1.84-1.67 (m, 4H), 1.42-1.28 (m , 2H), 1.17 (m, 4H), 0.69 (m, 6H).
실시예Example 12. 4,4'- 12.4,4'- 비스(O(9)-알릴히드로신코니디움Bis (O (9) -allylhydrocinconium -N--N- 메틸methyl )) 바이페닐Biphenyl 메탄  methane 디브로마이드Dibromide (6-1) (6-1)
실시예 11의 방법으로 얻은 화합물 5-1 (300mg, 0.317mmol)을 디클로로메탄 (7mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.35mL, 3.1mmol)과 알릴브로마이드 (271mg, 2.22mmol)를 넣고, 3시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (228mg)을 연노랑색의 고체로 수득하였다.Compound 5-1 (300 mg, 0.317 mmol) obtained by the method of Example 11 was suspended in dichloromethane (7 mL), followed by 50% aqueous potassium hydroxide solution (0.35 mL, 3.1 mmol) and allyl bromide (271 mg, 2.22 mmol). Put, and stirred at room temperature for 3 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. This was purified by column chromatography (dichloromethane / methanol) to give the desired product (228 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 8.97 (d, J = 4.5 Hz, 2H), 8.80 (d, J = 8.5 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H), 7.94 - 7.66 (m, 10H), 7.31 (d, J = 5.2 Hz, 4H), 6.33 - 6.19 (m, 4H), 6.10 (m, 2H), 5.40 (d, J = 6.5 Hz, 2H), 4.70 (d, J = 11.9 Hz, 4H), 4.61 - 4.50 (m, 2H), 4.33 - 4.18 (m, 4H), 4.11 (d, J = 6.7 Hz, 2H), 4.06 (s, 2H), 3.37 (m, 2H), 3.31 - 3.19 (m, 2H), 2.17 (m, 4H), 2.03 (m, 2H), 1.84 (m, 4H), 1.44 (m, 4H), 1.25 - 1.15 (m, 2H), 0.76 (t, J = 7.3 Hz, 6H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.97 (d, J = 4.5 Hz, 2H), 8.80 (d, J = 8.5 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H), 7.94- 7.66 (m, 10H), 7.31 (d, J = 5.2 Hz, 4H), 6.33-6.19 (m, 4H), 6.10 (m, 2H), 5.40 (d, J = 6.5 Hz, 2H), 4.70 (d , J = 11.9 Hz, 4H), 4.61-4.50 (m, 2H), 4.33-4.18 (m, 4H), 4.11 (d, J = 6.7 Hz, 2H), 4.06 (s, 2H), 3.37 (m, 2H), 3.31-3.19 (m, 2H), 2.17 (m, 4H), 2.03 (m, 2H), 1.84 (m, 4H), 1.44 (m, 4H), 1.25-1.15 (m, 2H), 0.76 (t, J = 7.3 Hz, 6H).
실시예Example 13. 4,4'- 13. 4,4'- 비스(퀴니움-N-메틸)바이페닐Bis (quinium-N-methyl) biphenyl 메탄  methane 디브로마이드Dibromide (5-2) (5-2)
25mL 둥근바닥 플라스크에 (-)-퀴닌 [(-)-quinine] (330mg, 1.02mmol)에 비스(4-(브로모메틸)페닐) 메탄 [bis(4-(bromomethyl)phenyl)methane] (200mg, 0.565mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 4시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (200mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (301 mg)을 연노랑색의 고체로 수득하였다.(-)-Quinine [(-)-quinine] (330 mg, 1.02 mmol) in bis (4- (bromomethyl) phenyl) methane [bis (4- (bromomethyl) phenyl) methane] (200 mg in a 25 mL round bottom flask , 0.565 mmol) was added, and the mixture was stirred under reflux at 110 ° C. for 4 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (200 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (301 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.81 (d, J = 4.5 Hz, 2H), 8.02 (dd, J = 9.2, 2.8 Hz, 2H), 7.75 (d, J = 4.5 Hz, 2H), 7.68 (d, J = 8.2 Hz, 4H), 7.48 (dd, J = 7.1, 2.4 Hz, 6H), 7.42 (d, J = 2.7 Hz, 2H), 6.70 - 6.55 (m, 4H), 5.75 (dddd, J = 17.2, 9.5, 6.8, 2.7 Hz, 2H), 5.47 (d, J = 12.3 Hz, 2H), 5.13 (m, 2H), 5.01 (m, 2H), 4.74 (d, J = 12.2 Hz, 2H), 4.39 - 4.24 (m, 2H), 4.12 (s, 2H), 4.02 (s, 6H), 3.90 (t, J = 8.8 Hz, 2H), 3.79 - 3.62 (m, 2H), 3.44 - 3.31 (m, 2H), 3.24 (m, 2H), 2.79 - 2.64 (m, 2H), 2.32 - 2.10 (m, 4H), 2.06 - 1.97 (m, 2H), 1.93 - 1.78 (m, 2H), 1.56 - 1.41 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.81 (d, J = 4.5 Hz, 2H), 8.02 (dd, J = 9.2, 2.8 Hz, 2H), 7.75 (d, J = 4.5 Hz, 2H) , 7.68 (d, J = 8.2 Hz, 4H), 7.48 (dd, J = 7.1, 2.4 Hz, 6H), 7.42 (d, J = 2.7 Hz, 2H), 6.70-6.55 (m, 4H), 5.75 ( dddd, J = 17.2, 9.5, 6.8, 2.7 Hz, 2H), 5.47 (d, J = 12.3 Hz, 2H), 5.13 (m, 2H), 5.01 (m, 2H), 4.74 (d, J = 12.2 Hz , 2H), 4.39-4.24 (m, 2H), 4.12 (s, 2H), 4.02 (s, 6H), 3.90 (t, J = 8.8 Hz, 2H), 3.79-3.62 (m, 2H), 3.44- 3.31 (m, 2H), 3.24 (m, 2H), 2.79-2.64 (m, 2H), 2.32-2.10 (m, 4H), 2.06-1.97 (m, 2H), 1.93-1.78 (m, 2H), 1.56-1.41 (m, 2 H).
실시예Example 14. 4,4'- 14. 4,4'- 비스(O(9)-알릴퀴니움-N-메틸)바이페닐Bis (O (9) -allylquinium-N-methyl) biphenyl 메탄  methane 디브로마이드Dibromide (6-2) (6-2)
실시예 13의 방법으로 얻은 화합물 5-2 (150mg, 0.150mmol)을 디클로로메탄 (3mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.35mL, 3.1mmol)과 알릴브로마이드 (0.128mg, 1.05mmol)를 넣고, 3시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (107mg)을 연노랑색의 고체로 수득하였다.Compound 5-2 (150 mg, 0.150 mmol) obtained by the method of Example 13 was suspended in dichloromethane (3 mL), followed by 50% aqueous potassium hydroxide solution (0.35 mL, 3.1 mmol) and allyl bromide (0.128 mg, 1.05 mmol). Was added, and stirred at room temperature for 3 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. This was purified by column chromatography (dichloromethane / methanol) to give the desired product (107 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.83 (d, J = 4.5 Hz, 2H), 8.04 (d, J = 9.1 Hz, 2H), 7.73 - 7.61 (m, 6H), 7.55 - 7.40 (m, 8H), 6.57 (m, 2H), 6.24 - 6.05 (m, 2H), 5.81 - 5.67 (m, 2H), 5.59 (d, J = 12.4 Hz, 2H), 5.46 (m, 2H), 5.28 (dd, J = 10.5, 1.6 Hz, 2H), 5.15 - 4.97 (m, 4H), 4.75 (d, J = 12.2 Hz, 2H), 4.50 (dd, J = 12.6, 5.3 Hz, 2H), 4.13 (s, 2H), 4.00 (m, 8H), 3.98 - 3.89 (m, 4H), 3.38 - 3.29 (m, 4H), 2.78 - 2.63 (m, 2H), 2.44 - 2.32 (m, 2H), 2.24 - 2.12 (m, 2H), 2.07 - 2.00 (m, 2H), 1.96 - 1.83 (m, 2H), 1.61 - 1.49 (m, 2H), 1.23 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.83 (d, J = 4.5 Hz, 2H), 8.04 (d, J = 9.1 Hz, 2H), 7.73-7.61 (m, 6H), 7.55-7.40 ( m, 8H), 6.57 (m, 2H), 6.24-6.05 (m, 2H), 5.81-5.67 (m, 2H), 5.59 (d, J = 12.4 Hz, 2H), 5.46 (m, 2H), 5.28 (dd, J = 10.5, 1.6 Hz, 2H), 5.15-4.97 (m, 4H), 4.75 (d, J = 12.2 Hz, 2H), 4.50 (dd, J = 12.6, 5.3 Hz, 2H), 4.13 ( s, 2H), 4.00 (m, 8H), 3.98-3.89 (m, 4H), 3.38-3.29 (m, 4H), 2.78-2.63 (m, 2H), 2.44-2.32 (m, 2H), 2.24- 2.12 (m, 2H), 2.07-2.00 (m, 2H), 1.96-1.83 (m, 2H), 1.61-1.49 (m, 2H), 1.23 (m, 2H).
실시예Example 15. 4,4'- 15.4,4'- 비스(신코니디움-N-메틸)바이페닐Bis (syncondium-N-methyl) biphenyl 메탄올  Methanol 디브로마이드Dibromide (7) (7)
25mL 둥근바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (151mg, 0.513mmol)에 비스(4-(브로모메틸)페닐)메탄올 [bis(4-(bromomethyl)phenyl)methanol] (100mg, 0.27mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (1.5mL) 중에서 1시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (20mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (70mg)을 연한 노랑색의 고체로 수득하였다.Bis (4- (bromomethyl) phenyl) methanol [-(-)-cinchonidine] (151 mg, 0.513 mmol) in a 25 mL round bottom flask [bis (4- (bromomethyl) phenyl) methanol] (100 mg, 0.27 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 1 hour in an ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) mixed solvent (1.5 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (20 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the target product (70 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (d, J = 4.5 Hz, 2H), 8.29 (d, J = 8.2 Hz, 2H), 8.10 (m, 2H), 7.89 - 7.78 (m, 5H), 7.74 (m, 5H), 7.64 (d, J = 8.4 Hz, 4H), 6.79 (d, J = 4.7 Hz, 2H), 6.55 (d, J = 4.7 Hz, 2H), 6.23 (d, J = 4.4 Hz, 1H), 5.90 (d, J = 4.5 Hz, 1H), 5.67 (m, 2H), 5.28 - 5.12 (m, 4H), 5.03 (d, J = 12.2 Hz, 2H), 4.95 (d, J = 10.5 Hz, 2H), 4.30 (m, 2H), 4.03 - 3.86 (m, 2H), 3.79 (d, J = 9.9 Hz, 2H), 3.35 - 3.12 (m, 4H), 2.70 (m, 2H), 2.16 - 1.91 (m, 6H), 1.82 (m, 2H), 1.33 - 1.21 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.29 (d, J = 8.2 Hz, 2H), 8.10 (m, 2H), 7.89-7.78 (m, 5H), 7.74 (m, 5H), 7.64 (d, J = 8.4 Hz, 4H), 6.79 (d, J = 4.7 Hz, 2H), 6.55 (d, J = 4.7 Hz, 2H), 6.23 (d, J = 4.4 Hz, 1H), 5.90 (d, J = 4.5 Hz, 1H), 5.67 (m, 2H), 5.28-5.12 (m, 4H), 5.03 (d, J = 12.2 Hz, 2H), 4.95 ( d, J = 10.5 Hz, 2H), 4.30 (m, 2H), 4.03-3.86 (m, 2H), 3.79 (d, J = 9.9 Hz, 2H), 3.35-3.12 (m, 4H), 2.70 (m , 2H), 2.16-1.91 (m, 6H), 1.82 (m, 2H), 1.33-1.21 (m, 2H).
실시예Example 16. 4,4'- 16.4,4'- 비스(O(9)-알릴신코니디움-N-메틸)바이페닐Bis (O (9) -allylicindium-N-methyl) biphenyl 메탄올  Methanol 디브로마이드Dibromide (8) (8)
실시예 15의 방법으로 얻은 화합물 7 (70mg, 0.073mmol)을 디클로로메탄 (1.4mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.11mL, 3.0mmol)과 알릴브로마이드 (88mg, 0.73mmol)를 넣고, 2시간 동안 상온에서 교반하였다. 물 (5 mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (25mg)을 연한 노랑색의 고체로 수득하였다.Compound 7 (70 mg, 0.073 mmol) obtained by the method of Example 15 was suspended in dichloromethane (1.4 mL), and then 50% aqueous potassium hydroxide solution (0.11 mL, 3.0 mmol) and allyl bromide (88 mg, 0.73 mmol) were added thereto. , And stirred at room temperature for 2 hours. After diluting the reaction solution with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the target product (25 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 8.98 (d, J = 4.5 Hz, 2H), 8.83 (d, J = 8.6 Hz, 2H), 8.14 (m, 2H), 7.96 (d, J = 7.4 Hz, 4H), 7.78 (m, 4H), 7.62 (d, J = 7.5 Hz, 2H), 7.57 - 7.39 (m, 4H), 6.51 (d, J = 11.9 Hz, 2H), 6.25 (m, 2H), 6.20 - 6.04 (m, 2H), 6.04 - 5.90 (m, 1H), 5.66 (m, 2H), 5.55 (s, 1H), 5.44 - 5.35 (m, 4H), 5.06 - 4.93 (m, 2H), 4.83 (d, J = 10.9 Hz, 2H), 4.76 - 4.47 (m, 4H), 4.24 (m, 4H), 4.13 - 3.92 (m, 4H), 3.43 (m, 2H), 3.33 - 3.16 (m, 2H), 2.68 (m, 2H), 2.11 (d, J = 13.8 Hz, 8H), 1.91 (d, J = 5.7 Hz, 2H), 1.40 (d, J = 11.7 Hz, 2H), 1.28 (d, J = 15.9 Hz, 2H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.83 (d, J = 8.6 Hz, 2H), 8.14 (m, 2H), 7.96 (d, J = 7.4 Hz, 4H), 7.78 (m, 4H), 7.62 (d, J = 7.5 Hz, 2H), 7.57-7.39 (m, 4H), 6.51 (d, J = 11.9 Hz, 2H), 6.25 (m, 2H ), 6.20-6.04 (m, 2H), 6.04-5.90 (m, 1H), 5.66 (m, 2H), 5.55 (s, 1H), 5.44-5.35 (m, 4H), 5.06-4.93 (m, 2H) ), 4.83 (d, J = 10.9 Hz, 2H), 4.76-4.47 (m, 4H), 4.24 (m, 4H), 4.13-3.92 (m, 4H), 3.43 (m, 2H), 3.33-3.16 ( m, 2H), 2.68 (m, 2H), 2.11 (d, J = 13.8 Hz, 8H), 1.91 (d, J = 5.7 Hz, 2H), 1.40 (d, J = 11.7 Hz, 2H), 1.28 ( d, J = 15.9 Hz, 2H).
실시예Example 17. 4,4'- 17.4,4'- 비스(히드로신코니디움-N-메틸)바이페닐Bis (hydrocinconium-N-methyl) biphenyl 메탄올  Methanol 디브로마이드Dibromide (7-1) (7-1)
25mL 둥근바닥 플라스크에 (-)-히드로신코니딘 [(-)-hydrocinchonidine] (152.2mg, 0.5134mmol)에 비스(4-(브로모메틸)페닐)메탄올 (bis(4-(bromomethyl)phenyl)methanol; 100mg, 0.2702mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (1.5mL) 중에서 1.5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (20mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (130mg)을 연한 주황색의 고체로 수득하였다.(-)-Hydrocinconidine [(-)-hydrocinchonidine] (152.2 mg, 0.5134 mmol) in a 25 mL round bottom flask with bis (4- (bromomethyl) phenyl) Methanol; 100 mg, 0.2702 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 1.5 hours in a mixed solvent (1.5 mL) of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2). The reaction mixture was cooled to room temperature, added dropwise to ether (20 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (130 mg) as a pale orange solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (m, 2H), 8.26 (m, 2H), 8.11 (d, J = 8.4 Hz, 2H), 7.90 - 7.79 (m, 4H), 7.77 - 7.56 (m, 10H), 6.73 (m, 2H), 6.53 (m, 2H), 6.26 - 6.16 (m, 1H), 5.91 - 5.84 (m, 1H), 5.24 - 5.03 (m, 2H), 4.89 (m, 2H), 4.63 - 4.37 (m, 2H), 4.27 (d, J = 10.9 Hz, 2H), 4.08 - 3.76 (m, 4H), 3.22 (d, J = 10.7 Hz, 4H), 2.18 - 1.87 (m, 8H), 1.76 (m, 6H), 1.32 (m, 2H), 1.16 (m, 4H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (m, 2H), 8.26 (m, 2H), 8.11 (d, J = 8.4 Hz, 2H), 7.90-7.79 (m, 4H), 7.77- 7.56 (m, 10H), 6.73 (m, 2H), 6.53 (m, 2H), 6.26-6.16 (m, 1H), 5.91-5.84 (m, 1H), 5.24-5.03 (m, 2H), 4.89 ( m, 2H), 4.63-4.37 (m, 2H), 4.27 (d, J = 10.9 Hz, 2H), 4.08-3.76 (m, 4H), 3.22 (d, J = 10.7 Hz, 4H), 2.18-1.87 (m, 8H), 1.76 (m, 6H), 1.32 (m, 2H), 1.16 (m, 4H).
실시예Example 18. 4,4'- 18.4,4'- 비스(O(9)-알릴히드로신코니디움Bis (O (9) -allylhydrocinconium -N--N- 메틸methyl )) 바이페닐Biphenyl 메탄올 디브로마이드 (8-1) Methanol Dibromide (8-1)
실시예 17의 방법으로 얻은 화합물 7-1 (90mg, 0.0935mmol)을 디클로로메탄 (1.6mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.14mL, 3.79mmol)과 알릴브로마이드 (118.7mg, 0.9813mmol)를 넣고, 2.5시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 얻은 고체를 컬럼크로마토그래피 (메틸렌클로라이드/메탄올)로 분리 정제하여 목적물 (87mg)을 연한 노랑색의 고체로 수득하였다.Compound 7-1 (90 mg, 0.0935 mmol) obtained by the method of Example 17 was suspended in dichloromethane (1.6 mL), followed by 50% aqueous potassium hydroxide solution (0.14 mL, 3.79 mmol) and allyl bromide (118.7 mg, 0.9813 mmol). ) Was added and stirred at room temperature for 2.5 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The obtained solid was separated and purified by column chromatography (methylene chloride / methanol) to obtain the target product (87 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (m, 2H), 8.82 (d, J = 8.5 Hz, 2H), 8.19 - 8.11 (m, 2H), 7.98 - 7.75 (m, 8H), 7.62 - 7.53 (m, 2H), 7.49 (m, 4H), 6.28 (m, 4H), 6.08 - 5.89 (m, 3H), 5.55 (m, 1H), 5.43 - 5.34 (m, 4H), 5.21 - 5.09 (m, 2H), 4.61 (m, 4H), 4.27 (m, 4H), 4.08 - 3.92 (m, 6H), 3.38 (d, J = 14.7 Hz, 2H), 3.22 (m, 2H), 2.14 (m, 4H), 2.04 (m, 6H), 1.39 (m, 4H), 1.23 (m, 2H), 0.77 (m, 6H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (m, 2H), 8.82 (d, J = 8.5 Hz, 2H), 8.19-8.11 (m, 2H), 7.98-7.75 (m, 8H), 7.62-7.53 (m, 2H), 7.49 (m, 4H), 6.28 (m, 4H), 6.08-5.89 (m, 3H), 5.55 (m, 1H), 5.43-5.34 (m, 4H), 5.21- 5.09 (m, 2H), 4.61 (m, 4H), 4.27 (m, 4H), 4.08-3.92 (m, 6H), 3.38 (d, J = 14.7 Hz, 2H), 3.22 (m, 2H), 2.14 (m, 4H), 2.04 (m, 6H), 1.39 (m, 4H), 1.23 (m, 2H), 0.77 (m, 6H).
실시예Example 19. 4,4'- 19.4,4'- 비스(신코니디움-N-메틸)바이페닐Bis (syncondium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (9) (9)
25mL 둥근바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (314mg, 1.07mmol)에 4,4'-옥시비스(브로모메틸)벤젠 [4,4'-oxybis((bromomethyl)benzene] (200mg, 0.56mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 4시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 메탄올-에테르로 재결정하여 목적물 (283 mg)을 연노랑색의 고체로 수득하였다.In a 25 mL round bottom flask, (-)-cinconidine [(-)-cinchonidine] (314 mg, 1.07 mmol) in 4,4'-oxybis (bromomethyl) benzene [4,4'-oxybis ((bromomethyl) benzene] (200 mg, 0.56 mmol) was added, and the mixture was stirred under reflux for 4 hours at 110 ° C. in a mixed solvent (3 mL) of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2). After cooling, the mixture was added dropwise to ether (50 mL) to precipitate a solid, and the resultant was filtered under reduced pressure, and the obtained solid was recrystallized from methanol-ether to give the target product (283 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (d, J = 4.5 Hz, 2H), 8.39 - 8.28 (d, 2H), 8.11 (d, J = 8.3, 1.4 Hz, 2H), 7.92 - 7.70 (m, 10H), 7.28 (d, J = 8.2 Hz, 4H), 6.74 (d, J = 4.8 Hz, 2H), 6.66 - 6.51 (m, 2H), 5.79 - 5.59 (m, 2H), 5.27 (d, J = 12.4 Hz, 2H), 5.19 (d, J = 17.2, 1.3 Hz, 2H), 5.11 (d, J = 12.2 Hz, 2H), 4.96 (d, J = 10.5, 1.4 Hz, 2H), 4.32 (m, 2H), 3.97 (t, J = 9.2 Hz, 2H), 3.81 (m, 2H), 3.41 (t, J = 11.6 Hz, 2H), 3.25 (m, 2H), 2.11 (m, 6H), 1.86 (m, 2H), 1.32 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.39-8.28 (d, 2H), 8.11 (d, J = 8.3, 1.4 Hz, 2H), 7.92- 7.70 (m, 10H), 7.28 (d, J = 8.2 Hz, 4H), 6.74 (d, J = 4.8 Hz, 2H), 6.66-6.51 (m, 2H), 5.79-5.59 (m, 2H), 5.27 (d, J = 12.4 Hz, 2H), 5.19 (d, J = 17.2, 1.3 Hz, 2H), 5.11 (d, J = 12.2 Hz, 2H), 4.96 (d, J = 10.5, 1.4 Hz, 2H) , 4.32 (m, 2H), 3.97 (t, J = 9.2 Hz, 2H), 3.81 (m, 2H), 3.41 (t, J = 11.6 Hz, 2H), 3.25 (m, 2H), 2.11 (m, 6H), 1.86 (m, 2H), 1.32 (m, 2H).
실시예Example 19-1. 3,3'- 19-1. 3,3'- 비스(신코니디움-N-메틸)바이페닐Bis (syncondium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (9-1) (9-1)
25 mL 둥근바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (223.2 mg, 0.758 mmol)에 3,3'-옥시비스(브로모메틸)벤젠 (3,3'-oxybis((bromomethyl) benzene; 150 mg, 0.421 mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3 mL) 중에서 5시간동안 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (100 mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 메탄올-에테르로 재결정하여 목적물 (227 mg)을 연갈색의 고체로 수득하였다.In a 25 mL round bottom flask, (-)-cinconidine [(-)-cinchonidine] (223.2 mg, 0.758 mmol) was added 3,3'-oxybis (bromomethyl) benzene (3,3'-oxybis (( bromomethyl) benzene; 150 mg, 0.421 mmol) was added, and the mixture was stirred under reflux for 5 hours in a mixed solvent of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (3 mL) for 5 hours. After cooling, the mixture was added dropwise to ether (100 mL) to precipitate a solid, followed by filtration under reduced pressure, and the obtained solid was recrystallized from methanol-ether to give the target substance (227 mg) as a light brown solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.00 - 8.94 (m, 2H), 8.31 (d, J = 7.6 Hz, 2H), 8.08 (m, 2H), 7.87 - 7.77 (m, 4H), 7.73 (m, 2H), 7.69 - 7.64 (m, 2H), 7.58 (m, 4H), 7.32 (m, 2H), 6.72 (d, J = 5.0 Hz, 2H), 6.51 (m, 2H), 5.66 (m, 2H), 5.35 - 5.08 (m, 6H), 4.99 - 4.88 (m, 2H), 4.30 (s, 2H), 3.94 (t, J = 8.6 Hz, 2H), 3.85 (m, 2H), 3.58 - 3.45 (m, 2H), 3.34 (d, J = 4.9 Hz, 2H), 2.79 (m, 2H), 2.17 - 1.82 (m, 8H), 1.24 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.00-8.94 (m, 2H), 8.31 (d, J = 7.6 Hz, 2H), 8.08 (m, 2H), 7.87-7.77 (m, 4H), 7.73 (m, 2H), 7.69-7.64 (m, 2H), 7.58 (m, 4H), 7.32 (m, 2H), 6.72 (d, J = 5.0 Hz, 2H), 6.51 (m, 2H), 5.66 (m, 2H), 5.35-5.08 (m, 6H), 4.99-4.88 (m, 2H), 4.30 (s, 2H), 3.94 (t, J = 8.6 Hz, 2H), 3.85 (m, 2H), 3.58-3.45 (m, 2H), 3.34 (d, J = 4.9 Hz, 2H), 2.79 (m, 2H), 2.17-1.82 (m, 8H), 1.24 (m, 2H).
실시예Example 20. 4,4'- 20. 4,4'- 비스(O(9)-알릴신코니디움-N-메틸)바이페닐Bis (O (9) -allylicindium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (10) 10
실시예 19의 방법으로 얻은 화합물 9 (180mg, 0.190mmol)를 디클로로메탄 (3mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 알릴브로마이드 (0.11mL, 1.33mmol)를 넣고, 4시간 동안 상온에서 교반하였다. 물 (3mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 에틸 에테르 (50mL)에 적가하여 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (200mg)을 연한 주황색의 고체로 수득하였다.Compound 9 (180 mg, 0.190 mmol) obtained by the method of Example 19 was suspended in dichloromethane (3 mL), and then 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and allyl bromide (0.11 mL, 1.33 mmol) were added thereto. , And stirred at room temperature for 4 hours. After diluting the reaction solution with water (3 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The solid obtained by dropwise addition to ethyl ether (50 mL) was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (200 mg) as a pale orange solid.
1H NMR (300 MHz, Chloroform-d) δ 8.99 (d, J = 4.4 Hz, 2H), 8.86 (d, J = 8.5 Hz, 2H), 8.15 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 8.3 Hz, 4H), 7.88 (m, 2H), 7.77 (m, 2H), 7.63 (s, 2H), 7.19 - 7.03 (m, 4H), 6.56 (d, J = 11.7 Hz, 2H), 6.23 (m, 2H), 6.19 - 6.07 (m, 2H), 5.67 (m, 2H), 5.49 - 5.32 (m, 6H), 4.98 (d, J = 10.4 Hz, 2H), 4.89 (m, 2H), 4.64 (m, 4H), 4.29 (m, 4H), 4.07 (m, 2H), 3.52 (m, 2H), 3.33 (m, 2H), 2.73 (m, 2H), 2.15 - 1.96 (m, 8H), 1.42 (m, 2H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.99 (d, J = 4.4 Hz, 2H), 8.86 (d, J = 8.5 Hz, 2H), 8.15 (d, J = 8.3 Hz, 2H), 8.02 ( d, J = 8.3 Hz, 4H), 7.88 (m, 2H), 7.77 (m, 2H), 7.63 (s, 2H), 7.19-7.03 (m, 4H), 6.56 (d, J = 11.7 Hz, 2H ), 6.23 (m, 2H), 6.19-6.07 (m, 2H), 5.67 (m, 2H), 5.49-5.32 (m, 6H), 4.98 (d, J = 10.4 Hz, 2H), 4.89 (m, 2H), 4.64 (m, 4H), 4.29 (m, 4H), 4.07 (m, 2H), 3.52 (m, 2H), 3.33 (m, 2H), 2.73 (m, 2H), 2.15-1.96 (m , 8H), 1.42 (m, 2H).
실시예Example 20- 20- 1: 31: 3 ,3'-, 3'- 비스(O(9)-알릴신코니디움-N-메틸)바이페닐Bis (O (9) -allylicindium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (10-1) (10-1)
실시예 19-1의 방법으로 얻은 화합물 9-1 (70 mg, 0.074 mmol)을 디클로로메탄 (2 mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25 mL, 6.77 mmol)과 알릴브로마이드 (0.043 mL, 0.518 mmol)를 넣고, 4시간 동안 얼음물에서 교반하였다. 물(2 mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 에틸 에테르 (50 mL)에 적가하여 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리정제하여 목적물 (60.0 mg)을 연노랑색의 고체로 수득하였다.Compound 9-1 (70 mg, 0.074 mmol) obtained by the method of Example 19-1 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.25 mL, 6.77 mmol) and allyl bromide (0.043 mL). , 0.518 mmol) was added and stirred in ice water for 4 hours. After diluting the reaction solution with water (2 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The solid obtained by dropwise addition to ethyl ether (50 mL) was purified by column chromatography (dichloromethane / methanol) to obtain the target product (60.0 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 8.95 (d, J = 4.5 Hz, 2H), 8.77 (d, J = 8.8 Hz, 2H), 8.12 (m, 2H), 8.04 (m, 2H), 7.87 (m, 2H), 7.75 (m, 2H), 7.65 (m, 2H), 7.48 (m, 2H), 7.35 (m, 2H), 7.18 (m, 2H), 6.35 (d, J = 11.7 Hz, 2H), 6.25 - 6.15 (m, 2H), 6.15 - 6.01 (m, 2H), 5.62 (m, 2H), 5.43 - 5.38 (m, 2H), 5.36 (m, 2H), 5.31-5.26 (m, 2H), 4.89 (m, 2H), 4.70 (d, J = 12.3 Hz, 2H), 4.62 (m, 2H), 4.56 - 4.47 (m, 2H), 4.24 (m, 4H), 4.03 (m, 2H), 3.81 - 3.65 (m, 2H), 3.53 (t, J = 11.6 Hz, 2H), 2.79 (m, 2H), 2.23 - 2.08 (m, 8H), 1.41 (m, 2H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.95 (d, J = 4.5 Hz, 2H), 8.77 (d, J = 8.8 Hz, 2H), 8.12 (m, 2H), 8.04 (m, 2H), 7.87 (m, 2H), 7.75 (m, 2H), 7.65 (m, 2H), 7.48 (m, 2H), 7.35 (m, 2H), 7.18 (m, 2H), 6.35 (d, J = 11.7 Hz , 2H), 6.25-6.15 (m, 2H), 6.15-6.01 (m, 2H), 5.62 (m, 2H), 5.43-5.38 (m, 2H), 5.36 (m, 2H), 5.31-5.26 (m , 2H), 4.89 (m, 2H), 4.70 (d, J = 12.3 Hz, 2H), 4.62 (m, 2H), 4.56-4.47 (m, 2H), 4.24 (m, 4H), 4.03 (m, 2H), 3.81-3.65 (m, 2H), 3.53 (t, J = 11.6 Hz, 2H), 2.79 (m, 2H), 2.23-2.08 (m, 8H), 1.41 (m, 2H).
실시예Example 21. 4,4'- 21.4,4'- 비스(O(9)-벤질신코니디움-N-메틸)바이페닐Bis (O (9) -benzylcinconium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (10-1-1) (10-1-1)
실시예 19의 방법으로 얻은 화합물 9 (50mg, 0.053mmol)를 디클로로메탄 (3mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 벤질브로마이드 (0.044mL, 0.37mmol)를 넣고, 2시간 동안 상온에서 교반하였다. 물 (3mL)로 반응액을 희석시키고, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 에틸 에테르 (50mL)에 적가하여 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (83mg)을 연한 주황색의 고체로 수득하였다.Compound 9 (50 mg, 0.053 mmol) obtained by the method of Example 19 was suspended in dichloromethane (3 mL), and then 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and benzyl bromide (0.044 mL, 0.37 mmol) were added thereto. , And stirred at room temperature for 2 hours. The reaction solution was diluted with water (3 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The solid obtained by dropwise addition to ethyl ether (50 mL) was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (83 mg) as a pale orange solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.87 (d, J = 6.2 Hz, 2H), 8.82 (d, J = 8.2 Hz, 2H), 8.60 (d, J = 9.0 Hz, 2H), 8.46 (d, J = 6.3 Hz, 2H), 8.30 (t, J = 8.1 Hz, 2H), 8.17 (t, J = 7.7 Hz, 2H), 7.83 (m, 2H), 7.61 (m, 2H), 7.43-7.38 (m, 10H), 6.90 (m, 2H), 6.50 - 6.41 (m, 4H), 5.71 (m, 2H), 5.24 (m, 2H), 5.16 (m, 2H), 5.01 (m, 4H), 4.40 (m, 2H), 4.22 - 4.15 (m, 2H), 4.03 - 3.88 (m, 4H), 3.38 (m, 4H), 2.72 (m, 2H), 2.30 (m, 2H), 2.02 (m, 2H), 1.85 (m, 2H), 1.60 (m, 2H), 1.25 (m, 2H). 0.86 (m, 2H) 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.87 (d, J = 6.2 Hz, 2H), 8.82 (d, J = 8.2 Hz, 2H), 8.60 (d, J = 9.0 Hz, 2H), 8.46 (d, J = 6.3 Hz, 2H), 8.30 (t, J = 8.1 Hz, 2H), 8.17 (t, J = 7.7 Hz, 2H), 7.83 (m, 2H), 7.61 (m, 2H), 7.43 -7.38 (m, 10H), 6.90 (m, 2H), 6.50-6.41 (m, 4H), 5.71 (m, 2H), 5.24 (m, 2H), 5.16 (m, 2H), 5.01 (m, 4H ), 4.40 (m, 2H), 4.22-4.15 (m, 2H), 4.03-3.88 (m, 4H), 3.38 (m, 4H), 2.72 (m, 2H), 2.30 (m, 2H), 2.02 ( m, 2H), 1.85 (m, 2H), 1.60 (m, 2H), 1.25 (m, 2H). 0.86 (m, 2 H)
실시예Example 22. 4,4'- 22.4,4'- 비스(히드로신코니디움-N-메틸)바이페닐Bis (hydrocinconium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (9-2) (9-2)
25mL 둥근바닥 플라스크에 (-)-히드로신코니딘 [(-)-hydrocinchonidine] (600mg, 2.02mmol)에 4,4'-옥시비스(브로모메틸)벤젠 [4,4'-oxybis((bromomethyl)benzene] (400mg, 1.12mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (6mL) 중에서 2시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 메탄올-에테르로 재결정하여 목적물 (2.346g)을 연노랑색의 고체로 수득하였다.In a 25 mL round bottom flask, (-)-hydrocinconidine [(-)-hydrocinchonidine] (600 mg, 2.02 mmol) in 4,4'-oxybis (bromomethyl) benzene [4,4'-oxybis ((bromomethyl ) benzene] (400 mg, 1.12 mmol) was added and stirred under reflux for 2 hours in a mixed solvent (6 mL) of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) at 110 ° C. The reaction mixture was cooled to room temperature. After cooling, the mixture was added dropwise to ether (50 mL) to precipitate a solid, and the resultant was filtered under reduced pressure, and the obtained solid was recrystallized from methanol-ether to give the target product (2.346 g) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.99 (d, J = 4.6 Hz, 2H), 8.31 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.3 Hz, 2H), 7.89 - 7.70 (m, 10H), 7.27 (d, J = 8.2 Hz, 4H), 6.74 (m, 2H), 6.55 (m, 2H), 5.21 (d, J = 12.7 Hz, 2H), 4.95 (d, J = 12.2 Hz, 2H), 4.27 (m, 2H), 3.92 (m, 2H), 3.44 (m, 2H), 3.31 - 3.20 (m, 4H), 2.08 (m, 4H), 1.96 (m, 2H), 1.77 (m, 4H), 1.34 (m, 2H), 1.16 (m, 4H), 0.71 (m, J = 7.1 Hz, 6H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.99 (d, J = 4.6 Hz, 2H), 8.31 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.3 Hz, 2H), 7.89 7.70 (m, 10H), 7.27 (d, J = 8.2 Hz, 4H), 6.74 (m, 2H), 6.55 (m, 2H), 5.21 (d, J = 12.7 Hz, 2H), 4.95 (d, J = 12.2 Hz, 2H), 4.27 (m, 2H), 3.92 (m, 2H), 3.44 (m, 2H), 3.31-3.20 (m, 4H), 2.08 (m, 4H), 1.96 (m, 2H ), 1.77 (m, 4H), 1.34 (m, 2H), 1.16 (m, 4H), 0.71 (m, J = 7.1 Hz, 6H).
실시예Example 23. 4,4'- 23. 4,4'- 비스(O(9)-알릴히드로신코니디움Bis (O (9) -allylhydrocinconium -N--N- 메틸methyl )) 바이페닐Biphenyl 에테르 디브로마이드 (10-2) Ether dibromide (10-2)
실시예 22의 방법으로 얻은 화합물 9-2 (150mg, 0.16mmol)을 디클로로메탄 (3mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 알릴브로마이드 (0.09mL, 1.10mmol)를 넣고, 2.5시간 동안 상온에서 교반하였다. 물 (3mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 에틸 에테르 (50mL)에 적가하여 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (135mg)을 연한 주황색의 고체로 수득하였다.Compound 9-2 (150 mg, 0.16 mmol) obtained by the method of Example 22 was suspended in dichloromethane (3 mL), followed by 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and allyl bromide (0.09 mL, 1.10 mmol). Was added and stirred at room temperature for 2.5 hours. After diluting the reaction solution with water (3 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The solid obtained by dropwise addition to ethyl ether (50 mL) was purified by column chromatography (dichloromethane / methanol) to obtain the desired product (135 mg) as a pale orange solid.
1H NMR (300 MHz, Chloroform-d) δ 8.98 (d, J = 4.1 Hz, 2H), 8.85 (d, J = 8.5 Hz, 2H), 8.16 (d, J = 8.4, 1.4 Hz, 2H), 8.00 (d, J = 8.8 Hz, 4H), 7.93 (m, 2H), 7.85 - 7.78 (m, 4H), 7.13 (d, J = 8.2 Hz, 4H), 6.45 (d, J = 11.8 Hz, 2H), 6.32 - 6.21 (m, 2H), 6.18 - 6.04 (m, 2H), 5.48 - 5.33 (m, 4H), 4.71 (m, J = 12.2 Hz, 2H), 4.61 (d, J = 11.5 Hz, 2H), 4.29 (m, 4H), 4.06 (m, 2H), 3.49 - 3.36 (m, 2H), 3.24 (m, 2H), 2.15 (m, 4H), 2.07 (m, 2H), 1.79 - 1.68 (m, 4H), 1.59 - 1.35 (m, 6H), 1.33 - 1.23 (m, 2H), 0.83 - 0.65 (m, 6H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.98 (d, J = 4.1 Hz, 2H), 8.85 (d, J = 8.5 Hz, 2H), 8.16 (d, J = 8.4, 1.4 Hz, 2H), 8.00 (d, J = 8.8 Hz, 4H), 7.93 (m, 2H), 7.85-7.78 (m, 4H), 7.13 (d, J = 8.2 Hz, 4H), 6.45 (d, J = 11.8 Hz, 2H ), 6.32-6.21 (m, 2H), 6.18-6.04 (m, 2H), 5.48-5.33 (m, 4H), 4.71 (m, J = 12.2 Hz, 2H), 4.61 (d, J = 11.5 Hz, 2H), 4.29 (m, 4H), 4.06 (m, 2H), 3.49-3.36 (m, 2H), 3.24 (m, 2H), 2.15 (m, 4H), 2.07 (m, 2H), 1.79-1.68 (m, 4H), 1.59-1.35 (m, 6H), 1.33-1.23 (m, 2H), 0.83-0.65 (m, 6H).
실시예Example 24. 4,4'- 24.4,4'- 비스(퀴니움-N-메틸)바이페닐Bis (quinium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (9-3)  (9-3)
25mL 둥근바닥 플라스크에 (-)-퀴닌 [(-)-quinine] (328mg, 1.01mmol)에 4,4'-옥시비스(브로모메틸)벤젠 [4,4'-oxybis((bromomethyl)benzene] (200mg, 0.56mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 3시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (541mg)을 연노랑색의 고체로 수득하였다.(-)-Quinine [(-)-quinine] (328 mg, 1.01 mmol) in a 25 mL round bottom flask [4,4'-oxybis ((bromomethyl) benzene] (200 mg, 0.56 mmol) was added, and the mixture was stirred under reflux for 3 hours in an ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) mixed solvent (3 mL) at 110 ° C. The reaction mixture was cooled to room temperature. Then, the mixture was added dropwise to ether (50 mL) to precipitate a solid, followed by filtration under reduced pressure, and the obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the target substance (541 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.82 (d, J = 4.4 Hz, 2H), 8.03 (d, J = 9.1 Hz, 2H), 7.76 (m, 6H), 7.50 (d, J = 9.2, 2.5 Hz, 2H), 7.39 (d, J = 2.6 Hz, 2H), 7.27 (d, J = 8.2 Hz, 4H), 6.70 (d, J = 4.2 Hz, 2H), 6.60 (m, 2H), 5.75 - 5.67 (m, 2H), 5.45 (d, J = 12.3 Hz, 2H), 5.12 (d, J = 17.3 Hz, 2H), 5.01 (d, J = 10.4 Hz, 2H), 4.73 (d, J = 12.3 Hz, 2H), 4.23 (m, 2H), 4.02 (s, J = 6.1 Hz, 6H), 3.86 (m, 2H), 3.68 (m, 2H), 3.41 (m, 2H), 3.25 (m, 2H), 2.72 (m, 2H), 2.18 (m, 4H), 2.02 (m, 2H), 1.86 (m, 2H), 1.46 (m, J = 11.7 Hz, 2H) 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.82 (d, J = 4.4 Hz, 2H), 8.03 (d, J = 9.1 Hz, 2H), 7.76 (m, 6H), 7.50 (d, J = 9.2, 2.5 Hz, 2H), 7.39 (d, J = 2.6 Hz, 2H), 7.27 (d, J = 8.2 Hz, 4H), 6.70 (d, J = 4.2 Hz, 2H), 6.60 (m, 2H) , 5.75-5.67 (m, 2H), 5.45 (d, J = 12.3 Hz, 2H), 5.12 (d, J = 17.3 Hz, 2H), 5.01 (d, J = 10.4 Hz, 2H), 4.73 (d, J = 12.3 Hz, 2H), 4.23 (m, 2H), 4.02 (s, J = 6.1 Hz, 6H), 3.86 (m, 2H), 3.68 (m, 2H), 3.41 (m, 2H), 3.25 ( m, 2H), 2.72 (m, 2H), 2.18 (m, 4H), 2.02 (m, 2H), 1.86 (m, 2H), 1.46 (m, J = 11.7 Hz, 2H)
실시예Example 25. 4,4'- 25.4,4'- 비스(O(9)-알릴퀴니움-N-메틸)바이페닐Bis (O (9) -allylquinium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (10-3) (10-3)
실시예 24의 방법으로 얻은 화합물 9-3 (100mg, 0.10mmol)를 클로로포름 (3mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 알릴브로마이드 (0.06mL, 0.70mmol)를 넣고, 2시간 동안 상온에서 교반하였다. 물 (3mL)로 반응액을 희석시킨 후, 디클로로메탄 (2 x 3mL)으로 추출한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후, 여과하여 감압농축하였다. 잔사를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (30mg)을 연갈색의 고체로 수득하였다.Compound 9-3 (100 mg, 0.10 mmol) obtained by the method of Example 24 was suspended in chloroform (3 mL), followed by 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and allyl bromide (0.06 mL, 0.70 mmol). Put, and stirred at room temperature for 2 hours. The reaction solution was diluted with water (3 mL), extracted with dichloromethane (2 x 3 mL), the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (30 mg) as a light brown solid.
1H NMR (300 MHz, Chloroform-d) δ 8.92 - 8.76 (m, 2H), 8.15 - 8.01 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 11.5 Hz, 2H), 7.21 (d, J = 9.0 Hz, 2H), 7.11 (m, 2H), 7.05 - 6.83 (m, 2H), 6.25 - 6.01 (m, 4H), 5.97 - 5.75 (m, 2H), 5.40 (m, 4H), 5.33 - 5.22 (m, 4H), 4.25 (d, J = 23.5 Hz, 4H), 4.03 (m, 4H), 3.93 (m, 2H), 3.88 - 3.80 (m, 4H), 3.62 (m, 2H), 3.41 (m, 2H), 2.61 (m, 2H), 2.44 (m, 2H), 2.21 (m, 2H), 2.07 - 1.96 (m, 6H), 1.57 - 1.44 (m, 2H), 1.13 - 1.08 (m, 4H), 0.84 (m, 4H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.92-8.76 (m, 2H), 8.15-8.01 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 11.5 Hz , 2H), 7.21 (d, J = 9.0 Hz, 2H), 7.11 (m, 2H), 7.05-6.83 (m, 2H), 6.25-6.01 (m, 4H), 5.97-5.75 (m, 2H), 5.40 (m, 4H), 5.33-5.22 (m, 4H), 4.25 (d, J = 23.5 Hz, 4H), 4.03 (m, 4H), 3.93 (m, 2H), 3.88-3.80 (m, 4H) , 3.62 (m, 2H), 3.41 (m, 2H), 2.61 (m, 2H), 2.44 (m, 2H), 2.21 (m, 2H), 2.07-1.96 (m, 6H), 1.57-1.44 (m , 2H), 1.13-1.08 (m, 4H), 0.84 (m, 4H).
실시예Example 26. 4,4'- 26. 4,4'- 비스(신코니디움-N-메틸)바이페닐Bis (syncondium-N-methyl) biphenyl 티오에테르  Thioether 디브로마이드Dibromide (11) (11)
25mL 둥근바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (700mg, 2.4mmol)에 비스(4-(브로모메틸)페닐)설판 [bis(4-(bromomethyl)phenyl)sulfane] (492mg, 1.32mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (5mL) 중에서 4.5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (781mg)을 선홍색의 고체로 수득하였다.Bis (4- (bromomethyl) phenyl) sulfane in (-)-cinconidine [(-)-cinchonidine] (700 mg, 2.4 mmol) in a 25 mL round bottom flask (492 mg, 1.32 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 4.5 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (5 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (781 mg) as a scarlet solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.97 (d, J = 4.5 Hz, 2H), 8.30 (d, J = 7.9 Hz, 2H), 8.10 (d, J = 8.5 Hz, 2H), 7.91 - 7.69 (m, 10H), 7.56 (m, 4H), 6.76 (m, 2H), 6.54 (m, 2H), 245.75 (m, 2H), 5.66 (m, 2H), 5.29 - 5.01 (m, 6H), 4.94 (m, 2H), 4.26 (m, 2H), 3.91 (m, 2H), 3.78 (m, 2H), 3.36 (m, 2H), 3.26 (m, 2H), 2.68 (m, 2H), 2.03 (m, 6H), 1.82 (m, 2H), 1.27 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.97 (d, J = 4.5 Hz, 2H), 8.30 (d, J = 7.9 Hz, 2H), 8.10 (d, J = 8.5 Hz, 2H), 7.91 -7.69 (m, 10H), 7.56 (m, 4H), 6.76 (m, 2H), 6.54 (m, 2H), 245.75 (m, 2H), 5.66 (m, 2H), 5.29-5.01 (m, 6H ), 4.94 (m, 2H), 4.26 (m, 2H), 3.91 (m, 2H), 3.78 (m, 2H), 3.36 (m, 2H), 3.26 (m, 2H), 2.68 (m, 2H) , 2.03 (m, 6H), 1.82 (m, 2H), 1.27 (m, 2H).
실시예Example 26-1. 3,3'- 26-1. 3,3'- 비스(신코니디움-N-메틸)바이페닐Bis (syncondium-N-methyl) biphenyl 설파이드Sulfide 디브로마이드Dibromide (11-1) (11-1)
10 mL 둥근바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (235 mg, 798 mmol)에 비스(3-(브로모메틸)페닐) 설파이드 (bis(3-bromomethylphenyl) sulfide; 165 g, 443 mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (2.5 mL) 중에서 4.5시간동안 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (200 mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리정제하여 목적물 (184 mg)을 연노랑색의 고체로 수득하였다.(-)-Cinconidine [(-)-cinchonidine] (235 mg, 798 mmol) in a 10 mL round bottom flask with bis (3- (bromomethylphenyl) sulfide (bis (3-bromomethylphenyl) sulfide; 165 g, 443 mmol), and the mixture was stirred under reflux for 4.5 hours in a mixed solvent (2.5 mL) of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2). The reaction mixture was cooled to room temperature, added dropwise to ether (200 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the target product (184 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (d, J = 4.5 Hz, 2H), 8.29 (d, J = 8.3 Hz, 2H), 8.15 - 8.01 (m, 5H), 7.84 - 7.73 (m, 9H), 7.54 (t, J = 7.9 Hz, 2H), 6.72 (d, J = 4.6 Hz, 2H), 6.52 (d, J = 5.1 Hz, 2H), 5.73 - 5.58 (m, 2H), 5.23 - 5.13 (m, 4H), 5.08 - 5.01 (m, 2H), 4.98 - 4.92 (m, 2H), 4.30 (m, 2H), 3.91 (t, J = 9.4 Hz, 2H), 3.82 - 3.71 (m, 2H), 3.39 (m, 2H), 2.69 (m, 2H), 2.17 - 1.97 (m, 8H), 1.82 (d, J = 4.1 Hz, 2H), 1.34 - 1.24 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.29 (d, J = 8.3 Hz, 2H), 8.15-8.01 (m, 5H), 7.84-7.73 ( m, 9H), 7.54 (t, J = 7.9 Hz, 2H), 6.72 (d, J = 4.6 Hz, 2H), 6.52 (d, J = 5.1 Hz, 2H), 5.73-5.58 (m, 2H), 5.23-5.13 (m, 4H), 5.08-5.01 (m, 2H), 4.98-4.92 (m, 2H), 4.30 (m, 2H), 3.91 (t, J = 9.4 Hz, 2H), 3.82-3.71 ( m, 2H), 3.39 (m, 2H), 2.69 (m, 2H), 2.17-1.97 (m, 8H), 1.82 (d, J = 4.1 Hz, 2H), 1.34-1.24 (m, 2H).
실시예Example 27. 4,4'- 27.4,4'- 비스(O(9)-알릴신코니디움-N-메틸)바이페닐Bis (O (9) -allylicindium-N-methyl) biphenyl 티오에테르  Thioether 디브로마이드Dibromide (12) (12)
실시예 26의 방법으로 얻은 화합물 11 (150mg, 0.156mmol)을 디클로로메탄 (3.5mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 알릴브로마이드 (133mg, 1.10mmol)를 넣고, 4시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (88mg)을 연한 주황색의 고체로 수득하였다.Compound 11 (150 mg, 0.156 mmol) obtained by the method of Example 26 was suspended in dichloromethane (3.5 mL), and then 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and allyl bromide (133 mg, 1.10 mmol) were added thereto. , And stirred at room temperature for 4 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the target product (88 mg) as a pale orange solid.
1H NMR (300 MHz, Chloroform-d) δ 8.97 (d, J = 7.6, 4.4 Hz, 2H), 8.85 (d, J = 8.9 Hz, 2H), 8.13 (d, J = 8.3, 4.8 Hz, 2H), 7.97 (m, 4H), 7.90 (m, 2H), 7.69 (m, 2H), 7.61 (m, 2H), 7.44 (d, J = 8.3 Hz, 4H), 6.60 (d, J = 11.9 Hz, 2H), 6.23 (m, 2H), 6.20 - 6.02 (m, 2H), 5.66 (m, 2H), 5.48 - 5.34 (m, 6H), 4.98 (d, J = 10.6 Hz, 2H), 4.91 (m, 2H), 4.62 (m, 4H), 4.29 (m, 4H), 4.12 - 3.99 (m, 2H), 3.52 - 3.41 (m, 2H), 3.27 (m, 2H), 2.73 (m, 2H), 2.17 (m, 4H), 2.10 (m, 2H), 1.41 (m, 2H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.97 (d, J = 7.6, 4.4 Hz, 2H), 8.85 (d, J = 8.9 Hz, 2H), 8.13 (d, J = 8.3, 4.8 Hz, 2H ), 7.97 (m, 4H), 7.90 (m, 2H), 7.69 (m, 2H), 7.61 (m, 2H), 7.44 (d, J = 8.3 Hz, 4H), 6.60 (d, J = 11.9 Hz , 2H), 6.23 (m, 2H), 6.20-6.02 (m, 2H), 5.66 (m, 2H), 5.48-5.34 (m, 6H), 4.98 (d, J = 10.6 Hz, 2H), 4.91 ( m, 2H), 4.62 (m, 4H), 4.29 (m, 4H), 4.12-3.99 (m, 2H), 3.52-3.41 (m, 2H), 3.27 (m, 2H), 2.73 (m, 2H) , 2.17 (m, 4H), 2.10 (m, 2H), 1.41 (m, 2H).
실시예Example 27-1. 3,3'- 27-1. 3,3'- 비스(O(9)-알릴신코니디움-N-메틸)바이페닐Bis (O (9) -allylicindium-N-methyl) biphenyl 설파이드Sulfide 디브로마이드Dibromide (12-1) (12-1)
실시예 26-1의 방법으로 얻은 화합물 11-1 (72 mg, 74.9 mmol)을 디클로로메탄 (1.5 mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.2 mL, 1.78 mmol)과 알릴브로마이드 (64 mg, 525 mmol)를 넣고, 3시간 동안 상온에서 교반하였다. Sodiumbromide와 물(5 mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 유기층을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리정제하여 목적물 (42 mg)을 연노랑색의 고체로 수득하였다.Compound 11-1 (72 mg, 74.9 mmol) obtained by the method of Example 26-1 was suspended in dichloromethane (1.5 mL), followed by 50% aqueous potassium hydroxide solution (0.2 mL, 1.78 mmol) and allyl bromide (64 mg). , 525 mmol) and stirred at room temperature for 3 hours. The reaction solution was diluted with sodium bromide and water (5 mL), the organic layer was separated, and the organic layer was dried over anhydrous magnesium sulfate and filtered. This was purified by column chromatography (dichloromethane / methanol) to give the target product (42 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 8.97 (d, J = 4.5 Hz, 2H), 8.83 (d, J = 8.7 Hz, 2H), 8.14 (dd, J = 8.4, 2.9 Hz, 4H), 7.95 - 7.84 (m, 4H), 7.77 (t, J = 7.3 Hz, 2H), 7.64 (m, 4H), 7.39 (t, J = 7.9 Hz, 2H), 6.61 (d, J = 12.0 Hz, 2H), 6.24 (m, 2H), 6.19 - 6.01 (m, 2H), 5.70 (ddd, J = 17.0, 10.5, 6.2 Hz, 2H), 5.46 - 5.33 (m, 6H), 5.06 - 4.89 (m, 4H), 4.78 - 4.59 (m, 4H), 4.42 - 4.23 (m, 4H), 4.09 (m, 2H), 3.47 - 3.33 (m, 2H), 3.31 - 3.17 (m, 2H), 2.65 (m, 2H), 2.22 (m, 2H), 2.07 (m, 4H), 1.87 (m, 2H), 1.45 (m, 2H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.97 (d, J = 4.5 Hz, 2H), 8.83 (d, J = 8.7 Hz, 2H), 8.14 (dd, J = 8.4, 2.9 Hz, 4H), 7.95-7.84 (m, 4H), 7.77 (t, J = 7.3 Hz, 2H), 7.64 (m, 4H), 7.39 (t, J = 7.9 Hz, 2H), 6.61 (d, J = 12.0 Hz, 2H ), 6.24 (m, 2H), 6.19-6.01 (m, 2H), 5.70 (ddd, J = 17.0, 10.5, 6.2 Hz, 2H), 5.46-5.33 (m, 6H), 5.06-4.89 (m, 4H ), 4.78-4.59 (m, 4H), 4.42-4.23 (m, 4H), 4.09 (m, 2H), 3.47-3.33 (m, 2H), 3.31-3.17 (m, 2H), 2.65 (m, 2H ), 2.22 (m, 2H), 2.07 (m, 4H), 1.87 (m, 2H), 1.45 (m, 2H).
실시예Example 28. 4,4'- 28.4,4'- 비스(히드로신코니디움-N-메틸)바이페닐Bis (hydrocinconium-N-methyl) biphenyl 티오에테르  Thioether 디브로마이드Dibromide (11-2) (11-2)
25mL 둥근바닥 플라스크에 (-)-히드로신코니딘 [(-)-hydrocinchonidine] (860mg, 2.90mmol)에 비스(4-(브로모메틸)페닐)설판 [bis(4-(bromomethyl)phenyl)sulfane] (600mg, 1.61mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (8mL) 중에서 2.5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (950mg)을 노란색의 고체로 수득하였다. (-)-Hydrocinconidine [(-)-hydrocinchonidine] (860 mg, 2.90 mmol) in a 25 mL round bottom flask with bis (4- (bromomethyl) phenyl) sulfane [bis (4- (bromomethyl) phenyl) sulfane (600mg, 1.61mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 2.5 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (8 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (950 mg) as a yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.00 (d, J = 4.7 Hz, 2H), 8.28 (d, J = 8.2 Hz, 2H), 8.12 (d, J = 8.3 Hz, 2H), 7.91 - 7.79 (m, 4H), 7.74 (m, 6H), 7.56 (m, 4H), 6.72 (m, 2H), 6.54 (m, 2H), 5.15 (m, 2H), 4.91 (m, 2H), 4.25 (m, 2H), 3.89 (m, 2H), 3.40 (m, 2H), 3.15 (m, 4H), 2.08 (m, 4H), 1.96 (m, 2H), 1.75 (m, 4H), 1.35 (m, 2H), 1.27 - 1.08 (m, 4H), 0.71 (m, 6H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.00 (d, J = 4.7 Hz, 2H), 8.28 (d, J = 8.2 Hz, 2H), 8.12 (d, J = 8.3 Hz, 2H), 7.91 7.79 (m, 4H), 7.74 (m, 6H), 7.56 (m, 4H), 6.72 (m, 2H), 6.54 (m, 2H), 5.15 (m, 2H), 4.91 (m, 2H), 4.25 (m, 2H), 3.89 (m, 2H), 3.40 (m, 2H), 3.15 (m, 4H), 2.08 (m, 4H), 1.96 (m, 2H), 1.75 (m, 4H), 1.35 (m, 2H), 1.27-1.08 (m, 4H), 0.71 (m, 6H).
실시예Example 29. 4,4'- 29.4,4'- 비스(O(9)-알릴히드로신코니디움Bis (O (9) -allylhydrocinconium -N--N- 메틸methyl )) 바이페닐Biphenyl 티오에테르  Thioether 디브로마이드Dibromide (12-2) (12-2)
실시예 28의 방법으로 얻은 화합물 11-2 (152mg, 0.157mmol)을 디클로로메탄 (2mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 알릴브로마이드 (135mg, 1.10mmol)를 넣고, 2시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (96mg)을 연한 노란색의 고체로 수득하였다.Compound 11-2 (152 mg, 0.157 mmol) obtained by the method of Example 28 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and allyl bromide (135 mg, 1.10 mmol). Put, and stirred at room temperature for 2 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (96 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 9.00 (d, J = 4.3 Hz, 2H), 8.89 (d, J = 8.7 Hz, 2H), 8.16 (d, J = 8.2 Hz, 2H), 7.94 (m, 6H), 7.82 (m, 2H), 7.46 (d, J = 8.5 Hz, 4H), 6.58 (d, J = 11.2 Hz, 2H), 6.19 (m, 4H), 6.15 - 6.01 (m, 2H), 5.49 - 5.33 (m, 4H), 4.81 (m, 4H), 4.49 (d, J = 11.3 Hz, 2H), 4.42 - 4.20 (m, 4H), 3.97 (m, 2H), 3.37 (m, 2H), 3.27 - 3.11 (m, 2H), 2.14 (m, 6H), 1.89 (m, 4H), 1.40 (m, 4H), 1.27 (m, 2H), 0.80 (t, J = 7.3 Hz, 6H). total H =68 1 H NMR (300 MHz, Chloroform- d ) δ 9.00 (d, J = 4.3 Hz, 2H), 8.89 (d, J = 8.7 Hz, 2H), 8.16 (d, J = 8.2 Hz, 2H), 7.94 ( m, 6H), 7.82 (m, 2H), 7.46 (d, J = 8.5 Hz, 4H), 6.58 (d, J = 11.2 Hz, 2H), 6.19 (m, 4H), 6.15-6.01 (m, 2H ), 5.49-5.33 (m, 4H), 4.81 (m, 4H), 4.49 (d, J = 11.3 Hz, 2H), 4.42-4.20 (m, 4H), 3.97 (m, 2H), 3.37 (m, 2H), 3.27-3.11 (m, 2H), 2.14 (m, 6H), 1.89 (m, 4H), 1.40 (m, 4H), 1.27 (m, 2H), 0.80 (t, J = 7.3 Hz, 6H ). total H = 68
실시예Example 30. 4,4'- 30. 4,4'- 비스(퀴니움-N-메틸)바이페닐Bis (quinium-N-methyl) biphenyl 티오에테르  Thioether 디브로마이드Dibromide (11-3) (11-3)
25mL 둥근바닥 플라스크에 (-)-퀴닌 [(-)-quinine] (200mg, 0.616mmol)에 비스(4-(브로모메틸)페닐)설판 [bis(4-(bromomethyl)phenyl)sulfane] (127mg, 0.343mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 2.5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (25mL)에 적가하여 고체를 석출시킨 후, 감압여과하고, 목적물 (320mg)을 주황색의 고체로 수득하였다. (-)-Quinine [(-)-quinine] (200 mg, 0.616 mmol) in bis (4- (bromomethyl) phenyl) sulfane [bis (4- (bromomethyl) phenyl) sulfane] (127 mg in a 25 mL round bottom flask , 0.343 mmol) was added, and the mixture was stirred under reflux at 110 ° C. for 2.5 hours in a mixed solvent (3 mL) of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2). The reaction mixture was cooled to room temperature, added dropwise to ether (25 mL) to precipitate a solid, and the resultant was filtered under reduced pressure and the desired product (320 mg) was obtained as an orange solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.82 (d, J = 4.5 Hz, 2H), 8.03 (d, J=9.0 Hz 2H), 7.80 - 7.69 (m, 6H), 7.52 (d, J= 8.1 Hz, 4H), 7.50 (m, 2H), 7.38 (d, J = 3.2 Hz, 2H), 6.70 (d, J = 4.1 Hz, 2H), 6.59 (m, 2H), 5.85 - 5.66 (m, 2H), 5.45 (d, J = 12.4 Hz, 2H), 5.12 (d, J = 17.3 Hz, 2H), 5.01 (d, J = 10.3 Hz, 2H), 4.73 (d, J = 12.5 Hz, 2H), 4.29 - 4.07 (m, 2H), 4.01 (s, 6H), 4.00-3.97 (m, 2H), 3.83 (m, 2H), 3.67 (m, 2H), 3.23 (m, 2H), 2.68 (m, 2H), 2.17 (m, 4H), 2.01 (m, 2H), 1.84 (m, 2H), 1.46 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.82 (d, J = 4.5 Hz, 2H), 8.03 (d, J = 9.0 Hz 2H), 7.80-7.69 (m, 6H), 7.52 (d, J = 8.1 Hz, 4H), 7.50 (m, 2H), 7.38 (d, J = 3.2 Hz, 2H), 6.70 (d, J = 4.1 Hz, 2H), 6.59 (m, 2H), 5.85-5.66 (m , 2H), 5.45 (d, J = 12.4 Hz, 2H), 5.12 (d, J = 17.3 Hz, 2H), 5.01 (d, J = 10.3 Hz, 2H), 4.73 (d, J = 12.5 Hz, 2H ), 4.29-4.07 (m, 2H), 4.01 (s, 6H), 4.00-3.97 (m, 2H), 3.83 (m, 2H), 3.67 (m, 2H), 3.23 (m, 2H), 2.68 ( m, 2H), 2.17 (m, 4H), 2.01 (m, 2H), 1.84 (m, 2H), 1.46 (m, 2H).
실시예Example 31. 4,4'- 31.4,4'- 비스(O(9)-알릴퀴니움-N-메틸)바이페닐Bis (O (9) -allylquinium-N-methyl) biphenyl 티오에테르  Thioether 디브로마이드Dibromide (12-3) (12-3)
실시예 30의 방법으로 얻은 화합물 11-3 (100mg, 0.10mmol)를 디클로로메탄 (1mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.23mmol)과 알릴브로마이드 (82mg, 0.67mmol)를 넣고, 5시간 동안 상온에서 교반하였다. Sodiumbromide와 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (39.4mg)을 연노랑색의 고체로 수득하였다.Compound 11-3 (100 mg, 0.10 mmol) obtained by the method of Example 30 was suspended in dichloromethane (1 mL), followed by 50% aqueous potassium hydroxide solution (0.25 mL, 2.23 mmol) and allyl bromide (82 mg, 0.67 mmol). Put, and stirred at room temperature for 5 hours. The reaction solution was diluted with sodium bromide and water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. This was purified by column chromatography (dichloromethane / methanol) to give the desired product (39.4 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.84 (d, J = 4.5 Hz, 2H), 8.04 (d, J = 9.1 Hz, 2H), 7.78 (d, J = 8.4 Hz, 4H), 7.65 (d, J = 4.5 Hz, 2H), 7.58 (d, J = 8.3 Hz, 4H), 7.51 (dd, J = 9.2, 2.6 Hz, 2H), 7.43 (m, 2H), 6.58 (m, 2H), 6.14 (m, 2H), 5.88 - 5.56 (m, 8H), 5.54 - 5.40 (m, 2H), 5.28 (m, 2H), 5.15 - 4.96 (m, 4H), 4.81 (d, J = 11.8 Hz, 2H), 4.51 (m, 2H), 4.02 - 3.89 (m, 10H), 2.72 (m, 2H), 2.38 (d, J = 12.8 Hz, 2H), 2.25 - 2.13 (m, 2H), 2.07 - 2.00 (m, 2H), 1.91 (m, 2H), 1.64 - 1.48 (m, 2H), 1.22 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.84 (d, J = 4.5 Hz, 2H), 8.04 (d, J = 9.1 Hz, 2H), 7.78 (d, J = 8.4 Hz, 4H), 7.65 (d, J = 4.5 Hz, 2H), 7.58 (d, J = 8.3 Hz, 4H), 7.51 (dd, J = 9.2, 2.6 Hz, 2H), 7.43 (m, 2H), 6.58 (m, 2H) , 6.14 (m, 2H), 5.88-5.56 (m, 8H), 5.54-5.40 (m, 2H), 5.28 (m, 2H), 5.15-4.96 (m, 4H), 4.81 (d, J = 11.8 Hz , 2H), 4.51 (m, 2H), 4.02-3.89 (m, 10H), 2.72 (m, 2H), 2.38 (d, J = 12.8 Hz, 2H), 2.25-2.13 (m, 2H), 2.07- 2.00 (m, 2H), 1.91 (m, 2H), 1.64-1.48 (m, 2H), 1.22 (m, 2H).
실시예Example 32. 4,4'- 32.4,4'- 비스(신코니디움-N-메틸)바이페닐Bis (syncondium-N-methyl) biphenyl 설폭사이드Sulfoxide 디브로마이드Dibromide (13) (13)
25mL 둥근바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (272mg, 1.38mmol)에 4,4'-설피닐비스-(브로모메틸)벤젠 (4,4'-sulfinylbis(bromomethyl)benzene; 200 mg, 0.815 mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 3시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (20mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 목적물 (320mg)을 연한 주황색의 고체로 수득하였다. 4,4'-sulfinylbis- (bromomethyl) benzene (4,4'-sulfinylbis (bromomethyl) in (-)-cinconidine [(-)-cinchonidine] (272 mg, 1.38 mmol) in a 25 mL round bottom flask ) benzene; 200 mg, 0.815 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 3 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (20 mL) to precipitate a solid, and then filtered under reduced pressure. The solid obtained was obtained as target product (320 mg) as a pale orange solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (d, J = 4.4 Hz, 2H), 8.33 (m, 2H), 8.10 (d, J = 8.4 Hz, 2H), 7.90 - 7.65 (m, 10H), 7.57 (d, J = 8.3 Hz, 4H), 6.78 (d, J = 4.7 Hz, 2H), 6.56 (m, 2H), 5.65 (m, 2H), 5.32 - 5.09 (m, 6H), 4.99 - 4.89 (m, 2H), 4.31 (m, 2H), 3.95 (m, 2H), 3.84 (m, 2H), 3.41 - 3.26 (m, 4H), 2.70 (m, 2H), 2.18 - 1.96 (m, 6H), 1.88 - 1.80 (m, 2H), 1.26 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.4 Hz, 2H), 8.33 (m, 2H), 8.10 (d, J = 8.4 Hz, 2H), 7.90-7.65 (m, 10H), 7.57 (d, J = 8.3 Hz, 4H), 6.78 (d, J = 4.7 Hz, 2H), 6.56 (m, 2H), 5.65 (m, 2H), 5.32-5.09 (m, 6H), 4.99-4.89 (m, 2H), 4.31 (m, 2H), 3.95 (m, 2H), 3.84 (m, 2H), 3.41-3.26 (m, 4H), 2.70 (m, 2H), 2.18-1.96 ( m, 6H), 1.88-1.80 (m, 2H), 1.26 (m, 2H).
실시예Example 33. 4,4'- 33. 4,4'- 비스(O(9)-알릴신코니디움-N-메틸)바이페닐Bis (O (9) -allylicindium-N-methyl) biphenyl 설폭사이드Sulfoxide 디브로마이드Dibromide (14) (14)
실시예 32의 방법으로 얻은 화합물 13 (85mg, 0.0804mmol)을 클로로포름 (2mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.08mL, 0.704mmol)과 알릴브로마이드 (68mg, 0.563mmol)를 넣고, 5시간 동안 상온에서 교반하였다. NaBr (5mL)과 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 클로로포름용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (30mg)을 연한 노란색의 고체로 수득하였다.Compound 13 (85 mg, 0.0804 mmol) obtained by the method of Example 32 was suspended in chloroform (2 mL), and then 50% aqueous potassium hydroxide solution (0.08 mL, 0.704 mmol) and allyl bromide (68 mg, 0.563 mmol) were added. Stir at room temperature for hours. The reaction solution was diluted with NaBr (5 mL) and water (5 mL), the organic layer was separated, and the chloroform solution was dried over anhydrous magnesium sulfate and filtered. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (30 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.01 (d, J = 4.5, 4.0 Hz, 2H), 8.29 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 8.3 Hz, 2H), 7.94 - 7.73 (m, 8H), 7.69 (d, J = 7.9 Hz, 2H), 7.62 - 7.54 (m, 4H), 6.45 (s, 2H), 6.16 (m, 2H), 5.80 - 5.61 (m, 2H), 5.69 (m, 2H), 5.34 - 5.24 (m, 2H), 5.29 (m, 2H), 5.22 - 5.09 (m, 4H), 5.00 (m, 4H), 4.38 (m, 2H), 4.03 (m, 6H), 3.77 (m, 2H), 3.55 - 3.25 (m, 4H), 2.71 (m, 2H), 2.28 (m, 2H), 2.11 (m, 2H), 2.03 (m, 2H), 1.88 (m, 2H), 1.43 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.01 (d, J = 4.5, 4.0 Hz, 2H), 8.29 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 8.3 Hz, 2H) , 7.94-7.73 (m, 8H), 7.69 (d, J = 7.9 Hz, 2H), 7.62-7.54 (m, 4H), 6.45 (s, 2H), 6.16 (m, 2H), 5.80-5.61 (m , 2H), 5.69 (m, 2H), 5.34-5.24 (m, 2H), 5.29 (m, 2H), 5.22-5.09 (m, 4H), 5.00 (m, 4H), 4.38 (m, 2H), 4.03 (m, 6H), 3.77 (m, 2H), 3.55-3.25 (m, 4H), 2.71 (m, 2H), 2.28 (m, 2H), 2.11 (m, 2H), 2.03 (m, 2H) , 1.88 (m, 2 H), 1.43 (m, 2 H).
실시예Example 34. 4,4'- 34.4,4'- 비스(히드로신코니디움-N-메틸)바이페닐Bis (hydrocinconium-N-methyl) biphenyl 설폭사이드Sulfoxide 디브로마이드Dibromide (13-1) (13-1)
25mL 둥근바닥 플라스크에 (-)-히드로신코니딘 [(-)-hydrocinchonidine] (411g, 1.39mmol)에 4,4'-설피닐비스-(브로모메틸)벤젠 (4,4'-sulfinylbis(bromomethyl)benzene; 300g, 0.815mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 5.5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (20mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (150mg)을 연한 주황색의 고체로 수득하였다.In a 25 mL round bottom flask, (-)-hydrocinconidine [(-)-hydrocinchonidine] (411 g, 1.39 mmol) was added 4,4'-sulfinylbis- (bromomethyl) benzene (4,4'-sulfinylbis ( bromomethyl) benzene (300 g, 0.815 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 5.5 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (20 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (150 mg) as a pale orange solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (d, J = 4.5 Hz, 2H), 8.31 (m, 2H), 8.10 (m, 2H), 7.90 - 7.62 (m, 10H), 7.61 - 7.36 (m, 4H), 6.76 (m, 2H), 6.55 (m, 2H), 5.25 (m, 2H), 5.01 (m, 2H), 4.31 (m, 2H), 3.94 (m, 2H), 3.50 (m, 2H), 3.38 - 3.29 (m, 4H), 2.07 (m, 4H), 1.94 (m, 2H), 1.76 (m, 4H), 1.33 (m, 2H), 1.16 (m, 4H), 0.75 - 0.62 (m, 6H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.31 (m, 2H), 8.10 (m, 2H), 7.90-7.62 (m, 10H), 7.61- 7.36 (m, 4H), 6.76 (m, 2H), 6.55 (m, 2H), 5.25 (m, 2H), 5.01 (m, 2H), 4.31 (m, 2H), 3.94 (m, 2H), 3.50 (m, 2H), 3.38-3.29 (m, 4H), 2.07 (m, 4H), 1.94 (m, 2H), 1.76 (m, 4H), 1.33 (m, 2H), 1.16 (m, 4H), 0.75-0.62 (m, 6H).
실시예Example 35. 4,4'- 35.4,4'- 비스(O(9)-알릴히드로신코니디움Bis (O (9) -allylhydrocinconium -N--N- 메틸methyl )) 바이페닐Biphenyl 설폭사이드Sulfoxide 디브로마이드Dibromide (14-1) (14-1)
실시예 34의 방법으로 얻은 화합물 13-1 (148mg, 0.140mmol)을 메틸렌클로라이드 (1.5mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 알릴브로마이드 (119mg, 0.980mmol)를 넣고, 0.5시간 동안 상온에서 교반하였다. NaBr (5mL)와 물 (5 mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로로메탄 용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (105mg)을 연한 노란색의 고체로 수득하였다.Compound 13-1 (148 mg, 0.140 mmol) obtained by the method of Example 34 was suspended in methylene chloride (1.5 mL), followed by 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and allyl bromide (119 mg, 0.980 mmol). Was added and stirred at room temperature for 0.5 hour. The reaction solution was diluted with NaBr (5 mL) and water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (105 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.02 (d, J = 4.4 Hz, 2H), 8.27 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H), 7.88 (m, 2H), 7.83 - 7.49 (m, 14H), 6.43 (m, 2H), 6.15 (m, 2H), 5.52 - 5.37 (m, 2H), 5.29 (m, 2H), 5.15 (m, 2H), 4.92 (m, 2H), 4.37 (m, 2H), 3.99 (m, 4H), 3.29-3.14 (m, 4H), 2.26 (m, 2H), 2.08 (m, 2H), 1.98 (m, 2H), 1.79 (m, 4H), 1.47 (m, 4H), 1.18 (m, 4H), 0.70 (t, 6H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.02 (d, J = 4.4 Hz, 2H), 8.27 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H), 7.88 (m, 2H), 7.83-7.49 (m, 14H), 6.43 (m, 2H), 6.15 (m, 2H), 5.52-5.37 (m, 2H), 5.29 (m, 2H), 5.15 (m, 2H ), 4.92 (m, 2H), 4.37 (m, 2H), 3.99 (m, 4H), 3.29-3.14 (m, 4H), 2.26 (m, 2H), 2.08 (m, 2H), 1.98 (m, 2H), 1.79 (m, 4H), 1.47 (m, 4H), 1.18 (m, 4H), 0.70 (t, 6H).
실시예Example 36. 4,4'- 36.4,4'- 비스(신코니디움-N-메틸)바이페닐Bis (syncondium-N-methyl) biphenyl 설폰Sulfone 디브로마이드Dibromide (15) (15)
25 mL 둥근바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (332mg, 1.27mmol)에 4,4'-설포닐비스-(브로모메틸)벤젠 [4,4'-sulfonylbis((bromomethyl)benzene)] (268mg, 0.663mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (6mL) 중에서 4 시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (100mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (576mg)을 선홍색의 고체로 수득하였다.In a 25 mL round bottom flask, (-)-cinconidine [(-)-cinchonidine] (332 mg, 1.27 mmol) 4,4'-sulfonylbis- (bromomethyl) benzene [4,4'-sulfonylbis ( (bromomethyl) benzene)] (268 mg, 0.663 mmol) was added and stirred under reflux at 110 ° C. for 4 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (6 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (100 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (576 mg) as a scarlet solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.96 (d, J = 4.6 Hz, 2H), 8.25 (m, 6H), 8.07 (m, 6H), 7.92 - 7.76 (m, 4H), 7.71 (m, 2H), 6.79 (d, J = 4.9 Hz, 2H), 6.52 (m, 2H), 6.60 - 6.42 (m, 4H), 5.65 (m, 2H), 5.28 (m, 2H), 5.15 (m, 2H), 4.93 (m, 2H), 4.29 (m, 2H), 3.92 (m, 2H), 3.77 (m, 2H), 3.25 (m, 2H) 2.64 (m, 2H), 2.19 - 1.91 (m, 8H), 1.78 (m, 2H), 1.23 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.96 (d, J = 4.6 Hz, 2H), 8.25 (m, 6H), 8.07 (m, 6H), 7.92-7.76 (m, 4H), 7.71 ( m, 2H), 6.79 (d, J = 4.9 Hz, 2H), 6.52 (m, 2H), 6.60-6.42 (m, 4H), 5.65 (m, 2H), 5.28 (m, 2H), 5.15 (m , 2H), 4.93 (m, 2H), 4.29 (m, 2H), 3.92 (m, 2H), 3.77 (m, 2H), 3.25 (m, 2H) 2.64 (m, 2H), 2.19-1.91 (m , 8H), 1.78 (m, 2H), 1.23 (m, 2H).
실시예Example 37. 4,4'- 37.4,4'- 비스(O(9)-알릴신코니디움-N-메틸)바이페닐Bis (O (9) -allylicindium-N-methyl) biphenyl 설폰Sulfone 디브로마이드Dibromide (16) (16)
실시예 36의 방법으로 얻은 화합물 15 (50mg, 0.05mmol)을 디클로로메탄 (1mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.20mL, 1.78mmol)과 알릴브로마이드 (43mg, 0.35mmol)를 넣고, 2.5시간 동안 상온에서 교반하였다. Sodiumbromide와 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (27mg)을 연노랑색의 고체로 수득하였다.Compound 15 (50 mg, 0.05 mmol) obtained by the method of Example 36 was suspended in dichloromethane (1 mL), and then 50% aqueous potassium hydroxide solution (0.20 mL, 1.78 mmol) and allyl bromide (43 mg, 0.35 mmol) were added thereto. Stir at room temperature for 2.5 hours. The reaction solution was diluted with sodium bromide and water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. This was purified by column chromatography (dichloromethane / methanol) to give the desired product (27 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 8.96 (d, J = 4.4 Hz, 2H), 8.69 (d, J = 8.6 Hz, 2H), 8.29 - 7.97 (m, 10H), 7.72 (m, 6H), 6.30 (d, J = 7.4 Hz, 4H), 6.11 (m, 10.6, 5.8 Hz, 2H), 5.59 (m, 2H), 5.45 - 5.24 (m, 6H), 4.93 (m, 4H), 4.51 (d, J = 13.1 Hz, 2H), 4.40 (d, J = 13.4 Hz, 4H), 4.29 (d, J = 8.6 Hz, 2H), 4.22 (d, J = 6.0 Hz, 4H), 3.67 - 3.33 (m, 4H), 2.77 (m, 2H), 2.05 (m, 6H), 1.48 - 1.34 (m, 2H).1 H NMR (300 MHz, Chloroform- d ) δ 8.96 (d, J = 4.4 Hz, 2H), 8.69 (d, J = 8.6 Hz, 2H), 8.29-7.97 (m, 10H), 7.72 (m, 6H) , 6.30 (d, J = 7.4 Hz, 4H), 6.11 (m, 10.6, 5.8 Hz, 2H), 5.59 (m, 2H), 5.45-5.24 (m, 6H), 4.93 (m, 4H), 4.51 ( d, J = 13.1 Hz, 2H), 4.40 (d, J = 13.4 Hz, 4H), 4.29 (d, J = 8.6 Hz, 2H), 4.22 (d, J = 6.0 Hz, 4H), 3.67-3.33 ( m, 4H), 2.77 (m, 2H), 2.05 (m, 6H), 1.48-1.34 (m, 2H).
실시예Example 38. 4,4'- 38.4,4'- 비스(히드로신코니디움-N-메틸)바이페닐Bis (hydrocinconium-N-methyl) biphenyl 설폰Sulfone 디브로마이드Dibromide (15-1)  (15-1)
25mL 둥근바닥 플라스크에 (-)-히드로신코니딘 [(-)-hydrocinchonidine] (660mg, 2.23mmol)에 4,4'-설포닐비스-(브로모메틸)벤젠 [4,4'-sulfonylbis((bromomethyl)benzene)] (500mg, 1.24mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (5mL) 중에서 4.5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (40mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (253mg)을 연한 노란색의 고체로 수득하였다.In a 25 mL round bottom flask, (-)-hydrocinconidine [(-)-hydrocinchonidine] (660 mg, 2.23 mmol) was added 4,4'-sulfonylbis- (bromomethyl) benzene [4,4'-sulfonylbis ( (bromomethyl) benzene)] (500 mg, 1.24 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 4.5 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (5 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (40 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (253 mg) as a pale yellow solid.
1H-NMR (300MHz, DMSO-d 6) δ 8.98 (d, J = 4.5 Hz, 2H), 8.26 (m, 6H), 8.07 (m, 6H), 7.83 (m, 4H), 7.72 (m, 2H), 6.72 (m, 2H), 6.53 (m, 2H), 5.31 (d, J = 12.2 Hz, 2H), 5.07 (d, J = 12.2 Hz, 2H), 4.32 (m, 2H), 3.95 (m, 2H), 3.50 (m, 2H), 3.26 (m, 4H), 2.24 - 1.99 (m, 4H), 1.94 (m, 2H), 1.74 (m, 4H), 1.34 (m, 2H), 1.16 (m, 4H), 0.70 (m, 6H). 1 H-NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.26 (m, 6H), 8.07 (m, 6H), 7.83 (m, 4H), 7.72 (m, 2H), 6.72 (m, 2H), 6.53 (m, 2H), 5.31 (d, J = 12.2 Hz, 2H), 5.07 (d, J = 12.2 Hz, 2H), 4.32 (m, 2H), 3.95 ( m, 2H), 3.50 (m, 2H), 3.26 (m, 4H), 2.24-1.99 (m, 4H), 1.94 (m, 2H), 1.74 (m, 4H), 1.34 (m, 2H), 1.16 (m, 4H), 0.70 (m, 6H).
실시예Example 39. 4,4'- 39.4,4'- 비스(O(9)-알릴히드로신코니디움Bis (O (9) -allylhydrocinconium -N--N- 메틸methyl )) 바이페닐Biphenyl 설폰Sulfone 디브로마이드Dibromide (16-1) (16-1)
실시예 38의 방법으로 얻은 화합물 15-1 (300mg, 0.31mmol)을 디클로로메탄 (10 mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.35mL, 3.1mmol)과 알릴브로마이드 (0.16mL, 1.9mmol)를 넣고, 2시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 에틸 에테르 (50mL)에 적가하여 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (270mg)을 연한 주황색의 고체로 수득하였다.Compound 15-1 (300 mg, 0.31 mmol) obtained by the method of Example 38 was suspended in dichloromethane (10 mL), followed by 50% aqueous potassium hydroxide solution (0.35 mL, 3.1 mmol) and allyl bromide (0.16 mL, 1.9 mmol). ) Was added and stirred at room temperature for 2 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The solid obtained by dropwise addition to ethyl ether (50 mL) was purified by column chromatography (dichloromethane / methanol) to give the desired product (270 mg) as a pale orange solid.
1H NMR (300 MHz, Chloroform-d) δ 8.96 (d, J = 4.5 Hz, 2H), 8.70 (d, J = 8.4 Hz, 2H), 8.22 - 8.19 (m, 4H), 8.14 - 8.11 (m, 2H), 8.00 (d, J = 8.2 Hz, 4H), 7.89 - 7.55 (m, 6H), 6.28 (m, 4H), 6.21 - 5.98 (m, 2H), 5.48 - 5.31 (m, 4H), 4.89 (d, J = 11.7 Hz, 2H), 4.52 (m, 2H), 4.38 (m, 4H), 4.21 (m, 4H), 3.56 - 3.35 (m, 2H), 3.27 (m, 2H), 2.17 (m, 4H), 2.03 (m, 2H), 1.91 (m, 4H), 1.51 - 1.29 (m, 4H), 1.29 - 1.05 (m, 2H), 0.73 (m, 6H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.96 (d, J = 4.5 Hz, 2H), 8.70 (d, J = 8.4 Hz, 2H), 8.22-8.19 (m, 4H), 8.14-8.11 (m , 2H), 8.00 (d, J = 8.2 Hz, 4H), 7.89-7.55 (m, 6H), 6.28 (m, 4H), 6.21-5.98 (m, 2H), 5.48-5.31 (m, 4H), 4.89 (d, J = 11.7 Hz, 2H), 4.52 (m, 2H), 4.38 (m, 4H), 4.21 (m, 4H), 3.56-3.35 (m, 2H), 3.27 (m, 2H), 2.17 (m, 4H), 2.03 (m, 2H), 1.91 (m, 4H), 1.51-1.29 (m, 4H), 1.29-1.05 (m, 2H), 0.73 (m, 6H).
실시예Example 40. 4,4'- 40.4,4'- 비스(신코니움-N-메틸)바이페닐Bis (cinconium-N-methyl) biphenyl 메타논Metanon 디브로마이드Dibromide (17) (17)
25mL 둥근바닥 플라스크에 (+)-신코닌 [(+)-cinchonine] (144mg, 0.49mmol)에 비스((4-브로모메틸)페닐)메타논 [bis(4-(bromomethyl)phenyl)methanone] (101mg, 0.27mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (5mL) 중에서 4시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (223mg)을 연노랑색의 고체로 수득하였다.(+)-Synconin [(+)-cinchonine] (144 mg, 0.49 mmol) in a 25 mL round bottom flask with bis ((4-bromomethyl) phenyl) methanone [bis (4- (bromomethyl) phenyl) methanone] (101 mg, 0.27 mmol) was added, and the mixture was stirred under reflux at 110 ° C. for 4 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (5 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (223 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.01 (d, J = 4.6 Hz, 2H), 8.38 (d, J = 8.7 Hz, 2H), 8.17 - 8.08 (m, 2H), 7.99 (m, 6H), 7.92 - 7.71 (m, 8H), 6.89 (m, 2H), 6.55 (m, 2H), 6.06 - 5.94 (m, 2H), 5.31 - 5.18 (m, 6H), 5.05 (d, J = 12.5 Hz, 2H), 4.28 (m, 2H), 3.98-3.78 (m, 4H), 3.52 (m, 2H), 3.06 (m, 2H), 2.66 (m, 2H), 2.30 (m, 2H), 1.84-1.72 (m, 6H), 1.09 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.01 (d, J = 4.6 Hz, 2H), 8.38 (d, J = 8.7 Hz, 2H), 8.17-8.08 (m, 2H), 7.99 (m, 6H), 7.92-7.71 (m, 8H), 6.89 (m, 2H), 6.55 (m, 2H), 6.06-5.94 (m, 2H), 5.31-5.18 (m, 6H), 5.05 (d, J = 12.5 Hz, 2H), 4.28 (m, 2H), 3.98-3.78 (m, 4H), 3.52 (m, 2H), 3.06 (m, 2H), 2.66 (m, 2H), 2.30 (m, 2H), 1.84-1.72 (m, 6 H), 1.09 (m, 2 H).
실시예Example 41. 4,4'- 41.4,4'- 비스(O(9)-알릴신코니움-N-메틸)바이페닐Bis (O (9) -allylconconium-N-methyl) biphenyl 메타논Metanon 디브로마이드Dibromide (18) (18)
실시예 40의 방법으로 얻은 화합물 17 (50mg, 0.052mmol)을 디클로로메탄 (3 mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 알릴브로마이드 (38mg, 0.31mmol)를 넣고, 2시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 디클로로메탄 (2 x 20mL)으로 추출한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후, 여과하여 감압농축하였다. 잔사를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (42mg)을 연한 주황색의 고체로 수득하였다.Compound 17 (50 mg, 0.052 mmol) obtained by the method of Example 40 was suspended in dichloromethane (3 mL), and then 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and allyl bromide (38 mg, 0.31 mmol) were added thereto. , And stirred at room temperature for 2 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 x 20 mL), the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane / methanol) to yield the desired product (42 mg) as a pale orange solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.00 (d, J = 4.5 Hz, 2H), 8.98 - 8.81 (m, 2H), 8.16 (m, 6H), 8.01 - 7.74 (m, 10H), 6.72 (d, J = 10.8 Hz, 2H), 6.23 (m, 2H), 6.20 - 6.06 (m, 2H), 5.99 - 5.84 (m, 2H), 5.44 - 5.20 (m, 12H), 4.55 (d, J = 11.7 Hz, 2H), 4.40 - 4.18 (m, 6H), 4.04 (dd, J = 11.9, 6.2 Hz, 2H), 3.58 (m, 2H), 2.91 (m, 2H), 2.60 (m, 2H), 2.37 (m, 2H), 2.01-1.88 (m, 4H) 1.13 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.00 (d, J = 4.5 Hz, 2H), 8.98-8.81 (m, 2H), 8.16 (m, 6H), 8.01-7.74 (m, 10H), 6.72 (d, J = 10.8 Hz, 2H), 6.23 (m, 2H), 6.20-6.06 (m, 2H), 5.99-5.84 (m, 2H), 5.44-5.20 (m, 12H), 4.55 (d, J = 11.7 Hz, 2H), 4.40-4.18 (m, 6H), 4.04 (dd, J = 11.9, 6.2 Hz, 2H), 3.58 (m, 2H), 2.91 (m, 2H), 2.60 (m, 2H ), 2.37 (m, 2H), 2.01-1.88 (m, 4H) 1.13 (m, 2H).
실시예Example 42. 4,4'- 42.4,4'- 비스(신코니움-N-메틸)바이페닐Bis (cinconium-N-methyl) biphenyl 메탄  methane 디브로마이드Dibromide (19) (19)
25mL 둥근바닥 플라스크에 (+)-신코닌 [(+)-cinchonine] (449mg, 1.52mmol)에 비스(4-(브로모메틸)페닐) 메탄 [bis(4-(bromomethyl)phenyl)methane] (300mg, 0.847mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (4mL) 중에서 5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (468mg)을 분홍색의 고체로 수득하였다.In a 25 mL round bottom flask, (+)-cinconine [(+)-cinchonine] (449 mg, 1.52 mmol) in bis (4- (bromomethyl) phenyl) methane [bis (4- (bromomethyl) phenyl) methane] ( 300 mg, 0.847 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 5 hours in a mixed solvent (4 mL) of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (468 mg) as a pink solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (d, J = 4.5 Hz, 2H), 8.37 (d, J = 7.4 Hz, 2H), 8.10 (dd, J = 8.4, 1.5 Hz, 2H), 7.87 - 7.79 (m, 4H), 7.79 - 7.69 (m, 6H), 7.50 (d, J = 8.3 Hz, 4H), 6.82 (d, J = 4.4 Hz, 2H), 6.56 - 6.47 (m, 2H), 6.11 - 5.92 (m, 2H), 5.25 (m, 2H), 5.21 (m, 2H), 5.15 (m, 2H), 5.04 (d, J = 12.4 Hz, 2H), 4.25 (t, J = 9.5 Hz, 2H), 4.15 (s, 2H), 4.04 - 3.87 (m, 4H), 3.49 (t, J = 11.3 Hz, 2H), 3.06 - 2.91 (m, 2H), 2.75 - 2.59 (m, 2H), 2.35 - 2.22 (m, 2H), 1.88 (m, 2H), 1.83 - 1.69 (m, 4H), 1.11 - 0.95 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.37 (d, J = 7.4 Hz, 2H), 8.10 (dd, J = 8.4, 1.5 Hz, 2H) , 7.87-7.79 (m, 4H), 7.79-7.69 (m, 6H), 7.50 (d, J = 8.3 Hz, 4H), 6.82 (d, J = 4.4 Hz, 2H), 6.56-6.47 (m, 2H ), 6.11-5.92 (m, 2H), 5.25 (m, 2H), 5.21 (m, 2H), 5.15 (m, 2H), 5.04 (d, J = 12.4 Hz, 2H), 4.25 (t, J = 9.5 Hz, 2H), 4.15 (s, 2H), 4.04-3.87 (m, 4H), 3.49 (t, J = 11.3 Hz, 2H), 3.06-2.91 (m, 2H), 2.75-2.59 (m, 2H ), 2.35-2.22 (m, 2H), 1.88 (m, 2H), 1.83-1.69 (m, 4H), 1.11-0.95 (m, 2H).
실시예Example 43. 4,4'- 43.4,4'- 비스(O(9)-알릴신코니움-N-메틸)바이페닐Bis (O (9) -allylconconium-N-methyl) biphenyl 메탄  methane 디브로마이드Dibromide (20) 20
실시예 42의 방법으로 얻은 화합물 19 (200mg, 0.212mmol)을 디클로로메탄 (7mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.35mL, 3.1mmol)과 알릴브로마이드 (181mg, 1.48mmol)를 넣고, 1.5시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이 용액을 감압증류하여 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (114mg)을 연노랑색의 고체로 수득하였다.Compound 19 (200 mg, 0.212 mmol) obtained by the method of Example 42 was suspended in dichloromethane (7 mL), and then 50% aqueous potassium hydroxide solution (0.35 mL, 3.1 mmol) and allyl bromide (181 mg, 1.48 mmol) were added thereto. Stir at room temperature for 1.5 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The solid obtained by distillation under reduced pressure was purified by column chromatography (dichloromethane / methanol) to obtain the target product (114 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 8.98 (d, J = 4.5 Hz, 2H), 8.94 (d, J = 7.6 Hz, 2H), 8.15 (dd, J = 8.5, 1.3 Hz, 2H), 8.03 - 7.58 (m, 10H), 7.29 (d, J = 8.5 Hz, 4H), 6.49 (d, J = 11.2 Hz, 2H), 6.22 - 6.16 (m, 2H), 6.10 (m, 2H), 5.92 (m, 2H), 5.46 - 5.47 - 5.22 (m, 12H), 4.70 (m, 2H), 4.43 (d, J = 11.9 Hz, 2H), 4.33 - 4.15 (m, 4H), 4.08 (s, 2H), 3.97 (m, 2H), 3.60 (t, J = 11.9 Hz, 2H), 2.96 - 2.79 (m, 2H), 2.62 (q, J = 8.3 Hz, 2H), 2.36 (t, J = 12.1 Hz, 2H), 1.99 - 1.88 (m, 4H), 1.10 (m, 2H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.94 (d, J = 7.6 Hz, 2H), 8.15 (dd, J = 8.5, 1.3 Hz, 2H), 8.03-7.58 (m, 10H), 7.29 (d, J = 8.5 Hz, 4H), 6.49 (d, J = 11.2 Hz, 2H), 6.22-6.16 (m, 2H), 6.10 (m, 2H), 5.92 (m, 2H), 5.46-5.47-5.22 (m, 12H), 4.70 (m, 2H), 4.43 (d, J = 11.9 Hz, 2H), 4.33-4.15 (m, 4H), 4.08 (s, 2H ), 3.97 (m, 2H), 3.60 (t, J = 11.9 Hz, 2H), 2.96-2.79 (m, 2H), 2.62 (q, J = 8.3 Hz, 2H), 2.36 (t, J = 12.1 Hz , 2H), 1.99-1.88 (m, 4H), 1.10 (m, 2H).
실시예Example 44. 4,4'- 44.4,4'- 비스(퀴니디움-N-메틸)바이페닐Bis (quinidium-N-methyl) biphenyl 메탄  methane 디브로마이드Dibromide (19-1) (19-1)
25mL 둥근바닥 플라스크에 (+)-퀴니딘 [(+)-quinidine] (330mg, 1.02mmol)에 비스(4-(브로모메틸)페닐) 메탄 [bis(4-(bromomethyl)phenyl)methane] (200mg, 0.565mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (4mL) 중에서 4시간동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (200mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (202mg)을 연노랑색의 고체로 수득하였다.(+)-Quinidine [(+)-quinidine] (330 mg, 1.02 mmol) in a 25 mL round bottom flask with bis (4- (bromomethyl) phenyl) methane] ( 200 mg, 0.565 mmol) was added, and the mixture was stirred under reflux at 110 ° C. for 4 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (4 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (200 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (202 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.80 (d, J = 4.5 Hz, 2H), 8.01 (d, J = 9.1 Hz, 2H), 7.77 (d, J = 4.5 Hz, 2H), 7.69 (d, J = 8.2 Hz, 4H), 7.53 - 7.39 (m, 8H), 6.81 (d, J = 4.2 Hz, 2H), 6.54 (d, J = 4.9 Hz, 2H), 6.13 - 5.95 (m, 2H), 5.30 - 5.18 (m, 4H), 5.15 (d, J = 12.6 Hz, 2H), 4.77 (d, J = 12.8 Hz, 2H), 4.32 - 4.18 (m, 2H), 4.14 (s, 2H), 4.06 (m, 8H), 3.89 (t, J = 9.1 Hz, 2H), 3.50 (t, J = 11.4 Hz, 2H), 3.03 - 2.86 (m, 2H), 2.69 (m, 2H), 2.47 - 2.34 (m, 2H), 1.94 - 1.87 (m, 2H), 1.84 - 1.68 (m, 4H).1 H NMR (300 MHz, DMSO- d 6 ) δ 8.80 (d, J = 4.5 Hz, 2H), 8.01 (d, J = 9.1 Hz, 2H), 7.77 (d, J = 4.5 Hz, 2H), 7.69 ( d, J = 8.2 Hz, 4H), 7.53-7.39 (m, 8H), 6.81 (d, J = 4.2 Hz, 2H), 6.54 (d, J = 4.9 Hz, 2H), 6.13-5.95 (m, 2H ), 5.30-5.18 (m, 4H), 5.15 (d, J = 12.6 Hz, 2H), 4.77 (d, J = 12.8 Hz, 2H), 4.32-4.18 (m, 2H), 4.14 (s, 2H) , 4.06 (m, 8H), 3.89 (t, J = 9.1 Hz, 2H), 3.50 (t, J = 11.4 Hz, 2H), 3.03-2.86 (m, 2H), 2.69 (m, 2H), 2.47- 2.34 (m, 2 H), 1.94-1.87 (m, 2 H), 1.84-1.68 (m, 4H).
실시예Example 45. 4,4'- 45. 4,4'- 비스(O(9)-알릴퀴니디움-N-메틸)바이페닐Bis (O (9) -allylquinium-N-methyl) biphenyl 메탄  methane 디브로마이드Dibromide (20-1) (20-1)
실시예 44의 방법으로 얻은 화합물 19-1 (100mg, 0.100mmol)을 디클로로메탄 (3mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.35mL, 3.1mmol)과 알릴브로마이드 (101mg, 0.828mmol)를 넣고, 3시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (63mg)을 연노랑색의 고체로 수득하였다.Compound 19-1 (100 mg, 0.100 mmol) obtained by the method of Example 44 was suspended in dichloromethane (3 mL), followed by 50% aqueous potassium hydroxide solution (0.35 mL, 3.1 mmol) and allyl bromide (101 mg, 0.828 mmol). Put, and stirred at room temperature for 3 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. This was purified by column chromatography (dichloromethane / methanol) to give the desired product (63 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 8.82 (d, J = 4.5 Hz, 2H), 8.04 (d, J = 9.2 Hz, 2H), 7.81 (d, J = 7.9 Hz, 6H), 7.40 (dd, J = 9.3, 2.7 Hz, 2H), 7.30 (d, J = 7.5 Hz, 4H), 6.18 - 6.01 (m, 4H), 5.92 (m, 2H), 5.50 - 5.25 (m, 8H), 4.26 - 4.10 (m, 6H), 4.08 (s, 2H), 4.02 (dd, J = 12.7, 6.2 Hz, 4H), 3.60 (t, J = 11.6 Hz, 2H), 2.85 (q, J = 9.8 Hz, 2H), 2.70 - 2.45 (m, 4H), 2.07 - 1.80 (m, 8H), 1.53 (m, 6H), 1.26 (m, 6H).1 H NMR (300 MHz, Chloroform- d ) δ 8.82 (d, J = 4.5 Hz, 2H), 8.04 (d, J = 9.2 Hz, 2H), 7.81 (d, J = 7.9 Hz, 6H), 7.40 (dd , J = 9.3, 2.7 Hz, 2H), 7.30 (d, J = 7.5 Hz, 4H), 6.18-6.01 (m, 4H), 5.92 (m, 2H), 5.50-5.25 (m, 8H), 4.26- 4.10 (m, 6H), 4.08 (s, 2H), 4.02 (dd, J = 12.7, 6.2 Hz, 4H), 3.60 (t, J = 11.6 Hz, 2H), 2.85 (q, J = 9.8 Hz, 2H ), 2.70-2.45 (m, 4H), 2.07-1.80 (m, 8H), 1.53 (m, 6H), 1.26 (m, 6H).
실시예Example 46. 4,4'- 46.4,4'- 비스(신코니움-N-메틸)바이페닐Bis (cinconium-N-methyl) biphenyl 메탄올  Methanol 디브로마이드Dibromide (21) (21)
25mL 둥근바닥 플라스크에 (+)-신코닌 [(+)-cinchonine] (75.5 mg, 0.256 mmol)에 비스(4-(브로모메틸)페닐)메탄올 [bis(4-(bromomethyl)phenyl)methanol] (50 mg, 0.135 mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (4mL) 중에서 4시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (20 mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (53 mg)을 연노랑색의 고체로 수득하였다.In a 25 mL round bottom flask, (+)-cinconin [(+)-cinchonine] (75.5 mg, 0.256 mmol) in bis (4- (bromomethyl) phenyl) methanol [bis (4- (bromomethyl) phenyl) methanol] (50 mg, 0.135 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 4 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (4 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (20 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the target product (53 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (d, J = 4.5 Hz, 2H), 8.35 (d, J = 8.5 Hz, 2H), 8.10 (m, 2H), 7.84 (m, 4H), 7.75 (d, J = 7.8 Hz, 6H), 7.64 (d, J = 7.9 Hz, 4H), 6.85 (d, J = 4.1 Hz, 2H), 6.50 (m, 2H), 6.23 (d, J = 4.4 Hz, 1H), 6.00 (m, 2H), 5.31 - 5.16 (m, 4H), 5.12 (d, J = 12.2 Hz, 2H), 4.95 (d, J = 12.5 Hz, 2H), 4.23 (m, 2H), 4.05 (s, 1H), 3.94 (m, 4H), 3.48 (d, J = 11.4 Hz, 2H), 2.99 - 2.81 (m, 2H), 2.65 (d, J = 9.2 Hz, 2H), 2.27 (m, 2H), 1.86 (m, 2H), 1.75 (m, 4H), 1.03 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.35 (d, J = 8.5 Hz, 2H), 8.10 (m, 2H), 7.84 (m, 4H) , 7.75 (d, J = 7.8 Hz, 6H), 7.64 (d, J = 7.9 Hz, 4H), 6.85 (d, J = 4.1 Hz, 2H), 6.50 (m, 2H), 6.23 (d, J = 4.4 Hz, 1H), 6.00 (m, 2H), 5.31-5.16 (m, 4H), 5.12 (d, J = 12.2 Hz, 2H), 4.95 (d, J = 12.5 Hz, 2H), 4.23 (m, 2H), 4.05 (s, 1H), 3.94 (m, 4H), 3.48 (d, J = 11.4 Hz, 2H), 2.99-2.81 (m, 2H), 2.65 (d, J = 9.2 Hz, 2H), 2.27 (m, 2H), 1.86 (m, 2H), 1.75 (m, 4H), 1.03 (m, 2H).
실시예Example 47. 4,4'- 47.4,4'- 비스(O(9)-알릴신코니움-N-메틸)바이페닐Bis (O (9) -allylconconium-N-methyl) biphenyl 메탄올  Methanol 디브로마이드Dibromide (22) (22)
실시예 46의 방법으로 얻은 화합물 21 (30mg, 0.0313mmol)을 디클로로메탄 (0.5 mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.05mL, 1.35 mmol)과 알릴브로마이드 (39.7mg, 0.329mmol)를 넣고, 3시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 유기층을 분리한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후 여과하였다. 이를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (20mg)을 연노랑색의 고체로 수득하였다.Compound 21 (30 mg, 0.0313 mmol) obtained by the method of Example 46 was suspended in dichloromethane (0.5 mL), followed by 50% aqueous potassium hydroxide solution (0.05 mL, 1.35 mmol) and allyl bromide (39.7 mg, 0.329 mmol). Put, and stirred at room temperature for 3 hours. The reaction solution was diluted with water (5 mL), the organic layer was separated, and the dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. This was purified by column chromatography (dichloromethane / methanol) to give the desired product (20 mg) as a pale yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 8.98 (d, J = 4.3 Hz, 2H), 8.96 - 8.88 (m, 2H), 8.15 (d, J = 8.7 Hz, 2H), 7.99 - 7.92 (m, 4H), 7.85 - 7.76 (m, 4H), 7.56 (d, J = 8.1 Hz, 2H), 7.51 - 7.46 (m, 4H), 6.59 - 6.44 (m, 2H), 6.18 (d, J = 6.8 Hz, 2H), 6.10 - 6.00 (m, 2H), 6.00 - 5.95 (m, 1H), 5.95 - 5.87 (m, 2H), 5.55 (s, 1H), 5.42 - 5.36 (m, 4H), 5.17 - 5.10 (m, 2H), 4.66 (m, 2H), 4.44 (m, 4H), 4.31 - 4.15 (m, 4H), 4.04 (m, 4H), 3.59 (d, J = 10.6 Hz, 2H), 3.49 (m, 2H), 2.63 (m, 2H), 1.95 (d, J = 20.1 Hz, 8H), 1.79 (d, J = 9.9 Hz, 2H), 1.41 (d, J = 19.8 Hz, 2H), 1.26 (m, 2H).1 H NMR (300 MHz, Chloroform-d) δ 8.98 (d, J = 4.3 Hz, 2H), 8.96-8.88 (m, 2H), 8.15 (d, J = 8.7 Hz, 2H), 7.99-7.92 (m, 4H), 7.85-7.76 (m, 4H), 7.56 (d, J = 8.1 Hz, 2H), 7.51-7.46 (m, 4H), 6.59-6.44 (m, 2H), 6.18 (d, J = 6.8 Hz , 2H), 6.10-6.00 (m, 2H), 6.00-5.95 (m, 1H), 5.95-5.87 (m, 2H), 5.55 (s, 1H), 5.42-5.36 (m, 4H), 5.17-5.10 (m, 2H), 4.66 (m, 2H), 4.44 (m, 4H), 4.31-4.15 (m, 4H), 4.04 (m, 4H), 3.59 (d, J = 10.6 Hz, 2H), 3.49 ( m, 2H), 2.63 (m, 2H), 1.95 (d, J = 20.1 Hz, 8H), 1.79 (d, J = 9.9 Hz, 2H), 1.41 (d, J = 19.8 Hz, 2H), 1.26 ( m, 2H).
실시예Example 48. 4,4'- 48.4,4'- 비스(신코니움-N-메틸)바이페닐Bis (cinconium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (23) (23)
25mL 둥근바닥 플라스크에 (+)-신코닌 [(+)-cinchonine] (314mg, 1.077mmol)에 4,4'-옥시비스(브로모메틸)벤젠 [4,4'-oxybis((bromomethyl)benzene) (200mg, 0.56mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 3시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (768mg)을 연분홍색의 고체로 수득하였다.4,4'-oxybis (bromomethyl) benzene in (+)-cinconin [(+)-cinchonine] (314 mg, 1.077 mmol) in a 25 mL round bottom flask ) (200 mg, 0.56 mmol) was added, and the mixture was stirred under reflux at 110 ° C. for 3 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (768 mg) as a pale pink solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.00 (d, J = 4.4 Hz, 2H), 8.36 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 8.4 Hz, 2H), 7.93 - 7.67 (m, 10H), 7.28 (d, J = 8.3 Hz, 4H), 6.82 (d, J = 3.7 Hz, 2H), 6.53 (m, 2H), 6.13 - 5.93 (m, 2H), 5.27 (s, 2H), 5.22 (d, J = 6.9 Hz, 2H), 5.13 (d, J = 12.3 Hz, 2H), 4.93 (d, J = 12.6 Hz, 2H), 4.21 (t, J = 10.1 Hz, 2H), 3.93 (m, 4H), 3.49 (m, 2H), 3.00 (m,2H), 2.67 (m, 2H), 2.30 (t, J = 11.5 Hz, 2H), 1.84 (m, 6H), 1.10 - 1.05 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.00 (d, J = 4.4 Hz, 2H), 8.36 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 8.4 Hz, 2H), 7.93 -7.67 (m, 10H), 7.28 (d, J = 8.3 Hz, 4H), 6.82 (d, J = 3.7 Hz, 2H), 6.53 (m, 2H), 6.13-5.93 (m, 2H), 5.27 ( s, 2H), 5.22 (d, J = 6.9 Hz, 2H), 5.13 (d, J = 12.3 Hz, 2H), 4.93 (d, J = 12.6 Hz, 2H), 4.21 (t, J = 10.1 Hz, 2H), 3.93 (m, 4H), 3.49 (m, 2H), 3.00 (m, 2H), 2.67 (m, 2H), 2.30 (t, J = 11.5 Hz, 2H), 1.84 (m, 6H), 1.10-1.05 (m, 2 H).
실시예Example 49. 4,4'- 49.4,4'- 비스(O(9)-알릴신코니움-N-메틸)바이페닐Bis (O (9) -allylconconium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (24)  (24)
실시예 48의 방법으로 얻은 화합물 23 (200mg, 0.21mmol)을 디클로로메탄 (3mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 알릴브로마이드 (0.12mL, 1.47mmol)를 넣고, 1.5시간 동안 상온에서 교반하였다. 물 (3mL)로 반응액을 희석시킨 후, 디클로로메탄으로 추출한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후, 여과하여 감압농축하였다. 잔사를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (270mg)을 주황색의 고체로 수득하였다.Compound 23 (200 mg, 0.21 mmol) obtained by the method of Example 48 was suspended in dichloromethane (3 mL), and then 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and allyl bromide (0.12 mL, 1.47 mmol) were added thereto. , And stirred at room temperature for 1.5 hours. The reaction solution was diluted with water (3 mL), extracted with dichloromethane, the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane / methanol) to give the desired product (270 mg) as an orange solid.
1H NMR (300 MHz, Chloroform-d) δ 8.99 (d, J = 4.4 Hz, 2H), 8.95 (d, J = 8.4 Hz, 2H), 8.15 (d, J = 8.4, 1.3 Hz, 2H), 8.02 - 7.98 (m, 8H), 7.81 (m, 2H), 7.17 - 7.10 (m, 4H), 6.57 (d, J = 11.8 Hz, 2H), 6.21 (m, 2H), 6.13 - 6.06 (m, 2H), 5.97 - 5.87 (m, 2H), 5.47 - 5.24 (m, 12H), 4.47 (d, J = 11.9 Hz, 2H), 4.35 - 4.11 (m, 6H), 4.05 - 3.97 (m, 2H), 3.62 (m, 2H), 2.90 (m, 2H), 2.65 (m, 2H), 2.38 (m, 2H), 1.95 (m, 4H), 1.11 (m, 2H) 1 H NMR (300 MHz, Chloroform- d ) δ 8.99 (d, J = 4.4 Hz, 2H), 8.95 (d, J = 8.4 Hz, 2H), 8.15 (d, J = 8.4, 1.3 Hz, 2H), 8.02-7.98 (m, 8H), 7.81 (m, 2H), 7.17-7.10 (m, 4H), 6.57 (d, J = 11.8 Hz, 2H), 6.21 (m, 2H), 6.13-6.06 (m, 2H), 5.97-5.87 (m, 2H), 5.47-5.24 (m, 12H), 4.47 (d, J = 11.9 Hz, 2H), 4.35-4.11 (m, 6H), 4.05-3.97 (m, 2H) , 3.62 (m, 2H), 2.90 (m, 2H), 2.65 (m, 2H), 2.38 (m, 2H), 1.95 (m, 4H), 1.11 (m, 2H)
실시예Example 50. 4,4'- 50.4,4'- 비스(퀴니디움-N-메틸)바이페닐Bis (quinidium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (23-1) (23-1)
25mL 둥근바닥 플라스크에 (+)-퀴니딘 [(+)-quinidine] (328.0mg, 1.01 mmol)에 4,4'-옥시비스(브로모메틸)벤젠 [4,4'-oxybis((bromomethyl)benzene) (200mg, 0.56mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 4시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (50mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (636mg)을 회백색의 고체로 수득하였다.(+)-Quinidine [(+)-quinidine] (328.0 mg, 1.01 mmol) in a 25 mL round bottom flask with 4,4'-oxybis (bromomethyl) benzene [4,4'-oxybis ((bromomethyl) benzene) (200 mg, 0.56 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 4 hours in a mixed solvent (3 mL) of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2). The reaction mixture was cooled to room temperature, added dropwise to ether (50 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (636 mg) as an off-white solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.81 (d, J = 4.5 Hz, 2H), 8.01 (d, J = 9.2 Hz, 2H), 7.95 (m, 2H), 7.82 - 7.72 (m, 4H), 7.61 - 7.37 (m, 8H), 6.86 (d, J = 3.7 Hz, 2H), 6.52 (m, 2H), 6.04-5.98 (m, 2H), 5.30 - 5.18 (m, 4H), 5.09 (d, J = 12.6 Hz, 2H), 4.76 (d, J = 12.6 Hz, 2H), 4.22 (m, 2H), 4.07 (s, 6H), 3.98 (m, 2H), 3.83 (m, 2H), 3.48 (m, 2H), 3.04 - 2.91 (m, 2H), 2.72 (m, 2H), 2.38 (m, 2H), 1.90 (m, 2H), 1.77 (m, 4H), 1.11 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.81 (d, J = 4.5 Hz, 2H), 8.01 (d, J = 9.2 Hz, 2H), 7.95 (m, 2H), 7.82-7.72 (m, 4H), 7.61-7.37 (m, 8H), 6.86 (d, J = 3.7 Hz, 2H), 6.52 (m, 2H), 6.04-5.98 (m, 2H), 5.30-5.18 (m, 4H), 5.09 (d, J = 12.6 Hz, 2H), 4.76 (d, J = 12.6 Hz, 2H), 4.22 (m, 2H), 4.07 (s, 6H), 3.98 (m, 2H), 3.83 (m, 2H) , 3.48 (m, 2H), 3.04-2.91 (m, 2H), 2.72 (m, 2H), 2.38 (m, 2H), 1.90 (m, 2H), 1.77 (m, 4H), 1.11 (m, 2H ).
실시예Example 51. 4,4'- 51.4,4'- 비스(O(9)-알릴퀴니디움-N-메틸)바이페닐Bis (O (9) -allylquinium-N-methyl) biphenyl 에테르  ether 디브로마이드Dibromide (24-1) (24-1)
실시예 50의 방법으로 얻은 화합물 23-1 (100mg, 0.10mmol)을 클로로포름 (3mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 알릴브로마이드 (0.06mL, 0.70mmol)를 넣고, 2시간 동안 상온에서 교반하였다. 물 (3mL)로 반응액을 희석시킨 후, 디클로로메탄 (2 x 3mL)으로 추출한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후, 여과하여 감압농축하였다. 잔사를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여, 목적물 (33mg)을 연갈색의 고체로 수득하였다.Compound 23-1 (100 mg, 0.10 mmol) obtained by the method of Example 50 was suspended in chloroform (3 mL), followed by 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and allyl bromide (0.06 mL, 0.70 mmol). Put, and stirred at room temperature for 2 hours. The reaction solution was diluted with water (3 mL), extracted with dichloromethane (2 x 3 mL), the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane / methanol) to afford the desired product (33 mg) as a light brown solid.
1H NMR (300 MHz, Chloroform-d) δ 8.92 - 8.76 (m, 2H), 8.15 - 8.01 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 11.5 Hz, 2H), 7.21 (d, J = 9.0 Hz, 2H), 7.11 (m, 2H), 7.05 - 6.83 (m, 2H), 6.25 - 6.01 (m, 4H), 5.97 - 5.75 (m, 2H), 5.40 (m, 4H), 5.33 - 5.22 (m, 4H), 4.25 (d, J = 23.5 Hz, 4H), 4.03 (m, 4H), 3.93 (m, 2H), 3.88 - 3.80 (m, 4H), 3.62 (m, 2H), 3.41 (m, 2H), 2.61 (m, 2H), 2.44 (m, 2H), 2.21 (m, 2H), 2.07 - 1.96 (m, 6H), 1.57 - 1.44 (m, 2H), 1.13 - 1.08 (m, 4H), 0.84 (m, 4H). 1 H NMR (300 MHz, Chloroform- d ) δ 8.92-8.76 (m, 2H), 8.15-8.01 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 11.5 Hz , 2H), 7.21 (d, J = 9.0 Hz, 2H), 7.11 (m, 2H), 7.05-6.83 (m, 2H), 6.25-6.01 (m, 4H), 5.97-5.75 (m, 2H), 5.40 (m, 4H), 5.33-5.22 (m, 4H), 4.25 (d, J = 23.5 Hz, 4H), 4.03 (m, 4H), 3.93 (m, 2H), 3.88-3.80 (m, 4H) , 3.62 (m, 2H), 3.41 (m, 2H), 2.61 (m, 2H), 2.44 (m, 2H), 2.21 (m, 2H), 2.07-1.96 (m, 6H), 1.57-1.44 (m , 2H), 1.13-1.08 (m, 4H), 0.84 (m, 4H).
실시예Example 52. 4,4'- 52. 4,4'- 비스(신코니움-N-메틸)바이페닐Bis (cinconium-N-methyl) biphenyl 티오에테르  Thioether 디브로마이드Dibromide (25)  (25)
25mL 둥근바닥 플라스크에 (+)-신코닌 [(+)-cinchonine] (200mg, 0.68mmol)에 비스(4-(브로모메틸)페닐)설판 [bis(4-(bromomethyl)phenyl)sulfane] (140mg, 0.38mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 2.5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (25mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (74mg)을 크림색의 고체로 수득하였다. In bis (4- (bromomethyl) phenyl) sulfane in (+)-cinconine [(+)-cinchonine] (200 mg, 0.68 mmol) in a 25 mL round bottom flask 140 mg, 0.38 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 2.5 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (25 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the target product (74 mg) as a cream solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.00 (d, J = 4.5 Hz, 2H), 8.35 (d, J = 9.0 Hz, 2H), 8.12 (d, J = 8.5 Hz, 2H), 7.92 - 7.70 (m, 10H), 7.58 (d, J = 8.2 Hz, 4H), 6.82 (m, 2H), 6.52 (m, 2H), 6.01 (m, 2H), 5.32 - 5.18 (m, 4H), 5.14 (m, 2H), 4.94 (d, J = 12.4 Hz, 2H), 4.22 (m, 2H), 3.92 (m, 4H), 3.49 (t, J = 11.1 Hz, 2H), 3.00 (m, 2H), 2.67 (m, 2H), 2.29 (m, 2H), 1.83 (m, 6H), 1.07 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.00 (d, J = 4.5 Hz, 2H), 8.35 (d, J = 9.0 Hz, 2H), 8.12 (d, J = 8.5 Hz, 2H), 7.92 7.70 (m, 10H), 7.58 (d, J = 8.2 Hz, 4H), 6.82 (m, 2H), 6.52 (m, 2H), 6.01 (m, 2H), 5.32-5.18 (m, 4H), 5.14 (m, 2H), 4.94 (d, J = 12.4 Hz, 2H), 4.22 (m, 2H), 3.92 (m, 4H), 3.49 (t, J = 11.1 Hz, 2H), 3.00 (m, 2H ), 2.67 (m, 2H), 2.29 (m, 2H), 1.83 (m, 6H), 1.07 (m, 2H).
실시예Example 53. 4,4'- 53. 4,4'- 비스(O(9)-알릴신코니움-N-메틸)바이페닐Bis (O (9) -allylconconium-N-methyl) biphenyl 티오에테르  Thioether 디브로마이드Dibromide (26) (26)
실시예 52의 방법으로 얻은 화합물 25 (150mg, 0.156mmol)을 디클로로메탄 (2mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.25mL, 2.2mmol)과 알릴브로마이드 (133mg, 1.09mmol)를 넣고, 2.5시간 동안 상온에서 교반하였다. 물 (5mL)로 반응액을 희석시킨 후, 디클로로메탄 (2 x 20mL)으로 추출한 후, 디클로메탄용액을 무수 황산마그네슘으로 건조한 후, 여과하여 감압농축하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (61mg)을 노란색의 고체로 수득하였다. Compound 25 (150 mg, 0.156 mmol) obtained by the method of Example 52 was suspended in dichloromethane (2 mL), and then 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and allyl bromide (133 mg, 1.09 mmol) were added thereto. Stir at room temperature for 2.5 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 x 20 mL), the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (61 mg) as a yellow solid.
1H NMR (300 MHz, Chloroform-d) δ 9.00 (m, 4H), 8.16 (d, J = 9.1 Hz, 2H), 7.97 (m, 6H), 7.83 (m, 4H), 7.47 (d, J = 8.6 Hz, 4H), 6.63 (m, 2H), 6.26 - 6.01 (m, 4H), 5.93 (m, 2H), 5.52 - 5.32 (m, 12H), 4.36 - 4.14 (m, 8H), 3.96 (m, 2H), 3.59 (m, 2H), 2.90 (m, 2H), 2.65 (m, 2H), 2.36 (m, 2H), 1.99 (m, 4H), 1.12 (m, 2H). 1 H NMR (300 MHz, Chloroform- d ) δ 9.00 (m, 4H), 8.16 (d, J = 9.1 Hz, 2H), 7.97 (m, 6H), 7.83 (m, 4H), 7.47 (d, J = 8.6 Hz, 4H), 6.63 (m, 2H), 6.26-6.01 (m, 4H), 5.93 (m, 2H), 5.52-5.32 (m, 12H), 4.36-4.14 (m, 8H), 3.96 ( m, 2H), 3.59 (m, 2H), 2.90 (m, 2H), 2.65 (m, 2H), 2.36 (m, 2H), 1.99 (m, 4H), 1.12 (m, 2H).
실시예Example 54. 4,4'- 54. 4,4'- 비스(퀴니디움-N-메틸)바이페닐Bis (quinidium-N-methyl) biphenyl 티오에테르  Thioether 디브로마이드Dibromide (25-1) (25-1)
25mL 둥근바닥 플라스크에 (+)-퀴니딘 [(+)-quinidine] (200mg, 0.617mmol)에 비스(4-(브로모메틸)페닐)설판 [bis(4-(bromomethyl)phenyl)sulfane) (127mg, 0.343mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 2.5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (25mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (320mg)을 와인색의 고체로 수득하였다.Bis (4- (bromomethyl) phenyl) sulfane in (+)-quinidine [(+)-quinidine] (200 mg, 0.617 mmol) in a 25 mL round bottom flask 127 mg, 0.343 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 2.5 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (25 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (320 mg) as a burgundy solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.81 (d, J = 4.5 Hz, 2H), 8.01 (d, J = 9.2, 2.7 Hz, 2H), 7.83 - 7.72 (m, 6H), 7.56 - 7.43 (m, 8H), 6.86 (m, 2H), 6.52 (m, 2H), 6.04 (m, 2H), 5.32 - 5.16 (m, 4H), 5.09 (m, 2H), 4.76 (m, 2H), 4.24 (m, 2H), 4.09 (s, 6H), 3.83 (m, 2H), 3.57 - 3.43 (m, 2H), 3.16 (m, 2H), 3.02 - 2.92 (m, 2H), 2.70 - 2.60 (m, 2H), 2.40 (m, 4H), 1.90 (m, 2H), 1.77 (m, 2H), 1.11 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.81 (d, J = 4.5 Hz, 2H), 8.01 (d, J = 9.2, 2.7 Hz, 2H), 7.83-7.72 (m, 6H), 7.56- 7.43 (m, 8H), 6.86 (m, 2H), 6.52 (m, 2H), 6.04 (m, 2H), 5.32-5.16 (m, 4H), 5.09 (m, 2H), 4.76 (m, 2H) , 4.24 (m, 2H), 4.09 (s, 6H), 3.83 (m, 2H), 3.57-3.43 (m, 2H), 3.16 (m, 2H), 3.02-2.92 (m, 2H), 2.70-2.60 (m, 2H), 2.40 (m, 4H), 1.90 (m, 2H), 1.77 (m, 2H), 1.11 (m, 2H).
실시예Example 55. 4,4'- 55. 4,4'- 비스(신코니움-N-메틸)바이페닐Bis (cinconium-N-methyl) biphenyl 설폭사이드Sulfoxide 디브로마이드Dibromide (27) (27)
25mL 둥근바닥 플라스크에 (-)-히드로신코나인 [(-)-hydrocinchonine] (272mg, 0.924mmol)에 4,4'-설피닐비스-(브로모메틸)벤젠 (4,4'-sulfinylbis(bromomethyl)benzene; 200mg, 0.543mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (3mL) 중에서 4.5시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (20mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (388 mg)을 연한 주황색의 고체로 수득하였다.In a 25 mL round-bottom flask, 4,4'-sulfinylbis- (bromomethyl) benzene (4,4'-sulfinylbis (bromomethyl) in (-)-hydrocinconine [(-)-hydrocinchonine] (272 mg, 0.924 mmol) ) benzene; 200 mg, 0.543 mmol) was added and stirred under reflux at 110 ° C. for 4.5 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (20 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (388 mg) as a pale orange solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.76 (d, J = 4.5 Hz, 2H), 8.27 - 8.07 (m, 2H), 7.87 (m, 2H), 7.80 - 7.32 (m, 10H), 7.30 - 7.17 (m, 4H), 6.68 (m, 2H), 6.30 (m, 2H), 5.93 - 5.65 (m, 2H), 5.13 - 4.66 (m, 8H), 4.02 (m, 2H), 3.94 - 3.61 (m, 4H), 3.25 (m, 6H), 2.19 - 1.86 (m, 2H), 1.58 (m, 6H), 0.89 - 0.73 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.76 (d, J = 4.5 Hz, 2H), 8.27-8.07 (m, 2H), 7.87 (m, 2H), 7.80-7.32 (m, 10H), 7.30-7.17 (m, 4H), 6.68 (m, 2H), 6.30 (m, 2H), 5.93-5.65 (m, 2H), 5.13-4.66 (m, 8H), 4.02 (m, 2H), 3.94- 3.61 (m, 4H), 3.25 (m, 6H), 2.19-1.86 (m, 2H), 1.58 (m, 6H), 0.89-0.73 (m, 2H).
실시예Example 56. 4,4'- 56. 4,4'- 비스(O(9)-알릴신코니움-N-메틸)바이페닐Bis (O (9) -allylconconium-N-methyl) biphenyl 설폭사이드Sulfoxide 디브로마이드Dibromide (28) (28)
실시예 55의 방법으로 얻은 화합물 27 (50mg, 0.052mmol)을 클로로포름 (2.0mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.15mL, 1.32mmol)과 알릴브로마이드 (45mg, 0.369mmol)를 넣고, 1시간 동안 상온에서 교반하였다. 증류수 (2mL)로 반응액을 희석시킨 후, 클로로포름 (2 x 20mL)으로 추출한 후, 클로로포름용액을 무수 황산마그네슘으로 건조한 후 여과하고 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리정제하여 목적물 (52mg)을 연한 노란색의 고체로 수득하였다.Compound 27 (50 mg, 0.052 mmol) obtained by the method of Example 55 was suspended in chloroform (2.0 mL), and then 50% aqueous potassium hydroxide solution (0.15 mL, 1.32 mmol) and allyl bromide (45 mg, 0.369 mmol) were added thereto. Stir at room temperature for 1 hour. The reaction solution was diluted with distilled water (2 mL), extracted with chloroform (2 x 20 mL), the chloroform solution was dried over anhydrous magnesium sulfate, filtered and filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the target product (52 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.02 (d, J = 4.5 Hz, 2H), 8.40 (d, J = 7.5 Hz, 2H), 8.13 (d, J = 8.6 Hz, 2H), 7.90 - 7.71 (m, 8H), 7.57 (m, 2H), 7.53 - 7.37 (m, 2H), 6.39 (m, 2H), 6.17 (m, Hz, 2H), 5.99 (m, 2H), 5.44 (d, J = 17.1 Hz, 3H), 5.35 - 5.19 (m, 7H), 4.66 (d, J = 12.4 Hz, 2H), 4.28 (m, 2H), 4.14 - 3.92 (m, 8H), 3.57 (m, 2H), 3.03 (m, 2H), 2.82 - 2.60 (m, 2H), 2.43 - 2.29 (m, 2H), 1.93 - 1.70 (m, 6H), 1.21 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.02 (d, J = 4.5 Hz, 2H), 8.40 (d, J = 7.5 Hz, 2H), 8.13 (d, J = 8.6 Hz, 2H), 7.90 -7.71 (m, 8H), 7.57 (m, 2H), 7.53-7.37 (m, 2H), 6.39 (m, 2H), 6.17 (m, Hz, 2H), 5.99 (m, 2H), 5.44 (d , J = 17.1 Hz, 3H), 5.35-5.19 (m, 7H), 4.66 (d, J = 12.4 Hz, 2H), 4.28 (m, 2H), 4.14-3.92 (m, 8H), 3.57 (m, 2H), 3.03 (m, 2H), 2.82-2.60 (m, 2H), 2.43-2.29 (m, 2H), 1.93-1.70 (m, 6H), 1.21 (m, 2H).
실시예Example 57. 4,4'- 57. 4,4'- 비스(신코니움-N-메틸)바이페닐Bis (cinconium-N-methyl) biphenyl 설폰Sulfone 디브로마이드Dibromide (29) (29)
25mL 둥근바닥 플라스크에 (+)-신코닌 [(+)-cinchonine] (656mg, 2.23mmol)에 4,4'-설포닐비스-(브로모메틸)벤젠 (4,4'-sulfonylbis(bromomethyl)benzene; 500mg, 1.24mmol)을 넣고, 에탄올:N,N-디메틸포름아미드:클로로포름 (5:6:2) 혼합용매 (8mL) 중에서 4시간 동안 110℃에서 환류교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 에테르 (40mL)에 적가하여 고체를 석출시킨 후, 감압여과하였다. 얻은 고체를 컬럼크로마토그래피 (디클로로메탄/메탄올)로 분리 정제하여 목적물 (321mg)을 연한 노란색의 고체로 수득하였다.4,4'-sulfonylbis- (bromomethyl) benzene (4,4'-sulfonylbis (bromomethyl) in (+)-cinconin [(+)-cinchonine] (656 mg, 2.23 mmol) in a 25 mL round bottom flask Benzene (500 mg, 1.24 mmol) was added thereto, and the mixture was stirred under reflux at 110 ° C. for 4 hours in a solvent mixture of ethanol: N, N-dimethylformamide: chloroform (5: 6: 2) (8 mL). The reaction mixture was cooled to room temperature, added dropwise to ether (40 mL) to precipitate a solid, and then filtered under reduced pressure. The obtained solid was separated and purified by column chromatography (dichloromethane / methanol) to obtain the desired product (321 mg) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ 8.98 (d, J = 4.5 Hz, 2H), 8.33 (d, J = 8.4 Hz, 2H), 8.24 (d, J = 8.1 Hz, 2H), 8.15 - 7.97 (m, 8H), 7.90 - 7.80 (m, 4H), 7.74 (m, 2H), 6.85 (m, 2H), 6.48 (m, 2H), 5.98 (m, 2H), 5.22 (m, 6H), 5.00 (m, 2H), 4.23 (m, 2H), 4.00 - 3.84 (m, 4H), 3.52 (m, 2H), 2.99 (m, 2H), 2.63 (m, 2H), 2.27 (m, 2H), 1.93 - 1.59 (m, 6H), 1.04 (m, 2H) 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.98 (d, J = 4.5 Hz, 2H), 8.33 (d, J = 8.4 Hz, 2H), 8.24 (d, J = 8.1 Hz, 2H), 8.15 -7.97 (m, 8H), 7.90-7.80 (m, 4H), 7.74 (m, 2H), 6.85 (m, 2H), 6.48 (m, 2H), 5.98 (m, 2H), 5.22 (m, 6H ), 5.00 (m, 2H), 4.23 (m, 2H), 4.00-3.84 (m, 4H), 3.52 (m, 2H), 2.99 (m, 2H), 2.63 (m, 2H), 2.27 (m, 2H), 1.93-1.59 (m, 6H), 1.04 (m, 2H)
실시예Example 58. 4,4'- 58. 4,4'- 비스(O(9)-알릴신코니움-N-메틸)바이페닐Bis (O (9) -allylconconium-N-methyl) biphenyl 설폰Sulfone 디브로마이드Dibromide (30) (30)
실시예 57의 방법으로 얻은 화합물 29 (50mg, 0.06mmol)을 메틸렌클로라이드 (2mL)에 현탁한 후, 50% 수산화칼륨 수용액 (0.20mL, 1.78mmol)과 알릴브로마이드 (47mg, 0.39mmol)를 넣고, 1시간동안 상온에서 교반하였다. 물(3 mL)로 반응액을 희석시킨 후, 디클로로메탄 (2 x 10mL)으로 추출한 후, 메틸렌클로라이드 을 무수 황산마그네슘으로 건조한 후, 여과하여 감압농축하였다. 잔사를 컬럼크로마토그래피 (디클로로메탄 /메탄올)로 분리정제하여 목적물 (55mg)을 연한 주황색의 고체로 수득하였다.Compound 29 (50 mg, 0.06 mmol) obtained by the method of Example 57 was suspended in methylene chloride (2 mL), and then 50% aqueous potassium hydroxide solution (0.20 mL, 1.78 mmol) and allyl bromide (47 mg, 0.39 mmol) were added thereto. Stir at room temperature for 1 hour. The reaction solution was diluted with water (3 mL), extracted with dichloromethane (2 x 10 mL), and the methylene chloride was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane / methanol) to yield the title compound (55 mg) as a pale orange solid.
1H NMR (300 MHz, DMSO-d 6) δ 9.01 (d, J = 4.5 Hz, 2H), 8.96 (d, J = 4.5 Hz, 1H), 8.24 (d, J = 8.3 Hz, 4H), 8.10 (m, 10H), 7.79 (m, 6H), 6.16 (m, 2H), 5.96 (m, 2H), 5.47 - 5.39 (m, 2H), 5.26 (m, 6H), 4.72 (m, 2H), 4.27 (m, 2H), 4.01 (m, 8H), 3.57 (m, 2H), 3.02 (m, 2H), 2.68 (m, 2H), 2.34 (m, 2H), 1.90 (m, 4H), 1.51 (m, 2H), 1.19 (m, 2H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.01 (d, J = 4.5 Hz, 2H), 8.96 (d, J = 4.5 Hz, 1H), 8.24 (d, J = 8.3 Hz, 4H), 8.10 (m, 10H), 7.79 (m, 6H), 6.16 (m, 2H), 5.96 (m, 2H), 5.47-5.39 (m, 2H), 5.26 (m, 6H), 4.72 (m, 2H), 4.27 (m, 2H), 4.01 (m, 8H), 3.57 (m, 2H), 3.02 (m, 2H), 2.68 (m, 2H), 2.34 (m, 2H), 1.90 (m, 4H), 1.51 (m, 2 H), 1.19 (m, 2 H).
시험예Test Example 1. 비대칭 상 이동 촉매 반응 조건하에서의 N-( 1.N- (under asymmetric phase transfer catalysis reaction conditions 디페닐메틸렌Diphenylmethylene )글리신 tert-부틸 에스테르의 알킬화반응Alkylation of Glycine Tert-Butyl Ester
상기 합성된 상전이 촉매의 효율성을 측정하기 위하여 하기 반응식 4에서와 같이, N-(디페닐메틸렌)글리신 tert-부틸에스테르를 기질로 한 벤질화 반응을 수행한 후, 생성된 결과물을 키랄 HPLC (chiral HPLC)로 광학순도를 측정하였다. 구체적으로, N-(디페닐메틸렌)글리신 tert-부틸 에스테르 (30mg, 0.102mmol)와 비대칭 상 이동 촉매 (1% 당량, 0.0010mmol)에 톨루엔/클로로포름 (부피비=7:3, 0.75mL)과 50% 수산화칼륨 수용액 (0.25mL, 13.0mmol)을 가한 후, 상기 반응액을 15℃로 냉각한 다음, 벤질 브로마이드 (1.2 당량, 14.5μL, 0.123mmol)을 가하고, 반응 혼합물을 실온에서 기질이 없어질 때까지 교반하였다. 반응 혼합물을 에테르 (20mL)로 희석한 후, 유기층을 물로 세척한 뒤, 무수 황산마그네슘으로 건조, 여과하고 감압농축하였다. 얻어진 잔사를 컬럼분리 (이동상; 헥산:초산에틸=50:1)하여 무색 액상의 목적물, 2-(벤즈하이드릴리덴아미노)-3-페닐프로피온 산 tert-부틸 에스테르를 얻었다. 얻어진 목적물의 광학 순도는 비대칭 고성능 액체 크로마토그래피로 측정하였으며, 이때, 기기 작동 조건은 다음과 같다. [① 컬럼: DAICEL Chiralcel OD, ②이동상: 헥산:2-프로판올 = 100:1, ③유속: 0.5 mL/min, ④측정온도: 20℃, ⑤검출기: 자외부흡광광도계 (파장: 254nm), ⑥ 머무름 시간: R 이성질체 (minor) 12.2분, S 이성질체 (major) 20.5분].In order to measure the efficiency of the synthesized phase transfer catalyst, a benzylation reaction based on N- (diphenylmethylene) glycine tert-butylester is performed as in Scheme 4 below, and the resulting product is subjected to chiral HPLC (chiral). HPLC) measured the optical purity. Specifically, toluene / chloroform (volume ratio = 7: 3, 0.75 mL) and N- (diphenylmethylene) glycine tert-butyl ester (30 mg, 0.102 mmol) and an asymmetric phase transfer catalyst (1% equivalent, 0.0010 mmol) were used. After adding% aqueous potassium hydroxide solution (0.25 mL, 13.0 mmol), the reaction solution was cooled to 15 ° C., then benzyl bromide (1.2 equiv, 14.5 μL, 0.123 mmol) was added and the reaction mixture was free of substrate at room temperature. Stir until. The reaction mixture was diluted with ether (20 mL), the organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to column separation (mobile phase; hexane: ethyl acetate = 50: 1) to give a colorless liquid target product, 2- (benzhydrylideneamino) -3-phenylpropionic acid tert-butyl ester. The optical purity of the obtained target product was measured by asymmetric high performance liquid chromatography, in which the instrument operating conditions were as follows. [① column: DAICEL Chiralcel OD, ② mobile phase: hexane: 2-propanol = 100: 1, ③ flow rate: 0.5 mL / min, ④ measurement temperature: 20 ℃, ⑤ detector: ultraviolet absorption photometer (wavelength: 254nm), ⑥ Retention time: R isomer 12.2 min, S isomer 20.5 min].
[반응식 4]Scheme 4
Figure PCTKR2017001270-appb-I000013
Figure PCTKR2017001270-appb-I000013
각각의 촉매 반응 결과는 표 1 및 표 2에 나타낸 바와 같다. Each catalytic reaction result is shown in Table 1 and Table 2.
[표 1]TABLE 1
Figure PCTKR2017001270-appb-I000014
Figure PCTKR2017001270-appb-I000014
Figure PCTKR2017001270-appb-I000015
Figure PCTKR2017001270-appb-I000015
Figure PCTKR2017001270-appb-I000016
Figure PCTKR2017001270-appb-I000016
[표 2]TABLE 2
Figure PCTKR2017001270-appb-I000017
Figure PCTKR2017001270-appb-I000017
Figure PCTKR2017001270-appb-I000018
Figure PCTKR2017001270-appb-I000018
상기 표 1 및 표 2에 나타낸 바와 같이, 비교예 1, 2의 모노 벤질 암모늄 촉매(10% 당량)인 경우, 대략 80% ee의 (S)-광학수율을 보인 반면, 본 발명의 촉매들은 1% 당량의 촉매와 1.2 당량의 벤질브로마아드 조건에서 95~99% ee 등의 높은 광학수율을 보였다. 또한, 비교예 3, 4의 모노 벤질 암모늄 촉매(10% 당량)인 경우, 대략 70% ee의 (R)-광학수율을 보인 반면, 본 발명의 촉매들은 1% 당량의 촉매와 1.2 당량의 벤질브로마아드 조건에서 최대 95% ee 등의 높은 광학수율을 나타내었다. 상기 결과로부터, 본 발명의 촉매는 적은 촉매양, 거의 당량의 시약의 적용으로만으로도 높은 광학수율을 나타내며, 간이한 공정으로 제조할 수 있는바, 공업적인 알파-아미노산의 제조에 폭넓게 응용될 수 있음을 알 수 있었다. As shown in Table 1 and Table 2, the monobenzyl ammonium catalysts of Comparative Examples 1 and 2 (10% equivalent) showed (S) -optical yield of approximately 80% ee, whereas the catalysts of the present invention were 1 High optical yields of 95-99% ee were shown under the conditions of% equivalent of catalyst and 1.2 equivalent of benzyl bromide. In addition, the monobenzyl ammonium catalysts (10% equivalent) of Comparative Examples 3 and 4 showed an (R) -optical yield of approximately 70% ee, while the catalysts of the present invention were 1% equivalent of catalyst and 1.2 equivalents of benzyl. High optical yields, such as up to 95% ee, were shown in bromide conditions. From the above results, the catalyst of the present invention exhibits high optical yield with only a small amount of catalyst and almost equivalent amount of reagents, and can be manufactured by a simple process, and thus can be widely applied to the production of industrial alpha-amino acids. And it was found.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

Claims (14)

  1. 하기 화학식 1로 표시되는 신코나 알칼로이드 화합물:Syncona alkaloid compound represented by the following formula (1):
    [화학식 1][Formula 1]
    Figure PCTKR2017001270-appb-I000019
    Figure PCTKR2017001270-appb-I000019
    상기 화학식 1에서, In Chemical Formula 1,
    X는 CH2-,-C(OH)H-, -C(=O)-, -O-, -S-, -S(=O)- 또는 -S(O2)-를 나타내고; X represents CH 2 —, —C (OH) H—, —C (═O) —, —O—, —S—, —S (═O) — or —S (O 2 ) —;
    R은
    Figure PCTKR2017001270-appb-I000020
    또는
    Figure PCTKR2017001270-appb-I000021
    을 나타내고;     R is
    Figure PCTKR2017001270-appb-I000020
    or
    Figure PCTKR2017001270-appb-I000021
    Represents;
    상기 R1은 수소, C1-C10 알킬 또는 C1-C5 알콕시를 나타내고;R 1 represents hydrogen, C 1 -C 10 alkyl or C 1 -C 5 alkoxy;
    상기 R2는 비닐 또는 에틸을 나타내고;R 2 represents vinyl or ethyl;
    상기 R3는 수소, C1-C10 알킬, 알릴, C5-C10 아릴, 나프탈렌-1-일-메틸 또는 안트라센-9-일-메틸을 나타내고; R 3 represents hydrogen, C 1 -C 10 alkyl, allyl, C 5 -C 10 aryl, naphthalen-1-yl-methyl or anthracene-9-yl-methyl;
    상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온, IO4 -, ClO4 - , R4SO3 -, OTf- 또는 HSO4 -를 나타내고; 및Wherein Y - is a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine, IO 4 -, ClO 4 - , R 4 SO 3 -, OTf - or HSO 4 - represents; And
    상기 R4는 C1-C4 알킬 또는 C5-C10 아릴이다. R 4 is C 1 -C 4 alkyl or C 5 -C 10 aryl.
  2. 제1항에 있어서, The method of claim 1,
    화학식 1의 X가 -CH2-, -C(OH)H- 또는 -C(=O)-인 경우,When X in Formula 1 is -CH 2- , -C (OH) H- or -C (= O)-,
    상기 R1은 수소 또는 C1-C5 알콕시를 나타내고;R 1 represents hydrogen or C 1 -C 5 alkoxy;
    상기 R2는 비닐 또는 에틸을 나타내고;R 2 represents vinyl or ethyl;
    상기 R3는 수소, C1-C10 알킬, 알릴 또는 C5-C10 아릴을 나타내고; 및 R 3 represents hydrogen, C 1 -C 10 alkyl, allyl or C 5 -C 10 aryl; And
    상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온인, 신코나 알칼로이드 화합물.Wherein Y − is a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine;
  3. 제1항에 있어서, The method of claim 1,
    화학식 1의 X가 -CH2-, -C(OH)H- 또는 -C(=O)-인 경우,When X in Formula 1 is -CH 2- , -C (OH) H- or -C (= O)-,
    상기 R1은 수소 또는 메톡시를 나타내고;R 1 represents hydrogen or methoxy;
    상기 R2는 비닐 또는 에틸을 나타내고;R 2 represents vinyl or ethyl;
    상기 R3는 수소 또는 알릴을 나타내고; 및 R 3 represents hydrogen or allyl; And
    상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온인, 신코나 알칼로이드 화합물.Wherein Y − is a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine;
  4. 제3항에 있어서, The method of claim 3,
    상기 신코나 알칼로이드 화합물은, 4,4'-비스(신코니디움-N-메틸)바이페닐 메타논 디브로마이드;The syncona alkaloid compound may be selected from the group consisting of 4,4'-bis (cinconium-N-methyl) biphenyl metanon dibromide;
    4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 메타논 디브로마이드;4,4'-bis (O (9) -allylicindium-N-methyl) biphenyl metanon dibromide;
    4,4'-비스(히드로신코니디움-N-메틸)바이페닐 메타논 디브로마이드;4,4'-bis (hydrocinconium-N-methyl) biphenyl metanon dibromide;
    4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 메타논 디브로마이드;4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl metanon dibromide;
    3,4'-비스(신코니디움-N-메틸)바이페닐 메타논 디브로마이드;3,4'-bis (cinconium-N-methyl) biphenyl metanon dibromide;
    3,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 메타논 디브로마이드;3,4'-bis (O (9) -allylicinium-N-methyl) biphenyl metanon dibromide;
    3,3'-비스(신코니디움-N-메틸)바이페닐 메타논 디브로마이드;3,3'-bis (cinconium-N-methyl) biphenyl metanon dibromide;
    3,3'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 메타논 디브로마이드;3,3'-bis (O (9) -allylconconium-N-methyl) biphenyl metanon dibromide;
    4,4'-비스(신코니디움-N-메틸)바이페닐 메탄 디브로마이드;4,4'-bis (cinconium-N-methyl) biphenyl methane dibromide;
    4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 메탄 디브로마이드;4,4'-bis (O (9) -allylicindium-N-methyl) biphenyl methane dibromide;
    4,4'-비스(히드로신코니디움-N-메틸)바이페닐 메탄 디브로마이드;4,4'-bis (hydrocinconium-N-methyl) biphenyl methane dibromide;
    4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 메탄 디브로마이드;4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl methane dibromide;
    4,4'-비스(퀴니움-N-메틸)바이페닐 메탄 디브로마이드;4,4'-bis (quinium-N-methyl) biphenyl methane dibromide;
    4,4'-비스(O(9)-알릴퀴니움-N-메틸)바이페닐 메탄 디브로마이드;4,4'-bis (O (9) -allylquinium-N-methyl) biphenyl methane dibromide;
    4,4'-비스(신코니디움-N-메틸)바이페닐 메탄올 디브로마이드;4,4'-bis (cinconium-N-methyl) biphenyl methanol dibromide;
    4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 메탄올 디브로마이드;4,4'-bis (O (9) -allylicindium-N-methyl) biphenyl methanol dibromide;
    4,4'-비스(히드로신코니디움-N-메틸)바이페닐 메탄올 디브로마이드;4,4'-bis (hydrocinconium-N-methyl) biphenyl methanol dibromide;
    4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 메탄올 디브로마이드;4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl methanol dibromide;
    4,4'-비스(신코니움-N-메틸)바이페닐 메타논 디브로마이드; 4,4'-bis (cinconium-N-methyl) biphenyl metanon dibromide;
    4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 메타논 디브로마이드;4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl metanon dibromide;
    4,4'-비스(신코니움-N-메틸)바이페닐 메탄 디브로마이드;4,4'-bis (cinconium-N-methyl) biphenyl methane dibromide;
    4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 메탄 디브로마이드;4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl methane dibromide;
    4,4'-비스(퀴니디움-N-메틸)바이페닐 메탄 디브로마이드;4,4'-bis (quinidium-N-methyl) biphenyl methane dibromide;
    4,4'-비스(O(9)-알릴퀴니디움-N-메틸)바이페닐 메탄 디브로마이드;4,4'-bis (O (9) -allylquinidium-N-methyl) biphenyl methane dibromide;
    4,4'-비스(신코니움-N-메틸)바이페닐 메탄올 디브로마이드; 및4,4'-bis (cinconium-N-methyl) biphenyl methanol dibromide; And
    4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 메탄올 디브로마이드로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 신코나 알칼로이드 화합물.4,4′-bis (O (9) -allylconconium-N-methyl) biphenyl methanol dibromide, a cinnacon alkaloid compound.
  5. 제1항에 있어서, The method of claim 1,
    상기 화학식 1의 X가 -O-, -S- 또는 -S(=O)-인 경우,When X in Formula 1 is -O-, -S- or -S (= O)-,
    상기 R1은 수소 또는 C1-C5 알콕시를 나타내고;R 1 represents hydrogen or C 1 -C 5 alkoxy;
    상기 R2는 비닐 또는 에틸을 나타내고;R 2 represents vinyl or ethyl;
    상기 R3는 수소, C1-C10 알킬, 알릴 또는 C5-C10 아릴을 나타내고; 및 R 3 represents hydrogen, C 1 -C 10 alkyl, allyl or C 5 -C 10 aryl; And
    상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온인, 신코나 알칼로이드 화합물.Wherein Y − is a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine;
  6. 제1항에 있어서, The method of claim 1,
    화학식 1의 X가 -O-, -S- 또는 -S(=O)-인 경우,When X in Formula 1 is -O-, -S- or -S (= O)-,
    상기 R1은 수소 또는 메톡시를 나타내고;R 1 represents hydrogen or methoxy;
    상기 R2는 비닐 또는 에틸을 나타내고;R 2 represents vinyl or ethyl;
    상기 R3는 수소, 알릴 또는 벤질을 나타내고; 및 R 3 represents hydrogen, allyl or benzyl; And
    상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온인, 신코나 알칼로이드 화합물.Wherein Y − is a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine;
  7. 제6항에 있어서, The method of claim 6,
    상기 신코나 알칼로이드 화합물은, 4,4'-비스(신코니디움-N-메틸)바이페닐 에테르 디브로마이드;The syncona alkaloid compound may be selected from the group consisting of 4,4'-bis (cinconium-N-methyl) biphenyl ether dibromide;
    4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl ether dibromide;
    4,4'-비스(O(9)-벤질신코니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-bis (O (9) -benzylcinconium-N-methyl) biphenyl ether dibromide;
    4,4'-비스(히드로신코니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-bis (hydrocinconium-N-methyl) biphenyl ether dibromide;
    4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl ether dibromide;
    4,4'-비스(퀴니움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-bis (quinium-N-methyl) biphenyl ether dibromide;
    4,4'-비스(O(9)-알릴퀴니움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-bis (O (9) -allylquinium-N-methyl) biphenyl ether dibromide;
    3,3'-비스(신코니디움-N-메틸)바이페닐 에테르 디브로마이드;3,3'-bis (cinconium-N-methyl) biphenyl ether dibromide;
    3,3'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 에테르 디브로마이드;3,3'-bis (O (9) -allylicinium-N-methyl) biphenyl ether dibromide;
    4,4'-비스(신코니디움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-bis (cinconium-N-methyl) biphenyl thioether dibromide;
    4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-bis (O (9) -allylicindium-N-methyl) biphenyl thioether dibromide;
    4,4'-비스(히드로신코니디움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-bis (hydrocinconium-N-methyl) biphenyl thioether dibromide;
    4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl thioether dibromide;
    4,4'-비스(퀴니움-N-메틸)바이페닐 티오에테르 디브로마이드;4,4'-bis (quinium-N-methyl) biphenyl thioether dibromide;
    4,4'-비스(O(9)-알릴퀴니움-N-메틸)바이페닐 티오에테르 디브로마이드;4,4'-bis (O (9) -allylquinium-N-methyl) biphenyl thioether dibromide;
    3,3'-비스(신코니디움-N-메틸)바이페닐 설파이드 디브로마이드;3,3'-bis (cinconium-N-methyl) biphenyl sulfide dibromide;
    3,3'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 설파이드 디브로마이드;3,3'-bis (O (9) -allylicindium-N-methyl) biphenyl sulfide dibromide;
    4,4'-비스(신코니디움-N-메틸)바이페닐 설폭사이드 디브로마이드;4,4'-bis (cinconium-N-methyl) biphenyl sulfoxide dibromide;
    4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 설폭사이드 디브로마이드;4,4'-bis (O (9) -allylicindium-N-methyl) biphenyl sulfoxide dibromide;
    4,4'-비스(히드로신코니디움-N-메틸)바이페닐 설폭사이드 디브로마이드; 4,4'-bis (hydrocinconium-N-methyl) biphenyl sulfoxide dibromide;
    4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 설폭사이드 디브로마이드; 4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl sulfoxide dibromide;
    4,4'-비스(신코니움-N-메틸)바이페닐 에테르 디브로마이드;4,4'-bis (cinconium-N-methyl) biphenyl ether dibromide;
    4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 에테르 디브로마이드;4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl ether dibromide;
    4,4'-비스(퀴니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-bis (quinidium-N-methyl) biphenyl ether dibromide;
    4,4'-비스(O(9)-알릴퀴니디움-N-메틸)바이페닐 에테르 디브로마이드; 4,4'-bis (O (9) -allylquinidium-N-methyl) biphenyl ether dibromide;
    4,4'-비스(신코니움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-bis (cinconium-N-methyl) biphenyl thioether dibromide;
    4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl thioether dibromide;
    4,4'-비스(퀴니디움-N-메틸)바이페닐 티오에테르 디브로마이드; 4,4'-bis (quinidium-N-methyl) biphenyl thioether dibromide;
    4,4'-비스(신코니움-N-메틸)바이페닐 설폭사이드 디브로마이드; 및 4,4'-bis (cinconium-N-methyl) biphenyl sulfoxide dibromide; And
    4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 설폭사이드 디브로마이드로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 신코나 알칼로이드 화합물.4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl sulfoxide dibromide, a cinnacon alkaloid compound.
  8. 제1항에 있어서, The method of claim 1,
    화학식 1의 X가 -S(O2)-인 경우, When X in Formula 1 is -S (O 2 )-,
    상기 R1은 수소 또는 C1-C5 알콕시를 나타내고;R 1 represents hydrogen or C 1 -C 5 alkoxy;
    상기 R2는 비닐 또는 에틸을 나타내고;R 2 represents vinyl or ethyl;
    상기 R3는 수소, C1-C10 알킬, 알릴 또는 C5-C10 아릴을 나타내고; 및 R 3 represents hydrogen, C 1 -C 10 alkyl, allyl or C 5 -C 10 aryl; And
    상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온인, 신코나 알칼로이드 화합물.Wherein Y − is a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine;
  9. 제1항에 있어서, The method of claim 1,
    화학식 1의 X가 -S(O2)-인 경우, When X in Formula 1 is -S (O 2 )-,
    상기 R1은 수소를 나타내고; R 1 represents hydrogen;
    상기 R2는 비닐 또는 에틸을 나타내고;R 2 represents vinyl or ethyl;
    상기 R3는 수소 또는 알릴을 나타내고; 및 R 3 represents hydrogen or allyl; And
    상기 Y-는 불소, 염소, 브롬, 및 요오드로 이루어진 군으로부터 선택되는 할로겐 음이온인, 신코나 알칼로이드 화합물.Wherein Y − is a halogen anion selected from the group consisting of fluorine, chlorine, bromine, and iodine;
  10. 제9항에 있어서, The method of claim 9,
    상기 신코나 알칼로이드 화합물은, 4,4'-비스(신코니디움-N-메틸)바이페닐 설폰 디브로마이드;The syncona alkaloid compound includes 4,4'-bis (syncondium-N-methyl) biphenyl sulfone dibromide;
    4,4'-비스(O(9)-알릴신코니디움-N-메틸)바이페닐 설폰 디브로마이드;4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl sulfone dibromide;
    4,4'-비스(히드로신코니디움-N-메틸)바이페닐 설폰 디브로마이드;4,4'-bis (hydrocinconium-N-methyl) biphenyl sulfone dibromide;
    4,4'-비스(O(9)-알릴히드로신코니디움-N-메틸)바이페닐 설폰 디브로마이드;4,4'-bis (O (9) -allylhydrocinconium-N-methyl) biphenyl sulfone dibromide;
    4,4'-비스(신코니움-N-메틸)바이페닐 설폰 디브로마이드; 및4,4'-bis (cinconium-N-methyl) biphenyl sulfone dibromide; And
    4,4'-비스(O(9)-알릴신코니움-N-메틸)바이페닐 설폰 디브로마이드로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 신코나 알칼로이드 화합물.4,4'-bis (O (9) -allylconconium-N-methyl) biphenyl sulfone dibromide, a cinnacon alkaloid compound.
  11. 제1항 내지 제10항 중 어느 한 항의 신코나 알칼로이드 화합물을 비대칭 상 이동 촉매 (Chiral phase-transfer catalyst)로 이용하는 알파-아미노산의 합성방법. A method for synthesizing alpha-amino acids using the synacona alkaloid compound of any one of claims 1 to 10 as a asymmetric phase-transfer catalyst.
  12. 제11항에 있어서, The method of claim 11,
    상기 합성방법은, 하기 반응식 1에 나타낸 바와 같이, 비대칭 상 이동 촉매로서 제1항 내지 제10항 중 어느 한 항의 신코나 알칼로이드 화합물의 존재 하에서, 화학식 Ⅰ 화합물과 화학식 Ⅱ 화합물을 반응시켜 화학식 Ⅲ 화합물을 제조하는 단계; 및 상기 단계에서 제조된 화학식 Ⅲ 화합물을 산성 조건에서 가수분해시켜 화학식 Ⅳ 화합물을 제조하는 단계를 포함하는, 알파-아미노산의 합성방법.The synthesis method is a compound of formula (III) by reacting a compound of formula (I) with a compound of formula (II) in the presence of a cinnaco alkaloid compound of any one of claims 1 to 10 as asymmetric phase transfer catalyst Preparing a; And preparing a compound of formula IV by hydrolyzing the compound of formula III prepared in the step under acidic conditions.
    [반응식 1]Scheme 1
    Figure PCTKR2017001270-appb-I000022
    Figure PCTKR2017001270-appb-I000022
    (상기 반응식 1에서, R'는 C2-C6 알킬, R''는 C2-C6 알킬 또는 C5-C10 아릴일 수 있다.). (In Scheme 1, R ′ may be C 2 -C 6 alkyl, R ″ may be C 2 -C 6 alkyl or C 5 -C 10 aryl.).
  13. 제12항에 있어서,The method of claim 12,
    상기 화학식 Ⅰ 화합물과 화학식 Ⅱ 화합물을 반응시키는 단계는, 10 내지 20℃ 조건에서 진행되는 것을 특징으로 하는, 알파-아미노산의 합성방법.The step of reacting the compound of formula (I) with the compound of formula (II), characterized in that proceeding at 10 to 20 ℃ conditions, the synthesis method of alpha-amino acid.
  14. 제12항에 있어서,The method of claim 12,
    상기 비대칭 상 이동 촉매는, 화학식 Ⅰ 화합물 1 당량에 대해 0.0005 내지 0.012 당량 범위로 사용하는 것을 특징으로 하는, 알파-아미노산의 합성방법.The asymmetric phase transfer catalyst, characterized in that used in the range of 0.0005 to 0.012 equivalents to 1 equivalent of the compound of formula (I).
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