JP6119022B2 - Pyridine derivative having axial asymmetry or salt thereof, process for producing the same, and asymmetric catalyst comprising the same - Google Patents

Description

  The present invention relates to a pyridine derivative having a binaphthyl group or a salt thereof, a production method thereof and an asymmetric catalyst comprising the same.

  Compounds having a binaphthyl group are widely used as asymmetric synthesis catalysts. For example, a transition metal complex using BINAP [(1,1-binaphthalene) -2,2-diylbis (diphenylphosphine)] represented by the following formula as a ligand may exhibit excellent performance as a catalyst for asymmetric synthesis. It is one of the known and most widely used asymmetric ligands. However, depending on the type and conditions of the reaction, when an asymmetric catalyst containing BINAP is used, the progress of the reaction may be insufficient or the enantioselectivity may be insufficient.

  Regarding the compound having a binaphthyl group, Patent Document 1 describes the following N-spiro asymmetric phase transfer catalyst having a binaphthyl group and a biphenyl group. According to this, natural or non-natural α-amino acid derivatives can be stereoselectively synthesized. However, the number of steps for synthesizing such an N-spiro asymmetric phase transfer catalyst is large, and the enantioselectivity may not be good, and an improvement has been desired.

  Non-Patent Document 1 discloses (S) -phenyl 4-benzyl-2- (4-methoxyphenyl) -5-oxo-4,5-dihydrooxazole-4 by a Stegrich rearrangement reaction using an asymmetric nucleophilic catalyst. It describes that -carboxylate can be obtained. However, the optically pure asymmetric nucleophilic catalyst used in this reaction is obtained by optically resolving a racemate a plurality of times using an optically active acid. There was a desire for improvement.

JP 2002-326992 A

Scott A. Shaw et al., J. Am. Chem. Soc., 2006, Vol.128, No.3, p.925-934

  The present invention has been made to solve the above-described problems, and an object thereof is to provide a pyridine derivative having a binaphthyl group or a salt thereof. It is another object of the present invention to provide an asymmetric catalyst comprising a pyridine derivative or a salt thereof, which can obtain an optically active substance suitably used for a pharmaceutical intermediate or the like with good enantioselectivity.

［式中、Ｒ^１〜Ｒ^６及びＲ^１’〜Ｒ^６’は、それぞれ独立して水素原子、炭素数１〜１０のアルキル基、炭素数２〜１０のアルケニル基、炭素数２〜１０のアルキニル基、炭素数１〜１０のアルコキシ基、炭素数６〜１５のアリール基、炭素数２〜１０のアシル基、炭素数７〜１５のアリールアルキル基、炭素数３〜１０のアルキルシリル基、炭素数２〜１０のアルコキシカルボニル基、炭素数１〜１０のアルキルチオ基、炭素数６〜１５のアリールチオ基、炭素数４〜１０の複素芳香環基、スルホニルオキシ基、アミノ基、アミド基、ニトロ基、水酸基、アリールシリル基、アリールアルキルシリル基、又はハロゲン原子であり、
Ｒ^７、Ｒ^７’、Ｒ^８及びＲ^８’は、それぞれ独立して水素原子、炭素数１〜１０のアルキル基、炭素数１〜１０のアルコキシ基、又はハロゲン原子であり、
Ｒ^９、Ｒ^９’、Ｒ^１０及びＲ^１０’は、それぞれ独立して水素原子、炭素数１〜１０のアルキル基、炭素数１〜１０のアルコキシ基、又はハロゲン原子である。］The above problem is solved by providing a pyridine derivative represented by the following general formula (1) or a salt thereof.

[Wherein R ^{1 to} R ⁶ and R ¹ ′ to R ⁶ ′ each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkyl group having 2 to 10 carbon atoms. An alkynyl group, an alkoxy group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, an acyl group having 2 to 10 carbon atoms, an arylalkyl group having 7 to 15 carbon atoms, an alkylsilyl group having 3 to 10 carbon atoms, C2-C10 alkoxycarbonyl group, C1-C10 alkylthio group, C6-C15 arylthio group, C4-C10 heteroaromatic ring group, sulfonyloxy group, amino group, amide group, nitro A group, a hydroxyl group, an arylsilyl group, an arylalkylsilyl group, or a halogen atom,
R ⁷ , R ⁷ ′, R ⁸ and R ⁸ ′ are each independently a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom,
R ⁹ , R ⁹ ′, R ¹⁰ and R ¹⁰ ′ are each independently a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom. ]

  At this time, the asymmetric catalyst comprising the pyridine derivative or a salt thereof is a preferred embodiment of the present invention.

［式中、Ｒ^１〜Ｒ^８及びＲ^１’〜Ｒ^８’は、前記一般式（１）と同義である。］
で示されるビナフチル誘導体を下記一般式（３）：

［式中、Ｒ^９、Ｒ^９’、Ｒ^１０及びＲ^１０’は、前記一般式（１）と同義であり、Ｘはハロゲン原子である。］
で示される４−ハロゲノピリジン誘導体の塩と反応させて上記一般式（１）で示されるピリジン誘導体又はその塩の製造方法を提供することによっても解決される。Moreover, the said subject is the following general formula (2):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
A binaphthyl derivative represented by the following general formula (3):

[Wherein, R ⁹ , R ⁹ ′, R ¹⁰ and R ¹⁰ ′ have the same meaning as in the general formula (1), and X is a halogen atom. ]
It is also solved by providing a method for producing a pyridine derivative represented by the above general formula (1) or a salt thereof by reacting with a salt of a 4-halogenopyridine derivative represented by formula (1).

［式中、Ｒ^１〜Ｒ^８及びＲ^１’〜Ｒ^８’は前記一般式（１）と同義である。］
で示されるアリルビナフチル誘導体を出発化合物として下記一般式（２）：

［式中、Ｒ^１〜Ｒ^８及びＲ^１’〜Ｒ^８’は、前記一般式（１）と同義である。］
で示されるビナフチル誘導体を得る工程を有するピリジン誘導体又はその塩の製造方法が本発明の好適な実施態様である。At this time, the following general formula (4):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
As a starting compound, an allylbinaphthyl derivative represented by the following general formula (2):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
A method for producing a pyridine derivative or a salt thereof having a step of obtaining a binaphthyl derivative represented by formula (II) is a preferred embodiment of the present invention.

［式中、Ｒ^１〜Ｒ^８及びＲ^１’〜Ｒ^８’は前記一般式（１）と同義である。］
で示されるジブロモビナフチル誘導体を出発化合物として下記一般式（４）：

［式中、Ｒ^１〜Ｒ^８及びＲ^１’〜Ｒ^８’は前記一般式（１）と同義である。］
で示されるアリルビナフチル誘導体を得る工程を有するピリジン誘導体又はその塩の製造方法が本発明の好適な実施態様である。At this time, the following general formula (5):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
A dibromobinaphthyl derivative represented by the following general formula (4):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
A method for producing a pyridine derivative or a salt thereof having a step of obtaining an allylbinaphthyl derivative represented by the formula is a preferred embodiment of the present invention.

［式中、Ｒ^１〜Ｒ^８及びＲ^１’〜Ｒ^８’は前記一般式（１）と同義である。］
で示されるビナフチル誘導体を出発化合物として下記一般式（５）：

［式中、Ｒ^１〜Ｒ^８及びＲ^１’〜Ｒ^８’は前記一般式（１）と同義である。］
で示されるジブロモビナフチル誘導体を得る工程を有するピリジン誘導体又はその塩の製造方法も本発明の好適な実施態様である。At this time, the following general formula (6):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
As a starting compound, a binaphthyl derivative represented by the following general formula (5):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
A method for producing a pyridine derivative or a salt thereof having a step of obtaining a dibromobinaphthyl derivative represented by the formula is also a preferred embodiment of the present invention.

［式中、Ｒ^１が炭素数１〜１０のアルコキシ基であり、Ｒ^１’が水素原子又は炭素数１〜１０のアルコキシ基である。］Moreover, the said subject is solved by providing the binaphthyl derivative shown by following General formula (7).

[Wherein, R ¹ is an alkoxy group having 1 to 10 carbon atoms, and R ¹ ′ is a hydrogen atom or an alkoxy group having 1 to 10 carbon atoms. ]

［式中、Ｒ^１が炭素数１〜１０のアルコキシ基であり、Ｒ^１’が水素原子又は炭素数１〜１０のアルコキシ基である。］Moreover, the said subject is also solved by providing the allyl binaphthyl derivative shown by following General formula (8).

[Wherein, R ¹ is an alkoxy group having 1 to 10 carbon atoms, and R ¹ ′ is a hydrogen atom or an alkoxy group having 1 to 10 carbon atoms. ]

  According to the present invention, a pyridine derivative having a binaphthyl group or a salt thereof can be synthesized. When the pyridine derivative of the present invention or a salt thereof thus obtained is used as an asymmetric catalyst, an optically active substance suitably used for a pharmaceutical intermediate or the like can be obtained with good enantioselectivity.

¹ is a ¹ H-NMR spectrum diagram of a compound represented by the formula (S)-(D) -1 obtained in Example 13. FIG. 2 is a ¹ H-NMR spectrum diagram of the compound represented by the formula (S)-(D) -2 obtained in Example 13. FIG. 2 is a ¹ H-NMR spectrum diagram of the compound represented by the formula (S)-(D) -3 obtained in Example 13. FIG. 4 is a ¹ H-NMR spectrum of a compound represented by the formula (S)-(D) -4 obtained in Example 13. FIG. 2 is a ¹ H-NMR spectrum of a compound represented by the formula (S)-(D) -5 obtained in Example 13. FIG. 2 is a ¹ H-NMR spectrum diagram of the compound represented by the formula (S)-(D) -6 obtained in Example 13. FIG. 2 is a ¹ H-NMR spectrum of a compound represented by the formula (S)-(D) -7 obtained in Example 13. FIG. 2 is a ¹ H-NMR spectrum diagram of a mixture of a compound represented by the formula (S)-(D) -8 obtained in Example 13 and an unreacted raw material compound. FIG. 2 is a ¹ H-NMR spectrum diagram of the compound represented by the formula (S)-(D) -9 obtained in Example 13. FIG. 2 is a ¹ H-NMR spectrum of a compound represented by the formula (S)-(D) -10 obtained in Example 13. FIG. ¹ is a ¹ H-NMR spectrum diagram of a compound represented by the formula (S)-(D) -11 obtained in Example 13. FIG. ¹ is a ¹ H-NMR spectrum diagram of a compound represented by the formula (S)-(F) -1 obtained in Example 15. FIG. 2 is a ¹ H-NMR spectrum diagram of a mixture of a compound represented by the formula (S)-(F) -2 obtained in Example 15 and an unreacted raw material compound. FIG. 2 is a ¹ H-NMR spectrum diagram of a mixture of a compound represented by the formula (S)-(F) -3 obtained in Example 15 and an unreacted raw material compound. FIG. 2 is a ¹ H-NMR spectrum diagram of a mixture of a compound represented by the formula (S)-(F) -4 obtained in Example 15 and an unreacted raw material compound. FIG.

  The pyridine derivative or salt thereof of the present invention is represented by the following general formula (1).

［式中、Ｒ^１〜Ｒ^６及びＲ^１’〜Ｒ^６’は、それぞれ独立して水素原子、炭素数１〜１０のアルキル基、炭素数２〜１０のアルケニル基、炭素数２〜１０のアルキニル基、炭素数１〜１０のアルコキシ基、炭素数６〜１５のアリール基、炭素数２〜１０のアシル基、炭素数７〜１５のアリールアルキル基、炭素数３〜１０のアルキルシリル基、炭素数２〜１０のアルコキシカルボニル基、炭素数１〜１０のアルキルチオ基、炭素数６〜１５のアリールチオ基、炭素数４〜１０の複素芳香環基、スルホニルオキシ基、アミノ基、アミド基、ニトロ基、水酸基、アリールシリル基、アリールアルキルシリル基、又はハロゲン原子であり、
Ｒ^７、Ｒ^７’、Ｒ^８及びＲ^８’は、それぞれ独立して水素原子、炭素数１〜１０のアルキル基、炭素数１〜１０のアルコキシ基、又はハロゲン原子であり、
Ｒ^９、Ｒ^９’、Ｒ^１０及びＲ^１０’は、それぞれ独立して水素原子、炭素数１〜１０のアルキル基、炭素数１〜１０のアルコキシ基、又はハロゲン原子である。］

[Wherein R ^{1 to} R ⁶ and R ¹ ′ to R ⁶ ′ each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkyl group having 2 to 10 carbon atoms. An alkynyl group, an alkoxy group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, an acyl group having 2 to 10 carbon atoms, an arylalkyl group having 7 to 15 carbon atoms, an alkylsilyl group having 3 to 10 carbon atoms, C2-C10 alkoxycarbonyl group, C1-C10 alkylthio group, C6-C15 arylthio group, C4-C10 heteroaromatic ring group, sulfonyloxy group, amino group, amide group, nitro A group, a hydroxyl group, an arylsilyl group, an arylalkylsilyl group, or a halogen atom,
R ⁷ , R ⁷ ′, R ⁸ and R ⁸ ′ are each independently a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom,
R ⁹ , R ⁹ ′, R ¹⁰ and R ¹⁰ ′ are each independently a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom. ]

In the general formula (1), R ^{1 to} R ⁶ and R ¹ ′ to R ⁶ ′ each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or a carbon number. 2-10 alkynyl group, C1-C10 alkoxy group, C6-C15 aryl group, C2-C10 acyl group, C7-C15 arylalkyl group, C3-C10 An alkylsilyl group, an alkoxycarbonyl group having 2 to 10 carbon atoms, an alkylthio group having 1 to 10 carbon atoms, an arylthio group having 6 to 15 carbon atoms, a heteroaromatic ring group having 4 to 10 carbon atoms, a sulfonyloxy group, an amino group, An amide group, a nitro group, a hydroxyl group, an arylsilyl group, an arylalkylsilyl group, or a halogen atom; Among them, as R ^{1 to} R ⁶ and R ¹ ′ to R ⁶ ′, a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, and a carbon number 7 to 15 arylalkyl groups and at least one substituent selected from the group consisting of halogen atoms are preferably used.

Examples of the alkyl group having 1 to 10 carbon atoms used for ^R 1 to R ⁶ and ^{R 1} 'to R ^6' in the general formula (1) may be a straight-chain or branched-chain alkyl groups, cyclic May be a cycloalkyl group. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, linear or branched alkyl groups such as n-hexyl group, isohexyl group, 2-ethylhexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group; cyclopropyl group, cyclobutyl group, Examples thereof include cycloalkyl groups such as cyclopentyl group, cyclohexyl group, cycloheptanyl group, cyclooctanyl group, cyclononanyl group, and cyclodecanyl group.

  The alkyl group having 1 to 10 carbon atoms may further have a substituent. Examples of the substituent include aryl groups such as a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group; a pyridyl group, a thienyl group, and a furyl group. Group, pyrrolyl group, imidazolyl group, pyrazinyl group, oxazolyl group, thiazolyl group, pyrazolyl group, benzothiazolyl group, benzoimidazolyl group, and the like; methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group , Sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, hexyloxy group, cyclohexyloxy group, heptyloxy group, octyloxy group, nonyloxy group, decyloxy group, dodecyloxy group Alkoxy groups such as Alkylthio groups such as ruthio group, ethylthio group, propylthio group and butylthio group; arylthio groups such as phenylthio group and naphthylthio group; trisubstituted silyloxy groups such as tert-butyldimethylsilyloxy group and tert-butyldiphenylsilyloxy group; acetoxy group An acyloxy group such as propanoyloxy group, butanoyloxy group, pivaloyloxy group, benzoyloxy group; methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec- Alkyl such as butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl group, etc. Xyloxycarbonyl group; alkylsulfinyl group such as methylsulfinyl group and ethylsulfinyl group; arylsulfinyl group such as phenylsulfinyl group; methylsulfonyloxy group, ethylsulfonyloxy group, phenylsulfonyloxy group, methoxysulfonyl group, ethoxysulfonyl group, phenyl Examples thereof include sulfonic acid ester groups such as oxysulfonyl groups; amino groups; hydroxyl groups; cyano groups; nitro groups; halogen atoms such as fluorine atoms, chlorine atoms, bromine atoms, iodine atoms;

  The alkenyl group having 2 to 10 carbon atoms may be linear or branched, and may be a vinyl group, allyl group, methylvinyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, cyclopropenyl. Group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group and the like. These alkenyl groups may have a substituent, and as the substituent, those similar to the substituents exemplified in the description of the alkyl group can be used.

  The alkynyl group having 2 to 10 carbon atoms may be linear or branched, and examples include ethynyl group, propynyl group, propargyl group, butynyl group, pentynyl group, hexynyl group, and phenylethynyl group. It is done. These alkynyl groups may have a substituent, and as the substituent, those similar to the substituents exemplified in the description of the alkyl group can be used.

  Examples of the alkoxy group having 1 to 10 carbon atoms include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, and n-pentyloxy group. , Isopentyloxy group, neopentyloxy group, n-hexyloxy group, isohexyloxy group, 2-ethylhexyloxy group, n-heptyloxy group, n-octyloxy group, n-nonyloxy group, n-decyloxy group, etc. Is mentioned. These alkoxy groups may have a substituent, and as such a substituent, a substituent other than the alkoxy group exemplified in the description of the alkyl group can be similarly used.

  Examples of the aryl group having 6 to 15 carbon atoms include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. These aryl groups may have a substituent, and as such a substituent, a substituent other than the aryl group exemplified in the description of the alkyl group, the above-described alkyl group, alkenyl group, alkynyl group, or the like is used. be able to.

  Examples of the acyl group having 2 to 10 carbon atoms include acetyl group, propionyl group, butyryl group, isobutyryl group, and benzoyl group. These acyl groups may have a substituent, and as the substituent, those similar to the substituents exemplified in the description of the alkyl group can be used.

  Examples of the arylalkyl group having 7 to 15 carbon atoms include benzyl group, 4-methoxybenzyl group, phenethyl group, and diphenylmethyl group. These arylalkyl groups may have a substituent, and as the substituent, those similar to the substituents exemplified in the description of the alkyl group can be used.

  Examples of the alkylsilyl group having 3 to 10 carbon atoms include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group and the like. These alkylsilyl groups may have a substituent, and as the substituent, those similar to the substituents exemplified in the description of the alkyl group can be used.

  Examples of the alkoxycarbonyl group having 2 to 10 carbon atoms include methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, allyloxycarbonyl group, n- Examples include butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl group, and benzyloxycarbonyl group. These alkoxycarbonyl groups may have a substituent, and as such a substituent, a substituent other than the alkoxycarbonyl group exemplified in the description of the alkyl group can be used.

  Examples of the alkylthio group having 1 to 10 carbon atoms include a methylthio group, an ethylthio group, a propylthio group, and a butylthio group. Examples of the arylthio group having 6 to 15 carbon atoms include a phenylthio group and a naphthylthio group. These alkylthio groups and arylthio groups may have a substituent, and as such a substituent, substituents other than the alkylthio group and arylthio group exemplified in the description of the alkyl group can be used similarly.

  Examples of the heteroaromatic group having 4 to 10 carbon atoms include pyridyl group, thienyl group, furyl group, pyrrolyl group, imidazolyl group, pyrazinyl group, oxazolyl group, thiazolyl group, pyrazolyl group, benzothiazolyl group, benzoimidazolyl group and the like. . These heteroaromatic ring groups may have a substituent, such as a substituent other than the heteroaromatic ring group exemplified in the description of the alkyl group, the above-described alkyl group, alkenyl group, alkynyl. A group or the like can be used.

  Examples of the sulfonyloxy group include a sulfonyloxy group having an alkyl group having 1 to 10 carbon atoms (hereinafter sometimes abbreviated as an alkylsulfonyloxy group), and a sulfonyloxy group having an aryl group having 6 to 15 carbon atoms (hereinafter referred to as an alkylsulfonyloxy group). And may be abbreviated as arylsulfonyloxy group). As the alkyl group having 1 to 10 carbon atoms and the aryl group having 6 to 15 carbon atoms, the same substituents as described above can be used. Examples of the alkylsulfonyloxy group include a methanesulfonyloxy group, an ethanesulfonyloxy group, an n-propanesulfonyloxy group, an isopropanesulfonyloxy group, an n-butanesulfonyloxy group, and a tert-butanesulfonyloxy group. These alkylsulfonyloxy groups may have a substituent, and as such a substituent, the same substituents as exemplified in the description of the alkyl group can be used, and a halogen atom is preferable as the substituent. Is mentioned. As the alkylsulfonyloxy group having a halogen atom, a trifluoromethanesulfonyloxy group or the like is preferably used. Examples of the arylsulfonyloxy group include a benzenesulfonyloxy group, a naphthalenesulfonyloxy group, and a biphenylsulfonyloxy group. These arylsulfonyloxy groups may have a substituent. Examples of the substituent include substituents other than the aryl group exemplified in the description of the alkyl group, the above-described alkyl group, alkenyl group, alkynyl group, and the like. And a suitable substituent includes an alkyl group. As the arylsulfonyloxy group having an alkyl group, a paratoluenesulfonyloxy group or the like is preferably used.

The amino group may be a primary amino group (—NH ₂ ), a secondary amino group, or a tertiary amino group. The secondary amino group is a mono-substituted amino group represented by —NHR ¹¹ (R ¹¹ is an arbitrary monovalent substituent), and R ¹¹ includes an alkyl group having 1 to 10 carbon atoms and 6 carbon atoms. -15 aryl group, acetyl group, benzoyl group, benzenesulfonyl group, tert-butoxycarbonyl group and the like. Specific examples of the secondary amino group include a secondary amino group in which R ¹¹ is an alkyl group such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a phenylamino group, and a naphthylamino group. Examples thereof include a secondary amino group in which R ¹¹ is an aryl group such as a group. In addition, the hydrogen atom of the alkyl group or aryl group in R ¹¹ may be further substituted with an acetyl group, a benzoyl group, a benzenesulfonyl group, a tert-butoxycarbonyl group, or the like. The tertiary amino group is a di-substituted amino group represented by —NR ¹¹ R ¹² (R ¹¹ and R ¹² are any monovalent substituent), and R ¹² is the same as R ^11. R ¹¹ and R ¹² may be the same or different from each other. Specific examples of the tertiary amino group include a dimethylamino group, a diethylamino group, a dibutylamino group, an ethylmethylamino group, a diphenylamino group, a methylphenylamino group, and the like, wherein R ¹¹ and R ¹² are substituted with an alkyl group and an aryl group. A tertiary amino group which is at least one selected from the group consisting of

The amide group is selected from the group consisting of —C (═O) NR ¹³ R ¹⁴ (R ¹³ and R ¹⁴ are a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, and an aryl group having 6 to 15 carbon atoms. An amide group represented by at least one). R ¹³ and R ¹⁴ may be the same or different from each other. As the alkyl group and aryl group in R ¹³ and R ^14, the substituents exemplified in the description of the alkyl group and aryl group can be used in the same manner.

  Examples of the arylsilyl group include a tert-butyldiphenylsilyl group, a triphenylsilyl group, and a dimethylphenylsilyl group. Examples of the arylalkylsilyl group include a tribenzylsilyl group. These arylsilyl groups and arylalkylsilyl groups may have a substituent, and as such a substituent, the same substituents exemplified in the description of the alkyl group can be used.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the above general formula (1), suitable substituents used for R ^{1 to} R ⁶ and R ¹ ′ to R ⁶ ′ include a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, and an alkoxy group having 1 to 10 carbon atoms. And at least one substituent selected from the group consisting of a group, an aryl group having 6 to 15 carbon atoms, an arylalkyl group having 7 to 15 carbon atoms, a sulfonyloxy group, and a halogen atom. From the viewpoint of good function as an asymmetric catalyst, among R ^{1 to} R ⁶ and R ¹ ′ to R ⁶ ′ in the general formula (1), R ¹ and R ¹ ′ are a hydrogen atom and a carbon number. At least one selected from the group consisting of an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, an arylalkyl group having 7 to 15 carbon atoms, a sulfonyloxy group, and a halogen atom; R ^{2 to} R ⁶ and R ² ′ to R ⁶ ′ are preferably hydrogen atoms, R ¹ and R ¹ ′ are alkyl groups having 1 to 10 carbon atoms, 1 carbon atom 10 alkoxy group, at least one substituent which the aryl group having 6 to 15 carbon atoms, an arylalkyl group of 7 to 15 carbon atoms, selected from the group consisting of sulfonyloxy group and halogen atom, and R ² to R ⁶ and ^{R 2} ' More preferably R 6 ^'is a hydrogen atom.

R ⁷ , R ⁷ ′, R ⁸ and R ⁸ ′ in the general formula (1) are each independently a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom. It is. As such an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms and a halogen atom, in the description of R ^{1 to} R ⁶ and R ¹ ′ to R ⁶ ′ in the general formula (1), The same substituents as those exemplified can be used. From the viewpoint of good function as an asymmetric catalyst, R ⁷ , R ⁷ ′, R ^8, and R ⁸ ′ in the general formula (1) are selected from the group consisting of a hydrogen atom and an alkyl group having 1 to 10 carbon atoms. It is preferably at least one substituent selected, more preferably at least one substituent selected from the group consisting of a hydrogen atom, a methyl group, and an ethyl group. More preferably, it is an atom.

R ⁹ , R ⁹ ′, R ¹⁰ and R ¹⁰ ′ in the general formula (1) are each independently a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom. It is. As such an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms and a halogen atom, in the description of R ^{1 to} R ⁶ and R ¹ ′ to R ⁶ ′ in the general formula (1), The same substituents as those exemplified can be used. From the viewpoint of good function as an asymmetric catalyst, it is preferable that R ⁹ , R ⁹ ′, R ¹⁰ and R ¹⁰ ′ in the general formula (1) are hydrogen atoms.

  The pyridine derivative of the present invention or a salt thereof described above may be a racemate, but from the viewpoint of easily obtaining an optically active compound without optical resolution when used as an asymmetric catalyst, The pyridine derivative or a salt thereof itself is preferably an optically active substance, and in this case, it becomes an axially asymmetric optically active substance. That is, an optically active substance represented by the following general formula (1-S) or the following general formula (1-R) is preferable.

［式中、Ｒ^１〜Ｒ^１０及びＲ^１’〜Ｒ^１０’は、前記一般式（１）と同義である。］

[Wherein, R ^{1 to} R ¹⁰ and R ¹ ′ to R ¹⁰ ′ have the same meaning as in the general formula (1). ]

［式中、Ｒ^１〜Ｒ^１０及びＲ^１’〜Ｒ^１０’は、前記一般式（１）と同義である。］

[Wherein, R ^{1 to} R ¹⁰ and R ¹ ′ to R ¹⁰ ′ have the same meaning as in the general formula (1). ]

The method for obtaining a pyridine derivative represented by the general formula (1) or a salt thereof of the present invention is not particularly limited, and a binaphthyl derivative represented by the following general formula (6) can be suitably synthesized as a starting compound. Hereinafter, ^{R 1} in the general formula (6) is a phenyl ^group, a binaphthyl derivative as a starting compound represented by the formula (6a) when R 2 to R ⁸ and ^{R 1 '~R 8'} is a hydrogen atom, Regarding a method for obtaining a pyridine derivative represented by the formula (1a) or a salt thereof when R ¹ in the general formula (1) is a phenyl group and R ^{2 to} R ¹⁰ and R ¹ ′ to R ¹⁰ ′ are hydrogen atoms This will be described with reference to the following chemical reaction formula (I). The binaphthyl derivative represented by the formula (6a) can be synthesized from 1,1′-binaphthol by a known method.

  First, N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) are added to the binaphthyl derivative represented by the formula (6a) as shown in the reaction 1 of the chemical reaction formula (I). Thus, a dibromobinaphthyl derivative represented by the formula (5a) that is dibrominated can be obtained.

  Examples of the solvent used in the reaction 1 include hydrocarbons such as benzene, toluene, xylene, cumene, hexane, heptane, and octane; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2- Halogenated hydrocarbons such as tetrachloroethane and chlorobenzene; ethers such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane and dimethoxyethane; esters such as ethyl acetate and butyl acetate; nitriles such as acetonitrile and propionitrile; dimethylformamide And amides such as N-methylpyrrolidone. A solvent may be used independently and may use 2 or more types together. Among these, hydrocarbon solvents and / or halogenated hydrocarbon solvents are preferably used. The amount of the solvent used is preferably 1 to 100 parts by mass and more preferably 1 to 50 parts by mass with respect to 1 part by mass of the binaphthyl derivative represented by the formula (6a).

  The amount of N-bromosuccinimide (NBS) used in the above reaction 1 is not particularly limited and is preferably 2 to 4 mol with respect to 1 mol of the binaphthyl derivative represented by the formula (6a). More preferably, it is 2.5 moles. The amount of azobisisobutyronitrile (AIBN) used in the reaction 1 is not particularly limited, and is 0.001 to 0.1 mol with respect to 1 mol of the binaphthyl derivative represented by the formula (6a). It is preferable that it is 0.01-0.1 mol. The reaction temperature in the reaction 1 is preferably 50 to 120 ° C., and the reaction time in the reaction 1 is preferably 2 to 10 hours, and more preferably 2 to 5 hours. .

  Subsequently, as shown in the above reaction 2, the allylbinaphthyl derivative represented by the formula (4a) can be obtained by reacting the dibromobinaphthyl derivative represented by the formula (5a) obtained by the reaction 1 with allylamine. it can. Here, the present inventors have confirmed that when 4-aminopyridine is reacted with the dibromobinaphthyl derivative represented by the formula (5a), the target reaction does not proceed and only a by-product is obtained. ing. Therefore, it is a preferred embodiment of the present invention to have the step of obtaining the allyl binaphthyl derivative represented by the general formula (4) from the dibromobinaphthyl derivative represented by the general formula (5). The allyl binaphthyl derivative represented by the general formula (4) thus obtained is very useful as an intermediate of the pyridine derivative or a salt thereof of the present invention. In particular, the allyl binaphthyl derivative represented by the following general formula (8) is an intermediate. It is very useful as a body.

［式中、Ｒ^１が炭素数１〜１０のアルコキシ基であり、Ｒ^１’が水素原子又は炭素数１〜１０のアルコキシ基である。］

[Wherein, R ¹ is an alkoxy group having 1 to 10 carbon atoms, and R ¹ ′ is a hydrogen atom or an alkoxy group having 1 to 10 carbon atoms. ]

The alkoxy group having 1 to 10 carbon atoms in the general formula (8) is the same as the alkoxy group exemplified in the description of R ^{1 to} R ⁶ and R ¹ ′ to R ⁶ ′ in the general formula (1). Things can be used.

  As the solvent used in the reaction 2, the same solvents as those exemplified in the description of the reaction 1 can be used, and among them, an ether solvent and / or a nitrile solvent are preferably used. The amount of the solvent used is preferably 1 to 100 parts by mass and more preferably 1 to 50 parts by mass with respect to 1 part by mass of the dibromobinaphthyl derivative represented by the formula (5a).

  The amount of allylamine used in the above reaction 2 is not particularly limited, and is preferably 3 to 8 mol and 3 to 4 mol with respect to 1 mol of the dibromobinaphthyl derivative represented by the formula (5a). Is more preferable. The reaction temperature in the reaction 2 is preferably 30 to 100 ° C., and the reaction time in the reaction 2 is preferably 2 to 20 hours, and more preferably 5 to 15 hours. .

  Subsequently, as shown in the above reaction 3, the allylbinaphthyl derivative represented by the formula (4a) is reacted with N, N-dimethylbarbituric acid (NDMBA) using a metal catalyst to obtain the formula (2a) The binaphthyl derivative shown by can be obtained. That is, it is a preferred embodiment of the present invention to have a step of obtaining the binaphthyl derivative represented by the general formula (2) from the allyl binaphthyl derivative represented by the general formula (4). The allyl binaphthyl derivative represented by the general formula (2) thus obtained is very useful as an intermediate of the pyridine derivative of the present invention or a salt thereof. In particular, the binaphthyl derivative represented by the following general formula (7) is an intermediate. As very useful.

［式中、Ｒ^１が炭素数１〜１０のアルコキシ基であり、Ｒ^１’が水素原子又は炭素数１〜１０のアルコキシ基である。］

[Wherein, R ¹ is an alkoxy group having 1 to 10 carbon atoms, and R ¹ ′ is a hydrogen atom or an alkoxy group having 1 to 10 carbon atoms. ]

The alkoxy group having 1 to 10 carbon atoms in the general formula (7) is the same as the alkoxy group exemplified in the description of R ^{1 to} R ⁶ and R ¹ ′ to R ⁶ ′ in the general formula (1). Things can be used.

  As the solvent used in the reaction 3, the same solvents as those exemplified in the description of the reaction 1 can be used, and among them, a halogenated hydrocarbon solvent is preferably used. The amount of the solvent used is preferably 1 to 100 parts by mass and more preferably 1 to 50 parts by mass with respect to 1 part by mass of the allylbinaphthyl derivative represented by the formula (4a).

It does not specifically limit as a metal catalyst used for the said reaction 3, The metal catalyst prepared by reaction of a metal complex and a ligand in the reaction system may be contained. As the ligand, for example, triphenylphosphine, trimethylphosphine, triethylphosphine, tris (n-butyl) phosphine, tris (tert-butyl) phosphine and the like are preferably used. Examples of the metal catalyst used in the above reaction 3 include PdCl ₂ , PdBr ₂ , Pd (OAc) ₂ , Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , Pd (dba) ₂ , Pd ₂ (dba) _3. , Pd (CF ₃ COO) ₂ , Pd (acac) ₂ , Pd (dppf) Cl ₂ , [Pd (allyl)] _{2 and} other palladium catalysts; NiCl ₂ , NiBr ₂ , NiCl ₂ (PPh ₃ ) _{2 and} other nickel catalysts A catalyst etc. are mentioned, A palladium catalyst is used suitably. Here, dba represents dibenzylideneacetone, acac represents acetylacetonate, and dppf represents diphenylphosphinoferrocene. Among palladium catalysts, palladium catalysts such as Pd (OAc) ₂ , Pd (PPh ₃ ) ₄ , [Pd (allyl)] ₂ , and Pd (dba) ₂ are more preferably used.

  The amount of the metal catalyst used in the reaction 3 is not particularly limited, and is preferably 0.001 to 0.1 mol with respect to 1 mol of the allyl binaphthyl derivative represented by the formula (4a). More preferably, it is 01-0.1 mol. The amount of N, N-dimethylbarbituric acid (NDMBA) used in the above reaction 3 is not particularly limited, and is 1 to 5 mol with respect to 1 mol of the allylbinaphthyl derivative represented by the formula (4a). Is preferable, and it is more preferable that it is 2-4 mol. The reaction temperature in the reaction 3 is preferably 30 to 100 ° C., and the reaction time in the reaction 3 is preferably 2 to 15 hours, and more preferably 5 to 10 hours. .

  Subsequently, as shown in the above reaction 4, the binaphthyl derivative represented by the formula (2a) is converted into a metal catalyst and 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxybiphenyl (RuPhos) in the presence of a base. Can be reacted with a salt of a 4-halogenopyridine derivative represented by the formula (3a) to obtain a pyridine derivative of the present invention represented by the formula (1a). That is, by reacting a binaphthyl derivative represented by the general formula (2) and a salt of a 4-halogenopyridine derivative represented by the general formula (3), a pyridine derivative represented by the general formula (1) or a salt thereof is produced. The method is a preferred embodiment of the present invention.

  As the solvent used in the above reaction 4, the same solvents as those exemplified in the description of the above reaction 1 can be used, and among them, hydrocarbon solvents and / or halogenated hydrocarbon solvents are preferably used. . The amount of the solvent used is preferably 1 to 100 parts by mass and more preferably 1 to 50 parts by mass with respect to 1 part by mass of the binaphthyl derivative represented by the formula (2a).

  Examples of the base used in the above reaction 4 include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium carbonate, lithium carbonate, potassium fluoride, cesium fluoride, cesium chloride, odor Cesium carbonate, cesium carbonate, potassium phosphate, methoxy sodium, t-butoxy potassium, t-butoxy sodium, t-butoxy lithium and the like, among which t-butoxy potassium, t-butoxy sodium, and potassium phosphate are included. At least one base selected from the group is preferably used. The amount of the base used is preferably 1 to 10 mol, and more preferably 2 to 5 mol, per 1 mol of the binaphthyl derivative represented by the formula (2a).

As the metal catalyst used in the reaction 4, the same metal catalyst as exemplified in the description of the reaction 3 can be used, and among them, a palladium catalyst is preferably used. Among palladium catalysts, palladium catalysts such as Pd (OAc) ₂ , Pd (PPh ₃ ) ₄ , [Pd (allyl)] ₂ , and Pd (dba) ₂ are more preferably used. The amount of the metal catalyst used in the reaction 4 is not particularly limited, and is preferably 0.001 to 0.1 mol with respect to 1 mol of the binaphthyl derivative represented by the formula (2a). More preferably, it is -0.1 mol.

  In the above reaction 4, 2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl (RuPhos) is preferably used. By using RuPhos, the target product can be obtained in high yield. The amount of RuPhos used in the reaction 4 is not particularly limited, and is preferably 0.001 to 0.1 mol with respect to 1 mol of the binaphthyl derivative represented by the formula (2a), and 0.01 to More preferably, it is 0.1 mol.

  As described above, in the reaction 4, the binaphthyl derivative represented by the formula (2a) is reacted with the salt of the 4-halogenopyridine derivative represented by the formula (3a), thereby the present invention represented by the formula (1a). The pyridine derivative can be obtained. Here, since the derivative represented by the formula (3a) is a salt, it has an advantage that it is excellent in handleability and stable. In the salt of the 4-halogenopyridine derivative represented by the formula (3a), X is a halogen atom, and examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. From the viewpoint that the reaction proceeds better, X is preferably a bromine atom. The present inventors have confirmed that the reaction does not easily proceed when X is a chlorine atom. Here, in the above reaction 4, since the reaction is performed in the presence of a base, the salt of the 4-halogenopyridine derivative represented by the formula (3a) exists as a 4-halogenopyridine compound in the reaction system, not as a salt. The reaction proceeds. The pyridine derivative of the present invention represented by the formula (1a) thus obtained is not a salt, but a salt of the pyridine derivative of the present invention can be obtained by adding an acid to react.

  The reaction temperature in the reaction 4 is preferably 50 to 120 ° C., and the reaction time in the reaction 4 is preferably 5 to 30 hours, and more preferably 10 to 20 hours. .

  Here, instead of the above reactions 1 to 4, as represented by the following chemical reaction formula (II), a binaphthyl derivative represented by the formula (6b) is used as a starting compound, and the reactions 1 ′ to 4 ′ represent the formula (1b). After obtaining the pyridine derivative shown, the pyridine derivative shown by the above formula (1a) can also be synthesized. As the reactions 1 'to 4', the same methods as in the reactions 1 to 4 are preferably employed.

As shown in the following reaction 5, to the pyridine derivative represented by the formula (1b), BBr ₃ was added and reacted at 0 ° C., triethylamine was further added and cooled to −78 ° C., and then anhydrous trifluoromethanesulfone. A pyridine derivative represented by the formula (1b ′) can be suitably synthesized by reacting at room temperature after adding an acid.

Is not particularly restricted but includes amount of BBr ₃ used in the above reaction 5, the relative pyridine derivative 1 mole of the formula (1b), is preferably from 1 to 5 mol, is 2-4 mole Is more preferable. The reaction temperature when the reaction is carried out using BBr ₃ is preferably −50 to 30 ° C., and the reaction time is preferably 1 to 10 hours.

  Moreover, it does not specifically limit as the usage-amount of the triethylamine used for the said reaction 5, It is preferable that it is 1-5 mol with respect to 1 mol of pyridine derivatives shown by Formula (1b), and is 2-4 mol. It is more preferable. Moreover, it does not specifically limit as the usage-amount of trifluoromethanesulfonic anhydride, It is preferable that it is 1-5 mol, and it is more preferable that it is 1-3 mol. The temperature at which trifluoromethanesulfonic anhydride is added is preferably −100 to −50 ° C., and more preferably −90 to −70 ° C. The reaction time is preferably 2 to 15 hours, and more preferably 5 to 10 hours.

Subsequently, as shown in the above Reaction 6, the pyridine derivative represented by the formula (1b ′) is reacted with PhB (OH) ₂ and a metal catalyst in the presence of a base to obtain the formula (1a). Can be synthesized.

  As the base used in the reaction 6, the same bases as exemplified in the description of the reaction 4 can be used. Moreover, as a metal catalyst used for the said reaction 6, the thing similar to the metal catalyst illustrated in description of the said reaction 3 can be used, A palladium catalyst is used suitably especially. The amount of the metal catalyst used in the above reaction 6 is not particularly limited, and is preferably 0.001 to 0.1 mol relative to 1 mol of the binaphthyl derivative represented by the formula (1b ′). More preferably, it is 01-0.1 mol.

  The reaction temperature in the reaction 6 is preferably 30 to 100 ° C., and the reaction time in the reaction 4 is preferably 5 to 30 hours, more preferably 10 to 20 hours. .

  The pyridine derivative of the present invention or a salt thereof obtained as described above is preferably used as an asymmetric catalyst. Specifically, it is suitably used for asymmetric synthesis reactions such as asymmetric acylation reaction, asymmetric nucleophilic addition reaction, asymmetric hydrogenation reaction, asymmetric cycloaddition reaction, asymmetric halogenation reaction and the like. As can be seen from Examples described later, the present inventors have confirmed that an optically active substance can be obtained with good enantioselectivity in an asymmetric nucleophilic addition reaction such as the Stegrich rearrangement reaction. Therefore, it can be seen that the pyridine derivative of the present invention or a salt thereof is very useful because an optically active substance suitably used for a chiral element or a pharmaceutical intermediate can be obtained with good enantioselectivity.

  Hereinafter, the present invention will be described more specifically with reference to examples.

Ar置換したナスフラスコに、文献（Kano, T. et al., Adv. Synth. Catal., 2007, 349, 556）に従って調製した(R)-2,2'-dimethyl-[1,1'-binaphthalen]-3-yl trifluoromethanesulfonate (1.27 g, 2.96 mmol)、phenylboronic acid (433 mg, 3.55 mmol)、1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (73 mg, 89 μmol)、aq. potassium phosphate (10 mL)、及びTHF (30 mL)を入れ、50℃で12時間攪拌した。反応混合液を室温に冷却後、H₂O (50 mL)に注ぎ、toluene (30 mL)で抽出後、brineで洗浄した。MgSO₄で乾燥し、エバポレータで溶媒を減圧留去して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: hexane/EtOAc = 20/1 to 10/1)で精製し、式（６ａ）で示される(S)-2,2'-dimethyl-3-phenyl-1,1'-binaphthalene (1.00 g, 2.81 mmol, 95% yield)を得た。Example 1
Synthesis Example 1 [Synthesis of binaphthyl derivative represented by formula (6a)]

(R) -2,2'-dimethyl- [1,1'- prepared in Ar substituted eggplant flask according to the literature (Kano, T. et al., Adv. Synth. Catal., 2007, 349, 556) binaphthalen] -3-yl trifluoromethanesulfonate (1.27 g, 2.96 mmol), phenylboronic acid (433 mg, 3.55 mmol), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (73 mg, 89 μmol) , Aq. Potassium phosphate (10 mL), and THF (30 mL) were added, and the mixture was stirred at 50 ° C. for 12 hours. The reaction mixture was cooled to room temperature, poured into H ₂ O (50 mL), extracted with toluene (30 mL), and washed with brine. It was dried over MgSO ₄ and the solvent was distilled off under reduced pressure with an evaporator to obtain a crude product. Purified by gradient silica gel column chromatography (SiO ₂ : hexane / EtOAc = 20/1 to 10/1), (S) -2,2′-dimethyl-3-phenyl-1,1 represented by the formula (6a) '-binaphthalene (1.00 g, 2.81 mmol, 95% yield) was obtained.

The physical property data of the binaphthyl derivative represented by the above formula (6a) are shown below.
Colorless solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ7.90 (t, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.85 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.51-7.44 (m, 4H), 7.44-7.37 (m, 3H), 7.27-7.20 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.03 (d , J = 7.8 Hz, 1H), 2.10 (s, 3H), 1.91 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 142.5, 141.4, 136.1, 135.8, 134.4, 132.9, 132.8, 132.4, 132.13, 132.10, 129.7, 128.9, 128.4, 128.2, 128.1, 128.0, 127.6, 127.0, 126.3, 126.2, 125.83, 125.79, 125.5, 125.1, 20.3, 18.3; HRMS (FAB ⁺ ) calcd.for C ₂₈ H ₂₃ [M + H ⁺ ] 359.1800, found 359.1813.

Ar置換したナスフラスコに、式（６ａ）で示される(S)-2,2'-dimethyl-3-phenyl-1,1'-binaphthalene (1.32 g, 3.67 mmol)、N-bromosuccinimide (NBS, 1.44 g, 8.08 mmol)、azobisisobutyronitrile (AIBN, 30 mg, 0.18 mmol)、及びbenzene (38 mL)を入れ、3時間加熱還流した。反応混合液を室温に冷却後、H₂O (50 mL)に注ぎ、toluene (30 mL)を加え抽出後、brineで洗浄した。MgSO₄で乾燥し、エバポレータで溶媒を減圧留去して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: トルエン)で精製し、式（５ａ）で示される(S)-2,2'-bis(bromomethyl)-3-phenyl-1,1'-binaphthalene (純度74%, 1.88 g)を得た。(Synthesis Example 2) [Synthesis of dibromobinaphthyl derivative represented by formula (5a)]

(S) -2,2'-dimethyl-3-phenyl-1,1'-binaphthalene (1.32 g, 3.67 mmol), N-bromosuccinimide (NBS, 1.44) represented by formula (6a) g, 8.08 mmol), azobisisobutyronitrile (AIBN, 30 mg, 0.18 mmol), and benzene (38 mL) were added and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into H ₂ O (50 mL), extracted with toluene (30 mL), and washed with brine. It was dried over MgSO ₄ and the solvent was distilled off under reduced pressure with an evaporator to obtain a crude product. Purified by gradient silica gel column chromatography (SiO ₂ : toluene), (S) -2,2′-bis (bromomethyl) -3-phenyl-1,1′-binaphthalene represented by the formula (5a) (purity 74% , 1.88 g) was obtained.

The physical property data of the dibromobinaphthyl derivative represented by the above formula (5a) are shown below.
Pale yellow foam. ¹ H NMR (600 MHz, CDCl ₃ ) δ8.04 (d, J = 8.4 Hz, 1H), 7.96-7.90 (m, 3H), 7.78 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 6.6 Hz, 2H), 7.54-7.44 (m, 5H), 7.33-7.27 (m, 2H), 7.16 (t, J = 8.7 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.39 (d, J = 10.2 Hz, 1H), 4.29 (d, J = 10.5 Hz, 1H), 4.25 (d, J = 10.5 Hz, 1H), 4.17 (d, J = 10.2 Hz, 1H) ; HRMS (FAB ⁺ ) calcd. For C ₂₈ H ₂₁ Br ₂ [M + H ⁺ ] 516.9992, found 516.9972.

Ar置換したナスフラスコに、式（５ａ）で示される(S)-2,2'-bis(bromomethyl)-3-phenyl-1,1'-binaphthalene (1.36 g, 2.62 mmol)、allylamine (0.65 mL, 8.66 mmol)、及びTHF (26 mL)を入れ、50℃で12時間加熱攪拌した。反応混合液を室温に冷却後、EtOAc (50 mL)を加えbrineで洗浄した。MgSO₄で乾燥し、エバポレータで溶媒を減圧留去して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: hexane/EtOAc = 10/1 to 2/1)で精製し、式（４ａ）で示される(S)-4-allyl-2-phenyl-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (711 mg, 1.72 mmol, 66% yield)を得た。(Synthesis Example 3) [Synthesis of allyl binaphthyl derivative represented by the formula (4a)]

(S) -2,2′-bis (bromomethyl) -3-phenyl-1,1′-binaphthalene (1.36 g, 2.62 mmol), allylamine (0.65 mL) represented by formula (5a) was added to an Ar-substituted eggplant flask. , 8.66 mmol) and THF (26 mL) were added, and the mixture was stirred with heating at 50 ° C. for 12 hours. The reaction mixture was cooled to room temperature, EtOAc (50 mL) was added, and the mixture was washed with brine. It was dried over MgSO ₄ and the solvent was distilled off under reduced pressure with an evaporator to obtain a crude product. Gradient column chromatography on silica gel and purified by _{(SiO 2 hexane / EtOAc = 10/1} to 2/1), represented by the formula (4a) (S) -4- allyl-2-phenyl-4,5-dihydro- 3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (711 mg, 1.72 mmol, 66% yield) was obtained.

The physical property data of the allyl binaphthyl derivative represented by the above formula (4a) are shown below.
Yellow solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ7.99-7.93 (m, 4H), 7.71 (bs, 2H), 7.55-7.45 (m, 6H), 7.43-7.39 (m, 2H), 7.29 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.28-7.23 (m, 1H), 5.82-5.74 (m, 1H), 5.02-4.94 (m, 2H), 3.91 (d, J = 12.0 Hz , 1H), 3.74 (d, J = 12.9 Hz, 1H), 3.47 (d, J = 12.9 Hz, 1H), 3.02 (dd, J = 13.4, 6.5 Hz, 1H), 2.86 (dd, J = 13.4, 6.5 Hz, 1H), 2.78 (d, J = 12.0 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 141.5, 140.6, 136.35, 136.32, 135.3, 133.2, 133.0, 132.8, 132.6, 131.6, 130.8 , 130.2, 129.4, 128.44, 128.41, 128.37, 128.3, 127.8, 127.70, 127.65, 127.2, 125.95, 125.89, 125.8, 125.5, 117.3, 58.5, 54.9, 51.4; HRMS (FAB ⁺ ) calcd.for C ₃₁ H ₂₆ N [M + H ⁺ ] 412.2065, found 412.2047.

Ar置換したナスフラスコに、式（４ａ）で示される(S)-4-allyl-2-phenyl-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (604 mg, 1.46 mmol)、N,N-dimethylbarbituric acid (NDMBA, 688 mg, 4.41 mmol)、palladium acetate(II) (6.6 mg, 29 μmol)、triphenylphosphine (31 mg, 0.12 mmol)、及びCH₂Cl₂ (15 mL)を入れ、8時間加熱還流した。反応混合液を室温に冷却後、toluene (30 mL)を加え、飽和炭酸水素ナトリウム水溶液で洗浄した。MgSO₄で乾燥し、エバポレータで溶媒を減圧留去して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: hexane/EtOAc = 2/1 to 1/20)で精製し、式（２ａ）で示されるビナフチル誘導体 (484 mg, 1.30 mmol, 89% yield)を得た。(Synthesis Example 4) [Synthesis of binaphthyl derivative represented by formula (2a)]

(S) -4-allyl-2-phenyl-4,5-dihydro-3H-dinaphtho [2,1-c: 1 ′, 2′-e] represented by formula (4a) was added to an Ar-substituted eggplant flask. azepine (604 mg, 1.46 mmol), N, N-dimethylbarbituric acid (NDMBA, 688 mg, 4.41 mmol), palladium acetate (II) (6.6 mg, 29 μmol), triphenylphosphine (31 mg, 0.12 mmol), and CH ₂ Cl ₂ (15 mL) was added and heated to reflux for 8 hours. The reaction mixture was cooled to room temperature, toluene (30 mL) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution. It was dried over MgSO ₄ and the solvent was distilled off under reduced pressure with an evaporator to obtain a crude product. The product was purified by gradient silica gel column chromatography (SiO ₂ : hexane / EtOAc = 2/1 to 1/20) to obtain a binaphthyl derivative (484 mg, 1.30 mmol, 89% yield) represented by the formula (2a).

The physical property data of the binaphthyl derivative represented by the above formula (2a) is shown below.
Orange solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ8.00-7.90 (m, 4H), 7.61 (bd, J = 7.2 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.52- 7.36 (m, 7H), 7.31-7.20 (m, 2H), 3.93 (d, J = 12.6 Hz, 1H), 3.88 (d, J = 12.6 Hz, 1H), 3.64 (d, J = 12.6 Hz, 1H ), 3.24 (d, J = 12.6 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 141.6, 140.1, 136.0, 135.3, 135.2, 133.4, 133.2, 132.6, 131.6, 130.9, 129.82, 129.75, 129.1 , 128.5, 128.45, 128.38, 127.62, 127.59, 127.3, 127.0, 126.0, 125.9, 125.8, 125.5, 49.1, 46.6; HRMS (FAB ⁺ ) calcd.for C ₂₈ H ₂₂ N [M + H ⁺ ] 372.1752, found 372.1768 .

Ar置換したネジ蓋付き試験管に、式（２ａ）で示されるビナフチル誘導体 (60 mg, 0.16 mmol)、式（３ａ）で示される4-bromopyridine hydrochloride (63 mg, 0.32 mmol)、NaOt-Bu (62 mg, 0.65 mmol)、2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos, 6.0 mg, 13 μmol)、palladium acetate(II) (1.5 mg, 6.5 μmol)、及びdimethoxyethane (1.6 mL)を入れ、90℃で15時間攪拌した。反応混合液を室温に冷却後、toluene (10 mL)とH₂O (10 mL)を加えてセライトろ過し、brineで洗浄した。MgSO₄で乾燥し、エバポレータで溶媒を減圧留去して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: EtOAc → CH₂Cl₂/MeOH = 5/1)で精製し、式（１ａ）で示される(S)-2-phenyl-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (60 mg, 0.13 mmol, 83% yield)を得た。(Synthesis Example 5) [Synthesis of pyridine derivative represented by formula (1a)]

In a test tube with an Ar-substituted screw cap, a binaphthyl derivative represented by the formula (2a) (60 mg, 0.16 mmol), 4-bromopyridine hydrochloride (63 mg, 0.32 mmol) represented by the formula (3a), NaOt-Bu ( 62 mg, 0.65 mmol), 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxybiphenyl (RuPhos, 6.0 mg, 13 μmol), palladium acetate (II) (1.5 mg, 6.5 μmol), and dimethoxyethane (1.6 mL) Stir at 90 ° C. for 15 hours. The reaction mixture was cooled to room temperature, added toluene (10 mL) and H ₂ O (10 mL), filtered through Celite, and washed with brine. It was dried over MgSO ₄ and the solvent was distilled off under reduced pressure with an evaporator to obtain a crude product. Purification by gradient silica gel column chromatography (SiO ₂ : EtOAc → CH ₂ Cl ₂ / MeOH = 5/1) and (S) -2-phenyl-4- (pyridin-4-yl) represented by the formula (1a) -4,5-dihydro-3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (60 mg, 0.13 mmol, 83% yield) was obtained.

The physical property data of the pyridine derivative represented by the above formula (1a) is shown below.
Pale yellow foam; ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09 (d, J = 5.7 Hz, 2H), 8.00-7.92 (m, 4H), 7.58-7.50 (m, 4H), 7.47 (d, J = 8.4 Hz, 1H), 7.42-7.20 (m, 7H), 6.37 (d, J = 5.7 Hz, 2H), 4.87 (d, J = 13.2 Hz, 1H), 4.66 (d, J = 12.6 Hz, 1H ), 3.97 (d, J = 12.6 Hz, 1H), 3.58 (d, J = 13.2 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 153.0, 149.9, 140.9, 140.0, 135.9, 135.5, 135.4 , 132.8, 132.7, 131.52, 131.48, 130.7, 129.9, 129.8, 129.5, 128.6, 128.50, 128.46, 127.7, 127.60, 127.55, 127.3, 126.5, 126.3, 126.2, 126.1, 108.5, 50.6, 46.0; IR (KBr) 3050 , 2362, 1592, 1507, 1233 cm -1;. HRMS (FAB +) calcd for C 33 H 25 N 2 [M + H +] 449.2018, found 449.1997.

Ar置換したナスフラスコに文献（Kano, T. et al., Adv. Synth. Catal., 2007, 349, 556）に従って合成した式（６ｂ）で示される(S)-3-methoxy-2,2'-dimethyl-1,1'-binaphthalene (811 mg, 2.60 mmol)、N-bromosuccinimide (1.02 g, 5.71 mmol)、azobisisobutyronitrile (21 mg, 0.13 mmol)、及びbenzene (13 mL)を入れ、2時間加熱還流した。反応混合液を室温に冷却後、H₂O (30 mL)に注ぎ、EtOAc (30 mL)を加え抽出後、brineで洗浄した。MgSO₄で乾燥し、エバポレータで溶媒を減圧留去して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: hexane/EtOAc = 20/1 to 10/1)で精製し、式（５ｂ）で示される(S)-2,2'-bis(bromomethyl)-3-methoxy-1,1'-binaphthalene (純度89%, 1.11 g, 2.38 mmol, 92% yield)を得た。Example 2
(Synthesis Example 6) [Synthesis of dibromobinaphthyl derivative represented by formula (5b)]

(S) -3-methoxy-2,2 represented by the formula (6b) synthesized according to the literature (Kano, T. et al., Adv. Synth. Catal., 2007, 349, 556) in an Ar-substituted eggplant flask. Add '-dimethyl-1,1'-binaphthalene (811 mg, 2.60 mmol), N-bromosuccinimide (1.02 g, 5.71 mmol), azobisisobutyronitrile (21 mg, 0.13 mmol), and benzene (13 mL) and heat for 2 hours. Refluxed. The reaction mixture was cooled to room temperature, poured into H ₂ O (30 mL), extracted with EtOAc (30 mL), and washed with brine. It was dried over MgSO ₄ and the solvent was distilled off under reduced pressure with an evaporator to obtain a crude product. Purified by gradient silica gel column chromatography (SiO ₂ : hexane / EtOAc = 20/1 to 10/1), and (S) -2,2′-bis (bromomethyl) -3-methoxy- represented by the formula (5b) 1,1'-binaphthalene (purity 89%, 1.11 g, 2.38 mmol, 92% yield) was obtained.

The physical property data of the pyridine derivative represented by the above formula (5b) is shown below.
Colorless foam. ¹ H NMR (600 MHz, CDCl ₃ ) δ8.02 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H) , 7.76 (d, J = 8.7 Hz, 1H), 7.51-7.43 (m, 2H), 7.34 (s, 1H), 7.28-7.24 (m, 1H), 7.14-7.10 (m, 1H), 7.08 (d , J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.41 (d, J = 9.6 Hz, 1H), 4.34 (d, J = 10.5 Hz, 1H), 4.24 (d, J = 10.5 Hz, 1H), 4.18 (d, J = 9.6 Hz, 1H), 4.12 (s, 3H); HRMS (FAB ⁺ ) calcd.for C ₂₃ H ₁₉ Br ₂ [M + H ⁺ ] 470.9784, found 470.9775 .

Ar置換したナスフラスコに、式（５ｂ）で示される(S)-2,2'-bis(bromomethyl)-3-methoxy-1,1'-binaphthalene (4.03 g, 8.57 mmol)、allylamine (2.12 mL, 28.3 mmol)、及びTHF (28 mL)を入れ、50℃で15時間加熱攪拌した。反応混合液を室温に冷却後、toluene (30 mL)を加えbrineで洗浄した。MgSO₄で乾燥し、エバポレータで溶媒を減圧留去して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: hexane/EtOAc = 5/1 to 1/1)で精製し、式（４ｂ）で示される(S)-4-allyl-2-methoxy-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (2.12 g, 5.80 mmol, 77% yield)を得た。(Synthesis Example 7) [Synthesis of allyl binaphthyl derivative represented by the formula (4b)]

(S) -2,2′-bis (bromomethyl) -3-methoxy-1,1′-binaphthalene (4.03 g, 8.57 mmol), allylamine (2.12 mL) represented by the formula (5b) was added to an Ar-substituted eggplant flask. , 28.3 mmol) and THF (28 mL) were added, and the mixture was heated and stirred at 50 ° C. for 15 hours. After cooling the reaction mixture to room temperature, toluene (30 mL) was added and washed with brine. It was dried over MgSO ₄ and the solvent was distilled off under reduced pressure with an evaporator to obtain a crude product. Purified by gradient silica gel column chromatography (SiO ₂ : hexane / EtOAc = 5/1 to 1/1) and represented by the formula (4b) (S) -4-allyl-2-methoxy-4,5-dihydro- 3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (2.12 g, 5.80 mmol, 77% yield) was obtained.

The physical property data of the allyl binaphthyl derivative represented by the above formula (4b) are shown below.
Colorless solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ7.99 (t, J = 8.1 Hz, 2H), 7.89 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H) , 7.56 (d, J = 9.0 Hz, 1H), 7.51-7.41 (m, 3H), 7.35 (s, 1H), 7.30 (bt, J = 7.8 Hz, 1H), 7.15 (bt, J = 7.8 Hz, 1H), 6.15-6.05 (m, 1H), 5.31 (d, J = 17.4 Hz, 1H), 5.26 (d, J = 9.6 Hz, 1H), 4.46 (d, J = 12.6 Hz, 1H), 4.06 ( s, 3H), 3.82 (d, J = 12.3 Hz, 1H), 3.30-3.22 (m, 2H), 3.12 (dd, J = 13.2, 6.0 Hz, 1H), 2.88 (d, J = 12.6 Hz, 1H ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 155.5, 137.2, 136.4, 134.9, 134.1, 133.6, 133.1 131.4, 128.4, 128.3, 127.8, 127.6, 127.5, 127.1, 126.9, 126.1, 126.0, 125.8, 125.4, 123.4, 117.7, 105.5, 58.8, 55.5, 55.0, 46.6; HRMS (FAB ⁺ ) calcd.for C ₂₆ H ₂₄ NO [M + H ⁺ ] 366.1858, found 366.1854.

Ar置換したナスフラスコに、式（４ｂ）で示される(S)-4-allyl-2-methoxy-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (2.12 g, 5.80 mmol)、N,N-dimethylbarbituric acid (2.72 g, 17.4 mmol)、palladium acetate(II) (26 mg, 0.12 mmol)、triphenylphosphine (122 mg, 0.46 mmol)、及びCH₂Cl₂ (29 mL)を入れ、6時間加熱還流した。反応混合液を室温に冷却後、CH₂Cl₂ (100 mL)を加え、飽和炭酸水素ナトリウム水溶液で洗浄し、MgSO₄で乾燥し、エバポレータで溶媒を減圧留去して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: 1 % Et₃N in EtOAc to EtOAc/MeOH 10/1 to 1/1)で精製し、式（２ｂ）で示される(S)-2-methoxy-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (1.77 g, 5.43 mmol, 94% yield)を得た。(Synthesis Example 8) [Synthesis of binaphthyl derivative represented by formula (2b)]

In an eggplant flask substituted with Ar, (S) -4-allyl-2-methoxy-4,5-dihydro-3H-dinaphtho [2,1-c: 1 ′, 2′-e] represented by the formula (4b) azepine (2.12 g, 5.80 mmol), N, N-dimethylbarbituric acid (2.72 g, 17.4 mmol), palladium acetate (II) (26 mg, 0.12 mmol), triphenylphosphine (122 mg, 0.46 mmol), and CH ₂ Cl ₂ (29 mL) was added and heated to reflux for 6 hours. The reaction mixture was cooled to room temperature, CH ₂ Cl ₂ (100 mL) was added, washed with saturated aqueous sodium hydrogen carbonate solution, dried over MgSO ₄ , and the solvent was distilled off under reduced pressure with an evaporator to obtain a crude product. . Purification by gradient silica gel column chromatography (SiO ₂ : 1% Et ₃ N in EtOAc to EtOAc / MeOH 10/1 to 1/1) and (S) -2-methoxy-4,5 represented by the formula (2b) -dihydro-3H-dinaphtho [2,1-c: 1 ', 2'-e] azepine (1.77 g, 5.43 mmol, 94% yield) was obtained.

The physical property data of the binaphthyl derivative represented by the above formula (2b) is shown below.
Orange solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ7.97 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 7.5, 1.5 Hz, 1H), 7.84 (bd, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.48-7.43 (m, 2H), 7.42 (ddd, J = 8.1, 6.8, 1.4 Hz, 1H), 7.33 (bd, J = 8.4 Hz, 1H ), 7.30 (s, 1H), 7.28-7.25 (m, 1H), 7.11 (ddd, J = 8.1, 6.8, 1.4 Hz, 1H), 4.48 (d, J = 12.9 Hz, 1H), 4.03 (s, 3H), 3.83 (d, J = 12.0 Hz, 1H), 3.50 (d, J = 12.0 Hz, 1H), 3.06 (d, J = 12.9 Hz, 1H), 1.85 (bs, 1H); HRMS (FAB ⁺ ) calcd.for C ₂₃ H ₂₀ NO [M + H ⁺ ] 326.1545, found 326.1561.

Ar置換したナスフラスコに、式（２ｂ）で示される(S)-2-methoxy-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (1.66 g, 5.06 mmol)、式（３ａ）で示される4-bromopyridine hydrochloride (1.97 g, 10.1 mmol)、NaOt-Bu (1.95 g, 20.2 mmol)、2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (94 mg, 0.20 mmol)、bis(dibenzylideneacetone)palladium(0) (57 mg, 0.10 mmol)、及びtoluene (25 mL)を入れ、90℃で15時間攪拌した。反応混合液を室温に冷却後、toluene (50 mL)とH₂O (50 mL)を加えてセライトろ過し、brineで洗浄してMgSO₄で乾燥し、エバポレータで溶媒を減圧留去して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: EtOAc→CH₂Cl₂/MeOH = 1/0 to 2/1)で精製し、式（１ｂ）で示される(S)-2-methoxy-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (1.61 g, 4.00 mmol, 79% yield)を得た。(Synthesis Example 9) [Synthesis of pyridine derivative represented by formula (1b)]

(S) -2-methoxy-4,5-dihydro-3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (1.66 g) represented by the formula (2b) , 5.06 mmol), 4-bromopyridine hydrochloride (1.97 g, 10.1 mmol), NaOt-Bu (1.95 g, 20.2 mmol), 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxybiphenyl (94 mg, 0.20 mmol), bis (dibenzylideneacetone) palladium (0) (57 mg, 0.10 mmol), and toluene (25 mL) were added, and the mixture was stirred at 90 ° C. for 15 hours. The reaction mixture was cooled to room temperature, added toluene (50 mL) and H ₂ O (50 mL), filtered through Celite, washed with brine, dried over MgSO ₄ , and the solvent was evaporated under reduced pressure using an evaporator. The product was obtained. Purification by gradient silica gel column chromatography (SiO ₂ : EtOAc → CH ₂ Cl ₂ / MeOH = 1/0 to 2/1) and (S) -2-methoxy-4- (pyridin- represented by the formula (1b) 4-yl) -4,5-dihydro-3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (1.61 g, 4.00 mmol, 79% yield) was obtained.

The physical property data of the pyridine derivative represented by the above formula (1b) is shown below.
Pale brown solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ8.27 (dd, J = 5.3, 1.7 Hz, 2H), 7.95 (dd, J = 8.1, 2.1 Hz, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.55-7.47 (m, 3H), 7.45 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.31 (ddd, J = 8.4 , 7.1, 1.4 Hz, 1H), 7.28 (s, 1H), 7.15 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 6.79 (dd, J = 5.3, 1.7 Hz, 2H), 5.40 (d, J = 13.2 Hz, 1H), 4.59 (d, J = 12.6 Hz, 1H), 3.95 (s, 3H), 3.78 (d, J = 12.6 Hz, 1H), 3.41 (d, J = 13.2 Hz, 1H) ; ¹³ C NMR (150 MHz, CDCl ₃ ) δ 154.7, 153.6, 150.1, 137.0, 135.2, 134.3, 133.4, 132.9, 131.5, 129.4, 128.4, 127.65, 127.57, 127.56, 127.3, 126.8, 126.6, 126.3, 126.1, 125.6, 123.9, 108.7, 106.3, 55.8, 50.8, 41.3; HRMS (FAB ⁺ ) calcd.for C ₂₈ H ₂₃ N ₂ O [M + H ⁺ ] 403.1810, found 403.1802.

Ar置換したナスフラスコに、式（１ｂ）で示される(S)-2-methoxy-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (80 mg, 0.20 mmol)、及びCH₂Cl₂ (2.0 mL)を入れ、0℃に冷却後、boron tribromide (1.0 M in CH₂Cl₂ solution, 0.48 mL, 0.48 mmol)を滴下した。0℃で３時間攪拌後、反応混合液をMeOH (20 mL)に注ぎ入れ、エバポレータで溶媒を減圧留去した。残渣の入ったナスフラスコをAr置換後、triethylamine (84 μL, 0.60 mmol)、及びCH₂Cl₂(2.0 mL)を加え、-78℃に冷却した。trifluoromethanesulfonic Anhydride (39 μL, 0.24 mmol)を加えた後、室温で8時間攪拌した。反応混合液に飽和塩化アンモニウム水溶液 (5 mL)、及びCH₂Cl₂ (20 mL)を加えた後、有機層を飽和炭酸水素ナトリウム水溶液で洗浄した。MgSO₄で乾燥し、エバポレータで溶媒を減圧留去して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: EtOAc→1% Et₃N in EtOAc)で精製し、式（１ｂ’）で示される(S)-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepin-2-yl trifluoromethanesulfonate (75 mg, 0.14 mmol, 72% yield)を得た。(Synthesis Example 10) [Synthesis of a pyridine derivative represented by the formula (1b ′)]

To an eggplant flask substituted with Ar, (S) -2-methoxy-4- (pyridin-4-yl) -4,5-dihydro-3H-dinaphtho [2,1-c: 1 ′ represented by the formula (1b) , 2'-e] azepine (80 mg, 0.20 mmol) and CH ₂ Cl ₂ (2.0 mL), after cooling to 0 ° C, boron tribromide (1.0 M in CH ₂ Cl ₂ solution, 0.48 mL, 0.48 mmol ) Was added dropwise. After stirring at 0 ° C. for 3 hours, the reaction mixture was poured into MeOH (20 mL), and the solvent was distilled off under reduced pressure with an evaporator. The eggplant flask containing the residue was substituted with Ar, triethylamine (84 μL, 0.60 mmol) and CH ₂ Cl ₂ (2.0 mL) were added, and the mixture was cooled to −78 ° C. After adding trifluoromethanesulfonic Anhydride (39 μL, 0.24 mmol), the mixture was stirred at room temperature for 8 hours. A saturated aqueous ammonium chloride solution (5 mL) and CH ₂ Cl ₂ (20 mL) were added to the reaction mixture, and then the organic layer was washed with a saturated aqueous sodium bicarbonate solution. It was dried over MgSO ₄ and the solvent was distilled off under reduced pressure with an evaporator to obtain a crude product. Purification by gradient silica gel column chromatography (SiO ₂ : EtOAc → 1% Et ₃ N in EtOAc) and (S) -4- (pyridin-4-yl) -4,5-dihydro represented by the formula (1b ′) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepin-2-yl trifluoromethanesulfonate (75 mg, 0.14 mmol, 72% yield) was obtained.

The physical property data of the pyridine derivative represented by the above formula (1b ′) is shown below.
Yellow solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ8.31 (d, J = 5.4 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 7.98 (dd, J = 8.1, 5.7 Hz, 2H), 7.93 (s, 1H), 7.60 (bt, J = 7.5 Hz, 1H), 7.57-7.50 (m, 3H), 7.43 (d, J = 9.0 Hz, 1H), 7.40-7.33 (m, 2H ), 6.77 (bd, J = 5.4 Hz, 2H), 5.13 (d, J = 13.5 Hz, 1H), 4.64 (d, J = 12.9 Hz, 1H), 3.78 (d, J = 12.9 Hz, 1H), 3.64 (d, J = 13.5 Hz, 1H); HRMS (FAB ⁺ ) calcd.for C ₂₈ H ₂₀ F ₃ N ₂ O ₃ S [M + H ⁺ ] 521.1147, found 521.1130.

Ar置換したナスフラスコに、式（１ｂ’）で示される(S)-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepin-2-yl trifluoromethanesulfonate (38 mg, 73 μmol)、phenylboronic acid (11 mg, 88 μmol)、1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (3.0 mg, 3.7 μmol)、aq. potassium phosphate (0.2 mL)、及びTHF (0.7 mL)を入れ、50℃で18時間攪拌した。反応混合液を室温に冷却後、H₂O (20 mL)に注ぎ、toluene (20 mL)で抽出後、brineで洗浄した。MgSO₄で乾燥し、エバポレータで溶媒を減圧留去して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: CH₂Cl₂/EtOAc = 8/1 to 4/1)で精製し、式（１ａ）で示される(S)-2-phenyl-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (純度80%, 33 mg)を得た。(Synthesis Example 11) [Synthesis of pyridine derivative represented by formula (1a)]

In an eggplant flask substituted with Ar, (S) -4- (pyridin-4-yl) -4,5-dihydro-3H-dinaphtho [2,1-c: 1 ′, 2 ′ represented by the formula (1b ′) -e] azepin-2-yl trifluoromethanesulfonate (38 mg, 73 μmol), phenylboronic acid (11 mg, 88 μmol), 1,1'-Bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (3.0 mg, 3.7 μmol), aq. potassium phosphate (0.2 mL), and THF (0.7 mL) were added, and the mixture was stirred at 50 ° C. for 18 hours. The reaction mixture was cooled to room temperature, poured into H ₂ O (20 mL), extracted with toluene (20 mL), and washed with brine. It was dried over MgSO ₄ and the solvent was distilled off under reduced pressure with an evaporator to obtain a crude product. Purification by gradient silica gel column chromatography (SiO ₂ : CH ₂ Cl ₂ / EtOAc = 8/1 to 4/1) and (S) -2-phenyl-4- (pyridin-4-) represented by the formula (1a) yl) -4,5-dihydro-3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (purity 80%, 33 mg) was obtained.

Ar置換したネジ蓋付き試験管に、式（２ｃ）で示されるビナフチル誘導体(58 mg, 0.16 mmol)、式（３ａ）で示される4-bromopyridine hydrochloride (50.9 mg, 0.26 mmol)、NaOt-Bu (75.1 mg, 0.78 mmol)、2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (Ruphos) (4.9 mg, 10.5 μmol)、bis(dibenzylideneacetone)palladium(0) (3.0 mg, 5.2 μmol)、及びトルエン (1.3 mL)を入れ、90℃で24時間攪拌した。反応混合液にH₂O (2 mL)を加えてセライトろ過し、トルエンで抽出してbrineで洗浄し、MgSO₄で乾燥し、エバポレータで溶媒を濃縮して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: hexane/EtOAc = 5/1(v/v) to 1%Et₃N to EtOAc + 1%Et₃N)で精製し、式（１ｃ）で示される(S)- 2,6-diphenyl-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (41.8 mg, 0.80 mmol, 61% yield)を得た。Example 3
(Synthesis Example 12) [Synthesis of pyridine derivative represented by formula (1c)]

In a test tube with an Ar-substituted screw cap, a binaphthyl derivative represented by the formula (2c) (58 mg, 0.16 mmol), 4-bromopyridine hydrochloride (50.9 mg, 0.26 mmol) represented by the formula (3a), NaOt-Bu ( 75.1 mg, 0.78 mmol), 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxybiphenyl (Ruphos) (4.9 mg, 10.5 μmol), bis (dibenzylideneacetone) palladium (0) (3.0 mg, 5.2 μmol), and toluene (1.3 mL) ) And stirred at 90 ° C. for 24 hours. H ₂ O (2 mL) was added to the reaction mixture, and the mixture was filtered through Celite, extracted with toluene, washed with brine, dried over MgSO ₄ , and the solvent was concentrated with an evaporator to obtain a crude product. Purification by gradient silica gel column chromatography (SiO ₂ : hexane / EtOAc = 5/1 (v / v) to 1% Et ₃ N to EtOAc + 1% Et ₃ N) (S) represented by the formula (1c) -2,6-diphenyl-4- (pyridin-4-yl) -4,5-dihydro-3H-dinaphtho [2,1-c: 1 ', 2'-e] azepine (41.8 mg, 0.80 mmol, 61 % yield).

The physical property data of the pyridine derivative represented by the above formula (1c) is shown below.
Colorless solid.mp 143-144 ° C; [α] _D ²⁰ -170.3 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97-7.95 (m, 6H), 7.55-7.31 (m, 16H), 6.03 (dd, J = 5.2, 1.6 Hz, 2H), 4.88 (d, J = 12.6 Hz, 2H), 3.66 (d, J = 12.6 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 152.3, 149.4, 140.7, 139.8, 136.2, 132.7, 131.1, 130.7, 129.9, 129.7, 128.5, 128.3, 127.6, 127.4, 126.4, 126.1, 108.3, 45.8; IR (KBr) 3053, 2925, 2852, 2360, 1593, 703 cm ^-1 ; HRMS (FAB ⁺ ) [M + H] ⁺ calcd. For C ₃₉ H ₂₉ N ₂ 525.2331, found 525.2331.

Ar置換したナスフラスコに、文献（Ooi, T. et al., J. Am. Chem. Soc. 2003, 125, 5139）に従って合成した式（６ｄ）で示される(S)-3,3’-dimethoxy-2,2'-dimethyl-1,1'-binaphthalene (6.19 g, 18.1 mmol)、N-bromosuccinimide (7.08 g, 39.8 mmol)、azobisisobutyronitrile (297 mg, 1.81 mmol)、及びbenzene (90.5 mL)を入れ、90℃で7時間攪拌した。反応混合液にH₂O (80 mL)を加えてトルエン (30 mL × 2)で抽出し、有機層を飽和重曹水、brineで洗浄し、MgSO₄で乾燥し、エバポレータで溶媒を濃縮して粗生成物を得た。再結晶 (CH₂Cl₂/hexane)で精製し、式（５ｄ）で示される(S)-2,2'-bis(bromomethyl)-3,3’-dimethoxy-1,1'-binaphthalene (7.39 g, 14.8 mmol, 82% yield)を得た。Example 4
(Synthesis Example 13) [Synthesis of dibromobinaphthyl derivative represented by formula (5d)]

(S) -3,3′- represented by the formula (6d) synthesized in accordance with the literature (Ooi, T. et al., J. Am. Chem. Soc. 2003, 125, 5139) in an Ar-substituted eggplant flask. dimethoxy-2,2'-dimethyl-1,1'-binaphthalene (6.19 g, 18.1 mmol), N-bromosuccinimide (7.08 g, 39.8 mmol), azobisisobutyronitrile (297 mg, 1.81 mmol), and benzene (90.5 mL) The mixture was stirred at 90 ° C. for 7 hours. H ₂ O (80 mL) was added to the reaction mixture, and the mixture was extracted with toluene (30 mL × 2). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO ₄ , and the solvent was concentrated with an evaporator. A crude product was obtained. (S) -2,2′-bis (bromomethyl) -3,3′-dimethoxy-1,1′-binaphthalene (7.39) represented by the formula (5d) is purified by recrystallization (CH ₂ Cl ₂ / hexane). g, 14.8 mmol, 82% yield).

The physical property data of the dibromobinaphthyl derivative represented by the above formula (5d) is shown below.
Colorless solid. [Α] _D ²⁰ -163.5 (c 0.22, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (d, J = 8.3 Hz, 2H), 7.44 (ddd, J = 8.3, 7.1 , 1.4 Hz, 2H), 7.33 (s, 2H), 7.11 (ddd, J = 8.3, 7.1, 1.4 Hz, 2H), 6.99 (bd, J = 8.3Hz, 2H), 4.35-4.26 (m, 4H) , 4.11 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ155.5, 136.4, 127.7, 127.3, 127.2, 126.7, 126.6, 124.1, 106.4, 55.8, 27.8; IR (KBr) 3060. 2935, 1599, 1170, 750 cm ^-1 ; HRMS (FAB ⁺ ) [M + H] ⁺ calcd. For C ₂₄ H ₂₁ Br ₂ O ₂ 500.9889, found 500.9881.

Ar置換したナスフラスコに、式（５ｄ）で示される(S)-2,2'-bis(bromomethyl)-3,3’-dimethoxy-1,1'-binaphthalene (1.58 g, 3.16 mmol)、allylamine (781 μL, 10.4 mmol)、アセトニトリル (31.6 mL)、及びトルエン (10.5 mL)を入れ、50℃で20時間攪拌した。反応混合液にH₂O (50 mL)を加えて酢酸エチル (50 mL × 2)で抽出し、有機層をH₂O (30 mL × 2)、brineで洗浄し、MgSO₄で乾燥し、エバポレータで溶媒を濃縮して式（４ｄ）で示されるアリルビナフチル誘導体の粗生成物を得た。粗生成物はそのまま次の反応に用いた。なお化合物分析用に粗生成物の一部をグラディエントシリカゲルカラムクロマトグラフィー (SiO₂: hexane/EtOAc = 3/1(v/v) to hexane/EtOAc = 2/1(v/v))で精製した。(Synthesis Example 14) [Synthesis of allyl binaphthyl derivative represented by the formula (4d)]

(S) -2,2′-bis (bromomethyl) -3,3′-dimethoxy-1,1′-binaphthalene (1.58 g, 3.16 mmol) represented by formula (5d), allylamine (781 μL, 10.4 mmol), acetonitrile (31.6 mL), and toluene (10.5 mL) were added, and the mixture was stirred at 50 ° C. for 20 hours. H ₂ O (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2) .The organic layer was washed with H ₂ O (30 mL × 2), brine, dried over MgSO ₄ The solvent was concentrated with an evaporator to obtain a crude product of an allylbinaphthyl derivative represented by the formula (4d). The crude product was used for the next reaction as it was. A part of the crude product was purified by gradient silica gel column chromatography (SiO ₂ : hexane / EtOAc = 3/1 (v / v) to hexane / EtOAc = 2/1 (v / v)) for compound analysis. .

The physical property data of the allyl binaphthyl derivative represented by the above formula (4d) is shown below.
Colorless solid. [Α] _D ²⁰ +438.8 (c 0.23, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, J = 8.3 Hz, 2H), 7.41 (ddd, J = 8.3, 6.8 , 1.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.28 (s, 2H), 7.10 (ddd, J = 8.3, 6.8, 1.3 Hz, 2H), 6.08-5.98 (m, 1H) , 5.23-5.14 (m, 2H), 4.36 (d, J = 12.4 Hz, 2H), 4.02 (s, 6H), 3.25 (dd, J = 13.2, 6.7 Hz, 1H), 2.98 (dd, J = 13.2 , 6.7 Hz, 1H), 2.78 (d, J = 12.4 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 155.4, 137.0, 136.4, 134.0, 127.5, 127.0, 126.8, 126.2, 125.9, 123.3, 117.3, 105.5, 59.0, 55.4, 46.6; IR (KBr) 2950, 2827, 1596, 1226, 752 cm ^-1 ; HRMS (FAB ⁺ ) [M + H] ⁺ calcd. For C ₂₇ H ₂₆ NO ₂ 396.1964, found 396.1967.

Ar置換した２ツ口フラスコに、式（４ｄ）で示されるアリルビナフチル誘導体の粗生成物、palladium(II) acetate (34.5 mg, 0.153 mmol)、triphenylphosphine (160 mg, 0.608 mmol)、1,3-dimethylbarbituric acid (NDMBA) (1.43 g, 9.15 mmol)、及びCH₂Cl₂ (30.4 mL)を入れ、40℃で13時間攪拌した。反応混合液に飽和重曹水(30 mL)を加えて、飽和重曹水、brineで洗浄し、MgSO₄で乾燥し、エバポレータで溶媒を濃縮して式（２ｄ）で示されるビナフチル誘導体の粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: EtOAc→1% Et₃N in EtOAc)で精製し、式（２ｄ）で示されるビナフチル誘導体 (1.08 g, 3.04 mmol, 96% yield)を得た。(Synthesis Example 15) [Synthesis of binaphthyl derivative represented by formula (2d)]

In an Ar-substituted two-necked flask, a crude product of an allylbinaphthyl derivative represented by the formula (4d), palladium (II) acetate (34.5 mg, 0.153 mmol), triphenylphosphine (160 mg, 0.608 mmol), 1,3- Dimethylbarbituric acid (NDMBA) (1.43 g, 9.15 mmol) and CH ₂ Cl ₂ (30.4 mL) were added and stirred at 40 ° C. for 13 hours. Saturated aqueous sodium bicarbonate (30 mL) was added to the reaction mixture, washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO ₄ , and the solvent was concentrated with an evaporator to give a crude product of the binaphthyl derivative represented by the formula (2d) Got. Purification by gradient silica gel column chromatography (SiO ₂ : EtOAc → 1% Et ₃ N in EtOAc) gave the binaphthyl derivative (1.08 g, 3.04 mmol, 96% yield) represented by the formula (2d).

The physical property data of the binaphthyl derivative represented by the above formula (2d) is shown below.
^{_{. Orange solid [α] D 20}} +388.5 (c 0.20, CHCl 3); 1 H NMR (400 MHz, CDCl 3) δ 7.83 (d, J = 8.3 Hz, 2H), 7.41 (ddd, J = 8.3, 6.8 , 1.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.29 (s, 2H), 7.11 (ddd, J = 8.3, 6.8, 1.3 Hz, 2H), 4.47 (d, J = 12.0 Hz , 2H), 4.03 (s, 6H), 3.04 (d, J = 12.0 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.8, 136.9, 133.9, 127.5, 127.3, 127.0, 126.8, 125.9, 123.4, 105.8, 55.5, 39.9; IR (KBr) 2934, 1595, 1231, 832, 748 cm ^-1 ; HRMS (FAB ⁺ ) [M + H] ⁺ calcd.for C ₂₄ H ₂₂ NO ₂ 356.1651, found 356.1661.

Ar置換したナスフラスコに、式（２ｄ）で示されるビナフチル誘導体(732.9 mg, 2.06 mmol)、式（３ａ）で示される4-bromopyridine hydrochloride (801.0 mg, 4.12 mmol)、NaOt-Bu (1.192 g, 12.4 mmol)、RuPhos (77.2 mg, 0.17 mmol)、bis(dibenzylideneacetone)palladium(0) (47.4 mg, 82.4 μmol)、及びトルエン (20.6 mL)を入れ、90℃で23時間攪拌した。反応混合液にH₂O (20 mL)を加えてセライトろ過し、トルエンで抽出してbrineで2回洗浄し、MgSO₄で乾燥し、エバポレータで溶媒を濃縮して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー(SiO₂: EtOAc to 2%Et₃N in EtOAc)で精製し、式（１ｄ）で示される(S)-2,6-dimethoxy-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (638.8 mg, 1.48 mmol, 72% yield)を得た。(Synthesis Example 16) [Synthesis of pyridine derivative represented by formula (1d)]

In an Ar-substituted eggplant flask, a binaphthyl derivative represented by the formula (2d) (732.9 mg, 2.06 mmol), 4-bromopyridine hydrochloride (801.0 mg, 4.12 mmol) represented by the formula (3a), NaOt-Bu (1.192 g, 12.4 mmol), RuPhos (77.2 mg, 0.17 mmol), bis (dibenzylideneacetone) palladium (0) (47.4 mg, 82.4 μmol), and toluene (20.6 mL) were added and stirred at 90 ° C. for 23 hours. H ₂ O (20 mL) was added to the reaction mixture, and the mixture was filtered through Celite, extracted with toluene, washed twice with brine, dried over MgSO ₄ , and the solvent was concentrated with an evaporator to obtain a crude product. (S) -2,6-dimethoxy-4- (pyridin-4-yl)-represented by the formula (1d) is purified by gradient silica gel column chromatography (SiO ₂ : EtOAc to 2% Et ₃ N in EtOAc). 4,5-dihydro-3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (638.8 mg, 1.48 mmol, 72% yield) was obtained.

The physical property data of the pyridine derivative represented by the above formula (1d) is shown below.
[Α] _D ²⁰ -293.7 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (dd, J = 5.2, 1.5 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.46-7.43 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.28 (s, 2H), 7.15 (ddd, J = 8.4, 7.2, 1.2 Hz, 2H), 6.85 (dd, J = 5.2, 1.5 Hz, 2H), 5.38 (d, J = 12.6 Hz, 2H), 3.96 (s, 6H), 3.36 (d, J = 12.6 Hz, 2H); ¹³ C NMR (100 MHz _{, CDCl 3) δ 154.5, 153.8} , 149.5, 137.1, 134.2, 127.5, 127.1, 126.7, 126.5, 125.7, 123.8, 108.8, 106.2, 55.7, 41.2; IR (KBr) 3421, 3003, 2937, 1507, 749 cm - ¹ ; HRMS (FAB ⁺ ) [M + H] ⁺ calcd.for C ₂₉ H ₂₅ N ₂ O ₂ 433.1916, found 433.1913.

Ar置換した２ツ口ナスフラスコに、式（１ｄ）で示される(S)-2,6-dimethoxy-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (86.3 mg, 0.200 mmol)、及び塩化メチレン (2.0 mL)を入れ、0℃に冷却し、BBr₃ (ca. 1.0 M CH₂Cl₂ solution) (0.72 mL, 0.72 mmol)を入れ、0℃で4時間攪拌した。反応混合液をメタノール (30 mL)に移し、エバポレータで溶媒を濃縮して粗生成物を得た。Ar置換した２ツ口ナスフラスコに、粗生成物、塩化メチレン (2.0 mL)、triethylamine (139 μL, 1.0 mmol)を入れ、-78℃に冷却してtrifluoromethanesulfonic anhydride (78.7 μL, 0.48 mmol)を加えた後、室温で13時間攪拌した。反応混合液にH₂O (5 mL)を加えて塩化メチレン (5 mL × 2)で抽出し、H₂O (5 mL)、brineで洗浄し、MgSO₄で乾燥し、エバポレータで溶媒を濃縮して粗生成物を得た。シリカゲルカラムクロマトグラフィー (SiO₂: hexane/EtOAc = 1/1(v/v))で精製し、式（１ｄ’）で示されるピリジン誘導体 (99.7 mg, 0.149 mmol, 75% yield)を得た。(Synthesis Example 17) [Synthesis of pyridine derivative represented by formula (1d ′)]

(S) -2,6-dimethoxy-4- (pyridin-4-yl) -4,5-dihydro-3H-dinaphtho [2,1] represented by the formula (1d) was added to an Ar-substituted two-necked eggplant flask. -c: 1 ', 2'-e] azepine (86.3 mg, 0.200 mmol) and methylene chloride (2.0 mL) were added, cooled to 0 ° C, and BBr ₃ (ca. 1.0 M CH ₂ Cl ₂ solution) ( 0.72 mL, 0.72 mmol) was added, and the mixture was stirred at 0 ° C. for 4 hours. The reaction mixture was transferred to methanol (30 mL), and the solvent was concentrated with an evaporator to obtain a crude product. Ar-substituted two-necked eggplant flask was charged with crude product, methylene chloride (2.0 mL), triethylamine (139 μL, 1.0 mmol), cooled to −78 ° C. and trifluoromethanesulfonic anhydride (78.7 μL, 0.48 mmol) was added. Then, the mixture was stirred at room temperature for 13 hours. Add H ₂ O (5 mL) to the reaction mixture, extract with methylene chloride (5 mL × 2), wash with H ₂ O (5 mL), brine, dry over MgSO ₄ and concentrate the solvent with an evaporator. To obtain a crude product. Purification by silica gel column chromatography (SiO ₂ : hexane / EtOAc = 1/1 (v / v)) gave a pyridine derivative represented by the formula (1d ′) (99.7 mg, 0.149 mmol, 75% yield).

The physical property data of the pyridine derivative represented by the above formula (1d ′) is shown below.
Colorless solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ8.33 (d, J = 6.0 Hz, 2H), 8.01 (bd, J = 7.6 Hz, 4H), 7.64 (ddd, J = 8.0, 6.0, 2.1 Hz, 2H), 7.46-7.41 (m, 4H), 6.79 (d, J = 6.0 Hz, 2H), 5.15 (d, J = 13.6 Hz, 2H), 3.59 (d, J = 13.6 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 152.9, 150.3, 144.5, 137.6, 133.2, 130.3, 128.8, 128.3, 128.1, 127.5, 126.0, 121.3, 118.7 (q, J = 318.4 Hz), 108.9, 42.7; HRMS (FAB ⁺ ) [M + H] ⁺ calcd. For C ₂₉ H ₁₉ F ₆ N ₂ O ₆ S ₂ 669.0589, found 669.0582.

Ar置換した２ツ口ナスフラスコに、文献（特開２００２−３２６９９２号公報）に従って合成した式（２ｅ）で示されるビナフチル誘導体 (201 mg, 0.367 mmol)、式（３ａ）で示される4-bromopyridine hydrochloride (143 mg, 0.734 mmol)、NaOt-Bu (212 mg, 2.21 mmol)、RuPhos (13.7 mg, 29.4 μmol)、bis(dibenzylideneacetone)palladium(0) (8.6 mg, 15.0 μmol)、及びトルエン (3.7 mL)を入れ、90℃で24時間攪拌した。反応混合液にクロロホルム (10 mL)、H₂O (5 mL)を加えてセライトろ過し、クロロホルムで抽出し、brineで2回洗浄してMgSO₄で乾燥し、エバポレータで溶媒を濃縮して粗生成物を得た。再結晶 (CHCl₃/hexane)で精製し、式（１ｅ）で示される(S)-2,6-di(naphthalen-2-yl)-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (187.4 mg, 0.300 mmol, 82% yield)を得た。Example 5
(Synthesis Example 18) [Synthesis of pyridine derivative represented by formula (1e)]

A binaphthyl derivative (201 mg, 0.367 mmol) represented by the formula (2e) and 4-bromopyridine represented by the formula (3a) synthesized according to the literature (Japanese Patent Laid-Open No. 2002-326992) were placed in an Ar-substituted two-necked eggplant flask. hydrochloride (143 mg, 0.734 mmol), NaOt-Bu (212 mg, 2.21 mmol), RuPhos (13.7 mg, 29.4 μmol), bis (dibenzylideneacetone) palladium (0) (8.6 mg, 15.0 μmol), and toluene (3.7 mL) ) And stirred at 90 ° C. for 24 hours. Chloroform (10 mL) and H ₂ O (5 mL) were added to the reaction mixture, and the mixture was filtered through Celite, extracted with chloroform, washed twice with brine, dried over MgSO ₄ , and the solvent was concentrated with an evaporator. The product was obtained. (S) -2,6-di (naphthalen-2-yl) -4- (pyridin-4-yl) -4,5- represented by the formula (1e) after purification by recrystallization (CHCl ₃ / hexane) Dihydro-3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (187.4 mg, 0.300 mmol, 82% yield) was obtained.

The physical property data of the pyridine derivative represented by the above formula (1e) is shown below.
Colorless solid.mp> 280 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 2H), 7.99 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.2 Hz, 4H), 7.83 (bd, J = 4.8 Hz, 4H), 7.57-7.49 (m, 10H), 7.36 (ddd, J = 8.2, 7.2, 1.4 Hz, 4H), 6.05 (d, J = 6.0 Hz, 2H), 4.96 (bd, J = 9.6 Hz, 2H), 3.79 (bd, J = 12.6 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 152.2, 149.4, 139.8, 136.2, 133.1, 132.8, 132.4, 131.3, 130.7, 130.3, 128.7, 128.6, 128.4, 128.3, 128.1, 128.0, 127.9, 127.7, 126.6, 126.5, 126.3, 126.2, 108.4, 46.1; IR (KBr) 3053, 2866, 2359, 1589, 749 cm ^-1 ; HRMS (FAB ⁺ ) [M + H] ⁺ calcd. For C ₄₇ H ₃₃ N ₂ 625.2644, found 625.2662.

Ar置換したネジ蓋付き試験管に文献（Akhatou, A. et al., Tetrahedron 2007, 63, 6232; Ooi, T. et al., J. Am. Chem. Soc. 1999, 121, 6519）に従って合成した式（２ｆ）で示されるビナフチル誘導体 (52 mg, 0.18 mmol)、式（３ａ）で示される4-bromopyridine hydrochloride (69 mg, 0.36 mmol)、NaOt-Bu (68 mg, 0.71 mmol)、1,3-Bis(diphenylphosphino)propane (2.9 mg, 7.1 μmol)、palladium acetate(II) (1.6 mg, 7.1 μmol)、及びtoluene (1.6 mL)を入れ、70℃で15時間攪拌した。反応混合液にトルエン(20 mL)を加え、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層をMgSO₄で乾燥し、エバポレータで溶媒を濃縮して粗生成物を得た。グラディエントシリカゲルカラムクロマトグラフィー (SiO₂: CH₂Cl₂/MeOH = 5/1 to 2/1)で精製し、式（１ｆ）で示される(S)-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine (58 mg, 0.16 mmol, 88% yield)を得た。Example 6
(Synthesis Example 19) [Synthesis of pyridine derivative represented by formula (1f)]

Synthesized into Ar-substituted tube with screw cap according to literature (Akhatou, A. et al., Tetrahedron 2007, 63, 6232; Ooi, T. et al., J. Am. Chem. Soc. 1999, 121, 6519) Binaphthyl derivative represented by the formula (2f) (52 mg, 0.18 mmol), 4-bromopyridine hydrochloride (69 mg, 0.36 mmol), NaOt-Bu (68 mg, 0.71 mmol), 1, 3-Bis (diphenylphosphino) propane (2.9 mg, 7.1 μmol), palladium acetate (II) (1.6 mg, 7.1 μmol), and toluene (1.6 mL) were added, and the mixture was stirred at 70 ° C. for 15 hours. Toluene (20 mL) was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over MgSO ₄ and the solvent was concentrated by an evaporator to obtain a crude product. Purification by gradient silica gel column chromatography (SiO ₂ : CH ₂ Cl ₂ / MeOH = 5/1 to 2/1) and (S) -4- (pyridin-4-yl) -4 represented by the formula (1f) , 5-dihydro-3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (58 mg, 0.16 mmol, 88% yield) was obtained.

The physical property data of the pyridine derivative represented by the above formula (1f) is shown below.
Colorless solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ8.29 (bd, J = 6.3 Hz, 2H), 7.95 (d, J = 8.9 Hz, 4H), 7.54-7.48 (m, 6H), 7.31 ( bt, J = 8.9 Hz, 2H), 6.75 (bd, J = 6.3 Hz, 2H), 4.63 (d, J = 12.6 Hz, 2H), 3.83 (d, J = 12.6 Hz, 2H); ¹³ C NMR ( 150 MHz, CDCl ₃ ) δ153.5, 150.3, 135.0, 133.5, 132.9, 131.5, 129.4, 128.5, 127.6, 127.4, 126.3, 126.1, 108.6, 50.7; HRMS (FAB ⁺ ) calcd.for C ₂₇ H ₂₁ N ₂ [M + H ⁺ ] 373.1705, found 373.1699.

上述のようにして得られたピリジン誘導体をそれぞれ不斉求核触媒として用いて、式（Ａ）で示される化合物に対する分子内転位反応を行った。ジクロロメタン溶媒中で0℃、12時間反応させ、1N HCl (4.0 mL)を加えてCH₂Cl₂ (5.0 mL)で2回抽出し、brineで洗浄してMgSO₄で乾燥し、エバポレータで溶媒を濃縮して粗生成物を得た。シリカゲルカラムクロマトグラフィー (SiO₂: hexane/Et₂O = 1/1(v/v))で精製し、式（Ｓ）−（Ｂ）で示される(S)-phenyl 4-benzyl-2-(4-methoxyphenyl)-5-oxo-4,5-dihydrooxazole-4-carboxylateを得た。得られた結果を表１にまとめて示す。表１（entry 4）から分かるように、式（１ｄ）で示されるピリジン誘導体を不斉求核触媒として用いた場合、良好なエナンチオ選択性86:14(72% ee)で式（Ｓ）−（Ｂ）で示される化合物が得られることが明らかになった。なお、式（Ｓ）−（Ｂ）で示される化合物は、第四級不斉炭素をもつアミノ酸誘導体として有用な化合物である。Example 7
(Synthesis Example 20) [Synthesis of Compound represented by Formula (S)-(B)]

Using the pyridine derivatives obtained as described above as an asymmetric nucleophilic catalyst, an intramolecular rearrangement reaction was performed on the compound represented by the formula (A). The reaction was carried out in a dichloromethane solvent at 0 ° C. for 12 hours, 1N HCl (4.0 mL) was added, extracted twice with CH ₂ Cl ₂ (5.0 mL), washed with brine, dried over MgSO ₄ and the solvent was removed with an evaporator. Concentration gave the crude product. Purified by silica gel column chromatography (SiO ₂ : hexane / Et ₂ O = 1/1 (v / v)), (S) -phenyl 4-benzyl-2- ( 4-methoxyphenyl) -5-oxo-4,5-dihydrooxazole-4-carboxylate was obtained. The obtained results are summarized in Table 1. As can be seen from Table 1 (entry 4), when the pyridine derivative represented by the formula (1d) is used as an asymmetric nucleophilic catalyst, the enantioselectivity is 86:14 (72% ee) and the formula (S)- It became clear that the compound shown by (B) was obtained. The compound represented by the formula (S)-(B) is a useful compound as an amino acid derivative having a quaternary asymmetric carbon.

実施例７において良好なエナンチオ選択性が示された式（１ｄ）で示される化合物を用いて、反応溶媒の検討を行った。反応溶媒としては、ジクロロメタン、トルエン、ジエチルエーテル（Ｅｔ_２Ｏ）、ジイソプロピルエーテル（ｉ−Ｐｒ_２Ｏ）、シクロペンチルメチルエーテル（ＣＰＭＥ）、ｔｅｒｔ−ブチルメチルエーテル（ＴＢＭＥ）、テトラヒドロフランをそれぞれ用いた。反応溶媒中で0℃、12時間反応させ、1N HCl (4.0 mL)を加えてCH₂Cl₂ (5.0 mL)で2回抽出し、brineで洗浄してMgSO₄で乾燥し、エバポレータで溶媒を濃縮して粗生成物を得た。シリカゲルカラムクロマトグラフィー (SiO₂: hexane/Et₂O = 1/1(v/v))で精製し、式（Ｓ）−（Ｂ）で示される化合物を得た。得られた結果を表２にまとめて示す。Example 8
(Synthesis Example 21) [Synthesis of Compound represented by Formula (S)-(B)]

The reaction solvent was examined using the compound represented by the formula (1d), which showed good enantioselectivity in Example 7. As the reaction solvent, dichloromethane, toluene, diethyl ether (Et ₂ O), diisopropyl ether (i-Pr ₂ O), cyclopentyl methyl ether (CPME), tert-butyl methyl ether (TBME), and tetrahydrofuran were used, respectively. The reaction was carried out in a reaction solvent at 0 ° C. for 12 hours, 1N HCl (4.0 mL) was added, extracted twice with CH ₂ Cl ₂ (5.0 mL), washed with brine, dried over MgSO ₄ and the solvent was removed with an evaporator. Concentration gave the crude product. Purification by silica gel column chromatography (SiO ₂ : hexane / Et ₂ O = 1/1 (v / v)) gave a compound represented by the formula (S)-(B). The obtained results are summarized in Table 2.

実施例７において良好なエナンチオ選択性が示された式（１ｄ）で示される化合物を用いて、反応温度の検討を行った。ジエチルエーテル溶媒中で12時間反応させ、1N HCl (4.0 mL)を加えてCH₂Cl₂ (5.0 mL)で2回抽出し、brineで洗浄してMgSO₄で乾燥し、エバポレータで溶媒を濃縮して粗生成物を得た。シリカゲルカラムクロマトグラフィー (SiO₂: hexane/Et₂O = 1/1(v/v))で精製し、式（Ｓ）−（Ｂ）で示される化合物を得た。得られた結果を表３にまとめて示す。Example 9
(Synthesis Example 22) [Synthesis of Compound represented by Formula (S)-(B)]

Using the compound represented by the formula (1d), which showed good enantioselectivity in Example 7, the reaction temperature was examined. React in diethyl ether solvent for 12 hours, add 1N HCl (4.0 mL), extract twice with CH ₂ Cl ₂ (5.0 mL), wash with brine, dry over MgSO ₄ and concentrate the solvent with an evaporator. To obtain a crude product. Purification by silica gel column chromatography (SiO ₂ : hexane / Et ₂ O = 1/1 (v / v)) gave a compound represented by the formula (S)-(B). The results obtained are summarized in Table 3.

A compound (39.2 mg, 0.10 mmol) represented by formula (A) and diethyl ether (1.0 mL) are placed in a test tube with a screw cap replaced with Ar, cooled to −78 ° C., and represented by formula (1d). (S) -2,6-dimethoxy-4- (pyridin-4-yl) -4,5-dihydro-3H-dinaphtho [2,1-c: 1 ', 2'-e] azepine (4.4 mg, 10.2 μmol) was added and stirred for 12 hours. Add 4M HCl in 1,4-dioxane (1.0 mL), concentrate the solvent with an evaporator, and remove the catalyst by silica gel column chromatography (SiO ₂ : hexane / Et ₂ O = 1/1 (v / v)). Thus, a crude product of (S) -phenyl 4-benzyl-2- (4-methoxyphenyl) -5-oxo-4,5-dihydrooxazole-4-carboxylate represented by the formula (S)-(B) was obtained. When the crude product was confirmed by 1H NMR, the reaction conversion rate was 25% and the enantioselectivity was 97: 3 (94% ee). The results obtained are summarized in Table 4.

また同様に、式（１ｄ）で示される化合物を用いてトルエン溶媒中で12時間反応させることにより、反応温度の検討を行った。得られた結果を表５にまとめて示す。表５（entry 5）から分かるように、トルエン溶媒中、-60℃で反応させた場合に、良好なエナンチオ選択性97:3(94% ee)で式（Ｓ）−（Ｂ）で示される化合物が得られることが明らかになった。Example 10
Synthesis Example 23 Synthesis of Compound represented by Formula (S)-(B)

Similarly, the reaction temperature was examined by reacting the compound represented by the formula (1d) in a toluene solvent for 12 hours. The obtained results are summarized in Table 5. As can be seen from Table 5 (entry 5), when the reaction is carried out in a toluene solvent at −60 ° C., good enantioselectivity is 97: 3 (94% ee) and is represented by the formula (S)-(B). It became clear that a compound was obtained.

A compound (38.8 mg, 0.10 mmol) represented by the formula (A) and toluene (1.0 mL) were placed in a test tube with a screw cap replaced with Ar, cooled to −20 ° C., and represented by the formula (1d) ( S) -2,6-dimethoxy-4- (pyridin-4-yl) -4,5-dihydro-3H-dinaphtho [2,1-c: 1 ', 2'-e] azepine (4.4 mg, 10.2 μmol ) Was added and stirred for 12 hours. 1N HCl (4.0 mL) was added, and the mixture was extracted twice with CH ₂ Cl ₂ (5.0 mL), washed with brine, dried over MgSO ₄ , and the solvent was concentrated with an evaporator to obtain a crude product. Purified by silica gel column chromatography (SiO ₂ : hexane / Et ₂ O = 1/1 (v / v)), (S) -phenyl 4-benzyl-2- ( 4-methoxyphenyl) -5-oxo-4,5-dihydrooxazole-4-carboxylate (40.5 mg, 0.10 mmol,> 98% yield) was obtained.

A compound (38.9 mg, 0.10 mmol) represented by the formula (A) and toluene (1.0 mL) were placed in a test tube with a screw cap substituted with Ar, and cooled to −78 ° C., and represented by the formula (1d) ( S) -2,6-dimethoxy-4- (pyridin-4-yl) -4,5-dihydro-3H-dinaphtho [2,1-c: 1 ', 2'-e] azepine (4.4 mg, 10.2 μmol ) Was added and stirred for 12 hours. Add 4M HCl in 1,4-dioxane (1.0 mL), concentrate the solvent with an evaporator, and remove the catalyst by silica gel column chromatography (SiO ₂ : hexane / Et ₂ O = 1/1 (v / v)). Thus, a crude product of (S) -phenyl 4-benzyl-2- (4-methoxyphenyl) -5-oxo-4,5-dihydrooxazole-4-carboxylate represented by the formula (S)-(B) was obtained. When a crude product was confirmed by 1H NMR, the reaction conversion rate was 45% and the enantioselectivity was 97: 3 (94% ee). The results obtained are summarized in Table 6.

式（１ｄ）で示される化合物を用いてシクロペンチルメチルエーテル（ＣＰＭＥ）溶媒中で12時間反応させることにより、反応温度の検討を行った。得られた結果を表７にまとめて示す。表７（entry 5）から分かるように、ＣＰＭＥ溶媒中、-60℃で反応させた場合に、良好なエナンチオ選択性97:3(94% ee)で式（Ｓ）−（Ｂ）で示される化合物が得られることが明らかになった。Example 11
Synthesis Example 24 Synthesis of Compound represented by Formula (S)-(B)

The reaction temperature was examined by reacting the compound represented by the formula (1d) in a cyclopentyl methyl ether (CPME) solvent for 12 hours. The results obtained are summarized in Table 7. As can be seen from Table 7 (entry 5), when the reaction is carried out in a CPME solvent at −60 ° C., the enantioselectivity is 97: 3 (94% ee) and is represented by the formula (S)-(B). It became clear that a compound was obtained.

A compound tube (38.9 mg, 0.10 mmol) represented by formula (A) and cyclopentyl methyl ether (1.0 mL) were placed in a test tube with a screw cap replaced with Ar, cooled to −78 ° C., and represented by formula (1d). (S) -2,6-dimethoxy-4- (pyridin-4-yl) -4,5-dihydro-3H-dinaphtho [2,1-c: 1 ', 2'-e] azepine (4.4 mg, 10.2 μmol) was added and stirred for 12 hours. Add 4M HCl in 1,4-dioxane (1.0 mL), concentrate the solvent with an evaporator, and remove the catalyst by silica gel column chromatography (SiO ₂ : hexane / Et ₂ O = 1/1 (v / v)). Thus, a crude product of (S) -phenyl 4-benzyl-2- (4-methoxyphenyl) -5-oxo-4,5-dihydrooxazole-4-carboxylate represented by the formula (S)-(B) was obtained. When the crude product was confirmed by 1H NMR, the reaction conversion rate was 36% and the enantioselectivity was 94: 6 (88% ee). The results obtained are summarized in Table 8.

式（１ｄ）で示される化合物を用いてジイソプロピルエーテル（ｉ−Ｐｒ_２Ｏ）溶媒中で12時間反応させることにより、反応温度の検討を行った。得られた結果を表９にまとめて示す。Example 12
Synthesis Example 25 Synthesis of Compound Represented by Formula (S)-(B)

The reaction temperature was examined by reacting the compound represented by the formula (1d) in a diisopropyl ether (i-Pr ₂ O) solvent for 12 hours. The obtained results are summarized in Table 9.

In a test tube with a screw cap replaced with Ar, the compound represented by the formula (A) (38.6 mg, 0.10 mmol) and diisopropyl ether (1.0 mL) were placed, cooled to −78 ° C., and represented by the formula (1d). (S) -2,6-dimethoxy-4- (pyridin-4-yl) -4,5-dihydro-3H-dinaphtho [2,1-c: 1 ', 2'-e] azepine (4.4 mg, 10.2 μmol) was added and stirred for 12 hours. Add 4M HCl in 1,4-dioxane (1.0 mL), concentrate the solvent with an evaporator, and remove the catalyst by silica gel column chromatography (SiO ₂ : hexane / Et ₂ O = 1/1 (v / v)). Thus, a crude product of (S) -phenyl 4-benzyl-2- (4-methoxyphenyl) -5-oxo-4,5-dihydrooxazole-4-carboxylate represented by the formula (S)-(B) was obtained. When the crude product was confirmed by 1H NMR, the reaction conversion rate was 10% or less. The obtained results are summarized in Table 10.

式（１ｄ）で示される化合物を用いてトルエン溶媒中で-60℃で12時間反応させることにより、カーボネート部位（Ｒ^１）及び保護基（Ｒ^２）の検討を行った。得られた結果を表１１にまとめて示す。また、式（Ｓ）−（Ｄ）−１〜（Ｓ）−（Ｄ）−１１で示される化合物の^１Ｈ−ＮＭＲチャートをそれぞれ図１〜１１に示す。なお、entry 8では、式（Ｓ）−（Ｄ）−８で示される化合物と未反応の原料化合物との混合物が得られたため、図８で示される^１Ｈ−ＮＭＲチャートでは、式（Ｓ）−（Ｄ）−８で示される化合物に由来するピークだけではなく、原料化合物に由来するピークも観測された。Example 13
Synthesis Example 26 Synthesis of Compound Represented by Formulas (S)-(D) -1 to (S)-(D) -11]

The carbonate moiety (R ¹ ) and protecting group (R ² ) were examined by reacting the compound represented by the formula (1d) in a toluene solvent at −60 ° C. for 12 hours. The obtained results are summarized in Table 11. In addition, ¹ H-NMR charts of the compounds represented by formulas (S)-(D) -1 to (S)-(D) -11 are shown in FIGS. In entry 8, since a mixture of the compound represented by the formula (S)-(D) -8 and the unreacted raw material compound was obtained, the ¹ H-NMR chart shown in FIG. Not only a peak derived from the compound represented by-(D) -8 but also a peak derived from the raw material compound was observed.

式（１ｄ）で示される化合物を用いてトルエン溶媒中で-60℃、12時間反応させることにより、触媒量の検討を行った。また、式（１ｄ）で示される化合物を3mol%用いてトルエン溶媒中で-60℃で反応させる際の反応時間の検討を行った。得られた結果を表１２にまとめて示す。Example 14
Synthesis Example 27 Synthesis of Compound represented by Formula (S)-(B)

The amount of catalyst was examined by reacting the compound represented by the formula (1d) in a toluene solvent at −60 ° C. for 12 hours. In addition, the reaction time when the compound represented by the formula (1d) was reacted at -60 ° C. in a toluene solvent using 3 mol% was examined. The results obtained are summarized in Table 12.

式（１ｄ）で示される化合物を用いてトルエン溶媒中で-60℃で12時間反応させることにより、基質適用範囲（Ｒ^３）の検討を行った。得られた結果を表１３にまとめて示す。また、式（Ｓ）−（Ｆ）−１〜（Ｓ）−（Ｆ）−４で示される化合物の^１Ｈ−ＮＭＲチャートをそれぞれ図１２〜１５に示す。なお、entry 2〜4では、それぞれ式（Ｓ）−（Ｆ）−２〜（Ｓ）−（Ｆ）−４で示される化合物と未反応の原料化合物との混合物が得られたため、図１３〜１５で示される^１Ｈ−ＮＭＲチャートでは、式（Ｓ）−（Ｆ）−２〜（Ｓ）−（Ｆ）−４で示される化合物に由来するピークだけではなく、原料化合物に由来するピークも観測された。Example 15
(Synthesis Example 28) [Synthesis of compounds represented by formulas (S)-(F) -1 to (S)-(F) -4]

The substrate application range (R ³ ) was examined by reacting the compound represented by the formula (1d) in a toluene solvent at −60 ° C. for 12 hours. The obtained results are summarized in Table 13. In addition, ¹ H-NMR charts of the compounds represented by formulas (S)-(F) -1 to (S)-(F) -4 are shown in FIGS. In entries 2 to 4, a mixture of the compound represented by the formulas (S)-(F) -2 to (S)-(F) -4 and an unreacted raw material compound was obtained. In the ¹ H-NMR chart represented by 15, not only the peak derived from the compound represented by the formula (S)-(F) -2 to (S)-(F) -4 but also the peak derived from the starting compound. Observed.

The physical property data of the compound represented by the formula (S)-(B) is shown below.
Colorless oil.Enantiomeric excess was determined by HPLC with Chiralcel OD-H column (hexane / iPrOH = 20/1 (v / v), flow rate = 0.525 mL / min, 40 ° C), t _R (R) 18.5 min and t _R (S) 24.3 min, 89.9% ee; ¹ H NMR (400 MHz, CDCl ₃ ) δ7.86-7.90 (m, 2H), 7.36-7.40 (m, 2H), 7.18-7.27 (m, 6H) , 7.10-7.13 (m, 2H), 6.92-6.96 (m, 2H), 3.86 (s, 3H), 3.73 (d. J = 13.6 Hz, 1H), 3.60 (d, J = 13.6 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 173.6, 164.5, 163.6, 163.1, 150.2, 132.8, 130.2, 129.5, 128.3, 127.6, 126.5, 121.1, 117.2, 114.2, 77.5, 55.5, 40.2.

Claims (8)

A pyridine derivative represented by the following general formula (1) or a salt thereof.

[Wherein R ^{1 to} R ⁶ and R ¹ ′ to R ⁶ ′ each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkyl group having 2 to 10 carbon atoms. An alkynyl group, an alkoxy group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, an acyl group having 2 to 10 carbon atoms, an arylalkyl group having 7 to 15 carbon atoms, an alkylsilyl group having 3 to 10 carbon atoms, C2-C10 alkoxycarbonyl group, C1-C10 alkylthio group, C6-C15 arylthio group, C4-C10 heteroaromatic ring group, sulfonyloxy group, amino group, amide group, nitro A group, a hydroxyl group, an arylsilyl group, an arylalkylsilyl group, or a halogen atom,
R ⁷ , R ⁷ ′, R ⁸ and R ⁸ ′ are each independently a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom,
R ⁹ , R ⁹ ′, R ¹⁰ and R ¹⁰ ′ are each independently a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom. ]   An asymmetric catalyst comprising the pyridine derivative according to claim 1 or a salt thereof. A method for producing a pyridine derivative represented by the general formula (1) or a salt thereof,
The following general formula (2):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
A binaphthyl derivative represented by the following general formula (3):

[Wherein, R ⁹ , R ⁹ ′, R ¹⁰ and R ¹⁰ ′ have the same meaning as in the general formula (1), and X is a halogen atom. ]
The method for producing a pyridine derivative or a salt thereof according to claim 1, wherein the salt is reacted with a salt of a 4-halogenopyridine derivative represented by the formula: The following general formula (4):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
As a starting compound, an allylbinaphthyl derivative represented by the following general formula (2):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
The manufacturing method of the pyridine derivative or its salt of Claim 3 which has the process of obtaining the binaphthyl derivative shown by these. The following general formula (5):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
A dibromobinaphthyl derivative represented by the following general formula (4):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
The manufacturing method of the pyridine derivative or its salt of Claim 3 or 4 which has the process of obtaining the allyl binaphthyl derivative shown by these. The following general formula (6):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
As a starting compound, a binaphthyl derivative represented by the following general formula (5):

[Wherein, R ^{1 to} R ⁸ and R ¹ ′ to R ⁸ ′ have the same meaning as in the general formula (1). ]
The manufacturing method of the pyridine derivative or its salt in any one of Claims 3-5 which has the process of obtaining the dibromo binaphthyl derivative shown by these. A binaphthyl derivative represented by the following general formula (7).

[Wherein, R ¹ is an alkoxy group having 1 to 10 carbon atoms, and R ¹ ′ is a hydrogen atom or an alkoxy group having 1 to 10 carbon atoms. ] An allyl binaphthyl derivative represented by the following general formula (8).

[Wherein, R ¹ is an alkoxy group having 1 to 10 carbon atoms, and R ¹ ′ is a hydrogen atom or an alkoxy group having 1 to 10 carbon atoms. ]

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