JP5450056B2 - Allylamine asymmetric hydrogenation method - Google Patents

Description

  The present invention relates to a method for producing an optically active amine derivative having affinity for a melatonin receptor and useful as a pharmaceutical or a pharmaceutical raw material.

A benzocycloalkene derivative having a physiological action such as melatonin receptor affinity is described in, for example, Patent Document 1 (Patent Document 2), and its optically active compounds are disclosed in Examples 65 to 68 and 70 of the publication. . Regarding the method for producing the optically active compound, a method using high performance liquid chromatography is described.
Ethylamide derivatives having melatonin-like action characteristics are described in, for example, Patent Document 3 (Patent Document 4), and Examples 36 to 39 of the publication describe an optical resolution method using D- or L-tartaric acid.
The tricyclic amide compound having melatonin receptor affinity is described in, for example, Patent Document 5 (Patent Document 6), but this publication does not specifically describe the optically active compound.
Further, compounds having melatonin-like action characteristics are described in, for example, Patent Document 7 (Patent Document 8), Patent Document 9 (Patent Document 10), and Patent Document 11, but there is no specific description about the optically active compound. .
On the other hand, the asymmetric hydrogenation reaction of enamines using rhodium and an optically active ferrocene ligand is described in, for example, Patent Document 12 and Patent Document 13, but the application to allylamine is described in the publication. Absent.
Further, the asymmetric hydrogenation reaction of allylamine using a transition metal-optically active phosphine complex is described in Patent Document 14, but there is no specific description of a rhodium-optically active ferrocene phosphine complex.
JP-A-8-134030 WO96 / 08466 JP-A-8-268987 EP-0728738 JP-A-8-239377 EP-0708099 JP-A-8-239353 EP-0721938 JP-A-8-231530 EP-0721497 WO95 / 29173 Publication WO2004 / 085378 WO2005 / 003135 Publication Japanese Patent Laid-Open No. 11-140073

In the method of obtaining an optically active compound by optical resolution using high performance liquid chromatography (HPLC), large-scale treatment is difficult, the production cost is high, and it is not suitable as an industrial production method.
Further, in the optical resolution method using D- or L-tartaric acid, the theoretical yield is 50% at the maximum, that is, only 50% of the raw material can be used at the maximum, and the operation is complicated. It is not preferable.
Therefore, as a method for producing optically active amine derivatives useful as pharmaceuticals having physiological effects such as affinity for melatonin receptor or raw materials for pharmaceutical synthesis, production on a large scale on an industrial scale that satisfies conditions such as yield, purity, and convenience The establishment of an efficient manufacturing method suitable for the production has been eagerly desired.

〔式中、Ｒ^１およびＲ^２はそれぞれ水素原子、置換基を有していてもよい炭化水素基または置換基を有していてもよい複素環基を示すか、あるいはＲ^１とＲ^２は隣接する炭素原子と一緒になって置換基を有していてもよいスピロ環を形成していてもよく、点線は上記Ｒ^１とＲ^２が結合して環を形成していてもよいことを示し、Ｘは（ＣＨ_２）_ｎ（ｎは１ないし４の整数を示す）、窒素原子、酸素原子または硫黄原子を示し、環Ａ_０は置換基を有していてもよい不飽和６員環を、環Ｂは置換基を有していてもよい５〜７員複素環を示す。〕で表される化合物またはその塩を、ロジウム−光学活性フェロセン系ホスフィン錯体触媒の存在下に、不斉水素化反応に付すことを特徴とする式

〔式中、＊は不斉中心を、その他の記号は前記と同意義を示す。〕で表される化合物の光学活性体またはその塩の製造法、
（２）環Ａ_０が置換基を有していてもよいベンゼン環である前記（１）項記載の製造法、
（３）式

〔式中、Ｒ^１およびＲ^２はそれぞれ水素原子、置換基を有していてもよい炭化水素基または置換基を有していてもよい複素環基を示すか、あるいはＲ^１とＲ^２は隣接する炭素原子と一緒になって置換基を有していてもよいスピロ環を形成していてもよく、点線は上記Ｒ^１とＲ^２が結合して環を形成していてもよいことを示し、Ｘは（ＣＨ_２）_ｎ（ｎは１ないし４の整数を示す）、窒素原子、酸素原子または硫黄原子を示し、Ａは置換基を有していてもよいベンゼン環を示し、ｍは１ないし３の整数を示す。〕で表される化合物またはその塩を、ロジウム−光学活性フェロセン系ホスフィン錯体触媒の存在下に、不斉水素化反応に付すことを特徴とする式

〔式中、＊は不斉中心を、その他の記号は前記と同意義を示す。〕で表される化合物の光学活性体またはその塩の製造法、
（４）Ｒ^１およびＲ^２が共に水素原子で、Ｘが（ＣＨ_２）_ｎ（ｎは１または２を示す）で、ｍが１または２で、環Ａが無置換である前記（３）項記載の製造法、
（５）ｎとｍが共に１である前記（４）項記載の製造法、
（６）（Ｅ）−２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イリデン）エチルアミンを不斉水素化反応に付し、（Ｓ）−２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチルアミンを製造する、前記（１）項記載の製造法、
（７）ロジウム−光学活性フェロセン系ホスフィン錯体触媒が、
式［ＲｈＸＹ］_２（式中、Ｘは配位結合性の有機もしくは無機配位子を、Ｙは非結合性アニオンを示す。）で表されるロジウム錯体と、
式

（式中、Ｒ^ａ１、Ｒ^ａ２、Ｒ^ｂ１、Ｒ^ｂ２、Ｒ^ｃ１およびＲ^ｃ２は、それぞれ独立して、置換されていてもよい炭化水素基または置換されていてもよい複素環基を示す。）で表される配位子とから調製される触媒である前記（１）項記載の製造法、
（８）ロジウム−光学活性フェロセン系ホスフィン錯体触媒が、
式［ＲｈｊＬｋＸｌＳｑ］Ｙｒ（式中、Ｌは
式

（式中、Ｒ^ａ１、Ｒ^ａ２、Ｒ^ｂ１、Ｒ^ｂ２、Ｒ^ｃ１およびＲ^ｃ２は、それぞれ独立して、置換されていてもよい炭化水素基または置換されていてもよい複素環基を示す。）で表される配位子を、
Ｘは配位結合性の有機もしくは無機配位子を、
Ｓは配位結合性溶媒分子を、
Ｙは非結合性アニオンを、
ｊは１以上の整数を、
ｋは１以上の整数を、
ｌは０以上の整数を、
ｑは０以上の整数を、
ｒは０以上の整数を
示す。）で表される触媒である前記（１）項記載の製造法、
（９）Ｘがシクロオクタジエンまたはノルボルナジエンであり、
Ｙが塩素、臭素またはヨウ素である
前記（７）項および（８）項記載の製造法、
（１０）式ＩＩＩａ、ＩＩＩｂまたはＩＩＩｃで表される配位子が、
１−［２−（ジフェニルホスフィノ）フェロセニル］エチルジシクロヘキシルホスフィン、
１−［２−ジ−（４−メトキシ−３，５−ジメチルフェニル）ホスフィノ］−フェロセニル］エチルジシクロヘキシルホスフィン、
１−［２−（ジ−２−フリルホスフィノ）−フェロセニル］エチルジ−ｔｅｒｔ−ブチルホスフィン、
１−［２−（２−ジフェニルホスフィノフェニル）フェロセニル］エチルジシクロヘキシルホスフィン、または
１−ジフェニルホスフィノ−２−［α−（Ｎ，Ｎ−ジメチルアミノ）−ｏ−ジフェニルホスフィノフェニル］メチル］フェロセン
である前記（７）項および（８）項記載の製造法、
（１１）前記（１）項記載の製造法で製造された式（Ｉ_０）の化合物の光学活性体またはその塩と
式Ｒ^３ＣＯＯＨ（式中、Ｒ^３は置換基を有していてもよい炭化水素基、置換基を有していてもよいアミノ基または置換基を有していてもよい複素環基を、その他の記号は前記（１）項記載と同意義を示す。）で表される化合物、その塩またはその反応性誘導体とを
反応させることを特徴とする式

〔式中、＊は不斉中心を、その他の記号は前記と同意義を示す。〕
で表される化合物の光学活性体またはその塩の製造法、
（１２）（Ｓ）−２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチルアミンを
Ｒ^３ＣＯＯＨ（式中、Ｒ^３はエチルである）の反応性誘導体と反応させ、
（Ｓ）−Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミドを製造する、前記（１１）項記載の製造法に関する。The present inventors have studied an asymmetric synthesis method of an optically active amine derivative by an asymmetric hydrogenation reaction of allylamine using a rhodium-optically active ferrocene-based phosphine complex. As a result of finding that a body can be obtained and making further efforts, the present invention has been completed.
That is, the present invention provides the formula (1)

[Wherein, R ¹ and R ² each represent a hydrogen atom, a hydrocarbon group optionally having substituent (s) or a heterocyclic group optionally having substituent (s), or R ¹ and R ² are A spiro ring which may have a substituent may be formed together with an adjacent carbon atom, and the dotted line indicates that R ¹ and R ² may be bonded to form a ring. X represents (CH ₂ ) _n (n represents an integer of 1 to 4), a nitrogen atom, an oxygen atom or a sulfur atom, and ring A ₀ is an unsaturated 6-membered ring which may have a substituent. , Ring B represents a 5- to 7-membered heterocyclic ring which may have a substituent. Or a salt thereof is subjected to an asymmetric hydrogenation reaction in the presence of a rhodium-optically active ferrocene-based phosphine complex catalyst.

[Wherein, * represents an asymmetric center, and other symbols are as defined above. A process for producing an optically active compound or a salt thereof,
(2) The process according to item (1), wherein ring A ₀ is an optionally substituted benzene ring,
(3) Formula

[Wherein, R ¹ and R ² each represent a hydrogen atom, a hydrocarbon group optionally having substituent (s) or a heterocyclic group optionally having substituent (s), or R ¹ and R ² are A spiro ring which may have a substituent may be formed together with an adjacent carbon atom, and the dotted line indicates that R ¹ and R ² may be bonded to form a ring. X represents (CH ₂ ) _n (n represents an integer of 1 to 4), a nitrogen atom, an oxygen atom or a sulfur atom, A represents a benzene ring which may have a substituent, and m represents An integer of 1 to 3 is shown. Or a salt thereof is subjected to an asymmetric hydrogenation reaction in the presence of a rhodium-optically active ferrocene-based phosphine complex catalyst.

[Wherein, * represents an asymmetric center, and other symbols are as defined above. A process for producing an optically active compound or a salt thereof,
(4) The above (3), wherein R ¹ and R ² are both hydrogen atoms, X is (CH ₂ ) _n (n is 1 or 2), m is 1 or 2, and ring A is unsubstituted. Manufacturing method described in the paragraph,
(5) The production method according to the above (4), wherein n and m are both 1,
(6) (E) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine is subjected to an asymmetric hydrogenation reaction, (S) 2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine is produced according to the production method described in (1) above,
(7) a rhodium-optically active ferrocene-based phosphine complex catalyst,
A rhodium complex represented by the formula [RhXY] ₂ (wherein X represents a coordination-bonding organic or inorganic ligand, Y represents a non-bonding anion);
formula

(In the formula, R ^a1 , R ^a2 , R ^b1 , R ^b2 , R ^c1 and R ^c2 each independently represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. The production method according to item (1), which is a catalyst prepared from a ligand represented by:
(8) A rhodium-optically active ferrocene-based phosphine complex catalyst,
Formula [RhjLkXlSq] Yr (where L is the formula

(In the formula, R ^a1 , R ^a2 , R ^b1 , R ^b2 , R ^c1 and R ^c2 each independently represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. The ligand represented by
X is a coordination bond organic or inorganic ligand,
S is a coordination bond solvent molecule,
Y is a non-binding anion,
j is an integer of 1 or more,
k is an integer of 1 or more,
l is an integer greater than or equal to 0,
q is an integer of 0 or more,
r represents an integer of 0 or more. The production method according to item (1), which is a catalyst represented by
(9) X is cyclooctadiene or norbornadiene,
The production method according to (7) and (8) above, wherein Y is chlorine, bromine or iodine,
(10) the ligand represented by formula IIIa, IIIb or IIIc is
1- [2- (diphenylphosphino) ferrocenyl] ethyldicyclohexylphosphine,
1- [2-di- (4-methoxy-3,5-dimethylphenyl) phosphino] -ferrocenyl] ethyldicyclohexylphosphine,
1- [2- (di-2-furylphosphino) -ferrocenyl] ethyl di-tert-butylphosphine,
1- [2- (2-diphenylphosphinophenyl) ferrocenyl] ethyldicyclohexylphosphine or 1-diphenylphosphino-2- [α- (N, N-dimethylamino) -o-diphenylphosphinophenyl] methyl] ferrocene The production method according to (7) and (8) above,
(11) The optically active form of the compound of the formula (I ₀ ) produced by the production method described in the above (1) or a salt thereof and the formula R ³ COOH (wherein R ³ has a substituent) A good hydrocarbon group, an amino group which may have a substituent, or a heterocyclic group which may have a substituent, other symbols are as defined in the above item (1). Or a salt thereof or a reactive derivative thereof.

[Wherein, * represents an asymmetric center, and other symbols are as defined above. ]
A process for producing an optically active compound of the compound represented by the formula:
(12) (S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine is R ³ COOH (wherein R ³ is ethyl) A) a reactive derivative,
(S) —N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is produced, which is described in (11) above Relates to the manufacturing method.

［式中の各記号は前記と同意義を示す。］
本発明において、式（Ｉ）で表される化合物の光学活性体は、下記の式（Ｉａ）または（Ｉｂ）で表される。

［式中の各記号は前記と同意義を示す。］In the present invention, the optically active form of the compound represented by the formula (I ₀ ) is represented by the following formula (Ia ₀ ) or (Ib ₀ ).

[Each symbol in the formula is as defined above. ]
In the present invention, the optically active form of the compound represented by the formula (I) is represented by the following formula (Ia) or (Ib).

[Each symbol in the formula is as defined above. ]

According to the production method of the present invention, an optically active amine derivative represented by the formula (Ia ₀ ), (Ib ₀ ), (Ia) or (Ib) can be produced with high reproducibility, high purity, high yield and a simple method. It can be efficiently produced on an industrial scale.
In particular, the production method of the present invention can also carry out the reaction under a relatively low hydrogen pressure of 1 to 10 kg / cm ² , and therefore has the advantage that the reaction equipment is simple.

As used herein, “halogen atom” includes fluorine, chlorine, bromine and iodine.
As used herein, the term “hydrocarbon group” of the term “hydrocarbon group which may have a substituent” includes, for example, an aliphatic hydrocarbon group, a monocyclic saturated hydrocarbon group, and an aromatic hydrocarbon group. A hydrogen group etc. are mentioned, A C1-C16 thing is preferable. Specifically, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, and an aryl group are used.
The “alkyl group” is preferably, for example, a lower alkyl group, such as a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. General purpose.
The “alkenyl group” is preferably, for example, a lower alkenyl group, and for example, C _2-6 alkenyl groups such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc. are generally used.
The “alkynyl group” is preferably, for example, a lower alkynyl group, for example, a C _2-6 alkynyl group such as ethynyl, propargyl, 1-propynyl, etc.
The “cycloalkyl group” is preferably, for example, a lower cycloalkyl group, for example, a C _3-6 cycloalkyl group of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
The “aryl group” is preferably a C _6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc., more preferably a C _6-10 aryl group, such as a phenyl group. Is widely used.
Examples of the substituent that the “hydrocarbon group” of the “hydrocarbon group optionally having substituent” may have include:
(1) halogen atoms (eg, fluorine, chlorine, bromine, iodine),
(2) Nitro group,
(3) a cyano group,
(4) hydroxyl group,
(5) A lower alkyl group which may have a substituent (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkoxy group, amino group, mono-C _{1 -6} alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 alkyl-carbamoyl group , Di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, and optionally halogenated C _1-6 alkyl- 1-5 substituents C _1-6 alkyl group optionally having a selected from carbonyl amino group; for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromo Til, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4,4,4-trifluoro Butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.)
(6) Lower alkoxy group which may have a substituent (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkoxy group, amino group, mono-C _{1 -6} alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 alkyl-carbamoyl group , Di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, and optionally halogenated C _1-6 alkyl- 1-5 may have a substituent group C _1-6 alkoxy group selected from carbonyl amino group; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyl Yloxy, such as optionally halogenated a C _1-6 alkoxy group such as trifluoromethoxy),
(7) amino group,
(8) Mono-lower alkylamino group which may have a substituent (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkoxy group, amino group, mono group) -C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 alkyl -Carbamoyl group, di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, and optionally halogenated C _{1- 6} alkyl - 1-5 good things -C be substituted _1-6 alkylamino group selected from carbonyl amino group; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamine Such as mono--C _1-6 alkylamino group such as Bruno,
(9) Di-lower alkylamino group which may have a substituent (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkoxy group, amino group, mono group) -C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 alkyl -Carbamoyl group, di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, and optionally halogenated C _{1- 6} alkyl - 1-5 may have a substituent group di -C _1-6 alkylamino group selected from carbonyl amino group; for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, jib Arylamino, such as di -C _1-6 alkylamino group such as N- ethyl -N- methylamino)
(10) a carboxy group,
(11) A lower alkylcarbonyl group which may have a substituent (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkoxy group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 alkyl-carbamoyl Group, di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, and optionally halogenated C _1-6 alkyl A C _1-6 alkyl-carbonyl group _optionally having 1 to 5 substituents selected from a carbonylamino group and the like; for example, a C _1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.),
(12) An optionally substituted lower alkoxycarbonyl group (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkoxy group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 alkyl-carbamoyl Group, di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, and optionally halogenated C _1-6 alkyl A C _1-6 alkoxy-carbonyl group optionally having 1 to 5 substituents selected from a carbonylamino group and the like; for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxy C _1-6 alkoxy-carbonyl groups such as carbonyl),
(13) a carbamoyl group,
(14) Mono-lower alkylcarbamoyl group which may have a substituent (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkoxy group, amino group, mono group) -C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 alkyl -Carbamoyl group, di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, and optionally halogenated C _{1- 6-} mono-C _1-6 alkyl-carbamoyl group optionally having 1 to 5 substituents selected from alkyl-carbonylamino group and the like; for example, mono-C _1-6 such as methylcarbamoyl and ethylcarbamoyl A Kill - carbamoyl group, etc.),
(15) Di-lower alkylcarbamoyl group which may have a substituent (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkoxy group, amino group, mono group) -C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 alkyl -Carbamoyl group, di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, and optionally halogenated C _{1- A} di-C _1-6 alkyl-carbamoyl group optionally having 1 to 5 substituents selected from _6- alkyl-carbonylamino group and the like; for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarba Di-C _1-6 alkyl-carbamoyl groups such as moyl),
(16) arylcarbamoyl group which may have a substituent (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkyl group, optionally halogenated) C _1-6 alkoxy group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group Carbamoyl group, mono-C _1-6 alkyl-carbamoyl group, di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, and halogenated optionally C _1-6 alkyl - 1-5 may have a substituent C _6-10 aryl selected from carbonyl amino group - carbamoyl group; for example, phenylcarbamoyl, naphthyl Etc. carbamoyl group), - C _6-10 aryl, such Rubamoiru
(17) Aryl group which may have a substituent (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _1-6 alkoxy group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, A carbamoyl group, a mono-C _1-6 alkyl-carbamoyl group, a di-C _1-6 alkyl-carbamoyl group, a C _6-10 aryl-carbamoyl group, a C _6-10 aryl group, a C _6-10 aryloxy group, and A C _6-10 aryl group _optionally having 1 to 5 substituents selected from an optionally halogenated C _1-6 alkyl-carbonylamino group; for example, phenyl, naphthyl, etc.),
(18) aryloxy group optionally having substituent (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkyl group, optionally halogenated) C _1-6 alkoxy group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group Carbamoyl group, mono-C _1-6 alkyl-carbamoyl group, di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, And a C _6-10 aryloxy group _optionally having 1 to 5 substituents selected from an optionally halogenated C _1-6 alkyl-carbonylamino group and the like; for example, phenyloxy, naphthyloxy C _6-10 a, such as Such as aryloxy group),
(19) A lower alkylcarbonylamino group which may have a substituent (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkoxy group, amino group, mono- C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 alkyl- A carbamoyl group, a di-C _1-6 alkyl-carbamoyl group, a C _6-10 aryl-carbamoyl group, a C _6-10 aryl group, a C _6-10 aryloxy group, and an _optionally halogenated C _1-6 A C _1-6 alkyl-carbonylamino group _optionally having 1 to 5 substituents selected from an alkyl-carbonylamino group and the like; for example, halogenated such as acetylamino, trifluoroacetylamino, etc. An optionally substituted C _1-6 alkyl-carbonylamino group),
(20) An oxo group or the like is used.
The “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” has 1 to 5 substituents, preferably 1 to 3 substituents at the substitutable position of the hydrocarbon group. When the number of substituents is 2 or more, each substituent may be the same or different.

As the term “heterocyclic group” of the term “heterocyclic group optionally having substituent (s)” used in the present specification, for example, 1 selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom Species or two, 5-14 membered (preferably 5-10 membered) (monocyclic, bicyclic or tricyclic, preferably 1 to 4 (preferably 1 to 3) heteroatoms, preferably Monocyclic or bicyclic) heterocyclic groups and the like. For example, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, 2-, 4- or 5-oxazolyl, 3-, 4 -Or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyrazolidinyl, 2-, 4 In addition to carbon atoms such as-or 5-imidazolyl, 2- or 4-imidazolinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, nitrogen atoms, oxygen atoms and sulfur atoms A 5-membered cyclic group containing 1 to 4 selected heteroatoms; for example, 2-, 3- or 4-pyridyl, N-oxide-2-, 3- or 4-pyridyl, 2-, 4- or -Pyrimidinyl, N-oxide-2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, piperidino, 2-, 3- or 4-piperidyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3 A hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom such as -thiazinyl, 1- or 2-piperazinyl, triazinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide-3- or 4-pyridazinyl 6-membered cyclic group containing 1 to 4 atoms; for example, indolyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolidinyl, 1,8-naphthyridinyl, dibenzofura Nil Bicyclic or tricyclic condensed rings containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms such as carbazolyl, acridinyl, phenanthridinyl, chromanyl, phenothiazinyl and phenoxazinyl A group (preferably a 5- or 6-membered ring group 1 or 2 in which the 5- or 6-membered ring may contain 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. A group formed by condensation with an individual) or the like. Among these, a 5- to 7-membered (preferably 5- or 6-membered) heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to the carbon atom is preferable.
Examples of the substituent that the “heterocyclic group” of the “heterocyclic group which may have a substituent” may have include the above-mentioned “hydrocarbon group that may have a substituent”, and Examples thereof include the groups exemplified as the substituent that the “hydrocarbon group optionally having substituent (s)” may have. Among these, preferably, for example,
(1) halogen atoms (eg, fluorine, chlorine, bromine, iodine),
(2) Lower alkyl group (eg, C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),
(3) a cycloalkyl group (eg, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
(4) Lower alkynyl group (eg, C _2-6 alkynyl group such as ethynyl, 1-propynyl, propargyl, etc.),
(5) Lower alkenyl groups (eg, C _2-6 alkenyl groups such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, etc.),
(6) Aralkyl groups (eg, C _7-12 aralkyl groups such as benzyl, α-methylbenzyl, phenethyl, etc.),
(7) aryl groups (eg, C _6-10 aryl groups such as phenyl and naphthyl, preferably phenyl groups),
(8) Lower alkoxy group (eg, C _1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.),
(9) aryloxy groups (eg, C _6-10 aryloxy groups such as phenoxy),
(10) Lower alkanoyl group (eg, formyl; C _1-6 alkyl-carbonyl group such as acetyl, propionyl, butyryl, isobutyryl, etc.),
(11) arylcarbonyl group (eg, C _6-10 aryl-carbonyl group such as benzoyl, naphthoyl, etc.),
(12) Lower alkanoyloxy groups (eg, formyloxy; C _1-6 alkyl-carbonyloxy groups such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.),
(13) Arylcarbonyloxy group (eg, C _6-10 aryl-carbonyloxy group such as benzoyloxy, naphthoyloxy, etc.),
(14) a carboxy group,
(15) Lower alkoxycarbonyl group (eg, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.),
(16) Aralkyloxycarbonyl groups (eg, C _7-12 aralkyloxy-carbonyl groups such as benzyloxycarbonyl),
(17) Carbamoyl group, (18) Halogeno lower alkyl group (eg mono-, di- or tri-halogeno-C _1- such as chloromethyl, dichloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, etc.) ₆ alkyl groups),
(19) an oxo group,
(20) an amidino group,
(21) imino group,
(22) amino group,
(23) mono-lower alkylamino groups (eg, mono-C _1-6 alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.),
(24) Di-lower alkylamino groups (eg, di-C _1-6 alkylamino groups such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, N-ethyl-N-methylamino, etc.),
(25) optionally having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to the carbon atom and one nitrogen atom which may have a substituent; Member cyclic amino group (eg, halogen atom, nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _1-6 alkoxy group, amino group, Mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxy group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 Alkyl-carbamoyl group, di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, optionally halogenated C _{1- 6} alkyl-carbonylamino groups, and oxo 1 to 5 substituents selected from a group and the like, containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and one nitrogen atom A 3- to 6-membered cyclic amino group which may be, N-ethylpiperazinyl)
(26) alkylenedioxy groups (eg, C _1-3 alkylenedioxy groups such as methylenedioxy and ethylenedioxy),
(27) a hydroxyl group,
(28) Nitro group,
(29) a cyano group,
(30) thiol group (mercapto group),
(31) a sulfo group,
(32) a sulfino group,
(33) phosphono group,
(34) sulfamoyl group,
(35) Mono-lower alkylsulfamoyl groups (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.) Mono-C _1-6 alkylsulfamoyl groups),
(36) Di-lower alkylsulfamoyl groups (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.) Di-C _1-6 alkylsulfamoyl group of
(37) Lower alkylthio group (eg, C _1-6 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio), (38) Arylthio group (eg, phenylthio, naphthylthio, etc.) C _6-10 arylthio group of
(39) Lower alkylsulfinyl groups (eg, C _1-6 alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.),
(40) arylsulfinyl group (eg, C _6-10 arylsulfinyl group such as phenylsulfinyl, naphthylsulfinyl, etc.),
(41) a lower alkylsulfonyl group (eg, a C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.),
(42) Arylsulfonyl groups (eg, C _6-10 arylsulfonyl groups such as phenylsulfonyl and naphthylsulfonyl) and the like are used.
The “heterocyclic group” of the “heterocyclic group which may have a substituent” has 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions of the heterocyclic group. When the number of substituents is 2 or more, each substituent may be the same or different.

As used herein, the term “amino group optionally having substituent (s)” includes, for example, the aforementioned “hydrocarbon group optionally having substituent (s)” and the “substituent”. The same or different groups selected from the groups exemplified as the substituents that the "hydrocarbon group optionally having" may have an amino group optionally having one or two Show. The substituent that this “amino group” may have is preferably a C _1-6 alkyl group that may have a substituent, or a C _6-10 aryl that may have a substituent. Group and the like. Examples of the substituent that the “C _1-6 alkyl group” and “C _6-10 aryl group” may have are the same as the substituents that the “hydrocarbon group” may have. Used.
As used herein, the term “optionally substituted hydroxy (hydroxyl)” refers to (1) a hydroxyl group or (2) a hydrogen atom of a hydroxyl group, for example, the above “having a substituent. A hydrocarbon group that may be present or a group that is exemplified as the substituent that may be possessed by the “hydrocarbon group that may have a substituent”. Examples of the “optionally substituted hydroxyl group” include a hydroxyl group, an optionally substituted C _1-6 alkoxy group, and an optionally substituted C _2-6 alkenyloxy. Group, C _2-6 alkynyloxy group which may have a substituent, C _3-6 cycloalkyloxy group which may have a substituent, C _6-14 which may have a substituent An aryloxy group etc. are mentioned. Preferred are a hydroxyl group, a C _1-6 alkoxy group which may have a substituent, a C _6-14 aryloxy group which may have a substituent, and the like. The “C _1-6 alkoxy group”, “C _2-6 alkenyloxy group”, “C _2-6 alkynyloxy group”, “C _3-6 cycloalkyloxy group”, and “C _6-14 aryloxy group” As the substituent that "may have", those similar to the substituent that the "hydrocarbon group" may have are used.

As used herein, the term “optionally substituted thiol group” refers to (1) a thiol group or (2) a hydrogen atom of a thiol group, for example, the above “having a substituent” A thiol group having one of the groups exemplified as the substituent that the “hydrocarbon group that may be substituted” or the “hydrocarbon group that may be substituted” may have. Examples of the “thiol group which may have a substituent” include, for example, a thiol group, a C _1-6 alkylthio group which may have a substituent, and a C _2-6 which may have a substituent. An alkenylthio group, an optionally substituted C _2-6 alkynylthio group, an optionally substituted C _3-6 cycloalkylthio group, an optionally substituted C _{6- And 14} arylthio group. Preferred are a thiol group, a C _1-6 alkylthio group which may have a substituent, a C _6-10 arylthio group which may have a substituent. The “C _1-6 alkylthio group”, “C _2-6 alkenylthio group”, “C _2-6 alkynylthio group”, “C _3-6 cycloalkylthio group”, and “C _6-14 arylthio group” are As the substituent that may be present, those similar to the substituent that may be possessed by the “hydrocarbon group” are used.
As used herein, the term “lower alkyl group” of the term “lower alkyl group optionally having substituent (s)” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert C _1-6 alkyl groups such as -butyl and the like. The “lower alkyl group” includes, for example, 1 to 3 substituents that the “hydrocarbon group” may have as a substituent. You may have.

As used herein, the term “spiro ring” of the term “optionally substituted spiro ring” means, for example, that R ¹ and R ² together with adjacent carbon atoms are bonded to the spiro atom. A ring containing 3 to 8 carbon atoms formed as, for example, lower cycloalkane (for example, C _3-8 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc.), lower cycloalkene (for example, C _3-8 cycloalkene such as cyclopropene, cyclobutene, cyclopentene, cyclohexene, etc.), preferably C _3-8 cycloalkane.
Examples of the substituent that the “spiro ring” may have include the groups exemplified as the substituent that the “heterocyclic group” may have. The “spiro ring” may have 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions of the spiro ring. When the number of substituents is 2 or more, The substituents may be the same or different.
Further, the “spiro ring” may be condensed with an aromatic ring (for example, a 6-membered aromatic ring such as a benzene ring and a pyridine ring).

などで表されるスピロ環を形成している場合などが好ましい。
Ｒ^１およびＲ^２としてさらに好ましくは、ともに水素原子である。R ¹ and R ² each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ¹ and R ² are adjacent carbon atoms And may form a spiro ring which may have a substituent. R ¹ and R ² are preferably each a hydrogen atom, a lower alkyl group (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, etc.) or an aryl group (eg, phenyl, 1-naphthyl, 2- A C _6-10 aryl group such as naphthyl), and the like, and particularly preferably a hydrogen atom or a C _1-6 alkyl group. R ¹ and R ² together with the adjacent carbon atom

The case where the spiro ring represented by these is formed is preferable.
R ¹ and R ² are more preferably both hydrogen atoms.

Ring A ₀ represents “an unsaturated 6-membered ring optionally having substituent (s)”.
Examples of the “unsaturated 6-membered ring” in the “unsaturated 6-membered unsaturated ring” represented by ring A ₀ include, for example, a 6-membered aromatic ring and a 6-membered partially saturated ring. Can be mentioned.
As the “6-membered aromatic ring”, for example,
(1) a benzene ring, and (2) a 6-membered fully unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring-constituting atoms (eg, pyridine) , Pyrimidine, pyridazine, pyrazine).
As the “six-membered partially saturated ring”, for example,
(1) a 6-membered partially saturated carbocycle (eg, cyclohexene, cyclohexadiene), and (2) a hetero atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atom as a ring constituent atom. A 6-membered partially saturated heterocyclic ring containing 1 unit is included. Such a “6-membered partially saturated heterocyclic ring” is preferably a 6-membered partially saturated heterocyclic ring containing 1 to 2 nitrogen atoms (eg, dihydropyridine, dihydropyrimidine, dihydropyridazine).
The “unsaturated 6-membered ring” is particularly preferably a benzene ring.
The “unsaturated 6-membered ring” of the “unsaturated 6-membered ring optionally having substituent (s)” represented by ring A ₀ is 1 or 2 (preferably 1) substituents at substitutable positions. You may have. Examples of such a substituent include a halogen atom, a hydrocarbon group that may have a substituent, an amino group that may have a substituent, a hydroxyl group that may have a substituent, and Examples include a thiol group which may have a substituent.
Preferred examples of the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” include, for example, alkyl groups (eg, C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, etc.) ), Alkenyl groups (eg, C _2-6 alkenyl groups such as vinyl), alkynyl groups (eg, C _2-6 alkynyl groups such as ethynyl), cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) And C _3-6 cycloalkyl groups) and aryl groups (eg, C _6-14 aryl groups such as phenyl). Of these, alkyl groups (eg, C _1-6 alkyl groups such as methyl) and alkenyl groups (eg, C _2-6 alkenyl groups such as vinyl) are preferred. The “alkyl group”, “alkenyl group”, “alkynyl group”, “cycloalkyl group”, and “aryl group” include, for example, 1 to 5 substituents that the “hydrocarbon group” may have. May be included, preferably 1 to 3.
Preferred examples of the “optionally substituted amino group” include an amino group, an optionally substituted C _1-6 alkylamino group, and an optionally substituted C group. _Examples include _6-10 arylamino group. Among them, an amino group, mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, dimethylamino, diethylamino, N-ethyl- N-methylamino etc.), C _6-10 arylamino group (eg phenylamino group etc.) and the like. The “C _1-6 alkylamino group” and “C _6-10 arylamino group” include, for example, 1 to 5 substituents that the “hydrocarbon group” may have, preferably 1 to You may have three.
Preferable examples of the “optionally substituted hydroxyl group” include a hydroxyl group and a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.) optionally having a substituent, An optionally substituted C _2-6 alkenyloxy group (eg, vinyloxy), an optionally substituted C _2-6 alkynyloxy group (eg, ethynyloxy), An optionally substituted C _3-6 cycloalkyloxy group (eg, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.), an optionally substituted C _6-14 aryloxy group ( Examples, phenoxy, etc.). Among them, a hydroxyl group, an optionally substituted C _1-6 alkoxy group (eg, methoxy, etc.), an optionally substituted C _6-14 aryloxy group (eg, phenoxy, etc.), etc. Is preferred. The “C _1-6 alkoxy group”, “C _2-6 alkenyloxy group”, “C _2-6 alkynyloxy group”, “C _3-6 cycloalkyloxy group”, “C _6-14 aryloxy group” Represents, for example, 1 to 5 substituents that the "hydrocarbon group" may have (preferably halogen atoms such as chlorine and fluorine; C _1-6 alkoxy groups such as methoxy and ethoxy). , Preferably you may have 1-3.
Preferable examples of the “optionally substituted thiol group” include a thiol group and an optionally substituted C _1-6 alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, etc. ), An optionally substituted C _2-6 alkenylthio group (eg, vinylthio), an optionally substituted C _2-6 alkynylthio group (eg, ethynylthio), a substituent An optionally substituted C _3-6 cycloalkylthio group (eg, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.), an optionally substituted C _6-14 arylthio group (eg, , Phenylthio, etc.). Of these, a thiol group, an optionally substituted C _1-6 alkylthio group (eg, methylthio), a C _6-14 arylthio group (eg, phenylthio) and the like are preferable. The “C _1-6 alkylthio group”, “C _2-6 alkenylthio group”, “C _2-6 alkynylthio group”, “C _3-6 cycloalkylthio group”, “C _6-14 arylthio group” For example, the above-mentioned “hydrocarbon group” may have 1 to 5 substituents (preferably halogen atoms such as chlorine and fluorine; C _1-6 alkoxy groups such as methoxy and ethoxy), preferably You may have 1-3.
Ring A ₀ is particularly preferably an unsubstituted benzene ring.

Ring A represents “an optionally substituted benzene ring”.
The “optionally substituted benzene ring” represented by ring A may have 1 or 2 (preferably 1) substituents at substitutable positions. For example, groups exemplified as the substituents that the “unsaturated 6-membered ring” may have may be mentioned.
Ring A is particularly preferably an unsubstituted benzene ring.

中でも好ましくは、
式

［式中、ｍは１ないし３の整数を示す。］
で表される５〜７員複素環（好ましくは５員）である。ｍは、好ましくは１または２であり、より好ましくは１である。
環Ｂで示される「置換基を有していてもよい５〜７員複素環」の「５〜７員複素環」は、置換可能な位置に１ないし３個（好ましくは１個）の置換基を有していてもよい。このような置換基としては、例えば、ハロゲン原子、置換基を有していてもよい炭化水素基、置換基を有していてもよいアミノ基、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよい複素環基が挙げられる。
該「ハロゲン原子」、該「置換基を有していてもよい炭化水素基」、該「置換基を有していてもよいアミノ基」、該「置換基を有していてもよい水酸基」、および該「置換基を有していてもよいチオール基」の好ましい例としては、環Ａ_０の置換基の好ましい例として例示したものと同様のものが挙げられる。
該「置換基を有していてもよい複素環基」の「複素環基」の好ましい例としては、例えば、炭素原子以外に窒素原子、酸素原子および硫黄原子から選ばれた１〜３個のヘテロ原子を含む５または６員複素環基などが用いられる。具体的には、例えば、１−、２−または３−ピロリジニル、２−または４−イミダゾリニル、２−、３−または４−ピラゾリジニル、ピペリジノ、２−、３−または４−ピペリジル、１−または２−ピペラジニル、モルホリニル、２−または３−チエニル、２−、３−または４−ピリジル、２−または３−フリル、ピラジニル、２−ピリミジニル、３−ピロリル、３−ピリダジニル、３−イソチアゾリル、３−イソオキサゾリルなどが挙げられる。特に好ましくは、６員含窒素複素環基（例、ピリジルなど）などが用いられる。該「置換基を有していてもよい複素環基」の置換基の好ましい例としては、例えば、ハロゲン原子（例、塩素、フッ素など）、Ｃ_1-6アルキル基（例、メチル、エチルなど）、Ｃ_1-6アルコキシ基（例、メトキシ、エトキシなど）、アラルキルオキシカルボニル基（例、ベンジルオキシカルボニルなどのＣ_7-12アラルキルオキシ−カルボニルなど）、アミノ基、モノ−Ｃ_1-6アルキルアミノ基（例、メチルアミノ、エチルアミノなど）、ジ−Ｃ_1-6アルキルアミノ基（例、ジメチルアミノ、ジエチルアミノなど）などが用いられる。
環Ｂは、特に好ましくは無置換である。The “5- to 7-membered heterocyclic ring” of the “optionally substituted 5- to 7-membered heterocyclic ring” represented by ring B is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom 1 to 2 types, 1 to 4 (preferably 1 or 2) heteroatoms containing 5 to 7 membered (preferably 5 membered) heterocycle.
As such a “5- to 7-membered heterocyclic ring”, preferably
(1) 5- to 7-membered aromatic heterocycle (eg, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, etc.), and (2) 5- to 7-membered non Aromatic heterocycles (eg, dihydropyrrole, dihydroimidazole, dihydropyrazole, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, dihydropyrazine, dihydro-1,4-oxazine, dihydro-1,4-thioxazine, dihydrofuran, dihydrothiophene, pyran , Dihydropyran, thiopyran, dihydrothiopyran, dihydrooxepin, dihydrothiepine, dihydroazepine, dihydro-1,4-diazepine, dihydro-1,4-oxazepine, dihydro-1,4-thiazepine, etc. And the like.
Moreover, as such a “5- to 7-membered heterocyclic ring”, a 5- to 7-membered (preferably 5-membered) heterocyclic ring having a hetero atom at a position b adjacent to ring A ₀ shown below is preferable,

Among them, preferably
formula

[Wherein, m represents an integer of 1 to 3. ]
Is a 5- to 7-membered heterocyclic ring (preferably 5-membered). m is preferably 1 or 2, and more preferably 1.
The “5- to 7-membered heterocycle” of the “optionally substituted 5- to 7-membered heterocycle” represented by ring B has 1 to 3 (preferably 1) substitutions at substitutable positions. It may have a group. Examples of such a substituent include a halogen atom, a hydrocarbon group that may have a substituent, an amino group that may have a substituent, a hydroxyl group that may have a substituent, and a substituent. Examples thereof include a thiol group which may have a group and a heterocyclic group which may have a substituent.
The “halogen atom”, the “hydrocarbon group optionally having substituent (s)”, the “amino group optionally having substituent (s)”, the “hydroxyl group optionally having substituent (s)” And preferable examples of the “thiol group optionally having substituent (s)” include those exemplified as the preferable examples of the substituent of ring A ₀ .
Preferred examples of the “heterocyclic group” of the “heterocyclic group which may have a substituent” include, for example, 1 to 3 selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. A 5- or 6-membered heterocyclic group containing a hetero atom is used. Specifically, for example, 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2 -Piperazinyl, morpholinyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl Etc. Particularly preferably, a 6-membered nitrogen-containing heterocyclic group (eg, pyridyl etc.) is used. Preferred examples of the substituent of the “heterocyclic group optionally having substituent (s)” include, for example, a halogen atom (eg, chlorine, fluorine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl, etc.) ), C _1-6 alkoxy group (eg, methoxy, ethoxy, etc.), aralkyloxycarbonyl group (eg, C _7-12 aralkyloxy-carbonyl, such as benzyloxycarbonyl), amino group, mono-C _1-6 alkyl An amino group (eg, methylamino, ethylamino, etc.), a di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.) and the like are used.
Ring B is particularly preferably unsubstituted.

X represents (CH ₂ ) _n (n represents an integer of 1 to 4, preferably 1 or 2, more preferably 1), a nitrogen atom, an oxygen atom or a sulfur atom. Of these, CH ₂ is preferable.

［式中の各記号は前記と同意義を示す。］
で表される部分として、
好ましくは、

［式中の各記号は前記と同意義を示す。］
である。ｍが１であるものがより好ましい。In formula (II ₀ ), formula (I ₀ ), formula (II), and formula (I), the formula

[Each symbol in the formula is as defined above. ]
As a part represented by
Preferably,

[Each symbol in the formula is as defined above. ]
It is. More preferably, m is 1.

The compound represented by the formula (II ₀ ) is preferably a compound represented by the formula (II), and particularly preferably, R ¹ and R ² are each a hydrogen atom, m is 1, and X is (CH ₂ ) _n. (Here, n is 1 or 2, preferably 1.).
Specific examples of the compound represented by the formula (II ₀ ) include (E) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine and the like. Is mentioned.

Examples of the salt of the compound represented by the formula (II ₀ ), formula (I ₀ ), formula (II) or formula (I) targeted in the present invention include pharmaceutically acceptable salts. For example, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.
Among these, pharmaceutically acceptable salts are preferable, and examples thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid when the compound has a basic functional group. , For example, salts with organic acids such as acetic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and when having an acidic functional group, Examples thereof include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and ammonium salts.

The compound represented by the formula (II ₀ ) or formula (II) or a salt thereof, which is a raw material compound in the production method of the present invention, is disclosed in, for example, JP-A-8-134030 (WO96 / 08466), JP-A-8- No. 268987 (EP-0728738), JP-A-8-239377 (EP-0708099), JP-A-8-239353 (EP-0721938), JP-A-8-231530 (EP) No. 0721497), WO95 / 29173, etc., or a method analogous thereto.
In the production method of the present invention, the compound represented by the formula (II ₀ ) or the formula (II) or a salt thereof is subjected to an asymmetric hydrogenation reaction in the presence of a rhodium-optically active ferrocene phosphine complex as a catalyst. A compound represented by formula (I ₀ ) or formula (I) is produced.

（式中、Ｒ^ａ１、Ｒ^ａ２、Ｒ^ｂ１、Ｒ^ｂ２、Ｒ^ｃ１およびＲ^ｃ２は、それぞれ独立して、置換されていてもよい炭化水素基または置換されていてもよい複素環基を示す。）で表される配位子とから調製される。The rhodium-optically active ferrocene-based phosphine complex used in the production method of the present invention has the formula [RhXY] ₂ (wherein X represents a coordinated organic or inorganic ligand, and Y represents a non-bonded anion. And a rhodium complex represented by the formula:

(In the formula, R ^a1 , R ^a2 , R ^b1 , R ^b2 , R ^c1 and R ^c2 each independently represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. And a ligand represented by:

（式中、Ｒ^ａ１、Ｒ^ａ２、Ｒ^ｂ１、Ｒ^ｂ２、Ｒ^ｃ１およびＲ^ｃ２は、それぞれ独立して、置換されていてもよい炭化水素基または置換されていてもよい複素環基を示す。）で表される配位子を、
Ｘは配位結合性の有機もしくは無機配位子を、
Ｓは配位結合性溶媒分子を、
Ｙは非結合性アニオンを、
ｊは１以上の整数を、
ｋは１以上の整数を、
ｌは０以上の整数を、
ｑは０以上の整数を、
ｒは０以上の整数を
示す。）で表される。
また、該触媒は単離して用いてもよい。Preferably, the rhodium-optically active ferrocene-based phosphine complex catalyst is
Formula [RhjLkXlSq] Yr (where L is the formula:

(In the formula, R ^a1 , R ^a2 , R ^b1 , R ^b2 , R ^c1 and R ^c2 each independently represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. The ligand represented by
X is a coordination bond organic or inorganic ligand,
S is a coordination bond solvent molecule,
Y is a non-binding anion,
j is an integer of 1 or more,
k is an integer of 1 or more,
l is an integer greater than or equal to 0,
q is an integer of 0 or more,
r represents an integer of 0 or more. ).
The catalyst may be used after being isolated.

Examples of the “coordinating organic or inorganic ligand” represented by X include dienes such as cyclooctadiene and norbornadiene, olefins such as ethylene and cyclooctene, halides such as chlorine, bromine and iodine, acetate, and acetylacetate. Examples thereof include carbonyl such as nato and carbon monoxide, and hydride, and cyclooctadiene or norbornadiene is preferable.
Examples of the “coordinating solvent molecule” represented by S include amines such as triethylamine, alcohols such as methanol, and aromatic compounds such as benzene and cumene, preferably methanol.
Examples of the “non-binding anion” represented by Y include halides such as chlorine, bromine and iodine, trifluoromethanesulfonate, boron tetrafluoride, perchloric acid and hexafluorophosphoric acid, preferably chlorine, bromine or iodine. It is.
j represents an integer of 1 or more.
k represents an integer of 1 or more.
l represents an integer of 0 or more.
q represents an integer of 0 or more.
r represents an integer of 0 or more.
The upper limit of the sum of k, l, q does not exceed the available coordination number of rhodium.
r is an integer determined to maintain electrical neutrality.
For example,
j is 1 or 2,
k is an integer of 1 or more,
l is an integer greater than or equal to 0,
q is an integer of 0 or more,
r represents an integer of 0 or more,
k, l, q, and r are integers consistent with the coordination number and valence of rhodium.
Normal,
j is 1 or 2,
k is an integer greater than or equal to 1 and less than or equal to 4,
l is an integer greater than or equal to 0 and less than or equal to 4,
q is an integer greater than or equal to 0 and less than or equal to 4,
r represents an integer of 0 or more and 2 or less.

Preferred ligands of the formula IIIa, IIIb or IIIc include
1- [2- (diphenylphosphino) ferrocenyl] ethyldicyclohexylphosphine,
1- [2-di- (4-methoxy-3,5-dimethylphenyl) phosphino] -ferrocenyl] ethyldicyclohexylphosphine,
1- [2- (di-2-furylphosphino) -ferrocenyl] ethyl di-tert-butylphosphine,
1- [2- (2-Diphenylphosphinophenyl) ferrocenyl] ethyldicyclohexylphosphine and 1-diphenylphosphino-2- [α- (N, N-dimethylamino) -o-diphenylphosphinophenyl] methyl] ferrocene Is mentioned.

The optical isomer of the ligand used in the present invention is appropriately selected depending on the configuration of the target compound. For example, as a particularly preferred ligand for obtaining a compound of the formula (I ₀ ) in the (S) configuration,
(R) -1-[(S) -2- (diphenylphosphino) ferrocenyl] ethyldicyclohexylphosphine,
(R) -1-[(S) -2-di- (4-methoxy-3,5-dimethylphenyl) phosphino] -ferrocenyl] ethyldicyclohexylphosphine,
(R) -1-[(S) -2- (di-2-furylphosphino) -ferrocenyl] ethyldi-tert-butylphosphine,
(R) -1-[(R) -2- (2-diphenylphosphinophenyl) ferrocenyl] ethyldicyclohexylphosphine, and (S) -1-diphenylphosphino-2-[(R) -α- (N, N-dimethylamino) -o-diphenylphosphinophenyl] methyl] ferrocene.
The ligand used in the present invention may have an adduct, and examples of the adduct include methanol and ethanol. The case where the ligand has an adduct is also within the scope of the present invention.

The reaction can be carried out by heating and stirring under a hydrogen pressure described below under pressure under an autoclave or the like.
The reaction can be performed in an organic solvent. Examples of the organic solvent include aromatic hydrocarbons (for example, toluene, benzene, chlorobenzene, etc.), aliphatic esters (ethyl acetate, n-propyl acetate, n-butyl acetate, etc.), ethers (isopropyl ether, diethyl ether, Tetrahydrofuran (THF), halogenated hydrocarbons (dichloromethane, dichloroethane, etc.), alcohols (methanol, ethanol, isopropanol, etc.) and amides (N, N-dimethylformamide, etc.). These solvents may be used alone or as a mixed solvent. Preferably, (1) alcohols, (2) a mixed solvent of alcohols and ethers, and more preferably (i) methanol, (ii) a mixed solvent of methanol and tetrahydrofuran, and the like.
In the reaction, the amount of the organic solvent used is usually 1 to 100 times the volume, preferably 2 with respect to 1 part by weight of the compound represented by the formula (II ₀ ) or (II) as the raw material compound (substrate). ~ 50 times capacity.

The amount of the rhodium-optically active ferrocene-based phosphine complex catalyst used in the reaction is 0.1 to 0.00001 times moles relative to the compound represented by the formula (II ₀ ) or (II) as the raw material compound (substrate). , Preferably it is 0.02-0.0001 times mole.
The reaction temperature in the reaction is usually -30 to 100 ° C, preferably 10 to 80 ° C, more preferably 20 to 50 ° C.
The hydrogen pressure in the reaction is usually 1 to 200 kg / cm ² , preferably 1 to 10 kg / cm ² .
The reaction time in the reaction is usually 0.5 to 48 hours, preferably 1 to 24 hours.
In the reaction, a Lewis acid, a proton acid or the like may be added to the reaction solution as desired.

In the reaction of the present invention, the conversion rate from the compound represented by the formula (II ₀ ) or (II) to the compound represented by the formula (Ia ₀ ), (Ib ₀ ), (Ia) or (Ib) is It can be obtained by the following method. That is, for example, an appropriate amount of the reaction solution after the reaction is sampled and a high-speed liquid using an appropriate chiral column known per se (for example, Chiralpak AS (manufactured by Daicel Chemical Industries, Ltd.), ULTRON ES-OVM (SHINWA CHEMICAL INDUSTRIES LTD.), Etc.) The amount of each enantiomer represented by the formula (II ₀ ) (II) can be measured by a chromatography (HPLC) method.
From the reaction solution obtained by the above reaction, optically active amine derivatives (Ia ₀ ) and (Ib ₀ ) which are optically active amine derivatives are obtained by a method known per se (eg, solvent extraction, phase transfer, crystallization, recrystallization, chromatography, etc.). ), (Ia) or (Ib) can be obtained.

The optically active amine derivative obtained by the asymmetric hydrogenation method of the present invention is useful as a raw material for pharmaceutical synthesis. For example, an optically active derivative of a compound represented by the formula (IV ₀ ) or a compound thereof synthesized from the optically active amine derivative (that is, an optically active derivative of a compound represented by the formula (I ₀ ) or a salt thereof) as a raw material. (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (generic name: ramelteon) included in the salt ) And the like exhibit excellent melatonin receptor affinity, particularly melatonin receptor agonist activity, are low in toxicity and have few side effects, and are useful as pharmaceuticals. That is, diseases that act as melatonin agonists or antagonists on mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.) and may be affected by melatonin It can be used as a preventive / therapeutic agent. “Diseases that may be affected by melatonin” include, for example, sleep disorders (eg, endogenous sleep disorders (eg, psychophysiological insomnia)), extrinsic sleep disorders, circadian rhythm disorders (eg, , Time zone change syndrome (time difference blur), shift work sleep disorder, irregular sleep-wake pattern, sleep phase regression syndrome, sleep phase advance syndrome, non-24-hour sleep awakening, etc., sleep-related complications, medical or psychiatric disorders (Eg, chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression, anxiety) sleep disorders, insomnia, etc.], neurodegenerative diseases (eg, senile dementia) , Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, spinocerebellar degeneration, multiple sclerosis (MS), etc., neuropsychiatric disorders (eg, Depression, anxiety, bipolar disorder, post-traumatic stress disorder (PTSD), seasonal depression, schizophrenia, etc., memory impairment (eg, senile dementia, mild cognitive impairment (MCI), amnesia ), Ischemic central neuropathy (eg, cerebral infarction, cerebral hemorrhage, cerebral edema, etc.), central nervous injury (eg, head trauma, spinal cord injury, whiplash etc.), vascular dementia (eg, multiple infarcts) Dementia, Binswanger disease, etc.), cancer, hyperinsulinemia, metabolic syndrome, obesity, diabetes, diabetic complications (eg, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc.), hyperTGemia (high) Lipemia), hypertension, cardiovascular disease (eg, ischemic heart disease (eg, myocardial infarction, angina pectoris, etc.), stroke, arteriosclerosis, arterial restenosis after PTCA, etc.), lower urinary tract disease Or disorders (eg, dysuria, urinary incontinence), osteoporosis, Ingrowth and neuroendocrine disorders, convulsions, glaucoma, headache, and the like irritable bowel syndrome. It is also effective for immune regulation, intelligence, mental stability, stress or ovulation regulation (eg, contraception).

〔式中、＊は不斉中心を、その他の記号は前記と同意義を示す。〕
で表される化合物の光学活性体またはその塩を製造することができる。
好ましくは、（Ｓ）−２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチルアミンを
Ｒ^３ＣＯＯＨ（式中、Ｒ^３はエチルである）の反応性誘導体と反応させ、
（Ｓ）−Ｎ−［２−（１，６，７，８−テトラヒドロ−２Ｈ−インデノ［５，４−ｂ］フラン−８−イル）エチル］プロピオンアミドを製造する。
式 Ｒ^３ＣＯＯＨで表される化合物の反応性誘導体としては、例えば、式 Ｒ^３ＣＯＯＨで表される化合物の酸ハロゲン化物（例、酸塩化物、酸臭化物など）、酸アミド（例、ピラゾール、イミダゾール、ベンゾトリアゾールなどとの酸アミドなど）、酸無水物（例、無水酢酸、無水プロピオン酸、無水酪酸などのＣ_１−６脂肪族カルボン酸無水物など）、酸アジド、活性エステル（例、ジエトキシリン酸エステル、ジフェノキシリン酸エステル、ｐ−ニトロフェニルエステル、２，４−ジニトロフェニルエステル、シアノメチルエステル、ペンタクロロフェニルエステル、Ｎ−ヒドロキシスクシンイミドとのエステル、Ｎ−ヒドロキシフタルイミドとのエステル、１−ヒドロキシベンゾトリアゾールとのエステル、６−クロロ−１−ヒドロキシベンゾトリアゾールとのエステル、１−ヒドロキシ−１Ｈ−２−ピリドンとのエステルなど）、活性チオエステル（例、２−ピリジルチオエステル、２−ベンゾチアゾリルチオエステルなど）などが用いられる。中でも、塩化プロピオニルおよび臭化プロピオニル等の、式 Ｒ^３ＣＯＯＨで表される化合物の酸ハロゲン化物が好ましい。An optically active form of the compound of formula (I ₀ ) or a salt thereof produced by the asymmetric hydrogenation method of the present invention is represented by the formula R ³ COOH (wherein R ³ is a hydrocarbon group optionally having substituent (s)). An amino group which may have a substituent or a heterocyclic group which may have a substituent, and other symbols are as defined in the above item (1)). Reacted with its salt or its reactive derivative

[Wherein, * represents an asymmetric center, and other symbols are as defined above. ]
The optically active form of the compound represented by these, or its salt can be manufactured.
Preferably, (S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine is R ³ COOH where R ³ is ethyl. A) a reactive derivative,
(S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is prepared.
As the reactive derivative of the compound represented by the formula R ³ COOH, for example, an acid halide of the compound represented by the formula R ³ COOH (e.g., acid chloride, acid bromide, etc.), acid amides (e.g., pyrazole, Acid amides with imidazole, benzotriazole, etc.), acid anhydrides (eg, C _1-6 aliphatic carboxylic acid anhydrides, such as acetic anhydride, propionic anhydride, butyric anhydride), acid azides, active esters (eg, Diethoxyphosphate, diphenoxyphosphate, p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, ester with N-hydroxysuccinimide, ester with N-hydroxyphthalimide, 1- Esters with hydroxybenzotriazole, 6-chloro-1-hydro An ester with xylbenzotriazole, an ester with 1-hydroxy-1H-2-pyridone, etc.), an active thioester (eg, 2-pyridylthioester, 2-benzothiazolylthioester, etc.) and the like are used. Among these, acid halides of compounds represented by the formula R ³ COOH such as propionyl chloride and propionyl bromide are preferable.

The reactive derivative is generally used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (IV ₀ ). This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene and cyclohexane, N, N-dimethyl Amides such as formamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, and sulfoxides such as dimethyl sulfoxide A solvent such as water or a mixed solvent thereof is preferred.
When compound (IV ₀ ) forms a salt, it can be subjected to the reaction after making it into a free form by a conventional method.
The reaction is carried out in a solvent. Examples of the solvent include ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, carbonization such as benzene, toluene, cyclohexane and hexane. Hydrogens, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile And a solvent such as a sulfoxide such as dimethyl sulfoxide or a mixed solvent thereof, among which tetrahydrofuran is preferable.
While the reaction time varies depending on the reagent and solvent to be used, it is generally 30 min to 48 hr, preferably 1 hr to 24 hr.
The reaction temperature is usually -20 to 100 ° C, preferably 0 to 50 ° C.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples, and may be changed without departing from the scope of the present invention.
“Room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C. The% in yield indicates mol / mol%.
All the reactions were performed in the presence of an inert gas such as argon gas or nitrogen gas, and the solvent used was dried and degassed. The chemical yield is an isolated yield or a yield obtained by high performance liquid chromatography. The optical purity (asymmetric yield) of the optically active substance was evaluated by enantiomeric excess (% ee). The enantiomer excess was determined by the following equation.
Enantiomeric excess (% ee) = 100 X [(R)-(S)] / [(R) + (S)] or 100 X [(S)-(R)] / [(R) + (S )]
(Wherein (R) and (S) indicate the absolute configuration of the enantiomer and the area of each enantiomer in high performance liquid chromatography.)
The following apparatus was used for the measurement of the spectrum in an Example.
¹ H nuclear magnetic resonance spectrum ( ¹ H-NMR): JNM-AL400 type (manufactured by JEOL)
Internal standard substance; Tetramethylsilane solvent; Chloroform-d ₁

Example 1
Preparation of (S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine Chloro (1,5-cyclooctadiene) rhodium (I) Dimer (1 mg) and (R) -1-[(S) -2- (di-2-furylphosphino) -ferrocenyl] ethyldi-tert-butylphosphine (2.7 mg) in methanol (0.5 ml) And stirred at room temperature for 30 minutes. This was added to a solution of (E) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine (20 mg) in methanol (0.5 ml), The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere of 0.7 MPa. When the reaction mixture was quantified by high performance liquid chromatography, the enantiomeric excess was 91.8% and the yield was 95.4%.
(High performance liquid chromatography conditions)
Column: CHIRALCELOD-RH (manufactured by Daicel Chemical Industries, Ltd.)
Moving bed: 0.1M KPF ₆ (pH = 2.0, phosphoric acid) / acetonitrile (volume ratio: 800/200)
Flow rate: 0.5 ml / min
Detection: UV (220 nm)
Temperature: 30 ° C

Example 2
Preparation of (S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine Chloro (1,5-cyclooctadiene) rhodium (I) Methanol (0.5 ml) was added to the dimer (1 mg) and (R) -1-[(S) -2- (diphenylphosphino) -ferrocenyl] ethyldicyclohexylphosphine-ethanol adduct (3.3 mg), Stir at room temperature for 30 minutes. This was added to a solution of (E) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine (20 mg) in methanol (0.5 ml), The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere of 0.7 MPa. When the reaction mixture was quantified by high performance liquid chromatography, the enantiomeric excess was 74.2% and the yield was quantitative.

Example 3
Preparation of (S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine Chloro (1,5-cyclooctadiene) rhodium (I) Dimer (1 mg) and (R) -1-[(S) -2-di- (4-methoxy-3,5-dimethylphenyl) phosphino) -ferrocenyl] ethyldicyclohexylphosphine (3.7 mg) to methanol ( 0.5 ml) and stirred at room temperature for 30 minutes. This was added to a solution of (E) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine (20 mg) in methanol (0.5 ml), The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere of 0.7 MPa. When the reaction mixture was quantified by high performance liquid chromatography, the enantiomeric excess was 73.0% and the yield was 95.1%.

Example 4
Preparation of (S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine Chloro (1,5-cyclooctadiene) rhodium (I) Dimer (1 mg) and (R) -1-[(R) -2- (2′-diphenylphosphinophenyl) ferrocenyl] ethyldicyclohexylphosphine (3.5 mg) were added with methanol (0.5 ml), and room temperature was added. For 30 minutes. This was added to a solution of (E) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine (20 mg) in methanol (0.5 ml), The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere of 0.7 MPa. When the reaction mixture was quantified by high performance liquid chromatography, the enantiomeric excess was 80.4% and the yield was 91.6%.

Example 5
Preparation of (S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine Chloro (1,5-cyclooctadiene) rhodium (I) Dimer (1 mg) and (S) -1-diphenylphosphino-2-[(R) -α- (N, N-dimethylamino) -o-diphenylphosphinophenyl) methyl] ferrocene (3.6 mg) Methanol (0.5 ml) was added to the mixture and stirred at room temperature for 30 minutes. This was added to a solution of (E) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine (20 mg) in methanol (0.5 ml), The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere of 0.7 MPa. When the reaction mixture was quantified by high performance liquid chromatography, the enantiomeric excess was 77.1% and the yield was 92.7%.

Example 6
Preparation of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide obtained in Example 1. (S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine was dissolved in tetrahydrofuran (1 ml) and 1N water was added at 0 ° C. Aqueous sodium oxide (0.15 ml) and propionyl chloride (0.011 ml) were added. Stir at room temperature for 2 hours. The reaction solution was purified by pTLC (n-hexane / ethyl acetate = 1/2), and the obtained solid was washed with diisopropyl ether to obtain 10 mg of a pale yellow solid. Yield 38.5%. When measured by high performance liquid chromatography, the enantiomeric excess was 96.1%.
(High performance liquid chromatography conditions)
Column: CHIRALPAK AD (manufactured by Daicel Chemical Industries, Ltd.)
Moving bed: n-hexane / ethanol (volume ratio: 900/100)
Flow rate: 0.5 ml / min
Detection: UV (220 nm)
Temperature: 30 ° C
¹ H-NMR (400 MHz, chloroform-d ₁ ) δ: 1.14 (3H, t, J = 7.6 Hz), 1.61-1.64 (2H, m), 1.83 (1H, m), 2.20 (1H, m), 2.17 (2H, q, J = 7.6 Hz) 2.28 (1H, m), 2.78-2.89 (2H, m), 3.10-3.38 (4H, m), 4.50-4.60 (2H, m), 5.41 (1H, br s), 6.61 (1H, d, J = 8.8 Hz), 6.95 (1H, d, J = 8.0 Hz).

  According to the production method of the present invention, optically active amine derivatives useful as various intermediates for various drugs, agricultural chemicals, and the like, and particularly as medicinal compounds having melatonin receptor affinity or optically active compounds used as synthetic intermediates thereof are substantially used. Can be obtained purely.

Claims (11)

formula

[Wherein, R ¹ and R ² each represent a hydrogen atom, a hydrocarbon group optionally having substituent (s) or a heterocyclic group optionally having substituent (s), or R ¹ and R ² are A spiro ring which may have a substituent may be formed together with an adjacent carbon atom, and the dotted line indicates that R ¹ and R ² may be bonded to form a ring. X represents (CH ₂ ) _n (n represents an integer of 1 to 4), a nitrogen atom, an oxygen atom or a sulfur atom, and ring A ₀ is an unsaturated 6-membered ring which may have a substituent. , Ring B represents a 5- to 7-membered heterocyclic ring which may have a substituent. Or a salt thereof is subjected to an asymmetric hydrogenation reaction in the presence of a rhodium-optically active ferrocene-based phosphine complex catalyst.

[Wherein, * represents an asymmetric center, and other symbols are as defined above. ] The manufacturing method of the optically active substance of the compound represented by this, or its salt. The production method according to claim 1, wherein Ring A ₀ is an optionally substituted benzene ring. formula

[Wherein, R ¹ and R ² each represent a hydrogen atom, a hydrocarbon group optionally having substituent (s) or a heterocyclic group optionally having substituent (s), or R ¹ and R ² are A spiro ring which may have a substituent may be formed together with an adjacent carbon atom, and the dotted line indicates that R ¹ and R ² may be bonded to form a ring. X represents (CH ₂ ) _n (n represents an integer of 1 to 4), a nitrogen atom, an oxygen atom or a sulfur atom, A represents a benzene ring which may have a substituent, and m represents An integer of 1 to 3 is shown. Or a salt thereof is subjected to an asymmetric hydrogenation reaction in the presence of a rhodium-optically active ferrocene-based phosphine complex catalyst.

[Wherein, * represents an asymmetric center, and other symbols are as defined above. ] The manufacturing method of the optically active substance of the compound represented by this, or its salt. The process according to claim 3, wherein R ¹ and R ² are both hydrogen atoms, X is (CH ₂ ) _n (n is 1 or 2), m is 1 or 2, and ring A is unsubstituted. .   The process according to claim 4, wherein n and m are both 1.   (E) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine was subjected to an asymmetric hydrogenation reaction, and (S) -2- The process according to claim 1, wherein (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine is produced. Rhodium-optically active ferrocene-based phosphine complex catalyst,
A rhodium complex represented by the formula [RhXY] ₂ (wherein X represents a coordination-bonding organic or inorganic ligand, Y represents a non-bonding anion);
formula

(In the formula, R ^a1 , R ^a2 , R ^b1 , R ^b2 , R ^c1 and R ^c2 each independently represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. The production method according to claim 1, wherein the catalyst is prepared from a ligand represented by: Rhodium-optically active ferrocene-based phosphine complex catalyst,
Formula [RhjLkXlSq] Yr (where L is the formula

(In the formula, R ^a1 , R ^a2 , R ^b1 , R ^b2 , R ^c1 and R ^c2 each independently represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. The ligand represented by
X is a coordination bond organic or inorganic ligand,
S is a coordination bond solvent molecule,
Y is a non-binding anion,
j is an integer of 1 or more,
k is an integer of 1 or more,
l is an integer greater than or equal to 0,
q is an integer of 0 or more,
r represents an integer of 0 or more. The production method according to claim 1, wherein the catalyst is represented by the following formula: In the rhodium-optically active ferrocene-based phosphine complex catalyst represented by the formula [RhjLkXlSq] Yr,
X is cyclooctadiene or norbornadiene;
The process according to claim 7 or 8, wherein Y is chlorine, bromine or iodine. A ligand of the formula IIIa, IIIb or IIIc is
1- [2- (diphenylphosphino) ferrocenyl] ethyldicyclohexylphosphine,
1- [2-di- (4-methoxy-3,5-dimethylphenyl) phosphino] -ferrocenyl] ethyldicyclohexylphosphine,
1- [2- (di-2-furylphosphino) -ferrocenyl] ethyl di-tert-butylphosphine,
1- [2- (2-diphenylphosphinophenyl) ferrocenyl] ethyldicyclohexylphosphine or 1-diphenylphosphino-2- [α- (N, N-dimethylamino) -o-diphenylphosphinophenyl] methyl] ferrocene The production method according to claim 7 or 8. A ligand of the formula IIIa, IIIb or IIIc is
(R) -1-[(S) -2- (diphenylphosphino) ferrocenyl] ethyldicyclohexylphosphine,
(R) -1-[(S) -2-di- (4-methoxy-3,5-dimethylphenyl) phosphino] -ferrocenyl] ethyldicyclohexylphosphine,
(R) -1-[(S) -2- (di-2-furylphosphino) -ferrocenyl] ethyldi-tert-butylphosphine,
(R) -1-[(R) -2- (2′-diphenylphosphinophenyl) ferrocenyl] ethyldicyclohexylphosphine, or (S) -1-diphenylphosphino-2-[(R) -α- (N , N-dimethylamino) -o-diphenylphosphinophenyl] methyl] ferrocene.