JP2005035933A - Method for producing nitrogen-containing condensed heterocyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a nitrogen-containing condensed heterocyclic compound useful as an intermediate for synthesizing various pharmaceuticals. <P>SOLUTION: The method for producing the nitrogen-containing condensed heterocyclic compound of formula(I)[ when ring A is a 5- to 10-membered aromatic ring, and at least one of the ring A and ring B has a nitrogen atom as a ring-constituent atom; Z is O, S or NR<SP>3</SP>( R<SP>3</SP>is a hydrocarbon group or the like ); and R<SP>2</SP>is a hydrocarbon group, heterocyclic group or acyl group ] or a salt thereof, is characterised in that a compound ( or a salt thereof ) where the R<SP>2</SP>-Z group in the formula(I) is halogen atom or OSO<SB>2</SB>R<SP>1</SP>group( R<SP>1</SP>is an alkyl ) is reacted with a compound of the formula:HZ-R<SP>2</SP>or a salt thereof in the presence of a catalyst, a ligand and a base. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing a nitrogen-containing fused heterocyclic compound useful as a synthetic intermediate for various pharmaceuticals.

［式中、Ｌ⁵は脱離基を；Ａ環は置換されていてもよい5−10員芳香環を；Ｒ^１およびＲ^２は同一または異なって、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；Ｘは結合手、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ_２−または−ＮＲ^３− （Ｒ^３は水素原子または置換されていてもよい炭化水素基を示す）を；Ｌａは結合手またはアルキレンを；Ｒ¹⁰は水素原子または置換されていてもよい炭化水素基を示す］で表される化合物とベンジルアルコール（PhCH₂OH）とを、塩基の存在下、反応に悪影響を及ぼさない溶媒中で反応させることにより、式

［式中の記号は前記と同意義を示す］で表される化合物を製造する方法（特許文献１参照）。 As a method for producing a nitrogen-containing fused heterocyclic compound, for example, the following method has been reported.
(1 set

[Wherein L ⁵ represents a leaving group; A ring represents an optionally substituted 5- to 10-membered aromatic ring; R ¹ and R ² are the same or different, and may represent a substituted hydrocarbon group or An optionally substituted heterocyclic group; X is a bond, —O—, —S—, —SO—, —SO ₂ — or —NR ³ — (R ³ is a hydrogen atom or optionally substituted) La represents a bond or alkylene; R ¹⁰ represents a hydrogen atom or an optionally substituted hydrocarbon group] and a benzyl alcohol (PhCH ₂ OH). By reacting in the presence of a base in a solvent that does not adversely affect the reaction,

[The symbol in a formula shows the same meaning as the above] The method of manufacturing the compound represented (refer patent document 1).

International Publication No. WO02 / 066274 Pamphlet

  Development of a production method that can obtain a nitrogen-containing fused heterocyclic compound useful as a synthetic intermediate for various drugs in a simple and high yield is desired.

［式中、Ｚは−Ｏ−、−Ｓ−または−ＮＲ³− （Ｒ³は水素原子または置換されていてもよい炭化水素基を示す）を；Ｒ²は置換されていてもよい炭化水素基、置換されていてもよい複素環基またはアシル基を；Ａ環はさらに置換基を有していてもよい5−10員芳香環を；Ｂ環は置換基を有していてもよい環を示し、Ａ環またはＢ環の少なくとも一方が環構成原子として窒素原子を有する］で表される含窒素縮合複素環化合物［以下、化合物（I）と略記することがある］の製造方法について検討した結果、式

［式中、Ｙはハロゲン原子または−ＯＳＯ₂Ｒ¹− （Ｒ¹はハロゲン化されていてもよいアルキル基を示す）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［以下、化合物（II）と略記することがある］と式： ＨＺ−Ｒ² ［式中、Ｚは−Ｏ−、−Ｓ−または−ＮＲ³− （Ｒ³は水素原子または置換されていてもよい炭化水素基を示す）を、Ｒ²は置換されていてもよい炭化水素基、置換されていてもよい複素環基またはアシル基を示す］で表される化合物［以下、化合物（III）と略記することがある］とを、触媒、配位子および塩基の存在下に反応させることにより、化合物（I）を簡便にかつ高収率で得られることを見出し、本発明を完成するに至った。
すなわち、本発明は、
１）化合物（II）またはその塩と化合物（III）またはその塩とを、触媒、配位子および塩基の存在下に反応させることを特徴とする、化合物（I）またはその塩の製造方法；
２）触媒がパラジウム触媒である前記１）記載の製造方法；
３）配位子がＢＩＮＡＰ化合物である前記１）記載の製造方法；
などに関する。 We have the formula

[In the formula, Z represents —O—, —S— or —NR ³ — (R ³ represents a hydrogen atom or an optionally substituted hydrocarbon group); R ² represents an optionally substituted hydrocarbon. A group, an optionally substituted heterocyclic group or an acyl group; ring A is a 5- to 10-membered aromatic ring which may further have a substituent; ring B is a ring which may have a substituent And at least one of ring A or ring B has a nitrogen atom as a ring-constituting atom], a method for producing a nitrogen-containing fused heterocyclic compound [hereinafter sometimes abbreviated as compound (I)] Result

[Wherein Y represents a halogen atom or —OSO ₂ R ¹ — (R ¹ represents an alkyl group which may be halogenated); other symbols are as defined above] Hereinafter, the compound (II) may be abbreviated] and a formula: HZ-R ² [wherein Z is —O—, —S— or —NR ³ — (R ³ may be a hydrogen atom or substituted, R ² represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted or an acyl group] [hereinafter referred to as compound (III) and The compound (I) can be easily obtained in a high yield by reacting in the presence of a catalyst, a ligand and a base, and the present invention has been completed. It was.
That is, the present invention
1) A process for producing compound (I) or a salt thereof, comprising reacting compound (II) or a salt thereof with compound (III) or a salt thereof in the presence of a catalyst, a ligand and a base;
2) The production method according to 1) above, wherein the catalyst is a palladium catalyst;
3) The production method according to 1) above, wherein the ligand is a BINAP compound;
And so on.

According to the production method of the present invention, a nitrogen-containing fused heterocyclic compound useful as a synthetic intermediate for various drugs can be obtained simply and in high yield.
The nitrogen-containing fused heterocyclic compound is, for example, a somatostatin receptor agonist (prophylactic / therapeutic agent for tumors, diabetes, diabetic complications, obesity, etc.) described in WO98 / 47882 or a synthetic intermediate thereof; The described preventive / therapeutic agent for diabetes or a synthetic intermediate thereof; the preventive / therapeutic agent for infectious disease described in EP-A119591 or a synthetic intermediate thereof; the tachykinin antagonist described in EP-A733632 (inflammatory, allergic) It is useful as a prophylactic / therapeutic agent for diseases, etc.) or a synthetic intermediate thereof.

Below, the definition of each symbol in compound (I), compound (II) and compound (III) will be described in detail.
Y represents a halogen atom or —OSO ₂ R ¹ — (R ¹ represents an alkyl group which may be halogenated).
Here, examples of the halogen atom include fluorine, chlorine, bromine, iodine and the like. Of these, bromine is preferable.
Examples of the “optionally halogenated alkyl group” represented by R ¹ include an optionally halogenated C _1-6 alkyl group (eg, methyl, ethyl, trifluoromethyl).
Y is preferably a halogen atom, more preferably bromine.

Examples of the “5-10 membered aromatic ring” in the “5-10 membered aromatic ring optionally having substituent (s)” for ring A include 5-10 membered aromatic hydrocarbon ring, 5-10 membered An aromatic heterocyclic ring is mentioned.
Preferable examples of the 5-10 membered aromatic hydrocarbon ring include benzene, naphthalene and the like.
A preferred example of the 5-10 membered aromatic heterocycle is a 5-10 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen in addition to carbon atoms as ring constituent atoms. Rings such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,3-triazole Pyridine, pyridazine, pyrimidine, triazine, benzofuran, isobenzofuran, benzo [b] thiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, 1,2- Benzisothiazole, 1H-benzotri Tetrazole, quinoline, isoquinoline and the like.
The “5- to 10-membered aromatic ring” represented by the A ring is preferably a benzene ring.

The “5-10 membered aromatic ring” may further have 1 to 3 substituents at substitutable positions. Examples of such a substituent include “halogen atom”, “nitro group”, “cyano group”, “C _1-3 alkylenedioxy group”, and “optionally substituted alkyl group having 1 to 10 carbon atoms”. ", An optionally substituted alkenyl group having 2 to 10 carbon atoms", "an optionally substituted alkynyl group having 2 to 10 carbon atoms", "an optionally substituted cyclohexane having 3 to 10 carbon atoms". Alkyl group "," optionally substituted cycloalkenyl group having 3 to 10 carbon atoms "," optionally substituted cycloalkadienyl group having 4 to 10 carbon atoms "," optionally substituted carbon " Formula 6-14 aryl group ”,“ optionally substituted heterocyclic group ”,“ acyl group ”,“ optionally substituted amino group ”,“ optionally substituted hydroxy group ”,“ substituted ” Thiol group that may have been And a “midino group”.

Here, examples of the “halogen atom” include fluorine, chlorine, bromine, iodine and the like.
Examples of the “C _1-3 alkylenedioxy group” include methylenedioxy, ethylenedioxy and the like.
As the `` alkyl group having 1 to 10 carbon atoms '' in the `` optionally substituted alkyl group having 1 to 10 carbon atoms '', for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t. -Butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl Etc.
Examples of the “alkenyl group having 2 to 10 carbon atoms” in the “optionally substituted alkenyl group having 2 to 10 carbon atoms” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1 -Butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl , 5-hexenyl, 1-heptenyl, 1-octenyl and the like.
Examples of the “alkynyl group having 2 to 10 carbon atoms” in the “optionally substituted alkynyl group having 2 to 10 carbon atoms” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3 -Butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like .

The “alkyl group having 1 to 10 carbon atoms”, “alkenyl group having 2 to 10 carbon atoms”, and “alkynyl group having 2 to 10 carbon atoms” have 1 to 3 substituents at substitutable positions. It may be.
Examples of such a substituent include a cycloalkyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms (eg, phenyl, naphthyl), an aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, oxazolyl). , Thiazolyl, quinolyl), non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl), aralkyl group having 7 to 13 carbon atoms, alkyl group having 1 to 4 carbon atoms, or carbon number Amino group which may be mono- or di-substituted with 2 to 8 acyl groups (eg, alkanoyl group, alkoxycarbonyl group), C1-C8 alkylsulfonylamino group, amidino group, C2-C8 acyl Group (eg, alkanoyl group, alkoxycarbonyl group), alkylsulfonyl group having 1 to 8 carbon atoms, or 1 to 4 carbon atoms A carbamoyl group which may be mono- or di-substituted with an alkyl group, a sulfamoyl group which may be mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms, a carboxyl group, a hydroxy group, 1 to 3 halogen atoms ( Example, fluorine, chlorine, bromine, iodine) which may be substituted with 1 to 6 carbon atoms, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) Good alkenyloxy group having 2 to 5 carbon atoms, cycloalkyloxy group having 3 to 7 carbon atoms, aralkyloxy group having 7 to 13 carbon atoms, aryloxy group having 6 to 14 carbon atoms (eg, phenyloxy, naphthyloxy) , A thiol group, an alkylthio group having 1 to 6 carbon atoms that may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine), 7 to 7 carbon atoms 3 aralkylthio group, arylthio group having 6 to 14 carbon atoms (eg, phenylthio, naphthylthio), sulfo group, cyano group, azide group, nitro group, nitroso group, halogen atom (eg, fluorine, chlorine, bromine, iodine) Etc.

Examples of the “cycloalkyl group having 3 to 10 carbon atoms” in the “optionally substituted cycloalkyl group having 3 to 10 carbon atoms” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicyclo [ 2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [ 4.2.1] nonyl, bicyclo [4.3.1] decyl and the like.
Examples of the “cycloalkenyl group having 3 to 10 carbon atoms” in the “optionally substituted cycloalkenyl group having 3 to 10 carbon atoms” include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2 -Cyclohexen-1-yl, 3-cyclohexen-1-yl, etc. are mentioned.
Examples of the “cycloalkadienyl group having 4 to 10 carbon atoms” in the “optionally substituted cycloalkadienyl group having 4 to 10 carbon atoms” include 2,4-cyclopentadien-1-yl, 2, 4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like can be mentioned.
Examples of the “aryl group having 6 to 14 carbon atoms” in the “optionally substituted aryl group having 6 to 14 carbon atoms” include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like.

Examples of the “heterocyclic group” in the “optionally substituted heterocyclic group” include non-aromatic heterocyclic groups and aromatic heterocyclic groups.
Examples of the non-aromatic heterocyclic group include a 5- to 7-membered monocyclic non-aromatic hetero group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. A cyclic group or a fused non-aromatic heterocyclic group can be mentioned. Examples of the non-aromatic condensed heterocyclic group include a 5- to 7-membered monocyclic non-aromatic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or one sulfur atom. And a group condensed with a 5-membered ring to be included.
Preferred examples of the non-aromatic heterocyclic group include 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, hexamethyleneimin-1-yl, oxazolidine-3-yl, thiazolidin-3-yl, and imidazolidine. -3-yl, 2-oxoimidazolidin-1-yl, 2,4-dioxoimidazolidin-3-yl, 2,4-dioxooxazolidine-3-yl, 2,4-dioxothiazolidine-3- Yl, 1,3-dioxoisoindol-2-yl, 5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl and the like.

As the aromatic heterocyclic group, for example, a 5- to 7-membered monocyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom Or a condensed aromatic heterocyclic group is mentioned. Examples of the condensed aromatic heterocyclic group include these 5- to 7-membered monocyclic aromatic heterocyclic groups and a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring, or one sulfur atom. And a group condensed with a 5-membered ring.
Preferable examples of the aromatic heterocyclic group include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- Pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, isoxazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1, 2,3-triazol-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-quinazolyl, 4-quinazolyl, 2-quinoxalyl, 2-benzofuryl, 3-benzofuryl, 2-benzothienyl, 3-benzothienyl, 2-benzoxazolyl, 2-benzothiazolyl, benzimidazol-1-yl, benzimidazol-2-yl, indol-1-yl, indol-3-yl 1H-indazol-3-yl, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyridin-6-i 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl, 1H-imidazo [4,5-b] pyrazin-2-yl and the like Can be mentioned.

The "optionally substituted cycloalkyl group having 3 to 10 carbon atoms", "optionally substituted cycloalkenyl group having 3 to 10 carbon atoms", "optionally substituted 4 to 10 carbon atoms". Examples of the substituent in the “cycloalkadienyl group”, “optionally substituted aryl group having 6 to 14 carbon atoms” and “optionally substituted heterocyclic group” include 1 to 3 halogen atoms ( Eg, fluorine, chlorine, bromine, iodine) optionally substituted with 1 to 6 carbon atoms; substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) A good alkenyl group having 2 to 6 carbon atoms; a cycloalkyl group having 3 to 10 carbon atoms; an aryl group having 6 to 14 carbon atoms (eg, phenyl, naphthyl); an aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, Oxazolyl, thi Zolyl); non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl); aralkyl group having 7 to 13 carbon atoms; alkyl group having 1 to 4 carbon atoms or 1 to 15 carbon atoms An amino group (amino, mono- or di-C _2-10 alkanoylamino, C _1-10 alkoxy-carbonylamino, carbamoylamino, mono-) which may be mono- or di-substituted with an acyl group (eg, alkanoyl group) Or di-C _1-10 alkyl-carbamoylamino, C _6-14 aryl-carbonylamino, C _3-10 cycloalkyl-carbonylamino, C _7-13 aralkyloxy-carbonylamino, mono- or di-C _1-10 Alkylsulfonylamino, C _6-14 arylsulfonylamino C _1-6 alkoxy-carbamoylamino); an amidino group; an acyl group having 2 to 8 carbon atoms (eg, an alkanoyl group); a carbamoyl group optionally mono- or disubstituted with an alkyl group having 1 to 4 carbon atoms; A sulfamoyl group which may be mono- or di-substituted by an alkyl group having 1 to 4 carbon atoms; a carboxyl group; an alkoxycarbonyl group having 2 to 8 carbon atoms; a hydroxy group; 1 to 3 halogen atoms (eg, fluorine, chlorine) , Bromine, iodine) optionally substituted with 1 to 6 carbon atoms; optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) An alkenyloxy group having 5 to 7 carbon atoms; a cycloalkyloxy group having 3 to 7 carbon atoms; an aralkyloxy group having 7 to 13 carbon atoms; an aryloxy group having 6 to 14 carbon atoms (eg, phenyloxy group) Thiol group; an alkylthio group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); aralkyl having 7 to 13 carbon atoms Thio group; arylthio group having 6 to 14 carbon atoms (eg, phenylthio, naphthylthio); sulfo group; cyano group; azide group; nitro group; nitroso group; halogen atom (eg, fluorine, chlorine, bromine, iodine) It is done. The number of substituents is, for example, 1 to 3.

Examples of the “acyl group” include the formula: —COR ⁴ , —CO—OR ⁴ , —SO ₂ R ⁴ , —SOR ⁴ , —PO ₃ R ⁴ R ⁵ , —CO—NR ^4a R ^5a , —CS—NR. ^4a R ^5a [wherein R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. R ^4a and R ^5a are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ^4a and R ^5a together with an adjacent nitrogen atom , Which may form an optionally substituted nitrogen-containing heterocyclic ring].
The “optionally substituted hydrocarbon group” represented by R ⁴ , R ⁵ , R ^4a or R ^5a is the “optionally substituted alkyl having 1 to 10 carbon atoms” exemplified as the substituent in the A ring. Group "," optionally substituted C2-C10 alkenyl group "," optionally substituted C2-C10 alkynyl group "," optionally substituted C3-C10 “Cycloalkyl group”, “optionally substituted cycloalkenyl group having 3 to 10 carbon atoms”, “optionally substituted cycloalkadienyl group having 4 to 10 carbon atoms” and “optionally substituted” Examples thereof include an “aryl group having 6 to 14 carbon atoms”, “an aralkyl group having 7 to 13 carbon atoms which may be substituted”, and an “arylalkenyl group having 8 to 13 carbon atoms which may be substituted”.

Examples of the “aralkyl group having 7 to 13 carbon atoms” in the “optionally substituted aralkyl group having 7 to 13 carbon atoms” include benzyl, phenethyl, naphthylmethyl and the like.
Examples of the “arylalkenyl group having 8 to 13 carbon atoms” in the “optionally substituted arylalkenyl group having 8 to 13 carbon atoms” include styryl and the like.
Examples of the substituent in these “optionally substituted aralkyl group having 7 to 13 carbon atoms” and “optionally substituted arylalkenyl group having 8 to 13 carbon atoms” include “optionally substituted”. What was illustrated as substituents, such as a C3-C10 cycloalkyl group, is mentioned. The number of substituents is, for example, 1 to 3.
Examples of the “optionally substituted heterocyclic group” represented by R ⁴ , R ⁵ , R ^4a or R ^5a include those exemplified as the substituent in the A ring.
The “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R ^4a and R ^5a together with the adjacent nitrogen atom is, for example, at least one nitrogen atom other than a carbon atom as a ring-constituting atom And a 5- to 7-membered nitrogen-containing heterocycle which may further contain 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Preferable examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like.
The nitrogen-containing heterocycle may have 1 to 2 substituents at substitutable positions. Examples of such a substituent include a hydroxy group, a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine), a C _7-13 aralkyl group ( Examples include benzyl and diphenylmethyl).

As preferable examples of the “acyl group”, formyl, carboxyl, carbamoyl, C _1-6 alkyl-carbonyl (eg, acetyl, butanoyl, isobutanoyl, isopentanoyl), C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl) , Ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl), C _6-14 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2-naphthoyl), C _6-14 aryloxy-carbonyl (eg, phenyloxycarbonyl, naphthyl) 1 to 3 substituents selected from C _7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl), mono- or di- (halogen atom and C _1-6 alkoxy-carbonyl) Have Optionally a C _1-6 also alkyl) - carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl, trifluoroacetic ethylcarbamoyl), C _6-14 aryl - carbamoyl (e.g., Phenylcarbamoyl), C _3-10 cycloalkyl-carbamoyl (eg, cyclopropylcarbamoyl), C _7-13 aralkyl-carbamoyl (eg, benzylcarbamoyl), C _1-6 alkylsulfonyl (eg, methylsulfonyl), C _{6 -14} arylsulfonyl (eg, phenylsulfonyl), nitrogen-containing heterocyclic-carbonyl optionally substituted with hydroxy-carbonyl (eg, pyrrolidinylcarbonyl, piperidinocarbonyl), C _1-6 alkylsulfini (Eg, methylsulfinyl), C _1-6 alkoxy-carbamoyl (eg, methoxycarbamoyl), aminocarbamoyl, hydroxycarbamoyl, thiocarbamoyl and the like.

Examples of the “optionally substituted amino group” include an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, and a cycloalkenyl having 3 to 10 carbon atoms. And an amino group which may be substituted with one or two substituents selected from a group, an aryl group having 6 to 14 carbon atoms and an acyl group.
Here, “C1-C10 alkyl group”, “C2-C10 alkenyl group”, “C3-C10 cycloalkyl group”, “C3-C10 cycloalkenyl group”, “ Examples of the “aryl group having 6 to 14 carbon atoms” and “acyl group” include those exemplified as the substituent in the A ring.
Suitable examples of substituted amino groups include mono- or di-C _1-10 alkylamino (eg, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C _2-10 alkenylamino (eg, diallylamino), mono- or di-C _3-10 cycloalkylamino (eg, cyclohexylamino), mono- or di-C _2-10 alkanoylamino (eg, acetylamino, propionylamino) , Butanoylamino, isobutanoylamino, isopentanoylamino), C _6-14 aryl-carbonylamino (eg, benzoylamino), C _6-14 arylamino (eg, phenylamino), carbamoylamino, mono- or Di-C _1-10 alkyl-carbamoylamino (eg, Methylcarbamoylamino, dimethylcarbamoylamino), C _1-10 alkoxy-carbonylamino (eg, methoxycarbonylamino), C _7-13 aralkyloxy-carbonylamino (eg, benzyloxycarbonylamino), C _3-10 cycloalkyl- Carbonylamino (eg, cyclopentylcarbonylamino, cyclohexylcarbonylamino), mono- or di-C _1-10 alkylsulfonylamino (eg, methylsulfonylamino, dimethylsulfonylamino), C _6-14 arylsulfonylamino (eg, phenylsulfonyl) Amino), C _1-6 alkoxy-carbamoylamino (eg, methoxycarbamoylamino) and the like.

Examples of the “optionally substituted hydroxy group” include, for example, an optionally substituted “alkyl group having 1 to 10 carbon atoms”, “an alkenyl group having 2 to 10 carbon atoms”, and “2 to 10 carbon atoms”. An alkynyl group, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms, or an aralkyl group having 7 to 13 carbon atoms. Examples thereof include an optionally substituted hydroxy group.
Here, "C1-C10 alkyl group", "C2-C10 alkenyl group", "C2-C10 alkynyl group", "C3-C10 cycloalkyl group", "Carbon Examples of the “C3-C10 cycloalkenyl group”, “C6-C14 aryl group” or “C7-C13 aralkyl group” include those exemplified as the aforementioned R ^{4 and the} like.
These “alkyl group having 1 to 10 carbon atoms”, “alkenyl group having 2 to 10 carbon atoms”, “alkynyl group having 2 to 10 carbon atoms”, “cycloalkyl group having 3 to 10 carbon atoms”, “3 carbon atoms” -10 cycloalkenyl group "," C6-C14 aryl group "and" C7-C13 aralkyl group "may have 1 to 3 substituents at substitutable positions. Good. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine), an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, and an alkanoyl group having 2 to 5 carbon atoms. Cyano group, carbamoyl group, hydroxy group, cycloalkyl group having 3 to 10 carbon atoms, carboxyl group, amino group, alkanoylamino group having 2 to 5 carbon atoms, and the like.

The substituted hydroxy group is preferably a halogen atom (eg, fluorine, chlorine, bromine, iodine), an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, or an alkanoyl group having 2 to 5 carbon atoms. Each having 1 to 3 substituents selected from a group, a cyano group, a carbamoyl group, a hydroxy group, a carboxyl group, an amino group, an alkanoylamino group having 2 to 5 carbon atoms, and a cycloalkyl group having 3 to 10 carbon atoms "Alkoxy group having 1 to 10 carbon atoms", "Alkenyloxy group having 2 to 10 carbon atoms", "Alkynyloxy group having 2 to 10 carbon atoms", "Cycloalkyloxy having 3 to 10 carbon atoms" Group "," cycloalkenyloxy group having 3 to 10 carbon atoms "," aryloxy group having 6 to 14 carbon atoms "," aralkyloxy group having 7 to 13 carbon atoms ", etc. .
Here, as the “C1-C10 alkoxy group”, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy, neopentyloxy Hexyloxy, heptyloxy, nonyloxy and the like.
Examples of the “alkenyloxy group having 2 to 10 carbon atoms” include allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy and the like.
Examples of the “C2-C10 alkynyloxy group” include ethynyloxy, propynyloxy, pentynyloxy and the like.
Examples of the “C3-C10 cycloalkyloxy group” include cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
Examples of the “C3-C10 cycloalkenyloxy group” include 2-cyclopentenyloxy and 2-cyclohexenyloxy.
Examples of the “C6-C14 aryloxy group” include phenoxy and naphthyloxy.
Examples of the “aralkyloxy group having 7 to 13 carbon atoms” include benzyloxy, phenethyloxy, naphthylmethyloxy and the like.

  The substituted hydroxy group is more preferably a halogen atom (eg, fluorine, chlorine, bromine, iodine), an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, or an alkyl group having 2 to 5 carbon atoms. It has 1 to 3 substituents each selected from an alkanoyl group, a cyano group, a carbamoyl group, a hydroxy group, a carboxyl group, an amino group, an alkanoylamino group having 2 to 5 carbon atoms, and a cycloalkyl group having 3 to 10 carbon atoms. And “an alkoxy group having 1 to 10 carbon atoms”, “a cycloalkyloxy group having 3 to 10 carbon atoms” or “aralkyloxy group having 7 to 13 carbon atoms”.

Examples of the “optionally substituted thiol group” include, for example, an optionally substituted “alkyl group having 1 to 10 carbon atoms”, “an alkenyl group having 2 to 10 carbon atoms”, and “2 to 10 carbon atoms”. “Alkynyl group”, “C3-C10 cycloalkyl group”, “C3-C10 cycloalkenyl group”, “C6-C14 aryl group” or “C7-C13 aralkyl group” The thiol group which may be substituted is mentioned.
Here, "C1-C10 alkyl group", "C2-C10 alkenyl group", "C2-C10 alkynyl group", "C3-C10 cycloalkyl group", "Carbon Examples of the “C3-C10 cycloalkenyl group”, “C6-C14 aryl group” or “C7-C13 aralkyl group” include those exemplified as the aforementioned R ^{4 and the} like.
These “alkyl group having 1 to 10 carbon atoms”, “alkenyl group having 2 to 10 carbon atoms”, “alkynyl group having 2 to 10 carbon atoms”, “cycloalkyl group having 3 to 10 carbon atoms”, “3 carbon atoms” -10 cycloalkenyl group "," C6-C14 aryl group "and" C7-C13 aralkyl group "may have 1 to 3 substituents at substitutable positions. Good. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine), an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, and an alkanoyl group having 2 to 5 carbon atoms. Cyano group, carbamoyl group, hydroxy group, cycloalkyl group having 3 to 10 carbon atoms, carboxyl group, amino group, alkanoylamino group having 2 to 5 carbon atoms, and the like.

The substituted thiol group is preferably a halogen atom (eg, fluorine, chlorine, bromine, iodine), an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, or an alkanoyl group having 2 to 5 carbon atoms. Each having 1 to 3 substituents selected from a group, a cyano group, a carbamoyl group, a hydroxy group, a carboxyl group, an amino group, an alkanoylamino group having 2 to 5 carbon atoms, and a cycloalkyl group having 3 to 10 carbon atoms "C1-C10 alkylthio group", "C2-C10 alkenylthio group", "C2-C10 alkynylthio group", "C3-C10 cycloalkylthio group" ”,“ C3-C10 cycloalkenylthio group ”,“ C6-C14 arylthio group ”,“ C7-C13 aralkylthio group ”and the like.
Examples of the “C1-C10 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, t.-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, Examples include heptylthio and nonylthio.
Examples of the “alkenylthio group having 2 to 10 carbon atoms” include allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio and the like.
Examples of the “C2-C10 alkynylthio group” include ethynylthio, propynylthio, pentynylthio and the like.
Examples of the “C3-C10 cycloalkylthio group” include cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
Examples of the “C3-C10 cycloalkenylthio group” include 2-cyclopentenylthio, 2-cyclohexenylthio and the like.
Examples of the “C6-C14 arylthio group” include phenylthio, naphthylthio and the like.
Examples of the “aralkylthio group having 7 to 13 carbon atoms” include benzylthio, phenethylthio, naphthylmethylthio and the like.
The substituted thiol group is more preferably an alkylthio group having 1 to 10 carbon atoms which may be substituted with a carbamoyl group.

As preferable specific examples of the “substituent” in the “5- to 10-membered aromatic ring” represented by the A ring,
1) a halogen atom;
2) a nitro group;
3) a cyano group;
4) C _1-3 alkylenedioxy group;
5) Halogen atom, hydroxy group, carboxyl group, C2-C8 alkoxycarbonyl group, carbamoyl group, cyano group, amino group, C2-C8 alkanoylamino group, C2-C8 alkoxycarbonylamino group A C _1-10 alkyl group or a C _2-10 alkenyl group optionally having 1 to 3 substituents each selected from an alkylsulfonylamino group having 1 to 8 carbon atoms;
6) optionally substituted hydroxy group [eg, halogen atom, alkoxy group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group, Each may have 1 to 3 substituents selected from a hydroxy group, a carboxyl group, an amino group, an alkanoylamino group having 2 to 5 carbon atoms, and a cycloalkyl group having 3 to 10 carbon atoms,
An alkoxy group having 1 to 10 carbon atoms, a cycloalkyloxy group having 3 to 10 carbon atoms, or an aralkyloxy group having 7 to 13 carbon atoms; a hydroxy group];
7) Acyl group [eg, formyl, carboxyl, C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, carbamoyl, aminocarbamoyl, hydroxycarbamoyl, mono- or di- (halogen atom and C _1-6 alkoxy- Optionally substituted with 1 to 3 substituents selected from carbonyl, C _1-6 alkyl) -carbamoyl, C _3-10 cycloalkyl-carbamoyl, C _7-13 aralkyl-carbamoyl, substituted with hydroxy A nitrogen-containing heterocycle-carbonyl (eg, pyrrolidinylcarbonyl, piperidinocarbonyl), C _1-6 alkylsulfonyl, C _1-6 alkylsulfinyl, thiocarbamoyl];
8) An optionally substituted amino group [eg, amino, mono- or di-C _2-10 alkanoylamino, C _1-10 alkoxy-carbonylamino, carbamoylamino, mono- or di-C _1-10 alkyl- Carbamoylamino, C _6-14 aryl-carbonylamino, C _3-10 cycloalkyl-carbonylamino, C _7-13 aralkyloxy-carbonylamino, mono- or di-C _1-10 alkylsulfonylamino, C _6-14 aryl Sulfonylamino, C _1-6 alkoxy-carbamoylamino];
9) an aryl group having 6 to 14 carbon atoms;
10) An optionally substituted thiol group [eg, an alkylthio group having 1 to 10 carbon atoms that may be substituted with a carbamoyl group];
11) An optionally substituted heterocyclic group [eg, a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a cyano group , Carbamoyl group, amino group, mono- or di-C _2-10 alkanoylamino group, C _1-10 alkoxy-carbonylamino group, carbamoylamino group, mono- or di-C _1-10 alkyl-carbamoylamino group, C _6-14 aryl-carbonylamino group, C _3-10 cycloalkyl-carbonylamino group, C _7-13 aralkyloxy-carbonylamino group, mono- or di-C _1-10 alkylsulfonylamino group, C _6-14 aryl 1 to 2 selected from a sulfonylamino group and a C _1-6 alkoxy-carbamoylamino group Aromatic substituents (preferably furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrrolyl, triazolyl) or non-aromatic heterocyclic groups (preferably Dioxoisoindole, 5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl)]];
12) an amidino group;
Etc.
The number of substituents is preferably 1 to 3, more preferably 1 to 2.

Examples of the ring in the “optionally substituted ring” represented by B ring include a 5-10 membered aromatic ring and a 5-10 membered non-aromatic ring.
Here, examples of the 5- to 10-membered aromatic ring include those exemplified as the “5- to 10-membered aromatic ring” in the “optionally substituted 5- to 10-membered aromatic ring” represented by the A ring. Examples of the 5-10 membered non-aromatic ring include a 5-10 membered non-aromatic hydrocarbon ring and a 5-10 membered non-aromatic heterocyclic ring.
Preferable examples of the 5-10 membered non-aromatic hydrocarbon ring include cycloalkane (eg, cyclopentane, cyclohexane, cycloheptane, cyclooctane), cycloalkene (eg, cyclohexene) and the like.
As a suitable example of a 5-10 membered non-aromatic heterocyclic ring, a 5-10 membered non-aromatic containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom Group heterocycles such as tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidine, oxopyridine and the like.
The ring represented by ring B is preferably a 5-10 membered non-aromatic heterocyclic ring, more preferably oxopyridine.

  Examples of the substituent in the “ring optionally having a substituent” represented by the B ring include those exemplified as the substituent in the A ring. The number of substituents is, for example, 1 to 3.

［式中、Ｒ⁶およびＲ⁷は同一または異なって、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；
Ｒ⁸はニトリル基または−Ｌ−ＮＨＲ⁹（Ｌは２価の炭化水素基を、Ｒ⁹は水素原子またはアミノ基の保護基を示す）を；
Ｘは結合手、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ₂−または−ＮＲ¹⁰−（Ｒ¹⁰は水素原子または置換されていてもよい炭化水素基を示す）を示す］である。 In compound (I) and compound (II), at least one of ring A or ring B has a nitrogen atom as a ring constituent atom. That is, at least one of A ring or B ring is a nitrogen-containing heterocycle.
Partial structure in compound (I) and compound (II)

[Wherein, R ⁶ and R ⁷ are the same or different and each represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
R ⁸ represents a nitrile group or —L—NHR ⁹ (L represents a divalent hydrocarbon group, R ⁹ represents a hydrogen atom or an amino group protecting group);
X represents a bond, —O—, —S—, —SO—, —SO ₂ — or —NR ¹⁰ — (R ¹⁰ represents a hydrogen atom or an optionally substituted hydrocarbon group). .

As the “optionally substituted hydrocarbon group” for R ⁶ and R ⁷ , those exemplified as the aforementioned R ^{4 and the} like can be mentioned.
Examples of the “optionally substituted heterocyclic group” for R ⁶ and R ⁷ include those exemplified as the substituent for the A ring.
R ⁶ is preferably an optionally substituted hydrocarbon group, more preferably an alkyl having 1 to 10 carbon atoms which may be substituted with a cycloalkyl group having 3 to 10 carbon atoms (eg, cyclopropyl). It is a group. R ⁶ is particularly preferably an alkyl group having 4 to 5 carbon atoms (eg, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl).
R ⁷ is preferably an optionally substituted hydrocarbon group. R ⁷ is more preferably a halogen atom (eg, fluorine, chlorine), a hydroxy group, a nitro group, an amino group, or an optionally halogenated alkyl group having 1 to 6 carbon atoms (eg, trifluoromethyl, methyl). ), An alkoxy group having 1 to 6 carbon atoms (eg, methoxy), an aromatic heterocyclic group (eg, quinolyl, thienyl) and a cycloalkyl group having 3 to 10 carbon atoms (eg, cyclopentyl). (Preferably 1 to 2) each may have a substituent,
An alkyl group having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl), an aryl group having 6 to 14 carbon atoms (eg, phenyl) or An aralkyl group having 7 to 13 carbon atoms (eg, benzyl, phenethyl, naphthylmethyl); Of these, an alkyl group having 1 to 10 carbon atoms (preferably butyl), an aryl group having 6 to 14 carbon atoms (preferably phenyl) and the like are preferable.

R ⁸ represents a nitrile group or —L—NHR ⁹ (the symbols are as defined above).
Examples of the “divalent hydrocarbon group” represented by L include (1) C _1-10 alkylene (eg, —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — ( _{CH 2) 4 -, - (} CH 2) 5 -, - (CH 2) 6 -, - CHCH 3 -, - C (CH 3) 2 -, - (CH (CH 3)) 2 -, - (CH ₂ ) ₂ C (CH ₃ ) ₂ —, — (CH ₂ ) ₃ C (CH ₃ ) ₂ — and the like);
(2) C _2-10 alkenylene (eg, —CH═CH—, —CH ₂ —CH═CH—, —CH═CH—CH ₂ —, —CH═CH—CH ₂ —CH ₂ —, —C ( _{CH 3) 2 -CH = CH -} , - CH 2 -CH = CH-CH 2 -, - CH 2 -CH 2 -CH = CH -, - CH = CH-CH = CH -, - CH = CH-CH ₂ -CH ₂ -CH ₂ -, etc.);
(3) C _2-10 alkynylene (eg, —C≡C—, —CH ₂ —C≡C—, —CH ₂ —C≡C—CH ₂ —CH ₂ —, etc.) and the like.
L is preferably C _1-10 alkylene, more preferably —CH ₂ —.
Examples of the “amino-protecting group” represented by R ⁹ include formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl), C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert -Butoxycarbonyl), benzoyl, C _7-13 aralkyl-carbonyl (eg, benzylcarbonyl), C _7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl, phthaloyl, N , N-dimethylaminomethylene, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C _2-6 alkenyl (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy) or nitro.
R ⁸ is preferably a nitrile group.

X represents a bond, —O—, —S—, —SO—, —SO ₂ — or —NR ¹⁰ — (R ¹⁰ is as defined above).
As the “optionally substituted hydrocarbon group” for R ¹⁰ , those exemplified as the aforementioned R ^{4 and the} like can be mentioned. Of these, an alkyl group having 1 to 10 carbon atoms (eg, methyl, ethyl) is preferable.
X is preferably a bond or -O-, more preferably a bond.

In the compound (III), Z represents —O—, —S— or —NR ³ — (R ³ represents a hydrogen atom or an optionally substituted hydrocarbon group). Of these, —O— or —NR ³ — is preferable.
As "optionally substituted hydrocarbon group" represented by R ³ may include those exemplified as such the R ^4. Of these, an alkyl group having 1 to 10 carbon atoms (eg, methyl, ethyl) is preferable.
As the “optionally substituted hydrocarbon group” for R ² , those exemplified as the aforementioned R ^{4 and the} like can be mentioned. Among them, an alkyl group having 1 to 10 carbon atoms (eg, methyl, tert-butyl), a cycloalkyl group having 3 to 10 carbon atoms (eg, cyclohexyl), an aralkyl group having 7 to 13 carbon atoms (eg, benzyl), etc. Is preferred.
Examples of the “optionally substituted heterocyclic group” and “acyl group” represented by R ² include those exemplified as the substituent in the A ring. Of these, C _1-6 alkyl-carbonyl (eg, acetyl, butanoyl), C _6-14 arylsulfonyl (eg, phenylsulfonyl), each optionally substituted with a hydroxy group, and the like are preferable.
In addition, when Z is —NR ³ — and R ² is an acyl group, the acyl group and R ³ may be bonded to form a nitrogen-containing heterocycle together with an adjacent nitrogen atom. Examples of such nitrogen-containing heterocycles include 2-oxopiperidine.

Compound (I), compound (II) and compound (III) may be used as salts if they can form a salt. Examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
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, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- And salts with toluenesulfonic acid.
Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

In the production method of the present invention, compound (I) or a salt thereof is produced by reacting compound (II) or a salt thereof with compound (III) or a salt thereof in the presence of a catalyst, a ligand and a base. To do.
This reaction is usually performed in a solvent that does not adversely influence the reaction.
Examples of the solvent that does not adversely influence the reaction include amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; halogenated carbonization such as chloroform and dichloromethane. Hydrogens; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane, diethyl ether and dimethoxyethane; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile and propionitrile It is done. These solvents may be used by mixing two or more kinds at an appropriate ratio. The solvent is preferably an amide and an aromatic hydrocarbon, more preferably an aromatic hydrocarbon. Of these, toluene is preferable.

Examples of the catalyst used in the production method of the present invention include transition metal compounds such as rhodium; palladium carbon, palladium acetate, tetrakis (triphenylphosphine) palladium, tetrakis (tri- (2-tolyl) phosphine) palladium, tetrakis ( Palladium catalysts such as tri- (2-furyl) phosphine) palladium; bis (acetylacetone) nickel, dichlorobis (triphenylphosphine) nickel, bis (1,5-cyclooctadiene) nickel, bis (1,10-phenanthroline) nickel And nickel catalysts; Raney nickel; Raney cobalt and the like. The catalyst is preferably a palladium catalyst, more preferably palladium acetate.
The amount of the catalyst to be used is generally 0.00001 to 10 molar equivalents, preferably 0.001 to 1 molar equivalents, relative to compound (II) or a salt thereof.
As a ligand used in the production method of the present invention, for example, 2,2'-bis (diphenylphosphino) -1,1'binaphthyl (BINAP), 2,2'-bis (di-0-tolylphosphino)- Examples include BINAP compounds such as 1,1 ′ binaphthyl; phosphine compounds such as triphenylphosphine, tri-tert-butylphosphine, and tri-cyclohexylphosphine. The ligand is preferably a BINAP compound, more preferably BINAP.
The amount of the ligand to be used is generally 0.00001 to 10 molar equivalents, preferably 0.001 to 1 molar equivalents, relative to compound (II) or a salt thereof.

Examples of the base used in the production method of the present invention include metal hydrides such as sodium hydride and potassium hydride; alkali metal alcoholates such as sodium methylate, sodium ethylate, sodium tert-butylate and potassium tert-butylate; water Alkali metal salts such as potassium oxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene) Examples include amines. The base is preferably an alkali metal alcoholate, more preferably sodium tert-butylate.
The amount of the base used is preferably 0.1 to 2 molar equivalents relative to compound (II) or a salt thereof.
The amount of compound (III) or a salt thereof to be used is generally 1 to 100 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (II) or a salt thereof.
The reaction temperature is usually −10 to 250 ° C., preferably 0 to 150 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 40 hours.
The thus obtained compound (I) or a salt thereof can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like. .

［式中、Ｒ¹¹はニトリル基またはＣ₂₋₇アルコキシカルボニル基を；その他の記号は前記と同意義を示す］である化合物［以下、化合物（IIa）と略記することがある］は、例えば以下のＡ1〜Ａ3法によって製造することができる。
以下の各反応において、原料化合物が塩を形成し得る場合には、原料化合物を塩として用いてもよい。このような塩としては、例えば化合物（Ｉ）の塩として前記したものが用いられる。 Compound (II) and compound (III) used as starting compounds in the production method of the present invention can be produced according to a method known per se.
For example, partial structure of compound (II)

[Wherein R ¹¹ is a nitrile group or a C _2-7 alkoxycarbonyl group; other symbols are as defined above] [hereinafter, may be abbreviated as compound (IIa)] It can be produced by the following methods A1 to A3.
In each of the following reactions, when the raw material compound can form a salt, the raw material compound may be used as a salt. As such salt, for example, those described above as the salt of compound (I) are used.

［式中、Ｒ¹²はＣ₁₋₆アルキル基を、Ｌ¹は脱離基を、その他の記号は前記と同意義を示す］
Ｒ¹²で示されるＣ₁₋₆アルキル基としては、例えばメチル、エチル、プロピル、イソプロピルなどが挙げられる。
Ｌ¹で示される脱離基としては、例えばハロゲン原子（例、塩素、臭素、ヨウ素）、ハロゲン化されていてもよいＣ_１−６アルキルスルホニルオキシ（例、メタンスルホニルオキシ、エタンスルホニルオキシ、トリフルオロメタンスルホニルオキシ）、置換基を有していてもよいＣ_６−１０アリールスルホニルオキシ、ヒドロキシなどが挙げられる。
該「置換基を有していてもよいＣ_６−１０アリールスルホニルオキシ」における「置換基」としては、例えばハロゲン原子（例、塩素、臭素、ヨウ素）、ハロゲン化されていてもよいＣ_１−６アルキルまたはＣ_１−６アルコキシなどが挙げられる。置換基の数は、例えば１ないし３個である。「置換基を有していてもよいＣ_６−１０アリールスルホニルオキシ」の具体例としては、ベンゼンスルホニルオキシ、ｐ−トルエンスルホニルオキシ、１−ナフタレンスルホニルオキシ、２−ナフタレンスルホニルオキシなどが挙げられる。
「脱離基」は、好ましくは、ハロゲン原子（例、塩素、臭素、ヨウ素）、メタンスルホニルオキシ、トリフルオロメタンスルホニルオキシ、ｐ−トルエンスルホニルオキシなどである。 [A1 method]
Among the compounds (IIa), the compound (IIa-1) in which X is —O— can be produced, for example, by the following method.

[Wherein R ¹² represents a C _1-6 alkyl group, L ¹ represents a leaving group, and other symbols are as defined above]
Examples of the C _1-6 alkyl group represented by R ¹² include methyl, ethyl, propyl, isopropyl and the like.
Examples of the leaving group represented by L ¹ include halogen atoms (eg, chlorine, bromine, iodine), optionally halogenated C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoro). Romethanesulfonyloxy), C _6-10 arylsulfonyloxy which may have a substituent, hydroxy and the like.
As the “substituent” in the “optionally substituted C _6-10 arylsulfonyloxy”, for example, a halogen atom (eg, chlorine, bromine, iodine), optionally halogenated C _1- etc. ₆ alkyl or _{C 1-6} alkoxy and the like. The number of substituents is, for example, 1 to 3. Specific examples of “ _optionally substituted C _6-10 arylsulfonyloxy” include benzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy, 2-naphthalenesulfonyloxy and the like.
The “leaving group” is preferably a halogen atom (eg, chlorine, bromine, iodine), methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy and the like.

(Process 1)
In this step, compound (IV) and compound (V) are reacted to produce compound (VI).
This reaction includes, for example, a method in which compound (IV) and compound (V) are directly condensed using a condensing agent, or a method in which a reactive derivative of compound (IV) and compound (V) are appropriately reacted. Done with.
Examples of the condensing agent include carbodiimide condensing reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide and hydrochloride thereof; and phosphoric acid condensing reagents such as diethyl cyanophosphate and diphenylphosphoryl azide. Carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate and the like.
Examples of the solvent used in the reaction using the condensing agent include amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as chloroform and dichloromethane. Aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane and diethyl ether; esters such as ethyl acetate, propyl acetate and butyl acetate; nitriles such as acetonitrile and propionitrile; acetone, 2 -Ketones such as butanone; water and the like. These solvents may be used by mixing two or more kinds at an appropriate ratio.
The amount of compound (V) to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (IV).
The amount of the condensing agent to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (IV).
When the carbodiimide-based condensation reagent is used as a condensing agent, an appropriate condensation accelerator (eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N- The reaction efficiency can be improved by using (hydroxyphthalimide). Moreover, when using the said phosphoric acid type | system | group condensing reagent as a condensing agent, reaction efficiency can be improved by adding organic amine bases, such as a triethylamine normally.
The amount of the above condensation accelerator or organic amine base used is usually 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (IV).
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 60 hours.

In the method using the reactive derivative of compound (IV), examples of the reactive derivative include acid anhydride, acid halide (eg, acid chloride, acid bromide), imidazolide, mixed acid anhydride (eg, methyl carbonate, ethyl). Carbonic acid, anhydride with isobutyl carbonic acid) and the like.
For example, when an acid halide is used as the reactive derivative of compound (IV), the reaction is performed in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include amines such as triethylamine, N-ethyldiisopropylamine, N-methylmorpholine and N, N-dimethylaniline; and alkali metal salts such as sodium bicarbonate, sodium carbonate and potassium carbonate.
Examples of the solvent that does not adversely influence the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane and diethyl ether; methyl acetate and ethyl acetate , Esters such as propyl acetate and butyl acetate; nitriles such as acetonitrile and propionitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; dimethyl sulfoxide and the like Sulfoxides; water and the like. These solvents may be used by mixing two or more kinds at an appropriate ratio.
The usage-amount of the reactive derivative of compound (IV) is 1-10 molar equivalent normally with respect to compound (V), Preferably it is 1-3 molar equivalent.
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 20 hours.
When a mixed acid anhydride is used as the reactive derivative of compound (IV), the reaction can be performed by, for example, reacting compound (IV) with a chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) as a base. The reaction is carried out by reacting in the presence and further with compound (V).
Examples of the base include amines such as triethylamine, N-methylmorpholine, N-ethyldiisopropylamine and N, N-dimethylaniline; and alkali metal salts such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate.
The amount of compound (V) to be used is generally 1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (IV).
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 20 hours.
The compound (VI) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
In addition, compounds (IV) and (V) used as raw material compounds in Step 1 can be produced according to a method known per se.

(Process 2)
In this step, compound (VII) is produced by reacting compound (VI) with a base in a solvent that does not adversely influence the reaction.
Examples of the base include metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; potassium hydroxide, sodium hydroxide, sodium bicarbonate, carbonate Examples include alkali metal salts such as potassium; amines such as pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene).
The amount of the base used is preferably 0.1 to 2 molar equivalents relative to compound (VI).
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; water; methanol, Alcohols such as ethanol and isopropanol; ketones such as acetone and 2-butanone; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide Etc. These solvents may be used by mixing two or more kinds at an appropriate ratio.
The reaction temperature is generally −10 to 150 ° C., preferably 0 to 110 ° C.
The reaction time is usually 0.5 to 20 hours.
The compound (VII) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and the like.

(Process 3)
In this step, compound (VII) is reacted with compound (VIII) to produce compound (IIa-1).
In the compound (VIII), the leaving group represented by L ¹ is a halogen atom, an optionally halogenated C _1-6 alkylsulfonyloxy, or an optionally substituted C _6-10 arylsulfonyloxy. In this case, this reaction is performed according to a conventional method in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undeca. Amines such as -7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t.-butoxide and sodium t.-butoxide .
The amount of the base used is preferably 1 to 5 molar equivalents relative to compound (VII).
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and diethyl ether; ketones such as acetone and 2-butanone; chloroform, dichloromethane, and the like. Halogenated hydrocarbons; N, N-dimethylformamide, N, N-dimethylacetamide, amides such as 1-methyl-2-pyrrolidone; Nitriles such as acetonitrile and propionitrile; Sulfoxides such as dimethylsulfoxide Can be mentioned. These solvents may be used by mixing two or more kinds at an appropriate ratio.
The reaction temperature is generally −50 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 20 hours.

When the leaving group represented by L ¹ in the compound (VIII) is hydroxy, this reaction can be carried out according to a method known per se, for example, the method described in Synthesis page 1 (1981), or the like. It is done according to the method.
This reaction is usually performed in the presence of an organic phosphorus compound and an electrophilic agent in a solvent that does not adversely influence the reaction.
Examples of the organic phosphorus compound include triphenylphosphine and tributylphosphine.
Examples of the electrophilic agent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, azodicarbonyldipiperazine, and the like.
The amount of the organic phosphorus compound and electrophilic agent used is preferably 1 to 5 molar equivalents relative to compound (VII).
Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N— Amides such as dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; Nitriles such as acetonitrile and propionitrile; Esters such as ethyl acetate, propyl acetate and butyl acetate; Sulfoxides such as dimethyl sulfoxide And the like. These solvents may be used by mixing two or more kinds at an appropriate ratio.
The reaction temperature is generally −50 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 20 hours.
The thus obtained compound (IIa-1) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like.
In addition, the compound (VIII) used as a raw material compound in the step 3 can be produced according to a method known per se.

［式中、Ｌ²は脱離基を、その他の記号は前記と同意義を示す］
Ｌ²で示される脱離基としては、前記Ｌ¹として例示したハロゲン原子、ハロゲン化されていてもよいＣ_１−６アルキルスルホニルオキシおよび置換基を有していてもよいＣ_６−１０アリールスルホニルオキシが挙げられる。 [A2 method]
Of the compounds (IIa), X is Xa (Xa is —S—, —SO—, —SO ₂ — or —NR ¹⁰ — (R ¹⁰ is as defined above)) (IIa— 2) can be produced, for example, by the following method.

[Wherein L ² represents a leaving group, and other symbols are as defined above]
As the leaving group represented by L ² , the halogen atom exemplified as the aforementioned L ¹ , an optionally halogenated C _1-6 alkylsulfonyloxy, and an optionally substituted C _6-10 arylsulfonyl Oxy is mentioned.

(Process 4)
In this reaction, compound (IX) is produced by reacting compound (VII) with a halogenating agent, a C _1-6 alkylsulfonylating agent or a C _6-10 arylsulfonyloxylating agent.
Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride and the like. In the reaction using a halogenating agent, amides such as N, N-dimethylformamide and N, N-dimethylacetamide may be used as a catalyst. The amount of the catalyst to be used is generally 0.0001 to 10 molar equivalents, preferably 0.001 to 3 molar equivalents, relative to compound (VII). In some cases, these catalysts may be used as a solvent.
Examples of the C _1-6 alkylsulfonylating agent include methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, and the like.
Examples of the C _6-10 arylsulfonyloxylating agent include benzenesulfonyl chloride, toluenesulfonyl chloride and the like.
The amount of the above halogenating agent, C _1-6 alkylsulfonylating agent and C _6-10 arylsulfonyloxylating agent to be used is generally 1-10 molar equivalents, preferably 1-3, relative to compound (VII). Molar equivalent.
This reaction is usually performed in a solvent that does not adversely influence the reaction.
Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; methyl acetate, Esters such as ethyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; nitriles such as acetonitrile and propionitrile; sulfoxides such as dimethyl sulfoxide and the like Is mentioned. These solvents may be used by mixing two or more kinds at an appropriate ratio.
This reaction may be performed in the presence of a base if necessary. Examples of such a base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4. 0] amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t.-butoxide.
The amount of the base used is preferably 1 to 5 molar equivalents relative to compound (VII).
The reaction temperature is usually −30 ° C. to 150 ° C.
The reaction time is usually 0.5 to 20 hours.
The compound (IX) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and the like.

(Process 5)
In this step, compound (IIa-2) is produced by reacting compound (IX) with compound (X).
This reaction is usually performed in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0]. Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t.-butoxide, sodium t-butoxide and the like .
The amount of the base to be used is preferably 1 to 5 molar equivalents relative to compound (IX).
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; acetone, 2- Ketones such as butanone; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; nitriles such as acetonitrile and propionitrile; sulfoxides such as dimethyl sulfoxide and the like Can be mentioned. These solvents may be used by mixing two or more kinds at an appropriate ratio.
The reaction temperature is generally −10 to 150 ° C., preferably 0 to 110 ° C.
The reaction time is usually 0.5 to 20 hours.

In the compound (IIa-2), a compound in which Xa is —S— can be converted to a compound in which Xa is —SO— or —SO ₂ — by subjecting it to an oxidation reaction.
The oxidation reaction is usually performed using an oxidizing agent in a solvent that does not adversely influence the reaction.
Examples of the oxidizing agent include hydrogen peroxide; organic peracids such as peracetic acid, perbenzoic acid, and metachloroperbenzoic acid; metal oxidizing agents such as manganese dioxide, potassium permanganate, and chromic acid; N-chlorosuccinimide, N -N-halocarboxylic amides such as bromosuccinimide and N-bromophthalimide; sodium hypochlorite, tert-butyl hypochlorite, cumene hydroperoxide and the like are used.
Examples of solvents that do not adversely influence the reaction include organic acids such as acetic acid and propionic acid; alcohols such as methanol, ethanol, propanol and isopropanol; aromatic hydrocarbons such as benzene, toluene and xylene; tetrahydrofuran, dioxane and diethyl Ethers such as ether; halogenated hydrocarbons such as chloroform and dichloromethane; ketones such as acetone and 2-butanone; N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone and the like Amides; Nitriles such as acetonitrile and propionitrile; Sulfoxides such as dimethyl sulfoxide; Water and the like. These solvents may be used by mixing two or more kinds at an appropriate ratio.
The reaction temperature is generally −50 to 120 ° C., preferably −20 to 100 ° C.
The reaction time is usually 0.5 to 20 hours.
The thus obtained compound (IIa-2) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like.
In addition, the compound (X) used as a raw material compound in the step 5 can be produced according to a method known per se.

［式中の記号は前記と同意義を示す］
（工程６）
本工程では、化合物（XI）と化合物（Ｖ）とを反応させて、化合物（VI）を製造する。
本反応は、前記工程1と同様にして行われる。
このようにして得られる化合物（VI）は、公知の分離精製手段、例えば濃縮、減圧濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフィーなどにより単離精製することができる。 Compound (VI) used as a raw material compound in Method A1 can also be produced according to Method B below.
[Method B]

[The symbols in the formula are as defined above]
(Step 6)
In this step, compound (VI) is produced by reacting compound (XI) with compound (V).
This reaction is performed in the same manner as in Step 1.
The compound (VI) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and the like.

［式中の記号は前記と同意義を示す］
（工程７）
本工程では、化合物（XII）と化合物（Ｖ）とを反応させて、化合物（XIII）を製造する。本反応は、前記工程1と同様にして行われる。
このようにして得られる化合物（XIII）は、公知の分離精製手段、例えば濃縮、減圧濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフィーなどにより単離精製することができる。
（工程８）
本工程では、化合物（XIII）と塩基とを反応させて、化合物（IIa−3）を製造する。本反応は、前記工程2と同様にして行われる。
このようにして得られる化合物（IIa−3）は、公知の分離精製手段、例えば濃縮、減圧濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフィーなどにより単離精製することができる。 [A3 method]
Among the compounds (IIa), the compound (IIa-3) in which X is a bond is, for example, the method described in JP-A-7-76573, JP-A-2000-72751, JP-A-2000-72675, etc .; It can be manufactured by a method according to the above.

[The symbols in the formula are as defined above]
(Step 7)
In this step, compound (XIII) is reacted with compound (V) to produce compound (XIII). This reaction is performed in the same manner as in Step 1.
The compound (XIII) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like.
(Process 8)
In this step, compound (IIa-3) is produced by reacting compound (XIII) with a base. This reaction is performed in the same manner as in Step 2.
The thus obtained compound (IIa-3) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like.

［式中の記号は前記と同意義を示す］である化合物（IIb）を製造することができる。 Among compounds (IIa), compound (IIa-4), in which R ¹¹ is a nitrile group, is subjected to a reduction reaction, and if necessary, further subjected to a protection reaction of an amino group, thereby obtaining a compound (II) , Partial structure

The compound (IIb) can be produced, wherein the symbols in the formula are as defined above.

Here, the reduction reaction is usually performed using a reducing agent in a solvent that does not adversely influence the reaction.
Examples of the reducing agent include metal hydrogen complex compounds (eg, sodium borohydride, sodium trimethoxyborohydride, lithium borohydride, lithium aluminum hydride, (2-methoxyethoxy) aluminum sodium); or the metal hydrogen Combinations of complex compounds and Lewis acids (eg, cobalt chloride, zinc chloride, tin chloride, boron trifluoride) are used.
The amount of the reducing agent to be used is preferably 1 to 10 molar equivalents relative to compound (IIa-4).
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; methanol, ethanol, Examples include alcohols such as propanol and isopropanol; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; water and the like. These solvents may be used by mixing two or more kinds at an appropriate ratio.
The reaction temperature is usually -20 to 150 ° C, preferably 10 to 100 ° C.
The reaction time is usually 0.5 to 20 hours.
When a combination of a metal hydride complex compound and a Lewis acid is used as the reducing agent, the amount of Lewis acid is usually 0.01 to 100 molar equivalents relative to compound (IIa-4).

The reduction reaction is also performed by catalytic reduction of compound (IIa-4) in a solvent that does not adversely influence the reaction in the presence of a catalyst.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; esters such as ethyl acetate and propyl acetate; methanol, ethanol and propanol And alcohols such as isopropanol; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; water and the like. These solvents may be used by mixing two or more kinds at an appropriate ratio. The reduction reaction may be performed in the presence of ammonia.
Examples of the catalyst include platinum (eg, platinum oxide, platinum black, platinum carbon), palladium (eg, palladium carbon, palladium acetate, palladium black, palladium chloride), nickel (eg, expanded nickel), rhodium ( Examples include rhodium carbon and rhodium alumina).
The usage-amount of a catalyst is 0.001-100g normally with respect to 1g of compounds (IIa-4).
The reaction temperature is usually 0 to 150 ° C, preferably 10 to 100 ° C.
The reaction time is usually 0.5 to 20 hours.

The amino group protecting reaction is carried out according to a method known per se. This reaction is performed, for example, in the same manner as in Step 1.
The compound (IIb) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The present invention will be described in more detail with reference to examples and reference examples below, but the present invention is not limited thereto.
Example 1
N- (3-cyano-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl) -2-hydroxyacetamide Palladium acetate (14.7 mg) and 2,2 under nitrogen flow '-Bis (diphenylphosphino) -1,1'binaphthyl (BINAP) (122.5 mg) was suspended in dimethyl sulfoxide (6 ml) and stirred at an internal temperature of 40 ° C. for 30 minutes. After the reaction solution was cooled to an internal temperature of 25 ° C., 6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile (0.5 g), sodium-tert-butylate ( 152 mg) and glycolamide (118 mg) were added, and the mixture was stirred at an internal temperature of 25 ° C. for 20 minutes. The reaction solution was stirred at an internal temperature of 98 ° C. for 2.5 hours and cooled to an internal temperature of 15 ° C. 0.5N HCl was added to the reaction solution to adjust the pH to 5 to 6, and the mixture was stirred at an internal temperature of 25 ° C. for 30 minutes. Ethyl acetate (30 ml) and water (10 ml) were added to the reaction liquid and the phases were separated, and the solvent was distilled off from the organic layer. The residue was subjected to silica gel column chromatography and eluted with hexane: ethyl acetate (1: 2, volume ratio). After evaporating the solvent of the eluate, the residue was recrystallized from ethyl acetate-hexane to obtain the title compound (0.25 g, yield 50.8%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.04 (6H, d, J = 6.7 Hz), 2.30-2.39 (1H, m), 2.71 (1H, t, J = 5.0Hz), 4.14 (2H, d, J = 7.4 Hz), 4.22 (2H, d, J = 5.0 Hz), 7.41-7.44 (2H, m), 7. 52-7.57 (4H, m), 7.89 (1H, dd, J = 8.7, 2.0 Hz), 8.48 (1H, s), 8.51 (1H, d, J = 5) .2Hz)
Example 2
4-butoxy-6-tert-butoxy-2-isobutyl-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile Palladium acetate (2.98 mg) and BINAP (24.8 mg) were added to toluene (2. 5 ml) and stirred at an internal temperature of 40 ° C. for 30 minutes. After cooling the reaction solution to an internal temperature of 25 ° C., 6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile (0.5 g) and sodium-tert-butylate ( 191 mg) was added. The reaction solution was stirred at an internal temperature of 25 ° C. for 20 minutes, and then stirred at an internal temperature of 98 ± 2 ° C. for 2.5 hours. The reaction mixture was cooled to an internal temperature of 15 ° C., acidified with 0.5N HCl (2.5 ml), and stirred at an internal temperature of 25 ± 2 ° C. for 30 minutes. Toluene (5 ml) was added to the reaction solution for liquid separation, and the organic layer was washed with water, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with hexane: ethyl acetate (5: 1, volume ratio). The solvent of the eluate was distilled off to obtain the title compound as crystals (0.48 g, yield 97.8%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.00 (6H, d, J = 6.7 Hz), 1.09 (3H, t, J = 7.4 Hz), 1.48 (9H, s) , 1.48-1.69 (2H, m), 1.86-1.95 (2H, m), 2.24-2.34 (1H, m), 4.01 (2H, d, J = 7.5 Hz), 4.16 (2 H, t, J = 6.5 Hz), 7.27 (1 H, dd, J = 8.8, 2.4 Hz), 7.36 (1 H, d, J = 2) .3 Hz), 8.36 (1H, d, J = 8.8 Hz)

Example 3
6- (Cyclohexyloxy) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile Palladium acetate (2.95 mg) and BINAP (24.5 mg) were added to toluene under a nitrogen stream. (5 ml) and stirred at an internal temperature of 40 ° C. for 30 minutes. After cooling the reaction solution to an internal temperature of 25 ° C., 6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile (0.5 g), cyclohexanol (0.279 ml) ) And sodium-tert-butylate (189 mg) were added, and the mixture was stirred at an internal temperature of 25 ° C. for 20 minutes. The reaction solution was stirred at an internal temperature of 98 ° C. for 2.5 hours, and then cooled to 15 ° C. The reaction mixture was acidified with 0.5N HCl (3 ml), and then stirred at an internal temperature of 25 ° C. for 30 minutes. To the reaction solution, 5 ml of toluene and 3 ml of water were added to separate the organic layer. The organic layer was washed with water and the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with toluene: ethyl acetate (5: 1, volume ratio). The solvent of the eluate was distilled off, and the residue was recrystallized from ethanol to obtain the title compound as crystals (0.35 g, yield 66.6%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.03 (6H, d, J = 6.7 Hz), 1.24-1.33 (3H, m), 1.46-1.55 (3H, m), 1.73-1.77 (2H, m), 1.86-1.91 (2H, m), 2.32-2.37 (1H, m), 4.13 (2H, d, J = 7.5 Hz), 4.12-4.22 (1 H, m), 6.64 (1 H, d, J = 2.4 Hz), 7.18 (1 H, dd, J = 8.9, 2 .5Hz), 7.40-7.44 (2H, m), 7.52-7.56 (3H, m), 8.44 (1H, d, J = 4.5Hz)
Example 4
6- (Benzylamino) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile Palladium acetate (2.95 mg) and BINAP (24.5 mg) were dissolved in toluene under a nitrogen stream. (5 ml) and stirred at an internal temperature of 40 ° C. for 30 minutes. After cooling the reaction solution to an internal temperature of 25 ° C., 6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile (0.5 g), benzylamine (0.285 ml) ) And sodium-tert-butylate (189 mg) were added, and the mixture was stirred at an internal temperature of 25 ° C. for 20 minutes. The reaction solution was stirred at an internal temperature of 98 ° C. for 2.5 hours, then cooled to 15 ° C., and 0.5N HCl (3 ml) was added to adjust the pH to around 8. Ethyl acetate (5 ml) was added to the reaction solution, and the mixture was stirred at an internal temperature of 25 ° C. for 30 minutes. Ethyl acetate (5 ml) was added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with hexane: ethyl acetate (2: 1, volume ratio). The solvent of the eluate was distilled off, and the residue was recrystallized from ethanol to obtain the title compound as crystals (0.48 g, yield 89.8%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.01 (6H, d, J = 6.7 Hz), 2.30-2.34 (1H, m), 4.09 (2H, d, J = 7.5 Hz), 4.23 (2 H, d, J = 5.5 Hz), 4.69 (1 H, t, J = 5.4 Hz), 6.21 (1 H, d, J = 2.3 Hz), 6.89 (1H, dd, J = 8.8, 2.3 Hz), 7.17-7.19 (2H, m), 7.26-7.32 (5H, m), 7.47-7 .49 (3H, m), 8.29 (1H, d, J = 8.8 Hz)

Example 5
6-tert-Butoxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile Palladium acetate (2.95 mg) and BINAP (24.5 mg) were added to toluene (2. 6 ml) and stirred at an internal temperature of 40 ° C. for 30 minutes. The reaction mixture was cooled to an internal temperature of 25 ° C., and 6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile (500 mg) and sodium-tert-butyrate (189 mg) Was added. The reaction solution was stirred at an internal temperature of 25 ° C. for 20 minutes, and then stirred at an internal temperature of 100 ° C. for 2.5 hours. The reaction mixture was cooled to an internal temperature of 15 ° C., acidified with 0.5N HCl (2.5 ml), and stirred at an internal temperature of 25 ± 2 ° C. for 30 minutes. Toluene (5 ml) was added to the reaction solution for liquid separation, and the organic layer was washed with water, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with hexane: ethyl acetate (6: 1, volume ratio). The solvent of the eluate was distilled off to give the title compound as crystals (0.48 g, yield 97.7%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.03 (3H, s), 1.05 (3H, s), 1.33 (9H, s), 2.30-2.39 (1H, m ), 4.14 (2H, d, J = 7.5 Hz), 6.78-6.79 (1H, m), 7.23-7.24 (1H, m), 7.39-7.43. (2H, m), 7.52-7.57 (3H, m), 8.42 (1H, d, J = 8.8 Hz)
Example 6
N- (3-Cyano-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl) -N, 4-dimethylbenzenesulfonamide Palladium acetate (5.9 mg) under a nitrogen stream And BINAP (49 mg) were added to toluene (6 ml), and the mixture was stirred at an internal temperature of 40 ° C. for 30 minutes. After cooling the reaction solution to an internal temperature of 25 ° C., N-methylbenzenesulfonic acid amide (486 mg), 6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile ( 0.5 g) and sodium-tert-butyrate (189 mg) were added. The reaction solution was stirred at an internal temperature of 25 ° C. for 20 minutes, and then stirred at an internal temperature of 100 ° C. for 7 hours. The reaction mixture was cooled to room temperature, acidified with 0.5N HCl (3 ml), and extracted with ethyl acetate. The organic layer was washed with water and the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with toluene: ethyl acetate (7: 1, volume ratio). After evaporating the solvent of the eluate, the residue was recrystallized from ethanol to give the title compound as crystals (252 mg, yield 39.6%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.04 (6H, d, J = 6.7 Hz), 2.32-2.44 (1H, m), 2.44 (3H, s), 3 .11 (3H, s), 4.15 (2H, d, J = 7.5 Hz), 7.09 (1H, d, J = 2.1 Hz), 7.21-7.23 (2H, m) 7.30-7.37 (5H, m), 7.50-7.53 (3H, m), 8.45 (1H, d, J = 8.7 Hz)

Example 7
N- (3-cyano-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl) propanamide Similar to Example 1 except that propionamide is used instead of glycolamide. To give the title compound (yield 42.3%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.03 (6H, d, J = 6.7 Hz), 1.18 (3H, t, J = 7.5 Hz), 2.29-2.38 ( 3H, m), 4.13 (2H, d, J = 7.5 Hz), 7.39-7.52 (6H, m), 7.65 (1H, s), 7.86 (1H, dd, J = 8.8, 2.1 Hz), 8.45 (1H, d, J = 8.8 Hz)
Example 8
N- (3-cyano-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl) -N-methylacetamide Implemented except that N-methylacetamide is used instead of glycolamide The title compound was obtained in the same manner as in Example 1 (yield 57.2%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.05 (6H, d, J = 6.7 Hz), 1.91 (3H, s), 2.32-2.41 (1H, m), 3 .24 (3H, s), 4.17 (2H, d, J = 7.5 Hz), 7.09 (1H, d, J = 1.8 Hz), 7.38-7.41 (2H, m) 7.48 (1H, dd, J = 8.5, 2.0 Hz), 7.57-7.59 (3H, m), 8.58 (1H, d, J = 8.5 Hz)

Example 9
2-Isobutyl-1-oxo-6- (2-oxopiperidin-1-yl) -4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile Implemented except that 2-piperidone was used instead of glycolamide The title compound was obtained in the same manner as in Example 1 (yield 42.6%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.03 (6H, d, J = 6.7 Hz), 1.91-1.96 (4H, m), 2.30-2.39 (1H, m), 2.51-2.55 (2H, m), 3.57-3.58 (2H, m), 4.16 (2H, d, J = 7.5 Hz), 7.19 (1H, d, J = 2.0 Hz), 7.41-7.44 (2H, m), 7.51-7.61 (4H, m), 8.54 (1H, d, J = 8.6 Hz)
Example 10
2-isobutyl-6-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile Similar to Example 2 except that sodium methylate is used instead of sodium-tert-butylate The title compound was obtained (yield 91.5%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.05 (6H, d, J = 6.7 Hz), 2.30-2.39 (1H, m), 3.74 (3H, s), 4 .14 (2H, d, J = 7.5 Hz), 6.65 (1H, d, J = 2.5 Hz), 7.20 (1H, dd, J = 8.9, 2.5 Hz), 7. 40-7.44 (2H, m), 7.53-7.57 (3H, m), 8.46 (1H, d, J = 8.9 Hz)

Example 11
2-isobutyl-6-isopropoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile The title compound was prepared in the same manner as in Example 3 except that isopropanol was used instead of cyclohexanol. Obtained (yield 93.3%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.03 (6H, d, J = 6.7 Hz), 1.27 (6H, d, J = 6.0 Hz), 2.30-2.39 ( 1H, m), 4.13 (2H, d, J = 7.5 Hz), 4.44-4.52 (1H, m), 6.62 (1H, d, J = 2.4 Hz), 7. 16 (1H, dd, J = 8.9, 2.4 Hz), 7.40-7.43 (2H, m), 7.52-7.57 (3H, m), 8.44 (1H, d , J = 8.9 Hz)
Example 12
6-anilino-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile The title compound was obtained in the same manner as in Example 4 except that aniline was used instead of benzylamine. (Yield 82.6%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.03 (6H, d, J = 6.7 Hz), 2.30-2.39 (1H, m), 4.12 (2H, d, J = 7.4 Hz), 6.07 (1 H, s), 6.70 (1 H, d, J = 2.2 Hz), 7.04-7.19 (3 H, m), 7.24-7.33 ( 3H, m), 7.39-7.52 (5H, m), 8.36 (1H, d, J = 8.8 Hz)

Example 13
6-Benzyloxy-3-tert-butoxycarbonylaminomethyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline Palladium acetate (1.4 mg) and BINAP (11.5 mg) under a nitrogen stream Was suspended in toluene (4 ml) and stirred at an internal temperature of 40 ° C. for 30 minutes. After cooling the reaction solution to room temperature, 3-tert-butoxycarbonylaminomethyl-6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline (150 mg), benzyl alcohol (0.064 ml) And sodium tert-butylate (44.5 mg) were added, and the mixture was stirred at an internal temperature of 25 ° C. for 20 minutes. Subsequently, the mixture was stirred at an internal temperature of 100 ° C. for 2.5 hours. The reaction solution was returned to room temperature, 0.5N HCl (0.75 ml) was added, and the mixture was extracted with toluene. After the extract was washed with water, the solvent was distilled off. The residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (4: 1, volume ratio). The solvent of the eluate was distilled off to obtain the title compound as crystals (59 mg, yield 37.8%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.99 (6H, d, J = 7.0 Hz), 1.42 (9H, s), 2.16-2.30 (1H, m), 4 .03 (2H, d, J = 7.4 Hz), 4.17 (2H, d, J = 5.0 Hz), 4.45 (1H, brs), 4.92 (2H, s), 6.35 (1H, d, J = 2.4 Hz), 7.09 (1H, dd, J = 2.4, 9.0 Hz), 7.17-7.37 (7H, m), 7.47-7. 52 (3H, m), 8.38 (1H, d, J = 9.0 Hz)

Reference example 1
Methyl 5-bromo-2-{[(cyanomethyl) (isobutyl) amino] carbonyl} benzoate 4-Bromophthalic anhydride (50.0 g) was dissolved in tetrahydrofuran (250 ml) and isobutylaminoacetonitrile (20 ml) at 20-30 ° C. 24.7 g) was added dropwise. The reaction mixture was stirred at 25 ° C. for 2 hours, 1N HCl (250 ml) was added dropwise at 20-30 ° C., and the mixture was stirred at the same temperature for 0.5 hour. Ethyl acetate (250 mL) was added to the reaction solution, and after extraction, ethyl acetate (125 mL) was added to the aqueous layer and extracted again. The organic layers were combined, washed with brine (250 ml) and dried over MgSO ₄ . The solvent was distilled off from the residue to obtain a pale red oil (84.4 g).
This oil (72.8 g) was dissolved in dimethylformamide (DMF) (202 ml), and potassium carbonate (27.5 g) was added at 20-30 ° C. After stirring the reaction solution at the same temperature for 0.5 hour, methyl iodide (14.9 ml) was added dropwise at the same temperature. The reaction solution was stirred at room temperature for 16 hours, and water (404 ml) was added dropwise at 20-30 ° C. Ethyl acetate (337 ml) was added to the reaction solution for extraction, and ethyl acetate (202 ml) was added to the aqueous layer for extraction again. The organic layers were combined, washed with brine, and dried over MgSO ₄ . The solvent was distilled off from the residue to obtain a pale red oil. To this oily substance was added isopropyl ether (IPE) (202 ml) to dissolve, and the solvent was distilled off (this operation was performed twice). IPE (674 ml) was added to the residue and the resulting mixture was heated to reflux with stirring for 1 hour. The reaction solution was cooled to 25 ° C. and stirred for 1 hour. The precipitated crystals were removed by filtration, washed with IPE (169 ml × 2), and methyl 4-bromo-2-{[(cyanomethyl) (isobutyl) amino] carbonyl} benzoate (29.9 g, yield 42.5%). ) The filtrates were combined and the solvent was distilled off. Then, n-hexane (337 ml) was added to the residue, and the mixture was stirred at 25 ° C. for 1 hour. The precipitated crystals were collected by filtration and washed with n-hexane to give the title compound (32.3 g, yield 45.9%).

Reference example 2
6-Bromo-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile 5-bromo-2-{[(cyanomethyl) (isobutyl) amino] carbonyl} methyl benzoate (20 0.0 g) was dissolved in methanol (40 ml) by heating and cooled to 20 ° C. A 28% (W / V) sodium methylate-methanol solution (21.9 g) was added dropwise to the reaction solution at 20-30 ° C. The reaction mixture was stirred at room temperature for 1 hr, and 1N HCl (124 ml) was added dropwise at 0-10 ° C. Water (276 ml) was added dropwise to the reaction solution at 0-30 ° C., followed by stirring at room temperature for 1 hour. The precipitated crystals were collected by filtration and washed with water (80 ml × 2) to give the title compound as crystals (17.0 g, yield 93.8%).
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 0.92 (6H, d, J = 6.7 Hz), 2.08-2.22 (1 H, m), 3.88 (2H, d, J = 7.4 Hz), 7.93 (1H, dd, J = 8.6, 1.8 Hz), 8.21 (1H, d, J = 8.6 Hz), 8.23 (1H, d, J = 1.9Hz)
Reference example 3
6-Bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile 6-bromo-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydroisoquinoline- 3-carbonitrile (3.0 g) was dissolved in DMF (15 ml). 1-Butane iodide (1.12 ml) was added to the resulting solution at 20-30 ° C., and potassium carbonate (1.36 g) was added at the same temperature. The reaction solution was stirred at room temperature for 18 hours, and water (15 ml) was added dropwise at 20-30 ° C. The reaction solution was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration and washed with water (15 ml × 2) (3.07 g).
The obtained crystals (2.50 g) were suspended in methanol (12.5 ml) and dissolved by heating. The resulting solution was gradually cooled to 25 ° C. over about 1 hour and then stirred at 25 ° C. for 2 hours. The precipitated crystals were collected by filtration and washed with methanol-water (1: 1, volume ratio; 2.5 ml) to obtain the title compound (1.88 g, yield 65.2%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.99-1.07 (9H, m), 1.54-1.67 (2H, m), 1.87-1.96 (2H, m) , 2.24-2.33 (1H, m), 4.02 (2H, d, J = 7.5 Hz), 4.17 (2H, t, J = 6.5 Hz), 7.77 (1H, dd, J = 8.6, 1.8 Hz), 7.98 (1H, d, J = 1.8 Hz), 8.31 (1H, d, J = 8.6 Hz)

Reference example 4
4-Bromo-2-benzoylbenzoic acid Aluminum chloride (11.8 g) was added to a mixture of benzene (5.16 ml) and o-dichlorobenzene (40 ml) and cooled to 2 ° C. 4-Bromophthalic anhydride (10 g) was added little by little while keeping the reaction solution at 10 ° C. or lower. The temperature of the reaction solution was raised to around 25 ° C. and stirred at the same temperature for 1 hour, then heated to 80 ° C. and stirred for 1 hour. The reaction solution was cooled to around 5 ° C., ethyl acetate (80 ml) was added dropwise at 25 ° C. or lower, and then water (40 ml) was added dropwise at 40 ° C. or lower. The organic layer was separated, washed with 4N HCl (40 ml) and then with water (40 ml), and the solvent was distilled off. Toluene (60 ml) and ethyl acetate (6 ml) were added to the residue, heated and dissolved at 80 ° C., and then gradually cooled to 25 ° C. The precipitated crystals were collected by filtration and added to a mixture of toluene (6 ml) and ethyl acetate (3 ml). The obtained mixture was heated to 96 ° C. to dissolve the crystals, cooled to 25 ° C. to precipitate crystals, further cooled to 5 ° C., and stirred at the same temperature for 1 hour. The obtained crystals were collected by filtration to give the title compound (6.34 g, yield 47.2%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 7.44 (2H, t, J = 7.8 Hz), 7.53-7.60 (2H, m), 7.71 (4H, m), 7 .94 (1H, d, J = 8.3 Hz)
Reference Example 5
6-Bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile 4-Bromo-2-benzoylbenzoic acid (6.24 g), toluene (81.1 g) and DMF (0.125 ml) was added with thionyl chloride (2.92 ml) under a nitrogen stream, and the mixture was stirred at 50 ° C. for 1.5 hours, and then the solvent was distilled off. Toluene (12.5 ml) and diisopropylethylamine (3.96 g) were added to the residue, and the temperature was raised to about 90 ° C. under a nitrogen stream to obtain a solution. Isobutylaminoacetonitrile (3.81 g) was added to the resulting solution, and the mixture was stirred at the same temperature for 3 hours. After the reaction solution was cooled to 25 ° C., 1N HCl (62.4 ml) was added and stirred. The organic layer was separated and washed with a 10% (W / W) aqueous sodium chloride solution, and then the solvent was distilled off. The residue was dissolved in ethanol (18.7 ml), acetic anhydride (2.51 g) and 1,8-diazabicyclo [5.4.0] -7-undecene (6.23 g) were added, and the mixture was stirred at 50 ° C. for 1 hour. Stir. Water (15.6 ml) was added dropwise to the reaction solution at 25 ° C., and the precipitated crystals were collected by filtration to give the title compound (6.34 g, yield 81.3%).
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.04 (6H, d, J = 6.7 Hz), 2.30-2.39 (1H, m), 4.15 (2H, d, J = 7.5 Hz), 7.39-7.44 (3 H, m), 7.55-7.60 (3 H, m), 7.76 (1 H, dd, J = 8.6 Hz, 1.9 Hz), 8.39 (1H, d, J = 8.6 Hz)

Reference Example 6
3-aminomethyl-6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline 6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline- 25% aqueous ammonia (2 ml) and developed nickel (1.5 ml) were added to a solution of 3-carbonitrile (3.0 g) in tetrahydrofuran (80 ml), and reacted at 50 ° C. and 1 MPa for 4.5 hours. The catalyst was removed by filtration, and the solvent of the filtrate was distilled off. Water was added to the residue and extracted with ethyl acetate. The extract was washed with saturated brine and dried (MgSO ₄ ). The solvent was distilled off to give the title compound as crystals (3.0 g, yield 99%).
¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.00 (6H, d, J = 6.7 Hz), 1.10 (2H, br), 2.25 (1H, m), 3.65 (2H, s), 4.20 (2H, d, J = 7.4 Hz), 7.07 (1H, d, J = 1.9 Hz), 7.08-7.28 (2H, m), 7.45- 7.54 (4H, m), 8.32 (1H, d, J = 8.6 Hz)
Reference Example 7
3-tert-butoxycarbonylaminomethyl-6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline 3-aminomethyl-6-bromo-2-isobutyl-1-oxo-4- Di-tert-butyl dicarbonate (6.3 g) was added to a solution of phenyl-1,2-dihydroisoquinoline (5.6 g) and 4-dimethylaminopyridine (20 mg) in tetrahydrofuran (50 ml), and the mixture was stirred at room temperature for 1 hour. . The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried (MgSO ₄ ). After distilling off the solvent, the residue was recrystallized from diethyl ether to obtain the title compound (6.6 g, yield 94%).
¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.00 (6H, d, J = 7.0 Hz), 1.43 (9H, s), 2.23 (1H, m), 4.06 (2H, d, J = 7.8 Hz), 4.19 (2H, d, J = 5.4 Hz), 4.50 (1H, bs), 7.08 (1H, d, J = 2.0 Hz), 7. 21-7.25 (2H, m), 7.48-7.56 (4H, m), 8.30 (1H, d, J = 8.8 Hz)

According to the production method of the present invention, a nitrogen-containing fused heterocyclic compound useful as a synthetic intermediate for various drugs can be obtained simply and in high yield.

Claims (3)

formula

[Wherein Y represents a halogen atom or —OSO ₂ R ¹ — (R ¹ represents an alkyl group which may be halogenated);
Ring A is a 5- to 10-membered aromatic ring which may further have a substituent;
Ring B represents a ring which may have a substituent, and at least one of ring A or ring B has a nitrogen atom as a ring constituent atom] or a salt thereof,
Formula: HZ—R ^{2 wherein} Z is —O—, —S— or —NR ³ — (R ³ represents a hydrogen atom or an optionally substituted hydrocarbon group), and R ² is substituted. A hydrocarbon group which may be substituted, a heterocyclic group which may be substituted or an acyl group] or a salt thereof in the presence of a catalyst, a ligand and a base. And the expression

[The symbol in a formula shows the same meaning as the above] The manufacturing method of the compound or its salt represented. The process according to claim 1, wherein the catalyst is a palladium catalyst. The process according to claim 1, wherein the ligand is a BINAP compound.