JP2001240591A - Heterocycle substituted cyclohexanone derivative, its intermediate and method for producing the same derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a heterocycle substituted cyclohexanone derivative that is useful as intermediate, such as medical and agrochemical supplies, liquid crystal, heat-resistance polymer and liquid crystal polymer. SOLUTION: It is the synthetic process of the heterocycle substituted cyclohexanone derivative shown by formula (5), and the reaction process is shown in the scheme. [In the formula, X shows a substitutable heterocycle of 5 or 6 membered ring which has at least one of N, O, and S, or a substitutable benzene condensed ring. Y shows CO2R6, CN, NO2, SO3R6, etc., R4, R5 and R6 show a substitutable alkyl group or a substitutable phenyl group that may form a 4 to 7 memebered cyclic compound by R4 and R5. R1, R2, and R3 show each a substitutable 1-6C alkyl group].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical intermediate, particularly an angiotensin II receptor antagonist (210th-ACS National).
Meeting, MEDI 063 and 209th-ACS National Meetin
g, ORGN 120) and the like, and a heterocyclic-substituted cyclohexenone derivative useful for the synthesis of an intermediate and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, as a method for producing a heterocyclic-substituted benzene derivative, a method of coupling an organometallic compound such as boron or tin with an aryl halide compound in the presence of a catalyst such as a Pd complex (Tetrahedron Letters, 36, 5247 ( 199
6), Tetrahedron Letters, 32, 2273 (1991)) and the like.

[0003]

The conventional method for producing a heterocyclic-substituted benzene derivative requires a reaction using an organometallic compound or the like under anhydrous conditions, a reaction under high-temperature and high-pressure conditions, and requires an expensive catalyst. There were many problems in equipment and cost in manufacturing. Furthermore, since the selectivity of the reaction is not always high, there are also problems such as generation of many by-products and complicated isolation and purification.

[0004]

SUMMARY OF THE INVENTION The present invention provides a novel method for producing a heterocyclic-substituted cyclohexenone derivative with high selectivity and high yield under mild reaction conditions using inexpensive raw materials. This derivative is very important as an intermediate for a new method for producing a novel heterocyclic-substituted benzene derivative different from the coupling method. That is, the present invention provides (1) general formula (1)

Embedded image [In the formula, X is a 5-membered or 6-membered optionally substituted heterocyclic ring having at least one of N, O, and S, or a condensed product of those optionally substituted with benzene (provided that The substituents may be the same or different from 1 to 3, and may be H, OH, an optionally substituted C _{1 to} C ₆ alkyl group, an optionally substituted C _{2 to} C ₆ alkenyl group, an optionally substituted alkynyl group C ₂ -C _6, optionally substituted C ₁ -C ₆ alkoxy group, may be substituted
Alkylthio group of ^{_{C 1 ~C 6, NR 4 R}} 5, halogen, NO _2, CN,
COR ⁶ , CO ₂ R ⁶ , CONR ⁴ R ⁵ , SO ₃ R ⁶ , SO ₂ NR ⁴ R ⁵ , SOR ⁶ , SO
^{_{2 R 6, OCOR 6, OCO}} 2 R 6, OCONR 4 R 5, OSO 2 R 6, a phenyl group which may be substituted, an optionally substituted phenoxy group, optionally substituted heteroaryl group or Y represents CO ₂ R ⁶ , CN, NO ₂ , SO ₃ R ⁶ , which represents a heteroaryloxy group which may be substituted, and which may form a 4- to 7-membered ring with adjacent substituents. , SO ₂ NR ⁴ R ⁵ , SO
R ⁶ , SO ₂ R ⁶ represents, R ⁴ , R ⁵ and R ⁶ represent H, an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted phenyl group, R ⁴ and R ⁵ may form a 4- to 7-membered ring. And a compound represented by the general formula (2)

Embedded image[Where R¹, R^TwoAnd R^ThreeIs H, optionally substituted C₁~
C₆Alkyl group, optionally substituted C_Two~ C₆Arche of
Nyl group, optionally substituted C_Two~ C₆An alkynyl group of
C which may be substituted₁~ C₆An alkoxy group, which is substituted
May be C₁~ C₆Alkylthio group, NR^FourR^Five, Haloge
N, NO_Two, CN, COR⁶, CO_TwoR⁶, CONR^FourR^Five, SO_ThreeR ⁶, SO_TwoNR
^FourR^Five, SOR⁶, SO_TwoR⁶, OCOR⁶, OCO_TwoR⁶, OCONR^FourR^Five, OSO
_TwoR⁶, An optionally substituted aryl group,
Phenoxy group, optionally substituted heteroaryl
A reel group or an optionally substituted heteroaryl
Represents a xy group, R^Four, R^FiveAnd R⁶Is defined as above
Show the same thing. Reacting the compound represented by
General formula (4) characterized by

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ represent the same as defined above. A method for producing a compound represented by the formula (2):
General formula (1)

Embedded image Wherein X and Y are the same as defined in (1). And a compound represented by the general formula (3)

Embedded image [Wherein, R ¹ , R ² and R ³ are the same as defined in (1), and Z represents a leaving group. A compound represented by the general formula (4):

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1). A method for producing a compound represented by the formula:
(3) General formula (4)

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1). Wherein the compound represented by the general formula (5) is subjected to a cyclization reaction.

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1). A method for producing a cyclohexenone derivative represented by the general formula (1):

Embedded image Wherein X and Y are the same as defined in (1). And a compound represented by the general formula (2)

Embedded image Wherein R ¹ , R ² and R ³ are the same as defined in (1). And reacting the compound represented by the general formula (4)

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1). A compound represented by the general formula (5):

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1). A method for producing a cyclohexenone derivative represented by the general formula (1):

Embedded image Wherein X and Y are the same as defined in (1). And a compound represented by the general formula (3)

Embedded image [Wherein R ¹ , R ² and R ³ represent the same as defined in (1), and Z represents the same as defined in (2). And reacting the compound represented by the general formula (4)

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1). A compound represented by the general formula (5):

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1). (6) a pyrrole in which X may be substituted, a furan which may be substituted, a thiophene which may be substituted, a pyrazole which may be substituted, Optionally substituted isoxazole, optionally substituted isothiazole, optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted Optionally substituted indole, optionally substituted benzofuran, optionally substituted benzothiophene, optionally substituted quinoline or optionally substituted isoquinoline, the substituent of which is H, OH, substituted which may be C ₁ -C ₆ alkyl group, optionally substituted
C ₁ -C ₆ alkoxy group, halogen, NR ⁴ R ⁵ , nitro group, C
N, CO ₂ R ⁶ , the production method according to any one of (1) to (5), which is an optionally substituted phenyl group or an optionally substituted phenoxy group, and (7) X is substituted Optionally substituted pyrrole, optionally substituted furan, optionally substituted thiophene, optionally substituted pyridine or optionally substituted indole,
The substituent is H, substituted optionally C ₁ may be -C ₆ alkyl group, optionally substituted C ₁ -C ₆ alkoxy group, halogen, NR ⁴ R ⁵ or nitro group, Y is CO ₂ R ⁶ , CN, N
The method according to any one of (1) to (5), which is O ₂ , SO ₃ R ⁶ or SO ₂ NR ⁴ R ⁵ , (8) X is a pyridine optionally substituted, substituent is H, optionally substituted C ₁ -C ₆ alkyl, optionally C ₁ ~ substituted
C _{6 is} an alkoxy group or halogen, and Y is CO ₂ R ⁶ , C
The method according to any one of (1) to (5), which is N, SO ₃ R ⁶ or SO ₂ NR ⁴ R ⁵ , (9) a general formula (4)

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1). A diketone derivative represented by the formula:
(10) General formula (5)

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1). A heterocyclic-substituted cyclohexenone derivative represented by the formula (11), pyrrole wherein X is optionally substituted, furan which may be substituted, thiophene which may be substituted, pyrazole which may be substituted, substituted Optionally substituted isoxazole, optionally substituted isothiazole, optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, optionally substituted pyrazine,
Optionally substituted indole, optionally substituted benzofuran, optionally substituted benzothiophene, optionally substituted quinoline or optionally substituted isoquinoline, wherein the substituent is H, OH , an optionally substituted alkyl group of C ₁ -C ₆ also, optionally substituted C ₁ -C ₆ alkoxy group, halogen, NR ⁴ R ^5, nitro, CN, CO ₂ R ^6, substituted A phenyl group which may be substituted or a phenoxy group which may be substituted (9)
Or (10) an intermediate or a heterocyclic-substituted cyclohexenone derivative according to (10), (12) a pyrrole optionally substituted with X, a furan optionally substituted, a thiophene optionally substituted, Pyridine, optionally substituted pyrimidine or optionally substituted indole, wherein the substituent is H, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C alkoxy groups of ₁ -C _6, halogen, NR ⁴ R ⁵ or nitro group, Y is ^{_{CO 2 R 6, CN, NO}} 2, SO 3 R 6 , or SO ₂ NR ⁴
The intermediate according to (9) or (10) or a heterocyclic-substituted cyclohexenone derivative represented by R ⁵ , (13) pyridine which may be substituted with X, and the substituent may be H or substituted A good C ₁ -C ₆ alkyl group, an optionally substituted C ₁ -C ₆ alkoxy group or halogen,
The intermediate or the heterocyclic-substituted cyclohexenone derivative according to (9) or (10), wherein Y is CO ₂ R ⁶ , CN, SO ₃ R ⁶ or SO ₂ NR ⁴ R ⁵ .

In general formulas (1) to (5), X
As, for example, optionally substituted pyrrole,
Optionally substituted furan, optionally substituted thiophene
Substituted, optionally substituted pyrazole, substituted
Imidazole, optionally substituted isothiazo
, Optionally substituted imidazole, substituted
Optionally oxazole, optionally substituted thiazo
, Optionally substituted pyridine, substituted
Pyridazine, optionally substituted pyrimidine,
Optionally substituted pyrazine, optionally substituted
Indole, optionally substituted benzo [b] fura
Benzo [b] thiophene, optionally substituted
Optionally substituted benz [d] imidazole, substituted
Optionally substituted benzo [d] oxazole, substituted
Optionally substituted benzo [d] thiazole, optionally substituted
Good purine, optionally substituted quinoline, substituted
Optionally substituted isoquinoline, optionally substituted syn
Norin, optionally substituted phthalazine, substituted
Optionally substituted oxazoline, optionally substituted quinoxa
Phosphorus, optionally substituted pteridine and the like;
More preferably, optionally substituted pyrrole, substituted
Optionally furan, optionally substituted thiophene,
Optionally substituted pyrazole, optionally substituted
Isoxazole, optionally substituted isothiazole
, Optionally substituted pyridine, optionally substituted
Good pyridazine, optionally substituted pyrimidine,
Optionally substituted pyrazine, optionally substituted
And substituted benzofurans, substituted
Optionally substituted benzothiophene, optionally substituted
Quinoline or optionally substituted isoquinoline
And more preferably an optionally substituted pillow
, Optionally substituted furan, optionally substituted
Thiophene, optionally substituted pyridine, substituted
Optionally substituted pyrimidine, optionally substituted
It is a doll. The substituent is, for example, substituted
May be C₁~ C₆Methyl group, ethyl group
Group, propyl group, isopropyl group, butyl group, tert-butyl group
Tyl, pentyl, hexyl, trifluoromethyl
Group, chloromethyl group, bromomethyl group, benzyl group
And the like; optionally substituted C_Two~ C₆As an alkenyl group of
Is vinyl, allyl, isopropenyl, butenyl
Group, pentenyl group, hexenyl group, styryl group, etc .;
C that may be replaced_Two~ C₆As the alkynyl group of
Nyl, propynyl, butynyl, pentynyl, etc.
And the like; optionally substituted C₁~ C₆As an alkoxy group
Is methoxy, ethoxy, propoxy, isopropo
Xy, butoxy, tert-butoxy, trifluoro
Methoxy group, benzyloxy group, etc .;
Good C₁~ C₆Examples of the alkylthio group include a methylthio group,
Tylthio, propylthio, butylthio, pentyl
Thio, hexylthio, benzylthio, etc .; NR^FourR^Five
As amino, methylamino, dimethylamino
Group, ethylamino group, diethylamino group, propylamido
, Isopropylamino, butylamino, tert-
Butylamino group, pentylamino group, hexylamino
Group, pyrrolidino group, piperidino group, morpholino group, ani
Lino group, etc .; halogens include fluorine, chlorine, bromine,
Udine; NO_Two; CN; COR⁶As formyl group, acetyl
Group, propionyl group, butyryl group, isobutyryl group,
Reryl, pivaloyl, benzoyl, toluoyl
Group, furanoyl group, nicotinoyl group, isonicotinoyl
Group, cinnamoyl group, etc .; CO_TwoR⁶As methoxycal
Bonyl, ethoxycarbonyl, propoxycarbonyl
Group, butoxycarbonyl group, tert-butoxycarbonyl
Group, benzyloxycarbonyl group, phenoxycarbo
Nyl group, etc .; CONR^FourR^FiveAs methylaminocarbonyl
Group, dimethylaminocarbonyl group, ethylaminocarbo
Nil group, diethylaminocarbonyl group, pyrrolidinocar
Bonyl group, piperidinocarbonyl group, morpholinocarbo
Nyl group, anilinocarbonyl group, etc .; SO_ThreeR⁶As
Toxisulfonyl group, ethoxysulfonyl group, pro
Poxysulfonyl group, butoxysulfonyl group, ben
Diloxysulfonyl group, phenoxysulfonyl group
Etc .; SO_TwoNR^FourR^FiveIs a sulfamoyl group, methyl sulf
Famoyl group, dimethyl sulfamoyl group, ethyl sulf
Famoyl group, diethylsulfamoyl group, propyls
Rufamoyl group, isopropylsulfamoyl group, butyric
Rusulfamoyl group, tert-butylsulfamoyl group,
Pentylsulfamoyl group, hexylsulfamoyl
Group, pyrrolidinosulfamoyl group, piperidinosulfa
Moyl group, morpholinosulfamoyl group, anilinosul
Famoyl group, etc .; SOR⁶As methylsulfinyl
Group, ethylsulfinyl group, propylsulfinyl group,
Butylsulfinyl group, benzylsulfinyl group,
Nylsulfinyl group, etc .; SO_TwoR⁶As methylsulf
Group, ethylsulfonyl group, propylsulfonyl group
Group, butylsulfonyl group, benzylsulfonyl
Group, phenylsulfonyl group, etc .; OCOR⁶As a
Sethoxy group, propionyloxy group, butyryloxy
Group, isobutyryloxy group, valeryloxy group, pivalo
Yloxy group, benzoyloxy group, toluoyloxy
Group, furanoyloxy group, nicotinoyloxy group, iso
Nicotinoyloxy group, cinnamoyloxy group, etc .; OC
O_TwoR⁶As methoxycarbonyloxy group, ethoxyca
Rubonyloxy group, propoxycarbonyloxy group,
Toxycarbonyloxy group, tert-butoxycarbonyl
Oxy group, benzyloxycarbonyloxy group, pheno
OCONR, such as a xycarbonyloxy group^FourR^FiveAs methyl
Aminocarbonyloxy group, dimethylaminocarbonyl
Oxy group, ethylaminocarbonyloxy group, diethyl
Aminocarbonyloxy group, pyrrolidinocarbonyloxy
Si group, piperidinocarbonyloxy group, morpholinocar
Bonyloxy group, anilinocarbonyloxy group, etc .; OS
O_TwoR⁶Are methanesulfonyloxy group, ethanesulfone
Phonyloxy group, propanesulfonyloxy group,
Tansulfonyloxy group, pentanesulfonyloxy
Si group, hexanesulfonyloxy group, benzene sulf
A sulfonyloxy group, a toluenesulfonyloxy group, and the like;
Examples of the optionally substituted phenyl group include hydroxyphenyl.
Phenyl, chlorophenyl, methylphenyl, tri
Fluoromethylphenyl group, methoxyphenyl group, tert
-Butoxyphenyl, benzyloxyphenyl,
Trifluoromethoxyphenyl group, phenoxyphenyl group
And the like.
Nonoxy group, hydroxyphenoxy group, chlorophenoxy
Group, methylphenoxy group, trifluoromethylphenoki
Si, methoxyphenoxy, trifluoromethoxy
Phenoxy, phenoxyphenoxy, etc .; substituted
Heteroaryl groups that may be present include furanyl groups,
Nil group, azolyl group, pyridyl group, indolyl group, substitution
As the optionally substituted heteroaryloxy group, azo
Riloxy group, pyridyloxy group, indolyloxy group
And the like. Preferably, H, even if substituted
Good C₁~ C₆Alkyl group, optionally substituted C₁~ C ₆
An alkoxy group, halogen, NO_Two, NR^FourR^FiveHas been replaced
Optionally substituted phenyl group, optionally substituted phenoxy
Group, COR⁶, CO_TwoR⁶, OCOR⁶Or OCO_TwoR⁶And especially preferred
H, methyl, methoxy, phenoxy,
Toxycarbonyl group, ethoxycarbonyl group, NO_Two,
It is a ethoxy group or a benzoyloxy group. Also of X
As a ring formed by adjacent substituents as a substituent
Is a cyclobutane ring, a cyclopentane ring, a cyclohexa
Ring, cycloheptane ring, oxetane ring, tetrahydro
Furan ring, furan ring, pyran ring, dioxolan ring, geo
Xan rings and the like. As Y, for example, CO_TwoR⁶As
Represents a methoxycarbonyl group, an ethoxycarbonyl group,
Poxycarbonyl group, butoxycarbonyl group, tert-butyl
Toxicoxycarbonyl, benzyloxycarbonyl, etc.
Etc .; CN; NO_Two; SO_ThreeR⁶As a methoxysulfonyl group,
Ethoxysulfonyl group, propoxysulfonyl group,
Butoxysulfonyl group, benzyloxysulfonyl
Group, phenoxysulfonyl group, etc .; SO_TwoNR^FourR^Fiveas
Sulfamoyl group, methylsulfamoyl group, dimethyl
Sulfamoyl group, ethylsulfamoyl group, diethyl
Sulfamoyl group, propylsulfamoyl group, isop
Ropylsulfamoyl group, butylsulfamoyl group, te
rt-butylsulfamoyl group, pentylsulfamoyl
Group, hexylsulfamoyl group, pyrrolidinosulfamo
Yl, piperidinosulfamoyl, morpholinosul
Famoyl group, anilino sulfamoyl group, etc .; SOR⁶When
Is a methylsulfinyl group, an ethylsulfinyl group,
Propylsulfinyl group, butylsulfinyl group, ben
SO: Sulfinyl group, phenylsulfinyl group, etc.
_TwoR⁶Are methylsulfonyl group, ethylsulfonyl group
Group, propylsulfonyl group, butylsulfonyl
Group, benzylsulfonyl group, phenylsulfonyl group
And the like. Preferably, CN, CO_TwoR⁶, NO_Two, SO_ThreeR
⁶Or SO_TwoNR^FourR^FiveAnd particularly preferably CN,
It is a cicarbonyl group or an ethoxycarbonyl group. Z
May be any substituent having the function of a leaving group.
For example, halogens such as fluorine, chlorine, bromine and iodine;
Alkoxy groups such as xy and ethoxy groups; amino groups,
Tylamino, dimethylamino, ethylamino, di
Ethylamino group, propylamino group, isopropylamino
Group, butylamino group, tert-butylamino group, pliers
Amino group, hexylamino group, pyrrolidino group, piperi
Amino groups such as dino group, morpholino group and anilino group;
Tansulfonyloxy group, ethanesulfonyloxy
Group, propanesulfonyloxy group, butanesulfoni
Luoxy group, pentane sulfonyloxy group, hexane
Sulfonyloxy group, benzenesulfonyloxy
Group, sulfonyl such as toluenesulfonyloxy group
An oxy group; an acetyloxy group, a propionyloxy group,
Butyryloxy group, isobutyryloxy group, valerio
Xy, pivaloyloxy, benzoyloxy,
Luoyloxy group, furanoyloxy group, nicotinoyl
Oxy group, isonicotinoyloxy group, cinnamoylo
Acyloxy groups such as a xy group; methoxycarbonyloxy
Si group, ethoxycarbonyloxy group, propoxycarbo
Nyloxy group, butoxycarbonyloxy group, tert-butyl
Toxylcarbonyloxy group, benzyloxycarbonyl
Alkoxycarbonyl groups such as oxy groups; phenoxyca
Rubonyloxy group, methylaminocarbonyloxy group,
Dimethylaminocarbonyloxy group, ethylaminocar
Bonyloxy group, diethylaminocarbonyloxy group,
Pyrrolidinocarbonyloxy group, piperidinocarbonyl
Oxy group, morpholinocarbonyloxy group, anilinoka
Aminocarbonyloxy group such as rubonyloxy group
And preferably, fluorine, chlorine, bromine and iodine
Halogen such as methoxy group and ethoxy group
Xy group; amino group, methylamino group, dimethylamino
Group, ethylamino group, diethylamino group, propylamido
, Isopropylamino, butylamino, tert-
Butylamino group, pentylamino group, hexylamino
Group, pyrrolidino group, piperidino group, morpholino group, ani
Amino groups such as lino groups; more preferably chlorine, odor
Element, iodine, methoxy group, methylamino group, dimethylamine
Mino group, ethylamino group, diethylamino group, pyrrolidi
, A piperidino group or a morpholino group. R¹, R^Two
And R^ThreeIs, for example, H; optionally substituted C₁~ C₆
Examples of the alkyl group of methyl, ethyl, propyl
Group, isopropyl group, butyl group, tert-butyl group, pen
Tyl, hexyl, trifluoromethyl, chloromethyl
Tyl, bromomethyl, benzyl, etc .; substituted
May be C_Two~ C₆As the alkenyl group of the vinyl group, a
Ryl, isopropenyl, butenyl, pentenyl
Group, hexenyl group, styryl group, etc .;
Good C_Two~ C₆Alkynyl groups such as ethynyl and propyl
Nyl, butynyl, pentynyl and the like; substituted
May be C₁~ C₆A methoxy group,
Toxic group, propoxy group, isopropoxy group, butoxy
Group, tert-butoxy group, trifluoromethoxy group, ben
A ziroxy group or the like; an optionally substituted C₁~ C₆Al
The alkylthio group includes methylthio, ethylthio,
Pyrthio, butylthio, pentylthio, hexyl
Thio group, benzylthio group, etc .; NR^FourR^FiveAs amino
Group, methylamino group, dimethylamino group, ethylamino
Group, diethylamino group, propylamino group, isopropyl
Amino group, butylamino group, tert-butylamino group,
Pentylamino group, hexylamino group, pyrrolidino group,
Piperidino group, morpholino group, anilino group, etc .; halogen
As fluorine, chlorine, bromine, iodine; NO_Two; CN; COR
⁶As formyl group, acetyl group, propionyl group,
Butyryl group, isobutyryl group, valeryl group, pivaloyl
Group, benzoyl group, toluoyl group, furanoyl group, nico
Tinoyl group, isonicotinoyl group, cinnamoyl group
Do; CO_TwoR⁶As methoxycarbonyl group, ethoxyca
Rubonyl group, propoxycarbonyl group, butoxycarbo
Nyl group, tert-butoxycarbonyl group, benzyloxy
Carbonyl group, phenoxycarbonyl group, etc .; CONR^FourR^Five
Are methylaminocarbonyl group, dimethylaminoca
Rubonyl group, ethylaminocarbonyl group, diethylamido
Nocarbonyl group, pyrrolidinocarbonyl group, piperidino
Carbonyl group, morpholinocarbonyl group, anilinocar
Bonyl group, etc .; SO_ThreeR⁶As methoxysulfonyl
Group, ethoxysulfonyl group, propoxysulfonyl
Group, butoxysulfonyl group, benzyloxysulfo
Such as a phenyl group and a phenoxysulfonyl group; SO_TwoNR^FourR^Fiveage
The sulfamoyl group, methylsulfamoyl group,
Tylsulfamoyl group, ethylsulfamoyl group, die
Tylsulfamoyl group, propylsulfamoyl group, a
Sopropylsulfamoyl group, butylsulfamoyl
Group, tert-butylsulfamoyl group, pentylsulfa
Moyl group, hexylsulfamoyl group, pyrrolidinosul
Famoyl group, piperidinosulfamoyl group, morpholine
Nosulfamoyl group, anilinosulfamoyl group and the like;
SOR⁶Are methylsulfinyl group, ethylsulfinyl
Group, propylsulfinyl group, butylsulfinyl
Group, benzylsulfinyl group, phenylsulfinyl group
Etc .; SO_TwoR⁶Are methylsulfonyl group, ethyls
Ruphonyl group, propylsulfonyl group, butylsulfur
Benzyl, benzylsulfonyl, phenylsulfo
Nyl group, etc .; OCOR⁶Acetyloxy group, professional
Pionyloxy, butyryloxy, isobutyryl
Xy, valeryloxy, pivaloyloxy, ben
Zoyloxy group, toluoyloxy group, furanoyloxy
Si group, nicotinoyloxy group, isonicotinoyloxy
Group, cinnamoyloxy group, etc .; OCO_TwoR⁶As methoki
Cicarbonyloxy group, ethoxycarbonyloxy group,
Propoxycarbonyloxy group, butoxycarbonyloxy
Xy group, tert-butoxycarbonyloxy group, benzyl
Oxycarbonyloxy group, phenoxycarbonyloxy
OCONR^FourR^FiveIs methylaminocarbonyl
Xyl group, dimethylaminocarbonyloxy group, ethyl alcohol
Minocarbonyloxy group, diethylaminocarbonylo
Xy group, pyrrolidinocarbonyloxy group, piperidinoca
Rubonyloxy group, morpholinocarbonyloxy group,
Nilinocarbonyloxy group, etc .; OSO_TwoR⁶As methane
Sulfonyloxy group, ethanesulfonyloxy group,
Propanesulfonyloxy group, butanesulfonylo
Xy group, pentane sulfonyloxy group, hexane sulf
Phonyloxy group, benzenesulfonyloxy group,
Ruensulfonyloxy group, etc .; may be substituted
Aryl groups such as hydroxyphenyl and chlorophenyl
Phenyl, methylphenyl, trifluoromethylphen
Nyl group, methoxyphenyl group, tert-butoxyphenyl
Group, benzyloxyphenyl group, trifluoromethoxy
Phenyl, phenoxyphenyl, naphthyl and the like;
Phenoxy group which may be substituted
Group, hydroxyphenoxy group, chlorophenoxy group,
Tilphenoxy group, trifluoromethylphenoxy group,
Methoxyphenoxy group, trifluoromethoxyphenoxy
Si group, phenoxyphenoxy group, etc .; even when substituted
Good heteroaryl groups include furanyl and thienyl
Group, azolyl group, pyridyl group, indolyl group, substituted
Azolyl is an optionally substituted heteroaryloxy group
Oxy group, pyridyloxy group, indolyloxy group, etc.
And H is preferably a methyl group, an ethyl group,
Propyl group, isopropyl group, butyl group, tert-butyl
Group, pentyl group, hexyl group, trifluoromethyl group,
Chloromethyl group, bromomethyl group, benzyl group, etc.
C that may be replaced₁~ C₆Alkyl group, hydroxyfe
Nyl group, chlorophenyl group, methylphenyl group, trif
Fluoromethylphenyl group, methoxyphenyl group, tert-
Butoxyphenyl, benzyloxyphenyl, tri
Such as fluoromethoxyphenyl and phenoxyphenyl
Any optionally substituted phenyl group, particularly preferably
H, methyl group, ethyl group, propyl group, isopropyl
Group, trifluoromethyl group, chloromethyl group,
Tyl, hydroxyphenyl, chlorophenyl,
Tylphenyl group, trifluoromethylphenyl group, meth
Xyphenyl group or trifluoromethoxyphenyl group
It is. R^Four, R^FiveAnd R⁶For example, H;
Examples of the alkyl group that may be present include a methyl group, an ethyl group,
Propyl group, isopropyl group, butyl group, tert-butyl
Group, pentyl group, hexyl group, etc .; may be substituted
Hydroxyphenyl, chlorophenyl
Phenyl, methylphenyl, trifluoromethylphen
Nyl, methoxyphenyl, trifluoromethoxy
Enyl group, phenoxyphenyl group and the like; NR^FourR
^FiveAre pyrrolidino, piperazino, morpholino
And the like, preferably, H, methyl group, ethyl
Group, propyl group, isopropyl group, pyrrolidinyl group,
A perazino group or a morpholino group, more preferably
Is H, methyl, ethyl, pyrrolidino or pipera
It is a dino group.

The preferred compound of the general formula (4) is 2
-Isonicotinoyl-5-oxohexanoic acid ethyl ester, 2-nicotinoyl-5-oxohexanoic acid ethyl ester, 2- (2-pyridylcarbonyl) -5-oxohexanoic acid ethyl ester, 2- (2-nitro-5-ethyl
Nicotinoyl) -5-oxohexanoic acid ethyl ester, 2- (2-chloro-5-nicotinoyl) -5-oxohexanoic acid ethyl ester, 2- (2-methoxy-5)
-Nicotinoyl) -5-oxohexanoic acid ethyl ester, 2- (2-pyrimidinylcarbonyl) -5-oxohexanoic acid ethyl ester, 2- (2-nitro-5-pyrimidinylcarbonyl) -5-oxohexanoic acid ethyl ester, 2- (2-chloro-5-pyrimidinylcarbonyl) -5-oxohexanoic acid ethyl ester, 2-
(2-methoxy-5-pyrimidinylcarbonyl) -5
Oxohexanoic acid ethyl ester, 2-isonicotinoyl-5-oxohexanenitrile, 2-nicotinoyl-
5-oxohexanoic acid ethyl ester, 2- (2-pyridylcarbonyl) -5-oxohexanenitrile, 2-
(2-Nitro-5-nicotinoyl) -5-oxohexanenitrile, 2- (2-chloro-5-nicotinoyl)-
5-oxohexanenitrile, 2- (2-methoxy-5
-Nicotinoyl) -5-oxohexanenitrile, 2-
(2-pyrimidinylcarbonyl) -5-oxohexanenitrile, 2- (2-nitro-5-pyrimidinylcarbonyl) -5-oxohexanenitrile, 2- (2-chloro-5-pyrimidinylcarbonyl) -5-oxohexanenitrile 2- (2-methoxy-5-pyrimidinylcarbonyl) -5-oxohexanenitrile, 1-isonicotinoyl-4-oxopentanesulfonic acid ethyl ester, 1-nicotinoyl-4-oxopentanesulfonic acid ethyl ester, 1- (2 -Pyridylcarbonyl)-
4-oxopentanesulfonic acid ethyl ester, 1-
(2-Nitro-5-nicotinoyl) -4-oxopentanesulfonic acid ethyl ester, 1- (2-chloro-5-
Nicotinoyl) -4-oxopentanesulfonic acid ethyl ester, 1- (2-methoxy-5-nicotinoyl)-
4-oxopentanesulfonic acid ethyl ester, 1-
(2-Pyrimidinylcarbonyl) -4-oxopentanesulfonic acid ethyl ester, 1- (2-nitro-5-pyrimidinylcarbonyl) -4-oxopentanesulfonic acid ethyl ester, 1- (2-chloro-5-pyrimidinylcarbonyl) 4-oxopentanesulfonic acid ethyl ester, 1- (2-methoxy-5-pyrimidinylcarbonyl) -4-oxopentanesulfonic acid ethyl ester, 1-isonicotinoyl-4-oxopentanesulfonamide, 1-nicotinoyl-4-oxo Pentane sulfonamide, 1- (2-pyridylcarbonyl) -4-oxopentane sulfonamide, 1- (2-nitro-5-
Nicotinoyl) -4-oxopentanesulfonamide,
1- (2-chloro-5-nicotinoyl) -4-oxopentanesulfonamide, 1- (2-methoxy-5-nicotinoyl) -4-oxopentanesulfonamide, 1-
(2-pyrimidinylcarbonyl) -4-oxopentanesulfonamide, 1- (2-nitro-5-pyrimidinylcarbonyl) -4-oxopentanesulfonamide, 1
-(2-chloro-5-pyrimidinylcarbonyl) -4-
Oxopentane sulfonamide, 1- (2-methoxy-
5-pyrimidinylcarbonyl) -4-oxopentanesulfonamide. Preferred compounds of the general formula (5) include ethyl 2- (4-pyridyl) -4-oxocyclohex-2-enecarboxylate and 2- (3
-Pyridyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester, 2- (2-pyridyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester, 2- (2-amino-5-pyridyl) ) -4-oxocyclohex-2-enecarboxylic acid ethyl ester, 2-
(2-Nitro-5-pyridyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester, 2- (2-chloro-5-pyridyl) -4-oxocyclohex-2-yl
Encarboxylic acid ethyl ester, 2- (2-methoxy-
5-pyridyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester, 2- (5-pyrimidinyl)-
4-oxocyclohex-2-enecarboxylic acid ethyl ester, 2- (2-amino-5-pyrimidinyl) -4-
Oxocyclohex-2-enecarboxylic acid ethyl ester, 2- (2-nitro-5-pyrimidinyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester,
2- (2-chloro-5-pyrimidinyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester, 2-
(2-methoxy-5-pyrimidinyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester, 2-
(4-pyridyl) -4-oxocyclohex-2-encarbonitrile, 2- (3-pyridyl) -4-oxocyclohex-2-encarbonitrile, 2- (2-pyridyl) -4-oxocyclohexyl C-2-enecarbonitrile, 2- (2-amino-5-pyridyl) -4-oxocyclohexyl-2-encarbonitrile, 2- (2-nitro-5-pyridyl) -4-oxocyclohexyl- 2-
Encarbonitrile, 2- (2-chloro-5-pyridyl) -4-oxocyclohex-2-encarbonitrile, 2- (2-methoxy-5-pyridyl) -4-oxocyclohex-2-encarbo Nitrile, 2- (5-pyrimidinyl) -4-oxocyclohex-2-enecarbonitrile, 2- (2-amino-5-pyrimidinyl)-
4-oxocyclohex-2-enecarbonitrile, 2
-(2-nitro-5-pyrimidinyl) -4-oxocyclohex-2-encarbonitrile, 2- (2-chloro-5-pyrimidinyl) -4-oxocyclohex-2-
Encarbonitrile, 2- (2-methoxy-5-pyrimidinyl) -4-oxocyclohex-2-encarbonitrile, 2- (4-pyridyl) -4-oxocyclohex-2-enesulfonic acid ethyl ester, 2- (3-pyridyl) -4-oxocyclohex-2-enesulfonic acid ethyl ester, 2- (2-pyridyl) -4-oxocyclohex-2-enesulfonic acid ethyl ester, 2
-(2-amino-5-pyridyl) -4-oxocyclohex-2-enesulfonic acid ethyl ester, 2- (2-
Nitro-5-pyridyl) -4-oxocyclohex-2
-Enesulfonic acid ethyl ester, 2- (2-chloro-
5- (pyridyl) -4-oxocyclohex-2-enesulfonic acid ethyl ester, 2- (2-methoxy-5-pyridyl) -4-oxocyclohex-2-enesulfonic acid ethyl ester, 2- (5- Pyrimidinyl) -4-oxocyclohex-2-enesulfonic acid ethyl ester, 2- (2-amino-5-pyrimidinyl) -4-oxocyclohex-2-enesulfonic acid ethyl ester,
2- (2-nitro-5-pyrimidinyl) -4-oxocyclohex-2-enesulfonic acid ethyl ester, 2-
(2-chloro-5-pyrimidinyl) -4-oxocyclohex-2-enesulfonic acid ethyl ester, 2- (2
-Methoxy-5-pyrimidinyl) -4-oxocyclohex-2-enesulfonic acid ethyl ester, 2- (4-
Pyridyl) -4-oxocyclohex-2-enesulfonamide, 2- (3-pyridyl) -4-oxocyclohex-2-enesulfonamide, 2- (2-pyridyl)
-4-oxocyclohex-2-enesulfonamide,
2- (2-amino-5-pyridyl) -4-oxocyclohex-2-enesulfonamide, 2- (2-nitro-
5-pyridyl) -4-oxocyclohex-2-enesulfonamide, 2- (2-chloro-5-pyridyl) -4
-Oxocyclohex-2-enesulfonamide, 2-
(2-methoxy-5-pyridyl) -4-oxocyclohex-2-enesulfonamide, 2- (5-pyrimidinyl) -4-oxocyclohex-2-enesulfonamide, 2- (2-amino-5 -Pyrimidinyl) -4-oxocyclohex-2-enesulfonamide, 2- (2-
Nitro-5-pyrimidinyl) -4-oxocyclohex-2-enesulfonamide, 2- (2-chloro-5-pyrimidinyl) -4-oxocyclohex-2-enesulfonamide, 2- (2-methoxy- 5-pyrimidinyl)
-4-oxocyclohex-2-enesulfonamide,
2- (4-pyridyl) -4-oxocyclohex-2-yl
Enesulfonic acid, 2- (3-pyridyl) -4-oxocyclohex-2-enesulfonic acid, 2- (2-pyridyl) -4-oxocyclohex-2-enesulfonic acid,
2- (2-amino-5-pyridyl) -4-oxocyclohex-2-enesulfonic acid, 2- (2-nitro-5-
Pyridyl) -4-oxocyclohex-2-enesulfonic acid, 2- (2-chloro-5-pyridyl) -4-oxocyclohex-2-enesulfonic acid, 2- (2-methoxy-5-pyridyl) 4-oxocyclohex-2-enesulfonic acid, 2- (5-pyrimidinyl) -4-oxocyclohex-2-enesulfonic acid, 2- (2-amino-5-pyrimidinyl) -4-oxocyclohexyl -2-
Enesulfonic acid, 2- (2-nitro-5-pyrimidinyl) -4-oxocyclohex-2-enesulfonic acid,
2- (2-chloro-5-pyrimidinyl) -4-oxocyclohex-2-enesulfonic acid, 2- (2-methoxy-5-pyrimidinyl) -4-oxocyclohex-2-yl
Ensulfonic acid and the like.

In the present invention, the general formulas (1) to (5)
Include, for example, hydrogen halides such as hydrogen chloride and hydrogen bromide; other inorganic acids such as sulfuric acid, nitric acid and phosphoric acid; organic sulfones such as methanesulfonic acid and p-toluenesulfonic acid. Acids; or other organic acids, such as trifluoroacetic acid and oxalic acid, may be used as salts, which are also included in the present invention. These can be used as an intermediate as a salt or after neutralizing an acid. In the present invention, the compounds represented by the general formulas (1) to (5) include:
For example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; transition metal salts such as copper salts and iron salts; organic bases such as pyridine salts and amine salts. Some salts, such as salts, form salts with bases. These are also included in the present invention, and can be used as an intermediate as a salt or after neutralizing a base. In the present invention, the compounds represented by the general formulas (1) to (5) may have optical isomers, geometric isomers and tautomers, in which case, the present invention provides It also includes the isomers and mixtures of the isomers in any proportion. Further, hydrates of the compounds represented by the general formulas (1) to (5) are also included.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The reaction steps are as follows.

Embedded image (Wherein X, Y, Z, R ¹ , R ² and R ³ are the same as defined above.) The general formula (1) as a starting material of the present synthesis method

Embedded image (Wherein X and Y are the same as defined above) are represented by J. Am. Chem. Soc., 7
2, 1352 (1950), etc., and can be synthesized by the general formula (2)

Embedded image Is a compound represented by Synth.Commun., 17, 809 (198
7), Synth.Commun., 21, 271 (1991) and Tetrahedron.
Letters, 24, 3477 (1983), etc., can be used for synthesis.

Embedded image Can be synthesized by applying methods such as Chemistry Letters, 1663 (1993) and Org. Syntheses Coll. Vol. 3, 305 (1955). First step: Production of compound represented by general formula (4) from compound represented by general formula (1) General formula (4)

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ are the same as defined above) are represented by the general formula (1)

Embedded image (Wherein X and Y represent the above) or a salt thereof in a solvent in the presence or absence of a base in a solvent represented by the general formula (2):

Embedded image Wherein R ¹ , R ² and R ³ are the same as defined above, or a compound of the general formula (3)

Embedded image (Wherein R ¹ , R ² , R ³ and Z are the same as defined above). The molar ratio of the compound represented by the general formula (1) and the compound represented by the general formula (2) or (3) to be subjected to the above reaction can be appropriately determined in consideration of reactivity and the like, but is preferably The ratio is 1: 4 to 4: 1, more preferably 1: 2 to 2: 1. Examples of the solvent used in the above reaction include aliphatic lower alcohols such as methanol and ethanol, aromatic hydrocarbons such as toluene, aliphatic esters such as ethyl acetate, ether hydrocarbons such as tetrahydrofuran, and organic chlorine solvents such as dichloromethane. Hydrocarbons, dimethylformamide, dimethylsulfoxide, acetonitrile, water and mixtures thereof. Preferably, aliphatic lower alcohols, aromatic hydrocarbons, ether hydrocarbons, water, and mixtures thereof are used. Reaction temperature is usually -20 ° C
To the solvent reflux temperature, and preferably from 0 ° C to the solvent reflux temperature. This reaction can also be performed without a solvent.
Alkali metal hydroxides such as KOH and NaOH, K
Alkali metal carbonates such as ₂ CO ₃ or Na ₂ CO _3, MeONa, EtONa
Alkali metal salts of aliphatic lower alcohols such as t-BuOK, alkali metal hydrides such as NaH, organic bases such as pyridine and triethylamine, and quaternary ammonium salts such as Triton B, and the like, preferably alkali metal hydroxides. Alkali metal carbonates, alkali metal salts of aliphatic lower alcohols, organic bases and quaternary ammonium salts. In addition, the amount of use is usually 0.001 to 10 equivalents to the compound represented by the general formula (1), preferably 0.05.
To 5 equivalents. The purification can be carried out by a commonly used method such as recrystallization, distillation and chromatography using silica gel. The general formula (4)

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ are the same as defined above) may be a salt thereof, for example, sodium salt, potassium salt, hydrochloride , Sulfate and the like. Second step: production of a compound represented by the general formula (5) from a compound represented by the general formula (4): general formula (5)

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ are the same as defined above) are represented by the general formula (4)

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ represent the above) or a salt thereof in a solvent in the presence of a base or an acid or a mixture thereof in the presence of a cyclization reaction. can do. As the solvent used in the above reaction, for example, aliphatic lower alcohols such as methanol and ethanol,
Aromatic hydrocarbons such as toluene, aliphatic esters such as ethyl acetate, ether hydrocarbons such as tetrahydrofuran, organic chlorine hydrocarbons such as dichloromethane, dimethylformamide, dimethyl sulfoxide, acetonitrile, water and mixtures thereof. Can be Preferably, aliphatic lower alcohols, aromatic hydrocarbons, ether hydrocarbons, water, and mixtures thereof are used.
The reaction temperature is usually from 0 ° C. to the solvent reflux temperature, preferably from 20 ° C. to the solvent reflux temperature. This reaction can also be performed without a solvent. Examples of the base include alkali metal hydroxides such as KOH and NaOH, alkali metal carbonates such as K ₂ CO ₃ and Na ₂ CO ₃ , alkali metal salts of aliphatic lower alcohols such as MeONa, EtONa and t-BuOK, and NaH. Alkali metal hydrides, such as pyridine, triethylamine, pyrrolidine, organic bases such as piperidine, quaternary ammonium salts such as Triton B, and the like, preferably an alkali metal hydroxide,
Alkali metal carbonates, alkali metal salts of aliphatic lower alcohols, organic bases and quaternary ammonium salts. Also,
The amount used is usually 0.01 to 10 equivalents, preferably 0.1 to 5 equivalents. The acid is an organic acid such as formic acid or acetic acid, or an inorganic acid such as hydrochloric acid or sulfuric acid, and is preferably an organic acid. The amount used is usually 0.01 to 1
It is 0 equivalents, preferably 0.1 to 5 equivalents. The above bases and acids can be used as a mixture, and are preferably mixed with an organic base and an organic acid. The mixing ratio of organic base: organic acid is 1:10 to 10: 1, preferably 1: 5 to 5: 1. The first step, the second step
By performing the steps under the same reaction conditions, the compound represented by the general formula (4)

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ are the same as defined above) without isolating the compound represented by the general formula (5)

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ represent the same as defined above). The purification can be carried out by a commonly used method such as recrystallization, distillation and chromatography using silica gel.

[0009]

The present invention will be described more specifically with reference to the following examples.

REFERENCE SYNTHESIS EXAMPLE Preparation of ethyl isonicotinoyl acetate Ethyl isonicotinate (5.0 g, 33.1 m)
mol) in toluene solution (100 ml), ethyl acetate (4.0 ml, 41.3 mmol) was added.
t-BuOK (5.6 g, 49.6 mmol) was added slowly. After stirring at room temperature for 4 hours, water was added to the reaction solution, and further neutralized with 5% hydrochloric acid. The organic layer was separated, washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with hexane to obtain ethyl isonicotinoyl acetate as pale brown crystals. (1.0 g, 15.7% yield) ¹ H-NMR (ppm, 300 MHz, CDCl ₃ ) δ 12.44 (1 H, s) 8.72 (2 H, d, J = 5.6 Hz) 7.62 (2H, d, J = 5.6 Hz) 5.77 (1H, s) 4.30 (2H, q, J = 7.1 Hz) 1.35 (3H, t, J = 7.1 Hz)

Example 1 Ethyl 2-isonicotinoyl-5-oxohexanoate (in the general formula (4), X is a 4-pyridyl group, Y is an ethoxycarbonyl group,
A compound wherein R ¹ , R ² and R ³ are H) isonicotinoyl acetic acid ethyl ester (1.0 g, 5.
Sodium ethoxide (35 mg, 0.518 mmol) was added to an ethanol solution (5 ml) of 18 mmol), and 400 mg of methyl vinyl ketone, 5.70 mmol were added.
l) was slowly added dropwise with ice cooling. After slowly bringing it to room temperature,
Stirred overnight. After ethanol was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate system).
-Isonicotinoyl-5-oxohexanoic acid ethyl ester was obtained as a pale yellow oil. (Yield 978 mg, Yield 71.8%) ¹ H-NMR (ppm, 300 MHz, CDCl ₃ ) δ 8.83 (2H, t, J = 1.8 and 4.8H)
z) 7.81 (2H, t, J = 1.8 and 4.8H
z) 4.40 (1H, dd, J = 6.4 and 7.0H
z) 4.15 (2H, q, J = 6.9 Hz) 2.60-2.70 (2H, m) 2.14-2.35 (2H, m) 2.15 (3H, s) 17 (3H, t, J = 6.9 Hz)

Example 2 Ethyl 2- (4-pyridyl) -4-oxocyclohex-2-enecarboxylate (in the formula (5), X is a 4-pyridyl group, Y is an ethoxycarbonyl group, R ¹ , R ² and R ³ are H) 2-Isonicotinoyl-5-oxohexanoic acid ethyl ester (978 mg, 15.2 mmol) in toluene solution (20 ml) was treated with acetic acid (137 mg, 5.57 mmol).
l) and piperidine (311 mg, 3.66 mmol)
Was added, and dehydration was performed under heating to reflux. After completion of the reaction, the reaction solution was cooled to room temperature, and after adding ethyl acetate, washed with water and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain ethyl 2- (4-pyridyl) -4-oxocyclohex-2-enecarboxylate as a brown oil. (Yield 523m
g, yield 57.4%) ¹ H-NMR (ppm, 300 MHz, CDCl ₃ ) δ 8.68 (2H, dd, J = 1.9 and 4.8)
Hz) 7.35 (2H, dd, J = 1.9 and 4.8H)
z) 6.50 (1H, s) 4.12 (2H, q, J = 6.9 Hz) 3.91 (1H, t, J = 4.6 Hz) 2.35-2.75 (4H, m) 1.63 (3H, t, J = 6.9Hz)

[0013]

According to the present invention, a heterocyclic-substituted cyclohexenone derivative useful for synthesizing intermediates such as pharmaceuticals and agrochemicals, liquid crystals, heat-resistant polymers, and liquid crystalline polymers can be selectively produced.
This synthesis method is an industrial method for selectively synthesizing an intermediate of a biphenyl derivative using inexpensive raw materials and requiring no special equipment or reaction conditions.

Claims (13)

[Claims] 1. A compound of the general formula (1)[Wherein X is a 5-member having at least one of N, O, and S]
Or a 6-membered optionally substituted heterocyclic or substituted ring
Condensates of those that may be exchanged with benzene (only
1 to 3 substituents may be the same or different
, H, OH, optionally substituted C₁~ C₆The alkyl of
Group, optionally substituted C_Two~ C₆Alkenyl group, substitution
C that may be_Two~ C₆Alkynyl group, substituted
May be C₁~ C₆An alkoxy group, which may be substituted
C₁~ C₆Alkylthio group, NR^FourR^Five, Halogen, NO_Two, CN,
COR⁶, CO_TwoR⁶, CONR^FourR^Five, SO_ThreeR⁶, SO_TwoNR^FourR^Five, SOR⁶, SO
_TwoR⁶, OCOR⁶, OCO_TwoR⁶, OCONR^FourR^Five, OSO_TwoR⁶Has been replaced
Optionally substituted phenyl group, optionally substituted phenoxy
Group, an optionally substituted heteroaryl group or substituted
Represents a heteroaryloxy group which may be
May form a 4- to 7-membered ring with a substituent adjacent to
), And Y is CO_TwoR⁶, CN, NO_Two, SO_ThreeR⁶, SO_TwoNR^FourR^Five, SO
R⁶, SO_TwoR⁶And R^Four, R^FiveAnd R⁶Is H, substituted
Good C₁~ C₆Or an alkyl group of which may be substituted
Represents a phenyl group, R^FourAnd R^FiveForm a 4- to 7-membered ring with
Is also good. And a compound represented by the general formula (2):[Where R¹, R^TwoAnd R^ThreeIs H, optionally substituted C₁~
C₆Alkyl group, optionally substituted C_Two~ C₆Arche of
Nyl group, optionally substituted C_Two~ C₆An alkynyl group of
C which may be substituted₁~ C₆An alkoxy group, which is substituted
May be C₁~ C₆Alkylthio group, NR^FourR^Five, Haloge
N, NO_Two, CN, COR⁶, CO_TwoR⁶, CONR^FourR^Five, SO_ThreeR ⁶, SO_TwoNR
^FourR^Five, SOR⁶, SO_TwoR⁶, OCOR⁶, OCO_TwoR⁶, OCONR^FourR^Five, OSO
_TwoR⁶, An optionally substituted aryl group,
Phenoxy group, optionally substituted heteroaryl
A reel group or an optionally substituted heteroaryl
Represents a xy group, R^Four, R^FiveAnd R⁶Is defined as above
Show the same thing. Reacting the compound represented by
General formula (4) characterized by the following:[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined as above
Show the same thing. ] The manufacturing method of the compound shown by this. 2. A compound of the general formula (1) [Wherein, X and Y are the same as defined in claim 1]. And a compound represented by the general formula (3): [Wherein, R ¹ , R ² and R ³ are the same as defined in claim 1, and Z represents a leaving group. Wherein a compound represented by the general formula (4) is reacted: [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1]. ] The manufacturing method of the compound shown by these. 3. A compound of the general formula (4) [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1]. Wherein the compound represented by the general formula (5) is subjected to a cyclization reaction. [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1]. The method for producing a cyclohexenone derivative represented by the formula: 4. A compound of the general formula (1) [Wherein, X and Y are the same as defined in claim 1]. And a compound represented by the general formula (2): [Wherein, R ¹ , R ² and R ³ are the same as defined in claim 1]. And a compound represented by the general formula (4): [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1]. A cyclization reaction is performed after synthesizing the compound represented by the general formula (5): [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1]. The method for producing a cyclohexenone derivative represented by the formula: 5. A compound of the general formula (1) [Wherein, X and Y are the same as defined in claim 1]. And a compound represented by the general formula (3): [Wherein R ¹ , R ² and R ³ represent the same as defined in claim 1, and Z represents the same as defined in claim 2]. And a compound represented by the general formula (4): [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1]. A compound represented by the general formula (5): [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1]. The method for producing a cyclohexenone derivative represented by the formula: 6. X is an optionally substituted pyrrole, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyrazole, an optionally substituted isoxazole, and an optionally substituted pyrrole. Optionally substituted isothiazole, optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted indole, substituted Good benzofuran,
Optionally substituted benzothiophene, is a good isoquinoline be also good quinoline or substituted substituted, the substituent is H, OH, substituted C ₁ optionally -C ₆ alkyl group, An optionally substituted C ₁ -C ₆ alkoxy group, halogen, NR ⁴ R ⁵ , nitro group, CN, CO
^{6. The} method according to claim 1, wherein ₂ R ^{6 is} a phenyl group which may be substituted or a phenoxy group which may be substituted. 7. A pyrrole, wherein X is optionally substituted,
Furan, thiof optionally substituted
Ene, optionally substituted pyridine or substituted
And the substituent is H, substituted
May be C₁~ C₆Alkyl group, even if it is substituted
Good C₁~ C₆Alkoxy group, halogen, NR ^FourR^FiveOr d
Toro group and Y is CO_TwoR⁶, CN, NO_Two, SO_ThreeR⁶Or SO_TwoNR^Four
R^FiveThe production method according to any one of claims 1 to 5, wherein 8. wherein X is good pyridine which may be substituted, the substituent is H, optionally substituted C ₁ -C ₆ alkyl group, optionally substituted good C ₁ -C ₆ An alkoxy group or a halogen, and Y is CO ₂ R ⁶ , CN, SO ₃ R ⁶ or SO ₂
NR ⁴ Process according to any one of claims 1 to 5 R ^5. 9. A compound of the general formula (4) [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1]. ] The diketone derivative represented by these. 10. A compound of the general formula (5) [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1]. The heterocyclic-substituted cyclohexenone derivative represented by the formula: 11. X is an optionally substituted pyrrole, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyrazole, an optionally substituted isoxazole, and an optionally substituted pyrrole. Optionally substituted isothiazole, optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted indole, substituted Benzofuran, optionally substituted benzothiophene, optionally substituted quinoline or optionally substituted isoquinoline, the substituent of which is H, OH, optionally substituted C ₁ -C ₆ alkyl group, optionally substituted C ₁ ~
C ₆ alkoxy group, halogen, NR ⁴ R ⁵ , nitro group, CN, C
The intermediate or the heterocyclic-substituted cyclohexenone derivative according to claim 9 or 10, wherein O ₂ R ^{6 is} an optionally substituted phenyl group or an optionally substituted phenoxy group. (12) a pyrrole or an optionally substituted pyrrole,
Optionally substituted furan, optionally substituted thio
Phen, optionally substituted pyridine, substituted
Pyrimidine or optionally substituted India
Wherein the substituent is H, optionally substituted C₁
~ C₆Alkyl group, optionally substituted C ₁~ C₆Al
Coxy group, halogen, NR^FourR^FiveOr a nitro group, and Y is
CO_TwoR⁶, CN, NO_Two, SO_ThreeR⁶Or SO_TwoNR^FourR^FiveClaim 9
Or the intermediate or heterocyclic-substituted cyclohexene described in 10
Xenon derivatives. 13. X is a good pyridine which may be substituted, the substituent is H, optionally substituted C ₁ -C ₆ alkyl group, optionally substituted good C ₁ -C ₆ An alkoxy group or a halogen, and Y is CO ₂ R ⁶ , CN, SO ₃ R ⁶ or SO ₂
The intermediate or the heterocyclic-substituted cyclohexenone derivative according to claim 9, which is NR ⁴ R ⁵ .