JP2001199934A - Phenol derivative and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a phenol derivative useful as an intermediate for pharmaceuticals, agrochemicals, liquid crystals, heat-resistant polymers, liquid crystal polymers, etc. SOLUTION: The objective phenol derivative is expressed by general formula [X is a (substituted)benzene ring; Y is CO2R6; and R1, R2 and R3 are each H].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical intermediate, particularly a farnesyltransferase inhibitor (J. Med. Chem., 4).
1, 4288 (1998)).
Also, the present invention relates to a phenol derivative useful as an intermediate such as a pesticide, liquid crystal, a heat-resistant polymer and a liquid crystalline polymer, and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, as a method for producing an aromatic ring-substituted phenol derivative, a method of coupling an organometallic compound and an aryl halide compound in the presence of a catalyst such as a Pd complex (J. Me.
d. Chem., 41, 4288 (1998)).

[0003]

The conventional methods involve a reaction under anhydrous conditions using an organometallic compound or the like, a reaction under high-temperature and high-pressure conditions, and require an expensive catalyst or the like in terms of production equipment and cost. There were many problems in terms of surface. 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 process for producing a highly selective phenol derivative using inexpensive raw materials under mild reaction conditions. That is, the present invention provides (1) general formula (1)

Embedded image[Wherein, X is an optionally substituted benzene ring, N, O, S
A 5- or 6-membered ring having at least one of
Optionally substituted heterocycle or optionally substituted
Condensates of these with benzene (provided that the number of substituents is 1-3
May be the same or different; H, OH,
May be C₁~ C₆Alkyl group of optionally substituted C_Two~
C₆An alkenyl group of optionally substituted C_Two~ C₆Alkini
Group, optionally substituted C₁~ C₆An alkoxy group, substituted
Alkylthio group, NR^FourR^Five, Halogen, NO_Two, C
N, COR⁶, CO_TwoR⁶, CONR^FourR^Five, SO_ThreeR⁶, SO_TwoNR^FourR^Five, SOR⁶, SO
_TwoR⁶, OCOR⁶, OCO_TwoR⁶, OCONR^FourR^Five, OSO_TwoR⁶, Even if replaced
Good phenyl group, optionally substituted phenoxy group, substituted
Heteroaryl group which may be substituted or which may be substituted
A heteroaryloxy group, further adjacent substituents
May form a 4- to 7-membered ring), and Y is CO_Two
R⁶, CN, NO_Two, SO_ThreeR⁶, SO_TwoNR^FourR^Five, SOR⁶, SO_TwoR ⁶And R
¹, R^TwoAnd R^ThreeIs H, optionally substituted C₁~ C₆The alkyl of
Group, optionally substituted C_Two~ C₆An alkenyl group, substituted
May be C_Two~ C₆Alkynyl group of the optionally substituted C₁~
C₆An alkoxy group, an optionally substituted alkylthio 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_TwoR⁶An optionally substituted phenyl group,
Phenoxy group, heteroaryl which may be substituted
Represents a group or a heteroaryloxy group which may be substituted.
Then R^Four, R^FiveAnd R⁶Is H, an alkyl group which may be substituted
Or a phenyl group which may be substituted;^FourAnd R^Five
May form a ring of 4 to 7, with
General formula characterized by oxidizing a xenon derivative
(2)

Embedded image [Wherein X, Y, R ¹ , R ² and R ³ are the same as defined above], (2) a method for producing a phenol derivative represented by the following general formula (2):

Embedded image Wherein X, Y, R ¹ , R ² and R ³ are the same as defined in (1), and a phenol derivative represented by the general formula (3) R ⁷ -Q (3) Wherein R ⁷ is an optionally substituted C ₁ -C ₆ alkyl group, COR
⁶ , CO ₂ R ⁶ , CONR ⁴ R ⁵ , Q represents a leaving group, and a compound represented by the general formula (4):

Embedded image Wherein X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined in (1). (3) (1) Formula (2)

Embedded image Wherein X, Y, R ¹ , R ² and R ³ are the same as defined in (1), and synthesize a phenol derivative represented by the formula: General formula (4)

Embedded image[Where X, Y, R¹, R^Two, R^ThreeAnd R⁷Is defined in (1)
Phenol derivative shown with]
(4) benzene in which X may be substituted
The production according to any one of (1) to (3), which is a ring.
The method, (5) wherein X has at least one of N, O, and S
A 6-membered or 6-membered optionally substituted heterocyclic ring or
Condensates of these optionally substituted benzenes
(1) The method according to any one of (1) to (3),
(6) X is an optionally substituted benzene ring;
The substituent of H is optionally substituted C₁~ C₆An alkyl group of
C which may be substituted₁~ C₆An alkoxy group, NR^FourR^Five,Halo
Gen, NO_TwoAn optionally substituted phenyl group or substituted
Is a phenoxy group, where Y is CO_TwoR⁶, CN, NO_Two, S
O_ThreeR⁶Or SO_TwoNR^FourR^FiveAnd R^Four, R^FiveAnd R⁶Is H, substitution
Alkyl group or phenyl which may be substituted
R ^FourAnd R^FiveMay form 4-7 rings
, R¹, R^TwoAnd R^ThreeIs H, optionally substituted C₁~ C₆No
Alkyl or phenyl which may be substituted
(7) The production method according to any one of (1) to (3),
X is optionally substituted pyrrole, even if X is substituted
Good furan, optionally substituted thiophene, substituted
Optionally substituted pyridine or optionally substituted
And the substituent is H, optionally substituted C₁
~ C₆Alkyl group of optionally substituted C₁~ C₆Alcoqui
Si group, halogen, NR^FourR^FiveOr NO_TwoAnd Y is CO_TwoR⁶, C
N, SO_ThreeR⁶Or SO_TwoNR^FourR^FiveAny of (1) to (3)
Or (8) X may be substituted.
Benzene ring, the substituent of which is H,
C₁~ C₆Alkyl group of optionally substituted C₁~ C₆Al
Coxy group, NR^FourR^Five, Halogen or NO_Two, Y is CO_TwoR⁶, CN,
SO_ThreeR⁶Or SO_TwoNR^FourR^FiveAnd R^Four, R^FiveAnd R⁶Is H, substitution
Alkyl group or phenyl which may be substituted
R^FourAnd R^FiveMay form 4-7 rings
, R¹, R^TwoAnd R^ThreeIs H, optionally substituted C₁~ C₆No
The alkyl group according to any one of (1) to (3),
Production method, (9) X is pyridine which may be substituted
Wherein the substituent is H, C which may be substituted₁~ C₆Archi
Group, optionally substituted C₁~ C₆An alkoxy group or ha
Logen, Y is CO_TwoR⁶, CN, SO_ThreeR⁶Or SO_TwoNR^FourR^Fiveso
The production method according to any one of (1) to (3),
(10) General formula (2)

Embedded image Wherein X, Y, R ¹ , R ² and R ³ are the same as defined in (1),
(11) General formula (4)

Embedded image Wherein X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined in (1).

In the general formulas (1) to (4) of the present invention, X represents, for example, an optionally substituted phenyl, an optionally substituted pyrrole, an optionally substituted furan, an optionally substituted furan. Thiophene, optionally substituted pyrazole, optionally substituted imidazole, optionally substituted isothiazole, optionally substituted imidazole, optionally substituted oxazole, optionally substituted Good thiazoles, optionally substituted pyridines, optionally substituted pyridazines, optionally substituted pyrimidines, optionally substituted pyrazines, optionally substituted naphthalenes, optionally substituted indoles Optionally substituted benzo [b] furan, optionally substituted benzo [b] thiophene, Optionally substituted benzo [d] imidazole, optionally substituted benzo [d] oxazole, optionally substituted benzo [d] thiazole, optionally substituted purine, optionally substituted Quinoline, optionally substituted isoquinoline, optionally substituted cinnoline, optionally substituted phthalazine, optionally substituted xazoline, optionally substituted quinoxaline, optionally substituted pteridine and the like Preferably, optionally substituted pyrrole, optionally substituted furan, optionally substituted thiophene, optionally substituted pyrazole, optionally substituted isoxazole, substituted Isothiazole, optionally substituted pyridine, optionally substituted pyridazine, Conversion which may be pyrimidine, pyrazine optionally substituted indole optionally substituted, benzofuran optionally substituted, optionally substituted benzothiophene, optionally substituted quinoline,
Optionally substituted isoquinoline, more preferably optionally substituted pyrrole, optionally substituted furan, optionally substituted thiophene, optionally substituted pyridine, optionally substituted Pyrimidine, and optionally substituted indole. Examples of the substituent include a C ₁ -C ₆ alkyl group which may be substituted, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a pentyl group, a hexyl group, and a trialkyl group. A fluoromethyl group, a chloromethyl group, a bromomethyl group, a benzyl group, and the like; as the optionally substituted C _{2 to} C ₆ alkenyl group, a vinyl group, an allyl group,
Isopropenyl group, butenyl group, pentenyl group, hexenyl group, styryl group, etc .; optionally substituted C ₂ -C ₆ alkynyl group may be ethynyl group, propynyl group, butynyl group, pentynyl group, etc .; Examples of the C ₁ -C ₆ alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, a trifluoromethoxy group, a benzyloxy group and the like;
Examples of the alkylthio group which may be substituted include a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, a hexylthio group and a benzylthio group;
NR ⁴ R ⁵ includes amino, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, te
rt-butylamino group, pentylamino group, hexylamino group, pyrrolidino group, piperidino group, morpholino group, anilino group, etc .; as halogen, fluorine, chlorine, bromine,
Iodine; NO ₂ ; CN; COR ⁶ includes formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, pivaloyl group, benzoyl group, toluoyl group, furanoyl group, nicotinoyl group, isonicotinoyl group, cinnamoyl group, etc. A methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a phenoxycarbonyl group and the like as CO ₂ R ⁶ ; a methylaminocarbonyl group as CONR ⁴ R ⁵ ; Dimethylaminocarbonyl group, ethylaminocarbonyl group, diethylaminocarbonyl group, pyrrolidinocarbonyl group, pipetidinocarbonyl group, morpholinocarbonyl group, anilinocarbonyl group, etc .; SO ₃ R ⁶ includes methoxysulfonyl group, Xisulfonyl group, propoxysulfonyl group, butoxysulfonyl group, benzyloxysulfonyl group, phenoxysulfonyl group, etc .; SO ₂ NR ⁴ R ⁵ includes sulfamoyl group, methylsulfamoyl group, dimethylsulfamoyl group, ethylsulfamoyl group , Diethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, butylsulfamoyl group, tert-butylsulfamoyl group,
A pentylsulfamoyl group, a hexylsulfamoyl group, a pyrrolidinosulfamoyl group, a piperidinosulfamoyl group, a morpholinosulfamoyl group, an anilinosulfamoyl group and the like; SOR ⁶ includes a methylsulfinyl group, an ethylsulfinyl group, Propylsulfinyl group,
Butylsulfinyl group, benzylsulfinyl group, phenylsulfinyl group, etc .; SO ₂ R ⁶ includes methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group, benzylsulfonyl group, phenylsulfonyl group, etc .; OCOR ⁶ is acetyl Oxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, pivaloyloxy, benzoyloxy, toluoyloxy, furanoyloxy, nicotinoyloxy, isonicotinoyloxy, cinnamoyl An oxy group;
OCO ₂ R ⁶ includes a methoxycarbonyloxy group, an ethoxycarbonyloxy group, a propoxycarbonyloxy group,
Butoxycarbonyloxy group, tert-butoxycarbonyloxy group, benzyloxycarbonyloxy group, phenoxycarbonyloxy group and the like; OCONR ⁴ R ⁵ includes methylaminocarbonyloxy group, dimethylaminocarbonyloxy group, ethylaminocarbonyloxy group, diethylaminocarbonyl An oxy group, a pyrrolidinocarbonyloxy group, a pipetidinocarbonyloxy group, a morpholinocarbonyloxy group, an anilinocarbonyloxy group and the like;
OSO ₂ R ⁶ includes a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group,
Butanesulfonyloxy group, pentanesulfonyloxy group, hexanesulfonyloxy group, benzenesulfonyloxy group, toluenesulfonyloxy group and the like; phenyl groups which may be substituted include hydroxyphenyl group, chlorophenyl group, methylphenyl group, trifluoromethylphenyl Group, methoxyphenyl group, tert
-Butoxyphenyl group, benzyloxyphenyl group, trifluoromethoxyphenyl group, phenoxyphenyl group and the like; phenoxy groups which may be substituted include phenoxy group, hydroxyphenoxy group, chlorophenoxy group,
A methylphenoxy group, a trifluoromethylphenoxy group, a methoxyphenoxy group, a trifluoromethoxyphenoxy group, a phenoxyphenoxy group and the like; as the optionally substituted heteroaryl group, a furanyl group, a thienyl group, an azolyl group, a pyridyl group, an indolyl group, Examples of the optionally substituted heteroaryloxy group include a furanyloxy group, a thienyloxy group, an azolyloxy group, a pyridyloxy group, and an indolyloxy group. Preferably, H, optionally substituted C ₁ -C ₆ alkyl group, optionally substituted C ₁ -C ₆ alkoxy group, halogen, N
O ₂ , NR ⁴ R ⁵ , an optionally substituted phenyl group, an optionally substituted phenoxy group, COR ⁶ , CO ₂ R ⁶ , OCOR ⁶ or OCO ₂ R ⁶
And particularly preferably, H, a methyl group, a methoxy group,
It is a phenoxy group, a methoxycarbonyl group, an ethoxycarbonyl group, NO ₂ , an acetoxy group or a benzoyloxy group. The ring formed between adjacent substituents as the substituent of X includes a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, an oxetane ring, a tetrahydrofuran ring, a furan ring, a pyran ring, a dioxolan ring, and a dioxane ring. And the like. As Y, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group and the like as CO ₂ R ⁶ ; CN; NO ₂ ; SO ₃ R ⁶ as methoxycarbonyl group Sulfonyl, ethoxysulfonyl, propoxysulfonyl, butoxysulfonyl, benzyloxysulfonyl, phenoxysulfonyl and the like;
SO ₂ NR ⁴ R ⁵ includes sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, ethylsulfamoyl, diethylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, butylsulfamoyl Moyl group, tert-butylsulfamoyl group, pentylsulfamoyl group, hexylsulfamoyl group, pyrrolidinosulfamoyl group, piperidinosulfamoyl group, morpholinosulfamoyl group, anilinosulfamoyl group, etc .; SOR ⁶ as methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, butylsulfinyl group, benzylsulfinyl group, phenylsulfinyl group and the like; SO ₂ R ⁶ as methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group,
Examples include a butylsulfonyl group, a benzylsulfonyl group, and a phenylsulfonyl group. Preferably, C
N, CO ₂ R ⁶ , NO ₂ , SO ₃ R ⁶ or SO ₂ NR ⁴ R ⁵ , and particularly preferably CN, methoxycarbonyl group or ethoxycarbonyl group. R ¹ , R ² and R ³ are, for example, H; and optionally substituted C ₁ -C ₆ alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl Group, hexyl group, trifluoromethyl group, chloromethyl group, bromomethyl group, benzyl group and the like; and optionally substituted C ₂ -C ₆ alkenyl groups include vinyl group, allyl group, isopropenyl group, butenyl group, A pentenyl group, a hexenyl group, a styryl group and the like; an optionally substituted C ₂ -C ₆ alkynyl group includes an ethynyl group, a propynyl group, a butynyl group and a pentynyl group; and an optionally substituted C ₁ -C ₆ alkoxy group Groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, trifluoromethoxy, benzyloxy and the like; Good alkylthio groups include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, benzylthio and the like; NR ⁴ R ⁵ is amino, methylamino, dimethylamino, ethylamino, diethylamino Group, propylamino group, isopropylamino group, butylamino group, tert-butylamino group,
Pentylamino group, hexylamino group, pyrrolidino group,
Piperidino group, morpholino group, anilino group, etc .; as halogen, fluorine, chlorine, bromine, iodine; NO ₂ ; CN; COR;
⁶ as formyl group, acetyl group, propionyl group,
Butyryl group, isobutyryl group, valeryl group, pivaloyl group, benzoyl group, toluoyl group, furanoyl group, nicotinoyl group, isonicotinoyl group, cinnamoyl group; CO ₂ R ⁶ includes methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxy Carbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, phenoxycarbonyl group, etc .; CONR ⁴ R ⁵
As a methylaminocarbonyl group, a dimethylaminocarbonyl group, an ethylaminocarbonyl group, a diethylaminocarbonyl group, a pyrrolidinocarbonyl group, a pipetidinocarbonyl group, a morpholinocarbonyl group, and an anilinocarbonyl group; and SO ₃ R ⁶ as methoxysulfonyl Group, ethoxysulfonyl group, propoxysulfonyl group, butoxysulfonyl group, benzyloxysulfonyl group, phenoxysulfonyl group, etc .; SO ₂ NR ⁴ R ⁵ includes sulfamoyl group, methylsulfamoyl group, dimethylsulfamoyl group, ethylsulfa Moyl group, diethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, butylsulfamoyl group, tert-butylsulfamoyl group, pentylsulfamoyl group, hexylsulfur Amoiru group pyrrolidinopyridine sulfamoyl group, piperidinyloxy ɽ sulfamoyl group, morpholinosulfamoyl sulfamoyl group, such as anisole Linus sulfamoyl group;
SOR ⁶ includes methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, benzylsulfinyl, phenylsulfinyl and the like; SO ₂ R ⁶ includes methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl , Benzylsulfonyl, phenylsulfonyl, etc .; OCOR ⁶ includes acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, pivaloyloxy, benzoyloxy, toluoyloxy, furanoyl Oxy group, nicotinoyloxy group, isonicotinoyloxy group, cinnamoyloxy group and the like; OCO ₂ R ⁶ includes methoxycarbonyloxy group, ethoxycarbonyloxy group,
Propoxycarbonyloxy group, butoxycarbonyloxy group, tert-butoxycarbonyloxy group, benzyloxycarbonyloxy group, genoxycarbonyloxy group, etc .; OCONR ⁴ R ⁵ includes methylaminocarbonyloxy group, dimethylaminocarbonyloxy group, ethylamino Carbonyloxy group, diethylaminocarbonyloxy group, pyrrolidinocarbonyloxy group, pipetidinocarbonyloxy group, morpholinocarbonyloxy group, anilinocarbonyloxy group and the like; as OSO ₂ R ⁶ methanesulfonyloxy group, ethanesulfonyloxy group, Propanesulfonyloxy, butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy A phenyl group which may be substituted, such as a hydroxyphenyl group, a chlorophenyl group, a methylphenyl group, a trifluoromethylphenyl group, a methoxyphenyl group, a tert-butoxyphenyl group,
Benzyloxyphenyl group, trifluoromethoxyphenyl group, phenoxyphenyl group and the like; phenoxy groups which may be substituted include phenoxy group, hydroxyphenoxy group, chlorophenoxy group, methylphenoxy group, trifluoromethylphenoxy group, methoxyphenoxy group, Trifluoromethoxyphenoxy group, phenoxyphenoxy group and the like; optionally substituted heteroaryl group is furanyl group, thienyl group, azolyl group, pyridyl group, indolyl group, and optionally substituted heteroaryloxy group is furanyloxy group; Thienyloxy group,
Examples include an azolyloxy group, a pyridyloxy group, an indolyloxy group, and preferably H is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or a tert- group.
Butyl group, a pentyl group, a hexyl group, trifluoromethyl group, chloromethyl group, bromomethyl group, a substituted have C ₁ may be -C ₆ alkyl group such as a benzyl group, hydroxyphenyl group, chlorophenyl group, methylphenyl Group,
Trifluoromethylphenyl group, methoxyphenyl group,
tert-butoxyphenyl group, benzyloxyphenyl group, trifluoromethoxyphenyl group, phenyl group which may be substituted such as phenoxyphenyl group, particularly preferably H, methyl group, ethyl group, propyl group, isopropyl group, trifluoromethyl Group, chloromethyl group, bromomethyl group, hydroxyphenyl group, chlorophenyl group,
A methylphenyl group, a trifluoromethylphenyl group, a methoxyphenyl group or a trifluoromethoxyphenyl group. R ⁴ , R ⁵ and R ⁶ are, for example, H; alkyl groups which may be substituted include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl; Examples of the phenyl group which may be used include a hydroxyphenyl group, a chlorophenyl group, a methylphenyl group, a trifluoromethylphenyl group, a methoxyphenyl group, a trifluoromethoxyphenyl group, a phenoxyphenyl group, and the like, and NR ⁴ R ⁵ includes pyrrolidinyl. Group, piperazinyl group, morpholinyl group and the like. As R ⁷ , for example, an optionally substituted C ₁ -C ₆ alkyl group may be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a pentyl group, a hexyl group, a benzyl group; Examples of COR ⁶ include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, pivaloyl group, benzoyl group, toluoyl group, furanoyl group, nicotinoyl group, isonicotinoyl group, cinnamoyl group and the like; CO ₂ R ⁶
As a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group,
tert-butoxycarbonyl group, benzyloxycarbonyl group, phenoxycarbonyl group and the like; CONR ⁴ R ⁵ includes methylaminocarbonyl group, dimethylaminocarbonyl group, ethylaminocarbonyl group, diethylaminocarbonyl group, pyrrolidinocarbonyl group, pipetidinocarbonyl Group, morpholinocarbonyl group, anilinocarbonyl group and the like. Q may be any substituent having a function as a leaving group.Examples include halogen such as chlorine, bromine and iodine, methanesulfonyloxy group, ethanesulfonyloxy group, trifluoromethanesulfonyloxy group, and benzenesulfonyloxy group. And a sulfonyloxy group such as a toluenesulfonyloxy group. Preferred compounds of the general formula (1) include ethyl 2-phenyl-4-oxocyclohex-2-enecarboxylate and ethyl 2- (4-nitrophenyl) -4-oxocyclohex-2-enecarboxylate 2- (4-chlorophenyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester,
2- (4-methoxyphenyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester, 2- (4-tolyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester, 2- (2- Tolyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester, 2-
(4-pyridyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester and the like. A preferred compound of the general formula (2) is 4-hydroxy-2-
Biphenylcarboxylic acid ethyl ester, 4-hydroxy-4'-nitrobiphenyl-2-ylcarboxylic acid ethyl ester, 4-hydroxy-4'-chlorobiphenyl-2-ylcarboxylic acid ethyl ester, 4-hydroxy-4'-methoxybiphenyl- 2-carboxylic acid ethyl ester, 4
-Hydroxy-4'-methylbiphenyl-2-ylcarboxylic acid ethyl ester, 4-hydroxy-2'-methylbiphenyl-2-ylcarboxylic acid ethyl ester, 4- (5-hydroxy-2-ethoxycarbonylphenyl) pyridine and the like. Can be Preferred compounds of the general formula (3) include methyl iodide, ethyl iodide, propyl iodide, pentyl iodide, hexyl bromide, benzyl chloride, benzyl bromide, 3-chloromethylpyridine and its hydrochloride, acetyl chloride , Methyl chlorocarbonate, ethyl chlorocarbonate, benzyl chlorocarbonate and the like. A preferred compound of the general formula (4) is 4- (3-pyridylmethoxy)-
2-biphenylcarboxylic acid ethyl ester, 4- (3-
Pyridylmethoxy) -4′-nitrobiphenyl-2-ylcarboxylic acid ethyl ester, 4- (3-pyridylmethoxy) -4′-chlorobiphenyl-2-ylcarboxylic acid ethyl ester, 4- (3-pyridylmethoxy) -4 ′ -Methoxybiphenyl-2-ylcarboxylic acid ethyl ester, 4-
(3-pyridylmethoxy) -4′-methylbiphenyl-2
-Ethyl carboxylate, 4- (3-pyridylmethoxy) -2′-methylbiphenyl-2-yl carboxylic acid ethyl ester, 4- (5- (3-pyridylmethoxy)-
2-ethoxycarbonylphenyl) pyridine and the like. In the present invention, compounds represented by the general formulas (1) to (4) include, for example, hydrogen halides such as hydrogen chloride and hydrogen bromide; other inorganic acids such as sulfuric acid, nitric acid and phosphoric acid; Some organic sulfonic acids such as sulfonic acid and p-toluenesulfonic acid; or other organic acids such as trifluoroacetic acid and oxalic acid can be used as salts, which are also included in the present invention. Is what is done. In the present invention, the general formulas (1) to (4)
Include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; transition metal salts such as copper salt and iron salt; Some compounds form salts with bases such as organic base salts such as amine salts. These are also included in the present invention. In the present invention,
The compounds represented by the general formulas (1) to (4) may include optical isomers, geometric isomers and tautomers, and in this case, the present invention provides a compound having one kind of isomer and number of isomers. It also includes mixtures of any ratio of the isomers of the species. Further, hydrates of the compounds represented by the general formulas (1) to (4) are also included.

[0006]

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, R ¹ , R ² , R ³ and R ⁷ are as described above.) The general formula (1) as a starting material of the present synthesis method

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ are as defined above) can be synthesized by a conventionally known method, but can also be synthesized as follows.

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

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, and the general formula (C)

Embedded image Can be synthesized by applying methods such as Chemistry Letters, 1663 (1993) and Org. Syntheses Coll. Vol. 3, 305 (1955).

First step: Preparation of compound of general formula (2) from compound of general formula (1) General formula (2)

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

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ are as defined above) can be produced by subjecting the compound to an oxidation reaction in a solvent. Examples of the solvent used in the above reaction include aliphatic alcohols such as methanol and ethanol, aromatic hydrocarbons such as toluene and cumene, aliphatic and aromatic esters such as ethyl acetate and methyl benzoate, tetrahydrofuran and diglyme. Ether hydrocarbons, organic chlorinated hydrocarbons such as dichloromethane and 1,2-dichloroethane, aliphatic hydrocarbons such as n-hexane, organic acids such as acetic acid, aliphatic and aromatic nitriles such as acetonitrile and phenylnitrile, and water And mixtures thereof. Preferably, an aromatic hydrocarbon,
Ether hydrocarbons, aliphatic hydrocarbons, organochlorine hydrocarbons, aliphatic and aromatic nitriles, organic acids, water and mixtures thereof. Reaction temperature is usually from room temperature to 4
00 ° C., preferably 50 ° C. to 300 ° C.
This reaction can also be performed without a solvent. As the oxidizing agent, metal oxides such as KMnO ₄ and MnO ₂ , platinum, palladium,
Examples include a simple substance of a platinum group element such as osmium, iridium, ruthenium, and rhodium or a salt thereof, a halogenating agent such as thionyl chloride or sulfuryl chloride, a quinone derivative such as DDQ, sulfur, and oxygen. Examples of the salts of platinum group elements include mineral salts such as hydrochlorides. Platinum group elements or their salts such as hydrochloric acid are activated carbon, graphite, silica, alumina, silica-alumina, zeolite, titania, magnesia, zirconia, diatomaceous earth,
It may be in the form of a suitable simple substance such as barium sulfate. The amount used is usually 0.001 to 20 equivalents, preferably 0.05 to 10 equivalents. These oxidation reactions can also be performed in the presence of oxygen. The purification can be carried out by a commonly used method such as recrystallization, distillation and chromatography using silica gel.

Second step: Preparation of a compound of the general formula (4) from a compound of the general formula (2)

Embedded image (Wherein X, Y, R ¹ , R ² , R ³ and R ⁷ are as defined above) are represented by the general formula (2)

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ are as defined above) and a compound of the general formula (3) R ⁷ -Q (3) (where R ⁷ and Q are as defined above) Can be produced by reacting the compound represented by with or without a base in a solvent. Examples of the solvent include aliphatic alcohols such as methanol and ethanol, aromatic hydrocarbons such as toluene and cumene, aliphatic and aromatic esters such as ethyl acetate and methyl benzoate, ether hydrocarbons such as tetrahydrofuran and diglyme, Examples include organic chlorinated hydrocarbons such as dichloromethane and 1,2-dichloroethane, aliphatic hydrocarbons such as n-hexane, aliphatic and aromatic nitriles such as acetonitrile and phenylnitrile, water, and mixtures thereof. Preferably, aromatic hydrocarbons, ether hydrocarbons, aliphatic hydrocarbons, organic chlorinated hydrocarbons, aliphatic and aromatic nitriles, water and mixtures thereof are used. The reaction temperature is usually from −20 ° C. to the solvent reflux temperature,
The temperature is preferably from 0 ° C. to the reflux temperature of the solvent. This reaction can also be performed without a solvent. Alkali metal hydroxides as bases such as KOH and NaOH, alkali metal carbonates such as K ₂ CO ₃ or Na ₂ CO _3, MeONa and EtONa and t-BuOK alkali metal salt of an aliphatic lower alcohol such as, pyridine Ya Examples thereof include an organic base such as triethylamine, a metal hydride such as sodium hydride, and an alkali metal salt of an organic acid such as sodium acetate. Preferred are alkali metal carbonates, organic bases and alkali metal salts of aliphatic lower alcohols. The amount used is usually 0.1 to 10 equivalents, preferably 0.5 to 5 equivalents. 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. Example 1 5-hydroxybiphenyl-2-carboxylic acid ethyl ester (a compound in which, in the general formula (2), X is a phenyl group, Y is an ethoxycarbonyl group, and R ¹ , R ^2, and R ³ are H) 4- Oxo-2-phenylcyclohex-2-enecarboxylic acid ethyl ester (100 mg, 0.41 mmol
l) was dissolved in toluene (5 ml), and DDQ (112 m
g, 0.49 mmol) and heated under reflux for 12 hours. After cooling, water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a residue. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to give 5-hydroxybiphenyl-2-
The carboxylic acid ethyl ester (70 mg, 70.7%) was obtained as a brown oil. 1H-NMR (ppm, 300 MHz, CDCl3) δ 7.82 (1H, d, J = 8.1 Hz) 7.20-7.45 (5H, m) 6.83 (1H, dd, J = 2.8 and) 8.7H
z) 6.78 (1H, d, J = 2.2 Hz) 4.05 (2H, d, J = 7.2 Hz) 0.98 (3H, t, J = 7.2 Hz)

[0010]

According to the present invention, it is possible to selectively produce an aniline derivative which is useful as an intermediate such as a medicinal and agricultural chemical, a liquid crystal, a heat-resistant polymer, and a liquid crystalline polymer. This synthesis method can provide a selective industrial production method of a phenol derivative using inexpensive raw materials and not requiring special equipment or reaction conditions.

Claims (11)

[Claims] 1. A compound of the general formula (1)[Wherein, X is an optionally substituted benzene ring, N, O, S
A 5- or 6-membered ring having at least one of
Optionally substituted heterocycle or optionally substituted
Condensates of these with benzene (provided that the number of substituents is 1-3
May be the same or different; H, OH,
May be C₁~ C₆Alkyl group of optionally substituted C_Two~
C₆An alkenyl group of optionally substituted C_Two~ C₆Alkini
Group, optionally substituted C₁~ C₆An alkoxy group, substituted
Alkylthio group, NR^FourR^Five, Halogen, NO_Two, C
N, COR⁶, CO_TwoR⁶, CONR^FourR^Five, SO_ThreeR⁶, SO_TwoNR^FourR^Five, SOR⁶, SO
_TwoR⁶, OCOR⁶, OCO_TwoR⁶, OCONR^FourR^Five, OSO_TwoR⁶, Even if replaced
Good phenyl group, optionally substituted phenoxy group, substituted
Heteroaryl group which may be substituted or which may be substituted
A heteroaryloxy group, further adjacent substituents
May form a 4- to 7-membered ring), and Y is CO_Two
R⁶, CN, NO_Two, SO_ThreeR⁶, SO_TwoNR^FourR^Five, SOR⁶, SO_TwoR ⁶And R
¹, R^TwoAnd R^ThreeIs H, optionally substituted C₁~ C₆The alkyl of
Group, optionally substituted C_Two~ C₆An alkenyl group, substituted
May be C_Two~ C₆Alkynyl group of the optionally substituted C₁~
C₆An alkoxy group, an optionally substituted alkylthio 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_TwoR⁶An optionally substituted phenyl group,
Phenoxy group, heteroaryl which may be substituted
Represents a group or a heteroaryloxy group which may be substituted.
Then R^Four, R^FiveAnd R⁶Is H, an alkyl group which may be substituted
Or a phenyl group which may be substituted;^FourAnd R^Five
May form 4 to 7 rings. ]
General formula characterized by oxidizing a xenon derivative
(2)[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined as above
Show the same thing. Production of phenol derivatives represented by
Law. 2. A compound of the general formula (2) [Wherein, X, Y, R ¹ , R ² and R ³ are the same as those defined in claim 1]. Formula phenol derivative represented ^{by] (3) R 7 -Q (} 3) [ wherein the alkyl group of R ⁷ is optionally substituted C ₁ -C _6, COR
⁶ , CO ₂ R ⁶ , CONR ⁴ R ⁵ , and Q represents a leaving group. Wherein a compound represented by the general formula (4) is reacted: [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as those defined in claim 1]. A method for producing a phenol derivative represented by the formula: 3. The method according to claim 1, wherein the compound has the general formula (2): [Wherein, X, Y, R ¹ , R ² and R ³ are the same as those defined in claim 1]. A phenol derivative represented by the following general formula (4) is synthesized, and then the method of claim 2 is carried out. [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as those defined in claim 1]. A method for producing a phenol derivative represented by the formula: 4. The process according to claim 1, wherein X is an optionally substituted benzene ring. 5. A 5-membered or 6-membered optionally substituted heterocyclic ring having X or at least one of N, O and S, or a condensed product of benzene and an optionally substituted heterocyclic ring. The method according to any one of claims 1 to 3. 6. X is an optionally substituted benzene ring.
Wherein the substituent is H, C which may be substituted₁~ C₆Archi
Group, optionally substituted C₁~ C₆An alkoxy group, NR
^FourR^Five, Halogen, NO_TwoA phenyl group which may be substituted or
Is an optionally substituted phenoxy group, and Y is CO_TwoR⁶, C
N, NO_Two, SO_ThreeR⁶Or SO_TwoNR^FourR^FiveAnd R^Four, R^FiveAnd R⁶
Is H, an optionally substituted alkyl group or an optionally substituted
A good phenyl group and R^FourAnd R^FiveForms 4-7 rings
May be R¹, R^TwoAnd R^ThreeIs H, optionally substituted C₁
~ C₆With an alkyl group or an optionally substituted phenyl group
The method according to any one of claims 1 to 3. (7) X is an optionally substituted pyrrole, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyridine or an optionally substituted indole, substituent is H, alkyl group optionally C ₁ -C ₆ substituted, unsubstituted or optionally C ₁ ~ and
An alkoxy group having C _6, halogen, NR ⁴ R ⁵ or NO _2,
Y is ^{_{CO 2 R 6, CN, SO}} 3 R 6 , or SO ₂ NR ⁴ a R ⁵ is claim 1
4. The production method according to any one of 3. (8) X is an optionally substituted benzene ring;
Wherein the substituent is H, C which may be substituted₁~ C₆Archi
Group, optionally substituted C₁~ C₆An alkoxy group, NR
^FourR^Five, Halogen or NO_Two, Y is CO_TwoR⁶, CN, SO_ThreeR⁶Or S
O_TwoNR^FourR^FiveAnd R^Four, R^FiveAnd R⁶Is H, may be substituted
An alkyl group or a phenyl group which may be substituted,
R^FourAnd R^FiveMay form a ring of 4 to 7 with R¹, R^TwoAnd
And R^ThreeIs H, optionally substituted C₁~ C₆Is an alkyl group of
The production method according to claim 1. 9. X is an optionally substituted pyridine, wherein the substituent is H, an optionally substituted C ₁ -C ₆ alkyl group, and an optionally substituted C ₁ -C ₆ alkoxy group. Or the halogen, and Y is CO ₂ R ⁶ , CN, SO ₃ R ⁶ or SO ₂ NR ⁴ R ⁵ , The production method according to claim 1. 10. A compound of the general formula (2) Wherein X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1. A phenol derivative represented by the formula: 11. A compound of the general formula (4) [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as those defined in claim 1]. A phenol derivative represented by the formula: