JP2001240582A - Aniline derivative, its intermediate and method for preparing the aniline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method that prepares high selectively an aromatic- substituted aniline derivative in the mild reaction condition. SOLUTION: An oxime derivative shown by formula (3) is prepared by reacting a cyclohexanone derivative shown by formula (1) and a hydroxylamine derivative shown by formula (2), and then an aniline derivative shown by formula (4) is prepared by elimination reaction. (In the formulae, X shows a substitutable aromatic ring, Y shows CO2R6, CN, NO2, SO3R6, SO2NR4R5, SOR6, SO2R6, and R1, R2 and R3 show H, a substitutable alkyl group, alkenyl group alkynyl group, and alkoxy group, R4, R5 and R6 show H, a substitutable alkyl group and phenyl group, the ring of 4-7 members may be formed by R4 and R5.).

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)) and aromatic ring-substituted aniline derivatives useful as intermediates for agricultural chemicals, liquid crystals, heat-resistant polymers and liquid-crystalline polymers, and a process for producing the same.

[0002]

2. Description of the Related Art Conventionally, an organometallic compound and an aryl halide compound have been used as a method for producing an aromatic ring-substituted aniline derivative.
A method of coupling in the presence of a catalyst such as a Pd complex (J. Med.
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]

DISCLOSURE OF THE INVENTION The present invention provides a novel method for producing an aromatic ring-substituted aniline derivative with high selectivity using inexpensive raw materials under mild reaction conditions.

That is, the present invention relates to (1) general formula (1)

Embedded image [Wherein X is an optionally substituted benzene ring, N, O, S
A 5- or 6-membered optionally substituted heterocyclic ring having at least one of H, OH, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₂ -C ₆ alkenyl group, an optionally substituted C ₂ ~
Alkynyl group C _6, optionally substituted C ₁ -C ₆ alkoxy group, an optionally substituted alkylthio group, 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 , optionally substituted phenyl group, optionally substituted phenoxy group, optionally substituted heteroaryl group or optionally substituted heteroaryloxy group, further adjacent 4 depending on the matching substituent
Or a 7-membered ring), Y is CO ₂ R ⁶ , CN, NO
^{_{2, SO 3 R 6, SO}} 2 NR 4 R 5, SOR 6, shows the ^{_{SO 2 R 6, R 1,}} R 2 and R ³ are H, optionally substituted C ₁ -C ₆ alkyl group,
Optionally substituted C ₂ -C ₆ alkenyl group, optionally substituted C ₂ -C ₆ alkynyl group, optionally substituted C ₁ -C ₆ alkoxy group, optionally substituted alkylthio group, 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 , OCO
R ⁶ , OCO ₂ R ⁶ , OCONR ⁴ R ⁵ , OSO ₂ R ⁶ , optionally substituted phenyl group, optionally substituted phenoxy group, optionally substituted heteroaryl group or substituted Represents a heteroaryloxy group, R ⁴ , R ⁵ and
R ⁶ represents H, an optionally substituted alkyl group or an optionally substituted phenyl group, and R ⁴ and R ⁵ represent ⁴ to 7
May be formed. The cyclohexenone derivative represented by the general formula (2) R ⁷ ONH ₂ (2) wherein R ⁷ is H, optionally substituted C ₁ -C ₆ alkyl group, optionally substituted C ₂ -C ₆ alkenyl group, C ₁ ~
Acyl group C _6, an alkoxycarbonyl group having C ₁ -C _6, which comprises reacting a hydroxylamine derivative represented by] shows a an optionally substituted phenyl group or sulfonyl group, the general formula (3)

Embedded image Wherein X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined above. A process for producing an oxime derivative represented by the general formula (3):

Embedded image [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined in (1). Wherein an elimination reaction of the oxime derivative represented by the general formula (4) is carried out.

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

Embedded image [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined in (1). The oxime derivative represented by the general formula (4) is synthesized by the following method (2).

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

Embedded image [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined in (1). A elimination reaction of an oxime derivative represented by the general formula (5):

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ represent the same as defined in (1), R ⁸ represents COR ⁹ or CO ₂ R ⁹ , and R ⁹
Represents H, an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted phenyl group. A method for producing a substituted aniline derivative represented by the general formula (5):

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ represent the same as defined in (1), and R ⁸ represents the same as defined in (4). Wherein R ^{8 of the} substituted aniline derivative represented by the general formula (4) is removed:

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1). And (6) a method for producing an aniline derivative represented by the following general formula (3):

Embedded image [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined in (1). The oxime derivative represented by the general formula (5) is then synthesized according to the method (4).

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ represent the same as defined in (1), and R ⁸ represents the same as defined in (4). The method for producing an N-substituted aniline derivative represented by the general formula (3)

Embedded image [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined in (1). Oxime derivative represented by the general formula (5)

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ represent the same as defined in (1), and R ⁸ represents the same as defined in (1). A N-substituted aniline derivative 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). (8) a method for producing an aniline derivative represented by the general formula (1):

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1). The cyclohexenone derivative represented by the general formula (6) R ¹⁰ R ¹¹ NH (6) [wherein R ¹⁰ and R ¹¹ are H, optionally substituted C ₁ -C ₆
It represents an alkyl group or an optionally substituted phenyl group, and R ¹⁰ and R ¹¹ may form a ring of 4 to 7. Characterized by reacting with an amine derivative represented by the formula:
General formula (7A) and / or (7B)

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ represent the same as defined in (1), R ¹⁰ and R ¹¹ represent the same as defined above, and R ¹² denotes a R ¹⁰ or R ^11. A method for producing an enamine and / or imine derivative represented by the formula:
(9) General formula (7A) and / or (7B)

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1), and R ¹⁰ , R ¹¹ and R ¹² are the same as defined in (8) Show things. A dehydrogenation reaction of an enamine and / or imine derivative represented by the general formula (8):

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ represent the same as defined in (1), and R ¹⁰ and R ¹¹ represent the same as defined in (8) . The method for producing an aniline derivative represented by the formula (7A)
And / or (7B)

Embedded image [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in (1), and R ¹⁰ , R ¹¹ and R ¹² are the same as defined in (8) Show things. The enamine and / or imine derivative represented by the following formula is synthesized, and then the method of (9) is carried out.

Embedded image[Where X, Y, R¹, R^TwoAnd R^ThreeIs also defined in (1)
Shows the same as^Ten, R¹¹And R¹²At (8)
Indicates the same as defined. Aniline represented by
Method for producing derivative, (11) X may be substituted
As described in any one of the above (1) to (10), which is a Zenzen ring
(12) X is at least one of N, O, and S
5- or 6-membered ring which may be substituted
An aromatic ring or an optionally substituted benzene condensate thereof
Production method according to any one of (1) to (10),
(13) X is an optionally substituted benzene ring,
The substituent is H, optionally substituted C₁~ C₆Archi
Group, optionally substituted C₁~ C₆An alkoxy group, NR
^FourR^Five, Halogen, NO_Two, Y is CO_TwoR⁶, CN, SO_ThreeR⁶Or SO_TwoNR
^FourR^FiveAnd R^Four, R^FiveAnd R⁶Is H, optionally substituted
An alkyl group or an optionally substituted phenyl group
R^FourAnd R^FiveMay form a ring of 4 to 7 with R¹, R^Two
And R^ThreeIs H, optionally substituted C₁~ C₆The alkyl of
The production according to any one of (1) to (10), which is a group
Method, (14) pyrrole optionally substituted with X, substitution
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 NO_Two
And Y is CO_TwoR⁶, CN and R¹, R^TwoAnd R^ThreeIs H
(1) The method according to any one of (1) to (10),
5) X is phenyl, chlorophenyl, methoxyphen
A nitro, nitrophenyl or aminophenyl group.
And Y is CO_TwoMe, CO_TwoEt or CN and R¹, R ^TwoAnd R^ThreeIs H
The production method according to any one of (1) to (10),
(16) X is pyridine which may be substituted,
Is a substituent of H, optionally substituted C₁~ C₆The alkyl of
Group, optionally substituted C₁~ C₆An alkoxy group or
Halogen and Y is CO_TwoR⁶, CN, SO_ThreeR⁶Or SO_TwoNR^FourR^Five
The production according to any one of (1) to (10), wherein
Method, (17) general formula (3)

Embedded image [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined in (1). An oxime derivative represented by the general formula (7A) and / or (7B):

Embedded image Wherein X, Y, R ¹ , R ² and R ³ are the same as defined in (1), and R ¹⁰ , R ¹¹ and R ¹² are the same as defined in (8) Is shown. An enamine and / or imine derivative 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). An aniline derivative represented by the formula (2)
0) General formula (8)

Embedded image [Wherein X, Y, R ¹ , R ² and R ³ represent the same as defined in (1), and R ¹⁰ and R ¹¹ represent the same as defined in (8). An aniline derivative represented by
(21) The compound according to any one of (17) to (20), wherein X is a benzene ring, (22) a 5- or 6-membered ring wherein X has at least one of N, O, and S (17) The compound according to any one of (17) to (20), which is a benzene condensate thereof, 23) X is a benzene ring which may be substituted, and the substituent is H, which may be C ₁ -C ₆ alkyl group, optionally substituted
Alkoxy groups ^{_{C 1 ~C 6, NR 4 R}} 5, halogen or NO _2, Y is CO ₂ R ^6, CN, a SO ₃ R ^6, or _{^{SO 2 NR 4 R 5, R}} 4, R
⁵ and R ⁶ are H, an optionally substituted alkyl group or an optionally substituted phenyl group, and R ⁴ and R ⁵ may form a ring of 4 to 7, and R ¹ , R ² And R ³ are H, an optionally substituted C ₁ -C ₆ alkyl group (17)
The compound according to any one of (1) to (20), (24) X
Is an optionally substituted pyrrole, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyridine or an optionally substituted indole, wherein the substituent is H, C that may be
₁ -C alkyl group having _6, optionally substituted C ₁ -C ₆ alkoxy group, halogen, NR ⁴ R ⁵ or NO _2, Y is CO ₂
R ^6, CN, a SO ₃ R ^6, or _{^{SO 2 NR 4 R 5 (17}} ) ~ (2
(25) X is a phenyl group, a chlorophenyl group, a methoxyphenyl group, a nitrophenyl group, an aminophenyl group, and Y is CO ₂ Me, CO
₂ Et or CN, and R ¹ , R ² and R ³ are H (17)
The compound according to any one of (20) to (20), (26) X
Is an optionally substituted pyridine, the substituent of which is
H, optionally substituted C ₁ -C ₆ alkyl group, an alkoxy group or a halogen good C ₁ -C ₆ substituted, Y is CO ₂ R ⁶ or CN (17) ~ The compound according to any one of (20).

In general formulas (1) to (8), X
As, for example, optionally substituted phenyl, optionally substituted naphthalene, optionally substituted pyrrole, optionally substituted furan, optionally substituted thiophene, optionally substituted Pyrazole,
Optionally substituted imidazole, optionally substituted isothiazole, optionally substituted imidazole, optionally substituted oxazole, optionally substituted thiazole, optionally substituted pyridine,
Optionally substituted pyridazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted naphthalene, optionally substituted indole, 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 which may be substituted, pteridine which may be substituted, and the like, preferably substituted Also phenyl, naphthalene optionally substituted, optionally substituted pyrrole,
Optionally substituted furan, optionally substituted thiophene, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted isothiazole, optionally substituted pyridine, substituted Optionally substituted pyridazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted indole, optionally substituted benzofuran, optionally substituted benzothiophene, substituted Quinoline which may be substituted, isoquinoline which may be substituted, and more preferably phenyl which may be substituted, naphthalene which may be substituted, pyrrole which may be substituted, and optionally substituted Franc,
An optionally substituted thiophene, an optionally substituted pyridine, an optionally substituted pyrimidine, and an optionally substituted indole.

The substituent is, for example, H, and the optionally substituted C ₁ -C ₆ alkyl group is methyl, ethyl, propyl, isopropyl, butyl, tert-alkyl.
Butyl group, pentyl group, hexyl group, trifluoromethyl group, chloromethyl group, bromomethyl group, benzyl group and the like; optionally substituted C ₂ -C ₆ alkenyl groups are vinyl group, allyl group, isopropenyl Group, butenyl group, pentenyl group, hexenyl group, styryl group, etc .; optionally substituted C ₂ -C ₆ alkynyl groups include ethynyl group, propynyl group, butynyl group, pentynyl group, etc .; optionally substituted C _{1 to} C ₆ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, trifluoromethoxy, benzyloxy and the like; optionally substituted alkylthio groups Is methylthio, ethylthio, propylthio, butylthio, pentylthio,
Hexylthio group, benzylthio group and the like; NR ⁴ R ⁵ includes an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a propylamino group, an isopropylamino group, a butylamino group, a tert-butylamino group, Pentylamino, hexylamino, pyrrolidino, piperidino, morpholino, anilino, etc .;
Halogen is fluorine, chlorine, bromine, iodine; NO ₂ ; C
N; 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 and the like; CO ₂ R ⁶ Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl and the like;
NR ⁴ R ⁵ includes methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, anilinocarbonyl and the like; SO ₃ R ⁶ Methoxysulfonyl, ethoxysulfonyl, propoxysulfonyl, butoxysulfonyl, benzyloxysulfonyl, phenoxysulfonyl and the like; SO ₂ NR ⁴ R ⁵
As a sulfamoyl group, a methylsulfamoyl group,
Dimethylsulfamoyl group, ethylsulfamoyl group,
Diethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, butylsulfamoyl 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, etc .; SO ₂ R methylsulfonyl group as ^6, ethylsulfonyl group, propyl sulfonyl group, butylsulfonyl group, a benzyl sulfonyl group, such as phenylsulfonyl group; a OCOR ⁶ acetyloxy group, propionyloxy group, butyl Aryloxy group, iso-butyryloxy group, valeryloxy group, pivaloyloxy group, benzoyloxy group, toluoyl group, Furano yl group, nicotinoyl group, isonicotinoyl group, etc. cinnamoyl group; OCO ₂ R ⁶ Methoxycarbonyloxy group, ethoxycarbonyloxy group, propoxycarbonyloxy group, butoxycarbonyloxy group, tert-butoxycarbonyloxy group, benzyloxycarbonyloxy group, phenoxycarbonyloxy group and the like; OCONR ⁴ R ⁵ is methylaminocarbonyl Oxy, dimethylaminocarbonyloxy, ethylaminocarbonyloxy, diethylaminocarbonyloxy, pyrrolidinocarbonyloxy, piperidinocarbonyloxy, morpholinocarbonyloxy Groups, such as anilinocarbonyl group; methanesulfonyl as OSO ₂ R ⁶ sulfonyl oxy group, ethane sulfonyl group, propane sulfonyl group, butane sulfonyloxy group, pen chest Gandolfo sulfonyloxy group, hexane sulfonyloxy group, benzenesulfonyl group, Toluenesulfonyloxy group and the like; optionally substituted phenyl groups include hydroxyphenyl, chlorophenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, tert-butoxyphenyl, benzyloxyphenyl, trifluorophenyl Methoxyphenyl group, phenoxyphenyl group and the like; optionally substituted phenoxy groups include phenoxy group, hydroxyphenoxy group, chlorophenoxy group, methylphenoxy group, trif Fluoromethylphenoxy group, methoxyphenoxy group, trifluoromethoxyphenoxy group,
Phenoxyphenoxy group and the like; optionally substituted heteroaryl group includes furanyl group, thienyl group, azolyl group, pyridyl group, indolyl group, and optionally substituted heteroaryloxy group includes furanyloxy group, thienyloxy group, Examples include 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, NO 2, NR 4 R 5}} , optionally substituted phenyl, optionally substituted phenoxy group, COR ^6, CO ₂ R ⁶ , OCOR ⁶
Or OCO ₂ R ⁶ , particularly preferably H, a methyl group,
It is a methoxy group, a phenoxy group, a methoxycarbonyl group, an ethoxycarbonyl group, NO ₂ , an acetoxy group or a benzoyloxy group. Further, as a ring formed by adjacent substituents as a substituent of X, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, an oxetane ring, a tetrahydrofuran ring, a furan ring,
Examples include a pyran ring, a dioxolan ring, and a dioxane ring.

As Y, for example, CO ₂ R ⁶ includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like; CN; NO ₂ ; S
Examples of O ₃ R ⁶ include a methoxysulfonyl group, an ethoxysulfonyl group, a propoxysulfonyl group, a butoxysulfonyl group, a benzyloxysulfonyl group, and a phenoxysulfonyl group; SO ₂ NR ⁴ R ⁵ includes a sulfamoyl group, a methylsulfamoyl group, and dimethyl. Sulfamoyl, ethylsulfamoyl, diethylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, butylsulfamoyl, tert-butylsulfamoyl, pentylsulfamoyl, hexyl Sulfamoyl group, pyrrolidinosulfamoyl group, piperidinosulfamoyl group, morpholinosulfamoyl group,
SOR ⁶ includes methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, butylsulfinyl group, benzylsulfinyl group, phenylsulfinyl group and the like; SO ₂ R ⁶ includes methylsulfonyl group, ethylsulfonyl group, Examples thereof include a propylsulfonyl group, a butylsulfonyl group, a benzylsulfonyl group, and a phenylsulfonyl group. Preferably, CN, CO ₂ R ⁶ , NO ₂ , SO ₃ R ⁶ or SO ₂ NR ⁴ R
^And particularly preferably CN, methoxycarbonyl group or ethoxycarbonyl group.

R ¹ , R ² and R ³ are, for example, H; an optionally substituted C ₁ -C ₆ alkyl group is a methyl group;
Ethyl group, propyl group, isopropyl group, butyl group, te
rt- butyl group, a pentyl group, a hexyl group, trifluoromethyl group, chloromethyl group, bromomethyl group, a benzyl group and the like; substituted The alkenyl group optionally C ₂ -C ₆ even if vinyl group, an allyl group, Isopropenyl, butenyl, pentenyl, hexenyl, styryl and the like;
The optionally substituted C ₂ -C ₆ alkynyl group includes an ethynyl group, a propynyl group, a butynyl group, a pentynyl group and the like; and the optionally substituted C ₁ -C ₆ alkoxy group includes a methoxy group and an ethoxy group. , A propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, a trifluoromethoxy group, a benzyloxy group; and the optionally substituted alkylthio group is a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group. ,
Hexylthio group, benzylthio group and the like; NR ⁴ R ⁵ includes an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a propylamino group, an isopropylamino group, a butylamino group, a tert-butylamino group, Pentylamino, hexylamino, pyrrolidino, piperidino, morpholino, anilino, etc .;
Halogen is fluorine, chlorine, bromine, iodine; NO ₂ ; C
N; 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 and the like; CO ₂ R ⁶ Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl and the like;
NR ⁴ R ⁵ includes methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, anilinocarbonyl and the like; SO ₃ R ⁶ Methoxysulfonyl, ethoxysulfonyl, propoxysulfonyl, butoxysulfonyl, benzyloxysulfonyl, phenoxysulfonyl and the like; SO ₂ NR ⁴ R ⁵
As a sulfamoyl group, a methylsulfamoyl group,
Dimethylsulfamoyl group, ethylsulfamoyl group,
Diethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, butylsulfamoyl 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, etc .; SO ₂ R methylsulfonyl group as ^6, ethylsulfonyl group, propyl sulfonyl group, butylsulfonyl group, a benzyl sulfonyl group, such as phenylsulfonyl group; a OCOR ⁶ acetyloxy group, propionyloxy group, butyl Aryloxy group, iso-butyryloxy group, valeryloxy group, pivaloyloxy group, benzoyloxy group, toluoyl group, Furano yl group, nicotinoyl group, isonicotinoyl group, etc. cinnamoyl group; OCO ₂ R ⁶ Methoxycarbonyloxy group, ethoxycarbonyloxy group, propoxycarbonyloxy group, butoxycarbonyloxy group, tert-butoxycarbonyloxy group, benzyloxycarbonyloxy group, phenoxycarbonyloxy group and the like; OCONR ⁴ R ⁵ is methylaminocarbonyl Oxy, dimethylaminocarbonyloxy, ethylaminocarbonyloxy, diethylaminocarbonyloxy, pyrrolidinocarbonyloxy, piperidinocarbonyloxy, morpholinocarbonyloxy Groups, such as anilinocarbonyl group; methanesulfonyl as OSO ₂ R ⁶ sulfonyl oxy group, ethane sulfonyl group, propane sulfonyl group, butane sulfonyloxy group, pen chest Gandolfo sulfonyloxy group, hexane sulfonyloxy group, benzenesulfonyl group, Toluenesulfonyloxy group and the like; optionally substituted phenyl groups include hydroxyphenyl, chlorophenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, tert-butoxyphenyl, benzyloxyphenyl, trifluorophenyl Methoxyphenyl group, phenoxyphenyl group and the like; optionally substituted phenoxy groups include phenoxy group, hydroxyphenoxy group, chlorophenoxy group, methylphenoxy group, trif Fluoromethylphenoxy group, methoxyphenoxy group, trifluoromethoxyphenoxy group,
Phenoxyphenoxy group and the like; optionally substituted heteroaryl group includes furanyl group, thienyl group, azolyl group, pyridyl group, indolyl group, and optionally substituted heteroaryloxy group includes furanyloxy group, thienyloxy group, An azolyloxy group, a pyridyloxy group, an indolyloxy group, etc., preferably H; methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, trifluoro C _1- which may be substituted such as methyl group, chloromethyl group, bromomethyl group, benzyl group, etc.
C ₆ alkyl group, hydroxyphenyl group, chlorophenyl group, methylphenyl group, trifluoromethylphenyl group, methoxyphenyl group, tert-butoxyphenyl group,
An optionally substituted phenyl group such as a benzyloxyphenyl group, a trifluoromethoxyphenyl group and a phenoxyphenyl group, particularly preferably H, a methyl group, an ethyl group, a propyl group, an isopropyl group, a trifluoromethyl group and a chloromethyl group , Bromomethyl, hydroxyphenyl, chlorophenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl or trifluoromethoxyphenyl.

R ⁴ , R ⁵ and R ⁶ are, for example, H; and optionally substituted alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and the like. hexyl group; a substituted as the phenyl group optionally hydroxyphenyl group, chlorophenyl group, methylphenyl group, trifluoromethylphenyl group, methoxyphenyl group, a trifluoromethoxyphenyl group, a phenoxyphenyl group and the like, NR ⁴ R
Examples of ⁵ include a pyrrolidino group, a piperazino group, a morpholino group, and the like, preferably H, a methyl group, an ethyl group, a propyl group, an isopropyl group, a pyrrolidinyl group, a piperazino group, or a morpholino group. A methyl group, an ethyl group, a pyrrolidino group or a piperazino group.

R ⁷ is, for example, H; and optionally substituted C ₁ -C ₆ alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and the like. Xyl group, trifluoromethyl group,
Chloromethyl group, bromomethyl group, benzyl group and the like; optionally substituted C ₂ -C ₆ alkenyl groups include vinyl group, allyl group, isopropenyl group, butenyl group, pentenyl group, hexenyl group, styryl group; C ₁ such as an acetyl group as the acyl group -C _6; C ₁ -C such a methoxycarbonyl group as alkoxycarbonyl group _6; substituted as a phenyl group optionally hydroxyphenyl group, chlorophenyl group, methylphenyl group , Trifluoromethylphenyl, methoxyphenyl, tert-butoxyphenyl, benzyloxyphenyl, trifluoromethoxyphenyl, phenoxyphenyl and the like;
Sulfonyl group, particularly preferably H, acetyl group, methoxycarbonyl group and sulfonyl group.

In R ⁸ , COR ⁹ includes, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, pivaloyl group, benzoyl group and toluoyl group; and CO ₂ R ⁶ includes methoxycarbonyl group and ethoxy group. Carbonyl group, propoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, phenoxycarbonyl group, etc., preferably formyl group, acetyl group, benzoyl group, particularly preferably formyl group, acetyl group It is.

R ¹⁰ and R ¹¹ are, for example, H; and the optionally substituted alkyl group is a methyl group, an ethyl group,
Propyl group, isopropyl group, butyl group, tert-butyl group, pentyl group, hexyl group, phenyl group which may be substituted phenyl group, hydroxyphenyl group,
A chlorophenyl group, a methylphenyl group, a trifluoromethylphenyl group, a methoxyphenyl group, a trifluoromethoxyphenyl group, and a phenoxyphenyl group.

Preferred compounds of the general formulas (1) to (8) include the following. Preferred compounds of the general formula (1) include 2-phenyl-4-oxocyclohex-2-enecarboxylic acid ethyl ester and 2- (4-
Nitrophenyl) -4-oxocyclohex-2-enecarboxylic acid ethyl ester, 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. Preferred compounds of the general formula (2) include hydroxylamine and its hydrochloride, sulfate, nitrate, phosphate, O-methylhydroxylamine and its hydrochloride,
O-benzylhydroxylamine and its hydrochloride; hydroxylamine-O-sulfonic acid;
Preferred compounds of the general formula (3) include 4-hydroxyimino-2-phenyl-cyclohex-2-enecarboxylic acid ethyl ester and 4-hydroxyimino-2- (4
-Tolyl) cyclohex-2-enecarboxylic acid ethyl ester, 4-hydroxyimino-2- (2-tolyl) cyclohex-2-enecarboxylic acid ethyl ester, 4-
Ethyl hydroxyimino-2- (4-methoxyphenyl) cyclohex-2-enecarboxylate, ethyl 4-hydroxyimino-2- (4-chlorophenyl) cyclohex-2-enecarboxylate, 4-hydroxyimino-2- (4-pyridyl) cyclohex-2-
Encarboxylic acid ethyl ester and their hydrochlorides,
Sulfate, acetate and the like can be mentioned. Preferred compounds of the general formula (4) include 5-aminobiphenyl-2-carboxylic acid ethyl ester, 5-amino-4′-methylbiphenyl-2-carboxylic acid ethyl ester, 5-amino-
4'-chlorobiphenyl-2-carboxylic acid ethyl ester, 5-amino-2'-methylbiphenyl-2-carboxylic acid ethyl ester, 5-amino-4'-methoxybiphenyl-2-carboxylic acid ethyl ester, 4- ( 5-amino-2-ethoxycarbonylphenyl) pyridine and their hydrochlorides, sulfates, acetates and the like.
Preferred compounds of the general formula (5) include ethyl 5-acetylaminobiphenyl-2-carboxylate,
Acetylamino-4'-methylbiphenyl-2-carboxylic acid ethyl ester, 5-acetylamino-4'-chlorobiphenyl-2-carboxylic acid ethyl ester, 5-acetylamino-2'-methylbiphenyl-2-carboxylic acid ethyl Ester, 5-acetylamino-4′-methoxybiphenyl-2-carboxylic acid ethyl ester, 4-
(5-acetylamino-2-ethoxycarbonylphenyl) pyridine and their hydrochlorides, sulfates, acetates and the like. Preferred compounds of the general formula (6) include methylamine, dimethylamine, ethylamine, diethylamine, benzylamine, tert-butylamine, methylbenzylamine, pyrrolidine, piperidine, morpholine and their hydrochlorides, sulfates, acetates and the like. Can be Preferred compounds of the general formula (7A) include 4-
Dimethylamino-2-phenyl-1,3-cyclohexadienecarboxylic acid ethyl ester, 4-dimethylamino-2- (4-tolyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-dimethylamino-2-
(2-tolyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-dimethylamino-2- (4-chlorophenyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-dimethylamino-2- (4 -Methoxyphenyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-dimethylamino-2- (4-
Pyridyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-pyrrolidinyl-2-phenyl-1,
3-cyclohexadienecarboxylic acid ethyl ester, 4
-Pyrrolidinyl-2- (4-tolyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-pyrrolidinyl-2- (2-tolyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-pyrrolidinyl-2 −
(4-chlorophenyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-pyrrolidinyl-2-
(4-methoxyphenyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-pyrrolidinyl-2-
(4-pyridyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-piperidino-2-phenyl-
1,3-cyclohexadienecarboxylic acid ethyl ester, 4-piperidino-2- (4-tolyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-piperidino-2- (2-tolyl) -1,3- Cyclohexadienecarboxylic acid ethyl ester, 4-piperidino-2-
(4-chlorophenyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-piperidino-2- (4
-Methoxyphenyl) -1,3-cyclohexadienecarboxylic acid ethyl ester, 4-piperidino-2- (4-
Pyridyl) -1,3-cyclohexadienecarboxylic acid ethyl ester. Preferred compounds of the general formula (7B) include 4-methylimino-2-phenylcyclohex-2-enecarboxylic acid ethyl ester,
Methylimino-2- (4-tolyl) cyclohex-2-
Encarboxylic acid ethyl ester, 4-methylimino-2
-(2-tolyl) cyclohex-2-enecarboxylic acid ethyl ester, 4-methylimino-2- (4-methoxyphenyl) cyclohex-2-enecarboxylic acid ethyl ester, 4-methylimino-2- (4-chlorophenyl) cyclohexyl Ethyl-2-enecarboxylate, 4-methylimino-2- (4-pyridyl) cyclohex-2-enecarboxylate, and hydrochlorides, sulfates and acetates thereof. Preferred compounds of the general formula (8) include ethyl 5-methylaminobiphenyl-2-carboxylate, ethyl 5-methylamino-4′-methylbiphenyl-2-carboxylate and 5-methylamino-4′-chloro Biphenyl-2-carboxylic acid ethyl ester, 5-methylamino-
2'-methylbiphenyl-2-carboxylic acid ethyl ester, 5-methylamino-4'-methoxybiphenyl-2
-Carboxylic acid ethyl ester, 4- (5-methylamino-2-ethoxycarbonylphenyl) pyridine, 5-dimethylaminobiphenyl-2-carboxylic acid ethyl ester, 5-dimethylamino-4'-methylbiphenyl-2
-Carboxylic acid ethyl ester, 5-dimethylamino-
4'-chlorobiphenyl-2-carboxylic acid ethyl ester, 5-dimethylamino-2'-methylbiphenyl-2
-Carboxylic acid ethyl ester, 5-dimethylamino-
4'-methoxybiphenyl-2-carboxylic acid ethyl ester, 4- (5-dimethylamino-2-ethoxycarbonylphenyl) pyridine, 5-benzylaminobiphenyl-2-carboxylic acid ethyl ester, 5-benzylamino-4'- Methyl biphenyl-2-carboxylic acid ethyl ester, 5-benzylamino-4'-chlorobiphenyl-2-carboxylic acid ethyl ester, 5-benzylamino-2'-methylbiphenyl-2-carboxylic acid ethyl ester, 5-benzylamino -4'-methoxybiphenyl-2-carboxylic acid ethyl ester, 4- (5-benzylamino-2-ethoxycarbonylphenyl) pyridine,
5-piperidinobiphenyl-2-carboxylic acid ethyl ester, 5-piperidino-4'-methylbiphenyl-2-
Carboxylic acid ethyl ester, 5-piperidino-4'-chlorobiphenyl-2-carboxylic acid ethyl ester, 5-
Piperidino-2'-methylbiphenyl-2-carboxylic acid ethyl ester, 5-piperidino-4'-methoxybiphenyl-2-carboxylic acid ethyl ester, 4- (5-piperidino-2-ethoxycarbonylphenyl) pyridine, 5-pyrrolid Ethyl dinylbiphenyl-2-carboxylate, ethyl 5-pyrrolidinyl-4'-methylbiphenyl-2-carboxylate, ethyl 5-pyrrolidinyl-4'-chlorobiphenyl-2-carboxylate, 5-pyrrolidinyl-2 '-Methylbiphenyl-2
-Carboxylic acid ethyl ester, 5-pyrrolidinyl-4 '
-Methoxybiphenyl-2-carboxylic acid ethyl ester, 4- (5-pyrrolidinyl-2-ethoxycarbonylphenyl) pyridine, and their hydrochlorides, sulfates,
Acetate and the like. The oxime derivative represented by the general formula (3) and the enamine and / or imine derivative represented by the general formulas (7A) and / or (7B) have two types of isomers, an entgegen form and a tuzamen form. Also encompasses these isomers and mixtures of these isomers in any ratio. Usually, both isomers are produced during the production process, and these can be separated by ordinary methods such as column chromatography.

In the present invention, compounds represented by the general formulas (1) to (6), (7A), (7B) or (8) 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 sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid; or salts with other organic acids such as trifluoroacetic acid and oxalic acid. Some of these can be performed, and these 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, compounds represented by the general formulas (1) to (6), (7A), (7B) or (8) include, for example, alkali metal salts such as sodium salt and potassium salt; magnesium salt and calcium Salts that form salts with bases such as alkaline earth metal salts such as salts; transition metal salts such as copper salts and iron salts; and organic base salts such as pyridine salts and amine salts. These are also included in the present invention, and they can be used as intermediates as salts or after neutralizing a base. In the present invention, the general formulas (1) to (6),
The compound represented by (7A), (7B) or (8) may have optical isomers, geometric isomers and tautomers, and in this case, the present invention relates to a kind of isomer And mixtures of any of the several isomers in any proportion. Further, hydrates of the compounds represented by the general formulas (1) to (6), (7A), (7B) or (8) are also included.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION

The reaction steps are as follows.

Embedded image (Where X, Y, R ¹ , R ² , R ³ , R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ and R ¹²
Indicates the same as defined above. )

General formula (1) which is a starting material of the present synthesis method

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ are the same as defined above). The compound represented by the formula It can also be synthesized.

Embedded image (Wherein X, Y, Z, 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).

Synthesis route 1 First step: Production of compound represented by general formula (3) from compound represented by general formula (1) General formula (3)

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

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ are the same as defined above) in a solvent in the presence or absence of an acid or a base in the general formula (2) R ⁷ ONH ₂ (2) (wherein R ⁷ is the same as defined above) and can be produced by condensation with a hydroxyamine derivative represented by the formula: Examples of the solvent used in the above reaction include aliphatic lower alcohols such as methanol and ethanol, aromatic hydrocarbons such as toluene, aliphatic hydrocarbons such as hexane, ether hydrocarbons such as tetrahydrofuran, and aliphatic esters such as ethyl acetate. , Acetonitrile, etc., aliphatic nitriles, water and mixtures thereof. Preferably, aliphatic lower alcohols, ether-based hydrocarbons, organic acids such as acetic acid, water, and mixtures thereof are used. This reaction can also be performed without a solvent. The reaction temperature is usually from −20 ° C. to the solvent reflux temperature, preferably from 0 ° C. to the solvent reflux temperature. 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 , MeONa and the like.
Examples include alkali metal salts of aliphatic lower alcohols such as EtONa and t-BuOK, alkali metal hydrides such as NaH, organic bases such as pyridine and triethylamine, and alkali metal salts of organic acids such as sodium acetate. Preferred are alkali metal hydroxides, alkali metal carbonates, alkali metal salts of aliphatic lower alcohols, organic bases and alkali metal salts of organic acids. Also, its usage 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.

Second step: Preparation of the compound represented by the general formula (4) from the compound represented by the general formula (3):

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

Embedded image (Wherein X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined above) by subjecting the compound represented by the formula (1) to elimination reaction in the presence of a metal catalyst in a solvent. Can be manufactured. As the solvent used in the above reaction, for example, aliphatic alcohols such as methanol and ethanol, aromatic hydrocarbons such as toluene and cumene, ether hydrocarbons such as diethylene glycol dimethyl ether and triethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane and the like Organic hydrocarbons, aliphatic hydrocarbons such as n-hexane, organic acids such as acetic acid, acetonitrile, water, and mixtures thereof. Preferably,
Aliphatic alcohols, aromatic hydrocarbons, aliphatic hydrocarbons,
Examples include ether hydrocarbons, organic acids, water, and mixtures thereof. This reaction can also be performed without a solvent.
The reaction temperature is usually from room temperature to 300 ° C, preferably 5 ° C.
0 ° C to 250 ° C. Examples of the metal catalyst include a simple substance of a platinum group element such as platinum, palladium, and rhodium or a salt thereof such as hydrochloric acid. Platinum group elements alone or their salts with hydrochloric acid, etc. are activated carbon, graphite,
It may be in a form supported on a suitable carrier such as silica, alumina, silica-alumina, zeolite, titania, magnesia, zirconia, diatomaceous earth, and barium sulfate. The amount used is usually 0.001 to 20 equivalents,
Preferably it is 0.05 to 10 equivalents. Platinum carbon, palladium carbon, rhodium carbon and the like can be mentioned, and preferred is palladium carbon. The use amount is usually 0.05 to 20 equivalents, preferably 0.1.
To 10 equivalents. The purification can be carried out by a commonly used method such as recrystallization, distillation and chromatography using silica gel.

Synthesis Route 2 The first step can be performed in the same manner as Synthesis Route 1. Second step: Conversion of the compound represented by the general formula (3) to the compound represented by the general formula (5) General formula (5)

Embedded image Wherein X, Y, R ¹ , R ² , R ³ and R ⁸ are the same as defined above. The aniline derivative represented by the general formula (3)

Embedded image (Wherein X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined above) or a salt thereof in the presence of a base in the presence of an acyl halide, an acid anhydride. The compound can be produced by reacting a product with an alkyl chloroformate and performing an elimination reaction. Examples of the solvent used in the above reaction include aromatic hydrocarbons such as toluene, aliphatic hydrocarbons such as hexane, halogenated hydrocarbons such as dichloromethane, ether hydrocarbons such as tetrahydrofuran, aliphatic esters such as ethyl acetate,
Examples include aliphatic nitriles such as acetonitrile and mixtures thereof. Preferably, aromatic hydrocarbons, aliphatic hydrocarbons, halogen-based hydrocarbons, ether-based hydrocarbons and mixtures thereof are used. This reaction can also be performed without a solvent. The reaction temperature is usually from −20 ° C. to the solvent reflux temperature, preferably from 0 ° C. to the solvent reflux temperature. Examples of the base include organic bases such as pyridine and triethylamine, and can also be used as a solvent at the same time. The amount used is usually 0.5 to a large excess, preferably 0.8 to 20 equivalents. Examples of the acyl halide include, for example, acetyl chloride and propionyl chloride; examples of the acid anhydride include acetic anhydride; examples of the alkyl chloroformate include methyl chlorocarbonate, ethyl chlorocarbonate, benzyl chlorocarbonate, and tert-chlorocarbonate.
t-butyl and the like, and they can be used in combination. Preferred are acetyl chloride, acetic anhydride and a combination thereof. Further, the amount of use is usually 0.8 to 10 equivalents, preferably 1 to 3 equivalents.
Is equivalent. The purification can be carried out by a commonly used method such as recrystallization, distillation and chromatography using silica gel.

Third step: Conversion of the compound represented by the general formula (5) to 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). The aniline derivative represented by the general formula (5)

Embedded image Wherein X, Y, R ¹ , R ² , R ³ and R ⁸ are the same as defined above, by hydrolysis in the presence of an acid or a base, or By catalytic reduction
It can be prepared by removing a R ^8. Examples of the solvent used in the above reaction include aliphatic lower alcohols such as methanol and ethanol, ether hydrocarbons such as tetrahydrofuran, aliphatic esters such as ethyl acetate, aliphatic nitriles such as acetonitrile,
Water and mixtures thereof. Preferably, aliphatic lower alcohols, ether hydrocarbons, water, and mixtures thereof are used. The reaction temperature is usually from −20 ° C. to the solvent reflux temperature, preferably from 0 ° C. to the solvent reflux temperature. Bases include alkali metal hydroxides such as KOH and NaOH, alkali metal carbonates such as K ₂ CO ₃ and Na ₂ CO ₃ , MeONa
And alkali metal salts of aliphatic lower alcohols such as EtONa and t-BuOK. Preferred are alkali metal hydroxides and alkali metal carbonates. The amount used is usually 0.1 to 10 equivalents, preferably 0.5 to 5 equivalents. Examples of the acid include inorganic salts such as hydrochloric acid and sulfuric acid. The amount used is usually 0.1 to 1
It is 0 equivalent, preferably 0.5 to 10 equivalents.
Examples of the catalyst used in the case of catalytic reduction include a simple substance of a platinum group element such as platinum, palladium and rhodium or a salt thereof. Examples of the salts of platinum group elements include mineral salts such as hydrochlorides. Platinum group elements or their salts are activated carbon, graphite, silica, alumina, silica-alumina, zeolite, titania, magnesia,
It may be in a form supported on a suitable carrier such as zirconia, diatomaceous earth, or barium sulfate. The amount of use is usually 0.001 to 20 equivalents, preferably 0.05 to 10 equivalents. The purification can be carried out by a commonly used method such as recrystallization, distillation and chromatography using silica gel.

Synthesis Route 3 First step: Preparation of compound represented by general formula (7A) and / or (7B) from compound represented by general formula (1) General formula (7A) and / or (7B)

Embedded image (Wherein X, Y, R ¹ , R ² , R ³ , R ¹⁰ and R ¹¹ represent the above,
R ¹² represents R ¹⁰ or R ¹¹ . The compound represented by the general formula (1)

Embedded image (Wherein X, Y, R ¹ , R ² and R ³ are the same as defined above) in a solvent in the presence or absence of an acid or a base in a solvent represented by the general formula (6): ¹⁰ R ¹¹ NH (6) (wherein R ¹⁰ and R ¹¹ are the same as defined above) or by condensation with an amine derivative or a salt thereof. As the solvent used in the above reaction, for example, an aromatic hydrocarbon such as toluene,
Examples include aliphatic hydrocarbons such as hexane, ether hydrocarbons such as tetrahydrofuran, and mixtures thereof. Preferably, an aromatic lower alcohol is used. The reaction temperature is usually from 0 ° C. to the solvent reflux temperature, preferably from room temperature to the solvent reflux temperature. KOH or NaOH as base
Alkali metal hydroxides such as, an alkali metal carbonate 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, an organic base such as pyridine or triethylamine, Examples thereof include alkali metal salts of organic acids such as sodium acetate. Preferred are alkali metal carbonates, organic bases and alkali metal salts of organic acids. Examples of the acid include organic acids such as acetic acid and p-toluenesulfonic acid. Also, its usage is usually 0.1
To 10 equivalents, preferably 0.5 to 5 equivalents. Further, a molecular sieve, titanium tetrachloride or the like can be used as a dehydrating agent. The purification can be carried out by a commonly used method such as recrystallization, distillation and chromatography using silica gel.

Third step: Preparation of the compound represented by the general formula (8) from the compound represented by the general formula (7A) and / or (7B)

Embedded image (Wherein X, Y, R ¹ , R ² , R ³ , R ¹⁰ or R ¹¹ are the same as defined above) or a salt thereof represented by the general formula (7A) / Or (7B)

Embedded image (Wherein X, Y, R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ and R ¹² are the same as defined above). It can be manufactured by performing. 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 And mixtures thereof. Preferably, aromatic hydrocarbons, ether hydrocarbons, aliphatic hydrocarbons, organic chlorinated hydrocarbons, aliphatic and aromatic nitriles, organic acids, and mixtures thereof are used. The reaction temperature is usually from room temperature to 400
° C, preferably from 50 ° C to 300 ° C. This reaction can also be performed without a solvent. KM as oxidizer
nO ₄ and MnO _2, metal oxides such as CrO _2, platinum, palladium, osmium, iridium, alone or a salt of a platinum group element such as ruthenium and rhodium, halogenating agents such as thionyl chloride or sulfuryl chloride, such as DDQ Quinone derivatives, sulfur, oxygen and the like. Examples of the salts of platinum group elements include mineral salts such as hydrochlorides. Platinum group element carriers or their salts such as hydrochloric acid are activated carbon,
Graphite, silica, alumina, silica-alumina,
It may be in a form supported on a suitable carrier such as zeolite, titania, magnesia, zirconia, diatomaceous earth, barium sulfate and the like. Its usage is usually 0.001 to 20
Equivalent, 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.

[0025]

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

Example 1 Ethyl 4-hydroxyimino-2-phenylcyclohex-2-enecarboxylate (in the general formula (3), X is a phenyl group, Y is an ethoxycarbonyl group, R ¹ , R ² and R Compound wherein ³ is H and R ⁷ is H) 4-oxo-2-phenylcyclohex-2-enecarboxylic acid ethyl ester synthesized by the method described in JP-A-11-49722 (1.0 g, 4.1 mmol) ) Was dissolved in ethanol (15 ml), hydroxylamine hydrochloride (285 mg, 4.1 mmol) and sodium acetate (336 mg, 4.1 mmol) were added, and the mixture was stirred at room temperature for 20 hours. After the solvent was distilled off, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate.
The solvent was distilled off to obtain a residue. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to give 4-hydroxyimino-2-phenylcyclohex-2-enecarboxylic acid ethyl ester (yield 1.06).
g, 88.5% yield) as a mixture of two isomers derived from the oxime. ¹ H-NMR (ppm, 300 MHz, CDCl ₃ ) Isomer 1 δ 7.70-8.30 (1H, br) 7.28-7.47 (5H, m) 6.65 (1H, s) 4.09 (2H, d, J = 7.0 Hz) 3.83 (1H, t, J = 4.5 Hz) 2.96 (1H, dt, J = 4.6 and 17.6H)
z) 2.46-2.58 (1H, m) 2.27-1.37 (1H, m) 2.03-2.13 (1H, m) 1.13 (3H, t, J = 7. 0 Hz) Isomer 2 δ 7.60-8.00 (1H, br) 7.27-7.55 (6H, m) 4.05 (2H, d, J = 7.0 Hz) 3.89 (1H, t) , J = 4.8 Hz) 2.10-2.70 (4H, m) 1.08 (3H, t, J = 7.0 Hz)

Example 2 5-aminobiphenyl-2-carboxylic acid ethyl ester (in the general formula (4), X is a phenyl group, Y is an ethoxycarbonyl group, R ¹ , R ² and R
A compound wherein ³ is H) 4-hydroxyimino-2-phenylcyclohexyl-2
-Enecarboxylic acid ethyl ester (300 mg, 1,1
6 mmol) in 2-methoxyethyl ether (6 ml)
And 5% Pd / C (150 mg) was added, and the mixture was refluxed for 1 hour under an argon stream. After cooling, 5% Pd / C was removed by filtration, and the solvent was distilled off. Silica gel column chromatography of the residue (hexane-ethyl acetate system)
To give 5-aminobiphenyl-2-carboxylic acid ethyl ester (230 mg, 82.1% yield) as pale yellow crystals. ¹ H-NMR (ppm, 300 MHz, CDCl ₃ ) δ 7.80 (1 H, d, J = 8.6 Hz) 7.25-7.45 (5H) 6.65 (1 H, dd, J = 2.1 and) 8.6H
z) 6.56 (1H, d, J = 2.1 Hz) 4.03 (2H, d, J = 7.0 Hz) 0.98 (3H, t, J = 7.0 Hz)

Example 3 Ethyl 5-acetylaminobiphenyl-2-carboxylate (in the general formula (8), X is a phenyl group, Y is an ethoxycarbonyl group, R ¹ and R ²
And R ³ is H, R ¹⁰ is H and R ¹¹ is an acetyl group.) 4-Hydroxyimino-2-phenylcyclohexyl-2
-Carboxylic acid ethyl ester (500 mg, 1.9
Pyridine (0.156 ml, 1.93 m)
mol) and 0.384 ml of acetic anhydride (150 mg, 3.
86 mmol) and stirred at 80 ° C. for 30 minutes.
After cooling to room temperature, acetyl chloride (0.275 ml, 3.86)
mmol) and stirred at 90 ° C. for 1 hour. After completion of the reaction, water was added to the reaction solution, and extracted with ethyl acetate.
The organic layer was washed successively with 5% aqueous HCl, saturated aqueous NaHCO3, and saturated saline. The residue obtained after distilling off the solvent was purified by silica gel column chromatography (hexane-ethyl acetate system), and ethyl 5-acetylaminobiphenyl-2-carboxylate (350 mg, 64.1% yield) was eluted. As yellow crystals, ethyl 5-diacetylaminobiphenyl-2-carboxylate (132 mg, 24.2% yield) was obtained as a pale yellow oil. 5-acetylaminobiphenyl-2-carboxylic acid ethyl ester ¹ H-NMR (ppm, 300 MHz, CDCl ₃ ) δ 7.85 (1 H, d, J = 8.3 Hz) 7.63 (1 H, d, J = 8. 7.26-7.50 (6H, m) 4.07 (2H, d, J = 7.0 Hz) 2.19 (3H, s) 0.98 (3H, t, J = 7.0 Hz) 5-Diacetylaminobiphenyl-2-carboxylic acid ethyl ester ¹ H-NMR (ppm, 300 MHz, CDCl ₃ ) δ 7.92 (1H, d, J = 8.0 Hz) 7.30-7.41 (5H, m) 7.17-7.24 (2H, m) 4.11 (2H, d, J = 6.9 Hz) 2.33 (6H, s) 00 (3H, t, J = 6.9 Hz)

[0029]

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 an aniline derivative using inexpensive raw materials and not requiring special equipment or reaction conditions.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) C07C 229/60 C07C 229/60 231/14 231/14 233/54 233/54 249/02 249/02 251 / 20 251/20 251/44 251/44

Claims (26)

[Claims] 1. A compound of the general formula (1) [Wherein X is an optionally substituted benzene ring, an optionally substituted naphthalene ring, a 5- or 6-membered ring having at least one of N, O, and S] Heterocycles or condensed products thereof which may be substituted with benzene (provided that the number of substituents may be the same or different from 1 to 3, and H, OH, optionally substituted C
₁ -C ₆ alkyl group, a substituted optionally optionally C ₂ be -C ₆ alkenyl group, optionally substituted C ₂ -C ₆ alkynyl group, optionally substituted C ₁ -C ₆ of Alkoxy group, optionally substituted alkylthio group, NR ⁴ R ⁵ , halogen, N
O 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, optionally substituted phenyl, phenoxy groups that may be substituted, an optionally substituted heteroaryl Y represents CO ₂ R ⁶ , CN, NO ₂ , SO ₂ , which represents an aryl group or an optionally substituted heteroaryloxy group, and may further form a 4- to 7-membered ring with adjacent substituents. ₃ R ⁶ , SO ₂ NR ⁴
R ^5, SOR ^6, shows the ^{_{SO 2 R 6, R 1,}} R 2 and R ³ are H, optionally substituted C ₁ -C ₆ alkyl group, optionally substituted C ₂ -C ₆ An alkenyl group of optionally substituted C ₂ -C ₆
Alkynyl group, optionally substituted C ₁ -C ₆ alkoxy group, an optionally substituted alkylthio group, 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 , optionally substituted phenyl group, optionally substituted phenoxy group, optionally substituted heteroaryl group or optionally substituted heteroaryloxy group, R ⁴ , R ⁵ and R ⁶ represent H, an optionally substituted alkyl group or an optionally substituted phenyl group, and R ⁴ and R ⁵ may form a ring of 4 to 7; The cyclohexenone derivative represented by the general formula (2) R ⁷ ONH ₂ (2) wherein R ⁷ is H, optionally substituted C ₁ -C ₆ alkyl group, optionally substituted C ₂ -C ₆ alkenyl group, C ₁ ~
Acyl group C _6, an alkoxycarbonyl group having C ₁ -C _6, which comprises reacting a hydroxylamine derivative represented by] shows a an optionally substituted phenyl group or sulfonyl group, the general formula (3) Embedded image Wherein X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as defined above. A method for producing an oxime derivative represented by the formula: 2. A compound of the general formula (3) [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as those defined in claim 1]. Wherein an elimination reaction of the oxime derivative represented by the general formula (4) is carried out. [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1]. A method for producing an aniline derivative represented by the formula: 3. The method according to claim 1, wherein the compound has the general formula (3): [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as those defined in claim 1]. Wherein the oxime derivative represented by the general formula (4) is synthesized and then the method of claim 2 is carried out. [Wherein, X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1]. A method for producing an aniline derivative represented by the formula: 4. A compound of the general formula (3)[Where X, Y, R¹, R^Two, R^ThreeAnd R⁷Is defined in claim 1
Shows the same thing as Oxime induction
General formula (5) characterized in that a body elimination reaction is carried out.[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Indicates the same thing as R ⁸Is COR⁹Or CO_TwoR⁹And R
⁹Is H, optionally substituted C₁~ C₆An alkyl group or
The phenyl group which may be substituted is shown. ]
A method for producing a substituted aniline derivative. 5. A compound of the general formula (5)[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Indicates the same thing as R ⁸Is defined in claim 4.
Indicates the same as R of the substituted aniline derivative represented by
⁸General formula (4) characterized by removing[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Show the same thing as the one. ] Of the aniline derivative shown
Manufacturing method. 6. The method according to claim 1, wherein the compound has the general formula (3):[Where X, Y, R¹, R^Two, R^ThreeAnd R⁷Is defined in claim 1
Shows the same thing as Oxime induction
A compound of the general formula
(5)[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Indicates the same thing as R ⁸Is defined in claim 4.
Indicates the same as N-substituted aniline derivatives represented by
Manufacturing method. 7. The method according to claim 1, wherein the compound has the general formula (3):[Where X, Y, R¹, R^Two, R^ThreeAnd R⁷Is defined in claim 1
Shows the same thing as Oxime induction
A compound is synthesized, and then the compound of the general formula (5) is prepared by the method of claim 4.[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Indicates the same thing as R ⁸Is defined in claim 1
Indicates the same as N-substituted aniline derivatives represented by
Is synthesized, and the method according to claim 5 is further performed, wherein the compound represented by the general formula (4) is[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Show the same thing as the one. ] Of the aniline derivative shown
Manufacturing method. 8. A compound of the general formula (1)[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Show the same thing as the one. Cyclohexenone represented by
The derivative is represented by the general formula (6) R^TenR¹¹NH (6) [wherein, R^TenAnd R¹¹Is H, optionally substituted C₁~ C₆
Represents an alkyl group or a phenyl group which may be substituted
Then R^TenAnd R¹¹May form 4 to 7 rings. ]so
Characterized by reacting with the amine derivative shown,
Formula (7A) and / or (7B)[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Indicates the same thing as R ^TenAnd R¹¹Is defined above
Indicates the same thing as R¹²Is R^TenOr R¹¹Is shown. ]so
Of the enamine and / or imine derivatives shown
Law. 9. A compound of the formula (7A) and / or (7B)[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Indicates the same thing as R ^Ten, R¹¹And R¹²Is claim 8
Indicates the same as defined in Ena shown by]
Dehydrogenation of min and / or imine derivatives
General formula (8) characterized by the following:[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Indicates the same thing as R ^TenAnd R¹¹Is defined in claim 8.
Indicates the same as the one defined. Aniline invitation
Manufacturing method of conductor. 10. The method according to claim 8, wherein the compound represented by the general formula (7A)
And / or (7B)[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Indicates the same thing as R ^Ten, R¹¹And R¹²Is claim 8
Indicates the same as defined in Ena shown by]
Synthesizing a min and / or imine derivative,
Performing the method of item 9, general formula (8)[Where X, Y, R¹, R^TwoAnd R^ThreeIs defined in claim 1
Indicates the same thing as R ^Ten, R¹¹And R¹²Is claim 8
Indicates the same as defined in [Ani]
Method for producing phosphorus derivative. 11. The process according to claim 1, wherein X is an optionally substituted benzene ring. (12) X is a 5- or 6-membered optionally substituted heterocyclic ring having at least one of N, O and S, or an optionally substituted benzene condensate thereof. 11. The production method according to any one of 1 to 10. 13. X is an optionally substituted benzene ring.
And the substituent is H, optionally substituted C₁~ C₆of
Alkyl group, optionally substituted C₁~ C₆The alkoxy of
Group, NR^FourR^Five, Halogen, NO_Two, Y is CO_TwoR⁶, CN, SO_ThreeR⁶Also
Is SO_TwoNR^FourR^FiveAnd R ^Four, R^FiveAnd R⁶Is H, substituted
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~ C₆
The alkyl group according to any one of claims 1 to 10,
Manufacturing method. (14) a pyrrole or a substituent in which X may be substituted;
Optionally substituted furan, optionally substituted thio
Phen, optionally substituted pyridine or substituted
And the substituent is H, substituted
C that may be ₁~ C₆An alkyl group of which is substituted
Good C₁~ C₆Alkoxy group, halogen, NR^FourR^FiveOr N
O_TwoAnd Y is CO_TwoR⁶, CN and R¹, R^TwoAnd R^ThreeIs H
The method according to claim 1. 15. X is a phenyl, chlorophenyl, methoxyphenyl, nitrophenyl or aminophenyl group, Y is CO ₂ Me, CO ₂ Et or CN, R ¹ , R 2
Process according to any one of claims 1 to 10 ² and R ³ are H. 16. X is an optionally substituted pyridine, wherein the substituent is H, an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted 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 10 R ^5. 17. A compound of the general formula (3) [Wherein, X, Y, R ¹ , R ² , R ³ and R ⁷ are the same as those defined in claim 1]. An oxime derivative represented by the formula: 18. A compound of the general formula (7A) and / or (7B) [Wherein X, Y, R ¹ , R ² and R ³ are the same as defined in claim 1, and R ¹⁰ , R ¹¹ and R ¹² are the same as defined in claim 8] Is shown. And / or an imine derivative represented by the formula: 19. 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. An aniline derivative represented by the formula: 20. The general formula (8) [Wherein X, Y, R ¹ , R ² and R ³ represent the same as defined in claim 1, and R ¹⁰ and R ¹¹ represent the same as defined in claim 8]. An aniline derivative represented by the formula: 21. The method according to claim 17, wherein X is a benzene ring.
The compound according to any one of the above. 22. The compound according to any one of claims 17 to 20, wherein X is a 5- or 6-membered heterocyclic ring having at least one of N, O and S, or a benzene condensate thereof. . (23) X is an optionally substituted benzene ring;
And the substituent is H, optionally substituted C₁~ C₆of
Alkyl group, optionally substituted C₁~ C₆The alkoxy of
Group, NR^FourR^Five, Halogen or NO_TwoAnd Y is CO_TwoR⁶, CN,
SO_ThreeR⁶Or SO_TwoNR^FourR ^FiveAnd R^Four, R^FiveAnd R⁶Is H, substitution
Optionally substituted alkyl group or substituted
Is a phenyl group, and R^FourAnd R^FiveForm 4-7 rings with
May be, R¹, R^TwoAnd R^ThreeIs H, optionally substituted C
₁~ C₆21. An alkyl group according to any one of claims 17 to 20.
2. The compound according to item 1. (24) a pyrrole or a substituent in which X may be substituted;
Optionally substituted furan, optionally substituted thio
Phen, optionally substituted pyridine or substituted
And the substituent is H, substituted
C that may be ₁~ C₆An alkyl group of which is substituted
Good C₁~ C₆Alkoxy group, halogen, NR^FourR^FiveOr N
O_TwoAnd Y is CO_TwoR⁶, CN, SO_ThreeR⁶Or SO_TwoNR^FourR^FiveIs
A compound according to any one of claims 17 to 20. 25. X is a phenyl, chlorophenyl, methoxyphenyl, nitrophenyl or aminophenyl group, Y is CO ₂ Me, CO ₂ Et or CN, and R ¹ , R ² and R ³ are 21. The compound according to any one of claims 17 to 20, which is H. 26. X is an optionally substituted pyridine, wherein the substituent is H, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₁ -C ₆ an alkoxy group or a halogen compound according to any one of claims 17 to 20 Y is CO ₂ R ⁶ or CN.