WO2001017971A1

WO2001017971A1 - Process for the preparation of 2,3-dihydroazepine derivatives

Info

Publication number: WO2001017971A1
Application number: PCT/JP2000/006011
Authority: WO
Inventors: Tomomi Ikemoto; Tatsuya Ito; Shoutarou Miura; Kiminori Tomimatsu
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 1999-09-06
Filing date: 2000-09-05
Publication date: 2001-03-15
Also published as: AU6870500A

Abstract

A process for preparing 2,3-dihydroazepine derivatives of general formula (II) or salts thereof inexpensively and simply, characterized by subjecting compounds of general formula (I) or salts thereof to ring-closing reaction in the presence of a carbonic diester, wherein R1 is an electron-withdrawing group; R?2, R3, R4, R5, R6 and R7¿ are each hydrogen, halogeno, optionally substituted amino, optionally substituted hydroxyl, an optionally substituted thiol group, optionally substituted hydrocarbyl, or an optionally substituted heterocyclic group, alternatively R?2 and R3, R4 and R5, R2 and R4, or R6 and R7¿ may be united to form a ring; R8 is hydrogen or optionally substituted hydrocarbyl; and R9 is optionally substituted hydrocarbyl, optionally substituted acyl, or substituted sulfonyl.

Description

Statement

Method for producing 2,3-dihydroazepine derivatives

The present invention relates to a 2,3-dihydroazepine derivative which is an intermediate useful for producing an anilide derivative having a CCR5 antagonistic activity, and a method for producing the same. Background art

Conventionally, there has been reported a method of synthesizing a 2,3-dihydrobenzazepine derivative by subjecting a diester derivative of anthranilic acid to ring closure by a Dieckmann-type cyclization reaction, followed by reduction and dehydration reactions ( Japanese Patent Application No. 111-17045, US Patent 4952573). However, this method uses reagents that are not suitable for mass synthesis, has a long number of steps, and requires complicated operations.

Under the circumstances described above, there is a demand for a method for producing 2,3-dihydroazepine derivatives that is inexpensive, simple, and more suitable for large-scale synthesis. Disclosure of the invention

As a result of various studies, the inventors of the present invention have found that a ring closure reaction is carried out in the presence of a carbonic acid diester by using a benzaldehyde having an amino group substituted at the 2-position ゃ a benzoic acid ester as an intermediate. -A method for producing dihydrobenzozepine derivatives inexpensively and easily has been found. As a result of further research based on these findings, the present invention has been completed.

That is, the present invention

( 1 set

[Wherein, R ¹ represents an electron-withdrawing group, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, or a substituted An optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ² and R ³ , R ⁴ and R ⁵ , R ² And R ⁴ or R ⁶ may combine to form a ring, R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group, R ⁹ represents an optionally substituted hydrocarbon group, A substituted or unsubstituted sacyl group or a substituted sulfonyl group] or a salt thereof in the presence of a diester carbonate.

Wherein each symbol is as defined above, or a method for producing a salt thereof;

(2) The production method according to the above (1), wherein R ¹ is an esterified carboxyl group;

(3) The production method according to the above (1), wherein R ⁸ is a hydrogen atom;

(4) The production method according to the above (1), wherein R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms;

(5) The production method according to (1), wherein R ⁹ is a P-toluenesulfonyl group or an alkyl group; Equation (6)

[Wherein, R ¹ represents an electron-withdrawing group, and R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, Represents an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, wherein R ² and R ³ , R ⁴ and R ^5, or R ² and R ⁴ are R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group; R ⁹ represents an optionally substituted hydrocarbon group, an optionally substituted acyl group or Represents a substituted sulfonyl group, and ring A represents a benzene ring which may have a substituent.] Or a salt thereof is subjected to a ring closure reaction in the presence of a carbonic acid diester. , Expression

Wherein each symbol is as defined above, or a salt thereof.

Equation (7)

[Wherein, R ⁶ and R ⁷ are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, and an optionally substituted A hydrocarbon group or an optionally substituted heterocyclic group; R ⁶ and R ⁷ may combine to form a ring; R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group; R ⁹ represents an optionally substituted hydrocarbon group, an optionally substituted acyl group or a substituted sulfonyl group], a compound represented by the formula:

[Wherein, Y represents a leaving group, R ¹ represents an electron withdrawing group, and R ² , R ³ , R ^4, and R ^{5 each} represent a hydrogen atom, a halogen atom, or an optionally substituted amino group. An optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ² and R ³ , R ⁴ and R ⁵ or R ² and R ⁴ may be combined to form a ring] or a salt thereof, and then subjected to a ring closure reaction in the presence of a carbonic acid diester,

Wherein each symbol is as defined above, or a salt thereof.

Equation (8)

[Wherein, R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ⁹ represents an optionally substituted hydrocarbon group, an optionally substituted acyl group or a substituted sulfonyl group. And ring A represents a benzene ring which may have a substituent; and a compound represented by the formula:

[Wherein, Y represents a leaving group, R ¹ represents an electron withdrawing group, and R ² , R ³ , R ^4, and R ^{5 each} represent a hydrogen atom, a halogen atom, or an optionally substituted amino group. An optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ² and R ³ , R ⁴ and R ⁵ or and R ⁴ May be combined with each other to form a ring], or a salt thereof, and then subjected to a ring closing reaction in the presence of a carbonic acid diester,

Equation (9)

[Wherein, R ¹ represents an electron-withdrawing group, and R ² , R ³ , R ⁴ , R ⁵ , R ^s and R ⁷ each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, An optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ² and R ³ , R ⁴ and R ⁵ , R ² And R ⁴ or R ⁶ and R ⁷ may combine to form a ring, R ^ie represents an optionally substituted hydrocarbon group, R ⁹ represents an optionally substituted hydrocarbon group, Or a substituted sulfonyl group which may be substituted] or a salt thereof is subjected to a ring closure reaction in the presence of a carbonic acid diester.

Wherein each symbol is as defined above (this compound may have any of an enol-type or keto-type structure) or a method for producing a salt thereof;

(10) The production method according to the above (9), wherein R ¹ is an esterified carboxyl group;

(11) The process according to the above (9), wherein R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms;

(12) The production method according to the above (9), wherein R ⁹ is a P-toluenesulfonyl group or an alkyl group;

(13)

[Wherein, R ¹ represents an electron-withdrawing group, and R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, Represents an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, wherein R ² and R ³ , R ⁴ and R ^5, or R ² and R ⁴ are R ^{1 ()} may represent a hydrocarbon group which may be substituted, and R ⁹ may represent a hydrocarbon group which may be substituted, an acyl group which may be substituted or Ring A represents a benzene ring which may have a substituent]. Wherein the salt of is subjected to a ring-closure reaction in the presence of a carbonic acid diester,

(14)

[Wherein, R ⁶ and R are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon represents a group or an optionally substituted heterocyclic group, R ⁶ and R ⁷ may form a ring, R ^'Q is indicates optionally substituted hydrocarbon group, R ⁹ Represents an optionally substituted hydrocarbon group, an optionally substituted acyl group or a substituted sulfonyl group] or a salt thereof,

5 R ⁴ [Wherein, Y represents a leaving group, R ¹ represents an electron withdrawing group, and R ² , R ³ , R ^4, and R ^{5 each} represent a hydrogen atom, a halogen atom, or an optionally substituted amino group. An optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ² and R ³ , R ⁴ and R ⁵ or R ² and R ⁴ may be combined to form a ring] or a salt thereof, and then subjected to a ring closure reaction in the presence of a carbonic acid diester,

(15)

In the formula, R ¹ * ¹ represents an optionally substituted hydrocarbon group, and R ⁹ represents an optionally substituted hydrocarbon group, an optionally substituted acyl group or a substituted sulfonyl group. And ring A represents a benzene ring which may have a substituent], or a salt thereof,

In the formula, Y represents a leaving group, R ′ represents an electron withdrawing group, and R ² , R ³ , R ⁴ and R ⁵ represent a hydrogen atom, a halogen atom, an amino group which may be substituted, Represents an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ² and R ³ , R ⁴ and R ⁵ Or R ² and R ⁴ may combine to form a ring], or a salt thereof, and then subjecting the compound to a ring closure reaction in the presence of a carbonic diester.

Equation (16)

[Wherein, R ¹ represents an electron-withdrawing group, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, or a substituted An optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ² and R ³ , R ⁴ and R ⁵ , R ² And R ⁴ or R ⁶ and R ⁷ may combine to form a ring, R ^s represents a hydrogen atom or an optionally substituted hydrocarbon group, and ring C may have a substituent A benzene ring] or a salt thereof is subjected to a deprotection reaction.

(17) The production method according to the above (16), wherein R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms;

(18) The production method according to (16), wherein R ⁸ is a hydrogen atom; (19) The production method according to the above (16), wherein ring C is a p-tolyl group;

[Wherein, R ¹ represents an electron-withdrawing group, and R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, Represents an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, wherein R ² and R ³ , R and R ^5, or R ² and R ⁴ are a bond R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted, and ring A and ring C each represent a benzene ring which may have a substituent.] Wherein the compound represented by the formula or a salt thereof is subjected to a deprotection reaction.

Wherein each symbol is as defined above, or a method for producing a salt thereof; Equation (2 1)

[Wherein, R ^la represents an esterified carboxyl group, an amidated carboxyl group, or a cyano group, and R ² , R ³ , R ⁴ , R ⁵ , R ^6, and R ⁷ are a hydrogen atom, a halogen atom, respectively. Represents an atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group. R ² and R ³ , R ⁴ and R ⁵ , R ² and R ⁴ or R ⁶ and R ⁷ may combine to form a ring, and R ⁸ is a hydrogen atom or an optionally substituted hydrocarbon Wherein the ring C represents a benzene ring which may have a substituent, or a salt thereof is subjected to an acid hydrolysis reaction.

Wherein each symbol is as defined above, or a salt thereof. (2 2) The production method according to the above (21), wherein R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms;

(23) The production method according to the above (21), wherein R ⁸ is a hydrogen atom;

(24) The production method according to the above (21), wherein ring C is a P-tolyl group;

Equation (2 5)

[In the formula, R ′ ^a represents an esterified carboxyl group, an amidated carboxyl group or a cyano group, and R ² , R ³ , R ⁴ and R ⁵ represent a hydrogen atom, a halogen atom, An optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ² and R ³ , R ⁴ and R ⁵ or R ² and R ⁴ may combine to form a ring, R ^s represents a hydrogen atom or an optionally substituted hydrocarbon group, and ring A and ring C each represent A benzene ring which may have a substituent] or a salt thereof is subjected to an acid hydrolysis reaction.

R 4 (Wherein each symbol is as defined above) or a method for producing a salt thereof;

In the formula, R ^s represents a hydrogen atom or a hydrocarbon group which may be substituted, and R ² , R ³ , R ⁴ ,

R ⁵ , R ^s and R ⁷ are each a hydrogen atom, a halogen atom, an amino group which may be substituted, a hydroxyl group which may be substituted, a thiol group which may be substituted, and which may be substituted Represents a hydrocarbon group or a heterocyclic group which may be substituted, R ² and R ³ ,

R ⁴ and R ⁵ , R ² and R ^4, or R ⁶ and R ⁷ may be combined to form a ring] or a salt thereof to an acylation reaction.

In the formula, R ¹ ′ represents a hydrogen atom or an optionally substituted hydrocarbon group, and other symbols have the same meanings as described above] or a method for producing a salt thereof;

(27) The production method according to the above (26), wherein R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms;

(28) The production method according to the above (26), wherein R ⁸ is a hydrogen atom;

(2 9) wherein R ¹¹ is a hydrogen atom (2 6) The process according; (30)

[Wherein, R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted, and R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom, a halogen atom, an amino group which may be substituted, A hydroxyl group which may be substituted, a thiol group which may be substituted, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R ² and R ³ , R ⁴ and or R ² and R ⁴ may combine to form a ring, and ring A represents an optionally substituted benzene ring] or a salt thereof is subjected to an acylation reaction. Feature, expression

[Wherein, R ¹¹ represents a hydrogen atom or a hydrocarbon group which may be substituted, and other symbols have the same meanings as described above] or a method for producing a salt thereof;

Equation (3 1)

[Wherein, R ′ ² , R ³ , R ⁴ and R ⁵ are each a hydrogen atom, a halogen atom, a substituted or unsubstituted amino group, a substituted or unsubstituted hydroxyl group, a substituted or unsubstituted thiol group Represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, wherein R ² and R ³ , R ⁴ and R ^5, or R ² and R ⁴ are bonded to form a ring R ^ga represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group or a substituted sulfonyl group, and R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group. And X represents an octylogen atom] and a salt thereof and a compound represented by the formula

[Wherein, ring B represents a benzene ring which may have a substituent, M represents _MgX ′, -B (0H) ₂ , one B (0R ^1S ) ₂ or —SnR ¹⁸ , and X ′ represents A halogen atom; R ¹⁸ represents a lower alkyl group; or a salt thereof.

(Wherein each symbol is as defined above) or a method for producing a salt thereof; (32) The method according to the above (31), wherein R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms. (33) The production method according to the above (31), wherein R ⁸ is a hydrogen atom;

(34) The production method according to the above (31), wherein R ^9a is a P-toluenesulfonyl group or an alkyl group;

(35) The production method according to the above (31), wherein R ^9a is a formyl group;

Equation (36)

^{^{Wherein, R 2, R \ R 4}} , R 5, R B and R ⁷ are each a hydrogen atom, a halogen atom, an optionally substituted amino group, hydroxy group which may be substituted, substituted A thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group; R ² and R ³ R ⁴ and R ⁵ , R ² and R ⁴ or R ⁶ and R ⁷ may combine to form a ring. However, the ring in which R ⁶ and R ⁷ are bonded to each other is not an unsubstituted benzene ring. Or a salt thereof;

(37) The compound according to (36), wherein R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms; (38) the compound according to (36), wherein R ^s is hydrogen atom;

Equation (39)

[Wherein, ring A ^a represents a benzene ring having ^a substituent, and R ² , R ³ , R ⁴ and R ⁵ are each a hydrogen atom, a halogen atom, an amino group which may be substituted, A hydroxyl group, a thiol group which may be substituted, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, wherein R ⁸ is a hydrogen atom or a hydrocarbon group which may be substituted; R ² and R ³ , R ⁴ and R ⁵ or R ² and R ⁴ may combine to form a ring] or a salt thereof;

(40) The compound according to the above (39), wherein R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms;

(41) The compound according to the above (39), wherein R ⁸ is a hydrogen atom;

(42) Ring A ^a is a formula

[Wherein ring B represents a benzene ring which may have a substituent (s)]. As used herein, the term “electron withdrawing group” includes, for example, (i) a carboxyl group which may be esterified or amidated, (ii) a formula — (CO) R ¹⁹ (wherein R ¹⁹ Represents hydrogen or a hydrocarbon group which may be substituted), (iii) nitrile group, (iv) nitro group, (V) Formula (S〇 _m ) R ²⁰ (wherein m indicates 1 or 2 And R ^2Q represents an ^optionally substituted hydrocarbon group.) (Vi) a group represented by the formula: PR ²¹ R ²² (wherein R ²¹ and R ²² each represent an ^optionally substituted hydrocarbon group) (Vii) a group represented by the following formula: (vii) Formula (PO) (OR ¹³ ) (OR ¹⁴ ) (wherein, R ¹³ and R ¹⁴ each represent hydrogen or an optionally substituted hydrocarbon group. (Viii) an aryl group which may be substituted, (ix) an alkenyl group which may be substituted, (X) a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (xi) Nitroso group or the like, preferably esterified or amidated force Rupoxyl group, group represented by the formula — (CO) R ¹⁹ , nitrile group, nitro group, formula (SO _m ) R groups represented by ^2G, the formula - PR ²¹ group represented by R ^22, wherein one (P_〇) (OR ¹³⁾ a group represented by (OR ^14), more preferably Carboxyl groups esterified (e.g., methoxycarbonyl, ethoxycarbonyl, esterified carboxyl group ₄ alkyl such t one-butoxycarbonyl), and the like.

As the “esterified carbonyl group” in the “carboxyl group which may be esterified or amidated” of the above (0), the formula (CO) OR ¹⁵ (where R ¹⁵ is hydrogen or substituted A hydrocarbon group which may be represented by the following formula). Examples of the “amidated carboxyl group” include a group represented by the formula — (CO) NR ¹⁶ R ¹⁷ (wherein R ¹⁶ and R ¹⁷ Each represents hydrogen or a hydrocarbon group which may be substituted, and R ¹⁶ and R ¹⁷ are bonded to each other and have a 5- to 7-membered (preferably 5- to 6-membered) cyclic amino (eg, tetrahydro Pyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.).

Furthermore, the expression in (vi) or (vii), R ²¹ and R ²² or R ¹³ and R ¹⁴ are bonded to each other, for example, lower (C ₂ _ ₆₎ alkylene (e.g., dimethylene, preparative Rimechiren, tetra Methylene, etc.), lower (C ₂ — ₆ ) alkenylene (eg, one CH ₂ — CH = CH—, — CH ₂ —CH ₂ — CH = CH—, one CH ₂ —CH = CH—CH ₂ one), lower (C ₄ - ₆₎ Arukajie two alkylene (e.g., - CH two CH- CH = CH-, etc.), etc., preferably lower (C ^) alkylene, more preferably form a lower (C ₂ _ ₄₎ alkylene These divalent groups may have a substituent. Examples of such a substituent include a hydroxyl group, a halogen, a (: trialkyl, _ ₄ alkoxy and the like.

As the "Ariru group" in the optionally substituted Ariru group (viii), for example, phenyl, C _6, such as naphthyl - such as ₁₄ Ariru, preferably. Aryl, and more preferably phenyl. The aryl group may have 1 to 3 substituents similar to the substituents that the “optionally substituted hydrocarbon group” described below may have.

The “alkenyl group” in the optionally substituted alkenyl group of the above (ix) includes, for example, alkenyl having 2 to 10 carbon atoms such as vinyl, allyl, crotyl, 2-pentenyl, 3-hexenyl and the like. etc., preferably such as a lower (C ₂ _ ₆₎ alkenyl Le, more preferably and vinyl. The alkenyl group may have one to three substituents similar to the substituents that the “optionally substituted hydrocarbon group” described below may have.

As the “hydrocarbon group” in the “optionally substituted hydrocarbon group” used in the present specification, for example,

(1) alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc .; And preferably lower (C ^ e) alkyl and the like);

(2) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl Le, cyclohexyl, etc. C ₃ _ ₇ cycloalkyl such as heptyl is like et be cyclohexylene);

(3) alkenyl (e.g., vinyl, Ariru (allyl), crotyl, 2-pentenyl, alkenyl carbon number 2-10, such as cyclohexenyl 3, preferably lower (C ₂ - _6), such as alkenyl and the like);

(4) cycloalkenyl (for example, cycloalkenyl having 3 to 7 carbon atoms such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl and the like);

(5) alkynyl (for example, alkynyl having 2 to 10 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl, 1_butynyl, 2-pentynyl, 3-hexynyl, Preferably lower (C ₂ _ ₆ ) alkynyl and the like;

(6) Ariru (. E.g., phenyl, C ₆ _ ₁₄ Ariru of naphthyl, preferably C ₆ - Ariru, more preferably like phenyl);

(7) Ararukiru (e.g., phenylene Lou - ₄ alkyl (e.g., benzyl, and the like Fuene chill etc.)); and the like. Among these, alkyl rather preferred, such as methyl, Echiru ^ _ ₄ Alkyl is more preferred, and methyl is particularly preferred.

The hydrocarbon group may have a substituent. Examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, and optionally substituted thiol. Group (eg, thiol, alkylthio, etc.), amino group which may be substituted (eg, amino, ₄ monoalkylamino, ₄ dialkylamino, tetrahydropyrrol, piperazine, piperidine, morpholine , thiomorpholine, pyrosulfate Ichiru, etc. 5-6 membered cyclic Amino, such as imidazole), esterified or amidated carboxyl group which may be (for example, carboxyl, alkoxycarbonyl, force Rubamoiru, mono C i_ ₄ alkyl force Rubamoyl, di-Ci- ₄ alkyl radical, etc.), halogen atom or C ぃ₄ alkoxy C ぃ₄ alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), halogen atom or C ₄ alkoxy which may be substituted with — 4 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy) and triflate Ruo Roe butoxy), formyl, C ₂ - ₄ Arukanoiru (eg, Asechiru, propionyl and the like), alkylsulfonyl (e.g., methanesulfonyl, etc. ethanesulfonyl) CI_ ₄ alkylsulfide el (eg, methanesulfinyl, E And the like. The number of substituents is preferably 1 to 3.

In the above formula, R ² and R ^3, R ⁴ and R ⁵ or R ² and R ⁴ are bonded to each other, for example, lower (C ₂ _ ₆₎ alkylene (e.g., dimethylene, Bok Rimechiren, etc. tetramethylene ), Lower (C ₂ — ₆ ) alkenylene (eg, — CH ₂ — CH = CH—, — CH ₂ — CH ₂ —CH = CH— — CH ₂ — CH = CH—CH ₂ —, etc.), lower (C ₄ — ₆ ) Al cadienylene (eg, CH = CH— CH = CH— etc.), preferably lower (C

! _ ₆ ) to form alkylene, more preferably lower (C ₂ ) alkylene Thus, a ring may be formed with adjacent carbon atoms. These divalent groups may have a substituent, and examples of the substituent, for example a hydroxyl group, a halogen, an alkyl, and a C i _ ₄ alkoxy.

In the above formula, the “halogen atom” represented by X, X ′, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ includes, for example, fluorine, chlorine, bromine, iodine, etc. Can be

In the above formula, the `` optionally substituted amino group '' represented by R ² , RR ⁴ , R ⁵ , R ⁶ and R ⁷ may be substituted with the aforementioned `` optionally substituted hydrocarbon group '' And the number of substituents may be any of 0 to 2, and when there are two substituents, the two substituents may be the same or different. Is also good. Further, the two substituents are bonded to each other to form a 5- to 7-membered (preferably 5- to 6-membered) cyclic amino group (eg, tetrahydropyrrol, piperazine, piperidine, morpholine) together with an adjacent nitrogen atom. Thiomorpholine, pyrrole, imidazole, etc.).

In the above formula, the `` optionally substituted hydroxyl group '' represented by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is the aforementioned `` optionally substituted hydrocarbon group '' And a hydroxyl group which may be substituted.

In the above formula, the `` optionally substituted thiol group '' represented by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ includes the aforementioned `` optionally substituted hydrocarbon '' And a thiol group which may be substituted with a “group”.

In the above formula, the “heterocycle” in the “optionally substituted heterocyclic group” represented by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is an oxygen atom, a sulfur atom, a nitrogen atom 5- to 7-membered aromatic containing at least 1 (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from atoms and the like Examples include a heterocyclic ring, a saturated or unsaturated non-aromatic heterocyclic ring (aliphatic heterocyclic ring), and the like. Here, the “aromatic heterocycle” is a 5- to 6-membered aromatic monocyclic heterocycle (for example, furan, thiophene, pyrrole, oxazolyl, isoxazolyl, thiazole, isothiazole, imidazole, pyrazole 1,2,3_oxaziazol, 1,2,4-oxaziazol, 1,3,4-oxaziazol, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4 —Thiadiazole, 1, 2,3_triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.), and the “non-aromatic complex ring”. For example, 5- to 7-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-saturated compounds such as pyrrolidine, tetrahydrofuran, thiolane, piberidine, tetrahydropyran, morpholine, thiomorpholine, piperazine, and pyran. An aromatic heterocyclic ring (aliphatic heterocyclic ring) or the like, or a 5- to 6-membered non-aromatic heterocyclic ring in which part or all of the above-mentioned aromatic monocyclic heterocyclic ring is saturated with a double bond. As the heterocyclic ring, a 5- to 6-membered aromatic ring is preferable, and furan, thiophene, pyrrole, pyridine (preferably a 6-membered ring) and the like are preferable.

Examples of the substituent that the heterocyclic ring may have include the same substituents as the substituent that the aforementioned “optionally substituted hydrocarbon group” may have, and the like. The number may be one to three.

In the above formula, R ¹ is preferably a carboxyl group or a cyano group which may be esterified or amidated, more preferably a carboxyl group or a cyano group which has been esterified or amidated, and particularly preferably esterified. Preferred are carboxyl groups. R ⁸ is preferably a hydrogen atom, and R ² , R ³ , R ⁴ and R ⁵ are preferably a hydrogen atom or an optionally substituted hydrocarbon group, more preferably a hydrogen atom, R ⁶ and R ⁷ is preferably bonded to each other to form an optionally substituted benzene ring. The R ⁹ or R ^9a, P- toluenesulfonyl group, C, _ ₆ alkyl groups, such as formyl group are preferable, p - toluenesulfonyl group, more preferably such _ ₆ Al kill group, is especially P- toluenesulfonyl group preferable. R "is preferably a hydrogen atom.

As the substituent which the “optionally substituted benzene ring” used in the present specification may have, the above-mentioned “optionally substituted hydrocarbon group” may have the optional substituent A substituent similar to the group; which may be bonded via a spacer (for example, a divalent group having 1 to 4 atoms constituting a straight-chain portion); An aryl group which may be optionally bonded (preferably, an aryl group which may be directly substituted or the above-mentioned "aryl group which may be substituted"), among which an electron donating group is preferable. Examples of the number of substituents include 1 to 4. Here, “spacer” is, for example, — (CH ₂ ) _a — [& represents an integer of 1 to 4 (preferably an integer of 1 to ₂ )], — (CH ₂ ) _b _X "— [b represents an integer of 0 to 3 (preferably an integer of 0 to 1), and X" represents an optionally substituted imino group (eg, lower (C ^) lower alkyl, lower (C ₃ _ ₇ ) cycloalkyl, formyl, lower (C ₂ _ ₇ ) lower alkanol, lower (such as: imino group optionally substituted by lower alkoxy-carbonyl, etc.), carboxyl group, oxygen atom or oxidized Represents an optional sulfur atom (eg, —S (〇) _n — (n is an integer from 0 to 2) etc.), — CH = CH—, one C3 C1, and —CO-NH— , — S〇 ₂ — NH— and the like (preferably — (CH ₂ ) _b — X "—, more preferably one CH ₂ —O—). Good benzene ring As attached, it may be a right or left binding hand but, preferably via the right bond to bind to "benzene ring which may be substituted".

In the above formula, the `` optionally substituted benzene ring '' represented by ring A includes the `` optionally substituted benzene ring '' represented by ring B directly or via the aforementioned spacer. A benzene ring (preferably a direct bond) is preferable. The substitution position of ring B is represented by the formula

Is preferred.

In the above formula, the “optionally substituted benzene ring” represented by ring B includes a halogen atom or C ₄ alkyl optionally substituted with C ₄ alkoxy (eg, trifluoromethyl, methyl Or a benzene ring which may have a substituent such as ethyl. When the number of the substituent is one, the substitution position is preferably the para position. In the above formula, the `` optionally substituted benzene ring '' represented by ring C is preferably the same as the `` optionally substituted benzene ring '' represented by ring B. Of these, a benzene ring having an alkyl group at the para-position is preferable, and a p-tolyl group is particularly preferable.

As the ring R ⁶ and R ⁷ are formed in combination, for example, C ₅ - ₇ Shikuroaruke emissions (eg, -1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 2-cyclohexene, 3-cyclohexylene cyclohexene, etc.), C ₅ _ ₆ cycloalkadiene (e.g., 2, 4 - Shikuropen evening Zhen, 2, 4-cycloheteroalkyl Kisajen, 2, 5-cycloheteroalkyl Kisaji E down, etc.) for 5-7 membered, such as (preferably 5- to 6-membered) unsaturated alicyclic hydrocarbon; 6-membered aromatic hydrocarbon such as benzene; 1 to 3 (preferably 1 to 3) heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like. Or 2 or more) of at least one (preferably 1 to 4, more preferably 1 to 2), a 5- to 7-membered aromatic heterocyclic ring, unsaturated non-aromatic heterocyclic ring (aliphatic heterocyclic ring) And the like.

Here, the “aromatic heterocyclic ring” is a 5- to 6-membered aromatic monocyclic heterocyclic ring (for example, furan, thiophene, pyrrole, oxazole, isooxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2 , 3-oxoxadiazole, 1,2,3-thiadiazole, 1,2,3-triazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.), and the "non-aromatic heterocyclic ring" Examples thereof include 5- to 6-membered non-aromatic heterocycles in which some of the double bonds of the aromatic monocyclic heterocycle described above are saturated.

The ring formed by the bonding of R ⁶ and R ⁷ is preferably a 5- to 6-membered aromatic ring, more preferably benzene, furan, thiophene, pyrrole, pyridine (preferably a 6-membered ring) and the like. Is preferred.

The ring formed by the bonding of R ⁶ and R ⁷ may have a substituent. Examples of the substituent include the “benzene ring” in the “optionally substituted benzene ring” described above. The same substituents as the substituents which may be substituted are mentioned, and 1 to 3 identical or different substituents may be substituted at any substitutable position.

Examples of the leaving group used in the present specification include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a formula _〇 (SO _m ) R, wherein m represents 1 or 2. And R represents an optionally substituted hydrocarbon group (preferably an optionally halogenated C ₄ alkyl, more preferably trifluoromethyl). Among them, a halogen atom is preferable, and a bromine atom is particularly preferable. Also, the expression

[Wherein the symbols are as defined above], when the compound represented by the formula (1) is subjected to a reductive N-alkylation reaction, Y and R ⁵ together with adjacent carbon atoms form a carbonyl group; formula

[Wherein each symbol has the same meaning as described above]. As this, the leaving group as Y, but are also Okiso group formed together with R ^5, in this case, the compound obtained after reductive N- alkylation reaction, R ⁵ represents a hydrogen atom , After the reductive N-alkylation reaction,

Wherein each symbol is as defined above, or a salt thereof;

[Wherein each symbol is as defined above], or a salt thereof. In the above formula, the optionally substituted sacyl group represented by R ⁹ or R ^9a

-(CO) R '(wherein, R' represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and the like. As the “optionally substituted heterocyclic group” represented by ′, those similar to the “optionally substituted heterocyclic group” represented by R ² , R ³ , KR ⁵ , R ⁶ and No. In the above formula, the “substituted sulfonyl group” represented by R ⁹ or R ^9a is represented by the formula (S （

₂ ) a group represented by R "(wherein, R" represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and the "substituted" represented by R " Examples of the `` optionally substituted heterocyclic group '' include the same as the `` optionally substituted heterocyclic group '' represented by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ Is mentioned.

In the above formula, the “lower alkyl” represented by R ¹⁸ includes lower (dialkyl) and the like.

Further, when the compound having the substituent is a basic compound according to the type of the substituent exemplified above, it can be converted to a salt using an acid according to a conventional method. Such an acid may be any acid as long as it does not hinder the reaction. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, and sulfamic acid, and formic acid Acetic acid, trifluoroacetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, succinic acid, malic acid, organic acids such as P-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, etc., and acidic amino acids such as aspartic acid and glutamic acid. Is mentioned. When the obtained compound is a salt, it is converted to a free base according to a conventional method. It may be converted.

On the other hand, when the compound having the substituent is an acidic compound according to the type of the substituent exemplified above, it can be converted to a salt using a base according to a conventional method. The salt with a base may be a salt with any base as long as it does not hinder the reaction, for example, a salt with an inorganic base, a salt with an organic base, a basic amino acid And the like. Suitable examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like. . Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. Salts with amines and the like can be mentioned. Preferable examples of the salt with a basic amino acid include salts with arginine, lysine, orditin and the like. When the obtained compound is a salt, it may be converted to a free acid according to a conventional method.

The reaction described in the above (1) is performed, for example, under the following reaction conditions.

( 1 set

Wherein each symbol is as defined above, or a salt thereof, is subjected to a ring closure reaction in the presence of a diester carbonate,

[Wherein each symbol is as defined above] or a salt thereof.

The reaction described in the above (1) is preferably performed in the presence of a base. Examples of the base include metal hydrides (eg, hydrides of alkali metals such as sodium hydride, potassium hydride, etc.), metal hydrocarbon (e.g., n- butyl lithium, compounds CI_ ₄ alkyl and alkali metal has a chemical bond directly attached, such as such), Arcola Ichito compound (eg, NaOMe, NaOEt, t-BuONa, t- BuOK, etc. Alcohols such as compounds in which the hydrogen of the hydroxyl group of an alcohol is replaced with an alkali metal, alkali metal hydroxides (eg, NaOH, K0H, etc.), and basic carbonates (eg, sodium salts, potassium salts, etc.) Metal salts or calcium salts, carbonates with alkaline earth metal salts such as magnesium salts, etc.), basic bicarbonates (eg, alkali salts such as sodium salts, potassium salts, etc.) Bicarbonates with metal salts, etc.), organic bases (eg, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4. 3.0) non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8_diazabic mouth [5.4.0] — 7-decene, etc.) Among them, metal hydride compounds (eg, sodium hydride, potassium hydride, etc.), alcoholates (eg, NaOMe NaOEt, t-BuONa, t-BuOK, etc.) are preferably used, and particularly, alcoholates ( For example, NaOMe, NaOEt, t-BuONa, t-BuOK, etc.) are preferably used. The amount of the base used in the reaction described in the above (1) is about 0.1 to 100 equivalents, preferably 1 to 5 equivalents.

Examples of the reaction solvent include a solvent containing a carbonic acid diester. It may be used alone, or an appropriate mixed solvent may be used. Solvents used for mixing include halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), aliphatic hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons (eg, benzene , Toluene, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, isopropyl ether (IPE), etc.), polar solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), formic acid esters (eg, formic acid alkyl ester), oxalic acid diesters (eg, such as oxalic acid di C i _ ₄ Al kill ester), protic solvents (e.g., methanol, ethanol, propanol Lumpur, isopropanol, n- blanking evening Nord , 2-methoxy alcohol, etc.) are used. And polar solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.) are preferably used. Examples of the carbonic acid diester include compounds represented by Z — 0 (CO) 〇—〇 ′, wherein Ζ and Z ′ each represent a hydrocarbon group which may be substituted. What is liquid at the reaction temperature for carrying out this reaction is desirable. In addition, Ζ and Z ′ are preferably the same, and as the diester carbonate, dialkyl carbonates such as dimethyl carbonate and getyl carbonate are preferably used. The reaction temperature is usually about -20 to 200 ° C, preferably about 10 to 100 ° C, and the reaction time is usually about 0.1 to 100 hours, preferably about 0.5 to 50 hours.

The reaction described in the above (6) is performed, for example, under the following reaction conditions.

Expression

Wherein each symbol is as defined above, or a salt thereof, To a ring closure reaction in the presence of

[Wherein each symbol is as defined above] or a salt thereof.

The reaction described in the above (6) is preferably carried out in the presence of a base. Examples of such a base include metal hydrides (eg, hydrides of alkali metals such as sodium hydride, potassium hydride, etc.), Metal hydrocarbons (eg, n-butyllithium, etc., compounds having a chemical bond in which C i_ ₄ alkyl is directly bonded to an alkali metal), alcoholates (eg, NaOMe, NaOEt, t-BuONa, t-BuOK) , Such as compounds in which the hydrogen of the hydroxyl group of an alcohol is replaced with an alkali metal, etc., alkali metal hydroxides (eg, NaOH, K0H, etc.), basic carbonates (eg, sodium salts, potassium salts, etc.) Alkaline metal salts such as lithium metal salts, calcium salts, magnesium salts, etc.), basic hydrogen carbonates (eg, alkalis such as sodium salts, potassium salts, etc.) Genus salts, bicarbonates, etc.), organic bases (eg, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4. 3. 0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo mouth [5.4.0] — 7-decene, etc.) Among them, metal hydride compounds (eg, sodium hydride, potassium hydride, etc.) and alcoholates (eg, NaOMe, NaOEt, t-BuONa, t-BuOK, etc.) are preferably used, and especially alcoholates (eg, , NaOMe, NaOEt, t-BuONa, t-BuOK, etc.) are preferably used. The amount of the base used in the reaction described in the above (6) is about 0.1 to 100 equivalents, preferably 1 to 5 equivalents. Examples of the reaction solvent include a solvent containing a carbonic acid diester. The carbonic acid diester may be used alone, or an appropriate mixed solvent may be used. Solvents used for mixing include halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), aliphatic hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons (eg, benzene , Toluene, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, isopropyl ether (IPE), etc.), polar solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), formic acid Ester (eg, formic acid (: ぃ₄ alkyl ester, etc.), oxalic acid diester (eg, dimethyl oxalate), protic solvent (eg, methanol, ethanol, propanol, isopropanol, n-butanol) And alcohols such as 2-methoxyethanol). , Polar solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), etc. As the carbonic acid diester, Z—〇 (CO) O—Z ′ [wherein, Z and Z ′ Represents a hydrocarbon group which may be substituted, respectively], and is preferably a liquid at the reaction temperature at which the present reaction is carried out. is preferably the same as the carbonic acid diester, carbonate-dimethyl-and di C i _ ₄ alkyl esters such as carbonate Jechiru are preferably used the reaction temperature is usually about -. 20 to 200 ° C, preferably about 10 To 100 ° C., and the reaction time is usually about 0.1 to 100 hours, preferably about 0.5 to 50 hours.

The reaction described in the above (7) is carried out, for example, under the following reaction conditions.

Expression

Wherein each symbol is as defined above, or a salt thereof, and

[Wherein each symbol is as defined above] or a salt thereof, followed by a ring closure reaction in the presence of a carbonic acid diester,

[Wherein each symbol is as defined above] or a salt thereof.

In this reaction, the two steps of N-alkylation reaction and dehydration condensation can be performed continuously in one pot, and the intermediate may or may not be isolated. It is preferable to carry out. This reaction is performed under different reaction conditions depending on the difference of Y.

When Y is a halogen atom, a group (preferably a halogen atom) or the like (preferably a halogen atom) represented by the formula: O (SO _m ) R wherein each symbol is as defined above, After the alkylation, the ring closure is carried out under the reaction conditions described in the above (1). The N-alkylation reaction is preferably performed in the presence of a base. Examples of such a base include metal hydrides (eg, hydrides of alkali metals such as sodium hydride and potassium hydride, etc.); hydrogen (eg, n- butyl lithium etc. (: such as a compound having a chemical bond Bok ₄ alkyl and alkali metal are directly bonded), alcoholates (e.g., NaOMe NaOE t t-BuONa, C such Bok BuOK ₄ Alcohols such as compounds in which the hydrogen of the hydroxyl group of an alcohol is replaced with an alkali metal), hydroxides of an alkali metal (eg, NaOH K0H), basic carbonates (eg, sodium salt, potassium salt, etc.) Carbonate with alkaline earth metal salts such as lithium metal or calcium salt, magnesium salt, etc., basic hydrogencarbonate (eg, hydrogencarbonate with alkali metal salt such as sodium salt, potassium salt, etc.) ), Organic bases (eg, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidin, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -17-decene, etc., among others, basic carbonates (eg, Alkali metal salts such as sodium salt, potassium salt or calcium salt, carbonate with alkaline earth metal salt such as magnesium salt, etc., preferably potassium carbonate) or 1,8-dia Bicyclo [5 4.0.] - 7-Undesen like and alcoholates (e.g., NaOMe NaOE t, t-BuONa, t- BuOK, etc.) and a mixture of preferably used. The amount of the base used in the reaction described in the above (7) is about 0.1 to 100 equivalents, preferably! ~ 5 equivalents.

Reaction solvents include halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), aliphatic hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.) ), Ethers (eg, tetrahydrofuran (THF), getyl ether, isopropyl ether (IPE), etc.), polar solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), diester carbonate (eg, , Dimethyl carbonate, dimethyl carbonate, etc. dialkyl carbonate ₄ alkyl esters, etc.), formic acid esters (eg, alkyl formic acid esters, etc.), oxalic acid diesters (eg, oxalic acid dialkyl _4- alkyl esters, etc.), protic solvents ( For example, methanol, ethanol, propanol, isopropanol, n-butanol, 2 Alcohols such as methoxyethanol). The reaction may be carried out using an appropriate mixed solvent, but among them, a mixed solvent of a diester carbonate and a polar solvent (preferably, DMF or the like) is preferably used. Can be

The reaction temperature is usually about -20 to 200 ° C (: preferably about 10 to 100 ° C), and the reaction time is usually about 0.1 to 100 hours, preferably about 0.5 to 50 hours.

When Y forms a carbonyl group together with R ⁵ and adjacent carbon atoms, after performing reductive N-alkylation under the following conditions, the ring is closed under the reaction conditions described in (1) above. It is done by doing. (In the product after reductive N-alkylation, R ⁵ represents a hydrogen atom.)

The reductive N-alkylation reaction (reductive amination reaction) is preferably performed in the presence of a reductive amination reagent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc. It is desirable to change the reaction conditions depending on the reagent.

For example, when sodium triacetoxyborohydride is used, an inert solvent, for example, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, getylether, dioxane, acetonitrile, dimethylformamide (DMF), or a mixture thereof is used. It can be performed in a solvent. Use this reagent in an amount of about 1 to 2 mol equivalent to 1 mol of raw material. The reaction is usually carried out at a temperature in the range of about 0 ° C to about 80 ° C for about 1 hour to about 40 hours. This reaction is preferably performed in an atmosphere of an inert gas (eg, nitrogen, argon, etc.).

The reaction described in the above (8) is performed, for example, in the following steps.

Expression

Wherein each symbol is as defined above, or a salt thereof, and

[Wherein each symbol is as defined above] or a salt thereof, W

37

Following a ring closure reaction in the presence of a carbonic acid diester, the formula

[Wherein each symbol is as defined above] or a salt thereof. The reaction described in the above (8) is performed, for example, under the same reaction conditions as the reaction described in the above (7).

The reaction described in the above (9) is carried out, for example, under the following reaction conditions.

Expression

Wherein each symbol is as defined above, or a salt thereof is subjected to a ring closure reaction in the presence of a carbonic acid diester,

[Wherein each symbol is as defined above] or a salt thereof.

The reaction described in the above (9) is preferably performed in the presence of a base. Examples of such a base include metal hydrides (eg, hydrides of alkali metals such as sodium hydride, potassium hydride, etc.), Metal hydrocarbons (eg, η-butyllithium, etc., compounds having a chemical bond in which C i _ ₄ alkyl is directly bonded to alcohol metal), alcoholates (eg, NaOMe, NaOEt, t-BuONa, t-BuOK, etc. — compounds in which the hydroxyl group hydrogen of 4 alcohols is replaced with an alkali metal, etc., alkali metal hydroxides (eg, NaOH, K0H, etc.), basic carbonates (eg, sodium salt, potassium) Salts such as alkali metal or calcium salts, carbonates with alkaline earth metal salts such as magnesium salts, etc.), basic bicarbonates (eg, sodium salts, potassium salts, etc.) Bicarbonate with rukari metal salt), organic base (eg, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4 3. 0] non-1-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabic mouth [5. 4.0] — 7_decene Among them, metal hydride compounds (eg, sodium hydride, potassium hydride, etc.), alcoholates (eg, NaOMe, NaOEt, t-BuONa, t-BuOK, etc.) are preferably used, and especially alcoholates ( For example, NaOMe, NaOEt, t-BuONa, t-BuOK, etc.) are preferably used. The amount of the base used in the reaction described in the above (9) is about 0.1 to 100 equivalents, preferably 1 to 5 equivalents.

Examples of the reaction solvent include a solvent containing a carbonic acid diester. It may be used alone, or an appropriate mixed solvent may be used. Solvents used for mixing include halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), aliphatic hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons (eg, benzene , Toluene, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, isopropyl ether (IPE), etc.), polar solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), formic acid Esters (eg, alkyl formate), oxalic acid diesters (eg, alkyl oxalate), protic solvents (eg, methanol, ethanol, propanol, isopropanol, n-butanol, 2-medium) Alcohols such as turkisena), etc. are used. Anionic solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.) are preferably used. Examples of the carbonic acid diester include compounds represented by Z—O (CO) Z ′, wherein Z and Z ′ each represent a hydrocarbon group which may be substituted. What is liquid at the reaction temperature for carrying out this reaction is desirable. Z and Z ′ are preferably the same, and as the diester carbonate, dialkyl carbonates such as dimethyl carbonate and getyl carbonate are preferably used. The reaction temperature is usually about −20 to 200 ° C., preferably about 10 to 100 ° C., and the reaction time is usually about 0.1 to 100 hours, preferably about 0.5 to 50 hours.

The reaction described in the above (13) is performed, for example, in the following steps.

Expression

[Wherein each symbol is as defined above] or a salt thereof. The reaction described in (13) above is performed, for example, under the same reaction conditions as the reaction described in (9) above.

The reaction described in (14) above is performed, for example, under the following reaction conditions.

Expression

Wherein each symbol is as defined above, or a salt thereof;

Wherein each symbol is as defined above, or a salt thereof, and then subjected to a ring closure reaction in the presence of a carbonic acid diester to obtain a compound represented by the formula

[Wherein each symbol is as defined above] or a salt thereof.

In this reaction, the two steps of the N-alkylation reaction and the dehydration condensation can be carried out continuously in one pot, and the intermediate may or may not be isolated. It is preferred to do so. This reaction is performed under different reaction conditions depending on the difference of Y.

When Y is a halogen atom, a group represented by the formula _0 (SO _m ) R, wherein each symbol is as defined above (preferably a halogen atom), an N-alkyl group is obtained under the following conditions: After the conversion, the ring is closed under the reaction conditions described in the above (1). The N-alkylation reaction is preferably performed in the presence of a base. Examples of such a base include metal hydrides (eg, hydrides of alkali metals such as sodium hydride and potassium hydride, etc.); hydrogen (eg, n- butyl lithium etc. (: such as a compound having a chemical bond Bok ₄ alkyl and alkali metal are directly bonded), alcoholates (e.g., NaOMe, NAOE and t-BuONa, t-BuOK, etc. A compound in which the hydrogen of the hydroxyl group of the C ぃ₄ alcohol has been replaced with an alkali metal), a hydroxide of the alkali metal (eg, NaOH, K0H, etc.), a basic carbonate (eg, sodium salt, Alkali metal salts such as potassium salts or calcium salts, carbonates with alkaline earth metal salts such as magnesium salts, etc.), basic bicarbonates (eg, alkali metal salts such as sodium salts, potassium salts, etc.) Bicarbonate, etc.), organic bases (eg, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidin, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] ] Non-1-5-ene, 1,4-diazabicyclo [2.2.2] Octane, 1,8-diazabicyclo [5. 4. 0] — 7-indene, etc.), among which basic carbonates (eg, alkali metal salts such as sodium salt and potassium salt or alkaline earth metal salts such as calcium salt and magnesium salt) Salts, preferably potassium carbonate) or 1,8-diazabicyclo [5.4.0] _7-ndecene and alcoholates (eg, NaOMe, NaOEt, t-BuONa, t-BuOK) And the like are preferably used. The amount of the base used in the reaction described in the above (14) is about 0.1 to 100 equivalents, preferably 1 to 5 equivalents.

Reaction solvents include halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), aliphatic hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.) ), Ethers (eg, tetrahydrofuran (THF), getyl ether, isopropyl ether (IPE), etc.), polar solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), diester carbonate (eg, , Dimethyl carbonate, dicarbonate such as getyl carbonate, etc., _{1 to} ₄ alkyl esters, etc., formate esters (eg, alkyl formate esters), diester oxalates (eg, dialkyl oxalate, etc.), protic solvents (eg, Methanol, ethanol, propanol, isopropanol, n-butanol, 2 Alcohols such as methoxyethanol), and the like, and an appropriate mixed solvent may be used for the reaction. Among them, a mixed solvent of a diester carbonate and a polar solvent (preferably, DMF or the like) is preferably used. .

The reaction temperature is usually about -20 to 200 ° (:, preferably about 10 to 100), and the reaction time is usually about 0.1 to 100 hours, preferably about 0.5 to 50 hours.

After Y is in the case of forming the carbonylation Le group together with R ⁵ and the adjacent carbon atoms, subjected to reductive N- alkylation the following conditions, row by ring closure reaction conditions of the above (1), wherein Will be (In the product after reductive N-alkylation, R ⁵ represents a hydrogen atom.)

The reductive N-alkylation reaction (reductive amination reaction) is preferably performed in the presence of a reductive amination reagent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc. It is desirable to change the reaction conditions depending on the reagent. For example, when sodium triacetoxyborohydride is used, an inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, getyl ether, dioxane, acetonitrile, dimethylformamide (DMF), or a mixture thereof is used. It can be performed in a solvent. Use this reagent in an amount of about 1 to 2 mol equivalent to 1 mol of raw material. The reaction is usually carried out at a temperature in the range of about 0 ° C to about 80 ° C for about 1 hour to about 40 hours. This reaction is preferably performed in an atmosphere of an inert gas (eg, nitrogen, argon, etc.).

The reaction described in the above (15) is performed, for example, in the following steps.

Expression

Wherein each symbol is as defined above, or a salt thereof, and

[Wherein each symbol is as defined above] or a salt thereof. The reaction described in the above (15) is performed, for example, under the same reaction conditions as the reaction described in the above (14).

The reaction described in (16) above is performed, for example, under the following reaction conditions.

Expression

Wherein each symbol is as defined above, or a salt thereof is subjected to a deprotection reaction;

[Wherein each symbol is as defined above] or a salt thereof.

This reaction is preferably performed in the presence of an acid. Examples of such an acid include inorganic acids (eg, hydrochloric acid, perchloric acid, sulfuric acid, etc.), organic acids (eg, methanesulfonic acid, trifluoroacetic acid, etc.). Among them, perchloric acid, sulfuric acid and the like are preferably used. The amount of the acid used in the reaction described in the above (16) is about 0.1 to 200 equivalents, preferably 5 to 50 equivalents.

Reaction solvents include aliphatic hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), polar solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0 ), Etc.), organic acids (eg, acetic acid, etc.), water, etc., and an appropriate mixed solvent may be used for the reaction. Among them, solvents such as n-hexane, benzene, toluene, acetic acid, etc. A mixed solvent of water and water is preferably used.

The reaction temperature is usually about 0-200 ° C, preferably about 30-150 ° C, and the reaction time is usually about 0.1-100 hours, preferably about 0.5-50 hours.

The reaction described in the above (20) is performed, for example, in the following steps.

formula

[Wherein each symbol is as defined above] or a salt thereof is subjected to a deprotection reaction;

[Wherein each symbol is as defined above] or a salt thereof. The reaction described in the above (20) is carried out, for example, under the same reaction conditions as the reaction described in the above (16).

The reaction described in (21) above is performed, for example, under the following reaction conditions.

formula

Wherein each symbol is as defined above, or a salt thereof, is subjected to an acid hydrolysis reaction,

In which each symbol is as defined above] or a salt thereof. Above (21) reactions described, for example, the aforementioned (16) can be carried out under the same reaction conditions and reactions described, by acid hydrolysis substituents R ^{1 a,} react with the nitrogen atoms to be converted to a carboxyl group By acid hydrolysis of the above substituted sulfonyl group, the reaction for deprotection can proceed simultaneously.

The reaction described in the above (25) is performed, for example, in the following steps.

formula

[Wherein each symbol is as defined above] or a salt thereof. The reaction described in the above (25) is performed, for example, under the same reaction conditions as the reaction described in the above (21).

The reaction described in (26) above is performed, for example, under the following reaction conditions.

formula

Wherein each symbol is as defined above, or a salt thereof, for an acylation reaction.

[Wherein each symbol is as defined above] or a salt thereof. This acylation reaction is carried out according to a usual acid-amide forming reaction. The acid-amide formation reaction may be performed according to any known method such as a peptide synthesis reaction. For example, M. Bodansky and MA Ondetti, Peptide Synthesis (P-marked tide Synthesis), Interscience, New York, 1966 ; The Proteins, by FM Finn and K. Hoftnann, Volume 2, edited by H. Nenrath, R. Shi Hill, Academic Press Inc., New York, 1976; Nobuo Izumiya, et al., "Peptide Synthesis" Fundamentals and experiments ", Maruzen Co., Ltd., 1985, etc., for example, azide method, chloride method, acid anhydride method, mixed acid anhydride method, DCC method, active ester method, Woodward reagent K. Method, carbonyldiimidazole method, redox method, DCCZHONB method, etc., WSC method, getyl cyanophosphate (DEPC) And the like. This reaction can be performed in a solvent. Examples of the solvent include anhydrous or water-containing N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, chloroform, dichloromethane, tetrahydrofuran (THF), dioxane, acetonitrile, or an appropriate mixture thereof. can give.

In this reaction, the acylating agent is usually used in an amount of about 1 to 2 mol per 1 mol of the starting compound. The reaction temperature is generally about -20 ° C to about 80, preferably about -10 ° C to about 40 ° C. The reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 40 hours. The reaction described in the above (30) is performed, for example, in the following steps.

Expression

Wherein each symbol is as defined above, or a salt thereof. The reaction described in the above (30) is performed, for example, under the same reaction conditions as the reaction described in the above (26).

The reaction described in (31) above is performed, for example, under the following reaction conditions.

Expression

Wherein each symbol is as defined above] or a salt thereof and a compound represented by the formula

Wherein each symbol is as defined above, or a salt thereof,

[Wherein each symbol is as defined above] or a salt thereof. This reaction may be carried out in the presence of a catalyst. Examples of such a catalyst include a catalyst containing a transition metal such as nickel and palladium, and more specifically, tetrakistriphenylphenylphosphine palladium, palladium acetate / Triphenyl phosphine Examples of the palladium catalyst include nickel catalysts such as NiCl ₂ (dppp) [dppp = 1,3-bis (diphenylphosphino) propane] and Ni (PPh ₃ ) ₄ [Ph = phenyl]. Triphenylphosphine palladium, palladium acetate / triphenylphosphine and the like are used.

The amount of the catalyst used in this reaction is about 0.01 to 100 mol, preferably 0.05 to 20 mol%.

This reaction is preferably performed in the presence of a base. Examples of such a base include basic carbonates (eg, alkali metal salts such as sodium salt and potassium salt or alkaline earth salts such as calcium salt and magnesium salt). Carbonates with similar metal salts), basic hydrogen carbonates (eg, hydrogen carbonate with alkali metal salts such as sodium and potassium salts), organic bases (eg, trimethylamine, triethylamine, diisopropylethylamine, Pyridine, Ν, Ν-dimethylaminopyridine, picoline, Ν-methylpyrrolidine, Ν-methylmorpholine, 1,5-diazabicyclo [4.3.0] non-1-ene, 1,4-diazabicyclo [2. 2. 2] octane, 1,8-diazavicic mouth [5.4.0] — 7-indene, etc., among others, but basic carbonates (eg, sodium Salts, alkali metal salts or calcium salts such as potassium salts, and carbonates of the alkaline earth metal salts such as magnesium salts, preferably such as potassium carbonate © beam) is preferably used. The amount of the base used in this reaction is about 0.1-100 equivalents, preferably) -20 equivalents.

Reaction solvents include halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), aliphatic hydrocarbons (eg, η-hexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.) ), Ethers (eg, tetrahydrofuran (THF), getyl ether, isopropyl ether (IPE), etc.), polar solvents (eg, dimethylformamide (DMF), dimethyl sulfoxide (DMS0), etc.), protic solvents (eg, For example, alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, and 2-methoxyethanol), water, and the like are used. The reaction may be carried out using an appropriate mixed solvent. Aromatic hydrocarbons such as toluene and protonic solvents such as methanol and ethanol A mixed solvent medium and is preferably used. The reaction temperature is usually about −20 to 200 ° C., preferably about 0 to 100 t :, and the reaction time is usually about 0.1 to 100 hours, preferably about 0.5 to 50 hours.

Usually, the benzene compound is used in an amount of about 0.1 to 100 equivalents, and preferably about 1 to 5 equivalents, based on the 2,3-dihydrobenzazepine compound.

Formula obtained by the reaction described in (1) above

[Wherein each symbol is as defined above] or a salt thereof,

[Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, or a substituted An optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group; R ² and R ³ , R ⁴ and R ⁵ , R ² and R ⁴ or R ⁶ and R ⁷ may combine to form a ring. However, the ring in which R ⁵ and R ⁷ are bonded to each other is not an unsubstituted benzene ring. Or a salt thereof; and a compound of the formula

In the formula, ring represents a benzene ring having a substituent, and R ² , R ³ , R ⁴ and R ⁵ are each a hydrogen atom, a halogen atom, an amino group which may be substituted, and a hydroxyl group which may be substituted. Represents a thiol group which may be substituted, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted; R ² and R ³ , R ⁴ and R ^5, or R ² and R ⁴ may be combined to form a ring] or a salt thereof is a novel compound, and is prepared by a method known per se. Condensation with an aniline derivative to synthesize the anilide derivative described in WO973210, WO99 / 3248, Japanese Patent Application No. 111-175035, etc. Useful as an intermediate for

In addition, the formula obtained by the reaction described in (31) above

[Wherein each symbol is as defined above], a salt thereof or a reactive derivative thereof is represented by the formula

[Wherein, R ²³ and R ²⁴ each represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group] or a compound thereof or a salt thereof.

(Such as a known condensation reaction described in W099Z32100, WO99 / 32468, etc.) to obtain the formula

The compound represented by [each symbol is as defined above] or a salt thereof can be produced. In the above formula, the “optionally substituted heterocyclic group” represented by R ²³ and R ²⁴ includes, for example, “substituted substituted” represented by R ² , R \ R ⁴ , R ⁵ , R ⁶ and R ⁷ And the like. "

In the above formula, R ²³ is preferably a chain hydrocarbon group which may be substituted (eg, alkyl or alkenyl which may be substituted respectively), and a lower alkyl group which may be substituted. Further preferred is a methyl group.

The R ^24, optionally substituted alicyclic hydrocarbon group (e.g., each optionally substituted cycloalkyl, such as cycloalkenyl; preferably, optionally substituted lower C ₃ _ ₈ cycloalkyl Alkyl group; more preferably cyclohexyl) or an optionally substituted alicyclic heterocyclic group (preferably an optionally substituted saturated alicyclic heterocyclic group (preferably a 6-membered ring group) More preferably, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrothiopyranyl or optionally substituted piperidyl; particularly preferably, tetrahydropyranil). BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in more detail with reference to the following Reference Examples and Examples. However, these are only examples and do not limit the present invention in any way. Example

Reference example 1

Synthesis of 2-hydroxymethyl-N-tosylaniline

After 2-hydroxymethylaniline (5. Og) was dissolved in THF (25 ml), pyridine (6.57 ml) was added. At -10 ° C or lower, P-toluenesulfonyl chloride (7.74g)

A THF (25 ml) solution was added dropwise, and the mixture was heated to room temperature and stirred for 2 hours. Water (25 ml) was added, and the mixture was extracted with ethyl acetate (25 ml). The organic layer was washed with 2N hydrochloric acid (20 ml) and saturated saline (20 ml × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated. To the rest

IPE (50 ml) was added after stirring for 0.5 hours at room temperature, and washed _c vacuum dried was filtrated crystals IPE (20 ml) 2-hydroxymethyl - N- Toshiruanirin (10. 7 g, yield 95. . 0 ^ to give the _{'H-NMR (CDC1 3,} (5, 300MHz); 1. 61 (1H, brs), 2. 38 (3H, s), 4. 40 (2H, s), 7. 00 -7.09 (2H, m), 7.20-7.28 (4H, m), 7.43 (1H, d, J-8.0Hz), 7.65 (2H, d, J = 8. (3Hz) Reference example 2

Synthesis of 2-formyl-N-tosylaniline

After dissolving 2-hydroxymethyl-N-tosylaniline (2.0 g) in acetone (30 ml), manganese dioxide (3.6 g) was added and the mixture was stirred at room temperature for 15 hours. The insoluble material was removed by filtration, washed with acetone (10 ml) and concentrated. After IPE (10 ml) was added to the residue and the mixture was stirred at room temperature for 0.5 hour, the crystals were collected by filtration and washed with IPE (5 ml). Drying under reduced pressure gave 2-formyl-N-tosylaniline (1.6 g, yield: 80 · 1%).

_{'H-NMR (CDC1 3,} (5, 300MHz);.. 2. 36 (3H, s), 7. 12-7 26 (3H, m), 7. 47-7 52 (1H, m), 7 58 (1H, d, J = 6.0 Hz), 7.67 (1H, d, J = 9.0 Hz), 7.77 (2H, d, J = 6.0 Hz), 9.82 (1H, s), 10.76 (1H, brs)

Reference example 3

Synthesis of 4-bromo-2-formyl-N-tosylaniline

2-Formyl-N-tosylaniline (1.0 g) and sodium acetate (0.33 g) in 90% aqueous acetic acid The mixture was suspended in the solution, and bromine (0.22 ml) was added, followed by stirring at room temperature for 2 hours. Bromine (0.02 ml) was added once every hour. 0.5N aqueous sodium thiosulfate (10 ml) was added, and the mixture was stirred at room temperature for 0.5 hour. The crystals were collected by filtration and washed with water (10 ml). Drying under reduced pressure gave 4-bromo-2-formyl-N-tosylaniline (1. g, yield 93.0).

_{'H-NMR (CDC1 3,} δ, 300MHz); 2.38 (3H, s); 7.26 (2H, d, J = 9.0Hz), 7.57-7.71 (3H, m), 7.76 (2H, d, J-9.0 Hz), 9.76 (1H, s), 10.65 (1H, s)

Example 1

Synthesis of 7-bromo-1-tosyl-2,3-dihydro-1-benzazepine-4-ethyl carboxylate 4-bromo-2-formyl-N-tosylaniline (1.0 g) and ethyl 4-bromobutyrate (0.61 g) Was dissolved in DMF (3 ml), potassium carbonate (0.58 g) was added, and the mixture was stirred at 70 for 6 hours. After cooling to room temperature, getyl carbonate (20πι1) and 2 (^ sodium ethoxide ethanol solution (1.44g) were added, and the mixture was stirred at room temperature for 3 hours. The organic layer was washed with saturated saline solution (5 ml × 3), 10% aqueous sodium chloride solution (5 ml), concentrated, dissolved in methanol (10 ml), and stirred under ice-cooling for 1 hour. The crystals were collected by filtration, washed with IPE (5 ml), dried under reduced pressure, and ethyl 7-bromo-1-tosyl-2,3-dihydro-1-benzoazepine-4-carboxylate (0.69 g, yield 54.0%) ) Was obtained.

_{'H-NMR (CDC1 3,} δ, 300MHz); 1.29 (. 3Η, t, J = 7 OHz), 2.35 (3H, s),

2.86 (2H, t, J = 5.7Hz), 3.86 (2H, t, J = 5.7Hz), 4.18 (2H, q, J = 7.OHz),

7.13 (2H, d, J = 8.OHz), 7.18 (1H, s), 7.41 (2H, d, J = 8.OHz), 7.44-7.53 (3H, m)

Synthesis of 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylic acid

7-Promototosyl-2,3-dihydro-1-benzazepine-4-ethyl carboxylate

(l. Og) was suspended in acetic acid (4 ml), and concentrated sulfuric acid (2 ml) was gradually added at room temperature. 9 (After heating with TC for 2 hours, water (0.2 ml) was added and the mixture was stirred for 6 hours. After concentration, the residue was ice-cooled and 10% aqueous sodium hydroxide (32 ml) and water (20 ml) were added. The insoluble material was removed by filtration and washed with water (5 ml) .2N hydrochloric acid (3.2 ml) was added to the filtrate, and the precipitated crystals were collected by filtration, washed with water (5 ml) and dried under reduced pressure. Bromo-2,3-dihydro-1-benzoazepine-4-carboxylic acid (0.5 g, yield 85.6¾) was obtained. 'H-NMR (DMSO-d ₆ , δ, 300 MHz); 2.69 (2H, t, J = 4.3 Hz), 3.20 (2H, t, J = 4.3 Hz),

6.67 (1H, d, J-8.7Hz), 6.92 (1H, brs), 7.16 (1H, dd, J = 8.7, 2.0Hz),

7.40 (1H, d, J = 2.0Hz), 7.45 (1H, s)

Example 3

Synthesis of 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylic acid Add formic acid (0.8 ml) to acetic anhydride (1.76 ml), heat to 60 ° C, and heat to the same temperature For 1 hour. After cooling, THF (10 ml) was added, and then a solution of 7-bromo-2,3-dihydro-to-benzobenzopine-4-carboxylic acid (1.0 g) in THF (10 ml) was added dropwise under ice cooling. The mixture was stirred at room temperature for 2 hours. After concentration, water (10 ml) and IN aqueous sodium hydroxide solution (6.0 ml) were added to the obtained residue, and the mixture was stirred at room temperature for 0.5 hour. 2N Hydrochloric acid (3.0 ml) was added, and the precipitated crystals were collected by filtration and washed with water (5 ml). Drying under reduced pressure gave 7-bromo-1-formyl-2,3-dihydro-1-benzoazepine-4-carboxylic acid (1.0 g, yield 94.2%).

'H-NMR (DMSO-d ₆ , δ, 30 bands); 2.73 (2Η, t, J = 5.2 Hz), 3.67 (2H, t, J = 5.2 Hz), 7.33 (1H, d, J-8.4Hz), 7.57 (1H, s), 7.61 (1H, d, J = 8.4Hz), 7.91 (1H, s), 8.48 (1H , s)

Example 4

Synthesis of Triformyl-7- (4-ethoxyphenyl) -2,3-dihydro-1-benzazepine-4-carboxylic acid

Under an argon atmosphere, 7-bromo-formyl-2,3-dihydro-to-benzobazepine-4-carboxylic acid (0.5 g) and 4-ethoxyphenylboronic acid (0.3 g) were dissolved in toluene (5.8 ml) and ethanol. The suspension was suspended in ethanol (2.1 ml), and triphenylphosphine (17.7 mg), palladium acetate (3.8 mg) and an aqueous solution of potassium carbonate (0.7 g) (2.1 ml) were added at room temperature. The mixture was heated to 65 and stirred at the same temperature for 3 hours. After allowing to cool, water (10 ml), THF (15 ml) and 2N hydrochloric acid (4 ml) were added, and ethyl acetate (15 ml) was added to carry out liquid separation. Ethyl acetate (15 ml) was added to the aqueous layer for extraction, and the organic layers were combined and washed with saturated saline (5 ml × 2). After drying over anhydrous magnesium sulfate, the mixture was concentrated. Isopropyl alcohol (IPA) (6 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour, and then stirred under ice cooling for 1 hour. The crystals were collected by filtration and washed with cold IPE (3 ml). The residue was dried under reduced pressure to give 0.5-formyl-7- (4-ethoxyphenyl) -2,3-dihydro-tribenzoazepine-4-carboxylic acid (0.54 g, yield 94.7%). 'H-NMR (DMSO-d _6l δ, 300 MHz); 1.35 (3H, t, J = 6.9 Hz), 2.75 (2H, m), 3.72 (2H, m), 4.08 (2H, t, J = 6.9 Hz ), 7.02 (2H, d, J = 8.6Hz), 7.40 (1H, d, J = 8.2Hz), 7.6-7.7 (3H, m), 7.74 (1H, s), 7.9 (1H, s), 8.53 (1H, s)

Reference example 4

Synthesis of methyl 5-bromo-N-tosylanthranilate

Methyl 5-bromoanthranilate (200 g) was dissolved in pyridine (600 ml), and p-toluenesulfonyl chloride (174 g) was added at room temperature. After stirring for 3 hours, water (600 ml) and ethyl acetate (3 L) were added to the reaction solution, and the mixture was separated. The organic layer was washed with 2N hydrochloric acid (200 ml × 3), 10% aqueous sodium chloride (500 ml × 3), and water (250 ml). IPE (IL) was added to the residue obtained by concentration, and the mixture was stirred at room temperature for 3 hours. The crystals were collected by filtration and washed with cold IPE (500 ml). Drying under reduced pressure gave methyl 5-bromo-N-tosylanthranilate (291 g, yield 87.1%). _{'H-NMR (CDC1 3,} a, 300MHz); 2.37 (3H, s), 3.88 (3H, s), 7.23 (2H, d, J = 8.2Hz),

7.53 (1H, dd, J = 8.9, 2.3Hz), 7.61 (1H, d, J = 8.9Hz), 7.72 (2H, d, J-8.2Hz),

8.03 (1H, d, J = 2.3Hz), 10.50 (1H, s)

Reference example 5

Synthesis of 4-bromo-2-hydroxymethyl-N-tosylaniline

Under an argon atmosphere, methyl 5-bromo-N-tosylanthranilate (0.5 g) was dissolved in toluene (5 ml), and diisobutylaluminum hydride (DIBALH) (4 ml) was added dropwise at room temperature. After stirring at room temperature for 0.5 hour, the mixture was ice-cooled and 5% sulfuric acid (10 ml) was added. Water (5 ml), toluene (5 ml) and ethyl acetate (10 ml) were added, and the mixture was separated. The organic layer was concentrated, and the obtained crystals were purified by silica gel column (n-hexane / ethyl acetate = 3/1) to give 4-bromo-2-hydroxymethyl-N-tosylaniline (0.44 g, yield 91.0). Obtained.

_{'H-NMR (CDC1 3,} δ, 300MHz); 2.39 (3Η, s), 2.47 (1H, s), 4.24 (2H, s),

7.22 (2E d, J = 8.3Hz), 7.25 (1H, s), 7.25-7.31 (2H, m), 7.62 (2H, d, J-8.3Hz) Reference example 6

Synthesis of 4-bromo-2-formyl-N-tosylaniline

4-Bromo-2-hydroxymethyl-N-tosylaniline (1.0 g) was suspended in acetone (5 ml), manganese dioxide (2.84 g) was added, and the mixture was stirred at room temperature for 15 hours. After filtering off the insoluble matter, it was washed with acetone (10 ml). The residue obtained after concentration is concentrated on a silica gel column (n- Hexane) to give 4-bromo-2-formyl-N-tosylaniline (0.55 g, 55.2% yield).

Reference Example 7

_4. Synthesis of ₄ -bromo- ₂ -formyl- _N -tosylaniline Under an argon atmosphere, VITRIDE (registered trademark) (37.5 g) was dissolved in toluene (35 ml) and cooled with ice. A solution of morpholine (12.5 ml) in toluene (25 ml) was added dropwise.

Under an argon atmosphere, methyl 5-bromo-N-tosylanthranilate (5. Og) was dissolved in toluene (50 ml) and cooled to -10. The previously prepared VITRIDE (registered trademark) solution was gradually added dropwise, followed by stirring at the same temperature for 2 hours. After water (50 ml) was gradually added dropwise, sulfuric acid / water = 1/4 (500 ml) was added. After liquid separation, the aqueous layer was extracted with ethyl acetate (100 ml × 2), and the organic layer was washed with water (400 ml × 4). The organic layer was concentrated, and the residue was purified by a silica gel column (toluene). Toluene (6 ml) was added to the obtained crystals, dissolved by heating, allowed to cool, and stirred for 0.5 hours. lPE (6 ml) was added, and the mixture was stirred at room temperature for 0.5 hour and under ice cooling for 1 hour. The crystals were collected by filtration and washed with IPE (5 ml). Drying under reduced pressure gave 4-bromo-2-formyl-N-tosylaniline (2.29 g, yield: 50.0%).

Reference Example 8

Synthesis of 4-bromo-2-formyl-N-tosylaniline

A suspension of 5-bromo-2-fluorobenzaldehyde (1.0 g), P-toluenesulfonamide (1.7 g), and potassium carbonate (1.4 g) in DMS0 (5 ml) was heated at 110-120 ° C for 1 hour. Stirred. Then, 2N hydrochloric acid (7.5 ml) was added, and the mixture was stirred at the same temperature for 1 hour. Cooled to room temperature and stirred for 3 hours. The precipitated crystals were collected by filtration and washed with water (10 ml). The crystals were dried under reduced pressure (40 ° C, 2 hours) to obtain 1.5 g (86% yield) of white crystals of 4-bromo-2-formyl-N-tosylaniline.

_{'H-NMR (CDC 1 3} , δ, 300MHz);. 2. 38 (3Η, s), 7. 26 (. 2H, d, J = 9 0Hz), 7. 57-7 71 (3H, m) , 7.76 (2H, d, J = 9.0 Hz), 9.76 (1H, s), 10.65 (1H, s).

Industrial applicability

According to the present invention, it is possible to produce a 2,3-dihydroazepine derivative in a short step, safely, and by a method suitable for mass synthesis.

Claims

The scope of the claims

1 set

[Wherein, R ′ represents an electron-withdrawing group, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom, a halogen atom, an amino group which may be substituted, An optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ² and R ³ , R ⁴ and R ⁵ , R ² And R ⁴ or R ⁶ and R ⁷ may combine to form a ring, R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ⁹ represents an optionally substituted hydrocarbon A group, a substituted or unsubstituted sacyl group or a substituted sulfonyl group] or a salt thereof in the presence of a diester carbonate.

[Wherein the symbols are as defined above] or a method for producing a salt thereof.

2. The method according to claim 1, wherein R ¹ is an esterified carboxyl group.

3. The process of Claim 1 which is wherein R ⁸ is a hydrogen atom.

4. The process according to claim 1, wherein R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms.

5. The production method according to claim 1, wherein R ⁹ is a P-toluenesulfonyl group or an alkyl group.

6 Expression

[Wherein, R ¹ represents an electron-withdrawing group, and R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, Represents an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, wherein R ² and R ³ , R ⁴ and R ^5, or R ² and R ⁴ are R ⁸ may represent a hydrogen atom or an optionally substituted hydrocarbon group, and R ⁹ may represent an optionally substituted hydrocarbon group or an optionally substituted acyl group. A ring or a substituted sulfonyl group, and ring A represents a benzene ring which may have a substituent] or a salt thereof in the presence of a carbonic acid diester. R, J

7 Expression

[Wherein, Y represents a leaving group, R ′ represents an electron withdrawing group, and R ² , R \ R ⁴ and R ^{5 each} represent a hydrogen atom, a halogen atom, an optionally substituted amino group, Represents an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ² and R ³ , and R ⁵ or R ² and R ⁴ may combine to form a ring] or a salt thereof, and then subjected to a ring closure reaction in the presence of a carbonic acid diester,

8. Expression

[Wherein, Y represents a leaving group, R ′ represents an electron withdrawing group, and R ² , R ³ , R ⁴ and R ⁵ represent a hydrogen atom, a halogen atom, and an optionally substituted amino group, respectively. An optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ² and R ³ , R ⁴ and R ⁵ or R ² and R ⁴ May be combined with each other to form a ring], or a salt thereof, and then subjected to a ring closing reaction in the presence of a carbonic acid diester,

9 Expression

[Wherein, R ¹ represents an electron-withdrawing group, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, or a substituted An optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ² and R ³ , R ⁴ and R ⁵ , R ² And R ⁴ or R ^s and R ⁷ may combine to form a ring, R ^{1 ()} represents an optionally substituted hydrocarbon group, and R ⁹ represents an optionally substituted hydrocarbon Or a substituted or unsubstituted sacyl group or a substituted sulfonyl group] or a salt thereof in the presence of a carbonic diester.

10. The method according to claim 9, wherein 10.Rt is an esterified carboxyl group.

11. The production method according to claim 9, wherein R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms.

12. The method according to claim 9, wherein R ⁹ is a p-toluenesulfonyl group or an alkyl group.

1 3.

[Wherein, R ¹ represents an electron-withdrawing group, and R ² , R ³ , and R ⁵ each represent a hydrogen atom, an octalogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, Represents an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and is bonded to R ² and R ³ , R ⁴ and R ^5, or R ² and R may form a ring Te, R ^{l ()} represents a hydrocarbon group which may be substituted, R ⁹ is optionally substituted hydrocarbon group, an optionally substituted Ashiru group or a substituted sulfonyl Wherein the ring A represents a benzene ring which may have a substituent, or a salt thereof is subjected to a ring closing reaction in the presence of a carbonic acid diester.

1 4.

[Wherein, R ⁶ and R ⁷ are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, and an optionally substituted A hydrocarbon group or an optionally substituted heterocyclic group, R ⁶ and R ⁷ may combine to form a ring, and R ^{1 ()} represents an optionally substituted hydrocarbon group; R ⁹ represents an optionally substituted hydrocarbon group, an optionally substituted acyl group or a substituted sulfonyl group] or a salt thereof;

In the formula, Y represents a leaving group, R ′ represents an electron withdrawing group, and R ² , R ³ , R ⁴ and R ⁵ represent a hydrogen atom, a halogen atom, an amino group which may be substituted, Even if it is replaced A good hydroxyl group, a thiol group which may be substituted, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R ² and R ³ , R ⁴ and R ^5, or R ² and R ⁴ may combine with each other to form a ring], or a salt thereof, and then subjected to a ring closure reaction in the presence of a carbonic acid diester,

1 5 Expression

[Wherein, R ^IG represents an optionally substituted hydrocarbon group, R ⁹ represents an optionally substituted hydrocarbon group, an optionally substituted acyl group or a substituted sulfonyl group, Wherein ring A represents a benzene ring which may have a substituent, or a salt thereof;

In the formula, Y represents a leaving group, I represents an electron withdrawing group, and R ² , R ³ , R ⁴ and R ⁵ are each a hydrogen atom, a halogen atom, an amino group which may be substituted, Represents an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ² and R ³ , R ⁴ and R ⁵ or R ² and R ⁴ may combine to form a ring] or a salt thereof, and then subjected to a ring closure reaction in the presence of a carbonic acid diester,

1 6 Expression

[In the formula, R ¹ represents an electron-withdrawing group, and R ² , R ³ R ⁴ , R ⁵ , R ⁶ and R ⁷ each represent a hydrogen atom, a halogen atom, an amino group which may be substituted, Good hydroxyl groups, Represents an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ² and R ³ , R ⁴ and R ⁵ , R ² and R ⁴ or R ⁶ and R ⁷ may combine to form a ring, R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group, and ring C represents an optionally substituted benzene ring] Wherein the compound represented by the formula or a salt thereof is subjected to a deprotection reaction.

^{^{1 7. R 2, R 3}} , R 4 and R ⁵ are process according to claim 1 6, wherein a hydrogen atom.

1 8. R ⁸ is A process according to claim 1 6, wherein a hydrogen atom.

19. The process according to claim 16, wherein ring C is a P-tolyl group.

2 0. Expression

[Wherein, R ¹ represents an electron-withdrawing group, and R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, Represents an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, wherein R ² and R ³ , R ⁴ and R ^5, or R ² and R ⁴ are R ⁸ may represent a hydrogen atom or a hydrocarbon group which may be substituted, and ring A and ring C each represent a benzene ring which may have a substituent.] Wherein the compound represented by the formula or a salt thereof is subjected to a deprotection reaction.

2 1.

[Wherein, R ^la is an esterified carboxyl group, an amidated carboxyl group Or a cyano group, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, Represents an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ² and R ³ , R ⁴ and R ⁵ , R ² and R ⁴ or R ⁶ and R ⁷ may combine to form a ring, R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group, and ring C represents an optionally substituted benzene ring] Wherein the compound represented by the formula or a salt thereof is subjected to an acid hydrolysis reaction.

^{^{2 2. R 2, R 3}} , R 4 and R ⁵ are process according to claim 2 1, wherein a hydrogen atom.

2 3. R ⁸ is A process according to claim 2 1, wherein a hydrogen atom.

24. The production method according to claim 21, wherein ring C is a P-tolyl group.

2 5 Expression

Wherein, R ^'a represents esterified force Rupokishiru group, amidated carboxyl group or Shiano ^{^{group, R 2, R 3, R}} 4 and R ⁵ are each a hydrogen atom, a halogen atom, optionally substituted an amino group which may be a hydroxyl group which may be substituted, substituted optionally Moyoi thiol group, a optionally substituted hydrocarbon group or optionally substituted have good heterocyclic group, and R ² R ³ , R ⁴ and R ⁵ or R ² and R ⁴ may combine to form a ring,

R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted, and Ring A and Ring C each represent a benzene ring which may have a substituent.] Formula, characterized in that it is subjected to a reaction

Wherein each symbol is as defined above, or a salt thereof.

2 6.

In the formula, R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted, and R ² , R ³ , R ⁴ ,

R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom, a halogen atom, an amino group which may be substituted, a hydroxyl group which may be substituted, a thiol group which may be substituted, and which may be substituted Represents a hydrocarbon group or a heterocyclic group which may be substituted, R ² and R ³ ,

R ⁴ and R ⁵ , R ² and R ⁴ or R ⁵ and R ⁷ may combine to form a ring] or a salt thereof, for the acylation reaction.

[Wherein, R ¹¹ represents a hydrogen atom or a hydrocarbon group which may be substituted, and other symbols have the same meanings as described above] or a salt thereof.

^{^{2 7. R 2, R 3}} , R 4 and R ⁵ are process according to claim 2 6, wherein a hydrogen atom.

2 8. R ⁸ is A process according to claim 2 6, wherein a hydrogen atom.

2 9. R ^{1 1} is process according to claim 2 6, wherein a hydrogen atom.

3 0. Expression

[Wherein, R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted, and R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom, a halogen atom, an amino group which may be substituted, Represents an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ² and R ³ , R ⁴ and R ⁵ Or R ² and R ⁴ may combine to form a ring, and ring A represents a benzene ring which may have a substituent.] Or a salt thereof is subjected to an acylation reaction Wherein the expression

[Wherein, R ′ ¹ represents a hydrogen atom or a hydrocarbon group which may be substituted, and other symbols have the same meanings as described above] or a salt thereof.

3 1.

Wherein R ² , R ³ , R ⁴ and R ⁵ are each a hydrogen atom, a halogen atom, a substituted or unsubstituted hydroxyl group, a substituted or unsubstituted hydroxyl group, a substituted or unsubstituted thiol group, Represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, wherein R ² and R ³ , R ⁴ and R ^5, or R ² and R ⁴ may be bonded to form a ring; R ^9a represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group or a substituted sulfonyl group, and R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group. X represents a halogen atom] and a salt thereof, and a compound represented by the formula

[Wherein ring B represents a benzene ring which may have a substituent, M is - MgX ', -B (0H) 2 -. B (0R l8) shows a ₂ or a SnR ^18, X' Represents a halogen atom, and R ' ⁸ represents a lower alkyl group], or a salt thereof.

^{^{3 2. R 2, R 3}} , R 4 and R ⁵ are process according to claim 3 1, wherein a hydrogen atom.

3 3. R ⁸ is A process according to claim 3 1, wherein a hydrogen atom.

34. The method according to claim 31, wherein ^R9a is a P-toluenesulfonyl group or an alkyl group.

35. The production method according to claim 31, wherein R ^9a is a formyl group.

3 6 Expression

[Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, or a substituted An optionally substituted thiol group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group; R ² and R ³ , R ⁴ and R ⁵ , R ² and R ⁴ or R ⁶ and R ⁷ may combine to form a ring. However, the ring in which R ⁶ and R ⁷ are bonded to each other is not an unsubstituted benzene ring. Or a salt thereof.

^{^{3 7. R 2, R 3}} , compound of claim 3 6, wherein R ⁴ and R ⁵ are hydrogen atoms.

3 8. 3. 6 compound according R ⁸ is a hydrogen atom.

3 9 Expression

[Wherein, ring A ^a represents a benzene ring having ^a substituent, and R ² , R ³ , R ⁴ and R ⁵ are each a hydrogen atom, a halogen atom, an amino group which may be substituted, A good hydroxyl group, a thiol group which may be substituted, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and R ⁸ is a hydrogen atom or a hydrocarbon group which may be substituted And R ² and R ³ , R ⁴ and R ⁵ or R ² and R ² may be combined to form a ring] or a salt thereof.

^{^{4 0. R 2, R 3}} , A compound according to claim 3 9 wherein R ⁴ and R ⁵ are hydrogen atoms.

4 1. 3. 9 A compound according R ⁸ is a hydrogen atom.

4 2. Ring A ^a is a formula

30. The compound according to claim 39, wherein the ring is a benzene ring represented by the formula: wherein ring B represents a benzene ring which may have a substituent.