WO2000021916A1 - Process for the preparation of amine derivatives - Google Patents

Abstract

A process for safely preparing methylamine derivatives by reacting an amine with trimethyl phosphite and an oxidizing agent such as N-halogenoamide; and novel {dimethyl}{N-[3-(4-methylphenyl)-8,9-dihydro-7H-benzocycloheptenecarbonyl]-4-aminobenzyl}{4-tetrahydropyranyl}ammonium compounds.

Description

 Specification

Method for producing amine derivatives

, '

Technical field

 The present invention relates to a method for producing an amine derivative. More specifically, the present invention provides (1) a method for producing a methylamine derivative; (2) MCP-1 (monocyte chemoattractant protein-1: monocyte chemoattractant protein-1) receptor antagonism, CCR5 antagonism and the like. Tetrahydrovirane-4-ylamine derivative, which is an intermediate useful for producing an anilide derivative having the same, and a method for producing the same; and (3) producing an anilide derivative having an MCP-1 receptor antagonism, a CCR5 antagonism, etc. Benzocyclo, a useful intermediate for

 'Derivatives and their preparation.

Background art

 (1) Compounds having a methyl group at the amine moiety are very important as pharmaceuticals, pesticides, chemicals and intermediates. Conventionally, the methylation reaction of amines is generally performed using methyl halide or dimethyl sulfate.

 In particular, quaternary ammonium salts are important because of their water solubility. In the synthesis of quaternary methyl ammonium salt, usually, a tertiary amine is used as a raw material, a quaternary methyl ammonium salt is synthesized with the above reagents, and then an anion species is subjected to a normal ion exchange operation, that is, an ion exchange resin or the like. By converting them to various salts.

 However, these reagents are highly volatile and their harms have been pointed out. In addition, it is difficult to obtain high-purity anion species of quaternary ammonium salts by ordinary ion exchange operations.

 (2) The tetrahydropyran-4-ylamine derivative was synthesized by treating tetrahydro-4H-pyran-4-one and an amine with sodium triacetoxyborohydride in dichloromethane. Japanese Patent Application No. 9-135 1480 (W09 9/32 100), Japanese Patent Application No. 9-351481 (WO 99/32468), Japanese Patent Application No. 10-2 18875, etc.

However, this method uses expensive reagents and highly toxic solvents, Not suitable for mass production.

 (3) On the other hand, a benzocycloheptene derivative having a tolyl group at the 3-position is synthesized by coupling a 3-halogenobenzocycloheptene derivative and a tolyl derivative.

, '■

A method has been reported (Japanese Patent Application No. 9-351480) (WO99 / 3210), a Japanese Patent Application No. 9-351480 (WO 9 9/3 2 4 6 8), Japanese Patent Application No. 10-2 1 8 8 7 5, Japanese Patent Application 10 0-2 3 4 3 8 8, etc.) Power This method is expensive It used many reagents and the operation was complicated.

Disclosure of the invention

 (1) Under the circumstances described above, a safe method for producing a methylamine derivative and a method for producing a high-purity quaternary methylammonium salt are desired.

 As a result of various studies, the present inventors have found a safe method for producing a methylamine derivative by reacting an amine with trimethyl phosphite and an oxidizing agent. The tertiary amines are reacted with trimethyl phosphite and N-halogenamide (or imide) to produce the corresponding quaternary methylammonium weak acid salt, and then contacted with a strong acid to form the corresponding anionic species. The present inventors have found a production method for obtaining high-purity quaternary methylammonium salt by performing ion exchange. As a result of further research, the present invention has been completed.

 (2) In view of the above situation, it is desired to establish an inexpensive and simple industrial method for producing tetrahydropyran-4-ylamine derivatives.

 As a result of various studies, the present inventors have found that an inexpensive and simple method for producing a tetrahydropyran-4-ylamine derivative can be obtained by reacting tetrahydrovirane-4-one with an amine under catalytic reduction conditions in the presence of a catalyst. As a result of further research, the present invention was completed.

 (3) On the other hand, in view of the above situation, there is a demand for an inexpensive and simple method for producing benzocycloheptene derivatives more suitable for mass synthesis.

As a result of various studies, the present inventors have found a method for producing a benzocycloheptene derivative having a tolyl group at the 3-position inexpensively and easily by using a biphenyl derivative as a starting material. The present invention has been completed. That is, the present invention

 (1) A method for producing a methylamine derivative, comprising reacting an amine with a trimethyl phosphite derivative and an oxidizing agent;

 (2) A method for producing a quaternary methyl ammonium salt, which comprises reacting a tertiary amine with a trimethyl phosphite derivative and an oxidizing agent;

 (3) The production method according to (1) or (2), wherein the oxidizing agent is N-halogenoamide;

(4) The method according to (1) or (2), wherein the oxidizing agent is N-halogenosuccinimide;

 (5) A method for producing a quaternary methylammonium salt, which comprises reacting a tertiary amine with a trimethyl phosphite derivative and N-octalogenamide, and contacting the acid with an acid (preferably, a) Reacting tertiary amines with trimethyl phosphite derivative and N-halogenamide to produce the corresponding quaternary methylammonium weak acid salt; b) contacting the resulting quaternary methylammonium weak acid salt with a strong acid A method for producing a quaternary methylammonium salt, which comprises performing ion exchange on the corresponding anion species);

(6) The process according to (5), wherein the N-halogenoamide is N-octalogenosuccinimide;

 Equation (7)

Wherein R represents an alkyl group which may be substituted, R ³ represents a hydrocarbon group which may be substituted, and ring A may further have a substituent other than the substituent R A compound represented by the formula: or a salt thereof, trimethyl phosphite and N-halogenosuccinimide, and contacting with an acid.

 [In the formula, W— represents a deprotonated acid, and the other symbols have the same meanings as described above. ] A method for producing a quaternary ammonium salt represented by the formula:

(8) The production method according to the above (7), wherein R ³ is a methyl group;

 Equation (9)

Reacting a compound represented by the formula or a salt thereof with trimethyl phosphite and N-halogenosuccinimide, and contacting with an acid.

 [Wherein, w- represents a deprotonated form of an acid. A method for producing a quaternary ammonium salt represented by the formula:

 Equation (10)

 [Wherein, Ms represents a mesyl group]

 (1 1)

And a compound represented by the formula

R ^J R ² NH

[Wherein, R ′ and R ² are the same or different and are each a hydrogen atom or an optionally substituted carbon atom. Shows a hydrogen group. Wherein the compound or salt thereof is reacted under catalytic reduction conditions.

 Two

 [Wherein each symbol has the same meaning as described above. A method for producing a compound represented by the formula

(12) The production method according to the above (11), wherein R ¹ and R ² are the same or different and each is a hydrogen atom or a methyl group;

 Equation (13)

 [In the formula, Me represents a methyl group. ] Or a salt thereof

 Equation (14)

[Wherein, R ³ represents an optionally substituted hydrocarbon group. ] Or a salt thereof represented by the formula

[Wherein, X represents a leaving group. ]

Reacting a compound represented by the formula:

 [Each symbol in the formula is as defined above. The method for producing a compound represented by the formula

(15) The production method according to the above (14), wherein R ³ is a methyl group;

 (16) The production method according to the above (15), wherein X is a halogen atom;

[Wherein, R ³ represents an optionally substituted hydrocarbon group. Wherein the compound or a salt thereof is reduced with hydrazine or a hydrate thereof in the presence of a catalyst.

[Each symbol in the formula is as defined above. The method for producing a compound represented by the formula

(18) The production method according to the above (17), wherein R ³ is a methyl group;

 (19) Formula obtained by the production method according to the above (17)

 Three

[式中、 R³は置換されていてもよい炭化水素基を示す。 ]で表される化合物又はそ の塩と式

[Wherein, R ³ represents an optionally substituted hydrocarbon group. ] Or a salt thereof represented by the formula

 [Wherein R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. Which is characterized by reacting

[Wherein each symbol has the same meaning as described above. (20) The method according to (19), wherein R ³ is a methyl group;

 Equation (2 1)

[Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. A formula characterized by being subjected to a reduction reaction

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

Equation (2 2)

[Wherein R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. formula

 Wherein X and H each represent a halogen atom, and Ph represents a phenyl group.

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

Equation (2 3)

〔式中、 Rは置換されていてもよいアルキル基を示し、 環 Aは置換基 R以外の置 換基をさらに有していてもよいベンゼン環を示す〕 で表される化合物またはその 塩； 、-

[Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof; ,-

Equation (2 4)

 [Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. A formula characterized by being subjected to a reduction reaction

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

Equation (25)

 Wherein R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R.

Equation (26) C00H

[Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. Wherein the compound is subjected to a ring closure reaction.

 (Wherein each symbol is as defined above) or a method for producing a salt thereof (27)

 [Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. Reacting with a carbenium ion or an equivalent thereof,

Wherein Y represents O or S, and R ^1a and R ^2a are each independently substituted A good hydrocarbon group, and the other symbols have the same meanings as described above.

 (28)

[Wherein, R represents an alkyl group which may be substituted, ring A represents a benzene ring which may further have a substituent other than the substituent R, Y represents 〇 or S, and R represents ^{1 a} and R ^{2 a} expressed by reduction compound in illustrating the optionally substituted hydrocarbon group, respectively] or a salt thereof;

 (29)

[Wherein, R represents an alkyl group which may be substituted, ring A represents a benzene ring which may further have a substituent other than the substituent R, Y represents 〇 or S, and R represents Wherein ^{1 a} and R ^2a each represent an optionally substituted hydrocarbon group.) The compound represented by the formula: or a salt thereof is reacted with a reducing agent and then reacted with an acid.

〔式中、各記号は前記と同意義を示す〕で表される化合物またはその塩の製造法； ( 3 0 ) 式

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

 [Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof;

 Equation (3 1)

 [Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. A formula characterized by being subjected to a reduction reaction

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

(32)

 [Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof;

 Equation (33)

 [Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. Reacting with Vilsmeier reagent, formula

 (Wherein each symbol is as defined above) or a method for producing a salt thereof (34)

[Wherein, R represents an alkyl group which may be substituted, and ring A represents a substituent other than the substituent R. A compound represented by the formula: or a salt thereof, which is subjected to an oxidation reaction.

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

(35)

[Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. formula

Characterized by reacting with a compound represented by the formula or a salt thereof,

Wherein each symbol is as defined above, or a method for producing a salt thereof. As the “amines” used in the present specification, for example,

Formula R ^a NH ₂ ;

R ^a R ^b NH; or

 ,-'

R ^a R ^b R ^c N;

[Wherein, R ^a , R ^b and R are the same or different and each represents a substituent, and R ^a and R ^b may be bonded to each other to form a cyclic amino with an adjacent nitrogen atom. ] Or a salt thereof. '

 Also, the above equation

R ^a NH ₂ (primary amine);

R ^a R ^b NH (secondary amine); and

Methylamine derivatives corresponding to R ^a R ^b R ^c N (tertiary amines) each have the formula

R ^a NHR ^m (secondary amine);

R ^a R ^b NR ^m (tertiary amine); and

R ^a R ^b R ^c N ⁺ R ^m (Quaternary ammonium)

[Wherein, R ^m represents an optionally substituted methyl group (preferably a methyl group), R ^a , R ^b and R ^c are the same or different and represent a substituent, and R ^a and R ^b are each other To form a cyclic amino with the adjacent nitrogen atom. Or a salt thereof.

The methylamine derivative represented by the above formula R ^a R ^b R ^c N + R ^m desirably forms a quaternary methylammonium salt. In this case, the counter anion includes a halogen atom anion ( Eg, CI—, Br—, I—, etc.), anions derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, tartaric acid, maleic acid Anions derived from organic acids such as acids, cunic acid, methanesulfonic acid, benzenesulfonic acid, and P-toluenesulfonic acid, and anions derived from acidic amino acids such as aspartic acid and dalmic acid Examples of the deprotonated form of the acid include C 1—, Br—, and Ms—.

As used herein, “trimethyl phosphite derivative” (trimethyl phosphite) And derivatives thereof), for example, the formula P (OR ^m ) 3

[In the formula, R ^m represents a methyl group which may be substituted (preferably a methyl group). Or a salt thereof.

 , * ■

In the above formula, examples of the substituent which the “methyl group” in the “optionally substituted methyl group” represented by R ^m may have include, for example, halogen (eg, fluorine, chlorine, bromine, Iodine, etc.), nitro, cyano, optionally halogenated C, -4 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C24 alkanol (eg, acetyl, propionyl) And the like, alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), aryl which may be substituted, and the like. The number of substituents is preferably 1 to 3.

Examples of the “aryl” in the “aryl which may be substituted” include, for example, phenyl, naphthyl and the like, and examples of the substituent which the “aryl” may have include halogen (eg, fluorine, chlorine) , Bromine, iodine, etc.), nitro, cyano, optionally halogenated ₄ alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated Ci-4 alkoxy (eg, methoxy) , E Bok alkoxy, Torifuruorome Bok alkoxy, Torifuruoroe Bok alkoxy, etc.), C ₂ - 4 Arukanoi Le (eg, Asechiru, propionyl, etc.), C i - 4 alkylsulfonyl (e.g., methanesulfonyl sulfonyl, etc. ethanesulfonyl) and the like The number of substituents is preferably 1 to 3.

As the “optionally substituted methyl group” for R ^m , methyl, benzyl and the like are preferable, and methyl is particularly preferable.

 In the above formula, the “alkyl group” in the “optionally substituted alkyl group” represented by R includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, C such as isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. Alkyl and the like are mentioned, among which lower (C ^ e) alkyl and the like are preferable, and methyl is particularly preferably used.

"Alkyl group" force in "optionally substituted alkyl group" represented by R Examples of the substituent which may be present include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, mercapto, amino, carboxyl, and optionally halogenated C i- 4 alkyl (e.g., triflate Ruo Russia, methyl, etc. Echiru), C alkoxy which may be halogenated (e.g., methoxy, E butoxy, triflumizole Ruo b methoxy, triflumizole Ruo b ethoxy, etc.), C ₂ - ₄ Arukanoi (Eg, acetyl, propionyl, etc.), C alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), and the number of substituents is preferably 13.

As the “optionally substituted alkyl group” represented by R, an unsubstituted alkyl group is preferable, and an unsubstituted lower (di- ₆ ) alkyl is preferable, and methyl is particularly preferable. .

 In the above formula, the `` substituent '' which ring A may further have in addition to the substituent R includes, for example, a halogen atom, nitro, cyano, optionally substituted alkyl, optionally substituted cyclo Alkyl, an optionally substituted hydroxy group, an optionally substituted mercapto group, an optionally substituted amino group, an optionally substituted acyl, a carboxyl group which may be esterified, a substituted A good aromatic group is used.

 Examples of the halogen as the “substituent” which the ring A may further have in addition to the substituent R include fluorine, chlorine, bromine and iodine, and fluorine and chlorine are particularly preferable.

As the alkyl in the optionally substituted alkyl as the “substituent” which the ring A may further have in addition to the substituent R, a straight-chain or branched alkyl having 110 carbon atoms, for example, Ci such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, noel, decyl. Alkyl, preferably lower (Ci-6) alkyl. Examples of the substituent in the optionally substituted alkyl include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, mercapto, amino, carboxyl, and halogenated. 4 alkoxy (eg, methoxy, ethoxy, trif) Examples include fluoromethoxy, trifluoroethoxy, etc.), C ₂ —alkanoyl (eg, acetyl, propionyl, etc.), alkylsulfonyl (eg, methanesulfonyl, benzenesulfonyl, etc.), and the number of substituents , 1-3 are preferred.

Examples of the cycloalkyl in the optionally substituted cycloalkyl as the “substituent” that the ring A may further have in addition to the substituent R include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl And C-cycloalkyl such as heptyl. Examples of the substituent in the optionally substituted cycloalkyl include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, mercapto, amino, carboxyl, and halogenated. Good C alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C ₂ -alkanol ( Examples include acetyl, propionyl, etc.) and C alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.). The number of substituents is preferably 1-3.

The substituent in the optionally substituted hydroxyl group as the “substituent” that the ring A may further have in addition to the substituent R includes (1) an optionally substituted alkyl (for example, methyl, C, alkyl, preferably lower (C,-) such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. ₆ ) alkyl and the like);

(2) cycloalkyl which may be substituted (for example, C ₃ -cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like);

(3) optionally substituted alkenyl (e.g., Ariru (al lyl), crotyl, 2 one-pentenyl, carbon number 2-1 0 alkenyl such as cyclohexenyl 3, preferably a low-grade (C ₂ - ₆₎ alkenyl Etc.);

(4) cycloalkenyl which may be substituted (for example, 2-cyclopentenyl, 7

 20

C3-C7 cycloalkenyl such as 2-cyclohexenyl, 2-cyclopentenylmethyl, and 2-cyclohexenylmethyl);

(5) an optionally substituted Ararukiru (e.g., phenylene Lou C, - ₄ alkyl (e.g.,

,-'

Benzyl, phenethyl and the like);

 (6) optionally substituted acyl (for example, alkanol having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isoptyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (eg, methanesulfonyl, ethanesulfonyl) Etc.);

 (7) substituents such as aryl which may be substituted (for example, phenyl, naphthyl and the like);

(1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) optionally substituted aryl, and (7) optionally substituted aryl include halogen (eg, fluorine) , Chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, mercapto, amino, carboxyl, optionally halogenated 4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), halogenated May be 4 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C _2-4 alkanol (eg, Cetyl, propionyl, etc.), _4- alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1-3.

 The substituent in the optionally substituted mercapto group as the `` substituent '' which the ring A may further have other than the substituent R includes the above `` the ring A further has a substituent other than the substituent R '' The same as the `` substituent in the optionally substituted hydroxyl group '' as the `` substituent '' may be mentioned.

(1) Alkyl which may be substituted (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, De C such as sill. Alkyl, preferably lower (d-6) alkyl and the like);

 (2) cycloalkyl which may be substituted (for example, cyclopropyl, cyclo

,-'

C37 cycloalkyl such as butyl, cyclopentyl, cyclohexyl and cycloheptyl);

(3) optionally substituted Ararukiru (e.g., phenylene Lou ₄ alkyl (e.g., benzyl, phenethyl) and the like);

 (4) aryl which may be substituted (eg, phenyl, naphthyl, etc.) is preferred, and the like;

(1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted aralkyl, and (4) optionally substituted aryl. Examples of the substituent that may be substituted include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, mercapto, amino, carboxyl, and optionally halogenated d-. ₄ alkyl (e.g., triflate Ruoromechiru, methyl, Echiru etc.), optionally halogenated C, - ₄ alkoxy (e.g., main Bok alkoxy, ethoxy, Torifuruorome Bok alkoxy, triflate Ruo b ethoxy, etc.), C ₂ Arukanoiru (Eg, acetyl, propionyl, etc.), d-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) The number of substituents, 1 to 3 are preferred.

The substituent of the optionally substituted amino group as the `` substituent '' which the ring A may further have other than the substituent R includes the above `` the ring A further has a substituent other than the substituent R '' And an amino group which may have 1 to 2 substituents similar to the "substituents in the optionally substituted hydroxyl group" as the "substituent", among which (1) Substitution Alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. -,. alkyl, preferably lower (C, - ₆₎ such as an alkyl and the like);

(2) cycloalkyl which may be substituted (for example, cyclopropyl, cyclo C3-7 cycloalkyl such as butyl, cyclopentyl, cyclohexyl, cycloheptyl and the like);

 (3) optionally substituted alkenyl (eg, allyl, crotyl, 2

, - A pentenyl, carbon number 2 to 1 0 alkenyl such as cyclohexenyl 3, preferably a low-grade - like (C _{2 6)} alkenyl);

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

 (5) optionally substituted acyl (for example, alkanol having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isoptyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (eg, methanesulfonyl, ethanesulfonyl) Etc.);

 (6) An amino group which may have 1 to 2 optionally substituted aryls (for example, phenyl, naphthyl, etc.),

The above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, ( 5) The optionally substituted acyl and the (6) optionally substituted substituents of halogen include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano , a hydroxyl group, a mercapto group, an amino group, a carboxyl group, a C ₄ alkyl which may be halogenated (eg, preparative Rifuruoromechiru, methyl, etc. Echiru), C may be halogenated, - ₄ alkoxy (e.g., methoxy , Ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanols (eg, acetyl, propionyl, etc.), C, -4 Alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.); and the number of substituents is preferably 1-3.

In addition, the amino group which may be further substituted as a “substituent” which ring A may further have in addition to the substituent R is a cyclic amino group (for example, when the substituents of the amino group are bonded to each other) , 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.) May be formed. The cyclic amino group may have a substituent. Examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, mercapto, amino, and carboxyl. Group, optionally halogenated C, -4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally octalogenated 4 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoromethyl) Ethoxy, etc.), C 2-4 alkanoyl (eg, acetyl, pentionyl, etc.), d-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), and the number of substituents is 1 ~ 3 are preferred. Ring A which may be further substituted as a `` substituent '' which ring A may further have in addition to substituent R includes:

 (1) hydrogen,

 (2) optionally substituted alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl) Alkyl, preferably lower (d-6) alkyl and the like);

(3) cycloalkyl which may be substituted (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. C _{3 7} Shikuroa alkyl such as heptyl cyclohexane and the like);

(4) an optionally substituted alkenyl (e.g., Ariru (AHyi), crotyl, 2 one pentenyl, alkenyl having 2 to 10 carbon atoms, such as cyclohexenyl 3, preferably a low-grade (C ₂ - ₆₎ alkenyl, etc. );

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

(6) An optionally substituted 5- to 6-membered monocyclic aromatic group (for example, phenyl, pyridyl, etc.) bonded to a carbonyl group or a sulfonyl group (eg, acetyl, propionyl) , Butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutane Carbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinyl, methanesulfonyl, ethanesulfonyl, etc.), and even if the above (2) is substituted, Good alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, and (6) optionally substituted 5 The substituents that the 6-membered monocyclic aromatic group may have include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, mercapto, amino, carboxyl group, optionally halogenated C, - ₄ alkyl (e.g., triflate Ruo Russia, methyl, E Butyl, etc.), optionally halogenated C alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanol (eg, acetyl, propionyl, etc.), d-4 alkyl Sulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.); and the number of substituents is preferably 1 to 3.

 The carboxyl group which may be further esterified as the “substituent” which ring A may further have in addition to the substituent R includes (1) hydrogen,

 (2) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, C, —, such as decyl, alkyl, preferably lower alkyl, etc.);

 (3) cycloalkyl which may be substituted (for example, C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like);

(4) an optionally substituted alkenyl (e.g., Ariru (allyl), crotyl, 2 one pentenyl, alkenyl having 2 to 10 carbon atoms, such as cyclohexenyl 3, preferably a low-grade (C ₂ - ₆₎ alkenyl, etc. );

(5) Cycloalkenyl which may be substituted (for example, 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl A cycloalkenyl having 3 to 7 carbon atoms such as tyl);

(6) optionally substituted aryl (eg, phenyl, naphthyl, etc.) bonded to a carbonyloxy group, preferably carboxyl, lower (C, -6) alkoxyl carbonyl, aryloxycarbonyl ( Examples thereof include those in which methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.) are bonded to a carbonyldioxy group, and the above-mentioned (2) optionally substituted alkyl, (3) cycloalkyl which may be substituted, (4) alkenyl which may be substituted, (5) cycloalkenyl which may be substituted, and (6) aryl which may be substituted. Substituents that may be substituted include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), Toro, cyano, hydroxyl, mercapto, amino, aminopropyl, optionally halogenated d-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated d — 4 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C _2-4 alkanol (eg, acetyl, propionyl, etc.), -4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) And the like, and the number of substituents is preferably 1 to 3.

The aromatic group in the optionally substituted aromatic group as the “substituent” which ring A may further have in addition to the substituent R is phenyl, pyridyl, furyl, chenyl, pyrrolyl, imidazolyl, pyrazolyl And 5- to 6-membered homo- or heterocyclic aromatic groups such as thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl. Examples of the substituent of these aromatic groups include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, mercapto, amino, carboxyl, and optionally halogenated _4- alkyl. (Eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C] —4 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), c ₂

-4 alkanoyl (eg, acetyl, propionyl, etc.), d-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) as, ;! ~ 3 are preferred.

 As for the “substituent” which ring A may further have in addition to substituent R, 1 to 2 substituents may be the same or different and may be substituted at any substitutable position on the ring.

As the “substituent” which ring A may further have in addition to the substituent R, a group which is inert to the reaction is preferable, and in particular, a lower (— 4) alkyl which may be halogenated (eg, methyl, Echiru, t one heptyl, triflumizole Ruo b methyl, etc.), optionally halogenated substituted lower (C, - ₄₎ alkoxy (e.g., methoxy, ethoxy, t chromatography butoxy, triflumizole Ruo b methoxy, etc.), halogen (Eg, fluorine, chlorine, etc.), nitro, cyano, amino optionally substituted with 1-2 lower (C, -4) alkyls (eg, amino, methylamino, dimethylamino, etc.), 5-6 members Cyclic amino (eg, 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, 4-morphonylyl, 4-thiomorphonyl, 1-imidazolyl, 4-tetrahydroviranyl, etc.) It is preferably used.

 Ring A is preferably a benzene ring having no substituent other than substituent R. The “oxidizing agent” used herein includes, for example, a halogenating agent such as N-halogenamide (including N-halogenimide) (eg, N-bromosuccinimide, N-chlorosuccinimide, N-chlorosuccinimide, -Eodosuccinimide, N-bromoacetamide, N-bromocaprolactam, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin, 5,5-dibromo-2 , 2-dimethyl-4,6-dioxo-1,3-dioxane, chloramine-I-T, chloramine-I, etc.), among which Ν-halogenosuccinimide (eg, Ν-bromosuccinic acid) Imide, chloro-succinimide, etc.) are preferably used.

As the "weak acid" used in the present specification, for example, succinimide, caprolactam and the like can be mentioned, and among them, succinimide and the like are preferably used. As used herein, the term “strong acid” includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, tartaric acid, maleic acid, cunic acid, methanesulfonate, benzenesulfonate,ト ル エ ン -toluenesulfonic acid, aspartic acid, dalmic acid and the like, among which hydrochloric acid, methanesulfonic acid and the like are preferably used. In the reaction according to the above (5), it is preferable to form a corresponding quaternary methylammonium weak acid salt by reacting a tertiary amine with a trimethyl phosphite derivative and an N-halogenamide, and the weak acid is preferably used. By bringing the salt into contact with an acid (preferably, an acid having a higher degree of ionization than the amide corresponding to N-halogenoamide; more preferably, a strong acid, etc.), ion exchange with the anionic species corresponding to the acid is easily performed It is possible to produce a quaternary methyl ammonium salt using a desired anion as a counter anion.

 As used herein, the term “leaving group” refers to, for example, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), sulfonyloxy group (eg, methanesulfonyloxy group, trifluorene sulfonylo group) Xy group, P-toluenesulfonyloxy group, etc.).

In the above formula, as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by RR ² and R ³ , for example,

(1) Alkyl which may be substituted (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isobentyl, neopentyl, hexyl, heptyl, octyl, Linear or branched alkyl groups such as Noel, decyl, pendecyl, tridecyl, tetradecyl, pendecyl, etc., preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , pentyl, Isopen chill, neopentyl, hexyl, heptyl, Okuchiru, nonyl, C WINCH _{1 0} alkyl and decyl, more preferably lower ((: Bok ₆₎ Ru and alkyl can be mentioned);

(2) optionally substituted cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl cyclohexane, which C ₃ of Shikurookuchiru - include ₈ cycloalkyl group);

(3) optionally substituted alkenyl (e.g., Ariru (al lyl), crotyl, 2 - pentenyl, 3 - to a carbon number of 2-1 0 alkenyl, such as cyclohexenyl, preferably a lower (C ₂ _ ₆₎ alkenyl Etc.);

(4) cycloalkenyl which may be substituted (for example, 2-cyclopentenyl, C3-C8 cycloalkenyl such as 2-cyclohexenyl, 2-cyclopentenylmethyl, and 2-cyclohexenylmethyl);

(5) alkynyl which may be substituted (for example, alkynyl having 2 to 10 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl and 3-hexynyl, preferably lower ( C ₂ _ ₆₎ an alkynyl and the like);

(6) an optionally substituted Ararukiru (e.g., phenylene Lou C ^ - ₄ alkyl (e.g., benzyl, phenethyl) and the like);

アルキル （例、 トリフルォ ロメチル、 メチル、 ェチルなど） 、 ハロゲン化されていてもよい C 1一 4アルコ キシ （例、 メトキシ、 エトキシ、 トリフルォロメトキシ、 トリフルォロエトキシ など） 、 C₂_₄アルカノィル （例、 ァセチル、 プロピオニルなど） 、 Ci_₄アルキ ルスルホニル （例、 メタンスルホニル、 エタンスルホニルなど） などが挙げられ、 置換基の数としては、 1〜3個が好ましい。 (7) aryl which may be substituted (for example, phenyl, naphthyl and the like); and the above-mentioned (1) alkyl which may be substituted, (2) cycloalkyl which may be substituted (3) alkenyl which may be substituted, (4) cycloalkenyl which may be substituted, (5) alkynyl which may be substituted, (6) aralkyl which may be substituted, and (7 ) The substituent which the aryl which may be substituted may have includes halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, mercapto, amino, carboxyl, May be halogenated

Alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C 1-4 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C ₂ _ ₄ alkanol (eg, Asechiru, propionyl, etc.), CI_ ₄ alkyl Rusuruhoniru (for example, methanesulfonyl, etc. ethanesulfonyl), and the like, the number of substituents, 1 to 3 are preferred.

As RR ² and R ³ , an optionally substituted alkyl, an optionally substituted cycloalkyl and the like are preferable, and among them, an optionally substituted alkyl is preferably used.

As the “optionally substituted hydrocarbon group” represented by RR ² and R ³ , an unsubstituted hydrocarbon group is preferable, and among them, an unsubstituted alkyl group is preferable. (C ^ ₆ ) alkyl and the like are preferable, and methyl is most preferably used.

In the above formula, examples of the “halogen atom” represented by X ′ include fluorine, chlorine, bromine, iodine, etc., and chlorine, bromine and the like are particularly preferably used. Further, when the compound having the substituent is a basic compound depending on the type of the substituent of R ¹ R ² and R ³ exemplified above, it is converted to a salt using an acid according to a conventional method. be able to. Such acids may be those that do not interfere with the reaction.

Any acid may be used, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, and sulfamic acid, formic acid, acetic acid, trifluoroacetic acid, tartaric acid, citric acid, fumaric acid, Organic acids such as maleic acid, succinic acid, malic acid, P-toluenesulfonic acid, methanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid. When the obtained compound is a salt, it may be converted to a free base according to a conventional method.

On the other hand, depending on the types of the substituents R ¹ , R ² and R ³ exemplified above, when the compound having the substituent becomes an acidic compound, it is converted to a salt using a base according to a conventional method. can do. 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, and a basic amino acid. And the like. Suitable examples of salts with inorganic bases include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts and ammonium salts. Can be Preferred examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine And the like. Preferred examples of the salt with a basic amino acid include, for example, 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.

Further, when the compound having the substituent is a basic compound depending on the types of the substituent R and the substituent of the ring A exemplified above, it can be converted to a salt using an acid according to a conventional method. it can. The 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; Formic acid, acetic acid, trifluoroacetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, succinic acid, malic acid, P-toluenesulfonic acid, meta Organic acids such as sulfonic acid and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid. When the obtained compound is a salt, it may be converted to a free base according to a conventional method.

 , -No

 On the other hand, when the compound having the substituent is an acidic compound depending on the types of the substituent R and the substituent of the ring A exemplified above, it can be converted to a salt using a base according to a conventional method. it can. Such a 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. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; 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, jetanolamine, triethanolamine, dicyclohexylamine, Ν, Ν′-dibenzylethylenediamine Salts with min and the like. Preferred examples of the salt with a basic amino acid include, for example, 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 amounts of the trimethyl phosphite derivative and the oxidizing agent used in the reaction described in the above (1) or (2) are about 0.5 to 100 equivalents (preferably about 0.5 to 50 equivalents) and about 0.5 to 100 equivalents, respectively. 5 to 100 equivalents (preferably about 0.5 to 50 equivalents).

 Reaction solvents include aliphatic hydrocarbons (eg, η-hexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, diisopropyl) Ethers), polar solvents (eg, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), protic solvents (eg, methanol, ethanol, etc.), esters (eg, phosphates) Limethyl, ethyl acetate, butyl acetate, etc.), ketones (eg, acetone, 2-butane nonone, etc.) and the like are used. Among them, tetrahydrofuran, trimethyl phosphate, butyl acetate and the like are preferably used.

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

 The amount of the acid used in the reaction described in the above (5), (7) or (9) is about 0.5 to 100 equivalents, preferably about 1 to 50 equivalents. Examples of the acid include those similar to the above-mentioned "weak acid" and "strong acid", and among them, a strong acid is preferably used. Reaction solvents include aliphatic hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), ethers (eg, tetrahydrofuran (THF), geethylether, diisopropyl) Ethers), polar solvents (eg, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), protic solvents (eg, methanol, ethanol, etc.), esters (eg, phosphorus Trimethyl acid, ethyl acetate, butyl acetate, and the like, and ketones (eg, acetone, 2-butanone, etc.) are used. Among them, tetrahydrofuran, trimethyl phosphate, butyl acetate and the like are preferably used.

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

 The target compound obtained in each of the above reactions can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

 In addition, the raw material compound and the target compound obtained in each of the above reactions may form a salt, may be a hydrate, or may be a non-hydrate.

 Such salts include, for example, salts with inorganic acids, salts with organic acids, salts with acidic amino acids, and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of the salt with an organic acid include salts with formic acid, acetic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, and the like. Preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.

When the compound having the substituent is an acidic compound depending on the types of the substituents of the starting compound and the amine to be the target compound, the compound can be converted to a salt using a base according to a conventional method. it can. As a salt with such a base, the reaction is hindered. Salts with any base may be used as long as they do not deteriorate, and examples thereof include salts with inorganic bases, salts with organic bases, and salts with basic amino acids. 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 and ammonium salt. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, jetanolamine, triethanolamine, dicyclohexylamine, Ν, Ν′-dibenzylethylenediamine. And the like. Preferred examples of the salt with a basic amino acid include, for example, 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 (11) above is performed, for example, under the following reaction conditions.

The catalyst used in the above reaction (1 1), wherein, for example, Pd- Rh-C, P t 2 0, Raney N i including but catalysts suitable for catalytic reduction, such as, inter alia Pd-C is It is preferably used. The amount of the catalyst used in the reaction is about 0.01 to 500%, preferably about 0.1 to 50% .As a hydrogen source, in addition to hydrogen, for example, formic acid, ammonium formate, isopropyl alcohol, or the like is used. Can be. The amount of the hydrogen source used in the reaction is about 0.5 to 100 equivalents, preferably about 1 to 10 equivalents.

Reaction solvents include aliphatic hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, etc.) ), Polar solvents (eg, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), protic solvents (eg, methanol, ethanol, etc.), among which tetrahydrofuran, Methanol, ethanol and the like are preferably used. The reaction temperature is usually about -30 to 200 ° C, preferably about 0 to 100 ° C, the reaction pressure is usually about 0 to 100 atm, preferably about 0 to 10 atm, and the reaction time is usually about 0. It is 1 to 24 hours, preferably about 1 to 10 hours.

 , '

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

 The reaction described in (14) above is preferably performed in the presence of a base. Examples of such a base include inorganic bases (eg, potassium carbonate, sodium carbonate, sodium hydroxide, etc.) and organic bases (eg, , Triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] -7-pentadecene, etc., alcohol (eg, sodium methylate, tert.-butoxypotassium, etc.), organometallic reagents (eg, n-butyllithium), sodium hydride, sodium amide, and the like. The amount of the base used in the reaction is about 0.1 to 50 equivalents, preferably about 0.5 to 10 equivalents.

 Reaction solvents include aliphatic hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, etc.) ), Polar solvents (eg, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), protic solvents (eg, methanol, ethanol, etc.), among which tetrahydrofuran, Methanol and the like are preferably used.

 The reaction temperature is usually about -70 to 200 ° C (: preferably about 0 to 100 ° C), and the reaction time is usually about 0.1 to 24 hours, preferably about 1 to 10 hours.

The reaction described in the above (17) is carried out, for example, under the following reaction conditions.

The catalyst used in the above reaction (1 7), wherein, for example, Pd- [;, Rh- C, Pt 2 0, Raney Ni, including but catalysts suitable for catalytic reduction, such as FeCl ₃ -C, Among them, Raney Ni, FeCl ₃ -C and the like are preferably used. The amount of the catalyst used in the reaction is about 0.01 to 500%, preferably about 0.1 to 50%. As the hydrogen source, hydrazine, hydrazine hydrate and the like can be used. The amount of hydrogen source used in the reaction is about 0.5 to 100 equivalents, preferably about 0.5 to 10 equivalents.

 Reaction solvents include aliphatic hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, etc.) ), Polar solvents (eg, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), protic solvents (eg, methanol, ethanol, etc.), among which tetrahydrofuran, Methanol, ethanol and the like are preferably used.

 The reaction temperature is usually about -30 to 200 ° C, preferably about 0 to 100 ° C, and the reaction time is usually about 0.1 to 24 hours, preferably about 0.5 to 10 hours.

 The target compound obtained in each of the above reactions can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

 The target compound obtained in each of the above reactions may form a salt, may be a hydrate, or may be a non-hydrate.

Such salts include, for example, salts with inorganic acids, salts with organic acids, salts with acidic amino acids, and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfo acid Acid and salts with P-toluenesulfonic acid. Preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid and the like.

 In addition, the formula obtained by the reaction described in (17) above

Can be condensed with a carboxylic acid, for example, according to the reaction shown below, to give an anilide derivative having MCP-1 receptor antagonism, CCR5 antagonism, and the like (Japanese Patent Application No. 9-135148). Japanese Patent Application No. (WO99 / 32100), Japanese Patent Application No. 9-35 1 481, Japanese Patent Application No. (W099 / 32468), Japanese Patent Application No. 10-2-188075, Japanese Patent Application No. - twenty three

_Which can produce the target compound described in

[Wherein, R ³ represents an optionally substituted hydrocarbon group (preferably a methyl group), R represents an optionally substituted alkyl group (preferably a methyl group), and ring A represents a substituent. A benzene ring which may further have a substituent other than R (preferably a benzene ring having no substituent other than the substituent R);

The condensation reaction between the carboxylic acid and the aniline derivative is carried out by a general acid-amide reaction. (Eg, ordinary peptide synthesis means, etc.). The means for peptide synthesis may be in accordance with any known method. For example, M. Bodansky and MA Ondetti, Peptide Synthesis, Intersia

,-'

New York, 1966; FM Finn and K. Hofmann, The Proteins, Volume 2, Editing of H. Nenrath, RL Hill, Academic Press Inc., New York, 1976; Nobuo Izumiya, et al. Author "Basic and Experimental Peptide Synthesis", Maruzen Co., Ltd., 1985, etc., for example, azide method, chloride method, acid anhydride method, mixed acid anhydride method, DCC method, active ester method,の 他 In addition to the method using Ward reagent K, the carbonyldiimidazole method, the redox method, the DCZHONB method, the WSC method, the method using getyl cyanophosphate (DEPC), and the like. This condensation reaction can be performed in a solvent. Examples of the solvent include solvents that do not adversely affect the reaction, such as amides such as anhydrous or water-containing N, N-dimethylformamide (DMF), sulfoxides such as dimethyl sulfoxide, tertiary amines such as pyridine, and chloroform. Examples thereof include halogenated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile and propionitrile, and an appropriate mixture thereof. The reaction temperature is usually about 1-20 ° C to about 50 ° C, preferably about 1-10 ° C to about 50 ° C.

30 ° C. The reaction time is about 1 to about 100 hours, preferably about 1 to about 40 hours.

 The anilide derivative obtained by the above reaction may be used, if necessary, in Japanese Patent Application No. 9-351.

No. 480 (W099 / 32100), Japanese Patent Application No. 9-1351481, Japanese Patent Application No. 10-218468, and Japanese Patent Application No. 10-2218875 and Japanese Patent Application No. 10-234388. According to the method, the compound can be converted to a quaternary ammonium compound by reacting with an alkyl halide (eg, methyl iodide, etc.).

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

 Examples of the reducing agent include metal hydride reducing agents (eg, bis-hydride (2-meth

Sodium aluminum, lithium diisobutylaluminum hydride, etc.) are used, and among them, lithium diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride and the like are preferably used. The amount of the reducing agent used in the reaction described in the above (21) is about 0.1 to 100 equivalents, preferably about 0.5 to 10 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), dimethyl ether, etc.), polar solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), among which halogen-based Solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, etc.) It is preferably used.

 The reaction temperature is usually about -70 to 200 ° C (preferably, about -50 to 20 ° C), and the reaction time is usually about 0.1 to 24 hours, preferably about 0.1 to 6 hours.

The reaction described in the above (22) is performed, for example, under the following reaction conditions.

C00H The reaction described in (22) above is desirably performed in the presence of a base. Examples of such a base include metal hydrides (eg, sodium hydride, potassium hydride, etc.), metal hydrocarbons ( Examples: n-butyllithium, etc.), alcoholates (eg, NaOMe, NaOEt, t-BuONa, t-BuOK, etc.), alkali metal hydroxides (eg, NaOH, K0H, etc.) However, among them, metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal hydrocarbons (eg, n-butyl lithium, etc.), alcoholates (eg, NaOMe, NaOEt, t- BuONa, t-BuOL, etc.) are preferably used. The amounts of the Wit Ug reagent and the base used in the reaction described in the above (22) are about 0.1 to 100 equivalents, and preferably 0.5 to 10 equivalents, respectively.

 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), dimethyl ether, etc.), polar solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), among which halogen-based Solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, etc.) It is preferably used.

The reaction temperature is usually about -70 to 200 ° (:, preferably, about -50 to 100 ° C), and the reaction time is usually about 0.1 to 24 hours, preferably about 0.1 to 6 hours. The reaction described in the above (24) is carried out, for example, under the following reaction conditions.

The catalyst used in the reduction reaction of (2 4) wherein, Pd- (:., Rh- Pt 2 0 including but catalysts suitable for catalytic reduction, such as, inter alia Pd-C is preferably used reaction The amount of the catalyst used is about 0.01 to 500%, preferably about 0.1 to 50% .As a hydrogen source, in addition to hydrogen, for example, formic acid, ammonium formate, isopropyl alcohol, or the like is used. The amount of hydrogen source used in the reaction is about 0.5 to 100 equivalents, preferably about 0.5 to 10 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), dimethyl ether, etc.), polar solvents (eg, dimethylformamide (DMF), dimethylsulfoxide (DMS0), etc.), protic solvents (eg, methanol, ethanol, etc.) And the like, among which protic solvents (eg, methanol, ethanol, etc.) are preferably used.

The reaction temperature is usually about -70 to 200 ° C, preferably about 0 to 100 ° C, the reaction pressure is usually about 0 to 100 atm, preferably about 0 to 5 atm, and the reaction time is usually about 0. It is 1 to 24 hours, preferably about 0.5 to 10 hours. Formulas obtained by the reactions described in (22) and (24) above

And a compound represented by the formula:

The compound represented by may form a salt, may be a hydrate, or may be a non-hydrate.

 Such salts include, for example, salts with inorganic bases, salts with organic bases, salts with basic amino acids and the like. Preferred 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 and ammonium salt. Preferred examples of salts with organic bases include, for example, trimethylamine, tridiethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N ,、 '-dibenzylethylenediamine And salts with min. Preferred examples of the salt with a basic amino acid include salts with arginine, lysine, orditin and the like.

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

 Me thod A (direct synthesis)

Examples of the reagent used in the reaction (Method A) described in (26) above include, for example, Phosphorus compounds (eg, polyphosphoric acid, phosphorus pentoxide, phosphorus oxychloride, etc.), acid anhydrides (eg, trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.), acids (examples) , Sulfuric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, etc.), and the amount of the reagent used for the reaction is usually about 1 to 500 times, preferably 1 to 50 times.

 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, etc.) may be used as the solvent. Among them, phosphorus compounds (eg, polyphosphoric acid, phosphorus pentoxide, phosphorus oxychloride, etc.), acid anhydrides (eg, trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.), Acids (eg, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.) are preferably used as reaction solvents.

 The reaction temperature is usually about 0-200 ° C, preferably about 50-150 ° C, and the reaction time is usually about 0.5-24 hours, preferably about 1-12 hours.

Method B (Method via acid halogen)

 The reaction (method B) described in the above (26) is carried out in the following two steps.

 (1) Synthesis of acid halogen

 Reagents used in the synthesis of acid halogens include, for example, halogenating agents (eg, oxalyl chloride, thionyl chloride, phosphorus oxychloride, etc.). The amount of the reagent used in the reaction is usually about 0.2 to 100 equivalents. It is preferably about 1-5 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, etc.). Among them, halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), ethers (eg, tetrahydrofuran (THF), dimethyl ether, etc.) And the like are preferably used. The reaction temperature is usually about -70 to 200 ° C, preferably about -10 to 100 ° C, and the reaction time is usually about 0.1 to 12 hours, preferably about 0.1 to 6 hours.

 (2) Synthesis of target compound

 Examples of the reagent used in the synthesis of the target product from an acid halide include a Lewis acid (eg, aluminum chloride, titanium chloride, tin chloride, iron chloride, etc.). 0.2 to 100 equivalents, preferably about 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, etc.). Among them, halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), ethers (eg, tetrahydrofuran (THF), diethyl ether, etc.) And the like are preferably used.

 The reaction temperature is usually about -70 to 200 ° C, preferably about -50 to 100 ° C, and the reaction time is usually about 0.1 to 24 hours, preferably about 0.1 to 12 hours.

 The reaction described in (27) above is performed, for example, under the following reaction conditions.

(2 7) The reagents used in the reactions described, for example, carbenium Niumu ion or an equivalent thereof (e.g., methyl orthoformate ZBF ₃ · Et ₂ 0, orthoformate E Ji Le ZBF ₃ 'E t ₂ 0, Among them, methyl ortho orthoformate BF ₃ ′ Et ₂₀ and ethyl ethyl orthoformate / BF ₃ .Et ₂₀ are preferably used. The amount of the reagent used in the reaction is usually about 0.1 to 100 equivalents, preferably 0.5 to 50 equivalents.

Reaction solvents include halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), aliphatic hydrocarbons (eg, n-hexane, etc.), aromatic hydrocarbons Element (eg, benzene, toluene, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, etc.) are used. Among them, halogen solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, etc.) are preferably used. The reaction temperature is usually about -200 to 100 ° C, preferably about -100 to 50 ° C, and the reaction time is usually about 0.1 to 24 hours, preferably about 0.5 to 12 hours.

In the above formula, examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ^la and R ^2a include, for example,

 (1) Alkyl which may be substituted (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, deyl) D-, such as syl, alkyl, preferably lower (C, -6) alkyl and the like);

 (2) optionally substituted cycloalkyl (for example, C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like);

(3) optionally substituted alkenyl (e.g., Ariru (allyl), crotyl, 2 - pentenyl, carbon number 2-1 0 such cyclohexenyl 3-alkenyl, preferably lower (C ₂ - ₆₎ alkenyl, etc. And the like);

 (4) cycloalkenyl which may be substituted (for example, cycloalkenyl having 3 to 7 carbon atoms such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.) );

(5) optionally substituted alkynyl (for example, alkynyl having 2 to 10 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl and 3-hexynyl, preferably lower (C ₂ - ₆₎ an alkynyl and the like);

(6) an optionally substituted Ararukiru (e.g., phenylene Lou ₄ alkyl (e.g., benzyl, phenethyl) and the like);

(7) aryl which may be substituted (for example, phenyl, naphthyl, etc.) and the like; (1) alkyl which may be substituted, (2) Optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted alkynyl, (6) optionally substituted (7) Examples of the substituent which the aryl which may be substituted or which the aryl may have include halogen (eg, fluorine, chlorine, bromine, iodine, etc.) nitro, cyano, hydroxyl, mercapto , Amino group, carboxyl group, optionally halogenated ₄ alkyl (eg, trifluoromethyl, methyl, ethyl, etc.) optionally halogenated C 4 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoro) Oroetokishi, etc.), c ₂

-4 alkanoyl (eg, acetyl, propionyl, etc.), 4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like, and the number of substituents is preferably 13.

 The reaction described in (29) above is performed, for example, under the following reaction conditions.

Examples of the reducing agent used in the reaction described in (29) include NaBH ₄ Li BH _{4 and the} like. Examples of the acid include inorganic acids (eg, hydrochloric acid, sulfuric acid, and the like). Examples include hydrochloric acid and sulfuric acid. The amount of the reducing agent and the acid used in the reaction is usually about 0.1100 equivalent, preferably 0.550 equivalent.

 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), geethylether, etc.), polar solvents (eg, DMF DMS0, etc.), protic solvents

(Eg, methanol, ethanol, etc.). Among them, protic solvents (eg, methanol, ethanol, etc.), halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), ethers (eg, tetrahydrofuran (THF), getyl) Ether, etc.) are preferably used. The reaction temperature is usually about -200 to 100 ° C, preferably about -50 to 100 ° C, and the reaction time is usually about 0.5 to 200 hours, preferably about 0.5 to 100 hours.

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

Examples of the reagent used in the reaction described in the above (31) include a reducing agent such as NaBH ₄ and LiBH ₄ . The amount of the reducing agent used in the reaction is usually about 0.1 to 100 equivalents, preferably 0.5 to 50 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, etc.), polar solvents (eg, DMF, DMS0, etc.), protic solvents

(Eg, methanol, ethanol, etc.). Among them, protic solvents (eg, methanol, ethanol, etc.), halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, Etc.) are preferably used.

 The reaction temperature is usually about -200 to 100 ° C, preferably about -50 to 50 ° C, and the reaction time is usually about 0.1 to 24 hours, preferably about 0.1 to 12 hours.

 Formula obtained by the reaction described in (31) above

The compound represented by may form a salt, may be a hydrate, or may be a non-hydrate.

Examples of such a salt include a salt with an inorganic base. Salts with inorganic bases Preferable examples thereof include alkali metal salts such as sodium salt and potassium salt.

 The reaction described in the above (33) is carried out, for example, under the following reaction conditions.

As the reagent used in the reaction described in the above (33), for example, a Vismeier reagent (eg, P0C1 ₃ ZDMF, S0C1 ₂ ZDMF, (C0C1) ₂ ZDMF, etc.) and the like, preferably P0C1 ₃ ZDMF, S0C1 ₂ / DMF, (C0C1) ₂ ZDMF and the like, and the amount of the reagent used in the reaction is usually about 0.1 to 100 equivalents, preferably 0.5 to 50 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, etc.), polar solvents (eg, DMF, DMS0, etc.), protic solvents

(Eg, methanol, ethanol, etc.). Among them, protic solvents (eg, methanol, ethanol, etc.), halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, Etc.) are preferably used.

 The reaction temperature is usually about -100 to 200 ° C, preferably about 0 to 150 ° C, and the reaction time is usually about 0.5 to 100 hours, preferably about 1 to 24 hours.

 The reaction described in (34) above is performed, for example, under the following reaction conditions.

上記 （3 4 ) 記載の反応において用いられる酸化剤としては、 例えば 過マンガ ン酸塩 （例、 過マンガン酸カリウムなど） 、 マンガン酸塩 （例、 マンガン酸カリ ゥムなど） 、 クロム酸塩 （例、 クロム酸、 Jones 試薬、 など） 、 亜塩素酸塩 （例、 亜塩素酸ナトリウムなど） 、 有機過酸化物 （例、 過酢酸、 m-クロ口過安息香酸、 など） 、 過酸化水素、 酸化銀 （1、 I I) 、 ペルォキソ硫酸 （例、 ペルォキソ一硫酸 など） 、 塩素酸塩 （例、 塩素酸ナトリウムなど） 、 硝酸など、 好ましくは亜塩素 酸塩 （例、 亜塩素酸ナトリウムなど） 、 有機過酸化物 （例、 過酢酸、 m-クロ口過 安息香酸、 など） 、 過酸化水素、 などが挙げられる。 反応に用いる酸化剤の量は 通常約 0. 1〜100当量、 好ましくは 0. 5〜50当量である。

Examples of the oxidizing agent used in the reaction described in (34) above include permanganate (eg, potassium permanganate, etc.), manganate (eg, potassium manganate) Chromium (eg, chromic acid, Jones reagent, etc.), chlorite (eg, sodium chlorite, etc.), organic peroxides (eg, peracetic acid, m-chloroperbenzoate) Acid, etc.), hydrogen peroxide, silver oxide (1, II), peroxosulfuric acid (eg, peroxomonosulfuric acid, etc.), chlorate (eg, sodium chlorate, etc.), nitric acid, etc., preferably chlorite ( Examples include sodium chlorite, etc., organic peroxides (eg, peracetic acid, m-chloroperbenzoic acid, etc.), hydrogen peroxide, and the like. The amount of the oxidizing agent used in the reaction is usually about 0.1 to 100 equivalents, preferably 0.5 to 50 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), geethylether, etc.), polar solvents (eg, DMF, DMS0, etc.), protic solvents

(Eg, methanol, ethanol, etc.). Among them, protic solvents (eg, methanol, ethanol, etc.), halogenated solvents (eg, methylene chloride, dichloroethane, chloroform, etc.), ethers (eg, tetrahydrofuran (THF), getyl ether, Etc.) are preferably used.

 The reaction temperature is usually about -100 to 200 ° (:, preferably about 0 to 150 ° C), and the reaction time is usually about 0.1 to 100 hours, preferably about 0.5 to 24 hours.

 Formula obtained by the reaction described in (34) above

The compound represented by may form a salt, may be a hydrate, or may be a non-hydrate.

Such salts include, for example, salts with inorganic bases, salts with organic bases, salts with basic amino acids and the like. Preferred 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 and ammonium salt. 'Suitable examples of salts with organic bases include, for example, trimethylamine, triethyl And salts thereof with amine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, Ν'-dibenzylethylenediamine and the like. Preferred examples of the salt with a basic amino acid include salts with arginine, lysine, orditin and the like.

 As a preferred embodiment of the present invention, for example, 4- (4-methylphenyl) benz nitrile is subjected to a reduction reaction, and is reacted with 3-carboxypropyltriphenylphosphonium bromide. ISubsequently, a ring closure reaction was performed to synthesize 3- (4-methylphenyl) -6,7,8,9-tetrahydro-5Η-benzocycloheptane-5-one, followed by carbedimation Reacts with a reducing agent, followed by a reaction with an acid, followed by an oxidation reaction to give 3- (4-methylphenyl) -8,9-dihydropene-7Η-benzocycloheptene-6-carboxylic acid 4- (4-methylphenyl) benznitrile is subjected to a reduction reaction, reacted with 3-carboxypropyltriphenylphosphonamide, and then subjected to a reduction reaction, followed by a ring closure reaction. 3- (4-methylphenyl)-6, 7, 8, 9 -Tetrahydro-5Η-benzocycloheptan-5-one is synthesized, reduced, reacted with a Vismeier reagent, and subjected to an oxidation reaction to give 3- (4-methylphenyl) -8,9 A method for producing -dihydro-7H-benzocycloheptene-6-carboxylic acid;

 In addition, the formula obtained by the reaction described in (34) above

Can be condensed with an aniline derivative according to, for example, the reaction shown below to obtain an anilide derivative (Japanese Patent Application No. 9-351480 (WO99Z3210). ), Japanese Patent Application No. 9-35 1 481, Japanese Patent Application No. (WO 99/32 468), Japanese Patent Application No. 10-210 The synthesis intermediate described in the specification of US Pat. No. 2,434,388 can be synthesized.

The above-mentioned condensation reaction between the carboxylic acid and the aniline derivative [the reaction described in (35) above] can be carried out according to a general acid-amide reaction (eg, ordinary peptide synthesis means, etc.). The means of peptide synthesis may be in accordance with any known method, for example, by P. Bodansky and A. Ondetti, Peptide Synthesis, In Yuichi Science, New York, 1966; "The Proteins" by M. Finn and K. Hofmann, Volume 2, edited by H. Nenrath, RL Hill, Academic Press, Inc., New York, 1976; Nobuo Izumiya, et al. Fundamentals and experiments ", Maruzen Co., Ltd., 1985, for example, azide method, chloride method, acid anhydride method, mixed acid anhydride method, DCC method, active ester method, Woodward reagent A method using K, a carbonyldiimidazole method, a redox method, a DCC / HONB method, a WSC method, a method using getyl cyanophosphate (DEPC), and the like can be mentioned. This condensation reaction can be performed in a solvent. Solvents that do not adversely affect the reaction include, for example, amides such as anhydrous or water-containing N, N-dimethylformamide (DMF), sulfoxides such as dimethylsulfoxide, tertiary amines such as pyridine, and chloroform. And halogenated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile and propionitrile, or an appropriate mixture thereof. The reaction temperature is usually about 20 ° C to 50 ° C, Preferably it is from about -10 ° C to about 30 ° C. The reaction time is about 1 to about 100 hours, preferably about 1 to about 40 hours.

Also, the formula used for the reaction

The compounds represented by are, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, and sulfamic acid, formic acid, acetic acid, trifluoroacetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, and succinic acid. Acid, malic acid, organic acids such as p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, etc .; salts with acidic amino acids such as aspartic acid and glutamic acid; and salts with inorganic bases. A salt with an organic base or a salt with a basic amino acid may be formed. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like. Can be Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, genoleamine, triethanolamine, dicyclohexylamine, N, Ν'-dibenzyldiethylenediamine Salts with min and the like. Preferable examples of the salt with a basic amino acid include salts with arginine, lysine, orditin and the like. Further, it may be a hydrate or a non-hydrate, but it is preferable that neither the amino group nor the hydroxyl group is protected.

Further, the anilide derivative obtained by the above reaction is disclosed in Japanese Patent Application No. 9-351480 (WO99 / 3210) and Japanese Patent Application No. 9-351481. (WO 9 9/32 468), the method described in Japanese Patent Application No. 10-218885 and Japanese Patent Application No. 10-234 388, Alternatively, after converting a hydroxymethyl group to a halogenomethyl group according to the method described in Reference Examples or Examples described later, amines (eg, secondary amines (Ν-methyl-Ν-tetrahydropyran-4-ylamine, etc.) Anilide derivatives having MCP-1 receptor antagonism, CCR5 antagonism, etc. by reacting with tertiary amines (such as Ν, Ν-dimethylamino-4-tetrahydropyran), etc. (Japanese Patent Application No. 9-35 1480) (WO 99/3210), Japanese Patent Application No. 9-351 481 (WO 99/3324) 8), the target compound described in Japanese Patent Application No. 10-218 875 and Japanese Patent Application No. 10-234 388).

,-■

Can be.

 The target compound obtained in each of the above reactions can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

 The present invention will be described in further detail with reference to the following Reference Examples and Examples. However, these are merely examples and do not limit the present invention in any way. In the present specification, unless otherwise specified, “%” indicates “wZw%”. Example

Example (1)-1

Production of trimethylbenzimidazole (using N-chloro succinimide) A solution of benzimidazole (0.59 g) and N-chloro succinimide (3.3 g) in THF (20 ml) was added to ice Under cooling, trimethyl phosphite (3. Oml) was added. The temperature was raised and the mixture was stirred under reflux conditions for 4 hours. After cooling, methylene chloride was added, and the mixture was washed with 1N aqueous sodium hydroxide and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by silica gel chromatography (methylene chloride / ethyl acetate = 2/1), and the effective fraction was concentrated to give trimethylbenzimidazole (0.15 g, 23% yield) as an oil. . HPLC and 匪 -band R were compared and compared with the standard.

84- 删 R (DMS0-d ₆ , δ, 300MHz); 3.84 (3Η, s), 7.26-7.40 (3H, m), 7.79-7.82 (1H, m), 7.86 (1H, s).

Example (1) One 2

Preparation of trimethylbenzimidazole (when N-bromosuccinimide is used) To a solution of benzimidazole (0.59 g) and N-bromosuccinimide (4.5 g) in THF (20 ml) Under ice cooling, trimethyl phosphite (3. Oml) was added. Raise the temperature and stir for 4 hours under reflux conditions Stirred. After cooling, the content of trimethylbenzimidazole was measured by HPLC to find that it was 0.17 g (yield 26%).

Example (1) One three

Dimethyl chloride- [N- [3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carbonyl] -4-aminobenzyl] -4-tetrahydrobiranylammonium (When using trimethyl phosphate as solvent)

 3- (4-methylphenyl) -N- [4-[(tetrahydrovirane-4-yl-N-methylamino) methyl] phenyl]-8, 9-dihydro-7H-benzocycloheptene-6- To a solution of carboxamide (0.50 g) and N-chlorosuccinimide (0.42 g) in trimethyl phosphate (5 ml) was added trimethyl phosphite (0.37 ml) under ice-cooling. The temperature was raised to 80 ° C., and the mixture was stirred for 6 hours. After allowing to cool, 1.8N-HC4 IPE (3 ml) and acetone (0.5 ml) were added, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration, and then washed with acetone / ethyl acetate (lml / 3ml). The crystals are dried under reduced pressure to give dimethyl chloride- [N- [3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carbonyl] -4-aminobenzyl] -4-tetrahydropyrani Luanmonium (0.49 g, 89% yield) was obtained.

'H- image _{R (DMS0 - d 6, δ} , 300MHz);. 1. 85-2 18 (6Η, m), 2. 34 (3H, s), 2. 64 (2H, m), 2. 78 (8H, m), 3.35 (2H, m), 3.50-3.75 (1H, m), 4.04-4.07 (2H, m), 4.46 (2H, s), 7.26-7.88 (12H, m), 10.22 (1H, s).

Example (1) 1-4

Dimethyl chloride- [N- [3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-caprolponyl] -4-aminobenzyl] -4-tetrahydrobiranylammonium (When butyl acetate is used as a solvent)

3- (4-methylphenyl) -N- [4-[(tetrahydrovirane-4-yl-N-methylamino) methyl] phenyl] -8,9-dihydro-7H-benzocycloheptene-6-carboxamide (0 Trimethyl phosphite (0.37 ml) was added to a solution of .50 g) and N-chloro succinimide (0.42 g) in butyl acetate (5 ml) under ice-cooling. The temperature was raised to 80 ° C., and the mixture was stirred for 11 hours. After cooling, 6N-hydrochloric acid aqueous solution (3 ml) was added and the mixture was concentrated. THF (5 ml) was added to the concentrate, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration, and then washed with acetone / ethyl acetate (lml / 4ml). The crystals are dried under reduced pressure to give dimethyl chloride- [N- [3- (4-methylphenyl) -8,9-dihydro-7H- Benzocycloheptene-6-carbonyl] -4-aminobenzyl] -4-tetrahydrovinyl diammonium (0.43 g, 78% yield) was obtained.

Example (1) — 5

Dimethyl- [N- [3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carbonyl] -4-aminobenzyl] -4-tetrahydrovinylammonium methanesulfonate Manufacture

 3- (4-methylphenyl) -N- [4-[(tetrahydrovirane-4-ylmethylamino) methyl] phenyl] -8,9-dihydro-7H-benzocycloheptene-6-carboxamide (1. Og) and N-chloro succinimide (0.56 g) in trimethyl phosphate (½1) were added under ice-cooling with trimethyl phosphite (0.50 ml). The temperature was raised to 80 ° C, and the mixture was stirred for 4 hours. After cooling, IPE (isopropyl ether) (7 ml), acetone (5 ml) and methanesulfonic acid (0.27 ml) were added, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration, and then washed with acetone / ethyl acetate (1 ml / 4 ml). The crystals are dried under reduced pressure to give dimethyl- [N- [3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carbonyl] -4-aminobenzyl] -4- Tetrahydrovinylalanmonium methanesulfonate (0.9 g, yield 75%) was obtained.

 Each analysis was performed on samples obtained from recrystallization (Ethanol).

mp.217-219 ° C (decomp.).

'H-NMR (DMS0-d ₆ , δ, 300ΜΗζ); 1.75-2.20 (6Η, m), 2.32 (3Η, s), 2.34 (3H, s), 2.64 (2H, m), 2.75-3.00 (8H , m), 3.30-3.45 (2H, m), 3.50-3.75 (1H, m), 4.00-4.25 (2H, m), 4.47 (2H, s), 7.25-7.90 (12H, m), 10.3 (1H , s).

Anal for C ₃₄ H ₄₂ N ₂ 0 ₅ S.

 Calcd: C, 69.12; H, 7.17; N, 4.74; S, 5.43.

Found: C, 69.14; H, 7.19; N, 4.82; S, 5.41.

Example (2) — 1

 Production of N, N-dimethyl-N-tetrahydropyran-4-ylamine:

To a mixture of 70 g of tetrahydro-4H-pyran-4-one and 394 g of a 24% solution of dimethylamine in tetrahydrofuran was added 7.0 g of ¾-Pd-C (wet) under nitrogen, and the mixture was stirred under hydrogen at 2 kgf / cm ² for 4.5 hours. . The catalyst was filtered and washed with tetrahydrofuran. Combine the filtrate and washings And concentrated. The residue was distilled under reduced pressure (65-75 ° C / 30 imnHg) to obtain the title compound as a colorless oil (74.6 g, yield 83%).

 'Η-- 丽 R (300MHz, CDC1,) δ: 1.5-1.6 (2Η, m), 1.7-1.8 (2H, m), 2.1-2.4 (7H, m),

,-'

 3.3-3.5 (2H, m), 3.9-4.1 (2H, m).

Example (2) — 2

 Preparation of N-methyl-N-tetrahydropyran-4-ylamine:

Tetrahydro-4H-pyran-4-one 25.To a 400 ml solution of Og in tetrahydrofuran, add 76.7 g of a 40% methanol solution of methylamine and 3.75 g of 5% -Pd-C (wet) under nitrogen, and add hydrogen. lower, 30 ° (:... , 5kgf / cm 2 was stirred after the completion of the reaction, the catalyst was filtered off and washed with tetrahydrofuran run filtrate and was washings combined concentrate residue was distilled under reduced pressure (70.5-71.5 ° C / 28 mmHg) to give the title compound (19.97 g, yield 69.4%) as a colorless oil.

_{Ή-NMR (300MHz, CDC1 3} ) δ: 1.3-1.5 (3H, m), 1.7-1.9 (2H, m), 2.42 (3H, s), 2.5-2.6 (1H, m), 3.3-3.5 (2H , m), 3.8-4.0 (2H, m).

Example (2) — 3

Production of N- (4-nitrobenzylyl) -N- (tetrahydropyran-4-yl) methylamine:

A suspension of 18.49 g of N-methyl-N-tetrahydropyran-4-ylamine and 22.18 g of potassium carbonate in 19 ml of Ν, Ν-dimethylformamide was stirred under ice-cooling, and 36.67 g of 4-nitrobenzyl bromide was added to N, N-dimethylformamide. A 76 ml solution was added dropwise. The ice bath was removed, and the mixture was stirred at room temperature for 3 hours. 570 ml of ethyl acetate was added, and the mixture was washed with 5% saline and water (three times). The mixture was extracted with 1N-hydrochloric acid and washed with ethyl acetate. Ethyl acetate was added to the aqueous layer, saturated aqueous sodium bicarbonate was added to make the mixture weakly alkaline, and the layers were separated. The organic layer was washed with water (3 times) and the solvent was distilled off to obtain the title compound (34.30 g, yield 85%) as a yellow oil.

_{Ή-MR (300MHz, CDC1 3} ) δ: 1.5-1.8 (4Η, m), 2.21 (3H, s), 2.5-2.7 (1H, m), 3.38 (2H, dt, J = ll.5, 2.5Hz ), 3.68 (2H, s), 4.0-4.1 (2H, m), 7.51 (2H, d, J-8.8Hz), 8.18 (2H, d, J = 8.8Hz).

Example (2) — 4

 Preparation of 4-[-methyl-N- (tetrahydrovirane-4-yl) aminomethyl] aniline'dihydrochloride:

-(4-Nitrobenzyl)--(tetrahydrovirane-4-yl) methylamine 17.23g 0.167 g of ferric chloride and 1.72 g of activated carbon Shirasagi A were added to a 173 ml solution of drofuran. Under reflux with heating, 11.69 ml of hydrazine monohydrate was slowly added dropwise, followed by stirring at 60 to 65 ° C for 4 hours. After standing to cool, insolubles were filtered and washed with tetrahydrofuran. After the filtrate and the washing were combined, the solvent was distilled off. Ethyl acetate was added to the residue, and the mixture was washed twice with saturated saline. After evaporating the solvent, the residue was dissolved in isopropyl alcohol, concentrated hydrochloric acid (13.94 ml) was added, the mixture was stirred at room temperature for 30 minutes, and then stirred under ice cooling for 1 hour. The obtained crystals were collected by filtration, washed with isopropyl alcohol, and dried to give the title compound (19.0 g, yield 94.0%) as pale yellow crystals.

'H- Awakening: _{R (300MHz, D 2 0)} δ:.. 1. 5-1 9 (4Η, m), 2. 45 (3H, s), 3. 22 (2H, t, J = l l 6 Hz), 3.3.3.4 (1H, m), 3.84 (2H, br d, J = l l. 6 Hz), 3.95 (1H, d, J = 13.0 Hz), 4.33 (1H, d, J = 13.0Hz), 7.21 (2H, d, J = 8.4Hz), 7.35 (2H, d, J = 8.4Hz).

Example (2) — 5

 Preparation of 4- [N-methyl-N- (tetrahydrovirane-4-yl) aminomethyl] aniline'dihydrochloride:

 To a suspension of 0.2 g of Raney nickel in 5 ml of methanol was added dropwise 0.97 ml of hydrazine monohydrate under ice cooling. Under ice-cooling, a solution of 1.Og of N- (4-nitrobenzyl) -N- (tetrahydropyran-4-yl) methylamine in 5 ml of tetrahydrofuran was added dropwise, followed by heating to room temperature. After the reaction was completed, insolubles were filtered and washed with tetrahydrofuran. After combining the filtrate and the washing, the solvent was distilled off. 20 ml of ethyl acetate and 10 ml of tetrahydrofuran were added to the residue, and the mixture was washed three times with a saturated saline solution. Under ice-cooling and stirring, 0.81 ml of concentrated hydrochloric acid was added, and the obtained crystals were collected by filtration, washed with isopropyl alcohol, dried, and dried to give the title compound (0.95 g, yield 81.1%) as pale yellow crystals. I got

Example (3)-1

 Synthesis of 4- (4-methylphenyl) benzaldehyde

After dissolving 4- (4-methylphenyl) benznitrile (200 g) in THF (2), at -15 to -5 ° C, VITRIDE (registered trademark) (sodium bis (2-methoxyethoxy) aluminum hydride) (300 g) The reaction solution was added to 20 v / v% sulfuric acid aqueous solution (2 L) while cooling with ice, and water (2 L) and ethyl acetate (2 L) were added, and the mixture was heated to 40 ° C. After separation, the aqueous layer was extracted with ethyl acetate / THF (3/1, 800 ml), and the organic layer was saturated with 5% saline (1 L). Washed with aqueous sodium hydrogen carbonate (1 L) and 5% saline (1 L). The organic layer was concentrated, IPA (isopropyl alcohol) (700 ml) was added to the residue, and the crystals were collected by filtration. Drying under reduced pressure gave 4- (4-methylphenyl) benzaldehyde (183 g, yield 90%).

Immediately.111-112 ° C.

Anal for C ₁₄ H _l2 0.

 Calcd: C, 85.68; H, 6.16.

Found: C, 85.61; H, 6.01.

'H- negation _{R (CDC1 3, 6, 300MHz} ); 2.41 (3H, s), 7.29 (2H, d, J = 8.1Hz), 7.54 (2H, d, J = 8.1Hz), 7.74 (2H, d , J = 8.4Hz), 7.93 (2H, d, J = 8.4Hz), 10.04 (1H, s). IR (KBr, v _m ; 1700, 1602, 1209, 1186, 1166, 809.

Example (3) — 2

 5- [4- (4-methylphenyl) phenyl] -4-pentenoic acid

 A suspension of 9-carboxypropyltriphenylphosphonamide (98.5 g) in THF (IL) was heated to 60 ° C, and a 28% sodium methylamine-methanol solution (89.0 g) was added thereto. And then add 4- (4-methylphenyl) benzaldehyde (30 g)

A THF (300 ml) solution was added dropwise, and the mixture was stirred for 1 hour as it was. The reaction solution was cooled to 40 ° C, and water (900 ml), potassium hydroxide (26 g) and IPE (isopropyl ether) (400 ml) were added thereto. After separation, the organic layer was extracted with 3% aqueous potassium hydroxide (600 ml and 500 ml). The aqueous layer was made acidic with 6N-hydrochloric acid solution and extracted with ethyl acetate / THF (600 ml / 600 ml). The organic layer was washed with 10% saline (1 L). The organic layer was concentrated, and water residue (30/70; 400 ml) was added to the residue, followed by stirring at room temperature for 1 hour and then at 5 ° C for 1 hour. The precipitated crystals were collected by filtration. Drying under reduced pressure gave 5- [4- (4-methylphenyl) phenyl] -4-pentenoic acid (36.7 & 90% yield).

mp. 198-199 ° C.

Anal for C ₁₈ H ₁₈ 0 ₂ .

 Calcd: C, 81.17; H, 6.81.

Found: C, 81.0; H, 6.68.

'H-圆 R (DMS0-d ₆ , δ, 300 MHz); 2.34 (3H, s), 2.39-2.41 (4H, m), 6.27-6.39 (1H, m), 6.46 (1H, d, J = 15.6 Hz), 7.26 (2H, d, J = 8.1Hz), 7.44 (2H, d, J = 8.1Hz), 7.54-7.60 (4H, m), 12.13 (1H, brs).

IR (KBr, Level ₃ ); 2730, 2653, 2578, 1691, 1496, 1255, 790.

Example (3) — 3

 5- [4- (4-methylphenyl) phenyl] pentanoic acid

 5- [4- (4-methylphenyl) phenyl] -4-pentenoic acid (48.2 g) in THF (1 solution)

Heated to 40 ° C. Under a nitrogen atmosphere, 5% Pd-C (wet, 2.4 g) was added, followed by hydrogen substitution,

Stir for 2 hours. Pd-C was removed and washed with THF (100 ml). Concentrate the filtrate to the residue

IPE (200 ml) was added, and the mixture was stirred at room temperature for 1 hour and then at 5 ° C for 1 hour. The precipitated crystals were collected by filtration. Drying under reduced pressure gave 5- [4- (4-methylphenyl) phenyl] pentenoic acid (47.2 g, yield 97%).

mp. 175-176 ° C.

_{Anal for C l8 H 20 O 2} .

 Calcd: C, 80.56; H, 7.51.

 Found: C, 80.67; H, 7.41.

_{'H-NMR (CDC1 3,} (5, 300MHz); 1.69-1.73 (4H, m), 2.38-2.40 (5H, m), 2.64-2.68

(2H, m), 7.21-7.24 (4H, m), 7.43-7.48 (4H, m).

IR (KBr, v _max ); 1700, 1500, 810.

Example (3)-4

 Synthesis of 3- (4-methylphenyl) -6,7,8,9-tetrahydro-5H-benzocycloheptan-5-one (method via acid chloride)

To a solution of 5- [4- (4-methylphenyl) phenyl] pentanoic acid (10.Og) in THF (100 ml) was added DMF (0.6 ml). At room temperature, oxalyl chloride (6.4 ml) was added dropwise and stirred for 30 minutes. After concentration, methylene chloride (100 ml) was added and dissolved, and aluminum chloride (7.5 g) was added at 10 ° C or lower. After stirring at the same temperature for 1 hour, the mixture was added to ice water (100 ml). After adding ethyl acetate (100 ml) and separating the solution, the organic layer was washed with 20% aqueous citric acid (72 ml X2), 20% saline (130 ml), 7% aqueous sodium bicarbonate (130 ml), and 20% saline (130 ml). And washed. After concentrating the organic layer, IPE (72 ml) was added and dissolved, silica gel (12 g) was added, and the mixture was stirred at room temperature for 30 minutes. The silica gel was removed and the filtrate was concentrated. The concentrate was purified by a silica gel column, and the effective fraction was concentrated. Add n-hexane to the concentrate, crystallize at -20 ° C, and dry the obtained crystals. Was. The crystals were dissolved by heating in methanol (40 ml), activated carbon (0.22 g) was added, and the mixture was stirred for 30 minutes. The activated carbon was removed by filtration, and the filtrate was concentrated. Methanol (22 ml) was dissolved in the concentrate by heating and cooled to room temperature. Water (4.4 ml) was added, and the mixture was stirred at 10 ° C or lower for 1 hour. The crystals are collected by filtration, and the crystals are dried under reduced pressure to give 3- (4-methylphenyl) -6,7,8,9-tetrahydro-5H-benzocyclohexane-5-one (3.4 g, yield 36%). %).

Anal for C ₁₈ H ₁₈ 0.

Cal cd: C, 86.36; H, 7.25.

Found: C, 86.54; H, 7.25.

_{'H-NMR (CDC1 3,} (5, 300MHz);. 1. 83-1 92 (4H, m), 2. 38 (3H, s), 2. 76 (2H, m), 2. 96 (2H , m), 7.22-7.26 (3H, m), 7.50 (2H, d, J = 8.0 Hz), 7.62-7.64 (1H, m), 7.95 ( (1H, d, J = 2.0 Hz)

Example (3) — 5

 Synthesis of 3- (4-methylphenyl) -6,7,8,9-tetrahydro-5H-benzocycloheptan-5-one (Method using PPA)

 5- [4- (4-Methylphenyl) phenyl] pentanoic acid (3. Og) was added to polyphosphoric acid (60 g), and the mixture was stirred at about 100 ° C. for 8 hours. The reaction solution was cooled to about 50 ° C, and while maintaining the temperature, ice (40 g) was added, followed by toluene (20 ml). After liquid separation, the aqueous layer was further extracted with toluene (5 ml). The organic layers were combined and washed with water (15 ml × 2), 25% aqueous ammonia (20 ml × 2), and water (20 ml). The organic layer was concentrated, and the residue was dissolved by adding acetone (2 ml), and cooled to 5 ° C. After the crystals were precipitated, water (4 ml) was added, and the mixture was stirred at the same temperature for 30 minutes. The crystals were collected by filtration, and the crystals were washed with acetone / methanol / water (1/1/2, 6 ml). Drying under reduced pressure gave 3- (4-methylphenyl) -6,7,8,9-tetrahydro-5H-benzocycloheptan-5-one (2.6 g, yield 95%).

Example (3) — 6

Synthesis of 3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carbaldehyde

To a solution of methyl orthoformate (0.31 ml) in methylene chloride (2 ml) at −30 ° C. was added boron trifluoride getyl ether complex (0.60 ml), the temperature was raised to 0 ° C., and the mixture was stirred for 15 minutes. . -Cool down to 65 ° C and add 3- (4-methylphenyl)-6,7,8,9-tetrahydro-5H- A solution of 5-one (0.5 g) in methylene chloride (1 ml) and diisopropylethylamine (103 ml) were added, and the mixture was stirred for 1 hour. The temperature was further raised to 0 ° C, and the mixture was stirred for 4.5 hours. Aqueous sodium bicarbonate solution (10 ml) was added while cooling on ice, and the mixture was extracted with ethyl acetate. 2v / v% of organic layer

After washing with aqueous sulfuric acid and saturated saline, the extract was dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain 6-dimethoxymethyl-3- (4-methylphenyl) -6,7,8,9-tetrahydro-5H-benzocycloheptan-5-one (0.65 g) as an oil. .

'H- Ran _{(CDC1 3, δ, 300MHz)} ; 1.67-1.75 (2H, m), 2.05-2.13 (2H, m), 2.38 (3H, s), 2.96-2.99 (2H, m), 3.12-3.19 (1H, m), 3.41 (3H, s), 3.43 (3H, s), 4.90 (1H, d, J = 6.8 Hz), 7.22-7.26 (3H, m), 7.50 (2H, d, J = 8.1 Hz), 7.59 (1H, dd, J = 7.9, 2.0 Hz), 7.83 (1H, d, J = 2.0 Hz).

 The oil was dissolved in ethanol (6 ml), sodium borohydride (0.30 g) was added at room temperature, and the mixture was stirred as it was for 3 hours. Under ice-cooling, 6N aqueous hydrochloric acid (2 ml) and ethyl acetate (6 ml) were added, and the mixture was stirred at room temperature for 2 days. After liquid separation, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The organic layer was concentrated to give an oil. The oily substance was purified by a silica gel column (n-hexane / ethyl acetate = 20/1), and the effective fraction was concentrated to give 3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene. -6-carbaldehyde (0.26 g, 50% yield) was obtained.

Immediate. 102-104 ° C.

Anal for C ₁₉ H ₁₈ 0.

Calcd: C, 86.99; H, 6.92.

Found: C, 86.63; H, 6.96.

E -丽_{R (CDC1 3, δ, 300MHz} ); 2.03 (2H, tt, J = 5.8, 5.3 Hz), 2.40 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 2.93 (2H, t, J = 5.3 Hz), 7.23-7.30 (4H, m), 7.47-7.51 (3H, m), 7.59 (1H, d, J = l.8 Hz), 9.59 (1H, s).

IR (nujol, cm- ¹ ); 1681, 1633, 1147, 1132, 806.

Example (3) — 7

 Synthesis of 3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carbaldehyde

3- (4-methylphenyl) -6,7,8,9-tetrahydro-5H-benzocycloheptane-5-year-old To a solution of toluene (4.lg) in THF (40 ml) was added sodium borohydride (0.74 g) under ice-cooling, and the mixture was stirred for 1 hour. The reaction solution was acidified by adding 1N-hydrochloric acid aqueous solution, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The organic layer was concentrated to give an oil. After the oily substance was purified by silica gel column (n-hexane / ethyl acetate = 16/1), the effective fraction was concentrated and the crystalline 5-hydroxy-3- (4-methylphenyl) -6,7,8,8 9-Tetra hydro-5H-benzocycloheptane (2. Og) was obtained.

'H- image _{R (CDC1 3, (5,} 300MHz):. 1. 76-1 82 (4H, m), 2. 38 (3H, s), 2. 75 (2H, m), 2. 93 ( 2H, m), 4.97 (1H, d, J = 7.1 Hz), 7.13-7.67 (7H, m).

 The above crystals (0.25 g) were dissolved in DMF (2.2 ml), and phosphorus oxychloride (1.4 ml) was added under ice cooling. The temperature was raised to 90 ° C, and the mixture was stirred for 16 hours. Water was added while cooling with ice, and ethyl acetate was extracted. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The organic layer was concentrated to give an oil (0.12 g). From HPLC and Ή-NMR, it was confirmed that the oil was 3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carbaldehyde.

Example (3)-8

 Synthesis of 3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carboxylic acid

 To a solution of methyl orthoformate (25.5 ml) in THF (80 ml) was added boron trifluoride getyl ether complex (36.2 ml) at -10 ° C, and the mixture was heated to 0 ° C and stirred for 30 minutes. -Cool to 10 ° C and add 3- (4-methylphenyl) -6,7,8,9-tetrahydro-5H-benzocycloheptan-5-one (10.Og) solution in THF (20ml), diisopropyl Ethylamine (61.6 ml) was added and stirred for 5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. After concentrating the organic layer, IPE and silica gel (20 g) were added, and the mixture was stirred for 15 minutes. After the silica gel was removed by filtration, the filtrate was concentrated to obtain an oily substance of 6-dimethoxymethyl-3- (4-methylphenyl) -6,7,8,9-tetrahydro-5H-benzocycloheptane-5-one (18.7 g) was obtained.

The oil was dissolved in ethanol (180 ml), sodium borohydride (4.5 g) was added at room temperature, and the mixture was stirred for 1 hour. Under ice-cooling, 6N aqueous hydrochloric acid (40 ml) was added, and the mixture was stirred at 65 ° C for 1 hour. The reaction solution was concentrated and extracted with ethyl acetate. The layers were separated, and the organic layer was washed with saturated saline. The organic layer is concentrated and the crystalline 3- (4-methylphenyl)-8, 9-dihydro-7H- Benzocycloheptene-6-carbaldehyde (14.6 g) was obtained.

 The above crystals were added to a mixed solution of toluene (150 ml) -methanol (70 nU), to which was added 30% aqueous hydrogen peroxide (5.4 ml), aqueous sodium dihydrogen phosphate (40 ml, pH = 2), and chlorine dioxide. Acid nato

 , '

Lithium water (7.2 g / 15 ml) was added. The reaction solution was stirred at 50 ° C for 1 hour. After cooling, 10% aqueous sodium thiosulfate (40 ml) was added, and the mixture was separated. 1N-potassium hydroxide aqueous solution was added, and toluene was distilled off. After washing the aqueous solution with IPE, the aqueous layer was adjusted to be acidic with 6N-hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution. The organic layer was concentrated, and isopropanol / water (15 ml / 15 ml) was added to the concentrate, followed by stirring for 1 hour under ice cooling. The precipitated crystals were collected by filtration and washed with isopropanol / water (10 ml / 10 ml). The crystals were dried under reduced pressure to give crystalline 3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carboxylic acid (6.lg, consistent yield 55%). .

 In each analysis, crystals obtained from recrystallization (acetone-water) were used.

Anal for C ₁₉ H, ₈ 0 ₂ .

Cal cd: C, 81.99; H, 6.52.

Found: C, 81. 91; H, 6.52.

_{'H- NMR (CDC1 3, δ} , 300MHz);.. 2. 07-2 13 (2H, m), 2. 39 (3H, s), 2. 67-2 71 (2H, m), 2. 86-2. 89 (2H, m), 7.20-7. 26 (4H, m), 7.43-7. 55 (3H, m), 7.91 (1H, s). ) — 9

 Synthesis of N- (4-hydroxymethylphenyl) -3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carboxamide

DMF (2 ml) was added to a solution of 3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carboxylic acid (200 g) in THF (L 6 L). Oxalyl chloride (125 ml) was added dropwise thereto under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction was concentrated and THF (2 L) was added to the concentrate. In another container, a THF (2 L) solution of p-aminobenzyl alcohol (106 g) and triethylamine (400 ml) was ice-cooled. The acid chloride solution prepared above was added dropwise thereto under ice cooling, and the mixture was stirred for 1 hour. Water (0.8 L) was added to the reaction solution, and the mixture was separated. The aqueous layer was further extracted with ethyl acetate (4 L). Combine the organic layers and wash with 1N hydrochloric acid aqueous solution (1.2 L x 3), saturated saline (1.2 L), saturated aqueous sodium hydrogen carbonate (0.8 L), and 15% saline (1.2 L x 2) did. The organic layer was concentrated, and ethyl acetate (1.6 L) was added thereto. The crystals are filtered and then The crystals were washed with ethyl acetate (0.6 L). The crystals were dried under reduced pressure to obtain N- (4-hydroxymethylphenyl) -3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carboxamide (263 g, yield 95%). Was.

 ,-

Ή over顺_{R (CDC1 3, δ, 300MHz} ); 2. 16 (. 2H, tt, J = 6 8, 5. 8Hz), 2. 39 (3H, s), 2. 72 (2H, t, J = 6.8 Hz), 2.88 (2H, t, J = 5.8 Hz), 4.67 (2H, s), 7.21-7.63 (12H, m) .Reference example 1

 Synthesis of N- (4-chloromethylphenyl) -3- (4-methylphenyl) -8,9-dihydroxy- 7H-benzocyclohepten-6-carboxamide

 N- (4-Hydroxymethylphenyl) -3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carboxamide (250 g) suspended in THF (2.5 L) After the suspension was cooled to 5 ° C, thionyl chloride (71.3 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (2.5 L) and 10% saline were added to the reaction solution, and the mixture was separated. The aqueous layer was further extracted with ethyl acetate (1.5 L). The organic layers were combined, and washed with 10% saline (1.5 L), saturated aqueous sodium hydrogen carbonate (1.5 L), and saturated saline (1.5 L × 2). The organic layer was dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration and further washed with ethyl acetate / THF (0.5 L / 0.5 L). The filtrate was concentrated, to which was added ethyl acetate (4.5 L), and then concentrated to 1.5 L. After the concentrate was stirred under ice cooling for 2 hours, the crystals were collected by filtration, and the crystals were washed with ethyl acetate / チ ル (1/2, 0.5 L). The crystals are dried under reduced pressure to give N- (4-chloromethylphenyl) -3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carboxamide (223 g, yield 85%) I got

_{'H-NMR (CDC1 3,} δ, 300MHz);.. 2. 13-2 19 (2Η, m), 2. 39 (3H, s), 2. 68-2 72 (2H, m), 2. 85-2.89 (2H, m), 4.58 (2H, s), 7.20-7.69 (12H, m).

Reference example 2

Synthesis of dimethyl chloride- [N- [3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carbonyl] -4-aminobenzyl] -4-tetrahydrovinylammonium

A solution of N, N-dimethylamino-4-tetrahydropyran (92 g) in DMF (950 ml) was heated to 50-55 ° C, and N- (4-chloromethylphenyl) -3- (4-methylphenyl) was added thereto. ) Drop a solution of -8, 9-dihydro-7H-benzocycloheptene-6-carboxamide (190g) in DMF (950ml) I dropped it. After stirring at the same temperature for 2 hours, acetone (1.9 L) was added while maintaining the same temperature, and the mixture was stirred for 30 minutes. The mixture was cooled to 30 ° C. in about 1 hour and stirred for 1 hour. The precipitated crystals were collected by filtration, and the crystals were washed with acetone (760 ml). The crystals are dried under reduced pressure to give a crude salt.

, -Dimethyl chloride- [N- [3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carbonyl] -4-aminobenzyl] -4-tetrahydrovinylalanmonium (229 g, 91% yield).

 Crude dimethyl chloride- [N- [3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carbonyl] -4-aminobenzyl] -4-tetrahydrovinylammonium ( 50 g) was added to water / ethanol (15/8/5; 400 DIO) and dissolved by heating to 55. C. Activated carbon (1.5 g) was added, heated to 70 ° C and stirred for 15 minutes. The filtrate was stirred at room temperature for 22 hours and under ice-cooling for 10 hours, and the precipitated crystals were collected by filtration, washed with ethanol (80 ml), and dried under reduced pressure to give purified dimethyl chloride- [N- [ 3- (4-methylphenyl) -8,9-dihydro-7H-benzocycloheptene-6-carbonyl] -4-aminobenzyl] -4-tetrahydrovinylalanmonium (40 g, yield 80%) Obtained.

'H-wake R (DMS0-df ₎ , (5, 300MHz); 1.85-2.18 (6H, m), 2.34 (3H, s), 2.64 (2H, m), 2, 78 (8H, m), 3.35 (2H, m), 3.50-3.75 (1H, m), 4.04-4.07 (2H, m), 4.46 (2H, s), 7.26-7.88 (12H, m), 10.22 (1H, s).

Reference example 3

 3- (4-Methylphenyl) 1 N— [4- [(N-tetrahydropyran-14-yl-1N-methylamino) methyl] phenyl] — 8,9-dihydro-17H-benzocycloheptene-1 6-carboxamide Synthesis of

3- (4-Methylphenyl) -18,9-dihydro-17H-benzocycloheptene-6-capillonic acid (0.2 g) in dichloromethane (5 ml) was added to a solution of oxalyl chloride (0 .19 ml) and dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 2 hours. After distilling off the solvent, the residue was dissolved in tetrahydrofuran, and 4-CN—methyl-1-N— (tetrahydropyran-14-yl) aminomethyl] aniline (0.17 g) and triethylamine (0.3 ml) in tetrahydrofuran (10 ml) The solution was added dropwise under ice-cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with water and saturated saline and then sulfuric anhydride Dried with magnesium. The solvent was distilled off under reduced pressure, and the precipitated crude crystals were recrystallized from ethyl acetate-hexane to give 3- (4-methylphenyl) -N- [4-[(N-tetrahydropyran-1-yl-N- Methylamino) methyl] phenyl] _8,9-dihydro-7H-benzocycloheptene-6-carboxamide (0.29 g) was obtained as colorless crystals.

m 161-162 ° C.

 'H-NMR ((5 pin, CDC): 1.59-1.77 (4H, m), 2.13-2.21 (2H, m), 2.21 (3H, s), 2.40 (3H, s), 2.55-2.75 (3H, m), 2.86-2.92 (2H, m), 3.37 (2H, dt, J = 2.8, 10.9Hz), 3.57 (2H, s), 4.01-4.07 (2H, m), 7.21-7.33 (4H, m) , 7.41-7.58 (7H, m), 7.63 (1H, s).

IR (KBr) v: 2938, 1651cm " ¹ .

Anal, for C32H36 2O2:

Calcd: C, 79.97; H, 7.55; N, 5.83.

Found: C, 79.63; H, 7.43; N, 5.64. Industrial applicability

 (1) According to the present invention, a methylamine derivative can be produced safely and by a method suitable for mass synthesis. In addition, a method for producing a quaternary methylammonium salt can be produced by a method having high purity and suitable for mass synthesis.

 (2) Further, according to the present invention, it is possible to produce a tetrahydropyran-4-ylamine derivative inexpensively, simply, and by a method suitable for mass synthesis. Further, the present invention provides a production method in which the generation of by-products is small and the generated by-products are easily separated, and the reaction conditions such as reaction temperature, reaction time, reaction reagent, and solvent are provided. A production method more suitable for mass synthesis is provided.

 (3) Further, according to the present invention, it is possible to produce benzocycloheptene having a tolyl group at the 3-position by an inexpensive and simple method suitable for mass synthesis. In addition, the present invention provides a production method in which the generation of by-products is small and the generated by-products can be easily separated, and the reaction conditions such as reaction temperature, reaction time, reaction reagent, and solvent are synthesized in a large amount. Provides a more suitable manufacturing method.

Claims

 The scope of the claims 1. A method for producing a methylamine derivative, comprising reacting an amine, a trimethyl phosphite derivative, and an oxidizing agent.  2. A method for producing a quaternary methyl ammonium salt, comprising reacting a tertiary amamine, a trimethyl phosphite derivative and an oxidizing agent.  3. The method according to claim 1, wherein the oxidizing agent is N-halogenamide.  4. The production method according to claim 1, wherein the oxidizing agent is N-halogenosuccinimide. 5. A method for producing a quaternary methyl ammonium salt, comprising reacting a tertiary amine, a trimethyl phosphite derivative with an N-halogenoamide, and contacting with an acid.  6. The method according to claim 5, wherein the N-octalogenoamide is N-octalogenosuccinimide. 7 Expression

Wherein R represents an alkyl group which may be substituted, R ³ represents a hydrocarbon group which may be substituted, and ring A may further have a substituent other than the substituent R A compound represented by the formula: or a salt thereof, trimethyl phosphite and N-octane genosuccinimide, and contacting with an acid.

 [In the formula, W— represents a deprotonated acid, and the other symbols have the same meanings as described above. ] A method for producing a quaternary ammonium salt represented by the formula: 8. The method according to claim 7, wherein R ³ is a methyl group.  9 Expression

Reacting a compound represented by the formula or a salt thereof, trimethyl phosphite and N-halogenosuccinimide, and contacting with an acid;

[Wherein, w- represents a deprotonated form of an acid. A method for producing a quaternary ammonium salt represented by the formula:  10. Expression

 [Wherein, Ms represents a mesyl group]  1 1. Expression

And a compound represented by the formula  R NH [Wherein, R ¹ and R ² are the same or different and are each a hydrogen atom or an optionally substituted carbon atom. Shows a hydrogen group. Wherein the compound or salt thereof is reacted under catalytic reduction conditions.

 [Wherein each symbol has the same meaning as described above. And a salt thereof. 1 2. R 'and R ² process according to claim 1 1, wherein the same or different and each represents a hydrogen atom or a methyl group.  1 3.

 [In the formula, Me represents a methyl group. Or a salt thereof. 1 4.

[Wherein, R ³ represents an optionally substituted hydrocarbon group. ] Or a salt thereof represented by the formula

[Wherein, X represents a leaving group. ] Reacting a compound represented by the formula:

 [Each symbol in the formula is as defined above. And a salt thereof. 15. The production method according to claim 14, wherein R ³ is a methyl group.  16. The production method according to claim 15, wherein X is a halogen atom.

[Wherein, R ³ represents an optionally substituted hydrocarbon group. Wherein the compound or a salt thereof is reduced with hydrazine or a hydrate thereof in the presence of a catalyst.

[Each symbol in the formula is as defined above. And a salt thereof. 18. The production method according to claim 17, wherein R ³ is a methyl group.  19. Formula obtained by the production method according to claim 17

[Wherein, R ³ represents an optionally substituted hydrocarbon group. ] Or a salt thereof represented by the formula

 [Wherein R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. Which is characterized by reacting

 [Wherein each symbol has the same meaning as described above. The method for producing a compound represented by the formula 2 0. R ³ is The process according to claim 1 9, wherein a methyl group. 2 1.

[Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. A formula characterized by being subjected to a reduction reaction

 [Wherein the symbols have the same meanings as described above], or a method for producing a salt thereof. 2 2.

[Wherein R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. formula

 Wherein X and H each represent a halogen atom, and Ph represents a phenyl group.

 [Wherein the symbols have the same meanings as described above], or a method for producing a salt thereof. 2 3.

Wherein R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R. , '  2 4. Expression

 [Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. A formula characterized by being subjected to a reduction reaction

 [Wherein the symbols have the same meanings as described above], or a method for producing a salt thereof. 2 5 Expression

 [In the formula, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. 2 6. Expression C00H [Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. Wherein the compound is subjected to a ring closure reaction.

 Wherein each symbol is as defined above, or a method for producing a salt thereof. 2 7.

 [Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. Reacting with a carbenium ion or an equivalent thereof,

Wherein Y represents O or S, and R ^1a and R ²³ are each independently substituted A good hydrocarbon group, and the other symbols are as defined above.] Or a salt thereof. 2 8.

[Wherein, R represents an alkyl group which may be substituted, ring A represents a benzene ring which may further have a substituent other than the substituent R, Y represents 〇 or S, and R represents ^{1 a} and R ^2a each represent an optionally substituted hydrocarbon group] or a salt thereof. 2 9 Expression

Wherein R represents an alkyl group which may be substituted, ring A represents a benzene ring which may further have a substituent other than the substituent R, Y represents O or S, and R represents ^la and R ^2a each represent a hydrocarbon group which may be substituted), a compound represented by the formula or a salt thereof is reacted with a reducing agent, and then reacted with an acid.

Wherein each symbol is as defined above, or a salt thereof. 3 0. Expression

 [In the formula, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof.  3 1.

 [Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. A formula characterized by being subjected to a reduction reaction

 [Wherein the symbols have the same meanings as described above], or a method for producing a salt thereof. 3 2.

Wherein R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R. 33. Expressions

 [Wherein, R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. Reacting with Vilsmeier reagent, formula

 Wherein each symbol is as defined above, or a method for producing a salt thereof. 34. Expressions

[Wherein, R represents an alkyl group which may be substituted, and ring A represents a substituent other than the substituent R. A benzene ring which may further have a substituent) or a salt thereof to an oxidation reaction.

 [Wherein the symbols have the same meanings as described above], or a method for producing a salt thereof. 3 5 Expression

 [Wherein R represents an alkyl group which may be substituted, and ring A represents a benzene ring which may further have a substituent other than the substituent R] or a salt thereof. Expression Reacting with a compound represented by H ゥ NCH ₂ 0H or a salt thereof,

 [Wherein the symbols have the same meanings as described above], or a method for producing a salt thereof.