WO2008072743A1

WO2008072743A1 - Method for producing anthranilamide compound by using novel pyrazole compound as intermediate

Info

Publication number: WO2008072743A1
Application number: PCT/JP2007/074166
Authority: WO
Inventors: Toru Koyanagi; Akihiro Hisamatsu
Original assignee: Ishihara Sangyo Kaisha, Ltd.
Priority date: 2006-12-15
Filing date: 2007-12-14
Publication date: 2008-06-19
Also published as: JP2009001541A

Abstract

Disclosed is a method for producing an anthranilamide compound or a salt thereof. Specifically disclosed is a method for producing an anthranilamide compound represented by the formula (I) below or a salt thereof, which is characterized in that a compound represented by the formula (II) below is diazotized and then reacted with copper halide, copper metal or an alkyl halide. (In the formula (I), X represents a halogen; R1 represents a halogen, an alkyl, a haloalkyl, an alkenyl, a haloalkenyl, an alkynyl, a haloalkynyl, an alkoxy, a haloalkoxy, an alkylcarbonyl, a haloalkylcarbonyl, an alkoxycarbonyl, a haloalkoxycarbonyl, a nitro, a formyl or a cyano; A represents an alkyl substituted with Y; and m represents a number of 0-4.) (In the formula (II), R1, A and m are as defined above.)

Description

Specification

Method for producing anthranilamido compound using novel pyrazole compound as intermediate

Technical field

[0001] The present invention relates to a method for producing an anthranilamide compound.

Background art

For example, Patent Document 1 discloses that anthranilamide compounds exhibit excellent effects as pest control agents in the field of agriculture and horticulture. On the other hand, Patent Document 2 and Patent Document 3 describe methods for producing specific anthranilamides.

[0003] Patent Document 1: International Publication Gazette WO 2005/077934

Patent Document 2: International Publication WO 2003/016282

Patent Document 3: International Publication WO 2003/016283

Disclosure of the invention

Problems to be solved by the invention

[0004] Various methods for producing anthranilamide compounds have been proposed! /. However, when producing anthranilamide compounds in which the 3-position of pyrazole is substituted with a halogen, it is necessary to use a highly toxic phosphorus halide such as phosphorus oxybromide for the halogenation. A method for producing the anthranilamide-based compound without using an agent was desired.

An object of the present invention is to provide a method for producing anthranilamide compounds in which the 3-position of pyrazole is substituted with halogen without using a highly toxic phosphorus halogenating agent.

Means for solving the problem

[0005] As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that if a compound having an amino group at the 3-position of pyrazole is used, it is toxic as a phosphorus halogenating agent in the halogenation reaction. The present invention was completed by discovering that it was possible to produce the target compound without using reagents. That is, the present invention provides a compound of formula (I):

[0006]

[0007] (In the formula, R represents halogen, anolequinole, haloalkyl, alkenyl, haloalkenyl, alkynole, noroanorequininore, anolecoxi, noanorecoxyl, anolequinolecanoleponinore, noronorenonorebonolere, anole Coxicanoreponinore, Noroanorecoxicanoreponinole, Nitro, Honoremil or Ciano, A is alkyl optionally substituted with Y, Y is selected from the group consisting of halogen, alkyl and haloalkyl C 1 -C cycloalkyl optionally substituted with at least one substituent, X is halogen and m is 0 to 4)

3 4

A method for producing an anthranilamide compound or a salt thereof, comprising the formula (II):

[0008]

[0009] (where

A and m are as described above), and then halogenated in the presence of copper halide, metal copper or alkyl halide o

The present invention also provides a formula (Π):

[0010] [Chemical 3]

(Where

A and m are as described above) or a salt thereof. The present invention also provides a compound of formula (III):

[0011] [Chemical 4]

Wherein R ² is alkyl optionally substituted with halogen; alkenyl optionally substituted with halogen; may be substituted with halogen! /, Alkynyl; or the phenyl moiety is halogen, alkyl, haloalkyl, A benzyl which may be substituted with 1 to 5 substituents selected from the group consisting of alkoxy, haloalkoxy, cyano and nitro;

A and m are as described above) or a salt thereof.

The present invention also provides a compound of formula (VI):

[0012] [Chemical 5]

[0013] (where

R ² and m are as described above) or a salt thereof.

Furthermore, the present invention provides a compound of formula (IV):

[0014] [Chemical 6]

[In the formula, R ³ represents a hydrogen atom; alkyl; alkenyl; alkynyl; A bis-carboxylic acid derivative represented by: a phenyl optionally substituted with 1 to 5 substituents selected from haloalkyl, alkoxy, haloalkoxy, cyano and nitro, wherein R ² is as described above; And its production method.

[0016] In each formula,

The alkyl or alkyl moiety in A and Y may be either linear or branched. Specific examples thereof include c to canolenoquinoles such as methyl, ethyl, propyl, isopropylenole, butinole, tertiary butinole, pentyl, and hexinore.

1 6

Is mentioned.

Also,

The alkeni or alkenyl moiety in R ² and R ³ may be either linear or branched. Specific examples thereof include bur, 1-propenyl, allyl, isopropenyl, 1-buteninole, 1,3-butagenenole, 1-C-Canorekeninore such as 1-hexenore.

2 6

Can be mentioned.

further,

The alkynyl or alkynyl moiety in R ² and R ³ may be either linear or branched. Specific examples include C 2 -C alkynyl such as Etul, 2 Butur, 2 Pentur, 3-hexyl.

2 6

Also,

Examples of the halogen in R ² , X and Y or the halogen as a substituent include each atom of fluorine, chlorine, bromine and iodine. The number of halogens as substituents may be 1 or 2 or more. When 2 or more, each halogen may be the same or different. Also, the halogen substitution position is! /.

[0017] The anthranilamide-based compound of the formula (I) or a salt thereof is produced by diazotizing the compound of the formula (I) and then halogenating in the presence of copper halide, copper metal or alkyl halide. The power to do S. The reaction using copper halide corresponds to the Sandmeyer reaction, and the reaction using copper metal corresponds to the reaction called Gattermann reaction.

The starting compound of formula (II) is N— [4-chloro-6 — [[α-methyl- (cyclopropyl) amino] carbonyl] -phenyl] —3-amino-1 (3-chloro Pyridine — 2 yl) 1 ピラ Pyrazole 5 Carboxamide, Ν— [2 Bromo 4 kuroguchi-ichi 6- [[α-Methyl- (cyclopropylmethyl) amino] carboninole] Phenyl] 3-Amino 1 (3- kuroguchi (Pyridine 2-yl) 1 ピラ Pyrazonole 5-Carboxamide, Ν— [ 4 Black mouth 2 Methylanol 6-[[a-Methylol (amino) amino] carbonyl

1—Pheninole] — 3 Amino 1— (3 Chloropyridine 1 2 Inole) 1 1H—Pyrazonole 1 5 Carboxamide, N— [2 Bromo 4 Chloro 6 [[(Cyclopropylmethinole) amino] Carboninore] —Phenyl] — 3 Amino 1- (2 Chloropyridine 1- 2 yl) 1 H-virazole-5-carboxamide can be used.

[0018] The diazotization reaction of the compound of the formula (Π) can be carried out by reacting the compound of the formula (Π) with sodium nitrite or alkyl nitrite. This reaction produces a diazo compound in which the amino group at the 3-position on the pyrazole ring of the compound of formula (Π) is a diazo group, and the diazonium compound is isolated or not subjected to a halogenation reaction without being isolated. used.

The halogenation reaction is carried out in the presence of copper halide, metal copper or alkyl halide after diazotizing the compound of formula (IV). The copper halide can be monovalent or divalent. As the alkyl halide, bromoform, carbon tetrachloride and the like can be used. In general, the halogenation reaction is performed by removing the diazo group of the diazo compound with copper halide or copper metal, and then adding the force of halide ions, or by desorbing the diazo group from the diazo compound. It proceeds by reacting with the generated radical force S and alkyl halides.

When metal copper is used for the reaction, it is necessary to supply halogen for halogenation. When copper halide is used, the halogen required for the reaction is supplied from copper halide.

[0019] The anthranilamide compound of the formula (I) produced by this reaction includes N [4 black mouth — 6- [[α-methinole (cyclopropylmethyl) amino] carbonino] phenyl] 3-butyl. Lomo 1— (3 x 2 pyridine) 1 Η Pyrazole 1 5 Carboxamide, Ν

[2 Bromo-4 Chloro-6 [[α-Methinole (cyclopropylmethinole) amino] Carbo Ninore] Fueninore] 3 Bromo 1- (3 Chloropyridine 2 Inole)-1Η -Pyrazo Noreno 1 5 Carboxamide, Ν— [4 Black Mouth 2 Methylolone 6 [[α Methylolone (Cyclopropylpyrmethyl) amino] Carbonol] -Phenyl] — 3-Bromo 1 (3-Chloropyridine 1

2 -yl) 1 Η Pyrazonole 5 Carboxamide, Ν— [2 Bromo 4 Black 6 [[(Cyclopropylmethinole) amino] carboninole] phenyl] 3-bromo-1-one (3-chloropyridine 2-yl) 1 H pyrazole-one 5-carboxamide, N- [2-bromo-4 — black mouth 6 — [[(Cyclopropylmethinole) amino] carbinole] —phenyl] — 3—Cro-Chain 1- 1 (3-Clo-Cubylpyridine 2-yl) 1 H-Pyrazole 5-Carboxamide and the like.

[0020] The compound of the formula (III) includes N [4 chloro-6 [[α-methyl- (cyclopropinoremethinole) amino] carboninole] phenyl] 3-t butyloxycarbonylamino 1 — (3 1 Pyrazole 1 H Pyrazole 1 5 Carboxamide, N— [2—Bromo-4 Chloro-6 — [[α-Methinole (cyclopropylmethinole) amino] carbonore] phenyl] 3—t Butoxycarbonylamino 1 1- (3 Chlomouth Pyridine 1 2-Inole) 1 1 H Pyrazole 1 5-Carboxamide, N [4 Chloro 1-Methyl 6 [[α-Methinole (Cyclopropylmethinole) amino] Carboninore] Feninore ] — 3— t-Butyloxycarbonylamino 1- (3-chlorodipyridine 1- 2-yl) 1 H Pyrazole 1- 5- carboxamide, N— [2 Bromo-4 chloro-6 [[(cyclopropyl Methinole) amino] force norboninole] —phenyl] — 3— t-butyloxycarbonylamino 1 1 (3-chloropyridin-2-inole) 1H—pyrazonole 5 force noreboxamide, N [4 chloro-6 [[α-methyl] (Cyclopropylmethinole) amino] carboninole] Fueninore] 3-Benzyloxynoreblonylamino 1- (3-chloropyridine 1 2-yl) 1 Η pyrazole 1 5-streptoxamide, Ν [2 bromo 4 kuroguchi 1 6 [[α-Methylolone (cyclopropylmethyl) amino] carboninole] phenyl] 3-benzyloxycarbonylamino 1- 1 (3-chloro-pyridine 1-yl) 1 Η pyrazole 5-carboxamide, Ν— [4—Black 1-Methyl 6- [[α-Methyleno (cyclopropylmethyl) amino] carbonyl] phenyl] 3 Monobenzyloxycarbonylamino 1 (3 Chlomouth pyridine-2-yl) 1H-virazole 5 carboxamide, Ν— [2 Bromo-4 Chloro-6 [[(Cyclopropylmethinole) amino] carboninole] monophenyl] 1 3-benzyloxycarbonylamino- 1 1 (3-chloropyridine 1 2 yl) 1H-pyrazole 1 5 carboxamide and the like.

[0021] The compound of the above formula (IV) includes 3 benzyloxycarbonylamino-1 1 (3-chloropyridine-2yl) 1H-5 pyrazole carboxylic acid, methyl 3 benzyloxy Cycarbonylamino 1- (3-chloro pyridine 2-yl) 1 H— 5 Pyrazole canole boxylate, ethyl 3-benzyloxycarbonylamino 1 1- (3-chloro pyridine 2-yl) 1H— 5-Pyrazolecarboxylate, bur 3-Benzyloxycarbonylamine 1- (3-chloro pyridine 2-yl) 1H— 5 Pyrazole carboxylate, ethul 3-benziloxycarbonylamino-1-1 (3-chloro pyridine) 1H— 5 Pyrazole carboxylate, phenyl 3 benzyloxycarbonylamine 1— (3 pyridine yl-2-yl) 1H— 5 Pyrazole carboxylate, 3-p methoxybenzyloxycarbonylamino-11 (3 —Hydropyridine 2yl) 1H— 5 Pyrazolecarboxylic acid, methyl 3-p methoxybenzyloxycarbonylami 1- (3-chloro pyridine-2-yl)-1H-5-pyrazolecarboxylate, phenyl 3-p methoxybenzyloxycarbonylamino 1- (3-chloro pyridine-2-yl) 1H-5 pyrazole carboxy 1- (3-chlorobutyridine-2-yl)-1H-5-pyrazole carboxylic acid, methyl 3-t-butyloxycarbonylamino-1 (3-chloropyridine-2) —Hil) 1H 5—Pyrazolecarboxylate, phenyl 3-t-butyloxycarbonyl nylamino 1— (3-chloropyridine 2-yl) 1 H—5 Pyrazole carboxylate, 3 aralkyloxycarbonylamino 1-1 (3-closed pyridine-2 yl) 1H-5-pyrazolecarboxylic acid, methyl 3-aryloxycarbonylamino-1-1 (3-closed-pyridine 1-2 yl) 1H-5 La tetrazole carboxylate, such as phenylene Honoré 3 Arinore O alkoxycarbonyl § Mino one 1- (3-black port pyridine one 2-I le) 1 H- 5-pyrazole carboxylate.

The compound of the above formula (VI) includes 2— [3 t-butyloxycarbonylamino-1 1 (3 —black pyridine 1 2 inore) 1 1H pyrazonole 1 5 inore] — 6 kuroguchi 1 4 H— 3, 1 Monobenzoxazine-4-one, 2— [3— t-Butoxycarbonylamino- 1 1 (3 — black pyridine 1 2 ynole) 1 1H — pyrazonole 1 5 ynole] — 8 Bromo 6 Black -4H- 3, 1-Benzoxazine 4 ON, 2-— [3-T-Butyloxycarbonylamino 1-- (3-Chronopyridine 1- 2-Inole) 1 1H-Pyrazonole 1- 5-Inole] — 6—Black- mouth 8 Methyl 4H— 3, 1—Benzoxazine 4one, 2— [3 Benzoxyxal Bonylamino-11 (3-chloro-pentylpyridine 2-yl) 1 H Pyrazonole 5-yl 6 Chloro-4H— 3, 1-Benzoxazine-4-one, 2-— [3-Benzyloxycarbonylamino-11 (3-chloro) 1 H pyrazonol 5 yl] 8—Bromo 6 Black 1 4H— 3, 1-Benzoxazine 1 4 ON, 2— [3 Benzyloxycarbonylamino 1 1- (3 — Black pyridine 1 2-Hil) 1 H-Pyrazole 5-Hil] -6-Chloro-8-Methinole 4H-3, 1-Benzoxazine-4-one.

[0023] Examples of the salt of the compound include any salt that is acceptable in agricultural chemicals.

For example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salts such as dimethyl ammonium salt and triethyl ammonium salt; Examples thereof include inorganic salts such as chlorate, sulfate, and nitrate; organic acid salts such as acetate and methanesulfonate.

The invention's effect

[0024] According to the method of the present invention, an anthranilamide compound having a halogen at the 3-position of pyrazole or a salt thereof can be efficiently produced without using a phosphorus halogenating agent. BEST MODE FOR CARRYING OUT THE INVENTION

[0025] The method for producing an anthranilamide compound or a salt thereof according to the present invention is described in detail below.

The anthranilamide compound of the formula (I) or a salt thereof can be produced according to the following reaction [A] to reaction [E] and a usual salt production method.

[0026] [Chemical 7]

[A]

H ₂ N

[0027] where

A, X and m are as described above _c Reaction [A] can be carried out by diazotizing the compound of formula (Π) and then halogenating it in the presence of copper halide, metal copper or halogenated alkyl. The reaction [Α] can be carried out, for example, in the following four modes.

As an embodiment of 1, the reaction [ii] includes a compound of formula (II) dissolved in an aqueous solution of an inorganic acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid, and an aqueous sodium nitrite solution is added to form a diazodium salt. Can be reacted with a copper (I) halide salt.

Examples of the copper (I) halide that can be used in the above reaction include cuprous chloride (CuCl) or cuprous bromide (CuBr). The amount of copper rogenide (I) used is equimolar or more, preferably 1.2 to 1.5 times the molar amount of the compound of formula (II).

The reaction can usually be carried out at −20 to 120 ° C., desirably 0 to 100 ° C. The reaction time is usually 0.5 to 12 hours.

In embodiment 2, reaction [A] is carried out by reacting a compound of formula (II) with an alkyl nitrite and copper halide (I) or copper halide ()) in the presence of a solvent. Do what you can to do.

Examples of alkyl nitrite that can be used in the above reaction include tert-butyl nitrite, i-pentyl nitrite, and i-butyl nitrite. Examples of the copper (I) halide include cuprous chloride (CuCl) and cuprous bromide (CuBr). Examples of copper and rogenide (II) include cupric chloride (CuCl 3) and cupric bromide (CuBr 2). The amount of nitrous acid alkyl ester that can be used in the reaction is at least equimolar, preferably 1.2 to 2.8 molar, relative to the compound of formula (Π). The amount of copper (I) halide and copper (II) halide to be used is equimolar or more, preferably 1.2 to 1.5 times the molar amount of the compound of formula (ii). As a solvent that can be used in this reaction, any solvent can be used as long as it is inert to the reaction. For example, one or two ethers such as jetyl ether, tetrahydrofuran, dioxane, dimethochetan; polar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, etc. The above can be selected as appropriate. This reaction can be carried out usually at −20 to 100 ° C., preferably 0 to 60 ° C., and the reaction time is usually about 0.5 to 24 hours. [0028] As an aspect of 3, the reaction [A] comprises dissolving the compound of the formula (II) in an aqueous solution of an inorganic acid containing a halogen such as hydrochloric acid or hydrobromic acid, and adding an aqueous sodium nitrite solution. This can be done by reacting metallic copper after forming a diazonium salt.

In the reaction using copper metal, an inorganic acid containing no halogen such as sulfuric acid can be used instead of an inorganic acid containing halogen. In this case, after forming a diazo salt, hydrochloric acid or bromide is formed. A halogen-containing compound such as hydrogen acid is added and reacted.

In embodiment 4, reaction [A] is carried out by reacting a compound of formula (Π) with an alkyl nitrite to form a diazo salt and then reacting with an alkyl halide. it can.

Examples of alkyl nitrite that can be used in the above reaction include t-butyl nitrite, i-pentyl nitrite, and i-butyl nitrite. Examples of the alkyl halide include bromoform, bromotrichloromethane, carbon tetrachloride, black mouth form, and carbon tetrabromide. The amount of the nitrite alkyl ester that can be used in the reaction is an equimolar amount or more, preferably 1.2 to 3.0 times the molar amount of the compound of the formula (Π). The amount of the alkyl halide that can also serve as a solvent is equimolar or more, preferably 10 to 100 times the molar amount of the compound of the formula (Π). Since the alkyl halide also serves as a solvent, no solvent is required in this reaction. The reaction can be carried out usually at 0 to 100 ° C, desirably 20 to 80 ° C, and the reaction time is usually about 0.25 to 6 hours.

[0029] The compound of the formula (Π) can be produced according to the following reaction [B].

[0030] [Chemical 8]

[0031] where:

R ² , A and m are as described above.

In the reaction [B], the compound of formula (III) is subjected to deprotection treatment to remove the protecting group represented by R ² O ₂ C, and the reaction is performed with the force S.

The deprotection treatment can be performed according to known materials. Known materials, PGM Wuts, TW Greene, reene s Protective Groups in Organic ^ ynthesi s ", 4 th ed. Wiley-Interscience (2007) , and the like.

Examples of deprotection treatments include reaction with Broensted acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, trifluoroacetic acid, methacrylic acid, trifluoromethanesulfonic acid, sulfuric acid; chlorides, chlorides such as trimethylsilyl chloride Reaction with trimethylsilyl iodide; reaction with hydrogen gas in the presence of palladium on carbon, palladium chloride, etc .; reaction with triethylsilane in the presence of palladium chloride, palladium acetate and the like.

In the above reaction, it is difficult to uniformly define the reaction conditions. In the case of the cleavage reaction with Broensted acids such as hydrogen chloride and trifluoroacetic acid, usually 20 to 80 ° C, preferably 0 to 50 °. The reaction can be carried out with C, and the reaction time is usually about 0.5 to 24 hours.

In the case of reacting with hydrogen gas in the presence of palladium on carbon, palladium chloride or the like, the reaction can usually be carried out at −10 to; 100 ° C., preferably 0 to 80 ° C. The reaction time is usually 0. . About 25-24 hours.

[0032] The deprotection treatment of reaction [B] can also be carried out according to a two-step reaction via a compound of formula (IX) described in reaction [C].

[0033] [Chemical 9]

[C]

[0034] In the formula, R ⁴ is methyl or ί>,

R ² , A and m are as described above. is there.

The first stage of the reaction [c] can be carried out by reacting the compound of the formula (III) with equimolar amounts of acetic acid or trifluoroacetic acid represented by the formula (VIII).

In order to accelerate this reaction, the reaction can be carried out in the presence of a Broensted acid such as hydrogen chloride, hydrogen bromide, methanesulfonic acid, or trifluoromethanesulfonic acid.

This reaction can be carried out usually at 0 to 150 ° C, preferably 60 to 120 ° C, and the reaction time is usually about 0.5 to 24 hours.

The second stage of reaction [C] can be accomplished by treating the compound of formula (IX) in an aqueous alkaline solution.

Examples of alkaline aqueous solutions include aqueous solutions of alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; aqueous solutions of alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; sodium carbonate and potassium carbonate. An aqueous solution of an alkali metal carbonate such as ammonia water can be used. Of these, it is preferable to use aqueous ammonia.

This reaction can be carried out usually at 0 to 110 ° C, desirably 10 to 100 ° C, and the reaction time is usually about 0.5 to 24 hours.

[0035] The compound of the formula (III) can be produced according to the following reaction [D].

[0036] [Chemical 10]

CD]

[0037] where:

R ² , A and m are as described above.

Reaction [D] is usually carried out by treating the compound of formula (VI) with an equimolar amount or more, preferably 1.5 to 5.0 moles of the compound of formula (VII) in the presence of a solvent. Can do. As the amine of the formula (VII), α-methyl-cyclopropylmethylamine, α-methyl-cyclopropylamine Rumethylamine, cyclopropylmethylamine and the like can be used. Any solvent may be used as long as it is inert to the reaction. For example, ethers such as jet ether, tetrahydrofuran, dioxane and dimethoxyethane; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and benzene; benzene, toluene and xylene Aromatic hydrocarbons: One or two or more polar aprotic solvents such as acetonitrile, dimethylhonolemamide, dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide can be appropriately selected. The reaction [D] is usually carried out at 0 to 120 ° C, preferably 20 to 80 ° C, and the reaction time is usually about 0.5 to 24 hours.

[0038] The compound of the formula (VI) can be produced according to the following reaction [E].

[0039] [Chemical 11]

[E]

[0040] where:

R ² and m are as described above.

The compound of formula (IV-1) that can be used in this reaction includes 3-t-butyloxycarbonylamino-1- (3-chloropyridine-2-yl) -1H-5-pyrazole carboxylic acid, 3 —Allyloxycarbonylamino-1 (3-chloro-pyridine-2-yl)-1H-5-pyrazolecarboxylic acid, 3-benzyloxycarbonylamino-1 (3-chloropyridine) 2 Hil) 1 H-5 pyrazole carboxylic acid, 1- (3 chloro pyridine 1 2-inole) -3- (p methoxybenzyloxycarbonylamino) 1H 5-pyrazole carboxylic acid and the like.

As the compound of formula (V), 2-amino-5-chlorobenzoic acid, 2-amino-3-bromo-5-chlorobenzoic acid, 2-amino-5-chloro-3-methylbenzoic acid, and the like can be used.

[0041] The reaction [E] is usually performed by reacting the compound of the formula (IV-1) with an acid chloride in the presence of a base and a solvent. This can be done by reacting with a compound of formula (V) in the presence of a base after conversion to an active derivative. Further, the reaction with the compound of the formula (V) can be carried out by adding an activator if necessary.

[0042] Reaction [E] can be carried out in the presence of a solvent, and a series of reactions can be carried out in the same solvent. Any solvent may be used as long as it is inert to the reaction. For example, halogenated hydrocarbons such as black benzene, dichlorobenzene, dichloromethane, black mouth form, carbon tetrachloride, dichloroethane, trichloroethane, dichloroethylene; pentane, hexane, heptane, octane, cyclohexane Aliphatic hydrocarbons such as: ethers such as diethyl ether, t-butylethyl ether, tetrahydrofuran, dioxane, dimethoxyethane; esters such as methyl acetate, ethyl acetate, propyl acetate; acetone, 2-butanone, 4-methyl- 2 One or more can be appropriately selected from ketones such as pentanone; polar aprotic solvents such as acetonitrile, propionitrile, N, N dimethylformamide, and the like.

[0043] As the acid chloride, it is possible to use black mouth carbonates, sulphoninorechloride, carboxylic acid chloride, and the like. Examples of the black mouth carbonate include black mouth methyl carbonate, black mouth ethyl carbonate, and black mouth isopropyl carbonate. Examples of sulphourel chloride include methane senorephonino chloride, propane senorephonino chloride, and benzene senorephonino chloride. Examples of the carboxylic acid chloride include acetyl chloride, propionyl chloride and the like, and methanesulfuryl chloride is particularly preferable. The amount of acid chloride used is 1.0 force, et al. 1.5 times mol, preferably 1.1 force, et al. 1.3 times mol for the compound of formula (IV-1). Examples of the base include pyridine, 2 picoline, 3 picoline, 2,6 noretidine, trimethinoreamine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, and 3-methylimidazole. The amount of the base used is 1.0 force, et al. 2.0 times monole, preferably 1.2 to 1.7 times monole with respect to the compound of formula (IV-1).

The reaction can usually be carried out at −30 to 60 ° C., desirably −10 to 40 ° C., and the reaction time is usually about 10 minutes to 1 hour.

[0044] The amount of the compound of the formula (V) to be reacted after converting the compound of the formula (IV-1) into an active derivative is 0.9 to from the compound of the formula (IV-1); Double moles, preferably about 1. 05 Double mole.

As the base used for the reaction with the compound of the formula (V), it is possible to use a different one that can be used in the active derivatization of the compound of the formula (IV-1). Examples of bases that can be used for the reaction include pyridine, 2 picoline, 3 picoline, 2, 6-trimethylamine, triethylamine,: min, 4 dimethylaminopyridine, and 3-methylimidazole. The amount of the base used is 2 to 4 times mol, preferably 2.9 to 3.5 times mol, of the compound of the formula (IV-1). The compound of formula (IV-1) and the base can be added as a mixed solution with a solvent. The reaction can usually be carried out at −30 to 60 ° C., desirably −10 to 40 ° C., and the reaction time is usually about 10 minutes to 1 hour.

[0045] Examples of the activator used for the reaction with the compound of the formula (V) include black ester carbonate and sulfochloride. Examples of the black mouth carbonate include black mouth methyl carbonate, black mouth carbonate, and black mouth isopropyl carbonate. Examples of sulphourel chloride include methanolenophonino chloride, propane senorephonino chloride, and benzene senorephonino chloride. The amount of the activator used is 1.0 to 1.5 times the mole of the compound of the formula (IV-1), more preferably 1 · ;! to 1 · 3 times monole.

The activator used for the reaction with the compound of the formula (V) can be the same as the acid chloride used for converting the compound of the formula (IV-1) into the active derivative. The activator can also be added in a mixture with a solvent.

The reaction is usually carried out at -30 to 60 ° C, desirably -10 to 40 ° C, and the reaction time is usually about 1 to 24 hours.

[0046] The compound of formula (III) can also be produced according to the following reaction [F].

[0047] [Chemical 12]

[0048] where

R ² , A and m are as described above.

In the reaction [F], the compound of the formula (IV-1) is usually converted into an active derivative such as an acid chloride or an acid anhydride, and then treated with the compound of the formula (X) in the presence of a base and a solvent. This can be done.

In order to convert to an acid chloride, thionyl chloride or oxalyl chloride can be used. In order to convert it into an acid anhydride, acetyl chloride, trifluoroacetyl chloride, or the like can be used. As a reagent to be converted into other active derivatives, chloroethyl carbonate, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride and the like can be used.

Conversion to the active derivative can usually be carried out by treating the compound of the formula (IV-1) with an equimolar amount or more of the above reagent. In addition, this reaction can be performed by adding a base, if necessary.

Examples of the base include pyridine, 2-picoline, 3-picoline, 2,6-noretidine, trimethinoreamine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 3-methinoreimidazole and the like. It is done. The amount of the base used is 1.0 to 2.0 times monole, preferably (1.2 to 1.7 times monole) with respect to the compound of the formula (IV-1).

In this reaction, a solvent may be used, and V or a deviation may be used as long as the solvent is inert to the reaction. For example, ethers such as jetinoreethenole, tetrahydrofuran, dioxane and dimethoxyethane; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and benzene; benzene, toluene and xylene Aromatic hydrocarbons such as: Acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, polar aprotic solvents such as dimethylol sulfoxide, etc. I'll do it.

The reaction can usually be carried out at −20 to 80 ° C., preferably 0 to 60 ° C., and the reaction time is usually about 0.5 to 2 hours.

[0049] Furthermore, the compound of formula (III) can be produced by treating the resulting reaction solution containing the active derivative with the compound of formula (X) usually in the presence of a base and a solvent. Bases include alkali metal hydrides such as sodium hydride and potassium hydride; charcoal Alkali metal carbonates such as sodium acid and potassium carbonate; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tertiary butoxide; Trimethylamine, Triethylamine, Triisopropylamine, Diisopropylethylamine , Pyridine, 4 dimethylaminopyridine, 2,6 dimethylviridine, 4 pyrrolidinopyridine, N methylmonoleolin, N, N dimethylaniline, N, N jetylaniline, N ethylyl N methinoreaniline, 1,8 diazabicyclo [5.4.0 ] One or two or more tertiary amines such as 17 undecene, 1,4-diazabicyclo [2.2.2] octane can be appropriately selected. The amount of the base used is 0.8 to 3 times mol, preferably 1 to 1.5 times mol with respect to the compound of the formula (X).

Any solvent may be used as long as it is inert to the reaction. For example, etherols such as diethyl ether, butyl methyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; Hydrogens; Aromatic hydrocarbons such as benzene, toluene, xylene; Aliphatic hydrocarbons such as pentane, hexane, heptane, octane, cyclohexane; Acetonitrile, propionitol, N, N dimethylformamide One or two or more kinds of polar aprotic solvents such as dimethylsulfoxide, hexamethylphosphoric triamide, sulfolane, dimethylacetamide, and N-methylpyrrolidone can be appropriately selected. The reaction is usually carried out at -20 to 120 ° C, preferably 0 to 40 ° C, and the reaction time is usually about 0.25 to 24 hours.

In addition, the reaction [F] can be usually carried out by treating the compound of the formula (IV-1) with the compound of the formula (X) and a condensing agent in the presence of a base and a solvent.

Examples of the condensing agent that can be used in this reaction include dicyclohexyl carpositimide 1-ethyl-3- (3-dimethylaminopropyl) carpositimide hydrochloride, diphenylphosphoryl azide, etc., and compounds of formula (IV-1) It is desirable to use equimolar or more with respect to.

Bases include trimethylamine, triethylamine, triisopropylamine, diisopropylethylenoleamine, pyridine, 3-picoline, 4-dimethylaminopyridine, N-methylmorpholine. One or more selected from tertiary amines such as phosphorus, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,4-diazabicyclo [2,2,2] octane, etc. be able to. The base can be used in an amount of 2- to 10-fold mol, preferably 2.2 to 7-fold mol based on the compound of the formula (X). The compound of the formula (IV-1) can be used in an amount of 0.5 to 2.0 times mol, preferably 1 · ;! to 1 · 5 times mol, of the compound of the formula (X).

Any solvent may be used as long as it is inert to the reaction. For example, ethers such as jet ether, tetrahydrofuran, dioxane and dimethoxyethane; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and benzene; benzene, toluene and xylene One or more aromatic hydrocarbons can be selected as appropriate from polar aprotic solvents such as acetonitrile, dimethylhonolemamide, dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide. Reaction [F] can usually be carried out at −20 to 80 ° C., preferably 0 to 60 ° C., and the reaction time is usually about 0.5 to 24 hours.

[0051] The compound of the formula (II) can also be produced according to the following production method.

[0052] [Chemical 13]

[G]

,

[0053] where

A and m are as described above.

The first step of obtaining the compound of formula (XI) can be carried out by treating the compound of formula (VI) with an equimolar amount or more of acetic acid or trifluoroacetic acid represented by formula (VIII).

The first step is hydrogen chloride, hydrogen bromide, methanesulfonic acid, The reaction can be promoted in the presence of Broensted acid.

The first step can be usually carried out at 0 to 150 ° C, desirably 60 to 120 ° C, and the reaction time is usually about 0.5 to 24 hours.

[0054] In the second step of obtaining the compound of the formula (IX), the compound of the formula (XI) is used in an equimolar amount or more, preferably 1.5 to 5.0 times moles of the compound of the formula (VII). Fi can be obtained by treatment in the presence of a solvent.

Any solvent may be used as long as it is inert to the reaction. For example, ethers such as jet ether, tetrahydrofuran, dioxane and dimethoxyethane; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and benzene; benzene, toluene and xylene One or more aromatic hydrocarbons can be selected as appropriate from polar aprotic solvents such as acetonitrile, dimethylhonolemamide, dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide. The second step can be usually carried out at 0 to 120 ° C, preferably 20 to 80 ° C, and the reaction time is usually about 0.5 to 24 hours.

[0055] The third step of obtaining the compound of the formula (ii) involves treating the compound of the formula (IX) with an aqueous alkaline solution.

The third step can be usually carried out at 0 to 110 ° C, preferably 10 to 100 ° C, and the reaction time is usually about 0.5 to 24 hours.

[0056] The compound of the above formula (IV-1) used in the above reaction [E] and reaction [F] can be produced according to the reaction [H].

Reaction)

[0057] [Chemical 14] [

(XVII)

(iv-1)

In the formula, R ⁵ is alkyl, R ⁶ is 2-furyl or α-styryl, and IT is as described above.

The aforementioned reaction [H] can be carried out according to the embodiment of reaction [I] or reaction [J].

[0059] Reaction [I]

Step (I-1): The compound of formula (XI-1) is reacted with the compound of formula (X-1) to produce a compound of formula (XIV-1).

[0060] [Chemical 15]

[

(XII-1) (XIV-1)

> 5,

[0061] In the formula, is as described above.

Step [1-1] can usually be performed in the presence of a solvent.

Any solvent may be used as long as it is inert to the reaction. For example, carboxylic acids such as formic acid, acetic acid, propionic acid and butyric acid; alcohols such as methanol, ethanol, propanol and isopropanol can be used. Of these, acetic acid is preferably used.

Step [1-1] can be usually carried out at 60 to 150 ° C, desirably 70 to 120 ° C, and the reaction time is usually 0.5 to 12 hours. Step (I 2): The compound of formula (XIV-1) is hydrolyzed to produce the compound of formula (XV-1)

Yes

[0062] [Chemical 16]

1-2]

(Xiv-1) (XV-1)

[0063] In the formula, IT is as described above.

Step [I 2] can usually be performed in the presence of a base and a solvent.

As the base, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or calcium hydroxide can be used.

Any solvent may be used as long as it is inert to the reaction. For example, it is possible to use alcohols such as methanol, ethanol, propanol, isopropanol alone or mixed with water.

Step [1-2] can usually be carried out at 10 to 120 ° C., preferably 30 to 80 ° C., and the reaction time is usually 0.5 to 12 hours.

Step (I3): A compound of formula (XVII-1) is reacted with an alcohol of formula (XVI) and diphenylphosphoryl azide.

[0064] [Chemical 17]

[ 13

(XV-) (XVII-1)

In the formula, R ² is as described above.

Step [13] can usually be performed in the presence of a base and a solvent. Bases include trimethylamine, triethylamine, triisopropylamine, diisopropinoreethinoleamine, 4-dimethylaminopyridine, N-methylmorpholine, 1,8-diazabicyclo [5, 4, 0] -7-undecene One or more can be selected as appropriate from tertiary amines such as 1,4-diazabicyclo [2,2,2] octane. The base can be used in an amount of 1 to 3 moles, preferably;! To 1 · 5 moles relative to the compound of the formula (XVI).

As a solvent, the alcohol of formula (XVI) can be used in a large excess relative to the compound of formula (XV-1). Examples of solvents inert to the reaction include ethers such as tetrahydrofuran, dioxane, and ethylene glycol jetyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; acetonitrile, propionitol, Polar aprotic solvent such as N, N-dimethylformamide, dimethyl sulfoxide, sulfolane; one or more selected from ketones such as 2-butanone, 3-pentanone, 4-methyl-2-pentanone, etc. can do.

Step [1-3] can usually be carried out at 50 to 150 ° C., preferably 80 to 120 ° C., and the reaction time is usually about 1 to 24 hours.

Step (I-1): The compound of formula (XVII-1) is reacted with an oxidizing agent to produce the compound of formula (IV-1).

[Chemical 18]

I one 4]

(XVI 1-1) In the formula, R ² is as described above.

Step [I-14] can usually be carried out in the presence of a solvent.

As an oxidizing agent, a permanganate such as potassium permanganate; a chromate complex such as pyridinium black chromate and pyridinium dichromate; ruthenium tetroxide; hydrogen peroxide; be able to.

Any solvent may be used as long as it is inert to the reaction. For example, Tons, 2 butanone, 3 pentanone, 4 methyl 2-pe, etc .; polar aprotic solvents such as acetonitryl, dimethylformamide; carboxylic acids such as acetic acid, propionic acid, butyric acid; ethyl formate, methyl acetate, One or more carboxylic acid esters such as ethyl acetate; pyridine; methylene chloride; benzene; 2-methyl-2-propanol; water can be appropriately selected.

In the step [I 4], the optimum reaction temperature varies depending on the oxidizing agent used. When ozone is used, it can usually be carried out at −100 to −20 ° C., desirably −80 to −50 ° C., and the reaction time is usually about 1 to 8 hours. When other oxidizing agents are used, the reaction can usually be carried out at 0 to 120 ° C, preferably 20 to 80 ° C, and the reaction time is usually about! To 48 hours.

[0068] The compound of the formula (ΧΠ-1) used in the step [I 1] is a known compound, and Gazzetta

It can be produced according to known materials such as Chimica Italiana 88, 879 (1958).

[0069] Reaction [J]

Step (J1): A compound of formula (XIV-2) is reacted with a compound of formula (XIII) to produce a compound of formula (XIV-2).

[0070] [Chemical 19]

[J

In the formula, R ⁵ is as described above.

Step CJ 1] can usually be performed in the presence of a solvent.

Step J-1] can usually be carried out at 60 to 150 ° C, desirably 70 to 120 ° C, Response time is usually 0.5 to 12 hours.

Step (J2): Hydrolyzing the compound of formula (XIV-2) to produce the compound of formula (XV-2)

[0072] [Chemical 20]

[0073] In the formula, IT is as described above.

Step CJ2] can usually be performed in the presence of a base and a solvent.

Step J2] can usually be carried out at 10 to 120 ° C, preferably 30 to 80 ° C, and the reaction time is usually 0.5 to 12 hours.

Step (J3): A compound of formula (XVII-2) is reacted with an alcohol of formula (XVI) and diphenylphosphoryl azide to produce a compound of formula (XVII-2).

[0074] [Chemical 21]

[J 3]

[0075] In the formula, IT is as described above.

Step [J-3] can usually be carried out in the presence of a base and a solvent. Bases include trimethylamine, triethylamine, triisopropylamine, diisopropinoreethinoleamine, 4-dimethylaminopyridine, N-methylmorpholine, 1,8-diazabicyclo [5, 4, 0] -7 undecene, One or more kinds of tertiary amines such as 1,4-diazabicyclo [2,2,2] octane can be appropriately selected. The base can be used in an amount of 1 to 3 moles, preferably;! To 1 · 5 moles relative to the compound of the formula (XVI).

In step J3], the alcohol of the formula (XVI) can be used as a solvent in a large excess relative to the compound of the formula (XV-2). In addition, as an inert solvent for the reaction, for example, etherofuranes such as tetrahydrofuran, dixane, ethyleneglycololegetinoreethenore; aromatic hydrocarbons such as benzene, toluene, xylene; , Propio Nitrinole, N, N Dimethylformamide, Dimethylsulfoxide, Sulfolane and other polar aprotic solvents; 2 Butanone, 3 Pentanone, 4-Methyl-2-Kenton such as 2-pentanone, etc. You can choose.

Step J3] can usually be carried out at 50 to 150 ° C, preferably 80 to 120 ° C, and the reaction time is usually about 1 to 24 hours.

[0076] The compound of the formula (IV-1) can be produced by reacting the compound of the formula (XVII-2) with an oxidizing agent. For the convenience of purification of the product, the compound of the formula (XVIII) (Step (J4) and Step (J5)).

Step (J4): A compound of formula (XVIII) is reacted with an oxidant to produce a compound of formula (XVIII).

[0077] [Chemical 22]

[J 4]

In the formula, IT is as described above.

Step CJ4] can usually be performed in the presence of a solvent.

The oxidizing agents include osmium tetroxide hydrogen peroxide, osmium tetroxide monoperiodic acid, Force that can use ruthenium tetroxide, ozone, etc. Ozone is suitable.

Any solvent may be used as long as it is inert to the reaction. For example, ketones such as acetone, 2 butanone, 3 pentanone, 4 methyl 2 pentanone; polar aprotic solvents such as acetate nitrile, dimethylformamide; carboxylic acids such as acetic acid, propionic acid, butyric acid; Carboxylic acid esters such as ethyl formate, methyl acetate, and ethyl acetate; alkyl halides such as methylene chloride and chloroformate; one or more of alcohols such as methanol, ethanol and isopropanol The power S is selected appropriately.

Step [J4] can usually be carried out at −100 to 0 ° C., desirably −80 to −50 ° C., and the reaction time is usually 1 to 12 hours.

Step (J5): A compound of formula (IV-1) is produced by reacting a compound of formula (XVIII) with an oxidizing agent.

[Chemical 23]

[G 5]

(XVII I) (IV-1) In the formula, R ² is as described above.

Step CJ5] can usually be performed in the presence of a solvent.

Oxidizing agents include permanganates such as potassium permanganate; chromic acid complexes such as pyridinium black chromate and pyridinium dichromate; silver oxide; ozone; oxygen; chlorine; Such halogens; it can be appropriately selected from halides such as potassium bromate, sodium chlorite, sodium bromate and sodium hypochlorite. Any solvent may be used as long as it is inert to the reaction. For example, ketones such as acetone, 2 butanone, 3 pentanone, 4-methyl-2-pentanone; polar aprotic solvents such as acetonitrile, dimethylformamide; carboxylic acids such as acetic acid, propionic acid, butyric acid Carboxylates such as ethyl formate, methyl acetate, ethyl acetate Stealth; Halogenated alkyls such as methylene chloride and blackform; Alcohols such as methanol, ethanol and 2-methyl-2-propanol; One or two or more can be appropriately selected from water, etc. .

Step J5] can usually be carried out at 0 to 120 ° C, preferably 20 to 80 ° C, and the reaction time is usually about 1 to 48 hours.

[0079] The compound of the formula (ΧΠ-2) used in the step [J 1] is a known compound, and can be produced according to known materials such as J. Chem. SOC, 3665 (1956). it can.

[0080] Among the carboxylic acid derivatives of the formula (IV) or salts thereof, the formula ( ³ ) wherein R ³ is other than hydrogen (

The compound of IV-2) is obtained by converting the compound of formula (IV-1) into the acid halide of formula (XIX),

It can be produced by reacting with an alcohol of (XX).

[0081] [Chemical 24]

[0082] In the formula, R " ^a is alkyl; alkenyl; alkynyl; phenyl optionally substituted with 1 to 5 substituents selected from nanogen, anolequinole, haloalkyl alkoxy, haloalkoxy, cyano and nitro. X is halogen and R ² is as described above.

The reaction for obtaining the acid halide of formula (XIX) from the compound of formula (IV-1) can be carried out by treating the compound of formula (IV-1) with an equimolar amount or more of a halogenating agent. .

Examples of the rogenating agent include thionyl chloride, oxalyl chloride, oxalic acid dichloride, phosphorus trichloride, and phosphorus pentachloride.

[0083] In the above reaction, a solvent may be used as long as it is inert to the reaction! For example, ethers such as jetyl ether, t-butyl ether, tetrahydrofuran, dioxane, dimethoxyethane; black benzene, dichlorobenzene, dichloromethane, black mouth form, carbon tetrachloride, dichloroethane, trichloroethane, dichloroethylene Halogenated hydrocarbons such as benzene, toluene, and xylene Aliphatic hydrocarbons; aliphatic hydrocarbons such as pentane, hexane, heptane, octane, and cyclohexane; esters such as methyl acetate, ethyl acetate, and propyl acetate; acetonitrile, propionitol, N, N One or more kinds of polar aprotic solvents such as dimethylformamide can be appropriately selected.

The reaction is usually carried out at −20 to 140 ° C., desirably −10 to; 120 ° C., and the reaction time is usually about 0.;! To 10 hours.

[0084] The reaction for obtaining the compound of the formula (IV-2) from the compound of the formula (XIX) can usually be carried out in the presence of a base and a solvent.

Bases include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metals such as sodium methoxide, sodium methoxide, and potassium tertiary butoxide. Alkoxides; trimethylamine, triethylamine, triisopropylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6 dimethylviridine, 4 pyrrolidinopyridine, N-methylol morpholine, N, N-dimethyla 1 from tertiary amines such as niline, N, N jetylaniline, N ethyl-N methenorea dilin, 1,8-diazabicyclo [5.4.0] -7 undecene, 1,4-diazabicyclo [2.2.2] octane, etc. Species or two or more can be selected as appropriate. The base can be used in an amount of 0.8 to 3 moles, preferably 1 to 1.5 moles, relative to the compound of formula (XIX).

[0085] The solvent may be an inert solvent for the reaction! /, Or may be a misaligned one! /. For example, etherols such as diethyl ether, butyl methyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; Hydrogen; Aromatic hydrocarbons such as benzene, toluene, xylene; Aliphatic hydrocarbons such as pentane, hexane, heptane, octane, cyclohexane; Acetonitrile, propionitol, N, N dimethylformamide One or more polar aprotic solvents such as dimethylsulfoxide, hexamethylphosphoric triamide, sulfolane, dimethylacetamide, N-methylpyrrolidone; water, etc. can be appropriately selected. Alcohols such as methanol, ethanol, propyl alcohol are compounds (XX) It is also an example and can be used as a solvent for the reaction.

The reaction is usually carried out at -20 to 120 ° C, preferably 0 to 40 ° C, and the reaction time is usually about 0.25 to 24 hours.

[0086] The compounds obtained by the above reaction [A] to reaction [K] may have isomers such as optical isomers and geometric isomers. Includes both body mixtures.

The present invention includes various isomers other than those described above within the scope of common technical knowledge in the technical field. In addition, depending on the type of isomer, the chemical structure may be different from the structure described in the above reaction formula. However, those skilled in the art who are involved in the technical field have the relationship of isomers and It can be fully recognized that it is within the scope of the invention.

[0087] Further, the present invention includes the following production methods.

(1) A method for producing a compound of the formula (Π) by the reaction [Β].

(2) By the reaction [Π], a compound of the formula (Π) is produced, the compound of the formula (Π) is diazotized, and then halogenated in the presence of copper halide, metal copper or alkyl halide. A process for preparing a compound of formula (I).

(3) A method for producing a compound of the formula (Π) by the reaction [C].

(4) A method for producing a compound of formula (III) by the reaction [D].

(5) A method for producing a compound of the formula (ii) by the reaction [D] and the reaction [B].

(6) By the reaction [D] and the reaction [B], the compound of the formula (Π) is produced, the compound of the formula (Π) is diazotized, and then in the presence of copper halide, metal copper or alkyl halide. To produce a compound of formula (I) by halogenation with

(7) A method for producing a compound of formula (VI) by the reaction [E].

(8) The compound of the formula (Π) is produced by the reaction [E], the reaction [D] and the reaction [B], the compound of the formula (Π) is diazotized, and then a copper halide, metal copper or halogen A process for producing a compound of formula (I) by halogenation in the presence of an alkyl halide.

(9) A method for producing a compound of the formula (IV-1) by the reaction [H].

(10) The above reaction], reaction [E], reaction [D] and reaction [B] are used to produce the compound of formula (Π). And then diazotizing the compound of formula (II), followed by halogenation in the presence of copper halide, metal copper or halogenoalkylene to produce the compound of formula (I).

(11) A method for producing a compound of the formula (IV-1) by the step [I 1], the step [I 2], the step [I 3] and the step [I 4] of the reaction [I].

(12) A method for producing a compound of the formula (IV-1) by the step CJ 1], the step CJ 2], the step [J 3], the step [J 4] and the step CJ 5] of the reaction CJ.

Example

In order to describe the present invention in more detail, examples will be described below, but the present invention should not be construed as being limited thereto.

(Example 1) Synthesis of 3-t-butyloxycarbonylamino-11- (3-chloropyridine 2-yl) -1- 1H 5-pyrazolecarboxylic acid

Process (1): Ethyl 1 (3-Chloropyridine 1-2-yl) 5-Furyl 1H-Pyrazol 3-Synthesis of 3-carboxylate

After adding 7.64 g of 3 chloro-2-hydrazinylpyridine to a solution of ethyl 2 furoyl viruvate 11 · 19 g in acetic acid (150 ml) at room temperature, the mixture was further stirred at room temperature for 1 hour. Next, the reaction solution was heated to 100 ° C. and reacted for 3 hours. After completion of the reaction, acetic acid was distilled off under reduced pressure, and extraction was performed by adding ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated Japanese brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 14.5 g (melting point: 116.7 ° C.) of the desired product.

'H-NMR (300MHz.CDC1) δ: 8.55 (dd, lH), 7.92 (dd, lH), 7.47 (m, lH), 7.32 (s, lH), 7.17

(s, lH), 6.32 (m, lH), 6.00 (d, lH), 4.45 (q, 2H), 1.43 (t, 3H).

Step (2): 1— (3-Chlorocyclic pyridine 1-yl) 5-Furyl 1 1H-Pyrazole 1-Power Synthesis of rubonic acid

Ethynole 1- (3-chloro-pyridine-2-yl) obtained in the previous step (1) 5-Frinole 1H-pyrazole-3 carboxylate 14.5 g was dissolved in a mixed solvent of 90 ml methanol and 45 ml water. Thereafter, 2.2 g of sodium hydroxide was added and reacted under reflux for 3 hours. After completion of the reaction, the solvent was distilled off, and water was added to the residue, followed by washing with ethyl ether. The aqueous layer was adjusted to pH 3 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, and then anhydrous Dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 19.9 g (melting point: 179.3 ° C.) of the desired product.

^: H-NMR (300 MHz. DMSO- d) δ: 8.61 (d, lH), 8.30 (d, lH), 7.75 (m, lH), 7.61 (s, lH), 7.1

6

6 (s, lH), 6.49 (m, lH), 6.24 (m, lH).

Process (3): 3-t-Butyloxycarbonylamino 1-1 (3-chloropyridine-2-yl) 5-5-Folinole 1H-pyrazole synthesis

1- (3 Chloropyridine 1- 2 yl) 5 furyl — 1H Pyrazole 1-carboxylic acid 8. Og obtained by repeating the previous step (2) 7.6 g of diphenolinophospholinoleazide After adding to 70 ml of ethanol, 4 g of diisopropylethylamine was added dropwise at room temperature, and the mixture was further stirred at room temperature for 30 minutes, and then the reaction solution was stirred with heating under reflux for 6 hours. After completion of the reaction, t-butanol was distilled off under reduced pressure, and extracted with ethyl acetate and water. The organic layer was washed with 10% hydrochloric acid, water, 1N aqueous sodium hydroxide solution and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 4 · 8 g of the desired product (melting point: 52.6 ° C). .

'H-NMR (300 MHz. DMSO-d) δ: 9.94 (s, lH), 8.56 (d, lH), 8.23 (d, lH), 7.69 (m, lH), 6.

6

82 (s, lH), 6.44 (m, lH), 6.09 (d, lH), 1.47 (s, 9H).

Step (4): 3-t-Butyloxycarbonylamino 1- (3-chloropyridine-2-yl) 1 1H Synthesis of 5-pyrazolecarboxylic acid

3-t-Butyloxycarbonylamino 1- (3-chloro-pyridine 2-yl) 5 obtained in the previous step (3) 5 Flinole 1H Pyrazole 2 · Og in 60 ml of acetone in potassium permanganate 6. After gradually adding 13 g at room temperature, the mixture was reacted at room temperature for 1 day. Next, 30 ml of ethanol was added and stirred overnight at room temperature. The reaction solution was filtered through celite, the celite layer was washed with ethanol, the filtrates were combined and concentrated under reduced pressure. The residue was extracted by adding jetyl ether and a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was adjusted to pH 3 with 10% hydrochloric acid under ice cooling, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (0.81 g, melting point: 124.8 ° C).

'H-NMR (300 MHz. DMSO-d) δ: 10.05 (s, lH), 8.51 (d, lH), 8.20 (dd, lH), 7.61 (m, lH),

6

1.46 (s, 9H). Example 2 N [2 Bromo 4 Chloro-6 [[α-Methinole (cyclopropylmethyl) amino] carboninole] -phenyl] 3 Bromo 1— (3 Chloroform 2 Pyridine 1 2yl) 1H-Pyrazole Synthesis of 5-carboxamide (1)

Step (1): 2— [3-T-Butoxycarbonylamino-1 1 (3-Chronopyridine 2 2-Inole) 1H Pyrazonore 5 Inole] 6 Chloro-8 Bromo-4H— 3, 1-Benzoxoxazine 4 Composition

3-t-butyloxycarbonylamino-1 1- (3-chloropyridine 1- 2 yl) 1H 5-pyrazolecarboxylic acid 1 · Og and pyridine 0.4 m 1 acetonitrile (10 ml) obtained by repeating Example 1 ) 0.3 ml of methanesulfonyl chloride was gradually added dropwise to the solution while maintaining the reaction temperature at 0 ° C, followed by stirring at the same temperature for 15 minutes. Next, a solution of 2-amino-3-bromo-5-chlorobenzoic acid 0 · 74 g and pyridine 0.84 ml of acetonitrile (5 ml) was gradually added dropwise to the solution while maintaining the reaction temperature at 0 ° C. For 15 minutes. Thereafter, 0.3 ml of methanesulfonyl chloride was gradually added dropwise to the solution at 0 ° C., followed by stirring at the same temperature for 1 hour and further at room temperature overnight. After completion of the reaction, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 1.4 g (melting point: 222.7 ° C.) of the desired product.

'H-NMR (300 MHz. DMSO-d) δ: 10.25 (s, lH), 8.55 (d, lH), 8.25 (d, lH), 8.22 (s, lH), 8.

6

04 (s, lH), 7.65 (dd, lH), 7.27 (s, lH), 1.49 (s, 9H).

Step (2): N [2 Bromo-4 Chloro-6 [[α-Methyleno (cyclopropylmethyl) amino] carbonyl] phenyl] 3-t-butyloxycarbonylamino 1 1 (3-chloro 1 2 pyridine 1 2 1) Synthesis of 1H pyrazole-5 carboxamide

2- [3-T-Butyloxycarbonylamino-1] obtained in the previous step (1) (1) (3-chloro-pyridine 2-inole) 1 1H pyrazono-re 5-inole]-6 1-bromo 8H- 3 , 1 Benzoxazine-4-one 0.5 g and α-methyl-cyclopropylmethylamine (65%) 0.6 g of acetonitrile (10 ml) was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure. did. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 0 · 34 g (melting point: 137.4 ° C.) of the desired product.

'H-NMR (300MHz, DMSO-d) δ: 10.23 (s, lH), 9.96 (s, lH), 8.32 (d, lH), 7.97 (d, 2H), 7. 81 (s, lH), 7.41 (m, 2H), 7.31 (s, lH), 3.16 (q, lH), 1.38 (s, 9H), 0.93 (d, 3H), 0.71 (m, lH), 0.24 (m, lH), 0.15 (m, lH), 0.03 (m, 2H).

[0091] Step (3): N [2 Bromo-4 Chloro-6 — [[α-Methyl (cyclopropylmethyl) amino] carbonyl] —Phenenole] — 3 Amino 1 ) Synthesis of 1H pyrazole-5-carboxamide

N- [2 Bromo-4 Chloro-6 [[a Methyl (cyclopropylmethinole) amino] carboninole Fueninore] -3—t-Butyloxycarbonylylamino 1- (3 Chloroform) obtained by repeating the previous step (2) 1 H pyrazole 1 5 pyrpamide 1 H pyrazole 1 0.2 trifluoroacetic acid 0.2 ml was added to 0.5 ml of methylene chloride solution 10 ml and stirred at room temperature overnight. Since the reaction was not complete, 2 ml of trifluoroacetic acid was further added and stirring was continued for 1 hour at room temperature to complete the reaction. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate, water and saturated brine in that order and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, 0.35 g (melting point: 139.8 ° C.) of the desired product was obtained.

'H-NMR (300MHz, DMSO-d) δ: 9.95 (s, lH), 8.27 (d, lH), 7.98 (m, 2H), 7.90 (d, lH), 7.

6

82 (s, lH), 7.33 (md, 2H), 6.40 (s, lH), 3.16 (q, lH), 0.95 (d, 3H), 0.68 (m, lH), 0.27 (m, lH), 0.1 6 (m, 2H), 0.06 (m, 2H).

[0092] Step (4): N— [2-bromo-4 chloro-6 [[a-methyl- (cyclopropylmethyl) amino] carboninole] -phenyl] — 3-bromo 1— (3-chloropyridine 1 2 —Yl)-1 H pyrazole-5-carboxamide synthesis

Odory 12g and 90% nitrous acid salt, cinole 0 · 091g of 10ml acetonitorinole in the night, obtained from the previous step (3) Ν— [2 Bromo 4 Chloro 6 [ [a-Methyl- (cyclopropylmethyl) amino] carbinole] -phenyl] 3 amino 1 1- (3-chloropyridine 1 2-yl) — 1H pyrazole-5 carboxamide 0 · 29 g of 10 ml acetononitrile solution at 0 ° After gradually dropping with C, the mixture was stirred at the same temperature for 2 hours and at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give the desired product 0.1 l lg (melting point: 260.6 ° C). )

'H-NMRCSOOMHZ, DMSO-d) δ: 10.34 (s, lH), 8.37 (d, lH), 8.18 (d, lH), 8.05 (d, lH), 7.

6

84 (s, lH), 7.50 (dd, lH), 7.44 (s, lH), 7.35 (s, lH), 3.17 (q, lH), 0.95 (d, 3H), 0.72 (m, lH), 0.25 (m, lH), 0.17 (m, lH), 0.05 (m, 2H).

Example 3 N— [2 Bromo-4 Chloro-6 [[α-Methyl- (cyclopropylmethyl) amino] carboninole] -phenyl] —3-Bromo 1— (3-Chloropyridine 1- 2-yl) -Synthesis of 1 H pyrazole-5 carboxamide (2)

Step (1): N— [2-Bromo-4-chloro-6-[[a-methyl- (cyclopropylmethyl) amino] carbonyl] phenyl] 3-t-butyloxycarbonylamino-11- (3-chloro-2-pyridine 1 2 yr) Synthesis of 1 H pyrazole and 1 carboxamide

3-t-butyloxycarbonylamino- 1 1 (3-chlorobutyl pyridine 2-yl) 1H 5-pyrazolecarboxylic acid 1 · 68 g obtained by repeating Example 1 and N— [a-methylol (Cyclopropylmethyl)] 2 amino-3 bromo 5 black mouth benzamide 1 · 58 g of acetonitrile with 30 ml of 3 picoline 2.8 g was added at room temperature, and then the reaction solution was cooled to −5 ° C. Next, 2.8 g of methanesulfonyl chloride was added dropwise while keeping the solution temperature between 5 ° C. and 0 ° C., and then kept in that temperature range for 2 hours. After completion of the reaction, extraction was performed by adding ethyl acetate and ice water to the reaction solution, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 2 · 2 g of the desired product (melting point: 144 · 6 ° C). .

^: H-NMR (300 MHz, DMSO-d) δ: 10.22 (s, lH), 9.95 (s, lH), 8.30 (d, lH), 7.96 (m, 2H), 7

6

.80 (s, lH), 7.40 (m, 2H), 7.30 (d, lH), 3.16 (q, lH), 1.37 (s, 9H), 0.65 (m, lH), 0.20 (m, lH), 0.02 (m, 2H).

Step (2): N [2 Bromo-4 Chloro-6 [[a-Methinole (cyclopropylmethyl) amino] carboninole] -phenyl] 3 Bromo 1- (3 2-Circle pyridine 1- 2 yl)-1 H Pyrazole 5 —Synthesis of carboxamide

N- [2 Bromo 4 Black mouth 6 [[a-Methyl- (cyclopropylmethylolamino) amino] carboninole] one phenole] 1 3-t-butyloxycarbonylamino- 1 in the previous step (1) One (3 1H-pyrazole-5 Carboxamide was used according to the methods of (3) and (4) of Example 2! /, The target product N— [2 Bromo 4 Chloro-6 — [[α— Methyl- (cyclopropylmethinole) amino] carboninole] vinylenol] 3-bromo-11 (3-chloro-pyridine-2-yl) 1Ηpyrazole-5-carboxamide was synthesized. (Example 4 IV) 3-Benzyloxycarbonylamino-11 (3-chloro-pyridine 2-yl) 1H Synthesis of 5-pyrazolecarboxylic acid (Production method using 2-furoyl bilbate as a raw material)

Process (1): 3-Benzyloxycarbonylamino-1 (3-chloropyridine 2-yl) —5-Frinole 1H-pyrazole synthesis

1- (3 2-chloropyridine pyridine 2-yl) obtained in step (2) of Example 1 5 Furyl 1H-pyrazole-3 strong rubonic acid 11.9 g, benzyl alcohol 4.89 g, diphenylphosphorinoleazide 12 4g and triethinoreamine 5. After escaping Og to 100ml of dioxin 90ml. The reaction was carried out at C for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and extraction was performed by adding ethyl acetate and water. The organic layer was washed with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 11.0 g of the target (melting point: 133.4 ° C). Obtained.

'H-NMR (300MHz.CDC1) δ: 8.51 (d, lH), 7.89 (d, lH), 7.41 (m, 5H), 7.28 (s, lH), 6.28 (m

, lH), 6.07 (d, lH), 5.24 (s, 2H).

Process (2): Synthesis of 3 Benzyloxycarbonylamino 1- (3-chloropyridine 2 yl)-1H-5-pyrazolecarboxylic acid

3 Benzyloxycarbonylamino-1 (3-chloropyridine-2-yl) -5 furyl 1H pyrazole 8 · 9 g obtained in the previous step (1) was dissolved in a mixed solvent of 70 ml of acetonitrile and 70 ml of carbon tetrachloride. Then, an aqueous solution (150 ml) of ruthenium chloride 0.70 g and sodium periodate 21.5 g was added and stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate and 1N hydrochloric acid were added to the residue and extracted. The organic layer was washed with water and then with a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer was adjusted to pH 3 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, and then anhydrous Dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 4.4 g of the desired product (melting point: 79.1 ° C)

)

^: H-NMR (300 MHz. DMSO— d) δ: 10.50 (s, lH), 8.51 (dd, lH), 8.18 (dd, lH), 7.61 (dd, l

6

H), 7.42-7.32 (m, 5H), 7.03 (s, lH), 5.17 (s, 2H).

(Experimental example 4 1 B) 3 Benzyloxycarbonylamino 1 1 (3 chloropyridine 1 2 inore) Synthesis of 1H 5-pyrazole carboxylic acid (Production method using 2, 4 dioxo 4-styrylbutanoic acid ethyl ester)

Process (1): 1 (3-Chloropyridine-2-yl) -3-Ethoxycarbolulu 5-Stillulu 1H-pyrazole synthesis

28 g of 2,4 dioxo 4-styrylbutyric acid ethyl ester and 16.3 g of 3 chloro-2-hydrazinylpyridine were dissolved in 250 ml of acetic acid, stirred at room temperature for 1 hour, heated to 100 ° C, and further reacted for 3 hours. . After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 26 g of the desired product (melting point: 143.1 ° C.).

'H-NMR (300MHz. CDC1) δ: 8.59 (dd, lH), 7.94 (dd, lH), 7.47 (dd, lH), 7.39-7.20 (m, 6

Three

Η), 7 · 12 (d, lH), 6.63 (d, lH), 4.44 (q, 2H), 1.42 (t, 3H).

Process (2): 1— (3-Chloropyridine-2-yl) -5-styryl 1H-pyrazole 3

1 (3 black pyridine-2-yl) -3 ethoxycarbonyl 1 5 pyrilazole 26 g obtained in the previous step (1) was dissolved in 250 ml of methanol, and then 3.5 g of sodium hydroxide 3.5 g in 40 ml of aqueous solution at room temperature. It was dripped. After completion of the dropwise addition, the mixture was reacted under reflux for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and water and ether were added to the residue for extraction. The aqueous layer was adjusted to pH 3 with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration, dissolved in ethyl acetate, washed with saturated Japanese brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product 20. Og (melting point: 237.0 ° C.).

'H-NMR (300MHz, DMSO-d) δ: 13.0 (s, lH), 8.65 (dd, lH), 8.33 (dd, lH), 7.78 (dd, lH)

6

7.51-7.24 (m, 7H), 6.71 (d, lH). [0096] Step (3): Synthesis of 3-Benzyloxycarbonylamino-11 (3-chloropyridine-2-yl) 5-styrinole 1H-pyrazole

1 obtained from the previous step (2) (3 Chloropyridine-2-yl) -5 Styryl 1H-Pyrazol Nore 3 Strong rubonic acid 20. Og, benzyl alcohol 7.3 g, diphenylphosphoryl azide 18.6 g and triethinorea Min Min 7.5 After diluting 5g to 200ml Di-Chan, 90. C reacted for 5 days between the temples. After completion of the reaction, the solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate and water. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 11.0 g (melting point: 106.8 ° C) of the desired product. It was.

'H-NMR (300MHZ DMSO— d) δ: 10.36 (s, lH), 8.60 (d, lH), 8.25 (d, lH), 7.65 (dd, lH

6

), 7.47-7.18 (m, l lH), 6.98 (s, lH), 6.70 (d, 2H), 5.18 (s, 2H).

Process (4): 3 Benzyloxycarbonylamino-1 (3-chloropyridine 2yl) 5-forminolide 1H-pyrazole synthesis

3 Benzyloxycarbonylamino-1 obtained in the previous step (3) 5 (Still pyridine 2 yl) 5 Stilil 1H Pyrazole 10 g of ethyl acetate (250 ml) in ozone-oxygen stream at 65 ° C I blew in for 4 hours. Dry nitrogen was blown into the reaction solution to drive out excess ozone, and then 5 ml of dimethylsulfide was added and stirred for 8 hours while gradually returning to room temperature. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give 5.2 g (melting point: 41.2 ° C) of the amorphous solid. )

'H-NMR (300MHz, DMSO—d) δ: 10.67 (s, lH), 9.79 (s, lH), 8.53 (dd, lH), 8.23 (dd, lH)

6

, 7.65 (s, lH), 7.65 (s, lH), 7.39 (m, 6H), 5.19 (s, 2H).

[0097] Step (5): Synthesis of 3 Benzyloxycarbonylamino-1 (3-chloropyridine-2yl) -1H-5-pyrazolecarboxylic acid

In the mixed solution of 3 benzyloxycarbonylamino-1 (3 chloropyridine pyridine 2-yl) -5 formyl 1H pyrazole 5.2 g obtained in the previous step (4), 100 ml of t-butanol and 100 ml of 2 methyl-2-butane, Sodium chlorite (80%) 14.5g and sodium dihydrogen phosphate dihydrate 18.2g 100ml aqueous solution was slowly added dropwise at room temperature, Stir for a while. After completion of the reaction, ethyl acetate and water were added for extraction, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.8 g (melting point: 79.1 ° C.) of the desired product.

^: H-NMR (300 MHz DMSO—d) δ: 10.50 (s, lH), 8.51 (dd, lH), 8.18 (dd, lH), 7.61 (dd,

6

lH), 7.42-7.32 (m, 5H), 7.03 (s, lH), 5.17 (s, 2H).

Example 5 N— [2 Bromo-4 Chloro-6 [[α-Methyl- (cyclopropylmethyl) amino] carboninole] -phenyl] —3-Bromo 1 (3-Chloropyridine 1-yl)- Synthesis of 1 H pyrazole-5-carboxamide (3)

Step (1): 2- [3-Benzyloxycarbonylamino-11 (3-chloro-pyridine 2-inole)-1H-pyrazonole 5inore] 8 Bromo 6 Black-and-white 4H— 3, 1-Benzoxazine 4 One-year-old synthesis

Example 4-3-Benzyloxycarbonylamino-1 obtained by repeating A- (1—3-chloropyridine 1- 2yl) 1H-5 pyrazole carboxylic acid 4 · 8 g and pyridine 1.8 ml acetonitrile To the (50 ml) solution, 1.3 ml of methanesulfonyl chloride was gradually added dropwise while maintaining the reaction temperature at 0 ° C., followed by stirring at the same temperature for 15 minutes. Next, a solution of 2 amino-3 bromo-5 chlorobenzoic acid 3.2 g and pyridine 3.6 ml of acetonitrile (3 Oml) was gradually added dropwise to the solution while maintaining the reaction temperature at 0 ° C. Stir for a minute. Thereafter, 1.3 ml of methanesulfonyl chloride was gradually added dropwise to the solution at 0 ° C., followed by stirring at the same temperature for 1 hour and further at room temperature overnight. After completion of the reaction, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration, washed with water and dried to obtain 6.4 g of the desired product (melting point: 246.7 ° C.).

^: H-NMR (300 MHz. DMSO— d) δ: 10.71 (s, lH), 8.55 (d, lH), 8.26 (d, lH), 8.19 (s, lH), 8.

6

H (s, lH), 7.67 (dd, lH), 7.45-7.29 (m, 6H), 5.21 (s, 2H).

Step (2): 2— [1— (3—Black pyridine 1-yl) 3-Trifluoroacetylamino — 1 H Pyrazonol 1 — 5-Inole] — 6—Black 1 8-Bromo 4H— 3, 1-benzoxazine 4 synthesis

2- [3 Benzyloxycarbonylamino-1 1 (3 chloropyridine 1 2 inore) 1 1H pyrazonore 1 5 inore] obtained in the previous step (1) — 8 Bromo 6 Black mouth 4H— 3, 1-Benzoxazine-4-one 5. A mixed solution of Og and 50 ml of trifluoroacetic acid was stirred overnight under reflux, and then the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain the desired product 2 · Og (melting point: 209.4 ° C).

^: H-NMR (300 MHz, DMSO— d) δ: 12.67 (s, lH), 8.57 (d, lH), 8.31 (d, lH), 8.20 (s, lH), 8.

6

13 (s, lH), 7.73-7.69 (m, lH), 7.48 (s, lH).

Step (3): N [2 Bromo-4 Chloro-6 [[α-Methinole (cyclopropylmethyl) amino] carbonyl] -phenyl] — 1— (3 Chloro pyridine 1- 2 yl) 3 Trifunoleo acetylyl 1H-Pyrazole 5 —Synthesis of carboxamide

2- [1 (3- (3-chloropyridine) -2-yl) 3-trifluoroacetinoleamino-1 1H-pyrazonol 1- (5-inole)] obtained in the previous step (2) -8-bromo 6-black 4-3 , 1-Benzoxazine-4-one 2. A solution of Og and α-methyl-cyclopropylmethylamine 2.0 g in acetonitrile (50 ml) was stirred at room temperature for 3 hours, and then the reaction solution was concentrated under reduced pressure. did. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 1.3 g of the desired product (melting point: 152.0 ° C.).

'H-NMR (300MHz, DMSO-d) δ: 12.44 (s, lH), 10.43 (s, lH), 8.37 (d, lH), 8.10 (d, lH),

6

8.05 (d, lH), 7.82 (s, lH), 7.65 (s, lH), 7.50-7.46 (m, lH), 7.42 (s, lH), 3.16 (q, lH), 0.95 (d, 3 H ), 0.71 (m, lH), 0.25 (m, lH), 0.15 (m, lH), 0.03 (m, 2H).

Step (4): N— [2 Bromo-4 Chloro-6 [[α-Methinole (cyclopropylmethyl) amino] carbonyl] —Phenenole] — 3 Amino 1 1- (3 Chloropyridine 1 2-yl) 1H Pyrazole Synthesis of 5-carboxamide

N- [2 Bromo 4 Black Mouth 6 [[a-Methylol (cyclopropylmethyl) amino] carbonyl] Phenylol] -1 1 (3 Black Mouth Pyridine-2 Yil)- 3-Trifluoroacetylamino-1H-pyrazole-5-carboxamide 1 · 2g and 28% ammonia water 50ml mixed solution was allowed to stir overnight at room temperature, then the reaction solution was concentrated under reduced pressure and the residue was Purification by column chromatography (eluent: ethyl acetate) gave 0.42 g of the desired product (melting point: 139.8 ° C).

'H-NMR (300MHZ DMSO-d) δ: 9.94 (s, lH), 8.24 (d, lH), 8.04 (d, lH), 7.87 (d, lH), 7 .77 (s, lH), 7.38 (s, lH), 7.33-7.27 (m, 2H), 6.35 (s, 2H), 3.16 (q, lH), 0.86 (d, 3H), 0.69 (m, l H), 0.23 (m, lH), 0.17 (m, lH), 0.02 (m, 2H).

Step (5): N [2 Bromo-4 Chloro-6 [[α-Methyl- (cyclopropylmethyl) amino] carboninole] -phenyl] — 3-Bromo 1- (3-Chloropyridine 1- 2-yl)- Synthesis of 1 H pyrazole-5-carboxamide

Odor 匕同（Π） 0 · 17g and 90% nitrous acid salt, quinole 0 · 12g of 10ml case 2 卜 linole dissolved in night, obtained in the previous step (4) Ν [2 Bromo 4 Chloro-6 [[a-Methinole (cyclopropylmethyl) amino] carbonyl] —Pheninole] — 3 Amino 1 1- (3 Closyl pyridine 1 2 yl) 1H Pyrazole 5 Carboxamide 0 · 41 g of 10 ml acetonitrile solution After gradually dropping at 0 ° C, the mixture was stirred overnight while gradually warming to room temperature. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2 /;! To 1/1) to obtain the desired product 0 • lg (melting point: 193.5) ° C) was obtained.

'H-NMR (300MHz, DMSO-d) δ: 10.34 (s, lH), 8.37 (d, lH), 8.18 (d, lH), 8.05 (d, lH), 7.

6

[0100] (Example 6) N— [2-bromo-4 chloro-6 [[a-methinole (cyclopropylmethyl) amino] carboninole] -phenyl] 3 bromo 1— (3-chloropyridine pyridine 2-yl) -1 H Pyrazole-Synthesis of 5-carboxamide ( ⁴ )

N— [2 bromo-4 chloro-6 — [[a methinole (cyclopropylmethyl) amino] carbonino]]-phenyl] —3-amino—obtained by repeating step (4) of Example 5 above 1— (3 Chloropyridine 1-2-yl) 1 H Pyrazole 1 5 Carboxamide 1 g of 7 ml bromoform solution, 90% 90% butyl nitrite 0.43 g was gradually added dropwise at 80 ° C, then stirred for 2 hours did. The reaction solution was cooled to room temperature, excess n-hexane was added, and the precipitate was collected by filtration to obtain the desired product (0 · 91 g, HPLC purity 86%).

Industrial applicability

[0101] According to the method of the present invention, pyrazole 3 can be prepared without using a highly toxic phosphorus halogenating agent. An anthranilamide compound having a halogen at its position or a salt thereof can be efficiently produced, and the obtained anthranilamide compound or a salt thereof is useful as a pest control agent in the field of agriculture and horticulture. In addition, the Japanese Patent Application 2006-339100 filed on December 15, 2006, the Japanese Patent Application 2007-128991 filed on May 15, 2007, and the May 24, 2007 application The entire contents of the specification, claims, and abstract of Japanese Patent Application No. 2007-137551 are incorporated herein by reference as the disclosure of the specification of the present invention.

Claims

Claim [1] Formula (I):

[Chemical 1]

(In the formula, R ¹ represents halogen, anolequinole, haloalkyl, alkenyl, haloalkenyl, alkynole, noroanorequininore, anolecoxy, noroanoreoxy, anolequinorecanoleponinore, noronorenocenoreboninore, anolecoxanono Reponinore, Noroanorexoxynoreponinore, Nitro, Honoremil or Ciano, A is alkyl optionally substituted by Y, Y is at least one selected from the group consisting of halogen, alkyl and haloalkyl C to C cycloalkyl optionally substituted with one substituent, X is halogen, and m is 0 to 4.

3 4

[Chemical 2]

(Where

A and m are as described above), and then halogenated in the presence of copper halide, metal copper or alkyl halide.

[2] Formula (III):

[Chemical 3]

(Wherein, R is halogen, anorequinole, haloalkyl, alkenyl, haloalkenyl, alkynole, noroanorequininore, anorecoxy, noanoreoxy, anorequinolecanoleponinore, noroanorequinolecanoleboninore, anolecoxanorepo Ninore, Noroanorexoxynoreponinore, Nitro, Honoremil or Ciano, wherein R ² is alkyl optionally substituted with halogen; may be substituted with norogen! /, Alkenyl; may be substituted with halogen Y! /, Alkynyl; or a phenyl moiety optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, anolenoquinole, haloalkyl, alkoxy, haloalkoxy, cyano and nitro, A is alkyl which may be substituted with Y, Y is halogen, alkyl and And C 1 -C cycloalkyl optionally substituted with at least one substituent selected from the group consisting of haloalkyl

3 4

And m is 0 to 4) to remove the protecting group represented by R ² 0 C 1 by deprotecting the compound represented by the formula (Π):

[Chemical 4]

(Where

The method according to claim 1, wherein A and m are as described above, and the compound is diazotized and then halogenated in the presence of copper halide, metal copper or alkyl halide.

Formula (IV-1):

[Chemical 5]

Wherein R ² is alkyl optionally substituted with halogen; alkenyl optionally substituted with halogen; may be substituted with halogen! /, Alkynyl; or the phenyl moiety is halogen, alkyl, haloalkyl, A compound represented by formula (V): a benzyl which may be substituted with 1 to 5 substituents selected from the group consisting of alkoxy, haloalkoxy, cyano and nitro

[Chemical 6]

(Wherein, R is halogen, anorequinole, haloalkyl, alkenyl, haloalkenyl, alkynole, noroanorequininore, anorecoxy, noanoreoxy, anorequinolecanoleponinore, noroanorequinolecanoleboninore, anolecoxanorepo A compound represented by the formula (VI): Ninore, Noroanorexoxynoreponinole, Nitro, Honoremil or Ciano, and m is 0-4.

[Chemical 7]

(Where

R ² and m are as described above)

Compounds of formula (VI) and formula (VII):

[Chemical 8

A-NH ₂ (VII)

Wherein A is alkyl optionally substituted by Y, Y is halogen, alkyl and halo Optionally substituted with at least one substituent selected from the group consisting of alkyl c to c

: Reaction of the compound represented by the formula (III)

[Chemical 9]

(Where

R ² , A and m are as described above); the compound of formula (III) is deprotected to remove the protecting group represented by R ² OC— (II)

[Chemical 10]

(Where

[4] Formula (XII):

[Chemical 11]

(XII)

Wherein R ⁵ is alkyl and R ⁶ is 2-furyl or α-styryl, and the formula (式):

[Chemical 12]

Is reacted with a compound represented by formula (XIV):

[Chemical 13]

(Wherein R ⁵ and R ⁶ are as described above), and the compound of formula (XIV) is hydrolyzed to form formula (XV):

[Chemical 14]

(Wherein R ⁶ is as described above), and a compound of formula (XV) and formula (XVI):

[Chemical 15]

R2-OH (XVI)

Wherein R ² is alkyl optionally substituted with halogen; alkenyl optionally substituted with halogen; may be substituted with halogen! /, Alkynyl; or the phenyl moiety is halogen, alkyl, haloalkyl, An alcohol represented by formula (1) selected from the group consisting of alkoxy, haloalkoxy, cyano and nitro, which is a benzyl which may be substituted with 1 to 5 substituents, and diphenylphosphoryl azide, (XVII):

[Chemical 16]

(Wherein R ² and R ⁶ are as defined above) and a compound of formula (XVII) is produced. The product and an oxidant, and the formula (IV-1):

[Chemical 17]

(Wherein R ² is as described above), and the compound of formula (IV-1) and the formula

[Chemical 18]

[Chemical 19]

(Where

R ² and m are as described above)

Compounds of formula (VI) and formula (VII):

[Chemical 20]

A- H ₂ (VII)

Wherein A is alkyl optionally substituted with Y, and Y is optionally substituted with at least one substituent selected from the group consisting of halogen, alkyl and haloalkyl. : Reaction of the compound represented by the formula (III)

[Chemical 21]

(Where

R ² , A and m are as described above); the compound of formula (III) is deprotected to remove the protecting group represented by R ² C 1; Formula (II)

[Chemical 22]

(Where

A and m are as described above); the compound of formula (Π) is diazotized and then halogenated in the presence of copper halide, metal copper or alkyl halide. The method of claim 1.

[5] Formula (Π):

[Chemical 23]

(In the formula, R ¹ represents halogen, anolequinole, haloalkyl, alkenyl, haloalkenyl, alkynole, noroanorequininore, anolecoxy, noroanoreoxy, anolequinorecanoleponinore, noronorenocenoreboninore, anolecoxanono Reponinore, Noroanorexoxynoreponinole, nitro, honoreyl or cyano, A is alkyl optionally substituted by Y, Y is halogen, alkyl Or a salt thereof, which may be substituted with at least one substituent selected from the group consisting of ru and haloalkyl, and is C to C cycloalkyl, and m is 0 to 4.

3 4

Formula (m):

[Chemical 24]

3 4

And m is 0-4) or a salt thereof.

Formula (VI):

[Chemical 25]

(Wherein, R is halogen, anorequinole, haloalkyl, alkenyl, haloalkenyl, alkynole, noroanorequininore, anorecoxy, noroanoreoxy, anorequinolecanoleponinore, noroanorequinolecanoleboninore, anorecoxinorepore Ninore, Noroanorekoxikanolepononire. Nitro, Honoremi R ² is alkyl which may be substituted with halogen; may be substituted with halogen! /, Alkenyl; may be substituted with halogen! /, Alkynyl; or phenyl moiety is halogen, A benzyl which may be substituted with 1 to 5 substituents selected from the group consisting of an anorequinole, haloalkyl, alkoxy, haloalkoxy, cyano and nitro, and m is 0 to 4. Or a salt thereof.

Formula (IV):

[Chemical 26]

(Wherein R ² is alkyl optionally substituted with halogen; alkenyl optionally substituted with halogen; alkynyl or phenyl moiety optionally substituted with neurogen is halogen, alkyl, haloalkyl, alkoxy, halo; alkoxy, it may also be substituted with one to five substituents selected from Shiano and nitro V, benzyl,; R ³ is a hydrogen atom; alkyl; Aruke two Honoré; alkynyl or halogen, Anorekinore, haloalkyl, alkoxy, A pyrazole carboxylic acid derivative or a salt thereof, which is a phenyl optionally substituted with 1 to 5 substituents selected from haloalkoxy, cyan and nitro.

Formula (IV-1):

[Chemical 27]

(Wherein R ² is alkyl optionally substituted by halogen; alkenyl optionally substituted by halogen; alkynyl or phenyl moiety optionally substituted by halogen is halogen, alkyl; And may be substituted with 1 to 5 substituents selected from kill, haloalkyl, alkoxy, haloalkoxy, cyano and nitro! /, Which is benzyl). Because

Step (1) is represented by the formula (XII):

[Chemical 28]

(Wherein IT is alkyl and R ⁶ is 2-furyl or α-styryl), and the formula (ΧΙΠ):

[Chemical 29]

I rT J ^cl (iii)

Reaction with a compound represented by N NHNH ₂ gives the formula (XIV):

[Chemical 30]

(Wherein R ⁵ and R ⁶ are as described above); step (2) is a step of hydrolyzing the compound of formula (XIV) obtained in step (1). Formula (XV)

[Chemical 31]

(Wherein, R ° is as described above) or a salt thereof; step (3) includes the compound of formula (XV) obtained in step (2), XVI):

[Chemical 32]

R ^ OH (xvi)

(Wherein R ² is as described above) and a diphenylphosphoryl azide are reacted, and the formula (XVII):

[Chemical 33]

(Wherein R ² or R ⁶ is as described above); and step (4) is a compound of formula (XVII) obtained in step (3) and an oxidizing agent. And a step of producing a pyrazole carboxylic acid derivative represented by the above formula (IV-1) or a salt thereof.

[10] The method according to claim 9, wherein the compound of the formula (XII) in which R ⁶ is 2-furyl is used as a starting compound in the step (1).

[11] The method according to claim 9, wherein the compound of the formula (XII) in which R ⁶ is α-styryl is used as a starting compound in the step (1).