JP2009001541A - Method for producing anthranilamide compound using new pyrazole compound as intermediate - Google Patents

Method for producing anthranilamide compound using new pyrazole compound as intermediate Download PDF

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JP2009001541A
JP2009001541A JP2007320102A JP2007320102A JP2009001541A JP 2009001541 A JP2009001541 A JP 2009001541A JP 2007320102 A JP2007320102 A JP 2007320102A JP 2007320102 A JP2007320102 A JP 2007320102A JP 2009001541 A JP2009001541 A JP 2009001541A
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halogen
alkyl
compound
1h
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Akihiro Hisamatsu
Toru Koyanagi
彰弘 久松
徹 小柳
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Ishihara Sangyo Kaisha Ltd
石原産業株式会社
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

A method for producing a specific anthranilamido compound or a salt thereof is provided.
SOLUTION: Formula (I):

Wherein X is halogen; R 1 is halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, nitro, formyl Or is cyano; A is alkyl substituted with Y; m is 0 to 4), and a salt of 3-aminopyrazole derivative as a raw material. Provided is a method for producing the anthranilamide compound or a salt thereof, wherein the amino group is diazotized and then reacted with copper halide, metal copper or alkyl halide.
[Selection figure] None

Description

  The present invention relates to a method for producing an anthranilamido compound.

  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 Documents 2 and 3 describe a method for producing a certain anthranilamide compound.

International Publication WO 2005/077934 International Publication WO 2003/016282 International Publication WO 2003/016283

  Various methods have been proposed for producing anthranilamide compounds. However, when producing an anthranilamide compound in which pyrazole 3-position is substituted with halogen, it is necessary to use a highly toxic phosphorus halogenating agent such as phosphorus oxybromide for the halogenation. There has been a demand for a method for producing the anthranilamide-based compound without using any of the above.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have used a compound having an amino group at the 3-position of pyrazole without using a toxic reagent such as a phosphorus-based halogenating agent in the halogenation reaction. The inventors have found that the target compound can be produced, and completed the present invention. That is, the present invention relates to the formula (I):

Wherein R 1 is halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, nitro, formyl or cyano, Is alkyl optionally substituted with Y, Y is C3-4 cycloalkyl optionally substituted with at least one substituent selected from the group consisting of halogen, alkyl and haloalkyl, and X is halogen , M is 0 to 4), an anthranilamide compound represented by the formula (II):

The present invention relates to a method of diazotizing a compound represented by the formula (wherein R 1 , A and m are as described above) and then halogenating in the presence of copper halide, metal copper or alkyl halide.
The present invention also provides a compound of formula (II):

(Wherein R 1 , A and m are as described above) or a salt thereof.
The present invention also provides a compound of formula (III):

Wherein R 2 is alkyl optionally substituted with halogen; alkenyl optionally substituted with halogen; alkynyl optionally substituted with halogen; or phenyl moiety is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano And benzyl optionally substituted with 1 to 5 substituents selected from the group consisting of nitro and nitro, and R 1 , A and m are as described above, or a salt thereof.
The present invention also provides a compound of formula (VI):

(Wherein R 1 , R 2 and m are as described above) or a salt thereof.
Furthermore, the present invention provides a compound of formula (IV):

Wherein R 3 is a hydrogen atom; alkyl; alkenyl; alkynyl; or phenyl optionally substituted with 1 to 5 substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and nitro. And R 2 is as described above); and a method for producing the same.

The alkyl or alkyl moiety in R 1 , R 2 , R 3 , R 5 , A or Y may be either linear or branched. Specific examples thereof include those of C1-6 such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl and hexyl.
The alkenyl or alkenyl moiety in R 1 , R 2 or R 3 may be either linear or branched. Specific examples thereof include those of C2-6 such as vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 1,3-butadienyl and 1-hexenyl.
The alkynyl or alkynyl moiety in R 1 , R 2 or R 3 may be either linear or branched. Specific examples thereof include those of C2-6 such as ethynyl, 2-butynyl, 2-pentynyl, and 3-hexynyl.
Examples of the halogen in R 1 , R 2 , R 3 , X or Y or the halogen as a substituent include fluorine, chlorine, bromine and iodine atoms. The number of halogens as a substituent may be 1 or 2 or more, and in the case of 2 or more, each halogen may be the same or different. The halogen substitution position may be any position.

The anthranilamide compound of formula (I) or a salt thereof can be prepared by diazotizing a compound of formula (II) and then halogenating it in the presence of copper halide, metal copper or alkyl halide. it can. The reaction using copper halide corresponds to a reaction called Sandmeyer reaction, and the reaction using metal copper corresponds to a reaction called Gattermann reaction.
Examples of the compound of the formula (II) as a starting material include N- [4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-amino-1- (3- Chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [2-bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3- Amino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [4-chloro-2-methyl-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl ] -Phenyl] -3-amino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [2-bromo-4-chloro-6-[[(cyclopropylmethyl) Amino] carbonyl] − Phenyl] -3-amino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide and the like can be used.

Diazotization of the compound of formula (II) can be carried out by reacting the compound of formula (II) 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 (II) is a diazo group, and the diazonium compound is used in the halogenation reaction without being isolated or isolated. Is done.
The halogenation is carried out in the presence of copper halide, metal copper or alkyl halide after diazotization of the compound of formula (II). As the copper halide, monovalent or divalent ones can be used, and as the halogenated alkyl, bromoform, carbon tetrachloride or the like can be used. The halogenation reaction is generally a radical generated by removing a diazo group of the diazo compound with copper halide or copper metal, and then adding a halide ion, or removing a diazo group from the diazo compound. Proceeds by reacting with 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 necessary for the reaction is supplied from copper halide.

  As an anthranilamide compound of the formula (I) produced by this reaction, N- [4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-bromo- 1- (3-Chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [2-bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl]- Phenyl] -3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [4-chloro-2-methyl-6-[[α-methyl- (cyclopropyl) Methyl) amino] carbonyl] -phenyl] -3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [2-bromo-4-chloro-6-[[ (Cyclopropyl Til) amino] carbonyl] -phenyl] -3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [2-bromo-4-chloro-6-[[ (Cyclopropylmethyl) amino] carbonyl] -phenyl] -3-chloro-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide and the like.

  Examples of the compound of the formula (III) include N- [4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-t-butyloxycarbonylamino-1- ( 3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [2-bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl]- 3-t-Butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [4-chloro-2-methyl-6-[[α-methyl- ( Cyclopropylmethyl) amino] carbonyl] -phenyl] -3-t-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [2-bromide] Mo-4-chloro-6-[[(cyclopropylmethyl) amino] carbonyl] -phenyl] -3-tert-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5 Carboxamide, N- [4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [2-bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [4-chloro-2-methyl-6-[[α-methyl- (cyclopropylmethyl) Amino] carbonyl] -phenyl] -3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide, N- [2-bromo-4-chloro-6- [ And [(cyclopropylmethyl) amino] carbonyl] -phenyl] -3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide.

  Examples of the compound of the formula (IV) include 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid, methyl 3-benzyloxycarbonylamino-1- (3 -Chloropyridin-2-yl) -1H-5-pyrazolecarboxylate, ethyl 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylate, vinyl 3-benzyl Oxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylate, ethynyl 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-5 Pyrazole carboxylate, phenyl 3-benzyloxycarbonylamino-1- (3-chloro Pyridin-2-yl) -1H-5-pyrazolecarboxylate, 3-p-methoxybenzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid, methyl 3-p -Methoxybenzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylate, phenyl 3-p-methoxybenzyloxycarbonylamino-1- (3-chloropyridin-2-yl) ) -1H-5-pyrazolecarboxylate, 3-t-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid, methyl 3-t-butyloxycarbonylamino- 1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylate, Nyl 3-t-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylate, 3-allyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid, methyl 3-allyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylate, phenyl 3-allyloxycarbonylamino-1- (3 -Chloropyridin-2-yl) -1H-5-pyrazolecarboxylate and the like.

  Examples of the compound of the formula (VI) include 2- [3-t-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazol-5-yl] -6-chloro-4H- 3,1-benzoxazin-4-one, 2- [3-tert-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazol-5-yl] -8-bromo-6 -Chloro-4H-3,1-benzoxazin-4-one, 2- [3-tert-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazol-5-yl]- 6-chloro-8-methyl-4H-3,1-benzoxazin-4-one, 2- [3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5- Yl] -6-chloro-4H-3,1-be Zoxazin-4-one, 2- [3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazol-5-yl] -8-bromo-6-chloro-4H-3, 1-benzoxazin-4-one, 2- [3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazol-5-yl] -6-chloro-8-methyl-4H -3,1-benzoxazin-4-one and the like.

  As a salt of the said compound, what is accept | permitted on agrochemical is contained. 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 dimethylammonium salt and triethylammonium salt; hydrochloride, perchlorate and sulfuric acid And inorganic salts such as salts and nitrates; organic acid salts such as acetates and methanesulfonates.

  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.

Below, the manufacturing method of the anthranilamide type compound or its salt concerning this invention is explained in full detail.
The anthranilamido compound of the formula (I) or a salt thereof can be produced according to the following reactions [A] to [E] and a usual salt production method.

In the formula, R 1 , A, X and m are as described above.
Reaction [A] can be carried out by diazotizing the compound of formula (II) and then halogenating it in the presence of copper halide, metal copper or alkyl halide. Reaction [A] can be carried out, for example, in the following four modes.
In the first embodiment, the reaction [A] is a method in which the compound of formula (II) is 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 diazonium salt. And then 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). Copper (I) halide is used in an amount of equimolar or more, preferably 1.2 to 1.5 moles per mole of the compound of formula (II).
The reaction is usually carried out at -20 to 120 ° C, preferably 0 to 100 ° C, and the reaction time is usually about 0.5 to 12 hours.
In the second embodiment, the reaction [A] comprises reacting the compound of formula (II) with an alkyl nitrite and copper (I) halide or copper (II) halide in the presence of a solvent. Can also be done.
Examples of the alkyl nitrite that can be used in the above reaction include t-butyl nitrite, i-pentyl nitrite, i-butyl nitrite, and the like. As the copper (I) halide, cuprous chloride is used. (CuCl) or cuprous bromide (CuBr); Examples of the copper (II) halide include cupric chloride (CuCl 2 ) and cupric bromide (CuBr 2 ). The alkyl nitrite that can be used in the reaction is equimolar or more, preferably 1.2 to 2.8 times mol of the compound of the formula (II), and is copper (I) halide or copper halide. (II) is an equimolar amount or more, desirably 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 that is inert to the reaction may be used. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane; acetonitrile, dimethylformamide, dimethyl One or more kinds can be appropriately selected from polar aprotic solvents such as acetamide, N-methylpyrrolidone, and dimethyl sulfoxide. Moreover, this reaction can be normally performed at -20-100 degreeC, desirably 0-60 degreeC, and the reaction time is about 0.5 to 24 hours normally.

In the third embodiment, the reaction [A] comprises dissolving the compound of formula (II) in an aqueous solution of an inorganic acid containing halogen such as hydrochloric acid or hydrobromic acid, and adding an aqueous sodium nitrite solution to form a diazonium salt. After forming, it can carry out by making metal copper react.
The reaction is usually carried out at -20 to 120 ° C, preferably 0 to 100 ° C, and the reaction time is usually about 0.5 to 12 hours.
In the reaction using copper, 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 diazonium salt, hydrochloric acid or hydrobromic acid is used. It can be carried out by adding a halogen-containing compound such as
As a fourth embodiment, the reaction [A] can be carried out by reacting the compound of formula (II) with an alkyl nitrite to form a diazonium salt and then reacting with an alkyl halide.
Examples of the nitrite alkyl ester that can be used in the above reaction include t-butyl nitrite, i-pentyl nitrite, i-butyl nitrite and the like. Examples of the alkyl halide include bromoform, bromotrichloromethane, Examples include carbon chloride, chloroform, and carbon tetrabromide. The alkyl nitrite that can be used in the reaction is equimolar or more, preferably 1.2 to 3.0 times the molar amount of the compound of the formula (II). The alkyl halide can also serve as a solvent, and is an equimolar amount or more, desirably 10 to 100 times the molar amount of the compound of the formula (II). Since the alkyl halide also serves as a solvent, no particular solvent is required in this reaction. Moreover, this reaction can be normally performed at 0-100 degreeC, desirably 20-80 degreeC, and the reaction time is about 0.25-6 hours normally.

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

In the formula, R 1 , R 2 , A and m are as described above.
Reaction [B] can be carried out by deprotecting the compound of formula (III) to remove the protecting group represented by R 2 O 2 C—.
The deprotection treatment can be performed according to known materials. Known materials include PGM Wuts, TW Greene, Greene's Protective Groups in Organic Synthesis, 4th 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, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid; chlorides such as acetyl chloride and trimethylsilyl chloride Reaction with a product; reaction with trimethylsilyl iodide; reaction with hydrogen gas in the presence of palladium-carbon, palladium chloride, etc .; reaction with triethylsilane in the presence of palladium chloride, palladium acetate, etc. .
In the above reaction, it is difficult to uniformly define the reaction conditions. However, in the case of a cleavage reaction with a Bronsted acid such as hydrogen chloride or trifluoroacetic acid, it is usually -20 to 80 ° C, preferably 0 to 50 ° C. The reaction time is usually about 0.5 to 24 hours.
Moreover, when making it react with hydrogen gas in presence of palladium-carbon, palladium chloride, etc., it can carry out normally at -10-100 degreeC, desirably 0-80 degreeC, and the reaction time is 0.25-normally. About 24 hours.

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

In the formula, R 4 is methyl or trifluoromethyl, and R 1 , R 2 , A, and m are as described above.
The first stage of the reaction [C] can be carried out by reacting the compound of the formula (III) with an equimolar amount or more of the 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 Bronsted 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 carried out by treating the compound of formula (IX) in an aqueous alkaline solution.
Examples of alkaline aqueous solutions include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkalis such as sodium carbonate and potassium carbonate. Metal carbonate; ammonia water or the like can be used, among which ammonia water is preferable.
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.

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

In the formula, R 1 , R 2 , A and m are as described above.
Reaction [D] is usually carried out by treating the compound of formula (VI) with equimolar or more, preferably 1.5 to 5.0 times moles of the compound of formula (VII) in the presence of a solvent. be able to.
As the amine of the formula (VII), α-methyl-cyclopropylmethylamine, α-methyl-cyclobutylmethylamine, cyclopropylmethylamine and the like can be used.
The solvent may be any solvent as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; halogens such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene Hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; one or more from polar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide Can be appropriately selected.
Reaction [D] can be normally performed at 0-120 degreeC, desirably 20-80 degreeC, and the reaction time is about 0.5 to 24 hours normally.

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

In the formula, R 1 , 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-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid, 3 -Allyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid, 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5 -Pyrazolecarboxylic acid, 1- (3-chloropyridin-2-yl) -3- (p-methoxybenzyloxycarbonylamino) -1H-5-pyrazolecarboxylic acid and the like can be mentioned.
As the compound of the formula (V), 2-amino-5-chlorobenzoic acid, 2-amino-3-bromo-5-chlorobenzoic acid, 2-amino-5-chloro-3-methylbenzoic acid and the like are used. be able to.

  Reaction [E] is usually carried out by reacting a compound of formula (IV-1) with an acid chloride in the presence of a base and a solvent to convert to an active derivative, and then reacting with a compound of formula (V) in the presence of a base. It can be performed by reacting. Moreover, the reaction with the compound of Formula (V) can add an activator further as needed.

  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 chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, dichloroethylene; pentane, hexane Aliphatic hydrocarbons such as ethyl ether, heptane, octane and cyclohexane; ethers such as diethyl ether, t-butyl ethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; esters such as methyl acetate, ethyl acetate and propyl acetate; 1 type or 2 types or more appropriately selected from ketones such as acetone, 2-butanone and 4-methyl-2-pentanone; polar aprotic solvents such as acetonitrile, propionitrile and N, N-dimethylformamide Do be able to.

As the acid chloride, chlorocarbonates, sulfonyl chlorides, carboxylic acid chlorides and the like can be used. Examples of the chlorocarbonate include methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate; examples of the sulfonyl chloride include methanesulfonyl chloride, propanesulfonyl chloride, benzenesulfonyl chloride; examples of the carboxylic acid chloride include acetyl chloride and propionyl chloride. Of these, methanesulfonyl chloride is preferred. This reagent is 1.0 to 1.5 times mol, desirably 1.1 to 1.3 times mol for the compound of formula (IV-1).
Examples of the base include pyridine, 2-picoline, 3-picoline, 2,6-lutidine, trimethylamine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 3-methylimidazole and the like. The base is 1.0 to 2.0 times mol, preferably 1.2 to 1.7 times mol for the compound of formula (IV-1).
The reaction is usually carried out at -30 to + 60 ° C, desirably -10 to 40 ° C, and the reaction time is usually about 10 minutes to 1 hour.

The compound of the formula (V) to be reacted after converting the compound of the formula (IV-1) into an active derivative is preferably 0.9 to 1.2 times mol of the compound of the formula (IV-1), preferably Is about 1.05 moles.
As the base, those used in the above active derivatization can be used, but other bases can also be used. Examples of the base that can be used for the reaction include pyridine, 2-picoline, 3-picoline, 2,6-lutidine, trimethylamine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 3-methylimidazole, and the like. The amount of these bases to be 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 also be added as a mixed solution 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 10 minutes to 1 hour.

As the activator, chlorocarbonate, sulfonyl chloride and the like can be used. Examples of the chlorocarbonate include methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate; examples of the sulfonyl chloride include methanesulfonyl chloride, propanesulfonyl chloride, benzenesulfonyl chloride, and the like. The activator is 1.0 to 1.5 times mol, more preferably 1.1 to 1.3 times mol of the compound of the formula (IV-1). The same activator as the aforementioned acid chloride can be used. 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.

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

In the formula, R 1 , R 2 , A and m are as described above.
Reaction [F] is usually treated with a compound of formula (X) in the presence of a base and a solvent after converting the compound of formula (IV-1) into an active derivative such as acid chloride or acid anhydride. This can be done.
To convert to acid chloride, thionyl chloride or oxalyl chloride can be used, and to convert to acid anhydride, acetyl chloride, trifluoroacetyl chloride or the like can be used. As a reagent to be converted into other active derivatives, ethyl chlorocarbonate, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride and the like can be used.
The reaction to be converted into the active derivative can usually be carried out by treating the compound of formula (IV-1) with an equimolar amount or more of the above reagent. In this reaction, a base can be added if necessary.
Examples of the base include pyridine, 2-picoline, 3-picoline, 2,6-lutidine, trimethylamine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 3-methylimidazole and the like. The base is 1.0 to 2.0 times mol, preferably 1.2 to 1.7 times mol for the compound of formula (IV-1).
In this reaction, a solvent may be used, and any solvent that is inert to the reaction may be used. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane; methylene chloride, Halogenated hydrocarbons such as chloroform, carbon tetrachloride and chlorobenzene; aromatic hydrocarbons such as benzene, toluene and xylene; polar non-polarities such as acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide One type or two or more types can be appropriately selected from a protic solvent and the like.
The reaction can be carried out usually at -20 to 80 ° C, preferably 0 to 60 ° C, and the reaction time is usually about 0.5 to 2 hours.

Next, 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; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metals such as sodium methoxide, sodium ethoxide and potassium tertiary butoxide Alkoxide; trimethylamine, triethylamine, triisopropylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-dimethylpyridine, 4-pyrrolidinopyridine, N-methylmorpholine, N, N-dimethylaniline, N, N- Tertiary amines such as diethylaniline, N-ethyl-N-methylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene, 1,4-diazabicyclo [2.2.2] octane Select one or more types from the above It can be. A base is 0.8-3 times mole with respect to the compound of Formula (X), 1-1.5 times mole can be used desirably.
The solvent may be any solvent as long as it is inert to the reaction. For example, ethers such as diethyl ether, butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane; chlorobenzene, dichlorobenzene, dichloromethane, chloroform, four Halogenated hydrocarbons such as carbon chloride, dichloroethane, trichloroethane and dichloroethylene; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane, hexane, heptane, octane and cyclohexane; acetonitrile , Polar aprotic such as propionitrile, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, sulfolane, dimethylacetamide, N-methylpyrrolidone 1 type (s) or 2 or more types can be suitably selected from a solvent etc.
The reaction can usually be carried out at -20 to 120 ° C, preferably 0 to 40 ° C, and the reaction time is usually about 0.25 to 24 hours.

Reaction [F] can be usually carried out by treating the compound of formula (IV-1) with the compound of 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 dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diphenylphosphoryl azide, and the like, and examples of the compound of formula (IV-1) include It is desirable to use equimolar or more.
Examples of the base include trimethylamine, triethylamine, triisopropylamine, diisopropylethylamine, pyridine, 3-picoline, 4-dimethylaminopyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene, , 4-diazabicyclo [2,2,2] octane can be appropriately selected from one or more of tertiary amines. A base can be used 2-10 times mole with respect to the compound of Formula (X), desirably 2.2-7 times mole. The compound of formula (IV-1) can be used in an amount of 0.5 to 2.0 times mol, preferably 1.1 to 1.5 times mol, of the compound of formula (X).
Any solvent may be used as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; halogens such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; one or more from polar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide Can be appropriately selected.
Reaction [F] can be normally performed at -20-80 degreeC, desirably 0-60 degreeC, and the reaction time is about 0.5 to 24 hours normally.

  Moreover, the compound of the said formula (II) can be manufactured also according to the following manufacturing method.

In the formula, R 1 , R 2 , R 4 , A and m are as described above.
The first step of obtaining the compound of the formula (XI) of [G] can be carried out by treating the compound of the formula (VI) with the acetic acid or trifluoroacetic acid represented by the equimolar or more of the formula (VIII). it can.
In order to accelerate this reaction, the reaction can be carried out in the presence of a Bronsted 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 step of obtaining the compound of the formula (IX) of [G] usually comprises the compound of the formula (XI) and the equimolar amount, preferably 1.5 to 5.0 times moles of the compound of the formula (VII). Can be carried out 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 diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; halogens such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; one or more from polar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide Can be appropriately selected.
This reaction can be carried out usually at 0 to 120 ° C., preferably 20 to 80 ° C., and the reaction time is usually about 0.5 to 24 hours.

The third step of obtaining the compound of formula (II) of [G] can be carried out by treating the compound of formula (IX) with an aqueous alkaline solution.
Examples of alkaline aqueous solutions include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkalis such as sodium carbonate and potassium carbonate. Metal carbonate; ammonia water or the like can be used, among which ammonia water is preferable.
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.

The compound of the said formula (IV-1) used by the above-mentioned manufacturing method [E] and [F] can be manufactured according to manufacturing method [H].
Manufacturing method [H]

In the formula, R 5 is alkyl, R 6 is 2-furyl or α-styryl, and R 2 is as described above.
The above-mentioned production method [H] can be carried out according to the production method [I] or [J].

Manufacturing method [I]
A step (I-1) of producing a compound of the formula (XIV-1) by reacting a compound of the formula (XII-1) with a compound of the formula (XIII).

In the formula, R 5 is as described above.
Reaction [I-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 are used. Of these, acetic acid is preferred.
The reaction [I-1] can usually be carried out at 60 to 150 ° C., preferably 70 to 120 ° C., and the reaction time is usually about 0.5 to 12 hours.
A step (I-2) of producing a compound of the formula (XV-1) by hydrolyzing the compound of the formula (XIV-1).

In the formula, R 5 is as described above.
Reaction [I-2] can usually be performed in the presence of a base and a solvent.
As the base, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide can be used.
The solvent may be any solvent as long as it is inert to the reaction. For example, alcohols such as methanol, ethanol, propanol, and isopropanol can be used alone or mixed with water.
The reaction [I-2] can be carried out usually at 10 to 120 ° C., preferably 30 to 80 ° C., and the reaction time is usually about 0.5 to 12 hours.
A step (I-3) of reacting a compound of the formula (XV-1) with an alcohol of the formula (XVI) and diphenylphosphoryl azide to produce a compound of the formula (XVII-1).

In the formula, R 2 is as described above.
Reaction [I-3] can usually be performed in the presence of a base and a solvent.
Examples of the base include trimethylamine, triethylamine, triisopropylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,4-diazabicyclo [2 , 2, 2] Octane, tertiary amines, and the like can be appropriately selected from one or more. The base can be used in an amount of 1 to 3 moles, preferably 1 to 1.5 moles based on the compound of the formula (XVI).
As the solvent, the alcohol of the formula (XVI) can be used in a large excess with respect to the compound of the formula (XV-1), and a solvent inert to the reaction, for example, tetrahydrofuran, dioxane, ethylene glycol diethyl ether Ethers such as: aromatic hydrocarbons such as benzene, toluene, xylene; polar aprotic solvents such as acetonitrile, propionitrile, N, N-dimethylformamide, dimethyl sulfoxide, sulfolane; 2-butanone, One or more kinds can be appropriately selected from ketones such as 3-pentanone and 4-methyl-2-pentanone.
The reaction [I-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.
A step (I-4) of producing a compound of the formula (IV-1) by reacting a compound of the formula (XVII-1) with an oxidizing agent.

In the formula, R 2 is as described above.
Reaction [I-4] can usually be performed in the presence of a solvent.
The oxidizing agent can be appropriately selected from permanganates such as potassium permanganate; chromic acid complexes such as pyridinium chlorochromate and pyridinium dichromate; ruthenium tetroxide; hydrogen peroxide; ozone and the like. .
Any solvent may be used as long as it is inert to the reaction. For example, ketones such as acetone, 2-butanone, 3-pentanone and 4-methyl-2-pentanone; acetonitrile, dimethylformamide and the like. Polar aprotic solvents; carboxylic acids such as acetic acid, propionic acid and butyric acid; carboxylic acid esters such as ethyl formate, methyl acetate and ethyl acetate; pyridine; methylene chloride; benzene; 2-methyl-2-propano- 1 type or 2 types or more can be appropriately selected from water and the like.
Reaction [I-4] has a different optimum reaction temperature depending on the oxidizing agent used. When ozone is used, it can be normally 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 1 to 48 hours.

  The compound of the formula (XII-1) used in the above reaction [I-1] is a known compound and can be produced according to known materials such as Gazzetta Chimica Italiana 88, 879 (1958).

Manufacturing method [J]
A step (J-1) of reacting a compound of the formula (XII-2) with a compound of the formula (XIII) to produce a compound of the formula (XIV-2).

In the formula, R 5 is as described above.
Reaction [J-1] can be normally performed in 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 are used. Of these, acetic acid is preferred.
Reaction [J-1] can be normally performed at 60-150 degreeC, desirably 70-120 degreeC, and the reaction time is about 0.5-12 hours normally The compound of Formula (XIV-2) is used. A step of producing a compound of formula (XV-2) by hydrolysis (J-2).

In the formula, R 5 is as described above.
Reaction [J-2] can be normally performed in presence of a base and a solvent.
As the base, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide can be used.
The solvent may be any solvent as long as it is inert to the reaction. For example, alcohols such as methanol, ethanol, propanol, and isopropanol can be used alone or mixed with water.
The reaction [J-2] can usually be carried out at 10 to 120 ° C., preferably 30 to 80 ° C., and the reaction time is usually about 0.5 to 12 hours.
A step (J-3) of producing a compound of formula (XVII-2) by reacting a compound of formula (XV-2) with an alcohol of formula (XVI) and diphenylphosphoryl azide.

In the formula, R 2 is as described above.
Reaction [J-3] can be normally performed in presence of a base and a solvent.
Examples of the base include trimethylamine, triethylamine, triisopropylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,4-diazabicyclo [2 , 2, 2] Octane, tertiary amines, and the like can be appropriately selected from one or more. The base can be used in an amount of 1 to 3 moles, preferably 1 to 1.5 moles based on the compound of the formula (XVI).
As the solvent, the alcohol of the formula (XVI) can be used in a large excess with respect to the compound of the formula (XV-2), and the solvent inert to the reaction, for example, tetrahydrofuran, dioxane, ethylene glycol diethyl ether Ethers such as: aromatic hydrocarbons such as benzene, toluene, xylene; polar aprotic solvents such as acetonitrile, propionitrile, N, N-dimethylformamide, dimethyl sulfoxide, sulfolane; 2-butanone, One or more types can be appropriately selected from ketones such as 3-pentanone and 4-methyl-2-pentanone.
The reaction [J-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.

It is possible to produce a compound of the formula (IV-1) by reacting a compound of the formula (XVII-2) with an oxidizing agent. However, for the convenience of purification of the product, the compound of the formula (XVIII) is temporarily used. It can also be manufactured.
A step (J-4) of producing a compound of formula (XVIII) by reacting a compound of formula (XVII-2) with an oxidizing agent.

In the formula, R 2 is as described above.
Reaction [J-4] can be normally performed in presence of a solvent.
As the oxidizing agent, osmium tetroxide-hydrogen peroxide, osmium tetroxide-periodic acid, ruthenium tetroxide, ozone and the like can be used, and ozone is preferable.
Any solvent may be used as long as it is inert to the reaction. For example, ketones such as acetone, 2-butanone, 3-pentanone and 4-methyl-2-pentanone; acetonitrile, dimethylformamide and the like. Polar aprotic solvents; carboxylic acids such as acetic acid, propionic acid and butyric acid; carboxylic acid esters such as ethyl formate, methyl acetate and ethyl acetate; alkyl halides such as methylene chloride and chloroform; methanol, ethanol One or two or more alcohols such as isopropanol can be appropriately selected.
The reaction [J-4] can usually be carried out at −100 to 0 ° C., preferably −80 to −50 ° C., and the reaction time is usually about 1 to 12 hours.
A step (J-5) of producing a compound of formula (IV-1) by reacting a compound of formula (XVIII) with an oxidizing agent.

In the formula, R 2 is as described above.
Reaction [J-5] can be normally performed in presence of a solvent.
Oxidizing agents include permanganates such as potassium permanganate; chromic acid complexes such as pyridinium chlorochromate and pyridinium dichromate; silver oxide; ozone; oxygen; chlorine, bromine, iodine, potassium bromate, It can be appropriately selected from halogens such as sodium chlorite, sodium bromite 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 and 4-methyl-2-pentanone; acetonitrile, dimethylformamide and the like. Polar aprotic solvents; carboxylic acids such as acetic acid, propionic acid and butyric acid; carboxylic acid esters such as ethyl formate, methyl acetate and ethyl acetate; alkyl halides such as methylene chloride and chloroform; methanol, ethanol 1 type or 2 types or more can be suitably selected from alcohols such as 2-methyl-2-propanol;
The reaction [J-5] 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.

  The compound of the formula (XII-2) used in the above reaction [J-1] is a known compound and can be produced according to known materials such as J. Chem. Soc., 3665 (1956).

Among the carboxylic acid derivatives of the formula (IV) or salts thereof, the compound of the formula (IV-2) in which R 3 is other than hydrogen is a compound of the formula (IV-1) which is an acid halogen of the formula (XIX). It can manufacture by making it react with the alcohol of a formula (XX) after converting into a compound.

Wherein R 3a is alkyl; alkenyl; alkynyl; phenyl optionally substituted with 1 to 5 substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and nitro, and X is halogen And R 2 is as described above.
The reaction for obtaining the acid halide of the formula (XIX) from the compound of the formula (IV-1) can be carried out by treating the compound of the formula (IV-1) with an equimolar amount or more of a halogenating agent.
Examples of the halogenating agent include thionyl chloride, oxalyl chloride, oxalic acid dichloride, phosphorus trichloride, phosphorus pentachloride and the like.

In this reaction, a solvent may be used, and any solvent may be used as long as it is inert to the reaction. For example, ethers such as diethyl ether, t-butyl ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane Halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, dichloroethylene; aromatic hydrocarbons such as benzene, toluene, xylene; pentane, hexane, heptane, octane, One or two aliphatic hydrocarbons such as cyclohexane; esters such as methyl acetate, ethyl acetate, propyl acetate; polar aprotic solvents such as acetonitrile, propionitrile, N, N-dimethylformamide, etc. seed The above can be selected as appropriate.
The reaction is usually carried out at -20 to 140 ° C, desirably -10 to 120 ° C, and the reaction time is usually about 0.1 to 10 hours.

The reaction for obtaining the compound of formula (IV-2) from the compound of 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 ethoxide and potassium tertiary butoxide. Alkoxide; trimethylamine, triethylamine, triisopropylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-dimethylpyridine, 4-pyrrolidinopyridine, N-methylmorpholine, N, N-dimethylaniline, N, N- Tertiary amines such as diethylaniline, N-ethyl-N-methylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene, 1,4-diazabicyclo [2.2.2] octane Select one or more types from the above It can be. A base is 0.8-3 times mole with respect to the compound of a formula (XIX), 1-1.5 times mole can be used desirably.

The solvent may be any solvent as long as it is inert to the reaction. For example, ethers such as diethyl ether, butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane; chlorobenzene, dichlorobenzene, dichloromethane, chloroform, four Halogenated hydrocarbons such as carbon chloride, dichloroethane, trichloroethane and dichloroethylene; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane, hexane, heptane, octane and cyclohexane; acetonitrile , Polar aprotic such as propionitrile, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, sulfolane, dimethylacetamide, N-methylpyrrolidone Solvent; 1 type (s) or 2 or more types can be suitably selected from water etc. Alcohols such as methanol, ethanol and propyl alcohol are also examples of the compound (XX), and a reaction reagent can be used as a solvent.
The reaction can usually be carried out at -20 to 120 ° C, preferably 0 to 40 ° C, and the reaction time is usually about 0.25 to 24 hours.

  The compounds obtained by the above reactions [A] to [K] may have isomers such as optical isomers and geometric isomers. In the present invention, both isomers and isomer mixtures are present. Is included. The present invention also includes various isomers other than those described above within the scope of technical common sense in the technical field. In addition, depending on the type of isomer, there may be a chemical structure different from the structure described in the above reaction formula, but those skilled in the art can sufficiently recognize that they are related to isomers. Obviously, it is within range.

The present invention also includes the following methods.
(1) A method for producing a compound of formula (II) by the reaction [B].
(2) By the reaction [B], a compound of the formula (II) is produced, the compound of the formula (II) 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 (II) 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 formula (II) by the reactions [D] and [B].
(6) The compound of formula (II) is produced by the above reactions [D] and [B], and after diazotizing the compound of formula (II), in the presence of copper halide, copper metal or alkyl halide. A process for producing a compound of formula (I) by halogenation.
(7) A method for producing a compound of formula (VI) by the reaction [E].
(8) A compound of the formula (II) is produced by the reactions [E], [D] and [B], and after diazotizing the compound of the formula (II), copper halide, metal copper or alkyl halide To produce a compound of formula (I) by halogenation in the presence of
(9) A method for producing a compound of the formula (IV-1) by the reaction [H].
(10) A compound of the formula (II) is produced by the reactions [H], [E], [D] and [B], and after diazotizing the compound of the formula (II), copper halide, metallic copper Alternatively, a method for producing a compound of formula (I) by halogenation in the presence of an alkyl halide.
(11) A method for producing a compound of the formula (IV-1) by the above reactions [I-1], [I-2], [I-3] and [I-4].
(12) A method for producing a compound of the formula (IV-1) by the above reactions [J-1], [J-2], [J-3], [J-4] and [J-5].

In order to describe the present invention in more detail, examples are described below, but the present invention is not limited thereto.
Example 1 Synthesis of 3-t-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid (1) Ethyl 1- (3-chloropyridin-2-yl) Synthesis of -5-furyl-1H-pyrazole-3-carboxylate To a solution of 11.19 g of ethyl 2-furoylpyruvate in acetic acid (150 ml) was added 7.64 g of 3-chloro-2-hydrazinylpyridine at room temperature. After that, 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 ethyl acetate and water were added for extraction. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated brine in that order, 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.
1 H-NMR (300 MHz, CDCl 3 ) δ: 8.55 (dd, 1H), 7.92 (dd, 1H), 7.47 (m, 1H), 7.32 (s, 1H), 7.17 (s, 1H), 6.32 (m , 1H), 6.00 (d, 1H), 4.45 (q, 2H), 1.43 (t, 3H).
(2) Synthesis of 1- (3-chloropyridin-2-yl) -5-furyl-1H-pyrazole-3-carboxylic acid Ethyl 1- (3-chloropyridin-2-yl obtained in the previous step (1) ) After dissolving 14.5 g of -5-furyl-1H-pyrazole-3-carboxylate in a mixed solvent of 90 ml of methanol and 45 ml of water, 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 was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 11.9 g (melting point: 179.3 ° C.) of the desired product.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 8.61 (d, 1H), 8.30 (d, 1H), 7.75 (m, 1H), 7.61 (s, 1H), 7.16 (s, 1H), 6.49 (m, 1H), 6.24 (m, 1H).

(3) Synthesis of 3-t-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -5-furyl-1H-pyrazole 1- (3- After adding 8.0 g of chloropyridin-2-yl) -5-furyl-1H-pyrazole-3-carboxylic acid and 7.6 g of diphenylphosphoryl azide to 70 ml of t-butanol, 4 g of diisopropylethylamine was added dropwise at room temperature. After stirring at room temperature for 30 minutes, the reaction solution was heated and stirred for 6 hours under reflux. 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 (melting point: 52.6 ° C.) of the desired product.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 9.94 (s, 1H), 8.56 (d, 1H), 8.23 (d, 1H), 7.69 (m, 1H), 6.82 (s, 1H), 6.44 (m, 1H), 6.09 (d, 1H), 1.47 (s, 9H).
(4) Synthesis of 3-t-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid 3-t-butyloxycarbonylamino obtained in the previous step (3) To a solution of 2.0 g of -1- (3-chloropyridin-2-yl) -5-furyl-1H-pyrazole in 60 ml of acetone was gradually added 6.13 g of potassium permanganate at room temperature, and then at room temperature for 1 day. Reacted. 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, and the filtrates were combined and concentrated under reduced pressure. The residue was extracted by adding diethyl 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 obtain 0.81 g of the desired product (melting point: 124.8 ° C.).
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 10.05 (s, 1H), 8.51 (d, 1H), 8.20 (dd, 1H), 7.61 (m, 1H), 1.46 (s, 9H).

Example 2 N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-bromo-1- (3-chloro-2-pyridine- Synthesis of 2-yl) -1H-pyrazole-5-carboxamide (1)
(1) 2- [3-t-Butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazol-5-yl] -6-chloro-8-bromo-4H-3,1 Synthesis of -benzoxazin-4-one 1.0 g of 3-t-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid obtained by repeating Example 1 Then, 0.3 ml of methanesulfonyl chloride was gradually added dropwise to a solution of 0.4 ml of pyridine in acetonitrile (10 ml) while maintaining the reaction temperature at 0 ° C., followed by stirring at the same temperature for 15 minutes. Thereto was gradually added dropwise a solution of 0.74 g of 2-amino-3-bromo-5-chlorobenzoic acid and 0.84 ml of pyridine in acetonitrile (5 ml) while maintaining the reaction temperature at 0 ° C. Stir for minutes. Finally, 0.3 ml of methanesulfonyl chloride was gradually added dropwise 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 of the desired product (melting point: 222.7 ° C.).
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 10.25 (s, 1H), 8.55 (d, 1H), 8.25 (d, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.65 (dd, 1H), 7.27 (s, 1H), 1.49 (s, 9H).
(2) N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-tert-butyloxycarbonylamino-1- (3-chloro Synthesis of 2-pyridin-2-yl) -1H-pyrazole-5-carboxamide 2- [3-tert-butyloxycarbonylamino-1- (3-chloropyridin-2-] obtained in the previous step (1) Yl) -1H-pyrazol-5-yl] -6-chloro-8-bromo-4H-3,1-benzoxazin-4-one and α-methyl-cyclopropylmethylamine (65%) 0. A 6 g solution of acetonitrile (10 ml) was stirred at room temperature for 1 hour, 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 0.34 g of the desired product (melting point: 137.4 ° C.).
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 10.23 (s, 1H), 9.96 (s, 1H), 8.32 (d, 1H), 7.97 (d, 2H), 7.81 (s, 1H), 7.41 (m, 2H), 7.31 (s, 1H), 3.16 (q, 1H), 1.38 (s, 9H), 0.93 (d, 3H), 0.71 (m, 1H), 0.24 (m, 1H), 0.15 ( m, 1H), 0.03 (m, 2H).

(3) N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-amino-1- (3-chloropyridin-2-yl ) -1H-pyrazole-5-carboxamide synthesis N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] obtained by repeating the previous step (2) -Phenyl] -3-t-butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide 0.5 ml of trifluoroacetic acid was added to 10 ml of methylene chloride solution. And stirred at room temperature overnight. Since the reaction was not completed, 2 ml of trifluoroacetic acid was further added and stirring was continued at room temperature for 1 hour 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.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 9.95 (s, 1H), 8.27 (d, 1H), 7.98 (m, 2H), 7.90 (d, 1H), 7.82 (s, 1H), 7.33 (md, 2H), 6.40 (s, 1H), 3.16 (q, 1H), 0.95 (d, 3H), 0.68 (m, 1H), 0.27 (m, 1H), 0.16 (m, 2H), 0.06 ( m, 2H).

(4) N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-bromo-1- (3-chloropyridin-2-yl ) -1H-pyrazole-5-carboxamide synthesis To a 10 ml acetonitrile solution of 0.12 g of copper (II) bromide and 0.091 g of 90% t-butyl nitrite, N- [2- Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-amino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5 A solution of 0.29 g of carboxamide in 10 ml of acetonitrile was gradually added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours and at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and 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 0.11 g (melting point: 260.6 ° C.) of the desired product.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 10.34 (s, 1H), 8.37 (d, 1H), 8.18 (d, 1H), 8.05 (d, 1H), 7.84 (s, 1H), 7.50 (dd, 1H), 7.44 (s, 1H), 7.35 (s, 1H), 3.17 (q, 1H), 0.95 (d, 3H), 0.72 (m, 1H), 0.25 (m, 1H), 0.17 ( m, 1H), 0.05 (m, 2H).

Example 3 N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-bromo-1- (3-chloropyridin-2-yl ) Synthesis of 1H-pyrazole-5-carboxamide (2)
(1) N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-t-butyloxycarbonylamino-1- (3-chloro Synthesis of 2-pyridin-2-yl) -1H-pyrazole-5-carboxamide 3-t-butyloxycarbonylamino-1- (3-chloropyridin-2-yl)-obtained by repeating Example 1 To a solution of 1.68 g of 1H-5-pyrazolecarboxylic acid and 1.58 g of N- [α-methyl- (cyclopropylmethyl)] 2-amino-3-bromo-5-chlorobenzamide in 30 ml of acetonitrile at room temperature, After adding 2.8 g of picoline, 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 to 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.).
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 10.22 (s, 1H), 9.95 (s, 1H), 8.30 (d, 1H), 7.96 (m, 2H), 7.80 (s, 1H), 7.40 (m, 2H), 7.30 (d, 1H), 3.16 (q, 1H), 1.37 (s, 9H), 0.65 (m, 1H), 0.20 (m, 1H), 0.02 (m, 2H).
(2) N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-bromo-1- (3-chloropyridin-2-yl ) -1H-pyrazole-5-carboxamide synthesis N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3 in the previous step (1) -T-Butyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide according to the methods of (3) and (4) of Example 2 -[2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-bromo-1- (3-chloropyridin-2-yl) -1H- Pyrazole-5-carboxamide Was synthesized.

Example 4-A Synthesis of 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid (Production using 2-furoylpyruvate as a raw material)
(1) Synthesis of 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -5-furyl-1H-pyrazole 1- (3-chloropyridine obtained in step (2) of Example 1 2-yl) -5-furyl-1H-pyrazole-3-carboxylic acid 11.9 g, benzyl alcohol 4.89 g, diphenylphosphoryl azide 12.4 g and triethylamine 5.0 g were added to 100 ml of dioxane, and then at 90 ° C. The reaction was performed for 3 hours. 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 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 (melting point: 133.4 ° C.) of the desired product.
1 H-NMR (300 MHz, CDCl 3 ) δ: 8.51 (d, 1H), 7.89 (d, 1H), 7.41 (m, 5H), 7.28 (s, 1H), 6.28 (m, 1H), 6.07 (d , 1H), 5.24 (s, 2H).
(2) Synthesis of 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid 3-benzyloxycarbonylamino-1- () obtained in the previous step (1) After dissolving 8.9 g of 3-chloropyridin-2-yl) -5-furyl-1H-pyrazole in a mixed solvent of 70 ml of acetonitrile and 70 ml of carbon tetrachloride, 0.70 g of ruthenium chloride and 21.5 g of sodium periodate Aqueous solution (150 ml) was added and stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and 1N hydrochloric acid. 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 was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.4 g (melting point: 79.1 ° C.) of the desired product.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 10.50 (s, 1H), 8.51 (dd, 1H), 8.18 (dd, 1H), 7.61 (dd, 1H), 7.42-7.32 (m, 5H) , 7.03 (s, 1H), 5.17 (s, 2H).

Experimental Example 4-B Synthesis of 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid (2,4-dioxo-4-styrylbutanoic acid ethyl ester as a raw material) Manufacturing method)
(1) Synthesis of 1- (3-chloropyridin-2-yl) -3-ethoxycarbonyl-5-styryl-1H-pyrazole 28 g of 2,4-dioxo-4-styrylbutanoic acid ethyl ester and 3-chloro- 16.3 g of 2-hydrazinylpyridine was 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 (melting point: 143.1 ° C.) of the desired product.
1 H-NMR (300 MHz, CDCl 3 ) δ: 8.59 (dd, 1H), 7.94 (dd, 1H), 7.47 (dd, 1H), 7.39-7.20 (m, 6H), 7.12 (d, 1H), 6.63 (d, 1H), 4.44 (q, 2H), 1.42 (t, 3H).
(2) Synthesis of 1- (3-chloropyridin-2-yl) -5-styryl-1H-pyrazole-3-carboxylic acid 1- (3-chloropyridin-2-yl) obtained in the previous step (1) After dissolving 26 g of -3-ethoxycarbonyl-5-styryl-1H-pyrazole in 250 ml of methanol, a 40 ml aqueous solution of 3.5 g of sodium hydroxide was added dropwise at room temperature. After completion of the dropwise addition, the mixture was reacted for 3 hours under reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, and then the residue was extracted with water and ether. 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 brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 20.0 g (melting point: 237.0 ° C.) of the desired product.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 13.0 (s, 1H), 8.65 (dd, 1H), 8.33 (dd, 1H), 7.78 (dd, 1H), 7.51-7.24 (m, 7H) , 6.71 (d, 1H).

(3) Synthesis of 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -5-styryl-1H-pyrazole 1- (3-chloropyridin-2-) obtained in the previous step (2) Yl) -5-styryl-1H-pyrazole-3-carboxylic acid (20.0 g), benzyl alcohol (7.3 g), diphenylphosphoryl azide (18.6 g) and triethylamine (7.5 g) were added to dioxane (200 ml), followed by reaction at 90 ° C. for 5 hours. I let you. 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.
1 H-NMR (300 MHz DMSO-d 6 ) δ: 10.36 (s, 1H), 8.60 (d, 1H), 8.25 (d, 1H), 7.65 (dd, 1H), 7.47-7.18 (m, 11H), 6.98 (s, 1H), 6.70 (d, 2H), 5.18 (s, 2H).
(4) Synthesis of 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -5-formyl-1H-pyrazole 3-benzyloxycarbonylamino-1- () obtained in the previous step (3) An ozone-oxygen stream was blown into an ethyl acetate (250 ml) solution of 10 g of 3-chloropyridin-2-yl) -5-styryl-1H-pyrazole at −65 ° C. for 4 hours. Dry nitrogen was blown into the reaction solution to drive out excess ozone, 5 ml of dimethyl sulfide was added, and the mixture was 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 obtain 5.2 g (melting point: 41.2 ° C.) of the desired product as an amorphous solid. Obtained.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 10.67 (s, 1H), 9.79 (s, 1H), 8.53 (dd, 1H), 8.23 (dd, 1H), 7.65 (s, 1H), 7.65 (s, 1H), 7.39 (m, 6H), 5.19 (s, 2H).

(5) Synthesis of 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid 3-benzyloxycarbonylamino-1- ( To a mixed solution of 5.2 g of 3-chloropyridin-2-yl) -5-formyl-1H-pyrazole, 100 ml of t-butanol and 100 ml of 2-methyl-2-butane, 14.5 g of sodium chlorite (80%) A 100 ml aqueous solution of 18.2 g of sodium dihydrogen phosphate dihydrate was gradually added dropwise at room temperature, followed by stirring for 48 hours. 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.
1 H-NMR (300 MHz DMSO-d 6 ) δ: 10.50 (s, 1H), 8.51 (dd, 1H), 8.18 (dd, 1H), 7.61 (dd, 1H), 7.42-7.32 (m, 5H), 7.03 (s, 1H), 5.17 (s, 2H).

Example 5 N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-bromo-1- (3-chloropyridin-2-yl ) Synthesis of 1H-pyrazole-5-carboxamide (3)
(1) 2- [3-Benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazol-5-yl] -8-bromo-6-chloro-4H-3,1-benzo Synthesis of Oxazin-4-one 4.8 g of 3-benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-5-pyrazolecarboxylic acid obtained by repeating Example 4-A and pyridine To 1.8 ml of acetonitrile (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. Thereto, a solution of 3.2 g of 2-amino-3-bromo-5-chlorobenzoic acid and 3.6 ml of pyridine in acetonitrile (30 ml) was gradually added dropwise while maintaining the reaction temperature at 0 ° C. Stir for minutes. Finally, 1.3 ml of methanesulfonyl chloride was gradually added again 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 (melting point: 246.7 ° C.) of the desired product.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 10.71 (s, 1H), 8.55 (d, 1H), 8.26 (d, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 7.67 (dd, 1H), 7.45-7.29 (m, 6H), 5.21 (s, 2H).
(2) 2- [1- (3-Chloropyridin-2-yl) -3-trifluoroacetylamino-1H-pyrazol-5-yl] -6-chloro-8-bromo-4H-3,1-benzo Synthesis of Oxazin-4-one 2- [3-Benzyloxycarbonylamino-1- (3-chloropyridin-2-yl) -1H-pyrazol-5-yl] -8- obtained in the previous step (1) A mixed solution of bromo-6-chloro-4H-3,1-benzoxazin-4-one (5.0 g) and trifluoroacetic acid (50 ml) 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 2.0 g of the desired product (melting point: 209.4 ° C.).
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 12.67 (s, 1H), 8.57 (d, 1H), 8.31 (d, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.73 −7.69 (m, 1H), 7.48 (s, 1H).

(3) N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -1- (3-chloropyridin-2-yl) -3- Synthesis of trifluoroacetylamino-1H-pyrazole-5-carboxamide 2- [1- (3-chloropyridin-2-yl) -3-trifluoroacetylamino-1H-pyrazole- obtained in the previous step (2) A solution of 2.0 g of 5-yl] -8-bromo-6-chloro-4H-3,1-benzoxazin-4-one and 2.0 g of α-methyl-cyclopropylmethylamine in acetonitrile (50 ml) at room temperature. After stirring for 3 hours, 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 1.3 g of the desired product (melting point: 152.0 ° C.).
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 12.44 (s, 1H), 10.43 (s, 1H), 8.37 (d, 1H), 8.10 (d, 1H), 8.05 (d, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 7.50−7.46 (m, 1H), 7.42 (s, 1H), 3.16 (q, 1H), 0.95 (d, 3H), 0.71 (m, 1H), 0.25 (m, 1H), 0.15 (m, 1H), 0.03 (m, 2H).
(4) N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-amino-1- (3-chloropyridin-2-yl ) -1H-pyrazole-5-carboxamide synthesis N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl obtained in the previous step (3) ] A mixed solution of 1.2 g of 1- (3-chloropyridin-2-yl) -3-trifluoroacetylamino-1H-pyrazole-5-carboxamide and 50 ml of 28% aqueous ammonia was allowed to stir at room temperature overnight. Thereafter, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.42 g (melting point: 139.8 ° C.) of the desired product.
1 H-NMR (300 MHz DMSO-d 6 ) δ: 9.94 (s, 1H), 8.24 (d, 1H), 8.04 (d, 1H), 7.87 (d, 1H), 7.77 (s, 1H), 7.38 ( s, 1H), 7.33-7.27 (m, 2H), 6.35 (s, 2H), 3.16 (q, 1H), 0.86 (d, 3H), 0.69 (m, 1H), 0.23 (m, 1H), 0.17 (m, 1H), 0.02 (m, 2H).
(5) N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-bromo-1- (3-chloropyridin-2-yl ) -1H-pyrazole-5-carboxamide synthesis To a 10 ml acetonitrile solution of 0.17 g of copper (II) bromide and 0.12 g of 90% t-butyl nitrite, N- [2 -Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-amino-1- (3-chloropyridin-2-yl) -1H-pyrazole-5 -A solution of 0.41 g of carboxamide in 10 ml acetonitrile was gradually added dropwise at 0 ° C and then stirred overnight while gradually warming to room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and 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 = 2/1 to 1/1) to obtain 0.1 g of the desired product (melting point: 193.5 ° C.). Obtained.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 10.34 (s, 1H), 8.37 (d, 1H), 8.18 (d, 1H), 8.05 (d, 1H), 7.84 (s, 1H), 7.50 (dd, 1H), 7.44 (s, 1H), 7.35 (s, 1H), 3.17 (q, 1H), 0.95 (d, 3H), 0.72 (m, 1H), 0.25 (m, 1H), 0.17 ( m, 1H), 0.05 (m, 2H).

Example 6 N- [2-Bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-bromo-1- (3-chloropyridin-2-yl ) Synthesis of -1H-pyrazole-5-carboxamide (4)
N- [2-bromo-4-chloro-6-[[α-methyl- (cyclopropylmethyl) amino] carbonyl] -phenyl] -3-amino obtained by repeating step (4) of Example 5 above -1- (3-Chloropyridin-2-yl) -1H-pyrazole-5-carboxamide To a 7 ml bromoform solution of 1 g, 0.43 g of 90% t-butyl nitrite was gradually added dropwise at 80 ° C. for 2 hours. Stir. The reaction solution was cooled to room temperature, excess n-hexane was added, and the precipitate was collected by filtration to obtain 0.91 g of the desired product (HPLC purity 86%).

Claims (11)

  1. Formula (I):
    Wherein R 1 is halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, nitro, formyl or cyano, Is alkyl optionally substituted with Y, Y is C3-4 cycloalkyl optionally substituted with at least one substituent selected from the group consisting of halogen, alkyl and haloalkyl, and X is halogen , M is 0 to 4), an anthranilamide compound represented by the formula (II):
    (Wherein R 1 , A and m are as described above), and then diazotized and then halogenated in the presence of copper halide, metal copper or alkyl halide. Method.
  2. Formula (III):
    Wherein R 1 is halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, nitro, formyl or cyano; 2 is alkyl which may be substituted with halogen; alkenyl which may be substituted with halogen; alkynyl which may be substituted with halogen; or the group in which the phenyl moiety is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and nitro Benzyl optionally substituted with 1 to 5 substituents selected from above, A is alkyl optionally substituted with Y, Y is at least one selected from the group consisting of halogen, alkyl and haloalkyl Horn A C3-4 cycloalkyl which may be substituted with substituent, m is leaving the protecting group represented a compound represented by was deprotected treated with R 2 O 2 C- and is) 0-4 Formula (II):
    (Wherein R 1 , A and m are as described above), and after diazotizing the compound of formula (II), the presence of copper halide, metal copper or alkyl halide The process according to claim 1, wherein the halogenation is carried out under.
  3. Formula (IV-1):
    Wherein R 2 is alkyl optionally substituted with halogen; alkenyl optionally substituted with halogen; alkynyl optionally substituted with halogen; or phenyl moiety is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano And benzyl optionally substituted with 1 to 5 substituents selected from the group consisting of nitro and formula (V):
    Wherein R 1 is halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, nitro, formyl or cyano, m Is a compound represented by formula (VI):
    (Wherein R 1 , R 2 and m are as described above);
    Compound of formula (VI) and formula (VII):
    Wherein A is alkyl optionally substituted with Y, and Y is C3-4 cycloalkyl optionally substituted with at least one substituent selected from the group consisting of halogen, alkyl and haloalkyl. And a compound represented by formula (III):
    (Wherein R 1 , 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 O 2 C—
    (Wherein R 1 , A and m are as described above), and after diazotizing the compound of formula (II), the presence of copper halide, metal copper or alkyl halide The process according to claim 1, wherein the halogenation is carried out under.
  4. Formula (XII):
    Wherein R 5 is alkyl and R 6 is 2-furyl or α-styryl, and the formula (XIII):
    And a compound represented by the formula (XIV):
    (Wherein R 5 and R 6 are as described above), and the compound of formula (XIV) is hydrolyzed to give formula (XV):
    (Wherein R 6 is as described above), and a compound of formula (XV) and formula (XVI):
    Wherein R 2 is alkyl optionally substituted with halogen; alkenyl optionally substituted with halogen; alkynyl optionally substituted with halogen; or phenyl moiety is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano And benzyl optionally substituted with 1 to 5 substituents selected from the group consisting of nitro and diphenylphosphoryl azide, and reacting with the formula (XVII):
    (Wherein R 2 and R 6 are as described above), a compound of formula (VII) and an oxidizing agent are reacted to form a compound of formula (IV-1):
    (Wherein R 2 is as described above) and a compound of formula (IV-1) and formula (V):
    Wherein R 1 is halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, nitro, formyl or cyano, m Is a compound represented by formula (VI):
    (Wherein R 1 , R 2 and m are as described above);
    Compound of formula (VI) and formula (VII):
    Wherein A is alkyl optionally substituted with Y, and Y is C3-4 cycloalkyl optionally substituted with at least one substituent selected from the group consisting of halogen, alkyl and haloalkyl. And a compound represented by formula (III):
    (Wherein R 1 , 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 O 2 C—
    (Wherein R 1 , A and m are as defined above); after diazotizing the compound of formula (II), the presence of copper halide, copper metal or alkyl halide The process according to claim 1, wherein the halogenation is carried out under.
  5. Formula (II):
    Wherein R 1 is halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, nitro, formyl or cyano, Is alkyl optionally substituted with Y, Y is C3-4 cycloalkyl optionally substituted with at least one substituent selected from the group consisting of halogen, alkyl and haloalkyl, m is 0-4 Or a salt thereof.
  6. Formula (III):
    Wherein R 1 is halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, nitro, formyl or cyano; 2 is alkyl which may be substituted with halogen; alkenyl which may be substituted with halogen; alkynyl which may be substituted with halogen; or the group in which the phenyl moiety is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and nitro Benzyl optionally substituted with 1 to 5 substituents selected from above, A is alkyl optionally substituted with Y, Y is at least one selected from the group consisting of halogen, alkyl and haloalkyl Horn A C3-4 cycloalkyl which may be substituted with substituent, or a salt thereof m is 0-4).
  7. Formula (VI):
    Wherein R 1 is halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, nitro, formyl or cyano; 2 is alkyl which may be substituted with halogen; alkenyl which may be substituted with halogen; alkynyl which may be substituted with halogen; or the group in which the phenyl moiety is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and nitro Or a salt thereof, which is benzyl optionally substituted with 1 to 5 substituents selected from above, and m is 0 to 4.
  8. Formula (IV):
    Wherein R 2 is alkyl optionally substituted with halogen; alkenyl optionally substituted with halogen; alkynyl or phenyl moiety optionally substituted with halogen is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and Benzyl optionally substituted with 1 to 5 substituents selected from nitro; R 3 is a hydrogen atom; alkyl; alkenyl; alkynyl or halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and nitro A pyrazole carboxylic acid derivative represented by the formula (1) or a salt thereof.
  9. Formula (IV-1):
    Wherein R 2 is alkyl optionally substituted with halogen; alkenyl optionally substituted with halogen; alkynyl or phenyl moiety optionally substituted with halogen is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano and A benzyl optionally substituted with 1 to 5 substituents selected from nitro), or a salt thereof,
    Step (1) Formula (XII):
    Wherein R 5 is alkyl and R 6 is 2-furyl or α-styryl, and the formula (XIII):
    And a compound represented by the formula (XIV):
    (Wherein R 5 and R 6 are as defined above);
    Step (2) The compound of formula (XIV) obtained in step (1) is hydrolyzed to give formula (XV):
    (Wherein R 6 is as defined above) or a salt thereof;
    Step (3) The compound of formula (XV) obtained in step (2) and formula (XVI):
    (Wherein R 2 is as defined above) and diphenylphosphoryl azide are reacted to give a formula (XVII):
    (Wherein R 2 or R 6 is as defined above); and step (4) a compound of formula (XVII) obtained in step (3) and an oxidizing agent. A method comprising a step of reacting to produce a pyrazole carboxylic acid derivative represented by the formula (IV-1) or a salt thereof.
  10. The process according to claim 9, wherein the compound of formula (XII) wherein R 6 is 2-furyl is used as the starting compound in step (1).
  11. The process according to claim 9, wherein the compound of formula (XII) wherein R 6 is α-styryl is used as the starting compound in step (1).
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