KR102031553B1 - Process for preparing pyrazole carbamide compounds - Google Patents

Abstract

The present invention relates to a novel method for manufacturing a pyrazole carboxamide compound having insecticidal effects on various pests of insects. Specifically, a manufacturing method of the present invention does not involve reflux conditions unlike conventional synthesis methods, and does not require complicated separation and purification processes to greatly simplify the manufacturing method, thereby being able to provide the pyrazole carboxamide compound in a very economical method.

Description

Process for preparing pyrazole carbamide compounds

The present invention relates to a novel process for preparing pyrazole carboxamide compounds having insecticidal effects on various pests of insects.

Pesticides that have been used in the past are represented by carbamate insecticides or organophosphorus insecticides. These insecticides exert their effects by inhibiting acetylcholinesterase, and the long-term use of these insecticides has made them resistant to them, requiring the development of new mechanisms of action.

Accordingly, the ryanodine receptor, a calcium ion channel, has emerged as a new target for controlling pests. Since homeostasis of calcium ions plays an important role, in particular, in muscle contraction, pesticides that bind to the lyanodine receptors can inhibit pest feeding and cause coma or paralysis, leading to death.

To date, commercially available insecticides that bind to the lyanodine receptor have been discovered by Nihon Nohyaku and co-developed by Bayer Crop Science, flubendiamide, Phoenix ^TM , Takumi ^TM , EP 1380209 A1. Chlorantraniliprole, Rynaxypyr ^™ , WO 01/070671 and cyantraniliprole, Cyazypyr ^™ , WO 04 / 067528). These insecticides exhibit pesticidal action by binding to the lianodine receptor and disrupting the calcium ion pathway, and are known to be particularly potent against moths.

A variety of companies include Bayer and Du Pont, including Syngenta, Sumitomo, Ishihara Sangyo Kaisha, and Nissan. More than 100 patents have been filed for the development of pesticides, but only three are commercially available: flubendiamide, chlorantraniliprole and cyanthraniliprole.

On the other hand, the present inventors have deepened the method for producing a pyrazole carboxamide compound, which is one of the conventional carbamate insecticides, using a intermediate prepared using a new production method to obtain a high purity carboxamide compound at a higher yield. It was confirmed that it can be prepared to complete the present invention.

EP 1380209 A1 WO 01/070671 WO 04/067528 KR 10-0866463 B1

An object of the present invention is to provide a novel synthesis method capable of producing a pyrazole carboxamide compound in high yield through simple reaction conditions compared to the existing synthesis method.

It is also an object of the present invention to provide a process for the preparation of pyrazole carboxamide compounds suitable for industrial mass production.

In order to achieve the above object, a novel method for preparing a pyrazole carboxamide compound substituted with carbamate is provided. In this case, the pyrazole carboxamide compound substituted with the carbamate may be a compound of Formula 1 below.

According to an embodiment of the present invention, a method of preparing a compound of Formula D may include: introducing a nitro group into a compound of Formula C, followed by a reduction reaction; And esterifying a compound of formula E with the compound of formula D to prepare a compound of formula 1.

[Formula 1]

[Formula C]

[Formula D]

[Formula E]

[In Formula 1, Formula C, Formula D and Formula E,

R ¹ and R ² are each independently hydrogen, C _{1- 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, _3- C ₁₀ cycloalkyl-amino, C _{1- 10} alkoxy, C _{1- 10} alkylthio, C _{1- 10} alkyl seolpayi carbonyl, C _{1- 10} alkyl sulfonyl, C _{6- 20} aryl, C _{6- 20} aryloxy, C _{6- 20} aryl C _{1 - 10} alkyl, hydroxy, cyano, nitro and halogen, said alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryl, aryloxy and aryl substituted by one or more halogens are each independently May be further substituted with;

R ³ is C _{6- 20} aryl, or C _{3- 20} heteroaryl, wherein aryl and heteroaryl are each independently halogen, C _{1- 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{1 - 10} alkoxy, halo C _{1 - 10} alkyl, halo C _{1 -10} alkoxy, hydroxy and cyano may be further substituted with one or more substituents selected from the group consisting of a furnace;

R ⁴ is C _{1- 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, C _{6- 20} aryl or C _{6 - 20} aryl C _{1 - 10} alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and alkyl is to be further substituted with one or more substituents selected from the group consisting of halogen or C _1-10 alkoxy; each independently Can;

R ⁵ is halogen, cyano, amino, hydroxy, thiol, thio when isocyanato, C _{1- 10} alkyl, halo C _1-10 alkyl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _1-10 alkoxy, halo C _{1 - 10} alkoxy, C _{1- 10} alkylthio, C _{1- 10} alkyl amino, C _{6- 20} aryl-amino, C _{1- 10} alkyl, C _{6 -20} aryl-amino, C _{1- 10} alkyl aminocarbonyl, C _{1- 10} alkyl seolpayi carbonyl, C _{1- 10 alkylsulfonyl, - (CH 2) n -Q} , - (CH 2 _{) n -OQ, - (CH 2} ) n -O- (CH 2) m -Q or - (CH _{2) n} is -SQ, wherein Q is C _{6- 20} aryl, C _{3- 20} heteroaryl or C _{3 20} and heterocycloalkyl, wherein n and m are each independently an integer of 1 to 3;

X ¹ is halogen;

Wherein said heteroaryl and heterocycloalkyl each independently comprise one or more heteroatoms selected from the group consisting of N, O and S.]

In the preparation method according to an embodiment of the present invention, the step of introducing a nitro group to the compound of Formula C, crystallization by adding a base after reacting with a nitrating agent including nitric acid, nitrous acid or a mixture thereof in a non-polar solvent It may be.

In the preparation method according to an embodiment of the present invention, the nonpolar solvent is hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, cyclohexane and tetra One or two or more mixed solvents selected from chloromethane and the like.

In the preparation method according to an embodiment of the present invention, the base is dimethylaminopyridine, pyridine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene And one or two or more mixtures selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide and the like.

In the production method according to an embodiment of the present invention, the base may be added to 0.1 to 10 parts by weight based on 100 parts by weight of the non-polar solvent.

In the production method according to an embodiment of the present invention, the reduction reaction may be carried out by adding a sulfur-containing salt containing an alkali metal or alkaline earth metal.

In the production method according to an embodiment of the present invention, the sulfur-containing salt is one selected from sulfite compounds, bisulfite compounds, thionite compounds, dithionite compounds and thiosulfate compounds, or the like. It may be a mixture of two or more.

In the preparation method according to an embodiment of the present invention, the compound of Formula C may be prepared by esterifying a compound of Formula A and a compound of Formula B in a polar solvent.

[Formula A]

[Formula B]

[Formula C]

[In Formula A, Formula B and Formula C,

R ¹ and R ² are each independently hydrogen, C _{1- 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, _3- C ₁₀ cycloalkyl-amino, C _{1- 10} alkoxy, C _{1- 10} alkylthio, C _{1- 10} alkyl seolpayi carbonyl, C _{1- 10} alkyl sulfonyl, C _{6- 20} aryl, C _{6- 20} aryloxy, C _{6- 20} aryl C _{1 - 10} alkyl, hydroxy, cyano, nitro and halogen, said alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryl, aryloxy and aryl substituted by one or more halogens are each independently May be further substituted with;

R ³ is C _{6- 20} aryl, or C _{3- 20} heteroaryl, wherein aryl and heteroaryl are each independently halogen, C _{1- 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{1 - 10} alkoxy, halo C _{1 - 10} alkyl, halo C _{1 -10} alkoxy, hydroxy and cyano may be further substituted with one or more substituents selected from the group consisting of a furnace;

R ⁵ is halogen, cyano, amino, hydroxy, thiol, cyano, thio, C _{1- 10} alkyl, halo C _{1 -10} alkyl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, , C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{1- 10} alkyl, halo C _{1 - 10} alkoxy, C _{1- 10} alkylthio, C _{1- 10} alkyl amino, C _{6- 20} arylaminocarbonyl, C _1-10 alkyl, C _{6 -20} aryl-amino, C _1-10 alkylamino-carbonyl, C _1-10 alkyl seolpayi carbonyl, C _{1-10 alkylsulfonyl, - (CH 2) n -Q} , - (CH 2) _{n -OQ, - (CH 2)} n -O- (CH 2) m -Q or - (CH _{2) n} is -SQ, wherein Q is C _{6- 20} aryl, C _{3- 20} heteroaryl or C _{3- 20} heterocycloalkyl, n and m, each independently, represent an integer of 1 to 3;

Wherein said heteroaryl and heterocycloalkyl each independently comprise one or more heteroatoms selected from the group consisting of N, O and S.]

In the preparation method according to an embodiment of the present invention, the compound of Formula C may be prepared under one or two or more mixed solvents selected from polar solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone have.

In the preparation method according to an embodiment of the present invention, the compound of Formula C may be prepared by further performing a solvent removal step after the esterification reaction.

According to the present invention, unlike the conventional synthesis method, it does not involve reflux conditions and does not require a complicated separation and purification process, thereby greatly simplifying the manufacturing method.

In addition, according to the present invention, it is possible to purify the synthetic intermediate and the final product pyrazole carboxamide compound by a method such as crystallization, and to improve the production yield, as well as excellent reproducibility thereof, economical and easy to mass production One manufacturing method can be provided.

Therefore, through the production method of the present invention useful for industrial mass production, it is possible to provide a pyrazole carboxamide compound having an insecticidal effect on various pests of insects in a very economical manner.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated more concretely. Unless otherwise defined in the technical terms and scientific terms used at this time, have a meaning commonly understood by those of ordinary skill in the art to which the present invention belongs, unnecessarily obscure the subject matter of the present invention in the following description Description of known functions and configurations that may be omitted.

As used herein, the term “pyrazole carboxamide compound” refers to a pyrazole carboxamide compound substituted with carbamate, and refers to a carbamate insecticide.

The term "alkyl" and substituents comprising alkyl herein also means organic radicals derived from straight chain or pulverized hydrocarbons.

In addition, the term "alkenyl" as used herein refers to an organic radical derived from a straight chain or pulverized hydrocarbon containing one or more double bonds, "alkynyl" refers to a straight or pulverized form containing one or more triple bonds Organic radicals derived from hydrocarbons.

The term "cycloalkyl" as used herein also means free radicals derived from fully saturated or partially unsaturated hydrocarbon rings of 3 to 9 carbon atoms, including when aryl or heteroaryl is fused.

The term "alkylamino" herein also denotes * -N (R ^a ) (R ^b ) and means a free radical comprising monoalkylamino or dialkylamino. In this case, R ^a may be hydrogen or C ₁ -C ₁₀ alkyl, and R ^b may be C ₁ -C ₁₀ alkyl.

In addition, the term "arylamino" is represented by * -N (R ^c ) (R ^d ) and means a free radical comprising monoarylano or diarylamino. In this case, R ^c may be hydrogen or hydrogen or C ₆ -C ₂₀ aryl, and R ^d may be C ₆ -C ₂₀ aryl.

The term "aryl" as used herein also means an organic radical derived from an aromatic hydrocarbon by one hydrogen removal, each ring containing 4 to 7, preferably 5 or 6 ring atoms, as appropriate. It includes a single or fused ring system, and includes a form in which a plurality of aryls are connected by a single bond. Examples include phenyl, naphthyl, biphenyl, terphenyl, anthryl, indenyl, fluorenyl, phenanthryl, triphenylenyl, pyrenyl, peryleneyl, chrysenyl, naphthacenyl, fluoranthenyl, and the like. It is not limited to this.

In addition, the term "heteroaryl" as used herein means an organic radical derived from an aromatic hydrocarbon by one hydrogen removal, and B, N, O, S, Se, -P (= O)-, -C (= Organic radicals derived from monocyclic or polycyclic aromatic hydrocarbons containing 4 to 7 ring atoms comprising at least one selected from O)-, Si and P, and the like, suitably 4 to 7 rings in each ring And, preferably, single or fused ring systems containing 5 or 6 ring atoms, up to the form in which a plurality of heteroaryls are linked by a single bond. For example, furyl, thiophenyl, pyrrolyl, pyranyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxdiazolyl, triazinyl, tetrazinyl, tria Monocyclic heteroaryl such as zolyl, tetrazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; And benzofuranyl, benzothiophenyl, isobenzofuranyl, benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, benzooxazolyl, isoindoleyl, indolyl, indazolyl, benzothiadia Polycyclic heteroaryls such as zolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinolizinyl, quinoxalinyl, carbazolyl, phenanthridinyl, and benzodioxolyl; And the like, but are not limited thereto.

The term "halogen" herein also means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms.

According to the synthesis method of the existing pyrazole carboxamide compound, additional reaction steps are required, such as the introduction of a protecting group for the selective reaction by using a starting material including an amine group and a nitro group at the same time, or with a low stability carbamate. Problems include the generation of excess reaction by-products by side reactions by substituted intermediates. In addition, since the starting material containing the amine group and the nitro group at the same time plays a major role in the increase of the synthetic unit price because of the high price, the research on a more economical manufacturing method was required.

Accordingly, the present inventors have solved the problem of the synthesis method of the existing pyrazole carboxamide compound, and as a result of repeated studies on the manufacturing method suitable for industrial mass production, improved production yield even under simple reaction conditions compared to the conventional synthesis method We have devised a new synthesis method that can be implemented.

Specifically, the present invention has a very simple reaction condition compared to the conventional synthesis method.

Unlike the conventional synthesis method, the production method according to the present invention does not involve reflux conditions and does not require complicated separation and purification processes, thereby greatly simplifying the reaction conditions. Thus, simple and efficient mass production is possible.

In addition, the present invention can realize a high yield and reproducibility compared to the conventional synthesis method.

Synthetic intermediates prepared through the preparation method according to the present invention are obtained in a solid state of high purity through a simple purification method such as crystallization, minimizing the production of reaction by-products to realize a high yield as well as to improve the reproducibility of each step have.

Hereinafter, the manufacturing method of the pyrazole carboxamide compound which concerns on this invention is demonstrated.

Method for producing a pyrazole carboxamide compound according to an embodiment of the present invention, by introducing a nitro group to the compound of formula (C) and then reducing the reaction, to prepare a compound of formula (D); And esterifying a compound of formula E with the compound of formula D to prepare a compound of formula 1.

[Formula 1]

[Formula C]

[Formula D]

[Formula E]

[In Formula 1, Formula C, Formula D and Formula E,

R ¹ and R ² are each independently hydrogen, C _{1- 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, _3- C ₁₀ cycloalkyl-amino, C _{1- 10} alkoxy, C _{1- 10} alkylthio, C _{1- 10} alkyl seolpayi carbonyl, C _{1- 10} alkyl sulfonyl, C _{6- 20} aryl, C _{6- 20} aryloxy, C _{6- 20} aryl C _{1 - 10} alkyl, hydroxy, cyano, nitro and halogen, said alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryl, aryloxy and aryl substituted by one or more halogens are each independently May be further substituted with;

R ³ is C _{6- 20} aryl, or C _{3- 20} heteroaryl, wherein aryl and heteroaryl are each independently halogen, C _{1- 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{1 - 10} alkoxy, halo C _{1 - 10} alkyl, halo C _{1 -10} alkoxy, hydroxy and cyano may be further substituted with one or more substituents selected from the group consisting of a furnace;

R ⁴ is C _{1- 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, C _{6- 20} aryl or C _{6 - 20} aryl C _{1 - 10} alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and alkyl is to be further substituted with one or more substituents selected from the group consisting of halogen or C _1-10 alkoxy; each independently Can;

R ⁵ is halogen, cyano, amino, hydroxy, thiol, thio when isocyanato, C _{1- 10} alkyl, halo C _1-10 alkyl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _1-10 alkoxy, halo C _{1 - 10} alkoxy, C _{1- 10} alkylthio, C _{1- 10} alkyl amino, C _{6- 20} aryl-amino, C _{1- 10} alkyl, C _{6 -20} aryl-amino, C _{1- 10} alkyl aminocarbonyl, C _{1- 10} alkyl seolpayi carbonyl, C _{1- 10 alkylsulfonyl, - (CH 2) n -Q} , - (CH 2 _{) n -OQ, - (CH 2} ) n -O- (CH 2) m -Q or - (CH _{2) n} is -SQ, wherein Q is C _{6- 20} aryl, C _{3- 20} heteroaryl or C _{3 20} and heterocycloalkyl, wherein n and m are each independently an integer of 1 to 3;

X ¹ is halogen;

Wherein said heteroaryl and heterocycloalkyl each independently comprise one or more heteroatoms selected from the group consisting of N, O and S.]

As described above, in the preparation method according to the present invention, a nitro group (* -NO ₂ ) is selectively introduced at the phenyl 6 position of the compound of Formula C, followed by reduction to amination and carbamate in the final step. It may be substituted with.

Thus, no further reaction step is required, such as introduction of a protecting group for the selective reaction. In addition, by introducing carbamate in the final step, improved overall yield can be achieved.

Specifically, the preparation method according to an embodiment of the present invention includes a step of introducing a nitro group into the compound of Formula (D) and two steps of amination of the nitro group.

First, the first step may be a step of crystallization by adding a base after reacting with the nitrating agent in a non-polar solvent.

In the first step, the degree of crystallization of the product can be adjusted by adding the base. Specifically, the crystal formation of the product in the first step is affected by the ratio of the non-polar solvent and the base to be added later. It is added in an amount of 0.1 to 10 parts by weight to crystallize the product in a short time.

In terms of crystallizing the product of high purity, the ratio (weight ratio) of the nonpolar solvent and the base may be specifically 100: 1 to 100: 10, and more specifically 100: 5 to 100: 10.

The nonpolar solvent may be one or two or more mixed solvents selected from hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, cyclohexane and tetrachloromethane. And specifically, it may be a halohydrocarbon solvent selected from dichloromethane, dichloroethane, trichloroethane, tetrachloroethane and the like.

The non-polar solvent may be added at 100 to 1,000 parts by weight based on 100 parts by weight of the starting material (compound of Formula C) in the reaction solution, specifically, 300 to 800 parts by weight, more specifically 500 to 800 parts by weight. Can be. In this case, the amount of base used may be determined according to the amount of the nonpolar solvent.

The nitrating agent may be added in the form of nitric acid, nitrous acid or a mixture thereof.

The nitrating agent may be used in an amount of 1 to 5 equivalents, specifically 1 to 3 equivalents, and more specifically 1 to 2 equivalents, based on 1 equivalent of the starting material (compound of Formula C).

In addition, the nitrating agent may be used together with one or more acids selected from triflic acid, methanesulfonic acid, sulfuric acid, sulfonic acid, and the like to further improve the reaction rate.

As an example, the acid is first introduced into the reaction unit in an amount of 1 to 5 equivalents based on 1 equivalent of the nitrating agent, and then the nitrating agent may be added.

The base is selected from dimethylaminopyridine, pyridine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, thixodium bicarbonate, sodium hydroxide, potassium hydroxide and the like. It may be one or a mixture of two or more.

For example, when the base is selected from sodium bicarbonate, sodium hydroxide and potassium hydroxide, it may be added to satisfy the weight ratio of the non-polar solvent and base described above after preparing a saturated aqueous solution including the same.

In the first step, the reaction may be performed at a temperature of 10 ° C or less. Specifically, the temperature condition of the first step may be -5 ° C to 10 ° C, more specifically 0 to 5 ° C.

It should be noted that the first step, in particular, is mainly influenced by crystal formation depending on the amount of base used in the process of adding a base after reacting with a nitrating agent.

Next, the second step may be a step of amination by reducing the nitro group introduced from the first step.

The second step may be performed by adding a sulfur-containing salt containing an alkali metal or an alkaline earth metal.

The sulfur-containing salt containing the alkali metal or the alkaline earth metal may be one or a mixture of two or more selected from sulfite compounds, bisulfite compounds, thionite compounds, dithionite compounds, thiosulfate compounds, and the like. have.

For example, the sulfur-containing salt may be one or two or more selected from sodium hydrosulfite, sodium bisulfite, sodium thionite, sodium dithionite and sodium thiosulfate.

The sulfur-containing salt may be added in 1 to 10 equivalents, based on 1 equivalent of the starting material (nitrated synthetic intermediate), specifically 3 to 10 equivalents, more specifically 5 to 10 equivalents. .

In the second step, the reaction may be performed at a temperature condition of 20 to 40 ℃. Specifically, the temperature conditions of the second step may be 20 to 30 ℃, more specifically, may be carried out at room temperature (about 25 ℃) conditions without additional heating process.

Specifically, the preparation method according to an embodiment of the present invention, the compound of Formula 1 includes the step of esterifying the compound of Formula E to the compound of Formula D.

The preparation method according to an embodiment of the present invention may provide a pyrazole carboxamide compound represented by Chemical Formula 1 by having a carbamate substitution step in a final step, thereby having more stability.

The esterification reaction may be carried out by adding 1 to 5 equivalents of the compound of Formula E based on 1 equivalent of the starting material (compound of Formula D). Specifically, the compound of Formula E may be added in 1 to 3 equivalents, more specifically 1 to 2 equivalents.

The esterification reaction may be carried out at a temperature of -10 to 40 ℃. Specifically, the temperature conditions may be -5 to 30 ℃, more specifically the temperature conditions may be carried out at 0 ℃ to room temperature conditions after the reaction material in the temperature conditions of -5 to 0 ℃.

According to the present invention, it does not require harsh reaction conditions and does not require complicated separation and purification processes, thereby greatly simplifying the production method.

In addition, according to the present invention, it is possible to purify the synthetic intermediate and the final product pyrazole carboxamide compound by a method such as crystallization, and to improve the production yield, as well as excellent reproducibility thereof, economical and easy to mass production One manufacturing method can be provided.

In addition, in the manufacturing method according to an embodiment of the present invention, each step may further include a solvent extraction step, a solvent removal (concentration) step using an organic solvent. However, the synthetic intermediates prepared through each step can be obtained in a high purity solid state through a simple purification method such as crystallization. In addition, with the use of highly purified synthetic intermediates, each step can minimize the production of reaction byproducts as well as achieve improved yields.

Therefore, the production method according to the present invention can provide a pyrazole carboxamide compound represented by Chemical Formula 1 in a very economical manner as well as provide a simplified manufacturing method and can be usefully applied to industrial mass production. It is expected to be.

In addition, in the method for preparing a pyrazole carboxamide compound according to an embodiment of the present invention, the compound of Formula C may be prepared by esterifying a compound of Formula A with a compound of Formula B in a polar solvent. .

[Formula A]

[Formula B]

[Formula C]

[In Formula A, Formula B and Formula C,

R ¹ and R ² are each independently hydrogen, C _{1- 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, _3- C ₁₀ cycloalkyl-amino, C _{1- 10} alkoxy, C _{1- 10} alkylthio, C _{1- 10} alkyl seolpayi carbonyl, C _{1- 10} alkyl sulfonyl, C _{6- 20} aryl, C _{6- 20} aryloxy, C _{6- 20} aryl C _{1 - 10} alkyl, hydroxy, cyano, nitro and halogen, said alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryl, aryloxy and aryl substituted by one or more halogens are each independently May be further substituted with;

R ³ is C _{6- 20} aryl, or C _{3- 20} heteroaryl, wherein aryl and heteroaryl are each independently halogen, C _{1- 10} alkyl, C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{1 - 10} alkoxy, halo C _{1 - 10} alkyl, halo C _{1 -10} alkoxy, hydroxy and cyano may be further substituted with one or more substituents selected from the group consisting of a furnace;

R ⁵ is halogen, cyano, amino, hydroxy, thiol, cyano, thio, C _{1- 10} alkyl, halo C _{1 -10} alkyl, C _{3- 10} cycloalkyl, C _{3- 10} cycloalkyl, C _{1 - 10} alkyl, , C _{2- 10} alkenyl, C _{2- 10} alkynyl, C _{1- 10} alkyl, halo C _{1 - 10} alkoxy, C _{1- 10} alkylthio, C _{1- 10} alkyl amino, C _{6- 20} arylaminocarbonyl, C _1-10 alkyl, C _{6 -20} aryl-amino, C _1-10 alkylamino-carbonyl, C _1-10 alkyl seolpayi carbonyl, C _{1-10 alkylsulfonyl, - (CH 2) n -Q} , - (CH 2) _{n -OQ, - (CH 2)} n -O- (CH 2) m -Q or - (CH _{2) n} is -SQ, wherein Q is C _{6- 20} aryl, C _{3- 20} heteroaryl or C _{3- 20} heterocycloalkyl, n and m, each independently, represent an integer of 1 to 3;

Wherein said heteroaryl and heterocycloalkyl each independently comprise one or more heteroatoms selected from the group consisting of N, O and S.]

According to the present invention, by using the compound of formula A and the compound of formula C prepared therefrom as a synthetic intermediate, improved total yield can be realized.

In addition, the preparation method of the compound of Formula C is determined that the reaction time and the reaction yield is determined according to various reaction conditions such as solvent, temperature, pressure during the reaction, but it can be seen that it can implement an improved reaction yield when performed in a polar solvent.

In particular, the polar solvent may be a ketone solvent.

The ketone solvent may include one or two or more mixed solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, and the like, specifically, acetone alone or a mixture of one or more of acetone and different ketone solvents. It may be a solvent.

The polar solvent may be added to 100 to 1,000 parts by weight, based on 100 parts by weight of the starting material (compound of Formula A) in the reaction solution, specifically 300 to 800 parts by weight, more specifically 500 to 800 parts by weight Can be.

In addition, the compound of formula C is carried out under the polar solvent conditions described above, thereby achieving a fast reaction rate, can be obtained in high yield and high purity. Thus, it may be used as a starting material for the next reaction immediately after the solvent removal step without further purification.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Prior to this, terms or words used in the specification and claims should not be construed as having a conventional or dictionary meaning, and the inventors should properly explain the concept of terms in order to best explain their own invention. Based on the principle that can be defined, it should be interpreted as meaning and concept corresponding to the technical idea of the present invention. Therefore, the embodiments described in the specification and the configuration shown in the drawings are only one of the most preferred embodiments of the present invention and do not represent all of the technical idea of the present invention, these can be replaced at the time of the present application It should be understood that there are various equivalents and variations.

The synthesis of all compounds was carried out using standard Schlenk or glove box under nitrogen atmosphere, except where noted, and the organic solvent used in the reaction was refluxed under sodium metal and benzophenone to remove moisture. Distilled and used.

Example 1

Preparation of Compound 1

Step 1.

Methanesulfonyl chloride diluted with 20 ml of acetone at -5 ° C was dissolved 80 ml of 15.77 g (52.5 mmol, 1.05 eq) of compound (B) and 9.73 ml (100 mmol, 2.0 eq.) Of 3-picoline. MsCl) 5.77 ml (75 mmol, 1.5 eq.) Was added slowly (temperature attention). After stirring for 10 minutes, under the same temperature, 6.608 g (50 mmol) of Compound (A) dissolved in 50 ml of acetone was slowly added thereto. Stirred at room temperature (25 ° C.) for 20 hours. After completion of the reaction, the solvent was extracted using ethyl acetate (EA), concentrated under reduced pressure and used in the next reaction without purification after vacuum drying.

Analysis condition:

HPLC-CH3CN / H2O = 70/30 & UV 254 nm, Flow rate: (0.5 mL / min)

HPLC retention time (Carboxylic acid 2.109min, Pro 4.875min)

Step 2.

13.43 (150 mmol, 3eq) of triflic acid (CF ₃ SO ₃ H) was added thereto, and 3.39 ml (75 mmol, 1.5eq) of nitric acid (HNO ₃ ) and 50 ml of dichloromethane (MC) were added at 4 ° C. After 20 minutes, a white solid (white nitronium salt) was formed, and Compound (C) (50 mmol) was dissolved in 100 ml MC and slowly added thereto. After the addition was completed, the mixture was stirred at room temperature for 2 hours.

After the completion of the reaction, 150 ml of saturated sodium bicarbonate (Sat. NaHCO ₃ ) (volume equivalent to total MC used) was slowly added at -5 ° C, and stirred for 20 minutes to obtain a compound (C-NO ₂ ). (2 step average yield = 93%).

¹ H NMR (300 MHz, CDCl ₃ ) δ = 9.46 (s, 1H), 8.47 (dd, J = 4.9, 1.6 Hz, 1H), 8.22 (s, 1H), 7.90 (dd, J = 8.1, 1.6 Hz , 1H), 7.78 (s, 1H), 7.42 (dd, J = 8.1, 4.9 Hz, 1H), 7.05 (s, 1H), 2.33 (s, 3H).

Analysis condition:

HPLC-CH3CN / H2O = 70/30 & UV 254 nm, Flow rate: (0.5 mL / min)

Step 3.

53.24 g (115.3 mmol) of compound (C-NO ₂ ) were dissolved in 900 ml tetrahydrofuran (THF) and 80 ml methanol (MeOH). To this, 1200 ml of water (H ₂ O) was added and 212.6 g (1038 mmol, 9 eq) of sodium hydrosulfite (85%) and 87.2 g (1038 mmol, 9 eq) of sodium bicarbonate were mixed and added little by little ( Bubble generation attention). After the addition was completed, the mixture was stirred at room temperature for 5 minutes.

After the reaction was completed, THF was removed. Then, the solvent was extracted using ethyl acetate (EA), and concentrated under reduced pressure. It was suspended in a small amount of EA and crystallized with ethyl ether (Et ₂ O) to give a compound (C-NH ₂ ) (yield = 90%).

¹ H NMR (300 MHz, CDCl ₃ ) δ = 10.00 (s, NH, 1H), 8.50 (dd, J = 4.7, 1.6 Hz, 1H), 8.20 (dd, J = 8.1, 1.6 Hz, 1H), 7.62 (dd, J = 8.1, 4.7 Hz, 1H), 7.44 (s, 1H), 6.85 (d, 2H), 5.49 (s, NH, 2H), 2.04 (s, 3H).

Analysis condition:

HPLC-CH3CN / H2O = 70/30 & UV 254 nm, Flow rate: (0.5 mL / min)

Step 4.

33.74 g (78.153 mmol) of Compound (C-NH ₂ ) was dissolved in 1000 ml of THF. Pyridine 19ml (235.56mmol, 3eq.) Was added thereto, cooled to -2 ° C, and a solution of 9.1ml (118.3mmol, 1.5eq) of methylchloroformate diluted in 10ml of THF for 10 minutes. Slowly added. After the addition was completed, the mixture was stirred for 5 minutes, the temperature was raised to room temperature, and the mixture was stirred for 1 hour.

After the reaction was completed, the resulting salt was filtered and concentrated under reduced pressure. After dissolving it in MC again, hexane was added to MC in the same amount, and concentrated under reduced pressure to produce a white solid. Thus, compound (1) was obtained (yield = 97%).

¹ H NMR (300 MHz, Chloroform-d) δ = 8.52 (s, 1H), 8.45 (d, J = 4.6 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H) , 7.41 (dd, J = 8.0, 4.6 Hz, 1H), 7.33 (s, 1H), 7.08 (s, 1H), 6.98 (d, J = 2.0 Hz, 1H), 3.81 (s, 3H), 2.29 ( s, 3H).

LC-MS Found: 490.9 calculated for C ₆ H ₁₂ ClNO ₂ 489.71.

Analysis condition:

HPLC-CH3CN / H2O = 70/30 & UV 254 nm, Flow rate: (0.5 mL / min)

Purity 99.63%

(Examples 2 to 5)

The compounds of Table 1 were prepared according to the preparation method of Example 1, and the identification data of these compounds are shown in Table 1 below.

Example No.
( ) Total yield
(%) Sympathy Resources
( ¹ H NMR; MS (ESI) m / z: [M ⁺ + H], Purity) Example 2 (R = iBu) 82 ¹ H NMR (300MHz, CDCl ₃ ) δ8.62 (s, 1H), 8.46 (d, J = 5.0Hz, 1H), 7.89 (d, J = 8.2Hz, 1H), 7.60 (s, 1H), 7.40 (dd, J = 8.0, 4.7 Hz, 1H), 7.34 (s, 1H), 6.96 (d, J = 4.3 Hz, 2H), 3.99 (d, J = 6.6 Hz, 2H), 2.29 (s, 3H) , 2.01-1.93 (m, 1 H), 0.96 (d, J = 6.6 Hz, 6H) .; MS (ESI) m / z 530.0 (Exact mass 530.05); Purity 99.83% Example 3 (R = n-Heptyl) 83 ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.60 (s, 1H), 8.47 (d, J = 4.6 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.40 (dd, J = 7.9, 4.7 Hz, 1H), 7.35 (s, 1H), 6.92 (s, 1H), 6.97 (s, 1H), 4.19 (t, J = 6.8 Hz, 2H), 2.29 (s, 3H), 1.74-1.61 (m, 2H), 1.41-1.21 (m, 8H), 0.93-0.82 (m, 3H) .; MS (ESI) m / z 572.1 (Exact mass 572.03); Purity 99.20% Example 4 (R = allyl) 81 ¹ H NMR (300MHz, CDCl ₃ ) δ8.50 (s, 1H), 8.46 (d, J = 4.8Hz, 1H), 7.90 (d, J = 7.8Hz, 1H), 7.65 (s, 1H), 7.40 (dd, J = 7.9, 4.7 Hz, 1H), 7.36 (s, 1H), 7.02 (s, 1H), 6.95 (s, 1H), 6.01-5.89 (m, 1H), 5.38 (d, J = 17.1 Hz, 1H), 5.32 (d, J = 10.4 Hz, 1H), 4.70 (d, J = 5.8 Hz, 2H), 2.30 (s, 3H) .; MS (ESI) m / z 514.3 (Exact mass 514.02); Purity 99.61% Example 5 (R = CH ₃ OCH ₂ CH _2- *) 79 ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.2 Hz, 2H), 7.90 (d, J = 8.1 Hz, 1H), 7.66 (s, 1H), 7.40 (dd, J = 7.9, 4.7 Hz, 1H), 7.35 (s, 1H), 7.03 (s, 1H), 6.97 (s, 1H), 4.37 (t, J = 4.4 Hz, 2H), 3.64 (t, J = 4.4 Hz, 2H) , 3.40 (s, 3 H), 2.29 (s, 3 H) .; MS (ESI) m / z 532.4 (Exact mass 532.03); Purity 99.38%

Example 6

In step 1 of Example 1, acetonitrile was used as a reaction solvent instead of acetone, and was carried out in the same manner as in Preparation Example 1 to obtain Compound (1).

Example 7

In Step 2 of Example 1, after the reaction type, using 225 ml of saturated sodium bicarbonate (Sat. NaHCO ₃ ), to obtain a compound (C-NO ₂ ).

Thereafter, using the compound (C-NO ₂ ) obtained in the preparation method, the compound (1) was obtained in the same manner as in the preparation method of Example 1 above.

As described above in detail a specific part of the present invention, it is apparent to those skilled in the art that the specific technology is only one embodiment, and the scope of the present invention is not limited thereto. Therefore, the substantial scope of the present invention will be determined by the appended claims and equivalents thereof.

Claims (10)

Under polar solvent,
Esterifying a compound of Formula A with a compound of Formula B to produce a compound of Formula C;
Preparing a compound of Chemical Formula D by introducing a nitro group into the compound of Chemical Formula C and then reducing the reaction; And
Preparing a compound of Chemical Formula 1 by esterifying a compound of Chemical Formula E with the compound of Chemical Formula D;
Including, method for producing a pyrazole carboxamide compound:
[Formula 1]

[Formula A]

[Formula B]

[Formula C]

[Formula D]

[Formula E]

In Chemical Formula 1, Chemical Formula A, Chemical Formula B, Chemical Formula C, Chemical Formula D, and Chemical Formula E,
R ¹ and R ² are each independently hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkylC _1-10 alkyl, C _3-10 cycloalkylamino, C _1-10 alkoxy, C _1-10 alkylthio, C _1-10 alkylsulfinyl, C _1-10 alkylsulfonyl, C _6-20 aryl, C _6-20 aryloxy, C _{6-20 arylC 1-10} alkyl, hydroxy, cyano, nitro or halogen, said alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryl, aryloxy and arylalkyl are each independently one or more halogens May be further substituted with;
R ³ is C _6-20 aryl or C _3-20 heteroaryl, wherein the aryl and heteroaryl are each independently halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{1 -10} may be further substituted with one or more substituents selected from the group consisting of alkoxy, _{haloC 1-10} alkyl, haloC _1-10 alkoxy, hydroxy and cyano;
R ⁴ is C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkylC _1-10 alkyl, C _6-20 aryl or C _{6 -20} arylC _1-10 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and arylalkyl are each independently further substituted with one or more substituents selected from the group consisting of halogen and C _1-10 alkoxy Can;
R ⁵ is halogen, cyano, amino, hydroxy, thiol, thiocyanato , C _1-10 alkyl, haloC _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkylC _1-10 Alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy, haloC _1-10 alkoxy, C _1-10 alkylthio, C _1-10 alkylamino, C _6-20 arylamino, C _1-10 alkylC _6-20 arylamino, C _1-10 alkylaminocarbonyl, C _1-10 alkylsulfinyl, C _1-10 alkylsulfonyl,-(CH ₂ ) _n -Q,-(CH ₂ ) _n -OQ,-(CH ₂ ) _n -O- (CH ₂ ) _m -Q or-(CH ₂ ) _n -SQ, wherein Q is C _6-20 aryl, C _3-20 heteroaryl or C _{3 -20} heterocycloalkyl, n and m, each independently, represent an integer of 1 to 3;
X ¹ is halogen;
The heteroaryl and heterocycloalkyl each independently comprise one or more heteroatoms selected from the group consisting of N, O and S. The method of claim 1,
Introducing the nitro group to the compound of Formula C,
Under nonpolar solvent,
A method for producing a pyrazole carboxamide compound which is crystallized by adding a base after reacting with a nitrifying agent including nitric acid, nitrous acid or a mixture thereof. The method of claim 2,
The nonpolar solvent,
Process for preparing pyrazole carboxamide compound, which is at least one selected from hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, cyclohexane and tetrachloromethane . The method of claim 2,
The base is,
At least one selected from dimethylaminopyridine, pyridine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, sodium bicarbonate, sodium hydroxide and potassium hydroxide, Process for the preparation of pyrazole carboxamide compound. The method of claim 2,
The base is,
Based on 100 parts by weight of the nonpolar solvent, 0.1 to 10 parts by weight of the preparation method of the pyrazole carboxamide compound. The method of claim 1,
The reduction reaction,
Method of producing a pyrazole carboxamide compound, which is carried out by adding a sulfur-containing salt containing an alkali metal or alkaline earth metal. The method of claim 6,
The sulfur-containing salts,
A method for producing a pyrazole carboxamide compound, which is at least one selected from a sulfite compound, a bisulfite compound, a thionite compound, a dithionite compound, and a thiosulfate compound. delete The method of claim 1,
The polar solvent is,
A method for producing a pyrazole carboxamide compound, which is at least one selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone. The method of claim 1,
Preparing a compound of Formula C, after
Solvent removal step; further comprising, method for producing a pyrazole carboxamide compound.