阅读说明：本技术 吡唑-4-甲酰胺衍生物的制备方法 (Process for preparing pyrazole-4-carboxamide derivatives ) 是由 栗原悠辅 佐藤孝纪 和须津绚濑 山田裕 于 2018-07-23 设计创作，主要内容包括：吡唑-4-甲酰胺衍生物的制备方法,其特征在于：使吡唑-4-甲酸酯与胺在溶剂中、在碱的存在下进行氨解反应而得到吡唑-4-甲酰胺衍生物时,无需从系统中除去副产的醇或酚即可完成反应。本发明提供与现有方法相比能够简便地且以高收率、高纯度得到可用作农业用杀菌剂的吡唑-4-甲酰胺衍生物的工业上的制备方法。(A process for the preparation of pyrazole-4-carboxamide derivatives, characterized in that: when a pyrazole-4-carboxylic acid ester and an amine are subjected to an ammonolysis reaction in a solvent in the presence of a base to obtain a pyrazole-4-carboxamide derivative, the reaction can be completed without removing by-produced alcohol or phenol from the system. The present invention provides an industrial production method capable of obtaining a pyrazole-4-carboxamide derivative useful as an agricultural fungicide in a high yield and a high purity in a simple manner as compared with conventional methods.)

1. A process for producing a pyrazole-4-carboxamide derivative represented by formula (1), characterized in that: in a process for producing a pyrazole-4-carboxamide derivative by aminolysis of a pyrazole-4-carboxylic acid ester represented by the formula (2) and an amine represented by the formula (3) in a solvent in the presence of a base, the reaction can be completed without removing by-produced alcohol or phenol from the system,

[ chemical formula 1]

In the formula, R¹Is hydrogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl or aryl;

R²is hydrogen atom, halogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl,C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl, aryl;

R³is hydrogen atom, halogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl or aryl;

qx is selected from Q1, Q2, Q3, Q4, Q5, Q6:

[ chemical formula 2]

In Q1, R⁴、R⁵、R⁶The same or different from each other, represent C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, R⁵And R⁶May be bonded to each other to form a C3-C6 cycloalkyl group;

v represents CH (R)⁷)、N(R⁸) Oxygen atom, sulfur atom, R⁷And R⁸Respectively represent a hydrogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group;

y represents a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, an SH group, a C1-C4 alkylthio group, a C1-C4 haloalkylthio group;

m is an integer of 0 to 3;

in Q2, Y¹Represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group;

n represents an integer of 1 to 5, and Y represents an integer of 2,3,4 or 5¹May be the same or different;

in Q3, Y¹And Z independently represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group;

p represents an integer of 1 to 4, and Y represents an integer of 2,3 or 4¹May be the same or different;

n represents an integer of 1-5, and when n is 2,3,4, 5, Z can be the same or different;

in Q4, R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴The same or different, represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, or R¹¹And R¹²And R¹³And R¹⁴May be bonded to each other to form a C3-C6 cycloalkyl group;

w represents a methylene group, a methine group substituted with a C1-C6 haloalkyl group, or a terminal-substituted vinyl group represented by the formula (4);

[ chemical formula 3]

Wherein T represents a C1-C6 haloalkyl group or a halogen atom;

in Q5, Y¹Represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group;

m represents an integer of 1 to 3, and Y represents an integer of 2 or 3¹May be the same or different;

g represents an oxygen atom, a sulfur atom, N (R)¹⁵)，R¹⁵Represents a hydrogen atom, a C1-C6 alkyl group;

in Q6, Y¹Represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group;

m represents an integer of 1 to 3, and Y represents an integer of 2 or 3¹May be the same or different;

g represents an oxygen atom, a sulfur atom, N (R)¹⁵)，R¹⁵Represents a hydrogen atom, a C1-C6 alkyl group;

[ chemical formula 4]

In the formula, R¹Is hydrogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl or aryl,

R²is hydrogen atom, halogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl or aryl;

R³is hydrogen atom, halogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl or aryl;

r is C1-C4 alkyl, phenyl which may be substituted;

[ chemical formula 5]

In formula (3), Qx represents any one substituent of Q1, Q2, Q3, Q4, Q5, Q6;

[ chemical formula 6]

In Q1, R⁴、R⁵、R⁶The same or different from each other, represent C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, R⁵And R⁶May be bonded to each other to form a C3-C6 cycloalkyl group;

v represents CH (R)⁷)、N(R⁸) Oxygen atom, sulfur atom, R⁷And R⁸Respectively represent a hydrogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group;

y represents a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, an SH group, a C1-C4 alkylthio group, a C1-C4 haloalkylthio group;

m is an integer of 0 to 3;

in Q2, Y¹Represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group;

n represents an integer of 1 to 5, and when n is 2,3,4 or 5, Y may be the same or different;

in Q3, Y¹And Z independently represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group;

p represents an integer of 1-4, and when p is 2,3 or 4, Y can be the same or different;

n represents an integer of 1-5, and when n is 2,3,4, 5, Z can be the same or different;

in Q4, R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴The same or different, represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, or R¹¹And R¹²And R¹³And R¹⁴May be bonded to each other to form a C3-C6 cycloalkyl group;

w represents a methylene group, a methine group substituted with a C1-C6 haloalkyl group, or a terminal-substituted vinyl group represented by the formula (4);

[ chemical formula 7]

Wherein T represents a C1-C6 haloalkyl group or a halogen atom;

in Q5, Y¹Represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group;

m represents an integer of 1 to 3, and Y represents an integer of 2 or 3¹May be the same or different;

g represents an oxygen atom, a sulfur atom, N (R)¹⁵)，R¹⁵Represents a hydrogen atom, a C1-C6 alkyl group;

in Q6, Y¹Represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group;

m represents an integer of 1 to 3, and Y represents an integer of 2 or 3¹May be the same or different;

g represents an oxygen atom, a sulfur atom, N (R)¹⁵)，R¹⁵Represents a hydrogen atom or a C1-C6 alkyl group.

2. The method of claim 1, wherein: the base used in the reaction is a metal alkoxide.

3. The method of claim 2, wherein: the metal alkoxide is at least one selected from the group consisting of lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide.

4. The method of claim 1, wherein: the solvent used in the reaction is an aprotic solvent.

5. The method of claim 1, wherein: after the reaction is completed, water is added to the reaction mixture to precipitate the target substance, and the precipitate is filtered and dried to obtain the pyrazole-4-carboxamide derivative.

6. The method of claim 1, wherein: after the reaction is completed, water is added to the reaction mixture, and the water layer is separated to remove unnecessary substances from the organic layer containing the target substance, and water is added to the organic layer from which the unnecessary substances have been removed to precipitate the target substance, followed by filtration and drying, thereby obtaining the pyrazole-4-carboxamide derivative.

Technical Field

The present invention relates to a process for the preparation of pyrazole-4-carboxamide derivatives.

Background

Pyrazole-4-carboxamide derivatives are useful as agricultural chemicals or intermediates thereof, and for example, patent document 1 (international publication No. 2013/186325) describes fluoroandazole (fluindapyr), patent document 2 (international publication No. 2003/070705) describes bixafen (bixafen), patent document 3 (international publication No. 2006/087343) describes fluxapyroxad, patent document 4 (international publication No. 2007/115765) describes isopyrazam (isopyrazam), patent document 5 (international publication No. 2007/048556) describes benzovindiflupyr (benzovindiflupyr), and patent document 6 (international publication No. 0737682) describes penthiopyrad (thiopyrad). These substances have excellent effects as agricultural fungicides, and are widely used for controlling diseases of crops in the world.

As a method for producing a carboxamide derivative, a method known as a method for producing a carboxamide derivative is described in patent document 2 (international publication No. 2003/070705), patent document 7 (international publication No. 2007/009717), and patent document 8 (international publication No. 2007/031323): a method in which an active form of the corresponding carboxylic acid, for example, an acid chloride, is reacted with an amine.

Patent document 3 (international publication No. 2006/087343) and patent document 9 (international publication No. 2005/123690) describe: a method in which a carboxylic acid is reacted with an amine in the presence of a condensing agent such as N, N' -dicyclohexylcarbodiimide or bis (2-oxo-oxazolidinyl) phosphinic chloride to obtain a carboxylic acid amide.

In the above method, after the corresponding carboxylic acid ester is hydrolyzed to form a carboxylic acid, it is necessary to prepare an acid chloride using a chlorinating agent such as thionyl chloride or oxalyl chloride, and there are problems that the number of steps until preparation of formamide is long, a reagent which is dangerous to handle is used for preparation of an acid chloride, and a large amount of waste acid and waste water are generated after the reaction.

In addition, in the method using a condensing agent, the following problems are involved in addition to the necessity of the hydrolysis step of the carboxylic ester as described above: waste which is difficult to separate from the target substance is generated after the reaction; the bis (2-oxazolidinyl) phosphinic chloride has carcinogenicity and is dangerous to operate.

On the other hand, in the ammonolysis reaction in which the target formamide is obtained by directly reacting a carboxylic acid ester with an amine in the presence of a base, the production process is shortened, it is not necessary to use a hazardous reagent because of no acid chlorination, the safety in operation is improved, and waste materials such as waste acid and waste water can be reduced, which makes it possible to provide an industrially advantageous production method.

As a prior art of a method for producing a pyrazole-4-carboxamide derivative by ammonolysis in the presence of a base, the following patent documents are listed. Patent document 10 (international publication No. 2012/055864) and patent document 11 (international publication No. 2012/175511).

Patent document 10 (international publication No. 2012/055864) describes: pyrazole-4-carboxamide derivatives can be prepared from pyrazole-4-carboxylic acid esters and amines using a large non-nucleophilic base such as potassium tert-butoxide, but such a method is not necessarily an industrial preparation method because it is limited to a non-nucleophilic base and silica gel chromatography is required for purification of a target substance.

Patent document 11 (international publication No. 2012/175511) describes: the pyrazole-4-carboxamide derivative can be produced from a pyrazole-4-carboxylic acid ester and an amine using a metal alkoxide as a base, but the reaction requires a step of removing the by-produced alcohol and toluene as a solvent by azeotropic distillation under reduced pressure in the system to complete the reaction, and the operation is complicated and the amount of waste liquid increases, and therefore, it is difficult to say that the method is advantageous as an industrial production method.

Disclosure of Invention

Problems to be solved by the invention

The present invention is intended to solve the problems associated with the prior art as described above and to provide an industrial production method by which a pyrazole-4-carboxamide derivative useful as an agricultural fungicide can be obtained in a high yield and a high purity in a simple manner as compared with the conventional methods.

Means for solving the problems

The present inventors have conducted intensive studies on a process for producing a pyrazole-4-carboxamide of formula (1) by aminolysis of a pyrazole formate of formula (2) with an amine of formula (3) in a solvent in the presence of a base, which is represented by the following reaction formula (a), and as a result, have found that: surprisingly, the reaction can be completed without removing from the system the by-produced alcohol or phenol which is required to be removed from the system in the conventional ammonolysis reaction, thereby completing the present invention. Namely, the present invention provides: an industrial production method which can obtain a pyrazole-4-carboxamide derivative represented by the formula (1) in high yield and high purity by a simple operation and can reduce the amounts of waste acid and waste water compared with conventional methods.

[ chemical formula 1]

Reaction formula (A)

R, R in the formulae (1), (2) and (3)¹、R²、R³Qx is as follows.

Effects of the invention

According to the process for producing a pyrazole-4-carboxamide derivative of the present invention, a pyrazole-4-carboxamide derivative useful as an agricultural fungicide can be obtained in a high yield and a high purity in a simple manner and in a high yield as compared with conventional methods by a short and simple operation, and can be used as an industrial production process.

Detailed Description

Hereinafter, the process for producing the pyrazole-4-carboxamide derivative according to the present invention will be specifically described based on the reaction formula (a).

The present invention relates to a process for producing a pyrazole-4-carboxamide derivative represented by formula (1) by aminolysis of a pyrazole-4-carboxylic acid ester represented by formula (2) and an amine represented by formula (3) in a solvent in the presence of a base, which is represented by reaction formula (a), wherein the reaction can be completed without removing by-produced alcohols or phenols from the reaction system.

The pyrazole-4-carboxamide derivative obtained by the above reaction is a compound represented by formula (1). In addition, the pyrazole-4-carboxamide derivative represented by formula (1) includes not only a single optical isomer or diastereoisomer form but also a racemic mixture, a diastereoisomer mixture, or a partially separated mixture of these compounds, due to the structure of the amine represented by formula (2).

Here, the racemic mixture and the diastereomer mixture refer to respective mixtures of isomers (racemic modification, diastereomer), and the partially separated mixture refers to a residual mixture obtained by separating a part of isomers constituting the racemic mixture and the diastereomer mixture (for example, in the case of racemic modification, a mixture of isomers in which the ratio of R form to S form is not 1: 1, which is generated by separating a part of R form or S form from the usual R form and S form of 1: 1).

The compound represented by the formula (1) is as follows.

[ chemical formula 2]

R in the formula (1)¹Is hydrogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl, aryl, preferably C1-C4 alkyl, particularly preferably methyl.

R²Is hydrogen atom, halogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl, aryl, preferably C1-C4 haloalkyl, particularly preferably difluoromethyl, trifluoromethyl.

R³Is hydrogen atom, halogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl or aryl, particularly preferably hydrogen atom.

Qx for amine residues is described later.

Pyrazole-4-carboxylic acid esters represented by the formula (2) as one of the starting materials are as follows.

[ chemical formula 3]

In the formula (2), R¹Is hydrogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl, aryl, preferably C1-C4 alkyl, particularly preferably methyl.

R²Is hydrogen atom, halogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl, aryl, preferably C1-C4 haloalkyl, particularly preferably difluoromethyl, trifluoromethyl.

R³Is hydrogen atom, halogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C4 alkylOxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 haloalkylthio, aralkyl, aryl, particularly preferably a hydrogen atom.

R is C1-C4 alkyl, optionally substituted phenyl, preferably C1-C4 alkyl, particularly preferably ethyl.

The amine represented by the formula (3) which reacts with the pyrazole-4-carboxylate represented by the formula (2) is as follows.

[ chemical formula 4]

In formula (3), Qx represents any of substituents (amine residues) of Q1, Q2, Q3, Q4, Q5, and Q6.

[ chemical formula 5]

In Q1, R⁴、R⁵、R⁶The same or different from each other, represent C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, R⁵And R⁶May be bonded to each other to form a C3-C6 cycloalkyl group, preferably a C1-C4 alkyl group, particularly preferably R⁴、R⁵、R⁶Is methyl.

V represents CH (R)⁷)、N(R⁸) Oxygen atom, sulfur atom, R⁷And R⁸Each independently a hydrogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, particularly preferably CH (R)⁷) In R⁷Is a hydrogen atom.

Y represents a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, an SH group, a C1-C4 alkylthio group, a C1-C4 haloalkylthio group, preferably a halogen atom, particularly preferably a fluorine atom.

m is an integer of 0 to 3, preferably 0 or 1, particularly preferably 1. The substitution position of the fluorine atom is particularly preferably the 7-position of the indanamine.

In Q2, Y¹Represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl groupC1-C6 alkoxy, C1-C6 haloalkoxy, SH group, C1-C6 alkylthio, C1-C6 haloalkylthio, preferably a hydrogen atom, C1-C6 alkyl, halogen atom.

n represents an integer of 1 to 5, and when n is 2,3,4 or 5, Y may be the same or different.

In Q3, Y¹And Z independently represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, preferably a hydrogen atom or a halogen atom.

p represents an integer of 1 to 4, and when p is 2,3 or 4, Y may be the same or different.

n represents an integer of 1 to 5, and when n is 2,3,4 or 5, Z may be the same or different.

In Q4, R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴The same or different, represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, preferably a hydrogen atom, a C1-C6 alkyl group. In addition, R¹¹And R¹²And R¹³And R¹⁴May be bonded to each other to form a C3-C6 cycloalkyl group, respectively.

W represents a methylene group, a methine group substituted with a C1-C6 haloalkyl group, or a terminal-substituted vinyl group represented by the formula (4).

[ chemical formula 6]

Wherein T represents a C1-C6 haloalkyl group or a halogen atom, preferably a chlorine atom.

In Q5, Y¹Represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, preferably a C1-C6 alkyl group.

m represents an integer of 1 to 3, and when m is 2 or 3, Y may be the same or different.

G represents an oxygen atom, a sulfur atom, N (R)¹⁵)，R¹⁵Represents a hydrogen atom or a C1-C6 alkyl group, preferably a sulfur atom.

In Q6, Y¹Represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, an SH group, a C1-C6 alkylthio group, a C1-C6 haloalkylthio group, preferably a C1-C6 alkyl group.

m represents an integer of 1 to 3, and when m is 2 or 3, Y may be the same or different.

G represents an oxygen atom, a sulfur atom, N (R)¹⁵)，R¹⁵Represents a hydrogen atom or a C1-C6 alkyl group, preferably a sulfur atom.

Examples of the pyrazole-4-carboxamide derivative represented by formula (1) include:

3-difluoromethyl-N- (7-fluoro-1, 1, 3-trimethyl-4-indanyl) -1-methyl-4-pyrazolecarboxamide: the generic name is fluoroandenazole amine (fluindapyr);

3- (difluoromethyl) -1-methyl-N- (3',4' -dichloro-5-fluorobiphenyl-2-yl) -pyrazole-4-carboxamide: the generic name bixafen;

3- (difluoromethyl) -1-methyl-N- (3',4',5' -trifluorobiphenyl) -pyrazole-4-carboxamide: under the generic name fluxapyroxad;

a mixture of the cis form (syn form) 3- (difluoromethyl) -1-methyl-N- ((1RS,4SR,9RS) -1,2,3, 4-tetrahydro-9-isopropyl-1, 4-methanonaphthalen-5-yl) pyrazole-4-carboxamide and the trans form (anti form) 3- (difluoromethyl) -1-methyl-N- ((1RS,4SR,9SR) -1,2,3, 4-tetrahydro-9-isopropyl-1, 4-methanonaphthalen-5-yl) pyrazole-4-carboxamide: the generic name is isopyrazam;

3- (difluoromethyl) -1-methyl-N- (9- (dichloromethylene) -1,2,3, 4-tetrahydro-1, 4-methanonaphthalen-5-yl) pyrazole-4-carboxamide: the generic name is benzovindiflupyr (benzovindiflupyr);

(RS) -N- [2- (1, 3-dimethylbutyl) -3-thienyl ] -1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxamide: the common name is penthiopyrad (penthiopyrad) and the like.

Examples of the pyrazole-4-carboxylate represented by the formula (2) and the amine represented by the formula (3) used in the preparation include: a compound having a substituent corresponding to a pyrazole-4-carboxamide derivative represented by the formula (1).

The process for producing a pyrazole-4-carboxamide derivative of the present invention is characterized in that: the process for producing a pyrazole-4-carboxylic acid amide represented by the formula (1) comprises subjecting a pyrazole-4-carboxylic acid ester represented by the formula (2) and an amine represented by the formula (3) to an ammonolysis reaction in a solvent in the presence of a base, wherein the reaction can be completed without removing by-produced alcohol or phenol from the system.

In the present invention, the feeding ratio of the pyrazole carboxylate represented by the formula (2) to the amine represented by the formula (3) in the ammonolysis reaction is as follows: the amount of pyrazolecarboxylate is in the range of 1.0 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to 1.0 equivalent of amine.

In the present invention, the base used in the ammonolysis reaction is preferably a metal alkoxide, and more preferably a metal alkoxide having a small volume. Specifically, there may be mentioned: lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide. Sodium methoxide and sodium ethoxide are particularly preferred.

The amount of the base used is preferably in the range of 1.0 to 7.0 equivalents, more preferably in the range of 1.0 to 5.0 equivalents, still more preferably in the range of 1.0 to 3.0 equivalents, particularly preferably in the range of 1.0 to 2.5 equivalents, and most preferably in the range of 1.4 to 2.5 equivalents, relative to 1.0 equivalent of the amine represented by the formula (3). When the amount is within this range, the target compound can be obtained in a high yield without removing by-produced alcohol or phenol from the system, and therefore, it is preferable that the reaction does not proceed and the yield does not tend to be improved when the amount of the base used is less than 1.0 equivalent.

In the present invention, the solvent used in the ammonolysis reaction is preferably an aprotic solvent. Specific examples of the solvent include: amide solvents such as N, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpyrrolidone, and N, N-dimethylformamide; sulfur-containing solvents such as dimethyl sulfoxide; hydrocarbon solvents such as benzene, toluene, and xylene; halogen-based solvents such as methylene chloride and dichloroethane. Among these aprotic solvents, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpyrrolidone, N-dimethylformamide, and dimethylsulfoxide are preferable, and N, N-dimethylacetamide, N-methylpyrrolidone, N-dimethylformamide, and dimethylsulfoxide are particularly preferable.

The solvent used herein means a reaction solvent used in the ammonolysis reaction, that is, a specific aprotic solvent, but when the aprotic solvent is used, the solvent present in the reaction system may be a mixed solvent containing a solvent other than the specific aprotic solvent so long as the effect of the present invention is exhibited, and the aprotic solvent used in the reaction herein means a solvent used in the reaction of the present invention. In this case, as the case where another solvent is present in such a reaction system, for example, there can be mentioned: a small amount of a solvent derived from the raw materials used may be mixed into the reaction system.

As the solvent to be mixed in a small amount, for example, in the case where a raw material substance used as a raw material is diluted in a solvent different from a solvent in which an ammonolysis reaction is carried out, when the raw material is used, a solvent in which the raw material is dissolved, for example, toluene, or a solvent in which a base used as a catalyst is dissolved (for example, an alcohol in a metal alkoxide) or the like may be partially mixed in the reaction solvent.

The water content in these reaction solvents is preferably 0.5% by mass or less, and particularly preferably 0.1% by mass or less. These aprotic solvents may be used alone or in combination of two or more kinds as a mixed solvent, and the mixing ratio may be any ratio.

The amount of the solvent used is in the range of 0.5 to 10.0 equivalents, preferably 2.0 to 5.0 equivalents, relative to the amine represented by formula (3), and the amine concentration is preferably 50% by mass or less. By carrying out the reaction using a solvent under such conditions, the target product can be obtained with high purity and high yield.

In the present invention, the temperature range in the ammonolysis reaction is usually from-20 ℃ to 140 ℃, preferably from 20 ℃ to 90 ℃.

In the present invention, the reaction time in the ammonolysis reaction is usually in the range of 1 to 10 hours, preferably in the range of 2 to 5 hours.

In the present invention, the metal alkoxide compound as the base is used in an excess amount of 1.0 to 7.0 equivalents or more relative to the amine, and the reaction is preferably carried out in the aprotic solvent, whereby the reaction can be completed without removing the alcohol or phenol generated by the aminolysis reaction of the ester and the amine from the reaction system. The reason for this is not clear, but is presumed to be due to the following possibility: the formamide, which is the target product generated as the reaction proceeds, is a metal salt by taking in metal ions (sodium ions and the like) in the reaction system, and the equilibrium of the reaction shifts in the direction of formamide generation, and the reaction may be completed without causing a reverse reaction. In addition, in this case, promotion of the uptake of metal ions of formamide by interaction with the solvent used in the reaction is also considered to be a major factor.

As a result, the pyrazole-4-carboxamide derivative obtained by adding water to the reaction mixture obtained and cooling the mixture is precipitated (precipitated) in the organic layer, whereby the pyrazole-4-carboxamide derivative can be obtained in high yield and high purity.

The amount of water required for precipitation is about 1.0 to 7.0 in terms of mass ratio to the solvent used, and about 10.0 to 180.0 in terms of molar ratio in terms of amine standard.

In the present invention, as described above, the pyrazole-4-carboxamide derivative can be obtained by a simple operation of adding water after the completion of the reaction, but before this, it is preferable to add water to the reaction mixture after the completion of the reaction and to separate the aqueous layer by washing the reaction mixture after the completion of the reaction with water before precipitating the pyrazole-4-carboxamide derivative, thereby removing unnecessary substances from the organic layer containing the target substance. The amount of water used for washing is in the range of 5 to 150 equivalents, preferably 10 to 50 equivalents, based on the amine represented by formula (3). Washing can be performed, for example, by adding water to the reaction mixture, stirring, allowing the mixture to stand to separate into an organic layer and an aqueous layer, and removing the aqueous layer.

In order to separate the organic layer and the aqueous layer, an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide may be added to improve the separation state, or an alkali metal chloride such as potassium chloride or sodium chloride, or an alkaline earth metal chloride such as calcium chloride may be added to facilitate separation of the organic layer and the aqueous layer by a salting-out effect or the like.

In short, in the present invention, the target compound can be obtained by precipitating the target compound by adding water after the reaction is completed, but in terms of removing inorganic substances (mainly, alkali metal hydroxide and the like) in the reaction mixture by washing with water and improving the purity of the pyrazole-4-carboxamide derivative, it is preferable to add water in two stages by the following method: the mixture was initially washed with water and separated into an organic layer and an aqueous layer, and water was added again to the separated organic layer to precipitate the target substance.

However, even in the case where the organic layer and the aqueous layer are not separated from each other as described above, the crystals of the pyrazole-4-carboxamide derivative precipitated by the addition of water are washed with water to achieve a purity equivalent to that in the case of separation, and in this case, the amount of water used for washing needs to be about 2 to 10 times that in the case of separation, and although the amount of water used is slightly increased, the purity and yield of the obtained pyrazole-4-carboxamide derivative are not changed.

As described above, the separation of the pyrazole-4-carboxamide derivative as the target compound is achieved by adding water directly to the reaction mixture after completion of the reaction or adding water to the organic layer obtained by washing and separating the reaction mixture to precipitate the pyrazole-4-carboxamide derivative as crystals, followed by solid-liquid separation. The temperature at which water is added to the reaction mixture after completion of the reaction depends on the reaction temperature, the solubility of the obtained pyrazole-4-carboxamide derivative, or the amount of the organic layer, but may be any temperature at which the target substance is not decomposed, and is usually preferably in the range of about 20 to 100 ℃, and more preferably in the range of about 40 to 90 ℃.

Then, by cooling, crystals can be obtained. In either method, regardless of whether or not washing separation is performed, it is preferable to wash the separated crystals and wash the mother liquor adhering to the crystals.

The obtained crystals are dried to obtain a highly pure pyrazole-4-carboxamide derivative represented by the formula (1). In this case, purification steps such as distillation, recrystallization, column chromatography and the like are not required at all.