JP2010083812A - Method for producing 5-aminopyrazole derivative - Google Patents

Abstract

（式中、Ｒ¹は、脂肪族基を表し、Ｒ²は、電子求引性基を表し、Ｒ³は、水素原子または置換基を表し、Ｘは、ハロゲン原子、−ＯＲまたはアミノ基を表す。Ｒは水素原子又は置換基を表す。）
【選択図】なしTo provide a method for producing a 5-aminopyrazole derivative represented by the general formula (3) in a simple, high yield and high purity.
The molar ratio of the compound represented by the general formula (2) and the hydrazine derivative represented by the general formula (1) is in a range of 1: 1.10 to 1: 5.00. A method for producing a 5-aminopyrazole derivative represented by the following general formula (3).

(Wherein R ¹ represents an aliphatic group, R ² represents an electron withdrawing group, R ³ represents a hydrogen atom or a substituent, and X represents a halogen atom, —OR or an amino group. R represents a hydrogen atom or a substituent.
[Selection figure] None

Description

  The present invention relates to a method for producing a 5-aminopyrazole derivative. More specifically, the present invention relates to a method for producing a 5-aminopyrazole derivative in a simple, high yield and high purity.

5-Aminopyrazole derivatives are useful compounds as intermediates for functional compounds such as photographic additives, sensitizing dyes, dyes, pigments, electronic materials, medical and agrochemicals, and their synthesis methods have been known for a long time. . For example, Patent Documents 1 and 2 disclose a method for quantitatively producing a 5-aminopyrazole derivative from 5-hydrazino-1,3-isophthalic acid and ethoxymethyldenmalononitrile. Under the conditions of Patent Document 1, it was found that the 5-aminopyrazole derivative obtained from methyl hydrazine and ethyl ethoxymethyldencyanoacetate contained isomers and the yield deteriorated. Depending on the steric factor of the hydrazine compound, it is presumed that the isomer is specifically produced as a by-product when the molecular structure substituted with hydrazine is small.
Patent Document 3 describes a synthesis example in which a 5-aminopyrazole derivative is derived from methylhydrazine and ethoxymethylidenemalononitrile. In Patent Document 3, the reaction not only lasts for less than 20 hours, but there is no description about the by-product of the isomer, but purification by recrystallization of the reaction mixture is necessary and the target product has not been quantitatively obtained. In order to aim at low-cost production, it is desired that the reaction is quantitative and there is no purification load. However, no technology has been found so far to suppress the by-product formation of the isomer and to advance the reaction quantitatively.
On the other hand, the synthesis of methylidene compounds such as ethoxymethylidenemalononitrile and ethoxymethyldene ethyl acetate is disclosed in Non-Patent Document 1. In any of the methods described, isolation of the target methylidene compound involves purification such as vacuum distillation and is not suitable for low-cost production. Moreover, although the catalyst aiming at the reaction rate improvement is made | formed, the remarkable effect is not acquired.
In the production of 5-aminopyrazole derivatives, in order to aim at further inexpensive synthesis, it is desired to quantitatively derive the methylidene compound as a raw material and subsequently produce 5-aminopyrazole. No technology has been found.

JP 2006-057076 A WO 06/082669 Pamphlet US Pat. No. 3,336,285 Reuben G. Jones, J.M. Am. Chem. Soc. , 74 4889 (1952).

  An object of the present invention is to provide a method for producing a 5-aminopyrazole derivative represented by the general formula (3) in a simple, high yield and high purity.

As a result of studying to overcome these conventional problems, it has been found that by using specific reaction conditions, the formation of secondary components can be suppressed and the target 5-aminopyrazole derivative can be isolated in high yield. That is, when producing the compound represented by the general formula (3), an excess of the compound represented by the general formula (1) is mixed with the compound represented by the general formula (2) at a low temperature. Thus, the generation of subcomponents was suppressed.
The above object of the present invention has been achieved by the following method.

[1]
The following general formula (1), wherein the molar ratio of the compound represented by the general formula (2) and the hydrazine derivative represented by the general formula (1) is 1: 1.10 to 1: 5.00. A method for producing a 5-aminopyrazole derivative represented by 3).

(Wherein R ¹ represents an aliphatic group, R ² represents an electron withdrawing group, R ³ represents a hydrogen atom or a substituent, and X represents a halogen atom, —OR or an amino group. R represents a hydrogen atom or a substituent.
[2]
In the said manufacturing method, water or alcoholic solvent or its mixed solvent is used as a reaction solvent, The manufacturing method as described in [1] characterized by the above-mentioned.
[3]
[1] The production method according to [1] or [2], wherein the production temperature is at least 20 ° C. or less in the production charge.
[4]
In the said manufacturing method, the process of following (A) and (B) is included, The manufacturing method in any one of [1]-[3] characterized by the above-mentioned.
(A) A step of reacting a compound represented by the following general formula (4) with a compound represented by the following general formula (5) to obtain a mixture containing the compound represented by the following general formula (2) (B) ) A step of producing a 5-aminopyrazole derivative represented by the general formula (3) by reacting a mixture containing the compound represented by the general formula (2) with the compound represented by the general formula (1).

(Wherein R ¹ represents an aliphatic group, R ² represents an electron withdrawing group, R ³ represents a hydrogen atom or a substituent, and X represents a halogen atom, —OR or an amino group. R represents a hydrogen atom or a substituent, and R ⁴ and R ⁵ each independently represents a leaving group.)
[5]
In the manufacturing method, the steps (A) and (B) are continuously performed. The manufacturing method according to [4], wherein
[6]
In the step (A), at least one selected from an acid anhydride or an acid having a pKa of -3 to 6 is used as a reaction accelerator in the process according to [4] or [5] Method.
[7]
In the step (A), the molar ratio of the compound represented by the general formula (5) to the reaction accelerator is used in the range of 1: 0.01 to 1: 5.00 [4] to [6] The production method according to any one of [6].

  According to the production method of the present invention, the 5-aminopyrazole derivative represented by the general formula (3) can be obtained simply and with high yield and high purity. Moreover, since it is also possible to perform the process of (B) with a water single solvent, it is a manufacturing method with a small load to an environment.

Hereinafter, implementation of the present invention will be described in detail.
First, some of the substituents used in this specification will be described. Examples of the substituent used in the present specification include the following groups (these groups are referred to as “substituent A”).
For example, halogen atom, alkyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group, cyano group, hydroxyl group, nitro group, carboxyl group, alkoxy group, aryloxy group, silyloxy group, heterocyclic oxy group, acyloxy group , Carbamoyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, amino group, acylamino group, aminocarbonylamino group, alkoxycarbonylamino group, aryloxycarbonylamino group, sulfamoylamino group, alkyl or arylsulfonylamino group Hydrazino group, mercapto group, alkylthio group, arylthio group, heterocyclic thio group, sulfamoyl group, sulfo group, alkyl or arylsulfinyl group, alkyl or arylsulfonyl group, acyl group, Lumpur oxycarbonyl group, an alkoxycarbonyl group, a carbamoyl group, an aryl or heterocyclic azo group, an imido group, a phosphino group, phosphinyl group, phosphinyloxy group, phosphinylamino group, a silyl group. These substituents may be further substituted, and examples of the further substituent include a group selected from the substituent group A described above.

  The aliphatic group used in this specification means an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, or a substituted alkynyl group. Moreover, the aromatic group used in this specification means an aryl group and a substituted aryl group.

  More specifically, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  Examples of the alkyl group include linear, branched, and cyclic substituted or unsubstituted alkyl groups, and also include cycloalkyl groups, bicycloalkyl groups, and tricyclo structures having many ring structures. An alkyl group (for example, an alkyl group of an alkoxy group or an alkylthio group) in a substituent described below also represents such an alkyl group. Specifically, the alkyl group is preferably an alkyl group having 1 to 30 carbon atoms, such as a methyl group, ethyl group, n-propyl group, isopropyl group, t-butyl group, n-octyl group, eicosyl group, A 2-chloroethyl group, a 2-cyanoethyl group, a 2-ethylhexyl group, and the like. The cycloalkyl group is preferably a substituted or unsubstituted cycloalkyl group having 3 to 30 carbon atoms, such as a cyclohexyl group or a cyclopentyl group. 4-n-dodecylcyclohexyl group and the like, and the bicycloalkyl group is preferably a substituted or unsubstituted bicycloalkyl group having 5 to 30 carbon atoms, that is, a bicyclic alkane having 5 to 30 carbon atoms to a hydrogen atom. A monovalent group such as a bicyclo [1,2,2] heptan-2-yl group, B [2,2,2] octan-3-yl group.

Examples of the alkenyl group include linear, branched, and cyclic substituted or unsubstituted alkenyl groups, and include cycloalkenyl groups and bicycloalkenyl groups. Specifically, the alkenyl group is preferably a substituted or unsubstituted alkenyl group having 2 to 30 carbon atoms, such as a vinyl group, an allyl group, a prenyl group, a geranyl group, an oleyl group, and the like. Is preferably a substituted or unsubstituted cycloalkenyl group having 3 to 30 carbon atoms, that is, a monovalent group obtained by removing one hydrogen atom of a cycloalkene having 3 to 30 carbon atoms, such as 2-cyclopentene-1 -Yl group, 2-cyclohexen-1-yl group and the like. As the bicycloalkenyl group, a substituted or unsubstituted bicycloalkenyl group, preferably a substituted or unsubstituted bicycloalkenyl group having 5 to 30 carbon atoms, That is, a monovalent group obtained by removing one hydrogen atom of a bicycloalkene having one double bond, for example, bicyclo [ , 2,1] hept-2-en-1-yl group, a bicyclo [2,2,2] oct-2-en-4-yl group and the like.
The alkynyl group is preferably a substituted or unsubstituted alkynyl group having 2 to 30 carbon atoms, such as an ethynyl group, a propargyl group, or a trimethylsilylethynyl group.

The aryl group is preferably a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, such as a phenyl group, a p-tolyl group, a naphthyl group, an m-chlorophenyl group, an o-hexadecanoylaminophenyl group, and the like. Can be mentioned.
The heterocyclic group is preferably a monovalent group obtained by removing one hydrogen atom from a 5- or 6-membered substituted or unsubstituted aromatic or non-aromatic heterocyclic compound, and more preferably a carbon number. It is a 3 to 30 5- or 6-membered aromatic heterocyclic group, and may be a monocyclic structure or a polycyclic structure in which two or more rings are condensed. Further, the heterocyclic group is preferably a heterocyclic group containing at least one of N, O, and S atoms. For example, thienyl, furyl, pyrrolyl, indolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, thiazolyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, oxazolyl, benzoxazolyl , Isoxazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, triazolyl group, pyridyl group, pyrazyl group, pyrimidyl Group, pyridazyl group, 1,3,5-triazyl group, quinolyl group, isoquinolyl group, phthalazinyl group and the like.
The alkoxy group is preferably a substituted or unsubstituted alkoxy group having 1 to 30 carbon atoms, such as a methoxy group, an ethoxy group, an isopropoxy group, a t-butoxy group, an n-octyloxy group, or a 2-methoxyethoxy group. Etc.

The aryloxy group is preferably a substituted or unsubstituted aryloxy group having 6 to 30 carbon atoms, such as a phenoxy group, 2-methylphenoxy group, 4-t-butylphenoxy group, 3-nitrophenoxy group, 2 -Tetradecanoylaminophenoxy group etc. are mentioned.
The silyloxy group is preferably a substituted or unsubstituted silyloxy group having 0 to 20 carbon atoms, such as a trimethylsilyloxy group or a diphenylmethylsilyloxy group.
Preferred examples of the heterocyclic oxy group include substituted or unsubstituted heterocyclic oxy groups having 2 to 30 carbon atoms, such as a 1-phenyltetrazole-5-oxy group and a 2-tetrahydropyranyloxy group.
The acyloxy group is preferably a formyloxy group, a substituted or unsubstituted alkylcarbonyloxy group having 2 to 30 carbon atoms, a substituted or unsubstituted arylcarbonyloxy group having 6 to 30 carbon atoms, such as an acetyloxy group, Examples include a pivaloyloxy group, a stearoyloxy group, a benzoyloxy group, and a p-methoxyphenylcarbonyloxy group.
The carbamoyloxy group is preferably a substituted or unsubstituted carbamoyloxy group having 1 to 30 carbon atoms, such as N, N-dimethylcarbamoyloxy group, N, N-diethylcarbamoyloxy group, morpholinocarbonyloxy group, N , N-di-n-octylaminocarbonyloxy group, Nn-octylcarbamoyloxy group and the like.

The alkoxycarbonyloxy group is preferably a substituted or unsubstituted alkoxycarbonyloxy group having 2 to 30 carbon atoms, such as a methoxycarbonyloxy group, an ethoxycarbonyloxy group, a t-butoxycarbonyloxy group, or an n-octylcarbonyloxy group. Etc.
The aryloxycarbonyloxy group is preferably a substituted or unsubstituted aryloxycarbonyloxy group having 7 to 30 carbon atoms, such as phenoxycarbonyloxy group, p-methoxyphenoxycarbonyloxy group, pn-hexadecyloxy. Examples include phenoxycarbonyloxy group.
The amino group includes an alkylamino group, an arylamino group, and a heterocyclic amino group, preferably an amino group, a substituted or unsubstituted alkylamino group having 1 to 30 carbon atoms, a substituted or unsubstituted group having 6 to 30 carbon atoms. Examples of the substituted anilino group include a methylamino group, a dimethylamino group, an anilino group, an N-methyl-anilino group, and a diphenylamino group.
The acylamino group is preferably a formylamino group, a substituted or unsubstituted alkylcarbonylamino group having 1 to 30 carbon atoms, a substituted or unsubstituted arylcarbonylamino group having 6 to 30 carbon atoms, such as an acetylamino group, Examples include pivaloylamino group, lauroylamino group, benzoylamino group, 3,4,5-tri-n-octyloxyphenylcarbonylamino group, and the like.

The aminocarbonylamino group is preferably a substituted or unsubstituted aminocarbonylamino group having 1 to 30 carbon atoms, such as a carbamoylamino group, an N, N-dimethylaminocarbonylamino group, or an N, N-diethylaminocarbonylamino group. And a morpholinocarbonylamino group.
The alkoxycarbonylamino group is preferably a substituted or unsubstituted alkoxycarbonylamino group having 2 to 30 carbon atoms, such as a methoxycarbonylamino group, an ethoxycarbonylamino group, a t-butoxycarbonylamino group, or an n-octadecyloxycarbonylamino group. Group, N-methyl-methoxycarbonylamino group and the like.
The aryloxycarbonylamino group is preferably a substituted or unsubstituted aryloxycarbonylamino group having 7 to 30 carbon atoms, such as phenoxycarbonylamino group, p-chlorophenoxycarbonylamino group, mn-octyloxyphenoxy. Examples thereof include a carbonylamino group.
The sulfamoylamino group is preferably a substituted or unsubstituted sulfamoylamino group having 0 to 30 carbon atoms, such as a sulfamoylamino group, N, N-dimethylaminosulfonylamino group, Nn- Examples include octylaminosulfonylamino group.

The alkyl or arylsulfonylamino group is preferably a substituted or unsubstituted alkylsulfonylamino group having 1 to 30 carbon atoms, a substituted or unsubstituted arylsulfonylamino group having 6 to 30 carbon atoms, such as a methylsulfonylamino group. Butylsulfonylamino group, phenylsulfonylamino group, 2,3,5-trichlorophenylsulfonylamino group, p-methylphenylsulfonylamino group, and the like.
The alkylthio group is preferably a substituted or unsubstituted alkylthio group having 1 to 30 carbon atoms, such as a methylthio group, an ethylthio group, and an n-hexadecylthio group.
Preferred examples of the arylthio group include substituted or unsubstituted arylthio groups having 6 to 30 carbon atoms such as a phenylthio group, a p-chlorophenylthio group, and an m-methoxyphenylthio group.
Preferred examples of the heterocyclic thio group include substituted or unsubstituted heterocyclic thio groups having 2 to 30 carbon atoms such as a 2-benzothiazolylthio group and a 1-phenyltetrazol-5-ylthio group.
The sulfamoyl group is preferably a substituted or unsubstituted sulfamoyl group having 0 to 30 carbon atoms, such as N-ethylsulfamoyl group, N- (3-dodecyloxypropyl) sulfamoyl group, N, N-dimethylsulfuryl group. Examples include a famoyl group, an N-acetylsulfamoyl group, an N-benzoylsulfamoyl group, and an N- (N′-phenylcarbamoyl) sulfamoyl group.

The alkyl or arylsulfinyl group is preferably a substituted or unsubstituted alkylsulfinyl group having 1 to 30 carbon atoms, a substituted or unsubstituted arylsulfinyl group having 6 to 30 carbon atoms, such as a methylsulfinyl group, an ethylsulfinyl group, phenyl. Examples thereof include a sulfinyl group and a p-methylphenylsulfinyl group.
The alkyl or arylsulfonyl group is preferably a substituted or unsubstituted alkylsulfonyl group having 1 to 30 carbon atoms, a substituted or unsubstituted arylsulfonyl group having 6 to 30 carbon atoms, such as a methylsulfonyl group, an ethylsulfonyl group, a phenyl group. A sulfonyl group, p-methylphenylsulfonyl group, etc. are mentioned.
The acyl group is preferably a formyl group, a substituted or unsubstituted alkylcarbonyl group having 2 to 30 carbon atoms, a substituted or unsubstituted arylcarbonyl group having 7 to 30 carbon atoms, a substituted or unsubstituted group having 2 to 30 carbon atoms. Heterocyclic carbonyl groups bonded to carbonyl groups at substituted carbon atoms, for example, acetyl, pivaloyl, 2-chloroacetyl, stearoyl, benzoyl, pn-octyloxyphenylcarbonyl, 2-pyridyl Examples thereof include a carbonyl group and a 2-furylcarbonyl group.
The aryloxycarbonyl group is preferably a substituted or unsubstituted aryloxycarbonyl group having 7 to 30 carbon atoms, such as phenoxycarbonyl group, o-chlorophenoxycarbonyl group, m-nitrophenoxycarbonyl group, pt- A butylphenoxycarbonyl group etc. are mentioned.

Preferred examples of the alkoxycarbonyl group include substituted or unsubstituted alkoxycarbonyl groups having 2 to 30 carbon atoms such as a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, and an n-octadecyloxycarbonyl group.
The carbamoyl group is preferably a substituted or unsubstituted carbamoyl group having 1 to 30 carbon atoms, such as a carbamoyl group, an N-methylcarbamoyl group, an N, N-dimethylcarbamoyl group, or an N, N-di-n-octyl group. Examples thereof include a carbamoyl group and an N- (methylsulfonyl) carbamoyl group.
The aryl or heterocyclic azo group is preferably a substituted or unsubstituted arylazo group having 6 to 30 carbon atoms, a substituted or unsubstituted heterocyclic azo group having 3 to 30 carbon atoms, such as phenylazo, p-chlorophenylazo, 5-ethylthio-1,3,4-thiadiazol-2-ylazo and the like.

Preferred examples of the imide group include an N-succinimide group and an N-phthalimide group.
Preferred examples of the phosphino group include substituted or unsubstituted phosphino groups having 0 to 30 carbon atoms, such as a dimethylphosphino group, a diphenylphosphino group, and a methylphenoxyphosphino group.
The phosphinyl group is preferably a substituted or unsubstituted phosphinyl group having 0 to 30 carbon atoms, such as a phosphinyl group, a dioctyloxyphosphinyl group, a diethoxyphosphinyl group, and the like.
Preferred examples of the phosphinyloxy group include substituted or unsubstituted phosphinyloxy groups having 0 to 30 carbon atoms such as a diphenoxyphosphinyloxy group and a dioctyloxyphosphinyloxy group.
The phosphinylamino group is preferably a substituted or unsubstituted phosphinylamino group having 0 to 30 carbon atoms, such as a dimethoxyphosphinylamino group or a dimethylaminophosphinylamino group.
The silyl group is preferably a substituted or unsubstituted silyl group having 0 to 30 carbon atoms, such as a trimethylsilyl group, a t-butyldimethylsilyl group, and a phenyldimethylsilyl group.

  Among the above substituents, those having a hydrogen atom may be substituted with the above substituent. Examples of such a substituent include an alkylcarbonylaminosulfonyl group, an arylcarbonylaminosulfonyl group, an alkylsulfonylaminocarbonyl group, and an arylsulfonylaminocarbonyl group. Examples thereof include a methylsulfonylaminocarbonyl group, a p-methylphenylsulfonylaminocarbonyl group, an acetylaminosulfonyl group, and a benzoylaminosulfonyl group.

The electron-withdrawing group in the present invention is a substituent having an electron-withdrawing property due to an electronic effect, and Hammett's substituent constant σp value, which is a measure of the electron-withdrawing property and electron-donating property of the substituent, is If used, it is a substituent having a large σp value. Examples thereof include a cyano group, a nitro group, a halogen atom, a sulfo group, a trifluoromethyl group, an alkoxycarbonyl group, and an acyl group.
Hammett's substituent constant σp value will be described briefly. Hammett's rule is an empirical rule proposed by LP Hammett in 1935 to quantitatively discuss the influence of substituents on the reaction or equilibrium of benzene derivatives, but this is widely accepted today. Substituent constants determined by Hammett's rule include σp value and σm value, and these values can be found in many general books. For example, JADean edition “Lange's Handbook of Chemistry” 12th edition 1979 (Mc Graw-Hill), “Chemical Fields”, Extra 122, 96-103, 1979 (Nankodo).

The production method of the present invention will be described.
The production method of the present invention is characterized in that the molar ratio of the compound represented by the general formula (2) and the hydrazine derivative represented by the general formula (1) is in the range of 1: 1.10 to 1: 5.00. And a method for producing a 5-aminopyrazole derivative represented by the following general formula (3).

(Wherein R ¹ represents an aliphatic group, R ² represents an electron withdrawing group, R ³ represents a hydrogen atom or a substituent, and X represents a halogen atom, —OR or NH. R represents a hydrogen atom or a substituent.

  Hereinafter, the compounds represented by the general formula (1), the general formula (2), and the general formula (3) will be described.

Hereinafter, the general formula (1) will be described.
R ¹ represents an aliphatic group and may further have a substituent.
Examples of the aliphatic group for R ¹ include the aliphatic groups described for the substituent A, and R ¹ is preferably an aliphatic group having 1 to 30 carbon atoms which may have a substituent. , R ¹ is particularly preferably an aliphatic group having 1 to 15 carbon atoms which may have a substituent. Among them, an unsubstituted aliphatic group is preferable, an alkyl group having 5 or less carbon atoms is more preferable, a methyl group, an isopropyl group, or a tert-butyl group is more preferable, and a methyl group or tert-Butyl group. In the case of these preferable groups, the raw material is inexpensive and excellent in availability, and the filterability is good in the production of 5-aminopyrazole.
When R ¹ has a substituent, examples of the substituent include the substituent A. Among the substituents A, excellent availability and filterability in production, from the viewpoint of productivity, an alkyl group having 1 to 15 carbon atoms, an aryl group having 1 to 15 carbon atoms, a halogen atom, a hydroxyl group, a cyano group, and 0 to carbon atoms. 15 amino groups, C1-C15 aminocarbonylamino groups, C1-C15 heterocyclic groups, C1-C15 acylamino groups, C1-C15 carbamoyl groups, C1-C15 A sulfamoylamino group, a sulfamoyl group having 0 to 15 carbon atoms, a sulfo group and a carboxyl group are preferable, and an alkyl group having 1 to 10 carbon atoms, a hydroxyl group, an amino group having 0 to 10 carbon atoms, and an alkyl group having 1 to 10 carbon atoms. Aminocarbonylamino group, C1-C10 heterocyclic group, C1-C10 acylamino group, C1-C10 carbamoyl group, C0-C10 sulfamoylamino , A sulfamoyl group having 0 to 10 carbon atoms, a sulfo group and a carboxyl group are more preferable, a hydroxyl group, an alkyl group having 1 to 5 carbon atoms, an amino group having 0 to 5 carbon atoms, a carbamoyl group having 0 to 5 carbon atoms, carbon Most preferred are a heterocyclic group having 1 to 5 carbon atoms, an acylamino group having 1 to 5 carbon atoms, a carbamoyl group having 1 to 5 carbon atoms, a sulfo group and a carboxyl group.
In summary, the general formula (1) used in the production method of the present invention is preferably a combination of the following (A) and (B).
(I) R ¹ represents an aliphatic group, more preferably a methyl group, an isopropyl group, or a tert-butyl group, and particularly preferably a methyl group or a tert-butyl group.
(B) When R ¹ has a substituent, the substituent is a hydroxyl group, an alkyl group having 1 to 5 carbon atoms, an amino group having 0 to 5 carbon atoms, a carbamoyl group having 0 to 5 carbon atoms, or 1 to 1 carbon atoms. Most preferred are 5 heterocyclic groups, acylamino groups having 1 to 5 carbon atoms, carbamoyl groups having 1 to 5 carbon atoms, sulfo groups and carboxyl groups.
As for the combination of R ^{1 of the} compound represented by the general formula (1) and the substituent that R ¹ can further have, a compound in which at least one of various substituents is the above-mentioned preferred group is preferable. Most preferred are compounds in which all substituents are the above preferred groups, and particularly preferred is when R ¹ is unsubstituted.

Next, general formula (2) will be described.
R ² represents an electron withdrawing group and may further have a substituent.
Examples of the electron withdrawing group in R ² include the electron withdrawing group described above, and preferably an electron withdrawing group having a σp value of 0.2 or more, such as a halogen atom, a nitro group, A cyano group, an alkyl or arylsulfonyl group, an acyl group, a carbamoyl group, a carboxyl group, a sulfamoyl group, a sulfo group, an alkoxycarbonyl group and an aryloxycarbonyl group, more preferably a cyano group, a carbamoyl group, a carboxyl group, a sulfamoyl group , A sulfo group, an alkoxysulfonyl group, an aryloxysulfonyl group, an alkoxycarbonyl group and an aryloxycarbonyl group, particularly preferably a cyano group, an alkoxysulfonyl group or an alkoxycarbonyl group. When R ² is an electron-withdrawing group, the raw material availability and reaction productivity are excellent, and the filterability during isolation of the 5-aminopyrazole derivative is excellent.
These groups may further have a substituent. As the further substituent, an alkyl group having 1 to 15 carbon atoms and an aryl group having 1 to 15 carbon atoms are preferable, an alkyl group having 1 to 10 carbon atoms and an aryl group having 1 to 10 carbon atoms are preferable, and the number of carbon atoms is 1 More preferred are an alkyl group of ˜5 and an aryl group of 1 to 5 carbon atoms.
R ³ represents a hydrogen atom or a substituent, and may further have a substituent. More preferably, R ³ is a hydrogen atom, a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an amino group, an alkylthio group, an arylthio group, a heterocyclic thio group, an alkyl or arylsulfinyl group, and an alkyl or arylsulfonyl group. More preferred are a hydrogen atom, a halogen atom, an alkyl group, an amino group, and an alkylthio group, and particularly preferred are a hydrogen atom, an alkyl group, and an alkylthio group. By selecting R ³ from these, it is possible to produce the 5-aminopyrazole derivative at low cost because of good productivity and filterability.
Examples of the substituent that R ³ can have include the substituent A. Among the substituents A, from the viewpoint of excellent availability of raw materials and filterability in the production of 5-aminopyrazole derivatives, from the viewpoint of productivity, an alkyl group having 1 to 15 carbon atoms, an aryl group having 1 to 15 carbon atoms, a halogen atom, Hydroxyl group, cyano group, amino group having 0 to 15 carbon atoms, aminocarbonylamino group having 1 to 15 carbon atoms, heterocyclic group having 1 to 15 carbon atoms, acylamino group having 1 to 15 carbon atoms, 1 to 15 carbon atoms Carbamoyl group, a sulfamoylamino group having 0 to 15 carbon atoms, a sulfamoyl group having 0 to 15 carbon atoms, a sulfo group and a carboxyl group are preferable, an alkyl group having 1 to 10 carbon atoms, a hydroxyl group, and 0 to 10 carbon atoms. An aminocarbonylamino group having 1 to 10 carbon atoms, a heterocyclic group having 1 to 10 carbon atoms, an acylamino group having 1 to 10 carbon atoms, and a carbamoyl having 1 to 10 carbon atoms. Group, a sulfamoylamino group having 0 to 10 carbon atoms, a sulfamoyl group having 0 to 10 carbon atoms, a sulfo group and a carboxyl group are more preferable, a hydroxyl group, an alkyl group having 1 to 5 carbon atoms, and a 0 to 5 carbon atom. Most preferred are an amino group, a carbamoyl group having 0 to 5 carbon atoms, a heterocyclic group having 1 to 5 carbon atoms, an acylamino group having 1 to 5 carbon atoms, a carbamoyl group having 1 to 5 carbon atoms, a sulfo group, and a carboxyl group.

X represents a halogen atom, —OR and an amino group, and R represents an aliphatic group, an aryl group and a heterocyclic group. These groups may have further substituents.
X more preferably represents a halogen atom, a hydroxyl group, an amino group, an alkoxy group or an aryloxy group, and these groups optionally further have a substituent. X is more preferably a halogen atom or an alkoxy group having 1 to 6 carbon atoms, and particularly preferably a methoxy group or an ethoxy group. When X represents these substituents, in order to derive the compound represented by the general formula (2), the availability of the raw material, the productivity in producing the compound represented by the general formula (2), It is excellent in non-crystallinity, and in producing the compound represented by the general formula (3), it has good productivity, excellent filterability, and suitability for production.
In summary, R ² , R ³ and X in the general formula (2) used in the production method of the present invention are preferably those composed of the following combinations (a) to (c).
(A) The electron withdrawing group represented by R ² is particularly preferably a cyano group, an alkoxysulfonyl group or an alkoxycarbonyl group.
(B) The hydrogen atom or substituent represented by R ³ is particularly preferably a hydrogen atom, an alkyl group or an alkylthio group.
(C) The halogen atom, —OR and amino group represented by X is particularly preferably a methoxy group or an ethoxy group.
As for the combination of R ² , R ³ and X of the compound represented by the general formula (2), a compound in which at least one of various R ² , R ³ and X is the above-mentioned preferred group is preferable, and more The compounds in which the various R ² , R ³ and X are the preferred groups are more preferred, and the compounds in which all R ² , R ³ and X are the preferred groups are most preferred.

  The compound represented by the general formula (2) is more preferably a compound represented by the general formula (2 ').

X and R ² have the general formula (2) have the same meanings as X and R ² in a preferred embodiment is also the same.
In summary, R ² and X in the general formula (2 ′) used in the production method of the present invention are preferably composed of the following combinations (a) and (b).
(A) The electron withdrawing group represented by R ² is particularly preferably a cyano group, an alkoxysulfonyl group or an alkoxycarbonyl group.
(B) The halogen atom, -OR and amino group represented by X is particularly preferably a methoxy group or an ethoxy group.
Note that the combination of R ^2, X in formula (2 ') and a compound represented by at least one of various R ^2, X is the above preferred group compounds are preferred, all R ^2, X Most preferred are compounds that are the preferred groups.
Furthermore, the compound represented by the general formula (2 ′) is more preferably a compound represented by the general formula (2 ″).

X is synonymous with X in the general formula (2), and preferred examples are also synonymous.
L represents -C (O)-and S (O) _2- . R ⁶ represents an aliphatic group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, a heterocyclic oxy group, or an amino group.

L represents -C (O)-and S (O) _2- . Preferably, -C (O)-.
R ⁶ represents an aliphatic group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, a heterocyclic oxy group, or an amino group. These groups may have further substituents. R ⁶ is preferably an alkoxy group, an aryloxy group and an amino group, more preferably an alkoxy group, and particularly preferably an alkoxy group having 1 to 5 carbon atoms.
By selecting the above, it is possible to procure an inexpensive raw material, and thus it is possible to manufacture at a low cost, and the productivity and filterability in manufacturing are improved.
In summary, X, L, and R ⁶ in the general formula (2 ″) used in the production method of the present invention are preferably composed of the following combinations (a) to (c).
(A) The halogen atom, -OR and amino group represented by X is particularly preferably a methoxy group or an ethoxy group.
(B) In —C (O) — and S (O) ₂ — represented by L, —C (O) — is more preferable.
(C) In the aliphatic group, aryl group, heterocyclic group, alkoxy group, aryloxy group, heterocyclic oxy group and amino group represented by R ⁶ , an alkoxy group having 1 to 5 carbon atoms is particularly preferred.
As for the combination of X, L and R ⁶ of the compound represented by the general formula (2 ″), a compound in which at least one of various X, L and R ⁶ is the above preferred group is preferable, and more More preferred are compounds in which the various X, L and R ⁶ are the above preferred groups, and most preferred are compounds in which all of X, L and R ⁶ are the above preferred groups.

  Although the following specific examples are given as a compound represented by General formula (2), this invention is not limited to these.

Hereinafter, the general formula (3) will be described.
R ^1, R ² and R ³ in the general formula (3) has the same meaning as R ^1, R ² and R ³ in the general formula (1) and general formula (2), also a preferred embodiment is also the same.
A plurality of compounds represented by the general formula (3) may be linked via R ¹ , R ² and R ³ . In this case, R ¹ , R ² and R ³ preferably represent a divalent organic group. The divalent organic groups represented by R ¹ , R ² and R ³ are oxy group —O—, thio group —S—, carbonyl group —CO—, sulfonyl group —SO ₂ —, imino group —NH—, and methylene group. It is preferably a group formed by —CH ₂ — and a combination thereof. More preferably, it is an oxy group —O—, a carbonyl group —CO—, a sulfonyl group —SO ₂ —, an imino group —NH—, or a methylene group —CH ₂ —, and more preferably an oxy group. It is a single or combination selected from —O—carbonyl group —CO—, imino group —NH—, and methylene group —CH ₂ —. If these divalent organic groups are selected, it is possible to produce inexpensive 5-aminopyrazole.
In summary, R ¹ , R ² and R ³ in the general formula (3) obtained by the production method of the present invention are preferably those composed of the following combinations (a) to (c).
(I) R ¹ represents an aliphatic group, more preferably a methyl group, an isopropyl group, or a tert-butyl group, and particularly preferably a methyl group or a tert-butyl group.
(B) The electron withdrawing group represented by R ² is particularly preferably a cyano group, an alkoxysulfonyl group or an alkoxycarbonyl group.
(C) The hydrogen atom or substituent represented by R ³ is particularly preferably a hydrogen atom, an alkyl group, or an alkylthio group.
As for the combination of R ¹ , R ² and R ³ of the compound represented by the general formula (3), a compound in which at least one of various R ¹ , R ² and R ³ is the above preferred group is preferable, More preferred are compounds in which a greater variety of R ¹ , R ² and R ³ are the above preferred groups, and most preferred are compounds in which all R ¹ , R ² and R ³ are the preferred groups.
The compound represented by the general formula (3) is more preferably a compound represented by the general formula (3 ′).

For R ¹ and R ² has the same meaning as R ^1, R ² described above, and preferred examples are also the same meanings.
In summary, R ¹ and R ² in the general formula (3 ′) obtained by the production method of the present invention are preferably composed of the following combinations (a) and (b).
(I) R ¹ represents an aliphatic group, more preferably a methyl group, an isopropyl group, or a tert-butyl group, and particularly preferably a methyl group or a tert-butyl group.
(B) The electron withdrawing group represented by R ² is particularly preferably a cyano group, an alkoxysulfonyl group or an alkoxycarbonyl group.
Note that the combination of R ¹ and R ² in the general formula (3 '), compounds represented by preferably various at least one preferred group is compounds of the R ¹ and R ^2, all the R ¹ and Most preferred are compounds wherein R ² is the preferred group.
Further, the compound represented by the general formula (3 ′) is preferably a compound represented by the general formula (3 ″).

For R ^1, R ⁶ and L, have the same meaning as above R ^1, R ⁶ and L, and preferred examples also have the same meanings.
In summary, R ¹ , R ⁶ and L in the general formula (3 ″) obtained by the production method of the present invention are preferably those composed of the following combinations (a) to (c).
(I) R ¹ represents an aliphatic group, more preferably a methyl group, an isopropyl group, or a tert-butyl group, and particularly preferably a methyl group or a tert-butyl group.
(B) In —C (O) — and S (O) ₂ — represented by L, —C (O) — is more preferable.
(C) In the aliphatic group, aryl group, heterocyclic group, alkoxy group, aryloxy group, heterocyclic oxy group and amino group represented by R ⁶ , an alkoxy group having 1 to 5 carbon atoms is particularly preferred.
As for the combination of R ¹ , R ⁶ and L of the compound represented by the general formula (3 ″), a compound in which at least one of various R ¹ , R ⁶ and L is the above preferred group is preferable, More preferred are compounds in which a greater variety of R ¹ , R ⁶ and L are the preferred groups, and most preferred are compounds in which all R ¹ , R ⁶ and L are the preferred groups.

  By selecting the general formula (3), more preferably the general formula (3 ′), and more preferably the general formula (3 ″), productivity at low cost and production, and filterability are improved. 5-aminopyrazole can be easily produced.

  Next, preferred examples of the general formula (3) are given as specific examples, but the present invention is not limited thereto.

  The compound of the present invention may exist as a tautomer depending on the type of substituent. Any tautomer in pure form, any mixture of tautomers is encompassed by the compounds of the present invention.

In the present invention, the compounds represented by the general formulas (1) to (5) may contain isotopes (eg, ² H, ³ H, ¹³ C, ¹⁵ N) in the structure. Good.

  The compounds used in the present invention include those accompanied with a counter salt by the synthesis process or isolation method. Any salt may be used, and examples thereof include halide ions, sulfate ions, nitrate ions, carbonate ions, sulfonate ions, phosphate ions, acetate ions, metal ions, and ammonium ions. Depending on the structure, an inner salt may be formed.

Hereinafter, the manufacturing method of the compound shown by General formula (3) is demonstrated.
In the present invention, the compound represented by the general formula (2) and the hydrazine derivative represented by the general formula (1) are used in a molar ratio of 1: 1.10 to 1: 5.00. Preferably it is the range of 1: 1.15 to 1: 4.00, More preferably, it is the range of 1: 1.20 to 1: 3.00.
By making the molar ratio of the compound represented by the general formula (2) and the hydrazine derivative represented by the general formula (1) within the above range, the formation of isomers can be suppressed, and the general formula (3) can be obtained in a high yield. The compound represented can be obtained and is preferable.
In the production method of the present invention, a reaction solvent is used, and the reaction solvent is preferably water or an alcoholic solvent or a mixed solvent of water or an alcoholic solvent.
As the alcoholic solvent, for example, an alkyl alcohol having 1 to 10 carbon atoms, an alkylene glycol having 2 to 10 carbon atoms and glycerin are preferable, and methanol, ethanol, i-propyl alcohol, ethylene glycol, propylene glycol, diethylene glycol and triethylene are more preferable. Ethylene glycol is mentioned. More preferred are methanol, ethanol and i-propyl alcohol. You may use water and these alcoholic solvents suitably as a mixed solvent in combination. By selecting these solvents, not only low-cost production is possible, but also the filterability when taking out 5-aminopyrazole as crystals is improved, and the chemical purity of 5-aminopyrazole is increased.
When using a mixed solvent of water or an alcoholic solvent, examples of the solvent to be mixed include hydrocarbon solvents, ether solvents, ester solvents, amide solvents, ketone solvents, nitrile solvents, and sulfoxide solvents. More preferably, it is C1-C10 hydrocarbon, C1-C10 ether, C1-C10 ester, C1-C10 amide, C1-C10 ketone, C1-C10. Nitriles and sulfoxide solvents having 1 to 10 carbon atoms, more preferably hydrocarbons having 1 to 10 carbon atoms and ethers having 1 to 10 carbon atoms. For example, n-pentane, n-hexane, n-heptane, toluene, and 2-ethylhexane are mentioned, More preferably, it is n-pentane, n-hexane, and toluene. By selecting these mixed solvents, 5-aminopyrazole can be obtained with high purity and high yield.
When a mixed solvent of water or an alcoholic solvent is used, the mixing ratio is not particularly limited, but is preferably in the range of 1:99 to 99: 1 by weight, and in the range of 1: 4 to 4: 1. More preferably. By selecting this condition, 5-aminopyrazole can be isolated as a crystal without loss.
In the case of a mixed solvent, either a uniform state or a non-uniform state in which layers are separated can be selected.

The amount of the mixed solvent used for the reaction is not particularly limited and can be appropriately selected depending on the type of the reaction system. Usually, the solvent is used in a mass ratio with respect to the hydrazine derivative of the general formula (1). About 0.5-100 times is appropriate respectively, 1-50 times are preferable, Most preferably, it is 1-20 times. By selecting this condition, productivity can be increased and inexpensive manufacturing becomes possible. It is also environmentally friendly because less waste solvent is used.
In the production method of the present invention, the reaction temperature is preferably 0 ° C to 100 ° C. More preferably, it is 0 degreeC-90 degreeC, More preferably, it is 4 degreeC-80 degreeC. By selecting this condition, decomposition of 5-aminopyrazole and by-product formation of isomers are suppressed, and the time required for heating can be shortened, so that low-cost production is possible.
The reaction time is preferably 20 minutes to 7 hours. More preferably, it is 30 minutes-6 hours, More preferably, it is 1 hour-5 hours. When this condition is selected, 5-aminopyrazole can be quantitatively obtained and an economical reaction time can be obtained, so that inexpensive production is possible.
In this step, the order of addition in the preparation of the compound represented by the general formula (2) and the hydrazine compound represented by the general formula (1) is arbitrary and is not particularly limited, but is preferably represented by the general formula (2) It is adding the compound represented and water or an alcoholic solvent, or the mixed solvent consisting thereof, and dripping the compound represented by General formula (1) in it.
The method for isolating the desired 5-aminopyrazole is not particularly limited. For example, the 5-aminopyrazole precipitated in the reaction is filtered, washed with the solvent described in the example of the reaction solvent and dried, or after the reaction is completed, the solvent described in the example of the reaction solvent is added and 5-aminopyrazole is added. Method of crystallizing, drying after isolation / washing, method of obtaining a residue after distilling off reaction solvent and excess raw material from reaction solution, and further extracting 5-aminopyrazole produced with solvent described in reaction solvent example Thereafter, a method of washing with water and drying the organic layer can be mentioned. More preferably, the method is a method in which the precipitated solid is filtered, but when the reaction proceeds quantitatively, a concentration method or a solvent extraction method is effective.
In summary, the production conditions for the compound represented by the general formula (1) are preferably those comprising a combination of (i) to (f).
(I) The molar ratio of the compound represented by the general formula (2) and the hydrazine derivative represented by the general formula (1) can be used in the range of 1: 1.10 to 1: 5.00, and particularly preferably 1: 1. .20 to 1: 3.00.
(B) The reaction solvent is water or an alcoholic solvent or a mixed solvent of water or an alcoholic solvent, and more preferably water or methanol, ethanol, i-propyl alcohol, ethylene glycol, propylene glycol, diethylene glycol and triethylene. A glycol alone or a mixed solvent of these with n-pentane, n-hexane and toluene.
(C) The mixing ratio of the mixed solvent (b) is in the range of 1: 4 to 4: 1 by weight.
(D) The solvent amount is preferably 1 to 20 times by mass ratio with respect to the hydrazine derivative of the general formula (1).
(E) The reaction temperature is particularly preferably 4 ° C to 80 ° C.
(F) The reaction time is particularly preferably 1 to 5 hours.
In addition, about the combination of the conditions in manufacture of the compound represented by General formula (1), manufacture in which at least 1 of various conditions is the said preferable conditions is preferable, and many more various conditions are the said preferable conditions. Some production is more preferred, and production with all of the above conditions being most preferred.

The manufacturing method preferably includes the following steps (A) and (B).
(A) A step of reacting a compound represented by the following general formula (4) with a compound represented by the following general formula (5) to obtain a mixture containing the compound represented by the following general formula (2) (B) ) A step of producing a 5-aminopyrazole derivative represented by the general formula (3) by reacting a mixture containing the compound represented by the general formula (2) with the compound represented by the general formula (1).

(In the formula, R ¹ represents an aliphatic group, R ² represents an electron withdrawing group, X represents a halogen atom, —OR or an amino group. R represents a hydrogen atom or a substituent, R ⁴ and R ⁵ each independently represent a leaving group.)

  Next, general formula (4) will be described.

  X in the general formula (4) has the same meaning as the description and preferred examples of X in the general formula (2).

R ⁴ and R ⁵ in the general formula (4) each independently represent a leaving group. That is, it represents a group that is easily eliminated by the reaction of general formula (4) and general formula (5).

The leaving group means that a new single covalent bond is formed by the nucleophilic reaction of the general formula (5) to the general formula (4), whereby the substituent of the general formula (4) is R ⁴ , R ⁵ and X It means that R ⁴ or R ⁵ is a substituent leaving from the carbon atom to be substituted. In general, these groups are called leaving groups. This R ⁴ or R ⁵ receives a proton and forms a stable nonion. As the reaction proceeds further, the previous covalent single bond is induced to a double bond, and either R ⁴ or R ⁵ remaining after the previous withdrawal is excluded from the molecule with protons in the molecule. In the above two types of reactions, the reaction does not proceed due to leaving group leaving ability, or it takes time to proceed. That is, the reactions of the general formula (4) and the general formula (5) are controlled by the leaving ability of the leaving groups R ⁴ and R ⁵ , and the reaction is more likely to proceed as the leaving is easier.

Preferable examples of R ⁴ and R ⁵ each independently represent a halogen atom, a hydroxyl group, an amino group, an alkoxy group, an aryloxy group, an alkylsulfonyloxy group or an arylsulfonyloxy group, more preferably 1 to 6 carbon atoms. An alkoxysulfonyl group, an alkylsulfonyloxy group having 1 to 6 carbon atoms, or an arylsulfonyloxy group having 6 to 12 carbon atoms, particularly preferably a methoxy group or an ethoxy group. Examples of the alkylsulfonyl or arylsulfonyl in the halogen atom, hydroxyl group, amino group, alkoxy group, aryloxy group, and alkylsulfonyloxy group or arylsulfonyloxy group include the preferred ones exemplified for the substituent A. .
In summary, R ⁴ and R ⁵ in the general formula (4) used in the production method of the present invention are preferably composed of the following combinations (a) and (b).
(A) The leaving group represented by R ⁴ is particularly preferably a methoxy group or an ethoxy group.
(B) The leaving group represented by R ⁵ is particularly preferably a methoxy group or an ethoxy group.
The combination of R ⁴ and R ⁵ of the compound represented by the general formula (4) is preferably a compound in which at least one of various R ⁴ and R ⁵ is the above-mentioned preferred group, and all R ⁴ and R 5 Most preferred are compounds wherein ⁵ is the preferred group.
The compound represented by the general formula (4) is more preferably a compound represented by the general formula (4 ′).

R ⁵ and X are as defined above for R ^5, X, and preferred examples are also the same meanings.
R ⁷ represents an aliphatic group, an aryl group, a heterocyclic group, an alkylsulfonyl group or an arylsulfonyl group, more preferably an aliphatic group, still more preferably an alkyl group, and particularly preferably an alkyl group having 1 to 10 carbon atoms. An alkyl group, most preferably an alkyl group having 2 to 5 carbon atoms. By selecting these groups, a high yield can be achieved and a low-cost production is possible when the compound represented by the general formula (2) is derived.
In summary, X, R ⁵ and R ⁷ in the general formula (4 ′) used in the production method of the present invention are preferably those composed of the following combinations (a) to (c).
(A) The halogen atom, -OR and amino group represented by X is particularly preferably a methoxy group or an ethoxy group.
(B) The leaving group represented by R ⁵ is particularly preferably a methoxy group or an ethoxy group.
(C) In the aliphatic group, aryl group, heterocyclic group, alkylsulfonyl group or arylsulfonyl group represented by R ⁷ , an alkyl group having 2 to 5 carbon atoms is particularly preferable.
The combination of X, R ⁵ and R ^{7 in} the compound represented by the general formula (4 ′) is preferably a compound in which at least one of various X, R ⁵ and R ⁷ is the above preferred group. More preferred are compounds in which many different X, R ⁵ and R ⁷ are the preferred groups, and most preferred are compounds in which all X, R ⁵ and R ⁷ are the preferred groups.
The compound represented by the general formula (4 ′) is more preferably a compound represented by the general formula (4 ″).

X is synonymous with X described above, and preferred examples are also synonymous.
R ⁷ and R ⁸ each independently represents an aliphatic group, an aryl group, a heterocyclic group, an alkylsulfonyl group or an arylsulfonyl group. An aliphatic group is more preferable, an alkyl group is more preferable, an alkyl group having 1 to 10 carbon atoms is particularly preferable, and an alkyl group having 2 to 5 carbon atoms is most preferable. By selecting these groups, a high yield can be achieved and a low-cost production is possible when the compound represented by the general formula (2) is derived.
In summary, X, R ⁷ and R ⁸ in the general formula (4 ″) used in the production method of the present invention are preferably those composed of the following combinations (a) to (c).
(A) The halogen atom, -OR and amino group represented by X is particularly preferably a methoxy group or an ethoxy group.
(B) In the aliphatic group, aryl group, heterocyclic group, alkylsulfonyl group or arylsulfonyl group represented by R ⁷ , an alkyl group having 2 to 5 carbon atoms is particularly preferable.
(C) In the aliphatic group, aryl group, heterocyclic group, alkylsulfonyl group or arylsulfonyl group represented by R ⁸ , an alkyl group having 2 to 5 carbon atoms is particularly preferable.
As for the combination of X, R ⁷ and R ⁸ of the compound represented by the general formula (4 ″), a compound in which at least one of various X, R ⁷ and R ⁸ is the above preferred group is preferable, More preferred are compounds in which a greater variety of X, R ⁷ and R ⁸ are the preferred groups, and most preferred are compounds in which all X, R ⁷ and R ⁸ are the preferred groups.

Although the following specific examples are given as a compound represented by General formula (4) below, this invention is not limited to these.

  Next, general formula (5) will be described.

R ² in the general formula (5) has the same meaning as the preferred examples and description of the R ² of the above general formulas (2) and (3).

  The compound represented by the general formula (5) is more preferably a compound represented by the general formula (5 ').

L and R ⁶ are synonymous with L and R ⁶ in the description of the general formula (2), and preferred examples are also synonymous.
That is, L and R ⁶ in the general formula (5 ′) used in the production method of the present invention are preferably those composed of the following combinations (a) and (b).
(I) In —C (O) — and S (O) ₂ — represented by L, —C (O) — is more preferable.
(B) In the aliphatic group, aryl group, heterocyclic group, alkoxy group, aryloxy group, heterocyclic oxy group and amino group represented by R ⁶ , an alkoxy group having 1 to 5 carbon atoms is particularly preferred.
The combination of X, L and R ⁶ of the compound represented by the general formula (5 ′) is preferably a compound in which at least one of various X, L and R ⁶ is the above preferred group. Most preferred are compounds wherein L and R ⁶ are the preferred groups described above.
The compound represented by the general formula (5 ′) is more preferably a compound represented by the general formula (5 ″).

R ⁶ has the same meaning as R ⁶ described in the general formula (2), and preferred examples are also the same.
Although the following specific examples are given as a compound represented by General formula (5), this invention is not limited to these.

Next, the reaction step (A) will be described.
The reaction step (A) is a mixture containing a compound represented by the following general formula (2) by reacting a compound represented by the following general formula (4) with a compound represented by the following general formula (5). Is a process of manufacturing.

The use ratio (molar ratio) of the compound represented by general formula (4) to the compound represented by general formula (5) in the reaction of general formula (4) and general formula (5) is preferably 1 to 3. More preferably, it is 1-2.5, More preferably, it is 1-2.0. By selecting this condition, the reaction can proceed quantitatively.
The solvent in the reaction of the general formula (4) and the general formula (5) is not particularly necessary, but can be used if it is inert to the reaction, for example, when stirring is required in the production. In that case, for example, an organic acid having 1 to 10 carbon atoms, water, a ketone having 1 to 10 carbon atoms, a nitrile having 1 to 10 carbon atoms, an alkyl alcohol having 1 to 10 carbon atoms, an alkylene glycol having 1 to 10 carbon atoms, C1-C10 ether, C1-C10 amide, C1-C10 sulfoxide, C1-C10 ester is mentioned. More preferably, an organic acid having 1 to 5 carbon atoms, water, a ketone having 1 to 5 carbon atoms, a nitrile having 1 to 5 carbon atoms, an alkyl alcohol having 1 to 5 carbon atoms, an alkylene glycol having 1 to 5 carbon atoms, carbon Examples thereof include ethers having 1 to 5 carbon atoms, amides having 1 to 5 carbon atoms, sulfoxides having 1 to 5 carbon atoms, and esters having 1 to 5 carbon atoms. Specifically, organic acids such as formic acid, acetic acid, propionic acid, water, acetone, methyl ethyl ketone, acetonitrile, propionitrile, butyronitrile, alcohol (for example, methanol, ethanol, isopropyl alcohol, etc.), ethyl acetate, butyl acetate, etc. Acetate, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), N, N-dimethylimidazolidinone (DMI), sulfolane, dimethyl sulfoxide ( DMSO) and hydrophilic organic solvents such as N-methylpyrrolidone (NMP). Moreover, it is also possible to mix and use these solvents. The solvent is preferably alcohol, organic acid, acetonitrile or acetone, and particularly preferably methanol, isopropanol, acetone, acetonitrile, acetic acid, DMF or DMAc. The amount of the solvent with respect to the general formula (5) is 100 times or less in mass ratio, more preferably 50 times or less, and further preferably 10 times or less. If it is 100 times or more, productivity is poor and uneconomical. By selecting these solvents and solvent amounts, 5-aminopyrazole can be produced with good productivity and good filterability at low cost.

The reactions of general formula (4) and general formula (5) can also be achieved without solvent (neat). In that case, a base may be accompanied. For example, organic bases and inorganic bases such as alkylamines having 1 to 10 carbon atoms, heterocyclic amines having 1 to 10 carbon atoms, and aromatic amines having 1 to 10 carbon atoms are preferable. More preferably, organic bases such as triethylamine, tributylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0] -7-undecene), lithium carbonate, sodium carbonate, potassium carbonate And inorganic bases such as sodium hydrogen carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide. Other examples of salts of organic acids and strong bases include lithium acetate, potassium acetate, sodium oxalate, and disodium ethylenediaminetetraacetate. Preferred is lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium acetate, sodium acetate, potassium acetate, triethylamine or pyridine, and more preferred is triethylamine, pyridine, lithium hydroxide, potassium hydroxide, lithium acetate, potassium acetate. It is.
By using these bases, the reaction can be accelerated, and the load on production can be reduced.

  The amount of the base relative to the general formula (5) is 0 to 5 times, more preferably 0 to 2 times, and still more preferably 0 to 1 time, in a molar ratio with respect to the general formula (5). .

In reaction temperature, 70 to 140 degreeC is preferable, 80 to 130 degreeC is more preferable, 85 to 120 degreeC is still more preferable. By selecting this temperature condition, the reaction is quantitative, the time can be shortened, the production load is small, and the decomposition of the raw material can be suppressed. When producing a mixture of the compound represented by the general formula (2) from the compound represented by the general formula (4) and the compound represented by the general formula (5), the subcomponents are distilled off at normal pressure. It is preferable. Further, it is preferable to flow or bubble the gas or distill off the auxiliary components under reduced pressure. As a gas used for flow or bubbling, nitrogen gas such as inert gas, argon gas, helium gas or air is preferably used, nitrogen gas or dry air is preferable, and nitrogen gas is preferably used.
Further, the timing for distilling off the subcomponent is not particularly limited, and it can be carried out during the reaction or after the reaction. More preferably, it is carried out during the reaction.
About the flow or bubbling at the time of distilling off said subcomponent, the gas flow rate is preferably 0.01 to 30 mL / min. More preferably, it is 0.1-30 mL / min, More preferably, it is 0.1-20 mL / min. By selecting these conditions, subcomponents can be distilled off economically and at high speed.

The reaction time is preferably 30 minutes to 12 hours, more preferably 1 hour to 11 hours, and further preferably 2 hours to 10 hours. If the reaction time is 30 minutes or longer, the reaction proceeds sufficiently, and if it is 10 hours or shorter, the target compound represented by the general formula (2) can be prevented from being decomposed.
In summary, the production conditions for the compound represented by the general formula (2) are preferably those comprising a combination of (i) to (h).
(A) The use ratio (molar ratio) of the compound represented by the general formula (4) to the compound represented by the general formula (5) in the reaction of the general formula (4) and the general formula (5) is preferably 1 to 1. 3, more preferably 1 to 2.5, and still more preferably 1 to 2.0.
(B) In the reactions of the general formulas (4) and (5), when a solvent is required, methanol, isopropanol, acetone, acetonitrile, acetic acid, DMF or DMAc is particularly preferable.
(C) When a solvent is required, the amount of solvent is 10 times or less with respect to General formula (5) by mass ratio.
(D) As the base which may be accompanied, triethylamine, pyridine, lithium hydroxide, potassium hydroxide, lithium acetate and potassium acetate are particularly preferable.
(E) The amount of the base is 0 to 1 times in terms of a molar ratio to the general formula (5).
(F) The reaction temperature is particularly preferably 85 ° C to 120 ° C.
(G) The reaction time is preferably 2 hours to 10 hours.
(H) The gas that can be used for the reaction is preferably nitrogen gas, and the flow rate is preferably 0.1 to 20 mL / min.
In addition, about the combination of the conditions in manufacture of the compound represented by General formula (1), the manufacture in which at least 1 of various conditions is the said preferable conditions is preferable, and more various conditions are the said preferable conditions. Some production is more preferred, and production with all of the above conditions being most preferred.

About the reaction process of (B), it is synonymous with the manufacturing conditions in the manufacturing method of General formula (3) mentioned above, and preferable conditions are also synonymous.
In the reaction step (B), the compound represented by the general formula (2) is changed to a mixture containing the compound represented by the general formula (2) obtained in the reaction step (A). ) Can be produced.
In the manufacturing method, it is preferable to further perform the steps (A) and (B).
That is, it is preferable to use the mixture of the compound represented by the general formula (2) obtained in the reaction step (A) as it is for the production of the 5-aminopyrazole derivative represented by the general formula (3). This case will be described in detail.
By continuously performing the steps (A) and (B), the precipitation of the compound represented by the compound (2) can be suppressed in the step (A), and the use of an unnecessary solvent can be avoided. Thus, it can be used as it is in the step (b). Furthermore, since it is not necessary to remove from the reaction kettle, there is no loss of the compound represented by the general formula (2) in the step (A), and the low cost production of the compound represented by the general formula (3) becomes possible. .

In the reaction step (B) in the production method of the present invention, the reaction mixture of the compound represented by the general formula (2) and the addition amount of the compound represented by the general formula (1) are included in the reaction mixture. The amount of the compound represented by the general formula (2) and the compound represented by the general formula (1) are preferably used in a molar ratio of 1: 1.10 to 1: 5.00, more preferably The range is from 1: 1.15 to 1: 4.00, particularly preferably from 1: 1.20 to 1: 3.00. By making the molar ratio of the reaction mixture of the compound represented by the general formula (2) and the hydrazine derivative represented by the general formula (1) within the above range, the formation of isomers can be suppressed and the general formula ( The compound represented by 3) can be obtained and is preferable.
The reaction temperature is not particularly limited and can be appropriately selected according to the type of reaction system and the concentration of the compound of the reaction species, but in the case of step (A), 0 ° C. to 100 ° C. is preferable. More preferably, it is 0 degreeC-90 degreeC, More preferably, it is 4 degreeC-80 degreeC. By selecting this condition, decomposition of 5-aminopyrazole and by-product formation of isomers are suppressed, and the time required for heating can be shortened, so that low-cost production is possible. In the case of (B) process, 70 to 140 degreeC is preferable, 80 to 130 degreeC is more preferable, and 85 to 120 degreeC is still more preferable. By selecting this temperature condition, the reaction is quantitative, the time can be shortened, the production load is small, and the decomposition of the raw material can be suppressed.

  In the case of the step (A), the reaction time is preferably 30 minutes to 12 hours, more preferably 1 hour to 11 hours, and further preferably 2 hours to 10 hours. If the reaction time is 30 minutes or longer, the reaction proceeds sufficiently, and if it is 12 hours or shorter, the target compound represented by the general formula (2) can be prevented from being decomposed. In the case of step (B), the reaction time is preferably 20 minutes to 7 hours. More preferably, it is 30 minutes-6 hours, More preferably, it is 1 hour-5 hours. When this condition is selected, 5-aminopyrazole can be quantitatively obtained and an economical reaction time can be obtained, so that inexpensive production is possible.

  In this step, the reaction mixture containing the compound represented by the general formula (2) by the reaction of the compound represented by the general formula (4) and the compound represented by the general formula (5) and the general formula (1) The order of addition in the preparation of the hydrazine compound to be prepared is arbitrary and is not particularly limited. Preferably, water or an alcoholic solvent or a mixed solvent thereof is added after completion of the step (A), and the general formula (1) ) Is added dropwise.

  The method for isolating the desired 5-aminopyrazole is not particularly limited. For example, the 5-aminopyrazole precipitated in the reaction is filtered, washed with the solvent described in the example of the reaction solvent and dried, or after the reaction is completed, the solvent described in the example of the reaction solvent is added and 5-aminopyrazole is added. Method of crystallizing, drying after isolation / washing, method of obtaining a residue after distilling off reaction solvent and excess raw material from reaction solution, and further extracting 5-aminopyrazole produced with solvent described in reaction solvent example Thereafter, a method of washing with water and drying the organic phase can be mentioned. More preferably, the method is a method in which the precipitated solid is filtered, but when the reaction proceeds quantitatively, a concentration method or a solvent extraction method is effective.

In the step (A), it is preferable to use at least one selected from an acid anhydride or an acid having a pKa of −3 to 6 as a reaction accelerator. By adding this reaction accelerator, it becomes possible to accelerate the reaction, shorten the production time, and produce 5-aminopyrazole at low cost.
As the acid anhydride, an acid anhydride having 2 to 10 carbon atoms is preferable. More preferably, an acid anhydride having 4 to 8 carbon atoms is preferred. For example, acetic anhydride, succinic anhydride, maleic anhydride, propionic anhydride, phthalic anhydride, pyrosulfuric acid, dinitrogen pentoxide, pyrophosphoric acid (diphosphoric acid), diphosphorus pentoxide (phosphorus tetraoxide) and trioxide Examples include acetic anhydride, succinic anhydride, propionic anhydride and pyrosulfuric acid, and more preferred are acetic anhydride, succinic anhydride and propionic anhydride.
The acid having a pKa of -3 to 6 is not particularly limited as long as it is in this range, but inorganic acids (also called mineral acids) and organic acids can be used. Examples of inorganic acids include hydrochloric acid, phosphoric acid, and sulfuric acid. Examples of organic acids include formic acid, acetic acid, propionic acid, methanesulfonic acid, oxalic acid, citric acid, chloroacetic acid, and trifluoroacetic acid, preferably acetic acid, propion. Acid and methanesulfonic acid are preferable, and acetic acid and methanesulfonic acid are more preferable. These acids may be used alone or in combination.
As the reaction accelerator in the present invention, acetic anhydride or acetic acid, or a combination of acetic anhydride and acetic acid is particularly preferable.

In the step (A), the molar ratio of the compound represented by the general formula (5) to the total reaction accelerator is preferably used in the range of 1: 0.50 to 1: 5.00.
Preferably it is 1: 1.00-1: 4.00, More preferably, it is 1: 1.20-1: 3.00. An amount of reaction accelerator in this range makes it possible to produce 5-aminopyrazole more economically.

The following may be considered as the reaction mechanism. The present inventors presume that the details of the reaction are as follows.
Scheme 1 represents a reaction mechanism by which the compound represented by the general formula (3) is derived. In the compound represented by the general formula (1), the nitrogen atom to which R ¹ is bonded nucleophilicly attacks the nitrile carbon atom, and then one nitrous atom attacks the carbon atom to which X is bonded. It is derived to a compound represented by the formula (1).
Scheme 2 represents a reaction mechanism in which an isomer of the compound represented by the general formula (1) as a subcomponent is generated. In the compound represented by the general formula (1), the nitrogen atom to which R ¹ is bonded is nucleophilic attacked to the carbon atom to which X is bonded, and one nitrogen atom terminal is nucleophilicly attacked to the nitrile carbon atom. An isomer of the compound represented by the formula (3) is formed.
The reaction proceeds in Scheme 3 under the condition where the compound represented by the general formula (1) is excessive. That is, after the addition of the first compound represented by the general formula (1) to form the intermediate 1, an excess of the second hydrazine attacked, and the first general formula (1) added The compound represented is derived into the compound represented by the general formula (3) while being eliminated.
From the above, when the compound represented by the general formula (1) is in a molar excess with respect to the compound represented by the general formula (2), an isomer of the compound represented by the general formula (3) is formed. It is considered that the desired compound represented by the general formula (3) can be quantitatively generated.
In addition, the following scheme does not limit the content of this invention at all, The manufacturing method of the compound represented by General formula (3) by another reaction route is also contained in this invention.

  Next, the present invention will be described in more detail with reference to examples.

  The synthesis scheme of the 5-aminopyrazole derivative (Exemplary Compound D-13) represented by the general formula (3) is shown below.

<Example 1: Production method of exemplary compound (D-13)>
(1) Synthesis of Compound A In a 2 L three-necked flask equipped with Dean Stark, trimethyl orthoformate 770.0 g (7.11 mol), methyl cyanoacetate 355.8 g (3.56 mol), and zinc chloride 48.52 g ( 0.36 mol) was mixed and stirred at an internal temperature of 90 ° C. After 30 minutes, the fraction was distilled off over 6 hours. A liquid residue was produced by column chromatography (developing solvent: hexane / ethyl acetate 1/1 v / v), and 256 g of Compound A was isolated. Yield 51.1%.
¹ H-NMR (400 MHz, d6-DMSO) 8.3 ppm (s, 1H), 4.1 ppm (s, 3H), 3.7 ppm (s, 3H)

(2) Synthesis of Exemplary Compound (D-13) 30 mL of ion-exchanged water was cooled to about 5 ° C., and 4.47 g (0.10 mol) of methyl hydrazine was added dropwise thereto. Subsequently, the mixture was stirred at an internal temperature of 65 ° C., and 10.0 g (0.07 mol) of Compound A was added thereto over 30 minutes. When this reaction mixture was analyzed by HPLC, it was found that it contained 0.2% of an auxiliary component that is considered to be an isomer of Exemplary Compound D-13. After the addition, the mixture was stirred for 30 minutes and cooled to room temperature. To this reaction mixture was added 5 g of sodium chloride. 150 mL of ethyl acetate was added and infiltrated, and the extraction operation was performed three times. The ethyl acetate phase was dried with mirabilite and then concentrated with an evaporator. The residue was recrystallized using ethyl acetate to obtain 6.6 g of white exemplified compound D-13. Yield 60.0%.

<Examples 2 to 4 and Comparative Examples 1 to 3: Production Method of Exemplary Compound (D-13)>
Subsequently, the compound was synthesized according to the reaction conditions of the exemplified compound D-13 except that the molar ratio of methylhydrazine to compound A was changed to the value shown in Table 1.

  <Synthesis Example 1: Production method of exemplary compound (M-18)>

50.0 g (0.34 mol) of triethyl orthoformate, 16.72 g (0.17 mol) of methyl cyanoacetate and 34.44 g (0.34 mol) of acetic anhydride were mixed and stirred at an internal temperature of 105 ° C. After stirring for 6 hours, the mixture was cooled to room temperature to synthesize Exemplified Compound M-18. When the production rate of M-18 was monitored by ¹ H-NMR, it was 92%. At this time, the remaining amount of the raw material methyl cyanoacetate (N-2) was 8%.

<Synthesis Examples 1 to 17: Production Method of Exemplary Compound (M-18)>
Subsequently, the molar ratio of triethyl orthoformate (O-3), acetic anhydride and acetic acid to methyl cyanoacetate (N-2) was mixed so as to have the values shown in Table 2, and the reaction was conducted under the conditions of Synthesis Example 1 above. Carried out.

<Example 5: Two-step integrated production method of exemplary compound (D-13)>
Example Compound D-13 was synthesized as it was using M-18 synthesized in Synthesis Example 3 in Table 2.
7.7 mL of methanol was added to 2.77 g (corresponding to 17.9 mmol) of the M-18 reaction mixture, and the mixture was cooled to 4 ° C. in an ice bath. Subsequently, 1.0 mL (25.0 mmol) of methyl hydrazine was added dropwise. After stirring at 4 ° C. for 1 hour, the temperature was raised to 50 ° C., and the mixture was stirred at that temperature for 2 hours. At this time, when the production rate (HPLC area%) of exemplary compound (D-13) was measured with HPLC (LC-10A made by Shimadzu Corporation) of the reaction solution, it was 93.9%. The isomer was 0.2%. Then, it cooled to room temperature and concentrated and dried by the rotary evaporator. The isolation yield was 101% and the purity was 94.0%.

<Examples 6 to 12, Comparative Examples 4 and 5: Integrated Production Method of Illustrative Compound D-13>
The reaction was performed in the same manner as in Example 5 except that the reaction conditions in Example 5 were changed as shown in Table 3. If the isolation method in the table is extraction, add 30 mL of ethyl acetate and 5 mL of water, shake well, separate the ethyl acetate layer, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Released. Crystallization was performed by adding 30 mL of hexane, filtering the precipitated crystals, washing with 20 mL of a mixed solvent of IPA / hexane 1/4, and drying. For the filtration operation, the solid deposited after the reaction was filtered off, washed with 20 mL of a mixed solvent of IPA / hexane 1/4 and dried.

  As mentioned above, when obtaining exemplary compound (D-13) of this invention, the quantity of the hydrazine compound represented by General formula (1) is molar ratio with respect to the compound represented by General formula (2). It has been found that when 1.10 or more is used, the by-product of the isomer of Exemplary Compound D-13 can be suppressed, and the yield is improved. Furthermore, the compound represented by the general formula (2) is produced by the reaction of the general formula (4) and the general formula (5), and the compound represented by the general formula (2) is used as it is without being isolated. It was found that the yield was improved.

Claims (7)

The molar ratio of the compound represented by the general formula (2) and the hydrazine derivative represented by the general formula (1) is used in the range of 1: 1.10 to 1: 5.00. A method for producing a 5-aminopyrazole derivative represented by 3).

(Wherein R ¹ represents an aliphatic group, R ² represents an electron withdrawing group, R ³ represents a hydrogen atom or a substituent, and X represents a halogen atom, —OR or an amino group. R represents a hydrogen atom or a substituent.   In the said manufacturing method, water or alcoholic solvent or its mixed solvent is used as a reaction solvent, The manufacturing method of Claim 1 characterized by the above-mentioned.   The manufacturing method according to claim 1, wherein at least a temperature in preparation for manufacturing is 20 ° C. or less. The manufacturing method according to claim 1, wherein the manufacturing method includes the following steps (A) and (B).
(A) A step of obtaining a mixture containing a compound represented by the following general formula (2) by reacting a compound represented by the following general formula (4) with a compound represented by the following general formula (5) (B ) A step of producing a 5-aminopyrazole derivative represented by the general formula (3) by reacting a mixture containing the compound represented by the general formula (2) with the compound represented by the general formula (1).

(Wherein R ¹ represents an aliphatic group, R ² represents an electron withdrawing group, R ³ represents a hydrogen atom or a substituent, and X represents a halogen atom, —OR or an amino group. R represents a hydrogen atom or a substituent, and R ⁴ and R ⁵ each independently represents a leaving group.)   5. The manufacturing method according to claim 4, wherein the steps (A) and (B) are continuously performed in the manufacturing method.   6. The process according to claim 4 or 5, wherein in the step (A), at least one selected from an acid anhydride or an acid having a pKa of -3 to 6 is used as a reaction accelerator.   In the step (A), the molar ratio of the compound represented by the general formula (5) to the reaction accelerator is used in the range of 1: 0.01 to 1: 5.00. 6. The production method according to any one of 6 above.