JP7742175B2 - Method for producing pyrazole compounds - Google Patents

Description

The present invention relates to a novel method for producing pyrazole compounds.

The following general formula (I)

(wherein Ar ¹ and Ar ² may be the same or different and represent a homocyclic or heterocyclic group which may have a substituent).
The compound represented by the formula (I) has tau aggregation inhibitory activity, β-secretase inhibitory activity, and Aβ aggregation inhibitory activity, and is known to be useful as a therapeutic agent for Alzheimer's disease (Patent Document 1).
The pyrazole compound (I) is described in the above Patent Document 1 as a compound represented by the following general formula (C):

(wherein Ar ¹ and Ar ² are the same as above)
It is described that the compound can be produced by reacting a diketone compound represented by the following formula with hydrazine or hydrazine hydrate.

JP 2012-229208 A

In the method described in Patent Document 1, hydrazine or hydrazine hydrate used as a raw material is highly flammable and toxic enough to be used as rocket fuel, making the method described in Patent Document 1 unsuitable for mass production. Furthermore, reactions using hydrazine cause side reactions and increase impurities. Furthermore, pyrazole compound (I) has poor solubility, making purification such as recrystallization or column purification difficult, making it difficult to obtain high-quality pyrazole compound (I) in large quantities.
Therefore, an object of the present invention is to provide a method for producing a pyrazole compound of high quality at a pharmaceutical level suitable for mass production.

Therefore, the present inventors have been studying methods for producing pyrazole compounds suitable for mass production and have unexpectedly found that by using carbazic acid esters instead of hydrazine, pyrazole compounds of high quality at pharmaceutical levels with fewer impurities can be produced under safe reaction conditions and in high yields, thereby completing the present invention.
That is, the present invention provides the following inventions [1] and [10].
[1] The following general formula (1)

(In the formula, ^R1 represents an aromatic group which may have a substituent, and ^R2 represents an aromatic group which may have a substituent, an aromatic group-alkyl group which may have a substituent, or an aromatic group-alkenyl group which may have a substituent. Hereinafter, these symbols have the same meaning.)
or a salt thereof with a carbazate ester,

(wherein R ¹ and R ² have the same meanings as defined above) or a salt thereof.
[2] The method according to [1], wherein the diketone compound of the general formula (1) or a salt thereof is reacted with a carbazate ester, and then a base is reacted therewith.
[3] The production method according to [1] or [2], wherein R ¹ is a mono-, tri-cyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, or a 5- to 10-membered mono-, tri-cyclic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the group is optionally substituted with 1 to 3 groups selected from an alkyl group, an alkoxy group, a halogen atom, a nitro group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, an acyl group, a hydroxyl group, an aromatic hydrocarbon group-alkyl group, a non-aromatic hydrocarbon ring group-alkyl group, an aromatic heterocyclic group-alkyl group, an aromatic heterocyclic group-alkoxy group, an aromatic hydrocarbon group-alkoxy group, a non-aromatic hydrocarbon ring group-alkoxy group, and a non-aromatic heterocyclic group-alkoxy group.
[4] The method according to [3], wherein R ¹ is a monocyclic, monocyclic, tricyclic, aromatic hydrocarbon group having 6 to 14 carbon atoms.

[5] The method according to [3], wherein R ¹ is a 5- to 10-membered, 1- to 3-cyclic aromatic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
[6] R ² is a monocyclic to tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, a monocyclic to tricyclic aromatic hydrocarbon-alkyl group having 6 to 14 carbon atoms, a monocyclic to tricyclic aromatic hydrocarbon-alkenyl group having 6 to 14 carbon atoms, a monocyclic to tricyclic 5-10-membered heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, a monocyclic to tricyclic 5-10-membered heterocyclic group-alkyl group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, or a monocyclic to tricyclic 5-10-membered heterocyclic group-alkenyl group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the group may include an alkyl group, an alkenyl group, an alkyl ... The method according to any one of [1] to [5], wherein the aryl group is optionally substituted with 1 to 3 groups selected from an alkoxyl group, a halogen atom, a nitro group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, an acyl group, a hydroxyl group, an aromatic hydrocarbon group-alkyl group, a non-aromatic hydrocarbon ring group-alkyl group, an aromatic heterocyclic group-alkyl group, a non-aromatic heterocyclic group-alkyl group, an aromatic heterocyclic group-alkoxyl group, an aromatic hydrocarbon group-alkoxyl group, a non-aromatic hydrocarbon ring group-alkoxyl group, and a non-aromatic heterocyclic group-alkoxyl group.
[7] The method according to [6], wherein R ² is a monocyclic, monocyclic, tricyclic, aromatic hydrocarbon group having 6 to 14 carbon atoms.
[8] The method according to [6], wherein R ² is a monocyclic, monocyclic, tricyclic, aromatic hydrocarbon-alkenyl group having 6 to 14 carbon atoms.
[9] The method according to [6], wherein R ² is a 5- to 10-membered, mono- to tri-cyclic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
[10] The method according to [6], wherein R ² is a heterocyclic group-alkenyl group having one to three rings and five to ten members and having one to three heteroatoms selected from nitrogen, oxygen, and sulfur.

The method of the present invention enables the mass production of high-quality pyrazole compounds or their salts, which are useful as therapeutic agents for Alzheimer's disease, under safe reaction conditions and with high yields.

The present invention relates to a method for producing a pyrazole compound represented by general formula (2) or a salt thereof, which comprises reacting a diketone compound represented by general formula (1) or a salt thereof with a carbazate ester, and is represented by the following reaction formula:

(wherein ^R3 represents a hydrocarbon group which may have a substituent)

The present invention will be described in detail below.
As used herein, the following terms have the meanings indicated below unless otherwise specified. The definitions below are intended to clarify, but not limit, the defined terms. If a term is not specifically defined herein, it is used in the sense that it would be commonly understood by one of ordinary skill in the art.
Examples of alkyl groups include linear or branched alkyl groups. Specific examples include linear or branched alkyl groups having 1 to 10 carbon atoms (C1 to C10), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 3-ethylpentyl, 4-ethylhexyl, 4-ethylheptyl, n-hexyl, isohexyl, isoheptyl, isooctyl, hexan-2-yl, 4-methylpentan-2-yl, 2,2-dimethylpropyl, 3,3-dimethylpentyl, and 3,3-dimethylbutyl. One embodiment includes a linear or branched alkyl group having 1 to 6 carbon atoms. Another embodiment includes a linear or branched alkyl group having 1 to 4 carbon atoms. Another embodiment includes a methyl, ethyl, n-propyl, or isopropyl group. In one embodiment, it is a methyl group or an ethyl group.
Examples of alkenyl groups include linear or branched alkenyl groups. Specifically, they are linear or branched alkenyl groups having 2 to 10 carbon atoms (C2 to C10), and the alkenyl group may have either a cis configuration or a trans configuration (Z configuration or E configuration) centered on a double bond. More specific examples include ethenyl (vinyl) groups, propenyl groups (e.g., prop-1-en-1-yl, prop-1-en-2-yl, and prop-2-en-1-yl (allyl) groups), and butenyl groups (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, and buta-1,3-dien-2-yl groups). In one embodiment, it is a C2-6 linear or branched alkenyl group. In one embodiment, it is a C2-C4 linear or branched alkenyl group. In one embodiment, it is an ethenyl group, a propenyl group, or a butenyl group.

Examples of alkylene groups include straight-chain or branched-chain alkylene groups having 1 to 10 carbon atoms (C1 to C10). Specific examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, methylmethylene, propylene, 2-methyltrimethylene, ethylethylene, 1,2-dimethylethylene, and 1,1,2,2-tetramethylethylene. One embodiment is a C1 to C6 straight-chain or branched-chain alkylene group. Another embodiment is a C1 to C4 straight-chain or branched-chain alkylene group. Another embodiment is a methylene, ethylene, trimethylene, tetramethylene, or 2-methyltrimethylene group. Another embodiment is a methylene, ethylene, or trimethylene group.
Furthermore, examples of the alkenylene group include straight-chain or branched-chain alkenylene groups having 2 to 10 carbon atoms (C2 to C10). Specific examples include vinylene groups, propenylene groups, butenylene groups, pentenylene groups, hexenylene groups, 1,3-butadienylene groups, and 1,3-pentadienylene groups. One embodiment is a C2 to C4 straight-chain or branched-chain alkenylene group. One embodiment is a vinylene group.
Examples of alkoxyl groups include groups in which an oxygen atom is bonded to the alkyl mentioned above (alkyl-O—), and specific examples include straight-chain or branched-chain alkyl-O—, such as straight-chain or branched-chain alkyl-O— having 1 to 10 carbon atoms (C1 to C10). In one embodiment, it is straight-chain or branched-chain alkyl-O— having C1 to C6. In one embodiment, it is straight-chain or branched-chain alkyl-O— having C1 to C4. In one embodiment, it is a methoxy group, an ethoxy group, an n-propyloxy group, or an isopropyloxy group. In one embodiment, it is a methoxy group or an ethoxy group.
Monoalkylamino is an amino group substituted with one of the above alkyl groups, and specific examples include mono-C1-C6 alkylamino groups. In certain embodiments, this is a methylamino group, an ethylamino group, etc. Dialkylamino is an amino group substituted with two of the above alkyl groups. Specifically, it is a di(C1-C6 alkyl)amino group. In certain embodiments, this is a dimethylamino group, a diethylamino group, etc.
Aromatic groups include aromatic hydrocarbon groups (also referred to herein as aryl) and aromatic heterocyclic groups (also referred to herein as heteroaryl).
Examples of aromatic hydrocarbon groups include mono-, tri-cyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms, and specific examples include a phenyl group, an indenyl group, a naphthyl group, a fluorenyl group, and an anthracenyl group. In one embodiment, the aromatic hydrocarbon group is a mono- or bicyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. In one embodiment, the aromatic hydrocarbon group is a phenyl group or a naphthyl group. In one embodiment, the aromatic hydrocarbon group is a phenyl group.
Examples of aromatic heterocyclic groups include 5- to 10-membered, mono- to tri-cyclic heterocyclic groups having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. An example of an aromatic heterocyclic group is a 5- or 6-membered aromatic heterocyclic group having 1 to 3 nitrogen atoms. Specific examples include a pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, furyl group, thienyl group, oxazolyl group, indolyl group, isoindolyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, and dibenzofuranyl group. Examples of the heterocyclic group include a pyridyl group, an indolyl group, and a dibenzofuranyl group.
Non-aromatic hydrocarbon ring groups include saturated hydrocarbon ring groups and unsaturated hydrocarbon ring groups.

Examples of saturated hydrocarbon ring groups include monocyclic, tricyclic, and tricyclic hydrocarbon groups having 3 to 14 carbon atoms (C3 to C14). Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl groups. In one embodiment, the group is a C3 to C6 cycloalkyl group, and in another embodiment, the group is cyclopropyl or cyclobutyl.
The unsaturated hydrocarbon ring group is a hydrocarbon ring group having 4 to 7 carbon atoms (C4 to C7) and having one or more unsaturated bonds, which may have a bridge or form a spiro ring, such as cyclobutanyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl.
The non-aromatic heterocyclic group is a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen as ring-constituting atoms. One embodiment is a 5- to 6-membered saturated or unsaturated non-aromatic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. One embodiment is a 5- to 6-membered, mono- to tricyclic, saturated or unsaturated non-aromatic heterocyclic group having 1 to 3 nitrogen or oxygen atoms.
Specific examples include azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, dioxanyl, tetrahydrothiopyranyl, and the like.
The unsaturated heterocyclic group is a ring group having one or more double bonds in the saturated heterocyclic ring.
The heterocyclic group includes the above-mentioned aromatic heterocyclic group and non-aromatic heterocyclic group.
The aralkyl group refers to an aryl-alkyl group. Here, the aryl is the aromatic hydrocarbon group described above, and the alkyl group is the alkyl group described above. Specific examples include phenyl-C1 to C6 alkyl groups and naphthyl-C1 to C6 alkyl groups.
The aralkyloxy group refers to an aryl-alkyl-O- group. Here, the aryl group is the above-mentioned aromatic hydrocarbon group, and the alkyloxy group is the above-mentioned alkyloxy group. Specific examples include a phenyl-C1-C6 alkyloxy group and a naphthyl-C1-C6 alkyloxy group.
The acyl group is a group having a carbonyl group (—CO—), such as a formyl group, a hydrocarbon group -CO—, an aromatic hydrocarbon group -CO—, or a heterocyclic group -CO—. Specific examples include a formyl group, a C2 to C6 alkanoyl group, an aromatic hydrocarbon group -CO group, and a heterocyclic group-CO group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Examples of the aromatic group represented by ^R1 include aromatic hydrocarbon groups (aryl groups) and aromatic heterocyclic groups (heteroaryl groups). Examples of the aromatic hydrocarbon group include mono-, tri-, and tricyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms, such as a phenyl group, an indenyl group, a naphthyl group, a fluorenyl group, and an anthracenyl group. Examples of the aromatic heterocyclic group include mono-, tri-, and tricyclic 5- to 10-membered heterocyclic groups having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, such as a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a furyl group, a thienyl group, an oxazolyl group, an indolyl group, an isoindolyl group, a quinolyl group, an isoquinolyl group, and a dibenzofuranyl group.
Among these, examples of the aromatic group represented by ^R1 include a mono- or bicyclic aromatic hydrocarbon group having 6 to 14 carbon atoms or a 5- to 10-membered mono- to tricyclic aromatic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of the aromatic group include a phenyl group, a naphthyl group, a benzimidazolyl group, a quinolyl group, an isoquinolyl group, an indolyl group, and a dibenzofuranyl group.
In one embodiment, examples of groups that can be substituted on the aromatic group represented by ^R1 include 1 to 3 groups selected from an alkyl group, an alkoxy group, a halogen atom, a nitro group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, an acyl group, a hydroxyl group, an aromatic hydrocarbon group-alkyl group, a non-aromatic hydrocarbon ring group-alkyl group, an aromatic heterocyclic group-alkyl group, a non-aromatic heterocyclic group-alkyl group, an aromatic heterocyclic group-alkoxyl group, an aromatic hydrocarbon group-alkoxyl group, a non-aromatic hydrocarbon ring group-alkoxyl group, a non-aromatic heterocyclic group-alkoxyl group, and the like.

In one embodiment, specific examples of the group that can be substituted on the aromatic group represented by R ¹ include a C1 to C6 alkyl group, a C1 to C6 alkoxyl group, a halogen atom, a nitro group, an acyl group, a cyano group, a di(C1 to C6) alkylamino group, a benzyl group, a phenethyl group, a benzyloxy group, a phenethyloxy group, a hydroxyl group, a pyridin-2-ylmethyl group, a pyridin-3-ylmethyl group, a pyridin-4-ylmethyl group, a 2-(pyridin-2-yl)ethyl ... and 1 to 3 groups selected from a 2-(pyridin-3-yl)ethyl group, a 2-(pyridin-4-yl)ethyl group, a pyridin-2-ylmethoxy group, a pyridin-3-ylmethoxy group, a pyridin-4-ylmethoxy group, a 2-(pyridin-2-yl)ethoxy group, a 2-(pyridin-3-yl)ethoxy group, a 2-(pyridin-4-yl)ethoxy group, a pyrrolin-2-ylmethoxy group, and a 2-(pyrolin-2-yl)ethoxy group.
In one embodiment, R ¹ is an aromatic hydrocarbon group having 6 to 14 carbon atoms which may be substituted with 1 to 3 groups selected from an alkyl group, an alkoxyl group, a halogen atom, a nitro group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, an acyl group, a hydroxyl group, an aromatic hydrocarbon group-alkyl group, a non-aromatic hydrocarbon ring group-alkyl group, an aromatic heterocyclic group-alkyl group, a non-aromatic heterocyclic group-alkyl group, an aromatic heterocyclic group-alkoxyl group, an aromatic hydrocarbon group-alkoxyl group, a non-aromatic hydrocarbon ring group-alkoxyl group, a non-aromatic heterocyclic group-alkoxyl group, and the like.
In one embodiment, R ¹ is a phenyl group optionally substituted with 1 to 3 groups selected from an alkyl group, an alkoxyl group, a halogen atom, a nitro group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, an acyl group, a hydroxyl group, an aromatic hydrocarbon group-alkyl group, a non-aromatic hydrocarbon ring group-alkyl group, an aromatic heterocyclic group-alkyl group, a non-aromatic heterocyclic group-alkyl group, an aromatic heterocyclic group-alkoxyl group, an aromatic hydrocarbon group-alkoxyl group, a non-aromatic hydrocarbon ring group-alkoxyl group, a non-aromatic heterocyclic group-alkoxyl group, and the like.

In one embodiment, R ¹ is a phenyl group optionally substituted with 1 to 3 substituents selected from a C1 to C6 alkyl group, a C1 to C6 alkoxyl group, a halogen atom, a nitro group, a cyano group, a di(C1 to C6 alkyl)amino group, a benzyl group, a phenethyl group, a benzyloxy group, a phenethyloxy group, a hydroxyl group, a pyridin-2-ylmethyl group, a pyridin-3-ylmethyl group, a pyridin-4-ylmethyl group, a 2-(pyridin-2-yl)ethyl group, a pyridin-2-ylmethoxy group, a pyridin-3-ylmethoxy group, a pyridin-4-ylmethoxy group, a 2-(pyridin-2-yl)ethoxy group, a pyrrolin-2-ylmethoxy group, a pyrrolin-3-ylmethoxy group, and a 2-(pyrrolin-2-yl)ethoxy group.

In one embodiment, R ¹ is a phenyl group, a 4-(pyridin-2-ylmethoxy)phenyl group, a 4-dimethylaminophenyl group, a 4-hydroxy-3-methoxyphenyl group, a 2-methoxy-4-(pyridin-2-ylmethoxy)phenyl group, a 4-dimethylaminophenyl group, a 2-[2-(piperidin-1-yl)ethoxy]-4-(pyridin-2-ylmethoxy)phenyl group, a 3-methoxy-4-(pyridin-2-ylmethoxy)phenyl group, a 2-hydroxy-4-(pyridin-2-ylmethoxy)phenyl group, a 3-(pyridin-2-ylmethoxy)phenyl group, a 2-methoxy-3-(pyridin-2-ylmethoxy)phenyl group, a 4-methoxy-3-(pyridin-2-ylmethoxy)phenyl group, a 3-methoxy- 5-(pyridin-2-ylmethoxy)phenyl group, 2-methoxy-5-(pyridin-2-ylmethoxy)phenyl group, 2-(pyridin-2-ylmethoxy)phenyl group, 4-methoxy-2-(pyridin-2-ylmethoxy)phenyl group, 5-methoxy-2-(pyridin-2-ylmethoxy)phenyl group, 2-nitro-5-(pyridin-3-ylmethoxy)phenyl group, 4-diethylamino-2-(pyridin-3-ylmethoxy)phenyl group, 4-dimethylaminophenyl group, 6-(1H-indole) group, 4-(dibenzo[b,d]furan) group, phenyl group, 3-methoxy-4-hydroxyphenyl group, 3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl group.

Examples of the aromatic group or aromatic group-alkyl group or aromatic group-alkenyl group represented by ^R2 include aromatic hydrocarbon groups (aryl groups) and aromatic heterocyclic groups (heteroaryl groups). Examples of aromatic hydrocarbon groups include mono- to tri-cyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms, such as phenyl, indenyl, naphthyl, fluorenyl, and anthracenyl. Examples of aromatic heterocyclic groups include mono- to tri-cyclic, 5- to 10-membered heterocyclic groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, benzimidazolyl, quinolyl, isoquinolyl, and dibenzofuranyl.
Among these, embodiments of the aromatic group represented by ^R2 or the aromatic group of the aromatic group-alkyl group or aromatic group-alkenyl group are mono- or bicyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms or mono- to tricyclic aromatic heterocyclic groups having 5 to 10 members and having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Some embodiments are phenyl, naphthyl, indolyl, benzimidazolyl, quinolyl, isoquinolyl, and dibenzofuranyl groups.
In one embodiment, the aromatic group-alkyl group and aromatic group-alkenyl group represented by ^R2 are aromatic group-C1 to C3 alkyl group and aromatic group-C2 to C3 alkenyl group, and in one embodiment, phenyl-C1 to C3 alkyl group, phenyl-C2 to C3 alkenyl group, indole-C1 to C3 alkyl group, indole-C2 to C3 alkenyl group, benzimidazole-C1 to C3 alkyl group, and benzimidazole-C2 to C3 alkenyl group.

In one embodiment, the groups which can substitute on the aromatic group, aromatic group-alkyl group, or aromatic group-alkenyl group represented by ^R2 include 1 to 3 groups selected from an alkyl group, an alkoxy group, a halogen atom, a nitro group, a cyano group, an acyl group, an amino group, a monoalkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, an acyl group, a hydroxyl group, an aromatic hydrocarbon group-alkyl group, a non-aromatic hydrocarbon ring group-alkyl group, an aromatic heterocyclic group-alkyl group, a non-aromatic heterocyclic group-alkyl group, an aromatic heterocyclic group-alkoxyl group, an aromatic hydrocarbon group-alkoxyl group, a non-aromatic hydrocarbon ring group-alkoxyl group, a non-aromatic heterocyclic group-alkoxyl group, and the like.
In one embodiment, specific examples of groups that can substitute on the aromatic group represented by ^R2 include 1 to 3 groups selected from a C1 to C6 alkyl group, a C1 to C6 alkoxyl group, a halogen atom, a nitro group, an acyl group, a cyano group, a di(C1 to C6)alkylamino group, a benzyl group, a phenethyl group, a benzyloxy group, a phenethyloxy group, a hydroxyl group, a pyridylmethyl group, a pyridylethyl group, a pyridylmethyloxy group, a pyridylethyloxy group, a pyrrolylmethyloxy group, and a pyrrolylethyloxy group.
In one embodiment, the aromatic group, aromatic group-alkyl group, or aromatic group-alkenyl group represented by ^R2 is an aromatic hydrocarbon group having 6 to 14 carbon atoms, a 5- to 10-membered heterocyclic group having 1 or 2 nitrogen atoms, an aromatic hydrocarbon-C1-C3 alkyl group having 6 to 14 carbon atoms, an aromatic hydrocarbon-C2-C3 alkenyl group having 6 to 14 carbon atoms, a 5- to 10-membered heterocyclic ring-C1-C3 alkyl group having 1 or 2 nitrogen atoms, or a 5- to 10-membered heterocyclic ring-C2-C3 alkenyl group having 1 or 2 nitrogen atoms. ^R2 may be substituted with 1 to 3 groups selected from a C1 to C6 alkyl group, a C1 to C6 alkoxyl group, a halogen atom, a nitro group, a cyano group, a di(C1 to C6 alkyl)amino group, a benzyl group, a phenethyl group, a benzyloxy group, a phenethyloxy group, a hydroxyl group, a pyridin-2-ylmethyl group, a pyridin-3-ylmethyl group, a pyridin-4-ylmethyl group, a 2-(pyridin-2-yl)ethyl group, a pyridin-2-ylmethoxy group, a pyridin-3-ylmethoxy group, a pyridin-4-ylmethoxy group, a 2-(pyridin-2-yl)ethoxy group, a pyrrolin-2-ylmethoxy group, a pyrrolin-3-ylmethoxy group, and a 2-(pyrolin-2-yl)ethoxy group.

[0039] The aromatic group or aromatic group-alkyl or aromatic group-alkenyl group represented by ^R2 may be exemplified by a phenyl group, a phenyl-C1-C3 alkyl group, a phenyl-C2-C3 alkenyl group, an indolyl group, an indole-C1-C3 alkyl group, an indole-C2-C3 alkenyl group, a benzimidazole-C1-C3 alkyl group, or a benzimidazole-C2-C3 alkenyl group. Some embodiments include a phenyl group, an (E)-2-phenylethenyl group, an (E)-2-(dibenzo[b,d]furan-4-yl)ethenyl group, an (E)-2-1H-indol-6-yl)ethenyl group, or a 1H-indol-6-yl group.
^R2 may be substituted with 1 to 3 groups selected from an alkyl group, an alkoxyl group, a halogen atom, a nitro group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an acyl group, a hydroxyl group, an aromatic hydrocarbon group-alkyl group, a non-aromatic hydrocarbon ring group-alkyl group, an aromatic heterocyclic group-alkyl group, a non-aromatic heterocyclic group-alkyl group, an aromatic heterocyclic group-alkoxyl group, an aromatic hydrocarbon group-alkoxyl group, a non-aromatic hydrocarbon ring group-alkoxyl group, a non-aromatic heterocyclic group-alkoxyl group, and the like.
In one embodiment, ^R2 is a phenyl group, a benzyl group, a (E)-2-phenylethenyl group, a (E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl group, a (E)-2-(4-dimethylaminophenyl)ethenyl group, a (E)-2-(1-methyl-indol-6-yl)ethenyl group, a (E)-2-(1-methylindol-2-yl)ethenyl group, a (E)-2-(1-methylindol-3-yl)ethenyl group, a (E)-2-(1-ethylindol-6-yl)ethenyl group, a (E)-2-(4-hydroxyindol-3 ... (E)-2-(4-nitroindol-3-yl)ethenyl group, (E)-2-(1H-indol-6-yl)ethenyl group, (E)-2-(2-methoxy-4-(pyridin-2-ylmethoxy)phenyl)ethenyl group, (E)-2-(4-dimethylaminophenyl)ethenyl group, (E)-2-(dibenzo[b,d]furan-4-yl)ethenyl group, 1H-indol-6-yl group, and (E)-2-(3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl)ethenyl group.

Example embodiments of the combination of a diketone compound of general formula (1) and a pyrazole compound of general formula (2) in the present invention are shown below.

(In the formula, ^Ar1 and ^Ar2 are the same or different and represent an aromatic hydrocarbon group; n1 and n2 each represent a number from 1 to 3; n1 ^R4s and n2 ^R5s are the same or different and represent a hydrogen atom, an alkyl group, an alkoxyl group, a halogen atom, a nitro group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, an acyl group, a hydroxyl group, an aromatic hydrocarbon group-alkyl group, a non-aromatic hydrocarbon cyclic group-alkyl group, an aromatic heterocyclic group-alkyl group, a non-aromatic heterocyclic group-alkyl group, an aromatic heterocyclic group-alkoxyl group, an aromatic hydrocarbon group-alkoxyl group, a non-aromatic hydrocarbon cyclic group-alkoxyl group, or a non-aromatic heterocyclic group-alkoxyl group; and multiple ^R4s and ^R5s may be the same or different. These symbols have the same meanings hereinafter.)

(In the formula, _L1 represents an alkylene group having 1 to 6 carbon atoms or an alkenylene group having 2 to 6 carbon atoms.)

(In the formula, _L1 has the same meaning as defined above, and ^R6 and ^R7 , as well as ^R8 and ^R9 , combine to form an aromatic heterocycle, which may further have 1 to 3 substituents selected from an alkyl group, an alkoxyl group, a halogen atom, a nitro group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, an acyl group, a hydroxyl group, an aromatic hydrocarbon group-alkyl group, a non-aromatic hydrocarbon ring group-alkyl group, an aromatic heterocyclic group-alkyl group, a non-aromatic heterocyclic group-alkyl group, an aromatic heterocyclic group-alkoxyl group, an aromatic hydrocarbon group-alkoxyl group, a non-aromatic hydrocarbon ring group-alkoxyl group, and a non-aromatic heterocyclic group-alkoxyl group.)

(n1, n2, ^R4 and ^R5 have the same meanings as above.)

( ^R6 and ^R7 , and ^R8 and ^R9 have the same meanings as above.)

(n1, n2, R ⁴ , R ⁸ and R ⁹ have the same meanings as above.)

( ^HAr1 and ^HAr2 may be the same or different and each represent an aromatic heterocyclic group, and _L1 , n1, n2, ^R4 and ^R5 have the same meanings as defined above.)

(HAr ¹ , HAr ² , n1, n2, R ⁴ and R ⁵ have the same meanings as above.)

( ^Ar1 and ^Ar2 each represent an aromatic hydrocarbon group, and n1, n2, ^R4 , and ^R5 have the same meanings as above.)

(n1, n2, ^R4 and ^R5 have the same meanings as above.)

( ^R6 and ^R7 , and ^R8 and ^R9 have the same meanings as above.)

(n1, n2, R ⁴ , R ⁸ and R ⁹ have the same meanings as above.)

(HAr ¹ , HAr ² , n1, n2, R ⁴ and R ⁵ have the same meanings as above.)

(Ar ¹ , HAr ² , n1, n2, R ⁴ and R ⁵ have the same meanings as above.)

( ^HAr2 , n1, n2, ^R4 and ^R5 have the same meanings as above.)
The diketone compound represented by general formula (1) or a salt thereof used as a raw material can be produced according to the method described in Patent Document 1.
That is, for example, it can be produced by reacting an aldehyde compound having R ¹ with a diketone compound having R ² .
This reaction can be achieved by reacting the aldehyde compound with the diketone compound in a solvent such as ethyl acetate in the presence of a base such as a primary amine or a secondary amine and a water scavenger such as trimethyl orthoformate, an alkyl borate, or boron oxide.

Examples of salts of the diketone compound (1) include hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as sulfate, nitrate, perchlorate, phosphate, carbonate, and bicarbonate; organic carboxylate salts such as acetate, oxalate, maleate, tartrate, and fumarate; organic sulfonate salts such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and camphorsulfonate; amino acid salts such as aspartate and glutamate; salts with amines such as trimethylamine salt, triethylamine salt, procaine salt, pyridine salt, and phenethylbenzylamine salt; alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as magnesium salt and calcium salt.

The carbazate (3) used in the method of the present invention includes carbazates having an optionally substituted hydrocarbon group as the ester residue R ³ .
Examples of hydrocarbon groups represented by ^R3 include hydrocarbon groups having 1 to 20 carbon atoms, preferably an aliphatic hydrocarbon group having 1 to 20 carbon atoms or an aromatic hydrocarbon group having 6 to 14 carbon atoms, more preferably an alkyl group having 1 to 20 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, even more preferably an alkyl group having 1 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, and even more preferably an alkyl group having 1 to 8 carbon atoms or a phenylalkyl group having 7 to 10 carbon atoms. Groups that can be substituted on these hydrocarbon groups include halogen atoms and alkoxyl groups.
Specific examples of carbazate esters include methyl carbazate, ethyl carbazate, isopropyl carbazate, t-butyl carbazate, and benzyl carbazate, due to their ease of availability.
These carbazates are less flammable and less toxic than hydrazine or hydrazine hydrate, and are therefore excellent raw materials for the mass synthesis of pyrazole compound (2) or a salt thereof.

The solvent used in the reaction of the diketone compound (1) or a salt thereof with a carbazate ester is preferably a solvent that makes the reaction solution acidic, specifically, a fatty acid such as acetic acid or propionic acid, or a mixed solvent of a fatty acid and an organic solvent.
Examples of organic solvents that can be used in combination with fatty acids include methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, isopropyl ether, methyl tert-butyl ether, ethyl acetate, acetonitrile, dimethylformamide, and dimethylacetamide.
In one embodiment, the mixed solvent is acetic acid and methanol.
From the viewpoints of the reaction rate and the amount of impurities, the reaction temperature is preferably 0° C. or higher, more preferably 20° C. or higher, and even more preferably 40° C. or higher, and the upper limit of the reaction temperature is preferably about 150° C. From the viewpoints of the reaction rate and the amount of impurities, the reaction time is preferably 1 hour or longer, more preferably 4 hours or longer, and the upper limit of the reaction time is preferably 24 hours or shorter. From the viewpoints of the reaction rate and the amount of impurities, the carbazate ester is preferably used in an amount of 1.0 mole or more, more preferably 2.5 moles or more, relative to the diketone compound (1).

In this reaction, depending on the reaction temperature, the type of carbazate ester used, and the amount of carbazate ester used, pyrazole compound (2) or a salt thereof may be obtained, or a compound in which the hydrogen atom on the pyrazole ring in general formula (2) is ^-COOR3 may be obtained.
More specifically, when the reaction temperature is 40°C or higher, for example, when the carbazate is t-butyl carbazate and the amount of the carbazate used is 2.5 moles or more relative to the diketone compound (1), the reaction proceeds almost to the formation of the pyrazole compound (2) or a salt thereof.
Therefore, when it is desired to proceed the reaction to the pyrazole compound (2) or a salt thereof, it is preferable to use 2.5 moles or more of carbazate ester relative to the diketone compound (1) and to set the reaction temperature at 40° C. or higher.

On the other hand, when the reaction temperature is below 40°C or when the amount of carbazate ester used is less than 2.5 moles relative to the diketone compound (1), some compounds of general formula (2) in which the hydrogen atom on the pyrazole ring is ^-COOR3 are obtained. Therefore, in this case, it is preferable to carry out a treatment to remove the ^-COOR3 (decarboxylation). This decarboxylation reaction can be carried out by concentrating the reaction solution and then reacting it with a base.
The base used may be either an organic base or an inorganic base, and examples of the organic base include primary amine compounds, secondary amine compounds, tertiary amine compounds, and quaternary ammonium compounds such as DBU (diazabicycloundecene), piperidine, diethylamine, triethylamine, and DIPEA (diisopropylethylamine). Examples of the inorganic base include potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and sodium hydroxide.
In one embodiment, DBU is potassium carbonate.
The amount of base used may be any amount so long as the system exhibits basicity. The decarbonization reaction is preferably carried out in a polar solvent, such as methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetonitrile, dimethylformamide, or dimethylacetamide, and is more preferably carried out in a primary alcohol solvent such as methanol.
In one embodiment, the solvent is methanol, ethyl acetate, or water.
From the viewpoints of the reaction rate and the amount of impurities, the reaction temperature is preferably 0° C. or higher, more preferably 20° C. or higher, and even more preferably 50° C. or higher, and the upper limit of the reaction temperature is preferably about 150° C. From the viewpoints of the reaction rate and the amount of impurities, the reaction time may be 1 hour or longer, but is preferably 24 hours or shorter.
In order to obtain a pyrazole compound (2) of higher quality, it is preferable to carry out the reaction of the diketone compound (1) with a carbazate ester under mild conditions and then carry out decarboxylation treatment by reacting with a base.

After the reaction is completed, the target compound, pyrazole compound (2) or a salt thereof, can be isolated by filtration, crystallization using a poor solvent and filtration, column purification, or the like.
The salt of the pyrazole compound (2) may be any pharmaceutically acceptable salt, and examples thereof include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as sulfate, nitrate, perchlorate, phosphate, carbonate, and bicarbonate; organic carboxylates such as acetate, oxalate, maleate, tartrate, and fumarate; organic sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and camphorsulfonate; amino acid salts such as aspartate and glutamate; salts with amines such as trimethylamine salt, triethylamine salt, procaine salt, pyridine salt, and phenethylbenzylamine salt; alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as magnesium salt and calcium salt. These salts of the pyrazole compound (2) can be obtained by conventional methods.
The method of the present invention not only uses a carbazate ester that is easier to handle than hydrazine or hydrazine hydrate, but also has the unexpected effect of increasing the reaction yield and providing a pyrazole compound (2) or a salt thereof with a high purity compared to the case where hydrazine or hydrazine hydrate is used.
One aspect of the present invention is a method for preparing a pharmaceutical composition, as follows:

or a pharmaceutically acceptable salt thereof, comprising the steps of:
(i) General formula (1)

(wherein R ¹ represents an aromatic group which may have a substituent, and R ² represents an aromatic group which may have a substituent, an aromatic-alkyl group which may have a substituent, or an aromatic-alkenyl group which may have a substituent).
or a salt thereof with a carbazate ester, to obtain a compound represented by the general formula (2)

(wherein R ¹ and R ² have the same meanings as defined above) or a chemically acceptable salt thereof,
(ii) optionally isolating and purifying the pyrazole compound (2) or a pharmaceutically acceptable salt thereof;
(iii) Mixing the resulting pyrazole compound (2) or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents or excipients.

The pyrazole compound (2) or a salt thereof obtained as described above can be prepared into a pharmaceutical composition by adding a pharmaceutically acceptable carrier, if necessary. The pharmaceutical composition may be either a solid composition or a liquid composition.
Pharmaceutically acceptable carriers used in the case of preparing a solid composition include inert excipients such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and/or magnesium aluminum metasilicate, and inert additives such as lubricants such as magnesium stearate, disintegrants such as sodium carboxymethyl starch, stabilizers, and solubilizers. Pharmaceutically acceptable carriers used in the case of preparing a liquid composition include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and commonly used inert diluents such as purified water or ethanol. The liquid composition may contain, in addition to the inert diluent, auxiliary agents such as solubilizers, wetting agents, and suspending agents, as well as sweeteners, flavors, fragrances, and preservatives.

The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.
Example 1
Synthesis of 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]ethenyl]-1H-pyrazole

5.00 g (11.05 mmol) of (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]hepta-1,6-diene-3,5-dione was suspended in 25 ml of acetic acid, and 2.88 g (27.66 mmol) of ethyl carbazate was added at room temperature, followed by stirring at 40°C for 15 hours. The resulting reaction solution was concentrated under reduced pressure at 50°C, and after distilling off the acetic acid, a mixture of 16.82 g (110.5 mmol) of DBU (diazabicycloundecene) and 12.5 ml of methanol was added to the concentrate, followed by stirring at room temperature for 30 minutes. The resulting reaction solution was heated to 50°C, and 85 ml of methanol was added, resulting in precipitation of the title compound. After confirming the precipitation, the mixture was cooled to 0°C and stirred for 1 hour. After stirring for 1 hour, the precipitated crystals were collected by filtration, washed with methanol, and dried under reduced pressure at 50° C. to obtain 4.16 g (yield 84.0%) of the title compound as a pale yellow powder having the following physical properties. The HPLC purity and content (titer) were measured, and the HPLC purity and content (titer) were 100.00% and 100.0%, respectively.
^1H NMR (δ, DMSO-d ₆ ): 3.87 (s, 3H), 5.23 (s, 3H), 6.43 (s, 1H), 6.66 (d, J = 8.8Hz, 1H), 6 .69 (s, 1H), 6.75 (d, J=2.4Hz, 1H), 7.00 (dd, J=9.6, 16.4Hz, 1H), 7. 3-7.38 (m, 5H), 7.51-7.56 (m, 4H), 7.86 (dt, J=1.6, 7.6Hz, 1H), 8.6 0 (ddd, J = 0.8, 1.6, 4.8Hz, 1H), 11.17 (s, NH), 12.86 (s, NH), MS (ESI ^- ) m/z 447.2 (M-1)

Example 2
Synthesis of 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]ethenyl]-1H-pyrazole

2.00 g (4.42 mmol) of (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]hepta-1,6-diene-3,5-dione was suspended in 20 ml of acetic acid, and 1.46 g (11.05 mmol) of t-butyl carbazate was added at room temperature. The mixture was stirred at 70°C for 23 hours. 60 ml of water was added to the resulting reaction solution at room temperature, and after stirring for 1 hour, the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure at 50°C to obtain 3.61 g (72.5% yield) of the title compound as a pale yellow powder. HPLC purity and content measurements revealed an HPLC purity of 98.53% and a content (titer) of 98.7%.

Reference example 1
Synthesis of 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]ethenyl]-1H-pyrazole

2.00 g (4.42 mmol) of (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]hepta-1,6-diene-3,5-dione was suspended in 22 ml of acetic acid, and 2.21 g (44.2 mmol) of hydrazine monohydrate was added at room temperature. The mixture was stirred at 60°C for 3 hours. After the resulting reaction solution was cooled to room temperature, 22 ml of methanol was added, and the mixture was further cooled to 0°C and stirred for 15 hours. After stirring for 15 hours, the precipitated crystals were collected by filtration, washed with methanol, and dried under reduced pressure at 50°C to obtain 1.35 g (67.8% yield) of the title compound as a light brown powder having the following physical properties. HPLC purity and content (titration) were measured, revealing a HPLC purity of 92.17% and a content (titration) of 87.0%.

Example 3
Synthesis of 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]ethenyl]-1H-pyrazole

By replacing acetic acid with propionic acid and carrying out the same synthesis procedure as in Example 1, 1.12 g (yield 56.2%) of the title compound was obtained as a pale yellow powder. HPLC purity and content (titration) were measured, revealing a purity of 98.47% and a content (titration) of 98.2%.

Example 4
Synthesis of 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]ethenyl]-1H-pyrazole

The same synthesis procedure as in Example 1 was carried out, except that acetic acid was replaced with acetic acid:methanol (mixing ratio 1:1), to give 1.62 g (yield 82.0%) of the title compound as a pale yellow powder.
The HPLC purity and content (titer) were measured, and the HPLC purity was 98.25% and the content (titer) was 99.1%.

Example 5
Synthesis of 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]ethenyl]-1H-pyrazole

The same synthesis procedure as in Example 1 was carried out, except that ethyl carbazate was replaced with methyl carbazate, to give 3.00 g (yield 60.7%) of the title compound as a pale yellow powder.
The HPLC purity and content were measured, and the HPLC purity was 98.37% and the content (titer) was 98.6%.

Example 6
Synthesis of 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]ethenyl]-1H-pyrazole

The same synthesis procedure as in Example 2 was carried out, except that t-butyl carbazate was replaced with benzyl carbazate, to give 3.42 g (yield 69.0%) of the title compound as a pale yellow powder.
The HPLC purity and content were measured, and the HPLC purity was 98.26% and the content (titer) was 98.9%.

Example 7
Synthesis of 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]ethenyl]-1H-pyrazole

By replacing DBU with potassium carbonate and carrying out the same synthesis procedure as in Example 1, 4.25 g (yield 85.7%) of the title compound was obtained as a pale yellow powder. HPLC purity and content (titration) were measured, revealing a purity of 98.50% and a content (titration) of 97.2%.

Example 8
Synthesis of 3,5-bis[(1E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazole

1.00 g (2.71 mmol) of (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione was suspended in 10 ml of acetic acid, and 2.83 g (27.2 mmol) of ethyl carbazate was added at room temperature, followed by stirring at 60°C for 19 hours. 30 ml of water was added to the resulting reaction solution at room temperature, and the mixture was stirred for 1 hour, after which the precipitated crystals were collected by filtration. The crystals were washed with water and then dried under reduced pressure at 50°C to obtain 928 mg (yield 93.8%) of the title compound as white crystals having the following physical properties. The HPLC purity was measured to be 97.54%.
^1H NMR (δ, DMSO-d ₆ ): 3.83 (s, 6H), 6.62 (s, 1H), 6.77 (d, J = 8.0Hz, 2H), 6.91-7.06 (m, 4H), 7.15 (s, 2H), 9.19 (s, OH x 2), 12.83 (s, NH), MS (ESI ⁺ ) m/z 465.1 (M+1)

Example 9
Synthesis of 3,5-bis[(1E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazole

2.00 g (5.43 mmol) of (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione was suspended in 20 ml of acetic acid, and 1.77 g (13.58 mmol) of t-butyl carbazate was added at room temperature. The mixture was stirred at 70°C for 23 hours. 60 ml of water was added to the resulting reaction solution at room temperature, and after stirring for 1 hour, the precipitated crystals were collected by filtration. The crystals were washed with water and then dried under reduced pressure at 50°C to obtain 1.95 g (97.6% yield) of the title compound as white crystals. HPLC purity was measured and found to be 96.86%.

Reference example 2
Synthesis of 3,5-bis[(1E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazole

0.50 g (1.36 mmol) of (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione was suspended in 5 ml of acetic acid, and 0.34 g (6.79 mmol) of hydrazine monohydrate was added at room temperature. The mixture was stirred at 60°C for 24 hours. 15 ml of water was added to the resulting reaction solution at room temperature, and after stirring for 1 hour, the precipitated crystals were collected by filtration. The crystals were washed with water and then dried under reduced pressure at 50°C to obtain 415 mg (79.5% yield) of the title compound as yellow crystals. HPLC purity was measured and found to be 92.73%.

Reference example 3
Synthesis of 3,5-bis[(1E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazole

2.00 g (5.43 mmol) of (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione was suspended in 20 ml of acetic acid, and 1.34 g (26.76 mmol) of hydrazine monohydrate was added at room temperature. The mixture was stirred at 60°C for 6 hours. 60 ml of water was added to the resulting reaction solution at room temperature, and after stirring for 1 hour, the precipitated crystals were collected by filtration. The crystals were washed with water and then dried under reduced pressure at 50°C to obtain 1.71 g (86.5% yield) of the title compound as yellow crystals. HPLC purity was measured and found to be 91.37%.

Example 10
Synthesis of 3,5-bis[(1E)-2-phenylethenyl]-1H-pyrazole

0.50 g (1.81 mmol) of (1E,6E)-1,7-bisphenyl-1,6-heptadiene-3,5-dione was suspended in 5 ml of acetic acid, and 2.39 g (18.08 mmol) of t-butyl carbazate was added at room temperature, followed by stirring at 60°C for 24 hours. The resulting reaction solution was concentrated under reduced pressure at 50°C, and after distilling off the acetic acid, a mixture of 2.75 g (18.06 mmol) of DBU (diazabicycloundecene) and 2.5 ml of methanol was added to the concentrate, and the mixture was stirred at 50°C for 30 minutes. The resulting reaction solution was concentrated under reduced pressure at 50°C, and after distilling off the methanol, an organic layer was obtained by separation with ethyl acetate and water. The organic layer was concentrated under reduced pressure at 50°C and purified by column chromatography to obtain 407 mg (yield 82.6%) of the title compound having the following physical properties as pale yellow crystals.
^1H NMR (δ, DMSO-d ₆ ): 6.79 (s, 1H), 7.15 (m, 4H), 7.29 (d, J = 6.4Hz, 2H), 7.39 (t, J = 7.2Hz, 4H), 7.57 (d, J = 7.2Hz, 4H), 13.06 (s, NH), MS (ESI ⁺ ) m/z 273.1 (M+1)

Reference example 4
Synthesis of 3,5-bis[(1E)-2-phenylethenyl]-1H-pyrazole

0.50 g (1.81 mmol) of (1E,6E)-1,7-bisphenyl-1,6-heptadiene-3,5-dione was suspended in 5 ml of acetic acid, and 680 mg (13.58 mmol) of hydrazine monohydrate was added at room temperature. The mixture was stirred at 50°C for 22 hours. The resulting reaction solution was concentrated under reduced pressure at 50°C, and the acetic acid was then distilled off. The organic layer was then separated using ethyl acetate and water to obtain an organic layer. The organic layer was concentrated under reduced pressure at 50°C and purified using a column to obtain 362 mg (73.4% yield) of the title compound as yellow crystals.

Example 11
Synthesis of 3-phenyl-5-[(1E)-2-phenylethenyl]-1H-pyrazole

0.45 g (1.80 mmol) of (4E)-1,5-phenyl-4-pentene-1,3-dione was suspended in 4.5 ml of acetic acid, and 2.38 g (18.01 mmol) of t-butyl carbazate was added at room temperature, followed by stirring at 60°C for 24 hours. The resulting reaction solution was concentrated under reduced pressure at 50°C, and after distilling off the acetic acid, a mixture of 5.48 g (36.00 mmol) of DBU (diazabicycloundecene) and 2.3 ml of methanol was added to the concentrate, and the mixture was stirred at 50°C for 30 minutes. The resulting reaction solution was concentrated under reduced pressure at 50°C, and after distilling off the methanol, an organic layer was obtained by separation with ethyl acetate and water. The organic layer was concentrated under reduced pressure at 50°C and purified by column chromatography to obtain 417 mg (yield 94.1%) of the title compound having the following physical properties as white crystals.
^1H NMR (δ, CDCl ₃ ): 6.75 (s, 1H), 7.01 (d, J = 16.4Hz, 1H), 7.10 (d, J = 16.4Hz, 1H), 7.23-7.30 (m, 4H), 7.36-7.40 (m, 4H), 7.73 (d, J = 8.0Hz, 1H), MS (ESI ⁺ ) m/z 247.1 (M+1)

Reference example 5
Synthesis of 3-phenyl-5-[(1E)-2-phenylethenyl]-1H-pyrazole

0.45 g (1.80 mmol) of (4E)-1,5-phenyl-4-pentene-1,3-dione was suspended in 4.5 ml of acetic acid, and 675 mg (13.48 mmol) of hydrazine monohydrate was added at room temperature. The mixture was stirred at 50°C for 5 hours. The resulting reaction solution was concentrated under reduced pressure at 50°C, and the acetic acid was then distilled off. The organic layer was then separated using ethyl acetate and water to obtain an organic layer. The organic layer was concentrated under reduced pressure at 50°C and purified using a column to obtain 375 mg (84.7% yield) of the title compound as white crystals.

Example 12
Synthesis of 3,5-bis[(1E)-2-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]ethenyl]-1H-pyrazole

By replacing (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]hepta-1,6-diene-3,5-dione in Example 1 with (1E,6E)-1,7-bis[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]-1,6-heptadiene-3,5-dione, 4.12 g (yield 83.0%) of the title compound was obtained.
^1H NMR (δ, DMSO-d ₆ ): 3.86 (s, 6H), 5.23 (s, 4H), 6.61 (s, 1H), 6.65 (d, J = 8.4Hz, 2H), 6 .73 (s, 2H), 6.97 (d, J=16.4Hz, 2H), 7.26 (d, J=16.8Hz, 2H), 7.36 (d d, J=4.8, 7.2Hz, 2H), 7.50 (d, J=7.6Hz, 2H), 7.55 (d, J=7.6Hz, 2H), 7.86 (d, J = 7.6 Hz, 2H), 8.60 (d, J = 5.2 Hz, 2H), 12.84 (s, NH), MS (ESI ^- ) m/z 545.3 (M-1)

Example 13
Synthesis of 3,5-bis[(1E)-2-(4-dimethylaminophenyl)ethenyl]-1H-pyrazole

By replacing (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]hepta-1,6-diene-3,5-dione in Example 1 with (1E,6E)-1,7-bis(4-dimethylaminophenyl)-1,6-heptadiene-3,5-dione, 1.48 g (yield 75.0%) of the title compound was obtained.
^1H NMR (δ, DMSO-d ₆ ): 2.93 (s, 12H), 6.58 (s, 1H), 6.72 (d, J = 4.4Hz, 2H), 6.81 (d, J = 16.4Hz, 2H), 7.02 (d, J = 16.4Hz, 2H), 7.37 (d, J = 8.8Hz, 2H), 12.72 (s, NH), MS (ESI ^- ) m/z 357.3 (M-1)

Example 14
Synthesis of 3,5-bis[(1E)-2-(1H-indol-6-yl)ethenyl]-1H-pyrazole

By replacing (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]hepta-1,6-diene-3,5-dione in Example 1 with (1E,6E)-1,7-bis(1H-indol-6-yl)-1,6-heptadiene-3,5-dione, 1.62 g (yield 81.9%) of the title compound was obtained.
^1H NMR (δ, DMSO-d ₆ ): 6.46 (s, 2H), 6.70 (s, 1H), 7.09 (d, J = 16.4Hz, 2H), 7.27-7.33 (m, 6H), 7.54 (s, 1H), 7.57 (s, 1H), 7.58 (s, 2H), 10.16 (s, NH x 2), MS (ESI ⁺ ) m/z 351.1 (M+1)

Example 15
Synthesis of 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-(4-dibenzofuran)ethenyl]-1H-pyrazole

By replacing (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]hepta-1,6-diene-3,5-dione in Example 1 with (1E,6E)-1-(1H-indol-6-yl)-7-(4-dibenzofuran)hepta-1,6-diene-3,5-dione, 1.52 g (yield 76.9%) of the title compound was obtained.
^1H NMR (δ, DMSO-d ₆ ): 6.44 (s, 1H), 6.92 (s, 1H), 7.05 (d, J = 16.4Hz, 1H), 7.29-7.68 (m, 10H), 7.74 (d, J = 7.2Hz, 1H), 7.8 3d, J = 6.4Hz, 1H), 8.08 (d, J = 6.8Hz, 1H), 8.20 (d, J = 7.6Hz, 1H), 11.19 (s, NH), 13.08 (s, NH), MS (ESI ^- ) m/z 400.2 (M-1)

Example 16
Synthesis of 3-(1H-indol-6-yl)-5-[(1E)-2-(4-dimethylaminophenyl)ethenyl]-1H-pyrazole

By replacing (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]hepta-1,6-diene-3,5-dione in Example 1 with (4E)-1-(1H-indol-6-yl)-5-(4-dimethylaminophenyl)-4-pentene-1,3-dione, 1.55 g (yield 78.2%) of the title compound was obtained.
^1H NMR (δ, DMSO-d ₆ ): 2.93 (s, 6H), 6.43 (s, 1H), 6.73 (d, J = 8.8Hz, 2H), 6.86 (d, J = 16.4Hz, 1H), 7.09 (d, J = 16. 4Hz, 1H), 7.38-7.46 (m, 4H), 7.56 (s, 1H), 7.80 (s, 1H), 11.20 (s, NH), 13.00 (s, NH), MS (ESI ^- ) m/z 327.2 (M-1)

Example 17
Synthesis of 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]ethenyl]-1H-pyrazole Using the following raw materials, a synthetic procedure similar to that of Example 1 was performed to obtain 578.84 g (yield 74.0%) of the title compound (compound of Example 1) as a pale yellow powder. Measurement of HPLC purity and content (titraton) revealed that the HPLC purity was 99.99% and the content (titraton) was 100.0%.
790 g (2.20 mol) of (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(pyridin-2-ylmethoxy)phenyl]hepta-1,6-diene-3,5-dione, 3.95 L of acetic acid,
Ethyl carbazate 454.40 g (4.36 mol),
A mixture of 2658 g (17.46 mol) of DBU (diazabicycloundecene) and 1.98 L of methanol,
Precipitation solvent: 13.43 L of methanol.

Claims (9)

The following general formula (1)
(wherein R ¹ represents an aromatic group which may have a substituent, and R ² represents an aromatic group which may have a substituent, an aromatic group-alkyl group which may have a substituent, or an aromatic group-alkenyl group which may have a substituent).
or a salt thereof with a carbazate ester,
(wherein R ¹ and R ² have the same meanings as defined above), or a salt thereof ,
(a) When the reaction temperature is 40° C. or higher or when the amount of the carbazate ester used is 2.5 moles or more relative to the diketone compound (1), the above reaction alone is sufficient.
(b) A method for producing a pyrazole compound or a salt thereof, wherein when the reaction temperature is lower than 40°C or the amount of the carbazate ester used is less than 2.5 moles relative to the diketone compound (1), a base is reacted after the reaction. 2. The method according to claim 1, wherein ^R1 is a mono-, tri-cyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, or a 5- to 10-membered mono-, tri-cyclic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and ^R1 is optionally substituted with 1 to 3 groups selected from an alkyl group, an alkoxy group, a halogen atom, a nitro group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, an acyl group, a hydroxyl group, an aromatic hydrocarbon group-alkyl group, a non-aromatic hydrocarbon ring group-alkyl group, an aromatic heterogroup-alkyl group, a non-aromatic heterocyclic group-alkyl group, an aromatic heterocyclic ring group-alkoxyl group, an aromatic hydrocarbon group-alkoxyl group, a non-aromatic hydrocarbon ring group-alkoxyl group, and a non-aromatic heterocyclic group-alkoxyl group . 3. The method according to claim 2 , wherein R ¹ is a monocyclic, monocyclic, or tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. 3. The method according to claim 2 , wherein R ¹ is a 5- to 10-membered, mono- to tri-cyclic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. R ² is a monocyclic to tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, a monocyclic to tricyclic aromatic hydrocarbon-alkyl group having 6 to 14 carbon atoms, a monocyclic to tricyclic aromatic hydrocarbon-alkenyl group having 6 to 14 carbon atoms, a monocyclic to tricyclic 5-10-membered heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, a monocyclic to tricyclic 5-10-membered heterocyclic-alkyl group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, or a monocyclic to tricyclic 5-10-membered heterocyclic group-alkenyl group having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, 5. The method according to any one of claims 1 to 4, wherein ² is optionally substituted with 1 to 3 groups selected from an alkyl group, an alkoxyl group, a halogen atom, a nitro group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, an acyl group, a hydroxyl group, an aromatic hydrocarbon group-alkyl group, a non-aromatic hydrocarbon ring group-alkyl group, an aromatic heterocyclic group-alkyl group, a non-aromatic heterocyclic group-alkyl group, an aromatic heterocyclic group-alkoxyl group, an aromatic hydrocarbon group-alkoxyl group, a non-aromatic hydrocarbon ring group- alkoxyl group, and a non-aromatic heterocyclic group-alkoxyl group. 6. The method according to claim 5 , wherein ^R2 is a monocyclic, monocyclic, tricyclic, or tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. 6. The method according to claim 5 , wherein ^R2 is a monocyclic, monocyclic, tricyclic, aromatic hydrocarbon-alkenyl group having 6 to 14 carbon atoms. 6. The method according to claim 5 , wherein ^R2 is a 5- to 10-membered heterocyclic group having one to three rings and one to three heteroatoms selected from nitrogen, oxygen, and sulfur. 6. The method according to claim 5 , wherein ^R2 is a heterocyclic group-alkenyl group having one to three rings and five to ten members and containing one to three heteroatoms selected from nitrogen, oxygen and sulfur.