JP2009035531A - Method for producing hydrazide compound and 1-substituted-1,2-dihydroindazol-3-one derivative, hydrazide compound and 1-substituted-1,2-dihydroindazol-3-one derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a new hydrazide compound or a 1-substituted-1,2-dihydroindazol-3-one derivative, and a hydrazide compound and a 1-substituted-1,2-dihydroindazol-3-one derivative. <P>SOLUTION: The method for producing a 1-substituted-1,2-dihydroindazol-3-one derivative comprises (1) producing a hydrazide compound from a 2-haloaryl acid chloride from hydrazine and (2) subjecting the hydrazide compound to an intramolecular coupling. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a novel hydrazide compound and a method for producing a 1-substituted-1,2-dihydroindazol-3-one derivative, and a hydrazide compound and a 1-substituted-1,2-dihydroindazol-3-one derivative.

1-Substituted-1,2-dihydroindazol-3-one represented by the following chemical formula is such that 2-position and 3-position of 1-indanone are each —NH, —NR (where R is an alkyl group, aryl group, etc. Is a bicyclic heterocyclic compound substituted with a substituent.

  The 1,2-dihydroindazol-3-one derivative is expected to be used as a mother nucleus of a pharmaceutical product. For this reason, many studies have been made in recent years.

For example, 1,2-dihydroindazol-3-one and its derivatives represented by the following chemical formula are known to be strong inhibitors of the enzyme 5-LPO (5-lipoxygenase).

This 1,2-dihydroindazol-3-one and its derivatives inhibit 5-LPO, thereby inhibiting in vivo synthesis of leukotrienes. Therefore, 1,2-dihydroindazol-3-one and its derivatives may be new therapeutic agents such as rheumatoid arthritis, asthma and inflammatory colitis that are closely related to the synthesis of leukotriene in vivo. Among the 1,2-dihydroindazol-3-one derivatives, compounds that are 2-position substituted compounds represented by the following chemical formula show the strongest activity. Thus, by changing the substituent in 1,2-dihydroindazol-3-one and its derivatives, it has a different action.

  The 1,2-dihydroindazol-3-one derivative can be synthesized, for example, as follows.

As shown in the following reaction formula, synthesis is carried out by Robinson cyclization reaction between acrylic acid ethyl ester and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde. An example is known (for example, see Non-Patent Document 1).

In addition, as shown in the following reaction formula, iodine at the 2-position of 5-substituted-2-iodobenzoic acid is converted to 5-substituted 2-hydrazinobenzoic acid with hydrazine and dehydrated to form an indazol-3-one derivative. A method is known (see, for example, Patent Document 1).

ロイ エイ．（Ｒｏｙ，Ａ．）、他２名、ジャーナル オブ ザ ケミカル ソサイティ（Ｊｏｕｒｎａｌ ｏｆ ｔｈｅ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ）、英国、ロイヤル ソサイエティ オブ ケミストリー（Ｒｏｙａｌ Ｓｏｃｉｅｔｙ ｏｆ Ｃｈｅｍｉｓｔｒｙ）、１９９９年、第２０巻、ｐ．３００１−３００４ アルカイツ， シー．（Ａｒｋａｉｔｚ，Ｃ．）、他３名、ジャーナル オブ オーガニック ケミストリー（Ｊｏｕｒｎａｌ ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ）、米国、アメリカン ケミカル ソサイティ（Ａｍｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ）、２００６年、第７１巻、ｐ．３５０１−３５０５ 国際公開第２００／５１２１０９６号パンフレット In addition, as shown in the following reaction formula, methyl anthranilate is subjected to aminolysis in the presence of 4-bromoaniline to give 2-methylaminobenzoic acid methyl ester, and then an oxidative cyclization reaction is performed to produce indazole. A method for obtaining a -3-one derivative is known (for example, see Non-Patent Document 2).

Roy A. (Roy, A.), two others, Journal of the Chemical Society, UK, Royal Society of Chemistry, 1999, Vol. 20, p. 3001-3004 Archaite, Sea. (Arkaitz, C.), three others, Journal of Organic Chemistry, USA, American Chemical Society, 2006, Vol. 71, p. 3501-3505 International Publication No. 200/51221096 Pamphlet

  However, in the methods described in Non-Patent Documents 1 to 3, there are (1) a number of processes required, (2) some manufacturing processes need to be at a high temperature or a low temperature, and temperature control is required. (3) Some of them are not suitable for the purpose of synthesizing derivatives.

  That is, the present invention has been made in view of the above problems, and its object is to easily synthesize 1-substituted-1,2-dihydroindazol-3-one derivatives under relatively mild conditions, and It is to provide a novel derivative using this.

  Another object of the present invention is to provide a method for producing a hydrazide, which is a reaction raw material for a 1-substituted-1,2-dihydroindazol-3-one derivative, and a novel hydrazide using the same. It is in.

  That is, the present invention is as follows.

（式中、Ａは酸性官能基を、Ｈｒは、ハロゲンを、Ｒ^１〜Ｒ^４は水素原子、置換されていてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、シアノ基、カルボキシル基、オキシカルボニル基、カルバモイル基、アミノ基、スルフィノ基、ハロゲンを意味する。Ｒ^１とＲ^２、Ｒ^２とＲ^３、Ｒ^３とＲ^４とは、それぞれ結合して環を形成していてもよい。）
下記一般式（ＩＩ）で表されるヒドラジンと、

（式中、Ｒは、置換基や分岐を有していてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、スルフィノ基、オキシカルボニル基を示す。）
を、反応させて、下記一般式（ＩＩＩ）で表されるヒドラジド体を製造する。

（式中、Ｒ^１〜Ｒ^４は、水素原子、置換されていてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、シアノ基、カルボキシル基、オキシカルボニル基、カルバモイル基、アミノ基、スルフィノ基、ハロゲンを意味する。Ｒ^１とＲ^２、Ｒ^２とＲ^３、Ｒ^３とＲ^４とは、それぞれ結合して環を形成していてもよい。Ａは、酸性官能基を示す。Ｒは、置換基や分岐を有していてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、スルフィノ基、オキシカルボニル基を示す。） The hydrazide of the present invention is
2-haloaryl acid (derivative) acid chloride represented by the following general formula (I);

(In the formula, A represents an acidic functional group, Hr represents a halogen, R ^{1 to} R ⁴ represent a hydrogen atom, an optionally substituted alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, an aryl group, a heterocyclic group, an acyl group, a cyano group, a carboxyl group, an oxycarbonyl group, .R ¹ to mean a carbamoyl group, an amino group, a sulfino group, a halogen And R ² , R ² and R ³ , R ³ and R ⁴ may be bonded to each other to form a ring.)
Hydrazine represented by the following general formula (II):

(Wherein R is an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an aryl thioether group, which may have a substituent or a branch, An aryl group, a heterocyclic group, an acyl group, a sulfino group, and an oxycarbonyl group are shown.)
To produce a hydrazide represented by the following general formula (III).

(Wherein R ^{1 to} R ⁴ are a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an arylthioether, which may be substituted. Group, aryl group, heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, halogen, R ¹ and R ² , R ² and R ³ , R ³ And R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, R represents an alkyl group, a cycloalkyl group, a substituent group or a branched group, Alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, aryl group, heterocyclic group Acyl group, a sulfino group, an oxy carbonyl group.)

（式中、Ｒ^１〜Ｒ^４は、水素原子、置換されていてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、シアノ基、カルボキシル基、オキシカルボニル基、カルバモイル基、アミノ基、スルフィノ基、ハロゲンを意味する。Ｒ^１とＲ^２、Ｒ^２とＲ^３、Ｒ^３とＲ^４とは、それぞれ結合して環を形成していてもよい。Ａは、酸性官能基を示す。Ｒは、置換基や分岐を有していてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、スルフィノ基、オキシカルボニル基を示す。）
下記一般式（ＩＶ）で表される１−置換−１，２−ジヒドロインダゾール−３−オン誘導体を製造する。

（式中、Ｒ^１〜Ｒ^４は、水素原子、置換されていてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、シアノ基、カルボキシル基、オキシカルボニル基、カルバモイル基、アミノ基、スルフィノ基、ハロゲンを意味する。Ｒ^１とＲ^２、Ｒ^２とＲ^３、Ｒ^３とＲ^４とは、それぞれ結合して環を形成していてもよい。Ａは、酸性官能基を示す。Ｒは、置換基や分岐を有していてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、スルフィノ基、オキシカルボニル基を示す。） The method for producing the 1-substituted-1,2-dihydroindazol-3-one derivative of the present invention comprises:
The hydrazide represented by the following general formula (III) is intramolecularly coupled in the presence of a catalyst,

(Wherein R ^{1 to} R ⁴ are a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an arylthioether, which may be substituted. Group, aryl group, heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, halogen, R ¹ and R ² , R ² and R ³ , R ³ And R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, R represents an alkyl group, a cycloalkyl group, a substituent group or a branched group, Alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, aryl group, heterocyclic group Acyl group, a sulfino group, an oxy carbonyl group.)
A 1-substituted-1,2-dihydroindazol-3-one derivative represented by the following general formula (IV) is produced.

(Wherein R ^{1 to} R ⁴ are a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an arylthioether, which may be substituted. Group, aryl group, heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, halogen, R ¹ and R ² , R ² and R ³ , R ³ And R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, R represents an alkyl group, a cycloalkyl group, a substituent group or a branched group, Alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, aryl group, heterocyclic group Acyl group, a sulfino group, an oxy carbonyl group.)

（式中、Ｒ^１〜Ｒ^４は、水素原子、置換されていてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、シアノ基、カルボキシル基、オキシカルボニル基、カルバモイル基、アミノ基、スルフィノ基、ハロゲンを意味する。Ｒ^１とＲ^２、Ｒ^２とＲ^３、Ｒ^３とＲ^４とは、それぞれ結合して環を形成していてもよい。Ａは、酸性官能基を示す。Ｒは、置換基や分岐を有していてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、スルフィノ基、オキシカルボニル基を示す。） The hydrazide form of the present invention is represented by the following general formula (III).

(Wherein R ^{1 to} R ⁴ are a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an arylthioether, which may be substituted. Group, aryl group, heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, halogen, R ¹ and R ² , R ² and R ³ , R ³ And R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, R represents an alkyl group, a cycloalkyl group, a substituent group or a branched group, Alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, aryl group, heterocyclic group Acyl group, a sulfino group, an oxy carbonyl group.)

（式中、Ｒ^１〜Ｒ^４は、水素原子、置換されていてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、シアノ基、カルボキシル基、オキシカルボニル基、カルバモイル基、アミノ基、スルフィノ基、ハロゲンを意味する。Ｒ^１とＲ^２、Ｒ^２とＲ^３、Ｒ^３とＲ^４とは、それぞれ結合して環を形成していてもよい。Ａは、酸性官能基を示す。Ｒは、置換基や分岐を有していてもよい、アルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アルキニル基、アルコキシ基、アルキルチオ基、アリールエーテル基、アリールチオエーテル基、アリール基、複素環基、アシル基、スルフィノ基、オキシカルボニル基を示す。） The 1-substituted-1,2-dihydroindazol-3-one derivative of the present invention is represented by the following general formula (IV).

(Wherein R ^{1 to} R ⁴ are a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an arylthioether, which may be substituted. Group, aryl group, heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, halogen, R ¹ and R ² , R ² and R ³ , R ³ And R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, R represents an alkyl group, a cycloalkyl group, a substituent group or a branched group, Alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, aryl group, heterocyclic group Acyl group, a sulfino group, an oxy carbonyl group.)

  By using the method of the present invention, a hydrazide compound and a 1-substituted-1,2-dihydroindazol-3-one derivative can be easily synthesized under relatively mild conditions, and a novel derivative using the same is provided. can do.

  The present invention is described in detail below. In the present invention, (1) a hydrazide is produced from 2-haloaryl acid chloride and hydrazine, and (2) the hydrazide is coupled intramolecularly to give 1-substituted-1,2-dihydroindazole-3. -To produce an on derivative.

[Hydrazide]
The hydrazide form of the present invention is produced by reacting 2-haloaryl acid chloride with hydrazine.

(2-haloaryl acid chloride)
The 2-haloaryl acid chloride is produced, for example, by reacting 2-haloaryl acid with thionyl chloride.

In the formula, A represents an acidic functional group, Hr represents a halogen, R ^{1 to} R ⁴ represent a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, which may be substituted. Group, alkylthio group, aryl ether group, aryl thioether group, aryl group, heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, halogen. R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ may be bonded to each other to form a ring.

The acidic functional group is A, such as a carbonyl group (-CO-), a sulfino group (-SO ₂ -) include divalent acidic functional groups, such as.

  Examples of the halogen that is Hr include iodo, bromine, and chlorine, and iodo and bromine are more preferable. In the above method, the 2-haloaryl acid is treated with thionyl chloride to form a chloride. Therefore, when chlorine is used as the halogen, the optimal reaction conditions such as increasing the reaction temperature (for example, 70 ° C.) It is necessary to select. In addition, when iodine is used, the yield is improved under the same conditions. On the other hand, under the same conditions, bromine has a lower yield than iodine. However, since bromine is cheaper than iodine, the production cost can be reduced.

R ^{1 to} R ⁴ are hydrogen atoms, optionally substituted alkyl groups, cycloalkyl groups, alkenyl groups, cycloalkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, aryl ether groups, aryl thioether groups, aryl groups, It means a heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, and halogen.

Examples of the alkyl group constituting R ^{1 to} R ⁴ include saturated aliphatic hydrocarbon groups having 1 to 20 carbon atoms, more preferably 1 to 6 carbon atoms. Specifically, alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group, n-pentyl group, and n-hexyl group. More preferably, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, and a tert-butyl group are exemplified. Moreover, these alkyl groups may have a substituent. The substituent is not particularly limited, and examples thereof include an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, and an amino group.

Examples of the cycloalkyl group constituting R ^{1 to} R ⁴ include saturated alicyclic hydrocarbon groups having 3 to 20 carbon atoms. Specific examples include cycloalkyl groups such as cyclopropyl, cyclohexyl, norbornyl, and adamantyl. These cycloalkyl groups may have a substituent such as an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, and an amino group, similarly to the above alkyl group.

Examples of the alkenyl group constituting R ^{1 to} R ⁴ include unsaturated aliphatic hydrocarbon groups having 2 to 20 carbon atoms. Specific examples include unsaturated aliphatic hydrocarbon groups containing a double bond such as a vinyl group, an allyl group, or a butadienyl group. Similarly to the alkyl group, it may have a substituent such as an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, or an amino group.

The cycloalkenyl group constituting R ¹ to R ^4, carbon atoms include unsaturated alicyclic hydrocarbon group containing a double bond having 2 to 20. Specific examples include a cyclopentenyl group, a cyclopentadienyl group, and a cyclohexenyl group. Similarly to the alkyl group, it may have a substituent such as an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, or an amino group.

The alkynyl group constituting R ¹ to R ^4, carbon atoms include unsaturated aliphatic hydrocarbon group containing a triple bond having 2 to 20. Specifically, an ethynyl group is exemplified. Similarly to the alkyl group, it may have a substituent such as an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, or an amino group.

Examples of the alkoxy group constituting R ^{1 to} R ⁴ include an aliphatic hydrocarbon group having an ether bond having 1 to 20 carbon atoms. Specifically, a methoxy group etc. are illustrated. The aliphatic hydrocarbon group may have a substituent such as an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, and an amino group, similarly to the above alkyl group.

The alkylthio group constituting R ¹ to R ^4, in which the oxygen atom of the ether bond of the alkoxy group is substituted with a sulfur atom. Similarly to the alkyl group, it may have a substituent such as an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, or an amino group.

Examples of the aryl group constituting R ^{1 to} R ⁴ include aromatic hydrocarbon groups having 6 to 40 carbon atoms. Specific examples include a phenyl group, a naphthyl group, a biphenyl group, a phenanthryl group, a terphenyl group, and a pyrenyl group. Similarly to the alkyl group, it may have a substituent such as an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, or an amino group.

Examples of the aryl ether group constituting R ^{1 to} R ⁴ include an aromatic hydrocarbon group having an ether bond having 6 to 40 carbon atoms. Specifically, a phenoxy group and the like are exemplified. Similarly to the alkyl group, it may have a substituent such as an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, or an amino group.

The aryl thioether group constituting R ¹ to R ^4, in which the oxygen atom of the ether bond of the aryl ether group is substituted with a sulfur atom. Similarly to the alkyl group, it may have a substituent such as an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, or an amino group.

Examples of the heterocyclic group constituting R ^{1 to} R ⁴ include an aliphatic ring or an aromatic ring having 3 to 20 carbon atoms and having atoms other than carbon in the ring. Specific examples include a group consisting of a pyran ring, a piperidine ring, a cyclic amide, a furanyl group, a thiophenyl group, an oxazolyl group, a pyridyl group, and a quinolinyl group. These heterocyclic groups may have a substituent such as an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, and an amino group, similarly to the above alkyl group.

The acyl group constituting R ^{1 to} R ⁴ refers to a group in which a carbonyl group is bonded to hydrogen, a hydrocarbon having 1 to 20 carbon atoms, or the like. Specifically, groups composed of an acetyl group and a benzoyl group are exemplified. These acyl groups may have a substituent such as an alkyl group, an aryl group, a heteroaryl group, a halogen, a nitro group, a sulfino group, and an amino group, similarly to the above alkyl group.

A hydrocarbon having 1 to 20 carbon atoms may be bonded to the oxycarbonyl group constituting R ^{1 to} R ⁴ . For example, t-butyl-oxycarbonyl group and the like.

A cyano group, a carboxyl group, a carbamoyl group, an amino group, a sulfino group, a halogen (fluorine, chlorine, bromine, iodine) and the like can also constitute R ^{1 to} R ⁴ .
[Synthesis of hydrazide]

It is hydrazine that is reacted with the 2-haloaryl acid chloride. Hydrazine refers to a compound in which the hydrogen atom of NH ₂ —NH ₂ is substituted with an organic group R as represented by the following general formula (II).

In the formula, R is an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an aryl thioether group, an aryl, which may have a substituent or a branch. A group, a heterocyclic group, an acyl group, a sulfino group and an oxycarbonyl group; These groups are the same as the groups constituting the above R ^{1 to} R ⁴ . Examples of the sulfino group include those in which an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group or the like as described above is bonded.

  Hydrazine may be used alone, or a hydrazine that forms a salt such as hydrazine hydrochloride may be used.

As shown in the following reaction formula, the hydrazide is synthesized by reacting 2-haloaryl acid (derivative) acid chloride with hydrazine or hydrazine salt together with a solvent at room temperature for a predetermined time. The reaction time is about 1 to 6 hours. In the formula, R ^{1 to} R ⁴ , A, and R are the same as described above.

  A known organic solvent can be used as the solvent to be used. For example, anhydrous tetrahydrofuran (THF), dichloromethane (DCM), dimethyl sulfoxide (DMSO), acetonitrile, dichloroethane and the like can be mentioned. These solvents may be used by adding a sodium hydride solution or the like. Depending on the hydrazine or hydrazine salt used in the reaction, the use of an organic solvent, a sodium hydride solution, and the like can be appropriately changed. Examples of the alkali that can be used include sodium hydride, potassium hydroxide, lithium hydroxide, triethylamine, and pyridine.

  According to the method of the present invention, for example, 2-iodobenzoic acid N′-phenyl-hydrazide, 2-iodobenzoic acid N′-tert-butyl-hydrazide, 2-iodobenzoic acid N ′-(4-nitrophenyl) -hydrazide 2-iodobenzoic acid N′-naphthalen-1-yl-hydrazide, 2-iodobenzoic acid N′-cyclohexyl-hydrazide, 2-iodobenzoic acid N ′-(2-methoxy-phenyl) -hydrazide, 2-iodo Novel hydrazides such as benzoic acid N′-quinolin-2-yl-hydrazide and 2-iodobenzoic acid N ″-(2,4,6-trichlorophenyl) -hydrazide can be produced. A novel hydrazide can be produced by changing the 2-haloaryl acid and hydrazine to be used.

(Another production method of hydrazide)
The hydrazide compound of the present invention can also be obtained by directly reacting 2-halobenzoic acid and hydrazine using a dehydration condensing agent. According to this method, when 2-halobenzoic acid to be used has a substituent such as when R ³ has a substituent, a hydrazide can be produced with high efficiency. Further, since there is no need to make a chloride of 2-halobenzoic acid, the reaction process can be shortened.

  As the dehydrating condensing agent, a known dehydrating condensing agent can be used. For example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), 1-hydroxybenzotriazole (HOBt), diphenyl phosphate azide (DPPA), and the like.

[Synthesis of 1-Substituted-1,2-Dihydroindazol-3-one Derivative]
As shown in the following reaction formula, the obtained hydrazide is cyclized intramolecularly using a catalyst to synthesize a 1-substituted-1,2-dihydroindazol-3-one derivative. In the formula, R ^{1 to} R ⁴ , A, and R are the same as described above.

(catalyst)
In the present invention, a copper catalyst is used as the catalyst. A well-known copper catalyst can be used for a copper catalyst, and the thing of any state of copper (zero valence), copper (monovalent), and copper (divalent) may be sufficient as it. For example, a halogenated material such as cuprous iodide or cuprous bromide may be used.

  Moreover, you may use an amino acid together with a copper catalyst. By using an amino acid in combination, the yield of the resulting 1-substituted-1,2-dihydroindazol-3-one derivative can be increased and the production of by-products can be reduced.

  There is no restriction | limiting in particular as an amino acid which can be used, A well-known amino acid can be used. Specifically, any of neutral amino acids, acidic amino acids, and basic amino acids may be used. Preferred amino acids are neutral amino acids. Examples of neutral amino acids include L-proline, but are not limited thereto. A plurality of amino acids may be used.

  The amount of catalyst used is 1 to 10 mol% for the copper catalyst and 10 to 30 mol% for the amino acid with respect to the substrate. In particular, when a combined catalyst of a copper catalyst and an amino acid is used, 1 to 5 mol% of copper iodide and at least a 1-substituted-1,2-dihydroindazol-3-one derivative can be synthesized.

(Reaction temperature)
The reaction can be performed by heating to room temperature to about 80 ° C. In the present invention, a similar yield can be obtained whether the reaction is performed at room temperature or the reaction is performed by heating. Therefore, the reaction is preferably performed at room temperature where the reaction conditions are mild.

(Production of 1-substituted-1,2-dihydroindazol-3-one derivatives)
The indole compound of the present invention is produced, for example, as follows.

  An alkali is put into a reaction vessel, and an organic solvent such as dimethyl sulfoxide (DMSO) is added.

  The reason why the alkali is added is to trap (neutralize) acidic substances such as hydrogen iodide to be generated. Examples of the alkali that can be used include sodium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, potassium phosphate, triethylamine, tetramethylguanidine, diazabicycloundecene (DBU) and the like.

  The organic solvent that can be used is not limited to DMSO, and includes known organic solvents such as tetrahydrofuran (THF), dichloromethane, acetonitrile, dichloroethane, and the like. In this production process, the organic solvent does not need to be dehydrated, and the hydrous solvent taken out from the storage container can be used as it is.

  Predetermined amounts of hydrazine, catalyst (copper catalyst, amino acid), alkali, and organic solvent are placed in a reaction vessel, and the reaction vessel is allowed to react with stirring under a nitrogen stream at room temperature to warming. Completion of the reaction is performed by confirming the disappearance of acid hydrazine. Distilled water is added to the reaction mixture to stop the reaction. This liquid is extracted using an organic solvent such as ethyl acetate to obtain an organic layer. The organic layer is washed with distilled water and saturated saline and dried using a desiccant such as anhydrous magnesium sulfate. The obtained organic layer is distilled under reduced pressure to obtain the desired 1-substituted-1,2-dihydroindazol-3-one derivative. Alternatively, the target product is collected by silica gel preparative thin layer chromatography or column chromatography. The kind of developing solvent, the mixing ratio, and the like vary depending on the 1-substituted-1,2-dihydroindazol-3-one derivative obtained. Further, the number of chromatographs is not limited to one, and may be performed a plurality of times.

  Using the production method of the present invention, a known 1-substituted-1,2-dihydroindazol-3-one derivative such as 1-phenyl-1,2-dihydroindazol-3-one can be obtained under mild conditions in a yield. Can be manufactured well. Also, 1-tert-butyl-1,2-dihydroindazol-3-one, 1- (4-nitrophenyl) -1,2-dihydroindazol-3-one, 1-naphthalen-1-yl-1,2-dihydro Indazol-3-one, 1-cyclohexyl-1,2-dihydroindazol-3-one, 1- (2-methoxyphenyl) -1,2-dihydroindazol-3-one, 1-quinolin-2-yl-1,2- A novel 1-substituted-1,2-dihydroindazol-3-one derivative such as dihydroindazol-3-one can be produced in good yield under mild conditions.

  Thus, various 1-substituted-1,2-dihydroindazol-3-one derivatives can be synthesized using the production method of the present invention. Further, when the obtained 1-substituted-1,2-dihydroindazol-3-one derivative is used as a raw material, various further advanced compounds can be obtained.

  EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to this Example.

  The analysis and separation / purification of the compounds were performed using the following measuring apparatus.

Infrared absorption (IR) spectrum: JASCO FT / IR-460 plus (absorption wavelength is shown in cm ⁻¹ ).

  Nuclear magnetic resonance (NMR) spectrum: JEOL JMTC-400 / 54 / SS 400 MHz (chemical shifts in the text are indicated by δ values)

  Melting point measuring device: BUCHI Melting point B-545

  FAB-MS: High resolution mass spectrum-Fast atom bombardment (HRMS-FAB): JEOL JMS-700 spectrometer.

  HRMS (ESI): High resolution mass spectrometry (Electrospray ionization): Hitachi Nano Frontier L

  Silica gel for column chromatography: BW-200 (Fuji Silysia)

Thin layer chromatography (TLC): MACHEREY-NAGEL DC-Fertigplatten SIL G-25 UV ₂₅₄ plate

[Synthesis of 2-halocarboxylic acid]
(Synthesis Example 1-1)
(Synthesis of 2-iodobenzoic acid acid chloride (2-Iodo-benzoyl-chloride (1)))
2-Iodobenzoic acid (1.98 g, 8.0 mmol) and thionyl chloride (10 ml) were added to a 50 ml eggplant-shaped flask, and a stir bar was added to cap the septum. After refluxing for 2 hours to stop the reaction, the reaction mixture was concentrated and azeotroped twice with benzene to obtain Compound 1 (2.2 g, total amount) as a yellow oil.
Thin layer chromatograph: Rf = 0.63 (hexane: ethyl acetate = 4: 1 (volume ratio));
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.07 (d, 1H, J = 7.3 Hz, one of Ar), 8.04 (d, 1H, J = 7.6 Hz, one of
Ar), 7.50 (t, 1H, J = 7.3 Hz, one of Ar), 7.25 (dd, 1H, J = 7.3, 7.6 Hz, one of Ar).
¹³ C-NMR (136 MHz, CDCl ₃ ) δ: 166.8, 141.8, 137.7, 134.1, 133.3, 128.2, 93.7.

(Synthesis Example 1-2)
(Synthesis of 2-bromobenzoic acid acid chloride (2-Bromo-benzoyl-chloride (29)))
2-Bromobenzoic acid (2.01 g, 10.0 mmol) and thionyl chloride (10 ml) were added to a 50 ml eggplant-shaped flask, a stir bar was added, and a Dimroth cooling ring equipped with a calcium chloride ring was attached. After refluxing for 2 hours to stop the reaction, the reaction mixture was concentrated and azeotroped twice with benzene to obtain Compound 29 (2.20 g, total amount) as a colorless oil.
Thin layer chromatograph: Rf = 0.51 (hexane: ethyl acetate = 9: 1 (volume ratio));
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.95 (dd, 2H, J = 12.7, 7.8 Hz, Ar), 7.40 (t, 1H, J = 7.8 Hz Ar), 7 .09-7.18 (m, 1H, Ar);
¹³ C-NMR (136 MHz, CDCl ₃ ) δ: 166.8, 141.8, 137.7, 134.1, 133.3, 128.2, 93.7.

(Synthesis Example 1-3)
(Acid chloride of 4-methyl-2-bromobenzoic acid (synthesis of 4-methyl-2-bromo-benzoyl-chloride (30)))
4-Methyl-2-bromobenzoic acid (0.22 g, 1.0 mmol) and thionyl chloride (10 ml) were added to a 50 ml eggplant-shaped flask, and a stirrer was added. Then, a Dimroth cooling ring equipped with a calcium chloride ring was added. It was attached. After refluxing for 2 hours to stop the reaction, the reaction mixture was concentrated and azeotroped twice with benzene to obtain a novel compound 30 (0.23 g, total amount) as a colorless oil.
Thin layer chromatograph: Rf = 0.57 (hexane: ethyl acetate = 9: 1 (volume ratio));
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.94 (d, 1H, J = 8.0 Hz, Ar), 7.46 (s, 1H, Ar), 7.17 (d, 1H, J = 8.5, Ar), 2.33 (s, 3H, Me);
¹³ C-NMR (136 MHz, CDCl ₃ ) δ: 165.3, 134.2, 131.3, 134.2, 128.3, 128.2, 122.0, 21.2.

(Synthesis Example 1-4)
(Acid chloride of 5-fluoro-2-bromobenzoic acid (synthesis of 5-Fluoro-2-Bromo-benzoyl-chloride (31)))
Add 5-fluoro-2-bromobenzoic acid (0.22 g, 1.0 mmol) and thionyl chloride (10 ml) to a 50 ml eggplant-shaped flask, and after adding a stir bar, place a Dimroth cooling ring equipped with a calcium chloride ring. It was attached. After refluxing for 2 hours to stop the reaction, the reaction mixture was concentrated and azeotroped twice with benzene to obtain Compound 31 (0.23 g, total amount) as a colorless oil.
Thin layer chromatograph: Rf = 0.57 (hexane: ethyl acetate = 9: 1 (volume ratio));
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.68 (dd, 1H, J = 8.5, 2.7 Hz, Ar), 7.59 (dd, 1H, J = 8.5, 4.). 9 Hz Ar), 7.09 (dt, 1H, J = 8.3, 2.7 Hz, Ar);
¹³ C-NMR (136 MHz, CDCl ₃ ) δ: 164.8, 162.3, 159.8, 136.2, 128.2, 121.7, 120.3, 115.7.

(Synthesis Example 1-5)
(Synthesis of 5-methoxy-2-bromobenzoic acid acid chloride (5-Methoxy-2-Bromo-benzoyl-chloride (32)))
After adding 5-methoxy-2-bromobenzoic acid (0.23 g, 1.0 mmol) and thionyl chloride (10 ml) to a 50 ml eggplant-shaped flask and adding a stir bar, a Dimroth cooling ring equipped with a calcium chloride ring is added. It was attached. After refluxing for 2 hours to stop the reaction, the reaction mixture was concentrated and azeotroped twice with benzene to obtain Compound 32 (0.24 g, total amount) as a colorless oil.
Thin layer chromatograph: Rf = 0.38 (hexane: ethyl acetate = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.40-7.54 (m, 2H, Ar), 6.87-6.92 (m, 1H, Ar), 3.78 (s, 3H, OMe);
¹³ C-NMR (136 MHz, CDCl ₃ ) δ: 166.7, 158.6, 135.4, 128.2, 120.5, 118.3, 111.5, 55.8.

(Synthesis Example 1-6)
(Synthesis of 2-chloro-chlorobenzoic acid acid chloride (2-Chloro-benzoyl-chloride (33)))
2-Chlorobenzoic acid (0.16 g, 1.0 mmol) and thionyl chloride (10 ml) were added to a 50 ml eggplant-shaped flask, a stir bar was added, and a Dimroth cooling ring equipped with a calcium chloride ring was attached. After refluxing for 2 hours to stop the reaction, the reaction mixture was concentrated and azeotroped twice with benzene to obtain Compound 33 (0.17 g, total amount) as a colorless oil.
Thin layer chromatograph: Rf = 0.54 (hexane: ethyl acetate = 9: 1 (volume ratio));
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.96 (dd, 1H, J = 8.0, 1.7 Hz, Ar), 7.34-7.41 (m, 2H, Ar), 7 .25-7.30 (m, 1H, Ar);
¹³ C-NMR (136 MHz, CDCl ₃ ) δ: 165.0, 134.4, 133.4, 131.4, 128.2 (2C), 127.0.

[Synthesis of acid hydrazine]
(Synthesis Example 2-1) Synthesis of 2-iodobenzoic acid N′-phenyl-hydrazide (2-Iodo-benzoic acid N′-phenyl-hydrazide (2)) 6 ml of phenylhydrazine (0.17 g, 1.6 mmol) Dissolved in dichloromethane (hereinafter referred to as “DCM”), 2 ml of 10% NaOH solution was added to the solution, and acid chloride 1 (0.45 g, 1.7 mmol) dissolved in 4 ml of DCM was added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the desiccant was filtered and the solvent was distilled off under reduced pressure. Silica gel chromatography (stepwise conditions: 100% hexane to 50% EtOAc in hexane) By subjecting, hydrazide body 2 is white crystals (0.38 g, yield: 67%) was obtained.
Thin layer chromatograph: Rf = 0.73 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (nuclear magnetic resonance) (400 MHz, CD ₃ OD) δ: 7.94 (d, 1H, J = 7.8 Hz, one of Ar), 7.46-7.50 (m, 2H, Ar ), 7.17-7.24 (m, 3H, Ar), 6.96-7.01 (m, 2H, Ar), 6.83 (t, 1H, J = 7.3 Hz, one of Ar). ;
¹³ C-NMR (nuclear magnetic resonance) (136 MHz, CD3OD) δ: 172.3, 149.8, 142.2, 141.1, 132.5, 130.0, 129.5, 129.3, 121. 3, 114.5, 93.5;
IR (infrared spectrum) (neat): 3244 (NH), 1654 (C═O), 1494 (CN), 1315, 913, 750, 689 cm ⁻¹ ;
m. p. (Melting point) 199 ° C-201 ° C.

Synthesis Example 2-2 Synthesis of 2-iodobenzoic acid N′-tert-butyl-hydrazide (2-Iodo-benzoic acid N′-tert-butyl-hydrazide (3)) tert-butylhydrazine hydrochloride (0. 78 g, 6.3 mmol) was dissolved in 18 ml of DCM and 12 ml of 10% NaOH solution was added to the solution. Further, acid chloride 1 (1.67 g, 6.3 mmol) dissolved in 4 ml of DCM was added and stirred vigorously at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering the desiccant and distilling off the solvent under reduced pressure, the residue was subjected to silica gel chromatography (stepwise conditions: 100% hexane to 50% EtOAc in hexane) to give hydrazide 3 (1.72 g) as white crystals. Yield: 86%).
Thin layer chromatograph: Rf = 0.36 (hexane: EtOAc = 1: 1);
¹ H-NMR (400 MHz, (CD ₃ ) ₂ CO) δ: 8.87 (br s, 1 H, NH), 7.89 (dd, 1 H, J = 1.0, 8.0 Hz, one of Ar) , 7.44 (ddd, 1H, J = 1.0, 1.2, 7.3 Hz, one of Ar), 7.37 (dd, 1H, J = 2.0, 7.6 Hz, one of Ar) 7.17 (ddd, 1H, J = 1.2, 2.0, 7.3 Hz, one of Ar), 1.16 (s, 9H, t-Bu);
¹³ C-NMR (136 MHz, (CD ₃ ) ₂ CO) δ: 168.8, 142.7, 140.4, 131.7, 129.4, 128.8, 93.6, 55.7, 27. 8 (3C).

Synthesis Example 2-3 Synthesis of 2-iodobenzoic acid N ′-(4-nitrophenyl) -hydrazide (2-Iodo-benzoic acid N ′-(4-nitro-phenyl) -hydrazide (4)) 4-Nitrophenylhydrazine (1.16 g, 7.6 mmol) was placed in a three-necked flask, and was replaced with nitrogen gas and capped with a septum. Next, acid chloride 1 (2.02 g, 7.6 mmol) dissolved in 40 ml of dry THF was added. The reaction was stopped by refluxing for 2 hours and confirming the disappearance of the starting material by TLC. The solvent was distilled off under reduced pressure and subjected to silica gel chromatography (stepwise conditions: 100% hexane to 50% EtOAc in hexane) to obtain hydrazide 4 (1.73 g, yield: 60%) as cream crystals. It was.
Thin layer chromatograph: Rf = 0.26 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.51 (s, 1H, NH), 9.33 (s, 1H, NH), 8.10 (d, 2H, J = 9.3 Hz, Ar), 7.95 (d, 1H, J = 7.8 Hz, one of Ar), 7.52 (d, 2H, J = 4.4 Hz, Ar), 7.22-7.28 (m, 1H, one of Ar), 6.95 (d, 2H, J = 9.0 Hz, Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 168.6, 154.7, 140.6, 139.4, 138.2, 131.6, 128.6, 128.2, 125.9, 110.9 , 93.7.

Synthesis Example 2-4 Synthesis of 2-iodobenzoic acid N′-naphthalen-1-yl-hydrazide (5-Iodo-benzoic acid N′-naphthalen-1-yl-hydrazide (5)) 1-naphthylhydrazine hydrochloride The salt (1.22 g, 6.3 mmol) was suspended in 18 ml DCM and 12 ml of 10% NaOH solution was added to the solution. Furthermore, acid chloride 1 (1.67 g, 6.3 mmol) dissolved in 4 ml of DCM was added and stirred vigorously at room temperature for 6 hours. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering the desiccant and distilling off the solvent under reduced pressure, the residue was subjected to silica gel chromatography (stepwise conditions: 100% hexane to 50% EtOAc in hexane) to give hydrazide 5 (1.80 g) as light brown crystals. Yield: 74%).
Thin layer chromatograph: Rf = 0.60 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.34 (s, 1 H, NH), 8.47 (br s, 1 H, NH), 8.28 (d, 1 H, J = 6.8 Hz, one of Ar), 7.97 (d, 1H, J = 7.0 Hz, one of Ar), 7.84 (dd, 1H, J = 1.7, 6.8 Hz, one of Ar), 7.22-7 .58 (m, 7H, naphthhalen), 7.04 (dd, 1H, J = 1.7, 7.0 Hz, one of Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 168.6, 143.8, 141.0, 139.6, 133.8, 131.4, 128.7, 128.1, 128.0, 126.3 , 125.8, 124.6, 122.3, 121.9, 118.6, 105.6, 93.7;
IR (neat): 3332, 3248 (NH), 1655 (C═O), 1516, 767 cm ⁻¹ ;
HRMS (high resolution mass _{spectrometry) (FAB (+)):} calcd for C 17 H 13 ON 2 I 388.0073; found, 388.0058;
m. p. 196 ° C-197 ° C.

Synthesis Example 2-5 Synthesis of 2-iodobenzoic acid N′-cyclohexyl-hydrazide (2-Ido-benzoic acid N′-cyclohexyl-hydrazide (6)) Cyclohexylhydrazine hydrochloride (0.51 g, 3.4 mmol) Was suspended in 9 ml DCM and 6 ml of 10% NaOH solution was added to the solution. Further, acid chloride 1 (0.90 g, 3.4 mmol) dissolved in 2 ml of DCM was added, and the mixture was vigorously stirred at room temperature for 5 hours. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered and the solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography (stepwise conditions: 100% hexane to 50% EtOAc in hexane), and further subjected to preparative TLC (hexane: EtOAc = 1: 1). The hydrazide 6 (0.12 g, 11% yield) as a colorless oil was obtained as a mixture of 71:29 amide rotamers.
Thin layer chromatograph: Rf = 0.36 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, CD ₃ Cl) δ: 7.85 (d, 0.7 H, J = 7.8 Hz, Ar), 7.78 (d, 0.3 H, J = 7.8 Hz, Ar) 7.32-7.47 (m, 1H, one of Ar), 7.20-7.27 (m, 2H, Ar), 7.07 (ddd, 1H, J = 7.6, 7.8, 23.4Hz, one
of Ar), 4.60 (t, 0.3 H, J = 10.9 Hz, Ar), 4.22 (br s, 1.4 H, NH), 3.60 (br s, 0.6 H, NH) 3.14 (t, 0.7H, J = 10.7 Hz) 0.90-2.02 (m, 11H, cyclohexane);
¹³ C-NMR (136 MHz, CD ₃ Cl) δ: 171.6, 144.0, 139.3, 138.4, 130.3, 129.5, 128.2, 128.1, 126.7, 126 6, 92.6, 92.4, 59.5, 53.9, 30.0, 28.5, 25.3, 25.1, 24.9;
IR (neat): 2929 (NH), 2856, 1629 (C═O), 1424 (cyclohexane), 1018, 752 cm ^−1.

(Synthesis Example 2-6) Synthesis of 2-iodobenzoic acid N ′-(2-methoxy-phenyl) -hydrazide (2-Iodo-benzoic acid N ′-(2-methoxy-phenyl) -hydrazide (7)) 2 -Methoxyphenylhydrazine hydrochloride (0.59 g, 3.4 mmol) was suspended in 9 ml DCM and 6 ml of 10% NaOH solution was added to the solution. Further, acid chloride 1 (0.90 g, 3.4 mmol) dissolved in 2 ml of DCM was added, and the mixture was vigorously stirred at room temperature for 5 hours. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Next, the desiccant was filtered and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (stepwise conditions: 100% hexane to 50% EtOAc in hexane), whereby hydrazide 7 (a pale orange crystal). 0.80 g, yield: 65%).
Thin layer chromatograph: Rf = 0.56 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.29 (s, 1H, NH), 7.92 (d, 1H, J = 8.0 Hz, one of Ar), 7.42-7.52 (m , 2H, Ar), 7.22 (dt, 1H, J = 1.7, 7.3 Hz, one of Ar), 6.95 (dd, 1H, J = 1.5, 7.6 Hz, one of Ar ), 6.91 (d, 1H, J = 8.0 Hz, one of Ar), 6.83 (ddd, 1H, J = 1.5, 7.3, 7.6 Hz, one of Ar), 6. 77 (dt, 1H, J = 1.5, 7.6 Hz, one of Ar), 3.83 (s, 1H, OMe);
¹³ C-NMR (136 MHz, CD ₃ Cl) δ: 168.4, 146.5, 140.9, 139.3, 137.8, 131.3, 128.6, 128.1, 120.7, 119 .3, 112.0, 110.4, 93.8, 55.5;
m. p. 154 ° C-155 ° C.

(Synthesis Example 2-7) Synthesis of 2-iodobenzoic acid N′-quinolin-2-yl-hydrazide (2-Iodo-benzoic acid N′-quinolin-2-yl-hydrazide (8)) 2-Hydrazinoquinoline (1.5 mmol, 0.24 g) was placed in the flask and replaced with nitrogen gas to cap the septum. Then acid chloride 1 (1.5 mmol, 0.40 g) dissolved in 12 ml dry THF was added. The reaction was stopped by refluxing for 2 hours and confirming the disappearance of the starting material by TLC. The THF layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Next, the desiccant is filtered, the solvent is distilled off under reduced pressure, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel chromatography (stepwise conditions: 100% hexane to 50% EtOAc in hexane) to give cream crystals. As a result, hydrazide 8 (0.16 g, yield: 28%) was obtained.
Thin-layer chromatograph Rf = 0.62 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.61 (s, 1 H, NH), 8.40 (s, 1 H, NH), 8.19 (d, 1 H, J = 8.8 Hz, one of Ar), 7.92 (d, 1H, J = 7.6 Hz, one of Ar), 7.79 (dd, 2H, J = 8.0, 9.0 Hz, Ar), 7.45-7.75. (M, 2H, Ar), 7.02-7.40 (m, 4H, Ar);
¹³ C-NMR (136 MHz, CDCl ₃ ) δ: 168.7, 146.1, 142.0, 140.2, 138.7, 138.5, 138.2, 131.9, 130.7, 129. 9, 128.6, 128.3, 128.1, 127.9, 127.5, 126.9, 126.2, 116.3, 92.3.

(Synthesis Example 2-8) 2-Iodobenzoic acid N ″-(2,4,6-trichlorophenyl) -hydrazide (2-Iodo-benzoic acid N ″-(2,4,6-trichloro-phenyl) -Synthesis of hydrazide (9)) 2,4,6-trichlorophenylhydrazine (0.48 g, 2.3 mmol) was placed in a 50 ml three-necked flask and replaced with nitrogen gas and capped with a septum. Then acid chloride 1 (0.61 g, 2.3 mmol) dissolved in 20 ml dry THF was added. The reaction was stopped by refluxing for 2 hours and confirming the disappearance of the starting material by TLC. The THF layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Next, the desiccant was filtered, the solvent was distilled off under reduced pressure, the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate and recrystallized to give a novel hydrazide 9 (0.69 g, 69%) as white crystals. )
Thin-layer chromatograph Rf = 0.72 (hexane: EtOAc = 4: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.53 (s, 1 H, NH), 7.89 (d, 1 H, J = 7.8 Hz, one of Ar), 7.38-7.49 (m , 3H, Ar), 7.19 (t, 1H, J = 6.6 Hz, one of Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 167.9, 140.9, 139.9, 139.6, 131.4, 128.8, 128.5, 127.9, 125.4, 124.8 93.9.
m. p. 204 ° C-205 ° C.

Synthesis Example 2-9 Synthesis of 2-bromobenzoic acid N′-tert-butyl-hydrazide (2-Bromo-benzoic acid N′-tert-butyl-hydrazide (34)) tert-butylhydrazine hydrochloride (0. 37 g, 3.0 mmol) was dissolved in 18 ml DCM and 12 ml of 10% NaOH solution was added to the solution. Furthermore, acid chloride 29 (0.66 g, 3.0 mmol) dissolved in 4 ml of DCM was added and stirred vigorously at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering the desiccant and evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography (stepwise: 100% hexane to 50% EtOAc in hexane), whereby hydrazide 34 (0.53 g, white crystals) was obtained. 65%) was obtained.
Thin-layer chromatograph Rf = 0.46 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 8.12 (br s, 1 H, NH), 7.41 (dd, 1 H, J = 1.0, 7.7 Hz, one of Ar), 7.27 ( dd, 1H, J = 1.7, 7.6 Hz, one of Ar), 7.18 (dt, 1H, J = 7.3, 1.2 Hz, one of Ar), 7.12 (dt, 1H, J = 7.8, 2.0 Hz, one of Ar), 4.63 (brs, 1H, NH), 1.04 (s, 9H, t-Bu);
¹³ C-NMR (136 MHz, DMSO) δ: 166.5, 136.0, 132.9, 130.9, 129.3, 127.0, 119.3, 55.2, 26.9 (3C);
IR (neat): 3382 (NH), 2969 (Ar), 2878 (t-Bu), 1648 (C = O), 1561, 1473, 1434, 1338, 853, 735 cm ⁻¹ ;
_{HRMS (FAB): calcd for C} 11 H 16 Br N 2 O 271.0419; found, 271.0449;
m. p. : 85-87 ° C.

Synthesis Example 2-10 Synthesis of 2-bromo-benzoic acid N′-phenyl-hydrazide (2-Bromo-benzoic acid N′-phenyl-hydrazide (35)) Phenyl hydrazine (0.48 g, 4.4 mmol) was prepared. Dissolved in 6 ml DCM, 2 ml of 10% NaOH solution was added to the solution. Further, acid chloride 29 (0.96 g, 4.4 mmol) dissolved in 4 ml of DCM was added and stirred vigorously at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering the desiccant and evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography (stepwise: 100% hexane to 50% EtOAc in hexane), whereby hydrazide 35 (0.52 g, 40% %).
Thin layer chromatograph Rf = 0.73 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.20 (s, 1 H, NH), 8.00 (br s, 1 H, NH), 7.70 (d, 1 H, J = 7.5 Hz, one of Ar), 7.44-7.53 (m, 2H, Ar), 7.36-7.45 (m, 1H, one of Ar), 7.17 (t, 2H, J = 7.9, Ar) ), 6.86 (d, 2H, J = 7.7 Hz, Ar), 6.73 (t, 1H, J = 7.2 Hz, Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 167.2, 149.1, 137.4, 133.0, 131.5, 129.2, 128.8 (2C), 127.8, 119.3 118.7 (2C), 112.4;
IR (neat): 3242 (NH), 3009 (Ar), 2920 (Me), 1656 (C═O), 1495 (Ar), 1317, 915, 752 cm ⁻¹ ;
m. p. : 170-172 ° C.

Synthesis Example 2-11 Synthesis of 2-bromobenzoic acid N ′-(4-nitro-phenyl) -hydrazide (2-Bromo-benzoic acid N ′-(4-nitro-phenyl) -hydrazide (36)) Dimroth 4-Nitrophenylhydrazine (0.46 g, 3.0 mmol) was placed in a 100 ml three-necked flask equipped with a condenser, and the septum was capped with nitrogen gas. Then acid chloride 29 (0.66 g, 3.0 mmol) dissolved in 40 ml dry THF was added. The reaction was stopped by refluxing for 2 hours and confirming the disappearance of the starting material by TLC. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (stepwise: 100% hexane to 50% EtOAc in hexane) to obtain hydrazide 36 (0.74 g, 74%) as brown crystals.
Thin-layer chromatograph Rf = 0.44 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.57 (s, 1H, NH), 9.35 (s, 1H, NH), 8.10 (d, 2H, J = 9.3 Hz, Ar), 7.73 (dd, 1H, J = 7.8, 1.0 Hz, one of Ar), 7.58 (dd, 2H, J = 7.3, 1.8 Hz, Ar), 7.51 (dt, 1H, J = 7.6, 1.2 Hz, 1H, one of Ar), 7.44 (dt, 1H, J = 7.6, 1.7 Hz, one of Ar), 6.93 (d, 2H, J = 7.3 Hz, one of Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 167.1, 154.7, 138.2, 136.8, 133.0, 131.8, 129.3, 127.8, 126.0, 119.2 , 110.9;
IR (neat): 3277 (NH), 1630 (C═O), 1596, 1505 (Ar), 1330, 1271, 1109, 839, 749, 687, 597 cm ⁻¹ ;
m. p. : 213-215 ° C.

Synthesis Example 2-12 Synthesis of 2-bromo-4-methyl-benzoic acid N′-phenyl-hydrazide (2-Bromo-4-methyl-benzoic acid N′-phenyl-hydrazide (37)) Phenylhydrazine (0 .11 g, 1.0 mmol) was dissolved in 6 ml of DCM and 2 ml of 10% NaOH solution was added to the solution. Further, acid chloride 30 (0.23 g, 1.0 mmol) dissolved in 4 ml of DCM was added, and the mixture was vigorously stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered and the solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography (stepwise: 100% hexane to 50% EtOAc in hexane) to give a novel hydrazide 37 (0.17 g) as white crystals. 54%).
Thin-layer chromatograph Rf = 0.39 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.11 (d, 1H, J = 2.7, NH), 7.96 (d, 1H, J = 2.4, NH), 7.54 (s , 1H, Ar), 7.39 (d, 1H, J = 7.8 Hz, one of Ar), 7.29 (d, 1H, J = 7.8 Hz, Ar), 7.16 (t, 2H, J = 7.3 Hz, one of Ar), 6.85 (d, 2H, J = 7.6 Hz, Ar), 6.72 (t, 1H, J = 7.3 Hz, Ar), 2.34 (s , 1H, Me);
¹³ C-NMR (136 MHz, DMSO) δ: 167.1, 149.1, 141.5, 134.4, 133.2, 129.0, 128.7, 128.2, 119.1, 118.6 , 112.3, 20.4;
IR (neat): 3242 (NH), 3029 (Ar), 2920 (Me), 1653 (C═O), 1496 (Ar), 1321, 1039, 917, 827, 760, 692 cm ⁻¹ ;
FAB (+)-MS (NBA): m / z (%) 306 (49) [MH ⁺ ], 289 (13), 199 (52), 197 (54), 136 (66);
m. p. : 134-135 ° C.

Synthesis Example 2-13 Synthesis of 2-bromo-5-fluoro-benzoic acid N′-phenyl-hydrazide (2-Bromo-5-fluoro-benzoic acid N′-phenyl-hydrazide (38)) Phenylhydrazine (0 .11 g, 1.0 mmol) was dissolved in 6 ml of DCM and 2 ml of 10% NaOH solution was added to the solution. Further, acid chloride 31 (0.24 g, 1.0 mmol) dissolved in 4 ml of DCM was added, and the mixture was vigorously stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered and the solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography (stepwise: 100% hexane to 50% EtOAc in hexane) to give a novel hydrazide 38 (0.09 g) as white crystals. 29%).
Thin-layer chromatograph Rf = 0.26 (hexane: EtOAc = 7: 3 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.57 (s, 1 H, NH), 7.99 (s, 1 H, NH), 7.74 (dd, J = 8.8, 4.9 Hz, 1 H , One of Ar), 7.43 (dd, 1H, J = 8.5, 3.2 Hz, one of Ar), 7.31 (dt, 1H, J = 8.5, 3.2 Hz, one of Ar ), 7.17 (t, 2H, J = 8.5 Hz, 1H, Ar), 6.88 (d, 2H, J = 7.8 Hz, Ar), 6.73 (t, 1H, J = 7. 3 Hz, Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 195.9, 162.2, 159.7, 148.4, 139.0, 138.9, 134.9, 134.8, 128.7, 118.7 118.6, 118.4, 116.5, 116.3, 114.1, 114.0, 112.4;
IR (neat): 3271 (NH), 3049 (Ar), 1656 (C═O), 1515 (Ar), 1465, 1262, 753 cm ⁻¹ ;
FAB (+)-MS (NBA): m / z (%) 310 (10) [MH ⁺ ], 290 [5], 176 [9], 136 [68], 107 [21], 89 [15], 77 [12];
m. p. : 170-172 ° C.

Synthesis Example 2-14 Synthesis of 2-bromo-5-methoxy-benzoic acid N′-phenyl-hydrazide (2-Bromo-5-methoxy-benzoic acid N′-phenyl-hydrazide (39)) Phenylhydrazine (0) .30 g, 2.8 mmol) was dissolved in 6 ml of DCM and 2 ml of 10% NaOH solution was added to the solution. Further, acid chloride 32 (0.70 g, 2.8 mmol) dissolved in 4 ml of DCM was added and stirred vigorously at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered and the solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography (stepwise: 100% hexane to 50% EtOAc in hexane) to give a novel hydrazide 39 (0.50 g) as white crystals. 56%).
Thin-layer chromatograph Rf = 0.51 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.17 (s, 1H, NH), 7.96 (s, 1H, NH), 7.58 (dd, 1H, J = 8.0, 0.73 Hz, one of Ar), 7.17 (t, 2H, J = 7.6 Hz, Ar), 7.02 (s, 1H, one of Ar), 6.99 (d, 1H, J = 3.2 Hz, one of Ar), 6.86 (d, 2H, J = 7.8 Hz, Ar), 6.72 (t, 1H, J = 7.3 Hz, Ar), 3.11 (s, 3H, MeO);
¹³ C-NMR (136 MHz, DMSO) δ: 166.7, 158.4, 149.0, 138.0, 133.9, 128.7, 118.6, 117.0, 114.9, 112.4 , 109.4, 55.7;
IR (neat): 3238 (NH), 3006 (Ar), 1649 (C═O), 1598, 1493 (Ar), 1242, 1239 cm ⁻¹ ;
FAB (+)-MS (NBA): m / z (%) 322 (12) [MH ⁺ ], 238 (14), 213 (8), 176 (9), 136 (65), 107 (21), 85 (42);
m. p. 153-155 ° C.

(Synthesis Example 2-14) Synthesis of 2-chloro-benzoic acid N′-phenyl-hydrazide (2-Chlorobenzoic acid N′-phenyl-hydrazide (40)) 6 ml of phenylhydrazine (0.32 g, 3.0 mmol) Was dissolved in DCM and 2 ml of 10% NaOH solution was added to the solution. Further, acid chloride 33 (0.53 g, 3.0 mmol) dissolved in 4 ml of DCM was added, and the mixture was vigorously stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered and the solvent was distilled off under reduced pressure. Then, the residue was subjected to silica gel chromatography (step%: 100% hexane to 50% EtOAc in hexane), whereby hydrazide 40 (0.25 g, 34, 34, white crystals) was obtained. %).
Thin-layer chromatograph Rf = 0.36 (hexane: EtOAc = 1: 1 (volume ratio));
^{1 H-NMR (400MHz, DMSO} ) δ: 10.20 (d, 1H, J = 2.0Hz, NH), 8.00 (d, 1H, J = 2.0Hz, NH), 7.37-7 .57 (m, 4H, Ar), 7.17 (t, 2H, J = 7.8 Hz, Ar), 6.84 (d, 2H, J = 8.5 Hz, Ar), 6.73 (t, 1H, J = 7.3 Hz, one of Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 166.2, 149.1, 135.3, 131.2, 130.2, 129.7, 129.2, 128.7, 127.2, 118.6 , 112.3;
IR (neat): 3265 (NH), 3007 (Ar), 1653 (C═O), 1598, 1494 (Ar), 1318, 1239, 916, 742 cm ⁻¹ ;
m. p. : 152-154 ° C.

Synthesis Example 2-15 Synthesis of N ′-(2-iodo-benzoyl) -hydrazinecarboxylic acid tert-butyl ester (N ′-(2-Iodo-benzoyl) -hydrazine carbonate acid tert-butyl ester (41)) Dimroth Tert-butylcarbazate (0.13 g, 1.0 mmol) was placed in a 20 ml three-necked flask equipped with a condenser, and the septum cap was replaced with nitrogen gas. Then acid chloride 28 (0.61 g, 2.3 mmol) dissolved in 6 ml dry THF was added. The reaction was stopped by refluxing for 2 hours and confirming the disappearance of the starting material by TLC. The THF layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Next, the desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (stepwise: 100% hexane to 50% EtOAc in hexane), whereby a novel hydrazide 41 (0. 27 g, 59%).
Thin-layer chromatograph Rf = 0.68 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 7.88 (d, 2H, J = 8.0 Hz, two of Ar), 7.50 (d, 1H, J = 6.6 Hz, one of Ar), 7 .39 (dt, 1H, J = 7.6, 1.0 Hz, one of Ar), 7.14 (dt, 1H, J = 6.1, 1.7 Hz, one of Ar), 6.90 (s , 1H, NH), 1.50 (s, 9H, t-Bu);
^{13 C-NMR (136MHz, DMSO} ) δ: 168.2,155.2,140.1,138.9,131.9,28.8,128.1,92.8,82.1,28.1 (3C);
IR (neat): 3333 (NH), 3262, 2976 (t-Bu), 1723, 1670 (C = 0), 1517 (Ar), 1498, 1367, 1253, 1157, 1013, 914, 860, 748 cm ⁻¹ ;
m. p. : 111-113 ° C.

(Synthesis Example 2-16) Synthesis of benzoic acid N ′-(2-iodo-benzoyl) -hydrazide (Benzoic acid N ′ (2-Iodo-benzoyl) -hydrazide (42)) Benzoylhydrazine (0.27 g, 2.0 mmol) was placed in a one-necked flask and replaced with nitrogen gas to cap the septum. Next, acid chloride 28 (0.54 g, 2.0 mmol) dissolved in 10 ml of dry THF was added. The reaction was stopped by refluxing for 2 hours and confirming the disappearance of the starting material by TLC. The THF layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Next, the desiccant was filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and recrystallized to obtain hydrazide 42 (0.26 g, 72%) as white crystals.
Thin-layer chromatograph Rf = 0.45 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.62 (s, 1H, NH), 10.34 (s, 1H, NH), 7.93 (d, J = 3H, 7.6 Hz, Ar), 7.60 (t, 1H, J = 7.1 Hz, Ar), 7.47-7.55 (m, 4H, Ar), 7.20-7.27 (m, 1H, Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 168.1, 165.6, 140.4, 139.6, 132.4, 131.9, 131.6, 128.9, 128.5, 128.0 , 127.6, 93.8;
IR (neat): 3241 (NH), 3057 (Ar), 1639 (C = 0), 1516 (Ar), 1486, 1287, 711 cm ⁻¹ ;
m. p. 185-187 ° C.

(Synthesis Example 2-17) 2-Iodo-benzoic acid of N ′-[(4-methylphenyl) sulfonyl] hydrazide (2-Iodo-benzoic acid N ′-[(4-methylphenyl) sulfonyl] hydrazide (43)) Synthesis p-Toluenesulfonylhydrazine (0.09 g, 0.5 mmol) was placed in a 20 ml three-necked flask equipped with a Dimroth condenser, and replaced with nitrogen gas to cap the septum. Next, acid chloride 28 (0.14 g, 0.5 mmol) dissolved in 5 ml of dry THF was added. The reaction was stopped by refluxing for 2 hours and confirming the disappearance of the starting material by TLC. The THF layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Next, the desiccant was filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and recrystallized to obtain hydrazide 43 (0.19 g, 92%) as white crystals.
Thin-layer chromatograph Rf = 0.21 (hexane: EtOAc = 7: 3 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.5 (d, 1H, J = 3.2 Hz, NH), 10.1 (d, 1H, J = 3.4 Hz, NH), 7.84 (d , 1H, J = 7.8 Hz, one of Ar), 7.79 (d, 2H, J = 8.3 Hz, Ar), 7.43 (t, 1H, J = 7.3 Hz, one of Ar), 7.36 (d, 2H, J = 8.0 Hz, Ar), 7.17 (d, 2H, J = 7.3 Hz, one of Ar), 2.36 (s, 3H, Me);
¹³ C-NMR (136 MHz, DMSO) δ: 167.2, 143.3, 139.7, 139.5, 136.2, 131.5, 129.3, 128.6, 128.0, 93.6 , 21.1;
IR (neat): 3285 (NH), 3153 (Ar), 1647 (C = 0), 1529, 1373, 1342, 1171, 733, 695 cm ⁻¹ ;
m. p. : 200-201 ° C.

(Synthesis Example 2-18) Synthesis of 2-iodo-benzoic acid N′-benzyl-hydrazide (2-Iodo-benzoic acid N′-benzyl-hydrazide (44)) Benzylhydrazine hydrochloride (0.16 g, 1.0 mmol) ) Was suspended in 4 ml of DCM and 3 ml of 10% NaOH solution was added to the solution. Further, acid chloride 28 (0.27 g, 1.0 mmol) dissolved in 2 ml of DCM was added, and the mixture was vigorously stirred at room temperature for 5 hours. After confirming the completion of the reaction by TLC, the DCM layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Next, the desiccant was filtered and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (stepwise: 100% hexane to 50% EtOAc in hexane), whereby a novel hydrazide body 44 (brown viscous solid) ( 0.21 g, 59%).
Thin-layer chromatograph Rf = 0.45 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 7, 86 (dd, 1 H, J = 8.0, 3.7 Hz, NH), 7, 77 (dd, 1 H, J = 8.0, 3.2 Hz, NH), 7.16-7.47 (m, 5H, Ar), 699-7.13 (m, 1H, Ar), 4.90 (d, 1H, J = 5.1 Hz, Ar), 4.46 (d, 1 H, J = 2.0 Hz, CH ₂ ), 3.67 (s, 1 H, NH);
¹³ C-NMR (136 MHz, DMSO) δ: 171.9, 168.9, 143.3, 141.0, 139.2, 138.3, 135.2, 134.8, 130.6, 129.5 , 129.0, 128.7, 128.6, 128.2, 128.0, 127.8, 127.6, 127.5, 127.0, 93.0, 92.4, 55.2, 53 .2;
IR (neat): 3320 (NH), 3212 (Ar), 3059 (CH ₂ ), 3029, 2921, 1648 (C = 0), 1424, 1250, 1016, 736 cm ⁻¹ .

Example 1
When the hydrazide 6 synthesized in Synthesis Example 2-5 was dissolved in a solvent so as to have a concentration of 10 ppm, the nematode was found to have an insecticidal effect. From this, it was found that the hydrazide 6 synthesized in Synthesis Example 5-1 may be used as an insecticide.

[Direct synthesis of acid hydrazine]
(Synthesis Example 3-1) Synthesis of 2-Bromo-benzoic acid N′-phenyl-hydrazide (2-Bromo-benzoic acid N′-phenyl-hydrazide (35)) , 1.0 mmol) is dissolved in anhydrous DMF (10 ml), 2-bromobenzoic acid (201.0 mg, 1.0 mmol), HOBt (butanol) .H 2 O (0.15 g, 1.1 mmol), triethylamine (0. 11 g, 1.1 mmol) and DCC (0.21 g, 1.1 mmol) were added, followed by stirring for 12 hours at 40 ° C. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with distilled water and saturated brine, By filtering the desiccant and evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (stepwise: 100% hexane to 50% EtOAc in hexane), so that (Synthesis Example 2-10) and A white hydrazide compound 35 (0.23 g, 78%) was obtained, which was the same compound, but the yield of the hydrazide compound was good compared to (Synthesis Example 2-10). Urea was generated and separation operation was difficult.

(Synthesis Example 3-2) Synthesis of 2-Bromo-benzoic acid N′-phenyl-hydrazide (2-Bromo-benzoic acid N′-phenyl-hydrazide (35)) , 1.0 mmol) is dissolved in anhydrous DMF (10 ml), 2-bromobenzoic acid (0.20 g, 1.0 mmol), HOBt (butanol) .H ₂ O (0.15 g, 1.1 mmol), DMAP ( 6.1 mg, 5 mol%) and EDC.HCl (0.21 g, 1.1 mmol) were added, followed by stirring for 12 hours at 40 ° C. The disappearance of the starting material was confirmed by TLC, distilled water was added, and the reaction was performed. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and anhydrous magnesium sulfate. By filtering the desiccant and distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (stepwise: 100% hexane to 50% EtOAc in hexane), which was the same as (Synthesis Example 2-10). A white hydrazide compound 35 (0.23 g, 80%) was obtained as a compound, and the yield of the hydrazide compound was good compared to (Synthesis Example 2-10). It was.

Synthesis Example 3-3 Synthesis of 2-Bromo-5-fluoro-benzoic acid N′-phenyl-hydrazide (2-Bromo-5-fluoro-benzoic acid N′-phenyl-hydrazide (38)) Argon-substituted eggplant In a flask, phenylhydrazine (0.11 g, 1.0 mmol) was dissolved in anhydrous DMF (10 ml), and 2-bromo-5-fluorobenzoic acid (0.22 g, 1.0 mmol), HOBt · H ₂ O (0 .15 mg, 1.1 mmol), DMAP (6.1 mg, 5 mol%) and EDC · HCl (0.21 g, 1.1 mmol) were added, and the mixture was stirred at 40 ° C. for 12 hours. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and recrystallized, and the same compound as (Synthesis Example 2-13), hydrazide 38 (0.50 g) as white crystals. 98%). Compared to (Synthesis Example 2-13), the yield was extremely good.

Synthesis Example 3-4 Synthesis of 2-Bromo-5-methoxy-benzoic acid N′-phenyl-hydrazide (2-Bromo-5-methoxy-benzoic acid N′-phenyl-hydrazide (39)) Argon-substituted eggplant In a flask, phenylhydrazine (0.11 g, 1.0 mmol) was dissolved in anhydrous DMF (10 ml), and 2-bromo-5-fluorobenzoic acid (0.22 g, 1.0 mmol), HOBt · H ₂ O (0 .15 mg, 1.1 mmol), DMAP (6.1 mg, 5 mol%) and EDC · HCl (0.21 g, 1.1 mmol) were added, and the mixture was stirred at 40 ° C. for 12 hours. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and recrystallized, and the same compound as (Synthesis Example 2-14), hydrazide 39 (0.50 g) as white crystals. 98%). Compared to (Synthesis Example 2-14), the yield was extremely good.

  From Synthesis Examples 3-1 to 3-4, it was found that acid hydrazide can be directly synthesized from 2-halobenzoic acid and hydrazine without using a salt oxide when a dehydrating condensing agent is used. Many of the salt oxides are unstable, and some of them cause a decrease in the yield of acid hydrazide. It has been found that the use of a dehydrating condensing agent can shorten the process and improve the yield of acid hydrazide.

[Synthesis of 1-Substituted-1,2-Dihydroindazol-3-one Derivative]
Synthesis Example 4-1 Synthesis of 1-phenyl-1,2-dihydroindazol-3-one (1-Phenyl-1,2-dihydro-indazole-3-one (10)) In a 30 ml three-necked flask Hydrazide 2 (0.17 g, 0.5 mmol), CuI (10 mg, 0.05 mmol, 10 mol%), L-proline (12 mg, 0.10 mmol, 20 mol%), K ₂ CO ₃ (0.14 g, 1.mol). 0 mmol), dry DMSO (5 ml) was added, and the mixture was reacted at 70 ° C. for 3 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered and the solvent was distilled off under reduced pressure to obtain indazole derivative 10 (0.096 g, yield: 91%) as purple crystals.
Thin layer chromatograph: Rf = 0.73 (hexane: EtOAc = 1: 1);
¹ H-NMR (400 MHz, DMSO) δ: 11.28 (s, 1H, NH), 7.76 (d, 2H, J = 8.5 Hz, Ar), 7.68 (d, 2H, J = 8) .3 Hz, Ar), 7.51 (dd, 2H, J = 7.8, 8.1 Hz, Ar), 7.44 (t, 1H, J = 7.8 Hz, one of Ar), 7.25 ( t, 1H, J = 7.3 Hz, one of Ar), 7.15 (dd, 1H, J = 7.1, 7.8 Hz, one of Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 156.3, 140.2, 139.2.129.5 (2C), 128.4, 124.8, 120.6 (2C), 120.5, 120 .3,114.8,110.3;
The spectrum data of the ¹ H-NMR and ¹³ C-NMR are as follows: ¹ H-NMR (300 MHz, DMSO) δ: 11.25 (brs, 1H), 7.77 (m, 2H), 7 .69 (br d, 2H, J = 7.4 Hz), 7.49 (m, 3H), 7.26 (br t, 1H, J = 7.4 Hz), 7.16 (br t, 1H, J = 7.5 Hz), ¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ: 156.6, 140.6, 139.6.129.9 (2C), 128.7, 125.1, 121.0 (2C), 120.9, 120.7, 115.1, 110.7. ).

Synthesis Example 4-2 Synthesis of 1-tert-Butyl-1,2-dihydroindazol-3-one (1-tert-Butyl-1,2-dihydro-indazol-3-one (11)) In a two-necked flask, hydrazide 3 (0.32 g, 1.0 mmol), CuI (19 mg, 0.10 mmol, 10 mol%), L-proline (23 mg, 0.20 mmol, 20 mol%), K ₂ CO ₃ (0. 28 g, 2.0 mmol) and dry DMSO (10 ml) were added, and the mixture was reacted at 70 ° C. for 3 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered and the solvent was distilled off under reduced pressure to obtain indazole derivative 11 (0.16 g, yield: 83%) as milky white crystals.
Thin layer chromatograph: Rf = 0.36 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 10.50 (s, 1 H, NH), 7.59 (d, 1 H, J = 8.1 Hz, one of Ar), 7.52 (d, 1 H, J = 8.8 Hz, one of Ar), 7.20 (ddd, 1H, J = 1.0, 1.2, 8.1 Hz, one of Ar), 6.92 (dd, 1H, J = 7.3). , 7.6 Hz, one of Ar), 1.54 (s, 9H, t-Bu);
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.81 (d, 1H, J = 8.0 Hz, one of Ar), 7.54 (d, 1H, J = 8.4 Hz, one of Ar), 7.38 (dd, 1H, J = 6.3, 8.5 Hz, one of Ar), 7.80 (dd, 1H, J = 6.6, 8.0 Hz, one of Ar), 1.51 ( s, 9H, t-Bu);
¹³ C-NMR (136 MHz, DMSO) δ: 153.0, 139.6, 126.4, 120.2, 118.2, 114.1, 111.9, 58.3, 29.3 (3C);
IR (neat): 2979 (NH), 1648 (C═O), 1538, 1209, 748 cm ⁻¹ ;
_{HRMS (ES1): calcd for C} 11 H 14 N 2 O 191.1179; found, 191.1182;
m. p. 115 ° C-117 ° C.

Synthesis Example 4-3 1- (4-Nitrophenyl) -1,2-dihydroindazol-3-one (1- (4-Nitro-phenyl) -1,2-dihydro-indazol-3-one (12 )) Synthesis In a 30 ml three-necked flask, hydrazide 4 (0.21 g, 0.55 mmol), CuI (11 mg, 0.055 mmol, 10 mol%), L-proline (13 mg, 0.11 mmol, 20 mol%), K ₂ CO ₃ (0.15 g, 1.1 mmol) and dry DMSO (10 ml) were added, and the mixture was reacted at 70 ° C. for 3 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering the desiccant and distilling off the solvent under reduced pressure, it was subjected to silica gel column chromatography (stepwise conditions: 100% hexane to 50% EtOAc in hexane), whereby indazole derivative 12 (0.070 g, 50 %).
Thin layer chromatograph: Rf = 0.63 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 11.88 (brs, 1H, NH), 8.39 (d, 2H, J = 7.6 Hz, Ar), 8.04 (dd, 3H, J = 9.2 Hz, 10.4 Hz, Ar), 7.87 (d, 1 H, J = 7.6 Hz, one of Ar), 7.63 (dd, 1 H, J = 7.6, 8.0 Hz, one of Ar), 7.33 (dd, 1H, J = 7.2, 7.6 Hz, one of Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 158.0, 145.5, 142.6, 139.3, 129.4, 125.5 (2C), 122.0, 120.9, 119.0 ( 2C), 116.6, 111.5;
m. p. 285 ° C-287 ° C.

(Synthesis Example 4-4) of 1-Naphthalen-1-yl-1,2-dihydroindazol-3-one (1-Naphthalen-1-yl-1,2-dihydro-indazole-3-one (13)) Synthesis In a 30 ml three-necked flask, hydrazide 5 (0.16 g, 0.41 mmol), CuI (8 mg, 0.041 mmol, 10 mol%), L-proline (9 mg, 0.081 mmol, 20 mol%), K ₂ CO ₃ (0.11 g, 0.82 mmol) and dry DMSO (10 ml) were added, and the mixture was reacted at 70 ° C. for 3 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering the desiccant and distilling off the solvent under reduced pressure, it was subjected to silica gel column chromatography (stepwise conditions: 100% hexane to 50% EtOAc in hexane) (one-spot column) to produce indazole derivative 13 (0 .10 g, yield: 96%).
Thin layer chromatograph: Rf = 0.48 (hexane: EtOAc = 4: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 11.22 (brs, 1H, NH), 8.05 (d, J = 8.3 Hz, 1H, one of Ar), 8.02 (dd, J = 2.0, 7.3 Hz, 1 H, one of Ar), 7.80 (d, 1 H, J = 7.8 Hz, one of Ar), 7.72 (d, 1 H, J = 8.3 Hz, one of Ar), 7.56-7.67 (m, 3H, Ar), 7.51 (dd, 1H, J = 7.1, 7.3 Hz, one of Ar), 7.33 (dd, 1H, J = 7.3, 7.8 Hz, one of Ar), 7.12 (dd, 1H, J = 7.3, 7.8 Hz, one of Ar), 7.07 (d, 1H, J = 8.5 Hz) , One of Ar);
¹³ C-NMR (136 MHz, CD ₃ Cl) δ: 156.3, 142.1, 135.7
134.3, 129.2, 128.3, 128.0, 128.0, 126.7, 126.6, 125.8, 123.9, 123.5, 120.4, 119.9, 113. 7, 109.8;
m. p. 235 ° C-237 ° C.

Synthesis Example 4-5 Synthesis of 1-cyclohexyl-1,2-dihydroindazol-3-one (1-Cyclohexyl-1,2-dihydro-indazol-3-one (14)) In a 30 ml three-necked flask Hydrazide 6 (0.070 g, 0.20 mmol), CuI (4 mg, 0.020 mmol, 10 mol%), L-proline (5 mg, 0.040 mmol, 20 mol%), K ₂ CO ₃ (0.056 g, .0 mol). 40 mmol), dry DMSO (10 ml) was added, and the mixture was reacted at 70 ° C. for 3 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, purification was performed by repeating preparative TLC (hexane: EtOAc = 1: 1) four times, and the indazole derivative 14 (0.027 g, yield: 60) as white crystals was purified. %).
Thin layer chromatograph: Rf = 0.34 (hexane: EtOAc = 1: 4 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 9.97 (s, 1H, NH), 7.61 (d, 1H, J = 8.0 Hz, one of Ar), 7.48 (ddd, 1H, J = 1.2, 7.2, 8.0 Hz, one of Ar), 7.22 (d, 1H, J = 8.3 Hz, one of Ar), 7.07 (dd, 1H, J = 7.2). , 7.6 Hz, one of Ar), 4.19 (ddt, 1H, J =, 3.7, 3.9, 11.7 Hz, one of cyclohexane) 1.59-1.85 (m, 6H, cyclohexane) ), 1.30-1.44 (m, 2H, cyclohexane), 1.06-1.24 (m, 2H, cyclohexane);
¹³ C-NMR (136 MHz, DMSO) δ: 160.3, 146.3, 131.1, 122.8, 120.8, 117.7, 112.3, 52.6, 30.6 (2C), 25.1, 25.0.

Synthesis Example 4-6 1- (2-Methoxyphenyl) -1,2-dihydroindazol-3-one (1- (2-Methoxyxy-phenyl) -1,2-dihydro-indazol-3-one (15 )) Synthesis In a 30 ml three-necked flask, hydrazide 7 (0.26 g, 0.70 mmol), CuI (13 mg, 0.070 mmol, 10 mol%), L-proline (16 mg, 0.14 mmol, 20 mol%), K ₂ CO ₃ (0.19 g, 1.4 mmol, 2 eg) and dry DMSO (10 ml) were added, and the mixture was reacted at 70 ° C. for 3 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, and it was subjected to silica gel column chromatography (stepwise conditions: 100% hexane to 50% EtOAc in hexane) to give indazole derivative 15 (0.038 g, yield) as yellow crystals. : 23%).
Thin layer chromatograph: Rf = 0.49 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 11.0 (br s, 1 H, NH), 7.70 (d, 1 H, J = 8.0 Hz, one of Ar), 7.29-7.42 ( m, 3H, Ar), 7.24 (d, 1H, J = 8.3 Hz, one of Ar), 7.01-7.09 (m, 3H, Ar), 3.77 (s, 3H, OMe) );
¹³ C-NMR (136 MHz, DMSO) δ: 156.0, 153.4, 141.3, 128.5, 128.3, 127.6, 127.3, 120.8, 119.9, 119.3 113.6, 112.8, 110.9, 55.5.

(Synthesis Example 4-7) of 1-quinolin-2-yl-1,2-dihydroindazol-3-one (1-Quinolin-2-yl-1,2-dihydro-indazol-3-one (16)) Synthesis In a 50 ml three-necked flask, hydrazide 8 (0.14 g, 0.36 mmol), CuI (7 mg, 0.36 mmol, 10 mol%), L-proline (8 mg, 0.73 mmol, 20 mol%), K ₂ CO ₃ (0.10 g, 0.72 mmol, 2 eg) and dry DMSO (20 ml) were added, and the mixture was reacted at room temperature for 3 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. Indazole derivative 16 (0.043 g, yield: 45%) was obtained by filtering the desiccant and evaporating the solvent under reduced pressure and subjecting it to silica gel column chromatography (stepwise conditions: 100% hexane to 50% EtOAc in hexane). Got.
Thin layer chromatograph: Rf = 0.75 (hexane: EtOAc = 1: 1 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 11.5 (br s, 1 H, NH), 8.43 (br s, 1 H, NH), 8.30-8.40 (m, 1 H, one of Ar ), 7.25-8.10 (m, 9H, Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 148.9, 145.6, 138.5, 130.5, 130.2, 130.2, 128.1, 127.8, 127.7, 127.6 , 126.5, 126.2, 124.9, 119.3, 117.3, 116.1.

(Synthesis Example 4-8) Synthesis of 1-tert-butyl-1,2-dihydroindazol-3-one (1-tert-Butyl-1,2-dihydro-indazol-3-one (11)) The hydrazide 34 (0.027 g, 0.1 mmol), CuI (1.9 mg, 0.10 mmol, 10 mol%), L-proline (2.3 mg, 0.020 mmol, 20 mol%), K ₂ CO ₃ (0.028 g, 2.0 mmol) and dry DMSO (10 ml) were added, and the mixture was reacted at room temperature for 12 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. By filtering the desiccant and distilling off the solvent under reduced pressure, an indazole derivative 11 (0.012 g, 65%) which is a milky white crystal, which is the same compound as (Synthesis Example 4-2), was obtained. As far as seen on TLC, it was judged that there was no by-product and the purity was high, and purification was not performed. Although the yield was worse than (Synthesis Example 4-2), the indazole derivative 11 having high purity was obtained.

Synthesis Example 4-9 Synthesis of 1-phenyl-1,2-dihydroindazol-3-one (1-Phenyl-1,2-dihydro-indazole-3-one (10)) In a 30 ml three-necked flask Hydrazide 35 (0.12 g, 0.4 mmol), CuI (7.6 mg, 0.04 mmol, 10 mol%), L-proline (9.2 mg, 0.08 mmol, 20 mol%), K ₂ CO ₃ (0. 055 g, 0.4 mmol) and dry DMSO (3 ml) were added, and the mixture was reacted at room temperature for 12 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. By filtering the desiccant and distilling off the solvent under reduced pressure, indazole derivative 10 (0.052 g, 62%), which is the same compound as (Synthesis Example 4-1), which is a purple crystal, was obtained. As far as seen on TLC, it was judged that there was no by-product and the purity was high, and purification was not performed. Although the yield was worse than (Synthesis Example 4-1), indazole derivative 10 having high purity was obtained.

Synthesis Example 4-10 1- (4-Nitrophenyl) -1,2-dihydroindazol-3-one (1- (4-Nitro-phenyl) -1,2-dihydro-indazol-3-one (12 )) Synthesis In a 30 ml three-necked flask, hydrazide 36 (0.13 g, 0.5 mmol), CuI (10 mg, 0.05 mmol, 10 mol%), L-proline (13 mg, 0.1 mmol, 20 mol%), K ₂ CO ₃ (0.14 g, 1.0 mmol) and dry DMSO (5 ml) were added and reacted at room temperature for 12 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering the desiccant and distilling off the solvent under reduced pressure, it is the same compound as (Synthesis Example 4-3) by subjecting it to silica gel column chromatography (stepwise: 100% hexane to 50% EtOAc in hexane). Indazole derivative 12 (0.065 g, 51%) as yellow crystals was obtained. The yield was almost the same as (Synthesis Example 4-3).

Synthesis Example 4-11 1-phenyl-6-methyl-1,2-dihydroindazol-3-one (1-phenyl-6-methyl-1,2-dihydro-indazol-3-one (45)) Synthesis In a 30 ml three-necked flask, hydrazide 37 (0.03 g, 0.1 mmol), CuI (1.9 mg, 0.02 mmol, 10 mol%), L-proline (2.3 mg, 0.02 mmol, 20 mol%) , K ₂ CO ₃ (0.03 g, 0.2 mmol) and dry DMSO (3 ml) were added, and the mixture was reacted at room temperature for 12 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. Indazole derivative 45 (14 mg, 63%) which is milky white crystals is obtained by filtering the desiccant and evaporating the solvent under reduced pressure, and then subjecting it to silica gel column chromatography (stepwise: 100% hexane to 50% EtOAc in hexane). It was.
Thin layer chromatograph: Rf = 0.56 (hexane: EtOAc = 3: 2 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 11.15 (s, 1H, NH), 7.67 (dd, 2H, J = 8.8, 1.2 Hz, Ar), 7.61 (d, 1H) , J = 7.3 Hz, one of Ar), 7.56 (s, 1H, one of Ar), 7.50 (t, 2H, J = 8.0 Hz, Ar), 7.24 (t, 1H, J = 7.3 Hz, Ar), 6.98 (d, 1H, J = 8.0 Hz, one of Ar), 2.44 (s, 1H, Me);
¹³ C-NMR (136 MHz, DMSO) δ: 156.2, 140.3, 139.8, 138.4, 124.6, 122.3, 120.6, 120.1, 113.0, 109.8 ;
IR (neat): 3477 (NH), 2961 (Ar), 2920 (Me), 1551 (C═O), 1499 (Ar), 1310, 1262, 1097, 1030, 802 cm ⁻¹ ;
_{HRMS (ES1): calcd for C} 14 H 12 N 2 O 225.1028; found, 225.1009;
m. p. 170-172 ° C.

(Synthesis Example 4-12) of 1-phenyl-5-fluoro-1,2-dihydroindazol-3-one (1-Phenyl-5-fluoro-1,2-dihydro-indazol-3-one (46)) Synthesis A hydrazide 38 (0.03 g, 0.1 mmol), CuI (1.9 mg, 0.02 mmol, 10 mol%), L-proline (2.3 mg, 0.02 mmol, 20 mol%) in a 30 ml three-necked flask , K ₂ CO ₃ (0.03 g, 0.2 mmol) and dry DMSO (3 ml) were added, and the mixture was reacted at room temperature for 12 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. A novel indazole derivative 46 (14 mg, 63%) that is milky white crystals is obtained by filtering the desiccant and evaporating the solvent under reduced pressure, and then subjecting it to silica gel column chromatography (stepwise: 100% hexane to 50% EtOAc in hexane). Got.
Thin layer chromatograph: Rf = 0.46 (hexane: EtOAc = 7: 3 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 11.34 (s, 1H, NH), 7.77 (dd, 1H, J = 9.3, 1.5 Hz, Ar), 7.66 (d, 2H) , J = 8.0 Hz Ar), 7.51 (t, 3H, J = 7.6 Hz, Ar), 7.33 (t, 1H, J = 9.0 Hz, one of Ar), 7.26 (t , 1H, J = 7.3 Hz, Ar);
¹³ C-NMR (136 MHz, DMSO) δ: 157.8, 156.0, 155.5, 139.9, 136.3, 136.2, 129.5, 125.0, 120.6, 117.4 , 117.1, 112.0, 104.9, 104.6;
FAB (+)-MS (NBA): m / z (%) 229 (12) [MH ⁺ ], 173 (8), 151 (32), 120 (12), 107 (27), 85 (43), 79 (29);
IR (neat): 3062 (Ar), 2665, 1659, 1561 (C═O), 1499 (Ar), 1276, 1072, 793, 757, 693 cm ⁻¹ ;
m. p. 195-197 ° C.

(Synthesis Example 4-13) of 1-phenyl-5-methoxy-1,2-dihydroindazol-3-one (1-Phenyl-5-methoxy-1,2-dihydro-indazol-3-one (47)) Synthesis In a 30 ml three-necked flask, hydrazide 39 (0.11 g, 0.3 mmol), CuI (6.3 mg, 0.03 mmol, 10 mol%), L-proline (7.7 mg, 0.06 mmol, 20 mol%) , K ₂ CO ₃ (0.09 g, 0.6 mmol) and dry DMSO (3 ml) were added, and the mixture was reacted at room temperature for 12 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. A novel indazole derivative 47 (44 mg, 56%) which is a yellow crystal is obtained by filtering the desiccant and evaporating the solvent under reduced pressure, and then subjecting it to silica gel column chromatography (stepwise: 100% hexane to 50% EtOAc in hexane). Got.
Thin layer chromatograph: Rf = 0.46 (hexane: EtOAc = 7: 3 (volume ratio));
¹ H-NMR (400 MHz, DMSO) δ: 7.70 (d, 1H, J = 9.7 Hz, one of Ar), 7.65 (d, 2H, J = 7.6 Hz, Ar), 7.49 (T, 2H, J = 7.3 Hz, Ar), 7.21 (t, 1H, J = 7.3 Hz, Ar), 7.15 (s, 1H, one of Ar), 7.09 (dd, 1H, J = 9.0, 2.4 Hz, one of Ar), 3.80 (s, 3H, OMe);
¹³ C-NMR (136 MHz, DMSO) δ: 156.0, 153.8, 140.4, 134.9, 129.5, 124.4, 120.0, 119.4, 115.0, 111.6 , 100.3, 55.5;
FAB (+)-MS (NBA): m / z (%) 241 (12) [MH ⁺ ], 169 (14), 136 (71), 107 (27), 85 (85), 77 (16);
IR (neat): 2938 (Ar), 2835 (Me), 1595 (C═O), 1498 (Ar), 1286, 1264, 1158, 1028, 755, 694 cm ⁻¹ ;
m. p. 158-160 ° C.

(Synthesis Example 4-14) Synthesis of 1-phenyl-1,2-dihydroindazol-3-one (1-Phenyl-1,2-dihydro-indazol-3-one (10)) In a 30 ml three-necked flask Hydrazide 40 (0.05 g, 0.2 mmol), CuI (4 mg, 0.02 mmol, 10 mol%), L-proline (5 mg, 0.04 mmol, 20 mol%), K ₂ CO ₃ (0.06 g, 0. 4 mmol), dry DMSO (3 ml) was added, and the mixture was reacted at 70 ° C. for 12 hours under a nitrogen stream. The disappearance of the starting material was confirmed by TLC, and distilled water was added to stop the reaction. Next, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered and the solvent was distilled off under reduced pressure, and then subjected to silica gel column chromatography (stepwise: 100% hexane to 50% EtOAc in hexane), so that (Synthesis Example 4-1) and (Synthesis Example 4-9). Indazole derivative 10 (27 mg, 66%) which is a purple crystal, which is the same compound as) was obtained. The yield was worse than in the cases of (Synthesis Example 4-1) and (Synthesis Example 4-9).

  From the above synthesis examples, it was found that 1-substituted-1,2-dihydroindazol-3-one derivatives can be easily produced in high yields by using the method of the present invention.

[Examination of reaction temperature]
The same procedure as in Synthesis Example 2-2 was conducted, except that the 1-substituted-1,2-dihydroindazol-3-one derivative 11 was reacted at room temperature for 3 hours. It was found that the yield of the 1-substituted-1,2-dihydroindazol-3-one derivative 11 was 82%, which was not much different from the yield of Synthesis Example 2-2 heated at 70 ° C. in 83%. Further, as can be seen from Synthesis Example 4-9, it was found that the reaction proceeds similarly at room temperature even when a hydrazide which is a brominated product is used. Thereby, it turned out that the method of this invention advances also at room temperature.

[Examination of reaction solvent]
The reaction was performed in the same manner as in Synthesis Example 2-2 except that the 1-substituted-1,2-dihydroindazol-3-one derivative 11 was reacted not with anhydrous DMSO but with unpurified canned DMSO. The yield of the 1-substituted-1,2-dihydroindazol-3-one derivative 11 was 97%, much higher than the yield of 83% in Synthesis Example 2-2 using anhydrous DMSO. Thereby, it turned out that the method of this invention may use an unpurified organic solvent.

[Examination of catalyst amount]
Synthesis of the 1-substituted-1,2-dihydroindazol-3-one derivative 11 was performed in the same manner as in Synthesis Example 2-2 except that CuI was changed to 5 mol% and 1 mol%. The yield of 1-substituted-1,2-dihydroindazol-3-one derivative 11 was 79% in the case of 5 mol%: 63% in the case of 1 mol%, and in Synthesis Example 2-2 using 10 mol% of CuI. Although the yield was lower than 83%, it was found that the yield was high. Thereby, it turned out that the method of this invention may reduce CuI.

[Examination of L-proline]
The synthesis of the 1-substituted-1,2-dihydroindazol-3-one derivative 11 was performed in the same manner as in Synthesis Example 2-2 except that L-proline was not used. The yield of the 1-substituted-1,2-dihydroindazol-3-one derivative 11 is 94%, which is greater than the yield of 83% in Synthesis Example 2-2 even when synthesized without using L-proline. Was expensive. However, since the 1-substituted-1,2-dihydroindazol-3-one derivative obtained by this method has low purity, purification was required. The yield after purification was 82%. On the other hand, the 1-substituted-1,2-dihydroindazol-3-one derivative obtained in Synthesis Example 2-2 can be isolated simply by performing a liquid separation operation. Thereby, in the method of this invention, it turned out that the specificity of reaction improves more using L-proline together.

[Examination of palladium catalyst]
In the synthesis of the 1-substituted-1,2-dihydroindazol-3-one derivative 11, except that a palladium catalyst [Pd (η ³ -C ₃ H ₅ ) Cl ₂ ] was used instead of CuI and L-proline. This was carried out in the same manner as in Synthesis Example 2-2. Although the production of the 1-substituted-1,2-dihydroindazol-3-one derivative 11 was confirmed, it could not be isolated because a number of by-products were produced.

Claims (5)

2-haloaryl acid chloride represented by the following general formula (I);

(In the formula, A represents an acidic functional group, Hr represents a halogen, R ^{1 to} R ⁴ represent a hydrogen atom, an optionally substituted alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, an aryl group, a heterocyclic group, an acyl group, a cyano group, a carboxyl group, an oxycarbonyl group, .R ¹ to mean a carbamoyl group, an amino group, a sulfino group, a halogen And R ² , R ² and R ³ , R ³ and R ⁴ may be bonded to each other to form a ring.)
Hydrazine represented by the following general formula (II):

(Wherein R is an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an aryl thioether group, which may have a substituent or a branch, An aryl group, a heterocyclic group, an acyl group, a sulfino group, and an oxycarbonyl group are shown.)
To produce a hydrazide represented by the following general formula (III).

(Wherein R ^{1 to} R ⁴ are a hydrogen atom, an optionally substituted hydrogen atom, an optionally substituted alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group. , alkylthio group, aryl ether group, aryl thioether group, an aryl group, a heterocyclic group, a cyano group, a carbonyl group, a carboxyl group, an oxycarbonyl group, a carbamoyl group, an amino group, a sulfino group, means a halogen .R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, and R has a substituent or a branch. Alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl Thioether group, an aryl group, a heterocyclic group, an acyl group, a sulfino group, an oxy carbonyl group.) The hydrazide represented by the following general formula (III) is intramolecularly coupled in the presence of a catalyst,

(Wherein R ^{1 to} R ⁴ are a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an arylthioether, which may be substituted. Group, aryl group, heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, halogen, R ¹ and R ² , R ² and R ³ , R ³ And R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, R represents an alkyl group, a cycloalkyl group, a substituent group or a branched group, Alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, aryl group, heterocyclic group Acyl group, a sulfino group, an oxy carbonyl group.)
A method for producing a 1-substituted-1,2-dihydroindazol-3-one derivative represented by the following general formula (IV):

(Wherein R ^{1 to} R ⁴ are a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an arylthioether, which may be substituted. Group, aryl group, heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, halogen, R ¹ and R ² , R ² and R ³ , R ³ And R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, R represents an alkyl group, a cycloalkyl group, a substituent group or a branched group, Alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, aryl group, heterocyclic group Acyl group, a sulfino group, an oxy carbonyl group.) 2-halocarboxylic acid chloride represented by the following general formula (I):

(In the formula, A represents an acidic functional group, Hr represents a halogen, R ^{1 to} R ⁴ represent a hydrogen atom, an optionally substituted alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, an aryl group, a heterocyclic group, an acyl group, a cyano group, a carboxyl group, an oxycarbonyl group, .R ¹ to mean a carbamoyl group, an amino group, a sulfino group, a halogen And R ² , R ² and R ³ , R ³ and R ⁴ may be bonded to each other to form a ring.)
Hydrazine represented by the following general formula (II):

(Wherein R is an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an aryl thioether group, which may have a substituent or a branch, An aryl group, a heterocyclic group, an acyl group, a sulfino group, and an oxycarbonyl group are shown.)
To produce a hydrazide represented by the following general formula (III),

(Wherein R ^{1 to} R ⁴ are a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an arylthioether, which may be substituted. Group, aryl group, heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, halogen, R ¹ and R ² , R ² and R ³ , R ³ And R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, R represents an alkyl group, a cycloalkyl group, a substituent group or a branched group, Alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, aryl group, heterocyclic group Acyl group, a sulfino group, an oxy carbonyl group.)
Intramolecular coupling of the obtained hydrazide in the presence of a catalyst,
A method for producing a 1-substituted-1,2-dihydroindazol-3-one derivative represented by the following general formula (IV):

(Wherein R ^{1 to} R ⁴ are a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an arylthioether, which may be substituted. Group, aryl group, heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, halogen, R ¹ and R ² , R ² and R ³ , R ³ And R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, R represents an alkyl group, a cycloalkyl group, a substituent group or a branched group, Alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, aryl group, heterocyclic group Acyl group, a sulfino group, an oxy carbonyl group.) A hydrazide represented by the following general formula (III).

(Wherein R ^{1 to} R ⁴ are a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an arylthioether, which may be substituted. Group, aryl group, heterocyclic group, acyl group, cyano group, carboxyl group, oxycarbonyl group, carbamoyl group, amino group, sulfino group, halogen, R ¹ and R ² , R ² and R ³ , R ³ And R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, R represents an alkyl group, a cycloalkyl group, a substituent group or a branched group, Alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, aryl thioether group, aryl group, heterocyclic group Acyl group, a sulfino group, an oxy carbonyl group.) A 1-substituted-1,2-dihydroindazol-3-one derivative represented by the following general formula (IV).

Wherein R ^{1 to} R ⁴ are a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an aryl ether group, an aryl thioether, which may be substituted. group, an aryl group, a heterocyclic group, an acyl group, a cyano group, a carboxyl group, an oxycarbonyl group, a carbamoyl group, an amino group, a sulfino group, means a halogen .R ¹ and ^R 2, ^{R 2} and ^R 3, ^{R 3} And R ⁴ may be bonded to each other to form a ring, A represents an acidic functional group, R represents an alkyl group, a cycloalkyl group, a substituent group or a branched group, Alkenyl group, cycloalkenyl group, alkynyl group, alkoxy group, alkylthio group, aryl ether group, arylthioether group, aryl group, heterocyclic group Acyl group, a sulfino group, an oxy carbonyl group.)