JP2013224315A - Process for production of n-phenyl-n'-phenylsulfonylpiperazine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an effective process for production of N-phenyl-N'-phenylsulfonylpiperazine derivatives and intermediates thereof.SOLUTION: There is provided a process for production of a compound shown by formula (III) by reaction of a compound shown by formula (I) (in the formula, R, R, R, Rand Reach independently represent hydrogen, a halogen, alkyl, alkyloxy and so forth) with an aromatic halogen compound having a specific substituent in a solvent in the presence of a palladium compound, an organic phosphorous compound and a base.

Description

  The present invention relates to a method for producing an N-phenyl-N′-phenylsulfonylpiperazine derivative.

N-phenyl-N′-phenylsulfonylpiperazine derivatives are known to exhibit various pharmaceutical activities. For example, Patent Document 1 has TXA2 receptor antagonistic inhibitory activity and has platelet condensation action, Patent Document 2 has TXA2 receptor antagonistic inhibitory activity, and its applicable diseases are thrombosis, myocardial infarction, It has arterial hypotension and hypertension, Patent Document 3 has hydroxysteroid dehydrogenase inhibitory activity, and its applicable diseases are type 2 diabetes and osteoporosis. Patent Document 4 has CRTH2 receptor antagonistic activity. It has an inhibitory activity, and it is disclosed that the applicable diseases are allergic rhinitis and asthma. Patent Document 5 discloses that it has DP receptor antagonistic inhibitory activity and the applicable diseases are allergic rhinitis and asthma. However, in order to produce an N-phenyl-N′-phenylsulfonylpiperazine derivative, it was necessary to require a multi-step process.
European Patent Application No. 76996 Japanese Patent Laid-Open No. 5-262755 International Publication No. 2006/105127 Pamphlet International Publication No. 2006/056752 Pamphlet International Publication No. 2007/037187 Pamphlet

  Provided is an efficient method for producing N-phenyl-N'-phenylsulfonylpiperazine derivatives and intermediates thereof.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、及びＲ^５はそれぞれ独立して、水素原子、ハロゲン原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいシクロアルキル、置換されていてもよいアルキルオキシ、置換されていてもよいアルキルチオ、アシル、置換されていてもよいアルキルオキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいアミノ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよい非芳香族複素環基）で示される化合物を、パラジウム化合物、有機リン化合物、及び塩基の存在下、式（ＩＩ）：

（式中、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、及びＲ^１０はそれぞれ独立して、水素原子、ハロゲン原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいシクロアルキル、ヒドロキシ、置換されていてもよいアルキルオキシ、置換されていてもよいアルキルチオ、アシル、置換されていてもよいアルキルオキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいアミノ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよい非芳香族複素環基；
Ｘはハロゲン原子、置換されていてもよいアルキルスルホニルオキシ、又は置換されていてもよいアリールスルホニルオキシ）で示される化合物と反応させることを特徴とする式（ＩＩＩ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、及びＲ^１０は前記と同意義）で示される化合物の製造方法、に関する。
なお、本工程は、溶媒を用いて行うことができる。Ｘがハロゲン原子の場合、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、及びＲ^１０のハロゲン原子はそれぞれ独立して、Ｘより反応性が低いハロゲン原子である。
さらに、本発明は、以下に示す２）〜２３）に関する。
２）式（Ｉ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、及びＲ^５は１）と同意義）で示される化合物、パラジウム化合物、有機リン化合物、及び塩基を反応させる工程Ａ、
及び式（ＩＩ）：

（式中、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、及びＸは１）と同意義）で示される化合物を添加する工程Ｂを包含する１）記載の製造方法、
なお、各工程は溶媒を用いて行うことができる。工程Ａは１５〜３０℃で、１５分〜２時間かけて行うことができる。
３）パラジウム化合物及び有機リン化合物を混合する工程Ｃ、
工程Ｃの混合物に、式（Ｉ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、及びＲ^５は１）と同意義）で示される化合物及び塩基を添加する工程Ｄ、
及び、工程Ｄの混合物に、式（ＩＩ）：

（式中、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、及びXは１）と同意義）で示される化合物を添加する工程Ｅを包含する１）記載の製造方法。
なお、各工程は溶媒を用いて行うことができる。工程Ｃは１５〜３０℃で、１５分〜２時間かけて行うことができる。
４）パラジウム化合物が酢酸パラジウムである１）〜３）のいずれかに記載の製造方法。
５）有機リン化合物がジアダマンチルブチルホスフィンである１）〜４）のいずれかに記載の製造方法。
６）スルフィン酸塩の存在下で行う１）、４）、及び５）のいずれかに記載の製造方法。
７）工程Ａでスルフィン酸塩の存在下で行う２）、４）、及び５）のいずれかに記載の製造方法。
８）工程Ｄでスルフィン酸塩の存在下で行う３）、４）、及び５）のいずれかに記載の製造方法。
９）スルフィン酸塩がパラ−トルエンスルフィン酸ナトリウムである６）〜８）のいずれかに記載の製造方法。
１０）Ｒ^４、Ｒ^５、Ｒ^６、及びＲ^１０が水素原子であり、Ｒ^１、Ｒ^２、及びＲ^９がそれぞれ独立して、水素原子、ハロゲン原子、又はアルキルであり、Ｒ^３がアルキルオキシ又はアルキルチオであり、Ｒ^７がヒドロキシ又は置換されていてもよいアルキルオキシであり、Ｒ^８がハロゲン原子、置換されていてもよいアルキル、置換されていてもよいアルキルオキシ、置換されていてもよいアルキルオキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいアミノ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよい非芳香族複素環基であり、Ｘがハロゲン原子である１）〜９）のいずれかに記載の製造方法。
１１）Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^６、及びＲ^１０が水素原子であり、Ｒ^９が水素原子又はハロゲン原子であり、Ｒ^３がアルキルオキシであり、Ｒ^７がヒドロキシであり、Ｒ^８がハロゲン原子、置換されていてもよいカルバモイル、置換されていてもよいアミノ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよい非芳香族複素環基であり、Ｘがハロゲン原子である１）〜９）のいずれかに記載の製造方法。
１２）１）〜１１）のいずれかに記載の製造方法により式（ＩＶ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^８、及びＲ^９は１）と同意義）で示される化合物を得る工程Ｆ、
及び、式（ＩＶ）で示される化合物を、塩基存在下、式（Ｖ）：

（式中、Ｒ^１１はアルキレン又はアルケニレン；Ｒ^１２は水素原子又はアルキル；Ｙはハロゲン原子、置換されていてもよいアルキルスルホニル、又は置換されていてもよいアリールスルホニル）で示される化合物と反応させ、式（ＶＩ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^８、及びＲ^９は１）と同意義；Ｒ^１１及びＲ^１２は前記と同意義）で示される化合物を得る工程Ｇ、Ｒ^１２がアルキルの場合は、さらに式（ＶＩ）で示される化合物を加水分解に付す工程Ｈを包含することを特徴とする、式（ＶＩＩ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^８、及びＲ^９は１）と同意義；Ｒ^１１は前記と同意義）で示される化合物の製造方法。
なお、各工程は溶媒を用いて行うことができる。
１３）Ｙがハロゲン原子である１２）記載の製造方法。
１４）Ｒ^１、Ｒ^２、及びＲ^９がそれぞれ独立して、水素原子、ハロゲン原子、又はアルキルであり、Ｒ^３がアルキルオキシ又はアルキルチオであり、Ｒ^８がハロゲン原子、置換されていてもよいアルキル、置換されていてもよいアルキルオキシ、置換されていてもよいアルキルオキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいアミノ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよい非芳香族複素環基であり、Ｒ^１１がアルキレンである１２）又は１３）載の製造方法。
１５）Ｒ^１、Ｒ^２、及びＲ^９がそれぞれ独立して、水素原子、ハロゲン原子、又はアルキルであり、Ｒ^３がアルキルオキシ又はアルキルチオであり、Ｒ^８がハロゲン原子、置換されていてもよいカルバモイル、置換されていてもよいアミノ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよい非芳香族複素環基であり、Ｒ^１１がメチレンである１２）〜１４）のいずれかに記載の製造方法。
１６）１）〜１１）のいずれかに記載の製造方法により式（ＶＩＩＩ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^９は１）と同意義；Ｚはハロゲン原子）で示される化合物を得る工程Ｉ、
及び、式（ＶＩＩＩ）で示される化合物を、有機ボロン酸と反応させる工程Ｊを包含することを特徴とする、式（ＩＸ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^９は１）と同意義；Ｗは置換されていてもよいアリール又は置換されていてもよいヘテロアリール）で示される化合物の製造方法。
なお、各工程は溶媒を用いて行うことができる。
１７）ピペラジンの溶液に、式（Ｘ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、及びＲ^５は１）と同意義）で示される化合物を添加する工程Ｋ、
反応液に水を添加し、有機溶媒で抽出する工程Ｌ、
工程Ｌで得た有機層に酸を添加して酸性とし、水で抽出する工程Ｍ、
工程Ｍで得た水層に塩基を添加してアルカリ性とし、結晶を析出させる工程Ｎを包含することを特徴とする式（Ｉ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、及びＲ^５は１）と同意義）で示される化合物の製造方法。
なお、ピペラジンの溶液が、トルエン溶液である場合は、工程Ｋ、Ｌ、Ｍ、Ｎ、及びＰは次の条件下で行うことができる。工程Ｋは４５〜８０℃で、１〜４時間かけて行うことができる。工程Ｌは４５〜８０℃で行うことができる。工程Ｍは、酸として１〜４モル／Ｌの塩酸を用いて、４５〜８０℃で行うことができる。工程Ｎは、塩基として１〜４モル／Ｌの水酸化ナトリウム水溶液を用いて、４５〜８０℃で行いアルカリ性にすることができる。さらに、１５〜３０℃で結晶を析出させることができる。
１８）Ｒ^１、Ｒ^２、Ｒ^４、及びＲ^５が水素原子であり、Ｒ^５がアルコキシである１７）記載の製造方法。
１９）式（ＸＩ）：

（式中、Ｘは１）と同意義）で示される化合物又はその反応性誘導体を、式（ＸＩＩ）：

（式中、Ｒ^１５及びＲ^１６はそれぞれ独立して、水素原子又はアルキル；Ｒ^１７はアルキル）で示される化合物と反応させ、式（ＸＩＩＩ）：

（式中、Ｘは１）と同意義；Ｒ^１５、Ｒ^１６、及びＲ^１７は上記と同意義）で示される化合物を得る工程Ｐ、
式（ＸＩＩＩ）で示される化合物を酸と反応させ、式（ＸＩＶ）：

（式中、Ｘは１）と同意義；Ｒ^１５及びＲ^１６は上記と同意義）で示される化合物を得る工程Ｑ、
及び、式（ＸＩＶ）で示される化合物を閉環させる工程Ｒを包含することを特徴とする、式（ＸＶ）：

（式中、Ｘは１）と同意義；Ｒ^１５及びＲ^１６は上記と同意義）で示される化合物の製造方法。
なお、各工程は溶媒を用いて行うことができる。
２０）式（ＸＶＩ）：

（式中、Ｘは１）と同意義；Ｒ^１８は水素原子又はアルキル）で示される化合物をハロゲン化させ、式（ＸＶＩＩ）：

（式中、Ｘは１）と同意義；Ｒ^１８は上記と同意義；Ｒ^１９はハロゲン原子）で示される化合物を得る工程Ｓ、
及び、式（ＸＶＩＩ）で示される化合物を式：Ｒ^２０ＣＯＯＮＨ_４（式中、Ｒ^２０は水素原子又はアルキル）で示される化合物と反応させる工程Ｔを包含することを特徴とする式（ＸＶＩＩＩ）：

（式中、Ｘは１）と同意義；Ｒ^１８及びＲ^２０は上記と同意義）で示される化合物の製造方法。
なお、各工程は溶媒を用いて行うことができる。
２１）式（ＸＩＸ）：

（式中、Ｘは１）と同意義；Ｒ^２１は置換されていてもよい５員環ヘテロアリール）で示される化合物、その製薬上許容される塩、又はそれらの溶媒和物。 The present inventors have found an industrially effective production method in which the following N-phenyl-N′-phenylsulfonylpiperazine derivatives and intermediates thereof can be produced in a simple, short process, and / or good yield. .
That is, the present invention provides: 1) Formula (I):

(Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, a substituted Optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkyloxy, optionally substituted alkylthio, acyl, optionally substituted alkyloxycarbonyl, optionally substituted carbamoyl , An optionally substituted amino, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group), a palladium compound, an organic In the presence of a phosphorus compound and a base, formula (II):

(Wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, or a substituted Optionally substituted alkynyl, optionally substituted cycloalkyl, hydroxy, optionally substituted alkyloxy, optionally substituted alkylthio, acyl, optionally substituted alkyloxycarbonyl, optionally substituted A good carbamoyl, an optionally substituted amino, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;
Wherein X is a halogen atom, an optionally substituted alkylsulfonyloxy, or an optionally substituted arylsulfonyloxy) compound represented by the formula (III):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are as defined above).
Note that this step can be performed using a solvent. When X is a halogen atom, the halogen atoms of R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are each independently a halogen atom that is less reactive than X.
Furthermore, the present invention relates to the following 2) to 23).
2) Formula (I):

(Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ have the same meanings as 1)), a step A in which a compound represented by formula (I), a palladium compound, an organic phosphorus compound, and a base are reacted.
And formula (II):

(Wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and X are as defined in 1)), including the step B of adding the compound represented by 1),
In addition, each process can be performed using a solvent. Process A can be performed at 15-30 degreeC over 15 minutes-2 hours.
3) Step C of mixing the palladium compound and the organophosphorus compound,
To the mixture of step C, formula (I):

(Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as defined in 1)) and a step D of adding a base and a base
And in the mixture of step D, formula (II):

(Wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and X are as defined in 1)), including the step E of adding the compound represented by 1).
In addition, each process can be performed using a solvent. Process C can be performed at 15-30 degreeC over 15 minutes-2 hours.
4) The production method according to any one of 1) to 3), wherein the palladium compound is palladium acetate.
5) The production method according to any one of 1) to 4), wherein the organic phosphorus compound is diadamantylbutylphosphine.
6) The production method according to any one of 1), 4) and 5), which is carried out in the presence of a sulfinate.
7) The production method according to any one of 2), 4) and 5), which is performed in the presence of a sulfinate in Step A.
8) The production method according to any one of 3), 4), and 5) performed in the presence of a sulfinate in Step D.
9) The production method according to any one of 6) to 8), wherein the sulfinate is sodium para-toluenesulfinate.
10) R ⁴ , R ⁵ , R ⁶ , and R ¹⁰ are hydrogen atoms, R ¹ , R ² , and R ⁹ are each independently a hydrogen atom, a halogen atom, or alkyl, and R ³ is alkyl Oxy or alkylthio, R ⁷ is hydroxy or optionally substituted alkyloxy, R ⁸ is a halogen atom, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted A good alkyloxycarbonyl, an optionally substituted carbamoyl, an optionally substituted amino, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocycle The production method according to any one of 1) to 9), wherein X is a halogen atom.
11) R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ¹⁰ are hydrogen atoms, R ⁹ is a hydrogen atom or a halogen atom, R ³ is alkyloxy, R ⁷ is hydroxy Yes, R ⁸ is a halogen atom, an optionally substituted carbamoyl, an optionally substituted amino, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted non-aromatic The manufacturing method in any one of 1) -9) which is a group heterocyclic group and X is a halogen atom.
12) Formula (IV): by the manufacturing method in any one of 1) -11):

(Wherein R ¹ , R ² , R ³ , R ⁸ , and R ⁹ are as defined in 1)) to obtain a compound represented by step F,
And a compound represented by formula (IV) in the presence of a base:

(Wherein R ¹¹ is alkylene or alkenylene; R ¹² is a hydrogen atom or alkyl; Y is a halogen atom, an optionally substituted alkylsulfonyl, or an optionally substituted arylsulfonyl). Formula (VI):

^{(Wherein, R 1, R 2, R} 3, R 8, and ^{R 9} is 1) and as ^{defined; R 11} and ^{R 12} Step G to give a compound represented by as ^{defined), R 12} is alkyl In the case of the formula (VII), further comprising the step H of subjecting the compound of the formula (VI) to hydrolysis:

(Wherein R ¹ , R ² , R ³ , R ⁸ and R ⁹ are the same as 1), and R ¹¹ is as defined above).
In addition, each process can be performed using a solvent.
13) The production method according to 12), wherein Y is a halogen atom.
14) R ¹ , R ² , and R ⁹ are each independently a hydrogen atom, a halogen atom, or alkyl, R ³ is an alkyloxy or alkylthio, and R ⁸ is a halogen atom, optionally substituted. Alkyl, optionally substituted alkyloxy, optionally substituted alkyloxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, optionally substituted aryl, optionally substituted The production method according to 12) or 13), which is a good heteroaryl or an optionally substituted non-aromatic heterocyclic group, and R ¹¹ is alkylene.
15) R ¹ , R ² , and R ⁹ are each independently a hydrogen atom, a halogen atom, or an alkyl, R ³ is an alkyloxy or alkylthio, and R ⁸ is a halogen atom, optionally substituted. A carbamoyl, an optionally substituted amino, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group, wherein R ¹¹ is methylene 12 ) To 14).
16) Formula (VIII): by the manufacturing method in any one of 1) -11):

(Wherein R ¹ , R ² , R ³ , and R ⁹ are the same as defined in 1), and Z represents a halogen atom).
And a process J comprising reacting a compound of formula (VIII) with an organoboronic acid, formula (IX):

(Wherein R ¹ , R ² , R ³ , and R ⁹ are the same as 1); W is an optionally substituted aryl or an optionally substituted heteroaryl).
In addition, each process can be performed using a solvent.
17) In a solution of piperazine, the formula (X):

(Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as defined in 1))
Step L, in which water is added to the reaction solution and extracted with an organic solvent
Step M in which acid is added to the organic layer obtained in Step L to make it acidic, and extraction is performed with water.
Formula (I) characterized in that it includes Step N in which a base is added to the aqueous layer obtained in Step M to make it alkaline and crystals are precipitated:

(Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as defined in 1)).
In addition, when the solution of piperazine is a toluene solution, the processes K, L, M, N, and P can be performed under the following conditions. Process K can be performed at 45-80 degreeC over 1-4 hours. Process L can be performed at 45-80 degreeC. Process M can be performed at 45-80 degreeC, using 1-4 mol / L hydrochloric acid as an acid. Step N can be performed at 45 to 80 ° C. using a sodium hydroxide aqueous solution of 1 to 4 mol / L as a base. Furthermore, crystals can be precipitated at 15 to 30 ° C.
18) The production method according to 17), wherein R ¹ , R ² , R ⁴ , and R ⁵ are hydrogen atoms, and R ⁵ is alkoxy.
19) Formula (XI):

(Wherein X is as defined in 1)) or a reactive derivative thereof is represented by the formula (XII):

(Wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom or an alkyl; R ¹⁷ is an alkyl) and a compound represented by the formula (XIII):

(Wherein X is the same as 1); R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above)
A compound of formula (XIII) is reacted with an acid to give a compound of formula (XIV):

(Wherein X is the same as 1); R ¹⁵ and R ¹⁶ are as defined above)
And a process R for ring-closing the compound represented by the formula (XIV):

(Wherein X is the same as 1); and R ¹⁵ and R ¹⁶ are as defined above).
In addition, each process can be performed using a solvent.
20) Formula (XVI):

(Wherein X is the same as 1); R ¹⁸ is a hydrogen atom or alkyl), and a compound represented by the formula (XVII):

(Wherein X is 1); R ¹⁸ is as defined above; R ¹⁹ is a halogen atom).
And a compound represented by the formula (XVII) comprising a step T of reacting a compound represented by the formula: R ²⁰ COONH ₄ (wherein R ²⁰ is a hydrogen atom or an alkyl), :

(Wherein X is the same as 1); and R ¹⁸ and R ²⁰ are as defined above).
In addition, each process can be performed using a solvent.
21) Formula (XIX):

(Wherein X is the same as 1); R ²¹ is an optionally substituted 5-membered heteroaryl), a pharmaceutically acceptable salt thereof, or a solvate thereof.

The meaning of each term is explained below. In the present specification, each term is used in a unified meaning, and is used in the same meaning when used alone or in combination with other terms.
In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. A fluorine atom, a chlorine atom, and a bromine atom are preferable.
In the present specification, “alkyl” includes a linear or branched monovalent hydrocarbon group having 1 to 8 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, etc. Is mentioned. Preferably, C1-C6 alkyl is mentioned. More preferably, C1-C4 alkyl is mentioned. In particular, when a carbon number is specified, it means “alkyl” having a carbon number within the range.
In this specification, “alkenyl” includes straight or branched monovalent hydrocarbon groups having 2 to 8 carbon atoms and having one or more double bonds. To do. For example, vinyl, allyl, 1-propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, 2-octenyl and the like can be mentioned. Preferably, C2-C6 alkenyl is mentioned. More preferably, C2-C4 alkenyl is mentioned.
In the present specification, “alkynyl” includes straight or branched monovalent hydrocarbon groups having 2 to 8 carbon atoms and having one or more triple bonds. . Examples include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-hexynyl, 2-heptynyl, 2-octynyl and the like. Preferably, C2-C6 alkynyl is mentioned. More preferably, C2-C4 alkynyl is mentioned.
In the present specification, “cycloalkyl” includes cycloalkyl having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferably C3-C6 cycloalkyl is mentioned.
In the present specification, “alkyloxy” includes methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, 2 -Pentyloxy, 3-pentyloxy, n-hexyloxy, isohexyloxy, 2-hexyloxy, 3-hexyloxy, n-heptyloxy, n-octyloxy and the like. Preferably, C1-C6 alkyloxy is mentioned. More preferably, C1-C4 alkyloxy is mentioned. In particular, when a carbon number is specified, it means “alkyloxy” having a carbon number within the range of the number.
In the present specification, “alkylthio” includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, 2-pentylthio, 3 -Pentylthio, n-hexylthio, isohexylthio, 2-hexylthio, 3-hexylthio, n-heptylthio, n-octylthio and the like. Preferably, C1-C6 alkylthio is mentioned. More preferably, C1-C4 alkylthio is mentioned. In particular, when a carbon number is specified, it means “alkylthio” having a carbon number within the range of the number.
In the present specification, as "alkylsulfonyl", methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentyl Examples include sulfonyl, 2-pentylsulfonyl, 3-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, 2-hexylsulfonyl, 3-hexylsulfonyl, n-heptylsulfonyl, n-octylsulfonyl and the like. Preferably, C1-C6 alkylsulfonyl is mentioned. More preferably, C1-C4 alkylsulfonyl is mentioned.
In the present specification, “alkyloxycarbonyl” includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, n-pentyloxycarbonyl and the like. Can be mentioned. Preferably, C1-C4 alkyloxycarbonyl is mentioned. Particularly preferred is C1-C2 alkyloxycarbonyl.
In the present specification, “acyl” includes alkylcarbonyl in which the alkyl moiety is the aforementioned “alkyl” or arylcarbonyl in which the aryl moiety is “aryl” described later. “Alkyl” and “aryl” may each be substituted by the substituents exemplified in “optionally substituted alkyl” and “optionally substituted aryl” described below. For example, acetyl, propionyl, butyroyl, benzoyl and the like can be mentioned.
In the present specification, “optionally substituted amino” means the above “alkyl”, the following “aryl”, the following “heteroaryl”, the “acyl”, the “alkyloxycarbonyl” and / or the “alkyl”. Includes amino optionally substituted 1 or 2 with sulfonyl. For example, amino, methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, benzylamino, acetylamino, benzoylamino, methyloxycarbonylamino, methylsulfonylamino and the like can be mentioned. Amino, methylamino, dimethylamino, ethylmethylamino, diethylamino, acetylamino, methylsulfonylamino and the like are preferable.
In the present specification, the “optionally substituted carbamoyl” includes an optionally substituted aminocarbonyl in which the optionally substituted amino moiety is the above “optionally substituted amino”. Examples include carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N, N-diethylcarbamoyl, N-benzylcarbamoyl, N-acetylcarbamoyl, N-methylsulfonylcarbamoyl and the like. It is done. Preferably, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-methylsulfonylcarbamoyl and the like can be mentioned.
In the present specification, “alkylene” means a linear or branched alkylene having 1 to 10 carbon atoms, such as methylene, 1-methylmethylene, 1,1-dimethylmethylene, ethylene, 1- Methylethylene, 1-ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1,1-diethylethylene, 1,2-diethylethylene, 1-ethyl-2-methylethylene, trimethylene, 1-methyl Trimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1-diethyl Trimethylene, 1,2-diethyltrimethylene, 2,2-diethyltrimethylene, 2-ethyl-2-methyltrimethylene, teto Methylene, 1-methyltetramethylene, 2-methyltetramethylene, 1,1-dimethyltetramethylene, 1,2-dimethyltetramethylene, 2,2-dimethyltetramethylene, 2,2-di-n-propyltrimethylene, etc. Is mentioned. In particular, a linear or branched alkylene having 2 to 6 carbon atoms is preferable.
In the present specification, “alkenylene” means a linear or branched alkenylene having 2 to 10 carbon atoms, such as ethenylene, 1-methylethenylene, 1-ethylethenylene, 1,2-dimethylethenylene. Lene, 1,2-diethylethenylene, 1-ethyl-2-methylethenylene, propenylene, 1-methyl-2-propenylene, 2-methyl-2-propenylene, 1,1-dimethyl-2-propenylene, 1, 2-dimethyl-2-propenylene, 1-ethyl-2-propenylene, 2-ethyl-2-propenylene, 1,1-diethyl-2-propenylene, 1,2-diethyl-2-propenylene, 1-butenylene, 2- Butenylene, 1-methyl-2-butenylene, 2-methyl-2-butenylene, 1,1-dimethyl-2-butenylene, 1,2-dimethyl-2- Teniren, and the like. In particular, linear or branched alkenylene having 2 to 6 carbon atoms is preferable.
In the present specification, “aryl” includes monocyclic or condensed cyclic aromatic hydrocarbons. This may be condensed with the above-mentioned “cycloalkyl” and the “non-aromatic heterocyclic group” described below at all possible positions. Whether aryl is a single ring or a fused ring, it can be attached at all possible positions. For example, phenyl, 1-naphthyl, 2-naphthyl, anthryl, tetrahydronaphthyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like can be mentioned. Preferably, phenyl, 1-naphthyl and 2-naphthyl are used. More preferably, a phenyl is mentioned.
In the present specification, the “non-aromatic heterocyclic group” is a non-aromatic 5- to 7-membered ring containing at least one oxygen atom, sulfur atom or nitrogen atom in the ring, or 2 Includes rings fused at least. For example, pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), pyrrolinyl (eg, 3-pyrrolinyl), imidazolidinyl (eg, 2-imidazolidinyl), imidazolinyl (eg, imidazolinyl), pyrazolidinyl (eg, 1-pyrazolidinyl, 2- Pyrazolidinyl), pyrazolinyl (eg, pyrazolinyl), piperidyl (eg, piperidino, 2-piperidyl), piperazinyl (eg, 1-piperazinyl), indolinyl (eg, 1-indolinyl), isoindolinyl (eg, isoindolinyl), morpholinyl (eg, Morpholino, 3-morpholinyl) and the like.
In the present specification, the “heteroaryl” includes a 5 to 6 membered aromatic ring containing at least one oxygen atom, sulfur atom or nitrogen atom in the ring. This may be condensed with the “cycloalkyl”, the “aryl”, the “non-aromatic heterocyclic group”, or other heteroaryl at all possible positions. Whether the heteroaryl is a single ring or a fused ring, it can be attached at all possible positions. For example, pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), imidazolyl (eg, 2 -Imidazolyl, 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isothiazolyl (eg 3-isothiazolyl), isoxazolyl (eg 3-isoxazolyl), oxazolyl (eg 2-oxazolyl) , 4-oxazolyl, 5-oxazolyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl (eg 2- Pyrazinyl), pyrimidinyl (eg 2-pyrimidinyl) , 4-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl), tetrazolyl (eg, 1H-tetrazolyl), oxadiazolyl (eg, 1,3,4-oxadiazolyl), thiadiazolyl (eg, 1,3,4-thiadiazolyl), Indolizinyl (eg, 2-indolidinyl, 6-indolidinyl), isoindolyl (eg, 2-isoindolyl), indolyl (eg, 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (eg, 3-indazolyl), purinyl ( For example, 8-purinyl), quinolidinyl (eg, 2-quinolidinyl), isoquinolyl (eg, 3-isoquinolyl), quinolyl (eg, 2-quinolyl, 5-quinolyl), phthalazinyl (eg, 1-phthalazinyl), naphthyridinyl (E.g. 2-naphthyridinyl), quinolanyl (e.g. 2-quinolanyl), quinazolinyl (e.g. 2-quinazolinyl), cinnolinyl (e.g. 3-cinnolinyl), pteridinyl (e.g. 2-pteridinyl), carbazolyl (e.g. 2- Carbazolyl, 4-carbazolyl), phenanthridinyl (for example, 2-phenanthridinyl, 3-phenanthridinyl), acridinyl (for example, 1-acrinidyl, 2-acrinidyl), dibenzofuranyl (for example, 1- Dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (eg, 2-benzoimidazolyl), benzoisoxazolyl (eg, 3-benzoisoxazolyl), benzoxazolyl (eg, 2-benzoxazolyl) ), Benzooxadiazolyl (e.g. 4 -Benzooxadiazolyl), benzoisothiazolyl (eg 3-benzoisothiazolyl), benzothiazolyl (eg 2-benzothiazolyl), benzofuryl (eg 3-benzofuryl), benzothienyl (eg 2-benzothienyl) , Dibenzothienyl (for example, 2-dibenzothienyl), benzodioxolyl (for example, 1,3-benzodioxolyl) and the like.
In the present specification, the “5-membered heteroaryl” includes an optionally selected 5-membered aromatic ring containing at least one oxygen atom, sulfur atom or nitrogen atom in the ring. For example, pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), imidazolyl (eg, 2 -Imidazolyl, 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isothiazolyl (eg 3-isothiazolyl), isoxazolyl (eg 3-isoxazolyl), oxazolyl (eg 2-oxazolyl) 4-oxazolyl, 5-oxazolyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (eg 1H-tetrazolyl), oxadiazolyl (eg 1,3,4-oxadiazolyl), thiadiazolyl (For example, 1, 3, 4 Thiadiazolyl) and the like.
In the present specification, examples of “arylsulfonyl” include phenylsulfonyl, naphthylsulfonyl and the like.

In the present specification, “optionally substituted alkyl”, “optionally substituted alkyloxy”, “optionally substituted alkylthio”, “optionally substituted alkylsulfonyl”, and “substituted” Examples of the substituent in “optionally substituted alkyloxycarbonyl” include alkyloxy, mercapto, alkylthio, halogen atom optionally substituted by 1 to 3 sites with a substituent selected from cycloalkyl, hydroxy, and substituent group A. , Nitro, cyano, carboxy, alkyloxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, acyl, optionally substituted with 1 to 3 substituents selected from substituent group B Aryl (for example, phenyl), substituted at 1 to 3 positions by a substituent selected from substituent group C An optionally substituted heteroaryl (for example, pyridyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl), which may be substituted by 1 to 3 substituents selected from the substituent group C; Suitable non-aromatic heterocyclic groups (for example, morpholinyl, pyrrolidinyl, piperazinyl), alkylsulfonyl and the like can be mentioned. These can be substituted 1 to 3 at all possible positions.
In the present specification, the substituent in “optionally substituted alkenyl”, “optionally substituted alkynyl”, and “optionally substituted cycloalkyl” is selected from substituent group D. Alkyloxy, mercapto, alkylthio, halogen atom optionally substituted by 1 to 3 positions by a substituent selected from alkyl, cycloalkyl, hydroxy, substituent group A optionally substituted by 1 to 3 positions by a substituent , Nitro, cyano, carboxy, alkyloxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, acyl, optionally substituted with 1 to 3 substituents selected from substituent group B Aryl (for example, phenyl), which may be substituted at 1 to 3 positions by a substituent selected from Substituent Group C A non-aromatic heterocyclic group (for example, morpholinyl) which may be substituted by 1 to 3 positions by a substituent selected from roaryl (for example, pyridyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl), substituent group C , Pyrrolidinyl, piperazinyl), alkylsulfonyl and the like. These can be substituted one or more at all possible positions.
In the present specification, “optionally substituted aryl”, “optionally substituted arylsulfonyl”, “optionally substituted heteroaryl”, “optionally substituted 5-membered heteroaryl” In addition, as the substituent in the “optionally substituted non-aromatic heterocyclic group”, alkyl, cycloalkyl, alkenyl, which may be substituted with 1 to 3 substituents selected from the substituent group D, Alkynyl, hydroxy, alkyloxy optionally substituted by 1 to 3 sites with a substituent selected from substituent group A, and 1 to 3 sites of aryloxy selected from substituent group B (for example, phenoxy) , Mercapto, alkylthio, halogen atom, nitro, cyano, carboxy, alkyloxycarbonyl, acyl, alkylsulfonyl, substituted An optionally substituted amino, an optionally substituted carbamoyl, an aryl optionally substituted by 1 to 3 substituents selected from the substituent group B (eg, phenyl), and a substituent group C. 1 to 3 heteroaryls optionally substituted by 1 to 3 substituents (for example, pyridyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl), or a substituent selected from substituent group C A non-aromatic heterocyclic group (for example, morpholinyl, pyrrolidinyl, piperazinyl) and the like, which may be used. These can be substituted one or more at all possible positions.
Substituent group A is phenyl optionally substituted by 1 to 3 sites with a substituent selected from a halogen atom and substituent group B.
Substituent group B is a halogen atom, alkyl, alkyloxy, cyano and nitro.
Substituent group C is a halogen atom and alkyl.
Substituent group D is a halogen atom and alkyloxy.

（式中、Ｘは１）と同意義）
で示される化合物のカルボキシ基部分（Ｃ（＝Ｏ）ＯＨ）が対応するハロゲン化物（例えば、Ｃ（＝Ｏ）Ｃｌ、Ｃ（＝Ｏ）Ｂｒ）、酸無水物（例えば、ギ酸との混合酸無水物Ｃ（＝Ｏ）−Ｏ−Ｃ（＝Ｏ）−Ｈ又は酢酸との混合酸無水物Ｃ（＝Ｏ）−Ｏ−Ｃ（＝Ｏ）−ＣＨ_３）、活性エステル（例えば、スクシンイミドエステル）等を意味する。 In the present specification, the “reactive derivative thereof” refers to the formula (XI):

(Where X is the same as 1))
The carboxy group moiety (C (═O) OH) of the compound represented by the formula (1) is a corresponding halide (eg, C (═O) Cl, C (═O) Br), acid anhydride (eg, mixed acid with formic acid) Anhydride C (= O) -OC (= O) -H or mixed acid anhydride C (= O) -OC (= O) -CH ₃ ) with acetic acid, active ester (eg succinimide ester) ) Etc.

In the compound represented by the general formula (I), groups of preferred substituents of R ^{1 to} R ⁵ are represented by (Ia) to (If). Those possible combinations of compounds are preferred.
R ¹ , R ² , R ⁴ , and R ⁵ are each independently (Ia) a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted alkynyl. An optionally substituted cycloalkyl, an optionally substituted alkyloxy, an optionally substituted alkylthio, an acyl, an optionally substituted alkyloxycarbonyl, an optionally substituted carbamoyl, a substituted An optionally substituted amino, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group is preferred, and (Ib) a hydrogen atom, a halogen atom, or Alkyl is more preferable, and (Ic) a hydrogen atom is most preferable.
R ³ is (Id) a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkyloxy, an optionally substituted An optionally substituted alkylthio, an acyl, an optionally substituted alkyloxycarbonyl, an optionally substituted carbamoyl, an optionally substituted amino, an optionally substituted aryl, an optionally substituted heteroaryl, or An optionally substituted non-aromatic heterocyclic group is preferred, (Ie) optionally substituted alkoxy or optionally substituted alkylthio is more preferred, and (If) alkoxy is most preferred.

Moreover, in the compound represented by the general formula (II), a group of preferable substituents of R ^{6 to} R ¹⁰ and X is represented by (Ig) to (Is). Those possible combinations of compounds are preferred.
R ⁶ and R ¹⁰ are each independently preferably (Ig) a hydrogen atom, a halogen atom, alkyl, or hydroxy, and more preferably (Ih) a hydrogen atom.
R ⁷ is (Ii) a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, hydroxy, substituted Optionally substituted alkyloxy, optionally substituted alkylthio, acyl, optionally substituted alkyloxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, optionally substituted aryl , An optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group is preferred, and (Ij) hydroxy or optionally substituted alkyloxy is more preferred, and (Ik) Hydroxy is most preferred.
R ⁸ is (Il) a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, hydroxy, substituted Optionally substituted alkyloxy, optionally substituted alkylthio, acyl, optionally substituted alkyloxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, optionally substituted aryl , An optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group is preferable. Furthermore, (Im) a halogen atom, an optionally substituted alkyl, an optionally substituted alkyloxy , Optionally substituted alkyloxycarbonyl, optionally substituted carbamoyl, substituted An optionally substituted amino, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group is more preferable, and further, an (In) halogen atom, a substituted More preferably an optionally substituted carbamoyl, an optionally substituted amino, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group, (Io) a halogen atom, an optionally substituted carbamoyl, or an optionally substituted heteroaryl is most preferred.
R ⁹ is (Ip) a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, hydroxy, substituted Optionally substituted alkyloxy, optionally substituted alkylthio, acyl, optionally substituted alkyloxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, optionally substituted aryl , An optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group is preferred, and (Iq) a hydrogen atom or a halogen atom is more preferred.
X is preferably an (Ir) halogen atom, an optionally substituted alkylsulfonyl, or an optionally substituted arylsulfonyl, and more preferably an (Is) halogen atom.

Moreover, in the compound represented by the general formula (III), a preferable group of substituents of R ^{1 to} R ⁵ and R ^{6 to} R ¹⁰ is the same as the above (Ia) to (Iq). Those possible combinations of compounds are preferred.
R ¹ , R ² , R ⁴ , and R ⁵ are each independently preferably (Ia), more preferably (Ib), and most preferably (Ic).
R ³ is preferably (Id), more preferably (Ie), and most preferably (If).
R ⁶ and R ¹⁰ are each independently preferably (Ig), and more preferably (Ih).
R ⁷ is preferably (Ii), more preferably (Ij), and most preferably (Ik).
R ⁸ is preferably (Il), more preferably (Im), more preferably (In), and most preferably (Io).
R ⁹ is preferably (Ip), and more preferably (Iq).

Moreover, in the compound represented by the general formula (IV), the preferred substituent groups of R ^{1 to} R ³ and R ^{8 to} R ⁹ are (Ia) to (If) and (Il) to (Iq). Is the same. Those possible combinations of compounds are preferred.
R ¹ and R ² are each independently preferably (Ia), more preferably (Ib), and most preferably (Ic).
R ³ is preferably (Id), more preferably (Ie), and most preferably (If).
R ⁸ is preferably (Il), more preferably (Im), more preferably (In), and most preferably (Io).
R ⁹ is preferably (Ip), and more preferably (Iq).

In the compound represented by the general formula (V), a group of preferred substituents for R ¹¹ , R ¹² and Y is represented by (It) to (Iy). Those possible combinations of compounds are preferred.
R ¹¹ is preferably (It) alkylene or alkenylene, more preferably (Iu) alkylene, and most preferably (Iv) methylene.
R ¹² is preferably (Iw) a hydrogen atom or alkyl, and more preferably (Ix) alkyl.
Y is preferably (Iy) a halogen atom, an optionally substituted alkylsulfonyl, or an optionally substituted arylsulfonyl, and more preferably (Iz) a halogen atom.

In the compound represented by the general formula (VI), groups of preferred substituents of R ^{1 to} R ³ , R ^{8 to} R ⁹ , R ¹¹ , and R ¹² are (Ia) to (If), ( Il) to (Iq) and (It) to (Ix). Those possible combinations of compounds are preferred.
R ¹ and R ² are each independently preferably (Ia), more preferably (Ib), and most preferably (Ic).
R ³ is preferably (Id), more preferably (Ie), and most preferably (If).
R ⁸ is preferably (Il), more preferably (Im), more preferably (In), and most preferably (Io).
R ⁹ is preferably (Ip), and more preferably (Iq).
R ¹¹ is preferably (It), more preferably (Iu), and most preferably (Iv).
R ¹² is preferably (Iw), and more preferably (Ix).

In the compound represented by the general formula (VII), groups of preferred substituents of R ^{1 to} R ³ , R ^{8 to} R ⁹ , and R ¹¹ are (Ia) to (If), (Il) to The same as (Iq) and (It) to (Iv). Those possible combinations of compounds are preferred.
R ¹ and R ² are each independently preferably (Ia), more preferably (Ib), and most preferably (Ic).
R ³ is preferably (Id), more preferably (Ie), and most preferably (If).
R ⁸ is preferably (Il), more preferably (Im), more preferably (In), and most preferably (Io).
R ⁹ is preferably (Ip), and more preferably (Iq).
R ¹¹ is preferably (It), more preferably (Iu), and most preferably (Iv).

In the compound represented by the general formula (VIII), the preferred substituent groups of R ^{1 to} R ³ , R ⁹ and Z are (Ia) to (If) and (Ip) to (Iq). And (IIa). Those possible combinations of compounds are preferred.
R ¹ and R ² are each independently preferably (Ia), more preferably (Ib), and most preferably (Ic).
R ³ is preferably (Id), more preferably (Ie), and most preferably (If).
R ⁹ is preferably (Ip), and more preferably (Iq).
Z is preferably (IIa) a halogen atom.

In the compound represented by the general formula (IX), the preferred substituent groups of R ^{1 to} R ³ , R ⁹ , and W are (Ia) to (If) and (Ip) to (Iq). And (IIb) to (IIc). Those possible combinations of compounds are preferred.
R ¹ and R ² are each independently preferably (Ia), more preferably (Ib), and most preferably (Ic).
R ³ is preferably (Id), more preferably (Ie), and most preferably (If).
R ⁹ is preferably (Ip), and more preferably (Iq).
W is preferably (IIb) an optionally substituted aryl or an optionally substituted heteroaryl, and more preferably (IIc) an optionally substituted heteroaryl.

Moreover, in the compound represented by the general formula (X), a preferable substituent group of R ^{1 to} R ⁵ is the same as the above (Ia) to (If). Those possible combinations of compounds are preferred.
R ¹ , R ² , R ⁴ , and R ⁵ are each independently preferably (Ia), more preferably (Ib), and most preferably (Ic).
R ³ is preferably (Id), more preferably (Ie), and most preferably (If).

In the compound represented by the general formula (XI), a group of preferred substituents for X is represented by (Ir) to (Is). Those possible combinations of compounds are preferred.
X is preferably the (Ir), and more preferably the (Is) halogen atom.

In the compound represented by the general formula (XII), a group of preferable substituents of R ^{15 to} R ¹⁷ is represented by (IId) to (IIf). Those possible combinations of compounds are preferred.
R ¹⁵ and R ¹⁶ are each independently preferably (IId) a hydrogen atom or alkyl, and more preferably (IIe) a hydrogen atom.
R ¹⁷ is preferably (IIf) alkyl.

In the compound represented by the general formula (XIII), the preferred substituent groups of R ^{15 to} R ¹⁷ and X are the same as the above (Ir) to (Is) and the above (IId) to (IIf). . Those possible combinations of compounds are preferred.
R ¹⁵ and R ¹⁶ are each independently preferably (IId), and more preferably (IIe).
R ¹⁷ is preferably the above (IIf).
X is preferably the (Ir), and more preferably the (Is) halogen atom.

In the compound represented by the general formula (XIV), the preferred substituent groups of R ^{15 to} R ¹⁶ and X are the same as the above (Ir) to (Is) and the above (IId) to (IIe). . Those possible combinations of compounds are preferred.
R ¹⁵ and R ¹⁶ are each independently preferably (IId), and more preferably (IIe).
X is preferably the (Ir), and more preferably the (Is) halogen atom.

In the compound represented by the general formula (XV), the preferred substituent groups of R ^{15 to} R ¹⁶ and X are the same as (Ir) to (Is) and (IId) to (IIe). . Those possible combinations of compounds are preferred.
R ¹⁵ and R ¹⁶ are each independently preferably (IId), and more preferably (IIe).
X is preferably the (Ir), and more preferably the (Is) halogen atom.

In the compound represented by the general formula (XVI), a group of preferable substituents for R ¹⁸ and X is the same as (Ir) to (Is) and (IIg). Those possible combinations of compounds are preferred.
R ¹⁸ is preferably (IIg) a hydrogen atom or alkyl, and more preferably (IIh) a hydrogen atom.
X is preferably the (Ir), and more preferably the (Is) halogen atom.

In the compound represented by the general formula (XVII), a group of preferable substituents of R ¹⁸ , R ¹⁹ , and X is the same as (Ir) to (Is) and (IIg) to (IIh), And (IIi). Those possible combinations of compounds are preferred.
R ¹⁸ is preferably (IIg) a hydrogen atom or alkyl, and more preferably (IIh) a hydrogen atom.
R ¹⁹ is preferably (IIi) a halogen atom.
X is preferably the (Ir), and more preferably the (Is) halogen atom.

In the compound represented by the general formula (XVIII), a group of preferred substituents of R ¹⁸ , R ²⁰ , and X is the same as (Ir) to (Is) and (IIg) to (IIh), And (IIj). Those possible combinations of compounds are preferred.
R ¹⁸ is preferably (IIg) a hydrogen atom or alkyl, and more preferably (IIh) a hydrogen atom.
R ²⁰ is preferably (IIj) a hydrogen atom or alkyl, and more preferably (IIi) a hydrogen atom.
X is preferably the (Ir), and more preferably the (Is) halogen atom.

In the compound represented by the general formula (XIX), a group of preferred substituents for R ²¹ and X is the same as (Ir) to (Is), and (IIk) to (IIl). Those possible combinations of compounds are preferred.
R ²¹ is preferably (IIk) 5-membered heteroaryl, and more preferably (IIl) furyl, thienyl, oxazolyl, pyrazolyl, oxadiazolyl, or thiadiazolyl.
X is preferably the (Ir), and more preferably the (Is) halogen atom.

  This production method is simple, short process, and / or high yield, and is useful as an industrial production method for N-phenyl-N′-phenylsulfonylpiperazine derivatives and intermediates thereof.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、及びＲ^５は１）と同意義）
出発化合物の式（Ｘ）で示される化合物は市販品を用いることができる。
Ａ製造方法とは、ピペラジンと式（Ｘ）で示される化合物から、工程Ｋ、工程Ｌ、工程Ｍ、工程Ｎ、及び工程Ｐの工程を経て式（Ｉ）で示される化合物を製造する方法である。
工程Ｋはピペラジンの溶液に、式（Ｘ）で示される化合物を添加する工程である。
添加するとは、加えること又は／及び反応することを意味する。
（Ｘ）で示される化合物に対して、ピペラジンは１．５〜５モル当量、好ましくは２．５〜３．５モル当量用いることができる。
ピペラジンの溶液の溶媒としては、ジクロロメタン、クロロホルム、ジオキサン、ベンゼン、トルエン、ヘキサン、酢酸エチル、テトラヒドロフラン、アセトニトリル、アセトン、及びＮ，Ｎ−ジメチルホルムアミドを単独又は混合して用いることができる。テトラヒドロフラン又はトルエンが好ましく、さらにトルエンがより好ましい。
式（Ｘ）で示される化合物を添加する場合は、１５℃〜溶媒還流温度、好ましくは４５〜８０℃で、１回又は適当な回数に分けて１５分〜２時間かけて加え、さらに、１５℃〜溶媒還流温度、好ましくは４５〜８０℃で、１５分〜２時間反応することができる。
式（Ｘ）で示される化合物が含有する溶液を加える場合は、１５℃〜溶媒還流温度、好ましくは４５〜８０℃で、１５分〜２時間かけて滴下し、さらに、１５℃〜溶媒還流温度、好ましくは４５〜８０℃で、１５分〜２時間反応することができる。
溶媒がトルエンの場合は、好ましくは６０〜７０℃で、好ましくは３０分〜１時間３０分かけて滴下し、さらに、好ましくは６０〜７０℃で、好ましくは３０分〜１時間３０分反応することができる。
工程Ｌは反応液に水を添加し、有機溶媒で抽出する工程である。
工程Ｌは４５〜８０℃で行うのが好ましい。溶媒がトルエンの場合は、５５〜６５℃で行うのが好ましい。
有機溶媒としては、トルエン、酢酸エチル、ジクロロメタン、クロロホルム、ヘキサンを用いることができる。トルエンが好ましい。
工程Ｍは工程Ｌで得た有機層に酸を添加して酸性とし、水で抽出する工程である。
酸としては、塩酸、臭化水素酸、硫酸、又は硝酸を用いることができる。塩酸が好ましく、１〜４モル／Ｌの塩酸がより好ましく、２モル／Ｌの塩酸がもっとも好ましい。
工程Ｍは４５〜８０℃で行うのが好ましい。溶媒がトルエンの場合は、５５〜６５℃で行うのが好ましい。
工程Ｎは工程Ｍで得た水層に塩基を添加してアルカリ性とし、結晶を析出させる工程である。
塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、又はそれらの水溶液を用いることができる。水酸化ナトリウム水溶液が好ましく、１〜４モル／Ｌの水酸化ナトリウム水溶液がより好ましく、２モル／Ｌの水酸化ナトリウム水溶液がもっとも好ましい。
工程Ｎは４５〜８０℃で塩基を添加してアルカリ性とするのが好ましい。溶媒としてトルエンを用いる場合は、５５〜６５℃で行うのが好ましい。１５〜３０℃で結晶を析出させるのが好ましい。 The A manufacturing method to the G manufacturing method, which are manufacturing methods of the present invention, will be described below. When a compound has an asymmetric point, a racemate or an optically active substance is included.
A Manufacturing method

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as 1))
A commercial item can be used for the compound shown by the formula (X) of a starting compound.
The A production method is a method for producing a compound represented by the formula (I) from piperazine and a compound represented by the formula (X) through the steps K, L, M, N and P. is there.
Step K is a step of adding a compound represented by formula (X) to a solution of piperazine.
Adding means adding or / and reacting.
Piperazine can be used in an amount of 1.5 to 5 molar equivalents, preferably 2.5 to 3.5 molar equivalents, relative to the compound represented by (X).
As a solvent for the solution of piperazine, dichloromethane, chloroform, dioxane, benzene, toluene, hexane, ethyl acetate, tetrahydrofuran, acetonitrile, acetone, and N, N-dimethylformamide can be used alone or in combination. Tetrahydrofuran or toluene is preferred, and toluene is more preferred.
When the compound represented by the formula (X) is added, it is added at 15 ° C. to the solvent reflux temperature, preferably 45 to 80 ° C., once or in appropriate times over 15 minutes to 2 hours. The reaction can be carried out at a temperature of from ℃ to a solvent reflux temperature, preferably from 45 to 80 ℃, for 15 minutes to 2 hours.
When adding the solution which the compound shown by Formula (X) contains, it is dripped at 15 degreeC-solvent reflux temperature, Preferably it is 45-80 degreeC over 15 minutes-2 hours, Furthermore, 15 degreeC-solvent reflux temperature The reaction can be carried out at 45 to 80 ° C. for 15 minutes to 2 hours.
When the solvent is toluene, it is preferably added dropwise at 60 to 70 ° C., preferably 30 minutes to 1 hour 30 minutes, and more preferably at 60 to 70 ° C., preferably 30 minutes to 1 hour 30 minutes. be able to.
Step L is a step of adding water to the reaction solution and extracting with an organic solvent.
It is preferable to perform the process L at 45-80 degreeC. When the solvent is toluene, it is preferably carried out at 55 to 65 ° C.
As the organic solvent, toluene, ethyl acetate, dichloromethane, chloroform, hexane can be used. Toluene is preferred.
Step M is a step of adding an acid to the organic layer obtained in Step L to make it acidic, and extracting with water.
As the acid, hydrochloric acid, hydrobromic acid, sulfuric acid, or nitric acid can be used. Hydrochloric acid is preferred, 1 to 4 mol / L hydrochloric acid is more preferred, and 2 mol / L hydrochloric acid is most preferred.
It is preferable to perform the process M at 45-80 degreeC. When the solvent is toluene, it is preferably carried out at 55 to 65 ° C.
Step N is a step in which a base is added to the aqueous layer obtained in Step M to make it alkaline, and crystals are precipitated.
As the base, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or an aqueous solution thereof can be used. A sodium hydroxide aqueous solution is preferable, a 1 to 4 mol / L sodium hydroxide aqueous solution is more preferable, and a 2 mol / L sodium hydroxide aqueous solution is most preferable.
Step N is preferably made alkaline by adding a base at 45 to 80 ° C. When using toluene as a solvent, it is preferable to carry out at 55-65 degreeC. Crystals are preferably deposited at 15 to 30 ° C.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５ _、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、及びＸは１）と同意義）
Ｂ製造方法とは、式（Ｉ）で示される化合物と式（ＩＩ）で示される化合物を溶媒中、パラジウム化合物、有機リン化合物、及び塩基の存在下、式（ＩＩＩ）で示される化合物を製造する方法である。
また、溶媒中、パラジウム化合物、有機リン化合物、塩基、及びスルフィン酸塩の存在下で行うことができる。
Ａ製造方法で得た式（Ｉ）で示される化合物を使用することができる。
式（Ｉ）で示される化合物に対して、式（ＩＩ）で示される化合物を０．５〜２モル当量、好ましくは０．７５〜１．５モル当量用いることができる。
式（Ｉ）で示される化合物に対して、パラジウム化合物を０．００２〜０．２モル当量、好ましくは０．００２〜０．１モル当量用いることができる。
式（Ｉ）で示される化合物に対して、有機リン化合物を０．００２〜０．２モル当量、好ましくは０．００２〜０．１モル当量用いることができる。
パラジウム化合物に対して，有機リン化合物を１〜８当量，好ましくは１〜２当量用いることができる。
式（Ｉ）で示される化合物に対して、塩基を０．８〜５モル当量、好ましくは２〜３モル当量用いることができる。
反応温度は、１５℃〜溶媒還流温度で行うことができる。
反応時間は、１〜２４時間で行うことができる。
パラジウム化合物としては、酢酸パラジウム、塩化パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム、ビス（トリ−オルト−トリルホスフィン）パラジウムジクロリド、ビス（トリフェニルホスフィン）パラジウムジクロリド、パラジウムアセチルアセトナト、パラジウム炭素、ジクロロビス（アセトニトリル）パラジウム、ビス（ベンゾニトリル）パラジウムクロリド、（１，３−ジイソプロピルイミダゾール−２−イリデン）（３−クロロピリジル）パラジウムジクロリドを用いることができる。酢酸パラジウムが好ましい。
溶媒としては、ジクロロメタン、クロロホルム、ジオキサン、ベンゼン、トルエン、ヘキサン、酢酸エチル、テトラヒドロフラン、アセトニトリル、アセトン、及びＮ，Ｎ−ジメチルホルムアミドを単独又は混合して用いることができる。トルエンが好ましい。
有機リン化合物としては、トリフェニルホスフィン、トリ（オルト−トリル）ホスフィン、９，９−ジメチル−４，５−ビス（ジフェニルホスフィノ）キサンチン、トリ（ｔｅｒｔ−ブチル）ホスフィン、ジ（ｔｅｒｔ−ブチル）メチルホスフィン、ジアダマンチルブチルホスフィン、１，１’−ビス（ジフェニルホスフィノ）フェロセン、１，２−ビス（ジフェニルホスフィノ）エタン、１，３−ビス（ジフェニルホスフィノ）プロパン、１，４−ビス（ジフェニルホスフィノ）ブタン、２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル、トリシクロヘキシルホスフィン、ジフェニルシクロヘキシルホスフィン，ジシクロヘキシルフェニルホスフィン、ジフェニルホスフィノフェロセン、２-（ジ−ｔｅｒｔ−ブチルホスフィノ）ビフェニル、トリ（ｔｅｒｔ−ブチル）ホスホニウムテトラフェニルボレート、ジ（ｔｅｒｔ−ブチル）メチルホスホニウムテトラフェニルボレートを用いることができる。ジアダマンチルブチルホスフィン、トリ（ｔｅｒｔ−ブチル）ホスフィンが好ましい。
また、パラジウム化合物と上記有機リン化合物の複合体であるビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリシクロヘキシルホスフィン）パラジウム、ジクロロビス（トリ−オルト−トリルホスフィン）パラジウムを用いることができる。
塩基としては、ナトリウムｔｅｒｔ−ブトキシド、ナトリウムｔｅｒｔ−ペントキシド、炭酸セシウム、炭酸ナトリウム、炭酸カリウム、及びそれらの水溶液を用いることができる。ナトリウムｔｅｒｔ−ペントキシドが好ましい。
スルフィン酸塩としては、メタンスルフィン酸ナトリウム、ベンゼンスルフィン酸ナトリウム、パラ−トルエンスルフィン酸ナトリウムを用いることができる。パラ−トルエンスルフィン酸ナトリウムが好ましい。
式（Ｉ）で示される化合物、式（ＩＩ）で示される化合物、パラジウム化合物、有機リン化合物、及び塩基を溶媒に添加する方法としては、ａ方法、ｂ方法、及びｃ方法を用いることができる。
ａ方法は、式（Ｉ）で示される化合物、式（ＩＩ）で示される化合物、パラジウム化合物、有機リン化合物、及び塩基を全て加え、所望によりスルフィン酸塩を加え、６０℃〜溶媒還流温度で反応する方法である。
ｂ方法は、式（Ｉ）で示される化合物、パラジウム化合物、有機リン化合物、及び塩基を加え、所望によりスルフィン酸塩を加え、１５〜３０℃で１５分〜２時間反応する工程Ａ後、さらに、式（ＩＩ）で示される化合物を加え、６０℃〜溶媒還流温度で反応する工程Ｂを包含する方法である。
ｃ方法は、パラジウム化合物及び有機リン化合物を加え、１５〜３０℃で１５分〜２時間反応する工程Ｃ、さらに、式（Ｉ）で示される化合物及び塩基を加える、所望によりスルフィン酸塩を加える工程Ｄ後、式（ＩＩ）で示される化合物を加え、６０℃〜溶媒還流温度で反応する工程Ｂを包含する方法である。
好ましくはｂ方法及びｃ方法であり、さらに好ましくはｃ方法である。
ｂ方法は、ａ方法に比べて、安定した反応収率で行うことができる。
ｃ方法は、ｂ方法に比べて、大量合成の際に安定した反応収率で行うことができる。
なお、シリカゲルカラムクロマトグラフィー、再結晶、又は／及び蒸留等の一般的な方法により、単離精製することができる。また、精製せずに次の反応に用いることもできる。 B manufacturing method

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ _, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and X are the same as 1))
The production method B is a compound represented by the formula (III) and a compound represented by the formula (II) in the presence of a palladium compound, an organic phosphorus compound, and a base in a solvent. It is a method to do.
Moreover, it can carry out in presence of a palladium compound, an organophosphorus compound, a base, and a sulfinate in a solvent.
A compound represented by the formula (I) obtained by the production method A can be used.
The compound represented by the formula (II) can be used at 0.5 to 2 molar equivalents, preferably 0.75 to 1.5 molar equivalents, relative to the compound represented by the formula (I).
The palladium compound can be used in an amount of 0.002 to 0.2 molar equivalent, preferably 0.002 to 0.1 molar equivalent, relative to the compound represented by the formula (I).
The organophosphorus compound can be used in an amount of 0.002 to 0.2 molar equivalent, preferably 0.002 to 0.1 molar equivalent, relative to the compound represented by the formula (I).
The organophosphorus compound can be used in an amount of 1 to 8 equivalents, preferably 1 to 2 equivalents, relative to the palladium compound.
The base can be used in an amount of 0.8 to 5 molar equivalents, preferably 2 to 3 molar equivalents, relative to the compound represented by the formula (I).
The reaction temperature can be 15 ° C to the solvent reflux temperature.
The reaction time can be 1 to 24 hours.
Examples of palladium compounds include palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene]. Dichloropalladium, bis (tri-ortho-tolylphosphine) palladium dichloride, bis (triphenylphosphine) palladium dichloride, palladium acetylacetonate, palladium on carbon, dichlorobis (acetonitrile) palladium, bis (benzonitrile) palladium chloride, (1,3 -Diisopropylimidazol-2-ylidene) (3-chloropyridyl) palladium dichloride can be used. Palladium acetate is preferred.
As the solvent, dichloromethane, chloroform, dioxane, benzene, toluene, hexane, ethyl acetate, tetrahydrofuran, acetonitrile, acetone, and N, N-dimethylformamide can be used alone or in combination. Toluene is preferred.
Examples of organic phosphorus compounds include triphenylphosphine, tri (ortho-tolyl) phosphine, 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthine, tri (tert-butyl) phosphine, and di (tert-butyl). Methylphosphine, diadamantylbutylphosphine, 1,1′-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (Diphenylphosphino) butane, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, tricyclohexylphosphine, diphenylcyclohexylphosphine, dicyclohexylphenylphosphine, diphenylphosphinoferrocene, 2- (di-tert- Butylphosphino ) Biphenyl, tri (tert-butyl) phosphonium tetraphenylborate, di (tert-butyl) methylphosphonium tetraphenylborate can be used. Diadamantylbutylphosphine and tri (tert-butyl) phosphine are preferable.
Also, bis (tri-tert-butylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (tricyclohexylphosphine) palladium, dichlorobis (tri-ortho-tolylphosphine), which is a complex of a palladium compound and the above organic phosphorus compound Palladium can be used.
As the base, sodium tert-butoxide, sodium tert-pentoxide, cesium carbonate, sodium carbonate, potassium carbonate, and an aqueous solution thereof can be used. Sodium tert-pentoxide is preferred.
As the sulfinate, sodium methanesulfinate, sodium benzenesulfinate, and sodium para-toluenesulfinate can be used. Sodium para-toluenesulfinate is preferred.
As a method of adding the compound represented by the formula (I), the compound represented by the formula (II), the palladium compound, the organic phosphorus compound, and the base to the solvent, the method a, the method b, and the method c can be used. .
Method a includes adding a compound represented by the formula (I), a compound represented by the formula (II), a palladium compound, an organophosphorus compound, and a base, and optionally adding a sulfinate, at 60 ° C. to a solvent reflux temperature. It is a method to react.
Method b comprises adding a compound represented by formula (I), a palladium compound, an organophosphorus compound, and a base, adding a sulfinate as required, and reacting at 15 to 30 ° C. for 15 minutes to 2 hours, and further after step A The method includes Step B in which a compound represented by the formula (II) is added and the reaction is performed at 60 ° C. to solvent reflux temperature.
Method c is a step C of adding a palladium compound and an organophosphorus compound and reacting at 15 to 30 ° C. for 15 minutes to 2 hours, adding a compound of formula (I) and a base, and optionally adding a sulfinate. This is a method including Step B in which a compound represented by the formula (II) is added after Step D and reacted at 60 ° C. to solvent reflux temperature.
The b method and the c method are preferable, and the c method is more preferable.
The method b can be performed with a stable reaction yield as compared with the method a.
The method c can be performed with a stable reaction yield during mass synthesis as compared with the method b.
In addition, it can be isolated and purified by a general method such as silica gel column chromatography, recrystallization, and / or distillation. It can also be used in the next reaction without purification.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^８、及びＲ^９は１）と同意義；Ｒ^１１及びＲ^１２は１２）と同意義）
Ｃ製造方法は、Ｂ製造方法で得た式（ＩＶ）で示される化合物と式（Ｖ）で示される化合物を溶媒中、塩基存在下で反応させ、式（ＶＩ）で示される化合物を製造する方法である。
式（ＩＶ）で示される化合物に対して、式（Ｖ）で示される化合物を０．８〜２モル当量、好ましくは１．２〜１．６モル当量用いることができる。
式（ＩＶ）で示される化合物に対して、塩基を１〜３モル当量、好ましくは１．５〜２．５モル当量用いることができる。
反応温度は、５℃〜溶媒還流温度、好ましくは７５〜８５℃で行うことができる。
反応時間は、３０分〜２４時間が好ましい。
必要であれば、式（Ｖ）で示される化合物に対してヨウ化カリウムを０．０５〜０．３モル当量用いることができる。
溶媒としては、ジクロロメタン、クロロホルム、ジオキサン、ベンゼン、トルエン、ヘキサン、酢酸エチル、テトラヒドロフラン、アセトニトリル、アセトン、Ｎ−メチルピロリドン、及びＮ，Ｎ−ジメチルホルムアミドを単独又は混合して用いることができる。Ｎ，Ｎ−ジメチルホルムアミドが好ましい。
塩基としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水酸化カリウム、又は水酸化セシウムを用いることができる。炭酸カリウム又は炭酸セシウムが好ましい。
Ｒ^１２が水素原子である場合は、Ｄ製造方法を行う必要はないが、Ｒ^１２がアルキルである場合、式（ＶＩ）で示される化合物を加水分解して式（ＶＩ）で示される化合物を得ることができる。
なお、シリカゲルカラムクロマトグラフィー、再結晶、又は／及び蒸留等の一般的な方法により、単離精製することができる。また、精製せずに次の反応に用いることもできる。 C manufacturing method

(Wherein R ¹ , R ² , R ³ , R ⁸ , and R ⁹ are the same as 1); R ¹¹ and R ¹² are the same as 12))
In the C production method, the compound represented by the formula (IV) obtained by the B production method and the compound represented by the formula (V) are reacted in a solvent in the presence of a base to produce the compound represented by the formula (VI). Is the method.
The compound represented by the formula (V) can be used at 0.8 to 2 molar equivalents, preferably 1.2 to 1.6 molar equivalents, relative to the compound represented by the formula (IV).
The base can be used at 1 to 3 molar equivalents, preferably 1.5 to 2.5 molar equivalents, relative to the compound represented by the formula (IV).
The reaction temperature can be 5 ° C to the solvent reflux temperature, preferably 75 to 85 ° C.
The reaction time is preferably 30 minutes to 24 hours.
If necessary, 0.05 to 0.3 molar equivalent of potassium iodide can be used with respect to the compound represented by the formula (V).
As the solvent, dichloromethane, chloroform, dioxane, benzene, toluene, hexane, ethyl acetate, tetrahydrofuran, acetonitrile, acetone, N-methylpyrrolidone, and N, N-dimethylformamide can be used alone or in combination. N, N-dimethylformamide is preferred.
As the base, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or cesium hydroxide can be used. Potassium carbonate or cesium carbonate is preferred.
When R ¹² is a hydrogen atom, it is not necessary to carry out the D production method. However, when R ¹² is alkyl, the compound represented by the formula (VI) is hydrolyzed to the compound represented by the formula (VI). Can be obtained.
In addition, it can be isolated and purified by a general method such as silica gel column chromatography, recrystallization, and / or distillation. It can also be used in the next reaction without purification.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^８、及びＲ^９は１）と同意義；Ｒ^１１及びＲ^１２は１２）と同意義）
Ｄ製造方法は、式（ＶＩ）で示される化合物を溶媒中、塩基存在下加水分解して式（ＶＩ）で示される化合物を製造する方法である。
式（ＶＩ）で示される化合物に対して、塩基を１〜１０モル当量、好ましくは２〜４モル当量用いることができる。
反応温度は、５℃〜溶媒還流温度、好ましくは５５〜６５℃を用いることができる。
反応時間は、３０分〜２４時間が好ましい。
溶媒としては、ジオキサン、ベンゼン、トルエン、ヘキサン、テトラヒドロフラン、メタノール、エタノール、Ｎ，Ｎ−ジメチルホルムアミド及び水を単独又は混合して用いることができる。メタノール／テトラヒドロフラン／水の混合溶媒が好ましい。
塩基としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、及びそれらの水溶液を用いることができる。水酸化ナトリウム水溶液が好ましい。
なお、シリカゲルカラムクロマトグラフィー、再結晶、又は／及び蒸留等の一般的な方法により、単離精製することができる。また、精製せずに次の反応に用いることもできる。 D manufacturing method

(Wherein R ¹ , R ² , R ³ , R ⁸ , and R ⁹ are the same as 1); R ¹¹ and R ¹² are the same as 12))
The D production method is a method for producing a compound represented by the formula (VI) by hydrolyzing a compound represented by the formula (VI) in a solvent in the presence of a base.
The base can be used in an amount of 1 to 10 molar equivalents, preferably 2 to 4 molar equivalents, relative to the compound represented by the formula (VI).
The reaction temperature may be 5 ° C to solvent reflux temperature, preferably 55 to 65 ° C.
The reaction time is preferably 30 minutes to 24 hours.
As the solvent, dioxane, benzene, toluene, hexane, tetrahydrofuran, methanol, ethanol, N, N-dimethylformamide and water can be used alone or in combination. A mixed solvent of methanol / tetrahydrofuran / water is preferred.
As the base, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and an aqueous solution thereof can be used. An aqueous sodium hydroxide solution is preferred.
In addition, it can be isolated and purified by a general method such as silica gel column chromatography, recrystallization, and / or distillation. It can also be used in the next reaction without purification.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^８、及びＲ^９は１）と同意義；Ｒ^１１及びＲ^１２は１２）と同意義）
Ｅ製造方法は、Ｂ製造方法で得た式（ＶＩＩＩ）で示される化合物を溶媒中、有機ボロン酸と反応して式（ＩＸ）で示される化合物を製造する方法である。
式（ＶＩＩＩ）で示される化合物に対して、有機ボロン酸を０．５〜３モル当量、好ましくは０．８〜１．５モル当量用いることができる。
反応温度は、３０℃〜溶媒還流温度が好ましい。
反応時間は、３０分〜２４時間が好ましい。
パラジウム化合物及び有機リン化合物存在下行うことができる。
パラジウム化合物としては、上記パラジウム化合物を用いることができる。酢酸パラジウムが好ましい。
有機リン化合物として、上記有機リン化合物を用いることができる。トリフェニルホスフィンが好ましい。
パラジウム化合物と有機リン化合物の複合体として、上記Ｂ製造方法に記載のパラジウム化合物と有機リン化合物の複合体を用いることができる。
有機ボロン酸としては、アリールボロン酸及びヘテロアリールボロン酸を用いることができる。フリルボロン酸及びチオフェンボロン酸が好ましい。
溶媒としては、ジオキサン、ベンゼン、トルエン、ヘキサン、テトラヒドロフラン、メタノール、エタノール、及びＮ，Ｎ−ジメチルホルムアミドを単独又は混合して用いることができる。ジオキサンが好ましい。
塩基としては、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、及びそれらの水溶液を用いることができる。炭酸ナトリウム水溶液が好ましい。
なお、シリカゲルカラムクロマトグラフィー、再結晶、又は／及び蒸留等の一般的な方法により、単離精製することができる。また、精製せずに次の反応に用いることもできる。 E Manufacturing method

(Wherein R ¹ , R ² , R ³ , R ⁸ , and R ⁹ are the same as 1); R ¹¹ and R ¹² are the same as 12))
The E production method is a method for producing a compound represented by the formula (IX) by reacting a compound represented by the formula (VIII) obtained by the B production method with an organic boronic acid in a solvent.
The organic boronic acid can be used in an amount of 0.5 to 3 molar equivalents, preferably 0.8 to 1.5 molar equivalents, relative to the compound represented by the formula (VIII).
The reaction temperature is preferably 30 ° C. to solvent reflux temperature.
The reaction time is preferably 30 minutes to 24 hours.
The reaction can be performed in the presence of a palladium compound and an organic phosphorus compound.
As the palladium compound, the above palladium compounds can be used. Palladium acetate is preferred.
The organophosphorus compound can be used as the organophosphorus compound. Triphenylphosphine is preferred.
As the complex of the palladium compound and the organic phosphorus compound, the complex of the palladium compound and the organic phosphorus compound described in the above B production method can be used.
As the organic boronic acid, aryl boronic acid and heteroaryl boronic acid can be used. Furylboronic acid and thiopheneboronic acid are preferred.
As the solvent, dioxane, benzene, toluene, hexane, tetrahydrofuran, methanol, ethanol, and N, N-dimethylformamide can be used alone or in combination. Dioxane is preferred.
As the base, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and an aqueous solution thereof can be used. A sodium carbonate aqueous solution is preferred.
In addition, it can be isolated and purified by a general method such as silica gel column chromatography, recrystallization, and / or distillation. It can also be used in the next reaction without purification.

（式中、Ｘは１）と同意義；Ｒ^１５、Ｒ^１６、及びＲ^１７は１９）と同意義）
Ｆ製造方法は、式（ＸＩ）で示される化合物又はその反応性誘導体を溶媒中、式（ＸＩＩ）で示される化合物と反応し、式（ＸＩＩＩ）で示される化合物を得る工程Ｐ、工程Ｐで得た式（ＸＩＩＩ）で示される化合物を酸と反応し、式（ＸＩＶ）で示される化合物を得る工程Ｑ、及び工程Ｑで得た式（ＸＩＶ）で示される化合物を閉環する工程Ｒを包含する式（ＸＶ）で示される化合物を製造する方法である。
工程Ｐにおいて、式（ＸＩ）で示される化合物に対して、式（ＸＩＩ）で示される化合物を０．５〜３モル当量、好ましくは０．８〜１．５モル当量用いることができる。
溶媒としては、ジオキサン、ベンゼン、トルエン、ヘキサン、テトラヒドロフラン、及び酢酸エチルを単独又は混合して用いることができる。
反応温度は、１５℃〜溶媒還流温度が好ましい。
反応時間は、３０分〜２４時間が好ましい。
式（ＸＩ）で示される化合物を用いる場合は、縮合剤として、Ｎ，Ｎ’−ジシクロヘキシルカルボジイミドを用いることができる。
また、式（ＸＩ）で示される化合物の反応性誘導体が酸クロリド誘導体の場合は、溶媒中、塩化チオニルと反応後、塩基存在下、式（ＸＩＩ）で示される化合物と反応することができる。
塩基としては、トリエチルアミンが好ましい。
工程Ｑにおいて、工程Ｐで得た式（ＸＩＩＩ）で示される化合物を酸と反応し、式（ＸＩＶ）で示される化合物を得ることができる。
式（ＸＩＩＩ）で示される化合物に対して、酸を２〜５０モル当量用いることができる。
反応温度は、３０℃〜溶媒還流温度が好ましい。
反応時間は、３０分〜２４時間が好ましい。
溶媒としては、ジオキサン、ベンゼン、トルエン、ヘキサン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、及び酸を単独又は混合して用いることができる。
酸としては、塩酸、臭化水素酸、硫酸、硝酸、及びパラ−トルエンスルホン酸を用いることができる。
工程Ｒにおいて、工程Ｑで得た式（ＸＩＶ）で示される化合物を閉環し、式（ＸＶ）で示される化合物を得ることができる。
ヘキサクロロエタン、トリフェニルフォスフィン、及び塩基存在下で行うことができる。
ヘキサクロロエタンは、式（ＸＩＶ）で示される化合物に対して、１〜５モル当量用いることができる。
塩基としては、トリエチルアミンが好ましく、式（ＸＩＶ）で示される化合物に対して、２〜１０モル当量用いることができる。
反応温度は、３０℃〜溶媒還流温度が好ましい。
反応時間は、３０分〜２４時間が好ましい。
溶媒としては、ジオキサン、ベンゼン、トルエン、ヘキサン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、及びアセトニトリルを単独又は混合して用いることができる。
なお、シリカゲルカラムクロマトグラフィー、再結晶、又は／及び蒸留等の一般的な方法により、単離精製することができる。また、精製せずに次の反応に用いることもできる。 F manufacturing method

(Wherein X is the same as 1); R ¹⁵ , R ¹⁶ and R ¹⁷ are the same as 19).
In the F production method, the compound represented by the formula (XI) or a reactive derivative thereof is reacted with the compound represented by the formula (XII) in a solvent to obtain a compound represented by the formula (XIII). Including the step Q of reacting the compound represented by the formula (XIII) obtained with an acid to obtain the compound represented by the formula (XIV), and the step R cyclizing the compound represented by the formula (XIV) obtained in the step Q This is a method for producing a compound represented by the formula (XV).
In Step P, the compound represented by the formula (XII) can be used at 0.5 to 3 molar equivalents, preferably 0.8 to 1.5 molar equivalents, relative to the compound represented by the formula (XI).
As the solvent, dioxane, benzene, toluene, hexane, tetrahydrofuran, and ethyl acetate can be used alone or in combination.
The reaction temperature is preferably 15 ° C. to solvent reflux temperature.
The reaction time is preferably 30 minutes to 24 hours.
When the compound represented by the formula (XI) is used, N, N′-dicyclohexylcarbodiimide can be used as the condensing agent.
Further, when the reactive derivative of the compound represented by the formula (XI) is an acid chloride derivative, it can react with the compound represented by the formula (XII) in the presence of a base after reacting with thionyl chloride in a solvent.
As the base, triethylamine is preferable.
In Step Q, the compound represented by the formula (XIII) obtained in Step P can be reacted with an acid to obtain the compound represented by the formula (XIV).
The acid can be used in an amount of 2 to 50 molar equivalents relative to the compound represented by the formula (XIII).
The reaction temperature is preferably 30 ° C. to solvent reflux temperature.
The reaction time is preferably 30 minutes to 24 hours.
As the solvent, dioxane, benzene, toluene, hexane, tetrahydrofuran, N, N-dimethylformamide, and an acid can be used alone or in combination.
As the acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and para-toluenesulfonic acid can be used.
In step R, the compound represented by formula (XIV) obtained in step Q can be cyclized to obtain the compound represented by formula (XV).
It can be performed in the presence of hexachloroethane, triphenylphosphine, and a base.
Hexachloroethane can be used at 1 to 5 molar equivalents relative to the compound represented by the formula (XIV).
As the base, triethylamine is preferable, and 2 to 10 molar equivalents can be used with respect to the compound represented by the formula (XIV).
The reaction temperature is preferably 30 ° C. to solvent reflux temperature.
The reaction time is preferably 30 minutes to 24 hours.
As the solvent, dioxane, benzene, toluene, hexane, tetrahydrofuran, N, N-dimethylformamide, and acetonitrile can be used alone or in combination.
In addition, it can be isolated and purified by a general method such as silica gel column chromatography, recrystallization, and / or distillation. It can also be used in the next reaction without purification.

（式中、Ｘは１）と同意義；Ｒ^１８、Ｒ^１９、及びＲ^２０は２０）と同意義）
Ｇ製造方法は、式（ＸＶＩ）で示される化合物を溶媒中、ハロゲン化して、式（ＸＶＩＩ）で示される化合物を得る工程Ｓ、及び工程Ｓで得た式（ＸＶＩＩ）で示される化合物を式：Ｒ^２０ＣＯＯＮＨ_４で示される化合物と反応する工程Ｔを包含する式（ＸＶＩＩＩ）で示される化合物を製造する方法である。
工程Ｓにおいて、式（ＸＶＩ）で示される化合物に対して、ハロゲンを０．５〜２モル当量、好ましくは０．８〜１．２モル当量用いることができる。
反応温度は、１０〜５０℃が好ましい。
反応時間は、３０分〜２４時間が好ましい。
ハロゲンとしては、塩素及び臭素を用いることができる。臭素が好ましい。
溶媒としては、ジクロロメタン、クロロホルム、ジオキサン、ベンゼン、トルエン、ヘキサン、テトラヒドロフラン、及びＮ，Ｎ−ジメチルホルムアミドを単独又は混合して用いることができる。
工程Ｔにおいて、式（ＸＶＩＩ）で示される化合物に対して、式：Ｒ^２０ＣＯＯＮＨ_４で示される化合物を１〜８モル当量、好ましくは１．５〜６モル当量用いることができる。
反応温度は、３０℃〜溶媒還流温度が好ましい。
反応時間は、３０分〜２４時間が好ましい。
式：Ｒ^２０ＣＯＯＮＨ_４で示される化合物としては、ギ酸アンモニウム又は酢酸アンモニウムが好ましい。
溶媒としては、ジオキサン、ベンゼン、トルエン、ヘキサン、テトラヒドロフラン、メタノール、エタノール、Ｎ，Ｎ−ジメチルホルムアミド、式：Ｒ^２０ＣＯＯＨで示されるカルボン酸、及び水を単独又は混合して用いることができる。式：Ｒ^２０ＣＯＯＨで示されるカルボン酸が好ましい。
なお、シリカゲルカラムクロマトグラフィー、再結晶、又は／及び蒸留等の一般的な方法により、単離精製することができる。また、精製せずに次の反応に用いることもできる。
上記式（ＸＶ）で示される化合物及び上記式（ＸＶＩＩＩ）で示される化合物等、上記式に示される化合物は、Ｎ−フェニル−Ｎ’−フェニルスルホニルピペラジン誘導体の重要中間体である。
上記の製造方法で生成される式（Ｉ）〜式（ＸＶＩＩＩ）で表わされる化合物の結晶は、粉末Ｘ線回折によってＸ線回折パターンを得ることができる。
粉末Ｘ線回折の測定条件は、管球ＣｕＫα線、管電圧４０Ｋｖ、管電流４０ｍＡである。結晶は、各回折角又は面間隔の値によって特徴づけられる（ｄｓｉｎθ＝ｎλ：ｎは整数、ｄは面間隔（単位：オングストローム）、θは回折角（単位：度）を意味する）。 G manufacturing method

(Wherein X is the same as 1); R ¹⁸ , R ¹⁹ , and R ²⁰ are the same as 20))
In the G production method, the compound represented by the formula (XVI) is halogenated in a solvent to obtain a compound represented by the formula (XVII), and the compound represented by the formula (XVII) obtained in the step S is represented by the formula : A method for producing a compound represented by the formula (XVIII) including a step T in which a compound represented by R ²⁰ COONH ₄ is reacted.
In Step S, halogen can be used at 0.5 to 2 molar equivalents, preferably 0.8 to 1.2 molar equivalents, relative to the compound represented by the formula (XVI).
The reaction temperature is preferably 10 to 50 ° C.
The reaction time is preferably 30 minutes to 24 hours.
As halogen, chlorine and bromine can be used. Bromine is preferred.
As the solvent, dichloromethane, chloroform, dioxane, benzene, toluene, hexane, tetrahydrofuran, and N, N-dimethylformamide can be used alone or in combination.
In Step T, the compound represented by the formula: R ²⁰ COONH ₄ can be used at 1 to 8 molar equivalents, preferably 1.5 to 6 molar equivalents, relative to the compound represented by the formula (XVII).
The reaction temperature is preferably 30 ° C. to solvent reflux temperature.
The reaction time is preferably 30 minutes to 24 hours.
The compound represented by the formula: R ²⁰ COONH ₄ is preferably ammonium formate or ammonium acetate.
As the solvent, dioxane, benzene, toluene, hexane, tetrahydrofuran, methanol, ethanol, N, N-dimethylformamide, a carboxylic acid represented by the formula: R ²⁰ COOH, and water can be used alone or in combination. A carboxylic acid represented by the formula: R ²⁰ COOH is preferred.
In addition, it can be isolated and purified by a general method such as silica gel column chromatography, recrystallization, and / or distillation. It can also be used in the next reaction without purification.
The compound represented by the above formula, such as the compound represented by the above formula (XV) and the compound represented by the above formula (XVIII), is an important intermediate of the N-phenyl-N′-phenylsulfonylpiperazine derivative.
Crystals of the compounds represented by the formulas (I) to (XVIII) produced by the above production method can obtain an X-ray diffraction pattern by powder X-ray diffraction.
The measurement conditions of powder X-ray diffraction are tube ball CuKα ray, tube voltage 40 Kv, tube current 40 mA. The crystal is characterized by the value of each diffraction angle or face spacing (dsin θ = nλ: n is an integer, d is the face spacing (unit: angstrom), and θ is the diffraction angle (unit: degree)).

In the present specification, the “solvate” includes, for example, solvates with organic solvents, hydrates and the like. When forming a solvate with an organic solvent, it may be coordinated with any number of organic solvent molecules. When forming a hydrate, it may be coordinated with any number of water molecules. Hydrates are preferred.
The term “the compound of the present invention” includes a pharmaceutically acceptable salt or a solvate thereof. For example, alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) ), And salts with organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, paratoluenesulfonic acid, etc.). These salts can be formed by a commonly performed method.
The compounds of the present invention are not limited to specific isomers, but include all possible isomers and racemates.

ピペラジン（Ａ−２、２２．７ ｇ、８９．５ ｍｍｏｌ）のテトラヒドロフラン（１８０ ｍＬ）溶液に、４−イソプロピルオキシベンゼンスルホニルクロリド（Ａ−３、２１．０ ｇ、８９．５ ｍｍｏｌ）のテトラヒドロフラン（３０ ｍＬ）溶液を室温下３０分かけて滴下した。反応液を室温下３０分撹拌後、水（２００ ｍＬ）を加え、酢酸エチルで抽出し、有機層を食塩水で洗浄した。有機層を２モル／Ｌ塩酸（１００ ｍＬ）で抽出した。不溶物をろ別後、水層を酢酸エチルで洗浄し、２モル／Ｌ水酸化ナトリウム水溶液でアルカリ性とした。析出した結晶を酢酸エチルに溶解し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、４−（イソプロピルオキシベンゼンスルホニル）ピペラジン（Ｂ−４、１９．９ ｇ、収率７８％）を白色結晶として得た。
融点：１３３．６〜１３３．７℃
１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.37 (d, J = 6.0 Hz, 6H), 2.95 (m, 8H), 4.63 (m, 1H), 6.94 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H).

実施例１ ｛２，３−ジフルオロ−５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸（Ｉ−１）の合成

中間体Ｎ−（４−イソプロピルオキシベンゼンスルホニル）ピペラジン（Ｂ−４）の合成

ピペラジン（Ａ−２、４４．０ ｇ、５１１ ｍｍｏｌ）のトルエン（２８０ ｍＬ）溶液に、４−イソプロピルオキシベンゼンスルホニルクロリド（Ａ−３、４０．０ ｇ、１７０ ｍｍｏｌ）のトルエン（１２６ ｍＬ）溶液を６５℃で１時間かけて滴下した。反応液を６５℃で１時間撹拌後、水（１９６ ｍＬ）を加え、６０℃にて分液後、有機層を食塩水で洗浄した。有機層を６０℃にて２モル／Ｌ塩酸（２１２ ｍＬ）で抽出した。水層をトルエンで洗浄し、６０℃にて２モル／Ｌ水酸化ナトリウム水溶液を加えアルカリ性とした。室温まで冷却後、生成した析出物をろ取し、４−（イソプロピルオキシベンゼンスルフォニル）ピペラジン（Ｂ−４、４４．７ ｇ、収率９２％）を白色結晶として得た。
融点およびＮＭＲのデータは参考例１で得られた化合物（Ｂ−４）と一致した。
粉末Ｘ線回折の結果を表１および図１に示す。
主なピークの回折角：２θ＝5.0，10.2，14.6，19.0，23.5度

第１工程 ２，３−ジフルオロ−５−ブロモフェノール（Ｂ−１）の合成
２，３−ジフルオロ−５−ブロモアニソール（Ａ−１、１．１５ ｇ）のジクロロメタン（５ ｍＬ）溶液に、氷冷下、１モル／Ｌ三臭化ホウ素−塩化メチレン溶液（７．５ ｍＬ）を滴下し、氷冷下２時間、室温下２時間撹拌した。反応液を氷水に注ぎ、濃塩酸を加え終夜撹拌した。反応液を酢酸エチルで抽出し、有機層を水酸化ナトリウム水溶液で抽出した。水層を希塩酸にて酸性として、酢酸エチルで抽出した。有機層を硫酸マグネシウムにて乾燥後、溶媒を減圧留去し、２，３−ジフルオロ−５−ブロモフェノール（Ｂ−１、８５０ ｍｇ、収率８１％）を油状物として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 5.36 (d, J = 3.6 Hz, 1H), 6.91 (ddd, J = 9.3 Hz, 6.3 Hz, 2.4 Hz, 1H), 6.97 (ddd, J = 6.6 Hz, 2.4 Hz, 2.4 Hz, 1H).

第２工程 ２，３−ジフルオロ−５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノール（Ｂ−２）の合成
アルゴン気流下、前記で合成した中間体４−（パラ−イソプロピルオキシベンゼンスルホニル）ピペラジン（Ｂ−４、１．１４ ｇ）、酢酸パラジウム（２２ ｍｇ）、パラ−トルエンスルフィン酸ナトリウム（３６ ｍｇ）、ナトリウムｔｅｒｔ−ペントキシド（１．１１ ｇ）のトルエン（７ ｍＬ）懸濁液に、ジアダマンチルブチルホスフィン（７２ ｍｇ）を加え、室温下３０分撹拌した。氷冷下、反応懸濁液に、第１工程で得た２，３−ジフルオロ−５−ブロモフェノール（Ｂ−１、７００ ｍｇ）、トルエン（３ ｍＬ）を加え、２時間加熱還流した。反応液を室温に冷却後、２モル／Ｌ塩酸（７ ｍＬ）を加え、トルエン抽出した。有機層を水、食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をカラムクロマトグラフィーにて精製し、２，３−ジフルオロ−５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノール（Ｂ−２、１．２８ ｇ、収率９３％）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.37 (d, J = 6.0 Hz, 6H), 3.14 (m, 8H), 4.63 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 5.48 (brs, 1H), 6.08 - 6.29 (m, 2H), 6.97 (d, J = 9.3 Hz, 2H), 7.69 (d, J = 9.3 Hz, 2H).

第３工程 ｛２，３−ジフルオロ−５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸メチルエステル（Ｂ−３）の合成
第２工程で得た２，３−ジフルオロ−５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノール（Ｂ−２、４１２ ｍｇ）のＮ、Ｎ−ジメチルホルムアミド（５ ｍＬ）溶液に、炭酸カリウム（２７６ ｍｇ）、ヨウ化カリウム（１７ ｍｇ）、ブロモ酢酸メチルエステル（１８９ μＬ）を加え、室温下２時間撹拌した。反応液を酢酸エチルにて希釈後、希塩酸、水、食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をカラムクロマトグラフィーにて精製し、｛２，３−ジフルオロ−５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸メチルエステル（Ｂ−３、４５２ ｍｇ、収率９３％）を淡紫色固体として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.38 (d, J = 6.0 Hz, 6H), 3.14 (s, 8H), 3.79 (s, 3H), 4.60-4.68 (m, 3H), 6.26 (brs, 1H), 6.30 - 6.37 (m, 1H), 6.98 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H).

第４工程 ｛２，３−ジフルオロ−５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸（Ｉ−１）の合成
第３工程で得た２，３−ジフルオロ−５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ酢酸メチルエステル（Ｂ−３、３６７ ｍｇ）のメタノール（３ ｍＬ）−テトラヒドロフラン（３ ｍＬ）混合溶液に、２モル／Ｌ水酸化ナトリウム水溶液（１．１４ ｍＬ）を加え、室温下２時間撹拌した。反応液にジエチルエーテルを加え、水で抽出した。水層を希塩酸でｐＨ４にし、酢酸エチルで抽出した。有機層を硫酸マグネシウムにて乾燥後、溶媒を減圧留去し、｛２，３−ジフルオロ−５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸（Ｉ−１、２６５ ｍｇ、収率７４％）を無色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.38 (d, J = 6.0 Hz, 6H), 3.00 (brs, 1H), 3.15 (s, 8H), 4.64 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 4.71 (s, 2H), 6.27 (brs, 1H), 6.32 - 6.39 (m, 1H), 6.98 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H).
粉末Ｘ線回折の結果を表２および図２に示す。
主なピークの回折角：２θ＝9.4，15.9，16.1，17.9，21.0，21.2度

実施例２ ｛２−ブロモ-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸（Ｉ−２）の合成

第１工程 ２−ブロモ−５−アミノアニソール（Ｂ−５）の合成
２−ブロモ−５−ニトロアニソール（Ａ−４、１１．６ ｇ、５０．０ ｍｍｏｌ）のメタノール（１５０ ｍＬ）溶液に、鉄（５．５９ ｇ、１００ ｍｍｏｌ）、塩化アンモニウム（５．３５ｇ、１００ ｍｍｏｌ）、水（７５．０ ｍL）を加え、１００℃で６時間攪拌した。反応液をセライトろ過し、ろ液を水で希釈後、希塩酸を加えて酸性とした。ジエチルエーテルで洗浄後、水層に水酸化ナトリウム水溶液を加えてアルカリ性とした。水層を酢酸エチルで抽出し、無水硫酸マグネシウムにて乾燥後、溶媒を減圧留去し、２−ブロモ−５−アミノアニソール（Ｂ−５、４．２０ g、収率４２％）を茶色粉末として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 3.8 (brs, 2H), 3.84 (s, 3H), 6.19 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H).

第２工程 ２−ブロモ−５−ヨードアニソール（Ｂ−６）の合成
第１工程で得た２−ブロモ−５−アミノアニソール（Ｂ−５、４．１２ ｇ、２０．４ ｍｍｏｌ）に濃塩酸（３２．０ ｍＬ）を加え、氷冷下、硝酸ナトリウム（３．３７ ｇ、４８．８ ｍｍｏｌ）の水溶液（１０．０ ｍＬ）を２０分間かけて滴下した。さらに、ヨウ化カリウム（９．９６ ｇ、６１．０ ｍｍｏｌ）の水溶液（１０．０ ｍＬ）を２０分間かけて滴下した。反応液を氷冷下で１時間攪拌後、ジエチルエーテルで抽出した。有機層をチオ硫酸ナトリウム水溶液と水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、２−ブロモ−５−ヨードアニソール（Ｂ−６、５．００ ｇ、収率６５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 3.88 (s, 3H), 7.17 (m ,2H), 7.22 (m, 1H).

第３工程 ２−ブロモ−５−ヨードフェノール（Ｂ−７）の合成
第２工程で得た２−ブロモ−５−ヨードアニソール（Ｂ−６、５．００ ｇ、１６．０ ｍｍｏｌ）の塩化メチレン（１０．０ ｍＬ）溶液に、氷冷下、１Ｍ 三臭化ホウ素−塩化メチレン溶液（３２．０ ｍＬ）を３０分間かけて滴下した。氷冷下で１時間攪拌後、室温で３時間攪拌した。反応液を氷水に注ぎ、濃塩酸を加えて室温で１時間攪拌した。ジエチルエーテルで抽出し、有機層を水酸化ナトリウム水溶液で抽出した。水層に希塩酸を加えて酸性とし、酢酸エチルで抽出した。有機層を水洗後、無水硫酸マグネシウムにて乾燥した。溶媒を減圧留去し、２−ブロモ−５−ヨードフェノール（Ｂ−７、４．３０ ｇ、収率９０％）を結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 5.48 (s, 1H), 7.14 (d, J = 1.8 Hz, 1H), 7.15 (s, 1H), 7.37 (d, J = 1.8 Hz, 1H).
粉末Ｘ線回折の結果を表３および図３に示す。
主なピークの回折角：２θ＝17.9，27.3，28.6度

第４工程 ２−ブロモ-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノール（Ｂ−８）の合成
アルゴン気流下、実施例１で得た４−（パラ−イソプロピルオキシベンゼンスルホニル）ピペラジン（Ｂ−４、１．０５ ｇ）、酢酸パラジウム（２２ ｍｇ）、パラ−トルエンスルフィン酸ナトリウム（３６ ｍｇ）、ナトリウムｔｅｒｔ−ペントキシド（１．１１ ｇ）のトルエン（７ ｍＬ）懸濁液に、ジアダマンチルブチルホスフィン（７２ ｍｇ）を加え、室温下３０分撹拌した。氷冷下、反応液に、第３工程で得た２−ブロモ−５−ヨードフェノール（Ｂ−７、１．００ ｇ）、トルエン（２ ｍＬ）を加え、２時間還流した。反応液を室温に冷却後、２モル／Ｌ塩酸（７ ｍＬ）を加え、酢酸エチル（１０ ｍＬ）にて希釈後、不溶物をろ去し、ろ液をトルエン抽出した。有機層を水、食塩水で洗浄した後、硫酸ナトリウムにて乾燥させた。溶媒を減圧留去して得られた残渣をカラムクロマトグラフィーにて精製し、２−ブロモ-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノール（Ｂ−８、８４５ ｍｇ、収率５６％）を白色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.37 (d, J = 6.0 Hz, 6H), 3.16 (m, 4H), 3.25 (m, 4H), 4.63 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 5.45 (s, 1H), 6.40 (dd, J = 9.0 Hz, 2.4 Hz), 6.58 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 1H), 7.69 (d, J = 9.0 Hz, 2H).
粉末Ｘ線回折の結果を表４および図４に示す。
主なピークの回折角：２θ＝6.1，12.2，17.5，19.0，19.4度

第５工程 ｛２−ブロモ-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸メチルエステル（Ｂ−９）の合成
第４工程で得た２−ブロモ-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノール（Ｂ−８、１７０ ｍｇ、０．３７ ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２．０ ｍＬ）溶液に、炭酸カリウム（１０３ ｍｇ、０．７５ ｍｍｏｌ）、ブロモ酢酸メチルエステル（０．０４２ mＬ、０．４５ ｍｍｏｌ）を加えて、室温で１８時間攪拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を希塩酸と水で洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒を減圧留去し、｛２−ブロモ-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸メチルエステル（Ｂ−９、１５０ ｍｇ、収率７６％）を無色粉末として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.37 (d, J = 6.0 Hz, 6H), 3.13-3.26 (m, 8H), 3.79 (s, 3H), 4.59 - 4.67 (m, 3H), 6.39-6.57 (m, 2H), 6.96 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H).

第６工程 ｛２−ブロモ-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸（Ｉ−２）の合成
第５工程で得た｛２−ブロモ-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸メチルエステル（Ｂ−９、１５０ ｍｇ、０．２８ｍｍｏｌ）のメタノール（２．０ ｍＬ）−テトラヒドラフラン（２．０ ｍＬ）溶液に２モル／Ｌ水酸化ナトリウム溶液（０．４３ ｍＬ、０．８５ ｍｍｏｌ）を加え、室温下３時間攪拌した。反応液を水に注ぎ、ジエチルエーテルで洗浄した。水層に希塩酸を加えて酸性にし、酢酸エチルで抽出した。有機層を水で洗浄後、無水硫酸マグネシウムにて乾燥、溶媒を減圧留去した。得られた粗結晶を酢酸エチル／ヘキサンで再結晶し、｛２−ブロモ-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸（Ｉ−２、１４２ ｍｇ、収率９７％）を無色結晶として得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δｐｐｍ： 1.30 (d, J = 6.0 Hz, 6H), 2.95 (brs, 4H), 3.02 (brs, 4H), 4.71 - 4.79 (m, 3H), 6.42 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H).
粉末Ｘ線回折の結果を表５および図５に示す。
主なピークの回折角：２θ＝9.6，18.2，19.9，20.6，21.6，22.0度

実施例３ ｛２−（３−フリル）-５−［４−（４−イソプロピルオキシベンゼンスルフォニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸（Ｉ−３）の合成

第１工程 ２−（３−フリル）-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノール（Ｂ−１０）の合成
実施例２で得た２−ブロモ-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノール（Ｂ−８、３００ ｍｇ）、３−フリルボロン酸（１１１ ｍｇ）、酢酸パラジウム（５ ｍｇ）、トリフェニルホスフィン（２３ ｍｇ）の１，４−ジオキサン（４ ｍＬ）溶液にアルゴン気流下、２モル／Ｌ炭酸ナトリウム水溶液（２ ｍＬ）を加え、６時間還流した。反応液を室温に冷却後、塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を水と食塩水で洗浄し、硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、得られた残渣をカラムクロマトグラフィーにて精製し、２−（３−フリル）-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノール（Ｂ−１０、１５５ ｍｇ、収率５３％）を無色鱗片晶として得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δｐｐｍ： 1.37 (d, J = 6.0 Hz, 6H), 3.17 (m, 4H), 3.27 (m, 4H), 4.63 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 6.51 (m, 2H), 6.61 (m ,1H), 6.97 (d, J = 9.0 Hz, 2H), 7.22 (d, J = 9.0 Hz, 1H), 7.50 (dd, J = 1.8 Hz, 1.5 Hz, 1H), 7.69 (d, J = 9.0 Hz, 2H), 7.74 (m, 1H).
粉末Ｘ線回折の結果を表６および図６に示す。
主なピークの回折角：２θ＝6.1，15.2，16.3，17.8，20.5，21.2，25.1度

第２工程 ｛２−（３−フリル）-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸メチルエステル（Ｂ−１１）の合成
第１工程で得た２−（３−フリル）-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノール（Ｂ−１０、１４０ ｍｇ、０．３２ ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２．０ ｍＬ）溶液に、炭酸カリウム（８７．３ ｇ、０．６３ ｍｍｏｌ）、ブロモ酢酸メチルエステル（０．０３６ ｍＬ、０．３８ ｍｍｏｌ）を加えて、室温で１８時間攪拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を希塩酸と水で洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒を減圧留去し、｛２−（３−フリル）-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸メチルエステル（Ｂ−１１、１１０ ｍｇ、収率６８％）を無色粉末として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.37 (d, J = 6.0 Hz, 6H), 3.23 (brs, 4H), 3.27 (brs, 4H), 3.84 (s, 3H), 4.58-4.68 (m, 3H), 6.50 (brs, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7.40-7.46 (m, 2H), 7.71 (d, J = 8.4Hz, 2H), 8.19 (s, 1H).

第３工程
第１工程で得た｛２−（３−フリル）-５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸メチルエステル（Ｂ−１１、１００ ｍｇ、０．１９ ｍｍｏｌ）のメタノール（２．０ ｍＬ）−テトラヒドラフラン（２．０ ｍＬ）溶液に２モル／Ｌ水酸化ナトリウム水溶液（０．２９ ｍＬ、０．５８ ｍｍｏｌ）を加え、室温下２時間攪拌した。反応液を水に注ぎ入れ、ジエチルエーテルで洗浄した。水層に希塩酸を加えて酸性にし、酢酸エチルで抽出した。有機層を水で洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒を減圧濃縮し、得られた粗結晶を酢酸エチル／ヘキサンで再結晶し、｛２−（３−フリル）-５−［４−（４−イソプロピルオキシベンゼンスルフォニル）−ピペラジン−１−イル］−フェノキシ｝−酢酸（Ｉ−３、８５ ｍｇ、収率８８％）を無色粉末として得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δｐｐｍ： 1.29 (d, J = 6.0 Hz, 6H), 2.97 (brs, 4H), 3.26 (brs, 4H), 4.79 - 4.70 (m, 3H), 6.52 (d, J = 9.0 Hz, 1H), 6.55 (s, 1H), 6.97 (s, 1H), 7.14 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 9.0 Hz, 1H), 7.66 (s, 1H), 7.67 (d, J = 9.0 Hz, 2H), 8.36 (s, 1H).

実施例４ ｛５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−（２−オキサゾリル）−フェノキシ｝−酢酸（Ｉ−４）の合成

第１工程 ４−クロロ−Ｎ−（２、２−ジメトキシエチル）−２−ヒドロキシベンズアミド（Ｂ−１２）の合成
４―クロロサリチル酸（Ａ−５、５０．０ ｇ、２９０ ｍｍｏｌ）の酢酸エチル（２００ ｍＬ）懸濁液に、室温下塩化チオニル（４１．４ ｇ、３４８ ｍｍｏｌ）を加え、３時間加熱還流した。反応液を室温まで冷却し、テトラヒドロフラン（５０ ｍＬ）で希釈し、アミノアセトアルデヒドジメチルアセタール（４２．６ ｇ、４０６ ｍｍｏｌ）、トリエチルアミン（１１０ ｍＬ、７８９ ｍｍｏｌ）のテトラヒドロフラン（２５０ ｍL）溶液に室温下滴下した。反応液を４０℃にて１時間攪拌後、室温に冷却し、水（３００ ｍL）を加え酢酸エチルで抽出した。有機層を２モル／Ｌ塩酸、１０％炭酸カリウム水溶液、水で洗浄した。溶媒を減圧濃縮し、４−クロロ−Ｎ−（２、２−ジメトキシエチル）−２−ヒドロキシベンズアミド（Ｂ−１２、６０．９ ｇ）の粗生成物を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.28 (d, 6H, J = 6.6 Hz), 4.27 (dqq, J = 7.8 Hz, 6.6 Hz, 6.6 Hz, 1H), 6.02 (brs, 1H), 7.00 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 8.4 Hz, 1.5 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 12.52 (brs, 1H).

第２工程 ４−クロロ−２−ヒドロキシ−Ｎ−（２−オキソエチル）ベンズアミド（Ｂ−１３）の合成
第１工程で得た粗製生物（Ｂ−１２、３０．０ ｇ）のテトラヒドロフラン（１２０ ｍＬ）溶液に２モル／Ｌ塩酸（１１６ ｍＬ、２３１ ｍｍｏｌ）を加え、６０℃にて１時間１５分攪拌した。反応液を室温まで冷却後、水（９０ ｍＬ）を加え、酢酸エチルで抽出し、有機層を２回水洗した。溶媒を減圧濃縮し、残渣をジイソプロピルエーテルで再結晶し、４−クロロ−２−ヒドロキシ−Ｎ−（２−オキソエチル）ベンズアミド（Ｂ−１３、１４．４ｇ、第１および第２工程通算収率４７％）を白色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 4.41 (s、1H), 4.43 (s、1H), 6.87 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 7.00 (brs, 1H), 7.01 (d, J = 2.1 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 9.78 (s, 1H), 12.13 (brs, 1H).

第３工程 ２−クロロ−２−（オキサゾール−２−イル）フェノール（Ｂ−１４）の合成
第２工程で得た４−クロロ−２−ヒドロキシ−Ｎ−（２−オキソエチル）ベンズアミド（Ｂ−１３、１．００ ｇ、４．６８ ｍｍｏｌ）とヘキサクロロエタン（２．２２ ｇ、９．３６ ｍｍｏｌ）のアセトニトリル（１０ ｍL）懸濁液に、室温下トリフェニルホスフィン（２．４６ ｇ、９．３６ ｍｍｏｌ）を加えて５分間攪拌後、トリエチルアミン（２．６１ ｍL、１８．７ ｍｍｏｌ）を加えた。反応液を室温下1時間、６０℃で１時間攪拌し、さらに６時間加熱還流した。反応液を室温まで冷却後、水（１０ ｍＬ）を加え酢酸エチルで抽出した。有機層を飽和食塩水、水にて洗浄した。溶媒を減圧濃縮し、残渣をメタノール／水より再結晶して２−クロロ−２−（オキサゾール−２−イル）フェノール（Ｂ−１４、７７９ ｍｇ、収率８５％）を白色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 6.94 (ddd, J = 8.4 Hz, 2.1 Hz, 0.3 Hz, 1H), 7.09 (d, J = 2.1 Hz、1H), 7.25 (d, J = 0.9 Hz, 1H), 7.70 (dd, J = 0.9 Hz, 0.3 Hz, 1H), 11.37 (brs, 1H).
粉末Ｘ線回折の結果を表７および図７に示す。
主なピークの回折角：２θ＝11.9，16.6，23.9，27.1度

第４工程 ５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−（２−オキサゾリル）−フェノール（Ｂ−１５）の合成
アルゴン気流下、実施例１で得た４−（パラ−イソプロピルオキシベンゼンスルホニル）ピペラジン（Ｂ−４、１．１２ ｇ）、酢酸パラジウム（２４ ｍｇ）、パラ−トルエンスルフィン酸ナトリウム（３９ ｍｇ）、ナトリウムｔｅｒｔ−ペントキシド（１．１８ ｇ）のトルエン（７ ｍＬ）懸濁液に、ジアダマンチルブチルホスフィン（７７ ｍｇ）を加え、室温下３０分撹拌した。氷冷下、反応液に第３工程で得た２−（２−オキサゾリル）−５−クロロフェノール（Ｂ−１４、７００ ｍｇ）、トルエン（３ ｍＬ）を加え、３時間還流した。反応液を室温に冷却後、２モル／Ｌ塩酸（７．５ ｍＬ）を加えた。生成した析出物をろ取し、５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−（２−オキサゾリル）−フェノール（Ｂ−１５、１．２７ ｇ、収率８０％）を淡茶色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.37 (d, J = 6.0 Hz, 6H), 3.19 (m, 4H), 3.39 (m, 4H), 4.63 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 6.54 (m, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7.18 (m, 1H), 7.63 (m, 1H), 7.67 - 7.71 (m, 3H).
粉末Ｘ線回折の結果を表８および図８に示す。
主なピークの回折角：２θ＝3.8，7.6，15.9，18.9，19.2，24.6，25.5度

第５工程 ｛５−［４−（４−イソプロピルオキシベンゼンスルフォニル）−ピペラジン−１−イル］−２−（２−オキサゾリル）−フェノキシ｝−酢酸メチルエステル（Ｂ−１６）の合成
第４工程で得た５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−（２−オキサゾリル）−フェノール（Ｂ−１５、２００ ｍｇ、０．４５ ｍｍｏｌ）、炭酸カリウム（９３ ｍｇ、０．６７ ｍｍｏｌ）、ヨウ化カリウム（１５ ｍｇ、０．０９ ｍｍｏｌ）、ブロモ酢酸メチルエステル（０．０６４ ｍＬ、０．６８ ｍｍｏｌ）のＮ，Ｎ−ジメチルホムアミド（１．６ ｍＬ）溶液を、９０℃で１時間攪拌した。氷冷下、反応液に２モル／Ｌ塩酸（０．２３ ｍＬ）、ＭｅＯＨ（５．０ ｍＬ）、水（５．０ ｍＬ）を加えた。得られた結晶をろ取し、｛５−［４−（４−イソプロピルオキシベンゼンスルフォニル）−ピペラジン−１−イル］−２−（２−オキサゾリル）−フェノキシ｝−酢酸メチルエステル（Ｂ−１６、２１２ ｍｇ、収率９１％）を白色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.37 (d, J = 6.0 Hz, 6H), 3.1４ (m, 4H), 3.4３ (m, 4H), 3.79 (s, 3H), 4.63 (m, 1H), 4.75 (s, 2H), 6.38 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 7.22 (d, 1H), 7.67 - 7.71 (m, 3H), 7.86 (d, J = 9.0 Hz, 1H).

第６工程 ｛５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−（２−オキサゾリル）−フェノキシ｝−酢酸（Ｉ−４）の合成
第５工程で得た｛５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−（２−オキサゾリル）−フェノキシ｝−酢酸メチルエステル（Ｂ−１６、６５ ｍｇ、０．１２６ ｍｍｏｌ）、４モル／Ｌ水酸化ナトリウム水溶液（８０ μＬ、０．３１５ ｍｍｏｌ）のＮ，Ｎ−ジメチルホムアミド（１ ｍＬ）溶液を一晩攪拌した。反応液に２モル／Ｌ塩酸（３１５ μＬ）、水（２．０ ｍＬ）を加え、氷冷下３０分間攪拌した。生成した結晶をろ取し、｛５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−（２−オキサゾリル）−フェノキシ｝−酢酸（Ｉ−４、５０．６ ｍｇ、収率８０％）を白色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.37 (d, J = 6.0 Hz, 6H), 3.16 (m, 4H), 3.42 (m, 4H), 4.63 (m, 1H), 4.77 (s, 2H), 6.40 (d, J = 2.7 Hz, 1H), 6.62 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 6.98 (d, J = 3.0 Hz, 2H), 7.27 (m, 1H), 7.67 - 7.72 (m, 3H), 7.79 (d, J = 3.0 Hz, 1H).
粉末Ｘ線回折の結果を表９および図９に示す。
主なピークの回折角：２θ＝4.1，13.6，16.7，20.1，23.6度

実施例５ ｛５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−イソプロピルカルバモイル−フェノキシ｝−酢酸（Ｉ−５）の合成

第１工程 ４−ヨードサリチル酸（Ｂ−１７）の合成
４−アミノサリチル酸（Ａ−６、５．００ ｇ）の濃塩酸（３０ ｍＬ）懸濁液に、氷冷下、亜硝酸ナトリウム塩（４．５０ ｇ）の水溶液（１２ ｍＬ）を２０分間かけて滴下した。さらにヨウ化カリウム（１３．５５ ｇ）の水溶液（１２ ｍＬ）を１５分かけて滴下し、氷冷下２時間撹拌した。反応液に酢酸エチル（６０ ｍＬ）を加え、撹拌後不溶物をろ去した。ろ液をチオ硫酸ナトリウム水溶液、水、食塩水にて洗浄後、硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、４−ヨードサリチル酸（Ｂ−１７、４．９７ ｇ）の粗生成物を得た。

第２工程 ２−ヒドロキシ−４−ヨウ化−Ｎ−イソプロピル−ベンズアミド（Ｂ−１８）の合成
第１工程で得た粗生成物（Ｂ−１７、４．９７ ｇ）、ＷＳＣＤ・ＨＣｌ（５．４２ ｇ）、ＨＯＢｔ（２．５４ ｇ）のＮ，Ｎ−ジメチルホルムアミド（２５ ｍＬ）溶液に、イソプロピルアミン（２．０ ｍＬ）を加え、室温下５時間撹拌した。反応液に１モル／Ｌ塩酸（１００ ｍＬ）を加え、酢酸エチルにて抽出した。有機層を希塩酸、水、食塩水にて洗浄し、硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、残渣に塩化メチレンを加え、不溶物をろ去した。ろ液を減圧濃縮し、得られた粗生成物をカラムクロマトグラフィーにて精製し、２−ヒドロキシ−４−ヨウ化−Ｎ−イソプロピル−ベンズアミド（Ｂ−１８、１．６７ ｇ、第１〜第２工程の通算収率１９％）を無色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.28 (d, J = 6.6 Hz, 6H), 4.27 (dqq, J = 7.8 Hz, 6.6 Hz, 6.6 Hz, 1H), 6.02 (brs, 1H), 7.00 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 8.4 Hz, 1.5 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 12.52 (brs, 1H).
粉末Ｘ線回折の結果を表１０および図１０に示す。
主なピークの回折角：２θ＝9.3，20.9，21.6，24.2度

第３工程 ２−ヒドロキシ−４−［４−（４−イソプロピルオキシベンゼンスルフォニル）−ピペラジン−１−イル］−Ｎ−イソプロピル−ベンズアミド（Ｂ−１９）の合成
アルゴン気流下、実施例１で得た４−（パラ−イソプロピルオキシベンゼンスルホニル）ピペラジン（Ｂ−４、１．４９ ｇ）、酢酸パラジウム（１８ ｍｇ）、パラ−トルエンスルフィン酸ナトリウム（２８ ｍｇ）、ナトリウムｔｅｒｔ−ペントキシド（１．１６ ｇ）のトルエン（７ ｍＬ）懸濁液に、ジアダマンチルブチルホスフィン（５７ ｍｇ）を加え、室温下３０分撹拌した。氷冷下、反応液に第２工程で得た２−ヒドロキシ−４−ヨード−Ｎ−イソプロピル−ベンズアミド（８００ ｍｇ）、トルエン（３ ｍＬ）を加え、４５分間還流した。反応液を氷冷し、２モル／Ｌ塩酸（８ ｍＬ）を加えた。生成した析出物をろ取し、２−ヒドロキシ−４−［４−（４−イソプロピルオキシベンゼンスルフォニル）−ピペラジン−１−イル］−Ｎ−イソプロピル−ベンズアミド（Ｂ−１９、１．０７ ｇ、収率８８％）を淡茶色結晶として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.25 (d, J = 6.6 Hz, 6H), 1.37 (d, J = 6.0 Hz, 6H), 3.15 (m, 4H), 3.58 (m, 4H), 4.24 (dqq, J = 7.8 Hz, 6.6 Hz, 6.6 Hz, 1H), 4.63 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 5.83 (brd, J = 7.8 Hz, 1H), 6.35 - 6.38 (m, 2H), 6.96 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 9.3 Hz, 1H), 7.68 (d, J = 9.0 Hz, 2H), 12.7 (brs, 1H).
粉末Ｘ線回折の結果を表１１および図１１に示す。
主なピークの回折角：２θ＝4.3，4.6，8.7，11.6，19.3度

第４工程 ｛５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−イソプロピルカルバモイル−フェノキシ｝−酢酸メチルエステル（Ｂ−２０）の合成
第３工程で得た２−ヒドロキシ−４−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−Ｎ−イソプロピル−ベンズアミド（Ｂ−１９、１７０ ｍｇ、０．３７ ｍｍｏｌ）、炭酸セシウム（１８０ ｍｇ、０．５５ ｍｍｏｌ）、ブロモ酢酸メチルエステル（０．０５２ ｍＬ、０．５５ ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２ ｍＬ）溶液を室温下３時間攪拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水、希塩酸、食塩水で洗浄した。溶媒を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（酢酸エチル／ヘキサン＝１／１）にて精製し、｛５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−イソプロピルカルバモイル−フェノキシ｝−酢酸メチルエステル（Ｂ−２０、１９５ ｍｇ、収率は定量的）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.27 (d, J = 6.6 Hz, 6H), 1.37 (d, J = 6.0 Hz, 6H), 3.16 (m, 4H), 3.36 (m, 4H), 3.87 (s, 3H), 4.64 (m, 1H), 4.66 (s, 2H), 6.23 (d, 1H), 6.58 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 8.12 (d, J = 9.0 Hz, 1H), 8.19 (d, J = 7.5 Hz, 1H).

第５工程 ｛５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−イソプロピルカルバモイル−フェノキシ｝−酢酸（Ｉ−５）の合成
第４工程で得た｛５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−イソプロピルカルバモイル−フェノキシ｝−酢酸メチルエステル（Ｂ−２０、１９０ ｍｇ、０．３６ ｍｍｏｌ）、４モル／Ｌ水酸化ナトリウム水溶液（２２０ μＬ、０．８９ ｍｍｏｌ）のＴＨＦ（１ ｍＬ）−ＭｅＯＨ（１ ｍＬ）溶液を一晩攪拌した。反応液に２モル／Ｌ塩酸（１ ｍＬ）を加え、酢酸エチルで抽出した。有機層を水、食塩水で洗浄した。溶媒を減圧濃縮し、｛５−［４−（４−イソプロピルオキシベンゼンスルホニル）−ピペラジン−１−イル］−２−イソプロピルカルバモイル−フェノキシ｝−酢酸（Ｉ−５、１６５ ｍｇ、収率８９％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δｐｐｍ： 1.24 (d, J = 6.3 Hz, 6H), 1.37 (d, J = 6.0 Hz, 6H), 3.14 (m, 4H), 3.35 (m, 4H), 4.65 (m, 1H), 4.71 (s, 2H), 6.29 (d, J = 2.4 Hz, 1H), 6.53 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 6.97 (d, J = 3.0 Hz, 2H), 7.66-7.72 (m, 3H), 7.84 (d, J = 8.7 Hz, 1H).
  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
  In the examples, the following abbreviations are used.
Me: methyl
DMSO: Dimethyl sulfoxide
MeOH: methanol

Reference Example 1 Synthesis of Intermediate 4- (Isopropyloxybenzenesulfonyl) piperazine (B-4)

To a solution of piperazine (A-2, 22.7 g, 89.5 mmol) in tetrahydrofuran (180 mL), 4-isopropyloxybenzenesulfonyl chloride (A-3, 21.0 g, 89.5 mmol) in tetrahydrofuran (A 30 mL) solution was added dropwise at room temperature over 30 minutes. The reaction mixture was stirred at room temperature for 30 minutes, water (200 mL) was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was extracted with 2 mol / L hydrochloric acid (100 mL). The insoluble material was filtered off, and the aqueous layer was washed with ethyl acetate and made alkaline with a 2 mol / L aqueous sodium hydroxide solution. The precipitated crystals were dissolved in ethyl acetate and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4- (isopropyloxybenzenesulfonyl) piperazine (B-4, 19.9 g, yield 78%) as white crystals.
Melting point: 133.6-133.7 ° C
1H-NMR (CDCl₃) Δppm: 1.37 (d, J = 6.0 Hz, 6H), 2.95 (m, 8H), 4.63 (m, 1H), 6.94 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H).

Example 1 Synthesis of {2,3-difluoro-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid (I-1)

Synthesis of intermediate N- (4-isopropyloxybenzenesulfonyl) piperazine (B-4)

To a solution of piperazine (A-2, 44.0 g, 511 mmol) in toluene (280 mL), 4-isopropyloxybenzenesulfonyl chloride (A-3, 40.0 g, 170 mmol) in toluene (126 mL) Was added dropwise at 65 ° C. over 1 hour. After the reaction solution was stirred at 65 ° C. for 1 hour, water (196 mL) was added, and after separation at 60 ° C., the organic layer was washed with brine. The organic layer was extracted with 2 mol / L hydrochloric acid (212 mL) at 60 ° C. The aqueous layer was washed with toluene and made alkaline by adding a 2 mol / L sodium hydroxide aqueous solution at 60 ° C. After cooling to room temperature, the generated precipitate was collected by filtration to obtain 4- (isopropyloxybenzenesulfonyl) piperazine (B-4, 44.7 g, yield 92%) as white crystals.
The melting point and NMR data were consistent with the compound (B-4) obtained in Reference Example 1.
The results of powder X-ray diffraction are shown in Table 1 and FIG.
Main peak diffraction angles: 2θ = 5.0, 10.2, 14.6, 19.0, 23.5 degrees

Step 1 Synthesis of 2,3-difluoro-5-bromophenol (B-1)
To a solution of 2,3-difluoro-5-bromoanisole (A-1, 1.15 g) in dichloromethane (5 mL) under ice cooling, a 1 mol / L boron tribromide-methylene chloride solution (7.5 mL) was added. ) Was added dropwise, and the mixture was stirred for 2 hours under ice cooling and 2 hours at room temperature. The reaction mixture was poured into ice water, concentrated hydrochloric acid was added, and the mixture was stirred overnight. The reaction solution was extracted with ethyl acetate, and the organic layer was extracted with an aqueous sodium hydroxide solution. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2,3-difluoro-5-bromophenol (B-1, 850 mg, yield 81%) as an oil.
¹H-NMR (CDCl₃) Δppm: 5.36 (d, J = 3.6 Hz, 1H), 6.91 (ddd, J = 9.3 Hz, 6.3 Hz, 2.4 Hz, 1H), 6.97 (ddd, J = 6.6 Hz, 2.4 Hz, 2.4 Hz, 1H) .

Second Step Synthesis of 2,3-difluoro-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenol (B-2)
Under an argon stream, the intermediate 4- (para-isopropyloxybenzenesulfonyl) piperazine (B-4, 1.14 g) synthesized above, palladium acetate (22 mg), sodium para-toluenesulfinate (36 mg), To a suspension of sodium tert-pentoxide (1.11 g) in toluene (7 mL) was added diadamantylbutylphosphine (72 mg), and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, 2,3-difluoro-5-bromophenol (B-1, 700 mg) and toluene (3 mL) obtained in the first step were added to the reaction suspension, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, 2 mol / L hydrochloric acid (7 mL) was added, and the mixture was extracted with toluene. The organic layer was washed with water and brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to obtain 2,3-difluoro-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenol (B -2, 1.28 g, yield 93%) was obtained as colorless amorphous.
¹H-NMR (CDCl₃) Δppm: 1.37 (d, J = 6.0 Hz, 6H), 3.14 (m, 8H), 4.63 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 5.48 (brs, 1H), 6.08-6.29 (m, 2H), 6.97 (d, J = 9.3 Hz, 2H), 7.69 (d, J = 9.3 Hz, 2H).

Step 3 Synthesis of {2,3-difluoro-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid methyl ester (B-3)
N, N-dimethylformamide of 2,3-difluoro-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenol (B-2, 412 mg) obtained in the second step ( 5 mL) solution was added potassium carbonate (276 mg), potassium iodide (17 mg), and bromoacetic acid methyl ester (189 μL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid, water and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to obtain {2,3-difluoro-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy}. Acetic acid methyl ester (B-3, 452 mg, 93% yield) was obtained as a pale purple solid.
¹H-NMR (CDCl₃) Δppm: 1.38 (d, J = 6.0 Hz, 6H), 3.14 (s, 8H), 3.79 (s, 3H), 4.60-4.68 (m, 3H), 6.26 (brs, 1H), 6.30-6.37 (m , 1H), 6.98 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H).

Fourth Step Synthesis of {2,3-difluoro-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid (I-1)
Methanol (3 mL) of 2,3-difluoro-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxyacetic acid methyl ester (B-3, 367 mg) obtained in the third step ) -Tetrahydrofuran (3 mL) mixed solution was added 2 mol / L sodium hydroxide aqueous solution (1.14 mL), and the mixture was stirred at room temperature for 2 hours. Diethyl ether was added to the reaction mixture, and the mixture was extracted with water. The aqueous layer was adjusted to pH 4 with dilute hydrochloric acid and extracted with ethyl acetate. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure, and {2,3-difluoro-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid ( I-1,265 mg, yield 74%) was obtained as colorless crystals.
¹H-NMR (CDCl₃) Δppm: 1.38 (d, J = 6.0 Hz, 6H), 3.00 (brs, 1H), 3.15 (s, 8H), 4.64 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 4.71 (s, 2H) , 6.27 (brs, 1H), 6.32-6.39 (m, 1H), 6.98 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H).
The results of powder X-ray diffraction are shown in Table 2 and FIG.
Main peak diffraction angles: 2θ = 9.4, 15.9, 16.1, 17.9, 21.0, 21.2 degrees

Example 2 Synthesis of {2-bromo-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid (I-2)

Step 1 Synthesis of 2-bromo-5-aminoanisole (B-5)
To a solution of 2-bromo-5-nitroanisole (A-4, 11.6 g, 50.0 mmol) in methanol (150 mL), iron (5.59 g, 100 mmol), ammonium chloride (5.35 g, 100 mmol) and water (75.0 mL) were added, and the mixture was stirred at 100 ° C. for 6 hours. The reaction solution was filtered through Celite, and the filtrate was diluted with water and acidified with dilute hydrochloric acid. After washing with diethyl ether, an aqueous sodium hydroxide solution was added to the aqueous layer to make it alkaline. The aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-bromo-5-aminoanisole (B-5, 4.20 g, yield 42%) as a brown powder. Got as.
¹H-NMR (CDCl₃) Δppm: 3.8 (brs, 2H), 3.84 (s, 3H), 6.19 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 7.25 (d, J = (8.7 Hz, 1H).

Second Step Synthesis of 2-bromo-5-iodoanisole (B-6)
Concentrated hydrochloric acid (32.0 mL) was added to 2-bromo-5-aminoanisole (B-5, 4.12 g, 20.4 mmol) obtained in the first step, and sodium nitrate (3. An aqueous solution (10.0 mL) of 37 g, 48.8 mmol) was added dropwise over 20 minutes. Further, an aqueous solution (10.0 mL) of potassium iodide (9.96 g, 61.0 mmol) was added dropwise over 20 minutes. The reaction solution was stirred for 1 hour under ice-cooling and extracted with diethyl ether. The organic layer was washed with an aqueous sodium thiosulfate solution and water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2-bromo-5-iodoanisole (B-6, 5.00 g, yield 65%).
¹H-NMR (CDCl₃) Δppm: 3.88 (s, 3H), 7.17 (m, 2H), 7.22 (m, 1H).

Step 3 Synthesis of 2-bromo-5-iodophenol (B-7)
To a solution of 2-bromo-5-iodoanisole (B-6, 5.00 g, 16.0 mmol) obtained in the second step in methylene chloride (10.0 mL) was added 1M boron tribromide under ice-cooling. -A methylene chloride solution (32.0 mL) was added dropwise over 30 minutes. The mixture was stirred for 1 hour under ice-cooling and then for 3 hours at room temperature. The reaction mixture was poured into ice water, concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hr. Extraction was performed with diethyl ether, and the organic layer was extracted with an aqueous sodium hydroxide solution. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2-bromo-5-iodophenol (B-7, 4.30 g, yield 90%) as crystals.
¹H-NMR (CDCl₃) Δppm: 5.48 (s, 1H), 7.14 (d, J = 1.8 Hz, 1H), 7.15 (s, 1H), 7.37 (d, J = 1.8 Hz, 1H).
The results of powder X-ray diffraction are shown in Table 3 and FIG.
Main peak diffraction angle: 2θ = 17.9, 27.3, 28.6 degrees

Fourth Step Synthesis of 2-bromo-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenol (B-8)
Under an argon stream, 4- (para-isopropyloxybenzenesulfonyl) piperazine (B-4, 1.05 g) obtained in Example 1, palladium acetate (22 mg), sodium para-toluenesulfinate (36 mg), To a suspension of sodium tert-pentoxide (1.11 g) in toluene (7 mL) was added diadamantylbutylphosphine (72 mg), and the mixture was stirred at room temperature for 30 minutes. Under cooling with ice, 2-bromo-5-iodophenol (B-7, 1.00 g) obtained in the third step and toluene (2 mL) were added to the reaction solution, and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, 2 mol / L hydrochloric acid (7 mL) was added, diluted with ethyl acetate (10 mL), insoluble material was filtered off, and the filtrate was extracted with toluene. The organic layer was washed with water and brine and then dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography, and 2-bromo-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenol (B-8) was purified. 845 mg, yield 56%) as white crystals.
¹H-NMR (CDCl₃) Δppm: 1.37 (d, J = 6.0 Hz, 6H), 3.16 (m, 4H), 3.25 (m, 4H), 4.63 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 5.45 (s, 1H) , 6.40 (dd, J = 9.0 Hz, 2.4 Hz), 6.58 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 1H), 7.69 (d, J = 9.0 Hz, 2H).
The results of powder X-ray diffraction are shown in Table 4 and FIG.
Main peak diffraction angles: 2θ = 6.1, 12.2, 17.5, 19.0, 19.4 degrees

Step 5 Synthesis of {2-bromo-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid methyl ester (B-9)
N, N- of 2-bromo-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenol (B-8, 170 mg, 0.37 mmol) obtained in the fourth step. To a dimethylformamide (2.0 mL) solution were added potassium carbonate (103 mg, 0.75 mmol) and bromoacetic acid methyl ester (0.042 mL, 0.45 mmol), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and {2-bromo-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid methyl ester (B-9, 150 mg, yield 76). %) As a colorless powder.
¹H-NMR (CDCl₃) Δppm: 1.37 (d, J = 6.0 Hz, 6H), 3.13-3.26 (m, 8H), 3.79 (s, 3H), 4.59-4.67 (m, 3H), 6.39-6.57 (m, 2H), 6.96 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H).

Step 6 Synthesis of {2-bromo-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid (I-2)
{2-Bromo-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid methyl ester (B-9, 150 mg, 0.28 mmol) obtained in the fifth step To a methanol (2.0 mL) -tetrahydrafuran (2.0 mL) solution of 2 mol / L sodium hydroxide solution (0.43 mL, 0.85 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was poured into water and washed with diethyl ether. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate / hexane to give {2-bromo-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid (I-2, 142 mg, 97% yield) was obtained as colorless crystals.
¹H-NMR (DMSO-d₆) Δppm: 1.30 (d, J = 6.0 Hz, 6H), 2.95 (brs, 4H), 3.02 (brs, 4H), 4.71-4.79 (m, 3H), 6.42 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H) .
The results of powder X-ray diffraction are shown in Table 5 and FIG.
Main peak diffraction angles: 2θ = 9.6, 18.2, 19.9, 20.6, 21.6, 22.0 degrees

Example 3 Synthesis of {2- (3-furyl) -5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid (I-3)

Step 1 Synthesis of 2- (3-furyl) -5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenol (B-10)
  2-bromo-5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenol (B-8, 300 mg), 3-furylboronic acid (111 mg) obtained in Example 2; To a 1,4-dioxane (4 mL) solution of palladium acetate (5 mg) and triphenylphosphine (23 mg) was added 2 mol / L aqueous sodium carbonate solution (2 mL) under an argon stream, and the mixture was refluxed for 6 hours. The reaction mixture was cooled to room temperature, aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to give 2- (3-furyl) -5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenol. (B-10, 155 mg, 53% yield) was obtained as colorless scale crystals.
¹H-NMR (DMSO-d₆) Δppm: 1.37 (d, J = 6.0 Hz, 6H), 3.17 (m, 4H), 3.27 (m, 4H), 4.63 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 6.51 (m, 2H) , 6.61 (m, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7.22 (d, J = 9.0 Hz, 1H), 7.50 (dd, J = 1.8 Hz, 1.5 Hz, 1H), 7.69 (d , J = 9.0 Hz, 2H), 7.74 (m, 1H).
The results of powder X-ray diffraction are shown in Table 6 and FIG.
Main peak diffraction angles: 2θ = 6.1, 15.2, 16.3, 17.8, 20.5, 21.2, 25.1 degrees

Second Step Synthesis of {2- (3-furyl) -5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid methyl ester (B-11)
Of 2- (3-furyl) -5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenol (B-10, 140 mg, 0.32 mmol) obtained in the first step To a N, N-dimethylformamide (2.0 mL) solution, potassium carbonate (87.3 g, 0.63 mmol) and bromoacetic acid methyl ester (0.036 mL, 0.38 mmol) were added, and at room temperature. Stir for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and {2- (3-furyl) -5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid methyl ester (B-11, 110 mg). Yield 68%) as a colorless powder.
¹H-NMR (CDCl₃) Δppm: 1.37 (d, J = 6.0 Hz, 6H), 3.23 (brs, 4H), 3.27 (brs, 4H), 3.84 (s, 3H), 4.58-4.68 (m, 3H), 6.50 (brs, 1H ), 6.62 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7.40-7.46 (m, 2H), 7.71 (d, J = 8.4Hz , 2H), 8.19 (s, 1H).

Third step
{2- (3-Furyl) -5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -phenoxy} -acetic acid methyl ester (B-11, 100 mg) obtained in the first step To a solution of 0.19 mmol) in methanol (2.0 mL) -tetrahydrafuran (2.0 mL) was added 2 mol / L aqueous sodium hydroxide solution (0.29 mL, 0.58 mmol). Stir for hours. The reaction solution was poured into water and washed with diethyl ether. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the resulting crude crystals were recrystallized from ethyl acetate / hexane to give {2- (3-furyl) -5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl]. -Phenoxy} -acetic acid (I-3, 85 mg, 88% yield) was obtained as a colorless powder.
¹H-NMR (DMSO-d₆) Δppm: 1.29 (d, J = 6.0 Hz, 6H), 2.97 (brs, 4H), 3.26 (brs, 4H), 4.79-4.70 (m, 3H), 6.52 (d, J = 9.0 Hz, 1H), 6.55 (s, 1H), 6.97 (s, 1H), 7.14 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 9.0 Hz, 1H), 7.66 (s, 1H), 7.67 (d, J = 9.0 Hz, 2H), 8.36 (s, 1H).

Example 4 Synthesis of {5- [4- (4-Isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2- (2-oxazolyl) -phenoxy} -acetic acid (I-4)

Step 1 Synthesis of 4-chloro-N- (2,2-dimethoxyethyl) -2-hydroxybenzamide (B-12)
To a suspension of 4-chlorosalicylic acid (A-5, 50.0 g, 290 mmol) in ethyl acetate (200 mL) was added thionyl chloride (41.4 g, 348 mmol) at room temperature, and the mixture was heated to reflux for 3 hours. . The reaction solution was cooled to room temperature, diluted with tetrahydrofuran (50 mL), and added dropwise to a solution of aminoacetaldehyde dimethyl acetal (42.6 g, 406 mmol) and triethylamine (110 mL, 789 mmol) in tetrahydrofuran (250 mL) at room temperature. did. The reaction mixture was stirred at 40 ° C. for 1 hour, cooled to room temperature, water (300 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2 mol / L hydrochloric acid, 10% aqueous potassium carbonate solution, and water. The solvent was concentrated under reduced pressure to obtain a crude product of 4-chloro-N- (2,2-dimethoxyethyl) -2-hydroxybenzamide (B-12, 60.9 g).
¹H-NMR (CDCl₃) Δppm: 1.28 (d, 6H, J = 6.6 Hz), 4.27 (dqq, J = 7.8 Hz, 6.6 Hz, 6.6 Hz, 1H), 6.02 (brs, 1H), 7.00 (d, J = 8.4 Hz, 1H) ), 7.18 (dd, J = 8.4 Hz, 1.5 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 12.52 (brs, 1H).

Second Step Synthesis of 4-chloro-2-hydroxy-N- (2-oxoethyl) benzamide (B-13)
2 mol / L hydrochloric acid (116 mL, 231 mmol) was added to a tetrahydrofuran (120 mL) solution of the crude product (B-12, 30.0 g) obtained in the first step, and the mixture was stirred at 60 ° C. for 1 hour and 15 minutes. did. The reaction mixture was cooled to room temperature, water (90 mL) was added, the mixture was extracted with ethyl acetate, and the organic layer was washed twice with water. The solvent was concentrated under reduced pressure, the residue was recrystallized with diisopropyl ether, and 4-chloro-2-hydroxy-N- (2-oxoethyl) benzamide (B-13, 14.4 g, total yield of the first and second steps was 47. %) As white crystals.
¹H-NMR (CDCl₃) Δppm: 4.41 (s, 1H), 4.43 (s, 1H), 6.87 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 7.00 (brs, 1H), 7.01 (d, J = 2.1 Hz, 1H) , 7.39 (d, J = 8.7 Hz, 1H), 9.78 (s, 1H), 12.13 (brs, 1H).

Step 3 Synthesis of 2-chloro-2- (oxazol-2-yl) phenol (B-14)
4-Chloro-2-hydroxy-N- (2-oxoethyl) benzamide (B-13, 1.00 g, 4.68 mmol) and hexachloroethane (2.22 g, 9.36 mmol) obtained in the second step. ) In acetonitrile (10 mL), triphenylphosphine (2.46 g, 9.36 mmol) was added at room temperature and stirred for 5 minutes, and then triethylamine (2.61 mL, 18.7 mmol) was added. It was. The reaction solution was stirred at room temperature for 1 hour and at 60 ° C. for 1 hour, and further heated to reflux for 6 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and water. The solvent was concentrated under reduced pressure, and the residue was recrystallized from methanol / water to give 2-chloro-2- (oxazol-2-yl) phenol (B-14, 779 mg, yield 85%) as white crystals.
¹H-NMR (CDCl₃) Δppm: 6.94 (ddd, J = 8.4 Hz, 2.1 Hz, 0.3 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1H), 7.25 (d, J = 0.9 Hz, 1H), 7.70 (dd, J = 0.9 Hz, 0.3 Hz, 1H), 11.37 (brs, 1H).
The results of powder X-ray diffraction are shown in Table 7 and FIG.
Main peak diffraction angles: 2θ = 11.9, 16.6, 23.9, 27.1 degrees

Step 4 Synthesis of 5- [4- (4-Isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2- (2-oxazolyl) -phenol (B-15)
Under an argon stream, 4- (para-isopropyloxybenzenesulfonyl) piperazine (B-4, 1.12 g) obtained in Example 1, palladium acetate (24 mg), sodium para-toluenesulfinate (39 mg), To a suspension of sodium tert-pentoxide (1.18 g) in toluene (7 mL) was added diadamantylbutylphosphine (77 mg), and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, 2- (2-oxazolyl) -5-chlorophenol (B-14, 700 mg) and toluene (3 mL) obtained in the third step were added to the reaction solution, and the mixture was refluxed for 3 hours. After cooling the reaction solution to room temperature, 2 mol / L hydrochloric acid (7.5 mL) was added. The produced precipitate was collected by filtration, and 5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2- (2-oxazolyl) -phenol (B-15, 1.27 g, collected) 80%) was obtained as light brown crystals.
¹H-NMR (CDCl₃) Δppm: 1.37 (d, J = 6.0 Hz, 6H), 3.19 (m, 4H), 3.39 (m, 4H), 4.63 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 6.54 (m, 1H) , 6.97 (d, J = 9.0 Hz, 2H), 7.18 (m, 1H), 7.63 (m, 1H), 7.67-7.71 (m, 3H).
The results of powder X-ray diffraction are shown in Table 8 and FIG.
Main peak diffraction angles: 2θ = 3.8, 7.6, 15.9, 18.9, 19.2, 24.6, 25.5 degrees

Fifth Step Synthesis of {5- [4- (4-Isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2- (2-oxazolyl) -phenoxy} -acetic acid methyl ester (B-16)
5- [4- (4-Isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2- (2-oxazolyl) -phenol (B-15, 200 mg, 0.45 mmol) obtained in the fourth step, N, N-dimethylformamide of potassium carbonate (93 mg, 0.67 mmol), potassium iodide (15 mg, 0.09 mmol), methyl bromoacetate (0.064 mL, 0.68 mmol) (1 .6 mL) solution was stirred at 90 ° C. for 1 hour. Under ice-cooling, 2 mol / L hydrochloric acid (0.23 mL), MeOH (5.0 mL), and water (5.0 mL) were added to the reaction solution. The obtained crystals were collected by filtration, and {5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2- (2-oxazolyl) -phenoxy} -acetic acid methyl ester (B-16, 212 mg, 91% yield) was obtained as white crystals.
¹H-NMR (CDCl₃) Δppm: 1.37 (d, J = 6.0 Hz, 6H), 3.14 (m, 4H), 3.43 (m, 4H), 3.79 (s, 3H), 4.63 (m, 1H), 4.75 (s, 2H ), 6.38 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 7.22 (d, 1H), 7.67- 7.71 (m, 3H), 7.86 (d, J = 9.0 Hz, 1H).

Step 6 Synthesis of {5- [4- (4-Isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2- (2-oxazolyl) -phenoxy} -acetic acid (I-4)
{5- [4- (4-Isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2- (2-oxazolyl) -phenoxy} -acetic acid methyl ester obtained in the fifth step (B-16, 65 mg, 0.126 mmol), 4 mol / L aqueous sodium hydroxide solution (80 μL, 0.315 mmol) in N, N-dimethylformamide (1 mL) was stirred overnight. 2 mol / L hydrochloric acid (315 μL) and water (2.0 mL) were added to the reaction solution, and the mixture was stirred for 30 minutes under ice cooling. The produced crystals were collected by filtration, and {5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2- (2-oxazolyl) -phenoxy} -acetic acid (I-4, 50.6). mg, yield 80%) was obtained as white crystals.
¹H-NMR (CDCl₃) Δppm: 1.37 (d, J = 6.0 Hz, 6H), 3.16 (m, 4H), 3.42 (m, 4H), 4.63 (m, 1H), 4.77 (s, 2H), 6.40 (d, J = 2.7 Hz, 1H), 6.62 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 6.98 (d, J = 3.0 Hz, 2H), 7.27 (m, 1H), 7.67-7.72 (m, 3H), 7.79 ( d, J = 3.0 Hz, 1H).
The results of powder X-ray diffraction are shown in Table 9 and FIG.
Main peak diffraction angles: 2θ = 4.1, 13.6, 16.7, 20.1, 23.6 degrees

Example 5 Synthesis of {5- [4- (4-Isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2-isopropylcarbamoyl-phenoxy} -acetic acid (I-5)

Step 1 Synthesis of 4-iodosalicylic acid (B-17)
A solution of 4-aminosalicylic acid (A-6, 5.00 g) in concentrated hydrochloric acid (30 mL) was added with an aqueous solution (12 mL) of sodium nitrite (4.50 g) over 20 minutes under ice cooling. And dripped. Further, an aqueous solution (12 mL) of potassium iodide (13.55 g) was added dropwise over 15 minutes, and the mixture was stirred for 2 hours under ice cooling. Ethyl acetate (60 mL) was added to the reaction mixture, and the insoluble material was removed by filtration after stirring. The filtrate was washed with aqueous sodium thiosulfate solution, water and brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 4-iodosalicylic acid (B-17, 4.97 g).

Second Step Synthesis of 2-hydroxy-4-iodinated-N-isopropyl-benzamide (B-18)
To a solution of the crude product (B-17, 4.97 g) obtained in the first step, WSCD · HCl (5.42 g), and HOBt (2.54 g) in N, N-dimethylformamide (25 mL). , Isopropylamine (2.0 mL) was added, and the mixture was stirred at room temperature for 5 hours. 1 mol / L hydrochloric acid (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water and brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, methylene chloride was added to the residue, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to give 2-hydroxy-4-iodinated-N-isopropyl-benzamide (B-18, 1.67 g, first to first The total yield of the two steps (19%) was obtained as colorless crystals.
¹H-NMR (CDCl₃) Δppm: 1.28 (d, J = 6.6 Hz, 6H), 4.27 (dqq, J = 7.8 Hz, 6.6 Hz, 6.6 Hz, 1H), 6.02 (brs, 1H), 7.00 (d, J = 8.4 Hz, 1H) ), 7.18 (dd, J = 8.4 Hz, 1.5 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 12.52 (brs, 1H).
The results of powder X-ray diffraction are shown in Table 10 and FIG.
Main peak diffraction angle: 2θ = 9.3, 20.9, 21.6, 24.2 degrees

Third Step Synthesis of 2-hydroxy-4- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -N-isopropyl-benzamide (B-19)
Under an argon stream, 4- (para-isopropyloxybenzenesulfonyl) piperazine (B-4, 1.49 g) obtained in Example 1, palladium acetate (18 mg), sodium para-toluenesulfinate (28 mg), To a suspension of sodium tert-pentoxide (1.16 g) in toluene (7 mL) was added diadamantylbutylphosphine (57 mg), and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, 2-hydroxy-4-iodo-N-isopropyl-benzamide (800 mg) and toluene (3 mL) obtained in the second step were added to the reaction solution, and the mixture was refluxed for 45 minutes. The reaction mixture was ice-cooled, and 2 mol / L hydrochloric acid (8 mL) was added. The produced precipitate was collected by filtration, and 2-hydroxy-4- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -N-isopropyl-benzamide (B-19, 1.07 g, collected). 88%) was obtained as light brown crystals.
¹H-NMR (CDCl₃) Δppm: 1.25 (d, J = 6.6 Hz, 6H), 1.37 (d, J = 6.0 Hz, 6H), 3.15 (m, 4H), 3.58 (m, 4H), 4.24 (dqq, J = 7.8 Hz, 6.6 Hz, 6.6 Hz, 1H), 4.63 (qq, J = 6.0 Hz, 6.0 Hz, 1H), 5.83 (brd, J = 7.8 Hz, 1H), 6.35-6.38 (m, 2H), 6.96 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 9.3 Hz, 1H), 7.68 (d, J = 9.0 Hz, 2H), 12.7 (brs, 1H).
The results of powder X-ray diffraction are shown in Table 11 and FIG.
Main peak diffraction angles: 2θ = 4.3, 4.6, 8.7, 11.6, 19.3 degrees

Fourth Step Synthesis of {5- [4- (4-Isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2-isopropylcarbamoyl-phenoxy} -acetic acid methyl ester (B-20)
  2-hydroxy-4- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -N-isopropyl-benzamide (B-19, 170 mg, 0.37 mmol) obtained in the third step, A solution of cesium carbonate (180 mg, 0.55 mmol) and bromoacetic acid methyl ester (0.052 mL, 0.55 mmol) in N, N-dimethylformamide (2 mL) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dilute hydrochloric acid and brine. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/1) to give {5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2- Isopropylcarbamoyl-phenoxy} -acetic acid methyl ester (B-20, 195 mg, yield was quantitative) was obtained.
¹H-NMR (CDCl₃) Δppm: 1.27 (d, J = 6.6 Hz, 6H), 1.37 (d, J = 6.0 Hz, 6H), 3.16 (m, 4H), 3.36 (m, 4H), 3.87 (s, 3H), 4.64 ( m, 1H), 4.66 (s, 2H), 6.23 (d, 1H), 6.58 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 8.12 (d, J = 9.0 Hz, 1H), 8.19 (d, J = 7.5 Hz, 1H).

Step 5 Synthesis of {5- [4- (4-Isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2-isopropylcarbamoyl-phenoxy} -acetic acid (I-5)
  {5- [4- (4-Isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2-isopropylcarbamoyl-phenoxy} -acetic acid methyl ester (B-20, 190 mg, 0.36) obtained in the fourth step mmol), 4 mol / L aqueous sodium hydroxide solution (220 μL, 0.89 mmol) in THF (1 mL) -MeOH (1 mL) was stirred overnight. 2 mol / L hydrochloric acid (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine. The solvent was concentrated under reduced pressure, and {5- [4- (4-isopropyloxybenzenesulfonyl) -piperazin-1-yl] -2-isopropylcarbamoyl-phenoxy} -acetic acid (I-5, 165 mg, yield 89%) Got.
¹H-NMR (CDCl₃) Δppm: 1.24 (d, J = 6.3 Hz, 6H), 1.37 (d, J = 6.0 Hz, 6H), 3.14 (m, 4H), 3.35 (m, 4H), 4.65 (m, 1H), 4.71 ( s, 2H), 6.29 (d, J = 2.4 Hz, 1H), 6.53 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 6.97 (d, J = 3.0 Hz, 2H), 7.66-7.72 (m, 3H), 7.84 (d, J = 8.7 Hz, 1H).

Compounds I-6 to I-43 were synthesized using the same method as above. Structural formulas and physical properties are shown in Tables 14-18.

  The present inventors have found an industrially effective production method in which N-phenyl-N′-phenylsulfonylpiperazine derivatives and intermediates thereof can be produced simply, in a short process and / or in good yield.

2 is a powder X-ray diffraction pattern and peak value of the crystal of the compound (B-4) obtained in Example 1. FIG. The vertical axis represents intensity, and the horizontal axis represents diffraction angle (2θ, unit: degree). 2 is a powder X-ray diffraction pattern of the compound (I-1) crystal obtained in Example 1 and its peak value. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2θ, unit: degree). 2 shows a powder X-ray diffraction pattern and a peak value of a crystal of the compound (B-7) obtained in Example 2. The vertical axis represents intensity, and the horizontal axis represents diffraction angle (2θ, unit: degree). 2 shows a powder X-ray diffraction pattern and a peak value of a crystal of the compound (B-8) obtained in Example 2. The vertical axis represents intensity, and the horizontal axis represents diffraction angle (2θ, unit: degree). 2 shows a powder X-ray diffraction pattern and a peak value of a crystal of the compound (I-2) obtained in Example 2. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2θ, unit: degree). 2 shows a powder X-ray diffraction pattern and a peak value of a crystal of the compound (B-10) obtained in Example 3. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2θ, unit: degree). It is the powder X-ray-diffraction pattern of the crystal | crystallization of the compound (B-13) obtained in Example 4, and its peak value. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2θ, unit: degree). It is the powder X-ray-diffraction pattern of the crystal | crystallization of the compound (B-14) obtained in Example 4, and its peak value. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2θ, unit: degree). 2 shows a powder X-ray diffraction pattern and a peak value of a crystal of the compound (I-4) obtained in Example 4. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2θ, unit: degree). It is the powder X-ray-diffraction pattern of the crystal | crystallization of the compound (B-18) obtained in Example 5, and its peak value. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2θ, unit: degree). It is the powder X-ray-diffraction pattern of the crystal | crystallization of the compound (B-19) obtained in Example 5, and its peak value. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2θ, unit: degree).

Claims (2)

Formula (XIX):

(In the formula, X is a halogen atom, an optionally substituted alkylsulfonyloxy, or an optionally substituted arylsulfonyloxy;
R ²¹ is furyl, thienyl, oxazolyl, pyrazolyl, or thiadiazolyl), a pharmaceutically acceptable salt thereof, or a solvate thereof. Formula (XI):

(Wherein X is as defined in claim 1), a compound represented by formula (XII):

(Wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom or an alkyl; R ¹⁷ is an alkyl) and a compound represented by the formula (XIII):

(Wherein X is as defined in claim 1; R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above)
A compound of formula (XIII) is reacted with an acid to give a compound of formula (XIV):

(Wherein X is as defined in claim 1; R ¹⁵ and R ¹⁶ are as defined above)
And a process R for ring-closing the compound represented by the formula (XIV):

(Wherein X is as defined in claim 1; R ¹⁵ and R ¹⁶ are as defined above).

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