JP4038837B2 - Process for producing fluorine-containing indole, benzofuran and benzothiophene derivatives - Google Patents

Description

［式中、Ｒ¹は低級アルキル基（ｎ−ブチル基、ｓｅｃ−ブチル基、メチル基等）または水素原子を表し、Ｘはトシルアミド基、メシルアミド基、水酸基またはメチルスルフィニル基を表す。］
で示されるβ,β−ジフルオロスチレン誘導体に、必要に応じて無水トリフルオロ酢酸［（ＣＦ₃ＣＯ）₂Ｏ］とトリエチルアミンを作用させた後、塩基を作用させることを特徴とする、式 化４
【化４】

（式中、Ｒ¹は前記と同じ意味を表し、ＹはＮ−トシル基、Ｎ−メシル基、酸素原子または硫黄原子を表す。）
で示される含フッ素ヘテロ環化合物の製造法を提供するものである。
本明細書において、「トシル」とあるは、ｐ−トルエンスルホニル基を表し、「メシル」とあるは、メタンスルホニル基を表す。
【０００３】
【発明の実施の形態】
以下、本発明の製造法について詳細に説明する。
式 化３で示される β,β−ジフルオロスチレン誘導体としては、例えば、
２ −（１−ブチル−２，２−ジフルオロビニル）−ｐ−トルエンスルホンアニリド
２ −（１−ｓｅｃ−ブチル−２，２−ジフルオロビニル）−ｐ−トルエンスルホンアニリド
２ −（１−メチル−２，２−ジフルオロビニル）−ｐ−トルエンスルホンアニリド
２ −（２，２−ジフルオロビニル）−ｐ−トルエンスルホンアニリド
２ −（１−ブチル−２，２−ジフルオロビニル）メタンスルホンアニリド
２ −（１−ｓｅｃ−ブチル−２，２−ジフルオロビニル）メタンスルホンアニリド
２ −（１−メチル−２，２−ジフルオロビニル）メタンスルホンアニリド
ｏ−（１−ブチル−２，２−ジフルオロビニル）フェノ−ル
ｏ−（１−ｓｅｃ−ブチル−２，２−ジフルオロビニル）フェノ−ル
ｏ−（１−メチル−２，２−ジフルオロビニル）フェノ−ル
１，１−ジフルオロ−２−（ｏ−メチルスルフィニルフェニル）−１−ヘキセン
１，１−ジフルオロ−３−メチル−２−（ｏ−メチルスルフィニルフェニル）−１−ペンテン
１，１−ジフルオロ−２−（ｏ−メチルスルフィニルフェニル）−１−プロペン等が挙げられる。
用いられる塩基としては、例えば、水素化ナトリウム、炭酸カリウム、炭酸ナトリウム、炭酸セシウム等のアルカリ金属の炭酸塩、ナトリウムメトキシド、ナトリウムエトキシド等のアルカリ金属の低級アルコキシド、トリエチルアミン等の有機アミン等が挙げられるが、一般に、 Ｘがトシルアミド基、メシルアミド基または水酸基のときは、塩基としては、水素化ナトリウムが用いられ、 Ｘがメチルスルフィニル基のときは、炭酸カリウム、炭酸ナトリウム、炭酸セシウム等のアルカリ金属の炭酸塩、ナトリウムメトキシド、ナトリウムエトキシド等のアルカリ金属の低級アルコキシド、トリエチルアミン等の有機アミン等が用いられる。
【０００４】
式 化４で示される含フッ素ヘテロ環化合物としては、例えば、
３−ブチル−２−フルオロ−１−トシルインド−ル
３−ｓｅｃ−ブチル−２−フルオロ−１−トシルインド−ル
２−フルオロ−３−メチル−１−トシルインド−ル
２−フルオロ−１−トシルインド−ル
３−ブチル−２−フルオロ−１−メシルインド−ル
３−ｓｅｃ−ブチル−２−フルオロ−１−メシルインド−ル
２−フルオロ−３−メチル−１−メシルインド−ル
２−フルオロ−１−メシルインド−ル
等の式 化５
【化５】

（式中、Ｒ¹は前記と同じ意味を表し、Ｒ²はトシル基またはメシル基を表す。）で示されるインド−ル誘導体；
３−ブチル−２−フルオロベンゾ［ｂ］フラン
３− ｓｅｃ−ブチル−２−フルオロベンゾ［ｂ］フラン
２−フルオロ−３−メチルベンゾ［ｂ］フラン
２−フルオロルベンゾ［ｂ］フラン
等の式 化６
【化６】

（式中、Ｒ¹は前記と同じ意味を表す。）
で示されるベンゾ［ｂ］フラン誘導体；および
３−ブチル−２−フルオロベンゾ［ｂ］チオフェン
３− ｓｅｃ−ブチル−２−フルオロベンゾ［ｂ］チオフェン
２−フルオロ−３−メチルベンゾ［ｂ］チオフェン
２−フルオロベンゾ［ｂ］チオフェン
等の式 化７
【化７】

（式中、Ｒ¹は前記と同じ意味を表す。）
で示されるベンゾ［ｂ］チオフェン誘導体が挙げられる。
式 化４の含フッ素ヘテロ環化合物は、医薬、農薬、染料等の有効成分として有用である。（例えば、M. J. Silvester, Adv. Heterocyclic Chem., 1994, 59, 1; idem, Aldrichimica Acta, 1991, 24, 31; Organofluorine Chemistry, Principles and Commercial Applications, ed. R. E. Banks, B. E. Smart and J. C. Tatlow, Plenum Press, New York, 1994.参照）
【０００５】
本発明において、Ｘがトシルアミド基、メシルアミド基または水酸基のときは、反応は一般的に、不活性ガス雰囲気（窒素ガス等）下、不活性溶媒（例えば、Ｎ，Ｎ−ジメチルホルムアミド（以下、ＤＭＦと記す）等）中で塩基を作用させることにより行う。反応温度は通常−１０℃〜１００℃であり、反応時間は通常１時間〜３０時間である。塩基の使用量は、式 化３で示されるβ,β−ジフルオロスチレン誘導体１モルに対し、通常１〜１．５モルの割合である。反応終了後の反応液は、水または必要に応じて緩衝液で処理した後、有機溶媒抽出、濃縮等の後処理を行うことにより、目的とする式 化４で示される含フッ素ヘテロ環化合物（ 式 化５で示されるインド−ル誘導体または式 化６で示されるベンゾ［ｂ］フラン誘導体）を単離することができる。必要に応じ、クロマトグラフィ−、蒸留等により、さらに精製することもできる。
【０００６】
本発明において、Ｘがメチルスルフィニル基のときは、反応は一般的に、無水トリフルオロ酢酸とトリエチルアミンを作用させた後、塩基を作用させることにより行う。
無水トリフルオロ酢酸とトリエチルアミンを作用させる際は、一般的に、不活性ガス雰囲気（窒素ガス等）下、不活性溶媒（例えば、ジクロロメタン等）中で行う。反応温度は通常−１０℃〜２０℃であり、反応時間は通常０．１時間〜５時間である。用いられる試薬の量は、式 化３で示されるβ,β−ジフルオロスチレン誘導体１モルに対し、無水トリフルオロ酢酸は、通常２〜５モルの割合であり、トリエチルアミンは、通常２〜５モルの割合である。
塩基を作用させる際は、反応は一般的に、不活性ガス雰囲気（窒素ガス等）下、アルコ−ル溶媒（例えば、メタノ−ル、エタノ−ル等）中で行う。反応温度は通常−１０℃〜１００℃であり、反応時間は通常１時間〜２０時間である。塩基の使用量は、式 化３で示されるβ,β−ジフルオロスチレン誘導体１モルに対し、通常２〜１０モルの割合である。無水トリフルオロ酢酸とトリエチルアミンを作用させることにより、式 化８
【化８】

（式中、Ｒ¹は前記と同じ意味を表す。）
で示される化合物となり、これにアルコ−ル溶媒中塩基を作用させて、系中で式化９
【化９】

（式中、Ｒ¹は前記と同じ意味を表す。）
で示されるチオラ−トが発生し、閉環する。反応終了後の反応液は、水または必要に応じて緩衝液で処理した後、有機溶媒抽出、濃縮等の後処理を行うことにより、目的とする式 化４で示される含フッ素ヘテロ環化合物（式 化７で示されるベンゾ［ｂ］チオフェン誘導体）を単離することができる。必要に応じ、カラムクロマトグラフィ−、蒸留等により、さらに精製することもできる。
【０００７】
式 化３で示される β,β−ジフルオロスチレン誘導体は下記の反応式 化１０、化１１、化１２または化１３に従ってもしくは準じて製造することができる。（Tetrahedron Letters, 1992, 33, 3779 ；Tetrahedron Letters, 1996, 37, 8799参照）
【化１０】

（式中、Ｔｓはトシル基を表し、ⁿＢｕはｎ−ブチル基を表し、ｅｑは当量を表し、ＴＨＦはテトラヒドロフランを表し、ｃａｔ．は触媒量を表し、Ｐｄ⁰はトリス（ジベンジリデンアセトニル）ビスパラジウム−クロロホルム（１／１）とトリフェニルホスフィンの混合物を表し、r.t.,4hは室温で４時間を表し、ＨＭＰＡはヘキサメチルホスホリックトリアミドを表す。）
【化１１】

（式中、Ｔｓはトシル基を表し、ⁿＢｕはｎ−ブチル基を表し、ｅｑは当量を表し、ＴＨＦはテトラヒドロフランを表し、Ｍｅはメチル基を表し、ｃａｔ．は触媒量を表し、Ｐｄ⁰はトリス（ジベンジリデンアセトニル）ビスパラジウム−クロロホルム（１／１）とトリフェニルホスフィンの混合物を表し、r.t.,16hは室温で１６時間を表し、ＨＭＰＡはヘキサメチルホスホリックトリアミドを表す。）
【化１２】

（式中、 ⁿＢｕはｎ−ブチル基を表し、ⁱＡｍはイソアミル基を表し、ｅｑは当量を表し、Ｍｅはメチル基を表し、r.t.,0.5hは室温で０．５時間を表し、ａｑ．は水溶液を表す。）
【化１３】

（式中、Ｔｓはトシル基を表し、ⁿＢｕはｎ−ブチル基を表し、ｅｑは当量を表し、ＴＨＦはテトラヒドロフランを表し、ｃａｔ．は触媒量を表し、Ｐｄ⁰はトリス（ジベンジリデンアセトニル）ビスパラジウム−クロロホルム（１／１）とトリフェニルホスフィンの混合物を表し、r.t.,3hは室温で３時間を表し、“Cp₂Zr"はジシクロペンタジエニルジルコノセンを表し、refluxは加熱還流を表す。）
【０００８】
【実施例】
以下、本発明を実施例にてさらに詳しく説明するが、本発明はこれらの例に限定されない。
実施例１ ３−ブチル−２−フルオロ−１−トシルインド−ル
窒素雰囲気下、室温で、NaH (31 mg, 61.8 % dispersion in mineral oil, 0.79 mmol) のDMF (0.5 mL)懸濁液に、２ −（１−ブチル−２，２−ジフルオロビニル）−ｐ−トルエンスルホンアニリド (232 mg, 0.63 mmol) のDMF (2.5 mL)溶液を加えた。 その混合物を８０℃で７時間攪拌した後、りん酸緩衝液 (pH 7)を加えて、反応を停止した。有機物を酢酸エチルで３回抽出後、抽出液を合わせて食塩水で洗浄し、 Na₂SO₄で乾燥した。減圧下に溶媒を除去した後、残さをシリカゲル薄層クロマトグラフィ−(ヘキサン酢酸エチル； 5：1) に付し、３−ブチル−２−フルオロ−１−トシルインド−ル (184 mg, 84%) を黄色液体として得た。.
¹H NMR (500 MHz, CDCl₃) d 0.86 (3H, t, J = 7.4 Hz), 1.21 (2H, tq, J = 7.4, 7.4 Hz), 1.53 (2H, tt, J = 7.4, 7.4 Hz), 2.34 (3H, s), 2.52 (2H, td, J = 7.4 Hz, J_HF = 0.8 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.23 (1H, ddd, J = 7.7, 7.7, 1.2 Hz), 7.28 (1H, ddd, J = 7.7, 7.7, 1.4 Hz), 7.33 (1H, dd, J = 7.7, 1.2 Hz), 7.73 (2H, d, J = 8.4 Hz), 8.08 (1H, d, J = 7.7 Hz).
¹³C NMR (126 MHz, CDCl₃) d 13.6, 21.3 (d, J_CF = 3 Hz), 21.5, 22.1, 30.5, 99.7 (d, J_CF = 11 Hz), 114.4, 118.9 (d, J_CF = 7 Hz), 124.0, 124.0 (d, J_CF = 4 Hz), 126.8, 128.1 (d, J_CF = 6 Hz), 129.8, 130.6, 134.7, 145.2, 147.4 (d, J_CF = 276 Hz).
¹⁹F NMR (470 MHz, CDCl₃/C₆D₆) 29.1 (1F, s) ppm.
IR (neat) 2960, 2930, 2860, 1660, 1455, 1395, 1190, 1180, 745, 690, 665 cm^-1.
MS (20 eV) m/z 345 (M⁺; 100), 190 (68), 148 (92).
HRMS calcd for C₁₉H₂₀O₂SNF 345.1199 (M⁺); found 345.1188.
Anal. Calcd for C₁₉H₂₀O₂SNF: C, 66.07; H, 5.84; N, 4.05. Found: C, 65.97; H, 5.90; N, 4.10.
【０００９】
実施例２ ３−ブチル−２−フルオロベンゾ［ｂ］フラン
窒素雰囲気下、０℃で、ｏ−（１−ブチル−２，２−ジフルオロビニル）フェノ−ル (94 mg, 0.44 mmol)のDMF (4 mL)溶液に、水素化ナトリウム (NaH, 21 mg, 61.8 % dispersion in mineral oil, 0.53 mmol)を加えた。その混合物を６０℃で２時間攪拌した後、りん酸緩衝液 (pH 7)を加えて、反応を停止した。有機物を酢酸エチルで３回抽出後、抽出液を合わせて食塩水で洗浄し、 Na₂SO₄で乾燥した。減圧下に溶媒を除去した後、残さをシリカゲル薄層クロマトグラフィ−(ヘキサン酢酸エチル；３０：1) に付し、３−ブチル−２−フルオロベンゾ［ｂ］フラン(68 mg, 80%)を無色液体として得た。.
¹H NMR (500 MHz, CDCl₃) d 0.94 (3H, t, J = 7.4 Hz), 1.39 (2H, tq, J = 7.4, 7.4 Hz), 1.66 (2H, tt, J = 7.4, 7.4 Hz), 2.57 (2H, td, J = 7.4 Hz, J_HF = 1.0 Hz), 7.19-7.25 (2H, m), 7.32-7.36 (1H, m), 7.40-7.45 (1H, m).
¹³C NMR (126 MHz, CDCl₃) d 13.8, 21.0 (d, J_CF = 3 Hz), 22.4, 30.7 (d, J_CF = 2 Hz), 90.6 (d, J_CF = 12 Hz), 110.8, 119.2 (d, J_CF = 6 Hz), 123.1 (d, J_CF = 4 Hz), 123.2, 129.3 (d, J_CF = 3 Hz), 147.1, 157.1 (d, J_CF = 278 Hz).
¹⁹F NMR (470 MHz, CDCl₃/C₆F₆) 42.0 (1F, s) ppm.
IR (neat) 2960, 2940, 2860, 1675, 1455, 1380, 1295, 1260, 1185, 1140, 740 cm^-1.
MS (20 eV) m/z 192 (M⁺; 43), 149 (100).
HRMS calcd for C₁₂H₁₃OF 192.0950 (M⁺); found 192.0918.
【００１０】
実施例３ ３−ブチル−２−フルオロベンゾ［ｂ］チオフェン
窒素雰囲気下、０℃で、１，１−ジフルオロ−２−（ｏ−メチルスルフィニルフェニル）−１−ヘキセン(93 mg, 0.36 mmol) のジクロロメタン (CH₂Cl₂, 3 mL)溶液に、無水トリフルオロ酢酸 (0.15 mL, 1.09 mmol) およびトリエチルアミン (0.15 mL, 1.09 mmol) を加えた。その混合物を０．５時間攪拌した後、揮発成分を留去し、残さをメタノ−ル(3 mL)に溶かした。その溶液に０℃でK₂CO₃ (300 mg, 2.17 mmol) を加え、室温で１時間攪拌した後、さらに２時間加熱還流した。りん酸緩衝液 (pH 7)を加えて、反応を停止後、有機物を酢酸エチルで３回抽出した。抽出液を合わせて食塩水で洗浄し、 Na₂SO₄で乾燥した。減圧下に溶媒を除去した後、残さをシリカゲル薄層クロマトグラフィ−(ヘキサン酢酸エチル；５０：1) に付し、３−ブチル−２−フルオロベンゾ［ｂ］チオフェン(62 mg, 82%)を無色液体として得た。
¹H NMR (500 MHz, CDCl₃ ) d 0.94 (3H, t, J = 7.5 Hz), 1.39 (2H, tq, J = 7.5, 7.5 Hz), 1.64 (2H, tt, J = 7.5, 7.5 Hz), 2.75 (2H, td, J = 7.5 Hz, J _HF= 1.3 Hz), 7.28 (1H, ddd, J = 7.6, 7.6, 1.4 Hz), 7.35 (1H, ddd, J = 7.6, 7.6, 0.9 Hz), 7.58 (1H, d, J = 7.9 Hz), 7.64 (1H, d, J = 7.9 Hz).
¹³C NMR (126 MHz, CDCl₃) d 13.8, 22.5, 23.6, 31.0 (d, J_CF = 2 Hz), 115.5 (d, J_CF = 10 Hz), 121.5 (d, J_CF = 6 Hz), 122.6, 124.0 (d, J_CF = 4 Hz), 124.6, 131.3 (d, J_CF = 2 Hz), 136.8 (d, J_CF = 6 Hz), 159.2 (d, J_CF = 289 Hz).
¹⁹F NMR (470 MHz, CDCl₃/C₆F₆) 29.1 (1F, s) ppm.
IR (neat) 2960, 2930, 2860, 1610, 1460, 1435, 1265, 1190, 1065, 755, 730 cm^-1.
MS (20 eV) m/z 208 (M⁺; 50), 165 (100).
HRMS calcd for C₁₂H₁₃SF 208.0722 (M⁺); found 208.0694.
Anal. Calcd for C₁₂H₁₃SF: C, 69.20; H, 6.29. Found: C, 68.94; H, 6.33.
【００１１】
実施例４ ２−フルオロ−１−トシルインドール
窒素雰囲気下、室温で、NaH (16 mg, 60.0% dispersion in mineral oil, 0.41 mmol
) のDMF (0.5 mL)懸濁液に、２ −（２，２−ジフルオロビニル）−ｐ−トルエンスルホンアニリド (105 mg, 0.34 mmol) のDMF (1.5 mL) 溶液を加えた。 その混合物を７０℃で２３時間攪拌した後、りん酸緩衝液 (pH 7)を加えて、反応を停止した。有機物を酢酸エチルで３回抽出後、抽出液を合わせて食塩水で洗浄し、 Na₂SO₄で乾燥した。減圧下に溶媒を除去した後、残さをシリカゲル薄層クロマトグラフィ−(ヘキサン-酢酸エチル； 3：1) に付し、２−フルオロ−１−トシルインド−ル (72 mg,73%) を無色液体として得た。
¹H NMR (500 MHz, CDCl₃) d 2.34 (3H, s), 5.91 (1H, d, J_HF = 3.4 Hz),
7.20-7.24 (3H, m), 7.29 (1H, ddd, J = 8.4, 7.3, 1.2 Hz), 7.36 (1H, d, J =7.9 Hz), 7.78 (2H, d, J = 8.2 Hz), 8.09 (1H, d, J = 8.4 Hz).
¹³C NMR (126 MHz, CDCl₃) d 21.6, 86.7 (d, J_CF = 12 Hz), 114.1, 120.7 (d, J_CF = 6 Hz), 124.1 (d, J_CF = 4 Hz), 124.2, 126.6 (d, J_CF = 5 Hz), 126.9, 130.0, 130.8, 134.9, 145.6, 150.8 (d, J_CF = 279 Hz).
¹⁹F NMR (471 MHz, CDCl₃/C₆D₆) 35.7 (1F, d, J_FH = 3 Hz) ppm.
IR (neat) 2950, 2930, 1625, 1450, 1385, 1245, 1175, 1090, 745, 690 cm^-1. MS (70 eV) m/z 289 (M⁺; 23), 155 (50), 134 (80), 91 (100).[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a fluorine-containing heterocyclic compound.
[Problems to be solved by the invention]
An object of the present invention is to provide a novel method for producing fluorine-containing indole, benzofuran and benzothiophene derivatives from β, β-difluorostyrene derivatives.
[0002]
[Means for Solving the Problems]
As a result of intensive studies, the inventors of the present invention have reacted the β, β-difluorostyrene derivative represented by the following formula 3 with trifluoroacetic anhydride and triethylamine as necessary, and then allowed the base to act, thereby allowing the following formula: It has been found that the fluorine-containing heterocyclic compound represented by Chemical Formula 4 can be produced efficiently, and has led to the present invention. That is, the present invention is represented by the formula 3
[Chemical 3]

[Wherein, R ¹ represents a lower alkyl group (n-butyl group, sec-butyl group, methyl group, etc.) or a hydrogen atom, and X represents a tosylamide group, a mesylamide group, a hydroxyl group, or a methylsulfinyl group. ]
A trifluoroacetic anhydride [(CF ₃ CO) ₂ O] and triethylamine are allowed to act on a β, β-difluorostyrene derivative represented by the formula, if necessary, and then a base is allowed to act.
[Formula 4]

(Wherein R ¹ represents the same meaning as described above, and Y represents an N-tosyl group, an N-mesyl group, an oxygen atom or a sulfur atom.)
A method for producing a fluorine-containing heterocyclic compound represented by the formula:
In the present specification, “tosyl” represents a p-toluenesulfonyl group, and “mesyl” represents a methanesulfonyl group.
[0003]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the production method of the present invention will be described in detail.
As the β, β-difluorostyrene derivative represented by the formula 3, for example,
2- (1-Butyl-2,2-difluorovinyl) -p-toluenesulfonanilide 2- (1-sec-butyl-2,2-difluorovinyl) -p-toluenesulfonanilide 2- (1-methyl-2) , 2-Difluorovinyl) -p-toluenesulfonanilide 2- (2,2-difluorovinyl) -p-toluenesulfonanilide 2- (1-butyl-2,2-difluorovinyl) methanesulfonanilide 2- (1- sec-butyl-2,2-difluorovinyl) methanesulfonanilide 2- (1-methyl-2,2-difluorovinyl) methanesulfonanilide o- (1-butyl-2,2-difluorovinyl) phenol o- (1-sec-butyl-2,2-difluorovinyl) phenol o- (1-methyl-2,2-difluorovinyl) phenol Nor 1,1-difluoro-2- (o-methylsulfinylphenyl) -1-hexene 1,1-difluoro-3-methyl-2- (o-methylsulfinylphenyl) -1-pentene 1,1-difluoro -2- (o-methylsulfinylphenyl) -1-propene and the like.
Examples of the base used include alkali metal carbonates such as sodium hydride, potassium carbonate, sodium carbonate and cesium carbonate, lower alkoxides of alkali metals such as sodium methoxide and sodium ethoxide, and organic amines such as triethylamine. In general, when X is a tosylamide group, a mesylamide group or a hydroxyl group, sodium hydride is used as the base, and when X is a methylsulfinyl group, an alkali such as potassium carbonate, sodium carbonate or cesium carbonate is used. Metal carbonates, alkali metal lower alkoxides such as sodium methoxide and sodium ethoxide, and organic amines such as triethylamine are used.
[0004]
As the fluorine-containing heterocyclic compound represented by the formula 4, for example,
3-butyl-2-fluoro-1-tosylindole 3-sec-butyl-2-fluoro-1-tosylindole 2-fluoro-3-methyl-1-tosylindole 2-fluoro-1-tosylindole 3-butyl-2-fluoro-1-mesylindole 3-sec-butyl-2-fluoro-1-mesylindole 2-fluoro-3-methyl-1-mesylindole 2-fluoro-1-mesylindole Formula 5
[Chemical formula 5]

In the formula, R ¹ represents the same meaning as described above, and R ² represents a tosyl group or a mesyl group.
3-butyl-2-fluorobenzo [b] furan 3-sec-butyl-2-fluorobenzo [b] furan 2-fluoro-3-methylbenzo [b] furan-2-fluorobenzo [b] furan 6
[Chemical 6]

(Wherein R ¹ represents the same meaning as described above.)
And 3-butyl-2-fluorobenzo [b] thiophene 3-sec-butyl-2-fluorobenzo [b] thiophene2-fluoro-3-methylbenzo [b] thiophene2- Formulas such as fluorobenzo [b] thiophene
[Chemical 7]

(Wherein R ¹ represents the same meaning as described above.)
The benzo [b] thiophene derivative shown by these is mentioned.
The fluorine-containing heterocyclic compound represented by the formula 4 is useful as an active ingredient for pharmaceuticals, agricultural chemicals, dyes and the like. (For example, MJ Silvester, Adv. Heterocyclic Chem., 1994, 59, 1; idem, Aldrichimica Acta, 1991, 24, 31; Organofluorine Chemistry, Principles and Commercial Applications, ed. RE Banks, BE Smart and JC Tatlow, Plenum Press , New York, 1994.)
[0005]
In the present invention, when X is a tosylamide group, a mesylamide group or a hydroxyl group, the reaction is generally conducted under an inert gas atmosphere (nitrogen gas or the like) under an inert solvent (for example, N, N-dimethylformamide (hereinafter referred to as DMF)). Etc.) etc.)), etc.). The reaction temperature is usually −10 ° C. to 100 ° C., and the reaction time is usually 1 hour to 30 hours. The amount of the base used is usually 1 to 1.5 mol with respect to 1 mol of the β, β-difluorostyrene derivative represented by the formula 3. After completion of the reaction, the reaction solution is treated with water or a buffer solution as necessary, and then subjected to post-treatment such as organic solvent extraction and concentration, whereby the desired fluorine-containing heterocyclic compound represented by Formula 4 ( An indole derivative represented by the formula 5 or a benzo [b] furan derivative represented by the formula 6 can be isolated. If necessary, it can be further purified by chromatography, distillation or the like.
[0006]
In the present invention, when X is a methylsulfinyl group, the reaction is generally carried out by reacting trifluoroacetic anhydride and triethylamine and then reacting with a base.
When trifluoroacetic anhydride and triethylamine are allowed to act, the reaction is generally carried out in an inert solvent (for example, dichloromethane) under an inert gas atmosphere (such as nitrogen gas). The reaction temperature is usually −10 ° C. to 20 ° C., and the reaction time is usually 0.1 hour to 5 hours. The amount of the reagent used is usually 2 to 5 moles of trifluoroacetic anhydride and 1 to 5 moles of triethylamine based on 1 mole of the β, β-difluorostyrene derivative represented by Formula 3. It is a ratio.
When a base is allowed to act, the reaction is generally carried out in an alcohol solvent (eg, methanol, ethanol, etc.) under an inert gas atmosphere (nitrogen gas, etc.). The reaction temperature is usually −10 ° C. to 100 ° C., and the reaction time is usually 1 hour to 20 hours. The amount of the base used is usually 2 to 10 moles per mole of the β, β-difluorostyrene derivative represented by the formula 3. By reacting trifluoroacetic anhydride and triethylamine, the formula
[Chemical 8]

(Wherein R ¹ represents the same meaning as described above.)
And a base in an alcohol solvent is reacted with this to form a compound of formula 9
[Chemical 9]

(Wherein R ¹ represents the same meaning as described above.)
The thiolate shown in FIG. After completion of the reaction, the reaction solution is treated with water or a buffer solution as necessary, and then subjected to post-treatment such as organic solvent extraction and concentration, whereby the desired fluorine-containing heterocyclic compound represented by Formula 4 ( A benzo [b] thiophene derivative represented by the formula 7 can be isolated. If necessary, it can be further purified by column chromatography, distillation or the like.
[0007]
The β, β-difluorostyrene derivative represented by the formula 3 can be produced according to or according to the following reaction formulas 10, 11, 12, or 13. (See Tetrahedron Letters, 1992, 33, 3779; Tetrahedron Letters, 1996, 37, 8799)
[Chemical Formula 10]

(In the formula, Ts represents a tosyl group, ⁿ Bu represents an ⁿ -butyl group, eq represents an equivalent, THF represents tetrahydrofuran, cat. Represents a catalytic amount, and Pd ⁰ represents tris (dibenzylideneacetonyl). ) Represents a mixture of bispalladium-chloroform (1/1) and triphenylphosphine, rt, 4h represents 4 hours at room temperature, and HMPA represents hexamethylphosphoric triamide.)
Embedded image

(In the formula, Ts represents a tosyl group, ⁿ Bu represents an ⁿ -butyl group, eq represents an equivalent, THF represents tetrahydrofuran, Me represents a methyl group, cat. Represents a catalytic amount, Pd ⁰ Represents a mixture of tris (dibenzylideneacetonyl) bispalladium-chloroform (1/1) and triphenylphosphine, rt, 16h represents 16 hours at room temperature, and HMPA represents hexamethylphosphoric triamide.)
Embedded image

(Wherein ⁿ Bu represents an n-butyl group, ⁱ Am represents an isoamyl group, eq represents an equivalent, Me represents a methyl group, rt, 0.5h represents 0.5 hour at room temperature, aq Represents an aqueous solution.)
Embedded image

(In the formula, Ts represents a tosyl group, ⁿ Bu represents an ⁿ -butyl group, eq represents an equivalent, THF represents tetrahydrofuran, cat. Represents a catalytic amount, and Pd ⁰ represents tris (dibenzylideneacetonyl). ) Represents a mixture of bis-palladium-chloroform (1/1) and triphenylphosphine, rt, 3h represents 3 hours at room temperature, “Cp ₂ Zr” represents dicyclopentadienylzirconocene, reflux represents the heating reflux To express.)
[0008]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these examples.
Example 1 3-Butyl-2-fluoro-1-tosylindole Into a DMF (0.5 mL) suspension of NaH (31 mg, 61.8% dispersion in mineral oil, 0.79 mmol) in a nitrogen atmosphere at room temperature, 2 A solution of-(1-butyl-2,2-difluorovinyl) -p-toluenesulfonanilide (232 mg, 0.63 mmol) in DMF (2.5 mL) was added. The mixture was stirred at 80 ° C. for 7 hours, and then the reaction was stopped by adding a phosphate buffer (pH 7). The organic matter was extracted three times with ethyl acetate, and the extracts were combined, washed with brine, and dried over Na ₂ SO ₄ . After removing the solvent under reduced pressure, the residue was subjected to silica gel thin layer chromatography (hexane ethyl acetate; 5: 1) to give 3-butyl-2-fluoro-1-tosylindole (184 mg, 84%). Obtained as a yellow liquid. .
¹ H NMR (500 MHz, CDCl ₃ ) d 0.86 (3H, t, J = 7.4 Hz), 1.21 (2H, tq, J = 7.4, 7.4 Hz), 1.53 (2H, tt, J = 7.4, 7.4 Hz) , 2.34 (3H, s), 2.52 (2H, td, J = 7.4 Hz, J _HF = 0.8 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.23 (1H, ddd, J = 7.7, 7.7, 1.2 Hz), 7.28 (1H, ddd, J = 7.7, 7.7, 1.4 Hz), 7.33 (1H, dd, J = 7.7, 1.2 Hz), 7.73 (2H, d, J = 8.4 Hz), 8.08 (1H, d, J = 7.7 Hz).
¹³ C NMR (126 MHz, CDCl ₃ ) d 13.6, 21.3 (d, J _CF = 3 Hz), 21.5, 22.1, 30.5, 99.7 (d, J _CF = 11 Hz), 114.4, 118.9 (d, J _CF = 7 Hz), 124.0, 124.0 (d, J _CF = 4 Hz), 126.8, 128.1 (d, J _CF = 6 Hz), 129.8, 130.6, 134.7, 145.2, 147.4 (d, J _CF = 276 Hz).
¹⁹ F NMR (470 MHz, CDCl ₃ / C ₆ D ₆ ) 29.1 (1F, s) ppm.
IR (neat) 2960, 2930, 2860, 1660, 1455, 1395, 1190, 1180, 745, 690, 665 cm ^-1 .
MS (20 eV) m / z 345 (M ⁺ ; 100), 190 (68), 148 (92).
HRMS calcd for C ₁₉ H ₂₀ O ₂ SNF 345.1199 (M ⁺ ); found 345.1188.
Anal. Calcd for C ₁₉ H ₂₀ O ₂ SNF: C, 66.07; H, 5.84; N, 4.05. Found: C, 65.97; H, 5.90; N, 4.10.
[0009]
Example 2 3-butyl-2-fluorobenzo [b] furan In a nitrogen atmosphere at 0 ° C., o- (1-butyl-2,2-difluorovinyl) phenol (94 mg, 0.44 mmol) of DMF ( To the solution (4 mL), sodium hydride (NaH, 21 mg, 61.8% dispersion in mineral oil, 0.53 mmol) was added. The mixture was stirred at 60 ° C. for 2 hours, and then the reaction was stopped by adding a phosphate buffer (pH 7). The organic matter was extracted three times with ethyl acetate, and the extracts were combined, washed with brine, and dried over Na ₂ SO ₄ . After removing the solvent under reduced pressure, the residue was subjected to silica gel thin layer chromatography (hexane ethyl acetate; 30: 1), and 3-butyl-2-fluorobenzo [b] furan (68 mg, 80%) was colorless. Obtained as a liquid. .
¹ H NMR (500 MHz, CDCl ₃ ) d 0.94 (3H, t, J = 7.4 Hz), 1.39 (2H, tq, J = 7.4, 7.4 Hz), 1.66 (2H, tt, J = 7.4, 7.4 Hz) , 2.57 (2H, td, J = 7.4 Hz, J _HF = 1.0 Hz), 7.19-7.25 (2H, m), 7.32-7.36 (1H, m), 7.40-7.45 (1H, m).
¹³ C NMR (126 MHz, CDCl ₃ ) d 13.8, 21.0 (d, J _CF = 3 Hz), 22.4, 30.7 (d, J _CF = 2 Hz), 90.6 (d, J _CF = 12 Hz), 110.8, 119.2 (d, J _CF = 6 Hz), 123.1 (d, J _CF = 4 Hz), 123.2, 129.3 (d, J _CF = 3 Hz), 147.1, 157.1 (d, J _CF = 278 Hz).
¹⁹ F NMR (470 MHz, CDCl ₃ / C ₆ F ₆ ) 42.0 (1F, s) ppm.
IR (neat) 2960, 2940, 2860, 1675, 1455, 1380, 1295, 1260, 1185, 1140, 740 cm ^-1 .
MS (20 eV) m / z 192 (M ⁺ ; 43), 149 (100).
HRMS calcd for C ₁₂ H ₁₃ OF 192.0950 (M ⁺ ); found 192.0918.
[0010]
Example 3 3-butyl-2-fluorobenzo [b] thiophene 1,1-difluoro-2- (o-methylsulfinylphenyl) -1-hexene (93 mg, 0.36 mmol) at 0 ° C. under nitrogen atmosphere To a dichloromethane (CH ₂ Cl ₂ , 3 mL) solution was added trifluoroacetic anhydride (0.15 mL, 1.09 mmol) and triethylamine (0.15 mL, 1.09 mmol). The mixture was stirred for 0.5 hour, then volatile components were distilled off, and the residue was dissolved in methanol (3 mL). K ₂ CO ₃ (300 mg, 2.17 mmol) was added to the solution at 0 ° C., and the mixture was stirred at room temperature for 1 hour, and further heated under reflux for 2 hours. Phosphate buffer (pH 7) was added to stop the reaction, and the organic matter was extracted three times with ethyl acetate. The extracts were combined, washed with brine, and dried over Na ₂ SO ₄ . After removing the solvent under reduced pressure, the residue was subjected to silica gel thin layer chromatography (hexane ethyl acetate; 50: 1) to give 3-butyl-2-fluorobenzo [b] thiophene (62 mg, 82%) colorless. Obtained as a liquid.
¹ H NMR (500 MHz, CDCl ₃ ) d 0.94 (3H, t, J = 7.5 Hz), 1.39 (2H, tq, J = 7.5, 7.5 Hz), 1.64 (2H, tt, J = 7.5, 7.5 Hz) , 2.75 (2H, td, J = 7.5 Hz, J _HF = 1.3 Hz), 7.28 (1H, ddd, J = 7.6, 7.6, 1.4 Hz), 7.35 (1H, ddd, J = 7.6, 7.6, 0.9 Hz) , 7.58 (1H, d, J = 7.9 Hz), 7.64 (1H, d, J = 7.9 Hz).
¹³ C NMR (126 MHz, CDCl ₃ ) d 13.8, 22.5, 23.6, 31.0 (d, J _CF = 2 Hz), 115.5 (d, J _CF = 10 Hz), 121.5 (d, J _CF = 6 Hz), 122.6, 124.0 (d, J _CF = 4 Hz), 124.6, 131.3 (d, J _CF = 2 Hz), 136.8 (d, J _CF = 6 Hz), 159.2 (d, J _CF = 289 Hz).
¹⁹ F NMR (470 MHz, CDCl ₃ / C ₆ F ₆ ) 29.1 (1F, s) ppm.
IR (neat) 2960, 2930, 2860, 1610, 1460, 1435, 1265, 1190, 1065, 755, 730 cm ^-1 .
MS (20 eV) m / z 208 (M ⁺ ; 50), 165 (100).
HRMS calcd for C ₁₂ H ₁₃ SF 208.0722 (M ⁺ ); found 208.0694.
Anal. Calcd for C ₁₂ H ₁₃ SF: C, 69.20; H, 6.29. Found: C, 68.94; H, 6.33.
[0011]
Example 4 2-Fluoro-1-tosylindole NaH (16 mg, 60.0% dispersion in mineral oil, 0.41 mmol under nitrogen atmosphere at room temperature
) In DMF (0.5 mL) was added a solution of 2- (2,2-difluorovinyl) -p-toluenesulfonanilide (105 mg, 0.34 mmol) in DMF (1.5 mL). The mixture was stirred at 70 ° C. for 23 hours, and then the reaction was stopped by adding a phosphate buffer (pH 7). The organic matter was extracted three times with ethyl acetate, and the extracts were combined, washed with brine, and dried over Na ₂ SO ₄ . After removing the solvent under reduced pressure, the residue was subjected to silica gel thin layer chromatography (hexane-ethyl acetate; 3: 1) to give 2-fluoro-1-tosylindole (72 mg, 73%) as a colorless liquid. Obtained.
¹ H NMR (500 MHz, CDCl ₃ ) d 2.34 (3H, s), 5.91 (1H, d, J _HF = 3.4 Hz),
7.20-7.24 (3H, m), 7.29 (1H, ddd, J = 8.4, 7.3, 1.2 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.78 (2H, d, J = 8.2 Hz), 8.09 (1H, d, J = 8.4 Hz).
¹³ C NMR (126 MHz, CDCl ₃ ) d 21.6, 86.7 (d, J _CF = 12 Hz), 114.1, 120.7 (d, J _CF = 6 Hz), 124.1 (d, J _CF = 4 Hz), 124.2, 126.6 (d, J _CF = 5 Hz), 126.9, 130.0, 130.8, 134.9, 145.6, 150.8 (d, J _CF = 279 Hz).
¹⁹ F NMR (471 MHz, CDCl ₃ / C ₆ D ₆ ) 35.7 (1F, d, J _FH = 3 Hz) ppm.
IR (neat) 2950, 2930, 1625, 1450, 1385, 1245, 1175, 1090, 745, 690 cm ^-1 .MS (70 eV) m / z 289 (M ⁺ ; 23), 155 (50), 134 ( 80), 91 (100).

Claims (1)

Formula 1

(In the formula, R ¹ represents a lower alkyl group or a hydrogen atom, and X represents a tosylamide group, a mesylamide group, a hydroxyl group, or a methylsulfinyl group.)
The β, β-difluorostyrene derivative represented by the formula is reacted with trifluoroacetic anhydride and triethylamine as necessary, and then with a base, and the formula 2

(Wherein R ¹ represents the same meaning as described above, and Y represents an N-tosyl group, an N-mesyl group, an oxygen atom or a sulfur atom.)
The manufacturing method of the fluorine-containing heterocyclic compound shown by these.