JP4158228B2 - Process for producing cyclopentenone derivative and cyclopentenone derivative - Google Patents
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Description
【０００１】
【発明の属する技術分野】
本発明はシクロペンテノン誘導体の製造法及びシクロペンテノン誘導体に関する。
【０００２】
【従来の技術】
シクロペンテノン誘導体はプロスタグランジン誘導体等の種々の生理活性化合物の製造中間体となり得ることから、かかるシクロペンテノン誘導体の効率の良い製造法の開発が望まれている。
【０００３】
【発明が解決しようとする課題】
本発明は、シクロペンテノン誘導体を高選択的に高収率で製造する製造法及びシクロペンテノン誘導体を提供することを課題とする。
【０００４】
【課題を解決するための手段】
本発明者等は鋭意検討した結果、下記、 一般式 化４で示されるジビニル＝ケトン誘導体に、トリメチルシリコン（１＋）＝クロロトリス（トリフルオロメタンスルホナト）ボラート（１−）（以下、ＴＭＳＢ（ＯＴｆ）3Ｃｌと記す）またはトリメチルシリコン（１＋）＝テトラキス（トリフルオロメタンスルホナト）ボラート（１−）（以下、ＴＭＳＢ（ＯＴｆ）4と記す）を作用させることにより、下記、一般式 化５で示される含フッ素シクロペンテノン誘導体を高選択的に高収率で製造できることを見出し、本発明に至った。
即ち、本発明は一般式 化４
【化４】
で示されるジビニル＝ケトン誘導体に、ＴＭＳＢ（ＯＴｆ）3ＣｌまたはＴＭＳＢ（ＯＴｆ）4を作用させる一般式 化５
【化５】
で示される含フッ素シクロペンテノン誘導体の製造法（以下、本発明製造法と称す）を提供する。
本発明は、さらに一般式 化６
【化６】
で示される含フッ素シクロペンテノン誘導体を提供する。
【０００５】
【発明の実施の形態】
以下、本発明製造法について詳細に説明する。
本発明製造法は、前記、一般式 化４で示されるジビニル＝ケトン誘導体に、ＴＭＳＢ（ＯＴｆ）3ＣｌまたはＴＭＳＢ（ＯＴｆ）4を作用させることにより行われる。
該反応は、通常、不活性ガス雰囲気下、不活性溶媒中で行われる。
反応温度の範囲は−８０℃〜１００℃であり、反応時間の範囲は０．１時間〜３０時間である。
反応に供される試剤の量は、一般式 化４で示されるジビニル＝ケトン誘導体１モルに対し、ＴＭＳＢ（ＯＴｆ）3ＣｌまたはＴＭＳＢ（ＯＴｆ）4の量は、０．８〜１．５モルの割合である。
不活性ガスとしては、例えば、窒素ガス、アルゴン等があげられる。
溶媒としては、例えば、ジクロロメタン等のハロゲン化炭化水素類、トルエン、ヘキサン、シクロヘキサン等の炭化水素類、ジエチルエ−テル、テトラヒドロフラン（以下、ＴＨＦと記す。）等のエ−テル類、またはそれらの混合溶媒があげられる。
反応終了後の反応液は、水または飽和重曹水溶液を加えた後、有機溶媒抽出、濃縮等の後処理操作を行うことにより、目的とする化合物を得ることができる。該化合物は、クロマトグラフィ−、蒸留等の操作により、さらに精製することもできる。
【０００６】
一般式 化４で示されるジビニル＝ケトン誘導体は、例えば、Bull.Chem.Soc.Jpn.,1992,65,2800-2806等に記載の方法に準じて製造することができる。
また、ＴＭＳＢ（ＯＴｆ）3Ｃｌ及びＴＭＳＢ（ＯＴｆ）4は、例えば、Angew.Chem.,Int.Ed.Engl.,1992,31,470-471、Tetrahedron Letters,1996,37,9401-9402等に記載の方法に準じて製造することができる。
【０００７】
本発明製造法により得られる一般式 化５で示される含フッ素シクロペンテノン誘導体としては、例えば、
３，４−ジブチル−２−フルオロ−２−シクロペンテノン
３−エチル−２−フルオロ−４−フェニル−２−シクロペンテノン
２−フルオロ−３−イソプロピル−４−フェニル−２−シクロペンテノン
２−フルオロ−４−フェニル−２−シクロペンテノン
３，５−ジエチル−２−フルオロ−４−プロピル−２−シクロペンテノン
２−フルオロ−３，４−ジフェニル−２−シクロペンテノン
等が挙げられる。
また、本発明製造法において用いられる、一般式 化４で示されるジビニル＝ケトン誘導体としては、例えば、
６−フルオロ−５，８−トリデカジエン−７−オン
４−フルオロ−１−フェニル−１，４−ヘプタジエン−３−オン
４−フルオロ−6−メチル−１−フェニル−１，４−ヘプタジエン−３−オン
４−フルオロ−１−フェニル−１，４−ペンタジエン−３−オン
６−エチル−４−フルオロ−３，６−デカジエン−５−オン
１，５−ジフェニル−２−フルオロ−１，４−ペンタジエン−３−オン
等が挙げられる。
【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 ３，４−ジブチル−２−フルオロ−２−シクロペンテノンの製造
６−フルオロ−５，８−トリデカジエン−７−オン５１ｍｇ（０．２４ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、窒素雰囲気下、室温で、ＴＭＳＢ（ＯＴｆ）4のジクロロメタン溶液（濃度０．２９Ｍ）０．８２ｍｌ（０．２４ｍｍｏｌ）を加えた。該混合物を１５分間攪拌した後、飽和重曹水溶液を加えた。水層をジクロロメタンで３回抽出した後、該抽出液を合わせ、これを飽和重曹水溶液、食塩水で順次洗浄した後、Ｎａ2ＳＯ4で乾燥し、減圧下に溶媒を留去した後、残渣をシリカゲル薄層クロマトグラフィー（展開溶媒：酢酸エチル：ヘキサン＝１：５）に付し、３，４−ジブチル−２−フルオロ−２−シクロペンテノン４５ｍｇ（０．２１ｍｍｏｌ）を淡黄色液体として得た。収率８９％。
1H-NMR (500 MHz, CDCl3) δ 0.92 (3H, t, J = 7.3 Hz), 0.95 (3H, t, J = 7.3 Hz), 1.18-1.44 (7H, m), 1.44-1.54 (1H, m), 1.54-1.64 (1H, m), 1.73-1.82 (1H, m), 2.09 (1H, d, J = 18.9 Hz), 2.19-2.28 (1H, m), 2.54 (1H, dd, J = 18.9, 6.0 Hz), 2.53-2.62 (1H, m), 2.69-2.75 (1H, m)
19F-NMR (471MHz, CDCl3/C6F6) 16.3 (1F, d, J = 5Hz) ppm
MS (70 eV) m/z 212 (M+; 81), 155 (61), 114 (100), 85 (59)
HRMS calcd for C13H21OF 212.1576 (M+); found 212.1563
【０００９】
実施例２ ３−エチル−２−フルオロ−４−フェニル−２−シクロペンテノンの製造
４−フルオロ−１−フェニル−１，４−ヘプタジエン−３−オン６０ｍｇ（０．５１ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、窒素雰囲気下、室温でＴＭＳＢ（ＯＴｆ）4のジクロロメタン溶液（濃度０．４１Ｍ）１．２５ｍｌ（０．５１ｍｍｏｌ）を加えた。該混合物を１５分間攪拌した後、飽和重曹水溶液を加えた。水層をジクロロメタンで３回抽出した後、該抽出液を合わせ、これを飽和重曹水溶液、食塩水で順次洗浄した後、Ｎａ2ＳＯ4で乾燥し、減圧下に溶媒を留去した後、残渣をシリカゲル薄層クロマトグラフィー（展開溶媒：酢酸エチル：ヘキサン＝１：５）に付し、３−エチル−２−フルオロ−４−フェニル−２−シクロペンテノン９０ｍｇ（０．４４ｍｍｏｌ）を淡黄色液体として得た。収率８８％。
IR (neat) 2980, 1725, 1665, 1455, 1355, 1105, 1065, 705 cm-1
1H-NMR (500 MHz, CDCl3) δ 1.05 (3H, t, J = 7.6 Hz), 2.02 (1H, br dq, J = 15.2, 7.6 Hz), 2.36 (1H, d, J = 19.0 Hz), 2.47 (1H, dq, J = 15.2, 7.6 Hz), 2.92 (1H, dd, J = 19.0, 6.1 Hz), 3.92 (1H, dd, J = 6.1 Hz, JHF = 6.1 Hz), 7.15 (2H, br d, J = 7.3 Hz), 7.28 (1H, br t, J = 7.3 Hz), 7.35 (2H, br t, J = 7.3 Hz)
13C-NMR (126 MHz, CDCl3) δ 10.9 (d, JCF = 2 Hz), 19.9, 41.6 (d, JCF = 5 Hz), 42.1 (d, JCF = 4 Hz), 127.2, 127.5, 129.1, 140.3 (d, JCF = 2 Hz), 155.0 (d, JCF = 277 Hz), 156.9 (d, JCF = 4 Hz), 197.5 (d, JCF = 19 Hz)
19F-NMR (471 MHz, CDCl3/C6F6) 16.8 (1F, d, J = 5 Hz) ppm
MS (70 eV) m/z 204 (M+; 40), 175 (100), 147 (29), 77 (26)
HRMS calcd for C13H13OF 204.0950 (M+); found 204.0950
【００１０】
実施例３ ２−フルオロ−３−イソプロピル−４−フェニル−２−シクロペンテノンの製造
4−フルオロ−６−メチル−１−フェニル−１，４−ヘプタジエン−３−オン５２ｍｇ（０．２３ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、窒素雰囲気下、室温で、ＴＭＳＢ（ＯＴｆ）4のジクロロメタン溶液（濃度０．５５Ｍ）０．４３ｍｌ（０．２４ｍｍｏｌ）を加えた。該混合物を１５分間攪拌した後、飽和重曹水溶液を加えた。水層をジクロロメタンで３回抽出した後、該抽出液を合わせ、これを飽和重曹水溶液、食塩水で順次洗浄した後、Ｎａ2ＳＯ4で乾燥し、減圧下に溶媒を留去した後、残渣をシリカゲル薄層クロマトグラフィー（展開溶媒：酢酸エチル：ヘキサン＝１：５）に付し、２−フルオロ−３−イソプロピル−４−フェニル−２−シクロペンテノン３８ｍｇ（０．１８ｍｍｏｌ）を淡黄色液体として得た。収率７４％。
IR (neat) 2971, 1724, 1658, 1456, 1315, 1070, 701 cm-1
1H-NMR (500 MHz, CDCl3) δ 1.05 (3H, d, J = 7.0 Hz), 1.12 (3H, dd, J = 7.0 Hz, JHF = 1.5 Hz), 2.35 (1H, d, J = 19.0 Hz), 2.48 (1H, sept, J = 7.0 Hz), 2.90 (1H, dd, J = 19.0, 7.0 Hz), 3.94 (1H, br dd, J = 7.0 Hz, JHF = 7.0 Hz), 7.17 (2H, br d, J = 7.3 Hz), 7.25-7.31 (1H, m), 7.34 (2H, br t, J = 7.3 Hz)
13C-NMR (126 MHz, CDCl3) δ 19.7 (d, JCF = 3 Hz), 20.6 (d, JCF = 2 Hz),28.4 (d, JCF = 2 Hz), 41.9 (d, JCF = 6 Hz), 42.3 (d, JCF = 4 Hz), 127.4, 127.6, 129.0, 140.8 (d, JCF = 2 Hz), 154.9 (d, JCF = 277 Hz), 160.3, 198.0 (d, JCF = 20 Hz)
19F-NMR (471 MHz, CDCl3/C6F6) 19.4 (1F, d, J = 5 Hz) ppm
MS (70 eV) m/z 218 (M+; 64), 175 (100), 140 (81)
HRMS calcd for C14H15OF 218.1107 (M+); found 218.1087
【００１１】
実施例４ ２−フルオロ−４−フェニル−２−シクロペンテノンの製造
４−フルオロ−1−フェニル−１，４−ペンタジエン−３−オン４２ｍｇ（０．２４ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、窒素雰囲気下、室温で、ＴＭＳＢ（ＯＴｆ）4のジクロロメタン溶液（濃度０．２９Ｍ）０．８１ｍｌ（０．２４ｍｍｏｌ）を加えた。該混合物を１５分間攪拌した後、飽和重曹水溶液を加えた。水層をジクロロメタンで３回抽出した後、該抽出液を合わせ、これを飽和重曹水溶液、食塩水で順次洗浄した後、Ｎａ2ＳＯ4で乾燥し、減圧下に溶媒を留去した後、残渣をシリカゲル薄層クロマトグラフィー（展開溶媒：酢酸エチル：ヘキサン＝１：５）に付し、２−フルオロ−４−フェニル−２−シクロペンテノン３３ｍｇ（０．１９ｍｍｏｌ）を無色固体として得た。収率７９％。
IR (KBr disk) 2929, 1731, 1648, 1340, 1078, 765, 701 cm-1
1H-NMR (500 MHz, CDCl3) δ 2.40 (1H, dd, J = 19.4, 1.8 Hz), 2.99 (1H, dd, J = 19.4, 6.4 Hz), 4.03-4.09 (1H, m), 7.00 (1H, d, J = 2.8 Hz), 7.18 (2H, dt, J = 7.3, 1.6 Hz), 7.29 (1H, tt, J = 7.3, 1.6 Hz), 7.36 (2H, br t, J = 7.3 Hz)
13C-NMR (126 MHz, CDCl3) δ 38.7 (d, JCF= 6 Hz), 42.5 (d, JCF = 4 Hz),126.9, 127.6, 129.1, 138.8 (d, JCF = 6 Hz), 140.9 (d, JCF = 2 Hz), 158.8 (d, JCF = 284 Hz), 198.3 (d, JCF = 19 Hz)
19F-NMR (471 MHz, CDCl3/C6F6) 23.1 (1F, d, J = 6 Hz) ppm
MS (70 eV) m/z 176 (M+; 100), 147 (58), 133 (44)
【００１２】
実施例５ ３，５−ジエチル−２−フルオロ−４−プロピル−２−シクロペンテノンの製造
６−エチル−４−フルオロ−３，６−デカジエン−５−オン６０ｍｇ（０．３０ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、窒素雰囲気下、室温で、ＴＭＳＢ（ＯＴｆ）4のジクロロメタン溶液（濃度０．２６Ｍ）１．２ｍｌ（０．３１ｍｍｏｌ）を加えた。該混合物を１５分間攪拌した後、飽和重曹水溶液を加えた。水層をジクロロメタンで３回抽出した後、該抽出液を合わせ、これを飽和重曹水溶液、食塩水で順次洗浄した後、Ｎａ2ＳＯ4で乾燥し、減圧下に溶媒を留去した後、残渣をシリカゲル薄層クロマトグラフィー（展開溶媒：酢酸エチル：ヘキサン＝１：５）に付し、３，５−ジエチル−２−フルオロ−４−プロピル−２−シクロペンテノン３９ｍｇ（０．２０ｍｍｏｌ）を淡黄色液体として得た。収率６５％。
IR (neat) 2962, 2933, 2875, 1722, 1688, 1461, 1380, 1355, 1116, 1022cm-1
13C-NMR (126 MHz, CDCl3) major isomer: δ 10.8, 11.2 (d, JCF = 2 Hz), 14.3, 19.5, 19.9, 24.8, 34.9 (d, JCF = 2 Hz), 41.3 (d, JCF = 3 Hz), 49.8 (d, JCF = 4 Hz), 153.6 (d, JCF = 277 Hz), 157.4 (d, JCF = 3 Hz), 200.5 (d, JCF = 17 Hz)
19F-NMR (471 MHz, CDCl3/C6F6) for 8/2 mixture 14.9 (0.2F, d, J = 5 Hz), 16.0 (0.8F, d, J = 6 Hz) ppm
【００１３】
実施例６ ２−フルオロ−３，４−ジフェニル−２−シクロペンテノンの製造
１，５−ジフェニル−２−フルオロ−１，４−ペンタジエン−３−オン６２ｍｇ（０．２５ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、窒素雰囲気下、室温で、ＴＭＳＢ（ＯＴｆ）4のジクロロメタン溶液（濃度０．５５Ｍ）０．４５ｍｌ（０．２５ｍｍｏｌ）を加えた。該混合物を１５分間攪拌した後、飽和重曹水溶液を加えた。水層をジクロロメタンで３回抽出した後、該抽出液を合わせ、これを飽和重曹水溶液、食塩水で順次洗浄した後、Ｎａ2ＳＯ4で乾燥し、減圧下に溶媒を留去した後、残渣をシリカゲル薄層クロマトグラフィー（展開溶媒：酢酸エチル：ヘキサン＝１：５）に付し、２−フルオロ−３，４−ジフェニル−２−シクロペンテノン３６ｍｇ（０．１４ｍｍｏｌ）を無色固体として得た。収率４８％。
IR (KBr disk) 1716, 1635, 1361, 1078, 701, 688 cm-1
19F-NMR (471 MHz, CDCl3/C6F6) 25.1 (1F, d, J = 6 Hz) ppm
MS (70 eV) m/z 252 (M+; 100), 223 (63), 146 (58), 120 (50)
【００１４】
参考製造例１ ４−フルオロ−１−フェニル−１，４−ヘプタジエン−３−オンの製造
４−フルオロ−１−フェニル−４−（フェニルスルフィニル）１−ヘプテン−３−オン１．２５ｇ（３．８ｍｍｏｌ）のベンゼン１０ｍｌ溶液を、１時間加熱還流した。減圧下に溶媒を留去した後、残渣をシリカゲル薄層クロマトグラフィー（展開溶媒：酢酸エチル：ヘキサン＝１：２０）に付し、４−フルオロ−１−フェニル−１，４−ヘプタジエン−３−オン４３１ｍｇ（２．０ｍｍｏｌ）を黄色液体として得た。収率５６％。
IR (neat) 2960, 1650, 1600, 1570, 1450, 1330, 1200, 1010, 760 cm-1
1H-NMR (500 MHz, CDCl3) δ 1.11 (3H, t, J = 7.5 Hz), 2.33 (2H, dquint, J = 7.6, 2.1 Hz), 6.18 (1H, dt, J = 34.7, 7.8 Hz), 7.23 (1H, dd, J = 15.6, 2.1 Hz), 7.38-7.43 (3H, m), 7.58-7.64 (2H, m), 7.80 (1H, d, J = 16.0 Hz)
13C-NMR (126 MHz, CDCl3) δ 13.0 (d, JCF = 2 Hz), 17.9 (d, JCF = 4 Hz), 119.6, 121.4 (d, JCF = 13 Hz), 128.6, 128.9, 130.8, 134.5, 145.1 (d, JCF = 2 Hz), 155.5 (d, JCF = 260 Hz), 182.7 (d, JCF = 31 Hz)
19F-NMR (471 MHz, CDCl3 / C6F6) 31.3 (1F, JFH = 31.3 Hz) ppm
MS (70 eV) m/z 204 ( M+; 44), 131 (69), 103 (100), 77 (57)
HRMS calcd for C13H13OF 204.0950 (M+); found 204.0959
【００１５】
参考製造例２ ４−フルオロ−１−フェニル−１，４−ペンタジエン−３−オンの製造
４−フルオロ−１−フェニル−４−（フェニルスルフィニル）１−ペンテン−３−オン２３０ｍｇ（０．７６ｍｍｏｌ）のベンゼン４ｍｌ溶液を、１時間加熱還流した。減圧下に溶媒を留去した後、残渣をシリカゲル薄層クロマトグラフィー（展開溶媒：酢酸エチル：ヘキサン＝１：５）に付し、４−フルオロ−１−フェニル−１，４−ペンタジエン−３−オン１２９ｍｇ（０．７３ｍｍｏｌ）を淡黄色液体として得た。収率９６％。
IR (KBr disk) 3103, 3030, 1660, 1640, 1610, 1450, 1360, 1070, 940, 900 cm-1
1H-NMR (500 MHz, CDCl3) δ 5.30 (1H, dd, J = 14.6, 3.4 Hz), 5.70 (1H, dd, J = 45.8, 3.4 Hz), 7.23 (1H, dd, J = 5.9, 2.1 Hz), 7.397.46 (3H, m), 7.46 (2H, dd, J = 36.6, 3.1 Hz), 7.84 (1H, dd, J = 15.9 Hz)
13C-NMR (126 MHz, CDCl3) δ 101.6 (d, JCF = 15 Hz), 119.2, 128.2, 129.0, 131.2, 134.3, 146.2 (d, JCF = 2 Hz), 160.6 (d, JCF = 269 Hz), 182.9 (d, JCF = 31 Hz)
19F-NMR (471 MHz, CDCl3/C6F6) 44.5 (1F, dd, JFH = 45.7, 14.6 Hz) ppm
MS (70 eV) m/z 176 ( M+; 67), 103 (100), 77 (70)
HRMS calcd for C11H9OF 176.0637 (M+); found 176.0609.
【００１６】
【発明の効果】
本発明製造法によれば、含フッ素シクロペンテノン誘導体を高選択的に高収率で製造することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a cyclopentenone derivative and a cyclopentenone derivative.
[0002]
[Prior art]
Since cyclopentenone derivatives can be intermediates for producing various physiologically active compounds such as prostaglandin derivatives, development of efficient production methods for such cyclopentenone derivatives is desired.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide a production method for producing a cyclopentenone derivative with high selectivity and a high yield, and a cyclopentenone derivative.
[0004]
[Means for Solving the Problems]
As a result of diligent study, the inventors of the present invention converted trimethylsilicon (1 +) = chlorotris (trifluoromethanesulfonate) borate (1-) (hereinafter, TMSB (OTf)) into a divinyl = ketone derivative represented by the following general formula 4 3 Cl) or trimethyl silicon (1 +) = tetrakis (trifluoromethanesulfonate) borate (1-) (hereinafter referred to as TMSB (OTf) 4 ), and represented by the following general formula 5 It has been found that a fluorine-containing cyclopentenone derivative can be produced with high selectivity and high yield, and has led to the present invention.
That is, the present invention has the general formula
[Formula 4]
General formula in which TMSB (OTf) 3 Cl or TMSB (OTf) 4 is allowed to act on the divinyl ketone derivative represented by formula 5
[Chemical formula 5]
A method for producing a fluorine-containing cyclopentenone derivative represented by the formula (hereinafter referred to as the production method of the present invention) is provided.
The present invention further relates to a general formula
[Chemical 6]
The fluorine-containing cyclopentenone derivative shown by these is provided.
[0005]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the production method of the present invention will be described in detail.
The production method of the present invention is carried out by allowing TMSB (OTf) 3 Cl or TMSB (OTf) 4 to act on the divinyl-ketone derivative represented by the general formula 4.
The reaction is usually performed in an inert solvent under an inert gas atmosphere.
The range of reaction temperature is -80 ° C to 100 ° C, and the range of reaction time is 0.1 hour to 30 hours.
The amount of the reagent used for the reaction is 0.8 to 1.5 mol of TMSB (OTf) 3 Cl or TMSB (OTf) 4 with respect to 1 mol of the divinyl = ketone derivative represented by the general formula 4. Is the ratio.
Examples of the inert gas include nitrogen gas and argon.
Examples of the solvent include halogenated hydrocarbons such as dichloromethane, hydrocarbons such as toluene, hexane, and cyclohexane, ethers such as diethyl ether and tetrahydrofuran (hereinafter referred to as THF), or a mixture thereof. Solvent.
After completion of the reaction, the target compound can be obtained by performing post-treatment operations such as organic solvent extraction and concentration after adding water or a saturated aqueous sodium bicarbonate solution. The compound can be further purified by operations such as chromatography and distillation.
[0006]
The divinyl ketone derivative represented by the general formula 4 can be produced, for example, according to the method described in Bull. Chem. Soc. Jpn., 1992, 65, 2800-2806, etc.
TMSB (OTf) 3 Cl and TMSB (OTf) 4 are described in, for example, Angew. Chem., Int. Ed. Engl., 1992, 31, 470-471, Tetrahedron Letters, 1996, 37, 9401-9402, etc. It can be produced according to the method.
[0007]
As the fluorine-containing cyclopentenone derivative represented by the general formula 5 obtained by the production method of the present invention, for example,
3,4-dibutyl-2-fluoro-2-cyclopentenone 3-ethyl-2-fluoro-4-phenyl-2-cyclopentenone 2-fluoro-3-isopropyl-4-phenyl-2-cyclopentenone 2 -Fluoro-4-phenyl-2-cyclopentenone 3,5-diethyl-2-fluoro-4-propyl-2-cyclopentenone 2-fluoro-3,4-diphenyl-2-cyclopentenone .
Further, as the divinyl = ketone derivative represented by the general formula 4 used in the production method of the present invention, for example,
6-Fluoro-5,8-tridecadiene-7-one 4-fluoro-1-phenyl-1,4-heptadien-3-one 4-fluoro-6-methyl-1-phenyl-1,4-heptadiene-3- On 4-fluoro-1-phenyl-1,4-pentadiene-3-one 6-ethyl-4-fluoro-3,6-decadien-5-one 1,5-diphenyl-2-fluoro-1,4-pentadiene -3-one etc. are mentioned.
[0008]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these examples.
Example 1 Preparation of 3,4-dibutyl-2-fluoro-2-cyclopentenone A solution of 6-fluoro-5,8-tridecadien-7-one 51 mg (0.24 mmol) in 3 ml of dichloromethane was added at room temperature under a nitrogen atmosphere. Then, 0.82 ml (0.24 mmol) of a solution of TMSB (OTf) 4 in dichloromethane (concentration 0.29M) was added. After stirring the mixture for 15 minutes, a saturated aqueous sodium bicarbonate solution was added. After the aqueous layer was extracted three times with dichloromethane, the extracts were combined, washed successively with a saturated aqueous sodium bicarbonate solution and brine, dried over Na 2 SO 4 , and the solvent was distilled off under reduced pressure. Is subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate: hexane = 1: 5) to obtain 45 mg (0.21 mmol) of 3,4-dibutyl-2-fluoro-2-cyclopentenone as a pale yellow liquid. It was. Yield 89%.
1 H-NMR (500 MHz, CDCl 3 ) δ 0.92 (3H, t, J = 7.3 Hz), 0.95 (3H, t, J = 7.3 Hz), 1.18-1.44 (7H, m), 1.44-1.54 (1H , m), 1.54-1.64 (1H, m), 1.73-1.82 (1H, m), 2.09 (1H, d, J = 18.9 Hz), 2.19-2.28 (1H, m), 2.54 (1H, dd, J = 18.9, 6.0 Hz), 2.53-2.62 (1H, m), 2.69-2.75 (1H, m)
19 F-NMR (471MHz, CDCl 3 / C 6 F 6 ) 16.3 (1F, d, J = 5Hz) ppm
MS (70 eV) m / z 212 (M + ; 81), 155 (61), 114 (100), 85 (59)
HRMS calcd for C 13 H 21 OF 212.1576 (M + ); found 212.1563
[0009]
Example 2 Preparation of 3-ethyl-2-fluoro-4-phenyl-2-cyclopentenone 4-fluoro-1-phenyl-1,4-heptadien-3-one 60 mg (0.51 mmol) in a 3 ml dichloromethane solution Under a nitrogen atmosphere, 1.25 ml (0.51 mmol) of TMSB (OTf) 4 in dichloromethane (concentration 0.41 M) was added at room temperature. After stirring the mixture for 15 minutes, a saturated aqueous sodium bicarbonate solution was added. After the aqueous layer was extracted three times with dichloromethane, the extracts were combined, washed successively with a saturated aqueous sodium bicarbonate solution and brine, dried over Na 2 SO 4 , and the solvent was distilled off under reduced pressure. Is subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate: hexane = 1: 5), and 90 mg (0.44 mmol) of 3-ethyl-2-fluoro-4-phenyl-2-cyclopentenone is pale yellow liquid. Got as. Yield 88%.
IR (neat) 2980, 1725, 1665, 1455, 1355, 1105, 1065, 705 cm -1
1 H-NMR (500 MHz, CDCl 3 ) δ 1.05 (3H, t, J = 7.6 Hz), 2.02 (1H, br dq, J = 15.2, 7.6 Hz), 2.36 (1H, d, J = 19.0 Hz) , 2.47 (1H, dq, J = 15.2, 7.6 Hz), 2.92 (1H, dd, J = 19.0, 6.1 Hz), 3.92 (1H, dd, J = 6.1 Hz, J HF = 6.1 Hz), 7.15 (2H , br d, J = 7.3 Hz), 7.28 (1H, br t, J = 7.3 Hz), 7.35 (2H, br t, J = 7.3 Hz)
13 C-NMR (126 MHz, CDCl 3 ) δ 10.9 (d, J CF = 2 Hz), 19.9, 41.6 (d, J CF = 5 Hz), 42.1 (d, J CF = 4 Hz), 127.2, 127.5 , 129.1, 140.3 (d, J CF = 2 Hz), 155.0 (d, J CF = 277 Hz), 156.9 (d, J CF = 4 Hz), 197.5 (d, J CF = 19 Hz)
19 F-NMR (471 MHz, CDCl 3 / C 6 F 6 ) 16.8 (1F, d, J = 5 Hz) ppm
MS (70 eV) m / z 204 (M + ; 40), 175 (100), 147 (29), 77 (26)
HRMS calcd for C 13 H 13 OF 204.0950 (M + ); found 204.0950
[0010]
Example 3 Preparation of 2-fluoro-3-isopropyl-4-phenyl-2-cyclopentenone
To a solution of 4-fluoro-6-methyl-1-phenyl-1,4-heptadien-3-one 52 mg (0.23 mmol) in dichloromethane 3 ml at room temperature under a nitrogen atmosphere, a solution of TMSB (OTf) 4 in dichloromethane (concentration) 0.55M) 0.43 ml (0.24 mmol) was added. After stirring the mixture for 15 minutes, a saturated aqueous sodium bicarbonate solution was added. After the aqueous layer was extracted three times with dichloromethane, the extracts were combined, washed successively with a saturated aqueous sodium bicarbonate solution and brine, dried over Na 2 SO 4 , and the solvent was distilled off under reduced pressure. Was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate: hexane = 1: 5), and 38 mg (0.18 mmol) of 2-fluoro-3-isopropyl-4-phenyl-2-cyclopentenone was obtained as a pale yellow liquid. Got as. Yield 74%.
IR (neat) 2971, 1724, 1658, 1456, 1315, 1070, 701 cm -1
1 H-NMR (500 MHz, CDCl 3 ) δ 1.05 (3H, d, J = 7.0 Hz), 1.12 (3H, dd, J = 7.0 Hz, J HF = 1.5 Hz), 2.35 (1H, d, J = 19.0 Hz), 2.48 (1H, sept, J = 7.0 Hz), 2.90 (1H, dd, J = 19.0, 7.0 Hz), 3.94 (1H, br dd, J = 7.0 Hz, J HF = 7.0 Hz), 7.17 (2H, br d, J = 7.3 Hz), 7.25-7.31 (1H, m), 7.34 (2H, br t, J = 7.3 Hz)
13 C-NMR (126 MHz, CDCl 3 ) δ 19.7 (d, J CF = 3 Hz), 20.6 (d, J CF = 2 Hz), 28.4 (d, J CF = 2 Hz), 41.9 (d, J CF = 6 Hz), 42.3 (d, J CF = 4 Hz), 127.4, 127.6, 129.0, 140.8 (d, J CF = 2 Hz), 154.9 (d, J CF = 277 Hz), 160.3, 198.0 (d , J CF = 20 Hz)
19 F-NMR (471 MHz, CDCl 3 / C 6 F 6 ) 19.4 (1F, d, J = 5 Hz) ppm
MS (70 eV) m / z 218 (M + ; 64), 175 (100), 140 (81)
HRMS calcd for C 14 H 15 OF 218.1107 (M + ); found 218.1087
[0011]
Example 4 Preparation of 2-fluoro-4-phenyl-2-cyclopentenone To a solution of 42 mg (0.24 mmol) of 4-fluoro-1-phenyl-1,4-pentadien-3-one in 3 ml of dichloromethane under a nitrogen atmosphere At room temperature, 0.81 ml (0.24 mmol) of a solution of TMSB (OTf) 4 in dichloromethane (concentration 0.29M) was added. After stirring the mixture for 15 minutes, a saturated aqueous sodium bicarbonate solution was added. After the aqueous layer was extracted three times with dichloromethane, the extracts were combined, washed successively with a saturated aqueous sodium bicarbonate solution and brine, dried over Na 2 SO 4 , and the solvent was distilled off under reduced pressure. Was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate: hexane = 1: 5) to obtain 33 mg (0.19 mmol) of 2-fluoro-4-phenyl-2-cyclopentenone as a colorless solid. Yield 79%.
IR (KBr disk) 2929, 1731, 1648, 1340, 1078, 765, 701 cm -1
1 H-NMR (500 MHz, CDCl 3 ) δ 2.40 (1H, dd, J = 19.4, 1.8 Hz), 2.99 (1H, dd, J = 19.4, 6.4 Hz), 4.03-4.09 (1H, m), 7.00 (1H, d, J = 2.8 Hz), 7.18 (2H, dt, J = 7.3, 1.6 Hz), 7.29 (1H, tt, J = 7.3, 1.6 Hz), 7.36 (2H, br t, J = 7.3 Hz )
13 C-NMR (126 MHz, CDCl 3 ) δ 38.7 (d, J CF = 6 Hz), 42.5 (d, J CF = 4 Hz), 126.9, 127.6, 129.1, 138.8 (d, J CF = 6 Hz) , 140.9 (d, J CF = 2 Hz), 158.8 (d, J CF = 284 Hz), 198.3 (d, J CF = 19 Hz)
19 F-NMR (471 MHz, CDCl 3 / C 6 F 6 ) 23.1 (1F, d, J = 6 Hz) ppm
MS (70 eV) m / z 176 (M + ; 100), 147 (58), 133 (44)
[0012]
Example 5 Preparation of 3,5-diethyl-2-fluoro-4-propyl-2-cyclopentenone 6-ethyl-4-fluoro-3,6-decadien-5-one 60 mg (0.30 mmol) in dichloromethane 3 ml To the solution, 1.2 ml (0.31 mmol) of a solution of TMSB (OTf) 4 in dichloromethane (concentration 0.26M) was added at room temperature under a nitrogen atmosphere. After stirring the mixture for 15 minutes, a saturated aqueous sodium bicarbonate solution was added. The aqueous layer was extracted three times with dichloromethane, and the extracts were combined, washed with a saturated aqueous sodium bicarbonate solution and brine, dried over Na 2 SO 4 , and the solvent was distilled off under reduced pressure. Was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate: hexane = 1: 5), and 39 mg (0.20 mmol) of 3,5-diethyl-2-fluoro-4-propyl-2-cyclopentenone was palely added. Obtained as a yellow liquid. Yield 65%.
IR (neat) 2962, 2933, 2875, 1722, 1688, 1461, 1380, 1355, 1116, 1022cm -1
13 C-NMR (126 MHz, CDCl 3 ) major isomer: δ 10.8, 11.2 (d, J CF = 2 Hz), 14.3, 19.5, 19.9, 24.8, 34.9 (d, J CF = 2 Hz), 41.3 (d , J CF = 3 Hz), 49.8 (d, J CF = 4 Hz), 153.6 (d, J CF = 277 Hz), 157.4 (d, J CF = 3 Hz), 200.5 (d, J CF = 17 Hz )
19 F-NMR (471 MHz, CDCl 3 / C 6 F 6 ) for 8/2 mixture 14.9 (0.2F, d, J = 5 Hz), 16.0 (0.8F, d, J = 6 Hz) ppm
[0013]
Example 6 Preparation of 2-fluoro-3,4-diphenyl-2-cyclopentenone To a solution of 62 mg (0.25 mmol) of 1,5-diphenyl-2-fluoro-1,4-pentadien-3-one in 3 ml of dichloromethane Then, 0.45 ml (0.25 mmol) of a solution of TMSB (OTf) 4 in dichloromethane (concentration 0.55 M) was added at room temperature under a nitrogen atmosphere. After stirring the mixture for 15 minutes, a saturated aqueous sodium bicarbonate solution was added. The aqueous layer was extracted three times with dichloromethane, and the extracts were combined, washed with a saturated aqueous sodium bicarbonate solution and brine, dried over Na 2 SO 4 , and the solvent was distilled off under reduced pressure. Was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate: hexane = 1: 5) to obtain 36 mg (0.14 mmol) of 2-fluoro-3,4-diphenyl-2-cyclopentenone as a colorless solid. . Yield 48%.
IR (KBr disk) 1716, 1635, 1361, 1078, 701, 688 cm -1
19 F-NMR (471 MHz, CDCl 3 / C 6 F 6 ) 25.1 (1F, d, J = 6 Hz) ppm
MS (70 eV) m / z 252 (M + ; 100), 223 (63), 146 (58), 120 (50)
[0014]
Reference Production Example 1 Production of 4-fluoro-1-phenyl-1,4-heptadien-3-one 1.25 g of 4-fluoro-1-phenyl-4- (phenylsulfinyl) 1-hepten-3-one (3. 8 mmol) in 10 ml of benzene was heated to reflux for 1 hour. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate: hexane = 1: 20) to give 4-fluoro-1-phenyl-1,4-heptadiene-3- 431 mg (2.0 mmol) of on was obtained as a yellow liquid. Yield 56%.
IR (neat) 2960, 1650, 1600, 1570, 1450, 1330, 1200, 1010, 760 cm -1
1 H-NMR (500 MHz, CDCl 3 ) δ 1.11 (3H, t, J = 7.5 Hz), 2.33 (2H, dquint, J = 7.6, 2.1 Hz), 6.18 (1H, dt, J = 34.7, 7.8 Hz ), 7.23 (1H, dd, J = 15.6, 2.1 Hz), 7.38-7.43 (3H, m), 7.58-7.64 (2H, m), 7.80 (1H, d, J = 16.0 Hz)
13 C-NMR (126 MHz, CDCl 3 ) δ 13.0 (d, J CF = 2 Hz), 17.9 (d, J CF = 4 Hz), 119.6, 121.4 (d, J CF = 13 Hz), 128.6, 128.9 , 130.8, 134.5, 145.1 (d, J CF = 2 Hz), 155.5 (d, J CF = 260 Hz), 182.7 (d, J CF = 31 Hz)
19 F-NMR (471 MHz, CDCl 3 / C 6 F 6 ) 31.3 (1F, J FH = 31.3 Hz) ppm
MS (70 eV) m / z 204 (M + ; 44), 131 (69), 103 (100), 77 (57)
HRMS calcd for C 13 H 13 OF 204.0950 (M + ); found 204.0959
[0015]
Reference Production Example 2 Production of 4-fluoro-1-phenyl-1,4-pentadien-3-one 4-fluoro-1-phenyl-4- (phenylsulfinyl) 1-penten-3-one 230 mg (0.76 mmol) Of benzene in 4 ml was heated to reflux for 1 hour. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate: hexane = 1: 5) to give 4-fluoro-1-phenyl-1,4-pentadiene-3- 129 mg (0.73 mmol) of on were obtained as a pale yellow liquid. Yield 96%.
IR (KBr disk) 3103, 3030, 1660, 1640, 1610, 1450, 1360, 1070, 940, 900 cm -1
1 H-NMR (500 MHz, CDCl 3 ) δ 5.30 (1H, dd, J = 14.6, 3.4 Hz), 5.70 (1H, dd, J = 45.8, 3.4 Hz), 7.23 (1H, dd, J = 5.9, 2.1 Hz), 7.397.46 (3H, m), 7.46 (2H, dd, J = 36.6, 3.1 Hz), 7.84 (1H, dd, J = 15.9 Hz)
13 C-NMR (126 MHz, CDCl 3 ) δ 101.6 (d, J CF = 15 Hz), 119.2, 128.2, 129.0, 131.2, 134.3, 146.2 (d, J CF = 2 Hz), 160.6 (d, J CF = 269 Hz), 182.9 (d, J CF = 31 Hz)
19 F-NMR (471 MHz, CDCl 3 / C 6 F 6 ) 44.5 (1F, dd, J FH = 45.7, 14.6 Hz) ppm
MS (70 eV) m / z 176 (M + ; 67), 103 (100), 77 (70)
HRMS calcd for C 11 H 9 OF 176.0637 (M + ); found 176.0609.
[0016]
【The invention's effect】
According to the production method of the present invention, a fluorine-containing cyclopentenone derivative can be produced with high selectivity and high yield.
Claims (1)
で示されるジビニル＝ケトン誘導体に、トリメチルシリコン（１＋）クロロトリス（トリフルオロメタンスルホナト）ボラート（１−）またはトリメチルシリコン（１＋）テトラキス（トリフルオロメタンスルホナト）ボラート（１−）を作用させることを特徴とする、一般式 化２
で示されるシクロペンテノン誘導体の製造法。General formula
And trimethyl silicon (1+) chlorotris (trifluoromethanesulfonate) borate (1-) or trimethylsilicon (1+) tetrakis (trifluoromethanesulfonate) borate (1-). And general formula 2
The manufacturing method of the cyclopentenone derivative shown by these.
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