CN111253303B - 一种合成3-硒-螺(2-环戊烯-1,3-吲哚)-4-酮的方法 - Google Patents
一种合成3-硒-螺(2-环戊烯-1,3-吲哚)-4-酮的方法 Download PDFInfo
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Abstract
本发明公开一种合成3‑硒‑螺(2‑环戊烯‑1,3‑吲哚)‑4‑酮的方法,具体是:在石英试管中依次加入吲哚炔酮0.3 mmol,二硒化物0.3 mmol,醋酸钠NaOAc 0.6 mmol,四氢呋喃THF 3mL,室温,太阳光照射下(或50瓦白光)搅拌反应。TLC跟踪监测,反应结束后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚=1:5)得产物。该反应在空气中进行,原料易得,无需使用过渡金属和氧化剂,不会引起安全问题和重金属残留问题,操作简便,产率可观,环境友好,具有良好的应用前景。
Description
技术领域
本发明涉及螺吲哚啉硒化合物的合成方法,具体是一种合成3-硒-螺(2-环戊烯-1,3-吲哚)-4-酮的方法。
背景技术
硒具有抗癌、抗氧化、调节蛋白质的合成等功能,有重要的生理学意义,因此含硒的化合物拥有广泛的药理活性《J. Med. Chem., 2016, 59, 1946–1959》。氮杂环化合物已被FDA证实在药物化学中的重要意义《E. Vitaku, D. T. Smith, J. T. Njardarson, J.Med. Chem. 2014, 57, 10257-10274》,而螺旋环化合物因其刚性和三维结构而受到广泛关注《(a) S. Mondal, S. R. Yetra, S. Mukherjee, A. T. Biju, Acc. Chem. Res.2019, 52, 425-436》。螺吲哚类药物是一种常见的结构支架,具有多种药理作用,存在于一系列具有生物活性的天然产物中,且在药物发现研究中占有突出地位《M. J. James, P.O’Brien, R. J. K. Taylor and W. P. Unsworth, Chem. Eur. J. 2016, 22, 2856-2881》。
发明内容
本发明的目的是提供一种绿色、方便快捷合成3-硒-螺(2-环戊烯-1,3-吲哚)-4-酮的方法。
实现本发明目的的技术方案是:
一种合成3-硒-螺(2-环戊烯-1,3-吲哚)-4-酮的方法,其合成方法通式如下:
R1为卤素、吸电子基、供电子基;
R2为芳基、烷基、杂环基等;
R3为芳基、杂环基;
合成方法,包括如下步骤:
(1)石英试管中依次加入吲哚炔酮0.3 mmol,二硒化物0.3 mmol,醋酸钠NaOAc0.6 mmol,四氢呋喃THF 3mL,空气氛围中,在太阳光或50瓦白光照射下,室温搅拌反应3 h,TLC跟踪监测;
(2)待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化粗品得产物。
步骤(2)所述快速柱色谱法纯化,洗脱剂为乙酸乙酯:石油醚 = 1:5。
本发明公开一种优良的合成螺环硒化合物的新方法,通过光引发合成含螺吲哚啉骨架的有机硒化合物,该方法中所需原料易得,反应中无过渡金属和氧化剂,不会引起安全问题和重金属残留问题,操作简单,产率可观,环境友好,有良好的应用前景。
具体实施方式
下面结合实施例中合成的12种3-硒-螺(2-环戊烯-1,3-吲哚)-4-酮化合物及结构表征对本发明内容作进一步的说明,但不是对本发明的限定。
实施例1:
2-苯基-3-(苯硒基)-螺(2-环戊烯-1,3-吲哚)-4-酮的合成:
石英试管中依次加入4-苯基-1-(1H-3-吲哚基)-3-丁炔-2-酮0.3 mmol,二苯基二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)中室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚 = 1:5),得黄色固体产物,熔点59-60 oC,产率81%;
1H NMR (400 MHz, CDCl3) δ = 7.98 (s, 1H), 7.50 (d, J = 7.7, 1H), 7.35– 7.24 (m, 3H), 7.23 – 7.15 (m, 2H), 7.08 – 6.99 (m, 4H), 6.98 – 6.92 (m,2H), 6.68 – 6.64 (m, 2H), 3.05 (d, J = 18.7, 1H), 2.72 (d, J = 18.7, 1H).13CNMR (100 MHz, CDCl3) δ = 201.7, 172.5, 172.1, 155.2, 139.4, 135.2, 133.1,133.0, 129.7, 129.0, 128.9, 127.9, 127.7, 127.5, 127.3, 126.5, 121.7, 121.5,67.5, 40.4。
实施例2:
2-(4-甲基苯基)-3-苯硒基-螺(2-环戊烯-1,3-吲哚)-4-酮的合成:
石英试管中依次加入4-(4-甲基苯基)-1-(1H-3-吲哚基)-3-丁炔-2-酮0.3 mmol,二苯基二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)中室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚 = 1:5),得黄色固体产物,熔点162-163 oC,产率75%;
1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.36– 7.32 (m, 3H), 7.25 – 7.21 (m, 2H), 7.14 – 7.10 (m, 3H), 6.82 (d, J = 8.1Hz, 2H), 6.63 (d, J = 8.1 Hz, 2H), 3.08 (d, J = 18.6 Hz, 1H), 2.74 (d, J =18.6 Hz, 1H), 2.14 (s, 3H).13C NMR (100 MHz, CDCl3) δ 201.7, 172.8, 172.5,155.3, 140.2, 139.7, 134.4, 132.9, 130.2, 129.0, 128.9, 128.7, 128.1, 127.5,127.4, 126.6, 121.8, 121.5, 67.4, 40.6, 21.2。
实施例3:
2-环丙基-3-苯硒基-螺(2-环戊烯-1,3-吲哚)-4-酮的合成:
石英试管中依次加入4-环丙基-1-(1H-3-吲哚基)-3-丁炔-2-酮0.3 mmol,二苯基二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)中室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚 = 1:5),得黄色固体产物,熔点110-111 oC,产率78%;
1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.50(m, 3H), 7.39-7.34 (m, 1H), 7.33-7.25 (m , 4H), 3.01 (d, J = 18.7 Hz, 1H),2.68 (d, J = 18.7 Hz, 1H), 1.57-1.49 (m, 1H), 1.08-1.01 (m, 1H), 0.82-0.73(m, 2H), 0.72-0.64 (m, 1H).13C NMR (100 MHz, CDCl3) δ 201.8, 172.6, 170.5,164.5, 162.0, 155.4, 139.4, 135.7, 133.4, 129.3, 129.2, 129.1, 128.9, 128.8,127.8, 127.6, 127.6, 122.0, 121.6, 115.4, 115.2, 67.7, 40.4。
实施例4:
2-(2-噻吩基)-3-苯硒基-螺(2-环戊烯-1,3-吲哚)-4-酮的合成:
在石英试管中依次加入1-(1H-3-吲哚基)-4-噻吩基-3-丁炔-2-酮0.3 mmol,二苯基二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)中室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚 = 1:5),得黄色固体产物,熔点164-165 oC,产率60%;
1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.60– 7.41 (m, 4H), 7.35 – 7.22 (m, 5H), 6.85 – 6.82 (t, J = 4.72Hz, 1H), 6.75(d, J = 3.7 Hz, 1H), 3.10 (d, J = 18.7 Hz, 1H), 2.75 (d, J = 18.7 Hz, 1H).13CNMR (100 MHz, CDCl3) δ 200.5, 174.2, 162.9, 154.7, 141.2, 134.5, 132.5,131.9, 131.6, 130.8, 129.2, 129.2, 128.9, 127.7, 127.5, 127.4, 122.1, 121.5,66.4, 40.7。
实施例5:
2-(4-甲氧基苯基)-3-苯硒基-螺(2-环戊烯-1,3-吲哚)-4-酮的合成:
在石英试管中依次加入4-(4-甲氧基苯基)-1-(1H-3-吲哚基) -3-丁炔-2-酮0.3mmol,二苯基二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)中室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚 = 1:3),得黄色固体产物,熔点108-109 oC,产率83%;
1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.42– 7.36(m, 3H), 7.31 – 7.22 (m, 2H), 7.19 – 7.12 (m, 3H), 6.78 (d, J = 8.8 Hz,2H), 6.57 (d, J = 8.8 Hz, 2H), 3.66 (s, 3H), 3.12 (d, J = 18.5 Hz, 1H), 2.76(d, J = 18.5 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 201.5, 173.1, 171.6, 160.8,155.1, 140.0, 133.3, 132.6, 129.0, 128.9, 128.6, 128.2, 127.4, 127.4, 125.4,121.8, 121.4, 113.4, 67.3, 55.0, 40.7。
实施例6:
2-苯基-5-溴-3-苯硒基-螺(2-环戊-烯-1,3-吲哚)-4-酮的合成:
在石英试管中依次加入4-苯基-1-(5-溴-1H-3-吲哚基)- 3-丁炔-2-酮0.3 mmol,二苯基二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)中室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚 = 1:5),得黄色油状产物,熔点183-184 oC,产率74%;
1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.53 – 7.43 (m, 2H), 7.40 –7.35 (m, 3H), 7.22 – 7.12 (m, 4H), 7.11 – 7.05 (m, 2H), 6.77 (d, J = 7.5 Hz,2H), 3.13 (d, J = 18.6 Hz, 1H), 2.79 (d, J = 18.6 Hz, 1H).13C NMR (100 MHz,CDCl3) δ 201.1, 172.9, 170.7, 154.2, 141.7, 135.9, 133.5, 132.8, 132.2,129.9, 129.0, 128.1, 127.8, 127.4, 126.5, 125.0, 123.1, 121.2, 77.3, 67.7,40.3。
实施例7:
2-(4-氟苯基)-3-苯硒基-螺(2-环戊烯-1,3-吲哚)-4-酮的合成:
在石英试管中依次加入4-(4-氟苯基)-1-(1H-3-吲哚基)-3-丁炔-2-酮0.3 mmol,二苯基二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)中室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚 = 1:5),得黄色固体产物,熔点151-152 oC,产率90%。
1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.43– 7.31 (m, 3H), 7.31 – 7.25 (m, 2H), 7.17 – 7.08 (m, 3H), 6.75 – 6.64 (m,4H), 3.15 (d, J = 18.7 Hz, 1H), 2.82 (d, J = 18.7 Hz, 1H).13C NMR (100 MHz,CDCl3) δ 201.6, 172.4, 170.3, 164.3, 161.8, 155.2, 139.2, 135.6, 133.2,129.1,δ 129.0 (d, J = 3.4 Hz), 128.7, 128.6, 127.6, 127.4 (d, J = 5.0 Hz),121.6 (d, J = 33.5 Hz), 115.1 (d, J = 21.8 Hz), 67.5, 40.2。
实施例8:
5-甲氧基-2-苯基-3-苯硒基-螺(2-环戊烯-1,3-吲哚)-4-酮的合成:
在石英试管中依次加入4-苯基-1-(5-甲氧基-1H-3-吲哚基)-3-丁炔-2-酮0.3mmol,二苯基二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚 = 1:3),得黄色固体产物,熔点150-151 oC,产率70%;
1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.37(dd, J = 7.7, 1.4 Hz, 2H), 7.21 – 6.99 (m, 7H), 6.87 (dd, J = 8.5, 2.4 Hz,1H), 6.82 – 6.71 (m, 3H), 3.77 (s, 3H), 3.13 (d, J = 18.7 Hz, 1H), 2.77 (d, J= 18.7 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 201.7, 172.3 , 170.2, 159.4, 148.8,141.2, 135.0, 133.0, 133.0, 129.7, 128.9, 127.9, 127.8, 127.5, 126.6, 122.1,113.8, 107.6, 67.4, 55.6, 40.8。
实施例9:
2-苯基-3-((4-氯苯基)硒基)-螺(2-环戊烯-1,3-吲哚)-4-酮的合成:
在石英试管中依次加入4-苯基-1-(1H-3-吲哚基)- 3-丁炔-2-酮0.3 mmol,1,2-双(4-氯苯基)二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚 = 1:5),得黄色固体产物,熔点184-185 oC,产率84%;
1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.56 (d, J = 7.1 Hz, 1H),7.51 (d, J = 7.1 Hz, 1H), 7.40 – 7.25 (m, 6H), 7.19 (t, J = 7.3 Hz, 1H), 7.12(t, J = 7.3 Hz, 2H), 6.80 (d, J = 7.2 Hz, 2H), 3.29 (d, J = 18.6 Hz, 1H),2.89 (d, J = 18.6 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 201.5, 174.0, 173.8,155.4, 139.3, 133.7, 133.3, 133.1, 131.9, 129.4, 129.0, 128.9, 127.8, 127.4,127.0, 126.4, 122.7, 120.9, 67.7, 40.1。
实施例10:
2-苯基-3-((4-甲氧基)硒基)-螺(2-环戊烯-1,3-吲哚)-4-酮的合成:
在石英试管中依次加入4-苯基-1-(1H-3-吲哚基)- 3-丁炔-2-酮0.3 mmol,1,2-双(4-甲氧基苯基)二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)中室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚=1:5),得黄色油状产物,产率70%;
1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.35– 7.27 (m, 3H), 7.25 – 7.19 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.01 (t, J =7.6 Hz, 2H), 6.69 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 3.69 (s,3H), 3.08 (d, J = 18.7 Hz, 1H), 2.74 (d, J = 18.7 Hz, 1H). 13C NMR (100 MHz,CDCl3) δ 201.9, 172.5, 170.8, 159.5, 155.2, 139.4, 136.0, 135.9, 133.1,129.5, 128.9, 127.8, 127.3, 126.5, 121.6, 121.5, 117.2, 114.5, 67.4, 55.1,40.3。
实施例11:
2-苯基-3-((3-氟)硒基)-螺(环戊(2)烯-1,3-吲哚)-4-酮的合成:
在石英试管中依次加入4-苯基-1-(1H-3-吲哚基)- 3-丁炔-2-酮0.3 mmol,1,2-双(3-氟苯基)二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)中室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚=1:5),得黄色固体产物,熔点64-65 oC,产率71%。
1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.61 – 7.56 (m, 1H), 7.52(d, J = 7.4 Hz, 1H), 7.38 – 7.09 (m, 9H), 7.05 – 7.00 (m, 1H), 6.84 – 6.79(m, 2H), 3.33 (d, J = 18.6 Hz, 1H), 2.92 (d, J = 18.6 Hz, 1H). 13C NMR (100MHz, DMSO-d6) δ 201.5, 174.5, 173.8, 162.0 (d, J = 247.1 Hz), 155.5, 139.4,133.4, 133.3, 130.8 (d, J = 2.4 Hz), 130.7 (d, J = 3.4 Hz), 129.5, 128.9,127.8, 127.0, 126.9 (d, J = 2.7 Hz), 126.4, 122.7, 120.9, 117.7 (d, J = 23.0Hz), 113.8 (d, J = 21.1 Hz), 67.8, 39.7。
实施例12:
2-苯基-3-((2-甲基)硒基(-螺(环戊(2)烯-1,3-吲哚)-4-酮的合成:
在石英试管中依次加入4-苯基-1-(1H-3-吲哚基)- 3-丁炔-2-酮0.3 mmol,1,2-双(2-甲基苯基)二硒醚0.3 mmol,NaOAc 0.6 mmol,THF 3mL,在空气中反应,在阳光(或50瓦白光)中室温搅拌3 h,TLC跟踪监测;待反应完成后,将混合物减压浓缩,并通过快速柱色谱法纯化残余物(乙酸乙酯:石油醚=1:5),得黄色固体产物,熔点70-71 oC,产率43%;
1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.56 – 7.50 (m, 2H), 7.37 –7.29 (m, 3H), 7.14 – 7.07 (m, 6H), 6.81 – 6.76 (m, 2H), 3.31 (d, J = 18.6 Hz,1H), 2.90 (d, J = 18.6 Hz, 1H), 2.25 (s, 3H). 13C NMR (100MHz, DMSO-d6) δ201.6, 174.0, 173.9, 155.4, 139.4, 138.1, 133.8, 133.3, 131.8, 130.0, 129.4,129.3, 128.9, 127.8, 127.2, 127.0, 126.7, 126.3, 122.6, 120.9, 67.8, 39.7,21.7。
对实施例的有机硒类化合物,通过体外抗肿瘤活性筛选,发现大部分化合物均具有较好的抗肿瘤活性,对胃癌细胞(MGC-803)、宫颈癌细胞(HeLa)、膀胱癌细胞(T-24)体外增殖进行测试,结果显示实施例2、实施例5、实施例7的化合物能有效的抑制肿瘤细胞的生长。实施例2和实施例5作用于MGC-803的IC50分别是7.2 μM、6.7 μM;实施例5和实施例7作用于HeLa的IC50分别是5.2 μM、7.6 μM;实施例7作用于T-24的IC50是8.0 μM,如下表所示:
另外,本发明化合物合成操作简单,原料易得,产率高,应用前景广泛。
Claims (2)
2.根据权利要求1所述的合成含 3-硒-螺(2-环戊烯-1,3-吲哚)-4-酮的方法,其特征在于:步骤(2)所述快速柱色谱法纯化,洗脱剂为乙酸乙酯:石油醚= 1:5。
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