CN110343042B - 一种2-((9-氢芴-9-基)甲基)丙二酸酯的合成方法 - Google Patents

一种2-((9-氢芴-9-基)甲基)丙二酸酯的合成方法 Download PDF

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CN110343042B
CN110343042B CN201910555223.7A CN201910555223A CN110343042B CN 110343042 B CN110343042 B CN 110343042B CN 201910555223 A CN201910555223 A CN 201910555223A CN 110343042 B CN110343042 B CN 110343042B
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李欢
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Abstract

本发明公开了2‑((9‑氢芴‑9‑基)甲基)丙二酸酯的合成方法。本发明通过三氟甲磺酸催化作用实现了2‑联芳基环丙基‑1,1‑二羧酸酯的开环环化反应合成了2‑((9‑氢芴‑9‑基)甲基)丙二酸酯。具体方法为使用六氟异丙醇做为反应溶剂，加入1～100mol％的三氟甲磺酸，在70℃加热条件下反应得到目标产物。本发明使用的原料容易制备，操作简单，收率高，普适性很广，方法可靠。

Description

一种2-((9-氢芴-9-基)甲基)丙二酸酯的合成方法
技术领域
本发明涉及有机化学合成技术领域，具体是指一种2-((9-氢芴-9-基)甲基)丙二酸酯的合成方法。
背景技术
含有3-(9-氢芴-9-基)丙酰基结构的化合物在药物化学有重要的应用价值。Smith等人合成了一种3-(9-氢芴-9-基)丙酸酯结构的化合物，对哺乳动物核糖核苷酸还原酶具有很强的抑制作用，IC50＝40-50μM(Bioorg.Med.Chem.Lett.2005,15,5146–5149)。Vederas等人合成了含有3-(9-氢芴-9-基)丙酰胺结构的多肽，对大肠杆菌和空肠弯曲菌具有较好的抑制作用(J.Med.Chem.2014,57,1127-1131)。
目前3-(9-氢芴-9-基)丙酸或其酯的合成方法都需要以9-氢芴或其类似物作为原料出发。Matsumoto等人使用9-氢芴和丙烯酸乙酯在四丁基氟化铵作用下制得3-(9-氢芴-9-基)丙酸乙酯，但收率仅有4％，而且有一些双加成的产物生成(Synthesis,1984,164-166)。
Figure BDA0002106687440000011
Ulijn等人使用类似的方法，将9-氢芴和3-溴丙酸甲酯在氢化钠作用下反应制得3-(9-氢芴-9-基)丙酸乙酯，但收率仅有20％(Chem.Commun.2013,49,10587-10589)。
Figure BDA0002106687440000012
Amin等人先将苯并芴制成苯并芴基甲酸酯，再在碱性条件下可以高效地跟丙烯酸甲酯加成，最后水解脱去跟芴基相连的酯基得到产物。(J.Org.Chem.1984,49,1091-1095；J.Org.Chem.1986,51,1206-1211)。Rice等人使用相同的策略跟丙烯腈加成也到了类似的结果(J.Org.Chem.1987,52,849-855)。该方法可以有效避免多加成产物的生成，但是合成步骤偏长。
Figure BDA0002106687440000021
Gualtieri等人使用9-氢芴-9-甲醛作为底物，先进行Wittig反应，再用钯碳催化氢化还原烯烃得到3-(9-氢芴-9-基)丙酸乙酯(J.Med.Chem.1985,28,1621-1628)。
Figure BDA0002106687440000022
但是使用Wittig试剂会产生大量的反应废弃物，而且使用昂贵的过渡金属也使得方法的经济性较差。
发明内容
本发明实施例所要解决的技术问题在于，提供一种原子经济性高，收率高，官能团兼容性好的2-((9-氢芴-9-基)甲基)丙二酸酯的合成方法。
为实现上述目的，本发明的技术方案是：在氮气氛围中，在强酸催化条件下，下式(Ⅰ)所示2-联芳基环丙基-1,1-二羧酸酯发生三元环开环和分子内芳基化环化反应，制得(Ⅱ)所示2-((9-氢芴-9-基)甲基)丙二酸酯。其反应式为：
Figure BDA0002106687440000031
上述式中，R是Et、Me、i-Pr；
Ar1是取代芳基，其取代基有甲基、硝基、卤素；
Ar2为取代芳基或杂芳基，芳基取代基有甲基、甲氧基、羟基、甲硫基、卤素、三氟甲基，杂芳基有噻吩、苯并噻吩、吲哚；
所述强酸催化剂为三氟甲磺酸；
所述溶剂为六氟异丙醇；
以摩尔比计算，式(Ⅰ)所示化合物在溶剂中的摩尔浓度为0.01mol/L；
以摩尔比计算，式(Ⅰ)所示化合物与三氟甲磺酸的摩尔比为1:0.01～1:1，一般为1:0.1；
制备(II)所示化合物，反应温度为70℃，反应时间2小时。
本发明人通过深入细致研究，发现一种过量强酸存在的条件下2-联芳基环丙基-1,1-二羧酸酯发生分子内开环环化反应，制得2-((9-氢芴-9-基)甲基)丙二酸酯的方法。该方法原子经济性高，收率高，官能团兼容性好。
本发明具有以下优点和创新之处：
(1)原料(式(Ⅰ)所示化合物)容易制备；
(2)三氟甲磺酸较为廉价，而反应一般仅需要催化量(10mol％)的三氟甲磺酸；
(3)2-((9-氢芴-9-基)甲基)丙二酸酯可以在一定的条件下高效转化为3-(9-氢芴-9-基)丙酸；
(4)这是2-芳基环丙基-1,1-二羧酸酯的分子内开环芳基化反应，适用的底物类型广泛，官能团兼容性优异。
本发明与现有技术相比较的有益效果：
采用本发明方法制备2-((9-氢芴-9-基)甲基)丙二酸酯品质高，收率高；原料(式(Ⅰ)所示化合物)容易制备，反应普适性很好，原子经济性高，反应条件相对温和，产物中带有的丙二酸酯结构适于后期多种衍生化反应。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将结合实施例对本发明作进一步地详细描述。
本实施例所用的原料均参照如下方法分两步合成：
Figure BDA0002106687440000041
第一步：在圆底烧瓶中加入2-联苯甲醛(100mmol)、丙二酸二乙酯(100mmol)、哌啶乙酸盐(10mmol)和甲苯(100mL)，安装油水分离器，加热回流分出反应产生的水。当原料全部反应完全后，减压整理除去溶剂，残留物通过柱层析提纯化，得到所述式所示产物B，产率为87％。
1H NMR(400MHz,CDCl3)δ7.67(s,1H),7.50-7.31(m,9H),4.28(q,J＝7.2Hz,2H),4.25(q,J＝7.2Hz,2H),1.28(t,J＝7.2Hz,3H),1.21(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ166.41,163.88,143.55,142.50,139.76,129.98,129.93,129.70,128.49,128.29,127.78,127.47,127.30,61.45,61.41,14.06,13.84.
Figure BDA0002106687440000042
第二步：在Schlenk瓶中加入NaH(103mmol)，氮气保护，加入N,N-二甲基甲酰胺(160mL)。冰水浴冷却，加入三甲基碘化亚砜(103mmol)，反应0.5小时。加入B(86mmol)的N,N-二甲基甲酰胺溶液(80mL)，先在冰水浴条件下反应0.5小时，再室温反应0.5小时。倒入到冰(100g)和饱和氯化铵溶液(60mL)的混合液中，用乙酸乙酯萃取两次，合并有机相，依次用水合饱和氯化钠溶液洗涤，再用无水硫酸钠干燥，最后减压蒸馏除去溶剂。残留物通过柱层析提纯化，得到所述式所示产物，产率为75％。
1H NMR(400MHz,CDCl3)δ7.46(d,J＝7.4Hz,2H),7.41-7.24(m,6H),7.05(d,J＝7.3Hz,1H),4.21-4.08(m,2H),3.89-3.84(m,2H),2.99(t,J＝8.8Hz,1H),2.19(dd,J＝5.6Hz,J＝8.0Hz,1H),1.65(dd,J＝5.6Hz,J＝9.2Hz,1H),1.22(t,J＝7.2Hz,3H),0.86(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ169.10,166.54,144.02,141.00,131.85,129.84,129.37,127.96,127.21,127.07,126.90,126.06,61.34,61.13,38.71,31.96,18.87,14.13,13.65。
实施例1：
Figure BDA0002106687440000051
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为92％。
1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.4Hz,2H),7.54(d,J＝7.4Hz,2H),7.38(t,J＝7.4Hz,2H),7.31(t,J＝7.4Hz,2H),4.09(m,3H),3.99-3.94(m,2H),3.19(t,J＝7.3Hz,1H),2.68-2.65(m,2H),1.15(t,J＝7.1Hz,6H).13C NMR(125MHz,CDCl3)δ169.36,145.51,141.29,127.40,126.95,124.86,119.91,61.35,48.86,45.34,31.69,13.89。
实施例2：
Figure BDA0002106687440000052
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为89％。
1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.5Hz,2H),7.52(d,J＝7.4Hz,2H),7.38(t,J＝7.3Hz,2H),7.31(t,J＝7.4Hz,2H),4.04(t,J＝5.7Hz,1H),3.52(s,6H),3.15(t,J＝7.2Hz,1H),2.72(dd,J＝5.9Hz,J＝7.0Hz,2H).13C NMR(125MHz,CDCl3)δ169.72,145.21,141.32,127.44,126.95,124.79,119.95,52.36,48.25,45.31,31.57。
实施例3：
Figure BDA0002106687440000061
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为49％。
1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.6Hz,2H),7.55(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.6Hz,2H),4.94-4.85(hept,J＝6.3Hz,1H),3.99(t,J＝6.4Hz,1H),3.21(t,J＝7.2Hz,1H),2.60(t,J＝6.4Hz,2H),1.18(d,J＝6.0Hz,6H),1.12(d,J＝6.0Hz,6H).13C NMR(125MHz,CDCl3)δ168.86,145.77,141.18,127.35,126.93(2C),124.92,119.89,68.88,49.48,45.33,31.71,21.52,21.47。
实施例4：
Figure BDA0002106687440000062
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为92％。
1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.5Hz,1H),7.63(d,J＝7.7Hz,1H),7.51(d,J＝7.4Hz,1H),7.37-7.34(m,2H),7.28-7.25(m,1H),7.18(d,J＝7.7Hz,1H),4.10-4.02(m,2H),3.99-3.91(m,3H),3.23(t,J＝7.3Hz,1H),2.69-2.57(m,2H),2.43(s,3H),1.17(t,J＝7.2Hz,3H),1.16(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)δ169.38,145.83,145.39,141.37,138.64,136.82,128.22,127.32,126.43,125.50,124.81,119.64,119.57,61.32,61.30,48.94,45.15,31.81,21.63,13.89。
实施例5：
Figure BDA0002106687440000071
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为93％。
1H NMR(400MHz,CDCl3)δ7.65(d,J＝3.0Hz,1H),7.63(d,J＝3.8Hz,1H),7.49(d,J＝7.4Hz,1H),7.34(t,J＝7.4Hz,1H)；7.23(dt,J＝0.8Hz,J＝7.8Hz,1H)；7.08(d,J＝2.1Hz,1H),6.93(dd,J＝2.3Hz,J＝8.3Hz,1H),4.09-4.03(m,2H),4.00-3.93(m,3H),3.87(s,3H),3.21(t,J＝7.2Hz 1H)；2.71-2.57(m,2H),1.16(t,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ169.35,169.33,159.41,147.34,145.00,141.25,134.18,127.37,125.76,124.69,120.59,119.07,113.60,110.39,61.33,55.50,48.76,45.36,31.79,13.88。
实施例6：
Figure BDA0002106687440000081
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为86％。
1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.5Hz,1H),7.65(d,J＝8.0Hz,1H),7.51(d,J＝7.4Hz,1H),7.42(s,1H),7.36(t,J＝7.4Hz,1H),7.30-7.26(m,2H),4.10-4.06(m,2H),4.02-3.94(m,3H),3.17(t,J＝7.2Hz,1H),2.72-2.59(m,2H),2.55(s,3H),1.16(t,J＝7.1Hz,6H).13C NMR(125MHz,CDCl3)δ169.27,169.23,146.27,145.08,140.85,138.65,137.14,127.44,126.72,126.11,124.76,123.14,120.11,119.63,61.35,61.33,48.72,45.21,31.54,16.21,13.85。
实施例7：
Figure BDA0002106687440000082
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.003mmol，0.01摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为83％。
1H NMR(400MHz,CDCl3)δ7.64(d,J＝7.5Hz,1H),7.60(d,J＝8.2Hz,1H),7.48(d,J＝7.5Hz,1H),7.34(t,J＝7.5Hz,1H),7.23(dt,J＝1.0Hz,J＝7.5Hz,1H),7.02(d,J＝2.2Hz,1H),6.87(dd,J＝2.3Hz,J＝8.2Hz,1H),5.46(s,1H),4.11-4.03(m,2H),4.02-3.91(m,3H),3.18(t,J＝7.2Hz,1H),2.68-2.64(m,2H),1.16(t,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ169.90,169.60,155.71,147.34,144.74,141.37,134.03,127.40,125.73,124.61,120.80,118.99,114.87,112.18,61.63,61.54,48.68,45.25,31.58,13.82,13.80。
实施例8：
Figure BDA0002106687440000091
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为84％。
1H NMR(400MHz,CDCl3)δ7.72(d,J＝7.4Hz,1H),7.66(s,1H),7.61(d,J＝8.1Hz,1H),7.53-7.49(m,2H),7.38(t,J＝7.2Hz,1H),7.35-7.31(m,1H),4.11-3.92(m,5H),3.14(t,J＝7.3Hz,1H),2.72-2.58(m,2H),1.18(t,J＝7.2Hz,3H),1.16(t,J＝7.2Hz,3H).13CNMR(125MHz,CDCl3)δ169.13,169.11,147.56,145.15,140.29,140.26,130.59,128.12,127.64,127.40,124.87,121.21,120.75,120.01,61.50,61.44,48.76,45.36,31.40,13.92,13.90。
实施例9：
Figure BDA0002106687440000092
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为83％。
1H NMR(400MHz,CDCl3)δ7.70-7.66(m,2H),7.52(d,J＝7.5Hz,1H),7.37(t,J＝7.4Hz,1H),7.29(t,J＝7.5Hz,1H),7.24(dd,J＝2.1Hz,J＝8.8Hz,1H),7.08(dt,J＝2.4Hz,J＝8.8Hz,1H),4.12-3.91(m,5H),3.16(t,J＝7.2Hz,1H),2.71-2.59(m,2H),1.19-1.14(m,6H).13C NMR(125MHz,CDCl3)δ169.15,163.41(d,J＝243.8Hz),147.74(d,J＝8.75Hz),145.30(d,J＝1.3Hz),140.41,137.27(d,J＝2.5Hz),127.56,126.62,124.82,120.87(d,J＝10.0Hz,),119.60,114.65(d,J＝22.5Hz),112.32(d,J＝22.5Hz),61.42,61.40,48.74,45.42(d,J＝2.5Hz),31.53,13.88。
实施例10：
Figure BDA0002106687440000101
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.09mmol，0.3摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为59％。
1H NMR(400MHz,CDCl3)δ7.84-7.78(m,3H),7.65(d,J＝8.0Hz,1H),7.58(d,J＝7.1Hz,1H),7.44-7.37(m,2H),4.11-3.92(m,5H),3.12(t,J＝7.2Hz,1H),2.78-2.63(m,2H),1.16(t,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ169.10,169.08,146.10,145.89,144.73,139.86,128.91(q,J＝32.1Hz),128.22,127.78,124.86(q,J＝3.8Hz),124.50(q,J＝270.4Hz),121.78(q,J＝3.8Hz),120.71,120.02,61.50,61.45,48.76,45.49,31.29,13.90,13.83。
实施例11：
Figure BDA0002106687440000102
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为92％。
1H NMR(400MHz,CDCl3)δ7.89(d,J＝7.7Hz,1H),7.55(d,J＝7.5Hz,1H),7.40-7.37(m,2H),7.30(dt,J＝0.9Hz,J＝7.4Hz,1H),7.21(t,J＝7.4Hz,1H),7.15(d,J＝7.5Hz,1H),4.08-3.98(m,3H),3.96-3.88(m,2H),3.15(t,J＝7.2Hz,1H),2.71(s,3H),2.69-2.62(m,2H),1.14(t,J＝7.1Hz,6H).13C NMR(125MHz,CDCl3)δ169.40,169.38,145.90,142.31,139.32,133.06,129.70,127.30,126.63,126.23,124.74,123.12,122.27,61.31,61.30,48.70,45.16,31.93,21.00,13.88。
实施例11：
Figure BDA0002106687440000111
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为93％。
1H NMR(400MHz,CDCl3)δ8.12(d,J＝7.6Hz,1H),7.50(d,J＝7.4Hz,1H),7.36(t,J＝7.5Hz,1H),7.29-7.25(m,2H),7.15(d,J＝7.5Hz,1H),6.89(d,J＝8.1Hz,1H),4.10-3.83(m,8H),3.20(t,J＝7.2Hz,1H),2.71-2.59(m,2H),1.17-1.12(m,6H).13C NMR(125MHz,CDCl3)δ169.38,169.37,155.89,147.51,144.78,140.56,129.28,127.93,127.30,125.95,124.14,123.83,117.05,109.36,61.31,55.28,48.73,45.60,31.76,13.86。
实施例13：
Figure BDA0002106687440000112
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.09mmol，0.3摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为77％。
1H NMR(400MHz,CDCl3)δ8.43(d,J＝7.7Hz,1H),7.54(d,J＝7.5Hz,1H),7.44-7.33(m,4H),7.23(t,J＝7.7Hz,1H),4.08-3.99(m,3H),3.95-3.87(m,2H),3.09(t,J＝7.2Hz,1H),2.75-2.63(m,2H),1.14(t,J＝7.1Hz,6H).13C NMR(125MHz,CDCl3)δ169.26,169.22,147.99,145.57,140.07,138.01,129.00,128.91,127.53,127.49,127.44,124.52,123.90,123.08,61.42,48.48,45.51,31.59,13.86,13.84。
实施例14：
Figure BDA0002106687440000121
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为90％。
1H NMR(400MHz,CDCl3)δ7.68(d,J＝7.4Hz,1H),7.52(d,J＝7.4Hz,1H),7.37-7.28(m,2H),6.89(d,J＝1.9Hz,1H),6.40(d,J＝1.9Hz,1H),4.12(t,J＝5.2Hz,1H),4.03-3.81(m,10H),3.04(t,J＝7.0Hz,1H),2.91-2.85(m,1H),2.71-2.64(m,1H),1.13(t,J＝7.2Hz,3H),1.11(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ169.66,169.48,161.40,157.32,146.53,143.49,141.33,127.07,126.92,124.82,124.77,119.77,97.61,96.28,61.04,61.01,55.54,55.15,48.61,43.89,29.91,13.83,13.80。
实施例15：
Figure BDA0002106687440000131
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为71％。
1H NMR(400MHz,CDCl3)δ7.72(d,J＝7.5Hz,1H),7.56(s,1H),7.52(d,J＝7.4Hz,1H),7.41(d,J＝7.7Hz,1H),7.36(t,J＝7.4Hz,1H),7.29(t,J＝7.4Hz,1H),7.12(d,J＝7.6Hz,1H),4.08-3.90(m,5H),3.20(t,J＝7.2Hz,1H),2.65-2.61(m,2H),2.44(s,3H),1.16(t,J＝7.0Hz,3H),1.14(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)δ169.38,145.93,142.65,141.41,141.30,137.06,127.86,127.30,126.78,124.84,124.54,120.50,119.75,61.31,61.29,48.87,44.97,31.83,21.45,13.86。
实施例16：
Figure BDA0002106687440000132
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为86％。
1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.4Hz,1H),7.53(d,J＝7.2Hz,1H),7.46(dd,J＝5.0Hz,J＝8.3Hz,1H),7.42-7.32(m,3H),6.99(dt,J＝2.4Hz,J＝8.8Hz,1H),4.10-3.91(m,5H),3.12(t,J＝7.2Hz,1H),2.67-2.64(m,2H),1.16(t,J＝7.0Hz,3H),1.15(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)δ169.28(d,J＝6.3Hz),163.90(d,J＝243.8Hz),146.34(d,J＝8.8Hz),140.79(d,J＝1.3Hz),140.43(d,J＝2.5Hz),127.58,127.56,125.95(d,J＝8.8Hz),124.94,120.18,113.83(d,J＝22.5Hz),107.01(d,J＝23.8Hz),61.41,61.40,48.70,44.84,31.57,13.88。
实施例17：
Figure BDA0002106687440000141
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为80％。
1H NMR(400MHz,CDCl3)δ7.74(d,J＝7.4Hz,1H),7.54(t,J＝7.5Hz,2H),7.40-7.32(m,3H),6.97(t,J＝8.8Hz,1H),4.29(t,J＝5.3Hz,1H),4.04-3.85(m,4H),3.07(t,J＝7.1Hz,1H),2.86-2.74(m,2H),1.16-1.11(m,6H).13C NMR(125MHz,CDCl3)δ169.30,169.05,161.04(d,J＝246.3Hz),145.22,144.61(d,J＝6.3Hz),140.56(d,J＝2.5Hz),130.70(d,J＝16.3Hz),129.66(d,J＝7.5Hz),127.63,127.60,124.98,120.32,115.81(d,J＝3.8Hz),113.94(d,J＝20.0Hz),61.29,61.25,48.68,43.90(d,J＝1.2Hz),30.18,13.83。
实施例18：
Figure BDA0002106687440000142
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.6mmol，2摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为62％。
1H NMR(400MHz,CDCl3)δ7.65(s,2H),7.58-7.56(m,2H),7.50(dd,J＝1.6Hz,J＝8.1Hz,2H),4.11-4.00(m,5H),3.11(t,J＝7.2Hz,1H),2.64(dd,J＝6.0Hz,J＝7.2Hz,1H),1.19(t,J＝7.1Hz,6H).13C NMR(125MHz,CDCl3)δ168.88,147.15,139.23,130.83,128.11,121.29,121.22,61.57,48.66,45.29,31.10,13.89。
实施例19：
Figure BDA0002106687440000151
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为88％。
1H NMR(400MHz,CDCl3)δ8.41(d,J＝1.8Hz,1H),8.31(dd,J＝2.0Hz,J＝8.4Hz,1H),7.87-7.84(m,2H),7.63-7.60(m,1H),7.47-7.44(m,2H),4.14(t,J＝6.4Hz,1H),4.12-3.93(m,4H),3.18(t,J＝7.3Hz,1H),2.78-2.64(m,2H),1.20-1.15(m,6H).13C NMR(125MHz,CDCl3)δ168.90,168.84,147.61,147.14,146.99,146.56,138.98,129.13,128.10,125.25,123.76,121.41,120.27,120.03,61.61,61.58,48.89,45.53,31.23,13.91,13.88。
实施例20：
Figure BDA0002106687440000152
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为34％。
1H NMR(400MHz,CDCl3)δ7.46(t,J＝7.2Hz,2H),7.33-7.30(m,2H),7.21(t,J＝7.5Hz,1H),7.13(d,J＝4.8Hz,1H),4.19-3.97(m,4H),3.83(t,J＝6.4Hz,1H),3.30(dd,J＝6.0Hz,J＝8.8Hz,1H),2.74(ddd,J＝5.3Hz,J＝9.0Hz,J＝14.1Hz,1H),2.38-2.31(m,1H),1.22(t,J＝7.2Hz,3H),1.18(t,J＝7.2Hz,3H).13C NMR(125MHz,CDCl3)δ169.26,169.17,149.69,148.62,143.23,138.22,127.42,127.25,125.10,124.56,122.78,118.87,61.43,61.42,49.29,43.19,31.15,13.98,13.90。
实施例21：
Figure BDA0002106687440000161
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为58％。
1H NMR(400MHz,CDCl3)δ7.49(dd,J＝1.2Hz,J＝7.5Hz,2H),7.38(d,J＝5.0Hz,1H),7.31(t,J＝7.4Hz,1H),7.27(d,J＝5.0Hz,1H),7.20(t,J＝7.2Hz,1H),4.26-4.16(m,2H),4.12-4.01(m,2H),3.96(dd,J＝5.1Hz,J＝8.7Hz,1H),3.51(dd,J＝5.9Hz,J＝9.1Hz,1H),2.74(ddd,J＝5.1Hz,J＝9.1Hz,J＝14.1Hz,1H),2.26(ddd,J＝5.9Hz,J＝8.8Hz,J＝14.3Hz,1H),1.26(t,J＝7.1Hz,3H),1.19(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ169.16,169.03,149.44,146.82,146.63,138.59,129.15,127.29,124.74,124.39,119.22,118.57,61.55,61.48,49.33,44.09,32.13,14.03,13.92。
实施例22：
Figure BDA0002106687440000162
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为88％。
1H NMR(400MHz,CDCl3)δ8.71(d,J＝8.2Hz,2H),7.99(d,J＝1.2Hz,1H),7.97(d,J＝1.6Hz,1H),7.89(d,J＝8.2Hz,2H),7.73(d,J＝8.2Hz,2H),7.59-7.51(m,4H),4.25(t,J＝5.1Hz,1H),3.86(qd,J＝7.1Hz,J＝10.8Hz,2H),3.63(qd,J＝7.1Hz,J＝10.8Hz,2H),2.96-2.93(m,2H),2.85(dd,J＝6.2Hz,J＝7.3Hz,1H),0.90(t,J＝7.1Hz,6H).13C NMR(125MHz,CDCl3)δ169.28,144.76,138.32,134.25,128.69,128.66,127.83,126.78,125.11,124.85,122.25,61.20,47.93,46.72,30.36,13.57。
实施例23：
Figure BDA0002106687440000171
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为82％。
1H NMR(400MHz,CDCl3)δ7.95(d,J＝8.4Hz,1H),7.89(d,J＝7.6Hz,1H),7.81(d,J＝8.4Hz,2H),7.73(d,J＝3.7Hz,1H),7.55(d,J＝7.6Hz,1H),7.47(d,J＝8.5Hz,1H),7.41(t,J＝7.3Hz,1H),7.31(t,J＝7.4Hz,1H),7.24(d,J＝8.2Hz,2H),7.14(d,J＝3.7Hz,1H),4.07-3.98(m,2H),3.96-3.86(m,2H),3.70(qd,J＝7.2Hz,J＝10.8Hz,1H),3.06(t,J＝7.1Hz,1H),2.75-2.64(m,2H),2.33(s,3H),1.12(t,J＝7.1Hz,3H),0.98(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ169.34,169.28,146.24,144.96,141.32,140.69,135.29,134.97,133.66,129.86,127.51,127.19,126.86,126.57,124.73,121.49,120.90,111.95,106.87,61.33,61.21,48.58,45.38,31.57,21.46,13.84,13.68。
实施例24：
Figure BDA0002106687440000181
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为78％。
1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.6Hz,1H),7.98(d,J＝5.6Hz,1H),7.86(d,J＝8.2Hz,1H),7.65(d,J＝5.5Hz,1H),7.60(d,J＝7.5Hz,1H),7.55(d,J＝8.2Hz,1H),7.46(t,J＝7.5Hz,1H),7.35(t,J＝7.5Hz,1H),4.14(t,J＝5.6Hz,1H),4.06-3.77(m,4H),3.06(t,J＝7.0Hz,1H),2.84-2.71(m,2H),1.12(t,J＝7.1Hz,3H),1.02(t,J＝7.1Hz,3H).13CNMR(125MHz,CDCl3)δ169.42,169.40,146.02,142.13,141.67,140.17,135.48,133.74,127.70,127.57,126.45,124.85,121.83,121.19,121.01,120.91,61.34,48.48,45.50,31.54,13.87,13.69。
实施例25：
Figure BDA0002106687440000182
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol)，氮气保护，加入六氟异丙醇(30mL)，再在搅拌下加入三氟甲磺酸(0.03mmol，0.1摩尔当量)，然后封口、70℃加热搅拌反应2小时。减压蒸馏除去溶剂和三氟甲磺酸，残留物通过柱层析纯化，得到所述式(Ⅱ)化合物，产率为60％。
1H NMR(400MHz,CDCl3)δ8.79(s,1H),7.85(dd,J＝3.1Hz,J＝5.8Hz,1H),7.62(d,J＝7.4Hz,1H),7.44-7.39(m,2H),7.34(t,J＝7.5Hz,1H),7.23-7.19(m,2H),7.12(t,J＝7.4Hz,1H),4.18-4.06(m,3H),3.99(qd,J＝7.1Hz,J＝10.7Hz,1H),3.84(dd,J＝5.3Hz,J＝8.3Hz,1H),3.40(dd,J＝5.4Hz,J＝9.9Hz,1H),2.87(ddd,J＝5.3Hz,J＝9.9Hz,J＝15.0Hz,1H),2.32(ddd,J＝5.4Hz,J＝8.4Hz,J＝14.0Hz,1H),1.21(t,J＝7.1Hz,3H),1.10(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ16.96,168.99,147.85,145.91,140.73,139.43,127.57,123.86,122.88,121.92,121.79,121.74,120.42,119.38,118.56,112.02,61.85,61.65,49.38,40.52,30.74,13.94,13.79。
以上所揭露的仅为本发明较佳实施例而已，当然不能以此来限定本发明之权利范围，因此依本发明权利要求所作的等同变化，仍属本发明所涵盖的范围。

Claims (3)

1.一种2-((9-氢芴-9-基)甲基)丙二酸酯的合成方法，其特征在于：在氮气气氛下，有机溶剂中，在酸催化剂催化的条件下，下式(Ⅰ)所示化合物发生分子内开环芳基化反应，制得(Ⅱ)所示2-((9-氢芴-9-基)甲基)丙二酸酯化合物，其反应式为：
Figure FDA0002106687430000011
上述式中，R是Et、Me或i-Pr；
Ar1是取代芳基，其取代基有甲基、硝基、卤素；
Ar2为取代芳基或杂芳基，芳基取代基有甲基、甲氧基、羟基、甲硫基、卤素、三氟甲基，杂芳基有噻吩、苯并噻吩、吲哚；
所述酸催化剂为三氟甲磺酸；
所述有机溶剂为六氟异丙醇；
反应温度为70℃，反应时间2小时。
2.根据权利要求1所述的合成方法，其特征在于，以摩尔比计算，式(Ⅰ)所示化合物在有机溶剂中的摩尔浓度为0.01mol/L。
3.根据权利要求1所述的合成方法，其特征在于，以摩尔比计算，式(Ⅰ)所示化合物与三氟甲磺酸的摩尔比为1:0.01～1:1。
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