CN110256247B - 2-((9-氢芴-9-基)甲基)丙二酸酯的合成方法 - Google Patents
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Abstract
本发明公开2‑((9‑氢芴‑9‑基)甲基)丙二酸酯的合成方法,本发明通过在强酸反应条件下的2‑联芳基环丙基‑1,1‑二羧酸酯的开环环化反应实现了2‑((9‑氢芴‑9‑基)甲基)丙二酸酯的合成。具体方法为使用二氯甲烷做为反应溶剂,加入1~10摩尔当量的三氟甲磺酸,在室温条件下反应得到目标产物。本发明使用的原料易得、操作简单、收率高,普适性广。特别是在克级以上规模制备时,本方法也极为可靠,而且分离纯化手段简单。
Description
技术领域
本发明属于有机化学物合成技术领域,具体是指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)。
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)。
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。
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)。
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下,有机溶剂中,在过量强酸(一般为6当量)存在的条件下,下式(Ⅰ)所示化合物发生分子内开环芳基化反应,制得(Ⅱ)所示化合物,其反应式为:
上述式中,R是Et、Me;
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、卤素、三氟甲基,杂芳基有噻吩、苯并噻吩、吲哚;
所述强酸为三氟甲磺酸;
所述溶剂为二氯甲烷;
反应温度为室温,反应时间1小时。
进一步设置是以摩尔比计算,式(Ⅰ)所示化合物在有机溶剂中的摩尔浓度为0.1mol/L。
进一步设置是以摩尔比计算,式(Ⅰ)所示化合物与三氟甲磺酸的摩尔比为 1:1~1:10。
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)2-联芳基环丙基-1,1-二羧酸酯易得,且容易制备;
(2)反应所用的酸催化剂三氟甲磺酸和溶剂二氯甲烷均很廉价,经济性较好;
(3)反应室温下进行,易于操作;
(4)反应适合大量制备,进行克级规模实验的时候,仅需要中和和萃取的后处理操作就能以很高的收率得到纯品;
(5)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;具体转换效率见实施例。
(6)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,给电子基团和吸电子基团都能兼容,杂芳基底物也能得到反应,产物中带有的丙二酸酯结构适于后期多种衍生化反应。
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,反应所用试剂均非常廉价,反应普适性好,原子经济性高,反应条件温和,适于大量制备。
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:
第一步:在圆底烧瓶中加入2-联苯甲醛(100mmol)、丙二酸二乙酯(100 mmol)、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=7.2 Hz,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.
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(60 mL)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:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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95%。
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(125 MHz,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:
氮气保护下在Schlenk管加入搅拌磁子、二氯甲烷(80mL)和三氟甲磺酸 (60mmol,6摩尔当量),再将上式(Ⅰ)化合物(10mmol)溶于二氯甲烷(10 mL)中,在搅拌下加入到反应管,然后封口、室温搅拌反应1小时。冰水浴冷却下用饱和碳酸氢钠溶液淬灭反应体系,产物用乙酸乙酯萃取(60mL×2),合并有机相,用饱和氯化钠溶液洗涤(60mL×2),无水硫酸钠干燥,减压蒸馏除去溶剂,得到所述式(Ⅱ)化合物,产率为98%。
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(125 MHz,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3:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(3mmol,10摩尔当量),然后封口、室温搅拌反应1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)δ7.76(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4:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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96%。
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(125 MHz,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:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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87%。
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:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(3mmol,10摩尔当量),然后封口、室温搅拌反应1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75%。
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7:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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)δ7.72(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8:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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)δ7.70-7.66(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9:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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)δ7.84-7.78(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(125 MHz,CDCl3)δ169.10,169.08,146.10,145.89,144.73,139.86,128.91(q,J=32.1 Hz),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10:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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95%。
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:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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81%。
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=8.1 Hz,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12:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(3mmol,10摩尔当量),然后封口、室温搅拌反应1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)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(125 MHz,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13:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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)δ7.68(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=5.2 Hz,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14:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(3mmol,10摩尔当量),然后封口、室温搅拌反应1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)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15:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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87%。
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=8.8 Hz,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16:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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)δ7.74(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(125 MHz,CDCl3)δ169.30,169.05,161.04(d,J=246.3Hz),145.22,144.61(d,J=6.3 Hz),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17:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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81%。
1H NMR(400MHz,CDCl3)δ7.65(s,2H),7.58-7.56(m,2H),7.50(dd,J=1.6 Hz,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18:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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66%。
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=6.4 Hz,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19:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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)δ7.46(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20:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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12%。
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21:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(1.8mmol,6摩尔当量),然后封口、室温搅拌反应1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85%。
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22:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(0.3mmol,1摩尔当量),然后封口、室温搅拌反应1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57%。
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=7.2 Hz,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23:
在Schlenk管加入搅拌磁子和上式(Ⅰ)化合物(0.3mmol),氮气保护,加入二氯甲烷(3mL),再在搅拌下加入三氟甲磺酸(0.6mmol,2摩尔当量),然后封口、室温搅拌反应1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65%。
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=7.1 Hz,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。
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)
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0.1mol/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1:1~1:10。
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