CN105111217B - 一种异吲哚二氢喹唑啉衍生物的合成方法 - Google Patents
一种异吲哚二氢喹唑啉衍生物的合成方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
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Abstract
本发明属于药物合成技术领域,特别涉及一种关于制备异吲哚二氢喹唑的合成工艺。以邻氰基苯甲醛及其衍生物和二苯芳基碘鎓三氟甲磺酸盐衍生物为原料,在铜催化剂的条件下,加入溶剂后,搅拌反应,色谱柱分离、洗脱,生成异吲哚喹唑啉衍生物。本反应用简单易得的原料,一锅法简便的合成了异吲哚二氢喹唑类衍生物,为合成异吲哚喹唑类衍生物提供了一条高效,绿色的合成新方法。
Description
技术领域
本发明属于药物合成技术领域,特别涉及一种关于制备异吲哚二氢喹唑的合成工艺。
背景技术
在医药方面,吲哚布洛芬(良好的消炎药,用于治疗风湿性关节炎、骨关节炎、椎关节强硬以及手术后、骨折、骨骼肌疼痛等)、DN-2327(抗焦虑药)和佐匹克隆(抗失眠药)等都含有异吲哚酮结构单元。喹唑啉类化合物具有强心、扩张血管、镇痛、驱蛔虫等作用,可以用于治疗高血压、头痛、胃肠紊乱和霍乱等疾病。
发明内容
本发明所解决的技术问题是:为了将异吲哚酮和喹唑啉连结在一个分子中,从而提供一种简单铜盐催化的,以邻氰基苯甲醛及其衍生物和二芳基碘鎓三氟甲磺酸盐衍生物为原料一锅煮发生反应,操作简单、绿色高效的合成异吲哚喹唑啉衍生物的方法,得到一系列多取代的异吲哚二氢喹唑啉多环化合物。
本发明所提供的铜催化合成异吲哚二氢喹唑啉衍生物的方法为,以邻氰基苯甲醛及其衍生物和二苯芳基碘鎓三氟甲磺酸盐衍生物为原料,加入适量溶剂后,搅拌反应,生成异吲哚喹唑啉衍生物,反应条件为:空气条件下,加热到65℃,反应时间为8-10小时,
其中,邻氰基苯甲醛及其衍生物和二苯芳基碘鎓三氟甲磺酸盐衍生物的摩尔配比为1:1,
铜催化剂为常见的碘化亚铜、溴化亚铜、三氟甲磺酸铜、氯化铜或高氯酸铜,
上述原料中,邻氰基苯甲醛及其衍生物可以是5-氟-2-甲酰基苯甲腈、4-溴-2-甲酰基苯甲腈或4-氯-2-甲酰基苯甲腈等,其中,2-氰基苯甲醛(邻氰基苯甲醛)直接购买,其他邻氰基苯甲醛衍生物按下述步骤制备:
(1)向反应瓶中加入R取代的甲基苯腈(5mmol)、NBS(25mmol)、过氧化苯甲酰(BPO,0.5mmol)和CCl4(15mL),加热回流16小时,TLC点半跟踪,反应结束后抽滤,滤饼用乙酸乙酯洗涤,旋干滤液,得到产物,产物无需进一步提纯,直接用于下一步反应;
(2)将上一步提纯后的产物(10mmol)用乙腈(10mL)溶解,将硝酸银(30mmol)用水(4mL)溶解,再将两者混合,然后加入圆底烧瓶中,加热回流20分钟后,冷却,抽滤,滤液用二氯甲烷萃取,无水硫酸钠干燥,旋干得到淡黄色产物,然后用甲醇洗涤,抽滤,得到白色固体,反应方程式如下:
原料二苯芳基碘鎓三氟甲磺酸盐衍生物结构式为
其中,当R基团为H、4-F、4-Br、3-Br、4-Cl、4-Ph、4-CH3、4-CH3时,都能在上述反应条件下,顺利反应得到相应的异吲哚二氢喹唑啉衍生物,
上述采用的溶剂为乙腈、二氯甲烷、甲苯、二甲基亚砜、N,N-二甲基甲酰胺、甲醇/水的混合溶液;溶剂用量为2mL/mmol邻氰基苯甲醛及其衍生物。
上述反应的后处理简便,只需要采用简单的柱色谱分离方法,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂进行洗脱,就可以得到纯净的取代异吲哚衍生物。
本发明的有益效果在于:异吲哚啉酮是一类重要的生物和药物活性的分子,在医学和药物学具有广泛的用途。我们首次使用邻氰基苯甲醛及其衍生物和二苯基碘鎓三氟甲磺酸盐为原料,通过反应来构建得到异吲哚啉酮母核,即异吲哚二氢喹唑啉衍生物,产率(以邻氰基苯甲醛及其衍生物的转化率计算)达65-84%。
附图说明
图1为对比实施例1中所生产的副产物的核磁图谱。
具体实施方式
本发明反应过程及以下各实施例中得到产物的结构式为:
实施例1
将2-氰基苯甲醛(1mmol),4-氟-2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(用量相对于2-氰基苯甲醛摩尔用量的5%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到65℃,反应8小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到目标化合物3a的产率为84%。
1H NMR(400MHz,CDCl3)δ8.11(d,J=7.5Hz,1H),8.00(d,J=7.6Hz,1H),7.96(d,J=7.6Hz,1H),7.79-7.74(m,3H),7.7.-7.57(m,3H),7.22-7.14(m,2H),6.57(s,1H),5.38(s,1H).13C NMR(125MHz,CDCl3)δ168.4,166.5,161.7,159.7,143.6,141.5,133.5,132.5,130.5,129.9,129.4,126.9,125.5,124.7,124.5,124.2,115.8,112.1,67.7,56.7.
HRMS(ESI)calcd for C22H14FN2O2([M+H]):357.1039found 357.1040.
对比实施例1
将邻氰基苯甲醛与二苯芳基碘鎓三氟甲磺酸盐衍生物的投料摩尔比设定为2:1,其余操作如实施例1不变:
将2-氰基苯甲醛(2mmol),4-氟-2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(用量相对于2-氰基苯甲醛摩尔用量的5%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到65℃,反应8小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,
收率为78%(以4-氟-2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐的转化率计算),但是生成的却是(副产物,其核磁图谱如附图1所示)的混合物(摩尔比为1:2)。
实施例2
将2-氰基苯甲醛(1mmol),4-氯-2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(用量相对于2-氰基苯甲醛摩尔用量的5%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到65℃,反应8小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到目标化合物3b的产率为74%。
1H NMR(400MHz,CDCl3)δ8.11(d,J=7.6Hz,1H),8.01(d,J=7.7Hz,1H),7.96(d,J=7.6Hz,1H),7.80-7.75(m,3H),7.70-7.59(m,3H),7.49-7.47(m,1H),7.40-7.39(m,1H),6.57(s,1H),5.38(s,1H).13C NMR(125MHz,CDCl3)δ168.5,166.4,143.6,133.1,132.4,131.9,130.8,130.0,129.4,129.3,136.4,125.5,124.7,124.6,124.2,67.7,56.6.
HRMS(ESI)calcd for C22H14ClN2O2([M+H]):373.0744found 373.0740.
实施例3
将2-氰基苯甲醛(1mmol),4-溴-2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(用量相对于2-氰基苯甲醛摩尔用量的5%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到65℃,反应8小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到目标化合物3c的产率为80%。
1H NMR(400MHz,CDCl3)δ8.10(d,J=7.5Hz,1H),8.02-7.94(m,2H),7.82-7.77(m,2H),7.72-7.54(m,5H),7.55-7.52(m,1H),6.57(s,1H),5.38(s,1H).13C NMR(125MHz,CDCl3)δ168.4,166.3,143.6,141.4,133.5,132.4,132.3,130.7,130.0,129.4,127.4,126.7,125.5,124.7,124.6,120.0,67.6,56.5.HRMS(ESI)calcd for C22H14BrN2O2([M+H]):417.0239found 417.0235.
HRMS(ESI)calcd for C22H14BrN2O2([M+H]):417.0239found 417.0235.
实施例4
将2-氰基苯甲醛(1mmol),3-溴-2,4,6-三甲基碘苯二苯基碘鎓三氟甲磺酸盐(1mmol),Cu(OTf)2(用量相对于2-氰基苯甲醛摩尔用量的5%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到65℃,反应8小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到目标化合物3d的产率为63%。
HRMS(ESI)calcd for C22H14BrN2O2([M+H]):417.0239found 417.0235.
实施例5
将2-氰基苯甲醛(1mmol),4-硝基-2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(用量相对于2-氰基苯甲醛摩尔用量的5%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到65℃,反应10小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到目标化合物3e的产率为62%。
实施例6
将2-氰基苯甲醛(1mmol),4-甲基-2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(用量相对于2-氰基苯甲醛摩尔用量的5%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到65℃,反应10小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到目标化合物3f的产率为74%。
实施例7
将2-氰基苯甲醛(1mmol),4-氟-2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(用量相对于2-氰基苯甲醛摩尔用量的5%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到65℃,反应10小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到目标化合物3g的产率为70%。
实施例8
将2-氰基苯甲醛(1mmol),4-溴-2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(用量相对于2-氰基苯甲醛摩尔用量的5%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到65℃,反应10小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到目标化合物3h的产率为74%。
实施例9
将2-氰基苯甲醛(1mmol),3-溴-2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(5mmol%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到80℃,反应10小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到目标化合物3i的产率为69%。
实施例10
将5-氟-2-甲酰基苯甲腈(1mmol),2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(5mmol%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到65℃,反应10小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到6-溴-3-(2,4,6-三甲基碘苯)-2-苯基异吲哚啉酮3j的产率为63%。
实施例11
将5-氟-2-甲酰基苯甲腈(1mmol),4-氟-2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(5mmol%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到65℃,反应10小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到目标化合物3k的产率为54%。
实施例12
将4-溴-2-甲酰基苯甲腈(1mmol),2,4,6-三甲基二苯基碘鎓三氟甲磺酸盐(1mmol),CuI(5mmol%)和2mL1,1-二氯乙烷加入到15mL试管中,加热到80℃,反应10小时,硅胶柱层析分离,再以石油醚与乙酸乙酯的混合溶剂(体积比1:1)为洗脱剂对产物进行洗脱,得到目标化合物3l的产率为68%。
Claims (2)
1.一种异吲哚二氢喹唑啉衍生物的制备方法,其特征在于:所述的制备方法为,以邻氰基苯甲醛及其衍生物和二苯芳基碘鎓三氟甲磺酸盐衍生物为原料,在铜催化剂的条件下,加入溶剂后,搅拌反应,色谱柱分离、洗脱,生成异吲哚喹唑啉衍生物,
其中,所述的邻氰基苯甲醛及其衍生物为5-氟-2-甲酰基苯甲腈、4-溴-2-甲酰基苯甲腈或2-氰基苯甲醛;
所述的二苯芳基碘鎓三氟甲磺酸盐衍生物结构式为
其中,所述R基团为H、4-F、4-Br、3-Br、4-Cl、4-Ph或4-CH3;
所述的反应条件为,空气条件下,加热到65℃,反应时间为8-10小时,邻氰基苯甲醛及其衍生物和二苯芳基碘鎓三氟甲磺酸盐衍生物的摩尔配比为1:1,所述的铜催化剂为碘化亚铜或三氟甲磺酸铜,所述的溶剂为1,1-二氯乙烷。
2.如权利要求1所述的异吲哚二氢喹唑啉衍生物的制备方法,其特征在于:所述的溶剂用量为2mL/mmol邻氰基苯甲醛及其衍生物。
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