CN116283467A - 一种合成二芳基烷基甲烷的方法 - Google Patents

一种合成二芳基烷基甲烷的方法 Download PDF

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CN116283467A
CN116283467A CN202310056611.7A CN202310056611A CN116283467A CN 116283467 A CN116283467 A CN 116283467A CN 202310056611 A CN202310056611 A CN 202310056611A CN 116283467 A CN116283467 A CN 116283467A
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曾小明
罗美明
凡飞
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Abstract

本发明公开了一种铬催化合成二芳基烷基甲烷化合物的方法，该方法以廉价易得的金属铬盐为催化剂，芳基格氏试剂为芳基供体，烷基磺酸酯为烷基源，醚为溶剂，将苄基吡啶醚在0～80℃搅拌反应2～24小时，生成相应的二芳基烷基甲烷化合物。本方法具有原料来源广泛、反应条件温和、底物适用范围广、产物类型多样、选择性高、步骤经济、反应体系干净等优点，避免了大量添加剂的使用和副产物的生成。

Description

一种合成二芳基烷基甲烷的方法
技术领域
本发明属于二芳基烷基甲烷化合物的制备技术领域，具体涉及一种以金属铬盐为催化剂，实现苄基吡啶醚与烷基磺酸酯及芳基格氏试剂三组分反应得到相应的二芳基烷基甲烷化合物的方法。
背景技术
二芳基烷基甲烷骨架广泛存在于生物活性分子和药物分子中，如市面上在售的心血管用药芬地林(Fendiline)、精神病用药匹莫齐特(Pimozide)、皮肤过敏用药托普帕敏(Tolpropamine)和抗乳腺癌生物活性分子等。二芳基烷基甲烷骨架的构建是合成这类药物分子的重要手段，它的合成研究与方法开发具有突出的实用价值和应用前景。
Figure BDA0004060633940000011
目前构建二芳基烷基甲烷骨架的方法主要依赖于烯烃类结构：最早以二芳基乙烯为原料，通过氢甲酰化和还原胺化过程制备(Chem.Eur.J.2007,13,1594–1601；Nat.Catal.2020,3,843–850)；接着以芳基烯烃为底物，借助过渡金属催化烯基1,2-双功能化反应制备(J.Am.Chem.Soc.2018,140,9801-9805；Org.Lett.2020,22,620-625)；最新研究以烷基烯烃为烷基源，金属镍催化烯基1,1-双功能化反应制备(CCS Chem.2020,2,576–582)。在上述合成方法中，存在着明显的不足和需要改进的地方。其中以二芳基乙烯为原料的反应在氢甲酰化过程中贵金属铑和氢气的使用，对生成成本和实验设备提出了更高的要求；同时该反应产物结构相对单一，不利于进一步的分子筛选。另外在以简单烯烃为底物的反应中，其双功能化过程存在突出的区域选择性问题，体系相对复杂，副产物多样，不益于扩大量生产。
发明内容
本发明的目的是提供一种原料来源广泛、反应条件温和、底物适用范围广、产物类型多样、选择性高、步骤经济、反应体系干净的制备二芳基烷基甲烷化合物的方法。本发明的方案是：将式中所示的苄基吡啶醚化合物、金属铬盐、烷基磺酸酯和芳基格氏试剂加入醚类溶剂中反应，反应完全后经分离得到二芳基烷基甲烷化合物。
本发明合成二芳基烷基甲烷化合物的反应通式：
Figure BDA0004060633940000021
式中，R1代表氢、烷基、烷氧基、三氟甲氧基、羟基、酰胺基、萘基、呋喃基、噻吩基、氟、溴等任意一种、两种或三种；R2代表氢、烷基、烷氧基、叔丁基、甲硫基、三氟甲氧基、环氧基、萘基等任意一种或两种；R3代表氢、烷基、芳基、苄基、三氟甲基、烯基、环烷基、噻吩基、氟、氯等任意一种或两种。
基于本发明所用催化剂包括二氯化铬、三氯化铬、乙酰丙酮铬或醋酸铬，优选为二氯化铬。
基于本发明的催化剂的加入量为苄基吡啶醚化合物摩尔量的0.5～20％，优选为苄基吡啶醚化合物摩尔量的2％。
基于本发明的烷基磺酸酯的加入量为苄基吡啶醚化合物摩尔量的1-3当量，优选为苄基吡啶醚化合物摩尔量的2当量。
基于本发明的芳基格氏试剂的加入量为苄基吡啶醚化合物摩尔量的1-5当量，优选为苄基吡啶醚化合物摩尔量的3-5当量。
基于本发明所用醚类溶剂包括四氢呋喃、2-甲基四氢呋喃或乙醚，优选为四氢呋喃。
基于本发明的反应温度为0～80℃，优选40℃。
基于本发明的反应时间为2～24小时，优选12小时。
本发明合成二芳基烷基甲烷化合物的具体制备过程描述如下：
在反应管中加入苄基吡啶醚化合物、0.02倍摩尔量二氯化铬和2倍摩尔量烷基磺酸酯，在氮气保护下加入1毫升四氢呋喃，搅拌5分钟之后加入3-5倍摩尔量芳基格氏试剂。反应体系放置于40℃条件下搅拌12小时。反应结束后，加入稀盐酸继续搅拌5分钟，随后用饱和碳酸氢钠水溶液中和至中性。反应液用乙酸乙酯萃取三次，合并有机相，有机相经无水硫酸钠干燥、抽滤和旋转蒸发除去溶剂得到粗产物，最后经硅胶柱层析得到相应的二芳基烷基甲烷化合物。
具体实施方式
以下的实施例，在于详细的说明本发明而非限制本发明。
实施例(如表一所示)。
表一
Figure BDA0004060633940000031
Figure BDA0004060633940000041
Figure BDA0004060633940000051
Figure BDA0004060633940000061
Figure BDA0004060633940000071
Figure BDA0004060633940000081
Figure BDA0004060633940000091
Figure BDA0004060633940000101
/>
Figure BDA0004060633940000111
/>

Claims (7)

1.一种铬催化合成二芳基烷基甲烷化合物的方法，其特征在于：将式中所示的苄基吡啶醚化合物、金属铬盐、烷基磺酸酯和芳基格氏试剂加入醚类溶剂中反应，反应完全后经分离得到二芳基烷基甲烷化合物：
Figure FDA0004060633930000011
式中，R1代表氢、烷基、烷氧基、三氟甲氧基、羟基、酰胺基、萘基、呋喃基、噻吩基、氟、溴等任意一种、两种或三种；
式中，R2代表氢、烷基、烷氧基、叔丁基、甲硫基、三氟甲氧基、环氧基、萘基等任意一种或两种；
式中，R3代表氢、烷基、芳基、苄基、三氟甲基、烯基、环烷基、噻吩基、氟、氯等任意一种或两种。
2.根据权利要求1所述的合成二芳基烷基甲烷的方法，其特征在于：催化剂铬盐的加入量为苄基吡啶醚化合物摩尔量的0.5～30％。
3.根据权利要求1所述的合成二芳基烷基甲烷的方法，其特征在于：烷基磺酸酯的加入量为苄基吡啶醚化合物摩尔量的1-3当量。
4.根据权利要求1所述的合成二芳基烷基甲烷的方法，其特征在于：芳基格氏试剂的加入量为苄基吡啶醚化合物摩尔量的1-5当量。
5.根据权利要求1所述的合成二芳基烷基甲烷的方法，其特征在于：在0～80℃下搅拌反应2～24小时。
6.醚类溶剂包括但不限于：四氢呋喃、2-甲基四氢呋喃或乙醚。
7.金属铬盐包括但不限于：二氯化铬、三氯化铬、乙酰丙酮铬或醋酸铬。
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