CN110590487B - 钌催化的苯环邻间位选择性氢氘交换反应 - Google Patents

钌催化的苯环邻间位选择性氢氘交换反应 Download PDF

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CN110590487B
CN110590487B CN201910933013.7A CN201910933013A CN110590487B CN 110590487 B CN110590487 B CN 110590487B CN 201910933013 A CN201910933013 A CN 201910933013A CN 110590487 B CN110590487 B CN 110590487B
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闫晓宇
赵亮亮
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Abstract

本发明公开了一种钌催化的苯环邻间位选择性氢氘交换反应。具体地，本发明提供了式Ⅰ所示氘标记化合物的制备方法，包括如下步骤：在二氯双(4‑甲基异丙基苯基)钌的催化下，在醋酸银和三苯基膦存在的条件下，式Ⅱ所示化合物和氘代乙酸进行反应得到式Ⅰ所示氘标记化合物。本发明采用二氯双(4‑甲基异丙基苯基)钌作为催化剂，拓宽了导向基团的适用范围，不局限于吡唑、吡啶等基团，如其他的氮杂芳香环，如：吡嗪，嘧啶，苯并咪唑等，都能很好的诱导苯环的邻、间位高效氢氘交换，最高能达到95％的氘代率。本发明反应能够同时实现苯环的邻间位氘代，能引入多个氘原子，为内标试剂的合成提供了另一种简单高效的方法，具有较高的社会效益和经济效益。

Description

钌催化的苯环邻间位选择性氢氘交换反应
技术领域
本发明涉及一种钌催化的苯环邻间位选择性氢氘交换反应，属于有机合成领域。
背景技术
氘标记化合物在有机反应机理分析、分析测试、材料科学、生命科学和医药学等领域有着十分重要的应用。基于氘标记化合物的同位素稀释质谱法已经广泛应用于定量分析，其受基质效应影响小，有着快速、准确、高灵敏度和重复性好的优点。氘标记药物分子也广泛应用于药物代谢过程分析和临床药物代谢动力学研究。苯环作为天然产物及药物分子中存在最为广泛的框架之一，因此实现苯环的氘代,尤其是选择性氘代一直是化学家们研究的重点。
通过过渡金属催化，如钯、铱、钌等，利用导向基团的定位来实现苯环的邻位氘代已经被广泛报道。最近，通过钯催化利用导向基团也成功的实现了苯环间位的氢氘交换反应。现有的方法，一方面最多只能引入两个氘原子，不利于在分析检测领域的应用，另一方面仍存在很大的底物局限性，需要对导向基团或是催化体系进行精心的设计，而这都需要花费较大的人力物力。因此，需要对现有方法进行改进。
发明内容
本发明的目的是提供一种氘标记化合物的制备方法，本发明采用二氯双(4-甲基异丙基苯基)钌([RuCl2(p-cymene)]2)作为催化剂，利用氮杂芳环的导向基团，通过加入三苯基膦(PPh3)作为配体以及醋酸银(AgOAc)作为添加剂，同时实现了苯环的邻、间位高效选择性氢氘交换反应。
本发明提供的式Ⅰ所示氘标记化合物的制备方法，包括如下步骤：
在二氯双(4-甲基异丙基苯基)钌的催化下，在醋酸银和三苯基膦存在的条件下，式Ⅱ所示化合物和氘代乙酸进行反应得到式Ⅰ所示氘标记化合物；
Figure BDA0002220770700000011
式中，
Figure BDA0002220770700000012
表示连接于苯环上的氮杂芳环；
R1表示连接于苯环的邻位、间位或对位上的取代基，为碳原子数为1～4的烷基、碳原子数为1～4的烷氧基或卤素，所述卤素优选为氟、氯或溴；
所述烷基优选为甲基，所述烷氧基优选为甲氧基。
上述的方法中，式Ⅱ所示化合物、所述二氯双(4-甲基异丙基苯基)钌、所述醋酸银和所述三苯基膦的的摩尔比可为1：0.025～0.05：0.15～0.3：0.15～0.3，具体可为1：0.025：0.15：0.15；
所述氘代乙酸的用量可为：1mmol式Ⅱ所示化合物：4～10mL所述氘代乙酸，优选1mmol式Ⅱ所示化合物：4mL所述氘代乙酸。
上述的方法中，所述反应在130℃～160℃的条件下进行；
所述反应的时间为18～36h，具体可为24h。
上述的方法中，所述氮杂芳环可为五元杂环或六元杂环。
上述的方法中，所述氮杂芳环具体可为吡唑、吡啶、吡嗪、嘧啶或苯并咪唑等。
本发明采用二氯双(4-甲基异丙基苯基)钌作为催化剂，拓宽了导向基团的适用范围，不局限于吡唑、吡啶等基团，如其他的氮杂芳香环，如：吡嗪，嘧啶，苯并咪唑等，都能很好的诱导苯环的邻、间位高效氢氘交换，最高能达到95％的氘代率。上述导向基团可以通过Suzuki反应、Ullmann反应、Buchwald-Hartwig反应等反应直接引入到苯环上。本发明反应能够同时实现苯环的邻间位氘代，能引入多个氘原子，为内标试剂的合成提供了另一种简单高效的方法，具有较高的社会效益和经济效益。
附图说明
图1为本发明方法制备的式Ⅰ-1所示化合物的核磁共振氢谱。
图2为本发明方法制备的式Ⅰ-2所示化合物的核磁共振氢谱。
图3为本发明方法制备的式Ⅰ-3所示化合物的核磁共振氢谱。
图4为本发明方法制备的式Ⅰ-4所示化合物的核磁共振氢谱。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
反应方程式如下式所示：
Figure BDA0002220770700000031
按照下述步骤制备氘代化合物：
向一干燥的密封管中加入大小合适的洁净磁子，随后称量0.2mmol的原料(式Ⅱ所示化合物)，加入封管中，再依次称量0.005mmol二氯双(4-甲基异丙基苯基)钌，0.03mmol醋酸银和0.03mmol三苯基膦并加入到封管中。向封管中置换好氮气氛围后，用注射器向封管中加入0.8ml[D4]-乙酸，密封。反应体系在150℃的条件下回流24小时，反应结束后向反应体系中加入碳酸氢钠和水，搅拌至无气泡产生，用乙酸乙酯萃取，加入硅胶后真空旋干进行拌样，之后通过柱层析进行分离，得到目标产物(式Ⅰ所示化合物)。
具体地得到如下化合物，[]内的数字表示氘代率：
式Ⅰ-1所示化合物：
Figure BDA0002220770700000032
氘代1-(4-甲基苯基)-1H-吡唑：淡黄色油状物，81％产率。1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.71(s,1H),7.58(d,J＝4.4Hz,2H),7.25(s,2H),6.45(m,1H),2.38(s,3H).13CNMR(100MHz,CDCl3)δ140.6,137.8,136.0,135.9,129.4(t,J＝24.2Hz),126.5,118.7(t,J＝24.4Hz),107.1(t,J＝13.5Hz),20.7.HR-MS:m/z calculated for:C10H6N2D6[M]+164.1221,Found:164.1226.1H NMR谱图如图1所示。可知结构正确。
式Ⅰ-2所示化合物：
Figure BDA0002220770700000041
氘代2-(4-甲基苯基)吡啶：黄色油状物，产率79％。1H NMR(400MHz,CDCl3)δ8.68(d,J＝4.8Hz,1H),7.90(s,2H),7.74-7.69(m,2H),7.28(s,2H),7.21-7.18(m,1H),2.41(s,3H).13C NMR(100MHz,CDCl3)δ157.3,149.1(t,J＝26.7Hz),138.7,136.6,136.3,128.9(t,J＝23.9Hz),126.2(t,J＝23.7Hz),121.5,120.2,21.0.HR-MS(ESI-TOF)m/z calculatedfor:C12H6ND5[M]+174.1205,Found:174.1213.1H NMR谱图如图2所示。可知结构正确。
式Ⅰ-3所示化合物：
Figure BDA0002220770700000042
氘代2-(4-甲氧基苯基)-1H-苯并咪唑：白色固体，产率96％。1H NMR(400MHz,DMSO)δ12.78(s,1H),8.14(s,2H),7.63-7.51(m,2H),7.18(d,J＝4.4Hz,2H),7.17,7.11(s,1H),3.83(s,3H).13C NMR(100MHz,DMSO)δ161.0,151.8,144.3,135.4,128.1(t,J＝25.6Hz),122.9,122.5,121.94,118.9,114.4(t,J＝22.6Hz),111.5,55.7.HR-MS(ESI-TOF)m/z calculated for:C14H8N2D4O[M]+228.1201,Found:228.1207.1H NMR谱图如图3所示。可知结构正确。
式Ⅰ-4所示化合物：
Figure BDA0002220770700000043
氘代2-(4-甲氧基苯基)吡嗪：淡黄色固体，产率89％。1H NMR(400MHz,CDCl3)δ8.97(d,J＝1.6Hz,1H),8.56(t,J＝2.0Hz,1H),8.42(d,J＝2.4Hz,1H),7.97(s,2H),7.02(s,2H),3.86(s,3H).13C NMR(100MHz,CDCl3)δ161.1,152.5,144.0,142.0,141.6,128.6,127.8(t,J＝24.1Hz),114.1(t,J＝25.5Hz),55.3.HR-MS(ESI-TOF)m/z calculated for:C11H5N2D5O[M]+191.1107,Found:191.1112.1H NMR谱图如图4所示。可知结构正确。
由上述分析可以看出，本发明方法能够同时实现苯环的邻间位的氘代，最高能达到95％的氘代率。

Claims (5)

1.式Ⅰ所示氘标记化合物的制备方法，包括如下步骤：
在二氯双(4-甲基异丙基苯基)钌的催化下，在醋酸银和三苯基膦存在的条件下，式Ⅱ所示化合物和氘代乙酸进行反应得到式Ⅰ所示氘标记化合物；
Figure FDA0003496281870000011
式中，
Figure FDA0003496281870000012
表示连接于苯环上的氮杂芳环；
R1表示连接于苯环的邻位、间位或对位上的取代基，为碳原子数为1～4的烷基、碳原子数位1～4的烷氧基或卤素。
2.根据权利要求1所述的制备方法，其特征在于：式Ⅱ所示化合物、所述二氯双(4-甲基异丙基苯基)钌、所述醋酸银和所述三苯基膦的摩尔比为1：0.025～0.05：0.15～0.3：0.15～0.3。
3.根据权利要求1或2所述的制备方法，其特征在于：所述反应在回流的条件下进行；
所述反应的时间为18～36h。
4.根据权利要求3所述的制备方法，其特征在于：所述氮杂芳环为吡唑、吡啶、吡嗪、嘧啶或苯并咪唑。
5.二氯双(4-甲基异丙基苯基)钌在催化式Ⅱ所示化合物的邻位和间位的氢氘交换反应中的应用；
Figure FDA0003496281870000013
式中，
Figure FDA0003496281870000014
表示连接于苯环上的氮杂芳环；
R1表示连接于苯环的邻位、间位或对位上的取代基，为碳原子数为1～4的烷基、碳原子数位1～4的烷氧基或卤素。
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