CN110357832A - 一种芳香胺类化合物及EphB4激酶抑制剂及其衍生物的制备方法 - Google Patents

一种芳香胺类化合物及EphB4激酶抑制剂及其衍生物的制备方法 Download PDF

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CN110357832A
CN110357832A CN201910610239.3A CN201910610239A CN110357832A CN 110357832 A CN110357832 A CN 110357832A CN 201910610239 A CN201910610239 A CN 201910610239A CN 110357832 A CN110357832 A CN 110357832A
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周强辉
陈树清
王鹏
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Wuhan University WHU
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Abstract

本发明提供一种芳香胺类化合物及EphB4激酶抑制剂及其衍生物的制备方法。以芳基硼酸或芳基硼酸酯和O‑苯甲酰基‑羟胺类化合物为起始原料，在钯催化剂、降冰片烯衍生物、碱的作用下，空气氛围，在30℃到100℃下于有机溶剂中搅拌反应，反应后分离提纯，即可得到芳香胺类化合物。该方法所使用的原料廉价易得且反应结束无卤离子残留、反应条件温和。同时，本发明还提供了一种合成EphB4激酶抑制剂及其衍生物的方法，在本发明合成的3,5位双胺化的卤代苯或类卤代苯的基础上只需要简单的一步就可以合成EphB4激酶抑制剂及其衍生物。

Description

一种芳香胺类化合物及EphB4激酶抑制剂及其衍生物的制备 方法
技术领域
本发明涉及一种芳香胺类化合物以及EphB4激酶抑制剂及其衍生物的合成方法，属于有机合成和药物化学领域。
背景技术
芳香胺类化合物广泛存在于具有生物活性的天然产物和医药试剂中，例如，已经上市的常用抗精神病药物阿立哌唑、抗II型糖尿病瑞格列奈、抗菌药物利奈唑胺和激酶抑制剂EphB4均含有芳香胺骨架结构。目前，通过C-N建的构建合成芳胺化合物的方法主要有：(1)铜催化的C-N键构建；(2)钯催化的C-N键构建；(3)镍催化的C-N键构建；(4)钴催化的C-N键构建；(5)无过渡金属参与的C-N键构建，以上所述方法只能得到位置特定的原位胺化的芳胺类产物，无法实现芳环其他惰性位点C-H键的直接胺化。
3,5-二(1-吗啉)苯胺作为EphB4激酶抑制剂的核心片段，现有的报道方法中主要利用较为昂贵的卤代硝基苯作为起始原料需要3步才能完成该中间体的合成，合成路线较长，成本较高。
发明内容
为了解决现有技术中存在的不足，本发明提供一种在芳基硼酸或硼酸酯邻位C-H键胺化合成芳香胺衍生物的方法，该方法实现了芳基硼酸或硼酸酯邻位胺化原位质子化、原料易得且不会存在卤素残留问题、操作简便、无需添加额外质子源和膦配体、反应条件温和且反应对水、氧不敏感。在合成邻位胺化的芳胺化合物方法的基础上，我们发明了一种高效合成EphB4激酶抑制剂的方法，该方法只需要三步，且初始原料4位卤素取代的芳基硼酸或芳基硼酸酯廉价易得，大大减少了合成步骤和成本，提高了合成效率。
本发明提供的技术方案具体如下：
一种合成芳香胺类化合物的方法，包括以下步骤：在空气氛围下，以芳基硼酸或芳基硼酸酯A为起始原料，以O-甲酰基-羟胺类化合物B为胺化试剂，以钯催化剂和降冰片烯衍生物为协同催化剂，以碱为促进剂，将以上物料置于30-100℃的有机溶剂中搅拌反应，反应结束后分离提纯，得到一元取代的芳香胺类化合物C或二元取代的芳香胺类化合物D，反应式为：
其中：
R1为氢、芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种；
R2为与Ar环并环的芳环、杂芳环或取代Ar环上氢的取代基，取代基为芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种或几种；n表示R2的个数，0≤n≤3；
R3为氢、C1-20烷基、芳基、杂环芳基；
R4为氢、芳基、杂环芳基、C1-20烷基；
R5、R6为与氮成环的杂环烷烃、杂芳环或氮上的取代基，取代基为氢、芳基、杂环芳基、C1-20烷基、酯基、酰胺基、磺酰基、烷氧基、叔丁氧羰基、苄氧羰基、苄基、对甲氧基苄基、烷酰基、磺酰基、邻苯二甲酰基、叠氮中的一种；
X、Y、Z为N或CH。
优选地，所述的降冰片烯衍生物，具有如下结构：
其中：
R7为五元环上的取代基，o代表取代基个数，0≤o≤8；
R8为双键上的取代基，p代表取代基个数，0≤p≤2；
R7、R8独立地选自金属离子M的羧酸盐、酯基、氰基、硝基、酰胺基、磺酰基、C1-10烷氧基、芳基、杂环芳基、C1-10烷基、卤素中的一种，其中M为Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+中的一种；o≥2时，各R7相同或不同；p＝2时，各R8相同或不同。
优选地，本发明的方法优选使用钯催化剂来促进反应，可采用的钯催化剂包括零价或者二价的钯盐，例如：Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(O2CCF3)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、[Pd(allyl)Cl]2等。可用商品化试剂，无需特殊处理。
本发明的方法优选使用碱来促进反应，可采用碳酸钠、碳酸钾、碳酸铯、醋酸钠、醋酸钾、醋酸铯、磷酸三钾、甲酸钾、氢氧化钠、叔丁醇钠等。可用商品化试剂，无需特殊处理。
优选地，所述的有机溶剂为甲醇、乙醇、异丙醇、叔丁醇、四氢呋喃、2-甲基四氢呋喃、***、二甲基乙二醚、甲基叔丁基醚、1,4-环氧六烷、1,3-环氧六烷、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈、二甲基亚砜中的一种或几种。
优选地，所述的协同催化剂为钯催化剂及降冰片烯，所述的钯催化剂为Pd(OAc)2，所述的碱为碳酸钾，所述的有机溶剂为1,4-二氧六环和二甲基亚砜。
本发明方法两种反应物的投料摩尔比为芳基硼酸或芳基硼酸酯:O-甲酰基-羟胺类化合物＝(1～10):1，优选为1.5:1。
本发明方法反应时间在48小时以内，反应温度为30～100℃。加热过程可采用油浴(例如硅油、石蜡油等)或者其它加热方式。
本发明优选在反应完成后对反应产物进行后处理，包括抽滤、浓缩和纯化。
所述抽滤过程可使用砂芯漏斗在减压的条件下过滤。
所述浓缩过程可采用常压蒸馏、减压蒸馏等方法，例如用旋转蒸发仪减压浓缩。
所述纯化过程是通过柱层析得到纯净的产物。
本发明还提供一种邻位胺化的芳香胺类化合物，采用上述的方法制备得到。
本发明还提供一种制备EphB4激酶抑制剂及其衍生物的方法，包括以下步骤：在空气氛围下，使4-卤素取代的苯硼酸或苯硼酸酯E和O-甲酰基-羟胺类化合物B在钯催化剂、碱和降冰片烯衍生物的作用下在有机溶剂中反应，得到中间体F，将所得中间体分离提纯，与胺试剂G经铜催化Ullmann胺化反应制得化合物EphB4激酶抑制剂或其衍生物H，反应式为：
其中：
W为氟、氯、溴、碘和三氟甲磺酸酯中的一种；
R5、R6为与氮成环的杂环烷烃、杂芳环或氮上的取代基，取代基为为氢、芳基、杂环芳基、C1-20烷基、酯基、酰胺基、磺酰基、烷氧基、叔丁氧羰基、苄氧羰基、苄基、对甲氧基苄基、烷酰基、磺酰基、邻苯二甲酰基、叠氮中的一种；
R9为氢、C1-20烷基、芳基、杂环芳基；
R10、R11为与氮成环的杂环烷烃、杂芳环或氮上的取代基，取代基为氢、芳基、杂环芳基、C1-20烷基、酯基、酰胺基、磺酰基、烷氧基、叔丁氧羰基、苄氧羰基、苄基、对甲氧基苄基、烷酰基、磺酰基、邻苯二甲酰基、叠氮中的一种。
所述的Ullmann胺化反应的方法和条件为本领域此类反应的常规方法和条件。
本发明还提供一种EphB4激酶抑制剂及其衍生物，采用上述的方法制备得到。
本发明的方法可以高效地制备芳香胺类化合物，和现有技术相比，本发明具有下列优势：
1、本发明所涉及的主要原料为芳基硼酸或芳基硼酸酯，此原料可用商品化试剂，无需特殊处理，且价格低廉，种类繁多；
2、本发明方法所涉及的反应操作简便且反应对水氧不敏感，相比于之前的反应需要在惰性气体保护下进行是一个重要的改进；
3、本发明方法所涉及的反应无需添加额外的配体与质子源，相比于之前的反应使用的膦配体和当量醇做质子源反应成本大大降低；
4、本发明方法所涉及的反应对官能团具有很好的容忍性和普适性，取代基可以为烷基、烷氧基、三氟甲基、三氟甲氧基、氰基、酯基、硝基、卤原子(F、Cl、Br、I)等。
5、本发明方法可以大量(克级)制备芳香胺类化合物，为工业化生产奠定了良好的基础。
6、本发明方法制备的3,5位双胺化的卤代苯(或类卤代苯)可以高效、快捷(只需要一步)地转化成EphB4激酶抑制剂及其衍生物。
具体实施方式
下面通过实例对本发明给予进一步说明，值得注意的是，本发明不仅限于下述的实施例。
实施例1：化合物I-1的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-1(黄色固体，产率84％)。1H NMR(400MHz,CDCl3):δ7.76–7.70(m,3H),7.42(t,J＝7.5Hz,1H),7.31(t,J＝7.5Hz,1H),7.28–7.25(m,1H),7.13(s,1H),3.94–3.91(m,4H),3.28–3.26(m,4H)；13C NMR(100MHz,CDCl3):δ149.2,134.6,129.0,128.8,127.6,126.9,126.5,123.7,119.1,110.2,67.1,49.9；HRMS(ESI-TOF):理论计算值：C14H16NO+[M+H+]214.1226,实测值：214.1228。
实施例2：化合物I-2的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、4-甲基-1-萘硼酸频哪醇酯(80.4mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-1(无色油状液体，产率68％)。1H NMR(400MHz,CDCl3):δ7.90(d,J＝8.3Hz,1H),7.74(d,J＝8.1Hz,1H),7.45(t,J＝7.5Hz,1H),7.38(t,J＝7.5Hz,1H),7.14(s,1H),7.02(s,1H),3.94–3.92(m,4H),3.28–3.26(m,4H),2.69(s,3H)；13C NMR(100MHz,CDCl3):δ148.8,135.4,134.9,128.2,127.5,126.2,124.0,123.5,119.8,108.7,67.1,49.9,19.8；HRMS(ESI-TOF):理论计算值：C15H18NO+[M+H+]228.1383,实测值：228.1382。
实施例3：化合物I-3的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、4-甲氧基-1-萘硼酸频哪醇酯(85.2mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-1(棕色油状液体，产率62％)。1H NMR(400MHz,CDCl3):δ8.13(d,J＝8.3Hz,1H),7.67(d,J＝8.2Hz,1H),7.44(t,J＝7.5Hz,1H),7.31(t,J＝7.5Hz,1H),6.75(s,1H),6.60(s,1H),4.00(s,3H),3.94–3.92(m,4H),3.27–3.25(m,4H)；13C NMR(100MHz,CDCl3):δ156.3,149.8,135.3,127.1,126.6,123.1,121.9,121.7,103.2,98.0,67.1,55.5,50.4；HRMS(ESI-TOF):理论计算值：C15H18NO2 +[M+H+]244.1332,实测值：244.1334。
实施例4：化合物I-4的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、4-溴-1-萘硼酸频哪醇酯(99.6mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-1(黄色油状液体，产率68％)。1H NMR(400MHz,CDCl3):δ8.08(d,J＝8.2Hz,1H),7.67(d,J＝7.5Hz,1H),7.58(d,J＝2.4Hz,1H),7.47–7.38(m,2H),7.07(d,J＝2.3Hz,1H),3.91–3.89(m,4H),3.26–3.23(m,4H)；13C NMR(100MHz,CDCl3):δ149.2,135.4,127.30,127.28,127.27,126.9,124.9,123.7,122.9,110.2,66.9,49.6；HRMS(ESI-TOF):理论计算值：C14H15BrNO+[M+H+]292.0332,实测值：292.0332。
实施例5：化合物I-5的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-芘硼酸频哪醇酯(98.4mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-1(黄色固体，产率70％)。1H NMR(400MHz,CDCl3):δ8.12(d,J＝7.6Hz,2H),8.03–8.01(m,2H),7.96–7.88(m,3H),7.72(s,2H),4.01–3.99(m,4H),3.47–3.45(m,4H)；13C NMR(100MHz,CDCl3):δ149.7,132.4,130.3,128.0,127.1,125.2,124.9,124.8,119.9,112.7,67.2,50.1；HRMS(ESI-TOF):理论计算值：C20H18NO+[M+H+]288.1383,实测值：288.1385。
实施例6：化合物I-6的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-甲基苯硼酸频哪醇酯(65.4mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-1(无色油状液体，产率70％)。1H NMR(400MHz,CDCl3):δ7.20–7.16(m,1H),6.75–6.71(m,3H),3.88–3.85(m,4H),3.17–3.14(m,4H),2.34(s,3H)；13C NMR(100MHz,CDCl3):δ151.5,139.0,129.2,121.1,116.7,113.0,67.1,49.6,21.9；HRMS(ESI-TOF):理论计算值：C11H16NO+[M+H+]178.1226,实测值：178.1229。
实施例7：化合物I-7的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-乙基苯硼酸频哪醇酯(69.6mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-1(无色油状液体，产率61％)。1H NMR(400MHz,CDCl3):δ7.21(t,J＝7.8Hz,1H),6.78–6.75(m,3H),3.89–3.86(m,4H),3.18–3.16(m,4H),2.63(q,J＝7.6Hz,2H),1.25(t,J＝7.8Hz,3H)；13C NMR(100MHz,CDCl3):δ151.5,145.4,129.2,119.9,115.6,113.2,67.1,49.6,29.3,15.8；HRMS(ESI-TOF):理论计算值：C12H18NO+[M+H+]192.1383,实测值：192.1385。
实施例8：化合物I-8的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-异丙基苯硼酸频哪醇酯(69.6mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-1(无色油状液体，产率44％)。1H NMR(400MHz,CDCl3):δ7.22(t,J＝7.8Hz,1H),6.81–6.74(m,3H),3.89–3.86(m,4H),3.18–3.16(m,4H),2.87(hept,J＝6.9Hz,1H),1.26(s,3H),1.25(s,3H)；13C NMR(100MHz,CDCl3):δ151.5,150.1,129.2,118.5,114.4,113.3,67.1,49.7,34.6,24.2；HRMS(ESI-TOF):理论计算值：C13H20NO+[M+H+]206.1539,实测值：206.1543。
实施例9：化合物I-9的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-三氟甲基苯硼酸频哪醇酯(81.6mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-1(无色油状液体，产率39％)。1H NMR(400MHz,CDCl3):δ7.37(t,J＝8.2Hz,1H),7.12–7.05(m,3H),3.88–3.86(m,4H),3.21–3.19(m,4H)；13C NMR(100MHz,CDCl3):δ151.52,131.63(q,J＝31.8Hz),129.76,124.40(q,J＝272.4Hz),118.58,118.57,116.37(q,J＝3.9Hz),112.00(q,J＝3.9Hz),66.86,48.97；19FNMR(376MHz,CDCl3)δ–62.7；HRMS(ESI-TOF):理论计算值：C11H13F3NO+[M+H+]232.0944,实测值：232.0946。
实施例10：化合物I-10的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-甲氧基苯硼酸频哪醇酯(70.2mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-10(无色油状液体，产率39％)。1H NMR(400MHz,CDCl3):δ7.22–7.17(m,1H),6.55–6.52(m,1H),6.46–6.44(m,2H),3.87–3.84(m,4H),3.80(s,3H),3.17–3.14(m,4H)；13C NMR(100MHz,CDCl3):δ160.7,152.8,123.0,108.6,104.8,102.3,67.0,55.3,49.4；HRMS(ESI-TOF):理论计算值：C11H16NO2 +[M+H+]194.1176,实测值：194.1177。
实施例11：化合物I-11的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-三氟甲氧基苯硼酸频哪醇酯(86.4mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-11(无色油状液体，产率38％)。1H NMR(400MHz,CDCl3):δ7.28–7.24(m,1H),6.83–6.80(m,1H),6.73–6.71(m,2H),3.87–3.85(m,4H),3.18–3.16(m,4H)；13C NMR(100MHz,CDCl3):δ152.7,150.4,130.2,120.6(q,J＝255.2Hz),113.6,111.8,108.2,66.8,48.9；19F NMR(376MHz,CDCl3)δ–57.47；HRMS(ESI-TOF):理论计算值：C11H13F3NO2 +[M+H+]248.0893,实测值：248.0895。
实施例12：化合物I-12的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯甲酸甲酯(78.6mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-12(黄色油状液体，产率75％)。1H NMR(400MHz,CDCl3):δ7.57(s,1H),7.53(d,J＝7.7Hz,1H),7.32(t,J＝7.9Hz,1H),7.10–7.07(m,1H),3.89(s,3H),3.87–3.85(m,4H),3.20–3.18(m,4H)；13C NMR(100MHz,CDCl3):δ167.4,151.3,131.1,129.3,121.1,120.1,116.4,66.9,52.2,49.2；HRMS(ESI-TOF):理论计算值：C12H16NO3 +[M+H+]222.1125,实测值：222.1125。
实施例13：化合物I-13的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-硝基苯硼酸频哪醇酯(74.7mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-13(黄色固体，产率77％)。1H NMR(400MHz,CDCl3):δ7.73–7.66(m,2H),7.40(t,J＝8.1Hz,1H),7.18(dd,J＝8.3,2.5Hz,1H),3.89–3.87(m,4H),3.26–3.24(m,4H)；13C NMR(100MHz,CDCl3):δ152.0,149.4,129.9,121.0,114.3,109.6,66.7,48.6；HRMS(ESI-TOF):理论计算值：C10H12N2NaO3 +[M+Na+]231.0740,实测值：231.0737。
实施例14：化合物I-14的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-甲基-3-氟苯硼酸频哪醇酯(70.8mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-14(黄色固体，产率77％)。1H NMR(400MHz,CDCl3):δ6.91(t,J＝9.0Hz,1H),6.74–6.67(m,2H),3.86–3.84(m,4H),3.08–3.05(m,4H),2.25(s,3H)；13C NMR(100MHz,CDCl3):δ156.1(d,J＝236.6Hz),147.7(d,J＝2.6Hz),125.2(d,J＝17.8Hz),119.3(d,J＝4.6Hz),115.3(d,J＝22.9Hz),114.9(d,J＝7.5Hz),67.1,50.5,15.1(d,J＝3.3Hz)；19F NMR(376MHz,CDCl3)δ–128.3；HRMS(ESI-TOF):理论计算值：C11H15FNO+[M+H+]196.1132,实测值：196.1133。
实施例15：化合物I-15的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-甲基-3-氟苯硼酸频哪醇酯(70.8mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-15(黄色油状液体，产率56％)。1H NMR(400MHz,CDCl3):δ6.49(s,1H),6.41(s,1H),6.39(s,1H),3.85–3.83(m,4H),3.15–3.13(m,4H),2.30(s,3H)；13C NMR(100MHz,CDCl3):δ163.9(d,J＝242.6Hz),152.8(d,J＝10.5Hz),140.7(d,J＝9.7Hz),111.7(d,J＝2.2Hz),107.3(d,J＝21.3Hz),99.8(d,J＝25.3Hz),66.9,49.1,21.9(d,J＝2.3Hz)；19F NMR(376MHz,CDCl3)δ–113.4；HRMS(ESI-TOF):理论计算值：C11H15FNO+[M+H+]196.1132,实测值：196.1135。
实施例16：化合物I-16的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-甲基-4-氯苯硼酸频哪醇酯(75.6mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-16(黄色油状液体，产率62％)。1H NMR(400MHz,CDCl3):δ6.69–6.68(m,2H),6.59(s,1H),3.85–3.83(m,4H),3.15–3.12(m,4H),2.29(s,3H)；13C NMR(100MHz,CDCl3):δ152.3,140.4,134.8,120.7,114.6,112.9,66.9,49.1,21.7；HRMS(ESI-TOF):理论计算值：C11H15ClNO+[M+H+]212.0837,实测值：212.0839。
实施例17：化合物I-17的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2,4-二甲基苯硼酸频哪醇酯(69.6mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-17(黄色油状液体，产率60％)。1H NMR(400MHz,CDCl3):δ6.57(s,3H),3.87–3.85(m,4H),3.16–3.14(m,4H),2.30(s,6H)；13C NMR(100MHz,CDCl3):δ151.5,138.8,122.1,113.8,67.1,49.7,21.8；HRMS(ESI-TOF):理论计算值：C12H18NO+[M+H+]192.1383,实测值：192.1387。
实施例18：化合物I-18的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯甲酸甲酯(82.8mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-18(无色油状液体，产率74％)。1H NMR(400MHz,CDCl3):δ7.68–7.66(m,2H),7.23(d,J＝7.6Hz,1H),3.89(s,3H),3.86–3.84(m,4H),2.94–2.92(m,4H),2.36(s,3H)；13C NMR(100MHz,CDCl3):δ167.3,151.4,138.5,131.3,128.8,124.7,120.2,67.4,52.3,52.1,18.3；HRMS(ESI-TOF):理论计算值：C13H18NO3 +[M+H+]236.1281,实测值：236.1283。
实施例19：化合物I-19的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2,4-二氟苯硼酸频哪醇酯(72.0mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-19(黄色油状液体，产率69％)。1H NMR(400MHz,CDCl3):δ6.39–6.32(m,2H),6.28(tt,J＝8.8,2.2Hz,1H),3.84–3.82(m,4H),3.15–3.13(m,4H)；13C NMR(100MHz,CDCl3):δ164.1(dd,J＝244.3,15.8Hz),153.4(t,J＝12.2Hz),98.0–97.7(m),94.6(t,J＝26.1Hz),66.6,48.4；19F NMR(376MHz,CDCl3):δ-119.0(s)；HRMS(ESI-TOF):理论计算值：C10H12F2NO+[M+H+]200.0881,实测值：200.0877。
实施例20：化合物I-20的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2,4-二甲氧基苯硼酸频哪醇酯(79.2mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-20(无色油状液体，产率52％)。1H NMR(400MHz,CDCl3):δ6.084–6.079(m,2H),6.05–6.04(m,1H),3.86–3.83(m,4H),3.78(s,6H),3.15–3.12(m,4H)；13C NMR(100MHz,CDCl3):δ161.6,153.4,94.8,91.9,67.0,55.4,49.5；HRMS(ESI-TOF):理论计算值：C12H18NO3 +[M+H+]224.1281,实测值：224.1276。
实施例21：化合物I-21的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、5-氟-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯甲酸甲酯(84.0mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-21(无色油状液体，产率52％)。1H NMR(400MHz,CDCl3):δ7.36(s,1H),7.20–7.17(m,1H),6.74(dt,J＝11.6,2.3Hz,1H),3.90(s,3H),3.87–3.84(m,4H),3.21–3.19(m,4H)；13C NMR(100MHz,CDCl3):δ166.5(d,J＝3.7Hz),163.6(d,J＝244.1Hz),152.8(d,J＝9.9Hz),132.5(d,J＝9.8Hz),112.0(d,J＝2.3Hz),107.2(d,J＝23.8Hz),106.5(d,J＝25.5Hz),66.7,52.5,48.6；19F NMR(376MHz,CDCl3):δ–111.4；HRMS(ESI-TOF):理论计算值：C12H15FNO3 +[M+H+]240.1030,实测值：240.1024。
实施例22：化合物I-22的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-(2-溴苯氧基)-甲基苯硼酸频哪醇酯(116.4mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-22(无色油状液体，产率55％)。1HNMR(400MHz,CDCl3):δ7.56(dd,J＝7.9,1.6Hz,1H),7.31–7.21(m,2H),7.09(s,1H),6.97–6.93(m,2H),6.88–6.83(m,2H),5.13(s,2H),3.88–3.86(m,4H),3.20–3.18(m,4H)；13C NMR(100MHz,CDCl3):δ155.1,151.7,137.7,133.5,129.5,128.6,122.3,118.5,115.2,114.1,114.0,112.6,71.0,67.0,49.3；HRMS(ESI-TOF):理论计算值：C17H19BrNO2 +[M+H+]348.0594,实测值：348.0589。
实施例23：化合物I-23的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-(2-碘苯氧基)-甲基苯硼酸频哪醇酯(130.8mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-23(无色油状液体，产率51％)。1HNMR(400MHz,CDCl3):δ7.79(dd,J＝7.8,1.6Hz,1H),7.30–7.25(m,2H),7.14(t,J＝1.9Hz,1H),7.00–6.95(m,1H),6.88–6.84(m,2H),6.72(td,J＝7.6,1.3Hz,1H),5.12(s,2H),3.88–3.86(m,4H),3.21–3.18(m,4H)；13C NMR(100MHz,CDCl3):δ157.3,151.7,139.6,137.7,129.6,129.4,123.0,118.4,115.2,114.2,112.9,87.0,71.0,67.0,49.4；HRMS(ESI-TOF):理论计算值：C17H19INO2 +[M+H+]396.0455,实测值：396.0454。
实施例24：化合物I-24的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-氟-6-甲基-5-吡啶硼酸频哪醇酯(71.1mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-24(无色油状液体，产率43％)。1HNMR(400MHz,CDCl3):δ7.56(s,1H),7.04(dd,J＝10.1,1.9Hz,1H),3.87–3.85(m,4H),3.10–3.07(m,4H),2.28(s,3H)；13C NMR(100MHz,CDCl3):δ154.5(d,J＝236.8Hz),138.2(d,J＝14.3Hz),134.5(d,J＝23.8Hz),131.6(d,J＝4.6Hz),128.2(d,J＝4.8Hz),66.9,50.4(d,J＝3.7Hz),17.8；19F NMR(376MHz,CDCl3):δ–78.1；HRMS(ESI-TOF):理论计算值：C10H14FN2O+[M+Na+]197.1085,实测值：197.1086。
实施例25：化合物I-25的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、2-甲氧基-6-甲基-3-吡啶硼酸频哪醇酯(74.7mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-25(无色油状液体，产率44％)。1HNMR(400MHz,CDCl3):δ6.25(d,J＝1.9Hz,1H),5.88(d,J＝2.0Hz,1H),3.88(s,3H),3.81–3.79(m,4H),3.23–3.21(m,4H),2.36(s,3H)；13C NMR(100MHz,CDCl3):δ165.6,158.6,156.6,102.9,90.3,66.6,53.4,46.9,24.7；HRMS(ESI-TOF):理论计算值：C11H17N2O2 +[M+H+]209.1285,实测值：209.1289。
实施例26：化合物I-26的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、5-喹啉硼酸频哪醇酯(76.5mg,0.3mmol)、4-苯甲酸吗啉酯(41.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-26(黄色固体，产率74％)。1H NMR(400MHz,CDCl3):δ6.25(d,J＝1.9Hz,1H),5.88(d,J＝2.0Hz,1H),3.88(s,3H),3.81–3.79(m,4H),3.23–3.21(m,4H),2.36(s,3H)；13C NMR(100MHz,CDCl3):δ165.6,158.6,156.6,102.9,90.3,66.6,53.4,46.9,24.7；HRMS(ESI-TOF):理论计算值：C11H17N2O2 +[M+H+]209.1285,实测值：209.1289。
实施例27：化合物I-27的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(110.4mg,0.8mmol)、降冰片烯(37.6mg,0.4mmol)、4-氟苯硼酸硼酸频哪醇酯(66.6mg,0.3mmol)、4-苯甲酸吗啉酯(82.8mg,0.4mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-27(白色固体，产率42％)。1H NMR(400MHz,CDCl3):δ6.18–6.16(m,2H),6.13(d,J＝2.1Hz,1H),3.85–3.82(m,8H),3.14–3.12(m,8H)；13C NMR(100MHz,CDCl3):δ164.8(d,J＝240.1Hz),153.5(d,J＝12.1Hz),98.4(d,J＝2.0Hz),94.9(d,J＝25.7Hz),66.9,49.3；19F NMR(376MHz,CDCl3):δ-109.7；HRMS(ESI-TOF):理论计算值：C14H20FN2O2 +[M+H+]267.1503,实测值：267.1502。
实施例28：化合物I-28的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(110.4mg,0.8mmol)、降冰片烯(37.6mg,0.4mmol)、4-氯苯硼酸硼酸频哪醇酯(71.4mg,0.3mmol)、4-苯甲酸吗啉酯(82.8mg,0.4mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-28(无色油状液体，产率47％)。1H NMR(400MHz,CDCl3):δ6.43(s,1H),6.42(s,1H),6.28(t,J＝2.1Hz,1H),3.84–3.82(m,8H),3.14–3.12(m,8H)；13C NMR(100MHz,CDCl3):δ153.1,135.8,108.0,101.5,66.9,49.3；HRMS(ESI-TOF):理论计算值：C14H20ClN2O2 +[M+H+]283.1208,实测值：283.1207。
实施例29：化合物I-29的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(110.4mg,0.8mmol)、降冰片烯(37.6mg,0.4mmol)、4-溴苯硼酸硼酸频哪醇酯(84.6mg,0.3mmol)、4-苯甲酸吗啉酯(82.8mg,0.4mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-29(无色油状液体，产率44％)。1H NMR(400MHz,CDCl3):δ6.57(s,1H),6.57(s,1H),6.32(t,J＝2.1Hz,1H),3.84–3.81(m,8H),3.14–3.11(m,8H)；13C NMR(100MHz,CDCl3):δ153.3,124.1,111.0,102.1,66.9,49.4；HRMS(ESI-TOF):理论计算值：C14H20BrN2O2 +[M+H+]327.0703,实测值：327.0704。
实施例30：化合物I-30的制备
Methyl 2-(bis(tert-butoxycarbonyl)amino)-3-(3,5-dimorpholinophenyl)propanoate(3ad)
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(110.4mg,0.8mmol)、降冰片烯(37.6mg,0.4mmol)、2-(二(叔丁氧羰基)氨基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)丙酸甲酯(151.5mg,0.3mmol)、4-苯甲酸吗啉酯(82.8mg,0.4mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-30(无色油状液体，产率26％)。1H NMR(400MHz,CDCl3):δ6.30–6.28(m,3H),5.13(dd,J＝10.5,4.8Hz,1H),3.84–3.81(m,8H),3.74(s,3H),3.32(dd,J＝14.0,4.8Hz,1H),3.17–3.12(m,1H)，3.12–3.09(m,8H),1.39(s,18H)；13C NMR(100MHz,CDCl3):δ171.1,152.5,151.9,139.2,109.9,102.7,83.0,67.1,59.4,52.4,49.9,36.8,28.0；HRMS(ESI-TOF):理论计算值：C28H43N3NaO8 +[M+Na+]572.2941,实测值：572.2941。
实施例31：化合物I-31的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酸哌啶酯(41.0mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-31(白色固体，产率57％)。1H NMR(400MHz,CDCl3):δ7.72–7.64(m,3H),7.39–7.35(m,1H),7.30–7.23(m,2H),7.12(d,J＝2.5Hz,1H),3.28–3.21(m,4H),1.79–1.73(m,4H),1.65–1.58(m,2H)；13C NMR(100MHz,CDCl3):δ150.2,134.8,128.6,128.4,127.5,126.8,126.2,123.2,120.3,110.5,51.2,26.0,24.5；HRMS(ESI-TOF):理论计算值：C15H18N+[M+H+]212.1434,实测值：212.1432。
实施例32：化合物I-32的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酸-4-甲基哌啶酯(43.8mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-32(黄色固体，产率70％)。1H NMR(400MHz,CDCl3):δ7.64–7.59(m,3H),7.33–7.29(m,1H),7.22–7.18(m,2H),7.06(s,1H),3.72–3.68(m,2H),2.73–2.66(m,2H),1.73–1.69(m,2H),1.55–1.42(m,2H),1.39–1.29(m,2H),0.93(d,J＝6.4Hz,3H)；13C NMR(100MHz,CDCl3):δ149.9,134.8,128.6,128.4,127.5,126.8,126.2,123.2,120.3,110.5,50.5,34.3,30.9,22.1；HRMS(ESI-TOF):理论计算值：C16H20N+[M+H+]226.1590,实测值：226.1592。
实施例33：化合物I-33的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酸-4-苯基哌啶酯(43.8mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-33(黄色固体，产率72％)。1H NMR(400MHz,CDCl3):δ7.74–7.69(m,3H),7.42–7.37(m,1H),7.35–7.18(m,8H),3.95–3.92(m,2H),2.93–2.86(m,2H),2.74–2.66(m,1H),2.02–1.91(m,4H)；13C NMR(100MHz,CDCl3):δ149.8,146.2,134.8,128.8,128.7,128.5,127.5,127.01,126.8,126.5,126.3,123.4,120.3,110.7,51.0,42.7,33.5；HRMS(ESI-TOF):理论计算值：C21H22N+[M+H+]288.1747,实测值：288.1747。
实施例34：化合物I-34的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酸-4-羟基哌啶酯(43.8mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-34(白色固体，产率73％)。1H NMR(400MHz,CDCl3):δ7.72–7.66(m,3H),7.41–7.37(m,1H),7.30–7.24(m,2H),7.13(d,J＝2.4Hz,1H),3.89–3.83(m,1H),3.68–3.63(m,2H),3.02–2.95(m,2H),2.07–2.01(m,2H),1.78–1.69(m,3H)；13C NMR(100MHz,CDCl3):δ149.2,134.7,128.8,128.5,127.5,126.8,126.3,123.4,120.1,110.7,68.0,47.8,34.3；HRMS(ESI-TOF):理论计算值：C15H18NO+[M+H+]228.1383,实测值：228.1378。
实施例35：化合物I-35的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酸-4-((叔丁基二甲硅基)氧基)哌啶酯(67.0mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-35(白色固体，产率45％)。1HNMR(400MHz,CDCl3):δ7.71–7.66(m,3H),7.40–7.36(m,1H),7.30–7.24(m,2H),7.14(d,J＝1.9Hz,1H),3.94–3.88(m,1H),3.57–3.51(m,2H),3.14–3.08(m,2H),1.96–1.90(m,2H),1.77–1.69(m,2H),0.91(s,9H),0.09(s,6H)；13C NMR(100MHz,CDCl3):δ149.5,134.8,128.7,128.4,127.5,126.8,126.3,123.3,120.0,110.5,67.6,47.1,34.5,26.0,18.5,-4.5；HRMS(ESI-TOF):理论计算值：C21H32NOSi+[M+H+]342.2248,实测值：342.2243。
实施例36：化合物I-36的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酸-4-羟甲基哌啶酯(47.0mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-36(紫色固体，产率83％)。1H NMR(400MHz,CDCl3):δ7.70–7.66(m,3H),7.40–7.36(m,1H),7.30–7.25(m,2H),7.14(s,1H),3.79–3.75(m,1H),3.66–3.53(m,3H),2.83–2.77(m,1H),2.66–2.60(m,1H),2.01–1.90(m,1H),1.87–1.67(m,4H),1.26–1.11(m,1H)；13C NMR(100MHz,CDCl3):δ149.9,134.7,128.7,128.5,127.5,126.8,126.3,123.4,120.4,110.8,66.2,53.8,51.0,38.7,27.2,24.8；HRMS(ESI-TOF):理论计算值：C16H20NO+[M+H+]242.1539,实测值：242.1547。
实施例37：化合物I-37的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酸-4-(羟基二苯基甲基)哌啶酯(77.4mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-37(黄色固体，产率53％)。1H NMR(400MHz,CDCl3):δ7.70–7.65(m,3H),7.53–7.51(m,4H),7.40–7.19(m,9H),7.10(s,1H),3.86–3.81(m,2H),2.84–2.77(m,2H),2.66–2.58(m,1H),2.13(s,1H),1.69–1.60(m,4H)；13CNMR(100MHz,CDCl3):δ149.5,145.9,134.7,128.7,128.5,128.4,127.5,126.8,126.3,125.9,123.4,120.2,110.6,79.7,50.7,44.3,26.6；HRMS(ESI-TOF):理论计算值：C28H28NO+[M+H+]394.2165,实测值：394.2169。
实施例38：化合物I-38的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、8-苯甲酸-1,4-二氧-8-氮杂螺[4.5]癸酯(52.6mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-38(黄色固体，产率57％)。1H NMR(400MHz,CDCl3):δ7.74–7.68(m,3H),7.43–7.39(m,1H),7.32–7.27(m,2H),7.16(d,J＝2.4Hz,1H),4.02(s,4H),3.47–3.42(m,4H),1.95–1.89(m,4H)；13C NMR(100MHz,CDCl3):δ148.9,134.7,128.8,128.5,127.5,126.8,126.3,123.4,120.1,110.8,107.3,64.5,48.2,34.7；HRMS(ESI-TOF):理论计算值：C17H20NO2 +[M+H+]270.1489,实测值：270.1489。
实施例39：化合物I-39的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酰氧基哌啶-3-甲酸乙酯(52.6mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-39(黄色油状液体，产率71％)。1H NMR(400MHz,CDCl3):δ7.74–7.69(m,3H),7.43–7.39(m,1H),7.32–7.29(m,2H),7.17(s,1H),4.21(q,J＝7.1Hz,2H),3.85–3.81(m,1H),3.63–3.59(m,1H),3.17–3.11(m,1H),2.95–2.88(m,1H),2.79–2.72(m,1H),2.09–2.06(m,1H),1.92–1.67(m,3H),1.31(t,J＝7.1Hz,3H)；13CNMR(100MHz,CDCl3):δ174.0,149.4,134.7,128.8,128.6,127.5,126.8,126.3,123.5,120.4,110.9,60.7,52.6,50.3,41.6,27.1,24.4,14.4；HRMS(ESI-TOF):理论计算值：C18H22NO2 +[M+H+]284.1645,实测值：284.1639。
实施例40：化合物I-40的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酰氧基哌啶-4-甲酸乙酯(52.6mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-40(黄色油状液体，产率59％)。1H NMR(400MHz,CDCl3):δ7.72–7.66(m,3H),7.41-7.37(m,1H),7.30–7.25(m,2H),7.12(d,J＝2.3Hz,1H),4.17(q,J＝7.1Hz,2H),3.75(dt,J＝12.4,3.2Hz,2H),2.86(td,J＝12.3,2.8Hz,2H),2.51–2.43(m,1H),2.15–1.86(m,4H),1.28(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δ175.0,149.5,134.7,128.8,128.6,127.5,126.8,126.3,123.5,120.2,110.8,60.6,49.7,41.2,28.2,14.4；HRMS(ESI-TOF):理论计算值：C18H22NO2 +[M+H+]284.1645,实测值：284.1639。
实施例41：化合物I-41的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酸-4-苯甲酰基哌嗪酯(61.8mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-41(黄色油状液体，产率43％)。1H NMR(400MHz,CDCl3):δ7.76–7.68(m,3H),7.49–7.39(m,6H),7.35–7.29(m,1H),7.26–7.24(m,1H),7.12(s,1H),3.99(brs,2H),3.64(brs,2H),3.35(brs,2H),3.21(brs,2H)；13C NMR(100MHz,CDCl3):δ170.5,148.8,135.7,134.5,130.0,129.1,129.0,128.7,127.6,127.2,126.9,126.6,124.0,119.8,111.2,50.3,50.1,47.7,42.2；HRMS(ESI-TOF):理论计算值：C21H21N2O+[M+H+]317.1648,实测值：317.1649。
实施例42：化合物I-42的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、4-苯甲酰氧基-1-哌嗪甲酸苄酯(67.8mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-42(黄色固体，产率50％)。1H NMR(400MHz,CDCl3):δ7.76–7.66(m,3H),7.44–7.28(m,7H),7.27–7.22(m,1H),7.11(s,1H),5.18(s,2H),3.71(t,J＝5.1Hz,4H),3.24(s,4H)；13C NMR(100MHz,CDCl3):δ155.4,149.0,136.7,134.5,129.0,128.9,128.7,128.2,128.1,127.6,126.9,126.5,123.9,119.9,111.1,67.4,49.9,43.9；HRMS(ESI-TOF):理论计算值：C22H23N2O2 +[M+H+]347.1754,实测值：347.1751。
实施例43：化合物I-43的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、4-苯甲酰氧基-1-哌嗪甲酸叔丁酯(61.2mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-43(白色固体，产率60％)。1H NMR(400MHz,CDCl3):δ7.76–7.67(m,3H),7.41(t,J＝7.1Hz,1H),7.34–7.24(m,2H),7.12(d,J＝2.3Hz,1H),3.63(t,J＝5.1Hz,4H),3.23(t,J＝5.2Hz,4H),1.50(s,9H)；13C NMR(100MHz,CDCl3):δ154.9,149.2,134.6,129.0,128.9,127.6,126.9,126.5,123.8,119.9,111.0,80.1,49.9,28.6；HRMS(ESI-TOF):理论计算值：C19H24N2NaO2 +[M+Na+]335.1730,实测值：335.1731。
实施例44：化合物I-44的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酸硫代吗啉酯(44.6mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-44(白色固体，产率56％)。1H NMR(400MHz,CDCl3):δ7.75–7.68(m,3H),7.44–7.40(m,1H),7.33–7.29(m,1H),7.22(dd,J＝9.0,2.5Hz,1H),7.13(m,1H),3.65–3.63(m,4H),2.83–2.81(m,4H)；13C NMR(100MHz,CDCl3):δ149.2,134.7,129.0,128.6,127.6,126.8,126.5,123.7,120.3,111.5,52.5,27.1；HRMS(ESI-TOF):理论计算值：C14H16NS+[M+H+]230.0998,实测值：230.0993。
实施例45：化合物I-45的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酸吡咯酯(38.2mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-45(白色固体，产率42％)。1H NMR(400MHz,CDCl3):δ7.70–7.62(m,3H),7.36–7.32(m,1H),7.17–7.14(m,1H),7.00(dd,J＝9.0,2.5Hz,1H),6.76(d,J＝2.4Hz,1H),3.43–3.40(m,4H),2.08–2.04(m,4H)；13C NMR(100MHz,CDCl3):δ146.0,135.4,128.9,127.7,126.4,126.3,125.9,121.3,115.8,104.8,48.0,25.7；HRMS(ESI-TOF):理论计算值：C14H16N+[M+H+]198.1277,实测值：198.1276。
实施例46：化合物I-46的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、1-苯甲酸环己亚胺酯(43.8mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-46(黄色油状液体，产率33％)。1H NMR(400MHz,CDCl3):δ7.69–7.65(m,2H),7.61(d,J＝8.3Hz,1H),7.36–7.32(m,1H),7.17–7.10(m,2H),6.88(d,J＝2.5Hz,1H),3.60–3.57(m,4H),1.88–1.84(m,4H),1.60–1.56(m,4H)；13C NMR(100MHz,CDCl3):δ146.9,135.5,129.0,127.5,126.2,126.0,121.4,115.3,104.6,49.6,28.0,27.2；HRMS(ESI-TOF):理论计算值：C16H20N+[M+H+]226.1590,实测值：226.1591。
实施例47：化合物I-47的制备
向装有磁力搅拌子的反应管中加入催化剂醋酸钯(4.5mg，0.02mmol)、碳酸钾(69.0mg,0.5mmol)、降冰片烯(37.6mg,0.4mmol)、1-萘硼酸频哪醇酯(76.2mg,0.3mmol)、O-苯甲酰基-N-苄基-N-甲基羟胺(48.2mg,0.2mmol)、二甲基亚砜(0.8mL)和1,4-二氧六环(2.0mL)，然后加热至70℃在空气保护氛围下反应12小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，滤液依次用水、饱和氯化钠水溶液洗一次、有机溶剂经干燥Na2SO4干燥，过滤、减压除去溶剂，柱层析提纯得化合物I-47(黄色油状液体，产率35％)。1H NMR(400MHz,CDCl3):δ7.68–7.61(m,3H),7.37–7.29(m,3H),7.26–7.24(m,3H),7.21–7.14(m,2H),6.95(d,J＝2.6Hz,1H),4.64(s,2H),3.09(s,3H)；13C NMR(100MHz,CDCl3):δ147.8,139.0,135.2,129.0,128.7,127.6,127.1,127.0,126.9,126.4,126.3,122.1,116.3,106.3,56.9,38.8；HRMS(ESI-TOF):理论计算值：C18H18N+[M+H+]248.1434,实测值：248.1427。
实施例48：化合物II-1的制备
方法一：在氩气体保护下，向干燥并装有磁力搅拌子的反应管中加入催化剂碘化亚铜(1.0mg，0.005mmol)、配体N1,N2-二(4-甲基-2-苯基)乙二酰胺(7.98mg,0.019mmol)、磷酸钾(44.5mg,0.21mmol)、芳基氯化物I-28(28mg，0.1mmol)、氨水(w/w 25％,46μL，0.3mmol)和二甲基亚砜(0.2mL)，然后在氩气保护氛围下120℃加热反应48小时。反应冷却至室温后，混合物直接柱层析提纯得化合物II-1(白色固体，产率61％),同时回收原料I-28(回收率32％)。
方法二：在氩气体保护下，向干燥并装有磁力搅拌子的反应管中加入催化剂氧化亚铜(1.2mg，0.008mmol)、配体N1-(2-甲基萘基),N2-(2-呋喃甲基)-乙二酰胺(2.32mg,0.008mmol)、氢氧化钾(11.8mg,0.21mmol)、芳基溴化物I-29(53mg，0.16mmol)、氨水(w/w25％,64μL，0.8mmol)和乙醇(0.2mL)，然后在氩气保护氛围下80℃加热反应24小时。反应冷却至室温后，混合物直接在减压下浓缩然后直接柱层析提纯得化合物II-1(白色固体，产率64％)。1H NMR(400MHz,CDCl3):δ5.92(t,J＝2.1Hz,1H),5.84(d,J＝1.9Hz,2H),3.83–3.81(m,8H),3.12–3.09(m,8H)；13C NMR(100MHz,CDCl3):δ153.5,148.1,95.8,95.3,67.1,49.7；HRMS(ESI-TOF):理论计算值：C14H22N3O2 +[M+H+]264.1706,实测值：264.1701。

Claims (8)

1.一种合成芳香胺类化合物的方法，其特征在于，包括以下步骤：以芳基硼酸或芳基硼酸酯A为起始原料，以O-甲酰基-羟胺类化合物B为胺化试剂，以钯催化剂和降冰片烯的衍生物为协同催化剂，以碱为促进剂，将以上物料置于30-100℃的有机溶剂中搅拌反应，反应结束后分离提纯，得到一元取代的芳香胺类化合物C或二元取代的芳香胺类化合物D，反应式为：
其中：
R1为氢、芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种；
R2为与Ar环并环的芳环、杂芳环或取代Ar环上氢的取代基，取代基为芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种或几种；n表示R2的个数，0≤n≤3；
R3为氢、C1-20烷基、芳基、杂环芳基；
R4为氢、芳基、杂环芳基、C1-20烷基；
R5、R6为与氮成环的杂环烷烃、杂芳环或氮上的取代基，取代基为为氢、芳基、杂环芳基、C1-20烷基、酯基、酰胺基、磺酰基、烷氧基、叔丁氧羰基、苄氧羰基、苄基、对甲氧基苄基、烷酰基、磺酰基、邻苯二甲酰基、叠氮中的一种；
X、Y、Z为N或CH。
2.根据权利要求1所述的方法，其特征在于：所述的降冰片烯衍生物，具有如下结构：
其中：
R7为五元环上的取代基，o代表取代基个数，0≤o≤8；
R8为双键上的取代基，p代表取代基个数，0≤p≤2；
R7、R8独立地选自金属离子M的羧酸盐、酯基、氰基、硝基、酰胺基、磺酰基、C1-10烷氧基、芳基、杂环芳基、C1-10烷基、卤素中的一种，其中M为Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+中的一种。
3.根据权利要求1所述的方法，其特征在于：所述的钯催化剂为Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(O2CCF3)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2或[Pd(allyl)Cl]2中的一种，所述的碱为碳酸钠、碳酸钾、碳酸铯、醋酸钠、醋酸钾、醋酸铯、磷酸三钾、甲酸钾、碳酸氢钾、氢氧化钾、氢氧化钠、叔丁醇钠中的一种或几种。
4.根据权利要求1所述的方法，其特征在于：所述的有机溶剂为甲醇、乙醇、异丙醇、叔丁醇、四氢呋喃、2-甲基四氢呋喃、***、二甲基乙二醚、甲基叔丁基醚、1,4-环氧六烷、1,3-环氧六烷、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈、二甲基亚砜中的一种或几种。
5.根据权利要求1所述的方法，其特征在于：所述的协同催化剂为钯催化剂及降冰片烯，所述的钯催化剂为Pd(OAc)2，所述的碱为碳酸钾，所述的有机溶剂为1,4-二氧六环和二甲基亚砜。
6.一种邻位胺化的芳香胺类化合物，其特征在于，采用权利要求1～5任一项所述的方法制备得到。
7.一种制备EphB4激酶抑制剂及其衍生物的方法，其特征在于，包括以下步骤：在空气氛围下，使4-卤素取代的苯硼酸或苯硼酸酯E和O-甲酰基-羟胺类化合物B在钯催化剂、碱和降冰片烯衍生物的作用下在有机溶剂中反应，得到中间体F，将所得中间体分离提纯，与胺试剂G经铜催化Ullmann胺化反应制得化合物EphB4激酶抑制剂或其衍生物H，反应式为：
其中：
W为氟、氯、溴、碘和三氟甲磺酸酯中的一种；
R5、R6为与氮成环的杂环烷烃、杂芳环或氮上的取代基，取代基为为氢、芳基、杂环芳基、C1-20烷基、酯基、酰胺基、磺酰基、烷氧基、叔丁氧羰基、苄氧羰基、苄基、对甲氧基苄基、烷酰基、磺酰基、邻苯二甲酰基、叠氮中的一种；
R9为氢、C1-20烷基、芳基、杂环芳基；
R10、R11为与氮成环的杂环烷烃、杂芳环或氮上的取代基，取代基为氢、芳基、杂环芳基、C1-20烷基、酯基、酰胺基、磺酰基、烷氧基、叔丁氧羰基、苄氧羰基、苄基、对甲氧基苄基、烷酰基、磺酰基、邻苯二甲酰基、叠氮中的一种。
8.一种EphB4激酶抑制剂及其衍生物，其特征在于，采用权利要求7所述的方法制备得到。
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111039813A (zh) * 2019-12-24 2020-04-21 江南大学 一种芳香族酰胺类化合物的合成方法
CN114213267A (zh) * 2021-12-15 2022-03-22 江苏超跃化学有限公司 一种利用氨解法制备2-氨基-3-甲基苯甲酸的方法
CN115433097A (zh) * 2022-08-24 2022-12-06 盐城师范学院 一种无金属制备4-丁氧基苯甲酸(2-二乙胺基乙基)酯的方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008132505A1 (en) * 2007-04-27 2008-11-06 Astrazeneca Ab N' - (phenyl) -n- (morpholin-4-yl-pyridin-2-yl) -pyrimidine-2, 4-diamine derivatives as ephb4 kinase inhibitors for the treatment of proliferative conditions
WO2009010794A1 (en) * 2007-07-19 2009-01-22 Astrazeneca Ab 2,4-diamino-pyrimidine derivatives
CN101668749A (zh) * 2007-02-28 2010-03-10 阿斯利康(瑞典)有限公司 新的嘧啶衍生物698
WO2011009695A1 (en) * 2009-07-21 2011-01-27 Universität Zürich New anti-angiogenic compounds
CN102558095A (zh) * 2011-12-13 2012-07-11 大连理工大学 一种芳香胺类化合物的制备方法
CN104744190A (zh) * 2015-03-26 2015-07-01 浙江大学 一种制备邻炔基苯胺衍生物的方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101668749A (zh) * 2007-02-28 2010-03-10 阿斯利康(瑞典)有限公司 新的嘧啶衍生物698
WO2008132505A1 (en) * 2007-04-27 2008-11-06 Astrazeneca Ab N' - (phenyl) -n- (morpholin-4-yl-pyridin-2-yl) -pyrimidine-2, 4-diamine derivatives as ephb4 kinase inhibitors for the treatment of proliferative conditions
WO2009010794A1 (en) * 2007-07-19 2009-01-22 Astrazeneca Ab 2,4-diamino-pyrimidine derivatives
WO2011009695A1 (en) * 2009-07-21 2011-01-27 Universität Zürich New anti-angiogenic compounds
CN102558095A (zh) * 2011-12-13 2012-07-11 大连理工大学 一种芳香胺类化合物的制备方法
CN104744190A (zh) * 2015-03-26 2015-07-01 浙江大学 一种制备邻炔基苯胺衍生物的方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CATHERINE BARDELLE 等: "Inhibitors of the tyrosine kinase EphB4. Part 3: Identification of non-benzodioxole-based kinase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
SHUQING CHEN 等: "Redox-neutral ortho-C–H amination of pinacol arylborates via palladium(II)/norbornene catalysis for aniline synthesis", 《CHEMICAL SCIENCE》 *
SHUQING CHEN 等: "The discovery of a Palladium(Ⅱ)-initiated borono-Catellani reaction", 《ANGEW. CHEM. INT. ED.》 *
ZHE DONG 等: "Ortho vs Ipso: Site-Selective Pd and Norbornene-Catalyzed Arene C-H Amination Using Aryl Halides", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111039813A (zh) * 2019-12-24 2020-04-21 江南大学 一种芳香族酰胺类化合物的合成方法
CN111039813B (zh) * 2019-12-24 2022-07-01 江南大学 一种芳香族酰胺类化合物的合成方法
CN114213267A (zh) * 2021-12-15 2022-03-22 江苏超跃化学有限公司 一种利用氨解法制备2-氨基-3-甲基苯甲酸的方法
CN114213267B (zh) * 2021-12-15 2024-02-23 江苏超跃化学有限公司 一种利用氨解法制备2-氨基-3-甲基苯甲酸的方法
CN115433097A (zh) * 2022-08-24 2022-12-06 盐城师范学院 一种无金属制备4-丁氧基苯甲酸(2-二乙胺基乙基)酯的方法

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