CN111675626A - 一种紫罗兰酮生物碱衍生物及医药用途 - Google Patents
一种紫罗兰酮生物碱衍生物及医药用途 Download PDFInfo
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Abstract
本发明提供一种具有抗乳腺癌转移作用的紫罗兰酮生物碱衍生物或其药学上可接受的盐,其结构如式I:
Description
技术领域
本发明涉及一种紫罗兰酮生物碱衍生物、制备方法及其作为抗乳腺癌转移药物的应用,属于药物化学研究领域。
背景技术
根据美国癌症学会期刊《临床医师癌症杂志》发表的“2018年全球癌症统计数据”报告,2018年全球将有大约1810万癌症新发病例和960万癌症死亡病例。新增1810万癌症病例中,亚洲占据近一半,960万癌症死亡患者中,亚洲占近七成,到2030年全球新增肿瘤病例将增加约50%。因此,肿瘤已经成为当前严重威胁人类生命健康的重大疾病之一。在大量临床病例中,肿瘤转移是导致恶性肿瘤患者死亡的最主要原因,约90%恶性肿瘤患者的死亡原因与肿瘤转移相关。因此,深入了解肿瘤转移的基本机制,寻求抑制肿瘤转移的新策略,发现抗肿瘤转移药物是有效预防和治疗恶性肿瘤转移的关键。
肿瘤转移是恶性肿瘤的重要生物学特征之一,肿瘤细胞的侵袭和转移是多阶段、多步骤、多因素和多基因相互协调作用的过程。肿瘤细胞的转移一般认为包括以下四个阶段:(1)肿瘤细胞间粘附能力降低,肿瘤细胞脱离原发肿瘤灶并粘附于基底膜;(2)脱落后的肿瘤细胞自分泌和诱导肿瘤间质细胞分泌多种蛋白酶降解细胞外基质及基底膜,迁移侵袭至血管;(3)侵入循环系统,随着血液迁移并粘附新部位的血管内皮细胞;(4)肿瘤细胞穿透血管壁后,在局部定居、增殖,并最后在特定的组织或者器官形成转移灶。
目前,在研的各种抗肿瘤转移化学药物是针对肿瘤转移的某一阶段的特定靶点进行药物发现与开发工作。例如,处于III期临床阶段的Cilengitide,是以整合素为靶点抑制肿瘤细胞粘附的药物,它作用于αvβ3受体和αvβ5受体,针对神经胶质细胞能够抑制血管生成[4]。作用于基质金属蛋白酶(MMP)的药物Batimastat(BB-94)能显著地抑制多种MMP亚型的活性,进而抑制肿瘤细胞利用MMP进行的侵袭,并抑制血管生成。血管内皮生长因子(VEGF)是新生血管形成的中心调控因子,它能增加血管的通透性,为肿瘤细胞的转移和扩散提供有利条件。Vandetanib(ZD-6474)通过作用于VEGF受体来抑制肿瘤血管生成,同时也抑制肿瘤细胞的增殖。
因此,干扰或阻断恶性肿瘤在宿主体内播散的过程,是延长生存期、提高生存质量和降低死亡率的最有效手段。另一方面,由于常规原发肿瘤切除后的抗肿瘤转移药物治疗是持续的、长期给药过程,理想的抗肿瘤转移药物不仅阻断肿瘤细胞在体内的侵袭转移,而且应该是非细胞毒药物或者毒副作用很低,不会对免疫系统造成损害。肿瘤化疗药物虽然能够杀死或者抑制肿瘤生长,但是由于均为细胞毒药物,杀死肿瘤细胞的同时,对正常细胞也造成很大的伤害。因此,理想的抗肿瘤转移药物应该是非细胞毒药物,毒副作用低。
116)本研究组发明专利公开了一种抗肿瘤转移作用的转筋草生物碱类化合物(申201010114809.9),进一步以活性成分Salignone为先导,合成了一系列衍生物,公开了发明专利《一种抗乳腺癌转移作用的孕甾烷生物碱衍生物及医药用途》(专利号201310749522.7)。。本研究组对转筋草中紫罗兰酮生物碱进行衍生合成,发现的抗肿瘤转移先导化合物ION-31a[Synthesis and anti-metastatic effects of novel chiralionone alkaloid derivatives,Hai-Jun Fang,Xiao-Ai Shou,Qian Liu,Chun-Chun Gan,Hong-Quan Duan,*Nan Qin**,European Journal of Medicinal Chemistry 101(2015)245-253],进一步衍生合成了大量的不同类型衍生物,经过或行筛选,大部分化合物显示了较强的抗乳腺癌转移活性,化合物N2,5,7,8,10,13,15,18,19,21,23-27,29,37-39,43,58-61,66,71的活性尤为突出。
发明内容
本发明的目的在于提供一种紫罗兰酮生物碱衍生物以及所述化合物在用于制备抗乳腺癌转移药物中的用途。
本发明是通过下述技术方案加以实现的:
一方面,本发明提供了一种紫罗兰酮生物碱衍生物或其药学上可接受的盐,其结构及合成路线如式1-4所示:
式1 紫罗兰酮生物碱衍生物N1-N28的合成路线
式2 紫罗兰酮生物碱衍生物N29-N40的合成路线
式3 紫罗兰酮生物碱衍生物N41-N48的合成路线
式4 紫罗兰酮生物碱衍生物N49-N73的合成路线
另一方面,本发明提供了一种孕甾烷生物碱衍生物或其药学上可接受的盐在制备抗乳腺癌转移药物方面的用途。
首先,本发明对合成的孕甾烷生物碱衍生物N1-N73进行了细胞毒性的测定,进一步以非细胞毒剂量进行了抗乳腺癌转移活性筛选。
各衍生物对乳腺癌细胞的毒性作用
MTT比色测定法的原理:此分析方法以还原3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)为基础,是一种检测细胞存活和生长状况的常用方法。MTT为一种通用的细胞染色剂,活细胞的线粒体中存在与NADP相关的琥珀酸脱氢酶,可将外源性黄色MTT还原为不溶性的蓝紫色结晶物甲臜(Formazane),并沉积在细胞中,死细胞此酶消失,MTT不被还原。用DMSO溶解Formazane后用酶标仪在550nm波长处检测光密度的变化大小,来衡量测试药物对细胞的生长抑制作用,进而评价细胞毒性。
实验步骤:将培养好的细胞用0.25%的胰酶消化,吸出胰酶后,用含10%FBS的培养液终止消化,混匀细胞悬液,计数调节密度为1x104,将调好的细胞悬液加于96孔板,每孔180ul,置于37℃,5%CO2的孵箱内培养24小时,24小时后加药,每个浓度5个复孔,加好药后继续置于37℃,5%CO2的孵箱内培养48小时,之后每孔加5mg/ml的MTT20ul,继续置于37℃,5%CO2的孵箱内培养4小时,4小时后取出96板,将上清吸出,每孔加100ul的DMSO,用酶标仪在570nm波长下测量吸光度。抑制率=(1-加药组OD值/空白组OD值)x 100%
抗乳腺癌转移活性评价 Transwell chemotaxis方法原理
在Transwell小室上腔直接将8μm孔径滤膜安放在侵袭腔室的上下腔室之间,肿瘤细胞通过变形运动穿过滤膜,用这种模型能够分析细胞运动能力的大小。在药物筛选时加入趋化诱导剂(趋化因子EGF),通过衡量与测试药物共培养的肿瘤细胞和空白组肿瘤细胞趋化穿过滤膜的细胞数量变化,来表达测试药物抑制肿瘤细胞的趋化迁移能力的大小,进而评价测试药物抗肿瘤转移的活性强弱。阳性对照为试剂LY294002(一种具有抗肿瘤转移作用的PI3K抑制剂)和先导化合物ION-31a。
实验步骤:
1.样品非细胞毒剂量的筛选:利用MTT法筛选出非细胞毒作用的样品浓度。
2.样品与细胞共培养:将细胞铺于6孔板,置于37℃,5%CO2的孵箱内培养24小时使其贴壁,24小时后以确定的浓度将样品加于6孔板内,37℃5%CO2孵箱内共孵育24小时。
3.趋化实验:将用样品处理过的细胞分别用0.25%的胰酶消化后,用含10%FBS的培养液终止消化,该细胞悬液1300rpm离心5分钟。将上清倒出,加0.1%的BM将细胞混匀后再次离心5分钟后,计数,将细胞密度调成5x105,放置在孵箱内备用。于冰上配置趋化因子EGF,加于趋化小室的下室,每孔30ul,将包被好的膜铺于下室上,放好胶垫,固定上室,将之前准备好的细胞悬液加到上室,每孔50ul,每个样品浓度3个复孔,加好后置于CO2孵箱内培养3.5h后取出,取出下室,刮去没有趋化过来的细胞,然后用三步染色试剂进行固定和染色,染色后将膜用石蜡油固定,于显微镜下计数。
4.统计计算方法:计数时,每个孔选取5个视野分别计数,取平均值,三个复孔再取平均即为该样品浓度下的趋化细胞数。数据用SPSS11.5进行处理,计算半数抑制率IC50。
计算公式:
实验结果
各优选衍生物对MB-MDA-231(人乳腺癌细胞)趋化迁移的半数抑制浓度(IC50)如表1所示:
表1 各衍生物抑制乳腺癌细胞趋化迁移的半数抑制浓度(IC50)
抗乳腺癌转移活性评价表明,优选化合物均在非细胞毒剂量下显示出抗乳腺癌转移活性,其中化合物N2,5,7,8,10,13,15,18,19,21,23-27,29,37-39,43,58-61,66,71的活性尤为突出。
具体实施方式
实施例1.
化合物N1-N3的合成方法:
称取1.0当量中间体7于反应瓶中,加适量丙酮或DMF溶解,加入3.0当量无水碳酸钾和3.0当量相应的溴代物,反应在回流搅拌,TLC监测至反应结束。向反应液中加入1mol/L氢氧化钠水溶液搅拌1h,用EA萃取,合并有机层,用无水硫酸镁干燥,过滤,浓缩得粗品。
化合物N1的合成
以溴乙酸乙酯为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-8∶1,V/V)得黄色油状物,产率为84.3%。1H NMR(400MHz,CDCl3):δ7.27(m,1H,Ar-H),7.09(m,2H,Ar-H),6.93(m,1H,Ar-H),5.80(s,1H,4-H),4.16(q,J=7.0Hz,2H,OCH2),3.77(s,2H,Ar-CH2),3.31(s,2H,Ar-CH2),2.63(t,J=6.8Hz,2H,9-H),2.35(d,J=17.4Hz,1H,2-H),2.01(d,J=17.4Hz,1H,2-H),1.95(d,J=1.0Hz,3H,13-H),1.84(t,J=5.2Hz,1H,6-H),1.72(m,1H,7-H),1.55(m,2H,8-H),1.43(m,1H,7-H),1.27(t,J=7.0Hz,3H,CH3),1.04(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.1(3-C),177.1(CO),165.4(5-C),163.0(d,J=244.2Hz,Ar-C),142.0(d,J=6.8Hz,Ar-C),129.8(d,J=8.1Hz,Ar-C),125.1(4-C),124.3(d,J=2.6Hz,Ar-C),115.5(d,J=21.2Hz,Ar-C),114.0(d,J=21.1Hz,Ar-C),60.3(OCH2),58.0(Ar-CH2),54.5(N-CH2),54.2(9-C),51.1(6-C),47.2(2-C),36.3(1-C),28.8(12-C),27.7(7-C),27.5(8-C),27.1(11-C),24.7(13-C),14.3(CH3).HR-ESIMSm/z 390.2428[M+H]+,calcd for C23H33FNO3,390.2444.
化合物N2的合成
以溴丙炔为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-8∶1.V/V)得黄色油状物,产率为82.7%。1H NMR(400MHz,CDCl3):δ7.26(m,1H,Ar-H),7.08(m,2H,Ar-H),6.94(m,1H,Ar-H),5.81(s,1H,4-H),3.61(s,2H,Ar-CH2),3.31(d,J=2.0Hz,2H,N-CH2),2.54(t,J=6.8Hz,2H,9-H),2.37(d,J=17.2Hz,1H,2-H),2.26(t,J=2.0Hz,1H,CH),2.02(d,J=17.2Hz,1H,2-H),1.97(s,3H,13-H),1.86(t,J=5.4Hz,1H,6-H),1.75(m,1H,7-H),1.58(m,2H,8-H),1.44(m,1H,7-H),1.05(s,3H,11-H),1.01(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.2(3-C),165.4(5-C),162.9(d,J=244.2Hz,Ar-C),141.4(d,J=3.9Hz,Ar-C),129.8(d,J=8.2Hz,Ar-C),125.0(4-C),124.5(d,J=2.6Hz,Ar-C),115.6(d,J=21.1Hz,Ar-C),114.1(d,J=21.0Hz,Ar-C),78.0(C),73.5(CH),57.4(Ar-CH2),53.5(9-C),51.1(6-C),47.1(2-C),41.5(N-CH2),36.3(1-C),28.7(12-C),27.8(7-C),27.2(11-Cand 8-C),24.7(13-C).HR-ESIMS m/z 342.2219[M+H]+,calcd for C22H29FNO,342.2233.
化合物N3的合成
以N-Boc-溴乙胺为原料,按上述方法制备,经硅胶柱色谱(PE∶EA=6∶1-4∶1,V/V)分离纯化得黄色油状物,产率为54.8%。1H NMR(400MHz,CDCl3):δ7.27(m,1H,Ar-H),7.04(m,2H,Ar-H),6.94(m,1H,Ar-H),5.80(s,1H,4-H),3.55(s,2H,Ar-CH2),3.19(m,2H,CH2),2.54(t,J=6.0Hz,2H,9-H),2.44(t,J=6.6Hz,2H,N-CH2),2.35(d,J=17.2Hz,1H,2-H),2.01(d,J=17.2Hz,1H,2-H),1.95(s,3H,13-H),1.82(t,J=5.2Hz,1H,6-H),1.68(m,1H,7-H),1.53(m,2H,8-H),1.44(s,9H,(CH3)3),1.35(m,1H,7-H),1.04(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.2(3-C),165.5(5-C),162.9(d,J=244.3Hz,Ar-C),155.9(CO),141.2(d,J=5.7Hz,Ar-C),129.8(d,J=8.1Hz,Ar-C),125.0(4-C),124.2(d,J=2.1Hz,Ar-C),115.4(d,J=21.2Hz,Ar-C),114.0(d,J=21.0Hz,Ar-C),79.1(C),58.2(Ar-CH2),54.3(N-CH2),53.5(9-C),51.0(6-C),47.1(2-C),38.0(CH2),36.3(1-C),28.7(12-C),28.4((CH3)3),28.0(7-C),27.2(11-C),26.9(8-C),24.8(13-C).HR-ESIMS m/z447.3002[M+H]+,calcd for C26H40FN2O3,447.3023.
实施例2.
化合物N4的合成方法
称取1.0当量化合物N1于反应瓶中,加入适量甲醇溶解,加入1.3当量氢氧化钾,于室温下搅拌,TLC监测至反应结束。加入饱和柠檬酸水溶液使pH=3并搅拌30min,用EA萃取,合并有机层,用无水硫酸镁干燥,过滤,浓缩得粗品,经硅胶柱色谱(DCM∶MeOH=30∶1,V/V)分离纯化得黄色油状物,产率为86.2%。1H NMR(400MHz,DMSO-d6):δ12.08(s,1H,OH),7.37(m,1H,Ar-H),7.18(m,2H,Ar-H),7.09(m,1H,Ar-H),5.71(s,1H,4-H),3.81(s,2H,Ar-CH2),3.32(s,2H,Ar-CH2),2.62(t,J=6.8Hz,2H,9-H),2.30(d,J=17.2Hz,1H,2-H).1.90(m,4H,13-H and 2-H),1.82(t,J=5.4Hz,1H,6-H),1.64(m,1H,7-H),1.49(m,2H,8-H),1.30(m,1H,7-H),0.96(s,3H,11-H),0.92(s,3H,12-H).13C NMR(100MHz,DMSO-d6):δ197.8(3-C),171.9(CO),165.6(5-C),162.2(d,J=241.7Hz,Ar-C),141.7(d,J=5.9Hz,Ar-C),130.1(d,J=8.2Hz,Ar-C),124.7(d,J=2.6Hz,Ar-C),124.2(4-C),115.3(d,J=21.2Hz,Ar-C),113.9(d,J=20.9Hz,Ar-C),57.2(Ar-CH2),54.2(N-CH2),53.6(9-C),50.0(6-C),46.8(2-C),35.9(1-C),28.3(12-C),26.9(7-C),26.5(11-C),24.0(8-C),21.0(13-C).HR-ESIMS m/z 362.2114[M+H]+,calcd for C21H29FNO3,362.2131.
实施例3.
化合物N5的合成方法
称取1.0当量化合物N3于反应瓶中,加入适量DCM溶解,冰浴下加入3.0当量三氟乙酸,于室温下搅拌,TLC监测至反应结束。加入1mol/L氢氧化钠水溶液搅拌,用DCM萃取,合并有机层,无水硫酸镁干燥,过滤,浓缩得黄色油状物,产率85.1%。1H NMR(400MHz,CDCl3):δ7.26(m,1H,Ar-H),7.05(m,2H,Ar-H),6.93(m,1H,Ar-H),5.80(s,1H,4-H),3.55(s,2H,Ar-CH2),2.74(t,J=5.6Hz,2H,N-CH2),2.50(t,J=5.6Hz,2H,N-CH2),2.42(t,J=6.8Hz,2H,9-H),2.34(d,J=17.6Hz,1H,2-H),2.01(d,J=17.6Hz,1H,2-H),1.94(s,3H,13-H),1.81(t,J=5.2Hz,1H,6-H),1.66(m,1H,7-H),1.53(m,2H,8-H),1.35(m,1H,7-H),1.02(s,3H,11-H),0.99(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.6(5-C),162.9(d,J=244.0Hz,Ar-C),142.6(d,J=6.9Hz,Ar-C),129.7(d,J=8.1Hz,Ar-C),125.0(4-C),124.2(d,J=2.6Hz,Ar-C),115.4(d,J=21.1Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),58.6(Ar-CH2),57.3(N-CH2),54.7(9-C),51.1(6-C),47.1(2-C),39.7(CH2),36.3(1-C),28.7(12-C),28.0(7-C),27.2(11-C),27.1(8-C),24.8(13-C).HR-ESIMS m/z 347.2480[M+H]+,calcdfor C21H32FN2O,347.2499.
实施例4.
化合物N6的合成方法
称取1.0当量N5于反应瓶中,加入适量DCM溶解,冰浴下加入5.0当量吡啶和5.0当量丁二酸酐,于室温下搅拌,TLC监测至反应结束。浓缩得粗品,经硅胶柱色谱(DCM∶MeOH=20∶1,V/V)分离纯化得黄色油状物,产率为73.5%。1H NMR(400MHz,DMSO-d6):δ12.08(s,1H,OH),7.79(s,1H,NH),7.34(m,1H,Ar-H),7.15(m,2H,Ar-H),7.05(m,1H,Ar-H),5.70(s,1H,4-H),3.59(s,2H,Ar-CH2),3.15(q,J=6.1Hz,2H,CH2),2.42(m,6H,CH2),2.31(m,3H,2-Hand CH2),1.91(s,3H,13-H),1.86(m,2H,2-H and 6-H),1.64(m,1H,7-H),1.48(m,2H,8-H),1.29(m,1H,7-H),0.97(s,3H,11-H),0.92(s,3H,12-H).13C NMR(100MHz,DMSO-d6):δ197.8(3-C),173.7(CO),170.8(CO),165.6(5-C),162.2(d,J=241.5Hz,Ar-C),143.0(d,J=6.3Hz,Ar-C),129.9(d,J=8.2Hz,Ar-C),124.4(d,J=2.6Hz,Ar-C),124.1(4-C),115.0(d,J=21.1Hz,Ar-C),113.5(d,J=20.7Hz,Ar-C),57.5(Ar-CH2),53.8(N-CH2),53.0(9-C),50.2(6-C),46.9(2-C),39.7(CH2),36.6(CH2),35.9(1-C),30.0(CH2),29.2(CH2),28.3(12-C),27.2(7-C),26.5(11-C),26.4(8-C),24.0(13-C).HR-ESIMS m/z 447.2638[M+H]+,calcd for C25H36FN2O4,447.2659.
实施例5.
化合物N7-N28的合成方法:
称取1.0当量中间体7和3.0当量相应的醛于反应瓶中,加适量甲醇溶解,加入0.2mL水,接着加入已经溶于甲醇中的0.5当量氯化锌和1.5当量氰基硼氢化钠,反应在30℃下搅拌,TLC监测至反应结束。将甲醇旋干,加入水和DCM并萃取,合并有机层,用无水硫酸镁干燥,过滤,浓缩得粗品。
化合物N7的合成
以吡啶-4-甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=12∶1-8∶1,V/V)得黄色油状物,产率为77.3%。1H NMR(600MHz,CDCl3):δ8.55(d,J=5.4Hz,2H,Ar-H),7.29(d,J=5.4Hz,2H,Ar-H),7.27(m,1H,Ar-H),7.09(m,2H,Ar-H),6.95(m,1H,Ar-H),5.80(s,1H,4-H),3.55(s,4H,Ar-CH2),2.42(t,J=6.9Hz,2H,9-H),2.33(d,J=17.4Hz,1H,2-H),2.02(d,J=17.4Hz,1H,2-H),1.90(s,3H,13-H),1.80(t,J=5.4Hz,1H,6-H),1.66(m,1H,7-H),1.55(m,2H,8-H),1.35(m,1H,7-H),1.01(s,3H,11-H),0.99(s,3H,12-H).13CNMR(150MHz,CDCl3):δ199.3(3-C),165.4(5-C),163.0(d,J=244.4Hz,Ar-C),149.8(C),148.9(C),141.8(d,J=7.1Hz,Ar-C),129.9(d,J=8.1Hz,Ar-C),125.2(4-C),124.1(d,J=2.6Hz,Ar-C),123.6(C),115.3(d,J=21.2Hz,Ar-C),114.1(d,J=21.0Hz,Ar-C),58.3(Ar-CH2),57.7(9-C),54.4(N-CH2-Ar),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.2(8-C),26.9(11-C),24.8(13-C).HR-ESIMS m/z 395.2479[M+H]+,calcd forC25H32FN2O,395.2499.
化合物N8的合成
以噻吩-2-甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=12∶1-8∶1,V/V)得黄色油状物,产率为78.6%。1H NMR(600MHz,CDCl3):δ7.26(m,1H,Ar-H),7.23(m,1H,Ar-H),7.12(m,2H,Ar-H),6.91(m,2H,Ar-H),6.89(m,1H,Ar-H),5.80(s,1H,4-H),3.77(s,2H,Ar-CH2),3.57(s,2H,Ar-CH2),2.45(t,J=6.6Hz,2H,9-H),2.35(d,J=17.4Hz,1H,2-H),2.01(d,J=17.4Hz,1H,2-H),1.92(s,3H,13-H),1.80(t,J=5.4Hz,2H,6-H),1.72(m,1H,7-H),1.56(m,2H,8-H),1.37(m,1H,7-H),1.03(s,3H,11-H),0.99(s,3H,12-H).13C NMR(150MHz,CDCl3):δ199.5(3-C),165.8(5-C),163.0(d,J=243.9Hz,Ar-C),142.8(d,J=7.5Hz,Ar-C),142.3(C),129.7(d,J=8.1Hz,Ar-C),126.5(C),125.5(C),125.1(4-C),124.9(C),124.2(d,J=2.0Hz,Ar-C),115.4(d,J=21.2Hz,Ar-C),113.9(d,J=21.0Hz,Ar-C),57.8(Ar-CH2),53.7(9-C),52.8(N-CH2-Ar),51.0(6-C),47.2(2-C),36.4(1-C),28.8(12-C),27.9(7-C),27.2(8-C),27.0(11-C),24.8(13-C).HR-ESIMS m/z 400.2102[M+H]+,calcd for C24H31FNOS,400.2110.
化合物N9的合成
以3-氟苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=12∶1-8∶1,V/V)得黄色油状物,产率为81.6%。1H NMR(400MHz,CDCl3):δ7.27(m,2H,Ar-H),7.09(m,4H,Ar-H),6.93(m,2H,Ar-H),5.79(s,1H,4-H),3.53(s,4H,Ar-CH2),2.41(t,J=6.8Hz,2H,9-H),2.33(d,J=10.8Hz,3H,13-H),2.03(d,J=10.8Hz,3H,13-H),1.90(s,3H,13-H),1.78(t,J=5.4Hz,1H,6-H),1.66(m,1H,7-H),1.54(m,2H,8-H),1.33(m,1H,7-H),1.01(s,3H,11-H),0.98(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),165.6(5-C),163.0(d,J=244.2Hz,Ar-C),142.3(d,J=6.9Hz,Ar-C),129.8(d,J=8.2Hz,Ar-C),125.1(4-C),124.2(d,J=2.4Hz,Ar-C),115.4(d,J=21.2Hz,Ar-C),113.9(d,J=21.0Hz,Ar-C),58.2(Ar-CH2),54.1(9-C),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),28.0(7-C),27.2(11-C),26.9(8-C),24.8(13-C).HR-ESIMS m/z 412.2437[M+H]+,calcd for C26H32F2NO,412.2452.
化合物N10的合成
以3,4-二氟苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=12∶1-8∶1,V/V)得黄色油状物,产率为83.5%。1H NMR(400MHz,CDCl3):δ7.29(m,1H,Ar-H),7.19(m,1H,Ar-H),7.11(m,4H,Ar-H),6.96(m,1H,Ar-H),5.82(s,1H,4-H),3.54(s,2H,Ar-CH2),3.51(s,2H,Ar-CH2),2.41(t,J=6.8Hz,2H,9-H),2.34(d,J=17.4Hz,1H,2-H),2.03(d,J=17.4Hz,1H,2-H),1.93(s,3H,13-H),1.81(t,J=5.4Hz,1H,6-H),1.66(m,1H,7-H),1.56(m,2H,8-H),1.36(m,1H,7-H),1.03(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.6(5-C),163.0(d,J=244.2Hz,Ar-C),150.3(dd,J1=246.3Hz,J2=12.7Hz,Ar-C),149.4(dd,J1=245.4Hz,J2=12.8Hz,Ar-C),142.1(d,J=4.0Hz,Ar-C),136.6(d,J=2.4Hz,Ar-C),129.8(d,J=8.1Hz,Ar-C),125.1(4-C),124.3(),124.1(d,J=2.6Hz,Ar-C),117.3(d,J=17,2Hz,Ar-C),117.0(d,J=16.9Hz,Ar-C),115.3(d,J=21.2Hz,Ar-C),114.2(d,J=21.1Hz,Ar-C),58.1(Ar-CH2),57.7(9-C),54.0(Ar-CH2),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.2(8-C),26.8(11-C),24.8(13-C).HR-ESIMS m/z 430.2341[M+H]+,calcd for C26H31F3NO,430.2358.
化合物N11的合成
以4-(三氟甲基)苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=12∶1-8∶1,V/V)得黄色油状物,产率为75.3%。1H NMR(400MHz,CDCl3):δ7.57(d,J=8.0Hz,2H,Ar-H),7.46(d,J=8.0Hz,2H,Ar-H),7.26(m,1H,Ar-H),7.08(m,2H,Ar-H),6.93(m,1H,Ar-H),5.80(s,1H,4-H),3.60(s,2H,Ar-CH2),3.54(s,2H,Ar-CH2),2.42(t,J=6.8Hz,2H,9-H),2.32(d,J=17.6Hz,1H,2-H),2.01(d,J=17.6Hz,1H,2-H),1.89(s,3H,13-H),1.78(t,J=5.4Hz,1H,6-H),1.64(m,2H,7-H),1.54(m,2H,8-H),1.00(s,3H,12-H),0.98(s,3H,11-H).13C NMR(100MHz,CDCl3):δ199.1(3-C),165.2(5-C),163.0(d,J=244.3Hz,Ar-C),142.8(Ar-C),142.1(d,J=6.9Hz,Ar-C),129.8(d,J=7.8Hz,Ar-C),128.8(Ar-C),125.3(Ar-C),125.2(4-C),124.2(q,J=270.2Hz,CF3),124.1(d,J=2.5Hz,Ar-C),115.4(d,J=21.2Hz,Ar-C),114.0(d,J=21.1Hz,Ar-C),58.4(Ar-CH2),54.3(Ar-CH2),51.1(6-C),47.2(2-C),36.3(1-C),28.7(12-C),28.0(7-C),27.1(8-C),27.0(11-C),24.7(13-C).HR-ESIMS m/z 462.2403[M+H]+,calcd for C27H32F4NO,462.2420.
化合物N12的合成
以4-甲基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=12∶1-8∶1,V/V)得黄色油状物,产率为78.9%。1H NMR(400MHz,CDCl3):δ7.22(m,3H,Ar-H),7.10(m,4H,Ar-H),6.90(m,1H,Ar-H),5.78(s,1H,4-H),3.51(s,4H,Ar-CH2),2.39(t,J=6.8Hz,2H,9-H),2.33(s,3H,CH3),2.32(d,J=17.2Hz,1H,2-H),1.99(d,J=17.2Hz,1H,2-H),1.89(s,3H,13-H),1.76(t,J=5.6Hz,1H,6-H),1.64(m,2H,7-H),1.52(m,2H,8-H),1.00(s,3H,12-H),0.97(s,3H,11-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.7(5-C),163.0(d,J=243.9Hz,Ar-C),142.8(d,J=6.8Hz,Ar-C),136.6(Ar-C),136.2(Ar-C),129.6(d,J=8.1Hz,Ar-C),129.2(Ar-C),129.0(Ar-C),128.7(Ar-C),127.1(Ar-C),125.1(4-C),124.2(d,J=2.1Hz,Ar-C),115.4(d,J=21.1Hz,Ar-C),113.7(d,J=21.1Hz,Ar-C),58.4(Ar-CH2),58.1(Ar-CH2),53.9(Ar-CH2),51.1(6-C),47.2(2-C),36.3(1-C),28.7(12-C),28.0(7-C),27.2(8-C),26.9(11-C),24.8(13-C),21.1(CH3).HR-ESIMS m/z 408.2682[M+H]+,calcd for C27H35FNO,408.2703.
化合物N13的合成
以4-甲氧基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=12∶1-8∶1,V/V)得黄色油状物,产率为77.2%。1H NMR(400MHz,CDCl3):δ7.25(m,3H,Ar-H),7.08(m,2H,Ar-H),6.91(m,2H,Ar-H),6.85(d,J=8.4Hz,1H,Ar-H),5.79(s,1H,4-H),3.79(s,3H,OCH3),3.51(s,2H,Ar-CH2),3.49(s,2H,Ar-CH2),2.39(t,J=6.8Hz,2H,9-H),2.32(d,J=17.2Hz,1H,2-H),2.00(d,J=17.2Hz,1H,2-H),1.89(s,3H,13-H),1.77(t,J=5.6Hz,1H,6-H).1.64(m,2H,7-H),1.54(m,2H,8-H),1.00(s,3H,12-H),0.98(s,3H,11-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),165.6(5-C),163.0(d,J=243.9Hz,Ar-C),158.7(Ar-C),142.8(d,J=6.4Hz,Ar-C),129.9(Ar-C),129.6(d,J=8.9Hz,Ar-C),125.1(4-C),124.2(d,J=2.6Hz,Ar-C),115.3(d,J=21.3Hz,Ar-C),113.7(d,J=20.8Hz,Ar-C),113.7(Ar-C),58.1(Ar-CH2),55.2(OCH3),53.9(Ar-CH2),51.1(6-C),47.16(2-C),36.3(1-C),28.7(12-C),28.0(7-C),27.2(8-C),26.9(11-C),24.8(13-C).HR-ESIMS m/z 424.2630[M+H]+,calcd for C27H35FNO2,424.2652.
化合物N14的合成
以4-乙氧基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=12∶1-8∶1,V/V)得黄色油状物,产率为76.4%。1H NMR(400MHz,CDCl3):δ7.19(m,3H,Ar-H),7.01(m,2H,Ar-H),6.84(m,1H,Ar-H),6.77(d,J=8.4Hz,1H,Ar-H),5.71(s,1H,4-H),3.95(q,J=6.8Hz,2H,OCH2),3.43(s,2H,Ar-CH2),3.41(s,2H,Ar-CH2),2.31(t,J=6.8Hz,2H,9-H),2.25(d,J=17.6Hz,1H,2-H),1.92(d,J=17.6Hz,1H,2-H),1.82(s,3H,13-H),1.69(t,J=5.4Hz,1H,6-H),1.56(m,2H,7-H),1.46(m,2H,8-H),1.33(t,J=6.8Hz,3H,CH3),0.93(s,3H,12-H),0.90(s,3H,11-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),165.6(5-C),163.0(d,J=243.7Hz,Ar-C),157.2(Ar-C),143.2(d,J=6.8Hz,Ar-C),130.1(Ar-C),129.5(d,J=8.1Hz,Ar-C),127.8(Ar-C),127.6(Ar-C),125.0(4-C),124.1(d,J=2.0Hz,Ar-C),120.3(Ar-C),115.4(d,J=21.2Hz,Ar-C),113.6(d,J=21.1Hz,Ar-C),111.4(Ar-C),64.1(OCH2),62.4(Ar-CH2),57.0(Ar-CH2),52.8(Ar-CH2),50.1(6-C),46.1(2-C),35.3(1-C),27.7(12-C),27.0(7-C),26.12(8-C),25.9(11-C),23.7(13-C),13.9(CH3).HR-ESIMS m/z 438.2775[M+H]+,calcd for C28H37FNO2,438.2808.
化合物N15的合成
以3-乙氧基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=12∶1-8∶1,V/V)得黄色油状物,产率为78.3%。1H NMR(400MHz,CDCl3):δ7.23(m,2H.Ar-H),7.09(m,2H,Ar-H),6.91(m,3H,Ar-H),6.85(d,J=7.2Hz,1H,Ar-H),5.79(s,1H,4-H),4.02(q,J=7.2Hz,2H,OCH2),3.53(s,2H,Ar-CH2),3.52(s,2H,Ar-CH2),2.41(t,J=6.8Hz,2H,9-H),2.32(d,J=17.2Hz,1H,2-H),1.90(s,3H,13-H),1.77(t,J=5.2Hz,1H,6-H),1.66(m,2H,7-H),1.53(m,2H,8-H),1.41(t,J=7.2Hz,3H,CH3),1.01(s,3H,12-H),0.98(s,3H,11-H).13C NMR(100MHz,CDCl3):δ199.2(3-C),165.5(5-C),163.0(d,J=244.0Hz,Ar-C),159.1(Ar-C),142.7(d,J=6.9Hz,Ar-C),141.1(Ar-C),129.6(d,J=8.1Hz,Ar-C),129.0(Ar-C),125.1(4-C),124.2(d,J=2.4Hz,Ar-C),120.9(Ar-C),115.4(d,J=21.3Hz,Ar-C),115.0(Ar-C),113.8(d,J=21.1Hz,Ar-C),112.9(Ar-C),63.3(OCH2),58.8(Ar-CH2),58.3(Ar-CH2),54.1(Ar-CH2),51.2(6-C),47.2(2-C),36.3(1-C),28.7(12-C),28.0(7-C),27.1(8-C),27.1(11-C),24.7(13-C),14.9(CH3).HR-ESIMS m/z 438.2787[M+H]+,calcd forC28H37FNO2,438.2808.
化合物N16的合成
以2-乙氧基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=12∶1-8∶1,V/V)得黄色油状物,产率为75.4%。1H NMR(400MHz,CDCl3):δ7.43(d,J=6.8Hz,1H,Ar-H),7.23(m,2H,Ar-H),7.11(m,2H,Ar-H),6.93(m,2H,Ar-H),6.83(d,J=8.0Hz,1H,Ar-H),5.78(s,1H,4-H),4.02(q,J=6.8Hz,2H,OCH2),3.62(s,2H,Ar-CH2),3.57(s,2H,Ar-CH2),2.43(t,J=6.8Hz,2H,9-H),2.32(d,J=17.2Hz,1H,2-H),1.99(d,J=17.2Hz,1H,2-H),1.89(s,3H,13-H),1.76(t,J=5.2Hz,1H,6-H),1.64(m,2H,7-H),1.54(m,2H,8-H),1.40(t,J=6.8Hz,3H,CH3),0.99(s,3H,12-H),0.97(s,3H,11-H).13C NMR(100MHz,CDCl3):δ198.4(3-C),164.7(5-C),162.0(d,J=243.9Hz,Ar-C),150.1(Ar-C),141.8(d,J=7.1Hz,Ar-C),130.1(Ar-C),127.9(Ar-C),128.6(d,J=8.1Hz,Ar-C),127.6(Ar-C),124.0(4-C),123.1(d,J=2.0Hz,Ar-C),114.3(d,J=21.3Hz,Ar-C),113.5(Ar-C),113.2(Ar-C),112.7(d,J=21.2Hz,Ar-C),63.6(OCH2),58.6(Ar-CH2),54.3(Ar-CH2),52.2(Ar-CH2),51.2(6-C),47.2(2-C),36.3(1-C),28.7(12-C),28.0(7-C),27.2(8-C),27.1(11-C),24.7(13-C),14.9(CH3).HR-ESIMS m/z 438.2776[M+H]+,calcd for C28H37FNO2,438.2808.
化合物N17的合成
以4-丁氧基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=12∶1-8∶1,V/V)得黄色油状物,产率为78.2%。1H NMR(400MHz,CDCl3):δ7.27(m,3H,Ar-H),7.11(d,J=8.0Hz,2H,Ar-H),6.94(m,1H,Ar-H),6.87(d,J=8.0Hz,2H,Ar-H),5.82(s,1H,4-H),3.97(t,J=6.4Hz,2H,OCH2),3.53(s,2H,Ar-CH2),3.50(s,2H,Ar-CH2),3.41(t,J=6.6Hz,2H,9-H),2.37(d,J=17.2Hz,1H,2-H),2.02(d,J=17.2Hz,1H,2-H),1.92(s,3H,13-H),1.78(m,3H,6-H,CH2),1.67(m,1H,7-H),1.53(m,4H,8-H,CH2),1.32(m,1H,7-H),1.03(s,3H,12-H),0.99(m,6H,11-H,CH3).13C NMR(100MHz,CDCl3):δ199.5(3-C),165.8(5-C),163.0(d,J=243.7Hz,Ar-C),158.3(Ar-C),142.8(d,J=6.9Hz,Ar-C),131.0(Ar-C),129.9(Ar-C),129.6(d,J=8.1Hz,Ar-C),125.0(4-C),124.2(d,J=2.0Hz,Ar-C),115.3(d,J=21.3Hz,Ar-C),114.2(Ar-C),113.7(d,J=21.2Hz,Ar-C),67.7(OCH2),58.0(Ar-CH2),53.8(Ar-CH2),51.1(6-C),47.1(2-C),36.3(1-C),31.4(CH2),28.7(12-C),28.0(7-C),27.2(8-C),26.9(11-C),24.8(13-C),19.3(CH2),13.9(CH3).HR-ESIMS m/z 466.3110[M+H]+,calcdfor C30H41FNO2,466.3121.
化合物N18的合成
以4-氰基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-6∶1,V/V)得黄色油状物,产率为76.2%。1H NMR(400MHz,CDCl3):δ7.63(d,J=7.6Hz,2H,Ar-H),7.45(d,J=7.6Hz,2H,Ar-H),7.29(m,1H,Ar-H),7.08(m,2H,Ar-H),6.96(m,1H,Ar-H),5.82(s,1H,4-H),3.60(s,2H,Ar-CH2),3.55(s,2H,Ar-CH2),2.42(t,J=6.4Hz,2H,9-H),2.34(d,J=17.4Hz,1H,2-H),2.04(d,J=17.4Hz,1H,2-H),1.92(s,3H,13-H),1.81(t,J=5.2Hz,1H,6-H),1.64(m,1H,7-H),1.55(m,2H,8-H),1.36(m,1H,7-H),1.02(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.5(5-C),163.0(d,J=244.5Hz,Ar-C),145.4(Ar-C),141.8(d,J=6.6Hz,Ar-C),132.2(Ar-C),129.9(d,J=8.0Hz,Ar-C),129.4(Ar-C),125.2(4-C),124.1(Ar-C),118.9(CN),115.3(d,J=21.0Hz,Ar-C),114.1(d,J=21.1Hz,Ar-C),110.9(Ar-C),58.4(Ar-CH2),58.3(9-C),54.3(Ar-CH2),51.0(6-C),47.1(2-C),36.3(1-C),28.8(12-C),27.9(7-C),27.1(8-C),26.8(11-C),24.8(13-C).HR-ESIMS m/z 419.2477[M+H]+,calcd for C27H32FN2O,419.2499.
化合物N19的合成
以4-硝基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-6∶1,V/V)得黄色油状物,产率为71.6%。1H NMR(400MHz,CDCl3):δ8.19(d,J=7.6Hz,2H,Ar-H),7.53(d,J=7.6Hz,2H,Ar-H),7.29(m,1H,Ar-H),7.09(m,2H,Ar-H),6.96(m,1H,Ar-H),5.82(s,1H,4-H),3.65(s,2H,Ar-CH2),3.57(s,2H,Ar-CH2),2.44(t,J=6.4Hz,2H,9-H),2.34(d,J=17.4Hz,1H,2-H),2.03(d,J=17.4Hz,1H,2-H),1.92(s,3H,13-H),1.82(t,J=5.2Hz,1H,6-H),1.64(m,1H,7-H),1.56(m,2H,8-H),1.36(m,1H,7-H),1.02(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.5(5-C),163.0(d,J=244.5Hz,Ar-C),147.5(Ar-C),147.1(Ar-C),141.8(d,J=6.8Hz,Ar-C),129.9(d,J=8.2Hz,Ar-C),129.1(Ar-C),125.2(4-C),124.1(d,J=2.6Hz,Ar-C),123.6(Ar-C),115.3(d,J=21.2Hz,Ar-C),114.2(d,J=21.1Hz,Ar-C),58.3(Ar-CH2),58.1(9-C),54.3(Ar-CH2),51.0(6-C),47.1(2-C),36.3(1-C),28.8(12-C),27.9(7-C),27.2(8-C),26.8(11-C),24.8(13-C).HR-ESIMS m/z 439.2374[M+H]+,calcd for C26H32FN2O3,439.2397.
化合物N20的合成
以4-异丙基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-8∶1,V/V)得黄色油状物,产率为76.8%。1H NMR(400MHz,CDCl3):δ7.28(m,3H,Ar-H),7.20(d,J=7.6Hz,2H,Ar-H),7.12(d,J=7.6Hz,2H,Ar-H),6.94(m,1H,Ar-H),5.82(s,1H,4-H),3.54(s,4H,Ar-CH2),2.91(m,1H,CH),2.42(t,J=6.0Hz,1H,9-H),2.35(d,J=17.2Hz,1H,2-H),2.02(d,J=17.2Hz,1H,2-H),1.91(s,3H,13-H),1.79(t,J=5.2Hz,1H,6-H),1.66(m,1H,7-H),1.55(m,2H,8-H),1.37(m,1H,7-H),1.26(d,J=6.8Hz,6H,(CH3)2),1.03(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.6(3-C),166.0(5-C),163.0(d,J=243.7Hz,Ar-C),147.8(Ar-C),142.8(d,J=6.6Hz,Ar-C),136.7(Ar-C),129.6(d,J=8.4Hz,Ar-C),128.7(Ar-C),127.3(Ar-C),126.8(Ar-C),126.3(Ar-C),125.0(4-C),124.2(d,J=2.1Hz,Ar-C),115.4(d,J=21.3Hz,Ar-C),113.7(d,J=20.9Hz,Ar-C),58.4(Ar-CH2),58.2(9-C),54.0(Ar-CH2),51.1(6-C),47.1(2-C),36.3(1-C),33.8(CH),28.7(12-C),27.9(7-C),27.2(8-C),26.9(11-C),24.8(13-C),24.1((CH3)2).HR-ESIMS m/z436.2904[M+H]+,calcd for C29H39FNO,436.3016.
化合物N21的合成
以4-二甲氨基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-8∶1,V/V)得黄色油状物,产率为73.2%。1H NMR(400MHz,CDCl3):δ7.26(m,1H,Ar-H),7.20(d,J=7.6Hz,2H,Ar-H),7.11(d,J=7.6Hz,2H,Ar-H),6.93(m,1H,Ar-H),6.73(d,J=7.4Hz,2H,Ar-H),5.81(s,1H,4-H),3.52(s,2H,Ar-CH2),3.49(s,2H,Ar-CH2),2.96(s,6H,N(CH3)2),2.41(t,J=6.4Hz,2H,9-H),2.34(d,J=17.2Hz,1H,2-H),2.02(d,J=17.2Hz,1H,2-H),1.93(s,3H,13-H),1.80(t,J=5.2Hz,1H,6-H),1.68(m,1H,7-H),1.55(m,2H,8-H),1.36(m,1H,7-H),1.03(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.6(3-C),166.0(5-C),162.9(d,J=244.0Hz,Ar-C),149.8(Ar-C),143.0(d,J=7.3Hz,Ar-C),129.7(Ar-C),129.5(d,J=8.3Hz,Ar-C),126.9(Ar-C),125.0(4-C),124.1(d,J=2.1Hz,Ar-C),115.3(d,J=21.1Hz,Ar-C),113.6(d,J=21.0Hz,Ar-C),112.5(Ar-C),58.0(Ar-CH2),57.9(9-C),53.7(Ar-CH2),51.1(6-C),47.1(2-C),40.7(N(CH3)2),36.3(1-C),28.7(12-C),27.9(7-C),27.2(8-C),26.9(11-C),24.8(13-C).HR-ESIMS m/z 437.2948[M+H]+,calcd for C28H38FN2O,437.2968.
化合物N22的合成
以4-二乙氨基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-8∶1,V/V)得黄色油状物,产率为72.6%。1H NMR(400MHz,CDCl3):δ7.26(m,1H,Ar-H),7.17(d,J=7.6Hz,2H,Ar-H),7.11(d,J=7.6Hz,2H,Ar-H),6.93(m,1H,Ar-H),6.66(d,J=7.4Hz,2H,Ar-H),5.82(s,1H,4-H),3.53(s,2H,Ar-CH2),3.47(s,2H,Ar-CH2),3.36(q,J=6.8Hz,4H,(CH2)2),2.39(m,3H,9-H and 2-H),2.02(d,J=17.2Hz,1H,2-H),1.93(s,3H,13-H),1.80(t,J=5.2Hz,1H,6-H),1.69(m,1H,7-H),1.56(m,2H,8-H),1.36(m,1H,7-H),1.17(t,J=6.8Hz,6H,(CH3)2),1.03(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.6(3-C),166.1(5-C),162.9(d,J=243.6Hz,Ar-C),146.9(Ar-C),143.1(d,J=6.7Hz,Ar-C),129.9(Ar-C),129.5(d,J=8.2Hz,Ar-C),125.5(Ar-C),124.9(4-C),124.2(d,J=2.1Hz,Ar-C),115.3(d,J=21.1Hz,Ar-C),113.6(d,J=21.1Hz,Ar-C),111.6(Ar-C),58.0(Ar-CH2),57.7(9-C),53.7(Ar-CH2),51.1(6-C),47.1(2-C),44.4((CH2)2),36.3(1-C),28.7(12-C),27.9(7-C),27.2(8-C),26.9(11-C),24.8(13-C),12.6((CH3)2).HR-ESIMS m/z 465.3265[M+H]+,calcd for C30H42FN2O,465.3281.
化合物N23的合成
以3-氰基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-6∶1,V/V)得黄色油状物,产率为78.6%。1H NMR(400MHz,CDCl3):δ7.64(s,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,1H,Ar-H),7.43(m,1H,Ar-H),7.28(m,1H,Ar-H),7.08(m,2H,Ar-H),6.94(m,1H,Ar-H),5.80(s,1H,4-H),3.57(s,2H,Ar-CH2),3.55(s,2H,Ar-CH2),2.42(t,J=6.8Hz,2H,9-H),2.32(t,J=17.2Hz,1H,2-H),2.01(d,J=17.2Hz,1H,2-H),1.92(s,3H,13-H),1.80(t,J=5.2Hz,1H,6-H),1.65(m,1H,7-H),1.55(m,2H,8-H),1.34(m,1H,7-H),1.02(s,3H,11-H),0.99(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),165.4(5-C),162.9(d,J=243.3Hz,Ar-C),141.8(d,J=6.7Hz,Ar-C),141.2(Ar-C),133.1(Ar-C),132.1(Ar-C),130.8(Ar-C),129.9(d,J=8.1Hz,Ar-C),129.2(Ar-C),125.2(4-C),124.2(d,J=4.3Hz,Ar-C),118.9(Ar-C),115.4(d,J=21.2Hz,Ar-C),114.1(d,J=21.0Hz,Ar-C),112.4(CN),58.3(Ar-CH2),58.0(Ar-CH2),54.2(9-C),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.2(11-C),26.8(8-C),24.8(13-C).HR-ESIMS m/z 419.2479[M+H]+,calcd for C27H32FN2O,419.2499.
化合物N24的合成
以2-氟-4-氰基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-6∶1,V/V)得黄色油状物,产率为75.4%。1H NMR(400MHz,CDCl3):δ7.59(m,1H,Ar-H),7.44(m,1H,Ar-H),7.28(m,2H,Ar-H),7.07(m,2H,Ar-H),6.94(m,1H,Ar-H),5.81(s,1H,4-H),3.67(s,2H,Ar-CH2),3.58(s,2H,Ar-CH2),2.44(t,J=6.8Hz,2H,9-H),2.32(t,J=17.2Hz,1H,2-H),2.01(d,J=17.2Hz,1H,2-H),1.92(s,3H,13-H),1.80(t,J=5.2Hz,1H,6-H),1.65(m,1H,7-H),1.57(m,2H,8-H),1.35(m,1H,7-H),1.02(s,3H,11-H),0.99(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),165.4(5-C),162.9(d,J=244.3Hz,Ar-C),160.6(d,J=248.4Hz,Ar-C),141.7(d,J=6.6Hz,Ar-C),132.6(d,J=14.0Hz,Ar-C),131.7(d,J=4.7Hz,Ar-C),129.9(d,J=8.2Hz,Ar-C),128.1(d,J=3.6Hz,Ar-C),125.2(4-C),124.1(d,J=4.3Hz,Ar-C),119.1(Ar-C),118.9(CN),117.6(d,J=2.6Hz,Ar-C),115.3(d,J=21.2Hz,Ar-C),114.1(d,J=21.1Hz,Ar-C),112.1(d,J=9.4Hz,Ar-C),58.4(Ar-CH2),54.5(9-C),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.2(11-C),26.8(8-C),24.8(13-C).HR-ESIMS m/z 437.2387[M+H]+,calcd for C27H31F2N2O,437.2404.
化合物N25的合成
以3-氰基-4-氟苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-6∶1,V/V)得黄色油状物,产率为76.5%。1H NMR(400MHz,CDCl3):δ7.58(m,2H,Ar-H),7.29(m,1H,Ar-H),7.18(m,1H,Ar-H),7.06(m,2H,Ar-H),6.95(m,1H,Ar-H),5.81(s,1H,4-H),3.54(s,4H,Ar-CH2),2.41(t,J=6.8Hz,2H,9-H),2.32(t,J=17.2Hz,1H,2-H),2.02(d,J=17.2Hz,1H,2-H),1.93(s,3H,13-H),1.81(t,J=5.2Hz,1H,6-H),1.64(m,1H,7-H),1.56(m,2H,8-H),1.34(m,1H,7-H),1.02(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),165.4(5-C),163.0(d,J=244.7Hz,Ar-C),162.2(d,J=256.8Hz,Ar-C).141.7(d,J=6.6Hz,Ar-C),136.8(d,J=14.0Hz,Ar-C),135.1(d,J=7.7Hz,Ar-C),133.1(Ar-C)-129.9(d,J=8.1Hz,Ar-C),125.2(4-C),124.1(d,J=4.3Hz,Ar-C),116.4(d,J=19.4Hz,Ar-C),115.3(d,J=21.3Hz,Ar-C),114.3(d,J=21.1Hz,Ar-C),114.1(CN),101.2(d,J=15.5Hz,Ar-C),58.2(Ar-CH2),57.2(Ar-CH2),54.5(9-C),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.2(11-C),26.8(8-C),24.8(13-C).HR-ESIMS m/z 437.2387[M+H]+,calcd for C27H31F2N2O,437.2404.
化合物N26的合成
以2-氯-3-氰基苯甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-6∶1,V/V)得黄色油状物,产率为77.4%。1H NMR(400MHz,CDCl3):δ7.81(d,J=7.6Hz,1H,Ar-H),7.58(d,J=7.6Hz,1H,Ar-H),7.37(m,1H,Ar-H),7.27(m,1H,Ar-H),7.07(m,2H,Ar-H),6.94(m,1H,Ar-H),5.80(s,1H,4-H),3.71(s,2H,Ar-CH2),3.60(s,2H,Ar-CH2),2.45(t,J=6.8Hz,2H,9-H),2.31(t,J=17.2Hz,1H,2-H),2.01(d,J=17.2Hz,1H,2-H),1.91(s,3H,13-H),1.79(t,J=5.2Hz,1H,6-H),1.64(m,1H,7-H),1.55(m,2H,8-H),1.32(m,1H,7-H),1.00(s,3H,11-H),0.99(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),165.4(5-C),162.9(d,J=244.5Hz,Ar-C),141.7(d,J=6.8Hz,Ar-C),139.2(Ar-C),136.0(Ar-C),134.4(Ar-C),132.6(Ar-C),129.9(d,J=8.1Hz,Ar-C),127.1(Ar-C),125.2(4-C),124.1(d,J=4.3Hz,Ar-C)-116.2(Ar-C),115.3(d,J=21.4Hz,Ar-C),114.2(d,J=21.0Hz,Ar-C),114.0(CN),58.6(Ar-CH2),55.4(Ar-CH2),54.7(9-C),51.0(6-C),47.0(2-C),36.3(1-C),28.7(12-C),28.0(7-C),27.2(11-C),26.9(8-C),24.8(13-C).HR-ESIMS m/z453.1994[M+H]+,calcd for C27H31ClFN2O,453.2019.
化合物N27的合成
以4-甲酰基-联苯-3-羧酸甲酯为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为76.5%。1H NMR(400MHz,CDCl3):δ8.28(m,1H,Ar-H),8.00(m,1H,Ar-H),7.78(m,1H,Ar-H),7.59(d,J=8.0Hz,2H,Ar-H),7.50(m,1H,Ar-H),7.43(d,J=8.0Hz,2H,Ar-H),7.27(m,1H,Ar-H),7.11(m,2H,Ar-H),6.93(m,1H,Ar-H),5.80(s,1H,4-H),3.94(s,3H,OCH3),3.60(s,2H,Ar-CH2),3.56(s,2H,Ar-CH2),2.44(t,J=6.8Hz,2H,9-H),2.34(d,J=17.2Hz,1H,2-H),2.01(d,J=17.2Hz,1H,2-H),1.90(s,3H,13-H),1.79(t,J=5.4Hz,1H,6-H),1.67(m,1H,7-H),1.56(m,2H,8-H),1.36(m,1H,7-H),1.02(s,3H,11-H),0.98(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),167.0(CO),165.7(5-C),162.9(d,J=244.1Hz,Ar-C),142.5(d,J=6.8Hz,Ar-C),141.1(Ar-C),139.1(Ar-C),138.8(Ar-C),131.4(Ar-C),130.6(Ar-C),129.6(d,J=8.2Hz,Ar-C),129.2(Ar-C),128.9(Ar-C),128.3(Ar-C),128.1(Ar-C),127.0(Ar-C),125.0(4-C),124.1(d,J=2.4Hz,Ar-C),115.3(d,J=21.1Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),58.3(Ar-CH2),58.2(Ar-CH2),54.0(9-C),52.2(OCH3),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.1(11-C),26.9(8-C),24.8(13-C).HR-ESIMS m/z 528.2883[M+H]+,calcd forC34H39FNO3,528.2914.
化合物N28的合成
以1-甲基-3-苯基-1H-吡唑-5-甲醛为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=6∶1-2∶1,V/V)得黄色油状物,产率为76.8%。1H NMR(400MHz,CDCl3):δ7.76(d,J=7.2Hz,2H,Ar-H),7.37(m,2H,Ar-H),7.28(m,2H,Ar-H),7.04(m,2H,Ar-H),6.95(m,1H,Ar-H),6.45(s,1H),5.79(s,1H,4-H),3.84(s,3H,N-CH3),3.56(s,4H,Ar-CH2),2.44(t,J=6.8Hz,2H,9-H),2.31(d,J=17.2Hz,1H,2-H),2.00(d,J=17.2Hz,1H,2-H),1.89(s,3H,13-H),1.77(t,J=5.2Hz,1H,6-H),1.60(m,1H,7-H),1.53(m,2H,8-H),1.31(m,1H,7-H),0.99(s,3H,11-H),0.97(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),165.5(5-C),162.8(d,J=244.6Hz,Ar-C),149.8(C),141.6(d,J=6.7Hz,Ar-C),140.6(Ar-C),133.3(C),129.8(d,J=8.3Hz,Ar-C).128.6(Ar-C),127.5(Ar-C),125.3(Ar-C),125.1(4-C),124.4(d,J=2.5Hz,Ar-C),115.5(d,J=21.1Hz,Ar-C),114.1(Ar-C),104.3(CH),58.4(Ar-CH2),54.2(9-C),50.9(Ar-CH2),49.5(6-C),47.0(2-C),36.8(N-CH3),36.3(1-C),28.7(12-C),27.9(7-C),27.1(11-C),26.6(8-C),24.8(13-C).HR-ESIMS m/z 474.2895[M+H]+,calcd for C30H37FN3O,474.2921.
实施例6.
化合物N29-N40的合成方法:
称取1.0当量中间体7和3.0当量相应的醛(8A-8L)于反应瓶中,加适量甲醇溶解,加入0.2mL水,接着加入已经溶于甲醇中的0.5当量氯化锌和1.5当量氰基硼氢化钠,反应在30℃下搅拌,TLC监测至反应结束。将甲醇旋干,加入水和DCM并萃取,合并有机层,用无水硫酸镁干燥,过滤,浓缩得粗品。
化合物N29的合成
以化合物8A为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为90.2%。1H NMR(400MHz,CDCl3):δ7.38(m,2H,Ar-H),7.25(m,3H,Ar-H),7.14(m,3H,Ar-H),7.01(m,2H,Ar-H),6.91(m,1H,Ar-H),5.79(s,1H,4-H)-3.78(s,3H,OCH3),3.69(s,2H,Ar-CH2),3.59(s,2H,Ar-CH2),2.45(t,J=6.8Hz,2H,9-H),2.33(d,J=17.2Hz,1H,2-H),2.00(d,J=17.2Hz,1H,2-H),1.89(s,3H,13-H),1.78(t,J=5.2Hz,1H,9-H),1.67(m,1H,7-H),1.58(m,2H,8-H),1.35(m,1H,7-H),1.00(s,3H,11-H),0.97(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.5(3-C),165.9(5-C),162.9(d,J=243.9Hz,Ar-C),158.5(d,J=246.6Hz,Ar-C),156.8(Ar-C),142.7(d,J=6.8Hz,Ar-C),131.2(Ar-C),130.6(d,J=3.5Hz,Ar-C),130.1(d,J=4.5Hz,Ar-C),129.6(d,J=8.2Hz,Ar-C),129.3(Ar-C),126.2(d,J=17.1Hz,Ar-C),125.7(d,J=15.5Hz,Ar-C),125.1(4-C),124.9(Ar-C),124.1(d,J=2.1Hz,Ar-C),123.4(d,J=3.9Hz,Ar-C),120.5(Ar-C),115.3(d,J=21.2Hz,Ar-C)-113.8(d,J=21.1Hz,Ar-C),111.0(Ar-C),58.2(Ar-CH2),55.6(OCH3),54.0(9-C),51.4(d,J=1.8Hz,Ar-CH2),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.1(11-C),27.0(8-C),24.7(13-C).HR-ESIMS m/z 518.2841[M+H]+,calcd for C33H38F2NO2,518.2871.
化合物N30的合成
以化合物8B为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为89.2%。1H NMR(400MHz,CDCl3):δ7.41(m,1H,Ar-H),7.26(m-4H,Ar-H),7.16(m,5H,Ar-H),6.92(m,1H,Ar-H),6.91(m,1H,Ar-H),5.79(s,1H,4-H),3.68(s,2H,Ar-CH2),3.59(s,2H,Ar-CH2),2.45(t,J=6.8Hz,2H,9-H),2.33(d,J=17.6Hz,1H,2-H)-2.19(s,3H,CH3),2.00(d,J=17.6Hz,1H,2-H),1.90(s,3H,13-H),1.78(t,J=5.2Hz,1H,9-H)-1.66(m,1H,7-H),1.57(m,2H,8-H),1.34(m,1H,7-H),1.00(s,3H,11-H),0.98(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.5(3-C),165.8(5-C),162.9(d,J=243.8Hz,Ar-C),158.1(d,J=246.6Hz,Ar-C),142.6(d,J=7.0Hz,Ar-C),136.5(Ar-C),135.8(Ar-C),130.3(d,J=8.9Hz,Ar-C),130.3(Ar-C),129.9(d,J=9.6Hz,Ar-C),129.6(d,J=8.2Hz,Ar-C),129.2(d,J=7.8Hz,Ar-C),127.9(Ar-C),125.9(d,J=15.4Hz,Ar-C),125.6(4-C),125.0(Ar-C),124.1(d,J=2.2Hz,Ar-C),123.6(d,J=4.0Hz,Ar-C),115.3(d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),58.3(Ar-CH2),54.1(9-C),51.4(Ar-CH2),51.1(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.1(11-C),27.0(8-C),24.8(13-C),20.0(d,J=2.6Hz,CH3).HR-ESIMS m/z502.2903[M+H]+,calcd for C33H38F2NO,502.2921.
化合物N31的合成
以化合物8C为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为87.9%。1H NMR(400MHz,CDCl3):δ7.46(m,2H,Ar-H),7.32(m,3H,Ar-H),7.25(m,1H,Ar-H),7.19(m,2H,Ar-H),7.11(m,2H,Ar-H),6.92(m,1H,Ar-H),5.79(s,1H,4-H),3.69(s,2H,Ar-CH2),3.60(s,2H,Ar-CH2),2.46(t,J=6.8Hz,2H,9-H),2.33(d,J=17.6Hz,1H,2-H),2.00(d,J=17.6Hz,1H,2-H),1.90(s,3H,13-H),1.78(t,J=5.2Hz,1H,6-H),1.67(m,1H,7-H),1.57(m,2H,8-H),1.34(m,1H,7-H),1.00(s,3H,11-H),0.97(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.5(3-C),165.9(5-C),162.9(d,J=243.8Hz,Ar-C),158.1(d,J=246.4Hz,Ar-C),142.5(d,J=7.0Hz,Ar-C),135.0(Ar-C),133.6(Ar-C),131.5(Ar-C),131.0(d,J=4.6Hz,Ar-C),130.2(d,J=3.2Hz,Ar-C),129.6(d,J=8.1Hz,Ar-C),129.5(Ar-C),126.9(d,J=16.9Hz,Ar-C),126.6(Ar-C),126.1(d,J=15.1Hz,Ar-C),125.0(4-C),124.1(d,J=2.4Hz,Ar-C),123.5(d,J=4.1Hz,Ar-C),115.3(d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),58.3(Ar-CH2),54.0(9-C),51.2(Ar-CH2),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C).27.2(11-C),27.0(8-C),24.8(13-C).HR-ESIMS m/z 522.2346[M+H]+,calcd for C32H35ClF2NO,522.2375.
化合物N32的合成
以化合物8D为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为89.4%。1H NMR(400MHz,CDCl3):δ7.62(s,1H,Ar-H),7.50(d,J=8.4Hz,1H,Ar-H),7.45(m,1H,Ar-H),7.36(m,1H,Ar-H),7.27(m,2H,Ar-H),7.19(m,1H-Ar-H),7.10(m,1H,Ar-H),6.92(m,1H,Ar-H),5.80(s,1H,4-H),3.69(s,2H,Ar-CH2),3.59(s,2H,Ar-CH2),2.45(t,J=6.8Hz,2H,9-H),2.33(d,J=17.2Hz,1H,2-H),2.00(d,J=17.2Hz,1H,2-H),1.91(s,3H,13-H),1.79(t,J=5.4Hz,1H,6-H),1.67(m,1H,7-H),1.58(m,2H,8-H),1.35(m,1H,7-H),1.01(s,3H,11-H),0.97(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.5(3-C),165.9(5-C),162.9(d,J=243.8Hz,Ar-C),158.1(d,J=246.4Hz,Ar-C),142.5(d,J=7.0Hz,Ar-C),135.0(Ar-C),133.6(Ar-C),131.5(Ar-C),131.0(d,J=4.6Hz,Ar-C),130.2(d,J=3.2Hz,Ar-C),129.6(d,J=8.1Hz,Ar-C),129.5(Ar-C),126.9(d,J=16.9Hz,Ar-C),126.6(Ar-C),126.1(d,J=15.1Hz,Ar-C),125.0(4-C),124.1(d,J=2.4Hz,Ar-C),123.5(d,J=4.1Hz,Ar-C)-115.3(d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),58.3(Ar-CH2),54.0(9-C),51.2(Ar-CH2),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.2(11-C),27.0(8-C),24.8(13-C).HR-ESIMS m/z 556.1963[M+H]+,calcd forC32H34Cl2F2NO,556.1986.
化合物N33的合成
以化合物8E为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1-V/V)得黄色油状物,产率为88.6%。1H NMR(400MHz,CDCl3):δ7.40(m,1H,Ar-H),7.25(m,1H,Ar-H),7.15(m,6H,Ar-H),7.05(m,1H,Ar-H),6.92(m,1H,Ar-H),5.80(s,1H,4-H),3.58(m,4H,Ar-CH2),2.45(t,J=6.4Hz,2H,9-H),2.34(s,3H,Ar-CH3),2.33(d,J=17.2Hz,1H,2-H),2.07(s,3H,Ar-CH3),2.00(d,J=17.2Hz,1H,2-H),1.90(s,3H,13-H),1.78(t,J=5.2Hz,1H,6-H)-1.67(m,1H,7-H),1.57(m,2H,8-H),1.34(m,1H,7-H),1.00(s,3H,11-H),0.98(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.8(5-C),162.9(d,J=243.8Hz,Ar-C),158.1(d,J=244.5Hz,Ar-C),142.6(d,J=6.9Hz,Ar-C),136.9(Ar-C),135.9(Ar-C),135.0(Ar-C),130.4(d,J=3.2Hz,Ar-C),130.1(d,J=4.4Hz,Ar-C),129.7(d,J=17.5Hz,Ar-C),129.5(d,J=10.5Hz,Ar-C),127.8(Ar-C),125.8(d,J=15.5Hz,Ar-C),125.2(Ar-C),125.0(4-C),124.1(d,J=2.3Hz,Ar-C),123.5(d,J=4.1Hz,Ar-C),115.3(d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),58.3(Ar-CH2),54.1(9-C),51.4(Ar-CH2),51.1(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.2(11-C),27.0(8-C),24.8(13-C),20.0(CH3),16.7(CH3).HR-ESIMS m/z 516.3050[M+H]+,calcd for C34H40F2NO,516.3078.
化合物N34的合成
以化合物8F为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为86.3%。1H NMR(400MHz,CDCl3):δ7.44(m,1H,Ar-H),7.26(m,2H,Ar-H),7.15(m,4H,Ar-H),7.00(m,1H,Ar-H),6.92(m,2H,Ar-H),5.79(s,1H,4-H),3.92(s,3H,OCH3),3.69(m,2H,Ar-CH2),3.60(s,2H,Ar-CH2),2.45(t,J=6.6Hz,2H,9-H),2.34(d,J=17.2Hz,1H,2-H),2.07(s,3H,Ar-CH3),2.00(d,J=17.2Hz,1H,2-H),1.90(s,3H,13-H),1.78(t,J=5.2Hz,1H,6-H),1.67(m,1H,7-H),1.57(m,2H,8-H),1.34(m,1H,7-H),1.00(s,3H,11-H),0.97(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.6(3-C),166.0(5-C),162.9(d,J=244.0Hz,Ar-C),158.2(d,J=247.6Hz,Ar-C),150.9(Ar-C),148.4(Ar-C),141.9(d,J=11.1Hz,Ar-C),142.5(d,J=7.0Hz,Ar-C),130.9(d,J=4.6Hz,Ar-C),130.3(Ar-C),129.6(d,J=3.2Hz,Ar-C),126.2(d,J=15.2Hz,Ar-C),124.9(4-C),124.4(d,J=13.2Hz,Ar-C),124.1(d,J=2.2Hz,Ar-C),123.7(Ar-C),123.3(d,J=16.8Hz,Ar-C),122.7(Ar-C),115.3(d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),112.9(Ar-C),58.3(Ar-CH2),56.3(OCH3),54.0(9-C),51.3(d,J=1.8Hz,Ar-CH2),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.1(11-C),27.0(8-C),24.7(13-C).HR-ESIMS m/z 536.2744[M+H]+,calcd for C33H37F3NO2,536.2776.
化合物N35的合成
以化合物8G为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为87.8%。1H NMR(400MHz,CDCl3):δ7.48(m,1H,Ar-H),7.26(m,2H,Ar-H),7.20(m,2H,Ar-H),7.13(m,4H,Ar-H),6.92(m,1H,Ar-H),5.79(s,1H,4-H),3.70(s,2H,Ar-CH2),3.60(s,2H,Ar-CH2),2.46(t,J=6.7Hz,2H,9-H),2.34(d,J=17.2Hz,1H,2-H),2.00(d,J=17.2Hz,1H,2-H),1.90(s,3H,13-H),1.79(t,J=5.2Hz,1H,6-H),1.66(m,1H,7-H),1.58(m,2H,8-H),1.34(m,1H,7-H),1.00(s,3H,11-H),0.98(s,3H,12-H).13CNMR(100MHz,CDCl3):δ199.5(3-C),165.8(5-C),163.0(d,J=243.9Hz,Ar-C),158.2(d,J=248.0Hz,Ar-C),150.8(dd,J1=246.5Hz,J2=13.1Hz,Ar-C),148.0(dd,J1=248.7Hz,J2=12.9Hz,Ar-C),142.4(d,J=6.7Hz,Ar-C),131.4(d,J=4.6Hz,Ar-C),130.1(Ar-C),129.6(d,J=8.1Hz,Ar-C),126.5(d,J=15.1Hz,Ar-C),126.2(d,J=1.3Hz,Ar-C),125.9(d,J=12.4Hz,Ar-C),125.0(4-C),124.1(d,J=2.0Hz,Ar-C),123.9(dd,J1=4.7Hz,J2=6.9Hz,Ar-C),122.3(dd,J1=2.5Hz,J2=16.6Hz,Ar-C),116.8(d,J=17.1Hz,Ar-C),115.3(d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),58.3(Ar-CH2),54.0(9-C),51.3(d,J=1.9Hz,Ar-CH2),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.1(11-C),27.0(8-C),24.7(13-C).HR-ESIMS m/z 524.2547[M+H]+,calcd for C32H34F4NO,524.2577.
化合物N36的合成
以化合物8H为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为89.5%。1H NMR(400MHz,CDCl3):δ7.43(m,1H,Ar-H),7.25(m,3H,Ar-H),7.17(m,3H,Ar-H),7.10(m,3H,Ar-H),6.92(m,1H,Ar-H),5.79(s,1H,4-H),3.69(s,2H,Ar-CH2),3.60(s,2H,Ar-CH2),2.46(t,J=6.7Hz,2H,9-H),2.34(d,J=17.2Hz,1H,2-H),2.33(s,3H,CH3),1.99(d,J=17.2Hz,1H,2-H),1.89(s,3H,13-H),1.78(t,J=5.2Hz,1H,6-H),1.67(m,1H,7-H),1.57(m,2H,8-H),1.34(m,1H,7-H),1.00(s,3H,11-H),0.97(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.5(3-C),166.0(5-C),163.0(d,J=244.0Hz,Ar-C),158.4(d,J=247.0Hz,Ar-C),158.3(d,J=245.5Hz,Ar-C),142.6(d,J=6.9Hz,Ar-C),131.3(d,J=5.1Hz,Ar-C),130.8(d,J=4.6Hz,Ar-C),130.4(d,J=2.2Hz,Ar-C),129.7(d,J=8.1Hz,Ar-C),128.9(d,J=2.0Hz,Ar-C),126.2(d,J=15.2Hz,Ar-C),152.2(d,J=17.7Hz,Ar-C),125.0(4-C),124.2125.0(d,J=23.8Hz,Ar-C),123.9(d,J=23.0Hz,Ar-C),123.7(d,J=4.0Hz,Ar-C),123.6(d,J=4.3Hz,Ar-C),123.3(d,J=16.6Hz,Ar-C),115.4(d,J=21.2Hz,Ar-C),113.9(d,J=21.1Hz,Ar-C),58.4(Ar-CH2),54.0(9-C),51.4(d,J=1.7Hz,Ar-CH2),51.1(6-C),47.1(2-C),36.4(1-C),28.7(12-C),28.0(7-C),27.2(11-C),27.0(8-C),24.8(13-C),14.8(d,J=4.3Hz,CH3).HR-ESIMS m/z 520.2814[M+H]+,calcd for C33H37F3NO,520.2827.
化合物N37的合成
以化合物8I为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为84.9%。1H NMR(400MHz,CDCl3):δ7.44(m,1H,Ar-H),7.27(m,2H,Ar-H),7.18(m,2H,Ar-H),7.11(m,2H,Ar-H),6.98(m,1H,Ar-H),6.92(m,2H,Ar-H),5.79(s,1H,4-H),3.94(s,3H,OCH3),3.60(s,2H,Ar-CH2),3.60(s,2H,Ar-CH2),2.46(t,J=6.6Hz,2H,9-H),2.33(d,J=17.2Hz,1H,2-H),2.33(s,3H,Ar-CH3),1.99(d,J=17.2Hz,1H,2-H),1.90(s,3H,13-H),1.78(t,J=5.2Hz,1H,6-H),1.66(m,1H,7-H),1.57(m,2H,8-H),134(m,1H,7-H),1.00(s,3H,11-H),0.97(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.6(3-C),166.0(5-C),163.0(d,J=243.8Hz,Ar-C),158.0(d,J=246.3Hz,Ar-C),155.3(Ar-C),142.6(d,J=6.9Hz,Ar-C),136.7(Ar-C),131.0(d,J=4.5Hz,Ar-C),130.1(d,J=2.8Hz,Ar-C),129.7(d,J=8.1Hz,Ar-C),127.1(d,J=17.0Hz,Ar-C),127.0(Ar-C),126.1(d,J=15.1Hz,Ar-C),125.0(4-C),124.2(d,J=2.4Hz,Ar-C),123.5(d,J=4.0Hz,Ar-C),123.3(Ar-C),122.2(Ar-C),115.3(d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),111.4(Ar-C),58.2(Ar-CH2),56.3(OCH3),54.0(9-C),51.3(Ar-CH2),51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.1(11-C),27.0(8-C),24.8(13-C).HR-ESIMS m/z 552.2465[M+H]+,calcd for C33H37ClF2NO2,552.2481.
化合物N38的合成
以化合物8J为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为83.6%。1H NMR(400MHz,CDCl3):δ7.77(d,J=8.4Hz,1H,Ar-H),7.66(m,1H,Ar-H),7.50(m,3H,Ar-H),7.26(m,3H,Ar-H),7.11(m,2H,Ar-H),6.92(m,1H,Ar-H),5.79(s,1H,4-H),3.71(s,2H,Ar-CH2),3.62(s,2H,Ar-CH2),2.48(t,J=6.8Hz,2H,9-H),2.34(d.J=17.2Hz,1H,2-H),1.99(d,J=17.2Hz,1H,2-H),1.91(s,3H,13-H),1.80(t,J=5.2Hz,1H,6-H),1.67(m,1H,7-H),1.58(m,2H,8-H),1.35(m,1H,7-H),1.01(s,3H,11-H),0.98(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.7(5-C),163.0(d,J=244.0Hz,Ar-C),157.9(d,J=247.1Hz,Ar-C),142.4(d,J=7.8Hz,Ar-C),139.7(Ar-C),133.1(Ar-C),132.6(Ar-C),132.0(d,J=4.8Hz,Ar-C),130.9(Ar-C),130.0(d,J=2.3Hz,Ar-C),129.6(d,J=8.1Hz,Ar-C),128.2(Ar-C),126.7(d,J=15.1Hz,Ar-C),125.9(d,J=16.1Hz,Ar-C),125.0(4-C),124.2(d,J=2.5Hz,Ar-C),124.0(d,J=6.2Hz,Ar-C),118.0(CN),115.3(d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),113.0(Ar-C),58.3(Ar-CH2),54.1(9-C),51.2(Ar-CH2),51.0(6-C),47.2(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.1(11-C),27.0(8-C),24.8(13-C).HR-ESIMS m/z 513.2695[M+H]+,calcd forC33H35F2N2O,513.2717.
化合物N39的合成
以化合物8K为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为80.7%。1H NMR(400MHz,CDCl3):δ8.05(m,1H,Ar-H),7.68(m,1H,Ar-H),7.55(m,1H,Ar-H),7.45(m,2H,Ar-H),7.25(m,3H,Ar-H),7.10(m,2H,Ar-H),6.92(m,1H,Ar-H),5.78(s,1H,4-H),3.64(s,2H,Ar-CH2),3.58(s,2H,Ar-CH2),3.60(s,2H,N-CH2),2.43(t,J=6.8Hz,2H,9-H),2.34(d,J=17.2Hz,1H,2-H),1.99(d,J=17.2Hz,1H,2-H),1.91(s,3H,13-H),1.80(t,J=5.4Hz,1H,6-H),1.67(m,1H,7-H),1.56(m,2H,8-H),1.33(m,1H,7-H),1.00(s,3H,11-H),0.98(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.5(3-C),165.9(5-C),162.9(d,J=243.8Hz,Ar-C),157.8(d,J=245.2Hz,Ar-C),149.1(Ar-C),142.4(d,J=6.9Hz,Ar-C),132.9(Ar-C),132.5(Ar-C),131.5(d,J=4.5Hz,Ar-C),130.8(Ar-C),129.6(d,J=8.2Hz,Ar-C),128.9(Ar-C),128.8(d,J=2.7Hz,Ar-C),126.0(d,J=15.0Hz,Ar-C),125.6(d,J=16.9Hz,Ar-C),125.0(4-C),124.5(Ar-C),124.3(d,J=4.0Hz,Ar-C),124.1(d,J=2.5Hz,Ar-C),115.3(d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),58.3(Ar-CH2),54.0(9-C),51.1(6-C),51.0(Ar-CH2),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.1(11-C),27.0(8-C),24.7(13-C).HR-ESIMS m/z 533.2485[M+H]+,calcdfor C32H35F2N2O3,533.2616.
化合物N40的合成
以化合物8L为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=10∶1-6∶1,V/V)得黄色油状物,产率为86.2%。1H NMR(400MHz,CDCl3):δ7.65(m,2H,Ar-H),7.52(m,1H,Ar-H),7.35(m,1H,Ar-H),7.25(m,3H,Ar-H),7.10(m,2H,Ar-H),6.93(m,1H,Ar-H),5.79(s,1H,4-H),3.70(s,3H,Ar-CH3),3.60(s,2H,Ar-CH2),3.60(s,2H,N-CH2),2.47(t,J=6.7Hz,2H,9-H),2.34(d,J=17.2Hz,1H,2-H),2.00(d,J=17.2Hz,1H,2-H),1.91(s,3H,13-H),1.80(t,J=5.4Hz,1H,6-H),1.67(m,1H,7-H),1.58(m,2H,8-H),1.35(m,1H,7-H),1.00(s,3H,11-H),0.98(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),165.7(5-C),163.0(d,J=243.9Hz,Ar-C),159.1(d,J=259.4Hz,Ar-C),158.0(d,J=248.2Hz,Ar-C),142.3(d,J=6.8Hz,Ar-C),136.5(d,J=3.0Hz,Ar-C),131.1(Ar-C),129.9(Ar-C),129.6(d,J=8.1Hz,Ar-C),126.8(d,J=14.8Hz,Ar-C),125.2(d,J=14.5Hz,Ar-C),125.0(4-C),124.7(d,J=4.3Hz,Ar-C),124.1(d,J=4.0Hz,Ar-C),121.3(d,J=16.4Hz,Ar-C),115.3(d,J=21.2Hz,Ar-C),113.9(d,J=21.1Hz,Ar-C),113.8(CN),102.1(d,J=16.6Hz,Ar-C),58.4(Ar-CH2),54.3(9-C),51.3(Ar-CH2).51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.2(11-C),27.0(8-C),24.8(13-C).HR-ESIMS m/z 531.2613[M+H]+,calcd forC33H34F3N2O,531.2623.
实施例7.
化合物N41-N48的合成方法:
称取1.0当量化合物和3.0当量相应的中间体(10A-10H)于反应瓶中,加适量DCM溶解,冰浴条件下滴加5.0当量三乙胺,于室温下搅拌,TLC监测至反应结束,浓缩得粗品。
化合物N41的合成
以化合物10A为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-4∶1,V/V)得黄色油状物,产率为74.3%。1H NMR(400MHz,CDCl3):δ7.80(m,2H,Ar-H),7.30(m,1H,Ar-H),7.14(m,4H,Ar-H),6.97(m,1H,Ar-H),6.40(s,1H,CH),5.82(s,1H,4-H),3.81(s,2H,Ar-CH2),3.66(s,2H,Ar-CH2),2.54(t,J=6.8Hz,2H,9-H),2.36(d,J=17.2Hz,1H,2-H),2.03(d,J=17.2Hz,1H,2-H),1.96(d,J=0.6Hz,3H,13-H),1.84(t,J=5.2Hz,1H,6-H),1.72(m,1H,7-H),1.61(m,2H,8-H),1.42(m,1H,7-H),1.04(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),170.6(C),165.5(5-C),163.8(d,J=248.5Hz,Ar-C),163.0(d,J=244.4Hz,Ar-C),161.4(C),141.5(d,J=7.0Hz,Ar-C),130.0(d,J=8.1Hz,Ar-C),128.7(d,J=8.3Hz,Ar-C),125.2(d,J=3.7Hz,Ar-C),125.1(4-C),124.2(d,J=2.6Hz,Ar-C),116.1(d,J=21.8Hz,Ar-C),115.4(d,J=21.2Hz,Ar-C),114.3(d,J=21.1Hz,Ar-C),101.2(CH),58.0(Ar-CH2),54.1(9-C),51.0(6-C),48.4(Ar-CH2),47.1(2-C),36.3(1-C),28.8(12-C),27.8(7-C),27.2(8-C),27.1(11-C),24.8(13-C).HR-ESIMS m/z 479.2489[M+H]+,calcd for C29H33F2N2O2,479.2510.
化合物N42的合成
以化合物10B为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-4∶1,V/V)得黄色油状物,产率为75.2%。1H NMR(400MHz,CDCl3):δ7.80(m,2H,Ar-H),7.30(m,1H,Ar-H),7.14(m,4H,Ar-H),6.97(m,1H,Ar-H),6.40(s,1H,CH),5.82(s,1H,4-H),3.81(s,2H,Ar-CH2),3.66(s,2H,Ar-CH2),2.54(t,J=6.8Hz,2H,9-H),2.36(d,J=17.2Hz,1H,2-H),2.03(d,J=17.2Hz,1H,2-H),1.96(d,J=0.6Hz,3H,13-H),1.84(t,J=5.2Hz,1H,6-H),1.72(m,1H,7-H),1.61(m,2H,8-H),1.42(m,1H,7-H),1.04(s,3H,11-H),1.01(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),170.6(C),165.5(5-C),163.8(d,J=248.5Hz,Ar-C),163.0(d,J=244.4Hz,Ar-C),161.4(C),141.5(d,J=7.0Hz,Ar-C),130.0(d,J=8.1Hz,Ar-C),128.7(d,J=8.3Hz,Ar-C),125.2(d,J=3.7Hz,Ar-C),125.1(4-C),124.2(d,J=2.6Hz,Ar-C),116.1(d,J=21.8Hz,Ar-C),115.4(d,J=21.2Hz,Ar-C),114.3(d,J=21.1Hz,Ar-C),101.2(CH),58.0(Ar-CH2),54.1(9-C),51.0(6-C),48.4(Ar-CH2),47.1(2-C),36.3(1-C),34.1(CH),28.8(12-C),27.8(7-C),27.2(8-C),27.1(11-C),24.8(13-C).HR-ESIMS m/z 495.2198[M+H]+,calcd for C29H33ClFN2O2,495.2215.
化合物N43的合成
以化合物10C为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=4∶1-2∶1,V/V)得黄色油状物,产率为75.6%。1H NMR(400MHz,CDCl3):δ7.96(d,J=8.4Hz,2H,Ar-H),7.77(d,J=8.4Hz,2H,Ar-H),7.30(m,1H,Ar-H),7.12(m,2H,Ar-H),6.98(m,1H,Ar-H),6.47(s,1H,CH),5.82(s,1H,4-H),3.83(s,2H,Ar-CH2),3.66(s,2H,Ar-CH2),2.54(t,J=6.8Hz,2H,9-H),2.36(d,J=17.2Hz,1H,2-H),2.03(d,J=17.2Hz,1H,2-H),1.96(d,J=1.0Hz,3H,13-H),1.85(t,J=5.2Hz,1H,6-H),1.72(m,1H,7-H),1.61(m,2H,8-H),1.42(m,1H,7-H),1.05(s,3H,11-H),1.01(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),171.6(C),165.4(5-C),163.0(d,J=244.4Hz,Ar-C),160.8(C),141.4(d,J=6.9Hz,Ar-C),132.8(Ar-C),130.0(d,J=8.3Hz,Ar-C),127.4(Ar-C),125.2(4-C),124.1(d,J=2.0Hz,Ar-C),118.3(CN),115.4(d,J=21.5Hz,Ar-C),114.3(d,J=20.7Hz,Ar-C),113.6(Ar-C),101.2(CH),58.0(Ar-CH2),54.2(9-C),51.0(6-C),48.5(Ar-CH2),47.1(2-C),36.3(1-C),34.1(CH),28.8(12-C),27.9(7-C),27.3(8-C),27.1(11-C),24.8(13-C).HR-ESIMS m/z486.2523[M+H]+,calcd for C30H33FN3O2,486.2557.
化合物N44的合成
以化合物10D为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=5∶1-3∶1,V/V)得黄色油状物,产率为76.3%。1H NMR(400MHz,CDCl3):δ7.00(d,J=8.0Hz,2H,Ar-H),7.29(m,3H,Ar-H),7.12(m,2H,Ar-H),6.96(m,1H,Ar-H),6.41(s,1H,CH),5.81(s,1H,4-H),3.79(s,2H,Ar-CH2),3.65(s,2H,Ar-CH2),2.53(t,J=7.0Hz,2H,9-H),2.40(s,3H,CH3),2.36(d,J=17.6Hz,1H,2-H),2.02(d,J=17.6Hz,1H,2-H),1.95(s,3H,13-H),1.84(t,J=5.2Hz,1H,6-H),1.72(m,1H,7-H),1.61(m,2H,8-H),1.42(m,1H,7-H),1.04(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),170.2(C),165.5(5-C),163.0(d,J=244.3Hz,Ar-C),162.2(C),141.6(d,J=7.0Hz,Ar-C),140.2(Ar-C),129.9(d,J=8.1Hz,Ar-C),129.6(Ar-C),126.6(Ar-C),126.1(Ar-C),125.1(4-C),124.2(d,J=2.5Hz,Ar-C),115.4(d,J=21.3Hz,Ar-C),114.2(d,J=21.1Hz,Ar-C),101.2(CH),58.0(Ar-CH2),54.0(9-C),51.0(6-C),48.4(Ar-CH2),47.1(2-C),36.3(1-C),28.7(12-C),27.7(7-C),27.2(8-C),27.1(11-C),24.7(13-C),21.4(CH3).HR-ESIMS m/z 475.2745[M+H]+,calcdfor C30H36FN2O2,475.2761.
化合物N45的合成
以化合物10E为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-4∶1,V/V)得黄色油状物,产率为75.8%。1H NMR(400MHz,CDCl3):δ7.74(d,J=8.0Hz,2H,Ar-H),7.29(m,1H,Ar-H),7.13(d,J=8.0Hz,2H,Ar-H),6.96(m,3H,Ar-H),6.38(s,1H,CH),5.81(s,1H,4-H),3.85(s,3H,OCH3),3.79(s,2H,Ar-CH2),3.65(s,2H,Ar-CH2),2.53(t,J=6.8Hz,2H,9-H),2.36(d,J=17.2Hz,1H,2-H),2.02(d,J=17.2Hz,1H,2-H),1.95(s,3H,13-H),1.84(t,J=5.4Hz,1H,6-H),1.72(m,1H,7-H),1.61(m,2H,8-H),1.42(m,1H,7-H),1.04(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),170.2(C),165.6(5-C),163.0(d,J=244.3Hz,Ar-C),161.9(C),161.0(Ar-C),141.6(d,J=6.9Hz,Ar-C),140.2(Ar-C),129.9(d,J=8.3Hz,Ar-C),128.2(Ar-C),125.1(4-C),124.2(d,J=2.4Hz,Ar-C),121.5(Ar-C),115.4(d,J=21.3Hz,Ar-C),114.3(Ar-C),114.2(d,J=21.1Hz,Ar-C),101.1(CH),58.0(Ar-CH2),55.4(OCH3),54.1(9-C),51.0(6-C),48.4(Ar-CH2),47.1(2-C),36.3(1-C),28.8(12-C),27.8(7-C),27.2(8-C),27.1(11-C),24.8(13-C).HR-ESIMS m/z 491.2679[M+H]+,calcd for C30H36FN2O3,491.2710.
化合物N46的合成
以化合物10F为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-6∶1,V/V)得黄色油状物,产率为71.4%。1H NMR(400MHz,CDCl3):δ8.34(d,J=8.8Hz,2H,Ar-H),7.99(d,J=8.8Hz,2H,Ar-H),7.31(m,1H,Ar-H),7.12(m,2H,Ar-H),6.96(m,1H,Ar-H),6.51(s,1H,CH),5.83(s,1H,4-H),3.84(s,2H,Ar-CH2),3.67(s,2H,Ar-CH2),2.56(t,J=6.8Hz,2H,9-H),2.36(d,J=17.2Hz,1H,2-H),2.03(d,J=17.2Hz,1H,2-H),1.96(s,3H,13-H),1.86(t,J=5.2Hz,1H,6-H),1.72(m,1H,7-H),1.62(m,2H,8-H),1.43(m,1H,7-H),1.05(s,3H,11-H),1.01(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),171.8(C),165.4(5-C),163.1(d,J=244.4Hz,Ar-C),160.5(C),148.7(Ar-C),141.3(d,J=6.9Hz,Ar-C),135.1(Ar-C),130.0(d,J=8.1Hz,Ar-C),127.7(Ar-C),125.2(4-C),124.3(Ar-C),124.1(d,J=2.4Hz,Ar-C),115.4(d,J=21.2Hz,Ar-C),114.4(d,J=21.1Hz,Ar-C),101.4(CH),58.0(Ar-CH2),54.3(9-C),51.0(6-C),48.5(Ar-CH2),47.1(2-C),36.3(1-C),28.8(12-C),27.8(7-C),27.2(8-C),27.1(11-C),24.8(13-C).HR-ESIMS m/z506.2433[M+H]+,calcdfor C29H33FN3O4,506.2455.
化合物N47的合成
以化合物10G为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-4∶1,V/V)得黄色油状物,产率为75.7%。产率为71.6%。1H NMR(400MHz,CDCl3):δ7.57(m,2H,Ar-H),7.46(m,1H,Ar-H),7.32(m,1H,Ar-H),7.15(m,3H,Ar-H),6.99(m,1H,Ar-H),6.44(s,lH,CH),5.84(s,1H,4-H),3.83(s,2H,Ar-CH2),3.68(s,2H,Ar-CH2),2.56(t,J=6.8Hz,2H,9-H),2.38(d,J=17.2Hz,1H,2-H),2.05(d,J=17.2Hz,1H,2-H),1.98(d,J=0.6Hz,3H,13-H),1.87(t,J=5.2Hz,1H,6-H),1.74(m,1H,7-H),1.63(m,2H,8-H),1.44(m,1H,7-H),1.07(s.3H,11-H),1.03(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),170.9(C),165.4(5-C),163.1(d,J=244.5Hz,Ar-C),163.0(d,J=245.3Hz,Ar-C),161.4(C),141.5(d,J=7.0Hz,Ar-C),131.1(d,J=8.6Hz,Ar-C),130.6(d,J=8.2Hz,Ar-C),129.9(d,J=7.9Hz,Ar-C),125.2(4-C),124.2(d,J=2.6Hz,Ar-C),122.5(d,J=2.5Hz,Ar-C),117.0(d,J=21.4Hz,Ar-C),115.4(d,J=21.2Hz,Ar-C),114.3(d,J=21.0Hz,Ar-C),113.8(d,J=23.0Hz,Ar-C),101.3(CH),58.0(Ar-CH2),54.1(9-C),51.0(6-C),48.4(Ar-CH2),47.1(2-C),36.3(1-C),29.7(12-C),28.8(7-C),27.8(8-C),27.2(11-C),24.8(13-C).HR-ESIMS m/z 479.2474[M+H]+,calcd for C29H33F2N2O2,479.2510.
化合物N48的合成
以化合物10H为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=8∶1-4∶1,V/V)得黄色油状物,产率为73.6%。1H NMR(400MHz,CDCl3):δ7.73(d,J=8.0Hz,2H,Ar-H),7.32(d,J=8.0Hz,2H,Ar-H),7.28(m,1H,Ar-H),7.12(m,2H,Ar-H),6.96(m,1H,Ar-H),.41(s,1H,CH),5.83(s,1H,4-H),3.80(s,2H,Ar-CH2),3.65(s,2H,Ar-CH2),2.95(m,1H,CH),2.53(t,J=6.8Hz,2H,9-H),2.36(d,J=17.2Hz,1H,2-H),2.02(d,J=17.2Hz,1H,2-H),1.95(s,3H,13-H),1.84(t,J=5.2Hz,1H,6-H),1.72(m,1H,7-H),1.61(m,2H,8-H),1.43(m,1H,7-H),1.28(d,J=6.8Hz,6H,(CH3)2),1.04(s,3H,11-H),1.00(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),170.2(C),165.6(5-C),163.0(d,J=244.3Hz,Ar-C),162.2(C),151.1(Ar-C),141.6(d,J=6.8Hz,Ar-C),129.9(d,J=8.1Hz,Ar-C),127.1(Ar-C),126.8(Ar-C),126.5(Ar-C),125.1(4-C),124.2(d,J=2.5Hz,Ar-C),115.4(d,J=21.4Hz,Ar-C),114.2(d,J=21.0Hz,Ar-C),101.3(CH),58.0(Ar-CH2),54.0(9-C),51.0(6-C),48.4(Ar-CH2),47.2(2-C),36.3(1-C),34.1(CH),28.8(12-C),27.7(7-C),27.2(8-C),27.1(11-C),24.8(13-C),23.9((CH3)2).HR-ESIMS m/z 503.3044[M+H]+,calcd for C27H35FN2O2,503.3074.
实施例8.
化合物N49和N62-N73的合成方法
称取1.0当量化合物16于瓶中,加适量DCM溶解,加入1.0当量无水碳酸钾,冰浴下缓慢滴加1.1当量苄溴,接着在冰浴中搅拌,TLC监测至反应结束。缓慢滴加1mol/L氢氧化钠水溶液淬灭反应,用DCM萃取三次,合并有机层并用无水硫酸镁干燥,过滤,浓缩得粗品。
化合物N49的合成
以3-氟-4-溴苄溴为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=4∶1-2∶1,V/V)得黄色油状物,产率为92.6%。1H NMR(400MHz,CDCl3):δ7.47(m,1H,Ar-H),7.12(m,1H,Ar-H),6.97(m,1H,Ar-H),5.82(s,1H,4-H),3.42(s,2H,Ar-CH2),2.37(m,3H,2-H,9-H),2.17(s,3H,10-H),2.03(d,J=17.2Hz,1H,2-H),1.98(s,3H,13-H),1.86(t,J=5.4Hz,1H,6-H),1.74(m,1H,7-H),1.57(m,2H,8-H),1.43(m,1H,7-H),1.05(s,3H,11-H),1.02(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.3(3-C),165.5(5-C),159.0(d,J=245.7Hz,Ar-C),141.4(d,J=6.5Hz,Ar-C),133.1(Ar-C),125.4(d,J=3.1Hz,Ar-C),125.1(4-C),116.6(d,J=22.0Hz,Ar-C),107.1(d,J=20.8Hz,Ar-C),61.5(Ar-CH2),57.7(9-C),51.1(6-C),47.2(2-C),42.2(10-C),36.3(1-C),28.8(12-C),27.8(7-C),27.2(8-C),27.1(11-C),24.7(13-C).HR-ESIMS m/z 396.1337[M+H]+,calcd for C20H28BrFNO,396.1338.
化合物N62的合成
以4-(三氟甲基)苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为50%。1H NMR(400MHz,CDCl3):δ7.58(s,1H,Ar-H),7.57(s,1H,Ar-H),7.44(m,2H,Ar-H),5.82(br s,1H),3.45(br s,2H),2.39(m,3H),2.20(m,3H),2.02(d,J=15.4Hz,1H),1.97(s,3H),1.86(m,1H),1.72(m,1H),1.60(m,2H),1.42(m,1H),1.12(s,3H),1.05(s,3H).13C NMR(100MHz,CDCl3):δ199.4,165.6,159.0(d,J=220.7Hz),143.4,129.1(d,J=5.7Hz),125.3(d,J=8.3Hz),125.2,125.1(d,J=2.8Hz),124.0(d,J=19.9Hz),62.0,57.7,51.1,47.1,36.2,29.7,28.8,27.5,27.2,27.1,24.7.FAB-MS显示分子离子峰为m/z:367[M+H]+,分子式为C21H28F3NO.
化合物N63的合成
以2-氟-6-硝基苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为48%。1H NMR(400MHz,CDCl3):δ8.36(s,1H,Ar-H),8.16(s,1H,Ar-H),7.18(s,1H,Ar-H),5.83(br s,1H),3.60(br s,2H),2.41(d,J=16.7Hz,1H),2.40(d,2H),2.00(s,3H),1.88(d,J=15.6Hz,1H),1.97(s,3H),1.76(m,1H),1.61(m,2H),1.45(m,2H),1.12(s,3H),1.06(s,3H).13C NMR(100MHz,CDCl3):δ198.8,164.3,163.8,139.2(d,J=9.5Hz),137.1,128.1,125.7,120.4,120.2,56.2,50.5,46.8,39.4,36.3,31.9,29.7,28.6,27.4,25.2,24.9.FAB-MS显示分子离子峰为m/z:362[M+H]+,分子式为C20H27FN2O3.
化合物N64的合成
以2-氟-4-氰基苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为51%。1H NMR(400MHz,CDCl3):δ7.46(s,1H,Ar-H),7.44(m,1H,Ar-H),7.33(s,1H,Ar-H),5.82(br s,1H),3.61(br s,2H),2.35(d,J=17.6Hz,1H),2.23(m,3H),2.05(m,2H),2.02(s,1H),1.98(s,3H),1.86(m,1H),1.72(m,1H),1.63(m,2H),1.42(m,1H),1.05(s,3H),1.01(s,3H).13C NMR(100MHz,CDCl3):13C NMR(100MHz,CDCl3):δ198.4,171,165.3,161.8,159.6(d,J=6.9Hz),132.1,128.0(d,J=8.1Hz),125.1,119.1(d,J=2.7Hz),118.9,60.3,59.8,57.8,54.8,42.5,36.3,30.8,28.9,27.8,24.5,14.1.FAB-MS显示分子离子峰为m/z:342[M+H]+,分子式为C21H27FN2O.
化合物N65的合成
以3,4-二氟苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为50%。1H NMR(400MHz,CDCl3):δ7.21(s,1H,Ar-H),7.10(m,2H,Ar-H),5.82(br s,1H),3.54(br s,2H),2.40(m,2H),2.36(d,J=16.0Hz 1H),2.25(s,3H),2.02(s,J=16.5Hz,1H),1.98(s,3H),1.86(m,1H),1.72(m,1H),1.65(m,1H),1.42(m,2H),1.06(s,3H),1.02(s,3H).13C NMR(100MHz,CDCl3):δ199.4,165.3,151.5(d,J=11.0Hz),149.0(d,J=13.4Hz),125.1(d,J=10.0Hz),118.1(d,J=20.0Hz),117.8,117.1(d,J=18.2Hz),117.0,67.0,54.7,53.2,51.2,47.2,41.3,36.3,28.8,27.9,26.6,24.7.FAB-MS显示分子离子峰为m/z:335[M+H]+,分子式为C20H27F2NO.
化合物N66的合成
以3,4-二氯苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为50%。1H NMR(400MHz,CDCl3):1H NMR(400MHz,CDCl3):δ7.46(s,1H,Ar-H),7.41(d,1H,J=8.7Hz,Ar-H),7.23(m,1H,Ar-H),5.82(br s,1H),3.50(br s,2H),2.44(m,2H),2.31(d,J=17.3Hz,1H),2.30(s,3H),2.02(s,J=17.4Hz,1H),1.98(s,3H),1.86(m,1H),1.72(m,1H),1.65(m,2H),1.41(m,2H),1.06(s,3H),1.02(s,3H).13C NMR(100MHz,CDCl3):δ199.4,165.4,136.4,132.4,130.9,130.5,128.4,125.1,60.7,57.7,51.2,47.2,41.3,36.3,29.7,28.8,27.9,27.3,26.6,24.7.FAB-MS显示分子离子峰为m/z:368[M+H]+,分子式为C20H27Cl2NO.
化合物N67的合成
以2-硝基苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为50%。1H NMR(400MHz,CDCl3):δ8.20(s,1H,Ar-H),8.18(s,1H,Ar-H),7.53(m,1H,Ar-H),7.27(m,1H,Ar-H),5.83(br s,1H),3.58(br s,2H),2.37(m,3H),2.22(m,3H),2.05(d,J=17.4Hz,1H),1.99(s,3H),1.87(m,1H),1.74(m,2H),1.61(m,1H),1.41(m,2H),1.06(s,3H),1.01(s,3H).13C NMR(100MHz,CDCl3):δ199.4,169.9,165.3,147.2,129.4,125.9,123.5,117.6,61.7,57.8,51.2,47.2,37.5,36.3,29.7,28.8,27.9,27.3,26.5,24.8.FAB-MS显示分子离子峰为m/z:344[M+H]+,分子式为C20H28N2O3
化合物N68的合成
以4-硝基苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为50%。1H NMR(400MHz,CDCl3):δ8.19(m,2H,Ar-H),7.50(m,2H,Ar-H),5.83(br s,1H),3.60(br s,2H),2.37(m,2H),2.19(m,2H),2.04(d,J=17.0Hz,1H),1.99(s,3H),1.88(m,1H),1.73(m,2H),1.60(m,2H),1.45(m,2H),1.06(s,3H),1.02(s,3H).13C NMR(100MHz,CDCl3):δ199.3,165.3,147.1,129.3,125.2,120.6,57.8,51.0,47.1,42.2,36.3,34.3,28.7,27.8,27.2,27.0,24.8.FAB-MS显示分子离子峰为m/z:344[M+H]+,分子式为C20H28N2O3.
化合物N69的合成
以4-溴苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为49%。1H NMR(400MHz,CDCl3):δ7.46(s,1H,Ar-H),7.44(s,1H,Ar-H),7.22(s,1H,Ar-H),7.20(s,1H,Ar-H),5.82(br s,1H),3.48(br s,2H),2.35(m,2H),2.21(s,1H),2.17(s,3H),2.02(d,J=17.2Hz,1H),1.97(s,3H),1.84(m,1H),1.71(m,1H),1.57(m,2H),1.41(m,1H),1.04(s,3H),1.00(s,3H).13C NMR(100MHz,CDCl3):δ199.4,165.6,163.0(d,J=243.7Hz),142.0(d,J=6.9Hz),129.6(d,J=8.1Hz),125.1,124.3(d,J=2.7Hz),115.6(d,J=21.1Hz),113.8(d,J=21.1Hz),62.0,57.7,51.2,47.2,42.3,36.3,28.8,27.9,27.3,27.2.24.7.FAB-MS显示分子离子峰为m/z:378[M+H]+,分子式为C20H28BrNO.
化合物N70的合成
以2-溴-4-甲氧基苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为50%。1H NMR(400MHz,CDCl3):δ7.51(s,1H,Ar-H),7.27(s,1H,Ar-H),6.86(s,1H,Ar-H),5.82(br s,1H),3.89(s,3H),3.41(br s,2H),2.41(m,2H),2.37(s,1H),2.23(s,3H),2.06(d,1H),2.00(s,3H),1.87(m,1H),1.72(m,1H),1.62(m,2H),1.41(m,1H),1.07(s,3H),1.03(s,3H).13C NMR(100MHz,CDCl3):δ199.4,165.5,155.3,139.1,129.4,125.1,111.8,111.3,60.1,57.1,56.3,51.1,47.1,41.6,36.3,29.7,28.7,27.8,27.0,26.7,24.8.FAB-MS显示分子离子峰为m/z:408[M+H]+,分子式为C21H30BrNO2.
化合物N71的合成
以3-苯氧基-4-乙氧基苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为50%。1H NMR(400MHz,CDCl3):δ7.44(s,1H,Ar-H),7.42(s,1H,Ar-H),7.38(s,1H,Ar-H),7.36(d,J=8.0Hz,2H,Ar-H),6.82(m,2H,Ar-H),6.79(m,1H,Ar-H),5.81(br s,1H),5.15(s,2H),3.93(s,3H),3.47(s,3H),2.42(s,2H),2.34(d,J=16.8Hz,1H),2.03(d,J=16.9Hz,1H),1.97(s,3H),1.86(m,1H),1.76(m,2H),1.72(m,2H),1.37(m,2H),1.04(s,3H),1.01(s,3H).13C NMR(100MHz,CDCl3):δ199.4,165.6,150.0,148.2,142.0,136.9,128.8,128.5,127.9,127.2,125.3,122.1,113.5(d,J=21.1Hz),70.0,61.3,56.3,50.8,50.7,47.0,42.3,36.3,28.8,27.9,27.3,27.2,24.7.FAB-MS显示分子离子峰为m/z:435[M+H]+,分子式为C28H37NO3
化合物N72的合成
以4-氯苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为50%。1H NMR(400MHz,CDCl3):δ7.31(s,1H,Ar-H),7.29(m,2H,Ar-H),7.26(s,1H,Ar-H),5.82(br s,1H),3.48(br s,2H),2.38(m,2H),2.03(d,J=18.4Hz,1H),2.23(s,3H),2.08(d,J=17.2Hz,1H),1.98(s,3H),1.85(m,1H),1.71(m,1H),1.63(m,2H),1.41(m,1H),1.04(s,3H),1.01(s,3H).13C NMR(100MHz,CDCl3):δ199.3,165.5,130.5,129.8,128.5,125.2,60.3,57.5,51.1,47.1,41.8,36.3,29.7,28.7,27.8,26.8,24.8.FAB-MS显示分子离子峰为m/z:334[M+H]+,分子式为C20H28ClNO.
化合物N73的合成
以3-氟-4-硝基苄溴为原料,按上述方法制备,粗品经凝胶柱色谱分离纯化(DCM∶MeOH=2∶1,V/V)得黄色油状物,产率为50%。1H NMR(400MHz,CDCl3):δ7.96(s,1H,Ar-H),δ7.50(s,1H,Ar-H),δ7.49(s,1H,Ar-H),5.82(br s,1H),3.75(br s,2H),2.55(s,2H),2.38(s,1H),2.34(s,3H),2.06(d,J=17.2Hz,1H),1.98(s,3H),1.87(m,1H),1.71(m,1H),1.68(m,2H),1.46(m,1H),1.06(s,3H),1.02(s,3H).13C NMR(100MHz,CDCl3):δ199.2,165.2,139.3,134.6,131.9,130.5,125.3,117.9,111.1,57.8,51.0,47.1,41.9,36.3,29.7,28.7,27.8,27.2,26.7,24.8.FAB-MS显示分子离子峰为m/z:344[M+H]+,分子式为C20H27FN2O3.
实施例9.
化合物N50-N61的合成方法
称取1当量化合物N49,加适量1,4-二氧六环:水(5∶1)溶解,加入1.8当量的取代苯硼酸,接着加入5当量无水碳酸钾和0.1当量四(三苯基膦)钯,反应回流搅拌,TLC监测至反应结束。旋干溶剂,加入DCM和水并萃取,合并有机层并用无水硫酸镁干燥,过滤,浓缩得粗品。
化合物N50的合成
以2-甲基苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=4∶1-2∶1,V/V)得黄色油状物黄色油状物,产率为74.6%。1H NMR(400MHz,CDCl3):δ7.26(m,3H,Ar-H),7.19(m,2H,Ar-H),7.11(m,2H,Ar-H),5.83(s,1H,4-H),3.51(s,2H,Ar-CH2),2.40(m,3H,9-H and 2-H),2.23(s,3H,10-H),2.20(s,3H,CH3),2.03(d,J=17.2Hz,1H,2-H),1.99(s,3H,13-H),1.88(t,J=5.2Hz,1H,6-H),1.76(m,1H,7-H),1.62(m,2H,8-H),1.45(m,1H,7-H),1.07(s,3H,11-H),1.02(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.6(5-C),159.5(d,J=244.3Hz,Ar-C),141.0(d,J=6.5Hz,Ar-C),136.6(Ar-C),135.6(Ar-C),131.2(d,J=4.2Hz,Ar-C),130.1(Ar-C),129.9(Ar-C),127.9(Ar-C),127.7(d,J=16.9Hz,Ar-C),125.6(Ar-C),125.0(4-C),124.2(d,J=2.9Hz,Ar-C),115.8(d,J=22.4Hz,Ar-C),61.8(Ar-CH2),57.7(9-C),51.1(6-C),47.1(2-C),42.4(10-C),36.3(1-C),28.8(12-C),27.9(7-C),27.3(8-C),27.2(11-C),24.8(13-C),19.9(d,J=2.9Hz,CH3).HR-ESIMS m/z 408.2703[M+H]+,calcd for C27H35FNO,408.2703.
化合物N51的合成
以2-氯苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=4∶1-2∶1,V/V)得黄色油状物,产率为79.3%。1H NMR(400MHz,CDCl3):δ7.48(m,1H,Ar-H),7.31(m,3H,Ar-H),7.25(m,1H,Ar-H),7.14(m,2H,Ar-H),5.83(s,1H,4-H),3.52(s,2H,Ar-CH2),2.40(t,J=6.8Hz,1H,9-H),2.39(d,J=17.2Hz,1H,2-H),2.24(s,3H,10-H),2.02(d,J=17.2Hz,1H,2-H),1.99(s,3H,13-H),1.88(t,J=5.2Hz,1H,6-H),1.75(m,1H,7-H),1.61(m,2H,8-H),1.44(m,1H,7-H),1.07(s,3H,11-H),1.02(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.5(3-C),165.7(5-C),159.6(d,J=245.6Hz,Ar-C),141.8(d,J=6.4Hz,Ar-C),134.8(Ar-C),133.6(Ar-C),131.7(Ar-C),131.2(d,J=3.5Hz,Ar-C),129.6(Ar-C),129.2(Ar-C),126.6(Ar-C),125.5(d,J=16.0Hz,Ar-C),125.0(4-C),124.1(d,J=3.1Hz,Ar-C),115.7(d,J=22.6Hz,Ar-C),61.8(Ar-CH2),57.8(9-C),51.1(6-C),47.1(2-C),42.3(10-C),36.3(1-C),28.8(12-C),27.9(7-C).27.3(8-C),27.1(11-C),24.8(13-C).HR-ESIMS m/z 428.2154[M+H]+,calcd for C26H32ClFNO,428.2156.
化合物N52的合成
以3,4-二氯苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=4∶1-2∶1,V/V)得黄色油状物,产率为76.2%。1H NMR(400MHz,CDCl3):δ7.64(m,1H,Ar-H),7.50(d,J=8.4Hz,1H,Ar-H),7.36(m,2H,Ar-H),7.15(m,2H,Ar-H),5.83(s,1H,4-H),3.50(s,2H,Ar-CH2),2.39(m,3H,9-H and 2-H),2.21(s,3H,10-H),2.02(d,J=17.2Hz,1H,2-H),1.99(s,3H,13-H),1.88(t,J=5.2Hz,1H,6-H),1.75(m,1H,7-H),1.61(m,2H,8-H),1.44(m,1H,7-H),1.07(s,3H,11-H),1.02(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.6(5-C),159.5(d,J=247.3Hz,Ar-C),142.1(d,J=6.2Hz,Ar-C),135.6(Ar-C),132.5(Ar-C),131.7(Ar-C),130.7(d,J=3.4Hz,Ar-C),130.3(Ar-C),130.1(Ar-C),130.0(Ar-C),128.2(d,J=3.1Hz,Ar-C),125.1(4-C),124.8(d,J=3.0Hz,Ar-C),116.4(d,J=22.7Hz,Ar-C),61.6(Ar-CH2),57.7(9-C),51.1(6-C),47.1(2-C),42.2(10-C),36.3(1-C),28.8(12-C),27.9(7-C),27.2(8-C and 11-C),24.8(13-C).HR-ESIMS m/z 462.1764[M+H]+,calcd for C26H31Cl2FNO,462.1767.
化合物N53的合成
以2,3-二甲基苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=4∶1-2∶1,V/V)得黄色油状物,产率为78.1%。1H NMR(400MHz,CDCl3):δ7.18(m,3H,Ar-H),7.09(m,3H,Ar-H),5.83(s,1H,4-H),3.52(s,2H,Ar-CH2),2.40(m,3H,9-H and 2-H),2.34(s,3H,CH3),2.24(s,3H,10-H),2.09(s,3H,CH3),2.04(d,J=17.2Hz,1H,2-H),1.99(s,3H,13-H),1.87(t,J=5.4Hz,1H,6-H),1.75(m,1H,7-H),1.62(m,2H,8-H),1.44(m,1H,7-H),1.07(s,3H,11-H),1.02(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.5(3-C),165.7(5-C),159.6(d,J=244.2Hz,Ar-C),141.4(d,J=6.2Hz,Ar-C),136.9(Ar-C),135.7(Ar-C),135.2(Ar-C),133.1135.2(Ar-C),131.3(d,J=4.1Hz,Ar-C),129.5(Ar-C),127.9(Ar-C),125.3(Ar-C),125.0(4-C),124.2(d,J=2.8Hz,Ar-C),115.6(d,J=22.7Hz,Ar-C),61.7(Ar-CH2),57.7(9-C),51.1(6-C),47.1(2-C),42.3(10-C),36.3(1-C),28.8(12-C),27.9(7-C),27.2(8-C and 11-C),24.8(13-C),20.6(CH3),16.7(CH3).HR-ESIMS m/z 422.2857[M+H]+,calcd for C28H37FNO,422.2859.
化合物N54的合成
以2,3-二氟苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=4∶1-2∶1,V/V)得黄色油状物,产率为79.4%。1H NMR(400MHz,CDCl3):δ7.32(m,1H,Ar-H),7.16(m,5H,Ar-H),5.83(s,1H,4-H),3.52(s,2H,Ar-CH2),2.39(m,3H,9-H and 2-H),2.22(s,3H,10-H),2.04(d,J=17.2Hz,1H,2-H),1.99(s,3H,13-H),1.88(t,J=5.4Hz,1H,6-H),1.74(m,1H,7-H),1.60(m,2H,8-H),1.45(m,1H,7-H),1.07(s,3H,11-H),1.02(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.7(5-C),159.7(d,J=247.8Hz,Ar-C),150.9(dd,J1=246.5Hz,J2=13.1Hz,Ar-C),148.0(dd,J1=248.7Hz,J2=13.0Hz,Ar-C),142.6(d,J=7.2Hz,Ar-C),131.1(dd,J1=1.7Hz,J2=3.1Hz,Ar-C),126.2(dd,J1=1.7Hz,J2=3.3Hz,Ar-C),125.7(d,J=12.2Hz,Ar-C),125.0(4-C),124.4(d,J=3.0Hz,Ar-C),123.9(dd,J1=4.8Hz,J2=7.0Hz,Ar-C),120.8(dd,J1=2.6Hz,J2=15.7Hz,Ar-C),116.7(d,J=17.1Hz,Ar-C),116.0(d,J=22.4Hz,Ar-C),61.7(Ar-CH2),57.8(9-C),51.1(6-C),47.1(2-C),42.3(10-C),36.3(1-C),28.8(12-C),27.9(7-C),27.3(8-C),27.2(11-C),24.7(13-C).HR-ESIMS m/z 430.2356[M+H]+,calcd for C26H31F3NO,430.2358.
化合物N55的合成
以2-氟-3-甲基苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=4∶1-2∶1,V/V)得黄色油状物,产率为81.7%。1H NMR(400MHz,CDCl3):δ7.31(m,1H.Ar-H),7.14(m,5H,Ar-H),5.82(s,1H,4-H),3.51(s,2H,Ar-CH2),2.39(m,3H,9-H and 2-H),2.33(s,3H,CH3),2.23(s,3H,10-H),2.03(d,J=17.2Hz,1H,2-H),1.98(s,3H,13-H),1.87(t,J=5.4Hz,1H,6-H),1.75(m,1H,7-H),1.61(m,2H,8-H),1.44(m,1H,7-H),1.06(s,3H,11-H),1.01(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.7(5-C),159.8(d,J=246.9Hz,Ar-C),158.3(d,J=245.7Hz,Ar-C),141.6(d,J=7.1Hz,Ar-C),131.3(d,J=2.0Hz,Ar-C),131.1(d,J=5.1Hz,Ar-C),128.9(d,J=1.3Hz,Ar-C),125.1(d,J=18.0Hz,Ar-C),125.0(4-C),124.2(d,J=3.0Hz,Ar-C),123.5(d,J=4.2Hz,Ar-C),123.1(d,J=16.3Hz,Ar-C),122.3(d,J=15.8Hz,Ar-C),115.8(d,J=22.5Hz,Ar-C),61.8(Ar-CH2),57.7(9-C),51.1(6-C),47.1(2-C),42.3(10-C),36.3(1-C),28.7(12-C),27.8(7-C),27.2(8-C),27.1(11-C),24.7(13-C),14.7(d,J=4.4Hz,CH3).HR-ESIMS m/z 426.2608[M+H]+,calcd for C27H34F2NO,426.2608.
化合物N56的合
以2-甲氧基苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=4∶1-2∶1,V/V)得黄色油状物,产率为83.6%。1H NMR(400MHz,CDCl3):δ7.35(m,3H,Ar-H),7.28(m,2H,Ar-H),7.10(m,2H,Ar-H),7.01(m,2H,Ar-H),5.82(s,1H,4-H),3.80(s,3H,OCH3),3.50(s,2H,Ar-CH2),2.39(m,3H,9-H and 2-H),2.23(s,3H,10-H),2.03(d,J=17.2Hz,1H,2-H),1.99(s,3H,13-H),1.87(t,J=5.2Hz,1H,6-H),1.73(m,1H,7-H),1.62(m,2H,8-H),1.44(m,1H,7-H),1.06(s,3H,11-H),1.02(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.7(5-C),159.9(d,J=246.1Hz,Ar-C),156.9(Ar-C),140.7(d,J=7.0Hz,Ar-C),131.5(d,J=3.9Hz,Ar-C),131.2(Ar-C),129.2(Ar-C),125.0(4-C),123.8(Ar-C),124.7(d,J=16.1Hz,Ar-C),124.0(d,J=3.0Hz,Ar-C),120.5(Ar-C),115.6(d,J=22.7Hz,Ar-C),111.0(Ar-C),61.8(Ar-CH2),57.6(9-C),55.6(OCH3),51.1(6-C),47.1(2-C),42.3(10-C),36.3(1-C),28.7(12-C),27.8(7-C),27.2(8-C),27.1(11-C),24.7(13-C).HR-ESIMS m/z 424.2651[M+H]+,calcd for C27H34FNO2,424.2652.
化合物N57的合成
以2-氟-3-甲氧基苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=4∶1-2∶1,V/V)得黄色油状物,产率为76.5%。1H NMR(400MHz,CDCl3):δ7.32(m,1H,Ar-H),7.13(m,3H,Ar-H),6.97(m,2H,Ar-H),5.82(s,1H,4-H),3.92(s,3H,OCH3),3.51(s,2H,Ar-CH2),2.39(m,3H,9-H and 2-H),2.23(s,3H,10-H),2.03(d,J=17.2Hz,1H,2-H),1.98(s,3H,13-H),1.87(t,J=5.2Hz,1H,6-H),1.75(m,1H,7-H),1.61(m,2H,8-H),1.44(m,1H,7-H),1.06(s,3H,11-H),1.01(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.7(5-C),159.9(d,J=246.1Hz,Ar-C),156.9(Ar-C),140.7(d,J=7.0Hz,Ar-C),131.5(d,J=3.9Hz,Ar-C),131.2(Ar-C),129.2(Ar-C),125.0(4-C),123.8(Ar-C),124.7(d,J=16.1Hz,Ar-C),124.0(d,J=3.0Hz,Ar-C),120.5(Ar-C),115.6(d,J=22.7Hz,Ar-C),111.0(Ar-C),61.7(Ar-CH2),57.7(9-C),56.3(OCH3),51.1(6-C),47.1(2-C),42.3(10-C),36.3(1-C),28.7(12-C),27.8(7-C),27.2(8-C),27.1(11-C),24.7(13-C).HR-ESIMS m/z442.2556[M+H]+,calcd for C27H34F2NO2,442.2558.
化合物N58的合成
以2-氯-3-甲氧基苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=3∶1-1∶1,V/V)得黄色油状物,产率为78.2%。1H NMR(400MHz,CDCl3):δ7.26(m,2H,Ar-H),7.14(m,2H,Ar-H),6.96(m,2H,Ar-H),5.82(s,1H,4-H),3.94(s,3H,OCH3),3.51(s,2H,Ar-CH2),2.40(m,3H,9-H and 2-H),2.23(s,3H,10-H),2.03(d,J=17.2Hz,1H,2-H),1.99(d,J=1.0Hz,3H,13-H),1.87(t,J=5.2Hz,1H,6-H),1.75(m,1H,7-H),1.61(m,2H,8-H),1.45(m,1H,7-H),1.06(s,3H,11-H),1.01(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.7(5-C),159.5(d,J=246.2Hz,Ar-C),155.3(Ar-C),141.9(d,J=7.1Hz,Ar-C),136.4(Ar-C),131.1(d,J=3.5Hz,Ar-C),126.9(Ar-C),125.5(d,J=16.1Hz,Ar-C),125.0(4-C),124.0(d,J=3.0Hz,Ar-C),123.4(Ar-C),122.2(Ar-C),115.7(d,J=22.1Hz,Ar-C),111.3(Ar-C),61.8(Ar-CH2),57.7(9-C),56.3(OCH3),51.1(6-C),47.1(2-C),42.4(10-C),36.3(1-C),28.8(12-C),27.8(7-C),27.3(8-C),27.2(11-C),24.7(13-C).HR-ESIMS m/z458.2265[M+H]+,calcd for C27H34ClFNO2,458.2262.
化合物N59的合成
以2-氰基苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=3∶1-1∶1,V/V)得黄色油状物,产率为79.5%。1H NMR(400MHz,CDCl3):δ7.78(d,J=7.2Hz,1H,Ar-H),7.66(m,1H,Ar-H),7.49(m,2H,Ar-H),7.37(m,1H,Ar-H),7.21(m,2H,Ar-H),5.83(s,1H,4-H),3.53(s,2H,Ar-CH2),2.41(m,3H,9-H and 2-H),2.23(s,3H,10-H),2.04(d,J=17.2Hz,1H,2-H),2.00(s,3H,13-H),1.88(t,J=5.2Hz,1H,6-H),1.76(m,1H,7-H),1.62(m,2H,8-H),1.46(m,1H,7-H),1.07(s,3H,11-H),1.02(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.5(3-C),165.8(5-C),159.4(d,J=247.1Hz,Ar-C),143.2(d,J=6.8Hz,Ar-C),139.5(Ar-C),133.3(Ar-C),132.6(Ar-C),131.0(Ar-C),128.1(Ar-C),125.1(4-C),124.6(d,J=3.2Hz,Ar-C),124.3(d,J=15.1Hz,Ar-C),118.2(CN),116.2(d,J=22.2Hz,Ar-C),112.8(Ar-C),61.7(Ar-CH2),57.8(9-C),51.1(6-C),47.1(2-C),42.3(10-C),36.3(1-C),28.8(12-C),27.8(7-C),27.3(8-C),27.2(11-C),24.8(13-C).HR-ESIMS m/z 419.2497[M+H]+,calcd for C27H32FN2O,419.2499.
化合物N60的合成
以2-氟-3-氰基苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(PE∶EA=3∶1-1∶1,V/V)得黄色油状物,产率为76.3%。1H NMR(400MHz,CDCl3):δ7.66(m,1H,Ar-H),7.49(m,2H,Ar-H),7.33(m,1H,Ar-H),7.20(m,2H,Ar-H),5.83(s,1H,4-H),3.53(s,2H,Ar-CH2),2.40(m,3H,9-H and 2-H),2.23(s,3H,10-H),2.04(d,J=17.2Hz,1H,2-H),2.00(d,J=1.0Hz,3H,13-H),1.88(t,J=5.2Hz,1H,6-H),1.76(m,1H,7-H),1.60(m,2H,8-H),1.47(m,1H,7-H),1.07(s,3H,11-H),1.02(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.4(3-C),165.7(5-C),160.3(d,J=259.4Hz,Ar-C),159.6(d,J=248.3Hz,Ar-C),143.4(d,J=6.6Hz,Ar-C),136.6(d,J=1.8Hz,Ar-C),136.5(d,J=1.7Hz,Ar-C),133.0(Ar-C),130.9(d,J=4.5Hz,Ar-C),125.1(4-C),124.8(d,J=4.4Hz,Ar-C),124.6(d,J=3.1Hz,Ar-C),119.7(d,J=15.4Hz,Ar-C),116.1(d,J=22.0Hz,Ar-C),114.0(CN),102.1(d,J=6.5Hz,Ar-C),61.7(Ar-CH2),57.8(9-C),51.1(6-C),47.1(2-C),42.3(10-C),36.3(1-C),28.8(12-C),27.9(7-C),27.3(8-C and 11-C),24.8(13-C).HR-ESIMS m/z 437.2404[M+H]+,calcd for C27H31F2N2O,437.2404.
化合物N61的合成
以3-乙酰氨基苯硼酸为原料,按上述方法制备,粗品经硅胶柱色谱分离纯化(DCM∶MeOH=50∶1-30∶1,V/V)得黄色油状物,产率为73.4%。1H NMR(400MHz,CDCl3):δ8.19(s,1H,Ar-H),7.68(s,1H,Ar-H),7.58(m,1H,Ar-H),7.35(m,2H,Ar-H),7.27(m,1H,Ar-H),7.11(m,1H,Ar-H),5.82(s,1H,4-H),3.49(s,2H,Ar-CH2),2.39(m,3H,9-H and 2-H),2.22(s,3H,10-H),2.17(s,3H,CH3),2.03(d,J=17.2Hz,1H,2-H),1.98(s,3H,13-H),1.87(t,J=5.2Hz,1H,6-H),1.73(m,1H,7-H),1.58(m,2H,8-H),1.42(m,1H,7-H),1.05(s,3H,11-H)-1.01(s,3H,12-H).13C NMR(100MHz,CDCl3):δ199.7(3-C),168.8(CO),166.3(5-C),159.6(d,J=246.5Hz,Ar-C),141.0(d,J=7.3Hz,Ar-C),138.3(Ar-C),136.3(Ar-C),130.4(d,J=3.5Hz,Ar-C),128.9(Ar-C),127.2(Ar-C),127.1(Ar-C),124.9(4-C),124.7(d,J=2.5Hz,Ar-C),120.4(d,J=2.6Hz,Ar-C),119.2(Ar-C),116.3(d,J=22.8Hz,Ar-C),61.7(Ar-CH2),57.6(9-C),51.1(6-C),47.1(2-C),42.4(10-C),36.3(1-C),28.7(12-C),27.9(7-C),27.3(8-C),27.2(11-C),24.8(13-C),24.5(CH3).HR-ESIMS m/z 451.2764[M+H]+,calcd for C28H36FN2O2,451.2761.
实施例10.
各衍生物的抗乳腺癌转移活性评价
具体实验方法及步骤如前文所述,实验结果见表2:
表2各衍生物抑制乳腺癌细胞趋化迁移的半数抑制浓度(IC50)
发明人认为,研究人员一直在寻找具有抗肿瘤转移活性的化合物,每获得一类具有可接受活性水平的化合物结构对于制备抗肿瘤转移药物都具有重要的意义。本发明依据本课题组前期发现的先导化合物ION-31a为基础,进行了大量的不同取代基、不同取代结构片段的衍生物设计与合成,所合成的73个衍生物均为本课题组首次合成的的衍生物。进一步通过细胞毒性和抗乳腺癌转移活性筛选实验,从中优选了26个活性衍生物,并进一步优选7个强活性衍生物,其抗乳腺癌转移活性与阳性对照LY294002相当或活性接近。
本领域技术人员难以根据现有技术中公开的普通紫罗兰酮生物碱的结构,经过如此大量的结构修饰,然后优选取代基并限定到较小的范围内,从而获得本发明要求保护的化合物,即本发明的化合物结构对于本领域技术人员来说并不是显而易见的。
进一步地,由于本发明首先经过细胞毒性筛选,剔除具有细胞毒性的衍生物,经活性测定的衍生物均为在非细胞毒剂量下、显示出抗乳腺癌转移作用,其中具有代表性的7个衍生物的活性与阳性对照LY294002相当(现有的抗肿瘤转移上市药物中,尚未有抗肿瘤转移的小分子合成药物上市)。这种不具有细胞毒性的抗乳腺癌转移活性化合物能够满足临床上防治癌症转移所需要的长期给药需求,可见本发明已经具有了显著的进步。本发明的化合物具有预料不到的技术效果,相对于一般意义上的抗肿瘤转移活性化合物来说,本发明具有更加重要的应用价值。
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