实施例12,5-二氢-10-甲氧基-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉-1H-[1]苯并吡喃并[3,4-f]喹啉实施例1A
于-20℃,用正丁基锂(100ml的2.4M己烷溶液,240mmol)和N,N,N’,N’-四甲基乙二胺(1.81ml,12mmol)顺序处理1,3-二甲氧基苯(33.2g,240mmol)的己烷(20ml)溶液,于23℃搅拌1.5小时,冷却至-78℃,用硼酸三异丙基酯(60.9ml,264mmol)的乙醚(60ml)溶液处理1.5小时,并加入另外的乙醚(150ml)以维持搅拌,于23℃搅拌2小时,倾入冰(150ml)和3M HCl(150ml)中,用乙酸乙酯提取。干燥(硫酸钠)提取物,过滤并浓缩,在此期间从溶液中沉淀出白色固体。过滤收集该固体并用己烷洗涤以提供所需的化合物。MS(DCI/NH3)m/z 200(M+NH4)+。实施例1B
于80℃,将实施例1A、5-硝基-2-溴代苯甲酸甲酯(25.8g,99.2mmol)、(21.7g,119mmol)、碳酸铯(97.1g,298mmol)和二氯双(三苯膦)钯(II)(3.5g,5.0mmol)在DMF(300ml)中的混合物搅拌24小时,冷却至23℃,用水(600ml)处理,用乙酸乙酯(800ml)提取。干燥(硫酸钠)提取物并浓缩,在此期间从溶液中沉淀出淡黄色固体。将该混合物置于冰箱中(-20℃)2小时,然后过滤得到所需的化合物。MS(DCI/NH3)m/z 318(M+H)+和335(M+NH4)+。实施例1C
于-78℃,用三溴化硼(25.0g,99.8mmol)处理实施例1B(11.1g,35.1mmol)的二氯甲烷(60ml)溶液,温热至23℃1小时,再冷却至-78℃,并用甲醇(100ml)处理。将该混合物温热至0℃,过滤收集沉淀物,从甲醇中重结晶得到所需的化合物。MS(DCI/NH3)m/z 275(M+NH4)+。实施例1D
于23℃,滴加甲基碘(22.8g,161mmol)处理实施例1C(10.7g,41.6mmol)和碳酸铯(20.0g,61.4mmol)在DMF(130ml)中的混合物,搅拌4小时,用水处理,用1∶1的乙酸乙酯/己烷提取。浓缩提取物,过滤生成的固体,用水(100ml)洗涤,真空干燥得到所需的化合物。MS(DCI/NH3)m/z 289(M+NH4)+。实施例1E
于23℃,用10%披钯炭(580mg)处理实施例1D(11.2g,41.3mmol)在二氧六环(400ml)中的悬浮液,于65℃加热,用氢处理,在大气压力下搅拌60小时,通过粉末状海贝壳(Celite_)趁热过滤,浓缩期间形成沉淀。过滤产物并真空干燥得到所需的化合物。浓缩母液至其原体积的一半,得到第二份所需的化合物。MS(DCI/NH3)m/z 242(M+H)+和259(M+NH4)+。实施例1F
于105℃,将实施例1E(4.0g,16.6mmol)和碘(1.7g,6.64mmol)的丙酮(380ml)溶液在1L密封的ACE玻璃高压容器中搅拌48小时,冷却至室温并浓缩。残留物经硅胶快速层析纯化,用0-12%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 322(M+H)+。实施例1G
于-78℃,用苯基锂(10.9ml,19.6mmol)的环己烷/乙醚溶液处理实施例1F(1.02g,3.18mmol)的THF(20ml)溶液,温热至-50℃,搅拌2小时,用饱和氯化铵处理,温热至至25℃,用乙酸乙酯提取。干燥(硫酸钠)提取物,过滤并浓缩,经硅胶快速层析纯化残留物,用20%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 400(M+H)+。实施例12,5-二氢-10-甲氧基-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉-1H-[1]苯并吡喃并[3,4-f]喹啉
于-78℃,用三乙基硅烷(2.91g,25.05mmol)和BF3·OEt2(0.95g,6.68mmol)处理实施例1G(0.67g,1.67mmol)的二氯甲烷(30ml)溶液,温热至室温,搅拌16小时,用饱和碳酸氢钠处理。干燥(硫酸钠)有机层,过滤并浓缩,残留物经硅胶快速层析纯化,用5%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DC/NH3)m/z 384(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.19(m,5H),6.9(dd,1H),6.76(s,1H),6.69(dd,1H),6.55(d,1H),6.43(d,1H),6.2(s,1H),5.38(s,1H),3.8(s,3H),1.83(s,3H),1.22(s,3H),1.14(s,3H);C26H25NO2的分析计算值:C,81.42;H,6.58;N,3.65。
实测值:C,81.28;H,6.30;N,3.47。实施例22,5-二氢-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉实施例2A
于-78℃,滴加1M二异丁基氢化铝的己烷溶液(47.6ml,47.6mmol)处理实施例1F(6.65g,20.69mmol)的二氯甲烷(500ml)溶液,搅拌2小时,顺序用饱和酒石酸钠钾水溶液(300ml)和乙酸乙酯(600ml)处理,剧烈搅拌4小时。用盐水洗涤提取物,干燥(硫酸钠),过滤并浓缩得到所需的化合物。MS(DCI/NH3)m/z 306(M-OH)+。实施例2B
于0℃,用对甲苯磺酸·H2O(1.2g,20wt%)处理实施例2A(4.20g,12.99mmol)的甲醇(150ml)溶液,搅拌30分钟,于室温下搅拌1小时,冷却至0℃30分钟并过滤。用己烷冲洗该固体,真空干燥得到所需的化合物。将滤液倾入饱和碳酸氢钠中并用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸钠),过滤并浓缩,残留物经硅胶快速层析纯化,用10-20%乙酸乙酯/己烷洗脱,得到另外的所需化合物。MS(DCI/NH3)m/z 306(M-OCH3)+。实施例22,5-二氢-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
用烯丙基三甲基硅烷(4.0ml,25.2mmol)处理实施例2B(2.50g,7.41mmol)的二氯甲烷(225ml)溶液,冷却至-78℃,滴加BF3·OEt2(3.1ml,25.2mmol)进行处理,于-78℃搅拌15分钟,温热至0℃30分钟,用饱和碳酸氢钠处理,用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸镁),过滤并浓缩。残留物经硅胶快速层析纯化,用5-20%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 348(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.96(d,1H),7.07(t,1H),6.71(d,1H),6.60(d,1H),6.52(d,1H),6.12(br s,1H),5.82(m,1H),5.76(dd,1H),5.44(br s,1H),5.01(m,2H),3.86(s,3H),2.44(m,1H),2.20(m,1H),2.16(s,3H),1.17(s,3H),1.16(s,3H);C23H25NO2的分析计算值:C,79.51;H,7.25;N,4.03。
实测值:C,79.35;H,7.30;N,3.89。实施例32,5-二氢-2,2,4,N-四甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉-10-胺实施例3A
如同实施例1E的方法处理实施例1C的溶液,得到所需化合物。MS(DCI/NH3)m/z 227(M+H)+。实施例3B
根据实施例1F的方法处理实施例3A的溶液,得到所需化合物。MS(DCI/NH3)m/z 308(M+H)+实施例3C
于-78℃,滴加三氟甲磺酸酐(1.39g,4.94mmol)处理实施例3B的产物(1.38g,4.49mmol)、三乙胺(1.92ml,13.77mmol)和4-二甲基氨基吡啶(100mg)的二氯甲烷(50ml)溶液,于-78℃搅拌30分钟,用15分钟缓慢温热至室温,倾入饱和氯化铵中,用乙酸乙酯提取。用水洗涤提取物,干燥(硫酸镁)、过滤并浓缩,残留物经硅胶快速层析纯化,用10%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 440(M+H)+。实施例3D
根据实施例2A、2B和2的方法处理实施例3C的产物以得到所需化合物。MS(DCI/NH3)m/z 466(M+H)+。实施例32,5-二氢-2,2,4,N-四甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉-10-胺
于90℃,将实施例3D的产物(0.165g,0.36mmol)、乙酸钯(II)(0.0016g,0.007mmol)、(S)-(-)-2,2’-双(苯基膦基)-1,1’-联萘(0.0055,0.008mmol)、叔丁醇钠(0.051g,0.53mmol)、甲胺(2.0M的THF溶液0.44ml,0.88mmol)的甲苯(0.5ml)溶液在密封的ACE玻璃高压容器中加热4小时,冷却至0℃,用乙酸乙酯(5ml)稀释,用0.5M HCl洗涤。干燥(硫酸钠)有机提取物,过滤并浓缩。残留物经硅胶快速层析纯化,用5-12%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 347(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.83(d,1H),6.94(dd,1H),6.62(d,1H),6.28(dd,1H),6.25(dd,1H),6.05(d,1H),5.86-5.74(m,2H),5.67(dd,1H),5.45(s,1H),5.40(q,1H),5.03(dd,1H),4.98(dd,1H),2.72(d,3H),2.16(s,3H),1.17(s,3H),1.15(s,3H);C23H26N2O的HRMS m/z计算值:346.2045(M+H)+。实测值:346.2049。实施例42,5-二氢-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉-10-羧酸甲酯
用乙酸钯(12.7mg,0.056mmol)处理实施例3D的产物(263mg,0.565mmol)、三乙胺(0.10ml,0.717mmol)、1,3-双(二苯基膦基)丙烷(26mg,0.063mmol)和DMSO(1.5ml)的甲醇(8ml)溶液,用一氧化碳饱和,在一氧化碳(1atm)下搅拌20分钟,加热至65℃3小时,冷却、用乙酸乙酯(100ml)稀释并过滤。用盐水洗涤滤液,干燥(硫酸镁)、过滤并浓缩。残留物经硅胶快速层析纯化,用5-10%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 376(M+H)+;1H NMRδ7.19(m,2H),7.03(dd,1H),6.78(d,1H),6.60(d,1H),6.30(m,1H),5.85(m,2H),5.46(m,1H),5.05(dm,1H),4.98(dm,1H),3.77(s,3H),2.30(m,2H),2.19(d,3H),1.21(s,3H),1.15(s,3H);C24H25NO3的HRMS m/z计算值:375.1834(M+H)+。实测值:375.1841。实施例510-乙烯基-2,5-二氢-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
用乙烯基三丁基锡烷(0.110ml,119mg,0.376mmol)处理实施例3D的产物(103mg,0.221mmol)和(1,3-双(二苯基膦基)二茂铁)氯化钯(II)-二氯甲烷(22mg,0.027mmol)的1-甲基-2-吡咯烷酮(2ml)溶液,加热至65℃24小时,冷却至室温,用饱和KF处理,用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸镁)、过滤并浓缩。残留物经硅胶快速层析纯化,用5%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 344(M+H)+;1H NMRδ7.22(d,1H),7.15(m,2H),6.99(dd,1H),6.83(dd,1H),6.63(d,1H),6.23(m,1H),5.87(ddm,1H),5.73(dd,1H),5.76(dd,1H),5.47(m,1H),5.33(dd,1H),5.03(dd,1H),4.98(dm,1H),3.77(s,3H),2.44(m,1H),2.28(m,1H),2.18(d,3H),1.21(s,3H),1.15(s,3H);C24H26NO的HRMS m/z计算值:344.2014(M+H)+。实测值:344.2011。实施例610-乙炔基-2,5-二氢-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉实施例6A
用三甲基甲硅烷基乙炔(174mg,1.76mmol)处理实施例3D的产物(25mg,0.054mmol)、四正丁基碘化铵(40mg,0.108mmol)、双(三苯膦)氯化钯(7.0mg,0.010mmol)、碘化铜(I)(3.8mg,0.020mmol)和三乙胺(0.15ml,0.717mmol)的DMF(0.75ml)溶液,加热至55℃3小时,用乙酸乙酯(20ml)稀释并过滤。用饱和氯化铵洗涤滤液,用乙酸乙酯提取水层。干燥(硫酸镁)合并的提取物,过滤并浓缩。将残留物加样于10×20cm,0.25mm硅胶TLC板上,用10%乙酸乙酯/己烷洗脱两次。用乙酸乙酯提取硅胶,得到所需的化合物。MS(DCI/NH3)m/z 414(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.36(d,1H),7.07(m,2H),6.90(dd,1H),6.60(d,1H),6.34(m,1H),5.80(m,2H),5.46(m,1H),5.04(dm,1H),4.97(dm,1H),2.35(m,1H),2.26(m,1H),2.17(d,3H),1.18(s,3H),1.17(s,3H),0.26(s,9H)。实施例610-乙炔基-2,5-二氢-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
顺序用冰醋酸(0.005ml)和1M四-正丁基氟化铵的THF溶液(0.050ml,0.050mmol)处理实施例6A的THF(2.5ml)溶液,于室温下搅拌18小时,根据实施例6A的方法纯化,得到所需化合物。MS(DCI/NH3)m/z 342(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.27(dd,1H),7.15(t,1H),7.07(d,1H),6.91(dm,1H),6.62(d,1H),6.34(m,1H),5.80(m,1H),5.46(m,1H),5.03(dm,1H),4.98(dm,1H),4.41(s,1H),2.44(m,2H),2.17(s,3H),1.18(s,6H);C24H23NO的HRMS m/z计算值:341.1780(M+H)+。实测值:341.1788。实施例72,5-二氢-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉-10-醇实施例7A
于23℃,顺序用咪唑(379mg,5.55mmol)和叔丁基二甲基甲硅烷基氯(418mg,2.78mmol)处理实施例3B(569mg,1.85mmol)的DMF(8ml)溶液,搅拌3小时,倾入水中,用2∶1己烷/乙酸乙酯(22ml)提取。用水和盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩。残留物经硅胶快速层析纯化,用25%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 422(M+H)+;实施例7B
如同实施例1G和1的方法处理实施例7A的产物,得到所需化合物。实施例72,5-二氢-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉-10-醇
于0℃,用1M四-正丁基氟化铵的THF溶液(3.37ml,3.37mmol)处理实施例7B的产物(0.90g,1.87mmol)的THF(12ml)溶液,用1小时温热至23℃,用水处理,并用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩。残留物经硅胶快速层析纯化,用10-30%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 370(M+H)+;1H NMR(300MHz,DMSO-d6)δ9.63(s,1H),9.16(d,1H),7.13-7.24(m,5H),6.74(s,1H),6.70(d,1H),6.8(d,1H),6.39(dd,1H),6.26(dd,1H),6.11(d,1H),5.37(s,1H),1.85(d,3H),1.22(s,3H),1.11(s,3H);C25H23NO2的HRMS m/z计算值:369.1729(M+H)+。实测值:369.1736。实施例810-(二氟甲氧基)-2,5-二氢-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉实施例8A
于0℃,顺序用叔丁醇钠(0.38g,3.6mmol)和溴代二氟甲烷(10ml)处理实施例3B(1.11g,3.6mmol)的DMF(10ml)溶液,于0℃搅拌6小时,温热至室温1小时,用饱和碳酸氢钠处理,并用乙酸乙酯提取。干燥(硫酸钠)提取物,过滤并浓缩。残留物经硅胶快速层析纯化,用5%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 436(M+H)+。实施例810-(二氟甲氧基)-2,5-二氢-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2B和2的方法处理实施例8A的产物得到所需化合物。MS(DCI/NH3)m/z 384(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.75(d,1H),7.20(t,1H),7.15(t,1H),6.83(dd,1H),6.81(dd,1H),6.63(d,1H),6.28(s,1H),5.89-5.75(m,2H),5.46(s,1H),5.04(dd,1H),4.96(dd,1H),2.48-2.40(m,1H),2.29-2.20(m,1H),2.18(s,3H),1.17(s,6H);C23H23F2NO2的HRMS计算值:383.1697(M+H)+。实测值:383.1693。实施例910-乙氧基-2,5-二氢-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉实施例9A
于0℃,用氢化钠(2.4mg 60%的矿物油分散体,0.01mmol)处理实施例3B的产物(28mg,.09mmol)的DMF(1.0ml)溶液,搅拌1小时,用乙基溴(20mg,.182mmol)处理,于室温下搅拌30分钟,用饱和碳酸氢钠处理,并用乙酸乙酯提取。干燥(硫酸钠)提取物,过滤并浓缩。残留物经硅胶快速层析纯化,用5%乙酸乙酯/己烷洗脱,得到所需的化合物。实施例910-乙氧基-2,5-二氢-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例9A的产物以得到所需化合物。MS(DCI/NH3)m/z 398(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.09(d,1H),7.20-7.15(m,5H),6.78(dd,2H),6.77(s,1H),6.69(d,1H),6.53(dd,1H),6.43(dd,1H),6.18(d,1H),5.39(d,1H),3.99-4.06(m,1H),1.85(d,3H),1.38(t,3H),1.22(s,3H),1.16(s,3H);C27H27NO2的HRMS m/z计算值:397.2042(M+H)+。实测值:397.2034。实施例102,5-二氢-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉-10-醇乙酸酯
于0℃,用乙酸酐(0.1ml,1.05mmol)处理实施例7的产物(20mg,0.05mmol)的吡啶(1ml)溶液,于室温下搅拌14小时并浓缩。用硅胶快速层析纯化残留物,用20%乙酸乙酯/己烷洗脱得到所需的化合物。MS(DCI/NH3)m/z 412(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.62(d,1H),7.21-7.16(m,5H),6.93(t,1H),6.77(s,1H),6.73(d,1H),6.65(dd,1H),6.62(dd,1H),6.32(s,1H),5.37(s,1H),2.30(s,3H),1.79(s,3H),1.22(s,3H),1.14(s,3H);C27H25NO3的HRMS计算值m/z:411.1 834(M+H)+。实测值:411.1842。实施例115-(3-溴代-5-甲基苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例2B的产物和(0.520g,1.54mmol)的二氯甲烷(50ml)溶液冷却至-10℃,滴加BF3·OEt2(0.57ml,4.62mmol)进行处理,于-10℃搅拌30分钟,滴加0.49M的3-溴代-5-甲基苯基溴化镁的乙醚(12.6ml)溶液进行处理,搅拌15分钟,用饱和碳酸氢钠处理,用乙酸乙酯提取。用盐水洗涤该提取物,干燥(硫酸钠)有机层,过滤并浓缩,残留物经硅胶快速层析纯化,用5%乙酸乙酯/己烷洗脱,得到所需的化合物。1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.22(s,1H),7.03(br d,1H),6.95(t,1H),6.74(s,1H),6.71(d,1H),6.59(d,1H),6.50(d,1H),6.26(d,1H),5.42(s,1H),4.04(s,1H),3.80(s,3H),2.18(s,3H),1.85(s,3H),1.23(s,3H),1.16(s,3H);C27H26NO2Br的HRMS m/z计算值:475.1147(M+H)+。实测值475.1143。实施例123-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-苯酚,乙酸酯实施例12A
于-78℃,用正丁基锂(2.5M的己烷液,20ml)处理3-甲氧基甲氧基苯基溴(10.85g,50.00mmol)的THF(300ml)溶液,温热至-30℃,再冷却至-78℃,用实施例1F处理,温热至-50℃,用饱和氯化铵猝灭,温热至室温,倾析并浓缩。用水处理残留物并用乙酸乙酯提取。用水和盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩,残留物经硅胶快速层析纯化,用20-25%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 460(M+H)+。实施例12B
用HCl饱和的甲醇(50ml)处理实施例12A的产物(2.30g,5.00mmol)的甲醇(10ml)溶液,搅拌18小时,倾入1∶1乙酸乙酯/饱和氯化铵中,用乙酸乙酯提取。用水和盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩,得到所需化合物。MS(DCI/NH3)m/z 416(M+H)+。实施例12C
用乙酰氯(0.51g,6.48mmol)处理实施例12B(2.45g,5.89mmol)和吡啶(2.33g,29.4mmol)的THF(100ml)溶液,搅拌4小时,使沉淀、倾析并浓缩。用饱和碳酸氢钠处理残留物并用乙酸乙酯提取。用水和盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩。残留物经硅胶快速层析纯化,用25-33%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 458(M+H)+。实施例123-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-苯酚,乙酸酯
如同实施例1的方法处理实施例12C的产物,得到所需化合物。MS(DCI/NH3)m/z 442(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.26(t,1H),7.07(d,1H),6.98-6.90(m,2H),6.85(s,1H),6.77(s,1H),6.71(d,1H),6.58(d,1H),6.46(dd,1H),6.23(s,1H),5.40(s,1H),3.79(s,3H),2.19(s,3H),1.85(s,3H),1.23(s,3H),1.14(s,3H);C28H27NO4·0.25H2O的分析计算值:C,75.40;H,6.21;N,3.14。实测值:C,75.76;H,6.21;N,2.84。实施例133-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-苯酚
用碳酸钾(2.00g,14.5mmol)的水溶液(6ml)处理实施例12的产物(0.8lg,1.84mmol)的THF(20ml)和甲醇(20ml)溶液,搅拌12小时,用饱和氯化铵猝灭,倾析、浓缩,用饱和碳酸氢钠处理并用乙酸乙酯提取。用水和盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩,得到所需的化合物。MS(DCI/NH3)m/z 400(M+H)+;1H NMR(300MHz,DMSO-d6)δ9.26(s,1H),8.00(d,1H),7.00(t,1H),6.92(t,1H),6.71-6.66(m,2H),6.63(d,1H),6.58-6.51(m,3H),6.44(dd,1H),6.15(s,1H),5.38(s,1H),3.80(s,3H),1.88(s,3H),1.24(s,3H),1.15(s,3H);C26H25NO3的分析计算值:C,78.17;H,6.30;N,3.50。实测值:C,77.82;H,6.42;N,3.26。实施例142,5-二氢-10-甲氧基-2,2,4-三甲基-5-[[3-(甲硫基)甲氧基]苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
于0℃,用5分钟滴加氢化钠(50mg,2.10mmol)处理实施例13的产物(420mg,1.05mmol)的DMF(40ml)的溶液,搅拌10分钟,用氯代甲基甲基硫化物(152mg,1.58mmol)处理,温热至室温,用饱和氯化铵处理并用乙酸乙酯提取。顺序用1M氢氧化钠和盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩。残留物经硅胶快速层析纯化,用5-17%乙酸乙酯/己烷洗脱,得到所需化合物。MS(DCI/NH3)m/z 460(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.14(t,1H),6.92(t,1H),6.83-6.68(m,5H),6.56(d,1H),6.47(d,1H),6.21(s,1H),5.40(s,1H),5.13(s,2H),3.80(s,3H),2.09(s,3H),1.97(s,3H),1.24(s,3H),1.16(s,3H);C28H29NO3S·0.5H2O的分析计算值:C,71.76;H,6.45;N,2.98。实测值:C,71.93;H,6.61;N,2.68。实施例15[3-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-苯基]二甲基氨基甲酸酯
如同实施例14的方法处理实施例13的产物和N,N-二甲基氨基甲酰氯,得到所需化合物。MS(DCI/NH3)m/z 471(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.22(t,1H),7.05(d,1H),6.93(t,2H),6.83(s,1H),6.77(s,1H),6.71(d,1H),6.57(d,1H),6.48(d,1H),6.23(d,1H),5.40(s,1H),3.80(s,3H),2.97(s,3H),2.85(s,3H),1.86(s,3H),1.24(s,3H),1.14(s,3H);C29H30N2O4的分析计算值:C,74.02;H,6.42;N,5.95。实测值:C,74.05;H,6.36;N,5.86。实施例165-[3-(2-呋喃基)-5-甲基苯基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
用氮气使实施例11的产物(0.253g,0.531mmol)的1-甲基-2-吡咯烷酮(25ml)溶液脱氧,用2-(三丁基甲锡烷基)呋喃(0.33ml,1.06mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷复合物(0.045g,0.005mmol)处理,加热至85℃13小时,冷却至室温,用乙酸乙酯和饱和KF稀释,搅拌3小时,用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸镁)、过滤并浓缩,残留物经硅胶快速层析纯化,用5-10%乙酸乙酯/己烷洗脱,得到所需化合物。MS(DCI/NH3)m/z 464(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.67(m,1H),7.31(d,2H),6.92(t,1H),6.92(s,1H),6.75(m,2H),6.72(d,1H),6.57-6.50(m,3H),6.23(m,1H),5.41(s,1H),3.78(s,3H),2.20(s,3H),1.89(s,3H),1.24(s,3H),1.17(s,3H);C31H29NO3的分析计算值:C,80.32;H,6.31;N,3.02。实测值:C,80.08;H,6.25;N,2.83。实施例172,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-甲基-5-(1-吗啉基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
顺序用双(二亚苄基丙酮)钯(O)(0.007g,0.012mmol)、(S)-(-)-双(二苯基膦基)-1,1’-联萘(0.022g,0.035mmol)、吗啉(15μl,0.173mmol)和叔丁醇钠(0.028g,0.289mmol)处理实施例11的产物(0.055g,0.115mmol)的甲苯(5ml)溶液,于85℃搅拌4小时,冷却至室温,用乙酸乙酯和水稀释,通过粉末状海贝壳(Celite_)过滤。用盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩,残留物经硅胶快速层析纯化,用10-33%乙酸乙酯/己烷洗脱,得到所需化合物。MS(DCI/NH3)m/z 483(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.97(d,1H),6.93(t,1H),6.68(m,2H),6.54-6.60(m,3H),6.49(d,1H),6.40(s,1H),6.18(br s,1H),5.40(s,1H),3.78(s,3H),3.65(m,4H),2.91(m,4H),2.09(s,3H),1.89(s,3H),1.21(s,3H),1.16(s,3H);C31H34N2O3·0.25H2O的分析计算值:C,76.44;H,7.14;N,5.75。实测值:C,76.61;H,7.35;N,5.47。实施例182,5-二氢-10-甲氧基-2,2,4-三甲基-5-(苯基亚甲基)-1H-[1]苯并吡喃并[3,4-f]喹啉
于-78℃,用10分钟滴加苄基溴化镁溶液(10ml的0.44M乙醚溶液,4.4mmol)处理实施例1F的产物(0.100g,0.31mmol)的THF(5ml)溶液,温热至室温,搅拌14小时,用饱和氯化铵处理,并用乙酸乙酯提取。干燥(硫酸钠)并浓缩提取物。使残留物溶于二氯甲烷(10ml)中,用对甲苯磺酸·H2O(0.059g,0.31mmol)处理,于室温下搅拌14小时,用2%氢氧化钠(10ml)处理,并用乙酸乙酯提取。残留物经硅胶快速层析纯化,用10%乙酸乙酯/己烷洗脱,得到为区域异构体混合物的所需化合物。通过HPLC(Microsorb,5%丙酮/己烷)分离区域异构体,但在室温下迅速互变为1∶1区域异构体混合物。MS(DCI/NH3)m/z 396(M+H)+。1H NMR(300MHz,DMSO-d6)异构体1:δ8.12(d,1H),7.16-7.03(m,5H),6.80-6.66(m,4H),6.45(s,1H),6.34(s,1H),5.0(s,1H),3.90(s,3H),1.84(s,3H),1.20(s,3H),0.91(s,3H);异构体2:δ8.23(d,1H),7.70(d,2H),7.37(t,2H),7.22(m,1H),7.03-7.16(m,3H),6.86(d,1H),6.55(s,1H),5.53(s,1H),5.45(s,1H),3.90(s,3H),1.97(s,3H),1.25(s,6H);C27H25NO2的HRMS计算值m/z:395.1885(M+H)+。实测值:395.1884。实施例195-(3,5-二氢苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例1F的产物和3,5-二氯苯基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 452(M+H)+;1H NMR(300MHz,DMSO)δ8.10(d,1H),7.51(t,Hz,1H),7.19(d,2H),7.03(dd,1H),6.87(s,1H),6.80(d,1H),6.67(d,1H),6.59(d,1H),6.36(s,1H),5.50(s,1H),3.87(s,3H),1.93(s,3H),1.29(s,3H),1.22(s,3H);13C NMR(75 MHz,DMSO)156.1,151.1,145.6,143.8,133.8,133.8,133.5,128.1,127.6,127.3,127.2,127.1,126.7,126.7,117.8,116.9,114.1,113.4,110.2,105.9,73.3,55.6,49.7,29.2,28.5,23.2;C26H23NO2Cl2的HRMS计算值:451.1106(M+H)+。实测值:451.1113。实施例205-丁基-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例1F的产物和正丁基锂,得到所需化合物。MS(DCI/NH3)m/z 364(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.94(d,1H),7.06(dd,1H),6.68(dd,1H),6.58(d,1H),6.54(dd,1H),6.08(s,1H),5.67(m,1H),5.44(s,1H),3.85(s,3H),2.15(s,3H),1.68(m,1H),1.41-1.22(m,5H),1.17(s,3H),1.14(s,3H),0.78(t,3H);C24H29NO2的分析计算值:C,79.30;H,8.04;N,3.85。实测值:C,79.10;H,8.14;N,3.72。实施例212,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-(三氟甲基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例1F的产物和3-三氟甲基苯基-溴化镁,得到所需化合物。MS(DCI/NH3)m/z 452(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.03(d,1H),7.55(m,1H),7.47(m,3H),6.93(dd,1H),6.88(s,1H),6.73(d,1H),6.58(d,1H),6.48(d,1H),6.29(s,1H),5.43(s,1H),3.79(s,3H),1.85(s,3H),1.23(s,3H),1.17(s,3H);C27H24F3NO2的分析计算值:C,71.82;H,5.35;N,3.10。实测值:C,71.73;H,5.44;N,3.05。实施例222,5-二氢-10-甲氧基5-(4-甲氧基苯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2C的方法处理实施例2B的产物和苯甲醚,得到所需化合物。MS(DCI/NH3)m/z 414(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.04(d,2H),6.90(dd,1H),6.78(dd,2H),6.70(dd,2H),6.60(dd,1H),6.41(dd,1H),6.18(s,1H),5.37(s,1H),3.79(s,3H),3.65(s,3H),1.83(s,3H),1.22(s,3H),1.13(s,3H);C27H27NO3的HRMS计算值:413.1991(M+H)+;实测值:413.1987。实施例235-(3-氯代苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例1F的产物和3-氯代苯基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 418(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.23-7.12(m,4H),6.90(dd,1H),6.77(s,1H),6.70(d,1H),6.55(dd,1H),6.44(dd,1H),6.18(d,1H),5.38(s,1H),3.79(s,3H),1.84(s,3H),1.22(s,3H),1.15(s,3H);C26H24NO2Cl的HRMS计算值:417.1496(M+H)+;实测值:417.1490。实施例242,5-二氢-10-甲氧基-2,2,4-三甲基-5-(3-甲基苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例1F的产物和3-甲基苯基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 398(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.94(d,1H),7.01-6.91(m,4H),6.84(dd,1H),6.66(s,1H),6.62(d,1H),6.48(dd,1H),6.38(dd,1H),6.11(d,1H),5.31(d,1H),3.72(s,3H),2.10(s,3H),1.78(d,3H),1.15(s,3H),1.09(s,3H);C28H27NO2的分析计算值:C,81.58;H,6.85;N,3.52。实测值:C,81.23;H,7.18;N,3.36。实施例25(±)-2,5-二氢-10-甲氧基-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉
实施例1的对映体。光谱数据与实施例1相同。[α]D=+85.1;保留时间=在Chiralcel OJ 4.6×250mm HPLC柱上11.68分钟;溶剂:95∶5己烷∶乙醇;流速:1ml/分。实施例26(±)-2,5-二氢-10-甲氧基-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉
实施例1的对映体。光谱数据与实施例1相同。[α]D=-84.9;保留时间=在Chiralcel OJ 4.6×250mm HPLC柱上15.27分钟;溶剂:95∶5己烷∶乙醇;流速:1ml/分。实施例275-(3,5-二甲基苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将在THF(5ml)中的实施例1F的产物(0.052g,0.162mmol)冷却至0℃,滴加0.38M 3.5-二甲基苯基溴化镁的二甲醚溶液(4.4ml,1.68mmol)处理,温热至室温,搅拌14小时,在饱和氯化铵和乙酸乙酯之间分配,并用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸镁)、过滤并浓缩。残留物经硅胶快速层析纯化,用10-25%的乙酸乙酯/己烷梯度液洗脱,得到所需的内半缩醛。
将该内半缩醛(0.043g,0.101mmol)溶于二氯甲烷(7ml)中,用三乙基硅烷(0.16ml,1.01mmol)处理,冷却至0℃,用BF3·OEt2(0.12ml,1.01mmol)处理,温热至室温,搅拌19小时,用饱和碳酸氢钠处理,用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸镁)并浓缩,残留物经硅胶快速层析纯化,用5-10%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 412(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),6.92(t,1H),6.78(m,3H),6.70(d,1H),6.69(s,1H),6.56(dd,1H),6.47(dd,1H),6.19(d,1H),5.39(s,1H),3.79(s,3H),2.11(s,6H),1.85(s,3H),1.22(s,3H),1.15(s,3H);C28H29NO2的分析计算值:C,81.72;H,7.10;N,3.40。实测值:C,81.59;H,7.54;N,3.16。实施例285-(4-氯代苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例1F的产物和4-氯代苯基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 418(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.24(q,4H),6.92(t,1H),6.76(s,1H),6.70(d,1H),6.57(d,1H),6.43(d,1H),6.24(br s,1H),5.20(br s,1H),3.79(s,3H),1.83(s,3H),1.24(s,3H),1.14(s,3H);C26H24NO2Cl的分析计算值:C,74.72;H,5.79;N,3.35。实测值:C,74.73;H,5.68;N,3.29。实施例295-(3,4-二甲基苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例1F的产物和3,4-二甲基苯基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 412(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.98(d,1H),6.94(s,1H),6.82(q,2H),6.78(d,1H),6.67(d,1H),6.53(d,1H),6.42(d,1H),6.17(s,1H),5.37(s,1H),3.78(s,3H),2.08(s,6H),1.84(s,3H),1.22(s,3H),1.14(s,3H);C28H29O2N·0.5H2O的分析计算值:C,79.97;H,7.19;N,3.33。实测值:C,79.94;H,7.25;N,2.98。实施例305-(4-氟代苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和4-氟代苯基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 402(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.03(d,1H),7.16(m,2H),7.03(t,2H),6.88(t,1H),6.71(s,1H),6.68(d,1H),6.55(d,1H),6.41(d,1H),6.22(s,1H),5.38(s,1H),3.79(s,3H),1.82(s,3H),1.23(s,3H),1.14(s,3H)。实施例315-[3,5-双(三氟甲基)苯基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和4-氟代苯基溴化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.98(s,1H),7.00(s,1H),6.93(d,1H),6.75(d,1H),6.59(d,1H),6.49(d,1H),6.38(s,1H),5.46(s,1H),3.79(s,3H),1.87(s,3H),1.21(s,3H),1.19(s,3H);C28H23O2F6N的HRMS m/z计算值:519.1633(M+H)+。实测值:519.1646。C28H23NO2F6·1.25H2O的分析计算值:C,62.05;H,4.74;N,2.58。实测值:C,61.96;H,4.70;N,2.35。实施例32(-)-5-(3,5-二氯苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
实施例19的对映体。光谱数据与实施例19相同。[α]D=-208.0;保留时间=在Regis(R,R)-WhelkO1 Kromasil 4.6×250mm HPLC柱上6.89分钟;溶剂:86∶10∶3己烷∶二氯甲烷∶乙醇;流速:1ml/分。实施例33(+)-5-(3,5-二氯苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
实施例19的-对映体。光谱数据与实施例19相同。[α]D=+210.7;保留时间=在Regis(R,R)-WhelkO1 Kromasil 4.6×250 mm HPLC柱上8.63分钟;溶剂:86∶10∶3己烷∶二氯甲烷∶乙醇;流速:1ml/分。实施例345-(3,5-二氟苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和3,5-二氟代苯基溴化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.05(m,1H),6.93(t,1H),6.79(s,3H),6.71(d,1H),6.59(9,1H),6.50(d,1H),6.30(s,1H),5.43(s,1H),3.81(s,3H),1.87(s,3H),1.23(s,3H),1.16(s,3H);C26H23O2F2N的HRMS m/z计算值:419.1697(M+H)+。实测值:419.1702。C26H23O2F2N·0.5H2O的分析计算值:C,72.88;H,5.65;N,3.27。实测值:C,72.62;H,5.58;N,3.06。实施例352,5-二氢-10-甲氧基-2,2,4,N-四甲基-N-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-胺
如同实施例2的方法处理实施例1F的产物和N-甲基苯胺,得到所需化合物。MS(DCI/NH3)m/z 306(M-NMePh)+;1H NMR(300MHz,DMSO-d6)δ8.03(d,1H),7.25(t,2H),7.08(m,2H),6.99(t,1H),6.86(s,1H),6.80(t,1H),6.70-6.65(m,2H),6.41(d,1H),6.26(br s,1H),5.39(br s,1H),3.87(s,3H),2.47(s,3H),1.74(s,3H),1.24(s,3H),1.11(s,3H);实施例36(-)-2,5-二氢-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
经在Chiralcel OJ上快速层析纯化实施例2的产物,用10%乙醇/己烷洗脱,得到所需化合物。[α]D=-1.8(c1.2,CHCl3);MS(DCI/NH3)m/z 348(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.96(d,1H),7.07(t,1H),6.71(d,1H),6.60(d,1H),6.52(d,1H),6.12(br s,1H),5.82(m,1H),5.76(dd,1H),5.44(br s,1H),5.01(m,2H),3.86(s,3H),2.44(m,1H),2.20(m,1H),2.16(s,3H),1.17(s,3H),1.16(s,3H);C23H25NO2的分析计算值:C,79.51;H,7.25;N,4.03。实测值:C,9.34;H,7.00;N,4.07。实施例37(+)-2,5-二氢-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
经在Chiralcel OJ上快速层析纯化实施例2的产物,用10%乙醇/己烷洗脱,得到所需化合物。[α]D=+2.1(c 1.1,CHCl3);MS(DCI/NH3)m/z 348(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.96(d,1H),7.07(t,1H),6.71(d,1H),6.60(d,1H),6.52(d,1H),6.12(br s,1H),5.82(m,1H),5.76(dd,1H),5.44(br s,1H),5.01(m,2H),3.86(s,3H),2.44(m,1H),2.20(m,1H),2.16(s,3H),1.17(s,3H),1.16(s,3H);C23H25NO2的分析计算值:C,79.51;H,7.25;N,4.03。实测值:C,79.29;H,7.01;N,3.92。实施例382,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和三乙基硅烷,得到所需化合物。MS(DCI/NH3)m/z 308(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.82(d,1H),7.05(t,1H),6.72(dd,1H),6.58(d,1H),6.57(dd,1H),6.13(d,1H),5.39(t,1H),5.10(s,2H),3.84(s,3H),2.02(d,3H),1.18(s,6H);C20H21NO2·0.1H2O的分析计算值:C,77.69;H,6.91;N,4.53。实测值:C,77.60;H,7.15;N,4.33。实施例394-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-N,N-二甲基苯胺
如同实施例2的方法处理实施例2B的产物和N,N-二甲基苯胺,得到所需化合物。MS(DCI/NH3)m/z 427(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.98(d,1H),6.95(d,2H),6.88(t,1H),6.57(d,1H),6.64(s,1H),6.53(m,3H),6.39(d,1H),6.14(d,1H),5.35(s,1H),3.79(s,3H),2.80(s,6H),1.84(s,3H),1.21(s,3H),1.13(s,3H);C28H30N2O2·0.25H2O的分析计算值:C,78.02;H,7.13;N,6.50。实测值:C,78.29;H,7.38;N,6.01。实施例402,5-二氢-10-甲氧基-2,2,4-三甲基-5-(5-甲氧基-2-噻吩基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和2-甲氧基噻吩,得到所需化合物。MS(DCI/NH3)m/z 420(M+H)+;1H NMR(500MHz,DMSO-d6)δ7.98(d,1H),6.97(d,1H),6.73(s,1H),6.67(d,1H),6.63(d,1H),6.46(d,1H),6.20(d,1H),6.18(s,1H),5.96(d,4H),5.39(s,1H),3.82(s,3H),3.72(s,3H),1.98(s,3H),1.21(s,3H),1.13(s,3H);C25H25NO3S的分析计算值:C,71.57;H,6.01;N,3.34。实测值:C,71.54;H,5.99;N,3.17。实施例412,5-二氢-10-甲氧基-2,2,4-三甲基-5-(5-丙基-2-噻吩基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和2-丙基噻吩,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),6.95(t,1H),6.84(s,1H),6.67(d,1H),6.61(d,1H),6.51(d,1H),6.46(d,1H),6.41(d,1H),6.18(m,1H),5.39 (s,1H),3.82(s,3H),2.59(t,2H),1.96(s,2H),1.50(h,2H),1.20(s,3H),1.14(s,3H),0.83(t,3H);C27H29NO2S的HRMS m/z计算值:431.1919(M+H)+;实测值:431.1911。实施例422,5-二氢-10-甲氧基-2,2,4-三甲基-5-[4-(1-吗啉基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和4-苯基吗啉,得到所需化合物。MS(DCI/NH3)m/z 469(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.00(d,2H),6.92(t,1H),6.76(d,2H),6.68(d,2H),6.55(d,1H),6.40(d,1H),6.16(m,1H),5.36(s,1H),3.79(s,3H),3.62(m,4H),3.05(m,4H),1.81(s,3H),1.22(s,3H),1.13(s,3H);C30H32N2O2·0.5H2O的分析计算值:C,75.45;H,6.96;N,5.87。实测值:C,75.46;H,6.69;N,5.31。实施例431-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-3,3-二甲基-2-丁酮
如同实施例2的方法处理实施例2B的产物和(2,2-二甲基-1-亚甲基丙氧基)三甲基硅烷,得到所需化合物。MS(DCI/NH3)m/z 406(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.95(d,1H),7.04(t,1H),6.71(d,1H),6.60(d,1H),6.41(d,1H),6.33(d,1H),6.15(br s,1H),5.43(s,1H),3.87(s,3H),3.26(m,1H),2.36(m,1H),2.13(s,3H),1.16(s,3H),1.15(s,3H),0.89(s,9H);C26H31NO3·0.33H2O的分析计算值:C,75.90;H,7.76;N,3.40。实测值:C,75.91;H,8.17;N,3.62。实施例442,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[H]苯并吡喃并[3,4-f]喹啉-5-腈如同实施例2的方法处理实施例2B的产物和氰基三甲基硅烷,得到所需化合物。MS(DCI/NH3)m/z 333(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.96(d,1H),7.20(t,1H),6.89(d,1H),6.84(s,1H),6.74(d,8H),6.73(d,1H),6.46(s,1H),5.51(s,1H),3.90(s,3H),2.22(s,3H),1.29(s,3H),1.09(s,3H);C21H20N2O2·0.25H2O的分析计算值:C,74.87;H,6.13;N,8.31。实测值:C,75.00;H,6.23;N,8.34。实施例451-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-2-丙酮
如同实施例2的方法处理实施例2B的产物和2-(三甲基甲硅烷氧基)-丙烯,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.96(t,1H),7.04(t,1H),6.71(d,1H),6.58(d,1H),6.48(d,1H),6.20(dd,1H),6.16(s,1H),5.4(s,1H),3.87(s,3H),2.91(q,1H),2.16(s,3H),2.04(s,3H),1.15(d,6H);C23H25O3N的HRMS m/z计算值:363.1834(M+H)+;实测值:363.1843;C23H25NO3·0.33H2O的分析计算值:C,74.79;H,7.00;N,3.79。实测值:C,74.77;H,7.14;N,3.67。实施例462,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-乙酸甲酯
如同实施例2的方法处理实施例2B的产物和1-甲氧基-1-(叔丁基二甲基甲硅烷氧基)乙烯,得到所需化合物。MS(DCI/NH3)m/z 380(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.11(t,1H),6.78(d,1H),6.66(d,1H),6.53(d,1H),6.27(d,1H),6.22(s,2H),5.52(s,1H),3.93(s,3H),3.67(s,3H),2.70(dd,1H),2.64(d,1H),2.27(s,3H),1.22(d,6H);C23H25O4N·0.5H2O的分析计算值:C,71.12;H,6.75;N,3.61。实测值:C,71.46;H,6.81;N,3.45。实施例472-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-1-苯基乙酮
如同实施例2的方法处理实施例2B的产物和1-苯基-1-(三甲基甲硅烷氧基)乙烯,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.72(d,2H),7.59(t,1H),7.40(t,2H),6.93(t,1H),6.70(d,1H),6.61(d,1H),6.43(d,1H),6.25(d,1H),6.18(s,1H),5.44(s,1H),3.90(s,3H),3.66(q,1H),2.95(d,1H),2.16(s,3H),1.16(s,6H);C28H27O3N的HRMS m/z计算值:425.1991(M+H)+;实测值:425.2005。实施例485-[2-(氯代甲基)-2-丙烯基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和2-氯代甲基-3-三甲基甲硅烷基-1-丙烯,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.96(d,1H),7.03(t,1H),6.69(d,1H),6.59(d,1H),6.44(d,1H),6.15(s,1H),5.96(dd,1H),5.45(s,1H),5.27(s,1H),4.95(s,1H),4.17(q,2H),3.87(s,3H),2.55(d,1H),2.26(dd,1H),2.20(s,3H),1.15(d,6H);C24H26O2ClN的HRMS m/z计算值:395.1652(M+H)+;实测值:395.1645;C24H26O2C1N·0.333H2O的分析计算值:C,71.73;H,6.69;N,3.49。实测值:C,71.71;H,6.32;N,3.35。实施例492,5-二氢-10-甲氧基-2,2,4-三甲基-(-亚甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-丙醇,乙酸酯
如同实施例2的方法处理实施例2B的产物和2-[(三甲基甲硅烷基)甲基]-2-丙烯-1-基乙酸酯,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.10(t,1H),6.75(dd,1H),6.65(d,1H),6.50(d,1H),6.18(s,1H),5.98(dd,1H),5.51(s,1H),5.16(s,1H),4.98(s,1H),4.48(q,2H),3.93(s,3H),2.25(s,3H),1.22(s,6H);C26H29O4N的HRMSm/z计算值:419.2097(M+H)+;实测值:419.2095;C26H29O4N·0.25H2O的分析计算值:C,73.65;H,7.01;N,3.30。实测值:C,73.83;H,6.91;N,3.20。实施例502,5-二氢-10-甲氧基-2,2,4-三甲基-5-(4-甲基苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例1F的产物和4-甲基苯基溴化镁,得到所需化合物。MS(DCI/NH3)M/z 398(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.02(q,4H),6.89(t,1H),6.72(s,1H),6.69(d,1H),6.55(d,1H),6.41(d,1H),6.18(br s,1H),5.37(br s,1H),3.79(s,3H),2.18(s,3H),1.83(s,3H),1.23(s,3H),1.14(s,3H);C27H27NO2的分析计算值:C,81.58;H,6.85;N,3.52。实测值:C,81.56;H,7.25;N,3.29。实施例515-(3-氟代-4-甲基苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和3-氟代-4-甲基苯基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 416(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.11(t,1H),6.95-6.84(m,3H),6.74(s,1H),6.71(d,1H),6.57(d,1H),6.46(d,1H),6.23(s,1H),5.39(s,1H),3.79(s,3H),2.11(s,3H),1.85(s,3H),1.22(s,3H),1.14(s,3H);C27H26NO2F的分析计算值:C,78.05;H,6.31;N,3.37。实测值:C,77.80;H,6.51;N,3.06。实施例525-(3-溴代苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例1F的产物和3-溴代苯基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 462(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.36(m,1H),7.30(m,1H),7.17(m,2H),6.93(t,1H),6.79(s,1H),6.72(d,1H),6.58(d,1H),6.48(d,1H),6.24(br s,1H),5.41(br s,1H),3.80(s,1H),1.85(s,3H),1.23(s,1H),1.16(s,1H)。实施例532,5-二氢-10-甲氧基-2,2,4-三甲基-5-(苯基甲基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和苄基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 398(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.31-7.18(m,3H),7.12(m,3H),6.75(d,1H),6.63(d,1H),6.46(d,1H),6.15(d,1H),5.93(dd,1H),5.43(s,1H),3.89(s,3H),2.98(dd,1H),2.74(dd,1H),2.23(s,3H),1.16(s,3H),1.15(s,3H);C27H27NO2·0.25H2O的分析计算值:C,80.67;H,6.89;N,3.48。实测值:C,80.78;H,7.08;N,3.26。实施例542,5-二氢-10-甲氧基-2,2,4-三甲基-5-丙基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和丙基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 350(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.94(d,1H),7.05(t,1H),6.69(d,1H),6.58(d,1H),6.54(d,1H),6.10(d,1H),5.70(m,1H),5.44(s,1H),3.85(s,3H),2.16(s,3H),1.70(m,1H),143-1.31(m,3H),1.16(s,3H),1.14(s,3H),0.83(t,3H);C23H27NO2的分析计算值:C,79.05;H,7.79;N,4.01。实测值:C,78.76;H,7.86;N,3.84。实施例555-(4-氟代苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和4-氟代苯基溴化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.99(d,1H),7.11(d,1H),6.92(m,2H),6.71(s,1H),6.68(s,1H),6.55(d,1H),6.43(d,1H),6.21(s,1H),5.39(s,1H),3.99(s,3H),2.11(s,3H),1.84(s,3H),1.22(s,3H),1.14(s,3H);C27H26O2NF的HRMS m/z计算值:415.1948(M+H)+;实测值:415.1947。实施例565-(3-氟代苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和3-氟代苯基溴化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.03(d,1H),7.22(q,1H),6.90(m,4H),6.78(s,1H),6.73(d,1H),6.56(d,1H),6.46(d,1H),6.24(s,1H),5.40(s,1H),3.79(s,3H),1.85(s,3H),1.20(s,3H),1.15(s,3H);C26H24O2NF的HRMS m/z计算值:402.1869(M+H)+;实测值:402.1865;C26H24O2FN·2.25H2O的分析计算值:C,70.65;H,6.50;N,3.17。实测值:C,70.56;H,6.18;N,2.83。实施例572,5-二氢-10-甲氧基-2,2,4,5-四甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和甲基碘化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.91(d,1H),7.02(8,1H),6.67(d,1H),6.54(s,1H),6.52(d,1H),6.08(s,1H),5.87(q,1H),5.43(s,1H),3.85(s,3H),2.16(s,3H),1.25(d,3H),1.18(s,3H),1.13(s,3H);C21H23O2N的HRMS m/z计算值:321.1729(M+H)+;实测值:321.1728。实施例582,5-二氢-10-甲氧基-2,2,4-三甲基-5-(1-甲基乙基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和2-丙基氯化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.99(d,1H),7.03(t,1H),6.57(d,1H),6.45(d,1H),6.53(d,1H),6.18(s,1H),5.45(s,1H),5.31(d,1H),3.85(s,1H),2.16(s,3H),1.79(m,1H),1.30(s,3H),1.01(s,3H),0.93(d,3H),0.62(d,3H);C23H27O2N的HRMS m/z计算值:349.2042(M+H)+;实测值:349.2041。实施例592,5-二氢-10-甲氧基-2,2,4-三甲基-5-(2-甲基丙基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和仲丁基氯化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.93(d,1H),7.03(t,1H),6.67(d,1H),6.51(q,2H),6.08(s,1H),5.77(dd,1H),5.43(s,1H),3.85(s,3H),2.18(s,3H),1.72(m,2H),1.76(d,6H),0.86(d,3H),0.74(d,3H);C24H29O2N的HRMS m/z计算值:363.2198(M+H)+;实测值:363.2208;C24H29NO2的分析计算值:C,79.30;H,8.04;N,3.85。实测值:C,79.63;H,7.83;N,3.89。实施例605-乙基-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和乙基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 336(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.92(d,1H),7.03(t,1H),6.67(d,1H),6.54(t,2H),6.10(s,1H),5.55(dd,1H),5.44(s,1H),3.84(s,3H),2.16(s,3H),1.63(m,1H),1.44(m,1H),1.15(s,6H),0.84(t,3H);C22H25O2N·2.25H2O的分析计算值:C,77.73;H,7.56;N,4.12。实测值:C,77.95;H,7.60;N,4.07。实施例612,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-甲亚胺酸乙酯
将实施例44的产物(0.040g,0.120mmol)的乙醇(5ml)溶液冷却至-5℃,用氯化氢气体饱和,于-5℃搅拌1 0分钟,于室温下搅拌14小时,用碳酸氢钠中和,用乙醚提取。干燥(硫酸钠)提取物,过滤并浓缩,得到所需化合物。MS(DCI/NH3)m/z 379(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.95(d,1H),7.32(s,1H),7.05(t,1H),6.69(t,2H),6.61(d,1H),6.22(s,1H),6.14(s,1H),5.44(s,1H),3.92(m,2H),3.82(s,3H),2.06(s,3H),1.20(s,3H),1.12(s,3H),1.02(t,3H)。实施例622,5-二氢-10-甲氧基-2,2,4-三甲基-(-亚甲基1H-[1]苯并吡喃并[3,4-f)喹啉-5-丙醇
用碳酸钾(0.080g,1.0mmol)处理实施例49的产物(0.060g,0.143mmol)的1∶1甲醇/水(10ml)溶液,于室温下搅拌24小时,用10%HCl中和,用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸镁),过滤并浓缩。残留物经快速硅胶层析纯化,用25%二氯甲烷/乙酸乙酯洗脱,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.72(d,2H),7.59(t,1H),7.40(t,2H),6.93(t,1H),6.70(d,1H),6.61(d,1H),6.43(d,1H),6.25(d,1H),6.18(s,1H),5.44(s,1H),3.90(s,3H),3.66(q,1H),2.95(d,1H),2.16(s,3H),1.16(s,6H);C28H27O3N的HRMS m/z计算值:425.1991(M+H)+;实测值:425.2005;实施例632,5-二氢-10-甲氧基-2,2,4,N,N-五甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-乙酰胺
用氢氧化锂的THF溶液水解实施例46的产物得到相应的酸,然后用1-(3-二甲基氨基丙基)-3-乙基碳二亚胺使该酸与N,N-二甲胺偶合,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.94(d,1H),7.04(t,1H),6.70(d,1H),6.59(d,1H),6.46(d,1H),6.26(d,1H),6.15(s,1H),5.44(s,1H),3.86(s,3H),2.88(q,1H),2.81(s,3H),2.55(s,3H),2.25(s,1H),2.19(s,3H),1.15(s,6H);C24H28O3N2的HRMS m/z计算值:392.2100(M+H)+;实测值:392.2104;C24H28N2O3的分析计算值:C,73.44;H,7.19,7.35;N,7.14。实测值:C,73.17;H,7.19;N,6.85。实施例642,5-二氢-10-甲氧基-2,2,4,N,N-五甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-乙胺
于室温下用氢化铝锂还原实施例63的乙醚溶液,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.93(d,1H),7.03(t,1H),6.68(8,1H),6.54(t,1H),6.12(s,1H),5.76(dd,1H),5.44(s,1H),3.85(s,3H),2.18(s,3H),2.05(s,6H),1.18(s,3H),1.14(s,3H);C24H30O2N2的HRMS m/z计算值:378.2307(M+H)+;实测值:378.2307。实施例65N-环丙基-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-乙酰胺
如同实施例63的方法处理实施例46的产物和环丙基甲胺,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.94(d,1H),7.70(d,1H),7.03(t,1H),6.68(d,1H),6.58(d,1H),6.43(d,),6.23(dd,1H),6.13(s,1H),5.43(s,1H),3.85(s,3H),2.51(m,2H),2.07(d,1H),2.03(s,3H),1.17(s,3H),1.13(s,3H),0.60(m,2H),0.31(s,2H);C25H28O3N2的HRMS m/z计算值:404.2100(M+H)+;实测值:404.2092。实施例662,5-二氢-10-甲氧基-2,2,4-三甲基-5-(2-丙炔基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和2-丙炔基溴化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.97(d,1H),7.06(t,1H),6.71(d,1H),6.56(q,2H),6.16(s,1H),5.88(q,1H),5.44(s,1H),3.86(s,3H),2.82(q,1H),2.41(q,1H),2.19(s,3H),1.16(s,3H);C23H23O2N的HRMS m/z计算值:345.1729(M+H)+;实测值:345.1738。实施例675-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-2(5H)-呋喃酮
如同实施例2C的方法处理实施例2B的产物和2-三甲基甲硅烷氧基呋喃,得到所需化合物。MS(DCI/NH3)m/z 390(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.11(d,1H),7.13(dd,1H),6.75(d,1H),6.72(d,1H),6.64(d,1H),6.37(d,1H),6.25(dd,1H),6.23(d,1H),5.83(d,1H),5.47(s,1H),5.12(dd,1H),3.87(s,3H),2.03(s,3H),1.30(s,3H),1.09(s,3H);C24H23NO4的分析计算值:C,74.02;H,5.95;N,3.60。实测值:C,73.89;H,5.94;N,3.5l。实施例685-(3-丁烯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例11的方法处理实施例2B的产物和3-丁烯基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 362(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.94(d,1H),7.05(t,1H),6.68(d,1H),6.58(d,1H),6.57(d,1H),6.10(s,1H),5.78(dddd,1H),5.65(dd,1H),5.44(s,1H),5.00(dd,1H),4.93(dd,1H),3.85(s,3H),2.16(s,3H),2.10(m,2H),1.78(m,1H),1.45(bm,1H),1.16(s,3H),1.14(s,3H);C24H27NO2的HRMS m/z计算值:361.2042(M+H)+;实测值:361.2039。实施例692,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-丙醇
于0℃,滴加0.5M 9-BBN(600μl,0.30mmol)处理在THF(4ml)中的实施例2的产物(52.0mg,0.15mmol),于室温下搅拌过夜,冷却至0℃,顺序用2.5M氢氧化钠(400μl,1.0mmol)和30%H2O2(250μl)处理,于室温下搅拌2小时,在1∶1的乙酸乙酯/水之间分配,并用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩。残留物经硅胶快速层析纯化,用30%乙酸乙酯/己烷洗脱,得到所需化合物。MS(DCI/NH3)m/z 366(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.94(d,1H),7.05(t,1H),6.68(d,1H),6.58(d,1H),6.53(d,1H),6.10(s,1H),5.70(dd,1H),5.44(s,1H),4.36(t,1H),3.85(s,3H),3.33(m,2H),2.16(s,3H),1.40-1.75(bm,4H),1.17(s,3H),1.14(s,3H);C23H27NO3的HRMS m/z计算值:365.1991(M+H)+;实测值:365.1991。实施例7010-乙基-2,5-二氢-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉实施例70A
于80℃,将实施例3C的产物(0.208g,0.493mmol)和四乙基锡(0.444g,1.89mmol)与(1,3-双(二苯基膦基)二茂铁)氯化钯(II)-二氯甲烷(0.039g,0.047mmol)在1-甲基-2-吡咯烷酮(3ml)中混合16小时并浓缩得到所需化合物。MS实施例7010-乙基-2,5-二氢-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1F、1G和1的方法处理实施例70A的产物,得到所需化合物。MS(DCI/NH3)m/z 382(M+H)+;1H NMR(300MHz,DMSO)δ7.37(d,1H),7.21-7.16(m,5H),6.85(dd,1H),6.75(s,1H),6.73(dd,1H),6.68(d,1H),6.58(dd,1H),6.21(s,1H),5.39(s,1H),3.02-2.75(m,2H)1.79(s,3H),1.24(s,3H),1.15(s,3H),1.15(m,3H);C27H27NO的HRMS m/z计算值:381.2093(M+H)+;实测值:381.2096。实施例712,5-二氢-2,2,4,10-四甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例70的方法处理实施例3C的产物和四甲基锡,得到所需化合物。MS(DCI/NH3)m/z 368(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.44(d,1H),7.21-7.12(m,5H),6.82(dd,1H),6.74(d,1H),6.71(s,1H),6.69(dd,1H),6.59(dd,1H),6.21(s,1H),5.39(s,1H),2.51(s,3H)1.80(s,3H),1.25(s,3H),1.16(s,3H);C26H25NO的HRMS m/z计算值:367.1936(M+H)+;实测值:367.1931。实施例725-(3,5-二氯苯基)-10-乙基-2,5-二氢-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例70A的产物和3,5-二氯苯基溴化镁,得到所需化合物。MS(DCI/NH
3)m/z 450(M+H)
+;
1H NMR(300MHz,DMSO-d
6)δ7.43(d,1H),7.43(t,1H),7.18(d,2H),6.91(dd,1H),6.80(dd,1H),6.78(d,1H),6.72(s,1H),6.62(dd,1H),6.35(s,1H),5.42(s,1H),3.15-2.75(m,2H)1.79(s,3H),1.27(s,3H),1.14(s,3H),1.13(t,3H);C
27H
25NOCl
2的HRMS m/z计算值:449.1313(M+H)
+;实测值:449.1330。实施例735-(3,5-二氯苯基)-2,5-二氢-2,2,4,N-四甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-10-胺
实施例73A
如同实施例72的方法处理实施例3C的产物和3,5-二氯苯基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 539(M+H)+。实施例735-(3,5-二氯苯基)-2,5-二氢-2,2,4,N-四甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-10-胺
如同实施例3的方法处理实施例73A的产物,得到所需化合物。MS(DCI/NH3)m/z 451(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.91(d,1H),7.45(dd,1H),7.20(m,2H),6.83(dd,1H),6.75(d,1H),6.71(s,1H),6.22(dd,1H),6.18(s,1H),6.17(dd,1H),5.57(d,1H),5.44(s,1H),2.65(d,3H)1.85(s,3H),1.24(s,3H),1.15(s,3H);C26H24N2OCl2的HRMS m/z计算值:450.1266(M+H)+;实测值:450.1267。实施例745-(3,5-二氯苯基)-2,5-二氢-2,2,4-三甲基-N-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉-10-胺
如同实施例3的方法处理实施例73A的产物和烯丙胺,得到所需化合物。MS(DCI/NH3)m/z 477(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.99(d,1H),7.49(dd,1H),7.27(d,2H),6.82(dd,1H),6.77(d,1H),6.75(s,1H),6.25(dd,1H),6.21(s,1H),6.20(dd,1H),5.95-5.86(m,1H),5.69-5.65(m,1H),5.48(s,1H),5.18-5.12(m,1H),5.11-5.06(m,1H),3.78-3.70(m,2H),1.88(s,3H),1.30(s,3H),1.20(s,3H);C28H26N2OCl2的HRMS m/z计算值:476.1422(M+H)+;实测值:476.1428。实施例752,5-二氢-2,2,4-三甲基-5-苯基-10-(2-丙炔基氧基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例9A的方法处理实施例7的产物和炔丙基溴,得到所需化合物。MS(DCI/NH3)m/z 408(M+H)+;1H NMR(300MHz,DMSO-d6)δ1.12(s,3H),1.23(s,3H),1.83(s,3H),3.59(t,1H),4.81(d,2H),5.39(br s,1H),6.19(br s,1H),6.47(d,1H),6.61(d,1H),6.71(d,1H),6.78(s,1H),6.90(t,1H),7.14-7.22(m,5H),8.02(d,1H);C28H25NO2的分析计算值:C,82.53;H,6.18;N,3.44。实测值:C,82.64;H,6.31;N,3.38。实施例762,5-二氢-2,2,4-三甲基-5-苯基-10-(2-丙烯基氧基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例9A的方法处理实施例7的产物和烯丙基溴,得到所需化合物。MS(DCI)m/z 410(M+H)+;1H NMR(300MHz,DMSO-d6)δ1.15(s,3H),1.23(s,3H),1.84(s,3H),4.51-4.64(m,2H),5.26(dq,1H),5.39(br s,1H),5.40(dq,1H),6.12(ddt,1H),6.21(br s,1H),6.44(dd,1H),6.55(dd,1H),6.69(d,1H),6.77(s,1H),6.88(t,1H),7.15-7.24(m,5H),8.06(d,1H);C28H27NO2的HRMS m/z计算值:409.2042(M+H)+;实测值:409.2039。实施例772,5-二氢-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉-10-甲醇
于-78℃及氩气下,滴加二异丁基氢化铝(1.0M)的环己烷溶液(0.400ml,0.40mmol)处理实施例4的产物(32mg,0.085mmol)的二氯甲烷(3ml)溶液,温热至0℃3.5小时,用Rochelle’s盐处理,分离并用乙酸乙酯提取。干燥(硫酸镁)提取物,过滤并浓缩。使残留物上两个10×20cm,0.25mm厚硅胶板,用己烷洗脱3次,然后用乙酸乙酯/己烷(10∶90)洗脱。刮下产物带并用乙酸乙酯提取,得到所需化合物。MS(DCI/NH3)m/z 348(M+H)+。1H NMRδ7.47(d,1H),7.14(m,2H),6.80(dd,1H),6.64(d,1H),6.17(m,1H),5.81(ddm,1H),5.73(dd,1H),5.46(m,1H),5.32(dd,1H),5.02(dm,1H),4.94(dm,1H),4.62(m,2H),2.30(m,2H),2.17(s,3H),1.19(s,3H),1.16(s,3H);C23H25NO2的HRMS m/z计算值:347.1885(M+H)+;实测值:347.1897。实施例782,5-二氢-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉-10-羧酸
如同实施例例3的方法处理实施例74的产物和氯代三(三苯基磷酸酯)氯化铑(I),得到所需化合物。MS(DCI/NH3)m/z 437(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.91(d,1H),7.44(dd,1H),7.19(d,2H),6.74(d,1H),6.70(s,1H),6.69(dd,1H),6.26(dd,1H),6.22(s,1H),6.11(dd,1.0Hz,1H),5.43(s,1H),5.15(s,2H),1.84(s,3H),1.23(s,3H),1.15(s,3H);实施例795-(3,5-二氯苯基)-10-乙氧基-2,5-二氢-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1G和1的方法处理实施例9A的产物和3,5-二氯苯基溴化镁,得到所需化合物。MS(DCI)m/z 466(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.10(d,1H),7.46(t,1H),7.13(d,2H),6.95(dd,1H),6.81(s,1H),6.72(d,1H),6.60(d,1H),6.51(d,1H),6.32(d,1H),5.44(s,1H),3.99-4.12(m,1H),1.87(s,3H),1.37(t,3H),1.23(s,3H),1.20(s,3H);C27H25NO2Cl2的HRMS m/z计算值:465.1262(M+H)+;实测值:465.1277。实施例805-(3,5-二氯苯基)-2,5-二氢-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-10-醇
如同实施例7B和7的方法处理实施例7A的产物和3,5-二氯苄基溴化镁,得到所需化合物。MS(DCI)m/z 438,440(M+H)+;1H NMR(300MHz,DMSO-d6)δ9.79(s,1H),8.18(d,1H),7.44(t,1H),7.12(dd,2H),6.79(d,1H),6.77(s,1H),6.73(d,1H),6.45(d,1H),6.28(dd,1H),6.23(d,1H),5.43(s,1H),1.87(d,3H),1.22(s,3H),1.16(s,3H);C25H21Cl2NO2的HRMS m/z计算值:437.0949(M+H)+;实测值:437.0955。实施例815-(3,5-二氯苯基)-2,5-二氢-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-10-基]甲基碳酸酯
如同实施例7B和7的方法处理实施例80的产物和氯代甲酸甲酯,得到所需化合物。MS(DCI/NH3)m/z 496(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.58(d,1H),7.45(t,1H),7.24(m,2H),7.02(t,1H),6.82(s,1H),6.80(dd,1H),6.75(dd,1H),6.74(d,1H),6.48(s,1H),5.43(s,1H),3.79(s,3H),1.79(s,3H),1.25(s,3H),1.13(s,3H);C27H23NO4C12的分析计算值:C,65.33;H,4.67;N,2.82。实测值:C,65.12;H,4.55;N,2.79。实施例822,5-二氢-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉-10-醇
如同实施例7B和7的方法处理实施例7A的产物和烯丙基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 334(M+H)+;1H NMR(300MHz,DMSO-d6)δ9.77(s,1H),8.10(d,1H),6.88(t,1H),6.58(d,1H),6.53(d,1H),6.35(d,1H),6.05(s,1H),5.89-5.72(m,2H),5.44(s,1H),5.03(d,1H),4.99(d,1H),2.50-2.40(m,1H),2.25-2.18(m,1H),2.16(s,3H),1.16(s,3H),1.15(s,3H);C22H23NO2的HRMS m/z计算值:333.1729(M+H)+;实测值:333.1734。实施例8310-(溴代二氟甲氧基)-2,5-二氢-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例7B和7的方法处理实施例82的产物和二溴二氟甲烷,得到所需化合物。MS(DCI/NH3)m/z 462(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.60(d,1H),7.21(t,1H),7.0(m,1H),6.95(dd,1H),6.64(d,1H),6.35(s,1H),5.89-5.76(m,2H),5.46(s,1H),5.04(dd,1H),4.96(dd,1H),2.55-2.44(m,1H),2.33-2.25(m,1H),2.18(s,3H),1.19(s,3H),1.17(s,3H);C23H22F2NO2Br的HRMS m/z计算值:461.0802(M+H)+;实测值:461.0815。实施例84[3-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯基]甲基碳酸酯
如同实施例10的方法处理实施例13的产物和氟代甲酸甲酯,得到所需化合物。MS(DCI/NH3)m/z 458(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.25(t,1H),7.12(d,1H),7.01(q,1H),6.90(q,2H),6.78(s,1H),6.72(d,1H),6.57(q,1H),6.44(q,1H),6.20(d,1H),5.39(s,1H),3.80(s,3H),3.63(s,3H),1.83(s,3H),1.22(s,3H),1.16(s,3H);C28H27NO5的分析计算值:C,73.50;H,5.94;N,3.06。实测值:C,73.63;H,6.20;N,2.86。实施例852,5-二氢-10-甲氧基-5-(3-甲氧基苯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和甲基碘,得到所需化合物。MS(DCI/NH3)m/z 414(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.13(t,1H),6.92(t,1H),6.75-6.67(m,5H),6.57(dd,1H),6.46(dd,1H),6.20(d,1H),5.39(s,1H),3.80(s,3H),3.63(s,3H),1.88(s,3H),1.22(s,3H),1.16(s,3H);C27H27NO3的分析计算值:C,78.42;H,6.58;N,3.38。实测值:C,78.58;H,6.55;N,3.23。实施例862,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-(2-丙烯基氧基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和烯丙基溴,得到所需化合物。MS(DCI/NH3)m/z 440(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.13(t,1H),6.92(t,1H),6.78-6.67(m,5H),6.56(d,1H),6.46(d,1H),6.20(d,1H),5.95(m,1H),5.40(s,1H),5.31(dd,1H),5.21(dd,1H),4.42(d,2H),3.80(s,3H),1.86(s,3H),1.23(s,3H),1.16(s,3H);C29H29NO3的分析计算值:C,79.24;H,6.64;N,3.18。实测值:C,78.87;H,6.46;N,3.07。实施例872,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-(苯基甲氧基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和苄基溴,得到所需化合物。MS(DCI/NH3)m/z 490(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.06(d,1H),7.40(m,5H),7.18(t,1H),6.97(t,1H),6.90-6.85(m,2H),6.80-6.74(m,3H),6.62(d,1H),6.48(d,1H),6.24(d,1H),5.45(s,1H),5.03(d,2H),3.85(s,3H),1.92(s,3H),1.29(s,3H),1.21(s,3H);C33H31NO3的分析计算值:C,80.95;H,6.38;N,2.86。实测值:C,80.81;H,6.24;N,2.96。实施例885-[3-(环丙基甲氧基)苯基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和环丙基甲基溴,得到所需化合物。MS(DCI/NH3)m/z 454(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.12(t,1H),6.92(t,1H),6.74-6.68(m,5H),6.55(d,1H),6.46(d,1H),6.20(s,1H),5.39(s,3H),3.79(s,3H),3.66(d,2H),1.86(s,3H),1.23(s,3H),1.16(s,3H),1.12(m,1H),0.50(q,2H),0.24(q,2H);C30H31NO3的分析计算值:C,79.44;H,6.88;N,3.08。实测值:C,79.12;H,6.72;N,2.99。实施例892,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-[2-(1-哌啶基)乙氧基]苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和1-(2-氯乙基)哌啶,得到所需化合物。MS(DCI/NH3)m/z 511(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.12(t,1H),6.92(t,1H),6.77-6.68(m,5H),6.57(d,1H),6.46(d,1H),6.20(d,1H),5.39(s,1H),3.91(t,2H),3.80(s,3H),2.55(t,2H),2.35(b,4H),1.92(s,3H),1.46(b,4H),1.36(b,2H),1.22(s,3H),1.16(s,3H);C33H38N2O3·0.5H2O的分析计算值:C,76.27;H,7.56;N,5.39。实测值:C,76.26;H,7.38;N,5.28。实施例905-(3-己氧基苯基)-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和己基碘,得到所需化合物。MS(DCI/NH3)m/z 484(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.09(t,1H),6.92(t,1H),6.75-6.67(m,5H),6.56(dd,1H),6.46(dd,1H),6.18(d,1H),5.40(s,1H),3.81(t,2H),3.79(s,3H),1.87(s,3H),1.60(m,2H),1.36-1.23(b,6H),1.22(s,3H),1.16(s,3H),0.86(t,3H);C32H37NO3的HRMS m/z计算值:483.2773(M+H)+;实测值:483.2776.实施例915-[3-(2,4-二硝基苯氧基)苯基]-2,5-二-氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和1-氟代-2,4-二硝基苯,得到所需化合物。MS(DCI/NH3)m/z 566(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.87(d,1H),8.38(dd,1H),7.88(d,1H),7.40(t,1H),7.20-7.08(m,2H),7.20-7.08(m,2H),6.81(s,1H),6.72(d,1H),6.68(d,1H),6.62(d,1H),6.46(dd,1H),6.24(d,1H),5.40(s,1H),3.78(s,3H),1.90(s,3H),1.19(s,3H),1.13(s,3H);C32H27N3O7的分析计算值:C,67.95;H,4.81;N,7.42。实测值:C,68.20;H,5.05;N,7.20。实施例922,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-(2-丙炔基氧基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和炔丙基溴,得到所需化合物。MS(DCI/NH3)m/z 566(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.13(t,1H),6.92(t,1H),6.80-6.68(m,5H),6.56(d,1H),6.48(d,1H),6.18(d,1H),5.39(s,1H),4.67(d,2H),3.80(s,3H),3.50(t,1H),1.87(s,3H),1.23(s,3H),1.16(s,3H);实施例933-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯酚4-甲苯磺酸酯
如同实施例例15的方法处理实施例13的产物和对甲苯磺酸氯,得到所需化合物。MS(DCI/NH3)m/z 554(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.99(d,1H),7.47(d,2H),7.36(d,4H),7.22(t,1H),7.13(d,1H),6.97(t,1H),6.85-6.78(m,2H),6.70(d,1H),6.68(s,1H),6.59(dd,1H),6.37(dd,1H),6.24(d,1H),5.39(s,1H),3.80(s,3H),2.43(s,3H),1.74(s,3H),1.24(s,3H),1.18(s,3H);C33H31NO5S的分析计算值:C,71.58;H,5.64;N,2.52。实测值:C,71.49;H,5.75;N,2.40。实施例944-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯酚乙酸酯
如同实施例12A-C的方法处理实施例1F的产物和4-甲氧基甲氧基苯基溴,得到所需化合物。MS(DCI/NH3)m/z 442(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.19(d,2H),6.99(d,2H),6.91(t,1H),6.79(s,1H),6.71(d,1H),6.58(d,1H),6.46(dd,1H),6.21(d,1H),5.39(s,1H),3.79(s,3H),2.19(s,3H),1.83(s,3H),1.22(s,3H),1.15(s,3H);C28H27NO4的分析计算值:C,76.16;H,6.16;N,3.17。实测值:C,75.79;H,6.24;N,3.03。实施例954-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯酚
如同实施例13的方法处理实施例94的产物,得到所需化合物。MS(DCI/NH3)m/z 400(M+H)+;1H NMR(300MHz,DMSO-d6)δ9.29(s,1H),8.05(d,1H),7.00(d,2H),6.95(t,1H),6.74(d,2H),6.72(s,1H),6.63-6.58(m,3H),6.44(dd,1H),6.15(s,1H),5.41(s,1H),3.83(s,3H),1.90(s,3H),1.28(s,3H),1.20(s,3H);C26H25NO3的分析计算值:C,78.17;H,6.30;N,3.50。实测值:C,78.59;H,6.20;N,3.12。实施例962,5-二氢-10-甲氧基-2,2,4-三甲基-5-[[4-(甲硫基)甲氧基]苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例例14的方法处理实施例95的产物,得到所需化合物。MS(DCI/NH3)m/z 460(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.17(d,2H),6.90(t,1H),6.82(d,2H),6.72(s,1H),6.69(d,1H),6.56(d,1H),6.42(d,1H),6.17(s,1H),5.38(s,1H),5.16(s,2H),3.80(s,3H),2.11(s,3H),1.85(s,3H),1.23(s,3H),1.16(s,3H);C28H29NO3S的分析计算值:C,73.17;H,6.35;N,3.04。实测值:C,72.86;H,6.62;N,2.69。实施例97[4-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯基]二甲基氨基甲酸酯
如同实施例15的方法处理实施例95的产物和二甲基氨基甲酰氯,得到所需化合物。MS(DCI/NH3)m/z 471(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.15(d,2H),6.98(d,2H),6.90(d,1H),6.76(s,1H),6.70(d,1H),6.57(d,1H),6.44(d,1H),6.22(d,1H),5.40(s,1H),3.80(s,3H),2.98(s,3H),2.85(s,3H),1.86(s,3H),1.23(s,3H),1.15(s,3H);实施例982,5-二氢-10-甲氧基-2,2,4-三甲基-5-[4-(苯基甲氧基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例95的产物和苄基溴,得到所需化合物。MS(DCI/NH3)m/z 490(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.40-7.28(m,4H),7.08(d,2H),6.90(t,1H),6.84(d,2H),6.72(s,1H),6.70(d,1H),6.55(d,1H),6.41(d,1H),6.15(s,1H),5.37(s,1H),4.96(s,2H),3.80(s,3H),1.85(s,3H),1.23(s,3H),1.15(s,3H);C33H31NO3的分析计算值:C,80.95;H,6.38;N,2.86。实测值:C,81.02;H,6.25;N,2.76。实施例992,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-(甲氧基甲氧基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和甲氧基甲基氯,得到所需化合物。MS(DCI/NH3)m/z 444(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.14(t,1H),6.92(t,1H),6.83-6.75(m,4H),6.70(d,1H),6.58(d,1H),6.47(q,1H),6.21(s,1H),5.40(s,1H),5.06(s,2H),3.80(s,3H),3.30(s,3H),1.89(s,3H),1.24(s,3H),1.16(s,3H);C28H29NO4的HRMS m/z计算值:443.2097(M+H)+。实测值:443.2098。实施例100[(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯基]1-吗啉羧酸酯
如同实施例例15的方法处理实施例13的产物和吗啉,得到所需化合物。MS(DCI/NH3)m/z 513(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.22(t,1H),7.05(d,1H),6.93(t,2H),6.83(s,1H),6.77(s,1H),6.71(d,1H),6.57(d,1H),6.48(q,1H),6.23(d,1H),5.40(s,1H),3.80(s,3H),3.60(t,4H),3.50(b,4H),1.86(s,3H),1.24(s,3H),1.14(s,3H);C31H32N2O5的HRMS m/z计算值:512.2311(M+H)+。实测值:512.2328。实施例1012,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-[(甲基亚磺酰基)甲氧基]苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
于0℃,用TeO2(1.6mg,0.01mmol)和乙酸(50mg,0.83mmol)顺序处理实施例14的产物(12mg,0.005mmol)的甲醇(1ml)溶液,于室温下搅拌过夜,用饱和碳酸氢钠处理并用二氯甲烷提取。用水和盐水洗涤提取物,干燥(硫酸镁)、过滤并浓缩得到MS(DCI/NH3)m/z 476(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(dd,1H),7.15(dt,1H),6.92(m,3H),6.78(t,1H),6.74(s,1H),6.70(d,1H),6.58(d,1H),6.47(d,1H),6.19(d,1H),5.40(d,1H),5.12(dd,1H),4.93(q,1H),3.79(d,3H),2.57(d,3H),1.87(d,3H),1.24(d,3H),1.16(d,3H);C28H29NO4S的HRMS m/z计算值:475.1817(M+H)+。实测值:475.1819。实施例102O-[3-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯基]酯
如同实施例16的方法处理实施例13的产物和硫代氨基甲酰氯,得到所需化合物。MS(DCI/NH3)m/z 487(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.22(t,1H),7.13(d,1H),6.92(t,1H),6.85(d,1H),6.78(s,1H),6.72(s,1H),6.59(d,1H),6.57(d,1H),6.45(d,1H),6.21(s,1H),5.39(s,1H),3.80(s,3H),3.29(s,3H),3.22(s,3H),1.86(s,3H),1.24(s,3H),1.14(s,3H)。实施例1032,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-(甲硫基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉实施例103A
于-78℃,用正丁基锂(2.5M在己烷中,6.00ml)处理3-溴代苯基甲氧基甲醚(3.50g,15.0mmol)的THF(150ml)中的溶液5分钟,温热至-30℃,冷却至-78℃,一次性用实施例1F处理,温热至-40℃,用饱和氯化铵猝灭,温热至室温,并使之沉降。倾出上清液并浓缩,残留物在水和乙酸乙酯之间分配。顺序用水和盐水洗涤有机层,干燥(硫酸钠)并浓缩。残留物经硅胶快速层析纯化,用20-25%乙酸乙酯/己烷洗脱,得到所需化合物。MS(DCI/NH3)m/z 476(M+H)+。实施例1032,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-(甲硫基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
于室温下,用BF3·OEt2(60mg,0.42mmol)处理实施例103A的产物(20mg,0.042mmol)和三乙基硅烷(49mg,0.42mmol)的二氯甲烷(lml)溶液,搅拌24小时,用饱和碳酸氢钠处理。用二氯甲烷提取水层,用1M氢氧化钠和盐水顺序洗涤合并的提取物,干燥(硫酸钠)、过滤并浓缩。残留物经硅胶快速层析纯化,用10-25%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 430(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.15(t,1H),7.05(s,1H),7.03(d,1H),6.93(t,1H),6.89(s,1H),6.74(s,1H),6.70(d,1H),6.57(d,1H),6.46(d,1H),6.19(d,1H),5.40(s,1H),3.78(s,3H),3.33(s,3H),1.88(s,3H),1.22(s,3H),1.16(s,3H);C27H27NO2S的HRMS m/z计算值:429.1 763(M+H)+。实测值:429.1764。实施例104O-[3-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯基]甲基羧硫代酸酯
如同实施例15的方法处理实施例95的产物和硫代氯代甲酸甲酯,得到所需化合物。MS(DCI/NH3)m/z 474(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.26(t,1H),7.12(d,1H),7.01(q,1H),6.89(t,1H),6.87(s,1H),6.78(s,1H),6.72(d,1H),6.57(q,1H),6.44(q,1H),6.20(d,1H),5.39(s,1H),3.78(s,3H),2.35(s,3H),1.83(s,3H),1.22(s,3H),1.16(s,3H);C28H27NO4S的分析计算值:C,71.01;H,5.74;N,2.95。
实测值:C,70.77;H,5.74;N,2.79。实施例105[3-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯基]三氟甲磺酸酯
于-78℃,滴加三氟甲磺酸酐(50μl,0.30mmol)处理实施例13的产物(100mg,0.25mmol)、三乙胺(70μl,0.5mmol)和4-二甲基氨基吡啶(催化量)的二氯甲烷(10ml)溶液,于-78℃搅拌30分钟,倾入饱和碳酸氢钠中,用乙酸乙酯提取。顺序用水和盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩。残留物经硅胶快速层析纯化,用15-85%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 532(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.44(t,1H),7.30(m,2H),7.17(s,1H),6.93(t,1H),6.83(s,1H),6.71(d,1H),6.57(d,1H),6.43(d,1H),6.28(d,1H),5.40(s,1H),3.78(s,3H),1.83(s,3H),1.22(s,3H),1.15(s,3H);C27H24NO5SF3的分析计算值:C,61.01;H,4.55;N,2.64。
实测值:C,61.17;H,4.60;N,2.51。实施例1065-[3-(4,5-二氢-4,4-二甲基-2-噁唑基)苯基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
用氮气吹洗实施例52的产物(92.9mg,0.20mmol)、2-三甲基甲锡烷基-4,4-二甲基噁唑啉(210mg,0.80mmol)和[1,1’-双(二苯基膦基)-二茂铁)二氯钯(II)(16mg,0.02mmol)的1-甲基-2-吡咯烷酮(2ml)溶液,加热至85℃3小时,在乙酸乙酯(50ml)和饱和KF(30ml)之间分配。搅拌1小时,通过海贝壳粉(Celite_)垫过滤。用水、盐水洗涤滤液,干燥(硫酸钠)、过滤并浓缩。残留物经硅胶快速层析纯化,用0-30%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 481(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.64(d,1H),7.62(s,1H),7.41(d,1H),7.32(t,1H),6.92(t,1H),6.82(s,1H),6.71(d,1H),6.56(dd,1H),6.47(dd,1H),6.25(d,1H),5.40(s,1H),4.02(s,2H),3.78(s,3H),1.84(s,3H),1.25(s,3H),1.22(s,6H),1.16(s,3H);C31H32N2O3·0.7H2O的分析计算值:C,75.49;H,6.85;N,5.68。
实测值:C,75.83;H,6.88;N,5.29。实施例1073-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯甲酸乙酯
将实施例106的产物(48mg,0.1mmol)在1.5M硫酸的乙醇(5ml)中的溶液回流16小时,冷却、倾入饱和碳酸氢钠中,用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩。残留物经硅胶快速层析纯化,用30%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 456(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.76(m,2H),7.48(d,1H),7.38(t,1H),6.91(t,1H),6.85(s,1H),6.72(d,1H),6.56(dd,1H),6.46(dd,1H),6.26(d,1H),5.40(s,1H),4.23(q,2H),3.78(s,3H),1.84(s,3H),1.25(t,3H),1.24(s,3H),1.16(s,3H);C29H30NO4的HRMS m/z计算值:456.2175(M+H)+。实测值:456.2175。实施例1083-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯甲酸
将实施例107的产物(20mg,0.04mmol)和LiOH·H2O(16.8mg,0.4mmol)在1∶1∶1的THF/甲醇/水(3ml)中搅拌48小时并浓缩。使残留物溶于1M氢氧化钠(2ml)中,用乙醚洗涤,用1M HCl处理至pH3,用乙酸乙酯提取。干燥(硫酸钠)提取物、过滤并浓缩,得到所需的化合物。MS(DCI/NH3)m/z 428(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,1H),7.73(m,2H),7.46(d,1H),7.35(t,1H),6.91(t,1H),6.83(s,1H),6.71(d,1H),6.55(dd,1H),6.46(dd,1H),6.22(d,1H),5.40(s,1H),3.78(s,3H),1.83(s,3H),1.24(s,3H),1.16(s,3H);C27H25NO4的分析计算值:C,72.86;H,5.89;N,3.28。
实测值:C,72.89;H,6.00;N,2.94。实施例1092,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-甲基-5-(2-丙烯基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例16的方法处理实施例52的产物和烯丙基三丁基锡,得到所需化合物。MS(DCI/NH3)m/z 438(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.99(d,1H),6.91(t,1H),6.80(m,3H),6.70(s,1H),6.68(d,1H),6.56(dd,1H),6.44(dd,1H),6.16(d,1H),5.78(ddt,1H),5.39(s,1H),4.94(dq,1H),4.88(dq,1H),3.78(s,3H),3.17(d,2H),2.13(s,3H),1.86(s,3H),1.22(s,3H),1.16(s,3H);C30H31NO2的分析计算值:C,82.35;H,7.14;N,3.20。
实测值:C,81.99;H,7.14;N,2.98。实施例1101-[3-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-5-甲基苯基]乙酮
用硅胶(1.0g)和甲酸(10滴)处理在二氯甲烷(20ml)中的实施例52的产物和三丁基(1-乙氧基乙烯基)锡,加热至40℃6小时,用水处理,用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸镁)、过滤并浓缩。残留物经硅胶快速层析纯化,用5-10%乙酸乙酯/己烷洗脱,得到所需的化合物。MS(DCI/NH3)m/z 440(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.61(s,1H),7.51(s,1H),7.28(s,1H),6.92(t,1H),6.80(s,1H),6.72(d,1H),6.56(dd,1H),6.49(dd,1H),6.24(m,1H),5.40(s,1H),3.78(s,3H),2.44(s,3H),2.26(s,3H),1.84(s,3H),1.23(s,3H),1.16(s,3H);实施例1113-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-5-三甲基苯甲醇
于0℃,用甲基氯化镁(3M在THF中,0.83μl)处理实施例110的产物(0.022g,0.050mmol)的THF(5ml)溶液,温热至室温,搅拌1小时,用饱和氯化铵处理,分离,用乙酸乙酯提取。用盐水洗涤提取物并干燥(硫酸镁)、过滤并浓缩得到所需的化合物。MS(DCI/NH3)m/z 456(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.98(d,1H),7.11(s,1H),7.08(s,1H),6.91(t,8H),6.78-6.63(m,3H),6.55(d,1H),6.46(d,1H),6.18(m,1H),5.39(s,1H),4.84(s,1H),3.73(s,3H),2.14(s,3H),1.88(s,3H),1.24(s,3H),1.23(s,3H),1.22(s,3H),1.16(s,3H)。实施例1125-[3-(2-呋喃基)苯基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例16的方法处理实施例52的产物和2-(三丁基甲锡烷基)呋喃,得到所需化合物。MS(DCI/NH3)m/z 456,450(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.0(d,1H),7.69(s,1H),7.48(d,1H),7.23(t,1H),7.05(d,1H),6.88(t,1H),6.81(s,2H),6.70(d,1H),6.54(m,2H),6.47(d,1H),6.23(s,1H),5.41(s,1H),3.78(s,3H),1.88(s,3H),1.24(s,3H),1.16(s,3H);C30H27NO3·H2O的分析计算值:C,77.07;H,6.25;N,3.00。
实测值:C,77.27;H,5.97;N,3.23。实施例1132,5-二氢-10-甲氧基-2,2,4-三甲基-5-[3-甲基-5-(1H-吡咯烷-1-基)苯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例17的方法处理实施例11的产物和吡咯烷,得到所需化合物。MS(DCI/NH3)m/z 467(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.97(d,1H),6.93(t,1H),6.67(s,1H),6.67(d,1H),6.56(d,1H),6.49(d,1H),6.22(s,1H),6.14(m,3H),5.39(s,1H),3.79(s,3H),3.04(m,4H),2.07(s,3H),1.92(s,3H),1.87(m,4H),1.21(s,3H),1.17(s,3H)。实施例1143-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-甲基)-5,N-二甲基苯胺
如同实施例17的方法处理实施例11的产物和甲胺,得到所需化合物。MS(DCI/NH3)m/z 427(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.98(d,1H),6.92(t,1H),6.67(d,1H),6.61(s,1H),6.56(d,1H),6.46(d,1H),6.18(br s,2H),6.14(br s,1H),6.10(s,1H),5.58(q,1H),5.38(br s,1H),3.79(s,3H),2.50(d,3H),2.04(s,3H),1.90(s,3H),1.22(s,3H),1.15(s,3H)。C28H30N2O2·0.5H2O的分析计算值:C,77.21;H,7.17;N,6.43。
实测值:C,77.65;H,7.13;N,5.97。实施例1153-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-5-甲基-N-(2-丙烯基)苯甲酰胺
如同实施例17的方法处理实施例11的产物和烯丙基胺,得到所需化合物。MS(DCI/NH3)m/z 453(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.98(d,1H),6.92(t,1H),6.67(d,1H),6.56(d,H),6.45(d,1H),6.24(br s,1H),6.14(m,3H),5.76(m,1H),5.63(t,1H),5.37(br s,1H),5.10(qd,1H),5.02(qd,1H),3.79(s,3H),3.50(m,2H),2.02(s,3H),1.89(s,3H),1.22(s,3H),1.15(s,3H)。C23H25NO2的分析计算值:C,79.51;H,7.25;N,4.03。
实测值:C,79.35;H,7.30;N,3.89。实施例1163-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-N-(2-甲氧基乙基)-5-甲基苯胺
如同实施例17的方法处理实施例11的产物和2-甲氧基乙胺,得到所需化合物。1H NME(300MHz,DMSO-d6)δ7.98(d,1H),6.95(t,1H),6.65(d,1H),6.60(s,1H),6.54(d,1H),6.44(d,1H),6.22(s,1H),6.17(s,2H),6.13(s,1H),5.41(t,10H),5.38(s,1H),3.79(s,3H),3.26(q,2H),3.20(s,3H),2.98(q,2H),2.03(s,3H),1.90(s,3H),1.22(s,3H),1.15(s,3H)。实施例1173-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-N-(2-丙烯基)苯胺
如同实施例17处理实施例52的产物和烯丙基胺,得到所需化合物。MS(DCI/NH3)m/z 439(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.99(d,1H),6.91(t,1H),6.86(t,1H),6.67(d,1H),6.63(s,1H),6.55(d,1H),6.44(m,2H),6.33(m,2H),6.14(d,1H),5.78(m,2H),5.37(s,1H),5.12(qd,1H),5.03(qd,1H),3.79(s,3H),3.51(m,2H),1.88(s,3H),1.22(s,3H),1.14(s,3H)。C29H30N2O2的分析计算值:C,79.42;H,6.89;N,6.39。
实测值:C,79.03;H,7.05;N,6.17。实施例118N’-[3-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)-5-甲基苯基]-N,N-二甲基脲
用1,4-二氮杂双环[2,2,2]辛烷(0.056g,0.495mmol)和氯代三(三苯膦)铑(I)(0.115g,0.124mmol)处理实施例115的产物(0.112g,0.247mmol)在10%乙醇/水(10ml)中的溶液,回流15小时,倾入5%HCl中,搅拌20分钟,用碳酸氢钠中和,用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸钠)、过滤并浓缩。残留物经硅胶快速层析纯化,用20-33%乙酸乙酯/己烷洗脱,得到所需的苯胺。
将该苯胺(0.030g,0.073mmol)溶于2∶1/甲苯:THF(7ml)中,顺序用二异丙基乙胺(38μl,0.218mmol)和N,N-二甲基氨基甲酰氯(20μl.0.218mmol)处理,回流18小时,冷却、用水处理,用乙酸乙酯提取。用盐水洗涤提取物,干燥(硫酸镁)、过滤并浓缩。残留物经硅胶快速层析纯化,用25-50%乙酸乙酯/己烷洗脱,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.15(s,1H),7.98(d,1H),7.10(br s,2H),6.91(t,1H),6.69(d,1H),6.63(s,1H),6.56(d,1H),6.54(s,1H),6.46(d,1H),6.16(br s,1H),5.38(s,1H),2.85(s,6H),2.09(s,3H),1.86(s,3H),1.24(s,3H),1.14(s,3H);C30H39N3O3的HRMS m/z计算值:484.2600(M+H)+。实测值:484.2601。实施例119N-[3-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)苯基]苯甲胺
如同实施例17的方法处理实施例11的产物和苄胺,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.97(d,1H),7.23(m,5H),6.80(m,2H),6.65(d,1H),6.59(s,1H),6.53(d,2H),6.49(s,1H),6.20(m,3H),6.16(t,1H),6.12(s,1H),5.35(s,1H),4.10(b,2H),3.78(s,3H),1.83(s,3H),1.22(s,3H),1.14(s,3H);C33H32O2N2的HRMS m/z计算值:488.2464(M+H)+。实测值:488.2468。实施例1205-[(3,5-二氯苯基)亚甲基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和3,5-二氯苄基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 464(M+H)+;1H NMR(300MHz,DMSO-d6)异构体1:δ8.17(d,1H),7.32(s,1H),6.96(s,2H),6.81-6.74(m,4H),6.45(s,2H),5.11(s,1H),3.93(s,3H),1.88(s,3H),1.22(s,3H),0.89(s,3H);异构体2:δ8.29(d,1H),7.78(s,2H),7.45(s,1H),7.23(t,1H),7.18(d,1H),7.16(d,1H),6.84(d,1H),6.66(s,1H),5.59(s,1H),5.47(s,1H),3.93(s,3H),1.96(s,3H),1.27(s,6H);C27H23Cl2NO2的HRMS m/z计算值:463.1106(M+H)+。实测值:463.1112。实施例1215-[(4-氯代苯基)亚甲基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和4-氯代苄基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 430(M+H)+;1H NMR(300MHz,DMSO-d6)异构体1:δ8.26(d,1H),7.75(d,Hz,2H),7.42(d,2H),7.18(t,2H),6.89(d,1H),6.74(d,1H),6.61(s,1H),5.54(s,1H),5.46(s,1H),3.91(s,3H),1.97(s,3H),1.26(s,6H);异构体2:δ8.13(s,1H),7.18(t,1H),7.04(d,2H),6.82-6.71(m,5H),6.46(s,1H),6.41(s,1H),5.04(s,1H),3.91(s,3H),1.84(s,3H),1.22(s,3H),0.90(s,3H);C27H24ClNO2的HRMS m/z计算值:429.1496(M+H)+。实测值:429.1500。实施例1222,5-二氢-10-甲氧基-2,2,4-三甲基-5-[[3-(三氟甲基)苯基]亚甲基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和3-三氟甲基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 464(M+H)+;1H NMR(300MHz,DMSO-d6)异构体1:δ8.28(d,1H),8.13(s,1H),7.98(d,1H),7.65-7.56(m,1H),7.33-7.39(m,1H),7.21(t,1H),6.83-6.78(m,2H),6.75(t,1H),6.64(s,1H),5.68(s,1H),5.48(s,1H),3.92(s,3H),1.99(s,3H),1.27(s,6H);异构体2:δ8.17(d,1H),7.65-7.56(m,1H),7.45(d,1H),7.39-7.33(m,1H),7.27(d,1H),7.17(t,1H),6.83-6.78(m,2H),6.75(t,1H),6.56(s,1H),6.40(s,1H),5.01(s,1H),3.92(s,3H),1.88(s,3H),1.19(s,3H),0.78(s,3H);C28H24F3NO2的HRMS m/z计算值:463.1759(M+H)+。实测值:463.1762。实施例1235-[(2,6-二氟苯基)亚甲基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和2,6-二氟苄基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 432(M+H)+;1H NMR(300MHz,DMSO-d6)异构体1:δ8.32(d,1H),7.19-7.08(m,3H),6.92(t,1H),6.81-6.76(m,2H),6.64(s,1H),6.54(d,1H),5.49(s,1H),5.46(s,1H),3.92(s,3H),2.11(s,3H),1.25(s,6H);异构体2:δ8.18(d,1H),7.38(t,1H),7.19-7.08(m,3H),6.81-6.76(m,2H),6.67(d,1H),6.21(s,1H),6.19(s,1H),4.96(s,1H),3.93(s,3H),1.91(s,3H),1.16(s,3H),0.61(s,3H);C27H23F2NO2的HRMS m/z计算值:431.1697(M+H)+。实测值:431.1704。实施例1245-[(2-氯代苯基)亚甲基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和2-氯代苄基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 430(M+H)+;1H NMR(300MHz,DMSO-d6)异构体1:δ8.11(d,1H),7.47(d,1H),7.40(d,1H),7.23-7.10(m,3H),6.84-6.74(m,2H),6.71(s,1H),6.66(s,1H),6.01(s,1H),5.47(s,1H),3.93(s,3H),2.02(s,3H),1.25(s,6H);异构体2:δ8.27(d,1H),8.18(d,1H),7.41(t,1H),7.26(d,1H),7.01(t,1H),6.84-6.74(m,4H),6.47(s,1H),6.37(s,1H),5.00(s,1H),3.93(s,3H),1.88(s,3H),1.18(s,3H),0.73(s,3H);C27H24ClNO2的HRMS m/z计算值:429.1496(M+H)+。实测值:429.1497。实施例1255-[(2,6-二氯苯基)亚甲基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和2,6-二氯苄基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 464(M+H)+;1H NMR(300MHz,DMSO-d6)异构体1:δ8.27(d,1H),7.16(m,2H),7.07(t,1H),6.81-6.76(m,3H),6.68(d,1H),6.30(s,1H),5.47(s,1H),4.90(s,1H),3.93(s,3H),1.96(s,3H),1.15(s,3H),0.59(s,3H);异构体2:δ8.37(d,1H),7.45(d,2H),7.31(t,1H),7.16(m,2H),6.77(m,1H),6.65(s,1H),6.44(d,1H),6.34(s,1H),5.60(s,1H),3.91(s,3H),2.20(s,3H),1.25(s,6H);C27H23Cl2NO2的HRMS m/z计算值:463.1106(M+H)+。实测值:463.1114。实施例1265-[(2-氟代苯基)亚甲基]-2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和2-氟代苄基溴化镁,得到所需化合物。MS(DCI/NH3)m/z 414(M+H)+;1H NMR(300MHz,DMSO-d6)异构体1:δ8.30(d,1H);8.23(m,1H),7.28(m,1H),7.19(t,1H),7.18(d,1H),6.93-6.75(m,3H),6.76(d,1H),6.65(s,1H),5.77(s,1H),5.49(s,1H),3.93(s,3H),2.01(s,3H),1.25(s,6H);异构体2:δ8.17(d,1H),7.28(m,2H),7.18(d,1H),7.14-7.06(m,2H),6.79(m,2H),6.72(d,1H),6.41(s,1H),6.38(s,1H),5.00(s,1H),3.93(s,3H),1.87(s,3H),1.18(s,3H),0.76(s,3H);C27H24FNO2的HRMS m/z计算值:413.1791(M+H)+。实测值:413.1788。实施例1272,5-二氢-10-甲氧基-2,2,4-三甲基-5-[(4,5-二氢-4,4-二甲基-2-噁唑基)亚甲基]-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和4,4-二甲基-2-噁唑啉-2-甲基锂,得到所需化合物。MS(DCI/NH3)m/z 417(M+H)+;1H NMR(300MHz,DMSO-d6)异构体1:δ8.34(d,1H),7.19(t,1H),6.83-6.78(m,2H),6.74-6.70(m,2H),5.48(s,1H),5.08(s,1H),3.98(s,2H),3.92(s,3H),1.99(s,3H),1.22(s,3H),1.20(s,9H);异构体2:δ8.06(d,1H),7.14(m,1H),6.80(m,1H),6.76(m,1H),6.72(m,1H),6.42(s,1H),5.96(s,1H),5.35(s,1H),3.90(s,3H),3.72(m,2H),1.93(s,3H),1.32(s,3H),1.20(s,6H),1.11(s,3H);C26H28N2O3的HRMS m/z计算值:417.2178(M+H)+。实测值:417.2176。实施例1282,5-二氢-10-甲氧基-2,2,4-三甲基-5-(2-吡啶基亚甲基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和2-甲基吡啶基锂,得到所需化合物。MS(DCI/NH3)m/z 397(M+H)+;1H NMR(300MHz,DMSO-d6)异构体1:δ8.50(m,1H),8.31(d,1H),8.25(d,1H),7.83(t,1H),7.20(d,1H),7.19(m,1H),6.95(d,1H),6.83(d,1H),6.78(d,1H),6.64(s,1H),5.77(s,1H),5.49(s,1H),3.92(s,3H),2.00(s,3H),1.27(s,6H);异构体2:δ8.43(m,1H),8.15(d,1H),7.48(t,1H),7.22(d,1H),7.15(d,1H),7.08(m,1H),6.88(d,1H),6.78(d,1H),6.77(t,1H),6.46(s,1H),6.38(s,1H),4.99(s,1H),3.92(s,3H),1.87(s,3H),1.21(s,3H),0.89(s,3H);C26H24N2O2的HRMS m/z计算值:397.1916(M+H)+。实测值:397.1923。实施例1292,5-二氢-10-甲氧基-2,2,4-三甲基-5-(2-噻吩基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和2-噻吩基锂,得到所需化合物。MS(DCI/NH3)m/z 391(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.38(d,1H),6.95(dd,1H),6.93(s,1H),6.81(dd,1H),6.68(d,1H),6.65(d,1H),6.64(d,1H),6.46(d,1H),6.21(d,1H),5.39(s,1H),3.81(s,3H),1.95(d,3H),1.21(s,3H),1.15(s,3H)。实施例1302,5-二氢-9,10-二甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同流程1和2所述处理1,2,4-三甲氧基苯得到所需化合物。MS(DCI/NH3)m/z 378(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.93(d,1H),6.82(d,1H),6.61(dd,2H),6.22(d,1H),5.81(ddt,1H),5.70(dd,1H),5.44(s,1H),5.01(m 2H),3.76(s,3H),3.67(s,3H),2.35(m,2H),2.16(s,3H),1.17(s,3H),1.16(s,3H)。实施例1315-(2-环己烯-1-基)-2,5-二氢-9,10-二甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如实施例130中所述处理1,2,4-三甲氧基苯,但用3-三甲基甲硅烷基环己烯代替烯丙基三甲基硅烷,得到所需化合物。MS(DCI/NH3)m/e 418(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.03(d,1H),8.01(d,1H),6.83(d,1H),6.82(d,1H),6.60-6.69(m,4H),6.31(d,1H),6.27(d,1H),5.6-5.8(m,4H),5.35-5.52(m,4H),5.11(m,1H),5.09(m,1H),3.77(s,6H),3.69(s,3H),3.68(s,3H),2.25(m,4H),2.13(s,3H),2.10(s,3H),1.95(m,4H),1.6(m,4H),1.31(s,3H),1.29(s,3H),1.07(s,3H),1.04(s,3H)。(249978)实施例1322,5-二氢-10-甲氧基-5-(3-甲基-3-丁烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和3-甲基-1-三甲基甲硅烷基-2-丁烯(根据Fleming等,Synthesis 1979,446.制备),得到所需化合物。MS(DCI/NH3)m/e(M+H)+376;1H NMR(300MHz,DMSO-d6)δ8.10(d,J=8Hz,1H),7.01(d,J=8Hz,1H),6.65(d,J=8Hz,1H),6.62(d,J=8Hz,1H),6.49(d,J=8Hz,1H),6.25(br s,1H),5.57(s,1H),5.55(dd,J=17,11Hz,1H),5.41(s,1H),4.64-4.56(m,2H),3.83(s,3H),2.14(s,3H),1.31(s,3H),1.01(s,3H),0.86(s,3H),0.83(s,3H);13C NMR(100MHz,DMSO-d6)δ156.31,153.48,145.02,143.74,133.05,128.73,127.10,126.82,126.27,119.20,118.15,114.05,113.11,110.85,109.36,105.24,78.33,55.69,49.12,44.84,29.53,26.14,23.53,23.43,23.35;C25H29NO2·1/4H2O的分析计算值:C,79.02;H,7.82;N,3.69。
实测值:C,79.09;H,7.94;N,3.59。实施例1332,5-二氢-10-甲氧基-5-(5,5-二甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和5,5-二甲基-1-三甲基甲硅烷基-2-环己烯(根据Tsuji等,j.Org.Chem.1996,61,5779的方法,由5,5-二甲基-3-环己烯-1-醇制备),得到所需化合物,为1.8∶1的不可分离的非对映体混合物。主要成分:MS(DCI/NH3)m/e(M+H)+416;1H NMR(300MHz,DMSO-d6)δ8.08(d,J=8Hz,1H),7.07(d,J=8Hz,1H),6.69(d,J=8Hz,1H),6.64(d,J=8Hz,1H),6.25(br s,1H),5.58(m,1H),5.62-5.71(m,1H),5.46(s,1H),5.45(d,J=10Hz,1H),3.86(s,3H),2.41-2.33(m,1H),2.11(s,3H),1.84-1.72(m,1H),1.68-1.48(m,2H),1.30(s,3H),1.35-1.21(m,1H),1.01(s,3H),0.76(s,3H),0.53(s,3H);C28H33NO2·1/2H2O的分析计算值:C,79.21;H,8.07;N,3.30。
实测值:C,79.31;H,7.75;N,3.11。次要成分1H NMR(300MHz,DMSO-d6)δ8.02(d,J=8Hz,1H),7.09(t,J=8Hz,1H),6.70(d,J=8Hz,1H),6.64(d,J=8Hz,1H),6.57(d,J=8Hz,1H),6.20(br s,1H),5.60-5.52(m,1H),5.50(d,J=10Hz,1H),5.14(m,1H),5.41(m,1H),3.86(s,3H),2.41-2.33(m,1H),2.09(s,3H),1.91-1.78(m,1H),1.68-1.48(m,2H),1.35-1.21(m,1H),1.28(s,3H),1.07(s,3H),0.92(s,3H),0.51(s,3H)。实施例134rel(5R,2’R)2,5-二氢-10-甲氧基-5-(2-氧代-3-四氢吡喃基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和3,4-二氢-6-(三甲基甲硅烷氧基)-2H-吡喃,得到41%的实施例134的产物和48%的实施例135的产物。MS(DCI/NH3)m/e 406(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.12(d,J=8Hz,1H),7.05(t,J=8Hz,1H),6.67(d,J=8Hz,1H),6.63(d,J=9Hz,1H),6.49(d,J=8Hz,1H),6.42(d,J=5Hz,1H),6.21(d,J=2Hz,1H),5.44(br s,1H),4.35-4.00(m,2H),3.86(s,3H),2.77-2.67(m,1H),2.17(s,3H),2.01-1.50(m,4H),1.27(s,3H),1.01(s,3H);13C NMR(100MHz,DMSO-d6)δ169.93,156.40,152.16,145.53,133.80,128.46,127.75,127.20,126.66,117.38,116.74,113.45,112.07,109.23,109.19,105.44,98.19,72.79,69.09,55.62,49.44,46.37,29.45,27.13,23.20,21.46,20.22,19.61;C25H27NO4·1/2H2O的分析计算值:C,72.44;H,6.81;N,3.38。
实测值:C,72.66;H,6.92;N,2.91。实施例135反式(5R,2’S)2,5-二氢-10-甲氧基-5-(2-氧代-3-四氢吡喃基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和3,4-二氢-6-(三甲基甲硅烷氧基)-2H-吡喃,得到41%的实施例135的产物和48%的实施例135A的产物。MS(DCI/NH3)m/e 406(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.12(d,J=8Hz,1H),7.05(t,J=8Hz,1H),6.67(d,J=8Hz,1H),6.63(d,J=9Hz,1H),6.49(d,J=8Hz,1H),6.42(d,J=5Hz,1H),6.21(d,J=2Hz,1H),5.44(br s,1H),4.35-4.00(m,2H),3.86(s,3H),2.77-2.67(m,1H),2.17(s,3H),2.01-1.50(m,4H),1.27(s,3H),1.01(s,3H);13C NMR(100MHz,DMSO-d6)δ169.93,156.40,152.16,145.53,133.80,128.46,127.75,127.20,126.66,117.38,116.74,113.45,112.07,109.23,109.19,105.44,98.19,72.79,69.09,55.62,49.44,46.37,29.45,27.13,23.20,21.46,20.22,19.61;C25H27NO4·1/2H2O的分析计算值:C,72.44;H,6.81;N,3.38。
实测值:C,72.66;H,6.92;N,2.91。实施例135A反式(5R,2’S)2,5-二氢-10-甲氧基-5-(2-氧代-3-四氢吡喃基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/e 406(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.06(d,J=9Hz,1H),7.06(d,J=8Hz,1H),6.70(d,J=8Hz,1H),6.65(d,J=9Hz,1H),6.50(d,J=8Hz,1H),6.27(d,J=8Hz,1H),6.21(d,J=2Hz,1H),5.46(s,1H),4.01-4.10(m,2H),3.87(s,3H),2.81(m,1H),2.14(m,3H),1.68-1.61(m,2H),1.27(s,3H),1.16-1.36(m,2H),1.03(s,3H);13C NMR(100MHz,DMSO-d6)δ172.14,156.33,150.95,145.21,134.18,127.71,127.38,127.20,126.73,118.09,116.66,113.53,112.78,110.56,105.45,71.40,66.76,55.52,49.49,29.46,27.38,23.69,21.05,20.79;C25H27NO4·1/4H2O的分析计算值:C,73.24;H,6.76;N,3.42。
实测值:C,72.89;H,7.07;N,3.05。实施例1362,5-二氢-10-甲氧基-5-(3-环戊烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和环戊烯-2-基三甲基硅烷,得到所需化合物,为两种非对映体(1.5∶1)的不可分离的混合物。MS(DCI/NH3)m/z 374(M+H)+;1H NMR(300MHz,DMSO-d6)主要的非对映体:δ8.05(d,1H),7.09(t,1H),6.72(d,1H),6.66(d,1H),6.58(d,1H),6.19(s,1H),5.77(ddd,1H),5.50(d,1H),5.43(s,1H),5.19(ddd,1H),3.87(s,3H),2.90(m,1H),2.43-2.15(m,2H),2.09(s,3H),1.97-1.70(m,2H),1.31(s,3H),1.09(s,3H);次要的非对映体:δ8.07(d,1H),7.08(t,1H),6.70(d,1H),6.66(d,1H),6.61(d,1H),6.22(s,1H),5.82-5.70(m,2H),5.48(d,1H),5.41(d,1H),3.88(s,3H),2.92(m,1H),2.30(m,1H),2.20(m,1H),2.15(s,3H),1.50(m,2H),1.33(s,3H),1.05(s,3H);C25H27NO2的HRMS m/z计算值:373.2042。实测值:373.2049。实施例1372,5-二氢-10-甲氧基-5-(3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和环己烯-2-基三甲基硅烷,得到所需化合物,为两种非对映体(1.1∶1)的不可分离的混合物。MS(DCI/NH3)m/z 388(M+H)+;1H NMR(300MHz,DMSO-d6)主要的非对映体:δ8.05(d,1H),7.06(t,1H),6.67(d,1H),6.64(d,1H),6.59(d,1H),6.19(s,1H),5.82(m,1H),5.72(m,1H),5.41(s,1H),5.40(d,1H),3.87(s,3H),2.29(m,1H),2.13(s,3H),1.95-1.80(m,2H),1.72-1.50(m,2H),1.38-1.10(m,2H),1.30(s,3H),1.02(s,3H);次要的非对映体:δ8.03(d,1H),7.07(t,1H),6.68(d,1H),6.63(d,1H),6.57(d,1H),6.15(s,1H),5.62(m,1H),5.54(m,1H),5.46(s,1H),5.09(m,1H),3.85(s,3H),2.29(m,1H),2.10(s,3H),1.95-1.80(m,2H),1.72-1.50(m,2H),1.38-1.10(m,2H),1.28(s,3H),1.05(s,3H);C26H29NO2的HRMS m/z计算值:387.2198。实测值:387.2206。实施例1382,5-二氢-10-甲氧基-5-(3-丁烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和2-丁烯基三甲基硅烷,得到所需化合物,为两种非对映体(1.3∶1)的不可分离的混合物。MS(DCI/NH3)m/z 362(M+H)+;1H NMR(300MHz,DMSO-d6)主要的非对映体:δ8.04(d,1H),7.05(t,1H),6.69(d,1H),6.64(d,1H),6.47(d,1H),6.16(s,1H),5.88(ddd,1H),5.54(d,1H),5.46(s,1H),4.93(ddd,1H),4.74(ddd,1H),3.86(s,3H),2.37(bm,1H),2.17(s,3H),1.30(s,3H),1.02(s,3H),0.71(d,3H);次要的非对映体:δ8.03(d,1H),7.08(t,1H),6.67(d,1H),6.64(d,1H),6.58(d,1H),6.10(s,1H),5.51(ddd,1H),5.47(d,1H),5.40(s,1H),4.78(ddd,1H),4.74(ddd,1H),3.86(s,3H),2.38(bm,1H),2.11(s,3H),1.28(s,3H),1.05(s,3H),1.01(d,3H);C24H27NO2的分析计算值:C,79.74;H,7.53;N,3.87。
实测值:C,79.41;H,7.63;N,3.43。实施例1392,5-二氢-10-甲氧基-5-(1-乙烯基-1-环己基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和2-亚环己基乙基三甲基硅烷,得到所需化合物。MS(DCI/NH3)m/z416(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.10(d,1H),7.00(t,1H),6.63(d,1H),6.60(dd,1H),6.47(dd,1H),6.20(dd,1H),5.45(s,1H),5.40(s,1H),5.14(dd,1H),4.81(dd,1H),4.53(dd,1H),3.85(s,3H),2.15(s,3H),1.78(m,1H),1.45-0.80(m,9H),1.32(s,3H),1.03(s,3H);C28H33NO2的分析计算值:C,80.93;H,8.00;N,3.37。
实测值:C,80.57;H,8.02;N,3.22。实施例1402,5-二氢-10-甲氧基-5-(4,4-二甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和(4,4-二甲基环己烯-2-基)三甲基硅烷,得到所需化合物,为非对映体的不可分离的混合物(2∶1)。MS(DCI/NH3)m/z 416(M+H)+;1H NMR(300MHz,DMSO-d6)主要的非对映体:δ8.07(d,1H),6.99(t,1H),6.63(d,1H),6.62(d,1H),6.48(d,1H),6.23(s,1H),5.72(d,1H),5.48(m,1H),5.40(m,2H),3.84(s,3H),2.16(s,3H),2.05(m,1H),1.75(bm,2H),1.30(s,3H),1.12(m,2H),1.02(s,6H),0.51(s,3H);次要的非对映体:δ8.04(d,1H),7.06(t,1H),6.68(d,1H),6.62(d,1H),6.57(d,1H),6.19(s,1H),5.68(dd,1H),5.50-5.38(m,3H),3.86(s,3H),2.14(s,3H),2.08(m,1H),1.71(m,1H),1.42(m,1H),1.30(s,3H),1.07(m,2H),1.02(s,3H),0.91(s,3H),0.84(s,3H);C28H33NO2的HRMSm/z计算值:415.2511。实测值:415.2527。实施例1412,5-二氢-10-甲氧基-5-(1-亚甲基-2-环己基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和1-(三甲基甲硅烷基甲基)环己烯,得到所需化合物,为非对映体的不可分离的混合物(4∶1)。MS(DCI/NH3)m/z 402(M+H)+;1H NMR(300MHz,DMSO-d6)主要的非对映体:δ8.07(d,1H),7.03(t,1H),6.65(d,1H),6.63(d,1H),6.40(d,1H),6.22(s,1H),5.89(d,1H),4.75(d,1H),4.56(d,1H),3.87(s,3H),2.38(m,1H),2.23(m,1H),2.21(s,3H),1.97(bm,2H),1.55-1.05(m,6H),1.34(s,3H),1.01(s,3H);次要的非对映体:δ8.09(d,1H),7.05(t,1H),6.68(d,1H),6.57(d,1H),6.56(d,1H),6.11(s,1H),5.86(d,1H),5.40(s,1H),4.33(d,1H),3.91(d,1H),3.87(s,3H),2.48(m,1H),2.22(m,1H),2.20(s,3H),1.94(bm,1H),1.75-1.05(m,6H),1.29(s,3H),0.97(s,3H);C27H31NO2的HRMSm/z计算值:401.2355。实测值:401.2351。实施例1422,5-二氢-10-甲氧基-5-(1-氧代-2-环己基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和1-(三甲基甲硅烷氧基)环己烯,得到所需化合物,为单一非对映体。MS(DCI/NH3)m/z404(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.04(d,1H),7.02(t,1H),6.67(d,1H),6.63(d,1H),6.39(d,1H),6.37(d,1H),6.17(s,1H),5.44(s,1H),3.80(s,3H),2.70(ddd,1H),2.25(m,2H),2.15(s,3H),1.84(bm,1H),1.62-1.25(m,4H),1.28(s,3H),1.09(m,1H),1.00(s,3H);C26H29NO3的HRMSm/z计算值:403.2147。实测值:403.2142。实施例143
2,5-二氢-10-甲氧基-5-(3-环辛烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和环辛烯-2-基三甲基硅烷,得到所需化合物,为两种非对映体的不可分离的混合物(7∶5)。MS(DCI/NH3)m/z416(M+H)+;1H NMR(300MHz,DMSO-d6)主要的非对映体:δ8.03(dd,1H),7.07(t,1H),6.62(d,1H),6.57(d,1H),6.39(d,1H),6.17(s,1H),5.59(m,2H),5.44(s,1H),5.14(dd,1H),3.88(s,3H),2.18(s,3H),2.04-0.84(m,17H);次要的非对映体:δ8.00(d,1H),7.00(t,1H),6.70(d,1H),6.66(d,1H),6.58(d,1H),6.12(s,1H),5.59(m,2H),5.48(s,1H),5.38(dd,1H),3.88(s,3H),2.18(s,3H),2.04-0.84(m,17H);C28H33NO2的HRMSm/z计算值:415.2511。实测值:415.2498。实施例1442,5-二氢-10-甲氧基-5-(3-环庚烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和环庚烯-2-基三甲基硅烷,得到所需化合物,为两种非对映体的不可分离的混合物(1∶1)。MS(DCI/NH3)m/z402(M+H)+;1H NMR(300MHz,DMSO-d6)非对映体A:δ8.04(d,1H),7.04(t,1H),6.68(d,1H),6.63(d,1H),6.51(d,1H),6.22(s,1H),5.97(m,1H),5.73(m,1H),5.58(m,1H),5.47(s,1H),3.87(s,3H),2.42-0.98(m,18H);非对映体B:δ8.01(d,1H),7.08(t,1H),6.70(d,1H),6.62(d,1H),6.56(d,1H),6.21(s,1H),5.58(m,2H),5.49(s,1H),5.32(m,1H),3.87(s,3H),2.42-0.98(m,18H);C27H31NO2的HRMSm/z计算值:401.2355。实测值:401.2351。实施例1452,5-二氢-10-甲氧基-5-(1-环己烯基甲基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和2-亚甲基环己基二甲基苯基硅烷,得到所需化合物。MS(DCI/NH3)m/z402(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.96(d,1H),7.05(t,1H),6.68(d,1H),6.58(d,1H),6.45(d,1H),6.10(s,1H),5.85(dd,1H),5.43(s,1H),5.18(bs,1H),3.85(s,3H),2.45-1.12(m,19H);C27H31NO2的HRMS m/z计算值:401.2355。实测值:401.2342。C27H31NO2的分析计算值:C,80.76;H,7.78;N,3.49。
实测值:C,80.76;H,8.00;N,3.25。实施例1462,5-二氢-10-甲氧基-5-(3,3-二甲基-6-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和(6,6-二甲基环己烯-2-基)二甲基苯基硅烷,得到所需化合物,为非对映体的不可分离混合物(5∶1)。MS(DCI/NH3)m/z416(M+H)+;1H NMR(300MHz,DMSO-d6)主要的非对映体:δ8.04(d,1H),7.06(t,1H),6.68(d,1H),6.63(d,1H),6.58(d,1H),6.21(s,1H),5.67(dd,1H),5.49-5.38(m,3H),3.86(s,3H),2.29-0.82(m,20H);次要的非对映体:δ8.01(d,1H),7.07(t,1H),6.68(d,1H),6.63(d,1H),6.57(d,1H),6.16(s,1H),5.56-5.33(m,3H),4.97(dd,1H),3.86(s,3H),2.29-0.82(m,20H);C28H33NO2的HRMSm/z计算值:415.2511。实测值:415.2527。C28H33NO2的分析计算值:C,80.93;H,8.00;N,3.37。
实测值:C,80.92;H,7.98;N,3.25。实施例1472,5-二氢-10-甲氧基-5-(2-溴代-3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和(2-溴代烯丙基)三甲基硅烷,得到所需化合物。MS(DCI/NH3)m/z426(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.08(t,1H),6.72(d,1H),6.62(d,1H),6.47(d,1H),6.17(s,1H),6.02(dd,1H),5.51(d,1H),5.47(s,1H),5.42(s,1H),3.87(s,3H),2.89(dd,1H),2.44(dd,1H),2.26(s,3H),1.17(s,3H),1.15(s,3H)。C23H24NO2Br的分析计算值:C,64.79;H,5.67;N,3.29。
实测值:C,64.70;H,5.65;N,3.09。实施例148-150
如同实施例2的方法处理实施例2B的产物(1.25g,3.70mmol)和1-[1’-叔丁基二甲基甲硅烷氧基-1’-甲氧基亚烷基]-2-环己烯,得到不饱和酯加成物的非对映体混合物(1.21g,73%),其可带入下一步骤。
将上面的混合物(1.20g,2.69mmol)溶于THF(100ml)中,冷却至0℃,通过注射器用Dibal-H(13.5ml 1M/己烷溶液,13.5mmol)缓慢处理,搅拌30分钟,用250ml饱和酒石酸钠钾水溶液和300ml乙酸乙酯稀释并搅拌过夜。分层,用乙酸乙酯提取水相两次,用盐水洗涤合并的有机层并干燥(MgSO4)。经硅胶层析纯化产生的残留物,用20%-30%甲基叔丁基醚的己烷液洗脱,得到实施例148-150。实施例148rel(5R,3’R)2,5-二氢-10-甲氧基-5-(1-羟甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/e418(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,J=8Hz,1H),7.07(t,J=8Hz,1H),6.69(d,J=8Hz,1H),6.63(d,J=9Hz,1H),6.57(d,J=8Hz,1H),6.17(d,J=2Hz,1H),5.50(d,J=10Hz,1H),5.39(br s,1H),5.05(br s,1H),4.42(t,1H),3.85(s,3H),3.64(d,J=6Hz,2H),2.27(n,1H),2.05(s,3H),1.95-1.86(m,2H),1.78-1.21(m,4H),1.28(s,3H),1.09(s,3H);C27H31NO3·1/2H2O的分析计算值:C,76.03;H,7.56;N,3.28。
实测值:C,76.34;H,7.71;N,3.20。实施例149rel(5R,3’S)2,5-二氢-10-甲氧基-5-(1-羟甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/e418(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.40(d,J=9Hz,1H),7.07(d,J=8Hz,1H),6.67(d,J=8Hz,1H),6.63(d,J=8Hz,1H),6.59(d,J=8Hz,1H),6.20(d,J=8Hz,1H),6.20(s,1H),5(78,J=sHz,1H),5.45(s,1H),5.37(d,J=10Hz,1H),4.60(dd,J=5Hz,1H),3.85(s,3H),3.75(s,2H),2.37(m1H),2.12(s,3H),1.70(m,2H),1.60(m,1H),1.30(s,3H),1.15(m,2H),1.02(s,3H);13C NMR(75MHz,DMSO-d6)δ156.3,151.5,145.0,139.6,133.7,130.2,128.0,127.1,126.9,120.8,120.3,118.5,116.5,113.0,110.2,105.2,105.2,76.2,65.1,55.6,49.4,36.9,29.6,26.8,23.7,21.3。实施例1502,5-二氢-10-甲氧基-5-(3-羟甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/e418(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.06(d,J=8Hz,1H),7.01(t,J=8Hz,1H),6.59(d,J=8Hz,1H),6.52(d,J=8Hz,1H),6.27(s,1H),6.03(s,1H),5.38(s,1H),5.23(m,1H),4.75(m,2H),3.81(s,3H),3.47(m,1H),2.95(m,1H),2.19(s,3H),1.70-1.35(m,6H),1.31(s,3H),1.03(s,3H);13CNMR(75MHz,DMSO-d6)δ156.4,154.4(145.1),132.9,129.2,128.0,127.6,126.9,126.1,119.3,118.6,114.3,113.1,109.0,105.5,73.5,64.4,55.9,49.2,48.6,29.7,26.5,25.6,24.3,23.5,18.3;C27H31NO3·1/4H2O的分析计算值:C,76.84;H,7.52;N,3.32。
实测值:C,76.93;H,7.73;N,3.18。实施例1512,5-二氢-10-甲氧基-5-(3-吲哚基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例2的方法处理实施例2B的产物和吲哚,得到所需化合物。MS(DCI/NH3)m/e423(M+H)+;1H NMR(300MHz,DMSO-d6)δ10.89(d,1H),8.01(d,1H),7.83(dd,1H),7.27(dd 1H),7.04(m,3H),6.80(t,1H),6.68(d,1H),6.54(s,1H),6.53(d,1H),6.28(d,1H),6.12(s,1H),5.35(s,1H),3.83(s,3H),1.89(s,3H),1.22(s,3H),1.14(s,3H);C28H26N2O2的分析计算值:C,79.59;H,6.20;N,6.62。
实测值:C,79.58;H,6.28;N,6.36。实施例152rel(5S,3’S)2,5-二氢-10-甲氧基-5-(1-甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例148的产物(0.512g,1.23mmol)溶于二氯甲烷(5ml)中,冷却至0℃,用(i-Pr)2NEt(0.32ml,1.84mmol)、甲磺酰氯(0.11ml,1.47mmol)处理,搅拌1小时。滴加三乙基硼氢化锂(4.70ml的1M/THF溶液,4.70mmol)处理该反应混合物,搅拌60分钟,用10ml 1M氢氧化钠、0.6ml 30%H2O2处理,搅拌2小时,用乙酸乙酯提取。用水、饱和碳酸氢钠水溶液、盐水洗涤有机层,干燥(硫酸镁)并浓缩。残留物经硅胶层析纯化,用5%,接着用7%乙酸乙酯的己烷液洗脱,得到为无色泡沫状的0.362g(74%)所需产物。MS(DCI/NH3)m/e402(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,J=8Hz,1H),7.06(t,J=8Hz,1H),6.68(d,J=8Hz,1H),6.64(d,J=8Hz,1H),6.56(d,J=8Hz,1H),6.16(s,1H),5.49(d,J=10Hz,1H),5.41(br s,1H),4.83(br s,1H),3.85(s,3H),2.31-2.17(m,1H),2.06(s,3H),1.99-1.21(m,6H),1.49(s,3H),1.29(s,3H),1.08(s,3H)。实施例153rel(5R,3’S)2,5-二氢-10-甲氧基-5-(1-甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例152的方法处理实施例149的产物,得到所需化合物。MS(DCI/NH3)m/e402(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.04(d,J=9Hz,1H),7.07(d,J=8Hz,1H),6.68(d,J=8Hz,1H),6.63(d,J=9Hz,1H),6.61(d,J=8Hz,1H),6.22(d,J=2Hz,1H),5.55(br s,1H),5.45(br s,1H),5.35(d,J=10Hz,1H),3.86(s,3H),2.34-2.18(m,1H),2.12(s,3H),1.97-0.88(m,6H),1.61(s,3H),1.30(s,3H),1.02(s,3H)。C27H31NO2·1/4H2O的分析计算值:C,79.87;H,7.82;N,3.45。
实测值:C,79.81;H,8.28;N,3.39。实施例154(-)(5S,3’S)2,5-二氢-10-甲氧基-5-(1-甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例152的产物经(R,R)WHELK-O1柱的HPLC,用2%乙醇的己烷液洗脱,得到所需化合物。[α]D 20-155.9°(c0.85,CHCl3);MS(DCI/NH3)m/e402(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,J=9Hz,1H),7.06(d,J=8Hz,1H),6.68(d,J=8Hz,1H),6.64(d,J=9Hz,1H),6.57(d,J=8Hz,1H),6.20(d,J=2Hz,1H),5.49(d,J=10Hz,1H),5.42(br s,1H),4.83(br s,1H),3.85(s,3H),2.30-2.18(m,1H),2.06(s,3H),1.97-1.20(m,6H),1.49(s,3H),1.29(s,3H),1.08(s,3H);C27H31NO2·1/4H2O的分析计算值:C,79.87;H,7.82;N,3.45。
实测值:C,79.80;H,8.15;N,3.41。实施例155(-)(5S,3’R)2,5-二氢-10-甲氧基-5-(1-羟甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例149的产物经(R,R)WHELK-O1柱的HPLC,用6%乙醇的己烷液洗脱,得到所需化合物。[α]D 20-233.9°(c1.27,CHCl3);MS(DCI/NH3)m/z418(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.05(d,J=9Hz,1H),7.08(d,J=8Hz,1H),6.68(d,J=8Hz,1H),6.63(d,J=9Hz,1H),6.61(d,J=8Hz,1H),6.23(br s,1H),5.78(br s,1H),5.46(br s,1H),5.37(d,J=10Hz,1H),4.65(t,J=6Hz,1H),3.86(s,3H),3.76(m,2H),2.36-2.22(m,2H),2.12(s,3H),1.87-1.77(m,2H),1.65-1.53(m,1H),1.30(s,3H),1.27-0.92(m,2H),1.02(s,3H)。实施例156(+)(5R,3’S)2,5-二氢-10-甲氧基-5-(1-羟甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例149的产物经(R,R)WHELK-O1柱的HPLC,用6%乙醇的己烷液洗脱,得到所需化合物。[α]D 20+234.6°(c1.10,CHCl3);MS(DCI/NH3)m/e418(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.05(d,J=9Hz,1H),7.07(t,J=8Hz,1H),6.68(d,J=8Hz,1H),6.63(d,J=9Hz,1H),6.61(d,J=8Hz,1H),6.22(br s,1H),5.78(br s,1H),5.45(br s,1H),5.37(d,J=10Hz,1H),4.63(t,J=6Hz,1H),3.86(s,3H),3.78-3.73(m,2H),2.36-2.22(m,2H),2.12(s,3H),1.87-1.77(m,2H),1.65-1.52(m,1H),1.34-0.93(m,2H),1.30(s,3H),1.02(s,3H)。实施例157(-)(5S,3’R)2,5-二氢-10-甲氧基-5-(1-甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例例152的方法处理实施例155的产物,得到所需化合物。MS(DCI/NH3)m/e(M+H)+402;1H NMR(300MHz,DMSO-d6)δ8.04(d,J=8Hz,1H),7.07(d,J=8Hz,1H),6.68(d,J=8Hz,1H),6.63(d,J=8Hz,1H),6.62(d,J=8Hz,1H),6.23(br s,1H),5.55(br s,1H),5.45(br s,1H),5.35(d,J=10Hz,1H),3.86(s,3H),2.33-2.18(m,1H),2.12(s,3H),1.95-1.45(m,4H),1.61(s,3H),1.34-0.88(m,2H),1.30(s,3H),1.02(s,3H);[α]D 20-224.1°(c 0.73,CHCl3);C27H31NO2·1/2H2O的分析计算值:C,78.99;H,7.86;N,3.41。
实测值:C,79.14;H,8.07;N,3.03。实施例158(+)(5R,3’S)2,5-二氢-10-甲氧基-5-(1-甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例152的方法处理实施例156的产物,得到所需化合物。MS(DCI/NH3)m/e402(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.04(d,J=9Hz,1H),7.07(d,J=8Hz,1H),6.67(d,J=8Hz,1H),6.63(d,J=9Hz,1H),6.59(d,J=8Hz,1H),6.22(br s,1H),5.55(m,1H),5.45(br s,1H),5.35(d,J=10Hz,1H),3.86(s,3H),2.27(m,1H),2.12(s,3H),1.94-1.05(m,6H),1.61(s,3H),1.30(s,3H),1.02(s,3H)。实施例1592,5-二氢-10-甲氧基-5-(1-氯代甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例148的产物(0.110g,0.264mmol)与甲磺酰氯(49μl,0.632mmol)、(i-Pr)2NEt(53μl,0.695mmol)、氯化锂(11mg,0.264mmol)在含有2滴DMF的2ml THF中混合,于室温下搅拌该反应混合物数小时。用乙酸乙酯稀释该反应混合物并用饱和碳酸氢盐水溶液、盐水洗涤,经硫酸镁干燥,经硅胶层析纯化,用20%乙酸乙酯的己烷液洗脱,得到为泡沫状的106mg(92%)所需化合物。MS(DCI/NH3)m/e436(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.03(d,J=8Hz,1H),7.08(t,J=8Hz,1H),6.66(dd,J=8Hz,2H),6.55(d,J=8Hz,1H),6.25(br s,1H),5.53(d,J=10Hz,1H),5.39(s,1H),5.25(s,1H),3.91(s,2H),3.84(s,3H),2.30(m,1H),2.05(s,3H),1.35-2.00(m,6H),1.30(s,3H),1.10(s,3H)。实施例160rel(5R,3’R)2,5-二氢-10-甲氧基-5-(1-甲氧基甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例152的方法处理实施例148的产物,但用甲醇钠代替三乙基硼氢化锂,得到所需化合物。MS(DCI/NH3)m/e432(M+H)+ 1H NMR(400MHz,DMSO-d6)δ8.02(d,J=9Hz,1H),7.07(t,J=8Hz,1H),6.69(d,J=9Hz,1H),6.64(d,J=9Hz,1H),6.57(d,J=9Hz,1H),5.53(d,J=10Hz,1H),5.11(s,1H),3.85(s,3H),3.58(dd,J=12+32Hz,1H),3.06(s,3H),2.30(br m,1H),2.07(s,3H),1.50-2.00(br m,4H),1.35(m,1H),1.30(s,3H),1.10(s,3H);13C NMR(100MHz,DMSO-d6)δ156.2,150.9,145.0,137.0,133.7,133.6,130.4,128.1,127.1,127.1,123.5,117.9,116.4,113.5,113.1,110.1,105.4,105.3,105.0,76.2,75.4,56.4,55.6,49.5,36.9,29.7,23.4,25.5,25.3,25.2,24.2,20.2。实施例161rel(5R,3’R)2,5-二氢-10-甲氧基-5-(1-甲硫基甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例152的方法处理实施例148的产物,但用硫代甲醇钠(sodium thiomethoxide)代替三乙基硼氢化锂,得到为白色泡沫状的所需化合物。MS(DCI/NH3)m/e448(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,J=8Hz,1H),7.08(t,J=8Hz,1H),6.69(d,J=8Hz,1H),6.65(d,J=9Hz,1H),6.57(d,J=9Hz,1H),6.23(s,1H),5.49(d,J=10Hz,1H),5.40(s,1H),5.00(s,1H),3.86(s,2H),2.30(br m,2H),2.07(s,3H),1.81(s,3H),1.40-1.78(br m,6H),1.30(s,3H),1.09(s,3H);13C NMR(100MHz,DMSO-d6)δ156.2,151.0,145.0,135.7,133.8,130.3,128.2,127.1,127.1,123.5,118.1,116.5,113.4,113.1,110.1,105.3,75.7,55.5,49.5,40.8,37.5,29.7,27.3,26.2,25.7(24.2),20.6,13.7。实施例162rel(5R,3’S)2,5-二氢-10-甲氧基-5-(1-乙酰氧基甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例149的产物(0.100g,0.239mmol)与乙酸酐(27μl,0.288mmol)、DMAP(2mg,催化量)、(i-Pr)2NEt(50μl,0.288mmol)在二氯甲烷(6ml)中混合。于室温下搅拌该反应混合物1小时,用乙酸乙酯稀释并用饱和碳酸氢盐水溶液、盐水洗涤,干燥(硫酸镁)、经硅胶层析纯化,用20%乙酸乙酯的己烷液洗脱,得到为白色固体的89mg(81%)所需化合物。MS(DCI/NH3)m/e460(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.05(d,J=8Hz,1H),7.08(d,J=8Hz,1H),6.68(d,J=8Hz,1H),6.64(d,J=8Hz,1H),6.62(d,J=8Hz,1H),6.23(s,1H),5.82(s,1H),5.46(s,1H),5.40(d,J=10Hz,1H),4.38(s,2H),3.86(s,3H),2.33(br m,1H),2.12(s,3H),2.03(s,3H),1.85(br m,2H),1.60(br m,1H),1.30(s,3H),1.02-1.28(br m,3H),1.02(s,3H)。C29H33NO4的分析计算值:C,75.79;H,7.24;N,3.05。
实测值:C,76.14;H,7.47;N,3.02。实施例163rel(5R,3’R)2,5-二氢-10-甲氧基-5-(1-乙酰氧基甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例162的方法处理实施例148的产物,得到为白色固体的所需化合物。MS(DCI/NH3)m/e460(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,J=8Hz,1H),7.08(t,J=8Hz,1H),6.70(d,J=8Hz,1H),6.65(d,J=8Hz,1H),6.58(d,J=8Hz,1H),6.18(s,1H),5.55(d,J=10Hz,1H),5.39(s,1H),5.16(s,1H),4.22(s,2H),3.85(s,3H),2.40(br,J=8Hz,1H),2.06(s,3H),1.96(s,3H),1.32-1.95(br m,3H),1.28(s,3H),1.06(s,3H);C29H33NO4的分析计算值:C,75.79;H,7.24;N,3.05。
实测值:C,75.53;H,7.32;N,2.84。实施例164rel(5R,3’R)2,5-二氢-10-甲氧基-5-(1-甲氧基甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例152的方法处理实施例149的产物,但用甲醇钠代替三乙基硼氢化锂,得到为白色泡沫状的所需化合物。MS(DCI/NH3)m/e432(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.05(d,J=9Hz,1H),7.07(t,J=8Hz,1H),6.67(d,J=8Hz,1H),6.64(d,J=8Hz,1H),6.60(d,J=8Hz,1H),6.59(d,J=8Hz,1H),6.20(s,1H),5.78(s,1H),5.45(s,1H),5.39(d,J=10Hz,1H),3.70(s,2H),3.14(s,3H),2.30(br m,1H),2.12(s,3H),1.81(br m,2H),1.60(br m,1H),1.30(s,3H),1.15(br m,2H),1.02(s,3H);C28H33NO3·1/4H2O的分析计算值:C,77.12;H,7.74;N,3.21。
实测值:C,77.17;H,7.55;N,3.15。实施例165rel(5R,3’R)2,5-二氢-10-甲氧基-5-(1-(N,N-二甲基氨基)甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例152的方法处理实施例148的产物,但用二甲胺代替三乙基硼氢化锂,得到为白色泡沫状的所需化合物。MS(DCI/NH3)m/e445(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,J=8Hz,1H),7.07(t,J=8Hz,1H),6.69(d,J=8Hz,1H),6.64(d,J=8Hz,1H),6.57(d,J=8Hz,1H),6.22(s,1H),5.50(d,J=10Hz,1H),5.39(s,1H),5.03(s,1H),3.85(s,3H),2.62(d,J=11Hz,1H),2.50(d,J=11Hz,1H),2.25(br s,1H),2.06(s,6H),1.98(s,3H),1.40-1.95(br m,6H),1.30(s,3H),1.25(br m,1H),1.11(s,3H);C29H36N2O2·3/4H2O的分析计算值:C,76.03;H,8.25;N,6.11。
实测值:C,75.90;H,7.81;N,5.90。实施例166rel(5R,3’S)2,5-二氢-10-甲氧基-5-(1-甲硫基甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例152的方法处理实施例149的产物,但用硫代甲醇钠代替三乙基硼氢化锂,得到为白色泡沫状的所需化合物。MS(DCI/NH3)m/e448(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.05(d,J=9Hz,1H),7.07(t,J=8Hz,1H),6.68(d,J=8Hz,1H),6.63(d,J=8Hz,1H),6.61(d,J=8Hz,1H),6.24(s,1H),5.71(s,1H),5.46(s,1H),5.39(d,J=10Hz,1H),3.86(s,3H),3.02(s,2H),2.17-2.41(br m,2H),2.11(s,3H),1.91-2.10(br m,2H),1.88(s,3H),1.30(s,3H),1.25(s,3H),1.05-1.25(br m,3H),1.02(s,3H);C28H33NO2S·1/2H2O的分析计算值:C,73.65;H,7.50;N,3.07。
实测值:C,73.37;H,7.46;N,2.97。实施例167rel(5R,3’R)2,5-二氢-10-甲氧基-5-(1-(N-吗啉代)甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例152的方法处理实施例148的产物,但用吗啉代替三乙基硼氢化锂,得到为白色泡沫状的所需化合物。MS(DCI/NH3)m/e487(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,J=9Hz,1H),7.07(t,J=8Hz,1H),6.68(d,J=8Hz,1H),6.65(d,J=8Hz,1H),6.56(d,J=8Hz,1H),6.22(s,1H),5.49(d,J=11Hz,1H),5.41(s,1H),5.04(s,1H),3.85(s,3H),3.52(br s,3H),2.68(d,J=12Hz,1H),2.56(d,J=12Hz,1H),2.25(br s,1H),2.15(br s,2H),2.05(s,3H),1.40-2.00(br m,6H),1.32(s,3H),1.20-1.28(br m,6H),1.17(s,3H);C31H38N2O3的分析计算值:C,76.51;H,7.87;N,5.76。
实测值:C,76.24;H,8.05;N,5.52。实施例168rel(5R,3’R)2,5-二氢-10-甲氧基-5-(1-(N-甲基-N-甲基磺酰基氨基)甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于0℃,将实施例170的产物(0.80g,0.186mmol)与甲磺酰氯(15μl,0.195mmol)、(i-Pr)2NEt(48μl,0.279mmol)和THF混合1.5小时。将该产物直接加入硅胶塞柱中,用己烷,接着用40%乙酸乙酯的己烷液洗脱,得到为白色固体的88mg(93%)所需化合物。MS(DCI/NH3)m/e509(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,J=9Hz,1H),7.08(t,J=8Hz,1H),6.69(d,J=8Hz,1H),6.65(d,J=9Hz,1H),6.58(d,J=9Hz,1H),6.20(s,1H),5.53(d,J=5Hz,1H),5.41(s,1H),5.11(s,1H),3.85(s,3H),3.46(d,J=13Hz,1H),3.24(d,J=13Hz,1H),2.82(s,3H),2.53(s,3H),2.30(br,1H),2.08(s,2H),1.5-2.0(br m,6H),1.35(br m,1H),1.30(s,3H),1.25(m,1H),1.11(s,3H);C29H36N2O4S的分析计算值:C,68.47;H,7.13;N,5.51。
实测值:C,68.20;H,7.09;N,5.36。实施例169rel(5R,3’S)2,5-二氢-10-甲氧基-5-(1-(N,N-二甲基氨基)甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例152的方法处理实施例149的产物,但用二甲胺代替三乙基硼氢化锂,得到为白色泡沫状的所需化合物。MS(DCI/NH3)m/e 445(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.05(d,J=9Hz,1H),7.05(t,J=8Hz,1H),6.67(d,J=8Hz,1H),6.63(d,J=8Hz,1H),6.60(d,J=8Hz,1H),6.213(s,1H),5.69(s,1H),5.46(s,1H),5.42(d,J=10Hz,1H),3.86(s,3H),2.70(br,1H),2.30(br m,1H),2.11(s,3H),2.05(br,4H),1.85(br,2H),1.56(m,1H),1.30(s,3H),1.10-1.25(m,3H),1.02(s,3H);C29H36N2O2·1/2H2O的分析计算值:C,76.79;H,8.22;N,6.18。
实测值:C,76.49;H,8.23;N,5.95。实施例170rel(5R,3’R)2,5-二氢-10-甲氧基-5-(1-(N-甲基氨基)甲基-3-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例152的方法处理实施例148的产物,但用甲胺代替三乙基硼氢化锂,得到为白色泡沫状的所需化合物。MS(DCI/NH3)m/e431(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,J=8Hz,1H),7.05(t,J=8Hz,1H),6.68(d,J=7Hz,1H),6.63(d,J=7Hz,1H),6.57(d,J=7Hz,1H),6.22(s,1H),5.76(s,1H),5.53(d,J=10Hz,1H),5.41(s,1H),5.14(br s,1H),3.85(s,3H),3.02(s,2H),2.30(br m,1H),2.22(s,3H),2.07(s,3H),1.74(br m,2H),1.80-1.4(br m,4H),1.30(s,3H),1.25(s,1H),1.10(s,3H);C28H33N2O2·1.25H2O的分析计算值:C,74.22;H,8.12;N,6.18。
实测值:C,74.05;H,7.81;N,6.00。实施例1712,5-二氢-10-甲氧基-5-(2-甲基-3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
用氮气使实施例147的产物(51mg,0.12mmol)和四甲基锡(66.5μl,0.048mmol)在1ml HMPA中的溶液脱气20分钟。加入二氯代双(三苯膦)钯(II)(9.8mg,0.012mmol),加热该反应混合物至85℃60小时,冷却至室温,与30ml乙酸乙酯和30ml饱和KF水溶液一起剧烈搅拌3小时。使该混合物通过硅藻土塞柱过滤,分离各层。用水、盐水洗涤有机层并干燥(硫酸钠)。浓缩后经硅胶层析(15%乙酸乙酯/己烷),得到所需化合物。MS(DCI/NH3)m/z362(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.94(d,1H),7.05(t,1H),6.68(d,1H),6.58(d,1H),6.42(d,1H),6.12(d,1H),5.91(dd,1H),5.44(s,1H),4.77(s,1H),4.54(s,1H),3.87(s,3H),2.43(m,1H),2.20(s,3H),2.09(m,1H),1.74(s,3H),1.16(s,3H)。C24H27NO2的HRMS m/z计算值:361.2042。实测值:361.2047。实施例1722,5-二氢-10-甲氧基-5-(1,3-丁二烯-2-基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据前述实施例的方法,处理实施例147的产物和三丁基(乙烯基)锡,得到所需化合物。MS(DCI/NH3)m/z374(M+H)+。1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.05(t,1H),6.70(dd,1H),6.60(d,1H),6.47(dd,1H),6.36(dd,1H),6.18(d,1H),5.95(dd,1H),5.43(s,1H),5.16(s,1H),5.12(s,1H),5.05(d,1H),5.00(d,1H),3.87(s,3H),2.55(dd,1H),2.22(dd,1H),2.10(s,3H),1.20(s,3H),1.12(s,3H)。实施例1732,5-二氢-10-甲氧基-5-(2-甲酯基-3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例147的产物(64mg,0.15mmol)、双(三苯膦)二羰基镍(144mg,0.225mmol)和三乙胺(42μl,0.30mmol)在5ml甲醇中的混合物回流16小时,冷却、在乙酸乙酯和水之间分配。用盐水洗涤有机层、干燥(硫酸钠)并浓缩。残留物经快速硅胶层析纯化(15%乙酸乙酯/己烷),得到所需化合物。MS(DCI/NH3)m/z406(M+H)+。1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.06(t,1H),6.70(dd,1H),6.60(d,1H),6.41(dd,1H),6.12(dd,1H),6.01(dd,1H),5.43(s,1H),5.36(s,1H),3.87(s,3H),3.68(s,3H),2.60(dd,1H),2.43(dd,1H),2.21(s,3H),1.20(s,3H),1.12(s,3H)。C25H27NO4的分析计算值:C,74.05;H,6.71;N,3.45。
实测值:C,73.81;H,6.61;N,3.38。实施例1742,5-二氢-10-甲氧基-5-(1,2-二羟基-3-丙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于0℃,用OsO4(370μl,0.144mmol)处理实施例2的产物(50mg,0.144mmol)的吡啶(3ml)溶液,于室温下搅拌48小时,用饱和亚硫酸氢钠(3ml)水溶液处理,搅拌4小时并通过Celite过滤。用乙酸乙酯反复洗涤Celite塞柱。用水、盐水洗涤有机滤液、干燥(硫酸钠)并浓缩。残留物经快速硅胶层析纯化(95∶5二氯甲烷/甲醇),得到所需化合物,为两种非对映体的不可分离的混合物(2∶1)。MS(DCI/NH3)m/z382(M+H)+。1H NMR(300MHz,DMSO-d6);主要的非对映体:δ7.94(d,1H),7.05(t,1H),6.67(d,1H),6.57(d,1H),6.53(d,1H),6.13-6.05(m,2H),5.42(s,1H),4.80(d,1H),4.38(t,1H),3.85(s,3H),3.65(bm,1H),3.19-3.00(m,2H),2.21(s,3H),1.83(m,2H),1.19(s,3H),1.11(s,3H);次要的非对映体:δ7.96(d,1H),7.07(t,1H),6.68(d,1H),6.58(d,1H),6.55(d,1H),6.13(s,1H),5.97(dd,1H),5.42(s,1H),4.50(t,1H),4.45(d,1H),3.85(s,3H),3.45-3.30(m,3H),2.23(s,3H),1.80-1.58(m,2H),1.21(s,3H),1.09(s,3H);C23H27NO4·0.35H2O的分析计算值:C,71.24;H,7.20;N,3.61。
实测值:C,71.24;H,7.28;N,3.49。实施例1752,5-二氢-10-甲氧基-5-(1,2-环氧-3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例174的产物(50mg,0.13mmol)、三苯膦(38mg,0.14mmol)、偶氮二羧酸二乙酯(25mg,0.14mmol)和3埃分子筛(50mg)在苯(5ml)中的混合物回流48小时,冷却、在乙酸乙酯和水之间分配。用水、盐水洗涤有机层、干燥(硫酸钠)并浓缩。残留物经快速硅胶层析纯化(8∶2己烷/乙酸乙酯),得到所需化合物,为两种非对映体的不可分离的混合物(1.3∶1)。MS(DCI/NH3)m/z364(M+H)+。1H NMR(300MHz,DMSO-d6);主要的非对映体:δ7.93(d,1H),7.09(t,1H),6.72(d,1H),6.60(d,1H),6.58(d,1H),6.14(s,1H),5.95(m,1H),5.44(s,1H),3.85(s,3H),3.04(m,1H),2.72(dd,1H),2.35(dd,1H),2.17(s,3H),2.05-1.35(m,2H),1.16(s,3H),1.14(s,3H);次要的非对映体:δ7.95(d,1H),7.08(t,1H),6.71(d,1H),6.59(d,1H),6.57(d,1H),6.15(s,1H),5.93(m,1H),5.44(s,1H),3.85(s,3H),2.90(m,1H),2.65(dd,1H),2.28(m,1H),2.17(s,3H),2.05-1.58(m,2H),1.17(s,3H),1.13(s,3H);C23H35NO3的HRMSm/z计算值:363.1834。实测值:363.1846。实施例1762,5-二氢-10-甲氧基-5-(1-(N-苯二酰亚氨基)-3-丙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例69的产物(250mg,0.68mmol)、苯邻二甲酰亚胺(103mg,0.7mmol)、三苯膦(184mg,0.7mmol)和偶氮二羧酸二乙酯(110μl,0.7mmol)在THF(15ml)中搅拌24小时,在乙酸乙酯和水之间分配。用水、盐水洗涤有机层、干燥(硫酸钠)并浓缩。残留物经快速硅胶层析纯化(3∶1己烷/乙酸乙酯),得到所需化合物。MS(DCI/NH3)m/z495(M+H)+。1H NMR(300MHz,DMSO-d6)δ7.88(d,1H),7.81(s,4H),6.82(t,1H),6.58(d,1H),6.42(d,1H),6.40(d,1H),6.10(s,1H),5.61(dd,1H),5.40(s,1H),3.78(s,3H),3.48(t,2H),2.16(s,3H),1.75-1.40(bm,4H),1.22(s,3H),1.16(s,3H);C31H30N2O4的HRMSm/z计算值:494.2206。实测值:494.2198。实施例1772,5-二氢-10-甲氧基-5-(1-氨基-3-丙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
用肼(12.8mg,0.4mmol)在回流的乙醇(8ml)中处理实施例176的产物(118mg,0.24mmol)16小时,冷却、过滤除去固体。浓缩滤液并经快速硅胶层析纯化(9.5∶0.5二氯甲烷/甲醇),得到所需化合物。MS(DCI/NH3)m/z365(M+H)+。1H NMR(300MHz,DMSO-d6)δ7.94(d,1H),7.05(t,1H),6.68(d,1H),6.57(d,1H),6.54(d,1H),6.08(s,1H),5.66(dd,1H),5.43(s,1H),3.85(s,3H),2.43(t,2H),2.17(s,3H),1.80-1.22(m,4H),1.16(s,3H),1.15(s,3H);C23H28N2O2·0.30H2O的分析计算值:C,74.69;H,7.79;N,7.57。
实测值:C,74.50;H,7.78;N,7.31。实施例1782,5-二氢-10-甲氧基-5-(1-(肼基羰基氨基)-3-丙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
用三光气(19mg,0.0646mmol)和三乙胺(50μl,0.36mmol)在回流的THF(6ml)中处理实施例177的产物(65mg,0.178mmol)3小时,冷却并浓缩得到粗品异氰酸酯。
用肼(4.5mmol)处理在THF(10ml)中的粗品异氰酸酯(0.089mmol),在氮气下搅拌2小时,浓缩,残留物经快速硅胶层析纯化(9∶1二氯甲烷/甲醇),得到所需化合物。MS(DCI/NH3)m/z423(M+H)+ 1H NMR(300MHz,DMSO-d6)δ7.94(d,1H),7.06(t,1H),6.79(br,1H),6.68(dd,1H),6.57(d,1H),6.54(dd,1H),6.22(bt,1H),6.10(d,1H),5.63(dd,1H),5.44(s,1H),3.96(bs,2H),3.85(s,3H),2.92(m,2H),2.15(s,3H),1.58-1.20(m,4H),1.16(s,3H),1.15(s,3H);C24H30N4O3的HRMS(M+H)+m/z计算值:423.2396。实测值:423.2413。实施例179(E)2,5-二氢-10-甲氧基-5-(2-甲酯基-1-乙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例44的产物(0.087g,0.26mmol)溶于二氯甲烷(10ml)中,冷却至-23℃,滴加0.52ml 1M Dibal-H/庚烷溶液(0.52mmol)进行处理,搅拌1小时。将该反应混合物倾入30ml的0.5M HCl中,搅拌30分钟,用乙酸乙酯提取,用盐水洗涤合并的有机物,干燥(硫酸钠)得到为黄色泡沫状的中间体醛。
将产生的黄色泡沫物溶于THF(8ml)中,冷却至0℃,用(三苯基亚正膦基(phosphoranylidene))乙酸甲酯(0.130g,0.39mmol),于室温下搅拌过夜,然后于45℃搅拌1小时。使该反应混合物冷却,用饱和氯化铵水溶液稀释,用乙酸乙酯提取,用盐水洗涤合并的有机物并干燥(硫酸镁)。产生的残留物经硅胶柱层析纯化,用90∶10-己烷∶乙酸乙酯洗脱,得到0.043g(42%)所需化合物,为黄色泡沫物。MS(DCI/NH3)m/e392(M+H)+。1H NMR(300MHz,DMSO-d6)δ7.99(d,J=9Hz,1H),7.05(t,J=8Hz,1H),6.86(dd,J=4,16Hz,1H),6.69(d,J=7Hz,1H),6.67(d,J=9Hz,1H),6.61(d,J=8Hz,1H),6.41(dd,J=2,4Hz,1H),6.26(d,J=2Hz,1H),5.63(dd,J=2,16Hz,1H),5.45(br s,1H),3.84(s,3H),3.56(s,3H),2.08(s,3H),1.19(s,3H),1.15(s,3H);13C NMR(100MHz,DMSO-d6)δ165.19,156.18,151.64,146.45,145.59,133.53,128.39,127.17,123.57,117.17,116.54,113.85,109.82,105.78,71.93,55.80,55.59,51.57,49.75,29.56,29.15,28.70,23.45;C24H25NO4·1/4H2O的分析计算值:C,72.80;H,6.49;N,3.54。
实测值:C,73.00;H,6.56;N,3.34。实施例180(Z)-2,5-二氢-10-甲氧基-5-(1-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例187的方法处理实施例179的中间体醛和乙基三苯基碘化鏻,得到所需化合物。MS(DCI/NH3)m/e348(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.90(d,J=8Hz,1H),6.97(t,J=6Hz,1H),6.67(d,J=8Hz,1H),6.52(d,J=8Hz,1H),6.48(d,J=12Hz,1H),6.26(d,J=7Hz,1H),6.10(s,1H),5.59(m,1H),5.41(s,2H),3.83(s,3H),2.08(s,3H),1.79(d,J=7Hz,3H),1.23(s,3H),1.11(s,3H)。13C NMR(125MHz,DMSO-d6)δ156.1,152.4,145.4,132.4,131.0,130.2,127.7,127.2,127.0,126.7,116.9,116.4,113.7,113.0,109.9,105.4,69.4,55.6,49.7,29.6,28.3,23.0,13.8;C23H25O2N·1.0H2O的分析计算值:C,75.59;H,7.45;N,3.83。
实测值:C,75.53;H,7.20;N,3.62。实施例181(E)2,5-二氢-10-甲氧基-5-(3-羟基-1-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于室温下,滴加15ml三氯化铝(0.230g,1.72mmol)的醚溶液处理氢化铝锂(0.200g,5.17mmol)的20ml醚悬浮液,搅拌15分钟,滴加20ml实施例179产物的醚溶液。于室温下搅拌1小时后,小心加入2ml水,接着滴加15%氢氧化钠,直至白色糊状物沉积于容器底部。倾出醚溶液,用乙醚洗涤该糊状物数次,用盐水洗涤合并的有机物并干燥(硫酸镁)。残留物经硅胶柱层析纯化,用25%及随后33%的乙酸乙酯的己烷液洗脱,得到0.195g(78%)所需化合物,为无色泡沫物。1H NMR(300MHz,DMSO-d6)δ7.95(d,J=8Hz,1H),7.01(t,J=8Hz,1H),6.64(d,J=9Hz,1H),6.61(d,J=9Hz,1H),6.52(d,J=8Hz,1H),6.18(br d,J=4Hz,1H),6.08(s,1H),5.73-5.66(m,1H),5.51(5.43,J=m Hz,1H),5.41(s,1H),4.65(t,J=5Hz,1H),3.83(s,3H),3.77(t,J=5Hz,2H),2.12(s,3H),1.19(s,3H),1.13(s,3H);C23H25NO3的MS(FAB)m/e计算值:363.183。实测值:363.1839。实施例182(E)2,5-二氢-10-甲氧基-5-(3-(N,N-二甲基氨基羰基氧基)-1-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于室温下,将实施例181的产物(0.035g,0.096mmol)溶于DMF(5ml)中,用氢化钠(0.012g,60%分散于油中,0.289mmol)中,搅拌10分钟,滴加N,N-二甲基氨基甲酰氯(44μl,0.481mmol)进行处理并搅拌30分钟。用10ml饱和氯化铵水溶液稀释该反应混合物,用乙酸乙酯提取,用水、盐水洗涤有机层,干燥(硫酸镁)、浓缩并经硅胶层析纯化,用25%接着用33%的乙酸乙酯的己烷液洗脱,得到0.033g(79%)所需化合物,为无色泡沫物。MS(DCI/NH3)m/e509(M+H)+。1H NMR(300MHz,DMSO-d6)δ7.94(d,J=9Hz,1H),7.02(t,J=8Hz,1H),6.66(d,J=8Hz,1H),6.63(d,J=9Hz,1H),6.53(d,J=8Hz,1H),6.17(m,2H),5.82(dd,J=16,4Hz,1H),5.49-5.42(m,1H),5.42(s,1H),4.31(d,J=6Hz,2H),3.82(s,3H),2.71(m,6H),2.09(s,3H),1.20(s,3H),1.12(s,3H);13C NMR(100MHz,DMSO-d6)δ156.1,155.1,151.8,145.4,133.0,131.5,130.0,129.8,127.6,127.0,126.8,117.3,116.9,113.7,113.5,110.0,105.6,72.9,63.8,55.7,55.6,49.7,29.3,28.5,28.4,23.3;C26H30N2O4的MS(FAB)m/e计算值:434.2206。实测值:434.2209。实施例183(E)2,5-二氢-10-甲氧基-5-(3-甲氧基甲氧基-1-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例181的产物(0.026g,0.072mmol)溶于二氯乙烷(5ml)中,冷却至0℃,用(i-Pr)2NEt(62μl,0.358mmol)和氯代甲基甲醚(16μl,0.215mmol)先后进行处理,移去冷浴,将该混合物加热至55℃14小时。使该混合物在乙酸乙酯和饱和氯化铵水溶液之间分配,用盐水洗涤有机层,干燥(硫酸镁)并经硅胶层析纯化,用10%乙酸乙酯的己烷液洗脱,得到0.012g(41%)所需化合物,为琥珀色油状物。1H NMR(300MHz,DMSO-d6)δ7.94(d,J=8Hz,1H),7.02(t,J=8Hz,1H),6.66(d,J=9Hz,1H),6.63(d,J=9Hz,1H),6.53(d,J=8Hz,1H),6.19(br,d J=3Hz,1H),6.14(d,J=2Hz,1H),5.78(dd,J=16,4Hz,1H),5.42(s,1H),4.31(ABq,J=8,6Hz,2H),3.84(m,2H),3.82(s,3H),3.09(s,3H),2.11(s,3H),1.20(s,3H),1.13(s,3H);C25H29NO4的MS(FAB)m/e计算值:407.2097。实测值:407.2090。实施例1842,5-二氢-10-甲氧基-5-(3-羟基-3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例44的产物(0.58g,1.74mmol)溶于二氯甲烷(40ml)中,冷却至-45℃,滴加2.09ml 1M Dibal-H/庚烷溶液(2.09mmol)进行处理,搅拌1小时。将该反应混合物倾入75ml的0.5M HCl中,搅拌30分钟,用乙酸乙酯提取,用盐水洗涤合并的有机物,干燥(硫酸钠)并浓缩得到0.55g为黄色泡沫状的粗品醛。
将得到的醛(0.048g,0.143mmol)溶于THF(5ml)中,冷却至0℃,然后用乙烯基溴化镁(0.72ml 1M/THF,0.72mmol)缓慢处理。搅拌15分钟后,将该混合物在乙酸乙酯和盐水之间分配,用乙酸乙酯提取水层,用盐水洗涤合并的有机物、干燥(硫酸钠)、浓缩并经硅胶柱层析纯化,用20%乙酸乙酯的己烷液洗脱,得到所需化合物(0.027g,53%),为不可分离的非对映体的1∶1混合物。主要成分:1H NMR(300MHz,DMSO-d6)δ7.97(d,J=8Hz,1H),7.04(t,J=8Hz,1H),6.68(d,J=8Hz,1H),6.59(d,J=8Hz,1H),6.48(d,J=8Hz,1H),6.03(br s,1H),5.61(s,1H),5.46(m,1H),5.36(m,1H),4.97-5.10(m,1H),4.87(m,1H),3.94(m,1H),3.85(s,3H),2.19(s,3H),1.23(s,3H),1.10(s,3H);次要成分:MS(DCI/NH3)m/e364(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.02(d,J=8Hz,1H),7.07(t,J=8Hz,1H),6.68(d,J=8Hz,1H),6.62(d,J=8Hz,1H),6.61(d,J=8Hz,1H),6.16(br s,1H),5.95(m,1H),5.58(s,1H),5.41(s,1H),4.97-5.10(m,2H),3.94(m,1H),.3.85(s,3H),2.11(s,3H),1.27(s,3H),1.01(s,3H);MS(DCI/NH3)m/e(M+H)+364;C23H25NO3·3/4H2O的分析计算值:C,73.29;H,7.09;N,3.72。
实测值:C,73.67;H,6.80;N,3.81。实施例1852-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)乙酰基异羟肟酸甲酯
将实施例46的产物(0.150g,0.395mmol)滴加到N,O-二甲基羟胺盐酸盐(0.192g,1.98mmol)和三甲基铝(1.0ml,2.0mmol)的溶液中,于40℃加热产生的混合物2小时,用甲醇猝灭,并在二氯甲烷和饱和的Rochelle’s盐水溶液之间分配。用饱和碳酸氢钠水溶液、盐水洗涤有机层,干燥(硫酸镁)。粗产物经快速硅胶层析纯化,用4%接着用10%乙酸乙酯的二氯甲烷液洗脱,得到所需化合物(62%),为白色泡沫物。MS(DCI/NH3)m/e409(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.79(d,J=8Hz,1H),7.05(dd,J=8Hz,1H),6.73(d,J=8Hz,1H),6.61(d,J=8Hz,1H),6.48(d,J=8Hz,1H),6.25(dd,J=2+10Hz,1H),6.16(s,1H),5.43(s,1H),3.87(s,3H),3.25(br s,3H),3.04(br s,3H),2.34(m,1H),2.18(s,3H),1.17(s,6H);C24H28N2O4的分析计算值:C,70.57;H,6.91;N,6.86。
实测值:C,70.74;H,7.11;N,6.59。实施例1862-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)乙醛
将实施例185的产物(0.334g,0.817mmol)溶于THF(20ml)中,冷却至-78℃,用在甲苯中的1M Dibal-H溶液(1.71ml,1.71mmol)处理5分钟,搅拌1小时。将该反应混合物倾入饱和酒石酸钠钾中,分离各层,用二氯甲烷提取水相,用饱和碳酸氢钠水溶液、盐水洗涤合并的有机物,干燥(硫酸镁)并经硅胶柱层析纯化,用30%乙酸乙酯的己烷液洗脱,得到0.265g(93%)所需化合物,为无色泡沫物。MS(DCI/NH3)m/e250(M+H)+;1H NMR(300MHz,DMSO-d6)δ9.65(s,1H),7.95(d,J=9Hz,1H),7.05(dd,J=8Hz,1H),6.73(d,J=8Hz,1H),6.60(d,J=8Hz,1H),6.45(d,J=8Hz,1H),6.35(dd,J=3+10Hz,1H),6.20(s,1H),5.45(s,1H),3.85(s,3H),2.85(m,1H),2.60(m,1H),2.15(s,3H),1.17(s,3H),1.15(s,3H);C22H23NO3·1/4H2O的分析计算值:C,74.66;H,6.69;N,3.96。
实测值:C,74.32;H,6.30;N,3.86。实施例1872,5-二氢-10-甲氧基-5-(2-亚环己基乙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将环己基三苯基溴化鏻(Grim,S.O.;Ambrus,J.H.;J.Org.Chem.1968,33,2993-2994.)(0.234g,0.55mol)悬浮于(5∶3)THF∶乙醚(8.0ml)中,冷却至-10℃,用220μl的2.5M正丁基锂处理,搅拌10分钟。将实施例186的产物加入在THF的溶液中,于室温下搅拌该反应物12小时,回流15分钟并使之冷却。加入乙醚,过滤并浓缩该反应物。产生的残留物经硅胶层析纯化,用10∶1-5∶1的己烷∶乙酸乙酯洗脱,得到0.033g(51%)所需化合物。m.p.130-135℃;MS(DCI/NH3)m/e416(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.03(t,J=9Hz,1H),6.67(d,J=8Hz,1H),6.57(d,J=9Hz,1H),6.50(d,J=8Hz,1H),6.11(s,1H),5.64(dd,J=10,10Hz,1H),5.43(s,1H),5.04(t,J=7Hz,1H),3.85(s,3H),2.10(s,3H),2.0(b,2H),1.81(t,J=7Hz,2H),1.45(b,3H),1.3(b,3H),1.17(s,3H),1.15(s,3H);13C NMR(300MHz,DMSO-d6)δ165.0,151.1,145.4,140.5,133.41,132.2,127.5,127.0,126.8,116.5,116.3,116.0,113.0,110.3,105.3,73.9,55.5,49.6,36.6,30.5,28.9,28.7,28.1,27.9,27.0,26.2,23.8。实施例1882,5-二氢-10-甲氧基-5-(2-亚环戊基乙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例187的方法处理实施例186的产物和环戊基三苯基溴化鏻(Ramirez,F.;Levy,S.JACS 1957,79,67-69.),得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.94(d,J=9Hz,1H),7.02(t,J=8Hz,1H),6.67(d,J=8Hz,1H),6.57(d,J=9Hz,1H),6.48(d,J=7Hz,1H),6.10(s,1H),5.56(dd,J=10,8Hz,1H),5.43(s,1H),5.22(b,1H),3.85(s,3H),2.14(s,6H),1.77(b,2H),1.49(b,4H),1.17(s,3H),1.14(s,3H);13C NMR(75MHz,DMSO-d6)δ156.1,151.2,145.4,144.6,133.4,132.3,127.6,127.0,126.8,116.4,116.1,115.3,113.3,113.1,110.3,105.3,73.6,55.6,49.6,33.1,29.0,28.7,28.0,25.8,25.7,23.8;C27H32O2N的HRMS(FAB)m/e计算值:401.2355。实测值:401.2342。实施例1892,5-二氢-10-甲氧基-5-(2-亚环庚基乙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例186的方法处理实施例186的产物和环庚基三苯基溴化鏻(Albright,T.A.;Freeman,W.J.,Schweizer,E.E..JACS 1974,97,2942-2943.),得到所需化合物。MS(DCI/NH3)m/e430(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.94(d,J=9Hz,1H),7.02(t,J=8Hz,1H),6.67(d,J=8Hz,1H),6.57(d,J=9Hz,1H),6.49(d,J=8Hz,1H),6.12(s,1H),5.69(dd,J=10,9Hz,1H),5.43(s,1H),5.12(t,J=7Hz,1H),3.85(s,3H),2.13(s,6H),1.90(b,2H),1.38(b,3H),1.27(m,4H),1.17(s,3H),1.14(s,3H),0.82(m,3H);13C NMR(75MHz,DMSO-d6)δ156.1,151.1,145.4,142.2,133.4,132.2,128.6,127.6,127.0,126.8,120.0,116.3,116.0,113.0,110.3,105.3,73.6,65.7,55.6,49.6,37.3,33.2,31.1,29.8,29.3,29.0,29.0,28.6,28.5,26.2,23.8,23.2;C29H35O2N2·3/4H2O的分析计算值:C,72.70;H,8.52;N,2.92。
实测值:C,72.50;H,8.11;N,2.47。实施例1902,5-二氢-10-甲氧基-5-(3-甲基-2-丁烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例187的方法处理实施例186的产物和异丙基三苯基碘化鏻,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.94(d,J=8Hz,1H),7.37(s,1H),7.03(t,J=8Hz,1H),6.67(d,J=7Hz,1H),6.57(d,J=8Hz,1H),6.49(d,J=8Hz,1H),6.11(s,1H),5.65(dd,J=10,9Hz,1H),5.43(s,1H),5.12(t,J=7Hz,1H),3.85(s,3H),2.14(s,3H),1.63(s,3H),1.31(s,3H),1.17(s,3H),1.15(s,3H);13C NMR(100MHz,DMSO-d6)δ156.1,151.1,145.4,133.4,132.8,132.2,127.6,127.0,126.9,119.8,116.4,116.1,113.3,113.1,110.3,105.3,73.7,55.6,49.6,31.5,29.0,28.7,25.6,23.8,17.5;C25H29O2N的HRMS(FAB)m/e计算值:375.2198。实测值:375.2189。实施例191反式2,5-二氢-10-甲氧基-5-(2-丁烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例186的方法处理实施例186的产物和乙基三苯基溴化鏻,得到所需化合物。MS(DCI/NH3)m/e362(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.96(d,J=8Hz,1H),7.05(dd,J=8Hz,1H),6.70(d,J=8Hz,1H),6.60(d,J=8Hz,1H),6.51(d,J=8Hz,1H),6.10(s,1H),5.72(dd,J=4+10Hz,1H),5.45(m,3H),3.86(s,3H),2.43(m,1H),2.20(m,1H),2.15(s,3H),1.30(d,J=5Hz,3H),1.17(s,3H),1.15(s,3H)。实施例192反式2,5-二氢-10-甲氧基-5-(2-戊烯-1-基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例187的方法处理实施例186的产物(0.050g,0.143mmol)和丙基三苯基溴化鏻(165.6mg,0.429mmol),得到所需化合物。MS(DCI/NH3)m/e376(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.95(d,J=9Hz,1H),7.05(dd,J=8Hz,1H),6.70(d,J=8Hz,1H),6.60(d,J=8Hz,1H),6.50(d,J=8Hz,1H),6.09(s,1H),5.70(dd,J=3,10Hz,1H),5.44(s,1H),5.38(ss,J=5Hz,2H),3.86(s,3H),2.41(m,1H),2.19(m,1H),2.15(s,3H),1.70(m,2H),1.15(s,6H),0.75(t,J=7Hz,3H)。实施例1932,5-二氢-10-甲氧基-5-(1,1-二氟代-1-丙烯-3-基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例187的方法处理实施例186的产物(0.050g,0.143mmol)和二苯基正磷基二氟甲烷(Edwards,M.L.等,Tet.Let.1990,31,5571-74),得到所需化合物。1H NMR(300MHz,DMSO-d6)δ7.98(d,J=8Hz,1H),7.08(t,J=8Hz,1H),6.71(d,J=9Hz,1H),6.62(d,J=9Hz,1H),6.57(d,J=9Hz,1H),6.17(s,1H),5.73(dd,J=4,10Hz,1H),5.46(s,1H),4.53(m,1H),3.86(s,3H),2.32(m,1H),2.16(s,3H),2.11(m,1 H),1.17(s,3H),1.15(s,3H);HRMS(FAB)m/e的计算值:383.1697。实测值:383.1689。实施例194(E)2-(2,5-二氢-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-5-基)2-丁烯酸甲酯
根据实施例179的方法处理实施例186的产物(0.040g,0.115mmol)和(三苯基亚正磷基)乙酸甲酯(115mg,0.344mmol,Aldrich),得到0.037g(80%)所需化合物,为白色泡沫物。MS(DCI/NH3)m/e406(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.95(d,J=9Hz,1H),7.07(dd,J=8Hz,1H),6.85(m,1H),6.72(d,J=8Hz,1H),6.60(d,J=8Hz,1H),6.50(d,J=8Hz,1H),6.15(s,1H),5.87(dd,J=3+10Hz,1H),5.80(d,J=14Hz,1H),5.45(s,1H),3.88(s,3H),3.65(s,3H),2.60(m 1H),2.45(m,1H),2.15(s,3H),1.15(br s,6H);13C NMR(75MHz,DMSO-d6)δ165.8,156.2,150.5,145.6,144.8,133.6,131.3,127.4,127.2,122.7,116.3,115.9,113.4,113.1,110.2,105.7,72.4,55.6,51.3,49.7,34.9,29.0,28.9,28.9,23.9;C25H27NO4·1/2 H2O的分析计算值:C,72.44;H,6.81;N,3.38。实测值:C,72.55;H,6.71;N,3.22。实施例195(E)2,5-二氢-10-甲氧基-5-(4-羟基-2-丁烯-1-基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
滴加含有氢化铝锂(0.044g,1.16mmol)和三氯化铝(0.041g,0.308mmol)的淤浆处理在乙醚中的实施例194的产物(0.063g,0.155mmol)1小时。用乙醚稀释该反应混合物,用2滴水和15%氢氧化钠先后处理,直至形成白色糊状物。倾出乙醚,用乙醚洗涤该糊状物两次。用饱和碳酸氢钠水溶液、盐水洗涤合并的有机物,干燥(硫酸镁)并经硅胶层析纯化,用6%和10%的乙酸乙酯的二氯甲烷液先后洗脱,得到0.031g(53%)所需化合物。MS(DCI/NH3)m/e378(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.94(d,J=9Hz,1H),7.07(dd,J=8Hz,1H),6.70(d,J=8Hz,1H),6.60(d,J=8Hz,1H),6.54(d,J=8Hz,1H),6.12(s,1H),5.70(dd,J=3+10Hz,1H),5.4-5.69(m,3H),4.63(dd,J=6Hz,1H),3.87(m,5H),3.31(s,3H),2.40(m,1H),2.15(s,3H),1.15(s,6H);C24H27NO3·1/4H2O的分析计算值:C,75.47;H,7.26;N,3.67。
实测值:C,75.62;H,7.40;N,3.59。实施例196(E)2,5-二氢-10-甲氧基-5-(4-(N,N-二甲基氨基羰基氧基)-2-丁烯-1-基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例200的方法处理实施例195的产物和二琥珀酰亚胺基(disuccinimidyl)碳酸酯,得到中间体琥珀酸酯。
根据实施例200的方法处理所述中间体琥珀酸酯和N,N-二甲胺,得到所需化合物。MS(DCI/NH3)m/e449(M+H)+;1H NMR(400MHz,DMSO-d6)δ7.95(d,J=9Hz,1H),7.07(t,J=8Hz,1H),6.70(d,J=8Hz,1H),6.59(d,J=8Hz,1H),6.52(d,J=8Hz,1H),6.09(s,1H),5.74(dd,J=3,10Hz,1H),5.65(m,1H),5.48(m,1H),5.43(s,1H),3.85(s,3H),3.79(d,J=5Hz,2H),2.45(m,1H),2.20(m,1H),2.15(s,3H),1.17(s,3H),1.16(s,3H);13C NMR(100MHz,DMSO-d6)δ156.1,150.9,145.5,133.6,132.0,129.0,128.6,127.4,127.1,127.0,116.2,115.9,113(3),113.2,110.3,105.4,73.5,72.0,56.9,55.6,49.7,35.0,28.9,23.3;C27H32N2O4的分析计算值:C,72.30;H,7.19;N,6.25。
实测值:C,72.10;H,7.11;N,5.98。实施例197(E)2,5-二氢-10-甲氧基-5-(4-(N-甲基氨基羰基氧基)-2-丁烯-1-基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例200的方法处理得自实施例196的中间体琥珀酸酯和甲胺,得到所需化合物。MS(DCI/NH3)m/e435(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.95(d,J=8Hz,1H),7.05(t,J=8Hz,1H),6.95(m,1H),6.70(d,J=8Hz,1H),6.57(d,J=8Hz,1H),6.52(d,J=8Hz,1H),6.08(s,1H),5.70(m,2H),5.50(m,1H),5.43(s,1H),4.35(d,J=5Hz,2H),3.85(s,3H),2.56(d,J=5Hz,3H),2.42(m,1H),2.20(m,1H),2.15(s,3H),1.15(s,6H);C26H30N2O4的分析计算值:C,71.87;H,6.96;N,6.45。
实测值:C,71.66;H,7.25;N,6.07。实施例198(E)2,5-二氢-10-甲氧基-5-(2-丁烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
使实施例195的产物(0.080g,0.212mmol)溶于二氯甲烷(10ml)中,冷却至-10℃,用(i-Pr)2NEt(55μl,0.318mmol)和甲磺酰氯(20μl,0.255mmol)先后进行处理,搅拌1小时,使之温热至室温。将该混合物再冷却至-10,滴加三乙基硼氢化锂(635μl,0.635mmol)处理,搅拌1小时,使之温热至室温,用5.0ml 1N氢氧化钠和0.11ml30%H2O2先后进行处理并搅拌30分钟。使该混合物在水和乙酸乙酯之间分配,用乙酸乙酯提取水层,用水、盐水洗涤合并的有机物并干燥(硫酸钠)。经硅胶层析纯化,用15∶1至7∶1的己烷∶乙酸乙酯洗脱,得到0.029g(38%)所需化合物。1H NMR(360MHz,DMSO-d6)δ7.93(d,J=9Hz,1H),7.04(t,J=8Hz,1H),6.68(d,J=8Hz,1H),6.57(d,J=8Hz,1H),6.51(d,J=7Hz,1H),6.11(s,1H),5.67(dd,J=10Hz,1H),5.41(t,J=9Hz,1H),5.34(t,J=11Hz,1H),3.85(s,3H),2.34(m,1H),2.15(s,3H),1.59(dd,J=5Hz,3H),1.17(s,3H),1.15(s,3H);13C NMR(300MHz,DMSO-d6)δ156.2,151.0,145.4,133.4,132.1,127.1,127.0,126.9,126.6,125.5,115.9,113.2,110.0,105.3,73.7,55.5,49.6,35.4,28.9,28.8,23.9,17.8;C24H28O2N的HRMS(FAB)m/e计算值:362.2120。实测值:362.2119。实施例1992,5-二氢-10-甲氧基-5-(2-羟乙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于-78℃,用在甲苯中的1M Dibal-H溶液(0.544ml,0.544mmol)处理实施例46的产物(0.100g,0.264mmol),温热至室温,用甲醇猝灭,并在二氯甲烷和饱和Rochelle’s盐水溶液之间分配。用1N HCl、饱和碳酸氢钠水溶液、盐水洗涤有机层并干燥(硫酸镁)。生成的粗产物经快速硅胶层析纯化,用10%乙酸乙酯的二氯甲烷液洗脱,得到(87%)所需化合物,为无色固体。MS(DCI/NH3)m/e352(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.95(d,J=8Hz,1H),7.05(dd,J=8Hz,1H),6.69(d,J=8Hz,1H),6.59(d,J=8Hz,1H),6.55(d,J=8Hz,1H),6.10(s,1H),5.95(dd,J=2,10Hz,1H),5.43(s,1H),4.61(t,J=6Hz,1H),3.84(s,3H),3.52(m,1H),2.20(s,3H),1.80(m,1H),1.50(m,1H),1.19(s,3H),1.16(s,3H)。实施例2002,5-二氢-10-甲氧基-5-(2-(N-苄基羰基氧基)乙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例199的产物(0.200g,0.57mmol)与N,N’-二琥珀酰亚胺基碳酸酯(0.217g,0.85mmol)、(i-Pr)2NEt(0.30ml,1.71mmol)和乙腈(2ml)混合,于室温下搅拌2小时,并在二氯甲烷和饱和碳酸氢钠水溶液之间分配。用盐水洗涤有机层,干燥(硫酸镁)、经硅胶层析纯化,用6%乙酸乙酯的二氯甲烷液洗脱,得到0.252g(90%)所述琥珀酸酯,为白色泡沫。
混合所述琥珀酸酯(0.020g,0.041mmol)、苄基胺(6.6μl,0.061mmol)和二氯甲烷(3ml),于室温下搅拌20分钟。用二氯甲烷稀释该反应混合物,用水、饱和碳酸钠水液、盐水洗涤有机层,干燥(硫酸镁)并经硅胶层析纯化,用20%乙酸乙酯的己烷溶液洗脱,得到19mg(97%)的所需化合物,为白色固体。MS(DCI/NH3)m/e485(M+H)+;1H NMR(400MHz,DMSO-d6)δ7.95(d,J=9Hz,1H),7.68(t,J=6Hz,1H),7.25(m,3H),7.07(t,J=8Hz,1H),6.71(d,J=8Hz,1H),6.59(dd,J=8Hz,1H),6.11(s,1H),5.86(d,J=8Hz,1H),5.40(s,1H),4.18(m,2H),4.00(m,2H),3.85(s,3H),2.12(s,3H),1.90(m,1H),1.71(m,1H),1.17(s,3H),1.15(s,3H);13C NMR(100MHz,DMSO-d6)δ156.3,156.1,150.7,145.6,139.7,133.5,131.9,128.2,127.5,127.2,127.1,127.0,126.7,116.3,115.9,113.2,113.2,110.2,110.1,105.6,70.3,60.2,55.6,49.6,43.7,31.5,28.8,28.7,23.8;C30H32N2O5·H2O的分析计算值:C,71.69;H,6.82;N,5.57。
实测值:C,71.45;H,6.83;N,5.56。实施例2012,5-二氢-10-甲氧基-5-(2-(N-吗啉代羰基氧基)乙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例200的方法处理得自实施例200的中间体琥珀酸酯和吗啉,得到所需化合物。MS(DCI/NH3)m/e465(M+H)+;1H NMR(400MHz,DMSO-d6)δ7.95(d,J=9Hz,1H),7.07(t,J=8Hz,1H),6.71(d,J=8Hz,1H),6.60(d,J=8Hz,1H),6.57(d,J=8Hz,1H),6.10(s,1H),5.88(dd,J=3+10Hz,1H),5.44(s,1H),4.05(m,2H),3.85(s,3H),3.75(m,4H),2.16(s,3H),1.85(m,1H),1.78(m,1H),1.16(s,3H),1.15(s,3H);13C NMR(100MHz,DMSO-d6)δ156.2,154.4,150.6,145.6,133.5,131.8,127.3,127.2,127.1,116(1),115.9,113.2,113.2,110.1,105.6,70.3,65.8,61(2),55.6,49.7,43.7,43.6,31.3,29.0,28.9,23.8;C27H32N2O5·1/4H2O的分析计算值:C,69.14;H,6.98;N,5.97。
实测值:C,68.96;H,7.05;N,5.94。实施例2022,5-二氢-10-甲氧基-5-(2-(N-(2-甲氧基乙基)氨基羰基氧基)乙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例200的方法处理得自实施例200的中间体琥珀酸酯和2-甲氧基乙胺,得到所需化合物。MS(DCI/NH3)m/e453(M+H)+;1H NMR(500MHz,DMSO-d6)δ7.95(d,J=8Hz,1H),7.13(m,1H),7.04(t,J=8Hz,1H),6.70(d,J=8Hz,1H),6.60(d,J=8Hz,1H),6.56(d,J=8Hz,1H),6.08(s,1H),5.85d(10,1H),5.45(s,1H),3.95(m,2H),3.85(s,3H),3.25(s,3H),3.12(m,2H),2.15(s,3H),1.92(m,1H),1.72(m,1H),1.15(d,6H);13C NMR(125MHz,DMSO-d6)δ156.1,156.1,150.7,145.6,133.5,131.9,127.6,127.1,127.1,116.3,116.0,113.2,113.2,110.2,105.6,70.7,70.3,60.0,57.8,55.6,49.6,31.5,28.8,28.8,23.8;实施例2032,5-二氢-10-甲氧基-5-(2-(N-甲基氨基羰基氧基氧基)乙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例200的方法处理得自实施例200的中间体琥珀酸酯和甲胺,得到所需化合物。MS(DCI/NH3)m/e409(M+H)+;1H NMR(500MHz,DMSO-d6)δ7.95(d,J=8Hz,1H),7.04(t,J=8Hz,1H),6.93(m,1H),6.70(t,J=8Hz,1H),6.60(d,J=8Hz,1H),6.56(d,J=8Hz,1H),6.08(s,1H),5.85d(10,1H),5.45(s,1H),3.95(m,2H),3.85(s,3H),2.59(d,3H),2.15(s,3H),1.92(m,1H),1.72(m,1H),1.15(d,6H);13C NMR(125MHz,DMSO-d6)δ156.6,156.1,150.7,145.6,133.5,131.9,127.5,127.2,127.1,116.3(116.0),113.2,113.2,113.2,105.6,70.3,60.0,55.6,49.6,31.5,28.8,28.8,26.9,23.7;C24H28N2O4的分析计算值:C,70.57;H,6.91;N,6.86。
实测值:C,70.30;H,6.91;N,6.58。实施例2042,5-二氢-10-甲氧基-5-(2-(N,N-二甲基氨基羰基氧基)乙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例200的方法处理得自实施例200的中间体琥珀酸酯和N,N-二甲胺,得到为白色固体的所需化合物。MS(DCI/NH3)m/e423(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.95(d,J=8Hz,1H),7.05(t,J=8Hz,1H),6.69(d,J=8Hz,1H),6.56(dd,J=8Hz,2H),6.12(s,1H),5.86(dd,J=3+10Hz,1H),5.44(s,1H),3.96(m,2H),3.85(s,3H),2.86(s,3H),2.83(s,3H),2.18(s,3H),1.95(m,1H),1.76(m,1H),1.15(s,6H)。实施例2052,5-二氢-10-甲氧基-5-(2-甲氧基甲氧基乙基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例199的产物(0.040g,0.114mmol)与氯代甲基甲醚(13μl,0.171mmol)、(i-Pr)2NEt(40μl,0.228mmol)和二氯甲烷(5ml)混合并加热至回流3小时。使该反应物在水和乙酸乙酯之间分配,用乙酸乙酯提取水层,用饱和碳酸氢钠水溶液、盐水洗涤合并的有机层,经硫酸镁干燥和硅胶层析纯化,用2%和5%乙酸乙酯的二氯甲烷液先后洗脱,得到45mg(40%)所需化合物。MS(DCI/NH3)m/e396(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.95(d,J=9Hz,1H),7.05(t,J=8Hz,1H),6.70(d,J=8Hz,1H),6.60(d,J=8Hz,1H),6.55(d,J=8Hz,1H),6.14(s,1H),5.89(dd,J=3+10Hz,1H),5.45(s,1H),4.55(s,2H),3.85(s,3H),3.58(m,1H),3.25(s,3H),2.18(s,3H),1.85(m,1H),1.65(m,1H),1.19(s,3H),1.13(s,3H);C24H29NO4·1/4H2O的分析计算值:C,72.07;H,7.43;N,3.50。
实测值:C,71.90;H,7.33;N,3.24。实施例2062,5-二氢-10-甲氧基-5-(2,2-二甲基乙氧基羰基氨基)甲基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉实施例206A2,5-二氢-10-甲氧基-5-(氨基甲基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于室温下,滴加5.0ml三氯化铝(0.59g,4.4mmol)醇溶液处理氢化铝锂(0.050g,1.31mmol)的10ml醚悬浮液,搅拌30分钟,滴加4.0ml实施例44的产物的醚溶液进行处理。于室温下搅拌1小时后,小心加入2.0ml水,接着滴加15%的氢氧化钠,直至形成白色糊状物。倾出乙醚液,用乙醚洗涤该糊状物数次。用盐水洗涤合并的有机物并干燥(硫酸钠)。残留物经硅胶柱层析纯化,用二氯甲烷∶甲醇(8∶1)洗脱,得到0.031g(69%)的氨基甲基类似物,该物质可直接进入下一步骤。实施例2062,5-二氢-10-甲氧基-5-(2,2-二甲基乙氧基羰基氨基)甲基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将上面的氨基甲基类似物(0.065g,0.19mmol)溶于二氯甲烷(6.0ml)中,冷却至0℃,用BoC2O(0.93g,0.42mmol)处理。使温热至室温过夜。加入10ml水,分离糊状物。用盐水洗涤有机层并干燥(硫酸钠)。残留物经硅胶柱层析纯化,用二氯甲烷∶甲醇(8∶1)洗脱,得到0.080g(95%)的所需化合物:m.p.130-135℃;1H NMR(400MHz,DMSO-d6)δ7.98(d,J=9Hz,1H),7.70(t,J=9Hz,1H),6.79(t,J=5Hz,1H),6.67(d,J=9Hz,1H),6.60(d,J=9Hz,1H),6.53(d,J=8Hz,1H),6.12(s,1H),5.80(dd,J=10,10Hz,1H),5.42(s,1H),3.85(s,3H),3.14(m,1H),2.86(m,1H),2.19(s,3H),1.47(s,3H),1.21(s,3H),1.12(s,3H),.84(m,1H);13C NMR(100MHz,DMSO-d6)δ156.1,155.5,150.9,145.4,133.4,131.5,129.5,128.6,127.8,126.9,117.1,116.4,113.4,112.7,110.5,105.3,77.7,72.3,67.4,55.6,49.5,41.5,29.8,29.2,28.3,28.2,23.4,23.2,22.3;C26H32N2O4的HRMS(FAB)m/e计算值:436.2362。实测值:436.2360。实施例2072,5-二氢-10-甲氧基-5-(乙氧基羰基氨基)甲基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
用三乙胺(21.0μl,0.14mmol)处理实施例206A的产物(0.047g,0.14mmol)的THF(10ml)溶液。接着滴加氯代甲酸乙酯(14.1μl,0.14mmol)。30分钟后,将该反应物倾入水中,用乙酸乙酯提取水层,用水洗涤合并的有机层1次,用盐水洗涤1次,干燥(硫酸钠)。残留物经硅胶柱层析纯化,用3∶2的己烷∶乙酸乙酯洗脱,得到0.047g(80%)的固体状所需化合物。1H NMR(300MHz,DMSO-d6)δ7.98(d,J=8Hz,1H),7.13(t,1H),7.03(t,J=8Hz,1H),6.67(d,J=8Hz,1H),6.57(d,J=8Hz,1H),6.54(d,J=8Hz,1H),6.13(s,3H),5.83(dd,1H),5.43(s,1H),3.94(m,2H),3.85(s,3H),3.13(m,1H),2.94(m,1H),2.21(s,3H),1.20(s,3H),1.17(s,3H),1.11(s,3H);13C NMR(75MHz,DMSO-d6)δ156.1,150.8,145.5,133.4,129.4,127.7,127.0,117.0,116.4,113.5,112.7,110.6,105.4,72.2,59.7,55.6,49.6,41.8,29.2,28.3,23.5,14.6;C24H28N2O4的HRMSm/e计算值:408.2049。实测值:408.2044。实施例2082,5-二氢-10-甲氧基-5-(乙酯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
向实施例61的产物中加入5%HCl水溶液、5.0ml水和足量的乙醇以使该溶液均匀。将其于35℃温热1小时,用饱和碳酸氢钠水溶液猝灭,调至pH7.0。用乙酸乙酯提取该反应物。用水、盐水洗涤有机物并干燥(硫酸钠)。残留物经硅胶柱层析纯化,用7∶1-5∶1-3∶2的己烷∶乙酸乙酯洗脱,得到0.041g(48%)的固体状所需化合物。MS(DCI/NH3)m/e380(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.90(d,J=9Hz,1H),7.04(t,J=8Hz,1H),6.64(d,J=8Hz,1H),6.61(m,2H),6.32(s,1H),6.21(s,1H),5.45(s,1H),3.90(m,2H),3.84(s,3H),1.17(s,3H),1.15(s,3H),.93(t,J=7Hz,3H),;13C NMR(100MHz,DMSO-d6)δ169.4,156.2,152.5,145.4,133.1,127.6,126.9,126.0,118.2,117.7,114.7,109.8,105.7,73.0,60.7,55.6,49.9,28.9,28.7,22.8,13.7;C23H25NO4·1/4H2O的分析计算值:C,71.95;H,6.68;N,3.65。
实测值:C,72.21;H,6.41;N,3.85。实施例2092,5-二氢-10-甲氧基-5-(环戊基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例11的方法处理实施例2B的产物和环戊基溴化镁,得到所需化合物。MS(DCI/NH3)m/e 376(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,J=8Hz,1H),7.03(t,J=8Hz,1H),6.65(d,J=8Hz,1H),6.59(d,J=9Hz,1H),6.52(d,J=8Hz,1H),6.20(s,1H),5.46(s,3H),3.85(s,3H),2.16(s,3H),1.50(m,5H),1.30(s,3H),1.16(m,3H),1.01(s,3H);13C NMR(100MHz,DMSO-d6)δ156.2,151.7,145.0,133.7,131.6,128.1,126.7,117.7,116.4,113.3,112.6,109.9,105.0,76.5,49.2,42.5,29.8,29.5,27.5,26.6,24.8,24.6,23.6;C25H29O2N·1/2H2O的分析计算值:C,78.09;H,7.86;N,3.64。
实测值:C,78.09;H,7.52;N,3.42。实施例2102,5-二氢-10-甲氧基-5-(1-甲基丙-1,2-二烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例11的方法处理实施例2B的产物和炔丙基溴化镁(Gaoni,Y.;Leznoff,C.C.;Sondheimer,F.J.Am.Chem.Soc.1968,90,4940-4945.),得到所需化合物。m.p.59-63℃;1H NMR(300MHz,DMSO-d6)δ7.84(d,J=8Hz,1H),7.03(t,J=6Hz,1H),6.68(d,J=6Hz,1H),6.55(d,J=8Hz,2H),6.04(s,1H),5.97(s,1H),5.40(s,1H),4.94(m,1H),4.23(m,1H),3.82(s,3H),2.11(s,3H),1.70(s,3H),1.21(s,3H),1.10(s,3H);13C NMR(100MHz,DMSO-d6)δ156.1,151.2,150.5,145.1,132.6,130.5,127.9,127.1,127.0,126.7,126.5,117(5),117.1,114.7,113.3,112.9,110.1,106.3,98.6,76.2,75.6,55.9,49.6,29.4,28.4,22.5,16.0;C24H25O2N的MS m/e计算值:359.1885。实测值:359.1893。实施例2112,5-二氢-10-甲氧基-5-(3,4,5-三氟苯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例11的方法处理实施例2B的产物和3,4,5-三氟苯基溴化镁,得到所需化合物。MS(DCI/NH3)m/e438(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.04(d,J=8Hz,1H),6.94-7.02(m,3H),6.77(s,1H),6.74(d,J=9Hz,1H),6.62(d,J=8Hz,1H),6.51(d,J=8Hz,1H),6.31(br s,1H),5.43(s,1H),3.81(s,3H),1.85(s,3H),1.23(s,3H),1.15(s,3H);C26H22NO2F3·1/4H2O的分析计算值:C,70.66;H,5.13;N,3.17。
实测值:C,70.89;H,5.19;N,2.93。实施例2122,5-二氢-10-甲氧基-5-(环己基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例11的方法处理实施例2B的产物和环己基溴化镁,得到所需化合物。MS(DCI/NH3)m/e308(M+H)+;主要的产物:1H MR(300MHz,DMSO-d6)δ8.03(d,J=9Hz,1H),7.05(t,J=8Hz,1H),6.72(d,J=8Hz,1H),6.61(d,J=9Hz,1H),6.59(s,1H),6.15(d,J=8Hz,1H),5.40(m,2H),3.86(s,3H),2.01(s,3H),1.61(m,1H),1.56-1.41(m,2H),1.35-0.96(m,6H),1.29(s,3H),1.18(s,3H),0.95-0.77(m,2H);C26H31NO2·1/2H2O的分析计算值:C,78.36;H,8.09;N,3.51。
实测值:C,78.24;H,7.72;N,3.70。实施例2132,5-二氢-10-甲氧基-5-(2-吡啶基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉实施例213A
于0℃,向实施例2A的产物(1.42g,4.39mmol)的THF(40ml)溶液中加入叔丁醇钾(1.48g,13.2mmol)的THF(13ml)溶液。于0℃搅拌该混合物45分钟,然后以滴加的方式导入TBSCl(1.46g,9.66mmol)的THF(9.5ml)溶液。于0℃搅拌该溶液30分钟,然后通过加入饱和氯化铵水溶液(10ml)猝灭,用乙酸乙酯(2×30ml)提取。用盐水(8ml)洗涤合并的有机部分并干燥(硫酸钠)。过滤并浓缩得到棕色残留物,将其通过快速层析纯化(用2%乙酸乙酯/二氯甲烷洗脱),得到为黄色固体的所需产物(994mg,2.28mmol,52%)。MS(DCI/NH3)m/z438(M+H)+。实施例2132,5-二氢-10-甲氧基-5-(2-吡啶基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于-78℃,通过将正丁基锂(680μl在己烷中的2.5M溶液,1.70mmol)加入2-溴代吡啶(285mg,1.80mmol)的THF(17ml)溶液中形成2-锂吡啶(1M在THF中)溶液。将该溶液搅拌20分钟,然后于-78℃滴加上面制备的醛(211mg,0.480mmol)的THF(2.0ml)溶液。于-78℃将该溶液搅拌30分钟,然后通过加入饱和氯化铵水溶液(7ml)猝灭,用乙酸乙酯(2×30ml)提取。用盐水(10ml)洗涤合并的有机部分并干燥(硫酸钠)。过滤并浓缩得到棕色残留物,其可不经进一步纯化而使用。
于23℃,将上面制备的粗品物质溶于THF(10ml)中并用四丁基氟化铵(500μl在THF中的1M溶液,0.500mmol)处理。1小时后,真空浓缩该反应混合物,并再悬浮于乙酸乙酯(20ml)中,然后用水(5ml)和盐水(5ml)洗涤并干燥(硫酸钠)。过滤并浓缩得到棕色残留物,其可不经进一步纯化而使用。
将粗残留物溶于THF(10ml)中,使该溶液冷却至0℃。向该溶液中加入三乙基膦(48mg,0.410mmol),接着加入1,1’-(偶氮二羰基)二哌啶(103mg,0.410mmol)的THF(1.5ml)溶液。于0℃将该溶液搅拌30分钟,然后于23℃搅拌7小时。浓缩该反应混合物并经快速层析纯化(用25%乙酸乙酯/己烷洗脱),得到为无色固体的所需产物(13mg,0.034mmol,8%)。MS(DCI/NH3)m/z385(M+H)+;1H NMR(300MHz,DMSO)δ8.45(br d,J=6.6Hz,1H),7.98(d,J=8.0Hz,1H),7.61(td,J=6.5,1.8Hz,1H),7.19-7.13(m,2H),6.91(t,J=6.6Hz,1H),6.72(s,1H),6.68(d,J=7.9Hz,1H),6.57(br d,J=6.7Hz,1H),6.44(dd,J=6.5,1.0Hz,1H),6.17(br s,1H),5.37(br s,1H),3.80(s,3H),1.80(s,3H),1.23(s,3H),1.13(s,3H);C25H25N2O2的HRMS(FAB)(M+H)+计算值:385.1916。实测值:385.1910。实施例2142,5-二氢-10-甲氧基-5-(3-吡啶基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如实施例213中所述制备所需化合物,收率49%。MS(DCI/NH3)m/z385(M+H)+;1H NMR(300MHz,DMSO)δ8.38(d,J=2.4Hz,1H),8.35(dd,J=5.6,2.0Hz,1H),8.02(d,J=8.0Hz,1H),7.49(br d,J=6.9Hz,1H),7.25(dd,J=6.9,5.5Hz,1H),6.92(t,J=6.9Hz,1H),6.86(s,1H),6.72(d,J=8.1Hz,1H),6.58(d,J=6.7Hz,1H),6.45(d,J=6.4Hz,1H),6.38(br s,1H),5.41(br s,1H),3.80(s,3H),1.83(s,3H),1.23(s,3H),1.15(s,3H);13C NMR(125MHz,DMSO)δ156.0,151.2,149.4,148.8,145.6,135.7,134.7,133.2,128.5,127.3,127.2,127.0,123.2,117.7,117.2,113.9,113.7,110.2,105.7,73.0,55.5,49.8,29.5,28.5,23.4;C25H25N2O2的HRMS(FAB)m/z计算值:385.1916(M+H)+。实测值:385.1915。C25H24N2O2的分析计算值:C,78.09;H,6.29;N,7.28。
实测值:C,76.98;H,6.60;N,6.93。实施例2152,5-二氢-10-甲氧基-5-(4-吡啶基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如实施例213中所述制备所需化合物,收率20%。MS(DCI/NH3)m/z385(M+H)+;1H NMR(300MHz,DMSO)δ8.43(br d,J=4.3Hz,2H),8.04(d,J=8.0Hz,1H),7.15(d,J=4.2Hz,2H),6.96(t,J=6.7Hz,1H),6.81(s,1H),6.75(d,J=7.9Hz,1H),6.59(d,J=6.8Hz,1H),6.53(d,J=6.8Hz,1H),6.37(br s,1H),5.43(br s,1H),3.79(s,3H),1.88(s,3H),1.26(s,3H),1.18(s,3H);13C NMR(125MHz,DMSO)δ156.1,151.4,149.4(2),148.2,145.6,133.4,133.3,128.3,127.3(2),127.0,122.9,117.9,117.0,113.9,110.2,105.6,105.0,103.0,73.4,49.8,29.4,28.6,23.2;C25H25N2O2的HRMS(FAB)m/z计算值:385.1916(M+H)+。实测值:385.1906。
采用流程1-21和实施例1-215中描述的化学方法,用核2制备实施例216-226的产物。实施例216(10-氯代-9-羟基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z368(M+H)+;1H NMR(300MHz,DMSO)δ9.34(s,1H),7.87(d,J=8Hz,1H),6.72(d,J=8Hz,1H),6.66(d,J=8Hz,1H),6.58(d,J=8Hz,1H),6.21(br s,1H),5.81-5.71(m,1H),5.62(dd,J=10,3Hz,1H),5.41(br s,1H),4.98(dd,J=10,2Hz,1H),4.93(dd,J=17,2Hz,1H),2.42-2.34(m,1H),2.26-2.20(m,1H),2.11(s,3H),1.16(s,3H),1.11(s,3H);C22H22ClNO2的HRMS(FAB)m/z计算值:367.1339。实测值:367.1336。实施例21710-氯代-9-羟基-5-苯基-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z404(M+H)+;1H NMR(300MHz,DMSO)δ9.46(s,1H),7.96(d,J=8Hz,1H),7.26-7.12(m,3H),7.14-7.07(m,1H),6.87(dd,J=8,2Hz,1H),6.72(d,J=8Hz,1H),6.68(s,1H),6.58(app s,2H),6.37(br s,1H),5.40(br s,1H),1.80(s,3H),1.26(s,3H),1.17(s,3H);C25H22ClNO2的HRMS(FAB)m/z计算值:403.1339。实测值:403.1344。实施例21810-氯代-9-羟基-5-(3-三氟甲基苯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z472(M+H)+;1H NMRδ9.45(s,1H),7.98(d,1H,J=8.5Hz),7.54(m,4H),6.85(d,1H,J=8.5Hz),6.75(m,2H),6.57(d,1H,J=8.5Hz),6.42(m,1H),5.39(m,1H),1.91(s,3H),1.24(s,3H),1.11(s,3H);C26H21ClF3NO2的计算值:471.1213。实测值:471.1216。实施例21910-氯代-9-羟基-5-(3,5-二甲基苯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z432(M+H)+;1H NMRδ9.52(s,1H),7.95(d,1H,J=8.5Hz),6.82(m,2H),6.71(m,2H),6.61(s,2H),6.36(m,1H),6.42(m,1H),5.40(m,1H),2.31(s,6H),1.92(d,3H,J=1.4Hz),1.24(s,2H),1.14(s,2H);C27H26ClNO2的HRMS(FAB)m/z计算值:421.1652。实测值:431.1650。实施例220rel-(5S,3’R)-9-羟基-10-甲氧基-5-[1-羟甲基-3-环己烯基)-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z438(M+H)+;1H NMR(300MHz,DMSO)δ9.56(s,1H),8.01(d,J=8Hz,1H),6.77(app s,2H),6.67(d,J=8Hz,1H),6.39(br s,1H),5.48(d,J=10Hz,1H),5.42(br s,1H),5.10(br s,1H),4.42(t,J=6Hz,1H),3.65(br d,J=6Hz,2H),2.28-2.18(m,2H),2.05(br s,3H),1.94-1.87(m,2H),1.75-1.64(m,1H),1.52-1.42(m,1H),1.36-1.27(m,1H),1.29(s,3H),1.10(s,3H);C26H28ClNO3的HRMS(FAB)m/z计算值:437.1758。实测值:437.1756。
如上处理核2的C-5内半缩醛-9-叔丁基二甲基甲硅烷基醚和3-环戊烯基三甲基硅烷,得到2∶1的非对映体产物混合物,将其经(R,R)WHELK-O1柱的HPLC,用2%乙醇的己烷液洗脱,得到各对映体。实施例221(-)2,5(S)-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-(3S-环戊烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉[α]23 D=-220°(c0.012,CHCl3);MS(DCI/NH3)m/z394(M+H)+;1H NMR(300MHz,DMSO-d6)δ9.55(s,1H),8.00(d,1H),6.75(d,1H),6.72(d,1H),6.63(d,1H),6.36(s,1H),5.73(ddd,1H),5.44(d,1H),5.40(s,1H),5.17(ddd,1H),2.78(m,1H),2.35(m,1H),2.15(m,1H),2.05(s,3H),1.80(m,1H),1.72(m,1H),1.27(s,3H),1.05(s,3H)。13C NMR(400MHz,DMSO-d6)δ148.7,146.0,144.0,134.0,133.6,132.7,129.9,127.9,127.0,123.7,116.6,115.8,115.4,114.2,112.4,76.1,49.6,48.2,31.7,29.8,27.8,27.3,24.4。实施例222(-)2,5(S)-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-(3R-环戊烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉[α]23 D=-232°(c0.010,CHCl3);MS(DCI/NH3)m/z394(M+H)+;1H NMR(300MHz,DMSO-d6)δ9.50(bs,1H),8.02(d,1H),6.75(d,1H),6.72(d,1H),6.63(d,1H),6.39(s,1H),5.74(ddd,1H),5.60(ddd,1H),5.46(s,1H),5.39(d,1H),2.83(m,1H),2.26(m,1H),2.14(m,1H),2.09(s,3H),1.55-1.40(m,2H),1.27(s,3H),1.01(s,3H)。13C NMR(400MHz,DMSO-d6)δ148.7,146.0,144.6,134.1,132.8,132.0,131.7,127.8,126.8,123.6,117.4,115.9,115.8,115.5,114.2,112.3,76.4,49.4,48.0,31.7,29.5,27.2,24.5,23.8。实施例22310-氯代-9-羟基-5-(3,5-二氯代苯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z472(M+H)+;1H NMRδ9.40(s,1H),8.01(d,1H,J=8.5Hz),7.43(m,4H),6.85(d,1H,J=8.5Hz),6.71(m,1H),6.57(d,1H,J=8.5Hz),6.42(m,1H),5.47(m,1H),1.81(s,3H),1.29(s,3H),1.09(s,3H);C25H20Cl3NO2的HRMS(FAB)m/z计算值:471.0559。实测值:471.0556。实施例224(+)(5R,3’S)2,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-(3-环戊烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉[α]23 D=+256°(c0.046,CHCl3);MS(DCI/NH3)m/z394(M+H)+;1H NMR(300MHz,DMSO-d6)δ9.50(bs,1H),8.02(d,1H),6.75(d,1H),6.72(d,1H),6.63(d,1H),6.39(s,1H),5.74(ddd,1H),5.60(ddd,1H),5.46(s,1H),5.39(d,1H),2.83(m,1H),2.26(m,1H),2.14(m,1H),2.09(s,3H),1.55-1.40(m,2H),1.27(s,3H),1.01(s,3H)。13C NMR(400MHz,DMSO-d6)δ148.7,146.0,144.6,134.1,132.8,132.0,131.7,127.8,126.8,123.6,117.4,115.9,115.8,115.5,114.2,112.3,76.4,49.4,48.0,31.7,29.5,27.2,24.5,23.8。实施例225(+)(5R,3’R)2,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-(3-环戊烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉[α]23 D=+244°(c0.165,CHCl3);MS(DCI/NH3)m/z394(M+H)+;1H NMR(300MHz,DMSO-d6)δ9.55(s,1H),8.00(d,1H),6.75(d,1H),6.72(d,1H),6.63(d,1H),6.36(s,1H),5.73(ddd,1H),5.44(d,1H),5.40(s,1H),5.17(ddd,1H),2.78(m,1H),2.35(m,1H),2.15(m,1H),2.05(s,3H),1.80(m,1H),1.72(m,1H),1.27(s,3H),1.05(s,3H)。13C NMR(400MHz,DMSO-d6)δ148.7,146.0,144.0,134.0,133.6,132.7,129.9,127.9,127.0,123.7,116.6,115.8,115.4,114.2,112.4,76.1,49.6,48.2,31.7,29.8,27.8,27.3,24.4。实施例22610-氯代-9-羟基-5-(3,4-二氟代苯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z440(M+H)+;1H NMRδ9.41(s,1H),7.94(d,1H,J=8.5Hz),6.96(m,3H),6.75(m,3H),6.57(d,1H,J=8.5Hz),6.45(m,1H),5.47(m,1H),1.81(s,3H),1.29(s,3H),1.09(s,3H);C25H20ClF2NO2的HRMS(FAB)m/z计算值:429.1150。实测值:429.1152。
采用流程1-21和实施例1-215中描述的化学方法,用核3制备实施例227的产物。实施例2279-10-亚甲基二氧基-5-苯基-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z298(M+H)+;1H NMR(200MHz,DMSO-d6)δ7.72(d,J=8.1Hz,1H),7.20(m,5H),6.82(s,1H),6.75(d,J=8.8Hz,1H),6.50(d,J=8.1Hz,1H),6.26(s,1H),6.27(d,J=8.8Hz,1H),6.05(s,1H),5.98(s,1H),5.4(s,1H),1.87(s,2H),1.20(s,2H),1.17(s,2H)。
采用流程1-21和实施例1-215中描述的化学方法,用核4制备实施例228-231的产物。实施例2285-(3-丙烯基)-9-氯代-10-乙烯基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMRδ7.93(d,1H,J=8.5Hz),7.20(d,1H,J=8.5Hz),6.70(d,1H,J=8.5Hz),6.64(d,1H,J=8.5Hz),6.34(m,1H),5.81(m,2H),5.46(m,1H),5.03(dm,1H,J=10.5Hz),4.98(dm,1H,J=17.1Hz),3.65(s,3H),2.44(m,1H),2.28(m,1H),2.18(s,3H),1.19(s,3H),1.17(s,3H);C23H25ClNO2的HRMS(ESI)m/z计算值:381.1495。实测值:381.1490。实施例2299-氯代-10-甲氧基-5-苯基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMRδ7.98(d,1H,J=8.5Hz),7.42(m,1H),7.21(m,5H),7.00(d,1H,J=8.5Hz),6.75(m,1H),6.57(d,1H,J=8.5Hz),6.42(m,1H),5.47(m,1H),3.65(s,3H),1.81(s,3H),1.29(s,3H),1.09(s,3H);C26H24ClNO2的HRMS(ESI)m/z计算值:417.1495。实测值:417.1497。实施例2305-(3-丙烯基)-9-氯代-10-二氟甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMRδ7.58(d,1H,J=8.5Hz),7.14(m,2H),6.80(dd,1H,J=7.3Hz),6.64(d,1H,J=8.5Hz),6.24(m,1H),5.81(m,2H),5.46(m,1H),5.02(dm,1H,J=10.5Hz),4.94(dm,1H,J=17.1Hz),2.30(m,2H),2.17(s,3H),1.19(s,3H),1.16(s,3H);质谱(ESI)m/z:418(M+H);C23H22ClF2NO2的计算值:417.1307。实测值:417.1304。实施例2319-氯代-10-二氟甲氧基-5-苯基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMRδ7.77(d,1H,J=8.5Hz),7.44(m,1H),7.22(m,5H),7.12(d,1H,J=8.5Hz),6.84(s,1H),6.76(t,1H,J=75Hz),6.74(d,1H,J=8.5Hz),6.51(m,1H),5.39(m,1H),1.78(s,3H),1.26(s,3H),1.14(s,3H);质谱(ESI)m/z:454(M+1);C26H22ClF2NO2的计算值:453.1307。实测值:453.1304。
采用流程1-21和实施例1-215中描述的化学方法,用核5制备实施例232-233的产物。实施例2328-氟代-10-甲氧基-5-苯基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMRδ7.95(d,1H,J=8.5Hz),7.30(m,2H),7.20(m,5H),7.00(d,1H,J=8.5Hz),6.82(s,1H),6.43(m,1H),5.38(m,1H),3.56(s,3H),2.17(s,3H),1.25(s,3H),1.13(s,3H);质谱(ESI)m/z:402(M+H);C26H24FNO2的计算值:401.1791。实测值:401.1795。C26H24FNO2的分析计算值:C,77.78;H,6.02;N,2.49。
实测值:C,77.66;H,5.90;N,2.28。实施例2335-(3-丙烯基)-8-氟代-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMRδ7.95(d,1H,J=8.5Hz),7.30(m,2H),7.20(m,5H),7.00(d,1H,J=8.5Hz),6.82(s,1H),6.43(m,1H),5.38(m,1H),3.56(s,3H),2.17(s,3H),1.25(s,3H),1.13(s,3H);质谱(ESI)m/z:402(M+1);C26H24FNO2的计算值:401.1791。实测值:401.1795。
采用流程1-21和实施例1-215中描述的化学方法,用核6制备实施例234的产物。实施例23410-甲氧基-9-氟代-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z366(M+H)+;1H NMR(300MHz,DMSO)δ7.87(d,J=8.5Hz,1H),7.00(dd,J=8.8,2.2Hz,1H),6.64(d,J=8.1Hz,1H),6.63(d,J=8.8Hz,1H),6.31(d,J=1.1Hz,1H),5.90-5.80(m,1H),5.79-5.75(m,1H),5.46(s,1H),5.05-4.95(m,2H),3.79(s,3H),2.17(d,J=1.1Hz,1H),1.17(s,6H);C23H24FNO2的HRMS计算值为366.1869。实测值:366.1869。
采用流程1-21和实施例1-215中描述的化学方法,用核7制备实施例235-296的产物。实施例23510-甲氧基-9-羟基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO)δ8.69(s,1H),7.92(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,1H),6.48(d,J=8.5,1H),6.16(d,J=1.7Hz,1H),5.81(ddt,J=17.3,10.3,6.6Hz,1H),5.67(dd,J=9.8,3.3Hz),5.44(s,1H),5.02(dd,J=10.3,1.8Hz,1H),4.98(dd,J=17.3,1.8Hz,1H),2.47-2.41(m,1H),2.34-2.27(m,1H),2.16(s,3H),1.18(s,3H),1.16(s,3H);13C NMR(75MHz,DMSO)δ145.8,145.1,143.9,142.9,134.4,133.4,132.7,127.5,126.5,117.8,117.0,116.3,116.1,114.3,113.6,112.4,73.3,59.3,49.7,36.4,29.2,28.9,23.9。MS(DCI/NH3)m/z364(M+H)+;C23H24N2O2的分析计算值:C,76.01;H,6.93;N,3.85。
实测值:C,75.85;H,7.18;N,3.66。实施例236(+/-)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-环己烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z404(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.01(d,1H),6.65(d,1H),6.62(d,1H),6.53(d,1H),6.27(d,1H),5.82-5.65(m,2H),5.45(s,1H),5.33(d,1H),3.65(s,3H),2.28(m,1H),2.12(s,3H),1.86(m,2H),1.55(m,1H),1.31(s,3H),1.26-1.14(m,3H),1.03(s,3H);13C NMR(400MHz,DMSO-d6)δ145.4,145.0,144.1,143.5,133.6,130.7,128.1,127.9,127.7,126.1,118.4,117.8,116.5,114.4,113.4,112.1,75.9,59.3,49.4,37.2,29.6,27.1,24.7,24.6,23.7,21.2。实施例237(+/-)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(1-甲基环己烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z718(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.66(s,1H),8.00(d,J=8.5Hz,1H),6.65(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,1H),6.55(d,J=8.5,1H),6.24(d,J=1.5Hz,1H),5.51(br s,1H),5.44(br s,1H),5.30(d,J=9.5Hz,1H),3.65(s,3H),2.30-2.20(m,1H),2.11(s,3H),1.80-1.54(m,3H),1.60(s,3H),1.30(s,3H),1.28-1.08(m,3H),1.03(s,3H);13C NMR(75MHz,DMSO-d6)δ145.3,144.9,144.0,143.6,134.7,133.5,130.9,128.0,126.1,121.8,118.3,117.9,116.5,114.3,113.3,112.1,76.2,59.3,49.4,37.5,29.6,29.5,27.1,24.5,23.8,23.7,21.6。实施例238(-)(5S,3’S)-9-羟基-5-[1-甲基-3-环己烯基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉[α]D=-158.8°;MS(DCI/NH3)m/z718(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.66(s,1H),8.00(d,J=8.5Hz,1H),6.65(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,1H),6.55(d,J=8.5Hz,1H),6.24(d,J=1.5Hz,1H),5.51(br s,1H),5.44(br s,1H),5.30(d,J=9.5Hz,1H),3.65(s,3H),2.30-2.20(m,1H),2.11(s,3H),1.80-1.54(m,3H),1.60(s,3H),1.30(s,3H),1.28-1.08(m,3H),1.03(s,3H);13C NMR(75MHz,DMSO-d6)δ145.3,144.9,144.0,143.6,134.7,133.5,130.9,128.0,126.1,121.8,118.3,117.9,116.5,114.3,113.3,112.1,76.2,59.3,49.4,37.5,29.6,29.5,27.1,24.5,23.8,23.7,21.6。C27H31NO3的分析计算值:C,77.67;H,7.48;N,3.35。
实测值:C,77.65;H,7.67;N,3.36。实施例239(+)(5R,3’R)-9-羟基-5-[1-甲基-3-环己烯基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉[α]D=+157.9°;MS(DCI/NH3)m/z718(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.66(s,1H),8.00(d,J=8.5Hz,1H),6.65(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,1H),6.55(d,J=8.5Hz,1H),6.24(d,J=1.5Hz,1H),5.51(br s,1H),5.44(br s,1H),5.30(d,J=9.5Hz,1H),3.65(s,3H),2.30-2.20(m,1H),2.11(s,3H),1.80-1.54(m,3H),1.60(s,3H),1.30(s,3H),1.28-1.08(m,3H),1.03(s,3H);13C NMR(75MHz,DMSO-d6)δ145.3,144.9,144.0,143.6,134.7,133.5,130.9,128.0,126.1,121.8,118.3,117.9,116.5,114.3,113.3,112.1,76.2,59.3,49.4,37.5,29.6,29.5,27.1,24.5,23.8,23.7,21.6。C27H31NO3的分析计算值:C,77.67;H,7.48;N,3.35。
实测值:C,77.65;H,7.67;N,3.36。实施例240(+)(5R,3’S)-9-羟基-5-[1-甲基-3-环己烯基]-10-甲氧基-2,2,4-三甲基-2,5-[α]D=+78.0°;MS(DCI/NH3)m/z718(M+H)+ 1H NMR(300MHz,DMSO-d6)δ8.74(s,1H),7.99(d,J=8.8Hz,1H),6.66(d,J=8.8Hz,1H),6.62(d,J=8.5Hz,1H),6.52(d,J=8.5Hz,1H),6.24(d,J=1.5Hz,1H),5.41(br s,1H),5.41(d,J=10.3Hz,1H),4.84(br s,1H),3.63(s,3H),2.34-1.35(m,7H),2.06(s,3H),1.49(s,3H),1.30(s,3H),1.09(s,3H);13C NMR(75MHz,DMSO-d6)δ145.3,145.0,144.0,143.2,135.5,133.3,131.3,128.4,126.2,120.5,118.1,117.9,116.5,114.4,113.5,112.0,75.3,59.3,49.5,36.8,29.4,27.5,25.0,24.1,23.7,20.2。C27H31NO3的HRMS计算值为417.2304。实测值:417.2305。实施例241(-)(5S,3’R)-9-羟基-5-[1-甲基-3-环己烯基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉[α]D=-79.4°;MS(DCI/NH3)m/z718(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.74(s,1H),7.99(d,J=8.8Hz,1H),6.66(d,J=8.8Hz,1H),6.62(d,J=8.5Hz,1H),6.52(d,J=8.5Hz,1H),6.24(d,J=1.5Hz,1H),5.41(br s,1H),5.41(d,J=10.3Hz,1H),4.84(br s,1H),3.63(s,3H),2.34-1.35(m,7H),2.06(s,3H),1.49(s,3H),1.30(s,3H),1.09(s,3H);13C NMR(75MHz,DMSO-d6)δ145.3,145.0,144.0,143.2,135.5,133.3,131.3,128.4,126.2,120.5,118.1,117.9,116.5,114.4,113.5,112.0,75.3,59.3,49.5,36.8,29.4,27.5,25.0,24.1,23.7,20.2。C27H31NO3的分析计算值:C,77.67;H,7.48;N,3.35。
实测值:C,77.55;H,7.56;N,3.34。实施例242rel-(5S,3’R)-9-羟基-5-[1-羟甲基-3-环己烯基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z434(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.72(s,1H),7.98(d,J=8.8Hz,1H),6.65(d,J=8.8Hz,1H),6.62(d,J=8.8Hz,1H),6.52(d,J=8.8Hz,1H),6.23(br s,1H),5.43-5.39(m,2H),5.06(br s,1H),4.44(t,J=5.1Hz,1H),3.69-3.67(m,1H),3.67(s,3H),2.32-2.22(m,1H),2.05(s,3H),1.94-1.88(m,2H),1.74-1.61(m,2H),1.55-1.45(m,2H),1.29(s,3H),1.10(s,3H);13C NMR(75MHz,DMSO-d6)δ145.4,145.0,144.0,143.1,140.4,133.5,131.2,128.2,126.2,120.5,118.0,118.0,116.5,114.4,113.5,112.1,75.4,65.6,59.4,49.5,37.0,29.8,27.8,25.8,25.1,24.3,20.3。C27H31NO4的分析计算值:C,74.80;H,7.21;N,3.23。
实测值:C,74.59;H,7.21;N,3.22。实施例243(+/-)(5S,3’R)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(1-甲基环己烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z718(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.66(s,1H),8.00(d,J=8.5Hz,1H),6.65(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,1H),6.55(d,J=8.5Hz,1H),6.24(d,J=1.5Hz,1H),5.51(br s,1H),5.44(br s,1H),5.30(d,J=9.5Hz,1H),3.65(s,3H),2.30-2.20(m,1H),2.11(s,3H),1.80-1.54(m,3H),1.60(s,3H),1.30(s,3H),1.28-1.08(m,3H),1.03(s,3H);13C NMR(75MHz,DMSO-d6)δ145.3,144.9,144.0,143.6,134.7,133.5,130.9,128.0,126.1,121.8,118.3,117.9,11 6.5,114.3,113.3,112.1,76.2,59.3,49.4,37.5,29.6,29.5,27.1,24.5,23.8,23.7,21.6。实施例244rel-(5S,3’R)-9-羟基-5-[1-甲氧基甲基-3-环己烯基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z448(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.75(s,1H),8.00(d,J=8.5Hz,1H),6.67(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,1H),6.54(d,J=8.5Hz,1H),6.27(d,J=1.5Hz,1H),5.46(d,J=9.9Hz,1H),5.38(br s,1H),5.21(br s,1H),4.33-4.29(m,1H),3.66-3.63(m,1H),3.65(s,3H),3.64(s,3H),2.32-1.45(m,7H),2.04(s,3H),1.29(s,3H),1.07(s,3H);C28H33NO4的分析计算值:C,75.14;H,7.43;N,3.13。
实测值:C,74.81;H,7.35;N,3.05。实施例2452,5-二氢-9-羟基-10-甲氧基-5-丙基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例251的方法处理核7的C-5内半缩醛-9-TBS醚和正丙基氯化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.66(s,1H),7.90(d,J=9Hz,1H),6.60(d,J=8Hz,1H),6.59(s,1H),6.49(d,J=9Hz,1H),6.14(br s,1H),5.57(m,1H),5.44(br s,1H),3.63(s,3H),2.15(s,3H),1.79-1.61(m,1H),1.48-1.08(m,5H),1.16(s,6H),0.78(t,J=7Hz,3H);13C NMR(75MHz,DMSO-d6)δ145.7,144.9,143.9,143.1,133.5,127.5,126.4,117.9,116.3,116.2,114.2,113.4,112.1,73.6,59.3,49.7,31.9,29.1,28.8,27.7,23.8,21.7,13.9;MS(DCI/NH3)m/e380(M+H)+;C24H29NO3·1/4H2O的分析计算值:C,75.07;H,7.74;N,3.65。
实测值:C,74.78;H,7.86;N,3.29。
如同上面的方法处理核7的C-5内半缩醛-9-TBS醚和3-环庚烯基三甲基硅烷,得到5∶1的非对映体产物混合物,将其经(R,R)WHELK-O1柱的HPLC,用2%乙醇的己烷液洗脱,得到两种左旋(levarotary)对映体。实施例246(-)(5S,3’S)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-环庚烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z418(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),7.96(d,1H),6.65(d,1H),6.64(d,1H),6.21(s,1H),5.55(ddd,1H),5.53(d,1H),5.46(s,1H),5.31(ddd,1H),3.65(s,3H),2.45(m,1H),2.14(m,3H),2.05-1.84(m,4H),1.46(m,1H),1.29(s,3H),1.27-1.15(m,4H),1.04(s,3H);13C NMR(400MHz,DMSO-d6)δ145.3,144.9,144.0,143.1,133.7,132.1,131.6,131.2,128.1,126.1,118.3,117.9,116.5,114.4,113.3,112.1,74.5,59.3,49.5,38.9,29.5,29.0,28.7,27.8,27.2,26.3,23.8;C27H31NO3的HRMS计算值为417.2304(M)+。实测值:417.2319。[α]23 D=-134°(c1.15,CHCl3);实施例247(-)(5S,3’R)-2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-环庚烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z418(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.66(s,1H),7.97(d,1H),6.65(d,1H),6.59(d,1H),6.45(d,1H),6.22(s,1H),5.93(ddd,1H),5.72(ddd,1H),5.50(d,1H),5.45(s,1H),3.65(s,3H),2.38(m,1H),2.13(s,3H),2.04(m,1H),1.82-1.70(m,2H),1.50-1.05(m,5H),1.30(s,3H),1.02(s,3H);13C NMR(400MHz,DMSO-d6)δ145.2,144.8,143.8,143.2,133.9,133.6,131.1,130.8,128.0,126.1,118.6,118.0,116.5,114.4,113.4,112.2,75.3,59.2,49.4,41.9,30.0,29.6,28.3,28.0,27.3,26.1,23.9;C27H31NO3的HRMS计算值为417.2304(M)+。实测值:417.2288。[α]23 D=-122°(c0.74,CHCl3)。实施例2482,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO)δ8.53(s,1H),7.93(d,J=8.7Hz,1H),7.20-7.14(m,5H),6.73(d,J=8.7Hz,1H),6.66(s,1H),6.42(d,J=8.9Hz,1H),6.33(d,J=8.7Hz,1H),6.22(d,J=1.7Hz,1H),5.37(s,1H),3.55(s,3H),1.80(s,3H),1.24(s,3H),1.14(s,3H);13C NMR(300MHz,DMSO)δ145.7,144.8,143.8,143.6,139.3,133.1,132.7,130.2,128.3,127.8,127.6,127.5,126.4,126.1,123.8,118.4,117.8,114.1,114.0,112.8,112.2,74.9,59.0,49.7,29.7,28.4,23.2;MS ESI m/e 400(M+H)+;C26H25NO2的HRMS计算值为399.1834。实测值:399.1839。实施例2492,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3,5-二氟苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO)δ8.68(s,1H),7.95(d,J=8.4Hz,1H),7.06(tt,J=9.2,2.2Hz,1H),6.82(dd,J=8.1,1.8Hz,2H),6.77(d,J=8.4Hz,1H),6.70(s,1H),6.48(d,J=8.4Hz,1H),6.42(d,J=8.4Hz,1H),6.32(d,J=1.5Hz),5.42(s,1H),3.56(s,3H),1.84(d,J=1.1Hz,3H),1.25(s,3H),1.15(s,3H);13C NMR(300MHz,DMSO)δ163.6(d,J=12.81Hz),160.4(d,J=12.81Hz),145.9,145.2,144.5,144.4,(t,J=7.93Hz),143.6,143.3,133.1,129.0,127.3,126.6,118.2,117.9,117.2,114.5(d,J=6.1Hz),112.4,111.4,103.5,73.8,64.9,59.1,49.9,29.6,28.5,23.2;MS ESI m/z 436(M+H)+;C26H22F2NO2的HRMS计算值为435.1646。实测值:435.1657。实施例2502,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3,4,5-三氟苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO)δ8.76(s,1H),8.02(d,J=8.4Hz,1H),7.08(dd,J=6.98,1.8Hz,1H),6.86(dd,J=7.3,2.2Hz,1H),6.83(d,J=8.8Hz,1H),6.73(s,1H),6.55(d,J=8.8Hz,1H),6.47(d,J=8.8Hz,1H),6.38(d,J=1.5Hz,1H),5.46(s,1H),3.62(s,3H),1.88(d,J=1.1Hz,3H),1.30(s,3H),1.13(s,3H);13C NMR(300MHz,DMSO)δ146.0,145.3,143.6,143.1,133.1,128.7,127.3,126.7,118.1(d,J=15.87Hz),117.1,116.0,115.9,115.8,114.05(d,J=9.16Hz),113.0,112.7,112.4,73.5,59.1,49.8,29.7,28.4,23.3。MS ESI m/z 454(M+H)+;C26H22F2NO2的HRMS计算值为453.1552。实测值:453.1571。实施例2515-丁基-2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
使核7的C-5内半缩醛-9-叔丁基二甲基甲硅烷基醚(0.057g,0.122mmol)溶于1,2-氯乙烷(5ml),冷却至-10℃,滴加BF3·OEt2(46ml,0.366mmol)进行处理。滴加正丁基氯化镁(0.19ml的2M/乙醚溶液,0.380mmol)的醚溶液处理生成的深绿色溶液。颜色转变为黄棕色。使该反应混合物在饱和碳酸氢钠水溶液和乙酸乙酯之间分配,用乙酸乙酯提取水层,用盐水洗涤合并的有机物,干燥(硫酸镁)并浓缩至黄色油状物。
使生成的黄色油状物溶于THF(5ml)中,冷却至0℃,用四丁基氟化铵溶液(0.14ml的1M/THF溶液,0.14mmol)进行处理。10分钟后,通过加入饱和氯化铵水溶液和pH7.0的缓冲液猝灭该混合物,分离各层。用乙酸乙酯提取水层,用盐水洗涤合并的有机物,干燥(硫酸镁)并浓缩。残留物经硅胶层析纯化,用25%乙酸乙酯的己烷液洗脱,得到0.032g(72%)所需的化合物。1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),7.90(d,J=8Hz,1H),6.60(d,J=8Hz,1H),6.59(s,1H),6.49(d,J=8Hz,1H),6.16(br s,1H),5.61(m,1H),5.44(br s,1H),3.63(s,3H),2.16(s,3H),1.77-1.63(m,1H),1.47-1.26(m,3H),1.17(s,3H),1.16(s,3H),0.83(m,3H);13C NMR(75MHz,DMSO-d6)δ145.7,144.9,143.9,143.1,133.5,133.3,127.5,126.4,117.9,116.3,114.2,113.4,112.1,73.2,59.3,49.7,34.1,29.1,28.9,23.9,18.6,13.4;MS(DCI/NH3)366 m/e(M+H)+;C23H27NO3·1.25H2O的分析计算值:C,71.20;H,7.66;N,3.61。
实测值:C,71.48;H,7.32;N,3.52。
如同上面的方法处理核7的C-5内半缩醛-9-TBS醚和3-环戊烯基三甲基硅烷,得到1∶1的非对映体产物混合物,将其经(R,R)WHELK-O1柱的HPLC,用2%乙醇的己烷液洗脱,得到各对映体。实施例252(-)(5S,3’S)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-环戊烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)390m/z(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.68(s,1H),8.01(d,1H),6.65(d,1H),6.62(d,1H),6.51(d,1H),6.22(s,1H),5.72(dd,1H),5.41(d,1H),5.40(s,1H),5.17(dd,1H),3.63(s,3H),2.90-2.80(m,1H),2.41-2.32(m,1H),2.23-2.10(m,1H),2.06-(s,3H),1.89-1.71(m,2H),1.30(s,3H),1.08(s,3H);13C NMR(400MHz,DMSO-d6)δ145.5,145.0,143.9,143.4,133.5,132.3,132.2,130.2,128.1,126.4,117.8,116.9,116.4,114.4,113.4,111.9,75.7,59.3,49.5,48.7,31.6,29.8,27.6,27.1,24.2;C25H27NO3的HRMS计算值:389.1991(M)+。实测值:389.1994。[α]23 D=-120°(c0.800,CHCl3)。实施例253(-)(5S,3’R)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-环戊烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)390m/z(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.67(s,1H),8.02(d,1H),6.65(d,1H),6.62(d,1H),6.53(d,1H),6.25(s,1H),5.77(ddd,1H),5.69(ddd,1H),5.47(s,1H),5.37(s,1H),3.66(s,3H),2.90(m,1H),2.34-2.13(m,2H),2.10(s,3H),1.55-1.41(m,2H),1.31(s,3H),1.04(s,3H);13C NMR(400MHz,DMSO-d6)δ145.5,144.9,144.0,143.9,133.6,132.0,131.7,131.5,127.9,126.2,117.7,117.6,116.5,114.4,113.3,111.9,76.1,59.3,49.4,48.6,31.7,29.5,27.1,24.6,23.7;C25H27NO3的HRMSm/z计算值:389.1991。实测值389.1998。[α]23 D=-132°(c0.76,CHCl3)。实施例2542,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3,4-二氟苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.65(s,1H),7.96(d,J=8.8Hz,1H),7.31-7.17(m,2H),6.98-6.95(m,1H),6.76(d,J=8.8Hz,1H),6.67(s,1H),6.48(d,J=8.4Hz,1H),6.38(d,J=8.4Hz,1H),6.29(d,J=1.5Hz),5.40(s,1H),3.57(s,3H),1.82(d,J=1.5Hz),1.25(s,3H),1.14(s,3H);13C NMR(75MHz,DMSO-d6)δ145.9,145.1,143.6,143.3,137.3,132.9,129.5,127.4,126.6,125.2,118.3,117.8,117.3,117.1,117.0,116.8,114.4,114.3,112.3,73.8,59.1,49.8,29.7,28.4,23.3;C26H22NO2F2的HRMS计算值为435.1646。实测值:435.1638。实施例2552,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(4-氟代苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)418(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.58(s,1H),7.95(d,J=8.8Hz,1H),7.23-7.19(m,2H),7.03(dd,J=8.8,8.8Hz,2H),6.74(d,J=8.8Hz,1H),6.66(s,1H),6.44(d,J=8.8Hz,1H),6.34(d,J=8.8Hz,1H),6.24(d,J=1.5Hz),5.38(s,1H),3.57(s,3H),1.80(d,J=1.5Hz),1.24(s,3H),1.14(s,3H);C26H24NO2F的HRMS计算值为417.1740。实测值:417.1745。实施例2562,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-氟代甲基苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS APCIm/z 468(M+H)+;1H NMR(300MHz,DMSO)δ8.62(s,1H),7.97(d,J=8.8Hz,1H),7.61-7.41(m,3H),7.36(s,1H),6.75(s,1H),6.44(d,J=8.4Hz,1H),6.35(d,J=8.4Hz,1H),6.30(d,J=1.5Hz,1H),5.40(s,1H),3.52(s,3H),1.80(d,J=1.5Hz,3H),1.24(s,3H),1.15(s,3H);13C NMR(300MHz,DMSO)δ145.9,145.0,143.5,140.9(d,J=17.01Hz),140.9,133.0,132.6,129.3,129.2,127.4,126.6,124.4,118.3,118.0,117.4,114.5(d,J=7.32Hz),112.3,74.2,58.9,49.8,29.5,29.4,23.3。C27H24F2NO2的HRMS计算值为467.1708。实测值:467.1708。实施例2572,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3,5-双三氟甲基苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS APCIm/z536(M+H)+;1H NMR(300MHz,DMSO)δ8.69(s,1H),8.00(d,J=8.8Hz,1H),7.96(s,1H),7.80(s,2H),6.90(s,1H),6.79(d,J=8.4Hz,1H),6.46(d,J=8.8Hz,1H),6.39(d,J=1.3Hz,1H),6.37(d,J=8.4Hz,1H),5.43(s,1H),3.51(s,3H),1.80(d,J=0.73Hz,3H),1.24(s,3H),1.15(s,3H);13C NMR(300MHz,DMSO)δ146.1,145.3,143.6,142.9,133.2,130.1,129.7,129.5,127.2,126.7,124.9,118.2,117.2,114.8,112.3,73.5,58.8,49.8,29.4,28.3,23.3。C28H22F6NO2的HRMS计算值为535.1582。实测值:535.1573。实施例2582,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-三氟甲基-4-氯代苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(APCI)m/z502(M+H)+;1H NMR(300MHz,DMSO)δ8.70(s,1H),7.97(d,J=8.8Hz,1H),7.70-7.60(m,3H),6.78(s,1H),7.55(s,1H),6.46(d,J=8.8Hz,1H),6.38(s,1H),6.36(d,J=8.8Hz,1H),5.41(s,1H),3.53(s,3H),1.79(s,3H),1.28(s,3H),1.14(s,3H);13C NMR(300MHz,DMSO)δ166.9,146.0,145.2,143.6,143.1,139.6,134.1,133.0,131.7,131.5,128.6,127.3,126.7,114.6,112.3,73.7,59.0,49.8,67.4,29.6,29.8,28.3,23.3,23.2,22.4,13.8,10.8。C27H22ClF2NO2的HRMS计算值为501.1319。实测值:501.1326。实施例2592,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(2-甲基丙基)-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例251的方法处理核7的C-5内半缩醛-9-叔丁基二甲基甲硅烷基醚和异丁基氯化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.69(s,1H),7.90(d,J=8Hz,1H),6.61(d,J=8Hz,1H),6.59(d,J=8Hz,1H),6.48(d,J=8Hz,1H),6.16(br s,1H),5.7 1(m,1H),5.44(br s,1H),3.63(s,3H),2.17(s,3H),1.82-1.60(m,2H),1.43-1.18(m,1H),1.17(s,3H),1.16(s,3H),0.97(d,J=7Hz,3H),0.76(d,J=7Hz,3H);13C NMR(75MHz,DMSO-d6)δ145.8,144.8,143.8,143.0,133.5,133.3,127.5,126.4,117.9,116.3,116.1,114.2,113.4,112.1,71.8,59.3,49.6,29.1,28.9,24.6,24.0,23.3,21.2。MS(FAB,高分辨)m/e C24H29NO3的计算值:379.2147。实测值:379.2159。实施例2602,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-氟代-4-氯代苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例251的方法处理核7的C-5内半缩醛-9-叔丁基二甲基甲硅烷基醚和3-氟代-4-氯代苯基溴化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.72(s,1H),7.91(d,J=8Hz,1H),6.59(d,J=8Hz,1H),6.59 6.48(d,J=8Hz,1H),6.16(br s,1H),5.71(m,1H),5.44(br s,1H),3.63(s,3H),2.17(s,3H),1.82-1.60(m,2H),1.43-1.18(m,1H),1.17(s,3H),1.16(s,3H),0.97(d,J=7Hz,3H),0.76(d,J=7Hz,3H)。实施例2612,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-丁烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例251的方法处理核7的C-5内半缩醛-9-叔丁基二甲基甲硅烷基醚和1-丁烯基-4-溴化镁,得到所需化合物。实施例2622,5-二氢-9-羟基-10-甲氧基-5-(苯基甲基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例251的方法处理核7的C-5内半缩醛-9-TBS醚和苄基溴化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),7.97(d,J=9Hz,1H),7.34-7.13(m,3H),7.11(s,1H),7.10(d,J=7Hz,1H),6.67(m,J=8Hz,1H),6.65(m,J=8Hz,1H),6.42(d,J=9Hz,1H),6.20(br s,1H),5.86(dd,J=10,3Hz,1H),5.42(br s,1H),3.69(s,3H),2.99(dd,J=10,14Hz,1H),2.77(dd,J=3,15Hz,1H),2.23(s,3H),1.16(s,3H),1.15(s,3H);13C NMR(125MHz,DMSO-d6)δ145.8,145.0,144.0,142.8,138.0,133.3,132.4,128.9(2C),121.1(2C),127.4,126.4,126.1,117.9,116.3,116.2,114.4,113.7,112.5,74.5,59.4,49.7,37.9,29.2,29.0,24.3;MS(DCI/NH3)m/e414(M+H)+;C27H27NO3·1/4H2O的分析计算值:C,77.58;H,6.63;N,3.35。实测值:C,77.70;H,7.07;N,3.19。实施例263(-)(5S,3’R)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-[1-乙基-3-环己烯基]-1H-[1]苯并吡喃并[3,4-f]喹啉
将得自实施例277的非对映体的混合物在Chiracel OJ HPLC上拆分,用己烷∶2-丙醇(95∶5)洗脱,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.67(s,1H),7.99(d,J=9Hz,1H),6.65(d,J=9Hz,1H),6.62(d,J=9Hz,1H),6.53(d,J=8Hz,1H),6.22(s,1H),5.44(d,J=12Hz,2H),5.30(d,J=10Hz,1H),3.62(s,3H),3.50-2.26(m,1H),2.11(s,3H),1.89-1.72(m,3H),1.25-1.17(m,2H),1.03(2,3H),.088(t,J=7Hz,3H);13C NMR(75MHz,DMSO-d6)δ145.4,144.9,144.0,143.7,140.1,133.6,130.9,127.9,126.1,120.0,118.2,117.8,116.6,114.3,113.3,112.0,76.2,59.3,49.4,37.7,30.2,29.6,27.7,27.2,24.9,23.7,21.6,12.3。实施例264(-)(S)5-环戊基-2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例251的方法处理核7的C-5内半缩醛-9-TBS醚和环戊基氯化镁。通过在(R,R)WHELK-O1柱经HPLC,用2%乙醇的己烷液洗脱,将生成的外消旋产物拆分成其成分对映体,得到作为第一洗脱物的所需化合物。1H NMR(300MHz,DMSO-d6)δ8.66(s,1H),8.00(d8,1H),6.63(d8,1H),6.61(d,J=8Hz,1H),6.48(d,J=8Hz,1H),6.24(br s,1H),5.45(br s,1H),5.35(d,J=10Hz,1H),3.65(s,3H),2.15(s,3H),2.12-1.97(m,1H),1.60-1.43(m,4H),1.42-1.22(m,2H),1.19-1.07(m,2H),1.31(s,3H),1.02(s,3H);MS(DCI/NH3)m/e(M+H)+392。实施例265(+)(R)5-环戊基-2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
通过在(R,R)WHELK-O1柱经HPLC,用2%乙醇的己烷液洗脱,将得自实施例264的外消旋产物拆分成其成分对映体,得到作为第二洗脱物的所需化合物。1H NMR(300MHz,DMSO-d6)δ8.66(s,1H),8.00(d8,1H),6.63(d8,1H),6.61(d,J=8Hz,1H),6.48(d,J=8Hz,1H),6.24(br s,1H),5.45(br s,1H),5.35(d,J=10Hz,1H),3.65(s,3H),2.15(s,3H),2.12-1.97(m,1H),1.60-1.43(m,4H),1.42-1.22(m,2H),1.19-1.07(m,2H),1.31(s,3H),1.02(s,3H);MS(DCI/NH3)m/e(M+H)+392。实施例2662,5-二氢-9-羟基-10-甲氧基-5-(3-丙炔基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例251的方法处理核7的C-5内半缩醛-9-TBS醚和炔丙基溴化镁(Caoni,Y.,Leznoff.C.C.,Sondheimer.J.Am.Chem.Soc.1968,90,4940-4945.),得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),7.92(d,J=9Hz,1H),6.63(d,J=9,8Hz,2H),6.54(m,1H),6.17(s,1H),5.82(dd,J=9,9Hz,1H),5.44(s,1H),3.68(s,3H),2.78(t,1H),2.44-2.36(m,2H),2.18(s,3H),1.17(d,J=5Hz,6H);13C NMR(75MHz,DMSO-d6)δ145.9,145.5,145.4,145.2,143.9,142.3,133.5,132.6,131.4,127.4,126.5,117.4,116.5,115.8,114.5,114.0,112.6,91.4,80.7,72.5,59.4,49.8,29.3,29.0,23.9,23.3,22.4。实施例2672,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(2-丙基)-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例251的方法处理核7的C-5内半缩醛-9-TBS醚和并丙基氯化镁,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.65(s,1H),7.99(d8,1H),6.64(d,J=8Hz,1H),6.61(d,J=8Hz,1H),6.51(d,J=8Hz,1H),6.22(br s,1H),5.44(br s,1H),5.26(d,J=10Hz,1H),3.64(s,3H),2.16(s,3H),1.85-1.67(m,1H),1.30(s,3H),1.02(s,3H),0.93(d,J=6Hz,3H),0.64(7,3H);13C NMR(75MHz,DMSO-d6)δ145.3,144.8,144.0,,143.7,133.5,131.6,128.2,126.1,118.4,117.9,116.5,114.3,113.2,112.0,77.7,59.3,49.4,30.7,29.7,27.2,23.9,19.5,17.9;MS(DCI/NH3)m/e(M+H)+366;C23H27NO3·1/4H2O的分析计算值:C,74.67;H,7.49;N,3.79。
实测值:C,74.81;H,7.39;N,3.67。实施例2682,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(5-甲氧基-2-噻吩基)-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例276的方法处理核7的C-5内半缩醛-9-TBS醚和2-甲氧基噻吩,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.63(s,1H),7.93(d,J=8Hz,1H),6.70(d,J=8Hz,1H),6.65(s,1H),6.50(d,J=8Hz,1H),6.39(d,J=9Hz,1H),6.28(d,J=3Hz,1H),6.23(br s,1H),5.97(d,J=3Hz,1H),5.38(br s,1H),3.72(s 3),3.59(s,3H),1.97(s,3H),1.22(s,3H),1.13(s,3H);13C NMR(75MHz,DMSO-d6)δ166.2,145.7,145.1,143.6,143.5,132.9,130.2,128.7,127.6,126.4,126.0,118.3,117.2,117.2,114.2,112.4,102.7,71.5,59.7,59.1,49.8,29.8,28.6,22.9;MS(DCI/NH3)m/e(M+H)+436;C25H25NO4S·1/4H2O的分析计算值:C,68.24;H,5.84;N,3.18。
实测值:C,68.52;H,6.19;N,3.00。实施例269(±)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(2,3,4,5,6-五氟苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
处理核7的C-5内半缩醛-9-TBS醚和五氟苯基溴化镁,得到所需化合物,将其经快速层析纯化,用4∶1己烷/乙酸乙酯洗脱。MS(DCI/NH3)m/z 490(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.75(s,1H),7.83(d,1H),6.82(s,1H),6.67(d,1H),6.44(d,1H),6.33(d,1H),6.19(s,1H),5.37(s,1H),3.53(s,3H),1.77(s,3H),1.17(s,3H),1.06(s,3H);13C NMR(400MHz,DMSO-d6)δ146.1,145.8,143.8,142.9,133.4,128.4,127.0,126.2,118.6,118.1,117.6,114.5,114.2,113.3,112.2,105.0,68.6,58.9,49.9,29.8,28.3,23.1;C26H20NO3F5·0.5H2O的分析计算值:C,62.65;H,4.25;N,2.81。
实测值:C,62.4;H,4.28;N,2.73。实施例270(+/-)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5(S)-(3(S)-1-羟甲基环戊烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z 420(M+H)+;1H NMR(400MHz,DMSO-d6)1H NMR(200MHz,DMSO-d6)δ8.77(s,1H),8.04(d,1H),6.67(d,1H),6.62(d,1H),6.52(d,1H),6.24(bs,1H),6.12(dd,1H),5.50(d,1H),5.42(bs,1H),2.64(s,2H),2.57(s,2H),2.75-1.09(m,14H)。实施例271(+/-)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5(S)-(3(S)-1-甲基羧酸酯环戊烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉
如同上面的方法处理核7的C-5内半缩醛-9-TBS醚和3-环己烯基三甲基硅烷,得到3∶2的非对映体产物混合物,将其经(R,R)WHELK-O1柱的HPLC,用2%乙醇的己烷液洗脱,得到各对映体。实施例272(-)(5S,3’S)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-环己烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z404(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),7.99(d,1H),6.65(d,1H),6.62(d,1H),6.52(d,1H),6.20(d,1H),5.61(ddd,1H),5.46(d,1H),5.41(s,1H),5.10(dd,1H),3.66(s,3H),2.27(m,1H),2.10(s,3H),1.99-1.72(m,2H),1.70-1.55(m,3H),1.35(m,1H),1.29(s,3H),1.06(s,3H);13C NMR(400MHz,DMSO-d6)δ145.4,145.0,143.4,143.0,133.5,131.0,128.9,128.1,126.4,126.3,117.9,116.5,114.4,113.5,112.1,75.2,59.3,49.5,36.9,29.7,27.6,25.5,24.6,24.3,20.0;[α]23 D=-162°(c0.11,CHCl3)。实施例273(-)(5S,3’R)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-环己烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z404(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.01(d,1H),6.65(d,1H),6.62(d,1H),6.53(d,1H),6.27(d,1H),5.82-5.65(m,2H),5.45(s,1H),5.33(d,1H),3.65(s,3H),2.28(m,1H),2.12(s,3H),1.86(m,2H),1.55(m,1H),1.31(s,3H),1.26-1.14(m,3H),1.03(s,3H);13C NMR(400MHz,DMSO-d6)δ145.4,145.0,144.1,143.5,133.6,130.7,128.1,127.9,127.7,126.1,118.4,117.8,116.5,114.4,113.4,112.1,75.9,59.4,49.4,37.2,29.6,27.1,24.7,24.6,23.7,21.2;[α]23 D=-158°(c0.50,CHCl3)。实施例2742,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(2-噻吩基)-1H-[1]苯并吡喃并[3,4-f]喹啉
通过用乙醚(2ml)稀释2-噻吩基锂(1.0ml的1M/THF溶液,1.0mmol),冷却至0℃,用氯化锌(1.1ml的1M/乙醚溶液,1.10mmol)处理,并使之升温至室温来制备0.24M的2-噻吩基氯化锌溶液。将生成的多相混合物剧烈搅拌过夜。
根据实施例251的方法处理核7的C-5内半缩醛-9-TBS醚和来自上面步骤的2-噻吩基氯化锌,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.65(s,1H),7.95(d,J=9Hz,1H),7.39(dd,J=5,1Hz,1H),6.85-6.82(m,2H),6.74(m,1H),6.72(d,J=8Hz,1H),6.48(d,J=8Hz,1H),6.37(d,J=9Hz,1H),6.28(br s,1H),5.39(br s,1H),3.59(s,3H),1.93(s,3H),1.22(s,3H),1.14(s,3H);13C NMR(75MHz,DMSO-d6)δ145.7,145.1,143.7,143.6,143.5,133.0,130.8,127.9,127.5,127.0,126.5,126.4,1 18.3,117.1,114.4,114.2,112.4,70.9,59.0,49.8,29.7,28.6,23.0;MS(DCI/NH3)m/e(M+H)+406;C24H23NO3S的分析计算值:C,71.09;H,5.72;N,3.45。
实测值:C,70.93;H,6.00;N,3.27。实施例275(±)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(2-甲基苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
处理核7的C-5内半缩醛-9-TBS醚和邻甲苯基溴化镁,得到所需化合物,将其经快速层析纯化,用4∶1己烷/乙酸乙酯洗脱。MS(DCI/NH3)m/z414(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.43(s,1H),7.79(d,1H),7.02(d,1H),6.92(dt,1H),6.72(t,1H),6.59(d,1H),6.55(s,1H),6.54(d,1H),6.24(d,1H),6.12(d,1H),6.07(s,1H),5.20(s,1H),3.48(s,3H),2.44(s,3H),1.54(s,3H),1.09(s,3H),0.98(s,3H);13C NMR(400MHz,DMSO-d6)δ145.9,145.0,143.9,143.6,137.5,136.6,132.6,130.6,130.5,128.8,128.1,127.6,126.4,124.9,118.7,118.2,117.8,114.1,114.0,111.7,73.7,59.2,49.8,30.0,28.3,22.5,19.3;C27H27NO3的分析计算值:C,78.42;H,6.58;N,3.39。
实测值:C,78.07;H,6.85;N,3.09。实施例2762,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(2-乙酰氧基甲基-3-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
使核7的C-5内半缩醛-9-TBS醚(0.150g,0.321mmol)溶于二氯甲烷(15ml),用2-[(三甲基甲硅烷基)甲基]-2-丙烯-1-基乙酸酯(0.180g,0.962mmol)处理,冷却至-78℃,滴加BF3·Et2O进行处理并温热至0℃。10分钟后,使该反应混合物在饱和碳酸氢钠水溶液和乙酸乙酯之间分配,分离各层,用乙酸乙酯提取水层,用盐水洗涤合并的有机物,干燥(硫酸镁)并浓缩。
使生成的黄色油状物溶于THF(10ml)中,冷却至0℃,用四丁基氟化铵溶液(0.35ml的1M/THF溶液,0.35mmol)进行处理。10分钟后,通过加入饱和氯化铵水溶液和pH7.0的缓冲液猝灭该混合物,分离各层。用乙酸乙酯提取水层,用盐水洗涤合并的有机物,干燥(硫酸镁)并浓缩。残留物经硅胶层析纯化,用25%乙酸乙酯的己烷液洗脱,得到0.125g(89%)所需的化合物。1H NMR(300MHz,DMSO-d6)δ8.74(s,1H),7.92(d,J=8Hz,1H),6.63(d,J=8Hz,1H),6.62(d,J=8Hz,1H),6.41(d,J=9Hz,1H),6.21(br s,1H),5.85(dd,J=2,10Hz,1H),5.44(s,1H),5.08(s,1H),4.92(s,1H),4.58(ABq,J=13,30Hz,2H),3.65(s,3H),2.23(m,2H),2.17(s,3H),1.99(s,3H),1.18(s,3H),1.15(s,3H);MS(DCI/NH3)m/e(M+H)+436;C26H29NO5的分析计算值:C,71.71;H,6.71;N,3.22。
实测值:C,71.34;H,6.98;N,3.12。实施例277(+)(5R,3’S)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-[1-乙基-3-环己烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
于-23℃,向77ml的二甲基苯基甲硅烷基甲基铜酸酯的0.36MTHF溶液(27.7mmol)(Fleming,L;Newton,T.W.J.Chem.Soc.PerkinTrans.I,1984,1805.)中加入3-乙基-环己-2-烯-1-酮(2.73g,27.0mmol)。于-23℃搅拌该混合物1小时,然后于0℃搅拌2小时,用N-苯基-双(三氟甲磺酰亚胺)(4.43g,26.4mmol)处理,使温热至室温并搅拌18小时。用饱和碳酸氢钠水溶液猝灭该反应混合物,通过硅藻土过滤,分离各层。用饱和碳酸氢钠水溶液、盐水洗涤有机层,干燥(硫酸钠)。产物经硅胶柱层析纯化,用己烷洗脱,得到为淡黄色油状物的中间体三氟甲磺酸酯。
于室温下,将上面的三氟甲磺酸酯(0.70g,1.28mmol)与三丁基氢化锡(0.92g,2.13mmol)在THF中混合并滴加到四(三苯膦)钯(0)(0.44g,3.5mmol)和氯化锂(0.45g,10.7mmol)的THF溶液中。滴加后,将该反应物回流24小时,冷却、通过硅藻土垫过滤,与饱和氟化钾溶液一起剧烈搅拌2小时。使该混合物通过硅藻土过滤,用乙酸乙酯稀释,分离各层。用饱和碳酸氢钠水溶液、盐水洗涤有机层并干燥(硫酸钠)。产物经硅胶柱层析纯化,用己烷洗脱,得到为无色油状物的3-乙基-3-二甲基苯基甲硅烷基-环己烯。
根据实施例276的方法处理核7的C-5内半缩醛-9-TBS醚和3-乙基-3-二甲基苯基甲硅烷基-环己烯,得到为非对映体混合物的产物,将其经(R,R)WHELK-O1柱的HPLC分离,用己烷∶乙醇(98∶2)洗脱,得到所需化合物。1H NMR(500MHz,DMSO-d6)δ8.01(d,J=8Hz,1H),6.63(d,J=8Hz,1H),6.61(d,J=9Hz,1H),6.53(d,J=9Hz,1H),6.20(s,1H),5.48(s,1H),5.44(s,1H),5.32(d,J=9Hz,1H),3.64(s,3H),2.26(m,1H),1.90-1.73(m,3H),1.60(m,1H),1.26-1.18(m,2H),1.03(s,3H),.088(t,J=7Hz,3H);13C NMR(50MHz,DMSO-d6)δ145.3,144.8,144.0,143.6,140.3,133.5,130.8,127.8,126.0,120.0,118.1,117.8,116.5,114.2,113.2,111.9,76.1,59.2,49.4,37.5,30.1,29.5,27.7,27.1,24.8,23.6,21.6,12.2;C28H33O3N的MS m/e计算值:431.2460。实测值:431.2467。
处理核7的C-5内半缩醛-9-TBS醚和环己基氯化镁,得到实施例278和279产物的混合物,将其经快速层析分离,用4∶1己烷/乙酸乙酯洗脱。实施例2782,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-环己基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z406(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.66(s,1H),7.96(d,1H),6.61(d,1H),6.59(d,1H),6.47(d,1H),6.18(d,1H),5.42(s,1H),5.30(d,1H),3.64(s,3H),2.13(s,3H),1.87(m,1H),1.60-1.48(m,3H),1.28(s,3H),1.20-0.80(m,7H),1.00(s,3H);13C NMR(400MHz,DMSO-d6)δ145.3,144.8,144.1,143.8,133.5,131.1,128.1,126.1,118.5,117.9,116.6,114.4,113.2,112.0,76.8,59.3,49.4,29.7,29.5,28.0,27.2,25.8,25.6,25.3,23.8;实施例2792,5,5-三氢-9-羟基-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z324(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.78(s,1H),7.81(d,1H),6.62(d,1H),6.57(d,1H),6.53(d,1H),6.22(s,1H),5.40(s,1H),5.05(s,2H),3.62(s,3H),2.01(s,3H),1.19(s,6H);13C NMR(400MHz,DMSO-d6)δ146.6,145.4,145.3,144.0,131.5,130.8,128.1,126.2,118.2,118.0,117.2,113.9,113.2,111.2,67.1,59.4,49.9,29.0,22.9;实施例2802,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(2-羟甲基-3-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例276的产物(0.032g,0.074mmol)溶于THF/甲醇/水(5ml/1ml/0.5ml)中,冷却至0℃,用碳酸钾(0.051g,0.367mmol)处理,使温热至室温并搅拌12小时。将该混合物在饱和氯化铵水溶液和乙酸乙酯之间分配,用乙酸乙酯萃取水层,用盐水洗涤合并的有机物,干燥(硫酸镁)并浓缩。残留物经硅胶层析纯化,用25%和50%乙酸乙酯的己烷液先后洗脱,得到0.022g(76%)所需的化合物。1H MR(300MHz,DMSO-d6)δ8.71(s,1H),7.92(d,J=9Hz,1H),6.62(d,J=9Hz,1H),6.61(d,J=8Hz,1H),6.41(d,J=8Hz,1H),6.18(d,J=1Hz,1H),5.86(dd,J=11,1Hz,1H),5.43(br s,1H),5.02(m,1H),4.80(t,J=6Hz,1H),4.74(br s,1H),3.90-3.78(m,2H),3.65(s,3H),2.50-2.36(m,1H),2.23-2.10(m,1H),2.19(s,3H),1.17(s,3H),1.18(s,3H);13C NMR(125MHz,DMSO-d6)δ145.9,145.8,144.9,143.8,142.8,133.2,132.8,127.6,126.4,117.7,116.2,116.2,114.2,113.6,112.6,110.6,72.1,63.7,59.4,49.7,35.4,29.2,28.9,23.9;MS(DCI/NH3)m/e(M+H)+394。实施例2812-[2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]-5-喹啉基]乙酸甲酯
根据实施例46的方法处理核7的C-5内半缩醛-9-TBS醚,得到中间体甲硅烷基化产物。1H NMR(300MHz,DMSO-d6)δ7.94(d,J=9Hz,1H),6.64(dd,J=9,3Hz,1H),6.49(d,J=9Hz,1H),6.27(s,1H),6.14(dd,J=10,3Hz,1H),4.45(s,1H),3.63(s,3H),3.61(s,3H),2.76-2.55(m,2H),2.20(s,3H),1.18(s,3H),1.16(s,3H),1.00(s,9H),0.21(s,3H),0.16(s,3H);MS(APCl)m/e(M+H)+510,(M-H)-508。
将上面的中间体甲硅烷基化的化合物(0.030g,0.058)溶于冷却至0℃的THF(1ml)中,用四丁基氟化铵(58μl的1M/THF溶液,0.058mmol)处理。5分钟后,将该混合物倾入饱和氯化铵水溶液并用乙酸乙酯提取。用盐水洗涤合并的有机层并干燥(硫酸镁)。产物经硅胶层析纯化,用40%的甲基叔丁基醚的己烷液洗脱,得到为白色固体的所需的化合物(0.019g,82%)。1H NMR(300MHz,DMSO-d6)δ8.80(s,1H),7.93(d,J=9Hz,1H),6.64(d,J=9Hz,1H),6.61(d,J=9Hz,1H),6.43(d,J=9Hz,1H),6.25(s,1H),6.10(dd,J=10,3Hz,1H),5.45(s,1H),3.66(s,3H),3.60(s,3H),2.77-2.52(m,2H),2.21(s,3H),1.18(s,3H),1.16(s,3H);MS(APCl)m/e(M+H)+396,(M-H)-394。实施例282(Z)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(2-丁烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
将得自实施例281的中间体甲硅烷基化的产物(0.445g,0.87mmol)溶于THF(4ml)中,冷却至0℃,滴加Dibal-H(2.69ml的1M/THF溶液,2.69mmol)进行处理,搅拌30分钟。将该反应混合物倾入100ml的饱和酒石酸钠钾水溶液和100ml乙酸乙酯的快速搅拌的混合物中并搅拌1小时。分离各层,用乙酸乙酯提取水层,用饱和碳酸氢钠水溶液、盐水洗涤合并的有机层并干燥(硫酸镁)。残留物经硅胶层析纯化,用20%和30%的甲基叔丁基醚的己烷液洗脱,接着用6%乙酸乙酯的二氯甲烷液洗脱,得到为白色固体的伯醇(0.293g,70%)。1H NMR(300MHz,DMSO-d6)δ7.92(d,J=9Hz,1H),6.65(d,J=9Hz,1H),6.61(d,J=9Hz,1H),6.57(d,J=9Hz,1H),6.21(s,1H),5.88(dd,J=10,3Hz,1H),5.43(s,1H),4.62(t,J=5Hz,1H),3.61(s,3H),2.19(s,3H),1.90-1.75(m,2H),1.62-1.47(m,2H),1.17(s,3H),1.15(s,3H),0.99(s,9H),0.20(s,3H),0.15(s,3H);MS(APCl)m/e(M+H)+482,(M-H)-480。
将草酰氯(22μl,0.249mmol)的THF(2ml)中的搅拌溶液冷却至-78℃,用DMSO(24μl,0.332mmol)处理,搅拌5分钟,滴加上面的伯醇(0.080g,0.166mmol)的2ml的THF溶液进行处理。将生成的混合物搅拌40分钟,用三乙胺(92.5μl,0.664mmol)处理,再搅拌10分钟并使温热至0℃。于0℃30分钟后,使该反应混合物在水和二氯甲烷之间分配,用二氯甲烷提取水层,干燥(硫酸镁)合并的有机层。产物经硅胶层析纯化,用20%和30%的乙酸乙酯的己烷液先后洗脱,得到为白色固体的醛(0.059g,73%)。1H NMR(300MHz,DMSO-d6)δ9.65(s,1H),7.93(d,J=9Hz,1H),6.67(d,J=9Hz,1H),6.65(d,J=9Hz,1H),6.48(d,J=9Hz,1H),6.33(m,2H),5.46(s,1H),3.63(s,3H),2.87(m,1H),2.65(m,1H),2.18(s,3H),1.19(s,3H),1.14(s,3H),1.00(s,9H),0.21(s,3H),0.15(s,3H);MS(APCl)m/e(M+H)+480,(M-H)-478。
将乙基三苯基溴化鏻(0.130g,0.351mmol)的THF∶Et2O(3ml,3∶2)的溶液冷却至0℃,滴加正丁基锂(140μl的2.5M/己烷溶液,0.351mmol)进行处理。于0℃,将生成的深红色溶液搅拌30分钟,冷却至-78℃,用上面的醛(0.056g,0.117mmol)的THF(2ml)溶液处理。于-78℃,将该反应混合物搅拌5分钟,温热至0℃40分钟,通过加入水猝灭。分离各层,用二氯甲烷提取水层,用盐水洗涤合并的有机层并干燥(硫酸镁)。产物经硅胶层析纯化,用5%-20%的乙酸乙酯的己烷梯度液洗脱,得到为白色固体的中间体甲硅烷基醚(0.050g,87%)。1H NMR(300MHz,DMSO-d6)δ7.92(d,J=9Hz,1H),6.65(d,J=9Hz,1H),6.63(d,J=9Hz,1H),6.20(s,1H),5.68(dd,J=10,3Hz,1H),5.43(m,3H),3.64(s,3H),2.15(s,3H),1.26(d,J=5Hz,3H),1.17(s,6H),1.00(s,9H),0.20(s,3H),0.15(s,3H);MS(APCl)m/e(M+H)+492,(M-H)-490。
将中间体甲硅烷基醚(0.038g,0.077mmol)溶于THF(3ml)中,冷却至0℃,用四丁基氟化铵(80ml的1M/THF溶液,0.080mmol)进行处理,将该混合物在乙酸乙酯和饱和氯化铵之间分配。用乙酸乙酯提取水层,用盐水洗涤合并的有机物,干燥(硫酸镁)并经硅胶层析纯化,用25%的乙酸乙酯的己烷液洗脱,得到所需化合物(0.024g,83%)。1H NMR(300MHz,DMSO-d6)δ8.71(s,1H),7.93(d,J=9Hz,1H),6.62(d,J=9Hz,1H),6.60(d,J=9Hz,1H),6.47(d,J=9Hz,1H),6.18(s,1H),5.62(dd,J=10,3Hz,1H),5.43(m,3H),3.64(s,3H),2.45-2.18(m,2H),2.15(s,3H),1.30(d,J=5Hz,3H),1.15(s,6H);MS(APCl)m/e的计算值:377.20。实测值(M+H)+378,(M-H)-376。实施例2832,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-甲基-2-丁烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
根据实施例282的方法处理得自实施例282的中间体醛和异丙基三苯基碘化鏻,得到所需化合物。1H NMR(300MHz,DMSO-d6)δ8.65(s,1H),7.91(d,J=9Hz,1H),6.62(d,J=9Hz,1H),6.60(d,J=9Hz,1H),6.46(d,J=9Hz,1H),6.14(s,1H),5.60(dd,J=9,3Hz,1H),5.43(s,1H),5.15(m,1H),3.64(s,3H),2.45-2.18(m,2H),2.15(s,3H),1.63(s,3H),1.32(s,3H),1.17(s,3H),1.16(s,3H);MS(APCl)m/e(M+H)+392,(M-H)-390。实施例284(+)(5S,3’S)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-环己烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z404(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.01(d,1H),6.65(d,1H),6.62(d,1H),6.53(d,1H),6.27(d,1H),5.82-5.65(m,2H),5.45(s,1H),5.33(d,1H),3.65(s,3H),2.28(m,1H),2.12(s,3H),1.86(m,2H),1.55(m,1H),1.31(s,3H),1.26-1.14(m,3H),1.03(s,3H);13C NMR(400 MHz,DMSO-d6)δ145.4,145.0,144.1,143.5,133.6,130.7,128.1,127.9,127.7,126.1,118.4,117.8,116.5,114.4,113.4,112.1,75.9,59.3,49.4,37.2,29.6,27.1,24.7,24.6,23.7,21.2;[α]23 D=+184°(c0.33,CHCl3)。实施例285(+)(5R,3’R)2,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-环己烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z404(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),7.99(d,1H),6.65(d,1H),6.62(d,1H),6.52(d,1H),6.20(d,1H),5.61(ddd,1H),5.46(d,1H),5.41(s,1H),5.10(dd,1H),3.66(s,3H),2.27(m,1H),2.10(s,3H),1.99-1.72(m,2H),1.70-1.55(m,3H),1.35(m,1H),1.29(s,3H),1.06(s,3H);13C NMR(400MHz,DMSO-d6)δ145.4,145.0,143.4,143.0,133.5,131.0,128.9,128.1,126.4,126.3,117.9,116.5,114.4,113.5,112.1,75.2,59.3,49.5,36.9,29.7,27.6,25.5,24.6,24.3,20.0;[α]23 D=+170°(c0.23,CHCl3)。实施例286(+)(5R,3’S)2,5(R)-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-环戊烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z390(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.67(s,1H),8.02(d,1H),6.65(d,1H),6.62(d,1H),6.53(d,1H),6.25(s,1H),5.77(ddd,1H),5.69(ddd,1H),5.47(s,1H),5.37(s,1H),3.66(s,3H),2.90(m,1H),2.34-2.13(m,2H),2.10(s,3H),1.55-1.41(m,2H),1.31(s,3H),1.04(s,3H);13C NMR(400MHz,DMSO-d6)δ145.5,144.9,144.0,143.9,133.6,132.0,131.7,131.5,127.9,126.2,117.7,117.6,116.5,114.4,113.3,111.9,76.1,59.3,49.4,48.6,31.7,29.5,27.1,24.6,23.7;[α]23 D=+136°(c0.355,CHCl3)。实施例287(+)(5R,3’R)2,5(R)-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-环戊烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z390(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.68(s,1H),8.01(d,1H),6.65(d,1H),6.62(d,1H),6.51(d,1H),6.22(s,1H),5.72(dd,1H),5.41(d,1H),5.40(s,1H),5.17(dd,1H),3.63(s,3H),2.90-2.80(m,1H),2.41-2.32(m,1H),2.23-2.10(m,1H),2.06(s,3H),1.89-1.71(m,2H),1.30(s,3H),1.08(s,3H);13C NMR(400MHz,DMSO-d6)δ145.5,145.0,143.9,143.4,133.5,132.3,132.2,130.2,128.1,126.4,117.8,116.9,116.4,114.4,113.4,111.9,75.7,59.3,49.5,48.7,31.6,29.8,27.6,27.1,24.2;[α]23 D=+116°(c0.800,CHCl3)。实施例288rel-(5S)-9-羟基-5-[(3R)-(1-甲氧基羰基)环己烯-3-基]-10-甲氧基-2,2,4-三甲基-2,5-二氢1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)462(M+H)+;1H NMR(200MHz,DMSO-d6)δ8.81(s,1H),8.07(d,J=8.5Hz,1H),6.72(d,J=8.5Hz,1H),6.70(d,J=8.5Hz,1H),6.60(d,J=8.5Hz,1H),6.42-6.41(m,1H),6.21(d,J=1.2Hz),5.57(d,J=10.2Hz,1H),1H),5.45(s,1H),2.71(s,2H),2.58(s,2H),2.56-2.48(m,2H),2.20-2.16(m,2H),2.08(d,J=1.2Hz),1.80-1.40(m,4H),1.25(s,2H),1.18(s,2H);C28H21NO5的HRMS计算值为461.2202。实测值461.2212。实施例2892,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(2-甲基-3-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉
将实施例276的产物(0.040g,0.092mmol)和二氯双(三苯膦)钯(II)(0.006g,0.009mmol)溶于二氧六环(5ml)中,加热至100℃,并用硼氢化钠(0.017g,0.460mmol)处理。使生成的黑色溶液冷却至室温,用水和乙酸乙酯稀释,通过硅藻土过滤。分离各层,用乙酸乙酯提取水层。用盐水洗涤合并的有机物,干燥(硫酸镁)并浓缩。经硅胶层析纯化,用25%的乙酸乙酯的己烷液洗脱,得到所需的产物(0.028g,80%),为无色泡沫物。1H NMR(300MHz,DMSO-d6)δ8.71(s,1H),7.92(d,J=8Hz,1H),6.62(d,J=8Hz,1H),6.61(d,J=8Hz,1H),6.41(d,J=8Hz,1H),6.18(d,J=1Hz,1H),5.83(dd,J=3,10Hz,1H),5.44(br s,1H),4.75(br s,1H),4.56(br s,1H),3.65(s,3H),2.50-2.41(m,1H),2.19(s,3H),2.16-2.07(m,1H),1.73(s,3H),1.18(s,3H),1.15(s,3H);13C NMR(125MHz,DMSO-d6)δ145.8,144.9,143.8,142.8,141.6,133.3,132.7,127.5,126.4,117.8,116.3,116.2,114.2,113.6,112.8,112.7,72.0,59.4,49.7,29.2,28.8,24.0,22.4;MS(DCI/NH3)m/e(M+H)+378;C24H27NO3的分析计算值:C,76.36;H,7.21;N,3.71。
实测值:C,76.06;H,7.17;N,3.39。实施例2909,10-二甲氧基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(ESI)m/z378(M+H)+;1H NMR(300MHz,DMSO)δ7.93(d,J=8.5Hz,1H),6.82(d,J=8.8Hz,1H),6.61(dd,J=4.4,4.4Hz,2H),6.22(d,J=1.4Hz,1H),5.83(ddt,J=16.9,10.3,3.1Hz,1H),5.70(dd,J=10.3,3.3Hz,1H),5.44(s,1H),5.44-4.96(m,2H),3.77(s,3H),3.67(s,3H),2.16(s,3H),1.17(s,3H),1.16(s,3H);C24H27NO3的HRMS计算值:377.1991。实测值:377.2001。实施例2919,10-二甲氧基-5-[3-环己烯基]-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(ESI)m/z418(M+H)+;1H NMR(300MHz,DMSO),异构体1:δ8.02(d,J=8.8Hz,1H),6.84(d,J=1.7Hz,1H),6.70-6.60(m,2H),6.27(d,J=0.6Hz,1H),5.80-5.60(m,2H),5.16-5.15(m,1H),3.77(s,3H),3.69(s,3H),2.13(s,3H),1.31(s,3H),1.07(s,3H);异构体2:δ8.01(d,J=8.81Hz,1H),6.80(d,J=0.7Hz,1H),6.64(m,2H),6.26(d,J=0.7Hz,1H),5.60-5.30(m,2H),5.09(s,1H),3.77(s,3H),3.68(s,3H),2.10(s,3H),1.29(s,3H),1.04(s,3H);C27H31NO3的HRMS计算值:417.2304。实测值:417.2299。实施例29210-甲氧基-9-乙氧基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO)δ7.94(d,J=8.8Hz,1H),6.79(d,J=8.8Hz,1H),6.60(d,J=8.8Hz,1H),6.55(d,J=8.8,1H),6.45(s,1H),5.85(ddt,J=17.3,10.3,6.6Hz,1H),5.43(d,J=9.2Hz),5.16(s,1H),5.09(dd,J=10.3,1.1Hz,1H),5.06(dd,J=17.3,1.1Hz,1H),4.91(s,1H),4.06-3.97(m,2H),2.62-2.52(m,1H),2.31-2.15(m,1H),2.24(s,3H),1.35(t,J=7.0Hz,3H),1.26(s,3H),1.07(s,3H);MS(DCI/NH3)m/z392(M+H)+;C26H27NO3的HRMS计算值:391.2147。实测值:391.2138。实施例29310-甲氧基-9-(3-丙烯基氧基)-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z404(M+H)+;1H NMR(300MHz,DMSO)δ7.93(d,J=9.0Hz,1H),6.83(d,J=8.8Hz,1H),6.61(d,J=9.0Hz,1H),6.59(d,J=8.8Hz,1H),6.23(d,J=1.5Hz,1H),6.15-6.02(m,1H),5.81(ddt,J=17.3,10.3,6.6Hz,1H),5.67(dd,J=9.8,3.3Hz),5.45(s,1H),5.44(dd,J=16.0,2.0Hz,1H),5.27(dd,10.6,2.0Hz,1H),5.03(dd,J=10.3,1.8Hz,1H),4.98(dd,J=17.3,1.8Hz,1H),4.56-4.53(m,1H),2.47-2.41(m,1H),2.34-2.27(m,1H),2.16(s,3H),1.17(s,3H),1.16(s,3H);C26H29NO3的HRMS计算值:403.2147。实测值:403.2150。实施例29410-甲氧基-9-(3-丙炔基氧基)-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z402(M+H)+;1H NMR(300MHz,DMSO)δ7.92(d,J=8.8Hz,1H),6.88(d,J=8.8Hz,1H),6.62(d,J=8.8Hz,1H),6.61(d,J=8.8,1H),6.24(d,J=1.7Hz,1H),5.81(ddt,J=17.3,10.3,6.6Hz,1H),5.72(dd,J=9.8,3.3Hz),5.44(s,1H),5.03(dd,J=10.3,1.8Hz,1H),4.99(dd,J=17.3,1.8Hz,1H),4.79(d,J=2.3Hz,2H),3.57(t,J=2.3Hz,1H),2.47-2.41(m,1H),2.34-2.27(m,1H),2.16(s,3H),1.17(s,3H),1.16(s,3H);C26H27NO3的HRMS计算值:401.1991。实测值:401.1978。实施例2952,5-二氢-9-乙酰氧基-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(400MHz,DMSO-d6)δ7.78(d,J=8.5,1H),6.81(d,J=8.5,1H),6.60(d,J=8.5,1H),6.57(d,J=8.9,1H),6.18(d,J=1.7,1H),5.80-5.70(m,2H),5.39(s,1H),4.99-4.90(m,2H),3.55(s,3H),2.39(br dd,2H),2.23(s,3H),2.10(d,J=0.9,3H),1.11(s,3H),1.10(s,3H);13C NMR(100MHz,DMSO-d6)δ169.3,148.5,148.0,146.4,138.6,134.1,133.7,132.2,127.4,126.3,120.8,118.3,117.4,116.3,115.1,113.9,112.7,73.7,60.0,49.9,36.7,29.4,29.1,23.9,20.6;MS(DCI/NH3)m/e406(M+H)+;C25H27NO4的分析计算值:C,74.05;H,6.71;N,3.45。
实测值:C,73.91;H,6.79;N,3.31。实施例2962,5-二氢-9-(4-N,N-二甲基氨基-4-氧代-丁酰基氧基)-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ7.86(d,J=8.8,1H),6.85(d,J=8.8,1H),6.68-6.62(m,2H),6.25(d,J=1.5,1H),5.89-5.75(m,2H),5.46(s,1H),5.06-4.96(m,2H),3.62(s,3H),3.00(s,3H),2.85(s,3H),2.83-2.67(m,4H),2.48(m,1H),2.26(m,1H),2.17(s,3H),1.18(s,3H),1.17(s,3H);13C NMR(75MHz,DMSO-d6)δ171.5,170.4,148.3,148.0,146.2,138.5,134.1,133.5,132.1,127.3,126.2,120.8,118.1,117.2,116.2,115.0,113.8,112.5,73.6,60.0,49.8,36.6,36.5,34.9,29.3,29.0,27.6,23.8;MS(DCI/NH3)m/e 491(M+H)+,508(M+NH4)+,C29H24N2O5的分析计算值:C,71.00;H,6.99;N,5.71。
实测值:C,70.88;H,7.10;N,5.49。
采用上述的化学方法,用核9制备实施例297-299。实施例2977-溴代-5-[3-环己烯基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(APCI)m/z466(M+H)+;1H NMR(300MHz,DMSO),异构体1:δ8.03(d,J=8.8Hz,1H),7.33(d,J=9.2Hz,1H),6.65(dd,J=8.8,1.7Hz,2H),6.35(d,J=1.3Hz,1H),5.91-5.43(m,4H),3.86(s,3H),2.14(s,3H),1.99(s,3H),1.31(s,3H),1.06(s,3H);异构体2:δ8.00(dd,J=8.8Hz,1H),7.33(d,J=9.2Hz,1H),6.65(dd,J=8.8,1.7Hz,1H),6.35(d,J=1.3Hz,1H),6.31(d,J=1.3Hz,1H),5.91-5.43(m,4H),2.12(s,3H),1.28(s,3H),1.03(s,3H);13C NMR(300MHz,DMSO)δ155.5,145.5,133.9,133.7,129.5,129.4,128.5, 127.9,127.7,127.2,127.0,125.6,118.1,115.5,113.2,113.1,106.9,102.3,77.2,76.5,55.8,49.4,37.6,36.7,29.5,29.6,27.4,26.9,25.6,24.6,24.2,23.6,21.1,19.8;C26H28NO2 79Br的HRMS计算值:465.1303。实测值:465.1284。C26H28NO2 81Br的HRMS计算值:467.1283。实测值:467.1281。C26H28BrNO2的分析计算值:C,66.95;H,6.05;N,3.00。
实测值:C,66.77;H,6.20;N,2.88。实施例29810-甲氧基-7-溴代-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(APCI)m/z426(M+H)+;1H NMR(300MHz,DMSO)δ7.93(d,J=8.8Hz,1H),7.33(d,J=9.2Hz,1H),6.71(d,J=9.2Hz,1H),6.60(d,J=8.5Hz,1H),6.25(d,J=1.5Hz,1H),5.94-5.80(m,2H),5.45(s,1H),5.0(m,2H),3.86(s,3H),2.17(d,J=1.5Hz,3H),1.17(s,6H);13C NMR(300MHz,DMSO)δ155.3,147.0,146.0,133.8,133.6,131.8,129.5,127.3,127.2,117.4,116.0,115.1,113.2,107.1,102.6,74.8,55.9,49.8,29.0,23.8;C23H24 79BrNO2的HRMS计算值:426.3502。实测值:426.3496。C23H24BrNO2的分析计算值:C,64.79;H,5.67;N,3.29。
实测值:C,65.08;H,5.73;N,3.18。实施例2997-溴代-5-[1-甲基-3-环己烯基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(APCI)m/z480(M+H)+;1H NMR(300MHz,DMSO)异构体1:δ8.02(d,J=8.5Hz,1H),7.55(d,J=5.9Hz,1H),7.37(d,J=2.6Hz,1H),7.31(d,J=1.8Hz,1H),6.67(dd,J=14.7,8.8Hz,1H),6.35(d,J=1.5Hz,1H),5.63(d,J=5.9Hz,1H),5.56-5.45(m,2H),3.86(s,3H),2.13(s,3H),1.61(s,3H),1.30(s,3H),1.02(s,3H);异构体2:δ8.00(d,J=8.5Hz,1H),7.54(d,J=5.9Hz,1H),7.35(d,J=1.8Hz,2H),6.67(dd,J=14.7,8.8Hz,2H),6.31(d,J=1.5Hz,1H),5.51(m,2H),3.86(s,3H),2.08(s,3H),1.50(s,3H),1.09(s,3H),0.92(s,3H);C27H30NO2 79Br的HRMS计算值:479.1460。实测值:479.1463。C27H30NO2 81Br的HRMS计算值:481.1439。实测值:481.1456。C27H30NO2 79Br的分析计算值:C,67.5;H,6.29;N,2.92。
实测值:C,67.08;H,6.38;N,2.54。
采用上述的化学方法,用核10制备实施例300。实施例30010-甲氧基-9-溴代-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z428(M+H)+;426;1H NMR(300MHz,DMSO)δ7.93(d,J=8.8Hz,1H),7.33(d,J=8.5Hz,1H),6.67(d,J=8.5Hz,1H),6.65(d,J=8.5Hz,1H),6.36(d,J=1.1Hz,1H),5.88-5.74(m,2H),5.46(s,1H),5.05-4.95(m,2H),3.62(s,3H),2.18(d,J=1.1Hz,3H),1.19(s,3H),1.16(s,3H);13C NMR(300MHz,DMSO)δ152.7,150.8,146.5,134.0,133.6,132.1,130.0,127.3,126.1,119.3,117.4,116.2,115.0,114.6,114.0,109.5,73.7,59.6,49.9,36.7,29.4,29.1,23.9;C23H24NO2 79Br的HRMS计算值:425.0990。实测值:425.0998。C23H24NO2 81Br的HRMS计算值:427.0970。实测值:427.0974。C23H24BrNO2的分析计算值:C,64.79;H,5.67;N,3.29。
实测值:C,64.99;H,5.98;N,3.13。
采用上述的化学方法,用核11制备实施例301-303。实施例3017,9-二溴代-10-甲氧基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(ESI)m/z504(M+H)+;1H NMR(300MHz,DMSO)δ7.57(d,J=8.9Hz,1H),7.65(s,1H),6.66(d,J=8.8Hz,1H),6.44(s,1H),5.95(dd,J=10.1,3.1Hz,1H),5.97-5.78(m,2H),5.47(s,1H),5.08-4.99(m,2H),3.62(s,3H),2.19(s,3H),1.20(s,3H),1.17(s,3H);13C NMR(300MHz,DMSO)δ152.1,147.4,147.0,133.6,132.7,132.0,131.7,128.3,127.1,126.3,120.5,117.6,115.9,115.3,114.0,113.8,110.0,106.6,75.2,59.7,49.9,36.8,29.6,29.2,23.7;C23H23 79Br2NO2的HRMS计算值:503.0096。实测值:503.0086。C23H23 79Br81BrNO2的HRMS计算值:505.0075。实测值:505.0075。实施例3027,9-二溴代-5-[环己烯-3-基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(ESI)m/z544(M+H)+;1H NMR(300MHz,DMSO),第一异构体:δ8.81(d,1H,J=8.83Hz),7.67(s,1H),6.70(d,1H,J=8.83Hz),6.59(s,1H),5.82-5.59(m,4H),5.50(s,1H),3.61(s,3H),2.49-2.27(m,2H),2.15(s,3H),2.04-1.81(m,2H),1.79-1.41(m,2H),1.32(s,3H),1.08(s,3H);第二异构体:δ7.9(d,1H,J=8.83Hz),7.66(s,1H),6.69(d,1H,J=8.83 Hz),6.54(s,1H),5.82-5.59(m,4H),5.45(s,1H),3.60(s,3H),2.49-2.27(m,2H),2.13(s,3H),2.04-1.81(m,2H),1.79-1.41(m,2H),1.30(s,3H),1.05(s,3H);C26H27 79Br2NO2的HRMS计算值:543.0409。实测值:543.0385。C26H27 79Br81BrNO2的HRMS计算值:545.0388。实测值:545.0396。实施例3037,9-二溴代-5-[1-甲基-3-环己烯基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(ESI)m/z560(M+H)+;1H NMR(300MHz,DMSO),异构体1:δ8.83(d,J=8.0Hz,1H),7.37(s,1H),6.70(d,J=8.8Hz,1H),6.58(s,1H),5.58(d,J=9.2Hz,1H),5.49(s,1H),3.61(s,3H),2.51-2.49(m,4H),2.14(s,3H),1.31(s,3H),1.29-1.20(m,4H),1.26(s,3H);异构体2:δ7.99(d,J=8.0Hz,1H),7.37(s,1H),6.71(d,J=8.8Hz,1H),6.55(s,1H),5.57(d,J=9.2Hz,1H),5.45(s,1H),3.59(s,3H),2.51-2.49(m,4H),2.09(s,3H),1.30(s,3H),1.29-1.20(m,4H),1.21(s,3H);C27H29Br2NO2的HRMS计算值:557.0565。实测值:557.0548。
采用上述的化学方法,用核12-17制备实施例304-310。实施例30410-甲氧基-7-(2-乙烯基)-5-(3-丙烯基0)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(ESI)m/z373(M+H)+;1H NMR(300MHz,DMSO)δ7.82(d,J=8.9Hz,1H),7.23(d,J=8.9Hz,1H),6.78(dd,J=11.0,6.8Hz,1H),6.61(d,J=8.9Hz,1H),6.49(d,J=8.5Hz,1H),5.99(d,J=1.7Hz,1H),5.74(dd,J=7.6,3.0Hz,1H),5.71-5.63(m,1H),5.57(dd,J=7.6,1.7Hz,1H),5.32(s,1H),5.00(dd,J=9.3,1.7Hz,1H),4.92(dd,J=10.2,1.7Hz,1H),4.83(dd,J=16.9,1.7Hz,1H),3.75(s,3H),2.06(s,3H),1.53-1.41(m,2H),1.24-1.15(m,3H),1.05(d,J=2.1Hz,1H);13C NMR(300MHz,DMSO)δ155.66,147.91,145.55,134.17,133.45,131.98,130.77,127.37,127.28,123.88,119.52,117.21,115.99,115.80,113.20,113.18,112.12,105.59,74.01,55.59,49.69,36.40,29.03,28.83,27.67,26.19,23.83,13.55;C25H27NO2的HRMS计算值:373.2042。实测值:373.2048。实施例30510-甲氧基-7-甲基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(ESI)m/z362(M+H)+;1H NMR(300MHz,DMSO)δ7.92(d,J=8.5Hz,1H),6.93(d,J=8.5Hz,1H),6.59(dd,J=5.5,2.6Hz,1H),6.10(s,1H),5.90-5.76(m,2H),5.44(s,1H),5.07-4.90(m,2H),3.82(s,3H),2.17(s,3H),2.08(s,3H),1.99(s,3H),1.16(s,3H),1.15(s,3H);13C NMR(300MHz,DMSO)δ154.2,148.5,145.4,134.5,133.4,131.9,127.8,127.4,127.1,118.2,117.0,116.3,116.0,113.1,112.9,104.8,73.6,55.5,49.6,36.5,28.9,28.8,23.8,15.0;C24H27NO2的HRMS计算值:361.2042。实测值:361.2045。实施例30610-甲氧基-7-乙酰基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(ESI)m/z390(M+H)+;1H NMR(300MHz,DMSO)δ7.88(d,J=8.8Hz,1H),7.59(d,J=8.8Hz,1H),6.84(d,J=8.8Hz,1H),6.62(d,J=8.8Hz,1H),6.22(d,J=1.5Hz,1H),6.01-5.97(m,1H),5.90-5.69(m,1H),5.46(s,1H),5.03-4.83(m,2H),3.93(s,3H),2.53(s,3H),2.20(d,J=1.5Hz,3H),1.19(s,3H),1.16(s,3H)。实施例307(+/-)2,5-二氢-9-甲基-10-甲氧基-2,2,4-三甲基-5-(1-甲基环己烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z416(M+H)+。实施例30810-甲氧基-7-甲基-9-甲基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z376(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.95(d,J=8.5Hz,1H),6.81(s,1H),6.62(d,J=8.5Hz,1H),6.17(d,J=1.5Hz,1H),5.89-5.76(m,2H),5.44(brs,1H),5.04(dd,J=10.3,1.8Hz,1H),4.94(dd,J=17.3,1.8Hz,1H),3.52(s,3H),2.46-2.40(m,1H),2.28-2.24(m,1H),2.18(s,3H),2.17(s,3H),2.07(s,3H),1.19(s,3H),1.14(s,3H)。C25H29NO2的HRMS计算值:375.2198。实测值:375.2214。实施例30910-氯-5-(3-丙烯基)-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z352(M+H)+;1H NMR(300MHz,DMSO)δ7.93(d,J=8Hz,1H),7.12-7.10(m,2H),6.90-6.84(m,1H),6.65(10,2Hz,1H),4.97(dd,J=17,2Hz,1H),2.47-2.26(m,2H),2.16(s,3H),1.23(s,3H),1.17(s,3H)。C22H22ClNO的HRMS(FAB)计算值:351.1390(M)+。实测值:351.1385。实施例310(+/-)2,5-二氢-10-氯-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z288(M+H)+;1H NMR(200MHz,DMSO)δ7.98(d,J=8Hz,1H),7.27-7.14(m,5H),6.97-6.80(m,2H),6.81(br s,1H),6.78-6.72(m,2H),6.44(br s,1H),5.40(br s,1H),1.81(br s,2H),1.26(s,2H),1.16(s,2H);C25H23ClNO的HRMS(FAB)计算值m/z:387.1390(M)+。实测值:287.1286。实施例3112,5-二氢-10-甲氧基-5-(3-(N-甲基-N-(甲酯基甲基)氨基羰基氧基)苯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和N-甲基-N-(甲基甘氨酸酯)氨基甲酰氯,得到所需化合物。MS(DCI/NH3)m/e529(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.21(m,1H),7.03(d,1H),6.92(m,3H),6.72(m,3H),6.55(d,1H),6.45(t,1H),5.40(s,1H),4.15(s,1H),4.05(s,1H),3.78(s,3H),3.65(s,3H),3.00(s,1H),2.88(s,2H),1.84(s,3H),1.22(s,3H),1.13(s,3H)。C31H32N2O6的分析计算值:C,70.43;H,6.10;N,5.29。
实测值:C,70.98;H,6.33;N,4.85。实施例3122,5-二氢-10-甲氧基-5-(3-(N-甲基-N-(N-甲基羰基)氨基羰基氧基)苯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和异氰酸甲酯,得到所需化合物。MS(DCI/NH3)m/e514(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.18(q,1H),8.01(d,1H),7.27(t,1H),7.06(t,2H),6.98(s,1H),6.91(t,1H),6.77(s,1H),6.70(d,1H),6.56(d,1H),6.46(d,1H),6.19(s,1H),5.38(s,1H),3.78(s,3H),3.19(s,3H),2.70(d,3H),1.84(s,3H),1.22(s,3H),1.14(s,3H)。C30H31N3O5·2H2O的分析计算值:C,65.55;H,6.41;N,7.60。
实测值:C,65.71;H,6.20;N,7.05,实施例3132,5-二氢-10-甲氧基-5-(3-(N-甲基氨基羰基氧基)苯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例13的产物和异氰酸甲酯,得到所需化合物。MS(DCI/NH3)m/e457(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.50(q,1H),7.21(t,1H),7.02(d,1H),6.92(dd,2H),6.80(s,1H),6.77(s,1H),6.70(dd,1H),6.56(d,1H),6.46(d,1H),6.18(s,1H),5.40(s,1H),3.80(s,3H),2.60(d,3H),1.86(s,3H),1.23(s,3H),1.15(s,3H)。C28H28N2O4·0.50H2O的分析计算值:C,72.33;H,6.27;N,6.01。
实测值:C,72.20;H,6.38;N,5.78。实施例3142,5-二氢-10-甲氧基-5-(3-(2-羟乙基)苯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于-78℃,用正丁基锂(2.5M在己烷中,5.80ml)处理3-(2’-甲氧基甲氧基)乙基苯基溴(3.55g,14.5mmol)的THF(150ml)溶液15分钟,温热至-30℃,冷却至-78℃,一次性用化合物
1F处理,温热至-50℃,用饱和氯化铵猝灭,温热至室温,并使之沉降。倾出上清液并浓缩,使残留物在水和乙酸乙酯之间分配。顺序用水和盐水洗涤有机层,干燥(硫酸钠)并浓缩。残留物经硅胶快速层析,用20-35%乙酸乙酯/己烷洗脱,得到0.82g(56%)标题化合物5-(3’-MOMO-苯基)半酮缩醇。MS(DCI/NH3)m/e 489(M+H)+
于室温下,用在甲醇(20ml)中的饱和氯化氢处理上面制备的半酮缩醇(0.70g,1.43mmol)的甲醇(10ml)溶液,搅拌18小时,倾入1∶1的乙酸乙酯/饱和氯化铵中。用乙酸乙酯提取分开的水层,顺序用水和盐水洗涤合并的乙酸乙酯层,干燥(硫酸钠)并浓缩,得到0.52g(82%)未掩蔽的半酮缩醇。MS(DCI/NH3)m/e444(M+H)+。
于室温下,用三氟化硼醚合物(1.42g,10mmol)处理上面制备的未掩蔽的半酮缩醇(0.45g,1.00mmol)和三乙基硅烷(1.16g,10mmol)的二氯甲烷(20ml)溶液,搅拌18小时,倾入1∶1的乙酸乙酯/饱和碳酸氢钠中。用乙酸乙酯提取分开的水层,顺序用水和盐水洗涤合并的提取物,干燥(硫酸钠)并浓缩,残留物经硅胶快速层析,用25-45%乙酸乙酯的己烷液洗脱,得到0.342g标题化合物MS(DCI/NH3)m/e428(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.00(m,5H),6.74(s,1H),6.70(d,1H),6.55(d,1H),6.45(d,1H),6.16(s,1H),5.39(s,1H),4.54(t,1H),3.79(s,3H),3.44(q,4H),2.59(t,2H),1.86(s,3H),1.22(s,3H),1.11(s,3H)。C28H29NO3的分析计算值:C,78.66;H,6.83;N,3.27。
实测值:C,78.48;H,6.85;N,3.29。实施例3152,5-二氢-10-甲氧基-5-(3-(2-甲磺酰基氧基乙基)苯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于0℃,用甲磺酰氯(64mg,0.56mmol)处理实施例314的产物(200mg,0.47mmol)和三乙胺(94mg,0.94mmol)的二氯甲烷(6ml)溶液,搅拌30分钟,用饱和碳酸氢钠猝灭。用二氯甲烷提取分开的水层,用盐水洗涤合并的有机层,干燥(硫酸钠)并浓缩。残留物经硅胶快速层析,用10-30%乙酸乙酯/己烷洗脱,得到0.30g(97%)标题化合物。MS(DCI/NH3)m/e506(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.18(s,1H),7.14(d,1H),7.09(d,1H),6.96(d,1H),6.90(t,1H),6.75(s,1H),6.70(d,1H),6.55(d,1H),6.45(d,1H),6.21(s,1H),5.39(s,1H),4.27(t,2H),3.79(s,3H),2.88(s,3H),2.87(t,2H),1.84(s,3H),1.24(s,3H),1.14(s,3H)。C29H31NO5S的分析计算值:C,68.88;H,6.17;N,2.77。
实测值:C,69.08;H,6.14;N,2.63。实施例3162,5-二氢-10-甲氧基-5-(3-(2-甲硫基乙基)苯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于室温下,用NaSMe(14mg,0.20mmol)处理实施例315的产物(10mg,0.02mmol)的DMF(1ml)溶液,搅拌2小时,用饱和碳酸氢钠猝灭。用乙酸乙酯提取。用盐水洗涤有机层,干燥(硫酸钠)并浓缩。残留物经硅胶快速层析,用10-30%乙酸乙酯/己烷洗脱,得到9mg(99%)标题化合物。MS(DCI/NH3)m/e458(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.11(t,1H),7.07(s,1H),7.02(d,1H),6.96(d,1H),6.90(t,1H),6.75(s,1H),6.70(d,1H),6.54(d,1H),6.44(d,1H),6.16(s,1H),5.39(s,1H),3.77(s,3H),2.70(t,2H),2.54(t,2H),1.91(s,3H),1.95(s,3H),1.21(s,3H),1.15(s,3H)实施例3172,5-二氢-10-甲氧基-5-(3-(2-(N,N-二甲基氨基羰基氧基)乙基)苯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例14的方法处理实施例314的产物和N,N-二甲基氨基甲酰氯,得到所需化合物。MS(DCI/NH3)m/e 499(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.00(m,5H),6.76(s,1H),6.70(d,1H),6.55(s,1H),6.44(d,1H),6.15(s,1H),5.39(s,1H),4.01(t,2H),3.78(s,3H),2.79(t,2H),2.77(s,3H),2.65(s,3H),1.84(s,s,3H),1.23(s,3H),1.15(s,3H)。C31H34N2O4的分析计算值:C,74.67;H,6.87;N,5.61。
实测值:C,74.45;H,6.73;N,5.45。实施例3182,5-二氢-10-甲氧基-5-(3-(2-(N,N-二甲基氨基)乙基)苯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例316的方法处理实施例315的产物和二甲胺,得到所需化合物。MS(DCI/NH3)m/e455(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.00(d,1H),7.09(t,1H),7.01(d,1H),6.97(m,2H),6.90(t,1H),6.73(s,1H),6.69(d,1H),6.55(d,1H),6.44(d,1H),6.16(s,1H),5.39(s,1H),3.79(s,3H),2.54(t,2H),2.25(t,2H),2.08(s,6H),1.87(s,3H),1.22(s,3H),1.17(s,3H)。实施例3192,5-二氢-10-甲氧基-5-环丙基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉实施例319A
于室温下,将实施例1F的产物(4.43g,13.7mmol)、4-氯代苯酚(9.28g,72.1mmol)和硫酸镁(8.69g,72.1mmol)的二氯甲烷(100ml)中的混合物搅拌12小时,用乙酸乙酯(200ml)稀释,分别用1M氢氧化钠水溶液(两次)和盐水洗涤,干燥(硫酸钠)并浓缩。残留物用热乙酸乙酯(25ml)研磨,得到所需的苯基缩醛。MS(DCI/NH3)m/e306(M-4-Cl-ph)+。实施例319B
于0℃,用通过使环丙基溴(363mg,3.0mmol)和镁(73mg,0.30mmol)在THF(1.5ml)中回流所制备的环丙基溴化镁处理实施例319A的产物(131mg,0.30mmol)在甲苯(20ml)中的溶液30分钟。使最终溶液温热至室温并搅拌12小时,用饱和氯化铵猝灭。分别用1M氢氧化钠水溶液(两次)和盐水洗涤有机层,干燥(硫酸钠)并浓缩。残留物经硅胶快速层析纯化,用5-15%乙酸乙酯/己烷洗脱,得到18mg(17%)的标题化合物。MS(DCI/NH3)m/e348(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.01(d,1H),7.04(t,1H),6.67(d,1H),6.60(d,1H),6.57(d,1H),6.16(s,1H),5.44(s,1H),5.42(d,1H),3.85(s,3H),2.12(s,3H),1.26(s,3H),1.05(s,3H),0.28(m,4H),0.08(m,1H)。实施例3202,5-二氢-10-甲氧基-5-乙烯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于-78℃,用三氟化硼醚合物(43mg,0.3mmol)处理2B(34mg,0.1mmol)和三丁基乙烯基锡(96mg)的二氯甲烷(2ml)溶液,使温热至室温并搅拌2小时。然后用饱和碳酸氢钠猝灭该反应物,分别用饱和碳酸氢钠和盐水洗涤有机层,干燥(硫酸钠)并浓缩,残留物经硅胶快速层析,用5-15%乙酸乙酯/己烷洗脱,得到27mg(81%)标题化合物。MS(DCI/NH3)m/e 334(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.93(d,1H),7.02(t,1H),6.63(dd,2H),6.54(d,1H),6.19(d,1H),6.10(s,1H),5.93(m,1H),5.42(s,1H),5.16(dt,1H),4.91(dt,1H),3.83(s,3H),2.11(s,3H),1.21(s,3H),1.13(s,3H)。实施例321反式2,5-二氢-10-甲氧基-5-(2-苯基乙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
在密封管中将实施例320的产物(13mg,0.039mmol)、碘代苯(12mg,0.058mmol)、乙酸钯(II)(18mg,0.008mmol)、三(邻-甲苯基)膦(3.6mg,0.012mmol)、三乙胺(12mg,0.12mmol)在乙腈(1ml)中的混合物加热至80℃4小时。除去溶剂后,残留物经硅胶快速层析,用5-15%乙酸乙酯/己烷洗脱,得到7mg(44%)标题化合物。MS(DCI/NH3)m/e410(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.99(d,1H),7.22(m,4H),7.19(m,1H),7.00(t,1H),6.67(d,1H),6.63(d,1H),6.57(d,1H),6.38(q,1H),6.34(d,1H),6.27(d,1H),6.14(s,1H),5.43(s,1H),3.82(s,1H),2.12(s,3H),1.22(s,3H),1.13(s,3H)。实施例3222,5-二氢-10-甲氧基-5-(2-苯基乙炔基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例320的方法处理实施例2B的产物和三丁基苯基乙炔基锡,得到所需化合物。MS(DCI/NH3)m/e408(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.92(d,1H),7.29(m,3H),7.16(m,2H),7.10(d,1H),6.78(d,1H),6.65(dd,1H),6.59(s,1H),6.23(s,1H),5.45(s,1H),3.87(s,3H),2.33(s,3H),1.28(s,3H),1.12(s,3H)。实施例323顺式2,5-二氢-10-甲氧基-5-(2-苯基乙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于室温下,将实施例322的产物(20mg,0.049mmol)、钯/硫酸钡(20mg)在吡啶(2ml)中的混合物搅拌12小时,用水猝灭,并用乙酸乙酯提取。用盐水洗涤有机层、干燥(硫酸钠)并浓缩。残留物经硅胶快速层析,用5%-15%的乙酸乙酯/己烷洗脱,得到13mg(75%)的标题化合物。MS(DCI/NH3)m/e410(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.97(d,1H),7.62(d,2H),7.48(t,2H),7.39(t,1H),7.03(t,1H),6.72(d,1H),6.63(d,1H),6.61(d,1H),6.52(d,1H),6.12(d,1H),6.10(s,1H),5.70(dd,1H),5.27(s,1H),3.87(s,3H),1.55(s,3H),1.17(s,3H),1.07(s,3H)。实施例3242,5-二氢-10-甲氧基-5-(2-甲基丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例320的方法处理实施例2B的产物和三丁基-(2-甲基丙烯基)锡,得到所需化合物。MS(DCI/NH3)m/e362(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.92(d,1H),6.99(t,1H),6.65(d,1H),6.58(d,1H),6.44(d,1H),6.24(d,1H),6.21(s,1H),5.40(s,1H),5.18(d,1H),3.85(s,3H),2.07(s,3H),1.84(s,3H),1.58(s,3H),1.23(s,3H),1.10(s,3H)C24H27NO2的分析计算值:C,79.74;H,7.52;N,3.87。
实测值:C,79.34;H,7.25;N,3.68。实施例325反式2,5-二氢-10-甲氧基-5-(1-环己烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例320的方法处理实施例2B的产物和三丁基-(1-环己烯基)锡,得到所需化合物。MS(DCI/NH3)m/e388(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.91(d,1H),7.00(t,1H),6.64(d,1H),6.60(d,1H),6.49(d,1H),6.02(s,1H),5.85(s,1H),5.39(s,1H),5.14(s,1H),3.81(s,3H),2.18(m,1H),2.03(s,3H),1.98(m,1H),1.81(m,1H),1.64(m,1H),1.42(m,3H),1.24(m,1H),1.22(s,3H),1.13(s,3H)C26H29NO2·1.25H2O的分析计算值:C,76.15;H,7.74;N,3.41。
实测值:C,76.12;H,7.34;N,3.21。实施例3262,5-二氢-10-(2-呋喃基)-5-(3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于70℃及氩气下,将三氟甲磺酸酯3C(得自原始专利申请)(196mg,0.421mmol)和2-(三丁基甲锡烷基)呋喃(0.250ml,0.79mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷复合物(25mg,0.031mmol)和四丁基碘化铵(25mg,0.068mmol)在无水NMP(6.5ml)中的磁力搅拌下的混合物加热5小时。使该反应物冷却至室温,用饱和氯化钠水液稀释,用乙酸乙酯(5×20ml)提取。干燥(硫酸镁)合并的有机层、过滤并浓缩。粗品物质经硅胶(16g)层析,用乙酸乙酯-己烷(10∶90)洗脱,得到混有原料的产物。将该物质上样于3块10×20cm,0.25mm厚的硅胶板上,用乙酸乙酯-己烷(5∶95)洗脱4次。刮下产物带并用乙酸乙酯提取,得到为粘稠糖浆状的23mg(0.044mmol,14%)所需呋喃:1HNMRδ7.67(d,1H,J=1.0Hz),7.18(t,1H,J=7.8Hz),7.08(m,1H),6.91(dd,1H,J=8.1Hz,J=1.4Hz),6.64(m,2H),6.35(d,1H,J=8.5Hz),6.25(d,1H,J=8.5Hz),6.14(m,1H),5.82(m,2H),5.43(s,1H),5.05(dd,1H,J=10.5Hz,J=1.5Hz),4.99(dd,1H,J=17.3Hz,J=1.5Hz),2.40(m,2H),2.19(s,3H),1.20(s,3H),1.12(s,3H);质谱(DCl)m/z 384(M+1)。C26H25NO2的分析计算值:C,81.43;H,6.57;N,3.65。
实测值:C,81.24;H,6.62;N,3.66。实施例3272,5-二氢-10-氰基-5-(3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于80℃及氩气下,将三氟甲磺酸酯3C(195mg,0.419mmol)、四(三苯膦)钯(0)和氰化锌(36mg,0.31mmol)在无水二氧六环(4.0ml)和水(1.0ml)中的磁力搅拌下的混合物加热48小时。使该反应物冷却至室温,用乙酸乙酯(25ml)稀释,用饱和氯化钠水溶液洗涤。用乙酸乙酯(2×20ml)提取水层。干燥(硫酸镁)合并的有机层、过滤并浓缩。粗品物质经硅胶(20g)层析,用乙酸乙酯-己烷(10∶90)洗脱,得到混有原料三氟甲磺酸酯的产物。将该部分纯净的腈上样于2块10×20cm,0.25mm厚的硅胶板上,用乙酸乙酯-己烷(5∶95)洗脱5次。刮下产物带并用乙酸乙酯提取,得到17.3mg(0.0505mmol,12%)所需腈:1H NMRδ7.87(d,1H,J=8.5Hz),7.46(dd,1H,J=7.5Hz,J=1.5Hz),7.27(t,1H,J=7.8Hz),7.19(dd,1H,J=8.1Hz,J=1.4Hz),6.71(d,1H,J=8.5Hz),6.57(m,1H),5.90(dd,1H,J=10Hz,J=3.6Hz),5.82(m,1H),5.49(m,1H),5.04(dm,1H,J=10.5Hz),4.98(dm,1H,J=17.3Hz),2.38(m,1H),2.30(m,1H),2.19(s,3H),1.20(s,3H),1.19(s,3H);质谱(APCI)m/z 343(M+1)。C23H22N2O的计算值:342.1732。实测值:342.1730。实施例3282,5-二氢-10-羧基-5-(3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于110℃及氩气下,将实施例4的产物(31mg,0.082mmol)和氰化钠(51mg,0.78mmol)在无水二甲亚砜(2.5ml)中的磁力搅拌下的混合物加热5小时。使该反应物冷却至室温,用饱和氯化钠水溶液稀释,用乙酸乙酯(5×20ml)提取。干燥(硫酸镁)合并的有机层、过滤并浓缩。将该粗品物质上样于两块10×20cm,0.25mm厚的硅胶板上,用乙酸乙酯-己烷(10∶90)洗脱2次,然后用乙酸乙酯-己烷(50∶50)洗脱3次。刮下产物带并用乙酸乙酯提取,得到为粘稠糖浆状的16mg(0.044mmol,54%)所需的羧酸:1H NMRδ7.16(m,2H),7.02(d,1H,J=8.5Hz),6.98(dd,1H,J=5.5Hz,J=3.7Hz),6.58(d,1H,J=8.5Hz),6.29(m,1H),5.82(m,2H),5.45(s,1H),5.05(dd,1H,J=10.5Hz,J=1.5Hz),4.98(dd,1H,J=17.3Hz,J=1.5 Hz),2.30(m,2H),2.18(s,3H),1.20(s,3H),1.16(s,3H);质谱(APCl)m/z362(M+1)。C23H23NO3的分析计算值:C,76.43;H,6.41;N,3.88。
实测值:C,76.24;H,6.46;N,3.66。实施例3292,5-二氢-10-(2-羟甲基)-5-(3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
在氩气下,向冷却至-78℃的实施例4的产物(32mg,0.085mmol)的无水二氯甲烷(3ml)的磁力搅拌下的溶液中滴加1.0M二异丁基氢化铝的环己烷溶液(0.400ml,0.40mmol)。使该反应物的温度升至0℃。3.5小时后,通过加入Rochelle’s盐水溶液猝灭该反应,分离各层。用乙酸乙酯(3×40ml)提取水层。干燥(硫酸镁)合并的有机层,过滤并浓缩。将该粗品物质上样于两块10×20cm,0.25mm厚的硅胶板上,用己烷洗脱,然后用乙酸乙酯-己烷(10∶90)洗脱3次。刮下产物带并用乙酸乙酯提取,得到为粘稠糖浆状的27mg(0.078mmol,91%)所需的醇:1HNMRδ7.47(d,1H,J=8.5Hz),7.14(m,2H),6.80(dd,1H,J=7.3Hz,J=1.8Hz),6.64(d,1H,J=8.5Hz),6.17(m,1H),5.81(ddm,1H,J=10.5Hz,J=17.1Hz),5.73(dd,1H,J=3.4Hz,J=10.5Hz),5.46(m,1H),5.32(dd,1H,J=6.3Hz,J=4.2Hz),5.02(dm,1H,J=10.5Hz),4.94(dm,1H,J=17.1Hz),4.62(m,2H),2.30(m,2H),2.17(s,3H),1.19(s,3H),1.16(s,3H);质谱(ESl)m/z 348(M+1)。C23H25NO2的计算值:347.1885。实测值:347.1897。实施例3302,5-二氢-10-甲酰基-5-(3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
在氩气下,将实施例329的产物(185mg,0.532mmol)和四丙基过钌酸(perruthenate)铵(205mg,0.583mmol)在无水二氯甲烷(10ml)中的磁力搅拌下的混合物搅拌1.5小时。将该反应物通过硅藻土过滤,用乙酸乙酯洗涤滤垫,浓缩滤液。粗品物质经硅胶(20g)层析,用乙酸乙酯-己烷(10∶90)洗脱,得到144mg(0.417mmol,78%)的所需醛:1H NMRδ10.11(s,1H),7.45(dd,1H,J=7.8Hz,J=1.2Hz),7.29(t,1H,J=7.8Hz),7.16(dd,1H,J=7.8Hz,J=1.4Hz),6.84(d,1H,J=8.5Hz),6.70(d,1H,J=8.5Hz),6.53(m,1H),5.91(dm,1H,J=10.0Hz),5.84(m,1H),5.51(s,1H),5.05(dm,1H,J=10.5Hz),4.97(dm,1H,J=17.3Hz),2.40(m,2H),2.21(s,3H),1.22(s,3H),1.18(s,3H);质谱(APCl)m/z 346(M+1)。C23H23NO2的计算值:345.1729。实测值:345.1732。实施例3312,5-二氢-10-氨基甲基-5-(3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
在氮气下,向实施例330(40mg,0.116mmol)和乙酸铵(77mg,1.0mmol)在无水甲醇(10ml)中的磁力搅拌下的溶液中加入氰基硼氢化钠(14mg,0.23mmol)。5小时后,通过加入10%碳酸钠猝灭该反应并用乙酸乙酯(3×40ml)提取。干燥(硫酸镁)合并的有机层,过滤并浓缩。将该粗品物质上样于两块10×20cm,0.25mm厚的硅胶板上,用己烷洗脱,然后用乙酸乙酯-己烷(20∶80)洗脱4次。刮下产物带并用乙酸乙酯提取,得到为粘稠糖浆状的8.0mg(0.023mmol,20%)所需胺:1H NMRδ7.55(d,1H,J=8.5Hz),7.14(m,2H),6.80(dd,1H,J=7.3Hz,J=1.8Hz),6.64(d,1H,J=8.5Hz),6.17(m,1H),5.81(ddm,1H,J=10.5Hz,J=17.1Hz),5.73(dd,1H,J=3.4Hz,J=10.5Hz),5.46(m,1H),5.02(dm,1H,J=10.5Hz),4.94(dm,1H,J=17.1Hz),4.62(m,2H),3.88(m 2H),2.30(m,2H),2.17(s,3H),1.19(s,3H),1.16(s,3H);质谱(ESl)m/z 347(M+1)。C23H26N2O的计算值:346.2045。实测值:346.2047。实施例3322,5-二氢-10-甲氧基甲基-5-(3-丙烯基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
在氩气下,向在冰浴上冷却的实施例329的产物(26mg,0.075mmol)在无水THF(2.0ml)中的磁力搅拌下的溶液中加入0.14ml 1M六甲基二硅叠氮化(disilazide)钾的己烷溶液。加入甲基碘(13.8mg,0.097mmol),使该反应物缓慢升至室温。用饱和氯化铵水溶液猝灭该反应并用乙酸乙酯(3×10ml)提取。干燥(硫酸镁)提取物,过滤并浓缩。将该粗品物质上样于3块10×20cm,0.25mm厚的硅胶板上,用乙酸乙酯-己烷(5∶95)洗脱4次。产物带用乙酸乙酯提取,得到25mg(0.069mmol,92%)所需甲醚:1H NMRδ7.34(d,1H,J=8.5Hz),7.11(m,2H),6.85(dd,1H,J=7.1Hz,J=2.4Hz),6.64(d,1H,J=8.5Hz),6.20(m,1H),5.81(dm,1H,J=10.2Hz),5.75(m,1H),5.46(s,1H),5.02(dm,1H,J=10.2Hz),4.93(dm,1H,J=17.3Hz),4.61(d,1H,J=11.2Hz)4.43(d,1H,J=11.2Hz)3.37(s,3H),2.33(m,1H),2.27(m,1H),2.17(s,3H),1.19(s,3H),1.17(s,3H);质谱(ESl)m/z 362(M+1);C24H27NO2的计算值:361.2042。实测值:361.2047。实施例3332,5-二氢-10-乙烯基-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉实施例333A2,5-二氢-10-乙烯基-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例3C的方法处理实施例7的产物和三氟甲磺酸酐,得到所需三氟甲磺酸酯。MS(ES1)m/z502(M+1)+。实施例3332,5-二氢-10-乙烯基-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例5的方法处理实施例333A的产物和乙烯基三丁基甲锡烷,得到所需化合物。MS(DCI/NH3)m/z380(M+H)+;1H NMR(300MHz,CDCl3)δ7.30-7.11(m,6H),7.02-6.89(m,3H),6.78(s,1H),6.76-6.68(m,2H),6.32(br s,1H),5.72(br d,J=11.4Hz,1H),5.40(br s,1H),5.30(br d,J=15.9Hz,1H),1.81(s,3H),1.26(s,3H),1.15(s,3H);13C NMR(125MHz,DMSO)δ151.3,145.7,138.8,137.3,133.3,133.0,131.2,128.5(2),128.3,128.2,128.0(2),127.8,127.4,126.6,123.9,120.8,118.1,116.2,114.5,113.6,75.3,50.0,30.0,28.7,23.2;C27H25NO的HRMS(FAB)m/z计算值:379.1936(M)+。实测值:379.1924。实施例3342,5-二氢-10-乙炔基-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例6A的方法处理实施例333A的产物和(三甲基甲硅烷基)乙炔,得到所需化合物。MS(DCI/NH3)m/z378(M+H)+;1H NMR(300MHz,DMSO)δ8.32(d,J=8.8Hz,1H),7.27-7.16(m,5H),7.01(dd,J=8.7,1.8Hz,1H),6.83(t,J=8.6Hz,1H),6.84-6.79(m,1H),6.81(br s,1H),6.74(d,J=8.6Hz,1H),6.42(br s,1H),5.41(br s,1H),4.38(s,1H),2.03(s,3H),1.24(s,3H),1.18(s,3H);13C NMR(125MHz,DMSO)δ150.9,146.4,138.8,133.1,130.7,128.6128.2(2),128.0(2),127.9,127.4,126.6,126.5,126.4,126.3,118.3,117.6,117.5,115.7,113.4,84.3,75.1,50.0,30.0,28.8,23.2;C27H23NO的HRMS(FAB)m/z计算值:377.1780(M)+。实测值:377.1779。实施例3352,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉-10-羧酸甲酯
如同实施例4的方法处理实施例333A的产物,得到所需化合物。mp150-2℃;MS(DCI/NH3)m/z412(M+H)+;1H NMR(300MHz,DMSO)δ7.36-7.30(m,2H),7.28-7.17(m,3H),7.12-7.01(m,2H),6.93-6.88(m,2H),6.84(d,J=8.7Hz,1H),6.70(d,J=8.9Hz,1H),6.40(br s,1H),5.40(br s,1H),3.79(s,3H),1.81(s,3H),1.26(s,3H),1.17(s,3H);13C NMR(125MHz,DMSO)δ169.9,151.2,146.1,138.3,132.5,130.3,128.8(2),128.1,128.0(2),127.7,127.4,127.0,126.6,124.9,122.9,119.6,117.7,117.5,114.2,75.7,52.2,50.0,30.0,28.6,23.2;C27H25NO3的分析计算值:C,78.81;H,6.12;N,3.40。
实测值:C,78.84;H,6.25;N,3.24。实施例3362,5-二氢-10-(羟甲基)-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于-50℃,向实施例335的产物(136mg,0.330mmol)的无水二氯甲烷(12ml)溶液中加入Dibal-H(1.65ml的1.0M庚烷溶液,1.65mmol)。用30分钟,将生成的橙色溶液逐渐温热至0℃,然后于0℃搅拌2小时。再于0℃将乙酸乙酯(5ml)加入该溶液中,以猝灭过量的Dibal-H试剂(通过该溶液的颜色由橙色转变为淡黄色来指示),然后用饱和氯化铵水溶液(5ml)处理该反应混合物。使该反应混合物在乙酸乙酯(40ml)和饱和Rochelle’s盐水溶液(酒石酸钠钾;35ml)之间分配。剧烈搅拌生成的混合物,直至观察到澄清分开的各层(约1小时)。分离各层,用乙酸乙酯(15ml)萃取水层。合并有机物,用盐水(10ml)洗涤,然后干燥(硫酸钠)。过滤并浓缩得到为无色泡沫状固体的所需化合物(116mg,0.302mmol,92%)。MS(DCI/NH3)m/z384(M+H)+;1H NMR(300MHz,DMSO)δ7.58(d,J=8.9Hz,1H),7.23-7.11(m,5H),6.98(dd,J=8.7,1.7Hz,1H),6.84(t,J=8.7Hz,1H),6.76(br s,1H),6.75(d,J=8.6Hz,1H),6.69(dd,J=8.7,1.8Hz,1H),6.26(br s,1H),5.40(br s,1H),5.37(dd,J=6.0,4.0Hz,1H),4.65(dd,J=11.5,6.0Hz,1H),4.54(dd,J=11.6,4.4Hz,1H),1.80(s,3H),1.24(s,3H),1.17(s,3H);13C NMR(125MHz,DMSO)δ151.0,145.6,139.0,137.0,133.1,131.4,128.4(2),128.1,128.0(2),127.7,127.6,126.2,124.8,123.7,118.6,118.0,116.0,113.9,75.1,61.9,49.9,29.9,28.7,23.3;C26H25NO2的分析计算值:C,81.43;H,6.57;N,3.65。
实测值:C,81.53;H,6.86;N,3.41。实施例3372,5-二氢-10-甲酰基-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于23℃,向实施例336的产物(50mg,0.130mmol)的二氯甲烷(6ml)溶液中加入四丙基过钌酸铵(60mg,0.16mmol)的二氯甲烷(14ml)溶液。15分钟后,将该反应混合物通过小硅胶塞柱过滤,用二氯甲烷冲洗,接着用1∶1的乙酸乙酯-己烷冲洗。浓缩滤液得到金色糖浆状物,将其经制备性薄层层析(3%乙酸乙酯/甲苯洗脱)纯化,得到为淡黄色泡沫状的所需化合物(19mg,0.050mmol,38%)。MS(DCI/NH3)m/z382(M+H)+;1H NMR(300MHz,DMSO)δ10.13(s,1H),7.31(dd,J=8.8,1.9Hz,1H),7.28-7.16(m,5H),7.12(d,J=8.7Hz,1H),7.05(dd,J=8.7,2.0Hz,1H),6.95(d,J=8.8Hz,1H),6.92(br s,1H),6.81(d,J=8.8Hz,1H),6.59(br s,1H),5.43(br s,1H),1.85(s,3H),1.27(s,3H),1.18(s,3H);13C NMR(125MHz,DMSO)δ191.4,151.9,146.8,138.3,133.2,131.5,131.4,130.8,128.6(2),128.1(2),128.0,127.2,126.6,121.5,121.4,118.1,115.5,114.2(2),75.8,50.2,30.1,29.0,23.1;C26H24NO的HRMS(FAB)m/z计算值:382.1807(M+H)+。实测值:382.1816。实施例3382,5-二氢-10-(甲氧基甲基)-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于0℃,向实施例336的产物(22mg,0.057mmol)的THF(2.0ml)溶液中加入KHMDS(110ml,0.5M在甲苯中溶液,0.057mmol)。15分钟后,加入碘代甲烷溶液,为在DMF中的溶液(100ml,81mg碘代甲烷在1.0ml DMF中的溶液,0.057mmol),于0℃再搅拌该溶液30分钟,移去冷浴,再于23℃搅拌该反应物1.5小时。用水(3ml)猝灭该反应,用乙酸乙酯(2×20ml)提取。用盐水(5ml)洗涤合并的有机层,然后干燥(硫酸镁),真空浓缩得到棕色油状物。将该残留物经制备性薄层层析(用10%乙酸乙酯/己烷洗脱)纯化,得到为无色泡沫状的所需产物(15mg,0.038mmol,66%)。MS(DCI/NH3)m/z98(M+H)+;1H NMR(300MHz,DMSO)δ7.40(d,J=8.9Hz,1H),7.19-7.10(m,5H),6.97-6.92(m,1H),6.94(s,1H),6.77-6.70(m,3H),6.29(br s,1H),5.39(brs,1H),4.58(d,J=11.1Hz,1H),4.39(d,J=11.1Hz,1H),3.28(s,3H),1.81(s,3H),1.26(s,3H),1.17(s,3H);13C NMR(125MHz,DMSO)δ151.0,145.7,138.8,132.9,132.6,131.5,128.4(2),127.8(2),127.8,127.7,127.5,126.1,125.7,124.4,118.3,117.9,116.6,113.9,75.2,72.5,57.2,49.9,29.9,28.7,23.3;C27H27NO2的HRMS(FAB)m/z计算值:397.2042(M)+。实测值:397.2039。实施例3392,5-二氢-10-乙烯基-5-氧代-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例5的方法处理实施例3C的产物和乙烯基三丁基锡烷,得到所需化合物。mp218-224℃;MS(DCI/NH3)m/z318(M+H)+,335(M+NH4)+;1H NMR(300MHz,DMSO)δ7.88(d,J=8.8Hz,1H),7.38(dd,J=8.8,6.6Hz,1H),7.29(s,1H),7.28(d,J=8.6Hz,1H),7.19(dd,J=17.3,11.1Hz,1H),7.13(d,J=8.7Hz,1H),7.03(br s,1H),5.75(dd,J=17.3,1.2Hz,1H),5.52-5.47(m,2H),1.97(s,3H),1.24(s,6H);13C NMR(125MHz,CDCl3)δ160.1,150.0,145.4,138.5,136.3,132.2,131.0,127.1,126.7,126.6,125.5,124.1,119.9,118.5,117.2,115.9,115.7,50.0,27.9(2),21.0;C21H19NO2的分析计算值:C,79.47;H,6.03;N,4.41。
实测值:C,79.28;H,5.97;N,4.20。实施例3405-(3-环己烯基)-2,5-二氢-10-乙烯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于-78℃,向实施例339的产物(100mg,0.300mmol)和3-(三甲基甲硅烷基)环己烯(139mg,0.900mmol)在二氯甲烷(6ml)中的磁力搅拌下的溶液中加入新蒸馏的BF3·OEt2(80ml,0.600mmol)。于-78℃将产生的绿棕色溶液搅拌15分钟,然后连续搅拌下用1小时使之缓慢升温至23℃。将该反应混合物倾入10%碳酸氢钠溶液(10ml)中,用乙酸乙酯(2×20ml)提取。用盐水(8ml)洗涤合并的有机部分并干燥(硫酸钠)。过滤并浓缩得到棕色残留物,将其经快速层析(用5%乙酸乙酯/己烷洗脱)纯化,得到为褐色泡沫状物的所需产物(356mg,0.186mmol,62%)。MS(DCI/NH3)m/z384(M+H)+;1H NMR(300MHz,DMSO)(对于主要的顺式非对映体)δ7.30(d,J=8.0Hz,1H),7.16-6.97(m,3H),6.95-6.88(m,1H),6.67(d,J=8.0Hz,1H),6.42(br s,1H),5.82-5.60(m,3H),5.52-5.44(m,2H),5.33(d,J=7.6Hz,1H),2.40-2.26(m,1H),2.17(s,3H),2.05-1.82(m,2H),1.70-1.53(m,2H),1.32(s,3H),1.31-1.07(m,2H),1.05(s,3H);13C NMR(125MHz,CDCl3)δ138.8,134.2,129.3(2),128.1(2),127.9(2),126.7,121.3,116.4,114.1,37.2,37.0,34.7,31.6,30.2,27.2,26.1,25.2,24.7,22.6,24.1,21.8(2),20.5,14.1;C27H29NO的分析计算值:C,83.57;H,7.66;N,3.60。
实测值:C,83.55;H,7.38;N,3.45。实施例3412,5-二氢-10-乙烯基-5-[1-甲基-3-环己烯基]-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例339的方法处理实施例339的产物和3-(二甲基苯基甲硅烷基)-3-甲基环己烯,得到所需化合物。mp198-201℃;MS(DCI/NH3)m/z 398(M+H)+;1H NMR(300MHz,DMSO)(对于主要的顺式非对映体)δ7.30(d,J=7.9Hz,1H),7.16-7.00(m,3H),6.92(dd,J=7.1,2.6Hz,1H),6.66(d,J=8.0Hz,1H),6.39(br s,1H),5.73(d,J=12.4Hz,1H), 5.52-5.41(m,3H),5.32(d,J=10.2Hz,1H),2.33-2.22(m,1H),2.14(s,3H),1.91-1.70(m,1H),1.87-1.65(m,1H),1.63-1.51(m,1H),1.60(s,3H),1.34-1.15(m,2H),1.31(s,3H),1.13-0.98(m,1H),,1.04(s,3H);C28H31NO的分析计算值:C,84.59;H,7.85;N,3.52。
实测值:C,84.46;H,7.81;N,3.37。实施例3422,5-二氢-5-(3-丙烯基)-10-甲硫基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
于0℃,向实施例3B的产物(120mg,0.390mmol)在无水DMF(1.0ml)中的磁力搅拌下的溶液中加入氢化钠(1 7mg,60%分散于矿物油中,0.430mmol)。在氮气下搅拌该混合物直至氢气的发生停止(1小时)。然后一次性加入固体二甲基硫代氨基甲酰氯(64mg,0.520mmol),于0℃继续搅拌30分钟。移去冷浴,于80℃加热该混合物45分钟。然后将该反应混合物倾入1%氢氧化钠(10ml)中,用乙酸乙酯(2×25ml)提取。用水(3×5ml)和盐水(3ml)洗涤合并的有机部分,然后干燥(硫酸镁),过滤并浓缩。使产生的棕色残留物经快速层析(用25%乙酸乙酯/己烷洗脱)纯化,得到形成的硫羰基氨基甲酸酯(thionocarbamate)(43mg,0.109mmol,28%),为黄色固体。MS(DCI/NH3)m/z348(M+H)+。
将上面制备的化合物(113mg,0.280mmol)置于敞口的管制瓶中并使之浸入加热至270-280℃的Woods金属浴中6分钟。使该反应物冷却,产生的深棕色残留物经快速层析(梯度洗脱液:20%至40%乙酸乙酯/己烷)纯化,得到热重排的硫代氨基甲酸酯产物(67mg,0.165mmol,59%),为黄色固体。MS(DCI/NH3)m/z348(M+H)+。
于-78℃、氮气下,向该重排的产物(500mg,1.26mmol)的无水甲苯(70ml)溶液中滴加Dibal-H(2.02ml,在庚烷中的1.0M溶液,2.02mmol),同时维持温度在-78℃。于-78℃将生成的桔红色溶液搅拌1.5小时,此时等份样品的TLC(用饱和氯化铵猝灭)指示转化为所需产物。还观察到一些较低Rf的物质(因过度还原产生的二醇)。于-78℃将乙酸乙酯(10ml)加入该溶液中,以猝灭过量的DIBAL-H试剂(通过该溶液的颜色由桔红色转变为淡黄色的颜色改变来指示),接着加入饱和氯化铵水溶液(15ml)。使该反应混合物在乙酸乙酯(150ml)和Rochelle’s盐水溶液(酒石酸钠钾;40ml)之间分配,剧烈搅拌生成的混合物,直至观察到澄清分开的各层。分离各层,用盐水(20ml)洗涤有机层,干燥(硫酸钠)并过滤。除去溶剂得到为淡黄色泡沫状物的内半缩醛(512mg),其可不经进一步纯化而使用。
于23℃,将该内半缩醛溶于甲醇(30ml)中,分次加入为固体的p-TsOH·H2O(50mg,25%w/w)。于23℃搅拌该混合物14小时,然后用饱和碳酸氢钠水溶液(10ml)猝灭,用乙酸乙酯(2×50ml)提取。合并有机部分,用盐水(20ml)洗涤并干燥(硫酸钠)。过滤并浓缩,得到黄色残留物,将其经快速层析(用5%乙酸乙酯/二氯甲烷洗脱)纯化,得到产物甲基缩醛(157mg,0.416mmol,两步骤33%),为黄色泡沫物。MS(DCI/NH3)m/z379(M-OCH3)+。
如同实施例2的方法处理上面制备的内半缩醛和烯丙基三甲基硅烷,得到C-5烯丙基化合物。MS(DCI/NH3)m/z421(M+H)+。实施例3432,5-二氢-5-(3-丙烯基)-10-甲硫基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
将硫代氨基甲酸酯(249mg,0.590mmol)和氢氧化钾(90mg,1.20mmol)在含水(1.5ml)的乙二醇(6ml)中的悬浮液回流加热1.5小时(均匀的溶液)。冷却该溶液并倾入冰(10g)中。用10%HCl酸化该混合物(pH4),然后用二氯甲烷(2×20ml)提取。干燥(硫酸钠)提取物,过滤并浓缩。产生的残留物经快速层析(用5%乙酸乙酯/二氯甲烷洗脱)纯化,得到近乎均匀的苯硫酚加合物(183mg),为被即刻使用的灰黄色固体:1H NMR(300MHz,DMSO-d6)δ7.72(d,J=8.0Hz,1H),7.08(dd,J=7.6,1.1Hz,1H),6.96(t,J=7.5Hz,1H),6.67(d,J=8.1Hz,1H),6.63(dd,J=7.5,1.2Hz,1H),6.28(br s,1H),5.88-5.70(m,2H),5.47(br s,1H),5.41(s,1H),5.03(dd,J=13.2,1.3Hz,1H),4.98(dd,J=18.4,1.3Hz,1H),2.48-2.21(m,2H),2.17(s,3H),1.20(s,3H),1.17(s,3H);MS(DCI/NH3)m/e350(M+H)+;
于0℃,用碳酸铯(50mg,0.153mmol)处理粗品苯硫酚(183mg)的DMF(10ml)溶液。10分钟后,加入碘代甲烷(25mg,0.176mmol)的DMF(0.7ml)溶液,于0℃将该溶液搅拌30分钟,然后于23℃搅拌2小时。用1∶1乙酸乙酯-己烷(100ml)稀释该混合物并用水(3×25ml)洗涤,然后用盐水(25ml)洗涤。干燥(硫酸钠)有机部分,过滤并浓缩。产生的残留物经快速层析(用5%乙酸乙酯/己烷洗脱)纯化,得到硫醚(65mg,0.179mmol,34%),为灰黄色固体:1H NMR(300MHz,DMSO-d6)δ7.82(d,J=8.1Hz,1H),7.11(t,J=7.6Hz,1H),6.98(br d,J=7.7Hz,1H),6.72(br d,J=7.6Hz,1H),6.62(d,J=8.0Hz,1H),6.27(br s,1H),5.88-5.70(m,2H),5.47(br s,1H),5.03(dd,J=13.3,1.1Hz,1H),4.99(dd,J=18.3,1.1Hz,1H),2.47(s,3H),2.46-2.33(m,1H),232-2.22(m,1H),2.18(s,3H),1.21(s,3H),1.17(s,3H);MS(CI/NH3)m/e364(M+H)+实施例344(+/-)2,5-二氢-9-(4-乙酰氨基丁酰基氧基)-10-甲氧基-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(APCI)m/z491(M+H)+;1H NMR(200MHz,DMSO-d6)δ7.94(t,1H),7.84(d,1H),6.88(d,1H),6.67(d,1H),6.64(d,1H),6.21(s,1H),5.87-5.78(m,2H),5.46(s,1H),5.06-4.96(m,2H),2.60(s,2H),2.16(dt,2H),2.62(t,2H),2.21-2.27(m,2H),2.18(s,2H),1.82(s,2H),1.79(m,2H),1.18(s,2H),1.17(s,2H)。实施例34510-(二氟甲氧基)-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例8A的方法处理实施例7的产物和溴代二氟甲烷,得到所需化合物。MS(CI/NH3)m/z420(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.80(s,J=8.8Hz,1H),7.26-7.15(m,5H),7.16-7.13(m,1H),6.97(t,J=8.1Hz,1H),6.82(br s,1H),6.74(d,J=8.9Hz,1H),6.72-6.67(m,1H),6.38(br s,1H),5.39(br s,1H),1.82(s,3H),1.24(s,3H),1.15(s,3H);C26H23F2NO2的HRMS(FAB)m/z计算值:419.1697(M)+。实测值:419.1714。实施例34610-(溴代二氟甲氧基)-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(ESI)m/z498(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.68(s,J=8.8Hz,1H),7.25-7.14(m,5H),7.03(t,J=8.2Hz,1H),6.89-6.84(m,1H),6.85(br s,1H),6.83-6.79(m,1H),6.74(d,J=8.6Hz,1H),6.46(br s,1H),5.40(br s,1H),1.81(s,3H),1.25(s,3H),1.15(s,3H);13C NMR(125MHz,DMSO-d6)δ152.34,146.44,145.97,138.38,133.02,130.51,128.61(2),128.07,127.92(2),127.33,126.86(2),119.16,117.82,116.68,115.84,115.32,114.28,114.12,75.60,49.93,29.90,28.72,23.26;C26H22 79BrF2NO2的HRMS(FAB)m/z计算值:497.0802(M+H)+。实测值:497.0790。C26H22 81BrF2NO2的HRMS(FAB)m/z计算值:499.0782(M+H)+。实测值:499.0793。实施例34710-(溴代二氟甲氧基)-5-苯基-2,2-二甲基-4-亚甲基2,3,4,5-四氢-1H-苯并吡喃并[3,4-f]喹啉MS(ESI)m/z498(M+H)+;1H NMR(300MHz,CDCl3)δ7.88(s,J=8.4Hz,1H),7.31-7.26(m,2H),7.19-7.12(m,3H),6.95(t,J=8.1Hz,1H),6.86-6.78(m,2H),6.64(brs,1H),6.58(d,J=8.5Hz,1H),4.94(s,1H),4.61(s,1H),4.17(br s,1H),2.45(br d,J=12.0Hz,1H),2.19(d,J=12.4Hz,1H),1.35(s,3H),1.14(s,3H);C26H22 79BrF2NO2的HRMS(FAB)m/z计算值:497.0802(M+H)+。实测值497.0790。C26H22 81BrF2NO2的HRMS(FAB)m/z计算值:499.0782(M+H)+。实测值499.0771。实施例3482,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-((2-氟代苯基)甲基)-1H-[1]苯并吡喃并[3,4-f]喹啉实施例34910-甲氧基-5-(5-甲基异噁唑-3-基)亚甲基-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和3,5-二甲基异噁唑的锂阴离子,得到所需化合物。MS(DCI/NH3)m/z401(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.33(d,1H,J=8.83Hz),7.7-7.5(m,1H),7.22(t,1H,J=8.09Hz),7.05(d,1H,J=1.1Hz),6.85(s,1H),6.79(d,1H,J=8.82Hz),5.61(s,1H),5.5(s,1H),3.93(s,3H),2.45(s,3H),1.96(d,3H,J=1.1Hz),1.20-1.30(s,6H)。实施例35010-甲氧基-5-(3-甲基异噁唑-5-基)亚甲基-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和3,5-二甲基异噁唑的锂阴离子,得到所需化合物。MS(DCI/NH3)m/z401(M+H)+;1H NMR(300MHz,DMSO-d6),异构体1:δ8.38(d,1H,J=8.83Hz),7.22(t,1H,J=8Hz),7.09(s,1H),6.87-6.81(m,2H),6.56(s,1H),5.65(s,1H),5.51(s,1H),3.93(s,3H),2.28(s,3H),1.95(s,3H),1.29(s,3H),1.26(s,3H);异构体2:δ8.16(d,1H,J=8.83Hz),7.18(t,2H,J=8Hz),7.06(s,1H),6.80-6.76(m,2H),6.46(s,1H),5.90(s,1H),5.21(s,1H),3.91(s,3H),2.08(s,3H),1.84(s,3H),1.26(s,3H),1.12(s,3H)。实施例35110-甲氧基-5-(4,5-二甲基-1,3-噁唑-2-基)亚甲基-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和2,4,5-三甲基噁唑的锂阴离子,得到所需化合物。MS(DCI/NH3)m/z415(M+H)+;1H NMR(300MHz,DMSO-d6),异构体1:δ8.36(d,1H,J=8.82Hz),7.24-7.20(m,1H),6.82(m,3H),6.25(s,1H),5.49(s,1H),3.92(s,3H),2.31(s,3H),2.09(s,3H),1.28(s,3H),1.2(m,6H);异构体2:δ8.09(d,1H,J=8.82Hz),7.16(m,1H),6.78-6.73(m,2H),5.41(s,1H),5.21(s,1H),3.91(s,3H),2.03(s,3H),1.89(s,3H),1.88(s,3H),1.25-1.15(m,6H)。实施例35210-甲氧基-5-(6-氯代吡啶-2-基)亚甲基-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和6-氯代-2-甲基吡啶的锂阴离子,得到所需化合物。MS(DCI/NH3)m/z431(M+H)+;1H NMR(300MHz,DMSO-d6):δ8.35(d,1H,J=4.7Hz),8.25(d,1H,J=8.1Hz),7.9(t,1H,J=7.7Hz),7.30(d,1H,J=7.7Hz),7.21(d,1H,J=8Hz),7.00(d,1H,J=8.1Hz),6.8(dd,2H,J=8.4,2.6Hz),6.72(s,1H),5.65(s,1H),5.51(s,3H),3.93(s,3H),1.99(s,3H),1.2(s,6H)。实施例35310-甲氧基-5-(吡啶-2-基)亚甲基-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和4-皮考啉基锂,得到所需化合物。MS(DCI/NH3)m/z397(M+H)+;1H NMR(300MHz,DMSO-d6),异构体1:δ8.52(d,2H,J=6.1Hz),8.17(d,1H,J=8.8Hz),7.2(t,1H,J=8.2Hz),6.96(s,1H),6.7(m,3H),6.66(s,2H),5.55(s,1H),4.53(s,1H),3.93(s,3H),1.81(d,3H,J=1.4Hz),1.27(s,6H);异构体2:δ8.32(d,2H,J=6.1Hz),8.19(d,1H,J=8.8Hz),7.17(t,1H,J=8.2Hz),6.99(s,1H),6.77(m,3H),6.45(s,2H),5.48(s,1H),5.05(s,1H),3.93(s,3H),1.81(d,3H,J=1.4Hz),1.27(s,6H)。实施例35410-甲氧基-5-(亚丁-3-烯基)-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和环丙基甲基溴的锂阴离子,得到所需化合物。MS(DCI/NH3)m/z360(M+H)+;1H NMR(300MHz,DMSO-d6):δ8.16(d,1H,J=8.8Hz),7.10(t,1H,J=7.7Hz),6.8-6.6(m,4H),6.47(s,1H),5.89-5.75(m,1H),5.41(s,1H),5.10-4.93(m,2H),4.67(t,1H,J=7.5Hz),3.88(s,3H),1.97(d,3H,J=1.3Hz),1.20(s,6H)。实施例35510-甲氧基-5-(1-甲基亚丙基)-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和仲丁基锂,得到所需化合物。MS(DCI/NH3)m/z362(M+H)+;1H NMR(300MHz,DMSO-d6):δ8.01(d,1H,J=8.09Hz),7.09(t,2H,J=8.09Hz),6.7(dd,2H,J=8.5,2.6Hz),6.65(d,1H,J=8.46Hz),6.37(d,1H,J=0.8Hz),5.4(s,1H),3.87(s,3H),1.86(d,3H,J=1.1Hz)1.48(s,3H),1.33(s,3H),1.08(s,3H),0.9(t,3H,J=7.3Hz)。实施例35610-甲氧基-5-(1-亚丁基)-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同实施例1B的方法处理实施例1F的产物和正丁基锂,得到所需化合物。MS(DCI/NH3)m/z362(M+H)+;1H NMR(300MHz,DMSO-d6):δ8.14(d,1H),7.07(t,1H),6.67(m,3H),6.07(s,1H),5.40(s,1H),4.71(t,1H),3.88(s,3H),2.29(q,1H),2.00(s,3H),1.43-1.36(m,2H),1.21(s,6H),0.88(t,3H)。实施例3572,5-二氢-10-甲氧基-2,2,4-三甲基-3-氧化物-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹啉实施例357A8-氨基-7-溴代-1-甲氧基-6H-苯并[c]苯并吡喃-6-酮
用N-溴代琥珀酰亚胺(2.2g,12.0mmol)处理实施例1E的产物(3.0g,12.0mmol)的DMF(100ml)溶液,搅拌40分钟,倾入900ml水中,搅拌5分钟,过滤收集产生的固体,干燥得到所需化合物。实施例357B7-溴代-1-甲氧基-6-苯基-6H-苯并[c]苯并吡喃-8-基胺
如同实施例1G和1的方法处理实施例357A的产物(2.0g,6.25mmol)和苯基锂,得到所需化合物。实施例357C1-(7-溴代-1-甲氧基-6-苯基-6H-苯并[c]苯并吡喃-8-基)乙-1-酮
于85℃、氮气下,将实施例357B的产物(1.23g,3.22mmol)、三丁基(1-乙氧基乙烯基)锡(1.4g,3.86mmol)和二氯双(三苯膦)钯(II)(263mg,0.322mmol)在NMP(30ml)中加热24小时。使该混合物在乙酸乙酯和饱和碳酸氢钠水溶液之间分配,通过硅藻土过滤。浓缩乙酸乙酯层,使残留物溶于乙腈中,用己烷(5×20ml)洗涤,浓缩。用1∶1体积的1N HCl/THF处理产生的残留物,搅拌30分钟,倾入冷的饱和碳酸氢钠中,用乙酸乙酯(5×25ml)提取。用盐水洗涤有机物,干燥(硫酸钠),经硅胶快速层析,用4∶1的己烷/乙酸乙酯洗脱,得到所需化合物。实施例357D1-(7-溴代-1-甲氧基-6-苯基-6H-苯并[c]苯并吡喃-8-基)乙-1-酮肟
将实施例357C的产物(700mg,2.03mmol)和羟胺盐酸盐(2.45g,30.4mmol)在乙醇(70ml)和吡啶(70ml)混合物中的溶液回流8小时,冷却并浓缩。使残留物溶于乙酸乙酯中,用水、盐水洗涤,干燥(硫酸钠)并浓缩,得到无需纯化的所需化合物。实施例3572,5-二氢-10-甲氧基-2,2,4-三甲基-3-氧化物-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹唑啉
将实施例357D产物(700mg,1.94mmol)、硫酸铜(105mg)和乙酸(3滴)在丙酮(30ml)中混合并回流8小时。使该混合物冷却并倾入水中,用乙酸乙酯(3×50ml)提取。合并有机物,用盐水洗涤,干燥(硫酸钠)并浓缩。用乙酸乙酯(30ml)研磨残留物,过滤收集黄色固体,得到所需化合物。MS(DCI/NH3)m/z401(M+H)+;1H NMR(300MHz,DMSO-d6):δ8.21(d,1H),7.30(s,1H),7.29-7.16(m,5H),7.00-6.92(m,2H),6.61(d,1H),6.57(s,1H),6.44(d,1H),3.72(s,3H),2.01(s,3H),1.55(s,3H),1.28(s,3H);C24H27NO2的HRMS m/z计算值:400.1787(M)+。实测值:400.1786。实施例3582,5-二氢-10-甲氧基-2,2,4-三甲基-5-苯基-1H-[1]苯并吡喃并[3,4-f]喹唑啉
在4个氢气压下,用Raney镍处理实施例357E的产物(80mg,0.2mmol)的甲醇溶液,搅拌24小时。通过硅藻土过滤该混合物,浓缩、产生的残留物经硅胶快速层析,用99∶1的乙酸乙酯/甲醇洗脱,得到所需化合物。MS(DCI/NH3)m/z385(M+H)+;1H NMR(300MHz,DMSO-d6):δ8.22(d,1H),7.26-7.15(m,5H),6.93(t,1H),6.79(s,1H),6.76(d,1H),6.73(s,1H),6.57(d,1H),6.44(d,1H),3.81(s,3H),2.00(s,3H),1.36(s,3H),1.21(s,3H);C25H24N2O2的HRMS m/z计算值:385.1916(M+H)+。实测值:385.1930。实施例3592,5-二氢-10-甲氧基-2,2-[螺(四氢-4-吡喃基)]-4-甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉实施例359A
于85℃、氮气下,将实施例357A的产物(1.3g,4.08mmol)、异丙烯基三甲基锡(3.3g,16.3mmol)和二氯双(三苯膦)钯(II)(330mg,0.40mmol)在NMP(30ml)中加热24小时。使该混合物在乙酸乙酯和饱和氟化钾水溶液之间分配,搅拌3小时,通过硅藻土过滤。用水(5×50ml)、盐水(5×50ml)洗涤乙酸乙酯层,干燥(硫酸钠)并浓缩。经硅胶快速层析,用3∶1的己烷/乙酸乙酯洗脱,得到所需化合物。实施例359
于80℃,将在5ml甲苯中的2-异丙烯基苯胺(56mg,0.2mmol)、四氢-4H-吡喃-4-酮(160mg,1.6mmol)和碘(25mg,0.1mmol)的混合物在ACE密封管中加热1小时,冷却、使该混合物在乙酸乙酯和10%硫代硫酸钠水溶液之间分配。用水、盐水洗涤乙酸乙酯层,干燥(硫酸钠)并浓缩,经硅胶快速层析,用3∶2的己烷/乙酸乙酯洗脱,得到为亮黄色粉末的所需香豆素。如同实施例2的方法处理生成的香豆素,得到所需化合物。MS(DCI/NH3)m/z390(M+H)+;1H NMR(300MHz,DMSO-d6):δ7.92(d,1H),7.07(t,1H),6.75(d,1H),6.70(d,1H),6.52(d,1H),6.24(s,1H),5.87-5.73(m,2H),5.71(s,1H),5.01(dd,1H),4.96(dd,1H),3.86(s,3H)3.75-3.39(m,4H),2.51-2.14(m,2H),2.20(s,3H),1.69-1.49(m,4H);C25H27NO3的HRMSm/z计算值:389.1991(M)+。实测值:389.1974。C25H27NO3的分析计算值:C,77.07;H,6.99;N,3.60。
实测值:C,76.92;H,7.28;N,3.64。实施例3602,5-二氢-10-甲氧基-2,2-[螺(己基)]-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同前面的实施例的方法,顺序用异丙烯基三丁基锡和环己酮处理实施例357A,得到所需化合物。MS(DCI/NH3)m/z388(M+H)+;1H NMR(300MHz,DMSO-d6):δ7.95(d,1H),7.06(t,1H),6.74(d,1H),6.70(d,1H),6.52(d,1H),6.05(s,1H),5.85-5.72(m,2H),5.58(s,1H),5.02(dd,1H),4.97(dd,1H),3.86(s,3H)2.42(m,1H),2.18(s,3H),2.16(m,1H),1.56-1.25(m,10H);C26H29NO2的HRMS m/z计算值:387.2198(M)+。实测值:387.2196。实施例3612,5-二氢-10-甲氧基-2,2-二乙基-4-甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同前面的实施例的方法,顺序用异丙烯基三丁基锡和3-戊酮处理实施例357A,得到所需化合物。MS(DCI/NH3)m/z376(M+H)+;1H NMR(300MHz,DMSO-d6):δ7.92(d,1H),7.05(t,J=8Hz,1H),6.68(d,1H),6.59(d,1H),6.51(d,1H),5.98(s,1H),5.86-5.77(m,2H),5.27(s,1H),5.04-4.95(m,2H),3.85(s,3H),2.42(m,1H),2.21(s,3H),2.15(m,1H),1.42-1.35(m,4H),0.83(t,3H),0.82(t,3H);C25H29NO2的HRMS m/z计算值:375.2198(M)+。实测值:375.2191。C25H29NO2的分析计算值:C,79.96;H,7.78;N,3.73。
实测值:C,79.74;H,7.89;N,3.54。实施例3622,5-二氢-10-甲氧基-2,2,3,4-四甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同前面的实施例的方法,顺序用1-甲基-1-丙烯基三丁基锡和丙酮处理实施例357A,得到所需化合物。MS(DCI/NH3)m/z362(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.97(d,1H),7.07(t,1H),6.70(d,1H),6.62(d,1H),6.53(d,1H),5.90(s,1H),5.76(m,1H),5.61(dd,1H),5.01-4.90(m,2H),3.87(s,3H),2.47(m,1H),2.18(m,1H),2.04(s,3H),1.76(s,3H),1.13(s,3H),1.09(s,3H);C24H27NO2的HRMS m/z计算值:361.2042(M)+。实测值:361.2055。实施例3632,5-二氢-10-甲氧基-2,2-二甲基-4-乙基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同前面的实施例的方法,顺序用1-亚甲基丙基三丁基锡和丙酮处理实施例357A,得到所需化合物。MS(DCI/NH3)m/z362(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.98(d,1H),7.07(t,1H),6.70(dd,1H),6.63(d,1H),6.53(dd,1H),6.12(bs,1H),5.78(m,1H),5.59(dd,1H),5.50(bs,1H),5.03-4.92(m,2H),3.86(s,3H),2.54-2.41(m,3H),2.11(m,1H),1.20(s,3H),1.10(s,3H),1.03(t,3H);C24H27NO2的HRMS m/z计算值:361.2042(M)+。实测值:361.2034。实施例3642,5-二氢-10-甲氧基-2,2,3-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉
如同前面的实施例的方法,顺序用(Z)-1-丙烯基三丁基锡和丙酮处理实施例357A,得到所需化合物。MS(DCI/NH3)m/z 348(M+H)+;1H NMR(300MHz,DMSO-d6)δ7.89(d,1H),7.04(t,1H),6.68(d,1H),6.52(d,1H),6.47(d,1H),6.21(s,1H),5.96(s,1H),5.88(m,1H),5.43(dd,1H),5.03(m,1H),4.96(m,1H),3.84(s,3H),2.35(m,1H),2.08(m,1H),1.83(s,3H),1.23(s,6H);C23H25NO2的HRMS m/z计算值:347.1885(M)+ 实测值:347.1879。实施例365Z-5-(亚苄基)-9-羟基-10-甲氧基-2,2,4-三甲基-1H-2,5-二氢-MS(DCI/NH3)412(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.93(s,1H),8.13(d,J=8.8Hz,1H),7.63(d,J=8.8Hz,2H),7.32-7.15(m,3H),6.77(d,1H),6.69(d,1H),6.66(d,1H),6.52(s,1H),5.46(s,1H),5.39(s,1H),3.65(s,3H),1.90(s,3H),1.20(s,6H);C27H25NO3的HRMS m/z计算值为411.1834。实测值:411.1821。实施例366Z-5-(2,5-二氟亚苄基)-9-羟基-10-甲氧基-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z(M+H)+448;1H NMR(300MHz,DMSO-d6)δ9.06(s,1H),8.29(d,J=9Hz,1H),7.96(m,1H),7.24(m,1H),7.11(m,1H),6.86(d,J=9Hz,1H),6.82(d,J=9Hz,1H),6.78(d,J=9Hz,1H),6.72(br s,1H),5.75(s,1H),5.48(s,1H),3.75(s,3H),1.99(s,3H),1.26(br s,6H);C27H23NO3F2的分析计算值:C,72.47;H,5.18;N,3.13。
实测值:C,72.21;H,5.31;N,3.09。实施例367Z-5-(3-氟代亚苄基)-10-氯代-9-羟基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z434(M+H)+;1H NMR(300MHz,DMSO)δ9.86(br s,1H),8.40(d,J=8.5Hz,1H),7.61(dt,J=8.6,1.8Hz,1H),7.60-7.52(m,1H),7.46-7.38(m,1H),7.15-7.02(m,1H),7.09(d,J=8.4Hz,1H),6.85(d,J=8.6Hz,1H),6.84(s,1H),6.78(d,J=8.6Hz,1H),5.68(s,1H),5.48(br s,1H),1.97(br s,3H),1.16(br s,6H);13C NMR(125MHz,DMSO)δ163.8,160.6,149.9,149.2,148.2,146.4,132.0,130.3,128.1,127.3,126.2,125.3,124.5,118.7,117.7,117.3,116.1,115.5,114.6,114.3,114.0,113.7,62.1,29.8,28.2,21.2;C26H21ClFNO2的HRMS(FAB)m/z计算值:433.1245(M)+。实测值:433.1237。实施例368Z-10-氯代-9-羟基-5-(2-亚甲基吡啶基)-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z417(M+H)+;1H NMR(300MHz,DMSO)δ9.79(br s,1H),8.51(ddd,J=5.9,1.6,1.0Hz,1H),8.43(d,J=8.6Hz,1H),8.24(dt,J=7.8,1.0Hz,1H),7.53(td,J=7.8,1.7Hz,1H),7.22(ddd,J=7.7,5.8,1.2Hz,1H),7.00(d,J=8.5Hz,1H),6.88(d,J=8.6Hz,1H),6.81(d,J=8.5Hz,1H),6.63(br s,1H),5.71(s,1H),5.51(br s,1H),2.00(br s,3H),1.28(br s,6H);13C NMR(125MHz,DMSO-d6)δ153.5,149.7,146.4,145.7,136.5,136.1,132.7,128.7,128.2,123.0,122.4,121.5,118.3,117.7,117.6,116.5,115.5,114.8,114.4,114.1,113.9,49.5,29.7,28.1,21.2;C25H21ClN2O2的HRMS(FAB)m/z计算值:416.1291(M)+。实测值:416.1288。实施例369Z-9-羟基-10-甲氧基-5-(2-亚甲基吡啶基)-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z413(M+H)+;1H NMR(300MHz,DMSO)δ9.08(br s,1H),8.55(ddd,J=5.3,1.4,1.0Hz,1H),8.32(d,J=8.6Hz,1H),8.30(br t,J=7.7Hz,1H),7.83(td,J=7.8,1.4Hz,1H),7.21(ddd,J=7.6,5.3,1.2Hz,1H),6.97(d,J=8.6Hz,1H),6.86(d,J=8.5Hz,1H),6.81(d,J=8.6Hz,1H),6.73(br s,1H),5.80(s,1H),5.54(br s,1H),3.78(s,3H),2.03(br s,3H),1.31(br s,6H);13C NMR(125MHz,DMSO-d6)δ158.4,149.1,148.2,146.6,139.5,136.0,133.1,128.8,125.7,124.6,122.9,121.0,119.4,118.2,117.3,116.9,115.8,115.1,114.7,114.0,111.5,73.3,50.2,29.9,28.1,22.3;C26H25N2O3的HRMS(FAB)m/z计算值:413.1865(M+H)+。实测值:413.1849。C26H24N2O3的分析计算值:C,75.71;H,5.86;N,6.79。
实测值:C,75.61;H,6.05;N,6.75。实施例3709-羟基-10-甲氧基-5-(3,5-二氟苯基)亚甲基-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ9.05(s,1H),8.24(d,J=9Hz,1H),7.41(m,2H),7.07(m,1H),6.85(d,J=8Hz,1H),6.80(d,J=9Hz,1H),6.76(d,J=9Hz,1H),6.70(br s,1H),5.57(s,1H),5.46(s,1H),3.72(s,3H),1.96(s,3H),1.27(br s,6H);13C NMR(75MHz,DMSO-d6)δ164.0(d),160.8(d),150.1,146.2,146.1,144.6,144.4,132.1,128.8,125.2,125.0,117.9,117.8,115.2,115.0,114.8,112.1,110.9,110.8,110.5,101.9,101.6,101.2,29.3,49.5,21.1(2xC);MS(DCI/NH3)m/e(M+H)+448。实施例3719-羟基-10-甲氧基-5-(3,4-二氟苯基)亚甲基-2,5-二氢-5-苯基-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ9.03(s,1H),8.22(d,J=9Hz,1H),7.79(m,1H),7.52(m,1H),7.41(m,1H),6.86(d,J=9Hz,1H),6.77(d,J=9Hz,1H),6.74(d,J=9Hz,1H),6.68(br s,1H),5.53(s,1H),5.45(s,1H),3.33(s,3H),1.95(s,3H),1.27(br s,6H);MS(DCI/NH3)m/e(M+H)+448。C27H23NO3F2的FAB HRMS计算值。实施例372(Z)9-羟基-10-甲氧基-5-((4-氟代苯基)亚甲基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ9.01(s,1H),8.19(d,J=9Hz,1H),7.77(d,J=9Hz,1H),7.76(d,J=9Hz,1H),7.22(d,J=9Hz,1H),7.18(d,J=9Hz,1H),6.84(d,J=8Hz,1H),6.75(d,J=9Hz,1H),6.72(d,J=9Hz,1H),6.66(s,1H),5.53(s,1H),5.45(s,1H),3.71(s,3H),1.96(s,3H),1.26(s,6H);13C NMR(75MHz,DMSO-d6)δ161.8,159.4,147.4,146.0,145.1,144.4,132.0,131.4,130.2,130.1,129.0,126.2,125.0,117.8,115.4,115.3,115.2,114.6,114.5,113.3,111.0,59.3,59.2,49.5,21.0;MS(DCI/NH3)m/z 430(M+H)+;C27H24NO3F的分析计算值:C,75.51;H,5.63;N,3.26。
实测值:C,75.64;H,5.97;N,3.03。实施例373(Z)9-羟基-10-甲氧基-5-([2,3-二氟苯基]亚甲基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ9.09(s,1H),8.27(d,J=9Hz,1H),8.04(d,J=9Hz,1H),7.33-7.20(m,2H),6.87(d,J=9Hz,1H),6.82(d,J=9Hz,1H),6.76(s,1H),6.75(d,J=9Hz,1H),5.75(s,1H),5.49(s,1H),3.73(s,3H),1.99(s,3H),1.26(s,6H);MS(DCI/NH3)m/z448(M+H)+;C27H23NO3F2的分析计算值:C,72.47;H,5.18;N,3.13。
实测值:C,72.17;H,5.03;N,2.95。实施例374Z-5-(3-氟代亚苄基)-10-甲氧基-9-羟基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ9.04(s,1H),8.22(d,1H),7.62-7.37(m,3H),7.10-7.02(m,1H),6.86(d,1H),6.78(d,1H),6.73(d,1H),6.70(s,1H),5.56(s,1H),5.46(s,1H),3.72(s,3H),1.96(s,3H),1.27(s,3H)。MS(DCI/NH3)m/z 430(M+H)+;C27H24NO3F·0.25 H2O的分析计算值:C,75.51;H,5.63;N,3.26。
实测值:C,74.84;H,6.17;N,2.91。实施例375rel-(5S,3’R)-9-羟基-5-[1-甲氧基甲基-3-环己烯基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z452(M+H)+;1H NMR(300MHz,DMSO)δ8.02(d,J=8.6Hz,1H),6.93(app s,2H),6.68(d,J=8.3Hz,1H),6.48(br s,1H),5.52(d,J=10.3Hz,1H),5.42(br s,1H),5.10(br s,1H),4.46(t,J=5.5Hz,1H),3.81(s,3H),3.65(br d,J=5.5Hz,2H),2.26-2.16(m,1H),2.08(br s,3H),1.95-1.88(m,2H),1.77-1.62(m,2H),1.57-1.44(m,1H),1.37-1.28(m,1H),1.30(s,3H),1.11(s,3H);13C NMR(125MHz,DMSO)δ150.4,146.0,144.9,140.7,133.9,132.7,127.9,127.0,124.3,119.8,117.7,116.7,115.7,115.4,112.5,110.7,75.9,65.5,56.4,49.6,36.6,29.7,27.9,25.9,25.0,24.4,20.3;C27H30ClNO3的HRMS(FAB)m/z计算值:451.1915(M)+。实测值:451.1922。实施例3769-羟基-10-甲氧基-5-乙基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(200MHz,DMSO-d6)δ8.70(s,1H),7.90(d,J=8Hz,1H),6.61(m,2H),6.51(d,J=8Hz,1H),6.16(br s,1H),5.52-5.40(m,2H),2.62(s,2H),2.09(s,2H),1.79-1.58(m,1H),1.52-1.27(m,1H),1.17(s,2H),1.15(s,2H),0.89(t,J=7Hz,2H);13C NMR(75MHz,DMSO-d6)δ145.8,145.0,142.9,142.0,122.5,122.4,127.6,126.4,118.0,116.4,116.1,114.2,112.5,112.2,75.1,59.2,49.7,29.2,28.8,25.5,22.8,10.4;MS(DCI/NH3)m/e(M+H)+252;C22H25NO2·1/2H2O的分析计算值:C,72.94;H,7.24;N,2.92。
实测值:C,72.78;H,7.40;N,2.74。实施例377(+/-)2,5-二氢-9-氰基甲氧基-10-甲氧基-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(200MHz,DMSO-d6)δ7.92(d,1H),6.95(d,1H),6.66(d,1H),6.62(d,1H),6.26(d,1H),5.86(m,2H),5.45(s,1H),5.12(s,2H),5.00(m,2H),2.69(s,2H),2.42(m,1H),2.26(m,1H),2.17(s,2H),1.18(s,2H),1.17(s,2H)。实施例3782,5-二氢-9-(4-N,N-二乙基氨基-4-氧代-丁酰氧基)-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(400MHz,DMSO-d6)δ7.78(d,J=8.5,1H),6.76(d,J=8.9,1H),6.60-6.55(m,2H),6.18(d,J=1.7,1H),5.80-5.70(m,2H),5.28(s,1H),4.98-4.90(m,2H),2.55(s,2H),2.28-2.17(m,4H),2.77-2.69(m,2H),2.68-2.57(m,2H),2.29(m,1H),2.19(m,1H),2.10(s,2H),1.11(s,2H),1.10(s,2H),1.06(t,J=7.2,2H),0.95(t,J=7.2,2H);13C NMR(100MHz,DMSO-d6)δ171.5,169.5,148.2,148.0,146.2,128.5,124.1,122.5,122.1,127.2,126.2,120.8,118.2,117.2,116.2,115.0,112.8,112.5,72.6,60.0,49.8,41.1,26.6,29.2,29.0,27.4,22.8,14.0,12.1;MS(ESI/NH3)m/e519(M+H)+,541(M+Na)+;C31H38N2O5的分析计算值:C,71.79,H,7.28,N,5.40。
实测值:C,71.50,H,7.28,N,5.28。实施例3792,5-二氢-9-(4-N-哌啶子基-4-氧代-丁酰氧基)-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(200MHz,DMSO-d6)δ7.78(d,J=8.4,1H),6.76(d,J=8.8,1H),6.61-6.55(m,2H),6.17(d,J=1.5,1H),5.82-5.68(m,2H),5.28(s,1H),4.99-4.89(m,2H),2.55(s,2H),2.27(m,4H),2.74(m,2H),2.61(m,2H),2.41(m,1H),2.18(m,1H),2.10(s,2H),1.51-1.16(m,6H),1.11(s,2H),1.10(s,2H);13C NMR(75MHz,DMSO-d6)δ171.7,168.9,148.5,148.2,146.5,128.7,124.2,122.8,122.2,127.5,12 6.5,121.0,118.4,117.5,116.4,115.2,114.0,112.8,72.8,60.2,50.0,45.9,42.4,26.8,29.5,29.2,27.7,26.1,25.5,24.2,24.1;MS(ESI/NH3)m/e 521(M+H)+,552(M+Na)+;C32H38N2O5的分析计算值:C,72.42,H,7.22,N,5.28。
实测值:C,72.16,H,7.26,N,5.09。实施例3802,5-二氢-9-(4-N-吗啉代-4-氧代-丁酰氧基)-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(400MHz,DMSO-d6)δ7.78(d,J=8.9,1H),6.77(d,J=8.5,1H),6.60-6.55(m,2H),6.18(s,1H),5.80-5.70(m,2H),5.28(s,1H),4.98-4.90(m,2H),2.55(s,2H),2.52-2.42(m,4H),2.40(m,4H),2.76(m,2H),2.65(m,2H),2.40(m,1H),2.20(m,1H),2.10(s,2H),1.11(s,2H),1.10(s,2H);13C NMR(100MHz,DMSO-d6)δ171.4,169.4,148.2,148.0,146.2,128.5,124.1,122.5,122.1,127.2,126.2,120.8,118.2,117.2,116.2,115.0,112.8,112.6,72.6,66.1,60.0,49.8,45.1,41.6,26.6,29.2,29.0,28.8,27.2,22.8;MS(ESI/NH3)m/e 522(M+H)+,555(M+Na)+;C31H36N2O6的分析计算值:C,69.90,H,6.81,N,5.26。
实测值:C,69.61,H,6.84,N,5.04。实施例3812,5-二氢-9-(4-N,N-二甲基氨基-4-氧代-丁酰氧基)-10-甲氧基-2,2,4-三甲基-5-(3,4,5-三氟苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(400MHz,DMSO-d6)δ7.90(d,J=8.5,1H),7.07-7.02(m,2H),6.80-6.70(m,2H),6.62(d,J=8.9,1H),6.44(s,1H),5.42(d,J=1.2,1H),2.54(s,2H),2.97(s,2H),2.82(s,2H),2.76-2.72(m,2H),2.67-2.64(m,2H),1.84(s,2H),1.25(s,2H),1.15(s,2H);13C NMR(100MHz,DMSO-d6)δ171.4,170.4,150.1(d,J=248),148.4,147.9,146.4,128.7,128.2(dd,J=251,49),126.5,122.2,128.2,127.1,126.5,121.0,118.5,117.9,116.1,114.8,112.0,112.8,112.6,72.7,59.7,49.9,26.5,24.9,29.7,28.9,28.6,27.6,22.2;MS(ESI/NH3)m/e 581(M+H)+,602(M+Na)+;C32H31F3N2O5的分析计算值:C,66.20,H,5.28,N,4.82。
实测值:C,66.17,H,5.46,N,4.65。实施例3822,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-5-二氟苯基甲基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.81(s,1H),7.95(d,J=8Hz,1H),7.10-7.03(m,1H),6.78(d,J=9Hz,2H),6.63(dd,J=9,9Hz,2H),6.41(d,J=9Hz,1H),6.22(s,1H),5.91(dd,J=10,10Hz,1H),5.40(s,1H),3.69(s,3H),3.06-2.98(m,1H),2.90-2.84(m,1H),2.19(s,3H),1.15(s,3H),1.12(s,3H);13C NMR(75MHz,DMSO-d6)δ163.8,163.6,160.6,160.4,145.9,145.2,144.1,142.6,142.4,142.3,133.4,131.7,127.4,126.5,117.8,116.5,116.2,114.5,113.9,112.3,112.2,111.9,102.1,101.7,101.4,73.5,59.5,49.7,29.1,29.0,24.1;C27H25O3F2N的HRMS计算值:m/e449.1803,实测值:449.1801;C27H25O3F2N0.05H2O的分析计算值:C,70.73;H,5.72;N,3.05;
实测值:C,70.52;H,5.79;N,2.91。实施例3832,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-(2-噻吩基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMRδ9.51(s,1H),7.95(d,1H,J=8.5Hz),7.40(dd,1H,J=5.1Hz,J=1.4Hz),6.82(m,2H),6.71(m,2H),6.61(s,2H),6.26(m,1H),5.40(m,1H),1.92(d,2H,J=1.4Hz),1.24(s,2H),1.14(s,2H);质谱(ESI)m/z:410(M+1);C22H20ClNO2S的计算值:409.0902。实测值:409.0902。实施例3842,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-环戊基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),7.99(d,J=8Hz,1H),6.63(d,J=9Hz,1H),6.61(d,J=9Hz,1H),6.48(d,J=8Hz,1H),6.27(br s,1H),5.45(br s,1H),5.35(d,J=10Hz,1H),3.65(s,3H),2.15(s,3H),2.11-1.97(m,1H),1.62-1.43(m,4H),1.41-1.26(m,2H),1.30(s,3H),1.21-1.06(m,2H),1.02(s,3H);MS(DCI/NH3)(M+H)+392。实施例3852,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-((2-氟代苯基)甲基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z418(M+H)+。实施例3862,5-二氢-9-羟甲基-10-甲氧基-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z378(M+H)+;1H NMR(500MHz,DMSO)δ7.93(d,J=8.2Hz,1H),7.16(d,J=8.3Hz,1H),6.67(d,J=8.1Hz,1H),6.63(d,J=8.3Hz,1H),6.27(br s,1H),5.87-5.75(m,2H),5.44(br s,1H),5.03(br d,J=10.3Hz,1H),4.98(br d,J=15.1Hz,1H),4.97-4.93(m,1H),4.57-4.48(m,2H),3.59(s,3H),2.55-2.46(m,1H),2.30-2.22(m,1H),2.19(s,3H),1.19(s,3H),1.16(s,3H);13C NMR(125MHz,DMSO)δ154.0,150.2,145.9,134.2,133.4,132.1,128.9,127.4,126.6,125.9,117.2,116.8,116.3,11 5.6,113.9,112.6,73.6,60.0,58.1,49.8,36.4,29.4,28.9,23.9;C24H27NO3的HRMS(FAB)m/z计算值:377.1991(M)+。
实测值:377.1985。实施例3872,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(1-戊烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.67(s,1H),7.88(d,J=9Hz,1H),6.59(d,J=9Hz,2H),6.48(d,J=8Hz,1H),6.14(s,1H),5.73-5.65(m,1H),5.61-5.57(m,1H),5.43(s,1H),4.94-4.86(m,2H),3.63(s,3H),2.15(s,3H),1.99-1.93(m,2H),1.73-1.69(m,1H),1.45-1.41(m,3H),1.16(s,6H);13C NMR(75MHz,DMSO-d6)δ145.7,144.9,143.9,143.0,138.4,133.4,133.3,127.5,126.4,117.9,116.2,116.1,114.7,114.2,113.4,112.1,73.5,59.3,49.7,32.5,31.7,29.1,28.9,24.6,23.8;C25H29O3N的MS计算值:m/e 391.2147,实测值:391.2153;C25H29O3N0.50H2O的分析计算值:C,74.97;H,7.55;N,3.50。
实测值:C,75.20;H,7.45;N,3.49。实施例3882,5-二氢-9-甲基羧酸酯-10-甲氧基-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z406(M+H)+,1H NMR(125MHz,DMSO)δ7.92(d,J=8.1Hz,1H),6.48(d,J=8.3Hz,1H),6.75(d,J=8.2Hz,1H),6.65(d,J=8.2Hz,1H),6.33(br s,1H),5.90-5.75(m,2H),5.46(br s,1H),5.04(dd,J=10.5,1.0Hz,1H),4.98(dd,J=15.4,1.0Hz,1H),3.82(s,3H),3.67(s,3H),2.54-2.42(m,1H),2.38-2.27(m,1H),2.18(s,3H),1.19(s,3H),1.16(s,3H);13C NMR(300MHz,DMSO)δ166.1,156.5,154.6,146.3,133.9,133.5,131.9,129.0,127.2,126.2,119.1,118.1,117.4,116.2,114.5,114.0,113.0,74.0,60.7,51.8,49.8,36.8,29.4,29.0,23.8;C25H27NO4的HRMS(FAB)m/z计算值:405.1940(M)+。实测值:405.1939。实施例3892,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-丙二烯基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.67(s,1H),7.93(d,J=9Hz,1H),6.57(dd,J=10,9Hz,2H),6.48(d,J=9Hz,1H),6.15-6.12(m,2H),5.41(s,1H),5.31(q,J=12Hz,1H),4.72-4.69(m,1H),4.59-4.49(m,1H),3.58(s,3H),2.14(s,3H),1.23(s,3H),1.10(s,3H);C23H23O3N的MS计算值:m/e361.1678,实测值:361.1671;C23H23O3N·0.5H2O的分析计算值:C,74.58;H,6.53;N,3.78;
实测值:C,74.98;H,6.56;N,3.83。实施例390(-)(5S,3’S)2,5-二氢-10-甲氧基-2,2,4-三甲基-5-(环戊烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.05(d,J=9Hz,1H),7.09(t,J=8Hz,1H),6.72(d,J=8Hz,1H),6.66(d,J=9Hz,1H),6.58(d,J=8Hz,1H),6.19(s,1H),5.77(dd,J=6,3Hz,1H),5.50(d,J=10Hz,1H),5.43(s,1H),5.19(dd,J=6,2Hz,1H),3.87(s,3H),2.90(m,1H),2.43-2.15(m,2H),2.09(s,3H),1.97-1.70(m,2H),1.31(s,3H),1.09(s,3H);13C NMR(75MHz,DMSO-d6)δ156.2,151.4,145.2,133.7,132.5,131.6,130.0,128.1,127.2,127.1,117.0,116.4,113.4,113.1,110.0,105.3,75.9,55.6,49.5,48.6,31.6,29.7,27.3,27.2,24.2;(DCI/NH3)m/z374(M+H)+,C25H27NO2的MS(FAB HRMS)计算值:m/e373.2042,实测值:373.2047。实施例391(-)(5S,3’S)2,5-二氢-10-甲氧基-2,2,4-三甲基-5-(环己烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.03(d,J=9Hz,1H),7.07(t,J=8Hz,1H),6.68(d,J=8Hz,1H),6.63(d,J=9Hz,1H),6.57(d,J=8Hz,1H),6.15(s,1H),5.62(m,1H),5.54(m,1H),5.46(s,1H),5.09(m,1H),3.85(s,3H),2.29(m,1H),2.10(s,3H),1.95-1.80(m,2H),1.72-1.50(m,2H),1.38-1.10(m,2H),1.28(s,3H),1.05(s,3H);13C NMR(75MHz,DMSO-d6)δ156.2,151.0,145.0,133.7,130.4,129.1,128.1,127.1,126.1,117.9,116.5,113.5,113.1,110.1,105.4,75.3,55.6,49.5,36.8,29.7,27.3,25.5,24.6,24.3,20.0;MS(DCI/NH3)m/z 388(M+H)+,C26H29NO2的MS(FAB HRMS)计算值:m/e 387.2198实测值:387.2204。[a]23 D=-138°(c0.114,CHCl3)。实施例392(-)(5S,3’R)2,5-二氢-10-甲氧基-2,2,4-三甲基-5-(环己烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.05(d,J=9Hz,1H),7.06(t,J=8Hz,1H),6.67(d,J=8Hz,1H),6.64(d,J=9Hz,1H),6.59(d,J=8Hz,1H),6.19(s,1H),5.82(m,1H),5.72(m,1H),5.41(s,1H),5.40(d,J=10Hz,1H),3.87(s,3H),2.29(m,1H),2.13(s,3H),1.95-1.80(m,2H),1.72-1.50(m,2H),1.38-1.10(m,2H),1.30(s,3H),1.02(s,3H);13C NMR(75MHz,DMSO-d6)δ156.3,151.4,145.0,133.8,130.0,128.3,127.9,127.5,127.1,126.9,118.5,116.4,113.4,113.0,110.2,105.3,76.1,55.6,49.4,37.1,29.6,26.8,24.7,23.6,21.2;MS(DCI/NH3)m/z 388(M+H)+;C26H29NO2的MS(FABHRMS)计算值:m/e 387.2198,实测值:387.2206。[α]23 D=-147°(c 0.080,CHCl3)。实施例393(-)(5S,3’R)2,5-二氢-10-甲氧基-2,2,4-三甲基-5-(环戊烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.07(d,J=9Hz,1H),7.08(t,J=8Hz,1H),6.70(d,J=8Hz,1H),6.66(d,J=9Hz,1H),6.61(d,J=8Hz,1H),6.22(s,1H),5.82-5.70(m,2H),5.48(d,J=13Hz,1H),5.41(d,J=10Hz,1H),3.88(s,3H),2.92(m,1H),2.30(m,1H),2.20(m,1H),2.15(s,3H),1.50-1.40(m,2H),1.33(s,3H),1.05(s,3H);13C NMR(75MHz,DMSO-d6)δ156.3,151.8,145.1,133.8,132.0,131.8,130.8,127.9,127.0,117.7,117.0,116.5,113.4,113.3,112.9,109.9,105.2,105.0,76.3,49.3,48.4,32.4,31.6,26.7,24.6,23.9,23.6;MS(DCI/NH3)m/z 374(M+H)+,C25H27NO2的MS(FABHRMS)计算值:m/e 373.2042,实测值:373.2049。实施例3942,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3(Z)-戊烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.71(s,1H),7.92(d,J=8Hz,1H),6.62(d,J=9Hz,1H),6.60(d,J=9Hz,1H),6.47(d,J=9Hz,1H),6.18(br s,1H),5.63(dd,J=4,9Hz,1H),5.43(br s,1H),5.36(m,2H),3.64(s,3H),2.44-2.33(m,1H),2.33-2.19(m,1H),2.15(s,3H),1.70(m,2H),1.16(s,6H),0.75(t,J=8Hz,3H);MS(DCI/NH3)(M+H)+392。实施例3952,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-乙酰氧基苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z 458(M+H)+;1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.92(d,1H),7.27(t,1H),7.12(d,1H),6.94(dd,1H),6.82(s,1H),6.72(d,1H),6.67(s,1H),6.44(d,1H),6.27(d,1H),6.20(s,1H),5.29(s,1H),2.55(s,2H),2.18(s,2H),1.81(s,2H),1.25(s,2H),1.12(s,2H)。实施例39610-二氟甲氧基-5-[[3-(甲硫基)甲氧基]苯基]-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)496(M+H)+;1H NMR(200MHz,DMSO-d6)δ7.80(d,J=8.5Hz,1H),7.21(t,JH-F=56Hz,1H),7.20-7.12(m,2H),6.99(t,1H),6.82-6.68(m,7H),6.29(d,J=1.1Hz,1H),5.40(s,1H),5.14(s,2H),2.08(s,2H),1.85(s,2H),1.22(s,2H),1.16(s,2H);C28H27NO2F2S的HRMS计算值为495.1680。实测值:495.1682。实施例3972,5-二氢-7-溴代-9-羟基-10-氯代-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z448(M+H)+;1H NMR(300MHz,DMSO)δ10.03(s,1H),7.90(d,J=8.5Hz,1H),7.00(app s,2H),6.63(d,J=8.4Hz,1H),6.43(br s,1H),5.92-5.77(m,2H),5.47(br s,1H),5.11-4.97(m,1H),2.44-2.26(m,2H),2.19(s,3H),1.22(s,3H),1.18(s,3H);13C NMR(125 MHz,DMSO-d6)δ156.7,150.2,148.6,144.0,139.1,136.3,135.5,130.8,129.2,124.4,117.6,115.9,115.2,114.0,111.6,75.9,51.6,48.3,35.5,29.8,27.9,24.0;C22H21 77BrClNO2的HRMS(FAB)m/z计算值:445.0444(M)+,实测值:445.0436。C22H21 79BrClNO2的HRMS(FAB)m/z计算值:447.0424(M)+,实测值:447.0413。C22H21BrClNO2的分析计算值:C,59.15;H,4.74;N,3.14。
实测值:C,59.31;H,4.85;N,3.22。实施例3982,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-羟苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z416(M+H)+;1H NMR(400MHz,DMSO-d6)9.22(s,1H),8.56(s,1H),7.92(d,1H),6.98(t,1H),6.71(d,1H),6.64(d,1H),6.58(m,2H),6.54(dd,1H),6.44(d,1H),6.22(d,1H),6.22(s,1H),5.27(s,1H),2.56(s,2H),1.82(s,2H),1.24(s,2H),1.12(s,2H)。实施例3992,5-二氢-9-甲硫基甲氧基-10-甲氧基-2,2,4-三甲基-5-(3-(甲硫基)甲氧基苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z526(M+H)+;1H NMR(400MHz,DMSO-d6)7.94(d,1H),7.14(t,1H),6.82-6.70(m,6H),6.50(d,1H),6.24(s,1H),5.29(s,1H),5.16(s,2H),5.14(s,2H),2.61(s,2H),2.14(s,2H),2.08(s,2H),1.82(s,2H),1.24(s,2H),1.16(s,2H)。实施例4002,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-(甲硫基甲氧基)苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z 476(M+H)+;1H NMR(400MHz,DMSO-d6)8.58(s,1H),7.92(d,1H),7.12(t,1H),6.82-6.6.71(m,4H),6.62(s,1H),6.42(d,1H),6.26(d,1H),6.25(s,1H),5.28(s,1H),5.12(s,2H),2.55(s,2H),2.07(s,2H),1.84(s,2H),1.22(s,2H),1.15(s,2H)。实施例4019-羟基-10-氯代-5-(苯基亚甲基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉1H NMRδ9.48(s,1H),7.98(m,1H),7.42(m,1H),7.22(m,5H),7.00(m,1H),6.71(m,1H),6.52(m,1H),6.42(m,1H),5.47(m,0.5H),5.12(m,0.5H),1.96(s,2H),1.02(s,2H),0.85(s,2H);质谱(DCI)m/z:416(M+1);C26H22ClNO2的计算值:415.1229。实测值:415.1229。实施例4022,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-([2-N,N-二甲基氨基甲酰基氧基]苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)504(M+NH4)+,487(M+H)+;1H NMR(400MHz,DMSO-d6)8.59(s,1H),7.92(d,1H),7.22(t,1H),7.09(d,1H),6.91(dd,1H),6.81(t,1H),6.72(d,1H),6.66(d,1H),6.44(d,1H),6.24(d,1H),6.27(s,1H),5.28(s,1H),2.55(s,2H),2.94(S,2H),2.82(s,2H),1.81(s,1H),1.24(s,2H),1.12(s,2H)。实施例4032,5-二氢-9-N,N-二甲基氨基甲酰基氧基-10-甲氧基-2,2,4-三甲基-5-([2-N,N-二甲基氨基甲酰基氧基]苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)575(M+NH4)+;1H NMR(400MHz,DMSO-d6)7.90(d,1H),7.25(t,1H),7.11(d,1H),6.95(dd,1H),6.85(s,1H),6.79(s,1H),6.75(d,1H),6.71(d,1H),6.52(d,1H),6.49(s,1H),5.41(s,1H),2.52(s,2H),2.02(s,2H),2.94(s,2H),2.89(s,2H),2.85(s,2H),1.84(s,2H),1.25(s,2H),1.15(s,2H)。实施例4042,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-乙基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ9.59(s,1H),7.91(d,J=8Hz,1H),6.75(s,2H),6.62(d,J=8Hz,1H),6.29(d,J=2Hz,1H),5.46(m,2H),2.14(s,3H),1.57(m,2H),1.19(s,3H),1.15(s,3H),0.89(t,J=7Hz,3H);C21H22NO2Cl的高分辨MS(APCI)m/e计算值:355.1339,实测值:355.1353。实施例4052,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-异丙基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ9.57(s,1H),8.02(d,J=8Hz,1H),6.76(s,2H),6.65(d,J=9Hz,1H),6.45(s,1H),5.45(s,1H),5.32(d,J=9Hz,1H),2.17(s,3H),1.70(m,1H),1.30(s,3H),1.02(s,3H),0.92(d,J=6Hz,3H),0.67(d,J=6Hz,3H);C22H24NO2Cl的HRMS(APCI)m/e计算值:369.1496,实测值:369.1492。实施例4069-羟基-10-甲氧基-5-(苯基亚甲基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)412(M+H)+;1H NMR(200MHz,DMSO-d6)δ8.92(s,1H),8.12(d,J=8.8Hz,1H),7.62(d,J=8.8Hz,2H),7.22-7.15(m,2H),6.77(d,1H),6.69(d,1H),6.66(d,1H),6.52(s,1H),5.46(s,1H),5.29(s,1H),2.65(s,2H),1.90(s,2H),1.20(s,6H);C27H25NO2的HRMS计算值411.1824。实测值:411.1821。实施例4072,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-丁基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ9.55(br s,1H),7.91(d,J=9Hz,1H),6.74(s,2H),6.61(d,J=8Hz,1H),6.26(d,J=1Hz,1H),5.56(dd,J=11,2Hz,1H),5.45(br s,1H),2.15(m,3H),1.64(m,1H),1.46(m,1H),1.31(m,4H),1.19(s,3H),1.15(s,3H),0.78(t,J=7Hz,3H);MS(DCI/NH3)m/e(M+H)+384。实施例4082,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(1-噻唑-2-基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.72(s,1H),8.02(d,J=8Hz,1H),6.88(s,1H),6.70(d,J=8Hz,1H),6.68(d,J=8Hz,1H),6.61(d,J=9Hz,1H),6.54(s,1H),6.20(s,1H),5.49(s,1H),3.72(s,3H),2.57(s,3H),2.30(s,3H),1.33(s,3H),1.14(s,3H);13C NMR(75MHz,DMSO-d6)δ182.9,182.5,181.3,179.8,169.8,167.9,165.5,163.8,154.6,154.4,153.6,151.7,151.3,150.0,127.0,96.8,87.2,67.6,65.7,60.3;MS(DCI/NH3)(M+H)+322。实施例4092,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-(2-甲基丙基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ9.59(br s,1H),7.91(d,J=9Hz,1H),6.75(d,J=8Hz,1H),6.73(d,J=8Hz,1H),6.62(d,J=8Hz,1H),6.28(d,J=2Hz,1H),5.70(dd,J=12,2Hz,1H),5.45(br s,1H),2.17(s,3H),1.68(m,2H),1.23(m,2H),1.19(s,3H),1.15(s,3H),0.98(d,J=6Hz,3H),0.75(d,J=7Hz,3H);MS(DCI/NH3)m/e(M+H)+384。实施例4102,5-二氢-9-羟基甲基-10-氯代-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z381(M)+;1H NMR(500MHz,DMSO)δ7.91(d,J=8.4Hz,1H),7.30(d,J=8.5Hz,1H),6.90(d,J=8.4Hz,1H),6.64(d,J=8.5Hz,1H),6.32(br s,1H),5.90-5.73(m,2H),5.47(br s,1H),5.28(t,J=5.1Hz,1H),5.04(dd,J=10.2,1.1Hz,1H),4.97(dd,J=10.2,1.1Hz,1H),4.64-4.50(m,2H),2.46-2.25(m,2H),2.17(br s,3H),1.21(s,3H),1.16(s,3H);C23H24ClNO2的HRMS(FAB)m/z计算值:381.1496(M)+。实测值:381.1495。实施例4112,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-丙基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ9.55(s,1H),7.90(d,J=9Hz,1H),6.74(s,2H),6.60(d,J=9Hz,1H),6.26(s,1H),5.59(d,J=9Hz,1H),5.45(s,1H),2.15(s,3H),1.65(m,1H),1.38(m,3H),1.19(s,3H),1.15(s,3H),0.82(t,J=7Hz,3H);13C NMR(75MHz,DMSO-d6)δ148.6,146.1,143.6,134.8,133.4,127.4,127.0,123.9,116.2,115.9,115.9,115.2,113.9,112.5,73.9,49.8,33.4,29.4,28.8,23.8,18.7,13.4;C22H24NO2Cl的高分辨MS(APCI)m/e计算值:369.1496,实测值369.1504。实施例4129-羟基-10-甲氧基-5-([3-氟代苯基]亚甲基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉1H NMR(200MHz,DMSO-d6)δ9.04(s,1H),8.22(d,1H),7.62-7.27(m,2H),7.10-7.02(m,1H),6.86(d,1H),6.78(d,1H),6.72(d,1H),6.70(s,1H),5.56(s,1H),5.46(s,1H),2.72(s,2H),1.96(s,2H),1.27(s,2H)。MS(DCI/NH3)m/z420(M+H)+;C27H24NO2F·0.25H2O的分析计算值:C,75.51;H,5.62;N,2.26。
实测值:C,74.84;H,6.17;N,2.91。实施例4139-羟基-10-氯代-5-([2-吡啶基]亚甲基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z417(M+H)+;1H NMR(200MHz,DMSO)δ9.79(br s,1H),8.51(ddd,J=5.9,1.6,1.0Hz,1H),8.42(d,J=8.6Hz,1H),8.24(dt,J=7.8,1.0Hz,1H),7.52(td,J=7.8,1.7Hz,1H),7.22(ddd,J=7.7,5.8,1.2Hz,1H),7.00(d,J=8.5Hz,1H),6.88(d,J=8.6Hz,1H),6.81(d,J=8.5Hz,1H),6.62(br s,1H),5.71(s,1H),5.51(br s,1H),2.00(br s,2H),1.28(br s,6H);13C NMR(125MHz,DMSO-d6)δ152.5,149.7,146.4,145.7,126.5,126.1,122.7,128.7,128.2,122.0,122.4,121.5,118.2,117.7,117.6,116.5,115.5,114.8,114.4,114.1,112.9,49.5,29.7,28.1,21.2;C25H21ClN2O2的HRMS(FAB)m/z计算值:416.1291(M)+。实测值:416.1288。实施例414rel-(5S)-9-羟基-5-[(3S)-(1-羟甲基)环己烯-3-基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(200MHz,DMSO-d6)δ8.49(s,1H),7.99(d,J=8.5Hz,1H),6.64(d,J=8.5Hz,1H),6.58(d,J=8.5Hz,1H),6.47(d,J=8.5Hz,1H),6.21(br s,1H),5.99(br s,1H),5.40(br s,1H),5.26-5.21(m,1H),4.81-4.72(m,2H),4.02-4.02(m,1H),2.61-2.58(m,1H),2.52(s,2H),2.00-2.95(m,1H),2.21(s,2H),1.61-1.40(m,4H),1.22(s,2H),1.28-1.24(m,2H),1.04(s,2H);C27H21NO4的分析计算值:C,74.80;H,7.21;N,2.22。
实测值:C,74.77;H,7.15;N,2.12。实施例415rel-(5S)-9-羟基-5-[(3S)-(1-甲氧基羰基)环己烯-3-基]-10-甲氧基-2,2,4-三甲基-2,5-二氢-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)462(M+H)+;1H NMR(200MHz,DMSO-d6)δ8.72(s,1H),8.04(d,J=8.5Hz,1H),6.90-6.87(m,1H),6.67(d,J=8.5Hz,1H),6.64(d,J=8.5Hz,1H),6.52(d,J=8.5Hz,1H),6.25-6.29(m,1H),5.50-5.44(m,2H),4.06-4.00(m,1H),2.66(s,2H),2.62(s,2H),2.20-2.27(m,1H),2.18-2.05(m,1H),2.12(s,2H),1.72-1.60(m,2H),1.25-1.24(m,2H),1.20(s,2H),1.04(s,2H);C28H21NO5的HRMS计算值461.2202。实测值:461.2196。C28H21NO5·0.25H2O的分析计算值:C,72.15;H,6.81;N,2.00。
实测值:C,72.06;H,7.06;N,2.82。实施例4162,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3,5-二氯苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS DCI m/z468(M+H)+;1H NMR(200MHz,DMSO)δ8.69(s,1H),7.96(d,J=8.8Hz,1H),7.44(t,J=1.8Hz,1H),7.17(d,J=1.8Hz,2H),6.76(d,J=8.4Hz,1H),6.70(s,1H),6.48(d,J=8.8Hz,1H),6.28(d,J=8.8Hz,1H),6.25(d,J=1.5Hz,1H),5.41(s,1H),2.57(s,2H),1.82(s,2H),1.25(s,2H),1.14(s,2H);13C NMR(200MHz,DMSO),δ145.9,145.2,142.6,142.1,122.7,122.0,128.8,127.6,127.2,127.1,126.6,118.2,117.9,117.2,114.5,112.2,72.7,59.0,49.8,29.6,28.2,22.2。C26H23ClFO3的HRMS计算值467.1066。实测值:467.1064。实施例417(-)(5S,3’S)2,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-(1-甲基环己烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z 422(M+H)+;1H NMR(300MHz,DMSO)δ9.55(s,1H),8.02(d,J=8.4Hz,1H),6.77(app s,2H),6.68(d,J=8.4Hz,1H),6.41(br s,1H),5.50-5.42(m,2H),4.88(br s,1H),2.23-2.15(m,1H),2.07(br s,3H),1.91-1.80(m,2H),1.76-1.63(m,2H),1.60-1.46(m,1H),1.50(br s,3H),1.38-1.28(m,1H),1.30(s,3H),1.09(s,3H);13C NMR(125MHz,DMSO)δ148.6,145.7,143.7,135.8,133.7,132.6,128.2,126.8,123.7,120.2,117.7,115.9(2),115.3,114.1,112.4,75.6,49.5,36.3,29.6,29.3,27.5,25.1,24.2,23.7,20.2;C26H28ClNO2的HRMS(FAB)m/z计算值:421.1809(M)+。实测值:421.1810。实施例418(-)(5S,3’R)2,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-(1-甲基环己烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z422(M+H)+;1H NMR(300MHz,DMSO)δ9.58(s,1H),8.05(d,J=8.4Hz,1H),6.79(ABq,J=8.0Hz,ΔnAB=14.4Hz,2H),6.67(d,J=8.3Hz,1H),6.47(br s,1H),5.49-5.46(m,2H),5.35(d,J=8.9Hz,1H),2.28-2.15(m,1H),2.12(br s,3H),1.93-1.80(m,1H),1.78-1.63(m,2H),1.64-1.51(m,1H),1.62(br s,3H),1.31(s,3H),1.25-1.13(m,2H),1.04(s,3H);13C NMR(125MHz,DMSO)δ148.7,145.8,144.2,135.1,134.0,132.1,127.9,126.7,123.7,121.4,118.0,116.0(2),115.4,114.2,112.4,103.4,76.4,49.5,37.1,29.5,27.2,24.5,23.8(2),21.6;C26H28ClNO2的HRMS(FAB)m/z计算值:421.1809(M)+。实测值:421.1816。实施例419(+)(5R,3’S)2,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-(1-甲基环己烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉[α]D 25+237.8°(c=0.5,CHCl3);MS(DCI/NH3)m/z422(M+H)+;1H NMR(300MHz,DMSO)δ9.58(s,1H),8.05(d,J=8.4Hz,1H),6.79(ABq,J=8.0Hz,ΔnAB=14.4Hz,2H),6.67(d,J=8.3Hz,1H),6.47(br s,1H),5.49-5.46(m,2H),5.35(d,J=8.9Hz,1H),2.28-2.15(m,1H),2.12(br s,3H),1.93-1.80(m,1H),1.78-1.63(m,2H),1.64-1.51(m,1H),1.62(br s,3H),1.31(s,3H),1.25-1.13(m,2H),1.04(s,3H);13C NMR(125MHz,DMSO)δ148.7,145.8,144.2,135.1,134.0,132.1,127.9,126.7,123.7,121.4,118.0,116.0(2),115.4,114.2,112.4,103.4,76.4,49.5,37.1,29.5,27.2,24.5,23.8(2),21.6;C26H28ClNO2的HRMS(FAB)m/z计算值:421.1809(M)+。实测值:421.1806。实施例420(+)(5R,3’R)2,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-(1-甲基环己烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉[α]D 25+147.5°(c=0.2,CHCl3);MS(DCI/NH3)m/z422(M+H)+;1H NMR(300MHz,DMSO)δ9.55(s,1H),8.02(d,J=8.4Hz,1H),6.77(app s,2H),6.68(d,J=8.4Hz,1H),6.41(br s,1H),5.50-5.42(m,2H),4.88(br s,1H),2.23-2.15(m,1H),2.07(br s,3H),1.91-1.80(m,2H),1.76-1.63(m,2H),1.60-1.46(m,1H),1.50(br s,3H),1.38-1.28(m,1H),1.30(s,3H),1.09(s,3H);13C NMR(125MHz,DMSO)δ148.6,145.7,143.7,135.8,133.7,132.6,128.2,126.8,123.7,120.2,117.7,115.9(2),115.3,114.1,112.4,75.6,49.5,36.3,29.6,29.3,27.5,25.1,24.2,23.7,20.2;C26H28ClNO2的HRMS(FAB)m/z计算值:421.1809(M)+。实测值:421.1794。实施例421(+/-)2,5-二氢-9-(4-N,N-二甲基氨基-4-氧代-丁酰氧基)-10-氯代-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(ESI)m/z495(M+H)+;1H NMR(200MHz,DMSO-d6)δ7.90(d,1H),6.99(d,1H),6.92(d,1H),6.64(d,1H),6.42(s,1H),5.81-5.76(m,2H),5.48(s,1H),5.07-4.94(m,2H),2.99(s,2H),2.84(s,2H),2.82-2.68(m,4H),2.41-2.27(m,2H),2.18(s,2H),1.20(s,2H),1.17(s,2H)。实施例422(-)2,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-环戊基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z296(M+H)+;1H NMR(400MHz,DMSO-d6)1H NMR(200MHz,DMSO-d6)δ9.50(bs,1H),8.04(s,1H),6.77(d,1H),6.72(d,1H),6.65(d,1H),6.42(d,1H),5.50(s,1H),5.42(d,1H),2.18-1.08(m,18H)。实施例4232,5-二氢-9-(4-N,N-二甲基氨基-4-氧代-丁酰氧基)-10-甲氧基-2,2,4-三甲基-5-(1-甲基乙基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(400MHz,DMSO-d6)δ7.92(d,J=8.5,1H),6.83(d,J=8.5,1H),6.71-6.65(m,2H),6.31(d,J=1.7,1H),5.46(br m,1H),5.37(d,J=9.7,1H),3.61(s,3H),3.00(s,3H),2.84(s,3H),2.80(m,2H),2.70(m,2H),2.17(s,3H),1.80(m,1H),1.31(s,3H),1.03(s,3H),0.95(d,J=6.4,3H),0.65(d,J=6.8,3H);13C NMR(125MHz,DMSO-d6)δ171.5,170.4,149.0,148.0,145.6,138.3,133.6,131.0,127.9,125.8,120.7,118.2,118.2,115.4,113.4,112.1,78.0,60.0,49.4,36.4,34.9,30.9,29.6,28.9,27.6,27.3,23.8,19.4,17.8;MS(ESI/NH3)m/e 493(M+H)+,515(M+Na)+;C29H26N2O5的HRMS m/z计算值:492.2624。实测值:492.2613。实施例4242,5-二氢-9-(4-N,N-二甲基氨基-4-氧代-丁酰氧基)-10-甲氧基-5-(苯基甲基)-2,2,4-三甲基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(500MHz,DMSO-d6)δ7.90(d,J=8.8,1H),7.29-7.26(m,2H),7.21(m,1H),7.09(d,J=7.0,2H),6.89(d,J=8.8,1H),6.66(d,J=8.8,1H),6.60(d,J=8.8,1H),6.25(d,J=1.8,1H),5.98(dd,J=10.1,2.5,1H),5.42(s,1H),2.67(s,2H),2.01(s,2H),2.97(m,1H),2.85(s,2H),2.84-2.81(m,2H),2.72-2.69(m,2H),2.22(s,2H),1.17(s,2H),1.14(s,2H);13C NMR(125MHz,DMSO-d6)δ171.5,170.4,148.2,148.1,146.2,128.4,127.6,122.4,121.9,128.9,128.2,127.2,126.2,126.2,120.8,118.2,116.2,115.2,112.9,112.6,74.8,60.1,49.7,28.2,24.9,29.2,29.1,28.9,27.6,24.2;MS(ESI/NH3)m/e541(M+H)+,562(M+Na)+;C33H36N2O5的分析计算值:C 72.21,H 6.71,N 5.18。
实测值:C 72.87,H 6.97,N 4.90。实施例4252,5-二氢-9-(4-N,N-二甲基氨基-4-氧代-丁酰氧基)-10-甲氧基-2,2,4-三甲基-5-(2-噻吩基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(500MHz,DMSO-d6)δ7.90(d,J=8.4,1H),7.40(dd,J=5.0,1.3,1H),6.96(s,1H),6.86(m,1H),6.80(m,1H),6.74-6.71(m,2H),6.57(d,J=8.4,1H),6.32(d,J=1.8,1H),5.41(s,1H),3.58(s,3H),2.98(s,3H),2.83(s,3H),2.77-2.74(m,2H),2.68-2.65(m,2H),1.95(d,J=1.1,3H),1.23(s,3H),1.15(s,3H);13C NMR(125MHz,DMSO-d6)δ171.1,170.2,148.6,147.5,146.0,142.8,138.4,132.8,130.1,128.0,127.2,126.3,126.1,125.9,125.8,120.4,118.4,116.8,115.8,114.3,112.3,70.9,59.5,49.7,36.2,34.7,29.5,28.7,28.5,27.4,22.8;MS(ESI/NH3)m/e 533(M+H)+,555(M+Na)+;C20H22N2O5S的分析计算值:C 67.65,H 6.06,N 5.26。
实测值:C 67.48,H 6.16,N 5.07。实施例4262,5-二氢-9-(4-N,N-二甲基氨基丁酰氧基)-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(500MHz,DMSO-d6)δ7.85(d,J=8.4,1H),6.86(d,J=8.4,1H),6.68-6.61(m,2H),6.25(d,J=1.5,1H),5.86-5.78(m,2H),5.46(s,1H),5.06-4.98(m,2H),2.61(s,2H),2.62(t,J=7.1,2H),2.47(m,1H),2.22(t,J=7.0,2H),2.25(m,1H),2.18(s,2H),2.16(s,6H),1.80(m,2H),1.18(s,2H),1.17(s,2H);13C NMR(125MHz,DMSO-d6)δ171.8,148.4,147.9,146.2,128.5,124.0,122.5,122.1,127.2,126.2,120.7,118.2,117.2,116.2,115.0,112.8,112.6,72.6,59.9,58.0,45.1,26.6,21.1,29.2,29.0,22.8,22.5;MS(ESI/NH3)m/e 477(M+H)+;C29H36N2O4的分析计算值:C 72.08,H 7.61,N 5.88。
实测值:C 72.77,H 7.74,N 5.64。实施例4279-(2-乙氧基-2-氧代-乙基氨基羰基)-氧基-10-甲氧基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)510(M+NH4)+,492(M+H)+,264;1H NMR(200MHz,DMSO-d6)δ8.21(t,J=6.0Hz,1H),7.86(d,J=8.5Hz,1H),6.86(d,J=8.5Hz,1H),6.64(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,1H),6.29(d,J=1.1Hz,1H),5.90-5.76(m,2H),5.45(br s,1H),5.04(dd,J=10.2,1.8Hz,1H),4.99(dd,J=17.2,1.8Hz,1H),4.12(q,J=7.0Hz,2H),2.85(d,J=6.0Hz,2Hz),2.65(s,2H),2.20-2.22(m,2H),2.17(d,J=1.1Hz,2H),1.21(t,J=7.0Hz,2H),1.18(s,2H),1.17(s,2H);C28H22N2O6的分析计算值:C,68.28;H,6.55;N,5.69。
实测值:C,67.97;H,6.59;N,5.62。实施例428(+/-)2,5-二氢-9-(3-乙酰胺基-丙酰氧基)-10-甲氧基-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(APCI)m/z477(M+H)+;1H NMR(200MHz,DMSO-d6)δ8.04(t,1H),7.85(d,1H),6.90(d,1H),6.68(d,1H),6.64(d,1H),6.26(s,1H),5.87-5.77(m,2H),5.46(s,1H),5.04(dd,1H),4.98(dd,1H),2.61(s,2H),2.40(q,2H),2.76(t,2H),2.52-2.44(m,1H),2.20-2.24(m,1H),2.18(s,2H),1.84(s,2H),1.18(s,2H),1.17(s,2H)。实施例429(+/-)2,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-苄基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z418(M+H)+;1H NMR(400MHz,DMSO-d6)1H NMR(200MHz,DMSO-d6)δ9.70(bs,1H),7.99(s,1H),7.20-7.08(m,5H),6.79(d,1H),6.67(d,1H),6.62(d,1H),6.19(d,1H),5.86(dd,1H),5.44(s,1H),2.98-2.84(m,2H),2.22(s,2H),1.19(s,2H),1.17(s,2H)。实施例4309-羟基-10-甲氧基-5-(苯基亚甲基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉(DCI/NH3)412(M+H)+;1H NMR(300MHz,DMSO-d6)δ8.93(s,1H),8.13(d,J=8.8Hz,1H),7.63(d,J=8.8Hz,2H),7.32-7.15(m,3H),6.77(d,1H),6.69(d,1H),6.66(d,1H),6.52(s,1H),5.46(s,1H),5.39(s,1H),3.65(s,3H),1.90(s,3H),1.20(s,6H);C27H25NO3的HRMS计算值411.1834,实测值:411.1821。实施例4319-(二甲基氨基硫代羰基)-氧基-10-甲氧基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)451(M+H)+;1H NMR(200MHz,DMSO-d6)δ7.84(d,J=8.8Hz,1H),6.80(d,J=8.8Hz,1H),6.65(d,J=8.8Hz,1H),6.62(d,J=8.8Hz,1H),6.26(d,J=1.7Hz,1H),5.90-5.76(m,2H),5.46(br s,1H),5.04(dd,J=10.2,1.8Hz,1H),4.98(dd,J=17.2,1.8Hz,1H),2.64(s,2H),2.29(s,2H),2.26(s,2H),2.22-2.22(m,2H),2.18(d,J=1.7Hz,2H),1.18(s,2H),1.16(s,2H);C26H20N2O2S.0.5H2O的分析计算值:C,67.94;H,6.79;N,6.09。
实测值:C,68.06;H,6.80;N,6.12。实施例432(+/-)2,5-二氢-9-(N-氨基甲酰基-2-氨基乙酰氧基)-10-甲氧基-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(APCI)m/z 464(M+H)+;1H NMR(200MHz,DMSO-d6)δ7.78(d,1H),6.79(d,1H),6.60(d,1H),6.57(d,1H),6.27(t,1H),6.18(bs,1H),5.80-5.70(m,2H),5.67(s,2H),5.28(s,1H),4.97(dd,1H),4.92(dd,1H),4.01(d,2H),2.55(s,2H),2.42-2.27(m,1H),2.22-2.16(m,1H),2.10(s,2H),1.11(s,2H),1.10(s,2H)。实施例433(+/-)2,5-二氢-9-(4-乙氧基-4-氧代-丁氧基)-10-甲氧基-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(200MHz,DMSO-d6)δ7.92(d,1H,J=8Hz),6.79(d,1H),6.62(d,1H,J=8Hz),6.58(d,1H,J=8Hz),6.18(d,1H,J=2Hz),5.82(m,1H),5.72(dd,1H,J=2Hz,J=9Hz),5.45(s,1H),5.05-4.97(m,2H),4.08(q,2H,J=5Hz),4.02-2.91(m,2H),2.70(s,2H),2.50(t,2H,J=5Hz),2.45(m,1H),2.21(m,1H),2.16(s,2H),2.00(五重峰,2H,J=5Hz),1.19(t,2H,J=5Hz),1.17(s,6H)。实施例434(+/-)2,5-二氢-9-(4-氧代-戊酰氧基)-10-甲氧基-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(APCI)m/z462(M+H)+;1H NMR(200MHz,DMSO-d6)δ7.78(d,1H),6.77(d,1H),6.59(d,1H),6.57(d,1H),6.18(s,1H),5.80-5.68(m,2H),5.28(s,1H),4.96(dd,1H),4.92(dd,1H),2.54(s,2H),2.79(dd,2H),2.70(dd,2H),2.41-2.16(m,2H),2.10(s,2H),2.09(s,2H),1.11(s,2H),1.10(s,2H)。实施例4352,5-二氢-9-羟基-10-氯代-2,2,4-三甲基-5-(3,4,5-三氟苯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMRδ9.20(s,1H),7.91(d,1H,J=8.5Hz),6.92(m,2H),6.88(m,2H),6.57(d,1H,J=8.5Hz),6.28(m,1H),5.45(m,1H),1.81(s,2H),1.29(s,2H),1.09(s,2H);质谱(DCI)m/z:458(M+1);C25H19ClF2NO2的计算值:457.1056。实测值:457.1054。实施例4362,5-二氢-9-甲硫基甲氧基-10-甲氧基-2,2,4-三甲基-5-烯丙基-1H-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)m/z424(M+H)+;1H NMR(400MHz,DMSO-d6)7.92(d,1H),6.88(d,1H),6.62(d,1H),6.60(d,1H),6.20(s,1H),5.81(m,1H),5.74(dd,1H),5.45(s,1H),5.24(s,1H),5.02(d,1H),4.99(d,1H),2.70(s,2H),2.45(m,2H),2.22(s,2H),2.18(s,2H),1.18(s,2H),1.17(s,2H)。实施例4372,5-二氢-9-(4-N,N-二乙基氨基-4-氧代-戊酰氧基)-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(400MHz,DMSO-d6)δ7.84(t,J=8.5Hz,1H),6.88(d,J=8.9,1H),6.68-6.62(m,2H),6.26(br s,1H),5.85-5.77(m,2H),5.45(br s,1H),5.05-4.97(m,2H),3.60(s,3H),3.34-3.21(m,4H),2.65(t,J=7.4,2H),2.45-2.41(m,3H),2.27(m,1H),2.17(s,3H),1.90(m,2H),1.18(s,3H),1.17(s,3H),1.12(t,J=7.0,3H),1.02(t,J=7.2,3H);13C NMR(100MHz,DMSO-d6)δ171.7,170.3,148.4,147.9,146.3,138.4,134.0,133.5,132.1,127.3,126.1,120.7,118.2,117.2,116.2,114.9,113.8,112.6,73.6,59.9,49.8,41.2,36.6,32.7,30.9,29.3,29.0,23.8,20.4,14.2,13.1;MS(ESI/NH2)m/e 533(M+H)+,555(M+Na)+;C22H40N2O5的分析计算值:C 72.15,H 7.57,N 5.26。
实测值:C 72.16,H 7.76,N 5.06。实施例4382,5-二氢-9-(4-N,N-二甲基氨基-4-氧代-戊酰氧基)-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(400MHz,DMSO-d6)δ7.77(d,J=8.5Hz,1H),6.81(d,J=8.9,1H),6.61-6.56(m,2H),6.19(d,J=1.7,1H),5.80-5.70(m,2H),5.28(s,1H),4.98-4.90(m,2H),2.71(s,2H),2.90(s,2H),2.76(s,2H),2.58(t,J=7.4,2H),2.28-2.25(m,2H),2.20(m,1H),2.10(s,2H),1.84(m,2H),1.11(s,2H),1.10(s,2H);13C NMR(100MHz,DMSO-d6)δ171.7,171.2,148.4,147.9,146.2,128.4,124.1,122.5,122.1,127.2,126.2,120.7,118.2,117.2,116.2,114.9,112.8,112.6,72.6,59.9,49.8,26.6,24.8,22.8,21.2,29.2,29.0,22.8,20.2;MS(ESI/NH3)m/e 505(M+H)+,527(M+Na)+;C30H36N2O5的分析计算值:C 71.40,H 7.19,N 5.55。
实测值:C 71.20,H 7.19,N 5.29。实施例4392,5-二氢-9-(4-N-哌啶子基-4-氧代-戊酰氧基)-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(400MHz,DMSO-d6)δ7.78(d,J=8.9Hz,1H),6.81(d,J=8.5,1H),6.61-6.55(m,2H),6.19(d,J=1.7,1H),5.80-5.70(m,2H),5.28(s,1H),4.98-4.90(m,2H),2.52(s,2H),2.25(m,4H),2.58(t,J=7.2,2H),2.29-2.25(m,2H),2.20(m,1H),2.10(s,2H),1.82(m,2H),1.51(m,2H),1.42(m,2H),1.26(m,2H),1.11(s,2H),1.10(s,2H);13C NMR(100MHz,DMSO-d6)δ171.7,169.6,148.4,147.9,146.2,128.4,124.0,122.5,122.1,127.2,126.1,120.7,118.2,117.2,116.2,114.9,112.8,112.6,72.6,59.9,49.8,45.8,41.9,26.6,22.8,21.2,29.2,29.0,26.0,25.2,24.0,22.8,20.4;MS(ESI/NH3)m/e 545(M+H)+,567(M+Na)+;C33H40N2O5的分析计算值:C 72.77,H 7.40,N 5.14。
实测值:C 72.50,H 7.42,N 4.99。实施例4402,5-二氢-9-(4-N-吗啉代-4-氧代-戊酰氧基)-10-甲氧基-2,2,4-三甲基-5-(2-丙烯基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(400MHz,DMSO-d6)δ7.77(d,J=8.5Hz,1H),6.81(d,J=8.5,1H),6.61-6.56(m,2H),6.19(s,1H),5.78-5.70(m,2H),5.28(s,1H),4.98-4.90(m,2H),2.52(s,2H),2.50(m,4H),2.29(t,J=4.7,4H),2.59(t,J=7.4,2H),2.41-2.27(m,2H),2.20(m,1H),2.10(s,2H),1.82(m,2H),1.11(s,2H),1.10(s,2H);13C NMR(100MHz,DMSO-d6)δ171.6,170.2,148.4,147.9,146.2,128.4,124.0,122.5,122.1,127.2,126.1,120.7,118.2,117.2,116.2,114.9,112.8,112.6,72.6,66.1,60.0,49.8,45.2,41.4,26.6,22.7,21.0,29.2,29.0,22.8,20.2;MS(ESI/NH3)m/e547(M+H)+,569(M+Na)+;C32H38N2O6的分析计算值:C 70.21,H 7.01,N 5.12。
实测值:C 69.99,H 7.06,N 4.91。实施例441(-)2,5-二氢-9-(4-N,N-二甲基氨基-4-氧代-戊酰氧基)-10-甲氧基-2,2,4-三甲基-5(S)-(3(S)-1-环戊烯-3-基)-1H-[1]苯并吡喃并[3,4-f]喹啉MS(APCI)m/z517(M+H)+;1H NMR(200MHz,DMSO-d6)δ7.94(d,1H),6.84(d,1H),6.69(d,1H),6.67(d,1H),6.22(s,1H),5.75(dd,1H),5.52(d,1H),5.42(s,1H),5.17(dd,1H),2.62(s,2H),2.99(s,2H),2.90-2.85(m,1H),2.84(s,2H),2.80(t,2H),2.68(t,2H),2.29-2.21(m,1H),2.25-2.12(m,1H),2.08(s,2H),1.92-1.74(m,2H),1.20(s,2H),1.08(s,2H)。实施例44210-甲氧基-9-(烯丙基氨基羰基)氧基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)464(M+NH4)+,447(M+H)+,264;1H NMR(200MHz,DMSO-d6)δ7.96(t,J=5.9Hz,1H),7.86(d,J=8.5Hz,1H),6.86(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,2H),6.28(d,J=1.5Hz,1H),5.90-5.76(m,2H),5.45(br s,1H),5.27-4.97(m,4H),2.71(m,1H),2.64(s,2H),2.41-2.22(m,2H),2.17(d,J=1.5Hz,2H),1.18(s,2H),1.17(s,2H);C27H20N2O4.0.25H2O的分析计算值:C,71.89;H,6.81;N,6.21。实测值:C,72.18;H,7.08;N,5.98。实施例44310-甲氧基-9-(环己基氨基羰基)-氧基-5-(3-丙烯基)-2,2,4-三甲基-1H-2,5-二氢-[1]苯并吡喃并[3,4-f]喹啉MS(DCI/NH3)506(M+NH4)+,489(M+H)+,264;1H NMR(200MHz,DMSO-d6)δ7.86(d,J=8.8Hz,1H),7.67(d,J=7.8Hz,1H),6.84(d,J=8.8Hz,1H),6.62(d,J=8.8Hz,1H),6.61(d,J=8.8Hz,1H),6.25(d,J=1.0Hz,1H),5.90-5.76(m,2H),5.45(br s,1H),5.04(dd,J=10.2,1.8Hz,1H),4.99(dd,J=17.2,1.8Hz,1H),4.02(br s,1H),2.62(s,2H),2.20-2.22(m,2H),2.17(d,J=1.0Hz,2H),1.86-1.52(m,5H),1.21-1.22(m,5H),1.18(s,2H),1.17(s,2H);C20H26N2O4的HRMS计算值488.2675。实测值:488.2670。实施例4442,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(3-噻吩基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.57(s,1H),7.91(d,J=9Hz,1H),7.35(dd,J=5,5Hz,1H),6.99(d,J=5Hz,1H),6.92(s,1H),6.68(d,J=9Hz,1H),6.64(s,1H),6.44(d,J=9Hz,1H),6.34(d,J=9Hz,1H),6.21(s,1H),5.38(s,1H),3.57(s,3H),1.87(s,3H),1.23(s,3H),1.13(s,3H);13C NMR(125 MHz,DMSO-d6)δ183.2,182.4,181.4,181.1,170.3,168.8,165.3,165.2,164.1,163.9,163.5,163.4,162.6,155.8,154.7,151.6,149.6,108.9,96.6,87.3,67.3,66.0,60.6;MS(DCI/NH3)(M+H)+406。实施例4452,5-二氢-9-羟基-10-甲氧基-2,2,4-三甲基-5-(4-(氟代苯基)甲基)-1H-[1]苯并吡喃并[3,4-f]喹啉1H NMR(300MHz,DMSO-d6)δ8.47(s,1H),7.94(d,J=8Hz,1H),7.33-7.31(m,1H),7.13-7.04(m,3H),6.62(dd,J=9,8Hz,2H),6.41(d,J=9Hz,1H),6.41(s,1H),5.82(dd,J=10,9Hz,1H),5.40(s,1H),3.69(s,3H),3.01-2.93(m,1H),2.81-2.76(m,1H),2.20(s,1H),1.15(s,3H),1.13(s,3H);13C NMR(75MHz,DMSO-d6)δ162.5,159.2,145.8,145.1,144.0,142.8,134.1,133.4,132.2,130.8,130.7,127.4,126.4,117.9,116.4,116.2,115.0,114.7,114.4,113.8,112.5,74.4,59.5,49.7,37.1,29.2,29.0,24.3;C27H26O3NF的MS计算值:m/e 431.1897,实测值431.1905;C27H26O3NF0.30H2O的分析计算值:C,74.23;H,6.14;N,3.21;
实测值:C,74.16;H,6.44;N,2.96。