CN114057755B - 一种基于环烯醚萜苷元的螺环吲哚酮类化合物的制备方法及用途 - Google Patents
一种基于环烯醚萜苷元的螺环吲哚酮类化合物的制备方法及用途 Download PDFInfo
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Abstract
本发明公开了一种基于天然环烯醚萜苷元的螺环吲哚酮类化合物的制备方法和用途,属于药物合成领域。本发明首次通过天然环烯醚萜苷元、氨基丙二酸二乙酯和亚苄基吲哚酮在BINOLs磷酸催化下合成螺环吲哚酮类化合物,其结构如式Ⅰ、式Ⅱ所示。本发明的制备方法具有简单易操作的特点,通过一步或几步有限的反应即可实现,不存在高温高压和强酸强碱的极端反应,反应原料简单易得,并对其进行了体外肿瘤活性测试及机制研究。本发明的化合物对肿瘤细胞具有较强的抑制作用,可作为抗肿瘤药物的先导化合物。
Description
技术领域
本发明涉及有机化学和药物化学领域,具体涉及一种基于环烯醚萜苷元的螺环吲哚酮类化合物的制备方法及用途。
背景技术
癌症是严重威胁人类生命的常见病和多发病,其死亡率仅次于心血管病而位居第二。由于人口增长和老龄化,2005年至2015年间癌症发病率增加了33%。根据国际癌症研究机构报道,2018年大约960万例癌症死亡,预计2025年将有大约2150万例新癌症病例。癌症正在成为人类的头号杀手,并成为全球最大的公共卫生问题之一。如今,中国癌症呈现年轻化、发病率和死亡率三线走高的趋势。因而研究与开发高效抗癌药物已成为急待解决的问题。
京尼平是京尼平苷的水解产物,京尼平苷主要存在于中国传统的药用植物栀子、杜仲等植物中,两者都具有多种药理活性,研究表明,京尼平苷的生物活性大多是通过其苷元京尼平来实现的,京尼平的体外抗肿瘤活性比京尼平苷更强,它对多种肿瘤细胞系都显示出细胞毒性作用,并可以通过多种机制对肿瘤细胞产生作用,但其抗肿瘤活性并不显著,且其在抗肿瘤方面衍生物的合成几乎没有报道。这限制了京尼平苷元在医药领域的应用。因此,如若对京尼平苷元进行合理化的结构修饰设计合成一些结构新颖且抗肿瘤活性更高的化学实体将对创新药物候选分子的发现具有重要的研究意义。
螺环吲哚酮类生物碱显示出不同程度的抗癌活性,其活性主要归因于氧化吲哚C3位置的螺环取代和氧化吲哚上的取代基。许多天然螺环吲哚酮类化合物,如SpirotryprostatinsA和B,也显示出良好的抗癌活性。更重要的是,一些以螺环吲哚酮为核心结构的化合物已经进入了临床前研究。
发明内容
为了解决现有技术不足的问题,本发明的目的在于提供一种基于环烯醚萜苷元的螺环吲哚酮类生物碱的制备方法及用途。该类化合物对肿瘤细胞具有较显著的抑制作用。
为实现上述目的,本发明采用的技术方案是:一种基于环烯醚萜苷元的螺环吲哚酮类化合物结构如式Ⅰ、式Ⅱ所示:
其中,R选自氢,卤素,三氟甲基中的一种;R1选自氢,卤素,三氟甲基,甲氧基,羧基,三氟甲氧基;R2选自甲基,吗啉环,四氢吡咯环;R3选自氢,乙酰基;X选自N或者CH。
其中,R选自卤素,甲氧基,三氟甲基,三氟甲氧基。
本发明所述式Ⅰ、式Ⅱ化合物选自如下化合物:
本发明式(Ⅰ)化合物的制备方法,式(Ⅲ-1)化合物与式(a)、式(b)化合物进行反应生成式(Ⅰ)化合物:
其中,R选自H、氯、三氟甲基;R1选自氢、卤素、三氟甲基、甲氧基、羧基、三氟甲氧基;R2选自甲基、吗啉环、四氢吡咯环;R3选自氢、乙酰基;X选自N或者CH。
本发明式(Ⅱ)化合物的制备方法,式(Ⅲ-2)化合物与式(c)、式(b)化合物进行反应生成式(Ⅱ)化合物:
其中,R选自卤素、甲氧基、三氟甲基、三氟甲氧基。
本发明的有益技术效果是:本发明首次以京尼平苷元为合成砌块,在BINOLs衍生的磷酸催化下通过1,3-偶极环加成反应,合成具有京尼平苷元的螺环吲哚酮类化合物。并在体外进行了对肿瘤细胞的抑制活性测试,体外测试结果显示该类化合物对人非小细胞肺癌HCC827、人高转移性肝癌细胞MHCC97H和人神经母细胞瘤SHSY-5Y具有较强的抑制活性。
具体实施方式
下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
本实施例所述(1R,4aS,7aS)-7-甲酰基-1-甲氧基-1,4a,5,7a-四氢环戊基[c]吡喃-4-羧酸甲酯的制备方法:
称取栀子苷元(Genipin)(1g,4.5mmol),装入25mL圆底烧瓶中,加入4mL甲醇,再加入一滴浓盐酸,在60℃下搅拌反应6h。向反应液加入1mol/L的氢氧化钠调节pH至7,减压浓缩,剩余物用乙酸乙酯萃取,萃取液用饱和食盐水洗涤,无水硫酸钠干燥,减压蒸干溶剂。加入20mL干燥的二氯甲烷溶解,加入活性二氧化锰3g(34mmol),室温反应24h。过滤除去二氧化锰,减压除去溶剂,残余物经柱色谱纯化(石油醚:乙酸乙酯=8:1,V/V)得到两个异构体,构型分别经2D-NOESY确认,其中目标产物A为主产物,白色固体250mg,产率60%,1H NMR(600MHz,CDCl3)δ2.44-2.54(m,1H),3.04-3.14(m,1H),3.25(dt,J=2.7,5.6Hz,1H),3.29(s,3H),3.76(s,3H),5.28(d,J=3.8Hz,1H),7.10-7.03(m,1H),7.47(d,J=1.3Hz,1H),9.77(s,1H).13C NMR(151MHz,CDCl3)δ32.66,40.52,42.15,51.26,56.29,98.14,110.45,145.29,150.70,155.77,167.71,189.33.MS(ESI)m/z:261.3[M+Na]+。
实施例2
本实施例所述(1R,4aS,7aS)-1-甲氧基-4-(吗啉-4-羰基)-1,4a,5,7a-四氢-氯戊[c]吡喃-7-甲醛的制备方法:
化合物M1(1g,4.2mmol)溶于5M KOH乙醇溶液中,回流2h,减压浓缩,重新溶于乙酸乙酯中,用1N盐酸溶液洗涤,再用饱和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到化合物3;在0℃,二氯甲烷中加入化合物C(200mg,0.88mmol),加入HoBt(338mg,3.16mmol)、EDCI(480mg,3.16mmol)和TEA(40mg,0.40mmol);将混合物搅拌10min,然后在溶液中加入吗啉(280mg,3.17mmol),在室温下搅拌过夜;将水加入反应液中,用二氯甲烷萃取三次;有机层用饱和盐水洗涤,在无水硫酸钠干燥,减压浓缩得化合物D;化合物D溶于二氯甲烷中,加入活化MnO2(3.6g,42mmol),室温搅拌24h;将混合物过滤,真空浓缩,在硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得Ea作为主要产物;无色油状液体500mg,产率46%,MS(ESI)m/z:294.0[M+H]+。
实施例3
本实施例所述(1R,4aS,7aS)-1-甲氧基-4-(吡咯烷-1-羰基)-1,4a,5,7a-四氢-氯戊[c]吡喃-7-甲醛的制备方法:
化合物M1(1g,4.2mmol)溶于5M KOH乙醇溶液中,回流2h,减压浓缩,重新溶于乙酸乙酯中,用1N盐酸溶液洗涤,再用饱和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到化合物3。在0℃,二氯甲烷中加入化合物C(200mg,0.88mmol),加入HoBt(338mg,3.16mmol)、EDCI(480mg,3.16mmol)和TEA(40mg,0.40mmol)。将混合物搅拌10min,然后在溶液中加入吡咯烷(225mg,3.17mmol),在室温下搅拌过夜;将水加入反应液中,用二氯甲烷萃取三次。有机层用饱和盐水洗涤,在无水硫酸钠干燥,减压浓缩得化合物D;化合物D溶于二氯甲烷中,加入活化MnO2(3.6g,42mmol),室温搅拌24h;将混合物过滤,真空浓缩,在硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得Ga作为主要产物。无色油状液体500mg,产率50%,MS(ESI)m/z:278.0[M+H]+。
实施例4
本实施例所述(E)-1-乙酰基-3-亚苄基吲哚-2-酮的制备方法:
在圆底烧瓶中加入2-吲哚酮(396mg,3.0mmol),苯甲醛(350mg,3.3mmol)和4mL无水乙醇,缓慢滴加哌啶52mg(0.6mmol),在80℃加热2h。有沉淀生成,沉淀过滤后用乙醇洗涤,得(E)-3-亚苄基吲哚-2-酮。将(E)-3-亚苄基吲哚-2-酮溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水MgSO4干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=60:1,V/V)得目标化合物(黄色固体542mg,产率54%)。产物鉴定结果:m.p.145-146℃;1H NMR(600MHz,CDCl3)δ8.34(d,J=8.2Hz,1H),7.91(s,1H),7.72(d,J=7.5Hz,1H),7.66(d,J=7.1Hz,2H),7.50(ddd,JJ=8.5,7.6,6.2Hz,3H),7.37–7.32(m,1H),7.05(td,J=7.7,0.9Hz,1H),2.79(s,3H);13C NMR(151MHz,CDCl3)δ170.91,168.62,140.28,138.71,134.42,130.28,130.07,129.21,128.81,124.49,122.16,121.88,116.75,27.00,26.93;HRMS(ESI):Calcd.for C17H13O2NNa[M+Na]+:286.0838;found:286.0831。
实施例5
本实施例所述(E)-1-乙酰基-6-氯-3-(3(三氟甲基)亚苄基)吲哚-2-酮的制备方法:
制备方法同例4,在圆底烧瓶中加入6-氯-2-吲哚酮(500mg,3.0mmol),3-三氟甲基苯甲醛(574mg,3.3mmol)和4mL无水乙醇,缓慢滴加哌啶52mg(0.6mmol),在80℃加热2h。有沉淀生成,沉淀过滤后用乙醇洗涤,得(E)-6-氯-3-(3(三氟甲基)亚苄基)吲哚-2-酮。将(E)-6-氯-3-(3(三氟甲基)亚苄基)吲哚-2-酮溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水MgSO4干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=60:1,V/V)得目标化合物(黄色固体321mg,产率31%)。产物鉴定结果:m.p.142-143℃;1H NMR(600MHz,CDCl3)δ8.35(dd,J=11.7,4.6Hz,3H),7.73(d,J=8.1Hz,1H),7.62(t,J=7.9Hz,1H),7.60(s,1H),7.53(d,J=8.2Hz,1H),7.25(dd,J=8.2,1.9Hz,1H),2.74(s,3H);13C NMR(151MHz,CDCl3)δ170.84,165.69,139.53,136.87,135.84,134.59,133.67,128.91,128.81,128.49,128.46,127.32,127.30,125.61,125.16,122.65,119.78,117.32,26.86;HRMS(ESI):Calcd.for C18H11O2NClF3Na[M+Na]+:388.0323;found:388.0311。
实施例6
本实施例所述(E)-1-乙酰基-5-氯-3-(3-氯-2-氟亚苄基)吲哚-2-酮的制备方法:
制备方法同例4,在圆底烧瓶中加入5-氯-2-吲哚酮(500mg,3.0mmol),2-氟-3-氯苯甲醛(521mg,3.3mmol)和4mL无水乙醇,缓慢滴加哌啶52mg(0.6mmol),在80℃加热2h。有沉淀生成,沉淀过滤后用乙醇洗涤,得(E)-5-氯-3-(2-氟-3-氯亚苄基)吲哚-2-酮。将(E)-5-氯-3-(2-氟-3-氯亚苄基)吲哚-2-酮溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水MgSO4干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=60:1,V/V)得目标化合物(黄色固体268mg,产率27%)。产物鉴定结果:m.p.141-142℃;1H NMR(600MHz,CDCl3)δ8.30(d,J=8.8Hz,1H),7.87(s,1H),7.59–7.55(m,2H),7.43(d,J=1.9Hz,1H),7.36–7.31(m,1H),7.26(t,J=7.9Hz,1H),2.78(s,3H);13C NMR(151MHz,CDCl3)δ170.55,167.23,139.09,132.80,131.16,131.15,130.69,130.22,130.16,130.13,128.04,127.68,124.88,124.85,122.70,122.40,119.55,118.07,26.79;HRMS(ESI):Calcd.for C18H10O2NCl2FNa[M+Na]+:372.0073;found:372.0083。
实施例7
本实施例所述(E)-1-乙酰基-6-氯-3-(4-(三氟甲基)亚苄基)吲哚-2-酮的制备方法:
制备方法同例4,在圆底烧瓶中加入6-氯-2-吲哚酮(500mg,3.0mmol),4-三氟甲基苯甲醛(574mg,3.3mmol)和4mL无水乙醇,缓慢滴加哌啶52mg(0.6mmol),在80℃加热2h。有沉淀生成,沉淀过滤后用乙醇洗涤,得(E)-6-氯-3-(4-(三氟甲基)亚苄基)吲哚-2-酮。将(E)-6-氯-3-(4-(三氟甲基)亚苄基)吲哚-2-酮溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水MgSO4干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=60:1,V/V)得目标化合物(黄色固体255mg,产率25%)。产物鉴定结果:m.p.143-145℃;1H NMR(600MHz,CDCl3)δ8.43(d,J=1.9Hz,1H),7.84(s,1H),7.59–7.51(m,3H),7.49(s,1H),7.35(d,J=6.7Hz,1H),7.06(dd,J=8.4,2.0Hz,1H),2.78(s,3H);13C NMR(151MHz,CDCl3)δ168.22,159.84,140.92,139.07,135.88,135.38,130.05,125.32,124.64,123.10,121.49,117.28,116.10,114.23,77.25,77.04,76.83,55.42,26.82;HRMS(ESI):Calcd.for C18H11O2NClF3Na[M+Na]+:388.0323;found:388.0311。
实施例8
本实施例所述(E)-1-乙酰基-6-氯-3-(3-(甲氧基)亚苄基)吲哚-2-酮的制备方法:
制备方法同例4,在圆底烧瓶中加入6-氯-2-吲哚酮(500mg,3.0mmol),3-甲氧基苯甲醛(449mg,3.3mmol)和4mL无水乙醇,缓慢滴加哌啶52mg(0.6mmol),在80℃加热2h。有沉淀生成,沉淀过滤后用乙醇洗涤,得(E)-6-氯-3-(3-(甲氧基)亚苄基)吲哚-2-酮。将(E)-6-氯-3-(3-(甲氧基)亚苄基)吲哚-2-酮溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水MgSO4干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=60:1,V/V)得目标化合物(黄色固体311mg,产率32%)。产物鉴定结果:m.p.141-143℃;1H NMR(600MHz,CDCl3)δ8.39(d,J=1.9Hz,1H),7.88(s,1H),7.67(d,J=8.4Hz,1H),7.42(t,J=7.9Hz,1H),7.21(d,J=7.5Hz,1H),7.13(s,1H),7.06–6.99(m,2H),3.86(s,3H),2.77(s,3H);13C NMR(151MHz,CDCl3)δ168.22,159.84,140.92,139.07,135.88,135.38,130.05,125.32,124.64,123.10,121.49,117.28,116.10,114.23,77.25,77.04,76.83,55.42,26.82;HRMS(ESI):Calcd.for C18H14O3NClNa[M+Na]+:350.0554;found:350.0546。
实施例9
本发明所述(E)-1-乙酰基-6-氯-3-(吡啶-4-基亚甲基)吲哚-2酮的制备方法:
制备方法同例4,在圆底烧瓶中加入6-氯-2-吲哚酮(500mg,3.0mmol),4-吡啶甲醛(353mg,3.3mmol)和4mL无水乙醇,缓慢滴加哌啶52mg(0.6mmol),在80℃加热2h。有沉淀生成,沉淀过滤后用乙醇洗涤,得(E)-6-氯-3-(吡啶-4-基亚甲基)吲哚-2酮。将(E)-6-氯-3-(吡啶-4-基亚甲基)吲哚-2酮溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水MgSO4干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=60:1,V/V)得目标化合物(黄色固体295mg,产率33%)。产物鉴定结果:m.p.138-139℃;1H NMR(600MHz,CDCl3)δ8.79(d,J=5.8Hz,2H),8.39(s,1H),7.76(s,1H),7.46(d,J=5.5Hz,1H),7.40(d,J=8.4Hz,1H),7.04(dd,J=8.4,1.9Hz,2H),2.77(s,3H);13C NMR(151MHz,CDCl3)δ170.91,168.62,140.28,138.71,134.42,130.28,130.07,129.21,128.81,124.49,122.16,121.88,116.75,27.00,26.93;HRMS(ESI):Calcd.for C16H12O2N2Cl[M+H]+:299.0582;found:299.0576。
实施例10
本发明所述(E)-1-乙酰基-6-氯-3-(3-甲氧基-5-(三氟甲基)亚苄基)吲哚-2-酮的制备方法:
制备方法同例4,在圆底烧瓶中加入6-氯-2-吲哚酮(500mg,3.0mmol),3-甲氧基-5-三氟甲基苯甲醛(673mg,3.3mmol)和4mL无水乙醇,缓慢滴加哌啶52mg(0.6mmol),在80℃加热2h。有沉淀生成,沉淀过滤后用乙醇洗涤,得(E)-6-氯-3-(3-甲氧基-5-(三氟甲基)亚苄基)吲哚-2-酮。将(E)-6-氯-3-(3-甲氧基-5-(三氟甲基)亚苄基)吲哚-2-酮溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水MgSO4干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=60:1,V/V)得目标化合物(黄色固体296mg,产率25%)。产物鉴定结果:m.p.140-142℃;1H NMR(600MHz,CDCl3)δ8.40(d,J=1.9Hz,1H),7.83(s,1H),7.52–7.49(m,1H),7.23(s,2H),7.06(dd,J=8.4,2.0Hz,1H),3.91(s,4H),2.77(s,3H);13C NMR(151MHz,CDCl3)δ170.86,170.59,167.82,165.68,160.16,159.66,141.27,137.02,136.58,136.26,126.71,124.84,122.99,119.74,119.70,119.61,117.91,117.88,117.59,117.52,117.27,112.26,112.23,55.80,26.79;HRMS(ESI):Calcd.for C19H14O3NClF3[M+H]+:396.0609;found:396.0616。
实施例11
本实施例所述(E)-1-乙酰基-6-氯-3-(3-(三氟甲氧基)亚苄基)吲哚-2-酮的制备方法:
制备方法同例4,在圆底烧瓶中加入6-氯-2-吲哚酮(500mg,3.0mmol),3-三氟甲氧基苯甲醛(627mg,3.3mmol)和4mL无水乙醇,缓慢滴加哌啶52mg(0.6mmol),在80℃加热2h。有沉淀生成,沉淀过滤后用乙醇洗涤,得(E)-6-氯-3-(3-(三氟甲氧基)亚苄基)吲哚-2-酮。将(E)-6-氯-3-(3-(三氟甲氧基)亚苄基)吲哚-2-酮溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水MgSO4干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=60:1,V/V)得目标化合物(黄色固体302mg,产率26%)。产物鉴定结果:m.p.135-136℃;1H NMR(600MHz,CDCl3)δ8.41(d,J=1.9Hz,1H),7.84(s,1H),7.59–7.51(m,3H),7.49(s,1H),7.35(d,J=6.7Hz,1H),7.06(dd,J=8.4,2.0Hz,1H),2.78(s,3H);13C NMR(151MHz,CDCl3)δ170.61,167.89,141.22,136.58,136.53,136.12,130.60,127.48,126.50,124.81,122.94,122.53,121.28,119.74,117.49,26.87,26.80;HRMS(ESI):Calcd.for C18H12O3NClF3[M+H]+:382.0452;found:382.03441。
实施例12
本实施例所述叔丁基(E)-4-((1-乙酰基-6-氯-2-氧吲哚-3-亚丙基)甲基)苯甲酸酯的制备方法:
制备方法同例4,在圆底烧瓶中加入6-氯-2-吲哚酮(500mg,3.0mmol),4-甲酰基苯甲酸叔丁酯(680mg,3.3mmol)和4mL无水乙醇,缓慢滴加哌啶52mg(0.6mmol),在80℃加热2h。有沉淀生成,沉淀过滤后用乙醇洗涤,得叔丁基(E)-4-((6-氯-2-氧吲哚-3-亚丙基)甲基)苯甲酸酯。将叔丁基(E)-4-((6-氯-2-氧吲哚-3-亚丙基)甲基)苯甲酸酯溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水MgSO4干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=60:1,V/V)得目标化合物(黄色固体368mg,产率31%)。产物鉴定结果:m.p.138-139℃;1H NMR(600MHz,CDCl3)δ8.39(d,J=1.9Hz,1H),8.11(d,J=8.3Hz,2H),7.89(s,1H),7.66(d,J=8.1Hz,2H),7.53(d,J=8.4Hz,1H),7.03(dd,J=8.4,2.0Hz,1H),2.77(s,3H),1.65(s,9H);13C NMR(151MHz,CDCl3)δ170.63,167.94,164.91,141.15,138.12,137.60,136.37,133.32,129.93,128.87,126.40,124.78,123.04,119.95,117.41,81.72,77.25,77.04,76.83,28.19,26.80;HRMS(ESI):Calcd.for C22H20O4NClNa[M+Na]+:420.1081;found:420.1073。
实施例13
本实施例所述(E)-1-乙酰基-3-(3-(三氟甲基)亚苄基)吲哚-2-酮的制备方法:
制备方法同例4,在圆底烧瓶中加入2-吲哚酮(396mg,3.0mmol),3-三氟甲基苯甲醛(574mg,3.3mmol)和4mL无水乙醇,缓慢滴加哌啶52mg(0.6mmol),在80℃加热2h。有沉淀生成,沉淀过滤后用乙醇洗涤,得(E)-3-(3-(三氟甲基)亚苄基)吲哚-2-酮。将(E)-3-(3-(三氟甲基)亚苄基)吲哚-2-酮溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水MgSO4干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=60:1,V/V)得目标化合物(黄色固体284mg,产率29%)。产物鉴定结果:m.p.121-123℃;1H NMR(600MHz,CDCl3)δ8.36(d,J=8.2Hz,1H),7.92(s,1H),7.87(s,1H),7.84(d,J=7.7Hz,1H),7.74(d,J=7.8Hz,1H),7.65(dd,J=16.0,8.4Hz,1H),7.56(d,J=7.8Hz,1H),7.38(t,J=7.6Hz,1H),7.07(t,J=7.6Hz,1H),2.80(s,3H);13C NMR(151MHz,CDCl3)δ170.78,168.21,140.66,136.05,135.27,132.19,130.93,129.45,127.61,126.44,126.41,125.90,125.88,124.68,122.08,121.28,117.00,116.81,26.98,26.92;HRMS(ESI):Calcd.For C18H12O2NF3Na[M+Na]+:354.0712;found:354.0705。
实施例14
本实施例所述(E)-1-乙酰基-3-(3-氯-2-氟亚苄基)-6-(三氟甲基)吲哚-2-酮的制备方法:
制备方法同例4,在圆底烧瓶中加入6-三氟甲基-2-吲哚酮(603mg,3.0mmol),2-氟-3-氯苯甲醛(521mg,3.3mmol)和4mL无水乙醇,缓慢滴加哌啶52mg(0.6mmol),在80℃加热2h。有沉淀生成,沉淀过滤后用乙醇洗涤,得(E)-3-(3-氯-2-氟亚苄基)-6-(三氟甲基)吲哚-2-酮。将(E)-3-(3-氯-2-氟亚苄基)-6-(三氟甲基)吲哚-2-酮溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水MgSO4干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=60:1,V/V)得目标化合物(黄色固体384mg,产率32%)。产物鉴定结果:m.p.120-122℃;1H NMR(600MHz,CDCl3)δ2.81(s,3H),7.25(t,J=7.8Hz,1H),7.36(dd,J=0.7,8.1Hz,1H),7.56(d,J=7.9Hz,2H),7.58(d,J=8.4Hz,1H),7.95(s,1H),8.66(s,1H).13C NMR(151MHz,CDCl3)δ26.80,114.04,119.60,121.70,122.66,123.52,124.25,124.90,127.7,128.16,130.26,130.97,132.38,132.88,133.41,140.73,156.1,167.13,170.72.HRMS(ESI):Calcd.For C18H10O2NClF4Na[M+Na]+:429.0710;found:429.0705。
实施例15
本实施例所述甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯的制备方法:
在圆底烧瓶中加入6-氯-2-吲哚酮(500mg,3mmol),化合物A(785mg,3.3mmol)和4mL甲醇,缓慢滴加哌啶52mg(0.6mmol),在室温搅拌24h,有沉淀生成,沉淀过滤后用甲醇洗涤,得甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯。再将其(1.2g,3.0mmol)溶于5mL四氢呋喃中,加入乙酸酐(4.5mL,15.0mmol)和碳酸钠(156mg,15.0mmol),在室温下搅拌12h,加水稀释,用乙酸乙酯萃取(3×50mL)。有机层用饱和食盐水洗涤(2×100mL),然后用无水硫酸钠干燥,粗品在硅胶柱上进行纯化(石油醚:乙酸乙酯=10:1,V/V)得目标化合物(黄色固体380mg,30%)。产物鉴定结果:m.p.136-137℃;1H NMR(600MHz,CDCl3)δ8.38(d,J=1.9Hz,1H),7.78(d,J=8.3Hz,1H),7.56(s,1H),7.42(s,1H),7.12(dd,J=8.3,1.9Hz,1H),6.57(s,1H),4.65(d,J=7.0Hz,1H),3.78(s,3H),3.54(s,3H),3.37(q,J=7.8Hz,1H),3.17(dd,J=18.5,8.4Hz,1H),2.97(t,J=7.3Hz,1H),2.74(s,3H),2.47–2.40(m,1H);13C NMR(151MHz,CDCl3)δ170.74,168.06,167.55,152.33,140.70,138.79,138.07,135.53,134.78,125.29,124.70,122.99,120.73,117.29,110.56,101.90,57.25,51.39,49.14,40.43,34.48,26.78;HRMS(ESI):Calcd.for C22H20O6NClNa[M+Na]+:452.0871;found:452.0858。
实施例16
本实施例所述BN的制备方法:
步骤一:在250mL三颈瓶中加入R-联萘酚(5g,1.8mmol)和160mL丙酮搅拌溶解。在氮气保护下加入碳酸钾(8g,6.0mmol)和碘甲烷(12g,0.8mol),加热回流24h,再加入碘甲烷(4g,0.3mol),回流12h,加热浓缩除去部分溶剂,冷却到25℃,加入150mL水搅拌8h,有沉淀产生,沉淀过滤后用水洗涤,干燥得R-1(4.5g,95%)。在干燥的250mL三颈瓶中加入150mL干燥的***和四甲基乙二胺(3.1g,27.0mmol),通入氮气,再加入1.6mol/L正丁基锂正己烷溶液(17mL,28.0mmol),在室温下搅拌30分钟,再加入R-1(3g,9.5mmol),室温下搅拌3h。在-78℃下缓慢加入硼酸三乙酯,加完后升温至室温,搅拌24h,然后在冷却至0℃,再加入75mL1mol/L HCl,搅拌2h,有机层依次用1mol/L HCl和饱和氯化钠溶液洗涤,减压浓缩,得R-2(3.1g,65%)。
步骤二:在50mL双颈瓶中加入R-2(750mg,1.9mmol),Ba(OH)2·8H2O(1.7g,5.5mmol)和Pd(PPh3)4,通入氮气,加入12mL 1,4-二氧六环、4mL水和2-溴代萘(4.5g,6.0mmol),在氮气保护下加热回流24h,将二氧六环除去,粗产物溶于75mL CH2Cl2中,用1mol/L HCl(2×50m L)和75mL饱和氯化钠溶液洗涤,并无水硫酸钠干燥。将粗品溶于75mL干燥CH2Cl2中,冷却至0℃,加入1mL BBr3,在室温下搅拌18h。再冷却至0℃,小心加入150mL水。有机相分离,用水(2×100mL)和100mL饱和氯化钠溶液洗涤有机相,用无水硫酸钠干燥,减压浓缩。残余物经柱色谱纯化(正己烷:二氯甲烷=1:1,V/V),得R-3(1.8g,70%)。
步骤三:在10mL的圆底烧瓶中加入R-3(300mg,0.43mmol),加入1mL的吡啶溶解,室温下滴加三氯氧磷(0.081mL,0.86mmol),快速搅拌6小时。加入1mL水,得到的两相悬浮液在室温下搅拌30min。加入二氯甲烷,分离有机相并用1mol/L HCl(2×20m L)和25mL饱和氯化钠溶液洗涤,并无水硫酸钠干燥。减压浓缩。残余物经柱色谱纯化(甲醇:二氯甲烷=1:90,V/V),得BN(280mg,86%)。产物鉴定结果:1H NMR(600MHz,CDCl3)δ7.40-7.44(m,2H),7.46(d,J=8.4Hz,1H),7.51(d,J=9.6Hz,1H),7.53-7.55(m,2H),7.56-7.58(m,2H),7.60-7.63(m,2H),7.85(dd,J=9.6Hz,1H),7.90-7.92(m,2H),7.93-7.96(m,3H),7.99(t,J=7.8Hz,2H),8.09(t,J=18.6Hz,2H),8.23(t,J=18.6Hz,3H),8.28(s,1H).13C NMR(151MHz,CDCl3)δ122.81,123.06,126.22,126.36,126.55,126.73,127.10,127.19,127.64,127.75,127.96,128.21,128.45,128.69,129.17,131.97,132.08,132.22,132.41,132.94,133.40,133.52,133.79,134.00,144.27.31P NMR(243MHz,CDCl3)δ3.60.MS(ESI-)m/z:599.1[M-H]-。
实施例17
本实施例所述氨基丙二酸二乙酯的制备方法:
在50mL圆底烧瓶中加入氨基丙二酸二乙酯盐酸盐(3.0g,14.2mmol),再加入30mL水溶解,然后加入NaHCO3(1.3g,15.6mmol),室温搅拌15min后,用AcOEt萃取3次,有机层用无水硫酸钠干燥,在真空下浓缩得氨基丙二酸二乙酯(2.3g,13.1mmol),无需进一步纯化。产物鉴定结果:MS(ESI)m/z:198.0[M+Na]+。
实施例18
本实施例所述1a的制备方法:
在10mL圆底烧瓶中加入(E)-1-乙酰基-3-亚苄基吲哚-2-酮(60mg,0.2mmol)、BN(10mg,0.02mmol)、化合物A(47mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌24-48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1a(20mg,20%)。产物结果鉴定:m.p.69-71℃;(c=0.2in CHCl3);1H NMR(600MHz,CDCl3)δ0.73(t,J=7.1Hz,3H),1.34(t,J=7.2Hz,3H),1.90-1.99(m,1H),2.59(s,3H),2.79(ddd,J=2.7,8.4,16.6Hz,1H),3.03(t,J=8.5Hz,1H),3.20(q,J=8.4Hz,1H),3.64(s,3H),3.71(m,5H),4.35(q,J=7.2Hz,1H),4.45(d,J=8.3Hz,1H),4.51(d,J=11.0Hz,1H),4.98(d,J=11.0Hz,1H),5.60(s,1H),6.80(d,J=7.4Hz,2H),7.00(t,J=7.6Hz,2H),7.06(t,J=7.4Hz,1H),7.19(td,J=0.9,7.5Hz,1H),7.24(m,1H),7.46(d,7.3Hz,1H),7.53(s,1H),7.96(d,J=8.1Hz,1H).13C NMR(151MHz,CDCl3)δ13.99,14.20,13.13,26.53,31.44,36.02,39.13,46.75,51.19,57.30,58.07,58.66,60.39,61.64,62.53,64.99,78.53,103.28,110.91,116.07,123.83,124.81,127.19,127.80,128.03,128.11,128.93,129.17,139.83,142.26,152.16,167.78,168.59,169.98,170.32,175.66.HRMS(ESI):Calcd.forC36H39O10N2[M+H]+:659.2599;found:659.2595。
实施例19
本实施例所述1b的制备方法:
制备方法同例18,在10mL圆底烧瓶中加入(E)-1-乙酰基-6-氯-3-(3(三氟甲基)亚苄基)吲哚-2-酮(66.2mg,0.2mmol)、BN(10mg,0.02mmol)、化合物A(47mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌24-48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1b(22mg,25%)。产物结果鉴定:m.p.69-70℃;(c=0.3in CHCl3);1HNMR(600MHz,CDCl3)δ0.84(t,J=7.1Hz,3H),1.32(t,J=7.1Hz,3H),1.93(dd,J=6.3,16.8Hz,1H),2.48(s,3H),2.68(dd,J=7.9,16.6Hz,1H),2.98(t,J=7.1Hz,1H),3.05(q,J=7.8Hz,1H),3.54(s,3H),3.70(s,3H),4.13(dq,J=7.0,14.2Hz,1H),4.25-4.34(m,2H),4.40(dq,J=7.2,14.3Hz,1H),4.52(d,J=7.0Hz,1H),4.70(d,J=11.8Hz,1H),5.06(s,1H),5.19(s,1H),7.18(d,J=7.6Hz,1H),7.26(t,J=7.7Hz,1H),7.29(s,1H),7.41(s,1H),7.42-7.49(m,3H),8.10(s,1H).13C NMR(151MHz,CDCl3)δ13.23,13.96,26.34,34.68,39.08,47.11,51.19,56.68,61.99,62.84,63.66,64.27,66.83,74.86,101.72,110.57,117.18,122.59,124.88,125.60,125.90,125.97,128.77,130.70,133.89,134.71,134.96,137.25,140.47,151.96,167.52,176.86,170.16,170.45,176.31.HRMS(ESI):Calcd.for C37H37O10N2ClF3[M+H]+:761.2083;found:761.2086。
实施例20
本实施例所述1c的制备方法:
制备方法同例18,在10mL圆底烧瓶中加入(E)-1-乙酰基-6-氯-3-(3-(甲氧基)亚苄基)吲哚-2-酮(65.4mg,0.2mmol)、BN(10mg,0.02mmol)、化合物A(47.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌24-48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1c(25mg,31%)。产物结果鉴定:m.p.65-66℃;(c=0.28in CHCl3);1HNMR(600MHz,CDCl3)δ0.83(t,J=7.1Hz,3H),1.33(t,J=7.2Hz,3H),1.96(ddd,J=1.6,9.2,16.7Hz,1H),2.60(s,3H),2.77-2.83(m,1H),3.01(t,J=8.0Hz,1H),3.20(q,J=8.4Hz,1H),3.60(s,3H),3.64(s,3H),3.72(s,3H),3.76-3.82(m,1H),3.83-3.92(m,1H),4.33(q,J=7.2Hz,2H),4.43(s,1H),4.45(d,J=4.5Hz,1H),4.90(d,J=11Hz,1H),5.63(s,1H),6.33(s,1H),6.41(d,J=7.7Hz,1H),6.64(dd,J=2.0,8.2Hz,1H),6.97(t,J=8.0Hz,1H),7.20(dd,J=1.9,8.2Hz,1H),7.39(d,J=8.2Hz,1H),7.53(s,1H),8.07(d,J=1.8Hz,1H).13C NMR(151MHz,CDCl3)δ13.27,13.97,26.45,29.70,36.15,39.11,46.26,51.23,56.06,57.35,57.84,58.65,61.81,62.66,64.55,78.55,103.25,110.87,113.25,114.04,116.71,120.59,124.80,125.85,129.18,129.50,134.69,134.87,140.67,141.99,152.19,159.27,167.76,168.36,169.79,170.19,175.35.HRMS(ESI):Calcd.forC37H40O11N2Cl[M+H]+:723.2315;found:723.2311。
实施例21
本实施例所述1d的制备方法:
制备方法同例18,在10mL圆底烧瓶中加入(E)-1-乙酰基-3-(3-氯-2-氟亚苄基)-6-(三氟甲基)吲哚-2-酮(81.4mg,0.2mmol)、BN(10mg,0.02mmol)、化合物A(47.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌24-48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1d(26mg,26%)。产物结果鉴定:m.p.58-60℃;(c=0.12in CHCl3);1H NMR(600MHz,CDCl3)δ0.86(t,J=7.1Hz,3H),1.30(t,J=7.2Hz,3H),1.99-2.06(m,1H),2.69(s,3H),2.76-2.87(m,1H),2.99(t,J=7.8Hz,1H),3.21(q,J=8.1Hz,1H),3.66(s,3H),3.73(s,3H),3.81-3.89(m,1H),3.90-4.00(m,1H),4.25-4.36(m,2H),4.55(d,J=8.1Hz,1H),4.72(d,J=10.7Hz,1H),5.15(d,J=10.6Hz,1H),5.75(s,1H),6.73-6.91(m,2H),7.14-7.19(m,1H),7.22(d,J=8.0Hz,1H),7.30(d,J=8.3Hz,1H),7.54(s,1H),8.41(s,1H).13C NMR(151MHz,CDCl3)δ13.27,13.85,26.32,27.22,29.33,36.20,38.95,46.11,51.09,51.27,57.27,59.50,62.10,62.81,63.68,80.21,102.77,110.83,113.27,121.06,122.67,123.55,124.14,124.83,126.74,129.99,130.17,131.03,131.25,140.72,141.14,152.15,167.66.HRMS(ESI):Calcd.for C37H36O10N2ClF4[M+H]+:779.1989;found:779.1982。
实施例22
本实施例所述1e的制备方法:
制备方法同例18,在10mL圆底烧瓶中加入(E)-1-乙酰基-6-氯-3-(吡啶-4-基亚甲基)吲哚-2酮(60.0mg,0.2mmol)、BN(10mg,0.02mmol)、Ea(47.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌24-48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1e(27mg,28%)。产物结果鉴定:m.p.75-76℃;(c=0.34inCHCl3);1H NMR(600MHz,CDCl3)δ0.84(t,J=7.2Hz,3H),1.32(t,J=7.1Hz,3H),1.74(s,2H),1.86–1.80(m,2H),1.98–1.87(m,2H),2.45–2.38(m,1H),2.60(s,3H),2.84–2.78(m,1H)),3.02(dd,J=11.8,6.9Hz,1H),3.44(s,3H),3.51–3.47(m,2H),3.68–3.59(m,1H),3.70(d,J=5.2Hz,1H),4.06–3.99(m,1H),4.31–4.25(m,1H),4.38(d,J=4.1Hz,1H),4.47–4.39(m,1H),4.64(d,J=4.7Hz,1H),5.09(s,1H),6.29(s,1H),6.82(d,J=6.1Hz,2H),7.26(dd,J=8.2,2.0Hz,1H),8.11(d,J=1.9Hz,1H),8.33–8.30(m,1H).13C NMR(151MHz,CDCl3)δ13.37,14.00,26.68,27.21,29.32,33.90,34.17,35.92,37.23,37.45,49.06,56.37,60.44,62.09,62.91,63.79,64.96,73.26,99.14,115.62,116.82,123.95,124.57,124.79,128.58,132.54,134.73,137.26,141.10,142.31,142.84,149.48,167.74,168.87,170.42,170.50,176.94.HRMS(ESI):Calcd.for C38H42O9N4Cl[M+H]+:733.2635;found:733.2629。
实施例23
本实施例所述1f的制备方法:
制备方法同例18,在10mL圆底烧瓶中加入(E)-1-乙酰基-6-氯-3-(吡啶-4-基亚甲基)吲哚-2酮(60.0mg,0.2mmol)、BN(10mg,0.02mmol)、Ga(47.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌24-48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1f(27mg,28%)。产物结果鉴定:m.p.102-103℃;(c=0.36inCHCl3);1HNMR(600MHz,CDCl3)δ0.83(t,J=7.2Hz,3H),1.32(t,J=7.1Hz,3H),2.41(dd,J=7.1,16.4Hz,1H),2.60(s,3H),2.85(br.s.,1H),2.98-3.03(m,1H),3.17(br.s.,2H),3.43(s,3H),3.45-3.52(m,2H),3.53-3.58(m,2H),3.59-3.66(m,4H),3.97-4.07(m,1H),4.24-4.32(m,1H),4.37(d,J=5.0Hz,1H),4.40-4.46(m,1H),4.70(d,J=4.3Hz,1H),5.09(s,1H),5.72(s,1H),6.81(d,J=6Hz,2H),7.25(dd,J=1.9,8.2Hz,1H),8.10(d,J=1.9Hz,1H),8.30-8.32(m,3H).13C NMR(151MHz,CDCl3)δ13.37,14.00,26.66,33.92,37.06,49.30,56.37,60.40,62.14,62.95,63.78,64.91,66.99,73.19,98.93,113.28,116.75,123.96,124.47,124.75,128.66,132.55,134.69,137.29,141.13,141.57,142.70,149.57,168.50,168.84,170.44,170.47,176.82.HRMS(ESI):Calcd.for C38H42O10N4Cl[M+H]+:749.2584;found:749.2579。
实施例24
本实施例所述1g的制备方法:
制备方法同例18,在10mL圆底烧瓶中加入(E)-1-乙酰基-6-氯-3-(3-(三氟甲氧基)亚苄基)吲哚-2-酮(60.0mg,0.2mmol)、BN(10mg,0.02mmol)、化合物A(47.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌24-48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1g(27mg,28%)。产物结果鉴定:m.p.51-53℃;(c=0.20in CHCl3);1H NMR(600MHz,CDCl3)δ0.83(t,J=7.1Hz,3H),1.33(t,J=7.2Hz,3H),1.97(ddd,J=1.7,9.2,16.8Hz,1H),2.60(s,3H),2.81(ddd,2.8,8.4,16.8Hz,1H),3.00(t,J=7.3Hz,1H),3.21(q,J=8.2Hz,1H),3.64(s,3H),3.72(s,3H),3.77-3.83(m,1H),3.83-3.90(m,1H),4.34(q,J=7.1Hz,2H),4.43(d,J=8.3Hz,1H),4.49(d,J=11.0Hz,1H),4.93(d,J=10.8Hz,1H),5.63(s,1H),6.69(s,1H),6.78(d,J=7.9Hz,1H),6.98(d,J=8.1Hz,1H),7.11(t,J=8.0Hz,1H),7.20(dd,J=1.9,8.2Hz,1H),7.37(d,J=8.2Hz,1H),7.54(s,1H),8.07(d,J=1.9Hz,1H).13C NMR(151MHz,CDCl3)δ13.27,13.96,26.41,29.70,36.23,39.06,46.24,51.25,57.25,57.28,58.56,61.90,62.78,64.44,78.57,103.13,110.83,116.81,120.64,120.76,124.67,125.04,125.13,126.61,129.67,129.87,135.10,135.93,140.49,141.64,148.94,152.20,167.70,168.16,169.67,170.04,175.21.HRMS(ESI):Calcd.for C37H36ClF3N2O11[M+H]+:777.2032;found:777.2014。
实施例25
本实施例所述1h的制备方法:
在10mL圆底烧瓶中加入叔丁基(E)-4-((1-乙酰基-6-氯-2-氧吲哚-3-亚丙基)甲基)苯甲酸酯(79.0mg,0.2mmol)、BN(10mg,0.02mmol)、化合物A(47.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌24-48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得8,将化合物8溶解于在DCM中,然后加入1mL TFA,在室温下搅拌3h,在真空下浓缩,在硅胶色谱柱上纯化(石油醚:乙酸乙酯:甲酸=2:1:0.1),得1h(28mg,33%)。产物结果鉴定:m.p.92-94℃;(c=0.33in CHCl3);1H NMR(600MHz,CDCl3)δ0.84(t,J=7.1Hz,3H),1.33(t,J=6.3Hz,3H),1.95(ddd,J=1.7,9.2,16.8Hz,1H),2.75-2.81(m,1H),3.01(t,J=7.4Hz,1H),3.19(q,J=8.1Hz,1H),3.64(s,3H),3.72(s,3H),3.75-3.82(m,1H),3.83-3.90(m,1H),4.34(q,J=7.1Hz,2H),4.43(d,J=8.3Hz,1H),4.53(d,J=11.0Hz,1H),5.00(d,J=11.0Hz,1H),5.61(s,1H),6.93(d,J=8.4Hz,2H),7.20(dd,J=1.9,8.2Hz,1H),7.41(d,J=8.2Hz,1H),7.53(s,1H),7.78(d,J=8.3Hz,2H),8.06(d,1.9Hz,1H).13C NMR(151MHz,CDCl3)δ13.27,13.96,26.49,36.23,39.03,46.18,51.28,57.36,57.64,58.81,61.96,62.70,62.83,64.45,78.82,103.09,110.80,116.86,124.86,125.06,125.13,128.31,130.06,130.07,135.08,139.62,140.58,141.65,167.74,168.13,169.60,170.03,170.56,175.13.HRMS(ESI):Calcd.for C37H38ClN2O12[M+H]+:737.2;found:737.2086。
实施例26
本实施例所述1i的制备方法:
在10mL圆底烧瓶中加入(E)-1-乙酰基-5-氯-3-(3-氯-2-氟亚苄基)吲哚-2-酮(69.8mg,0.2mmol)、BN(10mg,0.02mmol)、化合物A(47.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌24-48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1i(26mg,28%)。产物结果鉴定:m.p.54-55℃;(c=0.26in CHCl3);1H NMR(600MHz,CDCl3)δ0.91(t,J=7.1Hz,3H),1.29(d,J=7.2Hz,3H),2.05–1.99(m,1H),2.66(s,3H),2.82(ddd,J=16.8,8.4,2.8Hz,1H),2.99(t,J=7.5Hz,1H),3.20(q,J=8.2Hz,1H),3.68(s,3H),3.73(s,3H),4.01–3.90(m,2H),4.34–4.24(m,2H),4.54(d,J=8.1Hz,1H),4.68(d,J=10.7Hz,1H),5.16(d,J=10.6Hz,1H),5.73(s,1H),6.93–6.85(m,2H),7.05(d,J=2.1Hz,1H),7.17(td,J=7.4,1.7Hz,1H),7.20(dd,J=8.7,2.2Hz,1H),7.54(s,1H),8.05(d,J=8.7Hz,1H).13C NMR(150MHz,CDCl3)δ13.39,13.83,26.32,36.03,38.98,46.14,50.97,51.25,57.23,59.44,62.15,62.71,63.63,80.16,102.79,110.83,117.32,124.18,124.75,126.81,127.79,128.99,129.81,130.02,130.86,138.84,141.10,152.14,167.68,168.13,168.70,170.40,176.75.HRMS(ESI):Calcd.for C36H36Cl2FN2O10[M+H]+:745.1726;found:745.1711。
实施例27
本实施例所述1j的制备方法:
在10mL圆底烧瓶中加入(E)-1-乙酰基-3-(3-(三氟甲基)亚苄基)吲哚-2-酮(66.8mg,0.2mmol)、BN(10mg,0.02mmol)、化合物A(47.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌24-48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1j(23mg,17%)。产物结果鉴定:m.p.52-53℃;(c=0.56in CHCl3);1H NMR(600MHz,CDCl3)δ0.82(t,J=7.1Hz,3H),1.31(t,J=7.1Hz,3H),1.96(ddd,J=1.8,9.2,16.8Hz,1H),2.59(s,3H),2.75-2.82(m,1H),2.97-3.01(m,1H),3.19(q,J=8.2Hz,1H),3.62(s,3H),3.71(s,3H),3.76-3.82(m,1H),3.76-3.82(m,1H),4.30-4.35(m,2H),4.42(d,J=8.4Hz,1H),4.47(d,J=11.0Hz,1H),4.91(d,J=10.9Hz,1H),5.61(s,1H),6.68(s,1H),6.77(d,J=7.7Hz,1H),6.96(d,J=8.2Hz,1H),7.10(t,J=8.0Hz,1H),7.19(dd,J=1.9,8.2Hz,1H),7.36(d,J=8.2Hz,1H),7.52(s,1H),8.06(d,J=1.9Hz,1H).13C NMR(151MHz,CDCl3)δ13.23,13.96,26.34,34.68,39.08,47.11,51.19,56.68,61.99,62.84,63.66,64.27,66.83,74.86,101.72,110.57,117.18,122.59,124.88,125.60,125.90,125.97,128.77,130.70,133.89,134.71,134.96,137.25,140.47,151.96,167.52,176.86,170.16,170.45,176.31.HRMS(ESI):Calcd.for C37H38F3N2O10[M+H]+:727.2473;found:727.2486。
实施例28
本实施例所述1k的制备方法:
在10mL圆底烧瓶中加入(E)-1-乙酰基-6-氯-3-(4-(三氟甲基)亚苄基)吲哚-2-酮(73.1mg,0.2mmol)、BN(10mg,0.02mmol)、化合物A(47.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1k(23mg,25%)。产物结果鉴定:m.p.66-68℃;(c=0.28in CHCl3);1H NMR(600MHz,CDCl3)δ0.85(t,J=7.1Hz,3H),1.33(t,J=7.2Hz,3H),1.97(ddd,J=16.8,9.2,1.8Hz,1H),2.61(s,3H),2.80(ddd,J=16.8,8.2,2.9Hz,1H),3.02(dd,J=11.4,4.6Hz,1H),3.20(q,J=8.1Hz,1H),3.64(s,3H),3.73(s,3H),3.82–3.74(m,1H),3.93–3.83(m,1H),4.37–4.31(m,2H),4.43(d,J=8.3Hz,1H),4.52(d,J=11.0Hz,1H),4.96(d,J=10.9Hz,1H),5.59(s,1H),6.96(d,J=8.2Hz,2H),7.21(dd,J=8.2,2.0Hz,1H),7.34(d,J=8.2Hz,2H),7.41(d,J=8.2Hz,1H),7.53(s,1H),8.10(d,J=1.9Hz,1H).13C NMR(150MHz,CDCl3)δ13.29,13.97,26.51,36.26,39.05,46.19,51.27,57.33,57.34,59.00,61.93,62.79,64.33,78.90,103.07,110.84,116.93,124.88,125.06,125.10,125.29,128.62,129.97,135.14,137.78,140.69,141.73,152.18,167.67,168.10,169.60,170.03,175.15.HRMS(ESI):Calcd.for C37H37ClF3N2O10[M+H]+:761.2088;found:761.2061。
实施例29
本实施例所述1l的制备方法:
在10mL圆底烧瓶中加入(E)-1-乙酰基-6-氯-3-(3-甲氧基-5-(三氟甲基)亚苄基)吲哚-2-酮(73.1mg,0.2mmol)、BN(10mg,0.02mmol)、化合物A(47.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在25℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1l(20mg,15%)。产物结果鉴定:m.p.56-58℃;(c=0.37in CHCl3);1H NMR(600MHz,CDCl3)δ0.84(t,J=7.1Hz,1H),1.33(t,J=7.2Hz,1H),2.02–1.95(m,1H),2.60(s,1H)),2.83(ddd,J=16.7,8.4,2.8Hz,1H),2.99(t,J=8.1Hz,1H),3.22(q,J=8.2Hz,1H),3.63(s,1H),3.73(s,1H),3.90–3.80(m,1H),4.35(q,J=7.2Hz,1H),4.43(d,J=8.3Hz,1H),4.50(d,J=11.0Hz,1H),4.91(d,J=11.2Hz,1H),5.64(s,1H),6.50(s,1H),6.67(s,1H),6.87(s,1H),7.23(dd,J=8.2,1.9Hz,1H),7.41(d,J=8.2Hz,1H),7.54(s,1H).13C NMR(150MHz,CDCl3)δ13.28,13.97,14.13,26.36,29.70,36.23,39.06,46.26,51.26,55.43,57.29,57.32,58.35,61.91,62.81,64.43,78.26,103.16,109.86,110.83,116.87,117.09,117.63,124.67,124.97,125.25,129.76,135.11,136.14,140.47,141.56,152.21,159.48,167.70,168.17,169.78,170.06,175.05.HRMS(ESI):Calcd.forC38H39ClF3N2O11[M+H]+:791.2189;found:791.2172。
实施例30
本实施例所述1m的制备方法:
将1a溶解于6mL乙醇/CH2Cl2=5/1的混合溶液中,加入60μL 1M NaOH溶液,室温搅拌2h,然后加水。用二氯甲烷萃取两次,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到粗品,粗品用硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得1m(20mg,16%)。产物结果鉴定:m.p.69-71℃;(c=0.34in CHCl3);1H NMR(600MHz,CDCl3)δ0.77(t,J=7.1Hz,3H),1.32(t,J=7.2Hz,3H),1.93(ddd,J=1.6,9.0,16.7Hz,1H),2.78(ddd,J=2.7,8.4,16.8Hz,1H),3.03(t,J=7.5Hz,1H),3.20(q,J=8.3Hz,1H),3.64(s,3H),3.71(s,3H),3.75-3.85(m,2H),4.27-4.38(m,2H),4.46(d,J=2.2Hz,1H),4.48(s,1H),4.99(d,J=11.0Hz,1H),5.61(s,1H),6.60(d,J=7.7Hz,1H),6.89(d,J=7.5Hz,2H),7.01(td,2.8,7.5Hz,3H),7.06(t,J=7.2Hz,1H),7.12(t,J=7.7Hz,1H),7.38(d,J=7.5Hz,1H),7.53(s,1H).13C NMR(150MHz,CDCl3)δ13.18,13.94,35.93,39.09,46.38,51.20,53.44,56.91,57.28,58.54,61.49,62.38,64.91,77.81,103.29,109.39,110.95,122.17,124.56,127.30,127.76,128.52,128.64,129.08,134.10,140.53,142.37,152.18,167.86,168.97,170.21,175.96.HRMS(ESI):Calcd.for C34H37N2O9[M+H]+:617.2494;found:617.2479。
实施例31
本实施例所述1n的制备方法:
在10mL圆底烧瓶中加入甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯(85.8mg,0.2mmol)、BN(10mg,0.02mmol)、2-氟-3-氯苯甲醛(55.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在50℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1nn,将1nn溶解于6mL乙醇/CH2Cl2=5/1的混合溶液中,加入60μL 1M NaOH溶液,室温搅拌2h,然后加水。用二氯甲烷萃取两次,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到粗品,粗品用硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得1n(25mg,18%)。产物结果鉴定:m.p.107-109℃;(c=0.21in CHCl3);1H NMR(600MHz,CDCl3)δ0.89(t,J=7.1Hz,3H),1.33(t,J=7.2Hz,3H),1.68(t,J=7.3Hz,1H),1.77-1.85(m,1H),2.53-2.65(m,2H),3.16(s,3H),3.67(s,3H),3.81-3.95(m,2H),4.14(d,J=7.2Hz,1H),4.28-4.36(m,2H),4.46(d,J=10.9Hz,1H),5.23(d,J=10.9Hz,1H),5.28(s,1H),6.93(d,J=1.8Hz,1H),7.07(dd,J=1.8,8.1Hz,1H),7.18(t,J=7.9Hz,1H),7.32(s,1H),7.34(d,J=8.1Hz,1H),7.98(t,J=6.5Hz,1H),8.28(s,1H).13C NMR(151MHz,CDCl3)δ13.32,13.89,34.95,39.18,47.98,51.17,52.32,56.66,58.14,60.43,61.94,62.58,63.18,77.51,102.17,110.30,110.46,120.90,122.47,124.86,125.71,127.04,127.53,129.69,130.41,133.17,134.92,136.45,142.48,151.76,167.66,168.39,170.04,175.04.HRMS(ESI):Calcd.for C34H34Cl2FN2O9[M+H]+:703.1620;found:703.1602。
实施例32
本实施例所述1o的制备方法:
在10mL圆底烧瓶中加入甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯(85.8mg,0.2mmol)、BN(10mg,0.02mmol)、4-三氟甲基苯甲醛(57.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在50℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1oo,将1oo溶解于6mL乙醇/CH2Cl2=5/1的混合溶液中,加入60μL 1M NaOH溶液,室温搅拌2h,然后加水。用二氯甲烷萃取两次,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到粗品,粗品用硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得1o(26mg,18%)。产物结果鉴定:m.p.114-116℃;(c=0.18in CHCl3);1H NMR(600MHz,CDCl3)δ0.88(t,J=7.1Hz,3H),1.36(t,J=5.8Hz,3H),1.56(t,J=7.1Hz,1H),1.77-1.82(m,1H),2.55-2.65(m,2H),3.26(s,3H),3.66(s,3H),3.84-3.94(m,2H),4.17(d,J=7.3Hz,1H),4.32-4.38(m,3H),4.78(d,J=10.8Hz,1H),5.06(s,1H),6.93(d,J=1.8Hz,1H),7.06(dd,J=1.8,8.1Hz,1H),7.30(s,1H),7.31(d,J=8.2Hz,1H),7.62(d,J=8.2Hz,2H),7.83(d,J=8.1Hz,2H),8.53(br.s.,1H).13C NMR(151MHz,CDCl3)δ13.31,13.89,34.22,39.38,48.67,51.17,53.46,56.85,60.44,61.97,62.66,62.97,67.28,77.87,102.05,110.38,122.27,123.25,125.05,125.43,125.63,127.84,128.05,129.96,130.17,131.99,134.91,137.03,142.71,145.46,151.75,167.66,168.66,170.11,175.18.HRMS(ESI):Calcd.for C35H35ClF3N2O9[M+H]+:719.1978;found:719.1960。
实施例33
本实施例所述1p的制备方法:
在10mL圆底烧瓶中加入甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯(85.8mg,0.2mmol)、BN(10mg,0.02mmol)、3-三氟甲基苯甲醛(57.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在50℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1pp,将1pp溶解于6mL乙醇/CH2Cl2=5/1的混合溶液中,加入60μL 1M NaOH溶液,室温搅拌2h,然后加水。用二氯甲烷萃取两次,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到粗品,粗品用硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得1p(25mg,18%)。产物结果鉴定:m.p.97-99℃;(c=0.25in CHCl3);1H NMR(600MHz,CDCl3)δ0.88(t,J=7.1Hz,3H),1.36(t,J=7.2Hz,3H),1.53(t,J=7.3Hz,1H),1.81(dd,J=6.4,15.4Hz,1H),2.55-2.65(m,2H),3.27(s,3H),3.66(s,3H),3.82-3.94(m,2H),4.19(d,J=7.2Hz,1H),4.33(d,J=11Hz,1H),4.34-4.41(m,2H),4.79(d,J=10.8Hz,1H),5.06(s,1H),6.93(d,J=1.8Hz,1H),7.06(dd,J=1.8,8.1Hz,1H),7.30(t,4.0Hz,2H),7.49(t,J=7.7Hz,1H),7.57(d,J=7.8Hz,1H),7.89(d,J=7.8Hz,1H),7.97(s,1H),8.39(s,1H).13C NMR(151MHz,CDCl3)δ13.30,13.80,34.12,39.38,48.70,51.15,53.30,56.80,60.44,62.01,62.66,62.91,67.23,77.85,101.97,110.38,122.26,123.28,124.69,125.09,125.56,127.85,128.90,130.64,130.89,132.12,134.93,136.92,142.54,142.66,151.72,167.64,168.69,170.00,175.04.HRMS(ESI):Calcd.for C35H35O9N2ClF3[M+H]+:719.1978;found:719.1973。
实施例34
本实施例所述1q的制备方法:
在10mL圆底烧瓶中加入甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯(85.8mg,0.2mmol)、BN(10mg,0.02mmol)、3-三氟甲氧基苯甲醛(57.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在50℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1qq,将1qq溶解于6mL乙醇/CH2Cl2=5/1的混合溶液中,加入60μL 1M NaOH溶液,室温搅拌2h,然后加水。用二氯甲烷萃取两次,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到粗品,粗品用硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得1q(24mg,18%)。产物结果鉴定:m.p.82-84℃;(c=0.32in CHCl3);1H NMR(600MHz,CDCl3)δ0.89(t,J=7.1Hz,3H),1.37(t,J=7.2Hz,3H),1.56(t,J=7.4Hz,1H),1.80(dd,J=7.3,16.3Hz,1H),2.54-2.61(m,1H),2.63(dd,J=7.8,15.6Hz,1H),3.28(s,3H),3.66(s,3H),3.81-3.96(m,2H),4.21(d,J=7.1Hz,1H),4.30(d,J=10.8Hz,1H),4.32-4.41(m,2H),4.73(d,J=10.8Hz,1H),5.02(s,1H),6.93(d,J=1.8Hz,1H),7.07(dd,J=1.8,8.1Hz,1H),7.16(d,J=8.2Hz,1H),7.29(s,1H),7.31(s,1H),7.39(t,J=8.1Hz,1H),7.60-7.64(m,2H).13C NMR(151MHz,CDCl3)δ13.32,13.82,34.01,39.36,48.70,51.13,53.63,56.81,61.96,62.67,62.83,67.20,77.83,101.95,110.29,110.44,119.66,120.36,121.36,122.29,125.61,125.97,127.90,129.79,131.92,134.89,136.91,142.57,143.94,149.43,151.72,167.66,168.70,170.03,173.78.HRMS(ESI):Calcd.for C35H35ClF3N2O10[M+H]+:735.1927;found:735.1910。
实施例35
本实施例所述1r的制备方法:
在10mL圆底烧瓶中加入甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯(85.8mg,0.2mmol)、BN(10mg,0.02mmol)、3-氟-4-氯苯甲醛(49.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在50℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1rr,将1rr溶解于6mL乙醇/CH2Cl2=5/1的混合溶液中,加入60μL 1M NaOH溶液,室温搅拌2h,然后加水。用二氯甲烷萃取两次,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到粗品,粗品用硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得1r(25mg,18%)。产物结果鉴定:m.p.102-104℃;(c=0.36in CHCl3);1H NMR(600MHz,CDCl3)δ0.88(t,J=7.1Hz,3H),1.35(t,J=7.2Hz,3H),1.59(t,J=7.4Hz,1H),1.81(dd,J=7.4,16.4Hz,1H),2.60(ddd,J=2.5,8.0,11.1Hz,1H),2.65(dd,J=7.8,15.6Hz,1H),3.31(s,3H),3.67(s,3H),3.82-3.93(m,2H),4.22(d,J=7.2Hz,1H),4.30(d,J=10.7Hz,1H),4.32-4.39(m,2H),4.77(d,J=10.7Hz,1H),5.07(s,1H),6.93(d,J=1.8Hz,1H),7.07(dd,J=1.8,8.1Hz,1H),7.27(d,J=8.1,1H),7.32(s,1H),7.50(d,J=8.3Hz,1H),7.82(dd,J=1.7,8.3Hz,1H),8.07(d,J=1.6Hz,1H),8.22(brs.,1H).13CNMR(151MHz,CDCl3)δ13.29,13.81,34.18,39.36,48.80,51.18,53.69,56.81,60.43,62.06,62.69,62.83,66.57,77.73,101.85,110.41,121.99,122.29,123.80,125.48,127.07,127.64,128.23,131.48,131.95,132.56,135.03,136.68,140.90,142.61,151.71,167.59,168.56,169.87,174.80.HRMS(ESI):Calcd.forC35H34Cl2F3N2O9[M+H]+:753.1568;found:753.1562。
实施例36
本实施例所述1s的制备方法:
在10mL圆底烧瓶中加入甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯(85.8mg,0.2mmol)、BN(10mg,0.02mmol)、4-氯-3-氟-苯甲醛(69.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在50℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1ss,将1ss溶解于6mL乙醇/CH2Cl2=5/1的混合溶液中,加入60μL 1M NaOH溶液,室温搅拌2h,然后加水。用二氯甲烷萃取两次,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到粗品,粗品用硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得1s(21mg,14%)。产物结果鉴定:m.p.102-104℃;(c=0.36in CHCl3);1H NMR(600MHz,CDCl3)δ0.88(t,J=7.1Hz,3H),1.35(t,J=7.2Hz,3H),1.59(t,J=7.4Hz,1H),1.81(dd,J=7.4,16.4Hz,1H),2.60(ddd,J=2.5,8.0,11.1Hz,1H),2.65(dd,J=7.8,15.6Hz,1H),3.31(s,3H),3.67(s,3H),3.82-3.93(m,2H),4.22(d,J=7.2Hz,1H),4.30(d,J=10.7Hz,1H),4.32-4.39(m,2H),4.77(d,J=10.7Hz,1H),5.07(s,1H),6.93(d,J=1.8Hz,1H),7.07(dd,J=1.8,8.1Hz,1H),7.27(d,J=8.1,1H),7.32(s,1H),7.50(d,J=8.3Hz,1H),7.82(dd,J=1.7,8.3Hz,1H),8.07(d,J=1.6Hz,1H),8.22(brs.,1H).13C NMR(151MHz,CDCl3)δ13.29,13.81,34.18,39.36,48.80,51.18,53.69,56.81,60.43,62.06,62.69,62.83,66.57,77.73,101.85,110.41,121.99,122.29,123.80,125.48,127.07,127.64,128.23,131.48,131.95,132.56,135.03,136.68,140.90,142.61,151.71,167.59,168.56,169.87,174.80.HRMS(ESI):Calcd.forC35H34Cl2F3N2O9[M+H]+:753.1568;found:753.1562。
实施例37
本实施例所述1t的制备方法:
在10mL圆底烧瓶中加入甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯(85.8mg,0.2mmol)、BN(10mg,0.02mmol)、2-三氟甲基苯甲醛(48.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在50℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1tt,将1tt溶解于6mL乙醇/CH2Cl2=5/1的混合溶液中,加入60μL 1M NaOH溶液,室温搅拌2h,然后加水。用二氯甲烷萃取两次,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到粗品,粗品用硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得1t(22mg,15%)。产物结果鉴定:m.p.105-106℃;(c=0.53in CHCl3);1H NMR(600MHz,CDCl3)δ0.9(t,J=7.1Hz,3H),1.41(t,J=7.2Hz,3H),2.44-2.52(m,1H),2.54(dd,J=8.0,16.0Hz,1H),3.45(s,3H),3.63(s,3H),3.78-3.86(m,1H),3.87-3.95(m,1H),4.17(d,J=7.5Hz,1H),4.37(q,J=7.1Hz,2H),4.60(d,J=10.8Hz,1H),4.76(s,1H),5.09(d,J=10.9Hz,1H),6.95(d,J=1.8Hz,1H),7.11(dd,J=1.9,8.1Hz,1H),7.24(d,J=8.1Hz,1H),7.41(t,J=7.6Hz,1H),7.62(d,J=7.7Hz,1H),7.70(t,J=7.6Hz,1H),8.68(d,J=8.0Hz,1H),8.82(s,1H).13C NMR(151MHz,CDCl3)δ13.31,13.91,33.50,39.49,48.33,51.14,52.85,57.27,60.47,61.74,62.03,62.51,62.67,77.76,102.64,110.48,122.64,123.49,125.30,125.43,128.04,128.92.129.12,130.52,130.68,132.63,134.91,135.76,139.66,142.75,151.64,167.76,168.53,169.79,175.68.HRMS(ESI):Calcd.for C35H35ClF3N2O9[M+H]+:719.1978;found:719.1962。
实施例38
本实施例所述1u的制备方法:
在10mL圆底烧瓶中加入甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯(85.8mg,0.2mmol)、BN(10mg,0.02mmol)、3-溴苯甲醛(48.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在50℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1uu,将1uu溶解于6mL乙醇/CH2Cl2=5/1的混合溶液中,加入60μL 1M NaOH溶液,室温搅拌2h,然后加水。用二氯甲烷萃取两次,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到粗品,粗品用硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得1u(23mg,15%)。产物结果鉴定:m.p.87-89℃;(c=0.21in CHCl3);1H NMR(600MHz,CDCl3)δ0.88(t,J=7.1Hz,3H),1.41(t,J=7.2Hz,3H),1.59(t,J=7.5Hz,1H),1.78-1.83(m,1H),2.59(ddd,J=2.6,8.2,16.7,1H),2.64(dd,J=7.8,15.6Hz,1H),3.30(s,3H),3.67(s,3H),3.83-3.94(m,2H),4.20(d,J=7.3Hz,1H),4.29(d,J=10.8Hz,1H),4.38(q,J=7.2Hz,2H),4.68(d,J=10.8Hz,1H),4.99(s,1H),6.93(d,J=1.8Hz,1H),7.06(dd,J=1.9,8.1Hz,1H),7.22(t,J=7.8Hz,1H),7.28(s,1H),7.32(s,1H),7.43(dd,J=0.9,7.9Hz,1H),7.54(d,J=7.8Hz,1H),7.94(s,1H),8.35(s,1H).13C NMR(151MHz,CDCl3)δ13.32,13.94,34.12,39.42,48.75,51.18,53.57,56.94,61.99,62.72,62.87,67.34,77.85,102.08,110.36,110.44,122.26,122.67,125.58,126.13,127.92,129.98,130.78,131.02,131.80,134.87,137.03,142.60,143.70,151.77,167.71,168.72,170.04,175.11.HRMS(ESI):Calcd.for C34H35BrClN2O9[M+H]+:729.1209;found:729.1190。
实施例39
本实施例所述1v的制备方法:
在10mL圆底烧瓶中加入甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯(85.8mg,0.2mmol)、BN(10mg,0.02mmol)、3-氯苯甲醛(48.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在50℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1vv,将1vv溶解于6mL乙醇/CH2Cl2=5/1的混合溶液中,加入60μL 1M NaOH溶液,室温搅拌2h,然后加水。用二氯甲烷萃取两次,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到粗品,粗品用硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化,得1v(24mg,14%)。产物结果鉴定:m.p.104-105℃;(c=0.32in CHCl3);1H NMR(600MHz,CDCl3)δ0.88(t,J=7.1Hz,3H),1.41(t,J=7.2Hz,3H),1.58(t,J=7.5Hz,1H),1.79(dd,J=7.4,16.5Hz,1H),2.59(ddd,J=2.5,8.0,11.2Hz,1H),2.64(dd,J=7.8,15.7Hz,1H),3.30(s,3H),3.66(s,3H),3.83-3.94(m,2H),4.19(d,J=7.3Hz,1H),4.30(d,J=10.8,1H),4.38(q,J=7.2Hz,2H),4.68(d,J=10.8Hz,1H),4.99(s,1H),6.93(d,J=1.8Hz,1H),7.06(dd,J=1.8,8.1Hz,1H),7.27(s,1H),7.29(s,1H),7.31(s,1H),7.47-7.51(m,1H),7.80(s,1H),8.37(s,1H).13C NMR(151MHz,CDCl3)δ13.32,13.91,34.12,39.43,48.73,51.18,53.46,53.57,56.94,60.46,61.98,62.72,62.87,67.43,77.88,102.11,110.35,110.43,122.26,125.59,125.71,127.86,127.94,128.10,129.67,131.71,134.45,134.87,137.07,142.63,143.45,151.76,167.70,168.73,170.07,175.14.HRMS(ESI):Calcd.for C34H35Cl2N2O9[M+H]+:685.1714;found:685.1699。
实施例40
本实施例所述1w的制备方法:
在10mL圆底烧瓶中加入甲基(1R)-7-(((E)-1-乙酰基-6-氯-2-氧吲哚-3-亚基)甲基)-1-甲氧基-1,4a,5,7a-四氢环戊[c]吡喃-4-羧酸酯(85.8mg,0.2mmol)、BN(10mg,0.02mmol)、3-氟苯甲醛(45.3mg,0.2mmol)、4A分子筛(300mg)和2mL干燥的二氯甲烷中在25℃搅拌。再加入氨基丙二酸二乙酯(35mg,0.2mmol),反应混合物在50℃搅拌48h,反应完成后,通过柱色谱纯化(洗脱液:石油醚:乙酸乙酯=5:1,V/V)得1ww,将1ww溶解于6mL乙醇/CH2Cl2=5/1的混合溶液中,加入60μL 1M NaOH溶液,室温搅拌2h,然后加水。用二氯甲烷萃取两次,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到粗品,粗品用硅胶柱色谱(石油醚:乙酸乙酯=2:1,V/V)纯化得1w(21mg,15%)。产物结果鉴定:m.p.96-98℃;(c=0.31in CHCl3);1H NMR(600MHz,CDCl3)δ0.88(t,J=7.1Hz,3H),1.39(t,J=7.2Hz,3H),1.56(t,J=7.5Hz,1H),1.78(dd,J=7.4,16.1Hz,1H),2.58(ddd,J=2.5,8.0,11.2Hz,1H),2.62(dd,J=7.9,15.7Hz,1H),3.29(s,3H),3.66(s,3H),3.83-3.93(m,2H),4.18(d,J=7.3Hz,1H),4.30(d,J=10.8Hz,1H),4.37(q,J=7.2Hz,2H),4.69(d,J=10.8Hz,1H),4.96(s,1H),6.92(d,J=1.8Hz,1H),6.99(td,J=2.1,8.2Hz,1H),7.06(dd,J=1.8,8.1Hz,1H),7.30(s,2H),7.35(d,J=7.7Hz,1H),7.58(d,J=10.0Hz,1H),8.53(d,J=2.7Hz,1H).13CNMR(151MHz,CDCl3)δ13.31,13.88,34.08,39.44,48.67,51.17,53.59,56.93,60.46,61.96,62.70,62.89,67.54,77.89,102.17,110.35,110.40,114.50,114.66,114.83,114.97,122.25,123.27,125.60,127.99,129.81,129.85,131.47,134.84,137.16,142.71,144.02,144.07,151.76,162.65,163.88,167.71,168.75,170.14,171.28,175.25.HRMS(ESI):Calcd.for C34H35ClFN2O9[M+H]+:669.2010;found:669.1994。
实施例41本发明化合物对3种肿瘤细胞的抑制活性测试
采用MTT法,以人非小细胞肺癌HCC827、人高转移性肝癌细胞MHCC97H和人神经母细胞瘤SHSY-5Y为筛选对象,分别测试本发明化合物在体外对三种肿瘤细胞株生长的抑制作用。具体实验步骤如下:
1、接种细胞:用含10%胎牛血清的培养液(DMEM或者RMPI1640)配成单个细胞悬液,以每孔3000~15000个细胞接种到96孔。
2、加入待测化合物溶液:化合物用DMSO溶解,每种处理均设3个复孔。
3、显色:37摄氏度培养48小时后,细胞弃孔内培养液,每孔加MTT溶液和培养液。继续孵育2~4小时,使反应充分进行后测定光吸收值。
4.比色:选择492nm波长,多功能酶标仪读取各孔光吸收值,记录结果。利用IC50计算器计算得IC50。结果如表1所示结果见表1:
表1本发明化合物在体外的抗肿瘤活性测试结果
由表1可知,大部分化合物对人非小细胞肺癌HCC827、人高转移性肝癌细胞MHCC97H和人神经母细胞瘤SHSY-5Y具有一定的抑制作用,且对三种肿瘤细胞的抑制活性优于京尼平,特别是对人神经母细胞瘤SHSY-5Y具有较强的抑制作用,
尤其是化合物1g,1j,1l。说明该类化合物对神经母细胞瘤SHSY-5Y的选择性更强。含三氟甲基的化合物对三种肿瘤细胞具有较强的抑制作用,如化合物1g,1i,1j,1k,1l。说明三氟甲基对这类化合物的抗肿瘤活性具有重要的作用。
最后所应说明的是:以上实施例仅用以说明而非限制本发明的技术方案,尽管参照上述实施例对本发明进行了详细说明,本领域的普通技术人员应该理解:依然可以对本发明进行修改或者等同替换,而不脱离本发明的精神和范围的任何修改或局部替换,其均应涵盖在本发明的权利要求范围当中。
Claims (6)
6.根据权利要求1~3任一项所述基于环烯醚萜苷元的螺环吲哚酮类化合物在制备抗耐药肿瘤药物中的应用。
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