CN114805378A - 一种环氧化二苯并呫吨类抗癌先导化合物及其制备方法 - Google Patents
一种环氧化二苯并呫吨类抗癌先导化合物及其制备方法 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及环氧化二苯并呫吨类抗癌先导化合物的制备方法,属于有机合成技术领域。
背景技术
癌症是世界上最致命的病,很多癌症都具有较高的发病率和死亡率。特别是在亚洲,有数百万人死于这种疾病。目前,化疗仍是许多癌症的主要治疗方法之一。然而,化疗存在副作用高、耐药严重等缺陷,影响化疗疗效,甚至导致化疗失败。因此,寻找高效、低毒的新型抗癌药物用于临床治疗迫在眉睫。二苯并恶蒽是一类具有抗菌、抗炎、抗病毒活性的杂环化合物。由于二苯并恶蒽类化合物的药理应用,近年来越来越多的化学和药物研究者对苯并呫吨化合物类的进行广泛研究。王秀珍陈泳等人报道合成二苯并呫吨化合物并发现该类化合物具有抗肿瘤活性以及诱导肿瘤细胞发生凋亡。说明二苯并[a,kl]呫吨化合物的抗肿瘤生物活性比较显著,具有良好的抗肿瘤药物开发与应用前景,但是目前化合物还存在很多问题,水溶性和低毒性不够完善,因此需要解决此类问题使化合物能更好的开发应用。
发明内容
本发明的目的是提供一种活性显著、毒性较低的的抗癌先导化合物环氧化二苯并呫吨类抗癌先导化合物。
本发明的第二个目的是提供该物质的合成方法,合成过程中使用醇和过氧化氢作为溶剂和催化剂,催化剂简单易得且催化效果突出,反应条件温和,后处理简单产率高
本发明提供的第一个技术方案为:
一种环氧化二苯并呫吨类抗癌先导化合物,该化合物结构如下:
R选自:CH3或者CH2CH3
R3选自:H或者COOCH3或者CONH或者CONH(CH2)2OH
R4选自:COOCH3或者CONH2或者CONH(CH2)2OH。
进一步的,上述的环氧化二苯并呫吨类抗癌先导化合物的制备方法,依次包括下述步骤:
3)将0.5mmol反应底物加进20mL的溶剂中使原料恰好溶解,加入NaOH使溶液PH为8-9;
4)再加入3~4滴质量分数为30%的H2O2,室温下搅拌反应,TLC跟踪至原料消失,过滤,得到产物。
进一步的,上述的环氧化二苯并呫吨类抗癌先导化合物的制备方法,所述的反应底物为:
R选自:CH3或者CH2CH3
R1选自:H或者COOCH3或者CN或者CONH(CH2)2OH
R2选自:COOCH3或者CN或者CONH(CH2)2OH。
进一步的,上述的环氧化二苯并呫吨类抗癌先导化合物的制备方法,所述的溶剂为甲醇。
进一步的,上述的环氧化二苯并呫吨类抗癌先导化合物的制备方法,所述的溶剂为甲醇和二氧六环的混合物。
本发明在采用上述技术方案后,其具有的有益效果为:
本发明提供的技术方案对二苯并[a,kl]呫吨2,3位的双键进行环氧化生成环氧化合物,形成新的化合物,作为抗癌先导化合物,具有显著活性、低毒性,为能够更好的探究二苯并呫吨的药物开发应用做基础工作。
本发明提供的技术方案合成过程中使用醇和过氧化氢作为溶剂和催化剂,催化剂简单易得且催化效果突出,反应条件温和,后处理简单产率高
附图说明
图1是实施例1产物的HNMR;
图2是实施例1产物的CNMR;
图3是实施例1产物的HRMS;
图4是实施例2产物的HNMR;
图5是实施例2产物的CNMR;
图6是实施例2产物的HRMS;
图7是实施例3产物的HNMR;
图8是实施例3产物的CNMR;
图9是实施例3产物的HRMS;
图10是实施例4产物的HNMR;
图11是实施例4产物的CNMR;
图12是实施例4产物的HRMS;
图13是实施例5产物的HNMR;
图14是实施例5产物的CNMR;
图15是实施例5产物的HRMS;
图16是实施例6产物的HNMR;
图17是实施例6产物的CNMR;
图18是实施例6产物的HRMS;
图19是实施例10产物的HNMR;
图20是实施例10产物的CNMR;
图21是实施例11产物的HNMR;
图22是实施例11产物的CNMR;
图23是实施例12产物的HNMR;
图24是实施例12产物的CNMR;
图25是实施例12产物的HRMS。
具体实施方式
下面结合具体实施方式,对本发明的技术方案作进一步的详细说明,但不构成对本发明的任何限制。
本申请所涉及的反应方程式:
R选自:CH3、CH2CH3
R1选自:H、COOCH3、CN、CONH(CH2)2OH
R2选自:COOCH3、CN、CONH(CH2)2OH
R3选自:H、COOCH3、CONH2、CONH(CH2)2OH
R4选自:COOCH3、CONH2、CONH(CH2)2OH
实施例1
本实施例提供1-氧代-2,3-环氧-5,11-二甲酰胺基-13c-甲氧基-1,13c-二氢-二苯并[a,kl]-呫吨(11a)的制备方法。
起始物A:无水甲醇:30%H2O2的摩尔比为1:1:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-5,11-二甲酰胺基-13c-甲氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的甲醇,用10mg NaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应3h,过滤,滤渣为产物。
表征数据如下(参阅谱图1、图2、图3):
黄白色固体,Yield,73.8%,m.p.157.8-158.2℃,1H-NMR(500MHz,DMSO-d6)δ:8.50(s,1H),8.19(br,1H),8.14(d,J=9Hz,1H),8.12(d,J=1.5Hz,1H),8.06(br,1H),7.91(d,J=1Hz,2H),7.87(d,J=1.5Hz,1H),7.63(br,1H),7.48(d,J=9Hz,1H),7.39(br,1H),4.71(d,J=4.5Hz,1H),4.19(d,J=4.5Hz,1H),2.68(s,3H).13C-NMR(125MHz,DMSO-d6)δ:202.5,168.0,166.3,152.2,151.5,137.8,134.7,133.3,133.1,130.8,130.5,128.7,127.7,125.6,124.8,119.7,117.9,116.3,108.5,77.1,58.5,58.5,52.8,50.7.IR(KBr,cm-1)ν:3398,1726,1676,1577,1473,1396,1242,1053.HRMS calcd for C23H17N2O6[M+H]+417.10866,found[M+H]+417.10811。
实施例2
本实施例提供1-氧代-2,3-环氧-5,11-二甲氧羰基-13c-甲氧基-1,13c-二氢-二苯并[a,kl]-呫吨(11b)
起始物A:无水甲醇:30%H2O2的摩尔比为1:1:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-5,11-二甲氧羰基-13c-甲氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的甲醇,用10mg NaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应3h,过滤,滤渣为产物。
表征数据如下(参阅谱图4、图5、图6):
黄白色固体,Yield,67.0%,m.p.162.3-165.1℃,1H-NMR(500MHz,DMSO-d6)δ:8.67(s,1H),8.30(d,J=9Hz,1H),8.24(d,J=1.5Hz,1H),7.97(d,J=3Hz,2H),7.87(d,J=1.5Hz,1H),7.53(d,J=9Hz,1H),4.49(d,J=4.5Hz,1H),4.24(d,J=4.5Hz,1H),3.94(s,3H),3.93(s,3H).13C-NMR(125MHz,DMSO-d6)δ:202.2,166.4,165.0,152.2,152.1,135.6,134.2,133.9,133.1,131.3,130.5,128.3,126.6,126.1,125.4,121.7,118.3,118.2,108.6,77.0,58.2,53.1,52.6,52.5,50.9.IR(KBr,cm-1)ν:3448,2952,1718,1629,1577,1437,1291,1269,1199,1076,770.HRMS calcd for C25H19O8[M+H]+447.10799,found[M+H]+447.10744.
实施例3
本实施例提供1-氧代-2,3-环氧-5,11-二(N-羟乙基甲酰胺基)-13c-甲氧基-1,13c-二氢-二苯并[a,kl]-呫吨(11c)
起始物A:无水甲醇:30%H2O2的摩尔比为1:1:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-5,11-二(N-羟乙基甲酰胺基)-13c-甲氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的甲醇,用10mgNaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应3h,过滤,滤渣为产物。
表征数据如下(参阅谱图7、图8、图9):
黄白色固体,Yield,61.0%,m.p.172.3-174.5℃,1H-NMR(500MHz,DMSO-d6)δ:8.76(d,J=5.5Hz,1H),8.61(d,J=5.5Hz,1H),8.48(s,1H),8.15(d,J=9Hz,1H),8.11(d,J=1.5Hz,1H),7.90(d,J=9Hz,2H),7.88(dd,J=8Hz 1.5Hz,1H),7.49(d,J=9Hz,1H),4.79(q,J=5.5Hz,2H),4.73(d,J=4Hz,1H),4.21(d,J=4Hz,1H),3.57-3.54(m,4H),3.42-3.37(m,4H),2.66(s,3H).13C-NMR(125MHz,DMSO-d6)δ:202.4,166.4,164.7,152.2,151.5,138.0,134.8,133.3,133.0,131.1,130.5,128.3,127.8,125.4,124.6,119.6,118.0,116.1,108.5,77.1,60.1,59.9,58.5,52.8,50.7,42.7,42.6.IR(KBr,cm-1)ν:3364,2941,1726,1655,1545,1433,1390,1301,1050.HRMS calcd for C27H25N2O8[M+H]+505.16109,found[M+H]+505.16054.
实施例4
本实施例提供1-氧代-2,3-环氧-11-甲酰胺基-13c-甲氧基-1,13c-二氢-二苯并[a,kl]-呫吨(11d)
起始物A:无水甲醇:30%H2O2的摩尔比为1:1:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-11-甲酰胺基-13c-甲氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的甲醇,用10mg NaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应3h,过滤,滤渣为产物。
表征数据如下(参阅谱图10、图11、图12):
黄白色固体,Yield,61.8%,m.p.159.0-162.3℃,1H-NMR(500MHz,DMSO-d6)δ:8.47(s,1H),8.09(d,J=9Hz,2H),7.87(d,J=1.5Hz,2H),7.62(q,J=7Hz,2H),7.45(t,J=9Hz,2H),7.39(dd,J=7.5Hz 2Hz,1H),4.65(d,J=4.5Hz,1H),4.16(d,J=4Hz,1H),2.62(s,3H).13C-NMR(125MHz,DMSO-d6)δ:203.1,168.2,152.5,151.6,134.5,133.3,132.3,130.8,130.5,128.9,127.9,126.9,124.8,118.1,117.7,108.8,79.6,77.3,58.8,53.0,50.7,49.1.IR(KBr,cm-1)ν:3458,3161,1719,1681,1629,1583,1458,1393,1272,1256,803,760.HRMS calcd for C22H16NO5[M+H]+374.10285,found[M+H]+374.10230.
实施例5
本实施例提供1-氧代-2,3-环氧-11-甲氧羰基-13c-甲氧基-1,13c-二氢-二苯并[a,kl]-呫吨(11e)
起始物A:无水甲醇:30%H2O2的摩尔比为1:1:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-11-甲氧羰基-13c-甲氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的甲醇,用10mg NaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应4h,过滤,滤渣为产物。
表征数据如下(参阅谱图13、图14、图15):
黄白色固体,Yield,74.2%,m.p.170.2-171.1℃,1H-NMR(300MHz,CDCl3)δ:8.49(d,J=1.5Hz,1H),7.98(d,J=9Hz,1H),7.95(d,J=1.8Hz,1H),7.89(d,J=9Hz,1H),7.43(t,J=8.1Hz,1H),7.33(dd,J=7.5Hz 1.5Hz,1H),7.25(d,J=8.7Hz,1H),7.18(dd,J=8.4Hz 1.5Hz,1H),4.29(d,J=4.2Hz,1H),3.98(d,J=4.2Hz,1H),3.91(s,3H),2.74(s,3H).13C-NMR(75MHz,CDCl3)δ:201.7,167.0,152.8,152.3,134.6,133.8,133.0,131.3,131.1,130.3,127.9,126.2,125.9,125.5,117.9,117.5,59.1,53.3,52.2,50.8.IR(KBr,cm-1)ν:3409,2951,1712,1630,1459,1398,1290,1263,1199,798.HRMS calcd for C23H17O6[M+H]+389.10251,found[M+H]+389.10196.
实施例6
本实施例提供1-氧代-2,3-环氧-11-(N-羟乙基甲酰胺基)-13c-甲氧基-1,13c-二氢-二苯并[a,kl]-呫吨(11f)
起始物A:无水甲醇:30%H2O2的摩尔比为1:1:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-11-(N-羟乙基甲酰胺基)-13c-甲氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的甲醇,用10mg NaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应3h,过滤,滤渣为产物。
表征数据如下(参阅谱图16、图17、图18):
黄白色固体,Yield,95.0%,m.p.117.6-119.7℃,1H-NMR(500MHz,MeOD-d4)δ:8.39(s,1H),8.04(d,J=9Hz,1H),8.02(d,J=9Hz,1H),7.85(dd,J=9Hz 1Hz,1H),7.57-7.42(m,2H),7.40(d,J=9Hz,1H),7.33(d,J=7Hz,1H),4.49(d,J=4Hz,1H),4.03(d,J=4Hz,1H),3.78(t,J=5.5Hz,2H),3.33(d,J=5.5Hz,2H),2.75(s,3H).13C-NMR(125MHz,MeOD-d4)δ:201.9,168.6,152.6,151.7,134.1,133.5,132.3,131.1,130.4,129.9,127.8,127.7,125.7,123.2,117.4,117.3,116.9,108.5,77.1,60.1,58.4,52.7,49.4,42.1.IR(KBr,cm-1)ν:3422,2932,17193,1637,1542,1458,1396,1270,1069.HRMS calcd for C24H20NO6[M+H]+418.12906,found[M+H]+418.12851.
实施例7
本实施例提供1-氧代-2,3-环氧-5,11-二甲酰胺基-13c-乙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(12a)
起始物A:无水乙醇:30%H2O2的摩尔比为1:0.686:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-5,11-二甲酰胺基-13c-乙氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的乙醇,用10mg NaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应1.5h,过滤,滤渣为产物。
表征数据如下:
黄白色固体,Yield,92.1%,m.p.166.6-167.9℃,1H-NMR(300MHz,DMSO-d6)δ:8.55(d,J=6.0Hz,1H),8.29(s,1H),8.20(d,J=6.0Hz,1H),8.17(d,J=6.0Hz,1H),8.14(d,J=3.0Hz,1H),8.00(d,J=6.0Hz,1H),7.97(d,J=3.0Hz,1H),7.92(d,J=6.0Hz,1H),7.76(s,1H),7.53(d,J=9.0Hz,1H),7.50(s,1H),4.79(d,J=6.0Hz,1H),4.27(d,J=6.0Hz,1H),2.97-2.93(q,J=12.0Hz,1H),2.74-2.70(q,J=12.0Hz,1H),0.90-0.86(t,J=12.0Hz,3H).13C-NMR(125MHz,DMSO-d6)δ:202.8,168.2,166.6,151.2,150.3,137.9,134.9,133.8,132.6,128.9,128.7,128.5,124.8,120.7,118.4,116.8,115.8,113.0,76.7,73.4,71.0,53.7,52.9,15.5.IR(KBr,cm-1)ν:3353,3198,2925,2853,1663,1630,1397,1244,1208,1173,1011,801,669,508.HRMS calcd for C24H18N2NaO6[M+Na]+453.10626,found[M+Na]+453.10571.
实施例8
本实施例提供1-氧代-2,3-环氧-5,11-二甲氧羰基-13c-乙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(12b)
起始物A:无水乙醇:30%H2O2的摩尔比为1:0.686:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-5,11-二甲氧羰基-13c-乙氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的乙醇,用10mg NaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应2.5h,过滤,滤渣为产物。
表征数据如下:
黄白色固体,Yield,91.8%,m.p.179.6-181.6℃,1H-NMR(500MHz,DMSO-d6)δ:8.77(s,1H),8.41(d,J=10.0Hz,1H),8.34(s,1H),8.13(d,J=10.0Hz,1H),8.08-8.05(dd,J=5.0Hz 5.0Hz,1H),7.96(s,1H),7.64(d,J=10.0Hz,1H),4.96(d,J=5.0Hz,1H),4.34(d,J=5.0Hz,1H),4.03(t,J=10.0Hz,6H),3.01-2.98(q,J=15.0Hz,1H),2.79-2.74(q,J=25.0Hz,1H),0.94-0.91(t,J=15.0Hz,3H).13C-NMR(125MHz,DMSO-d6)δ:202.1,166.6,165.2,151.9,135.7,133.9,131.5,130.7,128.5,126.7,125.4,118.4,118.3,76.6,59.4,58.4,53.3,52.7,52.7,15.5.IR(KBr,cm-1)ν:3432,2954,1725,1578,1437,1334,1263,1226,1101,1078,1049,841,768,631.HRMS calcd for C26H21O8[M+H]+461.12364,found[M+H]+461.12302.
实施例9
本实施例提供1-氧代-2,3-环氧-5,11-二(N-羟乙基甲酰胺基)-13c-乙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(12c)
起始物A:无水乙醇:30%H2O2的摩尔比为1:0.686:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-5,11-二(N-羟乙基甲酰胺基)-13c-乙氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的乙醇,用10mgNaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应6h,过滤,滤渣为产物。
表征数据如下:
黄色固体,Yield,78.5%,m.p.177.5-179.7℃,1H-NMR(500MHz,DMSO-d6)δ:8.62(d,J=5.0Hz,1H),8.47(s,1H),8.45-8.43(dd,J=10.0Hz,1H),8.09(d,J=10.0Hz,1H),8.06(s,1H),7.99(d,J=5.0Hz,1H),7.87(s,1H),7.84(d,J=10.0Hz,1H),7.45(d,J=5.0Hz,1H),4.80(d,J=5.0Hz,1H),4.68(s,2H),4.28(d,J=5.0Hz,1H),3.57(m,4H),3.41-3.38(q,J=15.0Hz,4H),2.93-2.90(q,J=15.0Hz,1H),2.70-2.67(q,J=15.0Hz,1H),0.83-0.80(t,J=15.0Hz,3H).13C-NMR(125MHz,DMSO-d6)δ:203.2,166.7,165.1,152.1,150.2,149.2,134.9,132.6,130.6,130.5,130.1,128.6,128.0,125.4,124.6,118.3,116.5,109.5,71.0,60.3,60.1,52.9,42.9,42.7,31.8,29.6,22.6,15.5.IR(KBr,cm-1)ν:3367,2922,2850,1727,1645,1541,1302,1277,1064,829,818,731,621.HRMS calcd forC28H26N2NaO8[M+Na]+541.15869,found[M+Na]+541.15844.
实施例10
本实施例提供1-氧代-2,3-环氧-11-甲酰胺基-13c-乙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(12d)
起始物A:无水乙醇:30%H2O2的摩尔比为1:0.686:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-11-甲酰胺基-13c-乙氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的乙醇,用10mg NaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应5h,过滤,滤渣为产物。
表征数据如下(参阅谱图19、图20):
黄白色固体,Yield,66.1%,m.p.168.1-172.3℃,1H-NMR(500MHz,DMSO-d6)δ:8.48(s,1H),8.12(s,1H),8.10(s,1H),7.92(d,J=10.0Hz,1H),7.91(d,J=10.0Hz,1H),7.65(d,J=5.0Hz,1H),7.62(d,J=5.0Hz,1H),7.48(d,J=5.0Hz,1H),7.46(d,J=10.0Hz,1H),7.41(s,1H),7.40(s,1H),7.39(d,J=5.0Hz,1H),4.67(d,J=5.0Hz,1H),4.18(d,J=5.0Hz,1H),2.90-2.87(q,J=15.0Hz,1H),2.67-2.63(q,J=20.0Hz,1H),0.83-0.81(t,J=10.0Hz,3H).13C-NMR(125MHz,DMSO-d6)δ:203.1,168.2,152.3,151.3,134.5,133.4,133.2,132.2,130.7,130.5,128.9,127.9,126.8,124.7,118.1,118.1,117.7,109.7,76.7,59.0,58.9,53.0,21.3,15.5,14.6.IR(KBr,cm-1)ν:3430,3186,1729,1675,1615,1457,1393,1269,1251,1053,1000,810,755.HRMS calcd for C23H17NNaO5[M+Na]+410.10044,found[M+Na]+410.09989.
实施例11
本实施例提供1-氧代-2,3-环氧-11-甲氧羰基-13c-乙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(12e)
起始物A:无水乙醇:30%H2O2的摩尔比为1:0.686:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-11-甲氧羰基-13c-乙氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的乙醇,用10mg NaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应1.2h,过滤,滤渣为产物。
表征数据如下(参阅谱图21、图22):
黄白色固体,Yield,92.4%,m.p.171.1-174.6℃,1H-NMR(500MHz,DMSO-d6)δ:8.75(s,1H),8.37(d,J=10.0Hz,1H),8.11(d,J=5.0Hz,1H),8.06(d,J=10.0Hz,1H),7.75(d,J=5.0Hz,1H),7.72(d,J=5.0Hz,1H),7.61(d,J=10.0Hz,1H).7.51-7.50(dd,J=5.0Hz5.0Hz,1H),4.77(d,J=5.0Hz,1H),4.28(d,J=5.0Hz,1H),4.02(s,3H),3.00-2.97(q,J=15.0Hz,1H),2.77-2.74(q,J=15.0Hz,1H),0.98-0.95(t,J=15.0Hz,3H).13C-NMR(125MHz,DMSO-d6)δ:203.1,166.7,134.6,134.5,133.6,132.3,131.4,130.5,128.5,126.9,125.9,125.3,118.5,118.1,117.7,109.8,76.7,59.1,58.9,53.0,52.7,15.5.IR(KBr,cm-1)ν:2974,1717,1629,1458,1261,1240,1199,1117,1062,1011,955,918,804,784,764,673.HRMS calcd for C24H18NaO6[M+Na]+425.10011,found[M+Na]+425.09940.
实施例12
本实施例提供1-氧代-2,3-环氧-11-(N-羟乙基甲酰胺基)-13c-乙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(12f)
起始物A:无水乙醇:30%H2O2的摩尔比为1:0.686:2.52
制备方法:在50ml单口圆底烧瓶中加入0.5mmol起始物A:1-氧代-11-(N-羟乙基甲酰胺基)-13c-乙氧基-1,13c-二氢-二苯并[a,kl]呫吨,再加入20mL的乙醇,用10mg NaOH使溶液呈碱性,再加入30%H2O2,加入量为3至4滴/100mg,30℃下搅拌反应5h,过滤,滤渣为产物。
表征数据如下(参阅谱图23、图24、图25):
黄色固体,Yield,66.1%,m.p.122.8-125.5℃,1H-NMR(500MHz,DMSO-d6)δ:8.58(s,1H),8.44(d,J=5.0Hz,1H),8.12(d,J=10.0Hz,1H),8.10(d,J=10.0Hz,1H),7.94(d,J=10.0Hz,1H),7.88(d,J=10.0Hz,1H),7.63(s,1H),7.62(d,J=10.0Hz,1H),7.46(d,J=10.0Hz,1H),7.40(d,J=10.0Hz,1H),4.66(d,J=5.0Hz,1H),4.17(d,J=5.0Hz,1H),3.56(m,2H),3.36(m,2H),2.89-2.86(q,J=15.0Hz,1H),2.65-2.62(q,J=15.0Hz,1H),0.82-0.79(t,J=15.0Hz,3H).13C-NMR(125MHz,DMSO-d6)δ:204.2,166.7,152.3,151.3,150.4,149.5,134.5,133.4,131.6,131.0,130.0,128.6,128.5,126.5,124.2,122.4,118.5,118.1,117.7,71.2,60.3,53.9,53.0,42.7.IR(KBr,cm-1)ν:3391,2924,1729,1633,1539,1459,1397,1271,1241,1207,1071,801,770,670.HRMS calcd for C25H21NNaO6[M+Na]+454.12666,found[M+Na]。
申请人进一步给出本申请提供的化合物的效果,下面进一步给出本申请提供的技术方案在制备抗肝癌药物、抗胃癌药物或抗肺癌药物中的应用,以及试验数据。
将二苯并[a,kl]呫吨化合物溶解于溶剂中得到二苯并[a,kl]呫吨化合物溶液,所述的二苯并[a,kl]呫吨化合物溶液的摩尔浓度为0.06mol/L,加入FeCl3溶液,二苯并[a,kl]呫吨化合物与FeCl3的摩尔比为20:1,,在35℃-40℃下搅拌反应3-47h,TLC跟踪至二苯并[a,kl]呫吨化合物消失,加入HCl溶液和适量的水,乙酸乙酯萃取,有机相用无水硫酸钠干燥,旋干,所得粗产品进行硅胶柱层析分离和洗脱,得到β-烷氧基醇二苯并呫吨类化合物。
上述反应所涉及的反应方程式如下:
其中:R为H、CH3或CH2CH3;
R1为H、COOCH3或CONH(CH2)2OH;
R2为H、COOCH3、CONH(CH2)2OH或CONH2。
更具体地说:
当产物为1-氧代-2-甲氧基-3-羟基-13c-甲氧基-1,2,3,13c-四氢-二苯并[a,kl]-呫吨(1a1),1-氧代-2-羟基-3-甲氧基-13c-甲氧基-1,2,3,13c-四氢-二苯并[a,kl]-呫吨(1a2),原料中R为CH3,R1为H,R2为H;
当产物为1-氧代-2-乙氧基-3-羟基-13c-乙氧基-1,2,3,13c-四氢-二苯并[a,kl]-呫吨(2a1),原料中R为CH2CH3,R1为H,R2为H;
当产物为1-氧代-2-甲氧基-3-羟基-11-甲酰胺基-13c-甲氧基-1,2,3,13c-四氢-二苯并[a,kl]-呫吨(1c1),原料中R为CH3,R1为H,R2为CONH2;
当产物为1-氧代-2-乙氧基-3-羟基-11-甲氧羰基-13c-乙氧基-1,2,3,13c-四氢-二苯并[a,kl]-呫吨(2d1),原料中R为CH2CH3,R1为H,R2为COOCH3;
当产物为1-氧代-2-甲氧基-3-羟基-11-(N-羟乙基甲酰胺基)-13c-甲氧基-1,2,3,13c-四氢-二苯并[a,kl]-呫吨(1e1),原料中R为CH3,R1为CONH(CH2)2OH;
β-烷氧基醇二苯并呫吨类化合物抗肿瘤活性试验
采用MTT实验对分β-烷氧基醇二苯并呫吨类化合物体外抑制肿瘤细胞生长进行检测。
取代二苯并[a,kl]呫吨化合物:我们采用MTT实验对化合物体外抑制肿瘤细胞生长进行检测,分别选取人肝癌细胞株HepG2、人肝癌细胞株BEL-7402、人胃癌细胞株SGC-7901、人肺癌细胞株A549分别进行了筛选。具体方法为:将处于对数生长期的各肿瘤细胞株按8×104个/孔的细胞量接种至96孔板中,放置于培养箱中孵育24h,更换培养液后加入浓度梯度的各药物,使药物终浓度为10-6-10-4mol/L,每组设置3个平行复孔,且设置培养液空白对照孔。然后在培养箱中孵育48h,各孔都加入不含血清的培养基90μL和浓度为5mg/mL的MTT溶液10μL,然后在培养箱中培养4h,加入100μL DMSO微量振荡器中震荡15min后,采用酶标仪490nm处测定吸光度值。按下式计算细胞成活率:
表1部分β-烷氧基醇类二苯并呫吨的体外细胞毒性(IC50,μmol/L)
由表1可以看到,测试化合物对四种肿瘤细胞均显示较高的毒性;特别是化合物2a2,对SGC-7901的毒性为5.3μmol/L,2d1对Bel-7402和A549的光毒性分别为9.3μmol/L和6.3μmol/L。以上结果表明,通过本申请制备的化合物进一步开环反应制得的β-烷氧基醇二苯并呫吨类化合物是潜在的抗肿瘤药物。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其它的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (5)
2.权利要求1所述的环氧化二苯并呫吨类抗癌先导化合物的制备方法,其特征在于,依次包括下述步骤:
1)将0.5mmol反应底物加进20mL的溶剂中使原料恰好溶解,加入NaOH使溶液PH为8-9;
2)再加入3~4滴质量分数为30%的H2O2,室温下搅拌反应,TLC跟踪至原料消失,过滤,得到产物。
4.根据权利要求1所述的环氧化二苯并呫吨类抗癌先导化合物的制备方法,其特征在于,所述的溶剂为甲醇。
5.根据权利要求1所述的环氧化二苯并呫吨类抗癌先导化合物的制备方法,其特征在于,所述的溶剂为甲醇和二氧六环的混合物。
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