CN114394980B - 一种螺环螺缩酮类化合物的制备方法 - Google Patents
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Abstract
本发明公开了一种螺环螺缩酮类化合物的制备方法。由内酯化合物6转换成Weinreb酰胺4,并对羟基进行保护,通过格氏反应引入乙烯基后得到相应的ɑ,β‑不饱和酮3,在酸的催化下与含酚羟基或酮的化合物反应形成螺环螺缩酮类化合物。本发明公开了一类具有抗恶性疟原虫活性的螺环螺缩酮类化合物的制备方法,该制备方法所用原料成本低,化合物简单易得。所述的螺环螺缩酮类化合物及其药学上可接受的盐或者药学上可接受的溶剂合物可以用于治疗由于恶性疟原虫导致的疾病。
Description
技术领域:
本发明属于生物医药领域,具体涉及一种螺环螺缩酮类化合物的制备方法。
背景技术:
疟疾是影响人类生存的重大疾病,现在主要出现在热带和亚热带国家地区。疟疾由携带疟原虫的雌性蚊子叮咬而传染给人类,每年全球有数百万人因患疟疾而死亡。
治疗疟疾的药物喹啉类、叶酸拮抗剂和抗菌药都出现了耐药现象。目前,ART(青蒿素)及其衍生物(例如青蒿琥酯和二氢青蒿素/哌喹)是治疗疟疾的主力,挽救了数百万人的生命。为了克服耐药性,临床治疗使用两种或多种具有不同作用机理的疟疾药以产生协同作用。当前的临床一线药物治疗涉及基于青蒿素的联合疗法(ACTs),该疗法使用青蒿素衍生物与其他药物(如rumafen triazine,哌拉喹或阿莫二喹)以及奎宁组合(如奎宁-强力霉素)配合使用。这种鸡尾酒疗法暂时解决了对单一药物的耐药性问题。然而,随后出现的青蒿素耐药性使得疟疾的治疗面临巨大的挑战。克服疟原虫耐药性的方法除了联合用药外,仍以研发新的抗疟疾药物为主要方向。因此,如何研发出结构新颖、活性优越、靶点明确的新型抗疟疾药物,是当前国际上面临的共同难题。
发明内容:
本发明的第一个目的是提供一类新型抗疟疾药物,即螺环螺缩酮类化合物或其药用盐的制备方法。
本发明的螺环螺缩酮类化合物的制备方法,包括以下步骤:
反应式为:
由内酯化合物6转换成Weinreb酰胺4,并对羟基进行保护,通过格氏反应引入乙烯基后得到相应的ɑ,β-不饱和酮3,在酸的催化下与含酚羟基或酮的化合物反应形成螺环螺缩酮类化合物;
所述的螺环螺缩酮类化合物的结构式如式(I)所示:
其中,m,n=0-3;
X,Y=C、O或N;
R1=H、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-3烷氧基、C1-8烷基、C6-8芳基、C5-8含氮杂环、C5-8含氧杂环或C3-6环烷基。
优选,所述的含酚羟基或酮的化合物是间苯三酚、间苯二酚、4-羟基-6-甲基-2-吡喃酮、1,3-环己二酮、4-羟基香豆素或1,3-环戊二酮。
优选,所述的由内酯化合物6转换成Weinreb酰胺4,并对羟基进行保护,通过格氏反应引入乙烯基后得到相应的ɑ,β-不饱和酮3的反应式为以下任一所示:
优选,所述的螺环螺缩酮类化合物是如下所示的任一化合物:
优选,所述的螺环螺缩酮类化合物如以下结构式所示:
本发明的第二个目的是提供一种抗疟原虫药物,其含有上述螺环螺缩酮类化合物,或其药用盐或其溶剂合物作为活性成分。
本发明公开了一类具有抗恶性疟原虫活性的螺环螺缩酮类化合物的制备方法,该制备方法所用原料成本低,化合物简单易得。所述的螺环螺缩酮类化合物及其药学上可接受的盐或者药学上可接受的溶剂合物可以用于治疗由于恶性疟原虫导致的疾病。。
具体实施方式
下面结合具体实施例对本发明作进一步阐述。这些实施例仅是出于解释说明的目的,而不限制本发明的范围和实质。
实施例1本发明重要中间体3的合成:
第一步:称取化合物6(13.51mmol)于30mL干燥四氢呋喃中,加入试剂N,O-二甲基羟基胺盐酸盐(27.02mmol),充入氮气,加塞,放入干冰与丙酮混合液体中,降温至-20℃,滴加格氏试剂异丙基氯化镁(27.02mmol),反应1小时,TLC检测原料反应完全,加入饱和氯化铵溶液淬灭反应。乙酸乙酯(15ml)萃取3次,饱和氯化钠溶液洗涤有机相。将有机相浓缩经快速柱层析得到中间体然后,称取中间体(11.08mmol)于20mL二氯甲烷溶液中,加入咪唑(27.70mmol),搅拌溶解后加入三乙基氯硅烷(16.62mmol),室温反应1小时,TLC监控反应原料反应完全,饱和氯化铵溶液淬灭反应,乙酸乙酯(10ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到化合物4。
第二步:将化合物4(10.19mmol)溶于20mL干燥四氢呋喃中,充入氮气保护,降温至-20℃,缓慢滴加乙烯基氯化镁(20.38mmol),反应1小时。TLC检测原料反应完全后,饱和氯化铵溶液淬灭反应,乙酸乙酯(10ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到化合物3。
R1=H,氘,氟,氯,溴,碘,羟基,氨基,硝基,氰基,C1-3烷氧基,C1-8烷基,C6-8芳基,C5-8含氮杂环,C5-8含氧杂环,C3-6环烷基等。
具体详述如下:
实施例2本发明重要中间体3a的合成:
合成步骤参考实施例1,二氢香豆素为起始原料,经过3步得到化合物3a。
5a:1H NMR(500MHz,CDCl3)δ7.13-7.06(m,2H),6.92(dd,J=9.0,7.0Hz,1H),6.85-6.20(m,1H),3.62(s,3H),3.18(s,3H),2.93(t,J=4.0Hz,2H),2.87(t,J=6.5Hz,2H).13CNMR(125MHz,CDCl3)δ175.3,155.2,130.7,128.0,120.5,118.0,61.2,38.7,33.8,32.4,24.0.
4a:1H NMR(500MHz,CDCl3)δ7.18(dd,J=9.0,6.0Hz,1H),7.09-7.05(m,1H),6.88-6.85(m,1H),6.79(dd,J=9.0,7.5Hz,1H),3.59(s,3H),3.17(s,3H),2.94(t,J=7.5,Hz,2H),2.73(t,J=7.5,Hz 2H),1.01(t,J=8.0Hz,9H),0.81(q,J=8.0Hz,6H).13C NMR(150MHz,CDCl3)δ174.3,153.9,131.7,130.4,127.2,121.1,118.2,61.1,26.0,22.7,14.2,6.7,5.6.
3a:1H NMR(400MHz,Chloroform-d)δ7.17–7.03(m,2H),6.87(td,J=7.5,1.2Hz,1H),6.78(dd,J=8.0,1.2Hz,1H),6.35(dd,J=16,8Hz,1H),6.19(dd,J=16,1.2Hz,1H),5.80(dd,J=10.0,1.2Hz,1H),2.89(d,J=2.0Hz,4H),1.05-0.95(m,9H),0.78(q,J=8Hz,6H).13C NMR(125MHz,CDCl3)δ200.6,153.9,136.8,131.5,130.4,128.1,127.4,121.2,118.4,39.7,25.6,6.8,5.5.
实施例3本发明重要中间体3b的合成:
合成步骤参考实施例1,6-溴-3.4-二氢香豆素为起始原料,经过3步得到化合物3b。
5b:1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),7.15(d,J=3Hz,1H),7.12(dd,J=11,6Hz,1H),6.73(d,J=8.5Hz,1H),3.58(s,3H),3.12(s,3H),2.84-2.77(m,4H).13C NMR(125MHz,CDCl3)δ174.4,154.0,132.7,130.2,130.1,118.9,111.6,60.8,32.9,32.0,23.8.
4b:1H NMR(400MHz,Chloroform-d)δ7.27(s,1H),7.15(dd,J=11.2,6Hz,1H),6.63(d,J=8.4Hz,1H),3.60(s,3H),3.16(s,3H),2.86(t,J=7.6Hz,2H),2.67(t,J=8Hz,2H),0.97(t,J=8Hz,9H),0.76(t,J=22.4,8Hz,6H).13C NMR(100MHz,CDCl3)δ173.8,153.1,134.2,133.0,130.0,120.0,113.2,61.2,32.3,31.7,25.8,6.7,5.3.
3b:1H NMR(500MHz,Chloroform-d)δ7.22(d,J=2.5Hz,1H),7.15(dd,J=11,6Hz,1H),6.65(d,J=8.5Hz,1H),6.34(dd,J=28.5,1H),6.20(dd,J=18.5,16.5Hz,1H),5.82(dd,J=11.5,9.5Hz,1H),2.89-2.83(m,4H),0.98(t,J=7.5Hz,9H),0.76(q,J=8Hz,6H).13C NMR(125MHz,CDCl3)δ199.9,153.1,136.6,133.9,133.1,130.2,128.3,119.9,113.3,39.3,25.2,6.8,5.4.
实施例4本发明重要中间体3c的合成:
合成步骤参考实施例1,6-碘苯并二氢吡喃-2-酮为起始原料,经过3步得到化合物3c。
5c:1H NMR(600MHz,CDCl3)δ9.21(s,1H),7.38(dd,J=9.0,4.2Hz,2H),6.69(d,J=9.0,1H),3.65(s,3H),3.18(s,3H),2.84(s,4H).13C NMR(150MHz,CDCl3)δ175.0(s),155.4(s),139.2(s),136.91(s),131.2(s),120.7(s),82.2(s),61.25(s),33.81(s),32.47(s),23.63(s).
4c:1H NMR(500MHz,CDCl3)δ7.45(d,J=2.0Hz,1H),7.35(dd,J=10.5,6.0Hz,1H),6.53(d,J=8.5Hz,1H),3.61(s,3H),3.17(s,3H),2.87(t,J=7.5Hz,2H),2.69(t,J=8.0Hz,2H),0.98(t,J=8.0,Hz,9H),0.76(q,J=7.5Hz,6H).13C NMR(125MHz,CDCl3)δ174.0,154.0,139.0,136.2,134.8,120.5,83.5,61.3,32.4,31.8,25.7,6.8,5.4.
3c:1H NMR(500MHz,CDCl3)δ7.44(d,J=2.0Hz,1H),7.36(dd,J=11.0,6.0Hz,1H),6.55(d,J=8.5Hz,1H),6.37(dd,J=28.5,7.0Hz,1H),6.22(d,J=18.0Hz,1H),5.83(d,J=10.5Hz,1H),2.85-2.83(m,4H),1.00(t,J=8.0Hz,9H),0.78(q,J=7.5Hz,6H).13C NMR(125MHz,CDCl3)δ199.9,153.9,139.0,136.6,136.3,134.5,128.3,120.5,83.6,39.3,25.1,6.8,5.4.
实施例5本发明重要中间体3d的合成:
合成步骤参考实施例1,6-甲氧基苯并二氢吡喃-2-酮为起始原料,经过3步得到化合物3d。
5d:1H NMR(400MHz,Chloroform-d)δ8.48(s,1H),6.84–6.75(m,1H),6.67–6.58(m,2H),3.69(s,3H),3.58(s,3H),3.12(s,3H),2.83(tq,J=10.0,5.3,4.2Hz,4H).13C NMR(100MHz,CDCl3)δ174.8,153.3,148.7,129.0,118.0,115.7,112.8,61.0,55.6,33.4,32.1,24.3.
4d:1H NMR(400MHz,Chloroform-d)δ6.72–6.64(m,2H),6.57(dd,J=8.7,3.1Hz,1H),3.69(s,3H),3.56(s,3H),3.13(s,3H),2.90–2.81(m,2H),2.71–2.65(m,2H),0.95(t,J=7.9Hz,9H),0.78–0.66(m,6H).13C NMR(100MHz,CDCl3)δ174.0,153.7,147.5,132.4,118.6,115.8,111.7,61.03,55.4,32.2,31.9,26.1,6.6,5.2.
3d:1H NMR(600MHz,Chloroform-d)δ6.70(t,J=3.6,2H),6.61(dd,J=12,6Hz,1H),6.34(dd,J=28.2,6.6Hz,1H),6.20(dd,J=19.2,16.8Hz,1H),5.82(dd,J=11.4,9.6Hz,1H),3.74(s,3H),2.91–2.85(m,4H),1.63(s,1H),0.98(t,J=8.4Hz,9H),0.75(q,J=7.8Hz,6H).13C NMR(150MHz,CDCl3)δ200.5,153.8,147.7,136.7,132.4,128.2,118.8,115.9,111.9,55.7,39.6,6.9,5.4.
实施例6本发明重要中间体3e的合成:
合成步骤参考实施例1,6-丁基-四氢-2H-2-吡喃酮为起始原料,经过3步得到化合物3e。
5e:1H NMR(600MHz,Chloroform-d)δ3.64(s,3H),3.55–3.51(m,1H),3.13(s,3H),2.41(s,1H),1.76–1.64(m,2H),1.47-1.34(m,5H),1.31-1.21(m,3H),0.85(t,J=7.2Hz,3H).13CNMR(150MHz,CDCl3)δ174.8,71.2,61.25,4.16,37.1,32.2,31.6,27.9,22.8,20.4,14.1.
4e:1H NMR(400MHz,Chloroform-d)δ5.25(s,1H),3.62(s,3H),3.12(s,3H),2.36(t,J=7.6Hz,2H),1.70-1.54(m,2H),1.45-1.36(m,4H),1.28-1.20(m,4H),0.91(t,J=8Hz,9H),0.54(q,J=8Hz,6H).13C NMR(100MHz,CDCl3)δ174.6,72.2,72.2,61.2,53.5,36.9,36.9,32.2,27.6,22.9,20.7,14.1,7.0,5.1.
3e:1H NMR(400MHz,Chloroform-d)δ6.35(dd,J=17.7,10.5Hz,1H),6.21(dd,J=17.7,1.3Hz,1H),5.81(dd,J=10.5,1.3Hz,1H),3.69-3.62(m,,1H),1.73-1.61(m,2H),1.49-1.40(m,4H),1.32-1.29(m,2H),1.26-1.22(m,4H),0.95(t,J=8Hz,9H),0.89(t,J=4Hz,3H),0.59(q,J=8Hz,6H).13C NMR(100MHz,CDCl3)δ201.0,136.7,128.0,72.3,40.0,37.0,36.8,27.7,23.0,20.1,14.3,7.1,5.3.
实施例7本发明中间体3f的合成:
合成步骤参考实施例1,十一烷内酯为起始原料,经过3步得到化合物3f。
5f:1H NMR(500MHz,Chloroform-d)δ3.54(s,3H),3.44-3.39(m,1H),3.01(s,3H),2.42(t,J=7Hz,2H),1.71-1.64(m,1H),1.55-1.48(m,1H),1.27(d,J=9.3Hz,3H),1.17-1.09(m,10H),0.73-0.68(m,3H).13C NMR(125MHz,CDCl3)δ174.8,70.8,60.9,37.4,35.3,31.6,31.5,29.4,29.1,25.5,25.0,22.4,13.8.
4f:1H NMR(600MHz,Chloroform-d)δ3.68(s,3H),3.48(s,1H),3.17(s,3H),1.86-1.82(m,2H),1.72-1.64(m,2H),1.46-1.41(m,2H),1.28-1.24(m,10H),0.97-0.95(q,J=1.8,9H),0.87(t,J=6.9Hz,3H),0.59(dd,J=11.4,4.2Hz,6H).13C NMR(100MHz,CDCl3)δ175.1,77.5,77.2,76.8,71.8,61.3,37.4,32.0,31.6,29.9,29.4,25.5,22.8,14.2,7.04,6.7,5.9,5.2.
3f:1H NMR(400MHz,Chloroform-d)δ6.35(dd,J=12.8,7.2Hz,1H),6.22(dd,J=19.2,16.4Hz,1H),5.81(dd,J=11.6,9.2Hz,1H),3.72-3.69(m,1H),2.71-2.59(m,2H),1.87-1.79(m,1H),1.71-1.63(m,1H),1.46-1.40(m,2H),1.28-1.25(m,10H),0.95(t,J=8.0Hz,9H),0.90-0.87(m,3H),0.59(q,J=7.6Hz,6H).13C NMR(100MHz,CDCl3)δ201.0,136.7,128.0,,72.3,40.0,37.0,36.8,27.7,23.0,20.1,14.3,7.1,5.3.
实施例8本发明中间体3g的合成:
合成步骤参考实施例1,γ-苯基-γ-丁内酯为起始原料,经过3步得到化合物3g。
5g:1H NMR(500MHz,Chloroform-d)δ7.38–7.27(m,5H),7.21(t,J=7Hz,1H),4.78(t,J=6Hz,1H),3.60(s,3H),3.14(s,3H),2.00(q,J=7Hz,2H),0.97(t,J=8.0Hz,2H).
4g:1H NMR(500MHz,Chloroform-d)δ7.35-7.27(m,4H),7.26-7.19(m,1H),4.78(t,J=6.0Hz,1H),3.60(s,3H),3.14(s,3H),2.46(q,J=16.0Hz,2H),2.06-1.94(m,2H),,0.88(t,J=8.0Hz,9H),0.55-048(m,6H).13C NMR(125MHz,CDCl3)δ209.4,144.8,128.1,127.1,125.8,73.6,59.8,55.2,45.0,40.5,38.5,34.2,6.8,4.8.
3g:1H NMR(500MHz,Chloroform-d)δ7.31–7.28(m,4H),7.24-7.21(m,1H),6.32(dd,J=28.5,7Hz,1H),6.16(d,J=17.5Hz,1H),5.78(d,J=10.5Hz,1H),4.77(t,J=5.5Hz,1H),2.70-2.62(m,1H),2.60-2.53(m,1H),2.05–1.96(m,2H),0.88(t,J=8.0Hz,9H),0.58-0.46(m,6H).13C NMR(125MHz,CDCl3)δ200.7,145.0,136.7,128.2,127.9,127.2,125.9,73.7,35.4,34.6,6.9,4.9.
实施例9本发明终产物4001的合成:
将间苯三酚(0.255mmol,32.13mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.340mmol,78.80mg)搅拌至溶解,在冰浴环境下缓慢滴加5-(2-((三乙基硅基)氧基)苯基)戊-1-烯-3-酮(0.170mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物37mg,产率为78%。IR(neat,cm-1):3373,2931,1609,1516,1490,1460,1285,1226,1179,1143,1063,1046,1011,923,877,756.1H NMR(500MHz,CDCl3)δ7.12–7.05(m,2H),6.90-6.86(m,1H),6.75(d,J=8.0Hz,1H),5.97(d,J=2.5Hz,1H),5.86(d,J=2.5Hz,1H),3.26-3.19(m,1H),2.94-2.87(m,1H),2.76-2.68(m,2H),2.26–2.19(m,2H),1.98-1.89(m,2H).13C NMR(150MHz,CDCl3)δ155.1,154.3,153.8,152.3,129.1,127.4,122.2,121.01,117.2,102.2,97.0,96.3,95.9,31.0,30.8,21.0,15.1.
实施例10本发明终产物4002的合成:
将间苯三酚(0.203mmol,26mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.27mmol,62.7mg)搅拌至溶解,在冰浴环境下缓慢滴加5-(5-溴-2-((三乙基硅氧基)苯基)戊-1-烯-3-酮(0.135mmol,50mg)的叔丁醇与正己烷混合溶液(0.8ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物9.3mg,产率为20%。IR(neat,cm-1):3369,2961,2926,2853,1608,1478,1261,1226,1178,1145,1108,1060,1045,101,92,876,813.1H NMR(500MHz,CDCl3)δ7.24(d,J=2.5Hz,1H),7.15(dd,J=11.5,6.5Hz,1H),6.62(d,J=8.5Hz,1H),5.97(d,J=2.5Hz,1H),5.85(d,J=2.5Hz,1H),4.98(s,1H),4.78(s,1H),3.25-3.18(m,1H),2.90-2.84(m,1H),2.74–2.68(m,2H),2.53-2.18(m,2H),1.96–1.89(m,2H).13C NMR(125MHz,CDCl3)δ155.1,154.3,153.6,151.4,131.7,130.2,124.5,119.1,113.2,102.1,96.9,96.4,96.1,30.7,30.7,20.9,15.0.
实施例11本发明终产物4003的合成:
将间苯三酚(0.255mmol,32.15mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.680mmol,157.8mg)搅拌至溶解,在冰浴环境下缓慢滴加5-(5-碘-2-((三乙基硅氧基)苯基)戊-1-烯-3-酮(0.170mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物26mg,产率为37%。1H NMR(400MHz,CDCl3)δ7.42-7.41(m,1H),7.32(dd,J=10.8,6.4Hz,1H),6.50(d,J=8.4Hz,1H),5.97(d,J=2.4Hz,1H),5.84(d,J=2Hz,1H),5.40(s,1H),3.24-3.15(m,1H),2.90-2.82(m,1H),2.74-2.65(m,2H),2.24–2.15(m,2H),1.95–1.86(m,2H).13C NMR(150MHz,CDCl3)δ155.1,154.3,153.6,152.2,137.7,136.2,125.1,119.6,102.1,96.9,96.3,96.1,83.3,30.7,30.7,20.7,15.0.
实施例12本发明终产物4004的合成:
将间苯三酚(0.24mmol,30.3mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.31mmol,72.5mg)搅拌至溶解,在冰浴环境下缓慢滴加5-(5-甲氧基-2-((三乙基硅基)氧基)苯基)戊-1-烯-3-酮(0.16mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物4.8mg,产率为10%。IR(neat,cm-1):3375,2925,2852,1608,1496,1465,1282,1248,1205,1144,1063,1044,1011,929,908,877,818.1H NMR(500MHz,Chloroform-d)δ6.68–6.23(m,3H),5.96(d,J=2.5Hz,1H),5.85(d,J=2.5Hz,1H),5.07(s,1H),4.90(s,1H),3.75(s,3H),3.24-3.17(m,1H),2.92-2.85(m,1H),2.72-2.67(m,2H),2.24-2.16(m,2H),1.96–1.87(m,2H).13C NMR(150MHz,CDCl3)δ155.1,154.3,153.9,153.8,146.2,122.8,117.7,113.8,113.3,102.5,97.0,96.3,95.9,31.0,30.8,21.4,21.2,15.1.
实施例13本发明终产物4005的合成:
将间苯三酚(0.251mmol,31.68mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.3344mmol,77.81mg)搅拌至溶解,在冰浴环境下缓慢滴加7-((三乙基硅基)氧基)十一碳-1-烯-3-酮(0.167mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物17.4mg,产率为36%。IR(neat,cm-1):2935,2867,1622,1448,1276,1229,1149,1101,1052,1020,961,932,908.1H NMR(500MHz,CDCl3)δ5.98(d,J=3.6Hz,2H),4.59(s,2H),3.64-3.61(m,1H),2.70-2.67(m,2H),2.12-2.03(m,4H),1.96-1.91(m,2H),1.69-1.68(m,2H),1.58-1.49(m,4H),1.42-1.33(m,4H),0.72(d,J=3.5,3H).13C NMR(125MHz,CDCl3)δ151.7,151.2,150.2,104.2,104.0,96.4,95.8,70.7,35.8,34.4,32.1,31.1,27.5,22.5,19.0,16.0,14.2.
实施例14本发明终产物4006的合成:
将间苯三酚(0.229mmol,29.00mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.306mmol,71.00mg)搅拌至溶解,在冰浴环境下缓慢滴加6-((三乙基硅基)氧基)十三碳-1-烯-3-酮(0.153mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物2.6929g,产率为78%。1H NMR(500MHz,CDCl3)δ5.88(s,1H),5.30(s,1H),4.59(s,2H),4.18-4.10(m,1H),2.78-2.68(m,2H),2.28-2.00(m,6H),1.59-1.57(m,2H),1.27-1.23(m,10H),0.88-0.86(m,3H).
实施例15本发明终产物4007和4008的合成:
将间苯三酚(0.24mmol,26.4mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.31mmol,72.5mg)搅拌至溶解,在冰浴环境下缓慢滴加6-苯基-6-((三乙基甲硅烷基)氧基)己-1-烯-3-酮(0.16mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物0.020g,产率为44%。1H NMR(500MHz,CDCl3)δ7.36(m,1H),7.34(d,J=2.5Hz,1H),7.32-7.30(m,2H),7.24-7.20(m,2H),7.10(t,J=5Hz,1H),6.96(t,J=5Hz,1H),4.76(s,1H),2.88-2.79(m,1H),2.78-2.70(m,1H),2.68-2.59(m,1H),2.47-2.41(m,1H),2.38-2.23(m,1H),2.16-2.10(m,1H),2.02-1.98(m,1H),1.95-1.91(m,1H).13C NMR(125MHz,CDCl3)δ155.3,154.7,154.6,143.0,142.6,128.5,127.5,125.8,107.4,107.0,102.0,96.7,95.8,80.8,36.9,33.4,29.95,16.9.
1H NMR(500MHz,CDCl3)δ7.36(m,1H),7.32-7.30(m,2H),7.28(d,J=5Hz,1H),7.24-7.20(m,2H),7.10(t,J=5Hz,1H),5.99(d,J=5.5Hz,1H),5.22-5.12(m,1H),2.88-2.79(m,1H),2.78-2.70(m,1H),2.68-2.59(m,1H),2.47-2.41(m,1H),2.38-2.23(m,1H),2.16-2.10(m,1H),2.02-1.98(m,2H).
实施例16本发明终产物4009的合成:
将间苯二酚(0.255mmol,28.00mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.340mmol,78.80mg)搅拌至溶解,在冰浴环境下缓慢滴加5-(2-((三乙基硅基)氧基)苯基)戊-1-烯-3-酮(0.170mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物20mg,产率为44%。IR(neat,cm-1):3392,2928,1625,1597,1509,1491,1456,1303,1223,1180,1144,1094,1062,994,976,924,876,848,754.1HNMR(500MHz,CDCl3)δ7.13-7.03(m,2H),6.95(d,J=8.2Hz,1H),6.88(td,J=7.5,1.0Hz,1H),6.73(dd,J=8.0,1.0Hz,1H),6.38(dd,J=8.0,2.5Hz,1H),6.21(d,J=2.5Hz,1H),3.29-3.12(m,2H),2.77-2.65(m,2H),2.24-2.15(m,2H),1.99-1.91(m,2H).13C NMR(125MHz,CDCl3)δ154.9,153.1,152.3,129.8,129.1,127.3,122.3,121.0,117.2,114.6,108.5,104.0,96.4,31.5,31.2,21.2,20.4.
实施例17本发明终产物4010的合成:
将间苯二酚(0.203mmol,22mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.27mmol,62.7mg)搅拌至溶解,在冰浴环境下缓慢滴加5-(5-溴-2-((三乙基硅氧基)苯基)戊-1-烯-3-酮(0.135mmol,50mg)的叔丁醇与正己烷混合溶液(0.8ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物12.7mg,产率为27%。IR(neat,cm-1):2963,2929,1625,1598,1509,1479,1291,1262,1228,1178,1145,1097,1061,1020,995,975,876,808.1H NMR(500MHz,CDCl3)δ7.24(d,J=2.5Hz,1H),7.15(dd,J=11.5,6.5Hz,1H),6.95(d,J=8Hz,1H),6.61(d,J=8.5Hz,1H),6.40(dd,J=10.5,5.5Hz,1H),6.22(d,J=2.5Hz,1H),3.27-3.11(m,2H),2.73-2.65(m,2H),2.21-2.17(m,2H),1.97-1.89m,2H).13C NMR(125MHz,CDCl3)δ155.0,152.8,131.7,130.2,129.8,119.0,114.5,113.1,108.7,104.0,96.5,77.4,76.9,31.4,30.9,20.9,20.3.
实施例18本发明终产物4011的合成:
将间苯二酚(0.255mmol,28.05mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.680mmol,157.8mg)搅拌至溶解,在冰浴环境下缓慢滴加5-(5-碘-2-((三乙基硅氧基)苯基)戊-1-烯-3-酮(0.17mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物14mg,产率为21%。1H NMR(400MHz,CDCl3)δ7.43-7.42(m,1H),7.34-7.31(m,1H),6.96-6.94(m,1H),6.50(d,J=8.6Hz,1H),6.40(dd,J=10.8,5.6Hz,1H),6.22(dd,J=2.8Hz,1H),4.87(s,1H),3.27-3.10(m,2H),2.73-2.64(m,2H),2.12-2.16(m,2H),1.97-1.88(m,2H).13C NMR(125MHz,CDCl3)δ155.0,152.8,152.3,137.7,136.1,129.8,128.9,125.4,119.6,114.4,108.7,104.0,81.5,31.2,30.9,20.8,20.3.
实施例19本发明终产物4012的合成:
将间苯二酚(0.24mmol,26.4mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.31mmol,72.5mg)搅拌至溶解,在冰浴环境下缓慢滴加5-(5-甲氧基-2-((三乙基硅基)氧基)苯基)戊-1-烯-3-酮(0.16mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物15.9mg,产率为33%。IR(neat,cm-1):3375,2931,1624,1597,1509,1457,1296,1232,1143,1115,1064,1024,990,938,856,756,701.1H NMR(500MHz,CDCl3)δ6.95(d,J=8Hz,1H),6.68-6.63(m,3H),6.39(dd,J=11,6Hz,1H),6.22(d,J=2.5Hz,1H),3.76(s,3H),3.27-3.12(m,2H),2.73-2.64(m,2H),2.21-2.16(m,2H),1.97-1.89(m,2H),1.92(s,1H).13C NMR(125MHz,CDCl3)δ154.9,153.8,153.1,146.3,129.74,122.9,121.6,117.7,114.6,113.8,113.2,108.4,104.0,55.8,31.5,31.2,21.4,20.4.
实施例20本发明终产物4013的合成:
将间苯二酚(0.251mmol,27.66mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.3344mmol,77.81mg)搅拌至溶解,在冰浴环境下缓慢滴加7-((三乙基硅基)氧基)十一碳-1-烯-3-酮(0.167mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物21.6mg,产率为47%。1H NMR(500MHz,CDCl3)δ7.80(m,1H),7.52-7.49(m,1H),7.34-7.28(m,2H),3.72-3.66(m,1H),2.74-2.59(m,1H),2.5-2.56(m 1H),2.16-2.01(m,2H),2.02-1.98(m,1H),1.86-1.78(m,2H),1.73-1.68(m,2H),1.67-1.62(m,1H),1.44-1.30(m,4H),1.14-1.08(m,2H),0.74(t,J=7.5Hz,3H).13C NMR(150MHz,CDCl3)δ154.7,153.2,129.7,115.4,108.0,103.8,96.6,70.5,35.7,34.4,32.4,31.2,27.4,22.4,20.6,18.9,14.1.
实施例21本发明终产物4014的合成:
将间苯二酚(0.229mmol,25.00mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.306mmol,71.00mg)搅拌至溶解,在冰浴环境下缓慢滴加6-((三乙基硅基)氧基)十三碳-1-烯-3-酮(0.153mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物13.5mg,产率为30%。IR(neat,cm-1):3390,2928,2855,1625,1596,1509,1460,1298,1232,1154,1114,986,870.1H NMR(500MHz,CDCl3)δ6.88(d,J=8Hz,1H),6.34(d,J=8Hz,1H),6.27(dd,J=12,7.5Hz,1H),5.26(s,1H),4.30-4.25(m,1H),2.99-2.89(m,1H),2.67-2.61(m,1H),2.31-2.15(m,2H),2.11-2.06(m,1H),1.94-1.87(m,1H),1.86-1.81(m,1H),1.72-1.57(m,2H),1.46-1.40(m,1H),1.37-1.23(m,10H),0.87(q,J=6Hz,3H).13C NMR(150MHz,CDCl3)δ154.9,154.2,129.8,114.4,107.8,106.9,103.9,79.7,37.7,36.8,31.9,30.6,30.1,29.7,29.4,26.1,25.9,22.4,14.3.
实施例22本发明终产物4015的合成:
将间苯二酚(0.24mmol,26.4mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.31mmol,72.5mg)搅拌至溶解,在冰浴环境下缓慢滴加6-苯基-6-((三乙基甲硅烷基)氧基)己-1-烯-3-酮(0.16mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物20mg,产率为44%。1H NMR(500MHz,CDCl3)δ7.36-7.27(m,4H),7.25-7.21(m,1H),6.91(d,J=8.0Hz,1H),6.39-6.34(m,2H),5.32(t,J=7.0Hz,1H),3.12-2.98(m,1H),2.74-2.63(M,2H),2.45-2.27(m,2H),2.14-2.07(m,2H),2.05-2.00(m,1H).13CNMR(150MHz,CDCl3)δ155.2,143.2,129.9,128.4,127.5,127.4,126.3,125.8,114.2,108.2,108.0,107.3,103.5,83.5,33.4,30.7,22.8,14.3.
实施例23本发明终产物4016的合成:
将4-羟基-6-甲基-2-吡喃酮(0.255mmol,41.00mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.340mmol,78.80mg)搅拌至溶解,在冰浴环境下缓慢滴加5-(2-((三乙基硅基)氧基)苯基)戊-1-烯-3-酮(0.170mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物16mg,产率为33%。IR(neat,cm-1):2930,1707,1654,1586,1490,1449,1407,1376,1307,1226,1202,1143,1095,1057,988,946,920,864,841,753.1H NMR(500MHz,Chloroform-d)δ7.13-7.07(m,3H),6.94-6.91(m,1H),5.33(s,1H),3.19-3.04(m,2H),2.93-2.80(m,2H),2.79-2.74(m,2H),2.65(s,3H),2.28-2.19(m,2H).13C NMR(125MHz,CDCl3)δ164.9,162.3,160.2,152.9,129.3,129.2,127.7,127.3,121.6,117.2,100.5,99.4,30.8,30.5,20.6,19.8,15.3.
实施例24本发明终产物4017的合成:
将4-羟基-6-甲基-2-吡喃酮(0.251mmol,31.66mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.3344mmol,77.81mg)搅拌至溶解,在冰浴环境下缓慢滴加7-((三乙基硅基)氧基)十一碳-1-烯-3-酮(0.167mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物36.5mg,产率为74%。IR(neat,cm-1):2934,2865,1691,1650,1585,1509,1450,1409,1383,1307,1236,1205,1041,992,958,834.1H NMR(500MHz,CDCl3)δ5.76(s,1H),3.66-3.61(m,1H),2.19(s,3H),2.00-1.93(m,2H),1.84-1.80(m,1H),1.71-1.61(m,4H),1.57-1.51(m,2H),1.45-1.38(m,2H),1.27(t,J=5Hz,2H),1.23-1.17(m,3H),0.81(t,J=7.0Hz,3H).13C NMR(125MHz,CDCl3)δ165.2,162.6,160.1,100.6,99.4,99.0,71.5,35.6,33.8,31.7,30.7,27.4,22.5,19.9,18.7,15.5,14.1.
实施例25本发明终产物4018的合成:
将4-羟基-6-甲基-2-吡喃酮(0.229mmol,29.00mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.306mmol,71.00mg)搅拌至溶解,在冰浴环境下缓慢滴加6-((三乙基硅基)氧基)十三碳-1-烯-3-酮(0.153mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物36.1mg,产率为73%。IR(neat,cm-1):2928,2856,1711,1656,1589,1449,1407,1306,1204,1136,1112,1037,990,942,841.1H NMR(500MHz,CDCl3)δ5.66(d,J=7.5Hz,1H),4.17-4.13(m,1H),2.60-2.53(m,3H),2.27-2.17(m,2H),2.01-1.96(m,2H),1.92-1.83(m,3H),1.65-1.52(m,2H),1.48-1.38(m,1H),1.32(d,J=9.0Hz,1H),1.25-1.21(m,9H),0.84(t,J=6.5Hz,3H).13C NMR(125MHz,CDCl3)δ165.1,163.4,160.1,109.0,100.7,98.44,80.7,37.5,36.6,31.9,29.9,29.7,29.6,29.3,26.0,22.78,19.9,17.2,14.2.
实施例26本发明终产物4019的合成:
将4-羟基-6-甲基-2H-吡喃-2-酮(0.24mmol,26.4mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.31mmol,72.5mg)搅拌至溶解,在冰浴环境下缓慢滴加6-苯基-6-((三乙基甲硅烷基)氧基)己-1-烯-3-酮(0.16mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物20mg,产率为42%。IR(neat,cm-1):1707,1655,1589,1204,992.1H NMR(500MHz,CDCl3)δ7.35-7.27(m,5H),5.74(s,1H),5.29(t,J=7.0Hz,1H),2.72-2.56(m,3H),2.34-2.28(m,1H),2.18(s,3H),2.15-2.09(m,2H),2.06-1.93(m,2H).13CNMR(125MHz,CDCl3)δ164.9,163.3,160.2,141.7,128.6,127.8,125.6,109.1,100.7,98.6,81.5,36.8,33.0,29.7,19.9,17.0.
实施例27本发明终产物4020的合成:
将4-羟基香豆素(0.251mmol,40.70mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.3344mmol,77.81mg)搅拌至溶解,在冰浴环境下缓慢滴加7-((三乙基硅基)氧基)十一碳-1-烯-3-酮(0.167mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物10mg,产率为18%。1HNMR(500MHz,CDCl3)δ7.11-7.04(m,4H),6.88-6.80(m,4H),3.15-3.05(m,2H),2.93-2.89(m,2H),2.09-2.04(m,2H),1.84-1.77(m,2H).
实施例28本发明终产物4021的合成:
将4-羟基香豆素(0.229mmol,37.00mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.306mmol,71.00mg)搅拌至溶解,在冰浴环境下缓慢滴加6-((三乙基硅基)氧基)十三碳-1-烯-3-酮(0.153mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物4.5mg,产率为8.3%。IR(neat,cm-1):2935,1717,1634,1395,1041,909.1H NMR(500MHz,CDCl3)δ7.71(d,J=8Hz,1H),7.49(t,J=8Hz,1H),7.31(d,J=8.5Hz,1H),7.24(d,J=8Hz,1H),3.79-3,73(m,1H),2.79-2.64(m,2H),2.39-2.32(m,1H),2.23-2.18(m,1H),2.15-2.03(m,2H),2.02-1.94(m,2H),1.68-1.62(m,2H),1.56-1.48(m,2H),1.35-1.25(m,4H),0.83(t,J=7.0Hz,3H).13C NMR(125MHz,CDCl3)δ163.13,157.31,152.58,131.14,123.75,121.90,116.65,116.04,102.24,99.31,71.74,35.47,33.77,31.47,30.62,27.22,22.35,18.87,16.14,13.88.
实施例29本发明终产物4022的合成:
将4-羟基香豆素(0.229mmol,37.00mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.306mmol,71.00mg)搅拌至溶解,在冰浴环境下缓慢滴加6-((三乙基硅基)氧基)十三碳-1-烯-3-酮(0.153mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物4.5mg,产率为8.3%。IR(neat,cm-1):3221,2921,2852,1711,1618,1457,1395,1300,1215,1154,1062,1023,749.1H NMR(500MHz,CDCl3)δ7.71(d,J=8Hz,1H),7.49(t,J=8Hz,1H),7.31(d,J=8.5Hz,1H),7.24(d,J=8Hz,1H),4.29-4,23(m,1H),2.79–2.64(m,2H),2.39-2.32(m,1H),2.23-2.18(m,1H),2.15–2.03(m,2H),2.02–1.94(m,2H),1.68–1.62(m,2H),1.56-1.48(m,2H),1.35-1.25(m,8H),0.83(t,J=7.0Hz,3H).13CNMR(125MHz,CDCl3)δ198.3,171.3,169.4,142.7,128.5,127.7,126.1,125.6,111.7,108.6,81.3,38.1,36.9,33.4,30.0,29.8,29.0,28.9,21.2,16.25,16.1,14.3.
实施例30本发明终产物4023和4024的合成:
将4-羟基香豆素(0.24mmol,26.4mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.31mmol,72.5mg)搅拌至溶解,在冰浴环境下缓慢滴加6-苯基-6-((三乙基甲硅烷基)氧基)己-1-烯-3-酮(0.16mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物8mg,5.7mg,产率为15%,11%。1HNMR(500MHz,CDCl3)δ7.80(dd,J=9.5,6.5Hz,1H),7.52-7.49(m,1H),7.37-7.28(m,7H),5.37(t,J=7.0Hz,1H),2.89-2.71(m,3H),2.55-2.47(m,1H),2.35-2.31(m,1H),2.27-2.13(m,2H),2.09-2.02(m,1H).13C NMR(125MHz,CDCl3)δ163.1,158.2,152.8,142.2,131.5,128.6,127.7,125.88,123.91,122.26,116.77,116.02,109.44,101.52,84.12,38.35,33.83,29.84,17.87.
1H NMR(500MHz,CDCl3)δ7.72(dd,J=9.5,6.5Hz,1H),7.53-7.50(m,1H),7.33(dd,J=9.5,7.5Hz,1H),7.29-7.27(m,3H),7.25-7.19(m,3H),5.27(m,1H),2.87-2.71(m,2H),2.57-2.50(m,2H),2.41-2.32(m,1H),2.27-2.22(m,1H),2.21–2.13(m,2H).
实施例31本发明终产物4025的合成:
将1,3-环己二酮(0.255mmol,28.56mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.340mmol,78.80mg)搅拌至溶解,在冰浴环境下缓慢滴加5-(2-((三乙基硅基)氧基)苯基)戊-1-烯-3-酮(0.170mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物9mg,产率为19%。IR(neat,cm-1):3295,2937,2853,1710,1621,1491,1456,1395,1373,1303,1227,1161,1095,1057,974,923,838,755.1H NMR(600MHz,CDCl3)δ7.13-7.07(m,2H),6.93-6.90(m,1H),6.80(dd,J=9,6.6Hz,1H),3.15-3.05(m,1H),2.75-2.68(m,1H),2.50-2.46(m,2H),2.41-2.33(m,2H),2.30-2.27(m,2H),2.18-2.13(m,2H),1.95-1.88(m,3H),1.83-1.75(m,1H).13C NMR(125MHz,CDCl3)δ198.45,168.53,152.93,129.30,127.56,127.27,121.35,120.48,117.14,112.32,36.85,30.94,30.55,28.52,21.01,20.77,14.39.
实施例32本发明终产物4026的合成:
将1,3-环己二酮(0.251mmol,28.17mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.3344mmol,77.81mg)搅拌至溶解,在冰浴环境下缓慢滴加7-((三乙基硅基)氧基)十一碳-1-烯-3-酮(0.167mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物12.3g,产率为26%。1H NMR(500MHz,Chloroform-d)δ3.68-3.64(m,1H),2.40-2.33(m,2H),2.30-2.26(m,1H),1.97-1.85(m,2H),1.80-1.75(m,1H),1.64-1.55(m,2H),1.52-1.40(m,3H),1.31-1.21(m,11H),0.87(t,J=6.5Hz,3H).13C NMR(150MHz,CDCl3)δ198.5,168.6,112.5,98.6,71.0,36.9,35.6,33.8,31.9,31.0,28.7,27.5,22.4,21.2,18.8,14.6,14.2.
实施例33本发明终产物4027的合成:
将1,3-环己二酮(0.229mmol,26.00mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.306mmol,71.00mg)搅拌至溶解,在冰浴环境下缓慢滴加6-((三乙基硅基)氧基)十三碳-1-烯-3-酮(0.153mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物8.8mg,产率为19%。1H NMR(500MHz,Chloroform-d)δ4.51-4.45(m,1H),2.54-2.51(m,2H),2.34-2.28(m,2H),2.00-1.90(m,1H),1.89-1.85(m,2H),1.80-1.70(m,2H),1.60-1.52(m,3H),1.50-1.41(m,2H),1.40-1.34(m,2H),1.32-1.22(m,10H),0.88(t,J=6.5Hz,3H).13C NMR(125MHz,CDCl3)δ177.5,129.8,107.9,103.9,82.40,38.17,37.6,37.5,36.8,35.7,31.9,30.9,29.4,29.3,29.0,28.2,25.4,22.8,14.2.
实施例34本发明终产物4028的合成:
将环己烷-1,3-二酮(0.24mmol,26.4mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.31mmol,72.5mg)搅拌至溶解,在冰浴环境下缓慢滴加6-苯基-6-((三乙基甲硅烷基)氧基)己-1-烯-3-酮(0.16mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物9.4mg,产率为20%。isomer 1:IR(neat,cm-1):2921,2851,1652,1625,1392,1156,1115,1058,1024,1006,918.1H NMR(600MHz,CDCl3)δ7.36-7.30(m,5H),5.31(t,J=6.6Hz,1H),2.63-2.57(m,1H),2.46-2.43(m,2H),2.37(t,J=6.6Hz,3H),2.28-2.23(m,1H),2.14-2.04(m,3H),2.00-1.90(m,4H).13C NMR(150MHz,CDCl3)δ198.3,169.4,142.0,127.7,125.7,111.7,108.9,81.3,36.8,33.2,30.0,28.9,27.5,21.1,16.1.
isomer 2:1H NMR(600MHz,CDCl3)δ7.36-7.31(m,4H),7.28-7.27(m,1H),5.17(m,1H),2.46-2.40(m,3H),2.39-2.35(m,4H),2.26-2.19(m,2H),2.06-2.01(m,1H),2.00-1.96(m,3H),1.95-1.89(m,1H).13C NMR(150MHz,CDCl3)δ198.3,169.4,142.7,128.5,127.7,126.1,111.7,108.6,83.5,38.2,36.9,33.5,29.8,29.0,21.2,16.3.
实施例35本发明终产物4029的合成:
将1,3-环戊二酮(0.255mmol,24.99mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.340mmol,78.80mg)搅拌至溶解,在冰浴环境下缓慢滴加5-(2-((三乙基硅基)氧基)苯基)戊-1-烯-3-酮(0.170mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物3mg,产率为7%。IR(neat,cm-1):2924,1689,1632,1586,1490,1443,1402,1302,1219,1179,1163,1137,1081,1053,912,829,756.1H NMR(500MHz,CDCl3)δ7.13(t,J=8.0Hz,2H),6.94(t,J=7.5Hz,1H),6.80(d,J=8.0Hz,1H),3.22-3.15(m,1H),2.93-2.67(m,3H),2.56-2.34(m,4H),2.25-2.16(m,2H),2.03-1.97(m,1H),1.81-1.75(m,1H).13C NMR(125MHz,CDCl3)δ204.0,182.0,151.6,129.3,127.7,121.8,121.7,117.2,115.8,100.2,33.5,30.8,30.3,26.5,20.6,13.4.
实施例36本发明终产物4030的合成:
将1,3-环戊二酮(0.251mmol,24.64mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.3344mmol,77.81mg)搅拌至溶解,在冰浴环境下缓慢滴加7-((三乙基硅基)氧基)十一碳-1-烯-3-酮(0.167mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物8.5mg,产率为20%。IR(neat,cm-1):2928,2856,1729,1698,1633,1443,1403,1294,1231,1150,1113,1075,1025,948.1H NMR(500MHz,CDCl3)δ3.75-3.69(m,1H),2.54-2.51(m,2H),2.44-2.41(m,2H),2.33-2.25(m,1H),2.20-2.14(m,1H),2.04-1.97(m,1H),1.93-1.99(m,1H),1.88-1.83(m,1H),1.75-1.65(m,2H),1.60-1.54(m,2H),1.48-1.41(m,1H),1.39-1.30(m,3H),1.27-1.24(m,3H),0.84(t,J=6.5Hz,3H).13CNMR(125MHz,CDCl3)δ204.1,182.5,101.8,71.5,35.6,33.5,31.8,30.7,27.5,26.6,22.5,18.6,14.2,13.5.
实施例37本发明终产物4031的合成:
将1,3-环戊二酮(0.229mmol,22.00mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=1:3v/v),加入樟脑磺酸(0.306mmol,71.00mg)搅拌至溶解,在冰浴环境下缓慢滴加6-((三乙基硅基)氧基)十三碳-1-烯-3-酮(0.153mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=1:3v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物11.4mg,产率为25%。IR(neat,cm-1):2927,2856,1776,1179.1HNMR(500MHz,CDCl3)δ4.32-4.27(m,1H),2.50-2.46(m,1H),2.41-2.39(m,1H),2.27-2.21(m,2H),2.14-2.10(m,1H),2.03-1.94(m,1H),1.93-1.88(m,2H),1.82-1.74(m,2H),1.54-1.41(m,2H),1.36-1.25(m,12H),0.87(t,J=6.5Hz,3H).
实施例38本发明终产物4032的合成:
将1,3-环戊二酮(0.24mmol,26.4mg)溶于叔丁醇与正己烷混合溶液中(0.8ml,叔丁醇:正己烷=3:1v/v),加入樟脑磺酸(0.31mmol,72.5mg)搅拌至溶解,在冰浴环境下缓慢滴加6-苯基-6-((三乙基甲硅烷基)氧基)己-1-烯-3-酮(0.16mmol,50mg)的叔丁醇与正己烷混合溶液(0.4ml,叔丁醇:正己烷=3:1v/v),过夜反应。TLC检测原料反应完全后,饱和碳酸氢钠溶液淬灭反应,乙酸乙酯(1ml)萃取3次,饱和氯化钠溶液洗涤一次,回收有机相真空浓缩,经快速柱层析得到产物18.8mg,产率为65%。1HNMR(500MHz,CDCl3)δ7.37-7.27(m,5H),5.34(t,J=14Hz,1H),2.56-2.51(m,2H),2.50-2.46(m,2H),2.46-2.24(m,4H),2.19-2.12(m,1H),2.10-2.02(m,1H),2.01-1.88(m,2H).13C NMR(125MHz,CDCl3)δ203.8,182.9,142.3,128.6,127.9,125.7,115.1,111.3,81.8,38.2,33.5,33.3,29.6,26.8,14.9.
实施例39抗疟疾化合物的活性测试方案:
恶性疟原虫3D7(Plasmodiumfalciparum 3D7)体外培养,采用SYBR Green I法,测定合成化合物的体外抗疟活性。SYBR Green I法是使用含有DNA荧光染料的裂解液,把疟原虫裂解,继而与暴露出的疟原虫DNA结合,发出荧光,根据荧光强度换算DNA含量,即疟原虫量,从而反应疟原虫的生存状态。
操作步骤
1红细胞准备
用医用采血针和抗EDTA采血管采血加入红细胞保存液保存或离心,吸弃上层的血浆和白细胞,培养基洗两遍使用。
2疟原虫的体外培养
2.1疟原虫的复苏:
从液氮罐中取出恶性疟原虫3D737℃溶解,将虫血转移到离心管中,加入复苏液(16%山梨醇、0.9%氯化钠),混匀,室温静置,离心,弃上清,完全培养基(500mL RPMI1640-Hepes+0.6mL 200mM Hypoxanthine+2.5gAlbumax-II,过滤除菌)重悬,离心,弃上清,将虫血转移到培养瓶中,红细胞和完全培养基,混匀,静置CO2培养箱中培养。
2.2疟原虫的传代
2.2.1疟原虫镜检:培养瓶中的虫血重悬,吸取少量重悬液,离心,弃部分上清,留下与沉淀等体积培养基重悬,涂血片,自然干燥后,滴上无水甲醇固定,甩干或自然干燥,吉姆萨染色液染色,置于100倍油镜下观察,并计算红细胞内恶性疟原虫的感染率。
2.2.2疟原虫分瓶培养:取干净的细胞培养瓶,加入完全培养基,红细胞,根据感染率计算所需传代的比例加入红细胞和虫血沉淀。
2.3疟原虫的同步化:
镜检疟原虫感染率在3%以上并大部分疟原虫处于环状体时期进行同步化。吸弃上清培养液,重悬剩余虫血并将虫血转移至离心管中,加入5%山梨醇溶液,混匀,37℃水浴10min,中间间或颠倒混匀几次;离心后去上清;加入无血清培养基(RPMI1640-Hepe培养基),洗涤,离心去上清;加入完全培养基,适量红细胞后可继续培养。
3药物准备
已知待测药物的摩尔质量,计算所需(储存)浓度药物用量,万分天平称取适量药物至EP管中,用DMSO溶解完全,涡旋振荡器完全混匀,再按照梯度用DMSO稀释,稀释n个梯度。
4虫血配制
药物组及阴性对照组虫血配制:按照加入的虫血标准为0.5%感染率,2%红细胞压积(红细胞体积比),100μL/孔培养体系配制,其中药物与虫血比例为1:100v/v,DMSO占终体积的0.1%。
空白对照组虫血配制:配制空白对照完全培养基含2%压积新鲜红细胞。
铺板:按对应顺序将虫血悬液加入到96孔板中,100μL/孔,边缘孔用等量培养基填充,标记,培养箱37℃,5%CO2,培养72h。
5检测
培养72h后,按照0.2μL Sybrgree1/ml Lysis Buffer配制检测液按100μL/孔的体积加入检测液,37℃培养1h后,置于酶标仪上检测,激发光波长为485nM,发射光波长为535nM。
6结果判断
计算药物抑制率,拟合药物的IC50曲线,比较IC50值,判断药物抗疟活性的效果。
7实验结果:
螺环化合物抗恶性疟原虫P.f.3D7活性筛选结果见表1。每个化合物每个浓度三个复孔,阳性对照是青蒿素(ART)和氯喹(CQ)。,其中化合物4027、4001、4011、4008、4012、4002、4023表现出更好的抗疟活性。
表1:各化合物的抗恶性疟原虫P.f.3D7活性(IC50,μM)
化合物4027表现出显著的抗疟活性,IC50值为1.232±0.9032μM。
以上仅是本发明的优选实施方式,需要说明的是,上述实施方式不以任何形式限制本发明,凡采用等同替换或等效变换的方式所获得的技术方案,均落在本发明的保护范围内。
Claims (7)
1.一种螺环螺缩酮类化合物的制备方法,其特征在于,包括以下步骤:
反应式为:
上述反应式中的m和R1基团为与螺环螺缩酮类化合物相对应的基团;
具体步骤为:由内酯化合物6转换成Weinreb酰胺,并对羟基进行保护得到化合物4,通过格氏反应引入乙烯基后得到相应的ɑ,ß-不饱和酮3,在CSA的催化下与含酚羟基或酮的化合物反应形成螺环螺缩酮类化合物;
所述的含酚羟基或酮的化合物是间苯三酚、间苯二酚、4-羟基-6-甲基-2-吡喃酮、1,3-环己二酮、4-羟基香豆素或1,3-环戊二酮;所述的含酚羟基或酮的化合物是间苯三酚、间苯二酚、4-羟基-6-甲基-2-吡喃酮、1,3-环己二酮、4-羟基香豆素或1,3-环戊二酮;
所述的螺环螺缩酮类化合物是如下所示的任一化合物:
5.一种抗疟原虫药物,其特征在于,含有权利要求1中的螺环螺缩酮类化合物或其药用盐作为活性成分。
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