CN111892608A - 一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用 - Google Patents
一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用 Download PDFInfo
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Abstract
本申请公开的是有机合成领域中的一种具有光学活性的螺杂环2,3‑二氢苯并呋喃类化合物,具有如下结构:
Description
技术领域
本发明涉及有机合成领域,更具体的,本发明为一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用。
背景技术
2,3-二氢苯并呋喃砌块广泛存在众多天然产物与药物分子中,尤其是螺环2,3-二氢苯并呋喃骨架由于其独特的三维空间结构更是构成许多天然分子与药物活性化合物的核心结构单元。
鉴于螺环2,3-二氢苯并呋喃类化合物在有机合成化学与药物化学中的潜在应用价值,获得更多的具有实际应用的手性螺环2,3-二氢苯并呋喃类化合物,对于有效丰富手性2,3-二氢苯并呋喃化合物的种类与开展相关领域的药物化学研究具有重要意义。
发明内容
本发明针对现有技术的不足,提供一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用,为开展相关领域的药物化学研究提供依据。
本发明的一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物,如下式所示:
式中:n为0或1。
本发明的化合物,一般为黄色或淡黄色固体,易溶于二氯甲烷、甲苯、乙醇、乙酸乙酯、丙酮、二甲基亚砜等有机溶剂,难溶于水,具有热力学稳定性的特点。
进一步,当n=0时,R6各自独立地选自tBu或iPr;
相应的,R各自独立地选自Me、Et、nPr、iPr或Ph;
相应的,R1各自独立地选自H、Me、OMe、OCF3、F、Cl、Br、I或NO2;
相应的,R2各自独立地选自F、Cl或Br;
相应的,R3各自独立地选自Me、F、Cl或Br;
相应的,R1、R3也可以同时选自Me;
相应的,R4各自独立地选自Me、OMe、F、Cl或Br;
相应的,R5各自独立地选自Me、OMe、F、Cl或Br。
进一步,当n=1时,R6各自独立地选自tBu或iPr;
相应的,R各自独立地选自Me、Et、nPr、iPr或Ph;
相应的,R1各自独立地选自H、Me、OMe、OCF3、F、Cl、Br、I或NO2;
相应的,R2各自独立地选自F、Cl或Br;
相应的,R3各自独立地选自Me、F、Cl或Br;
相应的,R1、R3也可以同时选自Me;
相应的,R4各自独立地选自Me、OMe、F、Cl或Br;
相应的,R5各自独立地选自Me、OMe、F、Cl或Br。
本发明的化合物是通过以下方法制备,包括:步骤一、向有机溶剂中加入杂环重氮化合物、对苯醌甲基化物以及手性膦酸或手性膦酰亚胺,在-20℃~40℃的反应温度下搅拌9~84h;
步骤二、分离得到具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物。
其中,杂环重氮化合物结构如下式所示:
式中:当n=0时,
R1各自独立地选自H、Me、OMe、OCF3、F、Cl、Br、I或NO2;
R2各自独立地选自F、Cl或Br;
R3各自独立地选自Me、F、Cl或Br;
R1、R3也可以同时选自Me;
当n=1时,R各自独立地选自Me、Et、nPr、iPr或Ph;
相应的,R1、R2、R3各自独立地为H;
对苯醌甲基化物结构如下式所示:
式中:当R6=iPr时,R4各自独立地选自Me、OMe、F、Cl或Br;
相应的,R5各自独立地选自Me、OMe、F、Cl或Br;
当R6=tBu时,R4各自独立地选自Me、OMe、F、Cl或Br;
相应的,R5各自独立地选自Me、OMe、F、Cl或Br。
例如:将0.1mmol对苯醌甲基化物、0.2mmol 3-重氮氧化吲哚/4-重氮氧化异喹啉和0.05mmol(3.0mg)(R)-螺环手性膦酸Cat.D溶解于1mL或2mL甲苯中,在0℃或25℃的反应温度下,搅拌48-84小时;然后,反应液直接用柱层析法进行分离,得到相应的具有光学活性的螺[二氢苯并呋喃-2,3'-氧化吲哚/2,4'-氧化异喹啉]化合物。
进一步,所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物的光学纯度≧65%。
更进一步的,所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物的光学纯度≧80%。
再进一步的,所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物的光学纯度≧85%。
本发明目的在于,提供具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物作为活性成分在制备抗肿瘤药物中的应用。
具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物作为活性成分在制备抗肝癌药物中的应用的应用。
具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物作为活性成分在制备抗肺癌药物中的应用的应用。
经过抗肿瘤活性验证,本发明的化合物对肺癌细胞和肝癌细胞具有一定程度的抑制作用。
具体实施方式
本发明的化合物,反应原料的不同,生成的具体产物如下:
实施例1:
ee;[α]D 25=57.3(c 0.55,CH2Cl2);The ee was determined by HPLC(Chiralpak OD-H,i-PrOH/hexane=10/90,flow rate 0.8mL/min,λ=254nm,major diastereomer:tminor=7.0min,tmajor=9.7min).1H NMR(400MHz,CDCl3):major diastereomer:δ1.27(s,18H),2.62(s,3H),5.05(s,1H),5.14(s,1H),6.63(d,J=7.6Hz,1H),6.72(s,2H),7.00-7.04(m,2H),7.17-7.22(m,2H),7.29(t,J=8.2Hz,1H),7.37(t,J=7.8Hz,1H),7.61(d,J=7.2Hz,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ25.3,30.3,34.3,60.1,92.2,107.8,110.3,121.5,123.2,124.2,124.5,125.0,125.2,128.1,128.2,129.0,130.5,135.5,144.5,153.5,160.9,172.9.HRMS(ESI-TOF)calcd.for C30H34NO3[M+H]+456.2533;found:456.2528.
实施例2:
major diastereomer:δ1.28(s,18H),2.40(s,3H),2.61(s,3H),5.04(s,1H),5.14(s,1H),6.53(d,J=8.0Hz,1H),6.74(s,2H),7.00-7.03(m,2H),7.15-7.17(m,1H),7.20-7.22(m,1H),7.27-7.30(m,1H),7.43(s,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ21.3,25.3,30.3,34.3,60.0,92.2,107.6,110.3,121.5,124.7,124.9,125.0,125.2,128.1,128.2,129.0,130.6,132.8,135.5,142.0,153.5,161.0,172.9.HRMS(ESI-TOF)calcd.forC31H36NO3[M+H]+470.2690;found:470.2686.
实施例3:
MHz,CDCl3):major diastereomer:δ1.30(s,18H),2.60(s,3H),3.85(s,3H),5.04(s,1H),5.16(s,1H),6.56(d,J=8.8Hz,1H),6.75(s,2H),6.91(dd,J=2.6Hz,8.6Hz,1H),7.01-7.04(m,2H),7.21-7.24(m,2H),7.29(t,J=7.8Hz,1H);13C NMR(100MHz,CDCl3):majordiastereomer:δ25.3,30.3,34.3,56.2,60.3,92.4,108.3,110.3,111.1,115.2,121.5,124.5,125.0,125.2,128.1,129.0,129.4,135.5,137.8,153.5,156.5,160.8,172.7.HRMS(ESI-TOF)calcd.for C31H36NO4[M+H]+486.2639;found:486.2633.
实施例4:
5.17(s,1H),6.62(d,J=8.4Hz,1H),6.72(s,2H),7.00-7.04(m,2H),7.20(d,J=7.2Hz,1H),7.24-7.31(m,2H),7.54(d,J=1.2Hz,1H);13C NMR(100MHz,CDCl3):majordiastereomer:δ25.4,30.2,34.3,60.6,91.9,108.3,110.4,118.4,119.4,121.8,122.0,123.7,123.9,125.0,125.2,127.8,129.2,129.6,135.7,143.2,145.1(t,J=2.0Hz,1C),153.7,160.6,172.8.HRMS(ESI-TOF)calcd.for C31H33F3NO4[M+H]+540.2356;found:540.2351.
实施例5:
CDCl3):major diastereomer:δ1.30(s,18H),2.62(s,3H),5.02(s,1H),5.18(s,1H),6.58(dd,J=3.8Hz,8.6Hz,1H),6.74(s,2H),7.01-7.11(m,3H),7.21(d,J=7.2Hz,1H),7.30(t,J=7.8Hz,1H),7.37(dd,J=2.2Hz,7.4Hz,1H);13C NMR(100MHz,CDCl3):majordiastereomer:δ25.4,30.3,34.3,60.4,92.1,108.4(d,J=8.0Hz,1C),110.3,112.4(d,J=25.0Hz,1C),116.6(d,J=24.0Hz,1C),121.7,124.2,125.1,125.2,127.8,129.2,129.8(d,J=8.0Hz,1C),135.6,140.4,153.6,159.5(d,J=240.0Hz,1C),160.6,172.7.HRMS(ESI-TOF)calcd.for C30H33FNO3[M+H]+474.2439;found:474.2432.
实施例6:
CDCl3):major diastereomer:δ1.30(s,18H),2.62(s,3H),5.02(s,1H),5.18(s,1H),6.58(dd,J=3.8Hz,8.6Hz,1H),6.74(s,2H),7.01-7.11(m,3H),7.21(d,J=7.2Hz,1H),7.30(t,J=7.8Hz,1H),7.37(dd,J=2.2Hz,7.4Hz,1H);13C NMR(100MHz,CDCl3):majordiastereomer:δ25.4,30.3,34.3,60.4,92.1,108.4(d,J=8.0Hz,1C),110.3,112.4(d,J=25.0Hz,1C),116.6(d,J=24.0Hz,1C),121.7,124.2,125.1,125.2,127.8,129.2,129.8(d,J=8.0Hz,1C),135.6,140.4,153.6,159.5(d,J=240.0Hz,1C),160.6,172.7.HRMS(ESI-TOF)calcd.for C30H33ClNO3[M+H]+490.2143;found:490.2138.
实施例7:
CDCl3):major diastereomer:δ1.29(s,18H),2.61(s,3H),5.03(s,1H),5.17(s,1H),6.53(d,J=8.0Hz,1H),6.74(s,2H),7.00-7.05(m,2H),7.20(d,J=7.2Hz,1H),7.29(t,J=7.8Hz,1H),7.50(dd,J=2.0Hz,8.4Hz,1H),7.73(d,J=2.0Hz,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ25.4,30.3,34.3,60.3,91.8,109.2,110.3,115.5,121.8,124.3,125.1,125.2,127.4,127.7,129.2,130.4,133.2,135.6,143.4,153.6,160.6,172.5.HRMS(ESI-TOF)calcd.for C30H33BrNO3[M+H]+534.1638;found:534.1631.
实施例8:
CDCl3):major diastereomer:δ1.30(s,18H),2.60(s,3H),5.04(s,1H),5.18(s,1H),6.44(d,J=8.4Hz,1H),6.75(s,2H),7.00-7.05(m,2H),7.21(d,J=7.2Hz,1H),7.29(t,J=7.8Hz,1H),7.70(dd,J=1.6Hz,8.0Hz,1H),7.91(d,J=1.6Hz,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ25.3,30.3,34.3,60.3,91.6,109.8,110.3,121.7,124.2,125.0,125.1,127.7,129.1,130.6,132.9,135,6,139.1,144.1,153.6,160.5,172.3.HRMS(ESI-TOF)calcd.for C30H33INO3[M+H]+582.1500;found:582.1487.
实施例9:
CDCl3):major diastereomer:δ1.24(s,18H),2.66(s,3H),5.06(s,1H),5.17(s,1H),6.68(s,2H),6.72(s,1H),6.98-7.04(m,2H),7.17(d,J=7.2Hz,1H),7.22-7.28(m,1H),8.33(d,J=8.4Hz,1H),8.48(s,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ25.8,30.3,34.3,60.6,91.2,107.4,110.2,110.5,120.2,122.1,123.9,125.1,125.2,127.3,127.5,129.4,135.8,143.7,149.9,153.8,160.3,173.2.HRMS(ESI-TOF)calcd.for C30H33N2O5[M+H]+501.2384;found:501.2380.
实施例10:
major diastereomer:δ1.31(s,18H),2.35(s,3H),2.38(s,3H),2.86(s,3H),4.99(s,1H),5.16(s,1H),6.74(s,2H),6.91(s,1H),6.99-7.03(m,2H),7.21(d,J=7.6Hz,1H),7.26-7.30(m,2H);13C NMR(100MHz,CDCl3):major diastereomer:δ18.7,20.9,28.6,30.3,34.3,60.5,91.9,110.2,119.2,121.4,122.6,124.7,125.0,125.2,128.2,128.9,132.6,134.4,135.4,139.5,153.4,160.9,173.7.HRMS(ESI-TOF)calcd.for C32H37NO3[M+H]+484.2846;found:484.2843.
实施例11:
1H),6.65(d,J=2.0Hz,1H),6.75(s,2H),7.01-7.06(m,2H),7.18(dd,J=1.8Hz,7.8Hz,1H),7.21-7.23(m,1H),7.28-7.32(m,1H),7.54(d,J=8.0Hz,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ25.4,30.2,34.3,60.3,91.7,108.5,110.3,121.7,122.9,124.1,125.0,125.1,125.2,126.5,127.9,129.1,135.7,136.3,145.7,153.6,160.7,172.8.HRMS(ESI-TOF)calcd.for C30H33ClNO3[M+H]+490.2143;found:490.2137.
实施例12:
major diastereomer:δ1.31(s,18H),2.60(s,3H),5.01(s,1H),5.20(s,1H),6.73(s,2H),6.80(s,1H),7.01-7.05(m,2H),7.21(d,J=7.2Hz,1H),7.28-7.35(m,2H),7.48(d,J=8.0Hz,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ25.4,30.2,34.3,60.3,91.8,110.3,111.3,121.7,124.0,124.1,125.0,125.1,125.5,125.9,127.0,127.8,129.1,135.6,145.7,153.6,160.6,172.7.HRMS(ESI-TOF)calcd.for C30H33BrNO3[M+H]+534.1638;found:534.1635.
实施例13:
CDCl3):major diastereomer:δ1.25(s,18H),2.76(s,3H),4.94(s,1H),5.14(s,1H),6.67(s,2H),6.95-6.98(m,2H),7.05(d,J=8.8Hz,2H),7.15(d,J=5.2Hz,1H),7.24(t,J=6.8Hz,1H),7.35(s,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ27.8,30.2(d,J=12.0Hz,1C),34.3(d,J=12.0Hz,1C),60.7,92.1,110.3,118.3,120.1,121.7,123.8,124.1,125.0,127.8,129.1,130.5,131.0,135.7,147.3(d,J=237.1Hz,1C),153.7,160.7,172.6.HRMS(ESI-TOF)calcd.for C30H33FNO3[M+H]+474.2439;found:474.2432.
实施例14:
CDCl3):major diastereomer:δ1.32(s,18H),2.95(s,3H),4.98(s,1H),5.20(s,1H),6.72(s,2H),7.01-7.05(m,2H),7.09-7.12(m,1H),7.21(d,J=8.0Hz,1H),7.28-7.32(m,2H),7.50-7.52(m,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ28.6,30.3,34.3,61.0,91.8,110.3,115.3,121.7,122.7,123.9,124.0,125.0,125.1,127.8,129.2,131.2,132.5,135.7,140.2,153.8,160.9,173.3.HRMS(ESI-TOF)calcd.for C30H33BrNO3[M+H]+490.2144;found:490.2141.
实施例15:
CDCl3):major diastereomer:δ1.29(s,18H),2.93(s,3H),4.94(s,1H),5.18(s,1H),6.68(s,2H),6.98-7.02(m,3H),7.18(d,J=7.2Hz,1H),7.26(t,J=7.2Hz,1H),7.43-7.45(m,1H),7.51(d,J=7.2Hz,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ28.8,30.3,34.3,61.0,91.7,102.0,110.3,121.7,122.1,123.2,123.9,124.3,124.9,125.0,127.7,129.1,131.4,135.6,135.7,141.5,153.7,160.7,173.4.HRMS(ESI-TOF)calcd.forC30H33BrNO3[M+H]+534.1638;found:534.1636.
实施例16:
majordiastereomer:δ1.28(s,18H),4.06(d,J=16.0Hz,1H),4.92(d,J=16.0Hz,1H),5.15(s,1H),5.30(s,1H),6.34(d,J=8.4Hz,1H),6.48-6.49(m,2H),6.90(s,2H),7.01-7.06(m,2H),7.15-7.19(m,4H),7.30(t,J=7.8Hz,1H),7.35(dd,J=1.8Hz,8.2Hz,1H),7.81(d,J=2.0Hz,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ30.4,34.4,43.9,59.7,91.5,110.2,110.7,115.7,121.8,124.0,124.8,126.2,126.4,127.4,127.7,128.8,129.0,129.2,129.8,133.3,134.8,135.8,143.2,153.9,160.2,172.7.HRMS(ESI-TOF)calcd.forC36H36BrNO3[M+H]+610.1952;found:610.1949.
实施例17:
CDCl3):major diastereomer:δ1.30(s,18H),1.39(s,9H),5.06(s,1H),5.19(s,1H),6.75(s,2H),6.99-7.06(m,2H),7.20(d,J=7.2Hz,1H),7.30(t,J=7.6Hz,1H),7.55-7.57(m,1H),7.75-7.80(m,2H);13C NMR(100MHz,CDCl3):major diastereomer:δ28.0,30.3,34.4,61.2,84.1,91.0,110.3,117.0,118.0,121.9,123.7,125.1,125.2,127.0,127.2,129.4,129.6,133.6,136.0,139.5,148.5,153.8,160.4,170.5.HRMS(ESI-TOF)calcd.forC34H38BrNNaO5[M+Na]+642.1825;found:642.1824.
实施例18:
mg,51%yield;5:1dr,93%ee;[α]D 25=-19.5(c 0.39,CH2Cl2);The ee was determined byHPLC(Chiralpak OD-H,i-PrOH/hexane=10/90,flow rate 1.0mL/min,λ=254nm,majordiastereomer:tminor=11.0min,tmajor=5.7min).1H NMR(400MHz,CDCl3):majordiastereomer:δ1.29(s,18H),2.69(s,3H),4.97(s,1H),5.16(s,1H),6.52-6.61(s,3H),6.73(s,2H),7.07(dd,J=0.8Hz,8.0Hz,1H),7.50(dd,J=1.8Hz,8.2Hz,1H),7.72(d,J=1.6Hz,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ25.4,30.3,34.3,55.7,59.8,92.4,97.1,107.4,109.2,115.5,119.5,124.6,125.0,125.1,127.4,130.3,133.1,135.6,143.3,153.6,161.1,161.8,172.5.HRMS(ESI-TOF)calcd.for C31H34BrNNaO4[M+Na]+586.1563;found:586.1552.
实施例19:
NMR(400MHz,CDCl3):major diastereomer:δ1.29(s,18H),2.60(s,3H),4.97(s,1H),5.19(s,1H),6.53(d,J=8.4Hz,1H),6.71(s,2H),7.00-7.02(m,2H),7.08-7.11(m,1H),7.51(dd,J=2.0Hz,8.4Hz,1H),7.73(d,J=2.0Hz,1H);13C NMR(100MHz,CDCl3):majordiastereomer:δ25.5,30.3,34.3,59.7,92.5,109.4,111.2,115.6,122.0,123.6,125.1,125.5,126.7,127.5,129.7,133.4,134.5,135.7,143.4,153.8,161.3,172.1.HRMS(ESI-TOF)calcd.for C33H32BrClNO3[M+H]+568.1249;found:568.1242.
实施例20:
NMR(400MHz,CDCl3):major diastereomer:δ1.29(s,18H),2.61(s,3H),4.95(s,1H),5.20(s,1H),6.53(d,J=8.4Hz,1H),6.71(s,2H),7.05(d,J=7.6Hz,1H),7.15-7.17(m,2H),7.51(dd,J=1.6Hz,8.4Hz,1H),7.73(d,J=1.6Hz,1H);13C NMR(100MHz,CDCl3):majordiastereomer:δ25.4,30.3,34.3,59.7,92.4,109.3,114.0,115.6,122.1,123.5,124.9,125.1,126.0,127.3,127.5,129.6,133.4,135.7,143.3,153.8,161.4,172.1.HRMS(ESI-TOF)calcd.for C30H32Br2NO3[M+H]+612.0743;found:612.0740.
实施例21:
NMR(400MHz,CDCl3):major diastereomer:δ1.30(s,18H),2.34(s,3H),2.60(s,3H),4.99(s,1H),5.17(s,1H),6.52(d,J=8.0Hz,1H),6.74(s,2H),6.89(d,J=8.0Hz,1H),7.02(s,1H),7.09(d,J=8.0Hz,1H),7.49(d,J=8.0Hz,1H),7.72(s,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ21.1,25.4,30.3,34.3,60.4,91.9,109.2,109.8,115.5,124.3,125.2,125.6,127.4,127.7,129.5,130.4,131.1,133.1,135.6,143.4,153.6,158.5,172.6.HRMS(ESI-TOF)calcd.for C31H35BrNO3[M+H]+548.1795;found:548.1793.
实施例22:
min).1HNMR(400MHz,CDCl3):major diastereomer:δ1.27(s,18H),2.57(s,3H),3.75(s,3H),4.99(s,1H),5.16(s,1H),6.49(d,J=8.0Hz,1H),6.73(s,2H),6.77-6.82(m,2H),6.89(d,J=8.8Hz,1H),7.48(dd,J=1.8Hz,8.2Hz,1H),7.72(d,J=2.0Hz,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ25.4,30.3,34.3,56.2,60.6,92.1,109.2,110.3,111.1,114.3,115.5,124.0,125.2,127.4,128.6,130.2,133.1,135.6,143.3,153.7,154.5,155.1,172.6.HRMS(ESI-TOF)calcd.for C31H35BrNO4[M+H]+564.1744;found:564.1742.
实施例23:
NMR(400MHz,CDCl3):major diastereomer:δ1.30(s,18H),2.60(s,3H),3.75(s,3H),5.01(s,1H),5.19(s,1H),6.52(d,J=8.4Hz,1H),6.72(s,2H),6.89-6.92(m,2H),6.95-7.00(m,1H),7.51(dd,J=1.8Hz,8.2Hz,1H),7.75(d,J=2.0Hz,1H);13C NMR(100MHz,CDCl3):majordiastereomer:δ25.4,30.3,34.3,60.3,92.4,109.3,110.5(d,J=8.0Hz,1C),112.3(d,J=26.0Hz,1C),115.3(d,J=24.0Hz,1C),115.6,123.5,125.1,127.5,129.5(d,J=9.0Hz,1C),129.8,133.3,135.8,143.4,153.8,156.4,158.3(d,J=237.0Hz,1C),172.4.HRMS(ESI-TOF)calcd.for C30H32BrFNO3[M+H]+552.1544;found:552.1543.
实施例24:
NMR(400MHz,CDCl3):major diastereomer:δ1.28(s,18H),2.59(s,3H),4.98(s,1H),5.17(s,1H),6.50(d,J=8.0Hz,1H),6.70(s,2H),6.90(d,J=8.4Hz,1H),7.14(s,1H),7.21-7.24(m,1H),7.49(dd,J=2.0Hz,8.4Hz,1H),7.71(d,J=2.0Hz,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ25.5,30.3,34.4,60.2,92.4,109.4,111.2,115.6,123.4,125.1,125.2,126.7,127.5,129.1,129.7,130.1,133.4,135.8,143.4,153.9,159.2,172.2.HRMS(ESI-TOF)calcd.for C33H32BrClNO3[M+H]+568.1249;found:568.1245.
实施例25:
NMR(400MHz,CDCl3):major diastereomer:δ1.29(s,18H),2.61(s,3H),5.00(s,1H),5.19(s,1H),6.52(d,J=8.4Hz,1H),6.71(s,2H),6.88(d,J=8.4Hz,1H),7.30(s,1H),7.38(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),7.73(s,1H);13C NMR(100MHz,CDCl3):majordiastereomer:δ25.5,30.3,34.3,60.1,92.3,109.4,111.9,113.8,115.6,123.3,125.1,127.5,128.0,129.6,130.5,132.0,133.4,135.8,143.4,153.8,159.7,172.1.HRMS(ESI-TOF)calcd.for C30H32Br2NO3[M+H]+612.0743;found:612.0744.
实施例26:
major diastereomer:δ0.78(t,J=7.2Hz,3H),1.32(s,18H),3.06-3.14(m,1H),3.22-3.31(m,1H),4.80(s,1H),5.24(s,1H),6.64(s,2H),7.02(t,J=7.4Hz,1H),7.08(d,J=8.0Hz,1H),7.13(d,J=8.4Hz,1H),7.32-7.36(m,1H),7.56-7.60(m,1H),7.74-7.78(m,1H),7.85-7.87(m,1H),8.18-8.21(m,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ13.0,30.1,34.4,35.9,65.9,91.5,109.8,121.8,124.7,125.0,125.2,125.3,125.5,126.7,128.4,129.1,129.4,134.6,136.3,140.2,154.2,161.2,163.0,169.6.HRMS(ESI-TOF)calcd.for C32H35NO4[M+H]+498.2639;found:498.2636.
实施例27:
NMR(400MHz,CDCl3):major diastereomer:δ0.77(t,J=7.2Hz,3H),1.32(s,18H),3.07-3.15(m,1H),3.23-3.31(m,1H),4.74(s,1H),5.26(s,1H),6.60(s,2H),6.96-7.02(m,2H),7.13(d,J=1.6Hz,1H),7.57-7.62(m,1H),7.75-7.84(m,2H),8.19-8.21(m,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ12.9,30.0,34.3,35.8,65.1,92.1,110.6,121.9,124.2,124.5,125.0,125.3,125.5,125.6,128.3,129.1,134.5,134.6,136.3,139.4,154.2,161.8,162.7,169.4.HRMS(ESI-TOF)calcd.for C32H34ClNO4[M+H]+532.2249;found:532.2248.
实施例28:
NMR(400MHz,CDCl3):major diastereomer:δ0.77(t,J=7.0Hz,3H),1.32(s,18H),3.07-3.15(m,1H),3.20-3.31(m,1H),4.72(s,1H),5.26(s,1H),6.60(s,2H),6.92-6.94(m,1H),7.14-7.17(m,1H),7.28-7.32(m,1H),7.58-7.62(m,1H),7.75-7.83(m,2H),8.19-8.21(m,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ13.0,30.1,34.4,35.9,65.4,92.1,113.5,122.4,124.3,124.7,124.9,125.1,125.5,126.2,126.3,128.4,129.3,134.7,136.4,139.6,154.4,162.0,162.8,169.5.HRMS(ESI-TOF)calcd.for C32H34BrNO4[M+H]+576.1744;found:576.1744.
实施例29:
was determined by HPLC(Chiralpak OD-H,i-PrOH/hexane=5/95,flow rate 0.5mL/min,λ=254nm,major diastereomer:tminor=5.8min,tmajor=10.5min).1H NMR(400MHz,CDCl3):major diastereomer:δ0.78(t,J=7.0Hz,3H),1.33(s,18H),2.32(s,3H),3.06-3.15(m,1H),3.22-3.31(m,1H),4.76(s,1H),5.23(s,1H),6.64(s,2H),6.90(s,1H),7.02(d,J=8.4Hz,1H),7.13(d,J=8.0Hz,1H),7.55-7.59(m,1H),7.73-7.77(m,1H),7.84-7.86(m,1H),8.18-8.20(m,1H);13C NMR(100MHz,CDCl3):major diastereomer:δ13.1,21.0,30.2,34.4,35.9,66.0,91.6,109.3,124.7,125.1,125.3,125.5,125.8,126.6,128.3,129.0,129.8,131.2,134.6,136.3,140.4,154.2,159.2,163.0,170.0.HRMS(ESI-TOF)calcd.for C33H37NO4[M+H]+512.2796;found:512.2795.
抗肿瘤活性验证:
选取实施例21~25的化合物为代表,以人源肺癌细胞株(A549)和人源肝癌细胞株(HepG2)为受体,测试其体外抗肿瘤活性(MTT比色法)。
以实施例21的化合物为例进行说明,具体实验操作如:
(1)取对数生长期的人源肺癌细胞株(A549)或人源肝癌细胞株(HepG2),用含10%胎牛血清的新鲜DMEM培养基将细胞密度调至1×105cells·mL-1,接种于96孔板内,100μL/well,于37℃,5%CO2的培养箱内培养。
(2)细胞贴壁培养24h后换成无血清的新鲜培养液,同时进行加药处理。样品设剂量0.4,2,10和50μmol/mL,同时设空白对照组。
(3)细胞加药后继续培养48h后,将MTT染色液(10μL,0.5mg/mL)加入到培养基中,细胞于37℃下继续培养4小时。
(4)移去培养基,加入100μL二甲基亚砜用于溶解福尔马赞晶体,用酶标仪(ELx800,Bio-Tek,Winooski,VT,USA)在570nm下测定OD值,并计算实施例21化合物的IC50值。
实施例22~25化合物的肿瘤细胞抑制活性实验按照与实施例21类似的方法操作。
表1为实施例21~25的化合物对人肝癌细胞和人肺癌细胞增殖的抑制作用。
通过以上实验,结果表明本发明所涉及的化合物对肺癌细胞和肝癌细胞具有一定程度的抑制作用。
Claims (9)
2.根据权利要求1所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物,其特征在于:当n=0时,R6各自独立地选自tBu或iPr;
相应的,R各自独立地选自Me、Et、nPr、iPr或Ph;
相应的,R1各自独立地选自H、Me、OMe、OCF3、F、Cl、Br、I或NO2;
相应的,R2各自独立地选自F、Cl或Br;
相应的,R3各自独立地选自Me、F、Cl或Br;
相应的,R4各自独立地选自Me、OMe、F、Cl或Br;
相应的,R5各自独立地选自Me、OMe、F、Cl或Br。
3.根据权利要求1所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物,其特征在于:当n=1时,R6各自独立地选自tBu或iPr;
相应的,R各自独立地选自Me、Et、nPr、iPr或Ph;
相应的,R1各自独立地选自H、Me、OMe、OCF3、F、Cl、Br、I或NO2;
相应的,R2各自独立地选自F、Cl或Br;
相应的,R3各自独立地选自Me、F、Cl或Br;
相应的,R4各自独立地选自Me、OMe、F、Cl或Br;
相应的,R5各自独立地选自Me、OMe、F、Cl或Br。
4.根据权利要求1所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物,其特征在于:所述化合物的光学纯度≧65%。
5.根据权利要求4所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物,其特征在于:所述化合物的光学纯度≧80%。
6.根据权利要求5所述的具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物,其特征在于:所述化合物的光学纯度≧85%。
7.根据权利要求1~6任一所述的化合物作为活性成分在制备抗肿瘤药物中的应用。
8.根据权利要求1~6任一所述的化合物作为活性成分在制备抗肝癌药物中的应用。
9.根据权利要求1~6任一所述的化合物作为活性成分在制备抗肺癌药物中的应用。
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CN116082353A (zh) * | 2022-12-31 | 2023-05-09 | 浙江工业大学 | 一种二氢苯并呋喃螺吡咯酮的制备方法 |
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