CN111333604A - 一种3-氧代-异色满-4-酮衍生物及其合成方法 - Google Patents
一种3-氧代-异色满-4-酮衍生物及其合成方法 Download PDFInfo
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Abstract
Description
技术领域
本发明属于有机化学领域,具体涉及一种3-氧代-异色满-4-酮衍生物及其合成方法。
背景技术
3-氧-异色满-4-酮骨架是许多天然产物及药物活性分子的重要组成部分。例如,化合物terreinol,是从巴西菌株A.terreus中分离得到的代谢产物,其具有新颖的二氧螺环结构(Tetrahedron Lett.2004,45,53-55);eleganketal A是近来从海洋微生物Spicariaelegans KLA03中分离出来的多氧代螺环异色满酮化合物,其全甲基化衍生物具有良好的抗禽流感活性(J.Nat.Prod.2014,77,1718-1723);penicisochroman K,是从内生真菌Penicillium sp.BCC18034分离得到的3-羟基-异色满-4-酮(PhytochemistryLetters 2014,10,13-18)。这类化合物均具有良好的药理特性,比如抗氧化性、抗肿瘤、抗菌活性等。然而,这类具有重要生物活性的3-氧代-异色满-4-酮类化合物的合成方法较少(Tetrahedron2005,61,11882-11886;博士论文,抗球虫药常山酮的全合成及3H-spiro[isobenzofuran-1,3’-isochroman]骨架构筑研究,王亮,2017)。
此外,异色满类化合物的1位,在氧化条件下,很容易与亲核试剂发生交叉脱氢偶联反应,生成多取代的异色满类化合物。然而,如何有效地区域选择性的在3位发生氧化反应生成3-氧代-异色满类化合物,仍有许多问题亟待解决。异色满-4-酮类化合物同样存在相应问题。因此,发展更加高效的合成3-氧代-异色满-4-酮类化合物的方法,对发现具有重要生物活性的药物先导化合物是非常必要的。
发明内容
本发明针对现有技术的不足,旨在提供一种高效的、对于底物具有普适性的3-氧代-异色满-4-酮衍生物及其合成方法。
本发明3-氧代-异色满-4-酮衍生物,其结构通式为:
其中:R1为氢、烷氧基、硝基、氰基、酯基或卤素;R2为烷基。
本发明3-氧代-异色满-4-酮衍生物的合成方法,是以取代异色满-4-酮底物为起始原料,反应体系中加入氧化剂,该底物的3位则会与醇发生氧化反应得到目标产物。
本发明底物取代异色满-4-酮可通过如下制备路线的常规方法制得(Chem.Biol.Drug.Des.2018,91,756–762.):
邻溴苯甲醇2与溴代乙酸叔丁酯3发生取代反应生成4,经过水解生成羧酸5,5与N-甲基-N-甲氧基经过缩合生成Weinreb酰胺6,6在叔丁基锂条件下发生自身的环合反应得到各种取代的异色满-4-酮1。
本发明3-氧代-异色满-4-酮衍生物的合成方法,包括如下步骤:
将底物取代异色满-4-酮、醇、催化剂、氧化剂和有机溶剂进行混合,在25~100℃下反应12~72小时,反应结束后分离获得目标产物。
每0.1mmol取代异色满-4-酮使用0.1~1.0mmol的醇、0.01~0.02mmol的催化剂、0.1~0.3mmol的氧化剂和0.5~2mL的有机溶剂。
所述醇为脂肪醇。
所述催化剂为二甲胺、二乙胺、吡咯烷、哌啶中的任一种,优选为哌啶。
所述氧化剂为空气、双氧水、过氧叔丁醇中的任一种,优选为过氧叔丁醇。
所述有机溶剂为甲苯、二甲苯、三甲苯、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、正己烷中的一种或任意两种的混合溶剂,优选为甲苯。
所述分离是指使用薄层层析硅胶H柱在空气加压下进行柱层析,洗脱液为体积比100~20:1的石油醚/乙酸乙酯混合物;优选地,洗脱液为体积比为50~25:1的石油醚/乙酸乙酯混合物。
本发明反应过程示意如下:
本发明为验证底物的普适性,在上述优选条件下进一步提供一种异色满-4-酮与乙醇的反应,反应式和对应产物如下:
反应过程:将0.1mmol的1、0.3mmol的乙醇、0.015的催化剂哌啶和0.2mmol的过氧叔丁醇加入到1.0ml的甲苯中,在50℃下反应48小时。
可以看到,无论取代基的位置和电子性质如何,本发明的反应在优选条件下能够顺利进行,制备3-氧代-异色满-4-酮类化合物7。
为了深入验证本发明合成方法对各种底物具有广泛的应用性,本发明还研究了其他伯醇、仲醇和叔醇对反应的影响,提供如下反应:
上述反应过程:将0.1mmol的异色满-4-酮、0.3mmol的乙醇、0.015mmol的催化剂哌啶和0.2mmol的过氧叔丁醇加入到1.0ml的甲苯中,在50℃下反应48小时。
结果显示,其他的伯醇、仲醇以及叔醇对于区域选择性方面没有显著差异。
本发明制备3-氧代-异色满-4-酮类化合物的方法,从简单易得的异色满-4-酮底物和脂肪醇底物通过氧化反应得到,操作简便、反应条件温和、原料经济易得。本发明制备得到的3-氧代-异色满-4-酮类化合物,有望在医药研发领域得到广泛应用。
具体实施方式
以下通过具体的实施方式,对本发明的上述内容做进一步的详细说明,但不应将此理解为对本发明保护主题的任何限制。凡基于本发明上述内容所实现的技术方案均属于本发明的范围。本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。
实施例1:化合物7a的制备
将异色满-4-酮1a(14.8mg,0.1mmol)和催化剂哌啶(1.5mg,0.015mmol)加入到干燥的Schlenk管中,使用注射器在室温下将乙醇(13.8mg,0.3mmol)和甲苯(1mL)依次注入,最后加入过氧叔丁醇(18.0mg,0.2mmol)并将管密封。将所得混合物加热至50℃反应48小时,静置至室温。减压蒸发溶剂,残留物通过硅胶,柱色谱纯化(石油醚/乙酸乙酯=50/1~40/1),得到无色油状化合物7a,产率78%。
1H NMR(600MHz,CDCl3)δ8.04(d,J=7.8Hz,1H),7.55(t,J=7.5Hz,1H),7.39(t,J=7.6Hz,1H),7.19(d,J=7.7Hz,1H),5.20(d,J=15.4Hz,1H),5.04(s,1H),4.72(d,J=15.4Hz,1H),1.28(t,J=7.1Hz,3H).13C NMR(151MHz,CDCl3)δ189.91,142.38,142.35,133.19,130.91,121.89,98.67,64.88,61.31,22.60,14.99.HRMS(ESI)m/z(M+H)+calculated for C11H13O3:193.0859,observed:193.0555.
实施例2:化合物7b的制备
用底物7-甲基-异色满-4-酮代替异色满-4-酮,通过实施例1的方法,制备得到无色油状化合物7ba,产率70%。
1H NMR(400MHz,CDCl3)δ8.21(d,J=8.0Hz,1H),7.47(d,J=8.0Hz,1H),7.26(s,1H),5.44(d,J=15.4Hz,1H),5.29(s,1H),4.94(d,J=15.4Hz,1H),4.21(dt,J=14.4,7.2Hz,1H),4.04–3.98(m,1H),2.67(s,3H),1.55(t,J=7.1Hz,3H).13C NMR(151MHz,CDCl3)δ188.22,145.25,141.47,128.68,127.34,125.76,124.38,97.93,65.04,60.67,21.96,14.97.HRMS(ESI)m/z(M+H)+calculated for C12H15O3:207.1016,observed:207.1017.
实施例3:化合物7c的制备
用底物8-甲基-异色满-4-酮代替异色满-4-酮,通过实施例1的方法,制备得到无色油状化合物7c,产率77%。
1H NMR(600MHz,CDCl3)δ7.92(d,J=7.8Hz,1H),7.38(d,J=7.5Hz,1H),7.30(t,J=7.6Hz,1H),5.03(t,J=7.9Hz,2H),4.77(d,J=15.9Hz,1H),3.98–3.93(m,1H),3.78–3.73(m,1H),2.26(s,3H),1.29(t,J=7.1Hz,3H).13C NMR(151MHz,CDCl3)δ188.52,139.48,135.53,133.19,128.07,127.26,124.95,97.38,77.21,77.00,76.79,65.13,59.39,18.05,14.99.HRMS(ESI)m/z(M+H)+calculated for C12H15O3:207.1016,observed:207.1015.
实施例4:化合物7d的制备
用底物5-甲基-异色满-4-酮代替异色满-4-酮,同通过实施例1的方法,制备得到无色油状化合物7d,产率52%。
1H NMR(600MHz,CDCl3)δ7.40(t,J=7.6Hz,1H),7.16(d,J=7.6Hz,1H),7.02(d,J=7.6Hz,1H),5.21(d,J=15.3Hz,1H),4.97(s,1H),4.71(d,J=15.3Hz,1H),3.93(dq,J=9.6,7.1Hz,1H),3.73(dq,J=9.6,7.1Hz,1H),2.68(s,3H),1.29(t,J=7.1Hz,3H).13C NMR(151MHz,CDCl3)δ189.89,142.36,133.15,130.90,126.16,121.87,98.68,77.20,76.99,76.78,64.87,61.32,22.55,14.97,0.99.HRMS(ESI)m/z(M+H)+calculated for C12H15O3:207.1016,observed:207.1015.
实施例5:化合物7e的制备
用底物7-甲氧基-异色满-4-酮代替4-异色满酮,通过实施例1的方法,制备得到无色油状化合物7e,产率77%。
1H NMR(600MHz,CDCl3)δ8.02(d,J=8.7Hz,1H),6.90(dd,J=8.7,2.4Hz,1H),6.62(d,J=2.3Hz,1H),5.17(d,J=15.3Hz,1H),5.00(s,1H),4.66(d,J=15.3Hz,1H),3.93(dq,J=9.6,7.1Hz,1H),3.86(s,3H),3.74(dq,J=9.6,7.1Hz,1H),1.28(t,J=7.1Hz,3H).13CNMR(151MHz,CDCl3)δ187.30,164.20,143.88,129.86,121.57,114.27,108.11,97.95,77.20,76.99,76.78,65.06,60.79,55.55,14.98.HRMS(ESI)m/z(M+H)+calculated forC12H15O4:223.0965,observed:223.0960.
实施例6:化合物7f的制备
用底物丙醇代替乙醇,通过实施例1的方法,制备得到无色油状化合物7f,产率74%。
1H NMR(600MHz,CDCl3)δ8.05(d,J=7.8Hz,1H),7.55(dd,J=10.8,4.3Hz,1H),7.40(t,J=7.6Hz,1H),7.19(d,J=7.7Hz,1H),5.21(d,J=15.4Hz,1H),5.03(s,1H),4.71(d,J=15.4Hz,1H),3.84(dt,J=9.5,6.9Hz,1H),3.65(dt,J=9.5,6.6Hz,1H),1.70–1.64(m,2H),0.94(t,J=7.4Hz,3H).13C NMR(151MHz,CDCl3)δ188.34,141.42,134.03,128.12,127.63,127.22,124.03,98.01,77.20,76.99,76.78,71.25,60.62,22.73,10.48.HRMS(ESI)m/z(M+H)+calculated for C12H15O3:207.1016,observed:207.1018.
实施例7:化合物7g的制备
用底物正丁醇代替乙醇,同通过实施例1的方法,制备得到无色油状化合物7g,产率71%。
1H NMR(400MHz,CDCl3)δ8.05(d,J=7.7Hz,1H),7.56(td,J=7.6,1.2Hz,1H),7.40(t,J=7.6Hz,1H),7.19(d,J=7.7Hz,1H),5.20(d,J=15.4Hz,1H),5.02(s,1H),4.71(d,J=15.4Hz,1H),3.89(dt,J=9.5,6.8Hz,1H),3.68(dt,J=9.5,6.5Hz,1H),1.65–1.61(m,2H),1.43–1.36(m,2H),0.92(t,J=7.4Hz,3H).13C NMR(101MHz,CDCl3)δ188.45,141.46,134.12,128.13,127.69,127.28,124.10,98.05,77.36,77.04,76.72,69.48,60.64,31.55,19.25,13.84.HRMS(ESI)m/z(M+H)+calculated for C13H17O3:221.1172,observed:221.1173。
Claims (10)
3.根据权利要求2所述的合成方法,其特征在于包括如下步骤:
将底物取代异色满-4-酮、醇、催化剂、氧化剂和有机溶剂进行混合,在25~100℃下反应12~72小时,反应结束后分离获得目标产物。
4.根据权利要求3所述的合成方法,其特征在于:
每0.1mmol取代异色满-4-酮使用0.1~1.0mmol的醇、0.01~0.02mmol的催化剂、0.1~0.3mmol的氧化剂和0.5~2mL的有机溶剂。
5.根据权利要求3或4所述的合成方法,其特征在于:
所述醇为脂肪醇。
6.根据权利要求3或4所述的合成方法,其特征在于:
所述催化剂为二甲胺、二乙胺、吡咯烷、哌啶中的任一种。
7.根据权利要求6所述的合成方法,其特征在于:
所述催化剂为哌啶。
8.根据权利要求3或4所述的合成方法,其特征在于:
所述氧化剂为空气、双氧水、过氧叔丁醇中的任一种。
9.根据权利要求8所述的合成方法,其特征在于:
所述氧化剂为过氧叔丁醇。
10.根据权利要求3所述的合成方法,其特征在于:
所述分离是指使用薄层层析硅胶H柱在空气加压下进行柱层析,洗脱液为体积比100~20:1的石油醚/乙酸乙酯混合物。
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