CN104327025A - 一种4-芳基萘内酯类衍生物的制备方法 - Google Patents
一种4-芳基萘内酯类衍生物的制备方法 Download PDFInfo
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- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
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- C—CHEMISTRY; METALLURGY
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
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- C07F7/0805—Compounds with Si-C or Si-Si linkages comprising only Si, C or H atoms
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Abstract
本发明公开了一种4-芳基萘内酯类衍生物的制备方法。以炔丙醇和炔丙酸为原料,在20~90oC反应温度下,在有机溶剂中反应,经过浓缩、柱层析及重结晶纯化过程得到4-芳基萘内酯类衍生物,炔丙醇和炔丙酸的摩尔比为1:1~2。本发明反应原料易得,反应条件温和,工艺简单,操作便捷;所得4-芳基萘内酯类衍生物有潜在的良好的生物活性,并可以作为有机合成中间体使用。
Description
技术领域
本发明涉及一种4-芳基萘内酯类衍生物的制备方法。
背景技术
芳基萘内酯类化合物(Arylnaphthalenelignan lactones)是一类重要的天然木脂素,具有潜在的抗病毒、抗肿瘤、杀菌等生物活性,在有机合成以及药物化学中受到广泛关注。参考文献见J.Nat.Prod.,1989,52,367;Eur.J.Med.Chem.,2001,36,389;J.Org.Chem.,1995,60,4585;J.Org.Chem.,2003,68,854。现已知的芳基萘木脂素类化合物已经有超过30种,而这其中超过90%的化合物是以内酯的形式存在,这些萘内酯都是基于式1中所示两种骨架I和II,例如Retrojusticidine B,Justicidine E,Retrochinensin,Justicidine B,Taiwanin C,Chinensin等(见式2)。
传统的合成芳基萘内酯骨架的方法有两分子苯丙炔酸的自身缩合、还原反应,参考文献见Ber.,1895,28,2511;苯基丙炔醚的自身缩合、氧化反应,参考文献见J.Heterocycl.Chem.,1974,11,687,Chem.Pharm.Bull.,1964,12,1694;芳基炔、二氧化碳和含有离去基团的芳基丙炔之间的串联反应,参考文献见Green Chem.,2010,12,888,J.Org.Chem.,2008,73,6932,这些方法得到的都是1‐芳基萘内酯和4‐芳基萘内酯的混合物。而通过苯基丙炔酸苯基丙炔酯的自身缩合反应,参考文献见J.Org.Chem.,1966,31,2376,Tetrahedron,1966,22,1797;2,3‐二羟甲基萘或2,3‐二醛基萘的缩合反应,参考文献见Chem.Eur.J.,2011,17,12596,Chem.Commun.,2009,6741以及苯基丙炔酸丙炔酯和苯炔的[2+2+2]环加成反应,参考文献见Angew.Chem.Int.Ed.,2004,43,2436,Adv.Synth.Catal.,2007,349,647,则可以选择性地得到单一的芳基萘内酯骨架。
由于芳基萘内酯类衍生物通常具有较高的生物活性,而且经常能作为有机合成的重要中间体使用,因此开发简便、高效、快捷地合成芳基萘内酯类衍生物的方法,从而建立芳基萘内酯类衍生物的化合物库,进而筛选出具有良好活性的新药,有着重要的意义和重大的应用前景。
发明内容
本发明的目的是克服现有技术的不足,提供一种反应温和、操作简便的4-芳基萘内酯类衍生物的制备方法。
4-芳基萘内酯类衍生物的制备方法是:以炔丙醇和炔丙酸为原料,在20~90℃的反应温度下,在有机溶剂中反应1-24小时,经过浓缩、柱层析及重结晶纯化过程得到4-芳基萘内酯类衍生物;炔丙醇和炔丙酸的摩尔比为1:1~2;4-芳基萘内酯类衍生物结构式为:
式中:R1选自氢、C1~C6的烷基或环状烷基、三甲基硅基、苯基或取代的苯基;R2、R3选自氢、C1~C4的烷基或C1~C4的烷氧基;R4选自氢、苯基或取代的苯基;所述取代的苯基上的取代基是卤素、C1~C4的烷基或C1~C4的烷氧基。
所述的有机溶剂为二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、甲苯、四氢呋喃、乙腈、DMF、DMSO或1,4-二氧六环中的一种或二种。
本发明与现有技术相比,具有的有益效果:
1)反应条件温和;
2)不需要使用任何金属催化剂;
3)反应通用性强,底物普适性广;
4)投料和后处理都非常简单;
5)反应起始原料容易获得。
具体实施方式
4-芳基萘内酯类衍生物的制备方法是:以炔丙醇和炔丙酸为原料,在20~90℃的反应温度下,在有机溶剂中反应1-24小时,经过浓缩、柱层析及重结晶纯化过程得到4-芳基萘内酯类衍生物;炔丙醇和炔丙酸的摩尔比为1:1~2;4-芳基萘内酯类衍生物结构式为:
式中:R1选自氢、C1~C6的烷基或环状烷基、三甲基硅基、苯基或取代的苯基;R2、R3选自氢、C1~C4的烷基或C1~C4的烷氧基;R4选自氢、苯基或取代的苯基;所述取代的苯基上的取代基是卤素、C1~C4的烷基或C1~C4的烷氧基。
所述的有机溶剂为二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、甲苯、四氢呋喃、乙腈、DMF、DMSO或1,4-二氧六环中的一种或二种。
4-芳基萘内酯类衍生物反应式为:
本发明中炔丙醇原料可以按照文献或如下方法制备:
炔丙醇的制备方法:
方案一:在N2气氛的保护下,向100mL的三口瓶中,加入相应的炔(40mmol),干燥 的THF20mL,冷却至‐78℃,加入n‐BuLi(40mmol,2.5M,16mL),反应30min后缓慢滴加相应的二苯甲酮(40mmol in40mL dry THF),保温反应半小时后移至室温下继续反应2h。用NH4Cl饱和溶液终止反应,用二氯甲烷萃取3次,合并有机相,NaCl饱和溶液洗涤,无水Na2SO4干燥,过滤,25℃下,减压旋干滤液,经柱层析后得到相应的炔丙醇。
方案二:在N2气氛的保护下,在100mL的三口瓶中,在室温下注射入乙炔基溴化镁(10mmol,0.5M,20mL),然后滴加相应的二苯甲酮(10mmol in10mL THF),在50℃下反应过夜。反应结束后,用NH4Cl饱和溶液终止反应,用乙酸乙酯萃取3次,合并有机相,NaCl饱和溶液洗涤,无水Na2SO4干燥,过滤,25℃下,减压旋干滤液,经柱层析后得到相应的炔丙醇。
方案三:在N2气氛的保护下,向100mL的三口瓶中,加入PdCl2(PPh3)2(140mg,0.2mmol,2mol%),CuI(38mg,0.2mmol,2mol%)。慢慢滴入混合溶液(对溴碘苯10mmol,1,1‐二苯基‐2‐丙炔‐1‐醇10.5mmol,二异丙基胺10mL,THF10mL),反应过夜后,过滤,25℃下,减压旋干滤液,经柱层析后得到相应的炔丙醇。
以下实例将有助于理解本发明,但不限于本发明的内容:
实施例1
把1,1,3‐三苯基‐2‐丙炔醇(1毫摩尔)置于反应釜中,依次加入丙炔酸(1毫摩尔),氯仿5mL,在70℃搅拌反应24小时,反应完毕,减压浓缩溶剂至干,残留物在硅胶柱中用乙酸乙酯/石油醚(=1/20)过柱,获得浅黄色固体3,4‐二苯基萘内酯,产率54%;产物物理数据为m.p.185.5-186.5℃;1H-NMR(CDCl3)δ8.60(s,1H),8.12(d,1H,J=8.0Hz),7.65-7.58(m,2H),7.55-7.47(m,2H),7.36-7.33(m,2H),7.15(t,1H,J=7.2Hz),7.09-7.02(m,3H),6.69(d,2H,J=7.2Hz),6.51(d,1H,J=7.6Hz),6.41(s,1H)ppm;13C-NMR(CDCl3)δ170.7,141.9,136.3,135.5,135.5,135.4,133.7,130.0,130.0,129.0,128.9,128.6,128.5,128.2,128.1,127.9,127.3,126.9,126.3,126.1,123.0,83.2ppm;HRMS(ESI)calcd forC24H16O2,336.1150;found,336.1151.
实施例2
把1,1‐二苯基‐3‐叔丁基‐2‐丙炔醇(1毫摩尔)置于反应釜中,依次加入苯基丙炔酸(2毫摩尔),氯仿5mL,在70℃搅拌反应2.5小时,反应完毕,减压浓缩溶剂至干,残留物在硅胶柱中用乙酸乙酯/石油醚(=1/20)过柱,获得浅黄色固体3‐叔丁基‐4,9‐二苯基萘内酯,产率70%;产物物理数据为m.p.233.6‐234.6℃;1H‐NMR(CDCl3)δ7.99(d,1H,J=8.4Hz),7.86‐7.84(m,1H),7.59‐7.53(m,7H),7.51‐7.46(m,3H),7.44‐7.32(m,1H),7.37‐7.34(m,1H),5.56(s,1H),0.67(s,9H)ppm;13C‐NMR(CDCl3)δ169.0,141.3,140.0,137.6,134.9,134.9,134.6,133.2,132.6,130.4,129.9,129.8,129.4,128.5128.2,128.1,128.1,128.1,127.9,126.5,126.3,88.6,38.2,26.1ppm;HRMS(ESI)calcd forC28H24O2,392.1776;found,392.1782.
实施例3
把1,1‐二苯基‐2‐丙炔‐1‐醇(1毫摩尔)置于反应釜中,置换氩气,依次加入丙炔酸(2毫摩尔),氯仿5mL,在70℃搅拌反应2小时,反应完毕,减压浓缩溶剂至干,残留物在硅胶柱中用乙酸乙酯/石油醚(=1/20)过柱,获得浅黄色固体4‐苯基萘内酯,产率47%;产物物理数据为m.p.161.6‐162.6℃;1H‐NMR(CDCl3)δ8.52(s,1H),8.11‐8.09(m,1H),7.83‐7.80(m,1H),7.63‐7.49(m,5H),7.41‐7.38(m,2H),5.27(s,2H)ppm;13C‐NMR(CDCl3)δ171.2,138.4,135.8,134.8,134.1,133.7,130.1,129.3,129.0,129.0,128.4,126.8,126.4,125.9,123.0,69.6ppm;HRMS(ESI)calcd forC18H12O2,260.0837;found,260.0837.
实施例4
把1,1‐二苯基‐3‐环丙烷‐2‐丙炔醇(1毫摩尔)置于反应釜中,置换氩气,依次加入丙炔酸(2毫摩尔),1,2‐二氯乙烷5mL,在70℃搅拌反应2小时,反应完毕,减压浓缩溶剂至干,残留物在硅胶柱中用乙酸乙酯/石油醚(=1/20)过柱,获得白色固体3‐环丙烷基‐4‐苯基萘内酯,产率47%;产物物理数据为m.p.141.9‐142.9℃;1H‐NMR(CDCl3)δ8.50(s,1H),8.09(d,1H,J=8.0Hz),7.73(d,1H,J=8.4Hz),7.61‐7.50(m,5H),7.43(d,1H,J=6.8Hz),7.31(d,1H,J=6.8Hz),5.08(d,1H,J=8.0Hz),0.72‐0.66(m,1H),0.42‐0.31(m,2H),0.15‐0.08(m,1H),‐0.23‐‐0.30(m,1H)ppm;13C‐NMR(CDCl3)δ170.4,141.8,136.7,135.4,134.8,133.4,130.8,129.9,129.2,128.8,128.5,128.3,126.7,126.3,123.5,85.1,14.2,3.4,2.0ppm;HRMS(ESI)calcd forC21H16O2,300.1150;found,300.1152.
实施例5
把1,1‐二苯基‐3‐叔丁基‐2‐丙炔醇(1毫摩尔)置于反应釜中,置换氩气,依次加入丙炔酸(2毫摩尔),氯仿5mL,在20℃搅拌反应24小时,反应完毕,减压浓缩溶剂至干,残留物在硅胶柱中用乙酸乙酯/石油醚(=1/20)过柱,获得白色固体3‐叔丁基‐4‐苯基萘内酯,产率70%;产物物理数据为195.9‐196.9℃;1H‐NMR(CDCl3)δ8.50(s,1H),8.09‐8.07(m,1H),7.97‐7.94(m,1H),7.63‐7.46(m,6H),7.36(dd,1H,J1=7.2Hz,J2=7.2Hz),5.62(s,1H),0.64(s,9H)ppm;13C‐NMR(CDCl3)δ170.7,139.8,137.6,135.7,134.8,133.6,132.2,130.0,129.6,129.4,129.0,128.3,126.8,126.5,126.5,125.1,88.8,38.1,26.1ppm;HRMS(ESI)calcd forC22H20O2,316.1463;found,316.1465.
实施例6
把1,1‐二苯基‐3‐三甲基硅基‐2‐丙炔醇(1毫摩尔)置于反应釜中,置换氩气,依次加入丙炔酸(2毫摩尔),氯仿和甲苯1:1的混合溶剂5mL,在70℃搅拌反应2小时,反应完毕,减 压浓缩溶剂至干,残留物在硅胶柱中用乙酸乙酯/石油醚(=1/20)过柱,获得浅黄色固体3‐三甲基硅基‐4‐苯基萘内酯,产率57%;产物物理数据为m.p.141.4‐142.4℃;1H‐NMR(CDCl3)δ8.53(s,1H),8.09‐8.06(m,1H),7.87‐7.84(m,1H),7.58‐7.53(m,4H),7.52‐7.48(m,2H),7.44(d,1H,J=7.2Hz),5.74(s,1H),‐0.33(s,9H)ppm;13C‐NMR(CDCl3)δ171.8,142.5,136.9,134.8,132.9,132.2,131.6,130.1,129.6,129.4,128.8,128.7,128.6,126.7,126.1,125.7,123.0,78.6,‐3.67ppm;HRMS(ESI)calcd forC21H20O2Si,332.1233;found,332.1228.
实施例6
把1,1‐二对甲基苯基‐3‐叔丁基‐2‐丙炔醇(1毫摩尔)置于反应釜中,置换氮气,依次加入丙炔酸(2毫摩尔),乙腈5mL,在90℃搅拌反应1小时,反应完毕,减压浓缩溶剂至干,残留物在硅胶柱中用乙酸乙酯/石油醚(=1/20)过柱,获得白色固体3‐三甲基硅基‐4‐苯基萘内酯,产率60%;产物物理数据为m.p.191.2‐192.2℃;1H‐NMR(CDCl3)δ8.38(s,1H),7.85(d,1H,J=8.8Hz),7.82(s,1H),7.43‐7.31(m,4H),7.23(dd,1H,J1=1.6Hz,J2=7.6Hz),5.59(s,1H),2.54(s,3H),2.47(s,3H),0.63(s,9H)ppm;13C‐NMR(CDCl3)δ170.9,139.0,138.0,136.7,135.5,134.7,133.9,133.3,132.0,131.2,129.9,129.5,129.0,128.8,126.3,125.5,125.1,88.7,38.1,26.1,21.3ppm;HRMS(ESI)calcd forC24H24O2,344.1776;found,344.1767.
实施例7
把1,1‐二苯基‐3‐对甲基苯基‐2‐丙炔醇(1毫摩尔)置于反应釜中,置换氩气,依次加入丙炔酸(2毫摩尔),氯仿5mL,在70℃搅拌反应2小时,反应完毕,减压浓缩溶剂至干,残留物在硅胶柱中用乙酸乙酯/石油醚(=1/20)过柱,获得白色固体3‐三甲基硅基‐4‐苯基萘内酯,产率58%;产物物理数据为m.p.169.0‐170.0℃;1H‐NMR(CDCl3)δ8.60(s,1H),8.11(d,1H,J=8.4Hz),7.65‐7.57(m,2H),7.54‐7.46(m,2H),7.36‐7.31(m,2H),7.08(t,1H,J=7.6Hz),6.85(d,2H,J=8.0Hz),6.58(d,2H,J=8.0Hz),6.54(d,1H,J=7.6Hz),6.39(s,1H),2.23(s,3H)ppm;13C‐NMR(CDCl3)δ170.7,142.0,138.3,135.5,135.3,133.6,133.3,130.0,130.0,129.0,128.9,128.7,128.6,128.1,127.8,127.2,126.8,126.2,126.1,123.2,83.2,21.1ppm;HRMS(ESI)calcd forC25H18O2,350.1307;found,350.1310。
Claims (2)
1.一种4-芳基萘内酯类衍生物的制备方法,其特征在于:以炔丙醇和炔丙酸为原料,在20~90oC的反应温度下,在有机溶剂中反应1-24小时,经过浓缩、柱层析及重结晶纯化过程得到4-芳基萘内酯类衍生物;炔丙醇和炔丙酸的摩尔比为1:1~2;4-芳基萘内酯类衍生物结构式为:
式中:R1选自氢、C1~C6的烷基或环状烷基、三甲基硅基、苯基或取代的苯基;R2、R3选自氢、C1~C4的烷基或C1~C4的烷氧基;R4选自氢、苯基或取代的苯基;所述取代的苯基上的取代基是卤素、C1~C4的烷基或C1~C4的烷氧基。
2.根据权利要求1所述的一种4-芳基萘内酯类衍生物的制备方法,其特征在于所述的有机溶剂为二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、甲苯、四氢呋喃、乙腈、DMF、DMSO或1,4-二氧六环中的一种或二种。
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CN115521330A (zh) * | 2022-08-23 | 2022-12-27 | 淮北师范大学 | 一种含有炔基的α-硅醇类化合物及其制备方法 |
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CN115521330B (zh) * | 2022-08-23 | 2023-10-13 | 淮北师范大学 | 一种含有炔基的α-硅醇类化合物及其制备方法 |
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