CN116693530A - 一种桥联双环内酰胺类化合物的合成方法 - Google Patents
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Abstract
本发明公开了一种桥联双环内酰胺类化合物的合成方法,属于有机合成技术领域,以α‑酰基‑N‑芳基肉桂酰胺类化合物为底物,以叔丁醇钾为碱,以N,N‑二甲基甲酰胺为溶剂,一步合成桥联双环内酰胺类化合物,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,柱层析色谱分离即可得到桥联双环内酰胺类化合物,本发明的反应步骤仅有一步,过程简单;底物价廉易得;反应具有操作简单、官能团兼容性好等优点,应用前景广阔。
Description
技术领域
本发明属于有机合成技术领域,尤其涉及一种桥联双环内酰胺类化合物的合成方法。
背景技术
3-异喹酮类化合物是一类重要的桥联双环内酰胺类化合物,广泛存在于各种药理活性分子中,有机化学家们广泛关注的是这个关键片段使活性分子表现出不同的生物活性。这其中具有代表性的化合物包括抗上瘾化合物Ibogaine、抗乙酰胆碱活性化合物Dioscorine、逆转多药耐药活性化合物Lirofoline B和细胞凋亡抑制剂拮抗剂cIAP1等一些化合物。
目前,有许多的文献报道了这类桥环内酰胺化合物的合成方法,从合成策略上看,利用Diels–Alder反应、胺解反应、或以上方法组合来合成此类化合物。除此之外,通过上述合成策略,利用Nazarov试剂这类底物合成桥环化合物,通过设计的底物和环状Nazarov试剂反应构建桥环化合物。
通过Diels–Alder反应来构建桥环内酰胺及其衍生物的方法,常使用共轭环二烯类化合物作为起始原料来构建桥环支架,合成桥环内酰胺及其衍生物,比如文献:Posner,G.H.;Switzer,C.J.Org.Chem.1987,52,1642–1644报道了吡啶酮类化合物与丁基乙烯基醚在5kbar和50℃下反应56小时,形成了桥环加合物。Gary H.Posner,Victoria Vinader,J.Org.Chem.1992,57,4088–4097报道了2-吡啶酮与各类亲电烯烃在90–100℃下合成双环内酰胺化合物。R.C.Conyers,Tetrahedron Lett.2016,57,3344报道了强亲电性N-芳烃磺酰-2-吡啶酮-3-羧酸甲酯与溴化锌配合物,再与亲核性苯乙烯醚或苯氧二甲苯反应,得到逆电性Diels-Alder环加成物。这些文献中合成方法大多都是在高温高压下或在使用有毒试剂的条件下进行的,反应步骤多,不利于操作。
另一类是胺解反应构建桥环支架,比如文献:Robert B.Grossman,DhananjayS.Pendharkar,Ravindra M.Rasne,J.Org.Chem.2000,65,3255-3258报道了两个轴向CN基团和一个赤道状CH2CO2Et基团的化合物胺解反应产生顺式双环酰胺酰亚胺。Leyi Gong,J.Heather Hogg,James Collier,Bioorg.Med.Chem.Lett.2003,13,3597;TohruFukuyama,Nobuhiro Satoh,Takahiro Akiba,Angew.Chem.Int.Ed.2007,46,5734–5736;Beat Ernst,Oliver Schwardt,Bioorg.Med.Chem.2010,18,7239这些文献报道了环己基类化合物的非邻位带有氨基和酯基的底物在一定条件下胺解得到桥环内酰胺化合物。这类反应的底物比较受限制,需要有特定的基团才能发生氨解反应,产率通常不高。
还有一类是用Nazarov试剂构建桥环化合物,广泛的应用于各种罗宾逊型和双迈克尔加成环化,通过Nazarov试剂和另一组分受体来构建桥环化合物,比如文献:Xin Feng,Zhi Zhou,Rong Zhou,Qing Qing Zhou,Lin Dong,J.Am.Chem.Soc.2012,134,19942-19947;Rasmus Mose,MagnusE.Jensen,Gert Preegel,Karl Anker Angew.Chem.Int.Ed.2015,54,13630–13634;Wei Xiao,Qian Qian Yang,Zhi Chen,QinOuyang,Org.Lett.2018,20,236-239;这些文献报道了通过设计的环状Nazarov试剂和烯烃在手性有机碱的催化下合成桥环类化合物。Shu Mei Yang,Yi Ling Tsai,GanapuramMadhusudhan Reddy,J.Org.Chem.2017,82,9182-9190报道了利用Nazarov试剂和有机碱DABCO催化、合成高化学选择性的桥环化合物。Wenjun Liu,Shengtong Niu,Zhifei Zhao,Org.Lett.2020,22,7572-7576报道了在温和条件下,采用Nazarov试剂和无机碱催化1,2-二酮合成双环[3.2.1]-辛烯的立体发散反应。通过调节反应条件可得到桥接产物的两种立体异构体。这类文献都是在无机碱或有机碱的催化下进行环化,构建桥环化合物,通过Nazarov试剂构建桥环化合物的方法中底物的选择性受到极大的限制。
桥环内酰胺及其衍生物的重要性在化学课本中就能找到,随着对药物的生物活性研究、以及作为更大、更复杂有机分子的基本结构,对获得此类化合物新途径的需求正在不断扩大。虽然目前已经有许多文献报道了桥环内酰胺类化合物的合成方法,但是其中的问题也是明显的。如Diels–Alder反应是常用的构建环状化合物的方法,利用此类反应构建桥环化合物所用的大多是有毒试剂,并且需要高温高压克服能量势垒。通过胺解反应构建桥环支架需要特定的基团才能够进行,底物的范围受限。通过Nazarov试剂这类底物合成桥环化合物的过程相对容易和简单,但来源相对有限、取代基和结构多样性不足,而且它固有的生成平面的环状结构,限制了在桥接环化合物构造中的广泛应用。由此可见,尽管在过去的几十年里合成此类化合物已经取得了显著的合成进展,但目前并没有温和、灵活和高效的化学合成方法。
发明内容
为解决上述技术问题,本发明提出了一种桥联双环内酰胺类化合物的合成方法,具有绿色、简单、有效和高选择性的特点,本发明的合成方法是在无金属条件下进行,通过一步反应即可得到桥联双环内酰胺类化合物,此合成方法底物廉价,步骤简单,易于操作。
为实现上述目的,本发明提供了一种桥联双环内酰胺类化合物的合成方法,以α-酰基-N-芳基肉桂酰胺类化合物为底物,以叔丁醇钾(tBuOK)为碱,以N,N-二甲基甲酰胺(DMF)为溶剂,一步合成桥联双环内酰胺类化合物。
在本发明的合成方法中,反应步骤仅需一步,具有步骤简单、反应条件温和、官能团兼容性好、价格低廉等优点。
优选的,所述α-酰基-N-芳基肉桂酰胺类化合物的结构式如下:
取代基R1选自4-Me-C6H4-、3-Me-C6H4-、4-OMe-C6H4-、4-Cl-C6H4-、3-Cl-C6H4-、Ph-、4-CO2Et-C6H4-或3-CO2Et-C6H4-;
取代基R2选自4-Me-C6H4-、4-OMe-C6H4-、4-Cl-C6H4-或2-Furyl-。
优选的,反应在空气条件下进行。
优选的,反应在加热条件下进行。
优选的,反应温度为40℃。
优选的,反应时间为0.5-10小时,优选为0.5小时。
优选的,反应结束后还包括萃取除去溶剂,柱层析色谱分离。
优选的,本发明桥联双环内酰胺类化合物的合成路线如下:
取代基R1选自4-Me-C6H4-、3-Me-C6H4-、4-OMe-C6H4-、4-Cl-C6H4-、3-Cl-C6H4-、Ph-、4-CO2Et-C6H4-或3-CO2Et-C6H4-;
取代基R2选自4-Me-C6H4-、4-OMe-C6H4-、4-Cl-C6H4-或2-Furyl-(2-呋喃)。
本发明所使用的α-酰基-N-芳基肉桂酰胺类化合物是易得的化学品,优选在使用1.0当量的α-酰基-N-芳基肉桂酰胺类化合物、0.5当量的叔丁醇钾、N,N-二甲基甲酰胺5mL时,发生反应生成桥联双环内酰胺类化合物。
与现有技术相比,本发明具有如下优点和技术效果:
本发明合成方法步骤少,原料低廉且易于获得,技术难度低,易于操作。本发明合成方法避免了使用多步反应的过程,反应结束以后通过萃取除去溶剂,用柱层析色谱分离可得到目标产物,这些优点有利于本发明的合成方法工业应用时的绿色生产。
具体实施方式
现详细说明本发明的多种示例性实施方式,该详细说明不应认为是对本发明的限制,而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。
应理解本发明中所述的术语仅仅是为描述特别的实施方式,并非用于限制本发明。另外,对于本发明中的数值范围,应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值,以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明,否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料,但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入,用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时,以本说明书的内容为准。
在不背离本发明的范围或精神的情况下,可对本发明说明书的具体实施方式做多种改进和变化,这对本领域技术人员而言是显而易见的。由本发明的说明书得到的其他实施方式对技术人员而言是显而易见得的。本发明说明书和实施例仅是示例性的。
关于本文中所使用的“包含”、“包括”、“具有”、“含有”等等,均为开放性的用语,即意指包含但不限于。
实施例1
在15mL耐压管中加入N-(4-甲基苯基)-3-氧-2-(苯基亚甲基)丁酰胺(139.5mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol),以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌0.5小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:95mg,产率68%。
白色固体,产率:68%。1H NMR(400MHz,DMSO)δ9.86(s,1H),7.47(d,J=8.4Hz,2H),7.43(d,J=7.2Hz,2H),7.38(t,J=7.2Hz,2H),7.30(t,J=7.2Hz,1H),7.25(d,J=7.2Hz,2H),7.21(d,J=7.6Hz,2H),7.18(s,4H),7.12(d,J=7.2Hz,1H),7.08(d,J=8.4Hz,2H),6.98(s,1H),4.28(d,J=6.8Hz,1H),3.99(dd,J=10.8,5.6Hz,1H),3.36(d,J=6.8Hz,1H),2.92(dd,J=12.8,11.6Hz,1H),2.30(s,3H),2.24(s,3H),2.22(s,3H),2.14(dd,J=13.2,5.6Hz,1H).13CNMR(101MHz,DMSO)δ204.0,169.3,169.2,145.7,138.1,137.1,136.8,133.8,132.7,130.1,129.6,129.2,129.1,128.6,128.5,128.3,126.3,119.4,87.3,63.8,57.3,47.7,47.5,37.7,30.6,21.2,21.0.
实施例2
在15mL耐压管中加入N-(3-甲基苯基)-3-氧-2-(苯基亚甲基)丁酰胺(139.5mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol),以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌0.5小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:88mg,产率63%。
白色固体,产率:63%。1H NMR(600MHz,DMSO)δ9.87(s,1H),7.45–7.42(m,3H),7.40–7.35(m,3H),7.32–7.26(m,4H),7.22(t,J=7.2Hz,2H),7.17–7.11(m,5H),7.01(s,1H),6.84(d,J=7.2Hz,1H),4.32(d,J=6.6Hz,1H),3.99(dd,J=10.8,5.4Hz,1H),3.39(d,J=7.2Hz,1H),2.94(t,J=12.0Hz,1H),2.29(s,3H),2.251(s,3H),2.246(s,3H),2.16(dd,J=13.8,6.0Hz,1H).13C NMR(151MHz,DMSO)δ204.0,169.3,169.2,145.6,139.4,138.3,138.0,137.7,136.3,129.6,129.2,129.0,128.5,128.44,128.38,128.3,128.1,126.3,124.4,120.0,116.6,87.4,63.7,57.2,47.6,47.2,37.6,30.6,21.7,21.4.
实施例3
在15mL耐压管中加入N-(4-甲氧基苯基)-3-氧-2-(苯基亚甲基)丁酰胺(147.5mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol),以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌0.5小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:96mg,产率65%。
白色固体,产率:65%。1H NMR(400MHz,CDCl3)δ7.51-7.41(m,5H),7.28(d,J=7.6Hz,3H),7.21(t,J=7.2Hz,3H),7.16–7.12(m,3H),6.99(s,1H),6.92(d,J=8.8Hz,2H),6.81(d,J=8.8Hz,2H),5.62(s,1H),4.14(d,J=7.6Hz,1H),4.05(dd,J=10.8,5.6Hz,1H),3.79(s,3H),3.77(s,3H),3.29(d,J=7.6Hz,1H),2.87(dd,J=13.6,11.6Hz,1H),2.30(dd,J=13.6,5.9Hz,1H),2.22(s,3H).13C NMR(151MHz,CDCl3)δ203.4,170.0,169.8,159.2,157.0,143.6,136.8,129.8,129.7,129.2,128.9,128.5,128.2,127.4,126.6,122.1,114.4,114.2,86.5,64.0,55.5,55.4,55.0,48.7,46.7,37.4,30.6.
实施例4
在15mL耐压管中加入N-(4-氯苯基)-3-氧-2-(苯基亚甲基)丁酰胺(150.0mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol)、以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌1.0小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:90mg,产率60%。
白色固体,产率:60%。1H NMR(600MHz,DMSO)δ10.17(s,1H),7.60(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.43(d,J=7.8Hz,2H),7.38(t,J=7.2Hz,2H),7.32(dd,J=18.6,9.0Hz,5H),7.22–7.20(m,5H),7.12(t,J=6.6Hz,1H),4.23(d,J=7.2Hz,1H),4.02(dd,J=10.8,5.4Hz,1H),3.38(d,J=7.2Hz,1H),2.94(t,J=12.0Hz,1H),2.22(s,3H),2.14(dd,J=13.2,5.4Hz,1H).13C NMR(151MHz,DMSO)δ203.7,169.7,169.3,145.4,138.3,137.7,135.1,132.10,132.06,129.5,129.4,129.25,129.16,128.7,128.5,128.4,127.4,126.3,121.0,87.5,63.6,57.3,47.6,47.5,37.6,30.6.
实施例5
在15mL耐压管中加入N-(3-氯苯基)-3-氧-2-(苯基亚甲基)丁酰胺(150.0mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol),以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌1.0小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:90mg,产率52%。
白色固体,产率:52%。1H NMR(600MHz,DMSO)δ10.27(s,1H),7.84(s,1H),7.47(d,J=7.8Hz,1H),7.44(d,J=7.8Hz,2H)7.40–7.37(m,5H),7.33–7.26(m,4H),7.23–7.21(m,4H),7.13–7.09(m,2H),4.26(d,J=6.6Hz,1H),4.03(dd,J=10.8,5.4Hz,1H),3.39(d,J=6.6Hz,1H),2.97(t,J=13.2Hz,1H),2.24(s,3H),2.17(dd,J=13.2,4.2Hz,1H).13C NMR(151MHz,DMSO)δ203.6,170.0,169.3,145.4,140.6,137.61,137.57,133.6,132.7,131.0,130.3,130.2129.5,129.3,129.1,128.50,128.47,128.40,127.6,126.4,123.7,119.0,117.9,87.8,63.6,57.4 47.4,47.3,37.5,30.6.
实施例6
在15mL耐压管中加入3-氧-2-(苯基亚甲基)丁酰胺(132.5mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol),以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌2.0小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:70mg,产率53%。
白色固体,产率:53%。1H NMR(600MHz,DMSO)δ9.98(s,1H),7.59(d,J=7.8Hz,2H),7.44(d,J=7.2Hz,2H),7.39(q,J=8.4Hz,4H),7.32–7.26(m,8H),7.22(t,J=7.8Hz,2H),7.12(t,J=7.2Hz,1H),7.07(s,1H),7.01(t,J=7.2Hz,1H),4.29(d,J=7.2Hz,1H),4.02(dd,J=10.8,5.4Hz,1H),3.41(d,J=6.6Hz,1H),2.94(t,J=12.0Hz,1H),2.24(s,3H),2.17(dd,J=13.2,6.0Hz,1H).13C NMR(151MHz,DMSO)δ203.9,169.5,169.3,145.6,139.5,137.9,136.4,130.3,129.5,129.2,128.6,128.50,128.46,128.3,127.5,126.3,123.8,119.4,87.4,63.7,57.3,47.7,47.5,37.6,30.6.
实施例7
在15mL耐压管中加入N-(4-甲酸乙酯苯基)-3-氧-2-(苯基亚甲基)丁酰胺(168.5mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol),以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌10.0小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:96mg,产率57%。
白色固体,产率:57%。1H NMR(400MHz,DMSO)δ10.38(s,1H),7.98(d,J=8.4Hz,2H),7.89(d,J=8.8Hz,2H),7.71(d,J=8.4Hz,2H),7.45(d,J=8.0Hz,4H),7.39(t,J=7.2Hz,2H),7.33–7.30(m,2H),7.23–7.19(m,4H),7.13(d,J=6.0Hz,1H),4.34–4.24(m,5H),4.04(dd,J=10.4,5.2Hz,1H),3.47(d,J=6.8Hz,1H),2.98(t,J=12.0Hz,1H),2.24(s,3H),2.21–2.18(m,1H),1.30(q,J=7.2Hz,6H).13C NMR(151MHz,DMSO)δ203.6,170.2,169.2,165.9,165.7,145.3,143.5,140.8,137.6,130.8.130.5,129.6,129.5,129.3,128.9,128.6,128.5,128.4,126.4,124.9,118.9,87.9,63.7,61.2,60.9,57.4,47.5,47.3,37.6,30.6,14.7.
实施例8
在15mL耐压管中加入N-(3-甲酸乙酯苯基)-3-氧-2-(苯基亚甲基)丁酰胺(168.5mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol),以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌10.0小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:93mg,产率55%。
白色固体,产率:55%。1H NMR(400MHz,DMSO)δ10.31(s,1H),8.20(s,1H),7.98–7.89(m,3H),7.62(d,J=8.0Hz,1H),7.58–7.55(m,2H),7.46(t,J=7.6Hz,3H),7.39(t,J=8.8Hz,2H),7.34–7.21(m,6H),7.14(t,J=7.2Hz,1H),4.33–4.26(m,5H),4.06(dd,J=10.8,5.6Hz,1H),3.44(d,J=7.2Hz,1H),2.98(dd,J=13.2,11.6Hz,1H),2.26(s,3H),2.17(dd,J=13.2,5.6Hz,1H),1.31(t,J=7.2Hz,3H),1.28(t,J=7.2Hz,3H).13C NMR(151MHz,DMSO)δ203.7,170.0,169.5,166.0,165.8,145.6,139.7,137.6,136.6,135.0,130.9,130.6,129.7,129.6,129.2,129.0,128.5,128.4,128.3,126.3,124.4,123.8,119.9,87.7,63.6,61.29,61.27,57.3,47.6,47.4,37.6,30.6,14.6,14.6.
实施例9
在15mL耐压管中加入N-(4-甲基苯基)-2-[(4-甲基苯基)亚甲基]-3-氧丁酰胺(146.5mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol),以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌0.5小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:92mg,产率63%。
白色固体,产率:63%。1H NMR(600MHz,DMSO)δ9.84(s,1H),7.47(d,J=7.8Hz,2H),7.29(d,J=7.8Hz,2H),7.18–7.16(m,6H),7.12(d,J=7.8Hz,2H),7.07(d,J=8.4Hz,2H),7.00(d,J=7.8Hz,2H),6.95(s,1H),4.23(d,J=7.2Hz,1H),3.93(dd,J=10.2,5.4Hz,1H),3.32(d,J=7.2Hz,1H),2.88(dd,J=12.0,7.8Hz,1H),2.30(s,3H),2.28(s,3H),2.21(s,9H),2.13(dd,J=12.6,4.8Hz,1H).13C NMR(151MHz,DMSO)δ204.0,169.3,169.2,142.6,137.4,137.1,136.6,135.1,135.0,133.8,132.6,130.1,129.8,129.5,129.4,129.1,129.0,128.5,119.4,87.2,63.8,57.3,47.7,47.1,37.2,30.6,21.13,21.06,20.96,20.89.
实施例10
在15mL耐压管中加入N-(4-甲基苯基)-2-[(4-甲氧基苯基)亚甲基]-3-氧丁酰胺(154.5mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol),以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌1.0小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:88mg,产率57%。
白色固体,产率:57%。1H NMR(400MHz,DMSO)δ9.82(s,1H),7.46(d,J=8.4Hz,2H),7.31(d,J=8.4Hz,2H),7.18(s,4H),7.14(d,J=8.8Hz,2H),7.07(d,J=8.4Hz,2H),6.93(d,J=5.6Hz,2H),6.90(s,1H),6.76(d,J=8.8Hz,2H),4.21(d,J=7.2Hz,1H),3.89(dd,J=10.8,5.6Hz,1H),3.74(s,3H),3.69(s,3H),3.28(d,J=6.8Hz,1H),2.86(dd,J=12.8,12.4Hz,1H),2.30(s,3H),2.22(s,3H),2.20(s,3H),2.13(dd,J=13.2,5.2Hz,1H).13CNMR(151MHz,DMSO)δ204.1,169.3,169.2,159.1,157.7,137.4,137.1,136.6,133.8,132.6,130.6,130.1,129.80,129.75,129.5,129.0,119.4,114.5,113.7,87.2,64.0,57.6,55.5,55.4,47.8,46.7,36.8,30.6,21.1,20.9.
实施例11
在15mL耐压管中加入N-(4-甲基苯基)-2-[(4-氯苯基)亚甲基]-3-氧丁酰胺(157.0mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol),以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌3.0小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:97mg,产率62%。
白色固体,产率:62%。1H NMR(600MHz,DMSO)δ9.89(s,1H),7.48(dd,J=7.8,5.4Hz,4H),7.42(d,J=8.4Hz,2H),7.29(dd,J=15.6Hz,9.0Hz,4H),7.19(s,4H),7.09(d,J=8.4Hz,2H),7.05(s,1H),4.30(d,J=6.6Hz,1H),3.98(dd,J=10.8,5.4Hz,1H),3.33(d,J=6.6Hz,1H),2.93(t,J=11.4Hz,1H),2.30(s,3H),2.27(s,3H),2.22(s,3H),2.10(dd,J=13.2,5.4Hz,1H).13C NMR(151MHz,DMSO)δ203.9,168.5,168.4,144.0,136.6,136.4,133.1,132.7,132.3,131.0,130.6,130.0,129.7,129.2,128.74,128.72,128.0,119.0,86.8,63.2,56.6,46.9,46.3,36.6,30.2,20.7,20.5.
实施例12
在15mL耐压管中加入2-(2-呋喃亚甲基)-N-(4-甲基苯基)-3-氧丁酰胺(134.5mg,0.5mmol)、叔丁醇钾(28mg,0.25mmol),以5mL的N,N-二甲基甲酰胺做溶剂,在40℃下搅拌0.5小时,反应过程使用TLC监测,反应结束后通过萃取除去溶剂,用柱层析色谱分离得到白色固体:97mg,产率72%。
白色固体,产率:72%。1H NMR(600MHz,DMSO)δ9.99(s,1H),7.67(s,1H),7.54(d,J=7.8Hz,2H),7.48(s,1H),7.13(t,J=7.8Hz,4H),7.08(d,J=7.8Hz,2H),7.05(s,1H),6.51(d,J=2.4Hz,1H),6.43(s,1H),6.30(s,1H),5.99(d,J=2.4Hz,1H),4.44(d,J=5.4Hz,1H),3.89(dd,J=10.2,3.6Hz,1H),3.39(d,J=6.0Hz,1H),2.66(t,J=12.0Hz,1H),2.37(s,3H),2.28(s,3H),2.25(s,3H),2.22(dd,J=12.6,3.0Hz,1H).13C NMR(151MHz,DMSO)δ203.8,168.8,167.9,157.1,151.3,144.1,141.3,137.0,136.8,133.4,132.8,130.0,129.6,129.0,119.5,111.2,110.9,109.5,105.6,87.1,61.7,55.3,43.0,32.3,29.3,21.1,20.9.
以上,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应该以权利要求的保护范围为准。
Claims (7)
1.一种桥联双环内酰胺类化合物的合成方法,其特征在于,以α-酰基-N-芳基肉桂酰胺类化合物为底物,以叔丁醇钾提供碱环境,以N,N-二甲基甲酰胺为溶剂,一步合成桥联双环内酰胺类化合物。
2.根据权利要求1所述的合成方法,其特征在于,所述α-酰基-N-芳基肉桂酰胺类化合物的结构式如下:
取代基R1选自4-Me-C6H4-、3-Me-C6H4-、4-OMe-C6H4-、4-Cl-C6H4-、3-Cl-C6H4-、Ph-、4-CO2Et-C6H4-或3-CO2Et-C6H4-;
取代基R2选自4-Me-C6H4-、4-OMe-C6H4-、4-Cl-C6H4-或2-Furyl-。
3.根据权利要求1所述的合成方法,其特征在于,反应在空气条件下进行。
4.根据权利要求1所述的合成方法,其特征在于,反应在加热条件下进行。
5.根据权利要求5所述的合成方法,其特征在于,反应温度为40℃。
6.根据权利要求1所述的合成方法,其特征在于,反应时间为0.5-10小时。
7.根据权利要求1所述的合成方法,其特征在于,反应结束后还包括萃取除去溶剂,柱层析色谱分离。
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CN116693529A (zh) * | 2023-06-09 | 2023-09-05 | 河南师范大学 | 一种2-氮杂环[2.2.2]辛烷类化合物的合成方法 |
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CN116693529A (zh) * | 2023-06-09 | 2023-09-05 | 河南师范大学 | 一种2-氮杂环[2.2.2]辛烷类化合物的合成方法 |
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