CN113387955A - 一种1,2,3,4-四氢噌啉骨架类化合物及其合成方法 - Google Patents
一种1,2,3,4-四氢噌啉骨架类化合物及其合成方法 Download PDFInfo
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Abstract
本发明提供了一种1,2,3,4‑四氢噌啉骨架类化合物及其合成方法,属于噌啉类化合物的合成技术领域。本发明利用方便氧化的含氮不饱和酰肼为作用对象通过原位氧化等方案合成一系列重要的1,2,3,4‑四氢噌啉骨架类新化合物;该化合物的结构通式为:
Description
技术领域
本发明属于噌啉类化合物的合成技术领域,具体涉及一种1,2,3,4-四氢噌啉骨架类化合物及其合成方法。
背景技术
含氮化合物尤其是含氮杂环骨架广泛存在于药物、农用化学品、活性天然产物以及现代材料中,在人类的生命健康与生活生产中发挥着至关重要的作用。据对美国FDA药品数据库中的批准药物分析显示,获批的特效小分子药物中含有氮杂环的占有59%。另外,过去的五年中(2015-2020)FDA获批的164小分子中,含氮杂环药物占比高达88%,紧随其后是芳香骨架化合物占87%。由此可见含氮杂环化合物在有机小分子中的地位举足轻重,因此这类化合物的多样合成及其合成方法的不断革新便成了化学工作者亟需解决的重大课题与挑战(Current Opinion in Chemical Biology,2010,14(3):347-361;Journal ofMedicinal Chemistry,2014,57,10257-10274)。
噌啉,特别是那些与其他杂环融合的复杂噌啉由于其具有合成挑战性的骨架和广泛的抗炎、抗癌、抗菌和杀真菌剂等生物学活性,是合成化学和药物化学家的重要目标。
经典地,噌啉的von Richter合成方法是在酸性条件下通过2-乙炔基苯重氮前体环化来合成。尽管已开发出替代方法来获得具有多取代骨架的噌啉,但使用温和的反应条件和更稳定的起始原料的实例仍然很少(Arch.Pharm.Chem.Life Sci.2007,340,65–80)。
值得一提的是,1,2,3,4-四氢噌啉作为噌啉类骨架的衍生物也同样具有广阔的医药前景或活性化合物合成中间体的应用,目前关于四氢噌啉类骨架的化合物合成方法报道较少(J.Org.Chem.2018,83,6202-6209,Org.Chem.Front.,2018,5,1777–1781,Adv.Synth.Catal.2014,356,972–976)。
发明内容
本发明的目的在于提供一种1,2,3,4-四氢噌啉骨架类化合物及其合成方法,本发明以方便氧化的含氮不饱和酰肼为作用对象原位氧化产生含双氮的缺电子双烯体与分子内烯烃发生[4++2]极性环加成反应实现烯烃胺芳基化进而合成重要的含氮杂环化合物1,2,3,4-四氢噌啉骨架类化合物。
为了实现上述目的,本发明采用的技术方案如下:
一种1,2,3,4-四氢噌啉骨架类化合物,其结构通式如式I所示,
式中,R1、R2、R3、R4、R5任选自H、卤素、C1-C16的烷基、C1-C16的烷氧基、C1-C16的烷硫基、苯基、三氟甲基、甲氧羰基、硝基、羟基、醛基、羧基、氨基、酯基、硅烷基、硅氧基、苄氧基、酰胺基、酰氧基、胡椒基中的任意一种;R1、R2、R3、R4、R5全为H时,式I所示的基团即为苯基;R6任选自直链型或支链型烷基、环烷基型、芳基、杂芳基中的任意一种;R7、R8任选自H、直链型或支链型烷基、环烷基型、芳基、杂芳基中的任意一种。
本发明还提供了上述1,2,3,4-四氢噌啉骨架类化合物的合成方法,具体制备是将不饱和酰肼II、催化剂、碱、氧化剂和溶剂加入反应管后密封,置换保护气体或空气条件下,于-80~200℃下搅拌反应,通过后处理提纯产物I;具体合成路线如下:
式中,R1、R2、R3、R4、R5任选自H、卤素、C1-C16的烷基、C1-C16的烷氧基、C1-C16的烷硫基、苯基、三氟甲基、甲氧羰基、硝基、羟基、醛基、羧基、氨基、酯基、硅烷基、硅氧基、苄氧基、酰胺基、酰氧基、胡椒基中的任意一种;R1、R2、R3、R4、R5全为H时,式I所示的基团即为苯基;R6任选自直链型或支链型烷基、环烷基型、芳基、杂芳基中的任意一种;R7、R8任选自H、直链型或支链型烷基、环烷基型、芳基、杂芳基中的任意一种。
优选地,在本发明的一些实施方案中,所述不饱和酰肼II加入量为0.001M~0.15M、催化剂加入量为0.1%~1M、碱加入量为0.001M~0.15M、氧化剂加入量为0.001M~10M。
优选地,在本发明的一些实施方案中,所述氧化剂为TEMPO+BF4 -、TEMPO+PF6 -、TEMPO+ClO4 -、PhI(OAc)2、PhI(TFA)2中的任意一种。
优选地,在本发明的一些实施方案中,所述氧化剂采用电化学氧化方法代替。
优选地,所述催化剂选自TEMPO、4-AcNH-TEMPO、4-OH-TEMPO中的任意一种。
优选地,所述碱选自Li2CO3、K2CO3、Na2CO3、Cs2CO3、K3PO4、K2HPO4、KH2PO4、DBU、Et3N中的任意一种。
优选地,所述溶剂选自乙腈、苯甲腈、氯苯、二氯甲烷、1,2-二氯乙烷、四氢呋喃、二氧六环、乙醚、甲醇、乙醇中的任意一种或多种的任意比例混合。
优选地,所述保护气选自氮气、氩气中的任意一种。
本发明还提供了上述式I所示结构的1,2,3,4-四氢噌啉骨架类化合物或其药学上可接受的盐的用途,用于制备抗肿瘤药物或为抗肿瘤药物的筛选提供更多的候选分子或在制备具有1,2,3,4-四氢噌啉类结构单元药物中的用途。
本发明还提供了一种药物,包括有效量的所述的1,2,3,4-四氢噌啉骨架类化合物或其药学上可接受的盐以及药学上可接受的载体、赋形剂或辅助剂。
所述药物剂型为注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂。
与现有技术相比,本发明的有益技术效果:本发明使用不饱和酰肼环化合成1,2,3,4-四氢噌啉骨架类化合物,条件温和,不饱和酰肼兼容R1、R2、R3、R4、R5、R6、R7、R8多种取代基,底物范围广,简便可行;该方法制备的化合物结构新颖,同时兼容多个并环,预期这些化合物可为开发抗肿瘤药物提供更多的候选分子,经筛选用于制备抗肿瘤药物。
具体实施方式
下面结合具体实施例进一步详细说明本发明。除非特别说明,本发明实施例述及的实际均为本技术领域常规使用的试剂。
实施例1
2,2-二甲基-5-苯基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-1)
2,2-dimethyl-5-phenyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-1)的制备
将1.0M的酰肼II-1和2.0M的TEMPO+BF4-称入干燥的反应管中,加入MeCN,将反应体系置于schlenk管,通过三次置换气体使反应瓶内为氩气或者氮气氛围,最后使反应在一定温度范围内反应,通过TLC检测反应进程,当起始原料耗完时,停止反应。反应结束后减压旋转蒸发浓缩,粗品通过柱层析分离提纯得到结构式如下的I-1目标产物48.5mg,产率为83%。
白色固体;mp:115-116℃;1H NMR(400MHz,CDCl3):δ7.22-7.29(m,4H),7.01–7.17(m,5H),3.81-3.87(m,1H),3.08(dd,J1=16.4Hz,J2=5.6Hz,1H),2.84(dd,J1=16.4Hz,J2=10Hz,1H),2.23(dd,J1=13.2Hz,J2=8Hz,1H),1.74(dd,J1=13.2Hz,J2=3.2Hz,1H),1.25(s,6H);13C NMR(100.6MHz,CDCl3):δ176.2,149.1,141.6,129.8,129.0,126.5,125.1,124.4,123.5,122.7,121.3,46.0,39.8,38.2,34.7,27.3,26.9;ESI-HRMS:m/z Calcd for[C19H20N2O+H+]:293.1648,found 293.1653。
实施例2
2,2,8-三甲基-5-(对甲苯基)-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)酮(I-2)
2,2,8-trimethyl-5-(p-tolyl)-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-2)的制备
其具体制备过程同实施例1,只需将原料II-1替换为II-2,得到结构式如下的I-2目标产物56.3mg,产率为88%。
白色固体;mp:61-63℃;1H NMR(400MHz,CDCl3):δ7.15-7.17(m,2H),6.95(d,J1=8.8Hz,1H),6.77-6.81(m,2H),6.66-6.72(m,2H),3.75-3.81(m,7H),3.05(dd,J1=16.4Hz,J2=5.6Hz,1H),2.80(dd,J1=16.4Hz,J2=10.4Hz,1H),2.196(dd,J1=13.2Hz,J2=8.4Hz,1H),1.69(dd,J1=13.2Hz,J2=3.6Hz,1H),1.24(s,3H),1.18(s,3H);13C NMR(100.6MHz,CDCl3):δ175.5,156.7,155.4,143.3,135.7,125.7,123.6,123.5,114.0,113.6,112.9,55.30,55.26,44.6,39.6,38.1,35.1,26.8,26.7;ESI-HRMS:m/z Calcd for[C21H24N2O3+H+]:353.1860,found 353.1852。
实施例3
8-溴-5-(4-溴苯基)-2,2-二甲基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-3)
8-bromo-5-(4-bromophenyl)-2,2-dimethyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-3)
其具体制备过程同实施例1,只需将原料II-1替换为II-3,得到结构式如下的I-3目标产物64.7mg,产率为92%。
白色固体;mp:61-63℃;1H NMR(400MHz,CDCl3):δ7.15-7.17(m,2H),6.95(d,J1=8.8Hz,1H),6.77-6.81(m,2H),6.66-6.72(m,2H),3.75-3.81(m,7H),3.05(dd,J1=16.4Hz,J2=5.6Hz,1H),2.80(dd,J1=16.4Hz,J2=10.4Hz,1H),2.196(dd,J1=13.2Hz,J2=8.4Hz,1H),1.69(dd,J1=13.2Hz,J2=3.6Hz,1H),1.24(s,3H),1.18(s,3H);13C NMR(100.6MHz,CDCl3):δ175.5,156.7,155.4,143.3,135.7,125.7,123.6,123.5,114.0,113.6,112.9,55.30,55.26,44.6,39.6,38.1,35.1,26.8,26.7;ESI-HRMS:m/z Calcd for[C21H24N2O3+H+]:353.1860,found 353.1852。
实施例4
8-溴-5-(4-溴苯基)-2,2-二甲基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-4)
8-bromo-5-(4-bromophenyl)-2,2-dimethyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-4)
其具体制备过程同实施例1,只需将原料II-1替换为II-4,得到结构式如下的I-4目标产物88.2mg,产率为98%。
白色固体;mp:156-157℃;1H NMR(400MHz,CDCl3):δ7.36-7.40(m,2H),7.25-7.31(m,2H),7.10-7.13(m,2H),6.96(d,J=8.8Hz,1H),3.74-3.80(m,1H),3.06(dd,J1=16.8Hz,J2=5.6Hz,1H),2.82(dd,J1=16.8Hz,J2=10.0Hz,1H),2.23(dd,J1=13.2Hz,J2=8.4Hz,1H),1.75(dd,J1=13.2Hz,J2=3.2Hz,1H),1.25(s,3H),1.24(s,3H);13C NMR(100.6MHz,CDCl3):δ176.3,147.7,140.2,132.5,132.1,129.7,127.1,123.7,123.3,118.0,116.3,45.5,39.4,38.0,34.3,27.2,26.9;ESI-HRMS:m/z Calcd for[C19H18Br2N2O+H+]:448.9859,found 448.9866。
实施例5
8-溴-2,2-二甲基-5-苯基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-5)
8-bromo-2,2-dimethyl-5-phenyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-5)
其具体制备过程同实施例1,只需将原料II-1替换为II-5,得到结构式如下的I-5目标产物70.0mg,产率为94%。
1H NMR(400MHz,CDCl3):δ6.96-7.38(m,8H),3.76-3.85(m,1H),3.03-3.10(m,1H),2.78-2.86(m,1H),2.23(dd,J1=13.2Hz,J2=8.4Hz,1H),1.71-1.76(m,1H),1.25(s,6H);13C NMR(100.6MHz,CDCl3):δ176.0,148.5,140.7,131.9,129.5,129.0,126.5,124.9,123.8,122.7,121.7,115.8,45.3,39.4,37.9,34.4,27.1,26.8。
5-(4-溴苯基)-2,2-二甲基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-5’)
5-(4-bromophenyl)-2,2-dimethyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-5’)
1H NMR(400MHz,CDCl3):δ6.96-7.38(m,8H),3.76-3.85(m,1H),3.03-3.10(m,1H),2.78-2.86(m,1H),2.23(dd,J1=13.2Hz,J2=8.4Hz,1H),1.71-1.76(m,1H),1.23(s,6H);13C NMR(100.6MHz,CDCl3):δ176.2,148.1,141.0,132.2,129.8,129.0,126.9,125.0,123.8,122.4,121.7,117.2,45.9,39.7,38.0,34.4,27.1,26.7。
实施例6
10,10-二甲基-7-苯基-10,11,11a,12-四氢苯并[f]吡咯并[1,2-b]噌啉-9(7H)-酮(I-6)
10,10-dimethyl-7-phenyl-10,11,11a,12-tetrahydrobenzo[f]pyrrolo[1,2-b]cinnolin-9(7H)-one(I-6)
其具体制备过程同实施例1,只需将原料II-1替换为II-6,得到结构式如下的I-6目标产物65.0mg,产率为95%。
白色固体;1H NMR(400MHz,CDCl3):δ7.85(d,J=8.4Hz,1H),7.80(d,J=8.4Hz,1H),7.62(d,J=8.8Hz,1H),7.51-7.55(m,1H),7.42-7.46(m,1H),7.23-7.34(m,5H),7.12-7.16(m,1H),3.86-3.93(m,1H),3.48(dd,J1=16.8Hz,J2=5.6Hz,1H),3.03(dd,J1=16.8Hz,J2=10.4Hz,1H),2.33(dd,J1=13.2Hz,J2=8.4Hz,1H),1.89(dd,J1=13.2Hz,J2=2.4Hz,1H),1.29(s,3H),1.27(s,3H);13C NMR(100.6MHz,CDCl3):δ175.9,149.1,139.1,132.5,130.4,129.0,128.7,126.8,126.7,125.1,124.7,122.62,122.56,122.0,118.3,45.3,39.9,38.2,32.0,27.5,27.3;ESI-HRMS:m/z Calcd for[C23H22N2O+H+]:343.1805,found 343.1804。
2,2-二甲基-5-(萘-2-基)-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-6’)
2,2-dimethyl-5-(naphthalen-2-yl)-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-6’)
白色固体;1H NMR(400MHz,CDCl3):δ7.06-7.86(m,11H),3.82-3.92(m,1H),3.10(dd,J1=16.8Hz,J2=5.6Hz,1H),2.87(dd,J1=16.8Hz,J2=10Hz,1H),2.21(dd,J1=13.2Hz,J2=8.4Hz,1H),1.75(dd,J1=13.2Hz,J2=3.2Hz,1H),1.27(s,3H),1.26(s,3H);13CNMR(100.6MHz,CDCl3):δ176.3,146.8,141.6,133.5,130.9,129.9,129.2,127.0,126.6,126.3,125.3,125.1,124.9,123.7,122.9,121.7,117.8,45.9,39.7,38.2,34.7,27.3,26.9。
实施例7
2,2-二甲基-2,3,3a,4-四氢-1H-吡咯[1',2':2,3]哒嗪[5,6,1-jk]咔唑-1-酮(I-7)
2,2-dimethyl-2,3,3a,4-tetrahydro-1H-pyrrolo[1',2':2,3]pyridazino[5,6,1-jk]carbazol-1-one(I-7)
其具体制备过程同实施例1,只需将原料II-1替换为II-7,得到结构式如下的I-7目标产物12.8mg,产率为22%。
无色油;1H NMR(400MHz,CDCl3):δ8.44(d,J=8Hz,1H),7.90-7.94(m,1H),7.58(d,J=8Hz,1H),7.44-7.48(m,1H),7.25-7.28(m,1H),7.19(d,J=4.8Hz,2H),3.84-3.90(m,1H),3.07-3.21(m,2H),2.59(dd,J1=13.2Hz,J2=8.8Hz,1H),2.07(dd,J1=13.2Hz,J2=2.0Hz,1H),1.48(s,3H),1.36(s,3H);13C NMR(100.6MHz,CDCl3):δ176.5,139.1,134.4,126.2,123.8,121.6,120.7,120.14,120.07,119.7,118.9,117.0,111.4,51.3,38.7,37.8,34.4,28.5,26.6;ESI-HRMS:m/z Calcd for[C19H18N2O+H+]:291.1492,found 291.1496。
实施例8
12,12-二甲基-5,6,10,10a,11,12-六氢-13H-苯并[6,7]氮杂[3,2,1-ij]吡咯并[1,2-b]噌啉-13-酮(I-8)
12,12-dimethyl-5,6,10,10a,11,12-hexahydro-13H-benzo[6,7]azepino[3,2,1-ij]pyrrolo[1,2-b]cinnolin-13-one(I-8)
其具体制备过程同实施例1,只需将原料II-1替换为II-8,得到结构式如下的I-8目标产物61.0mg,产率为96%。
白色固体;mp:138-140℃;1H NMR(400MHz,CDCl3):δ7.08-7.13(m,2H),6.97-7.01(m,1H),6.88-6.94(m,4H),4.22-4.29(m,1H),3.56-3.65(m,2H),3.15(dd,J1=16.4Hz,J2=6Hz,1H),2.82-2.96(m,3H),2.48(dd,J1=13.2Hz,J2=8Hz,1H),1.82(dd,J1=13.2Hz,J2=3.6Hz,1H),1.30(s,3H),1.24(s,3H);13C NMR(100.6MHz,CDCl3):δ174.5,145.9,143.0,132.3,131.2,130.6,127.8,127.1,126.5,124.0,122.9,122.8,115.3,47.1,40.1,37.8,34.9,32.8,32.2,26.9,26.8;ESI-HRMS:m/z Calcd for[C21H22N2O+H+]:319.1805,found319.1809。
实施例9
5-丁基-2,2-二甲基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-9)
5-butyl-2,2-dimethyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-9)
其具体制备过程同实施例1,只需将原料II-1替换为II-9,得到结构式如下的I-9目标产物18.0mg,产率为33%。
无色油;1H NMR(400MHz,CDCl3):δ7.16(t,J=7.6Hz,1H),7.02(d,J=7.6Hz,1H),6.97(d,J=7.6Hz,1H),6.84(t,J=7.6Hz,1H),3.47-3.70(m,3H),3.00(dd,J1=15.6Hz,J2=4.4Hz,1H),2.72(dd,J1=15.6Hz,J2=11.2Hz,1H),2.35(dd,J1=13.2Hz,J2=8Hz,1H),1.71(dd,J1=13.2Hz,J2=3.6Hz,1H),1.48-1.61(m,2H),1.32-1.43(m,2H),1.28(s,3H),1.22(s,3H),0.91(t,J=7.6Hz);13C NMR(100.6MHz,CDCl3):δ174.8,144.3,129.5,127.2,121.5,120.5,117.1,55.7,46.0,39.6,38.0,36.5,28.5,27.7,26.6,20.3,13.9;ESI-HRMS:m/z Calcd for[C17H24N2O+H+]:273.1961,found 273.1966。
实施例10
5-环己基-2,2-二甲基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-10)
5-cyclohexyl-2,2-dimethyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-10)
其具体制备过程同实施例1,只需将原料II-1替换为II-10,得到结构式如下的I-10目标产物37.0mg,产率为62%。
白色固体;mp:105-106℃;1H NMR(400MHz,CDCl3):δ7.15(t,J=8Hz,1H),7.06(d,J=8Hz,1H),7.00(d,J=7.6Hz,1H),6.84(t,J=7.6Hz,1H),3.59-3.68(m,2H),2.94(dd,J1=16Hz,J2=4.8Hz,1H),2.73(dd,J1=16Hz,J2=11.2Hz,1H),2.30-2.35(m,2H),1.83-1.87(m,1H),1.68-1.76(m,3H),1.61-1.64(m,1H),1.45-1.55(m,1H),1.36-1.41(m,1H),1.30(s,3H),1.05-1.26(m,6H);13C NMR(100.6MHz,CDCl3):δ177.3,144.2,129.4,126.9,122.3,120.5,118.1,67.3,47.9,38.6,37.2,35.7,32.1,29.2,28.8,27.1,26.1,26.0,25.7;ESI-HRMS:m/z Calcd for[C19H26N2O+H+]:299.2118,found 299.2122。
实施例11
5-苄基-2,2-二甲基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-11)
5-benzyl-2,2-dimethyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-11)
其具体制备过程同实施例1,只需将原料II-1替换为II-11,得到结构式如下的I-11目标产物24.0mg,产率为39%。
白色固体;mp:129-131℃;1H NMR(400MHz,CDCl3):δ7.19-7.26(m,5H),7.13(d,J=6.8Hz,2H),7.00(d,J=7.6Hz,1H),6.86-6.90(m,1H),4.88(d,J=14.4Hz,1H),4.75(d,J=14.4Hz,1H),2.82(dd,J1=15.2Hz,J2=4Hz,1H),2.66-2.72(m,1H),2.56(dd,J1=15.2Hz,J2=11.2Hz,1H),2.05(dd,J1=13.2Hz,J2=8.4Hz,1H),1.49(dd,J1=13.2Hz,J2=4Hz,1H),1.19(s,3H),1.18(s,3H);13C NMR(100.6MHz,CDCl3):δ173.9,143.4,135.5,129.4,129.1,128.1,127.9,127.1,121.7,120.6,117.2,58.0,45.8,39.7,37.7,36.1,27.2,26.5;ESI-HRMS:m/z Calcd for[C20H22N2O+H+]:307.1805,found 307.1799。
实施例12
5-苯基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-12)
5-phenyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-12)
其具体制备过程同实施例1,只需将原料II-1替换为II-12,得到结构式如下的I-12目标产物34.8mg,产率为66%。
白色固体;mp:108-109℃;1H NMR(400MHz,CDCl3):δ7.27-7.29(m,4H),7.09-7.18(m,4H),7.00-7.04(m,1H),3.78-3.84(m,1H),2.99(dd,J1=16.4Hz,J2=5.6Hz,1H),2.86(d,J1=16.4Hz,J2=10.8Hz,1H),2.47-2.51(m,2H),2.26-2.36(m,1H),1.81-1.90(m,1H);13C NMR(100.6MHz,CDCl3):δ172.4,148.9,140.9,130.0,129.0,126.4,124.7,124.6,123.2,122.1,121.6,47.9,32.5,26.5,22.9;ESI-HRMS:m/z Calcd for[C17H16N2O+H+]:265.1335,found 265.1339。
实施例13
2-乙基-2-甲基-5-苯基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-13)和(I-13’)
2-ethyl-2-methyl-5-phenyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-13)and(I-13’)
其具体制备过程同实施例1,只需将原料II-1替换为II-13,得到结构式如下的I-13和I-13’目标产物58.1mg,产率为95%。
非对映体混合物的比例为1.5:1,无色油;ESI-HRMS:m/z Calcd for[C20H22N2O+H+]:307.1805,found 307.1813.
主产物:1H NMR(400MHz,CDCl3):δ7.22-7.29(m,4H),7.10-7.19(m,4H),7.01-7.06(m,1H),3.83-3.89(m,1H),3.06-3.14(m,1H),2.76-2.88(m,1H),2.05-2.12(m,1H),1.79dd,J1=13.2Hz,J2=4Hz,1H),1.52-1.69(m,2H),1.20(s,3H),0.91(t,J=7.6Hz,3H);13C NMR(100.6MHz,CDCl3):δ175.2,148.7,141.2,129.2,128.5,126.0,124.7,124.1,123.1,122.3,121.0,45.2,41.7,36.1,34.6,30.5,24.1,8.12;
副产物:1H NMR(400MHz,CDCl3):δ7.22-7.29(m,4H),7.10-7.19(m,4H),7.01-7.06(m,1H),3.76-3.80(m,1H),3.06-3.14(m,1H),2.76-2.88(m,1H),2.33(dd,J1=13.2Hz,J2=8.4Hz,1H),2.05-2.12(m,1H),1.52-1.69(m,2H),1.24(s,3H),0.84(t,J=7.6Hz,3H);13CNMR(100.6MHz,CDCl3):δ175.1,148.7,140.9,129.3,128.5,126.0,124.3,124.1,122.8,121.9,121.3,45.4,41.4,35.3,34.7,31.8,25.3,8.11。
实施例14
5'-苯基-1',5',10',10a'-四氢-3'H-螺[环丙烷-1,2'-吡咯并[1,2-b]噌啉]-3'-酮(I-14)
5'-phenyl-1',5',10',10a'-tetrahydro-3'H-spiro[cyclopropane-1,2'-pyrrolo[1,2-b]cinnolin]-3'-one(I-14)
其具体制备过程同实施例1,只需将原料II-1替换为II-14,得到结构式如下的I-14目标产物49.9mg,产率为86%。
白色固体;mp:101-102℃;1H NMR(400MHz,CDCl3):δ7.26-7.33(m,4H),7.08-7.16(m,4H),6.97-7.01(m,1H),3.82-3.87(m,1H),2.95-3.06(m,2H),2.58(dd,J1=12.8Hz,J2=8Hz,1H),1.68(d,J=12.8Hz,1H),1.26-1.31(m,1H),1.14-1.18(m,1H),0.71-0.81(m,2H);13C NMR(100.6MHz,CDCl3):δ174.1,148.4,140.4,129.3,128.3,125.8,124.0,123.7,122.1,121.4,121.0,46.0,32.6,32.3,18.3,15.9,10.7,;ESI-HRMS:m/z Calcd for[C19H18N2O+H+]:291.1492,found 291.1493。
实施例15
5'-苯基-1',5',10',10a'-四氢-3'H-螺[环丁烷-1,2'-吡咯并[1,2-b]噌啉]-3'-酮(I-15)
5'-phenyl-1',5',10',10a'-tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[1,2-b]cinnolin]-3'-one(I-15)
其具体制备过程同实施例1,只需将原料II-1替换为II-15,得到结构式如下的I-15目标产物40.7mg,产率为67%。
无色油;1H NMR(400MHz,CDCl3):δ7.24-7.31(m,4H),7.06-7.13(m,4H),6.96-7.00(m,1H),3.69-3.75(m,1H),2.98(dd,J1=16.4Hz,J2=4.8Hz,1H),2.60-2.73(m,2H),2.48-2.56(m,1H),2.33(dd,J1=13.2Hz,J2=8Hz,1H),2.10-2.21(m,2H),1.88-2.05(m,3H);13CNMR(100.6MHz,CDCl3):δ175.4,148.8,141.1,129.6,128.7,126.2,124.4,124.2,122.7,121.8,121.6,46.5,42.6,38.2,33.7,33.5,30.5,16.5;ESI-HRMS:m/z Calcd for[C20H20N2O+H+]:305.1648,found 305.1646。
实施例16
5'-苯基-1',5',10',10a'-四氢-3'H-螺[环戊烷-1,2'-吡咯并[1,2-b]噌啉]-3'-酮(I-16)
5'-phenyl-1',5',10',10a'-tetrahydro-3'H-spiro[cyclopentane-1,2'-pyrrolo[1,2-b]cinnolin]-3'-one(I-16)
其具体制备过程同实施例1,只需将原料II-1替换为II-16,得到结构式如下的I-16目标产物54.1mg,产率为85%。
无色油;1H NMR(400MHz,CDCl3):δ7.25-7.27(m,4H),7.06-7.16(m,4H),7.00-7.03(m,1H),3.79-3.85(m,1H),3.02(dd,J1=16.4Hz,J2=5.6Hz,1H),2.84(dd,J1=16.4Hz,J2=10Hz,1H),2.23(dd,J1=13.2Hz,J2=8.4Hz,1H),2.10-2.18(m,1H),2.01-2.08(m,1H),1.78-1.89(m,3H),1.63-1.75(m,2H),1.52-1.61(m,2H);13C NMR(100.6MHz,CDCl3):δ176.6,148.9,141.4,129.7,128.9,126.3,124.7,124.3,123.1,122.2,121.4,47.9,46.5,39.5,39.2,39.0,33.9,25.3,24.9;ESI-HRMS:m/z Calcd for[C21H22N2O+H+]:319.1805,found 319.1802。
实施例17
5'-苯基-1',5',10',10a'-四氢-3'H-螺[环己烷-1,2'-吡咯并[1,2-b]噌啉]-3'-酮(I-17)
5'-phenyl-1',5',10',10a'-tetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[1,2-b]cinnolin]-3'-one(I-17)
其具体制备过程同实施例1,只需将原料II-1替换为II-17,得到结构式如下的I-17目标产物57.0mg,产率为86%。
白色固体;mp:117-118℃;1H NMR(400MHz,CDCl3):δ7.22-7.28(m,4H),7.05-7.15(m,4H),7.00-7.04(m,1H),3.78-3.85(m,1H),3.08(dd,J1=16.8Hz,J2=5.6Hz,1H),2.79(dd,J1=16.4Hz,J2=10.4Hz,1H),2.22(dd,J1=13.2Hz,J2=8.4Hz,1H),1.79-1.83(m,3H),1.62-1.75(m,3H),1.42-1.45(m,2H),1.28-1.35(m,3H);13C NMR(100.6MHz,CDCl3):δ175.9,149.2,141.4,129.8,129.0,126.4,125.0,124.4,123.4,122.5,121.3,46.1,42.5,35.4,35.3,35.2,34.3,25.1,21.8,21.7;ESI-HRMS:m/z Calcd for[C22H24N2O+H+]:333.1961,found 333.1959。
实施例18
5'-苯基-1',5',10',10a'-四氢-3'H-螺[环庚烷-1,2'-吡咯并[1,2-b]噌啉]-3'-酮(I-18)
5'-phenyl-1',5',10',10a'-tetrahydro-3'H-spiro[cycloheptane-1,2'-pyrrolo[1,2-b]cinnolin]-3'-one(I-18)
其具体制备过程同实施例1,只需将原料II-1替换为II-18,得到结构式如下的I-18目标产物58.6mg,产率为99%。
白色固体;mp:141-143℃;1H NMR(400MHz,CDCl3):δ7.21-7.27(m,4H),7.06-7.15(m,4H),7.00-7.03(m,1H),3.79-3.86(m,1H),3.06(dd,J1=16.4Hz,J2=6Hz,1H),2.79(dd,J1=16.4Hz,J2=9.6Hz,1H),2.22(dd,J1=13.2Hz,J2=8.4Hz,1H),1.93-2.01(m,2H),1.73-1.82(m,3H),1.42-1.66(m,8H);13C NMR(100.6MHz,CDCl3):δ176.7,148.9,141.5,129.6,128.8,126.3,125.0,124.2,123.3,122.4,121.1,46.1,44.8,38.4,38.1,37.6,34.7,28.9,28.7,23.22,23.19;ESI-HRMS:m/z Calcd for[C23H26N2O+H+]:347.2118,found347.2112。
实施例19
2,2-二甲基-5,10-二苯基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-19)
2,2-dimethyl-5,10-diphenyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-19)
其具体制备过程同实施例1,只需将原料II-1替换为II-19,得到结构式如下的I-19目标产物67.8mg,产率为92%。
白色固体;mp:191-193℃;1H NMR(400MHz,CDCl3):δ7.29-7.37(m,7H),7.12-7.19(m,5H),6.92-6.96(m,1H),6.84(d,J=7.6Hz,1H),3.98(d,J=10Hz,1H),3.70-3.74(m,1H),1.99(dd,J1=13.2Hz,J2=8Hz,1H),1.82(dd,J1=13.6Hz,J2=2.4Hz,1H),1.35(s,3H),1.22(s,3H);13C NMR(100.6MHz,CDCl3):δ175.7,149.4,141.0,140.8,130.2,129.5,129.1,128.9,128.7,127.2,126.5,124.5,123.5,122.5,121.4,52.2,51.7,37.9,37.6,27.4,27.0;ESI-HRMS:m/z Calcd for[C25H24N2O+H+]:369.1961,found 369.1955。
实施例20
4,4-二甲基-7-苯基-2,3,3a,4,7,11b-六氢-1H-苯并[c]吡咯并[3,2,1-ij]噌啉-5(3a1H)-酮(I-20)
4,4-dimethyl-7-phenyl-2,3,3a,4,7,11b-hexahydro-1H-benzo[c]pyrrolo[3,2,1-ij]cinnolin-5(3a1H)-one(I-20)
其具体制备过程同实施例1,只需将原料II-1替换为II-20,得到结构式如下的I-20目标产物33.9mg,产率为51%。
白色固体;mp:154-155℃;1H NMR(400MHz,CDCl3):δ7.23-7.29(m,3H),7.17(d,J=7.6Hz,2H),7.10-7.13(m,2H),7.04-7.08(m,1H),6.97-6.99(m,1H),4.33(t,J=6.4Hz,1H),3.00-3.06(m,1H),2.01-2.07(m,1H),1.76-1.90(m,2H),1.59-1.71(m,2H),1.39-1.50(m,1H),0.96-1.13(m,7H);13C NMR(100.6MHz,CDCl3):δ175.3,148.3,142.6,129.9,128.8,127.7,126.6,125.0,123.7,122.8,122.6,50.9,43.0,41.2,34.6,26.8,24.0,22.6,20.4,18.4;ESI-HRMS:m/z Calcd for[C22H24N2O+H+]:333.1961,found 333.1959。
实施例21
5-苯基-1,2,2a,3,5,9b-六氢-4a,5-二氮杂戊烯[1,6-ab]萘-4(2a1H)-酮(I-21)
5-phenyl-1,2,2a,3,5,9b-hexahydro-4a,5-diazapentaleno[1,6-ab]naphthalen-4(2a1H)-one(I-21)
其具体制备过程同实施例1,只需将原料II-1替换为II-21,得到结构式如下的I-21目标产物51.1mg,产率为88%。
白色固体;mp:127-128℃;1H NMR(400MHz,CDCl3):δ7.19-7.29(m,6H),7.13-7.17(m,1H),7.05-7.09(m,2H),4.02(t,J=6.8Hz,1H),2.85-3.05(m,3H),2.22-2.28(m,1H),2.01-2.06(m,1H),1.82-1.93(m,1H),1.49-1.64(m,2H);13C NMR(100.6MHz,CDCl3):δ171.7,148.4,139.4,129.9,129.5,128.8,126.2,124.0,123.8,123.0,120.2,55.8,41.8,36.1,33.4,33.0,32.5;ESI-HRMS:m/z Calcd for[C19H18N2O+H+]:291.1492,found291.1488。
实施例22
8,8-二甲基-5-苯基-5,8,9,10,10a,11-六氢-7H-吡啶并[1,2-b]噌啉-7-酮(I-22)
8,8-dimethyl-5-phenyl-5,8,9,10,10a,11-hexahydro-7H-pyrido[1,2-b]cinnolin-7-one(I-22)
其具体制备过程同实施例1,只需将原料II-1替换为II-22,得到结构式如下的I-22目标产物50.2mg,产率为82%。
白色固体;mp:98-100℃;]1H NMR(400MHz,CDCl3):δ7.20-7.25(m,3H),7.12-7.17(m,2H),7.00-7.06(m,4H),3.90-3.95(m,1H),3.08(dd,J1=16.4Hz,J2=12Hz,1H),2.74(dd,J1=16.4Hz,J2=4.8Hz,1H),2.27-2.36(m,1H),2.00(td,J1=14Hz,J2=3.6Hz,1H),1.68-1.74(m,1H),1.61(dt,J1=14Hz,J2=3.6Hz,1H),1.41(s,3H),1.26(s,3H);13C NMR(100.6MHz,CDCl3):δ175.1,147.8,140.6,129.6,128.7,126.2,126.1,123.4,123.2,122.5,118.3,51.5,39.5,32.5,31.4,27.3,26.7,23.8;ESI-HRMS:m/z Calcd for[C20H22N2O+H+]:307.1805,found 307.1802。
实施例23
10-环丙基-5-苯基-1,5,10,10a-四氢吡咯并[1,2-b]噌啉-3(2H)-酮(I-23)
10-cyclopropyl-5-phenyl-1,5,10,10a-tetrahydropyrrolo[1,2-b]cinnolin-3(2H)-one(I-23)
其具体制备过程同实施例1,只需将原料II-1替换为II-23,得到结构式如下的I-23目标产物53.5mg,产率为88%。
非对映体混合物的比例为3.7:1,白色固体;ESI-HRMS:m/z Calcd for[C20H20N2O+H+]:305.1648,found 305.1649。
主产物:1H NMR(400MHz,CDCl3):δ7.74(d,J=8Hz,1H),7.06-7.33(m,8H),3.73-3.78(m,1H),2.20-2.58(m,3H),2.13-2.17(m,1H),2.01-2.07(m,1H),0.76-0.87(m,2H),0.52-0.62(m,2H),0.39-0.46(m,1H);13C NMR(100.6MHz,CDCl3):δ172.5,148.7,140.8,130.0,128.9,126.7,124.1,123.9,123.1,123.08,120.3,54.6,45.4,27.4,23.4,16.0,5.0,2.7;
副产物:1H NMR(400MHz,CDCl3):δ7.06-7.33(m,7H),6.99-7.03(m,1H),6.95(d,J=8Hz,1H),4.15-4.19(m,1H),2.20-2.58(m,5H),0.76-0.87(m,2H),0.52-0.62(m,2H),0.28-0.34(m,1H);13C NMR(100.6MHz,CDCl3):δ172.5,149.2,142.3,130.8,130.0,129.2,127.2,127.1,125.4,122.6,121.0,53.8,44.5,28.7,20.3,11.7,4.4,2.8。
以上所述仅为本发明的优选实施例,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的内容和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
2.一种如权利要求1所述1,2,3,4-四氢噌啉骨架类化合物的合成方法,其特征在于:具体是将不饱和酰肼II、催化剂、碱、氧化剂和溶剂加入反应管后密封,置换保护气体或空气条件下,于-80~200℃下搅拌反应,通过后处理提纯产物I;其合成路线如下:
式中,R1、R2、R3、R4、R5任选自H、卤素、C1-C16的烷基、C1-C16的烷氧基、C1-C16的烷硫基、苯基、三氟甲基、甲氧羰基、硝基、羟基、醛基、羧基、氨基、酯基、硅烷基、硅氧基、苄氧基、酰胺基、酰氧基、胡椒基中的任意一种;R1、R2、R3、R4、R5全为H时,式I所示的基团即为苯基;R6任选自直链型或支链型烷基、环烷基型、芳基、杂芳基中的任意一种;R7、R8任选自H、直链型或支链型烷基、环烷基型、芳基、杂芳基中的任意一种。
3.根据权利要求2所述的合成方法,其特征在于:所述不饱和酰肼II加入量为0.001M~0.15M、催化剂加入量为0.1%~1M、碱加入量为0.001M~0.15M、氧化剂加入量为0.001M~10M。
4.根据权利要求2所述的合成方法,其特征在于:所述氧化剂为TEMPO+BF4 -、TEMPO+PF6 -、TEMPO+ClO4 -、PhI(OAc)2、PhI(TFA)2中的任意一种。
5.根据权利要求2所述的合成方法,其特征在于:所述氧化剂采用电化学氧化方法代替。
6.根据权利要求2所述的合成方法,其特征在于:所述催化剂选自TEMPO、4-AcNH-TEMPO、4-OH-TEMPO中的任意一种。
7.根据权利要求2所述的合成方法,其特征在于:所述碱选自Li2CO3、K2CO3、Na2CO3、Cs2CO3、K3PO4、K2HPO4、KH2PO4、DBU、Et3N中的任意一种。
8.根据权利要求2所述的合成方法,其特征在于:所述溶剂选自乙腈、苯甲腈、氯苯、二氯甲烷、1,2-二氯乙烷、四氢呋喃、二氧六环、乙醚、甲醇、乙醇中的任意一种或多种的任意比例混合。
9.根据权利要求2所述的合成方法,其特征在于:所述保护气选自氮气、氩气中的任意一种。
10.权利要求1所述1,2,3,4-四氢噌啉骨架类化合物或其药学上可接受的盐在制备具有1,2,3,4-四氢噌啉类结构单元药物方面的用途。
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