CN113717179A - 一种螺吡唑啉吡咯酮类衍生物及其合成方法 - Google Patents
一种螺吡唑啉吡咯酮类衍生物及其合成方法 Download PDFInfo
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Abstract
本发明公开了一种高效制备螺吡唑啉吡咯酮类衍生物及其合成方法,属于农药中间体技术领域,在装有取代3‑芳亚甲基马来酰亚胺化合物、取代氯化腙类化合物的容器中加入合适的溶剂和合适的碱,在合适的反应温度下搅拌,反应结束后,过滤,滤液加入水或饱和食盐水溶液,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物螺吡唑啉吡咯酮类衍生物。该方法具有反应高效、方便快捷、底物适应性广、区域选择性高、产率高等优点,具有良好的工业应用前景。
Description
技术领域
本发明属于农药中间体技术领域,涉及一种螺吡唑啉吡咯酮类衍生物及其合成方法。
背景技术
螺杂环是一种特殊的骨架,因为它们存在于许多天然产物和生物活性分子中。目前,螺杂环化合物在新药发现领域发挥着重要作用,因为这种螺环框架可以减少与蛋白质结合后的构象熵损失。螺吡唑啉吡咯酮类作为一类重要的螺环化合物,也普遍存在于具有显著生物活性的化合物中,例如抗菌剂、抗炎剂、抗肿瘤剂、镇痛剂、RalA抑制剂、和4-磷酸二酯酶抑制剂等。在过去的十年中,大量有机合成工作者努力致力于高效合成结构多样的螺吡唑啉类化合物,并且已经开发了几种合成方法。其中,有机催化环加成反应是最常用的方法。尽管已经构建了许多螺吡唑啉衍生物的方法,但是含有五元含氮环的螺吡唑啉吡咯酮类的合成仍然较少。因此,开发简便高效的合成具有不同类型N-杂环的螺吡唑啉吡咯酮的策略是非常重要的。
吡唑啉是一类非常重要的五元含氮杂环,因为它们具有广谱的显著生物活性。鉴于吡唑啉与吡咯酮的药理和生物学活性,螺吡唑啉和吡咯酮部分的组合可能有助于药物发现。据我们所知,迄今为止,文献中对螺吡唑啉吡咯酮的合成研究较少,鉴于这些观点以及我们对合成结构新颖的螺环化合物的兴趣,因此本专利开发了一种取代3-芳亚甲基马来酰亚胺化合物、取代氯化腙类化合物在碱作用下发生环加成反应快速高效的构建螺吡唑啉吡咯酮类衍生物的合成方法,为此类化合物生物活性测试提供物质基础,同时为含有此骨架的医药中间体合成提供可靠的合成方法。
发明内容
本发明的目的是针对现有的技术存在的上述问题,提供一种螺吡唑啉吡咯酮类衍生物及其合成方法,具有反应高效、方便快捷、区域选择性高、操作简单、原料廉价易得等优势。
本发明的目的可通过下列技术方案来实现:
一种螺吡唑啉吡咯酮类衍生物,其特征在于,其结构式如下:
其中取代3-芳亚甲基马来酰亚胺化合物中R1是C6-C16烷基、环戊基、环已基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基、2-吡咯基、3-吡啶基等中的任意一种;
取代3-芳亚甲基马来酰亚胺化合物中R4是C5-C8的烷基、环丙基、环戊基、环已基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基等中的任意一种;
取代氯化腙类化合物R2是C5-C8的烷基、环丙基、环戊基、环已基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基等中的任意一种;
取代氯化腙类化合物R3是C5-C8的烷基、环丙基、环戊基、环已基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基等中的任意一种;
一种螺吡唑啉吡咯酮类衍生物的合成方法,其特征在于,包括如下步骤:在装有取代3-芳亚甲基马来酰亚胺化合物、取代氯化腙类化合物的容器中加入合适的溶剂和合适的碱,在合适的反应温度下搅拌,反应结束后加入水或饱和食盐溶液,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物螺吡唑啉吡咯酮类衍生物。
所述有机溶剂是选自二氯甲烷、三氯甲烷、乙腈、四氢呋喃、苯、甲苯、二甲苯、DMF、DMSO、甲醇、乙醇、三氟乙醇、六氟异丙醇、1,4-二氧六环、乙酸乙酯等中的任意一种。
所述合适温度为0℃-100℃。
所述的取代3-芳亚甲基马来酰亚胺化合物、取代氯化腙类化合物、碱之间的摩尔比为1.0:1.5:1.5。
所述的取代3-芳亚甲基马来酰亚胺化合物中R1是C6-C16烷基、环戊基、环已基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基、2-吡咯基、3-吡啶基等中的任意一种;
取代3-芳亚甲基马来酰亚胺化合物中R4是C5-C8的烷基、环丙基、环戊基、环已基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基等中的任意一种;
所述的取代氯化腙类化合物R2是C5-C8的烷基、环丙基、环戊基、环已基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基等中的任意一种;
取代氯化腙类化合物R3是C5-C8的烷基、环丙基、环戊基、环已基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基等中的任意一种。
所述的碱选自Na2CO3、NaOH、NaHCO3、K2CO3、Cs2CO3、NaOAc、Pyridine、Piperidine、Et3N、DIPEA、DBU、DMAP等中的一种。
本发明具有的有益效果:
本发明所提供一种不需要添加任何催化剂的条件下,温和的反应环境中用廉价易得的原料取代3-芳亚甲基马来酰亚胺化合物、取代氯化腙类化合物快速制备螺吡唑啉吡咯酮类衍生物,产物的选择性和收率高,具有良好的工业应用前景。
附图说明
图1是螺吡唑啉吡咯酮类衍生物的合成反应式。
图2是1,3,4,7-四苯基-2,3,7-三氮螺[4.4]壬-1-烯-6,8-二酮的1H NMR图。
图3是1,3,4,7-四苯基-2,3,7-三氮螺[4.4]壬-1-烯-6,8-二酮的13C NMR图。
具体实施方式
以下是本发明的具体实施例并结合附图,对本发明的技术方案作进一步的描述,但本发明并不限于这些实施例。
取代螺吡唑啉吡咯酮类衍生物的合成一般方法
如图1所示,本发明提供的螺吡唑啉吡咯酮类衍生物(I)的合成步骤为:在反应容器中加入0.15mmol氯化腙类衍生物(Ⅱ)(如:N-苯基苯甲肼酰氯等),取代3-芳亚甲基马来酰亚胺化合物(Ⅲ)(如:3-苄亚基-1-苯基吡咯烷-2,5-二酮等)0.1mmol,碱(如:Cs2CO3等)1.5mmol,然后加入2~3mL溶剂(如:DCM),室温反应,反应结束后加水或饱和盐溶液,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离或重结晶,即得目标产物。
7.01–6.94(m,2H),5.29(s,1H),3.00(d,J=19.0Hz,1H),2.76(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.69,172.41,150.85,143.45,134.59,131.19,131.07,129.75,129.57,129.22,129.21,129.08,128.94,128.86,128.42,126.92,126.20,124.23,119.49,75.99,60.49,36.09.HR-EI-MS(positive)m/z 480.1683[M+Na]+(calcd forC30H23N3O2Na 480.1688).
其1H NMR图如图2所示,其13C NMR图如图3所示。
(m,2H),5.85(s,1H),3.07(d,J=19.0Hz,1H),2.63(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.39,172.61,150.16,143.23,134.21,132.96,131.37,130.88,130.39,129.67,129.32,129.07,128.69,128.44,126.82,126.34,124.09,119.08,74.62,56.47,36.69.HR-EI-MS(positive)m/z 514.1299[M+Na]+(calcd for C30H22ClN3O2Na 514.1298).
7.14(m,3H),6.94–6.88(m,2H),5.24(s,1H),3.01(d,J=19.0Hz,1H),2.73(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.34,172.24,151.09,143.49,134.98,133.33,131.17,130.85,130.56,130.10,129.69,129.34,129.06,128.62,126.94,126.24,124.78,120.13,76.10,59.47,36.38.HR-EI-MS(positive)m/z 514.1299[M+Na]+(calcd forC30H22ClN3O2Na 514.1298).
7.21–7.13(m,3H),6.98(dd,J=8.3,1.5Hz,2H),5.26(s,1H),3.03(d,J=19.0Hz,1H),2.78(d,J=19.0Hz,1H),2.55(s,3H).13C NMR(101MHz,CDCl3)δ175.61,172.34,150.82,143.45,139.84,131.20,131.01,130.93,130.63,129.56,129.17,128.94,128.46,127.15,126.90,126.19,124.26,119.52,75.93,59.97,36.12,15.32.HR-EI-MS(positive)m/z 526.1565[M+Na]+(calcd for C31H25SN3O2Na 526.1565).
8.32–8.13(m,2H),7.67–7.55(m,4H),7.42–7.27(m,10H),7.22(td,J=7.1,1.3Hz,1H),6.88–6.74(m,2H),5.33(s,1H),3.00(d,J=19.0Hz,1H),2.70(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ174.64,171.91,151.36,149.10,143.39,137.32,135.12,131.01,130.41,129.73,129.32,129.15,128.81,126.89,126.27,125.59,123.99,121.13,76.36,58.88,36.77.HR-EI-MS(positive)m/z 525.1537[M+Na]+(calcd for C30H22N4O4Na525.1539).
7.46–7.27(m,10H),7.22(td,J=7.2,1.3Hz,1H),6.93–6.67(m,2H),5.32(s,1H),3.01(d,J=19.0Hz,1H),2.68(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ174.67,171.86,151.27,148.21,143.35,142.32,130.97,130.44,130.23,129.76,129.33,129.17,128.81,126.85,126.20,125.62,125.04,121.10,76.36,58.95,36.75.HR-EI-MS(positive)m/z 525.1537[M+Na]+(calcd for C30H22N4O4Na 525.1539).
1H),3.02(d,J=19.0Hz,1H),2.78(d,J=19.0Hz,1H),2.36(s,3H).13C NMR(101MHz,CDCl3)δ175.76,172.53,150.95,143.56,139.60,134.53,131.24,129.63,129.14,128.94,128.43,126.94,126.37,126.24,124.14,119.41,75.98,60.54,36.15,21.52.HR-EI-MS(positive)m/z 494.1843[M+Na]+(calcd for C31H25N3O2Na 494.1844).
1H),7.05–6.94(m,2H),6.93–6.72(m,3H),5.24(s,1H),3.77(s,3H),3.03(d,J=19.0Hz,1H),2.80(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.76,172.59,160.62,150.84,143.55,136.20,131.31,131.21,130.91,129.64,129.29,129.16,129.01,128.51,126.96,126.30,124.28,121.52,119.56,115.19,113.86,75.98,60.52,55.39,36.25.HR-EI-MS(positive)m/z 510.1792[M+Na]+(calcd for C31H25N3O3Na 510.1794).
7.07–6.98(m,2H),6.97–6.86(m,2H),5.26(s,1H),3.80(s,3H),3.00(d,J=19.0Hz,1H),2.78(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.90,172.46,159.84,150.86,143.50,131.29,131.18,130.40,129.58,129.23,128.98,128.41,126.95,126.34,126.22,123.99,119.17,115.11,75.93,60.06,55.32,35.90.HR-EI-MS(positive)m/z 510.1792[M+Na]+(calcd for C31H25N3O3Na 510.1794).
7H),7.26–7.21(m,3H),7.10–6.99(m,3H),6.91(t,J=7.6Hz,1H),5.77(s,1H),3.86(s,3H),3.11(d,J=19.0Hz,1H),2.57(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ176.21,172.90,156.66,149.33,143.06,131.55,130.23,129.50,129.25,128.82,128.40,126.76,126.10,122.75,121.65,117.43,110.88,73.83,55.77,53.94,35.86.HR-EI-MS(positive)m/z 510.1792[M+Na]+(calcd for C31H25N3O3Na 510.1794).
7.17–6.96(m,5H),6.81–6.61(m,2H),5.24(s,1H),2.98(d,J=19.0Hz,1H),2.97(s,3H),2.84(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ176.43,172.80,150.79,150.54,143.65,131.56,130.14,129.64,129.33,128.96,128.44,127.09,126.37,123.55,121.21,118.65,113.04,75.97,60.76,40.37,35.74.HR-EI-MS(positive)m/z 509.1950[M+Na]+(calcdfor C31H26N4O2Na 509.1953).
8H),7.33–7.27(m,3H),7.25–7.10(m,4H),7.00–6.92(m,2H),6.22(s,1H),2.95(d,J=19.0Hz,1H),2.47(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ176.46,172.39,150.14,143.22,134.34,131.60,131.30,131.17,130.30,129.84,129.63,129.43,129.23,128.98,128.80,128.44,127.82,126.91,126.54,126.12,125.93,123.73,121.84,119.24,118.64,75.33,55.46,36.27.HR-EI-MS(positive)m/z 530.1844[M+Na]+(calcd for C34H26N3O2Na530.1844).
2H),6.88–6.81(m,2H),4.19(t,J=5.2Hz,1H),3.34(s,2H),1.91-1.86(m,2H),1.47–1.19(m,9H),0.89-0.83(m,3H).13C NMR(101MHz,CDCl3)δ175.60,172.99,163.59,161.11,153.43,143.92,131.43,129.43,129.11,128.72,128.59,128.47,128.06,127.03,126.81,124.74,120.51,116.34,116.11,75.00,52.31,35.21,31.43,29.39,28.14,26.24,22.51,13.98.HR-EI-MS(positive)m/z 502.2473[M+Na]+(calcd for C31H33N3O2Na 502.2470).
7.17–7.09(m,3H),7.01–6.95(m,2H),5.29(s,1H),3.02(d,J=19.0Hz,1H),2.76(d,J=19.0Hz,1H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ175.74,172.48,151.09,143.67,139.25,134.76,131.26,129.72,129.57,129.23,129.18,128.93,128.80,128.30,126.92,126.24,124.15,119.52,75.95,60.54,36.17,21.41.HR-EI-MS(positive)m/z 494.1841[M+Na]+(calcd for C31H25 N3O2Na 494.1844).
6.97–6.95(m,2H),5.28(s,1H),3.01(d,J=19.0Hz,1H),2.75(d,J=19.0Hz,1H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ175.65,172.43,151.21,143.59,138.08,134.75,131.26,131.00,129.99,129.72,129.57,129.20,128.91,128.80,128.28,127.44,126.22,124.29,124.25,124.23,119.67,119.65,76.00,60.49,36.18,21.41.HR-EI-MS(positive)m/z494.1841[M+Na]+(calcd for C31H25 N3O2Na 494.1844).
7.00–6.93(m,2H),6.89–6.81(m,1H),5.27(s,1H),3.76(s,3H),3.01(d,J=19.0Hz,1H),2.765(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.66,172.43,159.59,150.95,143.51,134.79,132.45,131.30,129.80,129.63,129.47,129.24,128.94,126.27,124.38,119.70,115.43,111.82,76.10,60.56,55.29,36.24.HR-EI-MS(positive)m/z 510.1797[M+Na]+(calcd for C31H25 N3O3Na 510.1794).
(m,2H),7.02–6.95(m,2H),5.25(s,1H),3.03(d,J=19.0Hz,1H),2.74(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.53,172.30,149.66,143.18,134.56,134.26,132.98,131.21,129.92,129.71,129.69,129.29,129.16,129.10,129.06,129.04,126.75,126.23,125.01,124.59,119.70,76.20,60.20,36.15.HR-EI-MS(positive)m/z 514.1298[M+Na]+(calcd for C30H22ClN3O2Na 514.1298).
(m,3H),5.42(s,1H),3.00(d,J=19.0Hz,1H),2.76(d,J=19.1Hz,4H).13C NMR(101MHz,CDCl3)δ175.70,172.58,151.65,143.74,137.98,134.92,131.32,131.03,129.78,129.64,129.26,128.99,128.83,126.32,124.88,124.38,119.86,76.07,60.48,36.34,21.37.HR-EI-MS(positive)m/z 494.1844[M+Na]+(calcd for C31H25 N3O2Na 494.1844).
6.94(dd,J=8.3,1.5Hz,3H),5.25(s,1H),3.01(d,J=19.0Hz,1H),2.74(d,J=19.0Hz,1H),2.25(s,6H).13C NMR(101MHz,CDCl3)δ176.27,172.41,151.63,143.72,137.87,134.44,131.58,131.38,130.24,129.70,129.33,129.06,128.85,128.60,126.30,125.65,124.00,119.07,75.69,62.67,35.39,22.94.HR-EI-MS(positive)m/z 508.1998[M+Na]+(calcd for C32H27N3O2Na 508.2001).
7.05–6.95(m,4H),5.27(s,1H),3.03(d,J=19.0Hz,1H),2.77(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.56,172.30,146.72,143.93,143.26,134.31,131.25,129.65,129.30,129.06,126.25,124.58,119.93,111.75,111.59,75.79,60.56,35.87.HR-EI-MS(positive)m/z 498.1598[M+Na]+(calcd for C30H22FN3O2Na 498.1594).
2H),6.37–6.26(m,2H),5.21(s,1H),2.99(d,J=19.0Hz,1H),2.77(d,J=19.0Hz,1H).13CNMR(101MHz,CDCl3)δ175.69,172.39,164.47,161.99,150.13,143.51,134.47,131.25,129.88,129.67,129.26,129.03,128.83,127.41,126.26,124.43,119.67,115.76,115.54,76.17,60.49,36.21.HR-EI-MS(positive)m/z 470.1480[M+Na]+(calcd for C28H21N3O3Na470.1481).
=5.1,3.7Hz,1H),6.82(dd,J=3.7,1.1Hz,1H),5.25(s,1H),3.00(d,J=19.0Hz,1H),2.76(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.77,172.49,151.03,143.52,134.80,133.62,133.05,131.32,129.87,129.70,129.30,129.00,128.71,128.47,128.26,127.80,126.83,126.45,126.30,124.36,119.64,76.16,60.56,36.24.HR-EI-MS(positive)m/z486.1254[M+Na]+(calcd for C28H21N3O2SNa 486.1252).
7.8,1.7Hz,1H),7.48–7.29(m,16H),7.20–7.15(m,1H),7.04–6.98(m,2H),5.42(s,1H),3.05(d,J=19.0Hz,1H),2.79(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.53,172.27,146.90,143.27,134.82,134.28,131.20,129.65,129.40,129.23,129.08,128.96,127.62,127.33,127.22,126.19,124.34,119.63,76.13,61.35,36.03.HR-EI-MS(positive)m/z530.1844[M+Na]+(calcd for C34H25N3O2Na 530.1844).
7.19–7.12(m,3H),7.01–6.95(m,2H),5.27(s,1H),3.01(d,J=19.0Hz,1H),2.75(d,J=19.0Hz,1H),2.47(s,3H).13C NMR(101MHz,CDCl3)δ175.79,172.46,150.56,143.60,140.22,134.71,131.35,129.86,129.67,129.31,129.01,127.80,127.33,126.30,125.99,124.30,119.59,76.05,60.58,36.22,15.42.HR-EI-MS(positive)m/z 526.1566[M+Na]+(calcd for C31H25N3O2SNa 526.1565).
6.98–6.90(m,3H),6.70(d,J=8.4Hz,1H),5.23(s,1H),3.84(s,3H),3.83(s,3H),3.00(d,J=19.0Hz,1H),2.75(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.64,172.47,151.14,150.10,148.94,143.72,135.01,131.20,129.72,129.54,129.17,128.85,126.20,124.29,123.92,120.45,119.76,110.57,109.42,75.99,60.48,55.85,36.34.HR-EI-MS(positive)m/z 540.1899[M+Na]+(calcd for C32H27N3O4Na 540.1899).
2.95(d,J=19.0Hz,1H),2.72(d,J=19.0Hz,1H),1.21(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ175.12,171.89,142.78,141.22,134.41,131.15,129.81,129.45,129.25,129.13,128.77,126.22,125.69,120.27,76.54,61.59,59.70,35.61,14.20.HR-EI-MS(positive)m/z 498.2366[M+Na]+(calcd for C28H33N3O4Na 498.2369).
4.84(s,1H),2.88(d,J=19.0Hz,1H),2.70(d,J=19.0Hz,1H),1.53-1.42(m,1H),1.14–1.09(m,1H),0.94–0.79(m,3H).13C NMR(101MHz,CDCl3)δ176.30,172.56,157.04,144.35,133.99,131.38,129.66,129.55,129.29,128.99,126.31,123.85,119.31,76.03,63.13,35.25,9.91,9.01,8.14.HR-EI-MS(positive)m/z 444.1688[M+Na]+(calcd forC27H23N3O2Na 444.1688).
142.05,134.29,131.08,130.80,129.81,129.56,129.40–129.12(m),129.21,129.02,128.47,126.97,126.06,120.24,75.75,60.79,35.89.HR-EI-MS(positive)m/z 514.1296[M+Na]+(calcd for C30H22ClN3O2Na 514.1298).
2.76(d,J=19.0Hz,1H),2.40(s,3H).13C NMR(101MHz,CDCl3)δ176.02,172.55,150.55,143.47,139.66,134.72,131.45,131.29,129.83,129.47,129.37,129.35,129.11,129.07,129.04,128.95,128.52,127.03,126.33,125.09,120.30,116.38,76.11,60.65,36.10,21.75.HR-EI-MS(positive)m/z 494.1844[M+Na]+(calcd for C31H25N3O2Na 494.1844).
13C NMR(101MHz,CDCl3)δ175.68,171.42,150.97,145.85,133.92,133.61,131.22,130.38,130.12,129.89,129.62,129.59,129.52,129.45,129.41,128.68,127.33,126.06,119.34,115.13,104.15,73.61,62.74,34.97.HR-EI-MS(positive)m/z 505.1643[M+Na]+(calcdfor C31H22N4O2Na 505.1640).
3H).13C NMR(101MHz,CDCl3)δ177.38,172.43,146.08,138.96,138.59,138.47,135.30,131.72,131.57,129.82,129.24,128.86,128.60,128.48,128.37,128.25,126.52,126.17,60.39,35.75,20.58,19.44.HR-EI-MS(positive)m/z 508.2000[M+Na]+(calcd forC32H27N3O2Na 508.2001).
1H),2.58(d,J=19.0Hz,1H),2.37(s,3H),2.31(s,3H).13C NMR(101MHz,CDCl3)δ176.10,172.53,151.04,141.06,138.88,135.30,134.69,131.42,131.25,129.76,129.41,128.85,128.40,126.59,126.37,125.93,78.24,58.90,35.38,20.66,15.58.HR-EI-MS(positive)m/z 508.2000[M+Na]+(calcd for C32H27N3O2Na 508.2001).
Hz,1H),2.75(d,J=19.0Hz,1H).13C NMR(101MHz,CDCl3)δ175.74,171.51,150.55,144.55,135.96,133.59,131.15,130.40,129.90,129.60,129.51,129.35,129.31,129.26,128.51,127.19,126.24,121.96,114.54,74.38,62.14,34.98.HR-EI-MS(positive)m/z548.0905[M+Na]+(calcd for C30H21Cl2N3O2Na 548.0909).
134.12,131.07,130.65,129.83,129.45,129.35,129.20,129.10,129.05,128.50,127.04,126.02,122.07,121.89,121.64,118.22,117.22,117.00,75.89,60.91,35.77.HR-EI-MS(positive)m/z 532.1200[M+Na]+(calcd for C30H21ClFN3O2Na 532.1204).
本文中所描述的具体实施例仅仅是对本发明精神作举例说明。本发明所属技术领域的技术人员可以对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代,但并不会偏离本发明的精神或者超越所附权利要求书所定义的范围。
Claims (8)
1.一种螺吡唑啉吡咯酮类衍生物,其特征在于,其结构式如下:
其中取代3-芳亚甲基马来酰亚胺化合物中R1是C6-C16烷基、环戊基、环己基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基、2-吡咯基、3-吡啶基中的一种;
取代3-芳亚甲基马来酰亚胺化合物中R4是C5-C8的烷基、环丙基、环戊基、环己基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基中的一种;
取代氯化腙类化合物R2是C5-C8的烷基、环丙基、环戊基、环己基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基中的一种;
取代氯化腙类化合物R3是C5-C8的烷基、环丙基、环戊基、环己基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基中的一种。
2.一种合成权利要求1所述的螺吡唑啉吡咯酮类衍生物的方法,其特征在于,包括如下步骤:在装有取代3-芳亚甲基马来酰亚胺化合物、取代氯化腙类化合物的容器中加入合适的溶剂和合适的碱,在合适的反应温度下搅拌,反应结束后加入水或饱和食盐溶液,然后用有机溶剂萃取,干燥,减压蒸馏浓缩除去溶剂,粗产品经柱色谱分离,即得目标产物螺吡唑啉吡咯酮类衍生物。
3.根据权利要求2所述的螺吡唑啉吡咯酮类衍生物的合成方法,其特征在于,所述有机溶剂是选自二氯甲烷、三氯甲烷、乙腈、四氢呋喃、苯、甲苯、二甲苯、DMF、DMSO、甲醇、乙醇、三氟乙醇、六氟异丙醇、1,4-二氧六环、乙酸乙酯中的一种。
4.根据权利要求2所述的螺吡唑啉吡咯酮类衍生物的合成方法,所述的碱是选自Na2CO3、NaOH、NaHCO3、K2CO3、Cs2CO3、NaOAc、Pyridine、Piperidine、Et3N、DIPEA、DBU、DMAP中的一种。
5.根据权利要求2所述的螺吡唑啉吡咯酮类衍生物的合成方法,其特征在于,所述合适温度为0℃-100℃。
6.根据权利要求2所述的一种螺吡唑啉吡咯酮类衍生物的合成方法,其特征在于,所述的取代3-芳亚甲基马来酰亚胺化合物、取代氯化腙类化合物、碱之间的摩尔比为1.0:1.5:1.5。
7.根据权利要求2所述的一种螺吡唑啉吡咯酮类衍生物的合成方法,其特征在于,所述的取代3-芳亚甲基马来酰亚胺化合物中R1是选自C6-C16烷基、环戊基、环己基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基、2-吡咯基、3-吡啶基中的一种;
R4是选自C6-C16烷基、环戊基、环己基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基、2-吡咯基、3-吡啶基中的一种。
8.根据权利要求2所述的一种螺吡唑啉吡咯酮类衍生物的合成方法,其特征在于,所述的取代氯化腙类化合物中R2是C5-C8的烷基、环丙基、环戊基、环己基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基中的一种;
R3是C5-C8的烷基、环丙基、环戊基、环己基、金刚烷基、2-甲基苯基、2-乙基苯基、2-异丙基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-腈基苯基、2-硝基苯基、3-甲基苯基、3-乙基苯基、3-异丙基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-腈基苯基、3-硝基苯基、4-甲基苯基、4-乙基苯基、4-异丙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-腈基苯基、4-硝基苯基、萘基、2-呋喃基、2-噻吩基中的一种。
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