CN115417821A - 一种取代1,4-二氢哒嗪类衍生物及其制备与应用 - Google Patents

一种取代1,4-二氢哒嗪类衍生物及其制备与应用 Download PDF

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CN115417821A
CN115417821A CN202211078275.8A CN202211078275A CN115417821A CN 115417821 A CN115417821 A CN 115417821A CN 202211078275 A CN202211078275 A CN 202211078275A CN 115417821 A CN115417821 A CN 115417821A
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汪舰
孙绍发
汪钢强
袁成
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Abstract

本发明公开了一种1,4‑二氢哒嗪类衍生物及其合成方法，属于有机合成、医药、农药中间体技术领域，在装有取代5mL反应烧瓶中，将氯化腙、硫叶立德和无机碱加入干燥的溶剂中，然后加入有机碱并在室温下剧烈搅拌1小时，然后用NH4Cl(aq.)中和混合物，用DCM(3x2ml)萃取并用Na2SO4干燥。之后第二步是，将在DCE(2mL)中的CF3SO3H(5mol％)添加到浓缩混合物中并搅拌5分钟。通过TLC检测完全反应，然后通过快速柱(石油醚/乙酸乙酯＝40:1)纯化产物，即得目标产物1,4‑二氢哒嗪类衍生物，该方法具有反应高效、绿色环保、方便快捷、底物适应性广、产率高等优点，具有良好的工业应用前景。

Description

一种取代1,4-二氢哒嗪类衍生物及其制备与应用
技术领域
本发明属于有机合成、医药、农药中间体技术领域，涉及一种取代1,4-二氢哒嗪类衍生物及其制备与应用。
背景技术
哒嗪类化合物是含氮杂环家族分子的重要一员。它们是包括抗真菌、抗菌、抗炎、抗高血压活性等生物活性的核心结构单元。如作为钙敏化肌力药物左西孟旦、强心血管扩张剂匹莫苯、抗高血压药卡德拉嗪和抗炎药埃莫法松等市场上销售药物中都含有哒嗪骨架。在哒嗪衍生物中，二氢哒嗪也是一类备受关注的化合物，因为它们可能用作抗高血压剂、血管扩张剂和冠状动脉治疗剂，或作为解痉剂，特别是当C4上的取代基是芳香族时。1994年，Chiou报道了一种稠环的1,4-二氢哒嗪类药物作为一种白细胞介素-1阻滞剂显示出眼部抗炎活性等。由于1,4-二氢哒嗪类独特的药理及生理性质，在现报道的多种药物中进行结构修饰的报道，以进一步研究它们的生理活性和构效关系。
据我们所知，迄今为止，文献中通过氯化腙与硫叶立德合成1,4-二氢哒嗪类的研究较少，因此本专利开发了一种氯化腙与硫叶立德合成在碱作用下发生环化反应快速高效的构建多取代1,4-二氢哒嗪衍生物的合成方法，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1,4-二氢哒嗪类衍生物。
1,4-二氢哒嗪类衍生物，其特征在于，其结构式如下：
Figure BDA0003832611340000021
R1＝Ph或o-MePh或m-MePh或o-MeOPh或m-MeOPh或p-MeOPh或2，5-MeOPh或p-MeSPh或o-BrPh或m-CiPh或p-CiPh或2，4-CiPh或o-NO2Ph或m-NO2Ph或p-NO2Ph；
R2＝Ph或o-MePh或m-MePh或o-MeOPh或m-MeOPh或p-MeOPh或2，5-MeOPh或p-MeSPh或o-BrPh或m-CiPh或p-CiPh或2，4-CiPh或o-NO2Ph或m-NO2Ph或p-NO2Ph；
R3＝Ph或o-MePh或m-MePh或o-MeOPh或m-MeOPh或p-MeOPh或2，5-MeOPh或p-MeSPh或o-BrPh或m-CiPh或p-CiPh或2，4-CiPh或o-NO2Ph或m-NO2Ph或p-NO2Ph；
R4＝Ph或o-MePh或m-MePh或o-MeOPh或m-MeOPh或p-MeOPh或2，5-MeOPh或p-MeSPh或o-BrPh或m-CiPh或p-CiPh或2，4-CiPh或o-NO2Ph或m-NO2Ph或p-NO2Ph；
R5＝Ph或o-MePh或m-MePh或o-MeOPh或m-MeOPh或p-MeOPh或2，5-MeOPh或p-MeSPh或o-BrPh或m-CiPh或p-CiPh或2，4-CiPh或o-NO2Ph或m-NO2Ph或p-NO2Ph。
本发明的第二个目的是提供一种反应高效、绿色环保、方便快捷、操作简单、原料廉价易得的1,4-二氢哒嗪类衍生物的制备方法。
一种1,4-二氢哒嗪类衍生物的制备方法，其特征在于，包括步骤：在装有取代5mL反应烧瓶中，将氯化腙、硫叶立德和无机碱加入干燥的溶剂中。然后加入有机碱并在室温下剧烈搅拌1小时。然后用NH4Cl(aq.)中和混合物，用DCM(3x2ml)萃取并用Na2SO4干燥。之后第二步是，将在DCE(2mL)中的CF3SO3H(5mol％)添加到浓缩混合物中并搅拌5分钟。通过TLC检测完全反应，然后通过快速柱(石油醚/乙酸乙酯＝40:1)纯化产物，即得目标产物1,4-二氢哒嗪类衍生物。其反应式如下:
Figure BDA0003832611340000031
所述溶剂为水与有机溶剂的混合溶剂为乙腈、四氢呋喃、丙酮、DMF、DMSO、甲醇、乙醇、三氟乙醇、六氟异丙醇、1，4-二氧六环等中的任意一种。
所述的碱无机碱是选自Na2CO3、NaOH、NaHCO3、K2CO3、Cs2CO3、NaOAc、有机碱为Pyridine、Piperidine、Et3N、DIPEA、DBU、DMAP等中的一种，其中无机碱与有机碱之比率为1：1-1：3。在第二步中使用到的有机酸为三氟乙酸，三氟甲磺酸，对甲基苯磺酸等。
所述反应温度为0℃-100℃。
所述的取代氯化腙衍生物、硫叶立德衍生物、无机碱与有机碱混合物之间的摩尔比为1.0：1.2:3.0。
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，在温和的反应环境中用廉价易得的原料取代氯化腙、硫叶立德衍生物快速制备1,4-二氢哒嗪类衍生物，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1,4-二氢哒嗪类衍生物的制备反应式。
图2是(2-羟基苯基)(4-苯基-3-甲苯磺酰基-1H-吡唑-5-基)甲酮的1H NMR图。
图3是(2-羟基苯基)(4-苯基-3-甲苯磺酰基-1H-吡唑-5-基)甲酮的13C NMR图。
图4是1,4-二氢哒嗪类衍生物抗肿瘤活性结果图。
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1,4-二氢哒嗪类衍生物的合成一般方法
如图1所示，本发明提供的1,4-二氢哒嗪类衍生物(I)的合成步骤为：5mL反应烧瓶中，将氯化腙、硫叶立德和无机碱K2CO3加入干燥的溶剂中。然后加入有机碱并在室温下剧烈搅拌1小时。然后用NH4Cl(aq.)中和混合物，用DCM(3x2ml)萃取并用Na2SO4干燥。之后，将在DCE(2mL)中的CF3SO3H(5mol％)添加到浓缩混合物中并搅拌5分钟。通过TLC检测完全反应，然后通过快速柱(石油醚/乙酸乙酯＝40:1)纯化产物，即得目标产物1,4-二氢哒嗪类衍生物，粗产品经柱色谱分离或重结晶，即得目标产物。
体外抗肿瘤活性评价实验方法：
采用含有10％胎牛血清的高糖DMEM培养基对SMC-7721人肝癌细胞进行常规培养，细胞培养箱条件设置为5％CO2、37℃，每两天更换一次培养液，待细胞密度接近50％时进行胰酶消化、传代培养。选取生长状态好的细胞进行肿瘤抑制活性评价实验。具体方法为：将入选实验的SMC-7721细胞皿去培养液，用PBS缓冲液洗一次，加入1ml的胰酶进行消化，待细胞悬浮后，加入1ml培养液，缓慢吹打成细胞悬液，以每孔3000个/100uL接种于96孔板中。24h后，将待检测化合物用含10％胎牛血清的高糖DMEM培养液配置成终浓度为50umol\L的液体，加入到相应的孔板中，正常对照组加入和样品同等体积的DMSO，阳性药对照药物给予顺铂，终浓度为10umol\L。每个实验组均设置三个重复孔。加样完毕后，将培养板放入培养箱中培养24h。培养结束，弃培养液，用新鲜的高糖DMEM培养液按照10:1的比例配制CCK-8试剂工作液，100uL\孔，在培养箱中孵育1h，待显色时间结束，在450nm处用酶标仪测定每孔吸光度。依据下述公式进行计算待测化合物对SMC-7721细胞的抑制率。平行进行三次实验，结果以平均抑制率(％)±标准差表示。
抑制率＝100-[A(加药)-A(空白)]/[A(未加药)-A(空白)]X100％
Figure BDA0003832611340000051
＝7.6Hz,2H),7.44–7.40(m,3H),7.27(s,1H),7.25(s,1H),7.20–7.13(m,4H),7.02(td,J＝7.3,5.2Hz,2H),6.91(t,J＝7.5Hz,4H),6.85(d,J＝7.2Hz,1H),6.79(t,J＝7.4Hz,2H),6.28(s,1H).13C NMR(101MHz,CDCl3)δ197.33,194.62,151.11,146.72,142.78,140.71,136.43,134.93,133.00,132.63,130.15,129.97,129.17,128.70,128.49,127.39,127.24,125.58,124.94,103.30,43.98.HR-EI-MS(positive)m/z 519.2060[M+H]+(calcd forC36H27N2O2 +519.2067).
Figure BDA0003832611340000052
(m,2H),7.40–7.34(m,3H),7.28(s,1H),7.24(d,J＝7.3Hz,3H),7.14–7.07(m,4H),7.01–6.82(m,4H),6.77(td,J＝7.4,1.2Hz,2H),6.68(d,J＝7.9Hz,2H),6.18(s,1H),2.41(s,3H),2.08(s,3H).13C NMR(126MHz,CDCl3)δ196.69,194.57,150.42,146.42,143.86,142.89,140.37,137.75,135.05,133.61,132.82,130.03,129.42,129.28,128.93,128.68,128.40,127.90,127.34,125.40,124.90,103.68,43.79,21.77,21.27.HR-EI-MS(positive)m/z 547.2384[M+H]+(calcd for C38H31N2O2 +547.2380).
Figure BDA0003832611340000061
(101MHz,CDCl3)δ195.39,193.83,163.62,161.23,149.83,146.25,142.98,135.19,133.09,132.99,132.33,131.76,131.06,129.97,129.00,128.67,128.40,127.58,127.30,125.31,124.87,113.77,112.62,103.90,55.49,55.19,43.72.HR-EI-MS(positive)m/z579.2271[M+H]+(calcd for C38H31N2O4 +579.2278).
(1,3,6-三苯基-1,4-二氢哒嗪-4,5-二基)双([1,1'-联苯]-4-基甲酮)(3d)
Figure BDA0003832611340000062
7.12(m,4H),7.09–6.96(m,3H),6.88–6.78(m,3H),6.38(s,1H).13C NMR(101MHz,CDCl3)δ196.63,194.22,151.10,146.82,145.69,142.87,142.54,140.53,140.06,139.53,135.01,132.78,130.21,129.90,129.29,129.05(d,J＝12.1Hz),128.76(d,J＝2.2Hz),128.48,128.22,127.81–127.11(m),127.02,126.00,125.64,125.05,103.70,43.82.HR-EI-MS(positive)m/z 671.2688[M+H]+(calcd for C48H35N2O2 +671.2693).
Figure BDA0003832611340000071
193.15,151.49,146.85,142.59,139.70,139.04,135.96,134.62,134.52,132.42,130.72,130.45,130.07,129.58,128.96,128.83,128.57,127.46,127.35,125.90,125.01,102.78,43.50.HR-EI-MS(positive)m/z 587.1285[M+H]+(calcd for C36H25Cl2N2O2 +587.1288).
Figure BDA0003832611340000072
193.21,151.55,146.85,142.56,139.48,134.91,134.58,132.37,131.94,130.80,130.43,130.18,129.57,128.83,128.52,127.33,125.91,125.01,124.47,102.71,43.42.HR-EI-MS(positive)m/z 675.0282[M+H]+(calcd for C36H25Br2N2O2 +675.0277).
Figure BDA0003832611340000081
(101MHz,CDCl3)δ195.39,192.27,152.37,146.94,144.62,142.21,139.52,134.12,132.45,131.98,131.07,130.81,130.18,129.50,128.90,128.68,127.29,126.39,125.08,118.16,118.00,116.50,112.99,101.86,43.32.HR-EI-MS(positive)m/z 569.1979[M+H]+(calcd for C38H25N4O2 +569.1972).
Figure BDA0003832611340000082
6.87–6.75(m,4H),6.72–6.59(m,5H),6.29(d,J＝1.3Hz,1H),2.25(s,3H),2.08(s,3H).13CNMR(101MHz,CDCl3)δ200.93,195.25,151.75,146.65,142.59,141.27,137.39,137.04,135.13,134.83,132.50,131.25,130.86,130.00,129.99,129.03,128.59,128.27,127.82,127.53,127.30,125.61,125.27,124.79,124.39,104.25,46.00,20.34,19.46.HR-EI-MS(positive)m/z 547.2385[M+H]+(calcd for C38H31N2O2 +547.2380).
Figure BDA0003832611340000091
Hz,1H),6.27(s,1H),3.86(s,3H),3.63(s,3H).13C NMR(101MHz,CDCl3)δ197.04,194.28,159.76,158.32,151.31,146.79,142.73,142.05,137.61,134.94,132.65,130.22,129.63,129.26,128.77,128.45,127.43,125.65,124.94,121.82,121.47,120.40,116.18,113.69,112.70,103.18,55.55,55.21,44.04.HR-EI-MS(positive)m/z 579.2273[M+H]+(calcdfor C38H31N2O4 +579.2278).
Figure BDA0003832611340000092
1H),8.00(dd,J＝6.7,2.9Hz,2H),7.87–7.80(m,2H),7.74(t,J＝8.0Hz,1H),7.60(dt,J＝7.7,1.4Hz,1H),7.49–7.44(m,3H),7.40–7.27(m,2H),7.17(dt,J＝9.1,7.4Hz,3H),7.10–7.05(m,1H),6.96–6.90(m,2H),6.88–6.83(m,1H),6.79(dd,J＝8.0,6.5Hz,2H),6.36(s,1H).13C NMR(101MHz,CDCl3)δ194.19,191.12,152.41,148.49,146.85,146.59,142.20,141.72,137.26,134.85,134.25,134.12,132.01,130.84,130.08,129.92,129.00,128.66,127.57,127.36,126.45,125.26,124.36,124.22,123.77,101.76,43.19.HR-EI-MS(positive)m/z 609.1765[M+H]+(calcd for C36H25N4O6 +609.1769).
Figure BDA0003832611340000101
＝1.9Hz,2H),7.18(dd,J＝8.7,7.1Hz,2H),7.14–7.04(m,3H),6.99–6.84(m,7H),6.26(s,1H).13C NMR(101MHz,CDCl3)δ195.64,192.56,151.91,146.84,142.50,142.21,137.77,134.91,134.54,133.03,132.29,130.47,129.92,129.70,129.11,128.78,128.54,127.34,126.55,125.99,125.10,102.41,43.58.HR-EI-MS(positive)m/z 587.1285[M+H]+(calcdfor C36H25Cl2N2O2 +587.1288).
Figure BDA0003832611340000102
7.40(dd,J＝5.0,2.0Hz,3H),7.31–7.27(m,2H),7.14(t,J＝7.9Hz,2H),7.04–6.81(m,9H),6.37(d,J＝8.3Hz,1H),6.16(s,1H),3.97–3.86(m,6H),3.70(d,J＝5.6Hz,6H).13C NMR(101MHz,CDCl3)δ195.19,193.76,153.37,150.96,150.05,148.89,147.72,146.31,142.92,135.27,133.23,132.97,130.05,129.13,128.97,128.77,128.44,127.44,125.40,124.84,124.19,123.59,111.57,110.31,109.51,103.81,56.05,55.80,43.76.HR-EI-MS(positive)m/z 639.2493[M+H]+(calcd for C40H35N2O6 +639.2490).
Figure BDA0003832611340000111
(t,J＝7.7Hz,2H),7.12(d,J＝1.9Hz,1H),7.10–6.85(m,8H),6.21(s,1H).13C NMR(101MHz,CDCl3)δ194.24,191.37,152.10,146.87,142.36,140.15,137.93,135.48,134.30,133.88,133.34,132.20,131.21,130.87–130.55(m),129.78,129.43,128.92,128.64,128.41,127.62,127.33,126.22,125.16,102.04,43.11.HR-EI-MS(positive)m/z 655.0503[M+H]+(calcd for C36H23Cl4N2O2 +655.0508).
Figure BDA0003832611340000112
7.93(dd,J＝13.8,8.3Hz,2H),7.65–7.56(m,5H),7.51–7.29(m,10H),7.17(t,J＝7.7Hz,2H),7.07–6.91(m,3H),6.64–6.49(m,4H).13C NMR(101MHz,CDCl3)δ196.57,194.50,151.44,146.82,142.82,137.92,135.69,135.09,133.81,133.37,132.84,132.69,131.74,131.38,130.24,130.00,129.66,128.81,128.48,127.77,127.42,126.97,126.69,125.94,125.66,125.33,125.05,124.92,103.61,44.02.HR-EI-MS(positive)m/z 619.2385[M+H]+(calcd for C44H31N2O2 +619.2380).
Figure BDA0003832611340000121
(dd,J＝5.0,1.1Hz,1H),7.43(dd,J＝4.9,1.9Hz,3H),7.34–7.30(m,2H),7.23–7.15(m,5H),7.06–6.92(m,4H),6.84(dd,J＝3.8,1.2Hz,1H),6.51(dd,J＝5.0,3.8Hz,1H),5.99(s,1H).13C NMR(101MHz,CDCl3)δ188.57,185.81,149.55,145.65,144.78,142.78,142.57,134.93,134.81,134.38,132.90,132.65,131.13,130.19,129.37,128.77,128.52,127.32,126.50,125.58,125.03,103.34,44.60.HR-EI-MS(positive)m/z 531.1190[M+H]+(calcdfor C32H23N2O2S2 +531.1195).
Figure BDA0003832611340000122
Hz,1H),7.48–7.37(m,4H),7.34–7.27(m,1H),7.21–6.98(m,7H),5.59(s,1H),2.46(tt,J＝7.6,4.7Hz,1H),1.12(ddd,J＝7.8,6.2,3.9Hz,1H),1.08–1.01(m,2H),0.95(tdd,J＝9.5,7.2,5.3Hz,2H),0.85(dddd,J＝14.8,12.5,7.2,3.6Hz,2H),0.54–0.40(m,1H),0.23(tdd,J＝8.7,7.1,3.2Hz,1H).13C NMR(101MHz,CDCl3)δ205.65,198.42,149.42,146.22,142.80,134.97,133.60,130.01,129.79,128.63,128.38,127.26,125.44,124.92,104.93,47.03,21.09,17.93,12.73,11.82,11.44,11.05.HR-EI-MS(positive)m/z 447.2061[M+H]+(calcd for C30H27N2O2 +447.2067).
Figure BDA0003832611340000131
4H),7.35–7.30(m,1H),7.22–7.11(m,5H),7.05–6.99(m,2H),5.60(s,1H),2.31(s,3H),1.60(s,3H).13C NMR(101MHz,CDCl3)δ203.04,195.24,150.02,145.67,142.75,134.63,133.61,133.14,130.10,129.54,128.71,128.53,128.38,127.12,125.83,125.40,104.78,46.21,29.45,27.35.HR-EI-MS(positive)m/z 395.1757[M+H]+(calcd for C26H23N2O2 +395.1754).
Figure BDA0003832611340000132
7.05–6.98(m,2H),6.89(t,J＝7.5Hz,2H),6.77(d,J＝7.7Hz,2H),6.56(d,J＝7.9Hz,2H),6.26(s,1H),2.38(s,3H),2.00(s,3H).13C NMR(101MHz,CDCl3)δ197.72,194.66,151.38,147.02,142.97,140.91,140.43,139.36,136.55,132.92,132.11,129.70,129.46,129.12,128.68,128.40,128.39,127.35,127.14,125.40,124.89,103.07,43.93,21.44,21.07.HR-EI-MS(positive)m/z 547.2386[M+H]+(calcd for C38H31N2O2 +547.2380).
Figure BDA0003832611340000141
3H).13C NMR(101MHz,CDCl3)δ197.83,194.67,159.85,158.55,150.82,142.83,140.67,136.61,136.29,133.76,133.00,130.04,129.71,128.68,127.19,125.67,124.76,119.92,116.56,112.26,103.53,55.34,55.13,44.06.HR-EI-MS(positive)m/z 579.2273[M+H]+(calcd for C38H31N2O4 +579.2278).
Figure BDA0003832611340000142
6.23(s,1H).13C NMR(101MHz,CDCl3)δ197.32,194.41,161.57,150.04,145.98,142.51,140.57,136.31,133.18,130.98,130.18,129.43,129.04,128.63,127.42,125.88,125.00,115.92,115.71,114.94,114.72,103.34,43.93.HR-EI-MS(positive)m/z 555.1875[M+H]+(calcd for C36H25F2N2O2 +555.1879).
Figure BDA0003832611340000151
2H),7.63–7.57(m,1H),7.51(dd,J＝8.2,6.7Hz,2H),7.33–7.27(m,3H),7.24–7.14(m,5H),7.05–6.97(m,2H),6.91(dd,J＝8.1,6.7Hz,2H),6.66(dq,J＝12.8,7.6Hz,4H),6.27(s,1H),2.38(s,3H),1.93(s,3H).13C NMR(101MHz,CDCl3)δ197.64,194.73,151.39,146.96,142.89,140.90,138.34,136.61,134.90,132.90,130.93,129.80,129.13,128.70–128.20(m),128.04,127.03,125.53,124.92,124.57,103.41,44.06,21.45,20.76.HR-EI-MS(positive)m/z 547.2387[M+H]+(calcd for C38H31N2O2 +547.2380).
Figure BDA0003832611340000152
J＝7.3Hz,1H),7.52(t,J＝7.6Hz,2H),7.43–7.27(m,3H),7.24(s,1H),7.19(t,J＝7.7Hz,4H),7.07(t,J＝7.6Hz,2H),6.98(t,J＝7.5Hz,2H),6.93–6.68(m,4H),6.19(s,1H).13C NMR(101MHz,CDCl3)δ197.00,136.56,136.14,134.90,133.30,130.28,129.94,129.06,128.70,128.34,126.18,125.43,125.00,43.67.HR-EI-MS(positive)m/z 587.1281[M+H]+(calcd for C36H25Cl2N2O2 +587.1288).
Figure BDA0003832611340000161
5H),7.09(t,J＝7.4Hz,1H),7.02(t,J＝8.0Hz,2H),6.93(t,J＝7.6Hz,2H),6.27(s,1H).13CNMR(101MHz,CDCl3)δ196.93,148.58,147.14,141.70,136.36,135.91,133.69,132.88,129.83,128.62,126.79,125.30,124.71,123.94,122.24,105.16,43.56.HR-EI-MS(positive)m/z 609.1762[M+H]+(calcd for C36H25N4O6 +609.1769).
Figure BDA0003832611340000162
6.56–6.37(m,3H),6.25(s,1H),2.33(s,6H),1.88(s,6H).13C NMR(101MHz,CDCl3)δ197.90,194.83,151.66,147.13,142.96,141.02,138.18,136.74,134.87,132.81,132.24,131.83,130.67,129.61,129.11,128.32,126.75,125.50,125.26,124.90,103.37,44.15,21.33,20.63.HR-EI-MS(positive)m/z 575.2696[M+H]+(calcd for C40H35N2O2 +575.2693).
Figure BDA0003832611340000171
(m,2H),6.72–6.62(m,3H),6.52(s,1H).13C NMR(101MHz,CDCl3)δ198.04,195.10,151.12,146.62,142.83,136.82,134.15,133.09,132.92,132.34,132.12,130.20,129.18,128.79,128.59,128.00,127.70,127.02,126.14,125.73,125.00,124.35,104.61,43.93.HR-EI-MS(positive)m/z 619.2386[M+H]+(calcd for C44H31N2O2 +619.2380).
Figure BDA0003832611340000172
7.57(m,1H),7.54–7.48(m,2H),7.45–7.40(m,3H),7.21–7.15(m,3H),7.02–6.77(m,11H),6.26(s,1H),2.22(s,3H).13C NMR(101MHz,CDCl3)δ197.44,194.64,151.18,146.62,142.61,140.77,138.34,136.44,134.98,132.99,132.73,130.13,129.94,129.15,128.70,128.53,128.13,127.41,127.23,126.42,125.41,122.17,103.09,43.98,21.32.HR-EI-MS(positive)m/z 533.2221[M+H]+(calcd for C37H29N2O2 +533.2224).
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1,4-二氢哒嗪类衍生物，其特征在于，其结构式如下：
Figure FDA0003832611330000011
R1＝Ph或o-MePh或m-MePh或o-MeOPh或m-MeOPh或p-MeOPh或2，5-MeOPh或p-MeSPh或o-BrPh或m-CiPh或p-CiPh或2，4-CiPh或o-NO2Ph或m-NO2Ph或p-NO2Ph；
R2＝Ph或o-MePh或m-MePh或o-MeOPh或m-MeOPh或p-MeOPh或2，5-MeOPh或p-MeSPh或o-BrPh或m-CiPh或p-CiPh或2，4-CiPh或o-NO2Ph或m-NO2Ph或p-NO2Ph；
R3＝Ph或o-MePh或m-MePh或o-MeOPh或m-MeOPh或p-MeOPh或2，5-MeOPh或p-MeSPh或o-BrPh或m-CiPh或p-CiPh或2，4-CiPh或o-NO2Ph或m-NO2Ph或p-NO2Ph；
R4＝Ph或o-MePh或m-MePh或o-MeOPh或m-MeOPh或p-MeOPh或2，5-MeOPh或p-MeSPh或o-BrPh或m-CiPh或p-CiPh或2，4-CiPh或o-NO2Ph或m-NO2Ph或p-NO2Ph；
R5＝Ph或o-MePh或m-MePh或o-MeOPh或m-MeOPh或p-MeOPh或2，5-MeOPh或p-MeSPh或o-BrPh或m-CiPh或p-CiPh或2，4-CiPh或o-NO2Ph或m-NO2Ph或p-NO2Ph。
2.一种制备如权利要求1所述的1,4-二氢哒嗪类衍生物的方法，其特征在于，包括如下步骤：
步骤1)、在5mL反应烧瓶中，将氯化腙、硫叶立德和无机碱加入干燥的有机溶剂中；然后加入有机碱并在室温下剧烈搅拌1小时；
步骤2)、用NH4Cl水溶液中和步骤1)所得混合物，用3x2ml的DCM萃取后用Na2SO4干燥；
步骤3)、将在2mL，DCE中的添加有机酸到浓缩混合物中并搅拌5分钟；有机酸的浓度为5mol％，通过TLC检测完全反应，然后通过石油醚/乙酸乙酯＝40:1的快速柱纯化产物，即得目标产物1,4-二氢哒嗪类衍生物。
3.根据权利要求2所述一种1,4-二氢哒嗪类衍生物的制备方法，其特征在于，所述有机溶剂为乙腈、四氢呋喃、丙酮、DMF、DMSO、甲醇、乙醇、三氟乙醇、六氟异丙醇、1，4-二氧六环等中的任意一种。
4.根据权利要求2所述一种1,4-二氢哒嗪类衍生物的制备方法，其特征在于，所述的碱无机碱是选自Na2CO3、NaOH、NaHCO3、K2CO3、Cs2CO3、NaOAc、有机碱为Pyridine、Piperidine、Et3N、DIPEA、DBU、DMAP等中的一种，其中无机碱与有机碱之比率为1：1-1：3。
5.根据权利要求2所述一种1,4-二氢哒嗪类衍生物的制备方法，其特征在于，所述有机酸为三氟乙酸，三氟甲磺酸，对甲基苯磺酸中的一种。
6.根据权利要求2所述一种1,4-二氢哒嗪类衍生物的制备方法，其特征在于，所述反应温度为0℃-100℃。
7.根据权利要求2所述一种1,4-二氢哒嗪类衍生物的制备方法，其特征在于，所述的取代氯化腙衍生物、硫叶立德衍生物、无机碱与有机碱混合物之间的摩尔比为1.0：1.2:3.0。
8.一种1,4-二氢哒嗪类衍生物的应用，其特征在于，将权利要求-7所述的1,4-二氢哒嗪类衍生物用于抗肿瘤药物或抗肿瘤药物中间体。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11152274A (ja) * 1997-11-19 1999-06-08 Kowa Co 新規ピリダジン誘導体及びこれを有効成分とする医薬
CN110240568A (zh) * 2019-04-01 2019-09-17 兰州大学 三取代哒嗪类衍生物及其制备方法
CN112645882A (zh) * 2021-01-08 2021-04-13 温州大学新材料与产业技术研究院 一种1,6-二氢哒嗪衍生物的合成方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11152274A (ja) * 1997-11-19 1999-06-08 Kowa Co 新規ピリダジン誘導体及びこれを有効成分とする医薬
CN110240568A (zh) * 2019-04-01 2019-09-17 兰州大学 三取代哒嗪类衍生物及其制备方法
CN112645882A (zh) * 2021-01-08 2021-04-13 温州大学新材料与产业技术研究院 一种1,6-二氢哒嗪衍生物的合成方法

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