CN111233872A - 一种萘并三氮唑并二氮杂卓酮类化合物的制备方法 - Google Patents
一种萘并三氮唑并二氮杂卓酮类化合物的制备方法 Download PDFInfo
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- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 2
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
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Abstract
本发明涉及一种萘并三氮唑并二氮杂卓酮类化合物的制备方法,以N‑(8‑X‑萘‑1‑基)丙炔酰胺为起始原料(其中,X=Br,I),与叠氮钠在加热条件下反应,经过分离纯化可得到目标化合物萘并三氮唑并二氮杂卓酮。本发明采用一步法合成萘并三氮唑并二氮杂卓酮、它具由反应条件温和、反应时间短、便于操作等优点。为该类化合物在生物医药、材料、农药、精细化学品方面的应用研究提供有效的合成路线,具有重要潜在应用价值。
Description
技术领域
本发明属于有机合成领域,涉及一种萘并三氮唑并二氮杂卓酮类化合物的制备方法,即萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮类化合物的的制备方法。
背景技术
苯二氮杂卓酮和三氮唑是许多天然产物,生物活性化合物和药物中常见的重要杂环结构。1,4-苯二氮卓环被认为是最重要的药物优势骨架,而且在过去40年里,它一直在中枢神经系统(CNS)疾病的治疗中占据着主导地位。近年来,利用其它杂环来改性1,4-苯并二氮杂卓是调节其生物活性和选择性的常用策略。最近的文献表明,1,4-苯并二氮杂骨架与1,2,3-三氮唑的拼合体具有良好的生物活性,可作为蛋白酶抑制剂(Mohapatra,D.K.et alBioorg.Med.Chem.Lett.2009,19,5241)。在过去的几十年中,人们开发了几种合成方法来合成苯并三氮唑并二氮杂卓酮类化合物,例如Akritopoulou-zanze等人利用Ugi反应和【3+2】炔-叠氮合成苯并三氮唑并二氮杂卓酮类化合物(Tetrahedron Lett,2004,45,8439),该方法的缺点是需要制备有恶臭气味的异腈和有爆炸危险的有机叠氮化合物,这种方法不适合大规模生产。Vachhani,D.D.等人利用Ugi反应和铜催化【3+2】炔-叠氮化钠合成苯并二氮杂卓酮类,该方法的缺点是需要制备制备恶臭气味的异腈,并且需要用金属催化剂,这种合成方法同样不适合大规模生产(Eur.J.Org.Chem.2013,2013,1223)。综上所述,这些传统方法有一些局限性,包括需要在底物分子上预先引入叠氮基(-N3),苛刻的反应条件以及底物范围不广等。因此,开发原子经济的串联反应可以直接获得萘并三氮唑二氮杂酮的方法是十分必要的,这对于进一步研究它的药物活性的构效关系(SAR)提供简便的合成方法。
发明内容
要解决的技术问题
为了避免现有技术的不足之处,本发明提出一种萘并三氮唑并二氮杂卓酮类化合物的制备方法,是一种高效实用地合成三氮唑并二氮杂卓酮的新方法,不需要任何催化剂,将N-(8-X-萘-1-基)丙炔酰胺与叠氮化钠在加热条件下直接反应可以生成萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮类化合物。
技术方案
一种萘并三氮唑并二氮杂卓酮类化合物的制备方法,其特征在于步骤如下:
步骤1:以N-(8-X-萘-1-基)丙炔酰胺为起始原料,与叠氮钠在溶剂里反应加热至40~150℃条件下反应5~24小时;所述N-(8-X-萘-1-基)丙炔酰胺与叠氮化钠的摩尔比为1~2︰1~6;所述反应溶剂的用量为每毫摩尔萘胺使用5~10毫升的反应溶剂;
所述N-(8-X-萘-1-基)丙炔酰胺为:
其中:X=Br,I;
步骤2:分离纯化得到目标化合物萘并三氮唑并二氮杂卓酮
其中:取代基R1、R2、R3、R4、R5、、R6、R7、R8为C1~C16的烷基、烯基、炔基、芳基、卤素、氰基、三氟甲基、三氟甲磺基以及含氧、硫、氮的五元、六元杂环。
所述步骤2的分离纯化是:反应体系先经浓缩旋蒸,再以石油醚/乙酸乙酯混合溶液为洗脱剂,进行硅胶柱层析纯化分离。
所述反应溶剂为二氧六环、二甲基亚砜DMSO、N,N-二甲基甲酰胺DMF、N-甲基吡咯烷酮NMP、N,N-二甲基乙酰胺DMAc或N,N-二甲基丙烯基脲DMPU。
有益效果
本发明提出的一种萘并三氮唑并二氮杂卓酮类化合物的制备方法,以N-(8-X-萘-1-基)丙炔酰胺为起始原料(其中,X=Br,I),与叠氮钠在加热条件下反应,经过分离纯化可得到目标化合物萘并三氮唑并二氮杂卓酮。该方法具有无金属催化、条件温和、操作简单、产率高、底物官能团兼容性强等优点。
本发明采用一步法合成萘并三氮唑并二氮杂卓酮、它具由反应条件温和、反应时间短、便于操作等优点。为该类化合物在生物医药、材料、农药、精细化学品方面的应用研究提供有效的合成路线,具有重要潜在应用价值。
具体实施方式
现结合实施例对本发明作进一步描述:
本发明以以N-(8-X-萘-1-基)丙炔酰胺(2)为起始原料(其中,X=Br,I),与叠氮钠在适当的溶剂里加热条件反应,用TLC薄层板监测反应是否完毕,经过分离纯化可得到目标化合物萘并三氮唑并二氮杂卓酮(1)。
本发明制备萘并三氮唑并二氮杂卓酮的方法反应通式表示如下:
其中X代表卤素,X=Br,I。
具体实施方式一:本实施方式由N-(8-X-萘-1-基)丙炔酰胺(2)合成萘并三氮唑并二氮杂卓酮的方法按以下步骤实施:
以N-(8-X-萘-1-基)丙炔酰胺(2)为起始原料(其中,X=Br,I),与叠氮钠在适当的溶剂里加热条件反应,用TLC薄层板监测反应是否完毕,经过分离纯化可得到生成目标化合物萘并三氮唑并二氮杂卓酮(1)。
其中所述N-(8-X-萘-1-基)丙炔酰胺(2)为取代基R1、R2、R3、R4、R5、R6、R7、R8为C1~C16的烷基、烯基、炔基、芳基、卤素、氰基、三氟甲基、三氟甲磺基以及含氧、硫、氮的五元、六元杂环等。
具体实施方式二:本实施方式与具体实施方式一或二不同在于N-(8-X-萘-1-基)丙炔酰胺(2)与叠氮钠的摩尔比为(1~2):(1~6)。
具体实施方式三:本实施方式与具体实施方式一至四不同在于所述反应溶剂为二氧六环、二甲基亚砜(DMSO)、N,N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮(NMP)、N,N-二甲基乙酰胺(DMAc),N,N-二甲基丙烯基脲(DMPU)。
具体实施方式四:本实施方式与具体实施方式一至五不同在于每毫摩尔萘胺使用5~10毫升的反应溶剂。
具体实施方式五:本实施方式与具体实施方式一至六不同在于加热温度为40~150摄氏度。
具体实施方式六:本实施方式与具体实施方式一至七不同在于反应时间为5~24小时。
具体实施方式七:本实施方式与具体实施方式一至八不同在于反应体系经过浓缩旋蒸,再以石油醚/乙酸乙酯混合溶液为洗脱剂,进行硅胶柱层析纯化分离。
实施例一:7-甲基-9-苯基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1a的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-苯基丙炔酰胺2a(123mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1a,淡白色固体1a(89mg,0.28mmol,92%产率)。其核磁数据为1H NMR(400MHz,CDCl3)δ8.56(dd,J=7.6,1.2Hz,1H),7.93-7.90(m,3H),7.70(d,J=8.0Hz,1H),7.66(t,J=8.0Hz,1H),7.58(t,J=8.0Hz,1H),7.50-7.42(m,4H),3.57(s,3H).13C NMR(100MHz,CDCl3)δ157.32,152.63,136.97,134.91,131.53,129.97,129.20,129.08,129.04,128.20,126.51,126.41,125.49,125.24,121.67,121.24,119.15,40.85.高分辨质谱数据为HRMS(ESI)calcd for C20H14N4O(M+H)+327.1240,found,327.1240。
实施例二:7-甲基-9-苯基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1a的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-溴萘-1-基)-N-甲基-3-苯基丙炔酰胺2aa(108mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1a,淡白色固体(55mg,0.17mmol,56%产率)。其核磁数据为1H NMR(400MHz,CDCl3)δ8.56(dd,J=7.6,1.2Hz,1H),7.93-7.90(m,3H),7.70(d,J=8.0Hz,1H),7.66(t,J=8.0Hz,1H),7.58(t,J=8.0Hz,1H),7.50-7.42(m,4H),3.57(s,3H).13C NMR(100MHz,CDCl3)δ157.32,152.63,136.97,134.91,131.53,129.97,129.20,129.08,129.04,128.20,126.51,126.41,125.49,125.24,121.67,121.24,119.15,40.85.高分辨质谱数据为HRMS(ESI)calcd for C20H14N4O(M+H)+327.1240,found,327.1240。
实施例三:7-甲基-9-(4-甲基苯基)萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1b的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(4-甲基苯基)丙炔酰胺2b(129mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1b,淡白色固体(75mg,0.22mmol,73%产率)。1H NMR(400MHz,CDCl3)δ8.55(dd,J=7.6,1.2Hz,1H),7.90(dd,J=8.4,1.2Hz,1H),7.81(d,J=8.0Hz,2H),7.70(d,J=8.0Hz,1H),7.65(t,J=8.0Hz,1H),7.57(t,J=8.0Hz,1H),7.42(dd,J=7.6,1.2Hz,1H),7.29(d,J=8.0Hz,2H),3.56(s,3H),2.41(s,3H).13C NMR(100MHz,CDCl3)δ157.40,152.79,139.04,137.03,134.92,131.59,129.12,128.95,127.08,126.48,126.41,125.45,124.95,121.63,121.19,119.07,40.81,21.40.高分辨质谱数据为HRMS(ESI)calcd for C21H16N4O(M+H)+341.1397,found,341.1369。
实施例四:7-甲基-9-(4-乙基苯基)萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1c的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(4-乙基苯基)丙炔酰胺2c(132mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1c,淡白色固体(57mg,0.16mmol,54%产率)。1H NMR(400MHz,CDCl3)δ8.56(dd,J=7.6,1.2Hz,1H),7.90(dd,J=8.0,1.2Hz,1H),7.84(d,J=8.0Hz,2H),7.70(dd,J=8.0,1.2Hz,1H),7.65(t,J=8.0Hz,1H),7.57(t,J=8.0Hz,1H),7.42(dd,J=7.6,1.2Hz,1H),7.31(d,J=8.0Hz,2H),3.57(s,3H),2.71(q,J=7.6Hz,2H),1.29(t,J=7.6,3H).13C NMR(100MHz,CDCl3)δ157.44,152.82,145.30,137.05,134.93,131.62,129.13,129.04,127.78,126.49,126.43,125.47,124.94,121.67,121.20,119.11,40.85,28.76,15.39.高分辨质谱数据为HRMS(ESI)calcd for C22H18N4O(M+H)+355.1553,found,355.1553.
实施例五:7-甲基-9-(4-丙基苯基)萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1d的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(4-丙基苯基)丙炔酰胺2d(135mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1d,淡白色固体(66mg,0.18mmol,60%产率)。1H NMR(400MHz,CDCl3)δ8.55(dd,J=7.6,1.2Hz,1H),7.90(dd,J=8.4,1.2Hz,1H),7.83(d,J=8.0Hz,2H),7.70(d,J=7.6Hz,1H),7.65(t,J=8.0Hz,1H),7.57(t,J=8.0Hz,1H),7.42(dd,J=7.6,1.2Hz,1H),7.29(d,J=8.4Hz,2H),3.57(s,3H),2.69-2.58(m,2H),1.75-1.65(m,2H),0.98(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ157.47,152.83,143.81,137.07,134.94,131.64,129.14,128.96,128.39,127.29,126.51,126.46,125.48,124.92,121.70,121.22,119.14,40.88,37.96,24.38,13.89.高分辨质谱数据为HRMS(ESI)calcd forC23H20N4O(M+H)+369.1710,found,369.1709.
实施例六:7-甲基-9-(3,5-二甲基苯基)萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1e的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(3,5-二甲基苯基)丙炔酰胺2e(132mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1e,淡白色固体(95mg,0.27mmol,90%产率)。1HNMR(400MHz,CDCl3)δ8.55(dd,J=7.6,1.2Hz,1H),7.89(dd,J=8.0,1.2Hz,1H),7.69(d,J=7.6Hz,1H),7.65(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.49(s,2H),7.43(dd,J=7.6,1.2Hz,1H),7.07(s,1H),3.56(s,3H),2.40(s,6H).13C NMR(100MHz,CDCl3)δ157.32,153.06,137.68,137.14,134.97,131.67,130.87,129.80,129.15,126.88,126.51,126.46,125.48,125.20,121.74,121.27,119.16,40.88,21.39.高分辨质谱数据为HRMS(ESI)calcdfor C22H18N4O(M+H)+355.1553,found,355.1553.
实施例七:7-甲基-9-(4-甲氧基苯基)萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1f的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(4-甲氧基苯基)丙炔酰胺2f(132mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1f,淡白色固体(81mg,0.23mmol,76%产率)。1HNMR(400MHz,CDCl3)δ8.55(dd,J=7.6,1.2Hz,1H),7.91-7.88(m,3H),7.69(d,J=8.0Hz,1H),7.65(t,J=8.0Hz,1H),7.57(t,J=8.0Hz,1H),7.42(dd,J=8.0,1.2Hz,1H),7.01(d,J=8.8Hz,2H),3.87(s,3H),3.57(s,3H).13C NMR(100MHz,CDCl3)δ160.26,157.53,152.52,137.03,134.91,131.62,130.49,129.09,126.48,126.42,125.46,124.50,122.41,121.61,121.17,119.05,113.68,55.28,40.85高分辨质谱数据为HRMS(ESI)calcd for C21H16N4O2(M+H)+357.1346,found,357.1346.
实施例八:7-甲基-9-(4-甲氧基苯基)萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1f的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-溴萘-1-基)-N-甲基-3-(4-甲氧基苯基)丙炔酰胺2ff(132mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1f,淡黄色固体(95mg,0.27mmol,90%产率)。1HNMR(400MHz,CDCl3)δ8.55(dd,J=7.6,1.2Hz,1H),7.91-7.88(m,3H),7.69(d,J=8.0Hz,1H),7.65(t,J=8.0Hz,1H),7.57(t,J=8.0Hz,1H),7.42(dd,J=8.0,1.2Hz,1H),7.01(d,J=8.8Hz,2H),3.87(s,3H),3.57(s,3H).13C NMR(100MHz,CDCl3)δ160.26,157.53,152.52,137.03,134.91,131.62,130.49,129.09,126.48,126.42,125.46,124.50,122.41,121.61,121.17,119.05,113.68,55.28,40.85高分辨质谱数据为HRMS(ESI)calcd for C21H16N4O2(M+H)+357.1346,found,357.1346.
实施例九:9-(2-氯苯基)-7-甲基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1g的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(2-氯苯基)丙炔酰胺2g(133mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1g,淡黄色固体(93mg,0.26mmol,85%产率)。1H NMR(400MHz,CDCl3)δ8.60(d,J=7.6Hz,1H),7.92(d,J=8.0Hz,1H),7.73-7.63(m,3H),7.57(t,J=8.0Hz,1H),7.53-7.49(m,1H),7.45-7.37(m,3H),3.54(s,3H).13C NMR(100MHz,CDCl3)δ156.91,150.02,136.88,135.14,133.66,131.46,131.41,130.28,129.75,129.65,129.47,127.54,126.87,126.57,126.40,125.58,121.46,121.15,119.06,40.46.高分辨质谱数据为HRMS(ESI)calcd for C20H13ClN4O(M+H)+361.0851,found,361.0850.
实施例十:9-(4-氯苯基)-7-甲基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1h的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(4-氯苯基)丙炔酰胺2h(133mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1h,淡白色固体(79mg,0.22mmol,74%产率)。1H NMR(400MHz,CDCl3)δ8.55(d,J=7.6,1.2Hz,1H),7.93-788.(m,3H),7.71(d,J=8.0Hz,1H),7.66(t,J=8.0Hz,1H),7.58(t,J=8.0Hz,1H),7.46-7.42(m,3H),3.57(s,3H).13C NMR(100MHz,CDCl3)δ157.27,151.51,136.90,135.12,134.97,131.47,130.46,129.35,128.48,128.46,126.58,126.48,125.63,125.38,121.71,121.34,119.28,40.91.高分辨质谱数据为HRMS(ESI)calcd for C20H13ClN4O(M+H)+361.0851,found,361.0850.
实施例十一:9-(4-氯苯基)-7-甲基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1h的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-溴萘-1-基)-N-甲基-3-(4-氯苯基)丙炔酰胺2hh(133mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1h,白色固体(70mg,0.20mmol,65%产率)。1H NMR(400MHz,CDCl3)δ8.55(d,J=7.6,1.2Hz,1H),7.93-788.(m,3H),7.71(d,J=8.0Hz,1H),7.66(t,J=8.0Hz,1H),7.58(t,J=8.0Hz,1H),7.46-7.42(m,3H),3.57(s,3H).13C NMR(100MHz,CDCl3)δ157.27,151.51,136.90,135.12,134.97,131.47,130.46,129.35,128.48,128.46,126.58,126.48,125.63,125.38,121.71,121.34,119.28,40.91.高分辨质谱数据为HRMS(ESI)calcd for C20H13ClN4O(M+H)+361.0851,found,361.0850.
实施例十二:9-(3-氟苯基)-7-甲基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1i的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-溴萘-1-基)-N-甲基-3-(3-氟苯基)丙炔酰胺2i(129mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1i,淡白色固体(79mg,0.23mmol,75%产率)。1H NMR(400MHz,CDCl3)δ8.54(dd,J=7.6,1.2Hz,1H),7.91(dd,J=8.0,1.2Hz,1H),7.78-7.62(m,4H),7.58(t,J=8.0Hz,1H),7.48-7.40(m,2H),7.18-7.09(m,1H),3.57(s,3H).13C NMR(100MHz,CDCl3)δ162.52(d,JC-F=243Hz),157.15,151.25(d,J C-F=2Hz),136.89,134.96,132.01(d,JC-F=8Hz),131.43,129.72(d,JC-F=8Hz),129.37,126.60,126.47,125.63,124.86,124.85(d,J C-F=3Hz),121.77,121.40,119.32,116.16(d,J C-F=23Hz),115.96(d,J C-F=21Hz),40.94.高分辨质谱数据为HRMS(ESI)calcd for C20H13FN4O(M+H)+345.1146,found,345.1146.
实施例十三:9-(4-氟苯基)-7-甲基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1j的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(4-氟苯基)丙炔酰胺2j(129mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1j,淡白色固体(45mg,0.13mmol,44%产率)。1H NMR(400MHz,CDCl3)δ8.55(d,J=7.6Hz,1H),7.95-7.89(m,3H),7.71(d,J=8.0Hz,1H),7.66(t,J=8.0Hz,1H),7.58(t,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),7.17(t,J=8.8Hz,2H),3.57(s,3H).13C NMR(100MHz,CDCl3)δ163.31(d,JC-F=247Hz),157.37,151.74,136.97,135.00,131.55,131.14(d,JC-F=9Hz),129.31,126.57,126.50,126.14(d,JC-F=4Hz),125.62,125.16,121.73,121.31,119.28,115.28(d,JC-F=21Hz),40.91.高分辨质谱数据为HRMS(ESI)calcd for C20H13FN4O(M+H)+345.1146,found,345.1146.
实施例十四:4-(7-甲基-8-氧代-7,8-二氢萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-9-基)苯甲酸甲酯1k的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入4-(3-((8-碘萘-1-基)(甲基)氨基)-3-氧代丙-1-炔-1-基)苯甲酸甲酯2K(141mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1i,淡白色固体(84mg,0.22mmol,74%产率)。
1H NMR(400MHz,CDCl3)δ8.56(dd,J=7.7,1.2Hz,1H),8.15(d,J=8.0Hz,2H),8.02(d,J=8.0Hz,2H),7.92(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.66(t,J=8.0Hz,1H),7.58(t,J=8.0Hz,1H),7.44(d,J=7.6Hz,1H),3.95(s,3H),3.58(s,3H).13C NMR(100MHz,CDCl3)δ166.81,157.18,151.48,136.90,135.00,134.41,131.43,130.35,129.49,129.43,129.07,126.62,126.50,125.98,125.68,121.79,121.45,119.38,52.17,40.94.高分辨质谱数据为HRMS(ESI)calcd for C22H16N4O3(M+H)+385.1295,found,385.1295.
实施例十五:4-(7-甲基-8-氧代-7,8-二氢萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-9-基)苯甲腈1l的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(3-氟苯基)丙炔酰胺3-(4-氰基-苯基)-N-(8-碘萘-1-基)-N-甲基苯丙酰胺2l(131mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1l,淡白色固体(60mg,0.17mmol,57%产率)。1H NMR(400MHz,CDCl3)δ8.55(dd,J=7.6,1.2Hz,1H),8.09(d,J=8.4Hz,2H),7.93(dd,J=8.2,1.2Hz,1H),7.75(d,J=8.4Hz,2H),7.72(d,J=8.0Hz,1H),7.67(t,J=8.0Hz,1H),7.59(t,J=8.0Hz,1H),7.45(dd,J=7.6,1.2Hz,1H),3.58(s,3H).13C NMR(101MHz,CDCl3)δ157.03,150.49,136.69,134.99,134.49,131.94,131.25,129.68,129.61,126.67,126.51,126.24,125.81,121.77,121.53,119.48,118.76,112.42,40.98.高分辨质谱数据为HRMS(ESI)calcd for C21H13N5O(M+H)+352.1193,found,352.1192。
实施例十六:7-甲基-9-(萘-1-基)萘基[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1m的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘-1-萘基)-N-甲基-3-(萘-1-基)丙酰胺2m(138mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1m,淡白色固体(62mg,0.17mmol,55%产率)。1H NMR(400MHz,CDCl3)δ8.65(dd,J=7.6,1.2Hz,1H),7.98(d,J=8.2Hz,1H),7.95-7.89(m,2H),7.83(d,J=8.0Hz,1H),7.76-7.65(m,3H),7.63-7.53(m,2H),7.54-7.44(m,2H),7.40(d,J=7.6Hz,1H),3.46(s,3H).13C NMR(100MHz,CDCl3)δ156.70,151.97,136.98,135.14,133.62,131.94,131.57,129.63,129.42,128.66,128.42,127.84,127.32,126.55,126.47,126.44,125.85,125.54,125.30,125.05,121.47,121.08,119.16,40.56.高分辨质谱数据为HRMS(ESI)calcd for C24H16N4O(M+H)+377.1397,found,377.1396。
实施例十七:7-甲基-9-(萘-2-基)萘基[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1n的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘-1-萘基)-N-甲基-3-(萘-2-基)丙酰胺2n(138mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1n,淡白色固体(99mg,0.26mmol,88%产率)。1H NMR(400MHz,CDCl3)δ8.58(dd,J=7.6,1.2Hz,1H),8.49(s,1H),7.99-7.85(m,5H),7.74–7.62(m,2H),7.56(t,J=8.0Hz,1H),7.54-7.49(m,2H),7.44(dd,J=7.7,1.1Hz,1H),3.58(s,3H).13C NMR(100MHz,CDCl3)δ157.30,152.58,136.90,135.39,134.88,133.47,133.07,131.47,129.19,128.62,127.64,127.57,127.36,126.56,126.53,126.47,126.34,126.06,125.47,125.44,121.58,121.24,119.09,40.83.高分辨质谱数据为HRMS(ESI)calcd forC24H16N4O(M+H)+377.1397,found,377.1369。
实施例十八:7-甲基-9-(菲-9-基)萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1o的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(菲-9-基)丙酰胺2o(153mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1o,淡白色固体(89mg,0.21mmol,70%产率)。1H NMR(400MHz,CDCl3)δ8.78(d,J=8.4Hz,1H),8.74(d,J=8.4Hz,1H),8.68(dd,J=7.6,1.2Hz,1H),8.00(s,1H),7.96-7.91(m,2H),7.83(dd,J=8.4,1.2Hz,1H),7.73-7.65(m,4H),7.64-7.51(m,3H),7.40(dd,J=7.6,1.2Hz,1H),3.44(s,3H).13C NMR(100MHz,CDCl3)δ156.54,151.86,136.84,135.08,131.45,131.05,130.84,130.68,130.44,129.75,129.43,129.14,127.63,127.22,126.81,126.63,126.51,126.38,125.99,125.49,122.95,122.53,121.30,121.03,119.08,40.46.高分辨质谱数据为HRMS(ESI)calcd for C28H18N4O(M+H)+427.1553,found,427.1553。
实施例十九:7-甲基-9-(吡啶-3-基)萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1p的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(吡啶-3-基)丙炔酰胺(124mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1p,淡黄色固体(52mg,0.16mmol,53%产率)。1H NMR(400MHz,CDCl3)9.14(d,J=2.0Hz,1H),8.67(dd,J=4.8,1.6Hz,1H),8.56(dd,J=7.6,1.2Hz,1H),8.28(dt,J=8.0,2.0Hz,1H),7.92(dd,J=8.4,1.2Hz,1H),7.71(d,J=8.0Hz,1H),7.67(t,J=8.0Hz,1H),7.58(t,J=7.9Hz,1H),7.45-7.39(m,2H),3.57(s,3H).13C NMR(100MHz,CDCl3)δ157.04,149.89,149.77,149.62,136.73,136.42,134.97,131.29,129.49,126.60,126.43,126.27,126.02,125.66,122.96,121.60,121.35,119.31,40.85.HRMS(ESI)calcd for C19H13N5O(M+H)+328.1193,found,328.1192。
实施例二十:7-甲基-9-(噻吩-2-基)萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1q的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-3-(噻吩-2-基)丙炔酰胺2q(125mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1q,白色固体(89mg,0.27mmol,90%产率)。1H NMR(400MHz,CDCl3)δ8.50(dd,J=7.6,1.2Hz,1H),8.10(dd,J=3.6,1.2Hz,1H),7.90(dd,J=8.4,1.2Hz,1H),7.69(d,J=8.0Hz,1H),7.65(t,J=8.0Hz,1H),7.55(t,J=8.0Hz,1H),7.46(dd,J=5.2,1.2Hz,1H),7.40(dd,J=7.6,1.2Hz,1H),7.17-7.14(m,1H),3.61(s,3H).13C NMR(100MHz,CDCl3)δ157.20,147.34,136.80,134.85,131.44,131.33,129.25,129.22,127.84,127.36,126.51,126.38,125.45,123.51,121.39,121.06,119.24,40.92.HRMS(ESI)calcd for C18H12N4OS(M+H)+333.0805,found,333.0804。
实施例二十一:7-烯丙基-9-苯基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮(1r)的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-烯丙基-N-(8-碘萘-1-基)-3-苯丙炔酰胺2r(131mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1r,淡黄色固体(95mg,0.27mmol,90%产率)。1H NMR(400MHz,CDCl3)δ8.50(dd,J=7.6,1.2Hz,1H),7.96-7.85(m,3H),7.73-7.59(m,3H),7.57-7.38(m,4H),6.15-6.00(m,1H),5.44-5.27(m,2H),4.66-4.46(m,2H).13C NMR(100MHz,CDCl3)δ157.06,152.23,136.65,134.97,133.38,131.40,129.78,129.31,129.06,128.75,128.33,126.66,126.42,125.85,125.22,121.91,120.79,119.42,116.72,56.64.HRMS(ESI)calcdfor C22H16N4O(M+H)+353.1397,found,353.1396.
实施例二十二:7-苄基-9-苯基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1s的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-苄基-3-(3-氟苯基)丙炔酰胺2s(146mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1s,淡白色固体(56mg,0.14mmol,46%产率)。1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3)δ8.52(dd,J=7.6,1.2Hz,1H),7.94-7.87(m,3H),7.71-7.64(m,2H),7.49-7.38(m,5H),7.36-7.30(m,2H),7.30-7.26(m,3H),5.22(s,2H).13CNMR(100MHz,CDCl3)δ157.68,152.32,136.77,136.48,134.98,131.40,129.73,129.31,129.09,128.79,128.74,128.35,127.37,126.62,126.48,126.30,125.98,125.22,122.14,121.33,119.52,57.33.HRMS(ESI)calcd for C26H18N4O(M+H)+403.1553,found,403.1553.
实施例二十三:9-乙基-7-甲基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1t的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加N-(8-碘萘-1-基)-N-甲基-戊-2-炔酰胺2t(109mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1t,淡白色固体(46mg,0.16mmol,55%产率)。1H NMR(400MHz,CDCl3)δ8.50(d,J=7.6Hz,1H),7.87(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.53(t,J=7.6Hz,1H),7.37(d,J=7.6Hz,1H),3.57(s,3H),3.12(q,J=7.6Hz,2H),1.40(t,J=7.6Hz,3H).13C NMR(100MHz,CDCl3)δ157.69,156.57,136.98,135.05,131.60,129.10,126.37,125.34,125.04,121.04,120.57,118.85,40.45,20.06,13.28.HRMS(ESI)calcd for C16H14N4O(M+H)+279.1240,found,279.1240.
实施例二十四:7-甲基-9-丙基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1u的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-己-2-炔酰胺2u(113mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1u,淡白色固体(70mg,0.24mmol,79%产率)。1H NMR(400MHz,CDCl3)δ8.49(dd,J=7.6,1.2Hz,1H),7.87(dd,J=8.0,1.2Hz,1H),7.66(d,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7.53(t,J=8.0Hz,1H),7.36(dd,J=7.6,1.1Hz,1H),3.57(s,3H),3.08(t,J=7.6Hz,2H),1.90-1.80(m,2H),1.05(t,J=7.6Hz,3H).13C NMR(100MHz,CDCl3)δ157.70,155.36,136.98,135.03,131.61,129.08,126.37,126.35,125.34,125.26,121.06,120.59,118.84,77.32,77.00,76.68,40.47,28.44,22.27,14.04.HRMS(ESI)calcd forC17H16N4O(M+H)+293.1397,found,293.1396.
实施例二十五:7-甲基-9-戊基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1v的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-碘萘-1-基)-N-甲基-辛-2-炔酰胺2v(122mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1i,淡白色固体(32mg,0.10mmol,33%产率)。1H NMR(400MHz,CDCl3)δ8.49(dd,J=7.6,1.2Hz,1H),7.87(dd,J=8.0,1.2Hz,1H),7.66(dd,J=8.0,1.2Hz,1H),7.62(t,J=8.0Hz,1H),7.53(t,J=8.0Hz,1H),7.53(t,J=8.0Hz,1H),7.37(dd,J=7.6,1.2Hz,1H),3.57(s,3H),3.08(t,J=8.0Hz,2H),1.85-1.80(m,2H),1.41-1.38(m,4H),0.91(t,J=6.8Hz,3H).13C NMR(100MHz,CDCl3)δ157.70,155.57,136.99,135.03,131.61,129.07,126.37,126.35,125.33,125.18,121.06,120.58,118.83,40.48,31.70,28.64,26.48,22.47,14.03.HRMS(ESI)calcd for C19H20N4O(M+H)+321.1710,found,321.1709.
实施例二十六:6,7-二甲基-9-苯基萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮1w的合成路线:
向干燥装有磁子的10mL的Schlenk反应瓶中加入N-(8-溴-7-甲基萘-1-基)-N-甲基苯丙炔酰胺2w(113mg,0.3mmol),叠氮钠(39mg,0.4mmol),DMSO(3mL)。盖上橡皮塞反复抽真空冲氮气三次后,在氮气保护下100℃加热搅拌12h。反应结束后,体系用二氯甲烷萃取,合并有机相,经无水硫酸钠干燥后得到粗产品,再以石油醚/乙酸乙酯混合溶液为洗脱剂,经过硅胶柱层析纯化分离,得到1w,淡白色固体(58mg,0.17mmol,57%产率)。1H NMR(400MHz,CDCl3)δ8.08-7.98(m,2H),7.73(d,J=8.4Hz,1H),7.61(dd,J=8.0,1.2Hz,1H),7.53-7.41(m,5H),7.35(dd,J=7.6,1.2Hz,1H),3.52(s,3H),2.84(s,3H).13C NMR(101MHz,CDCl3)δ158.01,149.51,136.83,133.12,131.64,130.93,129.69,129.03,128.92,128.73,128.30,127.94,125.88,125.67,124.95,124.89,121.71,40.61,21.34.HRMS(ESI)calcdfor C21H16N4O(M+H)+341.1397,found,341.1396.
综上实验结果可见:采用本发明所述的化合物2与叠氮化钠反应的方法,能够在温和、简便的条件下高效地合成萘[1,8-ef][1,2,3]三氮唑[1,5-a][1,4]二氮杂卓-8(7H)-酮类化合物1,属于绿色化学工艺。
Claims (3)
1.一种萘并三氮唑并二氮杂卓酮类化合物的制备方法,其特征在于步骤如下:
步骤1:以N-(8-X-萘-1-基)丙炔酰胺为起始原料,与叠氮钠在溶剂里反应加热至40~150℃条件下反应5~24小时;所述N-(8-X-萘-1-基)丙炔酰胺与叠氮化钠的摩尔比为1~2︰1~6;所述反应溶剂的用量为每毫摩尔萘胺使用5~10毫升的反应溶剂;
所述N-(8-X-萘-1-基)丙炔酰胺为:
其中:X=Br,I;
步骤2:分离纯化得到目标化合物萘并三氮唑并二氮杂卓酮
其中:取代基R1、R2、R3、R4、R5、、R6、R7、R8为C1~C16的烷基、烯基、炔基、芳基、卤素、氰基、三氟甲基、三氟甲磺基以及含氧、硫、氮的五元、六元杂环。
2.根据权利要求1所述萘并三氮唑并二氮杂卓酮类化合物的制备方法,其特征在于:所述步骤2的分离纯化是:反应体系先经浓缩旋蒸,再以石油醚/乙酸乙酯混合溶液为洗脱剂,进行硅胶柱层析纯化分离。
3.根据权利要求1所述萘并三氮唑并二氮杂卓酮类化合物的制备方法,其特征在于:所述反应溶剂为二氧六环、二甲基亚砜DMSO、N,N-二甲基甲酰胺DMF、N-甲基吡咯烷酮NMP、N,N-二甲基乙酰胺DMAc或N,N-二甲基丙烯基脲DMPU。
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CN113185536A (zh) * | 2021-04-29 | 2021-07-30 | 河南师范大学 | 一种吡唑烷酮并苯并1,3-氧氮杂卓类化合物的合成方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030069234A1 (en) * | 2001-06-06 | 2003-04-10 | Medina Julio C. | CXCR3 antagonists |
US20110172205A1 (en) * | 2008-09-08 | 2011-07-14 | Merck Sharp & Dohme Corp. | Monocyclic amide cgrp receptor antagonists |
CN102344449A (zh) * | 2011-07-20 | 2012-02-08 | 中国科学院化学研究所 | 并杂环萘酰亚胺及其制备方法与应用 |
CN106892924A (zh) * | 2015-12-17 | 2017-06-27 | 四川科伦博泰生物医药股份有限公司 | 短效苯并二氮*衍生物、其制备方法及其用途 |
CN107629057A (zh) * | 2016-07-19 | 2018-01-26 | 上海勋和医药科技有限公司 | Bet蛋白抑制剂及其应用 |
-
2020
- 2020-03-20 CN CN202010200700.0A patent/CN111233872A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030069234A1 (en) * | 2001-06-06 | 2003-04-10 | Medina Julio C. | CXCR3 antagonists |
US20110172205A1 (en) * | 2008-09-08 | 2011-07-14 | Merck Sharp & Dohme Corp. | Monocyclic amide cgrp receptor antagonists |
CN102344449A (zh) * | 2011-07-20 | 2012-02-08 | 中国科学院化学研究所 | 并杂环萘酰亚胺及其制备方法与应用 |
CN106892924A (zh) * | 2015-12-17 | 2017-06-27 | 四川科伦博泰生物医药股份有限公司 | 短效苯并二氮*衍生物、其制备方法及其用途 |
CN107629057A (zh) * | 2016-07-19 | 2018-01-26 | 上海勋和医药科技有限公司 | Bet蛋白抑制剂及其应用 |
Non-Patent Citations (1)
Title |
---|
YOSHINOBU NAGAWA等,: ""Synthesis and reactivity of 1-(8-amino-1-naphthyl)-1H-1,2,3-triazoles"", 《SYNTHESIS》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113185536A (zh) * | 2021-04-29 | 2021-07-30 | 河南师范大学 | 一种吡唑烷酮并苯并1,3-氧氮杂卓类化合物的合成方法 |
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