CN109608407B - 一种二苯并七元含氮杂环化合物的合成方法 - Google Patents
一种二苯并七元含氮杂环化合物的合成方法 Download PDFInfo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明涉及化学合成技术领域,具体公开了一种二苯并七元含氮杂环化合物的合成方法,其是将氮取代苯胺和溴取代苯甲酸偶联反应,将产物的羧基酰胺化,再经Hofmann降解和有机碘氧化剂氧化成环得到二苯并七元含氮杂环化合物。该方法不需要加入金属试剂,具有操作简便、反应温和、收率高、环境友好且产物结构多样的优点。
Description
技术领域
本发明涉及化学合成技术领域,具体涉及一种二苯并七元含氮杂环化合物的合成方法。
背景技术
二苯并七元含氮杂环化合物被广泛应用于医药、农业、化工等行业。目前,含二苯并七元含氮杂环化合物的药物已广泛应用于现实生活中,如广泛应用的抗抑郁药二苯地平和组蛋白去乙酰化酶(HDAC)抑制剂。二苯并七元含氮杂环化合物还被用作基本骨架来合成其他具有理想生物活性的药物,如1,4- 苯并二氮杂卓衍生物被发现具有抗排斥特性;含有二苯并七元含氮杂环骨架的氯氮平是一种非常常用的抗精神病药物用于治疗精神分裂症。此外二苯并七元含氮杂环化合物在新药的发现中也起着很重要的作用,如用吡啶环取代一个苯环的哌仑西平,被认为是首选的用来治疗溃疡的M1胆碱受体拮抗剂。
目前,二苯并七元含氮杂环化合物的合成方法中,在成环反应中多采用金属催化剂,如铜、钯等,毒性较大,后处理麻烦;还有些反应中用到卤代化合物如三氯氧磷等催化分子内酰胺化反应得到二苯并七元含氮杂环化合物,这些卤化物的使用会对环境造成极大的污染和破坏。
发明内容
针对现有二苯并七元含氮杂环化合物的制备过程毒性和污染较大且后处理麻烦等问题,本发明提供一种二苯并七元含氮杂环化合物的合成方法。
为解决上述技术问题,本发明提供的技术方案是:
一种式(Ⅰ)所示的二苯并七元含氮杂环化合物的合成方法,其
在有机溶剂中,式(Ⅱ)化合物在碱和有机碘氧化剂的条件下,反应得到式(Ⅰ)所示的二苯并七元含氮杂环化合物,
其中,R1和R2分别选自:氢、C1-C10烷基、C1-C10烷氧基、C1-C10卤代烷基、C1-C10卤代烷氧基、卤素和硝基;
R3选自:C1-C10烷基、C1-C10卤代烷基、C1-C8环烷基、C1-C8卤代环烷基、苯基和卤代苯基。
优选地,所述有机溶剂为甲醇、乙醇、正丙醇、异丙醇、乙腈、四氢呋喃、二氯甲烷、三氯甲烷、乙醚、乙酸乙酯或丙酮,进一步优选的有机溶剂为甲醇;
优选地,所述的碱为碱金属碳酸盐、碱金属碳酸氢盐、碱金属磷酸盐、碱金属醇盐、碱金属氢氧化物或碱金属有机酸盐,进一步优选的碱为氢氧化钾;
优选地,所述的有机碘氧化剂为醋酸碘苯、二氯碘苯、[双(三氟乙酰氧基) 碘]苯、亚碘酰苯、邻碘酰基苯甲酸或戴斯-马丁氧化剂,进一步优选的有机碘氧化剂为亚碘酰苯;
优选地,反应的温度为-20~10℃,进一步优选为-10℃,反应时间 0.5~1h。
优选地,所述的碱相对于式(Ⅱ)化合物的用量摩尔比为1:1~3:1;进一步优选2:1。
优选地,所述的氧化剂相对于式(Ⅱ)化合物用量摩尔比为1:1~4:1,进一步优选1.5:1。
优选地,式(Ⅱ)化合物采用如下方法制备得到:
(1)式(Ⅴ)化合物和式(Ⅳ)化合物偶联反应生成式(Ⅲ)化合物;
(2)式(Ⅲ)化合物酰胺化生成式(Ⅱ)化合物;
所述的式(Ⅲ)-(Ⅴ)化合物的结构如下:
所述步骤(1)中,式(Ⅴ)化合物和式(Ⅳ)化合物在氮气保护下, 1,4-二氧六环为溶剂,加入氧化亚铜和氮甲基吗啡啉,回流进行偶联反应。
步骤(1)中,所述式(Ⅴ)化合物、式(Ⅳ)化合物、氧化亚铜、氮甲基吗啡啉的摩尔比为1:1:0.5:1.5,偶联反应温度为110℃,反应时间16h。
所述步骤(2)中,式(Ⅲ)化合物溶于N,N-二甲基甲酰胺后加入氨水、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑室温下进行酰胺化,所述室温是指10~30℃。
所述步骤(2)中,式(Ⅲ)化合物、NH3·H2O、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑的摩尔比为1:3~10:1.5:1.5,反应时间12h。
具体地,本发明的合成路线为:
本发明方法取得的有益效果在于:与现有化学合成领域相关技术相比,本发明第一次实现了在高价碘试剂氧化的条件下,以2-取代(苯基)氨基)苯甲酰胺衍生物为原料合成二苯并七元含氮杂环化合物。在该方法中,不需要加入金属试剂,经过Hofmann降解再经高价碘试剂氧化成环实现目标化合物二苯并七元含氮杂环化合物的合成。该方法具有操作简便、反应温和、收率高、环境友好且产物结构多样等优点。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1:5-甲基-5H-二苯[b,e][1,4]地西平-11(10H)-酮的合成
式(Ⅰ-1)所示5-甲基-5H-二苯[b,e][1,4]地西平-11(10H)-酮的合成途径如下:
具体步骤如下:
(1)式(Ⅲ-1)所示2-(甲基(苯基)氨基)苯甲酸的合成:
式(Ⅴ-1)化合物N-甲基苯胺(2.140g,20mmol)、式(Ⅳ-1)化合物邻溴苯甲酸(4.022g,20mmol)、氮甲基吗啡啉(3.4mL,30mmol)和氧化亚铜(1.440g,10mmol)混合在60mL1,4-二氧六环中,在氮气保护、回流温度下搅拌16小时,反应结束后将反应液冷却至室温,加入4M盐酸40mL有固体析出,过滤,用水(20mL*2)洗涤,得式(Ⅲ-1)2-(甲基(苯基)氨基)苯甲酸粗品2.321g,收率51.0%。
(2)式(Ⅱ-1)所示2-(甲基(苯基)氨基)苯甲酰胺的合成:
将上述产物2-(甲基(苯基)氨基)苯甲酸粗品(2.322g,约10mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(2.871g,15mmol)、1-羟基苯并三唑(2.030g,15mmol)和NH3·H2O(3.8mL,50mmol)在N,N-二甲基甲酰胺(20mL)中的混合物于室温下搅拌12h,用20mL水猝灭该混合物,有固体析出,过滤后柱层析得产物式(Ⅱ-1)所示2-(甲基(苯基)氨基)苯甲酰胺 0.620g,收率27.4%;检测图谱数据 :1H NMR(500MHz,CDCl3)δ8.27(dd, J=7.9,1.8Hz,1H),8.16(s,1H),7.49(td,J=7.6,1.8Hz,1H),7.37(td,J=7.6,1.3Hz,1H),7.26-7.20(m,2H),7.12(dd,J=7.9,1.3Hz,1H), 6.90(t,J=7.3Hz,1H),6.78(d,J=8.1Hz,2H),5.69(s,1H),3.20(s,3H);
13C NMR(125MHz,CDCl3)δ167.79,149.18,148.84,133.46,131.96, 130.57,129.39,128.32,126.96,120.20,116.10,40.94;
IR(KBr):3347.22,3129.98,1672.20,1593.48,1481.21,1374.47, 754.80。
(3)式(Ⅰ-1)所示5-甲基-5H-二苯[b,e][1,4]地西平-11(10H)-酮的合成:
将上述产物2-(甲基(苯基)氨基)苯甲酰胺(0.226g,1mmol)溶于10mL甲醇,冰盐浴降温至-10℃,加入氢氧化钾(0.112g,2mmol),氢氧化钾溶解后加入亚碘酰苯(0.330g,1.5mmol),在冰盐浴中反应0.5小时,反应结束后减压旋蒸,柱层析得产物5-甲基-5H-二苯[b,e][1,4]地西平-11(10H)-酮 0.193g,收率为85.6%。检测图谱数据 :1H NMR(500MHz,CDCl3)δ7.89(d, J=7.5Hz,1H),7.65(dt,J=7.9,1.9Hz,2H),7.57(t,J=7.4Hz,1H),7.48(td,J=7.7,7.2,1.2Hz,1H),7.43(d,J=8.0Hz,1H),7.41-7.34(m, 3H),3.91(s,3H);
13C NMR(150MHz,CDCl3)δ173.80,155.63,147.56,131.18,130.71, 130.01,129.91,129.86,124.78,120.61,116.74,56.44;
IR(KBr):3055.09,1631.15,1607.01,1588.71,1458.45,1349.13, 768.19,753.79,688.96,678.27;
HRMS[M+H]+(C14H12N2O):理论计算值:225.1029,实际值: 225.1036。
实施例2:
采用与实施例1相同的方法,反应温度以冰浴降至0℃代替冰盐浴降温至- 10℃,得到式(Ⅰ-1)化合物0.129g,收率为57.1%。
实施例3:
采用与实施例1相同的方法,以氢氧化钠代替氢氧化钾,得到式(Ⅰ-1) 化合物0.188g,收率为83.5%。
实施例4:
采用与实施例1相同的方法,以碳酸钾代替氢氧化钾,得到式(Ⅰ-1)化合物0.068g,收率为30.0%。
实施例5:
采用与实施例1相同的方法,以甲醇钠代替氢氧化钾,得到式(Ⅰ-1)化合物0.119g,收率为52.7%。
实施例6:
采用与实施例1相同的方法,以二氯甲烷代替甲醇,得到式(Ⅰ-1)化合物0.057g,收率为25.3%。
实施例7:
采用与实施例1相同的方法,以乙腈代替甲醇,得到式(Ⅰ-1)化合物 0.021g,收率为9.4%。
实施例8:
采用与实施例1相同的方法,以醋酸碘苯代替亚碘酰苯,得到式(Ⅰ-1) 化合物0.022g,收率为9.9%。
实施例9:3,5-二甲基-5H-二苯[b,e][1,4]地西平-11(10H)-酮的合成
式(Ⅰ-1)所示3,5-二甲基-5H-二苯[b,e][1,4]地西平-11(10H)-酮的合成途径如下:
具体步骤如下:
(1)式(Ⅲ-2)所示2-(甲基(对甲苯基)氨基)苯甲酸的合成:
式(Ⅴ-2)化合物N-甲基-对甲基苯胺(2.424g,20mmol)、式(Ⅳ-2) 化合物邻溴苯甲酸(4.022g,20mmol)、氮甲基吗啡啉(3.4mL,30mmol)和氧化亚铜(1.440g,10mmol)混合在60mL1,4-二氧六环中,在氮气保护、回流温度下搅拌16小时,反应结束后将反应液冷却至室温,加入4M盐酸40mL 有固体析出,过滤,用水(20mL*2)洗涤,得式(Ⅲ-2)2-(甲基(对甲苯基)氨基)苯甲酸粗品2.037g,收率42.2%。
(2)式(Ⅱ-2)所示2-(甲基(对甲苯基)氨基)苯甲酰胺的合成:
将上述产物2-(甲基(对甲苯基)氨基)苯甲酸粗品(2.037g,约8.4mmol)、 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(2.413g,12.6mmol)、1-羟基苯并三唑(1.706g,12.6mmol)和NH3·H2O(3.2mL,43mmol)在N,N-二甲基甲酰胺(16.8mL)中的混合物于室温下搅拌12h,用16.8mL水猝灭该混合物,用乙酸乙酯(30mL*3)萃取,有机层用水(30mL*3)、饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压除去有机溶剂,柱层析得产物式(Ⅱ-2)所示2-(甲基(对甲苯基)氨基)苯甲酰胺0.629g,收率30.1%。检测图谱数据 :1H NMR (500MHz,CDCl3)δ8.39(s,1H),8.27(dd,J=7.9,1.7Hz,1H),7.47(td, J=7.6,1.8Hz,1H),7.35(td,J=7.6,1.3Hz,1H),7.10(dd,J=7.9,1.2Hz, 1H),7.05(d,J=8.2Hz,2H),6.75-6.66(m,2H),5.70(s,1H),3.17(s,3H), 2.28(s,3H);
13C NMR(125MHz,CDCl3)δ167.64,149.41,147.01,133.43,131.93, 130.21,129.91,129.86,127.97,126.72,116.52,41.19,20.56;
IR(KBr):3308.33,3136.04,1673.79,1508.61,1481.67,1375.34, 815.74,774.67。
(3)式(Ⅰ-2)所示3,5-二甲基-5H-二苯[b,e][1,4]地西平-11(10H)- 酮的合成:
将上述产物2-(甲基(对甲苯基)氨基)苯甲酰胺(0.240g,1mmol)溶于 10mL甲醇,冰盐浴降温至-10℃,加入氢氧化钾(0.112g,2mmol),氢氧化钾溶解后加入亚碘酰苯(0.330g,1.5mmol),在冰盐浴中反应0.5小时,反应结束后减压旋蒸,柱层析得产物3,5-二甲基-5H-二苯[b,e][1,4]地西平- 11(10H)-酮0.215g,收率为90.2%。检测图谱数据 :1HNMR(500MHz,CDCl3) δ7.86(d,J=7.5Hz,1H),7.56(t,J=7.4Hz,1H),7.50(d,J=8.4Hz,2H), 7.47(t,J=7.6Hz,1H),7.41(d,J=8.0Hz,1H),7.15(d,J=8.3Hz,2H), 3.87(s,3H),2.29(s,3H);
13C NMR(125MHz,CDCl3)δ173.81,155.83,145.20,140.25,131.14, 130.70,130.35,130.00,124.75,120.42,116.69,56.48,20.90;
IR(KBr):3390.82,3094.45,2956.38,1668.28,1633.24,1576.54, 1504.86,1463.94,1370.97;
HRMS[M+H]+(C15H14N2O):理论计算值:239.1185,实际值: 239.1194。
实施例10:2,3-二甲氧基-5-甲基-5H-二苯[b,e][1,4]地西平-11(10H)-酮的合成
式(Ⅰ-3)所示2,3-二甲氧基-5-甲基-5H-二苯[b,e][1,4]地西平- 11(10H)-酮的合成途径如下:
具体步骤如下:
(1)式(Ⅲ-3)所示2-((3,4-二甲氧基苯基)(甲基)氨基)苯甲酸的合成:
式(Ⅴ-3)化合物3,4-二甲氧基-N-甲基苯胺(3.344g,20mmol)、式 (Ⅳ-3)化合物邻溴苯甲酸(4.022g,20mmol)、氮甲基吗啡啉(3.4mL, 30mmol)和氧化亚铜(1.440g,10mmol)混合在60mL1,4-二氧六环中,在氮气保护、回流温度下搅拌16小时,反应结束后将反应液冷却至室温,加入 4M盐酸40mL有固体析出,过滤,用水(20mL*2)洗涤,得式(Ⅲ-3)2-((3,4-二甲氧基苯基)(甲基)氨基)苯甲酸粗品2.379g,收率41.4%。
(2)式(Ⅱ-3)所示2-((3,4-二甲氧基苯基)(甲基)氨基)苯甲酰胺的合成:
将上述产物2-((3,4-二甲氧基苯基)(甲基)氨基)苯甲酸粗品(2.379g,约8.3mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(2.332g, 12.4mmol)、1-羟基苯并三唑(1.680g,12.4mmol)和NH3·H2O(3.1mL, 41mmol)在N,N-二甲基甲酰胺(16.6mL)中的混合物于室温下搅拌12h,用16.6mL水猝灭该混合物,有固体析出,过滤后柱层析得产物式(Ⅱ-3)所示2-((3,4-二甲氧基苯基)(甲基)氨基)苯甲酰胺1.540g,收率64.8%。检测图谱:1HNMR(400MHz,CDCl3)δ8.57(s,1H),8.27(dd,J=7.9,1.7Hz,1H), 7.47(ddd,J=8.0,7.3,1.8Hz,1H),7.34(ddd,J=8.5,7.4,1.3Hz,1H), 7.10(dd,J=8.0,1.2Hz,1H),6.79(d,J=8.7Hz,1H),6.40(dd,J=8.6, 2.7Hz,1H),6.32(d,J=2.8Hz,1H),5.94(s,1H),3.84(s,3H),3.73(s, 3H),3.16(s,3H);
13C NMR(125MHz,CDCl3)δ167.71,149.80,149.77,143.87,143.77, 133.36,131.91,129.86,127.66,126.55,112.26,108.06,102.59,77.39, 56.50,56.04,41.72;
IR(KBr):3291.83,3137.71,3057.94,2995.66,2952.63,2932.89, 2899.46,2830.24,1672.25,1591.56,1512.80,1448.82,1375.58,1246.67, 1028.49。
(3)式(Ⅰ-3)所示2,3-二甲氧基-5-甲基-5H-二苯[b,e][1,4]地西平- 11(10H)-酮的合成:
将上述产物2-((3,4-二甲氧基苯基)(甲基)氨基)苯甲酰胺(0.286g, 1mmol)溶于10mL甲醇,冰盐浴降温至-10℃,加入氢氧化钾(0.112g, 2mmol),氢氧化钾溶解后加入亚碘酰苯(0.330g,1.5mmol),在冰盐浴中反应0.5小时,反应结束后减压旋蒸,柱层析得产物2,3-二甲氧基-5-甲基- 5H-二苯[b,e][1,4]地西平-11(10H)-酮0.227g,收率为79.9%。检测图谱数据 :1H NMR(600MHz,CDCl3)δ7.89(d,J=7.5Hz,1H),7.61(dq,J=8.6,4.3Hz, 1H),7.52(d,J=4.1Hz,2H),7.36(dd,J=8.9,2.9Hz,1H),7.14(d, J=2.9Hz,1H),6.85(d,J=8.9Hz,1H),3.94(s,3H),3.87(s,3H),3.79(s, 3H);
13C NMR(150MHz,CDCl3)δ173.77,155.83,149.99,149.64,140.39, 131.10,130.67,129.63,124.62,116.67,112.03,110.22,104.95,57.11, 56.31,56.16;
IR(KBr):3361.77,2930.78,1634.80,1605.37,1513.58,1461.81, 1376.43,1263.30,1237.33,147.95,1016.55,755.79,680.02;
HRMS[M+H]+(C16H16N2O3):理论计算值:285.1240,实际值:285.1253。
实施例11:8-甲氧基-3,5-二甲基-5H-二苯[b,e][1,4]地西平-11(10H)-酮的合成
式(Ⅰ-4)所示8-甲氧基-3,5-二甲基-5H-二苯[b,e][1,4]地西平- 11(10H)-酮的合成途径如下:
具体步骤如下:
(1)式(Ⅲ-4)所示5-甲氧基-2-(甲基(对甲苯基)氨基)苯甲酸的合成:
式(Ⅴ-4)化合物N-甲基-对甲基苯胺(2.424g,20mmol)、式(Ⅳ-4) 化合物2-溴-5-甲氧基苯甲酸(4.621g,20mmol)、氮甲基吗啡啉(3.4mL, 30mmol)和氧化亚铜(1.440g,10mmol)混合在60mL1,4-二氧六环中,在氮气保护、回流温度下搅拌16小时,反应结束后将反应液冷却至室温,加入 4M盐酸40mL后用乙酸乙酯(100*4)萃取,有机层用氢氧化钠水溶液碱化 (1.000g氢氧化钠溶于20mL水),水层用3M盐酸酸化,直至无沉淀生成,过滤,用水(20mL*2)洗涤,得式(Ⅲ-4)5-甲氧基-2-(甲基(对甲苯基) 氨基)苯甲酸粗品1.286g,收率23.7%。
(2)式(Ⅱ-4)所示5-甲氧基-2-(甲基(对甲苯基)氨基)苯甲酰胺的合成:
将上述产物5-甲氧基-2-(甲基(对甲苯基)氨基)苯甲酸粗品(1.286g,约4.7mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1.354g, 7.1mmol)、1-羟基苯并三唑(0.958g,7.1mmol)和NH3·H2O(1.8mL, 24mmol)在N,N-二甲基甲酰胺(9.4mL)中的混合物于室温下搅拌12h,用 9.4mL水猝灭该混合物,有固体析出,过滤后柱层析得产物式(Ⅱ-4)所示5- 甲氧基-2-(甲基(对甲苯基)氨基苯甲酰胺0.490g,收率38.6%。检测图谱数据 :
1H NMR(500MHz,CDCl3)δ8.62(s,1H),7.82(d,J=2.7Hz,1H),7.06- 7.00(m,4H),6.69-6.60(m,2H),5.71(s,1H),3.88(s,3H),3.13(s,3H), 2.27(s,3H);
13C NMR(125MHz,CDCl3)δ167.14,157.95,147.16,142.08,130.99, 129.85,129.75,129.37,129.35,120.73,120.01,115.94,114.45,55.73, 40.94,20.40;
IR(KBr):3295.03,2938.72,2835.71,1674.09,1601.70,1576.48,1510.04,1492.23,1423.89,1364.13,1261.55,1056.27,1032.61,810.16。
(3)式(Ⅰ-4)所示8-甲氧基-3,5-二甲基-5H-二苯[b,e][1,4]地西平- 11(10H)-酮的合成:
将上述产物5-甲氧基-2-(甲基(对甲苯基)氨基苯甲酰胺(0.270g, 1mmol)溶于10mL甲醇,冰盐浴降温至-10℃,加入氢氧化钾(0.112g, 2mmol),氢氧化钾溶解后加入亚碘酰苯(0.330g,1.5mmol),在冰盐浴中反应0.5小时,反应结束后减压旋蒸,柱层析得产物8-甲氧基-3,5-二甲基- 5H-二苯[b,e][1,4]地西平-11(10H)-酮0.220g,收率为81.9%。检测图谱数据 :1H NMR(500MHz,CDCl3)δ7.49(d,J=8.3Hz,2H),7.33(d,J=8.7Hz,1H), 7.27(d,J=2.5Hz,1H),7.10(d,J=8.1Hz,2H),6.94(dd,J=8.6,2.5Hz, 1H),3.85(s,3H),3.79(s,3H),2.25(s,3H);
13C NMR(125MHz,CDCl3)δ173.61,161.97,148.47,145.38,140.02, 130.24,120.29,118.61,117.64,117.61,106.62,56.74,56.10,20.82;
IR(KBr):3030.53,2940.28,2836.14,1597.90,1505.14,1486.06, 1450.85,1435.61,1338.04,1273.79,1247.25,1028.78,816.64,726.11;
HRMS[M+H]+(C16H16N2O2):理论计算值:269.1291,实际值: 269.1300。
以上所述实施例中的各原料,本领域技术人员能够得到或根据现有技术制得。以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可作出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.一种式(Ⅰ)所示的二苯并七元含氮杂环化合物的合成方法,其特征在于,在有机溶剂中,式(Ⅱ)化合物在碱和有机碘氧化剂的条件下,反应得到式(Ⅰ)所示的二苯并七元含氮杂环化合物;
其中,R1和R2分别选自:氢、C1-C10烷基、C1-C10烷氧基、C1-C10卤代烷基、C1-C10卤代烷氧基、卤素和硝基;
R3选自:C1-C10烷基、C1-C10卤代烷基、C1-C8环烷基、C1-C8卤代环烷基、苯基和卤代苯基;
所述的有机碘氧化剂为醋酸碘苯、二氯碘苯、[双(三氟乙酰氧基)碘]苯、亚碘酰苯、邻碘酰基苯甲酸或戴斯-马丁氧化剂;
所述的碱为碱金属碳酸盐、碱金属碳酸氢盐、碱金属磷酸盐、碱金属醇盐、碱金属氢氧化物或碱金属有机酸盐;
反应的温度为-20~10℃,反应时间0.2~1h。
2.如权利要求1所述的二苯并七元含氮杂环化合物的合成方法,其特征在于,所述有机溶剂为甲醇、乙醇、正丙醇、异丙醇、乙腈、四氢呋喃、二氯甲烷、三氯甲烷、乙醚、乙酸乙酯或丙酮。
3.如权利要求2所述的二苯并七元含氮杂环化合物的合成方法,其特征在于,所述的有机溶剂为甲醇;和/或:
所述的碱为氢氧化钾;和/或:
所述的氧化剂为亚碘酰苯;和/或:
反应的温度为-10℃,反应时间0.5h。
4.如权利要求1所述的二苯并七元含氮杂环化合物的合成方法,其特征在于,所述的碱相对于式(Ⅱ)化合物的用量摩尔比为1:1~3:1;和/或:
所述的氧化剂相对于式(Ⅱ)化合物用量摩尔比为1:1~4:1。
5.如权利要求4所述的二苯并七元含氮杂环化合物的合成方法,其特征在于,所述的碱相对于式(Ⅱ)化合物的用量摩尔比为2:1;和/或:
所述的氧化剂相对于式(Ⅱ)化合物用量摩尔比为1.5:1。
7.如权利要求6所述的二苯并七元含氮杂环化合物的合成方法,其特征在于,所述步骤(1)中,式(Ⅴ)化合物和式(Ⅳ)化合物在氮气保护下,1,4-二氧六环为溶剂,加入氧化亚铜和氮甲基吗啡啉,回流进行偶联反应。
8.如权利要求7所述的二苯并七元含氮杂环化合物的合成方法,其特征在于,步骤(1)中,所述式(Ⅴ)化合物、式(Ⅳ)化合物、氧化亚铜、氮甲基吗啡啉的摩尔比为1:1:0.5:1.5,偶联反应温度为110℃,反应时间16h。
9.如权利要求6所述的二苯并七元含氮杂环化合物的合成方法,其特征在于,所述步骤(2)中,式(Ⅲ)化合物溶于N,N-二甲基甲酰胺后加入氨水、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑室温下进行酰胺化。
10.如权利要求9所述的二苯并七元含氮杂环化合物的合成方法,其特征在于,所述步骤(2)中,式(Ⅲ)化合物、NH3·H2O、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑的摩尔比为1:3~10:1.5:1.5,反应时间12h。
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