CN106588749B - 多取代咔唑类化合物及其合成方法和应用 - Google Patents
多取代咔唑类化合物及其合成方法和应用 Download PDFInfo
- Publication number
- CN106588749B CN106588749B CN201510698778.9A CN201510698778A CN106588749B CN 106588749 B CN106588749 B CN 106588749B CN 201510698778 A CN201510698778 A CN 201510698778A CN 106588749 B CN106588749 B CN 106588749B
- Authority
- CN
- China
- Prior art keywords
- arh
- methoxyphenyl
- cdcl
- nmr
- carbazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开一种多取代咔唑类化合物及其简洁的合成方法,即通过吲哚类化合物与2,3‑联烯醇反应得到3位联烯基取代的吲哚类化合物,再进一步发生环化反应和氧化反应,高选择性地合成多取代咔唑类化合物的合成方法。本发明方法操作简单,原料和试剂易得,反应具有高选择性,官能团兼容性较好,能同时引入多个取代基,产物易分离纯化,并且无需使用保护基,可直接得到多取代咔唑类化合物,适用于合成各种多取代咔唑类化合物。本发明还公开了多取代咔唑类化合物在制备调解GLP‑1分泌的药物中的用途。
Description
技术领域
本发明属于化学合成技术领域,具体涉及一种多取代咔唑类化合物及其简洁的合成方法和医药用途。
背景技术
咔唑结构广泛存在于自然界植物中,是一类非常重要的杂环化合物,具有重要的生理活性,许多含有咔唑结构的化合物都具有生物活性,如抗组胺剂,抗炎药,抗生素中有效成分中多数都含有咔唑结构(Advances in Nitrogen Heterocycles,JAI,Greenwich,1995;Vol.1,p 173;Progress in the Chemistry of Organic Natural Products,Springer,Wien,1987;Vol 52,p 159.)。另外,咔唑类衍生物在材料化学特别是有机材料化学中也有广泛应用(Org.Lett.,2009,11,2337;Org.Lett.,2010,12,5652.)。由于其潜在的应用价值,咔唑类化合物的合成具有重要意义。现有合成咔唑类化合物的方法大多有局限性,比如反应产率较低,选择性不理想,低原子经济性或反应条件比较苛刻等。并且,应用现有文献方法合成的咔唑类化合物大多数都是氮原子上有保护基的,合成过程中会涉及N-H的保护和去保护(Chem.Rev.2011,111,1954;Chem.Rev.2011,111,1994)。因此发展一种从简单易得的原料出发,高选择性合成N-H咔唑类化合物的方法将是对现有合成方法的重大突破。
人胰高血糖素样肽(GLP-1)由胰高血糖素原基因转录,经过翻译后修饰成为具有生物活性的多肽:GLP-1(7-37)和GLP-1(7-36)NH2。肠道L细胞分泌GLP-1需要依赖于小肠内腔的营养支持。GLP-1是一种潜在的抗高血糖激素,促进糖原依赖性胰岛素的分泌,抑制胰高血糖素的分泌。这种依赖于葡萄糖的作用机制非常重要,因为GLP-1并不刺激胰岛素的分泌,从而在血糖浓度处于正常空腹范围时不会造成低血糖。因此通过发现具有刺激GLP-1的化合物可以发展治疗2型糖尿病的药物。但现有文献中从未报道咔唑类化合物具有刺激GLP-1分泌的活性。
发明内容
本发明的目的在于提供一类多取代咔唑类化合物及其制备方法和医药用途。本发明通过吲哚类化合物与2,3-联烯醇反应得到3位联烯基取代的吲哚类化合物,再进一步发生环化反应和氧化反应,高选择性地合成多取代咔唑类化合物的方法,合成方法路线短,操作简单,具有很高的研究意义和实用价值。本发明还提出了所述多取代咔唑类化合物在制备具有刺激GLP-1分泌活性的药物中的应用。
本发明提出了一种多取代咔唑类化合物,其特征在于,所述多取代咔唑类化合物的结构如式(I)所示:
式(Ⅰ);
所述式(I)中,
R1~R2=H;烃基;芳基;
R3=氢;烃基;杂环基或芳基;其中,所述杂环基是噻吩、呋喃或吡啶;
R4~R7=氢;芳基;烃基;烃氧基;烃氧羰基;卤素;
R8=氢;烷基;芳基。
本发明提出了式(Ⅰ)所示的多取代咔唑类化合物的制备方法,以有机酸为催化剂,吲哚类化合物与2,3-联烯醇反应生成3位联烯基取代的多取代吲哚类化合物,该化合物再进一步高选择性地发生环化反应和氧化反应,得到本发明式(Ⅰ)所示的多取代咔唑类化合物。反应式如下:
反应式(a)。
反应式(a)中,R1~R2=H;烃基;芳基;
R3=氢;烃基;杂环基或芳基;其中,所述杂环基是噻吩、呋喃或吡啶;
R4~R7=氢;芳基;烃基;烃氧基;烃氧羰基;卤素;
R8=氢;烷基;芳基。
本发明式(Ⅰ)所示多取代咔唑类化合物的制备方法包括如下步骤:
步骤(1)吲哚类化合物与2,3-联烯醇高选择性发生反应合成3位联烯基取代的多取代吲哚类化合物:在氮气保护下向反应管中依次加入2,3-联烯醇、第一有机溶剂、吲哚类化合物、有机酸,第一温度下搅拌反应,快速柱层析,浓缩,得到3位联烯基取代的多取代吲哚类化合物;
步骤(2)在氮气保护下向反应瓶中依次加入步骤(1)得到的3位联烯基取代的多取代吲哚类化合物、第一有机溶剂,在第二温度下搅拌反应,然后再依次向反应瓶中加入金催化剂、银催化剂,继续在第二温度下搅拌反应后,快速柱层析,浓缩,得到粗产品;
步骤(3)在反应瓶中加入步骤(2)得到的粗产品、第二有机溶剂、二氯二氰基苯醌,在第三温度下搅拌反应后,用乙醚萃取,浓缩,快速柱层析,得到所述的式(Ⅰ)所示的多取代咔唑类化合物。
本发明还提出了一种多取代N-H咔唑类化合物结构式如下:
式(Ⅱ);
所示结构式(Ⅱ)中,R为烃基;烃氧基;烃氧羰基;卤素;氢;R1、R2分别为烃基;苯基,邻、间、对位烃基或烃氧基取代的苯基;氢;R3为烃基;苯基、杂环基或芳基;其中,所述的杂环基是噻吩、呋喃或吡啶;所述的芳基是邻、间、对位烃基或烃氧基取代的苯基。
优选地,式(Ⅱ)中,R为C1~C6的烷基或烷氧基或烷氧羰基;卤素;氢;R1为C1~C6的烃基;苯基;R2为C1~C6的烃基;氢;R3为苯基、杂环基或芳基;其中,所述的杂环基是噻吩、呋喃或吡啶;所述的芳基是邻、间、对位C1~C6烃基或烃氧基取代的苯基。
更优选地,式(Ⅱ)中,R为甲基、甲氧基、甲氧羰基、溴、氢;R1为甲基、乙基、丙基、异丙基、丁基、环己基、烯丙基、苄基、苯基、2-苯基乙基、3-苯基丙基;R2为氢;R3为苯基、4-甲氧基苯基、4-乙氧基苯基、3,4-二甲氧基苯基、3,4,5-三甲氧基苯基、3,4-OCH2OC6H3、噻吩基。
本发明所述式(Ⅱ)多取代N-H咔唑类化合物的制备方法,以有机酸为催化剂,N-H吲哚类化合物与2,3-联烯醇反应生成3位联烯基取代的多取代N-H吲哚类化合物,该化合物再进一步高选择性地发生环化反应和氧化反应,得到本发明式(Ⅱ)所示的多取代N-H咔唑类化合物。反应式如下:
反应式(b)。
反应式(b)中,R为烃基;烃氧基;烃氧羰基;卤素;氢;R1、R2分别为烃基;苯基,邻、间、对位烃基或烃氧基取代的苯基;氢;R3为烃基;苯基、杂环基或芳基;其中,所述的杂环基是噻吩、呋喃或吡啶;所述的芳基是邻、间、对位烃基或烃氧基取代的苯基。
本发明式(Ⅱ)所示的多取代N-H咔唑类化合物的制备方法包括如下步骤:
步骤(1)吲哚类化合物与2,3-联烯醇高选择性发生反应合成3位联烯基取代的多取代N-H吲哚类化合物:在氮气保护下向反应管中依次加入2,3-联烯醇、第一有机溶剂、N-H吲哚类化合物、有机酸,第一温度下搅拌反应,快速柱层析,浓缩,得到3位联烯基取代的多取代N-H吲哚类化合物;
步骤(2)在氮气保护下向反应瓶中依次加入步骤(1)得到的3位联烯基取代的多取代N-H吲哚类化合物、第一有机溶剂,在第二温度下搅拌反应,然后再依次向反应瓶中加入金催化剂、银催化剂,继续在第二温度下搅拌反应后,快速柱层析,浓缩,得到粗产品;
步骤(3)在反应瓶中加入步骤(2)得到的粗产品、第二有机溶剂、二氯二氰基苯醌,在第三温度下搅拌反应后,用乙醚萃取,浓缩,快速柱层析,得到所述的式(Ⅱ)所示的多取代N-H咔唑类化合物。
本发明式(Ⅰ)和/或式(Ⅱ)所示的多取代N-H咔唑类化合物的制备方法中:
所述第一有机溶剂包括1,2-二氯乙烷、二氯甲烷、氯仿等常用有机溶剂。
所述第二有机溶剂包括N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲亚砜等常用有机溶剂。
所述第一温度为-10-60℃;第二温度为-10-60℃;第三温度为0-40℃。
所述2,3-联烯醇与所述吲哚类化合物的摩尔比为1.0:1.0~2.0。优选地,所述2,3-联烯醇与吲哚类化合物的摩尔比为1.0:1.5。
所述有机酸包括一水合对甲苯磺酸、三氟乙酸、R-联萘酚磷酸酯等常见有机酸。所述有机酸与所述2,3-联烯醇的摩尔比为0.01~0.20:1。优选地,所述有机酸与所述2,3-联烯醇的摩尔比为0.05:1。
所述金催化剂包括三苯基膦一氯化金、三氯化金和一氯化金等常用金催化剂,所述金催化剂与所述3位联烯基取代的多取代吲哚类化合物的摩尔比为0.01~0.05:1。优选地,为0.05:1。
所述银催化剂包括六氟锑酸银、四氟硼酸银、六氟磷酸银、硝酸银、二三氟甲磺酸亚胺合银、三甲氟磺酸银等常用银催化剂,所述银催化剂与所述3位联烯基取代的多取代吲哚类化合物的摩尔比为0.01~0.05:1。优选地,为0.05:1。
所述二氯二氰基苯醌与所述3位联烯基取代的多取代吲哚类化合物的摩尔比为1.0~2.0:1.0。优选地,为1.2:1.0。
本发明制备方法创新发展了高选择性地合成多取代咔唑类化合物的新方法。本发明制备方法克服传统方法的弊端,包括以下优点:催化剂用量低,条件温和,官能团兼容性好,反应具有高选择性,产物易分离纯化,反应过程中吲哚类化合物的N-H无需保护,可以直接得到N-H咔唑类化合物。
本发明还提出了将所述式(Ⅰ)和/或式(Ⅱ)所示的多取代咔唑类化合物(包括多取代N-H咔唑类化合物)用于制备刺激GLP-1分泌的药物中的应用。
本发明还提出了将式(Ⅰ)和/或式(Ⅱ)所示的多取代咔唑类化合物(包括多取代N-H咔唑类化合物)具有刺激GLP-1分泌进而用于治疗2型糖尿病的药物中的应用。
本发明还提出了将式(Ⅰ)和/或式(Ⅱ)所示的多取代咔唑类化合物(包括多取代N-H咔唑类化合物)用于制备胰岛β细胞分泌促进剂中的应用,其中,所述多取代咔唑类化合物用于刺激GLP-1的分泌,GLP-1具有保护β细胞的作用,GLP-1可作用于胰岛β细胞促进胰岛素基因的转录、胰岛素的合成和分泌。
本发明还提出了将所述式(Ⅰ)和/或式(Ⅱ)所示的多取代咔唑类化合物(包括多取代N-H咔唑类化合物)用于制备胰岛α细胞分泌抑制剂中的应用,其中,所述多取代咔唑类化合物用于刺激GLP-1的分泌,GLP-1具有抑制胰岛α细胞分泌的作用。
本发明还提出了将式(Ⅰ)和/或式(Ⅱ)所示的多取代咔唑类化合物(包括多取代N-H咔唑类化合物)用于制备治疗和/或预防糖尿病药物中的应用。
其中,所述糖尿病为2型糖尿病。所述药物用于刺激GLP-1的分泌。其中,所述药物单独使用或与其他药物联合使用。
本发明还提出了一种药物组合物,包括至少一种如上所述的式(Ⅰ)和/或式(Ⅱ)所示的多取代咔唑类化合物(包括多取代N-H咔唑类化合物)以及药学上可接受的载体。
其中,所述药物组合物用于治疗和/或预防糖尿病。所述药物组合物被配制成可注射流体、气雾剂、乳膏、凝胶剂、片剂、丸剂、胶囊剂、糖浆剂或透皮贴剂。所述药物组合物被配制用于口服给药、皮下注射、肌肉注射、静脉注射、舌下给药、直肠给药、经皮给药或喷雾吸入。
具体实施方式
结合以下具体实施例和反应式,对本发明作进一步的详细说明,本发明保护不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。以下实施例有助于理解本发明,但不限制本发明保护范围。
注:以下实施例反应式中的equiv表示当量;mol表示摩尔,TsOH·H2O表示一水合对甲苯磺酸;DCE表示1,2-二氯乙烷;Au(PPh3)表示三苯基膦一氯化金;AgBF4表示四氟硼酸银;N2表示氮气;DDQ表示二氯二氰基苯醌;DMF表示N,N-二甲基甲酰胺。
实施例1 3-丁基-4-(4-甲氧基苯基)-9H-咔唑(001)的合成
反应式(1);
取一支干燥的反应管,氮气下抽换气三次。在氮气保护下,在反应管中依次加入1-(4-甲氧基苯基)-2-丁基-2,3-丁二烯-1-醇(463.4mg,2mmol)和1,2-二氯乙烷(10mL),搅拌下加入吲哚(351.7mg,3mmol)和一水合对甲苯磺酸(TsOH·H2O,18.9mg,0.1mmol)。反应在室温搅拌18小时,TLC跟踪表明反应完全,用短硅胶柱将反应液过滤,乙醚淋洗,旋去乙醚后快速柱层析分离(PE(石油醚)/EA(乙酸乙酯)=50:1-30:1)得到3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(474.9mg,72%):油状液体;1H NMR(300MHz,CDCl3)δ7.83(s,1H,NH),7.48(d,J=7.8Hz,1H,ArH),7.32-7.18(m,3H,ArH),7.14(t,J=7.5Hz,1H,ArH),7.04(t,J=7.4Hz,1H,ArH),6.82(d,J=8.4Hz,2H,ArH),6.71(d,J=1.8Hz,1H,ArH),4.74(s,1H,CH),4.62-4.43(m,2H,=CH2),3.77(s,3H,OCH3),2.10-1.95(m,2H,CH2),1.62-1.40(m,2H,CH2),1.40-1.22(m,2H,CH2),0.87(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ207.1,157.9,136.4,134.9,129.6,127.2,122.9,121.8,119.7,119.1,118.8,113.3,110.9,107.2,77.2,55.1,45.6,31.2,30.0,22.4,14.0;IR(neat)ν(cm-1)3419,3057,2997,2953,2928,2872,2857,2834,1955,1610,1583,1506,1456,1417,1337,1301,1246,1175,1094,1035,1011;MS(70ev,EI)m/z(%)331(M+,11.96),236(100);HRMS Calcd for C23H25NO(M+):331.1936,Found:331.1941.
取一支干燥的反应管,氮气下抽换气三次。在氮气保护下,加入3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(331.2mg,1mmol)和5mL 1,2-二氯乙烷并在0℃搅拌10分钟,然后加入三苯基膦一氯化金(24.7mg,0.05mmol)和四氟硼酸银(9.8mg,0.05mmol)并在0℃搅拌13.2小时,TLC跟踪表明反应完全,反应液过滤用短硅胶柱过滤,乙醚冲洗。旋去乙醚后得粗产物,将其转移到50mL圆底瓶中加,并加入5mL N,N-二甲基甲酰胺和二氯二氰基苯醌(272.8mg,1.2mmol),上述混合液在室温下搅拌5小时,TLC跟踪表明反应完全,加入10mL水淬灭,乙醚(萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,旋去溶剂,柱层析分离(PE(30-60℃)/EA=50:1-30:1)得到3-丁基-4-(4-甲氧基苯基)-9H-咔唑(243.6mg,74%):固体,熔点:124.7-125.7℃;1H NMR(300MHz,CDCl3)δ7.88(s,1H,NH),7.35-7.22(m,6H,ArH),7.08-7.02(m,2H,ArH),6.93-6.83(m,1H,ArH),6.78-6.70(m,1H,ArH),3.91(s,3H,CH3),2.55(t,J=7.8Hz,2H,CH2),1.55-1.38(m,2H,CH2),1.32-1.17(m,2H,CH2),0.80(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ158.7,139.8,137.6,135.6,132.4,132.3,130.5,127.0,125.1,123.5,122.3,122.2,118.9,113.9,110.2,109.4,55.3,34.6,32.2,22.5,13.9;IR(KBr)ν(cm-1)3404,3057,3032,2994,2955,2926,2857,2834,2533,1610,1515,1490,1451,1382,1333,1283,1244,1175,1151,1127,1105,1087,1033;MS(70ev,EI)m/z(%)329(M+,53.23),286(100);Elemental analysis calcd for C23H23NO:C,83.85;H,7.04;N,4.25.Found:C,83.64;H,7.10;N,4.09.
实施例2 3-丁基-4-(4-甲氧基苯基)-9H-咔唑(001)的合成
反应式(2);
按实施例1所述的方法,不同的是所用底物和试剂的用量为:1-(4-甲氧基苯基)-2-丁基-2,3-丁二烯-1-醇(1.3921g,6mmol),吲哚(1.0539g,9mmol),一水合对甲苯磺酸(57.2mg,0.3mmol)在30mL 1,2-二氯乙烷中室温搅拌13h得到3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(1.4958g,75%)(PE/EA=50:1-30:1-20:1):油状液体;1HNMR(300MHz,CDCl3)δ7.87(s,1H,NH),7.49(d,J=7.8Hz,1H,ArH),7.30(td,J=8.1Hz and1.1Hz,1H,ArH),7.26-7.18(m,2H,ArH),7.15(t,J=7.5Hz,1H,ArH),7.05(t,J=7.4Hz,1H,ArH),6.83(d,J=8.7Hz,2H,ArH),6.73(dd,J=2.4Hz and 0.9Hz,1H,ArH),4.75(s,1H,CH),4.60-4.45(m,2H,=CH2),3.78(s,3H,OCH3),2.08-1.97(m,2H,CH2),1.54-1.41(m,2H,CH2),1.40-1.24(m,2H,CH2),0.87(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ207.1,157.9,136.4,135.0,129.6,127.2,122.9,121.8,119.7,119.2,118.8,113.3,110.9,107.2,77.2,55.2,45.6,31.3,30.0,22.5,14.0.
3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(1.3231g,4mmol),三苯基膦一氯化金(99.1mg,0.2mmol)和四氟硼酸银(39.2mg,0.2mmol)在20mL 1,2-二氯乙烷中0℃反应17h,反应粗产物与二氯二氰基苯醌(1.0895g,4.8mmol)在20mL N,N-二甲基甲酰胺中室温反应5h得到3-丁基-4-(4-甲氧基苯基)-9H-咔唑(1.0039g,76%)(PE(30-60℃)/EA=50:1-30:1):固体;1H NMR(300MHz,CDCl3)δ7.96(s,1H,NH),7.40-7.20(m,6H,ArH),7.15-7.02(m,2H,ArH),6.88(t,J=6.8Hz,1H,ArH),6.74(d,J=7.2Hz,1H,ArH),3.93(s,3H,OCH3),2.55(t,J=7.4Hz,2H,CH2),1.58-1.40(m,2H,CH2),1.34-1.17(m,2H,CH2),0.81(t,J=7.1Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ158.7,139.8,137.6,135.6,132.4,132.3,130.5,127.0,125.1,123.5,122.3,122.2,118.9,113.9,110.2,109.4,55.3,34.6,32.2,22.6,14.0.
实施例3 3-甲基-4-(4-甲氧基苯基)-9H-咔唑(003)的合成
反应式(3);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丁基-2,3-丁二烯-1-醇(380.3mg,1mmol),吲哚(351.6mg,3mmol)和一水合对甲苯磺酸(TsOH·H2O,19.4mg,0.1mmol)在1,2-二氯乙烷(10mL)中反应11.7小时得到3-甲基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(377.9mg,65%)(PE/EA=30:1-20:1):油状液体;1H NMR(300MHz,CDCl3)δ7.89(s,1H,NH),7.62(d,J=8.1Hz,1H,ArH),7.42-7.30(m,3H,ArH),7.26(t,J=7.5Hz,1H,ArH),7.17(t,J=7.4Hz,1H,ArH),6.95(d,J=8.4Hz,2H,ArH),6.82(d,J=1.8Hz,2H,ArH),4.87(s,1H,CH),4.70-4.48(m,2H,=CH2),3.86(s,3H,OCH3),1.89(s,3H,CH3);13C NMR(75MHz,CDCl3)δ207.5,158.0,136.4,134.7,129.5,127.2,122.9,121.7,119.7,119.1,118.2,113.4,111.0,101.9,75.4,55.1,46.6,18.3;IR(neat)ν(cm-1)3418,3056,3003,2977,2947,2934,2908,2835,1957,1889,1610,1583,1547,1505,1456,1441,1417,1368,1338,1301,1247,1176,1150,1124,1094,1034,1011;MS(70ev,EI)m/z(%)289(M+,38.82),236(100);HRMS Calcd for C20H19NO(M+):289.1467,Found:289.1464.
3-甲基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(289.1mg,1mmol),三苯基膦一氯化金(24.7mg,0.05mmol)和四氟硼酸银(9.8mg,0.05mmol)在5mL 1,2-二氯乙烷中反应15.5小时,粗产物与二氯二氰基苯醌(272.8mg,1.2mmol)在5mLN,N-二甲基甲酰胺中反应5小时后得到3-甲基-4-(4-甲氧基苯基)-9H-咔唑(204.9mg,71%)(重蒸PE(30-60℃)/EA=50:1-30:1):固体,熔点:174.0~175.6℃;1H NMR(300MHz,CDCl3)δ7.91(s,1H,NH),7.42-7.18(m,6H,ArH),7.14-7.01(m,2H,ArH),6.96-6.72(m,2H,ArH),3.92(s,3H,OCH3),2.24(d,J=2.1Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ158.8,139.9,137.9,136.0,132.7,130.4,127.8,127.1,125.4,122.4,122.3,119.0,114.2,110.3,109.3,55.4,19.6;IR(KBr)ν(cm-1)3392,3052,3033,3005,2961,2917,2840,1610,1518,1491,1454,1443,1385,1332,1283,1242,1182,1150,1026;MS(70ev,EI)m/z(%)287(M+,100);Elemental analysis calcdfor C20H17NO:C,83.59;H,5.96;N,4.87.Found:C,83.84;H,6.03;N,4.72.
实施例4 3-丙基-4-(4-甲氧基苯基)-9H-咔唑(004)的合成
反应式(4);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丁基-2,3-丁二烯-1-醇(435.7mg,2mmol),吲哚(351.1mg,3mmol)和一水合对甲苯磺酸(18.9mg,0.1mmol)在10mL 1,2-二氯乙烷室温反应13.5小时得到3-丙基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(486.4mg,77%)(PE/EA=30:1-20:1):油状液体;1H NMR(300MHz,CDCl3)δ7.85(s,1H,NH),7.49(d,J=7.5Hz,1H,ArH),7.33-7.18(m,3H,ArH),7.15(t,J=7.4Hz,1H,ArH),7.05(t,J=7.5Hz,1H,ArH),6.82(d,J=8.4Hz,2H,ArH),6.72(d,J=1.5Hz,1H,ArH),4.74(s,1H,CH),4.65-4.45(m,2H,=CH2),3.81(s,3H,OCH3),2.15-1.90(m,2H,CH2),1.65-1.38(m,2H,CH2),0.91(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ207.1,157.9,136.4,135.0,129.6,127.2,122.9,121.7,119.6,119.1,118.7,113.4,111.0,107.0,77.1,55.1,45.6,33.6,21.1,13.9;IR(neat)ν(cm-1)3419,3056,2957,2931,2870,2835,1954,1886,1610,1583,1545,1509,1457,1417,1377,1337,1300,1245,1176,1124,1094,1034,1008;MS(70ev,EI)m/z(%)317(M+,20.30),236(100);HRMS Calcd for C22H23NO(M+):317.1780,Found:317.1779.
3-丙基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(317.1mg,1mmol),三苯基膦一氯化金(24.8mg,0.05mmol)和四氟硼酸银(9.6mg,0.05mmol)在5mL 1,2-二氯乙烷中0℃反应8.5小时,然后粗产物与二氯二氰基苯醌(272.9mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应12.5小时得到3-丙基-4-(4-甲氧基苯基)-9H-咔唑(210.4mg,67%)(重蒸PE(30-60℃)/EA=50:1~30:1):固体,熔点:144.0-145.4℃;1H NMR(300MHz,CDCl3)δ7.76(s,1H,NH),7.40-7.12(m,6H,ArH),7.04(d,J=8.4Hz,2H,ArH),6.88(t,J=6.8Hz,1H,ArH),6.75,(d,J=7.5Hz,1H,ArH),2.52(t,J=8.5Hz,2H,CH2),1.64-1.40(m,2H,CH2),0.82(t,J=7.4Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ158.6,139.8,137.6,135.6,132.4,132.0,130.5,127.0,125.1,123.4,122.3,122.1,118.8,113.9,110.2,109.4,55.2,34.6,25.4,14.1;IR(KBr)ν(cm-1)3392,3065,3032,2995,2955,2928,2866,2836,1608,1515,1492,1479,1452,1439,1408,1386,1322,1304,1285,1237,1179,1153,1127,1108,1084,1029;MS(70ev,EI)m/z(%)315(M+,59.29),286(100);Elemental analysis calcd for C22H21NO:C,83.78;H,6.71;N,4.44.Found:C,83.68;H,6.66;N,4.23.
实施例5 3-(2-苯乙基)-4-(4-甲氧基苯基)-9H-咔唑(005)的合成
反应式(5);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-苯乙基-2,3-丁二烯-1-醇(560.7mg,2mmol),吲哚(351.2mg,3mmol)和一水合对甲苯磺酸(19.1mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应23小时得到3-(2-苯乙基)-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(579.6mg,76%)(PE/EA=30:1-20:1):油状液体,1H NMR(300MHz,CDCl3)δ7.75(s,1H,NH),7.41(d,J=7.5Hz,1H,ArH),7.35-6.90(m,10H,ArH),6.80(d,J=8.1Hz,2H,ArH),6.63(d,J=1.5Hz,1H,ArH),4.75(s,1H,CH),4.68-4.45(m,2H,=CH2),3.74(s,3H,OCH3),2.78(t,J=7.8Hz,2H,CH2),2.42-2.10(m,2H,CH2);13CNMR(75MHz,CDCl3)δ207.2,158.0,142.1,136.4,134.7,129.6,128.5,128.2,127.2,125.7,122.9,121.8,119.7,119.2,118.4,113.4,110.9,106.7,77.9,55.1,45.9,34.2,33.0;IR(neat)ν(cm-1)3419,3058,3026,2994,2932,2935,1954,1882,1609,1583,1510,1455,1417,1337,1301,1246,1175,1094,1033,1011;MS(70ev,EI)m/z(%)379(M+,28.56),236(100);HRMS Calcd for C27H25NO(M+):379.1936,Found:379.1934.
3-(2-苯乙基)-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(379.1mg,1mmol),三苯基膦一氯化金(24.9mg,0.05mmol)和四氟硼酸银(9.6mg,0.05mmol)在5mL 1,2-二氯乙烷中0℃反应11.3小时,然后粗产物与二氯二氰基苯醌(272.8mg,1.2mmol)在5mLN,N-二甲基甲酰胺溶液中室温反应5小时得到3-(2-苯乙基)-4-(4-甲氧基苯基)-9H-咔唑(299.1mg,79%)(重蒸PE(30-60℃)/EA=30:1-20:1-15:1):固体,熔点:183.5-184.6℃;1HNMR(300MHz,CDCl3)δ7.94(s,1H,NH),7.40-7.08(m,9H,ArH),7.07(d,J=8.1Hz,2H,ArH),6.97(d,J=6.9Hz,2H,ArH),6.88(t,J=6.9Hz,1H,ArH),6.76(d,J=7.5Hz,1H,ArH),3.93(s,3H,OCH3),3.00-2.50(m,4H,2×CH2);13C NMR(75MHz,CDCl3)δ158.8,142.1,139.8,137.8,135.8,132.1,131.1,130.4,128.4,128.2,127.1,125.6,125.2,123.5,122.4,122.2,119.0,114.0,110.2,109.5,55.3,38.8,35.0;IR(KBr)ν(cm-1)3406,3026,2997,2954,2934,2853,2835,1610,1600,1518,1489,1449,1386,1332,1321,1283,1242,1176,1149,1102,1032;MS(70ev,EI)m/z(%)377(M+,20.14),286(100);Elemental analysiscalcd for C27H23NO:C,85.91;H,6.14;N,3.71.Found:C,85.72;H,6.09;N,3.49.
实施例6 3-(3-苯丙基)-4-(4-甲氧基苯基)-9H-咔唑(006)的合成
反应式(6);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-苯丙基-2,3-丁二烯-1-醇(587.7mg,2mmol),吲哚(351.7mg,3mmol)和一水合对甲苯磺酸(19.4mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应16.5小时得到3-(3-苯丙基)-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(582.5mg,74%)(PE/EA=30:1-20:1):1HNMR(300MHz,CDCl3)δ7.80(s,1H,NH),7.48(d,J=7.8Hz,1H,ArH),7.32-7.6.96(m,10H,ArH),6.81(d,J=8.1Hz,2H,ArH),6.69(d,J=1.8Hz,1H,ArH),4.74(s,1H,CH),4.68-4.45(m,2H,=CH2),3.75(s,3H,OCH3),2.60(t,J=7.7Hz,2H,CH2),2.18-1.96(m,2H,CH2),1.92-1.68(m,2H,CH2);13C NMR(75MHz,CDCl3)δ207.1,158.0,142.5,136.5,134.8,129.6,128.4,128.2,127.2,125.6,122.9,121.8,119.7,119.2,118.6,113.4,111.0,106.9,77.6,55.2,45.8,35.5,31.0,29.7;IR(neat)ν(cm-1)3425,3056,3024,3000,2957,2930,2854,2836,1954,1888,1606,1580,1509,1497,1458,1438,1417,1338,1320,1299,1251,1214,1175,1150,1106,1090,1062,1033,1012;MS(70ev,EI)m/z(%)393(M+,18.23),236(100);.HRMSCalcd for C28H27NO(M+):393.2093,Found:393.2097.
3-(3-苯丙基)-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(393.2mg,1mmol),三苯基膦一氯化金(24.6mg,0.05mmol)和四氟硼酸银(9.5mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应18.7小时,然后粗产物与二氯二氰基苯醌(271.8mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到3-(3-苯丙基)-4-(4-甲氧基苯基)-9H-咔唑(266.4mg,68%)(重蒸PE(30-60℃)/EA=30:1-10:1-5:1):固体,熔点:156.5-157.8℃;1H NMR(300MHz,CDCl3)δ7.96(s,1H,NH),7.40-7.10(m,9H,ArH),7.10-6.95(m,4H,ArH),6.88(t,J=7.1Hz,1H,ArH),6.75(d,J=8.1Hz,1H,ArH),3.94(s,3H,OCH3),2.70-2.42(m,4H,2×CH2),1.94-1.72(m,2H,CH2);13C NMR(75MHz,CDCl3)δ158.7,142.4,139.8,137.7,135.7,132.2,131.7,130.4,128.3,128.2,127.0,125.5,125.2,123.5,122.4,122.2,118.9,114.0,110.2,109.4,55.3,35.7,33.7,32.3;IR(KBr)ν(cm-1)3392,3382,3060,3028,3008,2962,2921,2855,1609,1515,1489,1465,1451,1440,1376,1324,1280,1240,1179,1032;MS(70ev,EI)m/z(%)391(M+,70.61),286(100);Elemental analysis calcd forC28H25NO:C,85.90;H,6.44;N,3.58.Found:C,86.09;H,6.50;N,3.41.
实施例7 3-异丙基-4-(4-甲氧基苯基)-9H-咔唑(007)的合成
反应式(7);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-异丙基-2,3-丁二烯-1-醇(436.5mg,2mmol),吲哚(351.3mg,3mmol)和一水合对甲苯磺酸(19.0mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应13小时得到3-异丙基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(505.6mg,80%)(PE/EA=30:1-20:1):油状液体;1HNMR(300MHz,CDCl3)δ7.81(s,1H,NH),7.50(d,J=7.8Hz,1H,ArH),7.32-7.18(m,3H,ArH),7.14(t,J=7.5Hz,1H,ArH),7.04(t,J=7.4Hz,1H,ArH),6.82(d,J=8.4Hz,2H,ArH),6.66(d,J=1.8Hz,2H,ArH),4.80(s,1H,CH),4.62-4.45(m,2H,=CH2),3.77(s,3H,OCH3),2.24-2.08(m,1H,CH),1.48(d,J=6.9Hz,3H,CH3),1.06(d,J=6.9Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ206.4,157.9,136.5,135.3,129.6,123.0,121.7,119.6,119.3,119.1,113.9,113.3,111.0,78.6,55.1,44.2,30.0,22.2;IR(neat)ν(cm-1)3418,3056,2959,2929,2867,2835,1953,1610,1583,1509,1457,1417,1381,1337,1300,1246,1176,1094,1036,1012;MS(70ev,EI)m/z(%)317(M+,14.96),236(100);HRMS Calcd for C22H23NO(M+):317.1780,Found:317.1782.
3-异丙基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(316.5mg,1mmol),三苯基膦一氯化金(24.6mg,0.05mmol)和四氟硼酸银(9.7mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应11.5小时,然后粗产物与二氯二氰基苯醌(272.3mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到3-异丙基-4-(4-甲氧基苯基)-9H-咔唑(118.8mg,38%)(重蒸PE(30-60℃)/EA=30:1-20:1):固体,熔点:205.3-207.1℃;1H NMR(300MHz,CDCl3)δ7.93(s,1H,NH),7.43(d,J=8.4Hz,1H,ArH),7.38-7.17(m,5H,ArH),7.08(d,J=8.4Hz,2H,ArH),6.88(t,J=6.2Hz,1H,ArH),6.68(d,J=7.8Hz,1H,ArH),3.93(s,3H,OCH3),3.10-2.90(m,1H,CH),1.20(d,J=6.9Hz,6H,2×CH3);13C NMR(75MHz,CDCl3)δ158.7,139.8,138.2,137.3,134.7,132.4,130.4,125.1,123.6,123.1,122.12,122.07,118.9,114.0,110.2,109.9,55.3,29.0,24.8;IR(KBr)ν(cm-1)3447,3031,3004,2958,2933,2864,2835,1897,1608,1516,1492,1451,1438,1387,1362,1333,1302,1284,1243,1179,1150,1106,1045,1030;MS(70ev,EI)m/z(%)315(M+,66.33),300(100);Elemental analysiscalcd for C22H21NO:C,83.78;H,6.71;N,4.44.Found:C,84.16;H,6.74;N,4.31.
实施例8 3-环己基-4-(4-甲氧基苯基)-9H-咔唑(008)的合成
反应式(8);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-环己基-2,3-丁二烯-1-醇(516.1mg,2mmol),吲哚(351.3mg,3mmol)和一水合对甲苯磺酸(18.9mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应14小时得到3-环己基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(639.6mg,90%)(PE/EA=30:1-20:1):油状液体;1HNMR(300MHz,CDCl3)δ7.76(s,1H,NH),7.49(d,J=7.8Hz,1H,ArH),7.30-7.16(m,3H,ArH),7.13(t,J=7.5Hz,1H,ArH),7.03(t,J=7.4Hz,1H,ArH),6.81(d,J=9.0Hz,2H,ArH),6.62(d,J=1.5Hz,2H,ArH),4.79(s,1H,CH),4.63-4.35(m,2H,=CH2),3.75(s,3H,OCH3),2.10-1.90(m,1H),1.90-1.45(m,5H),1.36-1.03(m,5H);13C NMR(75MHz,CDCl3)δ207.1,157.9,136.5,135.4,129.6,127.2,123.1,121.7,119.6,119.4,119.1,113.3,113.0,110.9,78.2,55.1,44.1,39.8,32.8,32.7,26.6,26.5,26.3;IR(neat)ν(cm-1)3420,3056,2925,2851,2245,1952,1884,1610,1583,1545,1509,1455,1417,1337,1300,1246,1176,1093,1034,1011;MS(70ev,EI)m/z(%)357(M+,16.06),237(100);HRMS Calcd for C25H27NO(M+):357.2093,Found:357.2096.
3-环己基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(357.6mg,1mmol),三苯基膦一氯化金(24.9mg,0.05mmol)和四氟硼酸银(9.8mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应12小时,然后粗产物与二氯二氰基苯醌(271.9mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到3-环己基-4-(4-甲氧基苯基)-9H-咔唑(245.5mg,69%)(重蒸PE(30-60℃)/EA=30:1-20:1):固体,熔点:207.5-208.5℃;1H NMR(300MHz,CDCl3)δ7.85(s,1H,NH),7.40(d,J=8.4Hz,1H,ArH),7.34-7.13(m,5H,ArH),7.05(d,J=8.7Hz,2H,ArH),6.95-6.80(m,1H,ArH),6.68(d,J=7.8Hz,1H,ArH),3.92(s,3H,OCH3),2.58(t,J=11.9Hz,1H,CH),1.89-1.36(m,7H),1.32-1.00(m,3H);13C NMR(75MHz,CDCl3)δ158.6,139.8,137.4,137.3,134.9,132.4,130.3,125.1,123.9,123.6,122.1,118.8,114.0,110.2,109.6,55.2,39.6,35.1,26.9,26.2;IR(KBr)ν(cm-1)3382,3057,3034,2999,2924,2848,1609,1516,1490,1450,1387,1330,1317,1284,1240,1179,1152,1119,1109,1030;MS(70ev,EI)m/z(%)355(M+,100);Elemental analysis calcd for C25H25NO:C,84.47;H,7.09;N,3.94.Found:C,84.86;H,7.15;N,3.69.
实施例9 3-烯丙基-4-(4-甲氧基苯基)-9H-咔唑(009)的合成
反应式(9);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-烯丙基-2,3-丁二烯-1-醇(432.6mg,2mmol),吲哚(351.3mg,3mmol)和一水合对甲苯磺酸(19.0mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应16小时得到3-烯丙基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(479.5mg,76%)(PE/EA=30:1-20:1):油状液体;1HNMR(300MHz,CDCl3)δ7.80(s,1H,NH),7.49(d,J=7.8Hz,1H,ArH),7.30-7.18(m,3H,ArH),7.14(t,J=7.5Hz,1H,ArH),7.04(t,J=7.4Hz,1H,ArH),6.87-6.75(m,2H,ArH),6.69(d,J=1.5Hz,1H,ArH),6.00-5.60(m,2H),4.78(s,1H,CH),4.63-4.38(m,2H,=CH2),3.75(s,3H,OCH3),2.79(d,J=1.5Hz,2H,CH2);13C NMR(75MHz,CDCl3)δ207.4,158.0,136.4,135.9,134.6,129.6,127.1,123.0,121.8,119.6,119.1,118.3,116.0,113.4,111.0,105.5,77.3,55.1,44.8,36.4;IR(neat)ν(cm-1)3420,3056,3000,2974,2953,2932,2905,2834,1956,1725,1638,1610,1583,1508,1457,1419,1337,1301,1246,1175,1094,1034,1011;MS(70ev,EI)m/z(%)315(M+,27.21),236(100);HRMS Calcd for C22H21NO(M+):315.1623,Found:315.1622.
3-烯丙基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(315.3mg,1mmol),三苯基膦一氯化金(24.9mg,0.05mmol)和四氟硼酸银(9.7mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应11.5小时,然后粗产物与二氯二氰基苯醌(272.3mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到3-烯丙基-4-(4-甲氧基苯基)-9H-咔唑(205.1mg,65%)(重蒸PE(30-60℃)/EA=30:1-20:1):固体,熔点:170.5-171.6℃;1H NMR(300MHz,CDCl3)δ7.94(s,1H,NH),7.38-7.16(m,6H,ArH),7.05(d,J=9.0Hz,2H,ArH),6.95-6.83(m,1H,ArH),6.80(d,J=7.8Hz,1H,ArH),6.05-5.80(m,1H),5.05-4.78(m,2H),3.91(s,3H,OCH3),3.32(d,J=6.3Hz,2H,CH2);13C NMR(75MHz,CDCl3)δ158.8,139.8,138.8,137.9,135.8,132.1,130.4,129.1,127.2,125.2,123.4,122.3,122.2,119.0,114.9,114.0,110.2,109.6,55.3,36.9;IR(KBr)ν(cm-1)3389,3023,3033,2998,2973,2939,2839,2048,1944,1873,1640,1608,1517,1489,1450,1382,1323,1285,1240,1178,1151,1126,1107,1030;MS(70ev,EI)m/z(%)313(M+,100);Elemental analysis calcd for C22H19NO:C,84.31;H,6.11;N,4.47.Found:C,84.38;H,6.11;N,4.26.
实施例10 3-苄基-4-(4-甲氧基苯基)-9H-咔唑(010)的合成
反应式(10);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-苄基-2,3-丁二烯-1-醇(532.4mg,2mmol),吲哚(351.3mg,3mmol)和一水合对甲苯磺酸(19.7mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应13小时得到3-苄基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(534.5mg,62%)(PE/EA=30:1-10:1):油状液体;1H NMR(300MHz,CDCl3)δ7.87(s,1H,NH),7.48-7.15(m,10H,ArH),7.15-7.02(m,1H,ArH),6.94-6.84(m,2H,ArH),6.76(d,J=1.8Hz,1H,ArH),4.74(s,1H,CH),4.43(dd,J=27.9Hz and14.7Hz,2H,PhCH2);13CNMR(75MHz,CDCl3)δ208.0,158.0,136.4,139.7,134.6,129.7,129.2,128.2,127.1,126.2,123.1,121.8,119.5,119.1,118.4,113.4,110.9,106.9,55.1,44.1,38.8;IR(neat)ν(cm-1)3418,3058,3027,2975,2932,2905,2835,1957,1889,1610,1583,1547,1506,1494,1455,1417,1382,1338,1301,1246,1175,1151,1095,1073,1032,1011;MS(70ev,EI)m/z(%)365(M+,15.06),236(100);HRMS Calcd for C26H23NO(M+):365.1780,Found:365.1787.
3-苄基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(365.2mg,1mmol),三苯基膦一氯化金(24.9mg,0.05mmol)和四氟硼酸银(9.4mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应12小时,然后粗产物与二氯二氰基苯醌(272.9mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应4小时得到3-苄基-4-(4-甲氧基苯基)-9H-咔唑(312.4mg,86%)(重蒸PE(30-60℃)/EA=30:1-15:1-10:1-5:1):固体,熔点:213.4-214.4℃;1H NMR(300MHz,CDCl3)δ7.96(s,1H,NH),7.37-7.06(m,9H,ArH),7.06-6.95(m,4H,ArH),6.89(t,J=6.6Hz,1H,ArH),6.79(d,J=8.1Hz,1H,ArH),2.56(t,J=7.8Hz,2H,OCH2O),1.62-1.38(m,2H,CH2),1.33-1.10(m,2H,CH2),3.95(s,2H,PhCH2),3.90(s,3H,OCH3);13C NMR(75MHz,CDCl3)δ158.9,142.6,139.8,138.0,136.2,132.1,130.5,128.8,128.1,127.9,125.5,125.3,123.5,122.4,122.2,119.0,114.0,110.2,109.6,55.3,38.4;IR(KBr)ν(cm-1)3392,3057,3030,3004,2968,2941,2844,1608,1517,1489,1464,1445,1382,1330,1316,1278,1241,1176,1025;MS(70ev,EI)m/z(%)363(M+,100);Elemental analysis calcd for C26H23NO:C,85.92;H,5.82;N,3.85.Found:C,85.90;H,5.78;N,3.62.
实施例11 3-苯基-4-(4-甲氧基苯基)-9H-咔唑(011)的合成
反应式(11);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-苯基-2,3-丁二烯-1-醇(503.9mg,2mmol),吲哚(351.2mg,3mmol)和一水合对甲苯磺酸(19.2mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应24小时得到3-苯基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(415.8mg,59%)(PE/EA=30:1-10:1):油状液体;1H NMR(300MHz,CDCl3)δ7.80(s,1H,NH),7.56-7.46(m,3H,ArH),7.34-7.08(m,8H,ArH),7.03(t,J=7.5Hz,1H,ArH),6.80(d,J=8.7Hz,2H,ArH),6.72-6.55(m,1H,ArH),5.40(s,1H,CH),4.95-4.60(m,2H,=CH2),3.74(s,3H,OCH3);13C NMR(75MHz,CDCl3)δ210.3,158.0,136.5,136.3,134.8,129.7,128.3,127.0,126.5,123.6,121.9,119.5,118.9,113.4,111.0,109.3,79.8,55.1,42.9;IR(neat)ν(cm-1)3418,3057,3030,30003,2956,2930,2835,2245,1937,1889,1609,1584,1550.,1455,1417,1338,1301,1247,1176,1124,1108,1093,1076,1033,1011;MS(70ev,EI)m/z(%)351(M+,15.79),236(100);HRMS Calcd for C25H21NO(M+):351.1623,Found:351.1628.
3-苯基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(351.6mg,1mmol),三苯基膦一氯化金(24.8mg,0.05mmol)和四氟硼酸银(9.8mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应12小时,然后粗产物与二氯二氰基苯醌(271.9mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到3-苯基-4-(4-甲氧基苯基)-9H-咔唑(188.6mg,54%)(重蒸PE(30-60℃)/EA=30:1-20:1):固体,熔点:183.6-184.4℃;1H NMR(300MHz,CDCl3)δ8.00(s,1H,NH),7.45(d,J=8.1Hz,1H,ArH),7.38-7.24(m,3H,ArH),7.24-7.06(m,7H,ArH),7.02(d,J=7.8Hz,1H,ArH),6.97-6.75(m,3H,ArH),3.80(s,3H,OCH3);13C NMR(75MHz,CDCl3)δ158.5,142.0,140.0,138.8,135.1,133.0,131.9,131.4,130.4,128.1,127.5,125.6,125.5,123.5,122.5,122.1,119.0,113.6,109.4,55.1;IR(KBr)ν(cm-1)3409,3050,3030,2955,2932,2834,2039,1894,1608,1517,1471,1439,1384,1334,1287,1243,1177,1152,1122,1106,1029;MS(70ev,EI)m/z(%)349(M+,100);Elemental analysis calcdfor C25H19NO:C,85.93;H,5.48;N,4.01.Found:C,85.84;H,5.47;N,3.82.
实施例12 3-丁基-4-(4-乙氧基苯基)-9H-咔唑(012)的合成
反应式(12);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-乙氧基苯基)-2-丁基-2,3-丁二烯-1-醇(492.2mg,2mmol),吲哚(351.3mg,3mmol)和一水合对甲苯磺酸(19.1mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应16.5小时得到3-丁基-4-(4-乙氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(417.7mg,61%)(PE/EA=50:1-30:1):油状液体;1H NMR(300MHz,CDCl3)δ7.84(s,1H,NH),7.49(d,J=8.1Hz,1H,ArH),7.28(d,J=8.1Hz,1H,ArH),7.24-7.18(m,3H,ArH),7.05(t,J=7.4Hz,1H,ArH),6.81(d,J=8.1Hz,2H,ArH),6.71(d,J=1.8Hz,1H,ArH),4.74(s,1H,CH),4.65-4.38(m,2H,=CH2),4.00(q,J=6.8Hz,2H,OCH2),2.15-1.88(m,2H,CH2),1.63-1.10(m,7H,2×CH2and CH3),0.87(t,J=7.1Hz,3H,CH3);13CNMR(75MHz,CDCl3)δ207.1,157.3,136.4,134.8,129.6,127.2,122.9,121.7,119.7,119.1,118.8,113.9,110.9,107.2,77.1,63.3,45.6,31.2,30.0,22.4,14.9,14.0;IR(neat)ν(cm-1)3419,3056,2977,2956,2929,2871,1955,1610,1582,1506,1478,1456,1417,1393,1337,1300,1243,1175,1116,1093,1049,1011;MS(70ev,EI)m/z(%)345(M+,19.95),250(100);HRMS Calcd for C24H27NO(M+):345.2093,Found:345.2088.
3-丁基-4-(4-乙氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(344.8mg,1mmol),三苯基膦一氯化金(24.9mg,0.05mmol)和四氟硼酸银(10.0mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应16小时,然后粗产物与二氯二氰基苯醌(272.7mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到化合物3-丁基-4-(4-乙氧基苯基)-9H-咔唑(245.9mg,72%)(重蒸PE(30-60℃)/EA=30:1-20:1):固体,熔点:156.0-157.7℃;1H NMR(300MHz,CDCl3)δ7.99(s,1H,NH),7.40-7.16(m,6H,ArH),7.06(d,J=8.4Hz,2H,ArH),6.88(t,J=7.2Hz,1H,ArH),6.76,(d,J=7.8Hz,1H,ArH),4.16(q,J=7.0Hz,2H,OCH2),2.55(t,J=7.8Hz,2H,CH2),1.57-1.35(m,5H,CH2and CH3),1.34-1.10(m,2H,CH2),0.81(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ158.1,139.8,137.6,135.7,132.4,132.3,130.5,127.1,125.2,123.6,122.4,122.3,118.9,114.5,110.2,109.4,63.5,34.7,32.3,22.6,15.0,14.0;IR(KBr)ν(cm-1)3393,3036,2976,2953,2928,2868,1609,1513,1489,1475,1451,1376,1326,1305,1280,1243,1180,1153,1114,1049,1017;MS(70ev,EI)m/z(%)343(M+,58.76),300(100);Elemental analysis calcd for C22H21NO:C,83.93;H,7.34;N,4.08.Found:C,84.05;H,7.35;N,3.93.
实施例13 3-丁基-4-(3,4-二氧亚甲基苯基)-9H-咔唑(013)的合成
反应式(13);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(3,4-二氧亚甲基苯基)-2-丁基-2,3-丁二烯-1-醇(492.3mg,2mmol),吲哚(351.6mg,3mmol)和一水合对甲苯磺酸(19.2mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应12小时得到3-丁基-4-(3,4-二氧亚甲基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(484.6mg,70%)(PE/EA=50:1-30:1-20:1):油状液体;1H NMR(300MHz,CDCl3)δ7.86(s,1H,NH),7.48(d,J=7.8Hz,1H,ArH),7.29(d,J=8.1Hz,1H,ArH),7.15(t,J=7.4Hz,1H,ArH),7.05(t,J=7.5Hz,1H,ArH),5.90(dd,J=4.2Hz and 0.9Hz,2H,OCH2O),4.71(s,1H,CH),4.65-4.40(m,2H,=CH2),2.12-1.92(m,2H,CH2),1.53-1.41(m,2H,CH2),1.41-1.22(m,2H,CH2),0.88(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ207.1,147.3,145.8,136.9,136.4,127.1,122.9,121.8,121.6,119.6,119.2,118.5,111.0,109.1,107.7,107.1,100.7,77.3,46.1,31.3,30.0,22.4,14.0;IR(neat)ν(cm-1)3418,3057,2956,2923,2872,2775,1955,1609,1505,1487,1455,1441,1417,1337,1243,1180,1125,1095,1039,1101;MS(70ev,EI)m/z(%)345(M+,25.03),250(100);HRMS Calcd for C23H23NO(M+):345.1729,Found:345.1730.
3-丁基-4-(3,4-二氧亚甲基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(345.3mg,1mmol),三苯基膦一氯化金(24.6mg,0.05mmol)和四氟硼酸银(9.8mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应12小时,然后粗产物与二氯二氰基苯醌(273.1mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应4.3小时得到3-丁基-4-(3,4-二氧亚甲基苯基)-9H-咔唑(267.7mg,78%)(重蒸PE(30-60℃)/EA=50:1-30:1):固体,熔点:134.4-135.1℃;1H NMR(300MHz,CDCl3)δ7.81(s,1H,NH),7.38-7.10(m,4H,ArH),7.02-6.68(m,5H,ArH),6.06(d,J=8.1Hz,2H,ArH),2.56(t,J=7.8Hz,2H,OCH2O),1.62-1.38(m,2H,CH2),1.33-1.10(m,2H,CH2),0.82(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ147.7,146.6,139.7,137.5,135.3,133.7,132.2,127.0,125.2,123.2,122.6,122.13,122.06,118.9,110.2,110.0,109.6,108.5,101.0,34.5,32.1,22.5,13.9;IR(KBr)ν(cm-1)3407,3054,3030,3009,2953,2924,2870,2857,2777,1620,1602,1506,1476,1452,1429,1398,1382,1335,1279,1237,1222,1175,1151,1122,1105,1075,1040,1014;MS(70ev,EI)m/z(%)343(M+,82.40),270(100);Elemental analysis calcd for C23H21NO:C,80.44;H,6.16;N,4.08.Found:C,80.70;H,6.13;N,3.85.
实施例14 3-苯基-4-(3,4-二氧亚甲基苯基)-9H-咔唑(014)的合成
反应式(14);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(3,4-二氧亚甲基苯基)-2-丁基-2,3-丁二烯-1-醇(532.1mg,2mmol),吲哚(350.5mg,3mmol)和一水合对甲苯磺酸(19.2mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应24小时得到3-苯基-4-(3,4-二氧亚甲基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(325.8mg,45%)(PE/EA=30:1-20:1-15:1):油状液体;1H NMR(300MHz,CDCl3)δ7.84(s,1H,NH),7.56-7.40(m,3H,ArH),7.34-7.21(m,3H,ArH),7.21-7.12(m,2H,ArH),7.11-7.01(m,1H,ArH),6.88-6.78(m,2H,ArH),6.77-6.68(m,2H,ArH),5.94-5.84(m,2H,CH2),5.38(s,1H,CH),4.90(d,J=12.3Hz,1H,one proton of=CH2),4.84(d,J=11.7Hz,1H,one proton of=CH2);13C NMR(75MHz,CDCl3)δ210.2,147.3,145.9,136.6,136.5,136.2,128.3,126.9,126.54,126.45,123.6,121.9,119.4,119.3,118.6,111.0,109.3,109.2,107.8,100.8,79.9,43.4;IR(neat)ν(cm-1)3426,3056,2975,2888,2775,2245,4937,1595,1486,1456,1440,1417,1337,1247,1124,1094,1039,1011;MS(70ev,EI)m/z(%)365(M+,57.91),250(100);HRMS Calcd for C25H19NO2(M+):365.1416,Found:365.1414.
3-苯基-4-(3,4-二氧亚甲基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(365.1mg,1mmol),三苯基膦一氯化金(24.6mg,0.05mmol)和四氟硼酸银(9.6mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应12小时,然后粗产物与二氯二氰基苯醌(273.3mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应4.3小时得到3-苯基-4-(3,4-二氧亚甲基苯基)-9H-咔唑(286.8mg,79%)(重蒸PE(30-60℃)/EA=30:1-20:1-15:1):固体,熔点:219.4-220.1℃;1H NMR(300MHz,CDCl3)δ8.11(s,1H,NH),7.55-7.28(m,4H,ArH),7.28-7.15(m,5H,ArH),7.12(d,J=8.1Hz,1H,ArH),7.00(t,J=7.1Hz,1H,ArH),6.88-6.70(m,3H,ArH),6.04(s,1H,one proton of CH2),6.00(s,1H,one proton of CH2);13C NMR(75MHz,CDCl3)δ147.4,146.5,141.8,140.0,138.8,134.9,133.3,133.0,130.3,128.1,127.5,125.7,123.8,123.3,122.5,122.1,119.1,110.9,110.4,109.6,108.2,100.9;IR(KBr)ν(cm-1)3393,3056,3024,2888,2776,1879,1600,1488,1473,1452,1383,1335,1308,1241,1215,1194,1151,1117,1039;MS(70ev,EI)m/z(%)363(M+,100);Elemental analysis calcdfor C25H19NO2:C,82.63;H,4.72;N,3.85.Found:C,82.34;H,4.78;N,3.60.
实施例15 3-乙基-4-(3,4,5-三甲氧基苯基)-9H-咔唑(015)的合成
反应式(15);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(3,4,5-三甲氧基苯基)-2-乙基-2,3-丁二烯-1-醇(528.5mg,2mmol),吲哚(351.2mg,3mmol)和一水合对甲苯磺酸(19.1mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应130小时得到3-乙基-4-(3,4,5-三甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(490.9mg,68%)(PE/EA=30:1-20:1-10:1):油状液体;1H NMR(300MHz,CDCl3)δ8.10(s,1H,NH),7.53(d,J=7.5Hz,1H,ArH),7.32(d,J=8.1Hz,1H,ArH),7.17(t,J=7.5Hz,1H,ArH),7.08(t,J=7.5Hz,1H,ArH),6.80-6.68(m,1H,ArH),6.59(s,2H,ArH),4.78(s,1H,CH),4.68-4.48(m,2H,=CH2),3.84(s,3H,OCH3),3.79(s,6H,OCH3),2.20-1.90(m,2H,CH2),1.07(t,J=7.4Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ206.9,152.7,138.5,136.4,136.2,127.1,122.9,121.8,119.5,119.1,118.3,111.0,108.5,105.7,77.8,60.8,56.0,46.9,24.5,12.4;IR(neat)ν(cm-1)3370,3051,3000,2963,2935,2875,2837,1955,1591,1505,1455,1418,1327,1235,1183,1127,1009;MS(70ev,EI)m/z(%)363(M+,66.83),296(100);HRMS Calcd for C23H25NO3(M+):363.1834,Found:363.1835.
3-乙基-4-(3,4,5-三甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(344.8mg,1mmol),三苯基膦一氯化金(24.8mg,0.05mmol)和四氟硼酸银(9.6mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应11.5小时,然后粗产物与二氯二氰基苯醌(272.6mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到化合物3-乙基-4-(3,4,5-三甲氧基苯基)-9H-咔唑(181.4mg,53%)(重蒸PE(30-60℃)/EA=30:1-20:1-10:1):固体,熔点:177.9-178.4℃;1H NMR(300MHz,CDCl3)δ8.14(s,1H,NH),7.45-7.15(m,4H,ArH),6.92(t,J=6.3Hz,1H,ArH),6.84(d,J=8.1Hz,1H,ArH),6.62(s,2H,ArH),4.02(s,3H,OCH3),3.79(s,6H,2×OCH3),2.63(q,J=7.5Hz,2H,CH2),1.19(t,J=7.7Hz,2H,CH2);13C NMR(75MHz,CDCl3)δ153.4,139.8,137.6,137.0,135.7,135.4,133.1,126.4,125.3,123.1,122.2,121.8,119.0,110.2,109.8,106.2,61.1,56.1,25.7,17.1;IR(KBr)ν(cm-1)3363,3054,3031,2961,2935,2864,2826,1596,1578,1510,1492,1444,1406,1346,1272,1221,1177,1124,1007;MS(70ev,EI)m/z(%)361(M+,100);Elemental analysis calcd for C23H23NO:C,76.43;H,6.41;N,3.88.Found:C,76.77;H,6.37;N,3.66.
实施例16 3-丁基-4-(2-噻吩基)-9H-咔唑(016)的合成
反应式(16);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(2-噻吩基)-2-乙基-2,3-丁二烯-1-醇(416.6mg,2mmol),吲哚(351.5mg,3mmol)和一水合对甲苯磺酸(19.6mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应11.7小时得到3-丁基-4-(2-噻吩基)-4-(1H-吲哚-3-基)-1,2-联烯(392.3mg,64%)(PE/EA=50:1-30:1):油状液体;1H NMR(300MHz,CDCl3)δ7.84(s,1H,NH),7.55(d,J=7.8Hz,1H,ArH),7.29(d,J=8.4Hz,1H,ArH),7.22-7.00(m,3H,ArH),6.98-6.78(m,3H,ArH),5.09(s,1H,CH),4.75-4.50(m,2H,=CH2),2.24-1.90(m,2H,CH2),1.60-1.38(m,2H,CH2),1.38-1.18(m,2H,CH2),0.85(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ206.6,147.2,136.3,126.8,126.2,125.1,123.5,122.9,121.9,119.6,119.3,117.9,111.1,107.4,77.8,41.7,30.6,30.0,22.4,14.0;IR(neat)ν(cm-1)3417,3104,3057,2955,2928,2869,2858,1955,1418,1547,1488,1456,1417,1378,1337,1275,1220,1150,1123,1094,1032,1010;MS(70ev,EI)m/z(%)307(M+,33.35),212(100);HRMS Calcd for C20H21NO(M+):307.1395,Found:307.1396.
3-丁基-4-(2-噻吩基)-4-(1H-吲哚-3-基)-1,2-联烯(307.2mg,1mmol),三苯基膦一氯化金(24.9mg,0.05mmol)和四氟硼酸银(10.0mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应12小时,然后粗产物与二氯二氰基苯醌(272.3mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到3-丁基-4-(2-噻吩基)-9H-咔唑(128.5mg,42%)(重蒸PE(30-60℃)/EA=50:1-30:1):固体,熔点:120.6-121.3℃;1H NMR(300MHz,CDCl3)δ7.80(s,1H,NH),7.49(dd,J=5.0Hz and 1.1Hz,1H,ArH),7.37-7.14(m,5H,ArH),7.08-6.98(m,1H,ArH),6.94(td,J=7.3Hz and 1.1Hz,1H,ArH),6.79(d,J=7.5Hz,1H,ArH),2.63(t,J=7.8Hz,2H,CH2),1.68-1.43(m,2H,CH2),1.39-1.27(m,2H,CH2),0.84(t,J=7.4Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ140.4,139.8,137.4,134.5,127.5,127.2,126.9,126.8,125.8,125.5,123.4,123.0,122.0,119.2,110.7,110.3,35.0,32.4,22.6,14.0;IR(KBr)ν(cm-1)3402,3065,2953,2926,2869,1618,1599,1490,1452,1439,1379,1335,1299,1277,1257,1233,1168,1152,1034;MS(70ev,EI)m/z(%)305(M+,58.85),262(100);Elementalanalysis calcd for C20H19NS:C,78.65;H,6.27;N,4.59.Found:C,79.01;H,6.32;N,4.43.
实施例17 1-丁基-3-乙基-4-(4-甲氧基苯基)-9H-咔唑(017)的合成
反应式(17);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-乙基-2,3-辛二烯-1-醇(519.6mg,2mmol),吲哚(351.3mg,3mmol)和一水合对甲苯磺酸(19.1mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应13小时得到1-丁基-3-乙基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(546.7mg,76%)(PE/EA=50:1-30:1):油状液体;1HNMR(300MHz,CDCl3)δ7.95-7.70(m,1H,NH),7.58-7.40(m,1H,ArH),7.32-7.08(m,4H,ArH),7.08-6.94(m,1H,ArH),6.88-6.58(m,3H,ArH),5.05-4.86(m,1H,=CH),4.76(s,1H,CH),3.88-3.65(m,3H,OCH3),2.15-1.90(m,2H,CH2),1.90-1.50(m,2H,CH2),1.30-0.93(m,7H,2×CH2and CH3),0.92-0.65(m,3H,CH3);13C NMR(75MHz,CDCl3)δ202.26,202.19,157.88,157.83,136.5,135.6,135.3,129.57,129.53,127.3,127.2,121.8,121.7,119.7,119.5,119.0,118.8,113.3,113.2,110.9,110.8109.6,109.2,94.2,94.1,55.1,46.1,31.6,31.5,29.1,29.0,25.1,25.0,22.1,22.013.93,13.87,12.6;IR(neat)ν(cm-1)3418,3057,2959,2923,2870,2835,1961,1885,1610,1583,1511,1456,1417,1376,1337,1301,1246,1175,1124,1093,1036,1011;MS(70ev,EI)m/z(%)359(M+,23.82),236(100);HRMS Calcd forC25H29NO(M+):359.2249,Found:359.2254.
1-丁基-3-乙基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(358.4mg,1mmol),三苯基膦一氯化金(24.9mg,0.05mmol)和四氟硼酸银(9.8mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应12小时,然后粗产物与二氯二氰基苯醌(272.3mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到1-丁基-3-乙基-4-(4-甲氧基苯基)-9H-咔唑(199.3mg,56%)(重蒸PE(30-60℃)/EA=50:1~30:1):固体,熔点:133.7-134.7℃;1HNMR(300MHz,CDCl3)δ7.98(s,1H,NH),7.38(d,J=7.8Hz,1H,ArH),7.34-7.21(m,3H,ArH),7.07(d,J=8.4Hz,2H,ArH),6.87(t,J=7.7Hz,1H,ArH),6.75(d,J=7.8Hz,1H,ArH),2.91(t,J=7.8Hz,2H,CH2),2.57(q,J=7.5Hz,2H,CH2),1.90-1.70(m,2H,CH2),1.61-1.40(m,2H,CH2),1.12(t,J=7.5Hz,3H,CH3),1.01(t,J=7.4Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ158.6,139.7,136.4,133.7,133.0,132.5,130.7,126.1,124.9,124.0,123.5,122.2,122.0,118.8,113.9,110.2,55.2,31.8,31.1,25.8,22.8,16.9,14.1;IR(KBr)ν(cm-1)3401,3003,2959,2928,2868,1610,1520,1494,1454,1388,1337,1287,1242,1180,1159,1109,1029;MS(70ev,EI)m/z(%)357(M+,100);Elemental analysis calcd for C25H27NO:C,83.99;H,7.61;N,3.92.Found:C,84.23;H,7.87;N,3.69.
实施例18 3-丙基-4-(4-甲氧基苯基)-5-甲基-9H-咔唑(018)的合成
反应式(18);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丙基-2,3-丁二烯-1-醇(435.5mg,2mmol),5-甲基-吲哚(393.1mg,3mmol)和一水合对甲苯磺酸(19.2mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应13小时得到3-丙基-4-(4-甲氧基苯基)-4-(5-甲基1H-吲哚-3-基)-1,2-联烯(486.5mg,74%)(PE/EA=50:1-30:1):油状液体;1H NMR(300MHz,CDCl3)δ7.85(s,1H,NH),7.41(d,J=6.9Hz,1H,ArH),7.28(d,J=8.7Hz,2H,ArH),7.15-6.96(m,2H,ArH),6.88(d,J=8.4Hz,2H,ArH),6.81(d,J=1.5Hz,1H,ArH),4.81(s,1H,CH),4.68-4.50(m,2H,=CH2),3.83(s,3H,OCH3),2.15-1.98(m,2H,CH2),1.70-1.47(m,2H,CH2),0.98(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ207.3,158.0,136.1,135.1,129.6,126.8,122.6,122.4,120.0,119.4,119.3,117.5,113.4,107.1,77.1,55.2,45.8,33.7,21.1,16.5,13.9;IR(neat)ν(cm-1)3425,3051,2957,2926,2870,2834,1955,1610,1584,1505,1455,1379,1342,1300,1247,1175,1120,1064,1035;MS(70ev,EI)m/z(%)331(M+,23.96),250(100);HRMS Calcd for C23H25NO(M+):331.1936,Found:331.1940.
3-丙基-4-(4-甲氧基苯基)-4-(5-甲基1H-吲哚-3-基)-1,2-联烯(331.2mg,1mmol),三苯基膦一氯化金(24.7mg,0.05mmol)和四氟硼酸银(9.8mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应12.8小时,然后粗产物与二氯二氰基苯醌(272.1mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到3-丙基-4-(4-甲氧基苯基)-5-甲基-9H-咔唑(168.1mg,51%)(重蒸PE(30-60℃)/EA=50:1-30:1):固体,熔点:167.8-168.8℃;1HNMR(300MHz,CDCl3)δ7.95(s,1H,NH),7.42-7.17(m,4H,ArH),7.15-6.96(m,3H,ArH),6.81(t,J=7.2Hz,1H,ArH),6.59(d,J=7.8Hz,1H,ArH),3.93(s,3H,OCH3),2.65-2.34(m,5H,CH3and CH2),1.63-1.35(m,2H,CH2),0.83(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ158.7,139.1,137.6,135.7,132.5,132.1,130.5,126.9,125.7,123.0,119.8,119.1,119.0,113.9,109.5,55.3,34.6,25.4,13.8;IR(KBr)ν(cm-1)3397,3050,3034,2963,2933,2866,2837,1608,1515,1479,1412,1379,1318,1283,1235,1173,1023;MS(70ev,EI)m/z(%)329(M+,64.95),300(100);.Elemental analysis calcd for C23H21NO:C,83.85;H,7.04;N,4.25.Found:C,83.68;H,7.05;N,3.98.
实施例19 3-丙基-4-(4-甲氧基苯基)-6-甲基-9H-咔唑(019)的合成
反应式(19);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丙基-2,3-丁二烯-1-醇(436.3mg,2mmol),6-甲基-吲哚(392.6mg,3mmol)和一水合对甲苯磺酸(19.3mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应19小时得到3-丙基-4-(4-甲氧基苯基)-4-(6-甲基1H-吲哚-3-基)-1,2-联烯(391.8mg,59%)(PE/EA=50:1):油状液体;1HNMR(300MHz,CDCl3)δ7.60(s,1H,NH),7.35(d,J=8.1Hz,1H,ArH),7.20(d,J=8.7Hz,2H,ArH),6.98(s,1H,ArH),6.67(d,J=8.1Hz,1H,ArH),6.80(d,J=8.7Hz,2H,ArH),6.59(s,1H,ArH),4.71(s,1H,CH),4.62-4.37(m,2H,=CH2),3.73(s,3H,OCH3),2.41(s,3H,CH3),2.10-1.85(m,2H,CH2),1.60-1.45(m,2H,CH2),0.90(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ207.1,157.9,136.9,135.1,131.4,129.5,125.1,122.3,120.9,119.3,118.4,113.3,111.0,107.1,77.1,55.1,45.7,33.6,21.6,21.1,13.9;IR(neat)ν(cm-1)3416,3027,2957,2929,2870,2831,1954,1718,1609,1583,1510,1455,1394,1337,1300,1246,1175,1153,1137,1092,1035;MS(70ev,EI)m/z(%)331(M+,21.07),250(100);HRMS Calcd forC23H25NO(M+):331.1936,Found:331.1939.
3-丙基-4-(4-甲氧基苯基)-4-(6-甲基1H-吲哚-3-基)-1,2-联烯(330.5mg,1mmol),三苯基膦一氯化金(24.9mg,0.05mmol)和四氟硼酸银(9.5mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应23.5小时,然后粗产物与二氯二氰基苯醌(271.7mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5.5小时得到3-丙基-4-(4-甲氧基苯基)-6-甲基-9H-咔唑(203.8mg,62%)(重蒸PE(30-60℃)/EA=50:1-30:1):固体,熔点:117.1-119.3℃1H NMR(300MHz,CDCl3)δ7.60-7.37(m,1H,NH),7.35-7.18(m,3H,ArH),7.14-7.94(m,3H,ArH),6.84-6.67(m,2H,ArH),6.67-6.55(m,1H,ArH),3.88(s,3H,OCH3),2.52(t,J=7.5Hz,2H,CH2),2.35(s,3H,CH3),1.65-1.40(m,2H,CH2),0.82(t,J=6.9Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ158.6,140.3,137.5,135.2,132.5,131.9,130.5,126.5,122.3,121.7,121.0,120.4,113.9,110.4,109.4,55.2,34.6,25.4,21.8,14.1;IR(KBr)ν(cm-1)3396,3066,3027,2987,2950,2925,2856,1855,1703,1629,1608,1515,1484,1438,1372,1316,1284,1239,1173,1134,1104,1084,1037;MS(70ev,EI)m/z(%)329(M+,67.90),300(100);Elemental analysis calcd for C23H23NO:C,83.85;H,7.04;N,4.25.Found:C,84.27;H,7.28;N,3.92.
实施例20 3-丙基-4-(4-甲氧基苯基)-7-甲基-9H-咔唑(020)的合成
反应式(20);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丙基-2,3-丁二烯-1-醇(435.8mg,2mmol),7-甲基-吲哚(393.9mg,3mmol)和一水合对甲苯磺酸(19.2mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应16.6小时得到3-丙基-4-(4-甲氧基苯基)-4-(7-甲基1H-吲哚-3-基)-1,2-联烯(506.0mg,76%)(PE/EA=30:1-20:1):油状液体;1H NMR(300MHz,CDCl3)δ7.70(s,1H,NH),7.33-7.05(m,4H,ArH),6.96(d,J=7.8Hz,1H,ArH),6.81(d,J=8.1Hz,2H,ArH),6.67(d,J=1.5Hz,1H,ArH),4.71(s,1H,CH),4.64-4.40(m,2H,=CH2),3.75(s,3H,OCH3),2.40(s,3H,CH3),2.06-1.83(m,2H,CH2),1.63-1.37(m,2H,CH2),0.91(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ207.1,157.9,135.1,134.7,129.5,128.3,127.4,123.4,119.1,118.1,113.3,110.6,107.1,77.1,55.1,14.5,11.7,21.5,21.1,13.9;IR(neat)ν(cm-1)3417,2957,2920,2863,2831,1954,1609,1583,1505,1455,1377,1323,1300,1246,1174,1093,1035;MS(70ev,EI)m/z(%)331(M+,22.52),250(100);HRMS Calcd for C23H25NO(M+):331.1936,Found:331.1939.
3-丙基-4-(4-甲氧基苯基)-4-(7-甲基1H-吲哚-3-基)-1,2-联烯(331.7mg,1mmol),三苯基膦一氯化金(24.7mg,0.05mmol)和四氟硼酸银(9.7mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应11.5小时,然后粗产物与二氯二氰基苯醌(272.1mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到3-丙基-4-(4-甲氧基苯基)-7-甲基-9H-咔唑(262.8mg,80%)(重蒸PE(30-60℃)/EA=50:1-30:1-20:1):固体,熔点:167.8-168.8℃;1H NMR(300MHz,CDCl3)δ7.83(s,1H,NH),7.36-7.26(m,4H,ArH),7.19(d,J=8.4Hz,1H,ArH),7.13-7.00(m,3H,ArH),6.52(s,1H,ArH),3.93(s,3H,OCH3),2.52(t,J=7.7Hz,2H,CH2),2.23(s,3H,CH3),1.53-1.40(m,2H,CH2),0.83(t,J=7.4Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ158.8,138.1,138.0,135.6,132.6,131.8,130.6,127.9,126.9,126.4,123.7,122.22,122.17,113.9,109.9,109.4,55.4,34.6,25.4,21.5,14.1;IR(KBr)ν(cm-1)3396,3032,2994,2957,2924,2859,2834,1876,1608,1515,1491,1463,1439,1375,1313,1284,1240,1177,1151,1105,1031;MS(70ev,EI)m/z(%)329(M+,65.23),300(100);Elementalanalysis calcd for C23H21NO:C,83.85;H,7.04;N,4.25.Found:C,84.18;H,7.06;N,4.10.
实施例21 3-丙基-4-(4-甲氧基苯基)-5-甲氧基-9H-咔唑(021)的合成
反应式(21);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丙基-2,3-丁二烯-1-醇(436.6mg,2mmol),5-甲氧基-吲哚(441.3mg,3mmol)和一水合对甲苯磺酸(19.3mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应7.2小时得到3-丙基-4-(4-甲氧基苯基)-4-(5-甲氧基-1H-吲哚-3-基)-1,2-联烯(476.5mg,69%)(PE/EA=50:1-30:1-15:1):油状液体;1H NMR(300MHz,CDCl3)δ7.84(s,1H,NH),7.23(d,J=8.4Hz,2H,ArH),7.13(d,J=9.0Hz,1H,ArH),6.95(s,1H,ArH),6.88-6.73(m,3H,ArH),6.68(d,J=1.5Hz,1H,ArH),4.69(s,1H,CH),4.64-4.40(m,2H,=CH2),3.78(s,3H,OCH3),3.76(s,3H,OCH3),2.08-1.88(m,2H,CH2),1.62-1.37(m,2H,CH2),0.91(t,J=7.4Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ207.1,157.9,153.5,134.8,131.6,129.5,127.6,123.8,118.3,113.3,111.7,106.8,101.7,77.1,55.8,55.1,45.6,33.6,21.0,13.9;IR(neat)ν(cm-1)3418,3030,2956,2926,2869,2833,1954,1722,1626,1609,1583,1510,1486,1455,1378,1351,1300,1246,1212,1173,1107,1035;MS(70ev,EI)m/z(%)347(M+,22.38),266(100);HRMS Calcd forC23H25NO2(M+):347.1885,Found:347.1887.
3-丙基-4-(4-甲氧基苯基)-4-(5-甲氧基-1H-吲哚-3-基)-1,2-联烯(347.2mg,1mmol),三苯基膦一氯化金(24.6mg,0.05mmol)和四氟硼酸银(9.6mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应11小时,然后粗产物与二氯二氰基苯醌(271.9mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到化合物3-丙基-4-(4-甲氧基苯基)-5-甲氧基-9H-咔唑(99.3mg,29%)(重蒸PE(30-60℃)/EA=30:1-20:1):固体,熔点:171.4-171.9℃;1H NMR(300MHz,CDCl3)δ7.86(s,1H,NH),7.40-7.14(m,5H,ArH),7.07(d,J=8.7Hz,2H,ArH),6.96-6.85(m,1H,ArH),6.18(d,J=2.4Hz,1H,ArH),3.90(s,3H,OCH3),3.53(s,3H,OCH3),2.54(t,J=7.8Hz,2H,CH2),1.64-1.45(m,2H,CH2),0.84(t,J=7.4Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ158.8,153.0,138.4,135.5,134.7,132.3,131.5,130.7,128.0,127.0,123.9,122.4,114.3,113.9,110.7,109.5,104.9,55.3,34.6,25.4,14.1;IR(KBr)ν(cm-1)3385,3034,2999,2961,2938,2871,2859,2829,1879,1610,1574,1522,1492,1474,1459,1437,1378,1322,1287,1246,1220,1177,1155,1109,1035;MS(70ev,EI)m/z(%)345(M+,100);Elemental analysis calcd for C23H23NO2:C,79.97;H,6.71;N,4.05.Found:C,80.28;H,6.69;N,3.88.
实施例22 3-丙基-4-(4-甲氧基苯基)-5-甲氧羰基-9H-咔唑(022)的合成
反应式(22);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丙基-2,3-丁二烯-1-醇(436.2mg,2mmol),5-甲氧羰基-吲哚(521.2mg,3mmol)和一水合对甲苯磺酸(19.1mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应24小时得到3-丙基-4-(4-甲氧基苯基)-4-(5-甲氧羰基-1H-吲哚-3-基)-1,2-联烯(394.5mg,53%)(PE/EA=20:1-10:1):油状液体;1H NMR(300MHz,CDCl3)δ8.71(bs,1H,NH),8.34(s,1H,ArH),7.85(d,J=8.4Hz,1H,ArH),7.38-7.05(m,3H,ArH),6.95-6.65(m,3H,ArH),4.76(s,1H,CH),4.65-4.35(m,2H,=CH2),3.89(s,3H,OCH3),3.74(s,3H,OCH3),2.15-1.88(m,2H,CH2),1.63-1.38(m,2H,CH2),0.90(t,J=7.4Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ207.0,168.5,158.0,139.1,134.5,129.4,126.8,124.4,123.0,122.5,120.9,120.1,113.4,110.8,106.9,77.3,55.0,51.7,45.3,33.6,20.9,13.7;IR(neat)ν(cm-1)3348,2955,2932,2871,2836,1955,1694,1615,1583,1510,1435,1359,1301,1246,1175,1108,1035;MS(70ev,EI)m/z(%)375(M+,14.19),294(100);HRMS Calcd for C24H25NO3(M+):375.1834,Found:375.1838.
3-丙基-4-(4-甲氧基苯基)-4-(5-甲氧羰基-1H-吲哚-3-基)-1,2-联烯(375.5mg,1mmol),三苯基膦一氯化金(24.6mg,0.05mmol)和四氟硼酸银(9.9mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应10.5小时,然后粗产物与二氯二氰基苯醌(273.1mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到3-丙基-4-(4-甲氧基苯基)-5-甲氧羰基-9H-咔唑(125.7mg,34%)(重蒸PE(30-60℃)/EA=30:1-20:1-10:1):固体,熔点:229.0-230.1℃;1H NMR(300MHz,CDCl3)δ8.31(s,1H,NH),8.00(d,J=7.8Hz,1H,ArH),7.44(s,1H,ArH),7.42-7.22(m,5H,ArH),7.13(d,J=8.7Hz,2H,ArH),3.96(s,3H,OCH3),3.80(s,3H,OCH3),2.57(t,J=7.8Hz,2H,CH2),1.70-1.46(m,2H,CH2),0.85(t,J=7.4Hz,3H,CH3);13CNMR(75MHz,CDCl3)δ167.7,159.1,142.5,138.0,136.0,133.0,131.8,130.3,127.8,126.8,124.8,123.2,122.6,120.8,114.2,109.7,109.6,55.4,51.7,34.6,25.3,14.1;IR(KBr)ν(cm-1)3296,3032,3000,2951,2930,2868,2835,1897,1689,1610,1585,1518,1491,1433,1386,1340,1299,1246,1182,1122,1033;MS(70ev,EI)m/z(%)373(M+,100);Elementalanalysis calcd for C24H23NO3:C,77.19;H,6.21;N,3.75.Found:C,76.89;H,6.26;N,3.56.
实施例23 3-丙基-4-(4-甲氧基苯基)-5-溴-9H-咔唑(023)的合成
反应式(23);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丙基-2,3-丁二烯-1-醇(436.3mg,2mmol),5-溴-吲哚(588.3mg,3mmol)和一水合对甲苯磺酸(19.6mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应12小时得到3-丙基-4-(4-甲氧基苯基)-4-(5-溴-1H-吲哚-3-基)-1,2-联烯(525.7mg,66%)(PE/EA=50:1-30:1-15:1):油状液体;1H NMR(300MHz,CDCl3)δ7.93(s,1H,NH),7.69(s,1H,ArH),7.33-7.18(m,3H,ArH),7.14(d,J=8.4Hz,1H,ArH),6.89(d,J=8.4Hz,2H,ArH),6.73(d,J=1.8Hz,1H,ArH),4.72(s,1H,CH),4.68-4.48(m,2H,=CH2),3.82(s,3H,OCH3),2.15-1.94(m,2H,CH2),1.66-1.47(m,2H,CH2),0.97(t,J=7.5Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ207.1,158.1,135.0,134.5,129.5,128.9,124.6,124.2,122.1,118.6,113.5,112.4,106.8,77.4,55.1,45.4,33.6,21.0,16.5,13.8;IR(neat)ν(cm-1)3426,2997,2957,2930,2870,2835,1954,1609,1583,1509,1459,1409,1301,1247,1175,1095,1035;MS(70ev,EI)m/z(%)397(M+(81Br),14.29),395(M+(79Br),12.99),314(100);HRMS Calcd for C22H22NO79Br(M+):395.0885,Found:395.0880.
3-丙基-4-(4-甲氧基苯基)-4-(5-溴-1H-吲哚-3-基)-1,2-联烯(395.8mg,1mmol),三苯基膦一氯化金(24.6mg,0.05mmol)和四氟硼酸银(9.6mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应10.5小时,然后粗产物与二氯二氰基苯醌(272.5mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到3-丙基-4-(4-甲氧基苯基)-5-溴-9H-咔唑(258.1mg,66%)(重蒸PE(30-60℃)/EA=30:1-20:1-10:1):固体,熔点:173.7-175.6℃;1H NMR(300MHz,CDCl3)δ8.06(s,1H,NH),7.42-7.17(m,6H,ArH),7.11(d,J=8.4Hz,2H,ArH),6.83(s,1H,ArH),3.97(s,3H,OCH3),2.54(t,J=7.8Hz,2H,CH2),1.63-1.35(m,2H,CH2),0.85(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ159.0,138.3,138.0,135.8,132.5,131.7,130.3,127.83,127.81,125.3,124.8,121.6,114.1,111.7,111.5,109.5,55.4,34.6,25.3,14.1;IR(KBr)ν(cm-1)3414,2999,2965,2935,2857,2837,1608,1572,1515,1486,1449,1376,1338,1315,1286,1231,1177,1110,1070,1054,1023;MS(70ev,EI)m/z(%)395(M+(81Br),37.61),393(M+(79Br),42.71),285(100);Elemental analysiscalcd for C22H19NOBr:C,67.01;H,5.11;N,3.55.Found:C,67.12;H,5.12;N,3.41.
实施例24 3-丙基-4-(4-甲氧基苯基)-6-溴-9H-咔唑(024)的合成
反应式(24);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丙基-2,3-丁二烯-1-醇(436.3mg,2mmol),6-溴-吲哚(588.1mg,3mmol)和一水合对甲苯磺酸(19.2mg,0.1mmol)在10mL 1,2-二氯乙烷溶液中室温反应24小时得到3-丙基-4-(4-甲氧基苯基)-4-(6-溴-1H-吲哚-3-基)-1,2-联烯(566.8mg,72%)(PE/EA=30:1-15:1):油状液体;1H NMR(300MHz,CDCl3)δ7.81(s,1H,NH),7.40-7.27(m,2H,ArH),7.20(d,J=8.1Hz,2H,ArH),7.17-7.05(m,1H,ArH),6.83(d,J=8.4Hz,2H,ArH),6.62(d,J=1.5Hz,1H,ArH),4.68(s,1H,CH),4.60-4.38(m,2H,=CH2),3.76(s,3H,OCH3),2.06-1.82(m,2H,CH2),1.60-1.35(m,2H,CH2),0.90(t,J=7.2Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ207.0,158.0,137.2,134.5,129.5,126.0,123.6,122.4,121.0,119.0,115.3,113.9,113.4,106.8,77.3,55.1,45.5,33.6,21.0,13.9;IR(neat)ν(cm-1)3425,2997,2957,2929,2870,2835,1955,1610,1583,1542,1510,1455,1394,1334,1301,1246,1175,1132,1095,1035;MS(70ev,EI)m/z(%)397(M+(81Br),17.14),395(M+(79Br),13.72),316(100);HRMS Calcd for C22H22NO79Br(M+):395.0885,Found:395.0882.
3-丙基-4-(4-甲氧基苯基)-4-(6-溴-1H-吲哚-3-基)-1,2-联烯(396.5mg,1mmol),三苯基膦一氯化金(24.3mg,0.05mmol)和四氟硼酸银(9.9mg,0.05mmol)在5mL 1,2-二氯乙烷溶液中0℃反应11小时,然后粗产物与二氯二氰基苯醌(271.9mg,1.2mmol)在5mL N,N-二甲基甲酰胺溶液中室温反应5小时得到3-丙基-4-(4-甲氧基苯基)-6-溴-9H-咔唑(295.9mg,75%)(重蒸PE(30-60℃)/EA=50:1-30:1):固体,熔点:151.2-152.7℃;1HNMR(300MHz,CDCl3)δ7.94(s,1H,NH),7.45-7.21(m,2H,ArH),7.21-7.17(m,2H,ArH),7.07(d,J=8.4Hz,2H,ArH),7.02-7.17(m,1H,ArH),6.55(d,J=8.1Hz,1H,ArH),3.93(s,3H,OCH3),2.52(t,J=7.7Hz,2H,CH2),1.60-1.40(m,2H,CH2),0.83(t,J=7.4Hz,3H,CH3);13CNMR(75MHz,CDCl3)δ158.8,140.5,137.6,135.6,132.7,132.0,130.3,127.6,123.2,122.5,122.2,121.8,118.7,114.0,113.1,109.5,55.3,34.5,25.3,14.1;IR(KBr)ν(cm-1)3398,3033,30004,2961,2926,2856,2837,2527,1885,1600,1515,1486,1438,1364,1324,1278,1236,1179,1132,1029;MS(70ev,EI)m/z(%)395(M+(81Br),36.49),393(M+(79Br),36.02),285(100);Elemental analysis calcd for C22H19NOBr:C,67.01;H,5.11;N,3.55.Found:C,67.22;H,5.10;N,3.37.
实施例25 3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(025)的合成
反应式(25);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丁基-2,3-丁二烯-1-醇(0.2mmol),吲哚(0.3mmol)和三氟乙酸(0.005mmol)在1mL 1,2-二氯乙烷溶液中室温反应24小时,得到3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯,核磁产率64%。
实施例26 3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(025)的合成
反应式(26);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丁基-2,3-丁二烯-1-醇(0.2mmol),吲哚(0.3mmol)和R-联萘酚磷酸酯(0.005mmol)在1mL 1,2-二氯乙烷溶液中室温反应12.5小时,得到3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯,核磁产率71%。
实施例273-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(025)的合成
反应式(27);
按实施例1所述的方法,不同的是所用底物和试剂为:1-(4-甲氧基苯基)-2-丁基-2,3-丁二烯-1-醇(0.2mmol),吲哚(0.3mmol)和一水合对甲基苯磺酸(0.002mmol)在1mL 1,2-二氯乙烷溶液中室温反应24.5小时,得到3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯,核磁产率44%。
实施例28 3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑(028)的合成
反应式(28);
按实施例1所述的方法,不同的是所用底物和试剂为:3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(0.2mmol),三苯基膦一氯化金(0.005mmol)和六氟锑酸银(0.005mmol)在1mL 1,2-二氯乙烷中室温反应42h,得到3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑,核磁产率72%。
实施例29 3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑(028)的合成
反应式(29);
按实施例1所述的方法,不同的是所用底物和试剂为:3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(0.2mmol),三苯基膦一氯化金(0.005mmol)和六氟磷酸银(0.005mmol)在1mL 1,2-二氯乙烷中室温反应17.5h得到3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑,核磁产率75%。
实施例30 3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑(028)的合成
反应式(30);
按实施例1所述的方法,不同的是所用底物和试剂为:3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(0.2mmol),三苯基膦一氯化金(0.005mmol)和二三氟甲磺酸亚胺合银(0.005mmol)在1mL 1,2-二氯乙烷中室温反应18h,得到3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑,核磁产率78%。
实施例31 3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑(028)的合成
反应式(31);
按实施例1所述的方法,不同的是所用底物和试剂为:3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(0.2mmol),三苯基膦一氯化金(0.005mmol)和三甲氟磺酸银(0.005mmol)在1mL 1,2-二氯乙烷中室温反应4.7h,得到3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑,核磁产率84%。
实施例323-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑(028)的合成
反应式(32);
按实施例1所述的方法,不同的是所用底物和试剂为:3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(0.2mmol),三氯化金(0.005mmol)和四氟硼酸银(0.005mmol)在1mL 1,2-二氯乙烷中室温反应12.5h,得到3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑,核磁产率66%。
实施例33 3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑(028)的合成
反应式(33);
按实施例1所述的方法,不同的是所用底物和试剂为:3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(0.2mmol),一氯化金(0.005mmol)和四氟硼酸银(0.005mmol)在1mL 1,2-二氯乙烷中室温反应12.3h,得到3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑,核磁产率71%。
实施例34 3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑(028)的合成
反应式(34);
按实施例1所述的方法,不同的是所用底物和试剂为:3-丁基-4-(4-甲氧基苯基)-4-(1H-吲哚-3-基)-1,2-联烯(0.2mmol),三苯基膦一氯化金(0.005mmol)和四氟硼酸银(0.005mmol)在1mL 1,2-二氯乙烷中-10℃反应18h得到3-丁基-4-(4-甲氧基苯基)-9H-1,4-二氢咔唑,核磁产率69%。
实施例35本发明制备的化合物刺激GLP-1分泌的作用
材料和方法
mSTC-1细胞
鼠源肠内分泌细胞STC-1如文献所述(Am.J.Pathol.1990Jun;136(6):1349-63.Rindi G,Grant SG,Yiangou Y,Ghatei MA,Bloom SR,Bautch VL,Solcia E,PolakJM.)。
AlphaLISA:7-37使用的标准品GLP-1多肽购自BACHEM(H67950)。
BSA购自MP#15240。用于细胞生长的平板购自Greiner,用于读取AlphaLISA的Proxi-plates plus购自Perkin ElmerTM。
细胞培养条件
STC-1细胞用高糖DMEM(含高浓度葡萄糖和L-谷氨酰胺;,Hyclone)培养液,在37℃、5%CO2及饱和湿度环境中贴壁培养。加入10%灭活的FBS(Invitrogen)、10mM HEPES(Invitrogen)和anti-biotic/anti mycotic(Invitrogen)以维持细胞生存。
在检测GLP-1分泌实验中,细胞以每孔加入80μL体系,12000的密度接种于铺有多聚赖氨酸的黑色透明底的384孔板中(Greiner or BD)。
GLP-1分泌实验
在实验当天检测前,采用洗板器(BioTech)将细胞用HBSS和0.1%BSA进行清洗,每次80μL/孔,清洗三次。然后每孔加入含0.1%BSA的50μL HBSS,100nL的化合物(004)、(008)、(011)、(013)、(019)、(023)。所述化合物的起始浓度为40μM,以2倍进行梯度稀释。37℃反应2h后,采用AlphaLISATM方法对384孔板中细胞上清所含的GLP-1进行定量检测。样品用Envision(Perkin ElmerTM)进行读数,此实验用合成的GLP-1多肽进行校准。
其中,化合物(004)、(008)、(011)、(013)、(019)、(023)的结构式如下:
数据处理和分析
对于单点检测,%stimulation(促进GLP-1分泌百分比)是将该样本GLP-1分泌量除以GLP-1分泌最多的样本。依据公式1和2分别计算刺激百分率和抑制百分率,每次检测设置最大和最小反应条件。
实验结果
(一)以下为不同浓度本发明实施例4、8、11、13、19和23制备的化合物对老鼠mSTC-1细胞刺激GLP-1酶分泌的活性实验结果
表1不同浓度化合物对老鼠mSTC-1细胞刺激GLP-1酶分泌的活性数据
由表1可见,本发明实施例4、8、11、13、19、23制备的多取代N-H咔唑类化合物(004)、(008)、(011)、(013)、(019)、(023)具有刺激GLP-1分泌的显著活性。
此外,除上述化合物(004)、(008)、(011)、(013)、(019)、(023)之外,针对式(Ⅱ)多取代N-H咔唑类化合物包括的其他结构的化合物,例如,化合物(001)、(003)、(005)-(007)、(009)、(010)、(012)、(014)-(018)、(020)-(022)、(024)等,本发明人也做了上述刺激GLP-1分泌活性的实验,均实现上述同样显著的刺激GLP-1酶分泌的活性。
参考上述同样的方法和步骤,在实验中,式(Ⅰ)所示化合物中,当R1~R2=H;甲基;丙基;正丁基;苯基;R3=氢;乙基;丙基;戊基;噻吩、呋喃;R4~R7=氢;芳基;甲基;丙基;正丁基;甲氧基;丁氧羰基;溴;氢;R8=氢;乙基;丙基;苯基时,也能达到上述同样的技术效果。
参考上述同样的方法和步骤,在实验中,当采用包含上述化合物的组合物时,也能达到同样的技术效果;其中,所述包含上述化合物的组合物可以是包含上述化合物和含BSA的溶液的组合物,也可以是包含上述化合物和淀粉、糊精、蔗糖、甘露醇、氯化钠、磷酸氢钙、硫酸钙、微晶纤维素、水等常用的药学上可接受的载体的组合物。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (10)
1.式(II)所示的多取代咔唑类化合物在制备刺激GLP-1分泌的药物中的应用,其特征在于,所述多取代咔唑类化合物的结构如式(Ⅱ)所示:
所述式(Ⅱ)中,
R为C1~C6的烷基;卤素;氢;
R1为C1~C6的烃基;苯基;
R2为氢;
R3为邻、间、对位C1~C6烃基或烃氧基取代的苯基;噻吩;呋喃;吡啶;3,4-OCH2OC6H3。
2.如权利要求1所述的应用中的多取代咔唑类化合物在制备胰岛β细胞分泌促进剂中的应用。
3.如权利要求1所述的应用中的多取代咔唑类化合物在制备胰岛α细胞分泌抑制剂中的应用。
4.如权利要求1所述的应用中的多取代咔唑类化合物在制备治疗和/或预防糖尿病药物中的应用。
5.如权利要求4所述的应用,其特征在于,所述糖尿病为2型糖尿病。
6.根据权利要求4所述的应用,其特征在于,所述药物单独使用或与其他药物联合使用。
7.一种用于刺激GLP-1分泌的药物组合物,其特征在于,包括至少一种如式(II)所示的多取代咔唑类化合物以及药学上可接受的载体,其中,所述多取代咔唑类化合物的结构如式(Ⅱ)所示:
所述式(Ⅱ)中,
R为C1~C6的烷基;卤素;氢;
R1为C1~C6的烃基;苯基;
R2为氢;
R3为邻、间、对位C1~C6烃基或烃氧基取代的苯基;噻吩;呋喃;吡啶;3,4-OCH2OC6H3。
8.如权利要求7所述的药物组合物,其特征在于,所述药物组合物用于治疗和/或预防糖尿病。
9.如权利要求7所述的药物组合物,其特征在于,所述药物组合物被配制成可注射流体、气雾剂、乳膏、凝胶剂、片剂、丸剂、胶囊剂、糖浆剂或透皮贴剂。
10.如权利要求7所述的药物组合物,其特征在于,所述药物组合物被配制用于口服给药、皮下注射、肌肉注射、静脉注射、舌下给药、直肠给药、经皮给药或喷雾吸入。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510683806 | 2015-10-20 | ||
CN201510683806X | 2015-10-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106588749A CN106588749A (zh) | 2017-04-26 |
CN106588749B true CN106588749B (zh) | 2019-02-01 |
Family
ID=58555518
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510698778.9A Active CN106588749B (zh) | 2015-10-20 | 2015-10-23 | 多取代咔唑类化合物及其合成方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106588749B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108383773B (zh) * | 2018-03-16 | 2020-11-13 | 大连理工大学 | 一种n-取代二苯并咔唑类化合物的制备方法 |
CN113548999B (zh) * | 2020-04-24 | 2023-04-28 | 复旦大学 | 消旋和手性3-(2,3-丁二烯基)氧化吲哚酮类化合物及制备方法及应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1729181A (zh) * | 2002-10-23 | 2006-02-01 | 格兰马克药品有限公司 | 可用于治疗炎性和变应性病症的新的三环化合物,它们的制备方法以及包含它们的药物组合物 |
CN103183691A (zh) * | 2011-12-29 | 2013-07-03 | 昆山维信诺显示技术有限公司 | 含有取代或非取代咔唑基的6-均三甲苯基-6H-6-硼杂苯并[cd]芘衍生物及制备方法及应用及含其的发光器件 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20140111214A (ko) * | 2013-03-08 | 2014-09-18 | 에스에프씨 주식회사 | 유기발광 화합물 및 이를 포함하는 유기전계발광소자 |
KR102147424B1 (ko) * | 2013-03-08 | 2020-08-25 | 에스에프씨 주식회사 | 유기발광 화합물 및 이를 포함하는 유기전계발광소자 |
-
2015
- 2015-10-23 CN CN201510698778.9A patent/CN106588749B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1729181A (zh) * | 2002-10-23 | 2006-02-01 | 格兰马克药品有限公司 | 可用于治疗炎性和变应性病症的新的三环化合物,它们的制备方法以及包含它们的药物组合物 |
CN103183691A (zh) * | 2011-12-29 | 2013-07-03 | 昆山维信诺显示技术有限公司 | 含有取代或非取代咔唑基的6-均三甲苯基-6H-6-硼杂苯并[cd]芘衍生物及制备方法及应用及含其的发光器件 |
Non-Patent Citations (2)
Title |
---|
Amino-Directed RhIII-Catalyzed C-H Activation Leading to One-Pot Synthesis of N-H Carbazoles;Qibai Jiang et al.;《Chem. Eur. J.》;20130107;第19卷;1903-1907 |
联烯的一些亲电加成及环化反应研究;郭彬杰;《中国博士学位论文全文数据库 工程科技Ⅰ辑》;20140815;B014-22 |
Also Published As
Publication number | Publication date |
---|---|
CN106588749A (zh) | 2017-04-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2283841C2 (ru) | Азолильные производные хинолина и хиназолина, содержащая их фармацевтическая композиция, их применение и способ лечения заболеваний | |
EP2539335B1 (en) | Process for the preparation of isoxazoline derivatives | |
EP2235015B1 (fr) | Derives de carboxam i d es azabicycliques, leur preparation et leur application en therapeutique. | |
EP2948147B1 (en) | N-substituted-5-substituted phthalamic acids as sortilin inhibitors | |
CN104822672B (zh) | 治疗性化合物和组合物以及其作为pkm2调节剂的用途 | |
CN106068265B (zh) | 用于治疗代谢病症的二氢吡啶酮mgat2抑制剂 | |
CN105339350B (zh) | 二氢吡啶酮mgat2抑制剂 | |
BR112014013228B1 (pt) | arila di-hidropiridinona e piperidinona, composição farmacêutica e uso como inibidores de mgat2 | |
TW200904804A (en) | Imidazolidinecarboxamide derivatives as inhibitors of lipases and phospholipases | |
CN106588749B (zh) | 多取代咔唑类化合物及其合成方法和应用 | |
KR20130065728A (ko) | Ahr 활성화제로서의 1,2-디히드로-4-히드록시-2-옥소-퀴놀린-3-카르복사닐리드 | |
Mali et al. | Synthesis of some antifungal and anti-tubercular 1, 2, 4-triazole analogues | |
CN107935910B (zh) | 含1′-茚醇拼接3-氧化吲哚类化合物及其制备方法及应用 | |
EP3247360B1 (en) | Heterocyclic inhibitors of monocarboxylate transporters | |
KR102537615B1 (ko) | 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 유도체 화합물 및 이를 포함하는 약제학적 조성물 | |
CN103626826B (zh) | 含偶氮键的糖原磷酸化酶抑制剂胆酸类衍生物、其制备方法及医药用途 | |
CN115232126B (zh) | 一种β-卡波林-1,2,3-三唑化合物及其制备方法与抗阿尔兹海默病的应用 | |
CA2974696A1 (en) | Pteridine dione monocarboxylate transporter inhibitors | |
CN107200731B (zh) | 一种含噻唑环吡啶酮衍生物及其制备方法和应用 | |
JP3012684B2 (ja) | チエノキノリン誘導体、チエノナフチリジン誘導体およびそれらの塩 | |
Zahra et al. | Synthesis of amantadine clubbed N-aryl amino thiazoles as potent urease, α-amylase & α-glucosidase inhibitors, kinetic and molecular docking studies | |
CN102311398A (zh) | 三氮唑类化合物及其制备方法和在制备组蛋白去乙酰化酶i抑制剂中的应用 | |
EP2396319A1 (fr) | Derives de 3-benzofuranyl-indol-2-one-3-acetamidopiperazines substitues, leur preparation et leur application en therapeutique | |
CA3088968A1 (en) | Dihydroindolizinone derivative | |
CN112939991B (zh) | 一种多取代螺四氢咔唑及其衍生物及其合成方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |