CN105085520B - 3‑(2‑硝基‑1‑苯乙基)‑2‑(2‑苯基咪唑并[1,2‑α]吡啶)类化合物 - Google Patents
3‑(2‑硝基‑1‑苯乙基)‑2‑(2‑苯基咪唑并[1,2‑α]吡啶)类化合物 Download PDFInfo
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- -1 nitro, 1 phenethyl Chemical group 0.000 title abstract description 22
- 150000004941 2-phenylimidazoles Chemical class 0.000 title abstract description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 80
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000007445 Chromatographic isolation Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- 239000003208 petroleum Substances 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000004185 ester group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 150000003222 pyridines Chemical class 0.000 claims 3
- PIAOLBVUVDXHHL-VOTSOKGWSA-N β-nitrostyrene Chemical compound [O-][N+](=O)\C=C\C1=CC=CC=C1 PIAOLBVUVDXHHL-VOTSOKGWSA-N 0.000 claims 1
- 230000004071 biological effect Effects 0.000 abstract description 4
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- 238000012986 modification Methods 0.000 abstract description 2
- 230000004048 modification Effects 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 238000000926 separation method Methods 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 238000010828 elution Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- JRTIDHTUMYMPRU-UHFFFAOYSA-N alpidem Chemical compound N1=C2C=CC(Cl)=CN2C(CC(=O)N(CCC)CCC)=C1C1=CC=C(Cl)C=C1 JRTIDHTUMYMPRU-UHFFFAOYSA-N 0.000 description 2
- 229950008673 alpidem Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- YRMLUAGKHYADKJ-UHFFFAOYSA-N necopidem Chemical compound C1=CC(CC)=CC=C1C1=C(CN(C)C(=O)CC(C)C)N2C=C(C)C=CC2=N1 YRMLUAGKHYADKJ-UHFFFAOYSA-N 0.000 description 2
- 229950002306 necopidem Drugs 0.000 description 2
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 2
- 229960001475 zolpidem Drugs 0.000 description 2
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 1
- GLJATYFHELDGEA-UHFFFAOYSA-N 1-chloro-4-(2-nitroethenyl)benzene Chemical class [O-][N+](=O)C=CC1=CC=C(Cl)C=C1 GLJATYFHELDGEA-UHFFFAOYSA-N 0.000 description 1
- JSPNBERPFLONRX-UHFFFAOYSA-N 1-methyl-4-(2-nitroethenyl)benzene Chemical compound CC1=CC=C(C=C[N+]([O-])=O)C=C1 JSPNBERPFLONRX-UHFFFAOYSA-N 0.000 description 1
- ZYRFCMKGPPUPFC-UHFFFAOYSA-N 2-(2-methylphenyl)-1h-imidazole-5-carboxylic acid Chemical class CC1=CC=CC=C1C1=NC=C(C(O)=O)N1 ZYRFCMKGPPUPFC-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- IXVCTTCVYGDFSO-UHFFFAOYSA-N 5-bromo-2-phenyl-1h-imidazole Chemical class BrC1=CNC(C=2C=CC=CC=2)=N1 IXVCTTCVYGDFSO-UHFFFAOYSA-N 0.000 description 1
- UKDAHYRLJGMRDQ-UHFFFAOYSA-N 5-chloro-2-phenyl-1h-imidazole Chemical class N1C(Cl)=CN=C1C1=CC=CC=C1 UKDAHYRLJGMRDQ-UHFFFAOYSA-N 0.000 description 1
- QCMGVJDUEYTLHF-UHFFFAOYSA-N FC=1N=C(NC1)C1=CC=CC=C1 Chemical class FC=1N=C(NC1)C1=CC=CC=C1 QCMGVJDUEYTLHF-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- BAXLBXFAUKGCDY-UHFFFAOYSA-N mebendazole Chemical compound [CH]1C2=NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CC=C1 BAXLBXFAUKGCDY-UHFFFAOYSA-N 0.000 description 1
- 229960003439 mebendazole Drugs 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种3‑(2‑硝基‑1‑苯乙基)‑2‑(2‑苯基咪唑并[1,2‑α]吡啶)类化合物及其制备方法,该化合物的结构通式为:,制备方法如下:在无水无氧条件下,将2‑芳基咪唑并[1,2‑α]吡啶和β‑硝基苯乙烯加入叔丁醇中,在氩气环境下、80℃反应12~24小时,反应结束后减压浓缩,进行色谱分离,得到目标产物。所得化合物结构中的咪唑并[1,2‑α]吡啶基团本身就具有良好的药物活性,经过修饰后的结构,可为其在生物活性方面的研究提供技术支持。另外该反应过程中不使用金属催化剂及添加剂,易于纯化,成本低廉。
Description
技术领域
本发明属于有机化合物合成及应用技术领域,具体涉及一种3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)类化合物及其制备方法。
背景技术
吡啶并咪唑及其衍生物是一类非常重要的氮杂环化合物。其结构存在于很多的天然产物和医用药物中,表现出较高的生物活性和药用潜力。在不断深入研究的基础上,科研工作者开发出了各种吡啶并咪唑衍生物。目前有几类吡啶并咪唑衍生物作为医药已经成功上市,比如镇静催眠药Zolpidem(唑吡坦),抗焦虑药物Alpidem(阿吡坦)和麻醉药Necopidem(奈可吡旦)等。如今,如何更方便快捷的制备吡啶并咪唑衍生物及开发其药用性已经成为人们的研究热点。
硝基苯乙烯类化合物不仅具有杀菌、抗肿瘤等生物活性,而且还是应用广泛的有机合成中间体,由于其结构中存在强吸电子基硝基,使得其易与亲电或亲核试剂发生加成反应。大量的科研成果表明,硝基化合物除了本身具有很广泛的用途外,而且还可以很灵活的转变为其他化合物,如胺、酮、醛等。
发明内容
本发明的目的是提供一种3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)类化合物及其制备方法,该方法简单易行、成本低且产物易于纯化。
为实现上述目的,本发明采用以下技术方案:
一种3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)类化合物,其特征在于:该化合物的结构通式为:
其中R1为H、卤素、烷基、烷氧基或酯基;R2为H、卤素、烷基、烷氧基、三氟甲基或酯基;R3为H、卤素、烷基或烷氧基。
一种3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)类化合物的制备方法,包括下述步骤:
(1)在无水无氧条件下,将2-芳基咪唑并[1,2-α]吡啶和2-硝基苯乙烯加入叔丁醇中,在氩气环境下、80℃反应12~24小时;
(2)反应结束后减压浓缩,进行色谱分离,得到目标产物。
所述2-芳基咪唑并[1,2-α]吡啶的通式为:
β-硝基苯乙烯的通式为:
其中:R1为H、卤素、烷基、烷氧基或酯基;
R2为H、卤素、烷基、烷氧基、三氟甲基或酯基;
R3为H、卤素、烷基或烷氧基。
所述步骤(1)中2-芳基咪唑并[1,2-α]吡啶与β-硝基苯乙烯的物质的量比为1:1~3,以0.1 mmol 2-芳基咪唑并[1,2-α]吡啶为基准,叔丁醇的用量为1~2 mL。
所述步骤(2)中色谱分离所用的洗脱剂为乙酸乙酯和石油醚按体积比为0~3:6~0混合。
本发明的有益效果:本发明为合成3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)类化合物提供了一条简便、易行的方法。所得化合物结构中的咪唑并[1,2-α]吡啶基团本身就具有良好的药物活性,经过修饰后的结构,可为其在生物活性方面的研究提供技术支持。另外该反应过程中不使用金属催化剂及添加剂,易于纯化,成本低廉。
具体实施方式
下面结合具体实例对本发明作进一步描述,在此发明的示意性实施例以及说明用来解释本发明,但并不作为对本发明的限定。
实施例1
本实施例化合物3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的2-苯基咪唑并[1,2-α]吡啶,0.2 mmol的β-硝基苯乙烯,2mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至1/3),得目标产品棕色固体,产率为99%。m.p. = 90 - 91℃. 1H NMR (600 MHz,CDCl3): δ 7.72 (d, J = 6.6 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.62 (d, J =6.6 Hz, 1H), 7.46 – 7.41 (m, 3H), 7.37 – 7.30 (m, 3H), 7.27 – 7.20 (m, 3H),6.74 (t, J = 6.6 Hz, 1H), 5.62 (t, J = 7.8 Hz, 1H), 5.08 (dd, J = 13.2, 7.8Hz, 1H), 4.96 (dd, J = 13.2, 7.8 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ145.5,145.2, 136.1, 134.4, 129.6, 129.2, 128.6, 128.5, 128.2, 126.9, 124.8, 123.3,118.1, 116.7, 112.8, 76.6, 39.3. HRMS (positive ESI): [M+H]+ calcd forC21H18N3O2 +: 344.1394. Found: 344.1397。
实施例2
本实施例化合物7-甲基-3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的7-甲基-2-苯基咪唑并[1,2-α]吡啶,0.2mmol的β-硝基苯乙烯,1mL叔丁醇。80℃反应12小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至2/5),得目标产品棕色固体,产率为99%。m.p. = 81 - 82℃. 1H NMR (600 MHz,CDCl3): δ7.61 - 7.58 (m, 3H), 7.45 - 7.39 (m, 4H), 7.35 – 7.29 (m, 3H), 7.20(d, J = 7.8 Hz, 2H), 7.56 (dd, J = 7.2, 1.2 Hz, 1H), 5.59 (t, J = 7.8 Hz,1H), 5.07 (dd, J = 13.2, 7.8 Hz, 1H), 4.95 (dd, J = 13.2, 7.8 Hz, 1H). 13C NMR(150 MHz, CDCl3): δ 145.7, 145.1, 136.3, 134.4, 129.5, 129.2, 128.6, 128.4,128.1, 126.9, 122.6, 116.4, 116.0, 115.5, 76.6, 39.2, 21.2. HRMS (positiveESI): [M+H]+calcd for: C22H20N3O2 +: 358.1550. Found: 358.1557。
实施例3
本实施例化合物7-甲氧基-3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的7-甲氧基-2-苯基咪唑并[1,2-α]吡啶,0.2 mmol的β-硝基苯乙烯,1mL叔丁醇。80℃反应18小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至2/5),得目标产品棕色固体,产率为99%。m.p. = 70 - 72℃. 1H NMR (600MHz, CDCl3) δ7.61 (dd, J = 6.6, 1.8 Hz, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.45 -7.38 (m, 3H), 7.36 - 7.29 (m, 3H), 7.20 (d, J = 7.8 Hz, 2H), 6.44 (dd, J =7.8, 2.4 Hz, 1H), 5.56 (t, J = 7.8 Hz, 1H), 5.06 (dd, J = 13.2, 7.8 Hz, 1H),4.93 (dd, J = 13.2, 7.8 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 158.0, 146.8,144.9, 136.3, 134.4, 129.5, 129.1, 128.6, 128.4, 128.2, 126.9, 123.9, 115.4,107.8, 95.2, 76.7, 55.6, 39.2. HRMS (positive ESI): [M+H]+calcd for: C22H20N3O4 +: 374.1499. Found: 374.1504。
实施例4
本实施例化合物6-氟-3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的6-氟-2-苯基咪唑并[1,2-α]吡啶,0.2 mmol的β-硝基苯乙烯,1mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至1/4),得目标产品棕色固体,产率为93%。m.p. = 77 -78℃. 1H NMR (600 MHz,CDCl3): δ7.68 – 7.64 (m, 2H), 7.47 – 7.43 (m, 3H), 7.39 – 7.33 (m, 3H), 7.21(d, J = 7.2 Hz, 2H), 7.15 (dt, J = 7.8, 1.8 Hz, 1H), 5.55 (t, J = 7.8 Hz,1H), 5.05 (dd, J = 13.2, 7.8 Hz, 1H), 4.95 (dd, J = 13.2, 7.8 Hz, 1H). 13C NMR(150 MHz, CDCl3): δ153.3 (d, J C-F = 236.7 Hz), 146.7, 142.8, 135.5, 133.9,129.7, 129.2, 128.8, 128.7, 128.5, 126.9 118.6 (d, J C-F = 9.0 Hz), 118.1,116.9 (d, J C-F = 22.5 Hz), 110.2 (d, J C-F = 40.5 Hz), 76.2, 39.3. 19F NMR (565MHz, CDCl3): δ-138.1. HRMS (positive ESI): [M+H]+ calcd for C21H17FN3O2 +:362.1299. Found: 362.1304。
实施例5
本实施例化合物6-氯-3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的6-氯-2-苯基咪唑并[1,2-α]吡啶,0.1 mmol的β-硝基苯乙烯,1mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至1/4),得目标产品棕色固体,产率为57%。m.p. = 77 - 78℃. 1H NMR (600 MHz,CDCl3): δ 7.76 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 9.6 Hz, 1H), 7.58 (dd, J =7.2, 1.8 Hz, 2H), 7.47 - 7.43 (m, 3H), 7.40 - 7.33 (m, 3H), 7.21 – 7.18 (m,3H), 5.58 (t, J = 7.8 Hz, 1H), 5.04 (dd, J = 13.2, 7.8 Hz, 1H), 4.95 (dd, J =13.2, 7.8 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ146.4, 143.5, 135.5, 133.8,129.7, 129.2, 128.8, 128.7, 128.5, 126.9, 126.3, 121.1, 118.4, 117.4, 76.3,39.2. HRMS (positive ESI): [M+H]+ calcd for: C21H17ClN3O2 +: 378.1004. Found:378.1009。
实施例6
本实施例化合物6-溴-3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的6-溴-2-苯基咪唑并[1,2-α]吡啶,0.2 mmol的β-硝基苯乙烯,1mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至1/5),得目标产品棕色固体,产率为54%。m.p. = 56 - 57℃. 1H NMR (600 MHz,CDCl3) δ 7.87 (s, 1H), 7.58 (d, J = 8.4 Hz, 3H), 7.44 (d, J = 6.0 Hz, 3H),7.39 - 7.33 (m, 3H), 7.28 (d, J = 9.6 Hz, 1H), 7.19 (d, J = 7.2 Hz, 2H), 5.56(t, J = 7.8 Hz, 1H), 5.04 (dd, J = 13.2, 7.8 Hz, 1H), 4.95 (dd, J = 13.2, 7.8Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 146.1, 134.6, 135.5, 133.8, 129.7, 129.2,128.8, 128.7, 128.5, 128.4, 126.9, 123.3, 118.7, 117.3, 107.7, 76.3, 39.2.HRMS (positive ESI): [M+H]+ calcd for: C21H17BrN3O2 +: 422.0499. Found: 422.0502。
实施例7
本实施例化合物6-甲基羧基-3-(2-硝基-1-苯乙基)-2-(2-苯基咪唑并[1,2-α]吡啶)的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的6-甲基羧基-2-苯基咪唑并[1,2-α]吡啶,0.2 mmol的β-硝基苯乙烯,1mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至2/5),得目标产品棕色固体,产率为40%。 m.p. = 112 - 114℃. 1H NMR(600 MHz, CDCl3): δ 8.49 (s, 1H), 7.70 (dd, J = 9.6, 1.2 Hz, 1H), 7.60 (d, J= 9.6 Hz, 1H), 7.53 (d, J = 7.8 Hz, 2H), 7.39 (d, J = 6.0 Hz, 3H), 7.32 -7.25 (m, 3H), 7.15 (d, J = 7.8 Hz, 2H), 5.58 (t, J = 7.8 Hz, 1H), 5.02 (dd, J= 13.2, 7.8 Hz, 1H), 4.92 (dd, J = 13.2, 7.8 Hz, 1H).13C NMR (150 MHz, CDCl3):δ 165.1, 147.0, 145.7, 135.7, 133.7, 129.7, 129.2, 129.0, 128.7, 128.5,127.4, 126.9, 124.5, 118.0, 117.3, 116.9, 76.3, 52.6, 39.1.HRMS (positiveESI): [M+H]+ calcd for: C23H20N3O4 +: 402.1488. Found: 402.1454。
实施例8
本实施例化合物3-(2-硝基-1-苯乙基)-2-对甲苯咪唑并[1,2-α]吡啶的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的2-对甲苯基咪唑并[1,2-α]吡啶,0.3 mmol的β-硝基苯乙烯,1mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至1/3),得目标产品棕色固体,产率为99%。m.p. = 107 - 108℃. 1H NMR (600MHz, CDCl3) δ7.71 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.51 (d, J =7.8 Hz, 2H), 7.36 - 7.29 (m, 3H), 7.26 (d, J = 8.4 Hz, 2H), 7.21 - 7.19 (m,3H), 6.72 (dt, J = 6.6, 1.2 Hz, 1H), 5.61 (t, J = 7.8 Hz, 1H), 5.08 (dd, J =13.2, 7.8 Hz, 1H), 4.96 (dd, J = 13.2, 7.8 Hz, 1H), 2.41 (s, 3H). 13C NMR (150MHz, CDCl3): δ 145.5, 145.2, 138.4, 136.2, 131.3, 129.5, 129.4, 129.1, 128.2,126.9, 124.7, 123.3, 118.0, 116.5, 112.7, 76.7, 39.3, 21.4. HRMS (positiveESI): [M+H]+ calcd for: C22H20N3O2 +: 358.1550. Found: 358.1558。
实施例9
本实施例化合物2-(4-叔丁基苯基)3-(2-硝基-1-苯乙基)咪唑并[1,2-α]吡啶的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的2-(4-叔丁基)咪唑并[1,2-α]吡啶,0.2 mmol的β-硝基苯乙烯,1mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至6/0),得目标产品棕色固体,产率为99%。m.p. = 110 - 112℃. 1H NMR (600MHz, CDCl3) δ7.71 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.57 (d, J =8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.34 - 7.27 (m, 3H), 7.20 - 7.17 (m,3H), 7.00 (t, J = 6.6 Hz, 1H), 5.64 (t, J = 7.8 Hz, 1H), 5.12 (dd, J = 13.2,7.8 Hz, 1H), 4.97 (dd, J = 13.2, 7.8 Hz, 1H), 1.35 (s, 9H). 13C NMR (150 MHz,CDCl3): δ 151.5, 145.4, 145.2, 136.2, 131.3, 129.5, 128.8, 128.1, 126.9,125.6, 124.7, 123.3, 118.0, 116.6, 112.7, 76.7, 39.3, 34.7, 31.3. HRMS(positive ESI): [M+H]+ calcd for: C25H26N3O2 +: 400.2020. Found: 400.2026。
实施例10
本实施例化合物2-(2-呋喃)-3-(2-硝基-1-苯乙基)咪唑并[1,2-α]吡啶的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的2-(2-呋喃)咪唑并[1,2-α]吡啶,0.2 mmol的β-硝基苯乙烯,1mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至1/3),得目标产品棕色油状物,产率为91%。1H NMR (600 MHz, CDCl3): δ7.77(d, J = 7.8 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.34- 7.27 (m, 5H), 7.18 (dt, J = 7.8, 1.2 Hz, 1H), 6.98 (d, J = 3.0 Hz, 1H),6.70 (dt, J = 6.6, 1.2 Hz, 1H), 5.56 (dd, J = 3.6, 1.8 Hz, 1H), 5.92 (t, J =7.8 Hz, 1H), 5.34 (dd, J = 13.2, 7.8 Hz, 1H), 5.18 (dd, J = 13.2, 7.8 Hz,1H). 13C NMR (150 MHz, CDCl3): δ149.1, 145.5, 142.6, 136.0, 135.7, 129.3,128.0, 127.1, 125.3, 123.4, 117.8, 116.9, 112.9, 111.9, 109.6, 76.6, 38.9.HRMS (positive ESI): [M+H]+ calcd for C19H16N3O3 +: 334.1186. Found: 334.1193。
实施例11
本实施例化合物2-(2-噻吩)-3-(2-硝基-1-苯乙基)咪唑并[1,2-α]吡啶的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的2-(2-噻吩)咪唑并[1,2-α]吡啶,0.2 mmol的β-硝基苯乙烯,1mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至1/4),得目标产品棕色油状物,产率为99%。1H NMR (600 MHz, CDCl3): δ7.68(d, J = 7.2 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.41 (dd, J = 4.8, 0.6 Hz,1H), 7.34 - 7.27 (m, 5H), 7.21 (d, J = 7.8 Hz, 2H), 7.17 (dt, J = 7.8, 1.2Hz, 1H), 7.09 (dd, J = 4.8, 3.6 Hz, 1H), 6.67 (dt, J = 6.6, 0.6 Hz, 1H), 5.84(t, J = 7.8 Hz, 1H), 5.26 (dd, J = 13.2, 7.8 Hz, 1H). 5.06 (dd, J = 13.2, 7.8Hz, 1H). 13C NMR (150 MHz, CDCl3): δ145.3, 139.0, 136.4, 135.5, 129.5, 128.2,127.7, 126.9, 126.8, 126.4, 125.2, 123.4, 118.0, 116.7, 113.0, 75.7, 38.9.HRMS (positive ESI): [M+H]+ calcd for C19H16N3O2S+: 350.0958 Found: 350.0965。
实施例12
本实施例化合物3-(2-硝基-1-(对甲苯基)乙基)-2-苯基咪唑并[1,2-α]吡啶的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的2-苯基咪唑并[1,2-α]吡啶,0.15mmol的β-硝基-4-甲基苯乙烯,1mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至1/3),得目标产品棕色油状物,产率为99%。1H NMR (600 MHz, CDCl3): δ7.72(d, J = 7.2 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 6.6 Hz, 2H), 7.45- 7.39 (m, 3H), 7.19 (ddd, J = 9.0, 6.6, 1.2 Hz, 1H), 7.15 (d, J = 7.8 Hz,2H), 7.08 (d, J = 7.8 Hz, 2H), 6.72 (dt, J = 6.6, 1.2 Hz, 1H), 5.57 (t, J =7.8 Hz, 1H), 5.05 (dd, J = 13.2, 7.8 Hz, 1H). 4.94 (dd, J = 13.2, 7.8 Hz,1H),2.31 (s, 3H). 13C NMR (150 MHz, CDCl3): δ145.4, 145.2, 138.0, 134.4,132.9, 130.2, 129.2, 128.6, 128.5, 126.8, 124.8, 123.5, 118.0, 116.8, 112.8,76.6, 40.0, 21.0. HRMS (positive ESI): [M+H]+ calcd for C22H20N3O2 +: 358.1550.Found: 358.1559。
实施例13
本实施例化合物3-(2-硝基-1-(对氟苯基)乙基)-2-苯基咪唑并[1,2-α]吡啶的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的2-苯基咪唑并[1,2-α]吡啶,0.2 mmol的β-硝基-4-氟苯乙烯,2mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至1/3),得目标产品棕色油状物,产率为99%。1H NMR (600 MHz, CDCl3): δ7.71(d, J = 7.2 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 6.0 Hz, 2H), 7.47- 7.42 (m, 3H), 7.24 (dt, J = 7.8, 0.6 Hz, 1H), 7.17 (dd, J = 8.4, 4.8 Hz,2H), 7.04 (t, J = 8.4Hz, 2H), 6.78 (t, J = 6.0 Hz, 1H), 5.57 (t, J = 7.8 Hz,1H), 5.03 (dd, J = 13.2, 7.8 Hz, 1H). 4.93 (dd, J = 13.2, 7.8 Hz, 1H). 13C NMR(150 MHz, CDCl3): δ162.3 (d, J C-F = 247.1 Hz), 145.4, 145.2, 134.2, 131.9,129.2, 128.71, 128.67, 125.0, 123.2, 118.2, 116.5 (d, J C-F = 21.3 Hz), 116.52,113.0, 76.7, 38.7. 19F NMR (565 MHz, CDCl3): δ-113.3. HRMS (positive ESI): [M+H]+ calcd for C21H17FN3O2 +: 362.1299. Found: 362.1308。
实施例14
本实施例化合物3-(2-硝基-1-(对氯苯基)乙基)-2-苯基咪唑并[1,2-α]吡啶的结构式为:
制备方法为:在标准真空线无水无氧操作下,往10 mL的史莱克管中加入0.1 mmol的2-苯基咪唑并[1,2-α]吡啶,0.2 mmol的β-硝基-4-氯苯乙烯,1mL叔丁醇。80℃反应24小时,将溶剂减压除去,柱色谱分离(硅胶200-300目,洗脱剂:乙酸乙酯/石油醚梯度淋洗,比例由0/6至1/3),得目标产品棕色固体,产率为99%。m.p. = 99 - 101℃. 1H NMR (600MHz, CDCl3): δ7.70 - 7.67 (m, 2H), 7.58 (d, J = 6.0 Hz, 2H), 7.46 - 7.42 (m,3H), 7.32 (d, J = 8.4 Hz, 2H), 7.23 (dt, J = 7.8, 1.2 Hz, 1H), 7.13 (d, J =8.4 Hz, 2H), 6.77 (dt, J = 6.6, 1.2 Hz, 1H), 5.57 (t, J = 7.8 Hz, 1H), 5.03(dd, J = 13.2, 7.8 Hz, 1H), 4.93 (dd, J = 13.2, 7.8 Hz, 1H). 13C NMR (150 MHz,CDCl3): δ 145.5, 145.3, 134.7, 134.2, 134.1, 129.7, 129.2, 128.7, 128.3,125.1, 123.1, 118.2, 116.2, 113.1, 76.5, 38.8. HRMS (positive ESI): [M+H]+calcd for C21H17ClN3O2 +: 378.1004. Found: 378.1010。
本发明的技术方案不限于上述具体实施例的限制,凡是根据本发明的技术方案做出的技术变形,均落入本发明的保护范围之内。
Claims (4)
1.一种3-(2-硝基-1-苯乙基)-2-(2-芳基咪唑并[1,2-α]吡啶)类化合物的制备方法,其特征在于包括下述步骤:
(1)在无水无氧条件下,将2-芳基咪唑并[1,2-α]吡啶和β-硝基苯乙烯加入叔丁醇中,在氩气环境下、80℃反应12~24小时;
(2)反应结束后减压浓缩,进行色谱分离,得到目标产物;所述
3-(2-硝基-1-苯乙基)-2-(2-芳基咪唑并[1,2-α]吡啶)类化合物的结构通式为:
其中R1为H、卤素、烷基、烷氧基或酯基;R2为H、卤素、烷基、烷氧基、三氟甲基或酯基;R3为H、卤素、烷基或烷氧基。
2.根据权利要求1所述的3-(2-硝基-1-苯乙基)-2-(2-芳基咪唑并[1,2-α]吡啶)类化合物的制备方法,其特征在于:所述2-芳基咪唑并[1,2-α]吡啶的通式为:
β-硝基苯乙烯的通式为:
其中:R1为H、卤素、烷基、烷氧基或酯基;
R2为H、卤素、烷基、烷氧基、三氟甲基或酯基;
R3为H、卤素、烷基或烷氧基。
3.根据权利要求1所述的3-(2-硝基-1-苯乙基)-2-(2-芳基咪唑并[1,2-α]吡啶)类化合物的制备方法,其特征在于:所述步骤(1)中2-芳基咪唑并[1,2-α]吡啶与2-硝基苯乙烯的物质的量比为1:1~3,以0.1 mmol 2-芳基咪唑并[1,2-α]吡啶为基准,叔丁醇的用量为1~2 mL。
4.根据权利要求1所述的3-(2-硝基-1-苯乙基)-2-(2-芳基咪唑并[1,2-α]吡啶)类化合物的制备方法,所述步骤(2)中色谱分离所用的洗脱剂为乙酸乙酯和石油醚按体积比为0~3:6~0混合。
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