CN104610253B - 2‑三氟甲基‑2‑羟基‑2‑(2‑芳基吡啶并[1,2‑α]咪唑)乙酸酯类化合物 - Google Patents
2‑三氟甲基‑2‑羟基‑2‑(2‑芳基吡啶并[1,2‑α]咪唑)乙酸酯类化合物 Download PDFInfo
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- FHUDAMLDXFJHJE-UHFFFAOYSA-N 1,1,1-trifluoropropan-2-one Chemical compound CC(=O)C(F)(F)F FHUDAMLDXFJHJE-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 21
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 34
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- 125000004185 ester group Chemical group 0.000 claims description 6
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- 238000000034 method Methods 0.000 claims description 4
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- 239000003863 metallic catalyst Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
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- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 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
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- 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
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- 229960001475 zolpidem Drugs 0.000 description 2
- YKEDVZKOLMCTAQ-UHFFFAOYSA-N 2-(4-methylphenyl)imidazo[1,2-a]pyridine Chemical class C1=CC(C)=CC=C1C1=CN(C=CC=C2)C2=N1 YKEDVZKOLMCTAQ-UHFFFAOYSA-N 0.000 description 1
- XIYPPJVLAAXYAB-UHFFFAOYSA-N 2-bromo-6-phenylpyridine Chemical compound BrC1=CC=CC(C=2C=CC=CC=2)=N1 XIYPPJVLAAXYAB-UHFFFAOYSA-N 0.000 description 1
- YTAGJMFBUAHVDP-UHFFFAOYSA-N 2-chloro-6-phenylpyridine Chemical compound ClC1=CC=CC(C=2C=CC=CC=2)=N1 YTAGJMFBUAHVDP-UHFFFAOYSA-N 0.000 description 1
- AXSUBWDOWSHTSC-UHFFFAOYSA-N 2-fluoro-6-phenylpyridine Chemical compound FC1=CC=CC(C=2C=CC=CC=2)=N1 AXSUBWDOWSHTSC-UHFFFAOYSA-N 0.000 description 1
- PSLAETIWKCTIGM-UHFFFAOYSA-N 2-iodo-6-phenylpyridine Chemical compound IC1=CC=CC(C=2C=CC=CC=2)=N1 PSLAETIWKCTIGM-UHFFFAOYSA-N 0.000 description 1
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
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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
Abstract
本发明公开了一种2‑三氟甲基‑2‑羟基‑2‑(2‑芳基吡啶并[1,2‑α]咪唑)丙酸酯类化合物极其制备方法,在无水无氧条件下,将2‑芳基吡啶并[1,2‑α]咪唑和三氟丙酮酸酯加入反应容器中,再加入二异丙基醚,将反应瓶在氩气环境下、0~60℃反应10~48小时;反应结束后减压浓缩,进行色谱分离,得目标产物。采用三氟甲基砌块的方式,合成了在医药领域常见的三氟甲基官能团,所得化合物带有羟基,脂基,方便进一步的成盐反应,为以后药物方向的应用解决了溶解性问题,所得化合物结构中的吡啶并[1,2‑α]咪唑基团具有良好的药物活性,该反应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2-三氟甲基-2-羟基-2-(2-芳基吡啶并[1,2-α]咪唑)乙酸酯类化合物及其制备方法。
背景技术
吡啶并咪唑是一类具有非常重要而且常见的氮杂环化合物[1]。其衍生物具有很好的生物活性:例如,抗病毒、抗溃疡和抗菌性。在此基础上,科研工作者对其进行了广泛的研究,通过探讨其构效关系,逐渐了解其性质。并将其广泛应用于药物结构中,由此产生了许多具有各种生物活性的吡啶并咪唑衍生物。其中有几类药物已经成功的上市,比如抗焦虑药物Alpidem(阿吡坦), Saripidem(沙立吡旦),麻醉药Necopidem(奈可吡旦)和镇静催眠药Zolpidem(唑吡坦)等。
三氟甲基(CF3)能够显著改变有机化合物的性质,继而改变其活性,毒性和稳定性,因此三氟甲基化合物在医药,农药和材料等领域获得广泛的关注。然而天然产物中含有三氟甲基的化合物非常少见,因此如何有效的构筑含三氟甲基化合物具有重要的意义。
发明内容
本发明的目的是提供一种2-三氟甲基-2-羟基-2-(2-芳基吡啶并[1,2-α]咪唑)乙酸酯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2-三氟甲基-2-羟基-2-(2-芳基吡啶并[1,2-α]咪唑)乙酸酯类化合物,其特征在于:该化合物的结构通式为:
其中R1为H,卤素,三氟甲基,烷基、烷氧基和酯基;R2为H,卤素,三氟甲基,烷基、烷氧基和酯基;R3为烷基。
一种2-三氟甲基-2-羟基-2-(2-芳基吡啶并[1,2-α]咪唑)乙酸酯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-芳基吡啶并[1,2-α]咪唑和三氟丙酮酸酯加入反应容器中,再加入二异丙基醚,将反应瓶在氩气环境下、0~60℃反应10~48小时;
(2)反应结束后减压浓缩,进行色谱分离,得目标产物。
所述2-芳基吡啶并[1,2-α]咪唑的通式为:
三氟丙酮酸酯的通式为:
其中:R1为H,卤素,三氟甲基,烷基、烷氧基和酯基;
R2为H,卤素,三氟甲基,烷基、烷氧基和酯基;
R3为烷基。
所述步骤(1)中2-芳基吡啶并[1,2-α]咪唑与三氟丙酮酸酯的物质的量比为1:1 ~5,以1 mmol 2-芳基吡啶并[1,2-α]咪唑为基准,二异丙基醚的用量为1~5 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0~100:100~0。
本发明的有益效果:本发明为合成2-三氟甲基-2-羟基-2-(2-芳基吡啶并[1,2-α]咪唑)乙酸酯类化合物提供了一条简便、易行的方法;该合成路线采用三氟甲基砌块的方式,有效的合成了在医药领域常见的三氟甲基官能团,利于该化合物在动物体内的代谢循环。所得化合物带有羟基,脂基,方便进一步的成盐反应,为以后药物方向的应用解决了溶解性问题。所得化合物结构中的吡啶并[1,2-α]咪唑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
下面结合具体实施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2-三氟甲基-2-羟基-2-(2-苯基吡啶并[1,2-α]咪唑基)乙酸乙酯的结构式为:
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-苯基吡啶并[1,2-a]咪唑,0.2 mmol的三氟丙酮酸乙酯,1 mL二异丙醚。25℃反应10小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为99%。m.p. = 164-165℃ 1H NMR (400 MHz, CDCl3): δ 8.78 (dd, J = 7.2, 0.8Hz, 1H), 7.56 (d, J =9.2Hz, 1H), 8.78 (s, 5H), 7,27 (ddd, J = 6.8, 5.2, 1.2Hz, 1H), 6.82 (td, J =7.2, 1.2Hz, 1H), 3.64 (dq, J = 7.2, 10.8Hz, 1H), 3.10 (dq, J = 7.2, 10.8Hz,1H), 0.92 (t, J = 7.2Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.7, 146.8, 145.6,134.1, 130.1, 128.53, 128.47, 126.1, 123.7, (q, J C-F = 284.7Hz), 117.2,112.7, 112.5, 76.4 (q, J C-F = 31.6Hz), 63.5, 13.2. 19F NMR (376 MHz, CDCl3): δ-74.1. HRMS (positive ESI): [M+H]+ calcd for C18H16 F3N2O3 +: 365.1108. Found:365.1106.
实施例2
本实施例的化合物2-三氟甲基-2-羟基-2-(7-甲基-2-苯基吡啶并[1,2-α]咪唑基)乙酸乙酯的结构式为:
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-苯基吡啶并[1,2-a ]咪唑,0.1 mmol的三氟丙酮酸乙酯,1 mL二异丙醚。40℃反应10小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为99%。 m.p.= 193-194℃. H NMR (400 MHz, DMSO-d 6): δ 8.71 (d, J = 7.2Hz, 1H), 8.65 (s,1H, -OH ), 7.43 - 7.36 (m, 6H), 8.78 (s, 5H), 6.89 (dd, J = 7.2, 1.6Hz, 1H),3.46 (dq, J = 7.2, 10.8Hz, 1H), 3.13 (dq, J = 7.2, 10.8Hz, 1H), 2.39 (s, 3H),0.88 (t, J = 7.2Hz, 3H). 13C NMR (100 MHz, DMSO-d 6): δ 164.9, 146.2, 145.5,136.7, 134.1, 129.6, 128.7, 127.5, 124.5 (q, J C-F = 285.2Hz), 115.0, 114.9,111.9, 76.1 (q, J C-F = 29.4Hz), 61.8, 20.5, 13.1. 19F NMR (376 MHz, DMSO-d 6):δ -74.5. HRMS (positive ESI): [M+H]+ calcd for C19H18F3N2O3 +: 379.1264. Found:379.1263.
实施例3
本实施例的化合物2-三氟甲基-2-羟基-2-(6-氟-2-苯基吡啶并[1,2-α]咪唑基)乙酸乙酯的结构式为:
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-苯基吡啶并[1,2-a]咪唑,0.3 mmol的三氟丙酮酸乙酯,2 mL二异丙醚。60℃反应24小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为99%。m.p. =202-203℃. 1H NMR (400 MHz, DMSO-d 6 ): δ 8.86(s, 1H, -OH), 8.82 (d, J = 3.2Hz,1H), 7.78 (dd, J = 10.0, 5.6Hz, 1H), 7.59 – 7.54 (m, 1H), 7.46 – 7.40 (m,5H), 3.48 (dq, J = 10.8, 7.2Hz, 1H), 3.16 (dq, J = 10.8, 7.2Hz, 1H), 0.89 (t,J = 7.2Hz, 3H). 13C NMR (100 MHz, DMSO-d 6 ): δ 164.4, 152.0 (d, J C-F= 231.8Hz),147.6, 142.9, 133.6, 129.5, 128.7, 127.7, 124.3 (q, J C-F = 285.0Hz), 118.0(d, J C-F = 25.7Hz), 117.8 (d, J C-F = 9.4Hz), 115.2 (d, J C-F = 41.8Hz), 114.1,75.8 (q, J C-F = 29.3Hz), 62.0, 13.0. 19F NMR (376 MHz, DMSO-d 6 ): δ -74.6, -139.6. HRMS (positive ESI): [M+H]+ calcd for C18H15F4N2O3 +: 383.1013. Found:383.1005.
实施例4
本实施例的化合物2-三氟甲基-2-羟基-2-(6-氯-2-苯基吡啶并[1,2-α]咪唑基)乙酸乙酯的结构式为:
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-苯基吡啶并[1,2-a]咪唑,0.3 mmol的三氟丙酮酸乙酯,1 mL二异丙醚。60℃反应30小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为91%。m.p. = 210- 211℃ 1H NMR (400 MHz, DMSO-d 6 ) δ 8.92 (s, 1H, -O H ), 8.89 (s, 1H), 7.76(d, J = 9.6Hz, 1H), 7.53 (dd, J = 9.6, 2.0Hz, 1H), 7.46 – 7.45 (m, 3H), 7.41– 7.38 (m, 2H), 3.48 (dq, J = 10.8, 7.2Hz, 1H), 3.16 (dq, J = 10.8, 7.2Hz,1H), 0.89 (t, J = 7.2Hz, 3H). 13C NMR (100 MHz, DMSO-d 6 ) δ 164.5, 147.4,143.5, 133.4, 129.5, 128.5, 127.8, 127.0, 125.9, 124.8 (q, J C-F = 284.9Hz),119.4, 113.4, 75.9 (q, J C-F = 29.5Hz), 62.1, 13.0. 19F NMR (376 MHz, DMSO-d 6 ):δ -74.6. HRMS (positive ESI): [M+H]+ calcd for C18H16ClF3N2O3 +: 399.0718. Found:399.0697.
实施例5
本实施例的化合物2-三氟甲基-2-羟基-2-(6-溴-2-苯基吡啶并[1,2-α]咪唑基)乙酸乙酯的结构式如下:
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-苯基吡啶并[1,2-a] 咪唑,0.5 mmol的三氟丙酮酸乙酯,5 mL二异丙醚。60℃反应40小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为91%。m.p. =214 - 215℃. 1H NMR (400 MHz, DMSO-d 6): δ 8.97 (s, 1H), 8.92 (s, 1H, -OH),7.71(d, J = 9.6Hz, 1H), 7.60 (dd, J = 9.6, 1.6Hz, 1H), 7.46 – 7.38 (m, 5H), 3.48(dq, J = 10.8, 7.2Hz, 1H), 3.15 (dq, J = 10.8, 7.2Hz, 1H), 0.89 (t, J =7.2Hz, 3H). 13C NMR (100 MHz, DMSO-d 6 ) δ 164.5, 147.2, 143.5, 133.3, 129.5,129.0, 128.5, 128.0, 127.7, 124.3 (q, J C-F = 285.5Hz) 76.0 (q, J C-F = 29.3Hz),62.1, 13.0. 19F NMR (376 MHz, DMSO-d 6 ): δ -74.6. HRMS (positive ESI): [M+H]+calcd for C18H16BrF3N2O3 +: 433.0213. Found: 433.0210.
实施例6
本实施例的化合物2-三氟甲基-2-羟基-2-(6-碘-2-苯基吡啶并[1,2-α]咪唑基)乙酸乙酯的结构式如下:
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-碘-2-苯基吡啶并[1,2-a]咪唑,0.5 mmol的三氟丙酮酸乙酯,5 mL二异丙醚。60℃反应48小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为95%。M.p. = 210– 211℃. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.06 (s, 1H), 8.87 (s, 1H, -OH), 7.63(dd, J = 9.2, 1.6Hz, 1H), 7.55 (d, J = 9.2Hz, 1H), 7.45 – 7.37 (m, 5H), 3.48(dq, J = 10.8, 7.2Hz, 1H), 3.14 (dq, J = 10.8, 7.2Hz, 1H), 0.88 (t, J =7.2Hz, 3H). 13C NMR (100 MHz, DMSO-d 6 ) δ 164.5, 146.7, 143.6, 133.5, 133.4,132.7, 129.6, 128.5, 127.7, 124.4 (q, J C-F= 284.7Hz), 118.4, 112.7, 112.6,75.9 (q, J C-F = 29.4Hz), 62.0, 13.0. 19F NMR (376 MHz, DMSO-d 6 ): δ -74.6. HRMS(positive ESI): [M+H]+ calcd for C18H16IF3N2O3 +: 491.0074. Found: 491.0068.
实施例7
本实施例的化合物2-三氟甲基-2-羟基-2-{2-(2`-噻吩)-吡啶并[1,2-α]咪唑基}乙酸乙酯的结构式如下:
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)-吡啶并[1,2-a ]咪唑,0.2 mmol的三氟丙酮酸乙酯,2 mL二异丙醚。室温反应10小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为99%。M.p. =198 - 199℃. 1H NMR (400 MHz, DMSO-d 6 ): δ 8.89 (s, 1H, -OH), 8.84 (d, J =7.2Hz, 1H), 7.70 (d, J = 5.2Hz, 1H), 7.68 (d, J = 9.2Hz, 1H), 7.43 (dd, J =8.4, 7.2Hz, 1H), 7.13 – 7.03 (m, 3H), 3.78 (dq, J = 10.8, 7.2Hz, 1H), 3.48(dq, J = 10.8, 7.2Hz, 1H), 0.93 (t, J = 7.2Hz, 3H). 13C NMR (100 MHz, DMSO-d 6 )δ 164.8, 145.1, 136.9, 135.6, 128.6, 128.3, 127.4, 127.0, 126.4, 124.5 (q,J C-F = 284.6Hz), 116.8, 112.8, 112.5, 76.2 (q, J C-F = 29.5Hz), 62.2, 13.2. 19FNMR (376 MHz, DMSO-d 6 ): δ -75.4. HRMS (positive ESI): [M+H]+ calcd forC16H14F3N2O3S+: 371.0672. Found: 371.0671.
实施例8
本实施例的化合物2-三氟甲基-2-羟基-2-{2-(2`-呋喃)-吡啶并[1,2-α]咪唑基}乙酸乙酯的结构式如下:
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)-吡啶并[1,2-a]咪唑,0.2 mmol的三氟丙酮酸乙酯,1 mL二异丙醚。室温反应10小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为80%。M.p. =183 - 184℃. 1H NMR (400 MHz, CDCl3): δ 14.02 (brs, 1H), 8.66 (d, J = 8.0Hz,1H), 8,53 (dd, J = 4.8, 0.8Hz, 1H), 8.06 (d, J = 7.2Hz, 1H), 7.95 (td, J =7.6, 1.6Hz, 1H), 7.70 (d, J = 5.2Hz, 1H), 7.37 – 7.30 (m, 2H), 6.87 (dt, J =7.2, 1.2Hz, 1H), 4.40 – 4.28 (m, 2H), 1.97 (t, J = 7.2Hz, 3H). 13C NMR (100MHz, CDCl3) δ 167.4, 151.5, 145.6, 145.4, 143.8, 139.0, 125.9, 125.2, 125.1,124.4 (q, J C-F = 286.2Hz), 124.3, 123.3, 118.9, 118.3, 113.7, 76.5 (q, J C-F =30.2Hz), 64.0, 13.9. 19F NMR (376 MHz, CDCl3): δ -77.8. HRMS (positive ESI):[M+H]+ calcd for C17H15F3N3O3 +: 366.1060. Found: 366.1058.
实施例9
本实施例的化合物2-三氟甲基-2-羟基-2-{2-(2`-吡啶)-吡啶并[1,2-α]咪唑基}乙酸乙酯的结构式如下:
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`-吡啶)-吡啶并[1,2-a]咪唑,0.2 mmol的三氟丙酮酸乙酯,1 mL二异丙醚。室温反应10小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为99%。M.p. =183 - 184℃. 1H NMR (400 MHz, CDCl3): δ 14.02 (brs, 1H), 8.66 (d, J = 8.0Hz,1H), 8,53 (dd, J = 4.8, 0.8Hz, 1H), 8.06 (d, J = 7.2Hz, 1H), 7.95 (td, J =7.6, 1.6Hz, 1H), 7.70 (d, J = 5.2Hz, 1H), 7.37 – 7.30 (m, 2H), 6.87 (dt, J =7.2, 1.2Hz, 1H), 4.40 – 4.28 (m, 2H), 1.97 (t, J = 7.2Hz, 3H). 13C NMR (100MHz, CDCl3) δ 167.4, 151.5, 145.6, 145.4, 143.8, 139.0, 125.9, 125.2, 125.1,124.4 (q, J C-F = 286.2Hz), 124.3, 123.3, 118.9, 118.3, 113.7, 76.5 (q, J C-F =30.2Hz), 64.0, 13.9. 19F NMR (376 MHz, CDCl3): δ -77.8. HRMS (positive ESI):[M+H]+ calcd for C17H15F3N3O3 +: 366.1060. Found: 366.1058.
实施例10
本实施例的化合物2-三氟甲基-2-羟基-2-{2-(3,5-二甲基-苯基)吡啶并[1,2-α]咪唑基}乙酸乙酯的结构式如下:
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-(3,5-二甲基-苯基)吡啶并[1,2-a]咪唑,0.2 mmol的三氟丙酮酸乙酯,2 mL二异丙醚。0℃反应10小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为99%。M.p. = 181 - 182℃. H NMR (400 MHz, DMSO-d 6): δ 8.83 (d, J = 6.8Hz, 1H), 8.66(s, 1H, -OH), 7.65 (d, J = 9.2Hz, 1H), 7.41 (dt, J = 8.0, 0.8Hz, 1H), 7.06– 6.99 (m, 4H), 3.51 (dq, J = 10.8, 7.2Hz, 1H), 3.10 (dq, J = 10.8, 7.2Hz,1H), 2.03 (s, 6H), 0.88 (t, J = 7.2Hz, 3H). 13C NMR (100 MHz, DMSO-d 6 ): δ164.8, 146.7, 145.0, 136.5, 133.8, 129.4, 128.7, 127.3, 126.0, 124.5 (q, J C-F= 282.6Hz), 116.8, 112.4, 76.1 (q, J C-F = 28.7Hz), 61.9, 20.8, 13.0. 19F NMR(376 MHz, DMSO-d 6): δ -74.5. HRMS (positive ESI): [M+H]+ calcd for C20H20F3N2O3 +: 393.1421. Found: 393.1419.
实施例11
本实施例的化合物2-三氟甲基-2-羟基-2-{2-(4-甲基-苯基)吡啶并[1,2-α]咪唑基}乙酸乙酯的结构式如下:
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-甲基-苯基)吡啶并[1,2-a ]咪唑,0.2 mmol的三氟丙酮酸乙酯,1 mL二异丙醚。室温反应10小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为99%。M.p. = 165 - 166℃. H NMR (400 MHz, DMSO-d 6) δ 8.83 (d, J = 7.2Hz, 1H), 8.67(s, 1H, -OH), 7.41 (ddd, J = 8.8, 6.8, 0.8Hz, 1H), 7.26 (q, J = 8.0Hz, 3H),7.03 (dt, J = 7.2, 1.2Hz, 1H), 3.50 (dq, J = 10.8, 7.2Hz, 1H), 3.17 (dq, J =10.8, 7.2Hz, 1H), 2.36 (s, 3H), 0.90 (t, J = 7.2Hz, 3H). 13C NMR (100 MHz,DMSO-d 6): δ 146.9, 146,5, 145.0, 137.6, 131.1, 129.5, 128.6, 128.1, 126.0,124.5 (q, J C-F = 285.6Hz), 116.8, 112.4, 76.2 ((q, J C-F = 29.2Hz), 61.9, 20.8,13.1. 19F NMR (400MHz, DMSO-d 6): δ -74.5. HRMS (positive ESI): [M+H]+ calcdfor C19H18 F3N2O3 +: 379.1264. Found: 379.1259.
实施例12
本实施例的化合物2-三氟甲基-2-羟基-2-{2-(4-甲氧基-苯基)吡啶并[1,2-α]咪唑基}乙酸乙酯的结构式如下:
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-甲氧基-苯基)吡啶并[1,2-a]咪唑,0.2 mmol的三氟丙酮酸乙酯,1 mL二异丙醚。室温反应10小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为99%。M.p.= 188 - 189℃. H NMR (400 MHz, DMSO-d 6): δ 8.83 (d, J = 7.2Hz, 1H), 8.67 (s,1H, -OH), 7.40 (t, J = 8.0Hz, 1H), 7.32 (d, J = 8.8Hz, 2H), 7.03 (dd, J =7.2, 0.8Hz, 1H), 7.00 (d, J = 8.8Hz, 2H), 3.80 (dq, J = 10.8, 7.2Hz, 1H),3.25 (dq, J = 10.8, 7.2Hz, 1H), 0.92 (t, J = 7.2Hz, 3H). 13C NMR (100 MHz,DMSO-d 6): δ 165.0, 159.3, 146.3, 145.0, 130.9, 128.6, 126.2, 125.9, 124.5 (q,J C-F = 284.6Hz), 116.8, 113.0, 112.34, 112.30, 76.2 (q, J C-F = 29.3Hz), 62.0,55.2, 13.1. 19F NMR (376 MHz, DMSO-d 6): δ -74.6. HRMS (positive ESI): [M+H]+calcd for C19H18F3N2O4 +: 395.1213. Found: 395.1208.
实施例13
本实施例的化合物2-三氟甲基-2-羟基-2-{2-(4-氟-苯基)吡啶并[1,2-α]咪唑基}乙酸乙酯的化学式如下:
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-氟-苯基)吡啶并[1,2-a]咪唑,0.2 mmol的三氟丙酮酸乙酯,1 mL二异丙醚。室温反应10小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为99%。 M.p. = 175 - 176℃. 1H NMR (400 MHz, DMSO-d 6): δ 8.84 (d, J = 7.2Hz, 1H), 8.87 (s, 1H, -OH),7.76 (d, J = 9.2Hz, 1H), 7.45 -7.41 (m, 3H), 7.28 (t, J = 8.8Hz, 2H), 7.06(t, J = 6.8Hz, 1H), 3.58 (dq, J = 10.8, 7.2Hz, 1H), 3.27 (dq, J = 10.8,7.2Hz, 1H), 0.94 (t, J = 7.2Hz, 3H). 13C NMR (100 MHz, DMSO-d 6): δ 164.9,162.1 (d, J C-F = 243.7Hz), 145.4, 145.0, 131.8 ((d, J C-F = 3.0Hz), 128.6, 126.2,124.4 ((q, J C-F = 285.1Hz), 116.9, 114.5 (d, J C-F = 81.3Hz), 112.6, 76.1 ((d,J C-F = 29.1Hz), 62.0, 13.1. 19F NMR (376 MHz, DMSO-d 6): δ -74.6, -113.4. HRMS(positive ESI): [M+H]+ calcd for C18H15F4N2O3 +: 383.1013. Found: 383.1007.
实施例14
本实施例的化合物2-三氟甲基-2-羟基-2-{2-(4-氯-苯基)吡啶并[1,2-α]咪唑基}乙酸乙酯的结构式如下:
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0.1mmol的2-(4-甲氧基-苯基)吡啶并[1,2-a]咪唑,0.2 mmol的三氟丙酮酸乙酯,1 mL二异丙醚。60℃反应24小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为99%。 M.p. = 187 – 188℃. 1H NMR (400 MHz, DMSO-d 6): δ 8.84 (d, J = 7.2Hz, 1H),8.77 (s, 1H, -OH ), 7.68 (d, J = 9.2Hz, 1H), 7.52 (d, J = 0.84Hz, 2H), 7.45(dd, J = 6.8, 0.8Hz, 1H), 7.41 (d, J = 0.84Hz, 2H), 7.06 (dt, J = 7.2, 1.2Hz,1H), 3.59 (dq, J = 10.8. 7.2Hz, 1H), 3.28 (dq, J = 10.8. 7.2Hz, 1H), 0.94 (t,J = 7.2Hz, 3H). 13C NMR (100 MHz, DMSO-d 6): δ 164.9, 145.2, 145.1, 133.3,132.8, 131.4, 128.6, 127.7, 126.3, 124.4 (q, J C-F = 285.3Hz), 116.9, 112.7,76.1 (q, J C-F = 29.3Hz), 62.1, 13.1. 19F NMR (376 MHz, DMSO-d 6): δ -74.6. HRMS(positive ESI): [M+H]+ calcd for C18H15F3N2O3Cl+: 399.0718. Found: 399.0714.
实施例15
本实施例的化合物2-三氟甲基-2-羟基-2-(2-苯基吡啶并[1,2-α]咪唑基)乙酸乙酯的结构式为:
制备方法为:在标准真空线无水无氧操作下,往50 mL的史莱克管中加入3.0 mmol的2-苯基吡啶并[1,2-a]咪唑,6.0 mmol的三氟丙酮酸乙酯,30 mL二异丙醚。室温反应10小时,有白色不溶物析出,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0/100至100/0),得目标产品白色固体,产率为99%。
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 (3)
1.一种2-三氟甲基-2-羟基-2-(2-芳基吡啶并[1,2-α]咪唑)乙酸酯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-芳基吡啶并[1,2-α]咪唑和三氟丙酮酸酯加入反应容器中,再加入二异丙基醚,将反应瓶在氩气环境下、0~60℃反应10~48小时;
(2)反应结束后减压浓缩,进行色谱分离,得目标产物;
所述2-三氟甲基-2-羟基-2-(2-芳基吡啶并[1,2-α]咪唑)丙酸酯类化合物的结构通式为:
;
所述2-芳基吡啶并[1,2-α]咪唑的通式为:
,
三氟丙酮酸酯的通式为:
;
其中:R1为H,卤素,三氟甲基,烷基、烷氧基和酯基;
R2为H,卤素,三氟甲基,烷基、烷氧基和酯基;
R3为烷基。
2.根据权利要求1所述的2-三氟甲基-2-羟基-2-(2-芳基吡啶并[1,2-α]咪唑)乙酸酯类化合物的制备方法,其特征在于:所述步骤(1)中2-芳基吡啶并[1,2-α]咪唑与三氟丙酮酸酯的物质的量比为1:1~5,以0.1 mmol 2-芳基吡啶并[1,2-α]咪唑为基准,二异丙基醚的用量为1~5 mL。
3.根据权利要求1所述的2-三氟甲基-2-羟基-2-(2-芳基吡啶并[1,2-α]咪唑基)乙酸酯类化合物的制备方法,其特征在于: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0~100:100~0。
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