CN107163036A - 一种含噻唑环5,6‑二取代吡啶‑2‑酮化合物及其制备方法 - Google Patents

一种含噻唑环5,6‑二取代吡啶‑2‑酮化合物及其制备方法 Download PDF

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CN107163036A
CN107163036A CN201710435689.4A CN201710435689A CN107163036A CN 107163036 A CN107163036 A CN 107163036A CN 201710435689 A CN201710435689 A CN 201710435689A CN 107163036 A CN107163036 A CN 107163036A
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thiazole ring
disubstituted pyridines
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谢文林
刘仁志
梅期宏
张金改
吴乙强
张慧霖
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Hunan University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached

Abstract

本发明公开了一种含噻唑环5,6‑二取代吡啶‑2‑酮化合物及其合成方法。该含噻唑环5,6‑二取代吡啶‑2‑酮化合物如式(I)所示，式（I）中，取代基R是H、C1‑6的烷基、F、Cl、Br、I、烷氧基、羟基、腈基、硝基、羧基和磺酸基。本发明通过三步反应合成目标产物，合成方法简洁、快速，符合原子经济性，且目标化合物收率较高，为进一步研究式（I）化合物或相关化合物提供了必要基础。

Description

一种含噻唑环5,6-二取代吡啶-2-酮化合物及其制备方法
技术领域
本发明涉及有机化学合成领域，具体涉及一种含噻唑环5,6-二取代吡啶-2-酮化合物及其制备方法。
背景技术
吡啶酮衍生物是存在于自然界的一类重要杂环化合物, 吡啶酮环广泛存在于天然生物碱和具有各种生物活性的合成化合物分子中。越来越多的研究表明吡啶酮类化合物具有消炎、镇痛、抗肿瘤和治疗帕金森氏症等药理活性。如3-羟基-4(1H)-吡啶酮由于它具有很强的配位能力，其衍生物1,2-二甲基-3-羟基-4(1H)-吡啶酮 (deferiprone, 去铁酮)临床上用于治疗地中海贫血患者由于输血导致铁超负荷症；4-羟基-2(1H)-吡啶酮类化合物是从植物和动物等内生菌的发酵液中分离提取得到的一类新型天然生物碱[如Tenellin, Funiculosin 和冬青生菌素H (IlicicolinH)等], 同时也是一类重要的药物及其合成中间体, 如抗真菌药环吡酮胺(Ciclopirox)、抗肿瘤药吉莫斯特(Gimeracil)等, 都含有4-羟基-2(1H)-吡啶酮的结构母核。因此开发简捷、高效合成吡啶酮衍生物的方法显得尤为重要。
发明内容
本发明的目的在于提供一种含噻唑环5,6-二取代吡啶-2-酮化合物及其制备方法。
本发明采用的技术方案：一种含噻唑环5,6-二取代吡啶-2-酮化合物，其化学结构式如式（I）所示：
式（I）中，取代基R是H、C1-6的烷基、F、Cl、Br、I、烷氧基、羟基、腈基、硝基、羧基或磺酸基。
一种含噻唑环5,6-二取代吡啶-2-酮化合物的制备方法，包括如下步骤：
(1) 中间产物1的制备
将2,3-二羟基吡啶溶于无水甲醇中，加入磷酸盐缓冲溶液，碘酸钠以及芳香胺于 容器中，室温下搅拌，TLC跟踪反应进程，待反应结束后加入大量的蒸馏水，静置过夜后，过滤得砖红色沉淀；将沉淀干燥，经柱层析得中间产物1；
(2) 中间产物2的制备:
取中间产物1、硫代氨基脲分别依次溶于无水乙醇中，室温下搅拌均匀，逐滴滴加浓硫酸，然后于65 ℃条件下反应，TLC跟踪反应进程，待反应完全后；趁热将反应液倒入容器中，加入蒸馏水，静置，过滤得橘黄色沉淀(中间产物2)；此中间产物2不需进一步纯化直接用于下一步合成；
(3) 目标化合物的制备
将中间产物2、2-溴苯乙酮和酸催化剂溶于无水乙醇中，所述中间产物2、2-溴苯乙酮和酸催化剂的物质的量之比为1∶2∶0.1，60-80℃下搅拌，TLC 跟踪反应进程，待反应完全，停止反应，将反应物冷却至室温，减压旋蒸除去溶剂，残留物进行柱层析，得到(I)式所示的目标化合物含噻唑环5,6-二取代吡啶-2-酮化合物。
以上各化合物均以反应式中各化合物下面序号加以区分，其中，R是H、C1-6的烷基、F、Cl、Br、I、烷氧基、羟基、腈基、硝基、羧基或磺酸基。
作为优选，步骤( 3 )中，所述的酸催化剂为冰乙酸。
作为优选，步骤( 3 )中，反应温度为65℃。
本发明采用氧化-迈克加成一锅法高效地合成了中间产物1，然后将中间产物1与氨基硫脲缩合得到中间产物2，此中间产物2不需进一步纯化可直接用于下一步目标化合物的合成，该合成方法简洁、快速，符合原子经济性，且目标化合物收率高，为进一步研究式I化合物或相关化合物提供了必要基础。
具体实施方式
以下通过具体实施例对本发明做进一步地详细说明，但不应将此理解为本发明上述主题的范围仅限于以下的实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
本发明所用仪器与试剂：
核磁共振仪：Bruker AV-II 500MHz NMR，TMS为内标，CDCl3为溶剂；红外光谱仪：
TFS-40型，KBr压片；熔点仪：XT-4型熔点测定仪。
所用试剂均为市售化学纯或分析纯。
本发明化合物制备途径如下：
3a: R=m-Cl; 3b: R=o-Cl; 3c: R=p-Cl; 3d: R=p-CH3; 3e: R=m-CH3; 3f：R=p-OCH3;
3g: R=o-OCH3; 3h: R=H; 3i: R=m-Br; 3j: R=o-CH3; 3k: R=p-Br; 3l: R=m-OCH3
(1)中间体化合物1a-1l的合成：
将 10mmol 2,3-二羟基吡啶溶于 20ml 的无水甲醇中，加入30ml的磷酸盐缓冲溶液，15mmol 氧化剂碘酸钠以及20mmol芳香胺于 150ml 的锥形瓶中，室温下搅拌，TLC跟踪反应进程，待反应结束后加入大量的蒸馏水，静置过夜后，过滤得砖红色沉淀。将沉淀干燥，经柱层析得中间产物1a-1l。
(2) 中间体化合物2a-2l的制备:
取4mmol 的中间产物1，5mmol 硫代氨基脲分别依次溶于 10 ml 的无水乙醇中，室温下搅拌均匀，逐滴滴加浓硫酸(0.15mL)，然后将反应移入油浴锅中，反应温度设为 65 ℃，TLC跟踪反应进程，待反应完全后。趁热将反应液倒入 250mL 锥形瓶中，加入 200mL 的蒸馏水，静置3~4个小时，过滤得中间产物 2a-2l。
(3) 目标化合物3的制备:
将中间产物2、2-溴丙酮和酸催化剂溶于无水乙醇中，所述中间产物2、2-溴丙酮和酸催化剂的物质的量之比为1∶2∶0.1，60-80℃下搅拌，TLC跟踪反应进程，待反应完全，停止反应，将反应物冷却至室温，减压旋蒸除去溶剂，残留物进行柱层析，得到(I)式所示的目标化合物3，即含噻唑环5,6-二取代吡啶-2-酮化合物。
3a, 5,6-二间氯苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 黄色固体，产率68％, 1H NMR (500 MHz, CDCl3) δ 13.56 (s, 1H), 8.07 (s, 1H), 7.82 (d, J =7.3 Hz, 2H), 7.42 – 7.36 (m, 3H), 7.34 – 7.30 (m, 2H), 7.27 (s, 1H), 7.23 (s,1H), 7.20 – 7.18 (m, 1H), 7.15 – 7.12 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.02(s, 1H), 6.96 (s, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.74 (s, 1H); 13C NMR (125MHz, CDCl3) δ 166.42 , 158.84 , 152.53 , 146.72 , 142.49 , 141.06 , 135.89 ,135.26 , 134.39 , 131.32 , 130.83 , 130.64 , 128.72 , 128.07 , 128.01 ,126.01 , 125.41 , 123.35 , 121.14 , 120.59 , 118.99 , 118.65 , 105.98 ,105.77; ESI MS m/z: 533 (M+H)+.
3b, 5,6-二邻氯苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 黄色固体，产率72％, 1H NMR (500 MHz, CDCl3) δ 13.57 (s, 1H), 7.94 (s, 1H), 7.84 – 7.81 (m,2H), 7.75 (s, 1H), 7.56 – 7.54 (m, 1H), 7.52 – 7.50 (m, 1H), 7.48 – 7.46 (m,1H), 7.42 – 7.39 (m, 2H), 7.38 – 7.35 (m, 1H), 7.35 – 7.31 (m, 2H), 7.18 –7.14 (m, 1H), 7.06 – 7.03 (m, 1H), 7.02 – 6.99 (m, 2H), 6.76 (s, 1H); 13C NMR(125 MHz, CDCl3) δ 166.48 , 158.86 , 152.49 , 142.62 , 142.55 , 136.77 ,134.37 , 130.84 , 130.79 , 130.29 , 128.73 , 128.25 , 128.20 , 128.08 ,127.71 , 126.27 , 126.03 , 125.96 , 125.76 , 123.70 , 122.07 , 120.75 ,105.88 , 105.71; ESI MS m/z: 533 (M+H)+.
3c, 5,6-二对氯苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 棕黑色固体，产率57％,1H NMR (500 MHz, CDCl3) δ 13.54 (s, 1H), 8.16 (s, 1H), 7.80 (d, J = 7.4Hz, 2H), 7.40 (d, J = 8.3 Hz, 3H), 7.38 – 7.33 (m, 3H), 7.32 – 7.28 (m, 1H),7.23 (s, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.00 (s, 1H), 6.88 (d, J = 8.3 Hz,2H), 6.65 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 166.52 , 158.94 , 152.47 ,143.96 , 142.39 , 138.29 , 134.40 , 131.42 , 130.70 , 130.32 , 129.68 ,128.71 , 128.44 , 128.21 , 128.05 , 125.99 , 122.24 , 105.83 , 104.81 ,29.71; ESI MS m/z: 533 (M+H)+.
3d, 5,6-二对甲苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 棕黑色固体，产率53％, 1H NMR (500 MHz, CDCl3) δ 13.51 (s, 1H), 8.09 (s, 1H), 7.82 (d, J =7.5 Hz, 2H), 7.41 – 7.38 (m, 2H), 7.32 – 7.29 (m, 1H), 7.25 (s, 1H), 7.23 (d,J = 4.6 Hz, 3H), 7.21 (s, 1H), 7.17 (d, J = 8.2 Hz, 2H), 6.98 (s, 1H), 6.85(d, J = 8.0 Hz, 2H), 6.62 (s, 1H), 2.38 (d, J = 3.8 Hz, 6H); 13C NMR (125 MHz,CDCl3) δ 166.83 , 159.10 , 152.37 , 142.83 , 142.04 , 137.04 , 134.90 ,134.55 , 133.39 , 132.58 , 130.78 , 130.12 , 128.93 , 128.65 , 127.93 ,125.99 , 121.70 , 120.59 , 105.40 , 103.22 , 29.70 , 20.93 , 20.90; ESI MS m/z: 493 (M+H)+.
3e, 5,6-二间甲苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 紫色固体，产率52％,1H NMR (500 MHz, CDCl3) δ 13.55 (s, 1H), 8.05 (s, 1H), 7.82 (d, J = 7.5Hz, 2H), 7.42 – 7.38 (m, 2H), 7.33 (d, J = 7.9 Hz, 1H), 7.32 – 7.28 (m, 3H),7.10 (d, J = 7.9 Hz, 1H), 7.06 (s, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.99 (s,1H), 6.94 (d, J = 7.4 Hz, 1H), 6.74 (d, J = 12.0 Hz, 2H), 6.70 (s, 1H), 2.39(d, J = 3.4 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 166.78 , 159.09 , 152.41 ,145.48 , 141.98 , 140.29 , 139.68 , 139.58 , 134.52 , 132.07 , 130.06 ,129.37 , 128.84 , 128.67 , 127.96 , 126.05 , 125.99 , 124.38 , 121.93 ,121.22 , 118.14 , 117.62 , 105.49 , 103.91 , 21.55 , 21.49; ESI MS m/z: 493(M+H)+.
3f, 5,6-二对甲氧苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 紫色固体，产率67％, 1H NMR (500 MHz, CDCl3) δ 13.50 (s, 1H), 8.14 (s, 1H), 7.81 (d, J =7.4 Hz, 2H), 7.41 – 7.38 (m, 2H), 7.32 – 7.28 (m, 1H), 7.21 (d, J = 8.8 Hz,2H), 7.11 (s, 1H), 6.99 (s, 1H), 6.98 – 6.96 (m, 3H), 6.95 (s, 1H), 6.90 (d,J = 8.7 Hz, 2H), 6.44 (s, 1H), 3.84 (d, J = 1.3 Hz, 6H); 13C NMR (125 MHz,CDCl3) δ 166.90 , 159.19 , 157.22 , 156.51 , 152.37 , 142.03 , 138.36 ,134.58 , 133.66 , 132.48 , 129.10 , 128.67 , 127.94 , 126.00 , 124.30 ,121.96 , 115.54 , 114.87 , 105.33 , 102.47 , 55.61 , 55.58 , 26.93; ESI MS m/z: 525 (M+H)+.
3g, 5,6-二邻甲氧苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 紫色固体，产率61％, 1H NMR (500 MHz, CDCl3) δ 13.56 (s, 1H), 8.09 (s, 1H), 7.82 (d, J =7.6 Hz, 2H), 7.42 – 7.38 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 2.8Hz, 1H), 7.31 – 7.29 (m, 2H), 6.99 (s, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.80(s, 1H), 6.76 (d, J = 5.6 Hz, 2H), 6.67 (d, J = 8.1 Hz, 1H), 6.54 – 6.49 (m,2H), 3.85 (s, 3H), 3.84 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.74 , 161.19 ,160.71 , 159.02 , 152.42 , 146.81 , 142.22 , 141.05 , 134.51 , 131.62 ,131.12 , 130.35 , 128.68 , 127.98 , 126.02 , 113.31 , 112.69 , 110.89 ,108.63 , 106.96 , 106.64 , 105.64 , 104.85 , 55.40 , 29.72; ESI MS m/z: 525(M+H)+.
3h, 5,6-二苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 棕黑色固体，产率57％, 1H NMR (500 MHz, CDCl3) δ 13.54 (s, 1H), 8.06 (s, 1H), 7.83 (d, J = 1.3Hz, 1H), 7.81 (s, 1H), 7.48 – 7.42 (m, 3H), 7.41 (s, 1H), 7.39 (d, J = 8.1Hz, 2H), 7.34 – 7.29 (m, 2H), 7.28 (s, 1H), 7.27 (s, 1H), 7.24 – 7.20 (m,1H), 7.14 – 7.11 (m, 1H), 6.99 (s, 1H), 6.96 (d, J = 7.4 Hz, 2H), 6.74 (s,1H); 13C NMR (125 MHz, CDCl3) δ 166.76 , 159.06 , 145.49 , 142.08 , 139.77 ,134.50 , 131.92 , 130.27 , 129.63 , 128.96 , 128.89 , 128.70 , 128.00 ,126.02 , 125.29 , 123.49 , 121.12 , 120.76 , 105.59 , 104.12; ESI MS m/z: 465(M+H)+.
3i, 5,6-二间溴苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 紫色固体，产率62％, 1H NMR (500 MHz, CDCl3) δ 13.61 (s, 1H), 8.04 – 7.98 (m, 1H), 7.84 –7.81 (m, 2H), 7.42 – 7.39 (m, 3H), 7.37 – 7.35 (m, 1H), 7.33 – 7.30 (m, 2H),7.26 (d, J = 1.6 Hz, 2H), 7.24 – 7.22 (m, 1H), 7.21 – 7.19 (m, 1H), 7.14 –7.12 (m, 1H), 7.02 (s, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.74 (s, 1H); 13C NMR(125 MHz, CDCl3) δ 190.29 , 165.53 , 157.79 , 145.78 , 140.13 , 132.95 ,130.50 , 129.87 , 127.92 , 127.85 , 127.71 , 127.30 , 127.14 , 125.34 ,125.00 , 122.91 , 122.84 , 122.59 , 122.23 , 118.42 , 118.15 , 104.85 , 29.89, 28.68 ; ESI MS m/z: 620 (M+H)+.
3j, 5,6-二邻甲苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 红色固体，产率71％, 1H NMR (500 MHz, CDCl3) δ 13.50 (s, 1H), 7.98 (s, 1H), 7.81 – 7.79 (m,2H), 7.40 – 7.36 (m, 3H), 7.31 (d, J = 5.4 Hz, 2H), 7.30 – 7.27 (m, 3H), 7.19(s, 1H), 7.14 – 7.12 (m, 1H), 7.12 – 7.09 (m, 1H), 6.96 (s, 1H), 6.84 (d, J =7.4 Hz, 1H), 6.39 (s, 1H), 2.32 (s, 3H), 2.18 (s, 3H); 13C NMR (125 MHz,CDCl3) δ 166.84 , 159.20 , 152.39 , 143.99 , 141.58 , 137.96 , 134.54 ,132.75 , 131.56 , 131.52 , 131.28 , 129.70 , 128.96 , 128.68 , 127.97 ,127.44 , 127.02 , 126.02 , 125.36 , 124.62 , 122.86 , 119.69 , 105.46 ,103.26 , 17.86 , 17.84 ; ESI MS m/z: 493 (M+H)+.
3k, 5,6-二对溴苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 紫色固体，产率50％, 1H NMR (500 MHz, CDCl3) δ 13.58 (s, 1H), 8.03 – 7.98 (m, 1H), 7.81 (d, J= 7.3 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.42 –7.39 (m, 2H), 7.32 (d, J = 7.3 Hz, 1H), 7.24 (s, 1H), 7.14 (d, J = 8.7 Hz,2H), 7.01 (s, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.69 (s, 1H); 13C NMR (125 MHz,CDCl3) δ 166.53 , 158.83 , 138.79 , 133.32 , 132.63 , 128.95 , 128.88 ,128.72 , 128.09 , 126.01 , 122.59 , 122.53 , 118.47 , 115.94 , 105.84 ,105.01 , 31.93 , 29.70 , 22.70 , 14.13; ESI MS m/z: 620 (M+H)+.
3l, 5,6-二间甲氧苯胺基-3-(4-苯基噻唑-2-基)亚联氨基吡啶-2-酮, 棕红色固体，产率55％, 1H NMR (500 MHz, CDCl3) δ 13.57 (s, 1H), 8.10 (s, 1H), 7.82 (d, J =7.4 Hz, 2H), 7.41 – 7.38 (m, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.33 – 7.32 (m,1H), 7.31 – 7.29 (m, 2H), 6.99 (s, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.80 (s,1H), 6.77 – 6.75 (m, 2H), 6.68 – 6.65 (m, 1H), 6.52 (d, J = 7.8 Hz, 1H), 6.50(s, 1H), 3.85 (s, 3H), 3.83 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.76 ,161.19 , 160.70 , 159.02 , 152.37 , 146.80 , 142.23 , 141.04 , 134.47 ,131.65 , 131.12 , 130.35 , 128.69 , 128.00 , 126.02 , 113.32 , 112.69 ,110.90 , 108.64 , 106.96 , 106.64 , 105.63 , 104.84 , 55.40 , 29.72 ; ESI MSm/z: 525 (M+H)+.

Claims (5)

1.一种含噻唑环5,6-二取代吡啶-2-酮化合物，其化学结构式如式（I）所示：
式（I）中，取代基R是H、C1-6的烷基、F、Cl、Br、I、烷氧基、羟基、腈基、硝基、羧基或磺酸基。
2.一种含噻唑环5,6-二取代吡啶-2-酮化合物的制备方法，其特征在于包括如下步骤：
(1) 中间产物1的制备:
将2,3-二羟基吡啶溶于无水甲醇中，加入磷酸盐缓冲溶液，碘酸钠以及芳香胺于 容器中，室温下搅拌，TLC跟踪反应进程，待反应结束后加入大量的蒸馏水，静置过夜后，过滤得砖红色沉淀；将沉淀干燥，经柱层析得中间产物1；
(2) 中间产物2的制备:
取中间产物1、硫代氨基脲分别依次溶于无水乙醇中，室温下搅拌均匀，逐滴滴加浓硫酸，然后于65 ℃条件下反应，TLC跟踪反应进程，待反应完全后；趁热将反应液倒入容器中，加入蒸馏水，静置，过滤得橘黄色沉淀，即中间产物2；此中间产物2不需进一步纯化直接用于下一步合成；
(3) 目标化合物的制备:
将中间产物2、2-溴苯乙酮和酸催化剂溶于无水乙醇中，所述中间产物2、2-溴苯乙酮和酸催化剂的物质的量之比为1∶2∶0.1，60-80℃下搅拌，TLC 跟踪反应进程，待反应完全，停止反应，将反应物冷却至室温，减压旋蒸除去溶剂，残留物进行柱层析，得到(I)式所示的目标化合物含噻唑环5,6-二取代吡啶-2-酮化合物。
3. 如权利要求2所述的含噻唑环5,6-二取代吡啶-2-酮化合物的制备方法，其特征在于所述 R是H、C1-6的烷基、F、Cl、Br、I、烷氧基、羟基、腈基、硝基、羧基或酸基。
4.如权利要求2所述的含噻唑环5,6-二取代吡啶-2-酮化合物的制备方法，其特征在于步骤(3)中，所述的酸催化剂为冰乙酸。
5.如权利要求2所述的含噻唑环5,6-二取代吡啶-2-酮化合物的制备方法，其特征在于步骤(3)中，所述的反应温度为65℃。
CN201710435689.4A 2017-06-11 2017-06-11 一种含噻唑环5,6‑二取代吡啶‑2‑酮化合物及其制备方法 Pending CN107163036A (zh)

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