CN104817552B - (e)‑n’‑芳基亚甲基‑4‑(香豆素‑3‑基)噻唑‑2‑酰肼类化合物制法和用途 - Google Patents
(e)‑n’‑芳基亚甲基‑4‑(香豆素‑3‑基)噻唑‑2‑酰肼类化合物制法和用途 Download PDFInfo
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- CN104817552B CN104817552B CN201510219007.7A CN201510219007A CN104817552B CN 104817552 B CN104817552 B CN 104817552B CN 201510219007 A CN201510219007 A CN 201510219007A CN 104817552 B CN104817552 B CN 104817552B
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Classifications
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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
- C07D417/04—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 directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
本发明公开了一种(E)‑N’‑芳基亚甲基‑4‑(香豆素‑3‑基)噻唑‑2‑酰肼类化合物及其制法和用途。该化合物具有如式（I）所示结构，制备方法是以水杨醛和乙酰乙酸乙酯为原料得到3‑乙酰基‑2H‑苯并吡喃‑2‑酮，再经溴代、关环、肼解反应得到4‑(2‑氧代‑2H‑苯并吡喃‑3‑基)噻唑‑2‑甲酰肼，最后与各种取代苯甲醛反应得到目标化合物。该化合物可以作为抗菌药物的原料，且制备方法原料简单易得，操作方便。（I）。
Description
技术领域
(E)-N’-芳基亚甲基-4-(香豆素-3-基)噻唑-2-酰肼即(E)-N’-芳基亚甲基-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼，本发明涉及 (E)-N’-芳基亚甲基-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼类化合物及其制备方法和在制备抗菌药物中的应用。
背景技术
随着抗菌药物的广泛应用，尤其是抗生素的滥用，近年来世界范围内的细菌的耐药性问题日益严重，并且呈现逐年上升的趋势，给感染性疾病的治疗带来极大的困难。特别是耐甲氧西林金黄色葡萄球菌（MRSA）、耐青霉素肺炎链球菌（PRSP）、多重耐药结核杆菌等多药耐药菌的出现，严重威胁人类的生命健康。
香豆素类化合物是一类植物的二级代谢产物，在多种植物中都有分布。许多含有香豆素类化合物的植物在亚洲作为药物使用已经有几千年的历史。香豆素类化合物具有多种生物活性，例如：抗氧化、抗肿瘤、抗炎、抗神经变性、抗疟疾、抗凝血、抗菌和抗真菌等。由于其独特的化学结构和多种多样的生物活性，香豆素类化合物已经成为设计和发现新药的重要先导化合物来源，开发它具有一定的理论意义和实际的价值，因此，我们设计合成了一类(E)-N’-芳基亚甲基-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼化合物。
发明内容
本发明的技术方案如下：
一类(E)-N’-芳基亚甲基-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼化合物，其特征是它们具有如式（I）所示结构通式：
（I）
其中：R1、R2、R3、R4、R5代表相互独立的是氢、卤素、烷基、氨基、烷基氨基、二烷基氨基、二芳基氨基、酰胺基、烷氧基、氰基、硝基、羧基、羟基、烷氧羰基、芳香环及其取代物、杂环及其取代物、三氟甲基、巯基、磺酰基、砜或亚砜、硫烷基、磺酰胺基或磺酰胺基取代物、胺甲酰、胺甲酸酯、尿素基团、羟胺、羟基酰胺，其任选1至5个取代基相互组合。
一种制备上述(E)-N’-芳基亚甲基-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼化合物的方法，它包括下列步骤：
步骤1：将水杨醛、乙酰乙酸乙酯、哌啶置于圆底烧瓶中，加入乙醇，回流反应5~24小时，停止反应，冷却到室温，加入水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，旋干，过硅胶柱分离纯化，得到黄色固体粉末3-乙酰基-2H-苯并吡喃-2-酮；所述的水杨醛、乙酰乙酸乙酯、哌啶的摩尔比为1：（1~5）：（0.1~4）；
步骤2：将3-乙酰基-2H-苯并吡喃-2-酮、对甲苯磺酸、N-溴代丁二酰亚胺置于圆底烧瓶中，加入DMF，50~160 ℃反应2~5 小时，停止反应，加入饱和硫代硫酸钠溶液，乙酸乙酯萃取，合并有机相，过硅胶柱色谱纯化，得白色固体粉末3-(2-溴乙酰基)-2H-苯并吡喃-2-酮；所述的3-乙酰基-2H-苯并吡喃-2-酮、对甲苯磺酸、N-溴代丁二酰亚胺的摩尔比为1：（1~5）：（1~10）；
步骤3：将3-(2-溴乙酰基)-2H-苯并吡喃-2-酮、硫代草酰胺乙酯置于圆底烧瓶中，加入甲醇，室温搅拌5~24小时，停止反应，加入水，乙酸乙酯萃取，合并有机相，过硅胶柱色谱纯化，得黄褐色固体粉末4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酸乙酯；所述的3-(2-溴乙酰基)-2H-苯并吡喃-2-酮、硫代草酰胺乙酯的摩尔比为1：（1~10）；
步骤4：将4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酸乙酯、水合肼置于圆底烧瓶中，加入乙醇，回流反应2~10，停止反应，冷却到室温，过滤，得白色固体粉末4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酰肼；所述的4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酸乙酯、水合肼的摩尔比为1：（1~20）；
步骤5：将4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酰肼、取代苯甲醛置于圆底烧瓶中，加入乙醇，回流反应2~10小时，冷却到室温，蒸除溶剂，过硅胶色谱柱分离，得白色固体粉末(E)-N’-(4-甲氧基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼；所述的4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酰肼、取代苯甲醛的摩尔比为1：（1~5）。
本发明所述的(E)-N’-芳基亚甲基-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼化合物对多种细菌都具有较好的抑制和杀灭活性，为抗菌药物的开发和应用提供了新的选择。
附图说明
图1是(E)-N’-芳基亚甲基-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼类化合物的制备路线图。
具体实施方式
以下的实施例在于详细说明本发明，而非限制本发明。
实施例一：3-乙酰基-2H-苯并吡喃-2-酮的制备
将水杨醛（1.22g，10 mmol）、乙酰乙酸乙酯（2.6g，20 mmol）、哌啶（0.5 mL）置于圆底烧瓶中，加入乙醇100 mL，回流反应12小时，TLC显示反应完毕，停止反应，冷却到室温，加入水300 mL，乙酸乙酯萃取（200 mL×3），合并有机相，无水硫酸钠干燥，过滤，旋干，过硅胶柱分离纯化，得黄色固体粉末1.5 g，收率79 %。1H NMR (CDCl3, 400 MHz) δ: 2.73 (s,3H), 7.33-7.35 (m, 2H), 7.64-7.69 (m, 2H), 8.51 (s, 1H).
实施例二：3-(2-溴乙酰基)-2H-苯并吡喃-2-酮的制备
将3-乙酰基-2H-苯并吡喃-2-酮（188 mg，1 mmol）、对甲苯磺酸（380 mg， 2mmol）、N-溴代丁二酰亚胺（354 mg， 2 mmol）置于圆底烧瓶中，加入DMF 10 mL，100 ℃反应2 小时，TLC显示反应完毕，停止反应，加入饱和硫代硫酸钠溶液，乙酸乙酯萃取，合并有机相，过硅胶柱色谱纯化，得白色固体粉末127 mg，收率 44 %。1H NMR (CDCl3, 400 MHz) δ:4.76 (s, 2H), 7.37-7.42 (m, 2H), 7.69-7.73 (m, 2H), 8.65 (s, 1H).
实施例三：4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酸乙酯的制备
将3-(2-溴乙酰基)-2H-苯并吡喃-2-酮（133 mg，1 mmol）、硫代草酰胺乙酯（399mg，3 mmol）置于圆底烧瓶中，加入10 mL甲醇，室温搅拌24小时，TLC显示反应完毕，停止反应，加入20 mL水，乙酸乙酯萃取，合并有机相，过硅胶柱色谱纯化，得黄褐色固体粉末 190mg，收率63 %。1H NMR (CDCl3, 400 MHz) δ: 1.49 (t, 3H, J = 7.2 Hz), 4.51 (q, 2H,J = 7.2 Hz), 7.32 (t, 1H, J = 8.0 Hz), 7.38 (d, 1H, J = 8.0 Hz), 7.58 (t, 1H,J = 8.0 Hz), 7.66 (d, 1H, J = 8.0 Hz), 8.74 (s, 1H), 8.92 (s, 1H).
实施例四：4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酰肼
将4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酸乙酯（301mg，1 mmol）、水合肼（100mg， 2 mmol）置于圆底烧瓶中，加入10 mL乙醇，回流反应，TLC显示反应完毕，停止反应，冷却到室温，过滤，得白色固体粉末208 mg，收率72%。1H NMR (d6-DMSO, 400 MHz) δ: 4.76(s, 2H), 7.46 (t, 1H, J = 8.0 Hz), 7.50 (d, 1H, J = 8.0 Hz), 7.69 (t, 1H, J =8.0 Hz), 7.76 (d, 1H, J = 8.0 Hz), 8.59 (s, 1H), 9.07 (s, 1H), 10.23 (s, 1H).
实施例五：(E)-N’-(4-甲氧基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（1）的制备
将4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酰肼（287 mg，1 mmol）、对甲氧基苯甲醛（204 mg，1.5 mmol）置于圆底烧瓶中，加入10 mL乙醇，回流反应5小时，TLC显示反应完毕，冷却到室温，蒸除溶剂，过硅胶色谱柱分离，得白色固体粉末319 mg，收率79%。1H NMR(d6-DMSO, 400 MHz) δ: 3.83 (s, 3H), 7.05 (d, 2H, J = 8.8 Hz), 7.47 (t, 1H, J= 8.0 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.69 (t, 1H, J = 8.0 Hz), 7.72 (d, 2H, J= 8.8 Hz), 7.84 (d, 1H, J = 8.0 Hz), 8.65 (s, 1H), 8.69 (s, 1H), 9.04 (s,1H), 12.10 (s, 1H). 13C NMR (d6-DMSO, 100 MHz) δ: 55.3, 114.44, 114.44,116.19, 118.95, 119.99, 124.92, 125.09, 126.47, 128.74, 129.00, 129.00,132.39, 140.50, 148.44, 150.09, 152.79, 155.24, 158.78, 161.20, 162.38.
实施例六：(E)-N’-(2-羟基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（2）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为邻羟基苯甲醛，收率78 %。1HNMR (d6-DMSO, 400 MHz) δ: 6.93-6.98 (m, 2H), 7.34 (t, 1H, J = 7.2 Hz), 7.46(t, 1H, J = 8.0 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.63 (d, 1H, J = 8.0 Hz), 7.70(t, 1H, J = 8.0 Hz), 7.86 (d, 1H, J = 8.0 Hz), 8.71 (s, 1H), 8.95 (s, 1H),9.05 (s, 1H), 10.95 (s, 1H). 13C NMR d6-DMSO, 100 MHz) δ: 116.2, 116.4, 118.9,118.9, 119.5, 120.0, 125.1, 125.1, 128.8, 128.9, 131.9, 132.4, 140.5, 148.5,149.7, 152.8, 155.3, 157.5, 158.8, 161.8.
实施例七：(E)-N’-(4-羟基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（3）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为对羟基苯甲醛，收率86 %。1HNMR (d6-DMSO, 400 MHz) δ: 6.87 (d, 2H, J = 8.8 Hz), 7.46 (t, 1H, J = 8.0 Hz),7.51 (d, 1H, J = 8.0 Hz), 7.61 (d, 2H, J = 8.8 Hz), 7.70 (t, 1H, J = 8.0 Hz),7.84 (d, 1H, J = 8.0 Hz), 8.61 (s, 1H), 8.69 (s, 1H), 9.05 (s, 1H), 10.22 (s,1H). 13C NMR (d6-DMSO, 100 MHz) δ: 115.8, 115.8, 116.2, 119.0, 120.0, 124.8,124.9, 125.1, 128.8, 129.2, 129.2, 132.3, 140.5, 148.4, 150.5, 152.8, 155.1,158.8, 159.8, 162.5.
实施例八：(E)-N’-(3,5-二叔丁基-2-羟基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（4）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为3,5-二叔丁基水杨醛，收率67%。1H NMR (d6-DMSO, 400 MHz) δ: 1.31 (s, 9H), 1.43 (s, 9H), 7.24 (d, 1H, J =2.0 Hz), 7.36 (d, 1H, J = 2.0 Hz), 7.47 (t, 1H, J = 8.0 Hz), 7.52 (d, 1H, J =8.0 Hz), 7.71 (t, 1H, J = 8.0 Hz), 7.84 (d, 1H, J = 8.0 Hz), 8.74 (s, 1H),8.86 (s, 1H), 9.02 (s, 1H), 12.03 (s, 1H), 12.61 (s, 1H). 13C NMR (d6-DMSO,100 MHz) δ: 29.3, 29.3, 29.3, 31.2, 31.2, 31.2, 33.9, 34.7, 116.2, 116.8,118.9, 120.0, 125.1, 125.4, 126.0, 126.2, 128.7, 132.5, 135.9, 140.5, 140.6,148.6, 152.8, 153.7, 154.9, 155.2, 158.8, 161.5.
实施例九：(E)-N’-(3,5-二氯-2-羟基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（5）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为3,5-二氯水杨醛，收率76 %。1H NMR (d6-DMSO, 400 MHz) δ: 7.44 (t, 1H, J = 8.0 Hz), 7.50 (d, 1H, J = 8.0Hz), 7.59 (s, 2H), 7.69 (t, 1H, J = 8.0 Hz), 7.88 (d, 1H, J = 8.0 Hz), 8.69(s, 1H), 8.84 (s, 1H), 9.00 (s, 1H), 12.05 (s, 1H). 13C NMR (d6-DMSO, 100 MHz)δ: 116.2, 118.9, 119.9, 121.0, 122.0, 125.1, 128.0, 128.9, 130.6, 132.4,140.5, 148.6, 148.7, 152.8, 156.1, 158.8, 160.9.
实施例十：(E)-N’-(3-羟基-4-甲氧基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（6）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为3-羟基-4-甲氧基苯甲醛，收率55 %。1H NMR (CDCl3, 400 MHz) δ: 3.83 (s, 3H), 7.01 (d, 1H, J = 8.0 Hz), 7.11(dd, 1H, J = 8.0 Hz, 2.0 Hz), 7.32 (d, 1H, J = 2.0 Hz), 7.47 (t, 1H, J = 8.0Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.69 (t, 1H, J = 8.0 Hz), 7.85 (d, 1H, J = 8.0Hz), 8.56 (s, 1H), 8.69 (s, 1H), 9.05 (s, 1H), 9.37 (s, 1H), 12.06 (s, 1H).13C NMR (d6-DMSO, 100 MHz) δ: 55.6, 111.9, 112.4, 116.2, 119.0, 120.0, 120.7,124.9, 125.1, 126.7, 128.8, 132.4, 140.5, 147.0, 148.4, 150.2, 150.4, 152.8,155.2, 158.8, 162.4.
实施例十一：(E)-N’-(3-氟-4-羟基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（7）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为3-氟-4-甲氧基苯甲醛，收率83%。1H NMR (CDCl3, 400 MHz) δ: 7.06 (t, 1H, J = 8.0 Hz), 7.41 (d, 1H, J = 8.0Hz), 7.46 (t, 1H, J = 8.0 Hz), 7.51-7.55 (m, 2H), 7.70 (t, 1H, J = 8.0 Hz),7.85 (d, 1H, J = 8.0 Hz), 8.60 (s, 1H), 8.69 (s, 1H), 9.04 (s, 1H), 10.49 (s,1H), 12. 15 (s, 1H). 13C NMR (d6-DMSO, 100 MHz) δ: 114.1, 114.3, 116.2, 118.0,119.0, 120.0, 124.8, 125.0, 125.1, 125.7, 128.8, 132.4, 140.5, 147.4, 148.5,149.4, 152.8, 155.3, 158.8, 162.3.
实施例十二：(E)-N’-(5-氯-2-羟基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（8）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为5-氯水杨醛，收率79 %。1H NMR(CDCl3, 400 MHz) δ: 6.96 (d, 1H, J = 8.8 Hz), 7.33 (dd, 1H, J = 8.8 Hz, 2.0Hz), 7.46 (t, 1H, J = 8.0 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.68-7.72 (m, 2H),7.86 (d, 1H, J = 8.0 Hz), 8.71 (s, 1H), 8.91 (s, 1H), 9.04 (s, 1H), 10.92 (s,1H). 13C NMR (d6-DMSO, 100 MHz) δ: 116.2, 118.3, 118.9, 120.0, 120.9, 123.1,125.1, 125.2, 126.8, 128.8, 131.2, 132.4, 140.5, 147.1, 148.6, 152.8, 155.5,156.0, 158.8, 161.7.
实施例十三：(E)-N’-(2-羟基-4-甲氧基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（9）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为4-甲氧基水杨醛，收率66 %。1H NMR (CDCl3, 400 MHz) δ: 3.79 (s, 3H), 6.51 (d, 1H, J = 2.0 Hz), 6.54 (dd,1H, J = 8.0 Hz, 2.0 Hz), 7.46 (t, 1H, J = 8.0 Hz), 7.49-7.53 (m, 2H), 7.70(t, 1H, J = 8.0 Hz), 7.85 (d, 1H, J = 8.0 Hz), 8.69 (s, 1H), 8.83 (s, 1H),9.03 (s, 1H), 11.10 (s, 1H). 13C NMR (d6-DMSO, 100 MHz) δ: 55.3, 101.1, 106.6,111.9, 116.2, 118.9, 120.0, 125.0, 125.1, 128.8, 130.7, 132.4, 140.5, 148.5,150.3, 152.8, 155.2, 158.8, 159.5, 162.1, 162.4.
实施例十四：(E)-N’-(2,4-羟基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（10）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为2,4-二羟基苯甲醛，收率81 %。1H NMR (CDCl3, 400 MHz) δ: 6.78 (s, 2H), 7.08 (s, 1H), 7.46 (t, 1H, J = 8.0Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.70 (t, 1H, J = 8.0 Hz), 7.86 (d, 1H, J = 8.0Hz), 8.70 (s, 1H), 8.87 (s, 1H), 9.06 (s, 1H), 10.25 (s, 1H), 10.81 (s, 1H).13C NMR (d6-DMSO, 100 MHz) δ: 113.0, 116.2, 117.2, 119.0, 119.2, 119.4, 120.0,125.0, 125.1, 128.8, 132.4, 140.5, 148.5, 149.0, 149.9, 150.3, 152.8, 155.4,158.8, 162.1.
实施例十五：(E)-N’-(3,4-羟基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（11）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为3,4-二羟基苯甲醛，收率77 %。1H NMR (CDCl3, 400 MHz) δ: 6.82 (d, 1H, J = 8.8 Hz), 6.99 (d, 1H, J = 8.8 Hz),7.30 (s, 1H), 7.46 (t, 1H, J = 8.0 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.70 (t,1H, J = 8.0 Hz), 7.85 (d, 1H, J = 8.0 Hz), 8.52 (s, 1H), 8.69 (s, 1H), 9.05(s, 1H), 9.81 (s, 1H). 13C NMR (d6-DMSO, 100 MHz) δ: 112.8, 115.6, 116.2,119.0, 120.0, 121.0, 124.8, 125.1, 125.3, 128.8, 132.4, 140.5, 145.8, 148.4,148.5, 150.7, 152.8, 155.1, 158.8, 162.5.
实施例十六：(E)-N’-(4-羟基-3,5-二甲氧基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（12）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为3,5-二甲氧基-4-羟基苯甲醛，收率59 %。1H NMR (CDCl3, 400 MHz) δ: 3.85 (s, 6H), 7.03 (s, 2H), 7.47 (t, 1H, J= 8.0 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.70 (t, 1H, J = 8.0 Hz), 7.83 (d, 1H, J= 8.0 Hz), 8.59 (s, 1H), 8.69 (s, 1H), 9.05 (s, 1H), 10.08 (s, 1H). 13C NMR(d6-DMSO, 100 MHz) δ: 56.0, 56.0, 104.9, 104.9, 116.2, 119.0, 120.0, 124.1,124.9, 125.1, 128.7, 132.4, 138.4, 140.5, 148.2, 148.2, 148.4, 150.9, 152.8,155.2, 158.8, 162.4.
实施例十七：(E)-N’-(4-氯苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（13）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为4-氯苯甲醛，收率88 %。1H NMR(CDCl3, 400 MHz) δ: 7.46 (t, 1H, J = 8.0 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.55(d, 2H, J = 8.8 Hz), 7.70 (t, 1H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.8 Hz), 7.85(d, 1H, J = 8.0 Hz), 8.71 (s, 1H), 9.04 (s, 1H), 11.05 (s, 1H). 13C NMR (d6-DMSO, 100 MHz) δ: 116.2, 118.9, 120.0, 125.1, 125.2, 128.8, 128.9, 128.9,129.0, 129.0, 132.4, 132.9, 135.0, 140.5, 148.5, 148.9, 152.8, 155.5, 158.8,162.1.
实施例十八：(E)-N’-(3-氯苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（14）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为3-氯苯甲醛，收率70 %。1H NMR(CDCl3, 400 MHz) δ: 7.45 (t, 1H, J = 8.0 Hz), 7.50-7.55 (m, 3H), 7.68-7.73(m, 2H), 7.80 (s, 1H), 7.86 (d, 1H, J = 8.0 Hz), 8.71 (s, 2H), 9.05 (s, 1H),11.12 (s, 1H). 13C NMR (d6-DMSO, 100 MHz) δ: 116.2, 118.9, 119.9, 125.1,125.2, 126.1, 126.4, 128.8, 130.1, 130.8, 132.4, 133.7, 136.2, 140.5, 148.5,148.5, 152.8, 155.7, 158.8, 162.0.
实施例十九：(E)-N’-(4-三氟甲基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（15）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为对三氟甲基苯甲醛，收率64 %。1H NMR (CDCl3, 400 MHz) δ: 7.46 (t, 1H, J = 8.0 Hz), 7.51 (d, 1H, J = 8.0Hz), 7.70 (t, 1H, J = 8.0 Hz), 7.84-7.86 (m, 3H), 7.78 (d, 2H, J = 8.8 Hz),8.72 (s, 1H), 8.80 (s, 1H), 9.04 (s, 1H), 11.47 (s, 1H). 13C NMR (d6-DMSO, 100MHz) δ: 116.2, 118.9, 120.0, 122.7, 125.1, 125.3, 125.8, 127.9, 127.9, 128.8,132.4, 137.9, 140.5, 141.0, 148.4, 148.5, 152.1, 152.8, 155.7, 158.8, 162.0.
实施例二十：(E)-N’-(2-氟苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（16）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为2-氟苯甲醛，收率72 %。1H NMR(CDCl3, 400 MHz) δ: 7.46-7.54 (m, 4H), 7.57 (d, 1H, J = 8.0 Hz), 7.71 (t, 1H,J = 8.0 Hz), 7.88 (d, 1H, J = 8.0 Hz), 8.06 (d, 1H, J = 8.0 Hz), 8.73 (s,1H), 9.05 (s, 1H), 9.13 (s, 1H), 12.54 (s, 1H). 13C NMR (d6-DMSO, 100 MHz) δ:116.2, 118.9, 120.0, 125.1, 125.3, 127.1, 127.7, 128.9, 130.0, 131.4, 131.9,132.4, 133.5, 140.5, 146.0, 148.6, 152.8, 155.7, 158.8, 162.0.
实施例二十一：(E)-N’-(3-氟苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（17）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为3-氟苯甲醛，收率85 %。1H NMR(CDCl3, 400 MHz) δ: 7.33 (t, 1H, J = 8.0 Hz), 7.46 (t, 1H, J = 8.0 Hz), 7.50-7.58 (m, 3H), 7.61 (d, 1H, J = 8.0 Hz), 7.70 (t, 1H, J = 8.0 Hz), 7.85 (d,1H, J = 8.0 Hz), 8.71 (s, 1H), 8.72 (s, 1H), 9.04 (s, 1H), 12.00 (s, 1H). 13CNMR (d6-DMSO, 100 MHz) δ: 113.3, 116.2, 118.9, 119.9, 123.7, 125.1, 125.2,128.8, 131.0, 132.4, 136.5, 140.5, 148.5, 148.8, 152.8, 155.6, 158.8, 161.2,162.0, 163.6.
实施例二十二：(E)-N’-(3-溴苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（18）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为3-溴苯甲醛，收率80 %。1H NMR(CDCl3, 400 MHz) δ: 7.44-7.48 (m, 2H), 7.50 (d, 1H, J = 8.0 Hz), 7.66-7.70(m, 2H), 7.76 (d, 1H, J = 8.0 Hz), 7.84 (d, 1H, J = 8.0 Hz), 7.95 (s, 1H),8.68 (s, 1H), 8.71 (s, 1H), 9.03 (s, 1H), 11.23 (s, 1H). 13C NMR (d6-DMSO, 100MHz) δ: 116.2, 118.9, 119.9, 122.2, 125.1, 125.2, 126.5, 128.8, 129.3, 131.1,132.4, 133.0, 136.4, 140.5, 148.4, 148.5, 152.8, 155.6, 158.8, 162.0.
实施例二十三：(E)-N’-(2-甲氧基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（19）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为2-甲氧基苯甲醛，收率75 %。1HNMR (CDCl3, 400 MHz) δ: 3.92 (s, 3H), 7.06 (t, 1H, J = 8.0 Hz), 7.14 (d, 1H,J = 8.0 Hz), 7.45-7.49 (m, 2H), 7.51 (d, 1H, J = 8.0 Hz), 7.71 (t, 1H, J =8.0 Hz), 7.87 (d, 1H, J = 8.0 Hz), 7.91 (d, 1H, J = 8.0 Hz), 8.70 (s, 1H),9.06 (s, 1H), 9.08 (s, 1H), 11.35 (s, 1H). 13C NMR (d6-DMSO, 100 MHz) δ: 55.5,116.2, 116.4, 118.9, 119.0, 119.5, 120.0, 125.1, 125.2, 128.8, 128.9, 131.9,132.4, 140.6, 148.5, 149.7, 152.8, 155.3, 157.5, 158.8, 161.8.
实施例二十四：(E)-N’-(3,4,5-三甲氧基苯基亚甲基)-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼（20）的制备
制备方法同实施例五，只是对甲氧基苯甲醛替换为3,4,5-三甲氧基苯甲醛，收率69 %。1H NMR (CDCl3, 400 MHz) δ: 3.73 (s, 3H), 3.86 (s, 6H), 7.05 (s, 2H), 7.46(t, 1H, J = 8.0 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.70 (t, 1H, J = 8.0 Hz), 7.83(d, 1H, J = 8.0 Hz), 8.64 (s, 1H), 8.69 (s, 1H), 9.05 (s, 1H), 10.46 (s, 1H).13C NMR (d6-DMSO, 100 MHz) δ: 55.3, 55.6 55.6, 115.8, 115.8, 116.2, 119.0,120.0, 124.8, 124.9, 125.1, 128.8, 129.2, 129.2, 132.4, 140.5, 148.4, 150.5,152.8, 155.1, 158.8, 159.8, 162.5.
实施例25：实施例制备得到的化合物对多种细菌的抑制活性测定：
采用最小杀菌浓度法对金黄色葡萄球菌、大肠杆菌、变性杆菌进行抑菌活性测定。最小杀菌浓度法的具体操作为：将一定质量的化合物溶于适量蒸馏水中，超声或加热使其充分溶解或分散，配成一定浓度的化合物水溶液；然后逐级稀释，得到一系列浓度梯度的待测溶液。在每个无菌小试管中加入 1mL 不同浓度的化合物水溶液，1mL 新鲜菌液（105CFU/mL），置于37 oC的摇床（180 rpm）培养箱中振荡培养24h。结束后取出，用微量移液器从每个小试管中分别吸取0.2 ml混合液加入到平板培养基上，用玻璃涂棒将菌液在平板上涂抹均匀，然后将平板倒置在37 oC的恒温培养箱中，培养24h，取出观察是否有菌落生长，以低于99%初始菌浓度生长的最低抗菌剂浓度为该抗菌剂的最小杀菌浓度。
活性的高低以最小杀菌浓度MBC来表示，MBC越小，此化合物的活性越高，抗菌活性越好，结果见表1.
表1. (E)-N’-芳基亚甲基-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼类化合物的抑菌活性测试结果。
由表1可以看出(E)-N’-芳基亚甲基-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼类化合物具有不同程度抗菌活性，其中化合物6、7、12对金黄色葡萄球菌、大肠杆菌、变性杆菌都具有较好的抑制活性。
上述只是本发明的较佳实施例，并非对本发明作任何形式上的限制。任何熟悉本领域的技术人员，在不脱离本发明技术方案范围的情况下，都可利用上述揭示的技术内容对本发明技术方案做出许多可能的变动和修饰，或修改为等同变化的等效实施例。因此，凡是未脱离本发明技术方案的内容，依据本发明技术实质对以上实施例所做的任何简单修改、等同变化及修饰，均应落在本发明技术方案保护的范围内。
Claims (1)
1.一种(E)-N’-芳基亚甲基-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼类化合物的制备方法，其特征在于包括以下几个步骤：
步骤1：将水杨醛、乙酰乙酸乙酯、哌啶置于圆底烧瓶中，加入乙醇，回流反应5~24小时，停止反应，冷却到室温，加入水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，旋干，过硅胶柱分离纯化，得到黄色固体粉末3-乙酰基-2H-苯并吡喃-2-酮；所述的水杨醛、乙酰乙酸乙酯、哌啶的摩尔比为1：（1~5）：（0.1~4）；反应式如下：
步骤2：将3-乙酰基-2H-苯并吡喃-2-酮、对甲苯磺酸、N-溴代丁二酰亚胺置于圆底烧瓶中，加入DMF，50~160 ℃反应2~5 小时，停止反应，加入饱和硫代硫酸钠溶液，乙酸乙酯萃取，合并有机相，过硅胶柱色谱纯化，得白色固体粉末3-(2-溴乙酰基)-2H-苯并吡喃-2-酮；所述的3-乙酰基-2H-苯并吡喃-2-酮、对甲苯磺酸、N-溴代丁二酰亚胺的摩尔比为1：（1~5）：（1~10）；反应式如下：
步骤3：将3-(2-溴乙酰基)-2H-苯并吡喃-2-酮、硫代草酰胺乙酯置于圆底烧瓶中，加入甲醇，室温搅拌5~24小时，停止反应，加入水，乙酸乙酯萃取，合并有机相，过硅胶柱色谱纯化，得黄褐色固体粉末4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酸乙酯；所述的3-(2-溴乙酰基)-2H-苯并吡喃-2-酮、硫代草酰胺乙酯的摩尔比为1：（1~10）；反应式如下：
步骤4：将4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酸乙酯、水合肼置于圆底烧瓶中，加入乙醇，回流反应，TLC显示反应完毕，停止反应，冷却到室温，过滤，得白色固体粉末4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酰肼；所述的4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酸乙酯、水合肼的摩尔比为1：（1~20）；反应式如下：
步骤5：将4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酰肼、取代苯甲醛置于圆底烧瓶中，加入乙醇，回流反应2~10小时，冷却到室温，蒸除溶剂，过硅胶色谱柱分离，得白色固体粉末(E)-N’-芳基亚甲基-4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-酰肼，结构如式（I）所示，反应式如下，其中：R1、R2、R3、R4、R5代表相互独立的是氢、卤素、烷基、烷氧基、三氟甲基、羟基，其任选1至5个取代基相互组合；所述的4-(2-氧代-2H-苯并吡喃-3-基)噻唑-2-甲酰肼、取代苯甲醛的摩尔比为1：（1~5）
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