CN104098513B - 一种吲唑化合物衍生物及其制备方法 - Google Patents
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- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Abstract
本发明涉及一种吲唑化合物衍生物及其制备方法，该化合物为6‑溴‑3‑乙酰基吲唑，制备方法如下：(1)化合物1(6‑溴‑吲哚)在亚硝酸钠及盐酸作用下生成化合物2；(2)化合物2用二碳酸二叔丁酯生成化合物3(Boc保护的吲唑甲醛)；(3)甲基溴化镁与化合物3生成化合物4；(4)化合物4在二氧化锰下，吲唑羟基被氧化为吲唑乙酰基，得到最终产物化合物5；所得终产物在治疗发炎相关疾病等方面具有广泛应用前景。
Description
技术领域
本发明涉及化合物合成领域，尤其是一种吲唑化合物衍生物及其制备方法。
背景技术
根据Preparation of heterocyclic propargylic alcoholcompounds as NF-κB inducing kinase inhibitors for treatinginflammations。U.S.Pat.Appl.Publ.(2012),US 20120214762A1 20120823等文献记载，吲唑化合物广泛存在于具有生物活性的药物分子中，在治疗发炎等疾病方面具有应用价值，以该化合物合成的衍生物，可能具有更加广泛的其它生物活性。可见，由于其良好的药理活性及潜在的药用价值，现阶段吲唑化合物衍生物的合成倍受关注。
发明内容
本发明所要解决的技术问题在于提供一种吲唑化合物衍生物。
本发明所要解决的另一技术问题在于提供上述吲唑化合物衍生物的制备方法。
为解决上述技术问题，本发明的技术方案是：
一种吲唑化合物衍生物，6-溴-3-乙酰基吲唑，其结构式为(Ⅰ)所示，
优选的，上述吲唑化合物衍生物，6-溴-3-乙酰基吲唑为土黄色固体，其核磁共振氢谱数据为：2.642(s,3H),7.463(d,1H),7.922(s,1H)，8.113(d，1H)，13.947(s，1H)。
上述吲唑化合物衍生物的制备方法，具体步骤如下：
(1)化合物1(6-溴-吲哚)在亚硝酸钠及盐酸作用下生成化合物2(吲唑甲醛)；
(2)化合物2用二碳酸二叔丁酯生成化合物3(Boc保护的吲唑甲醛)；
(3)甲基溴化镁与化合物3(Boc保护的吲唑甲醛)生成化合物4(吲唑乙醇)；
(4)化合物4在二氧化锰下，吲唑羟基被氧化为吲唑乙酰基，得到最终产物化合物(Ⅰ)(6-溴-3-乙酰基吲唑)，其中，
优选的，上述吲唑化合物衍生物的制备方法，所述化合物4作为中间产物，为新化合物。
上述吲唑化合物衍生物的制备方法的具体反应方程式如下：
本发明的有益效果是：
上述吲唑化合物衍生物的制备方法，是一种原料廉价、合成方法简单的6-溴-3-乙酰基吲唑的制备方法，其产物6-溴-3-乙酰基吲唑可以作为NF-kB靶点的抑制剂，在治疗发炎相关疾病等方面具有广泛应用前景。
附图说明
图1为6-溴-3-乙酰基吲唑的HNMR谱图。
具体实施方式
为了使本领域的技术人员更好的理解本发明的技术方案，下面结合具体实施方式对本发明所述技术方案作进一步的详细说明。
实施例1
一种吲唑化合物衍生物6-溴-3-乙酰基吲唑的制备方法，具体步骤如下：
(1)向70g亚硝酸钠的水溶液中加入20g化合物1(6-溴-吲哚)的丙酮:水(200ml:200ml)溶液；室温下，向体系中加入2N HCl溶液至pH为2.5左右；20min后，有红棕色气体放出，体系有粘稠物；10min后，TLC检测原料消失，停止反应，向体系中加入1.0L乙酸乙酯(EA)，两相分离，有机相用饱和碳酸氢钠(500ml*2)洗涤，无水硫酸镁干燥有机相，浓缩得22g化合物2，为黑色固体。TLC信息：原料Rf＝0.7，产品Rf＝0.6；展开剂：石油醚：乙酸乙酯(PE:EA)＝3：1；
(2)向22g化合物2的200ml DCM(二氯甲烷)溶液中分别加入15.5g三乙胺(Et3N)和0.5g 4-二甲氨基吡啶(DMAP)；然后一次性慢慢加入22.2g二碳酸二叔丁酯(Boc)，体系在室温下搅拌2h；2h后，TLC显示有少量原料，停止反应，浓缩，硅胶板样，中压制备分离得3g化合物3，为黄色固体。TLC信息：原料Rf＝0.05，产品Rf＝0.6；展开剂：PE:EA＝10：1，第(1)、(2)步产率9％；
(3)250ml三口瓶中装有3g化合物3的90ml THF溶液，氩气置换三次，体系降温至0℃；5min后,T＝-10℃，逐滴加入27.7ml甲基溴化镁，并控温在0℃左右，滴加过程中有固体析出；15min后,T＝-8℃，滴加完毕，体系自然回至室温搅拌过夜；18.5h后，LCMS(液相质谱)检测产品生成，停止反应，降温至0℃左右，向体系中逐滴加入饱和氯化铵(150ml)，有固体出现，加入EA(250ml)和水(50ml)，分液，水相用EA(200ml*2)萃取，合并有机相，无水硫酸镁干燥，浓缩得2.4g化合物4，为粘稠状黄色液体；
(4)向2.4g化合物4的240mlDCM溶液中加入8.66g二氧化锰，氩气保护下室温搅拌过夜；21h后，TLC显示原料消失，停止反应，硅藻土过滤，滤饼分别用DCM(150ml)、EA(150ml)、二氯甲烷：甲醇(DCM:MeOH)＝10:1(150ml)洗涤，合并有机相，浓缩得粗品，利用MTBE:PE＝2:11重结晶得终产品1.9g化合物(Ⅰ)，为土黄色固体。TLC信息：原料Rf＝0.5，产品Rf＝0.8。展开剂：PE:EA＝1：1；第(3)、(4)步产率86％。经测定，如图1所示，其氢谱数据为：2.642(s,3H),7.463(d,1H),7.922(s,1H)，8.113(d，1H)，13.947(s，1H)。
实施例1所述制备过程如下：
应用试验例
昆明种健康雄性小鼠30只，6周，质量18.5-22.5g，随机分成3组，每组10只，分为空白对照组(生理盐水灌胃给药)、阿司匹林组(200mg/kg灌胃给药)、试验组(实施例1所得终产物化合物(Ⅰ)，20mg/kg灌胃给药)，连续7d，第七天灌胃后1h，将3组小鼠均在小鼠右耳前、后面均匀涂二甲苯0.02mL，制备耳廓炎症模型。1h后后颈脱臼处死小鼠，沿耳廓基线剪下两耳，用直径8mm打孔器分别在两耳的同一部位打下圆耳片，称重精确到0.0001g。立即用电子天平分别称质量，以左右两耳质量差作为肿胀度，并计算其肿胀度和抑制率。
肿胀度＝右耳片重—左耳片重
抑制率＝(对照组平均肿胀度－给药组平均肿胀度)/对照组平均肿胀度*100％
试验结果显示，致炎后各组小鼠右耳立刻出现高度红肿现象。阿司匹林组和试验组对二甲苯所致的小鼠耳肿胀均有明显抑制作用，结果见表1。
表1
| 组别 | 左耳(mg) | 右耳(mg) | 肿胀度(mg) | 抑制率(％) |
| 空白对照组 | 12.5±1.1 | 24.1±2.7 | 11.7±3.3 | |
| 阿司匹林组 | 13.9±1.5 | 18.6±2.6 | 4.7±2.1 | 59.83％ |
| 试验组 | 12.9±0.9 | 17.8±1.6 | 4.9±1.8 | 58.12％ |
上述参照具体实施方式对该一种吲唑化合物衍生物及其制备方法进行的详细描述，是说明性的而不是限定性的，可按照所限定范围列举出若干个实施例，因此在不脱离本发明总体构思下的变化和修改，应属本发明的保护范围之内。
Claims (2)
1.一种吲唑化合物衍生物，其特征在于：为6-溴-3-乙酰基吲唑，其结构式为(Ⅰ)所示，
2.权利要求1所述的吲唑化合物衍生物的制备方法，其特征在于：具体步骤如下：
(1)化合物1在亚硝酸钠及盐酸作用下生成化合物2；
(2)化合物2用二碳酸二叔丁酯生成化合物3；
(3)甲基溴化镁与化合物3生成化合物4；
(4)化合物4在二氧化锰下，吲唑羟基被氧化为吲唑乙酰基，得到最终产物化合物(Ⅰ)，其中，
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| CA2465247A1 (en) * | 2001-10-26 | 2003-05-01 | Aventis Pharmaceuticals Inc. | Benzimidazoles and analogues and their use as protein kinases inhibitors |
| CN101080408A (zh) * | 2004-12-17 | 2007-11-28 | 霍夫曼-拉罗奇有限公司 | 三环杂环、它们的制备和作为药剂的应用 |
| CN101687808A (zh) * | 2007-06-21 | 2010-03-31 | 默克专利有限公司 | 吲唑酰胺衍生物 |
| CN103387565A (zh) * | 2013-07-29 | 2013-11-13 | 苏州明锐医药科技有限公司 | 阿西替尼的制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2465247A1 (en) * | 2001-10-26 | 2003-05-01 | Aventis Pharmaceuticals Inc. | Benzimidazoles and analogues and their use as protein kinases inhibitors |
| CN101080408A (zh) * | 2004-12-17 | 2007-11-28 | 霍夫曼-拉罗奇有限公司 | 三环杂环、它们的制备和作为药剂的应用 |
| CN101687808A (zh) * | 2007-06-21 | 2010-03-31 | 默克专利有限公司 | 吲唑酰胺衍生物 |
| CN103387565A (zh) * | 2013-07-29 | 2013-11-13 | 苏州明锐医药科技有限公司 | 阿西替尼的制备方法 |
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