CN107722001A - 一种制备3‑溴‑5‑氯‑1,8‑二氮杂萘的方法 - Google Patents
一种制备3‑溴‑5‑氯‑1,8‑二氮杂萘的方法 Download PDFInfo
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Abstract
本发明公开了一种制备3‑溴‑5‑氯‑1,8‑二氮杂萘的方法，以5‑溴‑5‑溴‑2‑氨基吡啶为起始原料，经过成环、氯化、还原得到3‑溴‑5‑氯‑1,8‑二氮杂萘，该化合物是新药研发重要的中间体。
Description
技术领域
本发明涉及一种重要医药中间体的制备方法，特别涉及化合物3-溴-5-氯-1,8-二氮杂萘及其合成方法。
技术背景
化合物3-溴-5-氯-1,8-二氮杂萘的结构式为：
该化合物是合成萘啶类衍生物的重要中间体。萘啶衍生物通过消耗ATP的蛋白质如激酶进行的信号传导的抑制、调节和/或调控其作用。结合ATP并利用其能量来改变构象、使底物磷酸化和启动信号级联放大的蛋白质已知来自许多类型，如激酶、磷酸酶、侣伴蛋白或异构酶。使用特定的工具和技术可以富集ATP-结合蛋白。作为癌症标志物的机理部分，Ser/Thr激酶和受体酪氨酸激酶是细胞信号传导中必需的磷酸化酶。细胞周期、存活、增值和细胞死亡是由细胞信号传导所调节的细胞过程，以允许组织生长、再生和处于内稳态或退化。因此，一些激酶是哺乳动物治疗的灵敏靶标。在不同的作为人激酶组的组成部分的激酶系列中，受体酪氨酸KDR可以刺激内皮细胞存活和增殖，条件是被VEGF胞外连接。然后，配体结合可以导致胞内磷酸化事件、即信号级联放大，最终导致增殖。
目前，未见有其他专利文献报道该化合物及其合成方法。
发明内容
本发明公开了一种3-溴-5-氯-1,8-二氮杂萘的合成方法，以5-溴-2-氨基吡啶为起始原料，经过成环、氯化、还原三步反应得到3-溴-5-氯-1,8-二氮杂萘，该化合物是合成萘啶衍生物的重要中间体。合成步骤如下：
(1)以5-溴-2-氨基吡啶为起始原料，与丙二酸二乙酯反应得到2，
(2)把2与氯化剂反应，得到3；
(3)把3进行还原，得到4
在一优选的实施方式中，所述的合成化合物2的反应所用的环化试剂选自丙二酸二乙酯；所述的氯化反应合成化合物3所用的氯化剂选自三氯氧磷；所述的还原反应合成化合物4所用的还原剂选自Pd/C-氢气。
在另一优选的实施方式中，其特征在于,所述的合成化合物2的反应所用溶剂选自四氢呋喃；所述的氯化反应合成化合物3所用的溶剂选自三氯氧磷；所述的还原反应合成化合物4所用的溶剂选自甲醇。
在再一优选的实施方式中，其特征在于,所述的合成化合物2的反应温度是溶剂的回流温度；所述的氯化反应合成化合物3所用的反应温度是溶剂的回流温度；所述的还原反应合成化合物4的反应温度是室温。
本发明涉及3-溴-5-氯-1,8-二氮杂萘及其合成方法，该化合物是合成合成萘啶衍生物的重要中间体，目前没有其他相关专利文献报道。
下面通过实施例对本发明作进一步的描述，这些描述并不是对本发明内容作进一步的限定。本领域的技术人员应理解，对本发明的技术特征所作的等同替换，或相应的改进，仍属于本发明的保护范围之内。
具体实施例方式
实施例1
(1)6-溴-1,8-二氮杂萘-2,4-二醇的合成
把30g的5-溴-2-氨基吡啶、24ml丙二酸二乙酯加入到160ml四氢呋喃中，搅拌，加热，回流4小时，冷却，减压浓缩，剩余物用层析柱分离得到37g产物。
(2)6-溴-2,4-二氯-1,8-二氮杂萘的合成
把第一步所得产物35g溶于200ml三氯氧磷，加热回流，反应12小时，把反应液倒入冰水中，用乙酸乙酯萃取，有机相用饱和食盐水洗三遍，再用无水硫酸钠干燥，减压浓缩，剩余物用层析柱分离得到产物18g油状物。
(3)3-溴-5-氯-1,8-二氮杂萘的合成
把15g 6-溴-2,4-二氯-1,8-二氮杂萘加入到200ml甲醇中，加入3g 10％Pd/C，通入氢气，室温反应2小时，过滤，收集滤液，浓缩，剩余物用层析柱分离得到产物7.8g。
Claims (6)
1.一种制备3-溴-5-氯-1,8-二氮杂萘的方法，以5-溴-2-氨基吡啶为起始原料，经过成环、氯化、还原三步反应得到3-溴-5-氯-1,8-二氮杂萘，合成路线如下，
2.根据权利要求1的方法，其特征为所述的3步反应是，
(1)以5-溴-2-氨基吡啶为起始原料，与丙二酸二乙酯反应得到2，
(2)把2与氯化剂反应，得到3；
(3)把3进行还原，得到4
3.根据权利要求1的方法，其特征在于,所述的合成化合物2的反应所用的环化试剂选自丙二酸二乙酯或丙二酸二甲酯中的一种或两种的混合物；所述的氯化反应合成化合物3所用的氯化剂选自氯化氢、三氯化磷、五氯化磷、三氯氧磷中的一种或几种的混合物；所述的还原反应合成化合物4所用的还原剂选自Pd/C-氢气、氢氧化钯/C-氢气、铁粉、锌粉、硼氢化钠、硼氢化钾中的一种或几种的混合物。
4.根据权利要求1的方法，其特征在于,所述的合成化合物2的反应所用溶剂选自四氢呋喃、N,N-二甲基甲酰胺、甲苯、甲醇、乙醇、正丙醇、异丙醇中的一种或几种的混合物；所述的氯化反应合成化合物3所用的溶剂选自四氢呋喃、二氯甲烷、氯仿、四氯化碳、氯化亚砜、三氯氧磷中的一种或几种的混合物；所述的还原反应合成化合物4所用的溶剂选自甲醇、乙醇、正丙醇、异丙醇中的一种或几种的混合物。
5.根据权利要求1的方法，其特征在于,所述的合成化合物2的反应温度是0℃-溶剂的回流温度；所述的氯化反应合成化合物3所用的反应温度是0℃-溶剂的回流温度；所述的还原反应合成化合物4的反应温度是0℃-溶剂的回流温度。
6.根据权利要求1的方法，其特征在于,所述的合成化合物2的反应温度是溶剂的回流温度；所述的氯化反应合成化合物3所用的反应温度是溶剂的回流温度；所述的还原反应合成化合物4的反应温度是室温。
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| CN104086543A (zh) * | 2014-06-19 | 2014-10-08 | 湖南华腾制药有限公司 | 一种制备4-氯-1,8-二氮萘的方法 |
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| CN104086543A (zh) * | 2014-06-19 | 2014-10-08 | 湖南华腾制药有限公司 | 一种制备4-氯-1,8-二氮萘的方法 |
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