CN103288757B - 6-氨基-7-羟基-3,4-二氢喹唑啉-4-酮的制备方法 - Google Patents
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Abstract
本发明揭示了一种6-氨基-7-羟基-3，4-二氢喹唑啉-4-酮的制备方法，其包括如下步骤：以3-氨基-4-羟基苯甲酸或3-氨基-4-羟基苯甲酸酯或3-氨基-4-羟基苯甲酰胺为原料，依次经硝化反应、还原反应以及成环反应，制备所述6-氨基-7-羟基-3，4-二氢喹唑啉-4-酮(I)。该工艺路线通过新型催化剂的使用，使硝化反应的选择性更强。同时，通过省略官能团的保护和脱保护等反应步骤，使得整个过程更为简洁、收率更高，更加经济环保。
Description
技术领域
本发明属于有机合成路线设计及其原料药和中间体制备技术领域，特别涉及一种用于替尼类抗肿瘤药合成所需中间体6-氨基-7-羟基-3，4-二氢喹唑啉-4-酮的制备方法。
背景技术
蛋白酪氨酸激酶(PTK)是最常见的生长因子受体，通过阻断酪氨酸激酶破坏肿瘤细胞的信号传递，从而达到抗肿瘤的目的。受体酪氨酸激酶抑制剂包括单靶点酪氨酸激酶抑制剂和多靶点酪氨酸激酶抑制剂。目前研究比较活跃的替尼类抗肿瘤药物就属于多靶点酪氨酸激酶抑制剂，具有抗前列腺癌、肺癌、胃癌、血癌、乳腺癌、肠癌、胰腺癌和胆癌等作用。
分析替尼类药物的分子结构，有很大一部分是以喹唑啉为核心的小分子化合物，如吉非替尼、厄洛替尼、埃克替尼和凡德他尼等已经在临床上表现出了很好的生物活性。特别地，新近上市的阿法替尼(Afatinib)和正在临床研究之中的卡奈替尼(Canertinib)、达克米替尼(Dacomitinib)则均具有6-位羟基和7-位氨基的喹唑啉结构。
已经公开的上述替尼类抗肿瘤药的制备主要有以下两类方法：世界专利第WO0250043A1号和WO03094921A2号分别报道了以4-氯-6-氨基-7-氟喹唑啉(V)和4-氯-6-氨基-7-甲氧基喹唑啉(VI)为起始原料的制备方法。
另外，利用6，7-位取代的3，4-二氢喹唑啉-4-酮通过氯化，形成的氯代物中间体(VIII)与苯胺衍生物发生4-位缩合反应，可方便地制备替尼类抗肿瘤药物的目标化合物。
由此可见，6-氨基-7-羟基-3，4-二氢喹唑啉-4-酮(I)将会成为制备上述6-氨基-7羟基喹唑啉衍生物的替尼类抗肿瘤药物的又一重要中间体。现有技术对该中间体的合成，必须通过硝化、还原、成环等步骤。而现有硝化技术中发烟硝酸和浓硫酸的使用，使得原料中裸露的氨基和羟基发生氧化、消去或取代等副反应，所以实际操着过程中，不得不对氨基和羟基进行必要的保护，而在完成硝化、还原等步骤后又需要脱除这些保护基团，从而使反应步骤增多，总收率降低。同时，现行硝化反应的选择性不强，易产生污染，不适应工业化要求。如果能开发出一条简单快捷、成本低廉且适合工业化制备6-氨基-7-羟基-3，4-二氢喹唑啉-4-酮(I)的制备方法，对于基于喹唑啉结构的抗肿瘤药物如阿法替尼(Afatinib)、卡奈替尼(Canertinib)和达克米替尼(Dacomitinib)等的生产和制备具有非常重要的现实意义。
发明内容
本发明的目的在于针对现有技术中的上述缺陷，提供一种改进的6-氨基-7-羟基-3，4-二氢喹唑啉-4-酮的制备方法，特别是通过固体酸催化的硝化反应，增强了硝化反应的活性和选择性，避免了氨基和羟基的保护和脱保护过程，使整个制备过程的原子经济性、工艺简洁性和环境友好性得到显著的提高。
为了实现上述目的，本发明所提供的主要技术方案如下：一种制备6-氨基-7-羟基-3，4-二氢喹唑啉-4-酮(I)的方法，
其特征在于所述制备方法包括如下步骤：以式(II)所示的3-氨基-4-羟基苯甲酸或3-氨基-4-羟基苯甲酸酯或3-氨基-4-羟基苯甲酰胺为原料，依次经硝化反应、还原反应以及成环反应，制备6-氨基-7-羟基-3，4-二氢喹唑啉-4-酮(I)。
此外，本发明还包括如下附属技术方案：
当所述化学式(II)中的R为羟基(OH)时，原料为3-氨基-4-羟基苯甲酸；当R为烷氧基(OR’)时，原料为3-氨基-4-羟基苯甲酸酯；当R为胺基(NH2)时，原料为3-氨基-4-羟基苯甲酰胺。
当所述R为烷氧基(OR’)时，其中的烷基R’为甲基、乙基、丙基、烯丙基、异丙基、正丁基、叔丁基、环己基、苄基或苯环上取代的苄基，优选甲基或乙基。
所述硝化反应的硝化剂为浓硝酸、硝酸铜、硝酸铋或硝酸锌，优选浓硝酸或硝酸锌。
所述硝化反应的催化剂为硫酸/三聚氰胺甲醛树脂、硫酸/聚乙烯吡咯烷酮(PVP)、硫酸/二氧化硅、三氯均三嗪(TCT)或磷酸二氢铝，优选三氯均三嗪或磷酸二氢铝。
所述硝化反应的催化剂用量为起始原料(II)物质量的1-10％，优选1-5％。
所述硝化反应的溶剂为二氯甲烷、氯苯、三氯甲烷、1，2-二氯甲烷、乙腈或水，优选乙腈或水。
所述硝化反应的温度为0-120℃，优选20-30℃。
所述6-氨基-7-羟基-3，4-二氢喹唑啉-4-酮为用于替尼类抗肿瘤药合成所需中间体。
相比于现有技术，本发明所涉及的替尼类抗肿瘤药物中间体6-氨基-7-羟基-3，4-二氢喹唑啉-4-酮的制备方法，该工艺路线通过新型催化剂的使用，使硝化反应的选择性更强。同时，通过省略官能团的保护和脱保护等反应步骤，使得整个过程更为简洁、收率更高，更加经济环保。
具体实施方式
本发明的核心在于新的硝化反应技术的运用，而还原和成环反应均为公知技术。下面通过数个具体的制备过程和方法对关键的硝化技术方案作进一步非限制性说明。
实施例一：
室温下，于反应瓶中加入3-氨基-4-羟基-苯甲酸甲酯(II)(3.4g，20mmol)、硝酸锌(4.2g，22mmol)、三氯均三嗪(0.11g，3％eq)和乙腈25mL。搅拌反应3小时。用无水硫酸钠干燥，减压回收溶剂，剩余物用乙酸乙酯重结晶，得淡黄色固体2-硝基-4-羟基-5-氨基苯甲酸甲酯(III)3.5g，收率为82.5％。
实施例二：
室温下，于反应瓶中加入3-氨基-4-羟基-苯甲酸甲酯(II)(3.4g，20mmol)、硝酸(70％，2.7mL，30mmol)、磷酸二氢铝(0.07g，1％eq)和乙腈20mL。搅拌反应2小时。加入碳酸氢钠溶液调节pH至中性，加入乙酸乙酯萃取，有机相用水洗涤，无水硫酸钠干燥。减压回收溶剂，剩余物用乙酸乙酯重结晶，得淡黄色固体2-硝基-4-羟基-5-氨基苯甲酸甲酯(III)3.7g，收率为87.3％。
实施例三：
室温下，于反应瓶中加入3-氨基-4-羟基-苯甲酸(II)(3.1g，20mmol)、硝酸锌(4.2g，22mmol)、三氯均三嗪(0.11g，3％eq)和乙腈25mL。搅拌反应4小时。用无水硫酸钠干燥，减压回收溶剂，剩余物用乙醇重结晶，得淡黄色固体2-硝基-4-羟基-5-氨基苯甲酸(III)3.2g，收率为80.8％。
实施例四：
室温下，于反应瓶中加入3-氨基-4-羟基-苯甲酰胺(II)(3.1g，20mmol)、硝酸锌(4.2g，22mmol)、三氯均三嗪(0.11g，3％eq)和乙腈25mL。搅拌反应2小时。用无水硫酸钠干燥，减压回收溶剂，剩余物用甲醇重结晶，得淡黄色固体2-硝基-4-羟基-5-氨基苯甲酰胺(III)3.1g，收率为78.3％。
需要指出的是，上述实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (7)
1.一种6-氨基-7-羟基-3,4-二氢喹唑啉-4-酮的制备方法，
其特征在于所述制备方法包括如下步骤：以3-氨基-4-羟基苯甲酸或3-氨基-4-羟基苯甲酸酯或3-氨基-4-羟基苯甲酰胺为原料，依次经硝化反应、还原反应以及成环反应，制备所述6-氨基-7-羟基-3,4-二氢喹唑啉-4-酮(I)，其中所述硝化反应的催化剂为三氯均三嗪。
2.根据权利要求1所述6-氨基-7-羟基-3,4-二氢喹唑啉-4-酮的制备方法，其特征在于：当所述原料为3-氨基-4-羟基苯甲酸酯时，其中的酯基为甲基、乙基、丙基、烯丙基、正丁基、叔丁基、环己基、苄基或苯环上取代的苄基。
3.根据权利要求1所述6-氨基-7-羟基-3,4-二氢喹唑啉-4-酮的制备方法，其特征在于：所述硝化反应的硝化剂包括浓硝酸、硝酸铜、硝酸铋或硝酸锌。
4.根据权利要求3所述6-氨基-7-羟基-3,4-二氢喹唑啉-4-酮的制备方法，其特征在于：所述硝化反应的催化剂用量为所述原料物质量的1-10％。
5.根据权利要求4所述6-氨基-7-羟基-3,4-二氢喹唑啉-4-酮的制备方法，其特征在于：所述硝化反应的溶剂为二氯甲烷、氯苯、三氯甲烷、乙腈或水。
6.根据权利要求3所述6-氨基-7-羟基-3,4-二氢喹唑啉-4-酮的制备方法，其特征在于：所述硝化反应的温度为0-120℃。
7.根据权利要求1至6中任一项所述6-氨基-7-羟基-3,4-二氢喹唑啉-4-酮的制备方法，其特征在于：所述6-氨基-7-羟基-3,4-二氢喹唑啉-4-酮为用于替尼类抗肿瘤药合成所需中间体。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000015638A1 (en) * | 1998-09-14 | 2000-03-23 | Dr. Reddy's Research Foundation | An improved process for the preparation of thiazolidine-2,4-dione derivatives |
| JP2002293773A (ja) * | 2001-03-30 | 2002-10-09 | Sumika Fine Chemicals Co Ltd | キナゾリン誘導体の製造方法 |
| WO2003064399A1 (fr) * | 2002-01-28 | 2003-08-07 | Ube Industries, Ltd. | Procede de production de derive de quinazolin-4-one |
| CN101613356A (zh) * | 2009-07-23 | 2009-12-30 | 东南大学 | 喹唑啉类四环衍生物及制备方法和在制药中的应用 |
| CN102898384A (zh) * | 2012-08-14 | 2013-01-30 | 邓俐丽 | 制备吉非替尼的中间体及所述中间体的制备方法 |
-
2013
- 2013-05-16 CN CN201310181150.2A patent/CN103288757B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000015638A1 (en) * | 1998-09-14 | 2000-03-23 | Dr. Reddy's Research Foundation | An improved process for the preparation of thiazolidine-2,4-dione derivatives |
| JP2002293773A (ja) * | 2001-03-30 | 2002-10-09 | Sumika Fine Chemicals Co Ltd | キナゾリン誘導体の製造方法 |
| WO2003064399A1 (fr) * | 2002-01-28 | 2003-08-07 | Ube Industries, Ltd. | Procede de production de derive de quinazolin-4-one |
| CN101613356A (zh) * | 2009-07-23 | 2009-12-30 | 东南大学 | 喹唑啉类四环衍生物及制备方法和在制药中的应用 |
| CN102898384A (zh) * | 2012-08-14 | 2013-01-30 | 邓俐丽 | 制备吉非替尼的中间体及所述中间体的制备方法 |
Non-Patent Citations (4)
| Title |
|---|
| Tyrosine Kinase Inhibitors. 8. An Unusually Steep Structure-Activity Relationship for Analogues of 4-(3-Bromoanilino)-6,7- dimethoxyquinazoline (PD153035), a Potent Inhibitor of the Epidermal Growth Factor Receptor;Alexander J. Bridges等;《J. Med. Chem.》;19960105;第39卷(第1期);第267-276页 * |
| 硝酸铜硝化水杨酸甲酯的绿色硝化方法研究;李霞等;《精细化工中间体》;20091231;第39卷(第6期);第40-43页 * |
| 磷酸二氢钾催化下甲苯的选择性硝化;刘丽荣等;《含能材料》;20080229;第16卷(第1期);第63-65页 * |
| 芳香烃清洁硝化催化剂;丁春丽等;《化工环保》;20041231;第24卷(第5期);第361-366页 * |
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