技术领域technical field
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。The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to an intermediate 6-amino-7-hydroxyl-3,4-dihydroquinone used in the synthesis of tinib antineoplastic drugs Process for the preparation of oxazolin-4-ones.
背景技术Background technique
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。Protein tyrosine kinase (PTK) is the most common growth factor receptor, by blocking the signal transmission of tyrosine kinase to destroy tumor cells, so as to achieve the purpose of anti-tumor. Receptor tyrosine kinase inhibitors include single-target tyrosine kinase inhibitors and multi-target tyrosine kinase inhibitors. At present, the active antineoplastic drug tinib is a multi-target tyrosine kinase inhibitor, which has anti-prostate cancer, lung cancer, gastric cancer, blood cancer, breast cancer, intestinal cancer, pancreatic cancer and gallbladder cancer.
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。Analyzing the molecular structure of tinib drugs, a large part of small molecular compounds with quinazoline as the core, such as gefitinib, erlotinib, icotinib and vandetanib, have been clinically used showed good biological activity. In particular, the newly marketed Afatinib (Afatinib) and Canertinib (Canertinib) and Dacomitinib (Dacomitinib) under clinical research all have quinine with 6-position hydroxyl and 7-position amino. The oxazoline structure.
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。The preparation of the disclosed above-mentioned tinib class antineoplastic drugs mainly contains the following two types of methods: World Patent No. WO0250043A1 and WO03094921A2 respectively reported the use of 4-chloro-6-amino-7-fluoroquinazoline (V) and 4 -A preparation method in which chloro-6-amino-7-methoxyquinazoline (VI) is a starting material.
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。In addition, by chlorination of 3,4-dihydroquinazolin-4-one substituted at the 6,7-position, the formed chlorinated intermediate (VIII) undergoes a 4-position condensation reaction with aniline derivatives, which can be conveniently Preparation of the target compound of tinib antineoplastic drugs.
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。It can be seen that 6-amino-7-hydroxyl-3,4-dihydroquinazolin-4-one (I) will become the anti-tumor agent for the preparation of the above-mentioned 6-amino-7-hydroxyquinazoline derivatives. Another important intermediate of drugs. The synthesis of this intermediate in the prior art must go through steps such as nitration, reduction, and ring formation. However, the use of fuming nitric acid and concentrated sulfuric acid in the existing nitration technology causes side reactions such as oxidation, elimination or substitution of the exposed amino groups and hydroxyl groups in the raw materials, so in the actual operation process, the amino groups and hydroxyl groups have to be protected. However, after the steps of nitration and reduction are completed, these protective groups need to be removed, so that the number of reaction steps increases and the overall yield decreases. At the same time, the selectivity of the current nitrification reaction is not strong, it is easy to produce pollution, and it does not meet the requirements of industrialization. If can develop a simple and quick, with low cost and be suitable for the preparation method of industrialized preparation 6-amino-7-hydroxyl-3,4-dihydroquinazolin-4-ketone (I), for the anti-oxidant based on quinazoline structure The production and preparation of tumor drugs such as Afatinib, Canertinib and Dacomitinib have very important practical significance.
发明内容Contents of the invention
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。The object of the present invention is to provide an improved 6-amino-7-hydroxyl-3,4-dihydroquinazolin-4-one preparation method for the above-mentioned defects in the prior art, especially through solid acid catalysis The nitration reaction enhances the activity and selectivity of the nitration reaction, avoids the protection and deprotection process of amino groups and hydroxyl groups, and significantly improves the atom economy, process simplicity and environmental friendliness of the entire preparation process.
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，In order to achieve the above object, the main technical scheme provided by the present invention is as follows: a method for preparing 6-amino-7-hydroxyl-3,4-dihydroquinazolin-4-one (I),
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)。It is characterized in that the preparation method comprises the following steps: 3-amino-4-hydroxybenzoic acid or 3-amino-4-hydroxybenzoic acid ester or 3-amino-4-hydroxybenzoic acid represented by formula (II) Amide is used as raw material, and 6-amino-7-hydroxyl-3,4-dihydroquinazolin-4-one (I) is prepared through nitration reaction, reduction reaction and ring-forming reaction in sequence.
此外，本发明还包括如下附属技术方案：In addition, the present invention also includes the following subsidiary technical solutions:
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。When R in the chemical formula (II) is a hydroxyl group (OH), the raw material is 3-amino-4-hydroxybenzoic acid; when R is an alkoxy group (OR'), the raw material is 3-amino-4-hydroxyl Benzoate; when R is amino (NH2 ), the starting material is 3-amino-4-hydroxybenzamide.
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。When the R is an alkoxy group (OR'), the alkyl group R' is methyl, ethyl, propyl, allyl, isopropyl, n-butyl, tert-butyl, cyclohexyl, benzyl A benzyl group or a benzyl group substituted on the benzene ring, preferably a methyl group or an ethyl group.
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。The nitrating agent for the nitration reaction is concentrated nitric acid, copper nitrate, bismuth nitrate or zinc nitrate, preferably concentrated nitric acid or zinc nitrate.
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。The catalyst of the nitration reaction is sulfuric acid/melamine formaldehyde resin, sulfuric acid/polyvinylpyrrolidone (PVP), sulfuric acid/silicon dioxide, trichloro-triazine (TCT) or aluminum dihydrogen phosphate, preferably trichloro-triazine or phosphoric acid Aluminum dihydrogen.
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％。The amount of catalyst used in the nitration reaction is 1-10%, preferably 1-5%, of the amount of the starting material (II).
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。The solvent of the nitration reaction is dichloromethane, chlorobenzene, chloroform, 1,2-dichloromethane, acetonitrile or water, preferably acetonitrile or water.
所述硝化反应的温度为0-120℃，优选20-30℃。The temperature of the nitration reaction is 0-120°C, preferably 20-30°C.
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。The 6-amino-7-hydroxyl-3,4-dihydroquinazolin-4-one is an intermediate required for the synthesis of tinib antineoplastic drugs.
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。Compared with the prior art, the preparation method of the intermediate 6-amino-7-hydroxyl-3,4-dihydroquinazolin-4-one involved in the present invention, the process route is through the new The use of the catalyst makes the nitration reaction more selective. At the same time, by omitting reaction steps such as protection and deprotection of functional groups, the whole process is simpler, the yield is higher, and it is more economical and environmentally friendly.
具体实施方式Detailed ways
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。The core of the present invention lies in the utilization of new nitration reaction technology, and reduction and ring formation reaction are all known technologies. In the following, several specific preparation processes and methods will be used to further non-limitatively illustrate the key nitration technical solutions.
实施例一： Embodiment one:
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％。At room temperature, add 3-amino-4-hydroxyl-benzoic acid methyl ester (II) (3.4g, 20mmol), zinc nitrate (4.2g, 22mmol), trichloro-s-triazine (0.11g, 3% eq) and acetonitrile 25mL. The reaction was stirred for 3 hours. Dry with anhydrous sodium sulfate, recover the solvent under reduced pressure, and recrystallize the residue with ethyl acetate to obtain 3.5 g of light yellow solid methyl 2-nitro-4-hydroxy-5-aminobenzoate (III). The yield is 82.5%.
实施例二： Embodiment two:
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％。At room temperature, add 3-amino-4-hydroxy-benzoic acid methyl ester (II) (3.4g, 20mmol), nitric acid (70%, 2.7mL, 30mmol), aluminum dihydrogen phosphate (0.07g, 1 %eq) and acetonitrile 20mL. The reaction was stirred for 2 hours. Sodium bicarbonate solution was added to adjust the pH to neutral, ethyl acetate was added to extract, the organic phase was washed with water, and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 3.7 g of methyl 2-nitro-4-hydroxy-5-aminobenzoate (III) as a pale yellow solid with a yield of 87.3%.
实施例三： Embodiment three:
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％。At room temperature, add 3-amino-4-hydroxy-benzoic acid (II) (3.1g, 20mmol), zinc nitrate (4.2g, 22mmol), trichloro-s-triazine (0.11g, 3%eq) into the reaction flask and acetonitrile 25mL. The reaction was stirred for 4 hours. Dry over anhydrous sodium sulfate, recover the solvent under reduced pressure, and recrystallize the residue from ethanol to obtain 3.2 g of light yellow solid 2-nitro-4-hydroxy-5-aminobenzoic acid (III), with a yield of 80.8%.
实施例四： Embodiment four:
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％。At room temperature, add 3-amino-4-hydroxyl-benzamide (II) (3.1g, 20mmol), zinc nitrate (4.2g, 22mmol), trichloro-s-triazine (0.11g, 3% eq ) and acetonitrile 25mL. The reaction was stirred for 2 hours. Dry over anhydrous sodium sulfate, recover the solvent under reduced pressure, and recrystallize the residue from methanol to obtain 3.1 g of light yellow solid 2-nitro-4-hydroxy-5-aminobenzamide (III), with a yield of 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。It should be pointed out that the above-mentioned embodiment is only to illustrate the technical concept and characteristics of the present invention, and its purpose is to enable those familiar with this technology to understand the content of the present invention and implement it accordingly, and cannot limit the protection scope of the present invention. . All equivalent changes or modifications made according to the spirit of the present invention shall fall within the protection scope of the present invention.
| Application Number | Priority Date | Filing Date | Title |
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| CN201310181150.2ACN103288757B (en) | 2013-05-16 | 2013-05-16 | Preparation method of 6-amino-7-hydroxyl-3,4-dihydroquinazoline-4-ketone |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310181150.2ACN103288757B (en) | 2013-05-16 | 2013-05-16 | Preparation method of 6-amino-7-hydroxyl-3,4-dihydroquinazoline-4-ketone |
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