CN106279057B - Ataluren的合成方法 - Google Patents
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
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Abstract
本发明公开了一种Ataluren的合成方法。该方法包括以下步骤：步骤1，化合物2在碱性条件下和盐酸羟胺反应得到中间体3；步骤2，在还原剂二乙氧基甲基硅烷和双(4‑硝基苯基)磷酸酯存在下，催化量的三苯基膦和等当量的四氯化碳和化合物4反应得到目标化合物Ataluren(1)。该方法原料易得，合成步骤简短，环境友好，后处理方便，具有良好的工业生产价值。
Description
技术领域
本发明涉及用于治疗杜氏肌营养不良症和囊性纤维化症的药物Ataluren的合成方法。
背景技术
杜氏肌营养不良症(DMD)是一种X染色体隐性遗传疾病，多发于男性。平均每3600个男婴中就有一例。其病因为位于X染色体上肌营养不良蛋白(dystrophin)的遗传基因发生突变，而肌营养不良蛋白是稳定肌肉组织细胞膜的一个重要部份。它最重要的功能是维持肌肉细胞的稳定性，使肌肉在收缩的过程中不会受到破坏，由于杜氏肌营养不良症患者缺少此种蛋白，其肌肉细胞从其出生以来便不断受到破坏和萎缩。囊性纤维化症(cysticfibrosis)是一种染色体隐形遗传疾病，主要影响肺部和消化系统，多见于欧罗巴人种，表现症状为呼吸困难、咳嗽时会伴随十分粘稠的液体、粪便脂肪含量很高。其病因为用于合成囊性纤维化跨膜传导调节因子(CFTR)蛋白的基因发生突变。CFTR与汗液、消化液、粘液的分泌有密切关系。当CFTR失去功能时分泌液就会变浓。直到上世纪末，这两类疾病患者的寿命都很短，严重影响生活质量。
虽然根治杜氏肌营养不良症和囊性纤维化症的药物尚未被发现，但对于控制病情及改善患者生活质量的药物不断地被研发。
Ataluren原名是PTC124，化学名称为3-(5-(2-氟苯基)-[1，2，4]-噁二唑-3-基)苯甲酸。是PTC公司(PTC Therapeutics)开发的一类用于治疗无义突变导致的杜氏肌营养不良症和囊肿性纤维化症的药物。
目前已经有众多的合成Ataluren的方法，如中国专利CN 101535284A等。还包括期刊Drug of the future，2008，33(9)，733；New J.Chem.，2014，38，3062-3070；Adv.Synth.Catal.，2014，356，3074-3082等。这些公开的专利或文献采用的合成方法主要存在以下缺点：
1.反应路线普遍比较长，总收率偏低；
2.某些合成过程中会产生二氧化硫、氯化氢等气体，环境污染严重；
3.噁二唑环构建过程需要使用到脱水剂，制备成本较高，不适合工业化生产。
发明内容
本发明的目的是提供一种Ataluren的合成方法，该方法合成路线短，环境友好，产物收率高，适合工业化生产。
为了达到上述目的，本发明提供了一种Ataluren的合成方法，具体合成路线如下式所示：
步骤1，化合物2在碱性条件下和盐酸羟胺回流反应，生产中间体3。
步骤2，在还原剂存在下，化合物4通过催化量的三苯基膦和等当量的卤化试剂活化，四丁基氟化铵催化下和化合物3反应，得到目标化合物Ataluren。
上述Ataluren的合成方法，其中，步骤2过程中的还原剂为二乙氧基甲基硅烷和双(对硝基苯基)磷酸酯。
上述Ataluren的合成方法，其中，步骤2过程中的卤化试剂选自四氯化碳，四溴化碳，三氯乙腈等，优选四氯化碳。
上述Ataluren的合成方法，其中，步骤2过程中的催化剂为四丁基氟化铵。
上述Ataluren的合成方法，其中，步骤2过程中反应所采用的温度为30-150℃，优选120℃。
具体实施方式
以下将通过实施例进一步描述本发明，但是，这些描述仅用于说明本发明，不是对本发明的限制。
一、化合物3的合成
实施例1
将3-氰基苯甲酸(2，147g，1mol)，盐酸羟胺(695g，10mol)和200mL乙醇混合。缓慢投入碳酸钾(1380g，10mol)，90℃油浴加热回流反应。薄层层析(TLC)追踪反应直至3-氰基苯甲酸耗尽。待反应液冷却后加水和乙酸乙酯，分液收集有机相，有机相加入适量无水硫酸钠干燥。减压浓缩得到白色固体化合物3，163.8g，收率91％。
二、Ataluren的合成
实施例2
往反应器中加入邻氟苯甲酸(4，140g，1mol)，化合物3(180g，1mol)，三苯基膦(52.4g，0.2mol)四氯化碳(152g，1mol)，二乙氧基甲基硅烷(202.6g，1.2mol)，双(对硝基苯基)磷酸酯(17.1g，0.05mol)，甲苯500mL。120℃油浴加热冷凝回流反应24小时。待反应液冷却后，用乙酸乙酯萃取，加入无水硫酸钠干燥，减压浓缩蒸干，柱层析得目标化合物Ataluren(1，184.6g)，白色固体，收率65％。
Claims (3)
1.一种Ataluren的合成方法，其特征在于该方法包含以下具体步骤：
步骤1，化合物2在碱性条件下和盐酸羟胺反应得到化合物3；
步骤2，在还原剂存在下，化合物4通过催化量的三苯基膦和等当量的卤化试剂活化，四丁基氟化铵催化下和化合物3反应，得到目标化合物Ataluren；
其中，步骤2中的卤化试剂为四氯化碳；步骤2中的还原剂为二乙氧基甲基硅烷和双(对硝基苯基)磷酸酯。
2.如权利要求1所述的Ataluren的合成方法，所述还原剂二乙氧基甲基硅烷和双(对硝基苯基)磷酸酯的摩尔比为1.2∶0.05。
3.如权利要求1所述的Ataluren的合成方法，其特征在于，步骤2过程中反应所采用的温度为30-150℃。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101970420A (zh) * | 2007-10-04 | 2011-02-09 | 默克雪兰诺有限公司 | 噁二唑衍生物 |
| CN102076670A (zh) * | 2008-06-24 | 2011-05-25 | Irm责任有限公司 | 调节g蛋白偶联受体的化合物和方法 |
| CN104056278A (zh) * | 2003-04-11 | 2014-09-24 | Ptc治疗公司 | 1,2,4-噁二唑苯甲酸化合物 |
| WO2016073545A1 (en) * | 2014-11-06 | 2016-05-12 | Concert Pharmaceuticals, Inc. | Phenyloxadiazole benzoic acids |
| US20170362192A1 (en) * | 2016-06-20 | 2017-12-21 | Scinopharm Taiwan, Ltd. | Process for preparing ataluren and its intermediates |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104056278A (zh) * | 2003-04-11 | 2014-09-24 | Ptc治疗公司 | 1,2,4-噁二唑苯甲酸化合物 |
| CN101970420A (zh) * | 2007-10-04 | 2011-02-09 | 默克雪兰诺有限公司 | 噁二唑衍生物 |
| CN102076670A (zh) * | 2008-06-24 | 2011-05-25 | Irm责任有限公司 | 调节g蛋白偶联受体的化合物和方法 |
| WO2016073545A1 (en) * | 2014-11-06 | 2016-05-12 | Concert Pharmaceuticals, Inc. | Phenyloxadiazole benzoic acids |
| US20170362192A1 (en) * | 2016-06-20 | 2017-12-21 | Scinopharm Taiwan, Ltd. | Process for preparing ataluren and its intermediates |
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Denomination of invention: Synthesis of Ataluren Effective date of registration: 20220914 Granted publication date: 20220415 Pledgee: Bank of China Limited Guangzhou Development Zone Branch Pledgor: Guangzhou Ming Pharmaceutical Technology Co.,Ltd. Registration number: Y2022980015134 |
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Date of cancellation: 20231023 Granted publication date: 20220415 Pledgee: Bank of China Limited Guangzhou Development Zone Branch Pledgor: Guangzhou Ming Pharmaceutical Technology Co.,Ltd. Registration number: Y2022980015134 |