CN103387565A - 阿西替尼的制备方法 - Google Patents
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Abstract
本发明揭示了一种阿西替尼(I)的制备方法，其制备步骤包括：以6-卤素-1H-吲哚(II)为原料，通过氧化重排反应得到6-卤素-3-甲酰基-1H-吲唑(III)，中间体(III)与N-甲基-2-巯基苯甲酰胺发生米吉塔(Migita)反应得到N-甲基-2-[(3-甲酰基-1H-吲唑-6-基)硫]苯甲酰胺(IV)，中间体(IV)与叶立德试剂(V)发生维狄希(witting)反应制得阿西替尼(I)。该制备方法原料易得，工艺简洁，经济环保，适合工业化生产。
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，特别涉及一种阿西替尼的制备方法。
背景技术
阿西替尼(Axitinib)是一种多靶点酪氨酸激酶抑制剂，可以抑制血管内皮细胞生长因子受体(VEGFR)、血小板衍生生长因子受体(PDGFR)和干细胞生长因子受体(c-KIT)。该药由美国辉瑞(Pfizer)制药公司开发，于2012年1月27日在美国首次上市，被批准用于治疗其他药物治疗无效的晚期肾癌(肾细胞癌)，商品名为Inlyta。
阿西替尼的化学名为：N-甲基-2-[(3-(1E-2-(吡啶-2-基)乙烯)-1H-吲唑-6-基)硫]苯甲酰胺，其结构式为：
有关阿西替尼制备方法研究已有报道，其核心步骤是在1H-吲唑母核的3-位和6-位分别引入乙烯吡啶基和邻苯甲酰胺巯基等侧链官能团，其引入方法和步骤主要有两种途径：
世界专利第WO2001002369号和第WO2006048745号报道了以6-硝基-1H-吲唑为起始原料(VI)，先经碘代、吡喃基保护和Heck反应，得到3-位修饰的中间体6-硝基-3-[1E-2-(吡啶-2-基)乙烯]-1-[N-(吡喃保护-2-基)]吲唑(VII)；中间体(VII)经过硝基的还原、桑德迈尔(Sandmeyer)反应、米吉塔(Migita)交叉偶联反应以及脱保护剂保护基反应制得阿西替尼(I)。该合成路线的特点是先通过Heck反应引入吲哚母环的3-位侧链，再通过Migita反应引入其6-位侧链。由于需要进行保护和脱保护反应，使整个合成步骤增多。同时，Heck反应和Migita反应均要使用贵金属钯催化剂，特别是Heck反应的收率偏低，使得制备成本加大。另外，中间体(VII)的硝基还原产物属于芳香胺类化合物，该中间体的存在会带来潜在的基因毒性物质残留的风险。
美国专利第US20060094881、世界专利第WO2006048744号和报道了另一条以6-碘-1H-吲唑(VIII)为起始原料的合成方法，化合物(VIII)与2-巯基-N-甲基苯甲酰胺发生米吉塔(Migita)反应得到N-甲基-2-[(1H-吲唑-6-基)硫]苯甲酰胺(IX)，中间体(IX)再通过吲唑环的3-位碘代及Heck反应可制得阿西替尼(I)。与前述制备方法相比，该制备路线的特点是先引入吲唑母环的6-位侧链，再引入其3-位侧链。由于不需要进行吲唑环氮原子的保护和脱保护，使整个步骤减少，收率也有所提高。
另外，《Organic Process Research&Development》2008年，第12卷第4期，第637-645页针对第二条合成路线，特别对Heck反应催化剂、配体和溶媒系统进行了优化和改进，也对原料药(API)的纯化进行了研究。改进后的方法，收率和质量均有提高。但是，无论何种路线或制备方法，均涉及Heck反应并使用昂贵的钯催化剂和相应的配体，不但收率偏低，也增加了重金属残留的潜在风险。
发明内容
本发明的目的在于针对现有技术中的缺陷，提供一种具有原料易得、工艺简洁且环保经济的阿西替尼的制备方法。
为实现上述发明目的，本发明采用了如下主要技术方案：一种阿西替尼(I)的制备方法，
其制备步骤包括：6-卤素(X)-1H-吲哚(II)为原料，与亚硝酸钠和盐酸发生氧化重排反应生成中间体6-卤素(X)-3-甲酰基-1H-吲唑(III)，中间体(III)与2-巯基-N-甲基苯甲酰胺发生米吉塔(Migita)反应得到中间体N-甲基-2-[(3-甲酰基-1H-吲唑-6-基)硫]苯甲酰胺(IV)，中间体(IV)与叶立德试剂(V)发生维狄希(Witting)反应得阿西替尼(I)。
此外，本发明还提出如下附属技术方案：
所述原料6-卤素(X)-1H-吲哚(II)中的卤素X为氟、氯、溴或碘，优选碘。
所述氧化重排反应的氧化剂为亚硝酸钠，投料量相对于原料6-卤素(X)-1H-吲哚(II)的摩尔比为1-5∶1，优选4∶1。
所述维狄希(Witting)反应的叶立德试剂(V)为溴化三苯基(2-亚甲基吡啶)内鏻盐、(O，O-二乙基-2-亚甲基吡啶)磷酸酯或(O，O-二苯基-2-亚甲基吡啶)磷酸酯，优选溴化三苯基(2-亚甲基吡啶)内鏻盐。
所述维狄希(Witting)反应的碱促进剂为甲醇钠、乙醇钠、叔丁醇钾、苯基锂或正丁基锂。
所述维狄希(Witting)反应的溶剂为四氢呋喃、二氧六环、N，N-二甲基甲酰胺、二甲亚砜、乙醚、异丙醚、乙腈、苯或甲苯，优选四氢呋喃。
所述维狄希(Witting)反应的温度为-100-0℃，优选-78℃。
相比于现有技术，本发明所涉及的阿西替尼(I)的制备方法，具有原料易得、工艺简洁和环保经济等特点，故而利于该原料药的工业化生产，促进其经济技术的发展。
具体实施方式
以下结合数个较佳实施例对本发明技术方案作进一步非限制性的详细说明。
实施例一：
于三颈反应瓶中加入6-碘-1H-吲哚(II)(2.42g，10mmol)、亚硝酸钠(2.76g，40mmol)和去离子水50mL，室温搅拌30分钟。30分钟内缓慢滴加6N盐酸8mL，使pH约为1-2，继续搅拌反应5小时。加入乙酸乙酯100mL，搅拌15分钟后分出有机层，水层再用乙酸乙酯萃取2次。合并有机相，无水硫酸钠干燥。减压回收溶剂，得棕色固体(粗品)6-碘-3-甲酰基-1H-吲唑(III)2.45g，收率90.4％。
实施例二：
在干燥和氮气氛下，于三口反应瓶中加入6-碘-3-甲酰基-1H-吲唑(III)(1.36g，5mmol)，用N，N-二甲基甲酰胺25mL溶解后，加入[1，1’-双(联苯-膦基)二茂铁]二氯化钯的二氯甲烷络合物0.18g和碳酸铯2.26g，室温搅拌15分钟后，加入2-巯基-N-甲基苯甲酰胺(1.0g，6mmol)，加热至80℃，搅拌反应12小时，冷却至室温，加入乙酸乙酯50mL，搅拌结晶。过滤，所得固体用二氯甲烷溶解后，过硅胶柱，所得液体浓缩结晶，过滤，滤饼依次用水和乙酸乙酯洗涤，得到棕色固体N-甲基-2-[(3-甲酰基-1H-吲唑-6-基)硫]苯甲酰胺(IV)0.95g，收率61.1％。
实施例三：
于三口反应瓶中加入溴化三苯基(2-亚甲基吡啶)内鏻盐(4.33g，10mmol，4eq)和四氢呋喃50mL，搅拌下冷却至-78℃，干燥氮气氛下滴加正丁基锂(4.7mL，1.6M，3eq)，滴毕，搅拌反应30分钟，升温至20℃，转入滴加漏斗待用。于三口反应瓶中加入N-甲基-2-[(3-甲酰基-1H-吲唑-6-基)硫]苯甲酰胺(IV)(0.78g，2.5mmol)和四氢呋喃25mL，降温至0℃，搅拌下滴加上述已经制备的叶立德溶液，滴毕搅拌反应30分钟。倾入饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取两次后，有机相浓缩后，经过硅胶柱层析(乙酸乙酯/正己烷)得到类白色固体阿西替尼(I)0.82g，收率为85.0％。
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 (9)
1.一种阿西替尼(I)的制备方法，
其特征在于所述制备方法，其制备步骤包括：以6-卤素-1H-吲哚(II)为原料，通过氧化重排反应得到6-卤素-3-甲酰基-1H-吲唑(III)，所述6-卤素-3-甲酰基-1H-吲唑(III)与N-甲基-2-巯基苯甲酰胺发生米吉塔反应得到N-甲基-2-[(3-甲酰基-1H-吲唑-6-基)硫]苯甲酰胺(IV)，所述N-甲基-2-[(3-甲酰基-1H-吲唑-6-基)硫]苯甲酰胺(IV)与叶立德试剂(V)发生维狄希反应制得阿西替尼(I)。
2.如权利要求1所述阿西替尼(I)的制备方法，其特征在于：所述原料6-卤素-1H-吲哚(II)中的卤素X为氟、氯、溴或碘。
3.如权利要求1所述阿西替尼(I)的制备方法，其特征在于：所述氧化重排反应的氧化剂为亚硝酸钠，投料量相对于原料6-卤素(X)-1H-吲哚(II)的摩尔比为1-5∶1。
4.如权利要求1所述阿西替尼(I)的制备方法，其特征在于：所述维狄希反应的叶立德试剂(V)为溴化三苯基(2-亚甲基吡啶)内鏻盐、(O，O-二乙基-2-亚甲基吡啶)磷酸酯或(O，O-二苯基-2-亚甲基吡啶)磷酸酯。
5.如权利要求1所述阿西替尼(I)的制备方法，其特征在于：所述维狄希反应的碱促进剂为甲醇钠、乙醇钠、叔丁醇钾、苯基锂或正丁基锂。
6.如权利要求1所述阿西替尼(I)的制备方法，其特征在于：所述维狄希反应的溶剂为四氢呋喃、二氧六环、N，N-二甲基甲酰胺、二甲亚砜、乙醚、异丙醚、乙腈、苯或甲苯。
7.如权利要求1或6所述阿西替尼(I)的制备方法，其特征在于：所述维狄希反应的溶剂优选四氢呋喃。
8.如权利要求1所述阿西替尼(I)的制备方法，其特征在于：所述维狄希反应的温度为-100-0℃。
9.如权利要求1或8所述阿西替尼(I)的制备方法，其特征在于：所述维狄希反应的温度优选-78℃。
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| CN113943271A (zh) * | 2020-07-15 | 2022-01-18 | 鲁南制药集团股份有限公司 | 一种阿昔替尼晶型及其制备方法 |
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