CN105461691B - 一种阿折地平的制备方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明涉及一种阿折地平的制备方法，采用氰乙酸与间硝基苯甲醛作为起始物料，二者进行Knoevenagel反应，生成化合物1；化合物1的氰基水解后生成化合物2；化合物2在DCC作用下与1‑二苯甲基‑3‑吖丁啶醇成脂生成化合物3；化合物3与3‑氨基巴豆酸异丙酯在碱性条件下进行Hantzsch合环生成阿折地平粗品；粗品经精制后得阿折地平精品。该方法操作简单，反应产物易于分离，适合工业化生产。
Description
技术领域
本发明涉及一种阿折地平的制备方法，属医药技术领域。
背景技术
阿折地平为第三代二氢吡啶类的代表药物，与第一代、第二代二氢吡啶类药物相比，其服用后作用时间长，扩血管后不引起反射性交感神经兴奋，不良反应小且几乎无负性肌无力作用。由于以上优点使阿折地平受到越来越多高血压心绞痛等病人的青睐。
阿折地平的合成方法主要有两种：
（1）化合物I与化合物II经Hantzsch反应制得阿折地平，例如CN103130700，CN102453023、EP0266922等均采用此法：
（2）化合物I、间硝基苯甲醛、乙酰乙酸异丙酯经一锅法制备阿折地平，例如CN100352818：
上述两种方法均要用到关键物料脒化物——化合物I。该物料的合成采用1-二苯甲基-3-氮杂环丁烷基氰基乙酸酯经Pinner法合成，此方法首先在酸性条件下对氰基化合物亲核加成生成中间体产物，再与氨供体反应生成脒化物。诸多专利（例如CN103130700、CN102453023等）均采用通盐酸气作为酸化条件，该操作对设备及人员的损害都较大。此外1-二苯甲基-3-氮杂环丁烷基氰基乙酸酯中除了含有氰基外还含有酯基，在酸化过程中，除了发生氰基水解外还能可能发生酯基水解，条件控制不好则生成较多酯水解副产物，因此在脒化物制备过程中要求无水操作，所用氯化氢，溶剂及氨气均要干燥。以上原因导致化合物1的生产受限制较大。
发明内容
本发明的目的是提供一种阿折地平的制备方法。
本发明的技术方案是一种阿折地平的制备方法，其特征在于依次通过下列步骤进行：
第一步 邻硝基苯甲醛与氰基乙酸反应制备化合物1；
第二步 化合物1水解得到酰胺化合物2；
第三步 化合物2与1-二苯甲基-3-吖丁啶醇反应制备化合物3；
第四步 化合物3与化合物4反应制备阿折地平。
根据本发明，第二步水解反应优选在KOH水溶液-乙醇体系中进行。
根据本发明，第三步反应在缩合剂作用下进行，所述缩合剂优选二环己基碳二亚胺。
根据本发明，第四步反应需要在碱作用下完成，所用碱优选甲醇钠。
根据本发明，反应得到的阿折地平粗品可以在正己烷-乙酸乙酯体系中重结晶，进行精制。
更为详细的，一种阿折地平的制备方法，其特征在于，
第一步 邻硝基苯甲醛与氰基乙酸在乙酸哌啶作用下，制备化合物1；
第二步 化合物1在KOH水溶液-乙醇体系中水解制备化合物2；
第三步 化合物2与1-二苯甲基-3-吖丁啶醇在二环己基碳二亚胺存在下，制备化合物3；
第四步 化合物3与化合物4在甲醇钠作用下，制备阿折地平。
本发明的有益效果是采用氰乙酸与间硝基苯甲醛作为起始物料，经Knoevenagel反应，氰基水解，酯化后生成中间体3，中间体3与3-氨基巴豆酸异丙酯经Hantzsch环合即可得到阿折地平。该方法操作简单，避免了化合物I的合成，并且各个中间体均易分离，较为适合工业化生产。
具体实施方式：
为更好的理解本发明内容，下面结合具体实施例作进一步说明，但本发明不仅局限于此。
实施例1
化合物1的合成
5L的反应瓶内，加入2L无水乙醇，6g冰乙酸，8.5g的哌啶20~30℃搅拌0.5h后加入氰乙酸170g，间硝基苯甲醛302g，在20~30℃下反应24h（TLC中控）。反应完毕后抽滤，滤饼用200ml无水乙醇淋洗，烘干的产品405g，收率93%，纯度98.5%。
化合物2的合成
5L的反应瓶内加入400g化合物1，1.5kg的30%KOH水溶液，2L的乙醇，加热至回流反应6h，降温至20~30℃，工业盐酸调节pH至1~2，有大量固体析出，抽滤，少量乙醇淋洗后烘干的产品381g，收率88%，纯度99%。
化合物3的合成
反应瓶中，加入200g化合物2，3.5L四氢呋喃与200g1-二苯甲基-3-吖丁啶醇，搅拌降温，在20℃加入缓慢加入二环己基碳二亚胺170g，加入完毕后缓慢升温至60~70℃，在此温度下反应10h，降温至20~30℃，抽滤，烘干后得化合物3粗品352g，将得到的粗品加入反应瓶内，加入2L的乙酸乙酯，加热溶清后降温至10~20℃析晶2h，抽滤烘干后得化合物3的精品289g，该步总收率74%，纯度99%。
化合物4的合成
将乙酰乙酸异丙酯150g加入反应瓶内，降温至-5～5℃，加入醋酸铵180g，25%的氨水200g，避光在此温度下反应18h，过滤，用100ml冰水冲洗滤饼得固体，将得到的固体在真空干燥箱内30℃烘干得129g，收率为86%，纯度99%。
阿折地平的合成
反应瓶内加入250g的化合物3，85g的化合物4, 2.5L的无水乙醇，50g甲醇钠，加热回流反应6h，反应完毕后减压蒸除溶剂，向反应瓶中加入2L的乙酸乙酯，2L的正己烷，加热重新溶解后缓慢降温至20~30℃析晶2h，抽滤，烘干后得阿折地平粗品278g，收率78%，纯度96%。
精制
将230g 阿折地平粗品加入至1.6 L正己烷与乙酸乙酯（V:V=1：1）的混合溶液中，缓慢升温至物料溶解，加入活性炭11.5g，搅拌0.5h，趁热过滤，滤液重新溶解后缓慢降温至0～10℃，抽滤，滤饼用230ml乙酸乙酯与正己烷（V:V=1：1）淋洗，烘干后得204.7g 阿折地平精品，收率89%，纯度99%。
Claims (4)
1.一种阿折地平的制备方法，其特征在于，依次经过下列反应步骤：
，
第一步邻硝基苯甲醛与氰基乙酸反应制备化合物1；
第二步化合物1水解得到酰胺化合物2；
第三步化合物2与1-二苯甲基-3-吖丁啶醇反应制备化合物3；
第四步化合物3与化合物4反应制备阿折地平。
2.根据权利要求1所述的制备方法，其特征在于，第四步反应在碱作用下完成。
3.根据权利要求1所述的制备方法，其特征在于，
第一步邻硝基苯甲醛与氰基乙酸在乙酸哌啶作用下，制备化合物1；
第二步化合物1在KOH水溶液-乙醇体系中水解制备化合物2；
第三步化合物2与1-二苯甲基-3-吖丁啶醇在二环己基碳二亚胺存在下，制备化合物3；
第四步化合物3与化合物4在甲醇钠作用下，制备阿折地平。
4.根据权利要求2所述的制备方法，其特征在于，第四步所述碱选自甲醇钠。
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| CN112592289B (zh) * | 2020-12-15 | 2022-09-20 | 内蒙古永太化学有限公司 | 一种加巴喷丁中间体的制备方法 |
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|---|---|---|---|---|
| CN103254122A (zh) * | 2013-06-19 | 2013-08-21 | 湖南师范大学 | 一种心血管药物尼伐地平的制备方法 |
| CN103509003A (zh) * | 2012-06-27 | 2014-01-15 | 威海威太医药技术开发有限公司 | 一种阿折地平的制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103509003A (zh) * | 2012-06-27 | 2014-01-15 | 威海威太医药技术开发有限公司 | 一种阿折地平的制备方法 |
| CN103254122A (zh) * | 2013-06-19 | 2013-08-21 | 湖南师范大学 | 一种心血管药物尼伐地平的制备方法 |
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