CN105384689A - 一种改进的醋酸艾司利卡西平的合成方法 - Google Patents
一种改进的醋酸艾司利卡西平的合成方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
本发明涉及一种改进的醋酸艾司利卡西平的合成方法，属药物化学领域。以(s)-10-羟基-10,11二氢-5H-二苯并[b,f]氮杂卓为原料，经乙酰氯酰化得到（s）-10-乙酰基-10,11二氢-5H-二苯并[b,f]氮杂卓，反应体系不经分离直接和氰酸钾在强酸型离子交换树脂存在下反应得到（s）-10-乙酰基-10,11二氢-5H-二苯并[b,f]氮杂卓-5-甲酰胺（醋酸艾司利卡西平），粗品经进一步纯化得到醋酸艾斯利卡西平。本发明所采用试剂廉价低毒，反应安全可靠，反应溶剂和树脂可回收再利用，后处理操作简便，环境友好，收率及纯度高，利于规模化的工业生产。
Description
技术领域
本发明涉及一种醋酸艾司利卡西平的合成和纯化方法，属药物化学领域。
背景技术
醋酸艾司利卡西平，化学名（s）-10-乙酰基-10,11二氢-5H-二苯并[b,f]氮杂卓-5-甲酰胺，由葡萄牙Bial公司研制的抗癫痫类药物，2009年10月在欧洲首次上市，并于2013年11月经FDA批准上市。可用于伴或不伴继发性全身性发作的成人癫痫患者的部分性发作的辅助治疗，且安全性好，神经精神副作用低，具有广阔的市场前景。
目前，已经报道了几种合成醋酸艾斯利卡西平的方法。发明专利WO2007012793（A1）（路线1）和CN101421245A（路线2）公布了以奥卡西平为原料，经不对称催化氢化制备醋酸艾司利卡西平的方法。如下所示：
以上两条路线都采用了价格昂贵的Ru做催化剂，反应条件也相对苛刻，增加了生产成本。
如路线3所示，RakeshwarBandichhor等（TetrahedronLetters54(2013)2841–2844）报道了采用10-甲氧基亚氨基芪为原料，经脱甲基后采用硼烷二甲硫醚溶液和(R)-2-甲基-CBS-恶唑硼烷为还原剂，实现了羰基的手性还原。羟基进行选择性乙酰化后与氯磺酰异腈酸酯反应得到醋酸艾司利卡西平。该合成方法避免了价格昂贵的Ru催化剂，但是在氨基甲酰基化反应过程中采用剧毒且价格较贵的氯磺酸异氰酸酯，增加了成本和污染，同时反映需要过夜时间较长。虽然作者尝试了尿素/HCl和异氰酸钠及异氰酸钠/对甲苯磺酸吡啶盐作为氨基甲酰基化试剂，但是存在收率低、转化不完全以及后处理麻烦等缺点，不利于工业生产。
综上，路线1和路线2成本较高，反应条件苛刻对设备要求高；路线3相对于路线1和2成本有所降低，但是采用了剧毒的氯磺酸异氰酸酯，增加了环境压力，而报道中采用的尿素以及氰酸钠的尝试方法无法满足工业生产的需求。
发明内容
本发明的目的是克服上述现有技术中反应试剂成本高、毒害大，反应路线长，原料转化率低及后处理复杂等缺点，提供一种改进的制备醋酸艾司利卡西平的合成方法。
为实现本发明的目的，本发明以化合物1为原料，在具体操作步骤中对反应溶剂、试剂、反应时间以及纯化方法等进行了筛选和优化，找到了操作方便，收率较高，质量较好，反应条件温和、适合工业化生产的合成方法。
本发明采用的技术方案如下：
（1）将化合物1、缚酸剂和溶剂加入到反应瓶中，冰浴条件下向体系中滴加乙酰氯，滴加完毕后继续反应。甲苯作为溶剂。所述缚酸剂选用碳酸氢钠、碳酸氢钾、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、三乙胺、吡啶、二异丙基乙胺、三叔丁基胺中的一种或几种。优选化合物1、缚酸剂和乙酰氯的摩尔比1:1.2:1.1。
（2）完毕后向体系内加入强酸型阳离子交换树脂，而后向体系中缓慢滴加氰酸钾溶液，滴加完毕后升温体系至70-80℃反应。经过滤，洗涤，得醋酸艾司利卡西平和树脂的混合物。强酸型阳离子交换树脂优选全氟磺酸树脂。
（3）将醋酸艾司利卡西平粗品和树脂的混合物溶于良性溶剂中，过滤除去树脂，搅拌下向体系中滴加惰性溶剂。滴加完毕后继续搅拌，过滤得醋酸艾司利卡西平。所述良性溶剂采用甲醇、异丙醇、乙醇、乙酸乙酯、DMF、DMSO、氯仿或二氯甲烷；惰性溶剂采用正己烷、石油醚、甲苯或二甲苯。
优选地，良性溶剂和惰性溶剂分别采用乙酸乙酯和二甲苯（体积比为1:4），二者可以通过蒸馏分离并可以重复利用；强酸性离子交换树脂经处理后可以循环利用。
与现有技术相比本发明具有如下优点：
（1）本发明采用乙酰氯对化合物1进行酰化，反应不经处理在强酸型离子交换树脂条件下和氰酸钾反应得到醋酸艾斯利卡西平，缩短了反应步骤和反应时间，降低了生产成本，并且收率达到90%以上；（2）反应所采用的原料廉价低毒，环境友好，反应条件温和；（3）通过向醋酸艾司利卡西平乙酸乙酯溶液中滴加二甲苯，实现产品的分离纯化，简单易操作，又提高了产品纯度，可到达99.7%（HPLC）。并且二者可以通过蒸馏分离，实现溶剂的套用；（4）强酸型离子交换树脂可以循环使用，降低了生产成本和环境污染。
通过以上步骤和反应条件的改进，使本发明在产品的成本、收率、纯度、操作步骤控制有了较大的提高，更适合工业化生产，具有很好的应用价值。
具体实施方式
为了更好地实施本发明，现举实施例对本发明作进一步说明，但是这些实施例仅是用于说明本发明，但实施例不是对本发明的限制。
实施例1
往500mL反应瓶中依次加入200mL甲苯，42g中间体1（(s)-10-羟基-10,11二氢-5H-二苯并[b,f]氮杂卓）、33ml三乙胺，随后在冰浴下搅拌，然后缓慢滴加17g乙酰氯，保持温度不超过10℃，滴加完毕后继续保温反应30分钟，TLC检测（展开剂：PE:EA=4：1）原料反应完毕。
向体系中加入全氟磺酸树脂，继续搅拌，而后向体系内滴加氰酸钾的水溶液（含氰酸钾18g），升温至70-80℃反应4小时。体系内出现大量浅黄色固体，过滤，滤饼用水洗涤。
将上述所得固体溶于100mL乙酸乙酯中，过滤除去树脂，然后向所得溶液中滴加400mL二甲苯，滴加过程中逐渐析出越来越多的白色沉淀。完毕后继续搅拌10分钟，过滤、干燥，得白色粉状醋酸艾司利卡西平53g，收率90%。产品纯度到达99.7%（HPLC）。
乙酸乙酯和二甲苯二者可以通过蒸馏分离并可以重复利用；强酸性离子交换树脂经处理后可以循环利用。
实施例2
步骤同上，不同之处在于步骤（1）所述缚酸剂选用碳酸氢钠和吡啶两种。最后制得白色粉状醋酸艾司利卡西平，收率91%。产品纯度到达99.7%（HPLC）。
Claims (4)
1.一种改进的醋酸艾司利卡西平的合成方法，其特征在于，包括以下步骤：
（1）将化合物1、缚酸剂和溶剂加入到反应瓶中，冰浴条件下向体系中滴加乙酰氯，滴加完毕后继续反应；所述缚酸剂选用碳酸氢钠、碳酸氢钾、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、三乙胺、吡啶、二异丙基乙胺、三叔丁基胺中的一种或几种；所述溶剂采用甲苯、二甲苯、甲醇、氯仿、二氯甲烷、四氢呋喃中的一种或几种；
（2）反应完毕后向体系内加入强酸型阳离子交换树脂，而后向体系中缓慢滴加氰酸钾溶液，滴加完毕后升温体系至70-80℃继续反应，经过滤，洗涤，得醋酸艾司利卡西平粗品；
（3）将醋酸艾司利卡西平粗品溶于良性溶剂中，过滤除去树脂，搅拌下向体系中滴加惰性溶剂，滴加完毕后继续搅拌，过滤得醋酸艾司利卡西平产品；所述良性溶剂采用甲醇、异丙醇、乙醇、乙酸乙酯、DMF、DMSO、氯仿或二氯甲烷；惰性溶剂采用正己烷、石油醚、甲苯或二甲苯。
2.根据权利要求1所述的醋酸艾司利卡西平合成方法，其特征在于，步骤（1）中化合物1、缚酸剂和乙酰氯之间的摩尔比例为1:1.2:1.1。
3.根据权利要求1所述的醋酸艾司利卡西平合成方法，其特征在于，步骤（2）中采用强酸型阳离子交换树脂选全氟磺酸树脂。
4.根据权利要求1所述的醋酸艾司利卡西平合成方法，其特征在于，步骤（3）所述溶剂采用良性溶剂和惰性溶剂的体积比为1:2—1:8。
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| US20050203297A1 (en) * | 2004-03-11 | 2005-09-15 | Sivakumar Bobba V. | Process for the preparation of carboxamide compounds |
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| CN114315719B (zh) * | 2020-09-30 | 2024-03-29 | 北京澳合药物研究院有限公司 | 一种新的醋酸艾司利卡西平制备方法 |
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