CN102952113B - 化合物5,6,7,8-四氢-6-[n,n-二[(2-噻吩)乙基]]氨基-1-萘酚、制备方法及应用 - Google Patents
化合物5,6,7,8-四氢-6-[n,n-二[(2-噻吩)乙基]]氨基-1-萘酚、制备方法及应用 Download PDFInfo
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Abstract
Description
技术领域
本发明属于医药领域,具体涉及5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚化合物、制备方法,以及作为罗替戈汀或其制剂杂质测定对照品的应用。
背景技术
帕金森症是一种常见的中老年神经系统变性疾病,多巴胺受体激动剂为治疗帕金森症的一类重要药物,目前临床使用的多巴胺受体激动剂有多巴胺激动剂类药物如罗替戈汀、普拉克索、罗匹尼罗、培高利特、卡麦角林等。
罗替戈汀(Rotigotine),(S)-5,6,7,8-四氢-6-[丙基[2-(2-噻吩基)乙基]氨基]-1-萘酚,分子式:C19H25NOS,结构如下所示,2007 年5 月美国 FDA 批准其上市,商品名为 NeuPro,用于早期继发性帕金森氏病和晚期帕金森氏病的辅助治疗。
药物的杂质是指药物中存在的无治疗作用或影响药物稳定性和疗效,甚至对人体健康有害的物质。杂质的来源,主要有两个:一是由生产过程中引入,包括未反应的起始原料、起始原料中包含的杂质的化学衍生物、合成副产物以及降解产物;二是在贮藏过程中受外界条件的影响,引起药物理化性质发生变化而产生。药品在临床使用中产生的不良反应除了与药品本身的药理活性有关外,有时与药品中存在的杂质也有很大关系。所以规范地进行杂质的研究,将直接关系到上市药品的质量及安全性。
通过了解杂质的化学结构和合成途径,以及通过鉴别影响终产物中杂质含量的参数,能够极大增强对药用活性物质的杂质的管理。对药用活性物质的杂质监控要求建立质量标准,确立合适的分离与检测条件,使杂质能得到很好控制;在质量标准中,目前普遍采用的杂质检测方法主要为高效液相色谱法(HPLC)等。
发明内容
本发明的目的在于提供一种作为罗替戈汀或其制剂杂质测定对照品的新化合物,化学名称:5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚,具有式Ⅰ结构式。
化合物Ⅰ
其中(*)标示手性中心,化合物Ⅰ可以是R或S构型化合物,或外消旋混合物。
化合物Ⅰ可以采用以下方法制备,使化合物Ⅱ与化合物Ⅲ反应:
化合物Ⅱ 化合物Ⅲ
化合物Ⅱ是R或S构型化合物,或外消旋混合物;R1选自甲基、三氟甲基、甲基苯基、硝基苯基,优选为 4-甲基苯基或4-硝基苯基,更优选为4-甲基苯基。
化合物Ⅰ可以作为罗替戈汀或其制剂的杂质定性或定量测定的对照品,具体可以采用高效液相色谱法进行测定。将化合物Ⅰ溶解在溶液中制备为对照品溶液,将罗替戈汀或其制剂溶解在溶液中制备为供试品溶液,采用高压液相色谱法分析,获得对照品溶液、供试品溶液的HPLC色谱图,对比对照品溶液、供试品溶液的HPLC色谱图中的出峰时间,确定供试品溶液含有化合物Ⅰ,对比对照品溶液及供试品溶液的HPLC色谱图中化合物Ⅰ的峰面积,按外标法测定出罗替戈汀或其制剂中化合物Ⅰ的重量百分比。
本发明的化合物Ⅰ用GC或HPLC测定时,该化合物纯度为至少80%,优选纯度为至少90%,更优选纯度为至少95%,最优选纯度为至少99%。
本发明同时提供一种高纯度的罗替戈汀,所述罗替戈汀含有重量百分比少于0.5%化合物Ⅰ。
附图说明
图 1是5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚的高分辨质谱图。
图 2-1是5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚对照品的HPLC色谱图。
图2-2是罗替戈汀化合物的HPLC 色谱图。
具体实施方式
以下通过实施例和试验例来进一步说明本发明,但不以任何方式限制本发明。
实施例1 5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚的制备
取5,6,7,8-四氢-6-氨基-1-萘酚5.0 g,对甲苯磺酸2-(2-噻吩基)乙基酯3.0 g,碳酸钠4.8 g和二甲苯100 ml混合后进行回流,回流反应48 h。降至室温,以适量水洗涤,加入活性炭进行脱色处理,抽滤,静置,保留有机相,减压浓缩,柱层析纯化,得到5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚1.7 g,核磁共振图谱归属见表1,高分辨质谱图见附图1。
表1 5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚核磁共振图谱归属
核磁共振结构编号如下
实施例2 (S)-5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚化合物的制备
(S)-5,6,7,8-四氢-6-氨基-1-萘酚5.0 g,对甲苯磺酸2-(2-噻吩基)乙基酯3.0 g,碳酸钠4.8 g和二甲苯100 ml混合后进行回流,回流反应48~50 h。降至室温,以适量水洗涤,加入活性炭进行脱色处理,抽滤,静置,保留有机相,减压浓缩,柱层析纯化,得到(S)-5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚1.7 g,核磁共振图谱归属见表2。
合物
表2 (S)-5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚核磁共振图谱归属
核磁共振结构编号如下
实施例3 (S)-5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚化合物的制备
(S)-5,6,7,8-四氢-6-氨基-1-萘酚5.0 g,对硝基苯磺酸2-(2-噻吩基)乙基酯3.3 g,碳酸钠4.8 g和二甲苯100 ml混合后进行回流,回流反应48~50 h。降至室温,以适量水洗涤,加入活性炭进行脱色处理,抽滤,静置,保留有机相,减压浓缩,柱层析纯化,得到(S)-5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚1.5 g。
实施例4(S)-5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚化合物的制备
(S)-5,6,7,8-四氢-6-氨基-1-萘酚5.0 g,甲磺酸2-(2-噻吩基)乙酯2.2 g,碳酸钠4.8 g和二甲苯100 ml混合后进行回流,回流反应48~50 h。降至室温,以适量水洗涤,加入活性炭进行脱色处理,抽滤,静置,保留有机相,减压浓缩,柱层析纯化,得到(S)-5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚1.3 g。
试验例1 5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚在测定罗替戈汀化合物杂质含量中作为对照品的应用
样品准备:
称取罗替戈汀适量,加乙腈-0.05%甲磺酸溶液(20:80)溶解制成每1ml中约含1 mg的溶液,为供试品溶液;精密称取5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚适量,用乙腈-0.05%甲磺酸溶液(20:80)溶解并定量稀释制成每1 ml中约0.001 mg的溶液,作为对照品溶液。
色谱条件:
用十八烷基键合硅胶为填充剂;以0.05%甲磺酸溶液(取甲磺酸0.5ml,用水稀释至1000 ml)为流动相A,乙腈/0.05%甲磺酸(取甲磺酸0.5 ml,用乙腈稀释至1000 ml)为流动相B,按下表进行梯度洗脱;柱温30℃;检测波长为220 nm,理论板数以罗替戈汀计应不得小于5000。取对照品溶液及供试品溶液各10 μl,注入高效液相色谱仪。
流动相梯度
附图 2-1 ,2-2分别是5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚与罗替戈汀化合物的HPLC 色谱图,按外标法计算,3批罗替戈汀化合物中5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚的含量均为0.5%以下。
试验例2 (S)-5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚在罗替戈汀微球制剂杂质含量中作为对照品的应用
样品准备:
取罗替戈汀缓释微球适量(约相当于罗替戈汀10 mg),精密称定,置10 ml量瓶中,加乙腈5 ml使溶解,加0.01 mol/L盐酸溶液稀释至刻度,摇匀,置离心管中,13000转/分钟离心5分钟,取上清液作为供试品溶液;精密称取(S)-5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚适量,用乙腈-0.05%甲磺酸溶液(20:80)定量稀释制成每1 ml中约0.005 mg的溶液,作为对照品溶液。
色谱条件:同试验例1
按外标法计算,3批罗替戈汀微球中(S)-5,6,7,8-四氢-6-[N,N-二[(2-噻吩)乙基]]氨基-1-萘酚的重量百分比均为0.5%以下。
Claims (7)
3.权利要求2所述制备方法,其特征在于R1选自4-甲基苯基或4-硝基苯基。
4.权利要求3所述制备方法,其特征在于R1选自4-甲基苯基。
5.权利要求1所述化合物作为罗替戈汀或其制剂杂质测定的对照品的应用。
6.一种用于测定罗替戈汀或其制剂杂质含量的方法,采用高压液相色谱法分析,其特征在于权利要1所述的化合物Ⅰ作为对照品。
7.权利要求6所述的方法,其特征在于将权利要求1所述化合物溶解在溶液中制备为对照品溶液,将罗替戈汀或其制剂溶解在溶液中制备为供试品溶液,采用高压液相色谱法分析,获得对照品溶液、供试品溶液的HPLC色谱图,对比对照品溶液、供试品溶液的HPLC色谱图中的出峰时间,确定供试品溶液含有权利要求1所述的化合物,按外标法测定出罗替戈汀或其制剂中权利要求1化合物的重量百分比。
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CN109580792A (zh) * | 2017-09-28 | 2019-04-05 | 安徽省庆云医药股份有限公司 | 一种液相色谱法分离测定罗替戈汀及其光学异构体的方法 |
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US20110313176A1 (en) * | 2008-12-26 | 2011-12-22 | Actavis Group Ptc Ehf | Processes for preparing highly pure rotigotine or a pharmaceutically acceptable salt thereof |
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CN102952113A (zh) | 2013-03-06 |
ES2625088T3 (es) | 2017-07-18 |
CA2842495A1 (en) | 2013-02-21 |
PL2744801T3 (pl) | 2017-10-31 |
US20140196523A1 (en) | 2014-07-17 |
EP2744801B1 (en) | 2017-02-15 |
KR101798558B1 (ko) | 2017-11-16 |
JP5986635B2 (ja) | 2016-09-06 |
RU2014106825A (ru) | 2015-08-27 |
JP2014527524A (ja) | 2014-10-16 |
KR20140061404A (ko) | 2014-05-21 |
US9012660B2 (en) | 2015-04-21 |
CA2842495C (en) | 2018-06-12 |
EP2744801A4 (en) | 2015-03-25 |
BR112014002669A2 (pt) | 2017-04-25 |
AU2012297492A1 (en) | 2014-02-06 |
AU2012297492B2 (en) | 2015-09-24 |
WO2013023433A1 (en) | 2013-02-21 |
EP2744801A1 (en) | 2014-06-25 |
RU2609807C2 (ru) | 2017-02-06 |
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