CN1306527A - 用于左西孟旦批次分析中的参比化合物 - Google Patents

用于左西孟旦批次分析中的参比化合物 Download PDF

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CN1306527A
CN1306527A CN99807544A CN99807544A CN1306527A CN 1306527 A CN1306527 A CN 1306527A CN 99807544 A CN99807544 A CN 99807544A CN 99807544 A CN99807544 A CN 99807544A CN 1306527 A CN1306527 A CN 1306527A
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R·巴克斯特伦
T·海因奥恩
T·豪塔－阿霍
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Abstract

本发明涉及哒嗪基衍生物(Ⅰ)及其在测定左西孟旦样品内潜在基因毒性杂质中作为参比化合物的应用。本发明还涉及一种用于测定左西孟旦样品内潜在基因毒性杂质的分析方法,其中用化合物(Ⅰ)作为参比化合物。左西孟旦是一种在心衰治疗中有效的药物。

Description

用于左西孟旦批次分析中的参比化合物
发明背景
本发明涉及[[4-(2-叠氮基-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈(Ⅰ)及其在左西孟旦合成的批次分析中，特别是在测定左西孟旦批次样品中潜在基因毒性杂质中作为参比化合物的应用。本发明还涉及一种测定左西孟旦批次样品中潜在基因毒性杂质的分析方法，其中用[[4-(2-叠氮基-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈(Ⅰ)作为参比化合物。
左西孟旦(levosimendan)，也就是[[4-(1,4,5,6,-四氢-4-甲基-6-氧代-3-哒嗪基)苯基]亚肼基]丙烷二腈的(-)对映体及其制备方法公开在例如EP565546B1中。左西孟旦可有效治疗心衰并且对肌钙蛋白具有显著的钙依赖性结合作用。WO93/21921中描述了左西孟旦在治疗心肌局部缺血中的用途。Sundberg,S等人在《美国心脏病学杂志》(Am.J.Cardiol.)1995；75；1061-1066中描述了左西孟旦在男性中血液动力效应。左西孟旦如下式所示：
Figure A9980754400041
临床研究业已证实了左西孟旦在心衰患者中的有益效果。
如EP565546B1所述，通过用亚硝酸钠和丙二腈处理(-)-6-(4-氨基苯基)-5-甲基-4,5-二氢-3(2H)-哒嗪酮可以以高纯度和几乎定量的收率制备左西孟旦。然而，现已在细菌诱变性实验(埃姆斯测验法)中发现合成的左西孟旦样品偶然会显示出潜在的基因毒性。
发明概述
迄今发现，左西孟旦的潜在基因毒性是由式(Ⅰ)的叠氮基衍生物杂质引起的：
该叠氮基衍生物是有效诱变剂，它在左西孟旦合成中可以生成足够在细菌诱变性试验中得出阳性结果的量。因此，该化合物，也称作[[4-(2-叠氮-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈，适合在左西孟旦合成的批次的常规分析中，特别是在测定左西孟旦批次内潜在基因毒性杂质中作为参比化合物。左西孟旦批次中化合物(Ⅰ)的存在表明必须进一步重结晶以便获得适合用作药物的左西孟旦原料。
附图简述
图1是[[4-(2-叠氮-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈标准品(0.4μg/ml)的HPLC色谱图。
图2是左西孟旦原料的HPLC色谱图。
发明详述
本发明提供一种具有结构(Ⅰ)的用于测定左西孟旦批次样品内潜在基因毒性杂质的参比化合物。本发明也提供一种用于测定左西孟旦批次样品内潜在基因毒性杂质的参比制剂，其中含有任选地与分析上可接受载体合用的化合物(Ⅰ)，和特别是基本上不存在哒嗪基衍生物。
本发明还提供化合物(Ⅰ)在测定左西孟旦批次样品内潜在基因毒性杂质中作为参比化合物的应用。
本发明还提供一种用于测定左西孟旦批次样品中的潜在基因毒性杂质的分析方法，其特征在于用化合物(Ⅰ)作为参比化合物，特别是当所述左西孟旦样品通过高压液相色谱(HPLC)分析时。
此外，本发明提供了一种用于测定左西孟旦批次样品中的潜在基因毒性杂质的分析方法，该方法包括通过将化合物(Ⅰ)溶解在溶液中制备参比标准溶液，通过将左西孟旦批次样品溶解在溶液中制备试验溶液，获得该参比标准溶液的HPLC色谱，获得该试验溶液的HPLC色谱并且测定出样品中化合物(Ⅰ)的浓度。
此处的术语“分析上可接受的载体”是指对定性或定量分析化合物(Ⅰ)没有妨碍作用的载体。选择适当的分析上可接受的载体为所属领域技术人员所熟知。分析上可接受的载体的一个实例是二甲基亚砜。
化合物(Ⅰ)可以通过用亚硝酸钠和丙二腈处理6-(4-氨基苯基)-5-甲基-4,5-二氢-3(2H)-哒嗪酮来制备，其中所用亚硝酸钠的摩尔数过量且自反应混合物中分离出(Ⅰ)。实施例1详细描述该方法。
左西孟旦批次的产物优选利用高压液相色谱(HPLC)分析。适用的仪器包括，例如C-8反相HPLC柱并且在360nm下UV检测。流动相是例如磷酸盐缓冲液pH2.1和乙腈的混合液。将左西孟旦溶于适当溶剂如二甲基亚砜、甲醇和水的混合液中。通过将化合物(Ⅰ)溶解在适当溶剂中制备参比溶液。在所用色谱条件下测定左西孟旦和化合物(Ⅰ)或其非对映异构体的保留时间。通过对比由样品溶液和参比溶液获得的色谱测定左西孟旦样品中(Ⅰ)的含量。该方法在实施例2中详细描述。
通过所属领域技术人员已知的方法如重结晶可以降低左西孟旦批次中有害杂质(Ⅰ)的含量。左西孟旦的重结晶可以由任何溶剂，优选丙酮来进行。
实施例
实施例1．[[4-(2-叠氮-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈(非对映异构体的混合物)的制备
将6-(4-氨基苯基)-4,5-二氢-5-甲基-3(2H)-哒嗪酮(153g,0.75mol)溶于乙酸(750ml)中。在10-20℃下将固体亚硝酸钠(210g,3.0mo1)缓慢加入溶液内。.加入后，在10-20℃下将混合物搅拌90分钟。将反应混合物迅速倾入丙二腈(150g,2.3mol)和水(1500ml)的20℃溶液内。在20-25℃下将所得混合物搅拌60分钟且随后过滤，用水洗涤。依次用四氢呋喃(300ml)和乙酸乙酯(1900ml)抽提湿固体。合并的提取液用硫酸钠干燥且真空下蒸发溶剂。残余物用乙酸乙酯(200ml)研制，过滤并真空下蒸发滤液。在硅胶上通过层析用甲苯-乙酸乙酯2∶1作为洗脱剂纯化残余物(8.0g)。由甲苯结晶后，非对映异构体的纯净混合物的收率是1.0g。通过由甲苯多重结晶浓缩该混合物中的主要组分，但对于分析目的，该混合物足够。1H-NMR(400MHz,DMSO-d6,σ)主要非对映异构体1.06(d,3H,J=6Hz),2.55(dd,1H,J=16Hz,11Hz),2.67(m,1H),2.78(dd,1H,J=16Hz,8Hz),7.59(d,1H,J=9Hz),7.62(d,1H,J=9Hz),12.6(broad s,1H),次要非对映异构体0.60(d,3H,J=7Hz),2,43(dd,1H,J=18Hz,2Hz),2.78(m,1H),3.14(dd,1H,J=8Hz,18Hz),7.54(d,1H,J=9Hz),7.61(d,1H,J=9Hz),12.6(宽s,1H).
实施例2．[[4-(2-叠氮-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈(Ⅰ)在HPLC色谱中作为参比化合物的应用
用于分析左西盂旦原料中化合物(Ⅰ)的HPLC(高压液相色谱)法是基于在具有在360nm下UV检测的C-8反相HPLC柱。流动相是由乙腈和磷酸盐缓冲液pH2.1组成。试剂：1．甲醇，HPLC级2．磷酸二氢钠,NaH2PO4×H2O,Merck3．正磷酸，H3PO4,Merck4．磷酸盐缓冲液pH2.1：
将1.8g磷酸二氢钠(NaH2PO4)溶于水中且加入2.0ml磷酸。如果必要，用2M氢氧化钠或1M磷酸调整pH，用水稀释至1000.0ml。5．二甲基亚砜，BDH6．乙腈，HPLC级7．溶剂：200ml甲醇和800ml水的混合液8．[[4-(2-叠氮-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈参比标准物标准溶液(化合物(Ⅰ)的参比制剂)：储备液：将10.00mg[[4-(2-叠氮-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈溶于存在于100ml容量瓶内的20ml二甲基亚砜中且用甲醇填充至指定体积。标准溶液1(50μg/ml)：用溶剂将5.00ml储备液稀释至10.0ml。标准溶液(0.4μ/ml=40ppm)：用溶剂将1.00ml储备液稀释至250.0ml。定量极限溶液(0.1μg/ml=10ppm)：用溶剂将5.00ml标准溶液2稀释至20.0ml。试验溶液
  将100mg试验样品溶于存在于l0ml容量瓶内的8ml二甲基亚砜中且用溶剂填充至指定体积。色谱条件：仪器：液相色谱仪检测器：UV-VIS，在360nm波长下检测色谱柱：对称C8,3.0μm,7.5cm×4.6mm炉温：室温流动相：A：磷酸盐缓冲液pH2.1B：乙腈％B    0分钟   20％5分钟   30％15分钟  30％     30分钟  90％流速：0.8ml/分钟注射体积：100μl运行时间：30分钟后时间：10分钟保留时间：左西孟旦约13分钟化合物(Ⅰ)次要非对映体异构体：约24分钟化合物(Ⅰ)主要非对映异构体：约25分钟体系适应性1．必须重复平行注射定量进行溶液；6次注射，RSD=10.0％方法
在符合体系适应性标准后，进行标准品和样品注射。计算
化合物(Ⅰ)的主要非对映异构体以ppm计的浓度应按照以下公式计算： C st · R x · 10 · 1000000 R st · W
Cst=在[[4-(2-叠氮-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈标准溶液中化合物(Ⅰ)的主要非对映异构体的浓度(mg/ml)
Rt=试验溶液的色谱中化合物(Ⅰ)的主要非对映异构体的峰面积
Rst=[[4-(2-叠氮-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈标准溶液中化合物(Ⅰ)的主要非对映异构体的峰面积w=样品重量10=样品的稀释因子(ml)
化合物(Ⅰ)的次要非对映异构体以ppm计的浓度应按照以下公式计算。用化合物(Ⅰ)的主要非对映异构体作为参比标准物： C st · R x · 10 · 1000000 R st · W · 1.023
Cst=在[[4-(2-叠氮-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈标准溶液中化合物(Ⅰ)的次要非对映异构体的浓度(mg/ml)
Rt=试验溶液的色谱中化合物(Ⅰ)的次要非对映异构体的峰面积
Rst=[[4-(2-叠氮-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈标准溶液中化合物(Ⅰ)的次要非对映异构体的峰面积
w=样品重量
10=样品的稀释因子(ml)
1.023=化合物(Ⅰ)的次要非对映异构体的校正因子
附图1中给出所得[[4-(2-叠氮-3-甲基-5-氧代四氢呋喃-2-基)苯基]亚肼基]丙烷二腈标准物(0.4μg/ml)的色谱。化合物(Ⅰ)的主要非对映异构体的保留时间是25.180分钟，化合物(Ⅰ)的次要非对映异构体是24.866分钟。附图2表示左西孟旦原料的色谱。

Claims (9)

1．一种化合物，其特征在于具有式Ⅰ的结构：及其非对映异构体
2．一种用于测定左西孟旦批次样品内潜在基因毒性杂质的参比制剂，其中含有权利要求1的化合物。
3．按照权利要求2的制剂，其中基本上不存在哒嗪基化合物。
4．一种用于测定左西孟旦批次样品内潜在基因毒性杂质的参比制剂，其中含有权利要求1的化合物和分析上可接受的载体。
5．按照权利要求4所述的制剂，其中基本上不存在哒嗪基化合物。
6．权利要求1所述化合物在测定左西孟旦批次样品内潜在基因毒性杂质中作为参比化合物的应用。
7．一种用于测定左西孟旦批次样品内潜在基因毒性杂质的分析方法，其特征在于用权利要求1的化合物作为参比化合物。
8．按照权利要求7所述的方法，其中左西孟旦批次的样品是通过高压液相色谱(HPLC)分析。
9．一种用于测定左西孟旦批次样品内潜在基因毒性杂质的分析方法，该方法包括通过将权利要求1的化合物溶解在溶液中制备参比标准溶液，通过将左西孟旦批次样品溶解在溶液中制备试验溶液，获得该参比标准溶液的HPLC色谱，获得该试验溶液的HPLC色谱并且测定出样品中权利要求1的化合物的浓度。
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CN105784895A (zh) * 2015-10-30 2016-07-20 成都欣捷高新技术开发有限公司 一种用高效液相色谱仪检测左西孟旦中杂质的方法
CN105817632A (zh) * 2015-01-09 2016-08-03 中国科学院宁波材料技术与工程研究所 片状粉末的制备装置及方法

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CN111474289A (zh) * 2019-10-31 2020-07-31 武汉嘉诺康医药技术有限公司 一种利用反相色谱分离分析左西孟旦中右西孟旦的方法
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CN105817632A (zh) * 2015-01-09 2016-08-03 中国科学院宁波材料技术与工程研究所 片状粉末的制备装置及方法
CN105784895A (zh) * 2015-10-30 2016-07-20 成都欣捷高新技术开发有限公司 一种用高效液相色谱仪检测左西孟旦中杂质的方法

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