CN103833641A - 一种奥替拉西钾的杂质化合物及其制备方法和用途 - Google Patents
一种奥替拉西钾的杂质化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种式Ⅰ化合物，同时公开了该化合物的制备方法及其在奥替拉西钾有关物质检查时作为杂质对照品的用途。本发明的实施有效的控制了奥替拉西钾的质量，对人民群众安全用药具有重要意义。
Description
技术领域
本发明涉及药物分析化学领域，尤其涉及一种奥替拉西钾的杂质化合物及其制备方法和用途。
背景技术
奥替拉西钾，英文名为Potassium oxonate，又名氧嗪酸钾，化学名：1,4,5,6-四氢-4,6-二氢-1,3,5-三嗪-2-羧酸钾。奥替拉西钾是抗癌复方药物替吉奥的主要成分之一，替吉奥最早由日本大鹏药品株式会社研制开发，被批准用于胃癌、非小细胞癌、结肠癌等多种癌症的治疗，主要由活性成分替加氟和两种生化调节剂吉美嘧啶、奥替拉西钾组成。
奥替拉西钾本身没有抗肿瘤活性，服用后该药物滞留在胃肠道中，选择性作用于乳清酸磷酸核糖基转移酶，阻断5-氟尿嘧啶磷酸化，从而抑制5-氟尿嘧啶在该位置的活化，以减少替加氟在胃肠道的毒副作用。
药物的有效成分的含量是反映药物纯度的重要标志，而药物中存在的杂质直接影响到药物的疗效并可能导致毒副作用的产生。药物杂质是在生产、储运过程中引进或产生的药物以外的其它化学物质，杂质的存在不仅影响药物的纯度，还会带来非治疗活性的毒副作用，必须进行研究控制。
奥替拉西钾作为替吉奥的主要成分之一，规范地进行奥替拉西钾杂质的研究，将直接关系到奥替拉西钾及替吉奥的质量及安全性。可见，奥替拉西钾杂质的制备意义重大，它可以用于奥替拉西钾生产中有关物质的检测，从而可以提高奥替拉西钾的质量标准，对人民群众安全用药具有重要的意义。
发明内容
本发明的目的在于提供一种奥替拉西钾的杂质化合物，分子式为C3H3N3O2，化学结构式如下：
该化合物通过紫外吸收光谱(UV)、红外吸收光谱(IR)、核磁共振谱(NMR)、质谱(MS)进行结构确证及分析如下：
一、紫外吸收光谱(UV)
该化合物在水、0.1mol/L HCl溶液、0.1mol/L NaOH溶液和甲醇中的UV谱图分别见附图1-附图4。
（1）附图1说明在水溶液中，峰1即λmax=236nm的吸收峰为该化合物中羰基结构R带跃迁吸收峰。
（2）附图2说明在0.1mol/L HCl溶液中，峰1即λmax=248nm的吸收峰为该化合物中羰基结构R带跃迁吸收峰。
（3）附图3说明在0.1mol/L NaOH溶液中，峰1即λmax=251nm的吸收峰为该化合物中羰基结构R带跃迁吸收峰。
（4）附图4说明在甲醇溶液中，峰1即λmax=236nm的吸收峰为该化合物中羰基结构R带跃迁吸收峰。
以上的紫外吸收光谱表明：本品中含有羰基结构。
二、红外吸收光谱(IR)
该化合物的IR谱图见附图5。
其中，3191cm-1,3091cm-1为伯胺、仲胺的N-H伸缩振动吸收，1756cm-1,1729cm-1为双酰亚胺羰基的C=O伸缩振动吸收，说明结构中含有双酰亚胺结构。
解析结果表明：该化合物的红外光谱图特征与目标化合物的化学结构基本相符合。
三、核磁共振谱(NMR)
该化合物的1H-NMR谱见附图6，13C-NMR谱见附图7。
由于用D2O做溶剂，所以在奥替拉西钾工艺杂质的1H核磁共振谱图中没有氢显示。由图7可知，碳的化学位移（ppm）为144.169、156.711、162.059，该化合物的分子结构中共有3个碳，这与目标化合物的化学结构相符。
四、质谱(MS)
该化合物的ESI质谱图见附图8。
质谱测得本品的分子离子峰[M+Na]+，其质荷比m/z为136.1，与目标化合物的分子离子峰(分子量为113.07)一致。
本发明的另一个目的在于提供该奥替拉西钾杂质化合物的制备方法，包括以下步骤：
A、溶解：将奥替拉西钾粗品用纯化水溶解，配制成10mg/ml的样品溶液；
B、分离制备：根据杂质的相对保留时间所显示的色谱保留行为确定制备色谱法的条件，用制备色谱法收集所述保留时间相对应的杂质；
C、脱盐：将步骤B中收集到的组分用凝胶柱进行脱盐；
D、将步骤C中得到的产品浓缩干燥得目标化合物。
所述的步骤B中采用二次制备，一次制备的条件为：流动相：KH2PO4水溶液（浓度：5.0g/L，磷酸调PH为2.0）：乙醇=96:4，流速：30ml/min，检测波长：220nm，柱温：室温，填料：十八烷基硅烷键合硅胶，进样量：5ml；收集保留时间8.9min处的目标峰对应的物质；
将一次制备收集的目标物质进行二次制备，二次制备的条件为：流动相A为KH2PO4水溶液（浓度：5.0g/L，磷酸调PH为2.0），流动相B为乙醇，梯度洗脱：
流速：30ml/min，检测波长：220nm，柱温：室温，填料：十八烷基硅烷键合硅胶，进样量：5ml；收集保留时间8.8min处的目标峰对应的物质。
所述的步骤C中所用凝胶柱填料为羟丙基葡聚糖凝胶，脱盐条件为：
（1）将二次制备所得物质，用纯化水溶解，用稀KOH溶液调PH至5.0后，配制成15mg/ml的样品溶液；
（2）上样量5ml，用超纯水洗脱除盐。
本发明还提供了该杂质化合物在奥替拉西钾有关物质检查时作为杂质对照品的用途。
奥替拉西钾有关物质检查时的HPLC条件为：色谱柱：Inertsil ODS-3V-C18柱（4.6×150mm,5μm）；流动相：水相︰有机相=900︰100（其中水相为向900ml纯化水中加入0.65g KH2PO4，溶解后加入10%四丁基氢氧化铵溶液2ml，混匀后用稀磷酸调节PH为3.2，有机相为甲醇）；流速：1.0ml/min；检测波长：220nm；进样量：10μl；柱温：35℃。
实验步骤：将奥替拉西钾用流动相溶解并定量稀释制成每1ml中约含奥替拉西钾1.0mg的溶液，作为供试品溶液；将奥替拉西钾杂质化合物用流动相溶解并定量稀释制成每1ml中约含5μg的溶液，作为对照溶液；精密量取供试品溶液与对照溶液各10μl，分别注入液相色谱仪，按上述条件进行高效液相色谱分析。
本发明的技术效果在于：本发明公开了奥替拉西钾在生产、储运过程中产生的一种重要的杂质化合物，此杂质化合物的含量多少直接影响奥替拉西钾及替吉奥的药物品质。本发明通过制备色谱法获取该化合物，并对其进行光谱分析从而确认该化合物的结构，并将其作为奥替拉西钾有关物质检测时的杂质对照品，从而有效的监控奥替拉西钾中的有关物质。本发明的实施有效的控制了奥替拉西钾的质量，对人民群众安全用药具有重要的意义。
附图说明
图1奥替拉西钾杂质化合物在水中的UV谱图。
图2奥替拉西钾杂质化合物在0.1mol/L HCl溶液中的UV谱图。
图3奥替拉西钾杂质化合物在0.1mol/L NaOH溶液中的UV谱图。
图4奥替拉西钾杂质化合物在甲醇中的UV谱图。
图5奥替拉西钾杂质化合物的IR谱图。
图6奥替拉西钾杂质化合物的1H-NMR谱图。
图7奥替拉西钾杂质化合物的13C-NMR谱图。
图8奥替拉西钾杂质化合物的MS谱图。
图9奥替拉西钾杂质化合物的HPLC谱图
图10奥替拉西钾的HPLC谱图
具体实施方式
以下是本发明的具体实施例，对本发明的技术方案做进一步的描述，但是本发明的保护范围并不限于这些实施例。凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
实施例1奥替拉西钾杂质化合物的制备
（1）准确称取奥体拉西钾粗品1.0g，用100ml纯化水溶解，配制成10mg/ml的一次制备样品溶液，混匀，超声，备用。
（2）一次制备条件为：流动相：KH2PO4水溶液（浓度：5.0g/L，磷酸调PH为2.0）：乙醇=96:4，流速：30ml/min，检测波长：220nm，柱温：室温，制备型号：创新通恒半制备液相系统，填料：十八烷基硅烷键合硅胶，进样量：5ml。
实验步骤：a、开机，用流动相平衡系统。
b、进样5ml，启动泵，开始洗脱。
c、目标峰保留时间约为8.9min，收集目标峰。
d、将收集样品用旋转蒸发仪浓缩，水浴温度35℃，大约10L浓缩至体积200ml，作为二次制备样品。
二次制备的条件为：流动相A为KH2PO4水溶液（浓度：5.0g/L，磷酸调PH为2.0），流动相B为乙醇，梯度洗脱：
流速：30ml/min，检测波长：220nm，柱温：室温，制备型号：创新通恒半制备液相系统，填料：十八烷基硅烷键合硅胶，进样量：5ml。
实验步骤：a、开机，用初始流动相平衡系统。
b、进样5ml，运行梯度，开始洗脱。
c、目标峰保留时间约为8.8min，收集目标峰。
d、将收集样品浓缩冻干。
（3）取二次制备冻干品，用水溶后用稀KOH溶液调节PH至5.0，配制成15mg/ml的样品溶液，上样5ml。
脱盐过程：水洗后进行上样，上样后用大约3ml超纯水进行滴加，之后加入超纯水进行除盐；在接完30ml/瓶×3后，第一瓶接出5ml，之后1ml/瓶，直到检测无盐后，再接5ml/瓶，检测无样品流出后即可停止收集，最后将收集到的除盐后样品浓缩干燥得目标杂质化合物。
实施例2奥替拉西钾杂质化合物作为杂质对照品的用途
色谱条件：色谱柱：Inertsil ODS-3V-C18柱（4.6×150mm,5μm），检测波长220nm，柱温35℃，流速1.0ml/min，流动相：水相︰有机相=900︰100（其中水相为：向900ml纯化水中加入0.65g KH2PO4，溶解后加入10%四丁基氢氧化铵溶液2ml，混匀后用稀磷酸调节PH为3.2；有机相为甲醇）。
实验步骤：将奥替拉西钾用流动相溶解并定量稀释制成每1ml中约含奥替拉西钾1.0mg的溶液，作为供试品溶液；将杂质化合物用流动相溶解并定量稀释制成每1ml中约含5μg的溶液，作为对照溶液；精密量取供试品溶液与对照溶液各10μl，分别注入液相色谱仪，按上述条件进行高效液相色谱分析，结果见附图9和附图10。
结果表明，附图10中保留时间14.087min的峰与附图9中保留时间13.725min的峰为奥替拉西钾杂质化合物的峰，附图10中15.249min的峰为奥替拉西钾的峰。
Claims (7)
1.一种奥替拉西钾的杂质化合物，化学结构式如下：
2.制备权利要求1所述的化合物的方法，采用制备色谱法，其特征在于包括以下步骤：
A、溶解：将奥替拉西钾粗品用纯化水溶解，配制成10mg/ml的样品溶液；
B、分离制备：根据杂质的相对保留时间所显示的色谱保留行为确定制备色谱法的条件，用制备色谱法收集所述保留时间相对应的杂质；
C、脱盐：将步骤B中收集到的组分用凝胶柱进行脱盐；
D、将步骤C中得到的产品浓缩干燥得目标化合物。
3.如权利要求2所述的方法，其特征在于步骤B中采用二次制备，
一次制备的条件为：流动相：KH2PO4水溶液（浓度：5.0g/L，磷酸调PH为2.0）：乙醇=96:4，流速：30ml/min，检测波长：220nm，柱温：室温，填料：十八烷基硅烷键合硅胶，进样量：5ml；收集保留时间8.9min处的目标峰对应的物质；
将一次制备收集的目标物质进行二次制备，二次制备的条件为：流动相A为KH2PO4水溶液（浓度：5.0g/L，磷酸调PH为2.0），流动相B为乙醇，梯度洗脱：
流速：30ml/min，检测波长：220nm，柱温：室温，填料：十八烷基硅烷键合硅胶，进样量：5ml；收集保留时间8.8min处的目标峰对应的物质。
4.如权利要求2所述的方法，其特征在于步骤C中所用凝胶柱填料为羟丙基葡聚糖凝胶。
5.如权利要求2或4所述的方法，其特征在于步骤C的脱盐条件为：
（1）将二次制备所得物质，用纯化水溶解，用稀KOH溶液调PH至5.0后，配制成15mg/ml的样品溶液；
（2）上样量5ml，用超纯水洗脱除盐。
6.权利要求1的化合物在奥替拉西钾有关物质检查时作为杂质对照品的用途。
7.如权利要求6所述的化合物的用途，其特征在于奥替拉西钾有关物质检查时的HPLC条件为：色谱柱：Inertsil ODS-3V-C18柱（4.6×150mm,5μm）；流动相：水相︰有机相=900︰100（其中水相为向900ml纯化水中加入0.65g KH2PO4，溶解后加入10%四丁基氢氧化铵溶液2ml，混匀后用稀磷酸调节PH为3.2，有机相为甲醇）；流速：1.0ml/min；检测波长：220nm；进样量：10μl；柱温：35℃。
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