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CN111830158B - 一种合成艾地骨化醇中间体的液相色谱检测方法 - Google Patents

一种合成艾地骨化醇中间体的液相色谱检测方法 Download PDF

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CN111830158B
CN111830158B CN202010694634.7A CN202010694634A CN111830158B CN 111830158 B CN111830158 B CN 111830158B CN 202010694634 A CN202010694634 A CN 202010694634A CN 111830158 B CN111830158 B CN 111830158B
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梁晓云
贾志强
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Dalian Making Charm Pharmaceutical Co ltd
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Abstract

本发明涉及一种合成艾地骨化醇中间体的液相色谱检测方法，属于分析化学领域。待测物包括：(1R,3aR,7aR)‑7a‑甲基‑1‑((R)‑6‑甲基‑6‑((三乙基硅基)氧基)庚烷‑2‑基)辛亥‑4H‑茚‑4‑酮及其异构体；液相色谱的条件为：固定相为：表面涂敷有纤维素‑三(3,5‑二甲苯基氨基甲酸酯)的硅胶；流动相为：以乙腈和水为流动相，进行梯度洗脱；检测器为：紫外检测器，检测波长为197‑210nm。

Description

一种合成艾地骨化醇中间体的液相色谱检测方法
技术领域
本发明涉及一种合成艾地骨化醇中间体的液相色谱检测方法，属于分析化学领域。
背景技术
艾地骨化醇是由日本中外制药株式会社开发的具有骨形成功能的活化型维生素D3衍生物，主要用于治疗骨质疏松，化学名(5Z,7E)-(1R,2R,3R)-2-(3-羟基丙氧基)-9,10-断胆甾-5,7,10(19)-三烯-1,3,25-三醇，结构式如式(Ⅰ)：
Figure GDA0003500326920000011
(1R,3aR,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮是合成艾地骨化醇的重要中间体，结构式如式(Ⅱ)：
Figure GDA0003500326920000012
(1R,3aR,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮在合成过程中，羰基α位易发生翻转产生羰基α位异构体(1R,3aS,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮，结构式如式(Ⅲ)，实现手性杂质的分离一直是分析化学领域的难点，而(1R,3aR,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮作为艾地骨化醇合成的重要中间体，其质量控制直接影响艾地骨化醇的质量，因此开发合适的方法实现(1R,3aR,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮及其异构体的分离分析，对实现艾地骨化醇的质量控制至关重要。
Figure GDA0003500326920000021
发明内容
本发明通过新的液相色谱检测方法，解决了上述的问题。
本发明提供了一种合成艾地骨化醇中间体的液相色谱检测方法，待测物包括：(1R,3aR,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮及其异构体；液相色谱的条件为：固定相为：表面涂敷有纤维素-三(3,5-二甲苯基氨基甲酸酯)的硅胶；流动相为：以乙腈和水为流动相，进行梯度洗脱，梯度洗脱条件如下：
时间(min) 水(％) 乙腈(％)
0 60 40
10 60 40
35 10 90
35.1 60 40
40 60 40
检测器为：紫外检测器，检测波长为197-210nm。
本发明优选为柱温为25-40℃。
本发明优选为流动相流速为0.5-1.0mL/min。
本发明优选为硅胶的形状为球形。
本发明优选为硅胶的粒径为5-10μm。
本发明优选为色谱柱的长度为150cm。
本发明优选为色谱柱的内径为2.1-4.6cm。
本发明优选为进样量为10-20μL。
本发明优选为(1R,3aR,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮的浓度为1.0-3.0mg/mL。
本发明有益效果为：
本发明所述方法采用紫外检测器进行检测，能够实现(1R,3aR,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮及其异构体的分离分析，及(1R,3aR,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮的质量控制，从而控制艾地骨化醇的质量。
附图说明
本发明附图3幅，
图1为本发明所述方法检测(1R,3aR,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮的结果图。
图2为本发明所述方法检测(1R,3aS,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮的结果图。
图3为实施例1所述方法检测(1R,3aR,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮及(1R,3aS,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮的结果图。
具体实施方式
下述非限制性实施例可以使本领域的普通技术人员更全面地理解本发明，但不以任何方式限制本发明。
实施例1
一种合成艾地骨化醇中间体的液相色谱检测方法，所述液相色谱检测方法为：
待测物包括：(1R,3aR,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮、(1R,3aS,7aR)-7a-甲基-1-((R)-6-甲基-6-((三乙基硅基)氧基)庚烷-2-基)辛亥-4H-茚-4-酮
液相色谱的条件为：
固定相为：大赛璐OD-H色谱柱，球形硅胶的粒径为5μm，色谱柱的长度为150mm，色谱柱的内径为2.1cm；
柱温为30℃；
进样量为10μL。
流动相为：以乙腈和水为流动相，进行梯度洗脱，流动相流速为0.5mL/min，梯度洗脱条件如下：
Figure GDA0003500326920000031
Figure GDA0003500326920000041
检测器为：紫外检测器，检测波长为210nm。检测结果见图1。

Claims (9)

1.一种合成艾地骨化醇中间体的液相色谱检测方法，其特征在于：待测物包括：式Ⅱ及式Ⅲ；
Figure FDA0003500326910000011
液相色谱的条件为：
固定相为：表面涂敷有纤维素-三(3,5-二甲苯基氨基甲酸酯)的硅胶；
流动相为：以乙腈和水为流动相，进行梯度洗脱，梯度洗脱条件如下：
时间(min) 水(％) 乙腈(％) 0 60 40 10 60 40 35 10 90 35.1 60 40 40 60 40
检测器为：紫外检测器，检测波长为197-210nm。
2.根据权利要求1所述合成艾地骨化醇中间体的液相色谱检测方法，其特征在于：柱温为25-40℃。
3.根据权利要求2所述合成艾地骨化醇中间体的液相色谱检测方法，其特征在于：流动相流速为0.5-1.0mL/min。
4.根据权利要求3所述合成艾地骨化醇中间体的液相色谱检测方法，其特征在于：硅胶的形状为球形。
5.根据权利要求4所述合成艾地骨化醇中间体的液相色谱检测方法，其特征在于：硅胶的粒径为5-10μm。
6.根据权利要求5所述合成艾地骨化醇中间体的液相色谱检测方法，其特征在于：色谱柱的长度为150mm。
7.根据权利要求6所述合成艾地骨化醇中间体的液相色谱检测方法，其特征在于：色谱柱的内径为2.1-4.6cm。
8.根据权利要求7所述合成艾地骨化醇中间体的液相色谱检测方法，其特征在于：进样量为10-20μL。
9.根据权利要求8所述合成艾地骨化醇中间体的液相色谱检测方法，其特征在于：式Ⅱ的浓度为1.0-3.0mg/mL。
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