CN108164521B - 一种帕瑞昔布钠降解杂质及其制备、检测方法和应用 - Google Patents
一种帕瑞昔布钠降解杂质及其制备、检测方法和应用 Download PDFInfo
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
本发明公开了式Ⅰ所示的帕瑞昔布钠的降解杂质及其制备方法，解决了现有技术中尚未有帕瑞昔布钠降解杂质研究的问题。本发明还公开了该降解杂质的应用，以及该降解杂质的高效液相色谱检测法。本发明为帕瑞昔布钠的质量研究、标准研究、稳定性研究、药品不良反应的机制研究提供了基础；同时，为帕瑞昔布钠的生产、包装、储存、运输及应用条件的选择提供依据。
Description
技术领域
本发明属于药物合成领域，具体涉及一种帕瑞昔布钠降解杂质及其制备、检测方法和应用。
背景技术
特耐是Pharmacia公司研发的首个可静脉给药和肌肉注射的特异性环氧合酶-2(COX-2)抑制剂伐地昔布(valdecoxib)的水溶性前体药物，属于抗关节炎药中的昔布类镇痛药，临床上可用于中度或重度术后急性疼痛的治疗。特耐的有效成分是帕瑞昔布钠(Parecoxib Sodium)，N-[[4-(5-甲基-3-苯基-4-异恶唑基)苯基]磺酰基]丙酰胺钠盐。
文献报道的帕瑞昔布钠合成路线较多，各工艺路线的区别主要体现在中间体3,4-二苯基-5-甲基异恶唑的制备工艺有差别。综合反应条件、工业化程度等因素分析认为帕瑞昔布钠的工业化合成工艺是以3,4-二苯基-5-甲基异恶唑为原料，经氯磺化、氨解、丙酰化、成盐等步骤实现帕瑞昔布钠的制备，其合成路线如下：
综合文献研究内容和合成工艺分析认为，帕瑞昔布钠的制备工艺中涉及强碱步骤，而且，帕瑞昔布钠结构本身属于碱性化合物，碱性条件可能导致其结构中的丙酰胺等活性基团在储存、运输或使用过程中发生降解，例如，帕瑞昔布钠的水解降解。
目前，针对帕瑞昔布钠降解杂质的研究资料较少，仅在文献CurrentPharmaceutical Analysis,2017,13,271-278中介绍了帕瑞昔布钠的氧化杂质和水解杂质。因此，我们在帕瑞昔布钠工艺研究过程中，对工艺中可能产生的工艺杂质进行研究的同时，对其降解杂质进行了考察，旨在为帕瑞昔布钠的质量研究和进一步制定合理的质量标准提供指导，为帕瑞昔布钠成品的储存、运输、使用等各个环节的条件提供依据，保证药品的质量、稳定性以及患者的用药安全。
发明内容
本发明的目的之一在于：针对帕瑞昔布钠的结构特点，以及其在生产、包装储存、运输过程中引入的降解杂质可能引起药品的质量、稳定性和用药风险的问题，提供一种帕瑞昔布钠的降解杂质，为帕瑞昔布钠的后续制剂工艺改进、质量研究、稳定性研究、以及包装储存和运输条件的选择等提供基础。
本发明的目的之二在于：提供该降解杂质的制备方法。
本发明的目的之三在于：提供该降解杂质的应用。
本发明的目的之四在于：提供包含该降解杂质的参比制剂。
本发明的目的之五在于：提供该降解杂质的高效液相色谱检测法。
为实现上述目的，本发明采用的技术方案为：
本发明所述的一种帕瑞昔布钠降解杂质，具有如式Ⅰ所示的结构：
优选地，为式I化合物药学上可接受的盐、溶剂化物。
本发明所述的降解杂质的制备方法，包括在碱作用下，式Ⅱ化合物在溶剂中发生关环反应制备式Ⅰ化合物：
进一步地，所述碱选自正丁基锂、仲丁基锂、甲基锂、叔丁基锂、己基锂、环己基锂、苯基锂中的任意一种或其组合，和氨基锂衍生物；其中，氨基锂衍生物选自二异丙基氨基锂、二(三甲基硅基)氨基锂中的一种或几种，优选二异丙基氨基锂。
本发明所述的降解杂质的制备方法包括式Ⅲ化合物在催化剂1条件下与联硼酸频那醇酯反应，随后在催化剂2条件下与式Ⅳ化合物发生偶联反应制备式Ⅰ化合物：
，其中，X选自氯、溴、碘。
其中，式Ⅱ化合物的合成参考US2003105334的方法进行制备；式Ⅳ化合物的合成参考Advanced Synthesis and Catalysis,2002,344(10)，1146-1151的方法进行制备。
进一步地，所述催化剂1和催化剂2均独立地选自醋酸钯、四(三苯基膦)钯、Pd/C、氯化钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯中的任意一种或几种。
进一步地，所述催化剂1和催化剂2催化的反应碱性条件下进行，所述碱选自磷酸钾、醋酸钾、醋酸钠、碳酸钾、碳酸钠、碳酸铯、碳酸锂中的任意一种或几种。
本发明的如式Ⅰ所示的帕瑞昔布钠降解杂质在检测帕瑞昔布钠中间体、原料药和/或制剂中的应用。该降解杂质可用于帕瑞昔布钠不良反应的机制研究，帕瑞昔布钠中间体、原料药和制剂生产的质量标准研究以及质量控制中作为对照品的应用。
本发明所述的一种检测帕瑞昔布钠中间体、原料药和/或制剂中杂质含量的参比试剂，包括如式Ⅰ所示的帕瑞昔布钠降解杂质。
本发明所述的一种检测帕瑞昔布钠降解杂质的高效液相色谱法，色谱条件为：色谱柱为以C8、C18或苯基键合硅胶为填料的分析色谱柱，以乙腈或乙腈-甲醇为流动相A，以pH为2.8～3.2的缓冲盐溶液为流动相B，按照等度或梯度洗脱程序进行洗脱。
与现有技术相比，本发明具有以下效果：
本发明提供了如式Ⅰ所示的帕瑞昔布钠降解杂质，为帕瑞昔布钠的质量研究、标准研究、稳定性研究、药品不良反应的机制研究提供了基础；同时，为帕瑞昔布钠的生产、包装、储存、运输及应用条件的选择提供依据。该降解杂质可在原料药和制剂生产的质量标准研究以及质量控制中作为对照品的应用。
本发明还提供了帕瑞昔布钠降解杂质的制备方法，该方法合成路线短，反应条件温和、操作简便，制得的帕瑞昔布钠降解杂质纯度高，可用于杂质对照品的制备。
本发明的检测法操作简便，结果准确，能使帕瑞昔布钠与其降解杂质达到基线分离。
附图说明
图1为式Ⅰ所示的帕瑞昔布钠降解杂质的核磁共振氢谱图(1H-NMR)。
图2为式Ⅰ所示的帕瑞昔布钠降解杂质的质谱图(MS)。
图3为本发明帕瑞昔布钠(24.243min)与其降解杂质(44.524min)的高效液相色谱图。
具体实施方式
本发明提供以下具体实施方式对本发明的内容做出更为详细的说明，但本发明的主题范围并不局限于以下具体实施例，凡是基于本发明内容对化合物基团、反应试剂、操作、反应步骤等作出的等同的替换或组合所实现的技术、工艺均属于本发明的范围。
实施例1
本实施例提供了式Ⅰ化合物的制备，其反应式如下：
具体操作为：依次将2.5g式Ⅱ化合物、30mL干燥四氢呋喃加入到圆底烧瓶中，氮气保护、-78℃低温条件下将11mL正丁基锂(1.6M)缓慢加入反应液中，加完后，继续搅拌反应2h；将反应液缓慢升温至室温反应过夜。向反应液中缓慢加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取，有机层干燥、浓缩，剩余物柱层析得到式Ⅰ化合物(R＝H)为一白色固体，约0.56g，收率：24％；HPLC纯度：96.3％。
式Ⅰ化合物：1H-NMR(CD3COCD3,400MHz)：δ＝8.04(d,J＝8.0Hz,1H),7.90(s,1H),7.72(d,J＝4.0Hz,1H),7.47～7.40(m,5H),3.10(q,J＝8.0Hz,2H),2.57(s,3H),1.29(t,J＝8.0Hz,3H)ppm。
MS-ESI(m/z):351.3(M-H)-。
实施例2
本实施例提供了式III化合物的制备，其反应式如下：
具体操作为：依次将4.5g 4-溴-2-甲氧羰基苯磺酰胺(制备方法参考文献Bioorganic&Medicinal Chemistry Letters 19(2009)6855–6861)、40mL干燥四氢呋喃加入到圆底烧瓶中，氮气保护条件下降温至0℃，将45mL乙基溴化镁溶液(1.0M，四氢呋喃溶液)缓慢滴入到反应液中，滴完后，继续搅拌30分钟后，将反应液缓慢升温至室温，搅拌反应过夜。向反应液中加入20mL水淬灭反应，乙酸乙酯萃取，有机层干燥，浓缩，剩余物进行柱层析纯化得到1.5g式Ⅲ化合物。
实施例3
本实施例提供了式Ⅰ化合物的制备，其反应式如下：
将实施例2中1.5g式Ⅲ化合物、1.7g联硼酸频那醇酯、0.3g[1,1'-双(二苯基膦)二茂铁]二氯化钯、1.2g醋酸钾、20ml 1,4-二氧六环加入到圆底烧瓶中，氮气保护下，将反应液缓慢升温至100℃反应5小时，将反应液冷却至室温，过滤，滤液浓缩，剩余物进行柱层析纯化后进行后续反应。
依次将上述产物、1.2g式Ⅳ化合物、0.2g四(三苯基膦)钯、10mL乙醇、5mL 2M碳酸钠溶液加入到圆底烧瓶中，搅拌条件下缓慢升温至回流反应。TLC监控反应进程。将反应液冷却至室温，加入20mL饱和食盐水，乙酸乙酯萃取，有机层干燥，浓缩，剩余物进行柱层析纯化得到式Ⅰ化合物为一白色固体，约0.5g，两步总收率：26％；HPLC纯度：97.8％。
实施例4
本实施例提供帕了瑞昔布钠光降解杂质的高效液相色谱检测法。
检测仪器：安捷伦1260高效液相色谱仪
色谱条件：色谱柱为Agilengt Eclipse XDB-C18 4.6*150mm 5um；柱温为40℃；流速为1.0ml/min；检测波长为215nm，以乙腈-0.01mol/L磷酸氢二钠溶液(30：70)为流动相等度洗脱，其中0.01mol/L磷酸氢二钠溶液用磷酸调pH至3.0。其用量为30：70。
样品的制备：取帕瑞昔布钠25mg置50ml容量瓶中，加40％乙腈溶液溶解并稀释刻度，摇匀，即得。
对照品的制备：取式Ⅰ化合物11mg、帕瑞昔布钠23mg置同一50ml容量瓶中，加40％乙腈溶液溶解并稀释刻度，摇匀，即得。
检测法：取样品及对照品溶液各10μl注入液相色谱仪，按所述的色谱条件测定，记录色谱图，完成测定；所得色谱图如图3所示。
结果显示，采用本实施例方法瑞昔布钠与其光降解杂质能够达到基线分离，检测迅速，结果准确。
实施例5
本实施例提供帕了瑞昔布钠光降解杂质的高效液相色谱检测法。
检测仪器：安捷伦1260高效液相色谱仪
样品的制备：取帕瑞昔布钠25mg置50ml容量瓶中，加40％乙腈溶液溶解并稀释刻度，摇匀，即得
对照品的制备：取式Ⅰ化合物11mg、帕瑞昔布钠25mg置同一50ml容量瓶中，加40％乙腈溶液溶解并稀释刻度，摇匀，即得。
梯度色谱条件：用十八烷基键合硅胶为填充剂(如Agilengt Eclipse XDB-C18；150mm×4.6mm,5μm)。检测波长为215nm，柱温为40℃，流速为每分钟1.0ml。
流动相A：乙腈-甲醇(4：1)
流动相B：0.1％磷酸溶液
梯度洗脱时间顺序如下:
| 时间(min) | 流动相A％ | 流动相B％ |
| 0 | 20 | 80 |
| 3 | 20 | 80 |
| 22 | 65 | 35 |
| 27 | 65 | 35 |
| 28 | 20 | 80 |
| 35 | 20 | 80 |
检测法：取样品及对照品溶液各10μl注入液相色谱仪，按所述的色谱条件测定，记录色谱图，完成测定。
结果显示，采用本实施例方法瑞昔布钠与其光降解杂质能够达到基线分离，检测迅速，结果准确。
上述实施例仅为本发明的优选实施方式之一，不应当用于限制本发明的保护范围，但凡在本发明的主体设计思想和精神上作出的毫无实质意义的改动或润色，其所解决的技术问题仍然与本发明一致的，均应当包含在本发明的保护范围内。
Claims (2)
1.一种帕瑞昔布钠降解杂质的制备方法，其特征在于，所述降解杂质具有如式Ⅰ所示的结构，所述制备方法为：依次将2.5g式Ⅱ化合物、30mL干燥四氢呋喃加入到圆底烧瓶中，氮气保护、-78℃低温条件下将11mL正丁基锂1.6M缓慢加入反应液中，加完后，继续搅拌反应2h；将反应液缓慢升温至室温反应过夜；反应式为：
2.根据权利要求1所述的降解杂质的制备方法，其特征在于，所述降解杂质为式I化合物药学上可接受的盐。
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