CN113801035A - 一种瑞戈非尼中间体杂质、制备方法及其用途 - Google Patents
一种瑞戈非尼中间体杂质、制备方法及其用途 Download PDFInfo
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Abstract
Description
技术领域
本发明属于药物化学领域,具体涉及一种瑞戈非尼中间体杂质、制备方法以及质量控制时作为杂质对照品的用途。
背景技术
瑞戈非尼(Regorafenib),化学名称为4-[4-[[[[4-氯-3-(三氟甲基)苯基]氨基]甲酰基]氨基]-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺,由德国拜耳医药保健公司研发,作为一种口服多激酶抑制剂,通过抑制多种蛋白质激酶,靶向作用于肿瘤生成、肿瘤血管发生和肿瘤微环境信号传导的维持。2013年2月25日美国食品与药品管理局(FDA)批准瑞戈非尼片剂用于治疗先前接受过伊马替尼和舒尼替尼治疗的局部晚期,不能手术切除或转移性胃肠道间质瘤(GIST)患者。2017年12月05日在中国上市,商品名为拜万戈/Stivarga。
WO2011/128261、WO05/009961、WO2016005874、WO2016051422以及WO2016101714等专利中均报道了以3-氟-4-氨基苯酚为起始原料,制备得到中间体化合物MH(N-甲基-4-(4-氨基-3-氟)苯氧基吡啶-2-甲酰胺),中间体MH再与4-氯-3-三氟甲基异氰酸苯酯制备得到瑞戈非尼的方法。
在瑞戈非尼的合成工艺研究中,本发明人发现,瑞戈非尼中间体MH中存在一种杂质,该杂质含量低且较难分离纯化,无法通过常规的方法分离得到。该杂质的存在影响了中间体MH甚至终产品瑞戈非尼的纯度。为了控制瑞戈非尼中间体MH及瑞戈非尼的产品质量,确保药品的安全性,我们对该杂质的结构、制备方法以及作为对照品的应用进行了深入研究,本发明基于以上原因产生。
发明内容
本发明提供一种瑞戈非尼杂质化合物、制备方法及其作为标准对照品在瑞戈非尼中间体MH及瑞戈非尼质量控制中的应用。
具体的讲,本发明一方面提供了一种结构全新的瑞戈非尼中间体杂质I,其具有以下结构:
该杂质首先发现于中间体MH中,但是由于该杂质的含量低,且分离纯化困难,因此无法按照常规的方法分离得到后,进行结构鉴定。本申请的发明人对合成工艺的原理进行了深入的分析,对可能产生的杂质进行了大量的制备工作,最终通过在相同HPLC条件下,保留时间的一致性以及结合核磁、质谱的表征手段,得到了该杂质的结构。
该杂质属于具有α,β不饱和羰基警戒结构的基因毒性杂质,为确保药品的安全性,基因毒性杂质的限度通常要远低于普通杂质限度,按照ICH M7的指导原则,基因毒性杂质要求每日摄取基因毒性杂质的量(TTC)不超过1.5μg,本品日最大剂量为160mg(无水物),按照该计算规则,该杂质的其限度为9ppm。计算公式如下:
限度(ppm)=TTC(ug/天)/日最大剂量(g/天)
=1.5(ug/天)/0.16(g/天)
=9ppm
由于该杂质限度极低,常规的高效液相方法的检测限难以达到该要求。为确保该杂质能够在产品中得到控制,需要开发在瑞戈非尼终产品的质量控制时,能够有效检测出该杂质的分析方法。
因此,本发明的另一方面提供了一种液质联用的分析方法,在该方法下,杂质I能够被有效的被检测出,具体如下:
仪器:岛津液相色谱仪(LC-20AD xR,SIL-20AC xR,CTO-20AC)。
色谱柱:用十八烷基硅烷键合硅胶为填充剂,Waters Atlantis T3,2.1mm×100mm,3μm。
色谱条件:0.5%甲酸溶液为流动相A,0.1%甲酸甲醇为流动相B,流速为0.3ml/min;柱温为40℃,样品室温度为4℃,检测坡长260nm,按表1进行线性梯度洗脱。
表1线性梯度洗脱程序
质谱仪器:Triple Quad 5500型三重串联四极杆质谱仪(美国AppliedBiosystems公司)。
具体质谱条件:正离子电喷雾(ESI+)模式电离;
多反应监测(MRM)模式进行测定;
Q1分辨率(Resolution Q1):Unit;
Q3分辨率(Resolution Q3):Unit;
碰撞气压力(CAD):9Psi;
雾化气压力(GS1):55Psi;
喷雾电压(IS):5500V;
气帘气压力(CUR):35Psi;
辅助气压力(GS2):55Psi;
离子源温度(TEM):500℃;
具体方法如下:
供试品溶液:取瑞戈非尼适量,精密称定,加甲醇溶解并定量稀释制成每1ml中约含0.5mg的溶液,作为供试品溶液。
杂质对照品溶液:取该杂质对照品适量,精密称定,加稀释剂使溶解并稀释制成每1ml中约含0.45μg的溶液,作为杂质对照品溶液。
灵敏度溶液:取杂质对照品溶液适量,用甲醇定量稀释制成每1ml中约含该杂质0.9ng,作为灵敏度溶液。
精密量取空白溶剂和灵敏度溶液各3μl,分别注入液质联用仪,记录离子流图,灵敏度溶液中各杂质峰高的信噪比均应不小于10;精密量取对照品溶液3μl,注入液质联用仪,记录离子流图;精密量取供试品溶液3μl,注入液质联用仪,记录离子流图;按外标法以峰面积计算该杂质的含量。
该方法的检测限0.54ppm和定量限1.8ppm。
该杂质在瑞戈非尼中间体MH的研究内容:
供试品溶液:取本品约25mg,精密称定,置100ml量瓶中,先加乙腈20ml使溶解,再加水稀释并定容至刻度,摇匀。
色谱柱:用十八烷基硅烷键合硅胶为填充剂,SymmetryShield RP18,4.6mm×150mm,3.5μm。
色谱条件:以磷酸盐缓冲液为流动相A,以乙腈-无水乙醇(60:40)为流动相B;按表2进行线性梯度洗脱;柱温为40℃;检测波长为230nm。精密量取供试品溶液10μl,注入液相色谱仪,记录色谱图。供试品溶液色谱图中如有杂质峰,按面积归一化法计算该杂质含量。
表2梯度洗脱程序表
本发明另一方面提供了四种该中间体杂质I的制备方法:
方法一:
具体步骤如下:
将化合物1与化合物2加入pH=7的磷酸氢二钠缓冲液反应瓶中,再加入酪氨酸酶,室温搅拌,通氧气,反应完成后,蒸干,柱层析得到瑞戈非尼杂质I。
方法二:
具体步骤如下:
将化合物1与化合物3加入pH=7的磷酸氢二钠缓冲液反应瓶中,再加入酪氨酸酶,室温搅拌,通氧气。反应完成后,蒸干,柱层析得到瑞戈非尼杂质I。
方法三:
具体步骤如下:
将化合物1和化合物4加入反应瓶中,降温,滴加冰乙酸,反应完毕后蒸干,柱层析得到瑞戈非尼杂质I。
方法四:
具体步骤如下:
(1)向化合物1中加入纯化水、乙醇。
(2)向化合物5中加入纯化水、乙醇。
(3)将步骤(2)中的溶液加入到步骤(1)的溶液中,再用20%的氨水将pH调节至9.5。
(4)加入6%过氧化氢水溶液,搅拌,反应结束后,萃取,干燥,过滤、蒸干,柱层析得到瑞戈非尼杂质I。
本发明另一方面是提供杂质I在瑞戈非尼中间体MH及瑞戈非尼质量控制中作为杂质对照品的应用。
本发明具有以下有益效果:
首先,本发明提供了一种结构全新的瑞戈非尼中间体杂质I,该杂质作为需要严格控制限度的基因毒性杂质,其发现极大的提高了瑞戈非尼的质量标准,为瑞戈非尼的安全用药提供保证。
其次,本发明提供了一种杂质I的检测方法,该方法灵敏度高,检测限低,能够有效的检测出瑞戈非尼终产品中含量极低的杂质I,为瑞戈非尼的质量控制提供保证。
同时,本发明提供了四种杂质I的制备方法,原料易得,工艺简单,获得的瑞戈非尼中间体杂质I收率高,纯度好,为瑞戈非尼原料以及制剂有关杂质的定性、定量研究提供保证。
附图说明
图1为杂质I在瑞戈非尼中间体MH质控中的HPLC谱图。
具体实施方式
下文结合具体实施例对本发明的多晶型及其制备方法做进一步的说明。下面实施例仅为示例性说明和解释本发明,凡是基于本发明上述内容实现的技术均为本发明保护范围内。除非另有说明,以下实施例中使用的原料和溶剂均为市售商品,或者通过已知方法制备。
NMR的测定是用Bruker Analytische Messtechnik GmbH核磁仪器,测定溶剂为氘代二甲基亚砜(DMSO-d6),内标为四甲基硅烷(TMS)。
酪氨酸酶(206-214):购买于上海赢瑞生物医药科技有限公司。
实施例1:瑞戈非尼杂质I的制备
将0.63g的化合物2、2.62g的化合物1加入带有50ml pH=7的磷酸氢二钠缓冲液中,再加入1mg的酪氨酸酶,室温搅拌,通氧气,反应完毕后,蒸干,柱层析(洗脱剂为甲醇:乙酸乙酯=1:8)得到瑞戈非尼杂质I。
1H-NMR(400MHz,DMSO-d6)δ5.18-5.26(s,2H),6.54-6.62(m,4H),6.67-6.70(m,2H),6.73-6.83(m,1H),7.02-7.07(m,1H),7.21-7.23(m,1H),8.16(s,1H),8.86(s,1H),9.93(s,3H)
MS(ESI,m/z):468[M+H]+
实施例2:瑞戈非尼杂质I的制备
将2g的化合物3、7.5g的化合物1加入带有150ml pH=7的磷酸氢二钠缓冲液中,再加入4mg的酪氨酸酶,室温搅拌,通氧气。反应完毕后,蒸干,柱层析(洗脱剂为甲醇:乙酸乙酯=1:8)得到瑞戈非尼杂质I。
实施例3:瑞戈非尼杂质I的制备
将1g的化合物4、3.5g的化合物1加入带有10ml纯化水的反应瓶中,降温,0℃滴加入0.6g的冰乙酸反应,反应完毕后蒸干,柱层析(洗脱剂为甲醇:乙酸乙酯=1:8)得到瑞戈非尼杂质I。
实施例4:瑞戈非尼杂质I的制备
向1.5g的化合物1于2ml纯化水、3ml乙醇中的溶液中加入0.47g的化合物5于1ml纯化水、3ml乙醇中的溶液,用1.5ml的20%的氨水将pH调节至9.5。加入10.5ml的6%过氧化氢水溶液,搅拌反应6小时,反应结束后,用二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤、蒸干,柱层析(洗脱剂为甲醇:乙酸乙酯=1:8)得到瑞戈非尼杂质I。
实施例5:杂质I作为有关物质的对照品测定瑞戈非尼中间体MH的有关物质。
供试品溶液:取本品约25mg,精密称定,置100ml量瓶中,先加乙腈20ml使溶解,再加水稀释并定容至刻度,摇匀。
测定法:精密量取供试品溶液10μl,注入液相色谱仪,记录色谱图。供试品溶液色谱图中如有杂质峰,按面积归一化法计算含量。
杂质化合物作为对照品测定瑞戈非尼中间体MH的有关物质检查结果如下:
批号 | A-1 | A-2 | A-3 | A-4 |
杂质I | 未检测到 | 未检测到 | 0.04% | 0.02% |
纯度 | 93.18% | 93.09% | 98.11% | 97.80% |
A-3批次检测有关物质图谱见附图1,保留时间为31.251分钟的峰为杂质I。
实施例6:杂质I作为有关物质的对照品测定瑞戈非尼的有关物质。
供试品溶液:取瑞戈非尼适量,精密称定,加甲醇溶解并定量稀释制成每1ml中约含0.5mg的溶液,作为供试品溶液。
杂质对照品溶液:取该杂质对照品适量,精密称定,加稀释剂使溶解并稀释制成每1ml中约含0.45μg的溶液,作为杂质对照品溶液。
灵敏度溶液:取杂质对照品溶液适量,用甲醇定量稀释制成每1ml中约含该杂质0.9ng,作为灵敏度溶液。
精密量取空白溶剂和灵敏度溶液各3μl,分别注入液质联用仪,记录离子流图,灵敏度溶液中各杂质峰高的信噪比均应不小于10;精密量取对照品溶液3μl,注入液质联用仪,记录离子流图;精密量取供试品溶液3μl,注入液质联用仪,记录离子流图;按外标法以峰面积计算该杂质的含量。
杂质化合物作为对照品测定瑞戈非尼的有关物质检查结果如下:
Claims (9)
6.一种权利要求1所述的瑞戈非尼中间体杂质化合物I在瑞戈非尼中间体MH质量控制中作为杂质对照品的应用。
7.一种权利要求1所述的瑞戈非尼中间体杂质化合物I在瑞戈非尼质量控制中作为杂质对照品的应用。
8.根据权利要求7所述的瑞戈非尼杂质化合物I的应用,其特征在于瑞戈非尼有关物质检查时的HPLC-Ms条件为:十八烷基硅烷键合硅胶为填充剂,0.5%甲酸溶液为流动相A,0.1%甲酸甲醇为流动相B,流速为0.3ml/min;柱温为40℃,样品室温度为4℃,检测坡长260nm,进行线性梯度洗脱。以质谱检测器为检测器,选择正离子电喷雾(ESI+)模式电离;多反应监测(MRM)模式进行测定。
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