CN111039854A - 一种新的扑尔敏氧化杂质及其制备工艺 - Google Patents
一种新的扑尔敏氧化杂质及其制备工艺 Download PDFInfo
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Abstract
Description
技术领域
本发明属于药物纯化领域,具体涉及一种新的扑尔敏氧化杂质及其制备工艺。
背景技术
马来酸氯苯那敏,又名扑尔敏,氯苯吡胺,马来拉敏,氯屈米通。是一种抗组胺类药,可通过对H1受体的拮抗起到抗过敏作用。主要用于鼻炎、皮肤黏膜过敏及缓解流泪、打喷嚏、流涕等感冒症状。结构式如下:
发明人经研究发现,马来酸氯苯那敏成品中普遍存在一种杂质,该杂质与马来酸氯苯那敏结构接近,分离纯度难度大。因此,如能够找到一种简单的方法制备出该杂质的纯品,就可以将其作为对照品对马来酸氯苯那敏成品进行质量控制,进一步提高马来酸氯苯那敏成品的纯度。
发明内容
本发明的目的在于提供一种新的扑尔敏氧化杂质,可作为扑尔敏杂质对照品,便于对产品生产和成品质量检测过程中杂质含量的控制。
本发明提供了一种扑尔敏氧化杂质,所述扑尔敏氧化杂质的结构如下所示:
进一步地,所述氧化剂为过氧化物,优选为间氯过氧苯甲酸或双氧水;
和/或,所述氯苯那敏和氧化剂的摩尔比为1:(1.5~3.5),优选为1:2.4;
和/或,所述反应是在碱性物质的存在下进行的,所述碱性物质优选为碳酸氢钠;所述氯苯那敏与碱性物质的质量比为20:(12~17),优选为20:14.8。
进一步地,所述反应的溶剂为有机溶剂,优选为低极性有机溶剂,更优选为二氯甲烷。
进一步地,所述反应温度为-20℃~0℃,优选为-10℃,反应时间为1~4h,优选为2h。
进一步地,所述方法还包括提纯步骤,所述提纯步骤为:相将反应结束后的体系中加入水洗涤,取有机层,然后在有机层中加入饱和食盐水洗涤,取有机相,浓缩干燥。
进一步地,所述提纯步骤还包括将干燥后的产物经过硅胶柱提纯,洗脱剂为二氯甲烷:甲醇体积比=10:1的溶液。
本发明还提供了上述扑尔敏氧化杂质作为对照品在对马来酸氯苯那敏进行质量控制中的用途。
本发明还提供了一种马来酸氯苯那敏的质量检测方法,它是采用高效液相色谱法检测,具体步骤如下:
a、供试品溶液制备:取马来酸氯苯那敏,加流动相溶解,即得;
b、对照品溶液制备:取上述的扑尔敏氧化杂质,加流动相溶解,即得;
c、分别吸取供试品溶液和对照品溶液注入色谱仪,色谱条件如下:
色谱柱:以十八烷基硅烷键合硅胶为填充剂;
流动相:以体积比为80:20的NH4H2PO4溶液和乙腈的混合溶液为流动相,其中,NH4H2PO4溶液的pH为3.0。
进一步地,所述步骤c的检测波长为225nm,进样量20ul,流速1.0ml/min;柱温35℃;
所述色谱柱为Ultimate XDB-C18;
所述供试品溶液中,马来酸氯苯那敏和流动相的质量体积比为100:10mg/ml;
所述对照品溶液中,扑尔敏氧化杂质和流动相的质量体积比为0.01:1mg/ml。
实验证明,在马来酸氯苯那敏成品中普遍存在该扑尔敏氧化杂质,由于其与马来酸氯苯那敏的结构接近,导致分离难度较大。但是本发明利用简单的工艺制备出了该扑尔敏氧化杂质,并能够将其作为对照品对马来酸氯苯那敏进行质量控制,具有非常好的应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为供试品样品3的高效液相色谱图。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
实施例1、本发明扑尔敏氧化杂质的制备
在500ml单口瓶中加入20g氯苯那敏和200ml二氯甲烷,搅拌溶解,降温至-10℃,加入14.8g碳酸氢钠,分批加入30.4g间氯过氧苯甲酸(m-CPBA),于-10℃反应2h,TLC监控反应完全,加入200ml水,搅拌分层,取有机层加入100ml饱和食盐水洗涤,取有机层加入无水硫酸钠干燥,得粗产物。然后取粗产物过硅胶柱(200~300目硅胶,柱长20cm,洗脱剂为二氯甲烷:甲醇=10:1v/v),得目标产物(即本发明扑尔敏氧化杂质)15g。收率72.37%,纯度97%。
目标产物的结构表征:MS(m/z):291[M+H]+.1H-NMR(600MHz,CDC13):δ2.637~2.889(m,2H,-CH2CH2N(CH3)2),3.131~3.183(s,6H,-N(CH3)2),3.223~3.313(m,2H,-CH2N(CH3)2),4.086~4.112(m,1H,-CHCH2CH2N(CH3)2),7.128~7.157(m,2H,Ar-H),7.254~7.285(m,4H,Py-H,Ar-H),7.574~7.602(m,1H,Py-H),8.556~8.564(m,1H,Py-H)。(注:Ar/-H代表苯环上的质子,Py-H代表吡啶环上的质子)
以下通过实验例证明本发明的有益效果。
实验例1、本发明扑尔敏氧化杂质作为阳性对照品在扑尔敏供试品质量检测中的作用
1、实验方法
依照高效液相法(通则0512)测定马来酸氯苯那敏供试品溶液中扑尔敏氧化杂质的含量。其中马来酸氯苯那敏为市售产品或按照已知方法(比如专利申请201910251936.4中记载的方法)制备得到的。
色谱条件与***适用性试验:以十八烷基硅烷键合硅胶为填充剂,色谱柱为Ultimate XDB-C18(4.6*300mm,5μm);以8.57g/L NH4H2PO4(用磷酸调pH3.0)-乙腈(80:20)为流动相;检测波长225nm;流速1.0ml/min;柱温35℃。取***适用性溶液20ul进样,氯苯那敏与氧化杂质分离度应符合要求。
对照品溶液:精密称取本发明实施例1制得的氧化杂质作为对照品,用甲醇制成1mg/ml的溶液,作为对照品储备液;量取对照品储备液适量,用流动相制成0.01mg/ml的溶液,作为对照品溶液。
***适用性溶液:精密称取马来酸氯苯那敏100mg,置于10ml容量瓶中,加入0.1ml对照品储备液,用流动相溶解并定容至刻度,作为***适用性溶液。
供试品溶液:精密称取马来酸氯苯那敏100mg,置于10ml容量瓶中,用流动相稀释定容,摇匀,作为供试品溶液,按照同样的方法配置7组。在上述色谱条件下测定,取空白溶液、***适用性溶液、对照品溶液、供试品溶液20μl,注入液相色谱仪。供试品溶液色谱图中如果显示扑尔敏氧化杂质峰,则按外标法以峰面积计算扑尔敏氧化杂质含量。
2、实验结果
结果如表1所示,7个供试品溶液中样品1~6中均检测到了扑尔敏氧化杂质,且含量均为0.002%。其中,样品3的色谱图如图1所示,其中流出时间为32.614min对应的峰即本发明扑尔敏氧化杂质的峰。
所以,马来酸氯苯那敏中确实含有本发明制得的扑尔敏氧化杂质。本发明制得的扑尔敏杂质可作为阳性对照品,对马来酸氯苯那敏产品生产和成品质量检测过程中的杂质含量进行更加准确的控制。
表1 供试品溶液中扑尔敏氧化杂质的含量
供试品编号 | 批号 | 含量 |
1 | LBNM-4-2019030801 | 0.002% |
2 | LBNM-4-2019031301 | 0.002% |
3 | LBNM-4-2019040201 | 0.002% |
4 | 20190501 | 0.002% |
5 | 20190502 | 0.002% |
6 | 20190503 | 0.002% |
7 | LBNM-2019102201 | 未检出 |
综上,本发明提供了一种新的扑尔敏氧化杂质及其制备工艺。实验证明,在马来酸氯苯那敏成品中普遍存在该扑尔敏氧化杂质,由于其与马来酸氯苯那敏的结构接近,导致分离难度较大。但是本发明利用简单的工艺制备出了该扑尔敏氧化杂质,并能够将其作为对照品对马来酸氯苯那敏进行质量控制,具有非常好的应用前景。
Claims (10)
3.根据权利要求2所述的方法,其特征在于:所述氧化剂为过氧化物,优选为间氯过氧苯甲酸或双氧水;
和/或,所述氯苯那敏和氧化剂的摩尔比为1:(1.5~3.5),优选为1:2.4;
和/或,所述反应是在碱性物质的存在下进行的,所述碱性物质优选为碳酸氢钠;所述氯苯那敏与碱性物质的质量比为20:(12~17),优选为20:14.8。
4.根据权利要求2所述的方法,其特征在于:所述反应的溶剂为有机溶剂,优选为低极性有机溶剂,更优选为二氯甲烷。
5.根据权利要求2所述的方法,其特征在于:所述反应温度为-20℃~0℃,优选为-10℃,反应时间为1~4h,优选为2h。
6.根据权利要求2~5任一项所述的方法,其特征在于:所述方法还包括提纯步骤,所述提纯步骤为:相将反应结束后的体系中加入水洗涤,取有机层,然后在有机层中加入饱和食盐水洗涤,取有机相,浓缩干燥。
7.根据权利要求6所述的方法,其特征在于:所述提纯步骤还包括将干燥后的产物经过硅胶柱提纯,洗脱剂为二氯甲烷:甲醇体积比=10:1的溶液。
8.权利要求1所述扑尔敏氧化杂质作为对照品在对马来酸氯苯那敏进行质量控制中的用途。
9.一种马来酸氯苯那敏的质量检测方法,其特征在于:它是采用高效液相色谱法检测,具体步骤如下:
a、供试品溶液制备:取马来酸氯苯那敏,加流动相溶解,即得;
b、对照品溶液制备:取权利要求1所述的扑尔敏氧化杂质,加流动相溶解,即得;
c、分别吸取供试品溶液和对照品溶液注入色谱仪,色谱条件如下:
色谱柱:以十八烷基硅烷键合硅胶为填充剂;
流动相:以体积比为80:20的NH4H2PO4溶液和乙腈的混合溶液为流动相,其中,NH4H2PO4溶液的pH为3.0。
10.根据权利要求9所述的质量检测方法,其特征在于:所述步骤c的检测波长为225nm,进样量20ul,流速1.0ml/min;柱温35℃;
所述色谱柱为Ultimate XDB-C18;
所述供试品溶液中,马来酸氯苯那敏和流动相的质量体积比为100:10mg/ml;
所述对照品溶液中,扑尔敏氧化杂质和流动相的质量体积比为0.01:1mg/ml。
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CN115160215A (zh) * | 2022-08-10 | 2022-10-11 | 南京联智医药科技有限公司 | 一种马来酸氯苯那敏氧化降解产物的合成方法 |
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CN113956197A (zh) * | 2021-09-29 | 2022-01-21 | 艾希尔(深圳)药物研发有限公司 | 一种马来酸氯苯那敏杂质的制备方法 |
CN115160215A (zh) * | 2022-08-10 | 2022-10-11 | 南京联智医药科技有限公司 | 一种马来酸氯苯那敏氧化降解产物的合成方法 |
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