CN113861057A - 一种磷酸奥司他韦中间体杂质化合物及其制备方法和用途 - Google Patents
一种磷酸奥司他韦中间体杂质化合物及其制备方法和用途 Download PDFInfo
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- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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Abstract
Description
技术领域
本发明属于药物化学技术领域,具体的,是涉及一种磷酸奥司他韦中间体杂质及其制备方法和用途。
背景技术
磷酸奥司他韦(商品名:达菲)是神经氨酸酶抑制剂,可以竞争性的与流感病毒神经氨酸酶的活动位点结合,通过干扰病毒从被感染的宿主细胞中释放,从而减少甲型和乙型流感的传播,被广泛用于甲型和乙型流感的预防和治疗。
化合物Ⅲ是制备磷酸奥司他韦重要中间体,其结构如下:
原研文献Organic Process Research&Development 1999,3,266274和OrganicProcess Research&Development 2004,8,86-91报导了由莽草酸为起始物料制备化合物Ⅲ,再由化合物Ⅲ制备磷酸奥司他韦的方法,但是在制备化合物Ⅲ时会产生与其结构相似的杂质Ⅰ,其结构如下所示:
迄今为止,关于该杂质的鉴别与去除均未报道,鉴于化合物Ⅲ是磷酸奥司他韦制备过程中的关键中间体,对其进行质量研究和杂质控制至关重要,因此有必要对该中间体杂质化合物I进行结构确认,分离和纯化等研究,并进一步对其含量进行控制。
发明内容
发明目的:本发明的目的是提供了一种磷酸奥司他韦中间体杂质及其制备方法和用途。
技术方案:本发明所述的一种磷酸奥司他韦中间体杂质化合物,其结构如式I所示:
进一步的,一种磷酸奥司他韦中间体杂质化合物的制备方法,制备路线如下:
其具体操作步骤如下:
化合物II在酸的催化下,在有机溶剂中反应制得磷酸奥司他韦中间体杂质化合物I。
进一步的,所述的酸为苯磺酸或氯化锌,优选氯化锌。
进一步的,所述的有机溶剂为二氯甲烷或甲苯,优选甲苯。
进一步的,一种磷酸奥司他韦中间体杂质化合物作为磷酸奥司他韦中间体杂质标准品或对照品的用途。
有益效果:本发明与现有技术相比,本发明对磷酸奥司他韦关键中间体杂质进行了研究,通过上述方法制备出的杂质,用以作为磷酸奥司他韦关键中间体质量研究中的杂质对照品;控制上述杂质在磷酸奥司他韦关键中间体III中含量不高于2%,对磷酸奥司他韦的中间体工业化生产具有重要的质量监控意义。
附图说明
图1是化合物Ⅰ的HPLC图谱,保留时间11.6min为化合物Ⅰ;
图2是化合物Ⅰ的MS图谱;
图3是化合物Ⅰ的碳谱(13C NMR);
图4是化合物Ⅰ的氢谱(1H NMR);
图5是化合物Ⅲ中化合物Ⅰ的HPLC图谱,保留时间10.08为化合物Ⅲ,保留时间11.6min为化合物Ⅰ。
具体实施方式
以下结合附图和具体实施例,对本发明做出进一步说明;在下面的描述中阐述了很多具体细节以便于充分理解本申请,但是本申请能够以很多不同于在此描述的其它方式来实施,本领域技术人员可以在不违背本申请内涵的情况下做类似改进,因此本申请不受下面公开的具体实施的限制。
本发明所述的一种磷酸奥司他韦中间体杂质化合物,其结构如式I所示:
进一步的,一种磷酸奥司他韦中间体杂质化合物,制备路线如下:
其具体操作步骤如下:
化合物II在酸的催化下,在有机溶剂中反应制得磷酸奥司他韦中间体杂质化合物I。
进一步的,所述的酸为苯磺酸或氯化锌,优选氯化锌。
进一步的,所述的有机溶剂为二氯甲烷或甲苯,优选甲苯。
进一步的,一种磷酸奥司他韦中间体杂质化合物作为磷酸奥司他韦中间体杂质标准品或对照品的用途。
实施例1
向反应瓶中加入化合物Ⅱ50g,氯化锌22g,甲苯200ml,水14g,升温至90℃反应3h,TLC监控原料无剩余,降至室温过滤除去固体,母液分出水相,有机相浓缩得到化合物Ⅰ粗品51g,收率96%。
将20g化合物Ⅰ用30%乙酸乙酯/正庚烷柱层析纯化,得到13g纯品化合物Ⅰ,收率65%,纯度99.19%。
式Ⅰ化合物的HPLC谱图如图1所示;式Ⅰ化合物的MS谱图如图2所示;式Ⅰ化合物的碳谱图如图3所示;式Ⅰ化合物的氢谱图如图4所示。
实施例2
向反应瓶中加入化合物Ⅱ20g,苯磺酸10.2g,甲苯80ml,水5.6g,回流反应3h,TLC监控原料无剩余,降至室温加入10%NaOH水溶液调剂pH至8-9,分出水相,有机相旋干得到17g化合物Ⅰ粗品,收率85%;
将5g化合物Ⅰ粗品溶于5ml甲醇中用制备液相精制分离,流动相为乙腈-水,10%-100%梯度洗脱,收集产品流份,减压浓缩得3.71g纯品化合物Ⅰ,收率74%,纯度98.13%。
实施例3
向反应瓶中加入化合物Ⅱ5g,氯化锌2.2g,二氯甲烷20ml,水1.5g,升温至40℃反应3h,TLC监控原料无剩余,降至室温过滤除去固体,并用20ml二氯甲烷淋洗滤饼,母液分出水相,有机相浓缩得到化合物Ⅰ粗品4.7g,收率88%;
将4.7g化合物Ⅰ粗品用30%乙酸乙酯/正庚烷柱层析纯化,得到2.4g纯品化合物Ⅰ,收率52%,纯度92.16%。
以上实施例的说明只是用于帮助理解本发明的核心思想;同时,对于本领域的一般技术人员,依据本发明的思想,在具体实施方式及应用范围上均会有改变之处,综上所述,本说明书内容不应理解为对本发明的限制。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114456097A (zh) * | 2022-02-23 | 2022-05-10 | 植恩生物技术股份有限公司 | 奥司他韦警示结构杂质及其制备方法 |
CN115626885A (zh) * | 2022-09-26 | 2023-01-20 | 植恩生物技术股份有限公司 | 奥司他韦警示结构杂质c10-b-zz7及其制备方法和用途 |
CN115850102A (zh) * | 2022-12-29 | 2023-03-28 | 浙江工业大学 | 一种奥司他韦的制备方法 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114456097A (zh) * | 2022-02-23 | 2022-05-10 | 植恩生物技术股份有限公司 | 奥司他韦警示结构杂质及其制备方法 |
CN115626885A (zh) * | 2022-09-26 | 2023-01-20 | 植恩生物技术股份有限公司 | 奥司他韦警示结构杂质c10-b-zz7及其制备方法和用途 |
CN115850102A (zh) * | 2022-12-29 | 2023-03-28 | 浙江工业大学 | 一种奥司他韦的制备方法 |
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