| 第 53 卷第 2 期 |  | Vol. 53 No. 2 | | 2023 年 4 月 | Apr 2023 |
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所屬欄目：醫藥及中間體
阿普斯特雜質(zhì)的合成 |
| 胡中元，唐旭靜，邢 磊，張曉玲，劉彥龍*
（正大天晴藥業(yè)集團股份有限公司研究院，江蘇 南京 210000） |
| 摘 要：為有效控制阿普斯特原料藥質(zhì)量并建立質(zhì)量標準，使用4-芐氧基-3-乙氧基苯甲醛為起始原料，與鹽酸羥胺縮合脫水后，經(jīng)加成、還原、與3-乙酰氨基鄰苯二甲酸酐縮合、Pd/C氫化脫芐基制得阿普斯特雜質(zhì)2-［1-（3-乙氧基-4-羥基苯基）-2-甲磺�；一�-4-乙�；被愡胚徇�-1，3-二酮，并優(yōu)化了合成工藝。優(yōu)化條件下，雜質(zhì)純度99.2%（HPLC），總收率55.4%。采用1H NMR、13C NMR和HRMS對其結構進(jìn)行表征確證。合成工藝合理、反應條件溫和，制備的雜質(zhì)純度高，可作為阿普斯特藥物質(zhì)量控制的雜質(zhì)對照品。 |
| 關(guān)鍵詞：阿普斯特；4-芐氧基-3-乙氧基苯甲醛；雜質(zhì) |
| 中圖分類(lèi)號：R914.5 文獻標識碼：A 文章編號：1009-9212（2023）02-0036-04 |
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| Synthesis of Apremilast Impurity |
| HU Zhong-yuan, TANG Xu-jing, XING Lei, ZHANG Xiao-ling, LIU Yan-long*
(Research Institute of Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nanjing 210000, China) |
| Abstract：In order to effectively control the quality of Apremilast and establish the quality standard, 4-benzyloxy-3-ethoxybenzaldehyde was used as the starting material, and 4-benzyloxy-3-ethoxybenzonitrile was obtained by condensation with hydroxylamine hydrochloride. Apremilast impurity N-(2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide was synthesized from 4-benzyloxy-3-ethoxybenzonitrile via addition, reduction, condensation with N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide, Pd/C-catalyzed hydrogenation, and purification with an overall yield about 55.4% and a purity of 99.2%(HPLC). The structure was confirmed by 1H NMR, 13C NMR and HRMS. The conditions for synthetic process were optimized. This synthetic process is reasonable and feasible, the reaction conditions are mild, and the impurity purity is high. It can be used as the impurity reference substance for the quality control of Apremilast. |
| Key words：Apremilast; 4-benzyloxy-3-ethoxybenzaldehyde; impurity |
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作者簡(jiǎn)介：胡中元（1986—），男，安徽蚌埠人，工程師，碩士，研究方向：藥物合成工藝（E-mail：164313963@qq.com）。
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聯(lián) 系 人：劉彥龍，高級工程師，研究方向：藥物合成工藝。
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收稿日期：2023-02-16
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