| 第 51 卷第 5 期 |  | Vol. 51 No. 5 | | 2021 年 10 月 | Oct 2021 |
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所屬欄目：醫藥及中間體
阿伐那非中間體N-1的合成及其相關(guān)雜質(zhì)研究 |
| 胡華南1，2，吳秀榮2，黃華南1，2，彭 游1，嚴 平1，葉友余2
（1. 九江學(xué)院 化學(xué)化工學(xué)院，江西 九江 332005；2. 九江善水科技股份有限公司，江西 九江 332700） |
| 摘 要：為加強對阿伐那非原料藥的質(zhì)量控制，研究了阿伐那非中間體N-1的合成及其工藝雜質(zhì)A、B和C引入的原因，并合成了阿伐那非中間體N-1雜質(zhì)A、B和C。以4-氯-2-甲硫基嘧啶-5-羧酸乙酯（1）為起始原料，經(jīng)過(guò)取代和氧化等反應得到阿伐那非中間體N-1，氧化物繼續與3-氯-4-甲氧基芐胺（2）反應得到雜質(zhì)B，氧化物在堿性條件下水解得到雜質(zhì)C，4-氯-2-甲硫基嘧啶-5-羧酸乙酯（1）與4-甲氧基芐胺經(jīng)過(guò)取代和氧化等反應得到雜質(zhì)A，目標化合物的結構經(jīng)過(guò)NMR與MS確證，純度達97.5%以上（HPLC），可作為阿伐那非中間體N-1質(zhì)量控制的雜質(zhì)對照品。 |
| 關(guān)鍵詞：阿伐那非；PDE5抑制劑；雜質(zhì) |
| 中圖分類(lèi)號：R914 文獻標識碼：A 文章編號：1009-9212（2021）05-0031-04 |
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| Synthesis of Avanafil Intermediate N-1 and Its Related Impurities |
| HU Hua-nan1,2, WU Xiu-rong2, HUANG Hua-nan1,2, PENG You1, YAN Ping1, YE You-yu2
(1. College of Chemistry and Chemical Engineering, Jiujiang University, Jiujiang 332005, China; 2. Jiujiang Shanshui Technology Co., Ltd., Jiujiang 332700, China) |
| Abstract：In order to strengthen the quality control of avanafil API, study on synthesis of avanafil intermediate N-1 and the reason of its A, B and C impurities that are introduced, and the synthesis of intermediate N-1 avanafil impurities A, B and C. Using ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate(1) as the starting material, avanafil intermediate N-1 was obtained through substitution, oxidation reaction, the oxide continued to react with 3-chloro-4-methoxybenzylamine(2) to obtain impurity B, the oxide is hydrolyzed under alkaline conditions to obtain impurity C, Ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (1) reacted with 4-methoxybenzylamine to obtain impurity A, the structure of the target compound by NMR and MS spectra, HPLC detection of purity was more than 99.5 %, can be used as intermediate avanafil N-1 quality control of impurity reference. |
| Key words：Avanafil; PDE5 inhibitors; impurity |
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基金項目：江西省教育廳科技項目（GJJ170962），國家自然科學(xué)基金項目（81660541）。
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作者簡(jiǎn)介：胡華南（1976—），男，江西九江人，副教授，博士，研究方向：有機及藥物中間體的合成（E-mail：hhn12192000@126.com）。
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收稿日期：2021-08-03
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