阿普斯特杂质的合成  

Synthesis of Apremilast Impurity

作　　者：胡中元 唐旭静 邢磊 张晓玲 刘彦龙 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)

机构地区：[1]正大天晴药业集团股份有限公司研究院,江苏南京210000

出　　处：《精细化工中间体》2023年第2期36-39,共4页Fine Chemical Intermediates

摘　　要：为有效控制阿普斯特原料药质量并建立质量标准,使用4-苄氧基-3-乙氧基苯甲醛为起始原料,与盐酸羟胺缩合脱水后,经加成、还原、与3-乙酰氨基邻苯二甲酸酐缩合、Pd/C氢化脱苄基制得阿普斯特杂质2-[1-(3-乙氧基-4-羟基苯基)-2-甲磺酰基乙基]-4-乙酰基氨基异吲哚啉-1,3-二酮,并优化了合成工艺。优化条件下,杂质纯度99.2%(HPLC),总收率55.4%。采用^(1)H NMR、^(13)C NMR和HRMS对其结构进行表征确证。合成工艺合理、反应条件温和,制备的杂质纯度高,可作为阿普斯特药物质量控制的杂质对照品。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 ^(1)H NMR,^(13)C 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.

关 键 词：阿普斯特 4-苄氧基-3-乙氧基苯甲醛 杂质 

分 类 号：R914.5[医药卫生—药物化学]