阿普斯特的合成工艺改进  

Improved synthetic process of apremilast

作　　者：王栋 钟健 王玲[2] 周志慧[2] 蒋海婷 罗鹏 王西芝 王崇益 WANG Dong;ZHONG Jian;WANG Ling;ZHOU Zhihui;JIANG Haiting;LUO Peng;WANG Xizhi;WANG Chongyi(Jiangsu Runan Pharmaceutical Co.,Ltd.Huai'an 223299;Research Institute,Jiangsu Chiatai Qingjiang Pharmaceutical Co.,Ltd.Huai'an 223001,China)

机构地区：[1]江苏润安制药有限公司,淮安223299 [2]江苏正大清江制药有限公司,淮安223001

出　　处：《中国药科大学学报》2021年第5期536-540,共5页Journal of China Pharmaceutical University

摘　　要：改进阿普斯特(APST)合成中的氢化还原反应工艺。以3-硝基邻苯二甲酸酐(4)和(S)-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲磺酰基)乙胺]-N-乙酰基-L-亮氨酸盐(7)为起始原料,经过胺化反应得到(S)-2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲磺酰基乙基]-4-硝基异吲哚啉-1,3-二酮(8),再以甲酸铵作为氢源,氢氧化钯碳为催化剂,将化合物8还原成(S)-2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲磺酰基乙基]-4-氨基异吲哚啉-1,3-二酮(9),最后与醋酐完成乙酰化反应得到APST。目标产物结构经比旋度、^(1)H NMR、^(13)C NMR、MS和元素分析等确证,胺化、还原和乙酰化3步反应总收率提高至67.0%。改进后的还原工艺,避开了氢化加压特种反应,降低了安全风险和生产成本,适合工业化生产,具有较高的商业价值。To optimize the process of hydrogenation reduction in the synthesis of apremilast(APST),3-nitrophthalic anhydride(4)and(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine-(S)-2-acetamido-4-methylpentanoate(7)were used as starting materials to synthesize(S)-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4-nitroisoindoline-1,3-dione(8)by amination.Then compound 8 was reduced to(S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindoline-1,3-dione(9)with ammonium formate as hydrogen source and palladium hydroxide as catalyst.Finally,apremilast was obtained by the acetylation reaction with acetic anhydride.The structure of the products were verified by optical rotation,^(1)H NMR,^(13)C NMR,MS and elemental analysis.And the total yield of three steps was increased to 67.0%.The improved reduction process can avoid the special reaction of hydrogenation and pressurization,and reduce the safety risk and production costs with high commercial value.

关 键 词：阿普斯特 磷酸二酯酶-4抑制剂 甲酸铵 合成 工艺改进 

分 类 号：R914[医药卫生—药物化学]