DOI: 10.16597/j.cnki.issn.1002-154x.2024.04.003
莫博替尼的合成方法改进
作者： 刘茜雅，张艳
单位： 江南大学生命科学与健康工程学院，无锡 214122
摘要： 本研究对表皮生长因子受体酪氨酸激酶抑制剂莫博替尼(TAK788)的合成方法进行了改进。以2,4-二羟基-5-嘧啶羧酸(1)为原料，通过与氯化亚砜回流反应得到中间体2,4-二氯嘧啶-5-甲酰氯(2)，再与异丙醇酯化得到2,4-二氯嘧啶-5-羧酸异丙酯(3)。随后，在三氯化铁催化下与N-甲基吲哚发生傅克反应得到关键中间体2-氯-4-(1-甲基-1H-吲哚-3-基)嘧啶-5-羧酸异丙酯(4)；4与4-氟-2-甲氧基-5-硝基苯胺在对甲苯磺酸一水合物催化下发生C-N偶联反应，得到2-[(4-氟-2-甲氧基-5-硝基苯基)氨基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-5-羧酸异丙酯(5)；5与N,N,N′-三甲基乙二胺亲核取代得到2-[(4-{2-(二甲氨基)乙基氨基}-2-甲氧基-5-硝基苯基)氨基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-5-羧酸异丙酯(6)；6在乙醇和氯化铵水溶液条件下通过铁粉还原得到2-[(5-氨基-4-{2-(二甲氨基)乙基氨基}-2-甲氧基苯基)氨基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-5-羧酸异丙酯(7)；7与3-氯丙酰氯经缩合反应得到2-[(5-(3-氯丙酰胺基)-4-{2-(二甲氨基)乙基氨基}-2-甲氧基苯基)氨基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-5-羧酸异丙酯(8)；最终在碱性条件下回流得到目标化合物莫博替尼，总收率为53.9%。
关键词： 表皮生长因子受体；莫博替尼；非小细胞肺癌；合成
Improved Synthesis of Mobocertinib
Authors: LIU Xiya, ZHANG Yan*
Affiliation: School of Life Science and Health Engineering, Jiangnan University, Wuxi 214122, China
Abstract: This paper improved the synthesis method of epidermal growth factor receptor tyrosine kinase inhibitor Mobocertinib (TAK788). Starting with 2,4-dihydroxy-5-pyrimidinecarboxylic acid (1) as raw material, intermediate 2,4-dichloropyrimidine-5-formyl chloride (2) was obtained by reflux reaction with thionyl chloride, and then esterified with isopropanol to obtain 2,4-dichloropyrimidine-5-carboxylic acid isopropyl ester (3). Subsequently, the key intermediate 2-chloro-4-(1-methyl-1H-indole-3-yl) pyrimidine-5-carboxylic acid isopropyl ester (4) was obtained by Friedel-Crafts reaction of 3 with N-methylindole catalyzed by ferric chloride. 2-((4-Fluoro-2-methoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indole-3-yl) pyrimidine-5-carboxylic acid isopropyl ester (5) was obtained by C-N coupling reaction of 4 with 4-fluoro-2-methoxy-5-nitroaniline catalyzed by p-toluenesulfonic acid monohydrate. 2-((4-(2-(dimethylamino))ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indole-3-yl) pyrimidine-5-carboxylic acid isopropyl ester (6) was obtained by nucleophilic substitution of 5 with N,N,N′-trimethylethylenediamine. 6 was reduced by iron powder under the condition of ethanol and ammonium chloride aqueous solution to obtain 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indole-3-yl) pyrimidine-5-carboxylic acid isopropyl ester (7). 2-((5-(3-chloropropanamido)-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indole-3-yl) pyrimidine-5-carboxylic acid isopropyl ester (8) was obtained by condensation reaction of 7 with 3-chloropropionyl chloride, and finally, the target compound Mobocertinib was obtained by refluxing under alkaline conditions with an overall yield of 53.9%.
Keywords: epidermal growth factor receptor; mobocertinib; non-small cell lung cancer; synthesis