莫博替尼的合成方法改进

Improved Synthesis of Mobocertinib

作者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,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),进而与异丙醇发生酯化反应得到2-4-二氯嘧啶-5-羧酸异丙酯(3)。随后,3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的催化下,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](甲基)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](甲基)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](甲基)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Mobocertinib,总收率为53.9%。

In this paper,the synthesis method of epidermal growth factor receptor tyrosine kinase inhibitor Mobocertinib(TAK788)was improved.Using 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%.