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目的合成磷酸肌醇3-激酶δ抑制剂idelalisib。方法以2-氟-6-硝基苯甲酸为原料,与苯胺缩合得到2-氟-6-硝基-N-苯基苯甲酰胺,然后与N-Boc-L-2-氨基丁酸反应得到(S)-N-(2-Boc-氨基丁酰基)-2-氟-6-硝基-N-苯基苯甲酰胺,经锌粉还原环合得到关键中间体5-氟-3-苯基-2-[(S)-1-Boc-氨基丙基]-4(3H)-喹唑啉-4-酮,该中间体经三氟乙酸水解脱Boc保护基得到5-氟-3-苯基-2-[(S)-1-氨基丙基]-4(3H)-喹唑啉-4-酮,再与6-氯嘌呤反应制得目标物idelalisib。结果与结论改进后的新工艺路线总收率为22.2%(以2-氟-6-硝基苯甲酸计),纯度为99.2%(HPLC法)。该路线具有反应条件温和,原料价廉、易得,操作简单等优点。
OBJECTIVE: To synthesize phosphoinositide 3-kinase δ inhibitor idelalisib. Methods 2-Fluoro-6-nitrobenzoic acid was used as the starting material to condense with aniline to obtain 2-fluoro-6-nitro-N-phenylbenzamide and then reacted with N-Boc-L-2-aminobutyric acid (S) -N- (2-Boc-aminobutyryl) -2-fluoro-6-nitro-N-phenylbenzamide was obtained by reductive cyclization of zinc powder to give 5-fluoro-3- Phenyl-2 - [(S) -1-Boc-aminopropyl] -4 (3H) -quinazolin-4-one, which was deprotected with trifluoroacetic acid to give 5-fluoro-3 - phenyl-2 - [(S) -1-aminopropyl] -4 (3H) -quinazolin-4-one and reacting with 6-chloropurine to obtain the target substance idelalisib. RESULTS AND CONCLUSION The improved yield of the new process route was 22.2% (based on 2-fluoro-6-nitrobenzoic acid) with a purity of 99.2% (HPLC method). The route has the advantages of mild reaction conditions, cheap raw materials, easy to obtain, simple operation and so on.