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目的对PI3K-δ抑制剂idelalisib的合成工艺进行研究。方法以2-氟-6-硝基苯甲酸为起始原料,经氯化、与苯胺缩合、水合肼还原、与(2S)-2-{[(1,1-二甲基乙氧基)羰基]氨基}丁酸缩合得到N-{(1S)-1-[({3-氟-2-[(苯基氨基)羰基]苯基}氨基)羰基]丙基}氨基甲酸-1,1-二甲基乙基酯,再经环合、脱保护基得到2-[(1S)-1-氨基丙基]-5-氟-3-苯基-4(3H)-喹唑啉酮,最后与6-溴-9H-嘌呤发生亲核取代反应得到目标化合物idelalisib。结果与结论idelalisib的总收率为30.8%(以2-氟-6-硝基苯甲酸计),纯度为99.9%,其结构经IR、MS、~1H-NMR、~(13)C-NMR确证。该路线未见文献报道,反应原料易得,反应条件温和,操作简便,为其中试放大奠定了基础。
Objective To study the synthesis of idelalisib, a PI3K-δ inhibitor. Methods 2-Fluoro-6-nitrobenzoic acid was used as the starting material. After chlorination, it was condensed with aniline and hydrazine hydrate was reduced to react with (2S) -2 - {[(1,1-dimethylethoxy) Carbonyl] amino} butanoic acid to give N - {(1S) -1 - [({3-fluoro- 2 - [(phenylamino) carbonyl] phenyl} amino) carbonyl] propyl} - dimethylethyl ester, followed by cyclization and deprotection to give 2 - [(1S) -1-aminopropyl] -5-fluoro-3-phenyl-4 (3H) -quinazolinone, Finally nucleophilic displacement reaction with 6-bromo-9H-purine to obtain the target compound idelalisib. RESULTS AND CONCLUSION The total yield of idelalisib was 30.8% (calculated as 2-fluoro-6-nitrobenzoic acid) with a purity of 99.9%. Its structure was confirmed by IR, MS, 1H-NMR and 13C- Confirmed. The route has not been reported in the literature, the reaction raw materials are readily available, the reaction conditions are mild, and the operation is simple, laying a solid foundation for the pilot enlargement.