“一锅法”合成帕珠沙星中间体的研究

“one-pot” Synthesis of Intermediate of Pazufloxacin

摘要:

以帕珠沙星中间体II，(S)-10-氰甲基-9-氟-2,3-二氢-3-甲基-7-氧代-7H-吡啶并[1,2,3-de]-1,4-苯并噁嗪-6-羧酸乙酯为原料，经环合、水解“一锅法”反应，制备帕珠沙星高级中间体IV，(S)-10-(1-环丙基甲酰)-9-氟-3-甲基-7-氧-3,7-二氢-2H-[1,4] 噁嗪[2,3,4-ij]喹啉6-羧酸。探讨了反应的碱、溶剂等对实验的影响。确定最佳的合成工艺条件为：n (化合物II)：n(1，2-二氯乙烷)：n（苄基三乙基氯化铵）：n(氢氧化钠) = 1：1.5：0.43：16.7，水作为溶剂，先室温搅拌5小时，随后回流2小时。反应具有条件温和、操作安全，成本低，绿色环保等优点。

Abstract:

(S)-10-(1-carbamoylcyclopropyl)-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H -[1,4]-oxazino[2,3,4-ij]quinoline-6-carboxylic acid, the senior intermediate of pazu- floxacin, was synthesiszed from (S)-ethyl 10-(cyanomethyl)-9-fluoro-3-methyl- 7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate, via a one-pot reaction of cyclopropanation and cyanide hydrolyzation. The reaction conditions were optimized as follows: n (Compound II): n(1,2-dichloroethane): n (Benzyltriethylam monium chloride):n(NaOH) = 1:1.5:0.43:16.7，stirred in water for 5h at room temperature and then reflux for 2h. The method has the advantages of mild reaction condition, safety, low cost, and environmental friendly.