Study On The Synthesis Of The Intermedia Of Gemifloxacin

Gemifloxacin is one of the new fluoroquinolones, chemical name: 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo -l,4-dihydro-l,8-naphthyridine-3-carboxylic acid, the merchandise is named Factive, also calling SB-265805, LB-20304.7-branched-chain is the most important part of the quinolones, and it has the decisive influence to the pharmacology activity. The work of this research is devoted to the efficient synthesis of 7-branched-chain: 4-aminomethy -3-methoxyiminopyrrolidiniurn ditrifluoroacetat ditrifiuoroacetat, and try to synthesize gemifloxacin by means of the borate chelate. Is in the hope of setting up rational and feasible synthetic route. The intermedias were characterized by IR spectra, MS spectra 1H-NMR spectra, the elemental analysis, the results showed that the structures of products were the same to the target compounds.Acrylonitrile and glycine ethyl ester hydrochloride were raw material in the addition reaction, with the molar ratio being: 2.5:1; PH=8; and the product was obtained with the yield of 60.6% for 6h at 55 ℃ . In the amino-protection reaction, di-t-butoxycarbonyldicarbonate as the amino-protection agent, dioxane-water as menstruum; (Boc)2O was 0.26mol/l; PH=8~9; reaction time was 6h, and the yield was 75.4%. The appropriate reaction conditions of cyclization reaction: NaOEt was 1.4 mole eq.; menstruum was CHCl3; and the product was obtained with the yield of 66.0% for 1.5h. The reduction reaction was carried out at -3℃ for lh, and 1.5 mole eq. LiAlH4 as the reducing agent, the yield achieved 73.0%. The oxidation reaction was carried out at 25℃ for 1.5h, and 1.5 mole eq. Corey as the oxidant, the yield achieved 74.0%. The appropriate reaction conditions of oximation reaction: 1.5 mole eq. of methoxyaminehydrochloride was added thereto and petroleum as menstruum; PH = 6; the yield achieved the product was obtained with the yield of 93.7% for 1h at 40℃. In the deprotection and salification reaction, trifluoroacetic/tetrahydrofuran as reaction system; reaction time was 20min; reaction temperature was 25℃; and the yield achieved 90.8%. B(OAc)3 as the chelate in the sequestration reaction, and the product was obtained with the yield of 90.4 % for 3h at 90 ℃, washed with water, then dried up at 45 ℃ under reduced pressure of -0.065Mpa. The appropriate reaction conditions of the last step: reaction time was 5h; reaction temperature was 60 ℃; the reaction menstruum was acetonitrile and the yield achieved 85.71%.