Synthesis Of Sitafloxacin Intermediate Aza Spiro Alkane

Fluoroquinolone antibiotics sitafloxacin has excellent antibacterial properties and little side effect. It is mainly used for severe refractory infectious diseases. In the molecular structure of sitafloxacin, chiral aza spiro alkane has an effect on the hydrophobicity and the pharmacokinetic of antibacterial spectrum about gram-negative bacteria.Synthesis of aza spiro alkane was the main research content of this article. The synthetic methods, cost-effective and possible to produce in large-scale, was explored by experiments. A brief outline about the research in quinolone antibacterial drugs, the development potential of sitafloxacin as well as the synthetic route of its two key intermediates was made after a review of relevant literature.The synthesis of ethyl acetoacetate as starting material is determined after advantages and disadvantages assessment of each synthesis about (S)-7-amino-5-azaspiro [2.4] heptane. After protection of carbonyl group in ethyl acetoacetate using ethylene glycol, the product reacts with a benzyl amine. N-benzyl-1-acetyl-cyclopropane carboxamide was obtained by cyclization. Then after bromination, cyclization, oximation of ketone carbonyl groups, reduction and so on,7-(t-butoxycarbonyl)amino-5-benzyl-5-aza-spiro[2.4]heptane was prepared.Process optimization for each step was made. The results were that:in carbonyl protection, the material ratio was n(ethylacetoacetate):n(ethylene glycol)=1:1.4, the catalyst amount was m(p-toluenesulfonic acid):m(raw material)=4.0%, the reaction time was 5h, the yield was 95.2%; in amine transesterification, the material ratio was n(2-methyl-1,3-dioxolan-2-acetate):n(benzylamine)=1:1.2, the concentration of sodium ethoxide was 1.33mol/L, the yield was 47.1%; in cyclization, the material ratio was n(N-benzyl-3-oxo-butyramide):n(1,2-dibromoethane)= 1:1.0, γ-CD was chosed as phase transfer catalyst at 70℃, the amount of catalyst was n(γ-CD):n(N-benzyl-3-oxo-butyramide)=0.1, the yield was 96.8%; in bromination, the materials ratio was n(N-benzyl-1-acetyl-cyclopropane carboxamide): n(ammonium bromide)= 1:1.1 at 60℃, the yield was 84.7%; in amino protection, the material ratio was n(5-benzyl-5-azaspiro[2.4]heptan-7-amine):n(Boc2O)=1:1.4, the reaction time was 2h, the yield was 79.5%. The reaction products were characterized by 1HNMR, GC, IR, MS.