The Synthesis Of Levofloxacin And Its Intermediates

Levofloxacin is a kind of excellent fluoroquinolone broad-spectrum antimicrobials, the antibacterial strength is 2 times that of ofloxacin, toxicity is lower than ofloxacin. Levofloxacin is widely used in clinic for the respiratory tract infection, urethral infection, eye infections, the treatment of intestinal infection.The article summarized the synthesis methods of levofloxacin, redesigned the levofloxacin synthesis process, and then the route has been optimized and improved. In the new synthesis route, the object compound was prepared from 2,3,4,5-tetrafluorobenzoic acid, via acyl chlorination, by condensation,(s)-(+)-2-aminopropanol displacement, cyclization, hydrolysis, and finally N-methyl piperazine condensation, the total yield is 56.2%. Compared with the original synthesis route, this synthesis route eliminated two reaction steps and reduced the cost of raw materials.This paper examined the process parameters such as feeding ratio, temperature and solvent on the influence of the product yield. The experiment determined the optimal process parameters: ethyl acetate:sodium hydride:ethyl formate:tetrafluorobenzoyl chloride=1:1:1.2:0.9, the reaction solvent was toluene, the reaction temperature was 0～5℃, synthesis of 2-formyl-3-oxy-3-(2,3,4,5-tetrafluoro phenyl)propionic acid ethyl, the yield was 85.1%. 2-formyl-3-oxy-3-(2,3,4,5-tetrafluoro phenyl)propionic acid ethyl: (s)-(+)-2-aminopropanol=1:1.2, the reaction solvent was toluene, the reaction temperature was 85～ 90℃, synthesis of 3-(1-hydroxyl propane-2-amino)-2-oxy-2-(2,3,4,5-tetrafluoro phenyl)ethyl acrylate, the yield was 97%. the acid-binding agent of cyclization was KF, the reaction temperature was 140℃, the reaction solvent was DMF, the yield of (s)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxy-7H-pyrido-[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester was 93.6%. And then by hydrolysis, N-methyl piperazine condensation, recrystallization, finally get the target compound levofloxacin. Feeding ratio above was molar ratio.The process has many advantages, such as cheaper raw material, simple procedure, short reaction period, high optical purity, higher yield, product purity over 99%. So it should have a good prospect for industrial application. The structure of the product was characterized by means of IR,1HNMR and MS.