Method for preparing levofloxacin

Abstract

The invention discloses a method for preparing levofloxacin, aiming at providing a method for preparing levofloxacin, with short production period, small pollution, high raw material utilization ratio, yield and purity and simple and convenient operation. The method comprises the following steps of: taking tetrafluorobenzoyl chloride as raw material to prepare S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxygen-7H-pyridino[1,2,3-de]-[1,4]- benzoxazine-6-carboxylic acid by a synthesis method, then reacting with alkali in organic solvent, and obtaining the levofloxacin. The method has the advantages that the tetrafluorobenzoyl chloride is utilized to react with S-3-(2-R1-2-R2-4-methyl imidazolidinyl) acrylic ester, and hydrolization is carried out directly while in post-treatment, and finally loopis closed, thus reducing reaction steps, shortening the reaction time and improving the reaction yield up to 85-90%. In preparing, organic or inorganic alkali is added, thus reducing the inventory amount of methyl piperazine and lowering the reaction cost and having good recovery rate.

Description

technical field [0001] The present invention relates to the production technology of medicine, specifically a kind of preparation method of levofloxacin. Background technique [0002] Levofloxacin (levofloxacin) is an antibiotic, which has achieved great success in clinical anti-infection treatment due to its high-efficiency, broad-spectrum, and low-toxic antibacterial properties. [0003] [0004] The synthesis research and process of levofloxacin have been continuously improved and improved in the past two decades. The main production methods are as follows: [0005] 1. Resolution method: including chromatographic resolution such as patent EP206283, 1986 and enzyme resolution such as document Biol.Chem.: 1987, 51, 1265, because the final resolution method is adopted, so there is a low yield in the reaction process , low atom utilization, relatively difficult optical purification and other shortcomings. [0006] 2. Prepare levofloxacin as starting material by tetrafluo...

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Problems solved by technology

[0005] 1. Resolution method: including chromatographic resolution such as patent EP206283, 1986 and enzyme resolution such as document Biol.Chem.: 1987, 51, 1265, because the final resolution method is adopted, so there is a low yield in the reaction process , low atom utilization, relatively difficult optical purification and other disadvantages

[0006] 2. Prepare levofloxacin as starting material by tetrafluorobenzoic acid, such as patent US4777253, 1988 and patent US5539110, 1996, etc., with 2,3,4,5-tetrafluorobenzoic acid as raw material, after acyl chloride and Condensation of diethyl malonate, partial hydrolysis decarboxylation, condensation with triethyl orthoformate, replacement of L-aminopropanol, cyclization, hydrolysis, and condensation with N-methylpiperazine, a total of 8 steps of reaction, the total yield Yield 21-39.2%, the defect of this route is that step is long, yield is low, especially the atom economy in the reaction is poor, the utilization rate of raw material is low, and the three wastes are more

[0007] 3. Using trifluoronitrobenzene or its derivatives as raw materials, such as EP0368410, 1990, EP0206283, 1989, US6872823, 2005, etc., first synthesize the key intermediate S-7,8-difluoro-3-methyl-3 , 4-dihydro-2H-1,4-benzoxazine, then condensed with diethyl ethoxymethylene malonate, cyclized, hydrolyzed, and refined with methylpiperazine to obtain levofloxacin .The main disadvantage is that the synthesis of the intermediate S-7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine has long steps, low yield and difficult optical purification Large and other disadvantages, it is difficult to be suitable for mass production

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