| The aim of this study was to obtain process parameters for industrial production of levofloxacin mesylate. The chiral (S)-(+)-2-aminopropanol was synthesized from L-lactamic acid. And then levofloxacin mesylate was synthesized from 2,3,4,5-tetrafluorobenzoic acid.(S)-(+)-2-aminopropanol was obtained from L-lactamic acid via esterification and reduction reactions. L-lactamic acid with biochemical purity was selected as starting material. The optimal conditions for esterification were L-lactamic acid and thionyl chride mixture in mole ratio 1:1.1, the dropwising temperature controlled between 0 and 5℃, and reaction kept at 38-40℃for 4h. The reduction was undertaken with mole ratio of the substrate and potassium borohydride at 1:2. Levofloxacin mesylate was synthesized from 2,3,4,5-tetrafluorobenzoic acid via acyl chlorination, condensation, partial hydrolysis and decarboxylization, amination-cyclization, and tosylate formation. The acyl chlorination was taked in 4h at reflux. Diethyl malonate condensation was controlled at the temperature between -10 to -5℃. The partial hydrolysis and decarboxylization for 6h and the triethyl orthoformate condensation for 4h were finished. The amination-cyclization was reacted with the substrate and (S)-(+)-2-aminopropanol in the mole ratio of 1:1.07 at 90℃for 10h. Dimethyl sulfoxide was the best solvent in the N-methylpiperazine condensation. With excessive sulfonic acid, the mixture of levofloxacin, purified water and active carbon in the ratio of 1:4:0.1 (g:ml:g) was heated at 60℃for 15 min for purification.The overall yield of levofloxacin mesylate was 39.25% with this new protocol while reference yield as 35%. The data of IR and NMR confirmed the composition and structure. The quality of the product met the specification of WS1-(X-187)-2003Z. The remarkable advantages of the new process were of mild reactive conditions, simple operation and excellent reproducibility, which provided feasible parameters for industrialization. |
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