Study On The Process For Preparation Of Key Intermediates Of Phosphomycin And Levofloxacin

Fosfomycin is a new type of broad-spectrum antimicrobial drugs, with unique chemical structure and antimicrobial mechanism.It has no cross-resistance with other antibiotics or antimicrobial agents and shows synergy.The novel process for synthesis of the key intermediate of Phosphomycin,(1R,2S)-(-)-cis-1,2-Epoxypropylphosphonic acid(R) -(+)-α- phenylethylamine salt,was studied in the first part of the dissertation,which was from propargyl alcohol and phosphorus trichloride by substitution,rearrangement and hydrolysis to give 1,2-propadienyl-phosphonic acid,subjected to catalytic hydrogenation, epoxidation with hydrogen peroxide and then resolution.The optimum process parameters were discussed and determined.The process parameters were optimized experimentally as follows: the substitution reaction solvent was dichloromethane,phosphorus trichloride:propargyl alcohol=2.0:1,the reaction temperature was 0-5℃,the reaction time was 3.0 h;the rearrangement reaction solvent was chloroform,the reaction temperature was reflux temperature,the reaction time was 10.0 h;the catalytic hydrogenation solvent was 50% ethanol-50%benzene,the reaction temperature was 45℃,the reaction pressure was 0.05 MPa,in the presence of 0.8%Lindlar catalyst;the oxidant was H₂O₂(30%),the catalyst was Na₂WO₄,CPPA:Na₂WO₄=50: 1,the reaction solvent was ethanol,the reaction temperature was 50℃. The total yield of(1R,2S)-(-)-cis-1,2-Epoxypropylphosphonic acid(R) -(+)-α- phenylethylamine salt is 24.10%.Levofloxacin is the third generation quinolone with broad spectrum antimicrobial and low toxicity,which is the national essential drugs.The novel process for synthesis of the key intermediate of Levofloxacin,(S)-ethyl9,10-difluoro-3-methyl-7-oxo-7-dihydro-2H-[1,4]o -xazino[1,2,3-de]quinoline-6-carboxylate,by condensation,S-(+)-2-aminopropanol displacement,and then cyclization,was studied in the second part of the dissertation.The optimum process parameters were discussed and determined.The process parameters were optimized experimentally as follows: sodium hydride:ethyl acetate:ethyl formate=1.1:1:1.2,the reaction solvent was toluene;tetrafluorobenzoyl chloride:sodium formyl ethyl acetate =1.0:1.05,the reaction temperature was 0-5℃,the reaction solvent was toluene;tetrafluorobenzoyl chloride:sodium formyl ethyl acetate:S-(+) -2 -amino-propanol = 1.0:1.05:1.2;the acid-binding agent of cyclization was KF,the reaction solvent was DMF.The total yield of(S)-ethy19,10-difluoro-3-methyl-7-oxo-7-dihydro-2H-[1,4]o-xazi -no[1,2,3-de]quinoline-6-carboxylate is 55.09%.It provided the theoretical basis and the feasible process parameters for the industrialization of(1R,2S)-(-)-cis-1,2-Epoxypropylphosphonic acid(R) -(+)-α- phenylethylamine salt and(S)-ethyl9,10-difluoro-3-methyl -7-oxo-7-dihydro-2H-[1,4]o-xazino[1,23-de]quinoline-6-carboxya -te.