Study On The Synthetic Method Of(2R,3S)-3-amino-2-methyl-4-oxo-1-azetidinesulfonic Acid

Azetreonam is the first clinic used drug of a new class of β-lactam antibiotics known as monobactams. The drug is actuvely against the majority of infections caused by aerobic Gram-negative bacteria.(2R,3S)-3-amino-2-methyl-4-oxo-l-azetidinesulfonic acid is the key intermediates of synthesis azetronam. As aztreonam is widely used in clinical, the market of its raw materials grows quickly. To strengthen research of the (2R,3S)-3-amino-2-methyl-4-oxo-l-azetidinesulfonic acid is of great significance.In this paper, based on analysis of existing synthetic route and several experiments, we developed a new synthetic process which is suitable for industrial production. The improved synthetic route takes L-threonine as raw material via esterification, ester aminolysis, protection of amino group by forming N-CBZ, hydroxyl group by forming methylsulfonte, subsequently sulfonation with chlorosulfonic acid, cyclization under alkaline conditions and deprotection by hydrogenation to synthesize (2R,3S)-3-amino-2-methyl-4-oxo-l-azeti-dinesulfonic acid. The main research results are as follows:(1) Esterification. In the esterification reaction, we found that Dowex50(H+)resin-thionyl chloride could replace the thionyl choride in the guarantee of the premise of the feedstock conversion, only0.9%amount of raw materials is remained, but the cation exchange resin in the improved process can be achieved for loop application, the amount of thionyl chloride was reduced by40%to the original process, saving the cost of production. We selected the reaction temperature of the esterification is60-65℃, on the basis of the raw material conversion completely, we reduced the reaction time form12to7hours.(2) Ammonolysis. The key factors that influences the reaction conversion rate in the reaction of ammonolysis is the reaction pressure. By investigating the key factors that affects the reaction pressure, we determined that the molar ratio of ammonia and L-threonine is10:1and the reaction temperature is60～65℃, under such conditions the conversion rate of the reaction is increased to96～97%, increased3%by the original process.(3) Amino protection reaction. When we replaced the pure water system with the mixed solvent of ethyl acetate-water, the problem of a viscous reaction system is greatly reduced, promoting the dispersion of the raw material, with the help of the orthogonal experiments, we determined that the preferred conditions of amino-protecting reaction process is that the reaction pH is controlled at about8.5, the dropping temperature of benzyl choroformate is keeped at5℃, the molar ratio of benzyl chloroformate and L-threonine is1.0:1. After optimization of the reaction conditions, the total yield of the three-step reaction is raised to85%, a6%increased in yield compared to the original process.(4) Methyl sulfonylation reaction. Taking L-threonine as raw material, we for the first time prepared4-methylsulfonyl-oxo-3-carbobenzyloxy-amin-L-threoninamide using one-pot process, the intermediate product was used without separation, purification, drying etc. step. In the new process, we used pyridine instead of triethylamine as the acid binding agent, while adding a small amount of DMAP, to reduce the side reactions of nucleophilic substituted. The orthogonal experiments was designed to determine the optimal process parameters of the mesylation reaction:the molar ratio of methanesulfonyl chloride and L-threonine is1:1, the molar ratio of pyridine and L-threonine is1:1.2and the dropping temperature or pyridine is keeped at3℃, After optimization of the former four-step reaction conditions, the total yield of the four-step reaction is raised to78.2%, a7.1%increased in yield compared to the original process.(5) Sulfonated-cyclization reaction. We designed orthogonal experiments to investigate the key factors that influences the yield of sulfonated reaction, determining the molar ratio of chlorosulfonic and4-methylsulfonyl-oxo-3-carboben-zyloxy-amino-L-threoninamide is1.3:1, the dropping temperature of chlorosulfonic is-5℃, the molar ratio of2-methyl pyridine and4-methylsulfonyl-oxo-3-carbobenzyloxy-amino-L-threoninamide is3.0:1. Examining the two key factors(cyclization reaction temperature and pH) that impacts cyclization reactions, we determined the optimum conditions for the cyclization reaction is that reaction temperature keeping at33～36℃, the pH of the reaction keeping at8.0-8.5. After optimization of the reaction parameters, the reaction yield of sulfonated-cyclization increased by about4%.(6) Catalytic hydrogenation. The main byproducts were isolated and purified, its structure was characterized, and analysed the important factors that influences the side reaction is the solvent type, the reaction temperature and pH. It is determined that the methanol-THF solvent system is the optimum reaction system, the optimal reaction temperature of the deprotection reaction is17℃and the pH of the reaction should be selected at6.5-7.0. After these reaction conditions were optimized, the yield of the catalytic hydrogenation reaction is raised to75%, increased by about2%compared with the original process.