Penem Key Medicinal Intermedia--Synthesis Of Azetidinone

Penem belongs to new-type beta-lactam antibiotics. Because these compounds which have both broad antibacterial spectra, including Gram-positive and Gram-negative species and stability to various beta-lactamases have received much attention as potential therapeutic agents. Its antibiotic function is remarkable. Compared with the antibiotic of carbapenem, it should have high security, its toxicity is low to kidney and central nervous system, and it is the first drug of being selected in curing the mediate bacterial infection. Since the first disclosure of penem antibiotic by Woodward, this kind of antibiotic has been developed rapidly, and become thefocus of the studies on antibiotic medicine.Chiral azetidinone is key medicament intermediate that synthesizes various kinds penem and carbapenem. The work of this research is devoted to the efficient synthesis of azetidinone, is in the hope of setting up rational and feasible synthetic route. The route of synthesis is studied and probed, the reaction that is involved has been improved, and we have optimized the process conditions, improved rate of the production, and have explained relevant response mechanism. We have succeed and realized in three-dimensional control and synthesize with 6-APA qua material, the total yield is 37% (at 6-APA count).The advantage of this technology is utilizing the resource advantage in Hebei province. This technology includes reaction of seven steps: [1] diazotized and brominates reaction; [2] esterifies reaction; [3] grignard reaction; [4] the hydroxyl is protected; [5] reduction reaction; [6] opening-ring reaction; [7] oxidation reaction. And replace reaction and esterifies reaction have been carried on condition optimizing and mechanism discussion. We have improved the purity of the products and rate of production. According to the mechanism of the exchange of metal-halogen, the time and temperature of reaction is proper extended, and the quality of reaction of grignard is improved. The rate of production of methyl 6-((lR)-hydroxyethyl)penicillanate has been improved in the reduction reaction, in which acetic acid ammonium take off the bromine using methanol as solvent and zinc powder as catalyst. Make it a condition that opening-ring reactionand oxidize reaction in keeping rate of production is not change, the time of reaction is shorten. Optimizing conditions of reaction and vast chiral-separate of the last step need further study. Oxygen instead of oxidant whether or not needs further research and confirmation also in the oxidation reaction...