Optimizing Production Process And Research Of Sulbactam Sodium

With fine selectivity,β-lactam antibiotics are very important anti-infective drugs. But, in the main structure of such antibiotics, there is aβ-lactam ring of a certain tension outside. Theβ-lactim is extremely sensitive to the external environment, and it is easy to hydrolysis and part, which may degrade the antibacterial activity ofβ-lactam antibiotics, even lead to loss of antibacterial effect completely. Therefore, clinical treatment of bacterial resistance has become a serious problem. Combiningβ-lactamase inhibitors withβ-lactam antibiotics in the treatment of resistant bacteria infections, which maintaining or even strengthening antibacterial activity of theβ-lactam antibiotics, is a rapid and effective method. Sulbactam was proved to be the penicillin sulfoxide possessing inhibiting effect. Penicillin sulfoxide is a typical beta-lactamase inhibitor. It was combined withβ-lactam ring antibiotics to protect antibiotics against damaging and improve its antibacterial activity by the way of inhibition of the enzyme. Thus, the process study of sulbactam sodium has great practical significance.Generally, the traditional synthesis routes of sulbactam sodium have two types. At the first route, substitution reaction is carried out in the organic phase of ethyl acetate, with sulfuric acid as medium; oxidation reaction is carried out permanganate of potash as oxidant; using nickel as catalyst at the reduction in autoclave. The total yield is 66.5%.At the second route, substitution reaction is carried out in the organic phase of dichloromethane, sulfuric acid as medium; oxidation reaction is carried out using permanganate of potash as oxidant; in the reduction, methanol was used as a solvent and magnesium as reducing medium. The total yield is 65%.In this dissertation, the process of sulbactam sodium based on the traditional process was researched, optimizing produce procedure of sulbactam sodium using 6-aminopenicillanic acid (6-APA) as raw materials by diazotization, di-bromidation, oxidation and reduction. Substitution reaction is carried out in inorganic phase of hydrobromic acid medium. Mixture of potassium permanganate with phosphoric acid was used as oxidant in oxidation reaction, and zinc powder as reductant in reduction reaction.In the course of experiment, consideration the influence of factors such as temperature, the ratio of reactive substances, reaction time, pH value, the ratio of oxidant mixture, reductant, the times of extraction and catalyst. Through a lot of experiments, the optimum route of preparation sulbactam sodium was determined: substitution reaction lasted 3.5h with cetyl trimethyl ammonium bromide as catalyst at 0°C when 6-APA: NaNO₂: HBr: Br₂ was 1:1:13:4 (mole ratio), oxidation reaction lasted 1h at 0～5°C when (II): permanganate of potash: phosphoric acid was 1:1.5:1.5 (mole ratio) and pH was 6.5; reduction react with zinc powder as reductant when (III): zinc was 1:6 (mole ratio) ,and extracted for three times with ethyl acetate; The final reaction lasted for 1h when (IV): CH₃ (CH₂) 4CH (CH₃) COONa was 1:1 (mole ratio).The total yield of reaction is of 69.67% (to (I) subtotal), which increased by nearly four percent than conventional processes (yield 65～66%). The process is simple, low cost, high yield, and suitable for industrial production.Finally, structure of the product was analyzed and investigated by melting point equipment, IR, ¹HNMR, HPLC and MS.