The Synthesis Of Aztreonam’s Key Intermediate

As the important branch of pharmaceutical industry, antibiotics have great development potential. With the development of human disease spectrum, it is inevitable to select and develop efficient and low toxicity antibiotics drugs, which is an important direction of development in the field of pharmaceutical synthesis.Aztreonam is a monocyclic β-lactam antibiotics which has been used in clinical, their production costs are mainly determined by the key intermediate-the main ring of aztreonam, that is (3S-trans)-3-amino-4-methyl-2-oxo-l-azacyclobutylsulfonic acid. At present the production of aztreonam’s key intermediate have some disadvantages which have resulted in lower profits for industrial production, such as harsh production, low yield, high cost and so on. So it is very necessary to exploit a synthetic route with high yield, low cost and mild reaction conditions. This would bring good economical and research value.In this paper, the synthesis of aztreonam’s key intermediate was achieved with L-threonine as raw material via esterification, protection of amino group, aminolysis, protection of hydroxyl group, sulfonation, cyclization and deprotection. The overall yield was33%, the specific rotation of product was measured,[α]=-45°(c%=0.5%, H2O).In this paper we explored and improved the experimental methods and conditions. Firstly, the HC1was used for catalyst in L-threonine esterification, it was passed into the L-threonine and a mixture of methanol.The reaction mixture was refluxed for3h. Then the HC1gas was continually passed into the reaction mixture until saturation. The reaction completed after3days at room temperature. After that we can obtained L-Thr methyl ester hydrochloride; It was adopted concentrated ammonia solution to aminolysis, the product was L-Thr amide hydrochloride.The (Boc)2O was applied to protect amino, the triethylamine was adopted as tied acid agent and THF/H2O was adopted as solvent system. After the there step reactions, we got the product of L-Thr amide hydrochloride protected by Boc, the there steps yield was75%; The hydroxyl of the L-Thr amide hydrochloride protected by Boc was protected by methanesulfonyl chloride, the yield was80%after the optimized conditions; In the sulfonation process, the acylamino was sulfonated by chlorosulfonic acid, the molar ratio of raw materials,2-methyl-pyridine and chlorosulfonic acid was1:6:3, the yield was93%; The cyclization process was under the alkaline conditions, both KHCO3and NaHCO3were adopted to catalyst, the effect of them were both good. Besides, our study found that the buffer solution was used to adjust the pH of reaction solution until neutral, then the separatory and extraction were conducted, which can greatly improve the extraction efficiency, increase yield and reduce the waste emissions; At last the formic acid was used to deprotection at40℃, we can get the target product. After optimizing conditions the yield was60%(calculated in the product of sulfonation). The overall process yield was33%.The chemical structures of compounds were confirmed by1H NMR. The physical and chemical properties of some compounds were determined. Such as melting point, optical rotation and so on.