Study On Synthesis Of 1-Tert-Butyloxycarbonyl-3-Azetidinone

1-tert-butyloxycarbonyl-3-azetidinone is an important pharmaceutical intermediate with wide application in the field of organic drug synthesis.At present,the synthesis method of 1-tert-butoxycarbonyl-3-azetidinone has the disadvantages of long route,harsh conditions,serious pollution,high cost and which limit the scale of its industrial production.In this paper,an unreported synthesis route was designed by using epichlorohydrin as starting material: The target compound 1-tert-butoxycarbonyl-3-azetidinone obtained by condensation with benzaldehyde,then hydrolysis,cyclization,amino protection and oxidation steps.The method has the advantages of short synthetic route,high yield,green process,easily obtained raw materials,convenient operation,low cost,etc.,and is suitable for industrial production.In the condensation-hydrolysis step,the optimum reaction conditions was obtained first through the single factor and then by orthogonal experiment: epichlorohydrin and benzaldehyde molar ratio of 1:1.0,reaction temperature 20-25?,reaction time 32 hours,the ammonia amount 0.88 equivalent,concentrated hydrochloric acid amount 0.94 equivalent.In the cyclization and amino protection step,the influence of different reaction solvents,water content of the solvents,solvent dosage,types of the used alkali and the dosage of the alkali were investigated on the yield and quality,discussed the effect of different crystallization solvent on purification of 1-tertbutoxycarbonyl-3-nitrogen heterocyclic butanol crude product,the optimum reaction condition was finally established as following: cyclization was finished in acetonitrile(water content is less than or equal to 2.0%)as well as the presence of 3.0 equivalents sodium bicarbonate under refluxing;amino is protected by BOC in 4 times volume(V/W)of methanol as well as 4.0 equivalent of sodium bicarbonate,then 1-butoxycarbonyl-3-nitrogen heterocyclic butanol was obtained after being refined by 4 times volume(V/W)of n-heptane.Its purity is more than 99.0%.Finally,the oxidation reaction was studied and the reaction mechanism of TEMPO oxidation was discussed.TEMPO oxidation system advantages and disadvantages by different auxiliaries were compared in the oxidation process.The optimal process condition of TEMPO/NaClO/KBr system and TEMPO/CaCl2/Oxone system were focused on through experiment and the TEMPO/CaCl2/Oxone system is assured to be the best.Furthermore,the optimum condition is following: the volume of 5 times(V/W)dichloromethane,1.0 equivalents of Oxone,0.01 equivalents of TEMPO,0.1 equivalents of CaCl2 exist can result ideal quality and yield of crude product.Followed by purification of 2.5 times(V/W)ethyl acetate,the purity of 1-tert-butoxycarbonyl-3-azetidinone can be more than 99.0% and the total yield of oxidation can be 86.5%.The product structure of each step was confirmed by ~1H NMR,13 C NMR,IR and MS.