Study On The Synthesis And Scale-up Of Linagliptin Of Intermediates

Diabetes is a common disease caused by the interaction of genetic and environmental factors, the reason of diabetes is the absolute or relative insulin secretion, due to the disorder of protein, fat, water and electrolytes and a series of metabolic and the increased glucose level is the main symbol. People are actively looking for new drugs to treat diabetes, but many drugs have some side effects. Thus search a new drugs with little toxicity is still important task of pharmaceutical and chemical workers.The DPP-4 inhibitors, a new antidiabetic drug, has the potential and unique improve islet cell function, which brings new choice for the protection and reverse of is let cell function in patients with type II diabetes. Llinagliptin is one of the DPP-4 inhibitor, it is effective and well tolerated for long-term glycemic control in type II diabetes, its mechanism of action and metabolism proved that is safe for treatment of type II diabetes, and it suggested that the prospect of linagliptin is broad and the market potential is enormous.8-bromo-3-methyl-xanthine is maternal linagliptin in molecular structure, is the key intermediate for the synthesis of linagliptin. This paper studied the synthesis of 8-bromo-3-methyl-xanthine, screening and optimization of synthetic route, using methyl urea and ethyl cyanoacetate as raw material through five steps to synthesis of the target product, the reaction yield, operation, production cost and the pilotscale experiments, which suggested that the rout is suitable for industrialized production, and according to test the melting point, high performance liquid chromatography (HPLC), nuclear magnetic resonance spectra(1-H-NMR), infrared bbsorption spectroscopy (IR), mass spectroscopy (MS), the results confirmed the structure and purity of compoundst. In the synthesis of 8-bromo-3 methyl xanthine in each step, the reaction temperature, reaction time, reducing agent, selection of reactant mixture ratio and other factors were optimized, we acquired the best the synthetic route.Considering of the safety, operation, costs and equipment conditions and other factors,we did three times of The pilotscale experiments. And we designed the processing plan of waste, the production process of the waste solvent, water for the recovery and purification treatment, which reduced the production cost and the pollution to the environment, and it provided a large amount of data for the 8-bromo-3-methyl-xanthine industrialized production and the declaration of linagliptin drug.