Study On The Synthetic Process Of Nicergoline

Nicergoline,a derivative of hemiergot alkaloids.In the 1970s,clinical research and application began.It has a wide range of uses:as a₁-adrenergic receptor antagonist,it can increase the blood flow of the patient’s blood vessels,arteries and brain by causing the patient’s blood vessels to dilate;it can increase choline And catecholamine neurotransmitter function;inhibits platelet aggregation;is beneficial to the absorption of oxygen and glucose by brain tissue,promotes and accelerates the metabolic activity of brain tissue neurons,and at the same time has the properties of neurotrophic,antioxidant and inflammatory factors.Therefore,it is mainly used clinically to treat chronic cerebral dysfunction and Alzheimer’s disease caused by insufficient peripheral blood supply.Because of its good medicinal activity,Nicergoline has a broad market prospect.In this paper,we first analyzed and compared the synthetic process route of Nicergoline through the previous literature research.From the aspects of yield,environmental friendliness,step length,mild reaction conditions,and difficulty of post-processing,we selected one of them.One route for in-depth research and optimization;that is,ergoline is used as the starting material to synthesize the target product Niergoline through three steps of photochemical reaction,methylation reaction and condensation reaction.We optimized the synthesis process of Nicergoline on a small scale.In the optimization of the synthesis of10a-methoxy-dihydroergoline（Intermediate 1）,under the premise of ensuring the yield,we changed the usage of sulfuric acid as the catalyst from The 22-fold equivalent has been reduced to 5 equivalents,and the amount of methanol used has been reduced from 30-fold equivalents to 7 equivalents.The raw material cost is greatly reduced;the purity of the intermediate product reaches 97%.In the methylation reaction,a polar aprotic amide solvent with a higher melting point is used to reduce the reaction temperature to below 20°C to avoid the formation of alcohol methylation products.The reaction product has less impurities and the raw materials are completely reacted.With a small amount of acetone beating,the product purity can reach 97.5%.In the optimization of the third-step condensation reaction,we replaced the condensation reagent DCC in the original route with CDI.Compared with the original route,it not only reduces the raw material cost,increases the yield,but also simplifies the post-processing operation.Finally,the finished product purity of Nicergoline was obtained after being refined with acetone,and the purity was determined to be 99.5%by HPLC.We optimized the synthetic route of Nicergoline,and obtained the optimal reaction yield conditions for each step of the reaction.We also tried to improve the original route of Nicergoline:First,dissolve ergoline in an aprotic solvent.,Methylation reaction with methylating reagent to generate 1-methylergotol,and then photochemical reaction of1-methylergotol and methanol under the catalysis of sulfuric acid to produce1-methyl-10a-methoxyl light Ergot alcohol（intermediate two）.Finally,the intermediate two and 5-bromonicotinic acid undergo condensation reaction to prepare Niergoline.Compared with the original route,the improved synthetic route of Nicergoline not only shortens the reaction time,but also significantly improves the yield and purity.After optimizing the Nicergoline,the process route:no inert gas protection is required,the amount of acid is small,the product quality is good,the yield is high,the reaction by-products are easy to recycle,the final product yield can reach more than 50%,and the product purity is 99%.The above is suitable for large-scale production of Nicergoline.