Synthesis Study Of Duloxetine Intermediates

Depression as a high incidence of the disease,not only seriously affects the normal life of patients,but also causes great losses to the society.Facing with this situation,it has great significance to research and develop a new antidepressant drug to solve this problem.Duloxetine,(S)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propanamine,isused as an antidpressant.By inhibiting the absorption of 5-serotonin(5-HT)and norepinephrine(NE),duloxetine blocks 5-HT and NE as the process of absorption and transport,which increases the content of two kinds of neurotransmitters to achieve the effect of antidepression.It was developed by Eli lilly and listed as antidepressant drug.In the process of develophing duloxetine,people fond it can be used to cure peripheral neuropathic pain,stress urinary incontinence,fibromyalgia and other symptoms.Compared with other antidepressant drugs,it has little side affects and much more safety,which can be limited to ease the patient's condition.Duloxetine has got good curative effect in clinical curing depression.S-(+)-N-methyl-3-(1-napthyloxy)-3-(2-thiophene)-propylamine is the most important intermediate during synthesis of Duloxetine.Referring to relevant literature,we compared the disadvantage and advantage of synthetic route by different raw material.And we summary a new doluxetine intermediate synthetic route:using thiophene as raw material,by Mannich reaction,reduction,split,Mitsunobu reaction,get S-(+)-Nmethyl-3-(1-napthyloxy)-3-(2-thiophene)-propylamine.Operation parameters,such as molar ratio of raw materials,solvent and resolution,were evaluated and optimized.Through a large number of experiments,we got the optimum reaction conditions and avoided the harsh experimental conditions.The systhesis route is cheap,simple and feasible to make a certain industrial value.In order to further explore the effects of experimental factors on the process,we systhsis the key intermediate of S-(+)-N,N-dimethyl-3-(1-naphthalene)-3-(2-thiophene)-1-propyl amine synthesis.Using THF as solvent,PPh3 and DIAD as catalyst,through the optimization of the Mitsunobu reaction conditions,we got the best condition on 35? and reaction time at 9 h.After practice,I got optimum reaction conditions and avoid harsh reaction conditions.The chemical structure of intermediates are characterized by MS and ~1H-NMR.