The Process Development And Enlarge Experiment Research For Atomoxetine Hydrochloride

Attention deficit hyperactivity disorder (ADHD), a chronic disease, is a behavioral disorder characterized by attention deficit hyperactivity disorder. ADHD is a frequent disease, and it is at the first place in the children's psychological clinic. It is estimated that the prevalence of adult ADHD is 2%to 7%,4% of adult ADHD need to be treated. The main clinical features are the attention dispersion, hyperpraxia, demanding behavior and a variety of mental disorders, patients are lead to live, work, social function damage and huge medical and social economic burden. Atomoxetine (Chemical Name:N-methyl-3-phenyl-3-(2-methylphenoxy)-propylamine hydrochloride; Commodity Name:Strattera; Molecular Formula:C17H21NO·HCI: Molecular Weight:291.82) is the first non central nervous stimulants treatment for ADHD approved by FDA. Based on the analysis of existing synthesis route of Atomoxetine and considered integrated product quality, yield, difficulty degree of material, the industrialization production, and many other factors, we start with 3-(dimethylamino) phenylethyl alcohol, go through substitution reaction, chiral resolution by mandelic acid, then apply mixed solvent for recrystallization. The route experiences laboratory and pilot production research, product structure identified by NMR, mass spectrometry, XRD experiment and turn out to be Atomoxetine Hydrochloride. This production method is simple, easy to carry out industrial production, using mixed solvent for the crystallization of chiral separation, reducing the impurity content in the product, reducing the cost of product, improving product safety, and obtaining a good economic and social benefits.The optimum experimental condition for synthesis of 3-(methylamino)-l-phenyl-l-acetone hydrochloride started with acetophenone in this paper:pH=3-4, refluxing reaction at 78.5? for 6 h, the yield can reach 62.84%. The optimum reaction temperature for synthesis of 3-(methylamino)-1-phenyl-propyl alcohol is 3?, toluene as extracting agent, n-hexane for recrystallization, the yield was 72.02%, the purity of 88.35%. Considering the actual situation in industrial production, we determine that 3-(methvlamino)-1-phenyl-prpyl alcohol as starting material to react with ortho fluorine toluene for synthesis of Tomoxetine racemization by substitution reaction, chiral resolution by mandelic acid, and then apply mixed solvent for crystallization. Validated by three batches of production and NMR, mass spectrometry. X-ray diffraction (XRD) experiments, the obtained product using this method turn out to be Atomoxetine Hydrochloride, the total yield is 30%, the purity of the product reached 99.85%. This route treaeted 3-(methylamino)-1-phenyl-propyl alcohol as starting material to react with ortho fluorine toluene for synthesis of Tomoxetine racemization by substitution reaction, is in conformity with the requirements of production, and the going on production technology achieves suscess. and this production technology be able to apply in industrial production...