The Synthesis Of Atomoxetine Hydrochloride

Attention Deficit Hyperactivity Disorder(ADHD)is a common childhood psycholo-gical disorders.Atomoxetine hydrochloride is the non-stimulating drug approved for the treatment of ADHD.It has the advantages of rapid onset,wide range of applications,fewer side effects,high security.The synthesis of atomoxetine hydrochloride and the res-olution of the atomoxetine hydrochloride to obtain(R)-atomoxetine hydrochloride were researched.After investigation of a series of synthetic routes of(R)-atomoxetine hyd-rochloride,the best synthetic processes had been determined which was suitable for scale production.The reported synthetic methods of atomoxetine hydrochloride were analyzed and discussed.The synthetic processes of atomoxetine hydrochloride was determined and established.Standard Mannich reaction condition were employed to synthesize?-dime-thylaminopropiophenone hydrochloride from acetophenone,paraformaldehyde and dimet-hylamine hydrochloride,which was reduced with sodium borohydride to form N,N-dimet-hyl-3-phenyl-3-hydroxypropylamine,and then with thionyl chloride to generate N,N-dim-ethyl-3-phenyl-3-chloropropylamine hydrochloride.O-cresol was first treated with sodium hydroxide to convert into sodium salt of o-cresol,which was condensed with chlorinated products to give N,N-dimethyl-3-(o-tolyloxy)-3-phenylproplamine by Williamson reaction,then with phenyl chloroformate by demethylation to obtain racemic atomoxetine.The yield was 40.5%.Atomoxetine was then resolved using S-(+)-mandelic acid and resulting atomoxetine was treated with hydrogen chloride to afford(R)-atomoxetine hydrochloride.Racemization of(S)-atomoxetine was occurred in the presence of potassium tert-butoxide.The recycling of racemization of(S)-atomoxetine.The recovery and recycling of S-man-delic acid.The resolution yield of 68.1%,[?]_D~2 ~5=-45.5°(c=1.02,methanol).Therefore,(R)-atomoxetine hydrochloride was synthesized using acetophenone as the starting material via seven steps,and the overall yield was 27.6%,compared with the method reported in the literature to improve the yield of 17%.The chemical structures of atomoxetine hydrochloride had been characterized by means of ~1H-NMR and IR.Specific rotation is consistent with the literature.