Synthesis Studies On Duloxetine And Its Analogues

Since the first generation of tricyclic antidepressants was discovered in the 1950s, Three generation antidepressants have been developed up to now. But one of the main drawbacks of the currently available antidepressants is their slow onset of action, namely, all antidepressants need to be administered for 2～6 weeks to produce a significant clinical improvement. Although the second-generation antidepressants of SSRIs have improved this lag, 2～4 weeks are still needed. Even the third-generation antidepressants with new mechanisms such as duloxetine and venlaxine still required 2 weeks of action. So antidepressants with rapid onset of action are critically required.To develop new antidepressants, in the paper duloxetine analogues were designed and synthesized based on the SSRI'plus'method. At first duloxetine reacts with chloroacetyl chloride, 3-chloro- propionyl chloride and 4-chlorobutanoyl chloride to obtain three chloro-acetylaminos compounds. These compounds are treated with 3 aromatic piperazidines by N-alkyl reaction and reduction to synthesize 2 series of 12 compounds, which were characterized by MS & NMR, and the results are satisfied.Synthetic methods of duloxetine were also reviewed and the new procedure for industrial manufacture of duloxetine was developed. Some expensive reagents such as NaH, phenyl chloroformate and NaBH4 were replaced by KOH, ethyl chloroformate and KBH₄. Resolution of racemic duloxetine by (S)-(+)-mandelic acid was discussed. A general and convenient procedure for the synthesis of 3-dimethylamino-1-aryl- 1-propanols, the key intermediate for duloxetine by one-step reduction with LAH/ THF in flux with good yield is described.