Synthesis Of Duloxetine Hydrochloride And Indiplon

The thesis is divided into two parts, the process development ofDuloxetine Hydrochloride, a recently marketed drug for the treatment ofsevere depression and the synthesis of Indiplon, another potentiallymarketable drug for the treatment of insomna.In the first part, a six-step synthetic route to Duloxetine Hydrochloride was developed. The synthesis started from commercially available2-acetylthiophene by a sequence of reactions including Mannich reaction, reduction by sodium borohydride, resolution with L-(+)-mandelic acid, etherification with 1-fluoronaphthalene, Von Braun demethylation and salt formation with hydrochloric acid /ether. Duloxetine Hydrochloride was eventually obtained in more than 98% optical purity by resolution using commercially available L-(+)-mandelic acid. This approach ismore applicable for industrial production compared with the reportedmethod by employing costly chiral auxiliary. The overall yield was13.7% in hundreds grams scale. The final product was fully characterizedby HPLC-MS,1HNMR,element analysis,IR,UV and DTA.In the second part, a seven-step synthetic route to Indiplon was realized.The synthesis started from commercially available 2-acetylthiophene anddimethylformamide dimethyl acetal by a sequence of reactions includingcondensation,cyclization, N-methylation. The overall yield of the synthesis is24.8%.This approach is industrially applicable for the production of Indiploncharacterized by its commercially available starting materials, easypurification processes for the synthetic intermediates and highly overall yieldof the final product.