The New Antidepressant Duloxetine Hydrochloride (duloxetine Hydrochloride) Synthesis And Process Optimization

Duloxetine Hydrochloride ((S) -N-methyl-3- (1-naphthalenyloxy) -3- (2-thio-phene) propylamine),trade name:Cymbalta, is a new kind of antidepressant. There are several methods to synthesize duloxitine, and the reported data for product recovery are among 6.8%~16%. The purpose of this study is to improve the duloxetine recovery for the process with 2-acetylthiophene as the initial raw material reported by reference by Mannich reaction, reduction, chiral resolution, condensation with 1-fluoronaphthalene and removing one methyl group from N group at alkali condition. Comparing with reference, the improved process divided the racemic intermediate synthesis and chiral resolution into two steps, resulting in the increase of optical purity of both intermediate and final product.Operation parameters, such as molar ratio of raw materials, solvent and resolution conditions, etc., were evaluated and optimized. The dry HC1, instead of concentrated HC1 solution, was used in the final salt-formation reaction. The overall recovery of hydrochloride Duloxetine reached 18.4%, which is higher than that with original process reported in the literature(13%). When the amount of raw material was increased up in 5L reactor, the final product yield reached 20.3%. The product purity of the product is higher than 99%, according to HPLC analysis, with optical resolution higher than 99.5%. The chemical structure of the product is also confirmed by element analysis, IR, NMR and MS.In order to further increase the product recovery and lower the production cost, it is necessary to utilize the left (R) - (+)-N,N-dimethyl-3-hydroxy-3-(2-thienyl) propylamine, which is the by-product in the chiral resolution step. The racemic reaction of the (R) -isomer must be performed, and then the racemic compound can be recycled. Therefore, the racemic reaction was studied in this work.With carbolic acid as solvent and salicylic acid as co-solvent, the racemic reaction conditions of (R) - (+) -N,N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine were examined and optimized. It was found that with acetic acid as solvent and 0.1 mol salicylic acid as co-solvent, the racemic reaction was carried out at 90℃, and the resolution ratio was 100% with 70% recovery after reaction for 8 hrs. When the amount of (R) - (+) -N,N-dimethyl-3-hydroxy-3- (2-thienyl)propylamine increased up to 200g in the same condition, the racemic ratio and product yield could reach 99.2% and 90.8%, respectively. The racemic product can be reused in the process. Sothe final yield of Duloxetine could reach more than 37% which was almost thiple of that reported in the literature. This racemic reaction has not reported yet in the literature.