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New antidepressant duloxetine hydrochloride (Duloxetine Hydrochloride) synthesis and process optimization

Author: XiaoHeQing
Tutor: ZuoPeiLin
School: Zhejiang University
Course: Biochemical Engineering
Keywords: Duloxetine hydrochloride Antidepressant Synthesis Process Improvement Racemic
CLC: TQ463.5
Type: Master's thesis
Year: 2006
Downloads: 454
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Abstract


Duloxetine (Duloxetine), tradename Cymbalta; Chemical name: (S)-N-methyl-3 - (1 - naphthalenyloxy) -3 - (2 - thienyl) propylamine is a novel antidepressant drugs. Duloxetine synthesis methods reported in the literature are more, but the yield is not high (6.8% to 16%). The main purpose of the present study to be improved to improve the yield of the product is a process route to 2 - acetyl thiophene as starting material synthesis duloxetine. The process is based on the characteristics of 2 - acetyl thiophene as the starting material, introduced by the Mannich reaction aminomethyl, then sodium borohydride reduction, L-() - chiral separation of mandelic acid with 1 - Fluoronaphthalene condensation, and finally under basic conditions, removal of a methyl group on the N to obtain the final product of duloxetine hydrochloride. Comparison with the literature of the process, thanks to a new process for the synthesis and chiral separation of racemate were the intermediates and the final product than curl has been steadily improving. Molar ratio on the reaction raw material, the optimization of the conditions of the reaction temperature, the amount of the solvent as well as the chiral separation of, and in the final product into a salt with dry HCl gas to replace the liquid hydrochloric acid, so that the total yield of 18.4% of the final product, high 13% reported in the literature. Each step reaction the feeding amount enlarge, the loss relative reduction, the total yield of the final product up to 20.3%. Measured by HPLC chemical content of ≥ 99%, the polarimetry content ≥ 99.5%, stable quality. Synthesis products were characterized by elemental analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, mass spectrometry and other conclusive evidence. The process is superior to the level of literature, is expected to be used for industrial production. To further increase the product yield and lower production costs, the key intermediate N, NZ-dimethyl-3 - hydroxy-3 - (2 - thienyl-yl) propylamine split byproducts (R)-isomer (R ) - ()-N, N-dimethyl-3 - hydroxy-3 - (2 - thienyl yl) propylamine rac. A carboxylic acid solvent, salicylaldehyde for the co-solvent, through the optimization of the racemization reaction conditions and found that the co-solvent for the acetic acid as solvent, 0.1 mole fraction of the salicylaldehyde in 90 ℃ (R) - () - N, N-dimethyl-3 - hydroxy-3 - (2 - thienyl group) propylamine racemization reaction, after 8h reaction, the product racemic rate of 100%, the yield of the product reached about 70 percent. Expand the feeding amount to 2L reaction flask reaction product of racemic average rate of 99.2%, the yield reached 90.8%. The racemic product can be re-used for synthesis duloxetine, duloxetine thereby greatly improve the yield, reduce the cost (total yield of more than 37%, which is about three times the yield of literature). The method of (R)-isomer of the racemic no foreign reports.

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