Process Optimization In The Synthesis Of Duloxetine Hydrochloride

Duloxetine hydrochloride, a 5 - HT and norepinephrine reuptake inhibitor (SNRI), which chemical name is (S)-N-methyl -3 - (1 - naphthyloxy) -3 - (2 - thienyl) -1 -propylamine hydrochloride and trade name is Cymbalta, can effectively inhibit 5 -serotonin and norepinephrine reuptake. In the clinical application, it is widely used to treat severe depression, female stress urinary incontinence and diabetic peripheral nerve pain. There are several reported methods to synthesize duloxetine. In order to optimize the synthesis of duloxetine hydrochloride, we comprehensively analyzed the influence of starting materials, catalyst and organic solvents on the yield of the final product and its costs. Finally, we choose 2-acetyl thiophene as the starting material to prepare duloxetine hydrochloride in the aqueous phase by six steps including one step with the biocatalysis of baker's yeast.Firstly, the synthesis of duloxetine includes six steps, which are Mannich reaction, sodium borohydride reduction, S-(+) mandelic acid resolution, ether formation, demethylation and salt formation. Through adjustment of the molar ratio of raw material, the amount of solvent, reaction temperature, reaction time or other various methods in every step, the yield of duloxetine hydrochloride has been significantly imcreased.Secondly, The baker's yeast is one of the cheap micro-organisms extensively used to catalyze most of the ester carbonyl asymmetric reduction reaction. Oxidoreductase richly presented in the baker's yeast can catalyze a variety of carbonyl compounds asymmetric reduction with highly stereoselective ability. Considering these advantages such as the cheap cost, abundant resources, safe and easy operation, and harmless to the human body, the baker's yeast should be paid more attention. This paper attempts to use baker's yeast to prepare duloxetine intermediates by asymmetric reduction, instead of the sodium borohydride reduction and S-(+) mandelic acid separation step in the original route. Meanwhile, we have compared the impact of various organic solvents on the biocatalysis of baker's yeast, and finally determined the water as a reactive solution.At last, the selection of inhibitors of organic solvents, the ratio of energy donor, the concentration of substrate, the amount of baker's yeast, the value of pH in the reactive system, reaction temperature, reaction time and other factors used in the asymmetric reduction have been comprehensively studied.In conclusion, we determined the optimal synthetic route with 2 - acetyl thiophene as the starting material and baker's yeast as the biocatalyst to prepare duloxetine hydrochloride and the total yield of the final product was 18.6%. So far, there is no such reports about the application of biocatalysis of baker's yeast in the asymmetric reduction published.