A kind of preparation method of duloxetine

Abstract

The invention provides a preparation method of duloxetine. The method uses 1-naphthol and 3-(2-thienyl)-2-acrolein as starting materials, and obtains (S) through an addition reaction under the action of a catalyst. )-3-(1-naphthyloxy)-3-(2-thienyl) propionaldehyde, then carry out imidization reaction with methylamine, and obtain duloxetine through reduction reaction. The raw materials of the invention are cheap and easy to obtain, do not need expensive 1-fluoronaphthalene, sodium hydride and a cumbersome splitting process, the cost is low, the technological process is safe and easy to operate, the amount of three wastes produced is small, and it is green and environmentally friendly, and the reaction atom economy is high. , the reaction selectivity of each step is high, the side reactions are few, and the optical purity and yield of the target product are high, which is beneficial to the green industrial production.

Description

technical field [0001] The invention relates to a preparation method of duloxetine, belonging to the fields of organic chemistry and medicinal chemistry. Background technique [0002] Duloxetine (Duloxetine, I), chemical name (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-l-propanamine, is produced by Lilly of the United States A dual serotonin and norepinephrine reuptake inhibitor developed by (Lilly) company was launched in the United States and Europe in 2004 and in China in 2007 for antidepressants. [0003] [0004] At present, the more economical and feasible synthetic route of duloxetine is obtained by using 2-acetylthiophene as raw material, and with paraformaldehyde and dimethylamine hydrochloride through Mannich reaction, reduction, resolution, etherification and demethylation. The target product, see Scheme 1. This route is described in detail in the paper "Synthetic Chemistry, 2004, 12(6), 551-553", Chinese Patent CN101391991A, US Patent US5023269 and World Pa...

AI Technical Summary

Problems solved by technology

[0007] This route needs to use (S)-mandelic acid to resolve the reduction product 3-N,N-dimethylamino-l-(thiophen-2-yl)-1-propanol to obtain S-3-N,N- Dimethylamino-l-(thiophen-2-yl)-1-propanol and racemization of R-3-N,N-dimethylamino-l-(thiophen-2-yl)-1-propanol, After resolution, multiple resolution-racemization-resolution cycles, the comprehensive recovery of the optically active intermediate S-3-N, N-dimethylamino-l-(thiophen-2-yl)-1-propanol The yield is only 66%, the operation is cumbersome, the atom economy is low, and the yield is low

The etherification step utilizes 1-fluoronaphthalene and S-3-N,N-dimethylamino-l-(thiophen-2-yl)-1-propanol for etherification, S-3-N,N-dimethylamino -l-(thiophen-2-yl)-1-propanol has low activity, and the etherification reaction requires strong base sodium hydride and higher reaction temperature, while strong base sodium hydride and higher reaction temperature will lead to thiophene ortho-carbon atoms The configuration is reversed, and partial racemization occurs, so that the optical purity of the obtained target product is low, it is difficult to purify, and it is difficult to obtain duloxetine with high optical purity

At the same time, the high price of 1-fluoronaphthalene is not conducive to the cost reduction of duloxetine

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