Method for preparing intermediate of duloxetine hydrochloride

Abstract

The invention relates to a method for preparing an intermediate of duloxetine hydrochloride. The method comprises the following steps: adding 2-acetylthiophene into concentrated hydrochloric acid for reacting, preparing a compound of a formula II, adding NaBH4 for reacting, and refining to prepare a compound of a formula III; taking the compound of the formula III and methyl tertiary butyl ether, adding S-mandelic acid for reacting, filtering, spraying, drying to obtain a white granular solid, dissolving the white granular solid in water, regulating a pH value, extracting by using dichloromethane, drying, and preparing S-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl) propylamine (a compound of a formula I) after drying. The invention provides a simple method, so that the raw materials are completely dissolved, namely the consumption of NaBH4 is reduced, a reduction reaction can be completely carried out, and the maximum reaction rate can be 95.6 percent. Meanwhile, the invention provides a method for improving resolution yield and purity, and the maximum yield can be 47.6 percent. According to the improved process, the reaction time is greatly reduced, the operation is simplified, and the total yield of the compound of the formula I which is synthesized in three steps is more than 36 percent.

Description

technical field [0001] The invention relates to a preparation method of an intermediate of an antidepressant duloxetine hydrochloride, belonging to the fields of organic chemistry and medicinal chemistry. technical background [0002] Duloxetine hydrochloride is a potent dual reuptake inhibitor of serotonin and norepinephrine with comparable affinity in the transport sites that bind serotonin and norepinephrine. Therefore, duloxetine hydrochloride has been used in the treatment of various diseases involving this function. After the advent of duloxetine hydrochloride, it was mainly used to treat severe depression, but in September 2004, the US FDA approved a supplementary indication for the treatment of diabetic extrinsic nerve pain. This drug is launched by Eli-Lilly Company of the United States, and its trade name is Cymbalta. It is an antidepressant with dual inhibitory effects on the reuptake of serotonin and norepinephrine. It is now the preferred antidepressant in cli...

AI Technical Summary

Problems solved by technology

The existing preparation process has incomplete dissolution of raw materials and incomplete reduction, which affects the reduction yield and purity, so that the chiral resolution in the next step is more seriously affected, so the inventor decided to improve the process

[0004] By studying the literature and verifying some of the literature, it is found that there are serious deficiencies in the existing technology: for example, when reducing, some literature uses 50% sodium hydroxide to adjust the pH, and when the pH is adjusted to 12, it still exists A large amount of insoluble matter seriously affects the reduction rate; when some documents are reduced, add a part of water first, and then add solid sodium hydroxide. Although this can dissolve the raw materials, it is easy to exotherm violently when adding solid sodium hydroxide. It is necessary to increase the cooling force to lower the temperature, and the instantaneous violent heat release can easily cause unknown damage to the raw materials

A lot of documents in one step of splitting just filter and want filter cake after adjusting pH with sodium hydroxide solution, easily cause a part of product to remain in the filtrate like this, prove that loss rate is as high as 3-10% through inventor's experiment; There are many documents that filter first, and then extract the filtrate with dichloromethane. Although this reduces the loss rate, it greatly increases the amount of labor

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