Synthesis method of dapoxetine

Abstract

The invention provides a synthesis method of dapoxetine. The method comprises: S1, dispersing (s)-3-amino-3-phenylpropionic acid or an ester compound thereof in a solvent, and carrying out a reflux reaction under the effect of a reducing agent to obtain (s)-amino-3-phenylpropanol; S2, dissolving (s)-amino-3-phenylpropanol in a formic acid aqueous solution, adding paraformaldehyde, conducting heating, and carrying out a reaction so as to obtain (s)-3-dimethylamino-3-phenylpropanol; and S3, dissolving (s)-3-dimethylamino-3-phenylpropanol in a solvent, dropwise adding the (s)-3-dimethylamino-3-phenylpropanol into an alkali solution for reaction at a relatively high temperature under the protection of nitrogen, and then adding 1-fluoronaphthalene for carrying out Williamson etherification reaction to obtain (s)-N,N-dimethyl-3-(1-naphthyloxy)amphetamine, namely dapoxetine. The synthesis method of dapoxetine has the advantages of cheap and easily available raw materials, no use of toxic and dangerous reagents, no reaction aggregation and material spraying phenomenon, simple process, and suitableness for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, in particular to a synthesis method of dapoxetine. Background technique [0002] Dapoxetine, chemical name: (S)-N,N-dimethyl-3-(naphthyl-1-oxyl)-phenylpropylamino, chemical structural formula: chemical structural formula is as follows: [0003] . [0004] Dapoxetine hydrochloride is the hydrochloride salt of (S)-N,N-dimethyl-3-(naphthyl-1-oxyl)-phenylalanine. In clinical trials, dapoxetine hydrochloride can not only As an antidepressant, the drug has new uses for controlling premature ejaculation symptoms in men. Therefore, as a selective serotonin reuptake inhibitor (SSRI), dapoxetine hydrochloride has a short half-life and few adverse reactions. It is used to treat premature ejaculation in men, and the effect is remarkable. [0005] The relevant synthetic route of dapoxetine hydrochloride reported in literature at present is as follows: [0006] (1) In 1992, Eli Lilly and Com...

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Problems solved by technology

[0011] This reaction route takes (s)-3-amino-3-phenylpropionic acid as the starting material, and obtains (s)-3-amino-3-phenylpropanol through the reduction of reducing agent and acid, and the aftertreatment needs to be Reflux treatment under alkaline conditions can easily cause some products to oxidize, reduce purity, and increase production costs

The third step is to add alkali in batches. The operation is cumbersome, the reaction is difficult to control, and it is easy to gather and spray materials, which is not suitable for industrial production.

[0017] The reaction route uses (s)-3-amino-3-phenylpropionate as the starting material, and after being reduced by the reduction system, it is quenched, filtered, and concentrated to directly obtain the intermediate of boroether. The actual product contains a large amount of The salt increases the amount of paraformaldehyde and formic acid used in the next step, which is not suitable for industrial production

In the third step, sodium hydride is used to form ether, all the materials are added and then the temperature is raised. The reaction process is difficult to control, and it is easy to gather and spray materials, which is not suitable for industrial production.

Wash with dilute hydrochloric acid to form a salt, the crystal form is difficult to control, and it is easy to obtain the monohydrate dapoxetine hydrochloride crystal form

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