Synthesis method of dapoxetine

A synthesis method and technology of dapoxetine, applied in the field of drug preparation, can solve the problems of difficult reaction control, increased production cost, complicated operation and the like, and achieve the effects of avoiding volatilization, saving costs and being cheap.

Pending Publication Date: 2022-01-04
HUNAN JIUDIAN PHARMA +1
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthesis method of dapoxetine
  • Synthesis method of dapoxetine
  • Synthesis method of dapoxetine

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0050] The synthetic method of dapoxetine of the present invention comprises the following steps:

[0051] S1. Disperse (s)-3-amino-3-phenylpropanoic acid or its esters in a solvent, and perform a reflux reaction under the action of a reducing agent to obtain (s)-amino-3-phenylpropanol;

[0052] S2. Dissolve (s)-amino-3-phenylpropanol obtained in step S1 in formic acid aqueous solution, add paraformaldehyde and heat up to react to obtain (s)-3-dimethylamino-3-phenylpropanol ;

[0053] S3. Dissolve the (s)-3-dimethylamino-3-phenylpropanol obtained in step S2 in a solvent, and under the protection of nitrogen, add it dropwise to the alkali solution at a higher temperature of >30°C to react, and then Adding 1-fluoronaphthalene takes place Williamson ether formation reaction to obtain (s)-N,N-dimethyl-3-(1-naphthyloxy)amphetamine, ie dapoxetine.

[0054] The reaction process of the present invention is as follows:

[0055] .

[0056] The synthetic method of dapoxetine of the...

Embodiment 1

[0068] Step S1. Preparation of intermediate 1: (s)-3-amino-3-phenylpropanol.

[0069] At 0~10°C, add 20.2kg of tetrahydrofuran into a 200L reaction kettle, stir, add 3.8kg of (s)-3-amino-3-phenylpropionic acid, add 1.74kg of sodium borohydride, and keep dropping at 0~20°C Add iodine-tetrahydrofuran solution (dissolve 5.9kg iodine in 10.1kg tetrahydrofuran solution and add dropwise for 5~6h), and the dripping is completed. Raise the temperature to reflux (60~70°C) and react for 14~18h, and the central control raw materials basically react completely. Cool down to below 20°C, add 9.0kg of methanol dropwise to quench, and add dropwise for 20~30min. The organic solvent was distilled off under reduced pressure until no obvious liquid drops flowed out to obtain a white oil. Add 22.8 kg of 20% (mass concentration) sodium hydroxide solution to the concentrate to adjust the pH value to 10~13, and stir at 25~35°C for 3 hours. Add dichloromethane for extraction, extract twice, 20.0kg ...

Embodiment 2

[0079] Step S1. Preparation of intermediate 1: (s)-3-amino-3-phenylpropanol.

[0080] At 0~10℃, add 33.0kg of tetrahydrofuran into a 200L reaction kettle, stir, add 6.2kg of (s)-3-amino-3-phenylpropionic acid methyl ester, add 2.79kg of sodium borohydride, keep 0~20 Add iodine-tetrahydrofuran solution dropwise at ℃ (dissolve 9.5kg iodine in 16.4kg tetrahydrofuran solution and add dropwise for 5~6h), and dropwise complete. Raise the temperature to reflux (60~70°C) and react for 14~18h, and the central control raw materials basically react completely. Cool down to below 20°C, add 14.7kg of methanol dropwise to quench, and add dropwise for 20~30min. The organic solvent was distilled off under reduced pressure until no obvious liquid drops flowed out to obtain a white oil. Add 37.2kg of 20% sodium hydroxide (mass concentration) solution to the concentrate to adjust the pH value to 10~13, and stir at 25~35°C for 3h. Add dichloromethane for extraction, extract twice, 30kg each ti...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
particle sizeaaaaaaaaaa
particle diameteraaaaaaaaaa
particle diameteraaaaaaaaaa
Login to view more

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...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/06C07C217/48C07C213/08C07C215/28
CPCC07C213/06C07C213/08C07C213/00C07B2200/07C07C217/48C07C215/28
Inventor 肖稳定胡俊石笑弋袁威冠苏前锋
Owner HUNAN JIUDIAN PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products