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Preparation method of optically pure (R)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride

A technology of propylamine hydrochloride and tolyloxy, applied in the field of chemistry, can solve problems such as complicated steps, and achieve the effects of simple steps, suitable promotion and high purity of finished products

Active Publication Date: 2020-06-19
HEFEI IND PHARMA INST CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to propose an optically pure atomoxetine hydrochloride preparation method aimed at the defects of cumbersome steps in the existing atomoxetine hydrochloride preparation method, which reduces costs and is safe and environmentally friendly

Method used

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  • Preparation method of optically pure (R)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride
  • Preparation method of optically pure (R)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride
  • Preparation method of optically pure (R)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride

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Embodiment 1

[0034] The present embodiment prepares optically pure atomoxetine hydrochloride according to the following method:

[0035] Step 1, add atomoxetine racemate (25.5g, 0.1mol) into 25ml of methanol at room temperature, stir and dissolve, then add 67.4g of dilute hydrochloric acid (10g of concentrated hydrochloric acid is diluted with 57.4g of purified water, about 0.1mol; total water About 63.8g (the sum of the amount of water added and the water content in concentrated hydrochloric acid), water: atomoxetine racemate (m / m) ≈ 2.5).

[0036] Step 2: Concentrate under reduced pressure (vacuum degree <-0.8MPa, temperature: 40±5°C) to remove methanol, raise the temperature until the reaction solution is clear, then slowly cool down to 25°C, add a small amount of seed crystals of atomoxetine hydrochloride (about 0.05g) , kept stirring for 2 hours, continued to cool down to 15°C, kept stirring for 2 hours, filtered, washed the filter cake with a small amount of cold water, and dried und...

Embodiment 2

[0038] The present embodiment prepares optically pure atomoxetine hydrochloride according to the following method:

[0039] Step 1, add atomoxetine racemate (25.5g, 0.1mol) into 25ml of methanol at room temperature, stir and dissolve, add 92.9g of dilute hydrochloric acid (10g of concentrated hydrochloric acid is diluted with 82.9g of purified water, about 0.1mol; total water About 89.3g (the sum of the amount of water added and the water content in concentrated hydrochloric acid), water: atomoxetine racemate (m / m) ≈ 3.5).

[0040] Step 2: Concentrate under reduced pressure (vacuum degree <-0.8MPa, temperature: 40±5°C) to remove methanol, raise the temperature until the reaction solution is clear, then slowly cool down to 25°C, add a small amount of seed crystals of atomoxetine hydrochloride (about 0.05g) , kept stirring for 2 hours, continued to cool down to 15°C, kept stirring for 2 hours, filtered, washed the filter cake with a small amount of cold water, and dried under re...

Embodiment 3

[0042] The present embodiment prepares optically pure atomoxetine hydrochloride according to the following method:

[0043] Step 1, add atomoxetine racemate (25.5g, 0.1mol) into 25ml of methanol at room temperature, stir and dissolve, then add 54.6g of dilute hydrochloric acid (10g of concentrated hydrochloric acid is diluted with 44.6g of purified water, about 0.1mol; total water About 51g (the sum of the amount of water added and the water content in concentrated hydrochloric acid), water: atomoxetine racemate (m / m) ≈ 2.5).

[0044] Step 2: Concentrate under reduced pressure (vacuum degree <-0.8MPa, temperature: 40±5°C) to remove methanol, raise the temperature until the reaction solution is clear, then slowly cool down to 25°C, add a small amount of seed crystals of atomoxetine hydrochloride (about 0.05g) , kept stirring for 2 hours, continued to cool down to 15°C, kept stirring for 2 hours, filtered, washed the filter cake with a small amount of cold water, and dried under...

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Abstract

The invention relates to a preparation method of (R)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride, belonging to the technical field of chemistry. According to the method, high-optical-purity atomoxetine hydrochloride can be prepared by salifying and crystallizing atomoxetine racemate and diluted hydrochloric acid and then performing recrystallizing with water. According to the invention, steps are simple, a chemical resolving agent and an organic solvent are not used, and the obtained finished product is high in purity and suitable for popularization.

Description

technical field [0001] The invention relates to a preparation method of (R)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride, which belongs to the field of chemical technology. Background technique [0002] (R)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride (the generic name is used below: atomoxetine hydrochloride) is a selective Norepinephrine reuptake inhibitor, used for the treatment of attention deficit / hyperactivity disorder, approved for domestic marketing in 2007, the chemical structure is as follows: [0003] [0004] The applicant searched and found that the effectiveness of atomoxetine hydrochloride (R type) mentioned in patents US4018895, EP0052492, and EP0721777 was about 2 times that of the racemic mixture, and 9 times that of S-atomoxetine hydrochloride. The European Pharmacopoeia (EP8.0) stipulates that the isomer S-atomoxetine hydrochloride in the product is not higher than 0.5%. The existing method for preparing atomoxetine hydroc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C217/48C07C213/10
CPCC07C213/08C07C213/10C07B2200/13C07C217/48
Inventor 何广卫刘为中王奎张强沈杰
Owner HEFEI IND PHARMA INST CO LTD
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