Preparation and detection method of dapoxetine hydrochloride isomer impurities

A technology for dapoxetine hydrochloride and isomers, which is applied in the field of preparation and detection of isomer impurities of dapoxetine hydrochloride, can solve problems such as not being unanimously recognized by people, and achieve mild reaction conditions and stereoselectivity High, simple synthesis process effect

Active Publication Date: 2020-04-17
盖天力医药控股集团制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Dapoxetine Hydrochloride [Dapoxetine Hydrochloride, i.e. (S)-N,N-dimethyl-α-[2-(1-naphthyloxy)ethyl]benzylamine hydrochloride] (Formula III) is a A selective serotonin reuptake inhibitor, which is structurally similar to fluoxetine and also has antidepressant effects, has not been unanimously approved for the treatment of depression and related affective disorders in early clinical trials, but research Researchers discover new use for drug that effectively controls premature ejaculation symptoms in young men

Method used

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  • Preparation and detection method of dapoxetine hydrochloride isomer impurities
  • Preparation and detection method of dapoxetine hydrochloride isomer impurities
  • Preparation and detection method of dapoxetine hydrochloride isomer impurities

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Experimental program
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Effect test

Embodiment 1

[0042] Step 1) Preparation of Boc-(S)-α-[2-(2-naphthyloxy)ethyl]benzylamine (Ⅵa)

[0043]Add 100mL dimethylformamide to a 500mL three-necked reaction flask, stir, add 20.0g (79mmol) of Boc-(S)-3-amino-3-phenylpropanol to dissolve, and control the internal temperature at 10~30°C under nitrogen protection. Slowly add 4.1g (103mol) of 60% sodium hydride at ℃, and after the degassing becomes gentle, add 11.6g (79mol) of 2-fluoronaphthalene, raise the temperature to 60~70℃ for 5~10 hours, and cool the reaction solution to 20~ 40°C, add 300mL purified water to quench the reaction, extract twice with 200mL ethyl acetate, combine the organic layers, wash twice with 200mL saturated brine, concentrate the organic layer under reduced pressure at 40~50°C, and obtain 26.4g after concentration, namely (Ⅵa ), HPLC purity 91.8%, yield 80.7%.

[0044] Step 2) Preparation of Boc-(R)-α-[2-(1-naphthyloxy)ethyl]benzylamine (Ⅵb)

[0045] Referring to the method of Example 1, 20.0g (79mmol) Boc-(S...

Embodiment 2

[0049] Step 1)~Step 2) Same as above;

[0050] Preparation of (R)-N,N-dimethyl-α-[2-(1-naphthyloxy)ethyl]benzylamine (Ⅶb)

[0051] Step 3) Referring to the method of step 3) in Example 1, feed 25.0g of Boc-(R)-α-[2-(1-naphthyloxy)ethyl]benzylamine to obtain 17.2g of off-white solid powder, Namely (R)-N,N-dimethyl-α-[2-(1-naphthyloxy)ethyl]benzylamine (VIIb), HPLC purity 97.5%, yield 91.2%.

Embodiment 3

[0053] Step 1)~Step 2) Same as above;

[0054] Step 3) Preparation of (R)-N,N-dimethyl-α-[2-(1-naphthyloxy)ethyl]benzylamine (VIIb)

[0055] Add 80mL of isopropanol to a 250mL three-necked reaction flask, stir, and add 15.0g (49mmol) of (S)-N,N-dimethyl-α-[2-(2-naphthyloxy)ethyl]benzylamine , add 6.8g (63mmol) of 34% hydrochloric acid dropwise, heat to dissolve, gradually cool down to -15~-5°C to crystallize for 5 hours, filter, and dry at 60~65°C for 10 hours to obtain 15.6g off-white solid powder, namely ( S)-N,N-Dimethyl-α-[2-(2-naphthyloxy)ethyl]benzylamine hydrochloride (I), HPLC purity 99.8%, yield 92.7%.

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Abstract

The invention discloses a preparation process for preparing a dapoxetine hydrochloride beta-isomer impurity shown as formula I and an enantiomer shown as formula II. The method comprises the following steps: taking optically pure Boc-(S) or (R)-3-amino-3-phenylpropanol as a raw material, performing condensation reaction with 2-fluoronaphthalene or 1-fluoronaphthalene, performing methylation reaction with formic acid-formaldehyde, and performing HCl salification reaction to obtain a target product dapoxetine hydrochloride beta-isomer or enantiomer impurity. Meanwhile, a detection method of isomer impurities is developed.

Description

technical field [0001] The invention relates to the technical field of chemical preparation, in particular to a method for preparing and detecting isomer impurities of dapoxetine hydrochloride. Background technique [0002] Dapoxetine Hydrochloride [Dapoxetine Hydrochloride, i.e. (S)-N,N-dimethyl-α-[2-(1-naphthyloxy)ethyl]benzylamine hydrochloride] (Formula III) is a A selective serotonin reuptake inhibitor, which is structurally similar to fluoxetine and also has antidepressant effects, has not been unanimously approved for the treatment of depression and related affective disorders in early clinical trials, but research Researchers have discovered a new use for the drug, which can effectively control premature ejaculation symptoms in young men. Eli Lilly and Johnson have successively conducted clinical trials on it, and announced that it has a short half-life, small adverse reactions, and significant effects in treating premature ejaculation symptoms. In February 2009, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C217/48G01N30/02
CPCC07C269/06C07C213/08G01N30/02G01N2030/047C07B2200/07C07C271/16C07C217/48
Inventor 李庆华
Owner 盖天力医药控股集团制药股份有限公司
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