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The preparation method of dapoxetine hydrochloride

A technology of dapoxetine hydrochloride and anhydrous sodium sulfate, which is applied in the field of drug preparation, can solve the problems of low optical purity of dapoxetine hydrochloride, long synthesis route steps, and immature synthesis methods, etc., and achieve easy large-scale production , easy operation and short production cycle

Active Publication Date: 2019-10-25
REYOUNG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthetic route has long steps, complex operation and low overall yield
[0011] Another example is the literature Oliver Torre, Vicente Gotor. Lipase-catalyzed resolution of chiral 1,3-amino alcohols: application in the asymmetric synthesis of (S)-dapoxetine [J]. Tetrahedron: Asymmetry, 2006, 17 (5): 860-866 etc. Although this type of method has obvious advantages, the synthetic method is still immature, and there are long steps in the route, high cost, and the problems of low optical purity of dapoxetine hydrochloride.

Method used

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  • The preparation method of dapoxetine hydrochloride
  • The preparation method of dapoxetine hydrochloride
  • The preparation method of dapoxetine hydrochloride

Examples

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Effect test

Embodiment 1

[0040] 1. Preparation of 3-(1-naphthyloxy)-1-phenyl-1-propanone

[0041] Weigh 8.351gK 2 CO 3 Put the solid in a 250ml three-necked flask, add 70ml N,N-dimethylformamide and blow nitrogen to maintain the nitrogen atmosphere, cool down to 0°C, add 8.002g of 1-naphthol, keep warm at 0°C for 0.5h, then add 8.508 g 3-chloropropiophenone was reacted at 15°C for 15h, then added to 250ml of water for crystallization, and suction filtered to obtain 8.997g of reddish-brown solid 3-(1-naphthyloxy)-1-phenyl-1-propanone, with a yield of 64.88 %.

[0042] 2. Preparation of (R)-(-)-3-(1-naphthyloxy)-1-phenyl-1-propanol

[0043]Dissolve 5.001g of 3-(1-naphthyloxy)-1-phenyl-1-propanone in 30ml of 1,4-dioxane, and add 21.7ml of (-)diisopinepinylborane at 80°C (1.0mol / LinTHF), after reacting at this temperature for 10h, slowly add 200ml of ice water, and stir for 30nin. The layers were left to stand, the aqueous phase was extracted with 72ml of ethyl acetate, then washed with saturated sod...

Embodiment 2

[0047] 1. Preparation of 3-(1-naphthyloxy)-1-phenyl-1-propanone

[0048] Weigh 2.417g of NaOH solid into a 250ml three-neck flask, add 70ml of N,N-dimethylformamide and blow nitrogen to maintain the nitrogen atmosphere, add 7.958g of 1-naphthol after cooling down to 0°C, and keep warm at 5°C for 5h. Then add 8.461g of 3-chloropropiophenone and react at 15°C for 40h, then add to 250ml of water for crystallization, and filter with suction to obtain 10.142g of reddish-brown solid 3-(1-naphthyloxy)-1-phenyl-1-acetone, Yield 73.14%.

[0049] 2. Preparation of (R)-(-)-3-(1-naphthyloxy)-1-phenyl-1-propanol

[0050] Dissolve 10.002g of 3-(1-naphthyloxy)-1-phenyl-1-propanone in 30ml of 1,4-dioxane, and add 31.585g of (-) diisopinepinyl boron chloride at 50°C 60% tetrahydrofuran solution of alkane, reacted at this temperature for 15h, then slowly added 200ml of ice water, and stirred for 30nin. The layers were left to stand, the aqueous phase was extracted with 72ml of ethyl acetate,...

Embodiment 3

[0054] 1. Preparation of 3-(1-naphthyloxy)-1-phenyl-1-propanone

[0055] Weigh 13.525g of KOH solid into a 500ml three-necked flask, add 250ml of N,N-dimethylformamide and blow nitrogen to maintain the nitrogen atmosphere, cool down to 0°C, add 30.728g of 1-naphthol, and keep warm at 0°C for 2h. Then add 32.671g of 3-chloropropiophenone and react at 50°C for 30h, then add to 700ml of water for crystallization, and filter with suction to obtain 39.362g of reddish-brown solid 3-(1-naphthyloxy)-1-phenyl-1-acetone, Yield 73.52%.

[0056] 2. Preparation of (R)-(-)-3-(1-naphthyloxy)-1-phenyl-1-propanol

[0057] 39.362g of 3-(1-naphthyloxy)-1-phenyl-1-propanone was dissolved in 100ml of tetrahydrofuran and nitrogen was passed through, and 60 % tetrahydrofuran A solution, react at this temperature for 20h, then slowly add 600ml of ice water, and stir for 30nin. Stand to separate the layers, extract the aqueous phase with 240ml ethyl acetate, then wash with saturated sodium bicarbon...

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Abstract

The invention belongs to the technical field of drug preparation and particularly relates to a preparation method of dapoxetine hydrochloride. The method comprises steps as follows: a compound 3 and alkali are dissolved in an organic solvent for a reaction, then, a compound 2 is added, an esterification reaction is performed, and a compound 4 is obtained; the compound 4 is subjected to asymmetric reduction by a chiral reducing agent in an organic solvent, and a compound 5 is obtained; the compound 5 reacts with MsCl, trimethylamine and 4-dimethylamino-pyridine in an organic solvent, dimethylamine hydrochloride is added for a further reaction, a product is added to water, extracted with ethyl acetate and steamed to form an oily substance, cooling, crystallization and suction filtration are performed, dapoxetine free alkali solids are obtained and dissolved in isopropanol, an isopropanol solution of hydrogen chloride is added and crystalized, and dapoxetine hydrochloride is obtained. The chemical purity and the optical purity are high, the quality is stable, operation is simple and convenient, the yield is high, the quality is stable, large-scale production is facilitated, the production cycle is shorter, and the synthesis route is shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of dapoxetine hydrochloride. Background technique [0002] Dapoxetine hydrochloride, the chemical name is (S)-N,N-dimethyl-3-(naphthyl-1-oxyl)-1-phenylpropan-1-amine hydrochloride , is a selective serotonin reuptake inhibitor, which has remarkable curative effect and broad market prospect for treating premature ejaculation in men. [0003] In addition, dapoxetine hydrochloride has a chiral structure, and the routes for synthesizing dapoxetine hydrochloride reported in literature and patents can be classified into two categories: one is to use a chiral resolving agent for resolution; the other is to carry out asymmetric Synthesis, the relevant literature route is as follows: [0004] The synthetic technique research of dapoxetine hydrochloride such as literature that adopts chiral resolving agent to be resolved; 1-Fluoronaphthalene ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/02C07C217/48C07C41/26C07C43/23C07C45/68C07C49/84C07B53/00
CPCC07B53/00C07B2200/07C07C41/26C07C45/68C07C213/02C07C217/48C07C43/23C07C49/84
Inventor 苗得足王福生苏艳华杨祥龙张丽萍李广
Owner REYOUNG PHARMA
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