Method for preparing (S)-N, N-dimethyl-3-(naphthol-1-oxygroup)-1- phenyl propyl group-1-amine

A technology of phenylpropyl and dimethyl, which is applied in the field of preparation of -N,N-dimethyl-3--1-phenylpropyl-1-amine, which can solve the problem of unfavorable environmental protection and high toxicity of formaldehyde , formaldehyde overflow and other problems, to achieve the effect of easy recycling, low price and low cost

Inactive Publication Date: 2013-02-27
YANGZHOU POLYTECHNIC INST
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Problems solved by technology

[0005] Literature (J. Org. Chem. 2010, 75, 237~240; Tetrahedron: Asymm.2007, 18 2099~2103 and CN 101367739) reported its methylation The method is formic acid and formaldehyde. The disadvantage of this method is that formaldehyde is highly toxic, which brings great pressure to labor protection and produces a large amount of waste water containing formaldehyde.
The method in the literature (Chinese Journal of New Drugs, 2008, 17(24), 2119~2121) uses formic acid / paraformaldehyde as the methylation reagent, although it solves the problem of formaldehyde pollution and labor protection in the feeding process, but the reaction process is also the same A large amount of formaldehyde overflows, and a large amount of waste water containing formaldehyde is formed after the reaction is completed, which is not conducive to environmental protection

Method used

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  • Method for preparing (S)-N, N-dimethyl-3-(naphthol-1-oxygroup)-1- phenyl propyl group-1-amine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1 Preparation of (S)-3-(naphthol-1-oxyl)-1-phenylpropyl-1-amine

[0020] The racemate 3-(naphthol-1-oxyl)-1-phenylpropyl-1-amine was prepared by the method in the literature (Chinese Journal of New Drugs, 2008, 17(24), 2119-2121).

[0021] Add racemate 3-(naphthol-1-oxyl)-1-phenylpropyl-1-amine (0.1mol), L-(+)-tartaric acid (0.25mol) into 150mL water and heat to reflux until clear transparent, add 20mL of n-butanol, continue to reflux for 20min, let cool to room temperature, precipitate a white solid, filter, and recrystallize the filter cake once with 50mL of water + 6mL of n-butanol, and add the obtained white crystals to sodium hydroxide solution (150mL, 5 %), refluxed for 2h, allowed to cool to room temperature, and an oily substance was precipitated, extracted with toluene until the aqueous layer had no product, and the resulting (S)-3-(naphthol-1-oxyl)-1-phenylpropyl-1- The toluene solution of the amine was directly used in the next reaction after be...

Embodiment 2

[0022] Example 2 Preparation of (S)-N,N-dimethyl-3-(naphthol-1-oxyl)-1-phenylpropyl-1-amine

[0023] The toluene solution of (S)-3-(naphthol-1-oxyl group)-1-phenylpropyl-1-amine obtained in Example 1 was added in a 500mL three-necked flask, and dimethyl carbonate (0.15mol ), anhydrous potassium carbonate (0.1mol), heat preservation at 60-80°C until the raw material (S)-3-(naphthol-1-oxyl group)-1-phenylpropyl-1-amine completely reacts, filter, filter The cake was washed with toluene (15mL×2), the filtrates were combined, and evaporated to dryness under reduced pressure (excess dimethyl carbonate was also evaporated and used for recycling), and the obtained oily substance was (S)-N,N- Dimethyl-3-(naphthol-1-oxyl)-1-phenylpropyl-1-amine (8.07 g), its chemical structure and absolute configuration were confirmed by hydrochloride formation.

[0024] Using different solvents, acid-binding agents, and reaction temperatures, the results are shown in Table 1

[0025] Table 1...

Embodiment 3

[0027] Example 3 Preparation of (S)-N,N-dimethyl-3-(naphthol-1-oxyl)-1-phenylpropyl-1-amine hydrochloride (dapoxetine hydrochloride)

[0028] (S)-N,N-dimethyl-3-(naphthol-1-oxyl)-1-phenylpropyl-1-amine (3.05g, 10mmol) obtained in Example 2 was dissolved in ethyl acetate Ester (16mL), slowly drop 0.1mol.L -1 Ethyl acetate solution of anhydrous hydrogen chloride until the pH value of the system is 2~3, after adding, stir for 1 hour, a white solid is precipitated, after centrifugation, pour off the supernatant, continue to add ethyl acetate (15mL), filter after stirring, the filter cake Wash with ethyl acetate (10 mL). M.p.=175.5~176.8℃, [ɑ] 20 D =+127.2°(C=1g·mL -1 ,CH 3 OH). 1 H NMR (DMSO- d 6 ): 2.567(d,3H,J=4Hz,CH 3 ) , 2.845(d,3H,J=4Hz, CH 3 ), 2.683~21757 (m,1H,2-position CH 2 ), 2.916~2.971 (m,1H,2-position CH 2 ), 3.655~3.712(m, 1H, 3-position CH), 4.101~4.149(m, 1H, 3-position CH 2 ), 4.713~4.742(m,1H,1-position CH), 6.73(d,J=8 Hz,1H,naphthalene ring-...

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Abstract

The invention discloses a method for preparing (S)-N, N-dimethyl-3-(naphthol-1-oxygroup)-1- phenyl propyl group-1-amine. (S)-3-(naphthol-1-oxygroup)-1- phenyl propyl group-1-amine serves as the raw materials, and dimethyl carbonate replaces formaldehyde in the prior art to serve as a methylation reagent to prepare the (S)-N, N-dimethyl-3-(naphthol-1-oxygroup)-1- phenyl propyl group-1-amine. On the basis, the (S)-N, N-dimethyl-3-(naphthol-1-oxygroup)-1- phenyl propyl group-1-amine is dissolved in ethyl acetate to further prepare (S)-N, N-dimethyl-3-(naphthol-1-oxygroup)-1- phenyl propyl group-1-amine hydrochloride. The method reduces environment pollution without increasing the cost, simplifies reaction operations, reduces requirements on equipment and can be used in industrial production easily.

Description

technical field [0001] The present invention relates to a preparation method of (S)-N,N-dimethyl-3-(naphthol-1-oxyl)-1-phenylpropyl-1-amine, in particular to (S)-3 -Dimethylation method of (naphthol-1-oxyl)-1-phenylpropyl-1-amine. Background technique [0002] (S)-N,N-Dimethyl-3-(naphthol-1-oxyl)-1-phenylpropyl-1-amine is the free base of dapoxetine hydrochloride, dapoxetine hydrochloride as Anti-premature ejaculation drugs have been listed in many countries. [0003] The (S)-N,N-dimethyl-3-(naphthol-1-oxyl)-1-phenylpropyl-1-amine involved has the following chemical structure: [0004] [0005] Literature (J. Org. Chem. 2010, 75, 237~240; Tetrahedron: Asymm.2007, 18 2099~2103 and CN 101367739) reported that the methylation method is formic acid and formaldehyde, the disadvantage of this method is that the toxicity of formaldehyde is relatively Large, it brings great pressure to labor protection and produces a large amount of waste water containing formaldehyde. The me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/48C07C213/08
Inventor 顾菲
Owner YANGZHOU POLYTECHNIC INST
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