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Preparation of agomelatine midbody, 2-(7-anisyl-1-naphthyl) ethylamine

A methoxyl and naphthyl technology, applied in the field of medicine, can solve the problems of high equipment requirements, low total yield, difficult industrial scale, etc., and achieve the effect of reducing one-step reaction, high total yield and safe operation

Active Publication Date: 2010-05-19
TIANJIN INSTITUTE OF PHARMA RESEARCH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] (1) With 7-methoxy tetralone (III) as the starting material, 7 steps of synthetic formula (II) compound have been used, with 2-(7-methoxy-1-naphthyl) acetamide (VII ) used 2 steps to synthesize (II) compound for the starting material, the steps are longer, and the total yield is low
[0010] (2) The reduction of 2-(7-methoxy-1-naphthyl)acetamide (VII) after dehydration requires high-pressure catalytic hydrogenation. According to literature reports, the pressure reaches 300 atmospheres and the reaction time is long (reaction overnight)
This method has high requirements for equipment, poor safety, and is difficult to transform into an industrial scale

Method used

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  • Preparation of agomelatine midbody, 2-(7-anisyl-1-naphthyl) ethylamine
  • Preparation of agomelatine midbody, 2-(7-anisyl-1-naphthyl) ethylamine
  • Preparation of agomelatine midbody, 2-(7-anisyl-1-naphthyl) ethylamine

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Add 15g of 2-(7-methoxy-1-naphthyl)acetamide (VII), 5.3g of sodium borohydride, 20.2g of boron trifluoride ethyl ether (47% content), and 300ml of tetrahydrofuran into the reaction flask, and reflux the reaction until the substrate disappears. Pour into dilute hydrochloric acid, extract twice with ethyl acetate, basify the aqueous layer with 10% sodium hydroxide, extract twice with ethyl acetate, combine the oil layers, dry over anhydrous magnesium sulfate, filter, recover ethyl acetate, evaporate Dry to give 2-(7-methoxy-1-naphthyl)ethylamine. Hydrochloric acid-ethyl acetate was added to precipitate a solid, which was filtered to obtain 12 g of off-white solid. The yield was 72.2%. The product is tested with a YRT-3 melting point apparatus, and the melting point of the product is 213-215° C. after testing. Then weigh 10 mg of the resulting product and dissolve it in 0.5 ml of organic solvent (DMSO-d 6 ), using Bruker AV400 to carry out NMR analysis on the sample, t...

Embodiment 2

[0026] Add 15g of 2-(7-methoxy-1-naphthyl)acetamide (VII), 7.6g of potassium borohydride, 101.3g of boron trifluoride ether, and 300ml of tetrahydrofuran into the reaction flask, and reflux until the substrate disappears. Pour into dilute hydrochloric acid, extract twice with ethyl acetate, alkalinize the aqueous layer with 10% sodium hydroxide, extract twice with ethyl acetate, combine the oil layers, dry over anhydrous magnesium sulfate, filter, pass through hydrochloric acid gas, solid Precipitated and filtered to obtain 13 g of off-white solid. The melting point is 214-215°C.

Embodiment 3

[0028] Add 10.8g of 2-(7-methoxy-1-naphthyl)acetamide (VII), 4.8g of sodium borohydride, 22g of aluminum trichloride, and 150ml of tetrahydrofuran into the reaction flask, and reflux until the substrate disappears. Add dilute hydrochloric acid, extract twice with ethyl acetate, alkalinize the aqueous layer with 10% sodium hydroxide, extract twice with ethyl acetate, combine the oil layers, dry over anhydrous magnesium sulfate, filter, add hydrochloric acid-ethyl acetate, solid Precipitated and filtered to obtain 12.8 g of off-white solid. The melting point is 213-215°C.

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Abstract

The invention aims at providing a preparation method of 2-(7-anisyl-1- naphthyl) ethylamine (II) which is an important midbody of agomelatine. The preparation method uses 2- (7-anisyl-1-naphthyl) acetamide (VII) as an initiative raw material, only needs one reaction step, has higher yield, abolishes high-voltage hydrogenation, has mild conditions and does not need special devices.

Description

technical field [0001] The invention belongs to the field of medicine. The invention relates to a preparation method of 2-(7-methoxy-1-naphthyl)ethylamine and its hydrochloride. Background technique [0002] Agomelatine (agomelatine), the chemical name is N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide (I), and its trade name is Valdoxan / Thymanax , the structural formula is as follows: [0003] [0004] Agomelatine is a new type of antidepressant, which is not only a melatonin (MT) receptor agonist, but also a 5-hydroxytryptamine (5-HT) 2C receptor antagonist. Agomelatine can effectively treat depression in adults, especially for major depressive disorder (MMD), and can effectively improve sleep parameters and maintain sexual function. [0005] [0006] The compound represented by formula (II) is an important intermediate 2-(7-methoxy-1-naphthyl)ethylamine for the synthesis of agomelatine. European patent specification EP0447285 reports the preparation method of a...

Claims

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Application Information

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IPC IPC(8): C07C217/60C07C213/08
Inventor 陈蔚潘毅陶勇
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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