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Method for preparing agomelatine

A technology with structural formula and methoxy group, applied in the new field of agomelatine preparation, can solve the problems of low atom utilization rate, unfavorable environmental protection and high production cost, and achieves mild reaction, simple post-processing, and reaction yield. high effect

Active Publication Date: 2013-01-16
JIANGXI SYNERGY PHARMA
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  • Abstract
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  • Application Information

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Problems solved by technology

[0018] In the reaction process of this route, compounds with relatively large molecular weights such as trifluoromethanesulfonic anhydride and phthalimide were introduced to participate in the reaction, but did not enter the final product agomelatine, and the utilization rate of atoms was not high, resulting in a large amount of Waste, not conducive to environmental protection and high production cost

Method used

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  • Method for preparing agomelatine
  • Method for preparing agomelatine
  • Method for preparing agomelatine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1: agomelatine

[0050] Step 1: Preparation of (7-methoxy-3,4-dihydro-2H-naphthalene-1-ylidene)acetonitrile

[0051]Put 200ml of ethylene glycol dimethyl ether, 17.0 g (0.71mol) of sodium hydrogen into a 1000ml four-necked bottle, control the temperature at 15±2°C, add 50g (0.28mol) of 7-methoxy-1-tetralone, and stir For 30 minutes, 70.4 g (0.40 mol) of diethyl nitrile methyl phosphate was added dropwise to the reaction solution at 15 ° C, and the drop was completed in 3 to 4 hours. The temperature was controlled at 10 ° C, and the reaction was stirred for 15 hours. It was detected that the reaction was complete, and the reaction solution was cooled to Below 5°C, slowly add 200ml of water dropwise for 30 minutes, then adjust the pH to 5~6 with hydrochloric acid, add 2×100ml of dichloromethane for extraction twice, concentrate the organic layer to dryness under reduced pressure, add 200ml of 95% ethanol to the residue , heated up to dissolve, stirred for 1 ho...

Embodiment 2

[0058] Example 2 agolametine

[0059] Step 1: Preparation of (7-methoxy-3,4-dihydro-2H-naphthalene-1-ylidene)acetonitrile

[0060] 50g (0.28mol) of 7-methoxyl-1-tetralone and 70.4g (0.40mol) of diethyl nitrile methyl phosphate were reacted in N,N-dimethylformamide under sodium hydrogen catalysis, the Step all the other operations are with the step 1 of embodiment 1.

[0061] Step 2: Preparation of 1-cyano-7-methoxy-1-naphthylmethanol propionate

[0062] Put 185g (0.75mol) of chlorobenzoquinone and 600ml of propionic acid into the reaction bottle, stir, and add 30g of (7-methoxy-3,4-dihydro-2H-naphthalene-1-ylidene) acetonitrile obtained in step 1 (0.15mol), stirred for 1 hour, heated to reflux, and reacted for 12 hours. Cool to room temperature, distill the reaction solution under reduced pressure, recover acetic acid, add 200ml of toluene to the residue, stir for 1 hour, filter, wash the filtrate twice with 2×200ml of 5% sodium bisulfite aqueous solution, and then wash wi...

Embodiment 3

[0067] Example 3 Agomelatine

[0068] Step 1: Preparation of (7-methoxy-3,4-dihydro-2H-naphthalene-1-ylidene)acetonitrile

[0069] 50g (0.28mol) of 7-methoxy-1-tetralone and 70.4g (0.40mol) of diethyl nitrile methyl phosphate are reacted in dimethyl sulfoxide under sodium hydrogen catalysis, and the rest of the steps are the same as Step 1 of Example 1.

[0070] Step 2: Preparation of 1-cyano-1-(7-methoxy-1-naphthyl)methanol butyrate

[0071] Put 272g (1.2mol) of dichlorodicyanobenzoquinone and 700ml of n-butyric acid into the reaction bottle, stir, and add (7-methoxy-3,4-dihydro-2H-naphthalene-1- Base) 30 g (0.15 mol) of acetonitrile, stirred for 1 hour, heated to reflux, and reacted for 12 hours. Cool to room temperature, distill the reaction solution under reduced pressure, recover acetic acid, add 200ml of toluene to the residue, stir for 1 hour, filter, wash the filtrate twice with 2×200ml of 5% sodium bisulfite aqueous solution, and then wash with 2×100ml of Water, ...

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Abstract

The invention discloses a method for preparing agomelatine represented by structural formula 1. The method includes that 7-methoxy-tetralone represented by structural formula 5 is reacted with dimethyl cyanomethylphosphonate in an aprotic polar solvent under the sodium hydride catalytic action to generate (7-methoxyl-3,4-dihydro-2H-naphthalene-1-subunit) acetonitrile represented by structural formula 4, under the presence of an aromatization reagent, the (7-methoxyl-3,4-dihydro-2H-naphthalene-1-subunit) acetonitrile represented by the structural formula 4 is reacted with an organic acid to generate 1-cyano-7-methoxyl-1-naphthyl alcohol ester represented by structural formula 3, hydrogenation reduction is performed in an ammonia containing alcohol solvent under the catalysis of raney nickel to generate 2-(7- methoxyl-1-naphthyl) ethylamine represented by structural formula 2, finally the 2-(7- methoxyl-1-naphthyl) ethylamine represented by the structural formula 2 is reacted with acetic anhydride to generate the agomelatine represented by structural formula 1, and the agomelatine is separated out in a solid form. The method for preparing the agomelatine represented by the structural formula 1 has the advantages that the synthetic route is short, the reaction conditions are simple and mild, the raw materials are cheap and easy to obtain, the method is environment-friendly, the product yield and purity are high and the like, and the method is suitable for mass industrial production.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a new method for preparing agomelatine. technical background [0002] Agomelatine, structural formula as shown in 1, system name: N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide, CAS number: 138112-76-2, by Servier Developed by the company and launched in Europe in 2009. Agomelatine is both the first melatonin receptor agonist and 5-hydroxytryptamine 2c (5HT2c) receptor antagonist. Possesses active activity in the treatment of major depressive disorder, seasonal affective disorder, sleep disturbance, cardiovascular disease, digestive system disease, jet lag-induced insomnia and fatigue, appetite disturbance and obesity. [0003] [0004] At present, there are many patents and documents on the synthesis of agomelatine, and the common synthetic routes are as follows: [0005] Route 1 (European Invention Patent Publication, Publication No. EP91400526) [0006] In 199...

Claims

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Application Information

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IPC IPC(8): C07C233/18C07C231/02
Inventor 蒋元森殷清华徐烘材蒋慧纲
Owner JIANGXI SYNERGY PHARMA
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