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Intermediate for preparing agomelatine and relevant preparation method

A technology for use and phase transfer catalyst, applied in the field of agomelatine and its intermediate preparation, can solve the problems of difficult to realize industrialization, expensive starting materials, etc., and achieve high industrial application value, moderate reaction conditions, and reaction operation. simple effect

Active Publication Date: 2012-07-04
浙江瑞博制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] The purpose of the present invention is to overcome the disadvantages of expensive starting materials and difficult industrialization in the prior art, and provide two new intermediate compounds and related preparation methods for the preparation of agomelatine

Method used

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  • Intermediate for preparing agomelatine and relevant preparation method
  • Intermediate for preparing agomelatine and relevant preparation method
  • Intermediate for preparing agomelatine and relevant preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Embodiment 1: Preparation of 1-bromo-7-methoxynaphthalene

[0078] Add 1-bromo-7-naphthol (5.6g, 0.025mol) successively in the 250ml four-neck round bottom flask, 100ml toluene, dimethyl sulfate (15.8g, 0.125mol) and tetramethylammonium bromide (0.25g, 0.0015mol), start mechanical stirring. 14.0 g of 50% KOH aqueous solution was added dropwise at 25-40°C. After dripping, continue to react. The reaction was monitored by TLC until the conversion of the starting material 1-bromo-7-naphthol was complete. After the reaction, 10ml of water was added, the temperature was raised to 55-60°C, and the temperature was kept for 1 hour. Separate layers, take the upper organic phase and discard the lower aqueous phase. The organic phase was washed successively with 5% aqueous sodium hydroxide and 5% aqueous sodium chloride. The solvent was evaporated to dryness to obtain 5.39 g of 1-bromo-7-methoxynaphthalene as a colorless waxy solid, with a yield of 90.94%.

[0079] 1 H NMR (...

Embodiment 2

[0081] Embodiment 2: Preparation of 1-bromo-7-methoxynaphthalene

[0082] In the 1000ml four-neck round bottom flask, add 1-bromo-7-naphthol (22.3g, 0.10mol) successively, 400ml toluene, dimethyl sulfate (63.2g, 0.125mol) and tetrabutylammonium bromide (1.0g, 0.003mol) to start the mechanical stirring. 56.0 g of 50% KOH aqueous solution was added dropwise at 10-15°C. After dripping, continue to react. The reaction was monitored by TLC until the conversion of the starting material 1-bromo-7-naphthol was complete. After the reaction, 100ml of water was added, the temperature was raised to 55-60°C, and the temperature was kept for 1 hour. Separate layers, take the upper organic phase and discard the lower aqueous phase. The organic phase was washed successively with 5% aqueous sodium hydroxide and 5% aqueous sodium chloride. The solvent was evaporated to dryness to obtain 22.52 g of 1-bromo-7-methoxynaphthalene as a colorless waxy solid, with a yield of 95.0%.

Embodiment 3

[0083] Embodiment 3: Preparation of 1-bromo-7-propoxynaphthalene

[0084] In the 250ml four-neck round bottom flask, add 1-bromo-7-naphthol (5.6g, 0.025mol) successively, 100ml toluene, dipropyl sulfate (22.8g, 0.125mol) and tetrapropylammonium bromide (0.4g, 0.0015mol), start mechanical stirring. 14.0 g of 50% KOH aqueous solution was added dropwise at 25-40°C. After dripping, continue to react. The reaction was monitored by TLC until the conversion of the starting material 1-bromo-7-naphthol was complete. After the reaction, 10ml of water was added, the temperature was raised to 55-60°C, and the temperature was kept for 1 hour. Separate layers, take the upper organic phase and discard the lower aqueous phase. The organic phase was washed successively with 5% aqueous sodium hydroxide and 5% aqueous sodium chloride. The solvent was evaporated to dryness to obtain 6.08 g of 1-bromo-7-propoxynaphthalene as a colorless waxy solid, with a yield of 91.83%.

[0085] MS (EI + ...

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Abstract

The invention relates to the technical field of preparation methods of carboxylic acid amide, in particular to the technical field of preparation methods of agomelatine and an intermediate thereof. The invention particularly relates to an intermediate of agomelatine and a relevant preparation method. The preparation method comprises the following steps of: undergoing an alkylation reaction on 1-halogen-7-naphthalene alkoxyl serving as a raw material to obtain a compound shown as a formula (2); undergoing a Grignard reaction on the obtained compound shown as the formula (2) to obtain a compound shown as a formula (3); reacting the obtained compound shown as the formula (3) with trifluoroacetic anhydride to obtain a compound shown as a formula (4), wherein the compound shown as the formula (4) is a novel intermediate compound for synthesizing agomelatine and a derivative thereof; reacting the compound shown as the formula (4) with sodium azide simultaneously to obtain a compound shown as a formula (5), wherein the compound shown as the formula (5) is a novel intermediate compound for synthesizing agomelatine and a derivative thereof; and undergoing simple type reactions such as hydrogenation reduction, electrophilic substitution and the like on the compound shown as the formula (5) to obtain agomelatine suitable for process production and a derivative thereof, wherein R1 is alkyl; and X is F, Cl, Br or I.

Description

technical field [0001] The invention relates to the technical field of preparation methods of carboxylic acid amides, in particular to the technical field of preparation methods of agomelatine and its intermediates. Background technique [0002] The melatonin receptor agonist antidepressant agomelatine was approved for marketing in the European Union on February 19, 2009, and its trade name is Agomelatine (Agomelatine), chemical name: N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide, is a kind of melatonin developed by Servier company in France 1，2 (MT 1 MT 2 ) receptor agonists, but also five serotonin 2c (5HT2c) receptor antagonists, clinically mainly used for the treatment of adult depression. [0003] [0004] With regard to the preparation of agomelatine, a lot of research work has been carried out. Among the existing synthetic routes, each route has its own characteristics, and also has certain shortcomings. At present, the common synthetic routes at home and abro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C247/10C07C217/60C07C213/02C07C69/63C07C67/08C07C231/02C07C233/18
Inventor 张现毅俞建斌高红军车大庆
Owner 浙江瑞博制药有限公司
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