A kind of production method of hydrogenation preparation agomelatine

A production method and hydrogen technology, which are used in chemical instruments and methods, preparation of organic compounds, preparation of carboxylic acid amides, etc., can solve problems such as difficult to achieve, and achieve the effects of improving reaction yield, reducing pollution and high yield

Inactive Publication Date: 2015-08-19
TIANJIN TAIPU PHARMA SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is mentioned in the literature that the formation of dimers can be minimized by using this process, but the refined product yield is only 89%, and the high-pressure hydrogenation equipment that requires continuous feeding is used, which is difficult to achieve under normal production conditions

Method used

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  • A kind of production method of hydrogenation preparation agomelatine
  • A kind of production method of hydrogenation preparation agomelatine
  • A kind of production method of hydrogenation preparation agomelatine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of agomelatine (compound I) by using acetyl chloride as acylating agent and triethylamine as acid-binding agent

[0032] In a dry 100L autoclave, add (7-methoxyl-1-naphthyl) acetonitrile 9.85kg (50mol), anhydrous tetrahydrofuran 39.4L, Raney-Ni 1.2kg, acetyl chloride 4.32Kg (55mol), triethylamine 11.1Kg (110mol), stir evenly, vacuumize and replace with nitrogen, vacuumize and replace with hydrogen (gas supplied by industrial steel cylinders, purity> 99%), control the hydrogen pressure at 1-1.5Mpa, control the temperature at 45°C, and react for 2 hours. After the reaction is complete, suck out the reaction solution from the autoclave, evaporate to dryness under reduced pressure, dissolve in ethyl acetate, wash with saturated sodium bicarbonate water until neutral, leave to separate layers, and evaporate the organic phase to dryness under reduced pressure to obtain the compound I, weighing 11.5kg, the purity is 99% (HPLC), and the yield of crude product is 95%...

Embodiment 2

[0034] Use acetic anhydride as an acylating agent and pyridine as an acid-binding agent to prepare agomelatine (compound I). In a dry 100L autoclave, add (7-methoxy-1-naphthyl) acetonitrile 9.85kg (50mol) , anhydrous tetrahydrofuran 39.4L, Raney-Ni 1kg, acetic anhydride 5.6Kg (55mol), pyridine 8.7Kg (110mol), stir evenly, vacuumize and replace with nitrogen, vacuumize and replace with hydrogen (gas supplied by industrial steel cylinders, purity > 99 %), the hydrogen pressure is controlled at 1-1.2Mpa, the temperature is controlled at 40°C, and the reaction is carried out for 1.5 hours. After the reaction was completed, the reaction solution was sucked out from the autoclave, evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate until neutral, left to separate layers, and the organic phase was evaporated to dryness under reduced pressure to obtain the compound 1, crude product 11.9kg, purity 99...

Embodiment 3

[0036] Preparation of agomelatine (compound I) with toluene as reaction solvent, acetic anhydride as acylating agent and triethylamine as acid-binding agent

[0037] In a dry 100L autoclave, add (7-methoxyl-1-naphthyl) acetonitrile 9.85kg (50mol), anhydrous tetrahydrofuran 39.4L, Raney-Ni 1kg, acetic anhydride 5.6Kg (55mol), triethylamine 11.1 Kg (110mol), after stirring evenly, vacuumize and replace with nitrogen, vacuumize and replace with hydrogen (gas supplied by industrial steel cylinders, purity > 99%), control the hydrogen pressure at 1-1.5Mpa, control the temperature at 60°C, and react for 3 hours. After the reaction was completed, the reaction liquid was sucked out from the autoclave, and after being evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate until neutral, allowed to stand for layers, and the organic phase was evaporated to dryness under reduced pressure. Compound I was ob...

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Abstract

The invention provides a new industrial production method for preparing agomelatine through hydrogenation, comprising the steps of mixing a compound as shown in a formula (II) with an acylation reagent in an anhydrous solvent; adding an acid-binding agent and a catalyst; introducing industrial hydrogen while stirring; and reacting under a certain pressure, thereby obtaining a compound (I). The method is characterized in that (7-methoxy-1-naphthyl) acetonitrile is taken as the raw material and the acylation reagent and the acid-binding agent are added, and finally, the target compound N-[2-(7-methoxynaphthalene-1-yl) ethyl) acetamide is prepared through catalytic hydrogenation. Compared with the prior art, the method is short in reaction time, few in reaction byproducts, high in reaction yield, simple in posttreatment, stable in product quality, low in production cost, and suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, and relates to a preparation method of a bulk drug, in particular to a new preparation method of agomelatine suitable for industrial production. Background technique [0002] Agomelatine or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide possesses valuable pharmacological properties as both the first melatonin receptor agonist and the 5 - Serotonin 2C (S-HTx) receptor antagonists. Animal experiments and clinical studies have shown that the drug has central nervous system activity, especially antidepressant, anti-anxiety, regulating sleep rhythm and regulating biological clock, etc. At the same time, it has few adverse reactions, no adverse effects on sexual function, and no drug withdrawal reaction . [0003] The synthesis method reported earlier in the patent EP0447285 uses 7-methoxy-1-tetralone as a starting material to prepare agomelatine through eight steps, and its average yi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/18C07C231/10
Inventor 周学福王志国魏文涛
Owner TIANJIN TAIPU PHARMA SCI & TECH DEV
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