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The preparation method of 2-(7-methoxyl-1-naphthyl)ethylamine

A methoxyl and naphthyl technology, which is applied in the field of preparation of agomelatine key intermediate 2-(7-methoxy-1-naphthyl)ethylamine, can solve the problem of potential safety hazards and the overall yield Low cost, high production cost and other issues, to achieve the effect of no safety hazard, short reaction route and low cost

Active Publication Date: 2015-12-02
SHANGHAI INST OF PHARMA IND CO LTD +1
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Problems solved by technology

[0008] (1) Using 7-methoxytetralone (2) as the starting material to synthesize the compound of formula II through 7 steps; starting from 2-(7-methoxy-1-naphthyl)acetamide (6) Starting material is synthesized formula II compound through 2 steps; Step is longer, and overall yield is low
[0009] (2) When the intermediate 2-(7-methoxyl-1-naphthyl)acetonitrile (7) is converted into the intermediate of formula II, high-pressure catalytic hydrogenation is required, and the literature reports that the pressure reaches 300 atmospheres, and the reaction time is long (reaction overnight)
The patented method uses Raney nickel catalysis. On the one hand, there is a hidden danger of heavy metals exceeding the standard, which affects the drug safety of patients; on the other hand, it also increases the difficulty and workload of product quality control.
[0011] Chinese patent 201010125681.6 uses lithium aluminum hydrogen as a reducing agent and 2-(7-methoxy-1-naphthyl) acetonitrile (7) as a raw material to prepare the intermediate of formula (II), but lithium aluminum hydrogen is flammable and explosive , expensive, also not suitable for industrial scale-up
[0012] Chinese patent 200910244386.X adopts sodium borohydride and nickel chloride system and 2-(7-methoxy-1-naphthyl)acetonitrile (7) as raw material to prepare the intermediate of formula (II), although the system has The advantages can be enlarged, but nickel chloride is still used for catalysis, and there is a hidden danger of heavy metal residues
However, boron trifluoride ether is a highly toxic substance, and it will be hydrolyzed immediately when it encounters moisture in the air to form highly toxic fluoride, which is not conducive to labor protection. The technology disclosed in this patent also has potential safety hazards
[0014] Chinese patent 200910244871.7 also discloses that the reduction system of sodium borohydride and aluminum trichloride can be used to prepare formula ( II) intermediate, but the applicant repeated the reaction conditions for research, the reduction reaction did not proceed
[0015] In summary, the reported methods for the synthesis of 2-(7-methoxy-1-naphthyl)ethylamine require special production equipment, low reaction safety, hidden dangers of heavy metal residues, low yields and production problems. Problems such as high cost are not conducive to industrial production

Method used

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  • The preparation method of 2-(7-methoxyl-1-naphthyl)ethylamine
  • The preparation method of 2-(7-methoxyl-1-naphthyl)ethylamine
  • The preparation method of 2-(7-methoxyl-1-naphthyl)ethylamine

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Embodiment 1

[0038] In the reaction flask, add 360ml of tetrahydrofuran, ZnCl 2 45.60g (0.335mol) and KBH 4 36.2g (0.67mol), stirring at room temperature for 2 hours; adding 36g (0.167mol) of 2-(7-methoxy-1-naphthyl)acetamide and 360ml of toluene, heating slowly, steaming out THF in the system, making the internal Temperature reaches 110°C, heat preservation and stirring for 8 hours;

[0039] Cool to room temperature, slowly drop ice water into the reaction system to terminate the reaction, pour the reaction solution into 200ml of 10% hydrochloric acid aqueous solution by weight, the pH value of the reaction system is about 2, filter, the filtrate is separated, and the toluene layer is discarded. The aqueous layer was basified with a 20% weight concentration sodium hydroxide solution to a pH of 11-12. Extract twice with 200ml of ethyl acetate, combine the extracts with MgSO 4 After drying, filtering, and evaporating to dryness, 32.0 g of light yellow oily substance 2-(7-methoxy-1-naphth...

Embodiment 2

[0041]In the reaction flask, add 2-methyltetrahydrofuran 360ml, ZnCl 2 34.08g (0.25mol) and KBH 4 27.0g (0.50mol), stirred at room temperature for 4 hours. 36 g (0.167 mol) of 2-(7-methoxy-1-naphthyl) acetamide and 360 ml of toluene were heated slowly to evaporate THF in the system to bring the internal temperature to 70°C and keep stirring for 6 hours. Cool to room temperature, slowly drop ice water into the reaction system to terminate the reaction, pour the reaction solution into 200ml of sulfuric acid aqueous solution with a weight concentration of 10%, the pH value of the reaction solution is between about 1, filter, the filtrate is separated, and the toluene layer discard. The aqueous layer was alkalized to pH 10 with 10% potassium hydroxide solution by weight. Extract with dichloromethane 150ml×2, combine the extracts with NaSO 4 Dry, filter, and evaporate to dryness to obtain 25.5 g of light yellow oily substance 2-(7-methoxy-1-naphthyl)ethylamine, yield 75.89%, MS...

Embodiment 3

[0043] In the reaction flask, add 360ml of tetrahydrofuran, ZnCl 2 22.76g (0.167mol) and KBH 4 18.04g (0.334mol), stirring at room temperature for 2 hours; adding 36g (0.167mol) of 2-(7-methoxy-1-naphthyl) acetamide and 360ml of toluene, heating slowly, distilling THF in the system, making the internal temperature reached 100°C, and kept stirring for 3 hours. Cool to room temperature, slowly drop ice water into the reaction system to terminate the reaction, pour the reaction solution into 300ml of 10% hydrochloric acid aqueous solution by weight, the pH value of the reaction solution is 2, filter, the filtrate is layered, the toluene layer is discarded, and the water layer is Alkaline with 20% sodium hydroxide solution by weight to pH 12-13. Extract with chloroform 150ml×2, combine the extracts with NaSO 4 After drying, filtering, and evaporating to dryness, 27.22 g of light yellow oily substance 2-(7-methoxy-1-naphthyl)ethylamine was obtained, with a yield of 81%, MS (m / z)...

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Abstract

The invention discloses a preparation method for 2-(7-methoxy-1-naphthyl)ethylamine. The preparation method comprises the following steps: adding 2-(7-methoxy-1-naphthyl)acetamide (a compound as represented by a formula III) in a solvent in the presence of Zn(BH4)2, carrying out a reduction reaction and collecting 2-(7-methoxy-1-naphthyl)ethylamine (a compound as represented by a formula II) from reaction products. The preparation method provided by the invention has the advantages of need for only one step, a short reaction route, reaction yield of almost 100%, low cost, no need for special reaction equipment, no need for monitoring of residual of heavy metal, no potential of safety hazards in the process of production and suitability for industrial production. A reaction equation is described in the specification.

Description

technical field [0001] The invention relates to a preparation method of agomelatine key intermediate 2-(7-methoxy-1-naphthyl)ethylamine Background technique [0002] 2-(7-methoxy-1-naphthyl)ethylamine (compound of formula II) is an important intermediate for preparing agomelatine, an antidepressant drug. Agomelatine (compound of formula I) is a new type of antidepressant, which is the first melatonin receptor agonist and has good antidepressant effect. Its onset of action is fast, and it has a good curative effect on depression and its accompanying symptoms such as anxiety and insomnia. It has few adverse reactions and high safety, and has good clinical application and development value. Its chemical name is N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (I), and its structural formula is as follows: [0003] [0004] The compound represented by formula (II) is the key intermediate 2-(7-methoxy-1-naphthyl)ethylamine for the synthesis of agomelatine. [0005] European paten...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/60C07C213/02
Inventor 李建其翁志洁王敬宇邴绍昌孙媛媛
Owner SHANGHAI INST OF PHARMA IND CO LTD
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