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Preparation method of ramelteon impurity

A technology for ramelteon and impurities, which is applied in the field of preparation of ramelteon impurities, and can solve problems such as the inability to synthesize monodebrominated products in a directional manner

Active Publication Date: 2020-02-11
SHANDONG ZOUPING DAZHAN NEW MATERIALS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aiming at the problem of being unable to synthesize monodebrominated products in a directional manner, the present invention provides a method for preparing ramelteon impurities to solve the above problems

Method used

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  • Preparation method of ramelteon impurity

Examples

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Effect test

Embodiment 1

[0030] A kind of preparation method of ramelteon impurity, concrete preparation steps are as follows:

[0031] (1) In terms of compound I, take 10.00g of compound I, put it in a reaction flask, add 60g of dichloromethane and 0.04g of N,N-dimethylformamide, stir to dissolve, and protect with nitrogen; control the temperature of the reaction solution at 20~30℃, add 4.76g of oxalyl chloride dropwise; keep the temperature for 1h after the dropwise addition; reduce the temperature of the reaction solution to -5~0℃, add 4.76g of aluminum trichloride in 4 batches, and react at 0~5℃ after the addition is completed 1h, the reaction was monitored by TLC; after the reaction, 40g of absolute ethanol A was added to quench the reaction at a temperature of 0-10°C. After the addition, the reaction was stirred at 0-15°C for 2h, filtered, and the filter cake was slurried with 40g of anhydrous ethanol B. After drying, 7.73 g of compound II was obtained with a yield of 81.5%.

[0032] (2) In ter...

Embodiment 2

[0044] A kind of preparation method of ramelteon impurity, concrete preparation steps are as follows:

[0045] (1) In terms of compound I, take 126.0g of compound I, put it in a reaction flask, add 800g of dichloromethane and 0.5g of N,N-dimethylformamide, stir to dissolve it, and protect it with nitrogen; control the temperature of the reaction solution at 20~30℃, add 60.0g of oxalyl chloride dropwise; keep the temperature for 1h after the dropwise addition is completed; reduce the temperature of the reaction solution to -5~0℃, add 60.0g of aluminum trichloride in 6 batches, 10.0g each time, after the addition is completed React at 0~5℃ for 1h, and TLC monitors the reaction; after the reaction is over, add 500g of absolute ethanol A at a temperature of 0~10℃ to quench the reaction, stir at 0~15℃ for 2h after the addition, filter, filter cake with 500g Water ethanol B was slurried and dried to obtain 102.4 g of compound II with a yield of 85.7%.

[0046](2) In terms of compou...

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Abstract

The invention relates to a preparation method of a ramelteon impurity, and belongs to the technical field of chemical synthesis. The preparation method comprises the following steps: (1) reacting a compound I with oxalyl chloride to generate an acyl chloride compound, adding aluminum trichloride, and carrying out a Friedel-Crafts reaction to generate a compound II; and (2) directionally generatinga compound III from the compound II under the action of Raney cobalt and hydrazine hydrate. The preparation method provides a novel and safe reduction condition for direct synthesis of the monosubstituted impurity, and the product does can be directly used as an impurity reference substance without purification, and also can be directly subjected to a subsequent impurity transfer experiment.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of ramelteon impurity. Background technique [0002] Ramelteon, English name: ramelteon, chemical name (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl) )Ethyl]propionamide, developed by Takeda Corporation of Japan, was approved by the FDA in September 2005 to be listed in the United States under the trade name Rozerem, which is the first drug in human history to be clinically used as a melatonin receptor agonist for the clinical treatment of insomnia , can be used for the treatment of insomnia that is difficult to fall asleep, and also has a definite curative effect on chronic insomnia and short-term insomnia. This product can selectively activate melatonin type 1 receptor and type 2 receptor (MT1, MT2), increase slow wave sleep (SWS) and rapid eye movement sleep (REW), thereby reducing insomnia. Ramelteon is the first non-ad...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/77
CPCC07D307/77Y02P20/55
Inventor 杨波马文斌任传栋林泉生卢俞志
Owner SHANDONG ZOUPING DAZHAN NEW MATERIALS
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