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Preparation method of epalrestat

A technology of epalrestat and catalyst, which is applied in the field of preparation of epalrestat, and can solve problems such as strong corrosion, safety accidents, unsuitability for industrial scale-up production, etc.

Active Publication Date: 2021-10-08
SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this synthetic method, glacial acetic acid is used as a reaction solvent, and glacial acetic acid is irritating and highly corrosive. It is very inconvenient to use glacial acetic acid in large quantities in industry and is likely to cause safety accidents; in addition, the use of a large amount of glacial acetic acid will cause difficulty in hazardous waste treatment. increase, which is not conducive to environmental protection
In short, this method has great hidden dangers in terms of safety and environmental protection, making this process unsuitable for industrial scale-up production

Method used

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  • Preparation method of epalrestat

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preparation example Construction

[0024] The invention provides a kind of preparation method of epalrestat, comprises the following steps:

[0025] 3-carboxymethylrhodanine, α-methylcinnamaldehyde, catalyst and water are mixed, followed by condensation reaction and acid neutralization to obtain crude epalrestat; the catalyst includes a basic catalyst and a phase transfer catalyst ;

[0026] The epalrestat crude product is mixed with an alcoholic organic solvent for recrystallization to obtain the epalrestat.

[0027] In the present invention, unless otherwise specified, all preparation materials are commercially available products well known to those skilled in the art.

[0028] In the present invention, 3-carboxymethylrhodanine, α-methylcinnamaldehyde, catalyst and water are mixed, followed by condensation reaction and acid neutralization to obtain the crude product of epalrestat; the catalyst includes a basic catalyst and a phase transfer catalyst.

[0029] In the present invention, the basic catalyst pre...

Embodiment 1

[0048] After mixing 3.2L of purified water and 0.8L of polyethylene glycol 400, 3-carboxymethylrhodanine (152.8g, 0.80mol) and α-methylcinnamaldehyde (140.0g, 0.96mol), then finally dropwise added 3-dimethylaminopropylamine (80.0mL, 0.64mol), kept stirring at 60°C for 2h, added 200mL concentrated hydrochloric acid (mass concentration was 37%) while cooling naturally, and cooled naturally After filtration, the obtained filter cake was rinsed with 1.0L of purified water, and dried in vacuum at 40°C for 2.0h to obtain crude epalrestat (yellow solid, 245.0g, 96%);

[0049] The epalrestat crude product (160.0g, 0.5mol) was mixed with 1000mL methanol, kept and stirred at 60°C for 2.0h, after natural cooling, filtered, and the obtained filter cake was rinsed with 200mL methanol, 40°C After vacuum drying for 2.0 h, epalrestat (139.2 g, yield 87%, purity 99.76%) was obtained.

[0050] The nuclear magnetic data of described epalrestat is: 1 H NMR (400MHz, CDCl 3 )δ13.46 (br, 1H), 7.6...

Embodiment 2

[0052] After mixing 3.6L of purified water and 0.4L of polyethylene glycol 400, 3-carboxymethylrhodanine (152.8g, 0.80mol) and α-methylcinnamaldehyde (140.0g, 0.96mol), then finally dropwise added 3-dimethylaminopropylamine (78.0mL, 0.64mol), kept stirring at 60°C for 2h, added 200mL concentrated hydrochloric acid (mass concentration was 37%) while naturally cooling, and cooled naturally After filtration, the obtained filter cake was rinsed with 1.0L of purified water, and dried in vacuum at 40°C for 2.0h to obtain crude epalrestat (yellow solid, 211.8g, 83%);

[0053] The epalrestat crude product (160.0g, 0.5mol) was mixed with 1000mL methanol, kept and stirred at 60°C for 2.0h, after natural cooling, filtered, and the obtained filter cake was rinsed with 200mL methanol, 40°C After vacuum drying for 2.0 h, epalrestat (136 g, yield 85%, purity 99.68%) was obtained.

[0054] The nuclear magnetic data of described epalrestat is: 1 H NMR (400MHz, CDCl 3 )δ13.46 (br, 1H), 7.63 ...

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Abstract

The invention relates to the technical field of medicines, in particular to a preparation method of epalrestat. The preparation method provided by the invention comprises the steps of mixing 3-carboxymethyl rhodanine, alpha-methylcinnamyl aldehyde, a catalyst and water, and sequentially carrying out condensation reaction and acid neutralization to obtain an epalrestat crude product, wherein the catalyst comprises a basic catalyst and a phase transfer catalyst; and mixing the epalrestat crude product with an alcohol organic solvent, and recrystallizing to obtain the epalrestat. The preparation method adopts water as a reaction solvent, and is safe and environment-friendly; the existing three procedures such as crude product preparation, acidification dissociation and recrystallization are simplified into two procedures such as crude product preparation and recrystallization, and the two procedures such as crude product preparation and acidification dissociation are combined into one, so that the procedures are simplified; and an alcohol organic solvent is adopted for recrystallization, so that recycling is facilitated.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of epalrestat. Background technique [0002] Epalrestat, chemical name is chemical name 5-[(1Z,2E)-2-methyl-3-phenylpropenylidene]-2-thio-2,4-thiazoldione-3-acetic acid, its chemical The structure is as follows: [0003] [0004] Epalrestat, a new type of aldose reductase inhibitor developed by Japan's Ono Company, was first launched in Japan in 1992 for the treatment of diabetic complications, such as neuropathy, corneal epithelial disease, retinopathy and microvascular disease. [0005] There have been many literature reports on the synthesis of epalrestat at home and abroad, most of which are prepared by the condensation reaction of 3-carboxymethylrhodanine and α-methylcinnamaldehyde. For example: Li Duxin ("Journal of Shanxi University (Natural Science Edition) 1995,18,413-415"), Yu Shuhai ("Chinese Journal of Pharmaceutical Industry" 1996,27,5-6) a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/36
CPCC07D277/36
Inventor 颜世强杨杰何淑旺曹焕英郭伟解春文胡醒
Owner SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD
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