Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide

A technology of pyrrolidineacetamide and hydroxyl, which is applied in the field of preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidineacetamide, can solve the problems of expensive raw materials, many steps, high cost, etc., and achieve simple procedures , the effect of increasing the purity

Inactive Publication Date: 2007-05-02
AHN GOOK PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method provides optically pure oxyracetam, its disadvantages are: expensive raw materials, low yield due to many steps, and high cost
Although it is possible to prepare chiral compounds according to these methods, the starting materials are expensive and not commercially available, and the method would not be applicable due to low competitive prices

Method used

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  • Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide
  • Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide
  • Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the preparation of (R)-3-chloro-2-hydroxy propionitrile

[0052] Into a 5 L 3-necked round bottom flask equipped with a thermometer, a pH meter and a stirrer, 400 g of water and 400 g of (R)-epichlorohydrin were sequentially added. 275 g of sodium cyanide dissolved in 347 g of water and 427 g of citric acid dissolved in 347 g of water were simultaneously added dropwise to the stirred solution. The pH and temperature of the reaction solution were maintained at 7.8-8.3 and 25°C-8.3°C, respectively. After the dropwise addition was completed, the temperature was raised to room temperature and stirred for another 10 hours. The reaction mixture was extracted with 2L (x2) ethyl acetate, and the organic layer was collected and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure to obtain the target product chiral 3-chloro-2-hydroxypropionitrile.

Embodiment 2

[0053] Embodiment 2: the preparation of (S)-3-chloro-2-hydroxy propionitrile

[0054] Into a 5 L 3-necked round bottom flask equipped with a thermometer, a pH meter and a stirrer, 400 g of water and 400 g of (S)-epichlorohydrin were sequentially added. 275 g of sodium cyanide dissolved in 347 g of water and 427 g of citric acid dissolved in 347 g of water were simultaneously added dropwise to the stirred solution. The pH and temperature of the reaction solution were maintained at 7.8-8.3 and 25°C-8.3°C, respectively. After the dropwise addition was completed, the temperature was raised to room temperature and stirred for another 10 hours. 200 g of brine was added to the reaction mixture. The reaction mixture was partitioned in 5 L of ethyl acetate, and the ethyl acetate layer was separated. To the ethyl acetate solution was added 50 g of anhydrous sodium sulfate and stirred for 30 minutes. After filtration, the filtrate was evaporated under reduced pressure. The concentra...

Embodiment 3

[0056] Embodiment 3: the preparation of methyl-(S)-4-chloro-3-hydroxybutyric acid

[0057] Into a 3 L 3-necked round bottom flask equipped with a thermometer, a pH meter and a stirrer, 439 g of methanol were sequentially added and the temperature was lowered to -20°C. 372g of hydrogen chloride gas was supplied to the solution, and the temperature was maintained at -5°C to 0°C, and 458g of (S)-3-chloro-2-hydroxypropionitrile was added dropwise. After the dropwise addition was completed, the reaction temperature was raised to 20°C-25°C and stirred for 12 hours. The reaction mixture was evaporated under reduced pressure to remove methanol. To the residue was added 664 g of water and stirred for 1 hour. The aqueous solution was then extracted with 1.5 L (x2) of ethyl acetate, and the organic layer was collected and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure. The residue was fractionally distilled to obtain 342 g...

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Abstract

The present invention relates to a process for the preparation of chiral 4-hydroxy-2-oxo-1-pyrrolidine acetamide. The process comprises adding sodium cyanide together with citric acid to a solution of chiral epichlorohydrin to obtain chiral 3-chloro-2-hydroxypropionitrile by ring opening reaction of the chiral epichlorohydrin, reacting the obtained product with an alcohol containing hydrochloride gas to obtain chiral 4-chloro-3-hydroxybutyric acid ester, and reacting the obtained product in a presence of a base with glycinamide or with glycine ester accompanied by ammonolysis with ammonia to produce the targeted chiral 4-hydroxy-2-oxo-1-pyrrolidine acetamide. The process according to the present invention provides optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide in high yield and in high purity, which is suitable for industrial mass-production.

Description

technical field [0001] The invention relates to a preparation method of optically pure 4-hydroxyl-2-oxo-1-pyrrolidineacetamide. More specifically, the present invention relates to a process for the preparation in high yields of optically pure 4-hydroxy-2-oxo-1-pyrrolidineacetamide of high purity by opening the epoxy ring of chiral epichlorohydrin 3-Chloro-2-hydroxypropionitrile is obtained and the resulting product is reacted with an alcohol containing hydrogen chloride gas to give 4-chloro-3-hydroxybutyrate, which is then reacted with glycinamide or subsequently with glycinate and ammonia. Background technique [0002] 4-Hydroxy-2-oxo-1-pyrrolidineacetamide (commercially known as "oxyracetam") represented by formula 1 is a drug used as a brain function enhancer or for alleviating dementia such as Alzheimer's disease or cardiovascular drugs for multi-infarct dementia: [0003] Formula 1 [0004] [0005] where the asterisks represent chiral centers. [0006] In the sy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/273A61P25/28C07D207/26
CPCC07D207/273A61P25/28A01F12/54A01F12/48
Inventor 金成镇林青雨夫昌镇吴贞薰金起贤李在宽元德权
Owner AHN GOOK PHARMA CO LTD
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