Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of optically active pure 1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone

A carbamoyl and pyrrolidone technology, applied in the field of drug synthesis, can solve the problems of low solubility of glycinamide hydrochloride, difficult to remove subsequent residues, troublesome product post-processing, etc., and achieves improved product purity, improved tailing, The effect of reducing production costs

Active Publication Date: 2016-08-03
HARBIN SANLIAN PHARMA CO LTD
View PDF6 Cites 9 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above preparation process is divided into (1) the free activation of glycinamide hydrochloride; (2) the condensation and cyclization of glycinamide and optically pure 4-halo-3-hydroxybutyrate; most of the literature reports All are to complete two-step reaction in ethanol system, and in fact, conventional inorganic base (sodium carbonate, salt of wormwood, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide) is all insoluble or Very slightly soluble, and the solubility of glycinamide hydrochloride itself in ethanol is not large, which causes the free reaction of glycinamide hydrochloride to be equivalent to the reaction of two solid phases, and the reaction efficiency is low; CN101723871 is obtained by adding phase Transfer catalysts are used to improve this situation to increase the reaction yield, but the usual phase transfer catalysts and products have excellent water solubility, and the subsequent residues are difficult to remove, which brings great trouble to the post-processing of the products

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of optically active pure 1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone
  • Preparation method of optically active pure 1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone
  • Preparation method of optically active pure 1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: Preparation of (S)-1-(carbamoyl)methyl-4-hydroxyl-2-pyrrolidone

[0032] Add sodium ethoxide / dehydrated ethanol solution [30.62g (0.45mol) / 500ml] into the three-necked flask, add 5.30g (0.05mol) of anhydrous sodium carbonate and 55.25g (0.50mol) of glycinamide hydrochloride, and stir at room temperature Evenly, heat up to reflux, keep reflux for 1h, add anhydrous sodium carbonate 53.00g (0.50mol) for the second time, stir and slowly add (S)-4-chloro-3-hydroxy-butyric acid ethyl ester 91.68g (0.55mol ), keep the reflux for about 20 hours.

[0033] Stop the reaction, filter out the inorganic salt while hot, and concentrate under reduced pressure to obtain a reddish-brown oily substance; add water to dissolve, wash with dichloromethane, and concentrate the aqueous phase under reduced pressure to obtain a reddish-brown oily substance;

[0034] Silica gel column chromatography, dichloromethane / methanol / ethanol system gradient elution (V / V / V=30 / 1~4 / 0~1), combin...

Embodiment 2

[0038] Example 2: Preparation of (R)-1-(carbamoyl)methyl-4-hydroxyl-2-pyrrolidone

[0039] Add potassium ethylate / absolute ethanol solution [29.45g (0.35mol) / 500ml] in the three-necked flask, add anhydrous potassium carbonate 20.73g (0.15mol) and glycinamide hydrochloride 55.25g (0.50mol), and stir at room temperature Evenly, heat up to reflux, keep reflux for 1h, add anhydrous potassium carbonate 103.65g (0.75mol) for the second time, stir and slowly add (R)-4-chloro-3-hydroxy-butyric acid ethyl ester 91.68g (0.55mol ), keep the reflux for about 20 hours.

[0040] After the reaction was completed, post-treatment was carried out in the same manner as in Example 1 to obtain 56.12 g of (R)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone, with a yield of 71.04%.

Embodiment 3

[0041] Example 3: Preparation of (S)-1-(carbamoyl)methyl-4-hydroxyl-2-pyrrolidone

[0042] Add sodium methoxide / anhydrous methanol solution [13.51g (0.25mol) / 500ml] into the three-necked flask, add 26.50g (0.25mol) of anhydrous sodium carbonate and 55.25g (0.50mol) of glycinamide hydrochloride, and stir at room temperature Evenly, heat up to reflux, keep reflux for 1h, add anhydrous sodium carbonate 66.25g (0.625mol) for the second time, stir and slowly add (S)-4-chloro-3-hydroxy-butyric acid ethyl ester 91.68g (0.55mol ), keep the reflux for about 26 hours.

[0043] After the reaction was completed, post-treatment was carried out in the same manner as in Example 1 to obtain 53.01 g of (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone, with a yield of 67.01%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to a preparation method of optically active pure 1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone. According to the method, optically active pure 4-halo-3-hydroxybutyrate and glycinamide hydrochloride are used as raw materials to synthesize optically active pure 1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone. By mixed bases feeding improved synthetic reaction, preparative silica gel packed column chromatography and gradient elution improved refining technology, the optically active pure 1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone product with its purity being greater than or equal to 99.5% can be obtained without recrystallization. In addition, yield is high, technological conditions are stable and controllable, operation is safe, simple and convenient, and three industrial wastes hardly exist. The preparation method is suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method for optically pure 1-(carbamoyl)methyl-4-hydroxyl-2-pyrrolidone. Background technique [0002] The common name of 1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone is Oxiracetam, which is a kind of pyrrolidone (cyclic GABOB) derivative and a drug for improving brain metabolism. 1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone is a racemate composed of two enantiomers, the left-handed (S) and the right-handed (R). [0003] Recently, there have been many studies on the synthesis methods of optically pure 1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone at home and abroad, especially the synthesis of L-(S)-1-(carbamoyl)methyl-4- Studies on the Synthesis of Hydroxy-2-Pyrrolidone. [0004] [0005] The synthesis methods provided by the methods of documents US2007 / 0185337A1 and WO2005 / 115978A1 all use (S)-4-halogenated-3-hydroxybutyric acid or its derivatives in alkaline conditi...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/273
Inventor 陈仲强金京龙吕敏李泉何勤王萍萍
Owner HARBIN SANLIAN PHARMA CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com