Preparation method of L-alpha-glycerophosphoryl choline

A technology of glycerophosphocholine and chlorinated glycerophosphorylcholine benzyl ether, which is applied in the field of preparation of chiral drugs, can solve the problems of low yield, uneven impurity composition, large waste water discharge, etc., and achieve high yield , the effect of good product purity

Active Publication Date: 2013-09-18
上海科利生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned extraction of L-α-GPC from natural substances has the following problems: due to the great differences in the sources of raw materials, and the uneven distribution of impurity components, the subsequent separation and purification process is complicated and complicated, resulting in unstable product quality, and the operation process is complicated. , leading to high industrial production costs
[0007] But the shortcoming of this method is: (1) raw material D-glycerol acetonide fork raw material is expensive, should not obtain
(2) The process is complicated, the discharge of wastewater is large, and the environment is polluted
(3) The yield is low, less than 50%
Due to the side reaction of self-polymerization of glycidol during the reaction process, the impurities produced are also difficult to remove

Method used

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  • Preparation method of L-alpha-glycerophosphoryl choline
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  • Preparation method of L-alpha-glycerophosphoryl choline

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Preparation of (S)-Benzyl Glycidyl Ether

[0039]

[0040] Take 324.4 grams (3mol) of benzyl alcohol and 60 grams (1.5mol) of sodium hydroxide, put them into a 500ml reaction bottle, stir and heat to 60-70°C, then add 92.5 grams of (R)-epichlorohydrin (1mol) dropwise, Control the reaction temperature around 65°C. After about 2 hours of dripping, keep the reaction at 60-70°C for 12 hours, and gas chromatography detects that the raw material (R)-epichlorohydrin has completely reacted. Cool to room temperature, adjust the pH value to 6-7 with dilute hydrochloric acid, and filter. The filtrate was washed with water (300mlX2). After separating the water layer, dry it overnight with anhydrous sodium sulfate, filter, collect the filtrate to vacuum distill excess benzyl alcohol, and then high vacuum distill the product (S)-benzyl glycidyl ether 130.5 g, the yield of this step is 80%.

Embodiment 2

[0042] Preparation of L-α-Glycerophosphocholine Benzyl Ether Chloride

[0043]

[0044] 146 g (0.5 mol) of phosphorylcholine chloride and 500 ml of absolute ethanol were heated under reflux until completely dissolved. Then 82 g (0.5 mol) of (S)-benzyl glycidyl ether was added dropwise. About 1.5 to 2 hours to drop. The reflux reaction was continued for 18 hours, and the reaction of (S)-benzyl glycidyl ether was detected by TLC to be complete. Atmospheric distillation recovers ethanol solvent. A colorless oil was obtained, which was directly put into the next reaction without further purification.

Embodiment 3

[0046] Preparation of L-α-Glycerophosphocholine Chloride

[0047]

[0048]The product from the previous step was transferred to a high-pressure reactor, 800 ml of ethanol, 20 g of 10% Pd / C catalyst were added, and high-pressure hydrogen was fed to 10 atmospheres. The reaction was closed and stirred for 24 hours until no hydrogen was absorbed. Open the hydrogen valve to release the hydrogen slowly. The reaction solution was filtered, and the ethanol solvent was recovered by normal pressure distillation to dryness, then 500 ml of ethanol was added, and the normal pressure distillation was again to dryness. A colorless oil was obtained. Then 400 ml of absolute ethanol and 100 ml of isopropanol were added and stirred at 0-3° C. for 20 hours to slowly crystallize. Filter and wash the filter cake with a small amount of ethanol. After vacuum drying, 113.6 g of the product was obtained, and the two-step yield was 78%.

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Abstract

The invention relates to a preparation method of L-alpha-glycerophosphoryl choline. The preparation method comprises the following steps of: firstly, condensing (R)-epoxy chloropropane with benzyl alcohol in the presence of strong base to prepare (S)-benzyl glycidyl ether; then enabling the (S)-benzyl glycidyl ether to react with choline phosphate chloride to obtain L-alpha-choline phosphate chloride benzyl ether; then removing the benzyl protection radial from the obtained L-alpha-choline phosphate chloride benzyl ether by Pd / C hydrogenation reaction, purifying, so as to obtain the L-alpha-glycerophosphoryl choline (GPC) finally. By adopting the cheap and easily available chiral epoxy chloropropane as the original raw material, the side reaction is avoided; and furthermore, the purity of product is good and the yield is high.

Description

technical field [0001] The invention belongs to the field of preparation of chiral drugs, in particular to a preparation method of L-alpha-glycerophosphocholine. Background technique [0002] L-α-Glycerophosphoryl Choline (L-α-GPC for short) is a naturally occurring water-soluble phospholipid metabolite in the body and a choline source for the synthesis of acetylcholine and phosphatidylcholine. Health function and medical application value. L-α-GPC can improve the cognitive ability of the brain, and even repair the partially damaged cognitive ability of patients with early senile dementia, and can protect liver tissue from toxic carbon tetrachloride and high-fat protein foods. The produced fatty acid penetrates, has anti-hyperlipidemia, protects blood vessels, and can promote the growth of adolescents and improve memory ability, so it is widely used in medicine, health products and functional foods. The chemical structural formula of L-α-GPC is as follows: [0003] [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/09
Inventor 李海林王世运张建现陈林张爱强
Owner 上海科利生物医药有限公司
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