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Citicoline and synthesizing method of citicoline not using phosphocholine chloride calcium

A technology of phosphorylcholine chloride and citicoline, applied in chemical instruments and methods, organic chemistry, preparation of sugar derivatives, etc., can solve problems such as affecting product quality, environmental pollution, and difficulty in removal

Inactive Publication Date: 2016-06-22
XINXIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The problem that this method exists is: in the reaction of cytidylic acid and morpholine, uses the DCC that has poison, after the reaction DCC becomes dialkyl urea, is very difficult to remove, finally remains in citicoline product, affect the quality of the product
Simultaneously, calcium phosphorylcholine chloride is used in the last step, and its synthesis produces a large amount of environmental pollution

Method used

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  • Citicoline and synthesizing method of citicoline not using phosphocholine chloride calcium
  • Citicoline and synthesizing method of citicoline not using phosphocholine chloride calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Add phosphoromorpholine dichloride (2.04g, 10mmol) into a three-necked flask, add triethylamine (3.45mL, 25mmol) and acetonitrile (50mL), stir, cool to 0-5°C, add ethylene glycol dropwise (0.62g, 10mmol), raise the temperature, keep the temperature at room temperature (25-30°C), and continue stirring for 2h. After the reaction, add saturated sodium bicarbonate solution (50 mL) and water, and stir for 10 minutes to consume excess dichlorophosphorylmorpholine. After suction filtration, the filtrate was collected, and the solvent was distilled off under reduced pressure to obtain a light yellow oily substance, namely ethylene glycol ester phosphoromorpholine, with a yield of 92%.

[0016] Add cytidylic acid (4.11g, 10mmol) to methanol (50mL), add ethylene glycol ester phosphoromorpholine (2.30g, 12mmol), add methanol (5mL) saturated with HCl gas, stir at room temperature for 10h, reduce The solvent was distilled off under pressure to obtain a light yellow oil, which was r...

Embodiment 2

[0019] Add phosphoromorpholine dichloride (500g, 2.5mol) into the reaction flask, add triethylamine (0.86L, 6.25mol) and acetonitrile (2L), stir, cool to 0-5°C, add ethylene glycol dropwise (155g, 2.5mol), raise the temperature, keep the temperature at room temperature (25-30°C), and continue stirring for 6h. After the reaction, add saturated sodium bicarbonate solution (1 L) and water, and stir for 30 minutes to consume excess dichlorophosphorylmorpholine. Suction filtration, the filtrate was collected, and the solvent was distilled off under reduced pressure to obtain a light yellow oil, which was azeotroped twice by adding toluene (100 mL) to remove residual hydrogen chloride, which was ethylene glycol ester phosphoromorpholine, with a yield of 90%.

[0020] Cytidylic acid (500g, 1.22mol) was added to methanol (1.5L), ethylene glycol ester phosphoromorpholine (281g, 1.46mol) was added, methanol (200mL) saturated with HCl gas was added, and the reaction was stirred at room t...

Embodiment 3

[0023] A method for synthesizing citicoline without phosphorylcholine calcium chloride, using dichlorophosphorylmorpholine as raw material, reacting with ethylene glycol to obtain ethylene glycol ester phosphoromorpholine; and then directly reacting with cytidine Condensation of glycosidic acid to obtain ethylene glycol ester phosphoryl cytidylic acid (5); finally, tributylamine ring-opens the ethylene glycol ester of ethylene glycol ester phosphoryl cytidylic acid to obtain citicoline.

[0024] The raw material dichlorophosphorylmorpholine of the method is cheap and easy to obtain, does not need DCC and calcium phosphorylcholine chloride, and obtains citicoline through three steps and a total yield of 78%. The reaction conditions are mild. And when the reaction scale is enlarged to 500g scale, the yield does not decrease. The application of the present invention provides a synthesis method for the synthesis of citicoline without using calcium phosphorylcholine chloride, whic...

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Abstract

The invention discloses a method for synthesizing citicoline and citicoline without using calcium phosphorylcholine chloride. Acylmorpholine is used as raw material, reacts with ethylene glycol to obtain ethylene glycol ester phosphoromorpholine, and then directly condenses with cytidylic acid to obtain ethylene glycol ester phosphoryl cytidylic acid, and finally tributylamine to ethylene glycol ester The ethylene glycol ester of phosphoromorpholine is ring-opened to give citicoline. There are three steps in the reaction, and the total yield is 78%. The method has cheap and easy-to-obtain raw materials, avoids the use of expensive and toxic DCC and calcium phosphorylcholine chloride, and the yield does not decrease significantly when the reaction scale is expanded to a scale of 500 g. The application of the present invention provides a new synthesis route for the synthesis of citicoline, and has potential application prospects.

Description

technical field [0001] The invention relates to a new synthesis method of medical molecules, in particular to a synthesis method of citicoline and citicoline without using phosphoric choline calcium chloride. Background technique [0002] Citicoline (CDP-choline, 1) is an important intermediate product in the biosynthesis of lecithin, an important component of the cell membrane. At the same time, it is also an important nucleic acid drug, which can improve the state of consciousness, regulate the tension of cerebrovascular movement, and improve the metabolic function of the brain. Clinically, it can treat craniocerebral trauma and postoperative coma Parkinson's syndrome, and can also treat tardive movement disorder, neurological deafness and tinnitus, cerebrovascular diseases and cerebellar and spinocerebellar ataxia. It has considerable curative effect on sequelae of stroke and Parkinson's syndrome. [0003] From the perspective of chemical structure, citicoline contains ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/00
CPCC07H19/10C07H1/00
Inventor 夏然陈磊山孙莉萍王艳
Owner XINXIANG UNIV
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