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Citicoline and synthetic method thereof

A technology of citicoline and its synthesis method, which is applied in the new field of synthesis of pharmaceutical molecules, and can solve problems such as affecting product quality, difficult separation, and difficult removal

Inactive Publication Date: 2016-07-06
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 process of synthesizing cytidylic acid with phosphorus oxychloride, the selectivity of phosphorus oxychloride and 5 ' hydroxyl reaction is poor, also can react with 2 ' hydroxyl, 3 ' hydroxyl simultaneously, cause yield Low, difficult to separate and other issues
In the reaction of cytidylic acid and morpholine, the poisonous DCC is used. After the reaction, DCC becomes dialkylurea, which is very difficult to remove, and finally remains in the citicoline product, affecting the quality of the product.

Method used

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  • Citicoline and synthetic method thereof
  • Citicoline and synthetic method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0017] Add dichloromethane (50mL) into the three-necked flask, add phosphorus oxychloride (1.8mL, 20mmol), cool down to 0-5°C, add dropwise morpholine (2.6mL, 30mmol), and control the dropping time at 30min Within a period of time, the dropwise addition was completed, the temperature was raised, and the temperature was kept at room temperature (25-30° C.), and the stirring reaction was continued for 2 h. Atmospheric pressure distills out dichloromethane, and then fractionates under reduced pressure to collect distillates with a boiling range of 124-126°C (1.33KPa) to obtain phosphoromorpholine dichloride.

[0018] Add cytidine (10g, 41.1mmol) into a three-necked flask, add solvent (50mL), stir, cool down to 0-5°C, add dichlorophosphorylmorpholine (10.0g, 49.3mmol) dropwise, and dropwise The time is within 30 minutes, the dropwise addition is completed, the temperature is raised, and the temperature is kept at room temperature (25-30° C.), and the reaction is continued to stir ...

Embodiment 2

[0021] Add 5'-phosphorylmorpholinocytidine (500 g, 1.3 mol) to methanol (2 L), add calcium phosphorylcholine chloride (370 g, 1.5 mol), add 0.13 mol of sulfuric acid, and keep the temperature at room temperature ~ 60 Any temperature between ℃, stirred and reacted for 15h, distilled off the solvent under reduced pressure, and the condensed product of 5'-phosphorylmorpholinocytidine and calcium phosphorylcholine chloride was dissolved in 1L of absolute ethanol under reflux, Cool down naturally, gradually add 200mL of water dropwise to the solution, citicoline can be precipitated. The preparation of the 5'-phosphorylmorpholinocytidine is the same as in Example 1.

Embodiment 3

[0023] Add cytidine (100g, 0.4mol) into a three-necked flask, add pyridine (500mL), stir, cool down to 0-5°C, add dichlorophosphorylmorpholine (100g, 0.5mol) dropwise, and control the dropping time The dropwise addition was completed within 30 minutes, the temperature was raised, and the temperature was kept at room temperature (25-30° C.), and the stirring reaction was continued for 2 hours. After the reaction was completed, 500 mL of saturated aqueous sodium bicarbonate solution was added and stirred for 20 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 recrystallized from absolute ethanol to obtain 5'-phosphorylmorpholinocytidine as a white solid.

[0024]Add 5'-phosphorylmorpholinocytidine (500 g, 1.3 mol) to methanol (2 L), add calcium phosphorylcholine chloride (370 g, 1.5 mol), add 0.13 mol of sulfuric acid, and keep t...

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Abstract

The invention discloses citicoline and a synthetic method thereof.The synthetic method includes subjecting cheap and easily available cytidine, serving as a raw material, and dichlorophosphoryl morpholine to condensation at a 5' position highly selectively so as to obtain 5'-phosphorylmorpholinylcytidine; subjecting the 5'-phosphorylmorpholinylcytidine and phosphocholine chloride calcium to condensation in solvents so as to obtain the citicoline.Total yield is up to 58% only by the two steps.The synthetic method is cheap in and easily available to raw materials, expensive cytidine monophosphate is unused, operation steps are simplified, and reaction scale can be expanded to synthesize 500 g of citicoline.The synthetic method has a potential application prospect by providing a novel citicoline synthetic route.

Description

technical field [0001] The invention relates to a new synthesis method of medical molecules, in particular to citicoline and its synthesis method. 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 traumatic brain injury and postoperative coma Parkinson's syndrome, and also treat tardive movement disorder, neurological deafness and tinnitus, cerebrovascular disease and cerebellar and spinocerebellar ataxia. It has considerable curative effect on sequelae of stroke and Parkinson's syndrome. [0003] The chemical synthesis method of citicoline reported in the literature mainly uses cytidylic acid as a raw material, and reacts wi...

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 夏然孙莉萍陈磊山苗超林
Owner XINXIANG UNIV
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