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Preparation method of citicoline sodium

A technology of citicoline sodium and phosphorylcholine chloride, which is applied in the field of biopharmaceuticals, can solve the problems of separation of difficult condensation agents and unsuitable products for medical use, and achieve the effects of easy removal, simple operation and high purity

Inactive Publication Date: 2016-11-23
陈建峰
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Technical problem to be solved by the present invention: Aiming at the problem that the product in the current chemical synthesis of citicoline sodium is difficult to separate from the condensing agent, resulting in a product that is not suitable for medicinal use, a preparation method of citicoline sodium is provided. The present invention Using phosphoric acid choline chloride calcium salt as raw material, first remove the crystal water in phosphoric acid choline chloride calcium salt by binary azeotropy with benzene, and then react phosphoric acid choline calcium salt with sodium carbonate to generate carbonic acid Calcium precipitation, filtration, to obtain viscous, react the viscous with acetyl chloride, react the product with cytidylic acid, and distill under reduced pressure to obtain the residue, finally crystallize and recrystallize with sodium hydroxide and ethanol to obtain the product, The invention has simple operation, acetyl chloride is easy to remove after adding water, and all solvents can be recycled, which is more environmentally friendly and has higher economic benefits. The product of the invention has a high purity of more than 98%, and is suitable for medicinal use

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0017] First, measure 200mL of benzene and add it to a three-necked flask with a splitter and a thermometer, place it in an oil bath, add 10g calcium phosphoric acid choline chloride to the three-necked flask, control the temperature of the oil bath at 120°C, and stir magnetically for 30 minutes. Obtain the phosphoric acid choline chloride calcium salt benzene mixed solution; Add 100mL0.5mol / L sodium carbonate solution to the above-mentioned phosphoric acid choline chloride calcium salt benzene mixed solution, magnetic stirring reaction 2h, produce white precipitate, filter, the filtrate is reduced pressure distillation to obtain a viscous substance; the above viscous substance was added to a three-necked flask equipped with a thermometer and a reflux condensing device, and placed in an oil bath, and 300mL tetrahydrofuran and 3g acetyl chloride were sequentially added to the three-necked flask, and the oil bath was controlled. Temperature at 75°C, magnetic stirring for 2 hours,...

example 2

[0020]First, measure 250 mL of benzene and add it to a three-necked flask with a splitter and a thermometer, place it in an oil bath, add 15 g of calcium phosphoric acid choline chloride to the three-necked flask, control the temperature of the oil bath at 125 ° C, and stir magnetically for 35 minutes. Obtain the phosphoric acid choline chloride calcium salt benzene mixed solution; Add 150mL0.5mol / L sodium carbonate solution to the above-mentioned phosphoric acid choline chloride calcium salt benzene mixed solution, magnetic stirring reaction 2.5h, produce white precipitate, filter, and filtrate Distill under reduced pressure to obtain a viscous substance; add the above viscous substance to a three-necked flask equipped with a thermometer and a reflux condensing device, and place it in an oil bath, and then add 350mL tetrahydrofuran and 4g acetyl chloride to the three-necked flask successively to control oil The bath temperature is 80°C, magnetically stirred for 2.5 hours, then...

example 3

[0023] First, measure 300 mL of benzene and add it to a three-necked flask with a splitter and a thermometer, place it in an oil bath, add 20 g of calcium phosphoric acid choline chloride to the three-necked flask, control the temperature of the oil bath at 130 ° C, and stir magnetically for 40 minutes. Obtain the phosphoric acid choline chloride calcium salt benzene mixed solution; Add 200mL0.5mol / L sodium carbonate solution to the above-mentioned phosphoric acid choline chloride calcium salt benzene mixed solution, magnetic stirring reaction 3h, produce white precipitate, filter, the filtrate is reduced pressure distillation to obtain a viscous substance; the above viscous substance was added to a three-necked flask equipped with a thermometer and a reflux condensing device, and placed in an oil bath, and 400mL tetrahydrofuran and 5g acetyl chloride were sequentially added to the three-necked flask, and the oil bath was controlled. Temperature at 85°C, magnetic stirring for 3...

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Abstract

The invention discloses a preparation method of citicoline sodium, and belongs to the technical field of biopharmacy. The preparation method comprises the steps that phosphorylcholine chloride calcium salt serving as a raw material and benzene are subjected to cbinary azeotrope to remove crystallization water in phosphorylcholine chloride calcium salt; phosphorylcholine chloride calcium salt reacts with sodium carbonate to generate a calcium carbonate precipitate, and filtering is conducted to obtain viscous materials; the viscous materials react with acetylchloride, a product reacts with cytidine monophosphate, and reduced pressure distillation is conducted to obtain residues; crystallization and recrystallizzation are conducted through sodium hydroxide and ethyl alcohol to obtain the product. According to the preparation method, operation is easy, acetylchloride is easy to remove by adding water, all the solvents can be recycled, better environmental friendliness and higher economic benefits are achieved, the purity of the product is high and reaches 98%, and the product is suitable for pharmaceutical purposes.

Description

technical field [0001] The invention relates to a preparation method of citicoline sodium, belonging to the technical field of biopharmaceuticals. Background technique [0002] Citicoline sodium, also known as citicoline sodium, is an activator of brain metabolism. As an intermediate in the endogenous synthesis of phosphatidylcholine, it can promote the synthesis of phospholipids in nerve cell membranes, and phospholipids are also important components for building biological membranes. After the central nervous system is injured, citicoline sodium participates in the repair and regeneration, plays a neuroprotective role, and also plays an important role in the transfer of nerve mediators and the conduction of bioelectricity. Citicoline sodium is mainly used clinically for head trauma and brain surgery accompanied by disturbance of consciousness, acute disturbance of consciousness in cerebral infarction, promoting the recovery of upper limb function in patients with stroke an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/02
CPCC07H19/10C07H1/02
Inventor 陈建峰孟浩影
Owner 陈建峰
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