Process for preparing citicoline sodium

A technology of citicoline sodium and phosphorylcholine, which is applied in the field of preparation of citicoline sodium, can solve the problems of high synthesis price, difficult condensation agent separation, and unsuitable products for medicinal use, and achieve high enzyme activation and reduce Adsorption capacity, effect of cost reduction

Active Publication Date: 2007-04-11
苏州正济药业有限公司
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Problems solved by technology

[0003] At present, the methods for preparing citicoline sodium include: 1. chemical synthesis, utilizing CMP (5'-cytidylic acid) and phosphorylcholine as reactants, and p-toluenesulfonyl chloride as condensation agent, in N-dimethylformamide Preparing by condensation in the presence of 717 (Cl - ) type anion exchange column and 711 (Cl - ) type concentrated column separation liquid alcohol precipitation to prepare citicoline sodium, its disadvantage is that it is difficult to separate from the condensing agent, and the product is not suitable for medicinal use; Alkali biosynthesis of citicoline sodium, the synthesis of enzymes and cell extracts requires the substrate CTP, and the synthesis price is high; ③ free cells and yeast cell-free extracts synthesize citicoline sodium, and the synthesis of free yeast requires a large amount of yeast, and Can only be used once and has many disadvantages

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[0031] The main reaction formula of the preparation method of Citicoline Sodium of the present invention is as shown in Figure 1. The present invention uses yeast enzyme as the reaction carrier, and uses 5'-cytidylic acid, phosphorylcholine, potassium hydroxide, and glucose as the main raw materials to carry out the production mode of biotransformation, uses activated carbon as the adsorption carrier, and uses Cl - Type ion exchange resin is used as the separation carrier for extraction and separation. The acidic pH is used as the adsorption condition, and the pH is between 2 and 6 for adsorption. The compound reagent with alcohol is used as the analysis reagent to extract and separate the analysis solution, and the alcohol solvent is used as the crystallization solvent to refine the finished product. As shown in Figure 2, the preparation method of citicoline sodium includes the following steps: ① Mix yeast, glucose, potassium hydroxide, phosphorylcholine, 5′-cytidylic acid an...

Embodiment 1

[0035] Mix 30 kg of quick-frozen yeast, 3 kg of phosphorylcholine, 1 kg of 5′-cytidylic acid, 10 kg of glucose, 2 kg of potassium hydroxide, and 800 kg of water, then adjust the temperature to 25°C, pH=6, and perform 65 rpm Stir the reaction for 6 hours to make it fully react; raise the temperature of the reaction solution to 50°C to inactivate, and perform liquid-solid separation; adjust the pH to 8.0, precipitate some basic proteins and nucleic acids, perform liquid-solid separation, and then adjust the pH to 2.5, Precipitate the acidic protein, carry out liquid-solid separation, and separate the precipitate; use activated carbon to adsorb and separate, PH=2.5, and wash with pure water; use ethanol alkali-soluble reagent for elution, and the eluate is desalted and decolorized, and the liquid is collected; wash Deliquification and vacuum concentration; add 2 times ethanol to the concentrated solution, crystallize, and separate the liquid and solid to obtain the crude product; ...

Embodiment 2

[0037] Mix 80 kg of quick-frozen yeast, 4 kg of phosphorylcholine, 4 kg of 5′-cytidylic acid, 16 kg of glucose, 4 kg of potassium hydroxide, and 1100 kg of water, adjust the temperature to 30°C, and add 0.5 kg of MgSO 4 Solution, PH=6, carry out stirring reaction at 120 rpm for 8 hours to make it fully react; heat the reaction solution to 70°C to inactivate, and carry out liquid-solid separation; adjust PH=10, part of the basic protein and nucleic acid precipitation, carry out Solid separation, and then adjust PH=4 to precipitate acidic protein, carry out liquid-solid separation, and separate precipitate; use activated carbon for adsorption separation, PH=4, wash with pure water; elute with ethanol alkaline reagent, eluent Carry out desalting and decolorization treatment, collect the liquid; eluate is concentrated in vacuum; add 2 times methanol to the concentrated solution, crystallize, and separate the liquid and solid to obtain the crude product; dissolve the crude product, ...

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Abstract

The present invention is process of preparing citicoline sodium. The preparation process includes the biotransformation of material including 5'-cytidylate, phosphorylcholine, potassium hydroxide and glucose with yeast as the biocatalyst; extraction and separation with active carbon as the adsorbing carrier, Cl- type ion exchange resin as the separating carrier and re-compounded water-alcohol mixture as the analyzing reagent; and product purification with alcohol solvent as the crystallizing solvent. Compared with available technology, the present invention has the advantages of high product yield and high product purity.

Description

technical field [0001] The invention relates to a method for preparing citicoline sodium, belonging to the technical field of biopharmaceuticals. Background technique [0002] Citicoline Sodium, also known as Citicoline, is an activator of brain metabolism, which can promote the synthesis of phospholipids in nerve cell membranes. It has the functions of repairing brain damage, resisting hypoxia, improving memory, and enhancing intelligence. It is widely used in clinical practice. . Therefore, the preparation method of citicoline sodium is a research subject that people are more concerned about. [0003] At present, the methods for preparing citicoline sodium include: 1. chemical synthesis, utilizing CMP (5'-cytidylic acid) and phosphorylcholine as reactants, and p-toluenesulfonyl chloride as condensation agent, in N-dimethylformamide Preparing by condensation in the presence of 717 (Cl - ) type anion exchange column and 711 (Cl - ) type concentrated column separation liq...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P19/30C12R1/85
Inventor 徐仁华徐敏郁其平
Owner 苏州正济药业有限公司
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