A kind of preparation method of citicoline

A technology of citicoline and choline chloride, applied in the field of preparation of citicoline, can solve problems such as increased operation intensity, increased cost, complicated process, etc., and achieves improved utilization rate, less pollution and conversion efficiency high effect

Inactive Publication Date: 2011-12-07
NANJING TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Phosphorylcholine is formed by dehydration and condensation of choline chloride and anhydrous phosphoric acid under high temperature conditions, which increases the number of equipment, complicates the process, greatly increases the operating intensity, and increases the cost

Method used

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  • A kind of preparation method of citicoline
  • A kind of preparation method of citicoline
  • A kind of preparation method of citicoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Yeast medium (g / L): glucose 40, urea 2.0, potassium dihydrogen phosphate 1.5, magnesium sulfate heptahydrate 0.5, zinc sulfate heptahydrate 4.0×10 -3 , ferrous sulfate heptahydrate 3.0×10 -3 , manganese chloride tetrahydrate 0.3×10 -3 , anhydrous calcium chloride 1.0×10 -3 , Biotin 0.05×10 -3 . Saccharomyces cerevisiae inoculum was 10%, cultured on a shaker at 120 rpm at 30°C for 24 hours, and centrifuged at 4000 rpm for 20 minutes. Take the yeast paste and store it at -7°C for later use.

Embodiment 2

[0045] Embodiment 2: Using CMP and choline chloride as substrates and glucose as energy donor to prepare citicoline

[0046] In a reaction tank with a capacity of 15L, prepare 60mM choline chloride, 0.20M sodium dihydrogen phosphate, 30mM CMP, 0.3M glucose, 50mM magnesium sulfate, 1mM potassium chloride, 2mM cysteine, using Example 1 2800 grams of Saccharomyces cerevisiae mud, 10 grams of cetyltrimethylamine ammonium bromide and 10 L of reaction liquid cultured by the described method were used to adjust the pH to 6.8 with sodium hydroxide, and stirred at a low speed for 10 hours at 37 ° C. , after the reaction, centrifugal precipitation, supernatant is carried out citicoline quantitative analysis, contains citicoline 14.9 grams per liter in the conversion liquid, and the conversion rate of citicoline reaches 97.4% (mol meter) .

Embodiment 3

[0047] Example 3: Preparation of Citicoline with Cytidine and Choline Chloride as Substrates and Glucose as Energy Donor

[0048] In a reaction tank with a capacity of 15L, prepare 150mM choline chloride, 0.5M potassium dihydrogen phosphate, 50mM cytidine, 0.5M glucose, 2mM magnesium sulfate, 5mM mannitol, and utilize the method described in Example 1 to cultivate 2700g of baker's yeast puree, 10g of Triton X-100 and 12L of reaction liquid, adjust the pH to 6.0 with sodium hydroxide, and stir at 32°C for 15 hours at a low speed. Quantitative analysis of citicoline was carried out, the conversion liquid contained citicoline 22.95 g / liter, and the conversion rate of citicoline reached 90% (in mol).

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Abstract

The invention discloses a preparation method of citicoline, which uses choline chloride, phosphate ion and cytidine monophosphate or its precursor as substrates, and uses glucose, fructose, sucrose or maltose as energy donors. Add small molecular chemical effect substances, and use permeable yeast cells to catalyze the preparation of citicoline. The present invention establishes a metabolic network model and analyzes metabolic fluxes, adopts small molecular chemical effect substances to regulate metabolic fluxes, thereby improving energy self-coupling and choline phosphorylation efficiency, and utilizes permeable yeast cells to efficiently prepare citicholine Alkali, the concentration of the product is greatly increased, and the utilization rate of the substrate is also improved.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceuticals, and in particular relates to a preparation method of citicoline. Background technique [0002] Citicoline, also known as citicoline sodium, is an activator of brain metabolism, which can promote the synthesis of lecithin 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 synthesis technology of citicoline is a research subject that people are more concerned about. [0003] Compared with CMP, which can be produced and supplied cheaply, although it has been reported that citicoline has chemical synthesis, enzymatic and microbial conversion synthesis, etc., the first two methods are too expensive and are no longer used. At present, the commonly used method is the microbial transformation method, which is synthesized by microbial cell enzymes, but ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P19/30C12R1/645
Inventor 应汉杰熊健汤佳鹏张磊李振江柏建新欧阳平凯
Owner NANJING TECH UNIV
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