Citicoline drug preparation and its new application of consciousness disorder in acute stage of cerebral infarction

A technology for citicoline and citicoline sodium, which is applied in the field of preparation of citicoline, can solve the problems of incomplete reaction of raw materials, side reactions, and high cost, and can solve the problems of post-processing difficulties and reaction conditions. Mild, reduced complexity effects

Active Publication Date: 2020-12-08
广东金城金素制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 1. Using calcium phosphoric acid choline chloride as the starting material, dehydration needs to be carried out with benzene, a class 1 solvent. The process is complicated, and at the same time, it will bring benzene solvent residue, which is not conducive to the production of subsequent preparations;
[0007] 2. A large amount of acid waste water and waste salts such as calcium carbonate and sodium chloride are produced during the synthesis process, and the environmental protection treatment is difficult. solvent-like), the production has high requirements on the corrosion resistance of the equipment, and the cost is high;
[0008] 3. The intermediates treated with acetyl chloride and solid phosgene are highly active substances, which are prone to side reactions, resulting in incomplete reaction of raw materials, low yield and low product content

Method used

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  • Citicoline drug preparation and its new application of consciousness disorder in acute stage of cerebral infarction
  • Citicoline drug preparation and its new application of consciousness disorder in acute stage of cerebral infarction
  • Citicoline drug preparation and its new application of consciousness disorder in acute stage of cerebral infarction

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preparation example Construction

[0046] Specifically, the present invention provides a kind of preparation method of citicoline sodium or its composition, described method comprises the following steps:

[0047] Step 1: Combine 5'-cytidylic acid and phosphorylcholine chloride (C 5 h 15 ClNO 4 P) Disperse in an aprotic organic solvent, add 1-propyl phosphoric acid cyclic anhydride (T 3 P) reaction, filter out the insolubles in the reaction solution, collect the filtrate;

[0048] Step 2: cooling the filtrate in step 1, separating out crystals, and filtering to obtain citicoline;

[0049] Step 3: Citicoline acid reacts with sodium base / salt to generate citicoline sodium, which is citicoline.

[0050] The synthetic route schematic diagram of the present invention is as follows:

[0051]

[0052] In step 1, the added 1-propyl phosphoric acid cyclic anhydride acts as a condensing agent to condense the 5'-cytidylic acid and phosphorylcholine chloride dispersed in the aprotic organic solvent. The activation...

Embodiment 1

[0129] Preparation of Citicoline Sodium:

[0130] Add 50g of 5'-cytidylic acid, 500ml of acetonitrile, and 36g of phosphorylcholine chloride into the reaction flask, start stirring, add 52g of 1-propylphosphoric acid cyclic anhydride at a rate of 2.0ml / min at 25°C, and stir after adding After 1 hour, the temperature was raised to reflux of the reaction system, and after 3 hours of reflux reaction, the temperature of the reaction system was lowered to 55°C and filtered while hot, and the filtrate was collected;

[0131] The filtrate was naturally cooled to 25°C, a large amount of crystals were precipitated, and citicoline acid was obtained by filtration, and the filtrate was applied to the next batch;

[0132] Dissolve the collected citicoline acid in 1000ml of purified water, raise the temperature to 35°C and stir to dissolve, then add sodium bicarbonate to adjust the pH value to 7.5. Cool the solution to 10°C, keep it warm for 45 minutes, and collect citicoline sodium by fil...

Embodiment 2

[0136] Preparation of Citicoline Sodium:

[0137] Add 50 g of 5'-cytidylic acid, 500 ml of acetonitrile, and 34.5 g of phosphorylcholine chloride into the reaction flask, start stirring, add 49.5 g of 1-propyl phosphoric acid cyclic anhydride at a rate of 1.5 ml / min at 30°C, and add After stirring for 0.75 hours, the temperature was raised to reflux of the reaction system, and after 5 hours of reflux reaction, the temperature of the reaction system was lowered to 60°C and filtered while it was hot, and the filtrate was collected;

[0138] The filtrate was cooled to 15°C, a large number of crystals were precipitated, and citicoline acid was obtained by filtration, and the filtrate was applied to the next batch;

[0139] Dissolve the collected citicoline acid in 1000ml of purified water, raise the temperature to 40°C and stir to dissolve, then add sodium bicarbonate to adjust the pH value to 7. Cool the solution to 10°C, keep it warm for 60 minutes, and collect citicoline sodiu...

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Abstract

The invention provides citicoline sodium or a composition thereof which contains the citicoline sodium with the content being 99.0 percent or above and application of the citicoline sodium or the composition in disturbance of consciousness in the acute period of cerebral infarction and further provides a preparation method of the citicoline sodium or the composition thereof. The preparation methodcomprises the following steps: dispersing 5'-cytidine monophosphate and phosphorylcholine chloride in an aprotic organic solvent, adding 1-propylphosphoric acid cyclic anhydride for reaction, filtering insoluble substances in a reaction liquid, and collecting a filtrate; cooling the filtrate, enabling crystals to precipitate, and performing filtering to obtain the citicoline acid; and performingreaction on the citicoline acid and the sodium alkali / salt to produce the citicoline sodium. For the preparation method provided by the invention, by selecting a suitable raw material and condensing agent, use of a large quantity of strong acidic condensing agents and highly toxic solvents, including pyridine and benzene, in a traditional chemical method process is avoided, and the quality of a product is improved.

Description

technical field [0001] The present invention relates to a preparation of citicoline, in particular to a preparation method of citicoline with short synthesis process route and high product quality, a citicoline pharmaceutical preparation and its use in the acute stage of cerebral infarction. New uses in obstacles. Background technique [0002] Citicoline (Citicoline Sodium or Citicoline Sodium) is an activator of brain metabolism, which can promote brain cell respiration, improve brain function, enhance the function of the ascending reticular structure activation system, promote wake-up, and reduce brain stress. Vascular resistance. The structural formula of citicoline is as follows: [0003] [0004] Citicoline is the most widely used nerve activator in clinical practice. At present, biological fermentation and chemical synthesis are commonly used to obtain citicoline. The biological fermentation method has a long fermentation period, low unit yield, complex component...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/10C07H1/00A61K31/7068A61P9/10A61P25/00A61P25/28
CPCA61P9/10A61P25/00A61P25/28C07H1/00C07H19/10
Inventor 马庆双傅苗青
Owner 广东金城金素制药有限公司
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