33818-15-4

Basic information

• Product Name: Citicoline sodium
• Synonyms: P'-[2-(TRIMETHYLAMMONIO)ETHYL]ESTER CYTIDINE 5'-(TRIHYDROGEN DIPHOSPHATE) INNER SALT MONOSODIUM;cytidine 5'-(trihydrogen diphosphate) p'-[2-(trimethylammonio)ethyl] ester inner salt monosodium salt;CYTIDINE-5'-DIPHOSPHOCHOLINE MONOSODIUM SALT;CYTIDINE-5'-DIPHOSPHOCHOLINE, NA;CYTIDINE-5'-DIPHOSPHOCHOLINE, SODIUM;CYTIDINE 5'-DIPHOSPHOCHOLINE SODIUM SALT;CYTIDINE 5'-DIPHOSPHOCHOLINE SODIUM SALT DIHYDRATE;CITICOLINE SODIUM SALT
• CAS NO: 33818-15-4
• Molecular Formula: C14H25N4NaO11P2
• Molecular Weight: 510.31
• EINECS: 251-689-1
• Product Categories: Miscellaneous Natural Products;Bases & Related Reagents;Heterocycles;Intermediates & Fine Chemicals;Nucleotides;Pharmaceuticals;Phosphorylating and Phosphitylating Agents;API
• Mol File: 33818-15-4.mol

Chemical Properties

• Melting Point: 259-268°C (dec.)
• Appearance: white/solid
• Storage Temp.: 2-8°C
• Solubility: H2O: 100mg/mL
• Water Solubility: Soluble in water (100 mg/ml).
• Merck: 13,2343
• BRN: 4110040
• CAS DataBase Reference: Citicoline sodium(CAS DataBase Reference)
• NIST Chemistry Reference: Citicoline sodium(33818-15-4)
• EPA Substance Registry System: Citicoline sodium(33818-15-4)

Safety Data

• Safety Statements: 24/25
• WGK Germany: 3
• F: 3-10-21
• Hazardous Substances Data: 33818-15-4(Hazardous Substances Data)

Usage

Uses

1. Used in Pharmaceutical Industry:
Citicoline sodium is used as a central nervous system medication for the treatment of acute traumatic brain injury, brain surgery, and disturbances of consciousness. It aids in the recovery of limb function in cases of paralysis due to stroke and is also used for other central nervous system disorders caused by acute injury, ischemic cerebrovascular disease, and vascular dementia.
2. Used in Neuroprotection:
Citicoline sodium acts as a neuroprotective agent in situations of hypoxia and ischemia, making it useful in the treatment of ischemic stroke and head trauma.
3. Used in Cognitive Enhancement:
Citicoline sodium is used to treat age-related memory loss, dementia, and other cognitive impairments. Research has shown that it increases the levels of phosphatidylcholine, which is essential for brain function, and might also decrease brain tissue damage when the brain is injured.
4. Used in Weight Management:
Citicoline sodium is used as a dietary supplement to help with weight management.
5. Used in Biochemical Research:
Citicoline sodium is used as a substrate for CDP (nucleoside diphosphate) kinase (2.7.4.6) to produce CTP, which supports DNA and RNA biosynthesis, and for ribonucleotide reductase to produce dCMP.
6. Used in the Synthesis of Membrane Phospholipids:
Citicoline sodium is an essential intermediate in the synthesis of phosphatidylcholine (PtdCho), the major phospholipid of cell membranes. It increases plasma adrenocorticotropic hormone (ACTH) levels and potentiates serum thyrotrophin (TSH) levels by activating the central cholinergic system.

Mechanism of action

Citicoline sodium can enhance the function of brain stem reticular formation, especially the ascending reticular activating system associated with human consciousness; enhance the function of the pyramidal system; inhibit the function of the external system of the cone, and promotes the recovery of the function of the system. For the treatment of sequelae of traumatic brain injury and cerebral vascular accident caused by the nervous system, it can also be used in the treatment of Parkinson's disease, senile dementia has a certain effect; for the treatment of cardiovascular and cerebrovascular diseases; it also have a certain effect for anti-aging, improving learning and memory.

Biochem/physiol Actions

Cytidine 5′-diphosphocholine (CDP-choline) plays an important role in the synthesis of phosphatidylcholine. It is also involved in the biosynthesis of acetylcholine, a neurotransmitter. CDP-choline has therapeutic effects against hypoxia, cerebral ischemia and traumatic brain injury. It also exhibits therapeutic effects against learning and memory disorders, drug addiction and Alzheimer′s and Parkinson′s diseases.

Safety

There are two forms of citicoline: citicoline sodium and citicoline free-base. Citicoline sodium is the form that is approved as a prescription medication in some European countries and throughout Asia. Citicoline free-base is the form that is available as a dietary supplement and food/beverage ingredient in the United States. In Europe, citicoline is approved as a Novel Food ingredient and is authorized to be used in food supplements up to 500 mg per day. It is also authorized to be used for Food for Special Medical Purposes (FSMPs) in amounts of 250 mg/serving and up to 1,000 mg per day.Citicoline free-base is produced in Japan by Kyowa Hakko Bio Co. Ltd. under the brand name of Cognizin. Cognizin is considered to be safe and received self-designated Generally Recognized As Safe (GRAS) status in 2009. In Europe, citicoline was approved as a Novel Food ingredient in 2014. Whereas most companies produce citicoline synthetically, Cognizin is produced using a patented, natural fermentation process. It is vegetarian and allergen-free. Kyowa Hakko manufactures and supplies Cognizin as a raw ingredient to many manufacturers around the world.

Metabolism

Citicoline can be administered orally, intramuscularly, or intravenously. Oral administration is most common because its bioavailability is approximately 92%. After oral ingestion, citicoline is hydrolyzed in the small intestine and liver into 2 major metabolites: cytidine and choline.Cytidine and choline enter the systemic circulation, where cytidine is further metabolized into uridine. Both uridine and free choline cross the blood-brain barrier. In the central nervous system, uridine is converted to cytidine triphosphate, choline is converted to phosphocholine, and the 2 combine to resynthesize CDP-choline.

Upstream product

• 1310-73-2 sodium hydroxide 
• 107-73-3 phosphorylcholine chloride 
• 30784-94-2 cytidine-5'-phosphodichloride 
• 63-37-6 cytidine monophosphate 
• 4826-71-5 phosphorylcholine chloride, calcium salt 
• 987-78-0 citicoline 
• 65062-75-1 O^2',O^3'-carbonyl-[5']cytidylic acid 

Relevant articles and documents

Efficient synthesis of cytidine diphosphate choline (CDP-choline) and its analogs

An efficient P(V)-N activation approach for the synthesis ofcytidine diphosphate choline (CDP-choline) and related ribo- and deoxyribonucleotide analogs has been established.

Method for synthesizing citicoline sodium

The invention discloses a method for synthesizing citicoline sodium, and belongs to the field of pharmaceutical intermediate nucleoside synthesis. Cytidine, phosphorus oxychloride and phosphorylcholine are used as raw materials, firstly, cytidine and phosphorus oxychloride are subjected to phosphorylation to obtain an intermediate, then the intermediate and phosphorylcholine are directly condensed without hydrolysis to obtain a condensation intermediate, finally, crude citicoline sodium is obtained through hydrolysis, and finished citicoline sodium is obtained through ion exchange resin treatment and refining. The HPLC purity of the finished product is more than 99.5%, the whole reaction only needs three steps, the reaction operation is simple, and the total yield reaches 80% or more.

Novel application of citicoline pharmaceutical preparation and cerebral infarction acute phase consciousness disorder thereof (by machine translation)

The invention also provides a method for preparing sodium metabieolin sodium or a, composition thereof, 99.0% wherein the method for preparing the sodium cyticoline sodium or the composition thereof comprises the following, steps of: uniformly dispersing the choline sodium and choline chloride in the aprotic organic solvent, in, an 5’ - aprotic organic solvent, 1 . (by machine translation)

Straightforward Ball-Milling Access to Dinucleoside 5′,5′-Polyphosphates via Phosphorimidazolide Intermediates

A solvent-assisted mechanochemical approach to access symmetrical and mixed dinucleoside 5,5′-polyphosphates is reported. Under ball-milling conditions, nucleoside 5′-monophosphates were quantitatively activated using 1,1′-carbonyldiimidazole, forming their phosphorimidazolide derivatives. The addition of a nucleoside 5′-mono-, di- or triphosphate directly led to the formation of the corresponding dinucleotides. Benefits of the reported one-pot method include the use of unprotected nucleotides in their sodium or acid form, activation by the eco-friendly 1,1′-carbonyldiimidazole, non-dry conditions, short reaction time, high conversion rates, and easy setup and purification. This work offers new perspectives for the synthesis of nucleotide conjugates and analogues, combining the phosphorimidazolide approach and milling conditions.

Preparation method of citicoline sodium

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.

CDP-Ethanolamine and CDP-Choline: One-pot synthesis and 31P NMR study

Herein we report a one-pot multi-step synthesis of the cofactors CDP-Ethanolamine and CDP-Choline starting from cytidine 5′-monophosphate and using commercially available and/or easily prepared reagents. While studying the 31P NMR spectrum of CDP-Ethanolamine, an unexpected characteristic for a pyrophosphate diester was observed as it showed a singlet or two doublets depending upon the pH. Therefore, further NMR studies were undertaken to investigate the pH dependence of the peak splitting pattern and measure the acid dissociation constants of the compounds.

A PROCESS FOR PREPARING PURE CITICOLINE (CDP-CHOLINE)

Disclosed herein is a process for preparing highly pure Citicoline (CDP-Choline) or sodium salt of Citicoline with the aid of dicarboxylic acid or its salts. The process of the present invention results in Citicoline with a purity of more than 99% measured by HPLC.

METHOD FOR PURIFICATION OF CYTIDINEDIPHOSPHORIC CHOLINE

A method of purifying cytidine diphosphate choline, which comprises contacting a cytidine diphosphate choline solution containing a nucleic acid analogue and having a pH of not less than 0.5 and not more than 5.0 with an H-type strongly acidic cation exchange resin, and eluting cytidine diphosphate choline adsorbed onto the resin with water or an aqueous solution having an ion concentration of not more than 0.1 mol/L to separate and purify the cytidine diphosphate choline.