Method for synthesizing citicoline sodium

Abstract

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.

Description

technical field [0001] The invention belongs to the field of pharmaceutical intermediates, in particular to a method for synthesizing citicoline sodium. Background technique [0002] Citicoline sodium, chemical name: monosodium salt of choline cytidine diphosphate, CAS number: 33818-15-4, molecular formula is C 14 h 25 N 4 NaO 11 P 2 , is a pyrimidine nucleoside derivative, which can be used to treat disturbance of consciousness after head trauma or brain surgery, and to promote the recovery of upper limb motor function in patients with stroke and hemiplegia. It has a certain effect on promoting the recovery of some brain functions . The methods currently reported in the literature are as follows: [0003] In 1971, Kiyomi Kikugawa and others reported that cytidylic acid and phosphorylcholine chloride were used as raw materials to synthesize citicoline sodium under the action of p-toluenesulfonyl chloride. During the reaction, a large amount of p-toluenesulfonyl chlorid...

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Problems solved by technology

The reaction conditions are relatively mild and the yield is moderate, but the post-treatment using 6 equivalents of DCI in the reaction process is cumbersome and the cost of raw materials is relatively expensive

[0005] In 2016, Xia Ran et al. reported the method of synthesizing citicoline sodium through cytidylic acid monomorpholine and calcium phosphorylcholine chloride, which synthesized cytidylic acid and dichlorophosphorylmorpholine under the action of alkali and catalyst. Monomorpholine nucleotide, obtain morpholine cytidylate with better selectivity and yield, then react with calcium phosphoric acid choline chloride to obtain citicoline sodium, the method uses morpholine cytidylic acid and phosphoric acid choline chloride Alkali reaction to obtain citicoline sodium, after the reaction is completed, an equivalent amount of morpholine hydrochloride waste will be produced, and the atom economy is poor

[0006] In 2019, Ren Yan Na et al. reported that genetically engineered living cells enhanced phosphorylcholine cytidyltransferase and choline overexpression kinase in living cells, thereby enhancing the choline conversion pathway and improving the biosynthesis of CDP-choline Base, this study provides a new paradigm for the biological production of CDP-choline in living cells, this method is currently only used in the laboratory research stage, and cannot be used for large-scale industrial production

[0007] Although the above methods can realize the synthesis of citicoline sodium, there are still unfavorable factors affecting industrialization such as complicated reaction operations, difficult access to biological enzymes, and large amounts of three wastes.

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