JPS6043079B2 - Method for producing choline cytidine diphosphate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an industrially advantageous method for producing choline cytidine diphosphate.

Cytidine diphosphate choline (hereinafter abbreviated as CDP choline) is a useful drug used for recovery of consciousness and functional impairment caused by brain trauma.

[Margins below] Various methods for producing CDP choline are known, for example, activated derivatives of cytidine-5'-phosphate (hereinafter abbreviated as 5'-CMP), such as 5'-C
A method of reacting MP amidate with phosphorylcholine (Japanese Patent Publication No. 42-1384, Japanese Patent Publication No. 46-2101, etc.),
A method of reacting 5'-CMP with an activated derivative of phosphorylcholine, such as phosphorylcholine amidate or phosphorylcholine chloridate (Japanese Patent Publication No. 45-474
7, Special Publication No. 52-161 [etc.], etc. are known.

However, these methods have disadvantages in that the reaction operations are complicated and the yield of the target product is low because they use highly hygroscopic and unstable amidate or chloridate as raw materials. moreover,
5'-CMP amidate is prepared from 5'-CMP, and phosphorylcholine amidate is usually prepared from phosphorylcholine calcium chloride, which requires a large number of steps and cannot be said to be an industrially advantageous method. On the other hand, 5'-
As a method for condensing CMP and phosphorylcholine,
A method of reacting 5'-CMP and phosphorylcholine in trichloroacetonitrile (Japanese Patent Publication No. 1983-1985),
A method of reacting 5'-CMP and phosphorylcholine in the presence of a condensing agent (Japanese Patent Publication No. 35-13024, Japanese Patent Publication No. 46-37
594, Japanese Patent Publication No. 46-18990, etc.), a method of reacting 5'-CMP and a halogenated phosphorylcholine metal salt in the presence of synchhexylcarposiimide (Japanese Patent Publication No. 50-3
7672, Special Publication No. 51-2863), etc. are known. However, regarding the former two, phosphorylcholine or phosphorylcholine chloride is an amorphous solid and has extremely unstable hygroscopicity, so these methods require complicated operations and have low yields of the target product. Although the latter method has somewhat improved the above-mentioned drawbacks, it uses an expensive condensing agent, the yield is not sufficient, and the operations are complicated, such as the need to separate the synchlohexyl urea produced in post-treatment. , which is not advantageous as an industrial manufacturing method. [Margins below] As a result of intensive research to develop a simple and industrially advantageous production method that does not have these drawbacks, the present inventors found that 5'-CMP and halogenated phosphorylcholine metal salts were combined into a sample of SO2CI ( In the formula, R represents a phenyl group or a phenyl group substituted with 1 to 3 lower alkyl groups) by carrying out the reaction in excess molar amount relative to the halogenated phosphorylcholine metal salt, the reaction can be carried out very easily and favorably. The present inventors have discovered that CDP choline can be produced in high yield and that fractionation of the target product can be easily carried out by conventional methods, leading to the completion of the present invention.

That is, according to the present invention, 5-CMP and a halogenated phosphorylcholine metal salt are reacted in the presence of a compound represented by the formula RSO2CI (wherein R is the same as above) in a molar excess relative to the halogenated phosphorylcholine metal salt. Accordingly, CDP choline can be produced.

Examples of the halogenated phosphorylcholine metal salts used in the present invention include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, etc. is preferably carried out at about 2 to 4 times the molar amount.

On the other hand, examples of compounds represented by the formula RSO2CI (wherein R is the same as above) include benzenesulfonyl chloride, baratoluenesulfonyl chloride, triisopropylbenzenesulfonyl chloride, mesitylenesulfonyl chloride, etc. The amount may be about 15 times or more, preferably about 2 to 5 times the molar amount of the phosphorylcholine metal salt. The reaction is carried out in the presence of a solvent, and suitable examples include formamide, dimethylformamide, pyridine, or a mixed solvent thereof, and amines such as triethylamine, tripropylamine, and tributylamine may also be added. A reaction temperature of about 0 to 70°C and a reaction time of 3 to 3 hours are sufficient. The target product may be isolated from the reaction mixture by a conventional method.

For example, after adding water to the reaction mixture to decompose the condensing agent, it is passed through an anion exchange resin to cause poor adsorption of the target product, then eluted with a dilute aqueous formic acid solution to collect the CDP choline fraction, and concentrated and dried to easily obtain the target product. can do. The present invention will be described in detail below with reference to Examples. Example 14
6.09 ml of valatoluenesulfonyl chloride was added to 10 ml of dimethylformamide, and then 2.6 V of phosphorylcholine calcium chloride was added while stirring, and the mixture was heated to 40'C.

Next, 5''-CMPly was added and stirred at 40°C for 1 hour. After the reaction was completed, ice water was added, the pH was adjusted to 9.5 with aqueous ammonia, and the mixture was applied to an anion exchange resin Dowex 1×2 (formic acid type) column manufactured by Dow Chemical Company. .0.005 after washing with water
When eluted with M formic acid, CDP choline was eluted first, so this fraction was collected and concentrated, and ethanol was added to the residue to obtain 0.7y of CDP choline. ) This compound gave a single ultraviolet absorption image at the same position as the standard CDP choline in Fuchishi electrophoresis, and the infrared absorption spectrum and nuclear magnetic resonance spectrum completely matched those of the standard.

Example 2 3 g of balatoluenesulfonyl chloride was added to 15 ml of pyridine, and then 2.6 y of phosphorylcholine calcium chloride was added with stirring, and the mixture was heated to 40°C.

Then valatoluenesulfonyl chloride 4y,5″-C
MPlg was added and the mixture was stirred at room temperature for 3 minutes. Thereafter, the same treatment as in Example 1 was carried out to obtain CDP choline 1.2y. Example 3
Add 7y of benzenesulfonyl chloride to 15ml of pyridine, and then add 2y of phosphorylcholine calcium chloride while stirring.
．． 6g was added and heated to 40°C.

Next, 5''-CMPly was added and stirred at 40°C for 1 hour.
I got f. Example 4 5 mt of pyridine and 5 mt of valatoluenesulfonyl chloride
．． 5y was added thereto, and then 2.5y of phosphorylcholine sodium chloride was added with stirring, and the mixture was heated to 40°C.

Next, 5''-CMPly was added and stirred at 40°C for 1 hour.
I got it. Example 5 To 15 ml of dimethylformamide was added 3 ml of tri-n-butylamine and 7.5 y of balatoluenesulfonyl chloride, and then 2 ml of phosphorylcholine calcium chloride was added under stirring.
．． 6q was added and heated to 40°C.

Claims (1)

[Claims] 1. Cytidine-5'-phosphoric acid and a halogenated phosphorylcholine metal salt are combined in a molar amount of 2 to 5 times that of the halogenated phosphorylcholine metal salt with the general formula RSO_2Cl (in the formula, R is a phenyl group, substituted with 1 to 3 lower alkyl groups) A method for producing choline cytidine diphosphate, characterized in that the reaction is carried out in the presence of a compound represented by (representing a phenyl group).