JPS5826893A - Preparation of phosphorylcholine compound - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as a raw material for the preparation of a remedy for obnubilation, under mild reaction conditions, with little side reactions, in high yield, by phosphorylating the easily available and easily handleable choline with phosphorus oxychloride in the presence of water and an organic solvent. CONSTITUTION:A phosphorylcholine compound can be prepared by phosphorylating a choline compound with phosphorus oxychloride in the presence of water and an organic solvent (e.g. chloroform, dichloroethane, etc.). The reaction is carried out by using the choline or its salt (e.g. an inorganic salt such as chloride, bicarbonate etc.) in the form of an aqueous solution, and using phosphorus oxychloride in an amount of >=0.5 times (as shown in the formula (3)), preferably >=1 times (as shown in formulas (1) and (2)) based on water. It is supposed that the reaction product of phosphorus oxychloride with water reacts with the choline compound, and accordingly, the reaction proceeds mildly. The use of organic solvent makes the homogeneous reaction system even by the use of an organic solvent which is insoluble in water, and accelerates the reaction. The objective compound can be easily separated by the present method.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention is a book regarding a novel method for producing phosphorylcholines.

Phosphorylcholine is an important substance as a raw material for choline cytidine syphosphate, which is used as a treatment for consciousness disorders.

Conventionally, the following methods are known as methods for producing phosphorylcholines.

fl) A method for reacting diphenylphosphoryl monochloride with choline chloride in water (J-Am.

Chem, Soc, Volume 69 (1947), No. 125
3 negative].

(2) A method of heating anhydrous choline or anhydrous choline chloride with birophosphoric acid, polyphosphoric acid, etc. at 150° C. under reduced pressure (Heilv, Chim.

Acta, Vol. 42 (1959), p. 1154].

(3) A method of reacting anhydrous choline with phosphorus oxychloride (Japanese Patent Publication No. 47-32970).

(4) Anhydrous a: Method of reacting phosphorus with orthophosphoric acid or phosphorus-producing inorganic salt (% Kaisho 52-113924
However, these conventional methods have problems in terms of safety or cost, and because they require the use of anhydrous choline, which is difficult to handle, they are not industrially advantageous.

In view of this background, the present inventors have conducted extensive research with the aim of developing an industrially advantageous method for producing phosphorylcholines, and have completed the present invention. That is, the gist of the present invention resides in a method for producing phosphorylcholines, which is characterized by phosphorylating cholines with phosphorus oxychloride in the presence of water and an organic solvent.

The present invention will be explained in detail below.

As the raw material choline in the method of the present invention, choline or its salts such as cyclized products, inorganic salts such as hydrogen carbonate, or organic acid salts such as dihydrogen citrate and hydrogen tartrate are used. can be used in the form of a water bath solution.

For example, choline chloride is widely commercially available in the form of a 75% aqueous solution, and can be used as is in the method of the present invention. However, if the amount of water relative to choline is large, a large amount of phosphorus oxychloride is necessarily required. Therefore, it is not economically advantageous. That is, in the method of the present invention, it is thought that phosphorus oxychloride and water react as described below, and the resulting product reacts with cholines.

-2HC1cl c1 The amount of phosphorus oxychloride is required to be at least 1 mole relative to choline, but when purines are used as an aqueous solution, it is necessary to increase the amount appropriately depending on the amount of water. That is, the amount of phosphorus oxychloride to be used, expressed as a molar ratio to water, is <0.5 times or more as shown in equation (3), preferably (11, (2
It is more than 1 times as large as the formula 1.

As described above, in this reaction, it is thought that the reaction product of phosphorus oxychloride and water reacts with choline, and therefore, the reaction can proceed mildly. Furthermore, by using an organic solvent, even if an organic solvent that is not uniformly soluble in water is used, the reaction system becomes a uniform solution, making it extremely easy to react.
It may be a mild reaction. Therefore, there are few side reactions, and the target product can be obtained in high yield.

As the organic solvent used in the method of the present invention, any general organic solvent that does not have an adverse effect on this reaction can be used. Examples include aromatic hydrocarbons such as xylene, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile, esters such as trimethylphosphoric acid, and nitro compounds such as nitromethane. Particularly preferred are chloroform and dichloroethane. , toluene.

Further, in the method of the present invention, when phosphorylating cholines in phosphorus oxychloride, water, and an organic solvent, a base such as pyridine may be mixed.

The reaction temperature is preferably carried out within the range of -10 to 120°C, with Fi 15 to 80°C being particularly preferred.

The phosphorylcholines produced by the method of the present invention have conventionally been
It can be easily isolated from the reaction solution by commonly known methods. For example, after the reaction, the reaction temperature medium is distilled off under reduced pressure, water is added to the residue to dissolve it, water is added to the reaction solution to separate the reaction solution, or the reaction solvent is extracted with an appropriate organic solvent.
After removal, the aqueous solution is processed. That is, the aqueous solution thus obtained is treated with an alkali hydroxide, such as NaOH,
KOH, LiOH, Ca(OH)z = Mg(OH
)z tBa(OH)z or alkali carbonate e.g. Na2
2 Cog * L i 2 CO3 to Cog +,
Neutralize with BILCO3, etc., add an organic solvent such as methanol or acetone if necessary, and take the precipitated inorganic phosphorus M from house to house. Then, concentrate the F solution or add methanol, ethanol, acetone, etc. as it is. By adding an organic solvent, the metal-resistant phosphorylcholines are precipitated,
Separate.

As described above, according to the method of the present invention, an aqueous solution of cholines that is generally commercially available, easily available, and easy to handle can be used, and phosphorylcholines can be obtained in high yield through a mild reaction. The industrial significance of this is extremely large.

Next, examples of the method of the present invention will be described.

Example 1 - 180 wj of dichloroethane and 160 g of phosphorus oxychloride were mixed, and 9.5 d of water was added dropwise while cooling.

To this mixture was added 4ON of 75th choline chloride (aqueous solution), and the mixture was stirred at 20° C. for about 15 hours. 150 mL of water was added to this, and the solvent was separated and removed to obtain an aqueous solution of phosphorylcholine chloride. This solution was adjusted to pH 10 with calcium hydroxide,
After the precipitated calcium phosphate was collected from each household, methanol was added to the solution, and the precipitates were collected from each household and dried to obtain calcium salt 49.6 II of phosphorylcholine chloride.

Yield is 70%.

In addition, in the above example, dichloroethane was not used and the other treatments were the same, but the reaction was very slow and the yield was about 10%.
It was just a chi.

Even when water-insoluble dichloroethane is used in the above examples, the reaction system remains uniformly in the form of a solution. Although the effect of the organic solvent used is not clear, it is clear from the above comparative examples that it has the effect of accelerating the reaction and increasing the yield.

Example 2 26.8 g of pyridine, 5 Qa of chloroform and 53.7 Ii of phosphorus oxychloride were mixed, and while cooling, 3
．． 3- was added dropwise. Add 75% choline chloride 13 to this mixture.
．． 3 II was added and stirred at 20° C. for about 7 hours.

Thereafter, the same treatment as in Example 1 was carried out to obtain 17.7fi of the calcium salt of phosphorylcholine chloride. The yield was 75%.

Example 3 Toluene 150111/and phosphorus oxychloride 128. 5 l of water was added dropwise while cooling. This mixture contains 75% choline chloride 40I! and about 6 at 50℃.
Stir for hours. Thereafter, the same treatment as in Example 1 was performed.

However, by using barium hydroxide instead of calcium hydroxide, the barium salt of phosphorylcholine chloride 54.6jl
I got it. The yield was 65 cm.

Example 4 180 w1 of dichloroethane and 49 g of phosphorus oxychloride were mixed, and while cooling, 369 g of 85% choline chloride was added.
The mixture was stirred at 0°C for about 6 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain 42.8 g of calcium salt of phosphorylcholine chloride. The yield was 60 cm.

As explained above, the part given in Example 4 is related to a typical illustration to help understanding of the present invention, and it is not a failure #y4
is not limited to these examples, and other modifications may be made within the gist of the invention.

Claims (1)

[Claims] A method for producing phosphorylcholines, which comprises phosphorylating cholines with phosphorus oxychloride in the presence of water and an organic solvent.