JPS60109596A - Production of cytidine 5'-diphosphocholine - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a drug for the recovery from the obnubilation and functional disorder, etc. caused by cerebral lesion, ecomonically in an industrial scale, by reacting cytidine phosphate with morpholino-oxo- dioxa-phosphorane in the presence of trimethylamine. CONSTITUTION:The objective compound can be produced by reacting (A) cytidine-5'-phosphate with (B) 2-morpholino-2-oxo-1,3,2-dioxa-phosphorane in the presence of (C) trimethylamine, in a polar organic solvent (preferably DMF, dimethylacetamide, etc.) or a mixture of the solvent and water, preferably at 80-120 deg.C for 5-20hr. EFFECT:It can be produced at a low cost with simple reaction operation.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an industrially advantageous method for producing cytidine-5'-syrine j1 macholine (hereinafter abbreviated as CDP-choline).

CDP-Choline consciousness and analysis during brain trauma: 11 eyesight disorder J, W
It is a useful medicine used for the recovery of the following, and various methods for its production are known. For example, '(1), cytidine-5'-
Method of condensing phosphoric acid (hereinafter abbreviated as 5'-CMP) and phosphorylcholine (Sho and Kosho 35 13024, 4)
6-37594. 4.6-21588 etc.), (2
), a method of reacting an activated derivative of 5' CNIP with phosphorylcholine (Japanese Patent Publication No. 4.2-1884゜1ji 4.
8-2101 etc.), (8), l of phosphorylcholine
Internalization 4 Dosho 4 5 - 4+ 7 4 7, 52-1611
5, etc.), (4.) Cytidine-5'-syrine I Requires Ethanolamine *', ABM Method (Special Publication 1989-65)
41 etc.) are known. However, these methods require the use of interesting reagents9, reaction media, and poor yields9.
This method has two or more disadvantages, and it is difficult to say that it is always an advantageous method in terms of engineering and Y.

The present inventors have discovered the drawbacks of such conventional methods.

CJ) is inexpensive, requires only 1711 reaction steps, and is industrially advantageous.
As a result of intensive research aimed at establishing a manufacturing method for P-choline, 5'
-CMI) and 2-morpholino-2-oxo-1.

8,2-diogizaphosphorane (hereinafter referred to as M 0 1) O
(abbreviated as P) in the presence of trimethylamine f Example 1
By tHi, the desired C1) can be obtained with good yield.
It was discovered that P-choline could be obtained and the present invention was completed.

That is, according to the present invention, 5'-CMP is one of the key points in the condensation reaction of amidates.
Regarding the solubility and reactivity of CM I) in solvents, there are known techniques such as 1, for example, as seen in Japanese Patent Publication No. 474.7 of 1983, using organic amine salts such as 5'-CMPf nitrate-n-butylamine salts. However, the present invention has the drawbacks of using limited orthochlorophenol as a solvent, 4A4I (, 4A4I), and the use of a special solvent. We were able to completely solve the problem of solubility in solvents.At the same time, by using MODOP one more time as a starting material, the high reactivity of amidates was maintained, and the presence of trimethylamine instantly converted CDP-choline. It has become possible to manufacture the desired product using an extremely simple method of conversion.

On the other hand, it is known that phosphorylcholine morphoresort can be produced by reacting MODOP with trimethylamine (for example, in the Special Publication (1979-94650)), but under the reaction conditions of this known technique, 5'- Even in the presence of CMPi, the reaction did not proceed.

The target CDP-choline was not obtained.

In addition, the reaction solution carried out by the method of the present invention was
When opened (detected with developing solvent Et 01-1: 0.5 M ammonium acetate = 2:l, ToB reagent), host 1J Ruco 9F was found. Phosphorylcholine mole 7 tridate is generated from this and trimethylamine, and C is formed from this n and 5'-CMP.
1) A reaction in which P-choline is produced (, MOT) OP
CDP from 5'-CMP and trimethylamine at once.
-This shows that choline is produced.The present invention will be explained in more detail. The starting material MODOP is a known compound that is easy to produce (Literature example: 'lh.

0bshch Khim. 36 928( 196(
5)).

The reaction is carried out in a bath medium in the presence of trimethylamine. The trimethylamine used is not only a base of 4, but also
5'-CMP) can also be used for the reaction as a trimethylamine base. Any solvent that does not inhibit the reaction may be used as a solvent, and suitable examples include polar organic solvents such as dimethylformamide, dimethylacetamide, formamide, dimethyl sulfoxide, dioxane, ethanol, and methanol, and mixed solvents of these and water. Can be mentioned.

The reaction temperature was slightly elevated. It is applied from 50°C to the boiling point of the solvent, preferably from 80°C to 12.0°C. A reaction time of 5 to 20 hours is sufficient. The separation of the target product from the reaction mixture is not limited to any particular method. For example, after the completion of 9 reactions, water is added. The target product was adsorbed through an anion exchange resin, and then eluted with a dilute formic acid aqueous solution, and the CDP-choline fraction was collected. # The target product can be easily obtained by condensation drying.

The present invention will now be described in detail with reference to Examples.

Example 1 81 nl of dimethylformamide, 1 tnl of water! ．． A mixed solvent of 2 and 5'-
〇MPlf, 1 ml of 80% trimethylamine water bath solution.

MODOPo. 7f was added in this order. The sealed reaction flask was stirred at 100"C for 12IIi'1'. After the reaction was completed, water was added and applied to a Diade Ion 5A11B (3, manufactured by Kasei Corporation: formic acid type) column. Water washing stage L1.UI
Bathe with M formic acid and collect the CDP-choline fraction Ol:,%
CDP-
Choline 1.15f was obtained.

This compound gives a single ultraviolet absorption gap at the same position as the floating product in F paper 1b, pneumatic excitation, infrared absorption spectrum, and single nuclear magnetic field. The spectrum completely matched the standard.

Example 2 CDP-choline 1.12 was ionized in the same manner as in Example 1 except that dimethylformamide was replaced with dimethylacetamide 8me.Example 8 A mixed solvent of ethanol 8-1 water 1me Then place the 5'-CMPlr into a pressure-resistant glass flask.

30'A) Limethylamine aqueous solution, MOL) (JP
o and 7f were added in this order. 8 sealed reaction flasks
The mixture was stirred at 0°C for 20 hours. Thereafter, by processing in the same manner as in Example 1, CD1)-choline 08 was obtained.

Example 4 8 ml of dimethylformamide, 1.2 f, M, 0 D of 5'-CMP)limethylamine salt in a combined bath medium of γ1
OPO,? Add f sequentially and heat to 100℃l 211. 11
1 stir. The following treatment was carried out in the same manner as in Example 1.

CDP-choline 0.87 was obtained.

Patent applicant: Kojin Co., Ltd.

Claims (1)

[Claims] Cytidine-5'-phosphorus IM1. React with 2-morpholino-2-oxo-1,3,2-dioxaphosphorane in the presence of wotrimethylamine in a 7-carbon organic bath medium or a mixed solvent of a polar organic solvent and water. Cytidine-5' characterized by
-Process for producing choline syphosphate.