JP3419028B2 - Method for producing phosphorylcholine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a phosphorylcholine derivative, and more particularly to a method for producing a phosphorylcholine derivative which is a phospholipid-like monomer having the same structure as a polar group of a phospholipid.

[0002]

2. Description of the Related Art Phospholipids are widely present in the biological world and are one of the main components constituting biological membranes. Some of the phospholipid-like monomers having the same structure as the polar group of the phospholipid have already been synthesized, and for example, a phosphorylcholine derivative, 2- (methacryloyloxy) ethyl-2 '-(trimethylammonium) The following method has been proposed for producing ethyl phosphate.

1) Phosphorus oxychloride is reacted with ethylene bromhydrin, and the obtained 2-bromoethyl phosphoryl dichloride is reacted with 2-hydroxyethyl methacrylate in an inert solvent in the presence of a tertiary base, and then hydrolyzed. Decompose. Next, a method of reacting the obtained 2-methacryloyloxyethyl-2-bromoethyl hydrogen phosphate with trimethylamine (JP-A-54-630)
No. 25). 2) After reacting phosphorus oxychloride with ethylene glycol in a cyclic manner and oxidizing with oxygen, in the presence of a tertiary base,
React with 2-hydroxyethyl methacrylate. A method of reacting the obtained 2- (2-oxo-1,3,2-dioxaphosphoryl) ethyl methacrylate with trimethylamine (JP-A-58-15491, JP-A-63-59391).
-222183, WO92 / 07885).

[0004] However, all of these conventional methods use a malodor control method in the final reaction to prevent malodorous substances (age 1).
The use of the toxic trimethylamine specified in Article 6) poses a problem in that the health of workers may be harmed, and there is a problem that the equipment and laws are greatly restricted. From such a point of view, in the case where a phosphorylcholine derivative is produced on a practical scale using trimethylamine as a raw material, the above-described conventional method cannot be said to be satisfactory at present.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above problems by using other harmless bases without using trimethylamine, and safely and efficiently.
In addition, it is an object of the present invention to propose a method for producing a phosphorylcholine derivative which can easily produce a phosphorylcholine derivative as a phospholipid-like monomer.

[0006]

According to the present invention, there is provided a compound represented by the general formula (1):

Embedded image [In the formula (1), X ¹ and X ² are a halogen atom, Y ⁻ is an anion, R ¹ , R ² and R ³ are a hydrogen atom or carbon atom 1
And represents alkyl groups 4 to 4. X ¹ and X ² , and R ^{1 to} R ³ may be the same or different. A halogenated phosphorylcholine derivative represented by the general formula (2):

Embedded image [Wherein A is a linear or branched alkylene group, m
And n is 0 or 1, and R ⁴ is a hydrogen atom or a methyl group. Is reacted with an acrylic acid derivative represented by the formula (1) in the presence or absence of a base while removing generated hydrogen halide, and then reacting the obtained reaction product with water to hydrolyze the product. General formula (3) characterized by

Embedded image [(3) In the formula, R ¹ , R ² and R ³ are a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ⁴ is a hydrogen atom or a methyl group, A is a linear or branched alkylene group, m and n Represents 0 or 1. R ^{1 to} R ³ may be the same or different. ] The method for producing a phosphorylcholine derivative represented by the formula:

The alkyl group represented by R ^{1 to} R ³ in the general formula (1) or (3) has 1 to 1 carbon atoms such as a methyl group, an ethyl group, a propyl group, an n-butyl group and an iso-butyl group. And 4 alkyl groups. ^Three of R ^{1 to} R ³ may be the same, three may be different,
Two may be the same.

The halogen atom represented by X ¹ or X ² in the general formula (1) includes fluorine, chlorine , bromine and iodine. Of these, chlorine and iodine are preferred. X ¹ and X ² may be the same or different.

[0009] Y in the general formula (1) ^- as an anion represented by a chlorine ion, a halogen ion such as iodide ion and a bromine ion, an acetate ion, bicarbonate ion, tartrate ion, etc. hydroxide ion and the like .

Specific examples of the halogenated phosphorylcholine derivative represented by the general formula (1) include 2-chloro chloride.
(Trimethylammonium) ethyl-dichlorophosphate, 2- (triethylammonium) ethyl iodide
Dichlorophosphate, 2- (dimethylethylammonium) ethyl chloride-dichlorophosphate, 2-chloride
(Tripropylammonium) ethyl-dibromophosphate, 2- (tributylammonium) ethyl-diiodophosphate, iodide chloride, 2-ammoniumethyl-dichlorophosphate and the like.

Such phosphorylcholine halide derivatives are known in the art by reacting phosphorus oxychloride (phosphoryl trichloride) with a corresponding ammonium compound such as 2-hydroxyethyltrimethylammonium chloride or 2-hydroxyethyltriethylammonium iodide. (Eg, Biomaterials, 198)
6, Vol. 7, March, 121-124).

The alkylene group represented by A in the general formula (2) or (3) includes a linear alkylene group having 1 to 4 carbon atoms such as a methylene group, an ethylene group, a trimethylene group, and a tetramethylene group; Examples thereof include a branched alkylene group having 3 to 4 carbon atoms such as a 1-methyltrimethylene group, a 2-methyltrimethylene group, an ethylethylene group, and a dimethylethylene group.

Specific examples of the acrylic acid derivative represented by the general formula (2) include 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate,
3-hydroxypropyl methacrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl acrylate, 2-hydroxybutyl methacrylate, 3-hydroxybutyl methacrylate, 4-hydroxybutyl methacrylate, 2-hydroxybutyl acrylate, 3- Examples thereof include hydroxybutyl acrylate, 4-hydroxybutyl acrylate, methacrylic acid, and acrylic acid.

Specific examples of the phosphorylcholine derivative represented by the general formula (3) include 2- (methacryloyloxy) ethyl-2 '-(trimethylammonium).
Ethyl phosphate, 2- (acryloyloxy) ethyl-2 '-(triethylammonium) ethyl phosphate, 3- (methacryloyloxy) propyl-2'-
(Trimethylammonium) ethyl phosphate, 3-
(Acryloyloxy) propyl-2 '-(methyldiethylammonium) ethylphosphate, 2-methyl-
3- (acryloyloxy) propyl-2 '-(trimethylammonium) ethyl phosphate, methacryloyl-2'-(triethylammonium) ethyl phosphate, acryloyl-2 '-(trimethylammonium) ethyl phosphate, 2- (methacryloyloxy) ethyl- 2'-ammonium ethyl phosphate,
2- (acryloyloxy) ethyl-2'-ammonium ethyl phosphate and the like.

The phosphorylcholine derivative represented by the general formula (3) can be obtained by converting the halogenated phosphorylcholine derivative represented by the general formula (1) and the acrylic acid derivative represented by the general formula (2) in the presence or absence of a base. The reaction product is produced by removing the generated hydrogen halide and reacting the obtained product with water to hydrolyze the product. As a method of removing hydrogen halide generated during the reaction, a method of removing by reacting with a base present in the reaction system or a method in which an inert gas is passed through the reaction solution in the absence of a base to outside the system. , A method combining these, and other methods. When the above reaction is performed using triethylamine as a base, the reaction is represented by the following reaction formula.

[0016]

Embedded image

The halogenated phosphorylcholine derivative represented by the general formula (1) and the acrylic acid derivative represented by the general formula (2) are in a molar ratio of halogenated phosphorylcholine derivative: acrylic acid derivative of 1: 0.1 to 1:10, Preferably, the reaction is performed at a ratio of 1: 0.8 to 1: 3.

Examples of the base that can be used in the reaction include tertiary amines such as triethylamine and pyridine, and sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like. Inorganic bases; solid bases such as ion exchange resins; Even if trimethylamine is used, the reaction proceeds, but since trimethylamine has a bad smell and is harmful, it is preferable to use another base. In the above reaction, since these bases and hydrogen halide generated with the progress of the reaction form a salt, the hydrogen halide is removed from the reaction system, the reaction further proceeds, and the reaction efficiency increases. .

The amount of the base used is 0.1 to 10 mol, preferably 0.5 to 3 mol, per 1 mol of the halogenated phosphorylcholine derivative. Even when a base is used, an inert gas may be passed to discharge the hydrogen halide out of the system. In this case, the reaction can be carried out using a smaller amount of the base than the amount of the base used.

[0020] The reaction of said even in the absence of a base, by passing an inert gas, by removing the resulting halogen hydrogen, can be carried out efficiently. When the reaction is carried out in the absence of a base, it is desirable that the amount of the inert gas passed is 0.1 to 20 times the amount of the generated hydrogen halide.

The reaction can be carried out by mixing a phosphorylcholine derivative, an acrylic acid derivative and a base in a reaction medium. When the inert gas is passed, the phosphorylcholine halide derivative and the acrylic acid derivative and, if necessary, the base are mixed in the reaction medium, and the inert gas can be passed through the mixture (reaction liquid). .

As the above-mentioned reaction medium, a medium such as an organic solvent which is inactive against the halogenated phosphorylcholine derivative can be used. Since the acrylic acid derivative dissolves in an ordinary organic solvent, when such a medium is used, the phosphorylcholine halide derivative may or may not be dissolved in the medium. A solvent in which both are not dissolved is not suitable as a reaction medium. As a reaction medium, chloroform, methylene chloride, benzene and the like can be preferably used.

The reaction conditions are such that the reaction temperature is -50 to +50.
° C, preferably -20 to + 30 ° C, a reaction time of 30 minutes to 7 hours, preferably 2 to 4 hours, and a reaction pressure of 0 to 20.
kgf / cm ² G, preferably it is desirable to 0~5kgf / cm ² G.

Then, the desired phosphorylcholine derivative is obtained by adding water to the reaction product produced by the above reaction and reacting the resultant, followed by hydrolysis. Water is preferably added to the reaction solution without separating the reaction product from the reaction solution, but may be added after separation. When water is added to the reaction solution, the salt formed from the base and the hydrogen halide is preferably removed by filtration or the like.
By adding water, the unreacted halogen atom bonded to the phosphorus atom in the reaction product, that is, the halogen atom X derived from the halogenated phosphorylcholine derivative is hydrolyzed to obtain the desired product.

The amount of water used is desirably 1 mol or more, preferably 1 to 5 mol, per mol of the halogenated phosphorylcholine derivative. The hydrolysis conditions are desirably a temperature of -50 to + 50 ° C, preferably -20 to + 30 ° C, and a time of 30 minutes to 7 hours, preferably 2 to 4 hours.

After completion of the hydrolysis, the target phosphorylcholine derivative is obtained by removing the base and the reaction medium. Thereafter, the purity can be improved by further performing purification using an ion-exchange resin, silica gel, alumina oxide, or the like, or purification using a difference in solubility in a solvent.

The phosphorylcholine derivative thus obtained has polymerizability, and as a phospholipid-like monomer, in addition to medical materials such as catheters, artificial organs and blood circuits,
It can be used as a raw material for contact lenses, cosmetics, water-absorbing agents, diagnostics, biosensors, etc.

[0028]

As described above, according to the method for producing a phosphorylcholine derivative of the present invention, the halogenated phosphorylcholine derivative represented by the general formula (1) is reacted with the acrylic acid derivative represented by the general formula (2). Therefore, even if harmful trimethylamine is not used as a malodorous substance, the target phosphorylcholine derivative can be safely and efficiently used by using another harmless basic substance or by passing an inert gas. In addition, it can be easily manufactured.

[0029]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. Reference Example 1 Synthesis of 2- (trimethylammonium) ethyl-dichlorophosphate 2-hydroxyethyltrimethylammonium chloride
2 mol, 0.2 mol of phosphorus oxychloride and 0.2 mol of triethylamine were added to 150 ml of dehydrated methylene chloride and subjected to a suspension reaction at 30 ° C. for 2 hours. After the reaction, triethylamine hydrochloride and methylene chloride were removed, and
(Trimethylammonium) ethyl-dichlorophosphate was obtained in 95% yield.

Reference Example 2 Synthesis of 2- (triethylammonium) ethyl-dichlorophosphate iodide 0.2 mol of 2-hydroxyethyltriethylammonium iodide, 0.2 mol of phosphorus oxychloride and 0.2 mol of triethylamine were dehydrated with methylene chloride. The mixture was charged into 150 ml and subjected to a suspension reaction at 30 ° C. for 2 hours. After the reaction, triethylamine hydrochloride and methylene chloride were removed, and 2- (triethylammonium) ethyl-dichlorophosphate iodide was obtained at a yield of 95%.

Example 1 2- (methacryloyloxy)
Synthesis of ethyl-2 '-(trimethylammonium) ethyl phosphate 0.2 mol of 2- (trimethylammonium) ethyl-dichlorophosphate obtained in Reference Example 1, 0.2 mol of 2-hydroxyethyl methacrylate and 0.2 mol of triethylamine Was added to 150 ml of dehydrated methylene chloride, and subjected to a suspension reaction at 0 ° C. for 2 hours under normal pressure . Triethylamine hydrochloride was removed by filtration, 0.2 mol of water was further added, and the mixture was reacted at 0 ° C. for 2 hours to carry out hydrolysis.

Hydrogen chloride was completely adsorbed using an ion exchange resin (Amberlite IRA-94S-HG, manufactured by Rohm and Haas ), and the pH was adjusted to 7.0. After removing methylene chloride, purification was carried out by dropping in hexane to give 2- (methacryloyloxy) ethyl-2 '.
-(Trimethylammonium) ethyl phosphate (in the general formula (3), R ^{1 to} R ³ are all methyl groups, R ⁴
Is a methyl group, n = 1, m = 1, and A is an ethylene group) in a yield of 65%. TLC, HPLC, FAB-MS and ¹
H-NMR analysis was performed. The analysis values are as follows.

TLC silica gel plate developing solution (methanol: acetic acid: water = 15: 4: 2) Single spot is detected at iodine color development Rf = 0.25. HPLC ODS column eluent (methanol: water = 70: 30) A single peak is detected at a retention time of 5.72 minutes at 210 nm UV detection. FAB-MS M / Z [M + H] ⁺ 296 (M = C ₁₁ H ₂₂ NO ₆ P) ¹ H-NMR (ppm / D ₂ O) 3 .26 (9H, s, -N- C H 3), 3.97 (2
H, m, -N-C H 2 -), 4.08~4.34 (6
H, m, -O-C H 2 -), 1.81 (3H, s, -C
_{-C H 3), 5.50 (1H} , s, -C H =), 6.0
3 (1H, s, -C H =)

Example 2 Synthesis of 2- (acryloyloxy) ethyl-2 '-(triethylammonium) ethyl phosphate 2- (triethylammonium) iodide obtained in Reference Example 2
0.2 mol of ethyl-dichlorophosphate, 0.2 mol of 2-hydroxyethyl acrylate and 0.2 mol of triethylamine were put into 150 ml of dehydrated methylene chloride, and subjected to a suspension reaction at 0 ° C. under normal pressure for 2 hours. Triethylamine hydrochloride was removed by filtration, 0.2 mol of water was further added, and the mixture was reacted at 0 ° C. for 2 hours to carry out hydrolysis.

Hydrogen iodide was completely adsorbed using an ion exchange resin (Amberlite IRA-94S-HG manufactured by Rohm and Haas ), and the pH was adjusted to 7.0. After removing methylene chloride, purification was carried out by dropping in hexane, and 2- (acryloyloxy) ethyl-2'-
65% by weight of (triethylammonium) ethyl phosphate (in the general formula (3), R ^{1 to} R ³ are all ethyl groups, R ⁴ is a hydrogen atom, n = 1, m = 1, and A is an ethylene group). In a yield of For purity confirmation, TLC, HPLC, FAB-MS and ¹ H
-NMR analysis was performed. The analysis values are as follows.

TLC silica gel plate developing solution (methanol: acetic acid: water = 15: 4: 2) A single spot was detected at iodine color Rf = 0.32. HPLC ODS column eluent (methanol: water = 70: 30). A single peak is detected at a retention time of 7.45 minutes at 210 nm UV detection. FAB-MS M / Z [M + H] ⁺ 324 (M = C ₁₃ H ₂₆ NO ₆ P) ¹ H-NMR (ppm / D ₂ O) 1 .33 (9H, t, -N- C H 3), 3.02~3.
63 (8H, m, -N- C H 2 -), 4.08~4.3
4 (6H, m, -O- C H 2 -), 5.80 (1H,
m, -CH = CH- H ), 6.11 to 6.62 (2H,
m, -C H = C H -H )

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-54-63025 (JP, A) JP-A-58-15491 (JP, A) JP-A-63-222183 (JP, A) International publication 92/7885 (WO, A1) (58) Field surveyed (Int. Cl. ⁷ , DB name) C07F 9/09 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (1) [In the formula (1), X ¹ and X ² are a halogen atom, Y ⁻ is an anion, R ¹ , R ² and R ³ are a hydrogen atom or carbon atom 1
And represents alkyl groups 4 to 4. X ¹ and X ² , and R ^{1 to} R ³ may be the same or different. And a halogenated phosphorylcholine derivative represented by the following general formula (2): [Wherein A is a linear or branched alkylene group, m
And n is 0 or 1, and R ⁴ is a hydrogen atom or a methyl group. Reacting with the acrylic acid derivative represented by the formula (1) in the presence or absence of a base while removing the generated hydrogen halide, and then reacting the obtained reaction product with water to hydrolyze it. General formula (3) characterized by the following: [(3) In the formula, R ¹ , R ² and R ³ are a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ⁴ is a hydrogen atom or a methyl group, A is a linear or branched alkylene group, m and n Represents 0 or 1. R ^{1 to} R ³ may be the same or different. ] A method for producing a phosphorylcholine derivative represented by the formula: