JP3419030B2 - 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), Y ^- represents an anion, and R ¹ , R ² and R ³ represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. R ¹ ~
R ³ may be the same or different. A choline derivative represented by the general formula (2):

Embedded image [In the formula (2), X ¹ and X ² represent a halogen atom, A represents a linear or branched alkylene group, m and n each represent 0 or 1, and R ⁴ represents a hydrogen atom or a methyl group. X ¹ and X ² may be the same or different. With a halogenated acrylic acid phosphate derivative represented by the formula (1) in the presence or absence of a base while removing the generated hydrogen halide, and then reacting the resulting reaction product with water to form a hydrolyzate. General formula (3) characterized by decomposition

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, respectively. 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.

[0008] Y in the general formula (1) ^- as an anion represented by a chloride ion, a halide ion such as iodide ion and bromide ion, an acetate ion, bicarbonate ion, tartrate ion, a hydroxide ion, etc. Is raised.

Specific examples of the choline derivative represented by the general formula (1) include 2-hydroxyethyltrimethylammonium hydroxide, 2-hydroxyethyltrimethylammonium iodide, 2-hydroxyethyltrimethylammonium bromide, and 2-hydroxyethyltrimethylammonium bromide. Ethyltrimethylammonium chloride, 2-hydroxyethyltrimethylammonium acetate, 2-hydroxyethyltrimethylammonium acid carbonate, 2-hydroxyethyltriethylammonium chloride, 2-hydroxyethylammonium chloride,
-Hydroxyethylmethyldiethylammonium chloride and the like.

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

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 halogenated acrylic acid phosphate derivative represented by the general formula (2) include:
-(Methacryloyloxy) ethyl-dichlorophosphate, 1-methyl-2- (methacryloyloxy) ethyl-dichlorophosphate, 1-methyl-2- (methacryloyloxy) ethyl-dibromophosphate, 2-
(Acryloyloxy) ethyl-dichlorophosphate, 1-methyl-2- (acryloyloxy) ethyl-
Dichlorophosphate, 3- (acryloyloxy) propyl-diiodophosphate, 2- (methacryloyloxy) -dichlorophosphate, 2- (acryloyloxy) -dichlorophosphate, 1-ethyl-2-
(Methacryloyloxy) ethyl-dichlorophosphate, 1-methyl-3- (methacryloyloxy) propyl-dibromophosphate, 1-ethyl-2- (acryloyloxy) ethyl-dichlorophosphate, 4-
(Methacryloyloxy) butyl-diiodophosphate, 1-methyl-3- (acryloyloxy) propyl-dichlorophosphate, 4- (acryloyloxy)
Butyl-dichlorophosphate and the like.

[0013] Such halogenated acrylic acid phosphate derivatives include phosphorus oxychloride (phosphoryl trichloride).
And a corresponding acrylic acid derivative such as 2-hydroxyethyl methacrylate or 2-hydroxyethyl acrylate by a known method (for example, Te
Trahedron Letters, 1985, Vo
l. 26, no. 9, 1167-1170).

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 prepared by converting the choline derivative represented by the general formula (1) and the halogenated acrylic acid phosphate derivative represented by the general formula (2) in the presence or absence of a base. The reaction is carried out in the presence while removing the generated hydrogen halide, and then the reaction product obtained is reacted with water and hydrolyzed. 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 choline derivative represented by the general formula (1) and the halogenated acrylic phosphate derivative represented by the general formula (2) are in a molar ratio of choline derivative: halogenated acrylic phosphate derivative of 1: 0.1 to 1: 1. It is desirable to react at a ratio of 10, preferably 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 acrylic acid phosphate 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.

The above reaction can be carried out efficiently even in the absence of a base by passing an inert gas to remove generated hydrogen halide. 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 choline derivative, a halogenated acrylic acid phosphate derivative and a base in a reaction medium. In the case where an inert gas is passed, a choline derivative and a halogenated acrylate phosphate derivative and, if necessary, a base are mixed in the reaction medium, and the inert gas is passed through the mixture (reaction liquid). it can.

As the above reaction medium, a medium such as an organic solvent which is inert to the halogenated acrylic acid phosphate derivative can be used. Since a halogenated acrylic acid phosphate derivative dissolves in an ordinary organic solvent, when such a medium is used, the choline 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, an unreacted halogen atom bonded to a phosphorus atom in the reaction product, that is, a halogen atom X derived from a halogenated acrylic acid phosphate derivative,
Is hydrolyzed to obtain the desired product.

The amount of water used is 1 mol or more, preferably 1 mol, per 1 mol of the halogenated acrylic acid phosphate derivative.
It is desirable to set the ratio to モ ル 5 mol. The hydrolysis is carried out at a temperature of -50 to + 50C, preferably -20 to +3.
It is desirable that the temperature is 0 ° C. and the time is 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 choline derivative represented by the general formula (1) is reacted with the halogenated acrylic acid phosphate 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 other harmless basic substances or by passing an inert gas. Good and easy to manufacture.

[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- (methacryloyloxy) ethyl-dichlorophosphate 0.2 mol of 2-hydroxyethyl methacrylate, 0.2 mol of phosphorus oxychloride and 0.2 mol of triethylamine were put into 150 ml of dehydrated methylene chloride, and the mixture was heated at 0 ° C. The reaction was performed for 4 hours. After the reaction, triethylamine hydrochloride and methylene chloride were removed, and 2- (methacryloyloxy)
Ethyl-dichlorophosphate was obtained in 95% yield.

Reference Example 2 Synthesis of 2- (acryloyloxy) ethyl-dichlorophosphate 0.2 mol of 2-hydroxyethyl acrylate, 0.2 mol of phosphorus oxychloride and 0.2 mol of triethylamine were put into 150 ml of dehydrated methylene chloride. The reaction was performed at 0 ° C. for 4 hours. After the reaction, triethylamine hydrochloride and methylene chloride were removed, and 2- (acryloyloxy) ethyl-dichlorophosphate was obtained at a yield of 95%.

Example 1 2- (methacryloyloxy)
Synthesis of ethyl-2 '-(trimethylammonium) ethyl phosphate 2- (methacryloyloxy) ethyl- obtained in Reference Example 1
0.2 mol of dichlorophosphate, 0.2 mol of 2-hydroxyethyltrimethylammonium chloride and 0.2 mol of triethylamine were treated with 150 m 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, and water was further added for 0.2%.
The reaction mixture was reacted at 0 ° C. for 2 hours to effect 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 0.2 mol of 2- (acryloyloxy) ethyl-dichlorophosphate obtained in Reference Example 2, 2-hydroxyethyl 0.2 mol of triethylammonium iodide and 0.2 mol of triethylamine were 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 and hydrogen iodide were 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- (acryloyloxy)
Ethyl-2 '-(triethylammonium) ethyl phosphate (in the general formula (3), phosphorylcholine wherein all of R ^{1 to} R ³ are an ethyl group, R ⁴ is a hydrogen atom, n = 1, m = 1, and A is an ethylene group) Derivative) in 65% yield. TLC, HPLC, FAB-
MS and ¹ H-NMR analyzes were 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), Y ^- represents an anion, and R ¹ , R ² and R ³ represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. R ¹ ~
R ³ may be the same or different. A choline derivative represented by the general formula (2): [In the formula (2), X ¹ and X ² represent a halogen atom, A represents a linear or branched alkylene group, m and n each represent 0 or 1, and R ⁴ represents a hydrogen atom or a methyl group. X ¹ and X ² may be the same or different. With the halogenated acrylic acid phosphate derivative represented by the formula (1) in the presence or absence of a base while removing the generated hydrogen halide, and then reacting the resulting reaction product with water to form a hydrolyzate. General formula (3) characterized by decomposition [(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, respectively. R ^{1 to} R ³ may be the same or different. ] A method for producing a phosphorylcholine derivative represented by the formula: