JPS6021599B2 - 2-methacryloxyethylphosphorylcholine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel compound 2-methacryloxyethylphosphorylcholine represented by the chemical formula and a method for producing the same.

The 2-methacryloxyethylphosphorylcholine of the present invention is used as a polymerization monomer, and the monomer is used as a copolymer with other monomers such as methyl methacrylate, and the monomer is used as a copolymer with other monomers such as polymethyl methacrylate. The copolymer obtained by graft polymerization to the polymer has excellent affinity for living tissues and is therefore useful as a material for artificial organs. In recent years, synthetic polymer materials have come to be widely applied to artificial organs, etc., and there has been a demand for synthetic polymer materials that are functionally related to living tissues.

The present inventors have proposed a polymeric material that is expected to have a favorable interaction at the interface between biological tissues and polymeric materials. As a result of intensive research to obtain a polymeric material with a structure similar to lipids, we synthesized a 2-methacryloxyethylphosphorylcholine monomer having a choline group similar to lecithin. It has been discovered that a polymer obtained by polymerization with a monomer (or polymer) of 1 has excellent compatibility with living tissue, and the present invention has been achieved based on this finding. The 2-methacryloxyethylphosphorylcholine of the present invention is a new compound and can be produced by the following method.

2-Hydroxyethyl methacrylate and 2-promoethylphosphoryl dichloride are reacted in an inert solvent in the presence of a tertiary base to synthesize the intermediate 2-methacryloxyethyl 2-bromoethylhydrodiene phosphate. It can be obtained by reacting the compound with trimethylamine.

In the present invention, any inert solvent used in synthesizing the intermediate 2-methacryloxyethyl 2-promoethylhydrodiene phosphite may be used as long as it does not participate in the reaction, such as ether,
Examples include chloroform, benzene, and tetrahydrofuran.

Further, as the tertiary base, pyridine, quinoline, triethylamine, etc., which are usually used as dehydrohalogenation agents, can be used. As for the reaction conditions, it is preferable to carry out the reaction at a low temperature (-20°C to room temperature) because the reactivity is very high, and further, 2-hydroxyethyl methacrylate is gradually added dropwise to the 2-bromoethylphosphoryl dichloride N. It is desirable to react with In addition, to synthesize 2-methacryloxyethyl 2-bromoethylhydrodiene phosphate to 2-methacryloxyethylphosphorylcholine, a methanol solution of trimethylamine is added to the former to react at room temperature, and then silver carbonate is added to desilver bromide. This is done by processing. The 2-methacryloxyethylphosphorine choline monomer of the present invention can be polymerized alone or together with other monomers or other polymers by the action of a radical polymerization initiator, similar to ordinary methacrylic acid ester monomers. Is possible.

The resulting copolymer of 2-methacryloxyethylphosphorylcholine and methyl methacrylate, as well as the graft copolymer of this monomer and polymethyl methacrylate, has a hemolytic index that is a measure of compatibility with living tissue. The results showed that it had excellent compatibility with living organisms. Such copolymers are used in catheters, artificial skin, contact lenses,
Useful as an implant material. Furthermore, copolymers obtained by copolymerizing the 2-methacryloxyethylphosphorylcholine of the present invention with monomers such as pinyl chloride, styrene, ester acrylate, and hydroxyethyl methacrylate, or other copolymers such as nylon and polyurethane, may also be used. Copolymers obtained by graft polymerization with polymers also have excellent biocompatibility and are similarly useful as artificial organ materials. EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to the Examples.

Example 1 Synthesis of 2-methacryloxyethylphosphorylcholine'
Synthesis of 112-bromoethylphosphoryl dichloride Attach a thermometer, a dropping funnel, and a condenser with a calcium chloride tube to the flask, and add 100 w of dehydrated and dried carbon tetrachloride.
210 parts of phosphorus oxychloride distilled from '' were added to the flask, and 124 parts of ethylene bromohydrin was added at 20°C in a water bath.

After the dropwise addition was completed, the mixture was allowed to stand overnight, and then gradually heated and refluxed for 30 minutes, followed by distillation and purification to obtain 2-promethylphosphoryl dichloride 146 (yield: 61%). colorless liquid b. p. m side sun damage 5.8~87.80○. (2'
Synthesis of 2-methacryloxyethyl 2-promoethylhydrodiene phosphate (b) A three-necked flask was equipped with a dropping funnel equipped with a thermometer, a thermometer, and a calcium chloride tube, and added to 175' of dehydrated chloroform. Dissolve and add 116.7 hours of 2-furomethylphosphoryl dichloride (1) to the flask.

175 secretions of dehydrated chloroform, 2-hydroxyethyl methacrylate 59.82 and dehydrated triethylamine 5
Add the solution in which 42 was dissolved into the dropping funnel, and add 120 qo
Gradually dripping onto the ice rope Azusa.

After the completion of the dropwise addition, the reaction was continued for an additional hour at 0°C, and then concentrated using a rotary evaporator. When cooled, triethylamiso hydrochloride gradually precipitates, and the precipitated solid is separated by furnace. Add 4.4 hours of triethylamine and 13.5 hours of water to the reaction solution.
The mixture was gradually added dropwise to neutralize it at ℃, and after being allowed to stand for 1 hour, the precipitated triethylamine hydrochloride was chopped in an oven. Add a small amount of hydroquinone to the furnace solution, then add a solution of 64.5 parts barium acetate dissolved in 120 parts water, and shake well for 1 hour under water cooling. Take out the water bottle, add hydrochloric acid to make an IN hydrochloric acid solution, add 100% of chloroform, shake well, and remove the organic layer. Extraction with chloroform is repeated three times, moss salt is added to the chloroform layer for dehydration, and the mixture is concentrated using a rotary evaporator to obtain a 95% residue. When this was recrystallized twice with carbon tetrachloride, Satoshi's 2-methacryloxyethyl 2-bromoethylhydrodiene phosphate (0) was obtained as colorless hollyhock-like crystals (yield 26%). ). mP. 456-46
．． 030.

Elemental analysis results Section ○) Section P, Japan Association) Analysis value
30.30 4.46 9.77 Calculated value
30.55 4.59 9.96 (C8th,
406PBr) IR (KBr): 1730 (C:
0), I64O (C=C), 129 melon uniform 1 (P=0)
NMR hexapod (CDCl3) [a'5.63[b16.17, (c'1.97, [d
14.13-4.83, [e}3.52, {fill.
46'31 Synthesis of 2-methacryloxyethylphosphorylcholine (m) Mix 80 parts of dehydrated methanol with 10 parts of trimethylamine liquefied with dry ice, and prepare 2-methacryloxyethyl 2-bromoethyl hydrogen phosphate (
0) Add and dissolve 6.3 hours.

After reacting for 2 days at 15 to 20°C, the mixture was concentrated using a rotary evaporator to obtain a pale pink, dregs-like liquid.

Dissolve this liquid in 50' methanol and then 2.
Add carbon dioxide for 5 nights, react at room temperature for 2 hours, and after filtering, concentrate the furnace liquid using a rotary evaporator to obtain a viscous liquid. This liquid was treated with silica gel column chromatography (chloroform/methanol/water = 65:2
5:4) to obtain 1.8 ml of crystalline 2-methacryloxyethylphosphorylcholine (yield: 28%).
). mp: 1 spot 141℃. Elemental analysis results 0■ Day■
N-coop P squad) analysis value 42.17 7.72 4.4
7 9.89 Calculated value 41.10 7.53 4.5
8 9.88 (as C,.day 2407NP) IR (K
Br) 9 spots (N 10 (CH3) 3), 1240 (P ni 0)
, 16 paper (CniC), 1715 (Cni0) NMR 6 legs (CDCl3) [a) 5.50 (b} 6.0 pieces [c11
．． 81, [d) 4.08-4.34, [e'3.97,
{f13.26 Example 2 Methyl methacrylate (MM
A) and 2-methacryloxyethylphosphorylcholine (
MPC) was copolymerized at the charging ratio shown in Table 1, and the hemolytic properties of the obtained copolymers were examined.

The polymerization conditions were as follows: methanol:dimethylformamide=1:1 was used as a solvent, MBN (0.9 mol %/monomer) was used as an initiator, and polymerization was carried out at 6 pm for 5 hours. After the polymerization, the reaction solution was reprecipitated using a methanol-ether system to obtain a white polymer. Films of these polymers were made by casting from a mixed solvent of chloroformomethanol and used in hemolysis tests. The hemolysis test was conducted as follows. A circular film with a diameter of 14 sides soaked in physiological saline for 3 days was placed on the bottom of a glass test tube, and physiological saline in which rat red blood cells were dispersed at a concentration of approximately 0.25% was gently poured over it. After that, it was placed in a constant temperature bath at 37q0 for 2 hours.

Since the dispersed red blood cells precipitated on the polymer surface, the supernatant was separated by centrifugation, and the hemolysis rate was determined by measuring hemoglobin produced by destruction of the blood cells and hemolysis using UV spectroscopy. The results are shown in Table 1. Table 1 By using MPC as a copolymerization component in the MMA-MPC copolymer, the melt plate rate is considerably lower than that of PMMA,
It was recognized that it has the effect of significantly improving biocompatibility.

Example 3 Graft copolymerization of MPC to polymethyl methacrylate (PMMA) and polystyrene (PSt) was carried out under the following conditions, and the hemolytic property of the graft copolymer was investigated.

Methanol solution containing penzoyl peroxide (13th evening/evening)
After soaking a polymer film of PMMA or PSt at 5 and 0 for 1 hour, the film was taken out and soaked at 60 qo for 1 hour.
．． After heat treatment for 5 hours, the mixture was soaked in a methanol solution of M-C (mixing ratio 2:1wt) and heated at 60 qo for 4 hours to perform graft copolymerization. Next, the obtained film was sufficiently extracted with water to remove the MPC homopolymer, and then a hemolysis test was conducted. The results are shown in Table 2. Table 2 A decrease in the hemolysis rate was observed by graft copolymerizing MPC with both PMMA and PSt.

Claims (1)

[Claims] 1 1 2-methacryloxyethylphosphorylcholine 2 2-Methacryloxyethyl 2'-bromoethylhydro is obtained by reacting 2-hydroxyethyl methacrylate and 2-bromoethylphosphoryl dichloride in an inert solvent in the presence of a tertiary base. 2- characterized in that diene phosphate is reacted with trimethylamine.
Method for producing methacryloxyethylphosphorylcholine.