JP3240696B2 - Diester monomer and its polymer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a diester monomer and a polymer thereof, and more particularly, to a polymer which can be used as a material for artificial organs or a surface modifier of a polymer material and a monomer used as a raw material thereof. Diester monomers that can be used.

[0002]

2. Description of the Related Art Conventionally, water-soluble monomers include N-vinylpyrrolidone, 2-hydroxyethyl methacrylate,
(Meth) acrylic acid and the like are known, and polymers obtained by polymerizing the monomers are used in biological fields such as contact lenses and cosmetics. However, the polymer has problems such as poor mechanical strength and adsorption of proteins, lipids, and the like, and is insufficient as a material directly related to living tissues such as artificial organs.

Therefore, there is a demand for the development of a material having a functional relationship with a living body, and various monomers having biocompatibility have been proposed. Examples of the biocompatible monomer include 2-methacrylphosphorylcholine having a phospholipid-like structure, which is a main component of a biological membrane (Japanese Patent Laid-Open No.
No. 4-63025) is known, and is applied to artificial organs, contact lenses, and artificial blood vessels.

[0004] However, the phosphorylcholine has a problem that it has poor thermal stability and copolymerizability because the polymer group is a methacryl group.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a monomer having a biocompatible phospholipid-like structure, and a novel biocompatible hydrophilic and biocompatible monomer obtained by polymerizing the monomer. It is to provide a polymer.

[0006]

According to the present invention, there is provided a diester monomer represented by the following general formula (hereinafter referred to as diester monomer 1).

[0007]

Embedded image

Further, according to the present invention, there is provided a polymer having a number average molecular weight of 1,000 to 500,000 obtained by polymerizing the diester monomer alone or with another copolymerizable vinyl monomer.

Hereinafter, the present invention will be described in more detail.

The diester monomer of the present invention is the diester monomer 1 represented by the general formula (2). In the case of the diester monomer 1, when n exceeds 8, the heat resistance and the copolymerizability when polymerized are lowered. When the number of carbon atoms of R ₃ , R ₄ or R ₅ exceeds 20, the hydrophilicity and the polymerizability decrease, so that it cannot be used. Further, R
_{When 2} is an alkyl group or hydroxylalkyl group having more than 20 carbon atoms, it cannot be used because production is difficult.

Specific examples of the diester monomer 1 include, for example, ethyl- (2'-trimethylammonioethyl ethyl phosphate) fumarate, isopropyl- (2'-
Ethyl trimethylammonioethyl phosphate fumarate, t-butyl- (2'-ethyl trimethylammonioethyl phosphate) fumarate, cyclohexyl- (2'-
Ethyl trimethylammonioethyl phosphate) fumarate, 2-hydroxyethyl- (2′-ethyl trimethylammonioethyl phosphate) fumarate, isopropyl
(2′-triethylammonioethyl phosphate) fumarate, sec-butyl- (2′-N, N-diethyl-N-methylammonioethyl phosphate) fumarate, ethyl- (2′-trimethylammonioethyl phosphate) Propyl phosphate fumarate, isopropyl- (2'-trimethylammonioethyl butyl phosphate) fumarate, isopropyl- (2'-trimethylammonioethyl ethoxyethyl phosphate) fumarate, t-butyl- (2'-
Triethylammonioethyl ethoxyethyl phosphate fumarate, isopropyl- (2'-trihydroxyethylammonioethyl ethyl phosphate) fumarate, ethyl- (2'-trimethylammonioethyl phosphate ethyl)
Malate, isopropyl- (2′-trimethylammonioethyl ethyl phosphate) malate, t-butyl- (2 ′
-Ethyl trimethylammonioethyl phosphate) malate, cyclohexyl- (ethyl 2'-trimethylammonioethylphosphate) malate, 2-hydroxyethyl-
(2′-trimethylammonioethyl ethyl phosphate) malate, isopropyl- (2′-triethylammonioethyl ethyl phosphate) malate, sec-butyl-
(Ethyl (2′-N, N-diethyl-N-methylammonioethyl phosphate)), Ethyl- (2′-trimethylammonioethyl phosphate) malate, Isopropyl- (2′-trimethylammonioethyl phosphate) Butyl) malate, isopropyl- (2'-trimethylammonioethyl ethoxyethyl phosphate) malate, t-
Butyl- (2'-trimethylammonioethyl phosphate butyl) malate, t-butyl- (2'-triethylammonioethyl phosphate ethoxyethyl) malate, isopropyl- (2'-trihydroxyethylammonioethyl phosphate ethyl) ) Malate and the like can be preferably mentioned.

To prepare the diester monomer 1,
For example, a fumarate derivative or a malate derivative such as alkyl-hydroxyethyl fumarate, and 2-chloro-2-
The diester is reacted with a phosphorane compound such as oxo-1,3,2-dioxaphosphorane in the presence of a tertiary amine such as trimethylamine in the range of 0 to 50 ° C. for 1 to 10 hours to form a diester. A monophosphorane monomer is obtained, and then the obtained diester monophosphorane monomer, a dehydrochlorinating agent such as a tertiary amine such as trimethylamine and pyridine, and a solvent such as acetonitrile are charged into a pressure-resistant container, and the drying atmosphere It can be obtained by, for example, filtering at 50 to 60 ° C. after sealing, washing the product with a cooled solvent, and the like.
At this time, it is preferable that the charged molar ratio of the diester monophosphorane monomer, the dehydrochlorinating agent and the solvent is 1: 1 to 10: 1 to 20. Further, the obtained product can be purified by a known method such as recrystallization or column chromatography.

The polymer of the present invention is a polymer obtained by polymerizing the diester monomer 1 alone or with another copolymerizable vinyl monomer. The number average molecular weight of the polymer is from 1,000 to 500,000, particularly from 2,000 to 3,000.
00000 is preferred. When the molecular weight is out of the above range, the synthesis is difficult.

The polymer of the present invention is not particularly limited as long as it has the diester monomer unit.

Other copolymerizable vinyl monomers that can be used in the polymer of the present invention include, for example,
Styrene, nuclear-substituted methylstyrene, α-methylstyrene, nuclear-substituted chlorostyrene, vinyl acetate, vinyl propionate, vinyl pivalate, methyl (meth) acrylate, ethyl (meth) acrylate, n-butyl (meth)
Acrylate, (meth) acrylic acid, (meth) acrylamide, 2-hydroxyethyl (meth) acrylate, ethyl vinyl ether, n-butyl vinyl ether, N-vinylpyrrolidone, vinyl chloride, vinylidene chloride, ethylene, propylene, isobutylene, acrylonitrile And monofunctional monomers such as allyl (meth) acrylate, di (meth) acrylate, diallyl phthalate, divinylbenzene, and methylene bisacrylamide. When used, they can be used alone or as a mixture. The content ratio of the other copolymerizable vinyl monomer is, for example, when the monofunctional monomer is used, 1 to 100 parts by weight based on 1 part by weight of the diester monomer.
00 parts by weight is preferred. If the content exceeds 10,000 parts by weight, the biocompatibility of the polymer is undesirably reduced. When the polyfunctional monomer is used, the amount is preferably 20 parts by weight or less based on 100 parts by weight of the diester monomer. In this case, a crosslinked polymer is obtained.

To prepare the polymer of the present invention, for example, the diester monomer 1 or the diester monomer 1 and the other copolymerizable vinyl monomer are subjected to bulk polymerization in the presence of a radical polymerization initiator. It can be easily obtained by performing radical polymerization or copolymerization by a known polymerization method such as suspension polymerization, solution polymerization, or emulsion polymerization. Examples of the radical polymerization initiator include benzoyl peroxide, lauroyl peroxide, diisopropyl peroxydicarbonate, t
-Butylperoxypivalate, t-butylperoxyisobutyrate, azobisisobutyronitrile, persulfate or persulfate-bisulfite can be preferably used. The amount of the radical polymerization initiator to be used is 0.01 to 100 parts by weight of all the raw material monomers used.
10 parts by weight is desirable, and 0.1 to 5 parts by weight is particularly preferred.

The polymerization reaction is preferably carried out at a polymerization temperature of 30 to 100 ° C. for a polymerization time of 5 to 72 hours by substituting the polymerization system with an inert gas such as nitrogen, carbon dioxide, helium or the like or under an atmosphere. preferable. At this time, a polymer having a narrow molecular weight distribution can be obtained by further performing a separation operation or the like.

[0018]

The monomer of the present invention is a novel compound having a phospholipid-like structure, and is excellent in radical polymerizability and heat stability. In addition, since the polymer is hydrophilic and biocompatible, it can be used as a material for contact lens materials and artificial organs.

[0019]

The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

[0020]

Example 1 A fumaric acid compound 1 shown in Table 1 was placed in a reaction vessel.
mol, 1.5 mol of an amine compound, and 600 ml of acetonitrile as a solvent, and a ring opening reaction was performed in an autoclave under a nitrogen atmosphere for 15 hours. After the completion of the reaction, the solution was filtered under reduced pressure to recover the target substance, which was washed several times with acetonitrile to obtain a crystalline product.
The obtained product was analyzed by elemental analysis (CHN), ¹ H-N
Upon identification by MR, it was found to be a fumaric acid diester monomer represented by the following structural formula 3. The measurement results are shown below.

[0021]

Embedded image

[0022]

Examples 2 to 6 Synthesis was performed in the same manner as in Example 1 except that the raw materials shown in Table 1 were used, and the obtained monomers were identified by elemental analysis and ¹ H-NMR.

The fumaric acid or maleic acid diester monomers obtained are shown in Table 1.

[0024]

[Table 1]

[0025]

Example 7 Azobisisobutyronitrile 20 mm as a radical polymerization initiator was added to 10 g of isopropyl- (2'-trimethylammonioethyl phosphate) malate.
40 ml of methanol containing ol / 1 was added and mixed,
Solution polymerization was performed at 60 ° C. for 20 hours by a sealed tube method. After the polymerization is completed, the obtained polymer solution is poured into hexane,
The precipitated polymer was filtered, washed and dried, and the polymerization rate was determined. The obtained polymer was analyzed by ¹ H-NMR, and as a result, CH ＝ CH (6.8
5 ppm), and it was confirmed that the double bond was cleaved. The molecular weight was measured by GPC, and other physical properties were measured using a transparent cast film of a polymer. The measuring method is shown below. Table 2 shows the measurement results.

A) Thermal stability A 1% aqueous solution of a monomer was subjected to a safety test at 60 ° C. for 24 hours.

B) Blood compatibility Evaluation was performed by the microsphere column method. Acrylic beads coated with the polymer were filled in a polyvinyl chloride tube (3 mm in diameter, 10 cm in length), and platelet-rich plasma was flowed into the tube using a syringe pump, and the number of platelets flowing out was counted.

[0028]

Examples 8 to 16 Polymerization was carried out in the same manner as in Example 7 except that the starting monomers shown in Table 2 were used, and the physical properties of the obtained polymers were measured. Table 2 shows the results.

[0029]

Comparative Examples 1 to 4 The procedure of Example 7 was repeated except that the starting monomers shown in Table 2 were used, and the physical properties of the obtained polymer were measured. Table 2 shows the results.

[0030]

[Table 2]

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-5-107511 (JP, A) JP-A-6-43408 (JP, A) JP-A-6-43407 (JP, A) JP-A-5-43407 107512 (JP, A) JP-A-5-177119 (JP, A) JP-A-54-63025 (JP, A) JP-A-60-214794 (JP, A) Table 6-510322 (JP, A) Makromol. chem. , 187 (1986), pp 853-862 (58) Fields investigated (Int. Cl. ⁷ , DB name) C08F 30/02 C07F 9/09

Claims (2)

(57) [Claims] 1. A diester monomer represented by the following general formula 1. Embedded image 2. A polymer having a number average molecular weight of 1,000 to 500,000, obtained by polymerizing the diester monomer according to claim 1 alone or with another copolymerizable vinyl monomer.