JPH0665677B2 - Diole having phospholipid-like structure and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a diol having a phospholipid-like structure and a method for producing the same.

[Conventional technology]

Biological membranes such as cells that make up the living body are singer-Nicolson
As known in the model, it is composed of phospholipids and proteins penetrating and adsorbing thereto. Recently, various artificial organs such as artificial hearts have been actively developed, including artificial kidneys. In the development of these artificial organs, selection of materials excellent in biocompatibility, especially antithrombogenicity in the area in contact with blood. Is important, and high mechanical strength and durability as a structural material are also required.

Currently, a method of forming endothelial cell tissue such as porous Teflon, a method of immobilizing an anticoagulant biomaterial such as heparin, a method of immobilizing a fibrinolytic substance such as urokinase on a material, or a material surface Microphase-separated structure materials that form a heterogeneous structure such as hydrophobic / hydrophilic or crystalline / amorphous have been put into practical use. In particular, polyurethane-based materials such as polyurethane or polyurethane-urea containing hydrophobic / hydrophilic segments in the form of blocks are the most promising, including their flexibility and durability, but are still biocompatible. Is not enough.

[Object of the Invention]

The present invention provides a diol having a structure similar to that of a phospholipid constituting a biological membrane and a method for producing the diol.

[Structure of Invention]

The present invention has the following general formula (I) The present invention relates to a diol represented by the formula (1), a method for producing the same, and application as a constituent component of a polyurea-based polymer.

Here, A represents a monovalent or divalent phenol residue which may be substituted with an alkyl group. n represents an integer of 1 or 2. When n is 1, R ¹ is an alkyl group having 1 to 6 carbon atoms, and R ² and R ³ are each independently an alkyl group having 1 to 6 carbon atoms and containing a hydroxyl group. When n is 2, R ¹ and R ² are each independently a C 1-6 alkyl group, and R ³ is a C 1-6 alkyl group containing a hydroxyl group. By reacting the compound of the general formula (I) with diisocyanates such as diphenylmethane diisocyanate and tolylene diisocyanate, a polyurethane-based polymer having a phospholipid-like structure constituting a biological membrane can be produced.

The compound of the general formula (I) of the present invention is a compound of the general formula (II) A (OH) n (II) in which 2-chloro-2-oxo-1 is added in the presence of a tertiary amine. Reacting with 3,3,2-dioxaphospholane to give a compound of general formula (III) A compound represented by the following formula (IV) By reacting a tertiary amine represented by
It can be produced very easily and in high yield.

To explain the present invention in detail, examples of the compound represented by the general formula (II) include various monohydric or dihydric phenols. Specific examples include monohydric phenols such as phenol and naphthol, dihydric phenols such as dihydroxybenzene, dihydroxygiphenyl and bisphenol, and alkyl-substituted products thereof.

The above compound is first prepared in the presence of a tertiary amine in the presence of 2-chloro-
The reaction is carried out with 2-oxo-1,3,2-dioxaphosphorane, and the tertiary amine usually includes trialkylamines such as trimethylamine and triethylamine. The amounts of both components and the tertiary amine used may be approximately equimolar to each other. The solvent used in the reaction is preferably one capable of dissolving both components, the tertiary amine and the reaction product, and examples thereof include diethyl ether and tetrahydrofuran. The reaction may be carried out by mixing the components in a solvent and reacting at -50 ° C to 0 ° C for 30 minutes to several hours. The compound represented by can be obtained almost quantitatively.

Next, the compound represented by the general formula (III) is reacted with a tertiary amine. As the tertiary amine, when n in the general formula (III) is 2, dimethylaminomethanol, dimethyl Aminoethanol, dimethylaminopropanol, dimethylaminobutanol, diethylaminoethanol, dimethylaminopentanol, diethylaminopropanol, dimethylaminohexanol, diethylaminobutanol, diethylaminopentanol,
Examples include monohydroxy tertiary amines such as diethylaminohexanol, and their alkylene oxide adducts. Further, when n in the general formula (III) is 1, dihydroxy tertiary amines such as diethanolmethylamine, diethanolethylamine, cyclohexyldiethanolamine or alkylene oxide adducts thereof can be mentioned. The amount used may be equimolar or more with respect to the compound represented by the general formula (III).

As the solvent used in the reaction, acetonitrile,
Methanol and dimethylformamide are preferred. The reaction may be carried out by mixing the two systems in a solvent and reacting at a temperature of about 0 ° C. to 200 ° C. for several hours to several tens of hours, and the compound represented by the general formula (I) can be obtained in high yield. Reaction product (I)
The compound of the formula can be easily purified by dissolving it in chloroform or methanol and then adding it to a large amount of acetone or diethyl ether for precipitation.

The compound of formula (I) thus obtained can be used to produce a polyurethane polymer by a known means of reacting it with a diisocyanate compound in the presence of a catalyst such as dialkylaminopyridine or tin laurate. The diisocyanate compound used here is not particularly limited, for example, hexamethylene diisocyanate, isophorone diisocyanate, dicyclohexylmethane diisocyanate, xylylene diisocyanate, tolylene diisocyanate, diphenylmethane diisocyanate,
Paraphenylene diisocyanate, or a prepolymer having isocyanate groups at both ends, such as Adiprene L-100, H-290 (manufactured by Kasei Apuziyon Co., Ltd.), Adiprene L-167, H-295 (manufactured by Kasei Apuziyon Co., Ltd., products First name) is suitable.

〔Example〕

 Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1 11 g (0.05 mol) of nonylphenol and triethylamine
150 ml of dried tetrahydrofuran of 5.6 g (0.055 mol)
In addition to 7.8 g (0.055 mol) of 2-
Chloro-2-oxo-1,3,2-dioxaphosphorane was added dropwise. During the dropping, the reaction temperature was kept at -20 ° C to -10 ° C.
After completion of dropping, stirring was continued for 2 hours under ice cooling. Further at room temperature 30
After reacting for minutes, the precipitated triethylamine hydrochloride was separated, and tetrahydrofuran was completely distilled off from the liquid. The residue was dissolved in 150 ml of dimethylformamide, 23.8 g (0.2 mol) of diethanolmethylamine was added, and the mixture was reacted in a pressure resistant reaction tube at 70 ° C. for 48 hours. After the reaction, dimethylformamide was distilled off under reduced pressure, washed with 20 ml of diethyl ether, dissolved in 20 ml of methanol, then
It was poured into 300 ml of diethyl ether to obtain the desired product represented by the following formula. The crude yield was almost 100%. Confirmation was performed by elemental analysis.

The results of elemental analysis are C (calculated value 59.31%, analytical value 59.37
%), H (calculated value 9.05%, analytical value 9.20%) and N (calculated value 3.14%, analytical value 3.21%).

Application Example 1 50 ml of 8.9 g (0.02 mol) of the diol obtained in Example-1
Was dissolved in acetone, and 5.0 g (0.02 mol) of diphenylmethane diisocyanate and a small amount of 4 (N, N-dimethylamino) pyridine were added, and the mixture was heated at 80-100 ° C for 2 hours. After the reaction, the urethane polymer was recovered by throwing it in a large amount of n-hexane. Confirmation was carried out by IR, and absorption with a polyurethane bond characteristic was observed at 1700 cm ^-1 . The chart is shown in FIG.

Example-2 20 g (0.088 mol) of bisphenol A was dissolved in 100 ml of tetrahydrofuran, and 25.2 g (0.18 mol) of 2 was dissolved at -20 ° C.
-Chloro-2-oxo-1,3,2-dioxaphosphorane was added dropwise. Then, 21.3 g (0.21 mol) of triethylamine was added at -20 ° C, and the mixture was kept at 0 ° C for 1 hour. After the reaction, triethylamine hydrochloride deposited was separated, and the liquid was dried under reduced pressure. The whole amount of this residue was dissolved in 50 ml of dimethylformamide, 14.84 g (0.17 mol) of dimethylaminoethanol was added, and the mixture was reacted by shaking at 75 ° C for 24 hours. Next, dimethylformamide was distilled off under reduced pressure at 45 ° C., washed with 20 ml of diethyl ether and dissolved in 20 ml of methanol, and this solution was poured into 300 ml of diethyl ether to obtain a starch syrup-like target compound represented by the following formula. Obtained. The crude yield was 61%.

Confirmation was performed by elemental analysis and IR. Elemental analysis is C
(Calculated value 52.42%, analytical value 52.27%) H (calculated value 7.17%,
Analysis value 7.20%) and N (calculation value 4.53%, analysis value 4.66)
%). The IR chart is shown in FIG.

Application Example 2 50 g of 5 g (0.0081 mol) of the diol obtained in Example-2
Dissolved in 2.0 g (0.008 mol) of diphenylmethane isocyanate and a small amount of 4
(N, N-Dimethylamino) pyridine was added and heated to 80-100 ° C for 2 hours. After the reaction, the urethane polymer was recovered by throwing it in a large amount of n-hexane. Confirmation by IR, 1700 cm
Absorption characteristic of polyurethane bond was observed at ^-1 . The chart is shown in FIG.

〔The invention's effect〕

According to the present invention, a diol having a novel phospholipid-like structure expected as a biocompatible material can be easily produced by reacting with diisocyanate to form a polyurethane.

[Brief description of drawings]

FIG. 1 is an IR chart of the polyurethane obtained in Application Example 1, FIG. 2 is an IR chart of the diol obtained in Example 2, and FIG. 3 is an IR chart of the polyurethane obtained in Application Example 2.

Claims (4)

[Claims] 1. A general formula (I) [Here, A represents a monovalent or divalent phenol residue which may be substituted with an alkyl group. n represents an integer of 1 or 2. When n is 1, R ¹ is an alkyl group having 1 to 6 carbon atoms, and R ² and R ³ are each independently an alkyl group having 1 to 6 carbon atoms and containing a hydroxyl group. When n is 2, R ¹ and R ² are each independently a C 1-6 alkyl group, and R ³ is a C 1-6 alkyl group containing a hydroxyl group. ] A diol having a phospholipid-like structure represented by: 2. In the general formula (I), n is an integer of ¹ , R ¹ is a methyl group, and R ² and R ³ are 2-hydroxyethyl groups. A diol having the described phospholipid-like structure. 3. In the general formula (I), n is an integer of 2, R ¹ and R ² are methyl groups, and R ³ is a 2-hydroxyethyl group. A diol having the described phospholipid-like structure. 4. General formula (II) A (OH) n (II) [In the formula (II), A represents a monovalent or divalent phenol residue which may be substituted with an alkyl group. n represents an integer of 1 or 2. ] The mono- or dihydroxy compound represented by the formula (II) is reacted with 2-chloro-2-oxo-1,3,2-dioxaphosphorane in the presence of a tertiary amine [In the formula (III), A and n have the same meanings as in the formula (II). ] The compound of the following general formula (IV) [When n is 1, in the formula (IV), R ¹ is an alkyl group having 1 to 6 carbon atoms, and R ² and R ³ are each independently an alkyl group having 1 to 6 carbon atoms and containing a hydroxyl group. is there. When n is 2, R ¹ and R ² are each independently an alkyl group having 1 to 6 carbon atoms, and R ³ is 1 to 6 carbon atoms containing a hydroxyl group.
Is an alkyl group. ] The manufacturing method of the diol which has the phospholipid-like structure represented by General formula (I) characterized by reacting the tertiary amine represented by these. [In the formula (I), A, n, R ¹ , R ² and R ³ have the same meanings as described above. ]