JPS61207395A - Diol having phospolipid-like structure and production thereof - Google Patents

Abstract

PURPOSE:To obtain the titled substance having a structure similar to phospholipid constituting biomembrane, by reacting a reaction product of a specific mono- or dihydroxy compound and 2-chloro-2-oxo-1,3,2-dioxasulfolane with a tertiary amine. CONSTITUTION:A compound (nonylphenol, etc.) shown by the formula I (A is mono-, or dihydroxy compound residue; n is 1 or 2) is reacted with 2-chloro-2- oxo-1,3,2-dioxasulfolane in the presence of a tertiary amine (e.g., triethylamine, etc.) to give a compound shown by the formula II, then reacted with a tertiary amine (e.g., diethanolmethylamine, etc.) shown by the formula III (when n=1, R<1> is alkyl, alkenyl, aralkyl, etc.; R<2> and R<3> are OH-containing alkyl, alkenyl, aralkyl, etc.; when n=2, R<1> and R<2> are alkyl, alkenyl, aralkyl, etc.; R<3> is OH- containing alkyl, alkenyl, aralkyl, etc.), to give the aimed diol (e.g., compound shown by the formula V) shown by the formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a diol having a phospholipid-like structure and a method for producing the same.

Biomembranes such as phospores that make up living organisms are called Singer-! It is known for its Ji Colson model.

It consists of phospholipids and proteins penetrating and adsorbing them. Recently, the development of various types of artificial organs such as artificial kidneys and artificial hearts has been active, but in the development of these artificial organs, materials with excellent age compatibility and antithrombotic properties, especially in areas that come into contact with blood, have been actively developed. The selection requires 1A,
In addition, good mechanical strength and durability as a structural material are also required.Currently, methods include forming endothelial cell tissue on porous Teflon, methods using anticoagulant substances such as heparin as materials, and methods using +161 materials such as urokinase. In particular, methods of immobilizing soluble substances on materials, and materials with separated structures such as "Micro 4T", which form heterogeneous structures such as hydrophobic/hydrophilic or crystalline/non-quality on the surface of materials, have been put into practical use. Polyurethane-based materials such as polyurethane or polyurethane urea containing hydrophobic/hydrophilic segments in the form of blocks, including their flexibility and durability,
Although it is considered to be the most promising material, its biocompatibility is still not sufficient.

[Purpose of the invention]

The present invention provides diols having a structure similar to phospholipids constituting biological membranes and methods for producing the same.

[Structure of the invention]

The present invention relates to a diol represented by the following general formula, its production method, and its application as a component of a polyurethane polymer.

[Here, A is a residue of a mono- or dihydroxy compound,
n and/or an integer of two, and when n is l, R'' is alkyl, alkenyl, aralkyl.

Alkaryl, alkyloxyalkyl, alkyloxyalkyl group, and! and R3 are each independently an alkyl group containing a hydroxyl group.

It is an alkenyl, aralkyl, alkaryl, alkyloxyalkyl, or alkyloxyalkyl group, and when n is 2, R1 and R1 are each independently an alkyl, alkenyl, alkaryl, alkyloxyargyl, or alkyloxyalkyl group. , R8 represents an alkyl, alkenyl, aralkyl, alkaryl, alkyloxyalkyl, or alkyloxyalkyl group containing a hydroxyl group. ] The compound of general formula (1) can be prepared by reacting it with diisocyanates such as diphenylmethane diisocyanate and tolylene diisocyanate.

Polyurethane-based polymers containing structures similar to phospholipids that constitute biological membranes can be produced.

The compound of general formula (1) of the present invention is a compound of general formula (II) A (
OH)n (1) to mono- or dihydroxy compounds.

In the presence of a tertiary amine --chloro-o-2-oxo-/, 3
．． -2-dioxaphosphorane is reacted with the general formula (I
By preparing a compound prepared by li) and then reacting it with a tertiary amine represented by the general formula 〇J, it can be prepared very efficiently and with a high sieving rate.

To explain in detail, examples of the compound represented by the general formula (IIJ) include mono- and dihydroxy compounds of each -.Specifically.

Monohydrocarbons (as C compounds, direct or branched alcohols such as methanol, ethanol, butanol, pentanol, hextenol, heptatool, octatool, nonanol, lauryl alcohol, mylythyl alcohol, pentadecanol, octadecanol, etc.) These allyl substituted products, alicyclic alcohols such as cyclobutanol, cyclopentanol, cyclohexanol, cycloheptatool, cyclooctatool, or their alkyl substituted products, phenol, naphthol, etc.
Enols or their alkyl, allyl, cycloalkyl substituted products, alcohols containing different rings such as furfuryl alcohol, methoxyethanol, methoxy 7' lovanol, methoxybutanol, ethoxypropanol,
Methoxypentanol, ethoxybutanol, methoxyhexanol, diethoxyglopanol, methoxyheptatool.

Ethers of polyhydroxy compounds such as methoxyphenol, methoxybenzyl alcohol, phenoxypropanol, phenoxybutanol, diphenoxyglycerin, acetoxyethanol, acetoxypropatol, acetoxybutanol, diacetoxyglycerol,
Examples include esters such as glycerol distearate, glycerol dioleate, and pentaerythritol trioleate, and monoethers or monoesters of polyalkylene glycols such as polyethylene glycol, polypropylene glycol, and polytetramethylene glycol.

As dihydroxy compounds, ethylene glycol, propanediol, butanediol, bentanediol, hexanediol, heptanediol, octanediol, nonanediol.

Linear or branched diols such as decanediol and octadecadiol, allyls thereof, alicyclic group substituted products, alicyclic diols such as cyclohexanediol, or alkyl substituted products thereof, dihydroxybenzene,
Dihydro-oxybiphenyl, bisphenol 7
Examples include cerol monostearate, esters of pentaerythritol dioleate, ethers such as phenoxyglycerin, and polyalkylene glycols such as polyethylene glycol, polypropylene glycol, and polytetramethylene glycol. The reaction is carried out with co-oxo 7.3-dioxaphosphorane, and the tertiary amine usually includes trialkylamines such as trimethylamine and triethylamine. The image component and the tertiary amine may be used in substantially equimolar amounts. The solvent used in the reaction is preferably one that can dissolve the first component, the tertiary amine, and the reaction product.

Examples include diethyl ether and tetrahydrofuran. The reaction involves mixing each component in a solvent.

If the reaction is carried out at -60°C to 0°C for 30 minutes to several hours, the compound represented by the following general formula (1) can be obtained almost quantitatively.

Next, the compound represented by the general formula l) is reacted with a tertiary amine. When n in the general formula I) is 2, dimethylamine methanol, dimethylaminoethanol, etc. are used as the tertiary amine. .

Dimethylaminopropanol, dimethylaminobutanol, diethylaminoethanol, dimethylaminopentanol, diethylaminoglopanol, dimethylaminohexanol, diethylaminobutanol, diethylaminopentanol, diethylaminohexanol, dimethylaminobenzyl alcohol, diethylaminomethylphenol, diethylamino-α-phenylethanol and alkylene oxide adducts thereof. Further, when n in the general formula l) is 7, dihydroxy tertiary amines such as jetanol methylamine, jetanol ethylamine, cyclohexyl diene//- amine, or alkylene oxide adducts of cholera can be mentioned.

The amount used may be at least equimolar to the compound represented by the general formula 1.

Solvents used during the reaction include acetonitrile,
Methanol and dimethylformamide are preferred. The reaction may be carried out by mixing the components in a solvent and allowing the reaction to occur at a temperature of about θ°C to 200°C for several hours to several tens of hours, and the compound represented by the general formula (1) can be obtained in high yield. The reaction product (1
) The intermediate compound #' thus obtained can be easily purified by dissolving the compound in chloroform or methanol and then adding it to a large amount of acetone or diethyl ether for precipitation. i. Polyurethane polymers can be produced by known means of reacting with a diisocyanate compound in the presence of a catalyst such as dialkylaminopyridine or tin laurate. The diisocyanate ratio compounds used here include, but are not limited to, % e, hexamethylene diisocyanate, isophorone diisocyanate, dicyclohexylmethane diisocyanate, xylylene diisocyanate, ) lylene diisocyanate, diphenylmethane diisocyanate, paraphenylene diisocyanate, etc. A prepolymer with incyanate groups at both ends, adiprene L-100,! (-Kota 0 (manufactured by Kasei Upjohn Co., Ltd., trade name), Adiprene L-/47.H-ko9! (manufactured by Kasei Upjohn Co., Ltd., trade name), etc. are suitable.

[Implementation file 3] Hereinafter, the present invention will be explained in more detail with reference to Examples.

The implementation was +-/nonylphenol//77 (0,0!mol) triethylamine salt/tetrahydrofuran/! 7. In addition to 01, while cooling to −20°C. /, p (0,0!i methyl) cochrochlore λ-okine/, 3,2-dioxaphosphorane was added dropwise. During the dropwise addition, the reaction temperature is -20°C to -70°C.
After the dropwise addition was completed, stirring was continued for 2 hours while cooling with water. After a further 30 minutes of reaction at room temperature, the precipitated triethylamine hydrochloride was separated and tetrahydrofuran was completely distilled off from the P solution. This residue was dissolved in /jO- dimethylformamide, %23i 77 (0,-mol) of jetanolmethylamine was added, and the mixture was reacted at 70° C. for 1 hour in a pressure-resistant reaction tube. Dimethylformamide was distilled off under reduced reaction pressure, washed with diethyl ether (2011d), dissolved in methanol (2011d), and then poured into diethyl ether (3θ0) to obtain the target product represented by the following formula. The yield was almost 100%. Confirmation was done by elemental analysis.

The result of elemental analysis was a (calculated value, 37%).

Analysis value! 37%), H (calculated value?, 03%1 analytical value? -20%) and N (calculated value J, /da%1 analytical value!
, -2/%). , rill (o, ocomoru)! 0- dissolved in acetone, r, og (0,0,
, 2 mol) of diphenylmethane diisocyanate and a small amount of II (N,N-dimethylamine)pyridine were added and heated at 20-100°C for 2 hours. n of person C after reaction
- The urethane polymer was recovered by pouring into hexane. Accreditation will be conducted by IR.

/700 cm-', absorption unique to polyurethane bonds was observed. A chart is shown in FIG.

Example-λ Bisphenol 12077 (0.0?t mol) 100
- dissolved in tetrahydrofuran and heated to -2j at -1θ℃
A drop of mλg (o, tr moles) of -mono-oxono, 3,2-dioxaphosphorane was retained. After the reaction, triethylamine hydrochloride precipitated was separated by F, and the %P solution was dried under reduced pressure. The entire amount of this residue was dissolved in rotIt dimethylformamide, lu, rKl (0.17 mol) dimethylaminoethanol was added, and the solution was dissolved for 2' at 3°C.
The reaction was allowed to shake for 1 hour. Next, dimethylformamide was distilled off at 4tj°C under reduced pressure, washed with 20-dimethyl ether, dissolved in 20-dimethyl ether, and this solution was poured into 300-dimethyl ether to form a starch syrup-like mixture expressed by the following formula. Obtained the desired object. The gross yield was 67%.

Confirmation was made by elemental analysis and IR. Elemental analysis is a
(Calculated value!-, Dako%1 analysis value j, 2.J7%) B (calculation value 7.17%, analysis value 7.20%) and N (total wg
fX, Gu! 3%1 analysis value<<, 44%). 1
A simple chart is shown in Figure 2.

Application voice 12 Dissolve the diol (tg<o, σoti mol) obtained in Example-1 in dimethyl sulfoxide of jO-, a.
o y (o,o or moles) of diphenylmethane diisocyanate and a small amount of g(h,m-dimethylamino)pyridine were added and heated to ro to 10[theta]C for 1 hour. After the reaction, the urethane polymer was recovered by pouring it into a large amount of n-hexane. Confirmation was carried out by Engineering R, / 700 (W
According to the present invention, a biocompatible material can be produced by reacting with a diisocyanate to form a polyurethane. It is possible to easily produce a novel diol with a structure similar to that of phospholipids, which is expected to be useful as a phospholipid.

[Brief explanation of the drawing]

Figure 7 is the engineering R chart of the polyurethane obtained in application -/, Figure 1 is the engineering R chart of the diol obtained in implementation f11-, and Figure 3 is the engineering R chart of the polyurethane obtained in application gAI J. It is. Applicant: Mitsubishi F-Hisei Kogyo Co., Ltd. Agent: Patent attorney: Long diameter - (7 others)

Claims (4)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [Here A is the residue of a mono- or dihydroxy compound, n
is an integer of 1 or 2, and when n is 1, R^1 is an alkyl, alkenyl, aralkyl, alkaryl, alkyloxyalkyl, or alkyloxyalkyl group, and R^2 and R^3 are each independently hydroxyl. an alkyl, alkenyl, aralkyl, alkaryl, alkyloxyalkyl, alkyloyloxyalkyl group containing a group, and when n is 2, R^1 and R^2 are each independently alkyl, alkenyl, aralkyl, alkaryl,
They are alkyloxyalkyl and alkyloxyalkyl groups, and R^3 represents an alkyl, alkenyl, aralkyl, alkaryl, alkyloxyalkyl, and alkyloxyalkyl group containing a hydroxyl group. ] A diol having a phospholipid-like structure. (2) In general formula (I), n is an integer of 1,
The diol having a phospholipid-like structure according to claim 1, wherein R^1 is a methyl group, and R^2 and R^3 are 2-hydroxyethyl groups. (3) In general formula (I), n is an integer of 2,
The diol having a phospholipid-like structure according to claim 1, wherein R^1 and R^2 are methyl groups, and R^3 is a 2-hydroxyethyl group. (4) General formula (II) A(OH)_n(II) [In formula (II), A represents a residue of a mono- or dihydroxy compound, and n represents an integer of 1 or 2. ] is reacted with 2-chloro-2-oxo-1,3,2-dioxaphosphorane in the presence of a tertiary amine to form the general formula (III) ▲Mathematical formula, chemical formula, table etc.▼(III) [In formula (III), A and n represent the same meanings as in formula (I) above. ] A compound represented by general formula (IV) is then produced. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) [In formula (IV), when n is 1, R^1 is alkyl, alkenyl, aralkyl. , alkaryl, alkyloxyalkyl, alkyloxyalkyl group, and R^2 and R^3 are each independently an alkyl, alkenyl, aralkyl, alkaryl, alkyloxyalkyl, alkyloyloxyalkyl group containing a hydroxyl group. ,
When n is 2, R^1 and R^2 are each independently an alkyl, alkenyl, aralkyl, alkaryl, alkyloxyalkyl, alkyloxyalkyl group, and R
^3 is alkyl, alkenyl, aralkyl, alkaryl, alkyloxyalkyl containing a hydroxyl group,
Represents an alkyloxyalkyl group. ] A method for producing a diol having a phospholipid-like structure represented by the general formula (I), which comprises reacting a tertiary amine represented by the formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the (I) formula, A, n, R^1, R^2 and R^3
represents the same meaning as above. ]