JPS646220B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing polyurethane, and in particular to a method for producing a novel polyurethane having excellent antithrombotic properties. Polyurethane is synthesized by a polyaddition reaction between an oligomer diol and a diisocyanate, and in addition to the properties of its constituent oligomers, desirable properties emerge due to the addition of elasticity and stiffness specific to polyurethane. Furthermore, the properties of the soft segment can be adjusted by controlling the type of diol segment and the degree of polymerization, and the chain can be easily re-extended. In this way, polyurethanes having a variety of structures and properties can be obtained. α-Amino acid oligomers have high dipole efficiency and can complex and transport metal ions, sugars, amino acids, etc. through dipole-ion interactions. Furthermore, when an α-amino acid oligomer is introduced into the main chain or side chain of a polymer compound, highly efficient and selective complex formation occurs due to intramolecular cooperation. α-Amino acid oligomers are generally highly polar;
It is a crystalline and rigid molecule. Therefore,
In polyurethane containing an α-amino acid oligomer as one component, heterogeneous segment (eg, hydrophilic-hydrophobic segment) chains have low compatibility, resulting in a non-uniform surface structure. Several examples have been found in which polymer membranes with non-uniform surface structures have good blood compatibility. Therefore, polyurethane produced from α-amino acid oligomers, alkylene diols, diisocyanates, etc. has the potential to be a membrane material with excellent mechanical properties that is antithrombotic and selectively permeable to solutes. Conceivable. Against this background, the present inventors have conducted extensive research in order to obtain polyurethane that is expected to have antithrombotic properties and selective permeability. It has been discovered that a polyurethane consisting of polytetramethylene glycol or other alkylene diol or isocyanate (amorphous, hydrophobic, flexible) provides a material with excellent antithrombotic properties.The present invention completed. That is, an object of the present invention is to provide a method for producing polyurethane having excellent selective permeability and antithrombotic properties, and the gist of the present invention is to provide a method for producing polyurethane having excellent selective permeability and antithrombotic properties. The present invention relates to a method for producing a polyurethane, characterized in that a polyurethane-like or cyclic dimer is subjected to a polyaddition reaction with a diisocyanate without the coexistence of an alkylene diol or an oligomer thereof. The present invention will be explained in detail below. Synthesis of polyurethane containing a linear dipeptide as one component: This product synthesizes a dipeptide diol by condensing an α-amino acid having a hydroxyl group in its side chain, and uses this as a chain extender in the coexistence of an alkylene diol or coexists with it. It can be obtained by carrying out a polyaddition reaction with an aliphatic diisocyanate. (A) Synthesis of linear dipeptide diol: L- as an α-amino acid having a hydroxyl group in the side chain.
An example using serine (hereinafter L-serine will be abbreviated as H-Ser-OH) will be described. H-Ser-
The linear dipeptide of OH activates the carboxyl terminal of Z-Ser-OH whose amino terminal is carbobenzyloxylated (hereinafter the carbobenzyloxy group is abbreviated as Z), and this is separately converted into H-Ser-OH.
H-, which is obtained by methyl esterifying the carboxyl group of
By condensation with Ser-OMe, a serine linear dipeptide with both terminal groups protected, namely Z-
Ser―Ser―OMe is obtained. To give a concrete example of this, 20g of H-Ser-
The OH is suspended in methanol, kept at 0° C., and hydrogen chloride gas is bubbled through for about 6 hours. Next, methanol was distilled off, and the resulting solid was recrystallized from methanol to obtain 17.7 g of H-Ser-OMe.HCl (yield 59%). The melting point of this substance is 162-165℃
It was confirmed by thin layer chromatography (hereinafter referred to as TLC) and infrared (hereinafter referred to as IR) spectrum that pure H-Ser-OMe.HCl was obtained. Add 8 g of H-Ser-OMe.HCl to a saturated aqueous solution of sodium bicarbonate, keep at about 20°C, and add 10 g of Z-Cl (1.1 of H-Ser-OMe.HCl) while stirring.
(double equivalent amount) was added dropwise and allowed to react for 4 hours. The separated oil layer was extracted with ethyl acetate, and the extract was diluted with 5%
After washing with hydrochloric acid and then water and drying over anhydrous sodium sulfate, ethyl acetate is distilled off. The obtained fixed product was recrystallized from a mixed solvent of pentane and ether to obtain 10.4 g of Z-Ser-OMe (yield: 80
%). The melting point of this product is 27-32℃, TLC,
Pure Z-Ser-OMe was determined by IR spectrum and high-performance liquid chromatography (hereinafter referred to as HPLC).
It was confirmed that the results were obtained. Dissolve 9.7g of Z-Ser-OMe in methanol,
5.75 g of hydrazine hydrate (3 times the equivalent of Z-Ser-OMe) was added, and the mixture was reacted at about 20°C for 24 hours. Next, ether is added and the mixture is further reacted at 0° C. for 5 to 6 hours. The precipitate was collected and recrystallized from a mixed solvent of methanol and ether to obtain 7.8 g of needle-like crystals of Z-Ser-NHNH ₂ . (Yield 80%). The melting point of this thing is
The temperature was 180-181°C, and it was confirmed by TLC and IR spectra that pure Z-Ser-NHNH ₂ was obtained. Z-Ser- obtained as above
Dissolve 7.59 g of NHNH ₂ in dimethylformamide and add 3.51 g of isoamyl nitrite (equimolar amount to Z-Ser-NHNH ₂ ) while stirring at -5°C.
Although it is thought that Z-Ser-N ₃ was generated in the solution, this product was subjected to the following reaction without being isolated. That is, 4.67 g of H-Ser-OMe・HCl (Z-Ser-NHNH ₂
A dimethylformamide solution (containing a small amount of triethylamine) of the same molar amount) was added, and the mixture was reacted at 0° C. for 2 days. The volatile components were distilled off, and the residue was extracted with ethyl acetate. This extract was washed with a 4% aqueous sodium bicarbonate solution, 3% hydrochloric acid, and water, dried over anhydrous sodium sulfate, and then the ethyl acetate was distilled off. did. The obtained solid was recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 3.3 g of needle-like crystals of Z-Ser-Ser-OMe (yield 32.3%). The melting point of this product is 142-144℃, and TLC, IR spectrum and elemental analysis show that it is pure Z-Ser-Ser-
It was confirmed that OMe was obtained. [α] ²⁴ _D of the methanol solution was −3.1°. The above reaction is expressed as follows. H―Ser―OHMeOH/HCl ――――――――→ H―Ser―OMe・
HCl ZCl ――→ Z―Ser―OMe・HClNH ₂ NH ₂ ――――→ Z― Ser―NHNH ₂ C ₅ H ₁₁ NO ₂ ――――――→ Z―Ser―N ₃ H－Ser－OMe・HCl ――――――――――――→ Z―Ser―Ser―OMe According to this method, the specified reaction proceeds without modification or interference even if the side chain group of serine is not protected, and it is extremely efficient. You can get Z-Ser-Ser-OMe. Z-Ser-Ser-OMe has the following chemical structure, and polyurethane can be synthesized by polyaddition reaction with diisocyanate as a diol component. (B) Synthesis of polyurethane containing linear dipeptide diol: Polyurethane is synthesized by polyaddition reaction of linear dipeptide diol with various diisocyanates, with or without mixing with alkylene diol. By adding MgO as a catalyst for this polyaddition reaction, the reaction rate can be adjusted. Here, polytetramethylene glycol with various degrees of polymerization (hereinafter polytetramethylene glycol is referred to as PTMG) is used as the alkylene diol.
1,6 hexamethylene diisocyanate (hereinafter abbreviated as HMDI) or methylene bis(4
-diisocyanatebenzene) (hereinafter referred to as MDI)
An example will be described in which the following is used. As can be seen from the examples below, polyurethanes with various properties can be synthesized depending on whether or not PTMG is added, the degree of polymerization of PTMG if PTMG is used, and the type of diisocyanate. Example 1 Polyurethane containing Z-Ser-Ser-OMe and HMDI [hereinafter this polyurethane will be referred to as PU (Z-
Production of 0.5 g of Z-Ser-Ser-OMe in 5 ml of dimethylformamide, and 0.006 g of MgO (abbreviated as Z-
(equivalent to 10 mol% of the concentration of Ser-Ser-OMe). Add 0.35ml of HMDI (Z-Ser-Ser-OMe) to this.
(corresponding to 1.5 times the molar concentration of ) dissolved in 3.5 ml of dimethylformamide was added, and the mixture was reacted at 50°C for 24 hours with stirring. The reaction system was purged with nitrogen for the first few hours. Thereafter, the solvent dimethylformamide was distilled off and the viscous solution was poured into water, yielding a viscous white polymer. Add this with distilled water 2
After washing twice to remove the unreacted diol, once with 0.1N hydrochloric acid to remove MgO, and twice with distilled water, it was dried over phosphorus pentoxide for 24 hours in the absence of light. In this way, a colorless, transparent and hard polyurethane was obtained. The solubility of this polyurethane is dimethylformamide, dimethylsulfoxide, phenol/ethanol mixed solvent, trifluoroethanol, H-
(C ₂ H ₄ ) _o - Soluble in CH ₂ OH (n = 1, 2, 3), water, acetonitrile, methanol, acetone, chloroform, benzene, dioxane, n -
It was insoluble in hexane. Figure 1 shows the IR spectrum of this polyurethane measured by the KBr method. In this IR spectrum, 1540 cm ^-1 (A
The absorption observed at 1655 cm ^-1 (points indicated by ) and 1655 cm -1 (B in the figure) is based on the amino group of the Z-Ser-Ser-OMe component. 1720-1730cm ^-1 (C in the diagram)
The broad absorption observed in Z-Ser-Ser-
This is based on the carbamate group and ester group of the OMe component, and it is thought that the absorption of the urethane bond that occurs with the production of polyurethane overlaps with this. That is, as the reaction progresses, 1720-
It is thought that the absorption at 1730 cm ^-1 increased significantly, and the final result was as shown in Figure 1. Also, on the contrary
The absorption based on isocyanate groups at 2300 cm ^-1 that appears strongly immediately after adding HMDI reacts with hydroxyl groups and changes into urethane bonds, so it rapidly attenuates as the reaction progresses, and in polyurethane, as shown in Figure 1. No absorption is observed. Based on these facts, the polyurethane obtained in the above reaction is considered to have the following structure. Example 2 Polyurethane containing Z-Ser-Ser-OMe and MDI [Hereinafter, this polyurethane will be referred to as PU (Z-
Production of Z-Ser-Ser-OMe in this example
Polyurethane using MDI was produced in the same manner as in Example 1 above. However, the catalyst MgO
was not used and the reaction was carried out at room temperature for 3 days. The obtained polyurethane was washed with methanol to remove residual reaction products, to obtain a hard polyurethane with a pale yellow tinge. The polyurethane obtained by this method is thought to have the following structure. The above polyurethane was dissolved in dimethylformamide and the viscosity at 30°C was measured.
[η=0.22. Under these conditions, the molecular weight calculated by applying the relationship between [η] and molecular weight reported for polymethyl methacrylate was approximately 100,000. Example 3 Polyurethane containing PTMG with a molecular weight of 1336 (hereinafter abbreviated as PTMG1336), HMDI, and Z-Ser-Ser-OMe [hereinafter, this polyurethane will be referred to as
PU (PTMG1336, HMDI, Z-Ser-Ser-
Production of 0.98 g of PTMG1336 in 7 ml of dimethylformamide and 0.235 ml of HMDI (abbreviated as PTMG).
(equivalent to twice the mole amount) in 2.5 ml of dimethylformamide, and after purging with nitrogen,
The reaction was carried out at 60°C for 3 hours. After that, 0.5g of Z-
Add a solution of Ser-Ser-OMe (equimolar to PTMG) in 4 ml of dimethylformamide, and heat at 50°C.
was allowed to react for 24 hours. Then, 0.015 ml of n-hexylamine (10 mol% of the originally used HMDI) was added.
) was added to convert the isocyanate group present at the end of the reaction product into a substituted urea and stabilize it. Polyurethane was taken out in the same manner as in Example 1, dissolved in dimethylformamide, poured into water, and purified by precipitation. Upon drying, a white, slightly viscous polyurethane was obtained. When this polyurethane was dissolved in dimethylformamide and its viscosity at 30°C was measured, it was found that [η] = 0.054. Under these conditions, the molecular weight calculated by applying the relationship between [η] and molecular weight reported for polystyrene was approximately 5000. PTMG with a molecular weight of 1100 (hereinafter abbreviated as PTMG1100) and PTMG with a molecular weight of 2117 (hereinafter referred to as PTMG2117)
Polyurethane was synthesized using the same procedure. However, in this case the PTMG
10 mol% MgO was added as a catalyst, and PTMG and
The reaction time for HMDI was 2 hours. Take out the polyurethane in the same manner as in Example 1 above,
After purification, a white polyurethane was obtained. PU obtained by this method (PTMG1100, HMDI, Z-Ser-Ser-
OMe) staining method (sample swollen with _CHCl3 )
Figure 2 shows the IR spectrum measured by inserting it between KBr plates. In this IR spectrum, 1530cm ^-1 (A in the figure
The absorption at 1) and the broad absorption at 1650 cm ^-1 (B in the figure) are based on the amino groups of the Z-Ser-Ser-OMe component. 1700cm ^-1 (C in the diagram)
The broad absorption observed in Z-Ser-Ser-
This is based on the carbamate group and ester group of the OMe component, and it is thought that the absorption of urethane bonds that occur with the formation of polyurethane overlaps with these. The absorption at 1100 cm ^-1 (D in the figure) is based on the alkyl ether group -CH ₂ -O-CH ₂ -, and the absorption at 750 cm ^-1 (E in the figure) is based on the tetramethylene group - (CH ₂ ). ₄ - and these indicate the existence of PTMG. Based on these facts, it is thought that the polyurethane obtained by the above reaction has the following structure. The solubility of this polyurethane is soluble in hexamethylphosphoamide, trifluoroacetic acid, dimethyl sulfoxide, dimethylformamide, methanol,
It was partially soluble in ethanol and methylene chloride, and insoluble in water, trimethyl phosphate, acetonitrile, dioxane, tetrahydrofuran, ethyl acetate, benzene, and chloroform. Example 4 Polyurethane containing PTMG1336, MDI, Z-Ser-Ser-OMe (hereinafter, this polyurethane will be referred to as PU (PTMG1336, MDI, Z-Ser-Ser-
Production of polyurethane using PTMG1336, MDI, Z-Ser-Ser-OMe) was carried out in accordance with the above Example 3 (catalyst
It was carried out in the same manner as in (example without using MgO).
However, the reaction time between PTMG1336 and MDI was 1 hour, and the final product was purified by pouring the dimethylformamide solution into methanol to cause precipitation. Upon drying, a pale yellow, elastic polyurethane was obtained. When this polyurethane was dissolved in dimethylformamide and its viscosity at 30°C was measured, it was found to be [η]=0.209. Under these conditions, the molecular weight calculated by applying the relationship between [η] and molecular weight reported for polymethyl methacrylate was about 80,000. Furthermore, polyurethane was synthesized using PTMG1100 and PTMG2117 in the same manner. Obtained PU (PTMG1100, MDI, Z-Ser-Ser-
OMe) is a white elastic polymer,
[η] = 0.36, and the converted molecular weight was approximately 330,000. Also
PU (PTMG2117, MDI, Z-Ser-Ser-OMe)
is a white elastic polymer, [η)=
0.40, and the equivalent molecular weight was approximately 450,000. The solubility of these polyurethanes is soluble in hexamethylphosphoamide, dimethylsulfoxide, dimethylformamide, water, trimethylphosphate, acetic acid trifluoride, acetonitrile, methanol, ethanol, dioxane, tetrahydrofuran, ethyl acetate, methylene chloride, and benzene. , was insoluble in chloroform. PU (PTMG1100, MDI, Z-Ser-Ser-
Figure 3 shows the IR spectrum of OMe) obtained by the smearing method.
Shown below. In the figure, the absorption assignments indicated by A to E are the same as in Figure 2, but are new in Figure 3.
Phenyl group at 1590cm ^-1 (F in the figure)

Absorption based on the formula was observed, confirming that MDI exists in the polyurethane chain. Based on these facts, the polyurethane obtained in the above reaction is considered to have the following structure. These polyurethanes have excellent film-forming properties. PU (PTMG1336, MGI, Z-Ser-Ser-
We measured the ATR-IR spectrum of a film produced by casting a dimethylformamide solution of OMe) on a glass plate, but no difference was observed between the two sides of the film. Synthesis of polyurethane containing a cyclic dipeptide as one component: In this product, a cyclic dipeptide diol is synthesized by cyclocondensation of an α-amino acid having a hydroxyl group in the side chain, and this is used as a chain extender in the coexistence of an alkylene diol (or coexistence). by carrying out a polyaddition reaction with an aliphatic or aromatic diisocyanate). (A) Synthesis of cyclic dipeptide diol: L- as an α-amino acid having a hydroxyl group in the side chain.
An example of using Senri will be described. Z-Ser-Ser synthesized by method (A) above
-Dissolve 1.5 g of OMe in 40 ml of methanol (saturated with HCl), add 0.3 g of Pd black, and bubble in hydrogen for about 5 hours. The solution was filtered and methanol was distilled off, and the resulting residue was washed several times with n-hexane to obtain 1.0 g of H-Ser-Ser-OMe.HCl (yield 93.6%). TLC and IR spectra confirmed that pure Z-Ser-Ser-OMe.HCl was obtained. H-Ser-Ser- obtained in this way
Dissolve 1.0 g of OMe・HCl in 41 ml of methanol (saturated with _NH3 ) (H-Ser-Ser-OMe
(concentration of 0.1M) and allowed to react at room temperature for 24 hours. The volatile components were distilled off and the residue was washed with n-hexane, yielding 0.55 g of needle-shaped crystals of dipeptide diol (hereinafter abbreviated as C-(Ser) ₂ ) in which L-serine was cyclized and condensed. (Yield 76.7%). The melting point of this product was 245-248°C, and elemental analysis and IR spectrum confirmed that pure C-(Ser) ₂ was obtained. The above reaction is expressed as follows. Z―Ser―Ser―OMeH ₂ /Pd ―――――――→ HCl/MeOHH―Ser― Ser―OMe・HClNH ₃ /MeOH ――――――――→ C (Ser) _2According to this method Even if the side chain hydroxyl group of serine is not protected, the specified reaction proceeds without modification or hindrance, and C-(Ser) ₂ can be obtained extremely efficiently. C(Ser) ₂ has the following chemical structure, and polyurethane can be synthesized by polyaddition reaction with diisocyanate as a diol component. (B) Synthesis of polyurethane containing cyclic dipeptide diol: Polyurethane is synthesized by mixing cyclic dipeptide diol with alkylene diol (without mixing the components) and performing a polyaddition reaction with various diisocyanates. Addition of MgO as a catalyst for the polyaddition reaction allows the reaction rate to be controlled. In the following examples, cases will be described in which PTMG with various degrees of polymerization is used as the alkylene diol and HMDI or MDI is used as the diisocyanate. Polyurethanes with various properties are synthesized depending on the degree of polymerization of PTMG, whether it is added or not, and the type of diisocyanate. Example 5 Polyurethane containing C-(Ser) ₂ and HMDI [hereinafter, this polyurethane will be referred to as PU [C-(Ser) ₂ ,
Production of HMDI]: 0.4 g of C-(Ser) ₂ obtained by the above (A)
Dissolve MgO in 50 ml of dimethylformamide and
Add 0.0093 g [corresponding to 10 mol% of the concentration of C-(Ser) _2] . Add this to 0.55ml of HMDI [C-
Add a solution of (Ser) ₂ (equivalent to 1.5 times the molar concentration of
The mixture was allowed to react for 24 hours with stirring. The reaction system was purged with nitrogen for the first few hours. After that, the PU (Z-Ser-Ser-OMe,
The product was separated and purified in the same manner as in the production of HMDI) to obtain a white powdery polyurethane. The solubility of this polyurethane is soluble in trifluoroacetic acid, partially soluble in dimethyl sulfoxide, phenol/ethanol mixed solvent, water, dimethylformamide, acetonitrile, methanol, acetone, chloroform, benzene, dioxane, n-
Hexane, H-(C ₂ F ₄ )n-CH ₂ OH(n-1,
2,3), and was insoluble in trifluoroethanol.
The polyurethane obtained by this method is thought to have the following structure. In the production of the above polyurethane,
Since HMDI is added in an amount 1.5 times the mole of C-(Ser) ₂ , both ends of the polyurethane produced are isocyanate groups. After carrying out the polyurethanization reaction for 24 hours, 0.635 g of p-nitroaniline was added,
React for 6 hours at room temperature. As a result, p-
A polyurethane with nitrophenyl urea groups is formed. The reaction solution was poured into 5% hydrochloric acid to precipitate the polyurethane, and the reprecipitation was repeated twice using a combination of dimethylformamide (solvent) and 5% hydrochloric acid (precipitating agent).The dimethylformamide solution was poured into a Sephadex column. The terminal p-nitrophenyl urea-terminated polyurethane was obtained. This is 10
% dimethyl sulfoxide- _d6 solution as 90MHz
¹ HNMR spectrum was measured, and the spectrum diagram shown in FIG. 4 was obtained. In Figure 4, signal A is at the -(CH ₂ ) ₆ - group of the HMDI segment, signal B is at the -CH ₂ -NH-COO- group of the urethane bond, and signal C is at the -CH< of the C-(Ser) ₂ segment. Based on this, signal D is at the O-H of the terminal p-nitrophenyl group,
Signal E is the m-H of the terminal p-nitrophenyl group.
Attributed to. From these facts, the above terminal p
-Nitrophenyl ureated polyurethane is thought to have the following structure. The value of n calculated from the ratio of the areas of D and E to the area of A in FIG. 4 is 13. That is, the molecular weight of PU [C-(Ser) ₂ , HMDI] obtained in this example is about 4,400. Example 6 Polyurethane containing C-(Ser) ₂ and MDI [hereinafter, this polyurethane will be referred to as PU [C-(Ser) ₂ ,
Production of polyurethane using C-(Ser) ₂ and MDI was carried out in the same manner as in Example 5 above. however,
No catalyst MgO was used and the reaction was carried out at room temperature for 3 days. After the reaction is completed, the solvent dimethylformamide is distilled off and concentrated, and the residue is poured into water to precipitate polyurethane. This was dried under reduced pressure over phosphorus pentoxide to obtain a light brown hard polyurethane. Figure 5 shows the IR spectrum of this polyurethane measured by the KBr method. In this IR spectrum,
The absorption observed at 1520 cm ^-1 (A in the figure) and 1660 cm ^-1 (B in the figure) is based on the amide group of the C-(Ser) ₂ component. The absorption observed at 1700 cm ^-1 (C in the figure) is based on urethane bonds that occur as polyurethane is produced. The absorption observed at 1585cm ^-1 (F in the figure) is MDI
It is based on the phenyl group of Based on these facts, the polyurethane obtained in the above reaction is considered to have the following structure. Example 7 Polyurethane containing PTMG1100, MDI, C-(Ser) ₂ [hereinafter this polyurethane will be referred to as PU]
Production of [PTMG1100, MDI, C-(Ser) ₂ ]: Dissolve 0.63 g of PTMG1100 in 6 ml of dimethylformamide, and dissolve 0.25 ml of MDI (equivalent to twice the mole of PTMG) in 3 ml of dimethylformamide. Mix with the dissolved solution, replace with nitrogen, and react at 60°C for 1 hour. Then 0.1g of C-(Ser) ₂
Add a solution of (equimolar to PTMG) dissolved in 20 ml of dimethylformamide and react at 50°C for 24 hours. After the reaction is completed, the solvent dimethylformamide is distilled off and concentrated, and water is poured into the residue to precipitate polyurethane. The precipitate was dried over phosphorus pentoxide to yield a pale yellow, elastic polyurethane. This polyurethane was dissolved in dimethylformamide and its viscosity at 30°C was measured.
[η]=0.16. Under these conditions, the molecular weight calculated by applying the relationship between [η] and molecular weight reported for polymethyl methacrylate was about 50,000. Polyurethane was synthesized using PTMG1336 and PTMG2117 in a similar manner. P.U.
(PTMG1336, MDI, C-(Ser) ₂ ) was a yellow elastic polymer, [η] = 0.35, and the equivalent molecular weight was approximately 310,000. Also, PU [PTMG2117, MDI,
C-(Ser) ₂ ] is a white elastic polymer,
[η] = 0.37, and the converted molecular weight was approximately 350,000. Figure 6 shows the IR spectrum of PU [PTMG1100, MDI, C-(Ser) ₂ ] obtained by the spreading method. In this spectrum, 1510-1540cm ^-1 (in the figure,
A), the absorptions observed at 1635-1675cm ^-1 (B in the figure), 1715cm ^-1 (C in the figure) and 1590cm ^-1 (F in the figure) are the same as in Fig. 5. , Figure 6
At 1100 cm ^-1 (D in the figure), there is an absorption based on the -CH ₂ -O-CH ₂ - group of the PTMG segment, and at 750 cm ^-1 (E in the figure), there is an absorption based on the -(CH ₂ ) ₄ - of the PTMG segment. Absorption based on groups has been observed,
The presence of PTMG segments in polyurethanes has been shown. Based on these facts, the polyurethane obtained in the above reaction is considered to have the following structure. The production of segmented polyurethane by the method of the present invention is not limited to the above-mentioned cases, but also includes other cases. For example, as an amino acid having a hydroxyl group as a component of dipeptide diol used in the production of polyurethane, not only serine mentioned above but also threonine and tyrosine can be used. These α-amino acids exist in D-form and L-form, and either of them may be used. It is also possible to use a mixture of both or a ceramic body. It is also possible to use a mixture of two or more different α-amino acids. In all these cases, both linear and cyclic dipeptides can be synthesized and used as raw materials for polyurethane production. In the case of linear dipeptides, the amino and carboxyl groups must be protected. In addition to carbobenzyloxy group, as a protecting group for amino group,
A t-butyloxycarbonyl group or a formyl group can be used. Furthermore, as a protecting group for a carboxyl group, benzyl ester or amide can be used in addition to methyl ester. In addition to the above-mentioned PTMG, examples of alkylene diols or oligomers thereof that can be used in producing polyurethane include polyethylene glycol, polypropylene glycol, oligoether diols such as ethylene glycol/propylene glycol copolymers, hexamethylene glycol, and neopentyl. Examples include low molecular weight diols such as glycols. Diisocyanates that can be used in the production of polyurethane include, in addition to the above-mentioned HMDI and MDI, aromatic diisocyanates such as toluene diisocyanate, phenylene diisocyanate, naphthalene diisocyanate, and xylene diisocyanate; Methylenebis(4-isocyanatocyclohexane), 1-carbomethoxy-1,6-
Aliphatic diisocyanates such as diisocyanate hexane may be mentioned. In addition to MgO, tin carboxylate [(C ₁₂ H ₂₅ COO) ₂ Sn] may be used as a catalyst for producing polyurethane. The polyurethane obtained by the method of the present invention has excellent antithrombotic properties, and the test results will be shown below together with comparative examples. Antithrombotic test The samples used in this test are as follows. Sample (1) Glass sample (2) PU (PTMG2117, MDI) (molecular weight 2117)
It is a polyurethane synthesized from PTMG and MDI and does not contain dipeptide diol components. ) Sample (3) PU (Z―Ser―Ser―OMe, MDI) Sample (4) PU (PTMG1100, Z―Ser―Ser―
OMe, MDI) Sample (5) PU [C-(Ser) ₂ , MDI] Sample (6) PU [PTMG1336, C-(Ser) ₂ , MDI] Sample (7) PU [PTMG2117, C-(Ser) ₂ , MDI] The above samples (2) to (7) were made into a dimethylformamide solution, placed in a watch glass made of the same glass as the above sample (1), the solvent was distilled off using an infrared lamp, and the solution was dried overnight under reduced pressure. and use it as a test sample. Sample (2) is a polyurethane containing no dipeptide diol component as described above, and was used for comparison with polyurethane samples (3) to (7) of the products of the present invention. Furthermore, for comparison, a watch glass without any treatment was used as sample (1). The test was conducted as follows. Take 30 ml of blood from the femoral artery of an adult female dog (weighing approximately 15 kg).
Add 4.5 ml of ACD solution (a solution consisting of citric acid, sodium citrate, and glucose), pour 2 ml of this solution onto each sample prepared above on a watch glass, and add 0.1 M calcium chloride solution. Add 0.2 ml of aqueous solution to initiate clotting. Distilled water is added every time a set period of time elapses to stop blood clots, and the formed blood clots are fixed in formalin and replaced with distilled water. Remove the wet clot with a spatula, place it between tissue paper to absorb excess water, and weigh. The results of the thrombus formation test are shown in the table below.

[Table] In the above table, the weight is in mg, and the % value is the relative weight % with respect to the clot weight after 15 minutes when glass (sample 1) is used as 100%. According to the above table, blood completely coagulates within 15 minutes on glass (Sample 1). Sample (2), a polyurethane containing no dipeptide diol component, exhibits intermediately good antithrombotic properties. In comparison, the antithrombotic properties of the polyurethane containing the dipeptide diol component of the present invention were as follows. First, as a diol component, Z-Ser-
For polyurethane containing Ser-OMe, PU (Z-Ser-Ser-OMe,
MDI) exhibits excellent antithrombotic properties, with a low coagulation rate of 30-40% even after 25 minutes. Among those containing PTMG, sample (4) PU (PTMG1100, Z-Ser-
Ser-OMe, MDI) exhibits excellent anti-blood properties. In polyurethane containing C-(Ser) ₂ as a diol component, sample (5) containing PTMG did not contain PU [C
- (Ser) ₂ , MDI] shows intermediately good antithrombotic properties, but it is slightly inferior to sample (3) containing a linear polypeptide diol component. On the other hand, among those containing PTMG, sample (6) PU [PTMG1336, C-(Ser) ₂ , MDI] containing PTMG with an intermediate molecular weight was 25
Even after several minutes had elapsed, the coagulation rate was low at 30-40%, demonstrating excellent antithrombotic properties. PU of sample (7) containing higher molecular weight PTMG [PTMG2117, C-(Ser) ₂ ,
MDI] showed moderately excellent antithrombotic properties. Polyurethane membranes are flexible and have smooth surfaces, and also exhibit fairly good antithrombotic properties based on their microphase-separated structure. In the present invention, it has been shown that by introducing a dipeptide diol component into a polyurethane membrane, its antithrombotic properties can be further improved. Also combined with dipeptide diol
It has been shown that the antithrombotic properties of polyurethane can be controlled by selecting the molecular weight of PTMG. The reason why the block copolymer of the present invention exhibits excellent antithrombotic properties as described above is due to the crystallinity, hydrophilicity, and rigidity of the dipeptide diol segment, and the amorphous, hydrophobic, and flexible properties of the PTMG and diisocyanate components. Based on the properties of the polyurethane membrane, the surface energy of the polyurethane film and the interfacial free energy with the blood are appropriate, resulting in the formation of a microphase-separated structure and the development of a domain structure. This is thought to be because it does not have a negative effect on the interaction with. Based on the above-mentioned excellent performance, the polyurethane material obtained by the present invention is suitable for various medical device materials that require antithrombotic properties, such as vascular catheters, shunts, extracorporeal blood transport circuits, and blood pumps for artificial hearts. Can be used. Furthermore, since the linear and cyclic dipeptide components have selective adsorption permeability for metal ions, amino acids, sugars, etc., it can be used as a permeable membrane for artificial kidneys. Since the peptide component has high CO ₂ permeability, it can be used as a gas exchange membrane for oxygenators, soft contact lens materials, and artificial skin materials. By changing the type and composition of the hydrophilic and hydrophobic components that make up polyurethane, interactions with blood proteins, platelets, etc. can be adjusted, making it a suitable base for biocleaners, bioseparators, bioactivators, etc. It can also be used as a material. What has been explained above and shown in the specific examples of implementation is related to typical examples to aid understanding of the present invention, and the present invention is not limited to these examples, but is intended to be understood according to the scope of the claims. However, other changes and modifications may be made within that scope.

[Brief explanation of the drawing]

Figure 1 shows the polyurethane PU (Z-Ser-Ser-OMe, HMDI) manufactured according to Example 1 in the text.
IR spectrum by KBr method, Figure 2 is Example 3
Polyurethane PU manufactured by
(PTMG1100, HMDI, Z-Ser-Ser-OMe)
Figure 3 shows the IR spectrum of the polyurethane PU produced in Example 4.
(PTMG1100, MDI, Z-Ser-Ser-OMe) by the spreading method. Figure 4 shows the polyurethane PU [C-
(Ser) ₂ , HMDI] 90MHz ¹ HNMR spectrum (measured as dimethyl sulfoxide-d ₆ solution, tetramethylsilane internal standard), Figure 5 shows the polyurethane PU [C-(Ser) _{2 ]} produced in Example 6. ，
MDI] IR spectrum by KBr method, Figure 6 shows the polyurethane PU produced in Example 7.
The IR spectra of [PTMG1100, MDI, C-(Ser) ₂ ] obtained by the smearing method are shown. In FIGS. 1, 2, 3, 5, and 6, the vertical axis is transmittance (%), and the horizontal axis is wave number (cm ^-1 ). In FIG. 4, the vertical axis is relative intensity, and the horizontal axis is chemical shift (ppm).

Claims (1)

[Claims] 1. A method for producing polyurethane, which comprises subjecting a linear or cyclic dimer of an α-amino acid having a hydroxyl group to a polyaddition reaction with a diisocyanate in the absence of alkylene diol or its oligomer.