POLYURETHANES BASED ON TERMINAL DIOL- AND DIAMINOPOLYPHOSPHAZENES AND THEIR HYDROGELS

Abstract

The present invention relates to polyphosphazenes, polyurethanes based on these polyphosphazenes, methods for their manufacture and hydrogels based on the polyurethanes. The invention further relates to the use of the hydrogels in medical, veterinary and agricultural applications. The terminal ends of the polyphosphazenes bear NCO-reactive hydrogen atoms for reaction with polyisocyanates.

Claims

1. A polyphosphazene of the general formula (I): ##STR00004## where: each radical R is, independent of other radicals R, an organic radical which does not contain a terminal group with an NCO-reactive hydrogen atom; each radical R.sub.1 is, independent of other radicals R.sub.1, an organic rest; each radical X is, independent of other radicals X, an organic rest; n is zero or a positive integer; characterized in that each radical ZH is, independent of other radicals ZH, a group comprising an NCO-reactive hydrogen atom.

2. The polyphosphazene according to claim 1, wherein at least one radical ZH is a hydroxyl group, a primary amino group or a secondary amino group.

3. The polyphosphazene according to claim 1 or 2, wherein at least one radical X comprises one of the following groups: —B—CH.sub.2—CH.sub.2—, —Si—CH.sub.2—CH.sub.2— or —S—CH.sub.2—CH.sub.2—, wherein the —CH.sub.2—CH.sub.2— groups are located between the B, Si or S atoms and a P atom to which radicals R.sub.1 are bond.

4. The polyphosphazene according to one of claims 1 to 3, wherein at least one radical X comprises one of the following groups: —(CH.sub.2).sub.m—B—, —(CH.sub.2).sub.m—Si— or —(CH.sub.2).sub.m—S— with m being an integer from 1 to 16, wherein the —(CH.sub.2).sub.m groups are located between the B, Si or S atoms and a radical ZH.

5. The polyphosphazene according to one of claims 1 to 4, wherein at least one radical X—ZH comprises the group —Ar—CH.sub.2—CH.sub.2—S—(CH.sub.2).sub.m—OH or —Ar—CH.sub.2—CH.sub.2—S—(CH.sub.2).sub.m—NH.sub.2 with m being an integer from 1 to 16 and Ar being a phenyl ring with or without additional substituents.

6. The polyphosphazene according to one of claims 1 to 5, wherein at least one radical R comprises an oxygen or nitrogen atom bound to a phosphorus atom of a phosphazene group and/or at least one radical R.sub.1 is a substituted or unsubstituted phenyl group.

7. A method of manufacturing a polyphosphazene according to the general formula (II), comprising reacting a C═C double bond-carrying compound of the general formula (III) with an element-hydrogen bond-carrying compound of the general formula H-E-L-ZH: ##STR00005## where: each radical E is, independent of other radicals E, B, Si or S; each radical L is, independent of other radicals L, an organic radical; each radical ZH is, independent of other radicals ZH, a group comprising an NCO-reactive hydrogen atom; each radical R is, independent of other radicals R, an organic radical which does not contain a terminal group with an NCO-reactive hydrogen atom; each radical R.sub.1 is, independent of other radicals R.sub.1, an organic rest; each radical Y is, independent of other radicals Y, an organic rest and n is zero or a positive integer.

8. A polyurethane polymer obtained by reacting a polyphosphazene (I) according to one of claims 1 to 6 with a polyisocyanate.

9. A method of manufacturing a polyurethane polymer comprising reacting a polyphosphazene (I) according to one of claims 1 to 6 with a polyisocyanate.

10. The polymer of claim 8 or the method of claim 9, wherein the polyisocyanate is an NCO-terminated prepolymer obtained by the reaction of a monomeric polyisocyanate and a polyether polyol.

11. The polymer of claim 10 or the method of claim 10, wherein the polyether polyol is a random copolymer of an alkylene oxide and a comonomer selected from: lactides, glycolides, cyclical dicarboxylic acid anhydrides and mixtures of at least two of the aforementioned compounds.

12. A hydrogel obtained by contacting a polyphosphazene (I) according to one of claims 1 to 6 and/or a polyurethane according to claim 8 with water.

13. The hydrogel of claim 12, further comprising, distributed within the hydrogel, a pharmaceutical compound, a pesticide, a herbicide, a pheromone or a combination of at least two of the aforementioned compounds.

14. A hydrogel according to claim 12 for use as a post-operative separator between internal organs of a human or an animal.

15. A hydrogel according to claim 13 for use as a delayed-release formulation for the pharmaceutical compound, pesticide, herbicide, pheromone or combination of at least two of the aforementioned compounds distributed within the hydrogel.

Description

EXAMPLES

[0074] The present invention will be further described in the following examples and figures without wishing to be limited to them.

Synthesis of α, ω-distyryl poly[(dichloro)phosphazenes](3)—FIG. 1

[0075] The synthesis of the chlorinated, styrene-functionalized, λ.sup.5-phosphane mediator was carried out according to literature (Wilfert, S.; Henke, H.; Schoefberger, W.; Brüggemann, O.; Teasdale, I., Chain-End-Functionalized Polyphosphazenes via a One-Pot Phosphine-Mediated Living Polymerization. Macromol. Rapid Commun. 2014, 35 (12), 1135-1141).

[0076] 4-(Diphenylphosphino)styrene (0.58 g, 2.01 mmol, 1 equiv.) and hexachloroethane (0.52 g, 2.21 mmol, 1.1 equiv.) were dissolved in 2 mL of anhydrous dichloromethane and stirred at room temperature for 24 h to yield dichlorodiphenyl(4-vinylphenyl)-λ.sup.5-phosphane, which was used for subsequent reactions without further purification. Yield: quantitative; .sup.31P{.sup.1H} NMR (121 MHz, CDCl.sub.3, δ): 63.33 (R.sub.3P═N—) ppm.

[0077] Dichlorodiphenyl(4-vinylphenyl)-λ.sup.5-phosphane (2.01 mmol, 1 equiv.) was reacted with N-(trimethylsilyl)-trichlorophosphoranimine (3.16 g, 14.08 mmol, 7 equiv.) in 5 mL of anhydrous dichloromethane and stirred at room temperature for 12 h to yield α-poly[(dichloro)phosphazene] 1, which was used for subsequent reactions without further purification. Yield: quantitative; .sup.31P{.sup.1H} NMR (121 MHz, CDCl.sub.3, δ): −18.19 (—Cl.sub.2P═N—), 8.09 (—PCl.sub.3), 19.50 (Ph.sub.3P═N—) ppm.

[0078] 4-(Diphenylphosphino)styrene (0.87 g, 3.08 mmol, 1 equiv.) and trimethylsilyl azide (1.39 g, 12.07 mmol, 4 equiv.) were dissolved in 25 mL of anhydrous dichloromethane. According to the .sup.31P NMR spectrum, the reaction was completed after stirring for 96 h at room temperature. Next, vacuum distillation was used to remove the excess of the azide in the solution after the reaction. This was achieved by transferring the solution into a Schlenk Tube and evaporating the solvent under reduced pressure obtaining the yellow, waxy-solid 1,1-diphenyl-N-(trimethylsilyl)-1-(4-vinylphenyl)-λ.sup.5-phosphanimine (N-organophosphoranimine) 2. Yield: 0.76 g (87%); .sup.1H NMR (300 MHz, CDCl.sub.3, δ): −0.18 (s, 1.5H, —CH.sub.3), −0.05 (s, 6H, —CH.sub.3), 0.08 (s, 0.5H, —CH.sub.3), 0.17 (s, 1H, —CH.sub.3), 5.34 (dd, 1H, —CH═CH.sub.2), 5.83 (dd, 1H, —CH═CH.sub.2), 6.74 (dd, 1H, —CH═CH.sub.2), 7.58 (m, 14H, -Ph.sub.3) ppm; .sup.31P{.sup.1H} NMR (121 MHz, CDCl.sub.3, δ): 0.49 (R.sub.3P═N—) ppm.

[0079] The N-organophosphoranimine 2 (1.13 g, 3.02 mmol, 1.5 equiv.) was dissolved in 8 mL of anhydrous dichloromethane, added to the solution of α-poly[(dichloro)phosphazene] 3 (2.01 mmol, 1 equiv.) in anhydrous dichloromethane and stirred at room temperature for 24 h until completion of the reaction, based on the .sup.31P NMR spectrum. The obtained solution of the end-capped α-ω-distyryl poly[(dichloro)phosphazene] 3 was used for subsequent reactions without further purification. Yield: quantitative; .sup.31P{.sup.1H} NMR (121 MHz, CDCl.sub.3, δ): −18.21 (—Cl.sub.2P═N—), 18.01 (—N═PPh.sub.3), 19.48 (Ph.sub.3P═N—) ppm.

Synthesis of α, ω-distyryl polyorganophosphazenes 4, 5 and 6—FIG. 2

[0080] Starting from 3, α, ω-distyryl polyorganophosphazenes were synthesized as follows:

[0081] The synthesis of α-ω-distyryl poly[bis(ethoxy)phosphazene] 4 was carried as follows: Sodium ethoxide was generated in situ by gradually dissolving sodium metal (1.17 g, 50.81 mmol, 1 equiv.) in anhydrous ethanol (29.67 mL, 0.54 mol, 10 equiv.) and stirring the solution for 48 h under a nitrogen stream, which was used to evaporate unreacted amounts of ethanol after the sodium metal was completely dissolved in the solution. The obtained solid white, dry sodium ethoxide (3.46 g, 50.81 mmol, 24.5 equiv.) was dissolved in 50 mL of anhydrous tetrahydrofuran and a solution of α-ω-distyryl poly[(dichloro)phosphazene] (1 equiv.) in 10 mL of anhydrous dichloromethane was added dropwise. According to the .sup.31P NMR spectrum, the reaction was completed after stirring for 96 h at room temperature. The solution was then centrifuged, the precipitate removed and the solvent was removed under reduced pressure to yield a solid-waxy brown-yellow product. Next, the polymer was dissolved in 10 mL of anhydrous ethanol and purified by dialysis against ethanol for 48 h (1 kDa cut-off). Finally, the solvent was removed under reduced pressure and the pale-yellowish product was dried further under vacuum at 45° C. for 24 h.

[0082] Yield: 1.40 g (41%); .sup.1H NMR (300 MHz, CDCl.sub.3, δ): 1.29 (br, 26H, —CH.sub.2—CH.sub.3), 4.15 (br, 18H, —CH.sub.2—CH.sub.3), 5.42 (br, 2H, —CH═CH.sub.2), 5.88 (br, 2H, —CH═CH.sub.2), 6.75 (br, 2H, —CH═CH.sub.2), 7.61 (br, 28H, -Ph.sub.3) ppm; .sup.31P{.sup.1H} NMR (121 MHz, CDCl.sub.3, δ): −1.39 (—Cl.sub.2P═N—), 13.76 (—N═PPh.sub.3), 15.08 (Ph.sub.3P═N—) ppm.

[0083] The synthesis of α-ω-distyryl poly[bis(glycine ethyl ester)phosphazene] 5 was synthesized as follows: Glycine ethyl ester hydrochloride (13.76 g, 98.57 mmol, 1 equiv.) was dissolved in 100 mL of anhydrous tetrahydrofuran, and triethylamine (27.25 mL, 0.197 mol, 2 equiv.) was added. The solution was stirred at room temperature for 48 h, filtered and the solvent removed under reduced pressure. The obtained glycine ethyl ester (5.24 g, 50.87 mmol, 24.5 equiv.) was dissolved in 40 mL of anhydrous tetrahydrofuran and triethylamine (14.05 mL, 0.102 mol, 49 equiv.) was added. Next, a solution of α-ω-distyryl poly[(dichloro)phosphazene] (1 equiv.) in 10 mL of anhydrous dichloromethane was added dropwise. According to the .sup.31P NMR spectrum, the reaction was completed after stirring for 24 h at room temperature. The solution was then filtered and the solvent removed under reduced pressure to yield a waxy, yellow product. Next, the polymer was dissolved in 10 mL of anhydrous ethanol and purified by dialysis against ethanol for 48 h (1 kDa cut-off). Finally, the solvent was removed under reduced pressure and the orange-yellowish product was dried further under vacuum at 45° C. for 24 h.

[0084] Yield: 2.68 g (50%); .sup.1H NMR (300 MHz, CDCl.sub.3, δ): 1.22 (br, 60H, —CH.sub.2—CH.sub.3), 3.70 (br, 40H, —NH—CH.sub.2—), 4.11 (br, 45H, —CH.sub.2—CH.sub.3), 5.41 (br, 2H, —CH═CH.sub.2), 5.88 (br, 2H, —CH═CH.sub.2), 6.74 (br, 2H, —CH═CH.sub.2), 7.60 (br, 28H, -Ph.sub.3) ppm; .sup.31P{.sup.1H} NMR (121 MHz, CDCl.sub.3, δ): 1.02 (—Cl.sub.2P═N—), 10.78 (—N═PPh.sub.3), 12.04 (Ph.sub.3P═N—) ppm.

[0085] The α-ω-distyryl poly[bis(N-(3-aminopropyl)morpholine)phosphazene] 6 was prepared by dissolving N-(3-aminopropyl)morpholine (6.36 mL, 43.55 mmol, 24.5 equiv.) in 40 mL of anhydrous tetrahydrofuran and adding triethylamine (12.04 mL, 87.10 mol, 49 equiv.). Next, a solution of α-ω-distyryl poly[(dichloro)phosphazene] (1 equiv.) in 10 mL of anhydrous dichloromethane was added dropwise. According to the .sup.31P NMR spectrum, the reaction was completed after stirring for 24 h at room temperature. The solution was then filtered and the solvent removed under reduced pressure to yield a waxy, orange-yellow product. Next, the polymer was dissolved in 10 mL of anhydrous ethanol and purified by dialysis against ethanol for 48 h (1 kDa cut-off). Finally, the solvent was removed under reduced pressure and the orange product was dried further under vacuum at 45° C. for 24 h.

[0086] Yield: 4.55 g (67%); .sup.1H NMR (300 MHz, CDCl.sub.3, δ): 1.67 (br, 26H, —CH.sub.2—CH.sub.2—CH.sub.2—), 2.41 (br, 80H, —CH.sub.2—CH.sub.2NH—CH.sub.2—), 2.88 (br, 26H, —NH—CH.sub.2—), 3.68 (br, 55H, —CH.sub.2—O—CH.sub.2—), 5.43 (br, 2H, —CH═CH.sub.2), 5.88 (br, 2H, —CH═CH.sub.2), 6.74 (br, 2H, —CH═CH.sub.2), 7.59 (br, 28H, -Ph.sub.3) ppm; .sup.31P{.sup.1H} NMR (121 MHz, CDCl.sub.3, δ): −3.57 (—Cl.sub.2P═N—), 11.25 (Ph.sub.3P═N—) ppm.

Functionalization the α-ω-Terminal Double Bonds of Polymer 6—FIG. 3

[0087] The following procedure describes an example of functionalization the α-ω-terminal double bonds of polymer 6 using the thiol-ene photoreaction with 6-mercapto-1-hexanol.

[0088] α-ω-distyryl poly[bis(N-(3-aminopropyl)morpholine)phosphazene] (300 mg, 0.0885 mmol, 1 equiv.) and 2,2-dimethoxy-2-phenylacetophenone (30 g, 10 w %) were dissolved in 5 mL of anhydrous ethanol in a non-UV-absorbing flask. Next, 6-mercapto-1-hexanol (23.77 mg, 0.117 mmol, 2 equiv.) was added. The flask was then sealed with a rubber septum and flushed with argon for 10 minutes. The solution was then stirred and irradiated with UV light at 4° C. overnight. Completion of the reaction was controlled by .sup.1H NMR spectroscopy. After the reaction was finished, the solvent was removed under reduced pressure. 20 mL of dichloromethane were added to re-dissolve the obtained α-ω-diol poly[bis(N-(3-aminopropyl)morpholine)phosphazene] and the solvent was removed again under reduced pressure to remove ethanol residues in the polymer. Finally, the polymer was dissolved in anhydrous tetrahydrofuran and used for subsequent reactions without further purification. Yield: quantitative.

Polyurethane Synthesis with Polyphosphazene Diols—FIG. 4

[0089] Poly(hexamethylene diisocyanate) (HDI biuret and oligomers; 1 NCO-equiv.) was added to a solution of α-ω-diol poly[bis(N-(3-aminopropyl)morpholine)phosphazene] (1 equiv.) in anhydrous tetrahydrofuran and stirred for 4 h at 50° C. After the reaction, the solvent was removed under reduced pressure and the solid, orange-yellowish polyurethane was dried further under vacuum at 45° C. for 24 h. Yield: quantitative; FT-IR (v): 3273 (—NH—), 3057 (—Ar—H), 2932-2807 (—CH.sub.2—), 1764 (—C═O—), 1688 (—NH—CO—), 1525 (—NH—CO—), 1233 (—P═N—), 860 (—P—N—) cm.sup.−1.