Synthesis and characterization of new hydrolytic-resistant dental resin adhesive monomer HMTAF

ABSTRACT Hydrolytic and enzymatic degradation of resin adhesives over time has been mainly attributed to secondary caries formation of methacrylate-based tooth-colored resin-based composite restorations. Ability of resin adhesive monomers to infiltrate into demineralized dentin forming stiff polymer matrix and potentially bonding to tooth structure is also a crucial property. The only commercially available antibacterial monomer, 12-methacryloyloxydodecyl pyridinium bromide (MDPB), is a quaternary ammonium methacrylate. This methacrylate monomer undergoes hydrolytic degradation, and could not bond to tooth structure. In this study, a new hydrolytic resistant monomer HMTAF was synthesized. It is methacrylamide-based monomer that, unlike methacrylate, is highly resistant to hydrolysis. Its molecular structure has particular functional groups; quaternary ammonium fluoride salt with potential antibacterial fluoride-releasing activity, hydroxyl and amide group with hydrogen bonding potential to dentin collagen. Hydroxyl group also increases monomer hydrophilicity for better penetration into water-saturated dentin and sufficient resin-dentin bond. The synthesized HMTAF and its polymer showed no hydrolytic degradation in acidic environment, while MDPB and its polymer were partially decomposed under this challenge. The conversion of monomer HMTAF to polymer was illustrated by FT-IR. The results indicated that HMTAF is highly resistant to hydrolysis, polymerizable and non-cytotoxic to Vero cell lines. It is a potential monomer to be incorporated into resin adhesives for improving hydrolytic and enzymatic resistance.


Synthesis of ammonium salt 1
Following the procedure of Perrault et al.,1 to a solution of benzaldehyde (2.70 mL, 21. 3 mmol) and epichlorohydrin ( 2. 00 mL, 25. 5 mmol) in ethanol ( 5. 30 mL) was added concentrated ammonium hydroxide (17.5 M, 2.25 mL, 38.2 mmol). The reaction mixture was heated at 40 ˚C overnight. The reaction mixture was concentrated under reduced pressure, and toluene ( 10 mL) was added to the resulting crude oil. Then a solution of hydrochloric acid (11.65 M, 3.40 mL, 39.8 mmol) was added over 5 min. The two-phase mixture was heated at 40 ˚C for 3 hours. The upper phase was extracted with water ( 3×20 mL) . The combined aqueous phase was concentrated under reduced pressure to give 3.56 g of ammonium salt 1 as yellow viscous oil. The crude oil was used without further purification.

Synthesis of Boc protected amine 2
A solution of 1-amino-3-chloropropan-2-ol hydrochloride (ammonium salt 1, 717.7 mg, 4.91 mmol) in methanol (3 mL) was placed into round bottom flask, and a solution of sodium bicarbonate (469 mg, 5.59 mmol) in water (1.7 mL) was added slowly. Then a solution of ditert-butyl dicarbonate (1.23 mL, 5.25 mmol) in methanol (2 mL) was added slowly, and the reaction mixture was stirred at room temperature overnight. Methanol was removed under reduced pressure. Methylene chloride (10 mL) and water (5 mL) were added to the crude oil.
After reaction was completed, acetone was removed under reduced pressure. Then methylene chloride (35 mL) was added into the crude product, and washed with water (3×35 mL). The methylene chloride layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 737 mg (70% yield) of iodo compound 3 as yellow viscous oil. Rf

Synthesis of compound 5
Triethylamine (96 µL, 0.69 mmol) was added to a solution of tert-butyl (3-amino-2hydroxypropyl)carbamate (amine 4, 130.5 mg, 0.69 mmol) in anhydrous THF (69 mL). Then the mixture was cooled to 0˚C and methacrylic anhydride (102 µL, 0.69 mmol) was added slowly. The reaction mixture was stirred for 5 h. THF in the resulting solution was removed under reduced pressure. Methylene chloride (60 mL) was added to the crude oil, and washed with saturated NaHCO3 (3×60mL). The methylene chloride layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give yellow viscous oil. The crude oil was purified by column chromatography with 4:1 hexane:ethyl acetate, followed by 100% ethyl acetate to give 169 mg (95% yield) of methacrylamide 5 as colorless viscous oil of. Rf

Synthesis of HMTAF
A solution of AgF (15.22 mg, 0.12 mmol) in water (3 mL) was added to a solution of 2hydroxy-3-methacrylamido-N,N,N trimethylpropan-1-aminium iodide (HMTAI, 39.4 mg, 0.12 mmol) in methanol (1 mL) under dimmed light for 10 min. AgI was precipitated, and removed by centrifugation. Methanol was removed under reduced pressure, and water was removed by freeze-drying process to give 15.50 mg (59% yield) of HMTAF as a pale yellow viscous oil.