N-(2-hydroxyethyl)prop-2-enamide

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 60.0 g of methanol were dissolved 19.14 g (67.63 mmol) of 12-methacrylamidododecanoic acid (MAD), 0.86 g (7.51 mmol) of N-hydroxyethylacrylamide (HEAA: Kohjin Co., Ltd.), and 0.33 g (1.97 mmol) of azobisisobutyronitrile (Nacalai Tesque, Inc.). Before use, azobisisobutyronitrile was recrystallized from methanol in the usual way. The solution was deaerated by bubbling argon for 60 minutes. The container was covered with a septum, and the polymerization was conducted by heating at 60° C. for 20 hours. After the completion of the polymerization reaction, the reaction solution was dropwise added into a large excess of diethyl ether, and the resulting precipitate was collected by filtration under suction. After drying under reduced pressure, 16.90 g of MAD/HEAA copolymer (90/10) was obtained (yield: 84.5%). Before use, azobisisobutyronitrile was recrystallized from methanol in the usual way by bubbling argon for 60 minutes After the completion of the polymerization reaction the resulting precipitate was collected by filtration under suction After drying under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hexafluoropropene (15 g, 0.10 mol) was added over 30 minutes (nitrogen atmosphere) at 0° C. to a stirred mixture of CH2═CH(CO)NHCH2CH2OH (6.25 g, 0.054 mol), acetonitrile (180 mL) and powdered K2CO3 (3.5 g). After complete addition, the stirred reaction mixture was gradually brought to room temperature (˜1 h). The resultant pale yellow solution was filtered, and the filtrate was concentrated at the rotary evaporator. The crude product was concentrated further at ˜2 mm Hg for 15 min on a vacuum line to afford 8.5 g of CH2═CH(CO)NHCH2CH2OCF2CFHCF3 as a light yellow, viscous liquid. EI/DIP MS: m/e 265 for M+ (C8H9F6NO); 19F NMR (CDCl3) δ−75.7 (m, 3F), −81.0 to −83.0 (ddm, 2 F), and −212.1 (m, 1 F) ppm. 1H NMR (CDCl3) δ 6.3 (dd, 1H), 6.2 (dd, 1H), 6.19 (dd, 1H), 5.7 (dd, 1H), 4.8 (dm, 1H, JHF=42 Hz), 4.1 (t, 2H) and 3.6 (dt, 2H). After complete addition the stirred reaction mixture was gradually brought to room temperature (˜1 h) The resultant pale yellow solution was filtered the filtrate was concentrated at the rotary evaporator The crude product was concentrated further at ˜2 mm Hg for 15 min on a vacuum line

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 300 mL three-necked flask, N-(2-hydroxyethyl)acrylamide (15.04 g, 0.100 mol), N,N-dimethylacrylamide (9.96 g, 0.100 mol), t-amyl alcohol (99.80 g), polymerization initiator VA-061 (Wako Pure Chemical Industries, Ltd., 0.0310 g, 0.124 mmol) were charged, and then equipped with a three-way stop-cock, a reflux condenser tube, a thermometer and a mechanical stirrer. The concentration of the monomer was 20% by weight. After degassing inside the three-necked flask using a vacuum pump and repeating replacement by argon three times, stirring was carried out at 70° C. for 1 hour, followed by temperature rise to 75° C. and further stirring for 4 hours. After completion of the polymerization, the polymerization reaction solution was cooled to room temperature and the solvent was distilled off by an evaporator, and then washed once with each of n-hexane/methanol (=200 mL/100 mL, 200 mL/100 mL, 100 mL/40 mL and 100 mL/60 mL). The solid component was dried overnight by a vacuum drying oven at 60° C. Liquid nitrogen was charged and the solid component was crushed by a spatula, and then dried by a vacuum drying oven at 60° C. for 3 hours. The thus obtained copolymer had a molecular weight of Mn: 109 kD, Mw: 660 kD (Mw/Mn=6.1). were charged equipped with a three-way After degassing inside the three-necked flask followed by temperature rise to 75° C. further stirring for 4 hours After completion of the polymerization the polymerization reaction solution the solvent was distilled off by an evaporator washed once with each of n-hexane/methanol (=200 mL/100 mL, 200 mL/100 mL, 100 mL/40 mL and 100 mL/60 mL) The solid component was dried overnight by a vacuum drying oven at 60° C Liquid nitrogen was charged the solid component was crushed by a spatula dried by a vacuum drying oven at 60° C. for 3 hours

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 300 mL three-necked flask, N-(2-hydroxyethyl)acrylamide (15.04 g, 0.100 mol), N,N-dimethylacrylamide (9.96 g, 0.100 mol), t-amyl alcohol (99.80 g), polymerization initiator VA-061 (Wako Pure Chemical Industries, Ltd., 0.0310 g, 0.124 mmol) were charged, and then equipped with a three-way stop-cock, a reflux condenser tube, a thermometer and a mechanical stirrer. The concentration of the monomer was 20% by weight. After degassing inside the three-necked flask using a vacuum pump and repeating replacement by argon three times, stirring was carried out at 70° C. for 1 hour, followed by temperature rise to 75° C. and further stirring for 4 hours. After completion of the polymerization, the polymerization reaction solution was cooled to room temperature and the solvent was distilled off by an evaporator, and then washed once with each of n-hexane/methanol (=200 mL/100 mL, 200 mL/100 mL, 100 mL/40 mL and 100 mL/60 mL). The solid component was dried overnight by a vacuum drying oven at 60° C. Liquid nitrogen was charged and the solid component was crushed by a spatula, and then dried by a vacuum drying oven at 60° C. for 3 hours. The thus obtained copolymer had a molecular weight of Mn: 109 kD, Mw: 660 kD (Mw/Mn=6.1). were charged equipped with a three-way After degassing inside the three-necked flask followed by temperature rise to 75° C. further stirring for 4 hours After completion of the polymerization the polymerization reaction solution the solvent was distilled off by an evaporator washed once with each of n-hexane/methanol (=200 mL/100 mL, 200 mL/100 mL, 100 mL/40 mL and 100 mL/60 mL) The solid component was dried overnight by a vacuum drying oven at 60° C Liquid nitrogen was charged the solid component was crushed by a spatula dried by a vacuum drying oven at 60° C. for 3 hours

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A synthetic pathway to compounds of the invention is depicted in scheme 1. Protected HEAA derivatives 3 and 10 were prepared respectively starting from 2-(tetrahydro-2H-pyran-2-yloxy)ethanol 1 (commercially available or obtained from THP selective monoprotection of diethylene glycol) and commercially available 2-(benzyloxy)ethanol 8. Fully protected 3 was obtained by a two steps procedure including formation of acid 2 by reaction of alcohol 1 with bromoacetic acid, followed by DIC/DMAP promoted coupling with benzyl alcohol. Further removal of THP protecting group afforded alcohol 4 which was coupled with acid 2 to give dimer 5 with 82% yield. Final deprotection by acidic treatment led to the obtention of desired alcohol 6, first building block for key trimer compound 11 obtention. This conversion also led to the formation of small amounts of alcohol 7, thus reflecting the instability of this latter in these conditions (probable intramolecular transesterification of the dimer alcohol 6). Attempts to obtain pure dimer 6 by flash chromatography gave only poor yields and crude residue was finally used for next step without further purification. were prepared respectively

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A synthetic pathway to compounds of the invention is depicted in scheme 1. Protected HEAA derivatives 3 and 10 were prepared respectively starting from 2-(tetrahydro-2H-pyran-2-yloxy)ethanol 1 (commercially available or obtained from THP selective monoprotection of diethylene glycol) and commercially available 2-(benzyloxy)ethanol 8. Fully protected 3 was obtained by a two steps procedure including formation of acid 2 by reaction of alcohol 1 with bromoacetic acid, followed by DIC/DMAP promoted coupling with benzyl alcohol. Further removal of THP protecting group afforded alcohol 4 which was coupled with acid 2 to give dimer 5 with 82% yield. Final deprotection by acidic treatment led to the obtention of desired alcohol 6, first building block for key trimer compound 11 obtention. This conversion also led to the formation of small amounts of alcohol 7, thus reflecting the instability of this latter in these conditions (probable intramolecular transesterification of the dimer alcohol 6). Attempts to obtain pure dimer 6 by flash chromatography gave only poor yields and crude residue was finally used for next step without further purification. were prepared respectively

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 60.0 g of methanol were dissolved 19.14 g (67.63 mmol) of 12-methacrylamidododecanoic acid (MAD), 0.86 g (7.51 mmol) of N-hydroxyethylacrylamide (HEAA: Kohjin Co., Ltd.), and 0.33 g (1.97 mmol) of azobisisobutyronitrile (Nacalai Tesque, Inc.). Before use, azobisisobutyronitrile was recrystallized from methanol in the usual way. The solution was deaerated by bubbling argon for 60 minutes. The container was covered with a septum, and the polymerization was conducted by heating at 60° C. for 20 hours. After the completion of the polymerization reaction, the reaction solution was dropwise added into a large excess of diethyl ether, and the resulting precipitate was collected by filtration under suction. After drying under reduced pressure, 16.90 g of MAD/HEAA copolymer (90/10) was obtained (yield: 84.5%). Before use, azobisisobutyronitrile was recrystallized from methanol in the usual way by bubbling argon for 60 minutes After the completion of the polymerization reaction the resulting precipitate was collected by filtration under suction After drying under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 60.0 g of methanol were dissolved 19.14 g (67.63 mmol) of 12-methacrylamidododecanoic acid (MAD), 0.86 g (7.51 mmol) of N-hydroxyethylacrylamide (HEAA: Kohjin Co., Ltd.), and 0.33 g (1.97 mmol) of azobisisobutyronitrile (Nacalai Tesque, Inc.). Before use, azobisisobutyronitrile was recrystallized from methanol in the usual way. The solution was deaerated by bubbling argon for 60 minutes. The container was covered with a septum, and the polymerization was conducted by heating at 60° C. for 20 hours. After the completion of the polymerization reaction, the reaction solution was dropwise added into a large excess of diethyl ether, and the resulting precipitate was collected by filtration under suction. After drying under reduced pressure, 16.90 g of MAD/HEAA copolymer (90/10) was obtained (yield: 84.5%). Before use, azobisisobutyronitrile was recrystallized from methanol in the usual way by bubbling argon for 60 minutes After the completion of the polymerization reaction the resulting precipitate was collected by filtration under suction After drying under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hexafluoropropene (15 g, 0.10 mol) was added over 30 minutes (nitrogen atmosphere) at 0° C. to a stirred mixture of CH2═CH(CO)NHCH2CH2OH (6.25 g, 0.054 mol), acetonitrile (180 mL) and powdered K2CO3 (3.5 g). After complete addition, the stirred reaction mixture was gradually brought to room temperature (˜1 h). The resultant pale yellow solution was filtered, and the filtrate was concentrated at the rotary evaporator. The crude product was concentrated further at ˜2 mm Hg for 15 min on a vacuum line to afford 8.5 g of CH2═CH(CO)NHCH2CH2OCF2CFHCF3 as a light yellow, viscous liquid. EI/DIP MS: m/e 265 for M+ (C8H9F6NO); 19F NMR (CDCl3) δ−75.7 (m, 3F), −81.0 to −83.0 (ddm, 2 F), and −212.1 (m, 1 F) ppm. 1H NMR (CDCl3) δ 6.3 (dd, 1H), 6.2 (dd, 1H), 6.19 (dd, 1H), 5.7 (dd, 1H), 4.8 (dm, 1H, JHF=42 Hz), 4.1 (t, 2H) and 3.6 (dt, 2H). After complete addition the stirred reaction mixture was gradually brought to room temperature (˜1 h) The resultant pale yellow solution was filtered the filtrate was concentrated at the rotary evaporator The crude product was concentrated further at ˜2 mm Hg for 15 min on a vacuum line

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hexafluoropropene (15 g, 0.10 mol) was added over 30 minutes (nitrogen atmosphere) at 0° C. to a stirred mixture of CH2═CH(CO)NHCH2CH2OH (6.25 g, 0.054 mol), acetonitrile (180 mL) and powdered K2CO3 (3.5 g). After complete addition, the stirred reaction mixture was gradually brought to room temperature (˜1 h). The resultant pale yellow solution was filtered, and the filtrate was concentrated at the rotary evaporator. The crude product was concentrated further at ˜2 mm Hg for 15 min on a vacuum line to afford 8.5 g of CH2═CH(CO)NHCH2CH2OCF2CFHCF3 as a light yellow, viscous liquid. EI/DIP MS: m/e 265 for M+ (C8H9F6NO); 19F NMR (CDCl3) δ−75.7 (m, 3F), −81.0 to −83.0 (ddm, 2 F), and −212.1 (m, 1 F) ppm. 1H NMR (CDCl3) δ 6.3 (dd, 1H), 6.2 (dd, 1H), 6.19 (dd, 1H), 5.7 (dd, 1H), 4.8 (dm, 1H, JHF=42 Hz), 4.1 (t, 2H) and 3.6 (dt, 2H). After complete addition the stirred reaction mixture was gradually brought to room temperature (˜1 h) The resultant pale yellow solution was filtered the filtrate was concentrated at the rotary evaporator The crude product was concentrated further at ˜2 mm Hg for 15 min on a vacuum line

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 300 mL three-necked flask, N-(2-hydroxyethyl)acrylamide (15.04 g, 0.100 mol), N,N-dimethylacrylamide (9.96 g, 0.100 mol), t-amyl alcohol (99.80 g), polymerization initiator VA-061 (Wako Pure Chemical Industries, Ltd., 0.0310 g, 0.124 mmol) were charged, and then equipped with a three-way stop-cock, a reflux condenser tube, a thermometer and a mechanical stirrer. The concentration of the monomer was 20% by weight. After degassing inside the three-necked flask using a vacuum pump and repeating replacement by argon three times, stirring was carried out at 70° C. for 1 hour, followed by temperature rise to 75° C. and further stirring for 4 hours. After completion of the polymerization, the polymerization reaction solution was cooled to room temperature and the solvent was distilled off by an evaporator, and then washed once with each of n-hexane/methanol (=200 mL/100 mL, 200 mL/100 mL, 100 mL/40 mL and 100 mL/60 mL). The solid component was dried overnight by a vacuum drying oven at 60° C. Liquid nitrogen was charged and the solid component was crushed by a spatula, and then dried by a vacuum drying oven at 60° C. for 3 hours. The thus obtained copolymer had a molecular weight of Mn: 109 kD, Mw: 660 kD (Mw/Mn=6.1). were charged equipped with a three-way After degassing inside the three-necked flask followed by temperature rise to 75° C. further stirring for 4 hours After completion of the polymerization the polymerization reaction solution the solvent was distilled off by an evaporator washed once with each of n-hexane/methanol (=200 mL/100 mL, 200 mL/100 mL, 100 mL/40 mL and 100 mL/60 mL) The solid component was dried overnight by a vacuum drying oven at 60° C Liquid nitrogen was charged the solid component was crushed by a spatula dried by a vacuum drying oven at 60° C. for 3 hours

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1000 mL three-necked round bottom flask is charged with a solution of 28.4 9 (250 mmol) cysteamine hydrochloride in 400 mL deionized water. 407 mg (1.5 mmol) α,α′-azodiiso-butyramidine dihydrochloride and 70.6 g (500 mmol) acryloyl morpholine and 28.8 g (250 mmol) N-hydroxyethyl acrylamide are added. An intensive cooler and an internal thermometer are connected to the flask. The apparatus is evacuated to 100 mbar and filled with argon. This is repeated five times. The mixture is heated to 60° C. for four hours and then cooled to room temperature. An analytical sample is freeze-dried and the monomer conversion is determined by 1H-NMR spectroscopy. No resonances corresponding to C═C double bonds can be detected, indicating >98% conversion of the monomer. The remaining mixture is adjusted to pH=10 by addition of 30% KOH solution. Salts and low molecular weight residues such as unreacted chain transfer agent are removed by reverse osmosis using a Millipore Proscale system equipped with a Millipore Helicon RO-4 Nanomax 50 membrane operating at a pressure of 15 bar. The product is isolated from the obtained retentate by freeze-drying. Yield: 85 g of a white powder. The concentration of amino-groups is determined by functional group titration, result 0.95 mmol/g NH2 corresponding to an average molecular weight of the co-telomer of 1050 g/mol. GPC-analysis indicates a monomodal molecular weight distribution and the absence of high molecular weight polymer. The apparatus is evacuated to 100 mbar filled with argon cooled to room temperature An analytical sample is freeze-dried The remaining mixture is adjusted to pH=10 by addition of 30% KOH solution Salts and low molecular weight residues such as unreacted chain transfer agent are removed by reverse osmosis equipped with a Millipore Helicon RO-4 Nanomax 50 membrane operating at a pressure of 15 bar The product is isolated from the obtained retentate by freeze-drying result 0.95 mmol/g NH2 corresponding to an average molecular weight of the co-telomer of 1050 g/mol