4-[2-(methylamino)ethyl]phenol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A separate solution of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine (A12) was prepared by mixing A12.HBr (100 g), triethylamine (360 mL) in methylene chloride (1000 mL). To this A12 solution was added slowly the above mentioned B13-Cl solution with agitation at room temperature. The reaction mixture was stirred for another one hr at room temperature after the addition was completed. The solid precipitate was removed by filtration and the filter cake was washed with methylene chloride. The combined methylene chloride solution was distilled until the pot temperature reached 55° C. To this residue, methanol (198 g) was added. The methanol of the resulted solution was removed by distillation until the pot temperature reached 70° C. The residue was cooled to room temperature and 15% NaOH/MeOH solution (460 mL) was added. The resulting solution was stirred at room temperature for 12 hr. The reaction mixture was acidified with 36% hydrochloric acid until the pH was between 3 and 5. The solution was set for distillation until the pot temperature reached 75° C. To the residue was added methylene chloride (200 mL) and 1N HCl (1500 mL) and stirred at 0° C. for 4 hr. The precipitate was collect by filtration to give 100 g (56% yield) of N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2). by mixing A12 To this A12 solution was added slowly the at room temperature after the addition The solid precipitate was removed by filtration the filter cake was washed with methylene chloride The combined methylene chloride solution was distilled until the pot temperature reached 55° C To this residue, methanol (198 g) was added The methanol of the resulted solution was removed by distillation until the pot temperature reached 70° C The residue was cooled to room temperature 15% NaOH/MeOH solution (460 mL) was added The resulting solution was stirred at room temperature for 12 hr The solution was set for distillation until the pot temperature reached 75° C To the residue was added methylene chloride (200 mL) and 1N HCl (1500 mL) stirred at 0° C. for 4 hr The precipitate was collect by filtration

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The previously prepared 2-bromo-5-hydroxy-4-methoxy benzoyl chloride (B13-Cl) in dichloromethane solution was transferred into the slurry of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine at about 5° C. and then stirred for about 0.5 hours under an atmosphere of nitrogen. The solution was concentrated under vacuum and then cooled to between 25 to 35° C. To this was then added a 15% w/v solution of NaOH in methanol (0.173 Kg sodium hydroxide in methanol 0.910 Kg) and was then heated to between 25 to 35° C. The solution was stirred for about 8 hours and then the pH was adjusted to between 2 to 5 with 32% hydrochloric acid (˜0.6 Kg). The solution was concentrated and the residue was cooled to about 30° C. Dichloromethane (6.628 Kg) and water (15 Kg) were added into the above mixture and then cooled to about 5° C. and was then stirred for about 2 hours. The solidified product was filtered and washed twice with dichloromethane (0.663 Kg each) to provide crude N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2). The solution was concentrated under vacuum To this was then added a 15% w/v solution of NaOH in methanol (0.173 Kg sodium hydroxide in methanol 0.910 Kg) was then heated to between 25 to 35° C The solution was stirred for about 8 hours The solution was concentrated the residue was cooled to about 30° C Dichloromethane (6.628 Kg) and water (15 Kg) were added into the above mixture cooled to about 5° C. was then stirred for about 2 hours The solidified product was filtered washed twice with dichloromethane (0.663 Kg each)

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The previously prepared 2-bromo-5-hydroxy-4-methoxy benzoyl chloride (B13-Cl) in dichloromethane solution was transferred into the slurry of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine at about 5° C. and then stirred for about 0.5 hours under an atmosphere of nitrogen. The solution was concentrated under vacuum and then cooled to between 25 to 35° C. To this was then added a 15% w/v solution of NaOH in methanol (0.173 Kg sodium hydroxide in methanol 0.910 Kg) and was then heated to between 25 to 35° C. The solution was stirred for about 8 hours and then the pH was adjusted to between 2 to 5 with 32% hydrochloric acid (˜0.6 Kg). The solution was concentrated and the residue was cooled to about 30° C. Dichloromethane (6.628 Kg) and water (15 Kg) were added into the above mixture and then cooled to about 5° C. and was then stirred for about 2 hours. The solidified product was filtered and washed twice with dichloromethane (0.663 Kg each) to provide crude N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2). The solution was concentrated under vacuum To this was then added a 15% w/v solution of NaOH in methanol (0.173 Kg sodium hydroxide in methanol 0.910 Kg) was then heated to between 25 to 35° C The solution was stirred for about 8 hours The solution was concentrated the residue was cooled to about 30° C Dichloromethane (6.628 Kg) and water (15 Kg) were added into the above mixture cooled to about 5° C. was then stirred for about 2 hours The solidified product was filtered washed twice with dichloromethane (0.663 Kg each)

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

Procedure: In a separate reaction vessel, a mixture of sodium hydroxide (0.603 Kg) and methanol (3.18 Kg) was stirred until the sodium hydroxide was completely dissolved and then N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine HBr salt (A12 HBr) (1 kg, by assay) in methanol (1.58 Kg) was added under an atmosphere of nitrogen. After stirring, the above mixture was concentrated to provide N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine as a slurry. The solution was cooled to about 5° C. under an atmosphere of nitrogen and then stirred for about 0.5 hours. In a separate reaction vessel was completely dissolved the above mixture was concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1000 mL of IPA was placed in a 3 L flask and cooled to 0° C. A steady stream of methylamine gas from a cylinder was slowly passed through the IPA until the total volume reached 1750 ml. 100 g of (2-[4-hydroxyphenyl]ethyl) bromide (A11) was added to the cooled methylamine IPA solution in several portions. The cooling bath was removed after all A11 was added. The reaction mixture was allow to warm to room temperature and continue to stir for another 10-12 h. The excess methylamine was distilled into another 1000 mL of pre-cooled to 0° C. IPA by heating the reaction mixture at 50° C. When most of the methylamine was distilled off, the bath temperature was raised to 100° C. and the IPA was distilled out. After most of the IPA had been distilled out, about 300 mL of IPA was added to the reaction mixture and distillation was continued to aid removal of the methylamine. After the volume was reduced to 250 mL, the reaction mixture was allowed to cool down to room temperature. The precipitate was collected by filtration and washed by toluene to give 104 g (90% yield) of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine as an HBr salt (A12 HBr). 1H NMR (CDCl3) δ 2.69 (3H, s, CH3), 2.90 (2H, t, J=7.2 Hz), 3.18 (2H, t, J=6.3 Hz), 6.76 (2H, d, J=8.7 Hz), 7.11 (2H, d, J=8.7 Hz) The cooling bath was removed after all A11 was added to warm to room temperature The excess methylamine was distilled into another 1000 mL of pre-cooled to 0° C IPA by heating the reaction mixture at 50° C When most of the methylamine was distilled off the bath temperature was raised to 100° C. the IPA was distilled out After most of the IPA had been distilled out about 300 mL of IPA was added to the reaction mixture and distillation removal of the methylamine to cool down to room temperature The precipitate was collected by filtration washed by toluene

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combine 4-(2-methylamino-ethyl)-phenol (1.0 g, 6.6 mmol), 6-chloronicotinamide (1.0 g, 6.6 mmol), and cesium carbonate (4.3 g, 13.2 mmol) in N,N-dimethylformamide (30 mL), stir and heat at 85° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator to yield the crude product (1.3 g). The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform then ethanol to yield 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (0.4 g, 1.5 mmol): 1H NMR (DMSO-d6, 300.00 MHz): 8.58 (d, 1H); 8.22 (dd, 1H); 7.26-7.23 (m, 2H); 7.05-7.02 (m, 3H); 3.32 (br, 2H); 2.69 (m, 5H); 2.29 (m, 4H) m/z=271.87 (M+1); HPLC=99% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM. Cool to room temperature evaporate on a rotary evaporator to yield the crude product (1.3 g) The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add dropwise via an addition funnel a solution of [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid methyl ester (13.0 g, 62.2 mmol) in tetrahydrofuran (100 mL) to a stirred solution at 0° C. of 11.0M lithium aluminum hydride in tetrahydrofuran (156 mL) and tetrahydrofuran (250 mL). Reflux for 18 hours, cool to 0° C., quench with saturated aqueous ammonium chloride then stir at room temperature for 3 hours. Filter off the aluminum salts, concentrate on a rotary evaporator, and dry under vacuum to yield 6.6 g of 4-(2-methylamino-ethyl)-phenol: 1H NMR (DMSO-d6, 300.00 MHz): 6.97 (d, 2H); 6.65 (d, 2H); 2.65-2.55 (m, 4H); 2.28 (s, 3H). Reflux for 18 hours quench with saturated aqueous ammonium chloride Filter off the aluminum salts concentrate on a rotary evaporator dry under vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add dropwise via an addition funnel a solution of [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid methyl ester (13.0 g, 62.2 mmol) in tetrahydrofuran (100 mL) to a stirred solution at 0° C. of 11.0M lithium aluminum hydride in tetrahydrofuran (156 mL) and tetrahydrofuran (250 mL). Reflux for 18 hours, cool to 0° C., quench with saturated aqueous ammonium chloride then stir at room temperature for 3 hours. Filter off the aluminum salts, concentrate on a rotary evaporator, and dry under vacuum to yield 6.6 g of 4-(2-methylamino-ethyl)-phenol: 1H NMR (DMSO-d6, 300.00 MHz): 6.97 (d, 2H); 6.65 (d, 2H); 2.65-2.55 (m, 4H); 2.28 (s, 3H). Reflux for 18 hours quench with saturated aqueous ammonium chloride Filter off the aluminum salts concentrate on a rotary evaporator dry under vacuum

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combine 4-(2-methylamino-ethyl)-phenol (1.0 g, 6.6 mmol), 6-chloronicotinamide (1.0 g, 6.6 mmol), and cesium carbonate (4.3 g, 13.2 mmol) in N,N-dimethylformamide (30 mL), stir and heat at 85° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator to yield the crude product (1.3 g). The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform then ethanol to yield 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (0.4 g, 1.5 mmol): 1H NMR (DMSO-d6, 300.00 MHz): 8.58 (d, 1H); 8.22 (dd, 1H); 7.26-7.23 (m, 2H); 7.05-7.02 (m, 3H); 3.32 (br, 2H); 2.69 (m, 5H); 2.29 (m, 4H) m/z=271.87 (M+1); HPLC=99% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM. Cool to room temperature evaporate on a rotary evaporator to yield the crude product (1.3 g) The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform