4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (1R,2S)-2-amino-1-(4-hydroxyphenyl)-propan-1-ol (495 mg) and ethyl N-[4-(2-bromoethyl)-2,6-dichloro-phenyl]aminoacetate (700 mg) in N,N-dimethylformamide (6 ml) was added N,N-diisopropylethylamine (343 μl), and the mixture was stirred for 7 hours at 70° C. The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloro-methane/ethanol=20/1) gave ethyl N-[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]-ethyl]phenyl]aminoacetate (510 mg). The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloro-methane/ethanol=20/1)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (1R,2S)-2-amino-1-(4-hydroxyphenyl)-propan-1-ol (495 mg) and ethyl N-[4-(2-bromoethyl)-2,6-dichloro-phenyl]aminoacetate (700 mg) in N,N-dimethylformamide (6 ml) was added N,N-diisopropylethylamine (343 μl), and the mixture was stirred for 7 hours at 70° C. The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloro-methane/ethanol=20/1) gave ethyl N-[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]-ethyl]phenyl]aminoacetate (510 mg). The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloro-methane/ethanol=20/1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1R,2S)-2-Amino-1-(4-hydroxyphenyl)propan-1-ol (70 mg) and ethyl 2-[4-(2-bromoethyl)-3-chlorophenoxy]-2-methyl-propionate (147 mg) were dissolved in N,N-dimethylformamide (2 ml), N,N-diisopropylethylamine (118 μl) was added to the solution, and the mixture was stirred for 2.5 hours at 80° C. After the reaction mixture was cooled, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate/ethanol=20/1) gave ethyl 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]-2-methylpropionate (98 mg). After the reaction mixture was cooled the resulting mixture was extracted with ethyl acetate The extract was washed with water dried over anhydrous magnesium sulfate the solvent was removed under reduced pressure Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate/ethanol=20/1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1R,2S)-2-Amino-1-(4-hydroxyphenyl)propan-1-ol (70 mg) and ethyl 2-[4-(2-bromoethyl)-3-chlorophenoxy]-2-methyl-propionate (147 mg) were dissolved in N,N-dimethylformamide (2 ml), N,N-diisopropylethylamine (118 μl) was added to the solution, and the mixture was stirred for 2.5 hours at 80° C. After the reaction mixture was cooled, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate/ethanol=20/1) gave ethyl 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]-2-methylpropionate (98 mg). After the reaction mixture was cooled the resulting mixture was extracted with ethyl acetate The extract was washed with water dried over anhydrous magnesium sulfate the solvent was removed under reduced pressure Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate/ethanol=20/1)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of ethyl 2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate (5.4 g), 10% palladium carbon (50% wet, 1.4 g), (1R,2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (3.0 g) and tetrahydrofuran (30 g) was stirred under a hydrogen atmosphere at 40° C. for 3 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene, and washed with water, an aqueous solution of sodium bicarbonate and brine successively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give ethyl (−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate (7.3 g). After the catalyst was removed by filtration the filtrate was concentrated under reduced pressure The residue was dissolved in toluene washed with water The organic layer was dried over anhydrous sodium sulfate the solvent was removed under reduced pressure

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of ethyl 2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate (5.4 g), 10% palladium carbon (50% wet, 1.4 g), (1R,2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (3.0 g) and tetrahydrofuran (30 g) was stirred under a hydrogen atmosphere at 40° C. for 3 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene, and washed with water, an aqueous solution of sodium bicarbonate and brine successively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give ethyl (−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate (7.3 g). After the catalyst was removed by filtration the filtrate was concentrated under reduced pressure The residue was dissolved in toluene washed with water The organic layer was dried over anhydrous sodium sulfate the solvent was removed under reduced pressure

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of ethyl 2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate (5.4 g), 10% palladium carbon (50% wet, 1.4 g), (1R,2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (3.0 g) and tetrahydrofuran (30 g) was stirred under a hydrogen atmosphere at 40° C. for 3 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene, and washed with water, an aqueous solution of sodium bicarbonate and brine successively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give ethyl (−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate (7.3 g). After the catalyst was removed by filtration the filtrate was concentrated under reduced pressure The residue was dissolved in toluene washed with water The organic layer was dried over anhydrous sodium sulfate the solvent was removed under reduced pressure

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of ethyl 2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate (5.4 g), 10% palladium carbon (50% wet, 1.4 g), (1R,2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (3.0 g) and tetrahydrofuran (30 g) was stirred under a hydrogen atmosphere at 40° C. for 3 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene, and washed with water, an aqueous solution of sodium bicarbonate and brine successively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give ethyl (−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate (7.3 g). After the catalyst was removed by filtration the filtrate was concentrated under reduced pressure The residue was dissolved in toluene washed with water The organic layer was dried over anhydrous sodium sulfate the solvent was removed under reduced pressure

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

Procedure: To a suspension of (1S,2R)-2-[2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl]isoindol-1,3-dione (1.0 g) in methanol (1.7 mL), methylamine in methanol (40% w/v; 3.5 mL) was added. The mixture was heated under reflux in argon atmosphere for 12 hours. After removing the solvent in vacua, the resulting residue was dissolved in tetrahydrofuran (3 mL) under heating. This solution was cooled and kept at room temperature. After removing the resulting precipitate by filtration, the mother liquor was concentrated in vacua. The resulting residue was recrystallized from ethyl acetate/methanol to obtain (1R, 2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (0.30 g: 54% yield, optical purity 100% e.e.). was added The mixture was heated under reflux in argon atmosphere for 12 hours After removing the solvent in vacua the resulting residue was dissolved in tetrahydrofuran (3 mL) under heating This solution was cooled kept at room temperature After removing the resulting precipitate by filtration the mother liquor was concentrated in vacua The resulting residue was recrystallized from ethyl acetate/methanol

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (1R,2S)-2-amino-1-(4-hydroxyphenyl)-propan-1-ol (495 mg) and ethyl N-[4-(2-bromoethyl)-2,6-dichloro-phenyl]aminoacetate (700 mg) in N,N-dimethylformamide (6 ml) was added N,N-diisopropylethylamine (343 μl), and the mixture was stirred for 7 hours at 70° C. The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloro-methane/ethanol=20/1) gave ethyl N-[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]-ethyl]phenyl]aminoacetate (510 mg). The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloro-methane/ethanol=20/1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropylamine (0.40 mL) was added to a mixture of ethyl 4′-(2-methanesulfonyloxyethoxy)biphenyl-4-carboxylate (0.32 g) and 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (0.32 g) in N,N-dimethylformamide (6 mL), and the mixture was stirred for 14 hrs at 80° C. After being cooled to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:methylene chloride/methanol=15/1) to afford ethyl 4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl-amino]ethoxy}biphenyl-4-carboxylate (0.22 g). After being cooled to room temperature the reaction mixture was partitioned between methylene chloride and water The organic layer was washed with water and brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (eluent:methylene chloride/methanol=15/1)

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

Procedure: Sodium triacetoxyborohydride (0.23 g) was added to a mixture of 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (0.082 g), methyl 3-isopropyl-3′,5′-dimethyl-4′-(2-oxo-propoxy)biphenyl-4-carboxylate (0.17 g) and acetic acid (0.03 mL) in tetrahydrofuran (2.5 mL) at room temperature with stirring, and the mixture was stirred at 50° C. for 4 hrs. After being cooled to room temperature, the reaction mixture was partitioned between a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:methylene chloride/methanol=9/1) followed by aminopropyl silica gel column chromatography (eluent:hexane/ethyl acetate=4/1) to afford methyl 4′-{(2RS)-2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)1-methylethylamino]propoxy}-3-isopropyl-3′,5′-dimethylbiphenyl-4-carboxylate (0.074 g). the mixture was stirred at 50° C. for 4 hrs the reaction mixture was partitioned between a saturated aqueous solution of sodium bicarbonate and ethyl acetate The organic layer was separated washed with water and brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (eluent:methylene chloride/methanol=9/1)