(1R)-2-amino-1-(3-chlorophenyl)ethanol

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

Procedure: Acetic acid (1 ml) and PtO2 (160 mg) were added to a solution of (R)-2-amino-1-(3-chlorophenyl) ethanol (600 mg) and 4-phenylcyclohexanone (610 mg) in methanol (30 ml), and hydrogen addition was carried out at room temperature. After consumption of the starting materials, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. Separation and purification by silica gel column chromatography (chloroform:methanol=30:1) gave 43 mg of (1R)-1-(3-chlorophenyl)-2-(4-phenylcyclohexylamino) ethanol (4.0% yield). was carried out at room temperature After consumption of the starting materials the catalyst was filtered off the filtrate was concentrated under reduced pressure Separation and purification by silica gel column chromatography (chloroform:methanol=30:1)

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

Procedure: To 274 mg (1.00 mmol) of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl methanesulfonate] were added 206 mg (1.20 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol and 194 mg (1.50 mmol) of dibutylamine, and the mixture was stirred at 60° C. for 24 hours under nitrogen atmosphere. The reaction mixture was added with a 10% aqueous solution of sodium hydroxide to be alkaline, and extracted twice with 30 ml of toluene. The toluene extract was dried over anhydrous sodium sulfate, and subjected to distillation of the solvent and to purification with silica gel chromatography to give 190 mg of 1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol as white crystals (yield: 54%). As a result of isolating and analyzing the isomers by high performance liquid chromatography using an optical resolution column (column: Chiralpack AD (trade name), Daicel Chemical Industries, Ltd.), the optical purity of the objective compound was 95.2% [(R,R)/(R,S)=95.2/4.8]. extracted twice with 30 ml of toluene The toluene extract was dried over anhydrous sodium sulfate subjected to distillation of the solvent and to purification with silica gel chromatography

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

Procedure: To 274 mg (1.00 mmol) of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl methanesulfonate] was added 206 mg (1.20 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol, and the mixture was stirred at 60° C. for 24 hours. The reaction mixture was added with a 10% aqueous solution of sodium hydroxide to be alkaline, and extracted twice with 30 ml of toluene. The toluene extract was dried over anhydrous sodium sulfate, and subjected to distillation of the solvent and to purification with silica gel chromatography to give 161 mg of 1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol as white crystals (yield: 46%). As a result of isolating and analyzing the isomers by high performance liquid chromatography using an optical resolution column (column: Chiralpack AD (trade name), Daicel Chemical Industries, Ltd.), the optical purity of the title compound was 95.8% [(R,R)/(R,S)=95.8/4.2]. extracted twice with 30 ml of toluene The toluene extract was dried over anhydrous sodium sulfate subjected to distillation of the solvent and to purification with silica gel chromatography

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

Procedure: To 274 mg (1.00 mmol) of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl methanesulfonate] was added 206 mg (1.20 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol, and the mixture was stirred at 60° C. for 24 hours. The reaction mixture was added with a 10% aqueous solution of sodium hydroxide to be alkaline, and extracted twice with 30 ml of toluene. The toluene extract was dried over anhydrous sodium sulfate, and subjected to distillation of the solvent and to purification with silica gel chromatography to give 161 mg of 1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol as white crystals (yield: 46%). As a result of isolating and analyzing the isomers by high performance liquid chromatography using an optical resolution column (column: Chiralpack AD (trade name), Daicel Chemical Industries, Ltd.), the optical purity of the title compound was 95.8% [(R,R)/(R,S)=95.8/4.2]. extracted twice with 30 ml of toluene The toluene extract was dried over anhydrous sodium sulfate subjected to distillation of the solvent and to purification with silica gel chromatography

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

Procedure: To 274 mg (1.00 mmol) of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl methanesulfonate] were added 206 mg (1.20 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol and 194 mg (1.50 mmol) of dibutylamine, and the mixture was stirred at 60° C. for 24 hours under nitrogen atmosphere. The reaction mixture was added with a 10% aqueous solution of sodium hydroxide to be alkaline, and extracted twice with 30 ml of toluene. The toluene extract was dried over anhydrous sodium sulfate, and subjected to distillation of the solvent and to purification with silica gel chromatography to give 190 mg of 1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol as white crystals (yield: 54%). As a result of isolating and analyzing the isomers by high performance liquid chromatography using an optical resolution column (column: Chiralpack AD (trade name), Daicel Chemical Industries, Ltd.), the optical purity of the objective compound was 95.2% [(R,R)/(R,S)=95.2/4.8]. extracted twice with 30 ml of toluene The toluene extract was dried over anhydrous sodium sulfate subjected to distillation of the solvent and to purification with silica gel chromatography

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

Procedure: To 274 mg (1.00 mmol) of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl methanesulfonate] was added 206 mg (1.20 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol, and the mixture was stirred at 60° C. for 24 hours. The reaction mixture was added with a 10% aqueous solution of sodium hydroxide to be alkaline, and extracted twice with 30 ml of toluene. The toluene extract was dried over anhydrous sodium sulfate, and subjected to distillation of the solvent and to purification with silica gel chromatography to give 161 mg of 1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol as white crystals (yield: 46%). As a result of isolating and analyzing the isomers by high performance liquid chromatography using an optical resolution column (column: Chiralpack AD (trade name), Daicel Chemical Industries, Ltd.), the optical purity of the title compound was 95.8% [(R,R)/(R,S)=95.8/4.2]. extracted twice with 30 ml of toluene The toluene extract was dried over anhydrous sodium sulfate subjected to distillation of the solvent and to purification with silica gel chromatography

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

Procedure: To 274 mg (1.00 mmol) of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl methanesulfonate] was added 206 mg (1.20 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol, and the mixture was stirred at 60° C. for 24 hours. The reaction mixture was added with a 10% aqueous solution of sodium hydroxide to be alkaline, and extracted twice with 30 ml of toluene. The toluene extract was dried over anhydrous sodium sulfate, and subjected to distillation of the solvent and to purification with silica gel chromatography to give 161 mg of 1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol as white crystals (yield: 46%). As a result of isolating and analyzing the isomers by high performance liquid chromatography using an optical resolution column (column: Chiralpack AD (trade name), Daicel Chemical Industries, Ltd.), the optical purity of the title compound was 95.8% [(R,R)/(R,S)=95.8/4.2]. extracted twice with 30 ml of toluene The toluene extract was dried over anhydrous sodium sulfate subjected to distillation of the solvent and to purification with silica gel chromatography

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

Procedure: To a solution of (R)-2-(3-chlorophenyl)oxirane (13 g, 84 mmol) in THF (84 mL) was added NaHMDS (1 M in THF) (252 mL, 252 mmol) slowly at 0° C. The reaction mixture was warmed up to room temperature and stirred for overnight. To the reaction mixture, water (33 mL, 2.5 mL/g) added. After stirring for 5 h at room temperature, solvent was removed in vacuo to about ¼ and partitioned by DCM. The bottom layer is a little cloudy and the top layer was a brown solution. Both layers were concentrated, which contained the desired (R)-2-amino-1-(3-chlorophenyl)ethanol (14 g, 97%). The combined products were used in next step without further purification. LCMS (m/z): 172.1 (MH+), 0.37 min. After stirring for 5 h at room temperature solvent was removed in vacuo to about ¼ partitioned by DCM Both layers were concentrated The combined products were used in next step without further purification 172.1 (MH+), 0.37 min.

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

Procedure: To a solution of (R)-2-(3-chlorophenyl)oxirane (13 g, 84 mmol) in THF (84 mL) was added NaHMDS (1 M in THF) (252 mL, 252 mmol) slowly at 0° C. The reaction mixture was warmed up to room temperature and stirred for overnight. To the reaction mixture, water (33 mL, 2.5 mL/g) added. After stirring for 5 h at room temperature, solvent was removed in vacuo to about ¼ and partitioned by DCM. The bottom layer is a little cloudy and the top layer was a brown solution. Both layers were concentrated, which contained the desired (R)-2-amino-1-(3-chlorophenyl)ethanol (14 g, 97%). The combined products were used in next step without further purification. LCMS (m/z): 172.1 (MH+), 0.37 min. After stirring for 5 h at room temperature solvent was removed in vacuo to about ¼ partitioned by DCM Both layers were concentrated The combined products were used in next step without further purification 172.1 (MH+), 0.37 min.

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

Procedure: The title compound was prepared from (2S)-2-{5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioic acid diethyl ester(which was obtained in Intermediate 34) and N-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 10) according to the procedures of Intermediate 18 and Example 1 as a yellowish solid; mp>130° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.19(t, J=7.0 Hz, 3 H), 1.22(t, J=7.0 Hz, 3 H), 1.70-3.00 (m,14 H), 2.92(s, 3 H), 3.50-3.90 (m, 2 H), 4.05(q, J=7.0 Hz, 2 H), 4.14(q, J=7.0 Hz, 2 H), 4.48(dd, J=8.0, 4.3 Hz, 1 H), 4.68(dd, J=8.7, 5.4 Hz, 1 H), 6.82(d, J=8.2 Hz, 1 H), 7.02(dd, J=8.2, 2.0 Hz, 1 H), 7.05(d, J=8.9 Hz, 2 H), 7.18(d, J=2.0 Hz, 1 H), 7.40(d, J=8.9 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z: 359.5 ((M+2H)2+, 100%); 718.2 (MH+, 20%); HRMS Calcd. for C33H44N6O9S2 (MH+): 718.2575. Found: 718.2581.

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

Procedure: The title compound was prepared from (2S)-2-{5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioic acid diethyl ester(which was obtained in Intermediate 34) and N-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 10) according to the procedures of Intermediate 18 and Example 1 as a yellowish solid; mp>130° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.19(t, J=7.0 Hz, 3 H), 1.22(t, J=7.0 Hz, 3 H), 1.70-3.00 (m,14 H), 2.92(s, 3 H), 3.50-3.90 (m, 2 H), 4.05(q, J=7.0 Hz, 2 H), 4.14(q, J=7.0 Hz, 2 H), 4.48(dd, J=8.0, 4.3 Hz, 1 H), 4.68(dd, J=8.7, 5.4 Hz, 1 H), 6.82(d, J=8.2 Hz, 1 H), 7.02(dd, J=8.2, 2.0 Hz, 1 H), 7.05(d, J=8.9 Hz, 2 H), 7.18(d, J=2.0 Hz, 1 H), 7.40(d, J=8.9 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z: 359.5 ((M+2H)2+, 100%); 718.2 (MH+, 20%); HRMS Calcd. for C33H44N6O9S2 (MH+): 718.2575. Found: 718.2581.

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

Procedure: The title compound was prepared from (2S)-2-{5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioic acid diethyl ester(which was obtained in Intermediate 34) and N-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 10) according to the procedures of Intermediate 18 and Example 1 as a yellowish solid; mp>130° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.19(t, J=7.0 Hz, 3 H), 1.22(t, J=7.0 Hz, 3 H), 1.70-3.00 (m,14 H), 2.92(s, 3 H), 3.50-3.90 (m, 2 H), 4.05(q, J=7.0 Hz, 2 H), 4.14(q, J=7.0 Hz, 2 H), 4.48(dd, J=8.0, 4.3 Hz, 1 H), 4.68(dd, J=8.7, 5.4 Hz, 1 H), 6.82(d, J=8.2 Hz, 1 H), 7.02(dd, J=8.2, 2.0 Hz, 1 H), 7.05(d, J=8.9 Hz, 2 H), 7.18(d, J=2.0 Hz, 1 H), 7.40(d, J=8.9 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z: 359.5 ((M+2H)2+, 100%); 718.2 (MH+, 20%); HRMS Calcd. for C33H44N6O9S2 (MH+): 718.2575. Found: 718.2581.