3-(3,5-difluorophenyl)propan-1-ol

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: Tosyl chloride (0.0814 mol) was added to a cooled (0°) solution of 3-(3,5-difluorophenyl)propanol (0.0407 mol) in pyridine (75 ml). The reaction was stirred 2 hours at 25°, then it was poured into ice/water and extracted into ethyl ether. The ethereal extracts were washed with 3N aqueous hydrogen chloride and water, then were dried over sodium sulfate and concentrated. The residue was dissolved in dimethylformamide (75 ml) and sodium azide (0.0814 mol) was added. The reaction was stirred 8 hours, then was diluted with water and extracted into ethyl acetate. The organic extract was washed with 3N aqueous hydrogen chloride and water, then dried over sodium sulfate and concentrated to yield 6.7 g (64%) of an oily product. extracted into ethyl ether The ethereal extracts were washed with 3N aqueous hydrogen chloride and water were dried over sodium sulfate concentrated The residue was dissolved in dimethylformamide (75 ml) The reaction was stirred 8 hours extracted into ethyl acetate The organic extract was washed with 3N aqueous hydrogen chloride and water dried over sodium sulfate concentrated

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

Procedure: Tosyl chloride (0.0814 mol) was added to a cooled (0°) solution of 3-(3,5-difluorophenyl)propanol (0.0407 mol) in pyridine (75 ml). The reaction was stirred 2 hours at 25°, then it was poured into ice/water and extracted into ethyl ether. The ethereal extracts were washed with 3N aqueous hydrogen chloride and water, then were dried over sodium sulfate and concentrated. The residue was dissolved in dimethylformamide (75 ml) and sodium azide (0.0814 mol) was added. The reaction was stirred 8 hours, then was diluted with water and extracted into ethyl acetate. The organic extract was washed with 3N aqueous hydrogen chloride and water, then dried over sodium sulfate and concentrated to yield 6.7 g (64%) of an oily product. extracted into ethyl ether The ethereal extracts were washed with 3N aqueous hydrogen chloride and water were dried over sodium sulfate concentrated The residue was dissolved in dimethylformamide (75 ml) The reaction was stirred 8 hours extracted into ethyl acetate The organic extract was washed with 3N aqueous hydrogen chloride and water dried over sodium sulfate concentrated

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

Procedure: Borane-tetrahydrofuran complex (0.095 mol) was added to a cooled (0°) solution of 3-(3,5-difluorophenyl)propanoic acid (0.043 mol) in tetrahydrofuran (75 ml). The reaction was stirred 2 hours at room temperature, then methanol was carefully added and the reaction was concentrated. The crude product was dissolved in ethyl ether, washed with water, dried over sodium sulfate and concentrated to yield 7 g (95%) of an oily product. Borane-tetrahydrofuran complex (0.095 mol) was added to the reaction was concentrated The crude product was dissolved in ethyl ether washed with water dried over sodium sulfate concentrated

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

Procedure: Borane-tetrahydrofuran complex (0.095 mol) was added to a cooled (0°) solution of 3-(3,5-difluorophenyl)propanoic acid (0.043 mol) in tetrahydrofuran (75 ml). The reaction was stirred 2 hours at room temperature, then methanol was carefully added and the reaction was concentrated. The crude product was dissolved in ethyl ether, washed with water, dried over sodium sulfate and concentrated to yield 7 g (95%) of an oily product. Borane-tetrahydrofuran complex (0.095 mol) was added to the reaction was concentrated The crude product was dissolved in ethyl ether washed with water dried over sodium sulfate concentrated

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

Procedure: Step 5 (A): N1-((1S,2S)-1-((R)-4-benzhydrylmorpholin-3-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-N3,N3-dipropylisophthalamide. To a solution of 3-(dipropylcarbamoyl)benzoic acid (Preparation E, 14 mg, 0.055 mmol) in dichloromethane (1 mL) was added Hunig's base (18 mg, 0.14 mmol) to make a clear solution and HATU (25 mg, 0.064 mmol) was then added. After stirring for 20 min, the reaction mixture was added (1S,2S)-2-amino-14R)-4-benzhydrylmorpholin-3-yl)-3-(3,5-difluorophenyl)propan-1-ol (Preparation D, (20 mg, 0.046 mmol) and the reaction mixture was stirred at rt overnight. Dichloromethane (100 mL) was added and washed with H2O (50 mL) twice, dried over Na2SO4, and concentrated to give the title compound as a crude product ready for next step without purification: 1H NMR (CD3OD, 500 MHz) δ 0.71 (3H, m), 1.01 (3H, m), 1.52 (2H, m), 1.74 (2H, m), 2.52 (1H, d, J=5 Hz), 2.63 (2H, dd, J=5, 15 Hz), 2.71 (1H, m), 3.12-3.19 (3H, m), 3.44-3.49 (3H, m), 3.94-3.99 (2H, m), 4.04 (1H, m), 4.58 (1H, m), 5.06 (1H, m), 5.50 (1H, s), 6.76 (1H, m), 6.92-6.95 (2H, m), 7.14-7.19 (3H, m), 7.25-7.32 (3H, m), 7.44 (2H, m), 7.49-7.55 (2H, m), 7.58 (2H, d, J=10 Hz), 7.63 (1H, s), 7.73-7.76 (1H, m). was then added Preparation D, (20 mg, 0.046 mmol) the reaction mixture was stirred at rt overnight washed with H2O (50 mL) twice dried over Na2SO4 concentrated

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

Procedure: Step 5 (A): N1-((1S,2S)-1-((R)-4-benzhydrylmorpholin-3-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-N3,N3-dipropylisophthalamide. To a solution of 3-(dipropylcarbamoyl)benzoic acid (Preparation E, 14 mg, 0.055 mmol) in dichloromethane (1 mL) was added Hunig's base (18 mg, 0.14 mmol) to make a clear solution and HATU (25 mg, 0.064 mmol) was then added. After stirring for 20 min, the reaction mixture was added (1S,2S)-2-amino-14R)-4-benzhydrylmorpholin-3-yl)-3-(3,5-difluorophenyl)propan-1-ol (Preparation D, (20 mg, 0.046 mmol) and the reaction mixture was stirred at rt overnight. Dichloromethane (100 mL) was added and washed with H2O (50 mL) twice, dried over Na2SO4, and concentrated to give the title compound as a crude product ready for next step without purification: 1H NMR (CD3OD, 500 MHz) δ 0.71 (3H, m), 1.01 (3H, m), 1.52 (2H, m), 1.74 (2H, m), 2.52 (1H, d, J=5 Hz), 2.63 (2H, dd, J=5, 15 Hz), 2.71 (1H, m), 3.12-3.19 (3H, m), 3.44-3.49 (3H, m), 3.94-3.99 (2H, m), 4.04 (1H, m), 4.58 (1H, m), 5.06 (1H, m), 5.50 (1H, s), 6.76 (1H, m), 6.92-6.95 (2H, m), 7.14-7.19 (3H, m), 7.25-7.32 (3H, m), 7.44 (2H, m), 7.49-7.55 (2H, m), 7.58 (2H, d, J=10 Hz), 7.63 (1H, s), 7.73-7.76 (1H, m). was then added Preparation D, (20 mg, 0.046 mmol) the reaction mixture was stirred at rt overnight washed with H2O (50 mL) twice dried over Na2SO4 concentrated

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

Procedure: Tosyl chloride (0.0814 mol) was added to a cooled (0°) solution of 3-(3,5-difluorophenyl)propanol (0.0407 mol) in pyridine (75 ml). The reaction was stirred 2 hours at 25°, then it was poured into ice/water and extracted into ethyl ether. The ethereal extracts were washed with 3N aqueous hydrogen chloride and water, then were dried over sodium sulfate and concentrated. The residue was dissolved in dimethylformamide (75 ml) and sodium azide (0.0814 mol) was added. The reaction was stirred 8 hours, then was diluted with water and extracted into ethyl acetate. The organic extract was washed with 3N aqueous hydrogen chloride and water, then dried over sodium sulfate and concentrated to yield 6.7 g (64%) of an oily product. extracted into ethyl ether The ethereal extracts were washed with 3N aqueous hydrogen chloride and water were dried over sodium sulfate concentrated The residue was dissolved in dimethylformamide (75 ml) The reaction was stirred 8 hours extracted into ethyl acetate The organic extract was washed with 3N aqueous hydrogen chloride and water dried over sodium sulfate concentrated

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

Procedure: Borane-tetrahydrofuran complex (0.095 mol) was added to a cooled (0°) solution of 3-(3,5-difluorophenyl)propanoic acid (0.043 mol) in tetrahydrofuran (75 ml). The reaction was stirred 2 hours at room temperature, then methanol was carefully added and the reaction was concentrated. The crude product was dissolved in ethyl ether, washed with water, dried over sodium sulfate and concentrated to yield 7 g (95%) of an oily product. Borane-tetrahydrofuran complex (0.095 mol) was added to the reaction was concentrated The crude product was dissolved in ethyl ether washed with water dried over sodium sulfate concentrated

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

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

Procedure: Tosyl chloride (0.0814 mol) was added to a cooled (0°) solution of 3-(3,5-difluorophenyl)propanol (0.0407 mol) in pyridine (75 ml). The reaction was stirred 2 hours at 25°, then it was poured into ice/water and extracted into ethyl ether. The ethereal extracts were washed with 3N aqueous hydrogen chloride and water, then were dried over sodium sulfate and concentrated. The residue was dissolved in dimethylformamide (75 ml) and sodium azide (0.0814 mol) was added. The reaction was stirred 8 hours, then was diluted with water and extracted into ethyl acetate. The organic extract was washed with 3N aqueous hydrogen chloride and water, then dried over sodium sulfate and concentrated to yield 6.7 g (64%) of an oily product. extracted into ethyl ether The ethereal extracts were washed with 3N aqueous hydrogen chloride and water were dried over sodium sulfate concentrated The residue was dissolved in dimethylformamide (75 ml) The reaction was stirred 8 hours extracted into ethyl acetate The organic extract was washed with 3N aqueous hydrogen chloride and water dried over sodium sulfate concentrated