2-(2,4,5-trifluorophenyl)ethanol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), 2-(2,4,5-trifluorophenyl)ethanol (47.0 mg, 0.267 mmol) and Ph3P-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DIAD (0.052 mL, 0.267 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(2,4,5-trifluorophenethoxy)phenyl)pyridin-3-yl)acetic acid (25.2 mg, 0.042 mmol, 79% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.60-7.46 (m, 2H), 7.21 (d, J=8.4 Hz, 1H), 7.08-6.87 (m, 3H), 5.85 (br. s., 1H), 4.26 (q, J=6.2 Hz, 2H), 3.23 (br. s., 1H), 3.07 (t, J=6.2 Hz, 2H), 2.85-2.73 (m, 1H), 2.43 (s, 3H), 2.16 (br. s., 1H), 2.05 (s, 3H), 1.96-1.86 (m, 1H), 1.48 (br. s., 1H), 1.29 (br. s., 1H), 1.17 (d, J=13.6 Hz, 1H), 1.13 (s, 9H), 1.01 (d, J=12.5 Hz, 1H), 0.84 (br. s., 3H), 0.59 (br. s., 3H). LCMS (M+H)=599.2. mixture was filtered to remove polymer concentrated Mixture was then cooled purified by prep-HPLC

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(2,4,5-trifluorophenyl)acetic acid (1 g, 5.26 mmol) in dry THF (20 mL) was carefully added over 2 min to solution of 2M LAH (10.52 mL, 10.52 mmol) at 0° C. The reaction mixture was allowed to warm to rt and was stirred for 6 h. The reaction was quenched with 0.5 mL of water (stir for 10 min), 0.5 mL of 15% NaOH/water (stir for 10 min), and then 1.0 mL of water. After stirring for 18 h, the mixture was filtered through celite. The filtrate was concentrated in vacuum. The residue was dried under high vacuum for 16 h to afford 2-(2,4,5-trifluorophenyl)ethanol (850 mg, 4.83 mmol, 92% yield) as a clear viscous oil, which was used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.11 (ddd, J=10.3, 8.7, 7.2 Hz, 1H), 6.93 (td, J=9.7, 6.6 Hz, 1H), 3.87 (t, J=6.5 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H). The reaction was quenched with 0.5 mL of water (stir for 10 min), 0.5 mL of 15% NaOH/water (stir for 10 min) After stirring for 18 h the mixture was filtered through celite The filtrate was concentrated in vacuum The residue was dried under high vacuum for 16 h

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(2,4,5-trifluorophenyl)acetic acid (1 g, 5.26 mmol) in dry THF (20 mL) was carefully added over 2 min to solution of 2M LAH (10.52 mL, 10.52 mmol) at 0° C. The reaction mixture was allowed to warm to rt and was stirred for 6 h. The reaction was quenched with 0.5 mL of water (stir for 10 min), 0.5 mL of 15% NaOH/water (stir for 10 min), and then 1.0 mL of water. After stirring for 18 h, the mixture was filtered through celite. The filtrate was concentrated in vacuum. The residue was dried under high vacuum for 16 h to afford 2-(2,4,5-trifluorophenyl)ethanol (850 mg, 4.83 mmol, 92% yield) as a clear viscous oil, which was used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.11 (ddd, J=10.3, 8.7, 7.2 Hz, 1H), 6.93 (td, J=9.7, 6.6 Hz, 1H), 3.87 (t, J=6.5 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H). The reaction was quenched with 0.5 mL of water (stir for 10 min), 0.5 mL of 15% NaOH/water (stir for 10 min) After stirring for 18 h the mixture was filtered through celite The filtrate was concentrated in vacuum The residue was dried under high vacuum for 16 h

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), 2-(2,4,5-trifluorophenyl)ethanol (47.0 mg, 0.267 mmol) and Ph3P-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DIAD (0.052 mL, 0.267 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(2,4,5-trifluorophenethoxy)phenyl)pyridin-3-yl)acetic acid (25.2 mg, 0.042 mmol, 79% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.60-7.46 (m, 2H), 7.21 (d, J=8.4 Hz, 1H), 7.08-6.87 (m, 3H), 5.85 (br. s., 1H), 4.26 (q, J=6.2 Hz, 2H), 3.23 (br. s., 1H), 3.07 (t, J=6.2 Hz, 2H), 2.85-2.73 (m, 1H), 2.43 (s, 3H), 2.16 (br. s., 1H), 2.05 (s, 3H), 1.96-1.86 (m, 1H), 1.48 (br. s., 1H), 1.29 (br. s., 1H), 1.17 (d, J=13.6 Hz, 1H), 1.13 (s, 9H), 1.01 (d, J=12.5 Hz, 1H), 0.84 (br. s., 3H), 0.59 (br. s., 3H). LCMS (M+H)=599.2. mixture was filtered to remove polymer concentrated Mixture was then cooled purified by prep-HPLC

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(2,4,5-trifluorophenyl)acetic acid (1 g, 5.26 mmol) in dry THF (20 mL) was carefully added over 2 min to solution of 2M LAH (10.52 mL, 10.52 mmol) at 0° C. The reaction mixture was allowed to warm to rt and was stirred for 6 h. The reaction was quenched with 0.5 mL of water (stir for 10 min), 0.5 mL of 15% NaOH/water (stir for 10 min), and then 1.0 mL of water. After stirring for 18 h, the mixture was filtered through celite. The filtrate was concentrated in vacuum. The residue was dried under high vacuum for 16 h to afford 2-(2,4,5-trifluorophenyl)ethanol (850 mg, 4.83 mmol, 92% yield) as a clear viscous oil, which was used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.11 (ddd, J=10.3, 8.7, 7.2 Hz, 1H), 6.93 (td, J=9.7, 6.6 Hz, 1H), 3.87 (t, J=6.5 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H). The reaction was quenched with 0.5 mL of water (stir for 10 min), 0.5 mL of 15% NaOH/water (stir for 10 min) After stirring for 18 h the mixture was filtered through celite The filtrate was concentrated in vacuum The residue was dried under high vacuum for 16 h