2-(3-methoxyphenyl)ethanol

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: The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (4.26 g, 28.0 mmol) and 2-(3-methoxyphenyl)ethanol (4.32 mL, 31.0 mmol) to give 8.54 g of the title compound (colorless crystal, yield: 92%).

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

Procedure: To a solution of 2-(3-methoxyphenyl)-ethanol (359 mg, 2.36 mmol) in DMF (13 mL) was added sodium hydride (62.3 mg, 2.59 mmol) at 0° C. and stirred for 15 min at this temperature. Then, a solution of butyl (4-chloroquinolin-6-ylmethylene)-amine (preparation was described in example 27b) (300 mg, 1.18 mmol) in DMF (3 mL) was added at 0° C. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 30 min. During this period, the color of the solution was changed from white to black and then to brown. Then, the reaction mixture was heated to 60° C. and stirred for 15 h. After cooling to room temperature, the mixture was diluted with saturated ammonium chloride solution and the organic compound was extracted into ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solvent was removed under the vacuum and the oily residue was dissolved in THF (3 mL) and 3 mL of HCl solution (3.0N) was added. The resulting solution was stirred for 2 h at room temperature. Then, it was neutralized with saturated sodium bicarbonate solution and the organic compound was extracted into ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solvent was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to obtain 133 mg (36.7% yield) of 4-[2-(3-methoxyphenyl)-ethoxy]-quinoline-6-carbaldehyde as a light yellow solid: EI-HRMS m/e calcd for C19H17NO3 (M+) 307.1208, found 307.1204. After addition stirred for 30 min During this period Then, the reaction mixture was heated to 60° C. stirred for 15 h After cooling to room temperature the organic compound was extracted into ethyl acetate (3×50 mL) The combined extracts were washed with brine solution dried over anhydrous magnesium sulfate After filtration of the drying agent the solvent was removed under the vacuum the oily residue was dissolved in THF (3 mL) 3 mL of HCl solution (3.0N) was added The resulting solution was stirred for 2 h at room temperature the organic compound was extracted into ethyl acetate (3×50 mL) The combined extracts were washed with brine solution dried over anhydrous magnesium sulfate After filtration of the drying agent the solvent was removed under the vacuum the residue was purified

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

Procedure: 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 (20 mg, 0.043 mmol), 2-(3-methoxyphenyl)ethanol (32.5 mg, 0.213 mmol) and Ph3P-resin (55.8 mg, 0.213 mmol) in THF (2 mL) was added DEAD (0.014 mL, 0.085 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)-5-(4-(3-methoxyphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (11.9 mg, 0.021 mmol, 48.5% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.26-7.18 (m, 2H), 7.07-6.98 (m, 3H), 6.94-6.87 (m, 2H), 6.82-6.78 (m, 1H), 5.81 (s, 1H), 4.31-4.17 (m, 2H), 3.31 (br. s., 2H), 3.04 (t, J=6.8 Hz, 2H), 2.86-2.76 (m, 1H), 2.43 (s, 3H), 2.16 (br. s., 1H), 2.05 (s, 3H), 1.98-1.92 (m, 1H), 1.50 (br. s., 1H), 1.36-1.23 (m, 1H), 1.17 (d, J=11.7 Hz, 1H), 1.12 (s, 9H), 1.02 (d, J=14.7 Hz, 1H), 0.85 (s, 3H), 0.61 (s, 3H). 2H of piperidine were not resolved. LCMS (M+H)=575.5. mixture was filtered to remove polymer concentrated Mixture was then cooled purified by prep-HPLC

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

Procedure: To a flask under argon was added 10.1 g (0.0661 mole) 3-methoxyphenethyl alcohol, 150 mL methylene chloride and 9.2 ml (0.0661 mole) triethylamine. The solution was cooled to 0° C. and 5.1 ml (0.0661 mole) methanesulfonyl chloride was added slowly. The reaction mixture was warmed to room temperature. After 24 hr, the reaction was washed with water and brine, and dried with MgSO4. The solvent was evaporated in vacuo to give 15.0 g of the product as a clear oil. The reaction mixture was warmed to room temperature the reaction was washed with water and brine dried with MgSO4 The solvent was evaporated in vacuo

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

Procedure: To a flask under argon was added 10.1 g (0.0661 mole) 3-methoxyphenethyl alcohol, 150 mL methylene chloride and 9.2 ml (0.0661 mole) triethylamine. The solution was cooled to 0° C. and 5.1 ml (0.0661 mole) methanesulfonyl chloride was added slowly. The reaction mixture was warmed to room temperature. After 24 hr, the reaction was washed with water and brine, and dried with MgSO4. The solvent was evaporated in vacuo to give 15.0 g of the product as a clear oil. The reaction mixture was warmed to room temperature the reaction was washed with water and brine dried with MgSO4 The solvent was evaporated in vacuo

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

Procedure: The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (4.26 g, 28.0 mmol) and 2-(3-methoxyphenyl)ethanol (4.32 mL, 31.0 mmol) to give 8.54 g of the title compound (colorless crystal, yield: 92%).

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: To a stirred mixture of 3-methoxyphenethyl alcohol (1.18 g, 7.8 mmol) and pyridine (0.75 ml, 9.3 mmol) in dry dichloromethane (10 ml) was added bromine (0.47 ml, 18.0 mmol) dropwise under nitrogen at 0° C. The orange solution was stirred at room temperature for 4 hours (hr). The reaction mixture was quenched by the addition of 10% sodium bisulfite aqueous solution., and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate, and concentrated to give crude products, which were purified by silica-gel column chromatography eluted with gradient of hexane and ethyl acetate (10:1, 8:1, 5:1) to give the title compound as a colorless oil (1.5 g, 83.2%). 1H-NMR (CDCl3): 7.43 (d, J=8.8 Hz, 1H), 6.83 (d, J=3.3 Hz, 1H), 6.67 (dd, J=8,8, 3.3 Hz, 1H), 3.91-3.81 (m, 2H), 3.78 (s, 3H), 2.99 (t, J=6.6 Hz, 2H). The reaction mixture was quenched by the addition of 10% sodium bisulfite aqueous solution , and extracted with dichloromethane The organic extracts were washed with brine dried over magnesium sulfate concentrated to give crude products, which were purified by silica-gel column chromatography eluted with gradient of hexane and ethyl acetate (10:1, 8:1, 5:1)