tert-butyl 3-hydroxy-2,2-dimethylpropanoate

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

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

Procedure: 1M lithium tri-tert-butoxy-aluminohydride/tetrahydrofuran solution (14 ml) was added dropwise to a solution of tert-butyl methyl 2,2-dimethyl-malonate (1.12 g) in tetrahydrofuran (30 ml) under nitrogen atmosphere over 15 minutes and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, a saturated ammonium chloride aq. solution and ethyl acetate were added and the organic layer was separated, washed with water and a saturated brine, dried over magnesium sulfate and concentrated in vacuo to give the titled compound (800 mg). MS (m/z): 175 [M+H]+. the mixture was heated to reflux for 2 hours the organic layer was separated washed with water a saturated brine, dried over magnesium sulfate concentrated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Hydroxy-2,2-dimethyl-propionic acid tert-butyl ester (137 mg) and sodium hydride (60%; 32 mg) were added to a solution of the compound obtained in Example 9 (1) (300 mg) dissolved in tetrahydrofuran (5 ml) and stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aq. solution and ethyl acetate were added and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=7:3→2:3) to give the titled compound (227 mg). MS (m/z):607 [M+H]+. The reaction mixture was cooled to room temperature the organic layer was separated washed with a saturated brine dried over magnesium sulfate concentrated in vacuo The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=7:3→2:3)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Hydroxy-2,2-dimethyl-propionic acid tert-butyl ester (137 mg) and sodium hydride (60%; 32 mg) were added to a solution of the compound obtained in Example 9 (1) (300 mg) dissolved in tetrahydrofuran (5 ml) and stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aq. solution and ethyl acetate were added and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=7:3→2:3) to give the titled compound (227 mg). MS (m/z):607 [M+H]+. The reaction mixture was cooled to room temperature the organic layer was separated washed with a saturated brine dried over magnesium sulfate concentrated in vacuo The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=7:3→2:3)

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

Procedure: By using 5-chloropyrazin-2-ol (700 mg) and tert-butyl hydroxypivalate (1402 mg), the procedure was carried out in the same manner as in Example 1-1) to obtain tert-butyl 3-[(5-chloropyrazin-2-yl)oxy]-2,2-dimethylpropanoate (1294.5 mg).

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

Procedure: By using 5-chloropyrazin-2-ol (700 mg) and tert-butyl hydroxypivalate (1402 mg), the procedure was carried out in the same manner as in Example 1-1) to obtain tert-butyl 3-[(5-chloropyrazin-2-yl)oxy]-2,2-dimethylpropanoate (1294.5 mg).

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In N,N-dimethylformamide (10 mL) were dissolved 5-bromo-2-chloropyridine (1000 mg) and tert-butyl 3-hydroxy-2,2-dimethylpropanoate (991 mg), and 60% sodium hydride (248 mg) was added to the solution under ice-cooling. The reaction mixture was stirred at room temperature for 6 hours, at 50° C. for 1 hour and 45 minutes, and then, at room temperature overnight. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ether. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 95:5) to obtain tert-butyl 3-(5-bromopyrimidin-2-yl)oxy-2,2-dimethylpropanoate (1.048 g). was added to the solution under ice- cooling at room temperature overnight cooling the mixture was extracted with ether The organic layer was separated washed with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 95:5)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In N,N-dimethylformamide (10 mL) were dissolved 5-bromo-2-chloropyridine (1000 mg) and tert-butyl 3-hydroxy-2,2-dimethylpropanoate (991 mg), and 60% sodium hydride (248 mg) was added to the solution under ice-cooling. The reaction mixture was stirred at room temperature for 6 hours, at 50° C. for 1 hour and 45 minutes, and then, at room temperature overnight. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ether. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 95:5) to obtain tert-butyl 3-(5-bromopyrimidin-2-yl)oxy-2,2-dimethylpropanoate (1.048 g). was added to the solution under ice- cooling at room temperature overnight cooling the mixture was extracted with ether The organic layer was separated washed with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 95:5)

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

Procedure: By using 2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)-imidazol-2-yl]-2-pyridyl]phenol (224 mg) and tert-butyl 3-hydroxy-2,2-dimethylpropanoate (284 mg), the procedure was carried out in the same manner as in Example 1-1) to obtain tert-butyl 2,2-dimethyl-3-[2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]propanoate (104 mg).

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

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

Procedure: Sodium hydride (60% wt in oil) (400 mg, 10 mmol) was added to a stirred solution of tert-butyl 3-hydroxy-2,2-dimethylpropanoate (57) (1.74 g, 10 mmol) in DMF (20 mL) at 0° C., after 30 min a solution of 2,5,8,11,14,17,20-heptaoxadocosan-22-yl methanesulfonate (2.79 g, 6.67 mmol) in DMF (10 mL) was added dropwise, and the reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction was quenched with water (100 mL) and the aqueous layer was extracted with DCM (2×100 mL), the combined organic layers were washed with brine (3×100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (120 g, 0-10% MeOH in EtOAc) to afford tert-butyl 25,25-dimethyl-2,5,8,11,14,17,20,23-octaoxahexacosan-26-oate (58) (1.59 g, 48%) as a colourless oil: 1H NMR (400 MHz, CDCl3) δ: 3.65-3.51 (m, 32H), 3.40 (s, 2H), 3.36 (s, 3H), 1.41 (s, 9H), 1.11 (s, 6H). was added dropwise The reaction was quenched with water (100 mL) the aqueous layer was extracted with DCM (2×100 mL) the combined organic layers were washed with brine (3×100 mL) dried (MgSO4) filtered concentrated in vacuo The crude product was purified by silica gel chromatography (120 g, 0-10% MeOH in EtOAc)

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

Procedure: To a solution of tert-butyl 3-hydroxy-2,2-dimethylpropanoate (353 mg, 2.03 mmol) and 2-(2-(benzyloxy)ethoxy)ethyl methanesulfonate (47) (500 mg, 1.82 mmol) in DMF (6 mL) at 0° C. was added NaH (60 wt % in oil) (109 mg, 2.73 mmol), and the reaction mixture was allowed to stir at RT for 30 min. The reaction mixture was quenched with sat. NH4Cl (aq.) (1 mL) diluted with water (20 mL) and washed with EtOAc (4×20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g, 0-40% Et2O in isohexane) to afford tert-butyl 3-(2-(2-(benzyloxy)ethoxy)ethoxy)-2,2-dimethylpropanoate (48) (619 mg, 96%) as a colourless oil: m/z 375 (M+Na)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 7.32-7.25 (m, 5H), 4.54 (s, 2H), 3.66-3.56 (m, 8H), 3.41 (s, 2H), 1.40 (s, 8H), 1.10 (s, 6H). The reaction mixture was quenched with sat. NH4Cl (aq.) (1 mL) diluted with water (20 mL) washed with EtOAc (4×20 mL) The combined organic layers were dried (MgSO4) filtered concentrated in vacuo The crude product was purified by silica gel chromatography (12 g, 0-40% Et2O in isohexane)