(3-(BROMOMETHYL)PHENYL)METHANOL

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 solution of (3-(bromomethyl)phenyl)methanol (8.78 g) and 3,4-dihydro-2H-pyran (5.99 mL) in THF (60 mL) was added p-toluenesulfonic acid monohydrate (415 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added an aqueous solution of sodium hydrogen carbonate (367 mg), and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (11.9 g) as a colorless oil. the mixture was extracted with ethyl acetate The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

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

Procedure: To a solution of (3-(bromomethyl)phenyl)methanol (8.78 g) and 3,4-dihydro-2H-pyran (5.99 mL) in THF (60 mL) was added p-toluenesulfonic acid monohydrate (415 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added an aqueous solution of sodium hydrogen carbonate (367 mg), and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (11.9 g) as a colorless oil. the mixture was extracted with ethyl acetate The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

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

Procedure: Under a nitrogen atmosphere, to a solution of methyl 3-(bromomethyl)benzoate (10.0 g) in toluene (100 mL) was added a 1.5 M solution (100 mL) of diisobutylaluminum hydride in toluene at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added methanol at 0° C., and the resulting white precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure to give a crude product of the title compound (8.83 g) as a colorless oil. This compound was used for the next step without further purification. the resulting white precipitate was filtered off The solvent in the filtrate was evaporated under reduced pressure

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

Procedure: Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and (3-(bromomethyl)phenyl)methanol. Yield 70%, white solid. 1H NMR (DMSO-d6, 400 MHz): δ1.29 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 4.47 (d, J=6.0 Hz, 2H), 4.54 (s, 2H), 5.15 (t, J=5.6 Hz, 1H) 5.2 (s, 2H), 7.25 (m, 3H), 7.32 (s, 1H), 7.82 (s, 1H) 8.20 (s, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.11 μM.

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

Procedure: Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and (3-(bromomethyl)phenyl)methanol. Yield 70%, white solid. 1H NMR (DMSO-d6, 400 MHz): δ1.29 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 4.47 (d, J=6.0 Hz, 2H), 4.54 (s, 2H), 5.15 (t, J=5.6 Hz, 1H) 5.2 (s, 2H), 7.25 (m, 3H), 7.32 (s, 1H), 7.82 (s, 1H) 8.20 (s, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.11 μM.

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

Procedure: 200 mg of 3-mercaptobenzaldehyde was dissolved in 6 ml of dimethylformamide, and 291 mg of 3-hydroxymethylbenzyl bromide and 402 mg of potassium carbonate were added. The mixture was stirred for 3 hours at room temperature. The solvent was evaporated, water and ethyl ether were added to the residue to extract it. The extract was worked up in a customary manner, and purified by silica gel column chromatography [Wakogel C-200, 10 g; eluting solvent: hexane/ethyl acetate=2/1] to give 190 mg (yield 51%) of 3-[3-(hydroxymethyl)benzylthio]benzaldehyde as a pale yellow oil. The solvent was evaporated water and ethyl ether were added to the residue to extract it purified by silica gel column chromatography [Wakogel C-200, 10 g; eluting solvent: hexane/ethyl acetate=2/1]

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

Procedure: 3-Bromomethylbenzyl alcohol (1.015 g, 5 mmol) and activated manganese (IV) oxide (10 g) in acetone (30 ml) were stirred at 20° C. for 22 h. The reaction mixture was filtered and the filtrate evaporated in vacuo to yield 3-bromomethylbenzaldehyde as a pale yellow liquid (547 mg, 55%). The reaction mixture was filtered the filtrate evaporated in vacuo

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

Procedure: Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and (3-(bromomethyl)phenyl)metanol. Yield 70%, white solid. 1H NMR (DMSO-d6, 400 MHz): δ1.29 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 4.47 (d, J=6.0 Hz, 2H), 4.54 (s, 2H), 5.15 (t, J=5.6 Hz, 1H) 5.2 (s, 2H), 7.25 (m, 3H), 7.32 (s, 1H), 7.82 (s, 1H) 8.20 (s, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.11 μM.

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

Procedure: Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and (3-(bromomethyl)phenyl)metanol. Yield 70%, white solid. 1H NMR (DMSO-d6, 400 MHz): δ1.29 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 4.47 (d, J=6.0 Hz, 2H), 4.54 (s, 2H), 5.15 (t, J=5.6 Hz, 1H) 5.2 (s, 2H), 7.25 (m, 3H), 7.32 (s, 1H), 7.82 (s, 1H) 8.20 (s, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.11 μM.

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

Procedure: To a solution of (3-(bromomethyl)phenyl)methanol (8.78 g) and 3,4-dihydro-2H-pyran (5.99 mL) in THF (60 mL) was added p-toluenesulfonic acid monohydrate (415 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added an aqueous solution of sodium hydrogen carbonate (367 mg), and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (11.9 g) as a colorless oil. the mixture was extracted with ethyl acetate The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)