4-(2-bromoethyl)phenol

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

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

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

Procedure: 1000 mL of IPA was placed in a 3 L flask and cooled to 0° C. A steady stream of methylamine gas from a cylinder was slowly passed through the IPA until the total volume reached 1750 ml. 100 g of (2-[4-hydroxyphenyl]ethyl) bromide (A11) was added to the cooled methylamine IPA solution in several portions. The cooling bath was removed after all A11 was added. The reaction mixture was allow to warm to room temperature and continue to stir for another 10-12 h. The excess methylamine was distilled into another 1000 mL of pre-cooled to 0° C. IPA by heating the reaction mixture at 50° C. When most of the methylamine was distilled off, the bath temperature was raised to 100° C. and the IPA was distilled out. After most of the IPA had been distilled out, about 300 mL of IPA was added to the reaction mixture and distillation was continued to aid removal of the methylamine. After the volume was reduced to 250 mL, the reaction mixture was allowed to cool down to room temperature. The precipitate was collected by filtration and washed by toluene to give 104 g (90% yield) of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine as an HBr salt (A12 HBr). 1H NMR (CDCl3) δ 2.69 (3H, s, CH3), 2.90 (2H, t, J=7.2 Hz), 3.18 (2H, t, J=6.3 Hz), 6.76 (2H, d, J=8.7 Hz), 7.11 (2H, d, J=8.7 Hz) The cooling bath was removed after all A11 was added to warm to room temperature The excess methylamine was distilled into another 1000 mL of pre-cooled to 0° C IPA by heating the reaction mixture at 50° C When most of the methylamine was distilled off the bath temperature was raised to 100° C. the IPA was distilled out After most of the IPA had been distilled out about 300 mL of IPA was added to the reaction mixture and distillation removal of the methylamine to cool down to room temperature The precipitate was collected by filtration washed by toluene

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 500 g 2-(4-hydroxyphenyl) ethanol was placed in a 5 L round bottom flask, to which 2960 g of 48% aq. HBr was added with stirring. The reaction mixture was placed in a bath at 75° C. After 2.5 h agitation 5 g of A11 seed crystals was added. The reaction mixture was stirred at this temperature for another 24 h. The reaction mixture was slowly cooled to 20° C. The precipitate was isolated by filtration and washed with 10% aq. sodium bicarbonate solution to give 700 g (96% yield) of the title product. 1H NMR (CDCl3); δ 3.10 (2H, t, J=7.8 Hz), 3.53 (2H, t, J=7.5 Hz), 6.80 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz). was added The reaction mixture was placed in a bath at 75° C After 2.5 h agitation 5 g of A11 seed crystals was added The reaction mixture was stirred at this temperature for another 24 h The precipitate was isolated by filtration washed with 10% aq. sodium bicarbonate solution

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

Procedure: Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-hydroxyphenethyl bromide. Yield: 31%. MS M+H calculated 396.16; found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.41 μM.

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

Procedure: Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-hydroxyphenethyl bromide. Yield: 31%. MS M+H calculated 396.16; found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.41 μM.

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

Procedure: Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-hydroxyphenethyl bromide. Yield: 31%. MS M+H calculated 396.16; found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.41 μM.

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

Procedure: (4-Hydroxyphenethyl) alcohol (1.50 g, 0.01086 mol) and 48 wt. % hydrobromic acid (10 ml) were heated at 100° C. for 1.5 h. After being cooled, the reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated in vacuo to give a raw product. Purification by flash chromatography (heptane/ethyl acetate 9:1) gave a pure product (2.01 g, 92%). 1H NMR (400 MHz, DMSO-d6): 2.99 (2H, t, 3J=7.4 Hz), 3.63 (2H, t, 3J=7.4 Hz), 6.68 (2H, d, 3J=8.5 Hz), 7.05 (2H, d, 3J=8.3 Hz), 9.24 (1H, s, —OH). After being cooled extracted with ethyl acetate The extracts were washed with water dried concentrated in vacuo to give a raw product Purification by flash chromatography (heptane/ethyl acetate 9:1)

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

Procedure: A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)piperidine (0.3 g), 4-hydroxyphenethyl bromide (0.21 g), sodium bicarbonate (0.3 g) and acetonitrile (15 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography, firstly on silica eluting with dichlorometbane containing methanol (0% up to 6%), and then on alumina eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as colourless microcrystals, yield 0.042 g, m.p. 135°-140° C. was heated under reflux for 5 hours The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml) the layers separated the aqueous layer extracted with dichloromethane (2×50 ml) The combined dichloromethane extracts were dried (MgSO4) concentrated in vacuo to give a gum which was purified by column chromatography, firstly on silica eluting with dichlorometbane containing methanol (0% up to 6%) on alumina eluting with dichloromethane containing methanol (0% up to 10%) concentrated in vacuo

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

Procedure: A mixture containing 3-(R,S)-(1-cyano-1,1-diphenylmethyl)piperidine (0.4 g), 4-hydroxyphenethyl bromide (0.32 g), sodium bicarbonate (0.5 g) and acetonitrile (15 ml) was heated under reflux for 4 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (50 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.267 g. was heated under reflux for 4 hours The mixture was concentrated in vacuo the residue partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (50 ml) The layers were separated the aqueous layer extracted with dichloromethane (3×20 ml) The combined dichloromethane extracts were dried (MgSO4) concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5%) concentrated in vacuo

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

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

Procedure: (4-Hydroxyphenethyl) alcohol (1.50 g, 0.01086 mol) and 48 wt. % hydrobromic acid (10 ml) were heated at 100° C. for 1.5 h. After being cooled, the reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated in vacuo to give a raw product. Purification by flash chromatography (heptane/ethyl acetate 9:1) gave a pure product (2.01 g, 92%). 1H NMR (400 MHz, DMSO-d6): 2.99 (2H, t, 3J=7.4 Hz), 3.63 (2H, t, 3J=7.4 Hz), 6.68 (2H, d, 3J=8.5 Hz), 7.05 (2H, d, 3J=8.3 Hz), 9.24 (1H, s, —OH). After being cooled extracted with ethyl acetate The extracts were washed with water dried concentrated in vacuo to give a raw product Purification by flash chromatography (heptane/ethyl acetate 9:1)