1-(2-bromoethyl)-2-methoxybenzene

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

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 6) and 2-methoxyphenethyl bromide. Yield: 52%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.80 (t, J=7.2 Hz, 2H), 3.51 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 4.03 (s, 2H), 5.17 (s, 2H), 6.85 (t, J=7.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.16-7.21 (m, 2H), 7.73 (s, 1H), 8.13 (s, 1H). MS M+H calculated 410.2; found 410.1. Melting point: 97-98° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.

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

Procedure: At rt, a solution of 1-(2-bromo-ethyl)-2-methoxy-benzene (1.0 g, 4.15 mmol) in abs. THF (5 mL) is added to Mg turnings (0.13 g, 5.35 mmol) suspended in abs. THF (5 mL) over a period of 20 min. The thus obtained Grignard reagent is then added at to an ice-cold solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid methoxy-methyl-amide (400 mg, 1.5 mmol) in THF (5 mL). The reaction mixture is stirred at rt for 1 h, quenched by adding sat. aq. NH4Cl (10 mL), diluted with water (100 mL) and extracted twice with DCM (100 mL). The combined organic extracts are dried over Na2SO4, filtered and evaporated. The resulting residue is purified by prep. HPLC to afford 3-(2-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]penta-len-4-yl)-propan-1-one (390 mg) as a colourless oil. LC-MS: tR=1.15 min, [M+1]+=341.21; 1H NMR (CDCl3): δ 7.22-7.14 (m, 2H), 6.90-6.81 (m, 2H), 3.82 (s, 3H), 3.20-2.90 (m, 5H), 2.79 (d, J=18.8 Hz, 1H), 2.38 (s, 3H), 1.88 (d, J=2.9 Hz, 2H), 1.12 (s, 3H), 0.72 (s, 3H). At rt quenched by adding sat. aq. NH4Cl (10 mL) diluted with water (100 mL) extracted twice with DCM (100 mL) The combined organic extracts are dried over Na2SO4 filtered evaporated The resulting residue is purified by prep

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

Procedure: At rt, a solution of 1-(2-bromo-ethyl)-2-methoxy-benzene (1.0 g, 4.15 mmol) in abs. THF (5 mL) is added to Mg turnings (0.13 g, 5.35 mmol) suspended in abs. THF (5 mL) over a period of 20 min. The thus obtained Grignard reagent is then added at to an ice-cold solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid methoxy-methyl-amide (400 mg, 1.5 mmol) in THF (5 mL). The reaction mixture is stirred at rt for 1 h, quenched by adding sat. aq. NH4Cl (10 mL), diluted with water (100 mL) and extracted twice with DCM (100 mL). The combined organic extracts are dried over Na2SO4, filtered and evaporated. The resulting residue is purified by prep. HPLC to afford 3-(2-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]penta-len-4-yl)-propan-1-one (390 mg) as a colourless oil. LC-MS: tR=1.15 min, [M+1]+=341.21; 1H NMR (CDCl3): δ 7.22-7.14 (m, 2H), 6.90-6.81 (m, 2H), 3.82 (s, 3H), 3.20-2.90 (m, 5H), 2.79 (d, J=18.8 Hz, 1H), 2.38 (s, 3H), 1.88 (d, J=2.9 Hz, 2H), 1.12 (s, 3H), 0.72 (s, 3H). At rt quenched by adding sat. aq. NH4Cl (10 mL) diluted with water (100 mL) extracted twice with DCM (100 mL) The combined organic extracts are dried over Na2SO4 filtered evaporated The resulting residue is purified by prep

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

Procedure: A mixture of triethylsilane (34.9 g, 0.3 mol), TFA (96 mL) and 2-bromo-1-(2-methoxy-phenyl)-ethanone (6.9 g, 30 mmol) is stirred at rt for 30 min before it is poured onto an ice/water mixture (600 mL). The mixture is neutralised by adding 2 N aq. NaOH and sat. aq. NaHCO3 (200 mL), and is extracted with DCM (2×200 mL). The combined organic extracts are dried over Na2SO4, filtered and evaporated. The obtained residue is purified by chromatography on silica gel (TBME:EA 40:1) to give 1-(2-bromo-ethyl)-2-methoxy-benzene (4.50 g) as a colourless liquid. LC: tR=1.00 min. is extracted with DCM (2×200 mL) The combined organic extracts are dried over Na2SO4 filtered evaporated The obtained residue is purified by chromatography on silica gel (TBME:EA 40:1)

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

Procedure: A mixture of triethylsilane (34.9 g, 0.3 mol), TFA (96 mL) and 2-bromo-1-(2-methoxy-phenyl)-ethanone (6.9 g, 30 mmol) is stirred at rt for 30 min before it is poured onto an ice/water mixture (600 mL). The mixture is neutralised by adding 2 N aq. NaOH and sat. aq. NaHCO3 (200 mL), and is extracted with DCM (2×200 mL). The combined organic extracts are dried over Na2SO4, filtered and evaporated. The obtained residue is purified by chromatography on silica gel (TBME:EA 40:1) to give 1-(2-bromo-ethyl)-2-methoxy-benzene (4.50 g) as a colourless liquid. LC: tR=1.00 min. is extracted with DCM (2×200 mL) The combined organic extracts are dried over Na2SO4 filtered evaporated The obtained residue is purified by chromatography on silica gel (TBME:EA 40:1)

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

Procedure: To a solution of 2-methoxyphenethyl bromide (1.07 g, 4.98 mmol) in 5 ml of CH2Cl2 was added BBr3 (9.5 ml, 1.0 M in CH2Cl2) at -78° C. and it was allowed to warm to rt over 1.5 h. The reaction mixture was poured into CH2Cl2 and was washed with brine, dried to afford 2-hydroxy phenethyl bromide. was washed with brine dried

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

Procedure: To a solution of 2-methoxyphenethyl alcohol (5.0 g, 32.6 mmol) in 40 ml of CH2Cl2 was added dimethylaminopyridine (DMAP) (10 mg), Et3N (11.4 ml, 81.8 mmol) and MsCl (5.05 ml, 65.2 mmol) at 0° C. After 1 h, the reaction mixture was poured into hexane and it was washed with aqueous NaHCO3 (2×), water and dried with MgSO4. Upon removal of the solvents, the residue was dissolved in 50 ml of acetone and LiBr (11.34 g, 130.6 mmol) was added. After the solution was heated at reflux for 16 h, it was poured into ether and washed with water, dried with MgSO4, filtered and dried to afford 2-methoxyphenethyl bromide. was washed with aqueous NaHCO3 (2×), water dried with MgSO4 Upon removal of the solvents the residue was dissolved in 50 ml of acetone After the solution was heated at reflux for 16 h washed with water dried with MgSO4 filtered dried

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

Procedure: To a solution of 2-methoxyphenethyl alcohol (5.0 g, 32.6 mmol) in 40 ml of CH2Cl2 was added dimethylaminopyridine (DMAP) (10 mg), Et3N (11.4 ml, 81.8 mmol) and MsCl (5.05 ml, 65.2 mmol) at 0° C. After 1 h, the reaction mixture was poured into hexane and it was washed with aqueous NaHCO3 (2×), water and dried with MgSO4. Upon removal of the solvents, the residue was dissolved in 50 ml of acetone and LiBr (11.34 g, 130.6 mmol) was added. After the solution was heated at reflux for 16 h, it was poured into ether and washed with water, dried with MgSO4, filtered and dried to afford 2-methoxyphenethyl bromide. was washed with aqueous NaHCO3 (2×), water dried with MgSO4 Upon removal of the solvents the residue was dissolved in 50 ml of acetone After the solution was heated at reflux for 16 h washed with water dried with MgSO4 filtered dried

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

Procedure: To a solution of 2-methoxyphenethyl alcohol (5.0 g, 32.6 mmol) in 40 ml of CH2Cl2 was added dimethylaminopyridine (DMAP) (10 mg), Et3N (11.4 ml, 81.8 mmol) and MsCl (5.05 ml, 65.2 mmol) at 0° C. After 1 h, the reaction mixture was poured into hexane and it was washed with aqueous NaHCO3 (2×), water and dried with MgSO4. Upon removal of the solvents, the residue was dissolved in 50 ml of acetone and LiBr (11.34 g, 130.6 mmol) was added. After the solution was heated at reflux for 16 h, it was poured into ether and washed with water, dried with MgSO4, filtered and dried to afford 2-methoxyphenethyl bromide. was washed with aqueous NaHCO3 (2×), water dried with MgSO4 Upon removal of the solvents the residue was dissolved in 50 ml of acetone After the solution was heated at reflux for 16 h washed with water dried with MgSO4 filtered dried

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 6) and 2-methoxyphenethyl bromide. Yield: 52%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.80 (t, J=7.2 Hz, 2H), 3.51 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 4.03 (s, 2H), 5.17 (s, 2H), 6.85 (t, J=7.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.16-7.21 (m, 2H), 7.73 (s, 1H), 8.13 (s, 1H). MS M+H calculated 410.2; found 410.1. Melting point: 97-98° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.

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

Procedure: To a solution of 2-methoxyphenethyl bromide (1.07 g, 4.98 mmol) in 5 ml of CH2Cl2 was added BBr3 (9.5 ml, 1.0 M in CH2Cl2) at -78° C. and it was allowed to warm to rt over 1.5 h. The reaction mixture was poured into CH2Cl2 and was washed with brine, dried to afford 2-hydroxy phenethyl bromide (quantitative). was washed with brine dried