methyl 2-(4-hydroxyphenoxy)acetate

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 title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), (4-hydroxy-phenoxy)-acetic acid methyl ester (commercially available), tri-n-butylphosphin and N,N′,N′-tetramethylazodicarboxamide. The compound was purified by preparative HPLC (phenomenex gemini column) eluting with a gradient of acetonitril:water (50:50 to 95:5). Colorless oil. MS (Turbo Spray): m/z=555.2 [M+H]. The compound was purified by preparative HPLC (phenomenex gemini column) eluting with a gradient of acetonitril:water (50:50 to 95:5)

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

Procedure: To a 100 ml round flask were added 1.512 g methyl (4-acetoxy-phenoxy)-acetate dissolved in 50 ml anhydrous methanol, 0.364 g sodium methoxide. The mixture was stirred at room temperature for 1 hour. To the stirred mixture was added dilute HCl to adjust pH to weak acidity. The solvent was removed by evaporation. To the residue was added water. The solution was extracted with ethyl acetate for three times. The extract was dried, filtrated and evaporated to obtain 1.004 g of a brown solid, yield 85%. 1H-NMR (400 MHz, DMSO-d6, δ ppm) δ 3.679 (3H, s), 4.646 (2H, s), 6.672 (2H, d), 6.754 (2H, d), 9.0 (1H, s). The solvent was removed by evaporation To the residue was added water The solution was extracted with ethyl acetate for three times The extract was dried filtrated evaporated

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

Procedure: A solution of 1-propylamine (4.1 ml) and methyl 4-hydroxyphenoxyacetate (3.64 g) in methanol (50 ml) was left to stand for 72 hours at ambient temperature. The solvent was evaporated in vacuo and the residue taken up in ethyl acetate. The solution was washed sequentially with 1M HCl (2×25 ml) and brine (30 ml), dried (MgSO4) and the solvent evaporated to give N-(1-propyl)-4-hydroxyphenoxyacetamide as a red oil, NMR: 0.95(t, 3H, CH3 ), 1.55(m, 2H, CH2), 3.3(q, 2H, CH2N), 4.4(s, 2H, CH2O), 6.5-6.7(broad s, 1H, OH), 6.8(s, 4H, phenyl-H); m/e 227 (M+NH4)+, 210(M+H)+. The solvent was evaporated in vacuo The solution was washed sequentially with 1M HCl (2×25 ml) and brine (30 ml) dried (MgSO4) the solvent evaporated

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

Procedure: A solution of 1-propylamine (4.1 ml) and methyl 4-hydroxyphenoxyacetate (3.64 g) in methanol (50 ml) was left to stand for 72 hours at ambient temperature. The solvent was evaporated in vacuo and the residue taken up in ethyl acetate. The solution was washed sequentially with 1M HCl (2×25 ml) and brine (30 ml), then dried (MGSO4) and the solvent evaporated to give N-(1-propyl)-4-hydroxyphenoxyacetamide as a red oil, NMR: 0.95 (t, 3H, CH3), 1.55 (m, 2H, CH2), 3.3 (q, 2H, CH2N), 4.4 (s, 2H, CH2O), 6.5-6.7 (broad s, 1H, OH), 6.8 (s, 4H, phenyl-H); m/e 227 (M+NH4)+, 210 (M+H)+. The solvent was evaporated in vacuo The solution was washed sequentially with 1M HCl (2×25 ml) and brine (30 ml) dried (MGSO4) the solvent evaporated

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

Procedure: A solution of 4-hydroxyphenoxyacetic acid (33.6 g) in methanol was treated with hydrogen chloride gas and left to stand at ambient temperature overnight. The solvent was removed in vacuo and the residue taken up in ethyl acetate. This solution was washed sequentially with saturated sodium hydrogen carbonate solution (2×100 ml) and brine (100 ml), then dried (MGSO4) and the solvent evaporated to give methyl 4-hydroxyphenoxyacetate as a colourless crystalline mass, m.p. 112°-114° C.; NMR: 3.8 (s, 3H, CH3), 4.55 (s, 2H, CH2), 6.75 (s, 4H, phenyl-H) 6.8-7.8 (broad s, 1H, OH); m/e 200 (M+NH4)+. left The solvent was removed in vacuo This solution was washed sequentially with saturated sodium hydrogen carbonate solution (2×100 ml) and brine (100 ml) dried (MGSO4) the solvent evaporated

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethylazodicarboxylate (0.47 ml) was added dropwise over 30 minutes to a stirred mixture of 1-(4-pyridyl)-4-piperidinol (534 mg), methyl 4-hydroxyphenoxyacetate (546 mg), triphenylphosphine (787 mg) and dry THF (30 ml) in an atmosphere of argon and cooled to 4° C. After 1 hour at 4° C., the mixture was allowed to reach ambient temperature and stirred for 48 hours. The solvent was removed by evaporation and the residue purified by flash chromatography on silica eluting with 5% v/v methanol/dichloromethane. Recrystallisation from ethyl acetate/hexane gave the title compound, 532 mg, as a white solid: m.p. 74°-76° C.; NMR (d6DMSO) δ 8.15(2H, bd), 6.89(6H, m), 4.71(2H, s), 4.50(1H, m), 3.70(2H, m), 3.69(3H, s), 3.23(2H, m), 1.96(2H, m), 1.62(2H, m); m/e 343 (M+H)+ ; calculated for C19H22N2O4 : C, 66.7; H, 6.5; N, 8.2. found: C, 66.2; H, 6.7; N, 8.2%. to reach ambient temperature The solvent was removed by evaporation the residue purified by flash chromatography on silica eluting with 5% v/v methanol/dichloromethane Recrystallisation from ethyl acetate/hexane

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethylazodicarboxylate (0.47 ml) was added dropwise over 30 minutes to a stirred mixture of 1-(4-pyridyl)-4-piperidinol (534 mg), methyl 4-hydroxyphenoxyacetate (546 mg), triphenylphosphine (787 mg) and dry THF (30 ml) in an atmosphere of argon and cooled to 4° C. After 1 hour at 4° C., the mixture was allowed to reach ambient temperature and stirred for 48 hours. The solvent was removed by evaporation and the residue purified by flash chromatography on silica eluting with 5% v/v methanol/dichloromethane. Recrystallisation from ethyl acetate/hexane gave the title compound, 532 mg, as a white solid: m.p. 74°-76° C.; NMR (d6DMSO) δ 8.15(2H, bd), 6.89(6H, m), 4.71(2H, s), 4.50(1H, m), 3.70(2H, m), 3.69(3H, s), 3.23(2H, m), 1.96(2H, m), 1.62(2H, m); m/e 343 (M+H)+ ; calculated for C19H22N2O4 : C, 66.7; H, 6.5; N, 8.2. found: C, 66.2; H, 6.7; N, 8.2%. to reach ambient temperature The solvent was removed by evaporation the residue purified by flash chromatography on silica eluting with 5% v/v methanol/dichloromethane Recrystallisation from ethyl acetate/hexane

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

Procedure: A mixture of methyl 4-hydroxyphenoxyacetate (25.50 g, 140.0 mmol) and potassium carbonate (18.67 g, 135.0 mmol) in 70 ml of DMF is heated to 75°, with stirring, for 40 min. The above methanesulfonate (10.66 g, 70.0 mmol) in 5 ml of DMF is added slowly over 5 min. The reaction mixture is allowed to stand at 60° overnight. To the cooled reaction mixture is added ice water, followed by cold sulfuric acid to bring it to pH 4-5. Additional water is added and the mixture is extracted with ether (3×). The combined ether extracts are washed with 1% sulfuric acid/1% potassium dihydrophosphate, with 1% potassium dihydrophosphate (2×), then hexane is added and the organic layer is washed with 10% sodium hydroxide (5×), with water and with brine; dried; filtered and the filtrate evaporated to give methyl (R)-(-)-4-(1-methylpropoxy)phenoxyacetate, [α]D20 - 20.672. is heated to 75° to stand at 60° overnight To the cooled reaction mixture the mixture is extracted with ether (3×) The combined ether extracts are washed with 1% sulfuric acid/1% potassium dihydrophosphate, with 1% potassium dihydrophosphate (2×) hexane is added the organic layer is washed with 10% sodium hydroxide (5×), with water and with brine dried filtered the filtrate evaporated

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

Procedure: A mixture of methyl 4-hydroxyphenoxyacetate (25.50 g, 140.0 mmol) and potassium carbonate (18.67 g, 135.0 mmol) in 70 ml of DMF is heated to 75°, with stirring, for 40 min. The above methanesulfonate (10.66 g, 70.0 mmol) in 5 ml of DMF is added slowly over 5 min. The reaction mixture is allowed to stand at 60° overnight. To the cooled reaction mixture is added ice water, followed by cold sulfuric acid to bring it to pH 4-5. Additional water is added and the mixture is extracted with ether (3×). The combined ether extracts are washed with 1% sulfuric acid/1% potassium dihydrophosphate, with 1% potassium dihydrophosphate (2×), then hexane is added and the organic layer is washed with 10% sodium hydroxide (5×), with water and with brine; dried; filtered and the filtrate evaporated to give methyl (R)-(-)-4-(1-methylpropoxy)phenoxyacetate, [α]D20 - 20.672. is heated to 75° to stand at 60° overnight To the cooled reaction mixture the mixture is extracted with ether (3×) The combined ether extracts are washed with 1% sulfuric acid/1% potassium dihydrophosphate, with 1% potassium dihydrophosphate (2×) hexane is added the organic layer is washed with 10% sodium hydroxide (5×), with water and with brine dried filtered the filtrate evaporated