methyl 2-(3-fluoro-4-hydroxyphenyl)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:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid (1.0 g, 5.87 mmol) in methanol (20 mL) was treated with a catalytic amount of sulfuric acid. The reaction was heated at 120° C. for 6 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester (1.05 g, 97.6%) as a white solid: mp 34-36° C.: EI-HRMS m/e calcd for C9H9FO3 (M+) 184.0535, found 184.0533. At this time, the reaction was concentrated in vacuo

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

Procedure: A mixture of 23.0 g of product from Example 60, 34.6 g of 1-bromotetradecane, 54.6 g of potassium carbonate and 250 ml of acetone is heated at reflux temperature for 48 hours. The cooled reaction is filtered and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-4.5% ethyl acetate/hexane) to give 46.3 g of the desired product as colorless prisms. is heated at reflux temperature for 48 hours The cooled reaction is filtered concentrated in vacuo The residue is purified by column chromatography (silica gel:0-4.5% ethyl acetate/hexane)

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

Procedure: A mixture of 23.0 g of product from Example 60, 34.6 g of 1-bromotetradecane, 54.6 g of potassium carbonate and 250 ml of acetone is heated at reflux temperature for 48 hours. The cooled reaction is filtered and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-4.5% ethyl acetate/hexane) to give 46.3 g of the desired product as colorless prisms. is heated at reflux temperature for 48 hours The cooled reaction is filtered concentrated in vacuo The residue is purified by column chromatography (silica gel:0-4.5% ethyl acetate/hexane)

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

Procedure: A mixture of 2.0 g of 3-fluoro-4-hydroxybenzeneacetic acid, 10 ml of methyl alcohol and 1 ml of concentrated sulfuric acid is heated at reflux temperature for 23.5 hours. The cooled solution is diluted with water and extracted with methylene chloride. The organic layer is washed with water, saturated sodium bicarbonate, water and saturated sodium chloride; dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:25% ethyl acetate/hexane) to give 1.9 g of the desired product. is heated at reflux temperature for 23.5 hours extracted with methylene chloride The organic layer is washed with water, saturated sodium bicarbonate, water and saturated sodium chloride dried concentrated in vacuo The residue is purified by column chromatography (silica gel:25% ethyl acetate/hexane)

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

Procedure: A mixture of 2.0 g of 3-fluoro-4-hydroxybenzeneacetic acid, 10 ml of methyl alcohol and 1 ml of concentrated sulfuric acid is heated at reflux temperature for 23.5 hours. The cooled solution is diluted with water and extracted with methylene chloride. The organic layer is washed with water, saturated sodium bicarbonate, water and saturated sodium chloride; dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:25% ethyl acetate/hexane) to give 1.9 g of the desired product. is heated at reflux temperature for 23.5 hours extracted with methylene chloride The organic layer is washed with water, saturated sodium bicarbonate, water and saturated sodium chloride dried concentrated in vacuo The residue is purified by column chromatography (silica gel:25% ethyl acetate/hexane)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester (15 g, 54.3 mmol) and benzyl bromide (9.28 g, 54.3 mmol) in DMF (50 mL), was K2CO3 (7.24 g, 54.3 mmol) added at an ambient temperature. The reaction mixture was heated to 60° C. and maintained for 2 hours. The reaction was cooled to room temperature and poured into H2O (150 mL). The organic compound was extracted with ether (150 mL) and washed with sat NaHCO3 (100 mL). The ether layer was dried over MgSO4, and concentrated under vacuum to afford the desired compound (12.9 g, 87.9%) as a white crystal. The crude compound was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.41-7.49 (m, 5H), 7.15-7.23 (m, 2H), 7.02-7.04 (m, 1H), 5.19 (s, 2H), 3.65 (s, 2H), 3.63 (s, 3H). LCMS 273.4 [MH+]. added at an ambient temperature maintained for 2 hours The reaction was cooled to room temperature The organic compound was extracted with ether (150 mL) washed The ether layer was dried over MgSO4 concentrated under vacuum

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

Procedure: To a solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid (20 g, 117.5 mmol) in MeOH (150 mL), was H2SO4 (3 drops) added. The reaction mixture was heated to reflux and maintained for 2 hours. The reaction was cooled to room temperature and 5 g of NaHCO3 was added portionwise. The reaction was concentrated under vacuum and dissolved in ether (200 mL). The ether layer was washed with sat. NaHCO3. The ether layer was dried over MgSO4, and concentrated under vacuum to afford the desired compound (19.9 g, 92%) as an oil. The crude compound was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.01-7.20 (m, 2H), 3.62 (s, 2H), 3.61 (s, 3H). LCMS 185.1 [MH+]. added The reaction mixture was heated to reflux maintained for 2 hours The reaction was concentrated under vacuum dissolved in ether (200 mL) The ether layer was washed with sat. NaHCO3 The ether layer was dried over MgSO4 concentrated under vacuum

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid (1.0 g, 5.87 mmol) in methanol (20 mL) was treated with a catalytic amount of sulfuric acid. The reaction was heated at 120° C. for 6 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester (1.05 g, 97.6%) as a white solid: mp 34-36° C.: EI-HRMS m/e calcd for C9H9FO3 (M+) 184.0535, found 184.0533. At this time, the reaction was concentrated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (prepared in Step A; 163 mg, 0.885 mmol) was diluted with DMSO (3 mL) followed by the addition of K2CO3 (122 mg, 0.885 mmol) and N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (prepared in Step B; 300 mg, 0.885 mmol). The reaction was stirred at 80° C. for 12 hours. The reaction was cooled, diluted with DCM and washed with 10% aq. sodium carbonate, water and brine. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified by silica gel chromatography, eluting with hexane:acetone (2:1) to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-3-fluorophenyl)acetate (200 mg, 46.4% yield). The reaction was cooled washed with 10% aq. sodium carbonate, water and brine The layers were separated the organic layer was dried over MgSO4 filtered concentrated The material was purified by silica gel chromatography eluting with hexane:acetone (2:1)