methyl 2-(3-fluorophenyl)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:; See reaction.notes.procedure_details.

Procedure: Methyl 2-(3-fluorophenyl)acetate (1.90 g, 11.3 mmol) and N-bromo succinimide (2.01 g, 11.3 mmol) were dissolved in CCl4 (80 ml). HBr (64 ul, 0.56 mmol) was added, and the mixture was stirred under reflux overnight. The mixture was cooled at room temperature, diluted with DCM, and washed with sat. NaHCO3, water and brine. The organic layer was dried (Na2SO4), filtered, and evaporated obtaining intermediate I15 (2.68 g, 96% yield). under reflux overnight washed with sat. NaHCO3, water and brine The organic layer was dried (Na2SO4) filtered evaporated obtaining intermediate I15 (2.68 g, 96% yield)

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

Procedure: Methyl 2-(3-fluorophenyl)acetate (1.90 g, 11.3 mmol) and N-bromo succinimide (2.01 g, 11.3 mmol) were dissolved in CCl4 (80 ml). HBr (64 ul, 0.56 mmol) was added, and the mixture was stirred under reflux overnight. The mixture was cooled at room temperature, diluted with DCM, and washed with sat. NaHCO3, water and brine. The organic layer was dried (Na2SO4), filtered, and evaporated obtaining intermediate I15 (2.68 g, 96% yield). under reflux overnight washed with sat. NaHCO3, water and brine The organic layer was dried (Na2SO4) filtered evaporated obtaining intermediate I15 (2.68 g, 96% yield)

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

Procedure: Methyl (3-fluorophenyl)acetate (1.51 g) was added dropwise to chlorosulphonic acid (7 mL) with stirring and ice cooling. The cooling bath was removed and the mixture was allowed to stand at room temperature for 16 hours before being carefully added to a mixture of ice and ethyl acetate. The organic layer was separated, washed with water, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give methyl (2-chlorosulfonyl-5-fluorophenyl)acetate (1.42 g) as a white solid. The cooling bath was removed before being carefully added to a mixture of ice and ethyl acetate The organic layer was separated washed with water dried (MgSO4) filtered The filtrate was concentrated in vacuo the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20%

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

Procedure: To a solution of 3-fluorophenylacetic acid (5.0 g, 32 mmol) in MeOH (25 mL) and CH2Cl2 (25 mL) at 0° C. was added trimethylsilyldiazomethane (2 M in hexane, 30 mL, 60 mmol). After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was azeotroped with toluene to give the crude methyl 3-fluorophenylacetate (5.6 g), which was used without further purification. Thus, the crude methyl 3-fluorophenylacetate obtained above (2.5 g, 15 mmol) was converted to the title compound (purified on silica gel) by reacting with 4-chlorobenzyl bromide (4.6 g, 22 mmol) and sodium hexamethyldisilazide (1 M in THF, 15 mL, 15 mmol) following the procedure described in Reference Example 10, Step A. 1H NMR (400 MHz, CD3OD): δ 7.35-6.88 (m, 8H), 3.92 (t, 1H), 3.60 (s, 3H), 3.34 (dd, 1H), 3.00 (dd, 1H). LC-MS: m/e 305 (M+Na)+ (3.9 min). the reaction mixture was concentrated to dryness the residue was azeotroped with toluene

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

Procedure: To a solution of 3-fluorophenylacetic acid (5.0 g, 32 mmol) in MeOH (25 mL) and CH2Cl2 (25 mL) at 0° C. was added trimethylsilyldiazomethane (2 M in hexane, 30 mL, 60 mmol). After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was azeotroped with toluene to give the crude methyl 3-fluorophenylacetate (5.6 g), which was used without further purification. Thus, the crude methyl 3-fluorophenylacetate obtained above (2.5 g, 15 mmol) was converted to the title compound (purified on silica gel) by reacting with 4-chlorobenzyl bromide (4.6 g, 22 mmol) and sodium hexamethyldisilazide (1 M in THF, 15 mL, 15 mmol) following the procedure described in Reference Example 10, Step A. 1H NMR (400 MHz, CD3OD): δ 7.35-6.88 (m, 8H), 3.92 (t, 1H), 3.60 (s, 3H), 3.34 (dd, 1H), 3.00 (dd, 1H). LC-MS: m/e 305 (M+Na)+ (3.9 min). the reaction mixture was concentrated to dryness the residue was azeotroped with toluene

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

Procedure: To a solution of 3-fluorophenylacetic acid (5.0 g, 32 mmol) in methanol (25 mL) and methylene chloride (25 mL) at 0° C. was added trimethylsilyldiazomethane (2 M in hexane, 30 mL, 60 mmol). After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was azeotroped with toluene to give the crude methyl 3-fluorophenylacetate (5.6 g), which was used without further purification. The crude methyl 3-fluorophenylacetate obtained above was converted to the title compound by reacting with 4-chlorobenzyl bromide (4.6 g, 22 mmol) and sodium hexamethyldisilazide (1 M in tetrahydrofuran, 15 mL, 15 mmol) following the procedure described in Reference Example 2, Step A. 1H NMR (400 MHz, CD3OD): δ 7.35-6.88 (m, 8H), 3.92 (t, 1H), 3.60 (s, 3H), 3.34 (dd, 1H), 3.00 (dd, 1H). LC-MS: m/e 305 (M+Na)+ (3.9 min). the reaction mixture was concentrated to dryness the residue was azeotroped with toluene

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

Procedure: To a solution of 3-fluorophenylacetic acid (5.0 g, 32 mmol) in MeOH (25 mL) and CH2Cl2 (25 mL) at 0° C. was added trimethylsilyldiazomethane (2 M in hexane, 30 mL, 60 mmol). After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was azeotroped with toluene to give the crude methyl 3-fluorophenylacetate (5.6 g), which was used without further purification. Thus, the crude methyl 3-fluorophenylacetate obtained above (2.5 g, 15 mmol) was converted to the title compound (purified on silica gel) by reacting with 4-chlorobenzyl bromide (4.6 g, 22 mmol) and sodium hexamethyldisilazide (1 M in THF, 15 mL, 15 mmol) following the procedure described in Reference Example 10, Step A. 1H NMR (400 MHz, CD3OD): δ 7.35-6.88 (m, 8H), 3.92 (t, 1H), 3.60 (s, 3H), 3.34 (dd, 1H), 3.00 (dd, 1H). LC-MS: m/e 305 (M+Na)+ (3.9 min). the reaction mixture was concentrated to dryness the residue was azeotroped with toluene

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

Procedure: To a solution of 3-fluorophenylacetic acid (5.0 g, 32 mmol) in methanol (25 mL) and methylene chloride (25 mL) at 0° C. was added trimethylsilyldiazomethane (2 M in hexane, 30 mL, 60 mmol). After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was azeotroped with toluene to give the crude methyl 3-fluorophenylacetate (5.6 g), which was used without further purification. The crude methyl 3-fluorophenylacetate obtained above was converted to the title compound by reacting with 4-chlorobenzyl bromide (4.6 g, 22 mmol) and sodium hexamethyldisilazide (1 M in tetrahydrofuran, 15 mL, 15 mmol) following the procedure described in Reference Example 2, Step A. 1H NMR (400 MHz, CD3OD): δ 7.35-6.88 (m, 8H), 3.92 (t, 1H), 3.60 (s, 3H), 3.34 (dd, 1H), 3.00 (dd, 1H). LC-MS: m/e 305 (M+Na)+ (3.9 min). the reaction mixture was concentrated to dryness the residue was azeotroped with toluene

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 3-fluorophenylacetate (prepared from 3 fluorophenylacetic acid (Aldrich Chem. Co., Madison, Wis.) via esterification with methanol catalyzed by gaseous HCl) in anhydrous N,N-dimethylformamide (40 mL) warmed to 70° C. was added methyl methacrylate (5.8 mL) and potassium tertbutoxide (0.55 gm). After 15 minutes, aqueous 1N HCl (75 mL) was added, and the mixture extracted with diethyl ether. The organic extracts were washed with H2O, brine, dried (Na2SO4, filtered and evaporated. The residue was dissolved in concentrated H2SO4 (80 mL)/H2O (20 mL), and warmed to 70° C. for 3 hours, then poured onto crushed ice, and the mixture extracted with ethyl acetate. The extracts were washed with H2O, brine, dried (Na2SO4, filtered and evaporated. The oily residue was dissolved in methanol (250 mL), and the solution saturated with gaseous HCl. After 30 minutes, the mixture was purged with nitrogen, and concentrated under reduced pressure. The oily residue was partitioned between H2O (500 mL), and ethyl acetate, and the organic layer washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound (10.9 gm, Rf (1:1 diethyl ether/SiO2)=0.4). the mixture extracted with diethyl ether The organic extracts were washed with H2O, brine dried (Na2SO4 filtered evaporated The residue was dissolved in concentrated H2SO4 (80 mL)/H2O (20 mL) poured onto crushed ice the mixture extracted with ethyl acetate The extracts were washed with H2O, brine dried (Na2SO4 filtered evaporated The oily residue was dissolved in methanol (250 mL) After 30 minutes the mixture was purged with nitrogen concentrated under reduced pressure The oily residue was partitioned between H2O (500 mL), and ethyl acetate the organic layer washed with water, brine dried (Na2SO4) filtered concentrated in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 3-fluorophenylacetate (prepared from 3 fluorophenylacetic acid (Aldrich Chem. Co., Madison, Wis.) via esterification with methanol catalyzed by gaseous HCl) in anhydrous N,N-dimethylformamide (40 mL) warmed to 70° C. was added methyl methacrylate (5.8 mL) and potassium tertbutoxide (0.55 gm). After 15 minutes, aqueous 1N HCl (75 mL) was added, and the mixture extracted with diethyl ether. The organic extracts were washed with H2O, brine, dried (Na2SO4, filtered and evaporated. The residue was dissolved in concentrated H2SO4 (80 mL)/H2O (20 mL), and warmed to 70° C. for 3 hours, then poured onto crushed ice, and the mixture extracted with ethyl acetate. The extracts were washed with H2O, brine, dried (Na2SO4, filtered and evaporated. The oily residue was dissolved in methanol (250 mL), and the solution saturated with gaseous HCl. After 30 minutes, the mixture was purged with nitrogen, and concentrated under reduced pressure. The oily residue was partitioned between H2O (500 mL), and ethyl acetate, and the organic layer washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound (10.9 gm, Rf (1:1 diethyl ether/SiO2)=0.4). the mixture extracted with diethyl ether The organic extracts were washed with H2O, brine dried (Na2SO4 filtered evaporated The residue was dissolved in concentrated H2SO4 (80 mL)/H2O (20 mL) poured onto crushed ice the mixture extracted with ethyl acetate The extracts were washed with H2O, brine dried (Na2SO4 filtered evaporated The oily residue was dissolved in methanol (250 mL) After 30 minutes the mixture was purged with nitrogen concentrated under reduced pressure The oily residue was partitioned between H2O (500 mL), and ethyl acetate the organic layer washed with water, brine dried (Na2SO4) filtered concentrated in vacuo