676621-95-7

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

Procedure: A mixture of 3-(4-fluorophenyl)-2,2-dimethyl-propionic acid ethyl ester (10.0 g, 44.6 mmol) and a solution of sodium hydroxide (25 g) in water (110 mL) was heated to reflux for 18 hours. The resulting solution was cooled to room temperature, then was stirred on ice and acidified to about pH 1 with concentrated aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed thoroughly with water, and dried under vacuum. The solid was stirred in dichloromethane, and the mixture was filtered to remove a residual gelatinous solid. The filtrate was concentrated to provide a pale yellowish solid (7.60 g, 87%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.14 (m, 2H), 6.98 (t, J=8 Hz, 2H), 2.88 (s, 2H), 1.22 (s, 6H). Mass spec (ES−) m/z 195.2 (M−H−, 100%). to reflux for 18 hours The resulting precipitate was collected by filtration washed thoroughly with water dried under vacuum The solid was stirred in dichloromethane the mixture was filtered to remove a residual gelatinous solid The filtrate was concentrated

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

Procedure: A mixture of 3-(4-fluorophenyl)-2,2-dimethyl-propionic acid ethyl ester (10.0 g, 44.6 mmol) and a solution of sodium hydroxide (25 g) in water (110 mL) was heated to reflux for 18 hours. The resulting solution was cooled to room temperature, then was stirred on ice and acidified to about pH 1 with concentrated aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed thoroughly with water, and dried under vacuum. The solid was stirred in dichloromethane, and the mixture was filtered to remove a residual gelatinous solid. The filtrate was concentrated to provide a pale yellowish solid (7.60 g, 87%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.14 (m, 2H), 6.98 (t, J=8 Hz, 2H), 2.88 (s, 2H), 1.22 (s, 6H). Mass spec (ES−) m/z 195.2 (M−H−, 100%). to reflux for 18 hours The resulting precipitate was collected by filtration washed thoroughly with water dried under vacuum The solid was stirred in dichloromethane the mixture was filtered to remove a residual gelatinous solid The filtrate was concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl isobutyrate (11.03 g, 95 mmol) in tetrahydrofuran (75 mL) was added dropwise to a mixture of a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 100 mL, 100 mmol) and tetrahydrofuran (100 mL) at −78° C. over 15 minutes. The resulting solution was stirred at −78° C. for 45 minutes, and then treated with a solution of 1-bromomethyl-4-fluorobenzene (11.5 mL, 92 mmol) in tetrahydrofuran (25 mL) over 5 minutes. The cooling bath was removed, and the reaction mixture was stirred for 18 hours at room temperature. 1.0 N aqueous hydrochloric acid was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with 1.0 N aqueous hydrochloric acid, dried over sodium sulfate, and concentrated under vacuum to provide a brown liquid (20.7 g, quantitative) used without further purification. 1H NMR (300 MHz, CDCl3) δ7.07 (m, 2H), 6.94 (t, J=9 Hz, 2H), 4.10 (q, J=7 Hz, 2H), 2.82 (s, 2H), 1.23 (t, J=7 Hz, 3H), 1.16 (s, 6H). The cooling bath was removed the reaction mixture was stirred for 18 hours at room temperature 1.0 N aqueous hydrochloric acid was added the layers were separated The aqueous phase was extracted with ethyl acetate the combined organic phases were washed with 1.0 N aqueous hydrochloric acid dried over sodium sulfate concentrated under vacuum to provide a brown liquid (20.7 g, quantitative) used without further purification

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

Procedure: A mixture of 3-(4-fluorophenyl)-2,2-dimethylpropionic acid ethyl ester (10.0 g, 44.6 mmol, see Part 1 of Example 25a) and a solution of sodium hydroxide (25 g) in water (110 mL) was heated at reflux for 18 h and cooled to room temperature. The solution was stirred on an ice bath and acidified with concentrated aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum. The residue was stirred with dichloromethane and filtered, and the filtrate was concentrated to provide an off-white solid (7.60 g, 87%). at reflux for 18 h The resulting precipitate was collected by filtration washed with water dried under vacuum The residue was stirred with dichloromethane filtered the filtrate was concentrated

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

Procedure: A mixture of 3-(4-fluorophenyl)-2,2-dimethyl-propionic acid ethyl ester (10.0 g, 44.6 mmol) and a solution of sodium hydroxide (25 g) in water (110 mL) was heated to reflux for 18 hours. The resulting solution was cooled to room temperature, then was stirred on ice and acidified to about pH 1 with concentrated aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed thoroughly with water, and dried under vacuum. The solid was stirred in dichloromethane, and the mixture was filtered to remove a residual gelatinous solid. The filtrate was concentrated to provide a pale yellowish solid (7.60 g, 87%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.14 (m, 2H), 6.98 (t, J=8 Hz, 2H), 2.88 (s, 2H), 1.22 (s, 6H). Mass spec (ES−) m/z 195.2 (M−H−, 100%). to reflux for 18 hours The resulting precipitate was collected by filtration washed thoroughly with water dried under vacuum The solid was stirred in dichloromethane the mixture was filtered to remove a residual gelatinous solid The filtrate was concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl isobutyrate (11.03 g, 95 mmol) in tetrahydrofuran (75 mL) was added dropwise to a mixture of a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 100 mL, 100 mmol) and tetrahydrofuran (100 mL) at −78° C. over 15 minutes. The resulting solution was stirred at −78° C. for 45 minutes, and then treated with a solution of 1-bromomethyl-4-fluorobenzene (11.5 mL, 92 mmol) in tetrahydrofuran (25 mL) over 5 minutes. The cooling bath was removed, and the reaction mixture was stirred for 18 hours at room temperature. 1.0 N aqueous hydrochloric acid was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with 1.0 N aqueous hydrochloric acid, dried over sodium sulfate, and concentrated under vacuum to provide a brown liquid (20.7 g, quantitative) used without further purification. 1H NMR (300 MHz, CDCl3) δ7.07 (m, 2H), 6.94 (t, J=9 Hz, 2H), 4.10 (q, J=7 Hz, 2H), 2.82 (s, 2H), 1.23 (t, J=7 Hz, 3H), 1.16 (s, 6H). The cooling bath was removed the reaction mixture was stirred for 18 hours at room temperature 1.0 N aqueous hydrochloric acid was added the layers were separated The aqueous phase was extracted with ethyl acetate the combined organic phases were washed with 1.0 N aqueous hydrochloric acid dried over sodium sulfate concentrated under vacuum to provide a brown liquid (20.7 g, quantitative) used without further purification