371-26-6

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 160 g of ethyl 4,4,4-trifluorobutyrate, a mixed solution of 123 g of potassium hydroxide, 900 ml of methanol and 80 ml of water was added under ice cooling and the mixture was further reacted at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was then partitioned between water and diethyl ether. The ether layer was extracted once with water and the water layer was combined with the aqueous layer which had already been partitioned. After adjusting the pH to about 1 by the addition of an aqueous 10% ice-cooled hydrochloric acid solution, the mixture was extracted three times with diethyl ether. The layers were combined and the combined ether layer was washed twice with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to give 131 g of 4,4,4-trifluorobutyric acid (yield: 98%). the mixture was further reacted at room temperature for 12 hours After the reaction solution was concentrated under reduced pressure the resulting residue was then partitioned between water and diethyl ether The ether layer was extracted once with water had already been partitioned by the addition of an aqueous 10% ice- cooled hydrochloric acid solution the mixture was extracted three times with diethyl ether the combined ether layer was washed twice with saturated saline dried over anhydrous magnesium sulfate Then, the solvent was distilled off under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 160 g of ethyl 4,4,4-trifluorobutyrate, a mixed solution of 123 g of potassium hydroxide, 900 ml of methanol and 80 ml of water was added under ice cooling and the mixture was further reacted at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was then partitioned between water and diethyl ether. The ether layer was extracted once with water and the water layer was combined with the aqueous layer which had already been partitioned. After adjusting the pH to about 1 by the addition of an aqueous 10% ice-cooled hydrochloric acid solution, the mixture was extracted three times with diethyl ether. The layers were combined and the combined ether layer was washed twice with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to give 131 g of 4,4,4-trifluorobutyric acid (yield: 98%). the mixture was further reacted at room temperature for 12 hours After the reaction solution was concentrated under reduced pressure the resulting residue was then partitioned between water and diethyl ether The ether layer was extracted once with water had already been partitioned by the addition of an aqueous 10% ice- cooled hydrochloric acid solution the mixture was extracted three times with diethyl ether the combined ether layer was washed twice with saturated saline dried over anhydrous magnesium sulfate Then, the solvent was distilled off under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 160 g of ethyl 4,4,4-trifluorobutyrate, a mixed solution of 123 g of potassium hydroxide, 900 ml of methanol and 80 ml of water was added under ice cooling and the mixture was further reacted at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was then partitioned between water and diethyl ether. The ether layer was extracted once with water and the water layer was combined with the aqueous layer which had already been partitioned. After adjusting the pH to about 1 by the addition of an aqueous 10% ice-cooled hydrochloric acid solution, the mixture was extracted three times with diethyl ether. The layers were combined and the combined ether layer was washed twice with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to give 131 g of 4,4,4-trifluorobutyric acid (yield: 98%). the mixture was further reacted at room temperature for 12 hours After the reaction solution was concentrated under reduced pressure the resulting residue was then partitioned between water and diethyl ether The ether layer was extracted once with water had already been partitioned by the addition of an aqueous 10% ice- cooled hydrochloric acid solution the mixture was extracted three times with diethyl ether the combined ether layer was washed twice with saturated saline dried over anhydrous magnesium sulfate Then, the solvent was distilled off under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To sodium hexamethyldisilazane (0.945 M in tetrahydrofuran) (667 mL, 0.63 mol) in tetrahydrofuran (0.9 L) at -78° C., under nitrogen, was added a solution of ethyl 4,4,4-trifluorobutyrate (90.6 mL) in tetrahydrofuran (100 mL). After stirring for 1.5 hour, to the vigorously stirred mixture was added methyl iodide (112 mL) as fast as possible. The reaction was warmed with a 0° C. bath for 2 hours. Methanol (1 L) and 1N lithium hydroxide (1.2 L) were added and stirring continued for 48 hours. The mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The combined organic phase was washed (brine), dried (MgSO4), and evaporated at 30° C. After combination with product from separate conversions of ethyl 4,4,4-trifluorobutyrate (97.79 g), distillation afforded 2-methyl-4,4,4-trifluorobutyric acid (173.24 g, 96%) as a brown solid-liquid contaminated with 4,4,4-trifluorobutyric acid and 2,2-dimethyl-4,4,4-trifluorobutyric acid; bp 48.0°-108° C. (9,900 Pa); GLC: tR =6.1 min. stirring continued for 48 hours extracted with ethyl acetate The combined organic phase was washed (brine) dried (MgSO4) evaporated at 30° C After combination with product from separate conversions of ethyl 4,4,4-trifluorobutyrate (97.79 g), distillation

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To sodium hexamethyldisilazane (0.945M in tetrahydrofuran) (667 mL, 0.63 mol) in tetrahydrofuran (0.9 L) at -78° C., under nitrogen, was added a solution of ethyl 4,4,4-trifluorobutyrate (90.6 mL) in tetrahydrofuran (100 mL). After stirring for 1.5 hour, to the vigorously stirred mixture was added methyl iodide (112 mL) as fast as possible. The reaction was warmed with a 0° C. bath for 2 hours. Methanol (1 L) and 1N lithium hydroxide (1.2 L) were added and stirring continued for 48 hours. The mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The combined organic phase was washed (brine), dried (MgSO4), and evaporated at 30° C. After combination with product from separate conversions of ethyl 4,4,4-trifluorobutyrate (97.79 g), distillation afforded 2-methyl-4,4,4-trifluorobutyric acid (173.24 g, 96%) as a brown solid-liquid contaminated with 4,4,4-trifluorobutyric acid and 2,2-dimethyl-4,4,4-trifluorobutyric acid; bp 48.0°-108° C. (9,900 Pa); GLC: tR =6.1 min. stirring continued for 48 hours extracted with ethyl acetate The combined organic phase was washed (brine) dried (MgSO4) evaporated at 30° C After combination with product from separate conversions of ethyl 4,4,4-trifluorobutyrate (97.79 g), distillation

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of diisopropylamine (19.5 mL) in tetrahydrofuran (200 mL) at 0° C. was treated with n-butyllithium (71 mL, 1.5M in hexanes). The resulting solution was stirred for 30 minutes at 0° C., then was cooled to -70° C. A solution of ethyl 4,4,4-trifluorobutyrate (14 mL) in tetrahydrofuran (150 mL) was slowly added to the lithium diisopropylamide solution and the resulting mixture was stirred at -70° C. for 30 minutes. A solution of iodomethane (11.5 mL) in tetrahydrofuran was added in one portion, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with water and evaporated. The residue was dissolved in methylene chloride, washed (10% (w/v) hydrochloric acid, water, and brine), dried (MgSO4), filtered, and evaporated. The resulting pale yellow liquid was purified by distillation to yield ethyl 4,4,4-trifluoro-2-methylbutyrate as a colorless liquid (7.8 g, 46%); bp 125°-128 ° C.; partial NMR: (300 MHz, CDCl3): 1.30 (m, 6H, CH3), CH2CH3), 2.15 (m, 1H, H-C(3)), 2.64 (m, 1H, H-C(3)), 2.72 (m, 1H, H-C(2)), 4.16 (q, 2H, OCH2). was cooled to -70° C the resulting mixture was stirred at -70° C. for 30 minutes the cooling bath was removed to warm to room temperature The reaction mixture was quenched with water evaporated The residue was dissolved in methylene chloride washed (10% (w/v) hydrochloric acid, water, and brine) dried (MgSO4) filtered evaporated The resulting pale yellow liquid was purified by distillation

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 4,4,4-trifluorobutyrate (1 g, 5.88 mmol) and diethyl oxalate (3.87 g, 26.5 mmol) was dissolved in ethanol. Sodium ethoxide (21% in ethanol, 2.09 g) was added to the solution, and the reaction mixture stirred for 0.5 hrs. Solvent was distilled, and the residue extracted with EtOAc/water. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed to give a clear liquid. MS (ESI): m/z 269.1 (M−1). The liquid was then dissolved in 3N HCl (20 mL), and the reaction mixture refluxed for 4 hrs. After cooling down, the reaction mixture was extracted with EtOAc. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed, and the residue used directly in the next step. MS (ESI): m/z 169.7 (M−1). Solvent was distilled the residue extracted with EtOAc/water The organic layers were collected dried over sodium sulfate After filtration, solvent was removed to give a clear liquid the reaction mixture refluxed for 4 hrs After cooling down the reaction mixture was extracted with EtOAc The organic layers were collected dried over sodium sulfate After filtration, solvent was removed

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 4,4,4-trifluorobutyrate (1 g, 5.88 mmol) and diethyl oxalate (3.87 g, 26.5 mmol) was dissolved in ethanol. Sodium ethoxide (21% in ethanol, 2.09 g) was added to the solution, and the reaction mixture stirred for 0.5 hrs. Solvent was distilled, and the residue extracted with EtOAc/water. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed to give a clear liquid. MS (ESI): m/z 269.1 (M−1). The liquid was then dissolved in 3N HCl (20 mL), and the reaction mixture refluxed for 4 hrs. After cooling down, the reaction mixture was extracted with EtOAc. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed, and the residue used directly in the next step. MS (ESI): m/z 169.7 (M−1). Solvent was distilled the residue extracted with EtOAc/water The organic layers were collected dried over sodium sulfate After filtration, solvent was removed to give a clear liquid the reaction mixture refluxed for 4 hrs After cooling down the reaction mixture was extracted with EtOAc The organic layers were collected dried over sodium sulfate After filtration, solvent was removed

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 4,4,4-trifluorobutyrate (1 g, 5.88 mmol) and diethyl oxalate (3.87 g, 26.5 mmol) was dissolved in ethanol. Sodium ethoxide (21% in ethanol, 2.09 g) was added to the solution, and the reaction mixture stirred for 0.5 hrs. Solvent was distilled, and the residue extracted with EtOAc/water. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed to give a clear liquid. MS (ESI): m/z 269.1 (M−1). The liquid was then dissolved in 3N HCl (20 mL), and the reaction mixture refluxed for 4 hrs. After cooling down, the reaction mixture was extracted with EtOAc. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed, and the residue used directly in the next step. MS (ESI): m/z 169.7 (M−1). Solvent was distilled the residue extracted with EtOAc/water The organic layers were collected dried over sodium sulfate After filtration, solvent was removed to give a clear liquid the reaction mixture refluxed for 4 hrs After cooling down the reaction mixture was extracted with EtOAc The organic layers were collected dried over sodium sulfate After filtration, solvent was removed

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 4,4,4-trifluorobutyrate (1 g, 5.88 mmol) and diethyl oxalate (3.87 g, 26.5 mmol) was dissolved in ethanol. Sodium ethoxide (21% in ethanol, 2.09 g) was added to the solution, and the reaction mixture stirred for 0.5 hrs. Solvent was distilled, and the residue extracted with EtOAc/water. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed to give a clear liquid. MS (ESI): m/z 269.1 (M−1). The liquid was then dissolved in 3N HCl (20 mL), and the reaction mixture refluxed for 4 hrs. After cooling down, the reaction mixture was extracted with EtOAc. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed, and the residue used directly in the next step. MS (ESI): m/z 169.7 (M−1). Solvent was distilled the residue extracted with EtOAc/water The organic layers were collected dried over sodium sulfate After filtration, solvent was removed to give a clear liquid the reaction mixture refluxed for 4 hrs After cooling down the reaction mixture was extracted with EtOAc The organic layers were collected dried over sodium sulfate After filtration, solvent was removed

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 160 g of ethyl 4,4,4-trifluorobutyrate, a mixed solution of 123 g of potassium hydroxide, 900 ml of methanol and 80 ml of water was added under ice cooling and the mixture was further reacted at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was then partitioned between water and diethyl ether. The ether layer was extracted once with water and the water layer was combined with the aqueous layer which had already been partitioned. After adjusting the pH to about 1 by the addition of an aqueous 10% ice-cooled hydrochloric acid solution, the mixture was extracted three times with diethyl ether. The layers were combined and the Combined ether layer was washed twice with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to give 131 g of 4,4,4-trifluorobutyric acid (yield: 98%). the mixture was further reacted at room temperature for 12 hours After the reaction solution was concentrated under reduced pressure the resulting residue was then partitioned between water and diethyl ether The ether layer was extracted once with water had already been partitioned by the addition of an aqueous 10% ice- cooled hydrochloric acid solution the mixture was extracted three times with diethyl ether the Combined ether layer was washed twice with saturated saline dried over anhydrous magnesium sulfate Then, the solvent was distilled off under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of lithium hydroxide monohydrate (324 g) in water (1.8 L) was added to a stirred solution of ethyl 4,4,4-trifluorobutyrate (436 g) in methanol (2.0 L) and dry tetrahydrofuran (2.0 L) and the suspension was stirred overnight. After the suspension was partially evaporated, the residue was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 6M hydrochloric acid and extracted with diethyl ether. The combined extracts were washed (brine), dried (MgSO4), and filtered. The filtrate was evaporated and the residue distilled (bp 165°-168° C.) to give 4,4,4-trifluorobutyric acid (347 g, 95%); mp 27°-30° C.; partial NMR; (300 MHz, CDCl3): 2.33-2.57 (m, 2H, CF3CH2), 2.66 (t, 2H, CH2CO2H). After the suspension was partially evaporated the residue was diluted with water washed with diethyl ether extracted with diethyl ether The combined extracts were washed (brine) dried (MgSO4) filtered The filtrate was evaporated the residue distilled (bp 165°-168° C.)