ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate

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:

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 2-methyl-4,4,4-trifluoroacetoacetate (50 g), under a blanket of nitrogen gas, is heated to 40° C. and treated with platinum (0.1 g of 5% Pt/C, 0.01% load) and triethylamine (0.2 g, 0.4 % load). Hydrogen is charged to a pressure of 5 bars, and the mixture agitated at 40° C. for 6h. After filtration to remove the catalyst, 48.5 g (96% yield) of ethyl 2-methyl-4,4,4-trifluoro-3-hydroxybutyrate is obtained. After filtration to remove the catalyst

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

Procedure: To a solution of ethyl 3-keto-2-methyl-4,4,4-trifluorobutanoate (20.1 g, 0.10 moles) in 250 ml of absolute ethanol, cooled in an ice bath, was added sodium borohydride (1.0 g, 0.25 moles) in portions with stirring. The cooling bath was removed and the reaction stirred at room temperature for 30 minutes. Acetone (5 ml) was added to quench any remaining sodium borohydride and the solvents removed by distillation at atmospheric pressure using a Vigreaux column. The residue was diluted with 200 ml of methylene chloride and poured into a separatory funnel containing 75 ml of a 1:1:1 mixture of saturated ammonium chloride:brine:water. The layers were separated and the aqueous phase extracted with methylene chloride (3×25 ml). The combined organic phase and methylene chloride extracts were dried over magnesium sulfate, filtered and distilled at atmospheric pressure to remove the solvents. The residue was then distilled at reduced pressure (20 mmHg) using a Vigreaux column to give ethyl 3-hydroxy-2-methyl-4,4,4-trifluorobutanoate, bp 78-84° C., 20 mmHg. The cooling bath was removed the reaction stirred at room temperature for 30 minutes Acetone (5 ml) was added to quench any remaining sodium borohydride the solvents removed by distillation at atmospheric pressure The residue was diluted with 200 ml of methylene chloride poured into a separatory funnel containing 75 ml of a 1:1:1 mixture of saturated ammonium chloride The layers were separated the aqueous phase extracted with methylene chloride (3×25 ml) The combined organic phase and methylene chloride extracts were dried over magnesium sulfate filtered distilled at atmospheric pressure to remove the solvents The residue was then distilled at reduced pressure (20 mmHg)

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

Procedure: Sodium hydride (7.05 g of a 50% oil dispersion, 0.15 mol) was washed 3 times with 25 ml of dimethoxyethane to remove the oil and then suspended in 220 ml of dimethoxyethane, under an argon atmosphere and cooled in an ice bath. A solution of ethyl 3-keto-4,4,4-trifluorobutanoate (25.77 g, 0.14 mol) in 25 ml of dimethoxyethane was added dropwise from an addition funnel to the stirred suspension. After the addition was completed, the cooling bath was removed and the reaction mixture stirred for 30 minutes past the cessation of hydrogen gas evolution. Methyl iodide (43.0 ml, 0.70 mole) was added by syringe and the reaction mixture refluxed overnight. The reaction was cooled to room temperature and poured into a separatory funnel containing a 1:1:1 mixture of saturated ammonium chloride:brine:water. The layers were separated and the aqueous phase extracted with 100 ml ether. The combined organic phase and ether extract was washed with brine, dried over magnesium sulfate and filtered. The solvents were removed by distillation at atmospheric pressure using a Vigreaux column leaving ethyl 3-keto-2-methyl-4,4,4-trifluorobutanoate as the pot residue. Rf: (EtAc/hexane--20:80) Sodium hydride (7.05 g of a 50% oil dispersion, 0.15 mol) was washed 3 times with 25 ml of dimethoxyethane to remove the oil cooled in an ice bath After the addition the cooling bath was removed the reaction mixture refluxed overnight poured into a separatory funnel containing The layers were separated the aqueous phase extracted with 100 ml ether The combined organic phase and ether extract was washed with brine dried over magnesium sulfate filtered The solvents were removed by distillation at atmospheric pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaOH (2.01 g, 50.5 mmol) was dissolved in water (30 mL) at 0° C. A sol. of hydroxylamine hydrochloride (1.75 g, 25.2 mmol) in water (30 mL) was added. Ethyl 2-methyl-4,4,4-trifluoroacetoacetate (5.00 g, 25.2 mmol) was added, and the mixture was stirred at 0° C. for 90 min. Aq. cone. HCl (26 mL) was added and the mixture was stirred for 1 h at 4° C. The mixture was filtered, and the precipitate was dried under high vacuum at 40° C. This delivered a first crop of title compound (0.56 g, 12%). The filtrate was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded a second crop of the title compound (1.81 g, 38%; total: 2.37 g, 50%). LC-MS: tR=0.58, ES+: not visible. the mixture was stirred for 1 h at 4° C The mixture was filtered the precipitate was dried under high vacuum at 40° C The filtrate was extracted with EtOAc (2×) extracts were dried over MgSO4 filtered the solvents were removed under reduced pressure Drying the residue under high vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaOH (2.01 g, 50.5 mmol) was dissolved in water (30 mL) at 0° C. A sol. of hydroxylamine hydrochloride (1.75 g, 25.2 mmol) in water (30 mL) was added. Ethyl 2-methyl-4,4,4-trifluoroacetoacetate (5.00 g, 25.2 mmol) was added, and the mixture was stirred at 0° C. for 90 min. Aq. cone. HCl (26 mL) was added and the mixture was stirred for 1 h at 4° C. The mixture was filtered, and the precipitate was dried under high vacuum at 40° C. This delivered a first crop of title compound (0.56 g, 12%). The filtrate was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded a second crop of the title compound (1.81 g, 38%; total: 2.37 g, 50%). LC-MS: tR=0.58, ES+: not visible. the mixture was stirred for 1 h at 4° C The mixture was filtered the precipitate was dried under high vacuum at 40° C The filtrate was extracted with EtOAc (2×) extracts were dried over MgSO4 filtered the solvents were removed under reduced pressure Drying the residue under high vacuum

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

Procedure: To a solution of 7.4 g (100.0 mmol) of isopropylhydrazine in 100 ml of ethanol was added dropwise under stirring 23.3 g (purity: 85.0%, 100.0 mmol) of ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate under ice-cooling so that the temperature in the reaction system did not exceed 10° C. After the dropwise addition, the whole was stirred at room temperature for 30 minutes. Then, 1 ml of concentrated hydrochloric acid was added into the reaction solution, followed by 2 days of stirring under refluxing. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was washed with n-hexane to obtain 18.1 g (yield: 87.0%) of 5-hydroxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole as white crystals (melting point: 150 to 153° C.). cooling so that the temperature in the reaction system did not exceed 10° C After the dropwise addition followed by 2 days of stirring under refluxing the solvent was removed by evaporation under reduced pressure Water was added to the residue followed by extraction with ethyl acetate The resulting organic layer was washed with water and saline successively, and then dried over anhydrous magnesium sulfate The solvent was removed by evaporation under reduced pressure the residue was washed with n-hexane

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

Procedure: To a solution of 7.4 g (100.0 mmol) of isopropylhydrazine in 100 ml of ethanol was added dropwise under stirring 23.3 g (purity: 85.0%, 100.0 mmol) of ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate under ice-cooling so that the temperature in the reaction system did not exceed 10° C. After the dropwise addition, the whole was stirred at room temperature for 30 minutes. Then, 1 ml of concentrated hydrochloric acid was added into the reaction solution, followed by 2 days of stirring under refluxing. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was washed with n-hexane to obtain 18.1 g (yield: 87.0%) of 5-hydroxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole as white crystals (melting point: 150 to 153° C.). cooling so that the temperature in the reaction system did not exceed 10° C After the dropwise addition followed by 2 days of stirring under refluxing the solvent was removed by evaporation under reduced pressure Water was added to the residue followed by extraction with ethyl acetate The resulting organic layer was washed with water and saline successively, and then dried over anhydrous magnesium sulfate The solvent was removed by evaporation under reduced pressure the residue was washed with n-hexane

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

Procedure: To a solution of 1.2 g (20.0 mmol) of ethylhydrazine in 20 ml of ethanol was added dropwise under stirring 4.4 g (20.0 mmol) of ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate under ice-cooling so that the temperature in the reaction system did not exceed 10° C. After the dropwise addition, the whole was stirred at room temperature for 30 minutes. Then, 1 ml of concentrated hydrochloric acid was added into the reaction solution, followed by 2 days of stirring under refluxing. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was washed with n-hexane to obtain 2.8 g (yield: 71.8%) of 1-ethyl-5-hydroxy-4-methyl-3-trifluoromethyl-1H-pyrazole as white crystals (melting point: 150 to 152° C.). cooling so that the temperature in the reaction system did not exceed 10° C After the dropwise addition followed by 2 days of stirring under refluxing the solvent was removed by evaporation under reduced pressure Water was added to the residue followed by extraction with ethyl acetate The resulting organic layer was washed with water and saline successively, and then dried over anhydrous magnesium sulfate The solvent was removed by evaporation under reduced pressure the residue was washed with n-hexane