methyl 4,4,4-trifluoro-3-oxobutanoate

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of Compound 4 (0.46 g, 3.1 mmol) and methyl-4,4,4-trifluoroacetoacetate (0.55 g, 3.2 mmol) in 7 mL CH3 SO3H is stirred at 20° C. for 48 hours. The reaction mixture is poured into 70 mL ice water, and the resulting precipitate is collected by filtration, washed with water, dried in vacuo at 60° C. for 16 hours to yield 240 mg (30%) of Compound 20 as an off-white powder. 1 H-NMR (DMSO-d6) δ 7.33 (d, 1 H), 6.99 (s, 1H). 19F-NMR (DMSO-d6) Φ 59.38 (s, 3F), 129.93 (t, J=9.9 Hz, 1H), 147.78 (d, J=9.3 Hz, 1F). the resulting precipitate is collected by filtration washed with water dried in vacuo at 60° C. for 16 hours

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

Procedure: A solution of Compound 4 (0.46 g, 3.1 mmol) and methyl-4,4,4-trifluoroacetoacetate (0.55 g, 3.2 mmol) in 7 mL CH3 SO3H is stirred at 20° C. for 48 hours. The reaction mixture is poured into 70 mL ice water, and the resulting precipitate is collected by filtration, washed with water, dried in vacuo at 60° C. for 16 hours to yield 240 mg (30%) of Compound 20 as an off-white powder. 1 H-NMR (DMSO-d6) δ 7.33 (d, 1 H), 6.99 (s, 1H). 19F-NMR (DMSO-d6) Φ 59.38 (s, 3F), 129.93 (t, J=9.9 Hz, 1H), 147.78 (d, J=9.3 Hz, 1F). the resulting precipitate is collected by filtration washed with water dried in vacuo at 60° C. for 16 hours

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into 6 mL of tetrahydrofuran were dissolved 7.5 mg of RuCl[(1R,2R)-p-TsNHCH(C6H5)CH(C6H5)NH2] (p-cymene), 5 mL of a mixture of formic acid-triethylamine (5:2 in molar ratio), 1.0 g of methyl 4,4,4-trifluoro-3-oxobutanoate, and the whole was stirred at 35° C. for 15 hours, followed by concentration under reduced pressure using an evaporator. To the resulting concentrate were added 10 mL of water and 10 mL of ethyl acetate, and then a saturated sodium carbonate aqueous solution was added thereto under stirring until the pH became 7 or higher. The ethyl acetate layer separated from the aqueous layer was concentrated to obtain optically active methyl 4,4,4-trifluoro-3-hydroxybutanoate. Upon the measurement under the above conditions, the optical purity and conversion were found to be 96.4% e.e. and 100%, respectively. followed by concentration under reduced pressure an evaporator To the resulting concentrate were added 10 mL of water and 10 mL of ethyl acetate a saturated sodium carbonate aqueous solution was added under stirring until the pH The ethyl acetate layer separated from the aqueous layer was concentrated

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 6 mL of methanol were added 5 mL of a mixture of formic acid-triethylamine (5:2 in molar ratio), 1.0 g of methyl 4,4,4-trifluoro-3-oxobutanoate, and 7.5 mg of RuCl[(1R,2R)-p-TsNHCH(C6H5)CH(C6H5)NH2] (p-cymene), and the whole was stirred at 35° C. for 15 hours, followed by concentration under reduced pressure using an evaporator. To the resulting concentrate were added 10 mL of water and 10 mL of ethyl acetate, and then a saturated sodium carbonate aqueous solution was added thereto under stirring until the pH became 7 or higher. The ethyl acetate layer separated from the aqueous layer was concentrated to obtain optically active methyl 4,4,4-trifluoro-3-hydroxybutanoate. Upon the measurement under the above conditions, the optical purity and conversion were found to be 94.6% e.e. and 100%, respectively. followed by concentration under reduced pressure an evaporator To the resulting concentrate were added 10 mL of water and 10 mL of ethyl acetate a saturated sodium carbonate aqueous solution was added under stirring until the pH The ethyl acetate layer separated from the aqueous layer was concentrated

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

Procedure: To a solution of 344 g (0.920 mole) crude product from Example b in 500 ml of tetrahydrofuran (THF) is passed 58 g (3.41 mole) of gaseous ammonia for 3 hours. The reaction mixture is concentrated and the residue (332 g) is recrystallized from hexane-ether to give 53.7 g (13% yield from methyl trifluoroacetoacetate) of the desired product as a white solid, m.p. 102°-106° C. for 3 hours The reaction mixture is concentrated the residue (332 g) is recrystallized from hexane-ether

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of crude 2-tert-butyl-5-cyclobutyl-2H-pyrazol-3-ylamine (2.0 g, 10.4 mmol) in AcOH (10 mL) was added 4,4,4-trifluoro-3-oxo-butyric acid methyl ester (3.5 g, 20.7 mmol). The reaction was then heated to 110° C. for 18 hr, at which time the reaction was cooled to room temperature, concentrated under reduced pressure, diluted with EtOAc, and quenched with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated under reduced pressure to give the title compound (3.2 g, quantitative yield). This material was used without further purification. LRMS m/z (APCl) 314 (M+1); 500 MHz 1H NMR (CDCl3) δ 6.66 (s, 1H), 3.78 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 2.49-2.39 (m, 2H), 2.34-2.26 (m, 2H), 2.06-1.85 (m, 2H), 1.75 (s, 9H). was cooled to room temperature concentrated under reduced pressure diluted with EtOAc quenched with a saturated aqueous solution of NaHCO3 The organic layer was dried over MgSO4 filtered through a fritted funnel concentrated under reduced pressure

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

Procedure: To a solution of 344 g (0.920 mole) crude product from Step 1 in 500 ml of tetrahydrofuran (THF) is passed 58 g (3.41 mole) of gaseous ammonia for 3 hours. The reaction mixture is concentrated and the residue (332 g) is recrystallized from hexane-ether to give 53.7 g (13% yield from methyl trifluoroacetoacetate) of the desired product as a white solid, m.p. 102°-106° C. for 3 hours The reaction mixture is concentrated the residue (332 g) is recrystallized from hexane-ether

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

Procedure: To a solution of 344 g (0.920 mole) crude product from Example b in 500 ml of tetrahydrofuran (THF) is passed 58 g (3.41 mole) of gaseous ammonia for 3 hours. The reaction mixture is concentrated and the residue (332 g) is recrystallized from hexaneether to give 53.7 g (13% yield from methyl trifluoroacetoacetate) of the desired product as a white solid, m.p. 102°-106° C. for 3 hours The reaction mixture is concentrated the residue (332 g) is recrystallized from hexaneether

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

Procedure: A solution of Compound 4 (0.46 g, 3.1 mmol) and methyl-4,4,4-trifluoroacetoacetate (0.55 g, 3.2 mmol) in 7 mL CH3 SO3H is stirred at 20° C. for 48 hours. The reaction mixture is poured into 70 mL ice water, and the resulting precipitate is collected by filtration, washed with water, dried in vacuo at 60° C. for 16 hours to yield 240 mg (30%) of Compound 20 as an off-white powder. 1 H-NMR (DMSO-d6) δ 7.33 (d, 1 H), 6.99 (s, 1H). 19F-NMR (DMSO-d6) Φ 59.38 (s, 3F), 129.93 (t, J=9.9 Hz, 1H), 147.78 (d, J=9.3 Hz, 1F). the resulting precipitate is collected by filtration washed with water dried in vacuo at 60° C. for 16 hours