4,4,4-trifluoro-3-oxobutanenitrile

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: A solution of methylhydrazine (5.0 g, 60 mmol) and 4,4,4-trifluoro-3-oxo-butyronitrile (9.8 g, 71 mmol) in EtOH (50 mL) was treated with conc. HCl (5 mL) and the resultant mixture was heated to reflux overnight. The solvent was removed in vacuo and the crude product was dissolved in EtOAc washed with saturated aq. Na2CO3 solution until the washings were pH 8. The organics were concentrated and purified by prep-HPLC to provide 2-methyl-5-trifluoromethyl-2H-pyrazol-3-ylamine (2.07 g, 21% yield). 1H NMR (300 MHz, DMSO-d6), δ 5.57 (s, 1 H), 5.54 (br s, 2 H), 3.55 (s, 3 H); MS (ESI) m/z: 166.1 (M+H+). to reflux overnight The solvent was removed in vacuo the crude product was dissolved in EtOAc washed with saturated aq. Na2CO3 solution until the washings The organics were concentrated purified by prep-HPLC

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

Procedure: A solution of methylhydrazine (5.0 g, 60 mmol) and 4,4,4-trifluoro-3-oxo-butyronitrile (9.8 g, 71 mmol) in EtOH (50 mL) was treated with conc. HCl (5 mL) and the resultant mixture was heated to reflux overnight. The solvent was removed in vacuo and the crude product was dissolved in EtOAc washed with saturated aq. Na2CO3 solution until the washings were pH 8. The organics were concentrated and purified by prep-HPLC to provide 2-methyl-5-trifluoromethyl-2H-pyrazol-3-ylamine (2.07 g, 21% yield). 1H NMR (300 MHz, DMSO-d6), δ 5.57 (s, 1 H), 5.54 (br s, 2 H), 3.55 (s, 3 H); MS (ESI) m/z: 166.1 (M+H+). to reflux overnight The solvent was removed in vacuo the crude product was dissolved in EtOAc washed with saturated aq. Na2CO3 solution until the washings The organics were concentrated purified by prep-HPLC

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

Procedure: A solution of ethyl trifluoroacetate (14.2 g, 0.1 mol) and anhydrous acetonitrile (5.0 g, 0.12 mol) in THF (100 mL) was added dropwise to a suspension of NaH (60%, 6.0 g, 0.15 mol) in THF (100 mL) at 80° C. The resulting mixture was heated to reflux overnight, and then cooled to RT. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc and 10% aq HCl. The organic layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo to yield crude 4,4,4-trifluoro-3-oxo-butyronitrile (15 g), which was used without further purification. The resulting mixture was heated to reflux overnight The reaction mixture was concentrated in vacuo the residue was diluted with EtOAc and 10% aq HCl The organic layer was washed with water and brine dried (MgSO4) concentrated in vacuo

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

Procedure: Following the procedure in Example 161A Step 3, m-tolylhydrazine hydrochloride (1.15 g, 7.30 mmol) and 4,4,4-trifluoro-3-oxobutanenitrile (1.0 g, 7.30 mmol) were reacted to give 1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (380 mg, 1.57 mmol, 22%). 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.20 (m, 4H), 5.82-5.61 (m, 3H), 2.59 (s, 3H); LC-MS (ESI) m/z 242 (M+H)+. were reacted

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

Procedure: (Trimethylsilyl)diazomethane (21 mL, 2M in diethyl ether) was added dropwise to a solution of 4,4,4-trifluoro-3-oxobutanenitrile (3.79 g, 26 mmol) in anhydrous diethyl ether (25 mL) previously cooled to 0° C. The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. The solvent was removed under reduced pressure to give 4,4,4-trifluoro-3-methoxybut-2-enenitrile, which was directly used in the next step without further purification. 1H NMR (300 MHz, CDCl3) d 5.00 (s, 1H), 4.16 (s, 3H). to slowly warm to room temperature The solvent was removed under reduced pressure

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

Procedure: (Trimethylsilyl)diazomethane (21 mL, 2M in diethyl ether) was added dropwise to a solution of 4,4,4-trifluoro-3-oxobutanenitrile (3.79 g, 26 mmol) in anhydrous diethyl ether (25 mL) previously cooled to 0° C. The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. The solvent was removed under reduced pressure to give 4,4,4-trifluoro-3-methoxybut-2-enenitrile, which was directly used in the next step without further purification. 1H NMR (300 MHz, CDCl3) d 5.00 (s, 1H), 4.16 (s, 3H). to slowly warm to room temperature The solvent was removed under reduced pressure

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4,4,4-trifluoro-3-oxobutanenitrile (2.056 g, 15 mmol) and phenylhydrazine hydrochloride (2.169 g, 15 mmol) in EtOH was heated at 90° C. for 8 hours. The reaction was quenched with water, basified with saturated NaHCO3 solution, and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as yellow solid (3.089 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.54 (m, 5H), 5.85 (s, 1H), 3.95 (br, 2H); LC-MS (ESI) m/z 228 (M+H)+. The reaction was quenched with water extracted with CH2Cl2 Extracts were dried over MgSO4 concentrated under reduced pressure dried under vacuum

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

Procedure: To a suspension of NaH (2.88 g, 120 mmol) in THF (70 mL) at 80° C. was dropped a solution of methyl 2,2,2-trifluoroacetate (10.244 g, 80 mmol) in MeCN (5.377 g, 130 mmol) over 40 minutes. The mixture was heated at 70° C. for 2 hours and stirred at room temperature overnight. The reaction was quenched with water, acidified with 10% HCl solution to pH 1, and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford 4,4,4-trifluoro-3-oxobutanenitrile as an oil (9.084 g, 83%). 1H NMR (300 MHz, CDCl3) δ 2.93 (s, 2H). The reaction was quenched with water extracted with CH2Cl2 Extracts were dried over MgSO4 concentrated under reduced pressure dried under vacuum

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

Procedure: To a suspension of NaH (2.88 g, 120 mmol) in THF (70 mL) at 80° C. was dropped a solution of methyl 2,2,2-trifluoroacetate (10.244 g, 80 mmol) in MeCN (5.377 g, 130 mmol) over 40 minutes. The mixture was heated at 70° C. for 2 hours and stirred at room temperature overnight. The reaction was quenched with water, acidified with 10% HCl solution to pH 1, and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford 4,4,4-trifluoro-3-oxobutanenitrile as an oil (9.084 g, 83%). 1H NMR (300 MHz, CDCl3) δ 2.93 (s, 2H). The reaction was quenched with water extracted with CH2Cl2 Extracts were dried over MgSO4 concentrated under reduced pressure dried under vacuum

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

Procedure: Following the procedure in Example 161A Step 3, m-tolylhydrazine hydrochloride (1.15 g, 7.30 mmol) and 4,4,4-trifluoro-3-oxobutanenitrile (1.0 g, 7.30 mmol) were reacted to give 1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (380 mg, 1.57 mmol, 22%). 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.20 (m, 4H), 5.82-5.61 (m, 3H), 2.59 (s, 3H); LC-MS (ESI) m/z 242 (M+H)+. were reacted