1-(2,2,2-trifluoroethyl)piperidin-4-one

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:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 1-(2,2,2-trifluoro-ethyl)-piperidin-4-one (WO 9621452). 1H-NMR (CD3OD; 400 MHz): δ 12.9 (br s, 1H), 9.62 (s, 1H), 8.21 (d, 1H, J=8.4 Hz), 7.63 (s, 1H), 7.38 (dd, 1H, J=8.4, 2.0 Hz), 7.24 (d, 1H, J=2.0 Hz), 5.73 (br s, 1H), 4.13 (m, 2H), 2.91-3.23 (m, 4H), 1.93-2.32 (m, 4H), 1.53 (m, 2H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30F3N5O2, 502.5 (M+H). found 502.2.

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

Procedure: The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 1-(2,2,2-trifluoro-ethyl)-piperidin-4-one (WO 9621452). 1H-NMR (CD3OD; 400 MHz): δ 12.9 (br s, 1H), 9.62 (s, 1H), 8.21 (d, 1H, J=8.4 Hz), 7.63 (s, 1H), 7.38 (dd, 1H, J=8.4, 2.0 Hz), 7.24 (d, 1H, J=2.0 Hz), 5.73 (br s, 1H), 4.13 (m, 2H), 2.91-3.23 (m, 4H), 1.93-2.32 (m, 4H), 1.53 (m, 2H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30F3N5O2, 502.5 (M+H). found 502.2.

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

Procedure: The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 1-(2,2,2-trifluoro-ethyl)-piperidin-4-one (WO 9621452). 1H-NMR (CD3OD; 400 MHz): δ 12.9 (br s, 1H), 9.62 (s, 1H), 8.21 (d, 1H, J=8.4 Hz), 7.63 (s, 1H), 7.38 (dd, 1H, J=8.4, 2.0 Hz), 7.24 (d, 1H, J=2.0 Hz), 5.73 (br s, 1H), 4.13 (m, 2H), 2.91-3.23 (m, 4H), 1.93-2.32 (m, 4H), 1.53 (m, 2H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30F3N5O2, 502.5 (M+H). found 502.2.

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

Procedure: 200 mg (0.596 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were initially charged in methanol (16 ml) and admixed with 75 μl (1.312 mmol) of acetic acid, and then 237 mg (1.312 mmol) of 1-(2,2,2-trifluoroethyl)piperidin-4-one were added. After stirring at RT for 15 min, 104 mg (1.67 mmol) of sodium cyanoborohydride were added and the mixture was stirred at RT for 2.5 h. Subsequently, within 2 days, the above-stated amounts of reagents (1-(2,2,2-trifluoroethyl)piperidin-4-one, acetic acid, sodium cyanoborohydride) were added three times, in order to achieve substantially full conversion. Thereafter, saturated aqueous sodium hydrogencarbonate solution (5 ml) was added to the reaction mixture, which was stirred vigorously for 10 min. Subsequently, the reaction mixture was extracted with water and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated and then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 269 mg of the title compound were obtained (90% of theory). the mixture was stirred at RT for 2.5 h Subsequently, within 2 days was stirred vigorously for 10 min Subsequently, the reaction mixture was extracted with water and ethyl acetate The phases were separated the aqueous phase was extracted twice with ethyl acetate The combined organic phases were washed with saturated aqueous sodium chloride solution dried over sodium sulfate filtered concentrated purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient)

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

Procedure: 200 mg (0.596 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were initially charged in methanol (16 ml) and admixed with 75 μl (1.312 mmol) of acetic acid, and then 237 mg (1.312 mmol) of 1-(2,2,2-trifluoroethyl)piperidin-4-one were added. After stirring at RT for 15 min, 104 mg (1.67 mmol) of sodium cyanoborohydride were added and the mixture was stirred at RT for 2.5 h. Subsequently, within 2 days, the above-stated amounts of reagents (1-(2,2,2-trifluoroethyl)piperidin-4-one, acetic acid, sodium cyanoborohydride) were added three times, in order to achieve substantially full conversion. Thereafter, saturated aqueous sodium hydrogencarbonate solution (5 ml) was added to the reaction mixture, which was stirred vigorously for 10 min. Subsequently, the reaction mixture was extracted with water and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated and then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 269 mg of the title compound were obtained (90% of theory). the mixture was stirred at RT for 2.5 h Subsequently, within 2 days was stirred vigorously for 10 min Subsequently, the reaction mixture was extracted with water and ethyl acetate The phases were separated the aqueous phase was extracted twice with ethyl acetate The combined organic phases were washed with saturated aqueous sodium chloride solution dried over sodium sulfate filtered concentrated purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient)

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

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

Procedure: The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 1-(2,2,2-trifluoro-ethyl)-piperidin-4-one (WO 9621452). 1H-NMR (CD3OD; 400 MHz): δ 12.9 (br s, 1H), 9.62 (s, 1H), 8.21 (d, 1H, J=8.4 Hz), 7.63 (s, 1H), 7.38 (dd, 1H, J=8.4, 2.0 Hz), 7.24 (d, 1H, J=2.0 Hz), 5.73 (br s, 1H), 4.13 (m, 2H), 2.91-3.23 (m, 4H), 1.93-2.32 (m, 4H), 1.53 (m, 2H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30F3N5O2, 502.5 (M+H). found 502.2.

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

Procedure: The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 1-(2,2,2-trifluoro-ethyl)-piperidin-4-one (WO 9621452). 1H-NMR (CD3OD; 400 MHz): δ 12.9 (br s, 1H), 9.62 (s, 1H), 8.21 (d, 1H, J=8.4 Hz), 7.63 (s, 1H), 7.38 (dd, 1H, J=8.4, 2.0 Hz), 7.24 (d, 1H, J=2.0 Hz), 5.73 (br s, 1H), 4.13 (m, 2H), 2.91-3.23 (m, 4H), 1.93-2.32 (m, 4H), 1.53 (m, 2H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30F3N5O2, 502.5 (M+H). found 502.2.

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

Procedure: 200 mg (0.596 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were initially charged in methanol (16 ml) and admixed with 75 μl (1.312 mmol) of acetic acid, and then 237 mg (1.312 mmol) of 1-(2,2,2-trifluoroethyl)piperidin-4-one were added. After stirring at RT for 15 min, 104 mg (1.67 mmol) of sodium cyanoborohydride were added and the mixture was stirred at RT for 2.5 h. Subsequently, within 2 days, the above-stated amounts of reagents (1-(2,2,2-trifluoroethyl)piperidin-4-one, acetic acid, sodium cyanoborohydride) were added three times, in order to achieve substantially full conversion. Thereafter, saturated aqueous sodium hydrogencarbonate solution (5 ml) was added to the reaction mixture, which was stirred vigorously for 10 min. Subsequently, the reaction mixture was extracted with water and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated and then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 269 mg of the title compound were obtained (90% of theory). the mixture was stirred at RT for 2.5 h Subsequently, within 2 days was stirred vigorously for 10 min Subsequently, the reaction mixture was extracted with water and ethyl acetate The phases were separated the aqueous phase was extracted twice with ethyl acetate The combined organic phases were washed with saturated aqueous sodium chloride solution dried over sodium sulfate filtered concentrated purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient)