2-amino-2-(4-chlorophenyl)ethanol

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: The tert-butyl 1-(4-chlorophenyl)-2-hydroxyethylcarbamate used in the above reaction was prepared as follows. 2-Amino-2-(4-chlorophenyl)acetic acid (12 g, 64.65 mmol) was stirred in THF (200 mL) and sodium borohydride (5.82 g, 153.87 mmol) was added in portions to the stirred mixture under nitrogen. A solution of iodine (16.41 g, 64.65 mmol) in THF (20 mL) was added dropwise maintaining the temperature below 15° C. using an ice bath. The resulting mixture was warmed to room temperature and stirred at reflux overnight. The reaction was quenched by the addition of methanol (40 mL). A portion of this solution was removed (50 mL) and partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure. The residue was purified by MPLC on silica using gradient elution (0 to 10% methanol/DCM). The desired product, 2-amino-2-(4-chlorophenyl)ethanol (1.318 g, 11.88%), was thus isolated as a colourless solid. was prepared maintaining the temperature below 15° C. at reflux overnight The reaction was quenched by the addition of methanol (40 mL) A portion of this solution was removed (50 mL) partitioned between ethyl acetate and water The organic layer was concentrated under reduced pressure The residue was purified by MPLC on silica using gradient elution (0 to 10% methanol/DCM)

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

実験手順: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (148 mg, 0.39 mmol) was added in one portion to a stirred solution of 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (134 mg, 0.37 mmol) and N-ethyldiisopropylamine (0.077 mL, 0.44 mmol) in NMP (3 mL). The mixture was treated with 2-amino-2-(4-chlorophenyl)ethanol (70 mg, 0.41 mmol) (CAS™ no. 179811-64-4, see US2006/0004045 for preparation). The dark solution was stirred for 16 hours at room temperature. The mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed twice with water and then brine. The organic solution was dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash silica chromatography on silica using gradient elution (1% methanol/DCM to 15% methanol/DCM). Product containing fractions were combined to give tert-butyl 4-(1-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (152 mg, 80%) as colourless solid. for preparation) The mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution The organic layer was washed twice with water The organic solution was dried over magnesium sulfate filtered evaporated The residue was purified by flash silica chromatography on silica using gradient elution (1% methanol/DCM to 15% methanol/DCM) Product containing fractions

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

実験手順: The title compound was prepared with 2-amino-2-(4-chlorophenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.4 g, 97%): 1H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.7 Hz, 2H), 7.21 (d, J=7.7 Hz, 2H), 6.81-6.51 (m, 8H), 6.41 (s, 1H), 5.70-5.44 (m, 1H), 3.20-2.82 (m, 2H); ESIMS m/z 518 ([M+H]+).

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

実験手順: The title compound was prepared with 2-amino-2-(4-chlorophenyl)ethanol (Chen, L.; et al., US 20060004045) and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.300 g, 68%): mp 94-97° C.; 1H NMR (300 MHz, CD3OD) δ 9.12 (s, 1H), 8.11 (d, J=6.8 Hz, 2H), 8.01 (d, J=6.9 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.3 Hz, 3H), 7.32-7.38 (m, 3H), 5.59 (s, 1H), 3.84-3.87 (m, 2H) (NH, OH not observed); ESIMS m/z 534 ([M+H]+).

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

実験手順: The tert-butyl 1-(4-chlorophenyl)-2-hydroxyethylcarbamate used in the above reaction was prepared as follows. 2-Amino-2-(4-chlorophenyl)acetic acid (12 g, 64.65 mmol) was stirred in THF (200 mL) and sodium borohydride (5.82 g, 153.87 mmol) was added in portions to the stirred mixture under nitrogen. A solution of iodine (16.41 g, 64.65 mmol) in THF (20 mL) was added dropwise maintaining the temperature below 15° C. using an ice bath. The resulting mixture was warmed to room temperature and stirred at reflux overnight. The reaction was quenched by the addition of methanol (40 mL). A portion of this solution was removed (50 mL) and partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure. The residue was purified by MPLC on silica using gradient elution (0 to 10% methanol/DCM). The desired product, 2-amino-2-(4-chlorophenyl)ethanol (1.318 g, 11.88%), was thus isolated as a colourless solid. was prepared maintaining the temperature below 15° C. at reflux overnight The reaction was quenched by the addition of methanol (40 mL) A portion of this solution was removed (50 mL) partitioned between ethyl acetate and water The organic layer was concentrated under reduced pressure The residue was purified by MPLC on silica using gradient elution (0 to 10% methanol/DCM)

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

実験手順: The tert-butyl 1-(4-chlorophenyl)-2-hydroxyethylcarbamate used in the above reaction was prepared as follows. 2-Amino-2-(4-chlorophenyl)acetic acid (12 g, 64.65 mmol) was stirred in THF (200 mL) and sodium borohydride (5.82 g, 153.87 mmol) was added in portions to the stirred mixture under nitrogen. A solution of iodine (16.41 g, 64.65 mmol) in THF (20 mL) was added dropwise maintaining the temperature below 15° C. using an ice bath. The resulting mixture was warmed to room temperature and stirred at reflux overnight. The reaction was quenched by the addition of methanol (40 mL). A portion of this solution was removed (50 mL) and partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure. The residue was purified by MPLC on silica using gradient elution (0 to 10% methanol/DCM). The desired product, 2-amino-2-(4-chlorophenyl)ethanol (1.318 g, 11.88%), was thus isolated as a colourless solid. was prepared maintaining the temperature below 15° C. at reflux overnight The reaction was quenched by the addition of methanol (40 mL) A portion of this solution was removed (50 mL) partitioned between ethyl acetate and water The organic layer was concentrated under reduced pressure The residue was purified by MPLC on silica using gradient elution (0 to 10% methanol/DCM)

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

実験手順: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (148 mg, 0.39 mmol) was added in one portion to a stirred solution of 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (134 mg, 0.37 mmol) and N-ethyldiisopropylamine (0.077 mL, 0.44 mmol) in NMP (3 mL). The mixture was treated with 2-amino-2-(4-chlorophenyl)ethanol (70 mg, 0.41 mmol) (CAS™ no. 179811-64-4, see US2006/0004045 for preparation). The dark solution was stirred for 16 hours at room temperature. The mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed twice with water and then brine. The organic solution was dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash silica chromatography on silica using gradient elution (1% methanol/DCM to 15% methanol/DCM). Product containing fractions were combined to give tert-butyl 4-(1-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (152 mg, 80%) as colourless solid. for preparation) The mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution The organic layer was washed twice with water The organic solution was dried over magnesium sulfate filtered evaporated The residue was purified by flash silica chromatography on silica using gradient elution (1% methanol/DCM to 15% methanol/DCM) Product containing fractions

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(4-chloro-phenyl)-2-hydroxy-ethylamine and DIEA to give 2-[1-(4-chloro-phenyl)-2-hydroxy-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 455 (MH+).

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

実験手順: The title compound was prepared with 2-amino-2-(4-chlorophenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.4 g, 97%): 1H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.7 Hz, 2H), 7.21 (d, J=7.7 Hz, 2H), 6.81-6.51 (m, 8H), 6.41 (s, 1H), 5.70-5.44 (m, 1H), 3.20-2.82 (m, 2H); ESIMS m/z 518 ([M+H]+).

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

実験手順: The title compound was prepared with 2-amino-2-(4-chlorophenyl)ethanol (Chen, L.; et al., US 20060004045) and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.300 g, 68%): mp 94-97° C.; 1H NMR (300 MHz, CD3OD) δ 9.12 (s, 1H), 8.11 (d, J=6.8 Hz, 2H), 8.01 (d, J=6.9 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.3 Hz, 3H), 7.32-7.38 (m, 3H), 5.59 (s, 1H), 3.84-3.87 (m, 2H) (NH, OH not observed); ESIMS m/z 534 ([M+H]+).