1,1,1-trifluoropropan-2-yl carbonochloridate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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: To a suspension of N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by addition of 1,1,1-trifluoropropan-2-yl chloroformate (⅓ of the material from Step A, 0.33 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 30 min and then evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (33.9 mg, off-white solid, 51%) upon lyophilization. 1H NMR (500 MHz, CDCl3, 50° C.). δ 8.42 (t, J=8.25 Hz, 1 H), 8.31 (brs, 1 H), 8.14 (s, 1 H), 7.59-7.78 (m, 2 H), 5.18-5.34 (m, 1 H), 4.78-4.93 (m, 1 H), 4.22-4.41 (m, 4 H), 3.47-3.55 (m, 2 H), 3.04 (s, 3 H), 2.88-3.07 (m, 2 H), 1.79 (m, 2 H), 1.60-1.75 (m, 2 H), 1.42 (d, J=6.60 Hz, 3 H).). LRMS (ESI) 548 (M+H)+. was added DIEP (70 μL, 0.40 mmol, Aldrich) evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 1,1,1-trifluoro-2-propanol (114.1 mg, 1.0 mmol, Matrix Scientific) and triphosgene (98 mg, 0.33 mmol, Aldrich) in ethyl ether (10 mL) at −40° C. was added pyridine (80 μL, 1.0 mmol, EMD) in ethyl ether (1.0 mL) dropwise. The reaction mixture was warmed to 0° C. and stirred for 6 h. The flask containing the above reaction mixture was put into a refrigerator overnight and then filtered. The filtrate was concentrated in vacuo in ice both to give a colorless oil which was used directly in the next step. The flask containing the above reaction mixture was put into a refrigerator overnight filtered The filtrate was concentrated in vacuo in ice both to give a colorless oil which

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 1,1,1-trifluoro-2-propanol (114.1 mg, 1.0 mmol, Matrix Scientific) and triphosgene (98 mg, 0.33 mmol, Aldrich) in ethyl ether (10 mL) at −40° C. was added pyridine (80 μL, 1.0 mmol, EMD) in ethyl ether (1.0 mL) dropwise. The reaction mixture was warmed to 0° C. and stirred for 6 h. The flask containing the above reaction mixture was put into a refrigerator overnight and then filtered. The filtrate was concentrated in vacuo in ice both to give a colorless oil which was used directly in the next step. The flask containing the above reaction mixture was put into a refrigerator overnight filtered The filtrate was concentrated in vacuo in ice both to give a colorless oil which

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

実験手順: To a suspension of N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by addition of 1,1,1-trifluoropropan-2-yl chloroformate (⅓ of the material from Step A, 0.33 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 30 min and then evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (33.9 mg, off-white solid, 51%) upon lyophilization. 1H NMR (500 MHz, CDCl3, 50° C.). δ 8.42 (t, J=8.25 Hz, 1H), 8.31 (brs, 1H), 8.14 (s, 1H), 7.59-7.78 (m, 2H), 5.18-5.34 (m, 1H), 4.78-4.93 (m, 1H), 4.22-4.41 (m, 4H), 3.47-3.55 (m, 2H), 3.04 (s, 3H), 2.88-3.07 (m, 2H), 1.79 (m, 2H), 1.60-1.75 (m, 2H), 1.42 (d, J=6.60 Hz, 3H)). LRMS (ESI) 548 (M+H)+. was added DIEP (70 μL, 0.40 mmol, Aldrich) evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid)

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

実験手順: To a suspension of N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by addition of 1,1,1-trifluoropropan-2-yl chloroformate (⅓ of the material from Step A, 0.33 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 30 min and then evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (33.9 mg, off-white solid, 51%) upon lyophilization. 1H NMR (500 MHz, CDCl3, 50° C.). δ 8.42 (t, J=8.25 Hz, 1H), 8.31 (brs, 1H), 8.14 (s, 1H), 7.59-7.78 (m, 2H), 5.18-5.34 (m, 1H), 4.78-4.93 (m, 1H), 4.22-4.41 (m, 4H), 3.47-3.55 (m, 2H), 3.04 (s, 3H), 2.88-3.07 (m, 2H), 1.79 (m, 2H), 1.60-1.75 (m, 2H), 1.42 (d, J=6.60 Hz, 3H)). LRMS (ESI) 548 (M+H)+. was added DIEP (70 μL, 0.40 mmol, Aldrich) evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 1,1,1-trifluoro-2-propanol (114.1 mg, 1.0 mmol, Matrix Scientific) and triphosgene (98 mg, 0.33 mmol, Aldrich) in ethyl ether (10 mL) at −40° C. was added pyridine (80 μL, 1.0 mmol, EMD) in ethyl ether (1.0 mL) dropwise. The reaction mixture was warmed to 0° C. and stirred for 6 h. The flask containing the above reaction mixture was put into a refrigerator overnight and then filtered. The filtrate was concentrated in vacuo in ice both to give a colorless oil which was used directly in the next step. The flask containing the above reaction mixture was put into a refrigerator overnight filtered The filtrate was concentrated in vacuo in ice both to give a colorless oil which

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: To a suspension of N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by addition of 1,1,1-trifluoropropan-2-ylchloroformate (⅓ of the material from Step A, 0.33 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 30 min and then evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (33.9 mg, off-white solid, 51%) upon lyophilization. 1H NMR (500 MHz, CDCl3, 50° C.). δ 8.42 (t, J=8.25 Hz, 1 H), 8.31 (brs, 1 H), 8.14 (s, 1 H), 7.59-7.78 (m, 2 H), 5.18-5.34 (m, 1 H), 4.78-4.93 (m, 1 H), 4.22-4.41 (m, 4 H), 3.47-3.55 (m, 2 H), 3.04 (s, 3 H), 2.88-3.07 (m, 2 H), 1.79 (m, 2 H), 1.60-1.75 (m, 2 H), 1.42 (d, J=6.60 Hz, 3 H). LRMS (ESI) 548 (M+H)+. was added DIEP (70 μL, 0.40 mmol, Aldrich) evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid)

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

実験手順: To a suspension of N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by addition of 1,1,1-trifluoropropan-2-yl chloroformate (⅓ of the material from Step A, 0.33 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 30 min and then evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC(C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (33.9 mg, off-white solid, 51%) upon lyophilization. 1H NMR (500 MHz, CDCl3, 50° C.). δ 8.42 (t, J=8.25 Hz, 1H), 8.31 (brs, 1H), 8.14 (s, 1H), 7.59-7.78 (m, 2H), 5.18-5.34 (m, 1H), 4.78-4.93 (m, 1H), 4.22-4.41 (m, 4H), 3.47-3.55 (m, 2H), 3.04 (s, 3H), 2.88-3.07 (m, 2H), 1.79 (m, 2H), 1.60-1.75 (m, 2H), 1.42 (d, J=6.60 Hz, 3H).). LRMS (ESI) 548 (M+H)+. was added DIEP (70 μL, 0.40 mmol, Aldrich) evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC(C18 column