tert-butyl N-[(3R,4R)-4-fluoropyrrolidin-3-yl]carbamate

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

実験手順: To a solution of (3R,4R)-benzyl 3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidine-1-carboxylate (3.0 g, 8.8 mmol) in MeOH (50 mL) was added wet Pd/C (0.3 g, 10%) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The resulting mixture was stirred at rt under hydrogen balloon for 3 hr. The reaction mixture was filtered and the filtrate was concentrated to afford the title compound (1.6 g, 88% yield) as light yellow oil that solidified on standing. The suspension was degassed under vacuum purged with hydrogen three times The reaction mixture was filtered the filtrate was concentrated

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 in analogy to Example 78-1 in Scheme 7 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and tert-butyl (trans-4-fluoropyrrolidin-3-yl)carbamate. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.71, 1.89 Hz, 1 H), 7.91-7.75 (m, 2 H), 7.62 (t, J=7.45 Hz, 1 H), 7.52 (d, J=8.59 Hz, 1 H), 7.45 (td, J=7.58, 3.28 Hz, 1 H), 7.32 (d, J=8.59 Hz, 1 H), 6.19 (s, 1 H), 5.18 (brs, 2 H), 5.06 (m, 1 H), 4.53 (brs, 2 H), 4.17 (m, 1 H), 4.03 (dd, J=9.98, 5.43 Hz, 1 H), 3.81-3.54 (m, 4 H), 3.45-3.35 (m, 1 H), 2.42 (s, 3 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 in analogy to Example 19-1 in Scheme 7 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1) and tert-butyl (trans-4-fluoropyrrolidin-3-yl)carbamate. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=2.27 Hz, 1 H), 7.78-7.68 (m, 2 H), 7.55 (dd, J=9.09, 1.52 Hz, 1 H), 7.52-7.42 (m, 2 H), 7.39 (dd, J=9.09, 2.27 Hz, 1 H), 6.28-6.21 (m, 1 H), 5.25 (d, J=15.66 Hz, 1 H), 5.10-4.95 (m, 1 H), 4.90-4.54 (m, 2 H), 4.65-4.40 (m, 1 H), 4.30-4.10 (m, 1 H), 4.05-3.59 (m, 1 H), 3.55-3.51 (m, 2 H), 3.40-3.35 (m, 3 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 in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl (trans-4-fluoropyrrolidin-3-yl)carbamate to afford an off-white powder. HPLC (Condition 4) tR=4.58 min, UPLC-MS (Condition 3) tR=0.83 min, m/z=467 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.01 (br. s, 1H) 3.20-3.39 (m, 3H) 3.47 (d, J=10.56 Hz, 2H) 3.55-3.82 (m, 1H) 4.76-4.94 (m, 1H) 6.41 (br. s, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.79-7.90 (m, 3H) 8.06 (s, 1H) 8.73 (br. s, 1H) 10.22 (s, 1H) 12.91-13.15 (m, 1H). to afford an off-white powder

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

実験手順: To a solution of (3R,4R)-benzyl 3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidine-1-carboxylate (3.0 g, 8.8 mmol) in MeOH (50 mL) was added wet Pd/C (0.3 g, 10%) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The resulting mixture was stirred at rt under hydrogen balloon for 3 hr. The reaction mixture was filtered and the filtrate was concentrated to afford the title compound (1.6 g, 88% yield) as light yellow oil that solidified on standing. The suspension was degassed under vacuum purged with hydrogen three times The reaction mixture was filtered the filtrate was concentrated

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 in analogy to Example 78-1 in Scheme 7 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and tert-butyl (trans-4-fluoropyrrolidin-3-yl)carbamate. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.71, 1.89 Hz, 1 H), 7.91-7.75 (m, 2 H), 7.62 (t, J=7.45 Hz, 1 H), 7.52 (d, J=8.59 Hz, 1 H), 7.45 (td, J=7.58, 3.28 Hz, 1 H), 7.32 (d, J=8.59 Hz, 1 H), 6.19 (s, 1 H), 5.18 (brs, 2 H), 5.06 (m, 1 H), 4.53 (brs, 2 H), 4.17 (m, 1 H), 4.03 (dd, J=9.98, 5.43 Hz, 1 H), 3.81-3.54 (m, 4 H), 3.45-3.35 (m, 1 H), 2.42 (s, 3 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 in analogy to Example 19-1 in Scheme 7 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1) and tert-butyl (trans-4-fluoropyrrolidin-3-yl)carbamate. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=2.27 Hz, 1 H), 7.78-7.68 (m, 2 H), 7.55 (dd, J=9.09, 1.52 Hz, 1 H), 7.52-7.42 (m, 2 H), 7.39 (dd, J=9.09, 2.27 Hz, 1 H), 6.28-6.21 (m, 1 H), 5.25 (d, J=15.66 Hz, 1 H), 5.10-4.95 (m, 1 H), 4.90-4.54 (m, 2 H), 4.65-4.40 (m, 1 H), 4.30-4.10 (m, 1 H), 4.05-3.59 (m, 1 H), 3.55-3.51 (m, 2 H), 3.40-3.35 (m, 3 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 in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl (trans-4-fluoropyrrolidin-3-yl)carbamate to afford an off-white powder. HPLC (Condition 4) tR=4.58 min, UPLC-MS (Condition 3) tR=0.83 min, m/z=467 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.01 (br. s, 1H) 3.20-3.39 (m, 3H) 3.47 (d, J=10.56 Hz, 2H) 3.55-3.82 (m, 1H) 4.76-4.94 (m, 1H) 6.41 (br. s, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.79-7.90 (m, 3H) 8.06 (s, 1H) 8.73 (br. s, 1H) 10.22 (s, 1H) 12.91-13.15 (m, 1H). to afford an off-white powder